School of Chemistry - Theses

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    Towards the synthesis of the emestrin family of natural products
    Fisher, Brendan ( 2018)
    A Cope rearrangement of a vinyl pyrrole epoxide (397) was utilised to form the dihydrooxepino[4,3-b]pyrrole core (398) of the emestrin family of natural products which involved the first examples of the dearomatisation of pyrrole in this type of rearrangement. It was found that an electron withdrawing ester substituent on the C2 position of the epoxide was essential for the [3,3]-rearrangement to occur. The vinyl pyrrole epoxides were synthesised in an efficient manner by a vinylogous Darzens reaction. Density functional calculations showed lower transition state energies for Cope rearrangements of epoxides with C2 esters when compared to the unsubstituted substrates which agreed with the observed experimental results. Silyl substituted vinyl bromide esters also participated in the Darzens reactions to give the desired vinyl pyrrole epoxides in good to excellent yields. Only the triethoxysilyl vinyl epoxide 313c underwent Cope rearrangement to provide the fully substituted emestrin core dihydrooxepine. The anion derived from an aryl bromosulfone did not give the Darzens product but underwent a previously unobserved stereoselective trimerization to afford the cyclohexene 343 as a single diastereoisomer. A mechanistic rationale involving SN2’ additions, [3,3]-Cope rearrangements and a stereoselective intramolecular conjugate addition was proposed and this was supported by density functional theory (DFT) calculations. A four-step total synthesis of biaryl ether natural product violaceic acid (11) is described. The steps include an SNAr reaction to afford the biaryl ether 136, tin chloride-mediated chemoselective reduction of the nitro group to amine 135. A Cu-mediated Sandmeyer reaction of 135 gave violaceic acid methyl ester 374 which is hydrolysed to give pure violaceic acid 11. An improved synthesis of the known biaryl iodide 119 is also described via a Sandmeyer reaction of amine 135.
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    A journey of synthetic chemistry towards immunogenic glycolipids and non-lipidic antigens
    Smith, Dylan Glendon Martin ( 2018)
    Microbes, both pathogenic and commensal, produce a wide range of glycolipids that act as unique molecular signatures. The ability of the human immune system to fight infection as well as to modulate commensal organisms are active areas of research. Microbial glycolipids are known to interact with the immune system though discrete protein families including CD1 and Mincle. The main challenge in the study of such systems is the difficulty in, and often impossibility of, obtaining pure, homogeneous material from natural sources. We synthesised four classes of molecules of both natural and unnatural origin to investigate their potential to modulate the human immune system through the CD1 and Mincle axes. Chapter 2 describes the synthesis of a range of cholesteryl α-glucosides that are found in members of the Helicobacter family, including the prominent gut bacterium Helicobacter pylori. As part of this work we investigated the effect of remote protecting groups on the sugar on the stereochemical outcome of glucosylation reactions. In chapter 3 we designed and synthesised a set of purely synthetic glycolipids drawing upon the structures of known Mincle agonists. We investigated these compounds for their ability to signal through Mincle as a prelude to the development of improved vaccine adjuvants that promote cellular and humoral immunity. Chapter 4 discloses the total synthesis of α-glucosyl and α-glucuronosyl diglycerides, found in both pathogenic and commensal organisms relevant to human health. Finally, we prepared a set of analogues of the unique, non-lipidic synthetic CD1d-restricted effector, PPBF, to explore structure activity relationships for T cell activation. In collaboration with immunologists, the synthetic glycolipids and non-lipidic antigens have been studied for their ability to activate CD1d-restricted natural killer T cells or for their ability to stimulate signalling through Mincle.