WO2003050105A2

WO2003050105A2 - Catalytic asymmetric synthesis of optically active compounds

Info

Publication number: WO2003050105A2
Application number: PCT/DK2002/000827
Authority: WO
Inventors: Nis Halland; Karl Anker JØRGENSEN; Tore Hansen
Original assignee: Cheminova A/S
Priority date: 2001-12-10
Filing date: 2002-12-09
Publication date: 2003-06-19
Also published as: AU2002358456A1

Abstract

A one step catalytic asymmetric process for the synthesis of an optically active compound of formula la or lb wherein R is selected from C1-7 alkyl, C1-7 haloalkyl, C1-7 alkoxy, C1-7 haloalkoxy, halogen and hydroxy; R3 is H or C1-4 alkyl; R4 is selected from H, C1-7 alkyl, C1-7 haloalkyl, C1-7 alkoxy, COOH, CO-C1-7 alkoxy and an optionally substituted aryl or heterocycle; AR represents C1-7 alkyl, optionally substituted aryl, an optionally substituted heterocycle or AR and R4 may be bridged together forming part of a ring system; X is O or S; m is a number between 0-4; comprising the step of reacting a compound of the formula 2 with a compound of formula 3 in the presence of a catalytic amount of a chiral nitrogen containing organic compound.

Description

CATALYTIC ASYMMETRIC SYNTHESIS OF OPTICALLY ACTIVE COMPOUNDS

Background

The present invention is related to a one step process for the catalytic asymmetric synthesis of optically active compounds of the formula 1

(1)

wherein R is selected from C_1-7 alkyl, C_1-7 haloalkyl, C_1-7 alkoxy, Cι_-7 haloalkoxy, halogen, and hydroxy; R₃ is H or C_1-4 alkyl;

R₄ is selected from H, C_1-7 alkyl, C_1-7 haloalkyl, Cj_-7 alkoxy, COOH, CO- C_1-7 alkoxy or an optionally substituted aryl or heterocycle; AR represents C_1-7 alkyl, optionally substituted aryl, an optionally substituted heterocycle, or AR and may be bridged together forming part of a ring system; X is O or S; m is a number between 0-4;

Compounds belonging to the above general formula 1 are known for their anticoagulant activity and use as rodenticides, and include Warfarin and Acenocou- marin which are known from US patents 2,427,578 and 2,648,682. Compounds of the formula (1) can also be used as intermediates in the synthesis of com- pounds having said properties, e.g. the compounds disclosed in US patents 3,574,234, 3,651,091 and 4,585,786. Due to the presence of a chiral centre, compounds of the formula 1 exist in two forms having the S or R configuration. Studies of Warfarin and Acenocoumarin (J. Phar. Pharmac, (1973), 25, 458 and Br. J. Clin. Pharmac. (1978), 5, 187) indicate that one of the enantiomers is more active than the other, i.e. respectively the S-enantiomer and R-enantiomer.

Nθ₂)

Well known processes for the synthesis of compounds of the formula 1 leads to a racemic mixure, i.e. equal amounts of both the R and S enan iomer, and in- volves the Michael addition of a compound of the formula 2 to a compound of the formula 3

(2) (3)

The reaction is usually performed in an organic solvent using a base or acid catalyst as described in US patents 2,427,578 and 2,648,682 or in water using ammonia, an organic amine or a phase-transfer catalyst as described in US patents 2,666,064 and 5,696,274 and Ivanov et al. (Arch. Pharm (1990), 323, 521).

Separation of the R and S enantiomers of both Warfarin and Acenocoumarin have been described previously. Using quinidine and quinine, West et al. (J. Am. Chem. Soc. (1961), 83, 2676 and US patent 3,239,529) resolved Warfarin in low yields to the S and R form respectively. S-Acenocoumarin was resolved using quinidine by Trager et al. (J. Med. Chem, (1979), 22, 1122). hi US patent 5,856,525 (and Tetrahedron Lett., (1996), 37, 8321) a method is described in which racemic Warfarin as the starting material is oxidised to the corresponding dehydrowarfarin using more than 1 equivalent CuCl as catalyst, then followed by a protection reaction, protecting the hydroxy group, before the chirality is introduced in the molecule by an asymmetric hydrogenation reaction using a chiral phospholane-Rh(I) complex as catalyst. One drawback is however, that one still needs to produce racemic Warfarin before one arrives at the desired single enantiomer by a multi step synthesis pathway and the fact that non- degradable metal catalysts are used. Further more, the reaction needs to be performed under strictly controlled conditions in order to avoid build up of unde- sired by-products.

Demir et al. (Turk. J. Chem, (1996), 20, 139) have shown how Warfarin in either its R or S form can be synthesised reacting 4-hydroxycoumarin with a stoichiometric amount of an optically active amine forming optically active enamines which are isolated. The optically active enamine is first treated with lithium diisopropyl amide (LDA), followed by the addition of benzylideneace- tone which has to be activated with an excess of a Lewis acid in order to obtain non-racemic Warfarin which is isolated in low to moderate yield and enantiose- lectivity. However, the use of multi-step reactions, a stochiometric amount of an optically active amine, LDA and two equivalents of a Lewis acid does not make the procedure suitable on an industrial scale.

Another procedure described by Cravotto et al. (Tetrahedron Asymmetry, (2001), 12, 707) utilizes a two step procedure comprising of a diastereoselective tandem Knoevenagel-hetero-Diels- Alder reaction between in situ generated 3- arylidene-2,4-chromanediones and wopropenyl ether and a deprotection step, for the asymmetric synthesis of Warfarin, Coumachlor and Acenocoumarin in moderate yield and enantioselectivity. The use of a stoichiometric amount of a chiral auxiliary and the two step synthesis of the enol ether in moderate yield us- ing more than stoichiometric amounts of a Lewis acid makes this procedure un- suitable for synthesis on a large scale.

A variety of enrichment and chiral separation methods have been described previously. By example, Armstrong et al. (Anal. Chem, (1994), 66, 4278) describes an adsorptive bubble separation method using different cyclodextrin collectors for enantiomeric enrichment of Warfarin, where the enantiomeric excess (ee) is reported to be up to 20%. Xaver de Vries et al (J. Chromatogr., (1993) 644, 315) describes a column liquid chromatography method using chiral stationary phases for the separation of enantiomers, and Fanali et al. (J. Chromatogr., (1998) 817, 91) describes a chiral separation method using capillary zone electrophoresis. However, these methods either do not provide an adequate resolution or are not suitable for industrial scale production. Thus, the prior art does not provide a method whereby compounds of the formula 1 can be produced enantiomerically pure in a single step on an industrial scale using environmentally friendly biodegradable catalysts which are non- metal based.

Summary of the invention

An object of the present invention is to provide a novel catalytic asymmetric one step process for making compounds of the formula la or lb

wherein R is selected from C_1-7 alkyl, C_1-7 haloalkyl, C_1-7 alkoxy, C_1-7 haloalkoxy, halogen and hydroxy; R₃ is H or Cι-₄ alkyl;

R₄ is selected from H, C_1-7 alkyl, C_1-7 haloalkyl, C_1-7 alkoxy, COOH, CO- C_1-7 alkoxy and an optionally substituted aryl or heterocycle; AR represents C_1-7 alkyl, optionally substituted aryl, an optionally substituted heterocycle or AR and R₄ may be bridged together forming part of a ring system; X is O or S; m is a number between 0-4; comprising the step of reacting a compound of the formula 2

with a compound of formula 3

in the presence of a catalytic amount of a chiral nitrogen containing organic compound.

The compounds of the formula la or lb may be converted into compounds of the formula 5 a or 5b respectively.

Detailed description of the invention

In a first embodiment, the present invention provides a one step catalytic asymmetric process for the synthesis of an optically active compound of formula la or lb

wherein R is selected from C_1-7 alkyl, Cι_-7 haloalkyl, C_1- alkoxy, C_1- haloalkoxy, halogen and hydroxy;

R₃ is H or C_1-4 alkyl;

R is selected from H, C_1-7 alkyl, Cι_-7 haloalkyl, Cι_-7 alkoxy, COOH, CO-

C_1-7 alkoxy and an optionally substituted aryl or heterocycle;

AR represents C_1-7 alkyl, optionally substituted aryl, an optionally substituted heterocycle or AR and R may be bridged together forming part of a ring system;

X is O or S; m is a number between 0-4; comprising the step of reacting a compound of the formula 2

with a compound of formula 3

in a solvent and in the presence of a catalytic amount of a chiral nitrogen containing organic compound.

In a preferred embodiment AR is selected from

wherein Y represents CH or N; W represents O, S, N-H or N-R; R₂ represents H or halogen;

Ri is selected from C₁.₇ alkyl, Cι_-7 haloalkyl, Cι- alkoxy, Cι_-7 haloalkoxy, halogen, CN and NO₂; In another preferred embodiment P is selected from H, C_1-7 alkyl, C1-7 haloalkyl, Cι_-7 alkoxy, CO-C₁.₇ alkoxy, phenyl, phenyl substituted with R,

in which D represents O, -OCH₂- , -CH₂O- -CH₂- -CH₂CH₂- or a single bond; n is a number between 0-5. h a more preferred embodiment R is C₁.7 alkoxy or halogen; Rι is halogen, Cι- haloalkyl or NO₂; R₃ is H; R₄ is selected from Cι- alkyl, Cι_-7 haloalkyl, CO-C_1-7 alkoxy, phenyl optionally substituted in the para-position, diphenyl optionally substituted in the para-position or benzyloxyphenyl optionally substituted in the para-position or AR and P^ together represents a C_2- alkylene chain; m is 0,1 or 2; n is 0 or 1.

In an even more preferred embodiment the reaction according to the invention is carried out between the following compounds of formula 2 and 3:

For convenience, certain terms employed in the specification, examples and claims are collected here.

The term "catalytic amount" is recognized in the art and means a sub- stoichiometric amount relative to a reactant. As used herein, a catalytic amount means from 0.0001 to 90 mole percent relative to a reactant, preferably from 0.001 to 50 mole percent, and more preferably from 0.1 to 20 mole percent relative to a reactant.

