Dissertations, Theses, and Capstone Projects

Date of Degree

6-2021

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor

Ryan P. Murelli

Committee Members

David Mootoo

Alexander Greer

Subject Categories

Chemistry | Organic Chemistry

Abstract

Cycloaddition chemistry has historically served as a robust route to stereo-rich and highly functionalized cyclic and heterocyclic compounds. Herein we describe our examination of 3-hydroxy-4-pyrone-derived oxidopyrylium cycloadditions in both mechanistic considerations as well as the unique synthetic advancements of their corresponding cycloadducts. Chapter 1 is a literature review where we specifically outline the use of oxidopyrylium cycloadditions in the synthesis of natural products. This includes the mention of previous syntheses prior to 2008, and a more thorough examination of the natural products synthesized from 2008 to present. The work exploits this chemistry as a facile route to highly complex 7-membered natural products, among other unique structures.

In Chapter 2, we look closer into the dimerization of the reactive intermediate in these cycloadditions, the oxidopyrylium ylide, and factors to which it is influenced by. Previously our lab found that 3-hydroxy-4-pyrone-derived dimers can be used as ylide surrogates in cycloaddition reactions. We found through kinetic and computational work that this was occurring via full reversibility of the dimer to the reactive ylide. In addition, the studies show that the methyl placement on isomers, maltol and allo maltol-derived ylides, substantially influences reactivity’s observed in both their dimerization and cycloaddition pathways. Due to steric factors, maltol-derived ylides were shown to have a higher energy barriers to dimerization, making it possible to trap out the ylide rapidly with electrophilic dipolarophiles. Allo maltol-derived ylides have lower energy barriers to dimerization, making trapping capabilities less efficient. We then showed that maltol-derived cycloadducts, to whose synthetic utility is not well known, undergoes rapid regiodivergent acid-mediated ring contraction cascades to guaiacol derivatives. These studies expanded upon the current known utility of 3-hydroxy-4-pyrone derived oxidopyrylium cycloadditions.

In Chapter 3 we continued to expand upon the synthetic utility of 3-hydroxy-4-pyrone derived cycloadducts by developing a route to 2-methoxytropones via a samarium iodide- mediated reductive ring opening approach. Previously, our lab had primarily explored acid-mediated approaches to biologically active highly oxygenated tropolones. However, the reductive ring opening provided a facile route to a novel A-C colchicine analog. Additionally, the A-C analog synthesized was shown to be highly atropisomerically stable, with computed energy barriers to rotation of greater than 35 kcal/mol, that was also supported experimentally. Biological assay data showed one atropisomer to be biologically active with a GI50 value of 0.4 micromolar, and was approximately 10 fold more potent than its enantiomer. This methodology is currently being applied to the synthesis of alternative analogs as well as in the total synthesis of colchicine.

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