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Copper-catalyzed radical C(sp3)‒N coupling has become a major focus in synthetic catalysis over the past decade. However, achieving this reaction manifold by using enzymes has remained elusive. In this study, we introduce a photobiocatalytic approach for radical benzylic C(sp3)‒N coupling using a copper-substituted nonheme enzyme. Using rhodamine B as a photoredox catalyst, we identified a copper-substituted phenylalanine hydroxylase that facilitates enantioconvergent decarboxylative amination betweenN-hydroxyphthalimide esters and anilines. Directed evolution remodeled the active site, resulting in high enantioselectivities for most substrates. On the basis of molecular modeling and mechanistic studies, we propose that the enzyme accommodates a copper-anilide complex that reacts with a benzylic radical. This study expands the scope of non-natural biocatalytic transition metal catalysis to copper-catalyzed radical coupling.
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This content will become publicly available on July 1, 2026
Cooperative Photometallobiocatalysis: Nonheme Fe Enzyme‐Catalyzed Enantioconvergent Radical Decarboxylative Azidation, Thiocyanation, and Isocyanation of Redox‐Active Esters
Abstract Cooperative catalysis with an enzyme and a small‐molecule photocatalyst has 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 to achieve enantioconvergent decarboxylative azidation, thiocyanation, and isocyanation of redox‐active esters via a radical mechanism. We repurposed and further evolved metapyrocatechase (MPC), a nonheme Fe extradiol dioxygenase not previously studied in new‐to‐nature biocatalysis, for the enantioselective C─N3, C─SCN, and C─NCO bond formation via 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 derivatization of these products furnished valuable compounds including enantioenriched amines, triazoles, ureas, and SCF3‐containing products. 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. Overall, cooperative photometallobiocatalysis with nonheme Fe enzymes provides a means to develop challenging asymmetric radical transformations eluding small‐molecule catalysis.
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- Award ID(s):
- 2400087
- PAR ID:
- 10617329
- Publisher / Repository:
- Wiley VCH
- Date Published:
- Journal Name:
- Angewandte Chemie International Edition
- Volume:
- 64
- Issue:
- 29
- ISSN:
- 1433-7851
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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