No description available.

The first research project described in this thesis is the development of new SPECT and PET imaging agents for group II metabotropic glutamate receptors (mGluR2/3). Investigation of these receptors is of great interest as they have been implicated in many psychiatric disorders. A small library of 1,5-benzodiazepinones were synthesised with potential radiolabelling sites incorporated in the 7- and 8-positions around the benzodiazepinone core. Once synthesised the binding affinity of the compounds with mGluR2 was determined using the [35S]GTPγS binding assay, which revealed them to be highly potent. Physicochemical properties were also investigated to determine whether compounds were likely to be brain penetrant. The 8-trifluoromethyl-7-methoxy and 8-iodo substituted compounds were found to have the required properties to be progressed. Work then focused on the synthesis of radiolabelling precursors of the hit compounds. The second research project outlined in thesis involves the synthesis of novel heterocycle containing α-amino acids. Previous work in the Sutherland group achieved the synthesis of enone containing amino acids from L-aspartic acid. Building upon this, such enones were employed to form a small library of phenylpyrazole containing amino acids. The fluorescence properties of these compounds were then investigated which revealed the naphthalene and nitrophenyl substituted analogues to be fluorescent and thus have potential to be used as peptide labels for fluorescence imaging.

The synthesis and characterisation of sixteen new complexes are reported. The use of the ligand edte (((HOCH2CH2)2NCH2CH2N(CH2CH2OH)2)), H4L1) has resulted in five new iron complexes. Two Fe6 complexes and an Fe3 complex display non-zero ground states of S = 5 and S = 3 respectively. An Fe12 complex which displays a unique cluster topology and an Fe2 dimer are also reported, both with a ground state S = 0. A further six new iron clusters are reported using bicine (((HOCH2CH2)2N(CH2COOH)), H3L2). Two homeo-structural Fe6 complexes display spin ground states of S = 5 and S = 4, whereas a mixed-valence Fe6 cluster has a ground state of S = 3 and a large magnetic anisotropy. Further measurements are needed below 1.8 K to confirm any SMM behaviour. In addition an Fe12 cluster with a unique core topology possesses a spin ground state of S = 0. Two remaining Fe6 clusters are still to be magnetically characterised. The final three iron complexes are reported using the ligand tricine (((HOCH2)3CNHCH2COOH)H4L3). Fe9 posesses a ground state S = 11/2. Magnetic characterisation of Fe7 and Fe12 complexes are still needed to determine the spin ground state of these clusters. Two new Cr(III) clusters are reported using bis-tris (((HOCH2)3CN(CH2CH2OH)2), H4L4), the first a simple monomer and the second a Cr4 tetramer characterised with a spin ground state S = 0.

The amphidinolide compounds represent an extensive array of marine natural products, a number of which demonstrate potent anti-cancer bioactivity in vitro. Amphidinolide C represents an attractive synthetic target due to a combination of potent bioactivity and complex molecular architecture. This project deals with a modular and convergent total synthesis approach to amphidinolide C from which two synthetic fragments of similar size and complexity, termed ‘northern’ and ‘southern’, were synthesised in a stereoselective fashion. The stereochemical commonality between the branched chains of the 2,5-trans tetrahydrofuran systems found within both fragments, led to the conclusion that a keystone common intermediate could be applied to the synthesis of each. Previous efforts within the group have shown that 2,5-trans tetrahydrofuran-3-ones could be prepared through a diastereoselective rearrangement of a free or metal-bound oxonium ylide generated from a metal carbenoid. This thesis details the scalable preparation of the intermediate tetrahydrofuranone through tandem oxonium ylide and [2,3]-sigmatropic rearrangement. Subsequent discussions show the applicability of the intermediate to forming the C-(18)—C-(34) fragment of amphidinolide C and the C-(18)—C-(29) fragment of amphidinolide F, through the use of palladium cross-coupling methodology; alternative methods found to prepare the ‘northern’ fragment are also discussed. Additionally, the C-(1)—C-(8) fragment was prepared from the common intermediate system, the key steps in this synthesis involved introduction of the C-(4) methyl group through homogeneous catalytic hydrogenation and Luche reduction to afford the C-(7) alcohol.

