Solid-phase synthesis of macrocyclic peptides via side-chain anchoring of the ornithine delta-amine

Peterse, E.; Meeuwenoord, N.J.; Elst, H. van den; Marel, G.A. van der; Overkleeft, H.S.; Filippov, D.V. (2022)

Article / Letter to editor

Cyclic peptides represent a popular class of macrocyclic drug candidates and therefore their solid phase synthesis has attracted much attention. In this contribution we present an efficient method of side-chain anchoring for ornithine and lysine residues to be used in the standard Fmoc-based synthesis of cyclic peptides via on-resin cyclization. We demonstrate that the side chain of ornithine and lysine protected with N-Bocgroup can efficiently be converted to the isocyanate which is then immobilized on Wang-type resin in almost quantitative yield. We further show the synthesis of four biologically active cyclic peptides employing the side chain ornithine anchoring. Our method is at least on a par with the previously reported methodologies in terms of yield and the purity of the final products and is arguably operationally more straightforward.

• All authors: Peterse, E.; Meeuwenoord, N.J.; Elst, H. van den; Marel, G.A. van der; Overkleeft, H.S.; Filippov, D.V.
• Date: 2022-03-22
• Journal: European Journal of Organic Chemistry
• Volume: 2022
• Issue: 11
• DOI: doi:10.1002/ejoc.202101341
• Link: https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/ejoc.202101341
• Sponsorship: NWO
• Grant number: Gravitation program 2013