Synthesis of L-cyclic tetrapeptides by backbone amide activation CyClick strategy

• Type of Material: Article
• Authors: Rachel Wills, Emory University; Victor Adebomi, Emory University; Caroline Spancake, Emory University; Ryan D. Cohen, Merck and Co. Inc.; Monika Raj, Emory University
• Language: English
• Date: 2022-10-05
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022 Published by Elsevier Ltd.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): https://doi.org/10.1016/j.tet.2022.133071
• Title of Journal or Parent Work: Tetrahedron
• Volume: 126
• Start Page: 133071
• Grant/Funding Information: This work was supported by grants (Grant No. CHE-1752654 and CHE-2108774) from National Science Foundation (NSF). Also, this work was supported by a grant (1R35GM133719-01) from the National Institute of Health (NIH) and Winship Pilot Grant by Emory.
• Keywords: Tetrapeptides; 4-imidazolidinone ring; CyClick chemistry; Macrocyclic peptides
• Research Categories: Biology, Cell; Chemistry, Organic

Abstract

Cyclic tetrapeptides exhibit high cellular permeability and a wide range of biological properties and thus have gained great interest in the field of medicinal chemistry. We synthesized highly strained 12-membered head to tail cyclic peptides with varying reactive amino acids, without oligomerization using the exclusively intramolecular CyClick chemistry. This occurs by a two-step process involving the low-energy formation of a 15 atom-containing cyclic imine, followed by a chemoselective ring contraction of the peptide backbone generating a highly strained 12 atom-containing cyclic tetrapeptide. This reaction exhibited high substrate scope and generated head to tail cyclic tetrapeptides with varying amino acids at the N-terminus, showing chemoselectivity without the need for side group protection.