The term 'enantiomeric excess' (ee) is well known in the art and is defined for a resolution of ab - a + b as

The value of ee will be a number between 0 and 100, zero being racemic and 100 being pure single enantiomer.

The term "alkyl" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups, having the number of carbon atoms designated (i.e. C₁-7 means one to seven carbons) in the hydrocarbon backbone. Moreover, the term alkyl as used throughout the specification and claims is intended to include both "unsubsti- tuted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, a hydroxyl, a car- bonyl, an alkoxyl, an ester, a phosphoryl, an amine, an amide, an imine, a thiol, a thioether, a thioesterj a sulfonyl, an amino, a nitro, an aryl, a heterocycle or an organometallic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. The term alkoxy as used herin refer to a -O-alkyl radical, where alkyl has the meaning as stated above. Representative alkoxy groups include methoxy, eth- oxy, propoxy, tert-butoxy and the like. The terms "haloalkyl" and "haloalkoxy" refer to an alkyl group and alkoxy group, as defined above, wherein one or more hydrogen atoms are replaced by a halogen atom.

The term "aryl" means a carbocyclic aromatic system containing one or two rings wherein such rings may be attached together in a pendent manner or may be fused. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol amines, imines, amides, carbonyls, carboxyls, ethers, thioethers, sulfonyls, ketones, aldehydes, esters or the like.

The term "heterocycle" refer to 4 to 10-membered ring structures, which ring structures include at least one heteroatom preferably selected from O, S or N, and which may be aromatic (heteroaryl). Examples of such structures include pyridin, pyrimidin, piperidine, triazole, thiophene, furan, morpholine, chroman, indole, oxazole etc. The heterocycle may be substituted in one or more ring positions as mentioned for the aryl groups. The term "halogen" designates F, CI, Br or I. When any variable may occur more than one time in any formula for a com- pound, its definition on each occurrence is independent of its definition at every other occurrence.

When two substituents are bridged together, they are joined through a bridging group, e.g via an alkylene, alkenylene, or alkynylene radical chain optionally with one or more of the carbon atoms substituted with a heteroatom, said chain optionally being substituted with one or more substituents.

The solvent employed in the reaction may be either protic, aprotic, mixtures of both or ionic liquids. Suitable protic solvents include, water, alcohols e.g. straight, branched or cyclic alkanols and halogenated alkanols, aromatic alco- hols; amines and organic acids. Suitable aprotic solvents include dioxane, tetrahydrofuran (THF), dimethylfor- mamide (DMF), N-methylpyrrolidone, dimethylsulfoxide (DMSO), pyridine, al- kanes and haloalkanes, ethers, ketones, nitriles, and nitroalkanes.

Asymmetric addition of a compound 2 to a compound of the formula 3 is performed under such conditions as to provide an ee of at least 30%, preferably, at least 50%, more preferably at least 70%, and even more preferably an ee of at least 80%. Any chiral nitrogen containing organic compound capable of induc- ing asymmetric addition can be used as catalyst. Preferred are catalyst having a primary or secondary nitrogen atom.

Examples of the chiral nitrogen containing organic compound used as catalyst include, but not limited to, the following compound (4):

HN Z (4)

Rio R9

wherein q is 0 or 1;

R₅, Re, R₇, R₈, which may the same or different represents H, C1-7 alkyl,

C₁-₇ haloalkyl, optionally substituted aryl, an optionally substituted heterocycle, Cι-C₄ alkyl substituted with aryl or a heterocycle or R5 and R together or R₇ and R₈ together may represent a carbonyl group or when q is 1, R₅ with either R₇ or R₈ may bebridged together forming part of a ring system;

R₉ and Rι₀, which may the same or different are selected from H, C1-7 alkyl, hydroxy, C₁-₇ alkoxy or R₉ and Rio may be bridged together forming part of a ring system. Z is S, O, CO, CH-Rπ, N-Rn wherein Rn is R₅;

In a preferred embodiment of the present invention, q is 1; R₅, Re, R₇, R₈ which may the same or different represents H, optionally substituted aryl preferably phenyl or benzyl, or methyl substituted with an optionally substituted heterocycle, or R₅ and R₇ together represents a C₃.₅ alkylene chain; Z is N-Rn wherein R_π represents H or Cι_-7 alkyl; R₉ and Rio are H or R₉ and Rio together represents a methylene bridge optionally substituted with COOH or CO-Cι_₇ alkoxy

In a more preferred embodiment the substituent pair (R₅/Re) is identical to the pair (R₇/R₈).

In an even more preferred embodiment the chiral nitrogen containing organic compound used as catalyst is chosen among the following, where the stereoconfiguration shown merely serves an illustrative purpose:

The selection of the stereochemistry of the catalyst depends on the stereochemistry of the desired compound. Thus, if the catalyst employed has a specific configuration and gives a product having the S-configuration, one would employ the catalyst having the opposite configuration in order to obtain the R-configured product. The catalyst can be bound to a support or unsupported. The amount of catalyst may be as high as 90 mole percent relative to either the compound 2 or 3, but it has been found that catalyst loading higher than approximately 50 mole percent, lower the yield of the product la or lb, and thus it is preferred to use lower amounts of catalyst. There is no lower limit to the amount of catalyst employed other than the cost and ease of separation of the catalyst from products and unreacted reactants. The catalyst may conveniently be separated from the final reaction mixture and reused in subsequent reactions according to the present invention. The reaction may conveniently be carried out at temperatures between -20°C and 120°C, preferably between 0-50°C.

The starting compounds (2), (3) and the chiral nitrogen containing organic compounds used as catalysts are commercially available or can be synthesised according to known methods.

The compounds of the formula la or lb, may further be reduced to a compound of the formula 5a or 5b, respectively, wherein the substituents are as defined above.

The reduction of the intermediate ketone compounds are effected by methods known per se, and include using, as a reducing agent, hydrides of alkali metals and boron. The compounds of the formula la or lb may or may not be isolated prior to the reduction.

Synthesis

General experimental procedure for the catalytic asymmetric Michael addition of 4-hydroxycoumarins or of 4-hydroxythiocoumarins to enones.

To a stirred solution of the 4-hydroxycoumarin or of 4-hydroxythiocoumarins (0.5 mmol) in a reaction inert organic solvent (2.0 mL) was added a catalyst (typically 10 mol %) and an enone (0.5 mmol), and the reaction mixture was stirred for the time given below. The reaction mixture was concentrated by rotary evaporation, redissolved in CH C1₂ and purified by flash chromatography on silica gel in a mixture of CH₂Cl₂/Et₂O. The enantiomeric excess (ee) of the products was determined by HPLC as described below in the examples.

Unless otherwise stated the reactions were performed at ambient temperature, but it is noted that lowering of the reaction temperature increases the enantiose- lectivity and decreases the reaction rate. In general, high reaction rates were obtained in protic organic solvents such as EtOH or MeOH due to superior solvation properties towards the 4- hydroxycoumarins. However, increased enantioselectivity was observed when aprotic solvents such as THF or CH₂C1₂ were used.

The addition of a base such as Et₃N, or amberlyst A21 ion exchange resin, was found to decrease the enantioselectivity due to a racemic base catalyzed Michael addition reaction. Addition of an acid such as HCl was found to significantly slow down the reaction due to inhibition af the catalyst. The addition of up to 5 eq. of water was found not to affect the reaction rate or the enantioselectivity. The reaction does not lead to unwanted by-products and unreacted starting materials are easily recovered and can be used in subsequent reactions of the present invention.

The invention is illustrated by the following non-limiting examples:

Example 1

Catalytic asymmetric synthesis of (S)-Warfarin (AR = Ph, R₃ = H, R₄ = CH₃, X = O)

To a stirred solution of 4-hydroxycoumarin (82.0 mg, 0.51 mmol) in 2.0 mL THF was added (4S,5S)-diphenyl-imidazolidine-2-carboxylic acid (13.4 mg, 0.05 mmol) and benzyUdeneacetone (73.1 mg, 0.50 mmol) and the resulting solution was stirred for 70 hours at ambient temperature. The reaction mixture was concentrated in vacuo and redissolved in CH₂C1₂ prior to purification by flash chromatography on silica in a mixture of Et₂O/CH₂Cl₂. After concentration in vacuo 95.9 mg (62%) (S)- Warfarin was obtained as a white solid in 79% ee as determined by HPLC in 2-propanol/hexane 1:1 with 0.1% TFA using a Daicel Chiralpak AD column. A single recrystallization from acetone/water increased enantioselectivity to >99.9%.

The product exists in a partly hemiketalized form which gives rise to di- astereomers. 1H NMR (CDCI3) δ 1.66 (s, 1.35H, CH₃ ketal), 1.70 (s, 1.35H, CH₃ ketal), 1.99 (m, 0.4H, CH₂ ketal), 2.28 (s, 0.3H, CH₃ keto), 2.39-2.55 (m, 1.4H, CH₂ ketal), 3.17 (br s, 0.9H, OH ketal, position is concentration dependent), 3.30 (dd, J = 19.4, 0.6 Hz, 0.1H, CH₂ keto), 3.85 (dd, J = 19.4, 10.3 Hz, 0.1H, CH₂ keto), 4.14 (dd, J = 11.1, 6.6 Hz, 0.45H, CH ketal) 4.28 (dd, J = 6.5, 3.3 Hz, 0.45H, CH ketal), 4.67 (dd, 10.2, 1.8 Hz, 0.1H, CH keto), 7.19-35 (m, 7H, ArH), 7.49 (br t, J = 8.1 Hz, 0.55H, ArH), 7.55 (dt, J = 1.6, 8.7 Hz, 0.45H, ArH), 7.80 (d, J = 7.9 Hz, 0.45H, ArH), 7.88 (dd, J = 7.9, 1.5 Hz, 0.45H, ArH), 7.93 (dd, J = 7.6 Hz, 0.1H, ArH) 9,19 (br s, 0.1H, OH keto, position is concentration dependent); ¹³C NMR (CDCI3) δ 27.8, 28.3, 30.3, 34.4, 35.0 35.5, 40.2, 42.8, 45.3 99.2, 100.7, 101.3, 104.3, 115.7, 116.1, 116.6, 116.8, 122.9, 123.2, 123.8, 124.1, 126.7, 127.2, 127.2, 127.4, 128.1, 128.4, 128.8, 129.4, 131.7, 132.2, 141.7, 143.4, 153.0, 153.1, 159.1, 159.9, 161.6, 162.4; HRMS m/z 331.0945 (M+Na⁺), calc. for Cι₉Hι₆O₄Na⁺ 331.0946.

