School of Chemistry - Theses
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ItemRadiolabelled peptides and amino acids for PET imaging of cancer( 2019)Cell surface receptors, which are overexpressed in cancerous tumours, are feasible molecular targets for tumour imaging. The transmembrane G-protein coupled receptor CXCR4 is overexpressed in tumours and has a crucial role in organ-specific metastasis of tumour cells. Cyclic pentapeptides such as FC131 and analogues have been developed to bind with high affinity and specificity to CXCR4. Unfortunately, when FC131 is radiolabelled and evaluated as a PET imaging agent, it demonstrates high retention in the liver due to its lipophilic character. Sulfonation of aromatic groups, such as the phenolic group in tyrosine, results in a significant reduction of a peptide’s lipophilic character. Evaluation of sulfonated FC131 peptide analogues as PET imaging agents has been undertaken. In addition to radiolabelled peptides, PET imaging using amino acids has shown promise for tumour detection. 18F containing radiolabelled amino acids are transported across the cell membranes by amino acid transporter proteins. As such, several approaches to synthesise fluorothreonine, fluoroaspartic acid and fluorotyrosine analogues have been examined.
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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.
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ItemMaterials development to achieve thermally robust high performance organic photovoltaic devices( 2017)Organic photovoltaic (OPV) devices utilize solution-processable organic semiconductor molecules as the photoactive component. OPVs offer an alternative to inorganic semiconductors (e.g. silicon solar panels) with the dominant advantage of cheap fabrication costs due to roll-to-roll (R2R) printing processes. This is the fundamental driving force behind OPV materials and realising them as a commercial product. The photocurrent generation process relies on precise thin film structure of an interconnected network of an electron rich (donor, D) material and an electron deficient (acceptor, A) material in the active layer. Excitation of an OPV device generates a coulombically bound exciton that requires an energy offset between D and A materials due to their differing electron affinities in close proximity to one another, where the exciton can be split into free charge carriers, a radical electron and radical hole. Optimisation of morphology of the active layer and interfaces between the D and A materials is essential to enable a good charge generation/separation process. Polymeric organic semiconductors are typically used as the light harvesting donor (D) material with fullerene derivatives as the A material. However, batch-to-batch variations limit the reproducibility of these polymeric materials, and a prominent shift has begun towards donor molecular materials (MMs) with electron deficient end groups, π-bridges and an electron rich core, typically denoted as A-π-D-π-A. MMs have advantages due to their discrete structure, relative ease of purification and have shown high power conversion efficiencies (PCEs) on par with polymer- based systems. Unfortunately the discrepancy of PCEs between lab scale devices (0.1mm2, 13%) and R2R devices (3 - 7%) is large, but the gap is closing. This is primarily due to the lack of high performance materials that are suitable for the R2R printing process. There are inherent problems between scaling from small area devices and R2R printed solar cells. Firstly, different active layer deposition processes between small area (spin cast) and R2R (Gravure) result in considerably thicker layers for R2R processes. Secondly, R2R printing requires thermal annealing (TA) treatment to dry the back electrode typically at 120 °C for 10 min. The MM benzodithiophene terthiophene rhodanine, BTR and polymeric donor, p-BDT- BT have demonstrated high PCEs with PC71BM for lab scale OPV devices of 9.3% and 9.4% PCE, respectively. BTR OPV devices also maintain high PCEs for thick active layers (~8% PCE, 400 nm thick films) making it an excellent candidate for printing application. However, TA treatment of both donor materials results in significant performance degradation of the respective OPV device. In this thesis targeted donor materials design is used to develop thermally robust, high performance OPV devices (>8% PCE) around the known polymeric donor, p-BDT-BT and MM, BTR to facilitate scale up from small area (lab scale) devices to flexible, R2R processed large area devices and industrial applicability. A synthetic optimization of both the p-BDT-BT and BTR materials was conducted to improve the quantity of material to enable further device processing optimisations. Only 30 mg of p- BDT-BT and <1 gram of BTR could easily be isolated per batch under the previous synthetic conditions. The synthesis of p-BDT-BT could not be improved upon, as the polymerisation was anomalous and the polymer weight could not be predicted using the Carothers equation. The synthetic route to obtain BTR was changed from a Stille cross coupling to a Suzuki-Miyaura cross coupling that proceeded with a key intermediate that was synthesised on 0.6 mol scale. The synthesis of two new series of MMs was investigated where the conjugation length of BTR was decreased or increased by 3-hexyl thiophene units to give the BXR series or the rhodanine electron deficient end group was changed for stronger electronegative moieties to give the BTA series. Both the BXR and BTA series were investigated for their chemical and physical properties to improve the PCE of OPV devices with PC71BM and maintain high performances after TA treatment. The