Position-Selective Modification of Cyclic Peptides by Histidine-Directed β-C(sp3)–H Arylation of Alanine

Abstract Herein we report a histidine-directed β-C(sp3)–H arylation method for the site-selective modification of alanine residues in cyclic peptides. Cyclic penta- to decapeptides with various cyclization patterns delivered Ala C–H arylated products in moderate-to-good yields and high positional selectivity. Both canonical α-amino acids and noncanonical β-, γ-, δ-, and ε-amino acids are compatible. Its synthetic utility was demonstrated via peptide bioconjugation with fluorophore, short peptide, and oleanolic acid.