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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
501

Análise enantiosseletiva da fluvastatina em plasma por eletroforese capilar / Enantioselective analysis of fluvastatin in plasma by capillary electrophoresis

Yokoya, Jennifer Michiko Chauca 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.
502

Synthèse et utilisation de nouveaux catalyseurs phosphorés à noyau ferrocénophane / New chiral phosphorus derivatives with ferrocenophane scaffolds : synthesis and catalytic behaviour

Néel, Mathilde 28 October 2011 (has links)
La catalyse est par définition l’utilisation d’une quantité sous stœchiométrique d’un composé accélérant une réaction, sans entrer dans son bilan réactionnel. Si le catalyseur est une molécule organique chirale, nous pouvons effectuer des réactions d’organocatalyse asymétrique. D’autre part, si les phosphines trivalentes sont largement employées comme ligands en catalyse organométallique, elles présentent également une réactivité complémentaire aux amines en organocatalyse. Une nouvelle phosphine chirale à noyau ferrocénophane, le FerroPHANE, a été récemment développée et utilisée avec succès au laboratoire. C’est dans ce contexte que s’inscrivent mes travaux de thèse portant à la fois sur l’étude de nouveaux processus catalytiques et la synthèse de nouveaux dérivés phosphorés chiraux. Tout d’abord, une réaction de cyclisation [3+2] entre des oléfines et des allénylphosphonates catalysée par le FerroPHANE a été développée (excès énantiomériques compris entre 84 et 91%). Dans un second temps, des groupements aryles ont été introduits sur le noyau ferrocénique du FerroPHANE afin de moduler sa réactivité et son énantiosélectivité. Enfin, une nouvelle famille de phosphoramidites chiraux à noyau ferrocénique a été synthétisée et utilisée dans la synthèse de complexes de platine. / Catalysis is the acceleration of a reaction by addition of a sub-stœchiometric amount of a compound. When catalyst is a chiral organic derivative, it is possible to obtain enantioenriched products by asymmetric organocatalysis. Moreover, if trivalent phosphines have been widely developed as ligand for organometallic catalysis, their reactivity is complementary to amines in organocatalysis. A new planar chiral phosphine with ferrocenophane scaffold was recently developed and successfully used in organocatalysed reactions by our team: FerroPHANE. In this context, we have been interesting both in the development of new enantioselective [3+2] cyclization reactions catalyzed by chiral trivalent phosphines and the development of new chiral phosphorus derivatives with ferrocenophane scaffolds. In a first part, new enantioselective [3+2] cyclization reactions between olefins and allenylphosphonates, catalyzed by FerroPHANE, have been successfully developed (enantiomeric excesses between 84 to 91%). In a second part, to modify the reactivity and the enantioselectivity of this new family of phosphines, aryl groups were introduced on the ferrocenyl scaffold. Finally, a new family of chiral phosphoramidites with ferrocenyl scaffold have been synthesized and applied to the synthesis of chiral platinum complexes.
503

Self-assembly of two-dimensional convex and nonconvex colloidal platelets

Pakalidou, Nikoletta January 2017 (has links)
One of the most promising routes to create advanced materials is self-assembly. Self-assembly refers to the self-organisation of building blocks to form ordered structures. As the properties of the self-assembled materials will inherit the properties of the basic building blocks, it is then possible to engineer the properties of the materials by tailoring the properties of the building blocks. In order to create mesoscale materials, the self-assembly of molecular building blocks of different sizes and interactions is important. Mesoscopic materials can be obtained by using larger building blocks such as nano and colloidal particles. Colloidal particles are particularly attractive as building blocks because it is possible to design interparticle interactions by controlling both the chemistry of the particles' surface and the properties of the solvent in which the particles are immersed. The self-assembly of spherical colloidal particles has been widely reported in the literature. However, advances in experimental techniques to produce particles with different shapes and sizes have opened new opportunities to create more complex structures that cannot be formed using spherical particles. Indeed, the particles' shape and effective interactions between them dictate the spatial arrangement and micro-structure of the system, which can be engineered to produce functional materials for a wide range of applications. The driving forces determining the self-assembly of colloidal particles can be modified by the use of external influences such as geometrical confinement and electromagnetic forces. Geometrical confinement, for example, has been used to design quasi two-dimensional materials such as multi-layered structures of spheres, dimers, rods, spherical caps, and monolayers of platelets with various geometries and symmetries. In this dissertation, we present three computer simulations studies using Monte Carlo and Molecular Dynamics simulations determining the self-assembly of monolayer colloidal platelets with different shapes confined in two dimensions. These particles have been selected due to recent experiments in colloidal particles with similar shapes. All the particles' models are represented by planar polygons, and three different effects affecting their self-assembly have been analysed: (a) the curvature of the particles' vertices; (b) the curvature of the particles' edges; and finally (c) the addition of functional groups on the particles' surface. These studies aim to demonstrate that the subtle changes on the particle's shape can be used to engineer complex patterns for the fabrication of advanced materials. Monte Carlo simulations are performed to study the self-assembly of colloidal platelets with rounded corners with 4, 5, and 6-fold symmetries. Square platelets provide a rich phase behaviour that ranges between disorder-order and order-order phase transitions. Suprisingly, the disk-like shape of pentagons and hexagons prevents the total crystallisation of these systems, even at a high pressure state. A hysteresis gap is observed by the analysis of compression and expansion runs for the case of square platelets and the thermodynamic method known as direct coexistence method is used to be accurately determined the point of the order-order transition. Further, unexpected results are obtained by performing Molecular Dynamics simulations in systems with platelets with 3, 4, 5, and 6-fold symmetries when all the sides of each polygon are curved. Macroscopic chiral symmetry breaking is observed for platelets with 4 and 6-fold symmetries, and for the first time a rule is promoted to explain when these chiral structures can be formed driven only by packing effects. This unique rule is verified also for platelets with the same curved sides as previously when functional chains tethered to either vertices or sides. Indeed, square platelets with curved sides confined in two dimensions can form chiral structures at medium densities when flexible chains tethered to either vertices or sides. Triangular platelets with curved sides can form chiral structures only when the chains are tethered to the corners, since the chains experience an one-hand rotation to sterically protect one side. When the chains are symmetrically tethered to the sides, local chiral symmetry breaking is observed as both left-hand and right-hand sides on each vertex are sterically protected allowing the same probability for rotation either in clockwise or anticlockwise direction.
504

