Monolayers composed of N-palmitoyl sphingomyelin (SM) or dipalmitoylphosphatidylcholine (DPPC) have been investigated at the air|water interface. Bilayers of these molecules have also been investigated at the Au(111)|water interface. Monolayer studies revealed differences in molecular area between the two molecules, despite identical headgroups, suggesting the sphingosine backbone of SM allows a more densely packed monolayer structure. Polarisation modulated infrared reflection-absorption spectroscopy studies of the corresponding bilayers revealed that the alkyl chain orientation is comparable in either layer at positive potential but changes at negative potential, concomitantly with changes in solvation. Bilayers of both molecules changed structure once the surface charge density measured with chronocoulometry became negative. Surface pressure-area isotherms, X-ray reflectometry and grazing incidence X-ray diffraction were used to investigate monolayers of glycolipids and their mixtures with DPPC. Unusual monolayer structures were found for single-component glycolipid monolayers. Monolayers composed of DPPC or SM mixed with biologically-relevant glycolipids were also investigated using isotherms. Glycolipid structures were chosen to emulate the structural features of the biologically active and potential drug target N-cerotic α galactosylceramide. Evidence was found for a specific interaction between DPPC and N-palmitoyl α-galactosylceramide but not between DPPC and N-palmitoyl β-galactosylceramide. A specific interaction between either glycolipid and SM was not observed.

The work presented in this thesis investigates the use of new luminescent lanthanide bis-amide DTPA complexes, both in solution and bound to gold and silica surfaces. The bis-amide arms have been modified with surface attachment groups consisting of disulphides, thioacetates and silyl ethers. Both sensitising and non-sensitising bisamides arms were attached to DTPA in order to develop the best lanthanide based sensor. When these visible and NIR emitting lanthanide complexes are bound to the surface they can be used to detect various small analytesm including benzoic acid, phthalic acid, isophthalic acid, picolinic acid, dipicolinic acid, quinaldic acid, dibenzoyl methane and curcumin. The detection of analytes was performed on surfaces and in solution allowing for comparisons between the two techniques to be made. Lanthanide complexes were attached to silica microparticles and they were used for detection of analytes under flow conditions; these studies were compared to surface and solution analyte detection. The lanthanide-based silica microparticles were developed further to show the advantages of bimodal luminescent silica microparticles. The development of self-assembled monolayers of the lanthanide complexes on gold were studied using surface plasmon resonance and ellipsometry.

The first ferrocene nucleic acid (FcNA) was reported by the Tucker group in 2012. Furnished with two nucleobases and two hydroxyl groups, the tetrasubstituted metallocene assumes the position traditionally occupied by the two sugars of a dinucleotide. This thesis describes the successful synthesis of two FcNA monomers; a tetrasubstituted dithyminyl variation and a disubstituted control compound bearing no nucleobases. These monomers were oligomerised, their binding characteristics assessed by thermal melting studies, and compared to other monomers belonging to the group. Through the study of these compounds the Tucker group has demonstrated that FcNA monomers behave similarly to conventional nucleic acids, displaying selective H-bonding and π-stacking interactions within a hybrid duplex. A preliminary methodology for the production of diguaninyl FcNA monomers was also explored. As published in 2014, the corresponding disubstituted systems, in which a hydroxyl and a nucleobase are linked through a sugar-like ferrocene unit, are also being investigated as potential nucleoside analogues. Adding to the groups growing library, a number of related compounds were synthesised in which the hydroxyl linker length, the planar chirality, the substitution pattern of the ferrocene and the nucleobase were varied. The compounds were electrochemically characterised and assessed for their biological activity which revealed interesting structure-activity-relationships involving both the redox potentials and chirality. Following the example of ferroquine and ferrocifen, in which existing pharmaceuticals are modified through the incorporation of ferrocene, the synthesis and preliminary biological activity of novel ferrocenyl β-blockers, in which the metallocene replaces the napthol unit of the prototypical β-blocker propranolol, is reported herein.

Presentation of antigens via cell-surface glycoproteins, such as MHC-I and CD1d, elicits an immune response. Antigen loading occurs in the endoplasmic reticulum with the help of chaperone proteins such as calreticulin. It has been shown that a Glc\(_1\)Man\(_3\) tetrasaccharide can be recognised. A biotinylated Glc\(_1\)Man\(_3\) was designed to bind to both calreticulin and streptavidin to allow isolation of the calreticulin–tetrasaccharide complex through pull-down experiments. The stereoselective synthesis of this biotinylated oligosaccharide is described. -galactosyl ceramide is the prototypical ligand of CD1d, its activation of iNKT cells produces a mixture of T\(_H\)1 and T\(_H\)2 cytokines, which limits its therapeutic application. Analogues that induce a biased cytokine response are therefore desirable. Analysis of the crystal structure of the CD1d–-GalCer–TCR complex reveals that the 6-OH and ring oxygen are not involved in binding. Analogues where these parts of the molecule have been excised, have led to the introduction of ThrCer and its cyclitol analogue ThrCer-6. We report a new and improved synthesis of ThrCer-6 and a series of analogues that were designed to elicit biased cytokine responses. Studies towards the preparation of ThrCer analogues involving modifications to the pseudo-glycosidic linkage are also described. Finally, the synthesis of ceramide analogues with the potential for conjugation through a photoreactive group to the CD1d protein are discussed.

