Les composés organiques présentant une chiralité portée par un atome de phosphore sont appelés composés P-chiraux, P-chirogéniques ou P-stéréogéniques. Ces composés trouvent des nombreuses applications dans l’industrie agrochimique et pharmaceutique, en tant qu’outils de coordination, mais surtout en catalyse organométallique asymétrique en tant que ligands privilégiés (Prix Nobel pour W. S. Knowles en 2001). Cependant, la synthèse de composés P-chiraux reste un défi majeur et les méthodes actuellement utilisées sont souvent difficiles à mettre en oeuvre et multi-étapes. Au cours de cette thèse nous nous sommes intéressés au développement d’une méthodologie efficace et inédite pour la synthèse de composés P-stéréogeniques. Notre approche est basée sur la réaction d’Atherton-Todd et implique le dédoublement cinétique dynamique lors d’un couplage entre un phénol portant un auxiliaire de chiralité, ie. le sulfoxyde, et un H-phosphinate racémique. De plus, la post-functionalisation des composés diastéréomériques P-chiraux ainsi obtenus est possible dans des conditions douces, permettant ainsi d’accéder à un large panel de composés P-stéréogeniques. Ainsi, cette nouvelle méthodologie permet de synthétiser, via un couplage O-P diastéréosélectif, des précurseurs originaux de composés P-chiraux variés. / Organic compounds having chirality on phosphorous atom, are called P-stereogenic, P-chirogenic or P-chiral compounds. These compounds are widely used in agrochemistry, pharmacy, coordination chemistry and in organometallic asymmetric catalysis, as one of the most important classes of chiral ligands (Nobel Prize 2001; W. S. Knowles). However, access to these P-stereogenic compounds, is challenging due to the complex, tedious and multi-steps synthetic methodologies. Herein, we report a highly efficient novel methodology to access P-stereogenic compounds, which often involves dynamic kinetic resolution (DKR) under modified Atherton-Todd reaction conditions, using a racemic H-phosphinate and an enantiopure phenol bearing a chiral sulfoxide moiety. Furthermore, the newly obtained O-P coupling product can potentially be post-functionalised under mild conditions to obtain various original P-stereogenic scaffolds. Thus, these O-P coupling products can be considered as highly potential precursors to access a variety of original P-stereogenic molecules.

Au cours de ce travail, nous avons démontré l’apport que pouvait avoir le développement de nouveaux complexes chiraux de platine et d’or pour la catalyse asymétrique et pour la découverte de nouvelles réactions de cycloisomérisation d’énynes. Dans la première partie, de nouveaux complexes de platine chiraux ont été utilisés pour effectuer la première étude systématique de la réaction de cycloisomérisation d’énynes 1,5 hydroxylées. Les composés bicycliques correspondant ont été obtenus avec de bons rendement et jusqu’à 81% d’excès énantiomérique. Par la suite, de nouveaux complexes chiraux d’or, possédant un ligand phosphahélicène ont permis d’obtenir de très bons résultats dans des réactions de cycloisomérisation d’énynes 1,6 (jusqu’à 86% ee). Des variations structurales des hélices phosphorées ont ensuite été effectuées, en changeant notamment le groupement P-menthyle par un substituant P-isopinocampheyle. Si les complexes d’or correspondant n’ont pas permis de donner des résultats important en catalyse, cela a permis d’avoir une meilleure connaissance de nos catalyseurs, et des substitutions nécessaires à de bonnes inductions asymétriques. D’autre part, ces nouveaux catalyseurs semblent donner des résultats prometteurs dans des réactions d’organocatalyse asymétrique. Enfin, l’exploration de la chimie des phosphéniums N-hétérocycliques comme ligands du platine a permis de se rendre compte de la faible stabilité de ces espèces, mais surtout des activités catalytiques très intéressantes que pouvaient obtenir ces catalyseurs dans des réactions de cycloisomérisation. Ce travail préliminaire démontre la « preuve de concept », qui ne demande qu’à être continué à l’avenir. / In this work, we have carried out the first systematic investigations on the enantioselective transition metal-promoted cycloisomerizations of 1,5-enynes with hydroxyl functions at their propargylic positions. These experiments have highlighted a series of platinacyclic NHC-complexes afforded bicyclo[3.1.0]hexanones in up to 81% enantiomeric excess. In the second part of our work we have prepared both known and new phosphahelicenes via the oxidative photocyclization of