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Harnessing Heterocyclic Arynes & Amides as Synthetic Building Blocks


This dissertation describes the study of two synthetic building blocks, heterocyclic arynes and amides, and their applications in synthetic organic chemistry. Heterocyclic arynes are highly reactive intermediates that act as electrophilic arene surrogates. In contrast, amides are tradionally considered to be robust functional groups. However, recently the acyl–nitrogen bond of amides have been activated under mild transition metal-catalysis to act as acyl electrophiles and form C–heteroatom and C–C bonds.

Chapter One reviews the field of heterocyclic arynes from a historial perspective with an emphasis on pyridyne and indolyne methodologies. Moreover, this chapter highlights the use of pyridynes, indolynes, and related strained intermediates in the synthesis of natural products.

Chapter Two describes the total syntheses of (–)-indolactam V and its C7-substituted natural product derivatives, (–)-pendolmycin, (–)-lyngbyatoxin A, and (–)-teleocidin A-2. The C4–N linkage is constructed with a distortion-controlled indolyne functionalization. The total synthesis of (–)-indolactam V provides a platform for the divergent syntheses of the other three natural products via a palladium-catalyzed cross-coupling to functionalize C7 and introduce a quaternary center.

Chapter Three pertains to accessing two new oxacyclic strained intermediates, the 4,5-benzofuranyne and the 3,4-oxacyclohexyne. In situ trapping of these intermediates affords an array of heterocyclic scaffolds and the experimentally-determined ratio of regioisomers are consistent with predictions made using the distortion/interaction model. In addition, oxygen-containing strained intermediates were found to provide access to greater selectivities from trapping experiments compared to their corresponding nitrogen-containing counterparts.

Chapter Four illustrates the synthesis of six new indole-based conjugated trimers and their photophysical properties. These conjugated trimers are generated using highly reactive indolyne intermediates in the presence of a palladium catalyst. In addition, this reactivity could provide access to a variety of trimeric cores, which could have further applications in new materials.

Chapter Five depicts the activation of the carbon–nitrogen bond of amides under nickel catalysis and the utility of amides as electrophilic acyl cross-coupling partners. We first investigated the conversion of amides to esters, which is a challenging and underdeveloped transformation. Density functional theory calculations provide insight into the thermodynamics and catalytic cycle of the amide-to-ester transformation. This report provides a way to harness amides as synthons and has led to the further use of amides in the construction of carbon–heteroatom or carbon–carbon bonds under nickel-catalysis.

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