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.

Vieira, Carolina Pinto 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.
505

Processos biocatalÃticos utilizando a casca da laranja da terra (Citrus aurantium L.) / Biocatalytic processes using the orange peel of the earth (Citrus aurantium L.)

Francisco Felipe Maia da Silva 24 January 2012 (has links)
Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / O Brasil à o maior produtor mundial de laranja e de suco de laranja, sendo este setor de grande importÃncia para economia brasileira, responsÃvel por gerar mais de 400 mil empregos e movimentar cifras de bilhÃes de reais por ano. Mas, este setor tambÃm à responsÃvel pela produÃÃo de grande quantidade de rejeitos industriais, que equivalem a 50% do peso da fruta, sendo estes resÃduos utilizados na maioria das vezes como raÃÃo animal. Portanto o uso eficiente destes rejeitos se faz necessÃrio em um mundo em que as reservas naturais vÃm se esgotando. Neste sentido a biocatÃlise mostra-se como uma ferramenta promissora no uso destes resÃduos, que possuem enzimas em sua constituiÃÃo, para obtenÃÃo de produtos de alto valor agregado, as substÃncias enantiopuras. A aplicaÃÃo de diferentes metodologias, prÃticas e de baixo custo, possibilitou a sÃntese de alcoÃis quirais com alto excesso enantiomÃrico (ee) e boas taxas de conversÃo. ReaÃÃes de hidrÃlise e reduÃÃo foram processadas em meio aquoso e, as reaÃÃes de esterificaÃÃo foram realizadas em solvente orgÃnico, utilizando as casca da laranja como fonte de biocatalisadores. O uso das cascas da laranja como fonte de biocatalisador apresentou resultados bastante promissores, demonstrando capacidade catalÃtica em vÃrias reaÃÃes (reduÃÃo/oxidaÃÃo, hidrÃlise/esterificaÃÃo) atravÃs de metodologias simples e de baixo custo. ConversÃes de 46,90-96,70% foram alcanÃadas nas reaÃÃes de biorreduÃÃo acompanhado de ee variando de 21,15-99,00%. Nas reaÃÃes de hidrÃlise verificaram-se taxas de conversÃes de 19,20-80,82% e ee variando de 9,60-45,52%. Jà nas reaÃÃes de esterificaÃÃo, ee acima de 99% foram observados e conversÃes maiores que 80% foram alcanÃadas. Portanto, este estudo abre precedentes para uma ampla faixa de aplicaÃÃo desta fonte de biocatalisador (cascas da laranja), que atualmente à considerado como um rejeito industrial, contribuindo sobremaneira para agregar valor a todo um setor produtivo e industrial no qual o Brasil à lÃder, a indÃstria de suco de laranja. / The Brazil is the producing greater of world of orange and orange juice, being this sector of great importance for Brazilian, responsible economy for generating 400 thousand jobs and more than and putting into motion ciphers of billions per year. But, this sector also is responsible for the production of great amount of industrial rejetcs, that are equivalent 50% of the weight of the fruit, being these used residues most of the time as animal ration. Therefore the use efficient of these rejetcs if makes necessary in a world where the natural reserves come if depleting. In this direction biocatalysis is presented as a promising tool in the use of these residues, that contains enzymes in its constitution, for attainment of products of high added value, the substances enantiopure. The application of different methodologies, practical and of low cost, made possible the chiral alcohols synthesis with high enantiomeric excess (ee) and good taxes of conversion. Hydrolysis reactions and reduction had been processed in aqueous way e, the reactions of esterification had been carried through in organic solvent, using the rind of the orange as source of biocatalysis for such reactions. The use of the peel of the orange as biocatalysis source presented resulted sufficiently promising, demonstrating catalytic capacity in some reactions (reduction/oxidation, hydrolysis/esterification) through simple methodologies and of low cost. Conversions of 46,90-96,70% had been reached in the reactions of bioreduction shown of ee varying of 21,15-99,00%. In the hydrolysis reactions taxes of 19,20-80,82% conversions and ee had been verified varying of 9,60-45,52%. Already in the esterification reactions, ee above of 99% had been observed and bigger conversions that 80% had been reached. From there, this study it opens precedents for an ample band of application of this source of biocatalysis (pells of the orange), that currently it is considered as one reject industrial, contributing excessively to add value all a productive and industrial sector in which Brazil is leader, the orange juice industry
506

