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

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(sp2 )-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(sp3 )-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(sp3 )-H and δ-C(sp2 )-H activation is demonstrated.