1,2,3-Triazoles have proven to be highly successful in ligand design due to their facile synthesis owing to the advent of the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The Cu(I) species necessary for the CuAAC reaction can be generated in situ with simple purification of the resulting 1,4-disubstituted products and has proven to be an outstanding method to prepare triazole-containing ligands. The present work focuses on the synthesis, characterization and photophysical investigation of triazole-containing transition metal complexes and their possible use in applications, such as LECs and biological cell imaging. To explore this wide topic different types of 1,2,3-triazole containing ligands including 2-(1-benzyl-1H-1,2,3-triazol-4-yl)pyridine as a bidentate ligand, 2,6-bis(1-phenyl-1H-1,2,3-triazol-4-yl)pyridine as a tridentate ligand and 1,4-bis((4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)benzene as a bridging ligand. were prepared and used with Re(I), Os(II), Ru(II) and Ir(III) transition metals. Chapter 2 deals with rhenium complexes [Re(CO)3(Bn-pytz)(X)]+/0 (X = Cl or substituted pyridine). The photophysical investigation indicates that the emission can be further shifted towards the blue by replacing the Cl- ligand with pyridine. Two of these complexes were utilised in preliminary tests as the phosphor in light-emitting electrochemical cell LEC devices. In Chapter 3 a series of osmium(II) complexes [Os(bpy)3−n(Bn-pytz)n](PF6)2 (where bpy = bipyridine, n = 1, 2, 3) were prepared and characterised. The progressive replacement of bpy by Bn-pytz leads to blue-shifted UV-visible electronic absorption and emission spectra. Successful separation of the fac and mer isomers of [Os(Bn-pytz)3](PF6)2 complexes was achieved, which exhibits phosphorescence (λem = 615 nm, in degassed acetonitrile). [Os(Bn-pytz)3][PF6]2 was shown to exhibit significant quenching of luminescence intensity in the presence of oxygen (Ksv = 83 atm-1). The water soluble chloride form of the complexes were prepared and were subjected to preliminary cellular uptake and luminescence imaging microscopy studies. The results from these studies reveal that the [Os(Bn-pytz)3]2+ is successfully taken up by two cancer cell lines. Bright emission from [Os(Bn-pytz)3]2+ can be seen by confocal microscopy with localisation at the lysosomes, however, no photodynamic therapy (PDT) activity is observed. Described in Chapter 4 is the synthesis, characterisation and photophysical investigation of an osmium(II) 2,6-bis(1-phenyl-1H-1,2,3-triazol-4-yl)pyridine (btzpy) complex. From photophysical investigations [Os(btzpy)2](PF6)2 exhibits phosphorescence (λem = 595 nm, τ = 937 ns, φem = 9.3% in degassed acetonitrile). The complex undergoes significant oxygen-dependent quenching of emission with a 43-fold reduction in luminescence intensity between degassed and aerated acetonitrile solutions (Ksv = 110 atm-1), demonstrating its capability as a singlet oxygen sensitiser. The water soluble chloride form of the complex was prepared on the basis of the photophysical properties and was subject to preliminary cellular uptake and luminescence microscopy imaging studies. The complex easily entered the HeLa and U2OS cancer cell lines with mitochondrial localisation observed with intense emission permitting imaging at reduced concentrations up to 1 μM. Long-term dose toxicity results show low toxicity in HeLa cells with LD50 >100 μM. Described in Chapter 5 is the synthesis and characterisation of a range of dinuclear supramolecular complexes, containing a bridging ligand incorporating the 1,2,3-triazole moiety. The homonuclear complexes ([Ir(ppy)2-L-Ir(ppy)2](PF6)2, [Ru(bpy)2-L-Ru(bpy)2](PF6)4, [Os(bpy)2-L-Os(bpy)2](PF6)4 and [Os(Bn-pytz)2-L-Os(Bn-pytz)2](PF6)4 and heteronuclear complex ([Ru(bpy)2-L-Ir(ppy)2](PF6)3 (where L = 1,4-{bis-4-(pyrid-2-yl)-1,2,3-triazol-1-yl methyl}benzene) were prepared. Photophysical studies show that the dinuclear species display greater luminescence intensities than their mononuclear model complexes. The emission spectra of the heteronuclear complex [Ru(bpy)2-L-Ir(ppy)2](PF6)3, exhibits features similar to those observed in the emission spectra of the mononuclear complexes [Ir(ppy)2-L](PF6) and [Ru(bpy)2-L](PF6)2. This indicates dual emission occurs from both the Ir- and Ru-centred chromophores (φem = 0.33% in acetonitrile). Interestingly the emission from the Ru-centred chromophore seems greatly enhanced relative to the emission of the Ru mononuclear analogue. This indicates partial energy transfer from Ir to Ru. The dual emission results in near white light emission and could be used for the devolpment of single component white light emitting phosphors.

