3-Nitrophthalic acid 2.04 was transformed into 2.10 in 38% yield. Vinylglycine derivative was synthesised from D-Methionine 2.12 in 42% yield. (For image see abstract in pdf) Compounds 2.10 and 2.16 were coupled using Grubbs' 2nd generation catalyst creating 2.25. Unfortunately attempts to oxidise the benzylic position were unsuccessful. (For image see abstract in pdf) An alternative approach was investigated using diene 2.40 derived from a precursor to 2.10 and allyl bromide 2.35. Attempts to displace bromide under anionic conditions were futile. The use of palladium formed conjugated dieneamine 2.65. (For image see abstract in pdf) Deprotection, oxidation and elaboration of 2.10 prior to cross metathesis allowed the synthesis of 2.114, which when subjected to radical conditions, formed a diastereomeric mixture of 2.220. (For image see abstract in pdf).

I. Synthesis and inhibitory activity of sialic acid derivatives targeting viral sialate-O-acetylesterases and sialate-O-acetyltransferases Sialate-O-acetylation is a common structural modification of sialic acid, which has been associated with many human disease states (including cancer and autoimmune disease). This highly regulated and tissue-specific modification is carried out by sialate- O-acetylesterase (SOAE) and sialate-O-acetyltransferase (SOAT) enzymes. The availability of these enzymes make inhibition studies a viable endeavour, considering that SOAT/SOAE inhibitors may provide interesting tools/drug leads for the development of antiviral compounds or treatments for various disease states. A synthesis of suitable 4-O- and 9-O-functionalised sialic acid derivatives has been established which enabled the investigation of 4- and 9-sialate-O-acetylesterase enzymes. Sialic acid derivatives were screened for the inhibition of a set of viral SOAEs and while no inhibition of 4-SOAE could be detected, a 9-O-methyl derivative showed inhibition of the recombinant influenza C virus SOAE. The functionalised sialic acid motif thus serves as an initial template for the design and synthesis of future sialic acid derivatives towards SOAT/SOAT inhibition. II. New tools for the characterization and investigation of influenza virus neuraminidases: towards novel influenza virus sensors Tamiflu™ (Oseltamivir), has been employed as a mimetic of the sialic acid “oxocarbenium” intermediate formed during enzymatic hydrolysis, leading to inhibition of virus-bound neuraminidase (NA) enzyme. Phospha-isosteres of oseltamivir provide access to monoesters which retain the efficacy of the pharmacophore and allow the synthesis of novel influenza neuraminidase-specific materials. Phospha-oseltamivir-stabilised gold nanoparticles (“TamiGold”) have been synthesised and NA inhibition studies with “small TamiGold” show activity against influenza virus strains investigated compared to control gold nanoparticles. The binding interactions displayed by “large TamiGold” may provide the basis for a colorimetric method of influenza detection and as such a novel prototype influenza sensor. To the best of our knowledge this is the first example of a multivalent approach to influenza virus binding utilising sialylmimetic scaffolds immobilised on a nanoparticle platform which specifically target the NA (instead of the hemagglutinin, HA). The synthesis of phospha-oseltamivir conjugates and their ligation to biological reporter groups afford small molecule tools with high affinity and selectivity towards influenza NA. These derivatives can be applied towards novel multivalent phospha-oseltamivir materials and used as novel diagnostics, independent of existing methods.

This thesis explores the behaviour of U(III) and U(IV) organometallic complexes towards small molecules, with respect to both their reductive activity and insertion chemistry. A range of mixed-sandwich U(IV) organyl complexes of the form U(η-C8H6{1,4-SiiPr3}2)(η-C5Me5)(R) (= U(COTTIPS2Cp*(R), where R = CH3, CH2Ph, CH2TMS, CH{TMS}2) have been synthesised and the products of their reactions with CO2, CO, and H2 (κ2-carboxylates, η2-acyls, and a monomeric terminal hydride) have been characterised – all of which are formed under mild conditions (< 1 atm of gas, sub-ambient temperature). The hydride also inserts CO2 to yield a formate, U(COTTIPS2)Cp*(κ2-O2CH), which is the first example of its kind, and inserts CO to form cis-enediolate, {U(COTTIPS2)Cp*}2(μ-κ1:κ1-OCH=CHO). A rare primary amido, U(COTTIPS2)Cp*(NH2), and its CO2 insertion product, U(COTTIPS2)Cp*(κ2-O2CNH2), have also been characterised. The latter is the first crystallographically characterised U(IV) primary carbamate. Deprotonation of the parent amido yield an anionic U(IV) terminal primary imido, [U(COTTIPS2)Cp*(NH)][K(18-crown-6)]. U(III) and U(IV) complexes containing a dianionic diamidoamine ligand, [N{SiMe3}(CH2CH2N{SiMe3})2]2- (= N'N'2) have been synthesised. It has been found that the migration of a SiMe3 group along the ligand backbone occurs spontaneously when bound to uranium. Reduction of the U(IV) compound U(N'N'2)Cp*Cl with KC8 yields either the U(III) product, U(N'N'2)Cp*, or bridging arene products, {U(N'N'2)}2(μ-η6:η6-C6H5R) (where R = H, Me), depending on the reaction stoichiometry. Further reactivity of these diamidoamine complexes with small molecules is also discussed.

