Rozprawy doktorskie na temat „Ligands – Synthesis”

Several series of ligands, designed to chelate silver(I) specifically in the presence of base metals, have been synthesised. The ligands include: - dithiodiamide compounds, prepared by the condensation of acetanilide derivatives with 1,2-dibromoethane; propanenitrile and propanoic ester derivatives prepared from pyridine-2-carbaldehyde via the Morita-Baylis-Hillman reaction; and novel malonamide ligands from the reaction of diethyl malonate with a range of primary amines. The malonamide derivatives were prepared under both conventional thermal and microwave-assisted conditions, the latter proving to be highly efficient. The ligands were all characterised using a combination of spectroscopic and, where appropriate, elemental analysis; in one case, the structural assignment was confirmed by single-crystal X-ray analysis. The fragmentation patterns in the electron-impact mass spectra of the malonamide derivatives have been explored using high-resolution and meta-stable peak scanning techniques. Complexes of the malonamide ligands with copper(II) and silver(I) have been synthesised, and examination of these complexes has revealed distinct differences in their co-ordination preferences towards silver(I) and copper(II). Tentative, computer-modelled structures for the complexes have been proposed using the available spectroscopic and elemental analysis data. Computer modelling, at the Molecular Mechanics level, has also been used to assess the capacity of the ligand systems to adopt conformations suitable for the chelation of tetrahedral silver(I). Solvent extraction studies have been undertaken using aqueous metal ion solutions and various organic solvents. The dithiodiamide derivatives typically presented solubility problems, but one of the ligands, N,N´-bis(3-chlorophenyl)-3,6-dithiaoctanediamide, exhibited significant but slow extraction of silver(I) into toluene. The malonamide derivatives, however, proved to be readily soluble in ethyl acetate and, in some cases, exhibited good to excellent selectivity for silver(I) in the presence of the base metals copper and lead. Atomic absorption analysis revealed rapid equilibration times (<15 min) and high extraction efficiencies over a wide pH range (2.78 - 9.0). Metal selectivity has been determined by ICP-MS analysis of the residual silver, copper and lead present in the aqueous phase after 15 min, and one of the ligands, N,N´-bis(2-benzylsulfanylethyl)malonamide, exhibits excellent (≥ 96 %) silver(I) specificity.

A series of polydentate POM-selective, sulfur-containing amide ligands have been synthesized from ro-dibromoalkanes and mercaptoacetanilide, The resulting 3,6- dithiaoctanediamides and 3,7-dithianonanediamides, some of which contain a polymerisable group, were all characterized by high-resolution MS, IR, I Hand I3C NMR spectroscopic methods. Various approaches to the polymerisable ligands were explored, the most efficient proving to be the incorporation of an allyl ether moiety in the mercaptoacetanilide. The corresponding Pd(U) and Pt(II) complexes were also prepared from the metal chloride salts and characterized by elemental analysis and spectroscopic methods. The NMR data indicates that both the cis- and transcomplexes were formed, while the IR data indicates cis- coordination of the chlorine . ligands. Molecularly imprinted polymers (MIP's), prepared using platinum(II) mercaptoacetanilide and 3,6-dithiadiamide complexes, showed high selectivity for , , palladium(II) [in the presence of Pt(II), CoCII), Cu(II) and Ni(II)] as determined by . ICP-MS analysis. The more kinetically inert Pt(II) ions however, slowly displaced Pd(II), confirming the Pt(II) selectivity of the MIP's. Solvent extraction studies were conducted to explore the selectivity of the 3,6- dithiaoctanediamides and 3,7-dithianonanediamides for Pd(U) over CoCII), Cu(U) and Ni(II). The ICP-MS data indicate that, in general, equilibration was achieved within ten minutes and that the longer-chain amides were less selective than the shorter-chain analogues.
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Poly(azolyl)borate ligands have proven to be extremely popular ligands since their introduction by Trofimenko in the late 60´s. The basic skeleton of these ligands involves usually three heterocycle units linked to a central boron apex via the azole nitrogen atoms. These ligands have been applied in diverse research areas such as homogeneous catalysis, materials science and bio-inorganic chemistry. More than 2000 papers, including books and reviews regarding the properties of these compounds, have been published. However, only a few synthetic methods for the preparation of such ligands have been reported and only a few examples of chiral borate-centred ligands are known. This thesis deals with the development of a novel synthetic route to tripodal borate ligands using B(NMe2)3 as the boron source. The mechanism of the reaction of this borane with azole heterocycles has been established by exploring the reactivity of a range of azoles. One of the major features of this new synthetic protocol is that it allows the formation of chiral tripodal ligands where the chiral groups are located either at the forth position at the boron atom or at the azole heterocycles. Coordination studies of the ligands have been undertaken and the metal complexes have been studied by a combination of spectroscopic and X- ray diffraction techniques. Preliminary application of the most representative ligands in the Asymmetric Transfer Hydrogenation (ATH) of prochiral ketones has been undertaken in collaboration with Prof. Dieter Vogt at the Technical University of Eindhoven.

The coordination chemistry of twenty chelating heterocyclic ligands, seven of which are new, is described. These ligands all contain heterocyclic ring systems that have previously received little attention in the literature. The specific ring systems involved are benzoxazoles, benzisoxazoles, benzothiazoles, benzotriazoles, 1,2,4- and 1,2,5- heterodiazoles, and the 1,4,2,5-dioxadiazene systems. Many of the complexes synthesised are of ruthenium(II). These include monoruthenium complexes of the type [Ru(bpy)2(L)] 2+, homodinuclear complexes {[(bpy)2Ru(µ-BL)Ru(bpy2)4+ with µ-BL representing a doubly bidentate bridging ligand} as well as heterodinuclear ruthenium/palladium and ruthenium/platinum {[(bpy)2Ru(µ-BL)MCl2]2+ with M = Pd/Pt} complexes. Also investigated are the coordination and supramolecular chemistry of many of the ligands with palladium(II), silver(I) and copper(II) metal ions. The X-ray crystal structures of five ligands and twenty complexes are described. An unexpected, previously unreported, heterocyclic transformation mediated by the Ru(bpy)22+ cation is also reported. A combination of multinuclear NMR, UV-visible spectroscopy, cyclic voltammetry and X-ray crystallography has been used to study the nature of the metal-ligand and metal-metal interactions in the complexes produced.

The most favoured amino acid in protein-nucleic acid interfaces is arginine due to the existence of the guanidinium group in its structure that can form good hydrogen-bonding geometries. In addition, the length of the side chain gives it a great deal of torsional freedom and therefore permits the guanidinium group to orient itself to interact with a wide range of targets through bidentate H-bonding. A torsional constraint for the guanidine group could be achieved by its conversion into a bicyclic framework, resulting in unidirectional hydrogen bonding with its targets and reducing the loss of the conformational entropy as a result of its binding. The aim of this research is to synthesise nucleic acid targeting oligopeptides which will include non-natural analogues of arginine as part of their sequence with the purpose of activating or inhibiting biological functions. The synthesis of different sized rings of bicyclic guanidine derivatives could be a means to control the hydrophobic interaction with DNA, with hydrophobicity increasing as the size of the ring of the bicyclic guanidine increases. In addition, the high basicity of guanidine leads to production of the corresponding guanidinium cation upon protonation. Therefore, the formation of guanidinium cation leads to hydrogen bonding and electrostatic interactions with anions like phosphate groups. So, the purpose of preparing differently sized rings of bicyclic guanidine in the current work is to compare their interactions with DNA. There are four themes in our research concerned with the design and synthesis of bicyclic guanidine derivatives and non-natural amino acids. The first theme concerns the synthesis of a protected bicyclic guanidine methylene amine that was achieved by utilising Boc-L-methioninol as a precursor and converting it to the corresponding azide. However, incorporation of this bicyclic guanidine into an amino acid moiety proved difficult and thus themodified amino acid was not formed. The second theme of the project considers a novel strategy to generate a bicyclic guanidine methylene alcohol with a variably sized ring in a high yield starting from an azido alkane amine and Boc-L-methionine as precursors. This modification to the route will open a promising way to produce the functionalised bicyclic guanidine. Bicyclic guanidine methylene chloride was synthesised that gave us a way to insert bicyclic guanidine into a tyrosine amino acid moiety so that a protected L-tyrosine possessing bicyclic guanidine with a differently sized ring could be synthesised. The third theme involved the new strategy towards the synthesis of bicyclic guanidine methylene amine followed by conjugation with Fmoc-Glu-OAll to produce a modified amino acid. The fourth, and final,theme of our research includes the preparation of dimers of bicyclic guanidine. Furthermore,a crystal structure for the protected bicyclic guanidine intermediate in this theme has also been obtained.