Post-combustion capture using amine-based solvents has been considered as the most viable technology for carbon capture, to mitigate industrial carbon dioxide (CO2) emissions; but the solvents show a number of shortcomings. Recently, ionic liquids (ILs) are suggested as possible alternative to amine-based solvents, for they can be molecularly engineered to match various target thermophysical properties. This work focused on the development of systematic approaches to design IL-based solvents for carbon capture purpose. The first focus of this work is to develop an insight-based based visual approach to determine potential IL solvents as substitute to conventional carbon capture solvents. This approach allows visualisation of high-dimensional problem to be visualised in two or three dimensions, and assist designers without mathematical programming background in IL design. Following that, a mathematical optimisation approach to design optimal IL solvent for CO2 capture purpose was developed as second focus of this thesis. This has been done by formulating the IL solvent design problem as mixed integer non-linear programming (MINLP) optimisation problem. The abovementioned approaches were developed to design task-specific ILs with high CO2 absorption capacity as substitute to common carbon capture solvents. However, studies show that such ILs are relatively more expensive and have higher viscosities. To reduce the cost and viscosity of solvent, task-specific IL can be mixed with conventional IL, ensuring CO2 solubility remains high, while viscosity and cost are acceptable. Hence, the previously developed visual approach was extended to design pure ILs and IL mixtures, specifically to capture CO2. In order to ensure the designed IL is performing at its optimum (highest CO2 solubility in this case), the operating conditions of the carbon capture process shall be considered because they will affect the thermophysical properties and CO2 solubility of ILs. Therefore, the forth focus of this work will be incorporation of operating temperature and pressure into design of IL solvents. Similarly, the design problem was formulated as MINLP problem and solved using mathematical optimisation approach, where operating temperature and pressure were defined as variables through disjunctive programming. Replacing solvent for carbon capture system to IL-based solvent or installing carbon capture system will affect the overall process, as this will affect the utilities consumption of carbon capture system. Therefore, process design has been integrated with IL design in this thesis, to study how the solvent substitution affects the entire process, and followed by retrofitting of the entire process including carbon capture system accordingly. The design problem was formulated and solved as MINLP problem. Finally, this thesis concludes with possible extensions and future works in this area of research work.

Influenza virus infection and the shikimic acid pathway are two of many examples of microbe-host interactions and microbial biosynthetic pathways that are interesting for investigation by means of small molecules. A particularly interesting structural motif common to both is the cyclohexenecarboxylic acid. In the former, this structural motif has been employed as a mimetic of the sialyl cation intermediate and forms the scaffold of the anti-influenza drug and neuraminidase inhibitor Oseltamivir (or TamifluTM). In the latter pathway, crucial modifications towards aromatic amino acids are carried out via shikimic acid, a cyclohexenecarboxylic acid, as a substrate. A straightforward method to replace the carboxylate moiety in such structures with a phosphonate would provide access to a wide variety of mimetics, for instance monoesters, that still retain a negative charge under physiological conditions usually required for bioactivity. The aim of this research project was to develop an efficient synthesis of the cyclohexenephosphonate scaffold from chiral pool precursors via two key steps, a Hunsdiecker-Barton iododecarboxylation followed by a palladiummediated coupling step to introduce the phosphonate moiety, thus giving a convenient access to interesting bioactive molecules. This approach has successfully been applied to the shikimic acid to afford ‘phospha'-shikimic acids and 3-dehydro-‘phospha'-shikimic acids, and further development of this strategy has led to the synthesis of ‘phospha'-Tamiflu and its derivatives from an Oseltamivir precursor.