conjugation compression/extension for the BXR series focused on changing the molecular size of the MM and its diffusion rates in a blend matrix with PC71BM, as BTR/PC71BM films show increased domain sizes (larger than exciton diffusion limits) upon TA treatment that may account for the loss in OPV device PCE. Furthermore, changing the conjugation length has impacts on the absolute energy levels of the HOMO and LUMO molecular orbitals and therefore its optoelectronic properties affecting charge generation and separation. This design strategy concluded by extending the π-bridge of the BTR MM chromophore by two (BQR) or four (BPR) 3-hexyl thiophene units in the π-bridge an improved device PCE (highest PCE of 9.4% for BQR) was achieved, and this high performance was maintained after TA treatment (8.9% PCE) with little change observed in the morphology of the blend. Increasing the electronegativity of the acceptor end groups of the BTA series directly impacts the HOMO and LUMO energy levels and intramolecular charge transfer state causing a red shift in the absorption profile. This results in increasing the amount of usable light in the spectrum to be converted to electrical current in OPV device operation. The subtle changes at the end of the MM will also impact the crystallinity and morphology of the blend active layer to achieve thermally robust OPV devices. However, only one of the five new BTA derivatives exhibited high PCEs in OPV devices with PC71BM, known as the BTB MM (8.8% PCE). All other BTA derivatives had PCEs of <5% under all annealing conditions tested and no improvement was observed for TA BTB devices, exhibiting the same degree of performance degradation as BTR devices. However, further device processing optimisations is required for these BTA materials as low fill factors (~60%) were obtained suggesting that they require different fabrication conditions to optimise the blend morphology and/or their electronic nature may be unfavourable for charge generation. Finally, the best performing MM, BQR was investigated using transient absorption spectroscopy to gain a better understanding of the charge generation/separation process of this system. Furthermore, as the MM BTR had been previously investigated under the same conditions this allowed a comprehensive picture to be established of these MM systems and their photogeneration charge behaviour. Whilst BQR OPV devices maintain high PCEs after TA treatment, TAS indicates a highly crystalline thin film is developed with passive solvent vapour annealing treatment (similar to BTR) but is enhanced upon TA treatment. This conclusion is based on the observation of two kinetic profiles of the radical cation (hole polaron) signal that can be spectroscopically probed. The behaviour may arise due to an electro-absorption (EA) signal where, as the formation of free charges proceeds, the exciton diffuses to an interface and the hole and electron remain coulombically bound but are localized on the respective donor and acceptor domains in the blend matrix. If a highly crystalline interface is present a dipole like electric field is generated assisting in the charge separation process. This EA effect is not commonly observed in OPV materials but has been attributed to one of the reasons for efficient charge generation/separation processes in high PCE OPV systems. Interestingly, this phenomenon was not seen in the BTR material but only in BQR and may be further evidence as to why this material maintains a high PCE after TA treatment. Collectively this thesis presents a synthetic design strategy for two classes of MM systems (BXR and BTA) designed around the BTR material. The importance of the molecular structure and morphological implications of these new MMs provides a greater understanding of the charge generation/separation processes for future materials design considerations to enable high performance large area flexible OPV devices to be fabricated and have commercial applicability.
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ItemSubstrates, substrate mimics and inhibitors of bacterial and fungal mannanases and transmannosidases( 2016)Glycoside hydrolases are a diverse group of enzymes that have been classified into more than 130 sequenced based families. Glycoside hydrolase family 76 (GH76) is poorly characterized and is populated exclusively by bacterial and fungal members. The only known biochemical function for members of this family has been described for bacterial enzymes, termed α-1,6-mannanases, which hydrolytically cleave α-1,6-mannans, such as those found in the fungal cell wall. Separately, it has been hypothesized that certain fungal members, termed DCW1 and DFG5, are transmannosidases, with the ability to cleave an α-mannosidic linkage within the glycosylphosphatidylinositol (GPI) glycan of cell wall proteins, and then catalyze the formation of a new glycosidic linkage to the cell wall glycan, resulting in covalent attachment of mannoproteins to the fungal cell wall. The first part of this thesis details part of a large collaborative effort dedicated to establishing a detailed chemical mechanism for the foundation member of glycoside hydrolase family 76, Aman6 α-1,6-mannanase from Bacillus circulans. In an effort to obtain non-hydrolyzable substrate mimics, a series of S-linked α-1,6-oligomannosides were synthesized using alternative [2+2+2] approaches that involve assembly from either the reducing end or the non-reducing end. In the first approach, involving construction from the reducing end, coupling of a disaccharide thioacetate with a 6’-iodo reducing end disaccharide, followed by activation of the resulting tetrasaccharide to a 6’’’-iodide, and iterative coupling