Synthesis and study of shape-persistent oligohydrazide macrocycles
Ferguson, Joseph S.
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This thesis describes the synthesis and study of shape-persistent oligoamide and oligohydrazide macrocycles. Specific focus is placed on a new class of oligohydrazide macrocycles. The synthesis of these molecules is directed by a folding-assisted macrocyclization reaction which allows for yields of macrocycles of up to 95%. Chapter 1 is a brief review of various methods of shape-persistent macrocycle preparation. Early methods relied on stepwise reactions which were tedious and labor intensive. More recently, efficient one-pot macrocyclizations have been developed using reversible or irreversible reactions. Chapter 2 discusses the highly efficient synthesis of oligoamide shape-persistent macrocycles. Based on the yields of acyclic oligoamide foldamers, a mechanism for the macrocyclization of the six-residue macrocycle is proposed. The proposed mechanism states that the formation of macrocyclic products is favored due to the steric hindrance associated with the formation of "overshoot" oligomers. High yields obtained during the formation of 14-, 16-, and 18-residue macrocycles prove that the proposed mechanism is reasonable. Chapter 3 discusses the highly efficient synthesis of oligohydrazide shape-persistent macrocycles. High yields obtained during the formation of a ten-residue macrocycle provide further support for the universal applicability of the mechanism proposed in Chapter 2. This mechanism also subsequently proves applicable in the synthesis of six-residue oligohydrazide macrocycles with pyridyl-based meta -units. Chapter 4 presents some solution and solid state behavior of the ten-residue oligohydrazide macrocycles. CD and UV spectra, TEM images, and planar lipid bilayer studies provide strong evidence that suggests that the macrocycles self-aggregate due to aromatic stacking interactions. The self-aggregation behavior will be utilized in the future for various applications.