School of Chemistry - Theses
Permanent URI for this collection
Search Results
1 - 4 of 4
-
ItemSynthesis of histrionicotoxin analogues using coventional and continuous flow approaches( 2011)The histrionicotoxins are a family of alkaloids, originally isolated from the skin extracts of the amphibian Dendrobatidae histrionicus, that display non-competitive inhibition of the nicotinic acetylcholine receptor. The biological activity of these compounds, combined with a protected natural source, has given rise to considerable interest from a synthetic chemistry standpoint. This manuscript describes the synthesis of 6,6,5-isoxazolidine scaffolds of the histrionicotoxin spirocycles, from bis-α,β-unsaturated nitrile intermediates of well defined stereochemistry, using both conventional batch-type and continuous flow techniques. A library of both racemic and enantiomeric examples of perhydrohistrionicotoxin and its conformationally restricted precursors has been synthesised. Additionally, analogues of perhydrohistrionicotoxin, one example bearing an epimeric centre and other species furnished with pendant side chains of increased length have been synthesised.
-
ItemStudies towards the synthesis of mulberry Diels-Alder adducts( 2011)The synthetic studies of mulberry Diels-Alder adducts are described. Two dehydroprenylarylbenzofuran adducts, mulberrofuran C hexamethyl ether (325) and mulberrofuran J hexamethyl ether (326) were obtained from the cycloaddition Diels-Alder reaction between diene dehydroprenylarylbenzofuran (118) and chalcone dienophile 264. Chalcomoracin hexamethyl ether (330) and mongolicin F hexamethyl ether (331) were also obtained from cycloaddition Diels-Alder reaction between the arylbenzofuran diene 118 and prenyl chalcone 267. Prenyl chalcone 267 was synthesised from commercially available 2,4-dihydroxyacetophenone 175 and 2,4-dihydroxybenzaldehyde 176 in four steps. An aldol condensation between methyl ethers acetophenone 262 and benzaldehyde 263 using Claisen-Schmidt condition afforded chalcone 264. Ortho-prenylation and [1,3]- rearrangement successfully furnished the desired chalcone 267. The dehydroprenylarylbenzofuran 118 was synthesised from a Suzuki coupling reaction between arylbenzofuran iodide 315 and dienylboronate 322. The key step in the synthesis of arylbenzofuran iodide 315 is the Sonogashira coupling reaction between alkyne 306 and iodide 310. Methanolysis of 313, followed by TBAF-induced cyclisation afforded the arylbenzofuran iodide 315 in good yield. Alkyne 306 was synthesised from commercially available 3,5-dihydroxybenzoic acid (262) in five steps. The iodide partner 310 was prepared from commercially available 3-methoxyphenol 311 in three steps. The stereochemistry of the endo adduct was confirmed by direct 1H NMR signals comparison of the product which was obtained from permethylation of chalcomoracin hexamethyl ether (330), with an authentic sample of chalcomoracin (47). The cis, trans-configuration of the endo adducts, mulberrofuran C hexamethyl ether (325) and chalcomoracin hexamethyl ether (330) was confirmed by 2D NMR spectroscopic analysis. From the analysis of variable temperature 1H NMR spectra, the exo adducts, mulberrofuran J hexamethyl ether (326) and mongolicin F hexamethyl ether (331) showed a significant restricted rotation. The deydroprenylchalcone adducts, kuwanon J heptamethyl ether (339) and kuwanon I heptamethyl ether (340) were also synthesised from a cycloaddition Diels-Alder reaction between a dehydroprenylchalcone 338 and a chalcone dienophile 267. The key Suzuki coupling reaction chalcone-iodide 337 and dienylboronate 322 afforded dehydroprenylchalcone 338. The chalcone iodide 337 was prepared from an aldol condensation between methyl ether derivatives of acetophenone 335 and benzaldehyde 263. The exo adduct, kuwanon I heptamethyl ether (340) appeared as a mixture of atropisomers as a result of significant restricted C3”-C4” rotation. This phenomenon was confirmed by 1H NMR variable temperature experiments. Since the global deprotection of mulberrofuran C hexamethyl ether (325) only led to incomplete demethylation and decomposition, orthogonal protecting groups were also investigated for the synthesis of mulberry Diels-Alder adducts. Debenzylation of adduct 368 using a Lewis acid, BCl3 and C6HMe5 at -78 °C gave the monobenzylated product 370. However, when the reaction was allowed to warm from -40 °C to 0 °C, an undesired product whose structure could not be determined was isolated. MOM deprotection of kuwanon V (77) was achieved using HCl to afford the cyclised product 407 which was found to be unstable. Attempts at deprotection of benzyl, methyl and MOM ether derivative of kuwanon V 415 were not successful.