Example 2

Catalytic asymmetric synthesis of (S)-Warfarin (AR = Ph, R₃ = H, R₄ = CH₃₎X = O)

To a stirred solution of 4-hydroxycoumarin (82.0 mg, 0.51 mmol) in 2.0 ml THF was added (4S)-benzyl-l-methyl-imidazolidin-2-carboxylic acid (5.5 mg, 0.025 mmol) and benzyUdeneacetone (73.1 mg, 0.50 mmol) and the resulting solution was stirred for 70 hours at ambient temperature. The reaction mixture was concentrated in vacuo and redissolved in CH₂C1₂ prior to purification by flash chro- matography on silica in a mixture of Et₂O/CH₂Cl₂. After concentration in vacuo 131.3 mg (85%) (S)- Warfarin was obtained as a white solid in 70% ee determined as in Example 1. Example 3

Catalytic asymmetric synthesis of (S)-Warfarin. Scale up and reuse of catalyst. (AR = Ph, R₃ = H, R₄ = CH_3jX = O)

1. Batch: To a stirred solution of 4-hydroxycoumarin (81 g, 0.50 mol) in THF (1 L) was added (4S)-benzyl-l-methyl-imidazolidin-2-carboxylic acid (5.5 g, 0.025 mol) and benzyUdeneacetone (73 g, 0.50 mol) and the resulting solution was stirred for 75 hours at ambient temperature. The reaction mixture was concentrated in vacuo to give an oil which was dissolved in 300 mL of boiling acetone. Subsequent addition of water (100 mL) and cooling to 5° C caused the product to precipitate. The product was filtered, washed once with ice cold ethanol (100 mL) and finally dried under vacuum. The yield of (S)-Warfarin 105 g (68%) with 55% ee determined as in Example 1.

2. Batch: The mother liquor and washings from Batch 1 was evaporated to dry- ness, and redissolved in THF (1 L). 4-Hydroxycoumarin (81 g, 0.50 mol) and benzyUdeneacetone (73 g, 0.50 mol) were added and the mixture was stirred for 90 hours at ambient temperature. The solvent was removed in vacuo and the oily residue was taken into boiling acetone (600 mL) and water (250 mL) followed by cooling to 5° C. The precipitated product was filtered and washed once with ice cold ethanol (100 mL). The yield of (S)- Warfarin 126 g (82%) with 60% ee determined as in Example 1.

Example 4

Catalytic asymmetric synthesis of (S)-Coumachlor (AR = 4-chlorophenyl, R₃ = H, R₄ = CH₃₎ X = O)

To a stirred solution of 4-hydroxycoumarin (82.0 mg, 0.51 mmol) in 2.0 mL CH₂C1₂ was added (4S,5S)-diphenyl-imidazolidine-2-carboxylic acid (13.4 mg, 0.05 mmol) and 4-chlorobenzylideneacetone (90.3 mg, 0.50 mmol) and the resulting solution was stirred for 110 hours at ambient temperature. The reaction mixture was purified by flash chromatography on silica in a mixture of Et₂O/CH₂Cl₂. After concentration in vacuo 133.4 mg (78%) (S)-Coumachlor was obtained as a white solid in 83% ee as determined by HPLC in 2- propanol/hexane 1:1 using a Daicel Chiralpak AD column. A single recrystalli- zation from acetone/water increased enantioselectivity to >99.9%. Absolute stereochemistry was assigned by X-ray crystallography. The product exists in a predominantly hemiketalized form which gives rise to diastereomers.

1H NMR (CDC1₃) δ 1.70 (s, 1.13H, CH₃ ketal), 1.75 (s, 1.53H, CH₃ ketal), 1.95 (m, 0.47H, CH₂ ketal), 2.30 (s, 0.33H, CH₃ keto), 2.37-2.50 (m, 1.33H, CH₂ ketal), 2.97 (s, 0.33 H, OH ketal, position is concentration dependent), 3.09 (s, 0.36 H, OH ketal, position is concentration dependent), 3.28 (dd, J = 19.8, 2.4 Hz, 0.1H, CH₂ keto), 3.86 (dd, J = 19.8, 10.8 Hz, 0.1H, CH₂ keto), 4.14 (dd, J = 11.3, 6.4 Hz, 0.5H, CH ketal), 4.21 (dd, J = 7.1, 3.6 Hz, 0.36H, CH ketal), 4.64 (dd, J = 10.9, 2.5 Hz, 0.13H, CH keto), 7.15-7.36 (m, 6H, ArH), 7.52 (dt, J = 1.6, 6.6 Hz, 0.66H, ArH) 7.57 (dt, J = 1.8, 6.9 Hz, 0.33H, ArH), 7.81 (dd, J = 6.6, 1.6 Hz, 0.5H, ArH), 7.88 (dd, J = 7.6, 1.6 Hz, 0.4H, ArH), 7.95 (dd, J = 7.5, 1.4 Hz, 0.1H, ArH), 9.56 (s, 0.1H, OH keto); ¹³C NMR (CD₂C1₂) δ 28.1, 35.2, 40.2, 42.6, 99.4, 100.6, 101.7, 103.8, 115.9, 116.2, 116.4, 116.7, 123.0, 123.2, 124.0, 124.2, 128.7, 128.8, 128.9, 129.2, 132.0, 132.3, 141.8, 142.7, 153.1, 159.6, 160.1, 161.6, 162.3; HRMS m/z 365.0558 (M+Na⁺), calc. for Cι₉Hι₅O₄ClNa⁺ 365.0557.

Example 5

Catalytic asymmetric synthesis of (R)-Acenocoumarin (AR = 4-nitrophenyl, R₃ = H, R₄ = CH_3; X = O) To a stirred solution of 4-hydroxycoumarin (82.0 mg, 0.51 mmol) in 2.0 ml THF was added (4R,5R)-diphenyl-imidazolidine-2-carboxylic acid (13.4 mg, 0.05 mmol) and 4-nitrobenzylideneacetone (95.6 mg, 0.50 mmol) and the resulting solution was stirred for 60 hours at ambient temperature. The reaction mixture was concentrated in vacuo and redissolved in CH₂C1₂ prior to purification by flash chromatography on silica in a mixture of Et₂O/CH₂Cl₂. After concentration in vacuo 109.7 mg (62%) (R)-Acenocoumarin was obtained as a white solid in 80% ee as determined by HPLC in 2-ρroρanol/hexane 50/50 with 0.1% TFA us- ing a Daicel Chiralpak AD column. The product exists in an almost exclusively hemiketalized form which gives rise to diastereomers.

1H NMR (CDC1₃) δ 1.73 (s, 1.13H, CH₃ ketal), 1.79 (s, 1.75H, CH₃ ketal), 1.93 (m, 0.53 H, CH₂ ketal), 2.34 (s, 0.12H, CH₃ keto), 2.39-2.52 (m, 1.40H, CH₂ ketal), 2.96 (s, 0.28H, OH ketal), 3.24 (s, 0.5H, OH ketal), 3.34 (dd, J = 20.3, 2.9 Hz, 0.04H, CH₂ keto), 3.90 (dd, J - 20.5, 11.1 Hz, 0.04H, CH₂ keto), 4.27 (m, 0.96H, CH ketal), 4.73 (dd, 12.6, 1.7 Hz, 0.04H), 7.25-7.44 (m, 4H, ArH), 7.54 (dt, J - 1.3, 7.7 Hz, 0.69H, ArH), 7.59 (dt, J = 1.3, 7.7 Hz, 0.31H, ArH), 7.82 (dd, J = 8.4, 1.3 Hz, 0.69H, ArH) 7.87 (dd, J = 8.4, 1.3 Hz, 0.31H, ArH), 8.12- 8.18 (m, 2H, ArH); ¹³C NMR ((CD₃)₂SO) δ 26.5, 27.2, 35.2, 35.3, 41.9, 99.7, 100.9, 101.0, 102.5, 115.4, 115.6, 116.4, 116.5, 122.8, 122.9, 123.1, 123.6, 124.2, 124.3, 128.6, 129.0, 132.3, 132.4, 145.7, 146.0, 152.4, 152.5, 152.6, 159.4, 159.8, 160.5, 161.1; HRMS m z 376.0798 (M+Na⁺), calc. for Cι₉Hι₅O₆NNa⁺ 376.0797.

