Synthesis of Chiral Sulfoxides by A Cyclic Oxidation-Reduction Multi-Enzymatic Cascade Biocatalysis

Graphical An unconventional biocatalytic oxidation-reduction cascade system with cofactor regeneration was established for the synthesis of enantiopure sulfoxides using prochiral sulfildes as substrates. Heteroaryl alkyl, aryl alkyl and dialkyl sulfoxides in R configuration were prepared in >90 % conversion with >90 % ee through the cascade catalysis of MsrA, Fus-SMO and three other auxiliary enzymes (Trx, Trx-R, and GDH). Optically pure sulfoxides are valuable organosulfur compounds extensively employed in medicinal and organic synthesis. In this study, we present a biocatalytic oxidation-reduction cascade system designed for the preparation of enantiopure sulfoxides. The system involves the cooperation of a low-enantioselective chimeric oxidase SMO (styrene monooxygenase) with a high-enantioselective reductase MsrA (methionine sulfoxide reductase A), facilitating “non-selective oxidation and selective reduction” cycles for prochiral sulfide oxidation. The regeneration of requisite cofactors for MsrA and SMO was achieved via a cascade catalysis process involving three auxiliary enzymes, sustained by cost-effective D-glucose. Under the optimal reaction conditions, a series of heteroaryl alkyl, aryl alkyl and dialkyl sulfoxides in R configuration were synthesized through this “one-pot, one step” cascade reaction. The obtained compounds exhibited high yields of >90 % and demonstrated enantiomeric excess ( ee ) values exceeding 90 %. This study represents an unconventional and efficient biocatalytic way in utilizing the low-enantioselective oxidase for the synthesis of enantiopure sulfoxides.