Synthesis and Functionalization of Azetidine‐Containing Small Macrocyclic Peptides

Saunders, George J.; Spring, Sam A.; Jayawant, Eleanor; Wilkening, Ina; Roesner, Stefan; Clarkson, Guy J.; Dixon, Ann M.; Notman, Rebecca; Shipman, Michael

Abstract

Cyclic peptides are increasingly important structures in drugs but their development can be impeded by difficulties associated with their synthesis. Here, we introduce the 3-aminoazetidine (3-AAz) subunit as a new turn-inducing element for the efficient synthesis of small head-to-tail cyclic peptides. Greatly improved cyclizations of tetra-, penta- and hexapeptides (28 examples) under standard reaction conditions are achieved by introduction of this element within the linear peptide precursor. Post-cyclization deprotection of the amino acid side chains with strong acid is realized without degradation of the strained four-membered azetidine. A special feature of this chemistry is that further late-stage modification of the resultant macrocyclic peptides can be achieved via the 3-AAz unit. This is done by: (i) chemoselective deprotection and substitution at the azetidine nitrogen, or by (ii) a click-based approach employing a 2-propynyl carbamate on the azetidine nitrogen. In this way, a range of dye and biotin tagged macrocycles are readily produced. Structural insights gained by XRD analysis of a cyclic tetrapeptide indicate that the azetidine ring encourages access to the less stable, all-trans conformation. Moreover, introduction of a 3-AAz into a representative cyclohexapeptide improves stability towards proteases compared to the homodetic macrocycle.

Citation

Saunders, G. J., Spring, S. A., Jayawant, E., Wilkening, I., Roesner, S., Clarkson, G. J., Dixon, A. M., Notman, R., & Shipman, M. (2024). Synthesis and Functionalization of Azetidine‐Containing Small Macrocyclic Peptides. Chemistry - A European Journal, 30(28), Article e202400308. https://doi.org/10.1002/chem.202400308

• Journal Article Type: Article
• Acceptance Date: Mar 13, 2024
• Online Publication Date: Apr 9, 2024
• Publication Date: May 17, 2024
• Deposit Date: Jul 29, 2024
• Publicly Available Date: Jul 29, 2024
• Journal: Chemistry – A European Journal
• Print ISSN: 0947-6539
• Electronic ISSN: 1521-3765
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 30
• Issue: 28
• Article Number: e202400308
• DOI: https://doi.org/10.1002/chem.202400308
• Public URL: https://durham-repository.worktribe.com/output/2639850