Example 6

Catalytic asymmetric synthesis of (S)-7-Fluorowarfarin (AR = Ph, R₃ = H, R₄ = CH₃, R = 7-flouro, X = O)

To a stirred solution of 7-flouro-4-hydroxycoumarin (90.0 mg, 0.50 mmol) in 2.0 mL THF was added (4S,5S)-diphenyl-imidazolidine-2-carboxylic acid (13.4 mg, 0.05 mmol) and benzyUdeneacetone (73.1 mg, 0.50 mmol) and the resulting solution was stirred for 130 hours at ambient temperature. The reaction mixture was concentrated in vacuo and redissolved in CH₂C1₂ prior to purification by flash chromatography on silica in a mixture of Et₂O/CH₂Cl₂. After concentration in vacuo 93.3 mg (57%) (S)-7-Fluoro warfarin was obtained as a white solid in 80% ee as determined by HPLC in 2-propanol/hexane 1 : 1 using a Daicel Chiralpak AS column. The product exists in a predominantly hemiketalized form which gives rise to diastereomers. 1H NMR (CDC1₃) δ 1.65 (s, 1.13H, CH₃ ketal), 1.70 (s, 1.5H, CH₃ ketal), 1.97 (dd, J = 13.5, 11.2 Hz, 0.48H, CH₂ ketal) 2.28 (s, 0.37H, CH₃ keto), 2.37-2.55 (m, 1.41H, CH₂ ketal), 3.22-3.35 (br, 0.95H, OH ketal), 3.82 (dd, J = 19.9, 10.5 Hz, 0.12H, CH₂ keto), 4.11 (dd, J = 11.4, 6.8 Hz, 0.49H, CH ketal), 4.24 (dd, J = 6.5, 2.9 Hz, 0.44H, CH ketal), 4.65 (dd, J = 9.9, 2.6 Hz, 0.07H, CH keto), 6.90- 7.05 (m, 2H, ArH), 7.18-7.33 (m, 6H, ArH), 7.76-7.94 (m, IH, ArH); ¹³C NMR ((CD₃)₂SO) δ 25.8, 27.2, 35.1, 36.0, 99.9, 101.1, 101.7, 102.5, 103.7, 103.9, 111.8, 112.0, 112.5, 112.6, 124.9, 125.0, 125.7, 126.0, 127.1, 127.3, 127.9, 128.3, 143.7, 143.8, 153.4, 153.6, 158.6, 159.2, 160.1, 160.6, 162,5, 165.0; HRMS m/z 349.0854 (M+Na÷), calc. for d₉Hι₅O₄FNa⁺ 349.0852.

Example 7

Catalytic asymmetric synthesis of (S)-7-Methoxywarfarin (AR = Ph, R₃ = H, R4 = CH_3> R = 7-methoxy, X = O)

To a stirred solution of 7-methoxy-4-hydroxycoumarin (96,1 mg, 0.50 mmol) in 2.0 mL THF was added (4S,5S)-diphenyl-imidazolidine-2-carboxylic acid (13.4 mg, 0.05 mmol) and benzyUdeneacetone (73.1 mg, 0.50 mmol) and the resulting solution was stirred for 125 hours at ambient temperature. The reaction mixture was concentrated in vacuo and redissolved in CH₂C1₂ prior to purification by flash chromatography on silica in a mixture of Et₂0/CH₂C1₂. After concentration in vacuo 115.2 mg (68%) (S)-7-Methoxywarfarin was obtained as a white solid in 78% ee as determined by HPLC in 2-propanol/hexane 1:1 using a Daicel Chiralpak AS column. The product exists in a predominantly hemiketalized form which gives rise to diastereomers.

1H NMR (CDC1₃) δ 1.66 (s, 1.36H, CH₃ ketal), 1.71 (s, 1.36H, CH₃ ketal), 1.95- 2.04 (m, 0.42H, CH₂ ketal), 2.30 (s, 0.28H, CH₃ keto) 2.39-2.56 (m, 1.36H, CH₂ ketal), 3.14 (s, 0.73H, OH ketal), 3.84 (s, 0.42H, OCH₃ keto), 3.85 (s, 1.36H, OCH₃ ketal), 3.88 (s, 1.36H, OCH₃ ketal), 4.13 (dd, J = 11.4, 6.8 Hz, 0.43H, CH ketal) 4.26 (dd, J = 7.1, 2.9Hz, 0.43H, CH ketal), 4.66 (dd, J = 10.3, 1.8 Hz, 0.14H, CH keto), 6.75-6.89 (m, 2H, ArH) 7.21-7.35 (m, 5H, ArH), 7.70 (d, J = 9.3 Hz, 0.43H, ArH), 7.78 (d, J = 9.8 Hz, 0.43H, ArH), 7.83 (d, J - 8.8 Hz, 0.14H, ArH), 9.40 (s, 0.12H, OH keto); ¹³C NMR (CDC1₃) δ 27.3, 27.8, 27.9, 34.6, 35.2, 40.3, 42.8, 42.9, 55.6, 55.7, 55.8, 98.6, 99.2, 99.3, 99.8, 99.9, 100.2, 100.6, 101.2, 108.8, 109.2, 112.1, 112.3, 112.4, 123.7, 123.8, 124.2, 126.4, 127.0, 127.1, 127.2, 128.0, 128.2, 128.6, 129.0, 142.1, 143.8, 154.4, 154.6, 160.0, 160.5, 162.4, 162.5, 162.9, 163.0; HRMS m/z 361.1052 (M+Na⁺), calc. for C₂₀Hι₈O₅FNa⁺ 361.1052.

Example 8

Catalytic asymmetric synthesis of (S)-6,8-Dichlorowarfarin (AR = Ph, R₃ = H, R₄ = CH_3; R = 6,8-dichloro, X = O)

To a stirred solution of 6,8-dichloro-4-hydroxycoumarin (115.5 mg, 0.50 mmol) in 2.0 mL THF was added (4S,5S)-diphenyl-imidazolidine-2-carboxylic acid (13.4 mg, 0.05 mmol) and benzyUdeneacetone (73.1 mg, 0.50 mmol) and the resulting solution was stirred for 150 hours at ambient temperature. The reaction mixture was concentrated in vacuo and redissolved in CH₂C1₂ prior to purification by flash chromatography on silica in a mixture of Et₂O/CH₂Cl₂. After con- centration in vacuo 123.3 mg (65%) (S)-6,8-Dichlorowarfarin was obtained as a white solid in 79% ee as determined by HPLC in 2-propanol/hexane 30:70 using a Daicel Chiralcel OD column. The product exists in a predominantly hemiketalized form which gives rise to diastereomers. 1H NMR (CDC1₃) δ 1.69 (s, 1.16H, CH₃ ketal), 1.73 (s, 1.45H, CH₃ ketal), 1.95- 2.04 (m, 0.48H, CH₂ ketal), 2.31 (s, 0.39H, CH₃ keto), 2.39-2.59 (m, 1.26H, CH₂ ketal), 3.20 (s, 0.34H, OH ketal), 3.31 (s, 0.48H, OH ketal), 3.34 (m, 0.13H, CH₂ keto), 3.86 (dd, J = 19.3, 9.1 Hz, 0.13 H, CH₂ keto), 4.16 (dd, J = 12.0, 6.9 Hz, 0.48H, CH ketal), 4.29 (dd, J = 6.9, 2.8 Hz, 0.39H, CH ketal), 4.67 (dd, J = 10.3, 1.9 Hz, 0.13H, CH keto), 7.20-7.37 (m, 5H, ArH), 7.53 (d, J = 2.3 Hz, 0.48H, ArH) 7.61 (d, J = 2.3 Hz, 0.39H, ArH), 7.68 (d, J = 2.3 Hz, 0.48H, ArH) 7.77 (d, J = 2.3 Hz, 0.39H, ArH), 7.85 (d, J = 2.3 Hz, 0.13H, ArH), 9.72 (br, OH keto); ¹³C NMR δ ((CD₃)₂SO) 25.8, 27.0, 35.3, 36.0, 41.2, 42.6, 100.5, 102.2, 103.5, 104.9, 118.1, 118.2, 120.9, 121.0, 121.1, 121.2, 125.8, 126.1, 127.2, 127.4, 127.9, 128.0, 128.3, 131.2, 143.3, 146.9, 157.6, 158.1, 158.8, 159.3; HRMS m/z 399.0163 (M+Na⁺), calc. for Cι₉Hι₄O₄Cl₂Na⁺ 399.0167.

Example 9

Catalytic asymmetric synthesis of 4-Hydroxy-3-(3-oxo-(lS),3-diphenyl-propyl)- chromen-2-one (AR = Ph, R₃ = H, R₄ = Ph R = H, X = O)

To a stirred solution of 4-hydroxycoumarin (82.0 mg, 0.51 mmol) in 2.0 mL THF was added (4S)-benzyl-l-methyl-imidazolidin-2-carboxylic acid (11.0 mg, 0.05 mmol) and trαπ5-l,3-diphenyl-2-propen-l-one (104.1 mg, 0.50 mmol) and the resulting solution was stirred for 130 hours at 50 °C. The reaction mixture was concentrated in vacuo and redissolved in CH₂C1₂ prior to purification by flash chromatography on silica in a mixture of Et₂0/CH₂C1₂. After concentration in vacuo 125.7 mg (68%) 4-Hydroxy-3-(3-oxo-(lS),3-diphenyl-propyl)- chromen-2-one was obtained as a white solid in 31% ee as determined by HPLC in 2-propanol hexane 30/70 with 0.1% TFA using a Daicel Chiralpak AS column.

1H NMR (CDC1₃) δ 3.74 (dd, J = 19.2, 2.4 Hz, IH, CH₂), 4.43 (dd, J = 19.2, 10.3 Hz, IH, CH₂), 4.90 (dd, J = 10.2, 2.4 Hz, IH, CH), 7.12-7.48 (m, 10H, ArH), 7.58 (t, J = 7.5 Hz, IH, ArH), 7.93 (dd, J = 7.7, 1.2 Hz, IH, ArH), 8.03 (d, J = 7.2 Hz, 2H, ArH), 9.85 (br, OH); ¹³C NMR (CDCI3) δ 35.3, 40.3, 108.2, 116.4, 116.8, 124.0, 124.1, 126.8, 128.2, 128.3, 128.8, 129.0, 131.9, 134.6, 135.9, 140.1, 153.0, 161.3, 162.3, 202.8; HRMS m/z 393.1102 (M+Na ), calc. for C₂₄Hι₈O₄Na⁺ 393.1103.

