UCLA

This dissertation describes the development of reaction methodologies that utilizeunconventional building blocks in chemical synthesis. One major effort involves the net hydrolysis of amides to give carboxylic acids via the nickel-catalyzed cleavage of traditionally inert amide C–N bonds. Additionally, the development of the first enantioselective reaction of amide electrophiles proceeding with the usage of a chiral catalyst through C–N bond activation is disclosed. At the other end of the reactivity spectrum, studies of minimally explored strained intermediates including cyclic 1,2,3-trienes and azacyclic 1,2,3-trienes are reported. These efforts expand on fundamental structure and reactivity of the cyclic trienes, give rise to new mechanistic understanding, and allow access to polycyclic products. Chapter one outlines the current state of the art in nickel and iron-catalyzed cross-couplings of traditionally inert electrophiles. Specifically, recent advances in base-metal-catalyzed reactions of phenol, aniline, ester, and amide derivatives that proceed via aryl or acyl C–O/C–N bond activation are described. This brief review chapter should provide context for some of the subsequent studies presented in this dissertation. Furthermore, summarizing recent efforts in this field is expected to highlight the utility of base-metal-catalyzed cross-couplings of traditionallyinert electrophiles in organic synthesis. Chapter two describes the development of a nickel-catalyzed net hydrolysis of amides. The methodology strategically employs a nickel-catalyzed esterification using 2-(trimethylsilyl)- ethanol, followed by a fluoride-mediated deprotection in a single-pot operation. The selectivity and mildness of this transformation are demonstrated through competition experiments and the net-hydrolysis of a complex valine-derived substrate. This strategy addresses a limitation in the field with regard to functional groups accessible from amides using transition metal-catalyzed C– N bond activation. Chapter three describes an enantioselective Mizoroki–Heck cyclization of amide electrophiles. In recent years, numerous cross-coupling reactions of amide electrophiles have been disclosed, however, this study constitutes the first known enantioselective variant proceeding through amide C–N bond activation using a chiral metal catalyst. Ligand design and reaction optimization are discussed, as well as a brief scope of the reaction. Additionally, the synthetic utility of the method is demonstrated through synthetic elaborations to enantioenriched, medicinally-relevant heterocycles and products bearing multiple stereocenters. This study establishes a proof-of-concept for using amide electrophiles in asymmetric catalysis. Chapter four 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, thus 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 in synthetic chemistry. Chapter five describes the mechanistic study of a C–C bond fragmentation that was observed in Chapter four studies. Experimental deuterium-labeling studies are combined with computational transition-state analysis to suggest that a carbonyl-retro-ene mechanism is operative. These studies demonstrate the synergy between experimental and theoretical chemistry and should promote the usage of both to better understand complex reaction mechanisms. Chapter six illustrates the development of the reactivity of strained azacyclic 1,2,3-trienes. Experiments show the precursor to the pyridone triene can be generated on gram-scale and that it can be trapped efficiently in (4+2) cycloadditions. Current and future efforts are focused on discovering the modes of reactivity available to these trienes, examining the regioselectivity of unsubstituted and substituted variants, and performing intramolecular trappings. These studies should provide predictive understanding for the reactivity and selectivity of a previously unexplored class of strained cyclic intermediate and should give access to diversely substituted pyridone products.