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Asymmetric Organocatalysis
Volume Editor: Benjamin List
With Contributions by
S. Arseniyadis · A. Berkessel · J.B. Brazier · K. Etzenbach-Effers
A. Erkkilä · J.M. Goss · D. Kampen · B. List · I. Majander
N.T. McDougal · P.M. Pihko · M. Pucheault · C.M. Reisinger
S.E. Schaus · O. Sereda · Y. Shi · A.C. Spivey · S. Tabassum
A. Ting · N.C.O. Tomkinson · M. Vaultier · R. Wilhelm
O.A. Wong
Editor
Prof. Dr. Benjamin List
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1
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list@mpi-muelheim.mpg.de
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Enough Organocatalysis?
These are exciting times for asymmetric organocatalysis. During the last decade,
the chemical community finally began considering the previously overlooked field
as the third pillar of asymmetric catalysis, complementing only enzymes and chiral
metal complexes. Now, countless academic groups around the world are entering
the area. And with regard to industrial applications, the question is not anymore, if
the pharmaceutical industry is going to use organocatalysis, but rather whether or
not there are still companies actually not using it.
Organocatalysts are purely organic molecules that function by removing or
donating electrons or protons from or to reaction substrates or transition states. This
situation defines four distinct areas: Brønsted acid and base catalysis and Lewis
acid and base catalysis. The field has roots back to the beginning of the 20th
century with Bredig’s now legendary studies on the use of natural alkaloids as
enantioselective catalysts. This line of research has subsequently been continued by
others, including Pracejus and Wynberg. Parallel studies by Hajos and Wiechert
using proline as aldolization catalyst were inspired by the seminal work of
Knoevenagel in the late 19th century. Few other organocatalysts were described
during those decades but, like proline and quinine, they were considered exotic,
isolated examples with a poorly understood mode of action. The situation changed
only at the beginning of this millennium when it was shown that aminocatalysis, the
activation of carbonyl compounds via enamine and iminium ion intermediates, is a
general catalysis concept. This discovery finally opened the door to understanding
and designing organocatalysts and to predicting their behavior. The concept of ami-
nocatalysis has since been applied to dozens of reaction types and literally hundreds
of variants. Moreover, the working principles of other Lewis base catalysts such as
carbenes and tertiary amines as well as that of Brønsted acid and base catalysts is
now appreciated and new reactions and catalysts are being designed and published
on a daily basis. These are fascinating developments, especially in light of a previ-
ous opinion we organic chemists have convinced ourselves of, namely that new
reactions can only be expected from the realm of transition metal chemistry. The
current developments leave us to either accept the fact that our perception may not
have been entirely correct or to continue to be “right” simply by arguing that
organocatalysis is not truly novel (and yet researching it anyway). Undebatable
though, at least in my opinion, is the success and usefulness of organocatalysis, the
ix
x Enough Organocatalysis!?
enormous amount of activities in the field, and the resulting constant need for
reflection and knowledge updates such as this volume.
So why the provocative title then? The term “organocatalysis” has been quite
useful in initially highlighting and subsequently popularizing an underappreciated
though fundamental catalysis principle. However, as time goes by and as more and
more organic catalyst motifs and concepts are being developed, the term might
become less and less accurate. In the field of transition metal catalysis, we speak of
“palladium catalysts” or invent a new “iron-catalyzed reaction” rather than stating
we are investigating “transition metal catalysis”. Similarly, in biocatalysis, we
specify which particular class of enzyme is being studied. I suggest that a similar
specification will ultimately take place in organocatalysis. We will find more and
more publications using “a phosphoric acid catalyst” or describing a “secondary
amine-catalyzed transformation” rather than an “organocatalytic reaction”. In that
sense: Yes, enough organocatalysis! Still, there is little doubt that the field will
continue to grow massively. It appears to me that there are still many ripe and deli-
cious fruits to be picked by creative and intrepid minds.
All four areas of organocatalysis are covered in this volume, providing an over-
view of the field from experts in their areas. I would like to wholeheartedly thank
all those who have contributed to making this volume such a wonderful and origi-
nal source of knowledge. I hope it will inspire you to apply organocatalytic methods
to solve some of your problems but possibly also to contribute solving some of the
remaining challenges of organocatalysis.
Mülheim, Summer 2009 Benjamin List
Contents
Noncovalent Organocatalysis Based on Hydrogen Bonding:

Elucidation of Reaction Paths by Computational Methods....................... 1
Kerstin Etzenbach-Effers and Albrecht Berkessel
Enamine Catalysis........................................................................................... 29
Petri M. Pihko, Inkeri Majander, and Anniina Erkkilä
Carbene Catalysts........................................................................................... 77
Jennifer L. Moore and Tomislav Rovis
Brønsted Base Catalysts................................................................................. 145

Amal Ting, Jennifer M. Goss, Nolan T. McDougal, and Scott E. Schaus
Chiral Ketone and Iminium Catalysts for Olefin Epoxidation.................. 201

O. Andrea Wong and Yian Shi
Amine, Alcohol and Phosphine Catalysts for Acyl Transfer Reactions.... 233
Alan C. Spivey and Stellios Arseniyadis
Secondary and Primary Amine Catalysts for Iminium Catalysis............. 281

John B. Brazier and Nicholas C.O. Tomkinson
Lewis Acid Organocatalysts........................................................................... 349

Oksana Sereda, Sobia Tabassum, and René Wilhelm
Chiral Brønsted Acids for Asymmetric Organocatalysis........................... 395

Daniela Kampen, Corinna M. Reisinger, and Benjamin List
Index................................................................................................................. 457
xi
Top Curr Chem (2010) 291: 1–27
DOI: 10.1007/128_2009_3
© Springer-Verlag Berlin Heidelberg 2009
Published online: 01 October 2009
Noncovalent Organocatalysis Based

on Hydrogen Bonding: Elucidation of Reaction
Paths by Computational Methods
Kerstin Etzenbach-Effers and Albrecht Berkessel
Abstract In this article, the functions of hydrogen bonds in organocatalytic

reactions are discussed on atomic level by presenting DFT studies of selected
examples. Theoretical investigation provides a detailed insight in the mechanism
of substrate activation and orientation, and the stabilization of transition states and
intermediates by hydrogen bonding (e.g. oxyanion hole). The examples selected
comprise stereoselective catalysis by bifunctional thioureas, solvent catalysis by
fluorinated alcohols in epoxidation by hydrogen peroxide, and intramolecular
cooperative hydrogen bonding in TADDOL-type catalysts.
Keywords Organocatalysis • hydrogen bonding • reaction mechanism on DFT

level • oxyanion hole • bifunctional thiourea catalysis • catalytic solvents
Contents
1 Introduction....................................................................................................................... 2
2 Catalytic Functions of Hydrogen Bonds........................................................................... 4
2.1 Hydrogen Bonds Can Preorganize the Spatial Arrangement
of the Reactants........................................................................................................ 4
2.2 Hydrogen Bonds Can Activate the Reactants by Polarization................................. 4
2.3 Hydrogen Bonds Can Stabilize the Charges of Transition
States and Intermediates.......................................................................................... 5
3 Case Studies...................................................................................................................... 5
3.1 Dynamic Kinetic Resolution (DKR) of Azlactones: Thioureas Can Act
as Oxyanion Holes Comparable to Serine Hydrolases............................................. 5
3.2 On the Bifunctionality of Chiral Thiourea: Tertiary-Amine Based Organocatalysts:
Competing Routes to C–C Bond Formation in a Michael-Addition........................ 12
K. Etzenbach-Effers and A. Berkessel ()

Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne, Germany
e-mail: berkessel@uni-koeln.de
2 K. Etzenbach-Effers and A. Berkessel
3.3Dramatic Acceleration of Olefin Epoxidation in Fluorinated Alcohols:

Activation of Hydrogen Peroxide by Multiple Hydrogen Bond Networks.............. 15
3.4 TADDOL-Promoted Enantioselective Hetero-Diels–Alder Reaction
of Danishefsky’s Diene with Benzaldehyde: Another Example
for Catalysis by Cooperative Hydrogen Bonding.................................................... 22
4 Epilog................................................................................................................................ 26
References............................................................................................................................... 26
1 Introduction
Organocatalysis has been a rapidly growing area of research over the last decade [1–3].
On a mechanistic basis, the vast array of organocatalytic transformations can be divided
into the two subgroups “covalent organocatalysis” and “noncovalent organocatalysis.”
In the former case, a covalent intermediate is formed between the substrate(s) and the
catalyst within the catalytic cycle. Typical examples are proline-catalyzed aldol reac-
tions which proceed via enamine intermediates [4], or cycloadditions, conjugate addi-
tions, etc. that proceed via iminium ions derived from enal substrates and amine
catalysts [5]. In contrast, noncovalent organocatalysis relies solely on noncovalent
interactions such as hydrogen bonding or the formation of ion pairs. Organocatalysis
had its roots in “covalent” processes, such as the proline-catalyzed Hajos-Parrish-Eder-
Sauer-Wiechert aldol condensation [6, 7]. However, the importance of hydrogen bond-
ing for (stereo) selective organocatalysis has also been recognized early, and the recent
past has seen tremendous development in this area as well [1, 8–10].
Hydrogen bonding to substrates such as carbonyl compounds, imines, etc.,
results in electrophilic activation towards nucleophilic attack (Scheme 1). Thus,
hydrogen bonding represents a third mode of electrophilic activation, besides
substrate coordination to, e.g., a metal-based Lewis acid, or iminium ion formation
(Scheme 1). Typical hydrogen bond donors such as (thio)ureas are therefore often
referred to as “pseudo-Lewis acids.”
Scheme 1 Three modes of carbonyl activation towards nucleophilic attack
Substrate activation by hydrogen bonding is related to, but different from

Brønsted acid catalysis [1–3, 10]. In the latter case, proton transfer from the cata-
lyst to the substrate(s) occurs. The terms “specific Brønsted acid catalysis” and
“general Brønsted acid catalysis” are used, depending on whether proton transfer
occurs to the substrate in its ground state, or to the transition state. In specific
Noncovalent Organocatalysis Based on Hydrogen Bonding 3
Brønsted acid catalysis, the substrate electrophile is reversibly protonated in a

pre-equilibrium step, prior to the nucleophilic attack (Scheme 2). In general acid
catalysis, however, the proton is (partially or fully) transferred in the transition
state of the rate-determining step (Scheme 2). Clearly, the formation of a hydrogen
bond precedes proton transfer.
Specific Brønsted-acid catalysis General Brønsted-acid catalysis

B
H H
X X
+ H-B
X
Nu Nu
X: O, NR
Scheme 2 Specific and general Brønsted-acid catalysis
Consequently, the processes most relevant to the topic of this chapter, i.e.,
“hydrogen bonds in organocatalytic transition states,” are (1) transition state stabi-
lization by pure hydrogen bonding (without full proton transfer) and (2) general
Brønsted acid/Brønsted base catalyzed reactions which are initiated by hydrogen
bonding but move further to distinct proton transfer.
At this point of the introduction, seminal contributions to the development and
understanding of organocatalysis by hydrogen bonding by Peter R. Schreiner and
coworkers need to be acknowledged. Their contribution cited in reference [11–14]
illustrate and highlight the concepts of electrophilic (i.e., Lewis acid like) substrate
activation by hydrogen bonding [11, 12], as well as oxyanion stabilization by
hydrogen bonding to organocatalysts [13, 14]. Furthermore, please note that hydro-
gen bonding as the basis of (mostly biologic) catalysis has been discussed and
analyzed, although not by computational means, as early as the 1970s and 1980s by
Jencks and Hine [15–17].
Up to now, only a few organocatalytic reactions of the above types have been
investigated with post-Hartree–Fock methods.1 Potential reasons are computational
costs, spatial and conformational flexibility (ab initio methods do not necessarily find
1
The Hartree–Fock theory neglects correlations between electrons. This means that one single elec-
tron is only subjected to an average potential by the other electrons of a system. This leads, e.g., to
errors in bond lengths and angles and dissociation energies. Therefore, more exact methods, the so-
called post Hartree–Fock methods were developed which are either based on perturbation theory
(e.g., second order Møller-Plesset-Perturbation theory, MP2), or on the variational principle (e.g.,
configuration interaction, CI or coupled cluster methods CC). Compared to the Hartree–Fock
method, these techniques are very time consuming. Alternative approaches to electronic structure are
density functional theory methods (DFT) in which the electron density distribution rather than the
many electron wave function plays a central role. Difficulties in expressing the exchange part of the
energy can be relieved by including a component of the exact exchange energy calculated from
Hartree–Fock theory. Functionals of this type are known as hybrid functionals. Widely used for DFT-
calculations is the hybrid functional B3LYP: a correlation functional developed by Becke combined
with an exchange term from Lee, Yang and Parr [18–20]. It provides in many cases access to quali-
tatively good results at computational costs comparable to Hartree–Fock methods.
the absolute minimum, but the minimum closest to a given starting structure – which
might turn out to be a relative minimum only), and the problem of properly treating
solvent effects. Nevertheless, some examples for quantum mechanically analyzed
reaction mechanisms exist and will be discussed in this chapter. They allow a detailed
insight at atomic level into organocatalyst function, and provide an especially detailed
view on the significance of hydrogen bonding. In the majority of current theoretical
publications dealing with organocatalysis, Becke’s [18, 19] three parameter hybrid
functional B3 and the Lee, Yang, and Parr correlation functional [20] LYP are used
in combination with standard split valence basis sets (for example 6-31G). In most
cases, polarization functions which allow a greater flexibility of angle are added [for
example, (d,p) means additional d-functions for second-row atoms, and additional
p-functions for hydrogen atoms] [21]. In some cases, diffuse functions (abbreviated
with +) are used as well, which allow an increased distance between nucleus and
electron (one plus sign indicates additional diffuse functions for nonhydrogen atoms
only; two plus signs indicate additional diffuse functions for hydrogen as well). They
are recommended for negatively charged molecules or for the description of lone pair
effects [21]. In this contribution, we focus solely on small metal free organocatalysts
(including catalytically active solvents). We also exclude covalently catalyzed reac-
tions, for example proline-catalyzed aldol reactions, although this reaction is well
investigated at DFT-level [22–29], and although a hydrogen bond is involved (the
carboxyl group of the proline catalyst activates the electrophile towards the attack by
the enamine by hydrogen bonding).
Transition states are clearly the most interesting stages of a reaction path.
Nevertheless, we also consider starting complexes and intermediates, provided that
they contribute useful information about the mode of operation of hydrogen bond
mediated catalysis.
2 Catalytic Functions of Hydrogen Bonds
2.1 Hydrogen Bonds Can Preorganize the Spatial

Arrangement of the Reactants
In cases where hydrogen bond donor/acceptor functions are attached to a (chiral)

scaffold, they can steer the assembly of a well defined catalyst–substrate complex.
The positions of hydrogen bond donors and acceptors determine the stereoselectivity
of the reaction.
2.2 Hydrogen Bonds Can Activate the Reactants by Polarization
The binding of substrates via hydrogen bonds (either as hydrogen bond acceptor or
as donor) is necessarily associated with changes in electron densities. In catalytic
systems, the resulting polarization leads to an activation of the reactants.
2.3 Hydrogen Bonds Can Stabilize the Charges of Transition

States and Intermediates
Hydrogen bonds are flexible with regard to bond length and angle. This feature is
of utmost importance when charge separation occurs along the reaction pathway,
and in particular in the transition state(s): hydrogen bonds have the ability to, e.g.,
contract and to thus stabilize developing (negative) charges. On the other hand,
when the product stage is approached, the hydrogen bonds can expand again, and
the product–catalyst complex can dissociate.
In hydrogen bond catalyzed reactions we find basically three different tasks that
hydrogen bonds can perform. (1) There are hydrogen bonds which just stabilize
charge in a transition state or intermediate. In these cases, the proton is shared
between the donor and the acceptor during the transition state, and remains attached
to the hydrogen bond donor afterwards. (2) In some transition states, however, a
second type of hydrogen bond can be encountered, which is shorter and leads to a
real proton transfer from the donor to the acceptor. By some authors this phenomenon
is termed a low barrier hydrogen bond (LBHB) [30]. In particular the lifetimes and
the binding energies of LBHBs still appear to be controversially discussed [31].
Apolar organic solvents as reaction media are reminiscent of hydrophobic binding
pockets of enzymes. In such surroundings, hydrogen bonds between hetero atoms
with matched pKs values can be very short and strong [30]. (3) A third class, the
so-called “cooperative hydrogen bonds,” play another important role. The latter are
typically intramolecular hydrogen bonds which can tune the intermolecular hydro-
gen bonding to, e.g., a substrate with regard to acidity (Brønsted acid assisted
Brønsted acid catalysis (BBA)) [32] and they are often observed in diols as for
example TADDOLs (a,a,a¢,a¢-tetraaryl-1,3-dioxolan-4,5-dimethanol) [33] or
BINOL (1,1¢-bi-2-naphthol)[34].
3 Case Studies
3.1 Dynamic Kinetic Resolution (DKR) of Azlactones:

Thioureas Can Act as Oxyanion Holes Comparable
to Serine Hydrolases
Our group recently reported that bifunctional (thio)urea – tert-amine organocatalysts

catalyze the alcoholytic DKR of azlactones (Scheme 3). The method affords highly
enantio-enriched N-protected a-amino acid esters [35–39]. We chose this transfor-
mation for a detailed computational study as the catalysis (both in terms of rate and
stereoselectivity) is solely effected by hydrogen bonding: activation of the azlactone
clearly hinges on H-bonding to the catalyst’s thiourea moiety, whereas the binding/
activation of the alcohol nucleophile occurs at the Brønsted-basic tert-amine.
Scheme 3 Example for the dynamic kinetic resolution of azlactones
This reaction encompasses a number of interesting features (general Brønsted acid/

Brønsted base catalysis, bifunctional catalysis, enantioselective organocatalysis, very
short hydrogen bonds, similarity to serine protease mechanism, oxyanion hole), and
we were able to obtain a complete set of DFT based data for the entire reaction path,
from the starting catalyst–substrate complex to the product complex.
3.1.1 The Calculated Reaction Path of the Alcoholytic

Ring Opening of Azlactones
For the calculations we used a simplified model system in which all substituents
were replaced by methyl groups (Scheme 4). Experimentally, the methyl substi-
tuted catalyst and methanol as nucleophile are active, but the enantiomeric excesses
obtained fall below those obtained with the tert-leucine amide-derived catalyst in
combination with allyl alcohol (Scheme 3).
Scheme 4 Model system for the DFT-calculations of the alcoholytic ring opening of azlactones
The first step of the catalytic process is the hydrogen bond directed assembly and
orientation of the reactants. In this example, the azlactone and methanol form a ternary
starting complex with the organocatalyst (Fig. 1) [39]. The pseudo-Lewis acidic thiou-
rea forms two bifurcated, nearly symmetric hydrogen bonds (2.147 Å, (O,H,N) = 155.5°
and 2.146 Å, (O,H,N) = 155.8°) to the carbonyl oxygen atom of the azlactone,
Fig. 1 The reaction path of the alcoholytic ring opening of azlactones: geometries and relative
electronic energies (kJ mol−1) of the stationary points (B3LYP/6-311++G(d,p)// B3LYP/6-
31++G(d,p), gas phase)
whereas the basic tertiary amino group binds the proton of the methanolic hydroxy
function (1.918 Å, (O,H,N) = 166.5°). The position of these two groups is defined by
the chiral scaffold of (1R, 2R)-cyclohexane-1,2-diamine (DACH).
As exemplified for the (R)-azlactone, in principle two modes of binding are
possible with this hydrogen bonding pattern. The orientation of the azlactone in
Fig. 1 (starting complex) leads to an attack to the re-side of the azlactone’s carbonyl
group. A 180° turn would result in a si-side attack, but this arrangement is disfavored
because of nonbonding interactions between the methyl group at the azlactone’s

center of chirality and the methyl group of the incoming alcohol nucleophile. An
energetically preferred arrangement for the (R)-azlactone results when the alcohol
is located at the re-site of the carbonyl group, preorganized for the subsequent
nucleophilic attack.
Once the reactants are bound to the catalyst (starting complex),2 polarization and
activation by three hydrogen bonds takes place. This process is evidenced by the
change of the natural charges of the free azlactone and methanol molecules com-
pared to their charges in the starting complex. The negative NBO (natural bond
order) charge of the carbonyl oxygen atom rises due to the bifurcated hydrogen
bonds donated by the thiourea moiety (−0.068 e). As a consequence, the positive
NBO charge of the carbonyl carbon atom increases (+0.047 e). Simultaneously, the
electron density at the oxygen atom of the methanol molecule is increased (−0.057 e),
due to the hydrogen bond between its hydroxy function and the tertiary amine
moiety of the catalyst. In summary, the catalytic system is now perfectly orientated
and activated by three hydrogen bonds for the following nucleophilic attack.
In the first transition state TS1 (Fig. 1) the hydrogen bonds decrease the activa-
tion energy by stabilizing the increasing charges at the participating oxygen atoms.
One of the bifurcated hydrogen bonds to the carbonyl oxygen atom is significantly
shortened to 1.861 Å (−0.285 Å, (O,H,N) = 157.2°, adjacent to the cyclohexane
ring). The negative charge of the attacking hydroxyl oxygen atom is stabilized by
an even stronger contraction (−0.739 Å to 1.183, (O,H,N) = 166.8°) of the hydro-
gen bond to the catalyst’s tertiary amine. Here we see an example for a special type
of hydrogen bond, as during nucleophilic attack, the proton is transferred along a
nearly linear ((O,H,N) = 166.8°) hydrogen bond from the donor alcohol to the
acceptor amine (“LBHB” with an O–H–N-distance of 1.360 Å (O–H) + 1.183 Å
(H–N) = 2.543 Å (O–N)).
From the first transition state (TS1, Fig. 1), the reaction path leads to the tetra-
hedral intermediate 1 (INT1). In the latter, the proton transfer from methanol to the
tertiary amine function is completed (from 1.183 to 1.059 Å), and the negative
charge at the former carbonyl oxygen atom reaches its maximum. This charge is
compensated by a further shortening of the bifurcated hydrogen bonds to 2.040 Å
(−0.103 Å) and 1.765 Å (−0.096 Å) (Fig. 1). The thiourea moiety thus forms an
“oxyanion hole” similar to the amide groups of the serine protease backbone [41].
In the following transition state TS2, the opening of the azlactone ring takes
place. The bond between the carbonyl carbon and ether oxygen atoms is stretched
from 1.545 to 1.832 Å. Negative charge is transferred from the carbonyl to the
ether oxygen atom in transition state 2 (TS2) (change in natural charge -0.102 e;
see Table 1 for a summary), and one of the bifurcated hydrogen bonds from the
2
The formation of a ternary complex is entropically disfavoured relative to binary ones. However,
kinetic and spectroscopic investigations [39] gave no indication of, e.g., a ping-pong mechanism,
and/or the involvement of covalent intermediates
Table 1 NBO charges of the stationary points (black: natural charge, red: change to the previous
stationary point B3LYP/6-31++G(d,p)
1 S
4O O 2 Me Me 1' 2'
N N Me
N3 N
H H H Me
3'
Me
O1 C2 N3 O4 N1’ N2’ N3’
Starting complex -0.540 +0.571 -0.472 -0.614 -0.660 -0.659 -0.570

TS1 -0.590 +0.563 -0.504 -0.736 -0.655 -0.685 -0.538
-0.050 -0.008 -0.032 -0.122 +0.005 -0.026 +0.032
INT1 -0.628 +0.564 -0.528 -0.834 -0.657 -0.699 -0.517
-0.038 +0.001 -0.024 -0.098 -0.002 -0.014 +0.021
TS2 -0.735 +0.572 -0.567 -0.737 -0.656 -0.692 -0.520
-0.107 +0.008 -0.039 +0.097 +0.001 +0.007 -0.003
INT2 -0.895 +0.614 -0.601 -0.629 -0.652 -0.683 -0.530
-0.160 +0.042 -0.034 +0.108 +0.004 +0.009 -0.010
TS3 -0.860 +0.620 -0.578 -0.624 -0.656 -0.673 -0.552
+0.035 +0.006 +0.023 +0.005 -0.004 +0.010 -0.022
Product(iminol) -0.776 +0.609 -0.553 -0.632 -0.659 -0.661 -0.577
+0.084 -0.011 +0.025 -0.008 -0.003 +0.012 -0.025
Product(amide) -0.671 +0.701 -0.654 -0.645 -0.668 -0.648 -0.555
+0.105 +0.092 -0.101 -0.013 -0.009 +0.013 +0.022
carbonyl oxygen to the thiourea moiety is cleaved. Two new bifurcated hydrogen
bonds (2.133 and 2.290 Å) to the (former) azlactone ether oxygen atom are formed
to stabilize the newly developing negative charge. As the ring opening proceeds, the
negative charge at the (former) azlactone ether oxygen atom increases to its
maximum (change in natural charge −0.162 e), and the intermediate 2 (INT2) is
reached. In this intermediate, the catalyst’s protonated tertiary amine and the
NH-group adjacent to the cyclohexane ring together form a charge-stabilizing
“oxyanion hole” (length of the hydrogen bonds 1.455 and 1.855 Å).
In the third transition state (TS3), the neutral catalyst is recovered by transferring
the proton back from the catalyst to the substrate. In other words, the (former) azlac-
tone ether oxygen atom deprotonates the tertiary ammonium ion. For proton transfer,
again an “LBHB” is formed (N–O distance 2.479 Å, (O,H,N) = 166.2°). In the prod-
uct complex, the catayst is neutral and the N-acylamino acid ester is bound in its iminol
form to the catalyst (Product(iminol)). Finally, an additional 66.6 kJ mol−1 are gained
by the subsequent iminol–amide tautomerization (Product(amide)) (Fig. 1).
Clearly, the strength of hydrogen bonds depends on the reaction medium.
In practice, the nonpolar solvent toluene is routinely used. It can be considered to
mimic a hydrophobic binding pocket of an enzyme and clearly supports the forma-
tion of moderate (1.5–2.2 Å) and even strong (1.2–1.5 Å) hydrogen bonds [42].
3.1.2 How Hydrogen Bonds Determine the Enantioselectivity

of the Alcoholytic Azlactone Opening
In order to explain the enantioselectivity of the alcoholytic azlactone opening, we cal-

culated the four possible ternary starting complexes (catalyst–azlactone–methanol)
re(R), re(S), si(R), and si(S) (Fig. 2), together with the first (and rate-determining) tran-
sition states. In the complexes re(R) and si(S), the methyl group bound to the azlac-
tone’s center of chirality and the methyl group of the attacking methanol are located on
Fig. 2 Four possible ternary (R/S)-azlactone–methanol–catalyst complexes optimized with B3LYP/6-

31+G(d)
opposite sides of the azlactone ring. As a consequence, there is no significant inter-

action between them. However, in the complexes re(S) and si(R), where both methyl
groups show significant steric interaction, there is pronounced nonbonding interaction
between them. This fact is reflected in the activation energies, with one exception: the
activation energy of si(S)ts is remarkably higher than that of re(R)ts, although the steric
interaction of the methyl groups is comparable. This effect is due to unfavorable charge
separation in the transition state. As the carbonyl oxygen atom develops a partial nega-
tive charge during the nucleophilic attack of the alcohol nucleophile, the charge separa-
tion is larger for si(S)ts (dipole moment of re(R)ts: 5.66 Debye, dipole moment of si(S)
ts: 6.08 Debye). Additionally, in re(R)ts, a lone pair of the lactone oxygen atom points
in the direction of the developing positive charge at the tertiary amine function of the
catalyst. Overall, in re(R)ts, the negative charge is distributed and stabilized on the
azlactone oxygen atoms more effectively than in si(S)ts.
In summary, the hydrogen bond pattern of the catalyst disfavors some princi-
pally possible arrangements due to steric interactions, and others due to a lack of
charge distribution and charge stabilization. In this example, re(R)ts remains as the
only favored transition state (see activation energies in Fig. 3).
Clearly, upon using the enantiomeric catalyst [(S,S) instead of (R,R)] the oppo-
site enantioselectivity of the overall process results. However, this effect is also
seen with catalysts that are of analogous configuration, but not derived from trans-
1,2-diaminocyclohexane (DACH). For example, the pseudo-ephedrine derived
catalyst shown in Scheme 5, having (S)-configuration at the centers of chirality,
shows some preference for the (S)-azlactone kinetically favors the (S)-azlactone in
alcoholytic ring opening [37].
Fig. 3 Relative Gibb’s free energies of the four ternary azlactone–methanol–catalyst complexes
and the corresponding transition states at 298 K, gas phase (B3LYP/6-311++G(d,p)// B3LYP/6-
31+G(d))
Scheme 5 Pseudo-ephedrine derived catalyst which

favors the ring opening of (S)-azlactones
3.2 On the Bifunctionality of Chiral Thiourea: Tertiary-Amine

Based Organocatalysts: Competing Routes to C–C Bond
Formation in a Michael-Addition
Takemoto et al. were the first to report that bifunctional organocatalysts of the
thiourea – tert-amine type efficiently promote certain Michael-reactions, e.g., the
addition of b-dicarbonyl compounds to nitro olefins (Scheme 6) [43–45].
Scheme 6 Enantioselective Michael-addition of acetylacetone to nitrostyrene catalyzed by a

bifunctional thiourea catalyst
Pápai et al. selected as model reaction the addition of 2,4-pentanedione

(acetylacetone) to trans-(R)-nitrostyrene, catalyzed by the bifunctional thiourea
catalyst shown in Scheme 6 [46]. The analogous Michael-addition involving dime-
thyl malonate and nitroethylene as substrates, and a simplified catalyst was calcu-
lated at the same level of theory by Liu et al. [47]. Himo et al. performed a density
functional study on the related cinchona-thiourea catalyzed Henry-reaction between
nitromethane and benzaldehyde [48].
As shown by Takemoto and coworkers, the nitro-Michael reaction shown in
Scheme 6 proceeds efficiently (within 1 h) at room temperature, affording the
Michael adduct in good yield (80%) and with high enantiomeric excess (89% ee,
with (R)-configuration of the major enantiomer) [44]. The theoretical analysis by
Pápai et al. revealed that both the nitroolefin (2.05 and 2.21 Å) (Fig. 4, left; adduct 1)
and the enol form of acetylacetone (1.94 and 2.40 Å) (Fig. 4, right; adduct 2) can
form two hydrogen bonds with the thiourea moiety of the catalyst. A proton transfer
from the coordinated enol to the amino function of the catalyst can easily take
place, as the transition state related to this process (TS2-3¢) represents only a rela-
tively small energy barrier (6.6 kcal mol−1) with respect to adduct 2 (see Fig. 4, 2)
and the resulting ion pair (3¢) is predicted to be only 2.2 kcal mol−1 (gas phase)
above 2 (0.7 kcal mol−1 in toluene) (see Fig. 5, 3¢).
The enolate anion in complex 3¢ is stabilized by three N–H...O bonds that involve
the protonated amine moiety (1.68 and 2.28 Å) and one of the N–H groups (1.80 Å)
of the thiourea. In complex 3″, the enolate is tilted from its original position to
maximize the number of N–H...O bonds. In this arrangement, all three N–H units
are involved in the hydrogen bond network.
Fig. 4 Optimized structures (B3LYP/6-31G(d)) of the most stable catalyst–substrate adducts.

Bond distances characteristic for hydrogen bonds are given in Ångstrom
Fig. 5 Optimized structures (B3LYP/6-31G(d)) of the stationary points located for the proton transfer
between the thiourea derived catalyst and the enol form of acetylacetone. Bond distances characteristic
for hydrogen bonds are given in Ångstrom, bonds broken or formed are shown in red
Two distinct reaction pathways can be envisioned for the C–C bond formation step
of this catalytic process (see Scheme 7). According to the mechanism proposed by
Takemoto et al. [44], the nitroolefin interacts with the thiourea moiety of complex 3¢
(Scheme 7, route A), forming a ternary complex, wherein both substrates are activated,
and C–C bond formation can occur to produce the nitronate form of the addition prod-
uct. Alternatively, the facile interconversion between 3¢and 3² may allow an interaction
of the nitroolefin with the cationic ammonium group of the protonated catalyst
(Scheme 7, route B). In both cases, ternary complexes result which are the precursor
for the C–C coupling step. On both routes, the hydrogen bonds to the nucleophilically
attacked nitrostyrene are contracted to compensate the development of negative charge
[route A: hydrogen bonds to the thiourea functionality: −0.160 and −0.316 Å (Fig. 6),
route B: hydrogen bonds to the protonated amino group: −0.437 and −0.546 Å (Fig. 7)].
Scheme 7 Two alternative reaction routes for the organocatalytic Michael-addition of acetylacetone
to nitrostyrene
Fig. 6 Optimized structures (B3LYP/6-31G(d)) of the stationary points located along route A.
Lengths of hydrogen bonds are given in Ångstrom, bonds broken or formed are indicated in red
Fig. 7 Optimized structures (B3LYP/6-31G(d)) of the stationary points located along route B.
Lengths of hydrogen bonds are given in Ångstrom, bonds broken or formed are indicated in red
Simultaneously, the hydrogen bonds to the nucleophile are stretched [route A:

hydrogen bonds to the protonated amino group: +0.134 and +0.180 Å (Fig. 6), route
B: hydrogen bonds to the thiourea functionality: +0.180 and −0.003 Å (Fig. 7)].
The C–C bond forming step also accounts for the enantioselectivity of the
overall process. In the transition states affording the (R)-product [TS 4–5 (Fig. 6),
TS 6–7 (Fig. 7)], the substrates are aligned in a staggered conformation along the
forming C–C bond, thus minimizing nonbonding interactions. Such favorable
orientation cannot be adopted in the transition states leading to the (S)-configurated
product: the electrophilic b-carbon atom of the Michael acceptor (nitrostyrene) is
displaced from its ideal position when the nucleophile attacks its si-face. C–C Bond
formation can only take place with a compromise of either the hydrogen bonding
catalyst–substrate interactions, or the staggered geometry of the reacting molecules.
These results underline the importance of the relative spatial arrangement of the
hydrogen bond donor and acceptor in a bifunctional catalyst. To obtain best asym-
metric induction, it should ideally be compatible only with the transition state
geometry leading to the desired product stereoisomer (Fig. 8).
Fig. 8 Organocatalytic Michael-addition: Energy profiles of paths A and B, both leading to

(R)-configurated product, as obtained from gas phase calculations (B3LYP/6-311G(d,p)// B3LYP/6-
31G(d))
3.3 Dramatic Acceleration of Olefin Epoxidation in Fluorinated

Alcohols: Activation of Hydrogen Peroxide by Multiple
Hydrogen Bond Networks
As a third example for an organocatalytic reaction, based on multiple hydrogen

bonding and mechanistically investigated by DFT, we selected olefin epoxidation
with hydrogen peroxide in fluorinated alcohol solvents, such as 1,1,1,3,3,3-hex-
afluoro-2-propanol (HFIP) (Scheme 8). Here we encounter a new type of catalytic
hydrogen bond: the cooperative hydrogen bond.
Scheme 8 Epoxidation of alkenes with hydrogen peroxide in HFIP as solvent
In this example the solvent – a fluorinated alcohol – forms higher order aggregates
and activates H2O2 for the epoxidation of electron rich olefins. HFIP accelerates this
oxidation reaction up to 100,000-fold (relative to that in 1,4-dioxane as solvent).
Which hydrogen bond network involving H2O2, olefin, and fluorinated alcohol gives
rise to such spectacular accelerations?
3.3.1 Hydrogen Bond Donor Features of HFIP
For understanding the catalytic properties of HFIP, it is necessary to take a closer

look at the hydrogen bond donor properties of HFIP, and the factors by which they
are influenced [50]. The hydrogen bond donor ability of fluorinated alcohols, and
in particular HFIP, is mainly dependent on two parameters: (1) the conformation of
the alcohol monomer along the C–O bond [49, 50, 51] and (2) the cooperative
aggregation to hydrogen bonded alcohol clusters [49, 50].
In a polarizable environment, the absolute minimum structure of HFIP carries
the OH synclinal (sc) or almost synperiplanar (sp) to the adjacent CH (Fig. 9) [49].
On the basis of quantum-chemical considerations as well as single-crystal X-ray
structures in which HFIP acts as hydrogen bond donor, HFIP always takes on such
an sc or even sp conformation. In this conformation, the hydrogen bond donor abil-
ity of HFIP is significantly increased (Figs. 10 and 11) [49].
Furthermore, the hydrogen bond donor ability of an HFIP hydroxyl group is greatly
enhanced upon coordination of a second or even third molecule of HFIP (Figs. 12 and
13). Aggregation beyond the trimer has no significant additional effect [49, 52].
Therefore, the following mechanistic investigation of the epoxidation of olefins
with hydrogen peroxide is constrained to reaction pathways which (1) involve HFIP
in an sc or even sp conformation and (2) to hydrogen bonded HFIP aggregates com-
prising up to four alcohol monomers.
3.3.2 The Catalytic Activity of HFIP in the Epoxidation Reaction
Kinetic investigations of the epoxidation of Z-Cyclooctene by aqueous H2O2 in

HFIP show that the reaction follows a first order dependence with respect to the
substrate olefin as well as to the oxidant, suggesting a monomolecular participation
of these components in the rate-determining step [52]. On the other hand, a rate
order of 2–3 with respect to the concentration of HFIP is observed for several cosolvents.
The large negative DS‡ of –39 cal mol−1 K points to a highly ordered TS of the rate-
determining reaction step: typical DS‡ values for olefin epoxidations by peracids
range from –18 to –30 cal mol−1 [53]. These experimental results provide the basis
Fig.9 Potential energy (a) and dipole moment (b) of HFIP vs (HOCH) dihedral angle in vac-
uum (black) and within a PCM (red)
Fig. 10 Single-crystal X-ray structures of HFIP: (a) view perpendicular to the helix axis;
(b) view along the helix axis
Fig. 11 Dependence of the properties of
monomeric HFIP on the conformation
highest H-bond most stable liquid
along the CO bond a
donor ability H phase conformer
H
F3C CF3
most stable gas
phase conformer
Fig. 12 LUMO energy (σ*OH) (a) and natural charge qH of the hydroxyl proton (b) vs aggregation
state of HFIP
X
F3C CF3
CF3 O n
H H
H qH
F3C O O eKS(s*
H-bond donor ability
OH)
F3C CF3
Fig. 13 Aggregation-induced hydrogen bonding enhancement of HFIP

for the calculations in which one to four molecules of HFIP are added to the
transition state of the reaction.
The first quantum-chemical investigation of the mechanism of olefin epoxidation
in fluoroalcohols was carried out by Shaik et al. [54]. In the absence of kinetic data,
a monomolecular mode of activation by the fluorinated alcohols for all reaction
pathways was assumed [54].
In this review, we compare the transition state which does not involve HFIP-
participation [TS(e,0)] with single-HFIP involvement [TS(e,1) and TS(e,1)¢]
(Fig. 14). Particular emphasis is then put on the twofold HFIP-activated complex
(Fig. 15) for a detailed inspection of the hydrogen bond assisted epoxidation. All
relevant characteristics of higher order activation (as shown, e.g., in Fig. 16) are
already present in the transition states TS(e,2) and TS(e,2)¢ (Fig. 15).
Fig. 14 Stationary-point structures for the epoxidation of ethene with hydrogen peroxide in the
absence and in the presence of one molecule of HFIP, optimized at RB3LYP/6-31 + G(d,p)
(selected bond lengths in Å; RB3LYP/6-311++G(d,p) results in parentheses)
presence of two molecules of HFIP, optimized at RB3LYP/6-31 + G(d,p)
presence of three to four molecule of HFIP, optimized at RB3LYP/6-31 + G(d,p)
In the 2:1 precomplex C(2) composed of HFIP and H2O2, hydrogen peroxide is
coordinated by the two alcoholic hydroxyl groups in a cyclic fashion, one HFIP
acting as a hydrogen bond donor towards the leaving OH (hydrogen bond length
1.767 Å), and the other one as a hydrogen bond acceptor (hydrogen bond length
1.906 Å), deprotonating the hydroxyl group which is transferred to be the epoxide
oxygen atom (C(2), Fig. 15). The “internal” hydrogen bond between the two fluori-
nated alcohols (hydrogen bond length 1.823 Å) cooperatively increases the hydro-
gen bond donor ability of the alcohol molecule which activates the leaving
OH-group. By this hydrogen bond pattern, a polarization of the O–O bond is
achieved (the donated and accepted hydrogen bonds are not equal in length and
angle), and an electron deficient oxygen is generated, ready for electrophilic attack
on the olefinic double bond. In the corresponding transition state (TS(e,2), Fig. 15)
the shorter hydrogen bond (in which HFIP acts as H-bond donor) is extremely
contracted to 1.409 Å (−0.358 Å) whereas the longer hydrogen bond (in which
HFIP acts as acceptor) is slightly decreased in length to 1.864 Å (−0.042 Å). The
acidity of the donor HFIP molecule is cooperatively increased by shortening of the
HFIP internal hydrogen bond from 1.823 to 1.692 Å (−0.131 Å).
A second potential reaction path (C(2)¢, TS(e,2)¢, Fig. 15) for twofold HFIP
activation was calculated, which differs from TS(e,2) with regard to the hydrogen
bond from H2O2 to HFIP. Here, a fluorine atom of the trifluormethyl group serves
as hydrogen bond acceptor, and not a second hydroxy function. Both transition
states are similar in energy but the corresponding precomplex C(2)¢, consisting of
H2O2 and two HFIP molecules, lies 18.4 kJ mol−1 above C(2).
An analysis of the hydrogen bonding parameters shows that, in all cases where
HFIP donates a hydrogen bond to the oxidant, this hydrogen bond is significantly
contracted in the transition state, usually by more than 0.3 Å. The result of this
significant contraction is the formation of a LBHB [30], characterized by an
increase in covalency which effectively exerts the pronounced stabilization of the
highly polar transition states through charge transfer. Hydrogen bonds between two
HFIP molecules show the same trend, being regularly shortened by ca. 0.1 Å. This
effect clearly indicates a cooperative enhancement of hydrogen bonding.
Additionally, we find a reduction of the (HCOH) dihedral angles in 14 of the 16
HFIP molecules within the 7 calculated reaction pathways. This result is in agree-
ment with the analysis of the hydrogen bonding properties of HFIP, as the hydrogen
bond donor ability is maximized toward the sp conformation of the alcohol.
Proceeding from the transition states to the resulting products, IRC analysis
demonstrates that along this reaction path, a subsequent and barrier-free, cascade-
like proton transfer towards the formation of the epoxide and water takes place.
Figure 17 shows the overall dependence of the activation parameters on the number
of HFIP molecules involved. Interestingly, the activation enthalpy of the epoxida-
tion decreases steadily from zero to fourth order in HFIP. As expected, the activa-
tion entropy −TDS‡ shows a continuous increase with increasing numbers of
specifically coordinated HFIP molecules. Due to the increasing entropic contribu-
tion, the value of DG‡ approaches saturation when three or four HFIP molecules are
involved. For methanol, however, no influence of explicit coordination of the sol-
vent on the activation parameters of oxygen transfer could be found, so it seems to
Fig. 17 Activation parameters vs number of HFIP molecules for the epoxidation of ethane within
a solution model at 298 K (RB3LYP/6-311++G(d,p)//RB3LYP/6-31 + G(d,p))
act solely as a polar reaction medium. In line with this result, no significant epoxi-
dation catalysis results from the use of methanol as solvent.
3.4 TADDOL-Promoted Enantioselective Hetero-Diels–Alder

Reaction of Danishefsky’s Diene with Benzaldehyde: Another
Example for Catalysis by Cooperative Hydrogen Bonding
The enantioselective hetero-Diels–Alder (HDA) reaction of carbonyl compounds

with 1,3-dienes represents an elegant access to optically active six-membered
oxo-heterocycles. Since the pioneering work of Rawal et al. in 2003 [55], the
enantioselective HDA reaction catalyzed by diols (such as TADDOLs) has become
a flourishing field of research [56].
In the catalytic system shown in Scheme 9, a hydrogen bond between one hydroxy
function of the diol catalyst and the carbonyl group of the substrate is regarded as
the driving force of catalysis. Here, the spatial orientation of the bulky a-1-naphthyl
substituents of the TADDOL (a,a,a¢,a¢-tetraaryl-1,3-dioxolan-4,5-dimethanol)
scaffold generates the chiral environment controlling the enantioselectivity of the
reaction.
Scheme 9 Enantioselective hetero-Diels–Alder (HDA) reaction of Danishefsky’s diene with

benzaldehyde
A similar Diels–Alder reaction was investigated at DFT-level by Houk and

co-workers [57]. Instead of using TADDOL, they selected one methanol mole-
cule, two methanol molecules and 1,4-butanediol in cooperative and bifurcated
coordination as catalysts. It was found that cooperative catalysis is generally the
favored route.
Ding, Wu et al. [58] used a model system consisting of benzaldehyde and a modi-
fied Danishefsky’s diene, in which the trimethylsilyl group was replaced by a methyl
group. They varied the aryl substituents of the TADDOL catalyst, and the results for the
most enantioselective 1-naphthyl substituted catalyst were presented in detail. The cen-
tral feature of this computational analysis is the use of the ONIOM method [59, 60] for
geometry optimization (Fig. 18): the substrates and the core of TADDOL were treated
with B3LYP/6-31G(d), while the substituents of the catalyst were modeled using sem-
iempirical PM3 [61, 62] level. The energies of the optimized structures were determined
by single point calculations with B3LYP/6-31G(d). X-ray crystal structures [33] of the
TADDOLs investigated were taken as starting geometries.
In the starting complex, there are three principal possibilities of hydrogen bonding
between TADDOL and benzaldehyde (Scheme 10). A bifurcated hydrogen bond
between the two hydroxy functions and the carbonyl group can be excluded, as
TADDOLs are well known to have an intramolecular hydrogen bond [33, 63].
Ding, Wu et al. found that structure optimizations resulted, without exception, in
the trans configuration, even if the initial structure was cis. This observation is
consistent with the crystal structures available for TADDOL adducts with carbonyl
compounds [33, 63].
Fig. 18 Application of the ONIOM method to the model system of the reaction
O O O O O O
H H H H H H
O O
O
H H
H
trans cis bifurcated
Scheme 10 Possible intermolecular hydrogen bonding patterns between benzaldehyde and

TADDOL
Upon formation of the trans adduct of benzaldehyde with TADDOL, the

intramolecular hydrogen bond is shortened by 0.128 Å, and the acidity of the sub-
strate binding hydroxy function is increased. The length of the intermolecular
hydrogen bond to the carbonyl group is 1.825 Å.
To rationalize the enantioselectivity of the TADDOL-catalyzed HDA reaction
between Danishefsky’s diene and benzaldehyde, eight possible diastereomeric
transition states of different regio- and stereochemistry should in principle be
considered for comprehensive analysis. The cycloaddition between the model diene
and benzaldehyde can take place along two regio-isomeric “meta” (C1–O6, C4–C5
bond formation) and “ortho” (C1–C5, C4–O6 bond formation) reaction channels.3
For both of these pathways, an exo- and an endo-approach can be formulated
(Scheme 11) [64].
The energy of the localized transition state for the “ortho” route (uncatalyzed reaction)
is 14 kcal mol−1 higher than that of the “meta” channel. Therefore, the “ortho” channel
can be excluded. Unlike the uncatalyzed transformation, the TADDOL-catalyzed HDA
Scheme 11 Regio- and stereoselectivity issues of the model hetero-Diels–Alder cycloaddition
3
Please note that the “ortho/meta” terminology is used in a different way in ref. 58. The assign-
ment used in here is based on the original formalism by Diels and Alder
reaction exhibited a clear energetic preference for the endo- over the exo-approach.
Thus, only endo transition states were considered. The number of possible reaction
paths/transition states is thus reduced from eight to two, namely endo-approach with
re- or si-face attack of the model diene to the activated benzaldehyde.
As can be seen from Fig. 19, the activation energy of the reaction in the presence
of the 1-naphthyl substituted TADDOL catalyst was reduced by 10.2 kcal mol−1, in
comparison with the uncatalyzed reaction (20.2 kcal mol−1). The reaction proceeds via
a concerted but asynchronous pathway, and no zwitterionic intermediate or transition
state corresponding to a stepwise Mukaiyama-aldol type pathway could be located.
The partial charges of the aldehyde carbonyl group are stabilized by an intermo-
lecular hydrogen bond to the TADDOL catalyst. In the organocatalytic reaction, the
C–C bond formation has progressed further (due to the more positively polarized
carbonyl carbon atom of the benzaldehyde) whereas the C–C bond formation lags
behind in the uncatalyzed reaction. The NBO charges indicate that there is a con-
siderable charge transfer of 0.49 e− from the donor diene to the activated aldehyde
acceptor in the transition state (TS-(Si)-4b), but in the uncatalyzed case the trans-
ferred charge does not exceed 0.27 e− (endo TS). This is due to the fact that both the
Fig. 19 Transition states involved in the cycloaddition (endo-mode) of the model diene with
benzaldehyde, both in the absence (TS-endo) and the presence (TS-(Si)-4b, TS-(Si)-4b) of the
TADDOL catalyst; corresponding activation energies [kcal mol−1](B3LYP/6-31G(d)//B3LYP/6-
31G(d):PM3)
cooperative intramolecular hydrogen bond (shortened by about 0.08 Å) and the

intermolecular hydrogen bond to the substrate (shortened by about 0.2 Å) reinforce
each other cooperatively in the transition state, and stabilize the developing nega-
tive charge at the carbonyl oxygen atom during nucleophilic attack. How can the
energetic preference of TS-(si)-4b over TS-(re)-4b be rationalized? Obviously,
nonbonding interactions of the 1-naphthyl groups of the TADDOL catalyst with
the phenyl ring of benzaldehyde in the re-transition state effect the observed
enantioselectivity.
4 Epilog
Multiple and specific hydrogen bonding has been recognized as a highly efficient
motif not only in enzymatic catalysis, but nowadays also in organocatalysis. Much
of our current mechanistic understanding is based on computational analysis of
such processes, ideally in combination with kinetic and spectroscopic methods.
It appears that naturally evolved catalytic motifs, such as the oxyanion hole, can be
“side-tracked” to accelerate a number of “anthropogenic” reactions involving inter-
mediates/transition states with a negatively charged oxygen atom. It is tempting to
speculate which other types of enzymatic rate accelerations by hydrogen bonding
might be suitable for adaptation to organocatalysis!
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Top Curr Chem (2010) 291: 29–75
DOI: 10.1007/128_2008_21
Published online: 21 May 2009
Enamine Catalysis
Petri M. Pihko, Inkeri Majander, and Anniina Erkkilä
Abstract The reversible reaction of primary or secondary amines with enolizable

aldehydes or ketones affords nucleophilic intermediates, enamines. With chiral
amines, catalytic enantioselective reactions via enamine intermediates become pos-
sible. In this review, structure-activity relationships and the scope as well as current
limitations of enamine catalysis are discussed.
Keywords Aldehydes and ketones • Alpha-functionalization • Amines • Enamine

catalysis • Organocatalysis
Contents
1 Introduction........................................................................................................................... 30
2 Catalytic Formation of Enamines......................................................................................... 31
2.1 A Brief History of Enamine Catalysis....................................................................... 31
2.2 Structural Requirements of Enamine Catalysis......................................................... 33
3 Highlights of Enamine Catalysis.......................................................................................... 41
3.1 Aldol and Related Reactions...................................................................................... 41
3.2 Mannich-Type Reactions........................................................................................... 50
3.3 Conjugate Addition Reactions................................................................................... 54
3.4 Heteroatom Functionalizations at the α-Carbon: a-Halogenations,
Oxygenations and Other Transformations............................................................... 57
4 Enamine Catalysis in the Synthesis of Complex Molecules................................................. 62
4.1 Domino Processes...................................................................................................... 62
4.2 Total Syntheses.......................................................................................................... 65
5 Directions for the Future....................................................................................................... 67
References................................................................................................................................... 68
P.M. Pihko ( ü)
Department of Chemistry, University of Jyväskylä, P. O. B. 35,
FI-40014 JYU, Jyväskylä, Finland
e-mail: Petri.Pihko@jyu.fi
I. Majander and A. Erkkilä,
Department of Chemistry, Helsinki University of Technology,
P. O. B. 6100, FI-02015 TKK, Espoo, Finland
30 P. M. Pihko et al.
1 Introduction
As nucleophiles, simple alkenes are typically so unreactive that only highly active
electrophiles, such as carbocations, peroxides, and halogens will react with them.
For the generation of carbon-carbon bonds, milder methods will often be required.
Fortunately, it is possible to increase the reactivity of alkene-type p-nucleophiles by
introducing electron-donating substituents. Substitution of one H with an OH or
OR gives an enol or a vinyl ether, which are already much better nucleophiles.
Using nitrogen instead of oxygen, one obtains even better nucleophiles, enamines.
Enamines are among the most reactive neutral carbon nucleophiles, exhibiting rates
that are even comparable to some charged nucleophiles, such as enolates [1, 2].
Most enamines, unfortunately, are sensitive to hydrolysis. The parent enamine,
N,N-dimethylvinylamine, has in fact been prepared [3], but appears to be unsta-
ble. Enamines of cyclic ketones and many aldehydes can readily be isolated,
however [4–7]. The instability of enamines might at first appear to diminish the
utility of enamines as nucleophiles, but actually this property can be viewed as an
added benefit: enamines can be readily and rapidly generated catalytically by
using a suitable amine and a carbonyl compound. The condensation of aldehydes
or ketones with amines initially affords an imine or iminium ion, which then
rapidly loses a proton to afford the corresponding enamine (Scheme 1).
R3 R4
N
H R3 R4 R3 R4
±H N ±H N
+
± H2O R1 R1
O
R2 R2
R1
iminium ion enamine
R2
Scheme 1 Enamine formation
This catalytic enamine formation is limited to aldehydes and ketones as starting

materials – it does not appear to be possible to prepare corresponding “enamines”,
i.e. N,O-ketene acetals, from esters in this fashion. Nevertheless, the preparation of
simple, reactive nucleophiles from normally electrophilic species, aldehydes and
ketones, in a catalytic fashion sounds highly attractive. Furthermore, the catalytic
nature of these reactions allows the use of chiral amines, and the further possibility
that these reactions can be rendered enantioselective. Enamines react readily with
a wide variety of electrophiles, and the range of reactions that can be catalyzed by
enamine catalysis is summarized in Scheme 2.
As a catalytic concept, asymmetric enamine catalysis has been the subject of
several recent reviews [8–23]. In this concept review, we will focus on some of
the key aspects of this mode of activation, and probe the current limitations and
possible future directions of enamine catalysis.
Enamine Catalysis31 3131
O
I
R1 O OH
O
R2
Br R1 R3
R1
R2
R2
"I+" R5
O HN
on
O
cti
F "Br +"
rea
R1 R1 R4
ol
R2
ald
R2 + h
"F " n nic
Ma
N
O O NO 2
Cl "Cl +" R1 conj.add.
R1 R2 R1 R6
R2 R2
R2
N Se
S R1
O
S N O
R1 R12 O N
O Se
R2 R1 R7
N
R2
O
O R8
O
R1 R11 O N R9
R1 N
R2 O R10 H
R1 N R2
H
R2
Scheme 2 A range of transformations can be promoted by enamine catalysis
2 Catalytic Formation of Enamines
2.1 A Brief History of Enamine Catalysis
The development of enamine catalysis parallels that of iminium catalysis (Scheme 3)

[24]. Like iminium catalysis, the concept took a long time to mature, and also
required a key discovery – the discovery of intermolecular proline-catalyzed aldol
reactions by List and coworkers in 2000 [23] – to set the field in motion. The time-
line of historical developments of enamine catalysis is outlined in Scheme 4.
The word “enamine” was coined in 1927 by Wittig [27]. However, at that time,
enamines were usually not considered as reactive intermediates. An early example
of enamine catalysis that was not explicitly recognized as enamine-based reaction
was the reaction of isatin with ketone nucleophiles (acetone and acetophenone),
first published by Lindwall and coworkers in 1932 [28, 31]. Later, the interconver-
sion of iminium ions and enamines in enzymatic reactions was recognized by
Westheimer [32, 354]. The first person to propose a modern enamine-based
Scheme 3 Parallels between iminium and enamine catalysis
mechanism for a catalytic reaction was Rutter, who in 1964 suggested an essen-
tially complete mechanism for aldolase reactions [29].
In stoichiometric enamine chemistry, the Stork group developed a range of highly use-
ful transformations in the 1950s and 1960s [5]. The first really useful enantioselective
enamine-catalyzed process, however, was the intramolecular aldol reaction known as the
Hajos–Parrish–Eder–Sauer–Wiechert process [30, 33, 34]. Perhaps surprisingly, although
the enamine-based mechanisms had been fully accepted for Nature’s aldolase enzymes,
the simple enamine mechanism for this reaction only became universally accepted in the
2000s. This was partly a result of conflicting data – in initial studies, Agami found a small
nonlinear effect that would have required the presence of more than one molecule of
proline in the transition state [35–40] but also partly due to the knowledge gap between
organic chemists and biochemists of the time, a point eloquently made by Barbas [41]. It
was only after the discovery of the intermolecular proline-catalyzed reaction in 2000 [23]
and further studies by List and coworkers as well as several key modeling studies by the
Houk group [42, 43] that the universality of the enamine catalysis concept became widely
1927 Wittig co ins the term "enamine"
1932 Lindwall discovers secondary amine-catalyzed a ldo l reaction between

acetophe none and isa tin
N O HO
O O H
3
N O ca t. O N
H H
1 2 4
1954 Stork demonstra tes that a variety of different α -acylations and α -alkylations are
feasible with stoichiometric enamines
Scheme 4 Historical development of enamine catalysis [25–30]

1964 Rutter proposes an essentially correct enamine-based mechanism f or aldola se

enzyme s
Enz Enz H Enz H H Enz
O N N O NH OH
NH2 H H H
R1 H R 1
R 1
H R2 R 1
R2
OH HO H OH OH
H H
X X X X
Enz Enz Enz Enz
1971 Discovery of the proline -catalyzed intramolecular aldol reaction - the Hajos-Parrish-
Eder-Sauer-Wiech ert reaction
O
O O N O O
H 6 OH cat. H
cat. dehydration
O O
O OH
5 7 8
2000 List, Barbas and Lern er discover the intermolecular p roline-ca ta lyzed aldo l reaction
O
N
O O H 6 OH O OH
H R cat. R
9 10 11
Scheme 4 (Continued)
accepted in the context of one of its oldest examples, the intramolecular aldol reaction. In
retrospect, the simplicity of the enamine catalysis concept looks obvious, but as we all
know, only in hindsight do we all have perfect vision.
2.2 Structural Requirements of Enamine Catalysis
2.2.1 The Structure of the Amine and the Resulting Enamine
In general, the most nucleophilic enamines are those where the nitrogen lone pair is
most effectively delocalized. This requires effective overlap of the lone pair with the
C = C p bond and maximum flattening (sp2 hybridization) of the enamine nitrogen.
The structure of the amine component has a profound influence on the propensity
to p-p delocalization. As an example, enamines derived from cyclic five-
membered ring amines, such as pyrrolidine, are more than thousand times more
nucleophilic than those derived from six-membered ring amines. In a series of
fundamental studies, the Mayr group has determined nucleophilicities of different
enamines, ranging from highly reactive pyrrolidine-derived amines to relatively
passive enaminones and pyrroles [44]. Differently substituted benzhydrylium

ions (12–14, see Table 1) were used as reactivity probes. Some of these results
are summarized in Table 1.
Table 1 Nucleophilicities of different enamines [44]

H H
H
F3C CF3
N 13 N N N
Ph2N 12 NPh2 14
Ph Ph
Enamine Nucleophilicity Rate constant k Rate constant k Rate constant k

parameter N with 14 with 12 with 13
15.91 3.32 × 105 − −

N
15
14.91 4.59 × 104 − −

N
16
15.06 4.57 × 104 − −

N
17
N
13.36 1.41 × 103 − −
18
N
11.40 3.35 × 101 3.38 × 105 −
19
N
20
12.06 − 7.44 × 105 −
N
21 8.52 − − 2.02 × 104
EtO O
N
22 5.02 − 1.93 −
The high reactivity of pyrrolidine-derived enamines can be explained by the

increased propensity of five-membered rings to accept sp2-hybridized atoms into
the ring compared to the six-membered rings. This phenomenon was first formu-
lated and explained by Herbert C. Brown and coworkers in 1954 [45]. A sp2 hybrid-
ized nitrogen atom allows better overlap between the C = C p system and the
nitrogen lone pair and therefore better delocalization of the nitrogen lone pair.
This increases the nucleophilicity of the enamine (a HOMO-raising effect,
Scheme 5). As such, the reactivity of enamines follows the order pyrrolidine-
E
p–π
O
O O R
O H
N N N N N =
O N
O
R R R R R
sp2 sp3
sp3-nature of the N atom
p+π
nucleophilicity
N
N
p
Scheme 5 Reactivity profile of enamines [2]
derived > acyclic amine-derived > piperidine-derived enamines [2, 44]. Additional
oxygen substituents further reduce the reactivity of enamines, and therefore mor-
pholine derivatives are even less reactive than piperidine derivatives.
Therefore it is perhaps not surprising at all that most of the successful enamine
catalysts are based on the pyrrolidine skeleton. A constellation of typical enamine
catalysts is presented in Fig. 1. Catalysts with a five-membered ring are clearly
dominant, whereas other ring sizes are clearly less popular. In recent years, primary
amines have emerged as interesting alternatives to the cyclic amine catalysts (top
left cloud in Fig. 1).
2.2.2 Additional Assistance from Acids and Hydrogen Bonding
In enantioselective enamine catalysis, the enamine can control the approach of the
electrophile either by the steric bulk of the enamine or by directing the electrophile
with an activating group. As can be readily observed with relatively unreactive
electrophiles, such as aldehydes, ketones or imines, additional assistance for cataly-
sis can be provided by suitably positioned hydrogen bond donors and/or other acids
(Scheme 6) [46].
Fig. 1 Typical enamine catalysts

‡ ‡
O δ− δ− N δ+
+ N O N δ+
or O
R H X
R R
aldehyde enamine
steric control hydrogen bonding assistance
Scheme 6 Steric control vs hydrogen bonding control in enamine catalysis
In addition, acid cocatalysts can assist the formation of the enamine. With very
basic, nucleophilic amines, such as pyrrolidine and its derivatives, acid catalysis is
not necessarily required for enamine formation. However, with less basic amines,
Brønsted or Lewis acids are often used to assist in enamine formation (Scheme 7).
N
H
O 24
pK a 11.26 N
benzene, rfx
23 16
Ph Me
N
H
O 25 Ph Me
N
pK a 4.70
cat. PTSA or ZnCl2
toluene or neat rfx
23 26
Scheme 7 Effect of pk a on the enamine formation
Enamine formation under acid catalysis has been extensively studied by several
groups [47–61]. The abstraction of an α-proton from the initially formed iminium
ion is a key step in the catalytic process. Whereas a strong acid cocatalyst has a
strong stabilizing effect on the iminium ion and aids its formation, a basic cocata-
lyst will assist for the enamine forming step. Thus the basicity of the counteranion
of the acid cocatalyst determines the rate of enamine formation. While a strong acid
is beneficial in the first iminium forming step, its conjugate base has only a weak
ability to remove the a proton. On the other hand, a relatively strong counter base
would favor the formation of the enamine, but the initial formation of the iminium
ion would be somewhat compromised. Hence both general acid and base cocataly-
sis has to be considered in enamine formation in addition to the choice of the cata-
lytic amine species.
Hine has demonstrated that simple amino acids, such as glycine and b-alanine, are
not capable of intramolecular deprotonation in the reaction with isobutyraldehyde-2-d
(Scheme 8) [62]. Apparently, the carboxylate moiety in the iminium ion intermediate
29 is a relatively weak base and, as such, external bases, present in the buffer used (e.g.
acetate ions), are largely responsible for the formation of the enamine intermediate 30.
O
H 3N n
H O H O O
O 28 O N n N + H2O
O H
H O H
D H H
H2 O D
27 buffer 29 30 31
Scheme 8 Amino acid-catalyzed dedeuteration of isobutyraldehyde-2-d
In contrast to amino acids, the Hine group demonstrated that certain 1,3-diamines are
capable of bifunctional catalysis, as evidenced by the anomalously high rates of enamine
formation compared to 1,2- and 1,4-diamines. They explained this result by invoking a
cyclic transition state where the 3-dimethylaminopropylamine catalyst forms an iminium
ion that is dedeuterated by the proximal dimethylamino group (Scheme 9). The deute-
rium exchange reactions with acetone-d6 were first order in amine and led to the rapid
formation of mono-, di- and triprotonated products. Apparently, the iminium ions
undergo deuterium exchange and hydrolyze to acetone at almost comparable rates.
n = 1: bifunctional catalysis
‡ O O
n
NH2 NMe2 D 3C CHD 2 D3C CH2D
O N
33 34 35
O
D 3C CD3 D
H2O
32 D3C N D3C CH 3
buffer D D H
36
cyclic transition state initial products
Scheme 9 Enamine formation via bifunctional catalysis
Momiyama and Yamamoto have recently demonstrated that acid cocatalysts can
even influence the outcome of enamine-mediated reactions [63]. In their studies of
the acid-catalyzed O- and N-nitroso aldol reaction, they found that the nature of the
acid catalyst dictates the regioselectivity of the reaction between preformed enam-
ine species A carboxylic acid catalyst promoted the O-nitroso aldol reaction
whereas a hydrogen bonding catalyst catalyzed the formation of an N-adduct, both
in high enantioselectivities(Scheme 10).
Gryko and coworkers studied the influence of an acid additive in the aldol reac-
tion catalyzed by a proline derivative equipped with an existing hydrogen bonding
Ar Ar
O O
OH
O O OH HO δ+
O
O R
H
O
H Ar Ar
N OH Ph δ– H
N N N
37 39 O
N O
Ph O - nitroso aldol
N - nitroso aldol
38 40
18
Scheme 10 Different acid catalysts lead to opposite regioselectivity
functionality (thioamide) [64, 65]. They observed that the addition of one equiva-
lent of acid per catalyst molecule enhanced the reaction rates significantly. A closer
inspection revealed that the nature of the acid additive has strong influence on the
reaction efficiency. A strong dependence was detected between the increasing
strength of the acetic acid derivatives and both the reaction rate and enantioselectivity
(Table 2). The catalyst salts of stronger inorganic acids as well as sulfonic acids
failed to promote the reaction. By NMR studies, the authors were able to observe
that the formation of iminium species between the catalyst salt and substrate cor-
related to high reaction efficiency. The iminium ion likely equilibrates with the
reactive enamine and thus enhances the reaction rate. Additionally, the acid cocatalyst
may stabilize the iminium ion of the formed product and push it towards hydrolysis
instead of retroaldolization which might compromise the reaction selectivity. Other
groups have reported that the addition of TFA cocatalyst to aldol reaction catalyzed
by alternative proline derivatives affords similar results [66, 67].
Table 2 The influence of an acid additive in the l-prolinethioamide-catalyzed aldol reaction
S
O N
H Ph
HN O OH
9
42·HX
O
NO2
H 43
NO2
41
Entry HX pKa Yield [%] ee [%]

1 AcOH 4.76 20 86
2 HCO2H 3.75 24 89
3 MIA 3.12 32 91
4 MBA 2.86 28 94
5 MCA 2.85 60 93
6 DCA 1.29 99 93
7 DFA 1.24 95 92
8 TFA 0.26 81 94
The effect of basic additive as well as water in proline catalyzed aldol reaction has
been studied extensively [192]. Furthermore, Zhou and Shan disclosed that hydrogen
bonding additives such as weak Brønsted acids successfully enhance both the effi-
ciency and the selectivity of the reaction. They suggested that their hydrogen bonding
BINOL additive enhanced the catalytic ability of proline by additional hydrogen
bonding interactions between the catalyst, additive, and approaching substrate [68].
Only a few reactions with a purely external cocatalytic acid source have been pub-
lished, and very few screening studies of the cocatalysts are available. Barbas and
coworkers studied the effects of Lewis and Brønsted acids in the pyrrolidine-catalyzed
aldol reaction [69]. They observed that acetic acid provided over twofold greater initial
reaction rates compared to the same reaction without acid. Interestingly, stronger acids
such as TfOH, PTSA and CSA gave slower reaction rates. Subsequently, Peng and
coworkers disclosed beneficial effect of substituted phenols in the same reaction [70].
Decreasing acidity of the cocatalyst increased the reaction rates. These observations are
consistent with the requirement of general acid catalysis for the iminium formation and
the general base catalysis for the subsequent enamine formation.
2.2.3 Conclusion – Two Types of Enamine Catalysts
In conclusion, successful enantioselective enamine catalysts can be divided into

two groups [16] (Scheme 11):
O
N
R2 N
H R2
R1
R1
aldehyde or amine catalyst enamine
ketone
Carbonyl, imine, azo X + reagents

etc. electrophiles (halogen electrophiles)
‡ ‡
Hydrogen R4 N N Steric
bonding / Z H X X bulk
Brønsted acid Y R2 R 2
control
control R3
R1 R1
Type A catalyst Type B catalyst
hydrolysis
R4
ZH O O
Y X
R3 R2 R2
1 1
R R
Scheme 11 The two modes of stereochemical steering with enamine catalysis

Type A: Includes an internal acid/hydrogen bond donor to orient the approach

of the electrophile
Type B: A bulky, nonacidic group is used to orient the enamine and to block the
approach of the electrophile from one side only
Type A enamine catalysts include simple amino acids, such as proline 6, and
most of their derivatives (such as the tetrazole 44 and various sulfonamides, e.g.
45). They are typically used for aldol, Mannich, a-amination and a-oxygenation
reactions – these are all reactions where the electrophile can readily be activated by
hydrogen bonding (Scheme 12) [8, 9, 12, 46].
O N
N
N N O Me
H OH H HN N Ph
N Ph
6 44
N N OTMS
O O Ph H H
S
N CF3 46 47
N H
H
45
Selected examples Selected examples
of Type A catalysts of Type B catalysts
Scheme 12 Selected examples of Type A and Type B catalysts
Type B enamine catalysts have been developed more recently. They include the
diarylprolinol ethers (developed by the Hayashi and Jørgensen groups, e.g. 47 and
its derivatives) [71–75] as well as the MacMillan imidazolidinone catalysts (e.g.
46) [76–78]. They excel in reactions where hydrogen bonding assistance is either
not required or is not essential, such as a-halogenation reactions as well as some
conjugate addition reactions (Scheme 12).
3 Highlights of Enamine Catalysis
In the following discussion, key reactions of enamine catalysis are summarized.

Present limitations of each method are also discussed. For more detailed treatment
of the reactions, the original publications as well as recent comprehensive reviews
[8–23] should be consulted.
3.1 Aldol and Related Reactions
Among the electrophilic reaction partners of the enamine nucleophiles, aldehydes and
ketones are arguably the most important class. The addition of an enamine to a carbo-
nyl compound affords aldol products after hydrolysis (Scheme 13). In this process,
one or two new stereogenic centers and one carbon-carbon bond are formed.
R O R
O OH
R3 R4 ±H N OH + H2O
N
R1 R4
R1 R4 R
R1 R2 R3
R3 −
R2 R2 N
H2
enamine iminium aldol product
intermediate
Scheme 13 Enamine-catalyzed aldol reaction
Usually, the component that forms the enamine is called aldol donor, and the
electrophilic carbonyl component is called acceptor (Scheme 14).
O O OH
O
R4 Aldehyde-ketone
R1 R1 aldols
H R4 2 R3
R2 R
X H
donor acceptor
Cat. N
H
O O OH
O
R4 Ketone-ketone
R 1 R1 aldols
R3 R4 2 R3
R2 R
donor acceptor
Scheme 14 Equilibria in aldol reactions with ketone and aldehyde acceptors
In spite of the attractiveness of the aldol manifold, there are several problems
that need to be addressed in order to render the process catalytic and effective.
The first problem is a thermodynamic one. Most aldol reactions are reversible.
Furthermore, the equilibrium is also just barely on the side of the products in the
case of simple aldehyde-ketone aldol reactions [79, 80]. In the case of ketone-
ketone aldol reactions, the equilibrium generally lies on the side of starting mate-
rials (Scheme 14). Overall, this means that relatively high concentrations of
starting materials should be used, and very often one of the components must be
used in excess.
A second, even more worrying problem is the side reaction, the formation of
condensation products. This process is essentially irreversible in most cases. The
condensation products can arise either from the aldol product or directly through a
Knoevenagel–Mannich type reaction where the enamine reacts with an iminium ion
[26, 81, 82]. The condensation process requires only an external Brønsted acid,
whereas the aldol process appears to require simultaneous activation of the carbo-
nyl electrophile by an internal Brønsted acid/hydrogen bond donor (Scheme 15).
Scheme 15 Double activation of reaction components by an enamine/iminium mechanism [81]
The delicateness of the aldol protocol has perhaps been one of the factors why
enamine catalysis of the aldol reaction did not emerge until the 1970s. The Hajos–
Parrish–Eder–Sauer–Wiechert reaction [30] (Scheme 16) was an important early
example of an intramolecular enamine-catalyzed aldol reaction. However, it was
not until 2000 when List, Barbas and Lerner demonstrated that the same reaction
can also be performed in an intermolecular fashion, using proline as a simple enam-
ine catalyst [26].
O
O O N O
H OH O
6 cat. H
dehydration
O O
O OH
5 7 8
Scheme 16 The Hajos-Parrish-Eder-Sauer-Wiechert reaction
Since 2000, remarkable advances in the utility of the enamine-catalyzed aldol

reaction have been made [83]. A massive effort has been devoted to the develop-
ment of more effective variants of proline [13, 26, 64, 68, 84–174]. In addition,
alternative amino acids and peptides bearing primary amino groups [175–184] as
well as axially chiral amines [185–187], chiral imidazolidinones [188] and cin-
chona alkaloid-derived amines [189] have been used successfully as aldol cata-
lysts. It should be noted, however, that most of these catalysts do not exceed
proline in their efficiency. The rates as well as the diastereoselectivities of the
reaction appear to be improved by the addition of water to the reaction mixture
[190–193]. The Hayashi [96] and Barbas [141] groups have both demonstrated
that aldol reactions can even be performed on water or in aqueous media using
hydrophobic derivatives of proline.
For improvements in the enantioselectivity of the aldol reactions, the highly
active catalysts developed by Gong and coworkers [194–196] as well as further
improvements by Singh and coworkers [197] deserve to be mentioned (Fig. 2).
These catalysts are one of the most active catalysts for the direct aldol reaction
between acetone and various aldehydes, with very high enantioselectivities.
The Gong group has also presented computational evidence [198] for an inter-
esting double hydrogen bonding activation mode [199] with these catalysts.
O Ph O CO2Et
Ph CO2Et
N N
N H N H
H OH H OH
48 49 O
Catalysts developed by Gong and co-workers N
N H
O H O
O Ph R1
Ph O R2 R3 H
Ph
N Ph
N H N Ph A possible
H OH N H activation mode
H OH
50 51
Catalysts developed by Singh and co-workers
Fig. 2 Double hydrogen bonding enamine catalysts developed by Gong and Singh
3.1.1 Ketone-Aldehyde and Ketone-Ketone Aldol Processes
Typical starting materials, catalysts, and products of the enamine-catalyzed aldol

reaction are summarized in Scheme 17. In proline-catalyzed aldol reactions, enan-
tioselectivities are good to excellent with selected cyclic ketones, such as cyclohex-
anone and 4-thianone, but generally lower with acetone. Hindered aldehyde
acceptors, such as isobutyraldehyde and pivalaldehyde, afford high enantioselec-
tivities even with acetone. In general, the reactions are anti selective, but there are
already a number of examples of syn selective enamine aldol processes [200, 201]
(Schemes 17 and 18, see below). However, syn selective aldol reactions are still
rare, especially with cyclic ketones.
6
RO 56: R = solid supports
57: R = TBDPS
O N CO2H N N
H N
N N SO2Ph N N
H H 54 O H 44 H
R
N N R
N N H H
H HO O OH
55·HX 48,49,51
Y R
O X
anti -aldol, 59
Y
X X = H, Me, aliphatic
Y = Me, aliphatic, aromatic,
donor, 52 CO2Et
Z = H, CO2R, PO(OR)2
O R = H, aliphatic, aromatic,
CCl3, 2: isatin
Z R
NH2
acceptor, 53
n -Pr
N
58 O OH
n -Pr
Y R
X
syn-aldol, 60
O
O
H
O
O H
63 41 NO2
O O
H
62 O NBn2
Selected
23 Selected H
donors H 66
O acceptors
61 64 O
O
CN O
9 CO2H
Ph O
H N
65 O 2 H
67
Scheme 17 Asymmetric aldol reactions with ketone donors
Ketone donors bearing a-heteroatoms are particularly useful donors for the
enamine-catalyzed aldol reactions (Scheme 18). Both anti and syn aldol products can
be accessed in remarkably high enantioselectivities using either proline or proline-
derived amide, sulfonamide, or peptide catalysts. The syn selective variant of this
reaction was discovered by Barbas [179]. Very recently, Luo and Cheng have also
described a syn selective variant with dihydroxyacetone donors [201], and the Barbas
group has developed improved threonine-derived catalysts 71 (Scheme 18) for syn
selective reactions with both protected and unprotected dihydroxyacetone [202].
O
PEPTIDE
N N
CATALYSTS H H
RO
O 70
N CO2H N SO2Ph
N
H H H O OH
6. 57, 58 55
Y R
O
X
Y anti - aldol, 74
X
X = OH, OR, Cl,
donor, 68
Y = Me, CH2OR, alkynyl
NH2 R = aliphatic, aromatic
O H
Ot-Bu
Z R NR2
H2N CO2H 72: R = Et
acceptor, 69 58: R = n - Pr
71
t - BuO O Ph
Ph
N Ph
H
NH2 OH O OH
73
Y R
X
syn - aldol, 75
X = OH, OTBS, OBn
Y = aliphatic, CH2OR
R = aromatic, COX
O
O
O H
81 H O
82 O
O O
77 OMOM O Selected
H acceptors O
76 Selected 31 O
OH donors O O O H
O H 64
80 41 CN
NO2
78 OH OH
Cl
79
Scheme 18 Asymmetric aldol reactions with heterosubstituted ketone donors
3.1.2 Aldehyde-Aldehyde Aldol Processes
Unlike most enantio- and diastereoselective direct aldol processes, the enamine-
catalyzed aldol reactions are also feasible with aldehyde donors. In a milestone
paper, Northrup and MacMillan reported in 2002 that aldehyde-aldehyde aldol
reactions can be carried out with proline [145]. They demonstrated that a range of
aliphatic aldehydes can be dimerized, with impressive enantioselectivities (>97%
ee in most cases). Importantly, different combinations of aldehyde acceptors and
donors were possible if the more reactive donor aldehyde was added via a syringe
pump. Recently, Maruoka and coworkers also discovered a syn selective variant of
the crossed-aldol reaction with aromatic and activated aldehydes as acceptors
[187]. What remains to be discovered is the syn selective variant of the crossed
aldol reaction with aliphatic aldehydes (Scheme 19).
Scheme 19 Asymmetric aldol reactions with aldehyde donors

As demonstrated by MacMillan and coworkers, a-oxygenated aldehydes are

very good reaction partners in the aldehyde-aldehyde crossed-aldol reaction. The
products are tetroses, and one further aldol step affords a range of hexoses, i.e. dif-
ferentially protected monosaccharides, in a two-step synthesis (Scheme 20) [203].
Scheme 20 A two-step aldol-based carbohydrate synthesis by Macmillan and co-workers
Aldehydes bearing a-hetero substituents also typically afford anti products, and
the general solution to syn selective a-heteroatom substituted aldehyde-aldehyde
aldol processes via enamine catalysis also still remains to be discovered.
Nevertheless, the anti process is remarkably useful because a variety of highly
substituted aldehydes can be accessed in a single operation using only very inex-
pensive catalysts, such as proline 6 or the phenylalanine-derived imidazolidinone
46 (Scheme 21) [114, 116, 117, 119–121, 188].
3.1.3 Substrate Scope and Current Limitations
A particularly acute problem in expanding the substrate scope of the reaction

is the scope of the acceptors. The catalyst must somehow differentiate
between the donor (to be activated via an enamine) and the acceptor (to be
activated only by hydrogen bonding). It is a relatively trivial task to perform
an aldol reaction with a nonenolizable acceptor, especially an aromatic alde-
hyde, and a good donor, such as acetone. However, the use of two substrates
that are both capable of significant enolization is a considerably more diffi-
cult problem. In most cases, chemists circumvent this problem by generating
the enolate in a separate enolizing step. This requires stoichiometric amounts
of the enolizing reagent and therefore this tactic cannot be used under cata-
lytic conditions.
O Me
N
CO2H N t-Bu
N O OH
H 6 Ph H 46
O
H R
H X
X anti - aldol, 103
donor, 101
X = OR, SBn, NR2
R = aliphatic, OR, SR
O
H R
acceptor, 102
O OH
H R
X
syn-aldol,104
O
O O
O
H
H H
106 SBn H 31 107 OTBS
O
N
Selected O O Selected
H donors O acceptors O
OMOM O H
105 H
H 108 Cl 105 OMOM
109
107 OTBS
Scheme 21 Asymmetric aldol reactions with heterosubstituted aldehyde donors
Ketones cannot generally be used as acceptors, at least not directly, due to

unfavorable equilibrium between the aldol product and the starting ketones.
However, highly reactive ketones [87, 88], such as isatin 2 [95] (Fig. 3) and
a-keto phosphonates (e.g. 112) [110] can readily be used as acceptors.
O O O O
OEt
CO2Et CO2H
O Bn P OEt
N
H O O O
2 110 111 112
Fig. 3 Reactive ketones as acceptors in aldol processes

At present, most enamine-catalyzed aldol reactions are reliable only with elec-
tron-poor aromatic aldehyde acceptors. In addition, a handful of aliphatic aldehydes
(e.g. isobutyraldehyde or pivalaldehyde) are often used as acceptors. The use of
unbranched aldehyde acceptors is difficult, and generally only modest yields have
been obtained. In addition, unsaturated aldehydes are curiously absent from the list
of commonly used acceptors. On a positive side, it should be noted that even poten-
tially racemizing a-chiral aldehydes have been employed as acceptors. As an exam-
ple, in the recent synthesis of callipeltoside C, MacMillan and coworkers were able
to employ protected Roche aldehyde 113 as a starting material (Scheme 22) [204].
Scheme 22 Proline-catalyzed aldol reaction in the synthesis of callipeltoside C
The simplest possible aldehyde donor, acetaldehyde, can also be used as the
donor! Very recently, Hayashi and coworkers discovered how to use acetaldehyde
in crossed-aldol reactions – the trick is to use diarylprolinol as the catalyst and to
optimize the reaction conditions carefully to prevent oligomerization of acetalde-
hyde. However, so far the acetaldehyde aldol reactions appear to be limited to
aromatic aldehyde acceptors [205].
3.2 Mannich-Type Reactions
In enamine-catalyzed aldol reaction, the donor aldehyde or ketone first forms an

enamine and then reacts with another aldehyde to form the aldol product. If imines
instead of aldehydes are used as acceptors, the end result is the formation of a
b-amino carbonyl compound, and the reaction is now called the Mannich reaction
[206, 207].
Although imines are less electrophilic than carbonyl compounds, they are also
more readily activated by acids or hydrogen bonding. For this reason, Mannich reac-
tions are often faster than the corresponding aldol reactions. It is not even necessary
to use preformed imines. In a typical three-component Mannich reaction, the accep-
tor imine is generated from an aromatic or otherwise protected primary amine.
The first asymmetric enamine-catalyzed Mannich reactions were described by
List in 2000 [208]. Paralleling the development of the enamine-catalyzed aldol
reactions, the first asymmetric Mannich reactions were catalyzed by proline, and a
range of cyclic and acyclic aliphatic ketones were used as donors (Schemes 24 and
25). In contrast to the aldol reaction, however, most Mannich reactions are syn
selective. This is presumably due to the larger size of the imine acceptor, forcing
the imine and the enamine to approach each other in a different manner than is pos-
sible with aldehyde acceptors (Scheme 23).
O O
O O
N H N H
PG
O N
R1 R1
R3 H H R3
R2 R2
Aldol transition state Mannich transition state
O OH PG
O HN
R1 R3 R1 R3
R2 R2
anti - product syn -product
Scheme 23 Transition states in aldol and Mannich reactions
Since the initial studies, the substrate scope has expanded to include heteroatom-
substituted ketones [208–216], cyclic ketones [217] and aldehydes [211, 218–226]
as donors, and formaldehyde-derived imines [218, 227–232] as well as glyoxylate-
derived imines [96, 220, 233–237] as acceptors. In addition, several alternative
catalysts to proline have been pursued [238–242].
The amine-catalyzed Mannich reaction has also been a subject of special
reviews [243, 244]. In general, yields and enantioselectivities of proline-catalyzed
Mannich reactions are very high. Initially, the reactions were restricted to imines
bearing an aromatic N-substituent, such as the p-methoxyphenyl (PMP) group. This
restriction considerably limited the usefulness of the protocol, because relatively
harsh conditions were required for the removal of the N-aryl protecting group.
However, recent developments by List and Enders [245] have expanded the scope
of the imine acceptors, and N-Boc-protected imines can now be used routinely
[246]. Even acetaldehyde can be used as the donor component with N-Boc imines
[247]!
The easiest way to perform a Mannich reaction is to use an excess of the ketone
donor and an aldehyde-amine pair to form the required imine in situ. This three-
component Mannich protocol is, however, mostly restricted to aromatic amines
(Scheme 24).
Scheme 24 Direct (3-component) Mannich reaction
The scope of the enamine-catalyzed Mannich reaction can be considerably

expanded by the use of preformed imines. These two-component Mannich reac-
tions can be either syn selective [91, 94, 136, 220, 222, 230–233, 245, 248–258]
(proline or its simple derivatives as catalysts) or anti selective [220, 259–268]
(Scheme 25). The anti selective reactions require somewhat more elaborate
catalysts but the enantioselectivities and diastereoselectivities are excellent in
both cases.
N
N
N N NX
H HN N N H
H OTMS
44 45: X = HSO2CF3
47 Y
N CO2H 54: X = HSO2Ph O HN
H 6 55: X = −(CH2)4−
R2
H
R1
X
Y syn - Mannich, 134
N
CO2H NHSO2CF3 X = H, aliphatic, OH, OR
1
R R2 Z = H, Me, aliphatic
128 132 R1 = aromatic, CF3, CO2Et,
N N
H 130,131 H R2 = H, aromatic
O NHSO2CF3 Y = Boc, Bn2, aromatic, CO2Ar
Z NH
X NH
129
Y
N H2N CO2H O HN
H OTMS 133
47 87 R2
H
R1
X
anti - Mannich, 135
X = aliphatic, OH
Z = H, aliphatic
R1= aromatic, CO2R
R2= H
Y = PMP
Boc
O N
O Bn Bn
N H
9 76 OH PMP 138 OMe 139 O
N
Selected donors O
O Selected acceptors N
for syn-Mannich H for syn-Mannich
O CO2Et
O O NO2 PMP
23 137 N 141
H 140 OEt
80 136 H
O
O
PMP
H N
90 PMP
N
O Selected donors O H
OEt
for anti-Mannich H 137
NO2
O Selected acceptors
76 OH 140
for anti-Mannich
23
Scheme 25 Two-component Mannich reactions

3.3 Conjugate Addition Reactions
Enamine nucleophiles react readily with soft conjugated electrophiles, such as a,b-
unsaturated carbonyl, nitro, and sulfonyl compounds [20–22]. Both aldehydes and
ketones can be used as donors (Schemes 27 and 28). These Michael-type reactions
are highly useful for the construction of carbon skeletons and often the yields are
very high. The problem, however, is the enantioselectivity of the process. Unlike
the aldol and Mannich reactions, where even simple proline catalyst can effectively
direct the addition to the C = O or C = N bond by its carboxylic acid moiety, in
conjugate additions the charge develops further away from the catalyst
(Scheme 26):
‡ δ− ‡
O
X N δ+
δ− N δ+
O H X
H X
R
in aldol reactions, the developing in conjugate addition reactions,

negative charge in the TS the developing charge is
is relatively close, allowing further away from the enamine
effective hydrogen bonding
assistance by the catalyst
Scheme 26 Aldol and conjugate addition reactions require different types of stabilization for the
transition state
Initially, proline and its analogues were used for the conjugate additions, with
only modest results. In some reactions, proline was totally ineffective, and proline-
derived diamines generally gave better selectivities [269, 270]. Good enantioselec-
tivities were only obtained after the development of more sophisticated
second-generation catalysts. Some of these catalysts include an additional hydro-
gen bond donor, such as thiourea moiety [271] or an acidic triflimide group [272],
whereas some of them simply rely on steric control [273]. The diarylprolinol
ethers, such as Jørgensen’s catalyst 47, perform very well in many conjugate addi-
tion reactions.
With aldehyde donors, the reactions are generally syn selective. A range of
acceptors can be used, including a,b-unsaturated nitro compounds [72, 270,
274–281], a,b-unsaturated ketones [71, 282–285], vinyl phosphonates [286]
and vinyl sulfones [287] etc. (Scheme 27). So far, no general anti selective
protocol for enamine-catalyzed conjugate additions with aldehyde donors has 392
been published. 393
H
N Bn
N NX
H 45,55 Bn N
H
145
N
H N t-Bu S
H
N N
144 Bn N N 146 O R2
H OTMS H H
47 O NH2 EWG
H
O R 1
H syn-Michael, 147
R1
R1 = aliphatic, Ph, OPh
142 R2 = H, aromatic, aliphatic
EWG = NO2, (SO2Ph)2, COR,
R2 (R = aliphatic)
EWG
143
O R2
EWG
H
1
R
anti - Michael, 148
O O
H H
O 90 31 O 151 153
H Selected donors NO2
for syn-Michael O Selected acceptors
for syn - Michael Ph
O H O 154
62
H 92 Bn 150 NO2
PhO2S SO2Ph
149 Ph 152
Scheme 27 Asymmetric enamine-catalyzed Michael additions with aldehyde donors
With ketone donors, both syn and anti selective reactions are possible.
Typically, a,b-unsaturated nitro compounds are used as acceptors. The major-
ity of these reactions are syn selective (Scheme 28) [94, 269, 271, 278, 279,
288–309]. This is a result of favored formation of the (E)-configured enamine
and favorable electrostatic interactions between the nitro group and the enam-
ine (Scheme 29) [290, 291, 310]. Of the known anti selective reactions, pri-
mary amine-thiourea catalysts such as 158 appear to perform best (Scheme 28)
[271, 299, 301].
N NX
H 45,55
Ph S
N O Ph
H N
N N N
H OH
H H O R3
144 NH2
6 158·AcOH EWG
1
R
O 2
R
R1 syn-Michael, 159
R2
R1 = Me, aliphatic
156 R2 = H, aliphatic, OR
EWG = NO2, COAr,
R3 (CO2R)2 (R = aliphatic)
Ph S
EWG N
H N Ph
157 N N
H H O R3
144 NH2
158·AcOH EWG
R1
2
R
anti-Michael, 160
R1 = Me, aliphatic
R2 = Me, OH, OMe
R3 = aromatic, aliphatic
O EWG = NO2
O Ph
Cl
61 9 O
154 NO2
O Selected donors NO2 Selected acceptors
for syn-Michael O O 163 NO2
for syn-Michael 164
O Ph Ph
S 80
161 162 Ph
165 EtO2C CO2Et
O 166
O S
O
76 OH 169
NO2
MeO Selected acceptors
Selected donors OMe
O for anti-Michael for anti-Michael NO2
167 Ph 170
168 154
162 NO2 NO2
Scheme 28 Asymmetric enamine-catalyzed Michael additions with ketone donors

Scheme 29 Explanation for the typical syn selectivity observed in the enamine-catalyzed conju-
gate addition reactions
3.4 Heteroatom Functionalizations at the a-Carbon:

a-Halogenations, Oxygenations and Other Transformations
A range of nitrogen, phosphorus, chalcogen (O, S, Se) and halogen electrophiles

react with enamines, resulting in a net a-functionalization of the carbonyl com-
pound. In the past five years, all of these reaction variants have been subjected to
asymmetric enamine catalysis, with excellent results.
3.4.1 a-Halogenations
In a-halogenations, hydrogen bonding assistance does not play the same important
role as it does in aldol and Mannich reactions. For this reason, proline and its amide
variants are generally not highly enantioselective catalysts. The more hindered
Jørgensen–Hayashi -type prolinol derivatives [71–74] as well as the MacMillan
imidazolidinones [76, 311–313] are typically the most enantioselective catalysts for
the halogenation of aldehydes (Scheme 30). The first enamine-catalyzed enantiose-
lective a-halogenations of aldehydes were independently reported in 2004 by
MacMillan and Jørgensen [74, 313].
It should be noted that, in spite of the similarity of the mechanism, each of the
halogenations appears to require its own optimal combination of catalyst and halo-
Scheme 30 α-Halogenations of aldehydes

genating agent [73, 74, 311, 313]. With the proper choice of halogenating agent and
catalyst, the reactions are often highly enantioselective, typically in the range of
90–95% ee. The a-halogenation of aldehydes is often easier to achieve and affords
higher enantioselectivities than a-halogenations of ketones. In addition to pyrrolidine-
type [74, 314] or imidazolidinone secondary amine catalysts, an interesting rota-
tionally restricted (atropisomerically pure) primary amine catalyst 180 has been
described by Jørgensen for the a-fluorination reactions [315]. Very recently, the
Maruoka group has described the use of axially chiral amine 182 for the a-iodination
reaction in excellent enantioselectivities [316].
Successful solutions to the a-halogenation of ketones have also emerged, but here the
problem is that sterically very hindered catalysts that work very nicely with aldehydes are
not active with ketones. Some current solutions to this problem are summarized in
Scheme 31 [314, 317, 318].
TBSO
N CO2H O
H F
121
Ph 197
NH
Ph N
H O
O 196 Cl
R R
198
R R Ph
NH R = aliphatic
195
Ph N
halogenating H O
agent 196 Br
R R
199
R = aliphatic
O
I
R R
200
O
Cl
N O
201
N 203 t-Bu t-Bu
Et Et
O F
O Ketone Halogenating
O
donors reagents
Br Br
N Cl 194
O O 190
23 O
202
Scheme 31 α-Halogenations of ketones

3.4.2 a-Oxygenation and a-Amination Reactions
In contrast with a-halogenations, a-oxygenation and a-amination reagents are

typically more Brønsted basic and therefore amenable to hydrogen bonding/
Brønsted acid catalysis. Typical a-oxygenation and a-amination reactions as well
as typical catalysts are summarized in Schemes 33 and 34. The prototype reagent
for a-aminations are electrophilic azodicarboxylate esters (210), [285, 319–324]
and for a-oxygenations, highly reactive nitrosobenzene 211 [325–327] is typically
employed. Enantioselectivities are very high and the reactions are often very rapid
(10–30 min).
The first a-amination reactions were reported simultaneously by List and
Jørgensen in 2002, [328, 329] and the a-amination of ketones was reported by
the Jørgensen group shortly thereafter [330]. Interestingly, although proline
was initially used by both groups for the amination reactions, the Jørgensen
group later used their own diaryl prolinol-derived catalyst 47 with very high
enantioselectivities but with an opposite configuration [71]. This result under-
lines the mechanistic difference between Type A (hydrogen bonding) and Type
B (steric control) enamine catalysts (Scheme 32). Type A and Type B catalysts
with the same configuration lead to opposite enantiomers of product in amina-
tion reactions (Fig. 4).
The a-oxygenation of aldehydes is a highly versatile reaction that affords the
oxygenated products in high yield and high enantioselectivity. In 2003, three different
groups (Zhong [331], MacMillan [332], and Hayashi [333]) independently reported
the use of nitrosobenzene for this reaction. The reaction is also applicable to ketones,
Scheme 32 Type A and Type B enamine catalysts afford opposite enantiomers in α-amination
reactions
Fig. 4 a-Halogenations with elemental chlorine? Perhaps the next bold step in enamine catalysis
as reported by Hayashi [333–335] and later by Córdova [336, 337]. Different

proline-derived catalysts have been reported by the Hayashi [338], Córdova [339],
Wang [340], and Ley groups [341, 342].
As illustrated in Schemes 33 and 34, catalysts capable of hydrogen bonding or
Brønsted acid activation (Type A catalysts) are generally highly effective and enan-
tioselective catalysts for a-oxygenation and a-amination reactions. With nitroso-
benzene, type A catalysts have so far been the only successful catalysts. The high
reactivity of the reagents and the double activation mode of the catalyst both contribute
to extremely high enantioselectivities typically observed in these processes.
Scheme 33 α-Aminations of aldehydes and ketones

Scheme 34 α-Oxygenations of aldehydes and ketones
The drawback of many of these reactions is the relatively low atom economy of
the reagents. Electrophilic nitrogen and oxygen reagents deliver only one or two N
or O atoms, but these atoms are often attached to a much heavier carbon chain. A
possible solution, at least in the case of oxygenations, is to use singlet oxygen. This
elegant idea was first realized by Cordova and co-workers [343–345]. Although the
yields and enantioselectivities are lower than those obtained with e.g. nitrosoben-
zene as the oxygen source, the method has obvious potential due to the low cost of
the reagent and should be explored further. Interestingly, even the Type B diarylpro-
linol silyl ether catalysts (47) will work with singlet oxygen as the electrophile.
4 Enamine Catalysis in the Synthesis of Complex Molecules
4.1 Domino Processes
The dual nature of enamine-iminium pairs allows unique possibilities for domino proc-
esses. Reactions of enamines with electrophiles afford electrophilic iminium ions that
are ready to react with another (internal or external) nucleophile. Conversely, reactions
of unsaturated iminium ions with nucleophiles afford enamines. Examples of intramo-
lecular enamine-catalyzed domino processes are depicted in Scheme 35. In all of these
reactions, both enamine and iminium mediated steps can be distinguished.
a Generic reaction type: Enamine-iminium / Enamine - Diels - Alder
R R R R
O N N
2 R2NH 2 Diels - Alder
R R R2
X Y
R1 X R1 X
Y Y R1
R R
N
2
enamine R
iminium
X 1
Y R
b Generic reaction type: Iminium - enamine
R R
N
R R R
O H N R N
R 2NH O enamine HO H
H O H iminium
R1
R1 X R1 R1
X X
c Double iminium / en amine

R
R R R R
N N R
O R1 N
R R R 1 exo - enamine
R2NH N endo - iminium
R1 R1 R
R1 N R1
R1 R N R
R
Scheme 35 Enamines and iminium ions in organocatalytic domino reactions
In the following discussion, selected examples of domino processes with an

enamine catalysis component are discussed. For further examples, several compre-
hensive reviews on the topic have recently appeared [8, 17, 24].
Yamamoto and coworkers described a highly enantioselective asymmetric
domino O-nitroso aldol-conjugate addition sequence using cyclic enones 221 and
aromatic nitroso compounds 222 as depicted in Scheme 36 [346]. A related reac-
tion with imines was also reported by Córdova and coworkers (Scheme 37) [228].
Scheme 36 Domino O-nitroso aldol-conjugate addition

Scheme 37 Domino imine aldol-conjugate addition
Domino processes can also be performed on open-chain compounds. MacMillan

and co-workers demonstrated this with their own imidazolidinone catalysts.
Conjugate addition of a nucleophilic heterocycle 231 to the a,b-unsaturated enal
230 followed by a-chlorination of the resulting enamine led to the syn products 234
in very high enantioselectivities and good syn:anti diastereoselectivities (Scheme 38)
[347]. Similar domino sequences, but with different nucleophile-electrophile part-
ners, were also reported independently by Jørgensen [348].
Scheme 38 Domino conjugate addition-halogenation
Even triple domino sequences are possible. A beautiful demonstration was pro-
vided by Enders and co-workers, who start their cascade by an enamine-catalyzed
conjugate addition of an aldehyde donor 235 to a a,b-unsaturated nitro compound
236 (Scheme 39). Following an iminium-catalyzed addition of the resulting nitro
aldehyde 240 to the unsaturated iminium ion 239, the resulting enamine 241
cyclizes and undergoes an aldol condensation reaction. Four contiguous stereogenic
centers are generated in a single operation in this domino sequence [349].
Scheme 39 A triple domino reaction from the Enders group
4.2 Total Syntheses
The ultimate test of any method lies in its applicability in challenging contexts,
such as total synthesis of natural products and industrial settings. While the
industrial applications of enamine catalysis are still mostly under development,
asymmetric enamine catalysis has already been used in several instances for the
synthesis of natural products. This area has been recently reviewed by
Christmann [19].
The following examples illustrate how different enamine-catalyzed reactions
can lead to remarkably short and highly enantio- and diastereoselective routes to
natural products.
The aldehyde-aldehyde aldol reactions were first used in a natural product
synthesis setting by Pihko and Erkkilä, who prepared prelactone B in only three
operations starting from isobutyraldehyde and propionaldehyde (Scheme 40).
Crossed aldol reaction under proline catalysis, followed by TBS protection,
afforded protected aldehyde 244 in >99% ee. A highly diastereoselective
Mukaiyama aldol reaction and ring closure with aqueous HF completed the
synthesis [112].
Scheme 40 Three-step synthesis of prelactone B
In nature, enamine catalysis is one of the most favored strategies for constructing
carbohydrate skeletons. The use of proline-catalyzed aldehyde-aldehyde aldol reac-
tions for carbohydrate synthesis was discussed in Sect. 3.1. Amino sugars can be simi-
larly constructed using enamine-catalyzed Mannich reactions, as exemplified by the
remarkably short synthesis of (+)-polyoxamic acid (and polyoxin J) by Enders and
coworkers (Scheme 41) [245]. The initial proline-catalyzed Mannich reaction afforded
the adduct 249 in 92% ee and >98:2 dr. Diastereoselective reduction with l-Selectride®,
followed by oxidative cleavage of the furan ring and deprotection (TFA), afforded
(+)-polyoxaminc acid in only four steps. This synthesis also nicely demonstrates the
advantages of the use of preformed Boc-imines in Mannich reactions.
Scheme 41 Synthesis of (+)-polyoxamic acid

