This dissertation presents the development of a synthetic strategy to produce various spiroligomer-based macrocycles that bridge the gap between organic molecules and small proteins. “Spiroligomers” (formerly known as “bis-peptides”) are a class of molecules produced by the assembly of “bis-amino acids”, molecules containing two amino acid regions on a single cyclic core. Each bis-amino acid is connected through pairs of amide bonds to form a diketopiperazine consequently eliminating single bond rotation and, therefore, avoids the complicated folding process common to the field of peptidomimetics. Spiroligomers are shape-programmable since the three-dimensional structure is controlled by the stereochemistry of the bis-amino acid monomers used in the synthesis, the connectivity of the monomers, and the number of monomers used. Furthermore, bis-amino acids can contain additional functional groups attached to multiple locations on the monomer which allows each spiroligomer, once synthesized, the ability to display these functional groups in predictable three-dimensional coordinates, with respect to each other. The synthesis of large spiroligomer-based structures requires the production of large amounts of bis-amino acid monomers. To this end, the scale of the synthesis of proline-based bis-amino acids from inexpensive trans-4-hydroxy-L-proline has been increased roughly 5-fold with respect to the previously published method. In addition to the time and solvent savings as a result of increasing the scale, the synthetic steps have been altered with considerations to ensure the production takes place in a convenient and environmentally friendly manner. Additionally, the desire to synthesize large spiroligomer-based structures means that the synthesis of each spiroligomer fragment must be as efficient and high-yielding as possible. To achieve this goal, a new synthetic approach to highly functionalized spiroligomers on solid support has been developed that results in increased yields relative to previously published methods. This new approach makes use of a protecting group, para-nitrobenzyl carbamate, which has not previously been incorporated in bis-amino acids as well as a pentafluorophenol ester activation strategy that also has not been in the synthesis of spiroligomers. Finally, an extendable synthetic route to spiroligomer-based macrocycles has been developed and representative macrocycles have been synthesized. This approach uses solid support to assemble multiple spiroligomers together through amino acids linkers before being cyclized in solution at dilute concentration to yield the desired macrocycles. Minimal functionality was included in the representative macrocycles to simplify structural information, confirmed by NMR and other means, and the macrocyclic structures were further investigated for host-guest activity using fluorescent, solvatochromic dyes. / Chemistry

La conception et l’élaboration de nouveaux ligands en chimie organométallique évoluent vers le design de ligands multifonctionnels afin d’augmenter l'affinité ligand/métal/substrat et de mimer les catalyseurs de la nature comme les enzymes, en activant de manière synergique les différents partenaires de la réaction. Il existe dans la littérature très peu d’exemples de complexes organométalliques présentant une fonctionnalité acide de Lewis. Dans notre étude, nous avons opté pour l’utilisation d’un atome de bore trivalent pendant. Malgré la forte utilisation des dérivés du bore en catalyse acide de Lewis pour l’activation de divers électrophiles, la conception de tels ligands ambiphiles, pour des complexes organométalliques, a été peu décrite et la réactivité peu étudiée. Ce travail a donc pour but d’explorer et de valider la viabilité de leurs préparations et de leurs utilisations.La première partie de ces travaux a été consacrée au développement de nouveaux complexes bifonctionnels métal/NHC/ester boronique pendant de Pd(II), Rh(I), Ru(II), Au(I) et Cu(I) et leurs applications en catalyse, afin d’accéder à de nouveaux modes d’activation de petites molécules.Dans la deuxième partie, un nouveau mode d’activation efficace de la liaison B-H des carbènes boranes incorporant un bras allylique ou homoallylique par des complexes de rhodium pour accéder à une famille de NHC-boranes cycliques énantioenrichis a été développé.Enfin, la troisième partie constitue la synthèse des travaux sur deux nouvelles familles de cations boronium macrocycliques et leurs applications dans la reconnaissance des anions. / Conception and elaboration of new ligands in organometallic chemistry evolved towards the design of multi-functional shape to increase the affinity ligand/metal/substrate to mimic nature’s catalysts, and to promote, in most cases, an increasing reactivity and selectivity in the catalytic process. Despite the significant development of N-heterocyclic carbene (NHC) ligands in organometallic chemistry since the last decade, complexes bearing pendant trivalent boron derivatives were so far overlooked.In this context, bifunctional ligands containing NHC and boron moieties have been developed and the corresponding Ag(I), Pd(II), Rh(I), Cu(I) and Ru(II) complexes were designed and prepared for a synergistic activation of both reaction partners by the metal center and the pendant Lewis acidic boron atom.During this work, B−H bond activation of NHC-boranes by a diphosphane-ligated cationic Rh complex was applied in an unprecedented intramolecular enantioselective hydroboration of simple olefins. This study led to a library of enantioenriched cyclic boranes in high yields (up to 94%) with high regio- (up to 100%) and enantioselectivities (er up to 99.2:0.8).As part of this work, new boronium macrocycles were synthesized in high yields and their anion binding ability was evaluated by fluorimetric and 1H NMR titration. These new macrocycles display high binding affinity for halides and oxoanions in the solid state, in solution and in the gas phase.

