A series of materials have been compared for their activity in the base catalysed condensation of acetone. Activities have been compared after extended times on stream (18 h) and under a H2 containing atmosphere at elevated pressure which is designed to mimic conditions applicable for the single stage transformation of acetone to MIBK. In general, catalysts without a strong hydrogenation function have been screened and so mesityl oxide is the dominant reaction product. However, 1%Pd5%MgO/SiO2 does exhibit high selectivity towards MIBK, demonstrating that single-stage conversion is possible under the conditions investigated. Catalytic activity is found to be a strong function of the material tested. However, when the influence of surface area is taken into account, a spectrum of area normalised conversion rates is evident. These rates were found to vary in the order 36.5% KNO3/Al2O3 > Li/MgO > 36.5% KNO3/ZrO2 > 36.5% KNO3/Zr(OH)4 > MgO derived from Mg(OH)2.MgCO3 > 14% KNO3/Al2O3 > MgO derived from Mg(OH)2 > 14% KNO3/Zr(OH)4 > ZrO2 > 14% KNO3/ZrO2 > Y-Zr(OH)4. When comparing materials produced from different precursors, differences in catalytic behaviour are apparent implying structure-sensitivity and/or the influence of different impurity contents. The role of dopant, additional phase level and precursor phase has also been examined demonstrating that all these parameters are important.

Vibrational Raman optical activity (ROA) which is the difference in the Raman scattering of left and right circularly polarised incident light, has recently emerged as a new and incisive probe of biomolecular structure. This thesis is based on new applications of ROA to some current biochemical problems. The first chapter is a brief explanation of the origin of chirality and the development of vibrational optical activity with special emphasis on ROA. Chapter 2 is a theoretical analysis of ROA and provides a fundamental explanation of the phenomenon. This involves a description as to how the ROA effect is generated using molecular property tensors. The third chapter concentrates on the instrumentation required to measure ROA and the importance of CCD detectors and holographic notch filters in establishing the technique with respect to biopolymers. Chapter 4 is a brief introduction to protein structure and includes an analysis of the strengths and weaknesses of current biophysical techniques used for structure determination. Chapters 5 and 6 describe detailed applications of ROA to polypeptides and native proteins. The polypeptides are a suitable starting point since from other spectroscopic techniques they are known to adopt certain conformations, such as -helix, -sheet and random coil. Native proteins are examined in Chapter 6 and the ability of ROA to detect not only secondary but also tertiary structure is highlighted. Chapter 7 is concerned with the important topics of the structure and dynamics of unfolded proteins, molten globules and ligand bound proteins. Finally, in the appendix there is a summary of the assignments made to secondary structure and to loops and turns.

This thesis is concerned with studies towards the total synthesis of labiatin A using metal carbenoid chemistry. The work described herein shows the most recent contribution to this field from our research group. Chapter I provides an introduction to metal carbenoids and their uses in organic synthesis. In particular, the synthesis of diazo carbonyl compounds, their decomposition by metal catalysts leading to the formation of metal carbenoids and the reactions involving metal carbenoids is described. A retrosynthesis of labiatin A involving the use of two metal-carbenoid transformations- intramolecular C-H insertion reaction and oxonium ylide formation followed by [2,3]-sigmatropic rearrangement- is presented. In Chapter II, the successful applications of these two reactions to the enantioselective synthesis of the tricyclic core of labiatin A is described. This is followed by the description of the different attempts to complete the synthesis of labiatin A. Finally, the exploration of a modified approach to the total synthesis of labiatin A is described. Chapter III provides the analytical support to this thesis.