Since many natural products, especially terpenoids, are highly oxygenated com-
pounds, methods that allow direct insertion of oxygen into the structure are
extremely useful. The proline-catalyzed a-oxygenation of aldehydes and ketones
with nitrosobenzene is thus a highly valuable transformation, and it is not surprising
that it has already found applications in total synthesis [350]. A particularly nice
example is provided by the use of both l- and d-proline in two diverse total synthe-
ses by the Hayashi group. Starting from achiral ketone 202, they synthesized both
panepophenantrin 255 [351] and fumagillol 257 [352] using either d- or l-proline
catalysts. In both cases, the key starting materials 254 and 256 were furnished in
>99% ee and excellent yield, using only 10 mol% of the inexpensive proline cata-
lyst (Scheme 42).
O O
N N
O 1) H OH O 1) H OH O
253 6
ONHPh 10 mol-% 10 mol-% ONHPh
PhN = O PhN=O
93% yield
O O O O >99% ee O O
254 202 256
OH
O
O
OH O
OMe
H O
O OH
H 257
OH f umagillol
OH
O
255
(+)-panepophenantrin
Scheme 42 Syntheses of (+)-panepophenantrin and fumagillol
5 Directions for the Future
Over the past eight years, enantioselective enamine catalysis has expanded in scope more
rapidly than perhaps any other field of asymmetric catalysis. From a handful of examples
within the realm of aldol catalysis known in the beginning of 2000, the field enamine
catalysis now comprises more than 50 different reactions, nearly 1000 different catalysts,
and more than 1000 examples! Still, major challenges remain to be solved.
Although most enamine-catalyzed reactions are highly enantioselective, rela-

tively high catalyst loadings are often required. Fortunately, this situation is
improving, and most enamine catalysts are relatively inexpensive – especially pro-
line and its simple derivatives – and as such even relatively high catalyst loadings
could be tolerated. A more serious problem in enamine catalysis is the relatively
narrow substrate scope, especially in aldol catalysis. As an example, at the time of
writing (March 2008), it is still not possible to use enamine catalysis for the direct,
chemoselective aldol reaction between acetaldehyde as the acceptor and propional-
dehyde as the donor (or vice versa!), or to dimerize propionaldehyde to generate a
syn aldol product in high ee and high diastereoselectivity. The three simplest alde-
hydes – formaldehyde, acetaldehyde, and propionaldehyde – have enormous poten-
tial in enamine catalysis, and their use as acceptors and donors should be explored
more vigorously.
Enamine catalysis clearly affords shorter synthetic routes to a variety of natural
product and drug targets [8, 19]. However, the full potential of enamine catalytic
methods has yet to be realized in more complex settings. For example, the a-halo-
genations of aldehydes, in spite of their high importance, have only rarely been used
in a total synthesis setting [353]. With so many attractive features – relatively benign
reaction conditions, easy-to-handle catalysts, and high enantioselectivities – it is
probably just a matter of time before the use of enamine catalysis in both academic
total syntheses and industrial process chemistry becomes a matter of routine.
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Top Curr Chem (2010) 291: 77–144
DOI: 10.1007/128_2008_18
Published online: 04 April 2009
Carbene Catalysts
Jennifer L. Moore and Tomislav Rovis
Abstract The use of N-heterocyclic carbenes as catalysts for organic transforma-

tions has received increased attention in the past 10 years. A discussion of catalyst
development and nucleophilic characteristics precedes a description of recent
advancements and new reactions using N-heterocyclic carbenes in catalysis.
Keywords Benzoin • Carbene • NHC • Nucleophilic Catalysis • Organocatalysis •

Redox • Stetter • Transesterification • Umpolung
Contents
1 Introduction......................................................................................................................... 79
2 Carbenes.............................................................................................................................. 79
3 Benzoin Reaction................................................................................................................ 81
3.1 Mechanism and Catalyst Design................................................................................ 81
3.2 Cross-Benzoin Reaction............................................................................................ 84
4 Stetter Reaction................................................................................................................... 90
4.1 Mechanism................................................................................................................. 91
4.2 Intramolecular Stetter Reaction................................................................................. 92
4.3 Intermolecular Stetter Reaction................................................................................. 101
4.4 Applications in Total Synthesis................................................................................. 105
5 Redox Reactions................................................................................................................. 109
6 Transesterification Reactions.............................................................................................. 125
6.1 Ring Opening Polymerization................................................................................... 130
7 Nucleophilic Catalysis........................................................................................................ 132
8 Conclusion.......................................................................................................................... 140
References................................................................................................................................. 141
T. Rovis (*ü)
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
e-mail: rovis@lamar.colostate.edu
78 J. L. Moore, T. Rovis
Abbreviations:
Ac acetyl
Ar aryl
BAL benzaldehyde lyase
BFD benzoylformate decarboxylase
Bmin butylmethylimidazolium
Bn benzyl
Boc tert-butoxycarbonyl
Bz benzoyl
Cy cyclohexyl
DABCO 1,4-diazabicyclo[1.2.2]octane
DBU 1,8-diazabicyclo[2.4.0]undec-7-ene
DCM dichloromethane
DIPEA diisopropylethylamine
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
Et ethyl
HOAt 1-hydroxy-7-azabenzotriazole
i-Pr isopropyl
KHMDS potassium bis(trimethylsiyl)amide
KPi buffer potassium phosphate buffer
Me methyl
Mes mesityl (2,4,6-trimethylphenyl)
Ms methanesulfonyl (mesyl)
MS molecular sieves
LiHMDS lithium bis(trimethylsilyl)amide
n-Bu normal-butyl
n-Hex normal-hexyl
n-Pr normal-propyl
NHC N-heterocyclic carbene
PEMP pentamethylpiperidine
Ph phenyl
Pr propyl
TBS tert-butyldimethylsilyl
t-Bu tert-butyl
TES triethylsilyl
Tf trifluoromethanesulfonyl (triflyl)
ThDP thiamin diphosphate
THF tetrahydrofuran
TIPS triisopropylsilyl
TMS trimethylsilyl
Tol para-tolyl
Ts para-toluenesulfonyl (tosyl)
Carbene Catalysts 79
1 Introduction
Since the isolation and characterization of stable imidazolylidene carbenes by

Arduengo in 1991 [1], chemists have been increasingly fascinated by their potential
as modifying ligands on transition metals. The direct use of azolidine-based
carbenes as catalysts in organic transformations, however, predates Arduengo’s
find by almost 50 years [2], not to mention the role that thiamin cofactor plays in
modifying a number of biochemical transformations. Even asymmetric catalysis
using chiral nucleophilic carbenes is over 40 years old, with Sheehan’s seminal
report appearing in 1966 [3]. That said, much of this early work attracted little
attention from the chemical community as a whole, largely due to poor efficiency,
selectivity or both. That situation has changed rather drastically in the past
10 years and the area has been reviewed both tangentially and specifically almost
a dozen times [4–14].
This review will focus on the use of chiral nucleophilic N-heterocyclic carbenes,
commonly termed NHCs, as catalysts in organic transformations. Although other
examples are known, by far the most common NHCs are thiazolylidene, imida-
zolinylidene, imidazolylidene and triazolylidene, I–IV. Rather than simply pre-
senting a laundry list of results, the focus of the current review will be to
summarize and place in context the key advances made, with particular attention
paid to recent and conceptual breakthroughs. These aspects, by definition, will
include a heavy emphasis on mechanism. In a number of instances, the asymmet-
ric version of the reaction has yet to be reported; in those cases, we include the
state-of-the-art in order to further illustrate the broad utility and reactivity of
nucleophilic carbenes.
2 Carbenes
Since the 1950s carbenes have shown great potential in the field of organic and
organometallic chemistry [15–17]. These neutral molecules contain a divalent car-
bon atom with six electrons in its valence shell and exist in either a singlet or triplet
state (Fig. 1a, b). Depending on the steric and electronic environment, carbene
compounds can be electrophilic or nucleophilic. NHCs contain heteroatoms on
either side of the carbene atom, which donate electron density into the vacant
p-orbital to enhance thermodynamic stability. For example, in carbene 1 the nitro-
gen lone pairs donate electron density into the empty p-orbital of the carbene car-
bon perpendicular to the plane of the ring, allowing for 6p aromatic stabilization
(Fig. 1c). The nitrogen atoms also stabilize the carbene via s withdrawal of electron
density from the carbene center. Steric hindrance contributes to kinetic stability. It
is notable that no single characteristic is responsible for producing isolable
carbenes; both electronic and steric factors are necessary for stability [16, 18].
Y Y NR2
X NR2
X
a singlet b triplet c stabilization
Fig. 1 Orbital representation of carbenes
N(i-Pr)2
N N
Me3Si P
N(i-Pr)2
1 2
Pioneering work by Wanzlick in the 1960s established nucleophilic saturated

and unsaturated carbenes as reactive intermediates, although he was unable to iso-
late them due to their inherent reactivity [19]. Nearly 30 years later, Arduengo and
Bertrand independently accomplished the first isolation of carbene species, 1 and
2, respectively [1, 20]. The synthesis of bisadamantyl imidazolylidine carbene 1 by
Arduengo is considered by some to be the first isolated carbene and was unequivo-
cally characterized by X-ray crystallography [4]. Since 1991, alkyl and aryl
N-substituents have been documented to provide stable, isolable carbenes. There
was concern that substituted aryl rings, which distort the plane of the carbene,
would affect stability but Arduengo disproved this by synthesizing 3 and 4 [21].
The mesityl (Mes) substituted carbene prevents conjugation between the phenyl
rings and the nitrogen centers, while p-tolyl substituents allow conjugation. Both
share the same chemical characteristics and demonstrate that substitution of aryl
rings has little effect on the stability of the carbene compound. Since the first isola-
tion, many groups have reported the synthesis and isolation of imidazole-, thiazole-,
and triazole-derived stable carbenes, some of which are stable enough to be bottled
and occasionally even commercially available [22].
Me Me
N N N N
Me Me Me Me
Me Me
3 4
The similarity between N-heterocyclic carbenes and electron-rich organophos-

phanes has been extensively studied and exploited in organometallic chemistry.
NHC-metal complexes have been shown to outperform analogous phosphine-metal
complexes in some organometallic transformations [23, 24]. Both compounds are
s-donors and exhibit little backbonding character. Most notable are the advances
made in coordination chemistry, olefin metathesis, and cross-coupling reactions
[25]. In addition to their use as ligands for transition metal catalysts, the use of
NHCs as organocatalysts has experienced increased interest in the past 15 years and
developed into a field of its own.
3 Benzoin Reaction
3.1 Mechanism and Catalyst Design
The benzoin reaction dates back to 1832 when Wöhler and Liebig reported that
cyanide catalyzes the formation of benzoin 6 from benzaldehyde 5, a seminal
example in which the normal mode of polarity of a functional group was reversed
(Eq. 1) [26]. This reversal of polarity, subsequently termed Umpolung [27], effec-
tively changes an electrophilic aldehyde into a nucleophilic acyl anion equivalent.
O
O
2 KCN Ph
Ph (1)
Ph H
OH
5 6
In 1903, Lapworth described his findings of the action of potassium cyanide on

benzaldehyde [28]. He postulated that cyanide adds to benzaldehyde to form V,
followed by proton transfer of the a-labile hyd rogen, forming intermediate VI
which is now referred to as an acyl anion equivalent. Addition to another molecule
of benzaldehyde occurs to form VII (Scheme 1). The unstable cyanohydrin of ben-
zoin VII then collapses to form benzoin and potassium cyanide. Additionally,
Lapworth tested the reversibility of the addition of cyanide to benzaldehyde by first
forming hydroxybenzyl cyanide (protonated variant of V) and subjecting it to ben-
zaldehyde and base, in which benzoin was recovered.
O KO CN
Ph H
Ph H V
OH
KCN
Ph K
VI N
O
O
HO CN H Ph
Ph
Ph Ph
OH Ph
OK
VII
Scheme 1 Lapworth’s proposed mechanism of the benzoin reaction

In 1943, more than a century after the initial report, Ukai et al. showed that thia-
zolium salts such as 7 and 8 catalyze the homodimerization of aldehydes in the
presence of base [2]. This discovery was paramount because, while cyanide ions are
inherently achiral, thiazolium salts can be modified to act as a source of chirality to
render the reaction enantioselective.
OH
Me
N Me
N
Br N S
Bn N S
H2N Cl
7 8
Breslow and co-workers elucidated the currently accepted mechanism of the

benzoin reaction in 1958 using thiamin 8. The mechanism is closely related to
Lapworth’s mechanism for cyanide anion catalyzed benzoin reaction (Scheme 2)
[28, 29]. The carbene, formed in situ by deprotonation of the corresponding thiazo-
lium salt, undergoes nucleophilic addition to the aldehyde. A subsequent proton
transfer generates a nucleophilic acyl anion equivalent known as the “Breslow inter-
mediate” IX. Subsequent attack of the acyl anion equivalent into another molecule
of aldehyde generates a new carbon – carbon bond XI. A proton transfer forms tet-
rahedral intermediate XII, allowing for collapse to produce the a-hydroxy ketone
accompanied by liberation of the active catalyst. As with the cyanide catalyzed ben-
zoin reaction, the thiazolylidene catalyzed benzoin reaction is reversible [30].
O N S
N S N S
H
Ph H Ph O
Ph OH Ph OH
VIII IX X
Base O
N S N S
Ph H
Cl
S
N OH
O
Ph
Ph Ph
Ph S
N O
OH O XI
Ph
Ph
XII OH
Scheme 2 Breslow’s proposed mechanism of the benzoin reaction

In 1966, Sheehan and Hunneman reported the first example of an asymmetric ben-
zoin reaction, using chiral thiazolium pre-catalyst 9 to yield benzoin 6 in 22% ee
(Scheme 3) [3]. The next significant advance occurred in 1974, when Sheehan and Hara
reported that adding steric bulk around the reactive site, 10, leads to increased asymmet-
ric induction in benzoin formation to 52% ee, although the yields remain low [31]. Many
groups have attempted to improve the enantioselectivity of the thiazolylidene catalyzed
benzoin reaction with modest success. In 1980, Tagaki and co-workers synthesized thia-
zolium salt 11 to study the benzoin reaction in a micellar two-phase media; despite the
fact that the enantiomeric excess of 35% ee was achieved, only a slight increase in yield
was observed [32]. López-Calahorra and co-workers designed the bis(thiazolin-2-yli-
dene) 12 in an effort to increase the rigidity of the active species, although the cyclohexyl
tethered catalyst provides low yield and 27% ee [33]. Yamashita and co-workers synthe-
sized lipid thiazolium salt 13 that produced benzoin in 18% ee [34].
O
O
2 catalyst Ph
Ph
Ph H base
OH
5 6
Me Me ClO4
Me Me
N S S N
I I
Cy N S
Br Me N N
O Br Me
O
Ph Me S S
9 10 11 12
9% 6% 20% 12%
22% ee 52% ee 35% ee 27% ee
Sheehan Sheehan Tagaki López-Calahorra
O
H
N
C16H33O N N O
S
O O N N Ph
C16H33O O Me Me N S
Me O ClO4
Br Ph TBSO OTf
13 14 15
OH
35% 66% 34%
18% ee 75% ee 20% ee
Yamashita / Tsuda Enders Leeper
Ts
N
Bn N S
N O
N Cl
N S OMs
TBSO N O S N N Ph
Ph Br
OTf O Ph
16 17 18 19
50% 91% 18% 45%
21% ee 16% ee 30% ee 80% ee
Leeper Leeper Rawal Leeper
Scheme 3 Catalyst development in the benzoin reaction

A breakthrough in the asymmetric benzoin reaction was achieved in 1996 when

Enders and co-workers introduced chiral triazolinylidene carbenes instead of thiazolyli-
dene carbenes. They utilized a variety of chiral triazolium salts that provided increased
yields and enantioselectivities, outperforming all previous thiazolium pre-catalysts [35].
The most active of these triazolium salts is 14, which affords benzoin in 75% ee and
66% yield. In 1997, Leeper and co-workers developed a series of rigid bicylic thiazo-
lium salts, 15–17, that they hypothesized would increase enantioselectivities by
restraining the rotation of the chiral side chain of the catalyst [36, 37]. Concurrently,
Rawal and Dvorak increased the enantioselectivity of the benzoin reaction with bicyclic
thiazolium salt 18 when compared to Leeper’s chiral bicyclic thiazolium salts 15–17
[38]. The reactivity and enantioselectivity remained low until Leeper and co-workers
exchanged the thiazolium framework for the more reactive triazolium pre-catalyst 19
and observed increased enantioselectivities, up to 80% ee [39]. In 2004, Takata and
co-workers introduced the use of chiral rotaxanes as an asymmetric environment for the
thiazolium catalyzed benzoin reaction, achieving modest enantioselectivities [40].
In 2002, Enders and co-workers took advantage of the bicyclic restriction first
introduced by Leeper and Rawal to develop catalyst 20. Use of this catalyst pro-
vides a number of benzoin derivatives 22a–h in up to 95% ee (Table 1) [41].
The stereochemistry of the benzoin reaction catalyzed by thiazolium and triazo-
lium pre-catalysts has subsequently been modeled by Houk and Dudding [42].
Table 1 Substrate scope of the asymmetric benzoin reaction [FX1]
O BF4
N
O
O N N Ph
Ar
t - Bu 10 mol% 20 Ar
Ar OH
KOt-Bu, THF
21 22
Entry 22 Ar Temp (°C) Yield (%) ee (%)
1 a Ph 18 83 90
2 b 4-FC6H4 18 81 83
3 c 4-FC6H4 0 61 91
4 d 3-ClC 6H4 0 85 86
5 e 4-MeC6H4 18 16 93
6 f 4-MeOC6H4 18 8 95
7 g 2-Furyl 0 100 64
8 h 2-Furyl −78 41 88
3.2 Cross-Benzoin Reaction
The benzoin reaction typically consists of the homocoupling of two aldehydes, which
results in the formation of inherently dimeric compounds, therefore limiting the syn-
thetic utility. The cross-benzoin reaction has the potential to produce four products, two
homocoupled adducts and two cross-benzoin products. Several strategies have been
employed to develop a selective cross-benzoin reaction, including the use of donor-
acceptor aldehydes, acyl silanes, acyl imines, as well as intramolecular reactions.
Müller and co-workers have developed an enantioselective enzymatic cross-

benzoin reaction (Table 2) [43, 44]. This is the first example of an enantioselective
cross-benzoin reaction and takes advantage of the donor-acceptor concept. This
transformation is catalyzed by thiamin diphosphate (ThDP) 23 in the presence of
benzaldehyde lyase (BAL) or benzoylformate decarboxylase (BFD). Under these
enzymatic reaction conditions the donor aldehyde 24 is the one that forms the acyl
anion equivalent and subsequently attacks the acceptor aldehyde 25 to provide a
variety of a-hydroxyketones 26 in good yield and excellent enantiomeric excesses
without contamination of the other cross-benzoin products 27. The authors chose
2-chlorobenzaldehyde 25 as the acceptor because of its inability to form a
homodimer under enzymatic reaction conditions.
HO OH
Me O P O P OH
N Me
O O
N
N S Cl
H2N
23
Table 2 Asymmetric enzymatic cross-benzoin reaction

O O Cl O Cl O
23, enzyme, Mg2+ R
H H KPi buffer, DMSO, 30 C
R R
OH Cl OH
24 25 26 27
not formed
Entry 26 R Enzyme Conversion (%) ee (%)

1 a 3-CN BFD H281 A >99 90
2 b 4-Br BFD H281 A 90 95
3 c 4-CF3 BFD H281 A 75 93
4 d 3,4-CH2O2 BAL 98 >99
5 e 3,4,5-(CH3O)3 BAL 82 >99
6 f 3,5-(CH3O)2 BAL >99 >99
In an effort to circumvent a homodimerization event acyl silanes have been used

to promote a cross-benzoin reaction. Initial reports by Johnson and co-workers
employed potassium cyanide to catalyze the regiospecific cross silyl benzoin reac-
tion to afford a single regioisomer in good yield (Eq. 2) [45–47].
30 mol% KCN O
O O
+ 10 mol% 18-crown-6 R'
R
R SiEt3 H R' o
Et2O, 25 C OSiEt3 (2)
28 29 30
51-95%
The proposed mechanism is as follows: initial cyanation of the acyl silane fol-
lowed by a [1,2]-Brook rearrangement yields acyl anion equivalent XIV (Scheme 4).
Subsequent attack by the acyl anion equivalent XV to the aldehyde leads to
tetrahedral intermediate XVI. After a 1,4-silyl migration, cyanide is regenerated,

and the desired a-siloxy ketone is formed.
Shortly after publishing the racemic cross silyl benzoin reaction, Johnson and
co-workers reported an enantioselective variant utilizing metallophosphite catalysis
[48]. The lithiophosphite adds to the acyl silane and proceeds through the remain-
OSiEt3
O CN
O R SiEt3 R CN
XIII XIV
R SiEt3
OSiEt3
CN R C
N
XV
O O
R'
R H R'
OSiEt3 O CN Et3SiO CN
OSiEt3 O
R R
R'
XVII XVI R'
Scheme 4 Proposed mechanism for the acyl silane cross-benzoin reaction
der of the mechanism in direct analogy to that observed with cyanide catalysis, with
the added benefit of asymmetric induction. As illustrated in Table 3, good yields
and enantioselectivities are achievable under these reaction conditions.
Table 3 Acyl Silane cross-benzoin reaction catalyzed by lithiophosphites

Ar Ar
O Me O O
O O
O P
5-20 mol% 34 R'
R Me O O H
R SiEt3 H R' n -BuLi, THF, 30 min
OSiEt3 Ar Ar
31 32 33
Ar = 2-FC6H4
34
Entry 33 R R’ Yield (%) ee (%)
1 a Ph Ph 84 82
2 b Ph 4-ClC6H4 75 82
3 c 4-ClC6H4 Ph 82 87
4 d Ph 4-OMeC6H4 87 91
5 e 4-ClC6H4 4-OMeC6H4 83 90
6 f 4-NMe2C6H4 Ph 86 86
7 g n-hexyl Ph 72 67
An alternative strategy to access cross-benzoin products is to tether the two reactive

partners. This approach has the disadvantages inherent to intramolecular reactions, but
it provides access to products produced by the coupling of aldehydes with ketones. In
2003, Suzuki and co-workers reported the intramolecular cross-benzoin reaction utiliz-
ing thiazolium pre-catalyst 35 to obtain products such as 37 and 38 (Eq. 3) [49].
OH
MeO Me
O N OMe
O N
Ph Br
N S
20 mol% 35
Me O Me (3)
70 mol% DBU, t-BuOH HO
O R O
R
36 R yield (%) dr
37 H 90 >20:1
38 CO2Et 79 >20:1
In concurrent and independent work, Suzuki and Enders found that tethered
keto-aldehydes undergo highly enantioselective cross-benzoin reactions using tria-
zolium based catalysts [50, 51]. The scope includes various aromatic aldehydes
with alkyl and aryl ketones (Table 4). Additionally, aliphatic substrate 39a is
cyclized in excellent enantioselectivity, albeit in 44% yield.
Table 4 Suzuki and co-workers enantioselective intramolecular cross-benzoin]
O
N
N N
O
BF4 O
OH
H 20-40 mol% 41 R
R
DBU, THF
39 O 40
Yield ee Yield ee
Entry 40 Product (%) (%) Entry 40 Product (%) (%)
1 a O 44 96 5 e O 74 85
OH OH
Me i - Pr
2 b O 70 96 6 f 91 98
OH O
Me OH
Me
OMe N O
3 c O 73 39 7 g O 73 99
OH OH
Me
O
O N O
4 d O 47 90
OH
Et
In a report by Enders and co-workers, triazolium pre-catalysts 42–44 were

shown to be competent in the cyclization of a variety of ketones (Table 5) [50].
Tetracyclic triazolium pre-catalyst 44 provides the enantioselectivities up to 98%.
N BF4 N BF4
N N Ph N N Ph
OR
R = TBS, 42
R = TIPS, 43 44
Table 5 Enders et al. enantioselective cross-benzoin reaction
O
O
10-20 mol% 44 R
H OH
O KOt - Bu, PhMe
45 R 46
Entry 46 R Yield (%) ee (%)
1 a Me 93 94
2 b Et 90 95
3 c n-Bu 85 98
4 d i-Bu 91 98
5 e Bn 43 93
Suzuki and co-workers have relayed this methodology into the synthesis of
(+)-sappanone B (Scheme 5) [52]. The authors found that catalysts previously
introduced by Rovis and co-workers led to inferior results; N-Ph catalyst 41 gave
significant elimination while N-C6F5 gave low enantioselectivities. By tuning the
electronics of the N-aryl substituent these workers identified 49 as providing the
optimal mix of reactivity and enantioselectivity. Commercially available 2-hydroxy-
4-methoxybenzaldehyde 47 was transformed into aldehyde 48, which upon treat-
ment with triazolium salt 49 in the presence of base was cyclized to afford (R)-50
in 92% yield and 95% ee and subsequently transformed into (+)-sappanone B.
O
O N CF3
O N N
H OMe Cl
MeO O
MeO OH 7.5 mol% 49 CF3
O
OMe Et3N, PhMe
47 48
O O
OH OH
OMe OH
MeO O OMe HO O OH
(R )-50 (+)-sappanone B
92% yield
95% ee
Scheme 5 Suzuki and co-workers synthesis of (+)-sappanone B

An additional means of performing a selective cross-benzoin was reported in

2001 when Murry and co-workers expanded benzoin methodology to include trap-
ping of acyl imines XIX formed in situ (Scheme 6) [53]. The authors chose to use
a-amido sulfones due to their stability and the relative ease of acyl imine libera-
tion. The parent reaction combines pyridine 4-carboxaldehyde 51 and tosylamide
52 in 98% yield in the presence of pre-catalyst 54 and triethylamine (Scheme 6).
OH
Me
I
O
O Tol Me N S H
SO2 O N Cy
10 mol% 54
H
Ph N Cy Et3N, DCM, 35 C N Ph O
N H
51 52 53
98%
Tol
SO2 O O
R N Cy R N Cy
H
XVIII XIX
Scheme 6 Murry, Frantz and co-workers trapping of in situ formed imines
This method accommodates aryl aldehydes with both electron-deficient and elec-
tron-rich aryl substitutents. Acetaldehyde is also a competent coupling partner,
providing the corresponding amido ketone in 62% yield. Acyl substitution of the
tosyl amide varies to include hydrogen, methyl, tert-butoxy, and phenyl producing
the desired a-amido ketones in moderate to high yields. Expansion of this meth-
odology to synthesize di- and tri-substituted imidazoles was reported by Murry
and co-workers (Scheme 7) [54].
Tol O R'''NH2 R' N

O SO2 O H
5 mol% 54 N R'' reflux, 12h R''
R N
R H R' N R'' Et3N, THF, 50 C R
H R' O R'''
XX
Ph N Ph N Ph N
Cy
N N N
H H Ph
N N HO2C
F
55 56 57
82% 82% 73%
Ph N Ph N
Ph Ph O N
N N Ph
OMe
N
N N
OMe OH N
58 59 60 Ph
80% 75% 76%
Scheme 7 Synthesis of imidazoles

Taking advantage of the acyl silane and imine methodologies, Scheidt and
co-workers illustrated the use of acyl silanes 61 and N-diarylphosphinoylimines 62
to form a-amino ketones 63 (Eq. 4) [55]. Utilizing thiazolium pre-catalyst 64, a
variety of acyl silanes, both alkyl and aryl, can be coupled efficiently. The reaction
conditions are tolerant of various aryl substitutions, providing high yields.
1. Me Me
P(O)Ph2 I O
H
O N Me N S
N Ph
30 mol% 64 R P Ph (4)
R SiMe2R' Aryl H
DBU, CHCl3, i-PrOH Aryl O
61 62 63
2. H2O 71-93%
Miller and co-workers have reported the use of thiazolylalanine-derived catalyst 65 to
render the aldehyde-imine cross-coupling enantioselective [56]. The authors comment
on the time sensitivity of this transformation and found that racemization occurs when
the reaction goes to complete conversion. Electron-deficient aldehydes are the most
efficient coupling partners for various tosylamides leading to the corresponding products
66, 68, and 69 (Scheme 8).
OBn
Me
O NHBoc
HN
O
NH
Me
O Me O
Tol S N H
SO2 O I N R''
H 15 mol% 65
Aryl N R'' 10 eq PEMP, DCM Aryl O
R H R
R' R'
O O
H H
N i-Pr N Ph
O O O
H O Cl
N Ph H
N Ph NO2
Ph
Ph O
Cl Ph O OMe OMe
66 67 68 69
100% 15% 63% 90%
76% ee 83% ee 79% ee 87% ee
Scheme 8 Miller and co-workers aldehyde imine cross-coupling catalyzed by thiazolylalanine-

derived catalysts
4 Stetter Reaction
Stetter expanded Umpolung reactivity to include the addition of acyl anion

equivalents to a,b-unsaturated acceptors to afford 1,4-dicarbonyls Eq. 5a
[57–60]. Utilizing cyanide or thiazolylidene carbenes as catalysts, Stetter
showed that a variety of aromatic and aliphatic aldehydes act as competent
nucleophilic coupling partners with a wide range of a,b-unsaturated ketones,
esters, and nitriles [61]. The ability to bring two different electrophilic partners
together and form a new carbon–carbon bond enhances the potential utility of
this transformation. When R’ = H, the reaction is quite versatile and provides
high yields of 70. Extensive work by Stetter and others in the development of
this reaction revealed that the presence of a b-substituent on the Michael
acceptor is a major limitation of this methodology; generally speaking, only
the most activated Michael acceptors result in synthetically useful yields Eq.
5b. It has been shown that the reaction time can be decreased significantly with
microwave irradiation [62]. Also, aldehydes can add to chalcone derivatives on
solid support in moderate yields [63].
O
O
R' catalyst R EWG a
R H EWG
R' = H, Ar base R'
70
(5)
O O
O NaCN Me
H
DMF b
Ph Me Ph O
Cl Cl
71
90%
4.1 Mechanism
Since mechanistic studies modeling the Stetter reaction have not yet been reported,
the proposed mechanism is based on that elucidated by Breslow for the thiazolium
catalyzed benzoin reaction (Scheme 9). The carbene, formed in situ by deprotonation
O N S
N S N S
H
Ph H Ph O
Ph OH Ph OH
XXI XXII XXIII
Base EWG
N S N S R
Cl
S
N OH
O
Ph EWG
Ph EWG S
N R
R O XXIV
Ph EWG
XXV R
Scheme 9 Proposed mechanism for the Stetter reaction

of the corresponding azolium salt, adds to the aldehyde to form XXI, which under-
goes proton transfer to form the acyl anion equivalent XXIII. Subsequent attack
into the Michael acceptor forms a new carbon–carbon bond XXIV and is followed
by a second proton transfer. Finally, tetrahedral intermediate XXV collapses to
form the ketone, accompanied by liberation of active catalyst.
4.2 Intramolecular Stetter Reaction
Almost 20 years after the initial report of the Stetter reaction, Ciganek reported
an intramolecular variant of the Stetter reaction in 1995 with thiazolium pre-
catalyst 74 providing chromanone 73 in 86% yield (Scheme 10) [64]. This
intramolecular substrate 72 has become the benchmark for testing the efficiency
of new catalysts. Enders and co-workers illustrated the first asymmetric variant
of the intramolecular Stetter reaction in 1996 utilizing chiral triazolinylidene
pre-catalyst 14 [65]. Despite moderate selectivity, the implementation of a chi-
ral triazolinylidene carbene in the Stetter reaction laid the foundation for future
work.
O O
OMe
H
OMe O
O O
72 O 73
N
HO
Me O N N Ph
Me
Cl
Me O ClO4
S N Bn Ph
74 14
Et3N, DMF, 25 C K2CO3, THF
86% 73%
60% ee
Scheme 10 Intramolecular Stetter reaction
In 2002, Rovis and co-workers developed a series of triazolium pre-catalysts,

75 and 76, and reported a highly enantioselective intramolecular Stetter reaction
[66]. These tetracyclic structures bear a fused-ring system in order to restrict
rotation, taking advantage of the concept first introduced by Leeper and Rawal,
and further provide the ability to add steric bulk on both sides of the reacting
site, blocking three of the four quadrants (Scheme 11, contrast Model A vs
Model B) [67].
O
N N
N N R N N R
Bn
BF4 BF4
75a, R = Ph 76a, R = Ph
75b, R = 4-OMeC6H4 76b, R = 4-OMeC6H4
75c, R = C6F5 76c, R = C6F5
N
N S N N
RCHO RCHO
N S N NN
R OH R OH
a b
Scheme 11 Thiazolylidene vs triazolinylidene steric capacities
These catalysts induce enantioselectivities in the resulting chromanones and

derivatives 78 in up to 97% ee (Table 6). A variety of heteroatom linkers on the
aldehyde tether are compatible under the reaction conditions allowing for the syn-
thesis of a variety of desired products in high yields and enantioselectivities.
Table 6 Variation of heteroatom linker in the intramolecular Stetter reaction

O O
H 20 mol% 75b or 76a OEt
R 20 mol% KHMDS R
OEt O
X X
xylenes, 25 C, 24h
77 O 78
Entry 78 X R Catalyst Yield (%) ee (%)
1 a O H 75b 94 94
2 b CH2 H 76a 90 92
3 c O 2-Me 75b 80 97
4 d S H 75b 63 96
5 e NMe H 75b 64 82
A wide range of a,b-unsaturated acceptors work well under standard reaction

conditions with pre-catalyst 75c (Table 7). Acceptors include a,b-unsaturated
esters, amides, alkyl ketones, and phosphine oxides, many of which provide the
products in greater than 90% ee [68, 69]. a,b-Unsaturated phenyl ketones, nitriles,
and thioesters also work, albeit with lower enantioselectivity. The scope has been
extended to include a variety of vinyl phosphonate precursors providing good
chemical yields and moderate to high enantioselectivity (entries 9 and 10).
Table 7 Rovis and co-workers Michael acceptor scope of the intramolecular Stetter reaction
O F
N
F
N N
O BF4 F
F O
H
H 20 mol % 75c F
EWG
20 mol % KHMDS
O EWG
toluene, 23 °C O
79 80
Yield ee Yield ee
O OMe Me
1 a O 94 95 6a f 94 92
O N
O OMe
O
O
2a b O O 94 93 7 g O CN 80 78
O
O O
O Ot-Bu O SEt
O O
3 a
c 94 97 8 h 85 70
O O
O O OEt
OH O P
Et OEt
4a d 94 92 9 i 65 80
O
O Ph
5 e O Ph 94 78 10 j O P 75 93
O Ph
O
O
OMe
Ent-75c used as pre-catalyst
a
Aliphatic substrates also perform well, forming five membered rings in good
yield and high enantioselectivity Eq. 6a. Typical Michael acceptors, however, are
not sufficiently electrophilic to induce cyclization to form six-membered aliphatic
rings. In order to effect this cyclization, use of a more electrophilic Michael accep-
tor, such as alkylidene malonate 83, was required Eq. 6b [70]. The difference in
reactivity is presumably due to the extra conformational freedom of the aliphatic
linker compared to the fused aromatic linker of substrate 79 coupled with potential
competing non-productive pathways.
O 20 mol% 76a O
CO2Et 20 mol% KHMDS CO2Et
a
PhMe, 25 C, 24h
81 82
81%
95% ee N BF4
N N Ph
Bn (6)
O CO2Et 20 mol% 76a O CO2Et
20 mol% KHMDS 76a
b
CO2Et CO2Et
PhMe, 25 oC, 24h
84
83 97%
82% ee
The scope of this methodology has been expanded to the synthesis of tetrasub-
stituted stereocenters by inducing the addition of aromatic and aliphatic aldehydes
to b,b-disubstituted Michael acceptors [71, 72]. While a series of catalysts were
examined, electron-deficient pre-catalyst 75c was found to be the most efficient for
this transformation (Table 8). Substrates with aromatic backbones readily undergo
reaction, forming benzofuranones in high yields and enantioselectivities up to 99%.
The scope includes oxygen, sulfur, and carbon linkers between the aldehyde and the
a,b-unsaturated ester. Most notably, quaternary carbon centers are formed in 95%
yield and 99% ee (entry 5).
Table 8 Substrate scope of b,b-disubstituted Michael acceptors

O F
N F
O N N O
R BF4 F
F R
CO2Me CO2Me
X 20 mol% 75c F X
85 20 mol% base, PhMe 86
Entry 86 X R Base Yield (%) ee (%)
1 a O Et Et3N 96 97
2 b S Et KOt-Bu 90 97
3 c S CH2CH2Ph KOt-Bu 91 99
4 d S Ph KOt-Bu 15 82
5 e CH2 Me Et3N 95 99
Catalysts 75c and 76a also induce cyclization of a variety of aliphatic substrates
for the construction of tetrasubstituted carbon centers in good yields and high enan-
tioselectivities (Scheme 12). Despite the success of carbon, nitrogen and oxygen
tethers, sulfide side chains have proven resistant to cyclization under optimized
conditions. By changing the linker to a sulfone 87, cyclization was accomplished
in 98% yield, albeit 80% ee.
O 20 mol% catalyst O
20 mol% KHMDS
R
R
EWG PhMe, 25 C, 24h EWG
X X
O O O
Pr Me nBu
S CO2Me N COMe COPh
O2 Ac
87 88 89
98% 65% 71%
80% ee 95% ee 98% ee
Scheme 12 Cyclization of b,b-disubstituted aliphatic substrates
The geometry of the Michael acceptor has been shown to play an important role
in the intramolecular Stetter reaction [70, 72]. In the case of salicylaldehyde derived
substrate 90, which contains a cis-1,2-disubstituted alkene, no reaction occurs
under standard reaction conditions. The same is not true with trisubstituted olefin
acceptors. Cyclization of b,b-disubstituted substrate (E)-91 provides cyclized prod-
uct in high yield and 97% ee Eq. 7. The corresponding (Z)-isomer gives a similar
yield although the enantioselectivity is decreased to 86%.
H CO2Et
90 (7)
O O
20 mol% 75c
Et
KOt-Bu, PhMe Et
CO2Me S CO2Me
S
(E )-91 92 90% yield, 97% ee
(Z )-91 92 89% yield, 86% ee
Utilizing prochiral a,a-disubstituted Michael acceptors, the Stetter reaction

catalyzed by 76a has proven to be both enantio- and diastereoselective, allow-
ing control of the formation of contiguous stereocenters Eq. 8 [73]. It is note-
worthy that a substantial increase in diastereoselectivity is observed, from 3:1
to 15:1, when HMDS, the conjugate acid formed upon pre-catalyst deprotona-
tion, is removed from the reaction vessel. Reproducible results and comparable
enantioselectivities are observed with free carbenes; for example, free carbene
95 provides 94 in 15:1 diastereoselectivity. The reaction scope is quite general
and tolerates both aromatic and aliphatic aldehydes (Table 9).
O O CO2Et
20 mol% catalyst H
H Me Me
PhMe, 23 oC, 24h
O CO2Et O
93 94
BF4 (8)
N N
N N Ph N N Ph
Bn Bn
76a 95
85-88% 88%
90% ee 90% ee
3:1 to 15:1 dr 15:1 dr
Table 9 Highly diastereoselective intramolecular Stetter reaction
O N O EWG
N N H
H R Bn R
20 mol% 98 CF3
O EWG PhMe, 23 oC, 24h O
96 97
Yield ee Yield ee
Entry 97 Product (%) (%) dr Entry 97 Product (%) (%) dr
O CO2Et O
1 a H 95 92 35:1 4 d O 80 95 18:1
H
Et
H
O
O
2 b 80 84 20:1 5 e O 94 99 50:1
O CO2Et O O
H H
Bn
H
O O Ph
O N
3 c 95 83 13:1 6 f H 80 88 15:1
O CO2Et O
H H
O
The observed diastereoselectivity of the protonation event may be explained by

Model C (Scheme 13). In Model C, an intermolecular proton transfer would yield
the minor diastereomer. Alternatively, the proton transfer may be intramolecular
and occur from the more sterically hindered face of the enolate, providing D.
N N
N N Ph N N Ph
Bn Bn
H R H
EtO O R O
O EtO O
O H O H
c d
Scheme 13 Intramolecular protonation
The mechanistic hypothesis was tested with experiments involving a pair of

substrates differing only in olefin geometry about the a,b-unsaturated ester. If the
assumption that proton transfer occurs faster than the bond rotation of converting
C to D is valid then the (E)- and (Z)-isomers are expected to produce opposite
diastereomers. In the event, (E)-99 provides 42:1 dr while (Z)-99 provides 1:6 dr
favoring the opposite diastereomer (Scheme 14).
O O CO2Me
20 mol% 98 H
CO2Me CO2Me
H
PhMe, 23 C, 24h H
O CO2Me O
(E ) -99 100
80%
92% ee
42:1 dr
O O CO2Me
20 mol% 98 H
CO2Me
H CO2Me
PhMe, 23 C, 24h H
CO2Me
O O
(Z ) -99 100
70%
38% ee
1:6 dr
Scheme 14 Complementary diastereoselectivity
The influence of stereocenters in the backbone has been investigated [74]. A

racemic substrate 101 can be subjected to standard Stetter reaction conditions
leading to disubstituted cyclopentanones 102. The reaction provides both cis and
trans diastereomers in high enantiomeric excess but with very poor diastereose-
lectivity (Table 10). Adding steric bulk did not significantly change the outcome
of the reaction (entry 2). The same trend was observed with substitution at the
3-position (entries 3 and 4). Alternatively, when substitution at 2-position is

present there is little catalyst control over the diastereoselectivity and the trans-
cyclopentanone is formed selectively in good yield (entry 5). Pre-existing stere-
ocenters have little to no effect on the diastereoselectivity of a Stetter cyclization
unless that center is alpha to the aldehyde, in which case a diminished enanti-
oselectivity is observed (entry 5).
Table 10 Effect of a pre-existing stereocenter on the Stetter reaction

O O
R'' R''
H O 20 mol% 75a or 76a
20 mol% KHMDS
R' OEt R' CO2Et
PhMe, 25 C
R R
(±)-101 102
Entry 102 R R’ R’’ Catalyst Yield (%) cis:trans ee (%)
1 a Me H H 75a 90 50:50 95/90
2 b i-Pr H H 76a 95 51:49 98/94
3 c H Me H 75a 97 50:50 94/98
4 d H Ph H 75a 96 50:50 96/98
5 e H H Bn 75a 95 85:15 <5/<5
Rovis and Liu have accomplished the desymmetrization of cyclohexadienones

by using triazolinylidene carbene 75b (Scheme 15) [75, 76]. Multiple hydrobenzo-
furanones 103–106 were synthesized in good yields and excellent enantio- and
diastereoselectivity. Generation of three co ntiguous stereocenters may be achieved
in >99% ee and 80% yield.
O
N
O O
N N
R' R' R' R'
BF4 OMe R''
R'' R'' 10 mol% 75b R'' O
R O R
O 10 mol% KHMDS O
PhMe, 25 C
O O O O
Me Me t -Bu t−Bu
H Me H H
O Me O O O
Me Me Me Me
O O O O
103 104 105 106
90% 64% 86% 80%
92% ee 99% ee >99% ee >99% ee
Scheme 15 Desymmetrization of cyclohexadienones

In this report the authors describe a surprising solvent effect on enantioselectivi-

ties. Alcoholic solvents afford the opposite enantiomer using the same enantiomeric
series of catalyst Eq. 9. This profound effect is presumably due to hydrogen bonding
in the transition state on the nucleophilic enol and/or the carbonyl acceptor Eq. 10.
These electrostatic interactions can be visualized with Models E and F. Although the
enantioselectivity is reversed the values remain lower than when toluene is used.
O
N
O N N
O
BF4 OMe
10 mol% 75b H (9)
Me O 10 mol% KHMDS O
O Me
O
H solvent 107
PhMe 90%, 88% ee
i-PrOH 65%, −63% ee
O
O
H O
O
O H
N H
O O a
Me O Me N O
N N O Me
N N O
107
MeO MeO
E
R
H O
O O
H O
N Me O
O H
R
O O H (10)
N N
H N O O b
Me Me
O N O
H N 108
RO O
MeO
H MeO
RO F
In 2004 and 2005, respectively, Bach and Miller independently described the use
of chiral thiazolium salts as pre-catalysts for the enantioselective intramolecular
Stetter reaction. Bach and co-workers employed an axially chiral N-arylthiazolium
salt 109 to obtain chromanone 73 in 75% yield and 50% ee (Scheme 16) [77].
Miller and co-workers found that thiazolium salts embedded in a peptide backbone
65 could impart modest enantioselectivity on the intramolecular Stetter reaction
[78]. In 2006, Tomioka reported a C2-symmetric imidazolinylidene 112 that is also
effective in the aliphatic Stetter reaction, providing three examples in moderate
enantioselectivities (Scheme 17) [79].
O
O
H catalyst
CO2Me
O CO2Me base
O
72 73
OBn
Me Me
S NHBoc
O HN
ClO4
N O
t-Bu NH I
Me
Me Me Me
S N
109 65
R = Me R = t-Bu
75% 67%
50 % ee 73% ee
Scheme 16 Bach and Miller catalysts
Ph Ph
Mes N N Mes
O BF4 O
10 mol% 112 COR
COR 5 mol% n-BuLi
PhMe, reflux
110 111 R yield (%) ee (%)
a OMe 74 76
b t-BuO 59 80
c Ph 33 63
Scheme 17 Tomioka’s catalyst in the Stetter
4.3 Intermolecular Stetter Reaction
While catalysts and reaction protocols are well established for the enantioselective
intramolecular Stetter reaction, asymmetric intermolecular Stetter products are
much more difficult to obtain using known methodologies. A report by Enders and
co-workers described the first asymmetric intermolecular Stetter reaction utilizing
n-butanal and chalcone [4]. When thiazolium salt 114 is used in this system the
reaction proceeds in 39% ee, albeit in 4% yield of 113. The authors comment that
both thiazolium and triazolium pre-catalysts perform poorly. The yield was
increased to 29% yield with thiazolium pre-catalyst 115 although a loss in enanti-
oselectivity was observed (Scheme 18) [80].
O
O O catalyst
Ph
base Me *
Me H Ph Ph
Ph O
113
Me Me Me Me
Me Me
N S N S
Ph Cl Ph Cl
OMe
114 115
4% 29%
39% ee 30% ee
Scheme 18 Enders et al. intermolecular Stetter reaction
In a related process, Johnson and co-workers have developed an asymmetric

metallophosphite-catalyzed intermolecular Stetter-like reaction employing acyl
silanes [81, 82]. Acyl silanes are effective aldehyde surrogates which are capable
of forming an acyl anion equivalent after a [1,2]-Brook rearrangement. The authors
have taken advantage of this concept to induce the catalytic enantioselective syn-
thesis of 1,4-dicarbonyls 118 in 89–97% ee and good chemical yields for a,b-
unsaturated amides (Table 11). Enantioselectivities may be enhanced by
recrystallization.
Table 11 Sila-Stetter reaction catalyzed by metallophosphites

iPr Ph Ph
1)
O O MeO
O
O P
O O
O O H
SiCyMe2 Me
R NMe2 Ph Ph
30 mol% 119, LiHMDS R
MeO
2) recrystallization O NMe2
116 117 3) HF.pyridine, MeCN, 25 C 118
Entry 118 R Yield (%) eea (%) eeb (%)

1 a Ph 68 90 99
2 b 3-MePh 67 93 99
3 c 4-ClPh 66 95 98
4 d N-Tosylindol-3-yl 60 97 97
5 e 2-Naphthyl 66 89 97
Before recrystallizationbAfter recrystallization
a
Scheidt and co-workers have shown that acyl silanes behave analogously
to aldehydes in the Stetter manifold, ultimately forming 1,4-dicarbonyls 120
in yields up to 75% [83, 84]. A range of acyl silanes are compatible in this
reaction Eq. 11.
HO
1. Me
Br
S
N Et
O
O H O 30 mol% 121
+ DBU, i - PrOH, THF Ar
R'
Ar SiMe3
(11)
R R' R O
2. H2O
120
R = H, Ph, CO2Et
R' = Me, t-Bu, OEt, OMe
In an extension of traditional Stetter methodology, Müller and co-workers have used

the Stetter reaction in a one-pot multicomponent reaction for the synthesis of furans and
pyrroles (Scheme 19) [85, 86]. The a,b-unsaturated ketone XXVI is formed in situ and
undergoes a Stetter reaction followed by a Paal-Knorr condensation.
HO
Me
X
Aryl I Aryl
2% (Ph3P)2PdCl2 O O
S N Me
1% CuI, Et3N, ∆
OH Aryl Ph R H 20 mol% 54 R Ph
O
XXVI then conc HCl,
Ph HOAc, ∆
NC NC N
N
S
O Ph Ph Ph
Ph Ph O Ph O
O F
O
122 123 124 125
79% 74% 46% 42%
Scheme 19 Synthesis of furans via one-pot multicomponent reaction
Pyrrole synthesis has been shown to be more general than furan (Table 12).
Scheidt and co-workers have subsequently shown that acyl silanes may again be
used as aldehyde surrogates in this protocol [83, 87].
Table 12 Synthesis of pyrroles via multicomponent reaction

Br NC
NC O
O 20 mol% 54
126 2% (Ph3P)2PdCl2
Ph then R'NH2
1% CuI, Et3N, ∆
R H HOAc, ∆
OH NC R Ph
N
XXVII
R'
Ph 128
127
Entry 128 R R’ Yield (%) Entry 128 R R’ Yield (%)
1 a Ph H 70 5 e Ph Bn 60
2 b 4-OMec6H4 H 60 6 f 2-furyl Bn 55
3 c n-Pentyl H 59 7 g Ph CH2CO2Et 54
4 d (CH2)5OH H 53 8 h Ph CH2CH2OH 57
Recently, Hamada and co-workers utilized the Stetter reaction in a cascade

sequence to produce dihydroquinolines, of type 131, in excellent yields Eq. 12 [88].
Although the scope of this reaction is limited to unsubstituted aryl aldehydes, the
compatibility of the carbene and palladium (0) catalysis is noteworthy.
HO
Me
Cl O
O SN Me
20 mol% 132 CO2Et
H
AcO CO2Et
(12)
5 mol% Pd(OAc)2 N
NHMs PPh3, i - Pr2NEt, t - BuOH Ms
129 130 131
97%
Scheidt and co-workers have reported the application of silyl-protected thiazolium

carbinols as stoichiometric carbonyl anions for the intermolecular acylation of nitroalkenes
[89]. While predominantly a discussion of racemic chemistry, a singular example illus-
trates that the newly formed stereocenter may be controlled by the addition of an equiva-
lent of a chiral thiourea 136 with the desired product 135 formed in 74% ee Eq. 13.
N
OSiEt3 CF3
I
S S
Me O
N H H
Cl F3C N N
Me H H
133 Me N NO2 (13)
136, Me4N.F Cy
Cl
NO2 CH2Cl2, –78 C 135
Cy 67%
134
74% ee
Markó and co-workers utilized the Stetter reaction in the synthesis of bicycloenedi-
ones, proceeding in moderate yields using stoichiometric thiazolium pre-catalyst 74
Eq. 14 [90]. Morita-Baylis-Hillman adducts 139 were formed in three steps from com-
mercially available starting materials 4-pentenal 138 and the corresponding cyclic
enones 137. The carbene induces a Stetter reaction followed by acetate elimination and
alkene isomerization into conjugation. The best results were obtained with 139c and
139d providing 1,4-dicarbonyls 140c and 140d, respectively, in 80% yield.
HO
O Me
Cl O
O OAc S N Bn
n
3 steps O 100 mol% 74
137
n
n H Et3N, EtOH, 78 oC (14)
O 139 O
140
H a n = 1, 50%
138 b n = 2, 66%
c n = 3, 80%
d n = 4, 80%
Suzuki and co-workers achieve aromatic substitution of fluoroarenes with a

variety of aldehydes in good yields [91, 92]. Imidazolilydene carbene formed from
143 catalyzes the reaction between 4-methoxybenzaldehyde 22a and 4-fluoroni-
trobezene 141 to provide ketone 142 in 77% yield (Scheme 20). Replacement of the
nitro group with cyano or benzoyl results in low yields of the corresponding
ketones. The authors propose formation of the acyl anion equivalent and subse-
quent addition to the aromatic ring by a Stetter-like process forming XXVIII,
followed by loss of fluoride anion to form XXIX.
O I O
Me N N Me
H
O2N F 25 mol% 143
MeO NaH, DMF O2N OMe
141 22a 142
77%
Me N N Me Me N N Me
Ar Ar
OH OH
F
O O
N N
O XXVIII O XXIX
Scheme 20 Aromatic substitution reaction catalyzed by NHCs
4.4 Applications in Total Synthesis
The first natural product synthesis that utilized the Stetter reaction was reported
by Stetter and Kuhlmann in 1975 as an approach to cis-jasmone and dihydrojas-
mone (Scheme 21) [93]. Thiazolium pre-catalyst 74 was effective in catalyti-
cally generating the acyl anion equivalent with aldehydes 144 and 145, then
adding to 3-buten-2-one 146 in good yield. Cyclization followed by dehydration
gives cis-jasmone and dihydrojasmone in 62 and 69% yield, respectively, over
two steps. Similarly, Galopin coupled 3-buten-2-one and isovaleraldehyde in the
synthesis of (±)-trans-sabinene hydrate [94].
O
O NaOH, H2O
O O
10 mol% 74 R Me EtOH, ∆, 6h R
R
H Me Et3N
O
146 Me
144 R = 147, 76% cis-jasmone, 81%
Et
145, R = n-pentyl 148, 78% dihydrojasmone, 89%
Scheme 21 Stetter and Kuhlmann’s synthesis of cis-jasmone and dihydrojasmone

Trost and co-workers relied on the Michael and the Stetter reaction to set the
relative stereochemistry for the core of hirsutic acid C (Scheme 22) [95]. The
Stetter reaction was accomplished in 67% yield with 2.3 equiv. of 3,4-dimethyl-
5-(2’-hydroxyethyl) thiazolium iodide 54 and 50 equiv. of triethylamine.
OH
Me
O O CN I CN
Me N S
9 steps
2.3 eq 54
O Et3N, i-PrOH
MeO2C MeO2C
CN H O
149 150 151
67%
O
HMe HMe
OH
5 steps Me Me
MeO2C MeO2C O
H H
152 (± )-hirsutic acid C
Scheme 22 Trost et al. synthesis of (±)-hirsutic acid C
The Stetter reaction has also been shown to be an important tool in the synthesis of
CI-981, also known as LIPITOR® [96]. Roth and co-workers demonstrate the ability
of commercially available starting materials 153 and 154 to couple in the presence of
20 mol% thiazolium pre-catalyst 121 (Scheme 23) [97, 98]. Amide 155 was obtained
in 80% yield and allowed for the convergent synthesis of CI-981 in nine steps.
HO
Me
Br
O O S N Et O CONHPh
CO2Me i -Pr
H i-Pr 20 mol% 121
Et3N, EtOH Ph O
F Ph F
153 154 155
80%
F
Me Me
O O O 3 steps OH OH O
155
H2N Ot-Bu N O Ca2+
Ph
2
156
i-Pr
PhHNOC
CI-981
Scheme 23 Roth et al. synthesis of LIPITOR®

In the late 1990s, Tius and co-workers described a formal total synthesis of
roseophilin [99, 100]. The Stetter reaction was well suited for the coupling of part-
ners 157 and 158 in the presence of 3-benzyl-5-(hydroxyethyl)-4-methyl
thiazolium chloride (Scheme 24).
HO
Me
O Cl O
O S N Bn
BzO 10 mol% 74 BzO O
H
i-Pr Et3N, 1,4-dioxane i-Pr
157 158 159
60%
OMe N
Cl
O
i-Pr
NH
roseophilin
7% overall yield
Scheme 24 Tius and co-workers synthesis of roseophilin
In the process of developing the Stetter reaction in ionic liquids, Grée and co-
workers applied their methodology to the synthesis of haloperidol (Scheme 25)
[101]. A variety of aromatic aldehydes react with methyl acrylate 160 when butyl-
methylimidazolium tetrafluoroborate [bmim][BF4] is used as solvent. In the synthe-
sis of haloperidol, electron-deficient aldehyde 153 was subjected to standard
reaction conditions with 160 to provide 161 in good yield.
O O
O 10 mol% 74 OMe
H
OMe Et3N, [bmin][BF4]
O
F F
153 160 161
67%
Cl
HO
F
N
O
haloperidol
Scheme 25 Grée and co-workers synthesis of haloperidol

Nicolaou and co-workers recently published a formal synthesis of (±)-platen-

simycin utilizing Stetter methodology [102]. Aldehyde 162 was treated with achiral
N-pentafluorophenyl pre-catalyst 164 and readily underwent cyclization to yield
163 as a single diastereomer (Scheme 26). After an additional seven steps late stage
intermediate 165 was formed to complete the formal synthesis.
F
N F
O N N O
BF4 F
F H
F O
H 100 mol% 164 Br
Br Et3N, CH2Cl2, 45 C
O
162 163
64%
OH
O O
Me O
7 steps O
N
H
OH OH
O
Me O
Me
165 (±)-platensimycin
Scheme 26 Nicolaou et al. formal synthesis of (±)-platensimycin
Rovis and Orellana have reported efforts toward the synthesis of FD-838
(Scheme 27) [103]. In four steps, the Stetter substrate 166 was obtained and under-
went cyclization readily with aminoindanol derived pre-catalyst 75c to produce
spirocycle 167 in good yield and 99% ee.
O F
N F
N N
O F O
BF4
O F O
NBn 20 mol% 75c F NBn
H O KHMDS, PhMe
O O O
166 167
O
Bn Ph
OH OH OMe
TESO O
4 steps NBn NBn
Me
O O O O
O O
168 FD-838
Me Et
Scheme 27 Rovis and Orellana’s efforts toward the synthesis of FD-838

5 Redox Reactions
The catalytic preparation of esters and amides under mild and waste free reaction
conditions using readily available starting materials is a desirable goal. The first
redox process of this type using heterocyclic carbenes was reported by Castells and
co-workers in 1977 in which aldehydes were oxidized to esters in one-pot in the
presence of nitrobenzene [104]. Furfural 169 is converted into methyl 2-furoate 170
in 79% yield Eq. 15. Nitrobenzene is the presumed stoichiometric oxidant for the
oxidation of the nucleophilic alkene XXX to the acyl azolium XXXI by successive
electron transfer events. The authors observe nitrosobenzene as a stoichiometric
byproduct. This type of reactivity is also observed when cyanide is used as the
catalyst. Miyashita has expanded the scope of this transformation using imida-
zolylidene carbenes [105–107].
Me Me
I
O O
S N Me
O PhNO2 O PhNO
H 10 mol% 64 OMe
Et3N, MeOH, 60 oC
169 170
79%
OH O
(15)
O S 2 e−,−H+ O S
Me Me
N PhNO2 N
Me Me
Me Me
XXX XXXI
In 2004, Bode and Rovis independently and concurrently reported the catalytic
coupling of reducible aldehydes and alcohols. This mode of reactivity is most
closely related to the work published by Wallach, who generated dichloroacetic
acid from chloral under cyanide catalysis in aqueous media [108]. Bode and co-
workers reported the catalytic, diastereoselective synthesis of b-hydroxy esters
from a,b-epoxy aldehydes using thiazolium pre-catalyst 173 Eq. 16a [109]. MeOH,
EtOH, and BnOH are effective nucleophiles providing upwards of >10:1 diastere-
oselectivity. Aziridinylaldehyde 174 has also been shown to provide the desired
N-tosyl-b-aminoester 175 in 53% yield Eq. 16b.
Me Me
Cl
S N Bn
O OH O
O 10 mol% 173
Ph H BnOH Ph OBn
a
8 mol% DIPEA
Me CH2Cl2, 30 C Me
171 172
89%
>10:1 dr
Ts
(16)
O 10 mol% 173 TsNH O
N
Ph H EtOH 8 mol% DIPEA Ph OEt b
CH2Cl2, 30 oC
174 175
53%
The proposed catalytic cycle for this reaction begins with the initial attack of the
in situ generated thiazolylidene carbene on the epoxyaldehyde followed by
intramolecular proton transfer (Scheme 28, XXXII–XXXIII). Isomerization occurs
to open the epoxide forming XXXIV which undergoes a second proton transfer
forming XXXV. Diastereoselective protonation provides activated carboxylate
intermediate XXXVI. Nucleophilic attack of the activated carboxylate regenerates
the catalyst and provides the desired b-hydroxy ester.
OH
O O
O H S
S R Me
R Me
R' N
O R' N Bn
O Bn Me
Me XXXIII
R H
XXXII
R'
Me Me O OH
S
R Me
S N Bn
R' N
Bn
Me
XXXIV
OH O
R OR''
OH O OH O
R'
S S
R R Me
Me
R' N R' N
Bn Bn
Me Me
XXXVI R''OH XXXV
Scheme 28 Proposed mechanism for the formation of b-hydroxy esters
Concurrently with Bode’s work, Rovis and co-workers reported an internal

redox reaction of a-haloaldehydes to provide a variety of esters in good yields
[110]. Triazolium salt 177 proved most effective for the transformation of
a-bromodihydrocinnamaldehyde 176 into the desired ester (Scheme 29). Activated

carboxylate XXXVII, similar to XXXVI (Scheme 28), is the proposed intermedi-
ate. Secondary and tertiary bromoaldehydes are also useful electrophiles, along
with secondary alcohols and phenols as nucleophilic partners in this acylation
reaction.
N Cl
O O R
N N Ph O
N
Ph H NuH 20 mol% 177 Ph
N N Ph Nu
Br Et3N, PhMe Ph
176 XXXVII
Me
O O O
Ph OEt Ph NHPh Ph O
178 179 180
78% 91% 65%
Scheme 29 Rovis and co-workers acylation reaction via activated carboxylate XXXVII
The reaction conditions are mild and generally tolerant of epimerizable stereo-
centers. For instance, the use of (S)-ethyl lactate 181 under the reaction conditions
produces desired ester 182 in 94% ee Eq. 17a. The subjection of racemic ethyl
lactate 181 to standard reaction conditions with chiral pre-catalyst 183 provides
ester 182 in 32% ee Eq. 17b. This result suggests that the catalyst is intimately
involved in the acylation event.
N Cl
O Me N N Ph O Me
OEt OEt a
Ph H HO 20 mol% 177 Ph O
Br O Et3N, PhMe O
176 181 182
99% ee 56%
94% ee
N Cl
(17)
O Me N N Ph O Me
OEt Bn OEt b
Ph H HO 20 mol% 183 Ph O
Br O Et3N, PhMe O
176 181 182
71%
32% ee
Bode and co-workers have shown that the outcome of internal redox reactions is
uniquely dependent on the base [111]. When diisopropylethyl amine is used in the
reaction of an enol and an alcohol, the initially generated homoenolate is protonated
more rapidly than the carbon–carbon bond formation of the homoenolate XXXIX to
another equivalent of enol (Scheme 30). Thus this reaction serves as a direct conversion
of an a,b-unsaturated aldehyde to the corresponding saturated ester 185 via XL.
N BF
4
O N N Mes O
R'OH 5 mol% 186
R H R OR'
DIPEA, THF, 60 C
184 185
OH Mes OH Mes H O Mes

N N N
R N R N Ar N
N N N
XXXVIII XXXIX XL
Scheme 30 Base dependent reactivity
Various aldehydes 184 and alcohols have been shown to be competent in the redox
esterification of unsaturated aldehydes in the presence of the achiral mesityl triazo-
lium pre-catalyst 186. Both aromatic and aliphatic enals participate in yields up to
99% (Table 13). Tri-substituted enals work well (entry 3), as do enals with additional
olefins present in the substrate (entries 4 and 7). The nucleophile scope includes pri-
mary and secondary alcohols as well as phenols and allylic alcohols. Intramolecular
esterification may also occur with the formation of a bicyclic lactone (entry 8).
Table 13 Bode and co-workers redox esterification

Yield Yield
Entry 185 Product (%) Entry 185 Product (%)
O O
1 a 97 5 e 86
Ph OMe n -Hex OEt
2 b O 86 6 f O 79
OMe Me OEt
MeO
3 c Me O 72 7 g Me 63
Ph OEt O Me Me
n -Pr O
4 d O 85 8 h O O 89
AllylO OMe O
AllylO OAllyl Ph O
Scheidt and co-workers have synthesized similar products using this reaction
manifold [112]. While results are limited to primary and secondary alcohols, the
authors provided a single example of the use of an amine nucleophile. The reaction
of cinnamaldehyde 187 and b-amino alkylidene malonate 188 provide amide
product 189, albeit in moderate yield Eq. 18.
I
O
O MeO2C CO2Me Me N N Me
+ CO2Me
5 mol% 190 Ph N 189
(18)
Ph H H2N H
DBU, PhMe CO2Me 51%
187 188 189
51%
Bode and co-workers further extended redox esterification to include carbon–

carbon bond breaking of formyl-cyclopropanes [113]. Both esters and thioesters are
formed in high yield and good enantioselectivities (Scheme 31). The N-mesityl
substituted triazolium salt 191 proved to be the most efficient pre-catalyst providing
complete suppression of the benzoin reaction. Electron-deficient substituents, such
as phenyl ketone, readily provide ester formation.
N Cl
O N N Mes
EWG 5 mol% 191 Nu
H NuH EWG
DBU, THF R O
R
Me
O Ph O O Me O O O
Ph OMe Ph OMe Ph OMe
192 193 194
90% 84% 96%
O n - Pr O O Ph O O Ph O
t-Bu OMe Ph SC12H25 Ph OH

195 196 197
95% 99% 92%
Scheme 31 Redox esterification of chiral enantioenriched formylcyclopropanes
In 2006, Zeitler demonstrated the use of alkynyl aldehydes in redox esterification

[114]. As in previous examples, the author proposes the formation of an activated
carboxylate that acts as an acylating agent Eq. 19. A variety of a,b-unsaturated
carboxylic esters 199 are formed in moderate yields with E-selectivity up to >95:5.
Cl
Mes N N Mes
O O
R 5 mol% 200
H R OR' (19)
KOt-Bu, THF
198 199
18-90% yield
In 2005, Rovis and Reynolds reported the synthesis of a-chloroesters from a,a-
dichloroaldehydes using chiral, enantioenriched not chirald pre-catalyst 75c [115].
As shown in Table 14, the reaction scope includes a variety of dichloroaldehydes
201 that afford desired esters 202 in good yields and enantioselectivities. The reac-
tion is compatible with various phenols, including electron-rich and electron-poor
nucleophiles. Standard reaction conditions accommodate a variety of aldehydes,
although substrates containing b-branching inhibit reactivity.
Table 14 Synthesis of a-chloroesters

O F
N F
N N
BF4 F O
O F
R ArOH 20 mol% 75c F R
H OAr
Cl Cl 2,6-dibromo-4-methylphenol
Cl
201 KH,18-crown-6, PhMe 202
Yield ee Yield ee
O O
1 a 79 93 4 d 65 89
Ph OPh Me OPh
Cl Cl
O OMe
2 b 76 90 5 e O 71 91
OPh
Ph O
Cl
MeO Cl
3 c O 75 84 6 f O 75 91
MeO2C(H2C)6 OPh Ph O
Cl Cl Cl
Rovis and Vora sought to expand the utility in alpha redox reactions to include the
formation of amides [116]. While aniline was previously demonstrated as an efficient
nucleophile in this reaction (Scheme 29), attempts to develop the scope to include
non-aryl amines as various primary and secondary amines resulted in low yields. The
discovery of a co-catalyst was the key to effecting amide formation (Table 15).
Various co-catalysts, including HOBt, HOAt, DMAP, imidazole, and pentafluorophenol,
are efficient and result in high yields of a variety of amides including those involving
primary and secondary amines with additional functionality.
Table 15 Amine scope of the redox amidation of a,a-dichloroaldehydes

F
N F
N N
BF4 F
O F O
20 mol% 164 F
Ph H RR'NH Ph NRR'
Cl Cl 20 mol% HOAt Cl
203 204 1eq BnOH, THF 205
Entry 205 RR’NH Yield (%) Entry 205 RR’NH Yield (%)
1 a EtNH2 89 5 e MeNHOMe 72
2 b CyNH2 85 6 f PhNH2 87
3 c t-BuNH2 73 7 g 3-ClC6H4NH2 82
4 d Et2NH 89 8 h 4-OMeC6H4NH2 85
When 2,2-dichloro-3-phenylpropanal 203 is subjected to standard reaction condi-

tions with chiral triazolium salt 75c, the desired amide is produced in 80% ee and 62%
yield Eq. 20. This experiment suggests that the catalyst is involved in an enantioselec-
tive protonation event. With this evidence in hand, the proposed mechanism begins with
carbene addition to the a-reducible aldehyde followed by formation of activated car-
boxylate XLII (Scheme 32). Acyl transfer occurs with HOAt, presumably due to its
higher kinetic nucleophilicity under these conditions, thus regenerating the carbene. In
turn, intermediate XLIII then undergoes nucleophilic attack by the amine and releases
the co-catalyst back into the catalytic cycle.
O O
20 mol% 75c
Bn
Ph H + BnNH2 HOAt, DABCO Ph N
PhMe H
Cl Cl Cl
203 206 207 (20)
62%
80% ee
O N
N O
R
H N N Ar N
R N R2NH
X R' O N
XLI R' XLIII
O N O
HX R N N R
N N NR2
R' N N R'
Ph OH
HOAt
XLII
Scheme 32 Proposed catalytic cycle of the redox amidation of a,a-dichloroaldehydes

As previously explored by Bode, other a-reducible substrates, such as a,b-

epoxy aldehyde and aziridinylaldehyde, are competent partners for redox reactions.
(Scheme 33) [109]. Various amines are compatible nucleophiles in this methodology
in which b-hydroxy amides are furnished in good yield and excellent diastereose-
lectivity. A similar reaction manifold was discovered concurrently by Bode and
co-workers using imidazole as co-catalyst [117].
O 10 mol% 164 XH O
X
R H
+ R''NH2 10 mol% imidazole R N
R''
DIPEA, t-BuOH H
R' R'
Ts
OH O OH O Me NH O
Bn O Bn
Ph N Ph N Ph N
H H H
Me Me Ot-Bu Me
208 209 210
86% 75% 72%
>19:1 dr 15:1 dr >19:1 dr
Scheme 33 Synthesis of b-hydroxy amides catalyzed by NHCs
In a related transformation, Bode and co-workers have demonstrated the utility of

homoenolate protonation in an azadiene Diels-Alder reaction catalyzed by aminoin-
danol derived N-mesityl pre-catalyst 214 [118, 119]. The cyclization products 213 are
obtained as a single diastereomer in excellent enantiomeric excess (Table 16).
Electron-deficient enals are used in order to increase the electrophilicity and reactiv-
ity of the compounds. After protonation of the homoeneolate moiety, an inverse
electron demand Diels-Alder is proposed to provide the desired cyclized product.
Table 16 Azadiene Diels-Alder reaction

O O
N
R N N Mes
H
O BF4 O Mes
211 O
10 mol% 214 R N ArO2S R
N N
ArO2S DIPEA, 1:1 PhMe/THF O N O
N R'
XLIV 213
H R'
Ar = p-OMeC6H4
212
Entry 213 R R’ Yield (%) ee (%)

1 a OEt Ph 90 99
2 b OEt 4-OMeC6H4 81 99
3 c OEt 4-COMeC6H4 55 99
4 d OEt 1-furyl 71 99
5 e OEt n-Pr 58 99
6 f Ot-Bu Ph 70 97
7 g Me Ph 51 99
8 h Me n-Pr 71 98
9 i Ph 4-OMeC6H4 52 99
In continuing efforts at expanding the utility of NHCs, the synthesis of

trisubstituted dihydropyran-2-ones employing chiral triazolium pre-catalyst
was described by Bode and co-workers in 2006 [120]. In a mechanism distinct
from earlier redox processes, this transformation proceeds via an enantioselec-
tive oxodiene Diels-Alder reaction to produce desired products in high yield
and excellent enantiomeric excess (Table 17). The high selectivity, as well as
the low catalyst loading and relatively fast reaction times, are impressive. The
substrate scope is quite broad and includes varying substitution on the enone
and aldehyde partners. Aromatic and aliphatic substitution is equally tolerated
and provides excellent enantioselectivities. Diminished diastereoselectivity of
aryl substitution is presumably due to epimerization of the cis-annulation prod-
uct. This is further evidenced by the observation that the diastereomeric ratio is
higher when the reaction is stopped before complete consumption of starting
material.
Homoenolates generated catalytically with NHCs can also be employed for
C-C and C-N bond formation. Bode and Glorius have independently accom-
plished the diastereoselective synthesis of g-butyrolactones by annulation of
enals and aldehydes [121, 122]. Bode and co-workers envisioned that increas-
ing the steric bulk of the acyl anion equivalent would allow reactivity at the
homoenolate position. While trying to suppress the competing benzoin and enal
dimerization the authors comment on the steric importance of the catalyst.
Thiazolium pre-catalyst 173 proved unsuccessful at inducing annulation.
N-mesityl substituted imidazolium salt 200 was found to provide up to 87%
yield and moderate diastereoselectivities (Scheme 34).
Table 17 Oxodiene Diels-Alder reaction

O
N
N N Mes
O O
O BF4
H R 0.5-2 mol% 214 O R
R' R''
Cl Et3N, EtOAc R' R''
215 216 217
Entry 217 R R’ R’’ Yield (%) ee (%) dr
1 a Ph Me CO2Me 88 99 >20:1
2 b Ph 4-BrC6H4 CO2Me 80 99 6:1
3 c n-C9H19 Me CO2Me 71 99 >20:1
4 d OTBS Ph CO2Me 80 97 3:1
5 e Ph CO2Et Cy 85 95 >20:1
6 f OTBS CO2Et p-Tol 70 99 >20:1
Cl
Mes N N Mes O
O O 8 mol% 200
O
Ar H H R DBU, 10:1 THF/t-BuOH
Ar
R
O O
O O
O
O O
O O
Ph Ph O
TIPS
MeO Ph
MeO
Br CO2Me Br
TIPS
218 219 220 221 222
79% 87% 76% 65% 67%
4:1 dr 5:1dr 4:1 dr 4:1 dr 5:1 dr
Scheme 34 Synthesis of g-butyrolactones
The proposed catalytic cycle is shown in Scheme 35 and begins with the imida-
zolylidene carbene adding to the enal. Proton transfer provides acyl anion equiva-
lent XLVII, which may be drawn as its homoenolate resonance form XLVIII.
Addition of the homoenolate to aldehyde followed by tautomerization affords L the
precursor for lactonization and regeneration of the carbene.
OH Mes OH Mes OH Mes

N N N
Ph Ph Ph
N N N
Mes Mes Mes
XLVI XLVII O XLVIII
O Mes H Ar
N
Ph
Ph OH Mes
N
Mes Ar N
XLV
O N
O Mes
XLIX
Ph H
Mes N N Mes Ph O Mes
Ar N
O O N
Mes
L
O
Ph
Ar
Scheme 35 Proposed mechanism of NHC catalyzed formation of g-butyrolactone

Concurrently, Glorius and co-workers reported the synthesis of g-butyrolactones

under similar reaction conditions [122, 123]. Glorius has extended this reactivity to
include trifluoromethyl ketones (Scheme 36). In addition to intermolecular reactions,
intramolecular homoenolate additions are possible in modest yield Eq. 21 [123].
O
O
O 5 mol% 200 O
Ar H Ar
Ph CF3 KOt - Bu, THF CF3
Ph
O O
O
O O
O
CF3 CF3
Ph CF3 Ph Ph
Ph
MeO Me2N
223 224 225
84% 92% 74%
1.9:1 dr 1.9:1 dr 2.3:1 dr
Scheme 36 Synthesis of g-butyrolactones from trifluoromethyl ketones and enals
O O
H 15 mol% 200
O
Me KOt-Bu, THF, 60 C
Me (21)
O
226 227
55%
The synthesis of g-lactams has been achieved under similar reaction conditions
(Table 18) [124]. Initially, Bode and co-workers screened a variety of acyl imines
in order to find suitable electrophiles. Control experiments provided evidence for
carbene addition to the acyl imine, yielding a stable complex with complete inhi-
bition of the desired reactivity. Reversibility of this addition was key to the
success of the reaction. N-4-Methoxybenzenesulfonyl imines 212 proved to be
the most efficient partners for lactamization with cinnamaldehydes 228 to pro-
vide g-lactams 229 in moderate yields and good diastereoselectivities. Notably,
no benzoin or Stetter products or their corresponding derivatives were observed
during this reaction.
Nair and co-workers reported the diastereoselective synthesis of spiro g-butyro-
lactones from 1,2-dicarbonyls [125]. The authors studied the reaction with
1,2-cyclohexane dione 230 which produces the desired lactone 232 in good yields
Eq. 22a. Isatins 233 are more reactive, but the products 235 are obtained as a 1:1
separable mixture of diastereomers Eq. 22b. The Nair research group extended this
methodology to include homoenolate addition to tropanone 236 to form bicyclic
d-lactones 238 Eq. 22c [126].
Table 18 NHC catalyzed annulation of enals and imines
Cl
ArO2S Mes N N Mes O

O N 15 mol% 200
NSO2Ar
R H H R' DBU, t-BuOH, 60 C
Ar = p-OMeC6H4 R
R'
228 212 229
Entry 229 R R’ Yield (%) dr
1 a Ph 4-MeC6H4 70 4:1
2 b Ph 3-OMe 69 3:1
3 c Ph 2-furyl 73 1.7:1
4 d Ph 61 8:1
Ph
5 e 4-MeC6H4 51 10:1
TIPS
O
O O
O O
O
6 mol% 200
Ar H a
DBU, THF
Ar
230 231 232
60-74%
O
O
R O Ar
R O b (22)
O 6 mol% 200
N Ar H O
R' DBU, THF N
Ar = Ph, 4-OMeC6H4 R'
R = H, Br
235
233 234
85-98%
O
O O
O 7 mol% 200
R c
R H KOt-Bu, THF
R = aryl, cyclohexenyl
236 237 238
27-62%
Nair and co-workers have continued their investigations into the catalytic reac-
tivity of NHCs to include the synthesis of trisubstituted cyclopentenes [127]. Under
mild reaction conditions the catalytically generated homoenolate adds conjugately
to a chalcone derivative 240, which then proceeds to furnish a cyclopentene 241 as
a single diastereomer in good yield Eq. 23. Compatible substituents include aryl
groups, possessing electron-releasing and electron-withdrawing substitutions as
well as one example where R and R′ are methyl.
R''
O O 6 mol% 200
R H R' R'' DBU, THF (23)
R R'
239 239 241
55-88% yield
Upon formation of intermediate LI, conjugate addition to a chalcone and subse-

quent proton transfer is proposed to lead to enolate LIII (Scheme 37). An intramo-
lecular aldol addition provides activated carboxylate LIV in which alkoxide
acylation regenerates the catalyst and delivers b-lactone LVI which, upon decar-
boxylation, gives rise to a trisubstituted cyclopentene.
Bode and co-workers rendered this transformation asymmetric allowing access to
cis-cyclopentenes 244 with high enantioselectivity (Table 19) [128]. Optimized reac-
tion conditions include the use of N-mesityl substituted aminoindanol derived triazo-
lium catalyst 214. When chalcone and derivatives we re subjected to the reaction
conditions, cis-cyclopentenes were formed selectively. Although the substrate scope is
also limited to b-aryl substituted enals, cis:trans ratios of up to >20:1 are observed.
In contrast to Nair, Bode and co-workers propose that cross-benzoin adduct
LVII is formed which then undergoes an oxy-Cope rearrangement to form LVIII
(Scheme 38). Tautomerization and intramolecular aldol reaction occurs following
the catalytic cycle proposed by Nair.
R' R'' R'' O
R'
OH
OH N
R
N
O R N
N LII
R H
LI
R'' O
N N
R'
R' O
R'' N
R
O
R N
R'
LVI O R'' LIII
R'
R'' O
R
O N
R O
N
R' O N
R'' N LIV
LV
R
Scheme 37 Proposed mechanism of trisubstituted cyclopentene formation

Table 19 Scope and selectivity of cyclopentene formation

O
N
N N Mes
R'
Cl
O O 10 mol% 214
R H MeO2C R' DBU, ClCH2CH2Cl
R CO2Me
242 243 40h
244
Entry 244 R R’ yield(%) cis:trans ee(%)
1 a Ph Ph 78 11:1 99
2 b Ph 4-MeOC6H4 58 5:1 99
3 c Ph 4-BrC6H4 50 11:1 99
4 d Ph 2-furyl 93 >20:1 98
5 e 4-BrC6H4 Ph 58 6:1 99
6 f 4-CF3C6H4 Ph 68 4:1 98
7 g 2-furyl Ph 53 5:1 99
8 h n-Pr Ph 25 14:1 96
O O
HO N HO N
Ph Ph
MeO2C Ph N N MeO2C Ph N N
LVII LVIII
Scheme 38 Proposed intermediates leading to cis-cyclopentenes
The authors describe a control experiment in which cross-benzoin product 245 was
subjected to standard reaction conditions with achiral triazolium pre-catalyst 191 yield-
ing retro-benzoin products, as well as cyclopentene product 247 Eq. 24. This result
additionally demonstrates the reversibility of the benzoin reaction. When trimethylsilyl-
protected 245 is treated under the same reaction conditions with ethanol as a nucleophile,
ketoester 248 is formed along with retro silyl-benzoin and Stetter products. This result
provides enough evidence that the cross-benzoin/oxy-Cope mechanism cannot be
dismissed.
N Cl
O Ph
N N Mes
OH
Ph 10 mol% 191 O O
Ph
DBU, ClCH2CH2Cl Ph H Ph Ph
Ph Ph Ph
245 242a 246 247
O Ph
Ph
EtO
Ph O
248 (24)
In 2007, Scheidt and co-workers reported the intramolecular desymmetrization of

1,3-diketones utilizing triazolium pre-catalyst 249 (Scheme 39) [129]. Generation of a
homoenolate is followed by b-protonation and aldol reaction. In accordance with the
proposed mechanism by Nair (Scheme 37), acylation occurs followed by loss of carbon
dioxide. Cyclopentenes are formed in enantioselectivities up to 94% ee. The scope of
this reaction is limited to aryl substitution of the diketone and alkyl substitution of R.
O
N BF4
Ph N N Mes
O R R
O Ph O
R'
O 10-20 mol% 249
H R
i - Pr2EtN, CH2Cl2, 40 C R'
R
R = aryl
R' = alkyl
Cl
Ph O
O
Ph O Ph
Me
Ph
Me Me
250 251 Cl 252
80% 76% 69%
93% ee 94% ee 83% ee
Scheme 39 Desymmetrization of 1,3-diketones
In a related paper, Scheidt and co-workers described a stereoselective formal

[3 + 3] cycloaddition catalyzed by imidazolinylidine catalyst 256 Eq. 25 [130].
Ultimately this is an intermolecular addition of the homoenolate intermediate to an
azomethine ylide followed by intramolecular acylation and presumably follows the
same mechanistic path as described previously. Pyridazinones are obtained as sin-
gle diastereomers in good to high yield from a number of aldehydes. Unfortunately
no reaction occurs with the presence of electron-withdrawing groups on the aryl
ring of the enal.
O O O
I
OMe O N OMe
N Mes N N Me
Ph N N
H 20 mol% 256 (25)
H Ph Ph Ph
DBU, CH2Cl2, 40 C
253 254 255
94%
In related methodology, Scheidt and co-workers have also reported the homoeno-
late addition to nitrones to produce products of a formal [3 + 3]. Upon treatment with
basic methanol LIX opens to generate hydroxylamines in good to excellent enantio-

and diastereoselectivities (Scheme 40) [131]. The scope of this reaction includes
electron-rich and electron-deficient enals with little deviation in the overall yield.
Scheidt and co-workers have also illustrated the oxidation of activated alcohols
to esters [132]. Oxidations of alcohols such as 260 provide the electrophile (acyl
donor) for a nucleophilic alcohol 261. Esters 262 are derived from propargylic,
allylic, aromatic, and hetero-aromatic substrates (Table 20). The nucleophilic
alcohol scope includes MeOH, n-BuOH, t-BuOH, 2,2,2-trichloroethanol,
2-methoxyethanol, and 2-(trimethylsilyl) ethanol.
In this transformation, manganese(IV) oxide oxidizes allylic or benzylic alco-
hols to aldehydes followed by nucleophilic attack of the in situ formed triazolinyli-
dene carbene (Scheme 41). The authors suggest the formation of an acyl anion
equivalent LX is slow in MeOH compared to oxidation to allow for an activated
carboxylate LXII.
O
N BF4
Ph N N Mes
O Ph O R OH
O Ph
N N
20 mol% 249
MeO Ph
R H R' H Et3N, CH2Cl2, −25 C R'
257 258 then NaOMe / MeOH 259
O
O
N
R Ph
R'
LIX
Scheme 40 Scheidt and co-workers formal [3 + 3] of enals and azomethine
Table 20 Alcohol to ester oxidation catalyzed by NHC

Cl
Mes N N Mes
O
10-50 mol% 200
R OH n-BuOH R On-Bu
1.5 eq DBU,15 eq MnO2
260 261 262
PhMe
Entry 262 R Yield (%) Entry 262 R Yield (%)
1 a 93 4 d Me 87
Ph
2 b 91 5 e O 65
Ph
Me EtO
3 c Ph 85 6 f 2-BrC6H4 70
OH Me O Me O Me
N N N
R N R N MnO2 Ar N
H
N N N
Me Me Me
LX LXI LXII
Scheme 41 Proposed intermediates leading to esters
6 Transesterification Reactions
The first examples of NHC catalyzed transesterification reactions were described

independently by Nolan and Hedrick in 2002 [133, 134]. Transesterification reac-
tions may appear trivial, but most methods are unselective between primary and
secondary alcohols [135].
Nolan and co-workers found that in the presence of 3, vinyl acetate acts as an
acylating agent of benzyl alcohol in excellent yield with a reaction time of only
5 min (Eq. 26a). A range of imidazolium catalysts perform well in this reaction, as
do strong inorganic bases. Employing NHCs as catalysts for acylation proved to be
highly selective for primary over secondary alcohols. As shown in (Eq. 26b), a 1:1
mixture of primary and secondary alcohols resulted in a 20:1 ratio of the corre-
sponding esters.
O Mes N N Mes
O
HOBn 0.5 mol% 3 a
Me O Me OBn
4Å MS, THF
263 264
100% yield
O HO 0.5 mol% 3 O O Me
HOBn Me
Me
b
Me O Me THF, rt, 5min Me OBn Me O
263 265 264 266
(26)
Mild reaction conditions and excellent selectivity provide a large scope of poten-
tial acylating agents that include a variety of alkyl and aryl methyl esters [133, 136].
As a further advantage over traditional methods, acid sensitive esters readily
undergo transesterification in quantitative yield (Table 21, entry 2).
In the absence of primary alcohols, secondary alcohols participate in transes-
terification reactions to provide good yields for most alcohols. No significant
electronic effect is observed when electron-releasing and electron-withdrawing
substitutents on aromatic secondary alcohols (Table 22, entries 2–4). A steric
effect is observed with cyclohexanol derivatives. Increasing the a-substituent from
hydrogen to methyl or tert-butyl dramatically decreases efficiency of transesterifi-
Table 21 NHC catalyzed transesterification
Mes N N Mes
O O
0.5 mol% 3
HOR''
R OR' 4Å MS, THF R OR''
267 268 269
Yield Yield
Entry 267 268 (%) Entry 267 268 (%)
1 O 99 3 O
Me HO Ph 93
Me O Me OEt
HO
Me
Me
2 O O 100 4 O HOBn 95
HO
MeO
Me O OMe
O
OMe
Table 22 NHC catalyzed transesterification with secondary alcohols
O Cy N N Cy
O
HOR 5 mol% 272
Me OMe Me OR
270 4Å MS 271
Entry 271 HOR Yield (%) Entry 271 HOR Yield (%)
1 a OH 94 5 e 92
OH
Me
OH OH
R
Me
R
2 b R=H 93 6 f R=H 93
3 c R = CF3 96 7 g R = Me 67
4 d R = OMe 85 8 h R = t-Bu 9
cation (Table 22, entries 6–8). Nolan and co-workers found that isolated
1,3-bis(cyclohexyl)-imidazol-2-ylidene performs more efficiently than the in situ
generated carbene for this transformation.
Nolan and co-workers have extended the scope of transesterification reactions to
include phosphonate esters as phosphorylating agents [137]. In this publication the
authors use dimethyl methylphosphonate 273 and benzyl alcohol with a variety of
imidazolylidene carbenes (Table 23). The use of molecular sieves to absorb methanol
leads to increased conversion; however, longer reaction times lead to decreased
Table 23 NHC catalyzed transesterification of phosphonate esters
O O O
R N N R
P HOBn P P
Me OMe 5 mol% catalyst Me OBn Me OBn
OMe OMe OBn
273 4Å MS, THF 274 275
Entry Catalyst R Time (h) Yield (%) 274/275
1 272 Cy 2 71 90:10
2 272 Cy 8 90 75:25
3 1 Adamantyl 2 35 100:0
4 276 t-Bu 2 32 100:0
5 3 Mes 18 0 –
Table 24 Amidation of unactivated esters with alkyl amines
O R''' Mes N N Mes

O R'''
R'' OH 5 mol% 3 OH
R OR' N R N
H THF
R''
276 277 279
Yield Yield
Entry Ester Amino alcohol (%) Entry Ester Amino alcohol (%)
O 8 O OH 66
OH H2N
H2N
R OR' O
R R’ 9 O OH 88
1 Bn Me 100 H2N
2 Ph Me 75 O
3 p-COMeC6H4 Me 87 10 N O Ph 86
4 p-CF3C6H4 Me 95
OMe H N OH
2
5 p-OMeC6H4 Me 31 11 O Me 77
6 Me Me 99 S
7 Me Bn 95 OMe Me
OH
H2N
product selectivity, as more diesterified product is observed (Table 23, entry 2).
This transformation is compatible with both in situ formed imidazolylidene carbene
and preformed carbene.
Movassaghi and Schmidt reported that amidation of unactivated esters also
occurs in the presence of carbene 3 when 1,2-amino alcohols are used [138]. A
representative sample of the range of esters 277 and amino alcohols 278 is shown
in Table 24. A few substrates proved problematic under standard reaction conditions,
entry 5, but the addition of anhydrous LiCl as an additive increases the yields
substantially.
A proposed mechanism for this transformation, provided in Scheme 42, is
based on the identification of alcohol-carbene complexes by Movassaghi and
Schmidt. Mesityl substituted imidazolinylidine carbene acts as a Brønsted
base as transesterification occurs to produce LXVII. Upon O → N acyl trans-
fer, the observed product is formed. The evidence provided for this mechanism
includes the control experiment in which LXVII is resubjected to the reaction
conditions and proceeds with amide formation. A similar mechanism has
recently been reported in a theoretical study of transesterification by Hu and
co-workers [139]. In light of this work, it seems reasonable to suggest a simi-
lar that mechanism is operative in the transesterification reactions discussed
throughout this section.
Mes O R
N OR'
O H O
N
Mes R O
R OR' Mes NH2
LXIII N O
H R' O
N
Mes
Mes H N
N 2
H O LXIV
N
Mes NH2
Mes
HOR' N
H R O
Mes N
HO O
N Mes R' O
H O
NH2 N LXV
R'
H2N
Mes LXVI
O O
NH2 OH
R O R N
H
LXVII
Scheme 42 Movassaghi et al. proposed catalytic cycle for amidation reaction
Suzuki and co-workers first published on the topic of enantioselective transes-

terification in 2004 [140, 141]. This process exploits C2-symmetric imidazolium
salts with various substitutions. When vinyl propionate 281 acts as the acyl donor,
ester 282 is isolated in 68% ee at 19% conversion, corresponding to an s value of
6.1 (Eq. 27).
Cl
R N N R
Me OH Me O Et
Me Me
O R = 1-napthyl O
3 mol% 283
O Et
t-BuOK, THF
280 281 282
68% ee
19% conversion
s = 6.1 (27)
Concurrently, Maruoka and co-workers illustrated the same reaction manifold to

produce the desired transesterification in high enantioselectivity [142]. Increasing
enantioselectivities and corresponding s factors were observed by changing the
acylating agent in the order of vinyl acetate, vinyl isobutyrate, vinyl pivalate, to the
highest enantioselectivity being achieved with vinyl diphenylacetate. The range of
aromatic substituted secondary alcohols that are competent nucleophiles include
both electron-rich and electron-deficient alcohols and provide desired esters in
good yields and very impressive s values up to 80 (Scheme 43).
NHCs have also been shown to promote the reaction of benzoins and methyl
acrylate to produce g-butyrolactones (Scheme 44) [143]. In the absence of dimeth-
ylimidazolium iodide, the reaction does not proceed. The mechanism is still under
investigation, although the authors propose that the transformation may proceed via
a tandem transesterification/intramolecular Michael addition LXVIII or Michael
O O
5 mol% 283
Ph HOR Ph
O t-BuOK, THF, −78 C OR
Ph Ph
O Me O Et O Me
Ph Ph Ph
O Ph O Ph O
Ph Ph Ph
F
284 285 286
s = 80 s = 38 s = 42
O Me O Me O Me
Ph Ph Ph
O O O
Ph Ph Ph
OMe
287 288 289
s = 48 s = 56 s = 47
Scheme 43 Maruoka et al. enantioselective acylation of secondary alcohols

addition/lactonization LXIX pathway. Aromatic aldehydes, for in situ benzoin

formation, are suitable substrates in this reaction.
I O
OH
R O Me N N Me
20 mol% 292 O R
R OMe
O t -BuOK, 4Å MS R
R = Br, Cl, F, Me, OMe THF O
290 291
32-76% yield
O OMe
O
O HO
R R
or
R R
O O
LXVIII LXIX
Scheme 44 NHC promoted synthesis of g-butyrolactones
6.1 Ring Opening Polymerization
As mentioned previously, Hedrick and co-workers have done extensive work in

the field of transesterification/ring opening polymerization (ROP). Their first
report came in 2002 in which they showed imidazolinylidene carbenes catalyze
transesterification to form biodegradable polyesters [134]. These research groups
have made contributions using NHCs to catalyze living polymerization of lactide
and lactone with narrow polydispersity and predictable molecular weight [144,
145]. Thiazol-, imidazol- and imidazolinylidene carbenes are competent catalysts
although the thiazolylidene carbene is the least active catalyst. The authors pro-
pose nucleophilic attack of lactide by the in situ generated or free carbene to
deliver intermediate LXX (Scheme 45). Proton transfer occurs with the alcohol
that acts as an initiator, followed by alkoxide addition and release of the carbene.
Stereoselective polymerization has been accomplished using an imidazolylidene
catalyst [146].
The Hedrick and Waymouth groups have also studied methods for generating
NHC catalysts in situ for ROP without an external base [147–150]. Thermal gen-
eration occurs readily with chloroform adduct 295 and pentafluorophenyl adduct
296 [147, 149]. Both compounds perform well as polymerization catalysts
although 296 is stable at room temperature unlike 295. (Imidazol-2-ylidene)
O
Me R X N R Me O
O X = S, N O
Me HO OR
Et3N, THF n
O O Me
293 294
O
Me O Mes
Me
O O N
O
O
Me O Me N
Mes
O LXX
ROH
Mes N N Mes
RO
Me O Mes
Me O O N
HO
O
HO OR O Me N
O Me RO Mes
LXXI
Scheme 45 Proposed mechanism for ROP
silver(I)chloride salts, such as 297, are efficient catalysts for ROP [150]. Lactide
polymerization has also been shown to occur with yttrium, titanium, and zinc
complexes [151, 152].
Me Et
N N
Mes N N Mes Mes N N Mes Ag Mes N N Mes
N Cl N
H CCl3 H C6F5 Et Me H OR
295 296 297 298
Most recently, Hedrick and co-workers have illustrated the use of alcohol
adducts 298 as a sufficient catalyst/initiators for ROP, therefore eliminating the
need for external alcohol [153]. These adducts undergo carbene formation at room
temperature in THF. Additional advantages of these adducts, compared to free
NHCs, is that they are not moisture sensitive and they provide the opportunity to
synthesize more complex polymers (Eq. 28a). Star polyesters can be generated in
one step (Eq. 28b).
O
Me
O
O O Me
Mes N N Mes
Me
O H 293 O O a
H O O H O OH
Mes N N Mes Me
n
O
n
300
299
O
N Mes Me
Mes N O O
O H O OH
Mes Me O
N n
293 O Me b
N O O H O Me
H O OH
Mes H Mes N N Mes O O
n
n Me
O
301 302
(28)
7 Nucleophilic Catalysis
Nguyen and co-workers have developed a method for the alkylation of meso-
epoxides by a preformed NHC·AlEt3 complex (Eq. 29) [117, 154]. This method is
a natural extension of previous work utilizing triethylaluminum and catalytic phos-
phines for ring opening of epoxides [155].
Me Me
i -Pr i -Pr
N N
i -Pr i -Pr Et
5 mol%, 305 BF4
O
AlEt3 (2eq), PhMe OH
303 304
93% yield (29)
A difference in reaction efficiency was observed depending on the catalyst used.

