Palladium-Catalyzed β-C(sp³)-H Arylation of Alanine at the Internal Position of Peptides

Late-stage peptide modification by C–H functionalization has been extensively investigated in the past decades. However, transition metal-catalyzed C(sp³)-H functionalization of amino acid residues at the internal positions of peptides remains underdeveloped due to the inhibition effect of peptide bonds (secondary amide). In the context, we herein report a backbone protection strategy, which enabled Pd-catalyzed β-C(sp³)-H arylation of internal alanine in peptides. Control experiment demonstrated that the backbone protecting group (p-methoxybenzyl, PMB) not only controlled the position-selectivity, but also improved the reactivity of C–H arylation. Further removal of the protecting group under mild and oxidative conditions to afford the backbone-unprotected peptides efficiently exhibited the synthetic utility of the developed protocol.