On‐resin head‐to‐tail cyclization of cyclotetrapeptides: optimization of crucial parameters

Cyclotetrapeptides are constrained cyclic peptides whose synthesis is considered a difficult task. A methodology based on on‐resin head‐to‐tail cyclization by anchoring the side chain of a trifunctional amino acid was investigated. A series of model cyclotetrapeptides containing the RGD sequence cyclo(Xaa‐Arg‐Gly‐Asp) (Xaa = Ala, Phe, Phg, D ‐Ala, D ‐Phe, D ‐Phg) was synthesized with no cyclodimerization by‐products. An evaluation and optimization study of all of the parameters directly involved in the ring closure was performed. Copyright © 2003 European Peptide Society and John Wiley & Sons, Ltd.