Late-Stage Stitching Enabled by Palladium-Catalyzed Tryptophan C4 Amination: Peptide Ligation and Cyclodimerization

Here, we report on methods for late-stage peptide diversification through palladium-catalyzed site-selective C(sp²)-H amination of tryptophan residues at the C4 position, utilizing tryptophan-amine cross-links. Our strategy enables practical access to C-N bonds, facilitating the construction of cyclopeptides via late-stage cyclodimerization of structurally complex peptides, which poses significant challenges for organic synthesis. The synthetic utility of this protocol is demonstrated through the synthesis of 30- to 38-membered macrocyclic peptides.