Protein phosphatases (PPases) are important enzymes which mediate dephosphorylation of proteins in eukaryotic cells. These enzymes are involved in a variety of cellular processes, and disruption of their activity has been shown to be involved in the development of diseases such as cancers and Alzheimer’s. Protein phosphatase inhibitors (PPIs) have been used to regulate the activity of these enzymes, and hence, control the development of the cellular processes related to them. However, the lack of potent and selective readily accessible PPIs is a major obstacle to the understanding of these complex biological pathways, and the development of reliable synthetic routes towards new PPIs has therefore generated a significant amount of interest. Several naturally occurring PPIs possess the “ADDA” residue , which has been shown to be crucial for their inhibitory activity. We would like here to report the synthesis of “ADDA”-isoforms such as enantio-ADDA 1 and enantio-iso-ADDA 2 through a convergent approach taking advantage of cross-metathesis methodology, non-aldol aldol and aza-Claisen rearrangements, as well as β-lactam chemistry. We envisage using our synthetic approaches as a platform to generate a wide range of novel “ADDA”-containing analogues, which might lead to the discovery of potent and selective PPIs, which could be generated in multi-gram scale.

During the course of the studies outlined in this thesis, a new short and efficient synthesis of PK11195 was developed using Pd(0)-mediated reactions to effect the key carbon-carbon bond forming reactions. PK11195 is a ligand that interacts with the translocator protein(TSPO) in the brain. During brain injury the concentration of TSPO increases, making TSPO an ideal and sensitive biomarker. Using single photon emission computed tomography along with [123I]PK11195, medical practitioners are able to visualize the receptor. In addition to the synthesis of PK11195, three other analogues were devised using the same methodology as for PK11195. Firstly, a Heck reaction was used to form the isoquinoline core, followed by a Suzuki reaction to couple the correct phenyl ring.

Within this work the effects of metal identity are investigated on the magnetic properties of a range of materials, in which different transition metals are shown to produce significantly different calculated magnetic coupling values when incorporated into the same structure. The model structures composed of transition metals mediated by hydrogen halide ligands of the form FHF-, ClHCl- and FHCl- enable the calculation of magnetic coupling values via hydrogen bonds (HBs), providing insight into a scarcely studied topic. The employment of the well known HF=35% functional, provides results anticipated to represent potential experimental trends. Interesting results are also reported which indicate a relationship between the binding energy of the atom and the level of coupling displayed. The quantum nature of the H atom, often difficult to localise, are also accounted for by use of a shooting algorithm in order to solve the one dimensional Schrödinger equation in relation to the hydrogen positions within the isotropic lattice. Hydrogen positions were fixed during geometry optimisations in order to obtain the E(x) potential energy curve required to allow this to be achieved. Both the <J> in which proton motion is incorporated and J coupling values from the optimised ground state structures, in which the atomic positions including the H positions underwent a full geometry optimisation, are presented. The electronic effects of incorporating different group one and group two metals into the related Prussian Blue (PB), Prussian Yellow (PY) and Prussian White (PW) model lattices are also presented. More specifically band gaps within these complexes are calculated from projected density of state (DOS) plots of the electrons within the atomic orbitals from a converged calculation in which the B3LYP functional (HF=20%) is employed. This functional has previously been shown to provide band gap energies in good agreement with experimental values. The results obtained confirm that the value of ~3eV, associated with an absorption in the yellow region, lies within the PY band gap range, indicated by the HOMO and LUMO orbitals within the DOS plot. Band gaps calculated directly from SCF energy differences do not agree well with experimental values or trends for the various group one PB complexes. A number of related metal containing bromanilic acid (BA) and chloranilic acid (CA) complexes are synthesised, crystallised and their structures, as determined by X-ray single crystal diffraction, reported. The structural packing of the molecules is analysed by defining a number or recurring unit within the structures in order to obtain key similarities. The structures are also broken down in to lower dimensional units composed of the individual components within the asymmetric unit and built up into higher dimensional units such as clusters, chains and planes that all intersect with one another in order to produce the overall three dimensional structures. In most cases the point of intersection is on a key symmetry element such as an inversion centre. Particularly short M-M contact distances are observed in a number of the complexes. This proves interesting within the related isomorphous complexes in which the main effect of incorporating a larger metal cation into the same structure is in the ionic repulsions between the metals. This is particularly interesting in more extended structures in which the metals exist in chains or planes that run along a particular direction of the unit cell. The specific increase in cell parameter can in most cases be explained as a consequence of the repulsion between the shortest M-M contacts. The effect is also observed in structures in which the metals exist as isolated clusters, and also displays some interesting consequential effects on other interactions. A variable pressure neutron single crystal diffraction experiment on a short asymmetric HB is also reported, in which one lattice is compressed significantly more than the other two, an effect that is explained by the change in contact distances with pressure.