A [5:5] ligand based on the bicyclic guanidine 1,4,6-triazabicyclo[3.3.0]oct-4-ene [Htbo] has been synthesised. Two of these tbo units have been linked via a carbon bridgehead to form a novel bidentate ligand. Based on the knowledge that the electronic properties and specific steric interactions at a metal can lead to new insights into the relationship between crystal structure and ligand activity, the synthesised compounds have been investigated as polydentate ligands on the assumption that that they could be used to precisely control coordination environment. The corresponding [6:6] system which is based on the bicyclic guanidine 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine) [hppH] has also been synthesised and its coordination to silyl groups investigated. 1,4,6-triazabicyclo[3.3.0]oct-4-ene (Htbo) has been deprotonated to form the [tbo]- anion, which has been assessed as a ligand at Li, Al and Zn centres, allowing direct structural comparison to be made with the [hpp]- analogues. The coordination chemistry of Htbo and its derivatives has been explored through formation of a variety of transition metal complexes. Additionally, crystal structures showed that Htbo coordinates to the metal through the N-imine atom as a monodentate ligand to form trigonal planar, tetrahedral, square planar and octahedral complexes. The bis (tbo) methane H2C{tbo}2 ligand was found to support a range of coordination geometries and upon coordination, ionic structures such as [Pd(H2C{tbo}2)2][Cl]2 were formed. The synthesis of the monosubstituted compound hppSiCl3 afforded a series of (hpp) silanes which were isolated and reacted with LiOAr (Ar= 2,6-tBu2C6H3), providing a proof of N-Si bond stabilisation using a metal. Five examples of pentacoordinated silicon species have been synthesised via the reaction of [hpp]- and R2SiCl2 (R= Ph, Me).

The Synaptonemal Complex (SC) is a proteinaceous structure that connects homologous chromosomes lengthwise during meiotic prophase. In budding yeast, the SC consists of two parallel axes that become connected by the central element protein, Zip1 that extends along the chromosome axes (Sym, Engebrecht et al. 1993). Extension of the SC is coordinated to crossover formation by a group of proteins known as the ‘ZMM's (Zip1, Zip2, Zip3, Zip4, Msh4, Msh5 and Mer3) (Borner, Kleckner et al. 2004). Work outlined here demonstrates a role for the mismatch repair paralogue, Msh4 in preventing SC extension from being de-coupled from crossover formation. Furthermore, increased temperature serves as a positive effector for this decoupling. These findings suggest that SC extension is highly regulated to ensure that it is coupled with crossing over. As well as its role in crossover formation (Storlazzi, Xu et al. 1996), the work outlined here demonstrates an independent role for Zip1 in promoting the segregation of non-exchange chromosome pairs (NECs). Zip1 pairs the centromeres of NECs in pachytene through to metaphase I, where it aids their segregation at the first meiotic division. The localisation and function of Zip1 at the centromeres of non-exchange chromosomes depends on Zip3 and Zip2, respectively. Zip1 is observed at the centromeres of all chromosomes following SC disassembly through to the first meiotic division, where it promotes the segregation of exchange pairs also. A model is suggested whereby Zip1 promotes the segregation of both non-exchange and exchange chromosome pairs by tethering homologous centromeres throughout meiotic prophase. Finally, a parallel pathway for NEC segregation is also described that depends upon the spindle checkpoint component, Mad3. When both ZIP1 and MAD3 are deleted, NECs segregate at random.

The focus of this thesis is the synthesis of novel palladium(0) complexes bearing the ligand 1,3,4,5-tetramethylimidazol-2-ylidene (ITMe), a small percentage buried volume N-heterocyclic carbene. These complexes have been assessed as mediators for the 1,2-additions of hetero element-element bonds to unsaturated organic moieties. In particular, Si-Si, Si-B and B-B bond additions to alkynes and azobenzenes were chosen as reactions of interest due to their challenging nature. Chapter 1 introduces the concept of transition metal mediated element-element additions to alkynes and includes a thorough review on the current literature state. Chapter 2 describes the first solution based synthesis of [Pd(ITMe)2] and its in situ reactivity with Me3SiSiMe3 under mild conditions to form the novel complex cis-[Pd(ITMe)2(SiMe3)2], the first NHC-bearing complex resulting from the oxidative addition of hexamethyldisilane to a palladium centre. The use of this complex as a pre-catalyst for the bis(silyl)ation of electronically and sterically challenging internal acetylenes using non-activated disilanes is reported. A series of novel 1,2-disilylstilbenes were synthesized in high yield and with 100% Z-stereoselectivity. Chapter 3 details the use of [Pd(ITMe)2(PhC≡CPh)], the first bis(N-heterocyclic carbene)Pd(0)-alkyne complex, as a highly reactive pre-catalyst in the silaboration of terminal and internal alkynes to yield a number of known and novel 1-silyl-2-boryl alkenes. Unprecedented mild reaction temperatures for terminal alkynes, short reaction times and low catalytic loadings are reported. During mechanistic studies, cis-[Pd(ITMe)2(SiMe2Ph)(Bpin)] was directly synthesized by oxidative addition of PhMe2SiBpin to [Pd(ITMe)2(PhC≡CPh)]. This represents a very rare example of a (silyl)(boryl)palladium complex. A plausible catalyst decomposition route was also examined. In Chapter 4, [Pd(ITMe)2(PhC≡CPh)] acts as a highly reactive pre-catalyst in the unprecedented homogeneous catalyzed diboration of terminal and internal alkynes, yielding a number of novel and known syn-1,2-diborylalkenes in a 100% stereoselective manner. DFT calculations conducted by our collaborators suggest that a similar reaction pathway to that proposed for platinum phosphine analogues is followed, and that destabilization of key intermediates by ITMe is vital to the overall success for the palladium-catalyzed B-B addition to alkynes. Chapter 5 reports the use of [Pd(ITMe)2(PhC≡CPh)] as a highly active pre-catalyst in the diboration and silaboration of azobenzenes to synthesize a series of novel functionalized hydrazines. The reactions proceed using commercially available diboranes and silaboranes under mild reaction conditions. Preliminary investigations into further reactivity of [Pd(ITMe)2(PhC≡CPh)], [Pd(ITMe)2] and cis-[Pd(ITMe)2(SiR3)2] (SiR3 = SiMe2Ph or SiMe3) are reported in Chapter 6. This includes the oxidative cleavage of Me3GeGeMe3 by [Pd(ITMe)2(PhC≡CPh)] to form the novel cis-[Pd(ITMe)2(GeMe3)2] and an initial study into the catalytic alkyne digermylations. The hydrogenation of diphenylacetylene to form Z-stilbene using an amine-borane and catalytic quantities of [Pd(ITMe)2(PhC≡CPh)] was also investigated. Finally, the stoichiometric reactions of allyl bromides with cis-[Pd(ITMe)2(SiR3)2] to form the novel complexes trans-[Pd(ITMe)2(SiR3)(Br)] are detailed.

