Photoinduced Cu-catalyzed chemo- and stereoselective histidine modification

Modification of peptides and proteins represents a challenge of reaction design as well as the most facile route to various and abundant conjugates. Due to the presence of multiple reactive sites on polypeptide molecules, achieving chemo- and stereoselective modifications poses a significant challenge. Herein, we report the highly chemo- and stereoselective modification of histidine-containing peptides via a photoinduced Cu-catalyzed 1,2-bifunctionalization reaction of alkynes. This reaction exhibits remarkable stereoselectivity ( Z / E ) and chemo-selectivity, specifically targeting the nitrogen atom at N -1 position of the histidine imidazole ring. Late-stage diversification of structurally complex peptides, radical precursors, and alkynes is achieved under mild conditions with high yields and excellent selectivity. Its utility has been demonstrated in a series of important complex natural products. Moreover, the batch and flow protocol described herein can be applied to obtain a broad series of alkenylated histidine-containing peptides.