The contamination by metals present in surface water causes problems to human health. The ultimate aim of this work is to determine the role of fine suspended sediment to the transport of metals in rivers. During the work, the ability of fine suspended sediment to carry a range of metals in the river water in different seasons was measured in different samples. Suspended sediment carries a substantial proportion of the metals in river water. The distribution of suspended particles is an important factor in controlling the availability of metals in the river water. Dissolved form, and adsorbed to the surface coating of suspended particulate matter are two ways to transport metals in rivers. Firstly, the work was carried out in the laboratory, using suspended sediment components, to assess metal uptake by different components, while later studies utilized natural suspended sediment to study metal transport in real situations. The water samples were taken for this research from tributaries of the River Kelvin; Craigton Burn, Allander Water, Craigmaddie, Glazert Water, Bothlin Burn, Luggie Burn, and Cameron Burn. The research tries to evaluate the concentrations of Ca, Fe, K, Mg, Mn, and Zn in suspended particles in these tributaries. The technique used two filters 1.2 µm and 0.2 µm to collect the suspended sediment from water samples. Some representative samples of kaolinite, bentonite, humic acid and iron oxides were used in the laboratory based studies to improve understanding the distribution of the heavy metals Cu, Pb and Zn between metals sorbed on the solid phase and metal `in the solution phase. The adsorption of the heavy metals Cu, Pb and Zn shows different response between these materials. In addition, the experiments were carried out to measure the distribution of copper, lead, and zinc between an aqueous phase and solid phase of mixed materials (composite) sediment. The results demonstrate that the fluvial system is one of the major modes of dispersing and transporting metals from soil and parent rocks. The overall results indicated that the large and fine particle sizes carry significant metals concentrations in the river system. The investigation of the suspended sediment phases offers additional information and understanding of the movement and behavior of metals within river water. The concentration of the particles > 1.2 µm is higher than that in the fine particles 1.2 and 0.2 µm diameter.

A major problem encountered during the industrial synthesis of isocyanates, is the loss of amine starting material through reaction with the hydrogen chloride (HC1) by-product. HC1 is formed by the phosgenation of polymeric amines and also by the subsequent decomposition of the carbamyl chloride, Equation (1). HC1 readily reacts with the polymeric amine to form an unwanted and highly insoluble amine hydrochloride salt. (Fig. 3620) Methylene dianiline (MDA) and 4-benzylaniline (4-BA) were used as models for the industrial amine starting material with their hydrochloride counterparts methylene dianiline dihydrochloride (MDA.2HC1) and 4-benzylaniline hydrochloride (4-BA.HC1) as models for the industrial waste material. To understand the forces controlling the structure and stability of these solid amine hydrochloride salts the sold state structures of MDA, MDA.2HCl, methylene dianiline monohydrochloride (MDA.HCl), 4-BA and 4-BA.HCl were investigated using single crystal X-ray diffraction which led to the determination of their lattice energies. The XRD studies were also used as a basis for Density Functional Theory (DFT) calculations. The information obtained from the solid state structures, combined with an investigation of the solution phase behaviour of 4-BA.HCl(s), resulted in the determination of a kinetic model for the recovery of amine starting material. The proposed reaction scheme describes the conditions under which the dissociation of 4-BA.HCl(s) can occur. Reaction in a closed system shows no amine production while reaction in an open system permits, within solubility limits, the complete consumption of solid waste to produce free amine. From these two extremes the conversion of waste hydrochloride salt in the industrial reactor can be rationalised.

