Solid phase synthesis of constrained 13-membered peptide macrocycles employing Fukuyama–Mitsunobu alkylations

Efficient strategies for the solid phase synthesis of constrained macrocyclic peptides are valuable tools for the generation of potentially biologically active compound libraries. In particular, the use of covalent linkers as hydrogen bond surrogates for the initiation and stabilization of α-helical secondary structures, resulting in the formation of a 13-membered macrocycle, is a validated approach. For these purposes, a straightforward synthetic pathway was developed, employing natural amino acids bearing usual protecting groups and mediated through two Fukuyama–Mitsunobu alkylation reactions on unprotected 1,3-propanediol on solid phase. The linear precursors were obtained in good purity and moderate yields, and the final cyclization step was carried out in solution.