Browsing by Author "Hunter, Roger"
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- ItemOpen AccessAn Activity-Based Proteomics Approach for Identifying Ajoene's S-thiolation Protein Targets in Blood and Cancer Cells(2021) Kusza, Daniel Andreas; Hunter, Roger; Kaschula, CatherineGarlic has been used as a medicinal plant since ancient times and is well-documented to produce several organosulfur compounds (OSCs) that show promising chemopreventative and therapeutic properties. The vinyl disulfide sulfoxide garlic rearrangement product, ajoene, is one of the phytochemicals in garlic that possesses a broad spectrum of biological activities against a variety of cancers both in vitro and in vivo. Our group's previous investigations into ajoene's cytotoxicity have shown that it modifies proteins by S-thioallylating redox-sensitive cysteine residues through a thioldisulfide exchange reaction. Further investigations into this exchange have been the primary aim of this PhD thesis using a biotinylation protocol for trapping out the said protein targets of ajoene to link them to anticancer signalling pathways. The thesis begins in Chapter One with an overview of the chemopreventative and antitumour activity of OSCs from garlic in which a particular emphasis is placed on OSC structure and mechanistic aspects of their cancer biology. Chapter Two discusses the various aspects of ajoene as the target natural product of the thesis. These include its biosynthesis and synthesis, in both native form and as derivatives, for SAR studies, for which a UCT synthesis is described. Mechanistic aspects of ajoene's cytotoxicity towards cancer cells in terms of S-thioallylation via disulfide exchange are then discussed at length. Of crucial importance for the chemical biology studies to follow was the conclusion that S-thioallylation by ajoene is regioselective at the vinyl sulfur, as well as effectively irreversible with suitably reactive cysteine thiol groups. Chapter Three presents an in-depth Chapter on the metabolism and pharmacokinetic properties of ajoene and selected derivatives in a murine xenograft model for human oesophageal cancer (WHCO1). This concluded, disappointingly, that no significant differences in terms of tumour volume, mass and growth rate were observed compared to an untreated control. A follow-up study using a small library of eight ajoene derivatives varying ajoene's different functional groups in a blood stability study, revealed a proportional relationship between the in vitro half-life in blood and the IC50 value for WHCO1 cancer cells. This led to mass spectrometry studies showing that ajoene Sthioallylates the βCys-93 residues in haemoglobin, a chemical modification that most likely explains both ajoene's blood instability and its lack of antitumour activity in vivo. Chapter Four describes the organic synthesis and characterisation of four biotin-ajoene chemical biology probes for chemical biology investigation of S-thiolation in which the background theory of activity-based protein profiling and biotin affinity purification is presented. In the synthesis of these probes, chemical stability emerged as a major stumbling block. Gratifyingly, after several trials, the fourth probe designed and constructed, using a simplified tether involving a convergent “Click”-strategy, turned out to be chemically stable. Subsequent biological validation studies confirmed that the probe retained cytotoxicity against cancer cell lines in vitro (human epithelial mammary gland adenocarcinoma cancer cells (MDA-MB-231) and WHCO1) and shared the same compound–target interaction as its parent ajoene; namely, the regioselective S-thiolation of cellular proteins. Chapter Five constitutes a proteomics study into ajoene's primary protein targets in the MDA-MB-231 cell line using our biotin-ajoene probe. Streptavidin-coated magnetic beads in conjunction with an affinity purification mass spectrometry protocol allowed the isolation and identification of 633 protein targets for ajoene in the MDA-MB-231 proteome. Pathway analyses revealed that ajoene interacts with several targets involved in the control of cell cycles (G2/M cell cycle checkpoint), energy metabolism (glycolysis and pentose phosphate pathway) and the regulation of protein metabolism (translation, folding, quality control and degradation), which supports previously reported cytotoxic modes of action for ajoene against MDA-MB-231 cancer cells. Importantly, we have validated that ajoene S-thioallylates glutathione S-transferase (GSTP1), which is a known cancer-therapy target in breast cancer. Overall, this study complements findings on the cancer-cell protein targets of allicin from crushed garlic, by identifying proteins regulating apoptotic and antiproliferative signalling pathways. These findings support the hypothesis that the anticancer activity of ajoene is due to its S-thioallylation of proteins essential to cellular functions. The thesis concludes with comprehensive experimental and reference sections.
