| Peptide macrocycles belong to a privileged subclass of compounds, having found applications that range from drug discovery to nanomaterials. However these ring-shaped molecules are difficult, and often impossible to prepare using traditional synthetic methods. As such, a great deal of research has emerged on developing novel solutions to address these challenges in synthesis. Aside from these contemporary strategies, which primarily focus on methods of ring-closure, there still exist few approaches that enable site-specific modification at a late stage of synthesis. We therefore sought to address this paucity through the incorporation of the strained, aziridine-2-carboxylic acid (Azy) residue into the backbone of cyclic tetrapeptides. By way of ring-opening with azide and thiol nucleophiles, we have demonstrated that highly regioselective structural modifications can be accomplished through that generation of macrocycles equipped with a beta-amino acid residue. Furthermore, we have capitalized on the reduced amidicity of the distorted aziridine amide bond in the development of a novel backbone modification strategy of an Azy-containing macrocyclic scaffold through the site-specific integration of various amino acid-containing fragments. Our efforts have unveiled a unique trend in the regioselectivity of N-acyl aziridine ring-opening reactions, and we have thus proposed a model to rationalize our findings. Finally, through our experience in the synthesis of Azy-containing derivatives, we have developed a highly scalable and reproducible strategy for the synthesis of elusive dimeric aziridine aldehyde analogues. |
