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The work reported in this thesis is divided into two distinct areas. The first involves the synthesis of monoaza- and diaza-[12]-ring macrocycles, with differing side-arm N-substituents. The twelve-membered macrocycles possess a convenient ring-size for exploring the stability and selectivity of complexation of small cations, in particular those from groups IA and IIA. Amide substituents on nitrogen were expected to function as effective σ-donors to cations with high charge density (e.g. Li (^+), Ca (^2)(^+)), because of their high ground state dipole moments. The effect of the length of the side-arms attached to nitrogen on the complexation has also been studied. Complexation behaviour has been probed using (^13)C NMR spectroscopy, titration calorimetry, and fast-atom bombardment mass spectroscopy. Copper (II) complexes of three of the [12]-ring cycles have also been characterised by X-ray crystallographic analysis. The second area involves the study of a series of macrocyclic ligands capable of forming homo- and hetero-dinuclear complexes. In particular, ligands containing the pyridyl-dithio (PyS(_2)) binding unit and a polyether chain linking the two sulphur atoms have been examined. The three binding atoms of each PyS (_2) group define three corners of a fairly rigid square planar environment which favours the formation of square planar d(^8) complexes. Accordingly, complexation with rhodium (I) [and (III)], palladium (II), and platinum (II) has been investigated: the structural properties of these complexes have been determined by the use of FT NMR and X-ray crystallography.

Les composés polymacrocycliques présentent un grand intérêt grâce à leurs caractéristiques remarquables de coordination. Pour la première fois, l’approche synthétique fonctionnelle aux diverses composés bi- et polycycliques contenant plusieurs fragments d’éthers aza-couronnes, aux cryptands et aux supercryptands à base d’éthers aza-couronnes a été élaborée par Krakowiak et ses collaborateurs au début des années 1990, par l’usage de simples réactions de substitution nucléophile. Actuellement, les composés hétéropolymorphes polymacrocycliques, capables de former des complexes polynucléaires avec différents métaux présentent le plus grand intérêt. Dans la grande majorité des travaux la synthèse de presque toutes les composés polymacrocycliques a été réalisée à l’aide des méthodes non orthodoxes, à l’exception des molécules, composées de plusieurs macrocycles porphyriques (de la diade et de la triade), pour l’obtention desquelles ont été appliquées les réaction de Suzuki, le couplage de Sonogashira et la réaction de Heck. Le laboratoire de synthèse organominérale de la Faculté de chimie de l’Université d’Etat de Moscou a accumulé une riche expérience dans l’utilisation de l’amination pallado-catalysée pour la synthèse de diverses composés macrocycliques et polymacrocycliques, et, actuellement, on étudie activement l’arylation cupro-catalysée des di- et polyamines. À cet égard, l’étude de l’amination cupro-catalysée pour la synthèse de composés polymacrocycliques qui contiennent comme connecteurs des diamines et des polyamines a permis développer des méthodes de catalyse métallique et d’obtenir de nouveaux types de conjugués polytopiques et polymacrocycliques, qui comprennent dans leur composition structurelle des fragments éthers aza-couronnes, porphyrines et calixarènes, étudiés pour leur capacité à détecter des cations des métalliques.Le but de ces recherches est de développer des méthodes catalytiques de synthèse de conjugués polymacrocycliques qui contiennent dans leur composition structurale des fragments éthers aza-couronnes, des porphyrines et des calix[4]arènes et d’étudier leurs capacités à détecter des cations métalliques. Pour atteindre cet objectif, il est nécessaire de résoudre les problèmes suivants: 1) établir la généralité de l’amination catalysée par le Cu(I) des dérivés éthers aza-couronnes et des porphyrines contenant des halogènes et de synthétiser les dérivés aminés; 2) développer des méthodes de la macrocyclisation catalytique pour obtenir des composés macrobicycliques et macrotricycliques qui contiennent dans leur structure des fragments éthers diaza-couronnes, des tétraazamacrocycles ( cyclènes et cyclames) et des calix[4]arènes; 3) modifier les composés macrocycliques et macrobicycliques par des substituants fluorophores, y compris des porphyrines; 4) à l’aide de la spectroscopie UV et de la fluorescence, étudier la liaison cations métalliques-polymacrocycles et identifier les détecteurs potentiels moléculaires fluorescents et colorimétriques. / Polymacrocyclic compounds are of great interest due to their unique coordination properties. The first convenient synthetic approach to various polycyclic compounds containing several azacrown-ether moieties, to cryptands and supercryptands, based on azacrown-ethers, has been developed by Krakowiak and coworkers in the beginning of 1990s using simple nucleophilic substitution reactions. At present time heteropolytopic polymacrocyclic compounds, capable of forming polynuclear complexes with various metals, attract the utmost interest. In the majority of publications dealing with the synthesis of polymacrocyclic compounds non-catalytic approaches were applied, except for several porphyrin dyads and triads, which were obtained using Suzuki, Sonogashira and Heck reactions. The laboratory of organoelement compounds of Chemistry Department of Lomonosov Moscow State University has a great experience of the application of Pd-catalyzed amination reactions for the synthesis of polymacrocyclic compounds, nowadays Cu-catalyzed arylation of di- and polyamines is under investigation. Bearing it in mind we have found the research for Cu-catalyzed amination to be important in synthesis of polymacrocyclic compounds containing di- and polyamine linkers; as well as the synthesis of new types of polytopic polymacrocyclic conjugates, bearing azacrown-ether, porphyrin and calixarene moieties, by means of Pd- and Cu-catalyzed reactions; and studying their properties as metal cations detectors.The aim of the research is to develop catalytic synthetic approaches to polymacrocyclic conjugates, bearing azacrown-ether, porphyrin and calix[4]arene moieties, and to study their abilities as detectors for metal cations. For this purpose it is necessary to carry out the following investigations: 1) to study the regularities of Cu(I)-catalyzed amination of halogen derivatives of azacrown-ethers and porphyrins and to synthesize corresponding amino derivatives; 2) to develop the methods for the catalytic macrocyclization aimed at the synthesis of macrobicyclic and macrotricyclic compounds, containing diazacrown-ether, cyclen, cyclam and calix[4]arene moieties; 3) to introduce fluorophoric fragments (including porphyrins) into macrocyclic and macrobicyclic compounds; 4) to investigate metal cations binding by thus synthesized polymacrocycles using UV and fluorescent spectroscopy, and to find possible fluorescent and colorimetric detectors among them.

