School of Chemistry - Theses
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ItemRadiolabelled peptides and amino acids for PET imaging of cancer( 2019)Cell surface receptors, which are overexpressed in cancerous tumours, are feasible molecular targets for tumour imaging. The transmembrane G-protein coupled receptor CXCR4 is overexpressed in tumours and has a crucial role in organ-specific metastasis of tumour cells. Cyclic pentapeptides such as FC131 and analogues have been developed to bind with high affinity and specificity to CXCR4. Unfortunately, when FC131 is radiolabelled and evaluated as a PET imaging agent, it demonstrates high retention in the liver due to its lipophilic character. Sulfonation of aromatic groups, such as the phenolic group in tyrosine, results in a significant reduction of a peptide’s lipophilic character. Evaluation of sulfonated FC131 peptide analogues as PET imaging agents has been undertaken. In addition to radiolabelled peptides, PET imaging using amino acids has shown promise for tumour detection. 18F containing radiolabelled amino acids are transported across the cell membranes by amino acid transporter proteins. As such, several approaches to synthesise fluorothreonine, fluoroaspartic acid and fluorotyrosine analogues have been examined.
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ItemSolution behaviour and photochromic properties of a new family of mixed-metal hybrid amino acid-polyoxometalates( 2017)Fifteen members of a new family of hybrid mixed-metal polyoxometalates (POM) that incorporate amino acid ligands of general formula (countercations)x[As4{M4}W44Y4O160(AA)8(H2O)12]n- (M4 = various combination of WVI / MoV/VI / VIV and YIII; AA = Gly or L- and D/L-Nle, countercation = MBAH, GlyH+, BAH, BTEA, n = 9-12) have been synthesized and studied. This work followed on from a preliminary study on the synthesis and characterization of the first compound from this family, which was a mixture of two structurally related hybrid POMs with mixed Mo/W addenda metals and in different redox states. Photo-reduction of the reaction solution by UV light afforded a co-crystallized mixture of a fully oxidized analogue and a 2 electron reduced species. Preliminary studies suggested that a central structural core of these hybrid POMs was the preferred site for both metal substitution and reduction. The first research question addressed in this thesis was whether it is possible to synthesize analogous hybrid POMs that are comprised of a 2e-reduced homometallic core, rather than a mixed-metal core. Careful synthetic investigation, followed by comprehensive characterisation studies using single crystal X-ray diffraction, elemental analysis, 1H NMR spectroscopy, TGA analysis, electrochemistry, infra-red and XPS spectroscopy indicated that a {MoV2MoVIW} mixed-metal, mixed-valence central core was obtained for all reduced analogues of these hybrid POMs. In contrast, the two oxidized members of this family obtained exhibit a homometallic, trinuclear {MoVI3} central core. Density functional theory calculations indicate that the core metal centers are the preferred site of reduction and that the corresponding molecular orbitals are significantly lower in energy for the tetrametallic versus the trimetallic case, consistent with the experimental results. The second research question addressed was whether these compounds are stable in solution and the amino acid ligands remain attached to the POM or exchange. Electronic absorption spectroscopy, SAXS experiments and circular dichroism spectroscopy were performed in aqueous and non-aqueous media, and in the presence or absence of excess amino acid. It was apparent that while the metal-oxo POM framework remains intact in particular solution conditions, exchange of the amino acid ligand can occur. Analogues containing both chiral and achiral amino acid ligands were synthesized, with chiral ligands able to induce chirality in the hybrid POMs. The apparent preference for incorporation of Mo over W in the central core of these hybrid POMs prompted the exploration of the incorporation of other addenda metals and three new vanadium-containing analogues (V/W and (V/Mo/W) were synthesized. All of these compounds possess a tetrametallic {VIV2W2} central core and the selectivity of the core metal sites follows the order: V > Mo > W. The solid and solution UV-Visible absorption experiments along with XPS spectroscopy confirmed the incorporation of V and V/Mo into the POM structures. The solution study revealed that the V-containing analogues are less stable than the Mo-containing species, probably due to higher overall negative charge on the polyanion. The final part of this thesis presents a study of the photochromic behavior of four different salts of a W-only analogue of the hybrid POM family with Gly ligands. Two of the compounds exhibit reversible photochromism associated with photoreduction, cycling from white to blue under UV irradiation and bleaching back to white following re-oxidation in air. The ability of the compounds to undergo photoreduction correlates with the orientation of the zwitterionic ammonium group of the glycine ligands and the intramolecular hydrogen bonding to the POM framework. The kinetics of coloration of these POMs were found to follow a pseudo second-order law, similar to that which governs the photochromism of POMs facilitated by intermolecular hydrogen bonding with organoammonium countercations.
