Supramolecular chemistry involves the study of noncovalent interactions that take place between molecules. A supramolecule or host-guest complex is formed when a noncovalentbinding or complexation event occurs between two such molecules. Hydrogen bonds, electrostatics, ?-stacking, hydrophobic effects and Van der Waals forces are all types of noncovalent interactions. The incorporation of redox active molecules into supramolecular systems is desirable, as they can be used as a convenient way of observing changes in a systems environment. This study involves the synthesis of a range of different redox active molecules, incorporated into supramolecular or materials devices. Firstly, two novel polymerisable flavin monomers have been synthesised. Attempts to polymerise these monomers, followed by characterisation to determine the physical and electronic properties were carried out. Secondly, a porphyrin system capable of binding to a flavin moiety has been prepared, and these complexes have been studied using physical and electrochemical techniques. This system offers an insight into the relationship between the porphyrin and flavin in nature. Furthermore, it would also serve to show how metals in close proximity to the flavin moiety can affect its supramolecular and electrochemical properties. A redox active ureidopyrimidinone system, capable of forming very strong dimer complexes, has been synthesised. This is able to tautomerise in solution, and using a combination of physical and electrochemical techniques, these supramolecular interactions have been studied. A polymer also displaying these properties has also been prepared and studied to understand the supramolecular properties it possesses. The results of this study will hopefully contribute significantly to the body of chemical research in the area of supramolecular and materials chemistry, with a variety of interesting results and scope for further expansion of these projects.

The influence of solvent and steric hindrance on the conversion of thiolsulfinates to trisulfides with hexamethyldisilathiane was investigated and a new polar mechanism, based on acceleration of the reaction by polar solvents and by fluoride ions, was proposed. The mono and dialkylation of 2,2-disubstituted 1,3-dithiane-1-oxides was investigated. Whereas those derived from menthone form only one diastereomer which cannot be alkylated further, those derived from acetone form two diastereomers. Only one of them can be alkylated further. Dehydration of the diastereomeric tertiary alcohols derived from directed aldol-reaction of γ-butyrolactones and methyl ketones yields diastereomeric conjugated enes in high yield and d.e. Michael-addition of benzyl thiols to these gives good yields and d.e. of the Michael-adducts. Deprotection of PMB-protected thiols with concomitant formation of disulfides was achieved by bromine in methanol or CH2Cl2. A seven-membered cyclic disulfide which contains the carbon backbone of the Perophora viridis trisulfide, albeit with two stereocentres in the incorrect configuration, was prepared.

Hydrometalation of α,β-unsaturated carbonyl compounds provides access to reactive metal enolates, which can then be trapped by a suitable electrophile. The coppercatalysed reductive aldol reaction involves hydrometalation of an α,β-unsaturated carbonyl compound, followed by an inter- or intramolecular aldol reaction. While there have been numerous examples of copper-catalysed reductive aldol reactions reported in the literature, the corresponding reductive Michael reaction has been relatively understudied. Herein, the copper-catalysed reductive Michael cyclisation of substrates containing two α,β-unsaturated carbonyl moieties is described. A range of structurally and electronically diverse substrates were prepared by various different methods. Both α,β-unsaturated ketones and esters underwent cyclisation, in the presence of a copper catalyst, a bisphosphine ligand, and a stoichiometric reductant, to afford 5- and 6- membered carbocyclic and heterocyclic products, with good-to-excellent levels of diastereo- and enantiocontrol. Furthermore, the diastereochemical outcome of these reactions is dependent on the specific reaction conditions used.

This thesis presents a modular palladium(II) template-directed synthetic strategy towards mechanically interlocked polymacrocyclic architectures, such as a Borromean link and linear [n]-catenanes. Central to the synthetic strategy is the use of the Huisgen-Meldal-Sharpless Cu(I)-catalysed 1,3-cycloaddition of azides to terminal alkynes (CuAAC) as a ring-closure procedure between complementary pairs of building blocks. The amalgamation of the palladium(II) [3+1]-template and CuAAC reaction is without methodological precedent and represents both an efficient and versatile procedure for the construction of interlocked architectures. Thematically, this thesis consists of three parts arranged in chronological order. Beginning with the synthesis towards a Borromean link, where the first successful palladium(II) template-directed double CuAAC ring-closure is documented. This is followed by the application of the “double-click” strategy to form a [3]catenane - the first such structure generated using metal ions other than Cu(I). Finally, the development of a modular CuAAC building block library is described, which was used to construct a [2]catenane and [3]catenane as well as later developments towards higher oligocatenanes.