with the same disaccharide thioacetate afforded an S-linked hexasaccharide, as well as the intermediate di- and tetrasaccharides. In the second approach, involving construction from the non-reducing end, coupling of the above disaccharide thioacetate with an anomeric S-trityl protected 6’-iodo disaccharide, afforded an S-trityl tetrasaccharide, which was converted was converted to a tetrasaccharide thioacetate, which was in turn coupled with the same anomeric S-trityl protected 6’-iodo disaccharide to afford the hexasaccharide, which was finally elaborated to the methyl thioglycoside. X-ray crystallographic studies with the catalytic domain of Aman6 (BcGH76) and the synthetic S-linked oligomannosides provided evidence only for binding of sugar residues in the -3/-2 subsites, and no active site spanning complexes could be obtained for the wildtype enzyme. However, mechanistically informative complexes were obtained with α-1,6-mannosylisofagomine (ManIFG) and an active-site spanning complex with α-1,6-mannopentaose and a catalytically disabled mutant. In tandem with combined quantum mechanics/molecular mechanics calculations, a conformational itinerary for the enzyme-catalyzed reaction was proposed. The second part of this thesis details efforts to develop a non-hydrolyzable trisaccharide homologue of ManIFG that contained only S-linkages. Building upon the methodology and key intermediates developed in the previous part, S-linked di- and trisaccharide isofagomines were readily assembled. Crystallographic studies with BcGH76 revealed the disaccharide to bind unexpectedly in the -3/-2 subsites; the trisaccharide bound in a more orthodox fashon in the -3/-2/-1 subsities, but even so bound without proper engagement with the catalytic machinery, and in particular the catalytic nucleophile. We conclude that the introduction of one or more S-linkages substantially perturbs the structure of the S-linked oligomannosides such that they are poor mimics of substrate. The final chapter of this thesis discloses the synthesis of a GPI anchor fragment. Two tetrasaccharides, α-Man-1,2-α-Man-1,6-α-Man-1,4-α-GlcN-OMe, and the corresponding acetamide, were prepared using a novel procedure inspired by previous work of F. Kong. The route is notable for use of only ester, acetal and amide protecting groups, and unlike previous work, the tetrasaccharides were deprotected. It is anticipated that these tetrasaccharides may prove of use in obtaining direct experimental evidence in support of mannoprotein cross-linking into th fungal cell wall catalyzed by the family GH76 enzymes DCW1/DFG5.
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ItemExploring the Petasis reaction through amino acid synthesis( 2015)The Petasis reaction was reviewed and shown to be a versatile and efficient reaction for the synthesis of nitrogen containing compounds and α-amino acids. Many different amines and amine equivalents can be used in the Petasis reaction, in conjunction with a wide variety of aryl and vinyl boronic acids and esters, and a small selection of aldehydes. Chiral reagents can enforce stereochemical control in the reaction. Certain chiral amines and chiral amine equivalents give the highest selectivity. Several limitations remained for the Petasis reaction: yields were low with sterically small amines and the organoborons were largely limited to aryl, heteroaryl and vinyl derivatives. These limitations were addressed to make the Petasis reaction a more well-rounded and useful synthetic method. tert-Butyl sulfinamide was explored as an amine equivalent and the kinetics of the Petasis reaction with this reagent were investigated through the use of in situ FT-IR and 1H NMR spectroscopy analysis. tert-Butyl sulfinamide and glyoxylic acid both had rate orders of one, whereas styrenyl boronic acid had a rate order of two. This accounted for an observed dramatic increase in reaction rate. A mechanism for this reaction system was proposed, in which the boronic acid acts as both a reagent and as a Lewis acid catalyst. Allyl boronic acid pinacol esters were synthesised by palladium catalysed borylation of allyl alcohols, and then reacted with tert-butyl sulfinamide and glyoxylic acid to yield allyl glycine derivatives. Isolated yields of the final amino acids were excellent, but the diastereoselective ratios achieved were low to moderate. The addition of scandium(III) triflate to the allyl-Petasis reaction gave excellent control over the syn/anti configuration of the product, resulting in diastereomeric ratios in the order of >20:1. However, stereochemical control at the α-carbon was still moderate. A mechanism was devised to explain this observation and several supporting reactions were conducted. N-Methyl tert-butyl sulfinamide was synthesised racemically in a single step from the commercially available tert-butyl sulfinyl chloride and methylamine solution. The product was isolated in a pure yield of 98%. Racemic N-methyl tert-butyl sulfinamide was applied to a modified allyl-Petasis reaction, which employed molecular sieves to promote the formation of the initial iminium ion, to yield N-methyl amino acids in a quick and efficient manner. The use of scandium(III) triflate gave excellent control of the syn/anti configurations. Enantiopure N-methyl tert-butyl sulfinamide was also synthesised and applied to the Petasis reaction, resulting in excellent yields and stereochemical control. This work demonstrated the robust and widely applicable nature of the Petasis reaction as a method to synthesise α-amino acids in an efficient manner. The Petasis reaction can therefore be utilised in the chemical total synthesis of more complex natural products containing unusual amino acids residues.