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Synthèse de motifs "2-méthyl-1,3-aminoalcools" par réaction de type Reformatsky asymétrique : vers la synthèse totale du (+)-triènomycinol / Synthesis of "2-methyl-1,3-aminoalcohol" moieties via an asymmetric Reformatsky type reaction : towards the total synthesis of (+)-trienomycinolBarbarotto, Marie 01 June 2012 (has links)
Ce travail de thèse porte dans une première partie sur le développement d’une réaction de type Reformatsky asymétrique appliquée à la synthèse de motifs « 2-méthyl-1,3-aminoalcools » syn, syn et syn, anti. Cette réaction met à l’honneur la chimie des sulfoxydes chiraux dont la présence sur le substrat permet de construire trois centres asymétriques contigus. En effet, dans une première étape, une réaction de type Reformatsy entre un précurseur chiral, un γ-bromo-β-cétosulfoxyde et différentes imines permet de former les deux premiers centres asymétriques. La sélectivité favorise de composé syn. Cette réaction est très sélective avec des sélectivités syn/anti allant jusqu’à 100/0. Ensuite, une réduction diastéréosélective des β-cétosulfoxydes obtenus à l’issue de la réaction de Reformatsky permet de former le troisième centre asymétrique avec une diastéréosélectivité totale. Ainsi, l’utilisation du DIBAL-H seul permet d’obtenir l’aminoalcool 1,3-syn alors que l’utilisation du système DIBAL-H/Yb(OTf)3 permet d’accéder à l’aminoalcool 1,3-anti avec dans les deux cas une diastéréosélectivité totale pour cette étape de réduction.Dans une deuxième partie, ce travail de thèse présente des avancées vers la synthèse totale du (+)-triènomycinol, une molécule naturelle à forte activité cytotoxique. Il s’agit d’un macrolactame à 21 chaînons comportant une partie triènique, une liaison peptidique, une stéréotriade syn, anti et un centre asymétrique isolé. La stratégie proposée consiste à construire tous les centres asymétriques en utilisant la chimie des sulfoxydes chiraux. En effet, la stéréotriade a été construite en utilisant la réaction dévloppée dans la première partie, à savoir une réaction de type Reformatsky asymétrique couplée à une réduction diastéréosélective à l’aide du système DIBAL-H/Yb(OTf)3. Le centre stéréogène isolé a lui aussi été construit grâce à la chimie des sulfoxydes chiraux, par réduction diastéréosélective d’un β-cétosulfoxyde à l’aide de DIBAL-H. Cette molécule a été découpée en deux fragments, un fragments « ouest » et un fragment « est » qui ont été couplés. De nombreuses étapes ont au préalable été mises au point sur un composé modèle. Par manque de temps et de matière, la synthèse totale du (+)-triènomycinol n’a pu être achevée. / In a first part, the aim of this PhD thesis was to develop an asymmetric Reformatsky type reaction for the synthesis of “2-methyl-1,3aminoalcohol” moieties. This reaction is based on the chemistry of chiral sulfoxides. Indeed, in a first step, an asymmetric Reformatsky type reaction between a γ-bromo-β-ketosulfoxide and different imines allows us to build two contiguous stereogenic centers. This reaction is very selective with a syn/anti selectivity reaching up to 100/0. In a second step, the β-ketosulfoxides obtained after the Reformatsky-type reaction were diastereoselectively reduced using either DIBAL-H or the system DIBAL-H/Yb(OTf)3 to afford the third stereogenic center with a total diastereoselectivity. To sum up, the use of DIBAL-H allowed us to obtain the aminoalcohol 1,3-syn, whereas the use of the system DIBAL-H/Yb(OTf)3 allowed us to synthesize the aminoalcohol 1,3-anti with a perfect diastereoselectivity in both cases.In a second part, this PhD thesis focused on the total synthesis of natural cytotoxic molecule, (+)-trienomycinol. This molecule is a macrolactam containing a syn, anti stereotriad, an isolated stereogenic center and a trienic unit. The proposed strategy was based on the use of chiral sulfoxides. The stereostriad was built using the strategy developed in the first part, the asymmetric Reformatsky reaction followed by a diastereoselective reduction with the system DIBAL-H/Yb(OTf)3. The isolated stereocenter was obtained by diastereoselective reduction of a β-ketosulfoxide with DIBAL-H. This molecule was divided into two parts: the “west” part and the “east” part which were coupled together. Many steps were first optimized on a model compound. Due to a lack of time and quantity, the total synthesis of (+)-trienomycinol could not be achieved.