Nouvelles voies de synthèse énantiosélective pour l'accès à des composés difluorométhylés / Development of new strategies to access enantiopure difluoromethylated compounds

Batisse, Chloé 07 December 2018 (has links)
En dépit de sa rareté au sein des produits naturels et des processus biologiques, le fluor joue un rôle de plus en plus important dans nos vies quotidiennes. Un atome de fluor ou un groupement fluoré, lorsqu’il fait partie d’une molécule biologiquement active, permet d’améliorer drastiquement ses propriétés physiques, chimiques et biologiques. Le groupement -CHF2, en plus de posséder les propriétés remarquables communes à de nombreuses espèces émergentes fluorées, est considéré comme un bioisostère des groupements hydroxyle, thiol et amino. Il peut également être engagé dans des liaisons de type hydrogène grâce à son proton acide. Cependant, les voies de synthèse permettant d’introduire stéréosélectivement le groupe -CHF2 sont encore peu nombreuses. Par exemple, seuls peu de groupes ont concentré leurs efforts sur la synthèse d’alcools α,α-difluorométhylés. Afin de remédier à ce manque de méthodologies, deux stratégies ont été imaginées au sein de notre équipe. La première consiste à utiliser un sulfoxyde α,α-difluorométhylé énantiopur en tant qu’inducteur de chiralité. La seconde méthode repose sur l’utilisation de cyclopeptoïdes chiraux lors de la difluorométhylation énantiosélective de dérivés carbonylés dans des conditions de catalyse à transfert de phase. Ces deux stratégies ainsi que les résultats qui ont été obtenus au cours de ce projet de thèse sont exposés dans le présent manuscrit. / Despite being largely absent from natural products and biological processes, fluorine plays an increasingly important role in numerous areas of our daily life. The presence of fluorine atoms or fluoroalkyl groups in bioactive molecules can indeed deeply modify their physical, chemical and biological properties. In addition to these outstanding properties common to many emerging fluorinated groups, the -CHF2 group has been shown to be an interesting bioisostere of hydroxyl, thiol and amine groups and a strong hydrogen bond donor. However, in contrast to enantioselective trifluoromethylation, the enantioselective introduction of a difluoromethyl group is still in its infancy. For instance only few examples in the literature describe the synthesis of enantioenriched α,α-difluoromethyl alcohols. As part of our study to overcome this scarcity, we envisaged two different strategies to synthesise these compounds. The first method aimed to access highly enantioenriched α,α-difluoromethyl alcohols by using an enantiopure aryl α,α-difluoromethyl sulfoxide as chiral and traceless auxiliary. Phase transfer catalysis was chosen as a second strategy for the enantioselective difluoromethylation of carbonyl derivatives in presence of chiral cyclopeptoïds. Those two methods and the results obtained are discussed in this manuscript.
507

Chiral aldimines in diastereoselective carbon nucleophile additions

Dema, Haythem Karim 27 July 2012 (has links)
No description available.
508

<em>η'</em> Decay to π<sup>+</sup>π<sup>-</sup>π<sup>+</sup>π<sup>−</sup>

Jafari, Ehsan 01 January 2018 (has links)
With the use of chiral theory of mesons [1], [2] we evaluate the decay rate of η′ → π+π−π+π−. Our theoretical study of this problem is different from the previous theo- retical study [3] and our predicted result is in a good agreement with the experiment. In this chiral theory we evaluate Feynman diagrams up to one loop and the decay rate is calculated with the use of triangle and box diagrams. The ρ0 meson includes in both type of diagrams as a resonance state. Divergent integrals in the loop calculations are regularized with the use of n-dimensional ’t Hooft-Veltman regularization technique. At the last step to obtain the decay rate, the phase space integral has been calculated.
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Chiral Separation of Amines by Non-Aqueous Capillary Electrophoresis using Low Molecular Weight Selectors