- ItemOpen AccessAn excursion into the synthesis of novel flavanones(2022) Mansoor, Rukaya; Hunter, RogerThe aim of this project was to develop new methodology for synthesizing flavanones asymmetrically in a manner that could be extended to the synthesis of novel indoloflavanone analogues. The designated approach was via an asymmetric aldol reaction catalysed by a chiral organocatalyst followed by an intramolecular Mitsunobu reaction. Following a review of the existing methodologies for the synthesis of racemic and asymmetric flavanones and various flavan analogues, an initial model reaction between acetophenone and para-nitrobenzaldehyde returned the aldol product using (S)- proline tetrazole as organocatalyst. Several experiments on optimization were conducted to identify the best stoichiometry/conditions as ketone (4): aldehyde (1): catalyst (10%): DMSO (2): H2O (2) at room temperature for three days, which returned the desired aldol product in 64% yield and a pleasing ee of 93%. Interestingly, it was found that the amount of water in the reaction played a role in dictating the stereogenicity of the product. Unfortunately, changing the ketone to the required 2- hydroxyacetophenone for a flavanone synthesis resulted in a very sluggish reaction, delivering the product in a very low conversion (~ 10%) after 3 days. This was attributed to the poor electrophilicity of the ketone carbonyl group in the enamine formation step because of the ortho electron-releasing phenolic hydroxyl group. For increasing the electrophilicity, the approach was changed to using a Knoevenagel condensation reaction between an activated β-ketoester derivative of 2- hydroxyacetphenone and para-nitrobenzaldehyde according to the optimised aldol reaction conditions. Although this successfully delivered chemically the required flavanone precursor with a satisfactory yield (77%), there was no enantioselectivity, which was attributed to either the chiral entity being too far away from the prochiral site or because of an increased rate of iminium ion hydrolysis prior to the oxa-Michael cyclisation step due to the electron-withdrawing ester group. Gratifyingly, however, this methodology could be applied to synthesis of a 2-indolylflavanone (in racemic form) as a B-ring indolylflavanone, setting up a prototype for a future, more detailed study. With regards to A-ring modification, 3-acetyl-2-hydroxyindole and various protected variants were tried out as the acetophenone partner in the methodology only to meet the same problems as described above due to strong electron donation into the carbonyl group. Similarly, we weren't able to extend this to a -ketoester variant via acetyl group C-carboxylation as before. Eventually, the problem was resolved by a C-3 acylation of N-Boc-2-indolone with cinnamoyl chloride, rendering a precursor for indoloflavanone synthesis via oxa-Michael cyclisation. Although the latter was not achieved because of time constraints, this acylation study opens up a novel entry for further study into the synthesis of A-ring indoloflavanones for biological evaluation.
- ItemOpen AccessAsymmetric Total Synthesis of the Pentacyclic Indole Alkaloid (+)-Tacamonine(2019) Ferreira, Jasmin; Hunter, Roger(+)-Tacamonine, a natural product isolated from the Central African plant Tabernaemontana eglandulosa, belongs to the relatively new tacaman class of pentacyclic monoterpenoid indole alkaloids. Its close structural similarity to the potent cerebral vasodilator (-)-vincamone has promoted several efforts towards its synthesis, culminating in the appearance of two asymmetric and seven racemic syntheses in the literature. This dissertation details the successful execution of our strategy for the concise, highly-efficient, asymmetric total synthesis of (+)-tacamonine. Chapter 1 serves as an introduction to the tacaman class, including the proposed biosynthesis for members of this class, followed by a review of the reported synthetic approaches to tacamonine. Chapter 2 details the evolution of our approach based on the use of key radical cyclization methodology to ultimately accomplish a total synthesis of the target. An investigation of the diastereoselectivity displayed in the radical cyclization step is also described through computational methods. Our route followed a novel ABC to ABCD to ABCDE ring-construction strategy, which first involved the synthesis of 3,4-dihydro--carboline as well as a chiral acid ester fragment that was acquired through Evans’ auxiliary-controlled alkylation chemistry. The latter set the absolute configuration at C-20 bearing the ethyl group in the D-ring, and thereafter, the two fragments were coupled together before being advanced to the radical cyclization precursor. Radical cyclization then led to the formation of the desired cis D/Ering junction in a diastereomeric ratio of 10:1, the major diastereomer displaying the required C-3/C-14 to C-20 anti-diastereoselectivity. Subsequent global reduction and oxidation/E-ring formation processes afforded the target in 8 steps over 10 operations in 25% overall yield and in 96% enantiomeric excess. X-Ray crystallographic structure determination provided conclusive evidence for the formation of the target.