Les 2,2´-bipyridines et leurs homologues, les N,N´-dioxydes, appartiennent à une classe de composés hétéroaromatiques très importante ayant montré de nombreuses applications dans le domaine de la chimie et principalement en synthèse asymétrique. Une des méthodes les plus performantes pour leurs synthèses s´est révélée être une réaction de cocyclotrimérisation d´alcynes en présence de dérivés nitriles.Une nouvelle variante de la réaction de cyclotrimérisation – cocyclotrimérisation de diynes halogénés avec des dérivés nitriles – permettant la formation de composés 2- et3-halogéno-pyridines a ainsi été développée. La réaction a été étudiée sur une large gamme de substrats permettant l´accès à une librairie de pyridines avec de bons rendements. La formation d´un sous-produit, issu d´un échange d´halogène, a été approfondie au cours de l´étude et son origine a été élucidée grâce à différentes expériences.Les 2-halogéno-pyridines ont été utilisées comme réactifs de départ pour la synthèse de ligands chiraux de type 2,2´-bipyridines. L´étape problématique s´est avérée être la réaction de dimérisation réductrice des 2-halogéno-pyridines donnant accès aux2,2-bipyridines correspondantes. L´efficacité de ces ligands chiraux de type 2,2´-bipyridinea été évaluée dans différentes réactions asymétriques catalysées par des métaux de transition telles que l´aldolisation de Mukaiyama, l´hydroxyméthylation, l´addition conjuguée, l´activation C–H d´indoles mais aussi la désymmétrisation d´époxydes meso, dans laquelle un des ligands bipyridines a montré une extraordinaire activité et robustesse. Ensuite, basées sur des analyses RMN, des calculs DFT et des analyses par diffraction des rayons X, les propriétés structurales de ce ligand ont été étudiées.De plus, une nouvelle famille de catalyseurs à chiralité axiale de type 2,2´-bipyridines N,N´-dioxydes a pu être synthétisée via 2 différentes approches, où seule l´étape clé de dimérisation diffère. La première approche, basée sur la réaction de dimérisation réductrice des 2-halogéno-pyridines, permet l´obtention d´un seul atropoisomère du N,N´-dioxydes cible après une séquence réactionnelle de 8 étapes tandis que la seconde approche, basée sur la réaction de dimérisation oxydante de pyridines N-oxydes, donne l´accès aux 2 atropoisomères en seulement 5 étapes. Le champs d´application de ces nouveaux catalyseurs de typeN,N´-dioxydes, en tant que base de Lewis, a été examiné dans l´allylation énantiosélective du benzaldéhyde ainsi que dans l´aldolisation de l´acétal de cétène trichlorosilylé en présence de l´acétophénone
2,2'-Bipyridines and their appropriate N,N'-dioxides form a significant class of heteroaromatic compounds, which has found application in various fields of chemistry and predominantly in asymmetric catalysis. One of the most powerful methods for their synthesis is cocyclotrimerization of alkynes with nitriles.A new variant of cyclotrimerization reaction – cocyclotrimerization of halodiynes with nitriles, which results in the formation of 2- and 3-halopyridines, has been developed. The reaction was studied on a wide range of substrates providing the pyridine products in good isolated yields. Formation of an unexpected product of halogen exchange reaction was observed during the course of the study and its origin was elucidated by experimental studies.The prepared 2-halopyridines were used as starting materials for syntheses of new chiral 2,2'-bipyridine ligands. The crucial step of their synthesis turned out to be the reductive dimerization of 2-halopyridines to the corresponding 2,2'-bipyridines. Application of the formed bipyridine ligands was then tested in various metal-catalyzed asymmetric reactions, namely Mukaiyama aldol reaction, hydroxymethylation, conjugate addition, C–H activation of indole and desymmetrization of meso-epoxides, in which one of the bipyridine ligands showed extraordinary activity and robustness. The structural properties of this ligand were then studied based on the NMR analyses, DFT calculations and single crystal X-ray analyses.New axially chiral 2,2'-bipyridine N,N'-dioxides were synthesized via two approaches, which differed in the type of the key dimerization step. While the first approach, based on the reductive dimerization of 2-halopyridines, furnished only one atropoisomer of the target N,N'-dioxide by an eight-step reaction sequence, the second approach, based on oxidative dimerization of pyridine-N-oxides, provided both atropoisomers in only five steps. The applicability of these novel N,N'-dioxides as Lewis base catalysts were then examined in the enantioselective allylation of benzaldehyde and aldol reaction of trichlorosilyl ketene acetal with acetophenone

Due to their highly interesting electroactive properties, complexes based on the sulphur heterocycle DMIT have been studied extensively for several decades. The literature is abundant with materials exhibiting semiconducting and metallic properties and up to early 2000 there are eight examples of DMIT based superconductors. In the case of the DMIT complexes, previous work has been constrained to the variation of the transition metal and/or the counter-anion. The work herein concerns the synthesis of a novel series of electroactive ligands, similar to the well-known DMIT species. In contrast to the DMIT ligand, our target derivatives incorporate two thioether and two dithiolate environments as the overall chelating entity. The thioether functionalities are linked via suitable spacer groups and this feature should present a major advantage over traditional DMIT complexes, by adding solubility and synthetic versatility to the overall nature of the complex. In addition to the metal complexes based on DMIT ligands, charge transfer (CT) halogen adducts of these DMIT ligands and their synthetic intermediates are described, providing highly interesting and novel solid state structures and atom-to-atom inter- and intra-molecular interactions.

For the purpose of incorporating indoles into organometallic complexes for catalysis, as well as in the generation of new heterocyclic systems, various reactions have been carried out at C2, C6 and C7 of the indole system. In order to achieve this, 3-substituted 4,6-dimethoxyindoles and 6-hydroxy- 4-methoxyindoles were necessary as starting materials. Consequently, a lithium-bromide-templated one-pot procedure for the synthesis of some 3-substituted 4,6-dimethoxyindoles and a selective demethylation procedure for 3-substituted 6-hydroxy-4-methoxyindoles were developed. Various kinds of novel methylene-bridged bi-, tri-, and tetradentate pyridyl-indole ligands were synthesised via Vilsmeier-Haack, Friedel-Crafts or electrophilic addition reactions on the indole heterocycle. However, their metal complexing properties were generally weak and variable. Nevertheless, some of the tridentate pyridylindole ligands showed strong anion binding to halides, whereas a remarkable ligand transformation occurred with a bidentate 2-pyridylindole ligand and zinc(II), giving a substituted indolo[2,3-c]pyrrolo-[3,2,1-ij]quinoline system. Two new types of tetradentate Schiff base ligands were prepared from 2-formyl-indoles and 7-formyl-6-hydroxyindoles, and diamines. These preformed ligands were reacted with first- and second-row transition metals to give neutral metal complexes. Novel heterocyclic systems such as 4H-pyrrolo[3,2,1-ij]quinolines, 3H-pyrrolo-[1,2-a]indoles, and 1H-furo[2,3-g]indoles were synthesised from 2-formyl-, 7-formyl-, and 6-hydroxyindoles, utilising mainly intra-molecular Wittig reactions, Claisen-Schmidt condensations or acid- and base-catalysed cyclisations. A common feature of the prepared 4H-pyrrolo[3,2,1-ij]quinolines and 3H-pyrrolo-[1,2-a]indoles was their intense fluorescent character, which was examined as well.

