I. Synthesis of Ascarosides for Chemical Biology Studies in Caenorhabditis elegans, II. A Photochemical Approach to Delavayine, and III. Remote Hydroxylation by Radical Translocation and Polar Crossover
Doctor of Philosophy (PhD)
The foci of this dissertation are the synthesis of analogs for chemical biology studies, synthetic chemistry method development (with an emphasis on photochemistry), and the application of these methods toward total synthesis. Chapter 1 outlines the synthesis of an array of pheromone analogs that are derivatives of the dideoxy sugar ascarylose. Referred to as ascarosides, such compounds have recently been shown to influence important biological processes in the model organism Caenorhabditis elegans. C. elegans secretes ascarosides into its environment, where the compounds then act as signaling molecules by providing information on factors like population density. Chapter 2 describes the biological impact of naturally occurring and synthetic ascarosides in C. elegans developmental and reproductive assays. Chemosensation of ascarosides results in downregulation of important signaling pathways, which are conserved in higher organisms, and our studies provide data on the effects of these processes. We hypothesize that knowledge gained from these studies can be extrapolated to provide insight for similar processes in higher organisms such as humans. In Chapter 3, a photochemical approach to total synthesis of the natural product delavayine is discussed. Alkaloids from the same family have shown biological activity via binding to human opioid receptors, which are responsible for producing analgesic and antidepressant effects. The photo-SN1 reaction, a process which produces a triplet phenyl cation intermediate, was utilized as a central reaction for initiation of a cascade cyclization event en route to delavayine. Chapter 4 details the development of a strategy for remote C-H functionalization using redox catalysis. The Tzo directing group was used to effect 1,6- and 1,7-hydrogen atom transfers from unactivated aliphatics. The resulting radicals were then oxidized by redox (or photoredox) catalysis to form a carbocation that was ultimately trapped by water or methanol. After loss of a proton, successfully hydroxylated or methoxylated products were isolated in moderate yields. This newly developed method was then applied to a concise total synthesis of the powerful antidepressant drug fluoxetine (Prozac®), beginning from a more inexpensive and simple starting material than current industrial methods.
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Hollister, Kyle Allen, "I. Synthesis of Ascarosides for Chemical Biology Studies in Caenorhabditis elegans, II. A Photochemical Approach to Delavayine, and III. Remote Hydroxylation by Radical Translocation and Polar Crossover" (2015). LSU Doctoral Dissertations. 1494.