Enzymatic Reduction of Adamantanones to Chiral Adamantanol Intermediates for the Synthesis of 11-β-Hydroxysteroid Dehydrogenase Inhibitors

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논문

Enzymatic Reduction of Adamantanones to Chiral Adamantanol Intermediates for the Synthesis of 11-β-Hydroxysteroid Dehydrogenase Inhibitors

학술지

Organic process research & development

저자명

Hanson, Ronald L.; Goldberg, Steven L.; Guo, Zhiwei; Tully, Thomas P.; Goswami, Animesh; Ye, Xiang-Yang; Robl, Jeffrey A.; Patel, Ramesh N.

초록

An enzymatic reduction process was developed to convert the ketone 2-(6-oxo-2-phenyladamantan-2-yl)acetic acid to the chiral alcohol 2-((2S, 6S)-6-hydroxy-2-phenyladamantan-2-yl)acetic acid and to convert the fluoro ketone 2-(2-(4-fluorophenyl)-6-oxoadamantan-2-yl)acetic acid to the chiral alcohol 2-((2S,6S)-2-(4-fluorophenyl)-6-hydroxyadamantan-2-yl)acetic acid. These chiral adamantanols are intermediates for the 11-β-hydroxysteroid dehydrogenase inhibitors 2-((2S,6S)-6-hydroxy-2-phenyladamantan-2-yl)-1-(3-hydroxyazetidin-1-yl)ethanone and 2-((2S,6S)-2-(4-fluorophenyl)-6-hydroxyadamantan-2-yl)-1-(3-hydroxyazetidin-1-yl)ethanone, respectively. Initial batches of both intermediates were prepared with a commercial ketoreductase giving yields near 100% with 96% ee. A more selective ketoreductase was purified 1800-fold from Candida utilis ATCC 42181 and then cloned and expressed in Escherichia coli. The reaction requires the cofactor NADPH which was regenerated during initial batches using a commercial glucose dehydrogenase. In later work a glucose dehydrogenase from Gluconobacter oxydans was cloned and expressed in the same E. coli strain together with the ketoreductase. To allow easy storage and shipment of the two enzymes, the E. coli cell paste was lyophilized to produce a stable form of the enzymes.Graphic Abstract <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2014/oprdfk.2014.18.issue-8/op5002098/production/images/medium/op-2014-002098_0006.gif'>

발행연도

2014

발행기관

American Chemical Society

ISSN

1083-6160

ISSN

1520-586x

권

호

페이지

pp.960-968