Enzymatic synthesis of chiral intermediates for drug development

Chirality is a key factor in the efficacy of many drug products and thus th e production of single enantiomers of drug intermediates has become increas ingly important in the pharmaceutical industry. Biocatalysis is now accepte d as a one of key methodologies for the preparation of chiral drug intermed iates and fine chemicals. The biocatalytic production of several key interm ediates in the synthesis of antihypertensive, anticholesterol, anti-Alzheim er's, beta3-receptor agonist, HIV-protease inhibitor, and other pharmaceuti cals is described. These includes (1) the synthesis Of L-6-hydroxynorleucin e from racemic 6-hydroxynorleucine, (2) the enzymatic synthesis of (S)-ally sine ethylene acetal by reductive deamination using phenylalanine dehydroge nase, (3) the synthesis of [4S-(4a,7a,10ab)]-1-octahydro-5-oxo-4-{[(phenylm ethoxy)carbonyl]-amino}-7H-pyrido-[2,1-b][1,3]thiazepine-7-carboxylic acid (BMS-199541-01) by enzymatic oxidation process using L-lysine-epsilon -amin otransferase, (4) the enzymatic synthesis of the lactol [3aS-(3a alpha ,4 a lpha ,7 alpha ,7a alpha)]-hexahydro-4,7-epoxyisobenzofuran-1(3H)-ol and cor responding lactone, (5) the microbial synthesis or (3R-cis)-1,3,4,5-tetrali ydro-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-on e, (6) the microbial oxygenation of 6-cyano-2,2-dimethyl-2H-1-benzopyran to the corresponding chiral epoxide and (+)-trans diol, (7) the enantioselect ive microbial reductions of N-[4-(2-chloroacetyl)phenyl]methanesulfonamide and (4-benzyloxy-3-methanesulfotiylamino)-2'-bromoacetophenone to the corre sponding (R)-alcohols, (8) the enzymatic resolution of racemic alpha -methy l phenylalanine amides by amidase, (9) the enantioselective hydrolysis of d iethyl methyl-(4-methoxyphenyl)-propanedioate by lipase PS-30, (10) the ena ntioselective microbial reduction of methyl 4-chloro-3-oxobutanoate, (11) t he enzymatic synthesis of ethyl (3S,5B)-dihydroxy-6-(benzyloxy)hexanoate, ( 12) the enantioselective hydrolysis of racemic epoxide 1-{2',3'-dihydrobenz o[b]furan-4'-yl}-1,2-oxirane by epoxide hydrolase, (13) the biocatalytic dy namic kinetic resolution of R,S-1-{2',3'-dihydrobenzo[b]furan-4'-yl}-ethane -1,2-diol, and (13) the diastereoselective microbial reduction of (IS)[3-ch loro-2-oxo-1-(phenylmethyl)propyl]carbamic acid 1,1-dimethylethyl ester.