The electropolymerisation of a range of 5-substituted indoles has been shown previously to result in the formation of redox-active films. The oxidation potentials of both the indole monomers and their polymers can be altered by substitution of the monomer with different electron-withdrawing groups. Both the indole monomers and polymers also have high fluorescence quantum yields. However the fluorescence wavelengths of the indole polymers are not tuneable by substitution. In this thesis the work on the electropolymerisation of indole(s) is extended to two monomers which have larger conjugated systems than the indoles; indolo{3,2,1-jk}carbazole (IC) and pyrrolo{3,2,1-jk} carbazole (PC). A combination of computational, electrochemical and spectroscopic techniques have been employed to investigate both these monomers and their polymers. Computational confidence tests have been performed on a range of small organic molecules to assess methods of calculating oxidation potentials, radical cation spin density distributions and excited states using the software Gaussian 98. Calculations have predicted the oxidation potentials of such molecules to within 0.19 V of their experimental values. These calculated oxidation potentials are systematically underestimated. Gaussian 98 has been used to calculate the radical cation spin density distribution of indole and has been found to reproduce the results of previous calculations performed using the software DMol³.  Configuration interaction singles (CIS) calculations incorrectly predicted the energetic ordering of the two lowest singlet excited states of indole and carbazole. However CIS correctly predicted the dipole moment of the ^IL_a state to be larger than the dipole moment of the ^IL_b state of indole. The oxidation potentials of IC and PC have been measured experimentally and calculated. IC and PC have both been electropolymerised to form redox-active polymers. IC forms a conducting film which has been shown to contain two different dimers by mass spectrometry and NMR. Although successful in predicting the ring positions at which indole(s) link during electropolymerisation, radical cation spin density calculations have been shown to be unsuccessful in predicting the linkage sites for IC. The mechanism of electropolymerisation of IC has been shown to be similar to the mechanism of electropolymerisation of indole(s) with initial film formation occurring in solution, followed by linkage of IC radical cations which are adsorbed on the electrode surface. The diffusion coefficient has been measured from Koutecky-Levich plots as 5.9 x 10^-5 cm² s^-1 (±2.0 x 10^-3). The rate of film formation for IC has been shown to be approximately 0.8 times that of indole-5-carboxylic acid and 0.7 times that of 5-cyanoindole. Steady-state fluorescence spectroscopy in solution at room temperature has shown both the IC and PC monomers and their polymers to be highly fluorescent. There is no significant difference between the equilibrium geometries and potential energy surfaces of the IC monomer in the ground and first singlet excited states. However such a difference does not exist between the ground and first singlet excited states of the PC monomer. The electropolymerisation of each monomer produces a number of emitting species which have more extensive p-electron delocalisation than the monomers. The emission from the IC dimer peaks at 408 nm. IC electropolymerisation has been shown to proceed in a similar manner to indole electropolymerisation, with the first step the formation of dimer followed by the linkage of dimer units to form longer polymer species. The IC polymer has been found to be fluorescent in the solid state.

Reactions of isolated carbonyl groups in ethene/propene-carbon monoxide alternating copolymers were accomplished by acid-catalysed condensation with alkene-1,2-diols (ethane-, propane-, butane- and hexane-1,2-diols) affording alkene-dioxolane copolymers. Oximation with hydroxylamine, <i>O</i>- methylhydroxylamine and <i>O</i>-benzylhydroxylamine resulted in complete conversion of the carbonyl groups to their oxime derivatives. In addition, the conversions of polyketoximes, derived from ethene/propene-carbon monoxide copolymers, to 1-acteoxyiminotrimethylene and 1-benzoxyimino-trimethylene polymers were achieved by treatment with acetic anhydride and benzoyl chloride, respectively. Reaction of 1,4-dione units in ethene/propene-carbon monoxide alternating copolymers has been investigated. Paal-Knorr reactions with aniline, benzylamine and glycine ethyl ester yielded poly(alkenepyrrole) derivatives. The conversion of the carbonyl groups in ethene/propene-carbon monoxide alternating copolymers to methoximes allowed directed a-substitution reactions to be carried out on the polymer backbone. Treatment with <i>n-</i>butyllithium followed by addition of electrophiles (e.g. iodomethane, 1-iodopropane, 1-bromobutane, benzyl bromide and allyl bromide) afforded the polymer products in which 20-38% of the a-<i>syn</i> methylene hydrogens were substituted. The <i>syn</i> selectivity of the lithiation process was established b treatment of the polymethoxime with BuLi/[<i>O</i>-²H]methanol and confirmed by the presence of deuterium signal in the ²H-NMR spectrum corresponding to those observed for the model compounds. Beckmann rearrangement reactions of model compounds [2.5-bis(tosyloxyimino)hexane, 2,5-bis(mesyloxyimino)hexane and 2,5-bis(hydroxyimino)hexane] were investigated and resulted in rearrangement products: <i>N,N'</i>-ethanediyl-bis-acetamide, <i>N</i>-acetyl-b-alaninemonomethylamide and <i>N,N'</i>-dimethylsuccinamide.

