Biocatalytic synthesis of chiral intermediates for antiviral and antihypertensive drugs

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.