Example 10

Catalytic asymmetric synthesis of 3-[3-(4-Chloro-phenyl)-(lR)-(5-chloro- thiophen-2-yl)-3-oxo-propyl]-4-hydroxy-chromen-2-one

(AR = 5-(2-chlorothiophen), R₃ = H, R₄ = 4-chlorophenyl, R = H, X = O)

To a stirred solution of 4-hydroxycoumarin (82.0 mg, 0.51 mmol) in 2.0 mL THF was added (4S)-benzyl-l-methyl-imidazolidin-2-carboxylic acid (11.0 mg, 0.05 mmol) and l-(4-chloro-phenyl)-3-(5-chloro-thiophen-2-yl)-propenone (141.6 mg, 0.50 mmol) and the resulting solution was stirred for 200 hours at 40 °C. The reaction mixture was concentrated in vacuo and redissolved in CH₂C1₂ prior to purification by flash chromatography on silica in a mixture of Et₂O/CH₂Cl₂. After concentration in vacuo 26.6 mg (12%) 3-[3-(4-Chloro- ρhenyl)-(lR)-(5-chloro-thiophen-2-yl)-3-oxo-propyl]-4-hydroxy-chromen-2-one was obtained as a brown solid in 33% ee as determined by HPLC in 2- propanol/hexane 50/50 with 0.1 % TFA using a Daicel Chiralpak AD column. 1H NMR (CDCI₃) δ 3.72 (dd, J = 19.1, 2.8 Hz, IH, CH₂), 4.36 (dd, J = 19.1, 9.3 Hz, IH, CH₂), 5.03 (br d, J = 9.3 Hz, IH, CH), 6.72 (d, J = 3.8 Hz, IH, thio- phene-H), 6.76 (d, J = 3.8 Hz, IH, thiophene-H), 7.24-7.32 (m, 2H, ArH), 7.45 (d, J = 8.6 Hz, IH, ArH), 7.52 (m, IH, ArH), 7.96 (d, 8.6 Hz, 3H, ArH), 9.70 (br s, OH); ¹³C NMR (CDC1₃) δ 33.4, 41.9, 106.5, 116.5, 116.6, 124.2, 124.3, 124.7, 125.6, 128.6, 129.4, 130.2, 132.4, 133.9, 141.4, 142.6, 152.9, 161.7, 162.4, 200.5; HRMS m/z 466.9885 (M+Na"), calc. for C₂₂Hι₄O SCl₂Na⁺ 466.9888.

Example 11

Catalytic asymmetric synthesis of 3-((lR)-Furan-2-yl-3-oxo-butyl)-4-hydroxy- chromen-2-one (AR = 2-furan, R₃ = H, R₄ = Me, R = H, X = O)

To a stirred solution of 4-hydroxycoumarin (82.0 mg, 0.51 mmol) in 2.0 mL THF was added (4S,5S)-diphenyl-imidazolidine-2-carboxylic acid (13.4 mg, 0.05 mmol) and furfurylideneacetone (68.1 mg, 0.50 mmol) and the resulting solution was stirred for 130 hours at ambient temperature. The reaction mixture was concentrated in vacuo and redissolved in CH₂C1₂ prior to purification by flash chromatography on silica in a mixture of Et₂O/CH₂Cl₂. After concentration in vacuo 57.2 mg (39%) 3-((lR)-Furan-2-yl-3-oxo-butyl)-4-hydroxy-chromen-2- one was obtained as a brown solid in 66% ee as determined by HPLC in 2- propanol/hexane 50/50 with 0.1% TFA using a Daicel Chiralpak AS column. The product exists in a predominantly hemiketalized form which gives rise to diastereomers.

1H NMR (CDCI₃) δ 1.63 (s, 0.7 IH, CH₃ ketal), 1.71 (s, 1.66H, CH₃ ketal), 2.22- 2.26 (m, 0.47H, CH₂ ketal), 2.28 (s, 0.63H, CH₃ keto), 2.30-2.37 (m, 0.55H, CH₂ ketal), 2.66-2.70 (m, 0.55H, CH₂ ketal), 3.31 (dd, J = 19.3, 2.8 Hz, 0.21H, CH₂ keto), 3.64 (dd, J - 19.3, 8.1 Hz, 0.21H, CH₂ keto), 4.15 (br, 0.23H, OH), 4.28-4.33 (m, 1.34H, CH ketal and OH), 4.74 (dd, J = 8.1, 2.8 Hz, 0.21H, CH keto), 6.11 (d, J = 3.1 Hz, 0.21H, furan-H), 6.14 (d, J = 3.1 Hz, 0.21H, furane- H), 6.17 (d, J = 3.3 Hz, 0.58H, furane-H), 6.30 (dd, J = 3.3, 2.0 Hz, IH, furane- H), 7.17-7.57 (m, 4H, ArH and furane-H), 7.77 (dd, J = 7.8, 1.0 Hz, 0.23H, ArH), 7.87 (dd, J = 7.8, 1.2 Hz, 0.55H, ArH), 7.92 (dd, J = 7.8, 1.2 Hz, 0.55H, ArH); ¹³C NMR (CDC1₃) δ 27.6, 28.1, 28.2, 29.4, 30.0, 30.5, 36.0, 38.3, 45.2, 99.2, 99.6, 99.8, 106.3, 106.5, 106.9, 110.6, 111.0, 115.6, 115.9, 116.4, 116.6, 116.7, 116.8, 122.9, 123.4, 123.8, 124.0, 124.1, 124.2, 131.8, 132.2, 132.4, 141.1, 141.5, 142.5, 152.8, 153.0, 154.1, 154.5, 159.5, 162.2, 162.9, 212.3; HRMS m/z 321.0742 (M+Na⁺), calc. for Cι₇Hι₄O₅Na⁺ 321.0739.

Example 12

Catalytic asymmetric synthesis of 4-Hydroxy-3-((lR)-3-oxo-cyclohexyl)- chromen-2-one

(AR,R₄ = CH₂CH₂CH₂, R₃ = H, R = H, X = O)

To a stirred solution of 4-hydroxycoumarin (82.0 mg, 0.51 mmol) in 2.0 mL THF was added (4S)-benzyl-l-methyl-imidazolidin-2-carboxylic acid (11.0 mg, 0.05 mmol) and 2-cyclohexen-l-one (63.4 μL, 0.50 mmol) and the resulting solution was stirred for 90 hours at ambient temperature. The reaction mixture was concentrated in vacuo and redissolved in CH₂C1₂ prior to purification by flash chromatography on silica in a mixture of Et₂O/CH₂Cl₂. After concentration in vacuo 11.1 mg (60%) 4-Hydroxy-3-(3-oxo-cyclohexyl)-chromen-2-one was ob- tained as a white solid in 65% ee as determined by HPLC, after TBS protection, in 2-propanol/hexane 40/60 using a Daicel Chiralpak AS column. The product exists in an exclusively hemiketalized form.

1H NMR (CDCI₃) δ 1.35-1.47 (m, IH, CH₂), 1.51-1.69 (m, 2H, CH₂), 1.77-1.87 (m, 2H, CH₂), 1.99-2.12 (m, 2H, CH₂), 2.25 (br d, J = 13.4 Hz, IH, CH₂), 3.34 (m, IH, CH), 5.00 (s, IH, OH), 7.15-7.22 (m, 2H, ArH), 7.42-7.46 (m, IH, ArH), 7.74 (dd, J = 7.8, 1.7 Hz, ArH); ¹³C NMR (CDCI₃) δ 19.1, 28.4, 29.4, 36.0, 38.7, 102.5, 102.9, 115.1, 116.6, 122.7, 123.9, 131.8, 152.8, 161.5, 162.7; HRMS m/z 281.0793 (M+Na⁺), calc. for Cι₅Hι₄O₄Na⁺ 281.0790. Example 13

Catalytic asymmetric synthesis of (4S)-(4-Chloro-phenyl)-4-(4-hydroxy-2-oxo- 2H-chromen-3-yl)-2-oxo-butyric acid methyl ester (AR = 4-chlorophenyl, R₃ = Η, R₄ = CO₂Me, R = Η, X = O)

To a stirred solution of 4-hydroxycoumarin (82.0 mg, 0.51 mmol) in 2.0 mL CΗ₂C1₂ was added (4S,5S)-diphenyl-imidazolidine-2-carboxylic acid (13.4 mg, 0.05 mmol) and 4-(4-chloro-phenyl)-2-oxo-but-3-enoic acid methyl ester (112.3 mg, 0.50 mmol) and the resulting solution was stirred for 200 hours at ambient temperature. The reaction mixture was purified by flash chromatography on silica in a mixture of Et₂O/CH₂Cl₂. After concentration in vacuo 91.0 mg (47%) (4S)-(4-Chloro-phenyl)-4-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-oxo-butyric acid methyl ester was obtained as a white crystalline solid in 31% ee as determined by HPLC in 2-propanol/hexane 50/50 with 0.1% TFA using a Daicel Chiralpak AS column. The product exists in an exclusively hemiketalized form which gives rise to diastereomers.

Η NMR (CDCI₃) δ 2.29-2.43 (m, 1.67H, CH₂), 2.70 (dd, J = 6.0, 1.6 Hz, 0.2H, CH₂), 2.74 (dd, J = 7.9, 1.6 Hz, 0.13H CH₂), 3.85 (s, 1.8H, OCH₃), 3.86 (s, 1.2H, OCH₃), 4.11 (dd, J = 11.6, 7.6 Hz, 0.67H, CH) 4.23 (dd, J = 7.4, 2.7 Hz, 0.33H, CH), 4.51 (s, 0.29H, OH), 4.69 (s, 0.58H, OH), 7.10-7.38 (m, 6H, ArH)

7.45-7.54 (m, IH, ArH), 7.71 (dd, J = 7.6, 1.6 Hz, 0.67H, ArH), 7.75 (dd, J = 7.6, 1.6 Hz, 0.33H, ArH); ¹³C NMR (CDCI₃) δ 33.2, 34.2, 35.2, 38.1, 54.2, 54.3, 95.5, 96.0, 102.6, 104.6, 115.1, 115.3, 116.8, 116.9, 124.3, 124.5, 128.7, 129.1, 129.5, 132.3, 132.5, 132.6, 133.4, 140.4, 141.1, 152.9, 153.0, 158.3, 158.7, 160.8, 161.8, 169.0, 169.2; HRMS m/z 409.0455 ( +Na⁴), calc. for C₂₀Hι₅ClO₆Na⁺ 409.0455.

