WO1993002207A1

WO1993002207A1 - Stereoselective synthesis of alcohols

Info

Publication number: WO1993002207A1
Application number: PCT/GB1992/001304
Authority: WO
Inventors: Patrick Barton; Michael Ivan Page
Original assignee: Imperial Chemical Industries Plc
Priority date: 1991-07-19
Filing date: 1992-07-16
Publication date: 1993-02-04
Also published as: AU2328992A; GB9115695D0; ZA925246B

Abstract

An optically active 1,2-diol is made by treating a mixture of optical isomers of a cyclic carbonate ester of a chiral 1,2-diol with a stereo-selective esterase or lipase, separating product diol from unhydrolysed carbonate and recovering desired isomer(s) from product diol and/or unhydrolysed carbonate.

Description

Stereoselective synthesis of alcohols

This invention relates to the synthesis of optically active alcohols, particularly 1,2-diols carrying alkyl or, particularly, aromatic substituents. Modern syntheses, especially of biologically active compounds, are often directed to a particular stereochemical configuration of the desired end compound. To this end, it is very useful to have intermediate compounds having a determined stereochemical configuration as substantially pure enantiomers. Conventional ways of making such intermediates usually rely on the well known chemical methods of resolving stereo-isomers.

This invention approaches the resolution of alcohols having a chiral carbon atom by enzymatic stereoselective hydrolysis of one stereoisomer of a corresponding ester, particularly a carbonate ester of a 1,2-diol.

US 4892822 describes the use of various esterase and lipase enzymes in exchange reactions with diphenyl carbonate, and Applied Microbiology and Biotechnology (1990) _* PP 633 describes using Acinetobacter calcoaceticus to hydrolyse phenyl oct-2-yl carbonate. However, there is no suggestion in either document that 1,2-diol carbonates can be used as enzyme substrates to resolve 1,2-diols.

The invention provides a method of making a 1,2-diol compound having an enantiomeric excess of a desired optical isomer (or isomers) by the steps of:

(a) treating a mixture of the optical isomers of a cyclic carbonate ester of a chiral 1,2-diol compound with a stereoselective esterase or lipase, whereby to preferentially hydrolyse one of said isomers to the corresponding diol;

(b) separating product diol from unhydrolysed carbonate; and

(c) recovering the desired isomer(s) of the diol from said product diol and/or said unhydrolysed carbonate.

The carbonate ester is, in particular, a compound of formula (I):

SUBSTITUTE SHEET 0

II c

(I)

where: R R_, R^ and R are each independently hydrogen, halogen,

1' alkyl or aryl, said alkyl optionally carrying one or more halogen, alkyl, alkoxy or aryl substituents and said aryl groups optionally carrying one or more halogen, alkyl, alkoxy or amino substituents; or any two of R. , R_, R_ and R. together with the carbon atom C and/or C, , form a 5-, 6- or 7- membered ring; with the proviso that R differs from R and/or R differs from

R such that the compound is chiral.

In formula (I) it is desirable that, of groups R and R , one at least is alkyl or (particularly) aryl; the other will typically be hydrogen. Most commonly R_ and R. are hydrogen but either or both can be alkyl or aryl. Alkyl groups, including those in substituents on other groups, are in particular C. to C₀

1 8 straight or branched chain or C and C_c cyclic groups. Aryl ι 3 O groups, including those in substituents on other groups, are particularly phenyl. Particularly suitable compounds are of formula (la):

ET 0

II c

where one of R and R is hydrogen and the other is C. to C₀

1 -i 1 8 straight or branched chain alkyl or C_c or C cycloalkyl or (particularly) phenyl and may be substituted as described above.

The stereoselective esterase or lipase preferentially hydrolyses one of the optical isomers of formula (I) leaving a significant enantiomeric excess of the other isomer in unhydrolysed material. The enantiomeric excess in a sample of an optically active compound is the difference in the concentrations of the two isomers divided by the sum of their concentrations and is usually expressed as a positive percentage of the isomer having the higher concentration. Suitable enzymes include Candida cylindracea lipase, pig pancreas lipase, Pseudomonas fluorescens lipase and Chromobacterium viscosum lipase (all commercially available from Biocatalysts Ltd, Treforest, South Wales) and, especially, pig liver esterase (commercially available from Sigma Chemicals) .

The conditions under which the enzymatic hydrolysis is carried out are not especially critical. Generally, the medium used will be aqueous or contain water mixed with a miscible or immiscible organic solvent but is most conveniently water. Desirably both the substrate and the enzyme will be dissolved in the medium. Typically the hydrolysis reaction will be carried out at a temperature in the range 15 to 45^SC, conveniently at about ambient, and at pH 5 to 8 especially 7 to 8. The concentration of the substrate will typically be 1 to 100,

SUBSTITUTE SHEET particularly 5 to 10 millimolar and of the enzyme 10 to 1000, particularly 50 to 250, mg.l

The starting material will usually be a racemic mixture of the enantiomers of the compound of formula (I) as products of chemical synthesis. Materials having a modest enantiomeric excess of the isomer can be treated to enhance the enantiomeric excess.

The compound of formula (I) can conveniently be made by esterifying the corresponding diol of formula (II):

OH OH

where R1,, R2_, R_3 and R4. are as defined above. The esterification can be carried out by conventional chemical methods such as reacting a diol (Ila) with phosgene or a carbonyl reagent such as triphosgene [bis(trichloromethyl)carbonate]. The invention includes a method of resolving an alcohol of formula II by esterifying it to form a compound of formula (I), selectively hydrolysing the ester and recovering an optically active alcohol using the method of the invention.

