This thesis describes the synthesis and new reactions of oxetan-3-ones. Chapter 1 gives an introduction to oxetanes and includes discussion of methods for their synthesis, their reactions, specifically those involving the use of oxetan-3-ones, and their relevance in medicinal chemistry and natural products. Chapter 2 begins with an introduction to multi-component reactions (MCRs) and moves on to describe our efforts in incorporating oxetanes into structurally diverse compounds using Passerini three-component reactions (P-3CRs) and Ugi four-component reactions (U-4CRs). A range of 3,3-disubstituted oxetanes are successfully made in 23-98% yield by reaction of oxetan-3-ones with various carboxylic acids and isocyanides. The synthesis of chiral 2-substituted oxetan-3- ones using the SAMP chiral auxiliary method is also demonstrated, specifically oxetan-3-one is converted into 2-benzyloxetan-3-one in 51% overall yield and 74% ee in three steps. Chapter 3 details our efforts towards the incorporation of the oxetane unit into tetrahydro-β-carbolines using the Pictet-Spengler reaction. Several oxetan-3-ones are demonstrated to take part in Pictet-Spengler reactions with tryptamine and tryptophan ethyl ester derivatives. The chemistry is successfully extended in azetidinones.

The original aim of this research was to prepare a series of metal - olefin complexes, and investigate the effect of the metal on the olefin. In particular, whether sufficient electron density could be withdrawn from the olefin, to make it susceptible to attack by carbon nucleophiles. Initial results with the n-propene cation, [n-C5H5Fe(CO)2C3H6]+ indicated that attack took place on the metal, in preference to the ligand. Attempts, in order to change the steric conditions around the metal, to prepare the analogous phosphine substituted complexes, for example, [n-C5H5Fe(CO)P¢'3C3H6]+ resulted in unexpected results. As a result the chemistry of the phosphine substituted system was studied in greater detail, particularly the properties of the unknown δ -propyl and δ-allyl derivatives, n-C5H5Fe(CO)r¢3R. These studies showed that hydride abstraction of the δ -propyl derivative, .n~C5rr5Fe(CO)r¢3CH2CH2CH3, did not give the n-propene cation,[n-c5H5Fe(CO)P¢3C3H6]+. This cation was, however, prepared on protonation of the d-allyl derivative, n-C5H5Fe(CO)r¢3CH2crr==CH2' but shown to be very unstable, readily losing propene. Similar n-propene cations have been shown to be sensitive to excess acid. A general mechanism is proposed, in which the n-propene cation loses propene, to give the unsaturated cation, which can then either react further with the nucleophiles, for example the acid anions, to yield covalent products, or, in the case of the tetrafluoroborate or hexafluorophosphate salts, can be isolated. The reaction of bromocarbonyltriphenylphosphine-n-cyclo- pentadienyliron, n-C H 5 Fc( CO )P¢3Br , with Lewis acids, was invesstigated as a route to the unsaturated cation, [n--C5R5Fe(CO)P¢3]. The reaction, however, cave a mixture of cationic species. The three that have been isolated so far are, [n-C5H5Fe(Co)P¢3J+, [n-G 5 II 5 Fe(CO)2P¢3]+' 'and [TC-C 5 H S Fe(CO )2-Br-( CO )2Fe(n-C 5 H 5 )] +. The phosphine lability observed in these reactions was typical of all derivatives in this system, for example, δ -allylcarbonyl- triphenylphosphine-n-cyclopentadienyliron, n-C5H5Fe(CO)P¢3CH2CHi=CH2 was thermally unstable, yielding triphenylphosphine and n-allyl- carbonyl-n-cyclopentadienyliron, 1t-C 5 H 5 Fe(CO)-TC-C 3 H 5. The kinetics of this reaction were studied, and used to suggest a mechanism for the reaction.