Example 14

Catalytic asymmetric synthesis of 3-(4-Hydroxy-2-oxo-2H-chromen-3-yl)- butyraldehyde (AR = Me, R₃ = H, R4 = H, R = H, X = 0)

To a stirred solution of 4-hydroxycoumarin (82.0 mg, 0.51 mmol) in 2.0 mL THF was added (4S, 5S)-diphenyl-imidazolidine-2-carboxylic acid (13.4 mg, 0.05 mmol) and crotonaldehyde (42 μL, 0.50 mmol) and the resulting solution was stirred for 140 hours at ambient teamperature. The reaction mixture was concentrated in vacuo and redissolved in CH₂C1₂ prior to purification by flash chromatography on silica in a mixture of Et₂O/CH₂Cl₂. After concentration in vacuo 23.2 mg (20%) 3-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-butyraldehyde was obtained as a colorless solid in 31% ee as determined by GC after acetyl protection of the hemiketalized form (Ac₂O, DMAP, rt, 12h) using a Chrompack Chirasil Dex-CB column. The NMR data given below are for the unprotected hemiketal which exists as an approximately 3.4:1 diastereomeric mixture. 1H NMR (CDC1₃) δ 1.32 (d, J = 7.0 Hz, 2.31H, major ds CH₃), 1.46 (d, J = 7.0 Hz, 0.69H, minor ds CH₃), 1.97-2.23 (m, 2H, both ds CH₂), 2.96 (m, 0.23H, minor ds CH), 3.07 (m, 0.77H, major ds CH), 4.63 (br, 0.23H, minor ds OH), 5.16 (br, 0.77H, major ds OH), 5.69 (m, 0.77H, major ds hemiketal CH), 5.83 (m, 0.23H, minor ds hemiketal CH), 7.16-7.22 (m, 2H, ArH), 7.43-7.47 (m, IH, ArH), 7.71-7.75 (m, IH, ArH); ¹³C NMR (CDCI₃) δ 19.7, 20.5, 23.9, 25.0, 34.4, 35.4, 93.9, 94.7, 105.5, 106.1, 115.6, 115.8, 116.5, 116.6, 122.8, 123.9, 124.0, 131.6, 131.7, 152.4, 152.6, 157.7, 158.6, 163.1, 163.2; HRMS m/z 255.0633 (M+Na⁺), calc. for Cι₃Hι₂0₄Na⁺ 255.0633.

Example 15

Catalytic asymmetric synthesis of 4-Hydroxy-3-(3-oxo-(lS)-pyridin-2-yl-butyl)- chromen-2-one

(AR = 2-pyridine, R₃ = H, Ri = Me, R = H, X = O)

To a stirred solution of 4-hydroxycoumarin (82.0 mg, 0.51 mmol) in 2.0 mL THF was added (4R,5R)-diphenyl-imidazolidine-2-carboxylic acid (13.4 mg, 0.05 mmol) and pyrimidalacetone(74.0 μL, 0.50 mmol) and the resulting solution was stirred for 60 hours at ambient temperature until all pyrimidalacetone was consumed. The reaction mixture was concentrated in vacuo and redissolved in CH₂C1₂ prior to purification by flash chromatography on silica in a mixture of MeOH/CH₂Cl₂. After concentration in vacuo 136.8 mg (88%) 4-Hydroxy-3-(3- oxo-(lS)-pyridin-2-yl-butyl)-chromen-2-one was obtained as a white crystalline solid in 65% ee as determined by HPLC in 2-propanol/hexane 50/50 with 0.1% TFA using a Daicel Chiralpak AS column. The NMR spectra were obtained at 60°C and is therefore an average of several rapidly interchanging conformations and as a consequence several carbon atoms were not observed. 1H NMR (CDC1₃, 60°C) δ 1.94 (s, 3H, CH₃), 2.79 (br, IH, CH₂), 3.05 (br, IH, CH₂), 4.76 (br, IH, CH), 7.23-727 (m, 3H, ArH), 7.48 (dt, J = 1.2, 7.9 Hz, IH, ArH), 7.73 (m, IH, ArH), 7.79 (m, IH, ArH), 7.95 (dd, J = 8.2, 1.3 Hz, IH, ArH), 8.41 (d, J - 4.9 Hz, IH, ArH); ¹³C NMR (CDC1₃, 60°C) δ 29.4, 38.9, 116.4, 122.8, 123.7, 123.9, 125.9, 131.8, 138.8, 146.4, 153.1, 161.7; HRMS m/z 332.0898 (M+Na⁺), calc. for Cι₈Hι₅O₄NNa⁺ 332.0898.

Example 16

Catalytic asymmetric synthesis of (S)-6,7-Dimethylwarfarin (AR = Ph, R₃ = H, R₄ = CH₃₎ R = 6,7-dimethyl, X = O)

To a stirred solution of 6,7-dimethyl-4-hydroxycoumarin hemihydrate (100.0 mg, 0.50 mmol) in 2.0 mL THF was added (4S)-benzyl-l-methyl-imidazolidin- 2-carboxylic acid (11.0 mg, 0.05 mmol) and benzyUdeneacetone (73.1 mg, 0.50 mmol) and the resulting solution was stirred for 110 hours at ambient temperature. The reaction mixture was concentrated in vacuo and redissolved in CH₂C1₂ prior to purification by flash chromatography on silica in a mixture of Et₂O/CH₂Cl₂. After concentration in vacuo 137.4 mg (82%) (S)-6,7- Dimethylwarfarin was obtained as a white solid in 66% ee as determined by HPLC in 2-proρanol/hexane 1:1 with 0.2 % TFA using a Daicel Chiralpak AD column. The product exists in a predominantly hemiketalized form which gives rise to diastereomers. 1H NMR (CDC1₃) δ 1.67 (s, 1.36H, CH₃ ketal), 1.68 (s, 1.36H, CH₃ ketal), 1.98 (m, 0.45H, CH₂ ketal), 2.28 (s, 1.5H, ArCH₃), 2.29 (s, 1.5H, ArCH₃), 2.32 (s, 0.28H CH₃ keto), 2.33 (s, 1.5H, ArCH₃), 2.36 (s, 1.5H, ArCH₃), 2.38-2.55 (m, 1.36H, CH₂ ketal), 3.22 (br s, 0.36H, OH ketal), 3.33-3.38 (m, 0.09H, CH₂ keto), 3.56 (br s, 0.45H OH ketal), 3.85 (dd, J = 19.6, 9.8 Hz, 0.09H, CH₂ keto), 4.15 (dd, J = 11.3, 6.6 Hz, 0.45H, CH ketal), 4.26 (dd, J = 6.8, 3.3 Hz, 0.45H, CH ketal), 4.68 (dd, J = 9.8, 1.9 Hz, 0.09H, CH keto), 6.98 (s, 0.45H, ArH ketal), 7.03 (s, 0.09H, ArH keto), 7.10 (s, 0.45H, ArH ketal), 7.18-7.34 (m, 5H, ArH), 7.51 (s, 0.45H, ArH ketal), 7.61 (s, 0.45H, ArH ketal), 7.65 (s, 0.09H, ArH keto), 9.40 (br, 0.09H, OH keto); ¹³C NMR (CDC1₃) δ 19.3, 19.4, 20.2, 20.3, 27.3, 27.8, 34.7, 35.4, 40.4, 42.9, 99.3, 100.3, 100.7, 102.9, 113.1, 113.5, 116.6, 117.0, 122.5, 123.0, 126.4, 127.0, 127.1, 127.2, 128.6, 129.0, 132.3, 132.9, 141.3, 142.0, 142.1, 143.9, 151.1, 151.3, 159.8, 160.3, 162.5, 163.0; HRMS m/z 359.1250 (M+Na⁺), calc. for C₂ιH₂₀O₄Na⁺ 359.1259.

Example 17

Catalytic asymmetric synthesis of 3-[3-(4'-Bromo-biphenyl-4-yl)-3-oxo-(lS)- phenyl-propyl]-4-hydroxy-chroman-2-one

(AR = Ph, R₃ = H, R₄ = 4-(4'-bromo)diphenyl, R = H, X = O)

To a stirred solution of 4-hydroxycoumarin (82.0 mg, 0.51 mmol) in 2.0 mL THF was added (4S, 5S)-diphenyl-imidazolidine-2-carboxylic acid (13.4 mg, 0.05 mmol) and l-(4'-bromo-biphenyl-4-yl)-3-phenyl-propenone (181.6 mg, 0.50 mmol) and the resulting solution was stirred for 200 hours at 50°C. The reaction mixture was concentrated in vacuo and redissolved in CH₂C1₂ prior to pu- rification by flash chromatography on silica in a mixture of Et₂O/CH₂Cl₂. After concentration in vacuo 26.6 mg (15%) 3-[3-(4'-Bromo-biphenyl-4-yl)-3-oxo- (lS)-phenyl-propyl]-4-hydroxy-chroman-2-one was obtained as a white crystalline solid in 49% ee as determined by HPLC in ethanol/hexane 20/80 with 0.1% TFA using a Daicel Chiralpak AS column.

1H NMR (CDC1₃) δ 3.82 (dd, J = 19.1, 2.3 Hz, IH, CH₂), 4.51 (dd, J = 19.1, 9.8 Hz, IH, CH₂), 4.51 (dd, J = 9.8, 2.3 Hz, IH, CH), 7.21-.7.38 (m, 5H, ArH), 7.42 (d, J = 7.9 Hz, 2H, ArH), 7.47-7.51 (m, 3H, ArH), 7.60 (d, J = 8.1 Hz, 2H, ArH), 7.67 (d, J = 8.3 Hz, 2H, ArH), 7.99 (dd, J = 8.0, 1.3 Hz, IH, ArH), 8.15 (d, J = 8.3 Hz, 2H, ArH), 9.88 (br, IH, OH);

¹³C NMR (CDCI₃) δ 35.3, 40.4, 108.2, 116.4, 116.8, 123.2, 124.0, 124.2, 126.9, 127.4, 128.3, 128.4, 129.0, 129.6, 131.9, 132.4, 134.8, 138.5, 140.0, 146.0, 153.0, 161.3, 162.3, 202.2.

