School of Chemistry - Theses
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ItemIt’s hip to be square: a cyclobutene diester approach to alkyl citrate natural products( 2018)This thesis features an enatiospecfic synthesis of a key alkyl citrate retron that was leveraged in the total syntheses of squalene synthase inhibitors (-)-CJ-13,982, (-)-CJ-13,981 and (-)-L-731,120 (featured in Org. Let. 2018, 20, 4255–4258). This key retron was prepared in 7 linear steps, requiring only 4 purification, with a 40% yield from (S)-(+)-γ-hydroxymethy-γ-butyrolactone. The synthesis highlights the application of a formal [2+2] cycloaddition and a remarkable acid-mediated rearrangement sequence to furnish the correct stereochemistry and oxidation level of the citrate moiety. This thesis demonstrates the shortest enantiospecifc total synthesis of (-)-CJ-13,981 to date, via the use of this key citrate retron, affording this natural product in 7.7% total yield over 10 steps. Efforts towards the squalene synthase inhibitor (-)-L-731,120 and the viridiofungins, a family of serine palmitoyl transferase inhibitors that have activity inhibiting hepatitis C replication, are also featured.
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ItemAmide assembly through Ag(I) promoted reaction of thioamides bearing self cleaving auxiliaries( 2018)Synthesis of amide bonds is an important issue in organic chemistry but is often overlooked as a contemporary challenge. Existing methods are reaching their limits and new chemical approaches are being developed. The Ag(I) promoted coupling reaction of thioamides with protected amino acids, recently reported in our group, leads to imide formation without epimerisation. This approach was shown to be general for various N-protected amino acids and peptides, including preparation of the pentapeptide thymopentin. However, hydrolysis of the imide is not always regioselective and occasionally results in undesired bond cleavage, leading us to investigate alternative solutions. Thioamides bearing a pendant nucleophile have been investigated as a general method for directed self cleavage of the imide. Amino acid derived o hydroxyphenacetyl thioamides have been applied to the Ag(I) promoted coupling reaction with various N-protected amino acids in good to excellent yields. Self immolative cleavage results in extrusion of benzofuranone to generate the desired amide bond. Application of this method to synthesise peptide based proteasome inhibitors was exemplified by the synthesis of epoxomicin natural product analogue and bortezomib analogue.
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ItemSynthesis and evaluation of Oncrasin based radiotracers for oncology( 2018)KRAS mutation status in cancer is an important contributing factor to development of cancerous tissue, with the mutation occurring in an estimated 1/3 of all cases of cancer, resulting in an aggressive phenotype. Development of a radiotracer based on the synthetic lethal Oncrasin-1 molecule was envisioned as a possible means of developing an imaging agent to identify and stage KRAS mutant tumours, with the potential to stratify patients into different treatment groups based off this. Small molecule drugs are routinely used as radiotracer leads, however, the mechanism of action of this compound is not well understood as it was identified in a synthetic lethal screen for KRAS. Despite the unknown mechanism of action, the ability of these compounds to differentiate between cancer types shows real promise as an imaging diagnostic to aid in the differentiation between cancer treatment groups and improve treatment outcomes. To evaluate if this class of compound as a potential radiotracer, 7 fluorine containing analogues and derivatives of Oncrasin-1 were synthesized along with the parent compound to evaluate their potencies relative to the parent Oncrasin-1 and investigate their potential to differentiate between tumours harbouring different kRAS mutation status. In this evaluation, potency is used as a surrogate marker for binding affinity, as development of radiotracers is a costly and resource intensive process. Along with the cold standards, precursors of the radiotracers were synthesized, initially through an attempted iodonium salt intermediate, however, it was discovered through the course of this work that the indole scaffold is incompatible with the oxidising conditions required to produce the hypervalent iodonium salt. Synthesis of an alternative pinacol boronic acid ester was therefore undertaken and precursors for 3 radiotracers were successfully produced, with a fourth radiotracer production being achieved through a post labelling reduction reaction. Radiosynthesis was successfully undertaken of 18F labelled KAM001, KAM002, KAM003 and KAM011, with decay corrected radiochemical yields between 10-18% for these radiotracers. 18F labelled KAM011 was successfully synthesized through a post labelling reduction of 18F labelled KAM001 resulting in a decay corrected radiochemical yield of 12%. Biological evaluation of compounds in colon cancer cell lines indicated improved potency and selectivity between the parent and two compounds tested in KRAS mutant cell lines and wild type cell lines, however, the potency testing in BRAF mutant cell lines gave inconclusive toxicity and cell cycle analysis. Preliminary radiotracer uptake studies were carried out in colon cancer cell lines and showed poor differentiation between KRAS mutant and KRAS wild type cell lines with the 18F KAM001 radiotracer. Further development in the understanding of these compounds since the beginning of this project indicate that the family of compounds likely have multiple mechanisms of action, with one of the molecular targets being identified as the enzyme Sulfotransferase 1A1, also known as SULT1A1, which has been shown to be abnormally expressed in many types of cancer, including breast cancer. Identification of SULT1A1 expression in breast tissue can be a marker of cancer, as upregulation of this enzyme is abnormal in this type of tissue. Identification of the presence of this enzyme also has potential value as a prognostic indicator as it has been associated with abnormal metabolism of drugs and has been linked to improved Tamoxifen response in oestrogen sensitive cancers. Potency testing of the compounds showed good differentiation between the commonly used MCF-7 and MDA-MB-231 breast cancer cell lines, with cell cycle analysis showing different trends depending on the substitution pattern in sensitive MCF-7 cell line but no discernible trend in the insensitive MDA-MB-231 cell line. Preliminary radiotracer uptake assays showed differentiation between the cell lines with the 18F labelled KAM001 and even better differentiation with the 18F labelled KAM011 tracer. Subsequent stability and metabolism studies indicated good tracer stability for the 18F labelled KAM011 tracer for the imaging period required. Imaging studies with the 18F labelled KAM011 tracer showed good differentiation of tumours, with high tumour to muscle ratio found in sensitive tumours and visually apparent internalization of radiotracer. In insensitive MDA-MB-231 cell lines a low tumour to muscle ratio was observed, with a build-up of radiotracer around the peripheral tissue still showing the tumour visually. This thesis outlines the methods and procedures of synthesizing cold standards, precursors, and radiotracers which were developed from the Oncrasin molecule. These molecules have been used in biological evaluation and imaging studies which have shown improved potency over the parent compound in cell culture as well as the ability to effectively differentiate between tumour types in both in vivo and in vitro models, with the potential for stratification of patient groups pending further investigation.
