This thesis details a methodology utilising various synthetic pathways towards cyclisation precursors suitable for use in Prins and carbonyl-ene cyclisations to effect 2,3,4-trisubstituted piperidines. Once the precursors were synthesised, we were interested in the stereochemical outcomes of the cyclisations, in particular identity and rational of the kinetic and thermodynamic products and their variation due to differing substituents on C2. Previous work in the Snaith group has addressed various other substitution patterns and 2,3,4-trisubstituted piperidines are central components of a vast array of drug targets and natural products, so it follows that these should also be sought via similar processes. Synthesis of the precursors proved to be much more challenging than anticipated, hence many different routes were investigated with fluctuating successes.

This thesis describes the synthesis and characterisation of phases related to schafarzikite (FeSb\(_2\)0\(_4\)). A range of Co\(_1\)\(_-\)\(_x\)Fe\(_x\)Sb\(_2\)\(_-\)\(_y\)Pb\(_y\)O\(_4\) (where x = 0, 0.25, 0.50 and 0.75; y = 0-0.75) compounds have been synthesised and characterised by a variety of techniques e.g. neutron powder diffraction (NPD), and thermogravimetric analysis. The refined lattice parameters for all compounds range between a = 8.4492(2) Å - 8.5728(2) Å and c = 5.9170(1) Å - 6.0546(2) Å (NPD, 300 K). The magnetic structures of Co\(_0\)\(_.\)\(_2\)\(_5\)Fe\(_0\)\(_.\)\(_7\)\(_5\)Sb\(_2\)O\(_4\) and Co\(_0\)\(_.\)\(_5\)\(_0\)Fe\(0\)\(_.\)\(_5\)\(_0\)Sb\(_2\)O\(_4\) have been shown to possess dominant A- type ordering as a result of overriding direct exchange interactions between intrachain transition metal cations, whilst all other phases show dominant C- type ordering consistent with 90˚ superexchange. Unusual negative susceptibility is seen and explained in several samples including CoSb\(_2\)O\(_4\). All phases are shown to display canted antiferromagnetic magnetic order. Oxidised intermediates are formed and characterised for the first time. This has been critically linked to the presence of Fe\(^2\)\(^+\) within these phases. There is evidence to suggest the excess oxygen is a peroxide and/or superoxide species. The synthesis of LiSbO\(_2\) is described and its structure determined: P2\(_1\)\(_/\)\(_c\) symmetry with a = 4.8550(3) Å, b = 17.857(1) Å, c = 5.5771(4) Å, β = 90.061(6)˚. Its electrical and thermal properties are described.

This project utilises the chemokine, CCL2, to build a selective delivery platform to target disease-causing monocyte subsets. Monocytes are white blood cells which form part of the innate immune system and are primarily responsible for pathogen engulfment and antigen presentation towards members of the adaptive immune system. Monocytes have been identified in a number of diseases such as liver fibrosis, rheumatoid arthritis and can even be recruited by cancers leading to tumour-protection from the immune system through socalled Tumour-Associated Macrophages (TAMs) and Myeloid-Derived Suppressor Cells (MDSCs). Interestingly, many of these diseases are caused by specific subsets of monocytes which express high levels of the chemokine receptor CCR2. This project has developed CCL2 as a delivery vehicle such that these monocyte subsets can be selectively targeted for fluorophore delivery. A series of CCL2 mutant sequences were conjugated with a range of fluorophores using click chemistry and these conjugates exhibited retained chemotactic function. This chemotaxis and intemalisation of the ligand is CCR2-mediated and disease-causing monocyte subsets were also shown to be targeted with the fluorescent chemokines. Finally, fluorescence microsocpy demonstrated that physicochemical variations of the fluorophore and linker allowed the subcellular localisation of fluorophores to be modulated, post ligand-receptor intemalisation.

Germinal Centres (GCs) play a central role in adaptive immunity; involving processes of cell migration, clonal expansion, hypermutation, and selection. To elucidate the role of affinity in regulating these processes, a technique for measuring B cell receptor affinity maturation in GCs in situ was developed. To facilitate interrogation of individual antibody-antigen interactions, atomic force microscopy (AFM) was chosen, offering nanometre positional resolution, and pico-Newton force sensitivity. Specificity of gold-coated AFM cantilevers towards the targeted receptors was achieved via a bespoke modification scheme, using self-assembled amine-terminated alkanethiol to facilitate attachment of the receptor specific antigen NP. Influences on molecule deposition and subsequent NP addition were investigated, as were control measures facilitating identification of successful modifications (Chapter 4). Effects of sample preparation techniques on AFM adhesion measurements were investigated (Chapter 5). Subsequently, the developed AFM technique was applied in interrogation of B cells and hybridomas – expressing receptors of varying affinity towards NP – and two GCs in tissue sections (Chapter 6). For the automated and unbiased evaluation of large amounts of varying AFM data, bespoke data analysis methods were developed. The project finds that AFM is capable of quantifying specific antibody-antigen interactions, but was unable to measure these in tissue sections. Possible reasons preventing such measurements are discussed.