La synthèse et l'étude de rotaxanes et de porphyrines sont deux domaines particulièrement actifs de la recherche en chimie. Cependant, les composés combinant les propriétés intéressantes de ces deux types de structures sont plus rares. De nouveaux multi-rotaxanes à base de porphyrines, dont la préparation représente un défi synthétique, sont décrits dans cette thèse.Des porphyrines liées à deux ou quatre anneaux coordinants ont été synthétisées. Des rails moléculaires à deux chélates ont été enfilés dans les anneaux grâce à l'effet template du cuivre(I); l'introduction de bouchons a mené à la formation de rotaxanes. Dans le cas du bis-macrocycle porphyrinique, un [4]rotaxane a été obtenu. Des études de complexation hôte/invité avec des ligands azotés rigides ont montré que ce rotaxane est un récepteur moléculaire qui peut s'adapter à la taille du substrat invité en se "gonflant" ou en se "dégonflant".Dans le cas du tétra-macrocycle porphyrinique, la formation d'un [3]rotaxane d'architecture originale a étéobservée.La synthèse d'un nouveau bis-macrocycle plus rigide est en cours. Ce composé sera utilisé pour la construction d'un [4]rotaxane, qui pourrait montrer un caractère de presse moléculaire capable de modifier la conformation d'un substrat invité en le comprimant. / Rotaxanes and porphyrins are two particularly active fields of research in chemistry. However,molecules that combine the interesting properties of these types of structures are not so common. In this thesis we describe new porphyrin-based multi-rotaxanes, whose syntheses constitute interesting challenges.Porphyrins linked to two or four coordinating macrocycles were synthesised. The "gathering-andthreading" effect of copper(I) was used to thread molecular rods through the rings; the subsequent introduction of stoppers led to the formation of rotaxanes. In the case of the porphyrinic bis-macrocycle a [4]rotaxane was obtained. Host/guest complexation studies with rigid nitrogen ligands showed that the rotaxane behaves as a distensible molecular receptor that can adopt an "inflated" or "deflated" conformation and adjust its shape to the size of the guest. In the case of the porphyrinic tetra-macrocycle the formation of a [3]rotaxane of novel architecture was observed.The synthesis of a new, more rigid bis-macrocycle is in progress. This compound will be used for the construction of a [4]rotaxane that could act as a molecular press able to change the conformation of a guest substrate by compression.

This thesis investigates the design and synthesis of macrocycles and examines their ion-pair recognition, anion recognition and interpenetrative assembly capabilities. Chapter One introduces the field of supramolecular chemistry. Key concepts in host–guest complexation and self-assembly are outlined, with particular emphasis on the design of host systems for anion and ion-pair recognition. Chapter Two details the synthesis and binding properties of a heteroditopic 1,2,3-triazole- containing macrocycle that exhibits cooperative ion-pair recognition. Solution and solid-state evidence shows that the triazole motif simultaneously binds anions and cations. The exten- sion of this work towards the formation of interlocked structures containing an expanded heteroditopic macrocycle and threading components is explored. Chapter Three discusses the design and syntheses of series of electron-deficient macrocycles based on imidazolium, pyridinium and triazole. These are investigated for anion binding ability and assembly of interpenetrative assemblies with electron-rich threading components. Chapter Four describes research into the formation of interpenetrative assemblies using neutral components. Their design is based around aromatic donor–acceptor interactions and halogen bonding. Chapter Five presents some conclusions from the research undertaken. Chapter Six provides titration protocols, Job plot approximations, experimental procedures and characterisation of the compounds described in this thesis. Appendix details additional X-ray crystallographic data.

