Microbial enantioselective ester hydrolysis for the preparation of optically active 4,1-benzoxazepine-3-acetic acid derivatives as squalene synthase inhibitors.
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.
Tarui
Naoki
N
Takeda Chemical Industries, Ltd., Pharmaceutical Research Division, Osaka, Japan.
Nakahama
Kazuo
K
Nagano
Yoichi
Y
Izawa
Motowo
M
Matsumoto
Kiyoharu
K
Kori
Masakuni
M
Nagata
Toshiaki
T
Miki
Takashi
T
Yukimasa
Hidefumi
H
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
C460619:(3,5)-(-)-5-phenyl-4,1-benzoxazepine-3-acetic acid; D001381:Azepines; D004791:Enzyme Inhibitors; D004952:Esters; D013186:Farnesyl-Diphosphate Farnesyltransferase