Backbone‐Enabled Directional Peptide Macrocyclization through Late‐Stage Palladium‐Catalyzed δ‐C(sp²)−H Olefination

Abstract

Abstract C−H activation methods for peptide macrocyclization have the potential to provide peptidomimetics and cyclic peptides with expanded structural diversity. Now, a highly versatile peptide macrocyclization strategy via late‐stage palladium‐catalyzed δ‐C(sp 2 )−H olefination of phenylalanine residues has been developed. This method utilizes peptide backbone amides as internal directing groups and allows facile macrocyclization of peptides in the N‐to‐C direction. Combined with the previously developed β‐C(sp 3 )−H arylation method for peptide macrocyclization in the C‐to‐N direction, a pair of palladium‐catalyzed reactions were obtained that are directionally orthogonal, and the first example of one‐pot synthesis of bicyclic peptides via Pd‐catalyzed β‐C(sp 3 )−H and δ‐C(sp 2 )−H activation is demonstrated.