This thesis presents the design, synthesis and physical studies of new structurally-varied cationic oligoheteroaromatic DNA binders in six chapters. Chapter 1 introduces DNA and its importance in modern science such as genetic and medicinal research. The interactions of DNA with small molecules are also discussed. A description is provided of click chemistry, a method for the synthesis and design of structurally-varied molecules, in this case designed to interact with DNA. Chapter 2 presents the synthesis of alkyne-substituted oligoheteroaromatic compounds by means of bromination, iodination, and Suzuki, Stille and Sonogashira cross-coupling reactions. These alkyne-substituted oligoheteroaromatic compounds were designed to be used as building blocks for click reactions. Chapter 3 describes the synthesis of azide-substituted oligoheteroaromatic compounds from amines by means of a safe method. The Pd-catalysed cross-coupling of azidesubstituted building blocks to form oligoheteroaromatics is also described. The azidesubstituted oligoheteroaromatic compounds were designed as building blocks complementary to the alkyne-substituted compounds described in Chapter 2. Chapter 4 presents the synthesis and characterisation of new π-conjugated molecules utilising click chemistry between alkyne- and azide-substituted compounds leading to a series of structurally-varied di- and tricationic oligoheteroaromatic putative DNA binders. Chapter 5 describes DNA-binding studies for the di- and tricationic oligoheteroaromatic compounds using a variety of biophysical techniques to quantify DNA binding and elucidate binding modes. Additionally, this chapter presents results from preliminary V exploration of the sequence selectivity of our cationic oligoheteroaromatics by comparing binding affinities and binding modes for two different sequences of DNA, viz. poly(dGdC)40 and poly(dA)80poly(dT)80. Chapter 6 presents the preliminary synthetic and DNA-binding studies of selected extended cationic oligoheteroaromatic compounds. Finally, this chapter presents the overall conclusions of the study, including selected comments and suggestions about future studies and applications.

In this investigation, cyclic voltammetry (CV), X-ray photoelectron spectroscopy (XPS) and rotating disc electrode (RDE) measurements of the oxygen reduction reaction (ORR) have been used to explore the complex three-phase Nafion-platinum-electrolyte interface. This interface is at the heart of the functioning membrane electrode assembly (MEA) of a fuel cell. CV was primarily used to analyse ultra-thin Nafion films, deposited (without contamination) onto various flat and stepped platinum and platinum bimetallic single crystal electrodes. For Pt{111}, XPS measurements were also used to determine Nafion surface layer thickness and to obtain surface chemical composition. CV results have shown that Nafion is a probe of adsorbed OH on platinum electrodes and for stepped surfaces, unusual structural sensitivity of Nafion-induced voltammetric peaks, ascribable to Nafion interactions with step sites, is observed as a function of average terrace width. Voltammetric results for palladium adlayers (up to two monolayers) adsorbed on Nafion coated Pt{111} and {100} in aqueous 0.1M HClO4, show the first layer palladium hydrogen underpotential deposition (HUPD) peak being much sharper and intense as compared to Nafion free surfaces. A similar phenomenon was found for platinum-palladium surface alloys in that Nafion adsorption would produce sharper, palladium HUPD peaks. This behaviour is ascribed to stronger specific adsorption of the Nafion sulphonate groups with palladium compared to platinum. It was interesting to note that for bismuth adlayers adsorbed onto Nafion coated Pt{111} and {100}, attenuation of HUPD features was identical whether or not Nafion was adsorbed but the Bi-OH redox features for Nafion coated surfaces exhibited marked differences, again ascribable to competitive adsorption of sulphonate and OH. Using RDE, it was found that the ORR for various Nafion coated Pt{hkl} electrodes was inhibited compared to Nafion free electrodes. The electrooxidation of formic acid on palladium modified, Nafion coated Pt{111}, in aqueous 0.1M HClO4, was found not to be affected by the presence of Nafion. However methanol electrooxidation was inhibited on palladium modified, Nafion coated Pt{111}. Finally a number of actual fuel cell electrocatalysts, provided by Johnson Matthey were characterised using CV. The {111} and {100} surface site densities were quantified using bismuth and germanium as surface probes. Comparisons between Nafion coated electrocatalysts and Nafion free electrocatalysts are also reported. It was found that only very marginal differences between the CV responses of both types of catalyst are recorded (in contrast to the single crystal data).

