Ligand-Enabled, Cysteine-Directed β-C(sp3)–H Arylation of Alanine in Linear and Cyclic Peptides: Overcoming the Inhibitory Effect of Peptide Bonds

Abstract

Peptide modification by coordination-assisted C(sp³)–H functionalization on the aliphatic side chains of residues at the internal positions remains underdeveloped because of the inhibitory effect of peptide bonds. Using S-alkyl cysteine as the directing group and 2-pyridones as the ligands of Pd catalysts, we developed a Pd-catalyzed β-C(sp³)–H arylation approach for highly position-selective modification of both linear and cyclic peptides at the internal positions. Control experiments supported that the S-alkyl cysteine acted as a N,S-bidentate directing group, and the choice of protecting groups on the sulfur atom was vital to retaining the coordinating ability and preventing the side reaction of cysteine. The result inspired us to discover a protecting group, 4-methoxy-3-nitrobenzyl (PMNB), which was stable under the reaction conditions to facilitate efficient C–H arylation and easily removed by a sequential four-step reaction. In addition, the facile transformation of S-methyl cysteine to dehydroalanine (Dha) and the desulfurization of S-(p-nitrobenzyl)cysteine to alanine under mild conditions further expanded the synthetic utilities of the established C–H arylation protocol.