Ligand–mediated coupling between metal centres is of fundamental importance in inorganic and materials chemistry. Bridging ligands involving azo groups as coordinating π–acceptors can yield complexes with interesting properties. This thesis describes the synthesis of a series of N–heterocyclic compounds containing the azo functionality, designed for potential coordination to the metal through the azo nitrogen and a N–heterocyclic ring. The azo ligands are divided into four categories; ligands based on azobispyridines, ligands containing pyrimidine and fused aromatic azine groups and ligands capable of coordinating in a bis–tridentate fashion to the metal centre. Ligands containing flexible imine subunits connected directly, or through different spacers, are also discussed. Overall twenty one ligands were synthesised, six of which are new compounds. The coordination and metallosupramolecular chemistry of these ligands with ruthenium(II) and silver(I) metal atoms was investigated. A total of thirty five ruthenium(II) and eleven silver(I) complexes were prepared, of which thirty eight were characterised by X–ray crystallography. Mononuclear and dinuclear ruthenium(II) complexes were synthesised and characterised by a combination of spectroscopic and structural techniques. UV/Visible absorption studies and electrochemical methods were used to investigate the nature of metal–ligand and metal–metal interactions. In the mononuclear Ru(II) complexes, N–heterocyclic azo ligands act as chelating ligands forming five–membered chelate rings involving azo–N and heterocyclic–N atoms. The non–coordinated pyridine ring of the azo ligand is twisted with respect to the azo–N atom and is directed towards the adjacent bipyridine rings. Studies reveal that these azo ligands posses extremely low–lying π*–orbitals and are electron deficient. X–Ray structural analysis of the dinuclear complexes revealed short inter–metal separations of ca. 4.9 Å and electrochemical studies indicate that these ligands mediate very strong interactions between the metal centres , due to the excellent π*–acceptor properties of the azo functionality. Varying the pyridine ring of the azo ligand to pyrimidines and fused N–aromatic rings has a considerable effect on the electronic properties of these complexes. Incorporation of a pyrimidine ring facilitates the stabilisation of azo anion radicals and leads to the formation of diruthenium(II) species, bridged by radical species. The X–ray crystal structures of both these complexes were determined. The use of the hexadentate ligands coordinating in a bis–tridentate manner mediate even stronger communication between the two ruthenium centres. Ligands containing bis–pyridylimines result in weaker coupling between the metal centres in dinuclear ruthenium(II) species. A complete absence in the inter–metal communication was observed with increasing the distance and/or flexibility between the two pyridylimine units, contrary to a previous reported claim. Reaction with different silver(I) salts afforded an array of one–dimensional coordination polymers and a discrete dinuclear complex depending on the coordination strengths of the anions. The metallosupramolecular assemblies obtained were characterised mainly by X–ray crystallography, elemental analysis and mass spectrometry.

An important aspect of clinical imaging techniques involves the use of complexed gamma or positron-emitting radionuclides, e.g. (^99m)Tc(γ, t1/2 = 6.02 h, 141 keV) for Single Photon Emission Tomography (SPET), (^62)Cu (β(^+),t1/2 = 9.74 min, 1.315 MeV) for Positron Emission Tomography (PET). With such radiopharmaceuticals in mind, two new classes of acyclic tetradentate ligands have been synthesised, featuring an N(_2)S(_2) donor system. This array of donor atoms is particularly attractive for its 'soft’ metal preference, favouring the complexation of radionuclides such as (^64)Cu and (^99m)Tc in diagnostic imaging of disease states, and (^186/188)Re (β(^-), t1/2 = 90h) in targeted radiotherapy. In both ligand systems the sulfur donor is adjacent to pentavalent phosphorus. Substitution at phosphorus allows easy modification of aryl or alkyl groups to vary the lipophilicity of the complex without affecting the binding properties. The first class of new ligands presented incorporate thiophosphinic acid groups which are more acidic than their corresponding phosphinates and carboxylates, increasing the stability of the complexes in acidic media. The synthetic routes to series of such ligands have been investigated and optimised. Initial attempts to access the aza- thiophosphinates via treatment of the sulfur-containing P(III) species with the diamine and paraformaldehyde failed to show any significant reaction. The best method of P=S bond formation was found to be via sulfur transfer to the corresponding P(V) phosphinate. The other class of ligands synthesised incorporate the dialkylthiophosphoryl group in conjunction with hydrazide or aminopyridyl moieties. The solid state structures of the ligands were determined by X-ray crystallography. The solution complexation behaviour of the ligands with a variety of metals, particularly copper and rhenium was studied. The thiophosphinic acid ligands form 1:1 complexes with copper(II) under dilute conditions and oligomeric complexes at high solution concentrations. The complexes formed with copper(II) and oxorhenium(V) appear to be charge neutral. Several of the dialkylthiophosphoryl ligands formed copper(I) complexes by spontaneous reduction of a copper(II) source, and redox behaviour was also shown towards oxorhenium(V). Some of the ligands radiolabel efficiently with technetium-99m and copper-64 and their preliminary evaluation shows promise for further development.

This thesis is divided into six chapters. The first is a review of general asymmetric synthesis, and considers in detail the palladium catalysed allylic substitution reaction, the 1,4-conjugate addition and the Heck reaction. The second deals with our general synthetic approach to the chiral ligands. Here we synthesized a range of ligands derived from chiral amino alcohols condensed with aryl and aliphatic ketones. We also synthesized chiral sulphur imine and phosphorus imine ligands. The third deals with applications of the ligands in the above reactions, and discusses the most successful ligands. In the palladium catalysed allylic displacement reaction, the sulphur imine ligands were the most successful ligands with ee of 96%. In the case of the 1,4-conjugate addition of diethylzinc to cyclic and acyclic enones, we were able to achieve excellent results using the phosphorus imine and the S–N ligands derived from pseudoephedrine and ketones, ee of >99% were obtained. Chapter four deals with asymmetric sulfoxidation and the effect of electron donating and withdrawing groups on the sulfoxidation. Here we demonstrated the inductive influence of the substituent on the ee of the sulfoxide. Chapter five deals with the conclusion. The sixth part of this thesis deals with the experimental procedures undertaken in this work.