Small molecules, such as oligopeptides can interact with nucleic acid targets and subsequently stimulate or supress biological functions. The purpose of this thesis was to produce nucleic acid targeting oligopeptides which contain non-natural amino acids as part of their sequence. Certain amino acids display selectivity for certain nucleobases. Arginine has a high propensity for being present at the binding interface of both protein-DNA and protein-RNA complexes. This thesis was aimed at the synthesis of two arginine analogues in which the guanidino side chain was locked in a bicyclic framework. It was expected that this would result in highly directional H-bonding capabilities of the side chains of the two analogues, which was predicted to give superior selectivity when discriminating between targets. This thesis discusses the synthetic routes undertaken in an attempt to produce these two analogues. The synthesis of the two analogues proceeded by quite different routes. The first entailed manipulation of a chiral starting material to ultimately produce the bicyclic guanidine. However, incorporation of the amino acid moiety proved difficult and thus is incomplete. However, there is scope for further work to build on the endeavours mentioned in this work. The attempted synthesis of the second analogue focused on the formation of a substituted triamine prior to cyclisation to give the bicyclic guanidine. This method also produced many problems and so the synthesis still requires further work. The thesis also details the design and synthesis of a peptide library with the majority of peptides possessing at least one arginine residue within their sequence. This produced a range of peptides in small quantities (nanomolar) which was screened against an enzyme-linked immunosorbent assay (ELISA). The results of the assay highlighted library members who displayed a binding affinity towards the oligonucleotide targets and from this their sequences were determined. Future work can be performed using these results so that binding association constants can be determined. Once the arginine analogues have been successfully synthesised these can be incorporated into these peptide sequences in place of the arginine residues.

Chiral hypervalent iodine compounds are used as environmentally friendly, mild, and selective oxidants for many organic transformations. In this thesis, enantiomerically pure chiral hypervalent iodine reagents have been synthesized and used in the functionalization of different types of alkenes. A highly enantioselective oxyamination of alkenes with N-sulfonyl ureas employing chiral lactic acid-based hypervalent iodine reagents giving a facile synthesis of enantiomerically pure 2- arylproline derivatives is described. This is the first example of stereoselective oxyamination reactions under metal-free conditions. Then oxidative rearrangement of aryl-substituted ketones induced by lactate acid-based chiral hypervalent iodine reagents via 1,2 migration of the aryl moiety in the presence of alcohol nucleophiles is described leading to the �-arylated and �-oxygenated carbonyl compounds in enantiomerically pure form. This is the first stereoselective rearrangement reaction mediated by chiral hypervalent iodine reagents. Finally, all experimental details and characterization of the compounds are described.

