This thesis describes the development of new methods for the synthesis of mono-, diand trihydroxylated tetrahydroxanthones which are structural elements of a range of important natural products including the anti-cancer agents known as the kigamicins. In Chapter One, work on the isolation, biological significance and chemical synthesis of xanthones, dihydroxanthones, and tetrahydroxanthones is reviewed, with special focus on the polycyclic tetrahydroxanthone natural products. Chapter Two describes the development of methods for the synthesis of tetrahydroxanthones mimicking the ABC rings of kigamicin A which contain a hydroxyl group at C-3 of the saturated ring. A 5 step synthesis of 228 was achieved via palladium catalysed assembly of tetrahydroxanthone nucleus, followed by enantiocontrolled reduction of the C=O group via asymmetric transfer hydrogenation, and glycosidation using a novel trichloroacetimidate donor 225. In Chapter Three, a short route to the cis and trans1,4-diol functionality found in the tetrahydroxanthone fragment of 1,3,5-trihydroxy-8-β-D-glucopyranosyl, puniceaside B, puniceaside C, albofungin, and simaomicins is achieved. Excellent enantiocontrol (99% ee) was realised through use of an asymmetric ketone transfer hydrogenation. Subsequent enolate hydroxylation with the Davis oxaziridine facilitated installation of the second hydroxyl group albeit with low levels of diastereocontrol. The structure of cis-277 was verified by X-ray crystallography after conversion to the corresponding diacetate 279. Similar enolate hydroxylations were used to access the triol substitution patterns found in kibdelones and isokibdelones. Attempts to develop synthetic routes to the fully functionalised A-ring fragments of the actinoplanones and kigamicins are described. This culminated in the preparation of advanced synthetic intermediate 322 in 4 steps from hydroxyl selenide tetrahydroxanthone. In a key step in this sequence, an unusual syn-selective dihydroxylation of a PMB-protected homoallylic alcohol (321) was unearthed. Finally, the biological effects of the new dihydroxanthones, dihydroxy, and trihydroxytetrahydroxanthones synthesised in the laboratory were evaluated against human pancreatic cancer cell line (PANC-1), grown separately in nutrient rich medium (NRM) and nutrient deprived medium (NDM). In Chapter Four, detailed experimental and characterisation data for the new compounds are described.

The ruthenium catalysed oxidation of 1-phenylethanol derivatives with the release of hydrogen gas has been studied. A hydrogen acceptor was introduced in an effort to elucidate the rate-determining step of the reaction. The transfer of hydrogen from complex alcohols to simple aldehydes and ketones was pursued as a process for obtaining simple alcohols for fuel cell applications. The Shvo catalyst was identified as being the most efficient catalyst for the oxidation of difficult substrates. A family of iron analogues of the Shvo catalyst were synthesised and studied as precatalysts for the oxidation of alcohols. Catalyst activation was achieved by the removal of a CO ligand using trimethylamine-N-oxide and the oxidation of 1-phenylethanol derivatives with acetone was studied. Simple aldehydes were evaluated as hydrogen acceptors and a novel formylation reaction was discovered. Asymmetric iron analogues of the Shvo catalyst were synthesised and applied to the asymmetric transfer hydrogenation of acetophenone using 5:2 formic acid/triethylamine. The synthesis of further analogues with a tethering group was investigated to improve catalyst stability and enantioselectivity. Novel chiral diamine and amino-alcohol ligands containing 1,2,3-triazole functionalities were developed as ligands for the asymmetric transfer hydrogenation of ketones. Tridentate diaminotriazoles provided the best activity and selectivity in the reduction reactions with Ru3(CO)12.

This project is concerned with the synthesis of Viscosity Modifiers (VMs) for use in gear box oils. The use of amines as precursors for initiators is also of interest due to their dispersant properties. Atom transfer radical polymerisation (ATRP) was used to prepare statistical copolymers of n-Butyl methacrylate and C12/15 methacrylate for use as VMs. These copolymers were first of a linear nature demonstrating that ATRP could be used to polymerise this monomer combination to give well defined polymers with a high degree of control. Thereafter, multi-functional initiators were used to synthesise core first stars with differing numbers of arms. Three, four, five and eight arm stars were successfully synthesised giving well defined polymers. These polymers were tested by Lubrizol for their viscometric properties. All were found to give significant improvements versus Lubrizol’s existing linear polymers in almost all respects. Although the core first stars gave a significant improvement in viscometric properties the costs of the core are relatively high for the application. Therefore the synthesis of arm first stars via ATRP was carried out. Design of experiment (DoE) was used to aid in the optimisation process and to interrelate any factors used in the design. The DoE process indicated two relationships between input factors, one of which was defined numerically. A range of polymers were synthesised on a larger scale for testing by Lubrizol for their viscometric properties. The polymers were found to have exceptional viscosity properties, compared to the baseline sample. The use of amines as precursors for initiators (forming amide initiators) was investigated. 4-Aminodiphenylamine (ADPA) was synthesised into an initiator suitable for ATRP and used in several polymerisations. It was found to have very low initiator efficiency. For this reason Single Electron Transfer Living Radical Polymerisation (SET-LRP) was employed to polymerise methyl acrylate from this initiator with near 100% initiator efficiency. A range of other amide initiators were also successfully used in polymerisations. A new solvent system for SET-LRP was also demonstrated. The addition of phenol to toluene promoted the disproportionation of Cu(I) allowing SETLRP to take place. Polymers were synthesised in this solvent mixture with high degrees of control over molecular weight with narrow Polydipersity indexs (PDI).

