Bringing Macrolactamization Full Circle: Self-Cleaving Head-to-Tail Macrocyclization of Unprotected Peptides via Mild N-Acyl Urea Activation.

We establish herein conditions for the cyclization of unprotected N-acyl urea-linked peptides to form macrocyclic peptides mediated by N-terminal cysteine. We report a detailed investigation of the parameters of the reaction, including variation of the reaction conditions, the C-terminal residue, and the macrocycle size. C-Terminal epimerization was not observed. The synthesis of macrocyclic targets ranging from tetrapeptides to the disulfide-linked 14-mer, sunflower trypsin inhibitor 1 are demonstrated. For most substrates, hydrolysis and head-to-tail dimer formation are avoided.