Experimental and Theoretical Investigations in Transition Metal Catalysed Reactions of Heterobicyclic Alkenes

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University of Guelph

Abstract

Over the past fifty years, transition metal catalysis has been pivotal in shaping economical, sustainable, and efficient strategies for the synthesis of pharmaceutically relevant small molecules. Despite substantial progress, the dynamic landscape of drug production demands continual innovation. This thesis addresses this imperative need through a multifaceted exploration of novel synthetic approaches, augmented by the insights provided by computational chemistry. The first endeavor involves the development of palladium- and nickel-catalysed intramolecular ring-opening reactions of aryl halide-tethered oxabicyclic alkenes. This work provides a selective pathway to synthesize tetracyclic compounds featuring the 1,2-dihydronaphthalen-1-ol core. Through strategic substrate design, the hydroxy intermediates are further directed towards functionalization, yielding bicyclo-[3.2.1]-lactone scaffolds (Chapter 2). Continuing the journey, the mechanism and origins of selectivity in the rhodium-catalysed ring-opening reactions of oxabicyclic alkenes with organoboronic acids is explored through a comprehensive computational study (Chapter 3). Next, the attention shifts to iridium/zinc co-catalysis for the ring-opening reactions of heterobicyclic alkenes with indole nucleophiles. This approach highlights a 100% atom-economic C–C bond formation. Computational insights into the mechanism and origins of selectivity enrich our understanding of this transformative methodology (Chapter 4). The final frontier explores cobalt-catalysed hydrogenation and deuteration reactions of heterobicyclic alkenes, utilizing H2O and D2O as the sole hydrogen and deuterium sources. Notably, Lewis-acid co-catalysts are harnessed to promote the reactions while catalyzing concurrent transesterification processes (Chapter 5). Throughout this Thesis, the symbiotic interplay between experimental investigations and computational insights paves the way for the development of novel synthetic methodologies and a deeper understanding of reaction mechanisms. The culmination of these endeavors contributes significantly to the ongoing evolution of drug discovery and production strategies.

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transition metal catalysis, bicyclic alkenes, organic chemistry, computational chemistry

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