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Authors: Clayman, Phillip
Advisors: Hyster, Todd K
Contributors: Chemistry Department
Subjects: Organic chemistry
Issue Date: 2021
Publisher: Princeton, NJ : Princeton University
Abstract: Enzymes, nature’s catalysts, are capable of incredible rate accelerations and unparalleled selectivities. Due to the biological importance of chiral compounds, methods for selectively synthesizing one enantiomer of a compound over the other are particularly relevant, and enzymes are ideally suited to this task. Moreover, enzymes offer several advantages over other modes of catalysis, particularly with regards to sustainability, and they can be optimized as catalysts by the Nobel Prize winning technique of directed evolution. These factors have led to the adoption of certain biocatalytic enzymes for the production of pharmaceutically relevant compounds on an industrial scale. However, despite these advances, the number of types of reactions catalyzed by enzymes is dwarfed by the diversity of transformations used in the rest of organic synthesis. The research described here focuses on the development of new reactivity in existing biocatalytic enzymes, such that known benefits of these enzymes can be applied towards new transformations. Of particular interest are new asymmetric radical transformations, as radicals have proved to be powerful intermediates in organic synthesis, but methods for controlling the stereoselectivity of radical reactions remain underdeveloped. By utilizing the latent photochemical activity of enzymatic cofactors, we enable access to new radical intermediates within enzyme active sites. Moreover, we can utilize these radicals to form carbon-carbon bonds and control the stereoselectivity of an important radical terminating step, hydrogen atom transfer. In the first project discussed, new photoenzymatic reactivity is enabled by the formation of a charge transfer complex between substrate and flavin cofactor within the active site of flavin-dependent ‘ene’-reductases. Irradiation of this complex allows for the generation of unstabilized alkyl radicals. In the second project discussed, new reactivity is the result of high reducing potentials obtained by directly exciting flavin. This enables the reduction of acrylamides via a novel single electron transfer mechanism. Finally, an initially promising but ultimately unsuccessful dual catalytic system is described, along with ongoing efforts towards a biocatalytic Reformatsky reaction.
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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