Diels-Alder Reactions in Multi-Ring Forming Processes

Abstract

The Diels-Alder reaction is one of the most powerful reactions available to the synthetic organic chemist. Its greatest strength is its ability to generate the most prevalent cyclic system, namely the six-membered ring, in one synthetic operation from a versatile array of substrates. This thesis explores the application of the Diels-Alder reaction to multi-ring forming processes. Chapter 1 - By way of introduction, the first chapter provides a brief commentary on the pursuit of efficiency in synthetic organic chemistry and, as a matter of course, the power of the Diels-Alder reaction as a multi-bond forming process. As a preamble, it signposts these important themes, which have driven the investigations conducted in this thesis. Chapter 2 - The second chapter encapsulates two separate pieces of synthetic work. Firstly, the diene-transmissive twofold Diels-Alder reaction sequence of [3]dendralene with relatively un-activated cyclic dienophiles is developed. This methodology permits access to a diverse array of polycyclic structures, with twenty structurally distinct tetracyclic frameworks prepared. Secondly, Chapter 2 reports the application of this methodology to the concise enantioselective synthesis of the popular synthetic target and biologically-important marine natural product, (+)-xestoquinone. Notably, this work a) constitutes the first application of the parent [3]dendralene in total synthesis; and b) constructs three out of the four carbocyclic rings of the natural product via a Diels-Alder reaction, resulting in the shortest preparation of the molecule to date. This work is presented as a journal article draft for submission to Science. Chapter 3 - In the third chapter, the pentacyclic marine natural products, (+)-xestoquinone and (+)-halenaquinone are introduced in detail. Previous syntheses of these natural products as well as structurally similar compounds are comprehensively and systematically reviewed to place the preceding synthetic work (Chapter 2) in context. Chapter 4 - In Chapter Four, the diene-transmissive Diels-Alder reaction sequence of parent and substituted [3]dendralenes is developed to use enantiomerically pure, readily available, cyclic dienophiles for the first time. This methodology builds upon the key Diels-Alder reaction sequence reported in the synthesis of (+)-xestoquinone (Chapter 2) and enables the rapid synthesis of a range of chiral polycyclic frameworks in enantiopure form. Chapter 5 - Chapter Five reviews the development and application of the intramolecular Diels-Alder reaction to total synthesis and takes the form of an invited journal article drafted for publication in Angewandte Chemie. The application of the Diels-Alder reaction to multi- ring forming events is explored from a different perspective to that examined throughout the rest of this thesis.