- ItemOpen AccessThe development of a radiolabelled macromolecule as a therapeutic agent for the treatment of cancer(2015) Driver, Cathryn Helena Stanford; Parker, Iqbal; Hunter, Roger; Zeevaart, Jan RijnOne of the major focus areas of anticancer therapy is the design of new radiotherapeutic agents that are able to specifically target and destroy cancer cells with minimal side effects and damage to healthy, normal cells. This thesis describes studies towards the synthesis of a macromolecular bioconjugate that was designed to: i) co-ordinate a radioisotope through a tetra-amine macrocycle (cyclam), ii) lead to passive tumour targeting via the EPR effect and a suitably large carrier such as human serum albumin and iii) induce active targeting through a glucose moiety recognised by the over-expressed glucose transporters on the surface of highly metabolically active cancer cells. The various cyclam functionalisation strategies explored were relatively unsuccessful, but eventually a bis-aminal cyclam was successfully converted, through nucleophilic substitution, into a precursor pro-conjugate: a di-functionalised cyclam containing a β-glycoside tether and a long chain primary alkylamine. The glycoside tether was synthesised via glycosylation of a glycosyl iodide with decandiol followed by oxidation of the terminal hydroxyl group to an acid chloride for cyclam acylation. The second linker attached to cyclam was synthesised by conversion of decanediol to a brominated alkyl amine. This amine would then be converted into a maleimide functionality suitable for Michael addition with a free thiol group contained within the proposed bio-carrier to form the desired bioconjugate. Further studies described towards the synthetic construction of the bioconjugate include: 1) The construction of a maleimide group 2) The attachment of an imaging radioisotope, ⠹⠹m Tc, or therapeutic isotope, ¹⠰³ Pd, to the pro- conjugate and other glucose-cyclam precursors 3) The determination of the potential uptake of the bioconjugate through glucose transporters by using a fluorescent dansyl-glucose compound as a model and monitoring its uptake into WHCO1 oesophageal cancer cells. 4) The HPLC analysis of the coupling of a glucose-maleimide model compound to bovine serum albumin to investigate the Michael addition of the free thiol in HSA to a maleimide 5) The development of a potentially alternative nanoparticle carrier by synthesis of palladium and magnetic nanoparticles with commercially available thioglucose or glucuronic acid moieties as the surface targeting and stabilising agent. In summary, this thesis outlines a number of synthetic, radiological and biological aspects towards the development of a fully functioning radiolabelled macromolecular bioconjugate that could be tested for improved targeted cancer radiotherapy.
- ItemOpen AccessDevelopment of HI-236 as an HIV NNRTI and as a component of novel bifunctional HIV-1 RT inhibitors of the type (NRTI)-spacer-(HI-236)(2009) Younis, Yassir Eltayeb; Hunter, Roger
- ItemOpen AccessDiscovery of benzamides and triarylimidazoles active against Plasmodium falciparum via haemozoin inhibition : high throughput screening, synthesis and structure-activity relationships(2015) Wicht, Kathryn Jean; Egan, Timothy J; Hunter, RogerNew antimalarials are desperately needed to overcome growing P. falciparum resistance to the current drugs. Successful quinoline-based drugs target haemozoin formation causing a cytotoxic accumulation of free haem (Fe(III)PPIX) in the parasite, a target which remains promising for future treatments. Much research has been undertaken on the quinoline antimalarials, which has led to several hypotheses of haemozoin inhibition and drug accumulation mechanisms, however, relatively few studies have been carried out for haemozoin antimalarials with alternate chemotypes. High throughput screening (HTS) can be used to identify novel scaffolds that inhibit β-haematin (βH - synthetic haemozoin) formation and which have favourable P. falciparum activities. In this project, HTS has been carried out on 43,520 small, organic, drug-like compounds as part of a larger screen of 144,330 Vanderbilt University Institute of Chemical Biology (VU) chemical library compounds and 530 were found to be good inhibitors of βH relative to the chloroquine (CQ) and amodiaquine (AQ) controls. A further 171 compounds were found to inhibit parasite growth, showing improved hit rates from previous HTS efforts. Two scaffolds (A=benzamides and B=triarylimidazoles) were selected for further analysis, whereupon analogues were synthesised.
