UC Davis

This dissertation details my academic investigations towards the completion of a Ph.D. in Chemistry performed in the laboratory of Prof. Annaliese Franz while working as a Graduate Student Researcher at the University of California, Davis. Organic chemistry has served as a powerful intermediary of the physical sciences as a template to design and develop small molecule entities with potent therapeutic potential. To access new and interesting drug scaffolds, reaction methodology must be developed to expand the arsenal of tools available to synthesize relevant scaffolds. As molecular architects, we strive to achieve near-perfect stereocontrol for our synthetic targets through asymmetric catalytic methods, often employing organocatalysts or metal-based catalysts to achieve the desired transformation in mild or moderate conditions, simple purification, and high atom-economy. Organic chemistry and reaction methodology also provides a platform to expand the current understanding of reaction mechanisms; the role of each reaction component, the physical organic chemistry forces in play, and the order of events necessary to achieve the desired outcome. Chapter 1 introduces spirooxindoles, a unique and versatile scaffold characterized by a spirocycle at the C-3 position of the oxindole core. In recent years, spirooxindoles have gained significant attention in medicinal chemistry and drug discovery with broad representation in alkaloid natural products and pharmaceutical lead compounds. A selection of organocatalytic asymmetric multicomponent cascade reactions and Lewis acid-catalyzed processes for the enantioselective synthesis of spirooxindoles are discussed with a focus on cyclization reactions of electron-deficient ketimine oxindoles, alkylidene oxindoles, and isatin compounds. Chapter 2 discusses my work towards the scandium-catalyzed [3 + 2] annulation of alkylidene oxindoles with allenylsilanes for the enantioselective formation of cyclopentene-spirooxindoles containing vinylsilanes. Using a Sc(OTf)2/PyBox/BArF complex, the annulation of allenylsilanes affords products with >94:6 dr and >90:10 er. The effect of the counterion and ligand to control selectivity is discussed. The transformation of the vinylsilane is demonstrated using cross-coupling, epoxidation, and Tamao-Fleming oxidation reactions. Additional investigations include the catalytic asymmetric annulation of isatin and attempts to expand this methodology to synthesize additional spiro-heterocycles. A series of competition experiments provide a comparison of nucleophilicity and reactivity between allyl- and allenylsilane nucleophiles under the optimized reaction conditions. In Chapter 3, a mechanism for the scandium-catalyzed asymmetric allylsilane annulation reaction is proposed and supported by reaction heat flow calorimetry, NMR, and in situ infrared spectroscopy. Previous studies of the nature of the scandium(III)-PyBox/BArF catalyst reveal optimal reaction rate is dependent on catalyst solubility, pre-complexation time and order of addition of the catalyst components. Ligand-accelerated catalysis is observed and attributed to the ligand reducing off-cycle oligomerization of allylsilane. To investigate the effects of ligand on rate acceleration, a small cohort of PyBox ligands were synthesized and investigated via in situ IR spectroscopy to elucidate the relative reaction rate when comparing ligand-types. The in situ reaction monitoring studies describe the effects of delayed and synchronous addition of nucleophile on reaction success and its connection to catalyst solubility and off-cycle events. The role of PyBox structure on catalyst activity is discussed as it relates to catalyst activity and turnover. Ligand-dependent acceleration is observed where sterically demanding ligands perform with a faster relative reaction rate. A quantitative analysis of initial reaction rates reveals ligands with fast turnover rates demonstrated a propensity to synthesize products with higher stereoselectivities. Chapter 4 introduces phytocannabinoids, such as non-psychotropic CBD derived from Cannabis sativa, which have demonstrated potential as a powerful therapeutic for a variety of neurological disorders. There is significant evidence supporting the benefits of CBD as a neuroprotective, antiepileptic, anxiolytic, antipsychotic, anti-inflammatory, antitumor, and anti-asthmatic agent but also as an antagonist of tetrahydrocannabinol’s (Δ9-THC) psychoactive effects. The Franz Laboratory has expertise in silicon chemistry and has developed synthetic methodology to access silicon-containing analogues of CBD and other cannabinoids. The incorporation of silyl-lipids is proposed to exploit the distinct elemental properties of silicon to modify the hydrophobic pharmacophore of CBD and to demonstrate and evaluate the impact of silyl lipids on conformation, pharmacokinetics, and biological activity with translational applications in small molecule therapeutics. We discuss the strategic and modular incorporation of a silyl group and preliminary biological studies that support our initial hypothesis.