The first project in this thesis describes our research reacting arynes with tertiary allyl amines to generate functionalised anilines via a benzyne induced aza-Claisen reaction. This process works in good to excellent yields and the methodology can be further applied to make benzannulated medium sized ring amine systems. The second project covered in this thesis details our studies in the generation of benzyne from benzoic acid. This process utilises palladium catalysis involving an ortho C-H activation of benzoic acid which generates a 5 membered palladacycle. This palladacycle then spontaneously decomposes with heat to generate palladium bound benzyne and carbon dioxide. The yield of benzyne was monitored by observing the amount of triphenylene formed in the process. Further synthetic applications in this process were limited, but it was shown that the benzyne could be reacted with alkynes to generate phenanthrene and naphthalene products. The third project in this thesis details our work on the insertion of benzyne into the C–S bond of thioesters. Using palladium catalysis and an o-trimethylsilylphenyl triflate benzyne precursor, a variety of thioethers were produced. The yields for this reaction were moderate to good but it was found that only aromatic substituents were tolerated on the thioester.

The olefin metathesis reaction is a well established and powerful method for the synthesis of alkenes. This reaction can be further classified into the intermolecular process known as cross-metathesis and the intramolecular process known as ring-closing metathesis. The aim of these studies is the use of the two variants of the metathesis reaction for the development of new methods for the synthesis of heteroaromatic structures, in particular the synthesis of polysubstituted pyridines.

The research presented herein is concerned with the exploration of rhodium-catalysed addition reactions with organoboranes encompassing the 1,4-addition enolate protonation to benzyl acrylate esters, and the synthesis of chiral organoboranes for use in the synthesis of natural products Hermitamides A and B. Chapter 1 introduces the area of rhodium-catalysed conjugate addition as a tool for asymmetric synthesis. An extensive discussion of this methodology is included and recent advances in the area will be highlighted. In addition to this some recently published alternatives to organoboranes are outlined and their use in rhodium-catalysed chemistry documented. Chapter 2 discusses the tandem process of rhodium-catalysed conjugate addition enolate protonation, a recently observed asymmetric development. By using a novel route to benzyl acrylic esters the synthesis of α,α′-dibenzyl esters is achieved in excellent yields and selectivity. This study highlights the fact that when dealing with 1,1-disubstituted activated alkenes it is more difficult to produce enantioselective results as the chirality is determined in the protonation step and not during insertion. Some insights into the mechanism are proposed based on the outcomes observed. Chapter 3 describes the total synthesis of Lyngbic Acid and related structures Hermitamides A and B. Synthesis of these natural products are achieved by synthesis of an enantiopure organoborane species and its subsequent coupling via rhodium catalysis. Some interesting insights into the addition of alkenyl organoborane species to unsubstituted 1,1-activated alkenes are detailed. Chapter 4 describes the synthesis and characterisation for the compounds discussed in the previous chapters.

