Repurposing Visible‐Light‐Excited Ene‐Reductases for Diastereo‐ and Enantioselective Lactones Synthesis

Abstract Repurposing enzymes to catalyze non‐natural asymmetric transformations that are difficult to achieve using traditional chemical methods is of significant importance. Although radical C−O bond formation has emerged as a powerful approach for constructing oxygen‐containing compounds, controlling the stereochemistry poses a great challenge. Here we present the development of a dual bio‐/photo‐catalytic system comprising an ene‐reductase and an organic dye for achieving stereoselective lactonizations. By integrating directed evolution and photoinduced single electron oxidation, we repurposed engineered ene‐reductases to steer non‐natural radical C−O formations (one C−O bond for hydrolactonizations and lactonization‐alkylations while two C−O bonds for lactonization‐oxygenations). This dual catalysis gave a new approach to a diverse array of enantioenhanced 5‐ and 6‐membered lactones with vicinal stereocenters, part of which bears a quaternary stereocenter (up to 99 % enantiomeric excess, up to 12.9 : 1 diastereomeric ratio). Detailed mechanistic studies, including computational simulations, uncovered the synergistic effect of the enzyme and the externally added organophotoredox catalyst Rh6G.