Published on Web 08/19/2008

Ligand Controlled Highly Regio- and Enantioselective Synthesis of

r-Acyloxyketones by Palladium-Catalyzed Allylic Alkylation of 1,2-Enediol
Carbonates
Barry M. Trost,* Jiayi Xu, and Thomas Schmidt
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received May 23, 2008; E-mail: bmtrost@stanford.edu

R-Hydroxy carbonyl compounds represent a structural type of both Table 1. Selected Optimization Studiesa
synthetic and biological importance. We previously noted that the enol
allyl carbonates of R-siloxycarbonyl compounds underwent smooth
palladium catalyzed decarboxylative asymmetric allylic alkylation
(AAA)1 to allylated R-siloxyaldehydes using a Pd complex bearing
the Lanth ligand regardless of the regioisomeric nature of the starting
Downloaded by STANFORD UNIV GREEN LIBR on October 23, 2009 | http://pubs.acs.org

material (i.e., I or II in eq 1).2 The regioselectivity may be interpreted entry substrate (R) ligand solvent yieldb 3/4c ee of 3d
as a faster equilibration between the Pd enolate A and B compared to 1 1a (TBS) Lanth dioxane 95% 1/33 -
the rate of alkylation which occurs faster via B (i.e., k > k2 > k1). 2 1a Lstd dioxane 93% 2.7/1 77%
3 1a Lstlb dioxane 93% 2.8/1 91%
However, if A and B exist as either tight ion-pairs or covalently bonded
Publication Date (Web): August 19, 2008 | doi: 10.1021/ja8038954

4 1a PHOX dioxane 77% 1/4.2 -17%

enolates as we proposed before,1c the Pd catalyst should be involved 5 1a Lnaph dioxane 91% 17/1 85%
in both R migration and enolate alkylation steps. Thus, by tuning the 6 1b (Ac) Lnaph dioxane 99% 49/1 82%
ligand and the potential migrating group, we envisioned that we could 7 1b Lnaph DME 99% 49/1 90%
8 1b Lanth DME 27% 3/2 25%
change the reaction pattern in favor of the formation of R-hydroxy- 9 1b Lstd DME 93% 25/1 79%
ketones III, which have attracted much attention because of their 10 1b Lstlb DME 53% 7/1 83%
versatile roles in organic synthesis.1k,3 Herein, we report our success 11 1b PHOX DME 46% 11/1 -11%
in the highly regio- and enantioselective synthesis of R-acyloxyketones 12 1c (Bz) Lnaph DME 95% 49/1 74%
13 1d (Piv) Lnaph DME 99% 49/1 94%
by such an approach. 14 2a (TBS) Lnaph dioxane 99% 1/49 -
15 2d (Piv) Lnaph DME 79% 1/49 -
16 2a (TBS) PHOX dioxane 88% 1/7.7 -18%
a
Unless otherwise indicated, all reactions were performed on a 0.2
mmol scale at 0.1 M concentration at 23 °C for 16 h, using 2.5 mol %
Pd2(dba)3CHCl3 and 5.5 mol % ligand. b The yields were combined
isolated yields of 3 and 4. c The molar ratios of 3 and 4 were
determined by 1H NMR of the crude products. d The ee values were
determined by HPLC on a chiral stationary phase.