1. A colourless mutant, strain 1M, of the extreme halophile Halobacterium salinarium strain 1 was shown to be more sensitive to changes of NaCl concentration than the wild-type. The levels and cellular distribution of several enzymes were determined in each strain and the sensitivity to changes of NaCl investigated for selected membrane bound and soluble enzymes. ATPase, acid phosphatase, alkaline phosphatase and glycerol dehydrogenase of both strains all showed typical halophilic enzyme responses with optimum activity only in the presence of 2-5 - 4·0M salt. 2. Malate dehydrogenase from strain 1 was extracted and purified. The purified preparation showed an 850 fold increase of specific activity Over the crude extract. The fluorescence probe 1- 8 AN was used to investigate possible conformational changes induced in the purified enzyme by variations of NaCl concentration. Results indicate that upon removal of salt ANS fluorescence is enhanced possibly implying that unfolding of the protein occurs. 3. The cell membrane of strain 1 and 1M has been prepared from cell envelopes and purified by gel- filtration on Agarose Some Purification resulted in the release of a low M. W. ( "V 2500) polar protein which contained some nucleotide material. Electron micrographs of crude and purified membrane showed abundant triple layered structures and vesicles typical of classical unit membrane structures. Urea caused the release of highly polar fractions which were isolated by PGE and characterised by gel-filtration and amino acid analysis. 4. The membrane lipid of strain 1 and 1M were extracted and a preliminary characterisation carried out. sides the lack of carotenoid in strain 1M other differences in the lipid composition were found between the two strains. train 1M contained less menaquinone and at least two different phospho-lipids. Lipid-free membrane protein was extracted by a method combining organic solvent extraction and gel- filtration. The membrane protein of both strains was shown to be a polar in character and heterogeneous by separation on PGE. A structural protein fraction which may b similar to SP obtained from other membrane sources was isolated from purified membrane. 5. Purified membrane was solubilised with mixed anionic detergents (sodium dodecyl sulphate, sodium cholate and sodium deoxycholate ) and separated by gel- filtration into protein-rich and lipid- rich fractions. The lipids from each of these fractions were extracted and compared with total mernbrane extracts. The lipid component of the protein-rich fraction appeared to contain mainly polar lipids. 6. The protein-rich and lipid-rich fractions were reaggregated in the presence of 10~ Mg2+ or 5mM spermine to form reconstituted membrane . Reconstituted membrane appeared in e. m. s to contain unit membrane structures . Like native membrane, reconstituted membrane could only be disrupted by anionic detergentst indicating that hydrophobic bonding was of prime importance in the interaction between protein and lipid. Experiments in which membrane protein was labelled with the florescent probe DNS indicated that the membrane protein and lipid fractions were stabilised to some extent when they interacted. However, significant differences were observed in the behaviour of dansylated native membrane and dansylated reassembled membrane indicating that the organisation of protein and lipid in each may not be directly comparable.

This thesis describes an approach to the problem of computing electronic charge distributions in molecules. The molecule is treated as a collection of atoms in assumed valence states. Sigma and pi electrons are separated from each other. The sigma electron distribution is computed using a valence state scheme the essence of which is a system of orbital charge equations, a unique equation for each type of bond. The form of orbital charge equation for a bond X - Y described by an M.O. Ψ = ciϕi + cjϕj where ϕi and ϕj are the bonding A.O.'s (usually hybrid) on X and Y respectively is N(XY) = kYXNyT - KXYNXT + IXY where N(XY) is the charge in orbital ϕi in the bond X-Y. kYX, kXY, IXY are all parameters and NXT, NYT are the total charges on X and Y excluding the charges in ϕi and ϕj. The interaction of the sigma electrons with the pi electrons is described in two ways. In the first method the interaction occurs through charge dependent inductive parameters hX in the expression αX = αC + kXβCC The sigma electron calculation is linked to a H.M.O. calculation to form an iterative method, the iterative self-consistent charge method - I.S.C.C.M. In the second approach a P.P.P. (σ + π) method is developed in which the sigma distribution provides a potential framework for the pi electrons. The Wμ terms in the diagonal matrix elements of the P.P.P. method are interpreted as valence state ionisation potentials (V.S.I.P.'s) of the pi orbitals and are expressed as functions of the charge distribution, sigma and pi. The advantages and disadvantages of the two approaches are discussed and the charges obtained using both methods are compared with other results in the literature.

This thesis presents the synthesis of two novel O-carboxyanhydrides derived from L-malic acid bearing 2,2,2-trichloroethyl- and 2-nitrobenzyl esters, followed by investigation of their ring-opening polymerisation to furnish chiral, functionalised poly(malic acid)s. A further report is made of the synthesis of two novel chiral cyclic carbonates bearing leucine derivatives coupled with amide and ester linkages, the ring-opening polymerisation is investigated and leads to the controlled synthesis of dihydroxyl telechelic poly(carbonate)s with inherent chirality. Finally, the synthesis of a cyclic carbonate bearing pendant glycidyl ether functionality is reported, followed by investigation of the homopolymerisation to yield a poly(carbonate) bearing pendant epoxide functionality, the first known report for a degradable polymer. The post-polymerisation functionalisation of this homopolymer by the addition of amines is investigated to allow a variety of functional groups to be incorporated.

