The Reactivity and Conformational Properties of Aziridine-containing Cyclic and Bicyclic Peptides and Their Derivatives

Cyclic and bicyclic peptides represent a vast class of molecules that are incredibly varied in their structure and function. Thus, methods regarding their synthesis and subsequent characterization of their conformational properties are invaluable in the understanding of these privileged scaffolds. Cyclic tetrapeptides in particular are a noteworthy subset because not only are they among the smallest of the peptide macrocycles, they also exhibit unusual conformational dynamics in solution. The ability to harness this flexibility would represent a powerful method to control target binding and cellular permeability of these molecules. We have demonstrated that aziridine cyclic tetrapeptides are perfectly poised to investigate these conformational nuances, where aziridine ring-opening of 12-membered rings yields exclusively 13-membered α3β architectures that contain a β-amino acid residue that is rich in stereochemical complexity. The disubstituted β-residue further acts as a rigidifying structural element that induces allylic strain and raises the barrier to cis-trans isomerization such that multiple conformations are energetically differentiated, resulting in conformational heterogeneity. From this, we sought to explore other methods in which rigidifying elements can be incorporated into cyclic peptide structures and decided to pursue the synthesis of bicyclic peptides. Since disulfides are well precedented in nature, we chose a transannular disulfide as a synthetic target, coupled with the peptide macrocyclization chemistry using aziridine aldehydes and isocyanides previously developed by our group in 2010. After careful consideration of cysteine protecting groups and the order of cyclization reactions, we have found that head-to-tail cyclization first followed by late-stage oxidative deprotection of a bis-acetamidomethyl protected peptide could successfully yield the desired disulfide-bridged peptide bicycle. With the combined understanding of conformational dynamics in small cyclic peptide systems and the knowledge of a bicyclic bridge synthesis, this work should provide ample context for future studies exploring the conformational tuning of peptide macrocycles with transannular constraints.Ph.D