olefins suitably made from phosphindole building blocks. We have demonstrated that this synthetic method allows modulation of the phosphahelicene structure. Gold(I) complexes have been prepared then from these phosphahelicenes. These complexes have been evaluated in the challenging field of the gold-catalyzed enantioselective cycloisomerizations of enynes. In the cycloisomerization of NTs tethered 1,6-enynes, we could obtain very high catalytic activity and good enantioselectivity, with up to 81% ee, by using the P-menthyl-substituted helicenes as chiral ligands. The cycloisomerization of 1,6-dien-8-ynes, which afforded bi- or tricyclic compounds in one step, at room temperature, in high yields and excellent enantiomeric excesses (up to 86% ee). Thus, we have demonstrated that phosphahelicenes-gold complexes represent a new class of efficient catalysts, which complements the few chiral gold catalysts known so far. The chiral phosphahelicenes above have been evaluated briefly in a totally different field, that is nucleophilic organocatalysis. The trivalent phosphahelicenes proved able to promote the enantioselective [3+2] cyclizations between olefins and allenes, giving cyclopentene derivatives in excellent enantiomeric excesses (up to 96% ee). Finally, we have investigated the use of N-heterocyclic phospheniums as ligands in transition metal catalysis, starting from platinum promoted cycloisomerizations as the model reactions. In doing these challenging, exploratory experiments, we have noticed a moderate stability of the few platinum-NHP complexes prepared so far. Nevertheless, the cationic Pt(0) complex (mesNHP)Pt(PPh₃)₂⁺OTf could be generated in situ. It displayed moderate but significant catalytic activity in the cycloisomerization of a 3-hydroxy-1,5-enyne (51% isolated yield). These experiments afford a proof-of-concept, but additional work is required to identify the most suitable metal/NHPs pairs leading to stable and efficient pre-catalysts. The cationic nature of the NHP ligands might open totally new perspectives in organometallic catalysis. Further studies on this topic will be carried out in our group in the near future.

A maioria dos agentes terapêuticos, freqüentemente prescritos, são formulados e comercializados sob a forma racêmica, embora para alguns deles, já tenha sido demonstrado que os efeitos farmacológicos e/ou tóxicos estejam relacionados apenas a um dos enantiômeros. Além disso, é conhecido o fato de que os enantiômeros podem apresentar perfis farmacocinéticos e farmacodinâmicos diferentes. Neste trabalho foram selecionados fármacos que fazem parte de dois grupos importantes no uso clínico. São fármacos freqüentemente prescritos, como os β-bloqueadores (atenolol, metoprolol, pindolol, betaxolol e nadolol) e os antiinflamatórios não-esteróides (ibuprofeno e flurbiprofeno ). Existem na literatura científica várias citações que descrevem o uso da cromatografia líquida de alta eficiência com fases estacionárias quirais (CLAE-FEQ) em estudos farmacológicos, mas não na análise quantitativa dos enantiômeros em preparações farmacêuticas. É conhecido o fato de que o método CLAE-FEQs oferece vantagens sobre as técnicas clássicas de separação e análise de estereoisômeros, especialmente para os enantiômeros. As separações enantioméricas diretas do atenolol, metoprolol, nadolol e betaxolol foram obtidas utilizando-se FEQ Chiralcel OD®. Os enantiômeros do pindolol foram separados com FEQ α-Burke 2® e os do ibuprofeno e do flurbiprofeno com FEQ do tipo WheIk-O 1®. Neste trabalho são apresentados métodos rápidos e sensíveis para determinação estereoespecífica do atenolol (AT), do metoprolol (MT) e do flurbiprofeno (FLU) em formulações farmacêuticas. A determinação quantitativa dos enantiômeros do atenolol e do metoprolol nos comprimidos foi realizada através de método cromatográfico validado. As condições analíticas foram padronizadas através do sistema de cromatografia líquida de alta eficiência, usando coluna do tipo carbamato de celulose tris-3,5-dimetilfenil, Chiralcel OD®, (250x4.6 mm, 10µm) como FEQ. As amostras foram cromatografadas à temperatura ambiente, com um volume de injeção de 20µ L. A detecção foi efetuada em 276 nm. Para o atenolol a fase móvel foi constituída de hexano:etanol:dietilamina:ácido acético (60:40:0,2:0,2 v/v/v/v), com vazão de 1,0 rnL/min. As curvas padrões do R-AT e do S-AT apresentaram boa linearidade entre 50,0-130,0µg/rnL, com coeficiente de correlação de 0,9991 e 0,9980 respectivamente. As amostras comerciais A, B, C e D