Initially we investigated the role of ligands by using carbonate 1a

(R ) tert-butyldimethylsilyl, TBS) as the substrate, which as we
reported previously, in the presence of Lanth decarboxylatively alkylated was exclusively generated in the presence of Lnaph (entry 14 and 15).
to the corresponding siloxyaldehyde 4a with high regioselectivity This suggests that the equilibrium between A and B is slower than
(Table 1, entry 1). PHOX ligands, which, similar to Lanth, have also the alkylation steps (k < k1, k2), in stark contrast to the reaction
been successfully used to catalyze the decarboxylative AAA of enol catalyzed by Lanth. The same reaction catalyzed by PHOX ligand
allyl carbonates, favored the formation of the aldehyde product in a (entry 16), however, gave a similar amount of aldehyde 4a (3a/4a )
ratio of 4.2 to 1; however, the ee of 3a was much lower (17%, entry 1/7.7) as in the reaction of entry 4 (3a/4a ) 1/4.2), implying a faster
4). In contrast to these results, varying our ligands to Lstd and Lstlb, equilibrium and comparably slower alkylation (k > k1 ≈ k2).
slightly favored the formation of the ketone product (entry 2 and 3). The scope of the reaction has been investigated and the results are
The best selectivity (3a/4a ) 17/1) was achieved by using Lnaph (entry summarized in Table 2. Besides the aromatic ketones (entry 1-5),
5). Replacement of OTBS with OAc almost completely suppressed enones such as 12b and 12d (entry 6 and 7), as well as aliphatic ketones
the formation of the aldehyde product (entry 6). Changing solvent from such as 14 and 16 (entry 8 and 9) can be obtained in good yields and
dioxane to 1,2-dimethoxyethane (DME), kept the excellent regio- high ee’s. In general, pivolate protected R-hydroxyketones have
selectivity but also improved the ee of 3b to 90% (entry 7).4 The ligand- moderately higher ee’s than the corresponding acetate protected ones;
dependence of the product distribution of 1b was similar to that of however, acetate is easier to be removed without loss of the enantio-
1a, although in all cases the ketone product was the major one (entry selectivity of the R-hydroxyketone. Substrates with a substituted allylic
8-11). Besides acetoxy other ester groups were also investigated, and moiety also reacted with full conversions, in some cases at slightly
3d with R ) pivaloyl (Piv) had the highest ee value (94%, entry 13). warmer temperature (40 °C) (entry 10-12). The dr’s of the corre-
Starting from 2 (R ) TBS or Piv), which, after decarboxylation initially sponding products are over 95/5, and the ee values of the major
generated the more stable Pd enolate B, only the aldehyde product diastereomers are higher than that of 3b. These high dr’s are reflected
11852 9 J. AM. CHEM. SOC. 2008, 130, 11852–11853 10.1021/ja8038954 CCC: $40.75  2008 American Chemical Society
 COMMUNICATIONS
a
Table 2. Reaction Scope

equilibration is much slower with these Pd enolates and shows a

ligand dependence. In the case of using Lnaph as ligand it is slower
than the alkylation, so that no migration is observed even above
room temperature. This supports the concept that the decarboxyl-
ative AAA of ketones reacts through a tight ion pair or covalently
bonded Pd enolate intermediates.
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health, General Medical Sciences
Grant GM13598, for their generous support of our programs. J.
Downloaded by STANFORD UNIV GREEN LIBR on October 23, 2009 | http://pubs.acs.org

Xu has been supported by Abbott Laboratories Fellowships. We

thank Chirotech (now Dow) for their generous gifts of ligands and
Johnson Matthey for gifts of palladium salts.
Publication Date (Web): August 19, 2008 | doi: 10.1021/ja8038954

Supporting Information Available: Experimental procedures and

characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.