L'évolution récente de la science écologique et durable nécessite des catalyseurs puissants, sophistiquées et dotés de propriétés spécifiques et accordables.Les catalyseurs bimétalliques qui contiennent deux ou plusieurs sites pour l'activation coopérative de substrats réagissant sur des centres métalliques voisins selon certaines conditions. Un certain nombre de squelettes, spécialement conçus pour générer des complexes exclusivement bimétalliques, ont été développés autour d'échafaudages de méthanodibenzodioxocine et de benzofurobenzofurane, y compris un certain nombre de ligands qui agissent comme donneurs de monophosphine dans deux centres métalliques différents. Ces ligands génèrent des espèces dinucléaires de manière fiable, mais les modes de coordination résultants sont imprévisibles.Ce travail de thèse présente la synthèse de ligands de tétraphosphine, dans lesquels des bras chélatants sont disponibles pour coordonner chacun des deux centres métalliques. La synthèse implique la préparation de 4,8-bis (sec-phosphines) de rac-6,12-méthano-12H-dibenzo [1,3] dioxocines et leur conversion en phosphines doublement chélatantes par l'élaboration de chaque fonctionnalité sec-phosphine en Les dérivés di (R) phosphinopropyle correspondants (R = Ph, Cy). Une étude de chimie de coordination préliminaire indique que l'environnement de coordination est fourni par ces ligands tétraphosphine binucléaires rigides. C’est ainsi que la préparation des complexes bimétalliques de PdII, PtII aurait été réalisé. Chacune des deux molécules de bras chélatants serait coordonnée à un métal. Enfin, des études préliminaires sur l'utilisation des ligands tétraphosphine comme supports pour la chimie de l'hydroformylation ont été réalisées. Les résultats actuels ne permettent pas encore d'établir définitivement un comportement coopératif entre les deux centres métalliques
: Recent developments in green and sustainable science require more powerful, sophisticated and tunable catalysts. Bimetallic catalysts contain two or more sites for the activation of substrates and, under optimal circumstances, can allow cooperative activation of reacting substrates on neighboring metal centers. A number of backbones, designed specifically to generate exclusively bimetallic complexes have previously been developed around methanodibenzodioxocin and benzofurobenzofuran scaffolds, including a number of ligands that act as monophosphine donors to two different metal centers. These ligands generate dinuclear species reliably, but the resulting coordination modes are unpredictable. This work presents the synthesis of tetraphosphine ligands, wherein chelating arms are available to coordinate each of the two metal centers. The synthesis involves preparation of 4,8-bis(sec-phosphines) of rac- 6,12-methano-12H-dibenzo[l,3] dioxocins and their conversion into doubly chelating phosphines through the elaboration of each sec- phosphine functionality into the corresponding di(R)phosphinopropyl derivatives (R= Ph, Cy). A preliminary coordination chemistry study indicates that the tightly defined coordination environment provided by these rigid binucleating tetraphosphine ligands under study allowed bimetallic complexes of PdII, PtII to be prepared, in which each of the two chelating arms molecule coordinates to one metal. Finally outline studies on the use of the tetraphosphine ligands as supports for hydroformylation chemistry were performed. The current results do not yet allow cooperative behavior between the two metal centers to be definitively established

This research concerns a new generation of phosphorus ligands bearing short and branched perfluoroalkyl or perfluoropolyether substituents of the fluorine content and their coordination chemistry as an alternative ligands and metal complexes having a potential application in fluorous biphase system in all common organic solvents. A series of new perfluoroalkylated arylphosphines with the general formula of P(C₆H₄-p-R)₃, where R = OC₂H₄OC₄F₉, OCH₂C₄F₉, or CH₂OCF₂ (OCF₂CF₂)₂OCF₃; aryl phosphonic acid ligands [R-p-C₆H₄P(O)(OH)₂], where R = OCH₂CH₂C₄F₉ or OCH₂CF₂ (OCF₂CF₂)₂OCF₃, and alkyl phosphinite and phosphonite ligands (Ph)ₓP(OR)₃₋ₓwhere R = CH₂CH₂C₄F₉, CH(CH₂OC₄F₉)₂, or CH₂CF₂(OCF₂CF₂)₂OCF₃ have been synthesised and fully characterised by ¹H, ¹⁹F, ³¹P, and ¹³C NMR spectroscopies, and mass spectrometry. The perfluoroalkylated phosphine, phosphinite, phosphonite ligands have been reacted with transition metal complexes to form complexes of the type cis and trans-[PtCl₂L₂], and [Cp*RhCl₂L]. The complexes were isolated and characterised using ¹H, ¹⁹F, and ³¹P NMR spectroscopies, mass spectrometry, and X-ray crystallography. The derivatised phosphonic acid ligands have been reacted with transition metal complexes as dianionic bidentate ligands to form coordination complexes of the type [Pt(O₃PR)(PPh₃)₂] and zirconium phosphonate Zr[O₃PC₆H₄-4-R]₂. The platinum complexes have been fully characterised by ¹H, ¹⁹F, and ³¹P NMR spectroscopies, and mass spectrometry. The zirconium phosphonates are immiscible in all the organic solvents. Therefore the characterisation was limited to ESEM and IR studies. A study into potential fluorous solubility of the synthesised ligands and their metal complexes was also undertaken. In this regard, the influence of the fluorine contents, and the electronic insulating groups on the organic/fluorous solubility rate was also examined.

The success of homogeneous asymmetric catalysis has been attributed to the structure and stereochemistry of the coordinated ligand(s). The most effective ligands are C₂-symmetrical bisphosphines containing either a rigid chiral backbone linking two PPh₂ units or a bisphosphine, DIPAMP containing two chiral phosphine units linked by an achiral backbone. The synthesis of P-chiral ligands of this type has been severely hindered by the lack of a general synthetic route allowing the incorporation of phosphorus chirality without the need for separation of diastereomeric precursors or resolution of intermediate enantiomers. The objective of this work was to develop a general synthetic route to homochiral bulky arylphosphines with substantial flexibility in the groups at phosphorus and extend the approach to new P-chiral bisphosphines. In one approach, diastereomerically pure (2R, 4S, 5R)-2,5-diphenyl-3,4-dimethyl-1,3,2-oxazaphospholidine was prepared directly from PhPCl₂ using l-ephedrine as a chiral auxiliary. Stereospecific oxidation using Bu^tOOH gave the corresponding P-oxide which was shown to have R-stereochemistry at phosphorus by single-crystal X-ray diffraction studies. The compound reacted regiospecifically with ortho-anisylmagnesium bromide to afford the product formed by P-O bond cleavage with >96% d.e. and with retention of configuration at phosphorus as demonstrated by single-crystal X-ray diffraction studies. The l-ephedrine residue was replaced by O-methyl under acid-catalysis with inversion of configuration and with >95% e.e., the reaction was monitored by ¹H n.m.r. spectroscopy which gave t_1/2 of ca. 30 min. Attempts to incorporate para-fluorophenol using similar conditions led to the isolation of the pyrophosphinate in low yield. The OMe residue in the methyl (ortho-anisyl)phenylphosphinate was readily displaced by aliphatic Grignard reagents giving the corresponding phosphine oxides with inversion of configuration and with >95% e.e. Displacement of methoxy using aryl magnesium bromides showed similar enantioselectivity but in lower chemical yield, however the corresponding arylmagnesium chlorides were more efficient. In a second approach, diastereomerically pure (2R, 4S, 5R)-2-chloro-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidine was prepared from PCl₃ and l-ephedrine. The compound underwent diastereoselective P-C1 cleavage with aryl Grignard and aryllithium reagents with net retention of configuration at phosphorus and with 90% d.e. Oxidation of the ortho-anisyl derivative afforded (2R, 4S, 5R)-2-(ortho-anisyl)-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidine-2-oxide which was subsequently reacted with a range of bulky aryl Grignard reagents to afford the corresponding biarylphosphinamides with retention of configuration at phosphorus. Subsequent acid-catalysed methanolysis and displacement of the methoxy residue with PhMgCl afforded a range of bulky arylphosphine oxides with defined configuration at phosphorus with >95% e.e. as determined by ¹H n.m.r. methods. (S)-ortho-anisyl (meta-anisyl)phenylphosphine oxide underwent regiospecific ortho-lithiation on the meta-anisyl ring which on quenching with D₂O afforded the corresponding 2-deuteride in 80% yield. The 2-iodo analogue was also prepared although in low chemical purity and is a key precursor to new axially dissymmetric bisphosphines containing chiral phosphorus centres. Other approaches to P-chiral ferrocenyl ligands and biaryl ligands are also described and modifications for further development are implicated. An X-ray crystallographic study of six aryl-oxazaphospholidines is also presented and demonstrates the influence of the substituents at phosphorus in determining the conformation of the 1,3,2-oxazaphospholidine ring. A comparison with solution ¹H n.m.r. data showed, in some cases, good correlation between the P-O-C-H dihedral angle and the corresponding solid state torsion angle.

