Enzymatic Primary Amination of Benzylic and Allylic C(sp3)–H Bonds

Abstract Aliphatic primary amines are prevalent in natural products, pharmaceuticals, and functional materials. While a plethora of processes are reported for their synthesis, methods that directly install a free amine group into C­(sp3)–H bonds remain unprecedented. Here, we report a set of new-to-nature enzymes that catalyze the direct primary amination of C­(sp3)–H bonds with excellent chemo-, regio-, and enantio­selectivity, using a readily available hydroxyl­amine derivative as the nitrogen source. Directed evolution of genetically encoded cytochrome P411 enzymes (P450s whose Cys axial ligand to the heme iron has been replaced with Ser) generated variants that selectively functionalize benzylic and allylic C–H bonds, affording a broad scope of enantio­enriched primary amines. This biocatalytic process is efficient and selective (up to 3930 TTN and 96% ee), and can be performed on preparative scale.