A novel resolution of a pharmaceutically important bridged bicyclic ketone intermediate via selective enzymatic reduction with a commercially available ketoreductase

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• 作者：Matthew D. Truppo ; Jaehon Kim ; Mark Brower ; Andrew Madin ; Michael G. Sturr and Jeffrey C. Moore
• 关键词：Ketoreductase ; Bicyclic ; Stereoselective ; Bridged ; Ketone
• 刊名：Journal of Molecular Catalysis B: Enzymatic
• 出版年：2006
• 出版时间：15 March 2006
• 年：2006
• 卷：38
• 期：3-6
• 页码：158-162
• 全文大小：108 K

文摘

An efficient route to the pharmaceutically important (6S,9R)-11-oxo-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene intermediate has been demonstrated via kinetic resolution of 11-oxo-5,6,7,8,9,10-hexahydro-6,9-methanobenzocyclooctene using a commercially available ketoreductase. Biocatalytics KRED 101 has been shown to selectively reduce the (6R,9S) enantiomer leaving behind the desired (6S,9R) enantiomer. This novel reaction is the first demonstration of a high yielding (44 % versus 50 % maximum theoretical yield) highly stereoselective (>99 % ee) resolution of a bicyclic ketone, via enzymatic reduction using a commercially available ketoreductase, where the stereochemistry of the substrate is determined by a bridged ring system. Several challenges were overcome, including enhancing the selectivity of the enzyme by controlling temperature and increasing substrate solubility by employing a combination of cyclodextrin and organic co-solvent in the aqueous reaction system.