Although the use of Ln(^2+) species as one electron reducing agents has recently become popular, relatively few processes have focused on the control of stereochemistry by the incorporation of chiral auxiliaries at the metal centre. This thesis discusses work aimed at the synthesis of chiral bis(pentaalkylcyclopentadienyl) and polyaza/oxo ligands for Ln(II) ions, and their subsequent application in asymmetric organic synthesis. Synthesis of enantiomerically pure bis(pentaalkylcyclopentadienyl) ligands was attempted via a novel double Nazarov cyclisation of 5,6-di-(methyl)-decane-3,8-dione. A competing intermolecular aldol reaction reduced the efficiency of this route, although subsequent work suggests that the alternative ketone, (3,4-RR/SS)-bis(2'- oxobutyl)tetrahydrofuran, could inhibit aldol formation. In addition, a route for bis(tetramethylcyclopentadienyl) ligands was developed via oxidative coupling of 4-(S)-isopropyl-3-propionyl-oxazolidin-2-one.A range of tetradentate polyaza/oxo ligands have been prepared and their application in enantioselective carbon-carbon bond formation, in particular the Barbier reaction between 2-octanone and bromobutane, investigated. Using N,N'-bis(3'- propionamide)cyclohexane-l,2-diamine, asymmetric induction and a marked acceleration in reaction rate was observed. This represents the first enantioselective Sm(II)-mediated Barbier reaction. The use of aryl ketones affords pinacols with low enantioselectivity.

In view of the rapidly growing interest in P2Y receptors and the lack of subtype selective ligands, especially antagonists, the aim of this study was to evaluate novel ligands of P2Y receptors. This was performed using putative P2Y-selective antagonists reviewed in the literature and by designing and synthesising novel peptide ligands. Bovine aortic endothelial (BAE) cells that co-express P2Yl and P2Y2 receptors and ECV304, a human cell line were used for this study. ECV304 were evaluated as a suitable model for studying P2Y receptor pharmacology using currently available agonists and antagonists in assays of second messengers. Results showed that ECV304 cells express two P2Y receptors, a P2Y2-like receptor and a P2Y11-like receptor. During the study doubt was cast as to the origin of the human cell line ECV304. It was thought that these cells had spontaneously transformed from human umbilical vein endothelial cells. In this study it was clearly demonstrated that ECV304 cells shared the same DNA fingerprint as T24/83 bladder cancer epithelial cells and were indeed not endothelial in origin. However, ECV304 cells are human cells natively expressing P2Y receptors and are a very useful research tool for studying P2Y receptor pharmacology. Reactive blue 2 is a P2 receptor antagonist, but it is not subtype-selective, having effects at both P2X and P2Y receptors. A recent study showed that derivatives of reactive blue 2: acid blue 129, acid blue 80, acid blue 25 and acid violet 34, are P2Y- versus P2Xselective. These four derivatives have been investigated in this study for their relative selectivity at P2Y1 versus P2Y2 receptors using stimulation of inositol phosphate turnover in BAE cells as a measure of activity. Acid blue 25 failed to antagonise either the P2Y1 or the P2Y2 receptor. The other three compounds were shown to be weak antagonists that were not subtype-selective and had activity that was not truly competitiveNovel peptide ligands have been designed to mimic extracellular domains of the human P2Y2 receptor. Surprisingly, these novel mimetic peptides had "agonist-like" properties. Peptides alone directly activated second messenger production in bovine aortic endothelial cells and ECV304, and also augmented agonist responses in ECV304 cells. Interestingly, analogues of mimetic peptides were also capable of enhancing sub-maximal doses of natural agonists in ECV304 cells. These findings represent a unique action of mimetic peptides as they have effects at nonpeptide P2Y receptors. These observations indicate an important role of extracellular domains, particularly the third extracellular loop, in signal transduction by P2Y2 receptors. Furthermore, the "agonist-like" activity of P2Y2 receptor mimetic peptides has important implications for the study of P2Y receptor activation and may have therapeutic potential e. g. in the treatment of cystic fibrosis. Finally, these findings may be equally applicable to the design of allosteric modulators of other G protein-coupled receptors

