Date of Degree

2-2018

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor(s)

Ryan P. Murelli

Committee Members

Emilio Gallicchio

Guillermo Gerona-Navarro

David R. Mootoo

Subject Categories

Medicinal-Pharmaceutical Chemistry | Organic Chemistry

Keywords

Three-component oxidopyrylium cycloaddition, hydroxytropolone, solid-phase synthesis, fluorous chemistry, alcohol incorporation, privileged scaffold

Abstract

Historically, natural products have provided unique research opportunities and challenges for organic synthesis, chemical biology, and medicinal chemistry due to their molecular complexity and effects on physiological systems. The total synthesis of natural products has not only produced novel reaction methods and strategies capable of efficiently generating complex structural motifs but also granted access to sufficient quantities of otherwise scarce natural product material for clinical evaluation. These synthetic efforts have facilitated the formation of a transdisciplinary partnership between chemistry, biology, and medicine that has been paramount in elucidating the chemical and pharmaceutical utility of natural products. Chapter I of this thesis will highlight several key examples of how natural products inspired synthetic methodology, small molecule drug and probe development, and the discovery of previously unknown biologically active scaffolds. A particular focus will be spent on the synthetic and biological endeavors made by our laboratory involving α-hydroxytropolones (αHTs).

αHTs are a subclass of troponoid natural products that possess promising activity against a broad range of therapeutically significant targets. In order to gain access to these molecules, our laboratory utilizes an oxidopyrylium cycloaddition/ring-opening strategy. During our synthetic investigations, we recently discovered a three-component oxidopyrylium cycloaddition that generates novel 8‑oxabicyclo[3,2,1]octene products. In Chapter II, the development and optimization of this synthetic method towards the construction of a library of new oxabicyclic species will be detailed. Initial attempts at applying the reaction towards αHT synthesis will also be discussed, as a tandem debenzylation/ring-opening procedure with benzyl-derived oxabicyclic intermediates is outlined. Further exploration of the utility of the three-component oxidopyrylium cycloaddition will be described in Chapter III and Chapter IV, as the first solid-phase and fluorous syntheses of αHTs are reported, respectively. The advantages and disadvantages of each strategy will be considered in these chapters, specifically pertaining to the efficiency of purification, incorporation/cleavage of solid-phase resins and fluorous tags, and modification of supported intermediates.

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