Desired product optically active diol can be recovered from the product diol or the unhydrolysed carbonate depending on which isomer is required, or, of course, from each if both isomers (separately) are wanted.

The invention is illustrated by the following Examples. All parts and percentages are by weight unless otherwise indicated.

SUBSTITUTE SHEET EXAMPLE 1

Synthesis of l-phenyl-l,2-ethanediol cyclic carbonate

1-phenyl-1,2-ethanediol (5g; 36 mMol) was dissolved in tetrahydrofuran (50 ml) and pyridine (1.5 ml) was added to the solution which was then cooled to 0°C for 30 min. A solution of triphosgene (2.5g; 8.4 mMol) in tetrahydrofuran (10 ml) was added slowly to the reaction mixture which was then stirred for 2 h at ambient temperature and thereafter at reflux temperature for a further hour. The tetrahydrofuran was removed by rotary evaporation and the resulting oil was poured into ice water and triturated. The title compound precipitated and was filtered off and dried. The product was recovered as a solid having a melting point of 53°C at a yield of 73% of theory. The structure of the product was confirmed as the title compound by H NMR, IR and gas chromatography-mass spectrometry (gc-ms)

^■**H NMR : 4.35 (t, IH, CH), 4.80 (t, IH, CH), 5.25 (t, IH, CH),

4.40 (m, 5H, aromatic H) IR (nujol mull) cm :

1783 (C=0), 1500 and 1600 (phenyl) gc-ms - only one peak was observed in the chromatogram of the product this gave ms m/e values of

: 164 (molecular ion), 119, 105, 91(C„H_CCH⁺) and 78. b o

Selective hydrolysis of l-phenyl-l,2-ethanediol cyclic carbonate l-phenyl-l,2-ethanediol cyclic carbonate (lg, 6.1mMol) was dissolved in dimethyl sulphoxide (280 ml) and made up to 1 litre with phosphate buffer (pH 7.4). Pig liver esterase (2 ml of a solution of 100 mg esterase in 9.1 ml phosphate buffer) was added and the hydrolytic reaction allowed to proceed at ambient temperature (ca 20°C). The reaction was monitored by sampling and analysing for the carbonate using high performance liquid chromatography and was continued until the carbonate peak area was half its original value. The remaining carbonate was extracted into ether, recovered by rotary evaporation and purified by column chromatography (silica 60 column eluted with 1:1 v/v hexane:ether). The carbonate was recovered with a yield

SUBSTITUTE SHEET of 80% (based on | of the starting carbonate) and had a measured optical rotation (at 20°C as a 1 M solution in CHCl_) of [α] = 31.6°. The carbonate was then hydrolysed using aqueous sodium hydroxide, extracting the diol produced into ethyl acetate, drying over magnesium sulphate and rotary evaporation. The diol was recovered in a yield of 70% of theory based on the recovered resolved carbonate and had a measured optical rotation (20°C, 1 M, CHC1₃) of [α]_D = 65.3°C.

The enantiomeric diol was recovered from the reaction mixture by extracting with ethyl acetate, drying over magnesium sulphate and rotary evaporation, in a yield of 85% of theory

(based on f of the starting carbonate) and had a measured optical rotation (20°C, 1 M, CHCl ) of -66°C. The values of measured optical rotation of the two diol enantiomers indicates nearly perfect resolution of the racemic carbonate starting material.

SUBSTI T

Claims

1 A method of making a 1,2-diol compound having an enantiomeric excess of a desired optical isomer or isomers by the steps of:

(a) treating a mixture of the optical isomers of a cyclic carbonate ester of a chiral 1,2-diol compound with a stereospecific esterase or lipase, whereby to preferentially hydrolyse one of said isomers to the corresponding diol;

(b) separating product diol from unhydrolysed carbonate; and

(c) recovering the desired isomer(s) from said product diol and/or said unhydrolysed carbonate.

2 A method according to Claim 1 in which the carbonate ester is a compound of formula I

O

II

where: R R_, R_ a d R are each independently hydrogen, halogen,

1' alkyl or aryl, said alkyl optionally carrying one or more halogen, alkyl, alkoxy or aryl substituents and said aryl optionally carrying one or more halogen, alkyl, alkoxy or amino substituents. any two of R. , R_, R_ and together with carbon atom C and/or C, form a 5-, 6- or 7- membered ring; with the proviso that R differs from R or R₃ differs from R such that the compound is chiral.

SUBSTITUTE SHEET 3 A method according to Claim 2 in which one of R and R_ is alkyl or aryl, either optionally carrying said substituent(s), and the other is hydrogen.

4 A method according to any one of the preceding claims in which R and R. are both hydrogen.

where one of R and R is hydrogen "and the other is C. to C straight J. 1 8 or branched chain alkyl or Co_c or C,b. cycloalkyl or (particularly) phenyl, and may carry one or more substituents as defined in Claim 2.

6 A method according to any one of the preceding claims in which the lipase is selected from Candida cylindracea lipase, pig pancreas lipase, Pseudomonas fluorescens lipase and Chromobacterium viscosum lipase, or the esterase is pig liver esterase.

7 A method of resolving an alcohol of formula II

which comprises esterifying it to form a compound of formula I and selectively hydrolysing the resulting ester by a method according to any one of Claims 1 - 6.