The A2A adenosine receptor (A2AAR) functions as a key non-redundant suppressor of inflammatory responses in vivo. However, whether it regulates activation of the JAK-STAT pathway utilised by many pro-inflammatory cytokines is unknown. Using a vascular endothelial cell model system, I have demonstrated that adenovirus-mediated expression of the human A2AAR conferred an ability of IFNα, leptin and a soluble IL- 6 receptor-α/IL-6 (sIL-6Rα/IL-6) trans-signalling complex to promote a time-dependent reduction in the levels of STAT proteins that was entirely due to proteasomal degradation. In terms of functional consequences, degradation was sufficient to attenuate sIL-6Rα/IL-6-stimulated STAT3-dependent up-regulation of vascular endothelial growth factor receptor-2 (VEGFR-2) and enhance eNOS expression. Degradation required JAK activity since A) it was blocked by preincubation with JAK inhibitor. B) STAT1 but not STAT3 was resistant to both tyrosine phosphorylation and down-regulation in response to leptin and C) a Tyr705→Phe mutated STAT3 was also resistant to cytokine-triggered degradation, suggesting that JAK-mediated phosphorylation of this residue is required to produce the effect. Consistent with this hypothesis, sIL-6Rα/IL-6 treatment of A2AAR-expressing cells resulted in the accumulation of polyubiquitylated endogenous and epitope-tagged recombinant wild-type but not Tyr705→ Phe-mutated STAT3. In addition the results show that inhibition of proteasome function was sufficient to block the inhibitory effect of the A2AAR on STAT3 phosphorylation, demonstrating that priming of STATs for degradation is the only mechanism responsible for the reduced cytokine-stimulated STAT phosphorylation observed in A2AAR-expressing cells. To date there is only one E3 ligase known for mediating STAT degradation which is SLIM protein. However, our results suggest the involvement of another E3 ubiquitin ligase in HUVECs, since we have been unable to detect SLIM message or protein in HUVECs under conditions in which STAT degradation occurs. In addition, while Tyr-phosphorylation is clearly the critical step in targeting STATs for degradation in A2AAR-expressing cells, it is unclear as to whether it functions simply as a classical phosphodegron, or whether the nuclear translocation that occurs as a result of phosphorylation is also important for localising the phosphorylated STAT dimer with the relevant E3 ubiquitin ligase. Together, these observations suggest a model whereby expression of the A2AAR in endothelial cells primes JAK-phosphorylated STATs for polyubiquitylation and subsequent degradation by the proteasome following cytokine treatment, and represents a previously unappreciated mechanism by which G-protein-coupled receptors can negatively regulate responsiveness to specific JAK-STAT-mobilising adipocytokines acting on the vascular endothelium.

Over the past three decades, numerous polycyclic ether natural products have been isolated from marine organisms. All of these unusual compounds possess a wide range of biological activities. In 1992, a new family of polyethers was discovered from the marine dinoflagellate Gambierdiscus toxicus: gambieric acids A–D, which show antifungal activity against a variety of filamentous fungi. The purpose of this thesis is to show the progress towards the synthesis of F–J ring system of gambieric acid A. First, the large scale synthesis of I–G ring fragment using the two directional ring closing metathesis developed in the laboratory is described including the improvements made to the previous synthesis. Subsequently, the efficient introduction of the methyl group of the F ring using a 1,4 addition with a cuprate reagent to an a,b-unsaturated lactone is discussed in detail. In addition, efficient introduction of the side chain to the J ring using a cyclic siloxane using a model system is also reported, after the exploration of ten different approaches. Finally, studies concerning the final stages of the synthesis are discussed.