Imidazolium salt 305 provides the highest yield of desired product. When pre-
formed complex 307 is subjected to the reaction conditions, trans-2-ethylcyclohex-
anol is detected by gas chromatography in 76% yield (Eq. 30). Alkylation starting
with free carbene 306 results in only 28% yield of desired alkylated epoxide.
KH AtEl3 Ar N N Ar
305 Ar N N Ar
Et
PhMe Al
Et Et
307 (30)
Wu et al. have added NHCs to their long list of methodologies for ring-
opening of aziridines [156]. The substrate scope is somewhat limited, although
non-activated aziridine, R = Bn, provides the desired product in 96% yield.
TMSN3, TMSI, and TMSCl prove to be competent nucleophiles (Scheme 46).
The reaction time is reduced to less than 1 h with activated substrates, R = Ts,
in nearly quantitative yield. The transformation is regioselective, providing
attack of the nucleophile on the less substituted carbon of the aziridine. The
authors suggest that a coordination of the NHC and trimethylsilyl azide forms
a hypervalent silicon complex that opens the aziridine (LXXII, Scheme 46).
Additionally, Wu and co-workers have shown regioselective ring-opening of
aziridines with acid anhydrides mediated by imidiazolinylidene 3 [157]. This path-
way requires the use of an electron withdrawing tosylated aziridine 310 in order
for the reaction to proceed. The mild reaction conditions allow for a variety of
products to be formed in high yields (Table 25).
Mes N N Mes
NHR
NR 5 mol% 3
TMSN3, THF N3
308 309
Ar N N Ar
RN
R2
Me
R1 N3 Si
Me
Me
LXXII
Scheme 46 Ring opening of aziridines catalyzed by NHCs
Table 25 NHC catalyzed acid anhydride ring opening of aziridines
R R NHTs
O O Mes N N Mes R OCOR''
NTs 5 mol% 3
R'' O R'' R' OCOR'' R' NHTs
R' DMF, 80 C
310 311 312 313
Yield (%)
Entry 312 Product Yield (%) Entry 312 Product (306/307)
NHTs NHTs
OCOMe
n-C6H13
OCOR
1 a R = Me 96 7 g R = Me 80
2 b R = Et 96 8 h R = Et 80
3 c R = Ph 91 9 i R = Ph 98
NHTs OCOR
OCOR NHTs
n-C4H9 Ph
4 d R = Me 94 10 j R = Me 70 (9:1)
5 e R = Et 81 11 k R = Ph 70 (10:1)
6 f R = Ph 99
In an attempt to use an acyl anion equivalent to open an aziridine, Wu and

co-workers isolated an unexpected ring opened product 316 (Eq. 31) [158]. The
authors found that the presence of oxygen was the determining factor between
benzoin formation and ester formation. No desired ketones were ever formed.
Various aromatic substituted aldehydes were treated under standard reaction condi-
tions to afford esters in good yields. 4-Methoxybenzaldehyde provided product in
only 40% yield, presumably due to the ease of aldehyde oxidation.
Cl
O Mes N N Mes NHTs
NTs 5 mol% 200
R H K2CO3, 18-crown-6 OCOR
R = Ar, i-Pr, Cy, vinyl
314 PhMe 316
315
40-95% (31)
The authors’ proposed mechanism involves initial attack of an in situ formed
carbene onto the aldehyde to produce tetrahedral intermediate LXXIII (Scheme 47).
Proton transfer would produce an acyl anion equivalent, but is inconsistent with
product formation. Instead SN2 displacement to produce ring opened intermediate
LXXIV is proposed, followed by proton transfer. At this point, molecular oxygen
apparently becomes involved to oxidize nucleophilic alkene LXXV. The active
catalyst is then regenerated and observed product is formed.
R
R NTs
TsN
R
R O
Mes
H N
O Mes R
H LXXIV N
O N
R Mes
N
R H Mes LXXIII
R NHTs
R O Mes
Mes N N Mes
N
R
LXXV N
NHTs Mes
O R
R R NHTs O2
R O R NHTs
R O Mes
O O
N R O Mes
R O
LXXVII N N
R
Mes LXXVI N
Mes
Scheme 47 Proposed mechanism of aziridine ring opening under aerobic reaction conditions
catalyzed by NHC
Table 26 Trifluoromethylation of aldehydes catalyzed by NHCs
N N
O OH
TMSCF3 0.5-10 mol% 1
R H R CF3
317 318 DMF 319
Entry 319 Product Yield (%) Entry 319 Product Yield (%)
1 a OH 73 4 e OH 84
Ph CF3 Ph CF3
2 b OH 86 5 f OH 85
CF3 CF3
Me
Cl
O
3 c OH 81 6 g OH 62
CyO Me
CF3 CF3
O
4 d OH 89 7 h OH 85
Me
Ph CF3 CF3
O2N
Trifluoromethylation can be achieved with the use of imidazolylidene carbene 1

[159]. Song and co-workers found this transformation is tolerant of both electron-
rich and electron-poor aldehydes (Table 26). Even enolizable aldehydes undergo
trifluoromethylation in 81% yield (entry 3). Selective reaction occurs with an alde-
hyde in the presence of a ketone in the substrate (entry 5). The use of activated
ketones as acceptors leads to tertiary alcohols in good yields (entries 7 and 8).
Song et al. extended this methodology to include cyanosilylation of aldehydes
and ketones (Eq. 32) [160]. They propose that NHC 276 interacts with TMSCN to
form complex LXXVIII followed by cyano group transfer to the aldehyde
(Scheme 48). The carbene is then regenerated and the desired product is obtained
when LXXIX fragments. Concurrently, Kondo, Aoyama and co-workers describe
similar reaction conditions for the synthesis of cyanohydrins in high yields [161,
162], while Suzuki and co-workers reported a cyanosilylation of aromatic and
aliphatic aldehydes in good yields [163].
t-Bu N N t-Bu
O OTMS
0.5 mol% 276
Me H
TMSCN
Me CN
(32)
THF, 10 min
320 321 322
95%
N t-Bu
t-Bu N
Me Si Me O
TMSCN Me
CN R R'
LXXVIII
N t-Bu
t-Bu N
N t-Bu
t-Bu N
Me Si Me
Me
OTMS
O R
CN
R R' LXXIX
NC R'
Scheme 48 Proposed mechanism for cyanosilylation of aldehydes and ketones
Kondo, Aoyama and co-workers expanded this chemistry to include aldimines

and ketimines in good yields under mild reaction conditions (Scheme 49) [164,
165]. Maruoka and co-workers also report cyanosilylation of tosyl and benzyl
imines [166].
She and co-workers took advantage of the acyl anion equivalent formed from the
addition of an NHC to an aldehyde to catalyze the formation of benzopyranones via
an intramolecular SN2 displacement (Scheme 50) [167]. Various aromatic alde-
hydes provide alkylation products in moderate yields when the leaving group is
either tosylate or iodide. No reaction was observed when phenyl or methyl was
placed alpha to the leaving group.
Cl
N Mes
Mes N
NX NHX
5 mol% 200 CN
TMSCN
R R' KOt-Bu, THF R R'
321
NHTs NHTs NHBoc
CN
Ph CN Cy CN Ph Me
323 324 325
97% 87% 80%
NHBn NHBn NHTs

CN CN CN
i-Pr i-Pr Ph Me Ph Ph
326 327 328
84% 93% 98%
Scheme 49 Representative products formed via cyanation of aldehydes

When an aromatic group is placed sy to the leaving group, a new set of prod-
ucts is formed 332 (Scheme 51). Benzofuranones are formed in poor to good
yields with no detection of the SN2 product. The authors argue that carbocation
intermediate LXXXII is formed due to stabilization at the benzylic position fol-
lowed by formation and subsequent nucleophilic attack of the acyl anion
equivalent.
HO
Me
I
O O
S
N Me
Br Br
H 25 mol% 54
OTs DBU, xylene, reflux
O O
329 330
76%
Scheme 50 Formation of benzopyranone via SN2 reaction catalyzed by NHC
O O
Ar 25 mol% 54
R R Me
OTs DBU, xylene, reflux O Ar
O
331 332
R = Br, OMe
Ar = Ph, 4-ClC6H4
Proposed mechanism:
O O O
Ar Ar Ar
H
OTs
O O O
LXXX LXXXI LXXXII
Scheme 51 NHC catalyzed substitution reaction
Fu and co-workers describe Umpolung reactivity of Michael acceptors catalyzed

by triazolinylidene carbenes (Eq. 33) [168]. Nucleophilic addition followed by
tautomerization renders the b position of the Michael acceptor nucleophilic, which
subsequently undergoes alkylation. Compatible leaving groups include Br, Cl, and
OTs. a,b-unsaturated esters, nitriles, and amides all provide good to excellent
yields of cyclized products.
Ph
N ClO4
EWG N N EWG
X MeO OMe
10 mol% 335
(33)
n K3PO4, glyme, 80 C n
n = 0-2
X = Br, Cl, OTs 334
333 48-94%
NHC catalyzed reactions have been expanded to include reactions such as aza-
Morita-Baylis-Hillman and Mukaiyama aldol reactions. Ye and co-workers illus-
trate the utility of NHCs in a reaction that is traditionally catalyzed by amines and
phosphines (Scheme 52) [169].
i-Pr i-Pr
N N
O O NHTs
NTs i-Pr i-Pr
10 mol% 336
Ar H Ar
n PhMe n
O NHTs O NHTs O
O NHTs
NHTs
Cl
Ph
Me OMe
337 338 339 340
96% 85% 82% 99%
O NHTs O NHTs O NHTs
Ph
Cl OMe
341 342 343
86% 98% 72%
Scheme 52 Reaction scope of the aza-Morita-Baylis-Hillman catalyzed by NHCs
Song and co-workers have taken a variety of aldehydes 344 and treated them
with N-adamantyl carbene 1 and trimethylsilyl ketene acetal 345 to produce
Mukaiyama aldol products 346 in good yield (Eq. 34) [170]. The carbene presum-
ably acts as a Lewis base to activate the silicon – oxygen bond in order to promote
reactivity of the enol silane. The catalyst loading can be reduced to as low as
0.05 mol% without a change in yield.
N N
OTMS OH
O
Me CO2Me
OMe 0.5 mol% 1 R (34)
R H Me Me
R = Ar, t-Bu, i-Pr Me THF, then HCl
344 345 346
60-91% yield
The authors presented one example of 2,2,2-trifluoroacetophenone as a coupling

partner with 345 (Eq. 35), suggesting that the reaction proceeds through a pentava-
lent silicon complex similar to that in Scheme 46.
OTMS OH
O Me 0.5 mol% 1 F 3C CO2Me
OMe Ph
Ph CF3 Me THF, then HCl Me Me (35)
347 345 348
87%
Silyl enol ethers are inherently less reactive than silyl ketene acetals but are
competent partners in this reaction with increased reaction times. Electron- defi-
cient aldehydes provide the highest yields while 4-methoxybenzaldehyde proceeds
in only 10% yield after 65 h (Eq. 36).
O OH O
OTMS
0.5 mol% 1
H Ph
Ph THF, 0 C, 65h
R then HCl R (36)
349 350a, R = OMe 10%
350b, R = Cl 60%
350c, R = NO2 84%
As shown in previous sections, NHCs promote acyl transfer in transesterifica-

tion reactions. In a similar manner, O → C acyl transfer can be achieved with
substrates such as 351 in the presence of 0.9–4 mol% of triazolium pre-catalyst
353 and KHMDS (Scheme 53). Moderate yields are obtained by varying substitu-
tion of the oxazole from R = Me, Ph, i-Bu, and i-Pr [171]. Deprotonation of the
triazolium salt followed by nucleophilic addition to the carbonate moiety of the
oxazole results in enolate intermediate LXXXIII and activated carboxylate
LXXXIV. Enolate addition and regeneration of the active catalyst provides
quaternary stereocenters 352.
OR' N BF O
O 4
N N Ph O
O O CO2R'
R 0.9-4 mol% 353 N R
N MeO
MeO KHMDS, THF
351 352
O N
O N N Ph
Ar N R
R'O O
LXXXIII LXXXIV
Scheme 53 NHC promoted O → C acyl transfer
Louie and co-workers have shown the utility of NHCs in the cyclotrimerization
of isocyanates [172]. Isocyanurates were obtained in excellent yield with catalyst
loading as low as 0.001 mol% (Eq. 37).
i-Pr i-Pr
N N O
Ph Ph
i-Pr i-Pr N N
Ph N C O 0.001 mol% 356 O N O (37)
354 neat Ph
355
98%
8 Conclusion
The use of stable nucleophilic carbenes as catalysts for organic transformations

has come a long way since Ukai’s original demonstration of their efficacy in the
benzoin reaction. The last 10 years in particular have seen a tremendous explo-
sion in interest in this area, with new reactivity manifolds having been developed
across a range of reaction subtypes. It is clear that with many of these shortcom-
ings remain – functional group compatibility, turnover frequency, turnover
number and, naturally, expansion of substrate type. The inherent tunability of
these catalysts promises great latitude in overcoming these issues. That, coupled
with an increase in new reactivity, from Umpolung type reactivity best exempli-
fied by the benzoin and Stetter reactions to redox catalysis, nucleophilic cataly-
sis and even Morita-Baylis-Hilman reactivity, suggests that nucleophilic carbene
catalysts will likely remain useful tools in organic synthesis for the foreseeable
future.
Acknowledgements The authors thank Jeffrey B. Johnson (Hope College), Javier Read de
Alaniz, Mark S. Kerr and the Rovis group (CSU) for their careful reading of the manuscript.
Support for our own efforts in this area has been provided by the National Science Foundation
(CAREER) and the National Institutes of General Medical Sciences (GM72586). J.L.M. thanks
the NIH for the Ruth L. Kirschtein NRSA pre-doctoral fellowship. T.R. thanks Johnson and
Johnson, Eli Lilly, and Boehringer Ingelheim for unrestricted support, and the Monfort Family
Foundation for a Monfort Professorship. T.R. is a fellow of the Alfred P. Sloan Foundation.
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Top Curr Chem (2010) 291: 145–200
DOI: 10.1007/128_2008_23
Published online: 23 April 2009
Brønsted Base Catalysts
Amal Ting, Jennifer M. Goss, Nolan T. McDougal, and Scott E. Schaus
Abstract Chiral organic Brønsted bases have emerged as highly efficient catalysts
for enantioselective transformations. Since their early use in enantiomeric separa-
tion processes, chiral organic Brønsted base catalysis has advanced significantly
to include both natural and designed catalysts. Insight into the mode of action of
the organocatalysts has promoted modifications in catalyst structures to expand the
application to numerous asymmetric reactions. Bifunctional catalysts, containing
both Brønsted base and H-activating functionalities, have proven to be very appli-
cable to an array of reaction types. The development of Brønsted base catalysts
containing or not containing H-activating moieties, has greatly impacted asym-
metric organocatalysis. This overview illustrates the recent developments in this
emerging field.
Keywords Asymmetric organocatalysis • Bifunctional catalyst • Brønsted base •

Chiral scaffold • Cinchona akaloid • Cyclohexane-diamine • Guanidine
Contents
1 Introduction......................................................................................................................... 146
2 Cinchona Alkaloids............................................................................................................ 147
2.1 Cinchona Alkaloids in Asymmetric Transformations............................................... 149
2.2 Asymmetric Conjugate Addition with Enones and Enals.......................................... 149
2.3 Asymmetric Conjugate Additions with Imines.......................................................... 152
2.4 Asymmetric Conjugate Addition with Diazo Substrates........................................... 155
2.5 Asymmetric Conjugate Addition with Nitroalkenes and Sulfones............................ 157
2.6 Asymmetric Conjugate Addition of Nitriles.............................................................. 160
2.7 Asymmetric Conjugate Additions with α-Ketoesters................................................ 161
2.8 Cycloaddition Reactions with 2-Pyrones................................................................... 162
3 Chiral Cinchona Alkaloid-Derived Thiourea...................................................................... 163
A. Ting, J.M. Goss, N.T. McDougal, and S.E. Schaus (*

ü)
Department of Chemistry, Center for Chemical Methodology and Library
Development Boston University, 24 Cummington Street, Boston, MA 02215, USA
e-mail: seschaus@bu.edu
146 A. Ting et al.
3.1 Asymmetric Conjugate Addition of Nitro-Olefins.................................................... 164

3.2 Asymmetric Conjugate Addition of Aldehydes and Enones..................................... 167
3.3 Asymmetric Conjugate Addition with Imines........................................................... 170
4 Chiral Cyclohexane-Diamine Catalysts.............................................................................. 172
4.1 Discovery and Mechanism......................................................................................... 172
4.2 Asymmetric Conjugate Additions.............................................................................. 173
4.3 Asymmetric Mannich Additions................................................................................ 180
4.4 Dynamic Kinetic Resolution...................................................................................... 184
5 Chiral Guanidine Catalysts................................................................................................. 185
5.1 Discovery and Mechanism........................................................................................ 186
5.2 Conjugate Additions.................................................................................................. 188
5.3 Asymmetric Diels-Alder Reactions........................................................................... 193
6 Additional Brønsted Base Catalysts.................................................................................... 194
6.1 Chiral Binaphthyl-Derived Amine............................................................................. 195
6.2 Chiral Paracyclophane-Derived Imine....................................................................... 195
7 Conclusion.......................................................................................................................... 197
References ............................................................................................................................... 198
1 Introduction
Chiral organic Brønsted bases have emerged as highly selective and efficient cata-
lysts for enantioselective synthesis. Initially described in 1913 for enantioselective
hydrocyanation to aldehydes [1] and later more broadly developed by Wynberg in
the 1970s and 1980s [2], chiral organic Brønsted base catalysis has evolved as the
result of mechanistic understanding and catalyst design to address challenges in
synthetic methodology. Over the past two decades, new catalyst development has
benefited significantly from mechanistic studies and insightful observations about
Brønsted base and hydrogen bond donor activation of substrates [3–6]. Bifunctional
catalyst design has been elegantly incorporated into catalyst design to activate both
nucleophiles and electrophiles during the bond formation process. These advances
in mechanistic understanding and catalyst design have resulted in an ever-increas-
ing number of new methodologies and synthetic transformations (Fig. 1).
The advent of chiral Brønsted base catalysis began with the recognition that the
Cinchona alkaloids serve as excellent catalysts [7–12] and privileged structures
Chiral Brønsted Base Catalysts Chiral Bifunctional Catalysts
Brønsted chiral
X H
Brønsted chiral base scaffold
X H
base scaffold
Y H Brønsted acid
Fig. 1 Chiral Brønsted bases catalyst design

Brønsted Base Catalysts 147
[13]. Systematic evaluation of structural variants led to a better understanding of the

properties crucial for enantioselective catalysis. The importance of a rigid backbone
with basic functionality and the absence or presence of a hydrogen-bond donor
within the same catalyst structure has resulted from these studies. Such realizations
have led to the synthesis of novel Cinchona alkaloid-based catalysts with modified
hydrogen-bond donor capabilities and broadened the scope of their utility. Later
developments have reinforced the understanding of this motif with the use of the
cyclohexane diamine by Jacobsen [14] and Takemoto [15]. The development of
these catalysts and the evolution of chiral organic Brønsted bases for enantioselec-
tive catalysis illustrate the importance of mechanistic insight achieved to date.
2 Cinchona Alkaloids
The direct role of Cinchona alkaloids in asymmetric synthesis proves its versatility
in the field of chiral base catalysts, promoters, and ligands. Early studies up until
the late 1980s on the use of Cinchona alkaloids in asymmetric synthesis were
conducted by Pracejus [16, 17], Morrison and Mosher [18], and Wynberg [16, 17].
Key development of reactions at that time included ketene chemistry used in
asymmetric b-lactone synthesis [19–23], and asymmetric induction in dihydroxy-
lation and desymmetrization [24–27]. The first catalytic enantioselective conju-
gate addition was documented in Wynberg’s [2] seminal work on Cinchona
alkaloid-catalyzed addition of cyclic b-ketoesters to methyl vinyl ketone (MVK).
The basicity of the quinuclidine nitrogen of Cinchona alkaloids combined with the
Brønsted acidic C(9)–OH, confers a bifunctional catalytic property to Cinchona
alkaloids (Fig. 2). Acting as a bifunctional organocatalyst or ligand, Cinchona
alkaloids are key contributors in asymmetric reactions and enantioselective trans-
formations of conjugate additions (Strecker, Baylis–Hillman, Michael, Mannich,
Aldol, and Henry), cycloaddition reactions, phase-transfer reactions (PTC), b-lactone
synthesis, aziridination, desymmetrization studies, decarboxylations, epoxidations,
and hydrogenations [7].
H
H OH
OH Bifunctional catalysis of cinchona alkaloids
N N
C(9) C(9)
H N X2O
N H C(6') chiral Brønsted base
*
1 cinchonine (C) 2 cinchonidine (CD) N NR3
C(9)
OCH3 quinuclidine nitrogen
OCH3
(C6') H H
(C6') OX1
OH
OH
N X1= H, for hydrogen-bonding
R C(9)
C(9)
N X2= R (any functional group), for steric tuning
H N
N H
4 R = CH = CH2, quinidine (QD)
3 quinine (Q) 5 R = CH2-CH3, dihydroquinidine (DHQD)
Fig. 2 Cinchona alkaloids as bifunctional catalysts

148 A. Ting et al.
The notable mode of stereoselectivity of Cinchona alkaloids is presented by

its pseudoenantiomeric pairs which can be employed to generate either enanti-
omer of chiral product. Key moieties that are central to Cinchona alkaloids are
the quinuclidine nitrogen and the adjacent C(9)–OH (the N–C(8)–C(9)–OH
moiety) (Fig. 2). In pseudoentiomeric alkaloids in the natural open conforma-
tion, the torsion angle N–C(8)–C(9)–O are opposite in sign: Q and CD are (−),
and thereby induce selectivity for one enantiomer, whereas QD and C are (+) and
afford the other enantiomer [28, 29].
Cupreines and cupreidines are pseudoenantiomers of Cinchona alkaloids with
the replacement of quinoline C(6¢)–OCH3 with an OH–group. The result is availa-
bility of an additional hydrogen-bonding moiety.
The focus of this review is to discuss the role of Cinchona alkaloids as
Brønsted bases in organocatalytic asymmetric reactions. Cinchona alkaloids
are Lewis basic when the quinuclidine nitrogen initiates a nucleophilic attack to
the substrate in asymmetric reactions such as the Baylis-Hillman (Fig. 3),
b-lactone synthesis, asymmetric a-halogenation, alkylations, carbocyanation of
ketones, and Diels-Alder reactions 30–39] (Fig. 4).
Lesser discussed is an equally significant and recent role of Cinchona alka-
loids as Brønsted bases. Cinchona alkaloids are mechanistically categorized as
Brønsted bases when the nitrogen moiety complexes to a proton (either via par-
tial deprotonation or protonation), resulting in the chiral intermediate species
essential to the stereodirecting and facial selectivity step. The earliest example
is Hiemstra and Wynberg’s [40] 1,4-addition of thiophenols to cyclohexenones.
The quinuclidine nitrogen deprotonates the thiol in conjunction with stabiliza-
tion of the enolate through hydrogen-bonding of the C(9)–OH moiety of the
catalyst.
Modified Cinchona alkaloids catalysts have been developed in the last two dec-
ades to enhance further the bifunctional mode of the catalyst. Derivations at the
C(9)–OH group, replacement of quinoline C(6¢)–OCH3 with a hydroxyl group to
enhance hydrogen bonding, syntheses of bis-Cinchona alkaloids, and development
of thiourea-derived Cinchona alkaloids are most notable.
H
H
S H N
H N H
O N
N H H
OH O
SH H
OCH3 O
OCH3
Fig. 3 Cinchona alkaloids as Lewis bases in the Baylis-Hillman reaction

OH
OH O CH3
O
O
R2 OR1 N
OR1
N H
CF3
R1 =
CF3
CH3 OH
O CH3
O O
N OR 1 O
N OR1
N H H
N H
O R2
O H H
R2 H
Fig. 4 Cinchona alkaloids as Brønsted base catalysts
2.1 Cinchona Alkaloids in Asymmetric Transformations
Asymmetric transformations that employ Cinchona alkaloids as Brønsted bases

will be discussed. Acting as a chiral Brønsted base, the quinuclidine nitrogen
together with hydrogen bonding moieties of the catalyst have promoted several
remarkable enantioselective reactions. The reactions highlighted here will focus
on asymmetric conjugate additions, subdivided into substrate categories of enones,
imines, azodicarboxylates, nitroalkenes, sulfones, nitriles, and a-ketoesters.
2.2 Asymmetric Conjugate Addition with Enones and Enals
The wide range of Michael donors and acceptors in 1,4-additions are of great util-
ity. Consequently, further exploration on the addition of a-substituted b-ketoester
addition to a,b-unsaturated ketones have captured the attention of many chemists.
The transformation is a versatile methodology to access all-carbon quaternary
stereocenters.
a,b-Unsaturated aldehydes are highly active towards nucleophilic reactions.
Using Cinchona alkaloids-derived catalysts, Deng et al. investigated the viability of
conjugate addition reactions with a,b−unsaturated aldehydes and 1,3-dicarbonyl
donors [41].
150 A. Ting et al.
Preliminary mechanistic studies show no polymerization of the unsaturated alde-

hydes under Cinchona alkaloid catalysis, thereby indicating that the chiral tertiary
amine catalyst does not act as a nucleophilic promoter, similar to Baylis-Hillman
type reactions (Scheme 1). Rather, the quinuclidine nitrogen acts in a Brønsted basic
deprotonation-activation of various cyclic and acyclic 1,3-dicarbonyl donors. The
conjugate addition of the 1,3-dicarbonyl donors to a,b-unsaturated aldehydes gener-
ated substrates with all-carbon quaternary centers in excellent yields and stereose-
lectivities (Scheme 2) Utility of these all-carbon quaternary adducts was demonstrated
in the seven-step synthesis of (+)-tanikolide 14, an antifungal metabolite.
<No polymerization of acrolein observed. >
Lewis base
(nucleophilic initiation) O O
O
O NR3 O H H
H O
H H polymerization
H
R3N
R3N
Scheme 1
OH OH
H OR H OR
N N
H N H N
Cl N Ph
DHQD-6a R= N QD-7a R=
Ph
O CN DHQD-6a (10 mol %) EtO2C CN

+ XX > 99% yield
H Ph CO2Et Ph
CH2Cl2, 6h 95.5 : 4.5 er
O
8 9 H
O O O O
O O
QD-7a (10 mol 5) C7H15CHI2
Ot-Bu Ot-Bu
8 + Ot-Bu
CH2Cl2, −24 C, 12h CrCl2 /DMF, THF
10 52% for 2 steps
11 O 12
H
C7H15
> 99 : 1 er
1. LiAlH4, Et2O
90%
2. 10%Pd/C, H2
for 3 steps
O 3. NaOCl, AcOH
OH O OH
O
mCPBA
C11H23 TfOH (cat.) C11H23

(+)-tanikolide 14 87% 13
> 99 : 1 er
Scheme 2
OH
H
OR
N
N H
R= (PHN)
Q-7b
O O O CF3
O O CF3 Q-7b (20 mol %) *
+ *
O CF3
O CF3 CH2Cl2, 23 oC, 2h 17 95% yield
15 16 O 93 : 7 dr, 97.5 : 2.5 er
O O O CF3
Q-7b (20 mol %) *
+ CH3 O CF3
15 *
CH2Cl2, 23 oC, 20h
Et Et O 19 83% yield
18 H3C 86 : 14 dr, > 99 : 1 er
Scheme 3.
The first organocatalyzed conjugate addition of a-substituted b-ketoester to

a,b-unsaturated ketones was presented by Deng et al. [42] (Scheme 3). Although
traditional Cinchona alkaloids were efficient catalysts for conjugate addition of
carbon nucleophiles to nitroalkenes and sulfones, replacement of the C(9)–OH
with an ester group (Q-7b) showed great improvement in stereoselectivity. The
reaction is applicable to a variety of cyclic and acyclic enones (16, 18).
Enantioselective organocatalytic conjugate additions such as Michael and aldol
reactions have been intensely studied under new catalysts. However, only a few
organocatalyzed Michael reactions have been developed. The reaction involves
construction of a new C–N bond that is very attractive for syntheses of molecules
with biological properties.
The majority of the Michael-type conjugate additions are promoted by amine-
based catalysts and proceed via an enamine or iminium intermediate species.
Subsequently, Jørgensen et al. [43] explored the aza-Michael addition of hydra-
zones to cyclic enones catalyzed by Cinchona alkaloids. Although the reaction
proceeds under pyrrolidine catalysis via iminium activation of the enone, and also
with NEt3 via hydrazone activation, both methods do not confer enantioselectivity
to the reaction. Under a Cinchona alkaloid screen, quinine 3 was identified as an
effective aza-Michael catalyst to give 92% yield and 1:3.5 er (Scheme 4).
Substitution of the C(9)–OH with an ester (21) reduced selectivity to 1:2 er
although yield was quantitative. Substitution of quinoline C(6¢)–OCH3 (20) with
OH resulted in quantitative yield but no enantioselectivity. Dihydroquinine (22)
gave the highest er of 1:6 with 84% yield (Scheme 4).
152 A. Ting et al.
2.3 Asymmetric Conjugate Additions with Imines
Highly enantioselective organocatalytic Mannich reactions of aldehydes and ketones

have been extensively studied with chiral secondary amine catalysts. These secondary
amines employ chiral prolines, pyrrolidines, and imidazoles to generate a highly active
enamine or iminium intermediate species [44]. Cinchona alkaloids were previously
shown to be active catalysts in malonate additions. The conjugate addition of malonates
and other 1,3-dicarbonyls to imines, however, is relatively unexplored. Subsequently,
Schaus et al. [45] employed the use of Cinchona alkaloids in the conjugate addition of
b-ketoesters to N-acyl aldimines. Highly enantioselective multifunctional secondary
amine products were obtained with 10 mol% cinchonine (Scheme 5).
OH OCH3 OCH3 R
H H H
OH OR' OH
N N N
N H N H N H
R' =
20 21 3 R = CH=CH2, Q
22 R = CH2-CH3, DHQ
H3C
NH catalyst % yield er
N O 20 mol% catalyst O
toluene, 2h 20 100 1:1
+ 21 100 1:2
* N Q-3 92 1 : 3.5
N
DHQ-22 84 1:6
23 24 25 CH3 H
R R
N N
O H CH3 O H CH3
Ar Ar
H N H N
N N
Ar Ar
O O
Scheme 4
O
O OCH3 1. 10 mol% cinchonine
CH2Cl2 H 3C HN OCH3
H3 C + O N
2. 1 mol% Yb(OTf)3 BnHN Ph
O OCH3 H Ph BnNH2
26 27 28 O OCH3
95% yield
97 : 3 er
Scheme 5
The optically pure Mannich adducts were further converted to chiral dihydropy-
rimidones via two steps to offer 5-benzylpyrimidone in 96% yield and 95:5 er
(Scheme 6).
Following the cinchonine-catalyzed results, Schaus et al. [46] reported the use
of cyclic 1,3-dicarbonyl donors to access adjacent quaternary-tertiary stereogenic
centers. Under similar reaction conditions cyclic b-ketoester and 1,3-diketones
afforded the corresponding Mannich adducts in excellent yields and stereoselectivi-
ties (Scheme 7). The methodology was also applicable to aryl propenyl imines (32)
– a class of novel aliphatic imines.
O 1) Pd(PPh3)4 O
BnNCO Bn
O HN O dimethylbarbituric acid N NH
H3C Ph 2) AcOH, EtOH H3C Ph
O OCH3 µwave, 120 oC O OCH3

10 min
29 95 : 5 er 76% yield
30 95 : 5 er
Scheme 6
O
OCH3
O O 5 mol% O HN OCH3
O N cinchonine
CH3 +
H Ph CH2Cl2
O
31 32 H3C
33 98% yield
97.5 : 2.5 dr, > 99 : 1 er
O
OCH3 5 mol%
O O cinchonine O HN OCH3
O N
X Y + CH2Cl2 X Ph
H Ph O
Y
34 27 35
O O
O HN OCH3 O HN OCH3
Ph Ph
O O
H3C H3CO
35a 98% yield 35b 98% yield

99 : 1 dr, 96.5 : 3.5 er 99 : 1 dr, 95 : 5 er
Scheme 7
154 A. Ting et al.
1,3-Dicarbonyl donors bearing a thioester has been applied in the Mannich reac-
tion to N-tosyl imines. Ricci presented an enantioselective decarboxylative addition
of malonic half thioester 37 to imine 38. In the Mannich-type addition, catalyst 36
deprotonates the malonic acid thioester followed by decarboxylation to generate a
stabilized thioacetate enolate. This stabilized anion reacts with facial selectivity to
the imine due to steric-tuning from 36 [47] (Scheme 8).
Based on prior results where Ricci used Cinchona alkaloids as phase-
transfer-catalysts, the group proceeded to look at hydrophosphonylation of imines [48].
Employing the chiral tertiary amine as a Brønsted base, a-amino phosphonates
products were synthesized in high yields and good selectivities.
In the initial screening of various Cinchona alkaloids, the addition of diethyl phos-
phate 41 to N-Boc imine 40 in toluene revealed the key role of the free hydroxyl
group of the catalyst. Replacing the C(9)–OH group with esters or amides only results
in poor selectivity. Quinine (Q) was identified as an ideal catalyst. A mechanistic
proposal for the role of quinine is presented. Hydrogen-bonding by the free C(9)-
hydroxyl group and quinuclidine base activation of the phosphonate into a nucle-
ophilic phosphite species are key to the reactivity of this transformation (Scheme 9).
O O Ts
O HN
S OH
36 20mol% S R
H 3C
+
THF, 3 days CH3
O Ts H3C 39
37 N 0 oC O
O
R H 38
N
Ts Ts
O HN O HN N H
S S
OH
H3C 36-βICPD
H 3C
O O 39b 76% yield
39a 61% yield
84.5 : 15.5 er 82 : 18 er
Scheme 8
Boc N
N H
Boc N
H 3-quinine HN CH3 O H
(10 mol%) O H
+ P O H3CO O
40 xylene, 4h, −20 oC Boc
O O N P O
CH3 O CH3
P O
H CH3 42 69% yield, 96 : 4 er H Ar
O CH3
41 CH3
O
P O
H CH3
O
CH3
Scheme 9
HCN
O
+
N 4310 mol% F3C N OCH3 OCH3
Ph H CH2Cl2 Ph CN
44 then (CF3CO)2O 4595% yield N N N N
96 : 4 er H H
O O
H H H
N N NN N
O O N O N HO C NN
N
F3C N F3C N
CN CN 43 CH3
CH3
H3CO Br
95 : 5 er 92.5 : 7.5 er
Scheme 10
New catalyst design further highlights the utility of the scaffold and functional
moieties of the Cinchona alkaloids. bis-Cinchona alkaloid derivative 43 was devel-
oped by Corey [49] for enantioselective dihydroxylation of olefins with OsO4. The
catalyst was later employed in the Strecker hydrocyanation of N-allyl aldimines.
The mechanistic logic behind the catalyst for the Strecker reaction presents a chiral
ammonium salt of the catalyst 43 (in the presence of a conjugate acid) that would
stabilize the aldimine already activated via hydrogen-bonding to the protonated
quinuclidine moiety. Nucleophilic attack by cyanide ion to the imine would give an
a-amino nitrile product (Scheme 10).
Molecular modeling of the reaction predicts attack of the CN− ion on the re face
of the N-allyl benzaldimine carbon to provide an (S)-adduct. The aromatic ring of
the imine and the quinuclidine hydrogen bond stabilizes the iminium above the
pyridazine, blocking the rear face of the imine bond. Nucleophilic attack by CN− is
therefore steered to attack from the re face.
2.4 Asymmetric Conjugate Addition with Diazo Substrates
The use of diazodicarboxylates has been recently explored in Cinchona alkaloid

catalyzed asymmetric reactions. Jørgensen [50] reported the synthesis of non-biaryl
atropisomers via dihydroquinine (DHQ) catalyzed asymmetric Friedel-Crafts ami-
nation. Atropisomers are compounds where the chirality is attributed to restricted
rotation along a chiral axis rather than stereogenic centers. They are useful key
moieties in chiral ligands but syntheses of these substrates are tedious.
Amongst the class of aryl and biaryl atropisomers used in chiral ligand develop-
ment, there are few reports where the nitrogen atom is directly attached to the aro-
matic ring. Jørgensen employed the use of chiral tertiary amines for deprotonation
of the hydroxy group on 2-naphthol 46 followed by addition of tert-butyl-azodicar-
boxylate 47. The corresponding aminated naphthol compound was obtained in 99%
yield and 95:5 er with enantiomers that are readily separable by HPLC. The chiral
product containing both an amino- and hydroxy-functionality were converted to
chiral ureas and anilides in good yields without racemization (Scheme 11).
156 A. Ting et al.
Another type of Cinchona alkaloid catalyzed reactions that employs azodicarbo-

xylates includes enantioselective allylic amination. Jørgensen [51–53] investigated
the enantioselective electrophilic addition to allylic C–H bonds activated by a chiral
Brønsted base. Using Cinchona alkaloids, the first enantioselective, metal-free
allylic amination was reported using alkylidene cyanoacetates with dialkyl azodi-
carboxylates (Scheme 12). The product was further functionalized and used in
subsequent tandem reactions to generate useful chiral building blocks (52, 53).
Subsequent work was applied to other types of allylic nitriles in the addition to
a,b-unsaturated aldehydes and b-substituted nitro-olefins (Scheme 13).
O
H O
NH2 5 dihydroquinidine t-BuO
N
OH (4 mol%) NH2 N Ot-Bu
Boc
+ N OH
N DCE
Boc
46 47 48 99% yield
95 : 5 er
Boc
N N
Boc
*
NH2 H NR
O
Scheme 11
49a (DHQ)2PYR
Boc H3CO2C Bn
10 mol%
H3CO2C N
Bn + N CN N Boc
CH2Cl2, −24 oC N
CN Boc Boc H
50 47 51 89% yield
99 : 1 er
EWG R *NHR3 EWG R

E EWG * R
EWG' H EWG' * EWG' EH

HNR3
CN H3CO2C Bn CO2CH3
H3C CO2CH3 H2, Pd / C
H3C CH3
NHBoc CN N Boc CN
N N
H3C Boc toluene Boc H H
H Bn N N Boc
Bn 80 oC, 23h
51 89% yield, 99 : 1 er Boc
52 86% yield
> 15 : 1 dr, 99 : 1 er 53 90% yield
99 : 1 er
Scheme 12
49b NC CN NO2
NC CN
(DHQD)2PYR 10 mol%
H
+ R
NO2 acetone −40 oC R
54 55 56
NC CN NO2 NC CN NO2 NC CN NO2

H H H
S
56a 98% yield 56b 93% yield 56c 82% yield

99 : 1 dr, 97.5 : 2.5 er 99 : 1 dr, 98.5 : 1.5 er 99 : 1 dr, 97 : 3 er
Scheme 13
Construction of new C–N bonds via azodicarboxylates has also been explored
in other types of reactions. In the conjugate addition to a-substituted a-cyanoac-
etates, new C–N bond formation also generates a chiral quaternary center. Using
cupreidine as the catalyst, Deng [54] obtained excellent yields and selectivity in
the reaction of tert-butyl azodicarboxylates with a-aryl a-cyanoacetates. At
around the same time, Jørgensen [55] investigated the use of Cinchona alkaloids,
including modified alkaloids cupreine, cupreidine, and b-isocupreidine (b-ICPD)
(36) to carry out similar transformations.
b-Isocupreidines are Cinchona alkaloid derivatives with limited conformational
flexibility and increased basicity and nucleophilicity due to the increased ring strain
of the tricyclic skeleton. The C(6¢)–OH on b-ICPD offers two different sites of
simultaneous activation of nucleophile and electrophile to enhance basicity and
sterics of intermediate species.
Jørgensen’s reactivity screen with various Cinchona alkaloids in the reaction of
azodicarboxylate and a-aryl a-cyanoacetates showed almost quantitative yields
with the catalysts, although b-ICPD 36 was superior in terms of enantioselectivity
(Scheme 14) . The types of esters on the azodicarboxylate had a significant impact
on selectivity, the bulkier the ester group (tert-butyl), the higher the enantioselectivity.
The reaction is robust enough towards others pro-nucleophiles such as acyclic and
cyclic b-ketoesters to provide almost quantitative yields and 95:5 er (59, 60). Aryl,
heteroaryl, and aliphatic groups were all functionally tolerated, including varied
electronic and steric properties.
2.5 Asymmetric Conjugate Addition with Nitroalkenes

and Sulfones
Michael-type addition of stabilized carbon donors to electron-withdrawing a,b-

unsaturated systems is an efficient method for C–C bond construction. The nitro-group
158 A. Ting et al.
O
NC
Ot Bu CN CH3
H
Ph 36-βICPD (5 mol%) t BuO N
57 Boc O
+ Ph
N
Boc toluene, −78 C, 96h O Boc N
N
N 47 58 99% yield N H
Boc > 99 : 1 er
OH
O O Et O
36-βICPD
+ 47 36-βICPD (5 mol%) H
Et OPh PhO * N
N Boc
CH3 toluene, rt, 16h CH3
O Boc 59 99% yield, 95 : 5 er
36-βICPD (5 mol%) O O
O O + 47
*
Ot-Bu 60 99% yield, 94.5 : 5.5 er
Ot-Bu toluene, −52 C, 66h
N N Boc
Boc H
Scheme 14
has been a useful functionality in conjugate-type additions in terms of improving

reactivity and also producing nitro-products for further derivations in syntheses.
In addition to the efficient catalysis of cupreines and cupreidines in asymmetric
reactions with azodicarboxylates, these catalysts also demonstrate keen selectivity
with conjugate additions of nitroalkenes. Deng [56] reported high stereoselectivity
for the conjugate addition of nitroalkenes to several classes of trisubstituted carbon
nucleophiles (Scheme 15). The products include either carbon- or hetero-substituted
quaternary and tertiary stereocenters. Various malonates, cyclic and acyclic b-ketoesters
were investigated to offer excellent diastereo- and enantioselectivity. b-Substituted
1,3-diketones also gave similar results. Trisubstituted compounds that do not belong
to the 1,3-dicarbonyl class also promised good results, such as various a-substituted
a-cyanoacetate 72.
Wang and co-workers [57, 58] reported several Michael-type enantioselective addi-
tions with nitro-olefins. Under neat conditions, 1,3-dinitro compounds were generated
in the 74 addition of nitroalkanes 75 to various b-substituted nitro-olefins (Scheme 15).
Other Michael-type involving nitro-olefins reactions were illustrated using triazole
donors 77 to offer good yields and high enantioselectivities (Scheme 16).
Mechanistically similar to nitroalkenes, vinyl sulfones in asymmetric conjugate
additions to trisubstituted carbon nucleophiles give chiral adducts with all-carbon
quaternary centers. Conjugate additions with a-substituted a-cyanoacetates (68)
generate useful building blocks functionalized with the –CN and –NO2 groups (s70,
72). Using the same modified Cinchona alkaloids for conjugate additions of
nitroalkenes, Deng [59] reported the asymmetric conjugate addition of vinyl sulfones
to a-aryl and a-aliphatic cyanoacetates (Scheme 17). Enantioselectivity was most
evidently related to the types of Cinchona alkaloids use. Cinchona alkaloids with
C(9)–OR and quinoline C(6′)–hydroxy moieties gave significantly higher enantiose-
lectivity than the traditional catalysts with C(9)–OH and quinoline C(6′)–OCH3
N
OH RO
OH
H H OR
OR N H
N H H
N O
H N
N H O H O
O H
QD-61 Q-21 R = H
Q-62b: R = Bn ON
Q-7b R = H3C
(PHN) O
R = PHN
CH3
O O
CH3 Q-7b (10 mol %) O CH3
H3 C
NO2 + O CH3 NO2
o
THF −60 C, 48h O
63 C(O)CH3
64
65 82% yield, 98 : 2 dr, > 99 : 1 er
O O S
NO2 O
Q-21 (10 mol %)
OEt NO2
S 66
THF −20 oC, 74h CO2Et
67
68 91% yield, 98 : 2 dr, > 99 : 1 er
O
NO2 O2N
+ OEt Q-21 (10 mol %)
O2 N NO2
69 CH3
THF −20 oC, 60h H3C CO2Et
70
71 78% yield, 92 : 8 dr, 96 : 4 er
O
69 Q-62a (10 mol %)
+ NC
NC NO2
OEt
THF −50 oC, 6d
CH3 72 H 3C CO2Et
73 77% yield, > 92 : 8 dr, > 99 : 1 er
Scheme 15
R1 2010 mol% R1 N N
O2N R2 N 2010 mol%
N
R2 NO2 N + N
74 + neat, RT NO2 77 H o
NO2−25 C, CH2 2
Cl * NO2
NO2 Ar
Ar 76 R R
75 78 79
CH3 N N N
O2N CH3 O2N O2N N N N
N N N
NO 2 NO 2 NO2 * NO2
* NO2 * NO2
Cl Cl S
76a 79% yield 76b 82% yield 76c 80% yield 79a 87% yield 79b 79% yield 79c
88 : 12 er 94 : 6 er 93.5 : 6.5 er 85 : 15 er 90 : 10 er 83% yield
78.5 : 21.5 er
Scheme 16
160 A. Ting et al.
EtO2C CN Q-7b (20 mol %) EtO2C CN

+ SO2Ph Ar * SO2Ph
Ar −25 C
80 81a 82
EtO2C CN EtO2C CN EtO2C CN

* SO2Ph * SO2Ph * SO2Ph
S
97.5 : 2.5 er 98.5 :1.5 er 98.5 :1.5 er
EtO2C CN Q-7b (20 mol %) EtO2C CN

+ SO2Ar R * SO2Ar CF3
R 0 C
Ar =
83 81b 84 CF3
EtO2C CN EtO2C CN
* SO2Ar H3C * SO2Ar
84a 100% conversion 84b 100% conversion

76% yield, 97 : 3 er 85% yield, 96 : 4 er
Scheme 17
groups. a-Aliphatic a-cyanoacetates (83) which are less applied in conjugate addi-
tions (compared to aryl cyanoacetates) due to poor reactivity, proceeded relatively
well in the addition to vinyl sulfones that have enhanced electrophilicity (81b).
2.6 Asymmetric Conjugate Addition of Nitriles
The efficiency with which modified Cinchona alkaloids catalyze conjugate additions
of a-substituted a-cyanoacetates highlights the nitrile group’s stereoselective role
with the catalyst. Deng et al. [60] utilized this observation to develop a one-step con-
struction of chiral acyclic adducts that have non-adjacent, 1,3-tertiary-quaternary
stereocenters. Based on their mechanistic studies and proposed transition state model,
the bifunctional nature of the quinoline C(6¢)–OH Cinchona alkaloids could induce a
tandem conjugate addition-protonation reaction to create the tertiary and quaternary
stereocenters in an enantioselective and diastereoselective manner (Scheme 18).
The 1,3-tertiary-quaternary stereocenter moiety is prevalent in natural products.
Deng et al. [61] proceeded to investigate the conjugate addition of 2-chloroacrylo-
nitrile 88 with trisubstituted carbon donors. a-Cyanoketones and b-ketoesters pro-
ceeded well to give products containing 1,3-tertiary-quaternary stereocenters in
high yield. Depending on the type of substituent on C(9) of the catalyst, both cyclic
and acyclic donors achieved high diastereo- and enantioselectivity.
The utility of 1,3-tertiary-quaternary stereocenters was highlighted in the 7-step

transformation of adduct 92 to diol 93. Diol 93 was previously demonstrated used by
Ohfune [62] as a key intermediate in a 22-step syntheses of manzacidin A, a bromopyr-
role alkaloid with interesting pharmacological profile as an a-adrenoreceptor blocker
and serotonin antagonist (Scheme 19).
2.7 Asymmetric Conjugate Additions with a-Ketoesters
The nitroaldol reaction, particularly involving ketones has been relatively unexplored
in the field of asymmetric organocatalysis. Employing cupreines and cupreidines as
catalysts, Deng [63] presented an enantioselective nitroaldol reaction of a-ketoesters
OCH3
RO RO
H OR
N HO N HO
N H
H H
H N H H H
O O
H N
QD-85 R = PHN PHN: CN N C
QD-86 R = Ac H3CS C H3CS
H H3C CN CH
CH3 3
Cl
QD-86
CN CN Cl
Cl (20 mol%)
O + H3CS
H3C CN
CN toluene CH3
SCH3 O
rt, 96h
87 88 89 71% yield
10 : 1dr, 98.5 : 1.5 er
O QD-86 O
Cl
+ (10 mol%) CN
CN CN
toluene CN Cl
90 88 rt, 4h
91 95% yield
20 : 1 dr, 98 : 2 er
Scheme 18
Br
CN Cl 7 steps 4 steps
BocN NBoc HN N
H3CS HO OH O
CN N CO2H
CH3 H 3C H H H
O H3C
O
92 71% yield 93 70% yield, 96 : 4 er
(−)-manzacidin A
10 : 1 dr, 98.5 : 1.5 er single diastereomer
Scheme 19
162 A. Ting et al.
(95). The all-carbon quaternary products formed are highly functionalized with a
nitro group, hydroxyl group, and an ester functionality (Scheme 20). Utility of these
substrates are demonstrated in subsequent functionalization in to chiral b-lactam 99b
and a-methylcysteine 101, a key intermediate in the total syntheses of mirabazoles
and thiangazole, natural products with antitumour and anti-HIV properties.
Toru and Shibata [64] investigated the use of fluorinated a-ketoester 103 in
the enantioselective direct aldol-type reaction of oxindoles. The use of Corey’s
U-shaped bis-Cinchona alkaloid 102 was essential in achieving high enantiose-
lectivities in the reaction, as compared to other modified Cinchona alkaloids.
The methodology is a facile approach to generate oxindoles containing two
stereogenic centers. The mechanistic model and stereodetermination of the
transition state is based on Corey’s model for (DHQD)2 PHAL as discussed
earlier in the chapter [49]. With the catalyst in open conformation, deprotona-
tion of the oxindole by the quinuclidine nitrogen results in an enolate that could
be stabilized via hydrogen bonding and p-stacking in the U-shaped pocket. The
si-face of the oxindole is blocked by the quinoline ring, forcing the pyruvate to
approach the re-face instead. This facial selectivity is further stabilized by
hydrogen-bonding and through the quinuclidine nitrogen (Scheme 21).
2.8 Cycloaddition Reactions with 2-Pyrones
Diels-Alder reactions of 2-pyrones are efficient methods towards construction of

bridged cyclohexene derivatives for natural product syntheses. Early studies by
OH
HO NO2
O DQ-94(5 mol %) H OR
OEt
OEt H3C *
H3C N
CH3NO2 (10 equiv.) O
O H N
95 CH2Cl2, −20 C, 14h 96 92% yield
98 : 2 er QD-94: R = Bz
HO NO2 Ra-Ni, H2 HO NH2 TfN3 HO N3 CO2Et

OEt (1atm) OEt CuSO4 (cat.) OEt PPh3 H3C *
R * H3C * H3C * NH
O O O CH3CN
97a R = CH3, 97.5 : 2.5 er 98a 99a 84% yield 100a 80% yield
97b R = Ph, 97.5 : 2.5 er
BF3 Et2O
H3CO
Ra-Ni, H2
(1atm) SH
HO NH2 i - PrMgCl OH O H3CO

NH2
OEt Ph *
Ph * S * CO2Et
NH
O CH3
99b 38% yield
98b 97.5 : 2.5 er 101 56% yield, 96 : 4 dr
Scheme 20
N
RO
N H
H H
Early example of Cinchona alkaloid catalyzed O O
Diels-Alder of 2-pyrone and α,β−unsaturated aldehyde
O H
O
O
R
O O
DHQD-106 (5 mol%) O O
O
O O R3
+ + R2
R1 R3 Et2O, rt
R3 R1 HO OCH3
O HO
R2 R2 O R1 (C6')
OH H OH
107 108 109a 109b
N C(9)
dienophile exo:endo yield er
H N
O 97:3 100 95 : 5
Ph DHQD-106 R = (PHN)
Ph
O
CH3
24:76 65 95.5 : 4.5
O
CH3
Scheme 21
Okamura and Nakatani [65] revealed that the cycloaddition of 3-hydroxy-2-py-

rone 107 with electron deficient dienophiles such as simple a,b-unsaturated
aldehydes form the endo adduct under base catalysis. The reaction proceeds
under NEt3, but demonstrates superior selectivity with Cinchona alkaloids. More
recently, Deng et al. [66], through use of modified Cinchona alkaloids, expanded
the dienophile pool in the Diels-Alder reaction of 3-hydroxy-2-pyrone 107 with
a,b-unsaturated ketones. The mechanistic insight reveals that the bifunctional
Cinchona alkaloid catalyst, via multiple hydrogen bonding, raises the HOMO of
the 2-pyrone while lowering the LUMO of the dienophile with simultaneous
stereocontrol over the substrates (Scheme 22).
3 Chiral Cinchona Alkaloid-Derived Thiourea
Urea and thiourea derivatives have long been recognized for their hydrogen-bonding
activity. Mechanistic studies of urea and thiourea catalysis were extensively studied by
Kelly in Diels-Alder reactions [67], and Etter who further elucidated the role of chiral
thioureas using crystallographic studies [68]. Jørgensen et al. further explored dual
hydrogen-bonding activation in Diels-Alder and Claisen rearrangements [69, 70].
164 A. Ting et al.
N
RO
N H
H H
Early example of Cinchona alkaloid catalyzed O O
Diels-Alder of 2-pyrone and α,β−unsaturated aldehyde
O H
O
O
R
O O
DHQD-106 (5 mol%) O O
O
O O R3
+ + R2
R1 R3 Et2O, rt
R3 R1 HO OCH3
O HO
R2 R2 O R1 (C6')
OH H OH
107 108 109a 109b
N C(9)
dienophile exo:endo yield er
H N
O 97:3 100 95 : 5
Ph DHQD-106 R = (PHN)
Ph
O
CH3
24:76 65 95.5 : 4.5
O
CH3
Scheme 22
After the initial elucidation of hydrogen bonding abilities of thiourea catalysts,

utility of these catalysts were relatively limited in terms of enantioselectivity and
application to reaction types. Subsequent modification to enhance stereodetermina-
tion via novel catalyst design was extensively explored by many groups, notably
Jacobsen, Takemoto, Connon, Dixon, and Soós. Key modifications that signifi-
cantly improve catalyst performance involved tethering Cinchona alkaloids and
electron-withdrawing groups to construct a highly functionalized chiral thiourea.
Novel asymmetric conjugate-type reactions have been accomplished with
Cinchona alkaloid-derived chiral thioureas, including less traditional reactions such
as asymmetric decarboxylation [71]. In the following discussion, asymmetric reac-
tions involving nitro-olefins, aldehydes and enones, and imines will be highlighted
(Fig. 5).
3.1 Asymmetric Conjugate Addition of Nitro-Olefins
Using the addition of dimethyl malonate to nitro-olefins as the model reaction,

Connon et al. [72] in 2005 reported a highly functionalized Cinchona alkaloid-derived
chiral thiourea. Key functional groups were identified to enhance the catalyst’s stere-
odirecting properties. Aside from the advantage of a bifunctional Cinchona alkaloid
tethered at the C(9) position to the thiourea, the thiourea N-aryl group was also sig-
nificant. By using a non-Lewis basic, electron-withdrawing 3,5-bis(trifluoromethyl)-
phenyl group, excellent yield and enantioselectivity was achieved (Scheme 23).
Other types of conjugate additions with chiral thioureas were also explored by
Connon. b-Substituted nitro-olefins were used in the conjugate addition reaction
with dimethyl chloromalonate 115 to generate chiral, functionalized nitrocyclopro-
panes [73]. Utility of the nitrocyclopropanes was demonstrated in the one-step
modification towards other functionalized chiral building blocks (Scheme 24).
The conjugate addition of nitro olefins under chiral Cinchona-thiourea catalysis
has shown promising results with a variety of Michael donors. Dixon conducted a
screen of various chiral thioureas and identified catalyst 117 as a versatile catalyst
that works well with b-substituted nitro-olefins (78) [74]. Aromatic, heteroaromatic
Cinchona alkaloid-derived chiral thiourea catalyst

X1= H, for hydrogen-bonding XO
X2= R (any functional group), for steric tuning C(6') chiral Brønsted base
*
NR3
N C(9)
*
N H Thiourea for
S H-bond activation
N H
N-Aryl group aids substrate binding orientation Ar
Fig. 5 Roles of Cinchona alkaloid-derived chiral thiourea catalyst
NO2 H
O O H3CO H3C
110 (2−5 mol %)
H3CO + 111 H3CO OCH3 N CF3
toluene
NO2
O O 0 °C, 30h NH
N
H3CO OCH3 H3CO S N CF3
H
112 113 92% yield, > 99 : 1 er 110
Scheme 23
H
H3CO H3C
NO2 1) 110 (2.0 mol %) H N CF3
114 THF, rt, 24h H3CO2C CO2CH3
S + NO2
O O 2) DBU (1.05 equiv) NH
HMPA (0.1 M) N
H3CO OCH3 S N CF3
rt, 24 h S H
Cl
115 116 71% yield 110
> 99 : 1 dr
Scheme 24
166 A. Ting et al.
and aliphatic nitro-olefins all demonstrated high enantioselectivities in good yields

(Scheme 25). The strongly electron-withdrawing 3,5-bis(trifluoromethyl)-phenyl
moiety was necessary to enhance enantioselectivity of the reaction.
Dixon [75] also investigated the use of unconventional carbon donors, such as
the mandelic acid derivative 119 in the highly stereoselective addition to b-substituted
nitro-olefins. The Michael product 120 was formed smoothly and can be converted
in simple one-step procedures to generate various chiral building blocks for syntheses
(Scheme 26).
NO2 O O H
R 117 (10 mol %)
78
CH2Cl2 H3CO OCH3
O O N CF3
−20 °C, 30 h NO2
R
H3CO OCH3 118 NH
112 N
S N CF3
H
O O O O O O 117
H3CO OCH3 H3CO OCH3 H3CO OCH3
NO2 NO2 NO2
O
118a 95% yield8 118b 93% yield 118c 82% yield
97 : 3 er 97.5 : 2.5 er 91 : 9 er
Scheme 25
NO2 F3C O N
Ph O CF3
69 117 (5.0 mol %) F3C
O NH
O O CF3 CH2Cl2(1.0 M) OCH3 N
0 °C, 48h Ph S N CF3
O CF3 NO2 H
120 77% yield 117
119
> 99 : 1 dr, 85 : 15 er
H3CO
O OCH3 O O O OH
K2CO3 CF3 K2CO3
O2N OH CH3OH O2N O CF3 O 2N OH
Ph Ph H2O Ph
Ph Ph Ph
99% yield 120 51% yield
n - PrNH2 Zn/HCl
CH2Cl2 reflux
nPr
O NH O
HN
O2N OH OH
Ph 99% Ph 98%
Ph
Ph
Scheme 26
3.2 Asymmetric Conjugate Addition of Aldehydes and Enones
Nitroaldol (Henry) reactions of nitroalkanes and a carbonyl were investigated by

Hiemstra [76]. Based on their earlier studies with Cinchona alkaloid derived
catalysts, they were able to achieve moderate enantioselectivities between aro-
matic aldehydes and nitromethane. Until then, organocatalyzed nitroaldol reac-
tions displayed poor selectivities. Based on prior reports by Soós [77], an
activated thiourea tethered to a Cinchona alkaloid at the quinoline position
seemed like a good catalyst candidate. Hiemstra incorporated that same moiety
to their catalyst. Subsequently, catalyst 121 was used in the nitroaldol reaction
of aromatic aldehydes to generate b-amino alcohols in high yield and high enan-
tioselectivities (Scheme 27).
Novel aldol-type reactions under Cinchona-derived chiral thiourea catalysis
was reported by Wang et al. [78]. In their report, a novel cascade Michael-aldol
reaction was presented. The reaction involves a tandem reaction catalyzed via
hydrogen-bonding with as little as 1 mol% catalyst loading to generate a product
with three stereogenic centers (Scheme 28). In the reaction of 2-mercaptobenzaldehyde
128 and a,b-unsaturated oxazolidinone 129, the desired benzothiopyran 130 was
formed smoothly in high yield and excellent stereoselectivity.
1,3-Dicarbonyl donors are excellent Michael donors in asymmetric conju-
gate addition to a,b-unsaturated ketones. Wang and co-workers [79] applied
chiral Cinchona-thiourea catalyst 131 to various carbon donors in the addition
to aromatic enones. A diverse array of nucleophiles, mainly 1,3-dicarbonyls
proceeded smoothly in the conjugate addition to a,b-unsaturated enone 132
(Scheme 29).
Soós [80] reported novel thiourea catalyst 134 in an efficient Michael reaction
between nitromethane and chalcones to access chiral nitrocarbonyls in high enan-
tioselectivity (Scheme 30).
O 121 (10 mol%) OH

OBn
NO2
N CH3NO2 + H THF, −20 C, 48h
N 122 123
124 90% yield, 96 : 4 er
NH
O 121 (10 mol%) OH
S NH NO2
H THF, −20 C, 24h
122 + N
N
Boc Boc
F3C CF3 126 95% yield, 95.5 : 4.5 er
125
121
Scheme 27
168 A. Ting et al.
S
H
H3CO N N chiral scaffold
N CF3 H H
N
NH O O H
N
S N CF3 O N Ar O S
H
127 H
O OH O O
O O
127 (1 mol%)
N O N O
H
+ Cl(CH2)2Cl, rt, 1h
S
SH
128 129 130 90% yield
> 20 : 1 dr, > 99 : 1 er
Scheme 28
H
H3CO H3C
R
O X Y N
131 (10 mol%) O CF3
X Y *
CH3 xylenes, rt
+ 132
CH3 NH
R 96h N
133 S N CF3
131 H
H3C(O)C C(O)CH3 NC CN CO2Et O 2N CO2Et

* O * O * O * O
CH3 CH3 CH3 CH3
133a 92% yield 133b 77% yield 133c 93% yield 133d 99% yield
95 : 5 er 94 : 5 er 95 : 5 er 95 : 5 er
Scheme 29
H
H3CO H3C
O
N CF3
Ph Ph 134 (10 mol%) O2N
135 O
NH
CH3NO2 toluene Ph Ph
25 °C, 122 h N
122 S N CF3
136 93% yield H
98 : 2 er 134
Scheme 30
Based on the results with chalcones, Soós expanded their substrate pool to look
at a,b-unsaturated N-acyl pyrroles (137) as a chalcone derivative [81]. Utility of the
products formed was demonstrated in the concise syntheses of the anti-inflamma-
tory drug (R)-rolipram (Scheme 31).
Utility of Cinchona-alkaloid derived chiral thioureas were used in Scheidt’s
group [82] for the enantioselective syntheses of flavanones. The quinoline-tethered
thiourea catalyst 140 displayed better stereodirecting properties than the corre-
sponding thiourea that is tethered to a chiral cyclohexadiamine (139). Under opti-
mized reaction conditions, flavanone 142 was obtained in 92% yield and 97:3 er;
the best er using catalyst 139 was 90:10 under similar conditions (Scheme 32).
O
127 (10 mol%) O2N O
CH3NO2 + Ar N
Ar N H
122 H3CO
137 138
H N CF3
O2N O2N O2N
O O O NH
N
N N N S N CF3
H
O 127
138b 93% yield 138c 81% yield

138a 93% yield 96.5 : 3.5 er
97.5 : 2.5 er 98 : 2 er
O2N O2 N NH
O O
O
N OCH3
aq. MeOH H2/Pd
H3CO H3CO H3CO
138d heating O O
O
(R ) -rolipram
Scheme 31
140 10 mol% O
OH O R
−25 C, toluene OBn
R N
then pTsOH, 80 C
CO2t-Bu
142 H N
141 CF3
O O S NH
N N CF3 S NH
H H
(CH3)2N
H H 139
142a 92% yield 142b 65% yield F3C CF3
97 : 3 er 90 : 10 er 140
Scheme 32
170 A. Ting et al.
Following work on Michael addition of triazoles to nitro-olefins (discussed in

Sect. 2.5), bifunctional chiral thiourea catalysts were used in the addition of tria-
zoles to chalcones [83]. The catalytic system was applicable to enones bearing
aromatic groups of varying electronic natures to provide good yields and moderate
selectivity. a-Cyanoacetates [84] were also applied in Michael addition to chal-
cones under similar catalytic conditions (Scheme 33).
3.3 Asymmetric Conjugate Addition with Imines
The aza-Henry reaction of imines to nitroalkanes promoted by modified Cinchona

alkaloids has been investigated by several groups. Optically active b-nitroamine
products are versatile functional building blocks. In 2005 and 2006, several reports
regarding use of chiral thioureas emerged, using nitroalkanes in the aza-Henry
reaction to various imines.
Ricci et al. [85] reported the use of a quinidine-derived chiral catalyst in the
asymmetric addition of nitromethane to N-Boc imine 40. At around the same
time, Schaus and co-workers used a dihydroquinidine-derive chiral thiourea
DHQD-134 applicable to nitromethane and nitroethane 149 [86]. The application
of nitroethane conveniently generates a tertiary stereogenic center in the b-nitroamine
product 151. The methodology presented by Schaus is also applicable to novel
H
H3CO
N CF3
NH
N
N 127 10 mol% N
O N S N CF3
N + N O
127
H
N Ar R CHCl3. RT
H Ar R CF3
77 143 144
chiral scaffold S
*
N N
N N CF3
N N
N O N O N H H
S H O
S N
R
O2N N
144a 85% yield 144b 69% yield N
81.5 : 18.5 er 78 : 22 er Ar
NC CO2Et H
H3CO H3C
145 127 10 mol% O
+ EtO2C * N CF3
O CHCl3. RT
*
CN NH
Ph Ph
146 147 84% yield (63/37, syn / anti) N
S N CF3
94 : 6 er/ 94.5 : 5.5 er (syn/ant i ) H
110
Scheme 33
a,b-unsaturated, aliphatic imines (150). Application of similar reaction condi-

tions to dimethyl malonate offered corresponding products in high enantioselec-
tivity that were converted to b-amino esters under Nef conditions (Scheme 34).
At around the same time, other groups further reported the deprotonation-
activation of malonates for the asymmetric addition to imines. Various malonates
and aromatic N-acyl imines produced high yielding adducts with excellent stereose-
lectivities [87, 88].
Asides from the application of imines on conjugate addition reactions, Deng [87,
88] reported the first asymmetric chiral thiourea catalyzed Friedel-Crafts reaction
of indoles with N-tosyl imines (Scheme 35). The reaction was receptive to various
aromatic, heteroaromatic, and aliphatic imines in good yield and high enantioselec-
tivity (Scheme 36).
Boc
CH3NO2 NH
Boc
N 127 (10 mol %) NO2
122 R H
H toluene H3CO
40 −24 °C, 32h 148 82% yield, 97 : 3 er H N CF3
O O NH
H 3C NO2
134 (10 mol %) N
149 N OCH3 H3CO NH S N CF3
CH2Cl2 H
NO2 QD-127: R = CH=CH2
H −10 °C, 48 h
DHQD-134: R = Et
O 150 O CH3
151 90% yield
91.5 : 9.5 dr, 98.5 : 1.5 er
Scheme 34
CO2Bn
N
BnO2C CF3
NH
H 154 152(10 mol %)
CO2CH3
O
toluene
O O O CO2CH3
−78 °C, 72 h F3C NH
H
H3CO OCH3 155 96% yield
112 98.5 : 1.5 er S NH
N
Boc 136 (20 mol %) Boc
N O O NH H
N
acetone CO2Bn
R H BnO OBn R
−60 °C, 36 h Q-152: R = H
CO2Bn
156 157 158
OR Q-153: R = OCH3
Boc Boc
NH NH
CO2Bn CO2Bn
S CO2Bn CO2Bn
158a 95% yield, 98.5 : 1.5 er 158b 55% yield, 94 : 6 er
Scheme 35
172 A. Ting et al.
4 Chiral Cyclohexane-Diamine Catalysts
Bifunctional catalysts have proven to be very powerful in asymmetric organic trans-

formations [3]. It is proposed that these chiral catalysts possess both Brønsted base
and acid character allowing for activation of both electrophile and nucleophile for
enantioselective carbon–carbon bond formation [89]. Pioneers Jacobsen, Takemoto,
Johnston, Li, Wang and Tsogoeva have illustrated the synthetic utility of the bifunc-
tional catalysts in various organic transformations with a class of cyclohexane-
diamine derived catalysts (Fig. 6). In general, these catalysts contain a Brønsted
basic tertiary nitrogen, which activates the substrate for asymmetric catalysis, in
conjunction with a Brønsted acid moiety, such as urea or pyridinium proton.
4.1 Discovery and Mechanism
In 1998, Jacobsen and co-workers synthesized and screened a library of peptide

catalysts for the asymmetric Strecker reaction [14]. The peptide catalysts were
H
H3CO
Ts Ts H N CF3
H N 127 (10 mol %) NH
N + NH
R H EtOAc R
50 °C, 36h N
NH S N CF3
159 160 161 H
127
Ts Ts Ts Ts
NH NH NH NH
NH O NH NH NH
97 : 3 er 98 : 2 er 97 : 3 er 98 : 2 er
Scheme 36
Bifunctional Cyclohexane-Diamine Catalysts
Y
N
*
H N
* Chiral
Brønsted Base
X X
X = steric/electronic functional groups
Y = Brønsted acid functional groups
Fig. 6 Role of bifunctional cyclohexane-diamine catalysts

synthesized on solid support, implementing structural variation. The authors found

that a particular library member, a thiourea imine chiral catalyst, promoted the
asymmetric Strecker reaction in high yield and enantioselectivity (Scheme 37).
Mechanistic and structural studies were conducted to investigate the mode of action
of the new catalyst [90]. In rate studies of the asymmetric Strecker reaction, the
authors found a first order dependence on both catalyst and HCN, and observed
saturation kinetics for the imine, implicating reversible formation of an imine-catalyst
complex. While the enantioselectivity of the reaction was largely attributed to the
thiourea-imine hydrogen bonding interaction, it was recognized that HCN addition
must take place away from the amino acid/amine portion. Similar to the dual activation
of the bifunctional Cinchona alkaloids, this introduced the possibility that the HCN
could be located near the imine portion of the catalyst, where a formal Brønsted
base interaction could activate the HCN for nucleophilic addition.
It was not long before the significance of the bifunctional catalyst was recognized.
The chiral cyclohexane-diamine catalyst has promoted various asymmetric organic
transformations including Strecker reactions, Michael additions, Mannich additions,
aldol condensations and dynamic kinetic resolutions. Early work by Jacobsen et al.
illustrated the scope of catalysis with the Strecker reaction [91]. A catalyst library of
70 small molecules was constructed, derivatives of a solid supported catalyst that had
previously provided good results for the asymmetric Strecker reaction. Upon screen-
ing, analogue catalyst 163 provided optimal results for the addition of HCN to imines
(Scheme 38). The broad scope of the reaction included aliphatic imines, and both
electron-donating and electron-withdrawing imines. The authors were also able to
promote the addition of HCN to cyclic isoquinoline (45d). The scope of the bifunc-
tional catalysts was further illustrated with the Strecker reaction of HCN to ketoimines
(Scheme 39), providing quaternary amino acids in high yield and enantiomeric excess
[92]. The methodology was applied to the synthesis of a-methyl phenylglycine in
quantitative yield. In addition, the authors found that the catalyst could be recycled
without degradation of enantioselectivity.
4.2 Asymmetric Conjugate Additions
Takemoto and co-workers reported the use of a similarly structured bifunctional catalyst
for the first enantioselective organocatalytic Michael addition of malonitrile to
O S
1. 2 mol% 162 H
N N
toluene, −78 °C, 24h F C N Bn N N
HCN + 3
O
H H
N
Ph H 2. TFAA
Ph CN
44 162 HO
45 78% yield
95.5 : 4.5 er
t-Bu OCH3
Scheme 37
174 A. Ting et al.
O
H
O N
1. 2 mol% 163 Bn N N
N toluene, −70 °C, 20h H H
HCN + F 3C N O N
Ph H 2. TFAA
Ph CN HO
44 45 78% yield 163: R=OCOt-Bu
95.5 : 4.5 er t-Bu R
O O
O
O
F 3C N F 3C N
F3 C N N CF3
F3 C N
CN CN
CN CN O
t-Bu CN
H3CO Br
45a 92% yield 45b 65% yield 45c 70% yield 45c 77% yield 45d 88% yield
85 : 15 er 93 : 7 er 92.5 : 7.5 er 91.5 : 8.5 er 95.5 : 4.5 er
Scheme 38
Bn H3C NHBn
N 2 mol% 163
HCN +
Ph CN
Ph CH3 toluene, −75 °C, 24-80h
164 165 97% yield
95 : 5 er
H3C NHBn H
H3C NHBn H 3C N
CN
t-Bu CN Ph CN OCH3
Br
165a >99% yield 165b 98% yield 165c 97% yield
96.5 : 3.5 er 85 : 15 er 96.5 : 3.5 er
Scheme 39
a,b-unsaturated imides [93]. The catalyst of choice contained a 3,5-trifluromethylphenyl-

thiourea moiety, as well as a tertiary substituted amine. The asymmetric Michael
addition was investigated with a variety of a,b-unsaturated imides (Scheme 40), and in
general, both aliphatic and aromatic unsaturated imides were achieved with high enan-
tioselectivies. Takemoto proposed that a Brønsted acid interaction existed between the
diketone of the electrophile and the thiourea moiety. A Brønsted base interaction
between the tertiary amine and the malonitrile tautomer provides the necessary
pre-transition state for good reactivity and enantioselectivity [94].
The scope of Michael additions with catalysts containing cyclohexane-diamine
scaffolds was broadened by Li and co-workers [95]. When screening for a catalyst
for the addition of phenylthiol to a,b-unsaturated imides, the authors found that
thiourea catalyst 170 provided optimal enantioselectivities when compared to
Cinchon alkaloids derivatives (Scheme 41). Electrophile scope included both cyclic
and acyclic substrates. Li attributed the enantioselectivity to activation of the diketone
electrophiles via hydrogen-bonding to the thiourea, with simultaneous deprotona-
tion of the thiol by the tertiary amine moiety of the diamine (170a and 170b). Based
on the observed selectivity, the authors hypothesized that the substrate-catalyst
CF3
O O Ph O O
10 mol% 166 S
NC CN + Ph N toluene, rt, 48-140h
NC
N F3C N N
CN H H
N
167 168 169 93% yield 166 H3C CH3
93.5 : 6.5 er
O t-Bu O O Ph O O Ph O O
O O
NC NC NC
NC N N Ph N N CH3
N H
CN CN CN
CN
92.5 : 7.5 er 96 : 4 er 92 : 8 er 90.5 : 9.5 er
CF3 CF3
S S
F3C N N F3C N N
H H N CH NC H H N CH
3 3
CH3 C N H CH3
O O H O O
R N R N
Scheme 40
CF3
O O SPh O O S
10 mol% 170
PhSH + Ph N Ph Ph N Ph F3C N N
H CH2Cl2, −40 °C, 72h H H H
N
171 172 173 98% yield 170 H3C CH3
87.5 : 12.5 er
O O OCH3
SPh O O SPh O O
H3C(H2C)2 N Ph N Ph
H Ph H
S S CH3
83.5 : 16.5 er 90 : 10 er 87 : 13 er 80 : 20 er
CF3 CF3
S S
F3 C N N F3C N N
H H N CH3 H H N CH3
H 3C H H3C H
O O O O
SAr R2 SAr
Ph N R2 Ph N
H H
R1
170a 170b R2
favored if R1 = CH3, R2 = H favored if R1 = H, R2 = CH3
Scheme 41
176 A. Ting et al.
association in 170b is the preferred pre-transition state. However, a change in selectivity

is observed for a-substituted-b-unsubstituted substrates, implying that steric constraints
favor the 170a-type pre-transition state.
The conjugate additions of thiols to a,b-unsaturated electrophiles was extended
by Wang [96]. Catalyst 166 promoted the addition of thioacetic acid to a variety of
enones, including aliphatic, aromatic and heteroaromatic substituents (Scheme 42).
Wang expanded the scope of the reaction to include asymmetric additions of thio-
acetic acid to nitro-olefins (Scheme 43) [97]. Thiourea catalyst 166 promoted the
addition reactions in high yields and high enantiomeric ratios for a variety of
b-substituted nitro-olefins.
The asymmetric conjugate additions with thiol nucleophiles was further
expanded to 2-mercaptobenzaldehydes [98]. Wang had previously developed a
domino Michael-aldol reaction promoted by Cinchona alkaloids, and now illus-
trated the utility of cyclohexane-diamine bifunctionalized catalysts for the domino
CF3
O
O O S
10 mol% 166 H3C S O
+
H 3C SH Ph Ph F3C N N
Et2O, rt, 3-24h Ph Ph H H
N
174 135 175 95% yield 166 H3C CH3
79 : 21 er
O O O O O
H3C S O H3C S O H3C S O H3C S O Ph S O
Ph Ph S
n-Bu CH3 Ph Ph
Cl S
HO
175a 97% yield 175b 95% yield 175c 97% yield 175d 90% yield 175e 41% yield
75.5 : 24.5 er 82.5 : 17.5 er 77.5 : 22.5 er 50 : 50 er 66.5 : 33.5 er
Scheme 42
O
O
2 mol% 166 H 3C S
+ NO2
H3C SH Ph NO2
Et2O, −15 °C, 0.75h Ph
176 69 177 93% yield
85 : 15 er
O
O
10 mol% 166 H3C S
+ NO2
H3C SH Ph NO2
Et2O, −15 °C, 1h Ph
176 178 179 92% yield
76 : 24 er
Scheme 43
Michael-aldol for 2-mercaptobenzaldehydes and maleimides. Use of catalyst 166

provided a variety of fused heterocycles in high yield and high enantiomeric ratios
(Scheme 44). The authors propose that the chiral catalyst simultaneously activates
the thiol and the maleimide via Brønsted base and acid interactions. It was proposed
that the pre-transition state arrangement of the catalyst and substrates determines
the stereochemical outcome.
Tsogoeva and co-workers illustrated the utility of the cyclohexane-diamine
bifunctional thiourea catalysts for both the asymmetric Strecker reaction and the
nitro-Michael reaction [99]. Upon screening previously successful catalysts, the
authors found that catalyst 182 catalyzes the asymmetric addition of HCN to vari-
ous aldimines with moderate selectivity (Scheme 45). The imidazole catalysts also
proved to be optimal in the Michael additions of acetone to b-substituted nitro-
olefins (Scheme 46). A variety of electron-donating, electron-withdrawing and
heteroaromatic nitro-olefins were incorporated, all yielding products in high enan-
tioselectivity. The authors hypothesized that the imidazole serves as a Brønsted
base during catalysis, through coordinating to the acetone tautomer, while the
thiourea functionality concurrently activates the nitro group through Brønsted acid
interaction (182a).
Takemoto and co-workers designed a small library of thiourea cyclohexane-
diamine derived catalysts for the Michael reaction of malonates to nitrolefins [15].
The authors observed an interesting trend in catalysis: the reaction only proceeded
enantioselectively and in decent yields when the catalyst possessed both thiourea
O O OH O
10 mol% 166 CF3
H N Ph
+ N Ph S
xylenes, 0 °C, 7h CH3
SH S
O F3C N N
128 180 181 90% yield O N
90 : 10 dr, 92 : 8 er H H CH3
OH O OH O H
OH O O
S
N Ph Ph N
N Bn N Ph H
S H3C S
S O si
O O O
O
75 : 25 dr, 90 : 10 er 95 : 5 dr, 97 : 3 er 87.5 : 12.5 dr, 91.5 : 8.5 er
Scheme 44
CH3 S
Ph Ph
Ph N N
N Ph 10 mol% 182 HN Ph H H
N
HCN +
toluene, −40 °C, 2.5h 182
Ph H Ph CN
183 184 24% yield N NH
81.5 18.5 er
Scheme 45
178 A. Ting et al.
and tertiary amine group moieties. When either functional group was removed, the
selectivity and yield suffered immensely (Scheme 47, Table 1). This suggested a
dual protonation-activation role from this class of catalysts characteristic of both
Brønsted acidic and Brønsted basic properties.
O NO2
O CH3 S
+ NO2
15 mol% 182
H 3C CH3 Ph N N
toluene, rt, 40h H3C Ph
185 69 186 55% yield H H N
93.5 : 6.5 er O O
N
NO2 NO2 NO2 H NH
O O O re N
O
S
H3C H3C H3C CH3
Br OCH3
186a 54% yield 186b 54% yield 186c 54% yield 182a
92 : 8 er 91.5 : 8.5 er 93 : 7 er
Scheme 46
CF3
CF3
S
S
F3 C N N
H H F3C N N
N H H
H3C CH3
166 187
CF3
O S
H3C N F3C N N
H H H
N NR2
H3C CH3
188 189:R = o - (CH2)2C6H4
NO2
O O
+ NO2 10 mol% catalyst EtO Ph
EtO Ph
toluene, rt, 24-48h O OEt
O OEt
190 69 191 86% yield
96.5 : 3.5 er
Scheme 47
t.1 Table 1
t.2 Entry Catalyst Yield (%) Er
t.3 1 NEt3 17 50:50

t.4 2 166 86 96.5:3.5
t.5 3 187 + NEt3 57 50:50
t.6 4 188 14 67.5:32.5
t.7 5 189 29 95.5:4.5
Using optimal bifunctional catalyst 166, the reaction scope was expanded to
aromatic, heteroaromatic, and aliphatic nitro-olefins. Catalyst 166 also promoted
the addition of a b-phenyl nitro-olefin to a-CH3-b-ketoester, achieving an asym-
metric quaternary center in high yield and high enantiomeric ratio (Scheme 48).
The potential application of this catalytic system was illustrated by Takemoto in
the application to a tandem conjugate addition towards the asymmetric synthesis of
(−)-epibatidine, a biologically active natural product [100, 101]. The authors
designed an enantioselective double Michael addition of an unsaturated functional-
ized b-ketoester to a b-aryl nitro-olefin. The asymmetric synthesis of the 4-nitro-
cyclohexanones was achieved in both high diastereoselectivity and enantioselectivity,
with the natural product precursor synthesized in 90% yield and 87.5:12.5 er
(Scheme 49). The target (−)-epibatidine was subsequently achieved in six steps.
Chen and co-workers utilized the chiral bifunctional catalysts to directly access
vinylogous carbon-carbon bonds via the asymmetric Michael addition of a,a-dicy-
ano-olefins to nitro-olefins [102]. The scope of the reaction was explored with a
variety of substituted a,a-dicyano-olefins and b-substituted nitro-olefins
(Scheme 50). The authors propose the catalyst’s tertiary amine functionality depro-
tonates the cyano-olefin, activating the nucleophile to add to the si-face of the
pre-coordinated nitro-olefin.
O NO2
10 mol% 166 O
CH3 + NO2
EtO Ph EtO
toluene, rt, 36h Ph
CH3
O OEt O OEt
192 69 193 82% yield
96.5 : 3.5 er
Scheme 48
O O O
NO2 N
O O 10 mol% 166
+ O
Oallyl H3CO
Cl N toluene, 0 °C, 5h
H Oallyl
H3CO
194 195 N
Cl
KOH, EtOH
6 steps OH O
N Cl
H
N Oallyl
H3CO
H NO2
N Cl
(-)-epibatidine
196 90% yield
87.5 : 12.5 er
Scheme 49
180 A. Ting et al.
4.3 Asymmetric Mannich Additions
The asymmetric Mannich addition of carbon nucleophiles to imines catalyzed by

the cyclohexane-diamine catalysts has developed significantly in the past decade.
List and co-workers reported the asymmetric acyl-cyanantion of imines catalyzed
by a cyclohexane-diamine catalyst [103]. Using a derivative of Jacobsen’s chiral
urea catalyst, the authors optimized reaction conditions and obtained chiral
N-acyl-aminonitriles in high yield and enantioselectivities (Scheme 51). The scope
of the reaction was explored with both aliphatic and aromatic imines, providing
good to high selectivities for a variety of substrates.
Takemoto and co-workers communicated that bifunctional organocatalyst 166
would promote aza-Henry reactions of phosphinoyl imines with nitroalkanes
(Scheme 52) [104]. The catalytic additions provided high selectivities and yields
F3C
S
NC CN NC CN NO2
N N
5 mol% 197 H H H
+ Ph NO2
Ph 197 H3C
N
CH3
CH2Cl2, 0 °C, 48h H
54 69 56 64% yield
93 : 7 er F3C
S
NC CN NO2 NC CN NO2 NC CN NO2
N N
H H H
O H H
Ph Ph N CH3
H H H O O
N H CH3
S
56d 35% yield 56e 66% yield 56f 31% yield CN
94 : 6 er 97 : 3 er 81.5 : 18.5 er
Ph CN
Scheme 50
Bn O
O N 1 mol% 198
+ H3C N
Bn
CH3 t-Bu S
H3C CN Ph H toluene, −40 °C
20-50h Ph CN N
199 200 H3C N N
201 94% yield H H
98 : 2 er O N
O O O 198 HO
O
Bn Bn Bn
H3C N H3C N H3C N Bn
H3C N t-Bu OPiv
CN CN CN
t-Bu CN
H3CO Cl
98 : 2 er 99 : 1 er 99 : 1 er 98 : 2 er
Scheme 51
for a range of aromatic imines. The scope of the reaction was extended to nitroal-
kanes, providing Henry-adducts in high yield, high diastereomeric ratios and high
enantioselectivity.
The authors propose that the thiourea functionality of the catalyst would coordi-
nate and activate the nitro-group via hydrogen bonding, while the catalyst’s tertiary
amine deprotonates the coordinated nucleophile to release active substrate for the
asymmetric step (Fig. 7).Takemoto further expanded the scope and application of
the methodology to the synthesis of CP-99,994, a neurokinin-1 (NK-1) receptor
antagonist. The 2,3,6-trisubstitued piperidine core was achieved in 75% yield
(Scheme 53). General methods were also developed to synthesize the piperidine
derivatives in high yield and good stereoselectivity.
Johnston and co-workers designed a novel BisAmidinecatalyst (HQuin-BAM)
for the asymmetric addition of nitroacetic acid derivatives to imines (Schemes 54
and 55) [105, 106]. The additions proceeded in high yield and high enantioselectivities
for nitromethane and nitroalkanes to both electron-donating and electron-
withdrawing aryl imines. While the mechanism of action is still undergoing inves-
tigation, the presence of the pyridinium proton is essential to the catalytic mode of
P(O)Ph2
Ph2(O)P HN
N 10 mol% 166
CH3NO2 + Ph
NO2
CH2Cl2, rt, 75h CF3
Ph H
122 202 203 87% yield
83.5 : 16.5 er S
P(O)Ph2 P(O)Ph2 P(O)Ph2 F3C N N

HN HN HN H H
N
NO2 S NO2 NO2 166 H3C CH3
Ph
CH3
H3C
81.5 : 18.5 er 82 : 18 er 73 : 27 dr
*major diastereomer 83.5 : 16.5 er*
Scheme 52
O
CF3 CF3 N Ot-Bu S H
S S Ar H Ar
O N N CH3
F3C N N F3C N N H H
R N
O H N
H H N H H N CH3 N O
H3C CH3 H CH3 H CH3
O O O O Ar
N N H Ot-Bu
R H R H
H
Boc
NH
NO2
Ar
R
Fig. 7 Proposed role of cyclohexane-diamine thiourea 166 for the asymmetric aza-Henry reaction
182 A. Ting et al.
Boc NO2
N NO2
10 mol% 166
+ NO2
+
Ph H MsO CH2Cl2, −20°C MsO HN Ph MsO HN Ph
204 205 Boc Boc
206a 98:2 er 206b 91.5 : 8.5 er
1. TFA O H
1. t-BuOK NH2 OCH3
2. K2CO3 NO2 N
2. AcOH, −78°C H
3. Zn, AcOH NaBH3CN, AcOH OCH3
N Ph N Ph N Ph
H H CH3OH, rt H
207 80% yield 208 trans:cis = 19:1 (−)-CP-99,994
(trans:cis = 9:1) (75% yield from 207)
Scheme 53
Boc Boc
10 mol% 209 HN OTf
CH3NO2 + N
neat, −20 °C NO2
Ph H Ph
HN
122 204 210 57% yield
NH
80 : 20 er N
H N 209
Boc Boc Boc
HN HN HN
NO2 NO2 NO2
Ph
CH3 CH3
O2N F3C
92 : 9 er 93 :7 dr, 79.5 : 20.5 er 95 : 5 dr, 92 : 8 er
Scheme 54
Boc
Boc 1. 5 mol% catalyst 211 HN
N
CO2t-Bu + toluene, −78°C CO2t-Bu OTf
H HN
NO2 2. NaBH4, CoCl2 NH2
Cl NH
212 Cl 213 214 88% yield N
H
83 : 17 dr, 94 : 6 er N
Boc Boc Boc

HN HN HN 211
CO2t-Bu PhO CO2t-Bu CO2CH3
NH2 NH2 NH2

F Cl
87.5 : 12.5 dr, 96.5 : 3.5 er 86 : 14 dr, 93.5 : 6.5 er 50 : 50 dr, 91 : 9 er
Scheme 55
action. The reaction proceeds without external base additives or pre-activation of

the nucleophile, presenting the possibility that the catalyst possesses bifunctional
Brønsted acid and base interactions during catalysis.
Recently, Takemoto and co-workers reported the use of bifunctional thiourea catalyst
166 for the aza-Henry reaction of nitroalkanes to N-Boc imines [107, 108]. Using a
catalytic amount of the bifunctional catalyst provided the corresponding aza-Henry

adducts in high yield and good enantiomeric ratio (Scheme 56). Both nitromethane
and substituted nitroalkanes provided optimal results with catalyst 166.
The scope of electrophiles was explored with malonates and b-ketoesters, providing
chiral amine adducts in high yield and enantioselectivities (Scheme 57) [109].
Addition of cyclic b-ketoesters was also explored with hydrazines, providing cyclic
and bicyclic chiral amines with quaternary centers in high enantiomeric ratios
(Scheme 58).
Jacobsen et al. found that cyclohexane-diamine bifunctional catalyst 216 promoted
the enantioselective hydrophosphonylation of N-benzyl imines [110]. Using a modified
CF3
Boc Boc
N 10 mol% 166 HN S
CH3NO2 +
toluene, −20 °C, NO2
Ph H Ph F3 C N N
H H
122 204 210 90% yield N
166 H3C CH3
97 : 3 er
Boc Boc Boc Boc Boc
HN HN HN HN HN
NO2 NO2 NO2 NO2 NO2
Ph Ph Ph Ph
Et (CH2)3OH
H3CO Ph OH
210d 71% yield 210e 90% yield 210f 80% yield 210g 84% yield 210i 75% yield
97 : 3 er 88 : 12 dr 92 : 8 dr 83 : 17 dr 75 : 25 dr
97.5 : 2.5 er 94.5 : 5.5 er 98.5 1.5 er* 95 :5 er*
Scheme 56
Boc
Boc HN
CO2Et N 10 mol% 166 CO2Et
+ CH2Cl2, −78 °C, 48h
Ph
CO2Et Ph H CO2Et
190 204 211 73% yield
98.5 : 1.5 er
O O
Boc H NHBoc
CO2CH3 N 10 mol% 166
Ph
+ CO2CH3
Ph H CH2Cl2, −20 °C, 96h
212 204 213 81% yield
91 : 9 dr, 78 : 22 er
O H NHBoc O H NHBoc O H NHBoc
Ph Ph Ph
CO2CH3 CO2CH3 CO2CH3

90 : 10 dr, 93.5 : 6.5 er 99 : 1 dr, 91.5 : 8.5 er 80 : 20 dr, 96 : 4 er
Scheme 57
184 A. Ting et al.
version of the bifunctional catalyst from their asymmetric hydrocyanation reaction,

optimal results were achieved for the enantioselective phosphorylation of imines
(Scheme 59). While the mechanism of the hydrophosphonylation is currently being
investigated, it is necessary that strong electron-withdrawing groups be present on the
phosphite for good reaction rate, suggesting that the imine moiety of the catalyst
activates the phosphite via Brønsted base interaction.
4.4 Dynamic Kinetic Resolution
Berkessel and co-workers have demonstrated the utility of the bifunctional

cyclohexane-diamine catalysts in the dynamic kinetic resolution of azalactones
(Schemes 60 and 61) [111, 112]. The authors proposed that the urea/thiourea
moiety of the catalyst coordinates and activates the electrophilic azlactone.
The allyl alcohol nucleophilicity is increased due to the Brønsted base interaction
with the tertiary amine of the catalyst.
O Boc O Boc
N 10 mol% 166
CO2CH3 + N NHBoc
N
Boc toluene, −78 °C, 3h CO2CH3
214 47 215 96% yield
91.5 : 8.5 er
O Boc O Boc O Boc

N NHBoc N NHBoc N NHBoc
CO2CH3 CO2CH3 CO2CH3

93.5 : 6.5 er 95 : 5 er 93.5 : 6.5 er
Scheme 58
Bn Bn
O N 10 mol% 216 NH
RO P H
+ OR
t-Bu H Et2O, 4 °C, 48-72h t-Bu P OR CH3 S
RO
O N
217 218 219 83% yield H3C N N
H H
R = o - nitrobenzyl 96.5 : 3.5 er O N
Bn Bn Bn 216 HO
NH NH NH
OR OR O OR
Ph P OR P OR P OR t-Bu OCOt-Bu
O O O
H3CO
99 : 1 er 98 : 2 er 96 : 4 er
Scheme 59
The authors proposed that the Brønsted base interaction on the catalyst is
imperative for reactivity. Catalysts lacking a basic amine moiety, specifically
mono- and bis-ureas, did not promote the asymmetric catalytic addition well, if at
all. In screening a variety of amine bases and bis-ureas, it became apparent that
presence of a Brønsted base was necessary for catalytic activity (Scheme 61) [113].
The reactivity was extremely low in absence of Brønsted base (Table 2, entry 2),
but slightly improved with presence of NEt3 (Table 2, entry 1). Combined, a chiral
Brønsted acid and Brønsted base increase conversion and showed some enantiose-
lectivity (Fig. 8).
5 Chiral Guanidine Catalysts
While the significance of the bifunctional Brønsted base catalysts has been
illustrated in the previous sections, few examples rely solely on a Brønsted base
interaction for asymmetric catalysis. However, in the past few decades, a novel
catalyst system has emerged as a powerful promoter of chiral transformations.
The guanidines have gained the reputation as super bases in organic transformations.
Bn
O Bn H CF3
5 mol% 166
OH + N O
O O
toluene, rt, 24h Ph N
O H
Ph O F3C N N
221 222 223 96% yield H H
86 : 14 er N
H3C CH3
166
Bn O Bn H
5 mol% 220
OH + N O
Ph N
O
CH3 t-Bu S
O toluene, rt, 48h H
O N
Ph H3C N N
221 222 223 98% yield H H
O N
88.5 : 11.5 er H3C CH3
220
Scheme 60
Table 2
Entry Catalyst Conversion (%) Er
1 NEt3 14 –
2 224 4 –
3 224 + NEt3 50 –
4 225 + NEt3 50 <51:49
5 226 + NEt3 33 55:45
186 A. Ting et al.
H3C CH3
O
X X
R1 R
N N 1 R1 R1
H H N N N N
H H CH3 H H
224
225 : X = O
R1 = 3,4-(CF3)2C6H3 226 : X = S
Bn O Bn H
OH O 5 mol% catalyst O
+ N Ph N
O toluene, rt, 48h H
O
Ph
221 222 223
Guanidine Catalysts
Scheme 61 X X
X N N
X X
X*
X
N N N N
H H
Brønsted Brønsted
Base Base
X = steric/electronic tuning functional groups
Fig. 8 Guanidine compounds as Brønsted base catalysts
Resonance stabilization of the conjugate acid of guanidine defines this class of

molecules as some of the strongest bases in organocatalysis [114].
5.1 Discovery and Mechanism
It was not until 1994 that Chinchilla and co-workers identified a synthesized a
chiral guanidine for asymmetric catalysis [115].
The authors reported the first chiral guanidine catalyzed addition of nitro-olefins
to aldehydes (Scheme 62, Table 3). While reactivity and selectivity were not opti-
mal, the discovery led to great developments in the field of asymmetric Brønsted
base catalysis.
Shortly after Chinchilla’s finding, Lipton and co-workers reported the use of a
dipeptide guanidine for the asymmetric catalytic Strecker reaction [116]. The
authors found that application of a dipeptide catalyst bearing an imidazole moiety
provided very low reactivity. However, use of the same dipeptide catalyst bearing a
more basic guanidine functional group provided high yields at low temperatures
and very high enantioselectivities for aromatic imines (Scheme 63).
The chiral guanidine’s role as a strong Brønsted base for the reactions of protic
substrates has been proposed. In 1999, Corey developed a C2-symmetric chiral
guanidine catalyst to promote the asymmetric Strecker reaction [117]. The addition
of HCN to imines was promoted high yields and high enantioselectivities for both
electron-withdrawing and electron-donating aromatic imines (Scheme 64).
Et Et Et Et Et Et
N CH3 N H3C N H3C N
H3C H3C CH3
Ph
Ph N N Ph Ph N N Ph Ph N N Ph N N
H H H H
227 228 229 230
O OH
10 mol% catalyst
CH3NO2 + i - Bu H i - Bu
NO2
122 231 THF, 7-24h 232
Scheme 62
Table 3
Entry Catalyst T (°C) Yield (%) Er
1 227 −45 40 67:33
2 227 −65 33 77:23
3 228 rt 77 53:47
4 229 rt 6 50:50
5 230 rt 60 52.5:47.5
Bn Bn O
N 2 mol% 234 HN H
HCN + N
HN
Ph H CH3OH, −25 °C Ph CN Ph NH N
200 235 97% yield 233
>99.5 : 0.5 er O H
N NH2
Bn Bn O
HN HN Bn
HN NH
O2N HN
CN CN
t-Bu CN Ph NH
Cl 234
235c 80% yield O
>99.5 : 0.5 er <55 :45 er 58.5 : 41.5 er
Scheme 63
Ph Ph
10 mol% 236 N
HCN + N Ph
PhCH3, −40°C, 20h HN Ph
Ph Ph
N N
H
Ph H Ph CN 236
183 184 96% yield
93 : 7 er
Ph Ph Ph
HN Ph HN Ph HN Ph
CN CN CN
Cl TBSO CH3
90.5 : 9.5 er 94 : 6 er 75 : 25 er
Scheme 64
188 A. Ting et al.
The group proposed that the hydrocyanate underwent a formal Brønsted base
interaction with the guanidine catalyst, thus activating the nucleophile for addition
(Fig. 9). In contrast to the bifunctional catalysts, the guanidines are basic enough to
activate the substrates without the need for secondary moieties.
5.2 Conjugate Additions
Tan and co-workers designed a guanidine catalyst similar to that of Corey’s cyclic
guanidine for the asymmetric addition of nitroalkanes to a,b-unsaturated ketones
[118]. Michael adducts were achieved in decent yields and moderate selectivities
(Scheme 65). The scope also included malonates as nucleophiles, providing g-nitro
adducts in high yields, although selectivities were degraded slightly (Scheme 66).
H C N
N N
Ph Ph Ph Ph
N N N N
H 236 H H
C
N
CHPh2 CHPh2
HN N
N
Ph CN Ph Ph
N N Ph H
184 183
H H
Ph2HC si
N C
N
H Ph
Fig. 9 Corey’s proposed catalytic cycle for chiral guanidine promoted hydrocyanation
N
O CH3 Ph O i-Pr i-Pr
20 mol% 237
H3C NO2 + H3C Ph
N
H
N
Ph Ph toluene, rt, 96h
CH3 NO2 237
240 135 241 23% yield
N
80.5 : 19.5 er t-Bu t-Bu
N N
H
238
O CH3 Ph O
20 mol% 238
H3C NO2 + N
Ph Ph toluene, rt, 120h H3C Ph Bn i-Pr
CH3 NO2 N N
240 135 241 20% yield H
239
77 : 23 er
Scheme 65
The degradation may be attributed to weaker interactions between the guanidine

and malonate, as nitroalkanes are well known to form tightly bound ion pairs in
non-polar solvents [119, 120]. The asymmetric induction may have been better for
the nitroalkanes because of the tight coordination.
Ma and co-workers extended use of chiral guanidine catalysts to the addition of
glycine derivatives to acrylates [121]. Addition products were achieved in high yield
with modest enantioselectivity (Scheme 67). The tert-butyl glycinate benzophenone
imines generally provided better enantiomeric ratios than the ethyl glycinate
benzophenone imines. Based on this observation, the authors hypothesized that an
imine-catalyst complex determines the stereochemical outcome of the product.
Another structurally modified guanidine was reported by Ishikawa et al. as a
chiral superbase for asymmetric silylation of secondary alcohols [122]. Soon after,
Ishikawa discovered that the same catalyst promoted asymmetric Michael additions
of glycine imines to acrylates [123]. The additions were promoted in good yield
and great asymmetric induction under neat reaction conditions with guanidine cata-
lyst 250 (Scheme 68). The authors deduced that the high conversion and selectivity
were due to the relative configuration of the three chiral centers of the catalyst in
O O H3CO2C CO2CH3
20 mol% 238 O
H3CO + H3C
OCH3 OCH3
toluene, rt, 93h H3C
O OCH3 O O
112 242 243 46% yield
62.7 : 32.5 er
O O H3CO2C CO2CH3
20 mol% 237 O
H3CO + Ph
OEt OEt
toluene, rt, 120h Ph
O OCH3 O O
112 244 245 86% yield
61.5 : 38.5 er
Scheme 66
O
O O CH3 NH CH3
20 mol% 246 Ph N
OEt
Ph N
OEt + OEt
THF, 48h Ph H Ph N N Ph
O OEt H 246 H
Ph −78 °C - −10 °C
247 248 249 99% yield
53.2 : 46.8 er CH3 NH2 CH3
O O O
Ph N N Ph
Ph N Ph N Ph N
OEt OEt Ot-Bu H H
H H H
Ph Ph Ph O O Et O
O OEt O Ot-Bu O Ot-Bu
249a 99% yield 249c 98% yield Ph OEt
249b 99% yield
53.2 : 46.8 er 65 : 35 er 65 : 35 er N H
Ph
Scheme 67
190 A. Ting et al.
absence of solvent. Also of interest is the observed reversal of stereochemistry

when the chiral center near the external nitrogen of the catalyst is changed from (S)
to (R). Based on these observations, the authors proposed an asymmetric pre-
transition state illustrating that one face of the nucleophile is blocked by the guani-
dine catalyst (Fig. 10).
Ishikawa and co-workers also reported a class of structurally modified guanidines
for promotion of the asymmetric Michael reaction of tert-butyl-diphenylimino-acetate
to ethyl acrylate [124, 125]. In addition to a polymer support design (Scheme 69), an
optical resolution was developed to achieve chiral 1,2-substituted ethylene-1,2-di-
amines, a new chiral framework for guanidine catalysis. The authors discovered that
incorporating steric bulk and aryl substituents in the catalyst did improve stereoselec-
tivitity, although the reactivity did suffer (Scheme 70, Table 4).
Terada and co-workers reported a novel guanidine catalyst with a chiral binaphthol
backbone for the asymmetric addition of dicarbonyl compounds to nitro-olefins [126].
Substitution on the binaphthol backbone dramatically increased enantioselectivity.
Ph Ph
O O O
20 mol% 250
Ph N + Ph N H3C N N CH
Ot-Bu OEt OEt 3
neat, 20 °C, 3d H N
Ph Ph
O Ot-Bu HO
252 248 253 87% yield
98.5 : 1.5 er Ph 250
O O O Ph Ph
20 mol% 251 Ph N
Ph N + OEt OEt
Ot-Bu
neat, 20 °C, 3d H3C N N CH
3
Ph Ph
O Ot-Bu N
252 248 253 17% yield HO
95.5 : 4.5 er Ph
251
Scheme 68
H
H3C N
N H
O H
H3C N
H
H
O
t -BuO C N
H
Fig. 10 Ishikawa’s proposed pre-transition state
for the Michael addition of glycines to unsaturated O
esters OEt
32
N
N
Ph N
254
CH3 Ph
OH
O O O
N + 254 / 252 = 2.4 Ph N
Ph OEt
Ot-Bu CH3
THF, 20 °C, 3-7d Ph CO2t-Bu
Ph
252 255 256 32% yield
72.5 : 27.5 er
Scheme 69
Ph Ph Ph
OH OH OH
N N N
H3C N N CH3 H3C N N CH3 PhH2C N N CH2Ph
H3C CH3
257 258 259
O O O
Ph N 10 mol% catalyst Ph N
Ot-Bu + OEt OEt
20 °C, 3-7d H
Ph Ph CO2t-Bu
252 248 253
Scheme 70
Table 4
Entry Catalyst Solvent Yield (%) Er
1 257 THF 26 89.5:10.5
2 257 None 77 96.5:3.5
3 258 THF 62 95:5
4 258 None 79 98.5:1.5
5 259 THF 27 99:1
6 259 None NR –
192 A. Ting et al.
More specifically, 3,5-di-tert-butylphenyl substitution on the 3,3¢-position of the

binaphthol backbone (260) provided overall best yields and selectivities. Using
catalyst 260, the authors expanded the scope of substrates to include aliphatic and
aromatic nitro-alkenes, and a-substituted b-ketoesters, while maintaining good
yields and enantiomeric ratios (Scheme 71).
Chiral compounds containing phosphorus-carbon bonds have found significant
roles in metal- and organo-based catalysis; therefore it is important to develop cata-
lytic methods to access such substrates. Few organocatalytic phospha-Michael
reactions exist, but recently Tan and co-workers reported an asymmetric addition of
phosphine oxides to nitro-olefins [127]. Using a derivative of Corey’s bicyclic
guanidine catalyst, the authors achieved chiral amino-phosphines in high yield and
high enantiomeric ratios (Scheme 72). The scope of the catalyst was illustrated with
electron-withdrawing and electron-donating b-aryl-nitro-olefins.
Terada expanded the phospha-Michael reaction to include diphenyl-phosphites
[128]. A novel binaphthol-derived guanidine catalyst promoted the addition in high
yields and enantioselectivities (Scheme 73). Functionalizing the external nitrogen
with a diphenylmethine moeity enhanced selectivities for a large scope of
nitro-olefin derivatives.
Tan and co-workers reported the Michael reactions of di-thiomalonates and
b-keto-thioesters to a range of acceptors, including maleimides, cyclic enones,
furanones and acyclic dioxobutenes [129]. Unlike dimethyl malonate, additions
with acidic thioesters proceeded in higher yields, and overall better enantioselec-
tivities (Scheme 74).
NO2
O O
2 mol% 260
H3CO
+ Ph
NO2 H3CO Ph
Et2O, −40 °C, 4-10 h
O OCH3 O OCH3
112 69 261 98 : 2 er
NO2 NO2
O O Br
H3CO H3CO
Ar
O OCH3 OCH3 O OCH3
H
261a 96% yield 261b >99% yield N
97 : 3 er 99 : 1 er N
N CH3
NO2 NO2 H
O O
Ar
H3CO H3CO Ph Ar = 3,5-(DBP)2C6H3
CH3
260
O OCH3 O OCH3
DBP = 3,5-di-t-BuC6H3
261c 79% yield 261d 82% yield
95.5 : 4.5 er 99 : 1 er
Scheme 71
Ph
Ph Ph P O
Ph P O 2 mol% 238 N
+ Ph
NO2
Ph
NO2 t-Bu t-Bu
H Et2O, −40 °C, 12-3 h N N
262 69 263 64% yield H 238
80 : 20 er
Ph R1 R1 R1
Ph
Ph P O R1 P O R1 P O R1 P O
Ph P O
NO2 NO2 NO2 Et
NO2
NO2
F Cl Cl
263a 92% yield 263b 95% yield 263c 94% yield 263d 94% yield 263e 73% yield
80 : 20 er 91 : 9 er 95.5 : 4.5 er 98 : 2 er 96.5 : 3.5 er
R1 = 2-napthyl
Scheme 72
OPh
OPh PhO P O
NO2 1 mol% 264
PhO P O
+ Ph
Ph
NO2
H t-BuOCH3, −40 °C
0.5 - 7h 266 94% yield
265 69
96 : 4 er
OPh OPh Ar
PhO P O PhO P O OPh
PhO P O H
NO2 O NO2 N
NO2 N
i-Bu
N Ph
Br H Ph
266a 98% yield 266b 79% yield 266c 84% yield Ar
97 : 3 er 94.5 : 5.5 er 90 : 10 er 264
Ar = 3,5-t-Bu2C6H3
Scheme 73
5.3 Asymmetric Diels-Alder Reactions
In 2006, Tan and co-workers reported the first asymmetric guanidine catalyzed Diels-
Alder addition of anthrone to maleimides (Scheme 75) [130]. The authors observed
very high yields and enantioselectivities using a derivative of Corey’s C2-symmetric
bicyclic guanidine catalyst. The addition of anthrones to maleimide also worked well
for substituted anthrones. Interestingly, the authors observed the oxidized product
when the anthrone was substituted at the meta-positions (Scheme 76).
194 A. Ting et al.
6 Additional Brønsted Base Catalysts
Many of the catalysts up until this point have been developed and applied to numer-
ous organic transformations. While these discoveries have illustrated the impor-
tance of Brønsted base catalyzed asymmetric transformations, expanding the scope
O O O
H N Et
20 mol% 238
H3CO + N Et H3CO
toluene, −50 °C, 20h O
O OCH3 O H3CO O
12 267 268 20% yield
73.5 : 26.5 er
O
O O O
H N Et
2 mol% 238
t-Bu-S + N Et t-Bu-S
toluene, −50 °C, 8h O
O Ph O Ph O
269 267 270 99% yield; 50 : 50 dr
(97 : 3 er, 97.5 : 2.5 er)
O O O
O O
H N CH3 H N Bn O
H
t-Bu S t-Bu S
O O t-Bu-S
t-Bu S O t-Bu S O
Ph O

