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Studies Toward the Synthesis of Exiguaquinol

  • Author(s): Schwarzwalder, Gregg Martin
  • Advisor(s): Vanderwal, Christopher D
  • et al.
Abstract

This dissertation describes our efforts to develop a total synthesis of the biologically active marine natural product exiguaquinol. Chapter 1 focuses on the isolation and structure elucidation of exiguaquinol, its biological significance as a Helicobacter pylori MurI inhibitor, and its proposed biogenesis from halenaquinol sulfate. In addition, synthetic efforts yielding related furanosteroid natural products halenaquinone and xestoquinone are discussed.

Chapter 2 details our synthesis of the tetracyclic core scaffold of exiguaquinol. While several functional groups were omitted in this endeavor, this model system was targeted in order to test the feasibility of our proposed strategy. Through a desymmetrizing aldol reaction, a thermal sulfoxide elimination, and a 5-exo reductive Heck cyclization, the tetracyclic core was prepared in 14 steps from commercially available starting materials. In the end, an unexpected stereochemical outcome involving the N-acyl hemiaminal was uncovered, which could be explained through a favorable internal hydrogen bonding arrangement between the alcohol and the C9 ketone. This phenomenon was simulated computationally by the Houk group for further understanding.

In Chapter 3, our efforts to apply this strategy to the first total synthesis of exiguaquinol are disclosed. After preparing the necessary naphthaldehyde, the pentacyclic framework was assembled using the strategy developed previously for the tetracyclic core. Although we were able to access exiguaquinol des-sulfate, the final regioselective sulfation was ultimately unsuccessful. Further studies regarding the regioselective installation of sulfate groups will be necessary to provide exiguaquinol.

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