The S.cerevisiae Ino80 chromatin remodelling complex is known to be involved in the DNA damage response at double strand breaks and has more recently also been shown to play a role at stalled replication forks. The many functions of this remodellor are likely to be mediated by different subunits of the complex. Interestingly, strains harbouring a deletion of the IES6 subunit are hypersensitive to hydroxyurea and fail to stabilise stalled replication forks, phenocopying strains lacking the catalytic subunit, INO80, indicating a role for Ies6 within the complex's response to DNA damage. Although largely uncharacterised, Ies6 contains a YL1 domain, which is a putative DNA binding domain. In vitro DNA binding gel shift assays with recombinant Ies6 showed that this protein does possess DNA binding activity. Recombinant Ies6 bound both Holliday Junction and Y-fork DNA, as well as linear duplex DNA, displaying a small but reproducible preference for the two branch-structured DNAs. Recombinant Ies6 containing mutations in the protein's C-terminal YL1 domain were generated and a quadruple mutant, ies6-T119A/K122A/S127A/T129A, exhibited significantly reduced DNA binding activity compared to the wild-type protein. The importance of the DNA binding activity was investigated in vivo, and, in contrast to the wild-type strain, the DNA binding mutant of IES6 failed to complement the deletion strain's HU-hypersensitivity. Interestingly, overexpression of Top3 or Cdk1, but not Top2 or Clb2 also rescued the ies6 deletion strain's HU-hypersensitivity to near wild-type levels. Further investigation revealed that Ies6 is also required for the maintenance of correct cellular ploidy, as in the absence of IES6, cellular ploidy is seen to increase prior to a drift towards unregulated ploidy and aneuploidy, which are hallmarks of cancer. Notably, the protein's ability to bind DNA correlated with its ability to maintain cellular ploidy. We therefore propose that the Ino80 chromatin remodelling complex Ies6 subunit plays an important role in the maintenance of genomic stability.

Part 1. Synthesis of Stereodefined Heterocyclic Rings. We wish to report the development of novel methodology for the synthesis of stereodefined heterocyclic rings, which could be used for the synthesis of natural products containing for example tetrahydrofuran motifs, such as members of the pamamycin family. Due to their ambivalent properties, organoaluminium reagents can easily react with acetals by transfering an alkyl group after prior coordination with the substrates. This work has led to the development of a novel cascade reaction. It involves the reaction of acetals with trialkylaluminium reagents, which is followed by a cyclisation reaction, generating consequently tetrahydrofuran or tetrahydropyran rings. In addition, investigation towards the synthesis of pyrrolidines was also carried out. Part 2. Investigation and Development of a Novel Cascade Reaction. The Bergman cycloaromatisation reaction is based on the formation of a biradical intermediate species and has been, over the years, a constant source of inspiration for scientists. Continued efforts over the last 40 years permitted, among other things, a better understanding of the mode of action of the enediyne antibiotics, a class of natural compounds with exceptional biological activities. The Parsons group recently developed a novel cyclisation reaction, which also generates a biradical species, and which could, after being trapped with a suitable alkene, lead to the formation of tricyclic molecules containing heterocyclic cores. As a result, we wish to further investigate this novel reaction and develop a tandem reaction, involving this reaction combined with a Diels-Alder reaction in order to generate pentacyclic molecules, in one synthetic operation, and from an acyclic precursor.