Enantiomerically pure β-branched-α-amino acids are important synthetic targets and a challenging group of compounds to prepare. A series of diastereoisomers of β-methylphenylalanine analogues have been prepared in enantiomerically pure form using a combination of chemo-and bio-catalysis. Starting from L-threonine methyl ester and proceeding <i>via </i>the vinyl halide with Suzuki chemistry, a range of β,β-disubstituted didehydroamino acids were obtained as their (<i>Z</i>)-isomers. Asymmetric hydrogenation of these alkenes, using either the [Rh(<i>R,R</i>)-Et-DuPhos(COD)BF₄ or [Rh(<i>S,S</i>)-Et-DuPhos(COD)]BF₄ catalyst, followed by hydrolysis, yielded two of the four possible sets of diastereoisomers of the β-branched amino acid. Subsequent stereoinversion, using a stereoselective amino acid oxidase in combination with a non-selective reducing agent, furnished the remaining two sets of diastereomers.

Chemical glycopeptide synthesis requires access to gram quantities of glyco-amino acid building blocks. An efficient and fast synthetic route has been developed for such building blocks with high yields using microwave-assisted Kochetkov amination as a key reaction. The resulting glyco-amino acid building blocks were successfully incorporated into target glycopeptides by Fmoc-solid phase peptide synthesis (SPPS) and were characterized by LC-MS and HRMS(FAB). The glycopeptides were used to investigate the effect of glycosylation on enzymatic cleavage of peptide bonds. At first, enzyme-cleavable linkers for solid-phase peptide and glycopeptide synthesis were developed. Commonly used hydroxymethyphenoxy linker (Wang Linker) in solid phase peptide synthesis was surprisingly susceptible to efficient cleavage to serine protease chymotrypsin. In order to investigate this observation further a broad range of amino acid residues were coupled to PEGA₁₉₀₀ resin using the Wang linker and subsequent treatment with chymotrypsin gave cleavage of the amino acids of the resin in quantitative yields. A similar strategy was also applied to a glyco-tripeptide and again chymotrypsin hydrolysis gave glycopeptide in quantitative yield. It was also established that not only the acid-labile linker (HMPA) but also base labile (HMBA) and unreactive ester (HOA) linkers could be cleaved using chymotrypsin. The solid supported peptide and glycopeptides were then used to study the effect of glycosylation on proteolytic hydrolysis of peptides with two different proteases such as chymotrypsin and thermolysin. Our hydrolysis results in combination with those of others show that protection from hydrolysis is highly dependent on the individual protease and also on the position of the glycosylation site in respect to the scissile bond.

The dynamic kinetic resolution of 2-phenyl-4-subsittuted-5(4<I>H</I>)-oxazolones 89a-g has been investigated as a method for the synthesis of optically active α-amino acid derivatives. The effects of lipase, [either Novozyme (<I>Candida antarctica </I>lipase B), or Lipozyme (<I>Rhizomucor miehei</I> lipase)], solvent, nucleophile, and the addition of external triethylamine to the reaction is described. When R<SUP>1</SUP> = Ph, an 88% yield and 98% enantiomeric excess (e.e.) of α-amino acid ester 96a was obtained with Novozyme<SUP>®</SUP> in acetonitrile as solvent. The synthesis of novel 5(4<I>H</I>)-oxazolones 129a-e, which are identified as key intermediates in the synthesis of a series of matrix metalloproteinase inhibitors 94, is described. Application of the lipase catalysed dynamic kinetic resolution conditions to 129a-e, afforded high yields (96%) and diastereomeric excesses (d.e.'s), (86%) of the resulting pseudodipeptides (2<I>R</I>,2'<I>S</I>)-127a-e and 130-132, by careful selection of the reaction conditions.(Figs. 1382A and 1382B).

