Catalytic Enantioselective Sulfur Alkylation of Sulfenamides for the Asymmetric Synthesis of Sulfoximines

Abstract

Sulfoximines are increasingly incorporated in agrochemicals and pharmaceuticals, with the two enantiomers of chiral sulfoximines often having profoundly different binding interactions with biomolecules. Therefore, their application to drug discovery and development requires the challenging preparation of single enantiomers rather than racemic mixtures. Here, we report a general and fundamentally new asymmetric synthesis of sulfoximines. The first S-alkylation of sulfenamides, which are readily accessible sulfur compounds with one carbon and one nitrogen substituent, represents the key step. A broad scope for S-alkylation was achieved by rhodium-catalyzed coupling with diazo compounds under mild conditions. When a chiral rhodium catalyst was utilized with loadings as low as 0.1 mol %, the S-alkylation products were obtained in high yields and with enantiomeric ratios up to 98:2 at the newly generated chiral sulfur center. The S-alkylation products were efficiently converted to a variety of sulfoximines with complete retention of stereochemistry. The utility of this approach was further demonstrated by the asymmetric synthesis of a complex sulfoximine agrochemical.