Abstract
Microbial enantioselective ester hydrolysis for the preparation of optically active (3R, 5S)-(−)-5-phenyl-4,1-benzoxazepine-3-acetic acid derivatives as potent squalene synthase inhibitors was investigated. Pseudomonas diminuta and Pseudomonas taetrolens hydrolyzed the racemic ethyl ester of the 5-(2-chlorophenyl) analogue to yield the (−)-carboxylic acid with excellent enantiomeric excess (>99% ee). We found that the (−)-enantiomer was an active inhibitor. Bulkiness of the ester moiety did not affect the enantioselectivity but did affect reac-tivity. The racemic ethyl ester of the 5-(2-methoxyphenyl) analogue, 5-(2,3-dimethoxyphenyl) analogue and 5-(2,4-dimethoxyphenyl) analogue were also hydrolyzed with Pseudomonas taetrolens to afford enantiomerically pure (−)-carboxylic acids in large scale. As another route to (3R,5S)-(−)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid [(−)-1c], the earlier intermediate (−)-2-amino-5-chloro-α-(2,3-dimethoxyphenyl)benzyl alcohol [(−)-12] was successfully obtained by asymmetric hydrolysis of (±)-5-chloro-α-(2,3-dimethoxyphenyl)-2-pivaloylaminobenzyl acetate with Pseudomonas sp. S-13 with >99% ee in kilogram scale followed by alkaline treatment. The product (−)-12 was converted to (−)-1c without racemization.
