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Biocatalytic synthesis of chiral intermediates for antiviral and antihypertensive drugs
Author(s) -
Patel Ramesh N.
Publication year - 1999
Publication title -
journal of the american oil chemists' society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.512
H-Index - 117
eISSN - 1558-9331
pISSN - 0003-021X
DOI - 10.1007/s11746-999-0139-7
Subject(s) - chemistry , reductive amination , norleucine , carbamic acid , enantiomeric excess , yield (engineering) , stereochemistry , alcohol dehydrogenase , enantiomer , mandelic acid , biocatalysis , diastereomer , amination , hydrolysis , hydantoin , organic chemistry , alcohol , enantioselective synthesis , amino acid , biochemistry , catalysis , reaction mechanism , materials science , methionine , metallurgy
The chiral intermediate (1 S ,2 R ) [3‐chloro‐2‐hydroxy‐1‐(phenylmethyl)propyl] carbamic acid, 1,1‐dimethylethyl ester 2a was prepared for the total synthesis of a human immunodeficiency virus protease inhibitor, BMS‐186318. The stereoselective reduction of (1 S ) [3‐chloro‐2‐oxo‐1(phenylmethyl)propyl] carbamic acid, 1,1‐dimethylethyl ester 1 was carried out using microbial cultures, among which Streptomyces nodosus SC 13149 efficiently reduced 1 to 2a . A reaction yield of 80%, enantiomeric excess (e.e.) of 99.8%, and diastereomeric purity of 99% were obtained for chiral alcohol 2a . Chiral l‐6‐hydroxy norleucine 3 , an intermediate in the synthesis of antihypertensive drug, was prepared by reductive amination of 2‐keto‐6‐hydroxyhexanoic acid 4 using beef liver glutamate dehydrogenase. The cofactor NADH required for this reaction was regenerated using glucose dehydrogenase from Bacillus sp. A reaction yield of 80% and e.e. of 99.5% were obtained for l‐6‐hydroxynorleucine 3 . To avoid the lengthy chemical synthesis of the ketoacid, a second route was developed in which racemic 6‐hydroxynorleucine [readily available from hydrolysis of 5‐(4‐hydroxybutyl) hydantoin 5 ] was treated with d‐amino acid oxidase from Trigonopsis variabilis to selectively convert the d‐isomer of racemic 6‐hydroxynorleucine to 2‐keto‐6‐hydroxyhexanoic acid 4 and l‐6‐hydroxynorleucine 3 . Subsequently, the 2‐keto‐6‐hydroxyhexanoic acid 4 was converted to l‐6‐hydroxynorleucine by reductive amination using glutamate dehydrogenase. A reaction yield of 98% and an e.e. of 99.5% were obtained.