98.5 : 1.5 er 98.5 1.5 er 97.5 : 2.5 er
Scheme 74
O
O O N Ph
10 mol% 271 O
+ N Ph
CH2Cl2, −20 °C, 4-8h
HO
O
272 180 272 90% yield
90.5 : 9.5 er
O O
N Bn N Ph
O Cl N
O Bn Bn
N N
H
Cl HO HO
Cl Cl 271
97.5 : 2.5 er 99.5 : 0.5 er
Scheme 75
OH O OH O OH O OH
10 mol% 271
+ N Ph
CH2Cl2, −20 °C, 4-8h
O H
274 180 O 275 80% yield
99.5 : 0.5 er
N
O Ph
OH O OH OH O OH
CN 10 mol% 271
+ NC
CH2Cl2, − 20 °C, 4-8h
274 272 H
NC
CN
276 90% yield
97 : 3 er
Scheme 76
of base catalysis is always an ongoing effort. This section will highlight the devel-
opment of new chiral Brønsted base catalysts undergoing development.
6.1 Chiral Binaphthyl-Derived Amine
Wang and co-workers reported a novel class of organocatalysts for the asymmetric
Michael addition of 2,4-pentandiones to nitro-olefins [131]. A screen of catalyst
types showed that the binaphthol-derived amine thiourea promoted the enantiose-
lective addition in high yield and selectivity, unlike the cyclohexane-diamine cata-
lysts and Cinchona alkaloids (Scheme 77, Table 5).
The best reactivity and selectivity was illustrated with the binaphthol derived
thiourea amine catalyst 277. The substrate scope was explored primarily with
b-aryl-nitro-olefins of both electron-donating and electron-withdrawing natures.
Yields and selectivities were high for the majority of substrates (Scheme 78).
6.2 Chiral Paracyclophane-Derived Imine
Recently, Kunz et al. reported a new organocatalyst for the asymmetric Strecker
reaction [132]. The paracyclophane-derived imine catalyst (280) promotes the
hydrocyanation of various imines, both aromatic and aliphatic (Scheme 79).
The authors identify the new paracyclophane derivative as a catalyst lacking a
hydrogen bond donor, and propose that addition is catalyzed by the Brønsted basic
imine moiety. Based on X-ray crystal data of the catalyst, it was hypothesized that
196 A. Ting et al.
H
OCH3 H3CO
H
H N CF3
OH
N NH
N H N
S N CF3
H
3 quinine (Q) 127
CF3 CF3
S
S
N N
H H
F3C N N CH3
H H N CF3
N
166 H3C CH3 CH3 277
O NO2
O
10 mol% catalyst
H3C + NO2
H3C Ph
Ph
THF, rt, 3-60 h
O CH3 O CH3
278 69 279
Scheme 77
Table 5
Entry Catalyst Yield (%) Er
t.1 1 3 52 58.5:41.5
t.2 2 127 47 98:2
3 166 92 92:8
t.3
4 277 93 97.5:2.5
t.4
t.5
t.6
O NO2
O
10 mol% 277
H3C + NO2
H3C Ph
Ph
Et2O, rt, 24h
O CH3 O CH3
278 69 279 87% yield
97.5 : 2.5 er
NO2 NO2 NO2

O O O
OBn
H3C H 3C H3C
O CH3 OCH3 O CH3 Cl O CH3 OCH3

98.5 : 1.5 er 98.5 : 1.5 er 94 : 6 er
Scheme 78
Fig. 11 Kunz’s hypothesized pre-transition state for the N

asymmetric hydrocyanation of imines promoted by a C
novel paracyclophane imine catalyst
H
N
H
OPiv
PivO O
O N
PivO H
OPiv OCH3
1. 2 mol% 280 O
HCN + N toluene, 20h
F3C N
−50 - −20 °C H
Ph H
Ph CN
2. (CF3CO)2O
44 45 55% yield OPiv OPiv O
85.5 : 14.5 er O N
PivO H
O O OPiv OCH3
O
Bn Bn 280
F3C N F3C N
F3C N H H
H
CN CN
i-Pr CN
H3CO
45e 20% yield 45f 87% yield 45g 87% yield
98 : 2 er 94 : 6 er 91 : 9 er
Scheme 79
the imine base moiety was key in coordination and deprotonation of HCN to create
a Brønsted acid environment to trap the imine substrate (Fig. 11). The anionic CN–
would add to the imine over the re face, as the si is blocked by the catalyst bulk.
7 Conclusion
The utility of chiral organic Brønsted bases highlighted illustrates the evolution of
the field and the catalyst design enabled through mechanistic understanding. The
products afforded by the methods highlighted in this review provides a significant
indication of how powerful the approach will be in providing ready access to chiral
compounds for use in synthesis. Progress in catalyst design and method develop-
ment has been the result of thoughtful mechanistic consideration of existing cata-
lyst structures and creative catalyst modification to address limitations. Conceptual
advances have been and will continue to be made as an increased emphasis is
placed on the synthetic utility of the products afforded by new methods. The syn-
thetic challenges in this area have resulted in the creation of novel catalysts and will
continue to inspire the imaginations of chemists [133].
198 A. Ting et al.
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Top Curr Chem (2010) 291: 201–232
DOI: 10.1007/128_2008_16
Published online: 05 June 2009
Chiral Ketone and Iminium Catalysts

for Olefin Epoxidation
O. Andrea Wong and Yian Shi
Abstract Organo-catalyzed asymmetric epoxidation has received much attention

in the past 30 years and significant progress has been made for various types of
olefins. This review will cover the advancement made in the field of chiral ketone
and chiral iminium salt-catalyzed epoxidations.
Keywords Asymmetric epoxidation • Chiral iminium salt • Chiral ketone
Contents
1 Introduction.......................................................................................................................... 202
2 Chiral Ketone-Catalyzed Epoxidations................................................................................ 202
2.1 C2-Symmetric Binaphthyl-Based and Related Ketones.............................................. 202
2.2 Ammonium Ketones................................................................................................... 205
2.3 Bicyclo[3.2.1]octan-3-ones and Related Ketones....................................................... 206
2.4 Carbohydrate-Based and Related Ketones................................................................. 207
2.5 Carbocyclic Ketones................................................................................................... 219
3 Chiral Iminium Salt-Catalyzed Epoxidations...................................................................... 223
3.1 Dihydroisoquinoline-Based Iminium Salts................................................................. 224
3.2 Binaphthylazepinium-Based Iminium Salts............................................................... 226
3.3 Biphenylazepinium-Based Iminium Salts.................................................................. 227
3.4 Acyclic Iminium Salts................................................................................................ 228
4 Conclusion........................................................................................................................... 228
References.................................................................................................................................. 229
O.A. Wong and Y. Shi (*ü)

Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
e-mail: yian@lamar.colostate.edu
202 O.A. Wong, Y. Shi
1 Introduction
Asymmetric epoxidation of olefins is an effective approach for the synthesis of enan-

tiomerically enriched epoxides. A variety of efficient methods have been developed
[1, 2], including Sharpless epoxidation of allylic alcohols [3, 4], metal-catalyzed
epoxidation of unfunctionalized olefins [5–10], and nucleophilic epoxidation of
electron-deficient olefins [11–14]. Dioxiranes and oxazirdinium salts have been
proven to be effective oxidation reagents [15–21]. Chiral dioxiranes [22–28] and
oxaziridinium salts [19] generated in situ with Oxone from ketones and iminium
salts, respectively, have been extensively investigated in numerous laboratories and
have been shown to be useful toward the asymmetric epoxidation of alkenes. In these
epoxidation reactions, only a catalytic amount of ketone or iminium salt is required
since they are regenerated upon epoxidation of alkenes (Scheme 1).
O
KHSO5 X
O
KHSO4 X
X = O or +NR2
Scheme 1 Ketone/iminium salt-catalyzed epoxidations
2 Chiral Ketone-Catalyzed Epoxidations
In 1984, Curci and coworkers reported asymmetric epoxidation of olefins with ketones
1 and 2 (Fig. 1), providing up to 12.5% ee for trans-b-methylstyrene [29]. Subsequently
(in 1995), they reported that fluorinated ketones 3 and 4 were more reactive than 1 and
2 for epoxidations, and up to 20% ee was obtained for trans-2-octene [30]. Furthermore,
these ketones are stable under epoxidation conditions and can be recovered with only
minor losses (2–5%) after work-up of the reactions. In the same year, several other
fluorinated ketones (5–7) were reported to be active for the epoxidation of some
alkenes, such as, trans-stilbene, trans-b-methylstyrene, and 6-chloro-2,2-dimethyl-
2H-1-benzopyran, but no enantioselectivity was observed [31].
2.1 C2-Symmetric Binaphthyl-Based and Related Ketones
In 1996 Yang and coworkers reported a series of binaphthyl-derived C2-symmetric

ketones (8) as epoxidation catalysts (a few examples are shown in Fig. 2)[32–34].
Chiral Ketone and Iminium Catalysts for Olefin Epoxidation 203
Me Me Me Me
Me O CF3 OMe
Me O O O
Ph
CF 3 *
Me
H Me Me
1 2 3 O 4
O O
O Me O
∗ OH
OR ∗
F Me ∗ CO2Et
F
F
5a, R = Me 7
5b, R = (-)-Menthyl 6
Fig. 1 Ketones 1–7
8a, X = H 8e, X = Me
O O 8b, X = Cl 8f, X = CH2OCH3
OX 8c, X = Br O O
XO
8d, X = 8g, X =
3 3'
O O
O
8h, X =
O
Fig. 2 Ketones 8
Ketone 8 epoxidizes a wide range of olefins in good yields. The steric hindrance
and electronegativity of the substituents (X) at positions 3 and 3’ greatly affect the
epoxidation reactivity and enantioselectivity. In general, para-substituted trans-
stilbenes are very effective substrates for the epoxidation using ketone 8 (Table 1,
entries 1–8, 16–18). The enantioselectivity for the epoxidation increases as the size
of the substituents increases. However, the size of the meta-substituents had little
effect on enantioselectivity. Later, Seki and coworkers extended the epoxidation
scope to cinnamates using ketone 8 (Table 1, entry 26) [35, 36].
Binaphthol- and biphenyl-derived ketones (9 and 10) were reported by Song and
coworkers in 1997 to epoxidize unfunctionalized alkenes in up to 59% ee (Fig. 3,
Table 1, entries 9, 10) [37, 38]. Ketones 9 and 10 were intended to have a rigid
conformation and a stereogenic center close to the reacting carbonyl group. The
reactivity of ketones 9 and 10 is lower than that of 8, presumably due to the weaker
electron-withdrawing ability of the ether compared to the ester. In the same year,
Adam and coworkers reported ketones 11 and 12 to be epoxidation catalysts for
several trans- and trisubstituted alkenes (Table 1, entries 11, 12). Up to 81% ee was
obtained for phenylstilbene oxide (Table 1, entry 25) [39].
A series of fluorinated biaryl ketones (13) was reported by Denmark and cow-
orkers in 1999 and 2002 (Fig. 4) [22, 40]. The introduction of fluorine atoms at the
α-position of the reacting carbonyl increased the efficiency of the epoxidation.
Fluorinated ketones 13b and 13c displayed high reactivity and good enantioselectivity
Table 1 Asymmetric epoxidation with ketones 8–16

Entry Substrates Catalyst Yield (%) ee (%)
1 Ph (R)-8a 91 47 (S,S)
Ph
2 (R)-8b 95 76 (S,S)
3 (R)-8c 92 75 (S,S)
4 (R)-8d 93 84 (S,S)
5 (S)-8e 93 56 (R,R)
6 (R)-8f 92 66 (S,S)
7 (R)-8g 90 77 (S,S)
8 (R)-8h 91 75 (S,S)
9 9 79 26 (S,S)
10 10 72 59 (S,S)
11 11 72a 38 (R,R)
12 12 67a 65 (R,R)
13 13b 46 94 (R,R)
14 15 27 30
15 16 93 64 (R,R)
p-tBu-Ph
16 p-tBu-Ph (R)-8b >90 91 (S,S)
17 (R)-8c >90 93 (S,S)
18 (R)-8d >90 95 (S,S)
19 Ph 13a 6a ndb
20 13b 80 88 (R,R)
21 13c 100a 85
22 14a 100a 86
23 14b 100a 83
Ph
24 16 99 82 (R,R)
Ph
Ph
25 Ph 12 70a 81
CO2Me
26 (R)-8a 75 74 (2R,3S)
a
Conversion (%)
b
Not determined
O O
O
O
O O O O O O Ph
O O Ph
Ph Ph
O O O O O
O
9 10 11 12

O O O
F F F
F
Me Me Me Me Me Me
13a 13b 13c
O O
F F
F F
F
14a 14b
O O
N N SO Ph O N N O
PhO2S 2
Ph Ph O O
HH
15 16
for trans-olefins (up to 94% ee was obtained for trans-stilbene oxide) (Table 1,
entries 13, 19–21). Also in 2002, Behar and coworkers reported a series of structur-
ally related fluorinated binaphthyl ketones (14) (Fig. 4) [41]. Among the ketones
studied, difluorinated ketone 14a and trifluorinated ketone 14b were found to be the
most reactive and enantioselective for the epoxidation of trans-b-methylstyrene
(Table 1, entries 22, 23).
Tomioka and coworkers reported ketones 15 and 16 as asymmetric epoxidation cata-
lysts (Fig. 5) [42, 43]. Ketone 15 was found to be prone to Baeyer-Villiger oxidation to
the lactone, thus giving low yield for the epoxidation (Table 1, entry 14). Epoxidation
results were much improved with tricyclic ketone 16 (Table 1, entries 15, 24).
2.2 Ammonium Ketones
Denmark and coworkers reported 4-oxopiperidinium salt 17 to be an effective cata-

lyst under biphasic conditions (Fig. 6) [44, 45]. The choice of the alkyl groups on
the nitrogen affects the lipophilicity of the ketone, thus influencing the partitioning
O
O Me + Me 2OTf −
N
OTf − Me Me
N+ +N
+ Me Me
N OTf −
R R' F
O
17 18 19
O O
+ Me Me 2OTf −
N
2OTf − + Ph Ph
N N N N N
+ + + +
O
Ph Ph
2OTf − Me Me 22
20 21
CO 2 Et
N O
X X AcO
OAc
O
AcO
O
O O
25
23a, X = F 24a, X = F
23b, X = OAc 24b, X = OAc
ability of the ketone and/or the dioxirane between the organic and aqueous phases.
The oxidation efficiency is also dependent on the counterion, and triflate anion was
found to be an effective one. Based on this study, a number of chiral ammonium
ketones were studied (Fig. 6) [22, 40, 44, 46, 47]. Tropinone-based rigid ammo-
nium ketone 18 showed good general reactivity, and up to 58% ee was obtained for
trans-stilbene oxide with 10% mol catalyst loading. Bis(ammonium) ketones 19–22
were also found to be active epoxidation catalysts. trans-b-Methylstyrene can be
epoxidized in up to 40% ee using ketone 20.
2.3 Bicyclo[3.2.1]octan-3-ones and Related Ketones
In 1998, Armstrong and coworkers reported tropinone-based fluorinated ketone

23a to give good enantioselectivities for several trans-olefins (Fig. 7) (Table 2,
entries 1, 6) [48, 49]. The replacement of the fluorine atom with an acetate group

Entry Substrates Catalyst Conv. (%) ee (%)
Ph
1 Ph 23a 100 76 (R,R)
2 23b 100 86a
3 24a 100 83a
4 24b 85 93a
5 25 100 81 (S,S)
Ph
Ph
6 Ph 23a 100 83 (R)
7 24b 71 98a (R)
eemax 100(epoxide ee/ketone ee)
a
(23b) and/or the replacement of the bridgehead nitrogen with an oxygen atom (24)
increased the enantioselectivity of the epoxidation [49–51]. Up to 98% eemax was
obtained for the epoxidation of phenylstilbene using ketone 24b (Table 2, entries
2–4, 7). However, it appears that ketone 24b is difficult to prepare in enantiomeri-
cally pure form. In 2006, enantiomerically pure tetrahydropyran-4-one 25 was
investigated to evaluate the role of the bicyclic framework in ketones 23 and 24
[52]. Absence of the bicyclic framework results in the reduction of enantioselectiv-
ity in some cases. However, trans-stilbene can still be epoxidized in 81% ee. This
result for ketone 25 suggested that the axial heteroatom plays an important role in
enantioselectivity (Table 2, entry 5).
2.4 Carbohydrate-Based and Related Ketones
2.4.1 Catalyst Development for the Epoxidation of trans- and Trisubstituted

Olefins
In 1996, ketone 26 was reported to be a highly effective epoxidation catalyst for a

variety of trans- and trisubstituted olefins [53]. Ketone 26 can be readily synthe-
sized from D-fructose by ketalization and oxidation (Scheme 2) [54–56]. The
enantiomer of ketone 26 (ent-26) can be obtained by the same methods from
L-fructose, which can be obtained from L-sorbose [57, 58].
OH O O O
O OH O O O O
[O]
OH H
+ OH O O
HO O
HO O O
26
Scheme 2 Synthesis of ketone 26

In ketone 26, the chiral control elements are close to the reacting carbonyl, thus
enhancing the stereochemical communications between the catalyst and the substrate.
The fused ring or quaternary centers are placed at the α-position to the carbonyl
group, which minimizes potential epimerization of the stereogenic centers.
Electron-withdrawing oxygen substituents inductively activate the carbonyl.
The epoxidation with ketone 26 was also found to be highly pH dependent. Earlier
epoxidations using in situ generated dioxirane were usually carried out at pH 7–8,
since Oxone rapidly autodecomposed at high pH value [59, 60]. In contrast, higher
pH was found to be beneficial to the epoxidation with ketone 26. For example, the
substrate conversion increased from ca. 5% with pH being 7–8 to >80% with pH >10
for trans-ß-methylstyrene. The optimal reaction pH value is around 10.5 [54, 61].
Because of the acidic nature of Oxone, the epoxidation with ketone 26 is performed
in buffer and with the addition of either K2CO3 or KOH to maintain a steady pH
throughout the reaction to ensure maximum conversion. Aqueous Na2B4O7•10H2O
solutions or a mixture of acetic acid and aqueous K2CO3 are commonly used as buff-
ers for this reaction. The increased epoxidation efficiency at higher pH is presumably
due to the suppression of Baeyer-Villiger oxidation of the ketone catalyst (Scheme 3)
and/or the increased nucleophilicity of Oxone toward the carbonyl group.
O
R1
R3
R2 O
O O −
HSO5 O
O O
R1
R3 O O
O
R2 O O
O O
26 O
O O B.V. 30
O
O O
OH and/or
O O O
O O O SO3
O O
O 27 O O
29 O OH
O O O O
O
O
SO42− O 31
O O
O
O SO3
28
Scheme 3 Ketone 26 catalyzed epoxidation
A catalytic amount of ketone 26 was used to investigate the substrate scope of

the asymmetric epoxidation. High enantioselectivities can be obtained for a wide
variety of trans- and trisubstituted olefins (Table 3, entries 1–4) [54]. Simple trans-
olefins, such as trans-7-tetradecene, can be epoxidized in high yield and enantio-
meric excess, indicating that this asymmetric epoxidation is generally suitable for
trans-olefins. 2,2-Disubstituted vinyl silanes are epoxidized in high ees (Table 3,
entries 5, 6) and enantiomerically enriched 1,1-disubstituted epoxides can be
Table 3 Asymmetric epoxidation with ketone 26

Entry Substrates Yield (%) ee (%)
Ph Ph
1 85 98 (R,R)
n-C6H13
2 n-C6H13 89 95 (R,R)
Ph
3 Ph 89 96 (R,R)
Ph
4 94 98 (R,R)
TMS
5 Ph 74 94 (R,R)
6 HO TMS 71 93 (R,R)
7 Ph OH 85 94 (R,R)
8 OH 82 90 (R,R)
Ph
9 Ph 77 97
a b
TMS
10a Ph 81 95
O
a b
OEt
11 a
89 94
12 78 93 (R,R)
13 60 93 (R,R)
OBz
14 82 93 (R,R)
OAc
15 Ph 66 91 (2S,3R)
a
Alkene a is selectively epoxidized
obtained via the desilylation of these epoxides [62]. Allylic and homoallylic alco-
hols are also effective substrates (Table 3, entries 7, 8) [63]. Enantioenriched vinyl
and propargyl epoxides can also be obtained in high ees by regio- and chemoselec-
tive epoxidations of conjugated dienes and enynes (Table 3, entries 9–13) [64–66].
The epoxidations of enol ethers and enol esters were also studied (Table 3, entries
14, 15) [67]. Enol esters generally gave higher enantioselectivities. The resulting
epoxide can undergo stereoselective rearrangement to give optically active
α-acyloxy ketones [68–70]. This rearrangement can operate through two different
pathways when different Lewis acids are used, resulting in either retention or inver-
sion of configuration. The kinetic resolution of racemic enol ester epoxide using
chiral Lewis acid was also examined. Good enantiomeric excess can be obtained
for both α-acyloxy ketone and the unreacted enol ester epoxide using [(R)-BINOL]2-
Ti(OiPr)4 as catalyst [69].
A high catalyst loading (typically 20–30 mol%) is usually required for the
epoxidation with ketone 26 because Baeyer-Villiger oxidation presumably decom-
poses the catalyst during the epoxidation. The fused ketal moiety in ketone 26 was
replaced by a more electron-withdrawing oxazolidinone (32) and acetates (33) with
the anticipation that these replacements would decrease the amount of decomposi-
tion via Baeyer-Villiger oxidation (Fig. 8) [71, 72]. Only 5 mol% (1 mol% in some
cases) of ketone 32 was needed to get comparable reactivity and enantioselectivity
with 20–30 mol% of ketone 26 [71]. Since dioxiranes are electrophilic reagents,
they show low reactivity toward electron-deficient olefins, such as α,b-unsaturated
esters. Ketone 33, readily available from ketone 26, was found to be an effective
catalyst towards the epoxidation of α,b-unsaturated esters [72].
While Oxone (2KHSO5•KHSO4•K2SO4) has been commonly used to gener-
ate dioxiranes from ketones, studies showed that epoxidation with ketone 26
can be carried out with a nitrile and H 2O2 as the primary oxidant, giving high
enantioselectivities for a variety of olefins (Scheme 4) [73–75]. Peroxyimidic
acid 34 is likely to be the active oxidant that reacts with the ketone to form
dioxirane under the epoxidation conditions. Mixed solvents, such as CH 3CN-
EtOH-CH2Cl2, improve the conversions for substrates with poor solubilities.
No slow addition is necessary for the epoxidation with H2O2. Additionally,
this epoxidation system is mild and greatly reduces the amount of solvent and
salts involved.
Two extreme epoxidation modes, spiro and planar, are shown in Fig. 9 [33, 34,
53, 54, 76–85]. Baumstark and coworkers had observed that the epoxidation of cis-
hexene of dimethyldioxirane was seven to nine times faster than the corresponding
epoxidation of trans-hexene [79, 80]. The relative rates of the epoxidation of
cis/trans olefins suggest that spiro transition state is favored over planar. In spiro
transition states, the steric interaction for cis-olefin is smaller than the steric interac-
tion for trans-olefin. In planar transition states, similar steric interactions would be
expected for both cis- and trans-olefins. Computational studies also showed that the
spiro transition state is the optimal transition state for oxygen atom transfer from
dimethyldioxirane to ethylene, presumably due to the stabilizing interactions
O
O O O
O O
N O
t BuO AcO O
O
AcO
O O
32 33

O
R1 NH
R3 H2O2
O RCN
R2 O O HOO R
34
O O
R1 O
R3
R2 26
O
O O O
O O
O H
O O
O O N H
O O
O O
36 35 R
R NH2
Scheme 4 Ketone 26 catalyzed epoxidation with H2O2 as the oxidant
O R O R
O R
O R
Spiro Planar
O R O
R
R Oxygen non-bonding Oxygen non-bonding
O R
orbital O orbital
Olefin π* orbital Olefin π* orbital
Fig. 9 The spiro and planar transition states for the dioxirane epoxidation of olefins
between the oxygen non-bonding orbital with the alkene p* orbital in the spiro
transition state [81–84].
The stereochemistry of the resulting epoxidation products using chiral ketones,
such as ketone 26, could provide new insights about the epoxidation transition
states. Studies showed that the epoxidation of trans- and trisubstituted olefins with
ketone 26 mainly goes through the spiro transition state (spiro A) (Fig. 10). Planar
transition state B competes with spiro A to give the opposite enantiomer [53, 54].
Hence, factors that influence the competition between spiro A and planar B will
also affect the enantiomeric excess of the resulting epoxides. Spiro A can be further
O O
O O
R3 O R1
O
R1 R R2
O 2 R3 O
O O O
O O O
Spiro (A) Planar (B)
R1 H H R1
R2 O R3 R3 O R2
Major enantiomer Minor enantiomer
Fig. 10 The competing spiro and planar transition states for the epoxidation with ketone 26
favored by conjugation of the alkene. Conjugation lowers the energy of the p*

orbital of the alkene and enhances the stabilizing interaction between the dioxirane
and the olefin (Fig. 9). Decreasing the size of R1 (further favoring spiro A) and/or
increasing the size of R3 (disfavoring planar B) can also result in higher ees for the
epoxidation. The transition state modes for ketone 26 were further supported by
results obtained from kinetic resolution of 1,6- and 1,3-disubstituted cyclohexenes
[86] and desymmetrization of cyclohexadiene derivatives [87].
2.4.2 Synthetic Applications of Ketone 26
The availability of ketone 26 and its effectiveness toward a wide variety of trans-
and trisubstituted olefins make the epoxidation with this ketone a useful method.
Other researchers have used ketone 26 in the synthesis of optically active complex
molecules. Some of these studies will be highlighted in this section.
In the enantioselective total synthesis of nigellamine A2 (39), Ready and cowork-
ers reported the selective epoxidation of 37 to obtain 38 (Scheme 5) [88]. Compound
O
N
OH OH O
H H H
Ketone 26 Nicotinic acid
Oxone O O
O DCC, DMAP
O O
OH O Ph OH O O O
Ph Ph
37 38 O
N
(+)-Nigellamine A2 (39)
Scheme 5 Synthesis of nigellamine A2

37 contains three double bonds; however, the desired one is preferentially epoxidized.
In this case, the conformation of the substrate appears to be an important factor as to
which face of the alkene gets epoxidized since the same diastereomer was generated
using either ketone 26 or ent-26 as the epoxidation catalyst.
Oxygenated triterpenoid marine natural products nakorone (43) and abudinol
(44) were synthesized by McDonald and coworkers in 2007 (Scheme 6) [89].
TolO2S
Me H Me
O O TMSO
H
Me Me
Me Me Me O
Me H
41 >20:1 dr TMS
42
Ketone 26
Oxone
76% Me
H
TolO2S H Me HO H
Me HO Me H OH
Me
H O O
Me Me H O Me
Me O
Me H H Me
Me Me Me ent-Abudinol (44)
ent-Nakorone (43)
40 TMS
Scheme 6 Syntheses of nakorone and abudinol
Stereocenters were introduced in the synthesis via asymmetric epoxidation of

triene-yne 40. Only two of the three more electron-rich alkenes were selectively
epoxidized, leaving the alkene closest to the sulfone group unreacted.
Polycyclic oxasqualenoid glabrescol was synthesized by Corey and coworkers
in order to confirm its structure. Several pentaoxacyclic compounds were synthe-
sized via epoxidation with ketone 26 followed by cyclizations [90]. Finally,
compound 48 was synthesized to match the properties of the naturally occurring
glabrescol, leading to the determination of the stereochemistry of glabrescol
(Scheme 7) [91].
McDonald and coworkers studied a series of tandem endo-selective and
stereospecific oxacyclization of polyepoxides by reaction with Lewis acid
[92–95]. Polyepoxides, such as 50, can be obtained from the epoxidation of
triene 49 with ketone 26 (Scheme 8). This cascade cyclization of polyepox-
ides provides an efficient method to synthesize substituted polycyclic ether
structures, which are present in a number of biologically active marine natu-
ral products.
In recent studies, Jamison and coworkers reported the formation of tetrahydro-
pyran via cascade epoxide-opening reactions in water (Scheme 9) [96]. In this
study, polytetrahydropyran precursor, such as 53, was synthesized from the epoxi-
dation of polyalkene 52.
O O
Ketone 26 CSA
O O
Oxone CH 2 Cl 2
OH HO OH HO
OH OH OH OH
45 46
H H
HO OH Me Me
Me Me
O
O O
O O H H
H H
Me Me
Me Me
O O
O O
H H
H H
OH OH
OH OH
47 Glabrescol (48)
Scheme 7 Synthesis of glabrescol
Me H H H Me H H H
O O
O
Ketone 26 O O O O
Me2N O
Oxone Me N O H H
H H H Me Me 2 H Me Me
49 50
Me H H H
1) BF 3-OEt 2 O O OAc
O
2) Ac2O
O O O
pyridine H H H Me Me
25% from 50 51
Scheme 8 Synthesis of polycyclic ether 51
H H
TBSO TBSO
Ketone 26 O O
Me Me
O Oxone O
H O H
52 53
H H H H
Me O O
1) TBAF, THF
2) H 2 O, 70  C Me O O
H H H H
54
Scheme 9 Synthesis of polytetrahydropyran 54

2.4.3 Catalyst Development for the Epoxidation of cis-Olefins, Styrenes,

and Other Olefins
In addition to the enantioselective epoxidation of trans- and trisubstituted olefins,

efforts have also been made for the asymmetric epoxidation of cis- and terminal
olefins. Glucose-derived ketone 55 was reported to be a highly enantioselective
catalyst for the epoxidation of various cis-olefins and certain terminal olefins (Fig. 11,
Table 4) [97–100]. The results of epoxidation with ketone 55 indicate that a p
O O
O
O O
O NR NR
O NBoc Rπ R
O O
R Rπ
O O O
O O O O
O O O
O 55
Spiro (C) Spiro (D)
Favored
Fig. 11 The competing transition states for the epoxidation with ketone 55
Table 4 Asymmetric epoxidation with ketone 55

Entry Substrates Yield (%) ee (%)
1 87 91 (1R,2S)
2 88 83 (1R,2S)
3 61 91 (3R,4R)
4 77 87 (2S,3R)
5 61 97
6 92 81 (R)
7 90 85 (R)
substituent on the substrate prefers to be proximal to the spiro oxazolidinone of

ketone 55 in the transition state (spiro C favored over spiro D, Fig. 11). When
epoxidation of l-phenylcyclohexene was carried out with ketone 26, the (R,R) epox-
ide was formed in 98% ee since spiro transition state E is favored over planar F.
However, when the same epoxidation was carried out with ketone 55, the epoxide
with absolute configuration (S,S) was obtained instead (Fig. 12). This suggests an
attraction between Rp of the olefin and the oxazolidinone is strong enough that
planar H is favored over spiro G.
A carbocyclic analogue of ketone 55 (56) was synthesized as a catalyst for elec-
tronic and conformational studies (Fig. 13) [101]. Ketone 56 was found to epoxi-
dize styrenes in higher ees (89–93% ee) and the opposite enantiomer for the
epoxidation of 1-phenylcyclohexene as compared to ketone 55. The X-ray structure
showed that ketones 55 and 56 have similar conformations (at least in the solid
state). These findings suggested that the replacement of the pyranose oxygen with
a carbon influences the epoxidation transition states via an electronic effect rather
than a steric effect. The replacement of the pyranose oxygen with a carbon may
have increased the beneficial secondary orbital interaction (between the non-bonding
O O
O O
Ph Ph
O Ph O
O O O
O O O O
O O
(R,R) Spiro (E) Planar (F)
Favored
O O
O O
NR NR Ph
Ph
O Ph O
O
O O
O O O O
O O
Spiro (G) Planar (H) (S,S)
Favored
Fig. 12 The competing transition states for the epoxidation of 1-phenylcyclohexene with
ketone 26 and ketone 55
Fig. 13 Ketone 56
orbital of the dioxirane and the p* orbital of the alkene) by raising the energy of the
non-bonding orbital of the dioxirane. Consequently, (R,R)-1-phenylcyclohexene
oxide is produced from the epoxidation with ketone 56 because spiro I is favored
over planar J (Fig. 14). In the case of styrene epoxidation with ketone 56, both spiro
transition states (desired spiro K and undesired spiro L) are further favored over
planar M due to the increased secondary orbital interaction (Fig. 15). The reduced
contribution of M leads to more enantioenriched styrene oxides.
The encouraging epoxidation results using ketone 55 led to the development of
a series of more readily available catalysts (57) (Fig. 16) [102, 103]. Phenyl group
substituted with hydrocarbons and electron-withdrawing groups gave better results
than other substitutions such as halogens or ethers. Ketones 57 are synthesized in
four steps from glucose and inexpensive anilines (Scheme 10), and large-scale
syntheses of these ketones are feasible [104]. Preliminary results indicated that
ketones 57 provide high enantioselectivity for a number of olefins, thus further
substrate scope exploration was done with these ketones.
Fig. 14 The competing transition states for the epoxidation of 1-phenylcyclohexene with
ketone 55 and ketone 56
Fig. 15 The competing transition states for the epoxidation of styrenes

Scheme 10 Synthesis of ketone 57
cis-b-Methylstyrenes were epoxidized in high conversion and ees (Table 5, entries

1, 2) [105]. The substrates bearing substituents are epoxidized with higher enantiose-
lectivities presumably because the substituents further enhance the interaction between
the phenyl group of the catalyst and the phenyl group of the olefin, thus further favor-
ing spiro N over spiro O (Fig. 17). Subsequently, a series of 6- and 8-substituted
chromenes were studied to further investigate this substituent effect [106]. For 6-sub-
stituted chromenes (e.g. Table 5, entries 5, 6), regardless of the substituent, the enanti-
oselectivities increased compared to non-substituted chromenes. However, the ees
increased for 8-substituted chromenes with electron-withdrawing groups (e.g. Table 5,
entries 7, 8) and decreased with electron-donating groups. The substituents at the
8-position likely influence the enantioselectivity via electronic effect. The substituents
at the 6-position might cause additional beneficial non-bonding interactions between
the substrate and the catalyst, thus further favoring spiro P over Q (Fig. 18). However,
such interaction is not feasible in the case of the 8-substituted chromenes (Fig. 18,
spiro R and S). N-Alkyl substituted ketone 58 (Fig. 16) also gave good enantioselec-
tivities for chromenes (Table 5, entries 4, 6, 8). This result suggested that van der Waal
forces and/or hydrophobic effects are possibly important factors in the beneficial inter-
action between the substrate and the N-substituent of the catalyst.
Styrenes [103], conjugated cis-dienes [107], and cis-enynes [108] are also
epoxidized with ketones 57 in high ees (Table 5, entries 9–14). No isomerization of
the epoxides was observed; therefore only cis-epoxides were obtained from cis-
olefins. Alkenes and alkynes appear to be effective directing groups to favor the
desired transition states T and V (Fig. 19).
Trisubstituted and tetrasubstituted benzylidenecyclobutanes can be readily
epoxidized and the resulting epoxides can be rearranged to 2-aryl cyclopentanones
with either retention or inversion of configuration using LiI or Et2AlCl, respectively
(an example of trisubstituted benzylidenecyclobutane is shown in Scheme 11) [109,
110]. This method provides a convenient way to obtain optically active 2-aryl
Fig. 17 The competing transition states for the epoxidation of β-methylstyrenes
cyclopentanones which have not been easily obtained otherwise. Furthermore, ben-
zylidenecyclopropanes are epoxidized and rearranged to obtain optically active
g-aryl-g-butyrolactones and g-aryl-g-methyl-g−butyrolactones in good enantioselec-
tivities (examples are shown in Scheme 12) [111]. Chiral cyclobutanones can also
be obtained by suppressing Baeyer-Villiger oxidation with more catalyst and less
Oxone. An epoxidation protocol with ketone 57 using H2O2 as primary oxidant was
also developed [112].
2.4.4 Other Carbohydrate-Based Catalysts
Shing and coworkers reported arabinose-derived uloses (59, 60) as epoxidation

catalysts, and phenyl stilbene can be epoxidized by 60 in up to 90% ee (Fig. 20)
[113–115]. In 2003, Zhao and coworkers reported aldehyde 61 to epoxidize trans-
stilbene in up to 94% ee [116].
2.5 Carbocyclic Ketones
A fused ring and a quaternary center α to the carbonyl group have been used as the
chiral control elements in ketones such as 26, 55–58 (Fig. 21). A series of pseudo
C2-symmetric ketones (62), bearing two fused rings on each side of the reacting
carbonyl, has been reported [117, 118]. A variety of olefins, including electron-
deficient olefins, could be epoxidized using only 5–10 mol% ketones 62 in good
yields and enantioselectivities (Table 6, entries 1, 2, 15–18).
In 1998, Yang and coworkers reported a series of (R)-carvone derived ketones (63)
containing a quaternary center at C2 and various substituents at C8 (Fig. 22) [119].
The ees of trans-stilbene oxide varied with different para and meta substituents
when 63b was used as the catalyst. The major contribution for the observed ee dif-
ference is from the n-p electronic repulsion between the Cl atom of the catalyst and
the phenyl group of the substrate. The substitution at C8 also influences the epoxi-
dation transition state via an electrostatic interaction between the polarized C8-X
bond and the phenyl ring on trans-stilbene (Table 6, entries 3–7, 10–14). In 2000,
Solladié-Cavallo and coworkers reported a series of fluorinated carbocyclic ketones
Table 5 Asymmetric Epoxidation with Ketone 57 and 58

1 57a 99 a
84
2 57a 79a 92
3 57b 100a 84
4 58 100a 84
5 57b 83a 93 (R,R)

6 58 71a 89 (R,R)
7 57b 95a 88
8 58 87a 89
9 57b 72 86 (R)
10 57b 86 90 (R)
11 57a 74 94
12 57a 64 94
13 57b 54 87
14 57a 76 93
a
Conversion (%)
Fig. 18 The competing transition states for the epoxidation of 6- and 8-substituted chromenes
Fig. 19 The competing transition states for the epoxidation of dienes and enynes
Scheme 11 Rearrangement of benzylidenecyclobutane oxide

Scheme 12 Rearrangements of benzylidenecyclopropane oxides
Fig. 21 Fused ring ketones 26, 55–58 and pseudo C2-symmetric ketones 62
(an example, 64, is shown in Fig. 22) [120–126]. Up to 90% ee can be obtained for
the epoxdation of trans-stilbene with ketone 64 (Table 6, entry 8). Bortolini and
coworkers reported asymmetric epoxidations using a series of keto bile acids as
dioxirane precursors (an example is shown in Fig. 22). Ketone 65, having substitu-
tion at C12, epoxidizes trans-stilbene in up to 98% ee (Table 6, entry 9) [127].

1 62a 95 90 (R,R)
2 62b 91 96 (R,R)
3 63a – 87.4
4 63b – 85.4
5 63c – 80.9
6 63d – 73.8
7 63e – 42.0
8 64 95a 90 (S,S)
9 65 50 98 (R,R)
10 X = tBu 63b – 87.3

11 X = Me 63b – 87.2
12 X=F 63b – 78.5
13 X = Br 63b – 74.8
14 X = OAc 63b – 71.5
15 62a 34 86 (2S,3R)
16 62b 35 89 (2S,3R)
17 62a 80 94 (2S,3R)
18 62b 85 96 (2S,3R)
a
Conversion (%)
3 Chiral Iminium Salt-Catalyzed Epoxidations
In 1976, the synthesis of oxaziridinium salt 66 was reported by Lusinchi and coworkers
(Fig. 23) [128–130]. Salt 66 was obtained by either methylation of the corresponding
oxaziridine with FSO3Me or oxidation of the corresponding iminium salt with
peracid. Subsequently, Hanquet and coworkers prepared oxaziridinium salt 67 by
methylation of the corresponding oxaziridine with Meerwein’s salt (Me3O+BF4−) or
oxidation of the N-methyl isoquinolinium fluoroborate salt with peracid [131, 132].
Fig. 23 Oxaziridinium salts 66–67
Isolated or in situ generated oxaziridinium salt 67 efficiently epoxidizes various

olefins in good yields [133–135].
3.1 Dihydroisoquinoline-Based Iminium Salts
In 1993, Bohé and coworkers synthesized enantiomerically pure oxaziridinium salt

71 by methylation with Meerwein’s salt and oxidation with mCPBA from dihydr-
oisoquinoline 68 (Scheme 13) [136, 137]. Alternatively, 71 could also be produced
by switching the reaction order. Epoxidations were carried out with either
Scheme 13 Synthesis of oxaziridinium salt 71
s toichiometric amounts of recrystallized 71 or catalytic amount of in situ generated

71. trans-Stilbene was epoxidized with 5 mol% of in situ generated 71 using
Oxone-NaHCO3 in MeCN-H2O in 80–90% conversion and 35% ee (Table 7, entry
1). Studies showed that the transition states of such reaction have strong ionic character
since the reaction rate increased in polar aprotic solvents such as nitrobenzene and
nitromethane. In 2000, Rozwadowska and coworkers reported the synthesis of the
enantiomer of iminium salt 69 (ent-69) [138, 139]. The enantioselectivity of epoxi-
dations using ent-69 are similar to those of 69.
Table 7 Asymmetric epoxidation with iminium salts 71, 74, 76–82

1 71 80–90a 35 (R,R)
2 74a 78 73 (R,R)
3 74cb 31 67 (R,R)
4 74a 68 40 (R,R)
5 74b 55 41 (S,S)
6 74c 100a 39 (S,S)
7 74cb 77 48 (R,R)
8 76 80 71 (R,R)
9 77 69 91 (S,S)
10 77b 81 89 (S,S)
11 78 64a 79 (S,S)
12 79 73 82 (S,S)
13 80 100a 29 (R,R)
14 81 100a 60 (S,S)
15 81b 100a 67 (S,S)
16 82 100a 69 (S,S)
17 74a 73 63
18 74b 64 49 (1S,2R)
19 74c 100a 47 (1S,2R)
20 74cb 98 59 (1R,2S)
21 77 66 95 (1R 2S)
22 77b 61 89 (1R,2S)
23 78 34a 71 (1R,2S)
24 79 68 83 (1R,2S)
25 80 95a 38 (1S,2R)
26 81 90a 41 (1S,2R)
27 81b 100a 65 (1R,2S)
28 82 85a 76 (1R,2S)
29 74cb 59 97 (1S,2S)
a
Conversion (%)
b
Non-aqueous Conditions
In 1998, Page and coworkers reported a series of dihydroisoquinoline-related

iminium salts which can be readily synthesized in three steps from a chiral amine
(Scheme 14) [140–143]. Among the catalysts tested for asymmetric epoxidation,
iminium salts 74 were found to be efficient catalysts (Fig. 24, Table 7, entries 2,
4–6, 17–19). Iminium salts 74a can epoxidize 4-phenyl-1,2-dihydronaphthalene in
up to 63% ee (Table 7, entry 17).
Scheme 14 Synthesis of iminium salt catalysts 74
Fig. 24 Iminium salts 74
Epoxidation reactions are normally carried out in aqueous conditions due to the
low solubility of Oxone in organic solvents. In 2004, Page and coworkers devel-
oped a non-aqueous condition for the epoxidation of olefins using iminium salt 74
with organic solvent soluble oxidant tetraphenylphosphonium monoperoxysulfate
(TPPP) [144–146]. Epoxidations can be carried out at lower temperatures in
organic solvent since the reaction mixture usually freezes under –8 °C with aqueous
conditions. Good enantioselectivites were obtained for the epoxidation of a number
of cis-olefins (Table 7, entries 29), and up to 97% ee was obtained for the epoxida-
tion of 2,2-dimethyl-6-cyanochromene by using iminium salt 74c (Table 7, entry
29) [145].
3.2 Binaphthylazepinium-Based Iminium Salts
In 1996, Aggarwal and coworkers synthesized binaphthyl-based iminium salt 76

via oxidation and methylation from binaphthylamine (Scheme 15) [147]. Catalyst
loading of 5 mol% is sufficient to catalyze the epoxidation of a number of olefins
in good yield. Up to 71% ee can be obtained for 1-phenylcyclohexene oxide using
this catalytic system (Table 7, entry 8).
Scheme 15 Synthesis of iminium salt catalyst 76

In 2004, Page and coworkers reported binaphthyl-based iminium salt 77 to be a

highly reactive and enantioselective catalyst for the epoxidation of trisubstituted ole-
fins (Fig. 25, Table 7, entries 9, 21) [148, 149]. Catalyst loading can be as low as
0.1 mol% to get comparable results with 5 mol% for the epoxidation of l-phenylcy-
clohexene. Iminium salt 77 was also employed in non-aqueous epoxidation reaction
(Table 7, entries 10, 22) and up to 81% yield and 89% ee were obtained for 1-phenyl-
cyclohexene oxide [150]. Lacour and coworkers reported iminium salts with
TRISPHAT [tris(tetrachlorobenzenediolato)phosphate(V)] as counterions (78). The
lipophilicity of TRISPHAT keeps the salt in the organic layer once it is dissolved.
The addition of catalytic 18-crown-6 brings KHSO5 into the organic layer and gener-
ally provides higher conversions (Table 7, entries 11, 23) [151]. Another set of
binaphthalene-fused azepinium salts was also reported recently by Page [152].
Among the catalysts studied, 79 was found to give the best results (up to 83% ee for
the epoxidation of 4-phenyl-1,2-dihydronaphthalene, Table 7, entry 24).
3.3 Biphenylazepinium-Based Iminium Salts
In 2002, Page and coworkers reported a series of biphenylazepinium-based imin-

ium salts (80, 81) to be reactive epoxidation catalysts (Fig. 26, Table 7, entries 13,
14, 25, 26) [143, 153]. Up to 60% ee could be obtained for the epoxidation of
Fig. 25 Iminium salts 77–79

1-phenylcyclohexene under aqueous conditions with iminium salt 81 (Table 7,

entry 14). In some cases, the enantioselectivity can be improved by using non-
aqueous epoxidation conditions (Table 7, entries 15, 27) [144, 150]. Iminium salt
82, having TRISPHAT as counterion, also reported by Lacour and coworkers, gives
higher enantioselectivity for the epoxidation of 4-phenyl-1,2-dihydronaphthalene
(Table 7, entry 28) [151, 154, 155].
3.4 Acyclic Iminium Salts
While most of the iminium salts studied are cyclic, several acyclic iminium salts
have also been investigated. In 1997, Armstrong and coworkers reported the use of
acyclic iminium salt 83 as chiral epoxidation promoter (Fig. 27) [156, 157].
1-Phenylcyclohexene oxide could be obtained in 100% conversion and 22% ee with
stoichiometric amounts of 83. In 2002 acyclic iminium salt 84, prepared from
L-prolinol, was investigated by Komatsu and coworkers, and cinnamyl alcohol was
epoxidized in 70% yield and 39% ee (Fig. 27) [158].
In 2001, Yang and coworkers studied the use of in situ generated acyclic iminium
salts as epoxidation catalysts [159]. Epoxidations of a number of alkenes proceed
with 20–50 mol% of amine 85 and aldehyde 86 with Oxone as the primary oxidant
(Fig. 28.) Methylstilbene can be obtained in 100% conversion and 59% ee.
4 Conclusion
Epoxidation of alkenes using chiral ketones and iminium salts has been extensively
studied in numerous laboratories over the past 10 years. Significant progress has
been made in this area. High enantioselectivities have been achieved for trans-,
trisubstituted, cis-, and certain terminal and tetrasubstituted olefins with chiral
ketones. The extensive study of the ketone-catalyzed epoxidation transition states
will provide a basis for the prediction of product stereochemistry and insight for the
further development of new catalysts. Chiral iminium salt catalysts are proven to be
highly active for the epoxidation of various olefins. Low catalyst loading and high
enantioselectivity have been achieved in a number of cases. Further studies of the
transition state model would be valuable for the development of chiral iminium salt
catalysts.
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Top Curr Chem (2010) 291: 233–280
DOI: 10.1007/128_2008_25
Published online: 05 June 2009
Amine, Alcohol and Phosphine Catalysts

for Acyl Transfer Reactions
Alan C. Spivey and Stellios Arseniyadis
Abstract An overview of the area of organocatalytic asymmetric acyl transfer

processes is presented including O- and N-acylation. The material has been ordered
according to the structural class of catalyst employed rather than reaction type with
the intention to draw mechanistic parallels between the manner in which the various
reactions are accelerated by the catalysts and the concepts employed to control
transfer of chiral information from the catalyst to the substrates.
Keywords Acylation • Asymmetric desymmetrisation • Esterification • Kinetic

resolution • Nucleophilic catalysis
Contents
1 Introduction......................................................................................................................... 235
2 Phosphine Catalysts............................................................................................................ 237
2.1 Phospholane-Based Systems...................................................................................... 238
3 tert-Amine Catalysts............................................................................................................. 241
3.1 Pyrrole-Based Catalysts............................................................................................. 242
3.2 (4-Dialkylamino)Pyridine-Based Catalysts............................................................... 243
3.3 Dihydroimidazole-Based Catalysts............................................................................ 256
3.4 N-Alkylimidazole-Based Catalysts............................................................................ 259
3.5 1,2-Di(tert-amine)-Based Catalysts........................................................................... 263
3.6 Quinine/Quinidine-Based Catalysts (e.g., Cinchona Alkaloids)............................... 265
A.C. Spivey (*)

Department of Chemistry, South Kensington Campus, Imperial College, London, SW7 2AZ, UK
e-mail: a.c.spivey@imperial.ac.uk
S. Arseniyadis (*)
Laboratoire de Chimie Organique, CNRS, ESPCI, 10 Rue Vauquelin, 75231 Paris Cedex 05,
France
e-mail: stellios.arseniyadis@espci.fr
234 A.C. Spivey and S. Arseniyadis
3.7 Imidazolone-Based Catalysts..................................................................................... 272

3.8 Piperidine-Based Catalysts........................................................................................ 273
3.9 Sulfonamide-Based Catalysts.................................................................................... 273
4 Alcohol Catalysts.................................................................................................................. 273
4.1 Trifluoromethyl-sec-Alcohol-Based Catalysts........................................................... 273
5. Concluding Remarks............................................................................................................ 275
References................................................................................................................................... 275
Abbreviations
Ac Acetyl
Alloc Allyloxycarbonyl
ASD Asymmetric desymmetrization
Bn Benzyl (CH2Ph)
Boc Tert-butoxycarbonyl
C Conversion
Cat Catalyst
Cbz Benzyloxycarbonyl
Cy Cyclohexyl
(DHQ)2AQN Hydroquinine anthraquinone-1,4-diyl diether
(DHQD)2AQN Hydroquinidine anthraquinone-1,4-diyl diether
4-DMAP 4-(Dimethylamino)pyridine
E Electrophile
ee Enantiomeric excess
ent Enantiomeric
er Enantiomeric ratio
Fmoc 9-Fluorenylmethyloxylacrbonyl
GABA g-Aminobutyric acid
GC Gas chromatography
HPLC High pressure liquid chromatography
KR Kinetic resolution
MS molecular seives
N/A Not available
Nap Naphthyl
NHC N-heterocyclic carbenes
NMR Nuclear magnetic resonance
nOe nuclear Overhauser effect
Nu Nucleophile
PBO P-aryl-2-phosphabicyclo[3.3.0]octane
Phe (S)-Phenylalanyl
PIP 2-Phenyl-2,3-dihydroimidazo[1,2a]pyridine
PIQ 2-Phenyl-1,2-dihydroimidazo[1,2a]quinoline
PKR Parallel KR
4-PPY 4-(Pyrrolidino)pyridine
rec SM Recovered starting material
s Selectivity factor
Amine, Alcohol and Phosphine Catalysts 235
sec Secondary
TADMAP 3-(2,2,-Triphenyl-1-acetoxyethyl)-4-dimethylamino)pyridine
TBDPS Tert-butyldiphenylsilyl
TBS Tert-butyldimethylsilyl
TES Triethylsilyl
TFA Trifluoroacetic acid
Trt Trityl (triphenylmethyl)
UNCA Urethane-protected a-amino acid N-carboxy anhydride
1 Introduction
The preparation of stereochemically-enriched compounds by asymmetric acyl trans-

fer using chiral nucleophilic catalysts has received significant attention in recent years
[1–8]. One of the most synthetically useful and probably the most studied acyl trans-
fer reaction to date is the kinetic resolution (KR) of sec-alcohols, a class of molecules
which are important building blocks for the synthesis of a plethora of natural prod-
ucts, chiral ligands, auxiliaries, catalysts and biologically active compounds. This
research area has been in the forefront of the contemporary ‘organocatalysis’ renais-
sance [9, 10], and has resulted in a number of attractive and practical KR protocols.
The mechanism by which chiral nucleophiles catalyze asymmetric acyl transfer
in the KR of sec-alcohols can be seen as a three-step process (Scheme 1) [2].
The first step involves attack of the chiral nucleophile on an achiral acylating
agent resulting in a chiral species which must be notably more reactive than the
parent achiral acylating agent in order to undergo attack by either enantiomer of the
racemic mixture of alcohols (step 2). This attack proceeds via two diastereomeric
transition states which should be significantly different in energy for the resolution
B . HX O
Cat:*
R X
Step 3 Step 1
B:
O
Cat*. HX
R Cat* X
Step 2
O
R O OH
R1 * R2 R1 +
_ R2
NB. The symbol indicates the stereochemistry determining step
Scheme 1 General catalytic cycle for the asymmetric acylation of sec-alcohols [2]
to occur. In the final step, the chiral nucleophile is regenerated, generally by the use
of a stoichiometric amount of base, and re-engaged in the catalytic cycle (step 3).
The efficiency of such a process, and therefore of the catalyst, is expressed by
the selectivity factor (s) which is defined as the ratio of the relative rate constants
for the two reacting enantiomers (1) [11]:
rate of fast-reacting enantiomer (1)

Selectivity =
rate of slow-reacting enantiomer
Typically, a catalyst becomes synthetically useful when s> 10. Indeed, with such
levels of selectivity one can isolate a synthetically usable amount of essentially enan-
tiomerically pure unreacted starting material by driving the reaction past 50% conversion.
With a process of high selectivity (e.g., s > 50), significant amounts of highly enantio-
merically enriched both unreacted starting material and product can be isolated at
close to 50% conversion. Unfortunately, the selectivity factor is not directly measurable
[11]. Its determination is based on measurements of parameters such as the conversion
(C), the enantiomeric composition of the substrate and product (enantiomeric excess,
ee, or preferably [12], enantiomeric ratio, er) and the time elapsed (t) [13]. Its deter-
mination is also prone to error [14], notably if the enantiomeric purity of the catalyst
is not absolute [15–18]. Despite these limitations in this review we have tried to
record s and C values as well as ee/er values where available.
In general, catalytic asymmetric acyl transfer reactions can be classified into
two main types depending on the nature of the nucleophile and the acyl donor
(Scheme 2) [2].
Type I Type II
KR KR
O O
X R' NuH O O O
NuH Nu R' + NuH +
X Nu X
R1 R2 cat.* R1 R2 R1 R2 R1 R2 cat.* R1 R2 R1 R2
(±) 50% 50% (±) 50% 50%
ASD (site-selective) ASD (site-selective)
O X O OO Nu
O HX
R R
HNu NuH HNu Nu R' 100% 100%
O R
achiral achiral R
X R' NuH
or or or or
cat.* O cat.*
HNu NuH HNu Nu R' O X O OO
100% HX Nu 100%
R R R R R R R R
meso meso
Addition (p-Nu, face selective) Addition (p-E, face selective)
O O
O NuH O
OTMS X R'
O 100% C Nu H 100%
R1 cat.*
R1 cat.* R' R1 R2 R1 R2
NB. cat.* denotes an enantiomerically highly enriched acyl transfer catalyst
Scheme 2 Classification of catalyzed asymmetric acyl transfer process [2]

Hence, a reaction of Type I will involve a racemic or achiral/meso nucleophile

which will react enantioselectively with an achiral acyl donor in the presence of a
chiral catalyst, while on the other hand, a reaction of Type II will associate an achiral
nucleophile and a racemic or achiral/meso acyl donor in the presence of a chiral
catalyst. In both cases, when a racemic component is implicated the process constitutes
a KR and the maximum theoretical yield of enantiomerically pure product, given
perfect enantioselectivity, is 50%. When an achiral/meso component is involved,
then the process constitutes either a site-selective asymmetric desymmetrisation
(ASD) or, in the case of p-nucleophiles and reactions involving ketenes, a face-
selective addition process, and the maximum theoretical yield of enantiomerically
pure product, given perfect enantioselectivity, is 100%.
Until the last decade or so, the only synthetically useful catalytic asymmetric acyl
transfer processes involved the use of hydrolytic enzymes; particularly lipases and
esterases [19–22]. However, the preparative use of enzymes can be associated with a
number of well documented limitations, including their generally high cost, stringent
operating parameters, low volumetric throughput, batch to batch irreproducibility, and
availability in just one enantiomeric form. The significant interest in developing small
molecule chiral organocatalysts capable of mediating these important asymmetric trans-
formations over the past decade or so is in large part a consequence of researchers
trying to overcome these limitations. Although interest in asymmetric acyl transfer by
chiral nucleophiles can be traced back to Wegler in 1932 [23], it was only in 1996 that
the groups of Vedejs [24] and Fu [25, 26] independently reported efficient asymmetric
acyl transfer processes involving synthetic nucleophilic catalysts derived from an
organophosphine and a pyrrole derivative, respectively. These two very different
classes of nucleophiles have been further developed into ‘state-of-the-art’ asymmetric
acylating agents of wide synthetic utility. As a direct consequence, the KR of a number
of sec-alcohols has been demonstrated with selectivity factors approaching those of
natural enzymes. These seminal discoveries inspired the development of many addi-
tional interesting chiral nucleophiles, many of which are capable of mediating asym-
metric acyl transfer with synthetically useful levels of selectivity. All these systems
will be covered in this review with emphasis being given to their proposed mechanism
of action, the interactions that govern their selectivity and the strategies and hypoth-
eses that were used to design the various catalyst topologies.
It should be noted that asymmetric acyl transfer can also be catalyzed by chiral
nucleophilic N-heterocyclic carbenes [27–32] and by certain chiral Lewis acid
complexes [33–37] but these methods are outside the scope of this review.
Additionally, although Type I and Type II p-face selective acyl transfer processes
have been reported to be catalyzed by some of the catalysts described in this review,
these also lie outside the scope of this review.
2 Phosphine Catalysts
The accelerating influence of nucleophiles such as pyridine in acyl transfer proc-

esses has been known for over a century [38] and has led to the development of a
wide variety of highly selective chiral catalysts incorporating this catalophore.
By contrast, the use of phosphines as catalysts is a more recent phenomenon and

the development of chiral phosphines has been less well explored, possibly also
because of synthetic difficulties associated with developing chiral nucleophilic
phosphorus-containing scaffolds.
2.1 Phospholane-Based Systems
In 1993, Vedejs [39, 40] and coworkers first reported that tributylphosphine could
catalyze the acylation of alcohols with carboxylic acid anhydrides, with a reactivity
similar to that of 4-dimethylaminopyridine (4-DMAP). Subsequent work in the
same group showed that the catalytic activity increased in line with phosphorous
nucleophilicity: aryl(dialkyl) phosphines were found to be more active than
diaryl(alkyl) phosphines, and trialkylphosphines were by far the most effective cata-
lysts. Indeed, P-acylphosphonium salts, generated in situ from the corresponding
trialkylphosphines in the presence of an appropriate acyl donor could, a priori, be
compared to N-acylammonium salts in terms of reactivity. In the context of develop-
ing chiral nucleophilic catalysts for acyl transfer, phosphines have the advantage of
being configurationally stable while tert-amines require built-in geometric con-
straints to prevent racemization/epimerization through pyramidal inversion. This
unique feature provides greater flexibility for the design of an efficient chiral phos-
phine catalyst as compared to a tert-amine-based one. In 1996, Vedejs disclosed that
Burk’s cyclic phosphine [41], trans-2,5-dimethyl-1-phenylphospholane (1), was a
promising nucleophilic catalyst for the resolution of aryl alky sec-alcohols [24].
Indeed, by using m-chlorobenzoic anhydride (2.5 eq) as the acylating agent in the
presence of phosphine 1 (16 mol%), s values of 12–15 were obtained, the optimal
substrate being 2,2-dimethyl-1-phenyl-1-propanol (Scheme 3) [24].
As encouraging as these results were, the authors were concerned that the relatively
poor reactivity of their catalyst left little scope for the introduction of additional
steric constraints that could potentially improve the selectivity. These concerns
appeared to be a real issue when initial structural modifications led to no major
improvement in either selectivity or reactivity. Worse, replacing the 5-membered
ring phosphine 1 by either the corresponding 6-membered ring phosphine 2 or the
O Cl
Me
O O OH
OH O
O 11 (16 mol %) P
t Bu + t Bu + t Bu Ph
CD2Cl2, rt
Cl Cl Me
s = 15
(±) (2.5 eq) 28.5% ee 81.8% ee 11
C = 25.3%
Scheme 3 Vedejs’ first generation phosphine catalyzed KR of an aryl alkyl sec-alcohol [24]
bicyclic phosphine 3 was totally detrimental to activity: no reaction was observed

using these congeners. The use of catalysts 4 and 5, however, did lead to good levels
of conversion, although the selectivities were rather low [42]. These results suggested
that the 5-membered ring was crucial for reactivity and therefore various modifica-
tions were considered in order to further improve the catalytic activity and selectivity.
Hence, catalyst 5 was prepared with the idea that a larger bias in the steric environment
around the phosphorous atom could be beneficial. Unfortunately, the selectivities
observed with 5 were considerably lower than the ones observed with the parent
catalyst 1. The next structural modification consisted in removing one of the adjacent
methyl substituents in order to improve access to the unshared electron pair of the
phosphorous atom. However, while significant rate improvement was observed with
catalyst 6, the selectivity dropped (s = 5.1). Finally, replacing the methyl substituent
by a tert-butyl (7) did lead to a slight increase in selectivity (s = 5.6), yet at the same
time the reactivity dropped considerably (Fig. 1) [42].
Following these initial results, modelling studies were performed in order to
identify the key structural features responsible for determining the selectivity in
these systems. It appeared from these studies that the conformational/rotational
flexibility of the P-phenyl substituent could be a crucial parameter. Indeed, catalysts
that adopted a geometry where the phenyl ring was perpendicular to the ring system
such as in 2 and 3 led to low selectivities, whereas catalysts that permitted the
phenyl ring to be more flexible and thus turn away from the adjacent alkyl groups
towards the neighbouring hydrogen atoms such as in 5, 6, and 7 were slightly more
selective. These observations led to the design of a new family of catalysts derived
from 2-phosphabicyclo[3.3.0]octane (PBO) containing a ring-fused P-aryl phos-
phine with a distinct geometry wherein the aryl ring is nearly coplanar with the
5-membered ring system. By placing the phosphorus atom in a bicyclic framework,
the authors anticipated that they would maximise the relevant C–P–Ar bond angle
and thus optimise the accessibility/nucleophilicity of the electron pair (Fig. 2) [16,
42–46].
The catalytic activity of phosphines 8 and 9 were first evaluated in the KR of
tert-butyl phenylcarbinol using the electron-deficient m-chlorobenzoic anhydride
as the achiral acylating agent. Interestingly, not only did these two catalyst display
Me
Ph PPh2 PPh2
P
P Me
Ph Me Me Me
Me
2 3 4
Me Me Me tBu
P P P
Ph Ph Ph
5 6 7
Fig. 1 Chiral phosphines screened by Vedejs as asymmetric acyl transfer catalysts [42]
Me
Me Me Me
H
Me Me
H H H H H P
H P H P H P H P Me
Ph Ph Ph Ph tBu
Me
8 9 10 11 12 tBu
Fig. 2 Vedejs’ PBO bicyclic phosphine catalysts [43–45]
>10-fold higher reactivity than the initial mono-cyclic phosphine 1, but it appeared
that the endo bicyclic phosphine 8 was significantly more reactive than the analogous
exo compound 9. The most promising derivatives were however the gem-dimethyl
catalysts 10, 11, and 12 which were found to react >100 times faster than the original
catalyst 1 while displaying high levels of selectivity. In particular, the 3,5-di-tert-
butylphenyl derivative 12, used in conjunction with isobutyric anhydride, was shown
to induce s values of 42–369 for a wide range of aryl alkyl sec-alcohols (Table 1)
[16]. These levels of selectivity are amongst the highest ever reported for non-enzy-
matic acylative KR and compare favourably with the selectivities observed when
using enzymes.
Table 1 Vedejs’ PBO catalyzed KR aryl alkyl sec-alcohols [16]
H
O P
H t Bu
OH O O 12 (99.7% ee) OH O iPr
Ar R
+ iPr O i Pr Ar R
+ Ar R
heptane t Bu
(±) (2.5 eq) 12
mol%
Entry Ar R T(°C) cat. C (%) eeA (%) eeE (%) s
1 Ph Me −20 2.5 29.2 3 93.3 42
2 Ph Bu −40 3.9 51.3 8 88.6 57
3 Pha,b t-Bu −40 4.9 45.8 3 93.1 67
4 2-Tol Me −40 3.5 48.5 7 95.7 142
5 Mesitylb,c Me −40 12.1 44.4 0 98.7 369
6 1-Nap Me −40 3.9 29.8 2 97.0 99
a
Bz2O used in place of (i-PrCO)2O
b
Toluene used as solvent
c
Catalyst of >99.9% ee used
Procedure for KR of an aryl alkyl sec-alcohol using catalyst 12: KR of (±)-1-(2-methylphe-

nyl)ethanol [16]
A solution of phosphine 12 (16 mg, 0.045 mmol; 99.7% ee) in deoxygenated n-heptane (74
mL) was added to an N2-purged flask containing (±)-1-(2-methylphenyl)ethanol (1.02 g,
7.5 mmol). After cooling the mixture to −40 °C, (i-PrCO)2O (3.05 mL, 18.4 mmol) was
added via syringe. After stirring for 14 h at −40 °C the mixture was quenched by addition
of isopropylamine (4 mL, 47 mmol). The solution was stirred at −40 °C for 10 min and the
flask was then allowed to warm to room temperature (ca. 1 h). After removal of the solvent
in vacuo, the residue was purified by FC on silica gel (CH2Cl2/hexanes, 2/3 → CH2Cl2) to
yield the ester as an oil [725 mg, 48%, 95.7% ee by chiral-HPLC on the alcohol obtained
by hydrolysis of an aliquot using NaOH/MeOH, 1/19] and the alcohol as an oil [482 mg,
46%, 90.2% ee by chiral-HPLC following additional purification by FC on silica gel
(EtOAc/hexanes, 1/5)]. The calculated selectivity value at 48.5% conversion was s= 142.
Vedejs et al. subsequently extended the substrate scope of their 2,5-di-tert-

butylphenyl PBO catalyst 12 to allylic alcohols for which they obtained moderate
to good selectivities (s = 4–82) (Scheme 4) [46].
O
H
OH O O OH O iPr P
R 12 (5 mol %) R R H t Bu
+ iPr O iPr +
R' R'' toluene, −40 °C R' R'' R' R''
tBu
(±) (2.5 eq) 12
OH OH OH OH OH OH OH OH OH
Bn Bn
Ph
s=4 s = 12 s = 21 s = 52 s = 55 s = 61 s = 82 s = 25 s = 52
41.7% eeA 66.4% eeA 67.3% eeA 89.8% eeA 96.1% eeA 48.9% eeA 64.2% eeA 99.9% eeA 56.4% eeA
C = 47.9% C = 48.1% C = 45.1% C = 56.4% C = 52.6% C = 34.0% C = 40.3% C = 67.2% C = 37.7%
Scheme 4 Vedejs’ PBO catalyzed KR of sec-allylic alcohols [46]
Procedure for KR of a sec-allylic alcohol using catalyst 12: KR of (±)-1-(3,4-dihydronaph-

thalen-1-yl)-ethanol [46]
1-(3,4-Dihydronaphthalen-1-yl)-ethanol (21 mg, 0.12 mmol) was added to a solution of
phosphine 12 (1.97 mg, 0.006 mmol) in toluene (1.2 mL). The solution was cooled to −40
°C and (i-PrCO)2O (50 mL, 0.3 mmol) was added via syringe. The reaction was stirred for
72 h, followed by quenching with iPrNH2 (120 mL, 1.4 mmol). After stirring for 15 min at
−40 °C the mixture was warmed to room temperature and concentrated in vacuo. 1H-NMR
(d6-acetone) revealed that 51% conversion to the ester had occurred and confirmed that 5
mol% of catalyst had been used. Purification by FC on silica gel (CH2Cl2/hexanes, 6/1)
gave the ester (86.7% ee by chiral-HPLC on the alcohol obtained by hydrolysis using
NaOH/MeOH, 1/19) and the alcohol (96.1% ee by chiral-HPLC). The calculated selectiv-
ity value at 51% conversion was s = 55.
3 tert-Amine Catalysts
As indicated in the introduction, Wegler and coworkers were the first to report suc-
cessful asymmetric acylation using naturally occurring tert-amine-based alkaloids
(e.g. brucine) in their KR studies on 1-phenylethanol [23]. While the selectivities
achieved were rather modest, proof-of-concept was thereby established.
Although, from a historical standpoint the cinchona alkaloids also occupy a

central position in the field owing to their use as catalysts for the alcoholative ASD
of meso anhydrides (a Type II process, see Scheme 2), the past few years have wit-
nessed an explosion of interest in the development of other classes of tert-amine-
based catalysts primarily for Type I processes.
It is worth noting here that an understanding of the detailed kinetic and thermo-
dynamic aspects of the catalytic cycles involved in both Type I and Type II proc-
esses has lagged significantly behind synthetic experimentation in this area [4].
However, this situation is rapidly being remedied by exciting physical organic and
computational work by the groups of Zipse and Mayer in Munich. Zipse has pub-
lished a series of detailed mechanistic analyses of alcohol acylation mediated by
pyridine derivatives [47–49], including a theoretical analysis of a number of the
stacking interactions postulated to mediate chirality transfer in some of the below
described chiral acyl transfer catalytic systems [50]. Mayer and Zipse have also
sought to establish new parameters for quantifying the nucleophilicities and carbon
basicities of a wide range of nitrogen and phosphorus-based compounds to aid
rationalisation of the relative reactivities of catalophores based on these units in all
organocatalytic transformations [51–53].
3.1 Pyrrole-Based Catalysts
The first class of amine-based nucleophilic catalysts to give acceptable levels of

selectivity in the KR of aryl alkyl sec-alcohols was a series of planar chiral pyrrole
derivatives 13 and 14, initially disclosed by Fu in 1996 [25, 26]. Fu and co-workers
had set out to develop a class of robust and tuneable catalysts that could be used for
the acylative KR of various classes of sec-alcohols. Planar–chiral azaferrocenes 13
and 14 seemed to meet their criteria. These catalysts feature of a reasonably nucle-
ophilic nitrogen and constitute 18-electron metal complexes which are highly stable
[54–58]. Moreover, by modifying the substitution pattern on the heteroaromatic
ring, the steric demand and hence potentially the selectivity of these catalysts could
be modulated.
Fu’s strategy to introduce chirality into an initially achiral species such as pyrrole
was based on the elimination of its two mirror planes – one mirror plane coplanar
with the heteroaromatic ring and one perpendicular mirror plane that passes through
the nitrogen and the mid-point of the C3–C4 bond. This was ingeniously achieved
in a conceptually stepwise fashion through p-complexation of the pyrrole ring to a
transition metal (MLn) thus installing top-from-bottom differentiation, followed by
the incorporation of a substituent in the 2-position of the heteroaromatic ring in
order to enable left-from-right differentiation (Fig. 3).
These structural modifications provided a well-differentiated and highly tuneable
chiral environment in the vicinity of the nucleophilic nitrogen as shown by the
promising selectivities observed in the KR of 1-phenyl- and 1-naphthylethanol. Indeed,
Pyrrole "Planar-chiral" pyrrole

R
N:
N:
H
MLn
2 mirror planes no mirror planes
View down the axis of the nitrogen lone pair:

..
top
H N R
bottom
MLn
left right
Differentiation top from bottom and left from right
Fig. 3 Fu’s design of a planar-chiral catalyst derived from pyrrole [69]
in this seminal study where diketene (1.2 eq) was employed as the acyl donor in the
presence of 10 mol% of catalyst 13, selectivities up to s = 6.5 were obtained
(Scheme 5) [25].
3.2 (4-Dialkylamino)Pyridine-Based Catalysts
Based on their initial results using pyrrole-based catalysts, and also wanting to
exploit the remarkable nucleophilic activity of 4-DMAP [59–63] first disclosed by
Litvinenko [64] and Steglich [65] in the late 1960s as a potent acylation catalyst,
Fu and co-workers set out to develop a second generation catalyst derived from a
4-DMAP framework but using the same chirality defining strategy described previ-
ously. However, as h6-complexation of a pyridine ring to an FeCp moiety (where
‘Cp’ is a cyclopentadienyl-derived ligand) would inevitably lead to a 19-electron
metal complex, they decided to fuse a 5-membered ring to the pyridine framework
and bind this second ring to the FeCp unit in a h5 fashion (Fig. 4) [64]. Although
this modification had the obvious consequence of moving the metal fragment away
from the nucleophilic nitrogen, their hope was that the steric demand of the FeCp
group might still furnish sufficient top-from-bottom differentiation to provide an
effective chiral environment.
Hence, the group developed a series of planar chiral ferrocenyl 4-DMAP and
4-(pyrrolidino)pyridine (4-PPY) derivatives (15–18) that have proved to be highly
versatile and efficient catalysts for many acyl transfer processes (Fig. 5) [25, 26,
66–82, 93, 99, 103, 105].
For example, a range of aryl alkyl sec-alcohols could be resolved in a highly
efficient way using pentaphenylcyclopentadienyl 4-DMAP catalyst 16 (1–2 mol%)
in conjunction with Ac2O (0.75 eq) as the acyl donor and Et3N (0.75 eq) as an auxiliary
O O CH2OR
OH OH O N
O 13 (10 mol %) Fe
+ +
O benzene, rt
13 R = TES
(±) (1.2 eq) s = 6.5 43% ee 14 R = TBS
(87% ee, C = 67%)
Scheme 5 Fu’s first generation planar-chiral catalyst for the KR of a sec-alcohol [25]
DMAP "Planar-chiral" DMAP

R
Me2N N: Me2N N:
H
MLn
2 mirror planes no mirror planes
R Me2N Me2N
N N N
R1 Fe R R1 Fe R1 R1 FeR1
1
R1 R1 R1 R1 R1 R1
R1 R1 R1
18-electron complex 18-electron complex

'planar-chiral' pyrrole 19-electron complex 'planar-chiral' DMAP
Fig. 4 Fu’s concept for a ‘planar-chiral’ 4-DMAP catalyst based on his pyrrole ‘planar-chiral’
prototype [69]
Me2N Me2N N N
N N N N
Fe Ph FePh Fe
Ph FePh
Ph Ph Ph Ph
Ph Ph
15 16 17 18
Fig. 5 Fu’s planar chiral ferrocenyl 4-DMAP and 4-PPY catalysts [66, 83]
base [80, 81]. Interestingly, both the rate and the selectivity of this reaction were
strongly solvent dependent. Indeed, the use of Et2O as the solvent and 2 mol% of
catalyst 16 provided s values of 12–52 at room temperature while the use of tert-
amyl alcohol as the solvent in the presence of 1 mol% of catalyst 16 afforded s
values of 32–95 at 0 °C (Table 2) [80, 81].
Procedure for KR of an aryl alkyl sec-alcohol using catalyst 16: KR of (±)-1-(2-methylphe-
nyl)ethanol [81]
In a glove-box, 1-(2-methylphenyl)ethanol (1.11, 8.14 mmol), tert-amyl alcohol (16 mL),
and Et3N (0.67 mL, 4.8 mmol) were added to a flask containing 16 (27.7 mg, 0.0419
mmol). A septum was added and the flask was removed from the glove box. After some
gentle heating to dissolve the catalyst, the flask was cooled to 0 °C. Ac2O (0.46 mL, 4.9
mmol) was added dropwise and after 25.5 h the reaction was quenched with MeOH (5 mL).
Table 2 Fu’s planar chiral ferrocenyl 4-DMAP catalyzed KR of sec-alcohols [80, 81]
Me2N
OH 16 (1–2 mol % ) OH OAc N
+ Ac2O + Ph FePh
Ar R Ar R Ar R Ph
Et3N (0.7 eq) Ph
(±) (0.75 eq) Ph
16
2 mol% 16, Et2O, room 1 mol% 16, tert-amyl alcohol,

temperature 0 °C
Entry Ar R C(%) eeA(%) eeE(%) sb C(%) eeA (%) eeE (%)a sb
1 Ph Me 61.9 95.2 58.7 14 55.5 98.9 79.2 43
2 Ph t-Bu 51.8 92.2 88.0 52 51.0 96.1 92.2 95
3 4-F-C6H4 Me 64.4 99.2 55.9 18 54.9 99.9 82.0 68
4 Ph CH2Cl 68.4 98.9 44.5 13 56.2 97.5 76.1 32
5 2-Tol Me 60.3 98.7 64.9 22 53.2 98.6 86.6 71
6 1-Nap Me 63.1 99.7 57.7 22 51.6 95.1 89.3 65
a
Determined following reduction to the alcohol using LiAlH4
b
Average of 2–3 runs
The mixture was passed through a short plug of silica gel to separate the catalyst from the
alcohol/acetate mixture (EtOAc/hexanes, 1/1 → 3/1 then Et3N/EtOAc, 1/9). The solution
of alcohol and acetate was concentrated in vacuo and the residue purified by FC on silica
gel (Et2O/pentane, 1/20 → 1/4) to afford the (R)-acetate (639 mg, 44%, 90.2% ee by chiral-
GC on the alcohol obtained by reduction using LiAlH4) and the (S)-alcohol (517 mg, 47%,
92.9% ee by chiral-GC). The calculated selectivity value at 50.7% conversion was s = 65.9.
The recovered catalyst was purified by FC on silica gel (EtOAc/hexanes, 1/1 → EtOAc/
hexanes/Et3N, 9/9/2), which provided 24.9 mg of pure catalyst 16 (90%).
Furthermore, Fu extended the substrate scope to allylic alcohols and showed that
substrates bearing a substituent geminal to the hydroxy group, trans-cinnamyl type
substrates, allylic alcohols with a substituent syn to the hydroxy group and tetrasub-
stituted allylic alcohols could be resolved with moderate to good selectivities (s =
4.7–64) (Scheme 6) [82].
Fu then successfully demonstrated the synthetic utility of this method by prepar-
ing a key intermediate in Brenna’s synthesis of (−)-baclofen through a KR protocol
which gave the desired compound in 40% yield and 99.4% ee (s = 37) on a 2-g scale
(Scheme 7) [82].
He also performed the KR of aldol intermediate 19 in the Sinha–Lerner synthe-
sis of epothilone A on a 1.2-g scale, thus affording the natural dextrorotatory enan-
tiomer in 47% yield and 98% ee (s = 107) (Scheme 8) [82].
Procedure for KR of an allylic sec-alcohol using catalyst 16: KR of allylic
alcohol(±)-19[82].
In the air, tert-amyl alcohol (8.75 mL) and Et3N (0.36 mL, 2.6 mmol) were added to a vial
containing alcohol (±)-19 (1.16 g, 4.42 mmol) and catalyst ent-16 (29.0 mg, 0.0439 mmol).
The vial was closed with a Teflon-lined cap and sonicated to help dissolve the catalyst. The
reaction mixture was cooled to 0 °C, and Ac2O (0.25 mL, 2.6 mmol) was added. After 42.5
h, the reaction was quenched with MeOH (0.25 mL). The mixture was passed through a
pad of silica gel (EtOAc/hexanes, 1/5 → EtOAc → Et3N/EtOAc, 1/1) to separate the cata-
ent-16 NMe2
OH OH OAc N
R (1-2.5 mol %) R R Ph Fe Ph
R' + Ac2O R' + R'
Et3N (0.4-0.75 eq) Ph Ph
R R R R R R Ph
(±) (0.75-1.5 eq) 0 °C,t-amyl alcohol ent-16
OH OH OH OH
Ph
s = 64 s = 17 s = 18 s = 29
99% eeA 93% eeA 97% eeA 99% eeA
C = 54% C = 58% C = 60% C = 59%
Scheme 6 Fu’s chiral planar ferrocenyl 4-DMAP catalyzed KR of sec-allylic alcohols [82]
OH OH OAc Me2N
16 (1 mol %) N
+ Ac2O + Ph FePh
Et3N (0.65 eq) Ph Ph
Cl t-amyl alcohol Cl Cl Ph
0 °C 16
(±) 99.4% ee 74% ee
(2.0 g) (0.65 eq) yield = 40% yield = 57%
s = 37
Scheme 7 Preparation of a (-)-baclofen intermediate using Fu’s planar chiral 4-DMAP [82]
OH O OH O AcO O NMe2
Me Me Me
Et ent-16 (1 mol %) Et Et N
+ Ac2O + Ph Fe Ph
Et3N (0.59 eq) Ph Ph
MeO t-amyl alcohol MeO MeO Ph
0 °C ent-16
(±)−19 (0.59 eq) (+)−20 (−)−21
(1.2 g) 98.0% ee 91.8% ee
yield = 47% yield = 52%
s = 107 (catalyst recovery = 95%)
Scheme 8 Preparation of an epothilone A intermediate using Fu’s planar chiral 4-DMAP ent-16 [82]
lyst ent-16 (27.6 mg, 95%) from the alcohol/acetate mixture. The solution of alcohol and
acetate was concentrated in vacuo and the residue purified by FC on silica gel (EtOAc/
hexanes, 1/9 → 1/4) to afford the acetate 21 (0.70 g, 52%, 91.8% ee by chiral-HPLC) and
the alcohol 20 (0.55 g, 47%, 98.0% ee by chiral-HPLC). The calculated selectivity value
at 51.6% conversion was s = 107.
Fu’s planar chiral ferrocenyl 4-DMAP derivative 16 is also the first organocatalyst
that has been reported to efficiently perform the KR of certain propargylic sec-alcohols
[83]. These KRs were achieved using 1 mol% of catalyst 16 and Ac2O as the acylating
agent in tert-amyl alcohol at 0 °C in the absence of a stoichiometric auxiliary base
(Et3N was found to catalyze a non-selective background reaction). Under these condi-
tions, moderate to good selectivities were achieved (s = 3.8–20) depending on the
nature of the substrate: an increase in the size of the alkyl group (R = Me → Et → i-Pr
→ t-Bu) lead to a dramatic decrease in selectivity with the best results being obtained
with unsaturated groups at the remote position of the alkyne (Table 3) [86].
Procedure for KR of a propargylic sec-alcohol using catalyst 16: KR of (±)-4-phenyl-3-
butyn-2-ol [83]
A vial containing (±)-4-phenyl-3-butyn-2-ol (73.0 mg, 0.500 mmol) and catalyst 16 (3.3
mg, 0.005 mmol) in tert-amyl alcohol (1.0 mL) was capped with a septum and sonicated
to help dissolve the catalyst. The resulting purple solution was cooled to 0 °C, and Ac2O
(35.4 mL, 0.375 mmol) was added by syringe. After 49 h, the reaction mixture was
quenched by the addition of a large excess of MeOH. After concentration in vacuo, the
residue was purified by FC on silica gel (EtOAc/hexanes, 1/9 → 1/1 then EtOAc/hexanes/
Et3N, 9/9/2) to afford the (R)-acetate (68.6% ee by chiral-GC) and the (S)-alcohol (96.0%ee
by chiral-GC on the acetate obtained following esterification). The calculated selectivity
value at 58.3% conversion was s = 20.2.
Fu’s planar chiral ferrocenyl 4-DMAP catalyst 16 was also shown to be effective
for the ASD of meso-diols as illustrated for the case of unusual meso-diol 22
(Scheme 9) [81].
Although a number of methods have been recently reported for the asymmetric
acylation of aryl alkyl sec-amines using stoichiometric amounts of chiral acylating
agents, notably by Shibuya [84], Atkinson [85–90], Murakami [91], Krasnov [92],
Fu [93], Arseniyadis [94–97], and Toniolo [98], the design of enantioselective acyl
transfer catalysts suitable for use with amines is becoming a major focus of current
interest for the synthetic community. This endeavour is particularly challenging due
to the high nucleophilicity of most amines, which allows easy achiral acylation
through direct reaction of these substrates with the achiral acyl source. Consequently,
only one effective catalytic system has been reported to date by Fu. This organo-
catalytic system relies on the use of O-carbonyloxyazlactone 23 as the stoichiomet-
ric acyl donor in combination with 10 mol% of planar chiral ferrocenyl 4-PPY 17
as the catalyst. After optimization studies, a variety of racemic primary amines
were successfully resolved with moderate to good selectivities (s = 11–27) (Scheme
10) [99].
Table 3 Fu’s planar chiral 4-DMAP catalyzed KR of sec-propargylic alcohols [83]

Me2N
OH 16 (1 mol %) OH OAc N
R + Ac2O
R
+ R Ph FePh
t -amyl alcohol, 0 °C Ph Ph
R' R' R'
Ph
(±) (0.75 eq) 16
Entry R R’ s eeA (%) eeE (%) C (%)

1 Me Ph 20 96 6 58
3 i-Pr Ph 11 93 5 63
4 t-Bu Ph 3.8 95 5 86
5 Me n-Bu 3.9 - 8 -
OH OAc Me2N
OH OH 16 (1 mol %) N
+ Ac2O Ph FePh
Et3N (1.5 eq) Ph Ph
t-amyl alcohol, 0 °C Ph
99.7% ee
22 (1.5 eq) 16
yield = 91%
Scheme 9 ASD of meso-diols catalyzed by Fu’s 4-DMAP catalyst 16 [81]
O
N
O OMe O
NH2 17 (10 mol %) N
tBu NH2 HN OMe Fe
O +
Ar R + N Ar R
CHCl3, −50 °C Ar R
β-Nap
17
(±) 23 (0.6 eq)
NH2 NH2 NH2 NH2 Me NH2 NH2
MeO F 3C
s = 12 s = 27 s = 11 s = 16 s = 16 s = 13
Scheme 10 Fu’s planar chiral ferrocenyl 4-PPY catalyzed amine KR [99]
Advantageously, in the context of subsequent synthetic manipulation, the

acylated products in these processes are carbamates (rather than amides). Fu proposed
a mechanistic pathway that involves rapid initial reaction of the catalyst with the
O-carbonyloxyazlactone to form an ion pair, followed by slow transfer of the
methoxycarbonyl group from this ion-pair to the amine in the enantioselectivity
determining step (Fig. 6) [99].
Procedure for KR of an a-chiral primary amine using catalyst 17: KR of (±)-1-phenylethyl-
amine [99]
Catalyst 17 (5.2 mg, 0.014 mmol), (±)-1-phenylethylamine (17.0 mg, 0.14 mmol) and
CHCl3 (2.5 mL) were added to a Schlenk flask under argon. The resulting purple solution
was cooled to −50 °C and a solution of O-carbonyloxyazlactone 23 (13.5 mg, 0.042 mmol)
in CHCl3 (0.15 mL) was added by syringe. After 4 h, additional O-carbonyloxyazlactone
23 (13.5 mg, 0.042 mmol) in CHCl3 (0.15 mL) was added. After 24 h in total the solution
was concentrated in vacuo and the residue purified by FC on silica gel (EtOAc/hexanes,
1/4) to afford the carbamate (7.3 mg, 29%, 79% ee by chiral-HPLC) and the amine which
was immediately acylated (Et3N, Ac2O, CH2Cl2, room temperature) and then purified by
FC on silica gel (EtOAc) to afford the acetamide (11.4 mg, 50%, 42% ee by chiral-GC). The
calculated selectivity value at 35% conversion was s = 13.
Fu and co-workers expanded the scope of amine KR to include indolines [100].