referentes a R-AT analisadas, apresentaram coeficiente de variação e percentual de recuperação de 1,15% e 101,06%; 0,74% e 99,25%; 1,05% e 102,57%; 0,84% e 101,57% respectivamente, já o coeficiente de variação e percentual de recuperação do S- AT nas amostras A, B, C e D foram 1,33% e 98,87%; 0,99% e 100,76%; 1,17% e 101,69%; 1,26% e 100,39%, respectivamente. Para o metoprolol a fase móvel foi constituída de hexano:etanol:dietilamina:ácido acético (40:60:0,2:0,2 v/v/v/v), com vazão de 0,8 rnL/min. As curvas padrões do R-MT e do S-MT apresentaram boa linearidade entre 30,0-110,0µg/rnL, com coeficiente de correlação de 0,9988 e 0,9990 respectivamente. A amostra comercial analisada, apresentou coeficiente de variação e percentual de recuperação de 0,86% e 98,62% para R-MT e de 1,40% e 99,39% para S-MT. Um método cromatográfico foi desenvolvido e validado para separação e quantificação enantiomérica do FLU na forma farmacêutica. As condições analíticas foram padronizadas através do sistema de cromatografia líquida de alta eficiência, usando coluna do tipo Whelk-O 1® (250x4,6 mm, 5,0 µm) como FEQ. As amostras foram cromatografadas à temperatura ambiente, com um volume de injeção de 20µ L. A detecção foi efetuada em 246 nm. A fase móvel foi constituída de hexano:etanol:ácido acético (95:05:0,2 v/v/v), com vazão de 0,9 rnL/min. A curva padrão do S-FLU apresentou boa linearidade entre 2,0-18,0 µg/mL, com coeficiente de correlação de 0,9993. A amostra comercial analisada apresentou coeficiente de variação e percentual de recuperação de 0,16% e 100,1% para R_FLU e 0,14% e 100,4% para S-FLU, respectivamente. Os métodos propostos permitam a separação quantitativa dos enantiômeros de AT, MT e FLU contidos nas formas farmacêuticas analisadas, com precisão e exatidão e que podem ser aplicados no controle de qualidade enantiomérico destes fármacos. / The majority of the therapeutic agents, frequently prescribed, are formulated and commercialized as racemic mixture, even so for some of them, it has been demonstrated that the pharmacological and/or toxic effect are confined only to one of the enantiomer. Besides, it is well known that the enantiomers can present different pharmacokinetic and pharmacodynamic profiles. In the present work we selected drugs belonging to two classes of clínical importance. These pharmaceuticals are widely prescribed in clinical practice such as, the beta-blockers (atenolol, metoprolol, pindoloI, betaxolol and nadolol) and the non-steroid anti-inflammatorydrugs (ibuprofen and flurbiprofen). Several references could be found in scientific literature that describes the use of high performance liquid chromatography with chiral stationary phase (HPLC-CSP) in pharmacological studies, seldom in the quantitative determination of enantiomers in pharmaceutical formulations. It is well known that the HPLC-CSP methods offer distinct advantages over classical techniques of isomeric separation and analysis, especially for the enantiomeric separation. The direct enantiomeric separation of atenolol metoprolol nadolol and betaxolol were obtained using CSP Chiralcel OD®.The enantiomers of pindolol were separate utilizing CSP α-Burke 2® and those of ibuprofen and the flurbiprofen with CSP Whelk-O 1®. In this work are presented efficient and sensitive methods for stereospecific determination of atenolol (AT), metoprolol (MT) and flurbiprofen (FLU) in pharmaceutical formulations. The stereoselective determination of atenolol and metoprolol in pharmaceuticals was performed through validated chromatographic method. The validation of liquid chromatographic methods was done utilizing a cellulose tris- 3,5-dimethylphenyl carbamate, Chiralcel OD®, (250x4.6 mm, 10µm)as CSP. The samples were analyzed at room temperature with injection volume of 20µL and UV detection was made at 276nm. In case of atenolol, the mobile phase was constituted of hexane:ethanol:diethylamine:acetic acid (60:40:0.2:0.2 v/v), with a flow rate of 1.0 mL/min. Separate standard curve for R-AT and S-AT showed good linearity over a concentration range from 50-130 µg/mL, with coefficient of correlation of 0.9991 and 0.998, respectively. The coefficient of variation and average recovery for R-AT in the samples A, B, C, and D were 1.15% and 101.06%; 0.74% and 99.25%; 1.05% and 102.57%; 0.84% and 101.57% respectively. The coefficient of variation and average recovery for S-AT in samples A, B, C and D were 1.33% and 98.87%; 0.99% and 100.76%; 1.17% and 101.69%; 1.26% and 100.39%, respectively. In case of metoprolol, the mobile