Synthesis and Applications of 3- and 5-Membered Azacycles: Natural Product Synthesis, Boron Heterocycles, and Molecular Probes

Nitrogen-containing heterocycles (azacycles) are ubiquitous in nature and are essential for the existence of life. This dissertation explores the synthesis and applications of azacycles in natural product synthesis, exploratory fundamental chemistry, materials science, and medicinal chemistry. After an introduction to azacycles and amphoteric molecules (Chapter 1), the following three chapters explore the applications of amphoteric molecules developed in the Yudin lab. Chapter 2 outlines a three-component Petasis borono-Mannich (PBM) reaction of aziridine aldehyde dimers to furnish syn-diamines. The chiral scaffolds were applied to ring-opening studies where an intriguing case of anchimeric assistance was found to govern regioselectivity. Chapter 3 discusses further application of the syn-diamines in the total synthesis of a 6-hydroxyceramide natural product found in the human epidermis. This was accomplished via a Meisenheimer rearrangement, a Lewis acid-catalyzed regioselective aziridine ring-opening, and a selective N-O bond cleavage. A number of unnatural 6-hydroxyceramide analogues were prepared, which were found to be non-toxic to yeast. Chapter 4 details the synthesis and applications of α-boryl aldoximes derived from amphoteric α-boryl aldehydes. Borylated oxadiazoles and isoxazoles were prepared via nitrile oxide chemistry, as well as a number of β-boryl-hydroxylamine derivatives en route to the synthesis of an unprecedented boron-containing azacycle. The final two chapters outline collaborative projects. Chapter 5 details a comparative study of triaryl-substituted boratriazaroles and their carbon-based analogues, and explores the role of the B-aryl substituent on photophysical properties. With p-CN substitution on the B-phenyl ring, a large Stokes shift was observed, which exhibited positive solvatochromism. Finally, Chapter 6 outlines a medicinal chemistry project utilizing fragment-based drug design. Triazole-containing small molecules were found to bind in an N-acetyllysine binding region of epigenetic protein SETDB1. Synthetic efforts towards molecular optimization of various regions of a triazole-containing biaryl system enabled the understanding of the steric and electronic requirements of this unexplored binding region.Ph.D.2019-11-03 00:00:0