The new Co(III) carbonate complexes [Co(uns-penp)(O₂CO)]ClO₄�H₂O and [Co(trpyn)(O₂CO)]ClO₄, containing tripodal tetraamine ligands, have been synthesised and characterised by microanalysis, �H, ��C and ⁵⁹Co NMR, mass spectrometry (MS) and UV-vis spectroscopy. In addition, the ⁵⁹Co NMR spectra have been obtained for two series of [Co(N₄)(O₂CO)]⁺ complexes containing aliphatic (N₄ = tren, baep, abap, trpn) and pyridyl (N₄ = tpa, pmea, pmap, tepa) tripodal tetraamine ligands and the complex [Co(dppa)(O₂CO)]⁺. The ⁵⁹Co NMR signal increases as [Delta] decreases, indicating there is less electron density at the Co(III) nucleus as the metal-ligand orbital overlap becomes poorer. A linear relationship was found to exist between the [Delta] for the individual complexes and their ⁵⁹Co NMR chemical shifts which follows the relationship: [Delta] = 29 174 + -0.89363 x [delta](⁵⁹Co) For the two series of [Co(N₄)(O₂CO)]+ complexes, plots of the magnetogyric ratio (γ) and [lambda][max] have y-intercepts that do not accurately correspond to the magnetogyric ratio of the bare cobalt nucleus (γ₀(Co)). This is due to the deviation of the complexes from pure octahedral symmetry. A fluxional process in the complex [Co(pmea)(O₂CO)]⁺ was investigated using variable temperate (VT) NMR. This was found to involve the inversion of a six-membered chelate ring about a pseudo mirror plane with a [Delta]G[double dagger] of 58 kJ mol⁻� at 25 �C. Mass spectra have been obtained for all the [Co(N₄)(O₂CO)]⁺ complexes, and these show a common fragmentation pattern for all the complexes except [Co(trpn)(O₂CO)]⁺, where CO₂ is lost from the molecular ion to give a [Co(N₄)O]⁺ adduct. Single crystal X-ray structural analyses were performed on [Co(abap)(O₂CO)]ClO₄ (orthorhombic, Pca2₁, a = 15.9744(11) Å, b = 8.6200(6) Å, c = 21.8568(15) Å, α = β = γ = 90�, Z = 8, R1 = 0.0350, wR2 = 0.0902), [Co(trpn)(O₂CO)]ClO₄�H₂O (monoclinic, P2₁/c, a = 11.9510(19) Å, b = 12.0740(19) Å, c = 12.917(2) Å, β = 117.56(4)�, α = γ = 90�, Z = 4, R1 = 0.0476, wR2 = 0.1188), [Co(tpa)(O₂CO)]ClO₄�2H₂O (triclinic, P-1, a = 16.2298(5) Å, b = 17.2291(5) Å, c = 17.3393(5) Å, α = 106.760(1)�, β = 92.809(1)�, γ = 108.004(1)�, Z = 8, R1 = 0.0349, wR2 = 0.0799), [Co(uns-penp)(O₂CO)]ClO₄�H₂O (triclinic, P-1, a = 6.7544(3) Å, b = 11.5523(5) Å, c = 12.3201(6) Å, α = 73.397(2)�, β = 89.749(2)�, γ = 84.551(2), Z = 2, R1 = 0.0277, wR2 = 0.0842) and [Co(trpyn)(O₂CO)]ClO₄ (monoclinic, P2₁/n, a = 12.2777(5) Å, b = 11.9322(4) Å, c = 27.9622(11) Å, β = 100.082(2)�, α = γ = 90�, Z = 8, R1 = 0.0435, wR2 = 0.1130). Rates of acid hydrolysis of [Co(N₄)(O₂CO)]⁺ (N₄ = baep, abap, trpn, tpa, pmea, pmap, tepa, uns-penp, dppa, trpyn, Me₃-tpa) complexes were measured by stopped flow or UV-vis spectroscopy (I = 1.0 mol L⁻�). The product of acid hydrolysis of [Co(pmea)(O₂CO)]⁺ has been indentified by X-ray crystallography as [Co(pmea)(OH₂)₂]�⁺ (triclinic, P-1, a = 9.7065(5) Å, b = 15.5645(8) Å, c = 11.5740(5) Å, α = 84.660(1)�, β = 123.255(1)�, γ = 104.283(1)�, Z = 2, R1 = 0.0402, wR2 = 0.1009). The acid hydrolysis reactions of the [Co(N₄)(O₂CO)]⁺ complexes containing aliphatic (N₄ = baep, abap, trpn) tripodal tetraamine ligands and [Co(tpa)(O₂CO)]⁺ and [Co(Me₃-tpa)(O₂CO)]⁺ have been investigated over the range [H₃O⁺] = 0.10 - 1.0 mol L⁻� Three processes were observed for the hydrolysis of [Co(baep)(O₂CO)]⁺, [Co(abap)(O₂CO)]⁺ and [Co(trpn)(O₂CO)]⁺ at all [H₃O⁺]. The first and second processes were thought to be [H₃O⁺] dependent, while the third was fit to a first order exponential decay and was [H₃O⁺] independent (k[obs] ~ 4.2 x 10⁻� s⁻� for [Co(baep)(O₂CO)]⁺, 3.8 x 10⁻� s⁻� for [Co(abap)(O₂CO)]⁺ and 3.5 x 10⁻� s⁻� for [Co(trpn)(O₂CO)]⁺). However, none of the processes could be confidently assigned to a step in the acid hydrolysis mechanism. The data obtained from the studies of [Co(tpa)(O₂CO)]⁺ and [Co(Me₃-tpa)(O₂CO)]⁺ showed a single first order [H₃O⁺] dependent process which was fit to the following expression: k[obs] = (k₁K[H₃O]⁺)/(1 + K[H₃O]⁺ This gave k₁ = 5.8 x 10⁻⁴ � 2.3 x 10⁻⁴ s⁻� and K = 0.13 � 0.06 L mol⁻� for [Co(tpa)(O₂CO)]⁺ at 25 �C and k₁ = 6.0 x 10⁻⁵ � 2.0 x 10⁻⁶ s⁻� and K = 0.38 � 0.02 L mol⁻� for [Co(Me₃-tpa)(O₂CO)]⁺ at 50 �C. Both values of K indicate that protonation of chelated carbonate is far from complete at [H₃O⁺] = 1.0 mol L⁻�. Comparative rates of acid hydrolysis at [H₃O⁺] = 6.0 mol L⁻� were obtained for the complexes [Co(tpa)(O₂CO)]⁺ (k[obs] = 1.79 x 10⁻� s⁻�, 25 �C), [Co(pmea)(O₂CO)]⁺ (k[obs] = 1.8 x 10⁻⁵ s⁻�, 25 �C), [Co(pmap)(O₂CO)]⁺ (k[obs] = 2.5 x 10⁻⁵ s⁻�, 50 �C), [Co(tepa)(O₂CO)]⁺ (k[obs] = 4.3 x 10⁻⁵ s⁻�, 25 �C) and [Co(trpyn)(O₂CO)]⁺ (k[obs] = 1.3 x 10⁻⁴ s⁻�, 50 �C) and at [H₃O⁺] = 1.0 mol L⁻� for the complexes [Co(uns-penp)(O₂CO)]⁺ (k[obs] = 2.9 x 10⁻� s⁻�, 25 �C) and [Co(dppa)(O₂CO)]⁺ (k[obs] = 2.7 x 10⁻⁴ s⁻�, 25 �C). The vast differences in the rates of acid hydrolysis can be rationalised on a steric basis. Bulkier ancillary ligands impede the direct protonation of an endo oxygen atom, or the transfer of a proton from the exo to an endo oxygen atom. The chelated bicarbonate complex [Co(trpyn)(O₂COH)]ZnCl₄�3H₂O has been synthesised and characterised by microanalysis and X-ray crystallography (orthorhombic, Pbca, a = 18.1820(66) Å, b = 14.7256(44) Å, c = 19.6344(68) Å, α = β = γ = 90�, Z = 8, R1 = 0.0435, wR2 = 0.1130). The first products of direct metallion of coordinated carbonate, under both acidic and neutral conditions, have been isolated and characterised by microanalysis and IR spectroscopy. The X-ray crystal structures of the bimetallic complexes [Co(Me-tpa)O₂COZnCl₃]�H₂O (triclinic, P-1, a = 8.262(1) Å, b = 11.290(1) Å, c = 13.766(2) Å, α = 95.314(4)�, β = 103.160(4)�, γ = 107.071(5)�, Z = 2, R1 = 0.0382, wR2 = 0.0940) and [Co(pmea)O₂COZnCl₃]�H₂O (triclinic, P-1, a = 8.2916(7) Å, b = 11.0999(11) Å, c = 14.0994(13) Å, α = 8.2916(7)�, β = 102.607(4)�, γ = 108.600(4)�, Z = 2, R1 = 0.0347, wR2 = 0.0770), and the trimetallic complex [(Co(trpyn)(O₂CO))₂Zn(H₂O)̀₄](ZnCl₄)₂�3H₂O (monoclinic, P2₁/c, a = 20.9734(17) Å, b = 17.3712(12) Å, c = 15.7635(13) Å, β = 111.376(4)�, α = γ = 90�, Z = 4, R1 = 0.0235, wR2 = 0.0517) have been obtained. In addition, the X-ray crystal structures of the complexes [Co(trpyn)(O₂CO)](Zn(OH)₂Cl₃)�4H₂O (triclinic, P-1, a = 7.4962(7) Å, b = 13.4019(11) Å, c = 13.6887(11) Å, α = 74.631(4)�, β = 82.893(4)�, γ = 82.324(4)�, Z = 2, R1 = 0.0268, wR2 = 0.0638) and [Co(tepa)(O₂CO)]₂(ZnCl₄)�3H₂O (triclinic, P-1, a = 9.9250(10) Å, b = 15.5561(13) Å, c = 15.8730(16) Å, α = 89.545(4)�, β = 85.019(5)�, γ = 72.714(4)�, Z = 2, R1 = 0.0291, wR2 = 0.0722) were obtained. These two complexes were synthesised under analogous conditions to the bi- and trimetallic complexes. However, in these cases metallation of chelated carbonate did not occur. DFT calculations have been used to calculate the relative energies of pairs of geometric isomers of [Co(N₄)(O₂CO)]⁺ complexes (N₄ = baep, abap, pmea, pmap, dppa, Me-tpa, Me₂-tpa). In all cases, except that of [Co(Me-tpa)(O₂CO)]⁺, the calculations correctly predict that the experimentally observed isomer is lower in energy. An electronic study on two series of [Co(N₄)(O₂CO)]⁺ complexes containing pyridyl (N₄ = tpa, pmea, pmap, tepa) and Me-pyridyl (N₄ = tpa, Me-tpa, Me₂-tpa, Me₃-tpa) tripodal tetraamine ligands correctly reproduces the observed trends in ⁵⁹Co NMR chemical shift and [Delta] values. A molecular orbital analysis of the two series of complexes shows that there is no significant difference between the highest energy occupied orbitals with the largest contribution from the coordinated oxygen atoms. Bond decomposition analyses of the two series of complexes indicate that there is also no difference in total bond energies. These results indicate that there is no electronic explanation for the large differences in reactivity towards acid that is observed experimentally. The first mononuclear complex containing chelated hydrogen phosphate, [Co(pmea)(O₂PO₂H)]ClO₄, has been synthesised and characterised using microanalysis, �H, ��C, ��P and ⁵⁹Co NMR, UV-vis spectroscopy and X-ray crystallography (monoclinic, P2₁/c, a = 8.7017(17) Å, b = 27.639(5) Å, c = 9.586(2) Å, β = 112.818(9)�, α = γ = 90�, Z = 4, R1 = 0.0443, wR2 = 0.1076). The X-ray crystal structure of [Co(pmeaH)(OH₂)Cl₂](CoCl₄)�H₂O (orthorhombic, P2₁2₁2₁, a = 12.6354(3) Å, b = 12.6354(3) Å, c = 15.8261(11) Å, α = β = γ = 90�, Z = 4, R1 = 0.0397, wR2 = 0.0954), in which the pmea ligand is coordinated in a hypodentate fashion, was also obtained. [Co(pmeaH)(OH₂)Cl₂](CoCl₄)�H₂O is thought to be an impurity in crude samples of [Co(pmea)Cl₂]Cl. The pK[a] of [Co(pmea)(O₂PO₂H)]⁺ was determined to be 4.99 � 0.02 by potentiometric titration. A ring inversion fluxional process, analogous to that observed for [Co(pmea)(O₂CO)]⁺, was found by VT-NMR to have a [Delta]G[double dagger] of 60 kJ mol⁻� at 35 �C. A ��P NMR spectrum, taken after the solution was left standing for approximately three hours, showed evidence of cleavage of the hydrogen phosphate chelate via a bimetallic hydrolysis mechanism. Attempts were also made to synthesise Co(III) complexes containing chelated phosphate ester ligands (monomethyl phosphate and monophenyl phosphate), with pmea as the ancillary ligand. ��P NMR spectra of the crude samples indicate that the monomethyl phosphate moiety is chelated to Co(III) (��P [delta] = 21.05 ppm). However, it is unclear whether the monophenyl phosphate is chelated or bridging between two Co(III) ions (��P [delta] = 14.36 ppm).

