Expedient access to pre-organized α-helix mimetics based on an isocinchomeronic acid core

Abstract

A previously reported terephthalamide-based α-helix mimetic was modified by introducing a pyridine nitrogen and converting a tertiary amide to a secondary amide, which afforded a second intramolecular hydrogen bond to further influence the projection of the i, i+3/4, and i+7 side chains from the same face of the scaffold. The existence of two intramolecular hydrogen bonds was confirmed by 1H NMR titration studies and molecular dynamics simulations. By virtue of the short and efficient route described herein, access to this new family of α-helix mimetics is straightforward. Moreover, the inclusion of a chiral center will permit the interrogation of the stereochemical impact on ligand–receptor binding.