PIII‐Directed Late‐Stage Ligation and Macrocyclization of Peptides with Olefins by Rhodium Catalysis

Transition metal-catalyzed C-H activation is a step-economical strategy for peptide functionalization. Herein, we report the method of late-stage peptide ligation and macrocyclization through rhodium-catalyzed alkylation of tryptophan residues at the C7 position. This method utilizes a N-Pt Bu2 directing group and tolerates various peptide and alkene substrates. Utilizing internal olefins, this study represents the first example of site-selective peptide C-H alkylation through deconjugative isomerization. Furthermore, our method provides access to peptide macrocycles with unique Trp(C7)-alkyl crosslinks and potent cytotoxicity towards cancer cells.