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Compuestos metal-orgánicos con propiedades multifuncionales / Matériaux hybrides métaux-organiques multifonctionnels / Metal-organic compounds with multifunctional propertiesBaldo Hurtado, Bianca 23 January 2018 (has links)
Le fait qu'un composé métal-organique contienne à la fois une partie organique et une partie inorganique, rend ces systèmes hautement modulables, de la dimensionnalité de leur structure aux propriétés obtenues. Ainsi, la chimie de coordination a été axée sur la synthèse de nouveaux matériaux à base de cations 3d et 4f, liés par des ligands organiques avec des groupes fonctionnels de nature chimique différente, ce qui permet de trouver à ces matériaux intéressants des propriétés telles que la luminescence, l'optique non linéaire et le magnétisme. En outre, la synthèse de composés métal-organique de dimensionnalité supérieur a été dominé par les longues durées de réaction, en plus de l'utilisation de solvants organiques exposés à des conditions de température et supérieures à celles utilisées dans des procédés de synthèse classique pression. Cependant, au cours des dernières années, l'intérêt s'est accru dans le développement de nouvelles techniques de synthèse avec des temps de réaction plus courts et plus favorables à l'environnement, tels que la mécanochimie et la sonochimie. Dans cette thèse, nous présentons la synthèse, la caractérisation structurale et optique de neuf composés de coordination basés sur le liant d'imidazole-4-acide acrylique. Les composés sont classés en deux types: (1) sur la base des cations nd, à l'intérieur qui sont les précurseurs du type [M(HIA)2(H2O)4] (M = CuII, NiII, CdII et ZnII), obtenu par synthèse mécanochimique, et le polymère de coordination {[Cd(H2IA)(HIA)(H2O)2]2∙H2O(NO3)2}n obtenu par sonochimique; et (2) des composés hétérométallique nd/4f, qui sont basées sur la Cu(II)/Eu(III), Cu(II)/Gd(III), Cu(II)/Ce(III) et cations Cd(II)/Ce(IV), tous obtenus par synthèse sonochimique. Il est à noter que les composés basés sur les cations Cu(II)/Ln(III) ont également été caractérisés magnétiquement. De plus, une famille de composés à base de Ni(II)/Ln(II), obtenue par synthèse structurale est rapportée. / The fact that metal-organic compound contains an organic and an inorganic part, makes these systems highly modulable, from the dimensionality of their structure to the properties that are obtained. For this reason during the last time, the coordination chemistry has been focused on the synthesis of new materials based on 3d and 4f cations, linked through organic ligand with functional groups of different chemical nature, which contribute to obtain new materials with interesting properties such as luminescence, non-linear optics and magnetism, among others. On the other hand, the synthesis of metal-organic compounds of greater dimensionality has been dominated by long reaction times, using organic solvents exposed to conditions of temperature and pressure higher than those used in traditional synthesis methods. However, the interest for new synthetic techniques with shorter reaction times and more friendly to the environment, such as mechanochemistry and sonochemistry has grown in last years. In this thesis, are reported the synthesis, structural and optical characterization of nine coordination compounds based on the imidazole-4-acrylic acid ligand. The compounds are classified into two types: (1) based on nd cations, which are the precursors of the type [M(HIA)2(H2O)4] (with M = CuII, NiII, CdII and ZnII), obtained by mechanochemical synthesis, and also the coordination polymer {[Cd(H2IA)(HIA)(H2O)2]2·H2O(NO3)2}n obtained by sonochemistry; and (2) nd/4f heterometallic compounds obtained by sonochemical synthesis, which are based on the CuII/EuIII, CuII/GdIII, CuII/CeIII and CdII/CeIV cations. It should be noted that the compounds based on the CuII/LnIII cations were also magnetically characterized. Additionally, a family of compounds based on NiII/LnII, obtained by structural synthesis is reported. Although, the H2IA ligand does not participate in the final product, the compounds are considered novel from the structural point of view, because the Ln2+ cation, had stabilized only in organometallic compounds until now. Finally, it is important to highlight that the thesis work presented has been carried out within the framework of a co-supervision between the Université de Rennes 1, France, and the Andrés Bello University, Chile, for which two stays were made in France, with six months of duration each one. The results presented were obtained in Laboratoire ISCR Institut des Sciences Chimiques in Rennes, France, and in the Laboratorio de Compuestos Polimetálicos, Chile.
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Synthèse et caractérisation de porphyrines chirales à destination de l'électronique moléculaire / Synthesis and characterisation of chiral porphyrins design for molecular electronic.Bernollin, Maud 25 October 2012 (has links)
Une nouvelle famille de porphyrines chirales bridées a été mise au point dans le but d'accéder à des systèmes présentant un processus redox irréversible, lié à une bistabilité conformationnelle, dans le but de les appliquer dans le domaine des mémoires moléculaires. Ces nouvelles porphyrines sont constituées de deux brides ancrées sur les quatre positions meso par des groupes cyclohexyle. Une amine secondaire a été insérée au centre des brides dans le but d'obtenir des métalloporphyrines présentant une seule conformation à l'équilibre pour une longueur de bride, un métal et un degré d'oxydation donnés et pour favoriser un changement conformationnel en fonction du degré d'oxydation d'un métal comme le manganèse. Pour cela, une nouvelle voie de synthèse des porphyrines bridées par pré-fonctionnalisation du dialdéhyde autour de la fonction amine a été conçue. Les porphyrines ont été caractérisées par spectroscopie RMN, spectroscopie UV-Visible et dichroïsme circulaire. Les conformations des bases libres, des complexes de zinc(II) et de nickel(II) ont été déterminées par RMN proton. Pour une longueur de bride de 9 atomes avec une amine secondaire, les conformations des complexes de zinc(II) et de nickel(II) sont respectivement αααα et ααββ. En partant de ce modèle, les complexes de manganèse(II) et de chloromanganèse(III) ont été synthétisés et caractérisés par spectroscopie UV-Visible, dichroïsme circulaire et RMN du carbone 13 afin d'étudier si des changements de conformation en fonction du degré d'oxydation du métal ont lieu. / A new family of chiral bridled porphyrins was designed in order to access systems presenting an irreversible redox process linked to a conformational switch. Such systems could be of high interest in the field of molecular memories. These new porphyrins are made of two bridles anchored to the four macrocycle meso positions through cyclohexyl groups. The first objective is to introduce a secondary amine in the centre of the bridles in order to allow metalloporphyrins with defined bridle length and specific metal with a given oxidation degree to be only under one conformation at equilibrium. The second objective is to favor a conformational switch dependent on the oxidation state of a redox metal such as manganese. To reach these goals, a new porphyrin synthetic pathway was established. The key steps of this new protocol were the synthesis of the bridle built around the central amine with two terminal aldehyde functions required for the macrocyle formation. Porphyrins were studied by NMR, UV-Visible and circular dichroism spectroscopies. The conformations of free base porphyrins, zinc(II) complexes and nickel(II) complexes were determined by 1H NMR. For a bridle with a chain length of 9 atoms including the secondary amine, the zinc(II) complex presents only an αααα conformation and nickel(II) complex an ααββ conformation. From these structural models, manganese(II) and chloromanganese(III) complexes were synthesised and characterised by UV-Visible spectroscopy, circular dichroism and 13C NMR in order to study the possible conformational switches dependent on the Mn redox state.
