P<sup>III</sup>‐Directed Late‐Stage Ligation and Macrocyclization of Peptides with Olefins by Rhodium Catalysis
Lei Liu, Xinlong Fan, Boning Wang, Hong Deng, Tianhang Wang, Jie Zheng, Jun Chen, Zhuangzhi Shi, Huan Wang
Abstract
Abstract 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 ‐P t Bu 2 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.