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 asymmetric nickel catalysis and palladium catalysis. Additionally, the study of alternative minimally explored strained intermediates including cyclic 1,2,3-trienes and 2,3-heterocyclic allenes are reported. These studies expand on fundamental understanding of structure and reactivity of strained compounds and give rise to diverse libraries of polycyclic products. Studies relating to the in situ generation of various strained cyclic intermediates are also reported. Specifically, these include experimental evaluation of the safety associated with the use of silyl triflates as benzyne precursors as well as the synthesis and evaluation of silyl tosylates as precursors to strained alkynes and allenes. Chapters one and two are related to the development of metal-catalyzed reactions of strained cyclic allenes. Chapter one describes the first catalytic asymmetric reaction involving a strained cyclic allene, which was achieved through the use of nickel catalysis. The scope of the asymmetric annulation reaction is reported, and computational studies performed in collaboration with the Houk Laboratory elucidate the origin of asymmetric induction in the transformation. Chapter two describes the development of a modular annulation reaction of strained allenes enabled by a palladium catalyst. This methodology employs aryl halides and cyclic allene precursors to generate fused heterocyclic products via the formation of two new bonds and a sp3 center. The development of these metal-catalyzed reactions demonstrates that despite their high reactivity and short lifetimes, strained cyclic intermediates can be efficiently engaged in catalysis, to access complex products, often 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 sp3-rich polycyclic products. These studies highlight the potential of these traditionally avoided species in synthetic chemistry. Chapter four details the study of unsymmetrical strained heterocyclic allenes, particularly 2,3-azacyclohexadienes. 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 2,3-azacyclic allenes for accessing complex nitrogen-containing heterocycles, and trends in the regio- and diastereoselectivity observed therein are explored through control experiments. The extension of this study to 2,3-oxacyclic allenes enables their generation under mild conditions for the first time, as well as the first demonstration of their reactivity in dipolar cycloadditions and transition metal-catalyzed reactions. Collectively, this study demonstrates the potential value of unsymmetrical aza- and oxacyclic allenes in heterocycle synthesis. Chapter five describes an evaluation of the safety profile associated with benzyne generation from a silyl triflate precursor which was performed in collaboration with the process development group at Boehringer Ingelheim. Calorimetric analysis supports the safe nature of generating high energy aryne intermediates from silyl triflates under fluoride-mediated conditions. Chapter six illustrates the development of an alternative precursor toward strained cyclic allenes and alkynes. Our studies of strained cyclic allenes revealed that, in some cases, silyl triflate precursors were inaccessible. This study shows that silyl tosylates can serve as alternative precursors to strained cyclic allenes and alkynes.