Chapter 1 provides an insight into the current areas of research that could provide answers to the global energy problems outlined in Appendix A, namely the reductive functionalisation of carbon oxides and as an extension to this, the activation of other small molecules. The review predominantly concentrates on the chemistry of the 5f elements which already contain examples of reductive functionalisation of carbon oxides, albeit in homogeneous phase. In addition the chapter provides an overview of the current research in surface science and by extension, the development of molecular models that mimic such surfaces. This synopsis provides an insight into the difficulties involved in this area of research and why molecular mimics are of vital importance. Using ligating Si-O bonds to mimic a silica surface, Chapter 2 outlines the research which enabled the development of a series of uranium siloxides, centred on the previously unreported pentakis(triarylsiloxy) uranate(IV) ion. Characterisation data and full analysis are included within this chapter which provided the basis for the investigations discussed in the following chapters. This chapter also presents an interesting UV-Vis analysis of the uranium siloxides which will enable a wider understanding of the f -elements and the role f -orbitals have on the chemistry and geometry of f -element molecules. Chapter 2 develops a deeper understanding of these complexes by investigating the mechanisms of formation and the chemistry of the U(Ph3SiO)5 fragment using ESI techniques in conjunction with NMR analysis. Chapter 3 investigates the reactivities of the uranium siloxides previously developed and discusses a new dioxo species and a rare and novel UV monooxo complex which was synthesised and successfully isolated. An analysis of other dioxo and monooxo complexes is included which allows the reader to develop an appreciation of how few and far between monooxo products are. In addition, previous examples of monooxo's are lacking characterisation data and are mostly products of oxygen atom donor reactions, not as a result of small molecule activation as is presented here. There is currently one previous example of such a system resulting from small molecule activation which is also discussed in this chapter. Chapter 4 investigates a second ligand system which could be used to mimic a silica surface. Whilst the ligand, tris tertbutoxy has been investigated previously, at the time of this work, the ligand had not been successfully used in relation to a uranium complex. The U3.5 species, [(U(OSi(OtBu)3)3)2(μ-η6:η6-tol))] is presented here alongside the complexes [((tBuO)3SiO)3U]2(μ2-O)3 and U(OSi(OtBu)3)4. During the development of this species, very similar species were published by another group and these syntheses and characterisation data are presented here as a comparison to the species developed as part of this work. Chapter 5 investigates the reactivities of the uranium siloxides developed in Chapter 4 including decomposition analysis and reactions with small molecules such as O2, I2 and CO2 and presents the resulting complexes some of which were developed by a Masters student working in collaboration with the author.

This thesis focuses on developing efficient, atom-economic synthesis routes for functionalised 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one libraries. 1,4-Benzodiazepines (BZDs) are often referred to as “privileged scaffolds” due to their important biological activities; therefore, finding new efficient methods for synthesising such analogues is highly desirable in pharmaceutical and medicinal research. Chapter 1 introduces the project detailing the biological importance and applications of BZDs. The classical synthetic routes towards BZDs and some of the limitations for efficient and rapid BZD-based library synthesis, followed by the aims of the project. Chapter 2 presents a late-stage C-H activation method for synthesising ortho-arylated 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, including a library of over twenty novel analogues. The microwave-mediated palladium catalysed arylation method is also applicable to nordazepam (7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one), the active metabolite of diazepam. Further diversification of the compounds is achieved by N-alkylation and/or H/D exchange, which affords elaborated pharmaceuticals. Chapter 3 describes an alternative catalytic visible light-mediated photoredox method for ortho-arylated 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-ones. The protocol uses aryldiazonium salts in refluxing methanol and showcases an interesting phenomenon known as the “nuisance effect” with 2- or 4-fluorobenzenediazonium salts. It results in both fluoroaryl and methoxyaryl- products, the latter result from a nucleophilic aromatic substitution (SNAr) on the fluorobenzenediazonium salt (nuisance effect). The results from biological tests of the benzodiazepine libraries against GABAA receptors indicated that the C-7 substituent is vital for activities in GABA and only the 7-chloro-benzodiazepines show any reasonable activities, although ortho arylation is detrimental to bioactivity. A computational DFT analysis of the reaction mechanism from our collaborators is also discussed in the Chapter. Chapter 4 contains a brief overview of C-H functionalisation protols. Moreover, in this Chapter, the photoredox C-H activation method combined with the nuisance effect are extended to other privileged scaffolds. This Chapter describes the synthesis of small libraries of 2-phenylpyridines and 1-phenyl-2-pyrrolidinones. The nuisance effect proves to be effective in creating small arrays of compounds from a single reaction and in X-ray screening arrays for biological testing. A number of 1-phenyl-2-pyrrolidinone analogues display promising biological activities towards NUDT7, a peroxisomal coenzyme A diphosphatase of current interest. Chapter 5 focuses on the synthesis of a series of N1-arylated 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-ones. The N-arylation occurs in one-step using a single 1,4-benzodiazepine precursor with unsymmetrical diaryliodonium salts in aqueous ammonia as a base. Chapter 6 reports the scale-up synthesis of 6-(1H-indol-4-yl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-4-acetic acid methyl ester, TC-AC-28. This BZD derivative is a highly selective bromo and extra terminal (BET) bromodomain inhibitor and a useful epigenetic tool compound. The near gram-scale, seven-step synthesis of this key chemical probe compound enabled it to be available for researchers through Tocris, one of our industry sponsors, and where I spent 3 months as part of my CASE award. Chapter 7 concludes the thesis and concentrates on future directions.