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Nitroxydes chiraux à squelette imidazolidin-4-one comme catalyseurs d'oxydation énantiosélective d'alcools par O2 / L'auteur n'a pas fourni de titre en anglaisCarbo Lopez, Marta 09 December 2014 (has links)
L'objectif de cette thèse était d'évaluer des nitroxydes chiraux à squelette imidazolidin-4-one comme catalyseurs d'oxydation énantiosélective d'alcools par le dioxygène. Pour cela, plusieurs nitroxydes avec différents substituants en position α ont été synthétisés afin de voir les effets possibles de chacun des groupements. Différents co-catalyseurs décrits dans la bibliographie ont été testés afin de faire ces réactions qui ont lieu à température ambiante et pression atmosphérique. Ces systèmes catalytiques peuvent se différencier selon s'ils utilisent ou pas de métal comme additif.La stratégie utilisée pour la synthèse des catalyseurs a été développée au laboratoire à partir de travaux sur des nitrones réalisés précédemment. Grâce à cette stratégie et à l'utilisation de différentes nitrones de départ, des analogues différemment substitués en position α peuvent être synthétisés rapidement en seulement deux étapes. En particulier, l'utilisation d'une nitrone chirale nous permettra l'obtention de catalyseurs énantiopurs qui pourront être utilisés pour les réactions d'oxydation énantiosélectives.Dans la première partie de notre étude, différents systèmes catalytiques ont été testés avec nos catalyseurs sur un substrat modèle : l'alcool benzylique. Les résultats obtenus nous ont aidé à déterminer : (1) la capacité des nitroxydes de type imidazolidin-4-one à agir en tant que catalyseurs pour les réactions d'oxydation aérobie ; (2) la différence de réactivité selon la substitution en position α ; (3) les systèmes catalytiques les plus efficaces avec nos catalyseurs ; (4) le type de substrats qui pourront être envisagés lors de l'oxydation énantiosélective.C'est ainsi la désymétrisation de diols conduisant à la formation d'atropoisomères qui a été envisagée. L'oxydation par le dioxygène de trois substrats a ainsi été testée avec plusieurs catalyseurs énantiopurs et un système catalytique à base de cuivre. Les résultats d'énantiosélectivité obtenus ont été variables selon le substrat et le catalyseur utilisés. Des résultats très encourageants ont été obtenus pour l'un des substrats, avec des excès enantiomériques d'environ 60 %.En parallèle avec les différentes réactions d'oxydation, des études de voltammétrie cyclique et de résonance paramagnétique électronique (RPE) ont aussi été réalisées. La voltammétrie cyclique nous a servi surtout pour expliquer la différence de réactivité de différents analogues selon leur substitution en position α. Avec la RPE, nous avons essayé de comprendre un peu plus l'organisation autour du cuivre des différents éléments qui font partie du système catalytique à base de cuivre utilisé pour les oxydations énantiosélectives.Grâce à tous ces travaux, nous avons démontré que les nitroxydes à squelette imidazolidin-4-one peuvent être utilisés en tant que catalyseurs pour l'oxydation aérobie d'alcools. Nous avons noté l'importance des substituants en position α qui jouent un rôle important sur la stabilité de l'espèce active, ce qui pourra faire varier l'efficacité de chaque composé. Les nitroxydes contenant le squelette imidazolidin-4-one ont aussi donné des bons résultats dans des réactions d'oxydation énantioséletive de diols benzyliques. / The aim of this thesis was to evaluate the use of chiral nitroxides containing an imidazolidin-4-one squeletton as enantioselective catalysts for the aerobic oxidation of alcohols. In this view, several nitroxides with different α substituents have been synthesized to investigate the influence of these groups. Several co-catalysts reported in the literature have been tested for the oxidation reactions that take place at room temperature and atmospheric pressure. These catalytic systems can be classified relatively to the presence or the absence of metal as additive.The strategy used for the catalyst synthesis has been developped in the laboratory from previous studies about nitrones. Using this strategy and different starting nitrones, several α-substituted analogues can be rapidly synthesized in only two steps. Particularly, the use of a chiral nitrone will permit the obtention of enantiopur catalysts that will be able used for the enantioselective oxidations.In the first part of our study, several catalytic systems have been tested with our catalysts with a reference substrate: benzylic alcohol. According to the results, we have been able to determine: (1) the capacity of imidazolidin-4-one nitroxides to behave as catalysts for the aerobic oxidations; (2) the difference of reactivity depending on the α substituents; (3) the more effective catalytic systems for our catalysts; (4) the scope of the reaction in order to determine the suitable substrates for enantioselective reactions.With all these results in hand, diol desymmetrization for the synthesis of atropoisomers has been considered. Dioxygen oxidation of three diols has been tested using different enantiopur catalysts with a copper-based catalytic system. The enantioselectivity obtained proved variable depending on the substrate and the catalyst used. Very encouraging results have been obtained for one of the substrate, with enantiomeric excess of about 60 %.At the same time as the oxidation reactions, cyclic voltammetry and electron paramagnetic resonance (EPR) studies have been carried out. Cyclic voltammetry has been useful to explain the difference of reactivity of the catalysts according the α substituents. Using the EPR, we have tried to understand the organisation around copper for the different species from the catalytic system used for the enantioselective oxidations.By means of this study, we have demonstrated that imidazolidin-4-one nitroxides can be used as catalysts for the aerobic oxidation of alcohols. The α substituents play an important role in the stability of the active species that can change the efficacity of each compound. Imidazolidin-4-one nitroxides have also given encouraging results in the enantioselective oxidation of benzylic diols.
