Düsseldorf, Univ., Diss., 2002. / Computerdatei im Fernzugriff.

Düsseldorf, Univ., Diss., 2002. / Computerdatei im Fernzugriff.

Düsseldorf, Universiẗat, Diss., 2002.

No description available.

Universiẗat, Diss., 2002--Jena.

Les analogues nucléosidiques constituent une famille importante d'agents thérapeutiques dans le traitement de maladies d'origine virale. Parmi ces composés, les nucléosides carbocycliques possèdent des propriétés biologiques intéressantes. Le premier chapitre de cette thèse est consacrée à la famille des neplanocines qui sont des carbonucleosides naturels. Nous avons détaillé l'interaction de ces composés avec leur principale cible, la S-adénosylhomocystéine hydrolase, ainsi que les différentes approches de synthèses de ces carbonucléosides et de leurs énantioméres avant de passer en revue leurs activités biologiques. Nous avons présenté dans le deuxième chapitre la première synthèse énantiosélective de la (éD)-néplanocine B. Le troisième chapitre est quant à lui axé sur la mise au point d'une synthèse de 3 '-halo-5'-norcarbonucléosides phosphonates ainsi qu’à l'évaluation de leurs activités antivirales. / Nucleosides analogues constitute an important family of therapeutic agents in the treatment of viral diseases. Among these compounds, carbocyclic nucleosides have interesting biological properties. The first chapter of this thesis is dedicated to a family of natural carbonucleosides, the neplanocins. We have presented their mode of action against S-adenosylhomocysteine hydrolase, as well as various syntheses of natural neplanocins and their enantiomers before reviewing their biological activities. In the second chapter, we described the first enantioselective synthesis of (¨D)-neplanocine B. The third chapter is devoted to the development of the synthesis of 3 '-halo-5¡¯-norcarbonucleosides phosphonates as well as the evaluation of their antiviral activities.

Phosphonates represent an important class of organophosphorus compounds. Their use as reagents in organic synthesis is prevalent, and there is a plethora of examples of biologically active compounds possessing the phosphonate moiety. To further our exploration of phosphonates as both reagents and biologically active compounds we have developed a one-flask protocol for the direct synthesis of phosphonates from benzylic and allylic alcohols. This transformation is unprecedented and is applicable to a range of substrates. Both electron rich and electron deficient benzylic alcohols react under the conditions developed. Furthermore, good yields are achieved when converting allylic alcohols to the corresponding allylic phosphonates. In at least one case, the one-flask protocol allows for phosphonate formation that was not achievable under the standard conditions. Bisphosphonates represent a significant subclass of phosphonates. Several nitrogenous bisphosphonates have found use in the clinic as treatments for bone-related disease including osteoporosis, and there is speculation that bisphosphonates that are enzyme-specific inhibitors may be used as cancer therapies. To develop our understanding of isoprenoid metabolism, we have prepared a range of bisphosphonates as potential inhibitors of geranylgeranyl pyrophosphate synthase. After much experimentation, an α-amino analog of a potent inhibitor of GGDPS has been synthesized and biological data is forthcoming. Furthermore, a new class of aromatic bisphosphonates, analogs of digeranyl bisphosphonic acid, has been synthesized and assayed. The bioassay results indicate that this series of compounds retains its specificity for the GGDPS enzyme, and that the dialkyl analogues retain much of their potency in the assays in spite of the increased steric bulk of the aromatic substructure. We have also begun the design and synthesis of compounds as potential inhibitors of Rab geranylgeranyl transferase (RGGTase). The lead compound, 3-PEHPC, is documented to inhibit RGGTase selectively, albeit at less than desirable concentrations. Using 3-PEHPC as the model compound we have elected to probe the impact of modifications on the hydrophilic "head" portion of the molecule. Using the phosphonophosphinate functionality as a surrogate for the phosphonocarboxylate moiety we have successfully synthesized digeranyl phosphonophosphinate. Initial assay data indicates that this novel phosphonophosphinate does not act upon GGDPS as does the analogous bisphosphonate substructure. The bioassay data to probe this compound's impact on RGGTase is forthcoming. Given the worldwide impact of tuberculosis infection and the emergence of drug-resistant strains of tuberculosis-causing pathogens, new and potent treatments for tuberculosis are necessary. We have engaged in the synthesis of several compounds as inhibitors of Rv2361c, an enzyme key to cell wall biosynthesis in Mycobacterium tuberculosis, the principle causative agent of tuberculosis in humans. To probe the impact of modifications at the C-9-position of the most potent of our Rv2361c inhibitors, we have made several analogues having phenyl and indole substituents. The in vitro enzyme assay data for the set of compounds has clarified understanding of the essential components of the pharmacophore, and helped to establish the direction for future efforts.

