Late-Stage N-Heteroarylation of Peptides Via α-C–H Functionalization of Glycine Residues by Shono-Type Oxidation

The Shono oxidation stands as a premier electrochemical method for the α-C-H functionalization of amines. While glycine esters serve as ideal substrates with immense synthetic potential, their electrochemical derivatization has historically been restricted primarily to C–C and C–P bond formation. Herein, we report the first electrochemical strategy for the direct N-heteroarylation of α-C-H bonds in Gly-containing natural products, drug molecules, and peptides via a controllable anodic oxidation pathway under transition-metal-free conditions. At the same time, modified target product 3x exhibited good inhibitory activities toward the SKOV3 and MDA-MB-231 cell lines, with IC 50 values of 9.94 ± 1.46 and 17.11 ± 3.67, respectively, far superior to the antitumor activities of unmodified substrate 1a (IC 50 > 50). Therefore, besides synthetic applications, this method also provides new possibilities for discovering potentially bioactive molecules.