Solid-Phase Synthesis of Macrocyclic Peptides via Side-Chain Anchoring of the Ornithine δ-Amine

Abstract

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-Boc-group 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.