Synthesis and Functionalization of Azetidine‐Containing Small Macrocyclic Peptides

• Published in: Chemistry : a European journal Vol. 30; no. 28; pp. e202400308 - n/a
• Main Authors: Saunders, George J., Spring, Sam A., Jayawant, Eleanor, Wilkening, Ina, Roesner, Stefan, Clarkson, Guy J., Dixon, Ann M., Notman, Rebecca, Shipman, Michael
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 17.05.2024; Wiley Subscription Services, Inc
• Subjects: Amino acids; azetidine; Biotin; Chemistry; Chemistry, Multidisciplinary; Conformation; cyclic peptides; Drug development; Dyes; functionalization; macrocyclization; Nitrogen; Peptides; peptidomimetics; Physical Sciences; Science & Technology; Substitution reactions; Synthesis; Vitamin B complex; cyclic peptides; functionalization; macrocyclization; azetidine; AMINO-ACIDS; peptidomimetics; CYCLIC TETRAPEPTIDES
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202400308

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. Incorporation of a 3‐aminoazetidine (3‐AAz) into peptide backbones improves head‐to‐tail cyclizations compared to unmodified peptides. The azetidine nitrogen can be readily functionalized using substitution or click chemistry. Crystal structure analysis reveals that a 3‐AAz modified cyclic tetrapeptide adopts an uncommon all‐trans conformation. The 3‐AAz provides stability to protease degradation compared to the unmodified macrocycle.