Research into molecular magnetism has undergone a revival over the past two decades following the discovery of Single Molecule Magnetism (SMM). Compounds which show this property have the potential to increase the storage capacity of magnetic media by many orders of magnitude compared to current generation devices. Developments in the field have come from synthesis involving mainly simple bridging ligands such as carboxylates, alkoxides, pyridonates and heterocyclic ligands. The use of phosphonic acid ligands in the synthesis of 4f-phosphonate or 3d-4f phosphonate clusters has recently begun to be explored, primarily for interest into their magnetic properties. The present work builds on studies which show that the reaction of oxo-centred metal triangles with phosphonate ligands can generate larger clusters retaining some motifs of the starting material. There are only few examples on the use of lanthanide carboxylates, such as [Ln2(O2CtBu)6(HO2CtBu)6] (Ln = Dy, Gd, Tb, Ho or Er) and/or a preformed cluster [Cr(III)3(µ3-O)(O2CtBu)6(H2O)3][O2CtBu] in combination with phosphonate ligands. This work investigates the use of bi-metallic lanthanide and tri-metallic transition metal starting materials in conjunction with the flexible tertiary-butylphosphonic acid ligand, to yield novel 4f-phosphonate and 3d-4f cages. Several Cr-4f phosphonate cages have been obtained, where each structure contains two oxo-centred {Cr3} triangles, bridged by phosphonates and lanthanides. Additionally, new 4f-phosphonate clusters have been synthesised by treating tertiary-butylphosphonic acid ligand with lanthanide nitrate salts or preformed lanthanide dimers. A number of 4f-phosphonate cages reported in the thesis show interesting structural or magnetic properties, for example, {Ln10P6} is the largest 4f-phosphonate odd number metal ring centred by a tenth metal site, the {Gd8P6} cluster demonstrates interesting MCE properties, and the {Dy4P2} complex is shown to be an SMM.

La manzamine A est un alcaloïde indolique d'origine marine découvert et isolé en 1986 par T. Higa et son groupe dans des éponges marines du genre Pellina et Haliclona. La Manzamine A montre d'intéressantes activités antibactériennes et antitumorales. La structure unique de la Manzamine A ainsi que ces propriétés biologiques et sa rareté a donné l'impulsion en vue de sa synthèse totale. Au cours d'études préliminaires menées au sein de notre laboratoire, divers dérivés tétracycliques, noyau de base des manzamines, ont été obtenus par polycyclisation anionique. Nous avons donc tenté de tirer avantage de cette nouvelle méthodologie pour synthétiser un analogue indolique. Dans un premier temps, nous avons étudié plus en détail notre polycyclisation anionique. Divers intermédiaires de notre processus en une étape ont pu être isolés ou observés. Ceci nous a permis de proposer un schéma réactionnel détaillé et d'expliquer le diastéréosélectivité des tétracycles isolés. Nous avons également développé une méthode générale et efficace pour synthétiser divers β-céto-phosphonates à partir des acides correspondants. Notre objectif suivant était d'obtenir le macrocyle à treize chaînons. Pour ce faire, pas moins de cinq approches différentes ont été étudiées. Même si nous n'avons jamais obtenu le macrocycle désiré, plusieurs intermédiaires-clés ont ainsi été synthétisés de manière courte et efficace prouvant ainsi la versatilité de notre méthode. Certaines approches peuvent encore faire l'objet d'investigations. Enfin, nous nous sommes attardés à la fonctionnalisation des tétracyles obtenus. Les aziridines et les diones correspondantes sont isolées avec de bons rendements.

Ruthenium-catalyzed cycloadditions of bicyclic alkenes with alkynyl phosphonates were investigated. In regard to the Ru-catalyzed [2+2] cycloadditions, the phosphonate moieties were found to be compatible, giving the corresponding cyclobutene cycloadducts in low to excellent yield (up to 96%). Alkynyl phosphonates showed lower reactivity than other heteroatom-substituted alkynes such as alkynyl halides, ynamides, alkynyl sulfides and alkynyl sulfones, and required a higher reaction temperature and much longer reaction time. To this end microwave heating was employed to expedite the reaction. While yields comparable to the conventionaly heated cycloadditions were not achieved, the reaction was much faster by microwave heating. In direct comparison over a 2 h period, yields were much greater in the microwave heated reactions. Computational studies determined that the electronic nature of the triple bond is sufficiently different in alkynyl phosphonates compared to other substituents. While investigating solvents of varying polarity in the microwave assisted [2+2] cycloaddition a new mode of reaction, previously unknown to this catalyst, was discovered. At elevated temperatures, in polar solvents, norbornadiene undergoes a Ru-catalyzed [2+2+2] homo Diels-Alder cycloaddition with alkynyl phophonates. This reaction was optimized to produce excellent yields with the model alkynyl phosphonate studied. Investigation of other alkynes revealed that the scope of this reaction may be limited to phosphonate substituted alkynes.