This thesis describes the development of new catalytic systems based upon iron complexes and their reactivity toward ethylene. First, we focused our interest on the synthesis of iron(III) precursors chelated by monoanionic ligand. Those complexes were obtained either by reaction of the monoanionic ligand with FeCl3 or through oxidation of the iron(II) complex. The second reaction led to binuclear complexes. Then, another aim of the thesis was to design new well-defined cocatalysts for the activation of iron complexes. The study of the reaction between an alcohol and the trimethylaluminum allowed us to reach this aim. Aluminum complexes adopted either a binuclear framework or a trinuclear one, depending on the nature of alcohol reagent. Besides this work, new iron(II) and nickel(II) complexes chelated by imino-imidazole ligands bearing a pendant donor function L were synthesized. All complexes have been evaluated for the oligomerization of ethylene in the presence of EtAlCl2 or MAO as cocatalyst. Only nickel complexes were active toward ethylene transformation.

This thesis deals with the study of oxazoline-based ligands in metal-catalyzed asymmetric reactions. The first part describes the synthesis of six new bifunctinal pyridine-bis(oxazoline) ligands and their applications in asymmetric metal-catalysis. These ligands, in addition to a Lewis acid coordination site, are equipped with a Lewis basic part in the 4-position of the oxazoline rings. Dual activation by means of this system was probed in cyanide addition to aldehydes. The second part is concerned with the synthesis of two pyridine-bis(oxazoline) ligands bearing bulky triazole groups in the 4-position of the oxazoline rings and a macrocyclic ligand consisting of a pyridine-bis(oxazoline) moiety and a diaza-18-crown-6 ether. The synthesis of these compounds benefits from the use of “click chemistry”. The ligands thus obtained were tested in different asymmetric catalytic reactions. Complexation studies with different bifunctional molecules that could bind into the cavity of the macrocycle were carried out using NMR spectroscopy. A third chapter is devoted to the synthesis of a supported pyridine-bis(oxazoline) catalyst and its use in catalysis. The pyridine-bis(oxazoline) ligand was efficiently connected to a polystyrene resin via a robust triazole linker. This resin could be employed in different metal-catalyzed asymmetric reactions and good results were obtained in terms of yield and enantioselectivity. Moreover, this polymer-bound ligand could be easily and efficiently recycled. Finally, the last part deals with the use of a hydroxy-containing phosphinooxazoline ligand in the hydrosilylation of imines and in the asymmetric intermolecular Heck reaction. A cationic iridium complex of this ligand was studied by NMR spectroscopy.
QC 20100914

Novel and potent ligands to the serotonin7 (5-HT7) receptor have been synthesized. The synthesized compounds include a set of substituted pyrimidines which show high affinity to the 5-HT7 receptor, synthesized by previously described methods [1,2] in high yield. Comparing the affinities of substituted pyrimidines to previously calculated models [3,4] yielded new hypotheses about the nature of interaction between the pyrimidine ligands and the 5-HT7 binding site. Several new series of compounds were synthesized by various methods to validate these hypotheses, including a conjugate addition to vinylpyrimidines [5]. These compounds include benzofurans, oximes, hydrazones, as well as a group of substituted piperazines. All series of compounds show affinity to the 5-HT7 receptor comparable to previously synthesized 5-HT7 ligands. Several of the synthesized ligands show affinity which exceeds that of currently available ligands. The synthesized compounds were evaluated quantitatively by calculating a three-dimensional quantitative structure-affinity relationship (3D-QSAR) for the 5-HT7 receptor. Evaluation of the calculated model validated qualitative assumptions about the data set as well as described regions of interaction in greater detail than previously available. These observations give further insight on the nature of ligand-binding site interactions with highly potent ligands such as 4-(3-furyl)-2-(N-methylpiperazino)pyrimidine which will lead to more potent 5-HT7 receptor ligands. Additionally, a model was calculated for affinity to the 5-HT2a receptor. Comparing this model to that calculated for affinity to the 5-HT7 receptor identified two regions which may be exploited in future sets of ligands to increase selectivity to the 5HT7 receptor.

