Late-Stage Functionalization and Diversification of Peptides by Internal Thiazole-Enabled Palladium-Catalyzed C(sp3)–H Arylation

Modification of peptides via late-stage C–H activation is an emerging strategy to construct bioactive peptidomimetic libraries with expanded structural diversity for drug discovery. Peptides with thiazole motifs in the backbone as amide surrogates often exhibit improved bioactivity and biostability. However, methods to synthesize this class of compounds with structural diversity are limited. Here, we report the development of a highly versatile strategy for late-stage palladium-catalyzed C(sp3)–H arylation of peptides. This protocol utilizes the thiazole motifs in the peptide backbone as internal directing groups and allows the regio- and site-selective arylation of β-C(sp3)–H and γ-C(sp3)–H bonds in peptide side chains. The high biocompatibility of this method to functionalize and ligate peptides with a variety of aryl donors, biomolecules, and fluorophores sets the stage for efficient construction of peptide libraries with featured backbone thiazole units.