Synfacts 2019; 15(05): 0569
DOI: 10.1055/s-0037-1612447
Peptide Chemistry
© Georg Thieme Verlag Stuttgart · New York

Efficient Macrocyclization of Small Peptides

Hisashi Yamamoto
Amit Banerjee
Roesner S, Saunders GJ, Wilkening I, Jayawant E, Geden JV, Kerby P, Dixon AM, Notman R, Shipman M. * University of Warwick, Coventry, UK
Macrocyclisation of Small Peptides Enabled by Oxetane Incorporation.

Chem. Sci. 2019;
10: 2465-2472
Further Information

Publication History

Publication Date:
15 April 2019 (online)



Cyclic peptides have recently emerged as a new source of drug molecules, but very few in clinical use are derived from natural sources. The main problem is associated with their synthesis, which often suffers from C-terminal epimerization, cyclooligomerization, and byproduct formation during macrocyclization. Shipman and co-workers have developed a simple, mild, and efficient macrocyclization strategy, which involves the incorporation of an oxetane ring, for synthesizing cyclic peptides in good yields by using an appropriate coupling reagent.



Cyclic peptide drugs are more useful than the linear peptides, but their synthesis is quite challenging. The present approach shows that macrocyclization of head-to-tail peptide can be improved by substituting one of the backbone amide C=O bonds with a simple oxetane ring. In addition, a variety of cyclic peptides with challenging ring sizes (tetra-, penta-, or hexapeptides) were synthesized. Further study showed that the bioactivity does not change upon replacing the amide C=O bond with an oxetane ring.