The application of nanoscience in various scientific fields is introduced in Chapter 1 by outlining some of the major drivers of this rapidly evolving field. Methods of nanoscale fabrication, utilizing both 'top-down' and 'bottom-up' approaches, are also introduced in this chapter. Nanoscale characterization techniques that allow the visualization of the 'nanoworld' are introduced in Chapter 2. Chapter 3 is concerned with the modification of Si\(_3\)N\(_4\) substrates with self-assembled monolayers (SAMs) of 3-aminopropyltrimethoxysilane (APTMS) via a vapour deposition method. This investigation was carried out by forming APTMS SAMs, from the solution phase, on both SiO\(_2\) and Si\(_3\)N\(_4\) substrates and comparing them to provide a model with which to compare SAMs formed by a novel vapour phase methodology. Chapter 4 further develops the work from Chapter 3 by chemically modifying Si\(_3\)N\(_4\) resonators with APTMS SAMs via vapour deposition. The chemically modified resonators were then used for the mass detection of citrate passivated Au nanoparticles and the results were compared to AFM and XPS studies of the same system but on planar substrates. Chapter 5 is concerned with the fabrication of a bioarray for the patterned immobilization of human spermatozoa cells. Such arrays would allow for the investigation of specific individual sperm cells. This could have a use in the field of artificial insemination. Chapter 6 utilizes citrate passivated Au nanoparticles to prepare composite PEO/Au nanoparticle solutions for the formation of sub-micron diameter electrospinning. Such fibres are electrospun from solutions of 4 different concentrations of PEO and then subsequently characterized by optical microscopy, AFM, TEM and DSC.

The perovskites LaSr₂Fe₂SbO₉ and La₂Sr₂Fe₃SbO₁₂ crystallise in P2₁/n space group with Fe³⁺ occupying the two crystallographically distinct six-coordinate sites in a ratio of approximately 1:2. Neutron diffraction data suggest a G-type long-range antiferromagnetism in both materials at 2 K and 300 K. The A site cation ordering in Ln₂SrFe₂O₇ (Ln = La, Nd, Eu) and La₂BaFe₂O₇ increases as the mismatch in A site cation size increases. These phases exhibit long-range antiferromagnetic ordering at 300 K and 2 K; the magnetic moments in La₂BaFe₂O₇ and Nd₂SrFe₂O₇ gradually rotate in the temperature ranges 210 K to 190 K and 17 K to 9 K, respectively. The fluorine incorporation into these phases happens via anion insertion and anion substitution. The partial cation ordering or large overall size of the A site cations allows accommodation of more F⁻ ions causing no change to the Fe oxidation state. Both CaMnO₃₋δ and SrFeO₃₋δ are amenable to phosphate and sulphate anion incorporation. The unit cell sizes increase with the increase of dopant level. The oxy-anion insertion stabilises the cubic structure in all doped phases of SrFeO₃₋δ, but only the higher phosphate levels of CaMnO₃₋δ phases. The anion incorporation induced some mixed ion valencies but failed to introduce extra oxygen vacancies.

Ionisation processes in gas-phase polyatomic molecules have been studied using threshold photoelectron photoion coincidence and selected ion flow tube techniques for cations and an electron attachment mass spectrometer for anions. Cation formation has been studied for fluoroform (CHF\(_3\)), octafluorocyclobutane (\(c\)-C\(_4\)F\(_8\)), octafluorocyclopentene (\(c\)-C\(_5\)F\(_8\)), monochloroethene (C\(_2\)H\(_3\)Cl), the three isomers of dichloroethene (C\(_2\)H\(_2\)Cl\(_2\)) (i.e. 1,1-dichloroethene, (\(Z\))-1,2-dichloroethene and (\(E\))-1,2-dichloroethene), trichloroethene (C\(_2\)HCl\(_3\)) and tetrachloroethene (C\(_2\)Cl\(_4\)). Comparison between the data from the photoionisation and the ion-molecule reactions show that the dominant charge-transfer mechanism is long-range in nature. Detailed studies of the reactions of cations with the three dichloroethenes have been performed to look for evidence of isomeric effects. Major differences are seen when the reactant ion is CF\(_3\)\(^+\); when 1,1-dichloroethene is the neutral reactant the only ionic product is C\(_2\)H\(_2\)Cl\(^+\), but if the neutral is 1,2-dichloroethene then the only product is CHCl\(_2\)\(^+\). Only minor differences are seen with other reagent ions. For the reactions of all six chloroethenes with CF\(_3\)\(^+\), product ions are observed which can only be formed by extensive rearrangement across the carbon-carbon double bond. Mechanisms are suggested involving bridged trigonal intermediates to explain the production of the different channels. Studies have been performed on several perfluorocarbons, CHF\(_3\), \(c\)-C\(_4\)F\(_8\) and \(c\)-C\(_5\)F\(_8\), due to their potential for use in industry. They are all excellent at etching substrates and have a lower global warming potential than the currently used gases. CHF\(_3\) shows signs of non-statistical dissociation following photoionisation, and is shown to react via a largely long-range charge transfer mechanism in the ion-molecule reactions studied. For \(c\)-C\(_5\)F\(_8\) the ground electronic state of the ion is found to be very weak under threshold conditions whilst being much more intense when He(I) photons are used. The existing electron attachment mass spectrometer is described, and also extensive modifications which have been made to this apparatus. The use of new electronics and acquisition system give excellent results in the new equipment. The new arrangement has been extensively characterised by studying attachment to seven molecules, including several perfluorocarbon molecules (e.g. the isomers of C\(_4\)F\(_8\)). Some isomeric effects on the measured rate coefficients are observed in the data.