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Synthèse de bicycles contraints originaux pour l’élaboration de nouveaux catalyseurs chiraux et de nouveaux foldamères / Synthesis of original constrained bicyclic compounds to develop new chiral catalysts and new foldamersMilbéo, Pierre 24 November 2017 (has links)
Les travaux présentés dans cette thèse ont eu pour objectif la valorisation d’une structures bicyclique bifonctionnelle à géométrie contrainte, celle de l’acide 2-aminobicyclo[2.2.2]octane 1-carboxylique (ABOC). La contrainte conformationnelle est une caractéristique particulièrement recherchée dans la conception d’agent chiraux pour la synthèse asymétrique ainsi que dans la synthèse de macromolécules se structurant spontanément (foldamères). Un travail sur la synthèse de petits peptides incorporant le (R) ou (S)-ABOC, a dans un premier temps conduit à l’identification d’un nouvel organocatalyseur bifonctionnel de la réaction d’aldolisation. Ce tripeptide incorporant en plus de l’ABOC un résidu proline en position N-terminale et un résidu Asp-OMe en position C-terminale a permis l’obtention d’excès énantiomérique élevés (jusqu’à 87%). Les analyses structurales ainsi que des calculs théoriques ont montré l’importance du bicycle de l’ABOC induisant la formation d’un coude dans la molécule et permettant la proximité des fonctions acide carboxylique (Asp) et amine secondaire (Pro) intervenant dans la catalyse. Dans un second temps, l’optimisation de la synthèse du (R) ou (S)-1,2-diaminobicyclo[2,2,2]octane (DABO) a permis de mettre en évidence l’impact important d’une double liaison endo-cyclique dans la réactivité de l’amine en tête de pont lors du réarrangement de l’acide carboxylique de l’ABOC en amine primaire. En effet, seules les conditions d’Hofmann appliqué au substrat présentant une insaturation dans le squelette bicyclique ont permis d’obtenir la diamine chirale avec de bon rendement. Cette nouvelle diamine vicinale chirale contrainte par un bicycle carboné a d’abord permis la synthèse de composés thiourée-amine autour du bicycle pour l’organocatalyse de la réaction d’addition de Nitro-Michael asymétrique. Cependant, et malgré les nombreux efforts d’optimisation, l’utilisation de ces molécules n’a jamais permis l’obtention d’excès énantiomériques supérieurs à 39%. En revanche, la synthèse de nouveaux ligands chiraux salen, salan et diamines secondaires basés sur le DABO et l’application des complexes de cuivre correspondants dans la catalyse de la réaction de nitroaldolisation asymétrique a abouti à l’obtention de bons rendements et d’une stéréosélectivité allant jusqu’à 86% d’excès énantiomériques. Le complexe donnant les meilleurs résultats a fait l’objet d’une étude DFT approfondie permettant de proposer la structure de l’état de transition le plus stable et de rationaliser la stéréosélectivité observée. Enfin la synthèse du DABO a permis d’entreprendre la synthèse de nouvelles oligourées mixtes homochirales se structurant en hélice-12/14 stables, alors qu’aucune structuration n’avait été observée lors de l’étude d’oligourées mixtes homochirales synthétisées à partir de l’ABOC. / The work presented in this thesis was aimed at the valorisation of a bicyclic bifunctional structure with constrained geometry, the 2-aminobicyclo[2.2.2]octane 1-carboxylic acid (ABOC). Conformational restriction is a particularly sought characteristic in chiral agent designed for asymmetric synthesis as well as in the synthesis of spontaneously structuring macromolecules (foldamers). A work on the synthesis of small peptides incorporating (R) or (S)-ABOC, initially led to the identification of a novel bifunctional organocatalyst for the aldolization. This tripeptide incorporating in addition to ABOC a proline residue in the N-terminal position and an Asp-OMe residue in the C-terminal position allowed to obtain high enantiomeric excess (up to 87%). Structural analysis as well as theoretical calculations showed the importance of the ABOC bicycle, inducing the formation of a turn in the molecule and allowing the proximity of the carboxylic acid (Asp) and secondary amine (Pro) functions involved in catalysis. The optimization of the synthesis of (R) or (S)-1,2-diaminobicyclo[2,2,2]octane (DABO) allowed to demonstrate the important impact of an endo-cyclic double bond in the reactivity of the bridgehead amine during the rearrangement of the carboxylic acid of the ABOC to the primary amine. Indeed, only the Hofmann conditions applied to the substrate exhibiting unsaturation in the bicyclic skeleton allowed to obtain the chiral diamine in good yield. This novel chiral vicinal diamine conformationally restricted by a carbon bicycle first allowed the synthesis of thiourea-amine compounds around the bicycle for the organocatalysis of the asymmetric nitro-Michael addition. However, despite many optimization efforts, the use of these molecules has never led to enantiomeric excesses greater than 39%. On the other hand, the synthesis of new chiral salen, salan and secondary diamines ligands based on DABO and the application of the corresponding copper complexes for the catalysis of the asymmetric nitroaldolization reaction resulted in good yields and a stereoselectivity up to 87% enantiomeric excess. The best-performing complex was subjected to a DFT study to propose the structure of the most stable transition state and to rationalize the high stereoselectivity. Finally, the synthesis of DABO allowed to undertake the synthesis of new homochiral mixed oligoureas structuring as stable 12/14-helices, while no structure had been observed during the study of homochiral mixed oligoureas synthesized from the ABOC.
