Synthesis and Evaluation of Densely-Functionalized Troponoids

Author

Danielle R. Hirsch, The Graduate Center, City University of New YorkFollow

Date of Degree

9-2018

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor

Ryan Murelli

Committee Members

Alexander Greer

Stephen Fearnley

Yu Chen

Subject Categories

Organic Chemistry

Keywords

troponoids, atropisomerism, atropselective halogenation

Abstract

Herein, we document our efforts to expand the scope of troponoid synthetic methodology towards densely-substituted scaffolds. This body of work has focused primarily on an oxidopyrylium cycloaddition/ring-opening strategy for the synthesis and biochemical evaluation of troponoids for assistance in a variety of medicinal chemistry studies. In Chapter 1, we outline the use of this synthetic strategy in the profiling of a library of synthetic αHTs against an aminoglycoside antibiotic resistance enzyme known as aminoglycoside-2’’-O-nucleotidyltransferase [ANT(2’’)-Ia]. Enzymatic mechanistic insights have been gleaned from an assessment of troponoid/antibiotic synergistic potential. In particular, two synthetic constructs were identified as promising antibiotic adjuvant candidates, demonstrating a capacity to rescue gentamicin activity while in the presence of ANT(2’’)-Ia-expressing bacteria. These results validate the oxidopyrylium cycloaddition/ring-opening method as a viable approach to generating new ANT(2’’)-Ia inhibitors, and provide some preliminary insight into the structural changes required for effective inhibition.

In Chapter 2, we report the expansion of this synthetic strategy to a class of molecules called 3,7-dihydroxytropolones, which have been indicated as promising leads in the development of antiviral, antimelanoma and antimalarial agents. These synthetic developments were applied in the synthesis of a prospective biosynthetic precursor to the natural products puberulic and puberulonic acid. Additionally, several new synthetic 3,7-dihydroxytropolones were identified as promising scaffolds for anti-HSV drug development. This synthetic work was further expanded towards additional investigations on the synthesis and physical evaluation of atropisomeric troponoids, as discussed in Chapters 3 and 4. The research described within these chapters aims to broaden our understanding of the physical properties of troponoids by using DFT and experimental techniques to assess the rotational barriers of a series of benzenoid and troponoid scaffolds, as well as by studying the atropselective bromination of a methoxytropolone. During the course of these studies, ¹H- and ¹³C-NMR experiments unveiled several mechanistic findings pertinent to future development of the reaction.

Collectively, the studies described in this thesis aim to broaden our understanding of the physical and biological properties of troponoids.

Recommended Citation

Hirsch, Danielle R., "Synthesis and Evaluation of Densely-Functionalized Troponoids" (2018). CUNY Academic Works.
https://academicworks.cuny.edu/gc_etds/2873