Synthetic studies of antibiotic natural products

Abstract

The work detailed in this thesis is directed towards the synthesis of natural products exhibiting antibiotic activity. In antibiotics, we have a readily available means to treat bacterial infection, yet bacterial resistance is increasingly limiting the effectiveness of antibiotics in the clinical setting. With the number of new antibiotics released on the market each year in steady decline, investigation into novel structures that possess potential as antibiotics is urgently needed. Chapter 1 contextualises the serious problem of antibiotic resistance and how it can be addressed. Approaches for development of new antibiotics are examined, with particular focus on the central role of natural products as lead compounds, as well as the contributions made by total syntheses. In chapter 2, recent research into the tetramic acid family of natural products is reviewed. These compounds have been shown to exhibit a diverse array of biological activities including antibiotic, antifungal, anti-HIV and anticancer. Particular attention is paid to the discovery of new structures of this family, our understanding of these structures, as well as the development of novel pathways for their synthesis. One such tetramic acid natural product, ravenic acid (2), inspired our synthetic work involving the preparation of a number of tetramic acid analogues, which is detailed in chapter 3. Our interest in the synthesis of ravenic acid stemmed from our involvement in the isolation and structural assignment of this molecule. We targeted a number of structurally related analogues of ravenic acid, to allow for structural determination a co-metabolite, which was of interest due to its potential as an antibiotic. Two pathways were pursued for the synthesis of the targeted tetramic acid analogues, with our efforts resulting in the identification of a new, highly unsaturated, tetramic acid natural product (69), structurally related to the known natural product, ravenic acid. Another group of natural products that we targeted for total synthesis were the xanthoquinodins (chapter 4). The novel structural features of these molecules, as well their diverse biological activity, and the lack of other synthetic attempts towards their preparation prompted our synthetic investigations. In this chapter we describe our retrosynthetic analysis and evolution of a synthetic strategy, with the primary goal of the research the synthesis of three molecules, representing subunits of the xanthoquinodins. The realisation of this goal required exhaustive trialling of various pathways for their preparation. Preliminary model studies towards the linking of the three subunits are also reported. Show more