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Renormalização de teorias efetivas em sistemas hadrônicos / Renormalization of effective theories in hadron systemsLuiz Paulo de Oliveira 18 September 2017 (has links)
A presente tese propõe-se a investigar a discussão que ocorre na literatura hadrônica de baixas energias com relação à renormalização de teorias efetivas não-perturbativas, no caso particular do sistema nucleon-nucleon. Os detalhes que tornam o problema não-trivial são a existência do potencial tensor devido à troca de um píon e o aspecto não-relativístico tanto da equação dinâmica (Lippmann-Schwinger ou Schrödinger) quanto da derivação do potencial. A teoria de perturbação quiral (PT), desenvolvida por Gasser e Leutwyler, tem se mostrado como a mais fiel representação da QCD em baixas energias. A extensão da PT para o setor envolvendo poucos nucleons foi realizada por Weinberg, através de um esquema de contagem de potências quiral (power counting). O power counting de Weinberg tem sido severamente criticado na literatura devido à sua não-renormalizabilidade, que possui estreita relação à divergência da troca de um píon. Recentemente, Staporoli estudou a inclusão de campos auxiliares capazes de absorver as divergências provenientes da troca de um píon. A natureza desses campos são escolhidas por critérios de grande número de cores na QCD. Neste trabalho, mostramos que a inclusão de um campo auxiliar vetorial na teoria efetiva, em ordem dominante, é um ingrediente capaz de absorver as divergências de curto alcance e fornecer resultados com muito boa concordância com as análises de ondas parciais do grupo de Nijmegen (PWA93). Desta maneira, este estudo instaura a renormalizabilidade do sistema de dois nucleons, ausente na proposta de Weinberg, além de ser uma alternativa de maior apelo físico e com menos procedimentos ad hoc, como na promoção de contra-termos sugerida por Nogga, Timmermans e van Kolck. / The present work aims at investigating the current discussion in the literature of low-energy hadron physics, concerning the non-perturbative renormalization of effective field theories, in particular, the case of a system with two nucleons. The details that make this issue non-trivial are the existence of a tensor potential due to the exchange of one pion, as well as the non-relativistic aspects of both the dynamical equation (Lippmann-Schwinger or Schrödinger) and the derivation of the nucleon-nucleon potential. Chiral perturbation theory (PT), developed by Gasser and Leutwyler, has been shown to be the most faithful representation of low energy QCD. The extension of PT to the sector involving few- nucleons was performed by Weinberg, through a power counting scheme. Weinberg\'s power counting has been severely criticized in the literature for its non-renormalizability, which is closely related to the divergence of the one-pion exchange. Recently, Staporoli studied the inclusion of auxiliary fields capable of absorbing divergences from the exchange of a pion. The nature of these fields are chosen by criteria of large number of colors in QCD. In this work, we show that the inclusion of a vector auxiliary field in the effective theory, at dominant order, is an ingredient capable of absorbing the short-range divergences and provides results with very good agreement with the partial wave analysis of the Nijmegen group (PWA93). In this way, this study establishes the renormalizability of the two nucleon system, absent in the Weinberg\'s proposal, besides of being an alternative with larger physical appealing and with less ad hoc procedures, as the promotion of counter-terms suggested by Nogga, Timmermans and van Kolck.
