Organic Reaction Selectivity via Metal-Catalysis: Discovery, Development, and Mechanistic Analysis of Nitrile, Ester, Arene, Azide, and Alkene Transformations
2019-03
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Organic Reaction Selectivity via Metal-Catalysis: Discovery, Development, and Mechanistic Analysis of Nitrile, Ester, Arene, Azide, and Alkene Transformations
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2019-03
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The focus of my doctoral dissertation is the discovery, development, and mechanistic analysis of metal-catalyzed organic reactions. My work highlights organometallic catalysis as a strategy to achieve each of the three main types of organic reaction selectivity: stereo-, regio-, and chemoselectivity. I accomplished this through the study of three distinct reactions: stereoselective Pd-catalyzed alkene cyanoamidation, regioselective Ir-catalyzed arene acylation, and chemoselective Pd-catalyzed azide to alkene diazo group transfer (DGT). The selectivity outcomes are explored both in terms of synthetic scope as well as mechanistic understanding. The execution of each project involved varying degrees of collaboration. Emphasis and detail are granted to my specific contributions to each project. PART I Historical Development of Metal-Catalyzed C–C Bond Coupling I provide a brief overview of the evolution of metal-catalyzed C–C bond coupling reaction design. Although not comprehensive of the entire field, the goal of this part is to acquaint the reader with the general concepts underpinning the chemistry involved with my projects. Thus, the primary iterations of organometallic catalytic systems that influenced my research are covered. PART II Mechanistic Model for Enantioselective Intramolecular Alkene Cyanoamidation via Palladium-Catalyzed C–CN Bond Activation I present our mechanistic investigation of Pd-catalyzed C−CN bond activation for intramolecular enantioselective alkene cyanoamidation. Experiments designed to probe key features of the mechanism included: Lewis acid/Lewis base additive effects, initial rates kinetics, natural abundance 13C KIE measurements, 13C label crossover experiments, and a linear solvation energy relationship (LSER) with enantioselectivity. We discovered multiple factors influencing enantioinduction, which provided evidence for the conformation of the chiral ligand during the enantio-determining step. Our analysis is expected to aide future application of asymmetric cyanoamidation in total synthesis. My specific contribution to this project was performing most of the reactions for both screening additive effects and 13C label crossover experiments. In addition, I performed all of the LSER experiments and data analysis. PART III Integrating Metal-Catalyzed C–H and C–O Functionalization to Achieve Sterically-Controlled Regioselectivity in Arene Acylation I detail the development and mechanistic analysis of sterics-controlled regioselective Ir-catalyzed arene acylation. This research marked a significant advancement in synthesis as well as organometallic catalytic mechanistic design. Regarding synthesis, the sterics-controlled regioselectivity we achieved contrasts with the electronics-controlled regioselectivity of acylation via electrophilic aromatic substitution (Friedel-Crafts) as well as acylation via directed metal-catalyzed C–H activation. Regarding the mechanism, we integrated two bond activations of common organic functional groups, a C–H and C–O bond, into a C–C bond coupling reaction. We utilized the C–O bond as an endogenous Ir oxidant and the O atom itself as an endogenous base to achieve the C–H activation. We explored this reaction through substrate screens of both the ester and arene components, kinetics studies, KIE studies, and computations. My specific contribution to this project included the synthesis of the salicylate ester substrate library, the execution of most of the acylations of these substrates, and data acquisition/analysis involved. In addition, I developed a model to explain our KIE experimental results. PART IV Chemoselectivity for Alkene Cleavage by Palladium-Catalyzed Intramolecular Diazo Group Transfer from Azide to Alkene I disclose our development of Pd-catalyzed intramolecular azide to alkene diazo group transfer (DGT), which grants chemoselectivity over competing aziridination. Our results indicate a mechanism distinct from other known metal-catalyzed azide/alkene reactions: nitrenoid/metalloradical and (3+2) cycloaddition. The structural design of the standard azide substrates permitted the synthesis of medicinally relevant N-heterocyclic structural cores. We achieved the chemoselective catalytic synthesis of 2-quinazolinones, as well as the non-catalytic synthesis of 1,3-benzodiazepinones via a unique aziridine ring expansion. This was an individual project with contribution from an undergraduate supervisee.
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University of Minnesota Ph.D. dissertation. March 2019. Major: Chemistry. Advisor: Christopher Douglas. 1 computer file (PDF); xix, 480 pages.
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Frost, Grant. (2019). Organic Reaction Selectivity via Metal-Catalysis: Discovery, Development, and Mechanistic Analysis of Nitrile, Ester, Arene, Azide, and Alkene Transformations. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/202909.
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