However, as the initial conditions developed for aryl alkyl sec-amines were unsuc-
cessful due to the low nucleophilicity of the catalyst, a few structural modifications
were introduced. Hence, after screening various catalysts and achiral acyl donors,
the use of a bulky pentacyclopentadienyl-derived catalyst in conjunction with an
O
O
O OMe
HN OMe PPY * tBu
O
Ar R N
2-Nap N
23 N
Fe
− 17 (PPY* )
NH2 O
O t-Bu O
Ar R
(±) PPY* OMe N
2-Nap
Fig. 6 Fu’s proposed mechanism for the 4-PPY-catalyzed KR of amines [99]
O-carbonyloxyazlactone led to a more effective catalytic system that could achieve

the desired KR with useful levels of selectivity; the best selectivities being obtained
when using 4-PPY derivative 24 (Ar = 3,5−Me2C6H3) (Scheme 11) [100].
It is noteworthy that a safer and more efficient synthesis of catalysts 15 and 16
was recently developed involving a classical resolution of racemic 15 and 16 using
commercially available tartaric acids [101].
In 1970, Steglich reported that 4-DMAP catalyzed the rearrangement of
O-acylated azlactones to their C-acylated isomers (‘the Steglich rearrangement’)
[60, 102]. This process effects C–C bond formation and concomitant construction
of a quaternary stereocenter. Building upon this foundation, first Fu [103] and
later Vedejs [104, 105], Johannsen [106] and Richards [107] have explored the
utility of chiral 4-DMAP/4-PPY derivatives to effect this type of rearrangement.
While Fu’s planar chiral ferrocenyl 4-DMAP catalyst 17 and Vedejs’ 3-(2,2-triphe-
nyl-1-acetoxyethyl)-4-dimethylamino)pyridine (TADMAP) catalyst 25a are very
effective in giving products generally with ee values > 90% and in almost quan-
titative yields [103, 104], Richards’ cobalt metallocenyl 4-PPY 26 and Johannsen’s
ferrocenyl 4-DMAP 27 give significantly lower levels of selectivity (25% and
45–67% ee, respectively) but have been less thoroughly investigated (Scheme 12)
[107,105].
Gröger has also reported a preliminary study on enantioselective acetyl migra-
tion in the Steglich rearrangement using one of Fu’s commercially available cata-
lysts and Birman’s tetramisole-based organocatalyst [108].
Analogous rearrangements have also been performed by both Fu [73] and Vedejs
[105] on O-acyl benzofuranones and O-acyl oxindoles to provide synthetic inter-
mediates potentially suitable for elaboration to diazonamide A and various oxin-
dole-based alkaloids such as gelsemine respectively. Peris has also examined both
Fu’s and Vedejs’ chiral 4-DMAP catalysts for effecting diastereoselective carboxyl
migrations of 3-arylbenzofuranones [109].
In addition to the planar chiral ferrocenyl catalysts 15–18, 24 developed by Fu,
a number of other chiral derivatives of 4-DMAP and 4-PPY [4, 47, 48] have been
explored by other groups as organocatalysts for KR of sec-alcohols. Contributions
have been made by the groups of Vedejs [104, 105, 110, 111], Fuji and Kawabata
24 (5 mol %) N
O
LiBr (1.5 eq) N
O Me R Fe R
R' Me + tBu R' R + R' R R
N O 18-crown-6 (0.75 eq) N N R
H N H R
Ac 24 (R = 3,5-Me2C6H3)
Ph Toluene, −10 °C
(±) 23 (0.65 eq)
Me CO2Et MeO
Me MeO
Me Me Me
N N N
H N N H
H H H
s = 25 s = 9.8 s = 18 s = 19 s = 13
94% ee 91% ee 91% ee 95% ee 92% ee
C = 55% C = 64% C = 55% C = 58% C = 60%
Scheme 11 Fu’s planar chiral ferrocenyl 4-PPY catalyzed indoline KR [100]
O
O OBn O O N
R 17 (2 mol %) BnO
O O N
N R Fe
t-amyl alcohol, 0 °C N
OMe OMe 17
R = Me, Et, Bn, Allyl

ee = 90-91%, yield = 93-94%
O
O OPh O O
R 25
5a (1 mol %) PhO N OAc
O R O
N t-amyl alcohol, 0 °C N H
CPh3
N
OMe OMe
25a
R = Me, Bn, Allyl, i-Bu
ee = 91–95%, yield = 90-99%
O
O OBn O O N
R 26 (1 mol %) BnO
O R O N
N toluene, −20 °C N
Co
Ph Ph
OMe OMe Ph Ph
26
R = Me
ee = 45-75%, yield = 70-100%
O
O OBn O O
R 27 (5 mol %) BnO
O R O
N t-amyl alcohol, 0 °C N
N
Fe
NMe2
OMe OMe
27
R = Bn
ee = 25%, yield = 69%
Scheme 12 Fu’s, Vedejs’, Johannsen’s and Richards’ chiral DMAP-catalyzed rearrangements of

O-acyl azlactones [103–107]
H
R O
N OH H
N OAc O
N H N CO2R' N NEt2
H N N
NR
tBu R O R'' O
N
N N Ar Ar
OMe N N N
N
28 (Vedejs) 25a R=CPh3 (Vedejs) 29 (Fuji) 30 (Kawabata) 31 (Morken) 32

2 (Spivey) 33 (Spivey)
25
5b R=Ph (Gotor)
O N
Ph R N
H
Amine, Alcohol and Phosphine Catalysts
O O
N N N
N N Bn N N R' N N
ArO OAr O Ar Ar O O HN NHAc
N N N N N
34 (Spivey) 35 (Kotsuki) 36 (Inanaga) 37 (Campbell) 38 (Campbell)

39 (Jeong)
N O S O O N
N O N O
H
N S N SO2Ph S
N N
N t Bu N HO Fe Bn N
N Ph Co Ph
Ar
Ar N Ph Ph
N
40 (Yamada) 41 (Connon) 27 (Johannsen) 42 (Diez) 43 (Lavacher) 26 (Richards)
Fig. 7 Chiral Derivatives of 4-DMAP and 4-PPY

251
[112–115], Morken [116], Spivey [117–127], Kotsuki [128, 129], Inanaga [130],
Campbell [131–134], Jeong [135], Yamada [136], Connon [137], Johannsen [106],
Díez [138], Levacher [139], Richards [107] and Gotor [140, 141] (Fig. 7).
Spivey and coworkers reported in 1999 the use of axially chiral analogs of
4-DMAP 32 and 33, which rely on the high barrier of rotation about an aryl–aryl
bond at the 3-position of 4-DMAP to produce atropisomers that are selective in the
acylation of sec-alcohols (Scheme 13) [117–127].
These catalysts show similar preferences to the Fu catalysts, but acylation
selectivities are 3–5 times lower for the derivatives disclosed so far. They do,
however, display higher catalytic activity than the analogous Fu catalysts which
should provide a window of opportunity for increasing selectivity further and allow
for KR of more intrinsically reactive substrates such as amines. sec-Alcohol KRs can
be carried out at −78 °C with 1 mol% catalyst. The high activity of these catalysts
can be attributed at least in part to the relatively unencumbered environment of the
nucleophilic pyridyl nitrogen and efficient conjugation between the 4-amino group
lone pair and the pyridine ring.
The axially chiral biaryl 4-DMAP 32 developed by Spivey [117–127] is relatively
readily prepared but only provides modest levels of selectivity for the KR of aryl
alkyl sec-alcohols: s £ 30 at −78 °C over 8–12 h or s £ 15 at room temperature in
~20 min (Table 4) [119].
In the late 1990s, Fuji and Kawabata also set out to develop an efficient catalyst
that would promote the enantioselective acylation of racemic alcohols. Their strategy
was based on the use of a 4-PPY-derived catalyst that would mimic the induced-fit
N NEt2
Ar Ar
N N
32 33
Scheme 13 Spivey’s axially-chiral analog of 4-DMAP in the KR of an alkyl aryl carbinol. [117–127]
Table 4 Spivey’s axially chiral 4-DMAP catalyzed KR of sec-alcohols [119]
O
OH NEt2
O O 32 (1 mol %) OH O iPr
Ar R + i Pr O iPr Ar R
+ Ar R
Et3N (0.75 eq) Ph N
(±) (1-2 eq) toluene, −78 °C 32
Entry R Ar (i-PrCO)2O C (%) eeA (%) eeE (%) s

1 Me 1-Nap 2 eq 17.2 18.6 89.3 21
2 Me 1-Nap 1 eq 22.3 26.3 91.4 29
3 Me Ph 2 eq 39.0 49.9 78.1 13
4 Me 2-Tol 2 eq 41.4 60.7 86.0 25
5 t-Bu Ph 2 eq 17.5 18.8 88.8 20
mechanism of enzymes by switching from an ‘open’ to a ‘closed’ conformation

when activated. As the introduction of a sterically demanding asymmetric centre
close to the nitrogen of the pyridine ring was known to reduce the catalytic activity,
the authors decided to place the stereogenic centre at a remote position hoping for
an induction through long-range chirality transfer. Catalyst 29 was thus synthesised
and tested on various racemic mono-benzoylated cis-diol derivatives at room tem-
perature [112]. These experiments were a success. Indeed, even though the selectivities
observed were rather moderate (s = 5.8–10.1), they offered a proof-of-concept for
the approach (Table 5) [113].
On the basis of NMR studies, Fuji and Kawabata proposed that catalyst 29 was
selective despite the distance between the stereogenic centres and the acyl pyridinium
carbonyl ‘active site’ as a result of a remote chirality transfer by face to face p−p
stacking interactions between the naphthalene substituent and the pyridinium ring.
Indeed, analysis of 1H NMR chemical shifts and nOe measurements confirmed that
catalyst 29 interconverted between two conformations (open and closed conformation)
depending on whether it was in the ‘free’ or acyl pyridinium state. The authors also
suggested that the relative orientation of the nucleophile was also ordered by p–p
stacking interactions as sec-alcohol nucleophiles incorporating an electron rich aryl
amide gave the highest selectivities (Fig. 8) [112].
Table 5 Fuji and Kawabata’s chiral 4-PPY catalyzed KR of racemic mono-benzoylated cis-diol
derivatives [113]
H
OH
OCOR O O 29 (5 mol %) OCOR N
+ OCOR H
+
n i Bu O i Bu Toluene, rt, 2–5 h n n
OH OCOiBu OH N
(±) (0.7 eq)
29
R = 4-Me2N-C6H4
Entry N Time C (%) eeA (%) s

1 1 4 71 97 8.3
2 2 3 72 99 10.1
3 3 4 70 92 6.5
4 4 5 73 92 5.8
HO H OH H
H i PrCOCl
H Hc HH
c Ha O
Ha
H N N CH3
H N N H
Hd Hb CH3
Hd Hb
29 (open conformation) 29·iPrCOCl (closed conformation)
Fig. 8 1NMR of Fuji’s and Kawabata’s catalyst and its acylpyridinium ion. Arrows designate
nOes observed in open and closed conformations [112]
Fuji and Kawabata further demonstrated the utility of their catalyst by successfully
achieving the KR of N-protected cyclic cis-amino alcohols [113]. Hence, by using
5 mol% of 4-PPY 29 in the presence of a stoichiometric amount of collidine in
CHCl3 at room temperature, a variety of cyclic cis-amino alcohol derivatives were
resolved with moderate to good selectivities (s = 10–21) (Table 6) [113].
Kawabata has most recently turned his attention to the regioselective O-acylation
of sugars using 4-PPY derivatives. Under appropriate conditions, 4-DMAP itself
was found to catalyze O-isobutyrylation of octyl-6-O-methyl- and octyl-6-O-TBS-
b-d-glucopyranoside at the 3-hydroxy position [142]. Using a chiral 4-PPY derivative
it was possible to catalyze either 4- or 6-O-isobutyrylation of octyl- b-d-glucopyrano-
side with high levels of regioselectivity [143].
These pioneering insights into the possibilities offered by harnessing p−p ordering
interactions to aid chirality transfer inspired many subsequent researchers in this
area to design systems that could benefit from p–p, cation–p and related ordering
interactions to achieve/enhance chirality transfer. In this context, Yamada and co-
workers developed a new family of chiral catalysts derived from the 4-DMAP
scaffold which achieved the KR of a range of sec-alcohols with interesting levels
of selectivity (Scheme 14) [136, 144].
Table 6 Fuji and Kawabata’s chiral 4-PPY catalyzed KR of cyclic cis-amino alcohol
derivatives [113]
H
O OH
OH O O 29 (5 mol %) OH N H
+ O i Pr
+
n
i Pr O i Pr collidine (1 eq) n n
NHPH2 NHPH2 NHP N
(±) (0.6-0.7 eq) CHCl3, rt, 9 h
29
P = 4-Me2N-C6H4CO
Entry n (i-PrCO)2O C (%) eeA (%) eeE (%) s

1 2 0.6 eq 58 93 68 17
2 1 0.7 eq 69 >99 44 >12
3 3 0.7 eq 69 97 46 10
40 (0.5 mol %) N O S
O
OH (iPrCO)2O (0.8 eq) N S
OH O iPr
R R' R R'
+ N tBu
NEt3(0.9 eq) R R'
tBuOMe, r.t. 40
(±)
OH OH OH OH OH
MeO O 2N
s = 7.6 s = 10 s = 8.9 s = 9.6 s = 9.8

89% ee 97% ee 98% ee 88% ee 94% ee
C = 65% C = 68% C = 72% C = 62% C = 65%
Scheme 14 Yamada’s chiral ‘conformation-switch’ catalyst applied to the KR of aryl alkyl sec-
alcohols [136, 144]
The design of these new catalysts was based on an early study by Yamada in
which he had shown via 1H NMR measurements, X-ray structural analyses and
DFT calculations that upon N-acylation, 3-substituted 4-DMAPs underwent a con-
formational switch governed by an intramolecular cation–p interaction between the
pyridinium ring and a thiocarbonyl group, thus providing a good facial control (Fig. 9)
[145]. Yamada further applied catalyst 40 to the desymmetrization of various meso-
diols with good selectivities using just 0.05–5 mol% of catalyst [145].
Most recently, Yamada et al. have applied their catalysts to the dynamic KR
(DKR) of cyclic hemiaminals by acylation to give products in up to 88% ee and
99% yield [146].
S
S S
S (iPrCO)2O N
N N N
t Bu
N N
O tBu O O
iPr
40 'open-conformation' 40·i PrCOCl 'closed-conformation'
Fig. 9 Yamada’s ‘conformation-switch’ catalyst [145]
Connon and co-workers [137, 147] also set out to develop a chiral catalyst which
operates via an ‘induced-fit’ mechanism. Derived from a 3-substituted 4-PPY and
possessing a pendant aromatic group, this new catalyst (41, Fig. 7) allowed moder-
ate to good selectivities to be achieved for a wide range of aryl alkyl sec-alcohols.
Connon [148] later showed that small improvements in selectivity could be obtained
by introducing electron-deficient aryl groups. Finally, he was able to expand the
substrate scope to include sec-alcohols obtained by Baylis–Hillman reaction
[148].
Similarly, Díez [138] developed a series of chiral 4-PPY catalysts containing a
sulfone side chain (42, Fig. 7); however, the selectivities obtained in the KR of
(±)-1-phenylethanol were rather modest (s < 2).
Campbell et al. at GlaxoSmithKline developed a related family of chiral catalysts
functioning through an ‘induced-fit’ mechanism. Based on a 4-(a-methyl)
prolinopyridine scaffold, these new catalysts (37, Fig. 7) allowed the KR of cis-
(±)-(p-N’,N’-dimethylbenzoyl)cyclohexan-1,2-diol and other racemic alcohols
with high selectivities [132, 149]. Interestingly, catalysts bearing a secondary amide
in the side chain led to relatively high selectivities (s = 8–13), whereas catalysts bearing
a tertiary amide or an ester were rather inefficient (s< 2). In the light of these
results, the authors suggested that hydrogen bonding was the key for obtaining
good selectivities. Following these initial results, Campbell developed a solid-
supported version of his catalyst (38, Fig. 7) with the advantage that it could be
recycled. Unfortunately, the selectivities obtained were slightly lower than the ones
obtained with the corresponding solution-phase catalyst [150, 151].
Kotsuki [128] reported a straightforward approach to the synthesis of chiral
4-PPY (35, Fig. 7) catalysts via high-pressure promoted nucleophilic aromatic
substitution of 4-chloropyridine and their application in the KR (±)-1-phenylethanol;

however, the selectivities obtained were very poor (up to 20% ee at 12% conversion).
Finally, Inanaga’s contribution to the development of chiral 4-dialkylaminopyrid-
ine based catalysts for enantioselective acyl transfer relied on the use of C2-symmetric
4-PPY derivative 36 (Fig. 7) [130]. This compound was obtained in an enantiopure
form by selective cleavage of a carbamate intermediate using SmI2, and allowed the
KR of various sec-alcohols with selectivity factors ranging from s = 2.1 to 14.
3.3 Dihydroimidazole-Based Catalysts
In 2004, Birman and coworkers set out to develop an easily accessible and highly
effective acylation catalyst based on the 2,3-dihydroimidazo[1,2-a]-pyridine
(DHIP) core. The first chiral derivative to be prepared and tested was (R)-2-phenyl-
2,3-dihydroimidazo[1,2-a]-pyridine 44 (H–PIP) [152]. Derived from (R)-2-
phenylglycinol, this catalyst afforded the KR of (±)-phenylethylcarbinol in 49% ee
at 21% conversion (s = 3.3). In order to improve the reactivity of the catalyst, the
authors decided to introduce an electron-withdrawing substituent on the pyridine
ring that would increase the electrophilicity of the acylated intermediate. Hence,
three new derivatives (Br–PIP, NO2–PIP and CF3–PIP) were synthesised and tested
under rigorously identical conditions [152]. One of these easily accessible com-
pounds, 2-phenyl-6-trifluoromethyl-dihydroimidazo[1,2-a]pyridine (45, abbrevi-
ated as CF3-PIP), proved to be particularly effective as, when combined with
(EtCO)2O and iPr2NEt, it resolved a variety of aryl alkyl sec-alcohols with good to
excellent selectivities (s = 26–85) (Table 7) [152].
Following these results, Birman suggested that the chiral recognition was
dependent on the p–p stacking interactions between the reactive acylated interme-
diate and the aryl moiety in the substrate (Fig. 10) [152].
Table 7 Birman’s CF3-PIP catalyzed KR of sec-alcohols [152]
O F 3C
OH O O 45 (2 mol %) OH O Et
Ar R + Et O Et Ar R + Ar R
N N
i Pr2NEt (0.75 eq)
(±) (0.75 eq) Ph
CHCl3, 0 °C 45
Entry Ar R t (h) C (%) s

1 Ph Me 8 32 26
2 Ph Et 8 39 36
3 Ph i-Pr 30 55 41
4 PH t-Bu 52 48 85
5 1-Nap Me 8 51 56
6 3-MeO-C6H4 Me 8 40 34
R H
H R
O OH OOH
F 3C N R F 3C N R
N N
Ph Ph
'favored' 'disfavored'
Fig. 10 p–p Stacking interactions in Birman’s system [152]
Procedure for KR of an aryl alkyl sec-alcohol using catalyst 45: KR of (±)-1-(1-naphthyl)-

1-ethanol [152]
A solution of (±)-1-(1-naphthyl)-1-ethanol (2.416 g, 14.0 mmol), DIPEA (1.93 mL, 10.5
mmol) and catalyst 45 (74 mg, 0.28 mmol) in CHCl3 (14 mL) was stirred at 0 °C for 15
min then treated with (n–PrO)2O (1.35 mL, 10.5 mmol). The mixture was stirred at 0 °C
for 10 h, at which time it was quenched with MeOH (10 mL), allowed to warm slowly and
left for 1 h at room temperature. The reaction mixture was diluted with CH2Cl2, washed
twice with 1 M HCl, then twice with saturated aqueous NaHCO3, and dried (NaSO4). The
solution was concentrated in vacuo and purified by FC on silica gel (Et2O/hexanes, 1/19 →
1/4) to give the ester (1.672 g, 52%, 82.5% ee by chiral-HPLC), and the alcohol (1.091 g,
45%, 98.8% ee by chiral-HPLC). The calculated selectivity value at 54.5% conversion was
s = 52.3. The aqueous phase obtained during the work up was basified with 0.5 M NaOH
and repeatedly extracted with CH2Cl2 (until the aqueous phase was pale-yellow), the
extract was dried (Na2SO4), concentrated in vacuo, and purified by FC on silica gel
(i-PrOH/hexanes, 1/19 → 1/9) to provide 50 mg of recovered catalyst 45 (68%).
In order to maximise this interaction, a second generation catalyst with an

extended p-system was designed based on an (R)-2-phenyl-1,2-dihydroimidazo[1,2a]
quinoline (PIQ) core (Fig. 11) [153, 154].
The 7-chloro derivative (Cl-PIQ) 46 was found to provide even better selectivity
and reactivity than CF3-PIP 45 for aryl alkyl sec-alcohols and, moreover, was effec-
tive for certain cinnamyl-based allylic sec-alcohol substrates (s = 17–117, Scheme
15) [153, 154].
Procedure for KR of an aryl alkyl sec-alcohol using catalyst 46: KR of (±)-1-(1-naphthyl)-
1-ethanol [152]
A solution of (±)-1-(1-naphthyl)-1-ethanol (2.416 g, 14.0 mmol), DIPEA (1.93 mL, 10.5
mmol) and catalyst 46 (74 mg, 0.28 mmol) in CHCl3 (14 mL) was stirred at
0 °C for 15 min then treated with (n–PrO)2O (1.35 mL, 10.5 mmol). The mixture was
stirred for 0 °C for 10 h, at which time it was quenched with MeOH (10 mL), allowed to
warm slowly and left for 1 h at room temperature. The reaction mixture was diluted with
CH2Cl2, washed twice with 1 M HCl, then twice with saturated aqueous NaHCO3, and
dried (NaSO4). The solution was concentrated in vacuo and purified by FC on silica gel
(Et2O/hexanes, 1/19 → 1/4) to give the ester (1.672 g, 52%, 82.5% ee by chiral-HPLC),
and the alcohol (1.091 g, 45%, 98.8% ee by chiral-HPLC). The calculated selectivity value
at 54.5% conversion was s = 52.3. The aqueous phase obtained during the work up was
basified with 0.5 M NaOH and repeatedly extracted with CH2Cl2 (until the aqueous phase
was pale-yellow), the extract was dried (Na2SO4), concentrated in vacuo, and purified by
FC on silica gel (i-PrOH/hexanes, 1/19 → 1/9) to provide 50 mg of recovered catalyst 46
(68%).
R R
H H
OH OH
O O
F 3C N R' N R'
N Cl N
Ph Ph
45 46·R'COCl
Fig. 11 Birman’s second generation catalyst [153, 154]
O Cl
OH O O 46 (2 mol %) OH O Et N N
Ar R
+ Et O Et Ar R + Ar R
i-Pr2NEt (0.75 eq) Ph
(±) (0.75 eq) CHCl3, 0 °C 46
OH OH OH OH OH
OH
O
s = 117 s = 74 s = 33 s = 57 s = 27 s = 17
96% ee 90% ee 79% ee 80% ee 86% ee 82% ee
C = 42% C = 51% C = 55% C = 55% C = 44% C = 38%
OH OH OH OH OH
OH
OMe
s = 59 s = 41 s = 17 s = 31 s = 22 s = 24
90% ee 84% ee 78% ee 77% ee 88% ee 79% ee
C = 50% C = 53% C = 47% C = 56% C = 32% C = 53%
Scheme 15 Birman’s Cl-PIQ catalyzed KR of sec-alcohols [153, 140]
Given that the Birman catalysts are readily prepared in just two steps from com-
mercially available enantiomerically pure phenylalaninol, these catalysts constitute
attractive alternatives to Fu’s planar chiral ferrocenyl catalysts 15–18.
Finally, while trying to evaluate the influence of the pyridine ring on the selectivity,
Birman disclosed yet another family of catalysts for the acylative KR of sec-benzylic
alcohols. Derived from commercially available tetramisole, benzotetramizole (BTM,
47) led to outstanding selectivities on a wide range of alcohols (s = 100–350,
Scheme 16) [155, 156].
It is noteworthy that BTM also allowed the KR of propargylic alcohols with
unprecedented levels of selectivity (s = 5.4–32) [157], as well as the KR of 2-oxa-
zolidinones through enantioselective N-acylation with selectivity values reaching s
= 450 [158].
O S
OH O O 47 (2 x 4 mol %) OH O Et N
N
Ar R
+ Et O Et Ar R + Ar R Ph
i Pr2NEt (0.75 eq)
47
(±) (0.75 eq) CHCl3, 0°C
OH OH HO OH
OH OH
s = 80 s = 109 s = 111 s = 166 s = 209 s = 108

87.7% eeA 85.9% eeA 87.0% eeA 98.0% eeA 96.3% eeA 91.9% eeA
C = 49% C = 47% C = 48% C = 51% C = 50% C = 50%
Scheme 16 Birman’s BTM catalyzed KR of sec-alcohols [155, 156]
3.4 N-Alkylimidazole-Based Catalysts
Miller and co-workers have taken a totally different approach to design an efficient
catalyst for enantioselective acylation. Their strategy relied on the use of a pep-
tide-based backbone incorporating a 3-(1-imidazolyl)-(S)-alanine unit as the cata-
lytic core. Upon treatment with an achiral acyl source these ‘biomimetic’
enantioselective acyl transfer catalysts allow the formation of an acyl imidazolium
ion in proximity to the chiral environment generated by the folding of the peptide
[3, 159–174].
The first catalyst of this type to be reported by Miller was tripeptide 48 in 1998
which adopts a b-turn type structure possessing one intramolecular hydrogen bond
[159]. In addition, this organocatalyst judiciously incorporates a C-terminal (R)-a-
methylbenzylamide which prompts p–p stacking interactions (Scheme 17) [159].
In order to increase the possibility of a kinetically significant peptide-substrate
interaction (enzyme mimic) which could lead to improved stereoselection, initial
KR experiments were performed on trans-1,2-acetamidocyclohexanol (Scheme 18)
[159].
Interestingly, tripeptide 48 catalyzed the KR of this amide-containing sec-alcohol
with moderate enantioselection (s £ 12.6) and high solvent-dependency. Indeed,
reactions that were carried out in polar solvents such as acetonitrile afforded lower
selectivities (s = 1.3) than those performed in apolar solvents such as toluene (s
=12.6). Considering that apolar solvents usually favour the formation of intramo-
lecular hydrogen bonds while polar solvents have a tendency to break these interac-
tions leading to a more flexible conformation, these results indicate a significant
correlation between conformational rigidity and degree of enantioselection. In addi-
tion, Miller and co-workers also observed that changing the configuration of the
proline from (S) to (R) induces a complete reversal of selectivity along with an
increase in the level of selectivity (Scheme 19) [160].
These results suggest not only that a single stereogenic centre can control the
stereochemical outcome of the KR reaction, but also that the increase in overall
O
O N
N H
N O
N H O Ac2O BocHN HN
O
BocHN
O HN
N
N
N
N
AcO O
48 48·Ac2O
Scheme 17 Miller’s first generation 3-(1-imidazolyl)-(S)-alanine containing peptide [159]
O
OH 48 (5 mol%) OH OAc N
N (S)
H O
+ Ac2O + BocHN HN
NHAc toluene, 0 °C NHAc NHAc O
N
(±) (1.0 eq) s = 12.6 N
(10 eq) 84% ee
yield = >90%
48
Scheme 18 Miller’s tripeptide catalyzed KR of a cyclic cis-amino alcohol derivative [160]
O
OH 49 (2 mol%) OH OAc N
+ Ac2O + N (R) H O
NHAc toluene, 0 °C NHAc NHAc N O H N Bn
N N O
(±) (4.8 eq) s = 28 73% ee Boc H OMe
98% ee 49
C = 58%
Scheme 19 Miller’s tetrapeptide catalyzed KR of a 1,2-amino alcohol derivative [160]
enantioselectivity can be attributed to an increase in the conformational rigidity of

the catalyst.
In order to validate this hypothesis, a series of octapeptide catalysts known to
possess four intramolecular hydrogen bonds [164] which confer conformational
rigidity were synthesised and screened for activity in the KR of (±)-trans-1,2-
acetamidocyclohexanol. Among them, (R)-proline containing octapeptide 50 (Fig. 12)
was found to afford an excellent level of enantioselection (s = 51) while its (S)-
proline analogue 51 (Fig. 12), which is structurally less well-defined, was substantially
less selective (s = 7) [164].
Unfortunately, none of these catalysts displayed practical levels of selectivity in
the KR of aryl alkyl sec-alcohols. Miller therefore embarked in the design of a third
generation catalyst that could enable the KR of a larger number of substrates. In this
context, he developed an elegant fluorescence-based activity assay which allowed
rapid screening of a large number of structurally unique catalysts. This protocol
based on proton-activated fluorescence led to the identification of octapeptide 52 as
a highly selective catalyst for the KR of aryl alkyl sec-alcohols but also alkyl sec-alcohols
O O
N O N O
N H HN i Pr N H HN i Pr
O iPr
i Pr O
O NH O NH O NH
NH
O iPr O iPr O
iPr HN i Pr HN i Pr HN i Pr
HN N
O O
O OMe N NHBoc O OMe
N NHBoc
N
50 (s = 51) 51 (s = 7)
Fig. 12 Examples of octapeptide catalysts [164]
for which lipases and other organocatalysts invariably perform poorly (Scheme 20)
[161, 164, 166, 167].
This strategy using rapid automated synthesis of libraries of peptides and fluo-
rescent screening of reactivity has allowed Miller to identify specific peptide-catalysts
for specific applications such as the KR of an intermediate en route to an aziridomi-
tosane [165, 169], the KR of certain tert-alcohols [166], the regioselective acylation
of carbohydrates [168], and finally the KR of N-acylated tert-amino alcohols with
s values from 19 to >50 (Scheme 21) [166].
Miller also explored the ASD of glycerol derivatives through an enantioselective
acylation process which relies on the use of a pentapeptide-catalyst which incorpo-
rates an N-terminal nucleophilic 3-(1-imidazolyl)-(S)-alanine residue [171]. Most
recently, Miller has probed in detail the role of dihedral angle restriction within a
peptide-based catalyst for tert-alcohol KR [172], site selective acylation of erythro-
mycin A [173], and site selective catalysis of phenyl thionoformate transfer in
polyols to allow regioselective Barton–McCombie deoxygenation [174].
Miller’s biomimetic approach inspired Ishihara [234] to develop a ‘minimal
artificial acylase’ for the KR of mono-protected cis-1,2-diols and N-acylated 1,2-
amino alcohols. Derived from (S)-histidine, Ishihara’s organocatalyst contains only
one stereogenic centre and incorporates a sulfonamide linkage in place of a
polypeptide chain to allow the NH group to engage as an H-bond donor with the
substrates (Fig. 13) [234].
In order to design this artificial acylase, Ishihara and co-workers compared the
catalytic activity of various imidazoles as well as the reactivity of carboxamides vs
sulfonamides. Interestingly, the more acidic sulfonamide catalyst induced higher
selectivities, thus suggesting that hydrogen-bonding may be a key factor for attaining
a high level of KR.
Based on an X-ray crystal structure analysis of 54, the authors proposed a
transition-state where the conformation of the acylammonium salt generated from
54 would be fixed by an attractive electrostatic interaction between the acyl–oxygen
and the imidazoyl-2-proton or a dipole minimization effect (Fig. 14) [177].
On the other hand, the H-bond between the sulfonylamino proton of the acylam-
monium salt and the carbamoyl oxygen preferentially promotes the acylation of the
N
N Ph OtBu
H O H O H O H O
N N N N
BocHN N N N OMe
O H O H O H O
OtBu NTrt
N
52
OH OH OAc
52 (2.5 mol%)
+ Ac2O +
toluene
(±) (1.5 eq) −65 °C
s = 20
OH OH OH OH
Ph
s > 50 s > 50 s=9 s=4
Scheme 20 Miller’s octapeptide catalyzed KR of sec-alcohols [164]
OH NHAc O
OH NHAc NHAc O
AcO N
53 (10 mol%) N H H HN
+ Ac2O + N
Cy
Et3N (20 eq) O Phe-OMe
toluene N NHBoc O N
(±) (50 eq) s = 40 H
−23 °C, 3 d
C = 37% 53
OH NHAc OHNHAc OHNHAc OHNHAc OH NHAc
O 2N
s = >50 s = 32 s = 40 s = 39 s = 19
C = 48% C = 40% C = 35% C = 38% C = 35%
Scheme 21 Miller’s tetrapeptide catalyzed KR of tert-alcohols [166]
i Pr i Pr
O O
O i Pr O
i Pr S S
NH N NH N
i Pr i Pr
N N
t Bu O O
Si Si
Ph Ph Ph Ph
54 55
Fig. 13 Ishihara’s minimal artificial acylase [234]
substrate by a proximity effect. Hence, catalyst 54 gave impressive levels of selec-

tivity for a wide range of both cyclic and acyclic substrates (Scheme 22) [234].
Procedure for KR of a monoprotected-1,2-diol using catalyst 54: KR of (±)-cis-N-(2-hy-
droxycyclohexanoxycarbonyl)pyrrolidine [234]
i Pr i Pr
O N
S O
i Pr O O
t Bu H NH
HO
Ph Si O i Pr
Ph N O
N
H
Fig. 14 Ishihara’s model for enantioselective acylation [234]
O O
O
O O 54 (5 mol %) O N O N
O N + i Pr O i Pr
+
i Pr2NEt (0.5 eq) OH O iPr
OH
CCl4, 0 °C, 3 h s = 87 O
(±) (0.5 eq) 97% ee 90% ee
C = 52%
O O
O N s = 93 O N s = 83
90% eeA 93% eeA i Pr O O
OH C = 49% C = 50% S
OH
NH N
O O i Pr i Pr
s = 68 s = 19 N
O N O N OTBDPS
82% eeA 64% eeA
OH C = 47% Ph OH C = 44% 54
Scheme 22 Ishihara’s histidine derivative catalyzed KR of mono-protected cis-diols [234]
To a solution of (±)-cis-N-(2-hydroxycyclohexanoxycarbonyl)pyrrolidine (0.25 mmol) and

catalyst 54 (0.0125 mmol) in CCl4 (2.5 mL) was added iPr2NEt (21.8 µL, 0.125 mmol) and
(iPrCO)2O (20.7 µL, 0.125 mmol). The reaction mixture was stirred at 0 °C for 3 h and
then treated with 0.1 M aq. HCl and extracted with EtOAc. The organic layer was washed
with sat. aq. NaHCO3, dried (Na2SO4) and concentrated to provide a crude mixture of the
unreacted alcohol (97% ee by chiral-HPLC) and acylated product (90% ee by chiral
HPLC). The calculated selectivity value at 51.9% conversion was s = 87.
3.5 1,2-Di(tert-amine)-Based Catalysts
Oriyama [178–183] and co-workers developed yet another family of chiral catalysts.
Derived from proline, these new catalysts were used in the KR of a number of cyclic
alcohols (5- to 8-membered rings) with selectivity factors ranging from 37 to 170 with
as low as 0.3 mol% of catalyst. While the exact reaction mechanism is not clear, the
authors proposed, based on analysis of 1H NMR chemical shift changes for signals
from the catalyst upon addition of the achiral acylating agent, that the diamine coordi-
nates in a bidentate fashion to the carbonyl carbon of the acid halide, which in turn
leads to sufficient catalyst rigidity to account for the high enantioselectivities.
Although this non-classical bonding situation is highly unusual, catalyst 55 represents

an extremely interesting catalyst class as it exhibits high selectivities whilst being
extremely easy to prepare (Scheme 23) [178].
In addition, Oriyama was the first to provide a practical protocol for the ASD of
meso-1,2-diols [179–182]. Thus, employing just 0.5 mol% of (S)-proline-derived
chiral diamine 56 in conjunction with benzoyl chloride as the stoichiometric acyl
donor in the presence of Et3N, asymmetric benzoylation of a variety of meso-diols
could be achieved with good to excellent enantioselectivities (66–96% ee) and
³80% yields (Scheme 24) [179–182].
Procedure for ASD of a meso-1,2-diol using catalyst 56: ASD of cis-1,2-cyclohexanediol
[180]
To 4 Å MS (400 mg) was added a solution of catalyst (S)-56 (3.3 mg, 0.0151 mmol) in
CH2Cl2 (2.5 mL) and the resulting reaction mixture was cooled to −78 °C. A solution of
Et3N (306 mg, 3.02 mmol) in CH2Cl2 (2.5 mL), a solution of cis-1,2-cyclohexanediol (351
mg, 3.02 mmol) in CH2Cl2 (20 mL) and a solution of BzCl (636 mg, 4.52 mmol) in CH2Cl2
(2.5 mL) were then added sequentially. After 3 h at −78 °C the reaction was quenched by
the addition of a phosphate buffer (pH 7) and extracted with Et2O. The combined organic
O 55 (0.003 eq) OBz

OH + Ph Cl N
N
R1 R2 Et3N (0.5 eq), 4Å MS R1 R2 Me
CH2Cl2, -78 °C, 3 h
(±) (0.75 eq) 20 < s < 200 55
OH OH OH OH
OH
Ph Ph Ph Br
s = 160 s = 37 s = 88 s = 20 s = 170
95% eeA 88% eeA 79% eeA 78% eeA 91% eeA
C = 48% C = 42% C = 47% C = 49% C = 43%
Scheme 23 Oriyama’s proline derived diamine catalyst [178]
R OH 56 (0.5 mol %) R OH N
+ BzCl N
R OH Et3N (1 eq), 4Å MS R OBz
(1.5 eq) CH2Cl2, −78 °C, 3 h 56
OH OH OH Ph OH Me OH
OBz OBz OBz Ph OBz Me OBz

96% ee 90% ee 66% ee 60% ee 94% ee
yield = 83% yield = 81% yield = 89% yield = 80% yield = 85%
Scheme 24 Oriyama’s proline diamine catalyzed ASD of meso diols [180]

extracts were dried (Na2SO4) and concentrated in vacuo. The residue was purified by FC on
silica gel (EtOAc/hexanes, 1/15) to afford cis-benzoyloxy-1-cyclohexanol (554 mg, 83%,
96% ee by chiral-HPLC).
Oriyama subsequently showed that this catalyst system was also effective for the
KR of various classes of sec-alcohols, notably b-halohydrins [188] and also certain
a-chiral primary alcohols such as glycerol derivatives [184]. A solid-supported version
of Oriyama’s catalyst developed by Janda was found to which induce comparable
levels of selectivity [185–187].
Most recently, Kündig has developed some related 1,2-di(tert-amine) catalysts
which can be readily prepared from pseudo-enantiomeric quincoridines. These cata-
lysts were shown to be more effective than those disclosed by Oriyama when applied
to the ASD of a meso-diol complex derived from [Cr(CO)3(h6–5,8-naphthoquinone)]
[188, 189].
3.6 Quinine/Quinidine-Based Catalysts
(e.g., Cinchona Alkaloids)
ASD of achiral and meso-anhydrides by ring opening with alcohols constitute Type
II asymmetric acyl transfer processes which can be catalyzed by either chiral Lewis
acids or bases [190–192]. Pioneering use of cinchona alkaloids as catalysts for
these transformations was carried out by the groups of Oda [193, 194] and Aitken
[195, 196] in the 1980s. This work provided the foundation for a significantly more
enantioselective system for the ASD of cyclic meso anhydrides developed by Bolm
employing a stoichiometric amount of the cinchona alkaloid quinidine (or its
pseudeoenantiomer quinine) as the catalyst [197]. Reactions of bicyclic and tricyclic
meso-anhydrides 57a–h with methanol in the presence of 110 mol% of quinidine
in a 1:1 toluene/CCl4 solvent system at −55 °C provided the corresponding hemiesters
with ³93% ee and ³84% yields. Use of quinine instead of quinidine generally pro-
vided ent-57a–h with similar levels of selectivity (Table 8). Mechanistically, it was
initially assumed that amine-catalyzed acylative KR of sec-alcohols and ASD of
achiral and meso-anhydrides involved nucleophilic attack by the amine onto the
anhydride to afford a reactive acylammonium species. However, due to steric fac-
tors, neither the quinoline nor the quinuclidine nitrogens of the cinchona alkaloids
are expected to be sufficiently nucleophilic to undergo such nucleophilic attack. In
this context, Oda suggested that cinchona alkaloids catalyzed the acylative KR of
sec-alcohols and the ASD of achiral and meso-anhydrides through a base activation
even though a synergetic combination of both mechanisms could not be ruled out.
Following the reaction, simple extraction provided access to both the hemiester
product and the alkaloid without chromatography and the recovered cinchona alka-
loid could be reused with no deterioration in the ee or yield. This method has found
use in the synthesis of b-amino alcohols and in natural product synthesis [198–201]
and has recently been reported as an Organic Syntheses method [202].
Table 8 Bolm’s quinidine/quinine promoted ASD of meso-anhydrides

OMe
quinidine (110 mol%)
H O methanol (3.0 eq) H OH
CO2Me
O N
toluene/CCl4 (1/1) CO2H
H O H N H
−55 °C, 60 h
quinidine
57a
H O H O H O H O
O O O
O O O O
O O O
O H O H O H O H O
O O
57b 57c 57d 57e 57f 57g 57h
Quinidin Quininea
Entry Anhydride ee (%) Yield (%) ee (%) Yield (%)
1 57a 93 98 87 91
2 57b 99 98 99 92
3 57c 96 96 93 94
4 57d 85 96 93 94
5 57e 95 97 93 99
6 57f 94 99 87 93
7 57g 95 93 93 99
8 57h 94 84 94 86
a
Quinine catalyzed reactions give enantiomeric products
Subsequently, Bolm developed a variant of this process which employed just a

sub-stoichiometric quantity of cinchona alkaloid [203]. In this method, 10 mol% of
quinidine was used in conjunction with a stoichiometric amount of pempidine to
prevent sequestration of the cinchona alkaloid by the acidic hemiester product.
The chiral hemiester products derived from various meso-anhydrides were obtained
with ³74% ee and ³94% yields (Table 9) [203].
Although both quinidine and pempidine can be recovered and reused, it is note-
worthy that pempidine is more expensive than quinidine and that this protocol
requires very long reaction times.
Procedure for ASD of a cyclic meso-anhydride using quinidine: ASD of bicyclo [2.2.1]
hept-5-ene-2,3-dicarboxylic acid endo cis-anhydride [204]
MeOH (0.122 mL, 3.0 mmol) was added dropwise to a stirred suspension of anhydride 57b
(164 mg, 1.0 mmol) and quinidine (0.357 g, 1.1 mmol) in a mixture of toluene and tetra-
chloromethane (1/1, 5 mL) at −55 °C under argon. The reaction mixture was stirred at this
temperature for 60 h. During this period, the material gradually dissolved. Subsequently,
the resulting clear solution was concentrated in vacuo to dryness, and the residue was dis-
solved in EtOAc. The solution was washed with 2N HCl and, after phase separation, fol-
lowed by extraction of the aqueous phases with EtOAc; the organic layer was dried
(MgSO4), filtered and concentrated in vacuo to provide the corresponding hemiester
(2R,3S)-3-endo-methoxycarbonyl-bicyclo[2.2.1]hept-5-ene-2-endo-carboxylic acid as a
white solid (192 mg, 98%, 99% ee by chiral-HPLC on the methyl 4-bromophenol diester).
To recover the alkaloid, the acidic aqueous phase was neutralised with Na2CO3 and
extracted with CH2Cl2. The combined organic phases were dried (MgSO4) and filtered.
Evaporation of the solvent yielded the recovered alkaloid almost quantitatively.
Table 9 Bolm’s quinidine catalyzed ASD of meso-anhydrides [203]
quinidine (10 mol%)

MeOH (3.0 eq) OMe
H O pempidine (1.0 eq) H
CO2Me
O OH
toluene/CCl4 (1/1) CO2H N
H O H
-55 °C, 60 h
57i N H
quinidine
Me Me
Me N Me
Me
pempidine
Entry Anhydride ee (%) Yield (%)

1 57b 90 98
2 57c 91 94
3 57e 89 96
4 57f 81 97
5 57i 74 98
Bolm has demonstrated the utility of the quinidine-mediated ASD of cyclic

meso-anhydrides by developing protocols for the conversion of the hemiester products
into enantiomerically enriched unnatural b-amino alcohols by means of Curtius
degradation [204]. A particularly practical variant of this procedure utilises benzyl
alcohol rather than methanol as the nucleophile in the quinidine-mediated ASD
reaction, allowing, following Curtius degradation, for hydrogenolytic deprotection
of both the benzyl ester and a N-CBz group to afford free b-amino alcohols in a
single step [205]. The Bolm method can also be used under solvent-free conditions
in a ball-mill [206].
In 2000, Deng was the first to report the use of readily available ‘Sharpless ligands’
to catalyze the enantioselective alcoholysis of meso-cyclic anhydrides [207].
Hence, the use of a catalytic amount of the bis-cinchona alkaloid (DHQD)2AQN
(5–30 mol%) in the alcoholysis of monocyclic, bicyclic and tricyclic succinic
anhydrides as well as glutaric anhydrides at −20 to −30 °C and in the absence of a
stoichiometric amount of an achiral base, provided the corresponding hemiesters in
good to excellent yields (72–99%) and with excellent enantioselectivities (91–98%
ee). Interestingly, the antipodal products could be easily obtained by employing the
pseudo-enantiomeric (DHQ)2AQN as the catalyst (Table 10) [208, 210].
The synthetic utility of this methodology was further demonstrated in a formal
synthesis of (+)-biotin by the same authors [211]. Following this work, various
reusable immobilised analogues of (DHQD)2AQN were reported to catalyze the
desymmetrization of a number of meso-cyclic anhydrides with good selectivities
[212–214].
Procedure for ASD of a cyclic meso-anhydride using (DHQD)2AQN as catalyst: ASD of

cis-cyclopentane-1,2-dicarboxylic acid anhydride [208–210]
Dry MeOH (32 mg, 40 µL, 1.0 mmol) was added dropwise to a stirred solution of cis-
cyclopentane-1,2-dicarboxylic acid anhydride 57e (14 mg, 0.1 mmol) and (DHQD)2AQN
(95%, 72.2 mg, 0.08 mmol) in dry Et2O (5 mL) under argon at −30 °C. The reaction mixture
was stirred at −30 °C until the starting material was consumed (TLC, 71 h). The reaction was
quenched by addition of HCl (1N, 3 mL) in one portion. The aqueous phase was extracted
with EtOAc (2×10 mL) and the combined organic phases dried (MgSO4) and concentrated
in vacuo to afford the hemiester as a clear oil (17 mg, 99%, 95% ee by 1H NMR on the
diastereomeric amides formed by coupling the hemiesters to (R)-1-naphthalen-1-yl-
ethylamine). The (DHQD)2AQN catalyst was recovered quantitatively by basification (pH
11) of the aqueous phase with aqueous KOH (1N), extraction with Et2O, drying of the Et2O
extracts (MgSO4) and concentration in vacuo.
Deng also showed that (DHQD)2AQN could catalyze the parallel KR (PKR) of
a variety of monosubstituted succinic anhydrides via asymmetric alcoholysis [215].
The nature of the solvent was found to have a significant influence on the selectivity.
Hence, increasing the size of the alcohol from methanol to ethanol resulted in
increased levels of enantioselectivity, albeit with reduced reaction rates. In this
context, 2,2,2-trifluoroethanol appeared to be the alcohol of choice as it allowed the
ASD of 2-methyl succinic anhydride (58a) with a remarkable level of selectivity.
Indeed, the use of (DHQD)2AQN (15 mol%) provided a mixture of two regioiso-
meric hemiesters 59a and 60a in a ~1:1 ratio with 93 and 80% ee respectively.
Table 10 Deng’s (DHQD)2AQN catalyzed ASD of achiral/meso-anhydrides [208, 210]
Et Et
(DHQD)2AQN N N
H O H O O
MeOH (10 eq) CO2Me H
H H H
O MeO O O OMe
Et2O CO2H
H O H N N
57a (DHQD))2AQN
H O H O O O O
O
O O O O iPr O
O
O H O H O O O O
57b 57e 57g 57j 57k 57ll
Entry Anhydride mol% cata T (°C)a Yield (%)a ee (%)a

1 57a 5(5) −20(−20) 97(95) 97(93)
2 57b 10(20) −30(−20) 82(82) 95(90)
3 57e 8(8) −30(−30) 99(90) 95(93)
4 57g 7(7) −20(−20) 95(92) 98(96)
5 57j 5(5) −20(−20) 93(88) 98(98)
6 57k 30(30) −40(−35) 70(56) 91(82)
7 571 30(30) −40(−35) 72(62) 90(83)
a
values in parentheses are for reactions using (DHQ)2 AQN that give enantiomeric products
Similarly, a variety of 2-alkyl and 2-aryl succinic anhydrides (58b−g) were resolved
with good to excellent enantioselectivities (66–98% ee) (Table 11) [216].
The synthetic utility of this PKR process was exemplified in a formal total
synthesis of the g-aminobutyric acid (GABA) receptor agonist (R)-baclofen
[215].
Procedure for PKR of a monosubstituted succinic anhydride using (DHQD)2AQN as cata-
lyst: PKR of (±)-2-methysuccinic anhydride [215]
2,2,2-Trifluoroethanol (0.73 mL, 10 mmol) was added to a solution of 2-methylsuccinic
anhydride 58a (114 mg, 1.0 mmol) and (DHQD)2AQN (95%, 180 mg, 0.2 mmol) in Et2O
(50.0 mL) at −24 °C. The resulting reaction mixture was stirred at this temperature until
the anhydride was consumed (TLC, 50 h). The reaction mixture was washed with aqueous
HCl (1N, 3 × 10 mL). The aqueous phase was extracted with Et2O (3 × 20 mL), the com-
bined organic phases dried (MgSO4) and then concentrated in vacuo. The residue was
purified by FC on silica gel (cyclohexane/butyl acetate/acetic acid, 50/1/1) to afford
hemiester 59a (77 mg, 36%, 93% ee by chiral-HPLC on the diastereomeric amides formed
by coupling the hemiesters to (R)-1-naphthalen-1-yl-ethylamine) and hemiester 60a (88
mg, 41%, 80% ee by chiral-HPLC on the diastereomeric amides formed by coupling the
hemiesters to (R)-1-naphthalen-1-yl-ethylamine). The (DHQD)2AQN catalyst was recov-
ered quantitatively by basification (pH 11) of the aqueous phase with aqueous KOH (2N),
extraction with EtOAc (3 × 15 mL), drying of the EtOAc extracts (MgSO4) and concentra-
tion in vacuo.
Deng also applied his (DHQD)2AQN-catalyzed asymmetric alcoholysis to urethane-

protected a-amino acid N-carboxy anhydrides (UNCAs) in order to access enantio-
merically enriched a-amino acid derivatives [216]. Hence, the KR of a variety of
alkyl and aryl UNCAs containing various carbamate protecting groups provided
carbamate protected amino esters with selectivity values s ranging from 23 to 170
[217]. It is worth noting that when these reactions were performed at higher temperatures
(such as room temperature), DKR could be achieved [218, 219]. Allyl alcohol was
Table 11 Deng’s (DHQD)2AQN catalyzed ASD of meso-anhydrides [216]

O O O
R (DHQD)2AQN (15 mol %) R R
O OCH2CF3 + OH
CF3CH2OH (10.0 eq) OH OCH2CF3
O
Et2O, −24 °C O O
(±)−58a–g 59a–g 60a–g
ee (%) Yield (%)
Entry R 59/60 59 60 59 60
1a Me (58a) 44/55 93 80 36 41
2 Et (58b) 40/60 91 70 38 50
3 n-C8H17 (58c) 42/56 98 66 38 41
4 Allyl (58d) 46/53 96 82 40 49
5b Ph (58e) N/A 95 87 44 32
6b 3-MeO-C6H4 (58f) N/A 96 83 45 30
7b 4-Cl-C6H4 (58g) N/A 96 76 44 29
found to be the optimal nucleophile, allowing a variety of UNCAs to be resolved

with high stereoselectivities (90–92% ee) and good yields (93–98%) [218]. The
resulting allyl esters could then be converted to the corresponding a-amino acids
via Pd-catalyzed deallylation (Table 12) [218].
The ready availability of the starting materials, the lack of special precautions to
exclude air and moisture from the reaction mixtures and the ease of recovery of
products make these DKR protocols attractive for the preparation of enantiomerically
highly enriched N-protected-a-amino acids.
Procedure for DKR of a UNCA using (DHQD)2AQN as catalyst: DKR of (±)-2,5-dioxo-
4-phenyl-3-oxazolidine carboxylic acid phenylmethyl ester [218]
A mixture of UNCA 61a (62.2 mg, 0.20 mmol) and 4 Å MS (20 mg) in anhydrous Et2O
(14.0 mL) was stirred at room temperature for 10 min and warmed to 34 °C, after which
(DHQD)2AQN (95%, 36.1 mg, 0.040 mmol) was added. The resulting mixture was stirred
for a further 5 min and then a solution of allyl alcohol in Et2O (1/99, 0.24 mmol) was
introduced dropwise via a syringe over a period of 1 h. The resulting reaction mixture was
stirred at 34 °C for 1 h, washed with aqueous HCl (2N, 2 × 3.0 mL) and brine (3.0 mL), dried
(Na2SO4) and concentrated to provide a light yellow solid. Purification by FC on silica gel
(EtOAc/hexanes, 1/9) gave (R)-allyl-(N-benzyloxycarbonyl)phenylglycinate 61a as a white
solid (63 mg, 97%, 91% ee by chiral-HPLC). The (DHQD)2AQN catalyst was recovered
quantitatively by washing the combined aqueous extracts with Et2O (2 × 2.0 mL) and then
basifying first with KOH (→ pH ~4) and then with Na2CO3 (→ pH ~11). The resulting solu-
tion was extracted with EtOAc (2 × 5.0 mL) and the combined organic extracts washed
with brine (2.0 mL), dried (Na2SO4) and concentrated in vacuo.
Table 12 Deng’s (DHQD)2AQN catalyzed DKR of UNCAs [218]
1) (DHQD)2AQN (20 mol %) Et Et

N N
O allyl alcohol (1.2 eq) O O O
R Et2O, 4Å MS R H
H H H
OH MeO OMe
CbzN O 2) Pd(PPh ) (0.1 eq)
O O
3 4 NCbz
O N N
morpholine (10.0 eq) (R)-62a-f (DHQD))2AQN
(±)-61a-f THF, 23 °C, 10 min
(R)-62a–f
Entry R T (°C)a t (h)a ee (%) Yield (%)
1 aPh 23(34) 1(1) 90 91
2 b 4-F-C6H4 23 1 90 93
3 c 4-Cl-C6H4 23 1 92 92
4 d 4-CF3-C6H4 23 1 90 88
5 e 2-Thienyl −30 2 92 93
6 f 2-Furyl 23(−30) 0.5(1) 89 86
a
Values in parentheses are for reactions using (DHQ)2AQN and give enantiomeric products
This methodology was also applied to substituted 1,3-dioxolane-2,4-diones

which represent potential precursors to enantiomerically enriched a-hydroxy acid
derivatives. Hence, Deng found that the alcoholative KR of a-alkyl-1,3-dioxolane-
2,4-diones using (DHQD)2AQN as the catalyst provides chiral a-hydroxy esters
with excellent selectivities (s = 49–133) [219]. As for the UNCAs, Deng found that
under appropriate conditions 1,3-dioxolane-2,4-diones could also be induced to
undergo DKR, sometimes at −78 °C although temperatures up to −20 °C proved
optimal for certain substrates. Thus, for a range of a-aryl-1,3-dioxolane-2,4-diones
63a−g, (DHQD)2AQN (10 mol%) catalyzed DKR to the corresponding esters
64a−g with excellent stereoselectivities (91–96% ee) and good yields (65–85%)
(Table 13) [219].
Procedure for DKR of an a-aryl-1,3-dioxolane-2,4-dione using (DHQD)2AQN as catalyst:
DKR of (±)-5-phenyl-1,3-dioxolane-2,4-dione [219]
A mixture of 5-phenyl-1,3-dioxolane-2,4-dione (63a) (178 mg, 1.0 mmol) and 4 Å MS
(100 mg) in anhydrous Et2O (50 mL) was stirred at room temperature for 15 min, then
cooled to −78 °C, after which (DHQD)2AQN (95%, 90.2 mg, 0.1 mmol) was added to the
mixture. The resulting mixture was stirred for a further 5 min and then EtOH (1.5 eq) was
added dropwise over 10 min by syringe. The resulting reaction mixture was stirred at −78
°C for 24 h. HCl (1N, 5.0 mL) was added to the reaction dropwise and the resulting mixture
was allowed to warm to room temperature. The organic phase was collected, washed with
aqueous HCl (1N, 2 × 5.0 mL) and the aqueous phase was extracted with Et2O (2 × 5.0
mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concen-
trated in vacuo. Purification by FC on silica gel (EtOAc/hexanes, 1/4) gave (R)-ethyl
mandalate (64a) as a white solid (128 mg, 71%, 95% ee by chiral-HPLC).
The mechanism by which cinchona-based catalyst systems effect such selective

ring-opening of anhydrides and related systems has been the subject of extensive
Table 13 Deng’s (DHQD)2AQN catalyzed DKR of 1,3-dioxolane-2,4-diones [219]
Et Et
O O N N
R (DHQD)2AQN (10 mol %)
R O O
OEt H
O O OH H H H
EtOH (1.5 eq), Et2O MeO O O OMe
O
(±)-63a-g (R )-64a--g N N
(DHQD)2AQN
Entry R T (°C) t (h) Yield (%) ee (%)

1 a Ph −78 24 71 95
2 b 4-Cl-C6H4 −78 24 70 96
3 c 4-CF3-C6H4 −78 24 85 93
4 d 4-i-Pr-C6H4 −20 8 68 91
5 e 1-Napa −40 14 74 91
6 f 2-Cl-C6H4 −60 10 66 62
7 g 2-Me-C6H4 −20 4 61 60
a
THF used as solvent and n-PrOH in place of EtOH
debate in the literature, and although a consensus has yet to emerge as to whether
nucleophilic or general base catalysis is primarily operational the current weight of
evidence seems to support the latter [190].
In line with this mechanistic interpretation, recently Connon [220] and Song
[222] have independently described the highly enantioselective ASD of cyclic
meso-anhydrides using a bifunctional thiourea-based organocatalyst 65 derived
from a cinchona alkaloid core. The choice of this catalyst was based on the premise
that it might selectively bind and activate the anhydride electrophile by hydrogen
bonding to the thiourea moiety and subsequently encourage attack at a single anhy-
dride carbonyl moiety through general-base catalysis mediated by the suitably
positioned chiral quinuclidine base (Fig. 15) [221].
Fujimoto has also described an asymmetric benzoylation system that is effective
for ASD of cyclic meso-1,3- and 1,4-diols and which employs phosphinite derivative
of quinidine 66 as the catalyst (Fig. 15) [224, 225].
The development of predictive transition state models for the interpretation of
selectivity data pertaining to the use of cinchona alkaloid derivatives in all the processes
described above is challenging due to the complex conformational behaviour of
these natural scaffolds (for example, it is well known that O-acylated quinidines
undergo major conformational changes upon protonation) [223]. Consequently,
hypotheses regarding the details of chirality transfer in these systems are notably
absent.
3.7 Imidazolone-Based Catalysts
Uozumi has explored a series of (2S,4R)-4-hydroxyproline-derived 2-aryl-6-

hydroxy-hexahydro-1H-pyrrolo[1,2-c]imidazolones as potential alternatives to
cinchona alkaloid-based catalysts for the alcoholative ASD of meso-anhydrides
(Fig. 16) [226]. Uozumi screened a small library of catalysts prepared by a four-
step, two-pot reaction sequence from 4-hydroxyproline in combination with an
aldehyde and an aniline. The most selective member, compound 67, mediated the
methanolytic ASD of cis-hexahydrophthalic anhydride in 89% ee when employed
at the 10 mol% level for 20 h at −25 °C in toluene [226].
N H H N
N N CF3 OPPh2
H H
MeO S MeO
CF3
N N
65 66
Connon/Song's bifunctional Fujimoto's phosphinite
catalyst derived from quinine derivative of quinidine
Fig. 15. Connon/Song’s and Fujimoto’s catalysts for alcoholative ASD of cyclic meso-anhydrides
and mono benzoylation of meso-diols respectively [220–225]
3.8 Piperidine-Based Catalysts
Irie has described the use of an optically active tripodal amine, (2S,6S)-2,6-bis(o-
hydroxyphenyl)-1-(2-pyridylmethyl)piperidine (68) as a potent catalyst for methano-
lytic ASD of cyclic meso-anhydrides (Fig. 16) [227]. This catalyst was envisaged
to adopt a helical conformation thereby providing a highly asymmetric environment
for the nucleophilic tert-amine lone pair whilst also allowing activation of the anhydride
substrate by the phenolic hydroxyl groups. In the event, ees up to 81% were obtained
for the methanolytic ASD of a cyclic meso-anhydride when employed at the 5
mol% level for 20 h at 0 °C in toluene [227].
3.9 Sulfonamide-Based Catalysts
Nagao has disclosed bifunctional chiral sulfonamide 69 as being effective for the
thiolytic ASD of meso-cyclic anhydrides in up to 98% ee when employed at the 5
mol% level for 20 h at room temperature in ether [228]. Catalyst 69 is a 1,2-diamine
derivative in which one of the nitrogens presents as an acidic NH group (part of an
electron deficient aryl sulfonamide) and the other as a nucleophilic/basic tert-amine
group with the intention to act synergistically in activation of the substrate carbonyl
function and thiol nucleophile respectively (Fig. 16) [228].
4 Alcohol Catalysts
4.1 Trifluoromethyl-sec-Alcohol-Based Catalysts
Oxygen-based nucleophiles can also be employed for the catalysis of acyl transfer.
For example, pyridine-N-oxide derivatives such as 4-DMAP-N-oxide have long been
known as such catalysts although, interestingly, these catalophores are reportedly
particularly efficient at mediating sulfonyl and phosphoryl transfer [229–230].
CF3
OH OH
O H N O
F 3C SO
n C8H17 N OH HN Ph
N
N
Me2N Ph
67 68 69
Uozumi's hexahydro-1H-pyrrolo Irie's tripodal-2,6-trans- Nagao's bifunctional
[1,2-c]imidazolone 1,2,6-trisubstituted piperidine chiral sulfonamide
Fig. 16 Uozumi’s, Irie’s and Nagao’s catalysts for alcoholative ASD of cyclic meso-anhydrides
[226–228]
Sammakia has developed a unique chiral O-nucleophilic acyl transfer catalyst 70

and shown that it is effective for the KR of a series of a-hydroxy acid [231] and
a-amino acid [232] derivatives. He found that by employing this catalyst at the 10 mol%
level in toluene at −26 to 0 °C it was possible to resolve a-acetoxy-N-acyloxazo-
lidinethiones with s values in the range 17–32 and a-(N-trifluoroacetyl)-N-
acyloxazolidinethiones with s values in the range 20–86 (Scheme 25) [231, 232].
The stereoselectivity-determining step is believed to involve attack of the hydroxyl
group of the catalyst on the active ester of the substrate with concomitant general base
catalysis form the proximal nitrogen of the catalyst to form an acyl catalyst intermedi-
ate. Attack of methanol on this intermediate, again with base catalysis from the
proximal nitrogen provides the ester product and regenerates the catalyst. The trifluor-
omethyl group is essential to modulate the acidity of the alcohol; the corresponding
methyl substituted alcohol is ~37 times less active [233]. This KR method is notable
for its success with cyclic amino acid derivatives making it nicely complementary to
the above described approach of Deng to acyclic amino acids. Sammakia has also shown
that the recovered oxazolidinethiones can be used directly in peptide coupling
reactions using (i-Pr)2EtN and HOBt.
CF3
OH OH
O H N O
F 3C SO
nC8H17 N OH HN Ph
N
N
Me2N Ph
67 68 69
Uozumi's hexahydro-1H-pyrrolo Irie's tripodal-2,6-trans- Nagao's bifunctional
[1,2-c]imidazolone 1,2,6-trisubstituted piperidine chiral sulfonamide
70 (10 mol %)
R R R
MeOH (30 eq)
AcO N O
AcO
N O + AcO
OMe
O S toluene O S O
(±) R = Ph, Bn, CH 2CH2Ph, Bu, i-Pr, Allyl
NMe2
s = 17-32, eerec SM = 91-99%, C = 54-59% OH
CF3
70 (10 mol %)
R R R 70
MeOH (30 eq)
TFA.H2N
N O
TFA.H2N
N OH + TFA.H2N
OMe
O S toluene O S O
(±) R = i-Pr, i-Bu, Allyl, CH2CH2SMe
s = 20-68, eerec SM = 90-99%, C = 52-57%
.TFA .TFA .TFA .TFA .TFA

NH NH
N O N O N N O N O N O
N N
H H H O S O S O S
O S O S
s = 20 s = 86 s = 22 s = 41 s = 40
96% eerec SM >99% eerec SM 98% eerec SM 93% eerec SM 96% eerec SM
C = 58% C = 53% C = 58% C = 52% C = 54%
Scheme 25 Sammakia’s chiral alcohol catalyzed KR of a-acetoxy- and a-(N-trifluoroacetyl)

amino acid-N-acyloxazolidinethiones [231, 232]
5. Concluding Remarks
Since the pioneering work of Vedejs and Fu using chiral phosphines and pyrrole
derivatives, respectively, a plethora of topologically diverse chiral nucleophilic
acylating agents incorporating many different catalytic cores have been developed in
laboratories across the globe. As a result, efficient systems have been developed for
the acylative KR and ASD of a range of sec-alcohols, meso-diols, sec-amines and
meso-anhydrides. In some cases, results can be compared favourably with hydrolytic
enzymes, usually with the advantage of ready access to enantiomeric catalysts.
However, much progress remains to be made; for example tert-alcohols remain
formidable substrates as do most classes of amine. Moreover, the development of
related chiral nucleophile catalyzed reaction manifolds for asymmetric silylation
[234–236], sulfonylation [237] and phosphorylation [238] remains relatively unex-
plored. For success to be achieved with these and other substrate/reaction classes
and for the efficiencies and selectivities of all the types of transformations dis-
cussed in this review to be optimised, additional mechanistic insight needs to
accrue. Structural detail relating to the nature of the interactions which are decisive
in orchestrating chirality transfer between the catalyst and substrate including
H-bonding and stacking interactions need to be understood in intimate detail and to
this end it is hoped that the focus brought to bear on these transformations in this
review may help to galvanise synthetic effort towards this goal.
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DOI: 10.1007/128_2008_28
Published online: 07 October 2009
Secondary and Primary Amine Catalysts

for Iminium Catalysis
John B. Brazier and Nicholas C.O. Tomkinson
Abstract Formation of iminium ions from the condensation of chiral second-

ary or primary amines with a,b-unsaturated aldehydes or ketones can be used
as an effective platform for the acceleration of a wide variety of catalytic asym-
metric cycloaddition and conjugate addition reactions. The reversible formation
of the active iminium ion species simulates the p-electronics and equilibrium
dynamics traditionally associated with Lewis acid activation of a,b-unsaturated
carbonyl compounds lowering the energy level of the LUMO associated with
the p-system and activating subsequent reaction. Importantly, these iminium ion
catalysed processes offer the opportunity to conduct reactions in the presence
of both moisture and air greatly adding to the practicality and general applica-
bility of the chemistry described. Proposed catalytic cycles and transition state
models for the induction of asymmetry provide reliable and robust predictive
tools for the outcome of reactions and high functional group tolerance suggests
this class of transformation will have broad application in the arena of synthetic
organic chemistry as the area matures. This review describes the rapid expan-
sion of iminium ion catalysis over recent years from its conceptual introduction
to the development of a whole new arsenal of highly practical and effective
methods with which to approach challenging and fundamental bond construc-
tion processes.
J.B. Brazier and N.C.O. Tomkinson (*ü)

School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
e-mail: tomkinsonnc@cardiff.ac.uk
282 J.B. Brazier and N.C.O. Tomkinson
Keywords Aminocatalysis • Conjugate addition • Cycloaddition • Iminium ion •

Organocatalysis
Contents
1 Basic Principles..................................................................................................................... 283
1.1 Introduction................................................................................................................ 283
1.2 Iminium Ion Catalysis: The Concept......................................................................... 283
1.3 Perspective and History.............................................................................................. 285
2 Secondary Amines as Catalysts............................................................................................ 286
2.1 Cycloaddition............................................................................................................. 286
2.2 Conjugate Addition.................................................................................................... 295
2.3 Using the Enamine Intermediate................................................................................ 309
2.4 1,2-Addition – An Important Consideration.............................................................. 323
3 Primary Amines as Catalysts................................................................................................ 325
3.1 [4+2] Cycloaddition................................................................................................... 325
3.2 [3+2] Cycloaddition................................................................................................... 326
3.3 Epoxide Formation..................................................................................................... 327
3.4 Conjugate Addition.................................................................................................... 328
4 Chiral Anions Using Secondary and Primary Amines as Catalysts..................................... 330
5 Applications in Synthesis...................................................................................................... 332
6 Mechanistic and Structural Investigations............................................................................ 336
7 Theoretical Investigations..................................................................................................... 337
8 Conclusions and Perspectives............................................................................................... 341
References................................................................................................................................... 342
Abbreviations
Alloc Allyloxycarbonyl
DCA Dichloroacetic acid
DIPEA N,N-Diisopropylethylamine
DNBA 2,4-Dinitrobenzoic acid
F-SPE Fluorous solid phase extraction
HFIP 1,1,1,3,3,3-Hexafluoro-2-propanol
IMDA Intramolecular Diels–Alder reaction
LUMO Lowest unoccupied molecular orbital
Ns 4-Nitrophenylsulfonyl
PMP 4-Methoxyphenyl
TCA Trichloroacetic acid
TES Triethylsilyl
TIPBA 2,4,6-Triisopropylbenzenesulfonic acid
TRIP 3,3′-Bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogen
phosphate
Secondary and Primary Amine Catalysts for Iminium Catalysis 283
1 Basic Principles
1.1 Introduction
At the heart of synthetic chemistry is the drive to develop novel, cleaner, more efficient
and selective transformations. To this end there has been a recent explosion of interest
in the use of metal-free processes to carry out functional group transformations, due to
the potential for academic, industrial, economic and environmental benefit. Of particu-
lar note in this area has been the use of small organic molecules to catalyse a number
of fundamental reactions that are an integral part of the synthetic organic chemist’s
toolkit [1]. The broader area of organocatalysis has caught the imagination of the syn-
thetic community over the past decade and development of this fast paced and exciting
field of contemporary research has been astounding.
One of the most prolific and successful areas of research within the subject of orga-
nocatalysis has been in the use of secondary and primary amines to accelerate trans-
formations via iminium ion and enamine catalysis [2]. This review will focus on the
use of iminium ion intermediates as a simple and effective method to activate a,b-
unsaturated aldehydes and ketones towards cycloaddition and conjugate addition proc-
esses. First, reactions that can be accelerated using iminium ion intermediates
generated from chiral secondary and primary amines are discussed. The use of second-
ary and primary amines in conjunction with chiral anions is then described. Exploitation
of the methodology within synthesis is explored, highlighting some of the real advan-
tages made available to the synthetic chemist by this technology. Finally, the mecha-
nistic, structural and theoretical contributions to the field that aid in the understanding
of mechanism, origin of asymmetric induction and reactivity are presented.
1.2 Iminium Ion Catalysis: The Concept
The broad spectrum of reactivity for a,b-unsaturated carbonyl compounds has

bestowed them a central role within synthesis. Depending upon the reaction con-
ditions adopted they can undergo nucleophilic addition reactions in a 1,2- or 1,4-
manner as well as cycloadditions across either of the p-bonds. Each of these
processes can introduce new chiral centres into the molecule and significantly
increase complexity, highlighting their importance. Acceleration of these reac-
tions is traditionally bought about with a Lewis acid which complexes to the
carbonyl group, lowering the energy of the LUMO associated with the p-system,
thus increasing reactivity. The fundamental concept of iminium ion catalysis,
reported in a seminal paper by MacMillan in 2000 [3], involves the reversible
condensation of a secondary amine salt 2 with an a,b-unsaturated aldehyde 1 to
give the corresponding iminium ion 3 (Fig. 1). Formation of this iminium ion
simulates the p-electronics and equilibrium dynamics traditionally associated
with Lewis acid activation lowering the energy of the LUMO of the p-system and
promoting subsequent reaction. Significantly, along with formation of the imin-
ium ion this equilibrium also results in a molecule of water 4. Consequently,

unlike many Lewis acid catalysed processes the reactions are inherently tolerant
of both moisture and air which has major ramifications for their simplicity and
practicality. The ability to generate C–C, C–O, C–N, C–S, C–P and C–H bonds
(the daily challenges of the synthetic chemist) under such mild conditions in high
yield and optical purity explains the exponential growth of organocatalysis in
such a short space of time.
Lewis acid activation

O O LA
cycloaddition O + LA
1,2-addition
Iminium ion activation
R1 2
O R1 R2 N R
1,4-addition + N + H2 O
H X
·HX
1 2 3 4
Fig. 1 The concept of iminium ion activation
The proposed catalytic cycles for the iminium ion catalysed Diels–Alder
cycloaddition and conjugate addition reactions are outlined in Fig. 2. The general
principles of these catalytic cycles can be used to understand each of the reactions
described within this review which all follow a similar mechanistic pathway. The
catalytic cycle consists of three principle steps:
Step 1: Iminium ion formation
Step 2: Key bond forming reaction (i.e. cycloaddition or conjugate addition)
Step 3: Iminium ion hydrolysis
O O O
CHO N N
H H
·HX Nu ·HX
5 5
Step 3 Step 1 Step 3 Step 1

H 2O H2 O H2 O H2
O
N N N N
7 + HX
X X X
Step 2 Step 2
6 8 6
Nu
NuH
Fig. 2 Catalytic cycles for the iminium ion activated Diels-Alder and conjugate addition reactions
Along with the secondary (or primary) amine 5 an equimolar amount of a co-acid
HX is also used in these reactions. This proton source facilitates iminium ion for-
mation and hydrolysis and in most cases is essential for catalytic activity.
Formation of the active iminium ion 6 (Step 1) is an equilibrium, generating a
molecule of water which forms an integral part of the catalytic cycle. On forma-
tion, the iminium ion can undergo the key bond forming reaction (Step 2).
Cycloaddition results in an iminium ion intermediate (7) and conjugate addition
results in an enamine (8). These intermediates (7 and 8) are then hydrolysed with
a molecule of water to give the observed product and regenerate active amine 5
turning over the catalytic cycle (Step 3).
1.3 Perspective and History
Given the importance of the field it is not surprising there have been a significant
number of reviews on organocatalysis. Several reviews [4–10] and highlights [2,
11–13] on the general area of organocatalysis have been published which are rel-
evant to the current discussion. More specialised reports on organocatalytic multi-
component [14], domino [15], tandem [16], conjugate addition [17–19] and
Morita–Baylis–Hillman reactions [20] also contain some details of iminium ion
catalysed processes. Polymer-supported immobilisation of many organic catalysts
has also been comprehensively reviewed [21]. An excellent review by de
Figueiredo and Christmann elegantly places the significance of organocatalysis
within the field of synthesis by showcasing the many uses of the reactions devel-
oped in the preparation of drugs and bioactive natural products [22]. Specifically
related to the current discussion, MacMillan has written an outstanding and per-
sonal review on the advent and development of iminium ion activation which
clearly sets out the scope and future challenges in the area [23]. Most recently, a
comprehensive review of the area has been provided by Pihko including many
insightful historical perspectives [24].
The use of iminium ion activation in cycloaddition reactions has some precedent
with synthetic and biogenetic examples. Baum showed that acetylinic iminium
compounds underwent facile [4+2] and [3+2] cycloaddition reactions and describes
them to be “among the best partners within these reactions” [25]. Baldwin has also
proposed an iminium ion accelerated [4+2] cycloaddition in the biosynthesis of the
Galbulimina type I alkaloids, highlighting the facile nature of these stoichiometric
reactions [26–28].
In a series of reports between 1991 and 1997 Yamaguchi showed that rubid-
ium salts of l-proline (9) catalysed the conjugate addition of both nitroalkanes
[29, 30] and malonates [31–33] to prochiral a,b-unsaturated carbonyl compounds
in up to 88% ee (Scheme 1). Rationalisation of the selectivities observed
involved initial formation of an iminium ion between the secondary amine of
the catalyst and the a,b-unsaturated carbonyl substrate. Subsequent deprotona-
tion of the nucleophile by the carboxylate and selective delivery using ion pair
control gave the observed products after hydrolysis of the resulting enamine.
A truly organocatalytic approach using a similar catalyst scaffold and transi-
tion state model was disclosed by Karwara and Taguchi who reported that
l-proline derived ammonium salt 10 (10 mol%) catalysed the conjugate addi-
tion of malonates to both cyclic and acyclic a,b-unsaturated ketones in up to
71% ee [34]. The transition state model proposed within this work suggests the
malonate is selectively delivered from one face of the iminium ion 11 leading
to enantioenriched products. Unfortunately, the scope of this process was not
explored to any significant extent and no subsequent reports have been dis-
closed; however, the results certainly stand as a tantalising prelude to more
recent discoveries.
CH2 (CO2t Bu)2

O O O
20 mol% 9
N 20 mol% CsF
ORb
H t
BuO 2C
9 CHCl3, rt, 48 h
CO 2tBu
88% ee, 65% yield
O O NMe3
CH 2(CO 2Bn)2
10 mol% 10 N CO 2Bn
N NMe3
H CO2 Bn
10 HFIP, PhMe CO2 Bn
OH
rt, 7 days CO 2Bn 11
71% ee, 61% yield malonate selectively
delivered from
top face of
α,β-unsaturated
iminium ion
Scheme 1 Iminium ion catalysed conjugate addition using proline derivatives
2 Secondary Amines as Catalysts
2.1 Cycloaddition
2.1.1 [4+2] Cycloaddition
Since its original discovery in 1928 [35] the Diels–Alder [4+2] cycloaddition has
evolved to become an integral transformation that is routinely exploited in the art
of total synthesis [36]. Development of asymmetric variants of this reaction has
received great attention and literature within the area is vast [37–40] providing
many of the guiding principles which are now adopted in catalyst design. Given the
importance and history of this reaction it is not surprising that it was also used as a
learning-ground for the development of iminium ion catalysis.
In the initial report by MacMillan, use of the imidazolidinonium salt 12·HCl to
generate iminium ion intermediates identified a new catalytic strategy for the acti-
vation of a,b-unsaturated carbonyl compounds towards cycloaddition [3]. Inherent
to the enantiofacial discrimination of substrates using this catalyst is the formation

of a single iminium ion upon condensation with an aldehyde. Of the two possible
iminium ions (13 and 14) from reaction of 12 with cinnamaldehyde, only 13 is
observed due to steric interactions between the geminal dimethyl group of the cata-
lyst and the a-carbon of the substrate disfavouring 14 (Fig. 3). The benzyl arm of
the catalyst blocks one diastereoface of the activated substrate and thus renders
subsequent transformations asymmetric. These simple, rational and creative factors
in catalyst design make understanding this chemistry extremely accessible height-
ening its great appeal.
O O
O N N
O
N 12·HCl
N + N
N H
–H 2O Ph Ph
Ph H H H
Ph
12
Ph Ph
13 14
Not observed
O
N
N
Si f ace
addition
Fig. 3 Mode of action for imidazolidinone catalyst 12
The imidazolidinonium salt 12·HCl was shown to be an excellent catalyst for the
Diels–Alder reaction of a,b-unsaturated aldehydes 15 (Scheme 2) [3]. Using just 5
mol% of the catalyst at room temperature in a methanol/water mixture (19:1),
adducts were obtained in excellent yield (75–99%) and enantiomeric excess (84–
93%). The simplicity of these transformations, operating at room temperature in the
presence of moisture and air without the need for rigorous purification of solvents
and reagents, makes these procedures highly practical and opened up a new area for
further research.
O O
N 5 mol% 12·HCl
+ +
N R CHO
MeOH/H 2O (19:1)
Ph H CHO R
R 23 °C, 16–24 h endo exo
12 15
R = Ph, furyl, alkyl
75–99% yield
84–93% ee
1:1 – 1:1.3 endo:exo
Scheme 2 [4+2] Cycloaddition of a,b-unsaturated aldehydes using imidazolidinone 12
The absolute stereochemistry of the products was shown to be consistent with a

transition state model in which the benzyl arm of the catalyst blocked the Re-face
of the dienophile from approach of the diene (Fig. 3). An attractive face–face p–p
interaction between the catalyst and substrate was proposed to stabilise this transi-
tion state. Other cyclic and acyclic dienes were also shown to be effective in the
Diels–Alder reaction of acrolein and crotonaldehyde catalysed by 12 (72–90%
yield; 85–96% ee).
The major deficiency in the use of 12 was the low levels of diastereoselectiv-
ity observed within these transformations; typical endo:exo ratios being in the
range from 1:1 to 1:1.3. Improvements in these levels have been achieved using
biaryl catalyst 16 and diarylprolinol silyl ether 17 (Scheme 3). Using 16 (12
mol%) as the catalyst in the Diels–Alder reaction between cyclopentadiene and
cinnamaldehyde allows impressive endo:exo selectivities of up to 1:13 to be
achieved (92% ee exo-adduct) [41, 42]. It should be noted that to achieve these
levels of selectivity, reactions must be performed at −20 °C for 160 h in trif-
luoromethyl benzene, adding an additional 4 equivalents of the diene through
the course of the reaction, which detracts from the practicality of the procedure.
Use of 17 is significantly more convenient, the reactions progressing at room
temperature with all but the most electron rich substrates being complete in less
than 30 h showing endo:exo ratios up to 1:6.7 [43]. The exo-selectivity observed
in these reactions is significant, in that it complements the endo-selectivity
observed in Lewis acid catalysed Diels–Alder reactions of b-substituted unsatu-
rated aldehydes. The precise origin of this selectivity is unknown, but an under-
standing may allow further enhancement.
O 12 mol% 16
4-t BuC6 H4
10 mol% TsOH·H 2 O R1 CHO
+ +
NHMe PhCF 3
NHMe R1 –60 to –20 °C, 144–160 h CHO R1
endo exo
4-t BuC6 H4 R 1 = Ph, Me, CO 2Et

16 72–90% yield
56–92% ee
1:5.5 – 1:>20 endo:exo
O 10 mol% 17
F3 C CF3
20 mol% TFA
CF3 + +
R2 CHO
PhMe 2
R2 CHO exo R
rt, 3–100 h endo
N R 2 = Ar, furyl, c hexyl, nBu, CO2Et
H OTES CF3 65–99% yield
17 64–97% ee
1:2.3 – 1:6.7 endo:exo
Scheme 3 Improved exo-selectivity using 16 and 17
Based on the observation that the majority of secondary amines shown to be

effective in iminium ion catalysed transformations were cyclic five-membered
nitrogen containing heterocycles, it was postulated that a highly nucleophilic
nitrogen was central to catalytic activity [44]. This proposal was reinforced by the
discovery that secondary amines with a-heteroatoms (a-effect nucleophiles)
provided an effective platform for the acceleration of iminium ion catalysed
transformations [44, 45]. This concept was elegantly applied by Ogilvie to a

series of conformationally rigid hydrazide catalysts which were shown to acceler-
ate the Diels–Alder cycloaddition using iminium ion activation. Although cata-
lytic activity of these systems was low compared with that of the imidazolidinone
catalysts, reactions proceeded at room temperature using water as the solvent [46,
47] providing the adducts with excellent levels of asymmetric induction. For
example, hydrazide 18 was shown to be effective at catalysing the reaction
between cyclopentadiene and a series of b-substituted aldehydes (78–94% yield;
80–96% ee) (Scheme 4). Ogilvie has also used these hydrazide catalysts to per-
form a series of qualitative kinetic and mechanistic studies which suggest that
iminium ion formation and hydrolysis are both rapid and it is the Diels–Alder
cycloaddition within the catalytic cycle which is the overall rate-determining step
(see Sect. 6 for further discussion) [48]. This should prove to be a crucial factor
in the design of more active catalysts for these transformations.
O 20 mol% 18
18.5 mol% TfOH R CHO
+ +
NH
N H2 O, 23 °C
O R 24 –48 h CHO R
Ph endo exo
18 R = Ar, Me
78 – 94% yield
80 – 96% ee
1:1.8 – 1:3.3 endo:exo
Scheme 4 Ogilvie hydrazide catalyst
Lee has shown that the structurally related sulfonyl hydrazine 19 provides a
more active catalyst scaffold. Reactions proceed to completion in brine at 0 °C–rt
in under 24 h, with respectable yields and enantioselectivities in many cases (71–
99% yield; 66–86% ee for endo; 83–96% ee for exo) however, diastereoselectivities
were once again poor (0.9:1–2.5:1 endo:exo) (Scheme 5) [49].
O 20 mol% 19
10 mol% TCA R CHO
+ +
NH
S N Brine, 0 °C or rt
O O Ph R 6–24 h CHO R
19 endo exo
i
R = Ar, Me, Pr
71– 99% yield
66–96% ee
0.9:1 – 2.5:1 endo:exo
Scheme 5 Lee sulfonyl hydrazine catalyst
Modifications to the architecture of the imidazolidinone catalyst provided the

furyl derivative (20) which proved to be a powerful catalyst for the catalytic asym-
metric Diels–Alder cycloaddition of simple a,b-unsaturated ketones [50]. Although
the scope of the a,b-unsaturated ketone was limited, the chemical challenge of
selectively forming a single tetra-substituted iminium ion is significant and this
report provides excellent insight into the key-problems faced in the design of cata-
lysts to recognise these substrates. Using 20 mol% of catalyst 20 as its perchlorate
salt, high levels of diastereoselectivity and enantioselectivity were achieved with a
series of diene and dienophile substrates (Scheme 6). It is of note that, in contrast
to the reactions of a,b-unsaturated aldehydes, the system favours formation of the
endo products. The system was also found to be efficient in the Diels–Alder
cycloaddition of cyclopentadiene with unsubstituted cyclic enones, although room
for improvement in the enantioselectivity still exists for the dienophiles cyclopen-
tenone (48% ee) and cyclohexenone (63% ee).
O
20 mol% 20·HClO4
R1 R2 + R1
+
C(O)R 2
H 2 O, 0 °C
2.5 h – 2.5 days C(O)R 2 R1
endo exo
O
R1 = alkyl
N
R2 = alkyl
N 24– 89% yield
Ph H O 0–92% ee
20 6:1 – 25:1 endo:exo
O R3 R3 O
20 mol% 20·HClO4
+
R4 EtOH, –30 °C R4
3–4.5 days
R3 = OMe, NHCbz, Me
R4 = Ph, Me
79–92% yield
85– 98% ee
>200:1 endo:exo
Scheme 6 Diels–Alder cycloaddition of a,b-unsaturated ketones
Application to both Type I and Type II intramolecular Diels–Alder cycloaddition

has also met with appreciable success, the most efficient catalyst for these reactions
being imidazolidinone 21 (Scheme 7) [51, 52]. The power of the intramolecular
Diels–Alder reaction to produce complex carbocyclic ring structures from achiral
precursors has frequently been exploited in synthesis to prepare a number of natural
products via biomimetic routes. It is likely that the ability to accelerate these reac-
tions using iminium ion catalysis will see significant application in the future.
Although the imidazolidinone catalysts used within these transformations are
simple, cheap, readily accessible and in some cases recyclable using acid/base
extraction, considerable efforts have been made to examine alternative methods to
separate and recycle the catalyst with good success. Examination of the structure of
imidazolidinone 22 shows two convenient points for the introduction of a polymer
or fluorous support, R1 and R2, both of which have been examined (Fig. 4). Curran
has shown that identical reactivity, diastereoselectivity and enantioselectivity can
be obtained using a fluorous tag (23) [53]. The catalyst can easily be recovered and
recycled using F-SPE with excellent yield, purity and levels of activity. Polymer- (24)
and silica-supported (25) imidazolidinones reported by Pihko [54] (R1 substitution)
O
Type I IMDA
H
O R
20 mol% 21·HX
n R MeCN/H2 O (49:1)
n
–20 to 25 °C, 16–72 h H
O
N HX = TFA, HCl, HClO 4 n = 1, 2
t R = Ph, vinyl, allyl
N Bu
10– 85% yield
Ph H
92–97% ee
21
1:2.5 – >20:1 endo:exo
O
Type II IMDA
O 20 mol% 21
20 mol% TsOH
Ph Ph
CHCl3 , rt, 41 h
65% yield
98% ee
99:1 endo:exo
Scheme 7 Imidazolidinone catalysed Type I and Type II IMDA reactions
O R1
N R 1 = CH3 R2 = H 12
R 1 = CH2 C 6H 4CH2 CH2 C8 F17 R2 = H 23
N
H R 1 = Janda JelTM R2 = H 24
22 R 1 = Silica support R2 = H 25
R 1 = n Bu R 2 = OPEG 26
R2
Fig. 4 Supported imidazolidinones
and Benaglia (26) [55] (R2 substitution) are also equally efficient and can be recov-
ered and reused by simple filtration. The use of siliceous and polymer coated meso-
cellular foams have also been investigated [56] (R2 substitution). Ionic liquids are also
an effective means to recover and recycle the parent imidazolidinone catalyst [57].
The [3+2] cycloaddition strategy provides an effective method to access valuable

intermediates for the construction of biologically important alkaloids, amino acids,
amino carbohydrates and b-lactams [58–62]. The reaction involves the concerted
pericyclic addition of a dipole and a dipolarophile and considerable efforts have
been made to render these reactions asymmetric using Lewis acid catalysis and
chiral auxiliaries [63].
The first report of an enantioselective organocatalytic [3+2] cycloaddition
between nitrones and a,b-unsaturated aldehydes was reported by MacMillan and
co-workers who showed that iminium ion activation was effective in this reaction
(Scheme 8) [64]. After a survey of seven catalysts the imidazolidinonium salt
12·HClO4 emerged as the most efficient system. The reactions were conducted in a
mixture of nitromethane and water at −20 °C in the presence of 20 mol% catalyst
O O 20 mol% 12·HClO4 R1 R1
N R1 O H 2O (6.0 equiv.) N O N O
N + R3 + R3
N CH 3 NO2 R2 R2
Ph H R2 R3 CHO CHO
–10 °C to –20 °C
12 96 –160 h endo exo
R 1 = Bn, allyl, Me
R 2 = Ar, c hex
R 3 = Me, H
66–98% yield
90–99% ee
4.3:1 – 99:1 endo:exo
Scheme 8 [3+2] Cycloaddition using the MacMillan imidazolidinone 12
giving the products in excellent yield (66–98%) with ee (90–99%). The transforma-
tions proved to be slow with reaction times varying between 96 and 160 h to deliver
the products in the yields observed. In an analogous fashion to that described for
the [4+2] cycloaddition, the transition state model to explain the sense of asym-
metric induction involved blocking of the Re-face of the a,b-unsaturated carbonyl
group by the benzyl arm of the catalyst (c.f. Fig. 3).
In a similar manner to the [4+2] cycloaddition, Benaglia has shown that a poly-
ethylene glycol supported imidazolidinone leads to similar levels of enantioselec-
tivity in the [3+2] cycloaddition of nitrones with a,b-unsaturated aldehydes when
compared to a non-supported catalyst, however, significantly lower chemical yields
were obtained, which deteriorated upon catalyst recycling [65].
In addition, Ogilvie has shown his hydrazide catalyst 18 (and derivatives) to be
effective for the [3+2] cycloaddition reaction [66].
Karlson and Högberg surveyed an interesting series of structurally diverse chiral
secondary amines in the [3+2] cycloaddition of nitrones 28 with 1-cycloalkene-1-
carboxaldehyde 29, during which proline derivative 27 emerged as the best catalyst
(Scheme 9) [67, 68]. The reaction selectively delivered the exo-product with ees
observed in the range 41–92%. Although reactions were once again slow (72–144
h), only 1 equivalent of each of the reaction partners was used together with 10
mol% of the catalyst 27.
Prolinol derived catalyst 30 has also been used in the [3+2] cycloaddition of
nitrones with a,b-unsaturated aldehydes (Scheme 10) [69]. Importantly, the reac-
tions proceed at room temperature in just 24 h, showing excellent levels of cata-
lyst activity, with uniformly high endo:exo ratios (11.5:1–99:1) and enantioselectivity
O 10 mol% 27·2HCl OH OH
R2 O H H
N N H 2O (1.3 equiv.) NaBH 4 +
H + O O
N
N R1 N R1
R1 DMF MeOH
27 –25 to 20 °C, 72–144 h R2 R2
28 29
endo exo
R 1 = Ph, furyl, vinyl, alkyl
R 2 = Ph, Bn, Me
49–76% yield
41–92% ee
1:8.1 – 1:99 endo:exo
Scheme 9 [3+2] Cycloaddition of nitrones with 1-cyclopentene-1-carboxaldehyde

O R1 R1
R1 O 10 mol% 30·HOTf N O N O
N + +
PhMe, rt, 24 h R2 R3 R2 R3
R2 R3
N O O
H OTMS endo exo
30 R 1 = Bn, Me
R 2 = Ph, Napth
R 3 = Me, H, CO2 Et
47–96% yield
66–95% ee
1:11.5 – 1:99 endo:exo
Scheme 10 [3+2] Cycloaddition using the diarylprolinol 30
for the endo-adduct (66–95% ee). Examination of catalyst 30·HOTf in a reaction

using cyclopentene carboxaldehyde 29 as the dipolarophile showed lower levels
of activity but an interesting preference for the endo-adduct, providing a comple-
mentary strategy to the work of Karlson and Högberg [67, 68]. Within this report it
was also disclosed that, of the six secondary amines examined, MacMillan imida-
zolidinone 21 proved to be a significantly more efficient catalyst for the [3+2]
cycloaddition of N-benzylidenebenzylamine N-oxide with crotonaldehyde (20
mol% catalyst, CH2Cl2/iPrOH (85:15), 4 °C, 12 h, 98:2 endo:exo, 97% ee); how-
ever, the scope of this catalyst has yet to be described in the primary literature.
The [3+2] cycloaddition has also been shown to be effective in the reaction of
azomethine imines 32 with a,b-unsaturated aldehydes by Chen and co-workers
[70]. A survey of seven catalysts revealed some interesting trends, with the diaryl-
prolinol derivative 31 giving the highest yields and selectivities (40–95% yield;
endo:exo 1:4.3–1:49; 77–96% ee for exo) with short reaction times (5–24 h) and
low catalyst loading (10 mol%) (Scheme 11). The reaction was particularly sensi-
tive to the amount of water present in the reaction medium and the choice of
co-acid. This phenomenon is a reoccurring theme in many of the publications in
the area of iminium ion catalysis and, as yet, no general explanation has been pro-
posed to account for these observations.
A final class of dipole shown to be effective in iminium ion catalysed [3+2]
cycloadditions are azomethine ylides derived from 35 [71] (Scheme 12). Vicario
showed that 20 mol% of diarylprolinol 33 catalysed the cycloaddition between
a,b-unsaturated aldehydes 34 and imines 35 (THF, 4 °C, 72 h) to give the densely
F 3C CF3 O O O
O 10 mol% 31·TFA
CF3 H 2O (3.3 equiv.)
N N R + 2 N R2
+ N N
N
THF, rt, 5–24 h
N R2
H R1 R1 CHO R1 CHO
OH CF3 32 endo exo
31
R 1 = Ar, alkyl
R 2 = Ph, alkyl
40 – 95% yield
77 – 96% ee
1:4.3 – 1:49 endo:exo
Scheme 11 [3+2] Cycloaddition of azomethine imines with a,b-unsaturated aldehydes

functionalised pyrrolidine skeleton 36 with excellent yield and selectivity (57–93%

yield, >19:1 endo:exo; 93–99% ee). Addition of water (4 equivalents) was found to
significantly accelerate the reaction, and the presence of a free hydroxyl group
within the catalyst structure was essential for the high selectivities observed. An
understanding of these intriguing observations should pave the way for further
development of this reaction.
O EtO 2C CO2 Et 20 mol% 33 OHC R1

H 2 O (4 equiv.)
+ N CO2 Et
THF, 4 °C, 72 h R2 N CO2 Et
N R1 R2 H
H OH 34 35 36
33 R1 = Ar, furyl, alkyl
R2 = Ar, furyl, vinyl
57–93% yield
>95:5 endo:exo
93–99% ee
Scheme 12 [3+2] Cycloaddition of azomethine ylides with a,b-unsaturated aldehydes
In comparison to the preceding classes of cycloaddition, the [4+3] process has

received far less attention, despite representing a powerful strategy with which to
access seven-membered rings. Harmata showed that imidazolidinone 21 could be
used to catalyse the reaction of substituted furans 38 and silyloxypentadienals 37
with high levels of enantioselectivity (Scheme 13) [72]. These high levels of selec-
tivity were not maintained for unsubstituted furans and much opportunity remains
to further develop this as a robust synthetic strategy.
O 20 mol% 21 O
N OR1 2 O 20 mol% TFA CH 2CHO
+ R R2
t
Bu CHO CH2 Cl2 O
N R2 R2
Ph H –78 to –35 °C
37 38
21 22–96 h
R 1 = trialkylsilyl
R 2 = Ph, alkyl
18–74% yield
81–90% ee
Scheme 13 [4+3] Cycloaddition using the imidazolidinone 21
2.1.4 Ene Reaction
An unexpected and potentially useful mode of reactivity was observed in the reac-
tion of cinnamaldehyde and cyclopentadiene catalysed by diarylprolinol silyl ether
39 [73]. Rather than observing a Diels–Alder adduct, the products resulting from
an ene reaction were isolated in excellent yield. The transformation was found to
be general for a series of b-aryl acroleins (40) with routinely excellent levels of
enantioselectivity. The reactions proceeded most efficiently when 4-nitrophenol

was used as the co-catalyst (Scheme 14). These findings are in marked contrast to
those reported by the same authors for the related diarylprolinol silyl ether 17
(Scheme 3) [43], showing that subtle changes in the structure of the catalyst can
lead to marked differences in the reaction outcome, suggesting that other significant
and interesting nuances in reactivity remain to be discovered.
O CHO CHO
10 mol% 39
20 mol% 4-nitrophenol
+ Ar + Ar
MeOH, rt, 2–20 h
N Ar
H OTBDMS 40 60–84% yield
39 77–95% ee
Scheme 14 Ene reaction of cyclopentadiene and b-aryl acroleins
2.2 Conjugate Addition
The conjugate addition reaction involves the attack of nucleophiles to electron

deficient double and triple bonds. The reaction leads to the formation of one, two
or even three new stereogenic centres and so considerable efforts have been made
to develop asymmetric methods, particularly under the influence of an external
chiral ligand or chiral catalyst. Transition metal catalysed methods have been devel-
oped for the addition of carbon-, nitrogen-, oxygen-, sulfur- and hydride based
nucleophiles and these areas are well documented [74–81]. Given the propensity of
a,b-unsaturated aldehydes and ketones to undergo conjugate addition processes
with a broad range of nucleophiles a number of methods have also been developed
for the addition of nucleophiles via iminium ion activation. These processes follow
similar principles to those described in the cycloaddition section, leading to a series
of powerful new methods with which to perform these important reactions. Recent
advances in organocatalytic conjugate addition reactions using many different
methods of activation have recently been reviewed [17–19].
2.2.1 C–C Bond Formation: Aromatic and Vinylic Alkylations
Formation of C–C bonds remains the ultimate challenge to the synthetic chemist.
The employment of new synthetic methods in complex target synthesis can be
frustrated by a lack of functional group tolerance and substrate specificity. These
problems can be somewhat alleviated within conjugate addition reactions by the
use of secondary amine catalysts where a number of important and highly selective
methods have been developed. Two principle classes of nucleophile have been
shown to be effective in the iminium ion activated conjugate addition of carbon
nucleophiles to a,b-unsaturated carbonyl systems: aryl, heteroaromatic and vinyl
nucleophiles, which undergo Friedel–Crafts type alkylation; and C–H acids such as
1,3-dicarbonyl compounds and nitroalkanes. Conjugate additions of this type of
nucleophile have emerged as reliable methods to form new C–C bonds in an effi-
cient and highly enantioselective manner which is exemplified by the numerous
applications of this synthetic strategy in target synthesis (Sect. 5).
In a series of important papers, MacMillan described the alkylation of electron
rich aromatic and heteroaromatic nucleophiles with a,b-unsaturated aldehydes,
using catalysts based upon the imidazolidinone scaffold, further establishing the
concept and utility of iminium ion activation. In line with the cycloaddition proc-
esses described above, the sense of asymmetric induction of these reactions can be
rationalised through selective (E)-iminium ion formation between the catalyst and
the a,b-unsaturated aldehyde substrate, with the benzyl arm of the catalyst blocking
one diastereoface of the reactive p-system towards nucleophilic attack (Fig. 3).
The initial report within this area described the regiospecific alkylation of
pyrroles using imidazolidinone 12 (20 mol%) as the catalyst [82]. A mixture of
THF and water provided optimal reaction conditions, but low temperatures (−60 °C
to −30 °C) were required to ensure the chemospecificity of the reaction. The functional
group tolerance at the b-position of the substrate and N-substitution on the pyrrole
nucleophile was explored (Scheme 15). It was noticed that subtle changes in the
nature of the co-acid altered selectivities and this had to be modified depending on
the substrates adopted.
O O
N 20 mol% 12·HX O
+
N N
N THF/H 2O (7:1)
R2 R1
Ph H R1 –60 to – 30 °C R2
12 42–104 h
R1 = Ar, alkyl, CH 2OBn, CO2 Me
HX = NCCH 2CO2 H, R2 = Bn, allyl, Me, H
TFA, TCA 72–90% yield
87–93% ee
Scheme 15 Conjugate addition of pyrrole nucleophiles using imidazolidinone 12
It was subsequently found that this strategy was also applicable to indole nucle-
ophiles, which reacted regiospecifically through the 3-position. Use of the pivalde-
hyde derived imidazolidinonium salt, 21·TFA provided the highest rate increases,
and a series of conjugate additions to a,b-unsaturated aldehydes provided the prod-
ucts in excellent yield (70–94%) with enantiomeric excess (89–97%) (Scheme 16)
[83]. In an interesting extension to this work, MacMillan found that using 3-substi-
tuted indoles as the nucleophile (e.g. 42) allowed intramolecular trapping of the
intermediate iminium species 43 by either nitrogen or oxygen nucleophiles, thus
providing a convergent cascade process for the preparation of architecturally
complex heterocyclic structures. For example, reaction of a series of tryptamine
derived indoles (42) with acrolein catalysed by imidazolidinone 41 directly gave
pyrroloindolines 44 in one step with excellent levels of absolute stereocontrol [84].
Within the report this method was further exemplified by the preparation of the
CHO
R4 R4
O O R1
N
+ R3 20 mol% 21·TFA R3
tBu
N N N
H CH 2Cl2 /H 2 O (9:1)
Ph R1
21 R2 –87 to –50 °C R2
3–120 h R1 = Ph, alkyl, CH2 OBz, CO2 Me
R2 = Bn, allyl, Me, H
R3 = H, Cl
R4 = Me, H, OMe
70– 94% yield
89– 97% ee
O
Indole
N
N
O H NCO2 R6
t
N O Bu
t Bu
N 20 mol% 41·TFA
H +
CH 2 Cl2 / H 2 O (6:1) NCO2 R6
41 N N H
N –85 °C, 24 –30 h
H R5 R5 43
42
H2 O
CHO
N
N CO2 R6
H
44 R5
R 5 = Bn, allyl, prenyl