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Adição de nucleofilos a ions N-aciliminios quirais e reações de ciclização promovidas por Pd(0) / Nucleophilic addition to chiral N-acyliminium ions and palladium(0)-mediated cyclization reactionsRobello, Luis Gustavo, 1975- 14 December 2006 (has links)
Orientador: Ronaldo Aloise Pilli / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-08T04:04:52Z (GMT). No. of bitstreams: 1
Robello_LuisGustavo_D.pdf: 7203530 bytes, checksum: a92a57231d7587b04ebb16da51b52419 (MD5)
Previous issue date: 2006 / Doutorado / Quimica Organica / Doutor em Ciências
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Influência da doença de Chagas na farmacocinética-farmacodinâmica dos isômeros do nebivolol e seus metabólitos em pacientes idosos metabolizadores rápidos para o CYP2D6 / Influence of Chagas disease on the pharmacokinetics-pharmacodynamics of nebivolol isomers in elderly patients CYP2D6 extensive metabolizers.Carolina Pinto Vieira 26 February 2016 (has links)
Os antagonistas adrenérgicos dos receptores ?, tais como o nebivolol, podem reduzir a mortalidade dos pacientes na fase crônica da doença de Chagas causada pelo Trypanossoma cruzi. O nebivolol está disponível na clínica como mistura racêmica dos isómeros d e l com duplo mecanismo de ação. O d-nebivolol é antagonista do receptor adrenérgico ?1, enquanto o l-nebivolol é responsável pelas propriedades vasodilatadoras do fármaco. O nebivolol é metabolizado principalmente por glicuronidação e metabolismo oxidativo dependente do CYP2D6, formando os glicuronídeos do nebivolol e os metabólitos hidroxilados do nebivolol, os quais contribuem para o antagonismo do receptor ?1 adrenérgico. O objetivo do presente estudo foi avaliar a influência da doença de Chagas na farmacocinética-farmacodinâmica dos isômeros do nebivolol e seus metabólitos em pacientes idosos metabolizadores rápidos para o CYP2D6. Foram investigados pacientes idosos portadores da doença de Chagas (n = 11) e idosos hipertensos (n = 11) previamente fenotipados como metabolizadores extensivos (EM) ou metabolizadores lentos (PM) para o CYP2D6, usando o metoprolol como fármaco marcador (21 EM e 1 PM). As coletas seriadas de sangue foram realizadas até 48 h após a administração de dose única oral de 10 mg de nebivolol racêmico. As concentrações plasmáticas dos isômeros individuais do nebivolol e glicuronídeos do nebivolol foram avaliadas por LC-MS/MS. O método mostrou linearidade nas concentrações de 15-3000 pg de cada isômero do nebivolol/mL de plasma e de 0,2-125 ng de cada isômero do glicuronídeo do nebivolol/mL de plasma. Os parâmetros farmacocinéticos foram avaliados usando o programa Phoenix (WinNonlin) e expressos em mediana, média e intervalo de confiança 95%. Os testes estatísticos foram utilizados para comparar os parâmetros farmacocinéticos entre os isômeros (teste de Wilcoxon) e entre os grupos (teste de Mann-Whithey); p < 0,05. A farmacocinética do nebivolol é estereosseletiva em pacientes idosos hipertensos portadores (9,7 vs.. 6,1 ng.h/mL) ou não (10,1 vs.. 5,4 ng.h/mL) da doença de Chagas forma crônica fenotipados como metabolizadores rápidos, com observação de maiores valores de AUC para o isômero l-nebivolol. A glicuronidação do nebivolol também é estereosseletiva em pacientes idosos hipertensos portadores (72,9 vs.. 311,6 ng.h/mL) ou não (65,3 vs.. 335,2 ng.h/mL) da doença de Chagas forma crônica fenotipados como metabolizadores rápidos, com observação de maiores valores de AUC para o isômero d-glicuronídeo. A doença de Chagas forma crônica não altera a farmacocinética e a capacidade de glicuronidação de ambos os isômeros do nebivolol em pacientes fenotipados como metabolizadores rápidos. Os valores de clearance do l-nebivolol (48,6 vs.. 14,3 L/h) e do d-nebivolol (48,4 vs.. 20,4 L/h) estimados pelo modelo populacional foram menores para os indivíduos fenotipados como metabolizadores lentos quando comparados com os ii metabolizadores rápidos do CYP2D6. O cálculo da biodisponibilidade dos isômeros individuais do nebivolol para os indivíduos metabolizadores rápidos (9% para o l-nebivolol e 5% para o d-nebivolol) e metabolizadores lentos (42% para o l-nebivolol e 29% para o d-nebivolol) do CYP2D6 permitiu inferir que o clearance não difere entre os isômeros na administração oral. As concentrações plasmáticas de nebivolol obtidas no presente estudo seguindo a administração de dose única oral de 10 mg de nebivolol racêmico a pacientes idosos hipertensos portadores ou não doença de Chagas não foram suficientes para detectar alterações nos intervalos PR, RR e QT, oriundos dos eletrocardiogramas, realizados nos mesmos tempos de colheita das amostras de sangue. Em conclusão, a doença de Chagas na forma crônica não alterou a farmacocinética e a farmacodinâmica dos isômeros do nebivolol nos idosos investigados. / Adrenergic antagonists in ? receptors, such as nebivolol may reduce mortality of patients in the chronic phase of Chagas disease caused by Trypanosoma cruzi. Nebivolol is available as a racemic mixture of d and l isomers with dual mechanism of action. The d isomer is a ?1 adrenergic receptor antagonist, while the l isomer is responsible for the drug vasodilatory properties. Nebivolol is primarily metabolised by glucuronidation and oxidative metabolism dependent on CYP2D6 to form glucuronide and hydroxylated metabolites of nebivolol, which contribute to the antagonism of adrenergic receptor ?1. This study aims to evaluate the effect of Chagas disease on the pharmacokinetics-pharmacodynamics of nebivolol isomers and its metabolites in CYP2D6 extensive metabolisers elderly patients. Hypertensive elderly patients with (n = 11) and without Chagas disease (n = 11) were previously phenotyped as