The major goal of this work is to develop and test a system capable of monitoring polymerisation processes in real time. Such a system should provide accurate conversion and molecular weight distribution data compared with results from manual sampling. Online monitoring techniques have been applied to the controlled radical polymerisation of methyl acrylate mediated by copper wire. Conversion has been measured using Near Infra-Red spectroscopy and conversion and molecular weight distributions monitored with rapid chromatography and the results compared with conventional analytical techniques in order to demonstrate the validity of the data. Parameters that affect the reaction have been varied in order to optimise conditions for synthesis and gain an insight into the reaction mechanism. Alcohols as additives in a non-polar solvent system for Cu(0) mediated polymerisation of methyl acrylate have been assessed. These reactions potentially facilitate the polymerisation of monomers for which polymerisation using copper metal would otherwise be inaccessible due to lack of solubility.

Chapter One provides a review of the literature relating to the isolation, structure elucidation, biological activity, and mode of action of the azinomycins. It also provides an overview of the synthesis and biological activity of simplified synthetic analogues. Chemical strategies towards the natural products are presented, as are proposals for the biosynthetic construction of these complex metabolites. Chapter Two describes our synthetic efforts towards simplified analogue 90 of azinomycin B, containing an amide substituent at N5, using the N16–C17 amide bond disconnection. These studies involved the synthesis of α-azido-β-hydroxy ester 125 in eight steps and 5% overall yield from L-methyl serinate. Further progression of 125 to fully elaborate the right-hand domain could not be achieved. Chapter Three explores a new approach to the azinomycins, based around the formation of the C7−N16 enamide bond using copper mediated cross-coupling methodology. Amides related to the left-hand domain of the azinomycins, 140 and 142, were demonstrated to undergo copper-mediated cross-couplings with phenyl iodide in yields of 19% and 64% respectively, demonstrating the potential of this approach. Methods for the synthesis of suitable coupling partners were explored. The most efficient route utilised the Eschenmoser sulphide contraction to elaborate Rpyroglutamic acid to bromoalkylidenepyrrolidine 184 in 7 steps and 16% overall yield. Initial studies into the amidation of 184 suggest that protection of the pyrrolidine nitrogen will be required to facilitate cross-linking. Chapter Four details the synthesis and biological evaluation of a range of new bisepoxides based on the azinomycin “left-hand” domain, which possess rigid linkers. The most potent of these analogues was identified as bisepoxide 203 (GI50 = 0.33 μM). All the new analogues displayed reduced potency compared to those based around aliphatic linkers, suggesting that they cannot readily adopt viable conformations for ISC formation. Chapter Five contains detailed experimental procedures for the new compounds described within this thesis.

Chapter One provides a review of the literature relating to the isolation, structure elucidation and biological activity of ficellomycin, a natural product with antibiotic activity. This chapter also provides an overview of published synthetic routes towards ficellomycin and l-azabicyclo[3.1.0]hexanes. Chapter Two describes our synthetic efforts to the l-azabicyclo[3.1.0]hexane core of ficellomycin. Initially, a model system developed in the group with a double cyclisation as key step was optimised. This involved the reduction of a 1,2-azido alcohol, using a solid-supported triphenylphosphine reagent, to an aziridine that undergoes conjugate addition onto a tethered dehydroamino acid in situ. Under these conditions, azido alcohol 94 led to the formation of the four stereoisomeric bicycles 45 alb, 142 alb, in 45% overall yield in a 3: I :5: I ratio. A second approach towards the natural product is also described. This involved the development of a system wherein the C-5 amino substituent is incorporated. Two open chain y-aldehydes 212 and 232, were made in 8 and 10 steps respectively from 168 using a sequence that involved anti-I,4-addition of azide onto 168, formation of Weinreb amides 211 and 231 and their chemoselective reduction as key steps. Reaction of these aldehydes with phosphonate 99 using DBN, produced alkenes 214 and 230 respectively, and exclusively, as the (Z)-isomers. Further stereocontrolled cyclisation to piperidines 220 and 235 possessing the required 38, 58, 6Rstereochemistry was achieved in good yields by hydrogenation using Lindlar's catalyst. We anticipate that these intermediates could be further advanced to the natural product. Chapter Three draws conclusions from the work to date, and discusses future options with respect to the completion of the synthesis to the natural product. Chapter Four contains detailed experimental procedures for the novel compounds described within this thesis.

