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

• Published in: Chemical & pharmaceutical bulletin Vol. 50; no. 1; pp. 59 - 65
• Main Authors: Tarui, Naoki, Nakahama, Kazuo, Nagano, Yoichi, Izawa, Motowo, Matsumoto, Kiyoharu, Kori, Masakuni, Nagata, Toshiaki, Miki, Takashi, Yukimasa, Hidefumi
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 2002; Maruzen; Japan Science and Technology Agency
• Subjects: 4,1-benzoxazepine-3-acetic acid; Animals; asymmetric hydrolysis; Azepines - chemistry; Azepines - metabolism; Azepines - pharmacology; Biological and medical sciences; Biotechnology; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Esters; Farnesyl-Diphosphate Farnesyltransferase - antagonists & inhibitors; Fundamental and applied biological sciences. Psychology; Health. Pharmaceutical industry; Humans; Hydrolysis; hypocholestemic agent; Industrial applications and implications. Economical aspects; Liver - drug effects; Liver - enzymology; Male; Other active biomolecules; Production of active biomolecules; Pseudomonas - metabolism; Pseudomonas sp. S-13; Pseudomonas taetrolens; Rats; Rats, Sprague-Dawley; squalene synthase; Stereoisomerism; Structure-Activity Relationship; Tumor Cells, Cultured; Pseudomonadales; Enantioselectivity; Enzyme; Transferases; Lactam; Enzyme inhibitor; Screening test; Farnesyl-diphosphate farnesyltransferase; In vitro; Cholesterol; Pseudomonas taetrolens; Asymmetric synthesis; Carboxylic acid; Chlorine Organic compounds; Bicyclic compound; Bacteria; Pseudomonadaceae; Aromatic compound; Chemical synthesis; Enantiomer(-); Antilipemic agent; Oxygen nitrogen heterocycle; Enzymatic reaction
• DOI: 10.1248/cpb.50.59
• EISSN: 1347-5223
• ISSN: 0009-2363

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.