extensive metabolizers (EM) or poor metabolizers (PM) for CYP2D6, applying metoprolol as a probe drug (21 EM and 1 PM). Serial blood samples were collected within 48 hours after a single oral dose administration of 10 mg racemic nebivolol. Plasma concentrations of nebivolol individual isomers and its glucuronides were measured by LC-MS/MS. The assay was linear over the rage of 15-3000 pg of each isomer of nebivolol/mL plasma and 0.2 to 125 ng of each isomer of nebivolol glucuronide/mL plasma. Pharmacokinetic parameters were evaluated applying Phoenix (WinNonlin) software and expressed as median, mean and 95% confidence interval. Statistical tests compared the pharmacokinetic parameters between isomers (Wilcoxon test) and between groups (Mann-Whithey test); p < 0.05. Pharmacokinetics of nebivolol is stereoselective in hypertensive elderly patients with (9.7 vs. 6.1 ng.h/mL) and without (10.1 vs 5.4 ng·h/mL) the chronic form of Chagas disease and phenotyped as extensive metabolisers, with higher AUC values for l-nebivolol. Nebivolol glucuronidation is also stereoselective in hypertensive elderly patients with (311.6 vs 72.9 ng.h/mL) and without (335.2 vs 65.3 ng.h/mL) the chronic form of Chagas disease and phenotyped as extensive metabolisers, with higher AUC values for d-glucuronide. The chronic form of Chagas disease does not alter the pharmacokinetics and glucuronidation capacity of either nebivolol isomers in patients phenotyped as extensive metabolizers. Clearance values for l-nebivolol (48.6 vs 14.3 L/h) and d-nebivolol (48.4 vs 20.4 L/h) estimated by the population model were lower for individuals phenotyped as CYP2D6 poor metabolisers compared to extensive metabolizers. Bioavailability calculation of individual nebivolol isomers for CYP2D6 extensive metabolisers (l-nebivolol 9%, d-nebivolol 5%) and poor metabolizers (l-nebivolol 42%, d-nebivolol 29%) made it possible to infer that clearance does not differ between the isomers in oral administration. Plasma concentrations of nebivolol observed in the present study following a single oral dose of 10 mg of racemic nebivolol to hypertensive elderly patients with and without Chagas disease were not sufficient to detect alterations in the PR, RR, and QT intervals in the electrocardiograms performed at the same iv times of blood sampling. In conclusion, Chagas disease in the chronic form did not alter the pharmacokinetics or pharmacodynamics of nebivolol isomers in the investigated elderly patients.
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Análise enantiosseletiva da fluvastatina em plasma por eletroforese capilar / Enantioselective analysis of fluvastatin in plasma by capillary electrophoresisJennifer Michiko Chauca Yokoya 04 September 2013 (has links)
Atualmente, as doenças cardiovasculares constituem as principais causas de morte no Brasil e no mundo. As estatinas são consideradas os agentes mais efetivos e mais bem tolerados para o tratamento do aumento excessivo dos níveis de colesterol no sangue, ou hipercolesterolemia. A fluvastatina (FLV), um fármaco hipolipêmico, de segunda geração, pertencente à classe das estatinas, e é comercializada como mistura racêmica, ou seja, uma mistura equimolar da (+)-3R, 5S-FLV e (-)-3S, 5R-FLV. Além disso, é descrito na literatura que o enantiômero (+)- 3R, 5S- FLV possui atividade cerca de trinta vezes maior do que seu antípoda, o que justifica a importância e necessidade de métodos para análise enantiosseletiva de fármacos que possuam um ou mais centros de assimetria. Assim, este trabalho teve como objetivo a extração dos enantiômeros da FLV de matriz biológica (plasma) utilizando uma técnica de eletromigração em capilar, a cromatografia eletrocinética (EKC). A análise da FLV por cromatografia eletrocinética empregou como técnica de concentração online o stacking por injeção de grande volume, em um capilar de sílica fundida não revestido, de 50,0 cm de comprimento efetivo e 75 ?m de diâmetro interno, solução tampão tetraborato de sódio 50 mmol L-1, pH 9,5; adicionado de 20 mmol L-1 de 2-hidroxipropil-?-ciclodextrina como eletrólito de corrida, tensão de +25 kV, temperatura de 15 °C, injeção hidrodinâmica (0,5 psi por 30 segundos) e detecção em 300 nm. A separação dos enantiômeros foi obtida com valores de resolução de 3,0 e eficiência de 255840 e 150056, e tempos de migração de 7,2 e 7,4 minutos para a (+)-3R, 5S- FLV e (-)-3S, 5R- FLV, respectivamente. O procedimento de preparo de amostra foi baseado na extração em fase sólido-líquida (SLE), com a adição de 0,5 mL de solução tampão fosfato de sódio 0,1 mol L-1 pH 7,0 em 0,5 mL de plasma, previamente fortificado com padrão de FLV. A amostra foi aplicada na coluna e depois de 15 minutos, a FLV foi eluída com 4 mL de éter etílico. O método analítico foi validado avaliando os parâmetros seletividade, linearidade, precisão e exatidão inter e intra-dia, limite de quantificação, carry-over, efeito matriz, integridade da diluição e estudos de estabilidade. Além disso, foi realizado o estudo de racemização. Os resultados apresentaram linearidade na faixa de concentração plasmática de 250 a 725 ng mL-1 para cada enantiômero, sendo o limite de quantificação a concentração de 250 ng mL-1. Os estudos de precisão e exatidão apresentaram valores aceitáveis, com variação menor do que 15%. Além disso, não foi observado efeito carry-over e as amostras foram estáveis quando submetidas a ciclos de congelamento e descongelamento, estabilidade de curta e longa duração, pós-processamento e não foi observada racemização dos enantiômeros. Em relação ao efeito matriz, procedimentos alternativos foram usados com sucesso para análise de amostras lipêmicas e hemolisadas de plasmas. Sendo assim, este é o primeiro método bioanalítico