References
(1) (a) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044. (b)
Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 2846. (c) Trost, B. M.;
Xu, J. J. Am. Chem. Soc. 2005, 127, 17180. For reviews on decarboxylative
AAA of simple ketones, see: (d) You, S.-L.; Dai, L.-X. Angew. Chem., Int.
Ed. 2006, 45, 5246. (e) Braun, M.; Meier, T. Angew. Chem., Int. Ed. 2006,
45, 6952. (f) Braun, M.; Meier, T. Syn. Lett. 2006, 5, 661. (g) Stoltz, B. M.;
Mohr, J. T. Chem. Asian J. 2007, 2, 1476. For more examples in metal
catalyzed AAA of simple ketones, see: (h) Trost, B. M.; Schroeder, G. M.
J. Am. Chem. Soc. 1999, 121, 6759. (i) Trost, B. M; Schroeder, G. M.
Chem.sEur. J. 2005, 11, 174. (j) Braun, M.; Laicher, F.; Meier, T. Angew.
Chem., Int. Ed. 2000, 39, 3494. (k) Yan, X. X.; Liang, C. G.; Zhang, Y.;
Hong, W.; Cao, B. X.; Dai, L. X.; Hou, X. L. Angew. Chem., Int. Ed. 2005,
44, 6544. (l) Graening, T.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127,
17192. (m) Bélanger, É.; Cantin, K.; Messe, O.; Tremblay, M.; Paquin, J.-
F. J. Am. Chem. Soc. 2007, 129, 1034. (n) Zheng, W.-H.; Zheng, B.-H;
Yan, Z.; Hou, X.-L. J. Am. Chem. Soc. 2007, 129, 7718. (o) Doyle, A. G;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2007, 46, 3701. (p) He, H.; Zheng,
X.-J.; Li, Y.; Dai, L.-X.; You, S.-L. Org. Lett. 2007, 9, 4339. (q) Braun,
M.; Meier, T.; Laicher, F.; Meletis, P.; Fidan, M. AdV. Synth. Catal. 2008,
350, 303.
(2) Trost, B. M.; Xu, J.; Markus, R. J. Am. Chem. Soc. 2007, 129, 282.
(3) Protocols for the asymmetric synthesis of R-hydoxyketones include oxidation
of enolates, enol ethers, or enol esters: (a) Davis, F. A.; Chen, B. C. In
Houben-Weyl: Methods of Organic Chemistry; Helmchen, G., Hoffmann,
R. W., Mulzer, J., Schaumann, E., Eds.; Georg Thieme Verlag: Stuttgart,
Germany, 1995; Vol. E 21, p 4497. (b) Davis, F. A.; Chen, B. C. Chem.
ReV. 1992, 92, 919, and references therein. (c) Hashiyama, T.; Morikawa,
K.; Sharpless, K. B. J. Org. Chem. 1992, 57, 5067. (d) Morikawa, K.; Park,
J.; Andersson, P. G.; Hashiyama, T.; Sharpless, K. B. J. Am. Chem. Soc.
1993, 115, 8463. (e) Zhu, Y.; Tu, Y.; Yu, H.; Shi, Y. Tetrahedron Lett.
1998, 39, 7819. Aminoxylation of ketones: (f) Momiyama, N.; Yamamoto,
a H. J. Am. Chem. Soc. 2003, 125, 6038. (g) Bøgevig, A.; Sundén, H.; Córdova,
All reactions were performed on a 0.2 mmol scale at 0.1 M in A. Angew. Chem., Int. Ed. 2004, 43, 1109. (h) Hayashi, Y.; Yamaguchi, J.;
DME at 23 °C for 16 h, using 2.5 mol % Pd2(dba)3CHCl3 and 5.5 mol Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed. 2004, 43, 1112. Benzoin-
% Lnaph; the yields were isolated yields and ee values were determined type reactions: (i) Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002,
by chiral HPLC. b Reaction was performed at 4 °C. c Reaction was 41, 1743. (j) Linghu, X.; Potnick, J. R.; Johnson, J. S. J. Am. Chem. Soc.
performed at 40 °C. d Greater than 95/5 dr. 2004, 126, 3070–3071. Reduction of 1,2-diketones: (k) Koike, T.; Murata,
K.; Ikariya, T. Org. Lett. 2000, 2, 3833. Oxidation of 1,2-diols: (l) Adam,
W.; Fell, R. T.; Saha-Moller, C. R.; Zhao, C.-G. Tetrahedron: Asymmetry
in the excellent ee’s of 29 and 30 by the hydrogenations of 20 and 22 1998, 9, 397. The rearrangement of R-tertiary hydroxyaldehydes: (m) Ooi,
respectively (eq 2). More interestingly, OR can be a functionalized T.; Saito, A.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 3220. (n) Ooi, T.;
Ohmatsu, K.; Maruoka, K. J. Am. Chem. Soc. 2007, 129, 2410. Alkylation: (o)
group as in 24, 26, and 28 (entry 13-15). Such functionality can be Andrus, M. B.; Hicken, E. J.; Stephens, J. C.; Bedke, D. K. J. Org. Chem.
useful in further structural elaboration as illustrated by the treatment 2005, 70, 9470.
(4) The absolute configuration was assigned by the NMR study of the
of 24 with Grubbs II catalyst to afford lactone 31 without any erosion corresponding O-methylmandelate ester. Trost, B. M.; Belletire, J. L.;
of enantioselectivity (eq 3). Godleski, S.; McDougal, P. G.; Balkovec, J. M.; Baldwin, J. J.; Christy,
In summary, the palladium-catalyzed decarboxylative AAA of M. E.; Ponticello, G. S.; Varga, S. L.; Springer, J. P. J. Org. Chem. 1986,
51, 2370.
1,2-enediol carbonates can be precisely controlled by the selection (5) Observed in the preparation of substrates. See Supporting Information for
of the ligand to generate either regioisomer. Interestingly, although details.
acyl migration in sodium enolates is fast even at -78 °C,5 such JA8038954
J. AM. CHEM. SOC. 9 VOL. 130, NO. 36, 2008 11853