This thesis describes the synthesis, characterisation and macroscopic properties of phosphate materials made from gypsum, CaSO4⋅2H2O, using inorganic chemical reactions. The aim was to reduce the degradation of gypsum based materials by water exposure, using strategies that included the complete conversion in hydrothermal conditions to a material having a much lower solubility, e.g. hydroxyapatite, Ca5(PO4)3OH, and coating/binding calcium sulfate crystallites with a more water resistant material. The hydrothermal conversion of gypsum to hydroxyapatite was a poorly understood reaction since all previous measurements on the intermediate and final products had been conducted after the reaction had been quenched, which may have resulted in the crystallisation of species that would not usually form. In–situ X-ray measurements described herein have provided new information about the kinetics and mechanism of this conversion. It has been found however, that this reaction is not viable with respect to stabilising gypsum to water degradation after unsuccessful attempts to increase the reaction kinetics. It was discovered in the in-situ measurements that the conversion proceeds from the outside, towards the centre of monoliths of porous vast gypsum samples and seems to be limited by the rate of ionic diffusion. Increases in reaction temperature caused the crystallisation of other species such as calcium sulfate hemihydrate, CaSO4⋅½H2O and monetite, CaHPO4, decreasing the stability of the product. A novel method of processing gypsum has been found, forming true composites of crystal sulfate anhydrite crystallites, bound by a water resistant phosphate coating. These composites which have the microscopic appearance of a ceramic, have been made for the first time and characterised using an array of analytical techniques such as X-ray diffraction, Fourier-transform infrared spectroscopy, scanning electron microscopy and 31P solid-state nuclear magnetic resonance, the latter being extremely informative of binder composition and allowing the identification of an interfacial layer between the anhydrite crystallites and phosphate coating. Physical measurements such as the dissolution kinetics have been made in order to understand the effect of composition on the kinetic stability of the composites to water exposure, related back to the chemical analysis. The phenomenon of thermal diffusion of calcium from anhydrite; thought to be responsible for the composites’ formation, coupled with an apparent lower thermal conductivity, also has exciting implications for other applications of gypsum such as the fireproofing of buildings.

Spirotetronate antibiotics are natural products that have been shown to have a broad spectrum of biological activities, including antiviral, antibacterial, antitumor and antimalarial activities. Two representatives of this group are quartromicins and chrolactomycin, which are produced by Amycolatopsis orientalis and Streptomyces sp. 569N-3 respectively. Based on other related natural products with known biosynthetic pathways, the biosynthetic routes for quartromicins and chrolactomycin were proposed and several strategies for locating the putative gene clusters directing the biosynthesis of these natural products were used. An FkbH-like protein was proposed to be specifically involved in the biosynthetic incorporation of a glycerol-derived three-carbon unit into the tetronate moieties of quartromicins and chrolactomycin. It was selected as a target to locate the biosynthetic gene clusters of tetronate natural products. After aligning sequences of known FkbH-like proteins, a set of degenerate oligonucleotide primers for amplification of fkbH-like genes was designed and tested. Fragments of fkbH-like sequences were amplified from several available strains and sequenced. Several genomic libraries were created and screened by PCR using the degenerate fkbH primers. After validating the library, clones containing the putative biosynthetic gene cluster were identified and sequenced. The obtained sequence data was then assembled and analysed. Coding sequences were identified, protein functions assigned and a biosynthetic route was proposed for the biosynthesis of quartromicins and chrolactomycin.

