A novel resolution of a pharmaceutically important bridged bicyclic ketone intermediate via selective enzymatic reduction with a commercially available ketoreductase |
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Authors: | Matthew D Truppo Jaehon Kim Mark Brower Andrew Madin Michael G Sturr Jeffrey C Moore |
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Institution: | Department of Bioprocess Research & Development, Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, NJ 07065, USA |
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Abstract: | 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. |
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Keywords: | Ketoreductase Bicyclic Stereoselective Bridged Ketone |
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