- ItemOpen AccessFluorescent ajoenes as a mechanistic probe for cancer(2010) Cotton, Jonathan; Hunter, Roger; Caira, Mino R; Parker, IqbalThis thesis describes the development and synthesis of several novel ajoene mimics. The first of which, (E/Z)-1,8-(Bis-p-methoxyphenyl)-2,3,7-trithia-octa-4-ene 7-oxide 17, was developed as a continuation of SAR studies performed by our group, involved the placing p-methoxyphenly groups on the termini of the ajoene pharmacophore.
- ItemOpen AccessThe formation of cyanoborate liquid clathrates with water or cresol as promoters(1996) Davis, Bridgit Helen; Hunter, Roger; Linder, Peter WIf host and guest components form a liquid clathrate only when a third component is present, the third component is a promoter of liquid clathrate formation. The importance of promoters was verified by promoting liquid clathrate formation in guest-host combinations which do not form liquid clathrates without a promoter. The validity of the conventional definition of liquid clathrates was probed with respect to the absence of host in the excess guest layer and with respect to the fixed maximum guest to host ratio. A model which allows for the effect of promoters on liquid clathrates was proposed. The II electron rich nature of the guest is important in the model, so the guests, furan, thiophene and benzene, were used to probe the dependence of cyanoborate liquid clathrate formation on the IT electron rich nature of the guest. Differences in the electronic nature of the promoters, water and cresol, caused differences in the ease of promoting cyanoborate liquid clathrate formation, in the stability and composition of the liquid clathrates formed, and in the interactions between the promoter and the components of the liquid clathrate (host anion, host cation and guest). In promoting liquid clathrate formation, the promoter separated the host cation-anion pairs so that the guest interacted favourably with the host cation. The guest to host ratio was dependent on the amount of promoter present in the liquid clathrate, and favourable interactions of the promoter with liquid clathrate components caused the liquid clathrate to expand as it accommodated increased amounts of promoter and guest. Favourable interaction of the promoter with the components of the liquid clathrate compensated for the energy required to separate the host cation-anion pairs.
- ItemOpen AccessHaematin-Quinoline interactions and structure-activity relationships in the antimalarial chloroquine and related compounds(2002) Kaschula, Catherine Hart; Egan, Timothy J; Hunter, RogerThe nature of the ferriprotoporphyrin IX (Fe(III)PPIX) antimalarial drug target and its interactions with aminoquinolines was investigated spectrophotometrically. The antiquity of malaria, which is caused by protozoan parasites of the genus Plasmodium, is demonstrated by the host specificity of over 100 parasite species found in reptiles, birds and mammals. The four species of plasmodia that infect man are P. vivax, P. malariae, P. ovale and P. falciparum; of which P. falciparum is the most deadly (Bruce-Chwatt 1981 ).
- ItemOpen AccessHemiaminals : a new chemotype for organocatalysis(2015) Ramaotsoa, Valerie; Hunter, RogerJorgensen and List introduced enantioselective α-amination of an aldehyde with an azodicarboxylate as the electrophile using L -proline enamine catalysis in 2002. Following borohydride reduction, the α-hydrazino alcohol was obtained in high yield (93-99%) and enantioselectivity (86-97%). Application of the enantioselective α-amination reaction to an acetal as a masked aldehyde was developed in our group recently, and in part I of this thesis results on extending this chemistry to the α-amination of N-protected hemiaminals from N-heterocycles are reported, in which it was found that the reaction only worked with the carbonyl group exo to the ring. In the case of the hemiaminal derived from N-Boc or N-CBz 2-pyrrolidinone an amination with proline catalyst in acetonitrile over 3 days gave α-aminated products in high ee (77-84%). N-N bond hydrogenolysis using Raney Nickel and hydrogen, followed by oxidation to the lactam afforded the N -protected α-amino lactam in high enantioselectivity (78% and 8 6 %). In part II the development of a mild reduction of the N-N bond of the α-hydrazino amination products of straight-chain aldehydes is reported. The corresponding oxazolidinone- hydrazides are reduced to their oxazolidinones via a modified E1cB elimination using ethyl bromomalonate and potassium carbonate in acetonitrile. The reactions gave high yields (76-96%) and ees (83-95%) with a good chemoselectivity profile.