-
ItemFundamental studies toward the production of high quality doped semiconductor nanocrystals( 2010)The synthesis and properties of materials on the nanoscale are distinct from those of their bulk counterparts. In particular, doped and alloyed semiconductor nanoparticles have the potential to form materials with desirable properties and with low levels of toxicity from readily-available, low-cost reagents. The reproducible synthesis of good quality, monodisperse, doped and alloyed nanoparticles is linked to the control afforded over the formation and growth kinetics, which must therefore be clearly understood. Control over nanoparticle syntheses relies heavily on the use of ligands, which bind to both the monomer and the particles as well as altering the nature of the reaction solution. Classical nucleation theory only describes the formation and growth of binary semiconductor nanoparticles in the absence of ligands. It also fails to take into account the behaviour of impurities, and so does not explain the formation and growth of ternary alloys. For practical reasons the properties of such nanomaterials must be fully characterisable and, ideally, predictable from their synthesis. The knowledge of highly accurate molar extinction co-efficients is critical to the characterisation of semiconductor nanoparticle systems. These co-efficients allow the full characterisation of such particles from their absorption spectra. In this thesis accurate, size-dependent molar extinction co-efficient values were determined for spherical cadmium selenide nanoparticles. These values were favourably compared to those predicted by SEPM theory and showed self-consistency across both the strong and weak confinement regimes. Observations of particle kinetics made using the new extinction co-efficient values suggest that particle concentration is quite stable over time, as compared to similar observations made using the previously established relation. Studies were then conducted to determine the effects of oleic acid, a metalbinding ligand, and trioctylphosphine (TOP), a chalcogen-binding ligand, on the nucleation and growth kinetics of cadmium sulphide nanoparticles. It was discovered that Ostwald ripening occurs earlier in the presence of higher concentrations of oleic acid, which causes larger nuclei to form and increases their growth rate. By contrast, TOP was shown to very strongly stabilise cadmium sulphide particles against dissolution and to suppress Ostwald ripening by retarding the growth phase. Much lower size distributions were obtained with a high concentration of TOP in the reaction solution. As a step toward the reproducible production of alloyed semiconductor nanoparticles, a series of cadmium-zinc-selenide (CdxZn1-xSe) nanoparticles was synthesised with values of x between 0 and 1. Particles with very high cadmium concentrations were found to be spherical, but even in the presence of low concentrations of zinc monomer rods were formed instead. A continuous redshift of the band gap energy with increasing mole fraction of cadmium in the particles demonstrated the predictable tunability of the band gap of these ternary alloys. Crucially, it was discovered that for all non-zero values of x a cadmium selenide core nucleates first, which then accretes both cadmium and zinc monomer stoichiometrically from the reaction solution. This means that the alloys are always cadmium-rich, highlighting a major obstacle to the reproducible synthesis of stoichiometric particles with low concentrations of dopant.
-
ItemSynthesis and biological applications of phospholipid-based chemical probes( 2010)Phosphoinositides play significant roles as secondary messengers to regulate a broad range of intracellular processes in a spatio and temporal manner, including signal transduction pathways, cell motility and cytokinesis, excocytosis and endocytosis, vesicular trafficking, as well as control of ion channels, pumps, and transporters. Their regulatory functions are achieved by directly recognition and interaction with a variety of phosphoinositide-binding proteins. Synthetic chemistry has played a defining role in further understanding of phosphoinositide interactome. Total syntheses of the palmitic acid and amino-terminal PI(3,4)P2 derivatives were performed. The dipalmitoyl derivatives were incorporated to form liposomes, and the amino-terminal analogues were conjugated to Affi-Gel 10 resins, both of which were used as affinity probes for proteomics studies via affinity experiments to investigate phosphoinositide interacting proteins/protein complexes. With colorectal carcinoma cell cytosolic extracts, 282proteins/protein complexes were identified as PI(3,4,5)P3 binding proteins. A morecomprehensive proteomic study was carried out for PI(3,4)P2 with cell extracts fromcytosol, membrane, and nucleus of colorectal carcinoma cells, giving 1134 proteins as PI(3,4)P2 interacting proteins/protein complexes including 126 proteins containing known phosphoinositide binding domains. Additionally, a number of novel proteins were identified as potential phosphoinositide binding proteins in our studies. The molecular functions, protein networks, and biological processes of identified proteins were analysed by submission to various databases to provide better knowledge of the involvement of phosphoinositides in intracellular signalling pathways. Therefore, our bioinformatics studies using phosphoinositide affinity probes provide initial detailed assessment of PI(3,4,5)P3 and PI(3,4)P2 interactome and suggest potential phosphoinositide functions and specificities for further biochemical characterisation by using other alternative biological techniques. Cardiolipin (diphosphatidylglycerol) is a unique phospholipid predominantly existing in the mitochondrial membranes throughout the eukaryotic and prokaryotic kingdom. It has been subsequently studied as the key phospholipid stimulating mitochondrial enzymes and regulating the mitochondria energy metabolism and cell apoptosis by interactions with a number of mitochondrial proteins. An amino-terminal cardiolipin derivative was totally synthesised and immobilised to Affi-Gel 10 beads to afford a novel cardiolipin affinity matrix. Pull-down experiments were undertaken; the results confirmed the binding interaction between cardiolipin and the HR1 domain of PRK2 protein. Furthermore, a novel cardiolipin biosensor chip has been developed by immobilisation of the amino-terminal cardiolipin derivative to the gold surface, and used as a powerful biological tool for clinical diagnosis of antiphospholipid syndrome (APS) via surface plasmon resonance (SPR) experiments. In order to facilitate protein co-crystallisation processes, a novel PI(4,5)P2 derivative containing adamantanecarbonyl groups as replacements of acyl side chains has been synthesised; synthesis towards metabolically stabilised phosphatidylinositol phosphorothioate derivatives was also undertaken.