La voie Hippo, découverte chez la Drosophile et conservée chez les mammifères, a été identifiée comme un élément essentiel dans le contrôle de la taille des organes. Cette cascade de kinases régule la phosphorylation de l’effecteur terminal YAP (ou de son paralogue TAZ), un coactivateur transcriptionnel reconnu comme oncogène. Sa fonction est médiée par sa translocation nucléaire et son interaction avec les facteurs de transcription TEAD, pour former le complexe YAP-TEAD qui active l’expression des gènes cibles responsable de la prolifération cellulaire et de la croissance des organes. La surexpression des protéines YAP/TAZ/TEAD dans de nombreux cancers perturbe l’équilibre de la voie Hippo et favorise la formation du complexe protéique causant une hyperprolifération et la propagation des cellules cancéreuses. Inhiber cette interaction protéine-protéine est une cible thérapeutique prometteuse pour concevoir de nouveaux anticancéreux. Dans cette optique, le laboratoire a considéré deux stratégies. La première consiste à cibler la protéine YAP en synthétisant des dipyrrines, représentant des fragments de la Vertéporfine dans le but de définir le motif minimal requis pour conserver l’activité biologique. Une seconde approche implique la synthèse de ligands de TEAD capable de se positionner au sein de l’interface 3. Basée sur des études de modélisation moléculaire, une famille avec un noyau central triazolique a été optimisée pour établir des relations structure-activité. Les molécules synthétisées sont actuellement en cours d’évaluation, grâce à la mise au point des tests biologiques et physicochimiques, et les premiers résultats ont permis d’identifier un composé prometteur. / The Hippo pathway, firstly described in Drosophila and highly conserved in mammals, has been demonstrated to play a crucial role in the organ size control. This kinase cascade regulates the phosphorylation of the downstream effector YAP (or its paralogue TAZ), a transcriptional coactivator with oncogenic activity. Its function is mediated by its nuclear translocation and interaction with the transcriptional factor TEAD, to form YAP-TEAD complex which activates the genes expression in charge of cell proliferation triggering organ growth. Overexpression of YAP/TAZ/TEAD protein in several cancers disrupts the Hippo pathway balance and urges on YAP-TEAD complex formation causing excessive proliferation and cancer development. Inhibiting this protein-protein interaction is thus a promising therapeutic target for the design of new anti-cancer drugs. In this goal, the laboratory has considered two strategies. The first one consists in targeting the YAP protein by synthesizing dipyrrins, representing Verteporfin fragments to define the minimal requirement yielding the expected biological activity. A second approach involves synthesizing TEAD ligands able to fit in specific interface 3. Based on molecular modeling, a triazole scaffold family was optimized to establish structure-activity relationship. Thanks to the biological and binding tests development, synthesized molecules evaluation is still in progress and the present first results have already allowed identifying a promising compound.

A new method for the synthesis of naphthalenes has been recently discovered. The Atom Transfer Radical Cyclisation (ATRC) of diverse 2-allylphenyl2',2',2'-trichloroacetates in the presence of a Cu complex afford schloronaphthalenes in good yields using either microwave or thermolytic methods of activation. A mechanism for the benzannulation reaction is proposed and experiments presented in order to validate this hypothesis. The use of 1,3-bis(2,6-diisopropylphenyl)imidazolium copper(I) chloride [(IPr)CuCl)] along with other metal carbenes is compared to the already reported CuCl/ligand system. Since the scope and synthetic utility of this new benzannulation reaction is restricted due to the use of the MW reactor, a solvent in which the thermal reaction can take place is reported, proving its efficiency in the synthesis of a range of substituted naphthalenes. The potential and versatility of the benzannulation reaction has been investigated. Studies towards the synthesis of gilvocarcin M which contains a tetracyclicaromatic core are presented. Gilvocarcins have potential use as anti-cancer agents and represent a member of the C-aryl glycosides found in natural products. Gilvocarcin M is a challenging target because there are a sparse number of total syntheses reported in the literature. The ATRC reaction of (vinyl)phenyl trichloroacetate has also been investigated, affording the synthesis of functionalised coumarins. The mechanism of this reaction has also been investigated, establishing that, in some cases, aretro-Kharasch reaction is observed.

2-Aryl-4,5-anti-diphenyloxazolines undergo nucleophilic dearomatising addition to the 2-aryl group when treated with secondary organolithiums at -78 °C in the presence of the deaggregating co-solvent DMPU. Quenching the reaction with methyl iodide gives a highly substituted conjugated diene. Quenching the reaction with a proton source gives a substituted unconjugated 1,4-diene. The stereochemistry of the anti-diphenyl oxazoline controls the diastereoselectivity of the nucleophilic addition; only one diastereoisomeric product is observed. Importantly these conditions allow the dearomatisation of phenyl rings; this moiety has proven resistant to nucleophilic dearomatisation in all but the harshest conditions. This thesis presents the application of this dearomatising reaction. First the scope of this method was explored towards the dearomatisation of phenyl rings with fluorine substituents, as precursors for fluorinated carbasugar analogues. Secondly amino-carbasugar analogues were synthesised. The dearomatisation of a 4-methoxy phenyl ring was used to construct a dearomatised carbocyclic skeleton, which was functionalised through a series of reactions to give fully substituted cyclohexanoid amino-carbasugar analogues. These amino carbasugars were synthesised without the use of protecting groups, in order to do this a number of chemoselective conditions were studied and chemoselective reactions were developed.