Cooperative Photometallobiocatalysis: Nonheme Fe‐Enzyme‐Catalyzed Enantioconvergent RadicalDecarboxylative Azidation, Thiocyanation and Isocyanation of Redox‐Active Esters

Cooperative catalysis with an enzyme and a smallmolecule photocatalyst has very recently emerged as a potentially general activation mode to advance novel biocatalytic reactions with synthetic utility. Herein, we report cooperative photobiocatalysis involving an engineered nonheme Fe enzyme and a tailored photoredox catalyst as a unifying strategy for the catalytic enantioconvergent decarboxylative azidation, thiocyanation and isocyanation of redox‐active esters via a radical mechanism. Through the survey and directed evolution of nonheme Fe enzymes, we repurposed and further evolved metapyrocatechase (MPC), a nonheme Fe extradiol dioxygenase not previously studied in new‐tonature biocatalysis, for the enantioselective C–N3, C–SCN and C– NCO bond formation through a radical rebound mechanism with an enzymatic Fe–X intermediate (X = N3, NCS, and NCO). A range of primary, secondary and tertiary alkyl radical precursors were effectively converted by our engineered MPC, allowing the syntheses of organic azides, thiocyanates and isocyanates with good to excellent enantiocontrol. Further chemical derivatization of these products furnished valuable compounds. Computational studies via DFT and MD simulations shed light on the mechanism as well as the binding poses of the alkyl radical intermediate in the enzyme active site and the π‐facial selectivity in the enantiodetermining radical rebound.