This work is concerned with the design and synthesis of the cheap, late first row transition metal complexes of Schiff base ligand systems. The prepared complexes readily afford systematic variation in order to probe potency and understand the role of metal, chelating ligands and anionic ligands when carrying out their cytotoxic effect. This study has lead to a better understanding of the action of these classes of complex and will be used to direct the design of new anti-cancer metallopharmaceuticals going forward. This thesis details the synthesis of a library of Schiff base macroacyclic ligands and their novel late first row transition metal complexes with varying anionic counterparts. The creation of a library with several degrees of variability provides a wide array of parameters to afford subtle variation in structure and chemistry e.g. denticity, co-ordination mode, chelate hole size, metal centred redox potentials, hydrolysis rates, co-ordinative saturation, lipophilicity, solubility and more. Complexation of the ligands was carried out by the free ligand and a novel macroacyclic metal template approach using the cheap late first row transition metal salts of Cobalt (II), Nickel (II), Copper (II) and Zinc (II) plus one Ru (III) complex. Structural studies of the 80 generated complexes was carried out by vibrational spectroscopy, elemental analysis, mass spectrometry, magnetic susceptibility and NMR. Single crystal X-ray structures have been determined with 20 reported in this thesis. All ligands act as tridentate ligands in all except one case to form monomeric distorted trigonal-bipyramidal, square-pyramidal or octahedral structures. In the case of zinc nitrate, the ligand L2PhMe acts as a tetradentate ligand to give a distorted octahedral structure. Paramagnetic NMR and solution magnetic susceptibility of paramagnetic complexes was achieved by the Evans NMR method and analysis of the solution NMR showed that L2R and L3R ligands display 2-fold symmetry and are likely either tetradentate in solution or a fast exchange between imine N-donar sites is occurring even down to -65°C. The majority of the resulting complexes of L1R were screened against a panel of three cancer cell lines. Several categories of complex were able to afford structure activity relationships. It was discovered that the ligand is indeed essential for activity of the metal salts against the panel of cell lines and it was largely discovered that the variation in 'tail group' and anionic coordinating ligands played little role in providing a dramatic variation in activity of the metal salt. In general all L1R complexes displayed moderate cytotoxicity showing a trend in activity with respect to the metal in the order RuIII≈CoII>CuII≈ZnII>NiII, over a 6 day exposure to the three cell panel RuIII was shown to be the most potent metal of the L1R series providing IC50 values of 4.6 (0.7) and 7.5 (1.2) μM against the DLD-1 and H460 cell lines respectively, which is Ca. 4.6 and 15 times less potent than cisplatin to the same cell panel respectively. RuIII was also discovered to be the only metal to provide an IC50 value from a 1 hour exposure to the DLD-1 cell panel. The value of 20.4 (3.5) μM is a moderate figure but again Ca. 10 fold less potent than cisplatin for the same test. The L2R and L3R complexes could not be screened by the same comprehension due to their low solubilities. However the lone screen that was possible from the very sparingly soluble complex [CuCl2(L3Bui)] gave the most exciting result and most potent complex of this thesis. After a 6 day exposure, [CuCl2(L3Bui)] gave IC50 values of 4.3 (0.1) and 2.9 (0.1) μM against the DLD-1 and H460 cell lines respectively. These values are merely 4 and 6 fold more than Cisplatin to the same cell lines respectively and demonstrates the potential of this class of complex as cytostatic agents. Further studies utilising a semi-quantitative DNA damaging assay, demonstrated that all first row complexes can damage DNA when in the presence of hydrogen peroxide, with the exception of ZnII complexes. CoII appeared to afford the greatest DNA damage with the most intsense bands for double strand breaks and the CuII complex of the ligand L3Bui also demonstrated a greater DNA damage as opposed to its L1Bui analogue.

Further investigations intending illucidate the mechanism of a newly discovered redox-alkylation reaction of azo dyes are presented. Preliminary results indicate that this reaction most probably proceeds via initial N-alkylation of the anion derived from an alpha-ketohydrazone. An investigation is continued to study the synthesis of macrocycle-carbohydrate-dye hybrids. The development of a modular approach to macrocycle assembly has enabled the synthesis of a library of pyridine-based macrocycles possessing multiple donor sites. A central dye scaffold, prepared from the SNAr reaction between halo-substituted azo dye and a disubstituted phenol, was decorated with a representative carbohydrate or macrocycle using Sharpless click chemistry. Also an "S3N-ligand azo-dye" conjugate has been synthesised with a view to the development of a sensor for heavy metal ions. Complexation of this system with Ag(I), Hg(II) and Cu(II) salts has been investigated. Complexation of the dye to metals results in a bathochromic shift in the absorption maximum of the azo dye, an effect which is most pronounced for Cu(II).The Kobayashi fragmentation has transformed the area of benzyne chemistry as it enables its generation from readily available precursors under mild reaction conditions. The controlled generation of benzyne in this manner has been utilised by many groups, allowing readily access to a variety of functionalised aromatic and heteroaromatic from simple precursors. During the course of a synthetic project, which was to utilise the Kobayashi fragmentation in a key intramolecular Diels-Alder reaction, we noticed that alternate modes of fragmentation/rearrangement accompanied the desired elimination reaction leading to benzyne generation. In particular, competing Fries or Smiles rearrangements became the major routes of fragmentation in appropriately functionalised substrates. The results of an investigation into the factors affecting the course of the Kobayashi fragmentation, together with the development of a novel bi-aryl synthesis are presented in this thesis.

