Sulfur Oxidation Unlocks Ene‐Reductase Catalysis for Stereoselective C(sp 3 )–S(VI) Bond Formation in β‐Sulfone‐carboxylic Acid Esters

ABSTRACT The enantioselective construction of C(sp 3 )─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(sp 3 )–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.