N-Heterocyclic carbenes as catalysts for substrates in the ester oxidation state

N-Heterocyclic carbenes (NHCs) are renowned for their ability to invert the polarity of an aldehyde, and for many years their application was centralized around the benzoin and Stetter reaction. The use of NHCs as organocatalysts in normal polarity transformations is severely underrepresented. This thesis describes investigations into novel reactions enabled NHC catalysis of substrates in the ester oxidation state. Addition of an NHC into an ester type substrate precludes proton transfer, and presents two orthogonal paths to reaction discovery. A good leaving group, such as a halogen, provides a novel method to access , unsaturated acyl azoliums, while a poor leaving group prevents elimination allowing reactivity of the tetrahedral hemiacetal alkoxide to be explored. Chapter One provides an introduction to NHCs in organocatalysis. Specifically, the reactivity of intermediates in the ester oxidation state (i.e. acyl azoliums), and the application of NHCs in normal polarity chemistry are discussed. Chapter Two investigates the reactivity of the hemiacetal alkoxide accessed via an enol ester and NHC catalyst. Through exploitation of ,-unsaturated enol esters, the first example of an NHC catalyzed anionic oxy-Claisen rearrangement was achieved. While a range of chiral catalysts failed to convert the parent enol ester 1a, the employment of a more reactive substrate allowed realization of an enantioselective Claisen variation. In addition, acyl fluorides and silyl enol ethers could participate in a tandem NHC catalyzed O acylation/Claisen rearrangement. Chapter Three details the development of an NHC catalyzed (4 + 2) cycloaddition/decarboxylation reaction. Acyl fluorides and TMS dienol ethers provided cyclohexadiene products in good yields as single diastereomers. To investigate the scope of the reaction two new methods for the preparation of 1 acyl 2 alkylcyclohexenes were also developed. These were achieved via regioselective formation of enol phosphates 79 and iron catalyzed coupling of Grignard reagents with bromoketones 81 In Chapter Four the mechanism of the NHC catalyzed (4 + 2) cycloaddition reaction is investigated. Through computational analysis and kinetic isotope effect studies the mechanism was found to involve a stepwise cycloaddition, beginning with a vinylogous Michael addition. In addition, theoretical calculations suggested that the -lactone was stable enough to exploit in subsequent transformations. This was achieved via reduction with lithium aluminium hydride or carbanion addition, with organolithium reagents. Together, these reactions provided diastereomerically pure, functionalized cyclohexene products 127 and 128 as single diastereomers. Chapter Five details efforts toward the preparation of pentacyclindole (130). The (4 + 2) cycloaddition/decarboxylation reaction developed in Chapter Three was proposed to function as a key step in the synthetic route toward the natural product. Unfortunately, problems in the preparation of the required TMS dienol ether, or protecting group incompatibility under the NHC catalyzed reaction conditions hampered progress toward the target molecule. The possible reasons for failure of this key process are discussed and a novel route toward pentacyclindole is introduced. Chapter Six provides a summary of the chemistry presented in this thesis and outlines future directions for the research. Finally, Chapter Seven outlines experimental procedures for compound preparation, and spectral data of the compounds introduced therein.