Concavine, a diterpene natural product was isolated from a strain of Clilocybe concava in 2005 and was the first diterpene alkaloid to be isolated from a mushroom. Chapter 1 presents the unprecedented core structure of this novel alkaloid consisting of a bicyclo(3.2.1)octane system linked with a oxazepane ring. Our retrosynthetic analysis highlighting the challenges for the synthesis of concavine is presented. Chapter 2 discusses the formation of the bicyclo [3.2.1]octane system and the installation of an oxazepane ring precursor. The different strategies used to form the five-membered ring and the regioselectivity issues surrounding the addition of the oxazepane ring precursor are discussed. The completion of the core structure of concavine and the end game is described in Chapter 3. While the strategy to use a sulfone group as a ketone precursor was not successful, the hydrolysis of a vinyl sulfide group was key to access the desired ketone and complete the total synthesis of concavine. In Chapter 4 the comparison between the reported data for concavine and our synthesised compound is described. The synthesis of a new epimer was undertaken to solve the mismatch in the data without success. Both the HCI and AcOH salts ofthe synthesised concavine were formed to investigate the impact of a protonated amine on the chemical shift compared to the free amine. A summary of the total synthesis of concavine is presented in Chapter 5. The successful sequence for the formation of concavine from the commercially available anhydride and the work to match the data with the reported natural product is summarised.

Chapter one reviews the use of acyl radicals and the various functional groups from which they have been derived. The earlier work on the use of dithiocarbamates as a source of acyl radicals has been progressed. Systems with the potential to follow either a 6-exo or competing 7-endo cyclisation pathway have been made. Chapter two is about the radical mediated reduction of the dithiocarbamate group. Previously reported dithiocarbamate group transfer reactions are reviewed along with existing methods for the reductive removal of the dtihiocarbamate and related xanthate groups. The development of conditions for a general method of the reduction is reported, with various examples being shown. Chapter three begins with a review of the synthesis of a range of twisted amides. The formation of a twisted amide precursor, containing a dithiocarbamate groups is reported. The attempts to form the bicyclic twisted amide, by used of carabamoyl radicals generated from dithiocarbamates are described. Chapter four discusses previous attempts at the synthesis of the natural occurring compound stemofoline. The attempted formation of the dithiocarbamate containing precursor for a 7-endo-trig cyclisation, 5-exo-trig transannular cyclisation, group transfer reaction to give the azatricyclic system, analogous to the tricyclic core of stemofoline is discussed.

Functional polymers are emerging as strong candidates for a variety of biomedical applications, but progress in this field is slow due to the difficulties associated with the synthesis of libraries of polymers. Polymeric scaffolds facilitate the rapid synthesis of such functional polymers by employing click chemistries as a tool for post-polymerisation modification. Acrylic and acetylene based polyhydrazides have been explored as potential scaffolds for the in situ screening of functionalised polymers for biomedical applications. Poly(acryloyl hydrazide) was prepared from commercially available starting materials using RAFT polymerisation in a three step synthesis, and its postpolymerisation modification using a variety of hydrophilic and hydrophobic aldehydes was investigated. Biocompatible solvents and reaction conditions were determined such that the postpolymerisation modification could be achieved with good yields or better. The applicability of the scaffold was shown during the in situ screening of functional polymers for siRNA delivery, which required no isolation or purification of candidate polymers. Poly(4-ethynylbenzohydrazide) was synthesised using rhodium catalysed polymerisation conditions, towards achieving a helical polymer scaffold. Despite the lack of solubility in aqueous solvents, the stability and post-polymerisation modification was analysed in a variety of conditions, opening the possibility of synthesising biodegradable mimics to naturally occurring helical moieties.