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ItemExploring the Petasis reaction through amino acid synthesis( 2015)The Petasis reaction was reviewed and shown to be a versatile and efficient reaction for the synthesis of nitrogen containing compounds and α-amino acids. Many different amines and amine equivalents can be used in the Petasis reaction, in conjunction with a wide variety of aryl and vinyl boronic acids and esters, and a small selection of aldehydes. Chiral reagents can enforce stereochemical control in the reaction. Certain chiral amines and chiral amine equivalents give the highest selectivity. Several limitations remained for the Petasis reaction: yields were low with sterically small amines and the organoborons were largely limited to aryl, heteroaryl and vinyl derivatives. These limitations were addressed to make the Petasis reaction a more well-rounded and useful synthetic method. tert-Butyl sulfinamide was explored as an amine equivalent and the kinetics of the Petasis reaction with this reagent were investigated through the use of in situ FT-IR and 1H NMR spectroscopy analysis. tert-Butyl sulfinamide and glyoxylic acid both had rate orders of one, whereas styrenyl boronic acid had a rate order of two. This accounted for an observed dramatic increase in reaction rate. A mechanism for this reaction system was proposed, in which the boronic acid acts as both a reagent and as a Lewis acid catalyst. Allyl boronic acid pinacol esters were synthesised by palladium catalysed borylation of allyl alcohols, and then reacted with tert-butyl sulfinamide and glyoxylic acid to yield allyl glycine derivatives. Isolated yields of the final amino acids were excellent, but the diastereoselective ratios achieved were low to moderate. The addition of scandium(III) triflate to the allyl-Petasis reaction gave excellent control over the syn/anti configuration of the product, resulting in diastereomeric ratios in the order of >20:1. However, stereochemical control at the α-carbon was still moderate. A mechanism was devised to explain this observation and several supporting reactions were conducted. N-Methyl tert-butyl sulfinamide was synthesised racemically in a single step from the commercially available tert-butyl sulfinyl chloride and methylamine solution. The product was isolated in a pure yield of 98%. Racemic N-methyl tert-butyl sulfinamide was applied to a modified allyl-Petasis reaction, which employed molecular sieves to promote the formation of the initial iminium ion, to yield N-methyl amino acids in a quick and efficient manner. The use of scandium(III) triflate gave excellent control of the syn/anti configurations. Enantiopure N-methyl tert-butyl sulfinamide was also synthesised and applied to the Petasis reaction, resulting in excellent yields and stereochemical control. This work demonstrated the robust and widely applicable nature of the Petasis reaction as a method to synthesise α-amino acids in an efficient manner. The Petasis reaction can therefore be utilised in the chemical total synthesis of more complex natural products containing unusual amino acids residues.
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ItemStudies of the interaction of metal complexes with ligands and biomolecules in the gas phase using mass spectrometry( 2005)Introduction of soft ionization techniques, such as electrospray ionization (ESI), has resulted in extensive use of mass spectrometry based techniques to study biomolecules in the gas phase. Despite thorough studies of the gas-phase chemistry of even-electron biomolecules, the examination of their odd-electron counterparts has to this point been much less extensive due to the inefficiency of ESI in generating such species. Among various methods that could be employed to generate and study odd-electron biomolecules in the gas phase, redox processes involving metal ions and homolytic cleavage of metallated amino acid or peptide derivatives would be attractive from a chemical perspective since, in principle, a wide range of metals and biomolecules or biomolecule derivatives could be explored. An important aspect of these approaches is that they can be carried out on a wide range of tandem mass spectrometers equipped with electrospray ionization and collision induced dissociation capabilities. (For complete abstract open document)