Date of Degree

9-2015

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor(s)

Ryan P. Murelli

Subject Categories

Chemistry | Organic Chemistry

Keywords

7-hydroxytropolones; 7-methoxytropolones; acid catalyzed ring opening; alpha-hydroxytropolones; medicinal chemistry; oxidopyrylium cycloaddition

Abstract

Chapter 1: This chapter gives a brief history of α-hydroxytropolones, how they were discovered and unique properties of these substrates. Included is a background on the bioactivity of these substrates in cellular targets such as bacteria, fungi, parasites, tumors and toxicity, as well as their ability to inhibit various metallo-based enzymes. Structure activity relationships studies are reviewed on important metalloenzymes HIV-Reverse Transcriptase (RT) and Inositol monophosphatase (IMPase). Finally the chapter finishes with a synthetic overview of α-hydroxytropolones including natural product targets such as puberulic acid, puberulonic acid, β-thujaplicinol, and β-hydroxytropolone.

Chapter 2: A brief review on β-hydroxy-γ-pyrone based oxidopyrylium cycloadditions will be presented as well as important oxidopyrylium cycloaddition/ring opening procedures to yield natural tropolone products. Research from the Murelli laboratory will be highlighted. This chapter will discuss a new synthetic route toward functionalized α-hydroxytropolones. A β-hydroxy-γ-pyrone intermolecular oxidopyrylium cycloaddition with a range of alkynes that was optimized to an efficient and high yielding process will be discussed. Next two ring catalyzed ring openings will be discussed; one that utilizes boron trichloride that attains α-hydroxytropolones and 7-methoxytropolones, and a triflic acid mediated sequence that yields exclusive 7-methoyxtropolones and furans. Finally, a new reaction with the oxidopyrylium species will be highlighted that shows the exchange of alcohols in these reactive species.

Chapter 3: Chapter three describes the background on three specific medicinal targets: ANT (2")-Ia, HIV RT RNase H, and HBV RT RNaseH and preliminary structure activity relationship studies with β-hydroxytropolones synthesized in this research are outlined.

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