This thesis focuses on the structure and reactivity of a variety of inorganic systems through the exploration of their electronic structure by employing density functional theoretical methods. Chapter 1, the introduction, outlines the theoretical approaches and includes a historical overview of the development of quantum theory. The theoretical methods and their applications are then described and discussed. The first chapter concludes with an overview of the work undertaken. Chapter 2 presents a historical background of the experimental and theoretical work done on traditional Group IV Ziegler-Natta catalysis inculding the generally accepted mechanisms believed to be employed when these systems are used to polymerise olifins. Furthermore, a description of the experimental results obtained when a non-traditional Ziegler-Natta catalyst was subjected to proplyene are given as a rationale for the calculations presented in Chapter 3. Chapter 3 presents a theoretical exploration of a novel class of olefin polymerization catalysts based on the tris(amido)titanium(IV) platform. Here, DFT has been used to probe the electronic structure of these compounds in order to provide a rationale for the catalytic activity that is associated with them as well as a possible new mechanism for this type of non-traditional catalyst. Furthermore, Chapter 4 takes a closer look at a large number of potential intermediates that are available for the polymerization reaction discussed in Chapter 3. In Chapter 5, a series of simple transition metal complexes are calculated and analysed to further understand key aspects of the system. The complexes represent a basic model of the novel catalysts found in Chapter 3 and contain the essential feature of π-acid-base chemistry within the coordination sphere.

The primary goal of this research project was to investigate the mechanism of a novel thermally activated cyclisation reaction discovered by Parsons et al. During these studies two novel reactions were discovered: For reaction see Abstract in pdf Reagents and Conditions: (i) Toluene 0.1M, reflux, 4h, 32%. For reaction see Abstract in pdf Reagents and Conditions: (i) Toluene, 0.01M, reflux, 4h, 53% Radical and ene pathways for the generation of these products were proposed. However, despite extensive empirical studies, no definitive proof for either mechanism was found. The breadth of the synthetic utility of the above reactions was also investigated by synthesizing various analogues. The general application of the Parsons' cyclisation to the synthesis of steroid cored and the complex natural product Jiadifenin was also investigated. Advanced intermediates were synthesised and invaluable information on reactivity was gained, however these investigations could not be completed due to time constraints

Exploitation of the asymmetric electron density at the crown of the oxazolidinone [221] allowed for high diastereofacial selectivity when converting the olefin to an epoxide. Regiocontrolled fragmentation of the epoxide enabled us to introduce the three essential stereocentres of the target alkaloid (-)-anisomycin [1] both contiguously and with the correct geometry. Installation of the remaining aromatic appendage allowed us to complete the molecular skeleton of the natural product; however, the synthetic step to facilitate this addition reaction also compromised the chiral integrity of the C2 position. Whilst the desired bioactive alkaloid, (-)-anisomycin [1] was not achieved upon completion of the synthesis, construction of the rare stereoisomer, (-)-2-epi-anisomycin [274] in a 9.4% overall yield demonstrates the routes future potential to deliver (-)-anisomycin [1]. For graphics please refer to abstract in pdf

