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Title: Synthesis of Heterocycles via Radical-Polar Crossover Cycloadditions
Authors: Garber, Jeffrey Alan Owen
Advisors: MacMillan, David W. C.
Contributors: Chemistry Department
Keywords: cycloaddition
photoredox catalysis
radical-polar crossover
Subjects: Organic chemistry
Issue Date: 2014
Publisher: Princeton, NJ : Princeton University
Abstract: This dissertation discusses how three influential approaches in organic chemistry method development are incorporated into a single strategy to design valuable new transformations. First, identifying new activation modes involves utilizing a single key intermediate to invent a variety of novel reactions. These intermediates introduce new bonds by radical or polar processes, depending on either an open or closed-shell pathway, respectively. Radical and polar approaches are often alternatively employed to accomplish orthogonal reactivity. However, a radical-polar crossover mechanism is a process where two crucial intermediates are sequentially accessed on the same substrate, one providing radical reactivity and the other providing polar reactivity, thereby allowing two distinct bond-forming processes to occur. Finally, cycloadditions are powerful coupling manifolds that combine two or more components into cyclic structures. The method is termed a heterocycloaddition if the constructed ring contains heteroatoms such as oxygen and nitrogen. This document describes three methodologies developed by combining the utility of specific reactive intermediates, a radical-polar crossover mechanism, and a heterocycloaddition manifold to rapidly access important heterocyclic compounds from simple starting materials. SOMO-organocatalysis enables enantioselective coupling of pi-nucleophiles such as styrenes and simple olefins with aldehydes by a radical umpolung process, allowing reactivity at the alpha-position of aldehydes and ketones that is orthogonal to closed-shell enamine reactivity. By employing aldehydes bearing pendent heteroatom nucleophiles, heterocycles are constructed using SOMO-organocatalysis in a radical-polar crossover mechanism. This strategy was applied to two mechanistically similar, but distinct, transformations to form enantioenriched pyrrolidine products or enantioenriched tetrahydropyran and tetrahydrofuran products. In addition to the reaction development and substrate scope, the important stereochemical and mechanistic steps for each process, as well as how they differ, are discussed. The radical-polar crossover heterocycloaddition strategy was also demonstrated to be general towards other activation mode strategies by the application of photoredox catalysis to the synthesis of diverse nitrogen-containing heterocycles. In this process, a pre-oxidized substrate is employed to achieve a redox neutral heterocycloaddition with a photocatalyst. Initial optimization, substrate scope and prospects for an enantioselective variant of this method are discussed.
Alternate format: The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog
Type of Material: Academic dissertations (Ph.D.)
Language: en
Appears in Collections:Chemistry

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