Cette thèse concerne la synthèse, la caractérisation et l'utilisation en catalyse de ligands à grand angle de morsure à base de phosphole. La première partie de ce travail traite d'études effectuées autour d'un ligand rigide basé sur le squelette xanthène, le XDPP. Après avoir caractérisé le premier complexe hydrure d'or présentant des ligands phosphorés, nous avons tenté de comprendre le mécanisme de la silylation déshydrogénative catalysée avec des complexes cationiques d'or avec une étude combinée expérimentale et théorique. Enfin, l'étude de la réactivité du XDPP vis-à-vis de la protonation a été abordée. Dans une deuxième partie, la synthèse diastéréosélective de composés à base de phospholes présentant un squelette hétéromacrocyclique flexible basé sur le squelette porphyrinoique, les calix-[1]phosphaferrocène-[2]phosphole-[1]hétérocycle, a été réalisée. Les premières études d'électrochimie menées sur ces macrocycles, ont montré une activité rédox intéressante avec le stockage d'au moins deux électrons réversiblement. Les études de coordination des macrocycles ont permis de synthétiser des complexes thermodynamiques et cinétiques. Les premiers essais de chélation intracavité réalisés avec des métaux (Ag, Pd) révèlent un ligand pouvant jouer le rôle de ligand à grand angle de morsure. Dans une dernière partie, le principe de fonctionnement d'une stratégie d'homologation et de pseudo-désymétrisation des phosphamétallocènes a été prouvé. Cette démarche pourrait permettre d'aboutir à la synthèse de macrocycles porphyrinogènes énantiopurs. La synthèse de phosphines énantiopures basées sur le squelette phosphaferrocène présentant une certaine modularité a été réalisée.

La thèse intitulée " New Functional Architectures for Molecular Recognition, Low Band Gap Conjugated Systems and Advanced Electrode Material " est structurée en quatre chapitres traitant de a) structures supramoléculaires tels que cryptands et bis-macrocycles; b) tetrahalo-1,3-diènes chiraux stériquement encombrées; c) blocs pour la synthèse de polymères faible gap conjugués d) architectures 3D conjugués à base de bithiophènes portant des EDOTs terminaux. Dans le premier chapitre, on présente deux nouvelles séries de précurseurs macrocycliques tripodaux possédant une symétrie C3 construites à partir de 1,3,5-triazine avec des groupes fonctionnels réactifs aux extrémités des bras. Les structures supramoléculaires obtenues par des réactions de couplage acétylénique catalysées par Cu sont également présentées. Les cryptands ont été fermés par dimérisation intermoléculaire et les bis-macrocycles ont été formés par des couplages intramoléculaires suivis par dimérisation intermoléculaire. Le deuxième chapitre présente l'étude de nouveaux atropisomères à base d'EE-tetrahalo-1,3- butadiène y compris la séparation des énantiomères, la détermination des barrières de rotation et des configurations absolues. Le troisième chapitre a été consacré à la synthèse des blocs à base de benzo [2,1-b:3,4-b']- dithiophène-4,5-dione utilisés pour obtenir des polymères conjugués à faible gap pouvant fonctionner comme matériau actif dans des cellules solaires organiques. Dans le dernier chapitre on décrie la synthèse et les propriétés électroniques de différents types de nouvelles architectures 3D conjuguées à base de bithiophène comportant des unités EDOTs terminales, en vue de la génération électrochimique de réseaux microporeux électroactifs conjugués. Il est montré que la taille, la surface active et les propriétés électroniques dépendent de la nature des blocs utilisés pour la construction des bras latéraux.