- ItemOpen AccessInsights into the mechanism of action of quinoline antimalarials against Plasmodium falciparum revealed by novel fluorescent analogues and chemical proteomics(2016) Woodland, John Geoffrey; Egan, Timothy J; Hunter, RogerFor centuries, quinoline-based drugs have formed the cornerstone of antimalarial treatment. Despite recent challenges posed by resistance, interest in these molecules persists. It is thus surprising that crucial details of their mechanism of action against the most virulent malaria parasite, Plasmodium falciparum, remain unresolved. This thesis develops new tools to generate deeper insights into the modes of action of the two major classes of the quinoline antimalarials against P. falciparum. These are the quinoline methanols, represented by the diastereomeric Cinchona alkaloids quinine and quinidine, and the 4-aminoquinolines, represented by chloroquine. Mechanistic studies of these antimalarials have typically focused on the inhibition of haemozoin biocrystallisation within the acidic digestive vacuole of P. falciparum. In order to conduct a comprehensive survey of the subcellular localisation of these antimalarials across the entire infected erythrocyte, a suite of novel fluorescent derivatives was designed and synthesised. Key physicochemical properties of these antimalarials were retained in order to preserve the interactions of these drugs with their putative target, ferriprotoporphyrin IX or Fe(III)PPIX. Versatile derivatisation of the alkaloids was enabled by a regioselective radical-mediated thiolene click reduction. 7-Nitrobenz-2-oxa-1,3-diazole (NBD) was identified as a suitable reporter fluorophore and was attached to the quinoline core by nucleophilic aromatic substitution. The length of the spacer chain between the quinoline and the fluorophore was varied by preparing NBD-labelled amino acids and their corresponding succinimidyl esters. A novel NBD-labelled chloroquine derivative was prepared by using its N-dealkylated analogue as a key intermediate. A single quinine derivative with an alternative fluorophore, bimane, was also prepared.
- ItemOpen AccessInterference with hemozoin formation represents an important mechanism of schistosomicidal action of antimalarial quinoline methanols(Public Library of Science, 2009) Soares, Juliana B R Corrêa; Menezes, Diego; Vannier-Santos, Marcos A; Ferreira-Pereira, Antonio; Almeida, Giulliana T; Venancio, Thiago M; Verjovski-Almeida, Sergio; Zishiri, Vincent K; Kuter, David; Hunter, RogerAuthor Summary Heme is an essential molecule to most living organisms, but once in a free state it exerts toxic effects. Blood-feeding organisms evolved efficient ways to detoxify free heme derived from hemoglobin digestion. A key mechanism present in some hematophagous organisms consists of the crystallization of heme into a pigment named hemozoin. Schistosoma mansoni is one of the etiologic agents of human schistosomiasis, a parasitic disease that affects over 200 million people in tropical and subtropical areas. Hemozoin formation represents the main heme detoxification pathway in S. mansoni . Here, we report that the antimalarial quinoline methanols quinine and quinidine exert schistosomicidal effects notably due to their capacity to interfere with hemozoin formation. When quinine or quinidine were administered intraperitoneally during seven days to S. mansoni -infected mice (75 mg/kg/day), both worm and eggs burden were significantly reduced. Interestingly, hemozoin content in female worms was drastically affected after treatment with either compound. We also found that quinine caused important changes in the cellular organization of worm gastrodermis and increased expression of genes related to musculature, protein synthesis and repair mechanisms. Together, our results indicate that interference with hemozoin formation is a valid chemotherapeutic target for development of new schistosomicidal agents.
