Solid-Phase Synthesis of Tris-Benzamides as α-Helix Mimetics

Small molecules mimicking alpha-helices are of great interest since numerous protein-protein interactions use helical structures at the interface. With a goal of generating libraries of alpha-helix mimetics, an efficient solid-phase synthetic method was developed to produce tris-benzamides. The tris-benzamide scaffold was designed to place three side-chain functional groups found at the i, i+4, and i+7 positions of an alpha-helix, emulating one helical face. The synthetic strategy involves simple and iterative reactions of removal of an allyl ester, formation of an amide bond via an O -> N acyl migration, and an O-alkylation. A small library of twenty tris-benzamides containing a variety of functional groups was prepared in high purity (83-99%) to demonstrate the versatility of the synthetic approach. This methodology allowed the facile and rapid construction of alpha-helix mimetics that would facilitate the identification of small molecules for target proteins.