In this work, force fields were developed to model flexible helical metalorganic framework solids (MOFs). Since no suitable force fields to model flexible MOFs had been reported, the study began by benchmarking an existing organic force field, CHARMM22, against Ni3(BTC)2(pyridine)6(4,5octanediol) 3. CHARMM22 force filed did produce a framework that retained its original threedimensional structure for the duration of the simulations, and did so at experimentally relevant temperatures provided a minimum number of 20 solvent molecules per unit cell were included. However, important inadequacies were found between the experimental crystal structure and the simulated one. Therefore a series of refinements of the force field were performed. The three best modified force fields were then used to simulate this MOF and a detailed analysis of its physical properties produced. A key conclusion from the development and testing cycle was that hydrogen bonding between the BTC and the hydroxyl groups of both the solvent and the framework alcohol molecules played a critical role in stabilizing the MOF. The transferability of these forcefields was tested against two new MOFs, for which experimental crystal structures had been reported: Ni3(BTC)2(pyridine)6(2,3butanediol) 3 (called MOF4) and Ni3(BTC)2(pyridine)6(1,2,6hexanetriol) 3 (called MOF6). One forcefield was found to give a good description of MOF4. For MOF6 however, competition for framework bonding between the diol and terminal hydroxyl group on the hexanetriol destabilized the framework with all three force fields. A stable MOF was produced only when the NiOT bond lengths were constrained to the experimental values. It was concluded that polarisation of ligand donor atoms by the Ni2+ needed to be incorporated in any future refinements of the forcefield. Finally, this study showed that the Ni3(BTC)2(pyridine)6(4,5octanediol) 3 MOF can display enantioselective properties. Solvent alcohol molecules of the same enantiomeric form as that incorporated into the framework were found to interact much more strongly with the framework than their enantiomer, and even formed enantiomer specific hydrogen bonds with the framework. Structural differences were also observed in solventBTC, solventNi and solvent pyridine geometries.

Metal complexes currently are currently of much interest in the field of anticancer drug development. Platinum complexes such as cisplatin, are now widely used in the clinic and have led to a focus on the synthesis of new classes of other metal-based complexes, such as ruthenium anticancer drugs. In order to understand the mechanism of action of these complexes and to improve structureactivity relationships thereof, a comprehensive study of the solution chemistry is important. In this thesis the mechanism and kinetic detail of the exchange of amino protons on one such class of complex, [(η6-biphenyl)Ru(N,N’- ethylenediamine)Cl]+ was investigated in detail. Stereospecific assignment of NH protons was carried out by NOESY NMR on a pyridine adduct [(η6- biphenyl)Ru(N,N’-ethylendiamine)(N-pyridine)]2+. Using 1H and 2H NMR spectroscopy, rates of exchange were observed at different pH values, temperatures and ionic strengths a series of N-H/2H exchange reactions were studied and the data collected. The data are consistent with an exchange mechanism involving proton abstraction from the amine, followed by favourable reprotonation on the lowerface (relative to the overhanging arene) of the Ru(N,N’- ethylendiamine) five membered ring. In chlorido complexes this leads to the exchange of lower proton at a rate of three times that of those on the upperface at 298 K. To investigate the effects of electron density on the ruthenium on the exchange rates a series of π-donor pyridine ligands (pyridine, 4-methylpyridine, 4- tert-butylpyridine, and 4-methoxypyridine) in the place of the chloride were studied. The exchange rates were also investigated and showed a correlation between the basicity of the pyridine derivative and the favourability of exchange on the lower face, increasing this bias upto 11 fold. Density functional theory calculations suggests that there is an overlap between the p-orbital of the (ethylenediamine) nitrogen and the π*-antibonding orbital on the Ru-N(Pyridine) bond and σ*- antibonding orbital on the Ru-Cl bond, in their respective complexes. This overlap is proposed as a stabilising force on the deprotonated nitrogen allowing for a negative charge to be more stabile in one lobe of the p-orbital preferential to another. Following abstraction of the proton, the lone pair on the nitrogen is stabilised by an antibonding orbital, the top face less is susceptible to proton addition. Since DNA is a potential target for these complexes, the changes in shape induced by metal binding were investigated using Ion-Mobility Mass Spectrometry for the first time. Also in this work, the first ion-mobility mass spectrometry studies of the collisional cross sections (CCSs) of small complexes (<100 Å2) is also presented. This was developed using a new glycine based calibrant. Following binding of [(η6-biphenyl)Ru(N,N’- ethylenediamine)Cl]+ to the DNA hexamer d(CACGTG) changes in CCS values between ruthenated and non-ruthenated hexamers were studied. The change in CCS between these was not additive and suggestive of some folding or intercalation occurring upon ruthenium binding. Finally, attempts were madeto investigate shape change induced in DNA by binding to cisplatin using Förster Resonance Energy Transfer Methods are described. To date these results are inconclusive but work in this field is ongoing.