Hedeland, Ylva January 2006 (has links)
<p>Three chiral selectors (diketogulonic acid, benzoxycarbonylglycylproline and ketopinic acid) have been introduced for enantioseparation of pharmacologically active amines in non-aqueous capillary electrophoresis. The use of organic solvents, instead of aqueous buffers in the background electrolyte facilitated ion-pair formation between the analytes and the chiral selectors. The enantioresolution was strongly affected by the choice of selector and organic solvent but also depended on the other electrolytes. The most important parameter for the enantioresolution, apart from the choice of chiral selector, was the direction and magnitude of the electro-osmosis. Thus, covalently coated capillaries were used to suppress and to reverse this flow. Furthermore, the alkali metal hydroxide added to the background electrolyte had a great influence on the electro-osmosis. Exchanging LiOH for NaOH, was found to decrease the electro-osmotic flow. Interestingly, the flow was altered from cathodic to anodic, with KOH, RbOH or CsOH added to the ethanolic BGE. The occurrence of a reversed electro-osmosis had a great positive effect on the enantioresolution. An appropriate choice of solvent and electrolytes promoted also fast chiral separations, e.g., the enantiomers of isoprenaline were resolved within one minute. </p><p>The capillary electrophoresis systems developed within this work were applied for enantiomeric purity determinations of different pharmaceutical forms of drug products. A detection limit of 0.033 % was achieved for <i>1S,2R</i>-ephedrine, the enantiomeric impurity in Efedrin®, when diketogulonic acid was used as the selector. </p><p>By using the pre-concentration technique, transient isotachophoresis, the peak efficiency was enhanced for the enantiomers of timolol. This facilitated the introduction of a higher concentration of the sample into the capillary electrophoretic system containing ketopinic acid as the selector, and lowered the detection limit from 2.5 % to 0.2 % for the enantiomeric impurity <i>R</i>-timolol compared with injection without transient isotachophoresis.</p><p>The volatility of the non-aqueous media in capillary electrophoresis facilitated the hyphenation to mass spectrometry. The partial filling technique ensured that the selector did not contaminate the mass spectrometer, and the separated enantiomers of e.g., pronethalol were detected in the selector-free zone. </p>
510

Chiral Separation of Amines by Non-Aqueous Capillary Electrophoresis using Low Molecular Weight Selectors

Hedeland, Ylva January 2006 (has links)
Three chiral selectors (diketogulonic acid, benzoxycarbonylglycylproline and ketopinic acid) have been introduced for enantioseparation of pharmacologically active amines in non-aqueous capillary electrophoresis. The use of organic solvents, instead of aqueous buffers in the background electrolyte facilitated ion-pair formation between the analytes and the chiral selectors. The enantioresolution was strongly affected by the choice of selector and organic solvent but also depended on the other electrolytes. The most important parameter for the enantioresolution, apart from the choice of chiral selector, was the direction and magnitude of the electro-osmosis. Thus, covalently coated capillaries were used to suppress and to reverse this flow. Furthermore, the alkali metal hydroxide added to the background electrolyte had a great influence on the electro-osmosis. Exchanging LiOH for NaOH, was found to decrease the electro-osmotic flow. Interestingly, the flow was altered from cathodic to anodic, with KOH, RbOH or CsOH added to the ethanolic BGE. The occurrence of a reversed electro-osmosis had a great positive effect on the enantioresolution. An appropriate choice of solvent and electrolytes promoted also fast chiral separations, e.g., the enantiomers of isoprenaline were resolved within one minute. The capillary electrophoresis systems developed within this work were applied for enantiomeric purity determinations of different pharmaceutical forms of drug products. A detection limit of 0.033 % was achieved for 1S,2R-ephedrine, the enantiomeric impurity in Efedrin®, when diketogulonic acid was used as the selector. By using the pre-concentration technique, transient isotachophoresis, the peak efficiency was enhanced for the enantiomers of timolol. This facilitated the introduction of a higher concentration of the sample into the capillary electrophoretic system containing ketopinic acid as the selector, and lowered the detection limit from 2.5 % to 0.2 % for the enantiomeric impurity R-timolol compared with injection without transient isotachophoresis. The volatility of the non-aqueous media in capillary electrophoresis facilitated the hyphenation to mass spectrometry. The partial filling technique ensured that the selector did not contaminate the mass spectrometer, and the separated enantiomers of e.g., pronethalol were detected in the selector-free zone.

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