Disrupted Ugi Reaction: Synthesis of Cyclic Peptides and Peptidomimetics

Cyclization is a technique often employed in the design of therapeutic agents and molecular probes to increase a molecule's affinity and selectivity towards enzyme or receptor target. Recent efforts have yielded a new method of piperazinone formation and peptide cyclization using unprotected aziridine aldehydes. The counterintuitive combination of a nucleophile and an electrophile in one molecule facilitates stitching of amino acids or linear peptides at high concentrations, thereby reducing reaction times. The scope of this reaction has been investigated with a variety of amino acids and peptides. The results differ from the initial studies and a new mechanism has been proposed that takes into account the substrate-dependent reactivity and formation of side-products. A variety of functionalization reactions, through aziridine ring-opening, have been reported. The ring-opened products have exhibited unique structural properties which have been investigated by ab initio calculations, X-ray crystallography, and NMR spectroscopy. Finally, the elements of scaffold design and aziridine ring-opening chemistry have been applied to the creation of inhibitors for Calpain, a disease-causing protease.Ph.D.2017-06-30 00:00:0