UCLA

This dissertation describes the development of methodologies that engage strained cyclic intermediates in complexity-generating reactions. One major effort involves the transition metal-catalyzed interception of strained cyclic allenes, which has been accomplished using palladium catalysis. Additionally, the study of alternative minimally explored strained intermediates including cyclic 1,2,3-trienes and heterocyclic 1,2,3-trienes are reported. These studies contribute to fundamental understanding of structure and reactivity of transient strained compounds and give rise to polycyclic products. Computational studies relating to the mechanism of strained intermediate generation from Kobayashi precursors are also reported. Chapters one and two are related to the development of palladium-catalyzed reactions of strained cyclic allenes. Chapter one describes the development of a modular annulation reaction of strained allenes and arylpalladium species. This methodology employs aryl halides and cyclic allene precursors to generate fused heterocyclic products via the formation of two new bonds and a new center. Chapter two described the development of a catalyst-controlled annulation reaction of strained allenes and -allylpalladium species. This methodology employs vinyl benzoxazinones and cyclic allenes precursors to generate two isomeric products with high selectivity based on the ligand employed. The development of these palladium-catalyzed reactions demonstrates that despite their high reactivity and short lifetimes, strained cyclic allenes efficiently engaged in catalytic processes, to access complex products, including examples with absolute stereocontrol. Chapter three describes the development of strained 1,2,3-cyclohexatrienes, which have remained underexplored historically, as synthetic building blocks. Studies of the reactivity of the unsubstituted 1,2,3-cyclohexatriene, as well as its mono- and disubstituted derivatives are reported, drastically expanding the scope of reactions known for such intermediates. Combined computational and experimental studies elucidate the factors controlling regioselectivity in reactions of an unsymmetrical strained triene. Furthermore, the potential utility of strained trienes in rapidly generating complex scaffolds is demonstrated through the integration of triene trapping reactions into multistep synthetic sequences to access polycyclic products. These studies highlight the potential of these traditionally avoided species for broader use in synthetic chemistry. Chapter four details the study of six-membered heterocyclic 1,2,3-trienes, particularly 4,5-didehydropyridones. Computational studies of the structure of such species, as well as the development of a synthetic route to access precursors to the same, are reported. Scope studies demonstrate the utility of six-membered azacyclic 1,2,3-trienes for accessing complex nitrogen-containing heterocycles, and trends in the regioselectivity observed therein are explored through computational studies. Collectively, this study demonstrates the value of six-membered azacyclic 1,2,3-trienes, a previously unexplored class of strained cyclic intermediates, in heterocycle synthesis, while pushing the limits of strained intermediate chemistry. Chapter five describes the reaction mechanisms of the fluoride-mediated generation of selected strained intermediates from Kobayashi precursors. We interrogate several mechanistic aspects using Density Functional Theory (DFT) calculations and find that the eliminations to form alkynes and alkenes can take place through primarily two different mechanisms. This study is one of the few theoretical studies on Kobayashi eliminations for the generation of strained intermediates. It is anticipated that this report will enable the rational design of new strained intermediate precursors for future uses in synthesis.