UCLA

This dissertation describes the development of a dealkenylative approach toward C(sp3)–N bond coupling which leverages the copper-catalyzed decomposition of hydroperoxyacetals, obtained by Criegee ozonolysis of alkenes, to produce alkyl radicals which subsequently undergo copper-mediated cross coupling with a variety of nitrogen nucleophiles. These methodologies allow for a diverse range of alkene substrates, many derived from naturally occurring and renewable terpenes, to be coupled with nitrogen nucleophiles to rapidly access several classes of valuable nitrogen-containing products of interest to the pharmaceutical, chemical biology, and materials chemistry sectors. This work provides a foundation for further development of transition metal-catalyzed deconstructive cross-coupling and establishes a novel paradigm for alkene reactivity as they relate to C(sp3)–N bond formation. The operational simplicity, cost-effective and accessible catalyst system, and novel reactivity suggest these methodologies could see widespread implementation in various industries, academic research, and total synthesis campaigns.Chapter One provides background information on the chemistry and reactivity that underpins the dealkenylative functionalization platform and establishes the context of the dissertation work in the broader historical context of ozonolysis and peroxide decomposition by transition metals. Despite the rich history in this area, its exploitation for cross-coupling chemistry went relatively unreported until recently. A perspective on traditional and modern approaches to C–N bond formation will also be described, with a focus on modern C–N copper-catalyzed coupling of relevance to the current study. Chapter Two describes the development of the aminodealkenylation reaction, wherein an alkene C(sp3)–C(sp2) σ-bond is used to construct a new C(sp3)–N bond with nitrogen nucleophiles. The unprecedented disconnections enabled by this deconstructive methodology allowed for rapid and economical access to pharmaceutical intermediates, enantiopure chiral amines, terpene-nucleoside conjugates as well as a novel, single-step nucleoside N-methylation protocol. Chapter Three describes mechanistic studies undertaken to unravel the role of the copper catalyst in the aminodealkenylation reaction. Data from kinetic profiling experiments, control experiments, and spectral data are discussed as they relate to the proposed mechanism. The identification of the copper catalyst operating by a previously undescribed cooperative copper ion-pair mechanism will be highlighted. Chapter Four discusses the development of the azide variant of the dealkenylation reaction manifold, dubbed azidodealkenylation. The application of this methodology toward the conversion of terpenes to pseudoalkaloid lactams will be detailed. Azidation strategies and their relevance will be generally discussed to provide context into the significance of the current work.