Example 18

Catalytic asymmetric synthesis of 4-Hydroxy-3-{3-oxo-(lR)-phenyl-3-[4-(4- trifluoromethyl-benzyloxy)-phenyl] -propyl} -chromen-2-one

(AR = Ph, R₃ = H, R₄ = 4-(4'-trifluoro-methyl)benzyloxyphenyl, R = H, X - O)

To a stirred solution of 4-hydroxycoumarin (82.0 mg, 0.51 mmol) in 2.0 mL THF was added (4R, 5R)-diphenyl-imidazolidine-2-carboxylic acid (26.8 mg, 0.10 mmol) and 3 -phenyl- 1- [4-(4-trifluoromethyl-benzyloxy)-phenyl]- propenone (191.2 mg, 0.50 mmol) and the resulting solution was stirred for 250 hours at 50°C. The reaction mixture was concentrated in vacuo and redissolved in CH₂C1₂ prior to purification by flash chromatography on silica in a mixture of Et₂O/CH₂Cl₂. After concentration in vacuo 30.7 mg (11%) 4-Hydroxy-3-{3-oxo- (lR)-phenyl-3-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-propyl}-chromen-2-one was obtained as a white solid in 37% ee as determined by HPLC in ethanol/hexane 10/90 with 0.1% TFA using a Daicel Chiralcel OD column. 1H NMR (CDCI3) δ 3.73 (dd, J = 18.9, 1.3 Hz, IH, CH₂), 4.42 (dd, J = 18.9, 9.7 Hz, IH, CH₂), 4.94 (br d, J = 9.7 Hz, IH, CH), 5.20 (s, 2H, OCH₂), 7.01 (d, J = 9.1 Hz, 2H, ArH), 7.20-7.32 (m, 5H, ArH), 7.40 (d, J = 7.9 Hz, 2H, ArH), 7.45- 7.51 (m, IH, ArH), 7.54 (d, J = 7.6 Hz, 2H, ArH), 7.66 (d, J = 7.6 Hz, 2H, ArH), 7.98 (dd, J = 7.7, 1.3 Hz, IH, ArH), 8.07 (d, J = 9.3 Hz, 2H, ArH), 10.1 (br, IH, OH); ¹³C NMR (CDCI3) δ 35.3, 39.8, 69.4, 108.3, 114.9, 116.3, 116.9, 123.9, 124.2, (125.80, 125.84, 125.88, 125.92, quartet from C next to CF₃), 126.8, 127.6, 128.2, 128.3, 129.3, 129.4, 131.4, 131.8, 140.1, 140.2, 153.0, 161.5, 162.3, 163.3, 201.0, CF₃ carbon not observed.

Example 19

In Table 1 is shown the results of the catalytic asymmetric synthesis of Warfarin (AR = Ph, R3 = H, R = CH₃, X = O) from 4-hydroxycoumarin and benzyUdeneacetone under various conditions.

Table 1

Loading Tern Yield

Catalyst Solvent time/h ee % (mol%) o %/.^a

10 CH₂C1₂ 70 rt 77 62(S)

5 CH₂C1₂ 70 rt 67 61(S)

10 EtOH 70 rt 69 47(S)

10 H₂0 90 rt 22 49(S)

(S,S)-

10 THF 70 Rt 77 61(S) diphenylethandiamme

(IR.2R)-

10 THF 90 Rt 79 56(R) cyclohexandiamine

(S)-phenylethylamine 10 THF 60 Rt 69 30(R)

Isolated yield after flash chromatography.

Example 20

In Table 2 is shown the results of the catalytic asymmetric Michael addition of 5 various 4-hydroxycoumarins to different enones at ambient temperatures unless otherwise stated.

Table 2

(R)m X AR R4 Catalyst/ Solvent Yield ee load- % % ing(mol%) -methoxy O Ph Me C3/10 THF 70 70

7-fluoro O Ph Me C3/10 THF 61 69 ,8-dichloro O Ph Me C3/10 THF 74 69 ,7-dimethyl O Ph Me C2/10 THF 57 76

H O 4-chlorophenyl Me Cl/10 CH₂C1₂ 68 87^a

H O 4-nitrophenyl Me Cl/10 THF 69 83

H O Ph Ph C3/10 THF 11 66

H O Ph Ph Cl/10 THF 3 79

H O -CH₂- CH₂- CH₂- C4/5 THF 66 62 H 0 2-furan Me C3/10 THF 62 56

H 0 2-pyridin Me C3/10 THF 96 31

H 0 4-chlorophenyl C0₂Me Cl/10 CH₂C1₂ 47 31

H O Ph CH₂C1 C2/10 THF 12 84

H 0 5-chloro-2-thienyl 4-chlorophenyl C3/10 THF 12 33^b

H 0 Ph 4-(4'-bromo)diphenyl Cl/10 THF 17 37

H 0 Ph 4-(4'-triπuoro-methyl)-

C3/20 THF 10 27 benzyloxyphenyl

H s Ph CH₃ C2/20 THF 68 69

Reaction was performed at 10°C. reaction was performed at 40 °C.

Catalysts

C1 C2

Example 21

Catalytic asymmetric synthesis of 3-(4-chloro-3-oxo-(lS)-phenyl-butyl)-4- hydroxy-chromen-2-one

(AR = Ph, R₃ = H, R₄ = CH₂C1, X = O) To a stirred solution of 4-hydroxycoumarin (82.0 mg, 0.51 mmol) in 2.0 mL THF was added (4S)-benzyl-l-methyl-imidazolidin-2-carboxylic acid (11.0 mg, 0.05 mmol) and α-chlorobenzylideneacetone (90.3 mg, 0.50 irimol) and the resulting solution was stirred for 150 hours at ambient temperature. The reaction mixture was concentrated in vacuo and redissolved in CH₂C1₂ prior to purification by flash chromatography on silica in a mixture of Et₂0/CH₂C1₂. After concentration in vacuo 60.6 mg (35%) 3-(4-chloro-3-oxo-(lS)-phenyl-butyl)-4- hydroxy-chromen-2-one was obtained as a white solid in 72% ee as determined by HPLC in 2-propanol/hexane 1:1 with 0.2% TFA using a Daicel Chiralpak AD column. The product exists in a hemiketalized form which gives rise to di- astereomers.

1H NMR (CDC1₃) δ 2.01-2.09 (m, 0.58H, CH₂ major diastereomer), 2.47-2.58 (m, 1.42H, CH₂ major and minor diastereomer), 3.63 (br s, 0.42H, OH minor diastereomer, position is concentration dependent), 3.71-3.92 (m, 2H, CH₂C1, ma- jor and minor diastereomer), 3.91 (br s, 0.58H, OH major diastereomer, position is concentration dependent), 4.24 (dd, J = 11.3, 7.1 Hz, 0.58H, CH major diastereomer), 4.37 (dd, J = 6.7, 3.0 Hz, 0.42H, CH minor diastereomer), 7.22- 7.39 (m, 7H, ArH), 7.54 (dt, J - 1.5, 7.8 Hz, 0.58H, ArH), 7.59 (dt, J = 1.6, 7.7 Hz, 0.42H, ArH), 7.84 (dd, J = 7.7, 1.6 Hz, 0.58H, ArH), 7.90 (dd, J = 8.4, 1.5 Hz, 0.42H, ArH); ¹³C NMR ((CD₃)₂SO) δ 34.7, 36.5, 38.6, 47.9, 48.5, 98.8, 99.9, 102.5, 103.8, 115.1, 115.2, 116.3, 116.4, 122.6, 122.7, 124.2, 124.3, 125.8, 126.2, 127.1, 127.5, 127.9, 128.4, 132.3, 143.3, 143.5, 152.3, 158; HRMS m/z 365.0557(M+Na⁺), calc. for Cι₉Hι₅O₄ClNa⁺ 365.0561.

Example 22:

Catalytic asymmetric synthesis of (S)-4-hydroxy-3-(2-oxo-l-phenyl-propyl)- thiochromen-2-one (AR = Ph, R₃ = H, R = CH₃, X = S)

To a stirred solution of 4-hydroxy-thiochromen-2-one (44.6 mg, 0.25 mmol) in 2.0 mL THF was added (4S)-benzyl-l-methyl-imidazolidin-2-carboxylic acid (11.0 mg, 0.05 mmol) and benzyUdeneacetone (36.6 mg, 0.25 mmol) and the resulting solution was stirred for 150 hours at ambient temperature. The reaction mixture was concentrated in vacuo and redissolved in CH C1₂ prior to purifica- tion by flash chromatography on silica in a mixture of Et₂O/CH₂Cl₂. After concentration in vacuo 62.3 mg (77%) (S)-4-hydroxy-3-(2-oxo-l-phenyl-propyl)- thiochromen-2-one was obtained as a white solid in 67% ee as determined by HPLC in 2-propanol/hexane 1:1 with 0.2% TFA using a Daicel Chiralpak AD column. The product exists in a hemiketalized form which gives rise to a 1:1 mixture of diastereomers.

1H NMR (CDC1₃) δ 1,67 (s, 1.50H, CH₃ one diastereomer), 1,69 (s, 1.50H, CH₃ one diastereomer), 1.96-2.06 (m, 0.50H, CH₂ one diastereomer), 2.32-2.57 (m, 1.50H, CH mixture of diastereomers), 3.23 (br s, 0.50H, OH one diastereomer, position is concentration dependent), 3.48 (br s, 0.5 OH, OH one diastereomer, position is concentration dependent), 4.28 (dd, J = 10.8, 7.2 Hz, 0.50H, CH one diastereomer), 4.47 (dd, J = 6.4, 3.5 Hz, 0.50H, CH one diastereomer), 7.13-7.55 (m, 8H, ArH, both diastereomers), 8.18 (d, J = 8.1 Hz, 0.50H, ArH one diastereomer), 8.26 (d, J = 8.1 Hz, 0.50H, ArH one diastereomer); ¹³C NMR (CDCI₃) δ 27.6, 28.0, 34.3, 36.2, 39.6, 42.5, 98.4, 99.9, 112.5, 115.6, 123.5, 123.9, 125.0, 125.1, 125.3, 125.8, 125.9, 126.1, 126.2, 126.3, 126.8, 127.0, 128.5, 129.1, 129.5, 129.6, 130.0, 135.6, 145.7 141.9, 144.3 159.4, 160.2, 183.2, 183.6 ; HRMS m/z 347.0719 (M+Na⁺), calc. for Cι₉Hι₆O₃SNa⁺ 347.0718.

