Selective functionalization of Trp residues via copper-catalyzed Ullmann coupling†

The modification of peptides can considerably change their functions, thus facilitating the development of peptides for use as drugs, therapeutics, and diagnostics, and in chemical biology. Transition-metal catalyzed cross-coupling is a promising method to accomplish peptide modification, but the chemoselective introduction of a new C(sp²)–N bond at a tryptophan residue is a challenging yet crucial task. Herein, the functionalization of peptides achieved through the copper-catalyzed Ullmann coupling of tryptophan with aryl halides containing multiple functional groups is reported, which enabled the arylation of the indole side chain of tryptophan. This method features remarkable tolerance of diverse functional groups, scalability, and distinct chemoselectivity toward tryptophan residues. The fusion of different functional groups demonstrated the potential utility of this approach, offering new avenues to modify the side chains of proteinogenic amino acids.