In this thesis the development of regiocontrolled gold-catalysed reactions for the synthesis of complex heterocycles are described. A new methodology for the formation of all-carbon fully substituted oxazoles was designed and developed, through a novel gold-catalysed intermolecular formal [3+2]-cycloaddition across the π-system of electron-rich internal alkynes by employing conjugated \(N\)-ylides as \(N\)-nucleophilic 1,3-\(N\),\(O\)-dipole equivalents. This intermolecular addition to unsymmetrical internal alkynes represents a considerable regioselectivity and reactivity challenge, as there are no examples of intermolecular atom-transfer nitrene addition. A new design of substrates incorporating an electron-rich π-system and a tethered oxidant or a nitrene delivery system was investigated. Several strategies towards the formation of these systems were proposed and the exhibiting limitations were identified. A novel gold-catalysed reaction has been developed for the formation of complex polycyclic systems, which involves a [1,5]-hydride transfer/cyclisation cascade of functionalised aromatic and aliphatic ynamides. Under mild conditions, the process rapidly generates three fused ring systems by the formation of three new C(sp\(^3\))-C(sp\(^3\)) bonds and up to four contiguous stereogenic centres, in a single manipulation.

This thesis documents the development and the first use of the Suspended Droplet Alloying process. This novel technique makes it possible to deposit a single discrete alloy specimen from its constituting elements every few seconds. Wire is used as a feedstock and the energy is provided by a laser beam. During alloying the melt is suspended from the feedstock itself eliminating all sources of contamination while the surface tension provides the vessel. While the technique has been designed as a tool for efficient alloying with potential use in combinatorial research environments. Its capabilities are comparable to laboratory scale argon arc melting and as such there is no limitation in the postsynthesis use of the created ingots. The thesis can be thought of as being divided into three virtual sections. The first section consisting of the development of the suspended alloying process itself including a study of the obtained samples. This includes the development of an efficient preparation strategy from the ingot to metallurgical specimen. In the second part the technique is used to deposit a large set of samples to demonstrate a possible real world application in screening for Tc transition temperatures across the ternary diagrams of Nb- Ti-Zr and Nb-Ti-Hf. The final part miniaturises the sample size and studies the changed process and the influencing factors on a series of Ti-Cu alloys. This miniaturisation not only improves the efficiency even further but can also deliver rapidly quenched samples.

Sulfonyl fluorides have recently been described as “privileged warheads” in chemical biology due to the right balance of reactivity and stability that these electrophiles possess. Peptido sulfonyl fluorides (β-PSFs) have shown to be particularly potent as proteasome inhibitors in recent years. Tuning the reactivity of the sulfonyl fluoride electrophilic trap may be crucial for modulating its biological action. The first part of this thesis describes the design and synthesis of peptido sulfonyl fluoride derivatives containing a substituent on the alpha position with respect to the sulfonyl fluoride electrophilic trap. Therefore, the chemical reactivity and biological activity of α-substituted sulfonyl fluorides (αSFs) were studied. Comparison with the previously described β-substituted sulfonyl fluorides (βSFs) was performed as an attempt to get a deeper insight into the importance of the immediate structural environment of the sulfonyl fluoride moiety. αSFs proved to be more reactive than βSFs towards nucleophilic substitution, including hydrolysis. However, it could not be clarified as yet if and how this is translated to the bioactivity of the resulting α-PSFs since the poor solubility of these molecules precluded a proper evaluation. The second part of this thesis describes the synthesis of a vinyl sulfonyl fluoride moiety as a new dual warhead class. The consecutive attack of the two nucleophiles of the proteasome active threonine on the double bond and the sulfonyl fluoride was proposed as the inhibition mechanism which should lead to the formation of a seven-membered covalent adduct. In vitro studies were designed in order to test this hypothesis. Although the formation of the proposed seven-membered ring structure could not be unambiguously demonstrated with the chosen model systems, the crystal structure confirmed this formation within enzymatic environment. Incorporation of vinyl sulfonyl fluoride warhead into peptide backbones (PVSF) resulted in strong proteasome inhibitors (IC50 = 99 and 218 nM).

