Development of Chiral Auxiliaries from (-)-Levoglucosenone and Biomimetic Synthesis of Mitchellenes B–H

Abstract

<p>There is an increasing urgency to transition from a petroleum-based economy using environmentally damaging extraction to a sustainable and environmentally friendly alternative. This change will require chemists to face the task of finding green platform chemicals to replace those produced from fossil commodities, a challenge which requires the development of chemistries that utilise materials abundant in nature. The aim of this thesis was to chemically modify molecules that derive from plants and convert them into biorenewable chemicals such as chiral auxiliaries (Part I) and scaffolds for drug discovery (Part <b>II</b>).</p> <p><b>Part I. Development of Chiral Auxiliaries from (-)-Levoglucosenone</b></p> <p>The first part of this work was focused on transforming the chiral cellulose pyrolysis product (-)-levoglucosenone (LGO, <b>II</b>) into chiral auxiliaries that could be prepared in bulk, enabling resource savings and waste reduction.</p> <p>After having developed a reliable and scalable preparation protocol of LGO (<b>II</b>) from cellulose (<b>I</b>) using sulfuric acid in polyethylene glycol (Chapter 2), <b>II</b> was converted into several auxiliaries (Chapter 3) that were compared in terms of simplicity and efficiency of synthesis, as well as diastereoselective induction in chemical transformations. Among those chiral auxiliaries prepared, was compound <b>III</b> that could be obtained in three steps with an overall yield of 86%. This work is of significance as <b>III</b> could be produced on scale (>200 g) from inexpensive chemicals without the need for chromatography. Auxiliary <b>III</b> was successfully employed in the Lewis acid catalysed Diels-Alder (<b>V</b>, Chapter 4) and sulfaMichael reactions (<b>X</b>, Chapter 5) allowing access to important chiral building blocks and targets (<b>VI–VIII</b>). The selectivity of the asymmetric transformations could be explained by p-stacking interactions of the diaryl system with the reacting double bond. The mechanism by which Lewis acids promoted selectivity was determined through low temperature NMR experiments (<b>XI</b>, Chapter 4).</p> <p><b>Part <b>II</b>. Biomimetic Synthesis of Mitchellenes B–H</b></p> <p>The second part of this work focused on examining the secondary metabolites of the Australian bush plant E. Sturtii as a source of both new chemistry and potential scaffolds with drug-like properties.</p> <p>The phytochemical investigation (Chapter 7) led to the discovery of four new natural products (<b>XVII–XX</b>) as well as large quantities (>20 g) of muurolane <b>XII</b> that could be isolated without the need for chromatography. During the investigations of the biosynthetic origins of the mitchellene family, <b>XII</b> was successfully converted into mitchellene B (<b>XVI</b>, Chapter 8) via a short and efficient series of domino processes. The key steps were redox isomerisation-esterification, dynamic kinetic resolution/Stetter reaction and reductionepimerisation. The synthesis was completed by an α-selenation with LDA/PhSeCl followed by an oxidative elimination using hydrogen peroxide affording <b>XVI</b> with an overall yield of 22%. Thus, the three additional stereocentres were selectively installed in only four steps. Starting from <b>XII</b>, the mitchellenes <b>XVII–XX</b> could also be obtained. <b>XVI</b> proved to be a particularly interesting scaffold for drug discovery, not just because it was abundant, but also for its substrate controlled stereoselective reactions on its double bond, without the need for ligands or catalysts for control. This led to the development of a screening library (Chapter 9) from which was identified two non-toxic, antifungal compounds (<b>XVII</b> and <b>XXIII</b>). During this work, an unusual syn-b,d-diarylation of <b>XVI</b> under Pd-mediated reductive Heck conditions (<b>XXVI</b>) was also discovered.</p>