TOPICS IN CONFORMATIONAL ANALYSIS AND MEDICINAL CHEMISTRY: I. HFIP SOLVATION MODULATES CONFORMATIONAL AND CONFIGURATIONAL EQUILIBRIA; II. SMALL MOLECULE APPROACHES IN TARGETING RNA AND RNA BINDING PROTEINS; AND III. BACKBONE EDITING OF OXIDIZED POLYETHYLENE VIA THE INTRAMOLECULAR SCHMIDT REACTION

This dissertation explores applications of physical organic chemistry, spanning solvent effects on conformational equilibrium, targeted drug discovery, and polymer functionalization. Chapter 1 establishes HFIP as a privileged solvent for controlling conformational equilibria, demonstrating its ability to impose substantial energetic penalties (ΔG up to 1.93 kcal/mol) on axial substituents in 1,3-dioxanes and other heterocycles through specific hydrogen-bonding interactions. Chapters 2–4 focus on drug discovery. Chapter 2 reveals fundamental challenges in designing HuR-targeting PROTACs, as the protein aberrantly engages linker moieties, precluding productive ternary complex formation. Chapter 3 addresses some of these limitations through replacement of the promiscuous hydroxamic acid warhead of KH-39 with amino acids, yielding selective HuR inhibitors (e.g., 3.04b, Ki = 530 nM) that avoid off-target HDAC inhibition and mutagenicity associated with hydroxamates. Chapter 4 deciphers structure-activity relationships of TPP riboswitch binders, identifying critical electrostatic and conformational requirements. This investigation enabled development of a second generation inhibitor, 4.17 (Kd = 57 nM), and serves as a proof-of-concept for RNA-targeted drug discovery. Chapter 5 transitions to polymer chemistry, demonstrating a tandem C–H oxidation/azide-mediated rearrangement to convert polyethylene into “PE-like” materials with tunable properties (e.g., crystallinity, degradability). This backbone-editing strategy enables modular installation of functional groups (esters, amides, chirality) and highlights potential for upcycling commodity plastics.