Chemo- and Stereoselective Cytochrome P450-BM3-Catalyzed Sulfoxidation of 1-Thiochroman-4-ones Enabled by Directed Evolution

Abstract

Directed evolution utilizing an unconventional approach to saturation mutagenesis has been applied to cytochrome P450-BM3 as a catalyst in the asymmetric sulfoxidation of 1-thiochroman-4-one and two derivatives thereof with complete chemoselectivity as well as (S)- and (R)-selectivity on an optional basis. Whereas wild-type P450-BM3 shows in the case of the parent compound poor enantioselectivity in slight favor of the (S)-sulfoxide (er=75:25), (S)-selectivity was enhanced to er=93:7, while reversal of enantioselectivity favoring the (R)-sulfoxide was also achieved (er=7:93). Two derivatives of the parent substrate underwent similar stereoselective sulfoxidation reactions. Sulfoxides of this type are of potential pharmaceutical interest. This biocatalytic approach nicely complements synthetic methods. (Figure presented.).