title: Microbial enantioselective ester hydrolysis for the preparation of optically active 4,1-benzoxazepine-3-acetic acid derivatives as squalene synthase inhibitors.
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 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-alpha-(2,3-dimethoxyphenyl)benzyl alcohol [(-)-12] was successfully obtained by asymmetric hydrolysis of (+/-)-5-chloro-alpha-(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.
authors.affiliation: Takeda Chemical Industries, Ltd., Pharmaceutical Research Division, Osaka, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tarui
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nakahama
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nagano
authors.forename: Motowo
authors.initials: M
authors.lastname: Izawa
authors.forename: Kiyoharu
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Masakuni
authors.initials: M
authors.lastname: Kori
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nagata
authors.forename: Takashi
authors.initials: T
authors.lastname: Miki
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Yukimasa
mesh_terms: D000818:Animals; D001381:Azepines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004952:Esters; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D006868:Hydrolysis; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D011549:Pseudomonas / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C460619:(3,5)-(-)-5-phenyl-4,1-benzoxazepine-3-acetic acid; D001381:Azepines; D004791:Enzyme Inhibitors; D004952:Esters; D013186:Farnesyl-Diphosphate Farnesyltransferase