Today, more than 70 % of clinically-used antibiotics are produced by Streptomyces species. However, it is estimated that only 1 % of secondary metabolites produced by these bacteria have been discovered to date. Chemical communication in bacteria is defined as producing and responding to signalling molecules, which govern physiological processes, including antibiotic production and morphological differentiation. By understanding the signalling mechanisms of such molecules, new bioactive metabolites, of value to society, can be discovered. Examples of well characterized signalling molecules include acylhomoserine lactones (AHLs) and γ-butyrolactones (GBLs). A recently-discovered novel class of signalling molecules, 2-alkyl-4-hydroxymethylfuran-3- carboxylic acids (AHFCAs), which induce methylenomycin antibiotic biosynthesis in S. coelicolor is being studied in our group. We have investigated the structure-activity relationship of AHFCAs with respect to induction of methylenomycin production. The methodology of Davis et al. has been applied and extended to synthesise a range of AHFCA analogues with different alkyl chains, as well as modifications to the hydroxymethyl and carboxyl groups and the heterocycle (Figure 2). The ability of the resulting library of compounds to induce methylenomycin production was investigated. Structural features that are important for the biological activity of the AHFCAS were identified. Surprisingly, several analogues had very similar biological activity to the natural products. In 2007, a biosynthetic pathway to γ-butyrolactones was proposed and AfsA was shown to be a key enzyme in this process. mmfL encodes an AfsA-like protein, which is hypothesised to catalyse the formation of a butenolide intermediate in methylenomycin furan biosynthesis. mmfH and mmfP encode a flavin-dependent monooxygenase and a phophatase, respectively. Here, we report biochemical characterisation of the MmfL, MmfP and MmfH enzymes as well as attemps to reconstitute the methylenomycin furan biosynthetic pathway in vitro.

We demonstrate the combination of supramolecular chemistry (multiple hydrogen bonding) with polymer colloidal sciences in the creation of interesting materials. This provides us an access to the unique structures and properties that [sic] not possible to [sic] traditional materials. We first developed cellular polymer films made from 2-ureido-4[H]-pyrimidinone (UPy) quadruple hydrogen bonded soft latexes. The films show colloidal crystalline-type Bragg diffraction features when exposed to solvents, and do not suffer excessive and deteriorative uptake of water and, more remarkably can absorb high amounts of organic solvents. Impressively, Pickering high internal phase emulsion gels can be prepared by using these UPy functionalized particles as stabilizers under extremely low shear stress and short time. Moreover, we first used the UPy functionalzed macromonomer as non-colvalently [sic] crosslinker to prepare thermo-sensitive nanogel particles which are conventionally made using covalent-bond crosslinkers. Templated high internal phase emulsion hydrogel monoliths stabilzed by these nanogels can be prepared through injection moulding, which also exhibit excellent thermo-responsive properties. Alternatively, we also first created interesting Janus micro-beads with highly anisotropic and tunable internal architecture based on complementary hydrogen bonding interactions, rather than UPy self-complementary interactions, by single emulsion-droplet microfluidic technique.

Within this thesis, research related to the synthesis of Pt(II) and Pt(IV) cyclometallated complexes involving both aryl and alkyl C-H activation is discussed. The introduction reviews literature relevant to C-H activation, cyclometallation and reductive elimination, both historic and current. Four pyridine based pro-ligands, all with a 4-fluorophenyl substituent and a varying alkyl substituent, were synthesised in order to study both aryl and alkyl C-H activation. Initial reactions with K2PtCl4 led to the cyclometallation of the phenyl ring via a reversible aryl C-H activation, which then resulted in a variety of Pt(II) complexes by the addition of different co-ligands. Oxidation of these Pt(II) species gave Pt(IV) complexes, which subsequently underwent isomerisation to give the thermodynamic product. For the DMSO derivatives this was shown to occur via five coordinate complexes stabilised by agostic interactions with the alkyl chain and resulted in the first crystallographically characterised oxygen bound DMSO Pt(IV) complexes. Pt(II) and Pt(IV) sp2 cyclometallated complexes, each with an sp3 agostic interaction, were isolated and characterised when using the more sterically demanding tbutyl derivative of the pro-ligand. Subsequent alkyl C-H activation of the tbutyl group was observed via an intra-molecular transcyclometallation reaction to give complexes with an sp3 cyclometallation. From these species a series of complexes with a C(sp2)^N^C(sp3) tridentate ligand were also synthesised. It was also noted that a reversible rollover reaction of the Pt(II) agostic complex occurred in DMSO solvent by exchanging the C(sp2)^N cyclometallation for a C(sp2)^C(sp2) cyclometallation via decyclometallation, rotation about the central C-C bond and subsequent C-H activation. Reductive elimination of a chloride ligand with both sp2 and sp3 cyclometallated carbons occurred to give functionalised phenyl rings and tbutyl groups, respectively. Steric interactions were shown to play a major role in these reactions.