Sulfur Oxidation Unlocks Ene‐Reductase Catalysis for Stereoselective C(sp3)–S(VI) Bond Formation in β‐Sulfone‐carboxylic Acid Esters

The enantioselective construction of C(sp3)─S stereocentres remains a major challenge in catalysis due to the distinct electronic and steric features of sulfur, compared to oxygen or nitrogen atoms, which complicate both stereocontrol and configurational stability at the C─S bond. Here, we report that the ene-reductase biocatalyst ENE-101 catalyses the highly enantioselective reduction of β-vinyl sulfones, enabling the direct formation of C(sp3)–S(VI) stereocentres in excellent yields and enantiomeric excesses (up to >99% ee). Whereas the corresponding β-vinyl sulfides are unreactive towards ENE-101, the S(II) to S(VI) oxidation activates the C═C bond toward enzymatic reduction. Computational studies reveal that the sulfone moiety enhances alkene electrophilicity and promotes favourable substrate orientation and binding within the ENE-101 active site. The biocatalyst exhibits broad substrate scope, tolerating diverse β-vinyl sulfones. This work establishes sulfur(VI) activation as an effective strategy to expand the reactivity landscape of ene-reductase biocatalysts for the asymmetric C─S bond formation.