- ItemOpen AccessIntramolecular Diels-Alder reactions of conformationally restricted systems(2000) Gordon, Richard Spencer; Bull, James R; Hunter, RogerIn the first phase of this investigation, the synthesis of triene systems, linked via a diester tether was investigated with the aim of studying the respective thermal Intramolecular Diels-Alder (IMDA) properties. It was envisaged that the diene and dienophile would be linked via a conformationally restricted spacer, trans-cyc1ohexane-l,2-dicarboxylic acid anhydride.
- ItemOpen AccessThe mechanism of the amidases: mutating the glutamate adjacent to the catalytic triad inactivates the enzyme due to substrate mispositioning(American Society for Biochemistry and Molecular Biology, 2013) Weber, Brandon W; Kimani, Serah W; Varsani, Arvind; Cowan, Donald A; Hunter, Roger; Venter, Gerhard A; Gumbart, James C; Sewell, Trevor BAll known nitrilase superfamily amidase and carbamoylase structures have an additional glutamate thatis hydrogen bonded to the catalytic lysine in addition to the Glu, Lys, Cys “catalytic triad.” In the amidase from Geobacillus pallidus, mutating this glutamate (Glu-142) to a leucine or aspartate renders the enzyme inactive. X-ray crystal structure determination shows that the structural integrity of the enzymeismaintained despite themutation with the catalytic cysteine (Cys-166), lysine (Lys-134), and glutamate (Glu- 59)in positions similar to those of the wild-type enzyme. In the case of the E142L mutant, a chloride ion is located in the position occupied by Glu-142 O 1 in the wild-type enzyme andinteracts with the active site lysine. In the case of the E142D mutant, this site is occupied by Asp-142 O1.In neither case is an atom located at the position of Glu-142 O 2 in the wild-type enzyme. The active site cysteine of the E142Lmutant was found to form aMichael adduct with acrylamide, which is a substrate of the wild-type enzyme, due to an interaction that places the double bond of the acrylamide rather than the amide carbonyl carbon adjacent to the active site cysteine. Our results demonstrate that in the wild-type active site a crucial role is played by the hydrogen bond between Glu-142 O 2 and the substrate amino groupin positioning the substrate with the correct stereoelectronic alignment to enable the nucleophilic attack on the carbonyl carbon by the catalytic cysteine.
- ItemOpen AccessMechanistic insights into the cancer cell cytotoxicity and blood stability of the garlic compound ajoene(2016) Kusza, Daniel Andreas; Hunter, Roger; Kaschula, Catherine HartAjoene, a garlic-derived natural product and its structural analogues are strongly cytotoxic to cancer cells. These compounds are however known to exhibit low blood stability and erythrocyte toxicity. This thesis reports on the synthesis of eight ajoene analogues designed to probe structure-activity relations into cancer cell cytotoxicity and blood stability. Structural variations included introduction of different solubility enhancing terminal groups (amide and phenol) as well as variations in the sulfoxide / vinyl-disulfide core. The phenol ajoene analogues were found to be more cytotoxic against WHCO1 oesophageal cancer cell proliferation than the corresponding amides. The structureactivity data support a thiolysis mechanism where ajoene forms a mixed disulfide with a reactive cysteine residue on a protein target which leads to both its cytotoxicity and blood instability. This in turn is mediated by the reactivity of the disulfide pharmacophore which is enhanced by the vinyl group. The sulfoxide functional group is perceived as modulating disulphide reactivity by an inductive electron-withdrawal through the aliphatic σ-framework. The dihydroajoenes emerged as attractive candidates for further cancer therapeutic development with improved blood stability with a half-life around 120 minutes and good cancer cell cytotoxicity (IC₅₀ of approximately 20 μM). A spectrophotometric and proteomic binding study demonstrated S-thiolation between ajoene and the cysteine 93 residue in the -subunit of haemoglobin which may explain the observed blood instability. A biotinylated ajoene analogue was designed and synthesised to identify ajoene's protein targets within the cancer cell. This was achieved using a convergent "Click"-strategy, involving azidated ajoene and biotin-alkyne. Both the biotin-ajoene and the azide-ajoene showed strong cytotoxicity against WHCO1 cancer cells. An immunoblotting experiment showed the successful biotinylation of haemoglobin, as a model protein by both whole probe and an in situ "Click"-reaction. This biotinylated probe can be used in future work to identify the ajoene protein targets in cancer cells.