This work describes an investigation into the solution-phase binding of anionic guests by bimacrocyclic lanthanide complexes. It outlines the preparation of different classes of complexes bearing two metallic domains, and the effects of association on both the complex and the guest. Chapter one provides a cursory introduction to the fundamental properties of the lanthanides with a focus on luminescence. A brief literature review is given on the use of emissive lanthanide probes for the sensing of analytes. Chapter two concerns the preparation and properties of a series of binuclear complexes in which the two centres are linked with a short spacer group, with the aim of selectively sequestering small anions such as the halides in solution. The concept of luminescence titration will be introduced and then used to assess the binding parameters of a selection of guests. Chapter three describes a related class of ditopic lanthanide complexes in which the two metal centres are separated by a semi-rigid butyne linking group. Luminescence studies are again used to evaluate the binding constants of homologous series of dianions to ascertain how the size, geometry and functionalization of the anionic guest impacts on binding. Chapter four explores the coordination of phosphate species and assesses the ability to bind biologically significant phosphates of some of the complexes from Chapter 3. Chapter five details an investigation into the effects on guest-selectivity of further lengthening the linking unit which separates the two macrocyclic binding domains. Chapter six summarises the work done throughout the thesis and draws some overarching conclusions, as well as highlighting areas for further study. Chapter seven describes the experimental procedures.

This work is concerned with the design and synthesis of the cheap, late first row transition metal complexes of Schiff base ligand systems. The prepared complexes readily afford systematic variation in order to probe potency and understand the role of metal, chelating ligands and anionic ligands when carrying out their cytotoxic effect. This study has lead to a better understanding of the action of these classes of complex and will be used to direct the design of new anti-cancer metallopharmaceuticals going forward. This thesis details the synthesis of a library of Schiff base macroacyclic ligands and their novel late first row transition metal complexes with varying anionic counterparts. The creation of a library with several degrees of variability provides a wide array of parameters to afford subtle variation in structure and chemistry e.g. denticity, co-ordination mode, chelate hole size, metal centred redox potentials, hydrolysis rates, co-ordinative saturation, lipophilicity, solubility and more. Complexation of the ligands was carried out by the free ligand and a novel macroacyclic metal template approach using the cheap late first row transition metal salts of Cobalt (II), Nickel (II), Copper (II) and Zinc (II) plus one Ru (III) complex. Structural studies of the 80 generated complexes was carried out by vibrational spectroscopy, elemental analysis, mass spectrometry, magnetic susceptibility and NMR. Single crystal X-ray structures have been determined with 20 reported in this thesis. All ligands act as tridentate ligands in all except one case to form monomeric distorted trigonal-bipyramidal, square-pyramidal or octahedral structures. In the case of zinc nitrate, the ligand L2PhMe acts as a tetradentate ligand to give a distorted octahedral structure. Paramagnetic NMR and solution magnetic susceptibility of paramagnetic complexes was achieved by the Evans NMR method and analysis of the solution NMR showed that L2R and L3R ligands display 2-fold symmetry and are likely either tetradentate in solution or a fast exchange between imine N-donar sites is occurring even down to -65°C. The majority of the resulting complexes of L1R were screened against a panel of three cancer cell lines. Several categories of complex were able to afford structure activity relationships. It was discovered that the ligand is indeed essential for activity of the metal salts against the panel of cell lines and it was largely discovered that the variation in ¿tail group¿ and anionic coordinating ligands played little role in providing a dramatic variation in activity of the metal salt. In general all L1R complexes displayed moderate cytotoxicity showing a trend in activity with respect to the metal in the order RuIII¿CoII>CuII¿ZnII>NiII, over a 6 day exposure to the three cell panel RuIII was shown to be the most potent metal of the L1R series providing IC50 values of 4.6 (0.7) and 7.5 (1.2) ¿M against the DLD-1 and H460 cell lines respectively, which is Ca. 4.6 and 15 iii times less potent than cisplatin to the same cell panel respectively. RuIII was also discovered to be the only metal to provide an IC50 value from a 1 hour exposure to the DLD-1 cell panel. The value of 20.4 (3.5) ¿M is a moderate figure but again Ca. 10 fold less potent than cisplatin for the same test. The L2R and L3R complexes could not be screened by the same comprehension due to their low solubilities. However the lone screen that was possible from the very sparingly soluble complex [CuCl2(L3Bui)] gave the most exciting result and most potent complex of this thesis. After a 6 day exposure, [CuCl2(L3Bui)] gave IC50 values of 4.3 (0.1) and 2.9 (0.1) ¿M against the DLD-1 and H460 cell lines respectively. These values are merely 4 and 6 fold more than Cisplatin to the same cell lines respectively and demonstrates the potential of this class of complex as cytostatic agents. Further studies utilising a semi-quantitative DNA damaging assay, demonstrated that all first row complexes can damage DNA when in the presence of hydrogen peroxide, with the exception of ZnII complexes. CoII appeared to afford the greatest DNA damage with the most intsense bands for double strand breaks and the CuII complex of the ligand L3Bui also demonstrated a greater DNA damage as opposed to its L1Bui analogue.