R 6 = allyl, tBu, Et
82–89% yield
89–90% ee
Scheme 16 Imidazolidinone catalysed alkylation of indoles
marine natural product (–)-flustramine B. Recently, Xiao has shown that catalyst 21
can be applied to an intramolecular ring closing alkylation of indole tethered a,b-
unsaturated aldehydes [85].
Addition of electron rich aromatic rings provides a particularly useful addition
to this portfolio of alkylative processes (Scheme 17) [86]. The presence of amine
directing groups on the aromatic nucleophile was found to be essential for the suc-
cessful outcome of these reactions. This directing group could be removed after the
conjugate addition step through an N-alkylation/reduction sequence. The most
efficient couplings were between electron deficient a,b-unsaturated aldehydes and
O O R3 R3 R1
N
CHO
t 10 mol% 21·HCl
N Bu +
Ph H R 1 2
R CH 2 Cl2 R 2
21 – 60 to 30 °C
0.3– 80 h
R1 = Ar, alkyl, CH 2OBz, CO2 Me
R2 = NMe 2, NBn 2,
N
65–97% yield
86–99% ee
Scheme 17 Conjugate addition of electron rich benzenes to a,b-unsaturated aldehydes

non-sterically demanding aromatics. In these cases where the donor and acceptor
were matched, catalyst loadings could be reduced down to just 1 mol% (40 h) with-
out erosion of either yield (87%) or ee (88%).
A major limitation of these alkylation reactions has been the regiospecificity
and/or need for directing groups of the nucleophile. MacMillan has overcome this
and expanded the scope of the reaction to include alkene nucleophiles by using
trifluoroborate salts (Scheme 18) [87]. This approach enables alkylation of the
2-position of indoles, complimenting the 3-selective alkylation shown in Scheme
16. One equivalent of hydrogen fluoride was found to be necessary in the reaction
in order to sequester the boron trifluoride generated.
O
N Ar Ar
BF3 K O 20 mol% 41·HCl CHO
t
N Bu HF (1.0 equiv.) R
H or + or
DME or DMF
41
N R –20 °C to rt
H 12–24 h CHO
X BF3 K X
R
X = O, NBoc
R = Ar, alkyl, CH2 OBz, CO2Me
69 –97% yield
87– 97% ee
Scheme 18 Conjugate addition of trifluoroborate activated p-nucleophiles
As a further example of the addition of electron rich heteroaromatics to electron

deficient alkenes, MacMillan has shown that g-butenolides can be prepared in one–
step by the addition of silyloxyfurans (45) to a,b-unsaturated aldehydes (Scheme 19)
[88]. Reactions were tolerant to substitution at the 4- and 5-positions of the furan
O
N O 20 mol% 21·DNBA O
R3
t H 2O (2 equiv.) O R2
N Bu +
Ph H R 2
OTMS CH2 Cl2 CHO
O
21 R1 –70 to –20 °C R3 R1
45
11–30 h
R 1 = Ph, alkyl, CH2 OBz, CO2 Me
R 2 = alkyl, H, CO2 Me
R 3 = Me, H
73–87% yield
84–99% ee
1:7 – 31:1 syn:anti
O MeO 2C O t
BuO2C O O
O CO 2Me O CO2 Me
47 48
CHO MeO 2C O OTIPS CHO
20 mol% ent-21·Tf OH 20 mol% ent -21·TFA
CO 2Me H 2 O (2 equiv.) 46 H 2O (2 equiv.) CO2 tBu
49 CHCl3 , –20 °C, 40 h THF, 4 °C, 43 h 50
65% yield 90% yield
97% ee 89% ee
1:22 syn:anti 11:1 syn:ant i
Scheme 19 Organocatalytic preparation of g-butenolides

ring 45 as well as at the b-position of the enal and proceeded with good levels of
relative and absolute stereocontrol (syn:anti 1:7–31:1; 84–99% ee). Depending
upon the steric bulk at the b-position of the enal substrate and the co-acid adopted,
the diastereoselectivity of the conjugate addition could be altered, the reactions still
proceeding with excellent ees. For example, addition of silyloxyfuran 46 to either
enal 47 or 48 catalysed by an imidazolidinonium salt of ent-20 gave anti-49 (97%
ee) and syn-50 (89% ee) products respectively. The later was readily converted into
the fermentation product spiculisporic acid.
Once again, a notable advantage provided by the alkylations described within this
section is the reactions are tolerant to air and proceed in wet solvents. This offers
significant operational simplicity over organometallic alternatives. Additionally,
each of the catalysts described is available in two synthetic steps, increasing the
accessibility of this chemistry. Expansion of the substrate scope with respect to
the enal coupling partner would further improve the utility of these reactions.
2.2.2 C–C Bond Formation: C–H Acids
As previously noted (Scheme 1), prior to the explosion of interest in iminium ion
catalysis as a platform for the activation of a,b-unsaturated carbonyl compounds in
2000, Yamaguchi [29–33] and Taguchi [34] showed that proline derived bi-func-
tional catalysts could provide an effective platform for the ion-pair controlled con-
jugate addition of malonates and nitroalkanes to a,b-unsaturated ketones with good
levels of stereocontrol.
The majority of recent contributions for the conjugate addition of C–H acids to
a,b-unsaturated carbonyl compounds catalysed through iminium ion intermediates
have come from the laboratories of Jørgensen. The ease with which 1,3-dicarbonyl
compounds and nitroalkanes can be deprotonated, together with the soft nature of
the nucleophile mean this is a particularly facile reaction which conveniently leads
to useful precursors for further synthetic manipulation.
The addition of malonates to a,b-unsaturated ketones provides a simple and rapid
entry to d-ketoesters and tetrahydroquinolines. After surveying a series of potential
donors and acceptors it was found that the addition of dibenzyl malonate (52) to a,b-
unsaturated ketones catalysed by imidazolidine 51 gave the products (53) with excep-
tional yields and levels of enantioselectivity [89]. A thorough examination of the scope
and limitations of the process showed a variety of substitution on the acceptor a,b-
unsaturated ketone was tolerated apart from steric bulk around the reactive carbonyl
centre (Scheme 20). In order to achieve the results reported, reactions were performed
using the nucleophile as the solvent. Despite this excess of dibenzyl malonate the reac-
tions were slow (150–288 h) showing the challenging nature of these substrates. In line
with the imidazolidinone catalysts described above, selectivities could be explained
through selective (E)-iminium ion formation, with the benzyl arm of the catalyst block-
ing the top face, forcing the nucleophile to approach from the Si-face. Catalyst 51 was
prepared in three steps from phenyl alanine [90] as a mixture of diastereoisomers and
was used as this mixture within the transformations described.
O O
N
BnO2 C CO 2Bn 10 mol% 51
CO2 H R2 + R2
N 0 °C to rt
Ph H 1 BnO 2C 1
R 52 150–288 h R
51 as solvent CO 2Bn
53
R 1 = Ar, hetAr, i Pr, CO 2Me
R 2 = alkyl
33 –99% yield
16 –99% ee
Scheme 20 Conjugate addition of dibenzyl malonate to a, b-unsaturated ketones
Application of this work to a domino process using 51 involves Michael addition

of b-ketoesters [91], b-diketones or b-ketosulfones [92] to a,b-unsaturated ketones
followed by an intramolecular aldol reaction provides highly functionalised
cyclohexanone building blocks with up to four contiguous chiral centres. Gryko has
also reported examples of this domino Michael/intramolecular aldol reaction in the
coupling of 1,3-diketones and methyl vinyl ketone using l-proline as catalyst [93].
Barbas developed this procedure further by introducing an asymmetric three-
component Michael reaction that should be applicable to many other conjugate
addition reactions. He used a Wittig olefination to prepare, in situ, an a,b-unsatu-
rated ketone that subsequently underwent a conjugate addition with malonates
(Scheme 21) [94]. The rate of the conjugate addition process was observed to be
considerably faster than the analogous reaction reported by Jørgensen which was
attributed to the presence of triphenylphosphine oxide within the reaction mixture.
CHO
NO2
N O NO2
O
CO 2H 10 mol% 51 CO2Bn
N PPh3 +
Ph H
CO2Bn PhMe CO2 Bn
51
65 °C, 1 h
CO2Bn 25 °C, 96 h 84% yield
91% ee
Scheme 21 Asymmetric three-component Michael reactions
Extension to cyclic Michael donors also met with marked success using imida-
zolidine catalyst 54 (10 mol%) (Scheme 22) [95]. Conveniently, the reactions pro-
ceeded at room temperature using dichloromethane as the solvent and 1.05
equivalents of the Michael donor, representing a substantial improvement in the
atom efficiency of the process. The synthetic utility of this transformation was
exemplified by the one-step preparation of the anticoagulant (S)-warfarin (R1 = Ph,
R2 = Me, R3 = H; 90% yield; 80% ee) which could be recrystallised to optical purity
(>99.9% ee) from acetone/water.
Use of a,b-unsaturated aldehydes as the substrate allows for a more efficient
conjugate addition of malonates, reaction times being reduced to 96 h. The optimal
reaction conditions involved addition of the malonate (1.0 equivalents) to an eth-
anolic solution of the a,b-unsaturated aldehyde (2.0 equivalents) at 0 °C in the
H OH OH R1 O
Ph N O
CO2 H 10 mol% 54 R2
N +
Ph R1 R2
H R 3 X O CH 2Cl2, rt, 60–200 h R3 X O
54
R1 = Ar, hetAr, alkyl
R2 = alkyl
R3 = H, OMe, F, Cl
X1 = S, O
65– 91% yield
79– 88% ee
Scheme 22 Conjugate addition of cyclic 1,3-dicarbonyl compounds to a,b-unsaturated ketones
presence of diarylprolinol derivative 55 (31–95% yield; 86–95% ee) (Scheme 23)

[96]. Simple conversion of the products to lactams 56, lactones 57 and piperidines
as single stereoisomers exemplifies the synthetic utility of this conjugate addition
process. Extension of this work to the addition of dinitropropanes allowed for the
formation of highly substituted cyclohexane ring systems generating five contigu-
ous stereocentres in one–pot with excellent levels of selectivity [97].
O
F3C CF 3
R1 O
CF3
CO 2R 2
57
N 1. NaCNBH 3, AcOH
H OTMS 2. SiO2 , CH2 Cl2
CF3
55
O Ph
PhCH2 NH2
O
R2 O2 C CO2R 2 10 mol% 55 NaBH(OAc)3 N
+
EtOH, 0 °C, 96 h CO2 R2
R1 R1 O
1
R CO 2R 2 CO2 R2
56
R 1 = Ar, hetAr
R 2 = Bn, Me
31–95% yield
86 –95% ee
Scheme 23 Conjugate addition of malonates to a,b-unsaturated aldehydes
Rueping has further developed this theme by showing that diarylprolinol ether
55 efficiently catalyses the addition of hydroxyquinones to a variety of a,b-unsatu-
rated aldehydes as a method for the preparation of both 1,4- and 1,2-naphthoqui-
nones with remarkable levels of enantioselectivity [98].
Jørgensen has also developed a one–pot three component coupling of 1,3-dicar-
bonyl compounds, a,b-unsaturated aldehydes and primary amines to give a series
of Hantzsch ester analogues [99].
Hanessian described the facile addition of cyclic and acyclic nitroalkanes to
cyclic a,b-unsaturated ketones using l-proline 58 as the catalyst (3–7 mol%) in the
presence of 2,5-dimethylpiperazine [100]. The reactions proceeded efficiently at
room temperature and consistently provided adduct 59 with increased levels of
enantioselectivity when compared with the rubidium prolinate method disclosed by
Yamaguchi [29] (Scheme 24). The presence of trace amounts of water in the reaction
was found to be essential, suggesting a hydrolytic step is involved in the catalytic
O 3–7 mol% 58 O
N CO2 H R1 2,5 dimethylpiperazine
H + NO2
L-proline R2 CHCl3 , rt, ~2.5 days
58 n n R1
O2 N R2
59
n =1, 2, 3
R 1 = alkyl
R 2 = alkyl, H
R 1,R2 = calkyl
30–88% yield
62–93% ee
Scheme 24 Conjugate addition of nitroalkanes to a,b-unsaturated ketones
cycle, however, a substantial nonlinear effect with respect to the ee of the proline
suggests a complex chiral catalytic system that requires further investigation to
reveal the precise mechanistic details of the reaction.
More recently, this class of reaction has been extended to encompass acyclic
a,b-unsaturated ketones as substrates using catalysts 60 and 51 (Fig. 5) [90, 101].
Although in general these reactions proceed well for the addition of symmetrically
a-disubstituted nitroalkanes a substantial challenge that remains is the addition of
non-symmetrical a-substituted nitroalkanes where low levels of diastereoselectiv-
ity in the addition product are observed (frequently 1:1). The histidine derived
imidazolidinone 61 was examined in the conjugate addition of nitroalkanes to a,b-
unsaturated aldehydes [102]. Although some encouraging enantioselectivities were
observed, the reaction was shown to be highly substrate specific and competing
1,2-addition of the nucleophile was found to be a substantial problem.
O
N N N
N
N CO 2H
N N N
H HN N Ph H H
N NH
60 51 61
Fig. 5 Catalysts for the conjugate addition of nitroalkanes to acyclic Michael acceptors
Suitable conditions for the highly selective conjugate addition of nitromethane

to a,b-unsaturated aldehydes were developed by Ye and co-workers [103]. Catalyst
loadings as low as 2 mol% were found to be effective with a range of substrates
(65–80% yield; 88–97% ee) (Scheme 25).
O 2–10 mol% 30 O
10 mol% LiOAc
+ MeNO2
MeOH/CH 2Cl2 (9:1) NO 2
N R rt, 40–100 h R
H OTMS
30 R = Ar, hetAr, alkyl
65–80% yield
88–97% ee
Scheme 25 Conjugate addition of nitromethane to a,b-unsaturated aldehydes

A synthetically more challenging C–H acid that represents a method for the
glyoxylation of a,b-unsaturated aldehydes is aminonitrile 62 [104]. Conjugate
addition of 62 catalysed by diarylprolinol ether 30 (20 mol%) provides adducts 63.
Reduction, protection and hydrolysis of these adducts leads to the glyoxylates 64
showing the impressive functional group tolerance of these transformations
(Scheme 26).
O
N 20 mol% 30 N CN
+ t BuO t BuO
CN PhMe, rt, 48 h CHO
N R1 O O R1
H OTMS 62 63
30 R 1 = Ph, hetAr, alkyl
3 steps
O
t
BuO OR2
O R1
64
R 2 = TBDMS, (–)-camphanoyl
27–38% yield (4 steps)
83–87% ee
3:1 – 16:1 dr
Scheme 26 Organocatalytic asymmetric nucleophilic glyoxylation
A promising new catalyst recently reported in this area is the novel dialkylpro-
linol ether 65 which was shown to be efficient for the addition of nitromethane,
dibenzyl malonate and even simple aldehydes (Scheme 27) [105], the majority of
reactions proceeding at room temperature using water as the solvent in the presence
of just 5 mol% catalyst. Of particular significance is the ability to use aldehydes 66
as the Michael donor to give 1,5-dicarbonyl compounds in reasonable yield (42–62%)
and high enantioselectivity (93–98% ee) given the challenging nature of the
transformation. No self-condensation of the aldehyde was reported.
2.2.3 C–O Bond Formation
1,3-Dioxygenated patterns are ubiquitous in nature and thus addition of an oxygen

nucleophile should provide a strategy of broad utility in target synthesis. Reports of
this addition using iminium ion catalysis are limited, probably because of the hard
nature of the oxygen nucleophile resulting in competing 1,2-addition to the carbo-
nyl or derived iminium ion. Jørgensen conveniently circumvented this problem
using aryl oximes as the nucleophile and provided a simple and effective route to
the 1,4-addition product using diarylprolinol ether 55 as the catalyst (Scheme 28)
[106]. The hydroxyl functionality was easily unmasked under standard hydrogenation
conditions to reveal the synthetically important 1,3-diol functionality. A limitation
of this protocol was aryl containing a,b-unsaturated aldehydes were unreactive
under these conditions.
O2 N R 1 = Ar, Me
57–71% yield
R1 O 87–98% ee
5 mol% 65
MeNO2 5 mol% PhCO2 H
H2 O, rt, 18 h
BnO2 C CO 2Bn
5 O 5 mol% 65
5 mol% PhCO2 H BnO2 C CO 2Bn
5
N
H OSiPh3 H 2O R1 O
R1 0–25 °C, 36–72 h
65
R1 = Ar
69–83% yield
O 82–99% ee
20 mol% 65
20 mol% PhCO2H
66 H 2 O, rt, 20–72 h
R2
R1 R 1 = Ar
R 2 = alkyl
O O 42–62% yield
R2 93–98% ee
4:1 – >98:1 dr
Scheme 27 Dialkylprolinol ether 65 for the organocatalytic Michael reaction
F3 C CF3 O OH
CF3 O 10 mol% 55
HO 10 mol% PhCO 2H NaBH 4
N
+
R O R O
PhMe, 4 °C, 1– 8 h MeOH
N Ph N N
H OTMS R
CF3
55 Ph Ph
R = alkyl, ester
62–75% yield
88–97% ee
Scheme 28 Conjugate addition of aryl oximes
Maruoka has found that simple alcohols can also be used in the oxy-Michael
reaction [107]. Using the axially chiral biaryl catalyst 67 (1 mol%) the conjugate
addition of methanol, ethanol and allyl alcohol to a,b-unsaturated aldehydes was
examined (Scheme 29). Despite moderate yields (55–83%) and enantioselectivities
(16–53% ee), the high activity of this catalyst suggests that further optimisation
4-t BuC 6H 4
O
R2
NHMe 1 mol% 67 O
+ R2 OH
NHTf PhMe/H2O (2:1) R1 O
R1 0 °C, 24–48 h
4- t BuC 6H 4 R 1 = alkyl
67 R 2 = allyl, Me, Et
55–83% yield
16–53% ee
Scheme 29 Conjugate addition of alcohols to a,b-unsaturated aldehydes

might prove fruitful. Disappointingly, the absolute sense of asymmetric induction

within these transformations was not determined preventing the development of a
working transition state model.
2.2.4 C–N Bond Formation
MacMillan expanded the portfolio of donors that could be used in the iminium ion
activated conjugate addition to encompass nitrogen nucleophiles [108]. The syn-
thetic challenge that needed to be overcome to achieve this transformation was
differentiation of the amine nucleophile inherent to the structure of the catalyst and
the amine nucleophile of the reagent. This dichotomy was circumvented by use of
N-silyloxycarbamates 68, which, in conjunction with the imidazolidinonium salt
ent-21·TsOH gave the 1,4-addition products in 69–92% yield and 87–97% ee
(Scheme 30). The strength of this protocol was further established by conversion of
a conjugate addition product to the N-protected b-amino acid 69 in two steps (66%
yield; 92% ee), and to the b-hydroxy-d-amino ester 70 in three steps (71% overall
yield; 92% ee). Related products of the conjugate addition of O-methyl-N-
hydroxycarbamates have also been used to provide effective substrates for Mannich
and aldol reactions revealing an important extension to this methodology [109].
CBz
O NH O
66% yield
N
Pr OH 92% ee
t Bu
N 69
Ph H
ent -21 1. NaClO 2
2. Zn, AcOH
PG OTBDMS PG = Cbz, Fmoc, Boc

O PG OTBDMS
N 20 mol% ent-21·TsOH N PR = alkyl, BnOCH 2 , CO2Me
+ H
P69–92% yield
68 CHCl3, –20 °C R O P87–97% ee
R 12–24 h
1. Ph3P=CHCO2 Me
2. TBAF
3. SmI2
Boc
NH OH O
71% yield
Pr O 92% ee
70
Scheme 30 Conjugate addition of N-silyloxycarbamates using iminium ion catalysis
Córdova has shown that using unprotected N-hydroxycarbamates 71 as the

nucleophile with diarylprolinol ether 30 as catalyst gave direct access to 5-hydrox-
yisoxazolidines 72 (91–99% ee) which are convenient precursors to b-amino alco-
hols and b-amino acids (Scheme 31) [110]. Interestingly, these reactions proceed
efficiently (3–16 h) without the need for an additional co-acid unlike the majority
of other iminium ion catalysed transformations, an unexpected result which
highlights the need for further mechanistic understanding.
O
PG
PG OH 20 mol% 30 N O
+ N
H CHCl3, 4 °C, 3–16 h OH
R
N R 71 72
H OTMS
30 PG = Boc, Cbz
R = Ar, alkyl, ester
75–94% yield
91–99% ee
Scheme 31 Direct preparation of 5-hydroxyisoxazolidines using diarylprolinol ether 30
Jørgensen [111] and Vicario [112] independently described the conjugate addi-
tion of both triazole and tetrazole based nucleophiles to a,b-unsaturated aldehyde
substrates as an alternative method for C–N bond formation. These reactions were
catalysed by the diarylprolinol and imidazolidinone scaffolds with equal efficiency
showing the complementarity and efficacy of both these catalyst architectures. In
addition, Jørgensen has also shown succinimide to be an effective Michael donor
(see Sect. 2.3.5 Scheme 49 for further details) [113].
Takasu examined a series of five imidazolidinone catalysts in the intramolecu-
lar conjugate addition of amides to a,b-unsaturated aldehydes to prepare a series
of tetrahydroisoquinolines [114]. Although yields were high for these organo-
catalytic transformations (70–90%), enantiomeric excesses were low (18–53%)
showing further optimisation with regards to the co-acid and solvent are neces-
sary to bring this potentially useful transformation in line with other reactions of
this class.
Fustero has devised an intramolecular version of the iminium ion catalysed
conjugate addition of nitrogen in the preparation of a series of simple pyrrolid-
ine and piperidine derivatives [115]. The reactions proceed in chloroform to
give the target heterocycles in good yield and excellent levels of stereocontrol
(Scheme 32).
F3 C CF3
20 mol% 55 X
CF3 H
N X CHO 20 mol% PhCO2 H NaBH 4 OH
n
PG n N
CHCl3 , –50 to –10 °C MeOH
N PG
H 22–96 h
OTMS CF3 n = 1, 2
55 X = CH 2, NCbz, O, S
PG = Boc, Cbz
30 – 80% yield
85 –96% ee
Scheme 32 Organocatalytic intramolecular aza-Michael reaction
2.2.5 C–S Bond Formation
Despite the prevalence of the C–S bond in nature and the importance of the sulfur
group in many biological processes the organocatalysed formation of C–S bonds
has received significantly less attention than C–N, C–O and C–C construction.
However, formation of this bond through the conjugate addition of a soft sulfur
nucleophile to a,b-unsaturated aldehydes is efficiently catalysed using iminium ion
catalysis [116]. Using diarylprolinol silyl ether 55 the addition of a series of sulfur
based nucleophiles to a variety of a,b-unsaturated aldehydes was shown to be
effective (73–87% yield; 89–97% ee). The products were isolated as their b-hydroxy
sulfide derivatives 73 after in situ reduction of the products (Scheme 33).
F3 C CF3
CF3 O 10 mol% 55 R2 R2
10 mol% PhCO 2H S NaBH 4 S
+ R2 SH
PhMe, –24 °C R1 O MeOH R1 OH
N R1
H OTMS 16–40 h 73
CF3
55 R1 = Ar, alkyl
R2 = Bn, t Bu, CH2 CO 2Et
73 – 87% yield
89– 97% ee
Scheme 33 Conjugate addition of sulfur based nucleophiles
2.2.6 C–P Bond Formation
Simultaneous publication of the iminium ion catalysed hydrophosphination of a,b-

unsaturated aldehydes by Melchiorre and Córdova showed diarylprolinol silyl ether
55 was effective in the conjugate addition of diphenylphosphine 74 [117, 118].
Direct transformation of the products allowed for one–pot methods for the prepara-
tion of b-phosphine alcohols 75 (72–85% yield; 90–98% ee), b-phosphine oxide
acids 76 (65% yield; 92% ee) and 3-amino phosphines 77 (71% yield; 87% ee)
(Scheme 34). These reports represent the first examples of the addition of P-centred
nucleophiles and the resulting highly functionalised products may well have further
use in asymmetric catalysis.
BH 3 R1 = Ar, alkyl
Ph2 P
72–85% yield
R1 OH 90–98% ee
75
NaBH4
MeOH, 0 °C
F3 C CF3 O
O
CF3 Ph 2P Ph 2P O
20 mol% 55·HCO2R 2 NaClO 4
+ Ph2 PH
CHCl3 , 4 °C, 20 min R1 O R1 O
74 76 H
N R1
H OTMS 1. BnNH2 /NaBH4 R 1 = Ar
CF3 R1 = Ar, hetAr, vinyl 1. PhMe 65% yield
55 R1 = alkyl, (CH2 )3 OBz 2. CH 3 CO 2H 92% ee
2. NaBH4
R2 = Ph, 2-FC 6H 4 , 4-NO 2C 6H 4
BH 3
Ph2 P R1 = Ph
71% yield
R1 N Ph 87% ee
77 H
Scheme 34 Addition of P-centred nucleophiles to a,b-unsaturated aldehydes
Jørgensen has shown that phosphites also act as effective phosphorous based
nucleophiles in the conjugate addition to a range of a,b-unsaturated aldehydes
using diarylprolinol silyl ether 55 as the catalyst [119]. The products were readily
transformed into the corresponding phosphinic acid derivatives and glutamic acid
analogues suggesting this work might have applications in medicinal chemistry.
2.2.7 C–H Bond Formation
The majority of chemical methods for the asymmetric hydrogenation of unsatu-

rated systems rely on the use of transition metal catalysts or stoichiometric amounts
of metal hydride. The chemical importance of this transformation has led to the
development of some of the most powerful and efficient methods in catalytic asym-
metric synthesis. Routinely used on the milligram to multi-tonne scale, they repre-
sent one of the biggest success stories of asymmetric catalysis [120].
Biochemical hydride–reduction using the cofactor NADH provided the inspiration
for the development of a Hantzsch ester mediated organocatalytic reduction of both enal
[121–123], and enone [124] substrates using imidazolidinone catalysts, providing a new
and efficient concept in asymmetric hydrogenations (Scheme 35) [125–127]. These
reactions are particularly mild and provide the products with excellent levels of absolute
stereocontrol. Three imidazolidinones, 21, 78 and 20, have been shown to be effective
at catalysing this transformation using similar reaction conditions. Many functional
groups that are not compatible with transition metal catalysed hydrogenations are toler-
ated within these reactions (e.g. CN, NO2), exemplifying the way in which iminium ion
catalysed reactions can both complement and augment many existing processes.
A fascinating observation within these transformations was that with certain
substrates, regardless of the stereochemical purity of the starting a,b-unsaturated
aldehyde, identical levels of asymmetric reduction were observed within the reac-
tion. For example, starting with either (E)-80, (Z)-80 or a 1:1 mixture of the two
O O O
N MeO2C CO2Me
t Bu
10 mol% 21·TCA
N +
Ph H i Pr dioxane, 13 °C, 48 h
Ar N Ar
21 H 79
1.02 equiv.
77– 90% yield
90 – 96% ee
O O O
N
EtO2C CO2Et
tBu 20 mol% 78·TFA
N +
H R1 R2 N CHCl3, –50 to –30 °C R1 R2
78 H 0.5–72 h
R 1 = Ar, c hex,
CO2Me,
R 1 = CH 2OTIPS, t Bu
R 2 = Me, Et
74 – 95% yield
91– 97% ee
O O
O
N t
BuO2C CO2t Bu 20 mol% 20·TFA
N + Et2 O, 0 °C, 1–25 h
Ph H O N R3 n
R3 n H
20
n = 0, 1, 2
R 3 = alkyl, c hex,
R 3 = COMe, CO2 Me
66 – 89% yield
88 – 96% ee
Scheme 35 Imidazolidinone catalysed hydride reduction of a,b-unsaturated aldehydes and ketones

stereoisomers, similar yields (83, 80, and 81% respectively) of (R)-79 were isolated
in 94% ee. Both (E)-80 and (Z)-80 can form the corresponding iminium ions 81
and 83 by condensation with an imidazolidinone. These iminium ions can then
interconvert through the common dienamine intermediate 82. Faster conjugate
reduction of the more stable iminium ion (81) accounts for the outcome of this
reaction (Fig. 6). During the reaction of prochiral unsaturated systems stereo-
chemical purity of the reactant is usually essential in order to observe high levels
of asymmetry in subsequent transformations. As preparation of geometrically pure
starting materials can frequently represent one of the toughest challenges within
synthesis, as a chemical tool, this stereoconvergent method represents a unique
and important strategy.
O O O
N N N
t t t
O N Bu N Bu N Bu O
Ph Ph Ph
Ar Ar Ar Ar Ar
(E )-80 81 82 83 (Z )-80
Ar = 4-NO2 C6 H4
(R )-79
Fig. 6 Imidazolidinone catalysed hydride reduction of diastereoisomeric a,b-unsaturated aldehydes
2.3 Using the Enamine Intermediate
In the proposed catalytic cycle for iminium ion accelerated conjugate addition reac-
tions (Fig. 2), the intermediate derived from the addition process is an enamine (8),
which is hydrolysed under the reaction conditions to deliver the product and regen-
erate the catalytically active secondary amine 5. A useful synthetic strategy involves
the exploitation of this reactive intermediate by subsequent reaction with a variety
of electrophiles providing a cascade process for the formation of two new bonds
(Fig. 7). The iminium ion (84) that results from trapping of the enamine is hydro-
lysed under the reaction conditions to reveal the densely functionalised product 85
and release the amine (5) back into the catalytic cycle. The high levels of enanti-
oselectivity observed from conjugate additions (see Sect. 2.2) make this method
even more powerful. Exploitation of the enamine intermediate in the construction
of C–O, C–N, C–C and C–X bonds by trapping with electrophiles in an intra- and
inter-molecular fashion is described below.
2.3.1 Epoxide Formation
Of the numerous catalytic asymmetric methods developed for the functionalisation of

alkenes, epoxidation has emerged as one of the most versatile and reliable methods
to aid in chemical synthesis. Since the pioneering work of Sharpless on allylic epoxi-
dation [128], sustained research efforts have delivered organometallic [129, 130] and
organocatalytic [131–133] strategies to epoxidise the majority of electron rich alkenes
[134]. More recently, catalytic asymmetric methods have also been realised for the
epoxidation of electron deficient systems [135–142]. These overall transformations
are also accessible through iminium ion catalysed procedures using a variety of stoi-
chiometric oxidants, the strategy for which is outlined below (Fig. 8). Conjugate addi-
tion of a nucleophilic oxygen incorporating a suitable leaving group (87) to an active
O O
E
R Nu R
85
N
H
·HX
5
H 2O H2 O
N N
E
X X
R Nu R
84
Nu
E R Nu
8
Fig. 7 Proposed catalytic cycle for the amino catalytic conjugate addition enamine trapping
sequence
O O
O
89
N
H
·HX
5
H2 O H 2O
N N
X
X
O
86
LG
O LG
N 87
O
LG
88
Fig. 8 Proposed catalytic cycle for the epoxidation of ab-unsaturated aldehydes

iminium ion (86) results in an intermediate enamine (88). Intramolecular trapping of

this enamine with expulsion of the oxygen tethered leaving group followed by imin-
ium ion hydrolysis results in the epoxidation product (89). The processes described
here all adopt this strategy and differ in the oxidant and catalyst used.
Jørgensen made the first contribution to the area using diarylprolinol ether 55
[143]. Hydrogen peroxide (35 wt% in H2O) emerged as the most effective oxidant
for the epoxidation of cinnamaldehyde in dichloromethane. Application of the
optimal reaction conditions to a series of a,b-unsaturated aldehydes showed equal
efficiency in both yield (63–90%) and enantiomeric excess (75–96%) using just 10
mol% of catalyst 55 (Scheme 36). These high selectivities were achieved at room
temperature in the presence of 10 mol% of the catalyst in just 4 h, providing a
highly practical process that should find many applications. Jørgensen has subse-
quently disclosed that the reactions can also be performed in an ethanol/water
mixture (3:1), although yields are substantially reduced (34–56%) and reaction
times extended to 16 h [144].
F3 C CF3
O 10 mol% 55 O
CF3 H 2 O2 (1.3 equiv.)
CH 2 Cl2 , rt, 4 h O
R1 R2 R1 R2
N
H OTMS CF3 R 1 = Ar, alkyl, CO2Et,
55 R 1 = CH2 OBn
R 2 = Me, H
63–90% yield
75–96% ee
9:1 – 49:1 dr
Scheme 36 Epoxidation of a,b-unsaturated aldehydes using hydrogen peroxide as oxidant
An alternative oxidant that has also been shown to be effective for the epoxida-
tion of a,b-unsaturated aldehydes is iminoiodinane 90, which acts as an in situ
source of iodosobenzene [145]. In a careful and thorough mechanistic investigation
using a 15N labelled catalyst it was shown that iodosobenzene bought about slow
catalyst degradation; however, use of 90 in the presence of acetic acid provided a
slow release of iodosobenzene to undergo the epoxidation process. Reactions pro-
ceeded at −30 °C in the presence of 20 mol% ent-21 as its perchlorate salt using 1.5
equivalents of the oxidant (Scheme 37). Most reactions reported gave the products
as single diastereoisomers highlighting a benefit of this methodology.
O O O
N
N I Ns 20 mol% ent -21·HClO4
+
t
Bu O
N CH 2Cl2 /AcOH (4:1)
Ph H R R
–30 °C, 6–16 h
1.5 equiv.
ent-21 R = Ar, alkyl
90 72–95% yield
88–97% ee
Scheme 37 Imidazolidinone promoted epoxidation of a,b-unsaturated aldehydes

N N
H OTMS H OH
30 33
Epoxidation of α,β-unsaturated Epoxidation of α,β-unsaturated
aldehydes ketones
Fig. 9 Alternative catalysts for organocatalytic asymmetric epoxidation
Córdova has also shown hydrogen peroxide to be an effective oxidant in the

epoxidation of a,b-unsaturated aldehydes using diarylprolinol ether 30 as the cata-
lyst (Fig. 9) [146, 147]. Within these reports it was also shown that the resulting
epoxy aldehydes could be used directly in either Wittig or Mannich reactions,
providing synthetically useful one–pot protocols to prepare densely functionalised
building blocks for further elaboration.
It is worth noting that use of unprotected diarylprolinol 33 provides an effective
platform for the epoxidation of a,b-unsaturated ketones [148, 149]. Within these
reports it was proposed that an alternative mode of activation of the substrate could
be taking place. Hydrogen bonding catalysis, rather than iminium ion formation,
could explain the results and would be consistent with the non-polar reaction
medium adopted within these reactions.
2.3.2 Aziridine Formation
Aziridines represent an important class of building block within synthesis. This

structural motif is also embedded within a number of biologically significant natu-
ral products, and thus robust and efficient methods for their construction represent
an important contribution to the synthetic toolkit. Córdova reported an enantiose-
lective aziridination of a,b-unsaturated aldehydes catalysed by diarylprolinol ether
30 using protected hydroxylamine 91 as the nitrogen source (Scheme 38) [150].
The reaction was proposed to proceed via iminium ion formation followed by
O O
R2 OAc 20 mol% 30
+ N
H N R2
CHCl3, rt to 40 °C
R1 91 0.5–5 h R1
N 92
H OTMS
30 R 1 = alkyl
R 2 = Cbz, Boc
54– 78% yield
84– 99% ee
Bn 4:1 – 10:1 dr
Cl
N
Cbz 10 mol% Cbz
O NH O NH 2 O
N S Pd/C, H 2
n n n
Pr 8 mol% DIPEA Pr OEt Pr OEt
93 94
EtOH (3 equiv.)
63% yield 100% yield
CH 2Cl2 , 30 °C, 15 h
Scheme 38 Organocatalytic aziridination of a,b-unsaturated aldehydes

conjugate addition of an O-acyl hydroxylamine, the resultant enamine then underwent

an intramolecular 3-exo-tet cyclisation, eliminating acetate, to give the observed
aziridine after hydrolysis. The products (92) were found to be sensitive to column
chromatography and extended reaction times, however, reasonable yields and
excellent levels of enantioselectivity could be obtained. A simple two-step sequence
could also convert formyl aziridine 93 to the corresponding b-amino ester (94),
further adding to the applicability of this work.
2.3.3 Cyclopropane Formation
The cyclopropane moiety is a fundamental class of functional group present in both

natural products and numerous therapeutic agents. It has provided the impetus for
significant breakthroughs in the use of metal carbenoids [151] and organocatalytic
ylide intermediates [152, 153] such that reliable methods exist for most disconnec-
tive strategies on this ring system.
In the context of iminium ion catalysed approaches to the formation of cyclopro-
panes, it has been shown that a,b-unsaturated aldehydes activated with secondary
amines can be used as substrates for cyclopropanation processes. The pioneering
work in this area was reported by MacMillan and co-workers, who showed that the
commercially available dihydroindole-2-carboxylic acid 95 efficiently accelerated
the reaction of a,b-unsaturated aldehydes 96 and stabilised sulfur ylides. Various
subtle factors within the catalyst’s design were found to be essential for attaining
the high levels of enantioselectivity observed [154]. It was reasoned that only the
(Z)-iminium ion 97 was formed to minimise van der Waals interactions that could
occur with the C-7 proton on the aromatic ring of the catalyst. The approach of the
incoming sulfur ylide was directed by an electrostatic interaction with the carboxy-
late of the catalyst causing the ylide to approach from the bottom face of the imi-
nium intermediate 98. Conjugate addition followed by ring closure with the
expulsion of dimethyl sulfide provided the cyclopropyl products in good yield
(64–85%) and with excellent levels of enantioselectivity (89–96% ee) (Scheme 39).
It was reported that one of the reactions was undertaken on a 1 mmol scale without
loss of yield or enantioselectivity, showing the robust nature of this work.
O
O
S 20 mol% 95 CO2 R1
CO2H N R
N + 2
H O CHCl3 , –10 °C, 24–48 h S
95 R1 R 2 CHO
96 R1 O
97 R2
R 1 = Ph, alkyl
H R 2 = Ar, tBu
N
64–85% yield
CO2 R1 89–96% ee
6:1 – 72:1 dr
S
98 R2
O
Scheme 39 Iminium ion catalysed cyclopropanation reactions

More recent reports from Córdova [155] and Wang [156] have described the
cyclopropanation of a,b-unsaturated aldehydes 99 with diethyl bromomalonates
100 and 2-bromo ethyl acetoacetate catalysed by a series of diarylprolinol deriva-
tives. Both describe 30 as being the most efficient catalyst in many cases and
optimal reaction conditions are similar. Some representative examples of this
cyclopropanation are shown in Scheme 40. The transformation results in the for-
mation of two new C–C bonds, a new quaternary carbon centre and a densely
functionalised product ripe for further synthetic manipulation. Triethylamine or
2,6-lutidine are required as a stoichiometric additive in order to remove the HBr
produced during the reaction sequence. The use of sodium acetate (4.0 equiva-
lents) as an additive led to subsequent stereoselective ring opening of the cyclo-
propane to give a,b-unsaturated aldehydes 101. It can be envisioned that these
highly functionalised materials may prove useful substrates in a variety of imin-
ium ion or metal catalysed transformations.
O 20 mol% 30 O
EtO 2C CO2 Et Et3N (1 equiv.)
+ CO2 Et
CHCl3, r t, 3–14 h CO2 Et
Br
N R R
H OTMS 99 100
30 R = Ar, alkyl, CO2 Et
50 –88% yield
93–99% ee
9:1 – 25:1 dr
10 mol% 30 O
MeO2 C CO2Me NaOAc (2 equiv.)
R
CDCl3, rt, 6.5 h
R CHO MeO 2C CO2 Me
101
Scheme 40 Iminium ion catalysed cyclopropanation using 2-bromoacetoacetate esters
Diarylprolinol ether 30 has also been used to accelerate the cyclopropanation of

a,b-unsaturated aldehydes with arsonium ylides with excellent levels of asymmet-
ric induction (95–98% ee) [157].
2.3.4 Other Electrophiles Intramolecular
Application of an organocatalytic domino Michael addition/intramolecular aldol

condensation to the preparation of a series of important heterocycles has recently
received much attention [158] with methods being disclosed for the preparation of
benzopyrans [159–161], thiochromenes [162–164] and dihydroquinolidines [165,
166]. The reports all use similar conditions and the independent discovery of each
of these reactions shows the robust nature of the central concept. A generalised
catalytic cycle which defines the principles of these reports is outlined in Fig. 10.
Formation of iminium ion 102 is followed by an intermolecular Michael addition
of an oxygen, sulfur or nitrogen based nucleophile (103) to give an intermediate
enamine (104). Intramolecular aldol condensation of this enamine with an aldehyde

and hydrolysis of the resulting iminium ion leads to the observed products (105) in
high yield and selectivity. Each process uses the structurally similar diarylprolinol
derivatives 30, 106, or 55 to afford the products. It is also worth noting that in the
preparation of benzopyrans (X = O), the addition of 4 Å molecular sieves was
found to lead to higher yields and selectivities despite the fact that water is inti-
mately involved within the proposed catalytic cycle [159–161].
Catalysts used O O
3 R2 N R2
R H
1 ·HX 1
X R R
5
105
N
H OPG H2 O X1 = O, S, NH
PG = TMS 130 R 1 = Ar, alkyl, CO 2Et
PG = TES 106 R 2 = H, calkyl
R 3 = Me, OMe, F, Cl
O N N
+ HX X
F 3C CF3 R2 R2
R3
CF 3 R1 R1 102
X
104 O
N
H OTMS CF 3 R3
55
XH
103
Fig. 10 Catalytic cycle for the organocatalytic domino Michael/intramolecular aldol condensation
Córdova has shown that it is also possible to isolate benzothiopyrans (71–98%

yield; 96–99% ee) prior to the elimination of water by using 2-mercaptoacetophe-
none as the starting material [167].
Jørgensen has reported a domino Michael/intramolecular aldol reaction of
2-mercapto-1-phenyl ethanone (107) and a,b-unsaturated aldehydes to give
tetrahydrothiophenes [168]. Depending upon the reaction conditions adopted the
regiochemical outcome could be controlled using the same catalyst (55) to give
products 108 or 109 simply by changing the additive used (Scheme 41). Using
benzoic acid as additive, tetrahydrothiophenes 108 were isolated in reasonable
O
10 mol% 55 HO
PhCO2H Ph R = alkyl
44–74% yield
PhMe, rt, 48 h R
S 90–96% ee
F 3C CF3
108
O O
CF 3
SH
+
N R
H OTMS
CF 3 107 10 mol% 55 HO
55 NaHCO3 R = alkyl
Ph 43–66% yield
PhMe, rt, 48 h S R
64–82% ee
O 109
Scheme 41 Divergent domino Michael/aldol reaction

yield and excellent levels of enantiomeric excess (44–74% yield; 90–96% ee).
Under the same reaction conditions (PhMe, rt, 48 h), but using sodium bicarbonate
as the additive, regioisomeric adducts 109 were the major products (43–66% yield;
64–82% ee). Rationalisation of this result invoked two separate catalytic cycles.
When benzoic acid was added, the catalyst 55 was involved in both the iminium ion
mediated conjugate addition and the enamine promoted aldol reaction. Use of a
base within the reaction mixture (NaHCO3) proceeded by an iminium ion catalysed
conjugate addition followed by hydrolysis and base catalysed intramolecular aldol
reaction. This important observation offers additional divergent properties of iminium
ion catalysed transformations that can be applied to further reaction design.
Using diarylprolinol ether 55 in conjunction with an additional base, a domino
Michael/aldol/intramolecular SN2 process has been developed that led to highly
functionalised epoxycyclohexanones 110, with excellent control of three of the
chiral centres generated (Scheme 42) [169]. Despite the apparent complexity, these
reactions proceed at room temperature in less than 24 h and the products contain
significant potential for a host of further transformations.
O
F3C CF 3 O O O 10 mol% 55
NaOAc K2CO3 CO2 R2
CF3 + OR 2 O
CH2 Cl2 , rt, 16 h DMF
Cl R1
R1 2– 6 h 110
N
H OTMS R 1 = Ph, alkyl,
CF3
55 CH2 OBn,
CH 2OTIPS
R 2 = allyl, alkyl
42–57% yield
86–97% ee
Scheme 42 Organocatalytic domino Michael/aldol/intramolecular SN2 reactions
Jørgensen has also reported a sequential Michael/Michael/aldol condensation

for the three component coupling of malonitrile 111 and a,b-unsaturated alde-
hydes that involves two iminium ion catalysed Michael additions followed by an
intramolecular aldol condensation (Scheme 43) [170]. Using diarylprolinol ether
55 (10 mol%) in a concentrated toluene solution of malonitrile 111 and 3 equiva-
lents of a,b-unsaturated aldehyde the reaction products can be isolated in just
1–48 h (57–89% yield; 97–99% ee). The atom efficiency of this three component
reaction is remarkable and the ability to prepare these complex products under
F3C CF 3 O O
CF3 NC 10 mol% 55
CN
+
R PhMe, rt, 1–48 h R R
N 111 NC CN
H OTMS CF3
R = Ar, allyl, alkyl
55
57–89% yield
97–99% ee
Scheme 43 Multicomponent Michael/Michael/aldol condensation reaction

such mild reaction conditions is outstanding. Preliminary attempts to introduce

two different a,b-unsaturated aldehydes selectively into this reaction sequence
through appropriate choice of a,b-unsaturated aldehyde substrates were highly
successful (for example: R = iPr and Ph gave 52% yield; >99% ee) and provide
an important proof of concept for the ultimate development of a general three
component coupling procedure.
List has reported a catalytic asymmetric reductive Michael cyclisation for the
formation of five- and six-membered rings and the generation of two contiguous
chiral centres [171]. Using imidazolidinonium salt 21·HCl (20 mol%) and a
Hantzsch ester (1.1 equivalents), substrates 112 smoothly underwent reductive
Michael cyclisation (dioxane, rt, 2–4 h) with excellent yields, diastereoisomeric
ratios and enantioselectivities (Scheme 44). This sequence was also applied to the
formation of trans-disubstituted cyclopentanes and cyclohexanes. The reaction
proceeds via an achiral conjugate reduction followed by an asymmetric Michael
cyclisation. Given the exceptional levels of enantioselectivity observed in the con-
jugate reduction of b,b-disubstituted enals [121–123], it seems likely that this
methodology could be used in an asymmetric conjugate reduction resulting in the
formation of three contiguous chiral centres.
O R2
O COR 1
N 1 EtO2 C CO2 Et
R 20 mol% 21·HCl
+ CHO
t
Bu R2 dioxane, rt, 2–4 h
N N
Ph H H
21 CHO R1 = Ar, Me, CO2 Et
112 R2 = H, CO 2Et
86–98% yield
86– 97% ee
15:1 – >50:1 dr
Scheme 44 Catalytic asymmetric reductive Michael cyclisation
Wang identified a series of Michael/Michael and Michael/aldol sequences cata-

lysed by diarylprolinol ethers that led directly to densely functionalised five-mem-
bered rings [172–174]. For example, highly diastereoselective and enantioselective
double Michael addition reactions were achieved by treatment of a,b-unsaturated
aldehydes with triester 113 catalysed by 30 (Scheme 45). Initial conjugate addition
O CO 2Et
CO2 Et
OHC
20 mol% 30
+
EtOH, rt, 12–24 h
N Ar Ar
H OTMS RO2 C CO2R RO2 C CO2 R
30 1 13 11 4
R = alkyl
85–93% yield
84–99% ee
9:1 – >20:1 dr
Scheme 45 Catalytic asymmetric Michael/Michael reactions

of the malonate gives an enamine intermediate that undergoes conjugate addition

onto the acrylate acceptor to give cyclopentane adducts 114 (85–93% yield; 9:1–
>20:1 dr; 84–99% ee) at ambient temperature in ethanol.
In a collection of insightful pieces of work Enders has incorporated an iminium
ion conjugate addition of nitroalkanes to a,b-unsaturated aldehydes into a triple
cascade reaction generating up to four contiguous stereocentres in one pot, again
indicative of the complexity attainable from superficially simple catalysts and tech-
niques [175–177] (Scheme 46).
O
O O
R1
20 mol% 30 R1
+
N R3 PhMe, 0 °C to rt R2 R3
H OTMS NO 2 16–24 h NO2
R2
30
R 1 = alkyl
R 2 = Ar, hetAr
R 3 = Ar, alkyl, H
29–58% yield
>99% ee
2:1 – 99:1 dr
Scheme 46 Enders triple cascade reaction
2.3.5 Other Electrophiles Intermolecular
In each of the tandem iminium ion/enamine cascade processes described above, the
enamine is trapped in an intramolecular fashion. The ability to perform the trapping
sequence in an intermolecular manner would allow for the one–pot introduction of
three points of diversity. MacMillan has realised this goal and described a series of
secondary amine catalysed conjugate addition–enamine trapping sequences with
a,b-unsaturated aldehydes using tryptophan derived imidazolidinone 115 to give
the products in near perfect enantiomeric excess (Scheme 47) [178].
O
N O O
10–20 mol% 115
t
Bu Cl
N 10 –20 mol% TFA
H + Nu + E
R EtOAc, – 60 to – 40 °C R Nu
115
N 4–60 h
R = Ph, alkyl, CH2 OAc, CO 2Et
Ph 67–97% yield
99% ee
9:1 – >25:1 dr
N
Nu =
O MeO S N O OTMS Ph O OTIPS
Bn
O
Cl Cl
E = Cl
Cl
Cl
Scheme 47 Intermolecular organo-cascade catalysis

Combination of the Hantzsch ester mediated transfer hydrogenation together with

chlorine (116) or fluorine (117) electrophiles allows for the formal addition of HCl or HF
across a double bond in a catalytic asymmetric manner (Scheme 48) [178]. Within this
paper the reactions were further refined by the use of two cycle-specific secondary
amines which effectively operated independently within the same reaction mixture.
Impressively, this allowed access to either diastereoisomer of the product depending
upon the absolute configuration of the catalyst used in the second step of the sequence.
O PhO2 S SO2 Ph
N
N
F
t
Bu 20 mol% 78·TCA 117 60% yield
N CHO
H Ph 99% ee
CHCl3 , –20 °C, 24 h THF/ i PrOH (9:1)
78 F 1:3 syn:anti
–20 °C, 30 h
t
O BuO2 C CO2 t Bu
O
+ Cl
Ph Cl
N
H Cl
Cl
Cl
20 mol% 78·TCA 116 70% yield
CHO
CHCl3 , –40 °C, 24 h CHCl3 , –40 °C Ph 99% ee
Cl 8:1 syn:anti
Scheme 48 Catalytic asymmetric formal addition of HCl or HF across a double bond
Córdova has described a reductive Mannich protocol that proceeds with high
chemo-, diastereo- and enantioselectivity [179]. Conjugate reduction of b,b-disub-
stituted enal 118 with Hantzsch ester 119 in the presence of 30 (10 mol%) and
benzoic acid (10 mol%) (63 h, −20 °C) followed by addition of a-iminoglyoxylate
120 and stirring for a further 24 h gave the product (121) with excellent levels of
relative and absolute stereocontrol (10:1–50:1 dr; 95–99% ee) (Scheme 49).
EtO2 C CO2 Et
O 10 mol% 30·PhCO2 H O 54–70% yield
+
95–99% ee
Ar N CHCl3 , –20 °C, 63 h Ar 10:1 – 50:1 dr
N H
H OTMS
1.1 equiv.
30 PMP
118 119 N 4 °C, 24 h
120 CO2 Et
PMP
HN
Ar CO2Et
CHO
121
Scheme 49 Organocatalytic asymmetric reductive Mannich reaction
Jørgensen reported the first catalytic asymmetric diamination procedure using an

iminium ion/enamine method [113]. Treatment of an a,b-unsaturated aldehyde with
succinimide 122 in the presence of diarylprolinol ether 55 (10 mol%) gave the conjugate
addition product (65–74%; 78–89% ee). Direct treatment of the crude reaction mixture
with DEAD (123) led to diamination product 124 with near perfect enantioselectivities
(39–40%; 99% ee) clearly showing the power of these transformations (Scheme 50).
CO2 Et
N
F3 C CF3 N EtO2 C
O EtO2 C 123
O 10 mol% 55 NH O
CF3 20 mol% NaOAc 40 mol% PhCO 2H N
+ HN EtO2 C O
CH 2Cl2, rt, 20 h CH2 Cl2, –24 °C
N R O 2.5 h R N
H OTMS CF3
55 122 124 O
R = ethyl,
n heptane
39–40% yield
99% ee
3:1– 4:1 dr
Scheme 50 syn-Selective diamination of a,b-unsaturated aldehydes
It is clear that, as understanding of the underlying principles of both iminium ion

and enamine catalysis improves, the true power of these cascade sequences will be
fully exploited. It can be expected that introduction of subsequent independent cata-
lytic cycles will add to the complexity and applicability of these processes and
provide highly regulated cascades that mimic the power of enzymatic pathways.
2.3.6 Morita–Baylis–Hillman Reaction
Since its original discovery the Morita–Baylis–Hillman reaction has received con-
siderable attention due to its potential as a powerful carbon–carbon bond forming
process [180]. The intriguing multi-step mechanism has provided the driving force
for the invention of a variety of catalytic asymmetric methods to accelerate this
reaction; however, there is still room for improvement with regards substrate scope
and reaction generality. Shi showed an iminium ion/enamine catalysed process was
viable for the coupling of methyl vinyl ketone (125) and a series of aromatic alde-
hydes (127) accelerated by a dual catalyst mixture of l-proline and imidazole [181].
The proposed catalytic cycle is outlined in Fig. 11. Iminium ion formation followed
by conjugate addition of imidazole gives intermediate enamine 126 which reacts
with an aldehyde to give 128. Elimination of imidazole and iminium ion hydrolysis
gives the Morita–Baylis–Hillman product (129) and releases both catalysts for
further reaction. Although 30 mol% of each catalyst was needed and the products
were isolated with low to negligible ee, this proof of concept provided excellent
precedent for further investigation. In the absence of either proline or imidazole the
reaction was reported to be ineffective showing that both these catalysts are critical
to catalytic activity.
Improvements in the enantioselectivities were observed using benzodiazepine 130
and l-proline (58) which catalysed the reaction of methyl vinyl ketone and a small
OH O O
Ar
125
129
N CO2 H
H
H2 O
H2 O
OH N CO2
HN N CO 2
N
Ar
N N
128
N CO 2
O
Ar
127 HN N 126
Fig. 11 Proposed catalytic cycle for the Morita–Baylis–Hillman reaction
series of aromatic aldehydes (54–76% yield; 31–83% ee) (Scheme 51) [182]. Although
the levels of enantioselectivity are short of those required for this technology to be
taken up as a general method, it might be expected that improvements are possible.
N O 5 mol% 130
OH O
H O 10 mol% 58
130 +
CHCl3 /THF (4:1) Ar
Ar
20 °C, 4–10 d
54–76% yield
N CO2 H
31– 83% ee
H
L-proline
58
Scheme 51 Morita–Baylis–Hillman reaction using the dual catalysts 130 and 58
The most efficient catalyst system for the Morita–Baylis–Hillman reaction of

methyl vinyl ketone has been reported by Miller [183, 184]. Use of l-proline (58)
(10 mol%) in conjunction with the N-methyl imidazole containing hexapeptide 131
(10 mol%) provided an efficient platform for the reaction of 125 with a series of
aromatic aldehydes 127 (52–95% yield; 45–81% ee) (Scheme 52). Importantly, it
was shown that the absolute configuration of the proline catalyst was the major
factor in directing the stereochemical outcome of the reaction and not the complex
peptide backbone.
Intramolecular versions of the Morita–Baylis–Hillman reaction have also
met with success using a dual Lewis acid/Lewis base catalyst system. Miller
has shown that a combination of N-methyl imidazole (132) (10 mol%) and
O
H
BocN
peptide
O 10 mol% 131
O OH O
10 mol% 58
N 131 +
N THF/CHCl3 (2:1) Ar
Ar
25 °C, 24 h
125 127 52–95% yield
45–81% ee
N CO2 H
H
L-proline
58
Scheme 52 Optimal catalyst system for the Morita–Baylis–Hillman reaction of methyl vinyl ketone
pipecolinic acid (133) (20 mol%) accelerates the intramolecular cyclisation of

a,b-unsaturated ketones 134 which proceeds at room temperature in a THF/
water mixture (46–68% yield; 51–80% ee) (Scheme 53) [185]. These highly
practical reaction conditions using commercially available catalysts suggests
that this should become a particularly useful method for the construction of
these highly functionalised products. Hong has also described an intramolecu-
lar reaction of a,b-unsaturated aldehyde 135 which gives the cyclic product 136
(77% yield; 96% ee) [186]. Expansion or reduction of the ring size led to a
substantial decrease in both yield and enantioselectivity observed, however, this
example shows excellent potential.
N N
O O 10 mol% 132 O OH
132 20 mol% 133
Ar Ar
THF/H 2O (3:1)
25 °C, 48 h
N CO2 H 134
H
133 46–68% yield
51–80% ee
N N
O O 10 mol% 132 O OH
132 10 mol% ent-58
CH 3CN
CO 2H 0 °C, 15 h
N 135 136
H
D-proline 77% yield
ent-58 96% ee
Scheme 53 Intramolecular Morita–Baylis–Hillman reaction
An interesting alternative intramolecular cyclisation was discovered by Jørgensen

and co-workers [187]. Although not strictly exploiting an enamine intermediate, the
transformation represents a secondary amine catalysed Morita–Baylis–Hillman
reaction leading to a series of highly functionalised cyclohexene products. Reaction
of the Nazarov reagent 137 with a,b-unsaturated aldehydes in the presence of the
diarylprolinol ether 30 led to the cyclohexene products 138 (49–68% yield; 86–96%
ee) via a tandem Michael/Morita–Baylis–Hillman reaction (Scheme 54).
O OH
O O 10 mol% 30
CO2 R2
10 mol% PhCO2 H
+ OR 2
N PhMe, rt, 18 h
H OTMS R1 HO R1
137 138
30
R1 = Ar, hetAr, CO2Et, alkyl
R2 = Et, t Bu, allyl
49–68% yield
86–96% ee
3:2 – 11:1 dr
Scheme 54 Organocatalytic Michael/Morita–Baylis–Hillman reaction
Although the precise mechanisms for each of these examples have yet to be
determined, a pathway involving iminium ion intermediates appears reasonable.
Further optimisation of the complex dual catalyst systems may well lead to a gen-
eral and robust procedure that will prove of considerable use in synthesis.
2.4 1,2-Addition – An Important Consideration
2.4.1 Condensation Reactions
A less developed but substantial opportunity for reaction of iminium ions is the
direct 1,2-addition of a nucleophile. Although this can reduce opportunities for
developing a catalytic procedure because of mechanistic considerations, appropriate
choice of substrates and reaction conditions has provided a number of successful
methods that adopt this mode of reactivity.
Barbas, one of the pioneers of enamine catalysis, has incorporated iminium ion
intermediates in complex heterodomino reactions. One particularly revealing exam-
ple that uses the complementary activity of both iminium ion and enamine interme-
diates is shown in Fig. 12 [188]. Within this intricate catalytic cycle the catalyst,
l-proline (58), is actively involved in accelerating two iminium ion catalysed trans-
formations: a Knoevenagel condensation and a retro-Michael/Michael addition
sequence, resulting in epimerisation.
It can be expected that inclusion of 1,2-addition reactions catalysed by iminium
ion intermediates will allow for further rapid introduction of architectural diversity
into simple building blocks through similar domino type processes addressing one
of the critical objectives in contemporary synthetic chemistry.
Care must also be taken when choosing the reaction partners within reactions.
Nucleophiles that have been reported to be effective in conjugate addition processes
can also undergo 1,2-addition reactions and these possibilities must be addressed in
reaction design. For example, aldehydes and ketones have been shown to undergo
a bis-indole alkylation sequence in the presence of achiral amine 139 (42–84%
yield; 1–10 mol% catalyst) [189]. This additional reactivity was exploited in the
Ar O
O L-proline
58 Ar O
R O 3
O
O
R
R O
CO2 H
N
O H
L-proline
2 58
R
O H2O
Ar
HO2C
N CO 2
N
R
O
H 2O
1
O
N CO2 H
O H
L-proline O
58
Ar
1 Iminium ion Knoevenagel condensation R

O
2 Enamine facilitated Diels-Alder reaction
3 Iminium ion epimerization
Fig. 12 Organocatalytic heterodomino reactions
synthesis of the naturally-occurring tris-indole 140 which was prepared directly by

the reaction of crotonaldehyde with 3 equivalents of indole (Scheme 55). It was
proposed this reaction proceeded via iminium ion formation followed by conjugate
addition of the first molecule of indole. Conversion of the resulting enamine back
to the iminium ion followed by the 1,2-addition of 2 further equivalents of indole
gave the observed product 140 in a respectable 51% isolated yield after three C–C
bond-forming reactions.
NH
O
H
N Ph 10 mol% 139·HCl
N +
H
O N MeOH, rt, 24 h NH
139 H
140 51%
HN
139·HCl
–H 2O Indole
(2 equiv.)
H Indole H
N Ph N Ph
N N
O O
HN
Scheme 55 1,2-Addition of indole to an iminium ion

Although condensation reactions usually result in achiral products they repre-

sent important additional reactivity of the active iminium ion which must be con-
sidered. Design of condensation reactions into cascade processes will provide
further intriguing catalytic sequences.
3 Primary Amines as Catalysts
The majority of transformations reported within the literature using the concept of
LUMO energy lowering iminium ion activation have used secondary amines as the
catalyst. Under the aqueous acidic reaction conditions inherent to this mode of
activation it is also possible to use primary amines as efficient catalysts where the
active species is the protonated imine 141 (Fig. 13). Although this is a somewhat
less explored avenue of research, initial results suggest it will become an equally
fruitful area with broad application.
H
O
R N R
+ NH 2·HX + H2 O
X
141
Fig. 13 Iminium ion activation using primary amines
In particular, the reduced steric bulk around the catalytic nitrogen has allowed
for expansion of the scope of these reactions to more hindered substrates such as
a-substituted acroleins and, importantly, a,b-unsaturated ketones, augmenting the
chemistry described in Sect. 2 of this report (Fig. 14).
N H
O N O NH2 N
H
R1 ·HX R1 R1 ·HX R1
R2 R2 R2 R2
secondary amine primary amine

catalyst catalyst
Fig. 14 Activation of a-substituted acroleins using primary and secondary amines
3.1 [4+2] Cycloaddition
Ishihara and Nakano reported a complex triamine catalyst which was effective for
the enantioselective Diels–Alder reaction of a-acyloxyacroleins [190]. They have
subsequently described binaphthyl catalyst 142 which gave higher yields and enan-
tioselectivities within the same transformation [191, 192]. Reaction of a range of
dienes and a-acyloxyacroleins in the presence of 142 (10 mol%) and
bis(trifluoromethanesulfonyl)amine (19 mol%) gave Diels–Alder adducts 143

(65–99% yield) in 67–91% ee (Scheme 56). In order to achieve these levels of
selectivity, reactions were performed at −75 °C for up to 48 h, revealing further
opportunities for improvement within this challenging area of research.
R3
10 mol% 142
R1 O R1
NH2 R3 19 mol% Tf 2 NH
+ O
NH2 R4 R5
R2 R5 O EtNO2 , –75 °C R2
O 10–48 h O
R4 O
142 143
1
R = Me, H
R2 = Me, H
R3 ,R4 = H, –CH2 CH 2 –, –CH 2 –
R5 = cC 6H 11 , cC 5 H9 , Ph2 CH,
R5 = p-TIPSOC6 H 4
65–99% yield
67–91% ee
Scheme 56 Diels–Alder reaction of a-acyloxyacroleins catalysed by binaphthylamine 142
An interesting expansion to the scope of dienes that could be adopted as partners

within the Diels–Alder cycloaddition was reported by Deng (Scheme 57) [193].
Reaction of 3-hydroxypyrones 145 with a broad range of a,b-unsaturated ketones
in the presence of the primary cinchona alkaloid 144 (5 mol%) provided the Diels–
Alder adducts with exceptional levels of asymmetric induction (up to 99% ee).
Within this report it was also shown that the related alkaloid 146 provided access
to the enantiomeric adducts with similar levels of asymmetric induction.
O
H 2N OH O O O
5 mol% 144 O O
N R1 O R2 O
R3 20 mol% TFA
+ +
O CH 2Cl2 , –30 to 0 °C 1 1 3
N R2 R HO R HO R2 R
144 96 h
145 O R3
endo ex o
O R1 = Ph, Me, H, Cl
R2 = Ar, hetAr , alkyl
N R3 = alkyl
51–98% yield
89–99% ee
N NH2
1:2.7 – 1:32 endo:ex o
146
Scheme 57 [4+2] Cycloaddition of 3-hydroxypyrones and a,b-unsaturated ketones
3.2 [3+2] Cycloaddition
Chen extended the scope of his iminium ion catalysed [3+2] cycloaddition with
azomethine imines (see Sect. 2.1.2) to encompass cyclic a,b-unsaturated ketone
substrates using primary amine 147 as the catalyst [194]. Interestingly, the presence
of molecular sieves improved the enantiomeric excesses obtained for the adducts,
despite the fact that water is an integral part of the catalytic cycle. This may provide
a reason for the long reaction times required (up to 120 h). Despite this, impressive
levels of asymmetric induction (86–95% ee) and high yields (up to 99%) were
achieved in these reactions (Scheme 58).
OH O R O R
10 mol% 147 H
N 20 mol% TIPBA
N + N N
THF, 4 Å MS N
n n
O 40 °C, 24–120 h H
N NH2
O
147
R = Ar, hetAr, alkyl
67–99% yield
86–95% ee
>99:1 endo:exo
Scheme 58 [3+2] Cycloaddition of azomethine imines with a,b-unsaturated ketones
3.3 Epoxide Formation
Pihko reported that effective turnover could be obtained using hindered primary
anilines as the catalyst for iminium ion accelerated processes. It was reasoned that
an iminium ion derived from aniline would be conjugated with the aromatic ring
slowing catalytic turnover (149). Use of a bulky o-substituted aniline 148 would
prevent this conjugation and lead to faster catalyst turnover providing a new plat-
form for design of novel catalytic architectures for challenging substrates such as
a-substituted acroleins (Scheme 59) [195]. This hypothesis was shown to be cor-
rect with the simple achiral aniline salt 148·TFA which efficiently catalysed the
epoxidation of a series of a-substituted a,b-unsaturated aldehydes using tert-
butylhydroperoxide as the oxidant. Asymmetric versions of this and related trans-
formations based on this catalyst design will certainly augment this area.
i
Pr 20 mol% 148·TFA
O t O
BuOOH
R R
NH 2 CH2 Cl2 , rt
O
i 1–7 h
Pr
148
R = alkyl
80–100% yield
i
Pr
i
Pr
N N N
H i H H
Pr
149 i
Pr
Iminium ion in Iminium ion not
conjugation in conjugation
Scheme 59 Epoxide formation using primary anilines as catalysts

List has provided access to chiral epoxides derived from cyclic a,b-unsaturated
ketones using the primary amine salt 146·2TFA [196]. Treatment of cyclohexenone
or cycloheptenone derivatives with the catalyst (10 mol%) and hydrogen peroxide
(1.5 equivalents) in dioxane (30–50 °C) gave the corresponding epoxide (92–99%
ee) (Scheme 60). Deng has subsequently reported that the same catalyst system
146·2TFA is also effective in the epoxidation of acyclic a,b-unsaturated ketones
using 1-methyl-1-phenylethylhydroperoxide as the oxidant with similar high levels
of asymmetric induction (96–97% ee) [197].
O O O
10 mol% 146·2TFA
N + H 2 O2 O
R2 2 R1 dioxane R2 2 R1
R R n
N NH 2 n 30–50 °C, 20–48 h
146 n1 = 1, 2
R1 = Bn, alkyl, H
R2 = Me, H
49– 85% yield
92– 99% ee
Scheme 60 Catalytic asymmetric formation of epoxides from a,b-unsaturated ketones
3.4 Conjugate Addition
The conjugate addition of carbon nucleophiles to a,b-unsaturated ketones using a

primary amine as the catalyst has recently met with success and broadens the sub-
strate scope using iminium ion activation. In an improved procedure from earlier
work [198] Deng found that the primary quinine derived amine 146 was effective
for the intermolecular conjugate addition of a,a-dicyanoalkenes to a,b-unsaturated
ketones to give the Michael adducts (51–98% yield; 89–99% ee) (Scheme 61)
[199]. Deng has since shown this reaction is equally effective using malononitrile
as the nucleophile [200]. This amine (146) has also been found to catalyse the addi-
tion of cyclic 1,3-dicarbonyl compounds to a,b-unsaturated ketones (55–98%
yield; 89–99% ee) [201]. Use of the pseudo-enantiomeric cinchonine derived ana-
logue leads to the opposite sense of asymmetric induction with similar levels of
enantiomeric excess being reported. Although both these reactions are slow (96 h
at 0 °C), the high yields and levels of stereocontrol suggest that further exploitation
of this amine in iminium ion activated processes should be fruitful. Exploitation of
this amine (146) in the C-3 alkylation of indole with a,b-unsaturated ketones has
also been shown to be effective with reasonable enantioselectivities (16–99% yield;
47–89% ee). Catalyst loadings for this transformation were high (30 mol%) and
low temperatures were frequently required (0 to −20 °C) [202].
Ishihara has reported an unusual enantioselective [2+2] cycloaddition of unacti-
vated alkenes with a-acyloxyacroleins catalysed by triamine 150 [203]. Although
the precise mechanistic details of this transformation are unclear at present, a possible
O
NC CN NC CN
R2
H
O 20 mol% 146·2TFA 1
R
+
R1 R2 THF, 0 °C, 96 h
X X
X 1 = CH2 , O, S
1
O R = Ar, alkyl
R2 = alkyl, calkyl
N 51– 98% yield
89 – 99% ee
N NH2
146 O
OH OH R2
O 20 mol% 146·2TFA 1
R
+
R1 R2 CH 2Cl2, 0 °C, 96 h
X O X O
R 3 R3
X 1 = NMe, O, S
R1 = Ar, alkyl
R2 = alkyl, calkyl
R3 = 6-Me, 5,7-
(Me)2 ,
R3 = 6-Br, H
55 –98% yield
89–99% ee
Scheme 61 Conjugate addition of C-based nucleophiles to a,b-unsaturated ketones
stepwise pathway involves iminium ion formation with the primary amine which
facilitates enantioselective conjugate addition of the electron rich alkene. Subsequent
intramolecular cyclisation of the resulting enamine onto the tertiary carbocation
then provides the observed products 151 and 152. These cycloadducts can be effi-
ciently ring expanded to the corresponding cyclopentanone by treatment with either
aluminium trichloride or TBAF, leading to an overall formal [2+3] cycloaddition
process (Scheme 62).
Ar
O O
O 10 mol% 150
O
Ar O 26 mol% HNTf2 AlCl 3
CHO O
+
O EtNO2 , rt, 12 h CH 2Cl2 i Ar
i
Pr i Pr
Pr 151 O
80% yield 61% yield
i
Bu 84% ee
N
NH
Ph
NH 2 150 Ar
O
O OH
20 mol% 150 O
Ar O 46 mol% HNTf2
+ CHO Bu 4NF·3H 2O O
O PrNO2 , –20 °C, 72 h THF, rt, 9.5 h
H H
152
24% yield 95% yield
90% ee 4.6:1 dr
Scheme 62 Enantioselective [2+2] cycloaddition of unactivated alkenes

4 Chiral Anions Using Secondary and Primary

Amines as Catalysts
A recent concept introduced into the field of iminium ion activation that shows
great promise for expanding the scope of both substrates and transformations is the
use of a chiral anion in association with a primary or secondary amine. The use of
non-reactive chiral anions as effective tools for the introduction of asymmetry in
transition metal, phase-transfer, Brønsted acid and organocatalysed processes is
currently receiving significant attention [204–208]. These isolated reports highlight
the potential strength of this organocatalytic methodology which will certainly
increase in scope.
List was the first to explore this possibility, examining the Hantzsch ester medi-
ated reduction of a,b-unsaturated aldehydes [209]. Using 20 mol% of the binaph-
thyl derived phosphonate salt of morpholine (153) in dioxane at 50 °C, a series of
b-aryl a,b-unsaturated aldehydes underwent transfer hydrogenation with Hantzsch
ester 154 with excellent levels of absolute stereocontrol (96–98% ee) (Scheme 63).
The method was also applied to the aliphatic substrates (E)-citral and farnesal to
give the mono-reduced products in 90% and 92% ee, respectively. Significantly, in
line with many of the chiral secondary amine catalysed transformations described
above the reactions follow a simple and practical procedure without the need for
exclusion of moisture and air.
i
i
Pr O
Pr
O O
i
Pr
N
O O H2
P R 20 mol% 153
O O +
i 153 MeO2 C CO2 Me dioxane, 50 °C, 24 h R
Pr
R = Me, CN, CF3, NO 2, Br
i 63–90% yield
N Pr
i H
Pr i 96–98% ee
Pr 154
Scheme 63 Asymmetric counteranion-directed catalysed transfer hydrogenation
Subsequently, List reported that although the method described above was not
applicable to the reduction of a,b-unsaturated ketones, use of a chiral amine in
conjunction with a chiral anion provided an efficient and effective procedure for the
reduction of these challenging substrates [210]. Transfer hydrogenation of a series
of cyclic and acyclic a,b-unsaturated ketones with Hantzsch ester 119 could be
achieved in the presence of 5 mol% of valine tert-butyl ester phosphonate salt 155
with outstanding levels of enantiomeric control (Scheme 64). A simple mechanistic
model explains the sense of asymmetric induction within these transformations
allowing for reliable prediction of the reaction outcome. It should also be noted that
matched chirality in the anion and amine is necessary to achieve high levels of
asymmetric induction.
i
i Pr
Pr
CO2 t Bu
O O
i
Pr H3 N
i Pr EtO 2 C CO2 Et
O O 5 mol% 155
P +
O O R N Bu 2O, 60 °C, 48 h R
n n
i 155 H
Pr n = 0, 1, 2
119
R = Ph, alkyl
68– 94% yield
iPr
i
Pr 84– 98% ee
Scheme 64 Enantioselective transfer hydrogenation of a,b-unsaturated ketones
In conjunction with the chiral anion TRIP (156) (10 mol%), diamine 157 (10
mol%) can be used in the catalytic asymmetric epoxidation of a,b-unsaturated
ketones (>90% ee) [196], while the secondary amine 158 (10 mol%) can be used
for the epoxidation of both di- and trisubstituted a,b-unsaturated aldehydes (92–
98% ee) (Fig. 15) [211]. The facile nature of these reactions, using commercially
available peroxides as the stoichiometric oxidant, together with the synthetic utility
of the epoxide products suggests application in target oriented synthesis.
i
i Pr
Pr
i
Pr
NH 2 O F3 C CF 3
O N
P H
O OH
NH 2
i
Pr
CF3 CF3
157 i
Pr 158
i
Pr
Epoxidation of 156 Epoxidation of
α,β-unsaturated ketones α,β-unsaturated aldehydes
Fig. 15 Amines used in conjunction with TRIP for the epoxidation of enones and enals
A further example of the use of a chiral anion in conjunction with a chiral amine
was recently reported by Melchiorre and co-workers who described the asymmetric
alkylation of indoles with a,b-unsaturated ketones (Scheme 65) [212]. The quinine
derived amine salt of phenyl glycine (159) (10–20 mol%) provided the best plat-
form with which to perform these reactions. Addition of a series of indole deriva-
tives to a range of a,b-unsaturated ketones provided access to the adducts with
excellent efficiency (56–99% yield; 70–96% ee). The substrates adopted within
these reactions is particularly noteworthy. For example, use of aryl ketones (R2 =
Ph), significantly widens the scope of substrates accessible to iminium ion activa-
tion. Expansion of the scope of nucleophiles to thiols [213] and oximes [214] with
similar high levels of selectivity suggests further discoveries will be made.
Ph
BocN O
H CO2 R1
R3 R3 R2
O
2 10–20 mol% 159
OMe +
NH 3 R1 R2 PhMe, rt to 70 °C
N R4 N R4
N 24 – 96 h
H H
H
159 R 1 = Ar, alkyl, CO2 Et
N
R 2 = Ph, alkyl, calkyl
R 3 = H, OMe, Cl
R 4 = H, Me
56 –99% yield
70 –96% ee
Scheme 65 Alkylation of indoles using a chiral anion/chiral amine combination
5 Applications in Synthesis
A true test for the applicability of any methodology is not only the level of its uptake by
the general synthetic community, but also its use in the synthesis of natural products and
molecules of biological significance. To this end there have been a number of applica-
tions in natural product synthesis of the iminium ion catalysed reactions discussed within
this review. This can be put down to the mild, efficient and user friendly reaction condi-
tions possible for many of the transformations, the ease of accessibility of the catalysts
reported (many are even commercially available) and the high functional group toler-
ance, all features eminently compatible with complex target synthesis. A comprehensive
review encompassing a variety of organocatalytic transformations in the synthesis of
drugs and bioactive natural products has been reported [22]. Within this section a
selected group of syntheses are described that serve to illustrate applications of cycload-
dition and conjugate addition processes. Additionally, each of these syntheses increase
the substrate scope compatible with iminium ion mediated transformations and expand
the horizon of the chemistry accessible using simple chiral amines as catalysts.
Tamiflu ((–)-oseltamivir phosphate, 165) is a potent inhibitor of neuraminidase
which has been stockpiled by governments worldwide as a precautionary measure
against a possible influenza pandemic. Fukuyama reported an efficient synthesis of this
compound which commenced with an iminium ion catalysed Diels–Alder reaction of
acrolein and dihydropyridine 160 catalysed by imidazolidinone ent-12 expanding the
scope of the dienes accessible using this chemistry. The crude product from the Diels–
Alder reaction (161) was converted into bromolactone 162 in two further steps (26%
overall yield; 99% ee). Functional group manipulation and Curtius rearrangement gave
the highly substituted bi-cycle 163 which was hydrolysed to give aziridine 164. This
was then converted to tamiflu (165) by a four-step sequence (Scheme 66) [215].
The scope of the dienophile partner within the Diels–Alder reaction was further
expanded in an insightful synthesis of (+)-hapalindole Q by Kerr and co-workers
[216]. Cycloaddition of N-protected indole 166 and substituted diene 167 catalysed
by imidazolidinonium salt 12·HCl (40 mol%) gave the densely functionalised
Diels–Alder adduct 168 (35% yield; 93% ee), which was converted to the target
alkaloid (169) in eight steps (Scheme 67).
O
N
N
Ph H
ent-12
CbzCl Cbz Cbz

N N
NaBH4 10 mol% ent -12·HCl 2 steps Br
N N O
MeOH
Cbz CHO O
–50 to –35 °C
160 MeCN/H2 O (19:1) 161 162 O
rt, 12 h 26% yield (over 4 steps)
99% ee
5 steps
O
O CO2 Et 4 steps CO 2Et Boc
NaOEt
BocN Br N
AcN EtOH
H 0 °C
NH 2.H3 PO4 H NAlloc MsO HNAlloc
ta miflu 8 7% y ield
1 65 1 64 1 63
Scheme 66 Iminium ion catalysed Diels–Alder reaction in the synthesis of tamiflu
O
N
N
Ph H
O
12
40 mol% 12·HCl 8 steps

+ NTs
DMF/MeOH/H2O SCN
N
Ts (9:9:1) O
166 167 rt, 36 h 168 NH
35% yield
93% ee
(+)- hapalindole Q
5.7:1 endo:ex o
169
Scheme 67 Iminium ion catalysed Diels–Alder reaction in the synthesis of (+)-hapalindole Q
The majority of syntheses reporting organocatalytic transformations use the high

levels of asymmetric induction frequently obtained to set key stereocentres in the
early stages of the synthesis. Burton and Holmes have reported a diastereoselective
IMDA in the late stages of the synthesis of the core of eunicellin revealing further
opportunities using the reported catalysts [217]. Treatment of the homo chiral a,b-
unsaturated aldehyde 170 (prepared in 18 steps from 2-deoxyribose) with 12 (5
mol%; CH3CN/H2O; rt) leads to the exo isomer 171 (67%) which represents the
core of the target natural product (Scheme 68). Complimentary to this result, the
use of ent-12 leads selectively to the endo isomer 172 (62%; 15:1 endo:exo). The
complexity and high selectivity observed pays tribute to the robust nature of the
imidazolidinone catalysts.
The power of intramolecular Diels–Alder reactions have also been exploited in
the synthesis of a number of natural products. MacMillan reported a concise and
highly practical synthesis of solanpyrone D [51, 218] and Koskinen described an
O O
N N
N N
Ph H Ph H
12 ent-12
PhMe2 Si PhMe2 Si PhMe2 Si

O
O OBn 5 mol% 12·HCl OBn 5 mol% ent -12·HCl O OBn
H H H H
H H MeCN/H 2O (19:1) MeCN/H2 O (19:1) H H
CHO rt, 16 h rt, 16 h CHO
O
171 170 172
67% yield 62% yield
single diastereoisomer 15:1 endo :exo
Scheme 68 Stereoselective iminium ion catalysed IMDA
IMDA strategy to access the core structure of amaminol A [52]. More recently,
Jacobs and Christmann reported the synthesis of amaminol B [219].
Jørgensen has exploited the conjugate addition reactions developed within his
laboratories in a highly effective one-step synthesis of warfarin [95] and the prepa-
ration of the antidepressant (–)-paroxetine [96] both using diarylprolinol 31. For
example, conjugate addition of dibenzyl malonate 52 to substituted cinnamalde-
hyde 173 (10 mol% 31; 72% yield; 86% ee) followed by reductive amination and
reduction gave piperidine 174 which represents a formal synthesis of (–)-paroxetine
(Scheme 69) [220]. Other examples of conjugate addition reactions that have been
exploited in synthesis include Liang and Ye’s conjugate addition of nitromethane to
a,b-unsaturated aldehydes in the preparation of (R)-baclofen [103] and Fustero’s
addition of nitrogen nucleophiles en route to (+)-sedamine, (+)-allosdamine and
(+)-coniine [115].
F3 C CF3
CF3
N
H OH CF3
31
Ph
O CHO
N
10 mol% 31 CO2Bn 2 steps
+ BnO 2C CO 2Bn
EtOH, 0 °C CO2 Bn
F F OH
96 h
F 173 52 174
72% yield
86% ee
Scheme 69 Iminium ion catalysed conjugate addition in the synthesis of paroxetine
The powerful enantioselective alkylation methodology developed by

MacMillan for the addition heteroaromatics and anilines to a,b-unsaturated
aldehydes was originally exploited in a synthesis of (–)-flustramine B [84]. The

preparation of the serotonin reuptake inhibitor BMS-594726 (176) also used
indole alkylation, significantly extending the scope of this reaction to include
a,b-disubstituted aldehydes as substrates [221]. The strength of the method was
highlighted by undertaking the synthesis on a 20g scale, the product from the
conjugate addition of indole 175 to enal 29 being isolated in an excellent 83%
yield (84% ee) (Scheme 70). The alkylation of pyrroles with a,b-unsaturated
aldehydes in an intramolecular fashion was developed by Banwell in the synthe-
sis of (–)-tashiromine [222]. The conjugate addition of electron rich aromatics
to a,b-unsaturated aldehydes has also been exploited in the synthesis of the
antitumour agent (+)-curcuphenol [223].
O
N
N
Ph H O
20
I O I NC
10 mol% 20·TFA 2 steps N
CHO
+
N CH2 Cl2 / i PrOH (6:1) N N
H –25 °C, 24 h H H
BMS-594726
175 29 83% yield 176
84% ee
Scheme 70 Iminium ion catalysed conjugate addition of indoles in the synthesis of BMS-594726
MacMillan reported a short and effective synthesis of spiculisporic acid which ele-
gantly exemplified his Mukaiyama–Michael addition of silyloxyfurans to a,b-unsatu-
rated aldehydes [88]. Robichaud and Tremblay augmented this in a formal synthesis of
compactin [224]. Within this report it was shown that low enantioselectivities were
obtained in the conjugate addition to acrolein. Use of b-silyl acrolein 177 circumvented
this and gave butenolide 178 in 95% yield and 82% ee. Conversion of adduct 178 to the
decalin (179) in eight steps resulted in a formal synthesis (Scheme 71).
O
N
t
N Bu
Ph H
21
O
O 4
20 mol% 21·DCA 4
TMSO O H 2O (5 equiv.) 8 steps

1
+ Me 3Si
1
CHCl3 O
Me 3Si H
–40 °C, 15 h HO
O OH
177 178 179
95% yield
82% ee
>30:1 sy n :anti
Scheme 71 Iminium ion catalysed Mukaiyama–Michael reaction in the synthesis of compactin

Hong and co-workers have described a formal [3+3] cycloaddition of a,b-

unsaturated aldehydes using l-proline as the catalyst (Scheme 72) [225]. Although
the precise mechanism of this reaction is unclear a plausible explanation involves
both iminium ion and enamine activation of the substrates and was exploited in the
asymmetric synthesis of (–)-isopulegol hydrate 180 and (–)-cubebaol 181. This
strategy has also been extended to the trimerisation of acrolein in the synthesis of
montiporyne F [226].
N CO2 H
H
L-proline
58
OH OH
O CHO CHO
O OH OH 8 steps OH OH
50 mol% 58
+ +
DMF
–10 °C, 16 h
180 181
80% ee 95% ee (–)-isopulegol (–)-cubebaol
hydrate
75% yield
Scheme 72 Iminium ion catalysed [3+3] addition in the synthesis of isopulegol hydrate and
cubebaol
6 Mechanistic and Structural Investigations
One of the most compelling features of iminium ion catalysis is the proposed mecha-
nistic rationale for the transformations, which leads to highly predictable reaction
outcomes. Despite impressive advances and the plethora of reactions reported efforts
to provide a detailed mechanistic understanding of the catalytic cycle are limited.
The reported work has focussed on the Diels–Alder cycloaddition and has provided
useful indicators that could be used in design of more active catalysts.
Ogilvie monitored the Diels–Alder reaction between cinnamaldehyde and
cyclopentadiene by 1H NMR using his hydrazide catalyst 18 and was able to
conclude that under the reaction conditions adopted (18·TfOH 100 mol%;
CD3NO2/D2O (19:1); 0.1 M) cycloaddition was the rate limiting step of the
catalytic cycle, iminium ion formation and hydrolysis being rapid [48]. In
addition, it was also shown that under these reaction conditions the key
cycloaddition step was reversible. Although this unexpected reversibility was
slow, the possibility of exploiting this in a dynamic resolution procedure
appears tempting.
Platts and Tomkinson reported a detailed quantitative study of the iminium ion
catalysed Diels–Alder reaction between cyclopentadiene and cinnamaldehyde
catalysed by trifluoromethyl pyrrolidine salt 182·HPF6 [227]. This combination of
secondary amine, co-acid and dienophile allowed the isolation and structural elu-
cidation of the reactive iminium ion intermediate. As a result it was possible to
CHO CF3
N
Ph H Ph
·HPF6
182·HPF6 Experimental activation barriers
Step 3 Step 1 Step 1: 23.9 kCal mol–1
H 2O H 2O
Step 2: 10.8 kCal mol–1
N N
Ph
X
X Step 2
Ph
Fig. 16 Kinetics of iminium ion catalysis using trifluoromethyl pyrrolidine
examine both iminium ion formation (step 1) and Diels–Alder cycloaddition (step
2) independently (Fig. 16). In line with Ogilvie’s observations it showed iminium
ion formation (k293 = (2.65 ± 0.35) × 10−3 dm −3 mol−1 s−1) and hydrolysis to be rapid
with Diels–Alder cycloaddition being rate limiting (k293 = (3.74 ± 0.02) × 10−4
dm−3 mol−1 s−1). From this study it was concluded that design of more active cata-
lysts should target lowering the energy level of the iminium ion LUMO. This
could conveniently be predicted through theoretical calculations prior to experi-
mental investigation and should prove of great use to those working in the field.
X-Ray crystal structures of the MacMillan imidazolidinones 12·HCl and ent-
12·HCl have been reported [228]. Iminium ions derived from a hydrazide [47] and
trifluoromethyl pyrrolidine [227] have also been characterised through
crystallography.
7 Theoretical Investigations
Despite the impact of iminium catalysis on the synthetic community, theoretical

investigations to understand the mechanism of the catalytic cycle, origins of asym-
metric induction and reactivity of catalysts have been limited.
Computational investigations have mainly focussed on examining the reactivity
of iminium ions (e.g. Diels–Alder reactions, conjugate additions etc.), although
some efforts have been made towards modelling the formation of iminium ions
(Fig. 2, Step 1). Platts studied the formation of iminium ions between acrolein and
a series of secondary ammonium chloride salts at the B3LYP/6–31+G(d,p) level
using an Onsager solvent model [229]. The model included an explicit molecule of
water and the results suggest that this is intimately involved in the reaction pathway,
acting as a ‘proton shuttle’. Based on these calculations Platts proposed that depro-
tonation of the amine is the rate determining step in iminium ion formation. This
differs from the traditional view of imine formation where attack on the carbonyl is
thought to be rate determining [230], but does suggest a reason why the choice of
solvent and the strength of the co-acid have such an impact on iminium catalysed
processes.
Diels–Alder cycloaddition reactions of iminium ions (Sect. 2.1.1) could take
place with either the C=N bond or the C=C bond acting as the dienophile. This
potential dual reactivity was investigated by Zora using the AM1 semi-empirical
method [231]. The results showed not only the preferred C=C reactivity (activation
barrier is 4.20 kCal mol−1 lower than for reaction with the C=N bond) but also sug-
gested that the reaction was stepwise.
The conjugate addition of nitroalkanes to a,b-unsaturated aldehydes (Sect.
2.2.2) has been investigated by Uggerud, who compared the uncatalysed, proton
catalysed and iminium ion catalysed additions [232]. The results suggested that
protonated acrolein was more activated towards addition than the iminium ion cata-
lysed process and also indicated that an intermediate oxazolidin structure 183,
unobserved experimentally, may be involved in the reaction pathway (Fig. 17) with
the transition state resembling that of a [3+2] cycloaddition process.
N
O
HO N
N
O
HO N
+7.4
kCal mol –1
–12.2
kCal mol–1
N
O
HO N
183
Fig. 17 Potential energy diagram for the addition of nitromethane to crotonaldehyde
The primary aim of the investigation and, perhaps, its greatest contribution, was
to evaluate the accuracy of the popular and computationally inexpensive DFT
method, B3LYP/6-31G(d), for investigating these reaction pathways. Comparisons
of the results with those obtained using a high level ab initio benchmark (G3)
showed that B3LYP/6-31G(d) performed exceptionally well with near quantitative
agreement for the energies of all intermediates and transition structures.
Studies using this method to investigate iminium ions and their reactions have
been undertaken by Houk who has concentrated principally on systems derived
from the imidazolidinones of MacMillan (Schemes 2 and 6). His investigations into
the geometries of iminium ions confirmed the predicted high selectivity for (E)-
iminium ions (Fig. 3) [233]. Intriguingly, the lowest energy iminium ion geometry
differs from that proposed by MacMillan (Fig. 3). This calculated structure shows
the phenyl ring of the benzyl group sitting above the imidazolidinone ring. The
conformation proposed by MacMillan is 0.3 kCal mol−1 higher in energy and the
lowest energy (Z)-isomer a further 0.9 kCal mol−1 above that (Fig. 18).
Fig. 18 The three lowest energy iminium ion conformations obtained by Houk
Additionally, investigations into imidazolidinone catalysed Diels–Alder reac-

tions (Schemes 2 and 6) [234] have shown that iminium ions of a,b-unsaturated
aldehydes and ketones have lower activation barriers for the Diels–Alder reaction
with cyclopentadiene than the parent compound (13 and 11 kCal mol−1, respec-
tively). It was also noted that transition structures show the formation of the bonds
is concerted but highly asynchronous.
Houk has also considered the alkylation reactions of pyrroles and indoles using
the same class of catalyst. The report addresses the fact that while catalyst 12 pro-
vides high ees in the alkylation of pyrroles (Scheme 15), the same is not true of
indoles and catalyst 21 is required instead (Scheme 16). A thorough examination of
the accessible transition states for the reaction of iminium ion 184 with pyrrole
and with indole led to the conclusion that the two reactions occur through different
transition states. Pyrrole adopts a closed transition state reminiscent of that of the
Diels–Alder reaction whereas indole adopts an open transition state (Fig. 19) [233].
Using this information in conjunction with a study into the preferred conforma-
tions of iminium ions generated from catalysts 12 and 21, Houk suggests that the
additional steric bulk of the tert-butyl group causes the benzyl arm of the catalyst
to shield better the Si face of the C=C double bond – a requirement for high ees in
an open transition state. For both the Diels–Alder and pyrrole/indole alkylation
N N
NH HN
N
H
0 0.3
kCal mol-1 kCal mol-1
N closed transition states
184
N N
N
H HN
HN
0 0.1
kCal mol-1 kCal mol-1
open transition states
Fig. 19 Lowest energy transition states for the addition of pyrrole and indole to iminium ions
reactions, the computational studies have enabled a rationalisation of the selectivi-

ties observed by experiment and have given an insight into the accessible conforma-
tions of the iminium ions.
In order to understand better the catalysis of the conjugate addition of heter-
oatom nucleophiles to a,b-unsaturated aldehydes by the diarylprolinol ether 55,
Jørgensen used DFT calculations (B3LYP/6-31G(d)) to investigate the intermedi-
ates and transition states involved in such reactions. For a triazole nucleophile, the
calculations predicted an ee of 90%, which was in good agreement with that
observed experimentally (92% ee) [111]. Most significantly, investigation of the
reaction pathway indicated that protonation of the enamine intermediate occurs by
water assisted proton transfer from the triazole nitrogen atom (Fig. 20). In the case
of phosphite nucleophiles, the study led to an understanding of the enantiocontrol
in the reaction allowing rationalisation of the conditions required for optimal
selectivity [119].
To date, the use of computational methods to investigate iminium ion catalysis
has been limited. The focus has been on rationalising the diastereo- and enantiose-
lectivities observed in the laboratory, but this has largely been retrospective and the
clear potential of these models as predictive tools for the design of improved cata-
lysts or even entirely new scaffolds has yet to be realised. There are few examples
of solid kinetic data in the literature making evaluation of the models difficult.
Ar
Ar
H
N
O H OTMS
H
N N Et
Ar = 3,5-(CF3) 2C 6 H3
N
Fig. 20 Water assisted proton transfer in an enamine intermediate

While the information has certainly advanced the understanding of the form of the
transition structures, the issues of counterion and explicit solvent effects have yet
to be addressed, largely as a result of limitations of the computational methods so
far employed.
8 Conclusions and Perspectives
The area of iminium ion catalysis has been an exciting and vibrant area of research
in recent years. Exploitation of this mode of activation for a,b-unsaturated alde-
hydes and, to a lesser extent, ketones has provided methods to catalyse a variety of
standard synthetic procedures in high yield and enantiomeric excess. Two principle
classes of catalyst have emerged from these investigations which are robust, reliable
and non-reaction specific: the imidazolidinones 185 and the diarylprolinol ethers
186. Many of these catalysts are available from commercial sources which will
undoubtedly accelerate their uptake over the coming years. Additionally, both
architectures are readily accessible in both enantiomeric forms from commercially
available starting materials, thus adding to their attraction. The general reaction
sequence to access these is outlined in Scheme 73 [3, 50, 145, 235, 236].
The key advantage that this class of catalysis offers to the synthetic community
lies in the true practicality of the transformations. The ability to carry out reactions
at room temperature in the presence of both moisture and air in high yield and opti-
cal purity can be viewed as the Holy-Grail of the synthetic chemist. Iminium ion
catalysis makes significant inroads into meeting these targets. Additionally, the
ability to apply this technology to tandem, cascade and multicomponent coupling
reactions allows for the formation of densely functionalised molecules from simple
achiral precursors in a single step [237]. The strategies and methods described
within this review form the basis of a simple and effective mode of activation for
key chemical building blocks and it can be expected that exciting advances will
continue to be disclosed.
Despite rapid progress in iminium ion catalysis it is still a maturing field and
significant challenges remain if it is to become a bench-mark method of choice. The
O
O OEt
N Step 1: MeNH 2 R 1 = Bn, CH2 Indole, H
2 steps R2
R 1 O
R1 NH2 N R3
H
Step 2: – H 2O R 2 = Me, t Bu, 5-Me-furyl
R2 R3 R 3 = Me, H
185
2 steps Ar
Step 1: ArMgBr Ar = Ph, 3,5-(CF 3) 2C 6H 3
Ar
N CO2 Et N Step 2: TMSCl
H H OTMS
186
Scheme 73 Preparation of imidazolidinone and diarylprolinol catalysts

obstacles to this advancement are becoming more apparent and key chemical chal-
lenges can be summarised as follows:
• Substrate scope – can a universal catalyst be developed for the activation of any
a,b-unsaturated aldehyde and ketone with multiple substitutions?
• Catalyst activity – can the activity of catalysts be increased to achieve similar
levels of yield and asymmetric induction with reduced catalyst loading?
• Catalyst activity – why are many of the selectivities and activities reported sensi-
tive to subtle changes in the amount of water present in the reaction medium and
the nature of the co-acid additive?
Although these are lofty goals, it can be certain that the synthetic community has
the drive, ambition and capabilities to rise to these challenges and the impetus to
continue development of the area is clear. An important factor in the realisation of
these goals will come from a more intimate understanding of mechanism and mode
of action which have remained under explored to date and certainly offer great
opportunity to those entering this competitive field of research.
In conjunction with both metal catalysed and other organocatalytic methods the
power of the synthetic chemist to construct more complicated targets will only
increase and have profound beneficial effects on society.
Acknowledgments The authors wish to thank the EPSRC for financial support.
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Top Curr Chem (2010) 291: 349–393
DOI: 10.1007/128_2008_17
Lewis Acid Organocatalysts
Oksana Sereda, Sobia Tabassum, and René Wilhelm
Abstract The term Lewis acid catalysts generally refers to metal salts like alu-
minium chloride, titanium chloride and zinc chloride. Their application in asym-
metric catalysis can be achieved by the addition of enantiopure ligands to these
salts. However, not only metal centers can function as Lewis acids. Compounds
containing carbenium, silyl or phosphonium cations display Lewis acid catalytic
activity. In addition, hypervalent compounds based on phosphorus and silicon,
inherit Lewis acidity. Furthermore, ionic liquids, organic salts with a melting point
below 100 °C, have revealed the ability to catalyze a range of reactions either in
substoichiometric amount or, if used as the reaction medium, in stoichiometric or
even larger quantities. The ionic liquids can often be efficiently recovered. The
catalytic activity of the ionic liquid is explained by the Lewis acidic nature of their
cations. This review covers the survey of known classes of metal-free Lewis acids
and their application in catalysis.
Contents
1 Introduction........................................................................................................................... 350
2 Silyl Cation-Based Catalysts................................................................................................ 351
3 Hypervalent Silicon-Based Catalysts.................................................................................... 356
4 Phosphonium Cation-Based Catalysts.................................................................................. 368
5 Carbocation-Based Catalysts................................................................................................ 372
6 Ionic Liquids......................................................................................................................... 379
7 Miscellaneous Catalysts........................................................................................................ 387
8 Conclusion............................................................................................................................ 388
References................................................................................................................................... 388
O. Sereda, S. Tabassum, and R. Wilhelm (* ü)

Clausthal University of Technology, Leibnizstr. 6, 38678 Clausthal-Zellerfeld, Germany
e-mail: rene.wilhelm@tu-clausthal.de
350 O. Sereda et al.
1 Introduction
Until recently the most popular method in asymmetric catalysis was the
application of metal complexes. This is not surprising, since the use of dif-
ferent metals, ligands and oxidation states makes it possible to tune selectiv-
ity and perform asymmetric induction very easily. Thus, the concept of
asymmetric catalysis has become almost synonymous with the use of metals
coordinated by chiral ligands [1,2]. In many examples the metal is a Lewis
acid [3].
Roles that are normally associated with metals as Lewis acids and as redox
agents [4,5], can be emulated by organic compounds. This review will intro-
duce the reader to the research field of Lewis acid organocatalysts. This field,
compared to other types of organocatalysts, which are highlighted in the other
chapters of this volume, is still limited. The number of asymmetric catalyzed
examples is small, and the obtained enantiomeric excess is sometimes low.
Therefore, this review will also cover a number of reactions promoted by achi-
ral catalysts. Nevertheless, due to the broad variety of possible reactions, which
are catalyzed by Lewis acids, this research field possesses a large potential.
Compounds containing carbenium, silyl or phosphonium cations can act as
Lewis acids. In addition, phosphorus- and silicon-based hypervalent compounds
display a Lewis acid catalytic activity. Furthermore, ionic liquids, organic salts
with a melting point below 100 °C, have shown the ability to catalyze a group of
reactions either in substoichiometric amount or, if used as the reaction medium,
in stoichiometric or even larger quantities. The solvents can be efficiently recov-
ered after the reaction. Each type of these compounds will be discussed in a
separate section.
This review will concentrate on metal-free Lewis acids, which incorporate
a Lewis acidic cation or a hypervalent center. Lewis acids are considered to
be species with a vacant orbital [6,7]. Nevertheless, there are two successful
classes of organocatalysts, which may be referred to as Lewis acids and are
presented in other chapter. The first type is the proton of a Brønsted acid cata-
lyst, which is the simplest Lewis acid. The enantioselectivities obtained are
due to the formation of a chiral ion pair. The other type are hydrogen bond
activating organocatalysts, which can be considered to be Lewis acids or
pseudo-Lewis acids.
There are some types of organic cations which cannot be placed under the heading
of Lewis acid organocatalyst. For example, one type is the chiral guanidinium salt
1 which has been used as a catalyst [8] in the Michael reaction. Due to the mode of
activation as shown in Scheme 1, this salt belongs to the hydrogen bond activating
organocatalysts. In this example, 1 gave only a racemic product (Scheme 1).
In addition, a chiral amidinium salt [9], which catalyzed the Diels-Alder reaction
with significant enantiomeric excess, would also belong to the class of hydrogen
bond activating organocatalysts.
Lewis Acid Organocatalysts 351
N
R1O OR2
N N
H H 1
X
O O
Nu
Scheme 1 Michael reaction
Another type would be ammonium cations of the types RNH3+, R2NH2+ or R3NH+
which could be considered to be Brønsted acids or hydrogen bond activating
organocatalysts. Fully substituted ammonium cations, R4N+, could interact with a
carbonyl group, lowering the electron density of its carbon atom. Yet, since the
ammonium cation does not possess an empty orbital to take up an electron pair, it is
not a Lewis acid. However, enantiopure ammonium salts have been used very effi-
ciently in asymmetric phase transfer catalysis, which has been reviewed [10–19].
One section in this review will deal with silyl cations, another with hypervalent
silicon compounds. The concept of hypervalent silicon compounds belongs, strictly
speaking, to the class of Lewis base catalysis. However, since a Lewis base forms
in situ with a silicon containing reagent or SiCl4 an intermediate, which functions
as a Lewis acid to activate substrates during the reaction, we would also present a
few examples in this review. Since silicon is a semimetal we leave it up to the reader
to decide whether silicon catalysts should be considered as organocatalysts.
Another semimetal is boron, which has been used for a long time as a Lewis acid,
e.g. BF3, and of which enantiopure derivatives have been applied very successfully.
Asymmetric boron catalysts have been reviewed [20–23] and will not be a part of this
article.
2 Silyl Cation-Based Catalysts
Silicon-based Lewis acids have been known for some time, and the related chem-
istry in catalysis has recently been reviewed [24]. Most examples in the literature
are mainly based on achiral species and will be discussed only briefly in this sec-
tion. In general, a broad variety of reactions can be catalyzed with compounds like
Me3SiOTf, Me3SiNTf2 or Me3SiClO4. One advantage over some metal Lewis acids
is that they are compatible with many carbon nucleophiles like silyl enol ethers,
allyl organometallic reagents and cuprates.
Overall, it is possible to divide the silyl Lewis acids into two groups, depending
on how strong the counter anion interacts with the silicon atom as shown in
Scheme 2. In the case where a very weakly coordinating anion is part of the com-
pound, one could consider that a free silyl cation is present. However, the silyl
cation is very strong and will be coordinated by solvent molecules like acetonitrile
or toluene [25, 26]. This complex could activate, for example, a carbonyl group.
Whether the carbonyl group replaces the solvent molecule is not known. In the case
R
O the bulkier the rests, the higher the reactivity
A R Si Solvent +
R R R R
O
R Si NTf 2 +
R R R
R R less strain
R
A R Si O A R Si Solvent
R R R
R R
R Si O + NTf2
O
R R
+ solvent A
R R
A: weakly coordinating anion e.g. B(C6F5)4
Scheme 2 Silyl based lewis acid catalysis
where a more coordinating anion is present, a neutral silicon molecule should be

postulated. A carbonyl oxygen could perform an exchange with the [NTf2] ligand.
The larger the three alkyl rests around the silicon atom are, the better the exchange
takes place, due to the release of strain, replacing the larger [NTf2] substituent with
a smaller carbonyl ligand [27–29].
In 1998 the groups of Jørgensen and Helmchen reported the preparation of the
chiral silyl cationic salt 2 (Scheme 3) [30]. This was the first time that a chiral silyl
cation was used as a catalyst in an enantioselective reaction. In order to ensure that
the silyl salt had a high reactivity, the almost chemically inert and non-coordinating
anions tetrakis[pentafluorophenyl]borate [TPFPB] and tetrakis[3,5-bis (trifluor-
omethyl)phenyl]borate [TFPB] were chosen as counter anions.
Si Me
(S)-2
a A = TPFPB
b A = TFPB
Scheme 3 Axial chiral silyl salt
The salt precursor was prepared according to the following route as shown in
Scheme 4. The desired enantiopure binaphthyl compound (S)-4 was made from
2-methylnaphtalene (3) over five steps, which also included a resolution step [31–33].
The final precursor (S)-5 was obtained in 41% yield via a deprotonation of (S)-4 fol-
lowed by the reaction with methyltrimethoxysilane and a subsequent reduction.
i) BuLi, TMEDA
5 steps ii) MeSi(OMe)3 Me
Si
iii) LiAlH 4 H
3 (S)-4 41% (S)-5
Scheme 4 Preparation of 5
Since silyl cations are highly reactive and moisture sensitive, the salts (S)-2a and
(S)-2b were prepared in situ from the air and moisture stable precursor (S)-5 via a
hydride transfer [34, 35] with trityl tetrakis[3,5-bis(trifluoromethyl)phenyl]borate
[Tr][TFPB] or trityl tetrakis[pentafluorophenyl]borate [Tr][TPFPB]. The authors
showed by 29Si-NMR studies that the desired salts were formed. The silyl salt
(S)-2a was then tested in the Diels-Alder reaction as shown in Scheme 5. A good
reactivity was found, and the product was obtained in 95% yield with higher than
95% endo selectivity at −40 °C in 1 h. However, only 10% ee was achieved.
O O 10 mol% (S)-2a
CD3CN
N O +
−40 °C O
95%
O N O
10% ee
> 95% endo
Scheme 5 Diels-Alder reaction
In addition, it was possible to show that salt (S)-2a could catalyze the aza-Diels-
Alder reaction as presented in Scheme 6. Benzylidene-2-methoxyaniline and
Danishefsky’s diene in the presence of 10 mol% catalyst at −40 °C gave the desired
product in 74% yield in just 2 h. Unfortunately, the obtained product was racemic.
MeO OTMS MeO

