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‐PtBu2 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. [ABSTRACT FROM AUTHOR]