Synthesis and structure of a small macrocyclic hexapeptide model for antiparallel β-sheet containing two restrained 2-(3′-aminopropynyl)-aniline reverse-turn mimetics

Abstract

A new reverse-turn mimetic containing a 2-(3′-aminopropynyl)-phenyl moiety in place of the natural i + 1 and i + 2 turn residues is described in which the key CC bond was formed from an N-protected propargylamine and 2-iodoaniline using Heck chemistry. Nucleophilic displacement of triflate from activated (2S)-2-hydroxyalkanoate esters by the anilino N-atom, with inversion at C-2, gave homochiral tripeptide mimetics. Two variants of these were coupled and the product was deprotected and then cyclised to give a stable cyclo-hexapeptide analogue that possessed an anti-parallel β-sheet structure as determined by NMR spectroscopy.