10 mol% (S)-2a
CD3CN
+ O N
N
MeO −40 °C
Ph 74% Ph
rac
Scheme 6 aza-Diels-Alder reaction
A second example of an enantiopure silicon-based catalyst was reported by the group

of Ghosez [27]. They concluded from the results of Simchen and Jonas [28] as
described above, that R3SiNTf2 compounds, bearing bulky chiral groups, should pos-
sess a good catalytic activity. Silylated sulfonimides from readily available (−)-myrte-
nal were obtained in few steps to give the desired precursors 6 shown in Scheme 7.
The salts were prepared in situ by transforming silane 6 to the corresponding silyl
chloride with HCl in CHCl3 followed by the treatment with AgNTf2.
R R
Si i) CHCl3, HCl Si
Ph NTf2
6 ii) AgNTf2 7
R = Et 67%
R = OMe 71%
R = OCH2Ph 86%
R = OCOPh 30%
Scheme 7 Preparation of catalysts 7
The catalysts were tested in the Diels-Alder reaction of cyclopentadiene and

methyl acrylate. The best result is given in Scheme 8. Catalyst 7 (R = OMe), bear-
ing an oxygen atom, which can stabilize the silicon center through coordination,
gave the product in 83% yield with an ee of 54% in favour of the endo product in
1.5 h. In case of 7 (R = Et) without an oxygen atom, a significantly lower ee of 7%
was observed. Next to toluene, solvents like ether, propionitrile or CH2Cl2 were
tested, but gave no desired product.
O
10 mol% 7 (R = OMe)
+ OMe
toluene
CO2Me
−78 C
83% endo:exo 99:1
54% ee
Scheme 8 Diels-Alder reaction
The same group reported the synthesis of enantiopure cycloalkylsilyl triflimides

[36]. Some examples are presented in Scheme 9. The precursors were prepared from
cyclohexenones and cyclopentanones, which were transferred in three steps into
racemic 2-aryl- and arylmethyl-3-dialkylphenylsilyl cycloalkanones. These were
resolved by preparative chiral HPLC. Next, the carbonyl function was removed to
give the desired precursors to the silyl triflimides. The latter were obtained in situ
directly by the treatment with HNTf2. The formation of these compounds could be
followed by 1H-NMR due to the signals of the methyl groups connected to the silicon
atom. The signals shifted from 0.20 ppm to 0.60 ppm. In addition a signal at 7.36 ppm
appeared due to the formation of benzene during the course of the reaction.
The salts were afterwards tested in the Diels-Alder reaction of methyl acrylate
and cyclopentadiene as depicted in Scheme 8. In contrast to the previous investigation
[27], CH2Cl2 was found to be a good solvent for the reactions. A 10 mol% catalyst was
prepared in situ, and the reaction was performed at −78 °C in the presence of 2,6-
di-tert-butyl-4-methylpyridine to trap any residual HNTf2. The best result was
obtained with compound 12 giving the product in high endo selectivity in 96% yield
and 50% ee. When −100 °C was chosen as the reaction temperature, 94% yield and
59% ee were reached in less than 2 h. Contrary to the previous example, catalyst 13
containing an oxygen atom, gave poor results with low endo selectivity and 35% ee.
The cyclopentane-based analogue 14 gave an ee of 56%; however, the endo/exo
selectivity was 32%. The results with catalyst 15 showed that an insertion of a meth-
ylene group between the cyclohexene ring and the 1-naphthyl group gave a significant
lower ee of 7% due to the higher conformational mobility in this catalyst.
PhO
Si Ph Si Ph Si Ph Si Ph
8 9 10 11
HNTf 2
CH 2Cl2
PhO
Si NTf2
Si NTf2 Si NTf2 Si NTf2
12 13 14 15
Scheme 9 Preparation of catalysts 12–15
Further on, Sawamura et al. [37] investigated the influence of different counter
anions on the catalytic activity of cationic silicon Lewis acids. In the studies an
achiral salt was used. In previous cases [30] acetonitrile was used as a solvent,
which is known to coordinate strongly the silicon cation species. Therefore, the
application of toluene as a solvent was investigated with a silicon cationic species.
Although even toluene coordinates a silicon cation [25, 38], an enhanced activity
compared to other solvents, was found. The achiral salt was prepared in situ from
triethylsilane and [Ph3C][B(C6F5)4] (17) as depicted in Scheme 10.
Et3SiH + [Ph3C][B(C6F5)4] [Et3Si(toluene)][B(C6F5)4] + Ph3CH

toluene
16 17 18 19
Scheme 10 Preparation of salt 18
The salt 18 was explored in the Mukaiyama aldol reaction with acetophenone,
and a yield of 96% was obtained after 1 h at −78 °C (Scheme 11). When Me3SiOTf
was used as a catalyst, a yield of 0% was observed. Me3SiNTf2 and Et3SiNTf2
resulted in 12% and 8% yield, respectively.
O OSiMe3 1 mol% 18 OH O
+
Ph Me Ph toluene Ph Ph
−78 C Me
96%
Scheme 11 Mukaiyama aldol reaction
In addition, the Diels-Alder reaction was found to be catalyzed by salt 18 giving the
endo-product in 97% yield in 1 h. Application of Me3SiOTf resulted in no product forma-
tion, while Me3SiNTf2 and Et3SiNTf2 gave a yield of 6 and 13%, respectively (Scheme
12). Both reactions proceeded in the same way in the presence of the proton scavenger
2,6-di-tert-butylpyridine with salt 18, which should rule out a proton promoted reaction.
1 mol% 18
+
CO2Me toluene
0 C CO2Me
97%
Scheme 12 Diels-Alder reaction catalyzed with salt 18
In summary, due to the low ees so far obtained with silyl-based Lewis acids,
there is still much room for optimization. The latter is a promising and worthwhile
task, considering the large number of reactions catalyzed by the achiral analogues
and their advantages over metal Lewis acids.
3 Hypervalent Silicon-Based Catalysts
Lewis bases in combination with silicon containing reagents can form in situ a Lewis
acid center, which can activate a substrate. Therefore, a few examples would be
presented in this section, although this type of catalysis is mainly considered to be
part of Lewis base catalysis. Due to the valence shell expansion capability of silicon,
Lewis bases tend to interact with vacant orbitals residing on the silicon. This interac-
tion of Lewis bases increases the electron density on the most labile ligand of the
silicon atom. Once the ligand is ionized or partially ionized, a positively charged sili-
con complex is formed, which acts as a Lewis acid due to its free 3d-orbitals respon-
sible for many organic transformations [24, 39–44] (Scheme 13).
δ δ
L X L X L X
δ δ
L D + Si L D Si
X L
D Si X
X
L X X L X X L X X
Lewis Lewis
base acid
Scheme 13 Lewis base Lewis acid pair
First, a few examples with silicon atom in one of the reaction partners will be
discussed. The asymmetric allylation of carbonyl compounds with an allylating
agent leads to homoallylic alcohols with two consecutive stereocenters along with
a carbon-carbon bond formation. The traditional method for this is the use of Lewis
acids that activate an electrophilic aldehyde towards nucleophilic attack of an allyl
metal reagent (Scheme 14) [2]. The use of the latter gives high enantioselectivity,
but lacks diastereoselectivity. This is because of the non-rigid transition state in the
reaction. In contrast, chiral Lewis base catalyzed allylations provide a dual mecha-
nism of activation, which involves binding of the Lewis base with a nucleophile
(trichlorosilane), thus generating a reactive hypercoordinated silicate species,
which further coordinates with aldehydes. Since the reactions proceed in the close
assembly of allyltrichlorosilane, aldehyde and chiral Lewis base, a high degree of
diastereoselectivity and enantioselectivity can be achieved [40].
Lewis acid activation

of aldehyde
LA
O O
LA OH
R H R H
R
H3C M H3C M
open transition
structure
chiral Lewis base catalyzed allylation
1 LB
R SiCl3
R1 SiCl3
R2
R2
O
LB
R H
LB
H LB
SiCl3 SiCl3 R1
O O SiCl3
R
R R R2 O
R 1 R2 R 1 R2
closed
transition structure dual activation of
aldehyde and allylating
agent
Scheme 14 Chiral Lewis base catalyzed allylation
The first example of a chiral Lewis base promoted allylation was given by
Denmark and coworkers in 1994 [45]. Stoichiometric amounts of chiral phospho-
ramide (R,R)-20 facilitated the enantioselective allylation (Scheme 15). There was
a complete stereochemical correlation between the geometry (E/Z) of allylsilane
and the diastereomeric ratio (syn/anti) of the products.
Me
N O
P
20
N N
Me
1.0 equiv.
OH
PhCHO
Me SiCl3 Ph
EIZ 99:1 CH2Cl2, −78 C Me
68%
98:2 anti:syn
66% ee
1.0 equiv. 20
OH
PhCHO
Me SiCl3 Ph
EIZ 1:99 CH2Cl2, −78 C Me
72%
2:98 anti:syn
60% ee
Scheme 15 Lewis base 20 catalyzed allylation

Similar results were reported by the Barret group by using stoichiometric amounts
of an enantiopure 2-(2-pyridinyl)-2-oxazoline [46]. In 1996, Iseki and Kobayashi
achieved a catalytic version of the asymmetric allylation [47]. They applied proline-
based chiral HMPA derivatives for the allylation. The catalyst 21 proved to be the best
one regarding catalyst loading down to 1 mol% (Scheme 16) [48].
OH
1 mol% 21
PhCHO + SiCl3
Ph
THF, −78 C
98% 88% ee
H H
H
N N 10 mol% 22
P N P N 83%, 88% ee
O O
N N
Pr 21 Pr 22
Pr Pr
Scheme 16 Lewis base 21 catalyzed allylation
Amine N-oxides, possessing the property of Lewis basicity, have also been
exploited in an enantioselective allylation. Malkov and Kočovsky prepared a series
of chiral N-oxide catalysts and found, that ligands 23 and 25 afforded good yield
and stereoselectivity (Scheme 17) [49–51].
10 mol% catalyst
OH
1 equiv. Bu4NI
PhCHO + SiCl3
5 equiv. iPr2NEt Ph
MeCN
N N N N
O O O
67%, 92% ee (S) 57%, 41% ee (R)
N
O
N N OMe
O
iPr iPr
75%, 96% ee (S) 60%, 87% ee (R)

in CH2Cl2
Scheme 17 Enantioselective Allylation with axial chiral N-oxides
Mechanistic analysis suggests that the N-oxide activates the trichlorosilane func-
tionality and the other nitrogen atom stabilizes the complex by chelation, thus lead-
ing to closed chair-like transition state [49, 52]. Scheme 18 shows the possible
transition state.
N Cl OH
Si O
N O Ph
Cl Ph
H
Scheme 18 Proposed Intermediate
Hayashi et al. achieved high catalytic activity by using axially chiral N-oxide
catalyst 27. As compared to other organic catalysts, the reaction proceeded much
faster, and high enantioselectivities were obtained with 0.01–0.1 mol% catalyst
loading [53–55]. In 2005, Hoveyda and Snapper used a novel proline-based
aliphatic N-oxide 28 for an asymmetric allylation (Scheme 19) [56].
Ph
HO N
O 27
O
HO N
Ph
OH
SiCl3
ArCHO + 0.1 mol% 27 Ar
i Pr2NEt, MeCN up to 98% ee
up to 96%
28 O O
N N Ph
H
OH
SiCl3
RCHO +
10 mol% 28 R
CH2Cl2 up to 92% ee
up to 89%
Scheme 19 Allylation catalyzed with Lewis base 27 and 28
In addition, Iseki et al. reported a highly enantioselective allylation reaction with

aliphatic and unconjugated aldehydes. They used chiral DMF derivatives and
observed a dramatic increase in the yield and enantioselectivity of the reaction,
when a stoichiometric amount of HMPA was employed [57, 58].
Next, enantiopure silicon allylation reagent will be presented, which already
inherits Lewis acidity. It is accepted that Lewis acidity of silicon, as well as its high
tendency to expand valence shell, increases [59, 60] if it is tetravalent and incorpo-
rated into strained four- or five-membered ring systems (strain-release Lewis acid-
ity) [61]. This corresponds to smaller energy gaps between sp3 and dsp3 orbitals of
a strained system as compared to an acyclic species.
Leighton has combined this concept of strained silacycles [62–66] with the
asymmetric allylation chemistry in a series of publications [60, 67–70]. Leighton’s
allylic silacyclopentane 29 [67] (Scheme 20) works equally for allylation of aro-
matic and aliphatic aldehydes in the absence of additional Lewis bases (promoter
activator) or Lewis acids with high yield and enantioselectivity. The mechanism of
the reaction is not completely understood, but it likely involves a cyclic transition
state with a trigonal bipyramidal geometry at a pentacoordinated silicon [59, 70].
p-BrC6H4
CH2Cl2
N 10 °C OH
RCHO Si
Cl N 69% (R=Ph) R
93% (R=Cy) (S)-42 (R=Ph):
p-BrC6H4 98% ee
(S)-52 (R=Cy):
29
96% ee
Scheme 20 Allylation with reagent 29
Furthermore, next to aldehydes, acylhydrazones have been used in the allyla-

tion reaction. Kobayashi and coworkers found that achiral phosphineoxides cata-
lyze the allylation of acylhydrazone [71, 72]. Next, a method for an asymmetric
allylation of N-acylhydrazone with chiral BINAP dioxide 30 was developed
(Scheme 21) [71, 72].
O
PPh2
PPh2
O
NHBz NHBz
N 2 equiv. 30 HN
EtO SiCl3 EtO
H +
CH2Cl2 −78 C
O 91% O
98% ee
Scheme 21 Allylation with Lewis base 30
The synthesis of tertiary carbinamines is an important goal in organic synthesis.

Leighton reported allylation of benzoylhydrazone by using the allylic silane reagent
31 giving tertiary carbinamines with high enantioselectivity in 24 h (Scheme 22)
[70]. This reaction is exceptional, since high enantioselectivity was achieved with
the diastereomeric mixture of the allylating reagent 31. There may be two possible
explanations [60]. First, by using 1.5 equiv. excess of 31, only the major diastere-
omer transfers an allyl group and the minor remains unreactive. Second, the reac-
tion proceeds through a hypervalent silicon intermediate, which is prone to a
pseudorotational process. More likely the stereogenic silicon fast epimerizes and
only one diastereomeric intermediate transfers the allyl group.
Me
NHBz Me NHBz
N ∗N CHCl3, 40 C HN
+ Si
Cl O 91% Ph
Ph Et Ph
Et
31 dr = 67:33 89% ee
Scheme 22 Allylation with reagent 31

Imidazoles/benzimidazoles and chiral carbinamines are of particular impor-

tance [73, 74]. Recently, Leighton et al. developed a method for enantioselec-
tive imidazole directed allylation of aldimines and ketimines [75] with an
analogue of 31.
Next to P(O) or N(O) Lewis bases, there are very rare cases where enantiopure
sulfoxides are used in combination with silanes. Kobayashi and coworkers reported
a highly diastereoselective and enantioselective allylation of hydrazones with chiral
sulfoxide 32 (Scheme 23) [76]. Massa [77, 78] and Barness [79] reported the asym-
metric allylation of aldehydes with enantiopure sulfoxides, respectively, with
moderate selectivity.
O
Me S
p-Tol
NHBz
NHBz R1 SiCl3 3 equiv. 32 HN
N
R2 CH2Cl2, 78 °C R
R R2 R1
up to 99%
up to 99% ee
Scheme 23 Allylation with sulfoxide 32
In the following a few examples of the asymmetric aldol reaction are given. Silyl
enol ethers (O-Si) resemble very much allylsilanes (C-Si) in terms of structure and
mode of action. That is why Lewis base catalyzed aldol reactions of silyl enol
ethers have been extensively studied. The first example of Lewis base catalyzed
asymmetric aldol reaction of trichlorosilyl enol ether with chiral phosphoramide
[80–91] was reported by Denmark et al. (Scheme 24).
Ph
Ph N O
P N
Ph N
Ph
OSiCl3 O OH
10 mol% 33
+ PhCHO Ph
CH2Cl2, −78 °C
94%
anti:syn 1:97
53% ee (syn)
Me
Ph N O
P N
Ph N
Me
OSiCl3 O OH
10 mol% 34
+ PhCHO Ph
CH2Cl2, −78 °C
95%
anti:syn 65:1
93% ee (anti)
Scheme 24 Lewis base catalyzed aldol reaction

The coordination state of the silyl enol ether in the transition state strongly
influences the diastereoselectivity (syn/anti). If a ligand is sterically demanding,
like phosphoramide 33, a boat-like transition state with a pentacoordinated sili-
cate is formed and affords the syn product in the reaction of trichlorosilyl enol
ether with benzaldehyde. In contrast, the less hindered ligand 34 gave the anti
product through a chair-like transition state with a hexacoordinated silicate
(Scheme 25).
Scheme 25 Proposed mechanism
Denmark utilized chiral base promoted hypervalent silicon Lewis acids for several
highly enantioselective carbon-carbon bond forming reactions [92–98]. In these
reactions, a stoichiometric quantity of silicon tetrachloride as achiral weak Lewis
acid component and only catalytic amount of chiral Lewis base were used. The
chiral Lewis acid species desired for the transformations was generated in situ.
The phosphoramide 35 catalyzed the cross aldolization of aromatic aldehydes as
well as aliphatic aldehydes with a silyl ketene acetal (Scheme 26) [93] with good
yield and high enantioselectivity and diastereoselectivity.
Me Me
N O O N
P P
N 5N
N N
Me Me
Me Me
5 mol% 35
O OSiMe2t Bu 1.1 equiv. SiCl4 OH O
R + CH2Cl2, −78 °C
OMe R OMe
(R= Ph) 86% (R= Cy)
(R= Ph): 93% ee
(R= Cy) 97% (R= Ph)
(R= Cy): 88% ee
Scheme 26 Cross aldolization

It was found that benzaldehyde reacts with E and Z configured silyl ketene acetals
to furnish identical aldol products [93] with high enantioselectivity. Neither diastere-
oselectivity nor enantioselectivity were affected by double bond geometry of the silyl
ketene acetal. This is an evidence for an acyclic transition state (Scheme 27).
Scheme 27 Cross aldolization with trisubstituted silyl ketene acetals
Catalytic amounts of 35 (1 mol%) also promoted the reaction of aromatic alde-

hydes with silyl ethers [94], vinylogous silicon enolates [95] and even with isocy-
anates in the presence of stoichiometric amount of SiCl4 [98]. The products were
isolated in high yield and enantioselectivity.
Next to phosphoramides, Denmark reported an axially chiral N-oxide to catalyze
the asymmetric aldol reaction of trichlorosilyl enol ethers with ketones [99].
Hashimoto reported an aldol reaction with 3 mol% of another axially chiral N-oxide
[100] which gave good yields and enantioselectivities.
Next, a few examples of asymmetric reductions with trichlorosilane are pre-
sented. An asymmetric reduction of ketones and imines was reported by Matsumura
and coworkers by using trichlorosilane as reductant and N-formyl pyrrolidine
derivative 36 as ligand (Scheme 28) [101, 102].
Scheme 28 Reduction of ketones and imines

Later, Malkov and Kočovsky reported the asymmetric reduction of imines

with N-methyl L-valine derivative 37 with high yield and enantioselectivity
(Scheme 29) [103].
HN
HN O
O
H
10 mol% 37
NPh 1.5 equiv. Cl3SiH NHPh
Ph Me CHCl3 Ph Me
94% 92% ee
Scheme 29 Reduction with catalyst 37
Next to the above presented use of SiCl4 for the in situ preparation of a Lewis
acid catalyst with a Lewis base for the aldol reaction, it is possible to apply this
compound as a reagent in the ring opening of epoxides leading to chlorinated
alcohols. Denmark [104] reported that the chiral phosphoramide 38 catalyzed the
asymmetric ring opening reaction of meso-epoxides in the presence of tetrachlo-
rosilane. Similar examples were provided by Hashimoto in 2002 [105], applying
the N-oxide 39 as catalyst (Scheme 30).
Scheme 30 Epoxide ring opening

Later in 2005, Hashimoto [106] reported the asymmetric ring opening reaction
of cyclohexane oxide with catalyst 30 and afforded the corresponding chlorohydrin
in high yield and enantioselectivity (Scheme 31).
Scheme 31 Epoxide ring opening catalyzed with Lewis base 30
Extending the application of his strained silacycle reagents, Leighton et al.

described a method for the enantioselective Friedel-Crafts alkylation with benzoyl-
hydrazones, catalyzed by an extraordinarily simple chiral silane Lewis acid. The
salient features of the chiral silane are: it can be prepared in bulk in a single step
from (S,S or R,R) pseudoephedrine and PhSiCl3, and after employing it in a reac-
tion, pseudoephedrine can be recovered in nearly quantitative yield during the
workup. The best example is shown in Scheme 32 in which, by employing chiral
silane 40, 92% yield and 90% ee of the product were achieved in 48 h [107].
Scheme 32 Enantioselective Friedel-Crafts alkylation
The catalyst, although applied in 1.5 equiv., also worked well with heteroarenes
in the alkylation reactions. A simple and most plausible mode for the enantioselec-
tivity of the Friedel-Crafts reaction has been shown in Scheme 33. It is evident from
the model that the arene would approach from the front (Si) face, as the back (Re)
face is blocked by the phenyl group present on the silicon.
ArH
CO2iPr
ArH
N N
Ph Si Ph
O
O N H Cl
Ph

Inspired by the previous results, Leighton et al. reported the enantioselective

[3 + 2] acylhydrazone-enol ether cycloaddition reaction by employing the same
pseudoephedrine-based chiral silane. The pyrazolidine product was obtained in
61% yield with 6:1 dr and 77% ee in 24 h. The use of tert-butyl vinyl ether led to
an improvement in both diastereoselectivity and enantioselectivity as shown in
Scheme 34 [108].
Ph O Ph
Si
Me N Cl
Me
Bz
NHBz 1.5 equiv.(S,S )−40 Ph HN N
Ph N ~2:1dr
OEt +
CH2Cl2, 23 °C OEt
H
61%
6:1 dr, 77% ee
Bz
NHBz 1.5 equiv. (S,S ) −40 Ph HN N
Ph N ~2:1 dr
Ot Bu + OtBu
H toluene, 23 °C
84%
96:4 dr, 90% ee
Scheme 34 Enantioselective [3+2] cycloaddition
In 2006 Leighton et al. reported that a chiral ligand carrying three functional
groups for attachment to tetrachlorosilane, proved to be a good ligand for the
efficient silane catalyst 42 in the cycloaddition reaction of enals with cyclopen-
tadiene. The catalyst was generated in situ by treatment of 41 with SiCl4 and
DBU in 4 h (Scheme 35) [109]. It was possible to assign the relative configura-
tion of compound 42 at the silicon center by the observation of NOE interactions
(Scheme 37).
Scheme 35 Preparation of 42
Simple changes to a sulphonamide group and substituents on the phenols pro-

duced a dramatic effect on the enantioselectivity in the reaction (Scheme 36).
p - Tosyl SO2Me
N N
Cl Cl
Si Si
N O N O
H t Bu
42a 42b
H t Bu
78 %, 94% ee (S) 75 %, 75% ee (R )
CHO
Me CHO 20 mol% 42a-b
+
CH2Cl2, −78 °C Me
Scheme 36 Diels-Alder reaction catalyzed by 42
It was proven that a five-membered strained ring is an essential component for

the Lewis acidity. Thus silane 43, being six-membered, is strain free and showed
no catalytic activity under identical reaction conditions (Scheme 37).
Ts
NOE N Cl
Si
t -Bu N O
H
H O t Bu
Ts N Si
H t Bu
Cl 43
t Bu
Scheme 37 Determining ring strain
The proposed mechanism is depicted in Scheme 38. The aldehyde is activated

due to coordination on the silicon atom. A hydrogen bond between the aldehyde
function and the benzyl substituted tertiary nitrogen atom stabilizes the transition
state, and the benzyl group ensures that the cyclopentadiene attacks the dienophile
only from one side.
Ts N Ts N
O N O N
Si Si CHO
Cl Cl
O
O H H
Finally, a few examples of the Morita-Baylis-Hillman reaction are provided,

where a silyl species functions as a Lewis acid co-catalyst. These examples could
have been presented in the previous section about silyl cation-based catalysts. Since
the enantiomeric induction originated in the present examples from a Lewis base,
we have listed these examples in this section.
The promoters of the so-called chalcogenide Morita-Baylis-Hillman reaction are

Kataoka and co-workers who employed sulfide and TiCl4 for dual Lewis acid-base
activation. Later, in 1996 the ability of the combination of sulfide/TBDMSOTf to
promote the reaction was reported [110]. Asymmetric version of the Baylis-Hillman
reaction has been achieved by using chiral sulfide in place of SMe2. The best ee was
94% in combination with a high yield of 88% in 5 h (Scheme 39) [111].
Scheme 39 Sulfide 44 catalyzed Morita-Baylis-Hillman reaction
In summary, it is possible to state that the field of the Lewis base catalyzed reactions
involving silane reagents is very well established and high enantioselectivities can be
obtained for several examples. As pointed out above, the research field has been only
briefly discussed in this review, since it is considered to be a Lewis base catalyzed
domain. Since the reactive intermediate is a Lewis acid, it was decided to discuss it in
the context of this article. Considering the examples where the silane reagent was
replaced by SiCl4 to generate in situ an active Lewis acid catalyst, one could argue that
it is also possible to place the reactions under the category of Lewis acid catalyzed reac-
tions. The presented example of the catalyzed Diels-Alder reaction with strained five-
membered silanes belongs undoubtedly to the field of Lewis acid organocatalysts.
4 Phosphonium Cation-Based Catalysts
In 2006 Terada and Kouchi reported the investigation of phosphonium salts in cataly-
sis [112]. A pentacoordinated phosphorus atom is a hypervalent [113] atom, which
has a formal valence shell of more than eight electrons. As shown in Scheme 40, it is
possible for the lower lying s* orbital of a P+ -EWG (Electron Withdrawing Group)
bond to take up a free electron pair of a Lewis base, in order to form a new bond. If
the new formed bond is trans to the EWG, the formed complex is more stable.
EWG EWG EWG

+ LB
P R P R or LB P R
R RR − LB R R
LB R
σ* P-EWG
Scheme 40 Hypervalent phosphorus atom

The authors prepared a series of different phosphonium salts of which a few

examples are given below. All incorporated electron withdrawing groups as shown
in Scheme 41.
CF3
O O O
CF3
P P P
OTf O OTf O OTf
44 45 46
CF3
O O O
P CF3
P P
OTf O OTf O
47 48 49 OTf
Scheme 41 Phosphonium salts
The salts were prepared from hydroxy phosphine oxides or phosphinates as

depicted in Scheme 42 after 1 h. The reactions were carried out with trifluorometh-
anesulfonic anhydride in the presence of 4Å molecular sieves, and it was shown by
31
P-NMR due to downfield shifts that the phosphonium salts were formed. However,
the salts could not be isolated and were prepared in situ for NMR studies and for
the application in catalysis.
Scheme 42 Preparation of phosphonium salts
In NMR investigations of the salts with DMF, it was possible to observe a shift
change in the case of salts 45 and 48. The other salts revealed no change. It appeared
that the five-membered ring of the catechol substituent is crucial for a high reactivity.
It is known that cyclic five-membered phosphorus compounds possess an enhanced
reactivity [114, 115]. Salt 45, incorporating two 5-membered rings, showed a stronger
interaction with DMF than salt 48. As shown in Scheme 43, an NOE was found
between the C3-proton of the catechol moiety and the formyl proton of DMF.
OTf
O
H
P O
O H
NOE 6.7 %
N
Me Me
Scheme 43 Mode of activation

The authors investigated the salts in the Diels-Alder reaction. In analogy to the
NMR experiments similar reactivities were found. As presented in Scheme 44, the
salts gave up to 91% yield in high endo-selectivity with cyclopentadiene and an
unsaturated amide in 4 h. The highest yield was obtained with salt 45, while for
example salt 47 gave only 7% and salt 49 gave only traces.
Scheme 44 Phosphonium salt catalyzed Diels-Alder reaction
By 1989 Mukaiyama had already explored the behaviour of phosphonium salts

as Lewis acid catalysts. It was possible to show that the aldol-type reaction of alde-
hydes or acetals with several nucleophiles and the Michael reaction of a,b-unsatu-
rated ketones or acetals with silyl nucleophiles gave the products in good yields
with a phosphonium salt catalyst [116]. In addition, the same group applied
bisphosphonium salts as shown in Scheme 45 in the synthesis of b-aminoesters
[117]. High yields up to 98% were obtained in the reaction of N-benzylideneaniline
and the ketene silyl acetal of methyl isobutyrate. Various analogues of the reaction
partners gave similar results. The bisphosphonium salt was found to be superior to
Lewis acids like TiCl4 and SnCl4, which are deactivated by the resulting amines.
Scheme 45 A bisphosphonium salt catalyzed reaction
Furthermore, phosphonium salts have been applied as catalysts in the TMSCN addi-
tion to aldehydes [118] and ketones [119]. Methyltriphenylphosphonium iodide [118]
was found to be a reasonably active catalyst for the addition of TMSCN to aldehydes
at room temperature by the group of Plumet. In general, the yields varied between 70%
and 97% in 24 h, depending on the aldehyde, applied in the reaction (Scheme 46).
However, the salt did not support the addition of TMSCN to ketones, with one excep-
tion, when the highly reactive cyclobutanone was applied in the reaction [120].
Scheme 46 TMSCN addition to aldehydes
In order to extend the reaction to further ketones, it was found by the group of
Tian [119], that benzyltriphenylphosphonium chloride was a suitable phosphonium
salt-based catalyst which gave the desired product in 92% yield in the reaction of
2-heptanone with TMSCN in 24 h (Scheme 47). The authors could show that it was
essential to apply the chloride salt in the reaction. In the case where a bromide
analogue was used, only a yield of 2.6% was found.
O 5 mol% [Ph3PBn][Cl] NC OTMS

+ TMSCN
CHCl3, rt
92%
Scheme 47 TMSCN addition to ketones
In the phosphonium iodide and chloride salt catalyzed TMSCN addition on

aldehydes and ketones, a double activation should exist. Not only the activation of
the ketones or aldehydes with the phosphonium cation is necessary, but also the
activation of the TMSCN by the soft Lewis base [I] or the harder Lewis base [Cl],
which can form a pentavalent silicon intermediate [121].
Phosphonium salts have also been used as co-catalysts in the DABCO catalyzed
Baylis-Hillman reaction of methyl acrylate with benzaldehyde [122]. Good results
were obtained with triethyl-n-butylphosphonium tosylate with up to quantitative
yields in some cases. The authors proposed that the phosphonium salt is rather
stabilizing the intermediate 50, shown in Scheme 48, and increasing therefore its
concentration rather than activating the benzaldehyde.
Scheme 48 Phosphonium Salts as co-catalysts in the Baylis-Hillman reaction
Finally, achiral phosphonium salts have been applied as Lewis acid catalysts in
some other reactions. The examples will be listed here but not discussed in more
detail. Phosphonium salts have been used as catalysts for the N,N-dimethylation of
primary aromatic amines with methyl alkyl carbonates giving the products in good
yields [123]. In addition acetonyltriphenylphosphonium bromide has been found to
be a catalyst for the cyclotrimerization of aldehydes [124] and for the protection/
deprotection of alcohols with alkyl vinyl ethers [125, 126]. Since the pKa of the salt
is 6.6 [127–130], the authors proposed that, next to the activation of the phospho-
nium center, a Brønsted acid catalyzed pathway is possible.
In summary, there are now several examples of phosphonium salt-based Lewis

acids as catalysts known, which have shown a good catalytic activity. However, an
asymmetric catalyzed reaction with an enantiopure phosphonium salt has not been
reported yet.
5 Carbocation-Based Catalysts
During the past decades, the scope of Lewis acid catalysts was expanded with several
organic salts. The adjustment of optimal counter anion is of significant importance,
while it predetermines the nature and intensity of catalytic Lewis acid activation of
the reactive species. Discovered over 100 years ago and diversely spectroscopically
and computationally investigated [131–133], carbocations still remain seldom repre-
sented in organocatalysis, contrary to analogous of silyl salts for example. The first
reported application of a carbenium salt introduced the trityl perchlorate 51
(Scheme 49) as a catalyst in the Mukaiyama aldol-type reactions and Michael trans-
formations (Scheme 50) [134–142].
Ph
Ph X = TrX
Ph
51
X = ClO4,TfO, SbCl4, BF4
Scheme 49 Carbocation based salt 51
Scheme 50 Carbocation catalyzed reactions

The reactions proceeded efficiently under mild conditions in short time. The
silyl enol ethers reacted with the activated acetals or aldehydes at –78 °C to give
predominant erythro- or threo-products [136, 137] respectively. In the same man-
ner, the aldol reaction of thioacetals, catalyzed by an equimolar amount of cata-
lyst, resulted in g-ketosulfides [139] with high diastereoselectivity. In the course
of this investigation, the interaction of silyl enol ethers with a,b-unsaturated
ketones, promoted by the trityl perchlorate, was shown to proceed regioselec-
tively through 1,2- [141] or 1,4-addition [138]. The application of the trityl salt
as a Lewis acid catalyst was spread to the synthesis of b-aminoesters [142] from
the ketene silyl acetals and imines resulting in high stereoselective outcome.
The undefined mechanism of the aldol-type Mukaiyama and Sakurai allylation
reactions arose the discussion and interest in mechanistic studies [143–145].
The proposed mechanism was proved to proceed through the catalytic activation of
the aldehyde and its interaction with the silyl ketene acetal or allylsilane producing
the intermediate. From that point the investigation is complicated with two possible
pathways that lead either to the release of TMS triflate salt and its electrophilic
attack on the trityl group in the intermediate or to the intramolecular transfer of
the TMS group to the aldolate position resulting in the evolution of the trityl catalyst
and the formation of the product (Scheme 51). On this divergence, series of experi-
mental and spectroscopic studies were conducted.
Me3SiO O TrO O
+ Me3SiOTf
Ph Ph
O OSiMe3
Ph Tr
O TrO OSiMe3
H
TrOTf OTf
Ph H Ph OTf
Me3
Me3SiO O Si
TrO O
OTf
Ph
Ph
The valuable and versatile study was conducted by the group of Bosnich [143]. The
defined nature and amounts of by-products in the reaction mixture allowed to judge
about the possible mechanism of the catalysis. It was proved that the aldolization and
allylation reactions proceed with the evolution of TMS salt that is itself a strong Lewis
acid and can catalyze the reaction in high rate (Scheme 52). The possible sources of
the TMS salt production in the reaction medium were investigated. The utilization of
a hindered base suppressed the influence of the silyl salt, and the rate of the reaction
was dramatically diminished. This consequence was considered to confirm that the
TMS salt can catalyze the reaction even in the undetectable quantities of 10−7 mol.
O OSiMe3
Ph SiMe3
O Me3SiO OSiMe3 Me3SiOTf Me3SiO O
H OTf
Me3SiOTf
Ph H Ph OTf Ph
Scheme 52 Trimethylsilyl catalyzed reaction
The further investigation of functionalized trityl cations with different counter

anions and TMS or TBS enolates, conducted by Chen [145], introduced the diben-
zosuberone-derived salt 52 [146] as a catalyst (Scheme 53).
X
X = Cl, SbCl6
t Bu 52
Scheme 53 Salt 52
The TBS ketene acetal was proposed to be the preferable silyl component, while
the rate of the TBS transfer to the aldolate group of the product decreased and did
not overtake the slow-acting carbenium catalysis (Scheme 54).
O OTBS OTBS O
20 mol% 52
+
Ph H O EtNO2 / CH2Cl2 Ph
O
(1 / 5)
−78 °C
anti/syn (55 / 45)
63%
Scheme 54 Salt 52 catalyzed Mukaiyama aldol reaction
The next investigation conducted by the group of Chen [147], involved the chiral
trityl salt 53 and thus brought clearness to a certain extent in the understanding of the
mechanism of the catalysis (Scheme 55). Since enantiomeric excess was achieved, the
carbenium-mediated catalysis should not be disregarded. The correlation of the results
manifested the concurrence of the catalytic species and dependence of their participa-
tion in the catalysis on the silyl substituents and counter ions in the trityl salts.
Et Et
Ar ClO4
53
Scheme 55 Enantiopure carbocation based salt 53
Over a reaction period of 3–6 h (Scheme 56) the enantioselectivity of the aldoli-
zation catalyzed by 53 decreased from 24% to 11% along with the increase of yield
from 52% to 99%. The decrease of the enantioselectivity with prolongation of reac-
tion time indicates the prevailing of the silyl-mediated catalysis, due to the slow
metathesis between tritylated aldolate and silyl salt. The best enantioselectivity of
50% together with just 22% yield was achieved when 1 equiv. of catalyst 53 was
used. This experiment points out the slow consumption of trityl ions as well as the
low rate of the silyl substitution of the trityl aldolate.
O OTBS 1 equiv. 53 OH O
+ ∗
Ph H OEt CH2Cl2, −78 °C Ph OEt
20%
50% ee
Scheme 56 Asymmetric Mukaiyama aldol reaction
The estimation of the conditions, suppressing the silyl-mediated catalysis and

preferable for the carbenium-promoting catalysis, is of significant importance to
introduce the chiral information in the product. Since it was observed that a carbe-
nium salt promoted the reaction and thus provided the enantioselectivity in the
outcome, the rigid conformation and the enhanced reactivity of the carbocation
may be the key requirement for the productive enantioselective carbenium catalysis
in the aldol-type additions.
The catalytic activity of the trityl moiety was unobjectionably adjusted in the
addition reaction of the allylstannanes to aldehydes [148]. In this allylation process
the trityl chloride 52, due to its disposition to partially ionic character of the halo-
gen bonding, was employed as a catalyst in the complementary tandem with weak
Lewis acid TMSCl (Scheme 57). The excess of the silyl component was necessary
in order to release the trityl catalyst from the intermediate to complete the catalytic
cycle. The achieved yield was 93%, when trityl chloride 52 was used.
O 20 mol% 52−Cl OH
+ SnBu3
TMSCl
Ph H Ph
CH2Cl2, 0 °C
93%
Scheme 57 Salt 52 catalyzed allylation
In order to enhance the catalytic activity of a carbocationic center, the novel

Lewis acid 54 was designed by Mukaiyama [149–152]. The 1-oxoisoindolium-
based carbenium salt 54 [149], possessing a weak coordinating borate counter
anion, proved to be a very active catalyst in the aldolization (Scheme 58) [150]. The
Mukaiyama aldol reaction was catalyzed by 1 mol% of salt 54 and proceeded in up
to 97% yield in 30 min.
N O
MeO
Me B(C6F5)4
1) 1 mol% 54
OTMS OH O
CH2Cl2, −78 °C
PhCHO + BnO
OMe 2) HCl aq, THF Ph OMe
97 % OBn
Scheme 58 Salt 54 catalyzed Mukaiyama aldol reaction

The catalytic activity of the oxoisoindolium salt 54 and 55 was compared to that
of trityl tetrakis[pentafluorophenyl]borate salts in the addition reaction of enol
acetate to benzaldehyde and glycosylation reaction (Scheme 59) [151, 152].
Scheme 59 Carbocation based salt 55 catalyzed glycosylation reaction
The utilization of compound 54 in the aldolization showed higher yield of the

product (92%) after 30 min, compared to that (73%) of a trityl catalyzed reaction.
The similar results were obtained in the glycosylation reaction: 85% (a/b ratio
9:91) and 72% (a/b ratio 10:90) respectively. The application of the highly hin-
dered tetrakis[pentafluorophenyl]borate anion is remarkably advantageous for the
stabilization of the positive charge in the carbocation 54 and at the same time pro-
motion of its accessibility to the interaction with a carbonyl species.
The development of the stable a-ferrocenyl carbocations 56 prompted the fur-
ther investigation of the carbenium salts in the Lewis acid catalyzed reactions
(Scheme 60). The group of Kagan [153–155] designed the o-substituted ferrocenyl
scaffold that allowed to avoid the placement of two aryl groups on the carbocation
and provided the stabilization and asymmetry, preventing the isomerization by the
facile rotation about the carbenium center. Being exploited in the Diels-Alder reac-
tion of cyclopentadiene with methacrolein, the catalyst 56 displayed a perfect
exo/endo diastereoselectivity of up to 99:1 in the presence of 4 Å MS resulting in
nearly quantitative yield (Scheme 60).
p-Tol
H
Ph
Fe
OTf
56
+ +
Me CHO CH2Cl2, −35 °C Me CHO
99%
CHO Me
99 :1
rac
Scheme 60 Ferrocene based salt 58 catalyzed Diels-Alder reaction

In contrast to these results, the group of Sammakia [156] reported that the reac-
tion can be actually catalyzed by the protic acid TfOH, released either by the
decomposition of the carbenium salt or by the nucleophilic attack of the diene on
the cation center with evolution of the proton.
Supplementary studies of the mechanism were conducted. The dependence of
the reaction rate on the nature of environment at the cationic carbon has shown that
the concurrent formation of the protic acid proceeds, if the substituents can undergo
the isomerization (Scheme 61), and thus the carbenium catalysis is utterly negligi-
ble. It was shown that the reaction was still catalyzed, even when a base was added
in order to rule out a TfOH catalyzed reaction. Obviously, the protonated base was
then a catalyst.
OTf
Fe Ph H − TfOH Fe Ph H
Scheme 61 Release of TfOH
While the ambiguity of the catalysis of the Diels-Alder reaction needs to be

carefully elucidated, the application of the ferrocenyl carbocations in the Mukaiyama
aldolization turned out evidently to be unrealisable due to their interaction with the
TMS enol ether that produces TMSOTf, which proved readily to catalyze the
aldolization [154].
Due to the extensively represented oxidative behaviour of the carbenium ions as
hydride abstractor or one-electron oxidant [157], attempts were made to employ the
carbocations as reagents. Recently the enantioselective outcome in a hydride trans-
fer reaction was reported [158, 159]. The abstraction of the exo hydrogen atoms
from the tricarbonyliron complex 57 resulted in a yield up to 70% and enantiose-
lectivity of 53% (Scheme 62) [158].
CO PF6 CO CO
OC CO OC CO OC CO
Fe Oi Pr Fe Oi Pr Fe Oi Pr
CH2Cl2 NaHCO3
+
iPrO i PrO 70%
O
53% ee
57 58 59 60
Scheme 62 Enantioselective hydride transfer reaction
The oxidative behaviour of the acridinium carbocations 61 was also explored by

the group of Lacour in the photoinduced electron transfer reaction [160]. In the
amount of 2 mol%, the achiral hindered acridinium salt 61 catalyzed the aerobic
photooxidation of the primary benzylic amine to benzylimine in the yield of 74%
(Scheme 63).
O
O
PrN
O
O BF4
2 mol% 61
Ph NH2 Ph NH
hv
74%
Scheme 63 Photo-oxidation catalyzed by salt 61
Finally, one example of trityl salt analogues in the phase-transfer catalysis is

presented. The highly stable triazatriangulenium cations 62 [161, 162] were just
recently introduced to the phase-transfer chemistry [163]. Persistent to strongly
basic and nucleophilic conditions, these salts revealed efficient catalytic activity in
addition reactions (Scheme 64). Modification of the alkyl side chains on nitrogen
allowed matching the fair hydro/lipophilicity with the optimised conditions in the
alkylation, epoxidation, aziridination and cyclopropanation reactions. The results
are comparable to those of tetrabutylammonium salts and in some cases showed
even a better outcome.
O O
10 mol% 62a CO2 Me
CO2Me
PhCH2Br Ph
CH2Cl2 / 50% KOH aq. R R
N N
20 °C, 99%
O O
10 mol% 62a O
N
Ph Ph 30% H2O2 Ph Ph
R
1 mol% Triton X-100
i Pr2O / 50% KOH aq. 62a R = (CH2)7CH3
20 °C, 44% 62b R = (CH2)2CH3
62c R = (CH2)5CH3
Cl
2 mol% 62b Cl
Ph
CHCl3 KOH
Ph
CH2Cl2, 40 °C, 68%
Cl
N Ts Ts
Na
N
2 mol% 62c
Ph
CH2Cl2 / H2O Ph
20 °C, 85%
Scheme 64 A stable triazatriangulenium based salt as phase-tranfer catalyst
So far, there has been only one example of a successful asymmetric catalyzed
reaction with an enantiopure carbocation-based salt. In this section it was possible
to learn, that a good understanding of a catalyzed reaction is necessary and that
possible achiral side reactions have a critical negative influence. Nevertheless,
carbocations can be highly active catalysts. However, this makes their application
sometimes difficult. One exception was the last presented example resembling a
moisture, base and nucleophilic stable trityl cation. In the next section ionic liq-
uids will be discussed, some of which can be also classified as carbocation-based
salts. However, they are far more stable but on the other hand possess a lower cata-
lytic activity.
6 Ionic Liquids
Ionic liquids, having per definition a melting point below 100 °C, and especially
room temperature ionic liquids (RTIL) have attracted much interest in recent years
as novel solvents for reactions and electrochemical processes [164]. Some of these
liquids are considered to be “green solvents” [165]. The scope of ionic liquids
based on various combinations of cations and anions has dramatically increased,
and continuously new salts [166–168] and solvent mixtures [169] are discovered.
The most commonly used liquids are based on imidazolium cations like 1-butyl-3-
methylimidazolium [bmim] with an appropriate counter anion like hexafluorophos-
phate [PF6]. Salts with the latter anion are moisture stable and are sometimes called
third generation ionic liquids.
The so-called second generation ionic liquids were prepared from organic cati-
ons and AlClx anions [170]. Since AlCl3 was present in these liquids, they were
used as catalysts in Lewis acid catalyzed reactions. Also many of the third genera-
tion ionic liquids have been used as solvents for catalytic reactions [171–174].
However, it is also known that third generation ionic liquids are capable of catalyz-
ing reactions, either in substoichiometric amounts or as reaction medium. This will
be discussed in this section.
There have been recently several reviews about the preparation and application
of chiral enantiopure ionic liquids [172, 175–177]. Unfortunately, often the evalu-
ation of the growing number of enantiopure ionic liquids concentrated more on
their behavior as chiral discrimination agents. Hence, the number of examples of
reactions catalyzed by enantiopure ionic liquids is rather small, and therefore this
section will also give an overview over catalyzed reactions with achiral ionic liq-
uids, rather than giving examples of enantiopure ionic liquids, which have not been
evaluated as reaction medium yet.
Examples, like the application of enantiopure ionic liquids in the copper cata-
lyzed enantioselective 1,4-addition of diethyl zinc to enones giving up to 76% ee,
will not be presented [178], since here the chiral ionic liquid, CIL, acts as a ligand
for a metal catalyzed reaction.
Furthermore, to clarify the difference between task specific ionic liquids (or also
called functionalized ionic liquids) and chiral ionic liquids, one very successful
example of a task specific ionic liquid 63 is presented in Scheme 65. This catalyst
with a loading of 15 mol% under neat conditions gave up to 100% yield and 99%
ee in the Michael addition of cyclohexanones to nitroolefins [179]. This catalyst
belongs to the field of the proline catalyzed reactions.
N N n Bu
N
H
63 BF4
Scheme 65 A task specific ionic liquid
In 1997 Howarth [180] reported the preparation of ionic liquids 65 and 66. They
reported that imidazolium cations can be used as Lewis acid centers in catalytic
amount rather than as solvent (Scheme 66). The bromide salts 65a and 66 were
prepared by a literature procedure [181] from TMS protected imidazole 64 and ethyl
bromide or (S)-1-bromo-2-methylbutane in refluxing toluene in 46 and 21% yield,
respectively. Salt 65a was converted into salt 65b with AgCF3COO in 89% yield.
Br
or
Br
N N N
or Br
N toluene, 110 °C N X N
TMS 65
64 a X = Br 66
AgCF3COO b X = CF3COO
Scheme 66 Preparation of chiral salt 66
The salts were investigated in the Diels-Alder reaction of crotonaldehyde with

cyclopentadiene (Scheme 67). The yields obtained were between 35% and 40%
with an endo:exo ratio of 90:10. The control reaction without the salt at −25 °C
gave no product. The observed ee with the enantiopure salt 66 was less than 5%.
Nevertheless, this was the first example which showed, that imidazolium-based
ionic liquids can be used in substoichiometric amounts as Lewis acid catalysts.
20 mol% 65 or 66
CHO −25 C
+ + CHO
CH2Cl2
CHO
Scheme 67 Ionic liquid catalyzed Diels-Alder reaction
Also the use of moisture stable ionic liquids as solvents in the Diels-Alder reac-
tion has been carried out, and in all examples an enhanced reaction rate was observed
[182, 183]. The application of pyridinium-based ionic liquids allowed the utilization
of isoprene as diene [184]. The chiral ionic liquid [bmim][L-lactate] was used as a
solvent and accelerated the reaction of cyclopentadiene and ethyl acrylate, however,
no enantiomeric excess was observed [183]. In addition several amino acid based
ionic liquids have been recently tested in the Diels-Alder reaction. Similar exo:endo
ratios were found but the product was obtained as racemate. The ionic liquids were
prepared by the addition of equimolar amounts of HNO3 to the amino acids [185].
Furthermore, an enantiopure imidazolium salt incorporating a camphor motive was
tested in the Diels-Alder reaction. No enantiomeric excess was found [186].
In order to investigate the origin of the catalytic activity of imidazolium-based

ionic liquids, the group of Welton [187] performed further studies, and it was pro-
posed that hydrogen bond activation plays an important part in the activation of a
dienophile in the Diels-Alder reaction. This was proposed due to observed hydro-
gen bonds between the imidazolium cation and the corresponding counter anion in
the salt. The reaction of methyl acrylate in the ionic liquid [bmim][BF4] with
cyclopentadiene gave the product in 72 h at 25 °C in 85% yield. When the
C2-methylated salt [bm2im][BF4] was applied as solvent, a similar yield of 84%
was obtained; however, the endo:exo ratio changed from 4.6 to 3.3. This was attrib-
uted to weaker hydrogen bond formation with the C4 and C5 protons compared to
the C2 proton in the first salt (Scheme 68).
endo:exo 4.6 endo:exo 3.3
Me MeO O H
MeO O
H H
N
+ H
+N Bu
N
Bu N
BF4 Me Me BF4
H
Scheme 68 Possible mode of activation
This would place imidazolium-based ionic liquids more to the hydrogen bond
activator organocatalysts. However, further studies by the group of Dyson showed
that when salt analogues with [NTf2] as the counter anion were used in the reaction,
the salt with a methyl group at the C2 position gave a better exo:endo selectivity,
indicating that hydrogen bonding capability is not the only reason for the activity
of the imidazolium ionic liquids, and other variables, like p-orbital interactions
have to be taken into account [188]. Recent calculations for an imidazolium salt
showed that the hydrogen bond of a C2-H of the imidazolium cation with a corre-
sponding counter anion is considerably different from that of conventional hydro-
gen bonds and not as strong as previously considered. The charge-charge interaction
of the ion pair was proposed to be the dominant interaction [189].
The ionic liquid [bmim][BF4] is known to catalyze the aza-Diels-Alder reaction
in the synthesis of pyrano- and furanoquinolines [190]. This reaction was also
catalyzed by the enantiopure bis-imidazolinium salt 67 in 67% yield with an
endo:exo ratio of 60:40 (Scheme 69) [191]. The product was obtained as a race-
mate. In addition the aza-Diels-Alder reaction with imines and Danishefsky’s
diene was catalyzed by the salt 67 giving racemic product. The salt and its ana-
logues could be easily prepared via the oxidation of the corresponding aminals
[192]. Investigation of the influence of the counter anion in achiral C2-substituted
imidazolinium salts, which can be also described as 4,5-dihydroimidazolium or
saturated imidazolium salts, in the aza-Diels-Alder reaction showed, that the cata-
lytic activity increased, the more lipophilic the counter anion and therefore the
more hydrophobic the salt was [193].
N N
N N
O
2 B[3,5−(CF3)2−C6H3]4
Ph O
N 10 mol% 67
+
Ph CH2Cl2 N Ph
67% H
Scheme 69 aza-Diels-Alder reaction catalyzed with salt 67
The chiral salt 68 has been recently prepared as shown in Scheme 70 in an over-
all yield of 60% from L-(-)ethyl lactate [194].
Me Me Me
BzBr, NaH LiAlH4
H OH H OBz H OBz
Et2O
CO2Et THF / DMF (2:1) CO2Et CH2OH
90%
89%
TsCl
pyridine
91%
N N Me Me
N N N [bmim][Br]
H OBz H OBz
BzO Br acetone, reflux 80 °C
CH2Br CH2OTs
68 86% 96%
Scheme 70 Preparation of Salt 68
The salt 69 was also prepared in a similar way from L-(+)-diethyl tartrate in an
overall yield of 44% (Scheme 71).
OBz N Br
N
N
Br N BzO
69
Scheme 71 Ionic liquid 69
The chiral ionic liquids 68 and 69 were tested in the Michael addition (Scheme
72) [194].
EtO2C CO2Et
O CO2Et O
10 mol% CIL
+
Ph Ph toluene, K2CO3 Ph * Ph
CO2Et
CIL 68 = 96%, 25% ee

CIL 69 = 95%, 10% ee
Scheme 72 Ionic liquid catalyzed Michael reaction

The salt 68 under solid phase transfer conditions gave a yield of 96% and 25%
ee at room temperature. Since the melting point of the CIL was over 40 °C, toluene
was used as a solvent. The influence of different anions in the salt was very low.
Compared to the [Br] counter anion, [PF6] resulted in 23% ee and [BF4] gave an ee
of 24%. When the polar solvents DMSO and DMF were investigated, a decrease of
the ee to 17 and 16% ee was observed. Salt 69 gave a lower ee of 10%. The enantio-
meric excess was determined by optical rotation.
Recently another enantiopure ionic liquid was tested in this reaction, and an ee
up to 15% was obtained with the ionic liquid 70 which was prepared in an overall
yield of 68% in two steps as shown in Scheme 73 [195].
Scheme 73 Preparation of ionic liquid 70
The achiral ionic liquid [bmim][BF4] was able to catalyze the three component reac-
tion of benzaldehyde, aniline and homophthalic anhydride in 90% yield. Next to the
major cis-isomer, 10% trans-isomer was isolated after 3 h (Scheme 74) [196]. Control
reactions in CH2Cl2 with 10 mol% [bmim][BF4] and without catalyst showed that in the
presence of the ionic liquid a high conversion in a short time was observed. Application
of polar solvents like methanol or acetonitrile made it necessary to increase the reaction
temperature to 70–80 °C, and the product was obtained in only 45–60% yield in a pro-
longed reaction time of 8–15 h. Further control reactions with [nBu4N][Cl] or [bmim]
[Cl] showed that the anion played a comparable important role as the cation, since no
product was formed. The author could demonstrate the generality of the reaction by the
application of a broad variety of benzaldehyde and aniline derivatives.
Scheme 74 Ionic liquid catalyzed three component reaction
The Biginelli reaction is also known to be catalyzed by the ionic liquids [bmim]
[BF4] and [bmim][PF6] under solvent-free conditions [197]. One example is shown
in Scheme 75. While a control reaction without ionic liquid gave no product, the
addition of just 0.4 mol% afforded a yield of 92% in 30 min. [Bmim][Cl] resulted
only in a yield of 56%, while [nBu4N][Cl] gave no yield. This indicated that both
the cation and the anion have an influence in catalyzing the reaction.
Scheme 75 Ionic liquid catalyzed Biginelli reaction
The imidazolium-based ionic liquid [bmim][BF4] has been used as a catalyst in

the aza-Michael reaction of various aliphatic amines to unsaturated compounds
with different electron withdrawing groups in good yields as shown in Scheme 76.
Water was used as the solvent in order to obtain up to 98% yield in 7 h. In the pre-
sented example, 95% yield in 7 h was achieved [198]. The ionic liquid could be
recovered and reused five times without loss of activity.
Scheme 76 Ionic liquid catalyzed aza-Michael reaction
The addition of thiols to a,b-unsaturated ketones with [bmim][PF6] in water was

investigated. It was found that product could be obtained in up to 95% yield in
10 min (Scheme 77) [199].
Scheme 77 Ionic liquid catalyzed thiol addition to a, b-unsaturated ketones
In addition, a Lewis acid behaviour was proposed in the cyclopropyl carbonyl

rearrangement catalyzed by [pmim][Br] as depicted in Scheme 78 [200]. The prod-
ucts were obtained in good yields up to 95% when stirred at rt in the ionic liquid.
By the application of sonication, the reaction time was decreased to 0.75 h.
Br Br
+ δ+ +
N N H N N
H11C5 Me O H11C5 Me
H
O
Ph Ph
Ph Ph
Ph −H2O Ph
Ph Ph
H
OH
Scheme 78 Ionic liquid catalyzed rearrangement

The ionic liquid [bmim][NTf2] catalyzed the aminohalogenation of electron-

deficient alkenes in good yields. This is the first time that this reaction was performed
in the absence of a metal catalyst. A representative example is presented in Scheme 79.
The authors found that the major regiomer was 71 [201].
Scheme 79 Ionic liquid catalyzed aminohalogenation of electrondeficient alkenes
The TMSCN addition on aldehydes has been reported to be catalyzed by the

ionic liquid [omim][PF6] [202]. The influence of the counter anion in activating the
TMSCN cannot be neglected, since the TMSCN addition on aldehydes can be also
catalyzed by a Lewis base. The imidazolinium-dithiocarboxylate 72 has been
recently shown to catalyze the reaction also in good yields up to 99% (Scheme 80)
[203]. One could assume, that the zwitterion incorporates a Lewis acid and Lewis
base center. The reaction did not proceed in the absence of the catalyst.
Scheme 80 TMSCN addtion to aldehydes catalyzed with zwitterion 72
Ionic liquids have been also explored in the Baylis-Hillman reaction [204–206].
The application of the enantiopure ionic liquid 73 in the Baylis-Hillman reaction by
Vo-Thanh [207] resulted in an enantiomeric excess of up to 44% with 1 equiv. of the
Lewis base catalyst DABCO (Scheme 81). It was shown that it was essential to have
a hydroxy group incorporated in the ionic liquid in order to obtain significant ee.
N C8H17
HO
Me OTf
O Ph 73 OH O
O
3 equiv.
+ OMe Ph OMe
Ph 1 equiv. DABCO
60%
44% ee
Scheme 81 Enantioselective Baylis-Hillman reaction in chiral ionic liquid 73
Recently the group of Leitner was able to achieve high enantioselectivities in the
aza-Baylis-Hillman reaction by the application of enantiopure ionic liquid with a
chiral anion (Scheme 82) [208].
CO2H CO2H
B
O O
Ts
Ts O NH O
N Me(C8H17)3N
+
10 mol% PPh3
39% Br
Br 84% ee
Scheme 82 Enantioselective aza-Baylis-Hillman reaction in a chiral anion based ionic liquid
Recently the group of D. W. Armstrong exploited the enantiopure ionic liquid 76

in the photoisomerization of dibenzobicyclo[2.2.2]octatrienes, and up to 12% ee was
reported (Scheme 83). The obtained ee was possible due to the addition of base in
order to deprotonate the carboxylic acid function of 74 resulting in a strong anion–
chiral cation interaction. In the absence of a base, lower values of ee were obtained,
and in the case that ester functions instead of carboxylic acid groups were present in
the molecule, only racemic product was found. Ionic liquid 77 gave up to 6.8% ee.
COOH HO 2C CO2 H
CO2H HO2 C
HOOC
CIL
+
NaOH
75
74
N
HO N
NMe3
Ph NTf2 O NTf2
76 77
12% ee 6.8 % ee
Scheme 83 A Photoisomerization in chiral ionic liquids 76 and 77
The enantiopure nicotinium-based ionic liquid 78 has been explored in the bio-
catalyzed kinetic resolution of 1-(4-methoxyphenyl)-ethanol with pseudomonas
cepacia lipase (Scheme 84) [209]. The ee obtained at room temperature without any
other co-solvent however was lower compared to other systems.
Me OH Me OH Me OAc
vinylacetate
Pseudomonas cepacia lipase
OMe N NTf2 OMe OMe

racemic Me Et 35% ee 69% ee
N 78
83% total recovery
Scheme 84 Kinetic resolution in chiral ionic liquid 78
Ionic liquids also showed a catalytic activity for the cyclocondensation of

a-tosyloxyketones with 2-aminopyridine [210], the nucleophilic substitution
of a-tosylketones with potassium salts of aromatic acids [211], the synthesis of aryl
hydrazones [212], the nucleophilic substitution reactions of highly functionalized
allyl halides [213], the alkylation of isobutene with 2-butene [214], the Nazarov cycli-
zation [215], the Pictet-Spengler reaction [216], the demethylation of N,N-
dimethylanilines with phenyl chloroformate [217], the alkylation of ammonium salts
[218], the aza-Michael reaction [219], the aza-Markovnikov’s addition with
N-heterocycles and vinyl esters [220], the ring opening of epoxides with thiophenols
[221], the a-halogenation of b-dicarbonyl compounds and cyclic ketones with
N-halosuccinimides [222], and the ring opening of epoxides with TMSCl [223]. The
listed examples were all carried out with achiral ionic liquids and will not be described
in further detail, since the presented achiral examples so far have already displayed in
general the catalytic activity of ionic liquids for different types of reactions.
Although the number of enantiopure ionic liquids as successful asymmetric
catalytic reaction media is still very limited, the research field has attracted con-
siderable attention. Due to the large number of possible applications in combina-
tion with the advantages of easy recoverability, the further development of the
field is very important. However, it shall be mentioned here that some reported
examples of catalytic activities of ionic liquids have to be investigated in more
detail. In particular, ionic liquids incorporating [BF4] and [PF6] have to be very
pure and normally should not be used with water for a prolonged time, since the
anions could decompose and release HF, which could be itself the cause of the
observed activity [164].
7 Miscellaneous Catalysts
Iodine has been reported to possess a mild Lewis acidity and can activate carbonyl
groups. It can for example catalyze the addition of pyrroles to a,b-unsaturated
ketones (Scheme 85) [224]. A mixture of pyrrol and 3 equiv. of ketone gave disub-
stituted products in up to 92% yield in 10 min with 10 mol% of iodine. In cases
when only 1.1 equiv. of ketone was applied in the reaction, mono- and disubstituted
products were isolated in few minutes in up to 95% yield in a ratio between 1:1 and
up to 1:5. N-Alkylated pyrroles also participated in the reaction in good yields.
O I2
+
N Ph N
H H I2
Ph O
N
H N
O Ph Ph O H Ph O
Scheme 85 Iodine catalyzed reaction

In addition, iodine successfully catalyzed the electrophilic substitution reaction

of indoles with aldehydes and ketones to bis(indonyl)methanes [225], the deprotec-
tion of aromatic acetates [226], esterifications [227], transesterifications [227], the
chemoselective thioacetalization of carbon functions [228], the addition of
mercaptans to a,b-unsaturated carboxylic acids [229], the imino-Diels-Alder
reaction [230], the synthesis of N-Boc protected amines [231], the preparation of
alkynyl sugars from D-glycals [232], the preparation of methyl bisulfate [233], and
the synthesis of b-acetamido ketones from aromatic aldehydes, enolizable ketones or
ketoesters and acetonitrile [234].
Iodine is known to catalyze the condensation of aldehydes, benzyl carbamate
and allyltrimethylsilane to homoallylic amines. However, in this case the involve-
ment of an in situ prepared [Me3Si] species was suggested to be the active catalyst
[235]. An iodine catalyzed acetalization of carbonyl compounds was reported,
where the active catalyst was believed to be hydroiodic acid [236].
Very recently, Ishirihara et al. [237] reported the application of a “chiral iodine
atom” through the reaction of NSI and a chiral nucleophilic phosphoramidite for
the halocyclization of homo(polyprenyl)arenes.
Next to iodine there is also another class of neutral Lewis acids known.
Tetracyanoethylene, dicyanoketene acetals and derivatives can catalyse reaction due
to their p-Lewis acid properties. They promoted the alcoholysis of epoxides [238],
tetrahydropyranylation of alcohols [239], monothioacetalization of acetals [240], and
carbon-carbon bond formation of acetals [241,242] and imines [243] with silylated
carbon nucleophiles.
Recently, Denmark reported, based on the Lewis base activation of Lewis acids
concept, a Lewis base catalyzed selenolactonization [244].
While the research filed of selenium catalyzed reactions appears to be promis-
ing, the application of iodine as a catalyst is of course limited, since the develop-
ment of an asymmetric version is not possible. Furthermore, much care has to be
taken, that the iodine is the active catalyst and not traces of HI.
8 Conclusion
It has been shown that metal-free Lewis acids have been applied as catalysts in a broad
variety of reactions. However, in several cases the asymmetric induction in the reactions
has to be improved. While many of the highly active salts are moisture sensitive, ionic
liquids with the right choice of cation and anion, are quite stable. Therefore their catalytic
Lewis acidic activity is weak. The research field presented still has much room for
improvement and further investigations and results are continuously reported in the
literature in an increasing number due to the large potential of metal-free Lewis acids.
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Top Curr Chem (2010) 291: 395–456
DOI: 10.1007/128_2009_1
Chiral Brønsted Acids for Asymmetric

Organocatalysis
Daniela Kampen, Corinna M. Reisinger, and Benjamin List
Abstract Chiral Brønsted acid catalysis is an emerging area of organocatalysis.

Since the pioneering studies of the groups of Akiyama and Terada in 2004 on the
use of chiral BINOL phosphates as powerful Brønsted acid catalysts in asymmetric
Mannich-type reactions, numerous catalytic asymmetric transformations involving
imine activation have been realized by means of this catalyst class, including among
others Friedel–Crafts, Pictet–Spengler, Strecker, cycloaddition reactions, transfer
hydrogenations, and reductive aminations. More recently, chiral BINOL phosphates
found application in multicomponent and cascade reactions as for example in an
asymmetric version of the Biginelli reaction. With the introduction of chiral BINOL-
derived N-triflyl phosphoramides in 2006, asymmetric Brønsted acid catalysis is
no longer restricted to reactive substrates. Also certain carbonyl compounds can be
activated through these stronger Brønsted acid catalysts. In dealing with sensitive
substrate classes, chiral dicarboxylic acids proved of particular value.
Keywords Asymmetric catalysis • BINOL • Dicarboxylic acids • N-Triflyl phos-

phoramides • Phosphoric acids • Strong chiral Brønsted acids
Contents
1 Introduction........................................................................................................................ 397
2 Chiral Phosphoric Acids.................................................................................................... 399
2.1 Pioneering Studies.................................................................................................... 399
2.2 Overview of Phosphoric Acids................................................................................. 403
2.3 Imines as Substrates.................................................................................................. 404
2.4 Other Substrates........................................................................................................ 434
3 Chiral N-Triflyl Phosphoramides....................................................................................... 441
4 Chiral Carboxylic Acids.................................................................................................... 450
5 Chiral Sulfonic Acids......................................................................................................... 453
6 Summary and Outlook....................................................................................................... 454
References................................................................................................................................ 454
D. Kampen, C. M. Reisinger, and B. List ()

Max-Planck-Institut für Kohlenforschung,
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
e-mail: list@mpi-muelheim.mpg.de
396 D. Kampen et al.
Abbreviations
Ac Acetyl
All Allylic substituent
Ar Aromatic substituent
BHT Butylated hydroxytoluene
BINAM 2,2¢-Diamino-1,1¢-binaphthyl
BINOL 1,1¢-Binaphthol
bmim 1-Butyl-3-methylimidazolium
Bn Benzyl
Boc tert-Butyloxycarbonyl
Bs Brosyl
tBu tert-Butyl
BV Baeyer–Villiger
Bz Benzoyl
cat Catalytic
Cbz Benzyloxycarbonyl
CSA Camphorsulfonic acid
Cy Cyclohexyl
DA Diels–Alder
DBU 1,5-Diazabicyclo[1.4.0]undec-5-ene
DCE 1,2-Dichloroethane
DFT Density functional theory
DHP 1,4-Dihydropyridine
DHPM 3,4-Dihydropyrimidin-2-(1H)-one
DMAP 4-Dimethylaminopyridine
dr Diasteriomeric ratio
ee Enantiomeric excess
equiv Equivalent(s)
Et Ethyl
EWG Electron-withdrawing group
h Hour(s)
HX Brønsted acid
HX* Chiral Brønsted acid
k Rate constant
M Metal
MCR Multicomponent reaction
Me Methyl
Mes Mesityl
min Minute(s)
MS Molecular sieves
NADH Nicotinamide adenine dinucleotide
Np Naphthyl
NuH Nucleophile
Chiral Brønsted Acids for Asymmetric Organocatalysis 397
p Para
Pent n-Pentyl
Ph Phenyl
PMB para-Methoxybenzyl
PMP para-Methoxyphenye
cPr Cyclopropyl
cPr Isopropyl
R Organic substituent
rac Racemic
RT Room temperature
TADDOL a,a,a¢,a¢-Tetraaryl-1,3-dioxolane-4,5-dimethanol
tert Tertiary
Tf Triflyl (trifluoromethanesulfonyl)
TMS Trimethylsilyl
TS Transition state
Ts Tosyl
VAPOL 4,4¢-Dihydroxy-2,2¢-diphenyl-3,3¢-biphenanthryl
1 Introduction
Chiral Lewis acid catalysts are powerful tools for asymmetric synthesis, combining
a metal or metaloid central atom with a chiral ligand [1, 2]. Such chiral Lewis acids
activate electrophiles 1 for a nucleophilic attack. Various metals can be used as the
center element (Scheme 1).
Y [M] M YH
Y NuH
− [M] R1 * Nu
R1 R2 M = chiral R1 R2 R2
Lewis acid
1
Y = O, NR3, lower LUMO
CH(EWG) than 1
Scheme 1 Lewis acid catalysis
Hydrogen would be the simplest center element. Indeed, chiral Brønsted acids
have emerged as a new class of organocatalysts over the last few years [3–13]. The
field of asymmetric Brønsted acid catalysis can be divided into general acid
catalysis and specific acid catalysis. A general acid activates its substrate (1) via
hydrogen bonding (Scheme 2, a), whereas the substrate (1) of a specific acid is
activated via protonation (Scheme 2, b).
H Y Y
Y
HX* H HX* 1
R1 1
R R 2 Y R R2
Nu
R2 1 1 1
R Nu
Y = O, NR3, R2 Y = O, NR3,
CH(EWG) CH(EWG)
+
NuH H
NuH Y
R2 NuH X*
Y HX* R1 R2
R1
a b
Scheme 2 Asymmetric Brønsted acid catalysis
t S
Bu
BnHN
N N
H H
O N
HO
2 t
Bu OMe
Jacobsen 1998
R R R
O O O O CO2H
P P
O OH O NHTf CO2H
R R R
(R )-3 (R )-4 (R )-5
Akiyama, Terada 2004 Yamamoto 2006 Maruoka 2007
Fig. 1 Chiral Brønsted acids
Brønsted acids such as thioureas 2 represent hydrogen-bonding catalysts.

Phosphoric acids 3, N-triflyl phosphoramides 4, and dicarboxylic acids 5 are exam-
ples of stronger specific Brønsted acids (Fig. 1).
In this review, we present asymmetric reactions catalyzed by stronger Brønsted
acids. The scope and limitations of chiral phosphoric acids, N-triflyl phospho-
ramides, and dicarboxylic acids are described considering articles published until
the middle of 2008. Although the mechanisms of a few transformations have been
investigated in some detail, they are not the focus of this review.
2 Chiral Phosphoric Acids
2.1 Pioneering Studies
Mannich reactions give rise to b-amino carbonyl compounds which are amenable
to further synthetic manipulations. Numerous stereoselective variants have been
achieved by means of different types of catalysts including both metal complexes
and organic molecules. In 2004, the groups of Akiyama and Terada independently
selected this transformation as a model reaction for the introduction of a novel
chiral motif to asymmetric catalysis [14, 15].
Axially chiral phosphoric acid 3 was chosen as a potential catalyst due to its
unique characteristics (Fig. 2). (1) The phosphorus atom and its optically active
ligand form a seven-membered ring which prevents free rotation around the P–O
bond and therefore fixes the conformation of Brønsted acid 3. This structural fea-
ture cannot be found in analogous carboxylic or sulfonic acids. (2) Phosphate 3
with the appropriate acid ity should activate potential substrates via protonation and
hence increase their electrophilicity. Subsequent attack of a nucleophile and related
processes could result in the formation of enantioenriched products via steren-
chemical communication between the cationic protonated substrate and the chiral
phosphate anion. (3) Since the phosphoryl oxygen atom of Brønsted acid 3 pro-
vides an additional Lewis basic site, chiral BINOL phosphate 3 might act as bifunc-
tional catalyst.
Phosphoric acids 3 bearing different aromatic substituents at the 3,3¢-positions
can be synthesized in a few steps starting from commercially available BINOL (6)
(Scheme 3). The key step involves a palladium-catalyzed cross-coupling of boronic
acid 7 and the respective aryl halide. Both the electronic and steric properties of
potential catalyst 3 can be tuned by a proper choice of the substituents at the 3,3¢-
positions. Besides a simple phenyl group, Akiyama et al. introduced monosubsti-
tuted phenyl derivatives as well as a mesityl group, whereas Terada and coworkers
focused on substituents such as biphenyl or 4-(2-naphthyl)-phenyl.
O O basic site
P
O OH Brønsted acidic site
Fig. 2 Brønsted acidic and basic R

sites of BINOL phosphates (R )-3
B(OH)2
OH OMe 1) RX, Pd(0)

OH OMe 2) BBr3
B(OH)2 R = aryl
(R)-6 (R)-7
R R
OH 1) POCl3 O O
P
OH 2) H2O O OH
R R
(R)-3
Scheme 3 Synthesis of BINOL phosphates according to Akiyama and Terada
The Akiyama group tested various BINOL phosphates 3 as catalysts for the
indirect Mannich reaction of aldimines 8 derived from 2-aminophenol with silyl
ketene acetals 9 (Scheme 4). All of these Brønsted acids furnished b-amino
ester 10a in (nearly) quantitative yields. Both the reaction rates (4–46 h) and the
enantioselectivities (27–87% ee) were strongly dependent on the nature of the
substituents at the 3,3¢-positions.
HO OH
OTMS
(R)-3 (30 mol%)
N + NH O
OMe toluene, −78 °C
Ph H Ph OMe
8a 9a 10a
R time [h] yield [%] ee [%]

R
H 22 57 0
O O
P 2,4,6-Me3-C6H2 27 >99 60
O OH
4-MeO-C6H4 46 99 52
R
(R)-3 4-NO2-C6H4 4 96 87
Scheme 4 Screening of catalysts
Phosphoric acid (R)-3d (10 mol%, R = 4-NO2-C6H4, Fig. 3) bearing p-nitrophenyl

substituents turned out to be the most powerful catalyst. It provided the desired
products 10 in good yields (65 to >99%), syn-diastereoselectivities (6:1 to >99:1)
and enantioselectivities (81–96% ee) (Scheme 5) [14].
R R
O O O O
P P
O OH O OH
R R
(R)-3 (R)-14
CF3 Me Me
Cl NO2 t
Bu
H
CF3 Me
a b c d e f g
h i j k l m
Me
i i
Pr Pr
i
Me Me
Pr Si
Me
i
Pr
i
Pr
Me Me
n o p q r
Fig. 3 Phosphoric acids derived from BINOL and H8-BINOL
OH
HO
OTMS
(R)-3d (10 mol%)
+ NH O
N OR3 toluene, −78 °C, 24 h
2 1
R R OR3
R1 H 2
R
8 9 10
R1 = aryl, 2-thienyl, R2 = alkyl, Ph3SiO 65 to >99%
PhCH=CH R3 = alkyl 6:1 to >99:1 syn/anti
81-96% ee
OH OH OH
NH O NH O NH O
OEt Ph OEt Ph OMe

S Me Bn OSiPh3
81%, 94:6 syn/anti 65%, 95:5 syn/anti 79%, >99:1 syn/anti
88% ee 90% ee 91% ee
Scheme 5 Mannich reaction of silyl ketene acetals

Detailed mechanistic investigations based on DFT computational studies were

disclosed by Yamanaka and Akiyama et al. in 2007 [16].
Terada et al. found the direct Mannich reaction between N-Boc-protected aldi-
mines 11 and acetyl acetone (12) to be catalyzed by different phosphoric acids 3
(Scheme 6). Varying the aromatic groups at the 3,3¢-positions influenced the yields
slightly (88–99%), but the enantioselectivities to a high degree (12–95% ee).
Boc
Boc NH O
N O O (R)-3 (2 mol%)
+ Ph
CH2Cl2, RT, 1 h
Ph H
11a 12 O 13a
R yield [%] ee [%]

R
H 92 12
O O
P
OH Ph 95 56
O
4-Ph-C6H4 88 90
R
(R)-3 4-(2-naphthyl)-C6H4 99 95
Scheme 6 Screening of catalysts
Sterically demanding BINOL phosphate (R)-3i (2 mol%, R = 4-(2-naphthyl)-

C6H4, Fig. 3) led to superior results. It gave protected b-amino ketones 13 in high
yields (93–99%) and enantioselectivities (90–98% ee) (Scheme 7) [15].
Boc
Boc NH O
N O O (R)-3i (2 mol%)
+ R
CH2Cl2, RT, 1 h
R H
11 12 O 13
93-99%
R = aryl 90-98% ee
R yield [%] ee [%]
4-Br-C6H4 96 98
2-Me-C6H4 94 93
1-naphthyl 99 92
Scheme 7 Mannich reaction of acetyl acetone

After having proven that BINOL phosphates serve as organocatalysts for asym-
metric Mannich reactions, Akiyama and Terada et al. reasoned that the concept of
electrophilic activation of imines by means of chiral phosphoric acids might be
applicable to further asymmetric transformations. Other groups recognized the
potential of these organocatalysts as well. They showed that various nucleophiles
can be used. Subsequently, chiral phosphates were found to activate not only
imines, but also other substrates.
2.2 Overview of Phosphoric Acids
The development of new asymmetric transformations calls for the synthesis of new
chiral catalysts with different electronic and steric properties (Fig. 3). BINOL
phosphates 3 bearing aromatic substituents or a triphenylsilyl group at the
3,3¢-positions as well as its partially hydrogenated analogs 14 were prepared
according to the pioneers’ protocol or slightly modified procedures. While most of
the substituents are introduced by a Suzuki cross-coupling, the introduction of a
few groups requires a Kumada cross-coupling. The synthesis of Brønsted acids 3r
and 14r bearing triphenylsilyl substituents involves an O–silyl to C–silyl
rearrangement as the key step.
Furthermore, phosphoric acids 15, 16, 17, and 18 derived from TADDOL,[17]
VAPOL, BINAM[18] or a bis-BINOL as well as a bisphosphoric acid 19 were
synthesized according to modified protocols (Fig. 4).
RR
R
O O O O N O
R O Ph
R P P P
O OH Ph O OH N OH
O
R
RR
(R,R)-15 (R)-17
(R)-16
O
O O
O O
OR P RO O O
P O O P
HO O
HO OH
(R,R)-18
(R,R)-19
Fig. 4 Other phosphoric acids

2.3 Imines as Substrates
2.3.1 Friedel–Crafts and Related Reactions
The Friedel–Crafts reaction is one of the most important and versatile tools for the
formation of carbon–carbon bonds in the synthesis of substituted aromatic and
heteroaromatic compounds present in numerous natural products and drugs.
Catalytic asymmetric variants using either metal complexes or organic molecules
attracted considerable attention over the last few years.
In 2004, Terada and coworkers reported the first asymmetric phosphoric acid-
catalyzed Friedel–Crafts alkylation (Scheme 8). Aldimines 11 reacted with com-
mercially available 2-methoxy furan (20) in the presence of BINOL phosphate
(R)-3q (2 mol%, R = 3,5-Mes2–C6H3) to provide access to N-Boc-protected 2-furyl
amines 21 in high yields (80–96%) and enantioselectivities (86–97% ee) [19].
Boc
Boc O HN
N (R)-3q (2 mol%)
+ OMe O
DCE, −35 °C, 24 h R OMe
R H
11 20 21
R = aryl, 80-96%
2-furyl 86-97% ee
R yield [%] ee [%]
4-MeO-C6H4 95 96
3-Br-C6H4 89 96
2-naphthyl 93 96
2-furyl 94 86
Scheme 8 Friedel–Crafts alkylation of 2-methoxy furan
Noteworthy, the reaction could be carried out on a 1-g scale employing only 0.5
mol% of catalyst 3q without a considerable loss in reactivity and selectivity (one
example: 95% yield, 97% ee).
Diazoesters 22 have an electronically unique a-carbon atom. (Scheme 9) They
are commonly used for the formation of aziridines 23 from imines 24. The interme-
diate (25) resulting from the addition of a-diazoesters 22 to the latter (24) can
undergo elimination of the proton at the a-position prior to extrusion of molecular
nitrogen. This interrupted aza–Darzens reaction allows for the direct alkylation of
diazoesters 22 via cleavage of a carbon–hydrogen bond.
R2
N aza-Darzens
reaction R2
1 CO2R3 N
R CO2R3
H N R1
N
25 23
R2 H CO2R3 catalyst
N +
R1 H N2
R2 Friedel-Crafts-type R2
24 22 N HN
reaction
CO2R3 CO2R3
R1 R1
H N
N N2
25
Scheme 9 Mechanism of a Friedel–Crafts-type alkylation of a-diazoesters
In conjunction with their Friedel–Crafts alkylation, Terada et al. found phos-

phoric acid (R)-3m (2 mol%, R = 9-anthryl) bearing a bulky 9-anthryl group to
mediate the asymmetric Friedel–Crafts-type reaction of a-diazoester 22a with
N-acylated aldimines 26 (Scheme 10). a-Diazo-b-amino esters 27 were obtained in
moderate yields (62–89%) and very good enantioselectivities (91–97% ee) [20].
O
O
t
H CO2 Bu (R)-3m (2 mol%) HN R2
N R2 +
N2 toluene, RT, 24 h CO2t Bu
R1
R1 H
N2
26 22a 27
1
R = aryl 62-89%
R2 = 4-Me2N-C6H4 91-97% ee
R1 yield [%] ee [%]
4-F-C6H4 74 97
4-Ph-C6H4 71 97
2-MeO-C6H4 85 91
Scheme 10 Friedel–Crafts-type alkylation of a-diazoesters
While its precise role remains unclear, the catalyst 3m is supposed not only to
activate the electrophile (26), but also to lower the nucleophilicity of the amide
nitrogen atom (Fig. 5). The latter interaction may account for a chemoselective
Friedel–Crafts-type alkylation versus an aza-Darzens reaction.
Fig. 5 Possible transition state R2 R1

CO2R3
O N N N
H H
O O
P
O O
Two years after the discovery of the first asymmetric Brønsted acid-catalyzed
Friedel–Crafts alkylation, the You group extended this transformation to the use of
indoles as heteroaromatic nucleophiles (Scheme 11). N-Sulfonylated aldimines 28
are activated with the help of catalytic amounts of BINOL phosphate (S)-3k (10
mol%, R = 1-naphthyl) for the reaction with unprotected indoles 29 to provide
3-indolyl amines 30 in good yields (56–94%) together with excellent enantioselec-
tivities (58 to >99% ee) [21]. Antilla and coworkers demonstrated that N-benzoyl-
protected aldimines can be employed as electrophiles for the addition of
N-benzylated indoles with similar efficiencies [22]. Both protocols tolerate several
aryl imines and a variety of substituents at the indole moiety. In addition, one example
of the use of an aliphatic imine (56%, 58% ee) was presented.
SO2R2 R3
SO2R2 R3 HN
N (S)-3k (10 mol%)
+
1 N toluene, −60 °C, 10 min-5 h R1
R H H
NH
28 29 30
R1 = aryl, Cy R3 = H, 5-MeO, 56-94%
2
R = 4-Me-C6H4, 5-Me, 6-Cl, 5-Br 58 to >99% ee
4-Br-C6H4
Me Ts Ts
Bs HN HN
HN
Ph Cy
Cl NH NH
NH
83%, 99% ee 91%, 94% ee 56%, 58% ee
Scheme 11 Friedel–Crafts alkylation of indoles
Moreover, phosphoric acid (S)-3r (5 mol%, R = SiPh3) bearing a bulky triphe-

nylsilyl group turned out to be a suitable catalyst for the asymmetric Friedel–Crafts
alkylation of N-alkyl pyrroles 31 with N-benzoyl-protected aldimines 32 (Scheme
12) [23]. 2-Pyrrolyl amines 33 were obtained in high yields (66–97%) and moderate
to high enantioselectivities (42 to >99% ee).
The incorporation of a CF3 group into organic molecules often leads to
significant changes in physical, chemical, and biological properties of the parent
R3 Bz
Bz HN
N (S)-3r (5 mol%) R3
+ R1
N CHCl3, −60 °C, 23-26 h
R1 H N
R2 R2
32 31 33
R2 = alkyl 66-97%
R1 = aryl 3 42 to >99% ee
R = 3-Et, 2-Bu
Bz Bz Bz
HN HN HN Et
N N N
F Me MeO All MeO Me
96%, 85% ee 66%, 91% ee 89%, 76% ee
Scheme 12 Friedel–Crafts alkylation of pyrroles
compound. Therefore, trifluoromethylated compounds have attracted considerable

attention in organic synthesis, medicinal and agrochemistry. In 2008, Ma et al.
applied imines 34 generated in situ from trifluoroacetaldehyde methyl hemiacetal
(35) and aniline 36 to an asymmetric Friedel–Crafts alkylation of unprotected
indoles 29 catalyzed by phosphoric acid (S)-3o (10 mol%, R = 2,4,6-iPr3-C6H2)
bearing 2,4,6-triisopropylphenyl substituents at the 3,3¢-positions of the binaphthyl
scaffold (Scheme 13) [24]. A range of substituted indoles 29 furnished the
F3C H
NH2 N
OH OMe
(S)-3o (10 mol%)
R R
F 3C OMe MeO OMe N 4 Å MS, CH2Cl2 N OMe
H RT, 24-96 h H MeO
OMe
35 36 29 37
R = alkyl, OMe, CO2Me, F, Cl 80-99%
79-98% ee
Ar Ar
HN − H 2O N
via:
F3 C OH F3C H
34
Ar = 3,4,5-(MeO)3-C6H2
F 3C H F 3C H F3 C H OH F2HC H
N N N with: N
Ar Ar Ar * Ar
F2HC OMe
Me
N 38
N N N
H H H H
Et
99%, 94% ee 99%, 98% ee 80%, 79% ee 99%, 94% ee
Scheme 13 Three-component Friedel–Crafts alkylation of indoles

Fig. 6 Proposed transition state H Ar

O O N
* P
O O H CF3
H N
corresponding trifluoromethyl-containing 3-indolyl amines 37 in high yields (80–

99%) along with good to excellent enantioselectivities (79–98% ee). The
methodology was further extended to the use of difluoroacetaldehyde methyl
hemiacetal (38).
Notably, the aminoalkylation reaction did not occur with N-protected indoles
revealing the crucial role of the free N–H group for the activation by the phos-
phoric acid. This prompted the authors to postulate the transition state model
depicted in Fig. 6.
2.3.2 Pictet–Spengler Reactions
The Pictet–Spengler reaction is the method of choice for the preparation of tetrahydro-
b-carbolines, which represent structural elements of several natural products such
as biologically active alkaloids. It proceeds via a condensation of a carbonyl com-
pound with a tryptamine followed by a Friedel–Crafts-type cyclization. In 2004,
Jacobsen et al. reported the first catalytic asymmetric variant [25]. This acyl-Pictet–
Spengler reaction involves an N-acyliminium ion as intermediate and is promoted
by a chiral thiourea (general Brønsted acid catalysis).
List and coworkers reasoned that BINOL phosphates (specific Brønsted acid
catalysis) could be suitable catalysts for an asymmetric direct Pictet–Spengler reac-
tion [26]. Preliminary experiments revealed that unsubstituted tryptamines do not
undergo the desired cyclization. Introduction of two geminal ester groups rendered
the substrates more reactive which might be explained by electronic reasons and a
Thorpe–Ingold effect. Tryptamines 39 reacted with aldehydes 40 in the presence of
phosphoric acid (S)-3o (20 mol%, R = 2,4,6-iPr3-C6H2) bearing 2,4,6-triisopropyl-
phenyl substituents to provide tetrahydro-b-carbolines 41 in high yields (40–98%)
and enantioselectivities (62–96% ee) (Scheme 14). The requirement of the geminal
diester functionality constitutes a limitation of this method. However, the corre-
sponding products 41 are amenable to further synthetic manipulations via diastere-
oselective functional group differentiations.
R1 R1
CO2Et O (S)-3o (20 mol%) CO2Et

CO2Et + toluene, Na2SO4
CO2Et
R2 H NH
N NH2 −30 °C, 3-6 d N
H H
R2
39 40 41
R1 = H, MeO R2 = aryl, alkyl 40-98%, 62-96% ee
MeO
CO2Et MeO
CO2Et CO2Et
CO2Et
N NH CO2Et
CO2Et
H NH
N NH
H N
Et H
Cy
98%
96% ee 76%, 88% ee 64%, 94% ee
NO2
Scheme 14 Direct Pictet–Spengler reaction
In 2007, Hiemstra et al. established a catalytic asymmetric Pictet–Spengler reac-

tion that proceeds via N-sulfenyliminium ions (Scheme 15) [27]. Treatment of
N-sulfenylated tryptamines 42 with aldehydes 40 and BINOL phosphate (R)-3f
(5 mol%, R = 3,5-(CF3)2–C6H3) afforded tetrahydro-b-carbolines. After completion
of the cyclization the sulfenyl group was cleaved by the use of HCl. This one-pot
1) (R)-3f (5 mol%)
toluene, 3 Å MS, BHT
O 0 °C, 0.5-24 h
Ph +
Ph NH
HN R H 2) HCl/PhSH N
N S Ph H
H R
42 40 43
R = aryl, alkyl 77-90%, 30-87% ee
R yield [%] ee [%]
Ph 77 82
Bn 90 87
Pent 87 84
i 77 78
Pr
Scheme 15 Pictet–Spengler reaction via N-sulfenyliminium ions

procedure furnished Pictet–Spengler products 43 in good yields (77–90%) and

satisfactory enantioselectivities (30–87% ee). The ease of introducing and removing
the sulfenyl substituent makes this method attractive. In a similar approach N-benzyl-
tryptamines were used as starting materials to give direct access to N-benzyl-protected
tetrahydro-b-carbolines [28].
The phosphoric acid-catalyzed protocols tolerate aromatic and aliphatic alde-
hydes and thus complement Jacobsen’s acyl-Pictet–Spengler reaction which is
limited to aliphatic aldehydes.
2.3.3 Transfer Hydrogenations and Reductive Aminations
Catalytic asymmetric hydrogenations are among the most important transforma-

tions in organic chemistry. Although numerous methods employing olefins or
ketones as substrates have been described, the corresponding hydrogenations or
transfer hydrogenations of imines are less advanced. Living organisms apply cofac-
tors such as nicotinamide adenine dinucleotide (NADH) for enzyme-catalyzed
reductions of imines.
Inspired by nature, two groups independently developed a biomimetic approach
using Hantzsch dihydropyridine 44a as a NADH analog in 2005 (Scheme 16) [29].
Rueping et al. reported the first asymmetric Brønsted acid-catalyzed transfer hydro-
genation of ketimines [30]. Chiral BINOL phosphate (R)-3f (20 mol%, R = 3,5-(CF3)2–
C6H3) mediated the reduction of aryl–methyl imines 45 with commercially available
Hantzsch ester 44a to a-branched amines 46 in good yields (46–91%) and enantiose-
lectivities (68–84% ee). List and coworkers introduced a new sterically congested
EtO2C CO2Et Rueping or List

PMP PMP
N conditions HN
+
R Me Me N Me R Me
H
45 44a 46
46-98%
R = aryl, iPr 68-93% ee
Rueping conditions: (R)-3f (20 mol%), benzene, 60 °C, 3 d

List conditions: (S)-3o (1 mol%), toluene, 35 °C, 2-3 d
R yield [%] ee [%]
Ph 96 88
4-NO2-C6H4 96 80
2-Me-C6H4 91 93
iPr 80 90
Scheme 16 Transfer hydrogenation of ketimines

phosphoric acid (S)-3o (R = 2,4,6-iPr3-C6H2) bearing 2,4,6-triiso-propylphenyl

substituents, which led to superior results. N-PMP-protected amines 46 can now be
obtained in higher yields (80–98%) with improved enantioselectivities (80–93% ee)
under milder reaction conditions [31]. The remarkably low catalyst loading (1 mol%)
was up to that time unprecedented in asymmetric Brønsted acid catalysis.
The catalytic asymmetric reductive amination is a powerful transformation for
the coupling of carbonyl compounds and amines and provides rapid access to stere-
ogenic C–N bonds. Despite its potential for the union of complex fragments, only
a few enantioselective protocols have been described. The first example of a phos-
phoric acid-catalyzed reductive amination of acetophenone with Hantzsch ester
44a followed by removal of the protecting group to furnish the corresponding free
amine (81% overall yield, 88% ee) was presented by the List group [31]. In 2006,
MacMillan et al. established a reductive amination in the presence of the new phos-
phoric acid (R)-3r (10 mol%, R = SiPh3) bearing bulky triphenylsilyl substituents
using the same hydride source (44a) (Scheme 17) [32]. Various aryl–alkyl as well
as alkyl–alkyl ketones 47 in combination with aromatic and heteroaromatic amines
48 were converted into the corresponding a-branched amines 49 in good yields
(49–92%) and high enantioselectivities (81–97% ee). Computational studies
revealed that torsionally constrained BINOL phosphate 3r should be generally
selective for the transfer hydrogenation of iminium ions derived from methyl
ketones 47. Particularly, reductive amination of 2-butanone (47a, R1 = Et) provided
2-amino butane (49a) in 71% yield and 83% ee.
EtO2C CO2Et
O (R)-3r (10 mol%) R2
+ 2 + HN
R NH2
R1 Me Me N Me benzene, 5 Å MS
R1 Me
H 40-50 °C, 1-4 d
47 48 44a 49
R1 = aryl, R2 = aryl, 49-92%
alkyl heteroaryl 81-97% ee
PMP N
HN PMP PMP
HN HN
F HN S
Me
Ph Me Et Me
Ph Me 49a
81%, 95% ee 70%, 91% ee 75%, 94% ee 71%, 83% ee
Scheme 17 Reductive amination of ketones for the preparation of a-branched amines
Since imines derived from alkyl-alkyl ketones are relatively unstable, reductive
amination may be more practical compared to imine reduction. Compared to the
reductive amination, which employs three equivalents of the ketone substrate, the
in situ imine generation/one-pot reduction protocol has the significant advantage
that it does not require an excess of the carbonyl compound.
The List group came up with a novel concept for a catalytic asymmetric reduc-
tive amination, which involves enolizable aldehydes (Scheme 18) [33].
O R3 R3 R3
+ R3NH2 (48) N HN N
1
R R1 R1 R1
H − H2O H H H
2
R R2 R2 R2
50 51 ent-51
racemization (krac)
[HX*]
4
R OOC COOR4
kfast kslow
N
H
R1 R1
NHR3 krac > kfast > kslow NHR3
2 2
R R
52 ent-52
Scheme 18 Dynamic kinetic resolution of enolizable aldehydes
In the presence of a primary amine (48) and chiral phosphoric acid (R)-3o (5
mol%, R = 2,4,6-iPr3-C6H2), a-branched aldehydes 50 undergo a quick racemiza-
tion via an imine/enamine tautomerization. Brønsted acid-catalyzed transfer hydro-
genation of one enantiomer (51) is faster than of the other (ent-51), which results
in the differentiation of the two enantiomers and therefore leads to the formation of
enantioenriched b-branched amines 52. This dynamic kinetic resolution could be
applied to a broad range of 2-substituted propionaldehydes 50 and electronically
different anilines 48 (Scheme 19). Unsymmetrical Hantzsch dihydropyridine 44b
was required to obtain high yields (39–96%) and enantioselectivities (40–98% ee).
Interestingly, an ethyl substituent at the a-position of precursor 50 was tolerated as
well.
O MeO2C CO2t Bu
1 (R)-3o (5 mol%) R1
R 3 NHR3
H + R NH2 +
Me N Me benzene, 5 Å MS R 2
R2 H 6 °C, 3 d
50 48 44b 52
R1= aryl,
39-96%
2-thienyl, alkyl R3 = aryl 40-98% ee
R2 = alkyl
Br CF3
tBu Ph
NHPMP NHPMP Ph
NHPMP Me Et N
92% H 54%
94% ee Me Me 90% ee
77%, 80% ee 92%, 98% ee
Scheme 19 Reductive amination of a-branched aldehydes for the preparation of b-branched amines
After having proven that simple ketimines can be subjected to phosphoric acid-
catalyzed transfer hydrogenations yielding optically active amines, Rueping and
coworkers extended this principle to more complex molecules in 2006. They
described the first enantioselective organocatalytic reduction of heteroaromatic
compounds as well as its application to natural product synthesis (Scheme 20) [34].
Treatment of 2-substituted quinolines 53 with 2.4 equivalents of Hantzsch ester 44a
and catalytic amounts of sterically demanding BINOL phosphate (R)-3l (2 mol%,
R = 9-phenanthryl) gave tetrahydroquinolines 54 in excellent yields (54–95%) and
enantioselectivities (87 to >99% ee). The utility of the partial reduction of readily
available quinolines 53 was demonstrated by the preparation of biologically active
alkaloids such as (+)-galipinine (55a) and (−)-angustureine (55b) in only two steps.
At a later date, the same group expanded the scope of the cascade transfer hydro-
genation of heteroaromatic compounds to 3-substituted quinolines[35] and
2,3,6-substituted pyridines [36]. The biomimetic reduction of 2- and 2,3-substituted
quinolines was also studied by the Du group to test their newly developed bis-
BINOL-derived phosphoric acid 18 (Fig. 4) [37].
EtO2C CO2Et
(R)-3l (2 mol%)
+
N benzene, 60 °C, 12-60 h N R
N R H
H
53 44a (2.4 equiv) 54
R = aryl, 54-95%
2-furyl, alkyl 87 to >99% ee
R yield [%] ee [%] (+)−galipinine (55a)

