Site-Selective and Stereoselective C(sp 3 )−H Pyridomethylation and Pyrimidomethylation of N-Heterocycles

Catalytic methods for the direct functionalization of aliphatic C-H bonds are highly valuable and sought-after tools for the construction of organic molecules and the late-stage elaboration of bioactive compounds and drugs. 1-3 Despite notable progress in the area of chemical and biological catalysis, 1-5 strategies for the undirected, asymmetric functionalization of aliphatic C-H bonds to form new carbon-carbon bonds remain limited. Herein, we report the development of a biocatalytic strategy for the asymmetric C(sp 3)-H functionalization of saturated Nheterocycles with high efficiency and enantioselectivity (up to 99% ee and 7,600 TON) via activation of 1,2,3-pyridotriazoles with engineered CYP119 catalysts. This system enables the direct installation of a methylpyridine substituent into an aliphatic C-H site of a variety of Nheterocyclic scaffolds, including tetrahydroquinolines, pyrrolidines, and others, offering direct access to optically active compounds that incorporate 'privileged' motifs widely used in medicinal chemistry and drug discovery. Adding to its synthetic utility, this methodology could be extended to stereoselective C(sp 3)-H pyrimidomethylation and applied to the late-stage C(sp 3)-H functionalization of drug-like polycyclic compounds and marketed drugs. Computational studies provide insights into the reaction mechanism and the molecular basis of protein-controlled stereoselectivity. This work expands the biocatalytic toolbox for asymmetric and late-stage C(sp 3)-H functionalization and it underscores the value of biocatalysis toward making available important chemical transformations neither found in nature, nor currently accessible via chemocatalysis.