Optically active compounds biotransformations

For many reasons, the pharmaceutical industry will continue to require facile synthetic routes to diastereoisomerically and enantiomerically pure chiral molecules. In order to achieve these goals, new asymmetric processes, especially catalytic asymmetric reactions, will be needed. Alternatively, there is great potential for the development of industrially useful biotransformations to produce complex optically active compounds. Genetic engineering will probably play an important role in such approaches. Nonetheless, the challenge to the organic chemist will remain. 

Stereoselective enzymatic hydrolyses of esters represent a further type of biotransformation that has been used for the synthesis of optically active organosilicon compounds. The first example of this particular type of bioconversion is illustrated in Scheme 15. Starting from the racemic (l-acetoxyethyl)silane rac-11, the optically active (l-hydroxyethyl)silane (5)-41 was obtained by a kinetic racemate resolution using porcine liver esterase (PLE E.C. 3.1.1.1) as the biocatalyst7. The silane (5)-41 (isolated with an enantiomeric purity of 60% ee bioconversion not optimized) is the antipode of compound (R)-41 which was obtained by an enantioselective microbial reduction of the acetylsilane 40 (see Scheme 8). 

Enantioselective enzymatic ester hydrolyses have also been used for the preparation of optically active silicon compounds with the silicon atom as the center of chirality. An example of this is the kinetic resolution of the racemic 2-acetoxy-l-silacyclohexane rac-(SiR,CR/SiS,CS)-79 with porcine liver esterase (PLE E.C. 3.1.1.1) (Scheme 16)65. Under preparative conditions, the optically active l-silacyclohexan-2-ol (SiS,CS)-80 was obtained as an almost enantiomerically pure product (enantiomeric purity >96% ee) in ca 60% yield [relative to (SiS,CS )-79 in the racemic substrate]. The biotransformation product could be easily separated from the nonhydrolyzed substrate by column chromatography on silica gel. 

Enantioselective enzymatic ester hydrolyses of prochiral trimethylsilyl-substituted diesters of the malonate type have been applied for the synthesis of the related optically active monoesters68. As an example of this particular type of biotransformation, the enantioselective conversion of the diester 82 is illustrated in Scheme 17. Hydrolysis of compound 82 in phosphate buffer, catalyzed by porcine liver esterase (PLE E.C. 3.1.1.1) or horse liver acetonic powder (HLAP), gave the optically active monoester 83 (absolute configuration not reported) in 86% and 49% yield, respectively. The enantiomeric purities... 

Enantioselective enzymatic amide hydrolyses can also be applied for the preparation of optically active organosilicon compounds. The first example of this is the kinetic resolution of the racemic [l-(phenylacetamido)ethyl] silane rac-84 using immobilized penicillin G acylase (PGA E.C. 3.5.1.11) from Escherichia coli as the biocatalyst (Scheme 18)69. (R)-selective hydrolysis of rac-84 yielded the corresponding (l-aminoethyl)silane (R)-85 which was obtained on a preparative scale in 40% yield (relative to rac-84). The enantiomeric purity of the biotransformation product was 92% ee. This method has not yet been used for the synthesis of optically active silicon compounds with the silicon atom as the center of chirality. 

Enantioselective enzymatic transesterifications have been used as a complementary method to enantioselective enzymatic ester hydrolyses. The first example of this particular type of biotransformation is the synthesis of the optically active 2-acetoxy-l-silacyclohexane (5 )-78 (Scheme 19). This compound was obtained by an enantioselective transesterification of the racemic l-silacyclohexan-2-ol rac-43 with triacetin (acetate source) in isooctane, catalyzed by a crude lipase preparation from Candida cylindracea (CCL, E.C. 3.1.1.3)62. After terminating the reaction at 52% conversion (relative to total amount of substrate rac-43), the product (S)-78 was separated from the nonreacted substrate by column chromatography on silica gel and isolated in 92% yield (relative to total amount of converted rac-43) with an enantiomeric purity of 95% ee. The remaining l-silacyclohexan-2-ol (/ )-43 was obtained in 76% yield (relative to total amount of nonconverted rac-43) with an enantiomeric purity of 96% ee. Repeated recrystallization of (R)-43 led to an improvement of enantiomeric purity by up to >98% ee. Compound (R)-43 has already earlier been prepared by an enantioselective microbial reduction of the l-silacyclohexan-2-one 42 (see Scheme 8)53. The l-silacyclohexan-2-ol (R)-43 is the antipode of compound (.S j-43 which was obtained by a kinetic enzymatic resolution of the racemic 2-acetoxy-l-silacyclohexane rac-78 (see Scheme 15)62. For further enantioselective enzymatic transesterifications of racemic organosilicon substrates, with a carbon atom as the center of chirality, see References 64 and 70-72. 

Analogous enantioselective biotransformations have been achieved with the silicon compounds 217 and 219, which were transformed into the respective optically active products (S)-218 (yield 90%, enantiomeric purity 84% ee) and (S)-220 (yield 80%, enantiomeric purity 76% ee) using growing cells of Kloeckera corticis (ATCC 20109)278,279. Particularly remarkable is the conversion of the hydridosilane 219 which could be performed without a noticeable degree of hydrolytic cleavage of the Si-H bond (incubation conditions pH 5.5, 27 °C). 

Stereoselective biotransformation with growing cells, resting free or immobilized cells, or isolated enzymes has been demonstrated to be a useful preparative method for the synthesis of centrochiral optically active organosilicon compounds [1-3]. In continuation of our own studies in this field, we have investigated stereoselective microbial transformations of rac-1-(4-fluorophenyl)-l-methyl-l-sila-2-cyclohexanone (rac-1) and rac-(Si5,CR/SiR,C5)-2-acetoxy-l-(4-fluorophenyl)-l-methyl-1-silacyclohexane [rac-(Si5,C/ /Si/f,C5)-3a]. We report here on (i) the synthesis of rac-1 and rac- SiS,CR/SiR,CS)-3a, (ii) the diastereoselective microbial reduction of rac-1 [— (Si5,C/ )-2a, (SiR,C5)-2a], and (iii) the enantioselective microbial hydrolysis of rac-(SiS,CR/SiR,CS)-3a [- (SiR,C5)-2a],... 

The 1S,2R stereoisomer 17 has been obtained via the Baker s yeast reduction of the unsaturated bromoketone 18 in 99% e.e. and 75% yields at 3 g/L. The reaction occurs presumably through the reduction of the initially formed saturated ketone 19. The fact that racemic bromoketone 20 is also reduced by yeast to the same enantiomer with complete stereoselectivity is evidence that the intermediate bromoketone 19 rapidly racemizes in the reaction medium. The efficiency of the latter biotransformation makes it preferable to the corresponding yeast reduction of the unsaturated compound (Scheme 7). The preparation of such enantiomerically pure compounds found significance in the preparation of optically active l-amino-2-indanol as ligand in the human immunodeficiency virus (HIV) protease inhibitor indinavir [47]. 

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