Synthesis of peptide-derived tetraoxazole containing macrocycles

Abstract

Natural macrocyclic peptides isolated from marine metabolites have shown interesting biological activities, including anticancer properties. In addition, they are highly pre-organized for metal inclusion due to their structural features, such as the presence of a cavity with perfectly located oxygen and nitrogen donors within the macrocyclic structure. This thesis pertains to the development of a synthetic approach towards the synthesis of natural macrocyclic structures. These macrocyclic peptides are made up of four oxazole rings connected by amide bonds with functionalized side chains. A synthetic strategy for the synthesis of natural peptide-derived macrocyclic analogues was developed using solution phase peptide synthesis. The synthesis of the tetraoxazole macrocycle is described in more detail where the synthesis started with the formation of a dipeptide by coupling two amino acids, followed by oxazole ring formation, and subsequent formation of the di-, tri-, and tetraoxazole peptide. All of the peptide bonds were obtained using O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate (HBTU) or 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl) with hydroxybenzotriazole (HOBt) with the base N,N-diisopropylethylamine (DIEA). Finally, macrocyclization of the linear unprotected tetraoxazole gave the macrocyclic structure. The macrocyclization was achieved efficiently by using (ethyl cyano(hydroxyimino)acetato)-tri-(1-pyrrolidinyl)-phosphonium hexafluorophosphate (PyOxim) as a coupling reagent under very dilute conditions. All structures were analyzed by 1H and 13C NMR. With the structural similarities to the macrocyclic peptides isolated from marine sources, this tetraoxazole macrocyclic peptide might be used as a chelating agent.