Harnessing Amides And Strained Cyclic Allenes As Building Blocks

This dissertation describes efforts in furthering the synthetic utility of amides, as well as developing strained cyclic allenes into useful synthetic building blocks. Amides were once thought of as a relatively inert functional group, however, recent advances in nickel-catalysis have begun to allow for the activation and interconversion of amides to other functional groups. This dissertation describes leveraging the unique reactivity of nickel to achieve the elusive transamidation reaction. Additionally, the development of strained cyclic allenes into useful synthetic building blocks is described. Specifically, studies pertaining to the use of cyclic allenes, including heterocyclic variants, in regioselective, enantiospecific, and enantioselective reactions is discussed. Moreover, the use and utility of alternate precursors to strained cyclic alkynes and allenes is disclosed. Chapter one details the development of a nickel-catalyzed transamidation reaction of secondary amides. This methodology relies on a two-step approach to enable the transamidation of secondary amides to provide secondary or tertiary amides. At the time of the first disclosure, this method provided the most general solution to the long-standing challenge of secondary amide transamidation. Chapter two describes an experimental and computational study of azacyclic allenes. This study shows the synthesis of several substituted azacyclic allene precursors, and their subsequent generations and trappings in cycloadditions. Moreover, we demonstrate that depending on the nature of the substituent on the allene termini, varying regioselectivities and levels of enantiospecificity can be observed. Additionally, the computational studies performed provide insight into the underlying reasons for the observed regioselectivities and enantiospecificities. This study highlighted the potential for cyclic allenes to be valuable building blocks in asymmetric synthesis. Chapter three details experimental studies of oxacyclic allenes and the first asymmetric synthesis of a cyclic allene precursor. Specifically, the development of a precursor to 3,4-oxacyclohexadiene, and its generation and trapping in (4+2), (3+2), and (2+2) cycloadditions is disclosed. Additionally, the first asymmetric synthesis of a silyl triflate cyclic allene precursor was achieved, as well as its enantiospecific trapping. In all, this study furthered the development of strained cyclic allenes as tools for asymmetric synthesis. Chapter four describes an experimental and computational study regarding the use of strained cyclic allenes in enantioselective metal-catalyzed reactions. This study depicts the development of the first catalytic asymmetric reaction involving a strained cyclic allene intermediate. Computations provided insight into the reaction mechanism and the origin of enantioselectivity. Ultimately, this study provides a framework for the further development of catalytic enantioselective reactions of strained cyclic allenes and other strained intermediates. Chapter five details the development of an alternative precursor towards strained cyclic allenes and alkynes. Throughout our studies of strained cyclic allenes, it was found that in some cases silyl triflate precursors were inaccessible. This study shows that silyl tosylates can serve as comparable precursors to strained cyclic allenes and alkynes. Additionally, competition experiments between silyl triflates and silyl tosylates to determine the difference in their reactivities are disclosed.