A previously unknown protein produced by an mRNA mutation has recently been identified in Alzheimer's patients. The protein, designated UbN, is composed of the first 75 residues of ubiquitin followed by an unrelated sequence of 20 residues. The synthesis of this 10.7kDa entity was carried out, as well as its purification which was based on a novel affinity support in conjunction with the tetrabenzofluoroene moiety. <i>In vitro</i> testing established how the protein could compromise the ubiquitin-dependent proteolytic system, hence exerting a toxic effect in Alzheimer's patients. The synthesis of an analogue of ubiquitin (76 residues, 8.5kDa), which contained the unnatural amino acid 2S, 4S-5-fluoroleucine in place of leucine at the 50 and 67 positions, has been carried out. A short purification and folding protocol was developed, and comparison of the analogue with the native structure was undertaken. A possible application of the analogue in the study of protein folding using ¹⁹F nmr has been examined.

The work described in this thesis has been concerned with the preparation of high vinylidene end-group polyisobutene using new initiating systems such as alkoxydifluoroboranes (ROBF<SUB>2</SUB>) and alkyldifluoroboranes (RBF<SUB>2</SUB>), and their adducts with ethanol and Brønsted acids (water, sulfuric acid, trifluorosulfonic acid, acetic acid and trifluoroacetic acid). In all cases, comparison is made with the currently used initiating system of a 1 : 1 complex of boron trifluoride with ethanol (BF<SUB>3</SUB>.EtOH). From nuclear magnetic resonance (NMR) spectroscopic studies, <I>n</I>-pentoxydifluoroborane (C<SUB>5</SUB>H<SUB>11</SUB>OBF<SUB>2</SUB>) and methoxydifluoroborane (CH<SUB>3</SUB>OBF<SUB>2</SUB>) were found to have a trimeric structure in deuteriochloroform, whilst both pentafluorophenoxydifluoroborane (C<SUB>6</SUB>F<SUB>5</SUB>OBF<SUB>2</SUB>) and phenoxydifluoroborane (C<SUB>6</SUB>H<SUB>5</SUB>OBF<SUB>2</SUB>) existed as mixtures of trialkoxyborane [(RO)<SUB>3</SUB>B] and boron trifluoride. In most cases, the addition of ethanol or Brønsted acids to alkoxydifluoroboranes led to decomposition of the latter and to the formation of complex mixtures of boron compounds, <I>viz</I>. monofluoroboranes [(RO)<SUB>2</SUB>BF], trialkoxyboranes and boron trifluoride. By comparison, acetic acid and trifluoroacetic acid did not decompose methoxydifluoroborane. Both <I>n</I>-butyldifluoroborane (C<SUB>4</SUB>H<SUB>9</SUB>BF<SUB>2</SUB>) and <I>n</I>-pentydifluoroborane (C<SUB>5</SUB>H<SUB>11</SUB>BF<SUB>2</SUB>) showed the same stability when their adducts with ethanol and trifluoroacetic acid were formed. These boron trifluoride derivatives and their adducts were evaluated as initiating systems for the carbocationic polymerisation of isobutene at low temperature with particular reference to their influence on the extent of conversion, molecular weight (<I>M<SUB>n</SUB></I>) and more importantly, vinylidene content of the resulting polyisobutene. From experimental results, it is evident that BF<SUB>3</SUB>.EtOH is a much more reactive initiating system than the adducts of ethanol with alkoxydifluoroboranes, which initiated the polymerisation of isobutene, but only when used in high concentrations, to produce polymers with a high vinylidene content (<I>ca</I>. 88%). Alkyldifluoroboranes, whether used with ethanol or trifluoroacetic acid as an initiator, proved to be inactive co-initiators for the polymerisation of isobutene. Of all the Brønsted acids used as initiators, trifluoroacetic acid produced polyisobutene in high yield when methoxydifluoroborane was used as the co-initiator. The molecular weight of the resulting polymer was found to be within the desired range (<I>M<SUB>n</SUB></I> 1000-1500) with a concomitant vinylidene end-group content of up to 75% being achieved.