Melanocortin receptors (MC1R-MC5R) belong to the G-protein coupled receptor superfamily. The interactions of peptide hormones (ACTH, alpha-, beta- and gamma-MSH) with the melanocortin receptors regulate multiple physiological functions in the human body. Pharmacological studies of the melanocortin receptors have revealed very broad biological effects including pigmentation, steroidogenesis, energy homeostasis, thermoregulation, anti-inflammation, nerve regeneration, sexual behavior, feeding behavior and memory, and others. Due to the lack of selectivity of the endogenous ligands (except ACTH) the exact biological roles of the melanocortin receptor subtypes have not been fully elucidated. The objectives of our research are the design and synthesis of new, selective and potent ligands for the melanocortin receptor subtypes to help elucidate their biological functions. Since the three-dimensional structures of the melanocortin receptors and their endogenous ligands are unknown, receptor structure-based design has not been applied. We have chosen a "classical" ligand-based design with the primary structure of an endogenous ligand, gamma-MSH, as a starting point. Our design strategy is to gain high selectivity and potency by fixing the spatial structure of this very flexible peptide ligand in hopes that we can induce the bioactive conformation. We have examined two strategies to constrain the peptide backbone. The first approach is based on global constraint of the peptides by cyclization. A group of 36 cyclic peptides has been synthesized using thioether bond formation as a cyclization step. Macrocyclic peptide ligands varied from 15- to 30-membered rings. The truncated sequence of gamma-MSH has been applied in the cyclic series. In the second strategy we have introduced a local constraint into the peptide backbone similar to a reverse turn structure. We have made a very radical change in ligand conformation by peptide complexation with a transition metal in different positions of the sequence. In this approach we have conserved all amino acid residues of gamma-MSH. All novel modified peptides have been synthesized by solid phase methodology. Preliminary biological studies indicate that we have identified very selective and potent ligands.

This thesis describes the synthesis and study of thirty four multidentate heterocyclic bridging ligands, twenty four of which are new compounds. A majority of these ligands incorporate a di-2-pyridyl coordination motif and are capable of chelation to a metal centre with the formation of a six-membered chelate ring, in contrast to the five-membered chelate rings formed by the majority of bridging ligands previously described in the literature. Four ligands were synthesised that represent the first examples of bridging heterocyclic ligands incorporating a [3]radialene core. The ligands described in this thesis are divided into three sections: those prepared from dipyridylmethane precursors, ligands with a di-2-pyridylamine chelating motif, and tripodal ligands, which are capable of facial coordination to an octahedral metal atom. The coordination and metallosupramolecular chemistry of these ligands were investigated with several different metal atoms, predominantly silver(I), copper(II) and palladium(II). With the dipyridylmethyl ligands and the di-2-pyridylarnine-based ligands, both discrete and polymeric structures were obtained, including dinuclear complexes, [2+2] dimeric complexes, molecular polyhedra and one-dimensional coordination polymers. Some novel structures, including a hexanuclear silver cage with an encapsulated fluoride anion and a triply cyclopalladated compound, are described. The tripodal ligands showed a preference for forming discrete complexes with M2L and M2L2 compositions, which included a new type of helicate. Bis(2,2'-bipyridyl)ruthenium complexes of the di-2-pyridylmethane-based and di-2-pyridylamine-based ligands are described and structurally characterised. Despite forming dinuclear complexes in many cases with palladium and copper, all the multidentate di-2-pyridylmethane-based ligands were surprisingly resistant to chelating their intended number of ruthenium atoms. Visible absorption spectroscopy and cyclic voItammetry was used to probe the nature of the metal-ligand and metal-metal interactions in these complexes. In combination with NMR spectroscopy, mass spectrometry and elemental analysis, X-Ray crystallography was used to characterise many of the complexes and metallosupramolecular species produced. The crystal structures of five ligands and fifty one complexes are described.

Thirty new nitrogen-containing ligands have been synthesised and the coordination chemistry of the majority of these has been investigated. The coordination chemistry of previously reported ligands related to these has also been investigated. The ligands contain a central benzene ring to which nitrogen-containing heterocycles have been appended via one or two linking atoms. In this manner, between two and six such groups have been attached to a benzene ring to give ligands which display a great variety of modes of coordination to transition metals. These complexes have been characterised by combinations of N.M.R. spectroscopy, mass spectrometry, elemental analysis and X-ray crystallography - the X-ray crystal structures of thirty one complexes have been determined. Among these thirty one structures are chelated and macrocyclic complexes containing monochiral ligands, a supramolecular ten-component cage containing a guest molecule, a new N₃(arene) mode of coordination, as well as a number of complexes in which arene-arene and metal-arene interactions are observed. Cyclometallated complexes of some of these ligands have also been prepared, the dynamic N.M.R. processes of which have been investigated by variable temperature ¹H N.M.R. methods.

Pharmaceutical Sciences
Ph.D.
Muscarinic receptors are G-protein-coupled receptors that mediate the response to acetylcholine released from parasympathetic nerves. Although five mAChR subtypes (M1-M5) share a high degree of homology, they display different physiological effects including controlling smooth muscle tone to neurotransmitter release in the CNS. Hence these receptor subtypes have been investigated as potential therapeutic targets for agents capable of treating Alzheimer's Disease, Parkinson's Disease, peptic ulcer disease, COPD, urinary incontinence, and muscle spasms. Our interest in the development of subtype selective muscarinic ligands led to previous reports detailing the identification of substituted lactones as lead muscarinic compounds. Later work involved molecular modifications of those leads that included the addition of aromatic groups with a variety of substitution patterns. These efforts led to an increase in receptor affinity and produced a lactone-based muscarinic ligand with an IC50 of 340nM. As a continuation of that work, additional novel ligands were designed based on the general pharmacophoric elements proposed for the lactone-based ligands. In that model, the lactone oxygens serve as H-bond acceptor moieties while different nitrogen containing heterocycles provide the requisite cationic group. These groups may be separated by linker groups of varying sizes. In order to synthesize the lactone-based ligands mentioned above, efficient synthetic routes are required for key precursors. These include but are not limited to: 1. A novel high yield synthesis of the hydroxyethyl-lactone precursor was designed using a carefully controlled Prins reaction. The method readily quenches a cationic intermediate and simultaneously protects hydroxyl groups in a single step. A mechanism for the new route to the precursor is proposed and its use in the preparation of the target compounds is presented 2. Microwave-assisted synthesis of various sterically hindered N-aryl piperazines has been developed allowing quick access to structurally diverse muscarinic ligands These synthesis along with other newly developed routes enabled ready access to 59 novel muscarinic ligands. The ligands were tested in a general muscarinic binding assay. The result was analyzed and SAR study was performed to direct ligand design. As a result of this work, ligand affinity was improved by over 100 folds compare to the lead molecules. Several promising compounds were selected and selectivity tested.
Temple University--Theses

The P2Y2 receptor (P2Y2R) has been implicated in a range of clinical conditions, including but not limited to: cystic fibrosis, dry eye syndrome and cancer. However, a lack of high quality, drug-like modulators and tool-like compounds means there is scope to develop ligands that can further probe P2Y2R function in vitro and in vivo. Assessment of the reported P2Y2R antagonists led to the conclusion that 5-((5-(2,8-dimethyl-5H-dibenzo[a,d][7]annulen-5-yl)-2-oxo-4-thioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-(1H-tetrazol-5-yl)furan-2-carboxamide (AR-C118925, 38) was the most drug-like P2Y2R antagonist and was chosen as a chemical starting point. Elaboration of the 2,8-dimethyl-5H-dibenzo[a,d]cyclohepten-5-yl moeity to a 7-chloro-2-methyl-4H-benzo[5,6]cyclohepta[1,2-d]thiazol-4-yl), led to the development of two potent, novel P2Y2R antagonists: MSG204 105 (pKB = 6.73 0.25, n = 3) and MSG249 119 (pKB = 7.06 0.02, n = 3), both of which exhibit improved physicochemical properties to AR-C118925 38 and provide more drug-like alternatives for future in vivo work. Structure activity relationships derived in developing these novel P2Y2R antagonists, has ultimately led to the development of multiple fluorescently-labelled P2Y2R ligands. Most notably, BODIPY 630/650 conjugate MSG260 193 (pKd = 6.99 0.04, n = 3) and BODIPY FL conjugate MSG262 195 (pKd = 6.88 0.01, n = 3), which have enabled the use of a novel P2Y2R BRET ligand-binding assay and provide a robust platform for future drug discovery programs.