Sunday, July 26, 2009
P11
Synthesis of ethyl-(3R,5S)-dihydroxy-6-benzyloxy hexanoates via diastereo- and enantioselective microbial reduction: Cloning and expression of a recombinant ketoreductase from Acinetobacter sp
Steven L. Goldberg, Zhiwei Guo, and Animesh Goswami. Process Research & Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, NJ 08903
Ketoreductases are present in various bacteria, yeast and fungi. Largely due to their high enantioselectivity, ketoreductases have been recognized and utilized as an important class of enzymes for biocatalytic applications in the chemical and pharmaceutical industries for the preparation of chiral alcohols. Chiral beta-hydroxy esters are useful intermediates for synthesizing bioactive chiral compounds. Biocatalytic reduction of ketoesters by ketoreductases offers an attractive route to optically pure beta-hydroxy esters. We have isolated a unique Acinetobacter sp. which contains an enzyme capable of stereoselectively reducing 3,5-dioxo-6-(benzyloxy)hexanoic acid ethyl ester its corresponding syn-diol. Subsequent studies revealed there were three reductases capable of acting on the diketo ester, but only one which could directly convert it to the desired diol. The latter ketoreductase was purified to homogeneity and the corresponding gene isolated from the parental bacterium. The gene was cloned into Escherichia coli and soluble reductase overexpressed to nearly 50% of the total protein. Cells or extracts of recombinant Escherichia coli efficiently reduced the diketoester to the corresponding syn-(3R,5S)-dihydroxy ester, a key intermediate required for the synthesis of a hydroxyl methyl glutaryl (HMG)CoA reductase inhibitor and other statin-type cholesterol-lowering drugs such as Lipitor (atorvastatin) and Crestor (rosuvastatin).
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