The Synthesis of Chromane Meroterpenoids via Biomimetic Cascade Reactions

Abstract

In the current climate of synthetic organic chemistry the development of efficient, practical organic synthetic methodologies is of the utmost importance. Of particular interest is the rapid generation of molecular complexity. The field of biomimetic synthesis uses natural product biosynthesis as a guide, or source of inspiration for laboratory total synthesis. Nature often employs cascade or domino reactions which are chemically predisposed to occur. In this thesis the biomimetic synthesis of several chromane (benzopyran) natural products is reported. Chapter 1 is an introductory essay on the development of biomimetic cascade reactions with several examples from the past 40 years. This chapter also introduces ortho-quinone methides, a reactive intermediate which visited frequently throughout this thesis. Chapter 2 describes the three-step divergent synthesis of rhodonoid C and D, and synthesis of the related alkaloid murrayakonine D. Herein a new bioinspired acid-catalysed (3+2) epoxyolefin cycloaddition produced two rings, three stereocentres, one C-C bond, and one C-O bond in a single step. In Chapter 3 the first asymmetric synthesis of (−)-bruceol – a caged pyranocoumarin meroterpenoid – is detailed. The concise three-step synthesis utilised a biomimetic cascade initiated by a chemoselective Jacobsen-Katsuki epoxidation (and kinetic resolution) as the key step. This reaction could also be catalysed by a bacterial cytochrome P450 monooxygenase enzyme. NMR analysis of synthetic bruceol lead to the discovery of isobruceol, an isomeric meroterpenoid which had been misidentified as bruceol. This was confirmed by re-isolation, total synthesis, and X-ray analysis of isobruceol. Chapter 4 covers the synthesis of several bruceol related natural products via photochemical reactions. Chromenes are intrinsically good chromophores, and as such mild solar irradiation of the chromene precursors to bruceol and isobruceol completed the synthesis of the “cyclol” natural products eriobrucinol, isoeriobrucinol A, and isoeriobrucinol B by intramolecular [2+2] cycloaddition reactions. These chromenes also underwent singlet oxygen ene reactions to complete the synthesis of protobruceols II – IV. Chapter 5 looks at the biosynthesis of seven unnamed prenylated bruceol derivatives. Speculating on the observed isolated compounds, it likely all seven natural products had the common precursor we coined “prenylbruceol A”. It had previously been suggested the biosynthesis of these compounds involves what we consider to be an unlikely C alkylation. We put forth an alternative proposal involving O alkylation, followed by Claisen and Cope rearrangements to reach the correct connectivity for an intramolecular hetero-Diels-Alder reaction. This hypothesis was the basis for an attempted biomimetic synthesis of prenylbruceol A. After this approach was unsuccessful two alternative approaches were taken which were also ultimately unsuccessful. In lieu of a total synthesis, the isolation of the prenylbruceols was revisited through a mild extraction of Philotheca myoporoides using the pressurised hot water extraction technique. Gratifyingly, the extraction yielded prenylbruceol A proving that it is indeed a natural product. The natural prenylbruceol A was then used in a semisynthesis of three other members of the family (prenylbruceols B – D) using singlet oxygen chemistry.