N O 89% (2 steps from 53a)
91% ee
2-F-C6H4 93 98 Me O
2-furyl 93 91
(−)−angustureine (55b)
Ph(CH2)2 90 90 79% (2 steps from 53b)
N
90% ee
Me
Scheme 20 Transfer hydrogenation of 2-substituted quinolines
Mechanistically, the Brønsted acid-catalyzed cascade hydrogenation of quino-

lines presumably proceeds via the formation of quinolinium ion 56 and subsequent
1,4-hydride addition (step 1) to afford enamine 57. Protonation (step 2) of the latter
(57) followed by 1,2-hydride addition (step 3) to the intermediate iminium ion 58
yields tetrahydroquinolines 59 (Scheme 21). In the case of 2-substituted precursors
enantioselectivity is induced by an asymmetric hydride transfer (step 3), whereas
for 3-substituted ones asymmetric induction is achieved by an enantioselective
proton transfer (step 2).
1,4-hydride 1,2-hydride
R addition R protonation R addition R
N step 1 N step 2 N step 3 N
H H H H
X* 56 57 X* 58 59
enantioselective
1,2-hydride
2-substituted addition
quinolines: step 3
N R N R
H H
X*
58a
enantioselective
R protonation R
3-substituted
quinolines: step 2
N N
H H
X*
57a 58b
Scheme 21 Mechanism of the transfer hydrogenation of quinolines
Furthermore, Rueping et al. applied phosphoric acid (R)-3l (0.1 or 1 mol%, R = 9-

phenanthryl) bearing 9-phenanthryl substituents to the asymmetric reduction of
benzoxazines 60a (X = O, Y = CH2), benzothiazines 60b (X = S, Y = CH2) and
benzoxazinones 60c (X = O, Y = CO) in good yields (50–95%) and excellent enan-
tioselectivities (90 to >99% ee) (Scheme 22) [38]. The corresponding architectures
61 represent structural elements of numerous natural products and pharmaceuticals.
In particular, the organocatalytic approach to enantioenriched dihydrobenzothi-
azines 61b (X = S, Y = CH2) complements metal-mediated hydrogenations, since
some metal catalysts are poisoned by sulfur-containing compounds.
Remarkably, the catalyst loading could be decreased to 0.01 mol% without a
considerable loss in reactivity and selectivity (one example: 90% yield, 93% ee).
A substrate/catalyst ratio of 10,000 to 1 has not been achieved in asymmetric metal-
free catalysis before.
X EtO2C CO2Et X
Y (R)-3l (0.1-1 mol%) Y
+
Me N Me CHCl3 or benzene N R
N R H RT or 60 °C, 12-24 h H
60 a-c 61 a-c
X = O, S; Y = CH2, C=O 50-95%
R = aryl, 2-thienyl 90 to >99% ee
O S O O
Br
N N N
H H H
S
93%, 98% ee 54%, 93% ee 81%, 90% ee
Scheme 22 Transfer hydrogenation of benzoxazines, benzothiazines and benzoxazinones

In 2007, Antilla and coworkers disclosed the first asymmetric organocatalytic

reduction of acyclic a-imino esters (Scheme 23) [39]. Chiral VAPOL phosphate
(S)-16 (5 mol%) served as a catalyst for the transfer hydrogenation of the latter (62)
employing commercially available dihydropyridine 44a to give both aromatic and
aliphatic a-amino esters 63 in very high yields (85–98%) and enantioselectivities
(94–99% ee).
R2 EtO2C CO2Et R2
N (S)-16 (5 mol%) HN
+
Me N Me toluene, 50 °C, 18-22 h
R1 CO2Et H R1 CO2Et
62 44a 63
R1 = aryl, alkyl 85-98%
R2 = PMP, Ph 94-99% ee
PMP
HN Ph PMP PMP
HN HN HN
CO2Et
Ph CO2Et Me CO2Et Hex CO2Et
Br
93%, 98% ee 94%, 95% ee 88%, 99% ee [a] 90%, 96% ee [a]
[a] imino ester generated in situ in the
presence of 4 Å MS
Scheme 23 Transfer hydrogenation of a-imino esters
While aromatic substrates are preformed, aliphatic precursors are generated in

situ from the corresponding a-keto esters and p-anisidine. The use of in situ-generated
a-imino esters generally gave identical enantioselectivities, but lower yields.
Products 63 can be readily transformed into a-amino acids. You et al. found chiral
phosphoric acid (S)-3m (1 mol%, R = 9-anthryl) bearing 9-anthryl groups to medi-
ate the transfer hydrogenation of a-imino esters of type 62 [40]. Moreover, their
catalyst turned out to be suitable for the asymmetric reduction of b,g-alkynyl
a-imino esters 64 using 2.2 equivalents of Hantzsch ester44a (Scheme 24) [41].
The corresponding trans-alkenyl a-amino esters 65 were obtained in moderate
yields (27–64%) along with good enantioselectivities (83–96% ee). Mechanistic
investigations revealed that the carbon-carbon triple bond is hydrogenated faster
than the carbon-nitrogen double bond. Although alkenyl a-amino esters 65 are
amenable to synthetic manipulations, they cannot be reduced further under the
present reaction conditions.
Detailed mechanistic investigations of transfer hydrogenations with Hantzsch
ester by means of DFT computational studies were carried out by the groups of
Goodman and Himo [42, 43].
PMP EtO2C CO2Et PMP

N HN
(S)-3m (1 mol%)
+
CO2t Bu Me N Me Et2O, RT R CO2t Bu
R H
64 44a (2.2 equiv) 65
27-64%
R = aryl 83-96% ee
R yield [%] ee [%]
Ph 58 94
4-Me-C6H4 42 95
3-F-C6H4 64 95
Scheme 24 Transfer hydrogenation of b,g-alkynyl a-imino esters
2.3.4 Mannich Reactions
Three years after the discovery of the asymmetric BINOL phosphate-catalyzed

Mannich reactions of silyl ketene acetals or acetyl acetone, the Gong group extended
these transformations to the use of simple ketones as nucleophiles (Scheme 25)
[44]. Aldehydes 40 reacted with aniline (66) and ketones 67 or 68 in the presence
of chiral phosphoric acids (R)-3c, (R)-14b, or (R)-14c (0.5–5 mol%, R = Ph,
4-Cl–C6H4) to give b-amino carbonyl compounds 69 or 70 in good yields (42 to
>99%), anti-diastereoselectivities (3:1–49:1), and enantioselectivities (72–98% ee).
O Ph
NH O
67 R1 69
(R)-3c (0.5 mol%) or
X (R)-14b (2 mol%) or
O X
(R)-14c (5 mol%)
+ PhNH2 + or or
R1 H toluene, 0 or 10 °C, 2-3 d
O Ph
NH O
40 66 68 70
2
R R 1
R2
R1 = aryl,
2-thienyl, c Pr X = CH2, O, S, NBoc 42 to >99%
R2 = aryl 3:1-49:1 anti/syn
72-98% ee
Ph
Ph NH O Ph Ph
NH O NH O NH O
Ph
S O2 N N
S Cl
Boc
74%, 8:1 anti/syn >99%, 4:1 anti/syn 83%, 5:1 anti/syn 63%
91% ee 91% ee 75% ee 70% ee
Scheme 25 Mannich reaction of simple ketones

This protocol complements Akiyama’s method which provides b-amino carbonyl

compounds as syn-diastereomers [14]. It tolerated aromatic, heteroaromatic, and
aliphatic aldehydes. Cyclic ketones, acetone, as well as acetophenone derivatives
could be employed. The use of aromatic ketones as Mannich donors was up to that
time unprecedented in asymmetric organocatalysis. Rueping et al. independently
expanded the scope of the asymmetric Brønsted acid-catalyzed Mannich reaction
of acetophenone [45].
In 2008, Akiyama and coworkers introduced a new chiral BINOL phosphate
bearing 2,4,6-triisopropylphenyl groups at the 3,3¢-positions as well as an iodine
atom at the 6,6¢-positions for a vinylogous Mannich reaction (Scheme 26) [46].
Aldimines 8 derived from 2-aminophenol were treated with 2-(trimethylsiloxy)
furan (71) and catalytic amounts of phosphoric acid 6,6¢-I2-(R)-3o (5 mol%, R =
2,4,6-iPr3–C6H2) to furnish g-butenolides 72 in high yields (30 to >99%), anti-
diastereoselectivities (2:1–49:1), and enantioselectivities (55–99% ee). The iodine sub-
stituents have an effect on the stereoselectivity. Compared to catalyst 3o, its
iodine-substituted analog 6,6¢-I2–3o increases the enantioselectivity (82% ee
instead of 74% ee), but decreases the diastereoselectivity (10:1 instead of 13:1).
Interestingly, calculations revealed that BINOL phosphates 3o and 6,6¢-I2–3o
exhibit the same dihedral angle (53°). Thus, the observed difference in stereoselec-
tivities might be explained by rather electronic than steric effects.
HO i i
Pr Pr
HO
HN I
6,6'-I2-(R)-3o (5 mol%)
N + i
O OTMS toluene, 0 °C, 15-31 h R O PrO
R H O P
O i OH
8 71 72 O Pr
R = aryl, 33 to >99% I
heteroaryl, 2:1−49:1anti/syn
alkyl 55-99% ee i
Pr i
Pr
R yield [%] anti/syn ee [%] 6,6'-I2-(R)-3o
Ph >99 10:1 82
3-NO2-C6H4 86 2:1 96
4-pyridyl 30 16:1 98
i [a] 84 7:1 92
Pr
[a] imine generated in situ in the presence of Na2SO4
Scheme 26 Vinylogous Mannich reaction of 2-(trimethylsiloxy)furan
The Schneider group independently reported an asymmetric vinylogous

Mannich reaction (Scheme 27) [47]. Addition of silyl dienolates 73 to N-PMP-
protected imines 74 was promoted by phosphoric acid (R)-3g (5 mol%, R = Mes)
with mesityl substituents to afford trans-a,b-unsaturated d-amino esters 75 in high
yields (66–94%) together with good enantioselectivities (80–92% ee).
PMP OTBS PMP

N (R)-3g (5 mol%) HN O
+
OEt THF/alcohols
R H R OEt
H2O (1.0 equiv)
74 73 -30 °C, 1-72 h 75
R = aryl,
heteroaryl, 66-94%
t 80-92% ee
Bu
R yield [%] ee [%]
4-Et-C6H4 88 92
3-Cl-C6H4 94 82
3-furyl 88 90
t 83 82
Bu
Scheme 27 Vinylogous Mannich reaction of silyl dienolates
2.3.5 Aza-Ene-Type Reaction
In 2004, Kobayashi et al. introduced enecarbamates as nucleophiles to asymmetric

catalysis [48]. The addition of enecarbamates to imines in the presence of a chiral
copper complex provides access to b-amino imines which can be hydrolyzed to the
corresponding b-amino carbonyl compounds [49].
Two years later, Terada and coworkers described an asymmetric organocatalytic
aza-ene-type reaction (Scheme 28) [50]. BINOL phosphate (R)-3m (0.1 mol%,
R = 9-anthryl) bearing 9-anthryl substituents mediated the reaction of N-benzoylated
aldimines 32 with enecarbamate 76 derived from acetophenone. Subsequent
hydrolysis led to the formation of b-amino ketones 77 in good yields (53–97%) and
excellent enantioselectivities (92–98% ee). A substrate/catalyst ratio of 1,000:1 has
rarely been achieved in asymmetric Brønsted acid catalysis before.
O 1) (R)-3m (0.1 mol%)
Bz toluene, RT, 5h Bz
N NH O
+ HN OMe
R H 2) H+/H2O R1 Ph
Ph
32 76 77
R = aryl, 53-97%
PhCH=CH 92-98% ee
R yield [%] ee [%]
3-Me-C6H4 83 93
4-CN-C6H4 97 98
1-naphthyl 88 95
PhCH=CH 81 93
Scheme 28 Aza-ene-type reaction

Noteworthy, the reaction can be conducted on a 1 g scale in the presence of only

0.1 mol% of catalyst 3m without a considerable loss in reactivity and selectivity
(one example: 89% yield, 95% ee). The authors’ mechanistic proposal relies on the
dual function of the phosphoric acid moiety and invokes a simultaneous activation
of both reaction partners through a hydrogen bonding network (Fig. 7).
Fig. 7 Working hypothesis CO2Me

N Ph
H
O O
* P R
O O H N
H
O
Ph
2.3.6 Aza-Henry Reaction
The aza-Henry reaction is an important tool for the preparation of compounds bear-
ing vicinal nitrogen-containing functional groups. Catalytic asymmetric methods
using either metal complexes or organic molecules were disclosed over the last
years. While metal-free variants employing imines as substrates are well-established,
the corresponding aza-Henry reaction of a-imino esters is less advanced. The latter
furnishes valuable intermediates for the synthesis of biologically active a,b-
diamino acids.
In 2008, the Rueping group reported the addition of nitroalkanes 78 to N-PMP-
protected a-imino esters 79 in the presence of chiral phosphoric acid (R)-14r (10
mol%, R = SiPh3) (Scheme 29) [51]. This transformation provided b-nitro-a-amino
esters 80 in good yields (57–93%), anti-diastereoselectivities (2:1–13:1) and enan-
tioselectivities (84–92% ee).
PMP
PMP R HN
N (R)-14r (10 mol%)
+ R
NO2 benzene, 30 °C, 12 h-7 d MeO2C
MeO2C H
NO2
79 78 80
R = alkyl, 57-93%, 2:1-13:1 anti/syn
4-Me-C6H4 84-92% ee
R yield [%] anti/syn ee [%]
Me 61 10:1 92
Bn 93 13:1 88
4-Me-C6H4 64 2/1 84
Scheme 29 Aza-Henry reaction

Fig. 8 Possible transition state
*
O O
P
O HO
O
H
O N
PMP N
MeO2C R
Mechanistically, the aza-Henry reaction presumably proceeds via a six-

membered transition state. Brønsted acid 14r is expected to activate both the
electrophile and the nucleophile (Fig. 8).
2.3.7 Addition of a Hydrazone
N,N-Dialkyl hydrazones derived from formaldehyde serve as powerful formyl

anion equivalents. Their asymmetric addition to imines gives rise to optically
active a-amino hydrazones which are amenable to further synthetic mani
pulations.
In 2007, Rueping et al. found chiral H8-BINOL phosphate (R)-14l (10 mol%,
R = 9-phenanthryl) with 9-phenanthryl groups to mediate the reaction of aldimines
11 with N-methylenepyrrolidin-1-amine (81a) (Scheme 30) [52]. N-Boc-protected
a-amino hydrazones 82 were obtained in satisfactory yields (48–82%) and enanti-
oselectivities (74–90% ee).
Boc
Boc H N HN
N (R)-14l (10 mol%)
+ N N
H CHCl3, 0 °C, 16 h R N
R H
H
11 81a 82
48-82%
R = aryl 74-90% ee
R yield [%] ee [%]
2-Br-C6H4 82 85
2-naphthyl 78 82
4-MeO-C6H4 71 77
Scheme 30 Addition of a hydrazone to imines

2.3.8 Strecker Reactions
One of the most important approaches to a-amino acids is based on the Strecker
reaction. Although there are already a number of catalytic asymmetric variants, the
cyanation of imines still challenges modern organic chemists.
In 2006, the Rueping group showed that chiral phosphoric acid (R)-3l (10
mol%, R = 9-phenanthryl) with 9-phenanthryl substituents promoted the addition
of HCN to N-benzylated aldimines 83 (Scheme 31) [53]. a-Amino nitriles 84 were
obtained in good yields (53–97%) along with high enantioselectivities (85–99% ee)
and could be transformed into the corresponding a-amino acids.
N R2 (R)-3l (10 mol%) HN R2

+ HCN
toluene, −40 °C, 2-3 d
R1 H R1 CN
83 84
R1 = aryl, heteroaryl 53-97%
R2 = Ph, PMP 85-99% ee
PMB Bn Bn
HN HN HN
CN O CN CN
F3 C O S
53%, 96% ee 88%, 93% ee 77%, 95% ee
Scheme 31 Strecker reaction
Furthermore, Rueping and coworkers applied their reaction conditions to the

cyanation of ketimines [54]. The use of N-benzylated imines derived from aryl–
methyl ketones generally gave comparable yields, but lower enantioselectivities.
However, this method furnished Strecker products bearing a quaternary stereogenic
center, which are valuable intermediates for the preparation of optically active a,a-
disubstituted a-amino acids.
2.3.9 Hydrophosphonylations
a-Amino phosphonic acids and their esters are of great value due to their function
as a-amino acid mimics in medicinal chemistry. They act as inhibitors of proteases
and phosphatases as well as exhibit antibacterial and antifungal activity. Consequently,
their catalytic asymmetric preparation has attracted considerable attention. A pow-
erful approach to a-amino phosphonates involves the hydrophosphonylation of
preformed imines. The direct combination of an aldehyde with an amine and a
phosphite is referred to as the Kabachnik–Fields reaction.
Akiyama et al. disclosed an asymmetric hydrophosphonylation in 2005 (Scheme

32) [55]. Addition of diisopropyl phosphite (85a) to N-arylated aldimines 86 in the
presence of BINOL phosphate (R)-3f (10 mol%, R = 3,5-(CF3)2–C6H3) afforded
a-amino phosphonates 87 in good yields (72–97%). The enantioselectivities were
satisfactory (81–90% ee) in the case of imines derived from a,b-unsaturated alde-
hydes and moderate (52–77% ee) for aromatic substrates.
R2
R2 OiPr (R)-3f (10 mol%) HN
N H i OiPr
+ P O Pr i
m-xylene, RT, 1-7 d R1 P O Pr
R1 H O
O
86 85a 87
1
R = aryl, alkenyl 72-97%
R2 = PMP, Ph 52-90% ee
PMP PMP Ph
O2 N HN HN HN
OiPr OiPr OiPr
i i
P O Pr P O Pr
i
Ph P O Pr
O O O
72%, 77% ee 76%, 81% ee 74%, 88% ee
Scheme 32 Hydrophosphonylation of preformed imines
Mechanistically the reaction is proposed to proceed via a nine-membered transi-

tion state with the chiral phosphoric acid simultaneously activating the imine by
protonation and the phosphite by coordinating to the hydroxyl group (Fig. 9).
Three years later, List and coworkers extended their phosphoric acid-catalyzed
dynamic kinetic resolution of enolizable aldehydes (Schemes 18 and 19) to the
Kabachnik–Fields reaction (Scheme 33) [56]. This transformation combines the
differentiation of the enantiomers of a racemate (50) (control of the absolute con-
figuration at the b-position of 88) with an enantiotopic face differentiation (creation
of the stereogenic center at the a-position of 88). The introduction of a new steri-
cally congested phosphoric acid led to success. BINOL phosphate (R)-3p (10
mol%, R = 2,6-iPr2-4-(9-anthryl)-C6H2) with anthryl-substituted diisopropylphenyl
groups promoted the three-component reaction of a-branched aldehydes 50 with
p-anisidine (89) and di-(3-pentyl) phosphite (85b). b-Branched a-amino phosphonates
88 were obtained in high yields (61–89%) and diastereoselectivities (7:1–28:1)
along with good enantioselectivities (76–94% ee) and could be converted into
H O OR
O O P
Ar OR
* P H
O O H
N
Fig. 9 Proposed activation mode Ar
the corresponding a-amino phosphonic acids. The protocol is limited to 2-aryl

acetaldehydes bearing a bulky alkyl substituent such as cyclohexyl, cyclopentyl or
isopropyl at the a-position. By contrast, a methyl group at the a-position resulted
in poor stereoselectivities.
PMP
O OMe NH
O (S)-3p (10 mol%) O
R2 + + H P O R2
H P O
H2 N cyclohexane, 5 Å MS
R1 O 50 °C, 7 d R1 O
50 89 85b 88
R1 = aryl, 2-thienyl 61-89%, 7:1-28:1 dr
R2 = alkyl 76-94% ee
PMP PMP
NH NH PMP PMP
O O NH NH
O O
P O P O Cy i
Pr
P O P O
O O Ph O Ph O
S
Cl
80%, 28:1 dr 61%, 20:1 dr 86%, 16:1 dr 85%, 17:1 dr
88% ee 94% ee 90% ee 90% ee
Scheme 33 Kabachnik–Fields reaction
2.3.10 Addition of Sulfonamides or Alcohols
The addition of sulfonamides or alcohols to imines gives rise to aminals which

represent structural elements of natural products and drugs. Recently, Antilla et al.
reported the first catalytic asymmetric variants of both transformations.
In 2005, they found chiral VAPOL phosphate (S)-16 (5–20 mol%) to mediate the
reaction of N-Boc-protected aldimines 11 with sulfonamides 90 (Scheme 34) [57].
N,N-aminals 91 were obtained in high yields (80–99%) and enantioselectivities
(73–99% ee).
Boc Boc
N H2N R2 (S)-16 (5-20 mol%) NH O O
+ S S 2
1 O O Et2O or toluene R1 N R
R H RT, 1-50 h H
11 90 91
R1 = aryl, 80-99%
R2 = aryl, Me 73-99% ee
2-thienyl
Boc Boc Boc

Boc NH O O NH NH
NH
S Ts Ts
Ms Ph N N N
Ph N H H
H H
Cl F3C S
86%, 93% ee 98%, 95% ee 99%, 99% ee 94%, 87% ee
Scheme 34 Synthesis of N,N-aminals by addition of sulfonamides to imines

Three years later, the same group showed that oxygen-containing nucleophiles
can also be used (Scheme 35) [58]. N-Benzoylated aldimines 32 were treated with
alcohols 92 in the presence of chiral BINOL phosphate (R)-3m (5 mol%, R =
9-anthryl) to provide N,O-aminals 93 in high yields (62–99%) and good enantiose-
lectivities (65–95% ee).
In general, enantioenriched aminals are prone to decompose or racemize in the
presence of a Brønsted acid . Remarkably, N,N-aminals 91 as well as N,O-aminals
93 are stable under Antilla’s reaction conditions.
Bz Bz
N (R)-3m (5 mol%) NH
+ R2OH
EtOAc, RT, 24 h 1
R 1
H R OR2
32 92 93
62-99%
R1 = aryl, Et R2 = alkyl 65-95% ee
Bz Bz Bz Bz
NH NH NH NH
t Me
Ph OBn Ph O Bu OMe Et OMe
92%, 93% ee 81%, 92% ee 91%, 84% ee 62%, 65% ee
Scheme 35 Synthesis of N,O-aminals by addition of alcohols to imines
2.3.11 Aza-Diels–Alder Reactions
The aza-Diels–Alder reaction is an important and versatile tool for the preparation
of nitrogen-containing heterocycles present in numerous natural products and drug
candidates. It involves the [4 + 2] cycloaddition of either an imine with an electron-
rich diene or an azabutadiene with an electron-rich alkene (inverse electron
demand). Catalytic asymmetric variants employing not only metal complexes, but
also organic molecules were disclosed over the last few years.
In 2006, Akiyama and coworkers established an asymmetric Brønsted acid-
catalyzed aza-Diels–Alder reaction (Scheme 36) [59]. Chiral BINOL phosphate
(R)-3o (5 mol%, R = 2,4,6-iPr3–C6H2) bearing 2,4,6-triisopropylphenyl groups
mediated the cycloaddition of aldimines 94 derived from 2-amino-4-methylphenol
with Danishefsky’s diene 95 in the presence of 1.2 equivalents of acetic acid .
Piperidinones 96 were obtained in good yields (72 to >99%) and enantioselectivi-
ties (76–91% ee). While the addition of acetic acid (pKa= 4.8) improved both the
reactivity and the selectivity, the use of benzenesulfonic acid (pKa= −6.5) as an
additive increased the yield, but decreased the enantioselectivity. A strong achiral
Brønsted acid apparently competes with chiral phosphoric acid 3o for the activa-
tion of imine 94 and catalyzes a nonasymmetric hetero-Diels–Alder reaction.
The role of acetic acid remains unclear.
HO OMe OH
(R)-3o (5 mol%)
AcOH (1.2 equiv)
N Me + toluene, −78 °C, 10-35 h Me N
R H OTMS R O
94 95 96
72 to >99%
R = aryl 76-91% ee
R yield [%] ee [%]
4-Cl-C6H4 72 84
Ph 99 80
1-naphthyl >99 91
Scheme 36 Aza-Diels–Alder reaction of Danishefsky’s diene
O O H O
* P
O O H N Me
Fig. 10 Proposed catalyst-imine interaction Ar H
The authors suggested the catalyst-imine interaction depicted in Fig. 10 for the
present Diels–Alder reaction. Imine 94 features a free hydroxyl group appropriate
for binding to the phosphoryl oxygen of the phosphoric acid moiety by hydrogen
bonding.
The same group expanded the scope of the aza-Diels–Alder reaction of electron-
rich dienes to Brassard’s diene 97 (Scheme 37) [60]. In contrast to Danishefsky’s
diene, it is more reactive, but less stable. Akiyama et al. found chiral BINOL phos-
phate (R)-3m (3 mol%, R = 9-anthryl) with 9-anthryl substituents to promote the [4
+ 2] cycloaddition of N-arylated aldimines 94 and Brassard’s diene 97. Subsequent
treatment with benzoic acid led to the formation of piperidinones 98. Interestingly,
the use of its pyridinium salt (3 mol%) resulted in a higher yield (87% instead of
72%) along with a comparable enantioselectivity (94% ee instead of 92% ee). This
method furnished cycloadducts 98 derived from aromatic, heteroaromatic, a,b-
unsaturated, and aliphatic precursors 94 in satisfactory yields (63–91%) and excel-
lent enantioselectivities (92–99% ee). NMR studies revealed that Brassard’s diene
97 is labile in the presence of phosphoric acid 3m (88% decomposition after 1 h),
but comparatively stable in the presence of its pyridinium salt (25% decomposition
after 1 h). This observation can be explained by the fact that the pyridinium salt is
a weak Brønsted acid compared to BINOL phosphate 3m.
HO OTMS 1) (R)-3m · py (3 mol%) OH

O
mesitylene, −40 °C
N Me + MeO 2) PhCO2H Me N
R H OMe R OMe
94 97 98
R = aryl, 2-furyl, 63-91%
PhCH=CH, alkyl 92-99% ee
R yield [%] ee [%]
4-Me-C6H4 90 95
2-Cl-C6H4 86 98
PhCH=CH 76 98
Cy 69 99
Scheme 37 Aza-Diels–Alder reaction of Brassard’s diene
Furthermore, Akiyama and coworkers applied phosphoric acid (R)-3m (10

mol%, R = 9-anthryl) to the asymmetric inverse-electron-demand hetero-Diels–
Alder reaction of N-2-hydroxyphenyl-protected aldimines 8 with vinyl ethers 99
(Scheme 38) [61]. Tetrahydroquinolines 100 were obtained in good yields
(59–95%), excellent syn-diastereoselectivities (24:1–99:1), and high enantioselec-
tivities (87–97% ee).
OR2
OR2 (R)−3m (10 mol%)
1 +
N R toluene, −10 or 0 °C, 10-55 h
OH N R1
H
OH
8 99 100
59-95%, 24:1-99:1 syn/anti
R1 = aryl R2 = alkyl 87-97% ee
OEt OnBu O
N N
H H N Ph
OH OH H
Me Br OH
59%, 99:1 syn/anti 86%, 99:1 syn/anti 95%, 99:1 syn/anti
91% ee 89% ee 97% ee
Scheme 38 Inverse-electron-demand aza-Diels–Alder reaction

In 2006, two groups independently developed an asymmetric Brønsted acid-

catalyzed aza-Diels–Alder-type reaction of N-aryl aldimines 86 with cyclohexenone
101 to provide isoquinuclidines 102 in good yields (51–84%), endo-diastereoselec-
tivities (3:1–9:1), and enantioselectivities (76–88% ee) (Scheme 39).
O Rueping or Gong
R2 conditions R2 R2
N + N or N
H H
R1 H O O
R1 R1
86 101 102 ent-102
R1 = aryl,
51-84%, 3:1-9:1 endo /exo
2-thienyl 76-88% ee
R2 = aryl
Rueping conditions: Gong conditions:

(R)-3j (10 mol%), AcOH (20 mol%) (R)-14c (5 mol%)
2
R = 4-Br-C6H4, toluene, RT R2 = PMP, toluene, 20 °C, 6 d
R1 yield [%] endo /exo ee [%] R1 yield [%] endo /exo ee [%]
Ph 71 4:1 86 Ph 76 5:1 87
4-Cl-C6H4 73 4:1 88 3-Br-C6H4 79 4:1 87
2-thienyl 70 4:1 88 4-Me-C6H4 81 5:1 83
major enantiomer: 102 major enantiomer: ent-102
Scheme 39 Aza-Diels–Alder-type reaction of cyclohexenone
On the one hand, Rueping’s protocol involved a combination of chiral BINOL

phosphate (R)-3j (10 mol%, R = 2-naphthyl) bearing 2-naphthyl substituents and
achiral acetic acid (20 mol%) [62]. While stronger Brønsted acid 3j is expected to
activate electrophile 86, the weaker Brønsted acid is proposed to facilitate the
keto–enol tautomerism of nucleophile 101 (Scheme 40)1. On the other hand, Gong
R2 HX*
N NHR2
X*
R1 H R1 H
86 104
O OH
H
Scheme 40 Activation of both the electrophile and the

nucleophile by Brønsted acids 101 103
1
pKa (dimethyl phosphate) = 1.29, pKa (acetic acid ) = 4.76
found H8-BINOL phosphate (R)-14c (5 mol%, R = 4-Cl–C6H4) with a 4-chloroph-

enyl group to be sufficient to obtain comparable results [63]. Both methods are
limited to aromatic or heteroaromatic imines.
Mechanistically, the present transformation probably comprises two steps.
Mannich reaction of in situ-generated cyclohexadienol 103 with iminium ion 104
is followed by an intramolecular aza-Michael reaction to furnish isoquinuclidine
102 (Scheme 41). Three stereogenic centers are created in this process.
HO NHR2
X*
R1
OH
NHR2 Mannich aza-Michael R2
+ N
X* H
R1 H O
R1
X* NHR2
103 104 102
H
HO 1
R
Scheme 41 Mechanism of the aza-Diels–Alder-type reaction of cyclohexenone
2.3.12 1,3-Dipolar Cycloaddition
The 1,3-dipolar cycloaddition of azomethine ylides with olefins gives rise to pyr-
rolidines which represent structural elements of organocatalysts, natural products,
and drug candidates. Asymmetric metal-catalyzed variants attracted considerable
attention over the last few years [64]. Recently, Vicario et al. reported an organo-
catalytic [3 + 2] cycloaddition of azomethine ylides and a,b-unsaturated aldehydes
mediated by a chiral secondary amine [65].
In 2008, Gong and coworkers introduced a new chiral bisphosphoric acid 19
(Fig. 4) that consists of two BINOL phosphates linked by an oxygen atom for a
three-component 1,3-dipolar cycloaddition (Scheme 42) [66]. Aldehydes 40 reacted
with a-amino esters 105 and maleates 106 in the presence of Brønsted acid 19 (10
mol%) to afford pyrrolidines 107 as endo-diastereomers in high yields (67–97%)
and enantioselectivities (76–99% ee). This protocol tolerated aromatic, a,b-unsaturated,
and aliphatic aldehydes. Aminomalonates as well as phenylglycine esters could be
employed as dipolarophiles.
Mechanistically, the [3 + 2] cycloaddition presumably proceeds via a dipole
coordinated by catalyst 19 (Fig. 11).
2.3.13 Multicomponent and Cascade Reactions
A multicomponent reaction (MCR) represents a sequence of bimolecular events

leading to products that incorporate essentially all atoms of three or more starting
materials. MCRs allow for the rapid and facile access to complex target structures
R4O2C CO2R4
O R2 CO2R4
(R,R)-19 (10 mol%)
+ + R2
R1 H H2N CO2R3 CO2R4
CH2Cl2, 3 Å MS R1 N CO2R3
RT, 24-96 h H
40 105 106 107
R1 = aryl, R2 = EtO2C, Ph 67-97% (endo)
R4 = alkyl 76-99% ee
alkenyl, Cy R3 = alkyl
MeO2C CO2Me MeO2C CO2Me MeO2C CO2Me
CO2Et CO2Et Ph
N CO2Et Cy N N CO2Me
CO2Et
MeO H H O2N H
87% (endo), 90% ee 74% (endo), 76% ee 92% (endo), 97% ee
Scheme 42 1,3-Dipolar cycloaddition
R2 CHO2R3
R1 N H
H O
O P
OR*
Fig. 11 Possible activation mode *RO
in one step. The combination of enantioselective organocatalysis and MCRs has

created a powerful synthetic tool as exemplified by several intriguing applica-
tions [67].
Recently, several research groups reported on the use of chiral BINOL phosphates
as Brønsted acid catalysts in MCRs involving imine activation.
Biginelli Reaction
In 2006, Gong and coworkers described the first highly enantioselective organo-
catalytic Biginelli reaction (Scheme 43). Starting from an aldehyde 40, thiourea or
urea 108, and acetoacetates 109, the Biginelli reaction furnished multifunctional-
ized 3,4-dihydropyrimidin-2-(1H)-ones (DHPMs) 110 or the respective thio-ana-
logs. H8-BINOL-based chiral phosphoric acid (R)-14b (10 mol%, R = Ph)
exhibited the highest catalytic efficiency and afforded the heterocyclic products
110 in moderate to good yields (40–86%) with high enantioselectivities (85–97%
ee) [68].
Simple phenyl substituents at the 3,3¢-positions were sufficient to achieve high
levels of enantiocontrol, which is in contrast to the substitution effect of many other
BINOL phosphate-catalyzed reactions. Indeed, increasing the size of the 3,3¢-sub-
stituents resulted in both decreased yields and enantioselectivities. The synthetic
utility of the catalytic asymmetric Biginelli reaction was demonstrated by the
preparation of the active pharmaceutical ingredient monastrol (110a) in two steps
CO2R2
O X O O HN
(R)-14b (10 mol%)
H2N NH2 *
R1 H OR2 CH2Cl2, 25 °C, 6 d X N R1
H
40 108 109 110
1 2 40-86%, 85-97% ee
R = aryl, Cy, PhCH=CH; R = alkyl; X = S, O
− H 2O − H2O
S
S X* S O O NH2
H HN O
N NH2 HX* N NH2 OR 2
R1 H R1 H R1 *
O OR2
CO2iPr CO2Et CO2Et CO2Et

HN HN HN HN
* * * Br OH
S N S N O N S N
H H H H
F
Br
86%, 91% ee 40%, 92% ee 51%, 97% ee 88% (two steps), 91% ee
monastrol (110a)
Scheme 43 Biginelli reaction: scope and proposed reaction pathway
and high optical purity (91% ee) from TBS-protected 3-hydroxy benzaldehyde,
thiourea, and ethyl acetoacetate. Importantly, the individual enantiomers of monas-
trol show distinct pharmaceutical properties.
Dihydropyridine Syntheses
In 2008, the same group developed an asymmetric three-component cyclization

reaction of cinnamaldehydes 111 and aromatic primary amines 48 with 1,3-dicar-
bonyl compounds 112 in the presence of a catalytic amount of H8-BINOL-based
chiral phosphate (S)-14l (10 mol%, R = 9-phenanthryl) (Scheme 44). Enantiomerically
enriched 4-aryl-substituted 1,4-dihydropyridines (DHPs) 113 were rapidly assem-
bled in moderate to high yields by means of this method (37–93%, 73–98% ee)
[69]. DHPs exhibit a broad range of pharmaceutical activities. Most prominent
among them is their role as an important class of organic calcium-channel modula-
tors for the treatment of cardiovascular diseases.
The scope was illustrated with 35 examples using various b-ketoesters as
well as acetylacetone as 1,3-dicarbonyl compound. The use of aliphatic a,b-
unsaturated aldehydes resulted in low yield and inferior enantioselectivity.
Transformation of the DHP products into other optically active heterocyclic
O O O (S )-14l (10 mol%) Ar2 N Ar1
*
Ar2NH2
Ar 1 H R 1
R 2 PhCN, 50 °C, 24-36 h
R1 COR2
111 48 112 113
R1 = alkyl; R2 = OR3, Me; R3 = alkyl 37-93%, 73-98% ee
− H2O − H 2O
O O H
O O
Ar2 R1 R2 O OH X*
N H
HX* (cat.) R2 R1
H R 2
R 1
Ar1 H Ar2
Ar1 N 1 Ar2
Ar * N
H H
X*
NO2
NO2
NO2
CO2Et COMe
* MeO F3C *
CO2Et CO2iPr CO2Et
* N * * N
N N N
PMP PMP PMP
OMe OMe
82%, 92% ee 53%, 97% ee 50%, 82% ee 75%, 96% ee 52%, 87% ee
Scheme 44 Three-component cyclization to 4-substituted DHPs: scope and proposed reaction

pathway
c ompounds, like tetrahydropyridines and piperidines, demonstrated their utility

as synthetic intermediates.
Prior to this work, Renaud and coworkers described an alternative phosphoric
acid-catalyzed approach to DHPs 113 commencing with b-enaminoesters such as
114 and cinnamaldehydes 111. Besides developing a catalytic nonasymmetric
protocol, the authors attempted a BINOL phosphate (S)-3k-catalyzed (R = 1-naph-
thyl) asymmetric version attaining moderate enantioselectivity (50% ee) (Scheme
45) [70].
Ph
Bn
NH O O CO2t Bu
(S)-3k *
Ot Bu Ph H CH2Cl2, Na2SO4, −7 °C
N
114 111a Bn 113a
50% ee
Scheme 45 DHP synthesis from a b-enaminoester and cinnamaldehyde

Reaction Cascades
In 2007, Zhou and List described a reaction cascade to substituted cyclohexylamines

115 starting from various 2,6-diketones 116 and p-alkoxyanilines 117 in the presence
of Hantzsch ester 44a and chiral phosphoric acid (R)-3o (10 mol%,
R = 2,4,6-iPr3-C6H2). The cis-3-substituted (hetero)cyclohexylamines 115 were
obtained in good to high yields (35–89%) along with high enantioselectivities in case
of aliphatic substituents (90–96% ee) and with somewhat lower enantioselectivity
in case of aromatic R1 groups (82% ee for R1 = 2-naphthyl). The cascade reactions
proceeds via sequential aldolization-dehydration-conjugate reduction-reductive ami-
nation steps and merges asymmetric Brønsted acid catalysis with enamine and imi-
nium catalysis. It is catalyzed by the chiral phosphoric acid and accelerated by the
achiral amine substrate 117, which is ultimately incorporated into the product.
OR 2
O OR2
(R) -3o(10mol%) HN
X O
cyclohexane, 5 Å MS
50 °C, 72 h
R1 NH 2 X
R1
H H
116 117 EtO 2C CO2 Et 115
R 1 = aryl, alkyl; R2 = Me, Et 35-89%
X = CH 2, O, S 2:1-99:1 cis/trans
N 82-96% ee(cis)
H
44a
- H2 O - H 2O
2 2 2
R O R O H H R O
X* EtO2 C CO2 Et X*
H H
NH N N
N
HX* H
X O - H2 O X X
R1 R1
R1
OEt OR 2 OR 2 OR2
HN HN HN HN
X n X i X O
Bu Bu Me
75%, 10:1 cis/trans 79%, 12:1 cis/ tr ans 73%, 2:1 cis/trans 72%, 99:1 cis/trans
90% ee cis 96% ee cis 82% ee cis 92% ee cis
Scheme 46 Multiple-reaction cascade to 3-substituted cyclohexylamines: scope and proposed

reaction pathway
A direct entry to valuable enantiomerically enriched tetrahydropyridines and azadec-

alinones 118 was provided by the Rueping group in 2008 [71]. A mixture of enamines
119 and vinyl ketones 120 in the presence of BINOL phosphate (R)-3m (5 mol%, R =
9-anthryl) and Hantzsch dihydropyridine 44a furnished the desired products in good
yields (42–89%) along with excellent enantioselectivities (89–99% ee) by means of a
multiple-reaction cascade comprising a Michael addition, isomerization, cyclization,
elimination, isomerization, and asymmetric transfer hydrogenation (Scheme 47). Each
step of the six-step sequence is catalyzed by phosphoric acid 3m.
R3 R3
(R)-3m (5 mol%)
R2 CHCl3 or benzene, 3 Å MS
NH2 O R1 R2 N R1
50 °C, 12-18 h H
119 120 118
H H
R1 = aryl, heteroaryl, alkyl; R2 = alkyl; EtO2C CO2Et 42-89%, 89-99% ee
R3 = EWG (CN, COAlkyl, CO2Me)
N
Michael H transfer
HX* HX* hydrogenation
addition 44a
R1 R1 R3
O HX* O R2 N R1
R3 R3 H X*
isomerization
R2 NH2 H2N R2 isomerization/
HX* protonation
HX* R3 HX* R3
cyclization R1
R2 N H2O R2 N R1
H OH H
elimination
O
NC MeO2C O
F
N N
H H N
H N Pent
OMe Br H
F
89%, 96% ee 54%, 99% ee 60%, 99% ee 66%, 89% ee
Scheme 47 Multiple-reaction cascade to tetrahydropyridines and azadecalinones: scope and

proposed reaction pathway
In 2007, Terada et al. extended their previously described chiral phosphoric acid-
catalyzed aza-ene-type reaction of N-acyl aldimines with disubstituted enecarbamates
(Scheme 28) to a tandem aza-ene-type reaction/cyclization cascade as a one-pot entry
to enantioenriched piperidines 121 (Scheme 48). The sequential process was ren-
dered possible by using monosubstituted 122 instead of a disubstituted enecarbamate
76 to produce a reactive aldimine intermediate 123, which is prone to undergo a
further aza-ene-type reaction with a second enecarbamate equivalent. Subsequent
intramolecular cyclization of intermediate 124 terminates the sequence. The optimal
chiral BINOL phosphate (R)-3h (2–5 mol%, R = 4-Ph-C6H4) provided the 2,4,6-sub-
stituted N-Boc-protected piperidines 121 in good to excellent yields (68 to > 99%)
and accomplished the formation of three stereogenic centers with high diastereo- and
excellent enantiocontrol (7.3:1 to 19:1 trans/cis, 97 to > 99% ee(trans)) [72].
Cbz Cbz
HN HN
Boc Cbz
N HN (R)-3h (2-5 mol%) Boc Boc
N N
R H H CH2Cl2, 0 °C, 1-5 h
R NH R NH
119 (2.1 equiv) Cbz Cbz
trans -118 cis -118
R = aryl, 2-furyl, PhCH=CH, MeO2C, Cy 68 to >99%, 7.3:1-19:1 trans/cis
97 to >99% ee(trans)
R yield [%] trans /cis ee(trans) [%]
via: Cbz Boc Cbz Cbz Boc Ph >99 19:1 >99

N HN N NH HN
and 2-furyl 76 7.3:1 99
H * R H * * R
MeO2C 84 7.3:1 98
120 121
Cy 68 15.7:1 97
Scheme 48 Tandem aza-ene-type reaction/cyclization cascade: scope and reaction intermediates
2.4 Other Substrates
2.4.1 Imine Surrogates
In 2007, two groups independently described asymmetric phosphoric acid-catalyzed

Friedel–Crafts alkylations of indoles. While You et al. chose the conventional
approach and employed imines as substrates (Scheme 11), Terada and coworkers
came up with a different concept and used electron-rich alkenes as precursors
(Scheme 49) [73]. Enecarbamates 125 reacted with indoles 29 in the presence of
BINOL phosphate (R)-3o (5 mol%, R = 2,4,6-iPr3–C6H2) bearing 2,4,6-triisopropyl-
phenyl substituents to provide N-Boc-protected 3-indolyl amines 126 in high yields
(63–98%) and enantioselectivities (90–96% ee).
Boc Boc R3
HN R3 HN
(R)-3o (5 mol%) 2
R 2 + R
H N CH3CN
R1 H 0-50 °C, 6-48 h R1 NH
125 29 126
(1:1 or >99:1 E/Z)
R3 = H, 5-MeO, 63-98%
90-96% ee
R1 = alkyl, Ph 5-Me, 5-Br, 6-Br,
R2 = H, Me 5-MeCO2
Boc Boc Boc

HN HN HN
Br
Ph i
Pr Et
NH NH NH
63%, 90% ee 69%, 94% ee 78%, 96% ee
Scheme 49 Friedel–Crafts reaction of enecarbamates and indoles

The geometry of the double bond of electron-rich alkene 125a plays an important
role. Starting from (E)- and (Z)-enecarbamate 125a respectively, product 126a was
obtained in comparable enantioselectivities (94% ee instead of 93% ee), but differ-
ent yields (69% instead of 93%) (Scheme 49).
These results suggest that both reactions proceed through the same intermediate
composed of an aldimine and BINOL phosphate 3o (Scheme 50). Protonation of
either (E)- or (Z)-enecarbamate 125a to furnish an iminium ion via ionic transition
states is considered as the rate-determining step. This mechanism is supported by
the observation that polar, but protophobic acetonitrile is a powerful solvent in
terms of reactivity. A significant advantage of Brønsted acid-catalyzed transforma-
tions of enecarbamates derived from aliphatic aldehydes is the in situ generation of
the corresponding imines since the latter are difficult to isolate. Terada’s approach
allows for the preparation of alkyl 3-indolyl amines and thus complements You’s
synthesis of mainly aryl ones.
Boc
HN
(E )-125a
H
Boc
Me HN
(R)-3o (5 mol%) NHBoc indole
or X*
CH3CN, 0 °C, 24 h − HX* Et
Et H
Boc NH
HN
(Z )-125a 126a
Me
H from (E)-125a: 69%, 94% ee
from (Z)-125a: 93%, 93% ee
Scheme 50 Friedel–Crafts alkylation of indoles with (E)- or (Z)-enecarbamates
Shortly after the discovery of the first asymmetric phosphoric acid-catalyzed

transformation of enecarbamates, Zhou et al. expanded the scope of the Friedel–Crafts
alkylation of indoles 29 with electron-rich alkenes to enamides 127 (Scheme 51) [74].
Ac R2
Ac R2 HN
HN (S)-3o (10 mol%)
+ R1
N toluene, 4 Å MS Me
R1 H 0-25 °C, 6-48 h NH
127 29 128
R2 = H, 5-MeO, 94-99%
R1 = aryl 73-97% ee
4-HO, 5-Br
Ac Ac Ac HO
MeO HN HN NH
Ph
Me F3C Me Me
NH NH NH
99%, 97% ee 98%, 93% ee 95%, 86% ee
Scheme 51 Friedel–Crafts reaction of enamides and indoles

BINOL phosphate (S)-3o (10 mol%, R = 2,4,6-iPr3-C6H2) turned out to be the catalyst
of choice and gave N-acetylated 3-indolyl amines 128 bearing a quaternary stere-
ogenic center in excellent yields (94–99%) with high enantioselectivities (73–97%
ee). Enamides derived from aryl-methyl ketones as well as indoles with various
substituents could be employed.
Mechanistically, the Brønsted acid-catalyzed Friedel–Crafts reaction presumably
involves a tautomerism of enamide 127 to the corresponding N-acetyl-protected
imine. Subsequent addition of indole 29 affords amide 128 (Scheme 52).
Ac R2
Ac HN
HN HX* NHAc indole
X* R1
− HX* Me
R1 Me R1
NH
127 128
Scheme 52 Mechanism of the Friedel–Crafts reaction of enamides and indoles
2.4.2 Aziridines
In 2007, Antilla and coworkers described the Brønsted acid-catalyzed desymmetrization

of meso-aziridines giving vicinal diamines [75]. In recent years, chiral phosphoric acids
have been widely recognized as powerful catalysts for the activation of imines.
However, prior to this work, electrophiles other than imines or related substrates like
enecarbamates or enamides have been omitted. In the presence of VAPOL-derived
phosphoric acid catalyst (S)-16 (10 mol%) and azidotrimethylsilane as the nucleophile,
aziridines 129 were converted into the corresponding ring-opened products 130 in good
yields and enantioselectivities (49–97%, 70–95% ee) (Scheme 53).
F3C
R CF3
O
N H
R N
R (S)-16 (10 mol%), TMSN3
CF3 O
DCE, RT, 21-91 h
R N3
F3 C
129 130
R = alkyl, aryl 49-97%
70-95% ee
NHR1 NHR1 NHR1 Me NHR1 Ph NHR1

O
N3 N3 N3 Me N3 Ph N3
130a
97%, 95% ee 64%, 91% ee 49%, 87% ee 88%, 86% ee 95%, 83% ee
R1 = bis(3,5-trifluoromethyl)benzoyl
Scheme 53 Desymmetrization of meso-aziridines

The proper choice of the nitrogen substituent at the aziridine moiety was found
to be crucial. Whereas both Boc and Cbz protecting groups resulted in the forma-
tion of the ring-opened product as the racemate in moderate yield, use of the
3,5-bis(trifluoromethyl)benzoyl group afforded product 130 in high yield and 95%
ee. The authors’ preliminary mechanistic studies suggest a silyl phosphate as the
catalytically active species, which is likely generated by displacement of the azide
in the first step of the reaction.
2.4.3 Trichloroacetimidates (Episulfonium Ion Precursors)
In 2008, Toste and coworkers reported the desymmetrization of meso-episulfonium

ions 131 generated in situ from ring closure of sulfides 132 featuring a b-trichloro-
acetimidate leaving group [76]. Chiral BINOL-derived phosphoric acid (S)-3o (15
mol%, R = 2,4,6-iPr3-C6H2) triggered the formation of the intermediate meso-epi-
sulfonium ions 131 through protonation of the trichloroacetimidate 132, followed by
liberation of trichloroacetamide (133) and concurrent ring closure. Ring opening of
the meso-episulfonium cations 131 paired with the resultant chiral phosphate coun-
teranion by various alcohols 92 occured in excellent yields of trans-b-alkoxy
sulfides 134 (90–98%) with high asymmetric induction (87–92% ee). Subsequent
proton transfer completes the catalytic cycle and regenerates the phosphoric acid
catalyst 3o (Scheme 54). Although phosphate 3o initiates this transformation by
protonation, it is mechanistically distinct from reactions where an imine is activated
by a Brønsted acid.
HN CCl3
Ph O Ph OR2
(S)-3o (15 mol%)
R2OH
toluene, RT, 12 h
Ph SR1 Ph SR1
132 92 134
R 1, R2 = alkyl 90-98%
87-92% ee
HX* Ph R2OH
SR1
Ph X*
O 131
H2N CCl3
133
Ph O Ph O Ph O
SO2Ph
Ph SMe Ph SBn Ph SMe

97%, 91% ee 94%, 87% ee 98%, 92% ee
Scheme 54 Desymmetrization of meso-episulfonium ions

2.4.4 Carbonyl Compounds
In 2008, Terada et al. developed an aza-ene-type reaction between ethyl glyoxylate

135 and various enecarbamates 136 and 137 catalyzed by BINOL phosphates (R)-
3b or (R)-3e (5 mol%, R = Ph or 4-tBu–C6H4) (Scheme 55) [77]. Whereas simple
enecarbamates 133 and (E)-enecarbamates 137 furnished the products 138 and 139
in high yields with high enantio- and diastereoselectivities (73–93%, 8.1:1 to >99:1
anti/syn, 95 to >99% ee(anti)), (Z)-isomers 137 gave poor results (11–74%, 1:1–
11.5:1 anti/syn, 8–28% ee(anti), 69–88% ee(syn)).
DFT computational studies suggest the presence of a double hydrogen bond
between the catalyst and ethyl glyoxylate (Fig. 12, a). On this basis the authors
rationalized the experimental observation that sterically demanding aryl groups at
the 3,3¢-positions of the binaphthyl core decrease the catalytic efficiency with
regard to activity as well as enantioselectivity. However, an alternative mechanism
involving bifunctional catalysis can also be envisaged (Fig. 12, b) [78]. This report
constitutes the first example of aldehyde activation by a BINOL-derived phosphoric
acid and is – although restricted to glyoxylates as reactive aldehydes – important
in this respect.
In the same year, chiral phosphoric acids were found to catalyze the enantioselective
Baeyer–Villiger (BV) oxidation of 3-substituted cyclobutanones 140 with aqueous
CO2Me CO2Me
O HN OH N OH O
(R)-3b (5 mol%) H3O+
EtO2C H R1 EtO2C R1
EtO2C R1
4 Å MS, CH2Cl2, RT, 1 h
135 136 138

R1 = Me, Ph R1 = Me: 78%, 95% ee
R1 = Ph: 93%, 95% ee
with (E)- and (Z)-enecarbamates:
CO2Me
O HN OH O OH O
R2 (R)-3e (5 mol%)
EtO2C H R1 EtO2C R 1 EtO2C R1
4 Å MS, CH2Cl2, RT, 1-24 h
then H3O+ R2 R2
135 137 anti-139 syn-139

R1 = alkyl, Ph; R2 = alkyl
OH O OH O OH O OH O
EtO2C Ph EtO2C Et EtO2C EtO2C Ph

Me Me Et
with (E)-137a: with (E)-137b: with (Z)-137c:

73%, >99:1 anti/syn 73%, 24:1 anti/syn 89%, 8.1:1 anti/syn 67%, 11.5:1 anti/syn
>99% ee(anti) 99% ee(anti) 99% ee(anti) 8% ee(anti)
53% ee(syn) 56% ee(syn) 98% ee(syn) 74% ee(syn)
Scheme 55 Aza-ene-type reaction between ethyl glyoxylate and various enecarbamates

CO2Me
a b N R1
H CO2Et H
O O O O H
* P O * P
O O H O O H O
CO2Et
Fig. 12 Proposed activation modes
O O
(R)-14n (10 mol%)
R O + H 2 O2
CHCl3, −40 °C, 18-36 h
R
140 141
R = aryl, alkyl 91-99%
55-93% ee
O O O O O O
O O O O
Ph Me F Bn
99% 99% 99% 91% 99%
88% ee 93% ee 84% ee 86% ee 58% ee
Scheme 56 Baeyer–Villiger oxidation of 3-substituted cyclobutanones
H
a b H O
R O
O O HO O O
* P * P O R
Fig. 13 Proposed working models O O O O O H
hydrogen peroxide (30%) as the oxidant by Ding and coworkers (Scheme 56) [79].
H8-BINOL-derived phosphoric acid (R)-14n (10 mol%, R = 1-pyrenyl) bearing bulky
1-pyrenyl groups at the 3,3¢-positions proved to be effective giving high yields of
g-lactone products 141 (91–99%) with good enantioselectivities (82–93% ee) in case of
3-aryl-substituted cyclobutanones. g-Lactones resulting from the BV oxidation of
3-alkyl-substituted substrates were still obtained in high yields (99%) albeit with mod-
erate enantioselectivities (55–58% ee).
The authors propose a working model relying on the commonly accepted
mechanism for BV reactions (Fig. 13, a). Thus the sense of asymmetric induction
is determined by the conformation of the Criegee intermediate, which is dictated by
the chiral environment created by the catalyst. However, an alternative noncova-
lent, bifunctional mechanism may be considered (Fig. 13, b) [80]. This work
represents the first example of a Brønsted acid-catalyzed asymmetric BV reaction

and features the highest enantioselectivity values attained in catalytic BV reactions of
3-substituted cyclobutanones with chemical catalysts.
2.4.5 Alkenes
Akiyama and coworkers extended the scope of electrophiles applicable to asym-

metric Brønsted acid catalysis with chiral phosphoric acids to nitroalkenes
(Scheme 57). The Friedel–Crafts alkylation of indoles 29 with aromatic and
aliphatic nitroalkenes 142 in the presence of BINOL phosphate (R)-3r (10 mol%,
R = SiPh3) and 3-Å molecular sieves provided Friedel–Crafts adducts 143 in high
yields and enantioselectivities (57 to >99%, 88–94% ee) [81]. The use of molecular
sieves turned out to be critical and significantly improved both the yields and
enantioselectivities.
N-Methyl indole gave inferior results under the optimized conditions (11%, 0% ee).
Therefore, the authors assume the reaction to proceed via a nine-membered transition
state with the phosphoric acid activating the nitroalkene and at the same time binding
the indole through a hydrogen bond to the indole N–H moiety (Fig. 14).
R1 R2
R 1
NO2 (R)-3r (10 mol%) NO2
N R2 3 Å MS, benzene/DCE (1:1)
H HN
−35 °C, 2-10 d
29 142 143
1 2 57 to >99%
R = H, Cl, Br, Me; R = aryl, thienyl, alkyl 88-94% ee
Br
S
Ph Ph Pr
NO2 NO2 NO2 NO2
HN HN Me HN HN
71%, 90% ee 72%, 90% ee 70%, 94% ee 70%, 90% ee
Scheme 57 Friedel–Crafts alkylation of indoles with nitroalkenes
N
O O H
O H
* P
O O N
Fig. 14 Proposed activation mode H O R2
In 2008, the Ackermann group reported on the use of phosphoric acid 3r (10
mol%, R = SiPh3) as a Brønsted acid catalyst in the unprecedented intramolecular
hydroaminations of unfunctionalized alkenes alike 144 (Scheme 58) [82]. BINOL-
derived phosphoric acids with bulky substituents at the 3,3¢-positions showed
improved catalytic activity compared to less sterically hindered representatives.
Remarkably, this is the first example of the activation of simple alkenes by a
Brønsted acid . However, the reaction is limited to geminally disubstituted pre-
cursors 144. Their cyclization might be favored due to a Thorpe–Ingold effect.
An asymmetric version was attempted by means of chiral BINOL phosphate (R)-3f
(20 mol%, R = 3,5-(CF3)2–C6H3), albeit with low enantioselectivity (17% ee).
Bn 3r (10 mol%) Bn
Ph N or (R)-3f (20 mol%) Ph N
H
Ph (CHCl2)2 or dioxane Ph
Me
130 °C, 20-23 h
144
3r: 97%
(R )-3f: 72%, 17% ee
Scheme 58 Intramolecular hydroamination of an unfunctionalized alkene
3 Chiral N-Triflyl Phosphoramides
Until 2006, a severe limitation in the field of chiral Brønsted acid catalysis was the
restriction to reactive substrates. The acidity of BINOL-derived chiral phosphoric
acids is appropriate to activate various imine compounds through protonation and
a broad range of efficient and highly enantioselective, phosphoric acid-catalyzed
transformations involving imines have been developed. However, the activation of
simple carbonyl compounds by means of Brønsted acid catalysis proved to be
rather challenging since the acid ity of the known BINOL-derived phosphoric acids
is mostly insufficient. Carbonyl compounds and other less reactive substrates often
require a stronger Brønsted acid catalyst.
Replacement of an X = O moiety by a strong electron acceptor, such as X = NTf,
is known to enhance significantly the acid ity of a Brønsted acid (Fig. 15) [83].
O O NTf NTf NHTf

O O
X X X
OH OH O
Ph OH Ph NHTf
a b pKa = 20.7 pKa = 11.1
X = RC, RS=O, etc.
pKa of a > pKa of b
Fig. 15 Enhancement of the acidity of a Brønsted acid by a strong electron acceptor

In 2006, Yamamoto and Nakashima picked up on this and designed a chiral

N-triflyl phosphoramide as a stronger Brønsted acid catalyst than the phosphoric
acids based on this concept. In their seminal report, they disclosed the preparation
of new chiral BINOL-derived N-triflyl phosphoramides and their application to
the asymmetric Diels–Alder (DA) reaction of a,b-unsaturated ketones with sily-
loxydienes [83]. As depicted in Scheme 59, chiral N-triflyl phosphoramides of
the general type 4 are readily synthesized from the corresponding optically active
3,3¢-substituted BINOL derivatives 142 through a phosphorylation/amidation
route.
R R R
OH POCl3, DMAP, Et3N O O TfNH2 O O

P P
OH CH2Cl2, 0 °C ~ RT, 2 h O Cl EtCN, RT ~ reflux O NHTf
R R R
145 (S)-4
(S)-4b: R = Ph
(S)-4o: R = 2,4,6-iPr3-C6H2
Scheme 59 Preparation of chiral BINOL-derived N-triflyl phosphoramides
Whereas the established phosphoric acids showed no catalytic activity, N-triflyl

phosphoramide (S)-4o (5 mol%, R = 2,4,6-iPr3–C6H2) proved to be a highly effec-
tive catalyst for the DA reaction of ethyl vinyl ketone (146) with various silyloxy-
dienes 147 giving ready access to highly enantioenriched endo-DA products 148 in
good yields (35 to >99%, 82–92% ee) (Scheme 60).
Me
O COEt
OSiR23
Et (S)-4o (5 mol%)
R1 R23SiO
Me toluene, -78 °C, 12 h
R1
146 147 148
R1, R2 = alkyl 35 to >99%
82-92% ee
Me Me Me
COEt COEt COEt
Me
COEt TIPSO TIPSO TIPSO
TBSO
Me OTBS OH OBz
43%, 92% ee >99%, 92% ee 35%, 82% ee >99%, 91% ee
Scheme 60 Diels–Alder reaction of ethyl vinyl ketone with silyloxydienes

The authors observed a significant difference in reactivity between N-triflyl

phosphoramides 4o and 4b. Catalyst 4b (R = Ph) furnished only a trace amount of
the desired DA product probably due to its rapid deactivation through silylation by
the silyloxydiene. In a control experiment, preformed silylated 4b turned out to be
no longer catalytically active. This observation confirms the crucial role of the
bulky 2,4,6-triisopropylphenyl substituents at the 3,3¢-positions of the binaphthyl
scaffold of 4o to suppress silylation under the reaction conditions. The Brønsted
acid-catalyzed DA reaction showed high functional group compatibility, tolerating
even free hydroxyl groups in contrast to metal Lewis acid-catalyzed versions.
In 2007, Rueping and coworkers developed a Brønsted acid-catalyzed asymmetric
Nazarov cyclization, which is one of the most versatile methods for the synthesis of
cyclopentenones [84]. This report constitutes the first example of an enantioselective
organocatalytic electrocyclic reaction (Scheme 61). Various BINOL phosphates were
found to mediate the cyclization of dienones 149 and furnished the corresponding
products 150 in good enantioselectivities (up to 82% ee). However, improved reactivity,
diastereo- and enantiocontrol was achieved by using N-triflyl phosphoramide (R)-
4l (2 mol%, R = 9-phenanthryl) as the catalyst. Thus, alkyl, aryl- as well as dialkyl-
substituted cyclopentenones 150 were obtained in good yields and diastereoselectivities
(45–92%, 1.5:1–9.3:1 cis/trans) along with high enantioselectivities (86–93% ee(cis),
90–98% ee(trans)) within short reaction times.
O O O R
O R1 (R)-4l (2 mol%) O O
R1 R1 O O
CHCl3, 0 °C, 1-6 h P
R2 NHTf
O
R2 R2
149 150
R
R1 = alkyl; R2 = alkyl, aryl 45-92%
1.5:1-9.3:1 cis/trans (R)-4l: R = 9-phenanthryl
86-93% ee(cis), 90-98% ee(trans)
HX*
H H H *X
O X* O X* O H
O R1 O R1 O R1
R2 R2 R2
4π conrot. H
O O
O O
Me Pr
O O
O O
Pr
O
Ph
O
92%, 9.3:1 cis/trans 85%, 3.2:1 cis/trans 68%, 86% ee 83%, 1.5:1 cis/trans
88% ee(cis), 98% ee(trans) 93% ee(cis), 91% ee(trans) 87% ee(cis), 92% ee(trans)
Scheme 61 Nazarov cyclization of dienones

Contrary to the cis-selective Brønsted acid-catalyzed Nazarov reaction, known

metal-catalyzed asymmetric versions often generate the trans-products. Since the
cis-cyclopentenones could be readily isomerized to the corresponding trans-products
without loss of optical purity (Scheme 62), the advantage of the organocatalytic
method is that it provides access to both diastereomers of 150 with high
enantioselectivity.
O O
O O
basic alumina
Et Et
CH2Cl2,RT, 24 h
Ph Ph
cis-147a trans-147a
92% ee 92% ee
Scheme 62 Isomerization of cis- to trans-cyclopentenones
Another study of the Rueping group revealing the great potential of N-triflyl
phosphoramides as chiral Brønsted acid catalysts deals with enantioselective 1,2-
and 1,4-additions of indoles 151 to b,g-unsaturated a-ketoesters 152 (Scheme 63) [85].
Among all the N-triflyl phosphoramides tested in the Friedel–Crafts alkylation of
indoles 151, only chiral H8-BINOL-derived N-triflyl phosphoramide derivative
(R)-153r (5 mol%, R = SiPh3) selectively triggered the conjugate addition (Scheme
64). All the other N-triflyl phosphoramides provided bisindole 154 as the major
product (Scheme 63).
Me
N
Ph O
O N-triflyl CO2Me
phosphoramides * CO2Me Ph
N Ph CO2Me or
N
Me Me N
148a 149a Me 151a
1,4-addition product bisindole
Scheme 63 Competing reaction pathways: 1,2- and 1,4-addition
The excellent chemoselectivity achieved with catalyst 153r may be attributed to

its steric properties: the bulky 3,3¢-silyl substituents (R = SiPh3) ensure an effective
shielding of the carbonyl group and thus prevent 1,2-addition. In the presence of
catalyst 153r (5 mol%), the reaction of N-methylindoles 151 and b,g-unsaturated
a-ketoesters 152 furnished the 1,4-addition products 155 in moderate to good
yields and enantioselectivities (43–88%, 80–92% ee) (Scheme 64).
O R1 Ar O SiPh3
R1 (R)-153r (5 mol%)
N Ar CO2R 2 CO2R2
CH2Cl2, -75 °C, 15-24 h O O
Me N P
151 152 155 O NHTf
Me
R1 = H, Br, Me; R2 = alkyl 43-88%
80-92% ee SiPh3
Me
(R)-153r
Ph O O O
CO2Et CO2Me CO2Me
N N N
Me 81%, 86% ee Me 70%, 90% ee Me 69%, 92% ee
Scheme 64 Conjugate addition of indoles to b,g-unsaturated a-ketoesters
An intriguing feature is that the previously unknown bisindoles 154 display

atropisomerism as a result of the rotation barrier about the bonds to the quaternary
carbon center. With the use of N-triflyl phosphoramide (R)-4l (5 mol%, R = 9-
phenanthryl), bisindole 154a could be obtained in 62% ee. Based on their experi-
mental results, the authors invoke a Brønsted acid-catalyzed enantioselective,
nucleophilic substitution following the 1,2-addition to rationalize the formation of
the bisindoles 154 (Scheme 65).
Me
Ph Ph N
HO CO2Me MeO2C MeO2C
CO2Me
Ph X*
HX* N-methyl indole Ph
N − H2 O N − HX*
N
Me Me X* Me N
1,2-addition product Me 154a
Scheme 65 Proposed mechanism for the formation of the bisindole products
In 2008, Yamamoto et al. disclosed an asymmetric 1,3-dipolar cycloaddition of

diarylnitrones 156 with ethyl vinyl ether (157) (Scheme 66). Under the influence of
the bulky chiral N-triflyl phosphoramide (S)-4s (5 mol%, R = 2,6-iPr2-4-Ad-C6H2),
the endo-products 158 were formed as the major diastereomers in good yields and
enantioselectivities (66 to >99%, 7:1–32:1 endo/exo, 70–93% ee(endo)) [86]. High
asymmetric induction was achieved only with electron-deficient aryl groups on
the nitrones.
A previously reported AlMe-BINOL catalyzed version features exo-selectivity.
In this respect, the present endo-selective process is in sharp contrast and shows
R1 + O− R1 R
N OEt (S)-4s (5 mol%) N O
OEt
CHCl3, −40 to −55 °C, 1 h O O
H R2 R2 P
156 157 158 O NHTf
R1 = aryl; R2 = aryl, heteroaryl 66 to >99%
6.7:1-32.3:1 endo/exo R
70-93% ee(endo) i
Pr
Cl
(S)-4s: R = Ad
F
N O i
Pr
OEt
Ph N O
N O OEt
OEt
Ph F3C O
85%, 24:1 endo/exo 66%, 13.3:1 endo/exo 90%, 7.3:1 endo/exo
70% ee(endo) 93% ee(endo) 87% ee(endo)
Scheme 66 1,3-Dipolar cycloaddition of diarylnitrones with ethyl vinyl ether 154
how asymmetric Brønsted acid and metal Lewis acid catalysis can complement
one another. The authors rationalized the observed diastereoselectivity by means of
transition state (TS) structures a and b. Additional hydrogen bonding may stabilize
the endo-selective TS a whereas TS b, which leads to the exo-product, seems to be
disfavored because of steric repulsion (Fig. 16).
In the same year, Enders and coworkers reported an asymmetric one-pot, two-
step synthesis of substituted isoindolines 159 in the presence of chiral N-triflyl
phosphoramide (R)-4e (10 mol%, R = 4-NO2-C6H4) (Scheme 67) [87]. The cascade
was triggered by a Brønsted acid-catalyzed aza-Friedel–Crafts reaction of indoles 29
and N-tosyliminoenoates 160 followed by a DBU-mediated aza-Michael cyclization
of intermediates 161 to afford the isoindolines 159 in high yields (71–99%) and
short reaction times (10 min to 4 h) along with good enantioselectivities (52–90% ee).
Longer reaction times (16 h to 10 days) caused increasing formation of the bisindole
byproduct 162 (Scheme 68) along with amplified optical purity of isoindolines 159.
favored TS a disfavored TS b
H EtO
EtO R2 H R2
O O
X* H N H X* H N H
R1 R1
Fig. 16 Proposed transition state structures endo exo
R1
NH R1
NTs NH
R1 R2
(R)-4d (10 mol%) DBU
N conditions A or B R2 15 min R2
H NHTs
NTs
CO2R3
29 160 CO2R3
CO2R3
R1 = H, Br, OMe, CO2Me; R2 = H, F; R3 = alkyl 161 159
conditions A: CH2Cl2, RT, 10 min-4 h
MeO Br NO2
NH NH NH NH
F
NTs NTs NTs NTs O O
P
O NHTf
CO2Me CO2t Bu CO2Me CO2Me
94%, 90% ee 93%, 52% ee 85%, 82% ee 75%, 82% ee
conditions B: PhCl or PhCl/CHCl3 (1:1), RT, 16 h-10 d NO2

(R)-4d
71%, 96% ee 34%, 98% ee 57%, >98% ee 52%, >98% ee
Scheme 67 One-pot, two-step synthesis of substituted isoindolines
Thus, isoindolines 159 could be obtained in excellent enantioselectivies albeit with

decreased yield (31–71%, 96 to >98% ee).
This observation denotes a stereoablative kinetic resolution taking place during
the acid-catalyzed step, which was confirmed in experiments with racemic interme-
diate 161a giving scalemic Friedel–Crafts product 161a at 55% conversion upon
treatment with N-triflyl phosphoramide (R)-4d and indole (Scheme 68).
NH NH NH
(R)-4d (10 mol%)

NHTs indole (0.55 equiv) NHTs
PhCl, RT, 2 d NH
55% conv.
CO2Me CO2Me CO2Me
racemic 161a 161a, 66% ee bisindole byproduct 162
H
NH N NH
X*
HX* indole
X* X*
NH2Ts
− TsNH2
CO2Me CO2Me CO2Me
Scheme 68 Stereoablative kinetic resolution

An asymmetric intermolecular carbonyl-ene reaction catalyzed by 1 mol% of

chiral N-triflyl phosphoramide (R)-4t (1 mol%, R = 4-MeO-C6H4) was developed
by Rueping and coworkers (Scheme 69) [88]. Various a-methyl styrene derivatives
163 underwent the desired reaction with ethyl a,a,a-trifluoropyruvate 164 to
afford the corresponding a-hydroxy-a-trifluoromethyl esters 165 in good yields
along with high enantioselectivities (55–96%, 92–97% ee). The presence of the
trifluoromethyl group was crucial and the use of methyl pyruvate or glyoxylate
instead of 164 resulted in lower reactivities or selectivities.
OMe
O (R)-4t (1 mol%) F3C OH

O O
Ar F3C CO2Et o-xylene, 10 °C, 22-60 h Ar CO2Et P
O NHTf
163 164 165
55-96%
92-97% ee
(R)-4t OMe
F3C OH F3C OH F3C OH

CO2Et CO2Et CO2Et F3C OH
Me Cl Ph CO2Et
92%, 96% ee 55%, 93% ee 93%, 95% ee 76%, 96% ee
Scheme 69 Carbonyl-ene reaction of a-methyl styrenes and ethyl a,a,a-trifluoropyruvate
In 2008, Yamamoto et al. further modified the parent chiral N-triflyl phosphoramide
structure by substitution of the oxygen in the P=O bond with sulfur or selenium.
This should increase the acidity and reactivity of the Brønsted acid according to the
general rule that acidity increases as it descends in a column of the periodic table
due to better stabilization of the conjugate base in a larger size atom 2. Various N-triflyl
thio- or selenophosphoramides were synthesized from optically active BINOL
derivatives by thio- or selenophosphorylation with PSCl3 or PCl3 followed by oxi-
dation with selenium powder and amidation of the intermediate thio- or seleno-
phosphoryl chlorides with TfNH2. Among all the catalysts tested, chiral N-triflyl
thiophosphoramide (S)-166u (5 mol%, R = 4-tBu-2,6-iPr2-C6H2) showed the best
catalytic potential in the asymmetric protonation reaction of various six- and seven-
membered cyclic silyl enol ethers 167 with phenol as an achiral proton source
(Scheme 70) [89]. a-Substituted cyclic ketones 168 were obtained in excellent
yields (95–99%) with good enantioselectivities (54–90% ee), particularly in case of
aryl-substituted silyl enol ethers.
2
for example: pKa (PhOH) = 18.0, pKa (PhSH) = 10.3, pKa (PhSeH) = 7.1
OTMS O
R (S)-166u (5 mol%) R
PhOH (1.1 equiv)
toluene, RT, 6-40 h
n n
167 168
R = aryl, alkyl 95-99%
54-90% ee
R
R n yield [%] ee [%]
O S
Ph 1 97 82 P
O NHTf
2-Naphthyl 1 99 86
2-Naphthyl 2 97 90
R
4-MeOC6H4 1 98 84
iPr
2-MeOC6H4 1 97 72
Cy 1 96 64 t Bu
(S)-166u: R =
iPr
Scheme 70 Enantioselective protonation of silyl enol ethers
Cycloheptanones attained better enantioselectivity values than their six-membered

analogs and the use of alkyl-substituted silyl enol ethers resulted in only moderate
enantioselectivities. Indeed, replacement of P=O by P=S or P=Se in the phospho-
ramide catalyst led to improved results in terms of reactivity as well as enantioselec-
tivity. The catalyst loading could be decreased to 0.05 mol% without a deleterious
effect on the enantioselectivity (one example). Optimization experiments revealed
the critical influence of the achiral proton source on the reactivity and enantio
selectivity. This observation suggests a two-step mechanism for the protonation reac-
tion (Scheme 71).
HX* PhOH [PhOH2]+[X*]−
OTMS O
TMS
R [PhOH2]+[X*]− O R
or HX* H
X* R
PhOH PhOTMS
167 168
Scheme 71 Proposed reaction path

4 Chiral Carboxylic Acids
The key feature of Brønsted acid catalysis is often the choice of a catalyst with the
appropriate acidity for particular substrate classes. Whereas less reactive substrates
require stronger Brønsted acids than the widely used phosphoric acids for activa-
tion, acid-sensitive substrates tend to decompose under strongly acidic conditions.
Thus, weaker Brønsted acid catalysts may prove beneficial.
In 2005, Yamamoto and Momiyama reported on the use of chiral carboxylic acids
in asymmetric nitroso aldol reactions of achiral enamines (Scheme 72) [90]. Catalytic
amounts of (S)-1-naphthyl glycolic acid ((S)-169) (30 mol%) led to the selective
formation of O-nitroso aldol products 170 in good yields with high enantioselectivi-
ties (63–91%, 70–93% ee) using piperidine-derived enamines 171 and nitrosoben-
zene (172) as an electrophile. The conformational rigidity of catalyst 169 may result
from an internal hydrogen bond between the carboxylic acid moiety and the oxygen
lone pair of the hydroxyl group and accounts for the good selectivities observed.
N O
O 169 (30 mol%) O Ph O
N
N H
Ph Et2O, −88 ~ −78 °C, 12 h OH
n n
R R R R OH
171 172 170 169
R = H, Me, OAlkyl 63-91%
n = 0, 1 70-93% ee
O O
O O Ph O Ph O
N N
O Ph H H O Ph
N N
H H
Me Me O O
77%, 92% ee 91%, 90% ee 83%, 93% ee 63%, 70% ee
Scheme 72 Asymmetric nitroso aldol reactions of achiral enamines
Exclusive formation of the N-nitroso aldol product from similar starting materials
was observed in the presence of 1-naphthyl TADDOL (30 mol%) in toluene (63–
81%, 65–91% ee; n = 1, 2).
In 2007, Maruoka et al. introduced chiral dicarboxylic acids consisting of two
carboxylic acid functionalities and an axially chiral binaphthyl moiety. They applied
this new class of chiral Brønsted acid catalyst to the asymmetric alkylation of diazo
compounds with N-Boc imines [91]. The preparation of the dicarboxylic acid cata-
lysts bearing aryl groups at the 3,3¢-positions of the binaphthyl scaffold follows a
synthetic route, which has been developed earlier in the Maruoka laboratory [92].
Dicarboxylic acid (R)-5v (5 mol%, R = 4-tBu-2,6-Me2-C6H2) in the presence of 4Å

molecular sieves displayed the optimal conditions for the investigated Friedel–
Crafts-type reactions of various arylaldehyde-derived N-Boc imines 11 with tert-
butyldiazoacetate 22a or dimethyl diazomethylphosphonate 173 (Scheme 73). In
both cases the corresponding products 174 and 175 were obtained in good yields
with high enantioselectivities (38–89%, 85–96% ee). Notably, the reaction of
N-Boc imine 11a (R1 = Ph) with 22a in the presence of phosphoric acid 3a (10
mol%, R = H) furnished beside the a-diazo-b-amino esters 174a (R1 = Ph) a con-
siderable amount of the E/Z isomers of the corresponding enecarbamate.
Boc NHBoc R
N H CO2t Bu (R)-5v (5 mol%), 4 Å MS
1 CO2t Bu
N2 CH2Cl2, 0 °C, 5-72 h R CO2H
R1 H
N2
CO2H
11 22a 174
R1 = aryl, 2-furyl 38-89%
85-96% ee R
R1 yield [%] ee [%]
Me
2-tolyl 53 90
t Bu
4-tolyl 79 95 (R)-5v: R =
4-ClC6H4 89 96
Me
4-MeOC6H4 72 95
Boc H PO(OMe)2 (R)-5v (5 mol%), 4 Å MS NHBoc

N
PO(OMe)2
N2 CH2Cl2, 0 °C, 46-85 h R2
R2 H
N2
11 173 175
R2 = aryl, 2-furyl 40-89%
R2 yield [%] ee [%] 92-96% ee
Ph 68 96
4-tolyl 68 96
4-ClC6H4 81 96
4-MeOC6H4 40 95
Scheme 73 Friedel–Crafts-type alkylation of diazo compounds with N-Boc imines
In 2008, the same group employed chiral dicarboxylic acid (R)-5v (5 mol%, R
= 4-tBu-2,6-Me2-C6H2) as the catalyst in the asymmetric addition of aldehyde N,N-
dialkylhydrazones 81 to aromatic N-Boc-imines 11 in the presence of 4 Å molecu-
lar sieves to provide a-amino hydrazones 176, valuable precursors of a-amino
ketones, in good yields with excellent enantioselectivities (35–89%, 84–99% ee)
(Scheme 74) [93]. Aldehyde hydrazones are known as a class of acyl anion equiv-
alents due to their aza-enamine structure. Their application in the field of asym-
metric catalysis has been limited to the use of formaldehyde hydrazones (Scheme
30). Remarkably, the dicarboxylic acid-catalyzed method applied not only to for-
maldehyde hydrazone 81a (R1 = H) but also allowed for the use of various aryl
aldehyde hydrazones 81b (R1 = Ar) under slightly modified conditions. Prior to this
Boc NHBoc
N H NN (R)-5v (5 mol%), 4 Å MS
NN
CHCl3 R1
R1 H R2 −20 °C, 4 h (with R2 = H) R2
−30 °C, 96 h (with R2 = aryl)
11 81a-b 176
R1 = aryl, 2-furyl; R2 = H, aryl 35-89%
84-99% ee
NHBoc NHBoc NHBoc NHBoc

NN NN NN NN
Ph Ph
H Ph Me Ph
Cl
76%, 99% ee 66%, 95% ee 51%, 92% ee 77%, 90% ee
Scheme 74 Addition of aldehyde hydrazones to N-Boc-imines
report, this class of practical acyl anion equivalents was completely unexplored in
asymmetric synthesis. In the present transformation dicarboxylic acid 5v featured
higher catalytic efficiency in terms of both activity and asymmetric induction
compared to phosphoric acid (R)-14j earlier employed by the Rueping group
[52].
Chiral dicarboxylic acid (R)-5g (5 mol%, R = Mes) bearing simpler mesityl-
substituents at the 3,3¢-positions was found to catalyze efficiently the trans-
selective asymmetric aziridination of N-aryl-monosubstituted diazoacetamides 177
and aromatic N-Boc imines 11 (Scheme 75) [94]. In sharp contrast to previous
reports on this generally cis-selective sort of aziridination, this method exhibited
unique trans-selectivity and afforded exclusively the trans-aziridines 178 in moderate
to good yields along with excellent enantioselectivities (<20–71%, 89–99% ee).
The 1,2-aryl shift products 179 were observed as side products in varying ratios
(178:179= 56:44–90:10). Diazoacetamides were chosen instead of diazoesters. Due
O
Boc H Boc BocHN O R
O
N NHAr2 (R)-5g (5 mol%), 4 Å MS N
1 2 NHAr2 CO2H
N2 toluene, 0 °C, 2-8 h Ar NHAr
Ar1 H Ar1
CO2H
11 177 178 179
<20-71%, >20:1 trans / cis R
89-99% ee
178:179 = 56:44-90:10 Me
Boc Boc Boc Boc (R)-5g: R = Me

O O O O
N N N N
Cl
Ph Ph Ph Ph Me
Me OMe
61%, 97% ee 50%, 91% ee 51%, 99% ee 61%, 97% ee
178:179 = 90:10 178:179 = 77:23 178:179 = 73:27 178:179 = 87:13
Scheme 75 Aziridination of diazoacetamides and N-Boc imines

to their inherent lower a-acidity they are capable of resisting proton abstraction in
the course of the reaction, which renders aziridine formation via the aza-Darzens
route possible. The intervention of a different mechanism is reflected in the inverted
enantiofacial selectivity compared to the previously reported dicarboxylic acid-
catalyzed Mannich reactions of diazoesters [91].
5 Chiral Sulfonic Acids
In 2006, Xu and Xia et al. revealed the catalytic activity of commercially available
d-camphorsulfonic acid (CSA) in the enantioselective Michael-type Friedel–Crafts
addition of indoles 29 to chalcones 180 attaining moderate enantiomeric excess
(75–96%, 0–37% ee) for the corresponding b-indolyl ketones 181 (Scheme 76)
[95]. This constitutes the first report on the stereoselectivity of d-CSA-mediated
transformations. In the course of their studies, the authors discovered a synergistic
effect between the ionic liquid BmimBr (1-butyl-3-methyl-1H-imidazolium bro-
mide) and d-CSA. For a range of indoles 29 and chalcone derivatives 180, the
preformed BmimBr-CSA complex (24 mol%) gave improved asymmetric induc-
tion compared to d-CSA (5 mol%) alone, along with similar or slightly better yields
of b-indolyl ketones 181 (74–96%, 13–58% ee). The authors attribute the beneficial
effect of the BmimBr-d-CSA combination to the catalytic Lewis acid activation of
Brønsted acids (LBA). Notably, the direct addition of BmimBr to the reaction mix-
ture of indole, chalcone, d-CSA in acetonitrile did not influence the catalytic
efficiency.
O BmimBr-D-CSA complex (24 mol%) R Ar1 O

R or D-CSA (5 mol%)
N Ar1 Ar2 CH3CN, RT, 12 h Ar2
H
HN
29 180 181
R = H, 5-Br
− 74-96%
Br
N+ N BmimBr-D-CSA: 13-58% ee
O D-CSA: 0-37% ee
D-CSA SO3H BmimBr
Ph O Cl O Ph O
Ph Ph
HN HN HN OMe
BmimBr-D-CSA: 96%, 19% ee BmimBr-D-CSA: 92%, 29% ee BmimBr-D-CSA: 85%, 26% ee
D-CSA: 76%, 18% ee D-CSA: 96%, 0% ee D-CSA: 75%, 21% ee
Scheme 76 Michael-type Friedel–Crafts addition of indoles to chalcones

6 Summary and Outlook
Specific Brønsted acid catalysis is a popular field within the domain of asymmetric
organocatalysis. Since the introduction of stronger chiral Brønsted acids as power-
ful catalysts for enantioselective synthesis in 2004, numerous asymmetric Brønsted
acid-catalyzed transformations have been developed.
Chiral phosphoric acids mediate the enantioselective formation of C–C, C–H,
C–O, C–N, and C–P bonds. A variety of 1,2-additions and cycloadditions to imines
have been reported. Furthermore, the concept of the electrophilic activation of imines
by means of phosphates has been extended to other compounds, though only a few
examples are known. The scope of phosphoric acid catalysis is broad, but limited to
reactive substrates. In contrast, chiral N-triflyl phosphoramides are more acidic and
were designed to activate less reactive substrates. Asymmetric formations of C–C,
C–H, C–O, as well as C–N bonds have been established. a,b-Unsaturated carbonyl
compounds undergo 1,4-additions or cycloadditions in the presence of N-triflyl
phosphoramides. Moreover, isolated examples of other substrates can be electrophil-
ically activated for a nucleophilic attack. Chiral dicarboxylic acids have also found
utility as specific acid catalysts of selected asymmetric transformations.
Given the wide range of chiral catalysts with different acidities and structures, we
anticipate new asymmetric transformations to arise in the near future. One challenge
that is likely to be addressed includes the Brønsted acid-catalyzed activation of new
substrate classes such as unactivated carbonyl compounds or simple olefins, which
will presumably require the design of even stronger chiral acids. There will probably
be further advances in the area of Brønsted acid-catalyzed multicomponent and
cascade reactions for the construction of complex molecules such as natural prod-
ucts or pharmaceuticals. Although stronger chiral Brønsted acids are mainly used as
catalysts for asymmetric synthesis in academia, it is likely that they will ultimately
be employed in industry as well. Furthermore, mechanistic studies along with com-
putational methods will presumably be applied to aid in the understanding and dis-
covery of new asymmetric Brønsted acid-catalyzed processes. It will definitely be
quite exciting to follow the development of the field over the next years.
Acknowledgments We thank Dr. Pilar García García and Steffen Müller for proofreading the
manuscript. B.L. thanks the current and previous members of his group for their contributions to
the field of asymmetric Brønsted acid catalysis. Generous support by the Max Planck Society, the
Deutsche Forschungsgemeinschaft (Priority Program Organocatalysis SPP1179), and the Fonds
der Chemischen Industrie (Kekulé fellowship to C.M.R., Silver Award to B.L.) is gratefully
acknowledged.
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Index
A Aziridinylaldehyde, 109
Abudinol, 213 Aziridomitosane, 261
Acetylacetone, to nitrostyrene, 12 Azlactones, alcoholytic DKR, 5
O-Acyl azlactones, 250 dynamic kinetic resolution (DKR), 5
Acyl transfer, catalyzed asymmetric, 236 Azodicarboxylate esters, 60
Acylase, artificial, 261
Acylation, 233
1,2-Addition, 323 B
Alcohol catalysts, 273 Baclofen, 246, 269
sec-Alcohols, kinetic resolution, 235 Benzaldehyde lyase (BAL), 85
Aldehydes, 29 Benzhydrylium ions, 34
a-aminations, 61 Benzoin, 77
asymmetric conjugate addition, 167 reaction, 81, 83
cyanosilylation, 136 Benzopyranone, 137
a-halogenations, 58 Benzotetramizole, 258
a-oxygenations, 62 Benzoylformate decarboxylase (BFD), 85
Aldol reactions, 41 Benzylidenecyclobutane oxide, 221
Aldolase enzymes, 31 Bicyclo[3.2.1]octan-3-ones, 206
N-Alkylimidazole-based catalysts, 259 Bicycloenediones, 104
Alpha-functionalization, 29 Bifunctional catalyst, 145
tert-Amine catalysts, 241 Binaphthylazepinium-based iminium
Amines, 29 salts, 226
primary, 325 Binaphthyl-based ketones, C2-symmetric, 202
Amino acid esters, enantio-enriched Binaphthyl-derived amine, chiral, 195
N-protected, 5 BINOL (1,1′-bi-2-naphthol), 5, 395
Aminocatalysis, 281 Biphenylazepinium-based iminium salts, 227
Ammonium ketones, 205 1,3-Bis(cyclohexyl)-imidazol-2-ylidene, 126
Anions, chiral, amines as catalysts, 330 Brønsted acids, 3
Asymmetric catalysis, 395 catalysis (BBA), 5
Asymmetric desymmetrisation (ASD), strong chiral, 395
233, 237 Brønsted base, 3, 145
Asymmetric epoxidation, 201 catalysts, 194
Asymmetric organocatalysis, 145 g-Butyrolactones, 118
Azadecalinones, 433 NHC promoted synthesis, 130
Azadiene Diels-Alder reaction, 116
Aza-ene-type reaction, 418
Aza-Henry reaction, 419 C
Aziridines, 436 C–C bond formation, Michael-addition, 12
ring opening, 133 Callipeltoside C, 50
457
458 Index
Carbenes, 77, 79 4-Dimethylaminopyridine (4-DMAP), 238

Carbocation-based catalysts, 372 N,N-Dimethylvinylamine, 30
Carbocyclic ketones, 219 Dioxiranes, 202
Carbohydrate-based ketones, 207 Domino conjugate addition-halogenation, 64
Carbonyl activation, nucleophilic attack, 2 Domino imine aldol-conjugate addition, 64
Carbonyl compounds, 1,3-dienes, Domino O-nitroso aldol-conjugate addition, 63
hetero-Diels–Alder (HDA), 15 Domino processes, 62
O-Carbonyloxyazlactone, 247 Dynamic kinetic resolution (DKR), 5
Carboxylic acids, chiral, 450
Catalysis, nucleophilic, 77, 132
Catalysts, design, 81 E
primary amines, 325 Enals, asymmetric conjugate addition, 149
secondary amines, 286 Enamines, catalytic formation, 31
Catalytic solvents, 1 catalysis, 29, 31
Chiral scaffold, 145 synthesis of complex molecules, 62
a-Chloroesters, 114 intermediates, 309
Cinchona alkaloids, 145, 147, 265 Enaminones, 34
asymmetric transformations, 149 Enecarbamates, 434
derived amines, 44 Enones, asymmetric conjugate addition,
Conjugate additions, 54, 188, 281, 295, 328 149, 167
asymmetric, 173 Episulfonium ion precursors, 437
Cross-benzoin reaction, 84 Epothilone A, 245
Cupreidine, 157 Epoxidations, asymmetric, 201
Cupreine, 157 chiral ketone-catalyzed, 202
Cycloaddition, 281, 286 Epoxides, 327
[3+2]Cycloaddition, 326 Esterification, 233
[4+2]Cycloaddition, 325
Cyclohexadienones, desymmetrization, 99
Cyclohexane-diamine, 145 F
catalysts, chiral, 172 FD-838, 108
Cyclohexylamines, 432 Fluorinated alcohols, 15
Cyclopentenes, 120 Formylcyclopropanes, 113
Friedel–Crafts reaction, 404
Fumagillol, 67
D
Danishefsky’s diene, benzaldehyde, 22
DFT, 1 G
(4-Dialkylamino)pyridine-based catalysts, 243 Gelsemine, 249
1,3-Diamines, 38 Glabrescol, 213
1,2-Di(tert-amine)-based catalysts, 263 Guanidine, 145
Diazo substrates, asymmetric conjugate catalysts, chiral, 185
addition, 155
Diazonamide A, 249
Dicarboxylic acids, 395 H
Dichloroaldehydes, 115 Hajos–Parrish–Eder–Sauer–Wiechert process,
Diels-Alder reactions, asymmetric, 193 31, 43
Dihydroimidazole-based catalysts, 256 Halogenations, 57
Dihydroisoquinoline, 224 Haloperidol, 107
based iminium salts, 224 Hartree–Fock, 3
Dihydrojasmone, 105 Hetero-Diels–Alder reaction, TADDOL-
Dihydropyridine, 425, 430 promoted enantioselective, 22
Dihydroquinine (DHQ), 151, 155 Hexafluoro-2-propanol (HFIP), 15
1,3-Diketones, desymmetrization, 123 Hirsutic acid C, 106
2,2-Dimethyl-6-cyanochromene, 226 Hydrazones, 420
Index 459
Hydrobenzofuranones, 99 M
Hydrogen bonds, 1 Mannich additions, asymmetric, 180
activation of reactants by polarization, 4 Mannich-type reactions, 50
catalytic functions, 4 Metallophosphites, 102
networks, activation of hydrogen
peroxide, 15
organocatalytic transition states, 3 N
spatial arrangement of reactants, 4 Nakorone, 213
stabilization of charges of transition states, 5 NHC, 77
Hydrogen peroxide, 15 Nicotinamide adenine dinucleotide
Hydrophosphonylation, 421 (NADH ), 410
2-Hydroxy-4-methoxybenzaldehyde, 89 Nigellamine, 212
Nitriles, asymmetric conjugate addition, 160
Nitroalkenes, asymmetric conjugate
I addition, 157
Imidazoles, 89 Nitroolefins, 12
Imidazolidinones, 57 asymmetric conjugate addition, 164
catalysts, 41 Nitroso aldol reaction, 38
Imidazolone-based catalysts, 272 Nucleophilic catalysis, 233
3-(1-Imidazolyl)-(S)-alanine, 260
Imines, 404
asymmetric conjugate addition, 152, 170 O
Iminium ion, 281 Olefin epoxidation, 15
catalysis, 283 Organocatalysis, 1, 29, 77, 281
Iminium salts, acyclic, 228 tertiary-amine based, 12
catalyzed epoxidations, chiral, 223 Oxazirdinium salts, 202, 223
chiral, 201 Oxindole-based alkaloids, 249
Iminol–amide, 9 Oxodiene Diels-Alder reaction, 117
Indolines, 248 Oxyanion hole, 1
Ionic liquids, 379 Oxygenations, 57
Isatin, ketone nucleophiles, 31
Isobutyraldehyde-2-d, amino acid-catalyzed
dedeuteration, 38 P
b-Isocupreidine (b-ICPD), 157 Panepophenantrin, 67
cis-Jasmone, 105 Paracyclophane-derived imine, chiral, 195
N,O-Ketene acetals, 30 Pempidine, 266
a-Ketoesters, asymmetric conjugate 4-Phenyl-1,2-dihydronaphthalene,
addition, 161 epoxidation, 228
2-Phosphabicyclo[3.3.0]octane (PBO), 239
Phosphine catalysts, 237
K Phospholane-based systems, 238
Ketone-catalyzed epoxidations, chiral, 202 Phosphonate esters, NHC catalyzed
Ketones, 29 transesterification, 127
a-aminations, 61 Phosphonium cation-based catalysts, 368
chiral, 201 Phosphoric acids, 395
cyanosilylation, 136 chiral, 399
a-halogenations, 59 Pictet–Spengler reactions, 408
a-oxygenations, 62 Piperidine-based catalysts, 273
Kinetic resolution, 233 Platensimycin, 108
Polyoxamic acid, 66
Prelactone B, 66
L Proline-catalyzed aldol reactions, 2
Lewis acid catalysis, 397 Prolinethioamide-catalyzed aldol reaction, 39
Low barrier hydrogen bond (LBHB), 5 Pseudo-ephedrine, 11
460 Index
Pseudo-Lewis acids, 2 Sulfones, asymmetric conjugate

2-Pyrones, cycloaddition reactions, 162 addition, 157
Pyrroles, 34 Sulfonic acids, chiral, 453
based catalysts, 242
Pyrrolidine, 33
4-(Pyrrolidino)pyridine (4-PPY), 243 T
Tanikolide, 150
Tetrahydro-b-carbolines, 408
Q Thiamin diphosphate (ThDP), 85
Quinine/quinidine-based catalysts Thiazolylidene carbene, 110
Thiourea catalysis, bifunctional, 1
Thioureas, chiral, bifunctionality, 12
R Cinchona alkaloid-derived, 163
Redox reactions, 77, 109 oxyanion holes, 5
Ring opening polymerization, 130 N-Tosyl-b-aminoester, 109
Room temperature ionic liquids (RTIL), 379 Transesterifications, 77, 125
Roseophilin, 107 NHC catalyzed, 126
trans-Sabinene hydrate, 105 Triazolinylidene carbene, 124
Tributylphosphine, 238
Trichloroacetimidates, 437
S Trifluoromethyl-sec-alcohol-based
Sappanone B, 89 catalysts, 273
Serine hydrolases, 5 N-Triflyl phosphoramides, 395, 441
Silicon-based catalysts, hypervalent, 356 BINOL-derived, 442
Silyl cation-based catalysts, 351 3-(2,2-Triphenyl-1-acetoxyethyl)-4-
Silyl enol ethers, 139 dimethylamino)pyridine
Steglich rearrangement, 249 (TADMAP), 249
Stetter reactions, 77, 90
intermolecular, 101
intramolecular, 92 U
Strecker reactions, 421 Umpolung, 77
Styrenes, epoxidation, 217 Urethane-protected a-amino acid N-carboxy
Sulfonamide-based catalysts, 273 anhydrides (UNCAs), 267

Asymmetric Organocatalysis

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291

Topics in Current Chemistry

Asymmetric Organocatalysis Anthracycline Chemistry and Biology I

ISSN 0340-1022 e-ISSN 1436-5049

Library of Congress Control Number: 2009941524

 Springer-Verlag Berlin Heidelberg 2010

Cover design: WMXDesign GmbH, Heidelberg, Germany

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com)

Prof. Dr. Kendall N. Houk Prof. Dr. Steven V. Ley

Prof. Dr. Christopher A. Hunter Prof. Dr. Massimo Olivucci

Prof. Dr. Barry M. Trost Prof. Dr. Henry Wong

Topics in Current Chemistry is included in Springer’s eBook package Chemistry

You will find information about the

Aims and Scope

Noncovalent Organocatalysis Based on Hydrogen Bonding:

Brønsted Base Catalysts................................................................................. 145

Chiral Ketone and Iminium Catalysts for Olefin Epoxidation.................. 201

Secondary and Primary Amine Catalysts for Iminium Catalysis............. 281

Lewis Acid Organocatalysts........................................................................... 349

Chiral Brønsted Acids for Asymmetric Organocatalysis........................... 395

Noncovalent Organocatalysis Based

Kerstin Etzenbach-Effers and Albrecht Berkessel

Abstract In this article, the functions of hydrogen bonds in organocatalytic

Keywords Organocatalysis • hydrogen bonding • reaction mechanism on DFT

K. Etzenbach-Effers and A. Berkessel ()

3.3Dramatic Acceleration of Olefin Epoxidation in Fluorinated Alcohols:

Scheme 1 Three modes of carbonyl activation towards nucleophilic attack

Substrate activation by hydrogen bonding is related to, but different from

Brønsted acid catalysis, the substrate electrophile is reversibly protonated in a

Specific Brønsted-acid catalysis General Brønsted-acid catalysis

Scheme 2 Specific and general Brønsted-acid catalysis

2 Catalytic Functions of Hydrogen Bonds

2.1 Hydrogen Bonds Can Preorganize the Spatial

In cases where hydrogen bond donor/acceptor functions are attached to a (chiral)

2.2 Hydrogen Bonds Can Activate the Reactants by Polarization

2.3 Hydrogen Bonds Can Stabilize the Charges of Transition

3.1 Dynamic Kinetic Resolution (DKR) of Azlactones:

Our group recently reported that bifunctional (thio)urea – tert-amine organocatalysts

Scheme 3 Example for the dynamic kinetic resolution of azlactones

This reaction encompasses a number of interesting features (general Brønsted acid/

3.1.1 The Calculated Reaction Path of the Alcoholytic

because of nonbonding interactions between the methyl group at the azlactone’s

Starting complex -0.540 +0.571 -0.472 -0.614 -0.660 -0.659 -0.570

3.1.2 How Hydrogen Bonds Determine the Enantioselectivity

In order to explain the enantioselectivity of the alcoholytic azlactone opening, we cal-

Fig. 2 Four possible ternary (R/S)-azlactone–methanol–catalyst complexes optimized with B3LYP/6-

opposite sides of the azlactone ring. As a consequence, there is no significant inter-

Scheme 5 Pseudo-ephedrine derived catalyst which

3.2 On the Bifunctionality of Chiral Thiourea: Tertiary-Amine

Scheme 6 Enantioselective Michael-addition of acetylacetone to nitrostyrene catalyzed by a

Pápai et al. selected as model reaction the addition of 2,4-pentanedione

Fig. 4 Optimized structures (B3LYP/6-31G(d)) of the most stable catalyst–substrate adducts.

Simultaneously, the hydrogen bonds to the nucleophile are stretched [route A:

Fig. 8 Organocatalytic Michael-addition: Energy profiles of paths A and B, both leading to

3.3 Dramatic Acceleration of Olefin Epoxidation in Fluorinated

As a third example for an organocatalytic reaction, based on multiple hydrogen

Scheme 8 Epoxidation of alkenes with hydrogen peroxide in HFIP as solvent

3.3.1 Hydrogen Bond Donor Features of HFIP

2.1 Hydrogen Bonds Can Preorganize the Spatial

2.3 Hydrogen Bonds Can Stabilize the Charges of Transition

3.1 Dynamic Kinetic Resolution (DKR) of Azlactones:

3.1.1 The Calculated Reaction Path of the Alcoholytic

3.1.2 How Hydrogen Bonds Determine the Enantioselectivity

3.2 On the Bifunctionality of Chiral Thiourea: Tertiary-Amine

3.3 Dramatic Acceleration of Olefin Epoxidation in Fluorinated

3.4 TADDOL-Promoted Enantioselective Hetero-Diels–Alder