Methodology for the synthesis of peptide <i>C</i>-terminal aldehydes has been investigated. Modification of a linker system, based on a terabenzosuberyl construct, has been demonstrated to be suitable for the synthesis of peptide <i>C</i>-terminal semicarbazones. The route has been fully optimised to yield a series of peptide <i>C</i>-terminal semicarbazones and the corresponding peptide aldehydes. The chemical synthesis of deglycosylated human interferon-gamma (143 residues) has been carried out. The purification of this protein has been investigated and a short purification protocol developed which is sufficiently general to allow application to other similar protein systems. Purification and characterisation of the synthetic interferon-gamma molecule has been completed and folding of the molecule attempted.

<i>RS</i>-a<i>-</i>Amino acids bearing a b- or g-substituent have been prepared using standard methods for a-amino acid synthesis. The deracemisation of <i>RS</i>-a-amino acids, using D-amino acid oxidase (DAAO) from <i>Trigonopsis variabilis</i> and hydride reducing agents, has been investigated. The enzyme has been shown to tolerate the b- and g-substituted a-amino acids as substrates. The use of NaCNBH₃ for the deracemisation of acyclic a-amino acids has been demonstrated for the first time. Screening of a random library of organisms was undertaken to identify novel oxidase enzymes for use in the deracemisation reaction. The screen revealed five organisms that were able to oxidase L-phenylalanine to phenylpyruvic acid, indicating possible L-amino acid oxidase activity. In the screening for monoamine oxidase the assay methods employed lacked the sensitivity to identify conversion of benzylamine to benzaldehyde. For the first time the cyclic oxidation-reduction sequence used for the deracemisation of <i>RS</i>-a-amino acids has been extended to encompass the deracemisation of racemic amines. The deracemisation of <i>RS</i>-a-methylbenzylamine, using an enantioselective monoamine oxidase and ammonia:borane as reducing agent, has been shown to proceed with moderate yields and high selectivity.

Ti^IV compounds have pronounced anticancer, antiviral and antibacterial activities, and titanocene dichloride (TDC) is currently on phase II clinical trials as an anticancer drug. However, the biological chemistry and mechanisms of action of Ti^IV are poorly understood. Proteins and nucleic acids are expected to be biological targets for Ti^IV. Human transferrin (hTF) is a bilobal serum glycoprotein (80 kDa) which transports Fe^III to cells <i>via</i> receptor-mediated endocytosis. A structurally similar periplasmic iron binding protein (FBP, 34 kDa) is present in some pathogenic bacteria and is required for virulence. In this thesis, the aqueous coordination chemistry of Ti^IV with the phenolate ligand <i>N,N'-</i>ethylene-bis-(<i>o</i>-hydroxyphenylglycine)(H₄ehpg) was investigated as a model for Ti-hTF (or FBP) interactions. Ti^IV forms 7-coordinae monomer (<i>rac</i>) and dimer (<i>meso</i>) complexes with H₄ehpg (<i>rac + meso</i>) with novel stereo-selectivity. ¹H and ³¹P NMR studies show that TDC binds selectivity to H₄ehpg at neutral pH, but preferentially to adenosine triphosphate (APT) at pH values below 5; Ti^IVtransfers from Ti^IV-ehpg to ATP at acidic pH values. The interactions of TDC with hTF and that of Ti₂-hTF with ATP have characteristics which could allow transferrin to act as a mediator for titanium delivery to tumour cells. TDC reacts rapidly with apo-hTF under extra-cellular conditions and binds in the specific Fe^III sites with release of the Cp and Cl ligands. Ti^IV is readily released from Ti₂-hTF at endosomal pH (ca 5.0) and in the presence of ATP. Ti₂hTF competes effectively for cell uptake of ⁵⁹Fe-hTF into BeWo cancer cells. TDC binds strongly to the phosphate group of nucleotides in aqueous solution and Ti^IV binds to the phosphodiester groups of nucleotides in the less polar solvent <i>N,N</i>-dimethylformamide. This behaviour contrasts with that of the anticancer drug cisplatin which binds mainly to N-sites of nucleobases, and may account for the intracellular localisation behaviour of Ti^IV drugs.