- ItemOpen AccessMethodology studies on the synthesis of chiral, non-racemic aza-quaternary centres(2015) Petersen, Wade Frank; Hunter, RogerThe synthesis of chiral, non-racemic aza-quaternary centres is one of the biggest challenges in current organic synthesis. Many natural products contain them and as a privileged biological motif they are of interest to medicinal chemistry. The structural complexities of these functionalities invites the development of new methodologies for their synthesis. The experimental part of the thesis appears in two Chapters. Chapter Two describes studies aimed at the enantioselective synthesis of chiral, non-racemic aza-quaternary centres via reagent -based approaches. In the first part studies are directed towards developing ephedrine -derived stoichiometric chiral aminating reagents in enantioselective nitrogen transfer, while in the second part of the Chapter the emphasis shifts to using an organocatalysis approach involving an ephedrine -hydrazide organocatalyst in conjunction with enantioselective amination methodology using an azodicarboxylate. Chapter Three shifts to a substrate -controlled approach based on using chiral malonate -imidazolidinones as a template for amination. Using KHMDS as base it has been shown that the enolate of α -substituted chiral malonate-imidazolidinones can be azidated with trisyl azide in excellent diastereoselectivity in yields > 92 % and dr ≥ 97:3 by chiral HPLC. The products were subsequently transformed to α,α-disubstituted α-serine derivatives by a series of chemoselective steps: reduction of azide with Zn / AcOH, removal of the chiral auxiliary with LiSEt followed by reduction of the resultant thioester with lithium-tri-tert-butoxyaluminium hydride in up to 75 % yield over 4 steps. The methodology opens up the way towards establishing a general methodology for synthesizing quaternized amino acids with a broad range of R groups, both natural and unnatural in type.
- ItemOpen AccessNew CO₂ chemistry for fine chemical synthesis(2011) Msutu, Ath'enkosi; Hunter, RogerThere is a great need in the chemical industry for developing CO2 as a C1 building block as an important step towards "green chemistry". CO2 is also attractive as a chemical feedstock because it is readily available, inexpensive, nontoxic and it can replace toxic building blocks such as phosgene and CO. Industrially, megatons of CO2 are used each year for the production of urea, inorganic carbonates, salicylic acid, and polycarbonates, yet this is still miniscule compared to the immense potential that is still yet to be harnessed in using this versatile building block. This thesis discusses how a novel methodology was developed for synthesising a benzotriazole (Bt) urea directly from CO2 in a two-step, one-pot synthesis. The procedure involves trapping CO2 with a primary or secondary amine in the presence of DBU, and reaction of the resultant carbamate salt with triphenylphosphine and chlorobenzotriazole (BtCl) to produce Bt ureas in moderate to high yields. The Bt group may serve as a leaving group in nucleophilic substitution reactions, therefore it is also shown here how the Bt urea presents itself as a precursor for an array of useful organic intermediates. These intermediates include ureas, amides, S-thiocarbamates and sulfonylureas.
- ItemOpen AccessNew methodology for the organocatalysed α-Amination reaction(2015) Msutu, Ath'enkosi; Hunter, RogerResearch into organocatalyzed asymmetric reactions has been a rapidly growing and competitive field in recent times, wherein amino catalysis is widely used for the asymmetric functionalisation of carbonyl compounds. Since its simultaneous publication by List and Jørgensen, the organocatalysed α-amination reaction has become a key method for asymmetric heteroatom functionalisation of carbonyl compounds. Herein we report the first application of this methodology to acetals, with the ultimate goal of applying the methodology to the asymmetric desymmetrisation of bis-acetals as a novel contribution to this growing field. Following extensive optimisation, acidic reaction conditions for the reaction were established in which dibenzyl azodicarboxylate (DBAD) was used as the aminating agent and (S)-(-)-5-(2-pyrrolidinyl)-1H-tetrazole as the preferred organocatalyst. The desired aminated products were obtained in high yields and enantioselectivities. The reaction showed broad substrates cope in its application to ketals, dioxolanes and lactols. A hydrazide N-N bond cleavage methodology was also developed for the aminated products in oxazolidinone form. This methodology is based on Magnus' alkylation / E1CB strategy. The novel contribution here is using ditheyl bromoacetate as an alkylating agent and as a better elimination partner. A range of bis-acetals were synthesised via three synthetic routes using malonate-, sulfone and cyclopentene-based synthesis strategies. The acetal reaction was used for the desymmetrisation of two of these bisacetals as a proof of concept. This is a feat not achieved with the more reactive dicarbonyl analogue.