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ItemTowards the synthesis of the emestrin family of natural products( 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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ItemTailor-made covalent organic-inorganic polyoxometalate hybrids: versatile platforms for the elaboration of novel molecular architectures( 2018)Covalent organic-inorganic polyoxometalate (POM or POMs) hybrids constitute versatile platforms for the elaboration of functional molecular architectures. This Ph.D. research project aimed to synthesize novel organic-inorganic POM hybrids using pre- and post-functionalization methods. The synthesis of organic-inorganic hybrids starting from POMs, known as direct functionalization, is a well-established synthetic procedure. However, as the complexity of the targeted functional system increases, a multi-step strategy relying on the post-functionalization of preformed hybrid POMs is necessary. Herein, both approaches are explored. Following hybridization of POM surfaces using organic units, ranging from small groups to large polymeric chains, this work provides a significant step forward in the rational design and synthesis of POMs, which permits the elaboration of POM based nanomaterials. At first, boronic acids and esters ligands were selected for POMs’ post-functionalization. Three organoboron functionalized Anderson-Evans and one organoboron functionalized Lindqvist POM were synthesized using Schiff base chemistry; with the general formulas of the Anderson-Evans POM hybrids being [MnIIIMo6VIO18((OCH2)3)CN=CHC6H4(B(OR)2)2]3− (where R = H, Me), [MnIIIMo6VIO18((OCH2)3)CN=CHC6H4(BO2(CH2)3)2]3-, with the formula of the Lindqvist POM hybrid being [VV6O13{(OCH2)3CN=CHC6H4B(OH)2}2]2-. These compounds have been characterized in the solid state by single-crystal X-ray diffraction (XRD), FT-IR spectroscopy and elemental analysis and in solution using Nuclear Magnetic Resonance (NMR) spectroscopy. This work has further been extended to organosilane functionalized mono and di lacunary Keggin POMs. Two organoboron functionalized Keggin POMs were synthesized using N, N'-dicyclohexylcarbodiimide (DCC) coupling; with the general formulas being [β2-SiW11O39{O(Si(CH2)3NHC=O-C12H17BO2)2}]4- and [γ-SiW10O36{O(Si(CH2)3NHC=OC12H17BO2)2}]4-. These compounds have been characterized in the solid state by FT-IR spectroscopy and elemental analysis and in solution using NMR spectroscopy. Later, the employment of microwave-assisted synthesis permitted the generation of novel mixed metal tris(alkoxo)molybdovanadates. The reaction of [β-Mo8O24]4- and [H3V10O28]3- with pentaerythritol or tris(hydroxymethyl)aminomethane yielded compounds with the general formula [V3Mo3O16(O3-R)]2- where R = C5H8OH or C4H6NH2. Post-synthetic esterification of the alcohol derivative yielded the acylated derivative [V3Mo3O16(O3-R)]2- where R = C7H11O2. Single-crystal X-ray Diffraction (XRD), NMR spectroscopy, High-Resolution Mass Spectrometry (HR-MS) and FT-IR spectroscopy have been used in combination to rationalize the structural isomerization observed within these systems. The rational design and synthesis of two novel covalent organic-inorganic hybrid polymers via Atom Transfer Radical Polymerization (ATRP), composed of either a Lindqvist POM macro initiator of formula [V3Mo3O19{(OCH2)3CNHC=OC(CH3)2Br}]2- or an Anderson-Evans POM macro initiator of formula [MnIIIMo6O18{(OCH2)3CNHC=OC(CH3)2Br}2]3- and pH-responsive poly(2 (diethylamino)ethyl methacrylate) (PDEAEMA) polymer, was investigated. POM macro initiators were characterized using single-crystal X-ray diffraction (XRD), 1H NMR spectroscopy, FT-IR spectroscopy, UV-Vis and elemental analysis; while POM-polymer hybrids were characterized using 1H NMR spectroscopy, FT-IR spectroscopy, thermogravimetric analysis (TGA) and UV-Vis spectroscopy to assess the integrity of the POM units. These POM-polymer hybrids self-assemble into nanoparticles via copolymerization with poly(2-(diethylamino)ethyl methacrylate)-b-poly(ethylene glycol) (PDEAEMA-b-PEG), when the pH is increased above the pKa of PDEAEMA. Dynamic Light Scattering (DLS) studies were conducted to investigate the size distribution of the nanoparticles, while disassembly studies proved that they respond to biologically relevant pH variations. These observations were supported by Cryo-TEM imaging which provided valuable direct visualization of the nanoparticles. Importantly, growing polymer chains from POM macro initiators offers an excellent control over the loading of the POM clusters inside the nanoparticles.
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ItemA journey of synthetic chemistry towards immunogenic glycolipids and non-lipidic antigens( 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.