First, PMMA (poly(methyl methacrylate)) colloidal spheres were synthesised using surfactant free emulsion polymerisation (SFEP) process. The effects of temperature, monomer concentration and seeding in the SFEP process were investigated. PMMA colloidal crystals were fabricated using two different self-assembly techniques; the vertical deposition via evaporation and a modified floating (air-water interface) technique. The floating technique made it possible to fabricate 2D and 3D colloidal crystals with controlled thickness through multiple depositions. Once self-assembled, the PMMA colloidal crystals were used as templates to synthesise different 2D and 3D metal oxide inverse opal structures. Different colloidal crystal templating techniques including vacuum assisted and horizontal templating via sol-gel infiltration were used to produce highly ordered inverse opal structures. A comprehensive temperature dependent study on the formation of 3D TiO2 inverse opals was carried out. Successful synthesis of different metal oxide hollow spheres was made possible using a simple sol-gel templating approach. By using seeded polymerisation combined with template-directed synthesis, sphere-in-sphere hollow spheres were successfully synthesised, with independent compositions for both the inner and outer spheres. By using a modified templating technique, it was possible to synthesise bilayered inverse opals with different metal oxide layers. A successful production of such a bilayered/heterojunction system was realised. By using secondary templating combined with a chemical bath deposition (CBD) process, it was also possible to grow ZnO nanorods onto this bilayered inverse opal structure producing a hierarchical hybrid nanostructure. This novel structure was further sensitised by narrow band gap CdSe/ZnS core-shell quantum dots and used in PEC water splitting experiments. The results were very promising and showed stepwise increase in photoefficiency for every step in the synthesis of the novel hierarchical structure of quantum dot sensitised ZnO nanorods on bilayered TiO2/ZnO inverse opal. Increasing surface area, enhancing charge separation, faster charge transport, better light scattering and visible light absorption all played their parts in such a sequential photoenhancing system. Bilayered TiO2/ZnO inverse opal was also used as a photoanode material in dye sensitised solar cell (DSSC) devices and showed improved photoenhancement. The photonic crystal properties of ZnO inverse opal was investigated by coupling it to potassium titanate (K2Ti4O9) nanobelts. Such configuration showed higher photoefficiency in DSSC devices compare to a single system of titanate. In summary, these strategies offer a novel approach for the synthesis of hierarchical structures with each part playing a role in enhancing light harvesting for better energy conversion.

The chemistry of ambiphilic molecules, such as phosphine-boranes, has experienced a resurgence in interest, in part due to the emergence of Frustrated Lewis Pairs (FLPs). With a 2-atom bridge to separate the phosphine and borane units, the unsaturated, 1-borata-4-phosphoniacyclobut-2-enes R2BC(R)=C(Ph)PPh2 have been investigated. Their solid state data has been complemented by DFT studies, with a view towards controlling the geometry around a metal centre in order to position the Lewis acid unit over the Lewis basic metal centre without forming an adduct. The reactivity of the saturated and unsaturated phosphine-boranes has been also probed with a series of Lewis-basic metals. It was found that while the saturated systems readily coordinate to group 9 and 10 metals, the phosphorus-boron bond of the unsaturated systems remains too strong for coordination. Therefore, attempts to disrupt the strong P-B bond were made using pyridine. Phosphaalkynes of the type RMe2SiC≡P have been prepared from RSiMe2CH2Cl, by converting the 'CH2Cl' unit into 'CH2PCl2', before dehydrochlorination. The ruthenaphosphaalkenyls [Ru{P=CH(SiMe2R)}Cl(CO)(PPh3)2] are then prepared in high yield from the corresponding phosphaalkynes (P≡CSiMe2R, R = Ph, tolyl, nBu, p-CF3-C6H4) through hydroruthenation with [RuHCl(CO)(PPh3)3]. The first solid-state structural data of these ruthenaphosphaalkenyls is described and complemented by DFT studies of the precedent [Ru(P=CHtBu)Cl(CO)(PPh3)2)] alongside silyl based systems, allowing the visualisation of molecular orbitals and calculated NMR data. The silyl systems mimic the previously reported propensity toward electrophilic addition shown by Ru{P=CH(tBu)}Cl(CO)(PPh3)2]. However, the presence of the silyl group also appears to modify the reactivity compared to that previously published for [Ru{P=CH(tBu)}Cl(CO)(PPh3)2]; demonstrated by the addition of HCl to form the saturated P-C linkage shown in [RuCl2(CO)(PPh3)2{P(HCl)CH2SiMe2R}]. The ruthenaphosphaalkenes also exhibit reactivity with nucleophiles (pyrazolates) to form novel bridging pyrazolyl η2–phosphaalkenic compounds of the type [Ru(CO){κ3-N,C,P-P(PzR',R")CH(SiMe2R)}(PPh3)2], building on earlier work within the group.