Enantioselective microbial reduction of substituted acetophenones

Abstract The chiral intermediate ( S )-1-(2′-bromo-4′-fluoro phenyl)ethanol 2 was prepared by the enantioselective microbial reduction of 2-bromo-4-fluoro acetophenone 1 . Organisms from genus Candida , Hansenula , Pichia , Rhodotorula , Saccharomyces , Sphingomonas and Baker's yeast reduced 1 to 2 in >90% yield and 99% enantiomeric excess (ee). In an alternative approach, the enantioselective microbial reductions of methyl, ethyl, and tert -butyl 4-(2′-acetyl-5′-fluorophenyl) butanoates 3 , 5 , and 7 , respectively, were demonstrated using strains of Candida and Pichia . Reaction yields of 40–53% and ee's of 90–99% were obtained for the corresponding ( S )-hydroxy esters 4 , 6 , and 8 . The reductase, which catalyzed the enantioselective reduction of ketoesters was purified to homogeneity from cell extracts of Pichia methanolica SC 13825. It was cloned and expressed in Escherichia coli with recombinant cultures used for the enantioselective reduction of keto methyl ester 3 to the corresponding ( S )-hydroxy methyl ester 4 . On a preparative scale, a reaction yield of 98% and an ee of 99% was obtained.