A rapid flow method for the production of radical-anions for electron spin resonance (e.s.r.) observation is described whereby liquid ammonia solutions of sodium and substrate are mixed in the cavity of the spectrometer. The mixing-cell consists of several capillary tubes placed in a glass jacket narrowing at one end to form a nozzle. Liquid ammonia soltelons are passed under pressure of nitrogen through capillary tubes and interstices and radical-anlons can be observed within a few milliseconds of mixing. Results are presented in five chapters. The reduction of pyridine and substituted pyridines is described in ChapterII; with the exception of one mono- and all dicarboxylic acid derivatives, simple monomer radical-anions are formed. Pyridinecarboxylic acids ionise in liquid ammonia solution and in some cases the ionized proton attaches itself to the radical-anion forming an N- protonated species. N- protonation is also seen for pyridine itself when reduced in the presence of a large excess of ethanol, a strong acid in ammonia. A complementary static reduction technique is used to observe reduction on a longer time scale where several dimeric products are observed, for example 2,6-dimethylpyridine gives 2,2',6,6'-tetramethyl-4,4'-dipyridyl radical-anion. Carbon halogen bond-cleavage occurs rapidly when aryl hallides, except fluorides, are reduced (Chapter III). The halogen atom in fluorobenzonitriles shows varying degrees of lability; for example, a mixed spectrum of halogenated and dehalogenated radical-anions is seen for para-fluorobenzonitrile while even after the insertion of a one second delay between points of mixing and observation only the halogenated radical-anion is observed for meta-fluorobenzonitrile. Aromatic carboxylic acid reduction (Chapter IV) produces the expected radical-anions, with the exception of two nitro di-acids which produce a mixture of radicals on the flow system, and a spectrum possibly corresponding to a radical-anion similar to the parent nitro di-acid on static reduction. Analysis of the major flow spectrum again indicates a protonated species. Styrenes and benzamides show non-equivalent ring protons resulting in complex spectra (Chapters V and VI). The 'alpha effect' is used in Hückel and McLachlan molecular orbital calculatlons for styrenes where one ortho ring position is given a small Coulomb integral value. The results of the reduction of some -unsaturated ketones are discussed in Chapter VI. Analysis of the spectrum of mesityl oxide radical-anion is straightforward, while slow 'ring-flip' from one conformer to another is responsible for inequivalent methylene protons in isophorone and 2-cyclohexen-1-one.

Derivatives of enantiomerically pure 1,2-cyclohexanediamine and 1,2- diphenylethanediamine have been synthesised and used as organocatalysts for asymmetric reactions. The derivatives of 1,2-diphenylethanediamine have been employed for C-C, C-N bond formation reactions to determine their efficacy and selectivity. Compound 278 has shown high efficiency and selectivity for addition of aldehydes to DEAD. Novel Ru-metal complexes containing enantiomerically pure N,N-dialkylated-1,2- diamine ligands have been synthesised. Complexes 299 and 302 were used to study asymmetric transfer hydrogenation of ketones and imines. These complexes were found to be selective for the imine reduction compared to ketones reductions under the conditions used. Results obtained by these complexes also provided support for the proposal that reduction of the ketones involves a cyclic concerted mechanism for the transfer of hydrogen, while reduction of imines involves transfer of hydride from the complex through an ‘open’ transition state. Asymmetric transfer hydrogenations of α,α-disubstituted ketones were carried out using Ru-3C-tethered catalyst 181. Results obtained for asymmetric transfer hydrogenation of these compounds show that unsaturation or an aromatic group in substitution at the α-position of the ketone gave products of high enantioselectivity. This may be due to the interaction between η6-arene ring of Ru-complex and the group placed on the α-position of the ketone.