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 head-to-tail on-resin cyclization by anchoring the side-chain of trifunctional amino acids 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 the parameters directly involved in the ring closure of constrained cyclopeptides was performed.