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A key missing tool in the chemist’s toolbox is an effective biocatalyst for macrocyclization. Macrocycles limit the conformational flexibility of small molecules, often improving their ability to bind selectively and with high affinity to a target, making them a privileged structure in drug discovery. Resorcylic acid lactones (RALs) are a class of fungal macrocyclic polyketides that exhibit anti-cancer and anti-malarial activity among others. The thioesterases (TEs) found in the biosynthetic pathways for the zearalenone (Zea) and radicicol (Rdc) resorcylic acid lactones are responsible for macrocyclization and show promising traits as biocatalysts. These RAL TEs show the highest substrate tolerance of any polyketide thioesterase to date. These TEs can efficiently cyclize 12- 18-membered rings, 14-membered macrolactams, and amino acid containing substrates. Their robustness is evident in their ability to retain activity after lyophilization/re-suspension and in high DMSO concentrations. Furthermore, the ability of Zea and Rdc TEs to macrocyclize depsipeptide substrates illustrates the first time a polyketide synthase TE has efficiently processed a peptide-containing substrate. The unique substrate tolerance of this class of TEs shows great potential as a viable biocatalyst. Herein we describe the synthesis and enzymatic results of diverse group of substrates, with the TEs from the radicicol and zearalenone biosynthetic pathways, as well initial results on the chemoenzymatic synthesis of asperterrestide A.

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Two series of oxa-amide ionophores based on 2-phenylglycerol and cis-cis- 1,3,5-cyclohexanetriol with ligand coordination numbers of 4, 5 and 6 have been synthesised and studied. Complexation of the ligands with group Ia and IIa metal ions was studied using IR, (^13)C NMR and electrospray mass spectroscopy. Potentiometric membrane electrodes have been prepared and their performance evaluated using a fixed interference method. Ionophores based on the hexadentate cyclohexyl triamide show excellent Na(^+)/K(^+) selectivity (-logK (^pot)(_Na,K) = 3.1), and the pentadentate analogue shows good Li(^+)Na(^+) selectivity (-logK (^pot)(_Na,K) = 2.2), Ligands based on 2-phenylglycerolexhibited good Ca(^2+) selectivity which was highest for the hexadentate triamide. The attempted synthesis of two 14-crown-4 fluorophores is reported as well as the synthesis and evaluation of an 18-crown-6 based fluorophore. The 18-crown-6 fluorophore shows a bathochromic fluorescent shift in the presence of potassium ions. Additionally a fluorophore was prepared based on a tri (napthylmethyl oxaamide) derivative of cis-cis-1,3,5-cyclohexane and its fluorescence characteristics assessed. A reduction in fluorescence intensity was observed with increasing concentrations of calcium and sodium ions.