The work describes the preparation and properties of several simple quinolizinium salts particularly hydroxyquinolizinium derivatives. 1- and 2-Hydroxyquinolizinium salts have been prepared in high yields from 1-oxo-1,2,3,4-tetrahydroquinolizinium bromide. The 2-hydroxyquinolizinium ion has also been converted to the related compound, 2-quinolizone. Some 1,2-dihydroxyquinolizinium salts have been prepared. 1-Hydroxyquinolizinium salts are shown to be phenolic, readily undergoing acetylation, brominaiion and coupling with diazotised aniline. However, nitration is abnormal giving a series of compounds having zwitterionic structures. The 2-hydroxyquinolizinium salts behave to some extent as phenols but 2-quinolizone, as expected, has properties resembling the 2- and 4-pyridones. The rearrangements of 1-oximino- 1,2,3,4-tetrahydroquinolizinium bromide have been investigated and total syntheses of both possible Beckmann rearrangement products are reported. Under certain acid conditions the oxime rearranges to give aminohydroxyquinolizinium salts. These have been formulated as 1-amino-2-hydroxy and 1-amino-4-hydroxyquinolizinium compounds. Attempts have been made to synthesise the 1- and 3-oxo pyrido[1,2a]-azepinium systems. Although the preparation of the unsubstituted compounds has not been successful several compounds in the 1-oxo pyrido[1,2a]-azepinium series have been synthesised.

The work described in this Thesis is concerned with the identification of the chain carriers in polymerisation systems involving acid and Lewis-acid catalysts. In a preliminary study of the spectroscopic and conductimetric properties of carbonium ions derived from carbinols and olefins it was found that the phenylethanols are dehydrated by strong mineral acids to the corresponding olefins before protonation takes place (Chapter Two). The protonation of triphenylethylene gives a classical carbonium ion which can react with excess of olefin to produce a radical ion (Chapter Three). The protonation of tetraphenylethylene gives a highly conjugated carbonium ion in which the proton is attached to one of the phenyl groups and not to the ethylenic double bond (Chapter Three). The kinetics of the protonation of styrene by excess anhydrous perchlorio acid and the spectroscopic properties of the 1-phenylethyl carbonium ion obtained in this reaction have been studied (Chapter Four). Styrene is polymerised by perchloric acid and other acidic catalysts without formation of carbonium ions, and it has been shown that, in the case of HCl04, the intermediate responsible for the polymerisation is the 1-phenylethyl perchlorate ester. The polymerisation kinetics have been investigated and the results agree with those of other authors where they overlap. Other monomers, acenaphthylene and N-vinylcarbazole, behave similarly to styrene (Chapter Four). These ester-catalysed polymerisations have been called pseudocationic. The pseudocationic polymerisation of styrene by perchlorio acid is followed by formation of styryl ions, a complicated reaction which has been studied in some detail. True cationic polymerisation has also been observed during this work, and it was found that carbonium ions are very powerful chain carriers giving reaction rates at least 100 times greater than the corresponding esters (Chapter Four). In the course of this work the spectra of many carbonium ions have been fully characterised.

The 1- ethoxyvinyl esters of a variety of acids have been prepared, and isolated in some cases. In other cases their presence was demonstrated by their spectra and chemical properties. Thus 1-ethoxyvinyl thiolates and sulphonates were isolated , characterised and were found to be readily attacked by nucleophiles. Monoesters of sulphuric acid reacted with ethoxyacetylene to give 1- ethoxyvinyl sulphates, attempts to purify these compounds being unsuccessful. They were, however, successfully used to prepare the coenzyme analogue adenosine-5'-sulphatophosphate in up to 45% yield. The 1-ethoxyvinyl esters of pyruvic and oxalic acids were prepared and found to undergo rearrangement on heating to 70 degrees. Carbon monoxide and B-keto esters were the products. A five centre rearrangement in the first case, and a five centre followed by a four centre rearrangement in the second case has been suggested for the mechanisms of these rearrangements. Although the diethoxyvinyl esters of phthalic acid could not be isolated (although this was possible when terephthalic acid was used) phthaloyl protected amino acids and esters were prepared by activation of phthalic acid using ethoxyaoetylene in the presence of a free amino acid or its ester. The reaction was conducted successfully in aqueous and non-aqueous solvents, and when an optically active aminoacid was used, no racemisation was detected. This method holds potentialities both for protection and for end group labelling of peptide hydrolysis fragments. Polynucleotides containing thymidylate and deoadenylate residues were synthesised using DCC as the condensing reagent. One of the mononucleotides was labelled with 32P so that nearest-neighbour base sequence analyses could be conducted on the polymeric products. The results of these analyses suggest that the base sequence is essentially random, but that thymidylate residues predominate over deoxyadenylute residues in the ratio of 27.5 in the polymers. Reasons for this predominance have been suggested. The chemistry of alkolkynes and of enol esters has been reviewed and a survey has been made of recent techniques of polynucleotide synthesis. The structure, biosynthesis and properties of nucleic acids and coenzymes have also been reviewed.