Bicycle synthesis through peptide macrocyclization using aziridine aldehydes followed by late stage disulfide bond installation

Abstract

We present a method that can be applied to generate medium-sized peptidomimetic macrocycles equipped with disulfide bonds. The reaction hinges on amphoteric aziridine aldehydes and their ability to bridge the ends of linear peptides in the presence of isocyanides. Aziridine aldehyde dimers enable the initial cyclization, which is followed by site-specific aziridine ring-opening with sodium azide. Subsequent to that, thallium-induced oxidative disulfide bond formation furnishes the final product. The NMR characterization of the molecules obtained using this method indicates that conformationally well-behaved systems are readily accessible. The site-specific introduction of azide functionality should open the doors to subsequent functionalization using well-established protocols.