School of Chemistry - Theses

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Start date: 2021 × Subject: Acyloins × Subject: Chemistry ×

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    Synthesis of Myxobacteria Metabolites and Analogues and Development of Metal Complexes for the Mukaiyama Hydrogen Atom Transfer Reaction
    Ricca, Michael ( 2022)
    The spirangiens are a series of spiroketal containing polyketide natural products which are potently active against human and mouse cancer cell lines, and interleukin 8 expression. Oxidation at the C20 position occurs after polyketide synthesis is complete. Acyclic compounds lacking oxidation at the C20 position have been isolated, but never cyclic species; as such C20 deshydroxy spirangiens could be undiscovered natural products. This work saw the completion of the synthesis of a C20 deshydroxy derivative of spirangien M522, utilising a series of asymmetric aldol reactions to construct the polyketide backbone. A cross metathesis reaction followed by spirocyclisation forged the core, which was elaborated to by a Roush crotylation/Weix coupling sequence. Cell death, and cell growth inhibition assays in immortalised bone marrow derived macrophages (murine) and colon adenocarcinoma cells (murine), indicated that derivative retained its activity, and that C20 oxidation was not crucial for bioactivity. The Mukaiyama-Isayama hydration reaction hydrates a polar or non polar alkene to an alcohol via a C centred radical. Under Mn, Co or Fe catalysis, with phenylsilane in an alcoholic solvent, a metal hydride species forms which is able to facilitate hydrogen atom transfer (HAT) and generate the requisite radical. In the absence of oxygen alkene reduction occurs, and this also represents a major side product in the Mukaiyama hydration. In the presence of a Michael acceptor, the radical can undergo coupling, forging a new C-C bond. Three cis-beta octahedral complexes with a SALPN type ligand; Mn(SALPN)acac and Co(SALPN)acac were synthesised. These complexes were active in the Mukaiyama hydration of esters and ketones, and Fe(SALPN)acac successfully catalysed olefin coupling reactions. Compared to the control catalysts, the new complexes, showed superior reactivity (reduced side product formation, lower catalyst loading) or unusual reactivity (promotion of an acyloin rearrangement). Furthermore, the cobalt complex facilitated the synthesis of 7 acyloin natural products.