Biocatalytic, Intermolecular C−H Bond Functionalization for the Synthesis of Enantioenriched Amides

Abstract Directed evolution of heme proteins has opened access to new‐to‐nature enzymatic activity that can be harnessed to tackle synthetic challenges. Among these, reactions resulting from active site iron‐nitrenoid intermediates present a powerful strategy to forge C−N bonds with high site‐ and stereoselectivity. Here we report a biocatalytic, intermolecular benzylic C−H amidation reaction operating at mild and scalable conditions. With hydroxamate esters as nitrene precursors, feedstock aromatic compounds can be converted to chiral amides with excellent enantioselectivity (up to >99 % ee ) and high yields (up to 87 %). Kinetic and computational analysis of the enzymatic reaction reveals rate‐determining nitrenoid formation followed by stepwise hydrogen atom transfer‐mediated C−H functionalization.