The discovery of alternative solid base catalysts to replace homogeneous catalysts currently used in the industrial synthesis of biodiesel could remove the need for atom and energy inefficient routes to the desired biofuel product, and allow for the possibility of a continuous production process. Hydrotalcites have shown promise as catalysts in the transesterification of triglycerides with methanol to form biodiesel; however their activity is hampered by slow diffusion of the bulky triglycerides through the microporous hydrotalcite structure and poor accessibility of the active sites. This thesis has examined the synthesis of hydrotalcites via novel routes in an attempt to improve base site accessibility to triglycerides feedstocks in order to enhance catalytic performance. Macropore introduction into MgAl hydrotalcites helps to overcome mass transport limitations and increase their activity 10-fold for the transesterification of olive oil. Hydrotalcites prepared on an alumina support through a novel grafting and hydrothermal protocol form well-ordered crystallites on the high surface area oxide support. The resulting hydrotalcite-coated aluminas exhibit activities comparable to macroporous hydrotalcites of similar Mg:Al stoichiometries. Hydrotalcites prepared on alumina-grafted SBA-15 and macroporous-mesoporous SBA-15 employing the same grafting and hydrothermal synthesis are also extremely active in triglyceride transesterification, with the hierarchical macroporous-mesoporous outperforming the purely mesoporous SBA-15 support. Comparative studies on non-porous solid bases derived from nanocrystalline MgO reveal that Cs doping via co-precipitation confers superior activity for tributyrin transesterification. X-ray absorption spectroscopy has been applied to probe the local chemical environment of Cs atoms within such Cs-doped MgO, and the catalytically active phase identified as Cs2Mg(CO3)2(H2O)4. Cs-MgO is an order of magnitude more active for the transesterification of bulky triglycerides and olive oil than the undoped, parent MgO nanocrystals.

Aristolochene synthase from Penicillium roqueforti(PR-AS) is sesquiterpene synthase that catalyses the Mg2+-dependent conversion of farnesyl diphosphate FDP to (+)-aristolochene. Through the use of site directed mutagenesis, fluorinated FDPs and an aza-analogue of the eudesmane cation, the reaction was previously shown to involve germacrene A and eudesmane cation as intermediates. The subsequent series of rearrangements that transform the eudesmane cation to (+)-aristolochene have not been investigated previously. To probe the carbocationic nature of these 1,2-hydride and methyl shifts, new aza-analogues were designed to mimic the geometric and electrostatic properties of postulated carbocation intermediates in the catalytic mechanism of PR-AS. Here is described the synthesis of both enantiomers of 10-aza-eremophilane in enantiomerically pure from the common precursor (4S)-limonene oxide and their analysis as inhibitors of PR-AS. The synthesis of (7R,4S,5S)-10-aza-eremophilane cation was accomplished in 8 steps, starting from a known keto ester that in turn was obtained by degradation of (-)-limonene oxide. An identical synthetic protocol was repeated from (4R)-limonene oxide to give the enantiomer of 10-aza-eremophilane cation. Inhibition studies with compound (7R,4S,5S)-10-aza-eremophilane indicated that this ammonium salt acted as a moderate competitive inhibitor of PR-AS (Ki = 38 μM), and showed that eremophilane cation is likely a true intermediate on the pathway from FDP to aristolochene during PR-AS catalysis. The inhibition potency of 10-aza-eremophilane was increased by the addition of diphosphate PPi (Ki = 2.9 μM). This synergetic kinetic effect suggests that the possible involvement of PPi as a stabilizing anion for the eremophilane carbocation in PR-AS biosynthesis. Inhibition studies of the enantiomer of (7R,4S,5S)-10-aza-eremophilane cation, (7S,4R,5R)-10-aza-eremophilane cation, which has incorrect stereocenteres, with PR-AS indicated that this ammonium salt was a poor inhibitor of PR-AS (Ki = 1.03 mM). The data obtained for this compound highlight the chiral environment of the active site of PR-AS, and more importantly supports the postulate that terpene synthases form a product-like contour at their active site that steers the carbocationic cascade catalyzed by PR-AS toward the production of a single enantiomer. iv In the second part of the present work, progress was made towards the stereoselective synthesis of 5-aza-eudesmane cation. This teriary amine is a structural mimic of the 5-eudesmane carbocation, another putative intermediate in the reaction cascade catalysed by PR-AS. However, this tertiary amine was not obtained with desired stereochemistry, nevertheless, two diastereoisomers of the desired compound were obtained.