desenvolvido, rápido e confiável, para quantificar os enantiômeros da FLV em amostras de plasma por EKC usando a SLE como técnica de preparo de amostra. / Nowadays, cardiovascular diseases are the main causes of death in Brazil and worldwide. Statins are considered the most effective and well tolerated agents for the excessive increase in cholesterol blood levels, or hypercholesterolemia. Fluvastatin (FLV), a hypolipidemic second generation drug belongs to statin drug class, and it is commercialized as a racemate, that is, a equimolar mixture of (+)-3R, 5S- FLV and (-)-3S, 5R- FLV. Moreover, literature describes that (+)-3R, 5S- FLV enantiomer activity is thirty times higher than its antipode, which justifies the importance and necessity of methods for the stereoselective analysis of drugs which possess one or more than one asymmetry centers. Thus, this work aims the extraction of FLV enantiomers from a biological matrix (plasma) using one of the electromigration techniques, the EKC. FLV analysis by EKC employed large volume sample stacking as sample on-column concentration technique using a fused-silica capillary with 50.0 cm effective length and 75 ?m internal diameter, 50 mmol L-1 sodium tetraborate buffer, pH 9,5 plus 20 mmol L-1 2-hydroxipropyl-?-cyclodextrin as a background electrolyte, voltage of +25 kV, temperature of 15ºC, with sample injected in hydrodynamic injection mode (0,5 psi for 30 seconds) and detection using a diode array detector set at 300 nm. The enantiomers resolution was achieved with a resolution value of 3.0, and efficiency of 255840 and 150056, migration times of 7.2 and 7.4 minutes for (+)-3R, 5S- FLV and (-)-3S, 5R- FLV, respectively. Supported liquid extraction was the chosen sample preparation procedure, with the addition of 0.5 mL of 0.1 mol L-1 pH 7.0 phosphate buffer to 0.5 mL of plasma, the mixture was applied to the column and allowed to wet for 15 minutes, 4 mL of ethyl ether was then applied to the top of the column, allowed to percolate by gravity and the eluted solvent was collected in an ambar tube, the solvent was submitted to evaporation under nitrogen flow and the residue was ressuspended for injection in the capillary electrophoresis equipment. The analytical method was validated covering selectivity, linearity, within-run and between-run precision and accuracy, limit of quantification, carry-over, matrix effect, dilution integrity and stability studies parameters. The racemization study was also performed. The results support that the analytical method is linear in the range of concentrations from 250 to 725 ng mL-1for each enantiomer, and the limit of quantification was 250 ng mL-1; the method is precise and accurate, with variation under 15%. Besides, no carry-over effect was observed, and both enantiomers showed to be stable under thaw and freeze cycles, short and long term stability studies, autosampler stability, and also no racemization was observed. Related to matrix effect, alternative procedures were employed sucessfully in case of analysis of lipemeic and hemolized matrices. So, this is the first bioanalytical method developed, fast and reliable, to quantify FLV enantiomers in plasma samples using EKC with SLE as sample preparation procedure.
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Non-equilibrium self-assembly : from shear flows to magnetic fields / Auto-assemblages hors-équilibre : des écoulements fluidiques aux champs magnétiquesMarichez, Vincent 04 November 2016 (has links)
Cette thèse s’articule autour de trois projets principaux indépendants les uns des autres. En premier lieu, nous avons développé une méthode de résolution chirale innovante reposant sur l’écoulement de Taylor-Couette et ne nécessitant donc pas l’utilisation d’une phase stationnaire. Les résultats de cette étude sont présentés dans le chapitre 2. En parallèle, nous nous sommes également investis en chimie supramoléculaire et avons notamment commencé à explorer l’effet d’un faible champ magnétique (< 2 T) sur le processus d’auto-assemblage de motifs moléculaires paramagnétiques. Nos efforts expérimentaux sont consignés dans le chapitre 3, chapitre à la fin duquel nous discutons de l’intérêt des états hors-équilibre dissipatifs, en particulier en chimie supramoléculaire. Ces derniers sont d’ailleurs (encore aujourd’hui) une branche énigmatique de la thermodynamique dans la mesure où de tels systèmes ne sont encore décrits par aucun principe thermodynamique (à l’inverse des systèmes à l’équilibre, parfaitement décrits par la thermodynamique classique) rendant leur prédiction compliquée. Dans le chapitre 4, nous exposons notre tentative de description d’un système dissipatif (un oscillateur de pH tout organique) au moyen de mesures calorimétriques à flux continu. Ces trois projets, bien que très différents, s’articulent néanmoins tous autour d’une philosophie commune : l’auto-assemblage loin de l’équilibre. / This thesis deals with three main projects, which are loosely related to one another. Chapter one introduces the progress made in the field of mechanical chiral resolution. The second chapter of this thesis shows the development of a resolution method based on Taylor-Couette flow, and how nonequilibrium self-assembly amplifies the resolution process. The third chapter describes our efforts to control non-equilibrium self-assembly by using weak magnetic fields (<2T). Finally, in chapter four, we show our attempts to describe non-equilibrium dissipative states using continuous-flow calorimetry. All chapters contain elements of non-equilibrium self-assembly or non-equilibrium systems, hence the title: “Non-equilibrium self-assembly: from shear flows to magnetic fields”
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