Macrocyclic Peptide Synthesis

Abstract

Significance: The synthesis of novel macrocyclic peptides containing Pro-Gly sequences was achieved by exploiting oligomerization/cyclization/ cleavage sequential reactions on an oxime resin 1. Thus, the liner peptide sequence 5 (resin loading: 0.3 mmol/g) was prepared from 1 and Boc-Ala-OH via the standard solid-phase peptide synthetic method. The removal of the Boc group, followed by the oligomerization/cyclization/cleavage reaction with DIPEA in DMF, afforded cyclic peptides 6a-c in 51% (6a/6b/6c = 91:8:1). The methodology was applied to the three linear sequences of six to eight amino acids containing a Pro-Gly-Pro-Gly unit to give nine novel large macrocyclic peptides.Comment: Solvents (DMF or CH 2 Cl 2 ) and resin loading (0.3-1.2 mmol/g) in the oligomerization/ cyclization/cleavage reaction affected the yield and the ratio of the cyclic peptide oligomers. The cyclization of linear peptides is often quite difficult to achieve in high yield with all L-amino acid residues (