Synthesis of catalysts

General experimental procedure for the synthesis of imidazolidine-2-carboxylic acid catalysts. To a solution of a chiral diamine in CH₂C1₂ was added 1.0 equivalent of gly- oxylic acid monohydrate and the reaction mixture was allowed to stir at ambient temperature for 15 hours in a closed vessel. After evaporation of the solvent the solid catalysts were dried under vacuum and were afterwards ready for use or could be stored for months.

Example A

Synthesis of (4R,5R)-diphenyl-imidazolidine-2-carboxylic acid

To a solution of (R,R)-diphenylethanediamine (636.9 mg, 3.0 mmol) in 50 ml CH₂C1₂ was added glyoxylic acid monohydrate (276.2 mg, 3.0 mmol) and the reaction mixture was stirred for 15 hours in a closed vessel. The solvent was removed by rotary evaporation giving a quantiative yield of (4R,5R)-diphenyl- imidazolidine-2-carboxylic acid as a 1:1 mixture of diastereomers obtained as a white powder which was dried further under vacuum.

1H NMR ((CD₃)₂CO) δ 4.01 (d, J = 9.0 Hz, IH, PhCH), 4.30 (d, J = 9.0 Ηz, 1Η, PhCH), 5.29 (s, 1Η, aminal-Η), 7.09-7.11 (m, 3Η, NH and OH), 7.21-7.28 (m, 10H, ArH);

Example B

Synthesis of (4S)-Benzyl-l-methyl-imidazolidin-2-carboxylic acid

(S)-Phenylalanine-N-methylamide was prepared in quantitative yield from L- phenylalanine as described by Macmillan et al. (J. Am. Chem. Soc. (2000), 122, 4243-44 (supporting information)). (S)-Phenylalanine-N-methylamide (15.0 g, 84 mmol) was reduced with LiAlH₄ (6.3 g) at reflux in THF for 12 hours until the starting material had disappeared (TLC) and then quenched with a minimal amount water, filtered and extracted with CH₂C1₂ to yield (SyN'-methyl-S- phenyl-propane-l,2-diamine (12.4g, 90%) as a colourless liquid. To a solution of (S^N^methyl-S-phenyl-propane-l^-diamine (680 mg, 4.1 mmol) was added 1.0 eq. of glyoxylic acid monohydrate (381 mg, 4.1 mmol) and the reaction mixture was stirred for 15 hours at room temperature. The solvent was removed by rotary evaporation giving a quantiative yield of (4S)-Benzyl-l-methyl- imidazolidin-2-carboxylic acid as a 2:1 mixture of diastereomers obtained as a yellow powder which was dried under vacuum.

1H NMR (CDCI3) δ 2.52- 2.93 (m, 2H, CH₂N), 2.84 (s, IH, NCH₃), 2.89 (s, 2H, NCH₃), 3.01 (dd, J = 13.4, 6.3 Hz, 0.33H, PhCH₂), 3.21 (dd, J = 13.4, 5.8 Hz, 0.67H, PhCH₂), 3.41-3.48 (m, 0.67H, PhCH₂), 3.64-3.71 (m, 0.33H, PhCH₂), 3.74 (kvintet, J = 6.8 Hz, 0.67H, CH), 4.01 (kvintet, J = 6.7 Hz, 0.33H, CH), 4.12 (s, 0.33H, CHCOOH), 4.19 (s, 0.67H, CHCOOH), 7.20-7.31 (m, 5H, ArH); ¹³C NMR (CDCI3) δ 38.4, 39.4, 39.7, 40.5, 57.5, 58.3, 58.4, 59.2, 81.9, 84.7, 126.9, 127.0, 128.7, 128.8, 129.0, 129.2, 137.4, 137.5, 169.2, 169.6; HRMS m/z 243.1100 (M+Na⁺), calc. for Cι₂Hι₆N₂O₂Na⁺ 243.1109.

Reduction of the ketone

The ketone functionality can be stereoselectively reduced by L-selectride (lithium tri-s-butylborohydride) to the corresponding alcohol as shown below for (S)-Warfarin.

Example

To a solution of (S)-Warfarin (30.8 mg, 0.1 mmol, 97% ee) in THF at -78°C was added L-selectride (260 μL 1.0 M solution in THF, 0.26 mmol) and the reaction mixture was alloved to stir for 12 hours at -78°C, until full conversion was achieved before it was quenched with saturated amoniumchloride solution and extracted with CH₂C1₂. After concentration in vacuo the diastreomeric ratio was measured to 7.8:1 by 1H-NMR and the diastereomers separated by flash chromatography in MeOH/CH₂Cl₂ yielding the optically pure (S)-Warfarin alcohol which decomposes upon standing. Spectral data for the major diastereomer are shown below.

1H NMR (CDCI3) δ 1.32 (d, J = 5.8 Hz, 3H, CH₃), 2.16-2.25 (m, IH, CH₂), 2.52-2.60 (m, IH, CH₂), 3.96-4.03 (m, IH, CHOH), 4.70 (dd, J = 7.4, 5.9 Hz, IH, PhCH), 7.19-7.27 (m, 3H, ArH), 7.31-7.36 (t, J = 7.4 Hz, 2H, ArH), 7.43- 7.51 (m, 3H, ArH), 7.77 (dd, J = 7.7, 1.4 Hz, IH, ArH); HRMS m/z 333.1104 (M+Na^"1"), calc. for Cι₉H₁₈O₄Na⁺ 333.1103.

Claims

P A T E N T C L A I M S

1. A process for the catalytic asymmetric synthesis of an optically active compound of the formula la or lb

wherein R is selected from Cι_-7 alkyl, Cι- haloalkyl, Cι_-7 alkoxy, Cι_-7 haloalkoxy, halogen, and hydroxy; R3 is H or C_M alkyl; R₄ is selected from H, Cι_-7 alkyl, Cι- haloalkyl, Cι_-7 alkoxy, COOH, CO- Cι_-7 alkoxy or an optionally substituted aryl or heterocycle;

AR represents Cι_-7 alkyl, optionally substituted aryl, an optionally substituted heterocycle or AR and R₄ may be bridged together forming part of a ring system; X is O or S; m is a number between 0-4; comprising the step of reacting a compound of the formula 2

with a compound of the formula 3

in the presence of a catalytic amount of an chiral nitrogen containing organic compound.

2. A process according to claim 1 wherein AR is selected from

wherein Y represents CH or N; W represents O, S, N-H or N-R;

Ri is selected from Cι_-7 alkyl, Cι- haloalkyl, Cι_-7 alkoxy, Cι- haloalkoxy, halogen, CN and NO₂;

R₂ represents H or halogen.

3. A process according to claim 1 wherein R₄ is selected from H, Cι_-7 alkyl, Ci-₇ haloalkyl, Cι_-7 alkoxy, CO-Cι-₇ alkoxy, phenyl, phenyl substituted with R, or R is

in which D represents O, -OCH₂-, -CH₂O- -CH₂- -CH₂CH - or a single bond; n is a number between 0-5.

4. A process according to claim 2 or 3 wherein R is Cι_-7 alkoxy or halogen; Ri is halogen, C_M haloalkyl or NO₂; R₃ is H; R is selected from C₁-₄ alkyl, C₁-₇ haloalkyl, CO-Cι_-7 alkoxy, phenyl optionally substituted in the para-position, diphenyl optionally substituted in the para-position or benzyloxyphenyl optionally substituted in the para- position or AR and R₄ together represents a C_2-4 alkylene chain; m is 0,1 or 2; n is 0 or 1.

5. A process according to claim 4 wherein AR is selected from phenyl, 4- nitrophenyl, 4-chlorophenyl and 5-chloro-2-thienyl.

6. A process according to claim 5 wherein R₄ is selected from methyl, diphenyl, 4-(4'-bromo)diphenyl, 4-chlorophenyl and 4-(4'-trifluoromethyl)- benzyloxyphenyl.

7. A process according to claim 1 in which the chiral nitrogen containing organic compound contains a primary or secondary nitrogen atom.

8. A process according to claim 7 in which the chiral nitrogen containing organic compound is a compound of the formula 4

wherein q is 0 or 1 ; R₅, RQ, Rη, R₈, which may the same or different represents H, C_1-7 alkyl,

Cι_-7 haloalkyl, optionally substituted aryl, an optionally substituted heterocycle, Cι-C₄ alkyl substituted with aryl or a heterocycle or R₅ and Rδ together or R₇ and R₈ together may represent a carbonyl group or when q is 1, R5 with either R₇ or R₈ may be bridged together forming part of a ring system;

R₉ and Rι₀, which may the same or different are selected from H, C₁-7 alkyl, hydroxy, Cι_-7 alkoxy or R₉ and Rio may be bridged together forming part of a ring system;

Z is S, O, C=O, CH-Rn, N-Rn where R_u is R₅.

A process according to claim 8, wherein q is 1 ;

R₅, Re, Ri, R₈ which may the same or different represents H, optionally substituted aryl or methyl substituted with an optionally substituted heterocycle, or R₅ and R₇ together represents a C₃-₅ alkylene chain; Z is N-Rn wherein Ru represents H or C₁.7 alkyl;

R₉ and Rio are H or R9 and Rio together represensts a methylene bridge optionally substituted with COOH or CO-Cι-7 alkoxy.

10. A process according to claim 9 wherein the substituent pair (R₅/Rό) is identical to the pair ( z/Rs).

11. A process according to the any of the proceeding claims which further comprises reducing a compound of the formula la or lb to a compound of the formula 5 a or 5b respectively