Enzymatic Synthesis of Chiral Intermediates for Drug Development

Abstract

Chirality is a key factor in the efficacy of many drug products and thus the production of single enantiomers of drug intermediates has become increasingly important in the pharmaceutical industry. Biocatalysis is now accepted as a one of key methodologies for the preparation of chiral drug intermediates and fine chemicals. The biocatalytic production of several key intermediates in the synthesis of antihypertensive, anticholesterol, anti-Alzheimer’s, β3-receptor agonist, HIV-protease inhibitor, and other pharmaceuticals is described. These includes (1) the synthesis of L-6-hydroxynorleucine from racemic 6-hydroxynorleucine, (2) the enzymatic synthesis of (S)-allysine ethylene acetal by reductive deamination using phenylalanine dehydrogenase, (3) the synthesis of [4S-(4a,7a,10ab)]-1-octahydro-5-oxo-4-{[(phenylmethoxy)carbonyl]-amino}-7H-pyrido-[2,1-b][1,3]thiazepine-7-carboxylic acid (BMS-199541–01) by enzymatic oxidation process using L-lysine-ϵ-aminotransferase, (4) the enzymatic synthesis of the lactol [3aS-(3aα,4α,7α,7aα)]-hexahydro-4,7-epoxyisobenzofuran-1(3H)-ol and corresponding lactone, (5) the microbial synthesis of (3R-cis)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-one, (6) the microbial oxygenation of 6-cyano-2,2-dimethyl-2H-1-benzopyran to the corresponding chiral epoxide and (+)-trans diol, (7) the enantioselective microbial reductions of N-[4-(2-chloroacetyl)phenyl]methanesulfonamide and (4-benzyloxy-3-methanesulfonylamino)-2'-bromoacetophenone to the corresponding (R)-alcohols, (8) the enzymatic resolution of racemic α-methyl phenylalanine amides by amidase, (9) the enantioselective hydrolysis of diethyl methyl-(4-methoxyphenyl)-propanedioate by lipase PS-30, (10) the enantioselective microbial reduction of methyl 4-chloro-3-oxobutanoate, (11) the enzymatic synthesis of ethyl (3S,5R)-dihydroxy-6-(benzyloxy)hexanoate, (12) the enantioselective hydrolysis of racemic epoxide 1-{2',3'-dihydrobenzo[b]furan-4'-yl}-1,2-oxirane by epoxide hydrolase, (13) the biocatalytic dynamic kinetic resolution of R,S-1-{2',3'-dihydrobenzo[b]furan-4'-yl}-ethane-1,2-diol, and (13) the diastereoselective microbial reduction of (1S)-[3-chloro-2-oxo-1-(phenylmethyl)propyl]carbamic acid 1,1-dimethylethyl ester. 1 Introduction 2 Antihypertensive Drugs 3 Thromboxane A2 Antagonists 4 Calcium Channel Blocking Drugs 5 Potassium Channel Openers 6 Antiarrhythmic Agents 7 β3-Receptor Agonists 8 Anticholesterol Drugs 9 Microbial Resolution10 Anti-Alzheimer Drugs11 HIV Protease Inhibitors12 Conclusion