Peptide−Heterocycle Hybrid Molecules: Solid-Phase Synthesis of a 400-Member Library of N-Terminal 2-Iminohydantoin Peptides

Abstract

A method for the heterocyclic modification of the N-terminus of a peptide is described. Reaction of the N-terminal amino group of solid-supported peptides with arylisothiocyanates generates a thiourea intermediate, as in the first step of Edman degradation. Treatment of the resin-supported peptide-thioureas with Mukaiyama's reagent (2-chloro-1-methylpyridinium iodide) generates an electrophilic carbodiimide functionality, which undergoes rapid intramolecular trapping by the adjacent amide group to give a 2-iminohydantoin ring at the N-terminus of the peptide. The dehydrothiolation step in the presence of Mukaiyama's reagent prevents Edman degradation from occurring, in essence leading to a "diversion" of the Edman degradation. Cleavage from the resin then releases the hybrid molecules incorporating a 2-iminohydantoin ring conjugated onto a peptidic fragment. A 400-member library of the iminohydantoin-peptide hybrids was synthesized using this approach, starting from a chlorotrityl resin-supported tripeptides.