Unprotected N-H aziridine aldehydes are surprisingly stable compounds which can undergo reactions in the absence of protecting groups. In total, three different transformations were explored during my Master’s thesis. The conversions include the dissociation of the aziridine aldehydes, which exist as dimers, and their subsequent re-dimerization in various solvents. The development of mixed aziridine aldehyde adducts and their attempted modifications will also be discussed. Finally, the discovery of N-H aziridine compounds containing a 1,3-dicarbonyl functionality will be discussed, as will their attempted transformations.

Unprotected N-H aziridine aldehydes are surprisingly stable compounds which can undergo reactions in the absence of protecting groups. In total, three different transformations were explored during my Master’s thesis. The conversions include the dissociation of the aziridine aldehydes, which exist as dimers, and their subsequent re-dimerization in various solvents. The development of mixed aziridine aldehyde adducts and their attempted modifications will also be discussed. Finally, the discovery of N-H aziridine compounds containing a 1,3-dicarbonyl functionality will be discussed, as will their attempted transformations.

While unprotected amino aldehydes are typically not isolable due to imine formation and consequent polymerization, stable unprotected aziridine aldehydes are useful and available reagents. Moreover, reversible hemiacetal and hemiaminal formation enable these compounds to reveal both their electrophilic and nucleophilic functional groups. This exceptional arrangement allows for aziridine aldehyde dimers to participate in and disrupt the mechanisms of an array of well-known organic reactions, including isocyanide-based multicomponent reactions. The scope and selectivity patterns of aziridine aldehyde induced amino acid or peptide macrocyclization have been investigated. A small library of constrained tri-, tetra-, and penta-peptide macrocycles – representing the most difficult cyclic peptides to synthesize – has been prepared. The scope of aziridine aldehyde participation in multicomponent reactions was also expanded to Ugi and Passerini reactions that do not employ tethered amine and acid functional groups. In order to facilitate cellular imaging of peptide macrocycles a fluorescent isocyanide reagent was prepared and applied to prepare mitochondrial targeting macrocycles. Thioester isocyanide reagents were synthesized to enable rapid assembly of cycle-tail peptides through ligation technology.

Due to inherent rigidity of oligoproline peptides, forcing the C- and N-terminus in proximity for cyclization can be of significant challenge. To address this issue, a cyclization condition involing the help of amphoteric aziridine aldehydes has been developed. This one step cyclization protocol generally proceeds in high yields and goes to completion in relatively short period of time. Despite their cyclic nature, the resulting molecules display spectroscopic characteristics of polyproline II helices. These macrocycles should facilitate systematic studies of various conformational states of polyproline-containing protein regions.

Due to inherent rigidity of oligoproline peptides, forcing the C- and N-terminus in proximity for cyclization can be of significant challenge. To address this issue, a cyclization condition involing the help of amphoteric aziridine aldehydes has been developed. This one step cyclization protocol generally proceeds in high yields and goes to completion in relatively short period of time. Despite their cyclic nature, the resulting molecules display spectroscopic characteristics of polyproline II helices. These macrocycles should facilitate systematic studies of various conformational states of polyproline-containing protein regions.

While unprotected amino aldehydes are typically not isolable due to imine formation and consequent polymerization, stable unprotected aziridine aldehydes are useful and available reagents. Moreover, reversible hemiacetal and hemiaminal formation enable these compounds to reveal both their electrophilic and nucleophilic functional groups. This exceptional arrangement allows for aziridine aldehyde dimers to participate in and disrupt the mechanisms of an array of well-known organic reactions, including isocyanide-based multicomponent reactions. The scope and selectivity patterns of aziridine aldehyde induced amino acid or peptide macrocyclization have been investigated. A small library of constrained tri-, tetra-, and penta-peptide macrocycles – representing the most difficult cyclic peptides to synthesize – has been prepared. The scope of aziridine aldehyde participation in multicomponent reactions was also expanded to Ugi and Passerini reactions that do not employ tethered amine and acid functional groups. In order to facilitate cellular imaging of peptide macrocycles a fluorescent isocyanide reagent was prepared and applied to prepare mitochondrial targeting macrocycles. Thioester isocyanide reagents were synthesized to enable rapid assembly of cycle-tail peptides through ligation technology.