A series of highly-strained cyclic tetrapeptides were efficiently synthesized via peptide hydrazide based ligation, reported by Liu et al. Upon mild oxidative activation, the peptide hydrazide was transformed into a highly active peptide azide intermediate and then in situ converted into a peptide 4-mercaptophenylacetic acid (MPAA) thiol ester, which underwent native chemical ligation (NCL)-mediated cyclization to afford the desired cyclic tetrapeptides. After radical desulfurization, the product with alanine residue at the ligation site can be obtained.
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