Studies on the Total Synthesis of Some Biologically Active Natural Products: Neocosmosin A and the Discoipyrroles

Abstract

The body of this thesis is comprised of four scientific journal articles and a patent. It is preceded by an overview that contextualizes all of this submitted/published work. The first major part of this thesis is comprised of Publication 1. This is a review concerned with the chemical syntheses of the cochliomycins, including congener A, and certain related resorcylic acid lactones (RALs). pecifically, Publication 1 reviews the recently published literature on the cochliomycins and related, co-occurring RALs and is accompanied by a brief commentary on the source organisms and certain of their biological properties. It serves to contextualize some of the author’s other published research incorporated in the thesis. The second major part of this thesis is comprised of Publication 2. This details work concerned with establishing the true structure of the marine-derived RAL neocosmosin A. Specifically, the structure, A, originally assigned to neocosmosin A was synthesized with the key steps involving olefin-cross metathesis, ring-closing metathesis, palladium- catalyzed Meinwald rearrangement and Mitsunobu esterification reactions. A late-stage and simple modification to the reaction sequence also provided the enantiomer B that, in fact, represents the true structure of the natural product. The third major part of this thesis is comprised of Publication 3. This details the development of modular total syntheses of the marine-derived alkaloids discoipyrroles A and B. Specifically, the intermediates C and D (see below) were prepared from (parent) pyrrole using Ullmann-Goldberg and Suzuki-Miyaura cross-coupling, Vilsmeier-Haack formylation, electrophilic bromination, and Wittig olefination reactions as key steps. A late stage MoOPH-mediated oxidative cyclization reaction was then employed to assemble the novel heterobicyclic core of the target discoipyrroles. The fourth major part of this thesis is comprised of Publication 4. This details the first total synthesis of the most structurally complex member of the small family of marine- derived discoipyrroles, namely congener D. This synthesis, which used methodology developed during the course of the aforementioned syntheses of the discoipyrroles A and B, involved, as key steps, the MoOPH-mediated oxidative cyclization of precursor E and this was followed by conjugate addition and redox processes. The fifth and final part of this thesis is comprised of Publication 5. This patent details inventions related to methods for preparing a variety of discoipyrrole-like compounds and novel analogues, as well as pharmaceutical compositions comprising these compounds and their possible use in therapeutic settings. For example, compound F, which incorporates a discoipyrrole-like core structure, was synthesized in four steps from indole and involving the aforementioned MoOPH-mediated oxidative cyclization as one of the key processes. The Appendices to the thesis are comprised of a series of reports arising from single- crystal X-ray analyses of certain key compounds synthesized by the author. Drs Jas Ward, Paul Carr or Anthony Willis, members of the Research School of Chemistry’s Crystallographic Analysis Unit, conducted these analyses. Show more