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

Author:
Arbour, Christine A., Belavek, Kayla J., Tariq, Rooha, Mukherjee, Subha, Tom, Janine K., Isidro-Llobet, Albert, Kopach, Michael E., Stockdill, Jennifer L.
Source:
Journal of organic chemistry 2018 v.84 no.2 pp. 1035-1041
ISSN:
1520-6904
Subject:
Helianthus annuus, chemical structure, cysteine, hydrolysis, macrocyclization reactions, organic chemistry, peptides, trypsin inhibitors, urea
Abstract:
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.
Agid:
6271440