- ItemOpen AccessNew methodology for the synthesis of chiral, non-racemic a-tertiary amine centres: application to the synthesis of the marine alkaloid lepadiformine(2016) Andrijevic, Ana; Hunter, RogerThe development of new methodology for the synthesis of a chiral, non-racemic quaternary carbon bearing an α-nitrogen (an α-tertiary amine or ATA) continues to be an active area of modern research in current synthetic organic chemistry. As a privileged biological scaffold, ATAs are widespread amongst bioactive natural products, providing an inspiration in their complex architecture to synthetic chemists in drug discovery programmes. Three experimental endeavours comprise this project, which are presented as separate sections of Chapter 2. The first part focuses on new methodology for all-carbon quaternization based on an auxiliary-based diastereoselective alkylation of an auxiliary-malonate, in which an imidazolidinone auxiliary provided excellent facial selectivities in the alkylation in conjunction with KHMDS as the base. Five derivatives were generated in high yields (>85 %) and selectivities (dr >95:5). Extension of the methodology to generate ATAs using the auxiliary-malonate system forms the basis of the second section. This was achieved via a modified Curtius rearrangement protocol performed on quaternary carboxylic acids, in turn obtained from a chemoselective cleavage of a PMB ester malonate-auxiliary system. The ATA products were obtained in high yields and with retention of stereoselectivity, and following the non-destructive removal of the auxiliary by methanolysis, produced enantioenriched α,α-disubstituted alanine and phenylalanine methyl esters. Additional steps on other suitable derivatives furnished α-quaternary proline and lysine derivatives, all in high ees (96 – 98 %). The methodology offers a general approach to the production of enantioenriched ATAs, and in particular, access to both natural and unnatural α,α-disubstituted amino acids. Application to an attempted synthesis of lepadiformine is described in the final section, whereby the ATA of the alkaloid is constructed in an acyclic form employing the newly developed methodology. Reductive (non-destructive) removal of the auxiliary provided an amino alcohol derivative that was further elaborated via a sequence involving ring-closing metathesis, hydrogenation, hydroxyl group oxidation and Grignard addition to afford a functionalised A-ring of lepadiformine A, with key functionality in place for elaboration to the target. However, dehydration of the tertiary alcohol from the Grignard step, although successful in a related model study, led to problems, bringing the total synthesis endeavour to a close. In spite of this setback, the divergent nature of the approach allows for new designs in the synthetic plan, particularly regarding the order of which the functionalised A ring from this work is elaborated into the A/B/C target.
- ItemOpen AccessNovel acyclic nucleotide phosphonates against RNA viruses(2012) Bowden, Gregory David; Hunter, RogerAcyclic nucleotide phosphonates (ANPs) have been used for years as successful anti-viral agents against diseases such as HIV/AIDS and hepatitis while the drug ribavirin is one of the only drugs available for the treatment of RNA-viral infections which mainly affect the developing world. The large and unmet need for anti-RNA viral treatments has prompted this study into the design and synthesis of a range of ANPs, which includes a series of ribavirin-based ANP derivatives. The series of compounds was synthesised from a diisopropyl protected phosphonomethoxyethyl (PME) synthon and included an arylethynyltriazole derivative which was produced via a Sonogashira palladium catalysed cross-coupling reaction. A selection of these compounds was then deprotected to their corresponding phosphonic acids via a bromotrimethylsilane mediated phosphonate ester hydrolysis. In one example, a bis(pivaloyloxymethyl) prodrug variant was produced in order to probe a general synthesis for prodrug protected ANP derivatives. All new compounds were characterised by NMR, IR, and Mass spectroscopic techniques.
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