Discovery and total synthesis of biologically significant fungal metabolites

Abstract

Presented within this thesis is research focused on the discovery and total synthesis of a number of fungal metabolites which are biologically significant. The massive impact and potential of fungi and their metabolites for the pharmaceutical industry is discussed. The preparation of three different classes of fungal metabolites is presented, as well as the purification and elucidation of two classes of fungal metabolites. A review of pharmaceuticals used in Australia with their origins from fungal metabolites is presented in chapter one. A brief account of the discovery of the active metabolites is presented, along with details on the preparation of semi-synthetic derivatives or fungal metabolite inspired compounds. Chapter two details the synthetic investigation of the pestalotiopsones, chromone based fungal metabolites isolated from an endophytic fungus found in the mangrove Rhizophora mucronata. Ultimately, the first total synthesis of pestalotiopsone A (2.1) was achieved, from commercially available 3,5-dimethoxybenzoic acid. Subsequently, the first syntheses of pestalotiopsone B (2.2), C (2.3) and F (2.6) were achieved. The absolute configuration of pestalotiopsone D (2.4) and E (2.5) were elucidated through total synthesis of both the R and S enantiomers, allowing for the assignment of the stereochemistry of the natural compounds as the (+)-(S) enantiomers. Biological evaluation of the synthetic compounds against a panel of bacterial human pathogens was performed. Chapter three describes research towards the preparation of the cytosporone class of fungal metabolites, specifically those containing the rare 3-isochromanone skeleton. The work resulted in the syntheses of cytosporone A (3.1), (+/-)-C (3.3) and N (3.14) and the first syntheses of cytosporone J (3.10) and K (3.11). The synthesised natural products were evaluated for their biological activity against a number of clinical strains of human pathogens with all compounds displaying antibiotic activity. In chapter four, the investigation of newly isolated boletopsins is presented. Boletopsin 11 (4.11) and 12 (4.12) are p-terphenyl dibenzofuran compounds, isolated from the Papua New Guinean medicinal mushroom Boletopsis sp. The discovery and first syntheses of these fungal metabolites, along with the preparation of boletopsin 7 (4.7) are reported allowing for investigation of their antibiotic activity. Additionally, the preparation of tri- and tetra- brominated boletopsins is detailed resulting in the elucidation of two new natural products, boletopsin 13 (4.57) and 14 (4.15). Biological evaluation of the synthetic compounds and intermediates against a panel of bacterial human pathogens was performed. The work described in chapter five includes the elucidation of three fungal metabolites from a Chaetomium sp. of fungus. The isolation of the Chaetomium sp. from emu scat, and the purification and structure elucidation of chaetoglobosin A (5.1), B (5.3) and D (5.4) are detailed, along with the presentation of full spectroscopic data. The data obtained for the isolated fungal metabolites matched that presented in the literature.