Microbial Enantioselective Ester Hydrolysis for the Preparation of Optically Active 4, 1-Benzoxazepine-3-acetic Acid Derivatives as Squalene Synthase Inhibitors^<1)>

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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 reactivity. 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 wich Pseudomonas sp.S-13 with >99% ee in kilogram scale followed by alkaline treatment. The product(-)-12 was converted to(-)-1c without racemization.
社団法人日本薬学会の論文
2002-01-01