The folding of a protein from a linear chain of amino acids into its functional native state is one of the most widely investigated yet enigmatic events to take place in the natural world. An ever‐increasing number of proteins and peptides are known to fold, or “misfold”, into protease‐resistant amyloid fibrils that share a common cross‐β structure, despite having no apparent sequence homology. Self‐assembly of particular proteins or peptides into amyloid is believed to be the molecular basis of many diseases, including Alzheimer's Disease, Type II diabetes and the transmissible spongiform encephalopathies. More recent evidence suggests a functional, non‐pathogenic role for amyloid in certain organisms, which has inspired its use as a biomaterial. In order to understand these diseases and exploit amyloid for industrial use using a bottom‐up design approach, detailed knowledge of the assembly process and structure of amyloid is required. Many short peptides are known to assemble into amyloid‐like fibres in vitro that have very similar properties to those formed in vivo. These “model systems” can give deeper insight into what triggers, drives and influences self‐assembly. Furthermore, they can provide more detailed structural information than is often obtained from larger amyloid‐forming proteins. Using two short peptides (the yeast prion fragment GNNQQNY and the designed peptide KFFEAAAKKFFE), which form amyloid-like microcrystals that have been structurally characterised previously, the roles of particular residues in assembly and structure were investigated. Results reveal that aromatic residues are fundamental determinants of assembly and may contribute to polymorphic propensity. Furthermore, non‐aromatic sequence changes can have dramatic effects on fibril morphology both at a macromolecular level and in the underlying peptide packing arrangement. Structural variations were found between amyloid‐like fibres and microcrystals formed from the same peptide, which has implications for how to examine amyloid structure in the future. The balance of conditions required for proteins or peptides to adopt specific conformations is very fine. Polymorphism may be an inherent property of amyloidogenic proteins and peptides and detailing the structural intricacies of each form will be essential from both a biomedical and industrial perspective.

The meta photocycloaddition between a substituted aryl ring and alkene affords architecturally complex tricylic intermediates that have been utilised to investigate three different areas of synthetic organic chemistry. Firstly, a novel palladium catalysed oxidative fragmentation/cyclisation of the Z-but-2-ene-1,4-diol and anisole derived meta photocycloadduct 30 was investigated. It was proposed that a meso π-allyl palladium intermediate was generated during the course of the oxidative cyclisation process and it was hoped that a desymmetrisation reaction could be achieved by attaching a homochiral ligand to the palladium core and result in the enantioenrichment of the cyclised product. Unfortunately under the conditions used only a racemic mixture of products was obtained. Secondly, the use of nitrogen in exchange for oxygen in the oxidative cyclisation procedure was investigated with a view to preparing a conformationally constrained bicyclic amino acid. Installation of the amino group at the photocycloaddition stage failed and derivatisation of the hydroxyl group of the allyl alcohol/anisole derived photoadduct resulted in an undesired fragmentation. Acid induced fragmentation of the allyl alcohol/anisole derived photoadduct 25 and subsequent triflation of the hydroxyl followed by displacement with azide, reduction with Lindlar's catalyst and protection, afforded the requisite amide. Cyclisation with phenylselenylchloride and concomitant oxidation furnished the cyclised amide. Finally, the total synthesis of gelsemine was investigated. Building on the results of a previous researcher in the group an advanced intermediate derived from the meta photocycloaddition of allyl alcohol/anisole failed to undergo the desired palladium catalysed alkoxycarbonylation to assemble the key quaternary centre of the oxindole group. Reaction of the allyl alcohol/anisole photoadduct with N-chlorosulfonyl isocyanate afforded an alternative route forward and subsequent synthetic modifications led to an attempted intramolecular Heck spirocyclisation reaction, which led to the formation of a spirooxindole centre that was epimeric to gelsemine. Utilisation of the diol photoadduct afforded functionality which would allow construction of the pyrrolidine ring prior to forming the spirooxindole centre. The same synthetic route was applied to afford the hydroxyl group, where epimerisation of the oxidised product, a further oxidation and Curtius rearrangement furnished the exo carbamate 154. The system now had the requisite functionality present to complete the total synthesis of gelsemine.