phase was constituted of hexane:ethanol:diethylamine:acetic acid (40:60:0.2:0.2 v/v), with a flow rate of 0.8 m L/min. Separate standard curve for R-MT and S-MT showed good linearity over a concentration range fIom 30-110 µg/mL, with coefficient of correlation of 0.9988 and 0.9990, respectively. The coefficient of variation and average recovery for R-MT in sample analyzed was 0.86% and 98.62% and for S-MT was 1.40% and 99.39%, respectively. A high performance liquid chromatographic method is developed and validated for enantiomeric separation and quantitative determination of FLU in pharmaceutical preparation. A WheIk-O 1® column (250x4.6 mm, 5µm)was used as chiral stationary phase (CSP). The mobile phase was constituted of hexane:ethanol:acetic acid (95:05:0.2 v/v/v), at a flow rate of 0.9 rnL/min and UV detection at 246nm. All experiments were done at ambient temperature. The S-FLU standard curve showed linearity over a concentration range from 2-18µg/mL, (R2 = 0.9993). The coefficient of variation and average recovery of R-FLU were 0.16% and 100.13% and for S-FLU were 0.14% and 100.4%; respectively. The proposed methods permits quantitative separation of AT, MT and FLU enantiomers in pharmaceutical formulations studied with precision and accuracy. The proposed validated methods can be used in the enantiomeric quality controI of referred pharmaceutical drugs.

L'utilisation des matières premières renouvelables dans la synthèse des molécules organiques ou les additifs alimentaires, les pesticides et les polymères a trouvé un intérêt croissant ces dernières années pour des raisons économiques aussi bien qu'écologiques. Au cœur des produits naturels on trouve les terpènes provenant essentiellement des bioressources et représentant une grande famille de molécules naturelles. Ils offrent un potentiel important pour l'accès à des produits à haute valeur ajoutée en utilisant des outils catalytiques sélectifs, tout en respectant le principe d'économie d'atomes. Les réactions cascades basées sur les processus d’(auto)transfert d'hydrogène, générant uniquement de l'eau et des sels non toxiques comme produits secondaires sont particulièrement propres, efficaces et attractives du point de vue de la valorisation durable des terpènes. Dans ce contexte, nous avons développé un nouveau système catalytique et efficace pour l’amination réductrice des alcools allyliques en présence de différentes amines en utilisant des complexes de ruthénium(II). Cette méthode a été appliquée à une large gamme d'alcools allyliques terpéniques tels que le géraniol, le nérol et le phytol, ce qui a permis leur valorisation d’une façon chimiosélective, ne générant que l’eau et le dioxyde de carbone comme sous produits bénins. La fonctionnalisation sp3 C-H des azaterpènes cycliques a été ensuite réalisée avec différents terpènes aldéhydes en présence de complexe de ruthénium(II). Ces transformations ont permis la production d'une petite librairie de N-et C-azaterpenes. Certains de ces terpènes alcaloïdes ont montré une bonne activité antibactérienne. Par la suite, la synthèse de nouveaux complexes chiraux [Ru(Cp’)] (IV) à partir de (+)-nopinone, un monoterpène issu de l’oxydation de β-pinène a été réalisée. L'application de ces complexes dans l'allylation asymétrique de carbonate de cinnamyle par le phénol a montré une bonne régio- et énantiosélectivité. / The use of renewable feedstock in the synthesis of organic molecules such as food additives, pesticides and polymers, has found increasing interest over recent years due to economic as well as ecological reasons. At the heart of natural products are terpenes derived essentially from bioresources and they represent a large family of natural molecules, which have a moderate cost. They offer a significant potential for the access to products with high added value using selective catalytic tools, respecting the principle of atom economy. Catalytic reactions involving hydrogen (auto)transfer, generating only water and non-toxic salts as byproducts are particularly clean, efficient and attractive methods from a sustainable point of view for the valorization of terpenes. In this context we have developed a new and efficient catalytic system for reductive amination of allylic alcohols in the presence of various amines using arene ruthenium(II) complex. The application of this method to a wide range of terpenic allylic alcohols like geraniol, nerol and phytol allowed the formation of new azaterpenes in good yield and high chemoselectivity generating only water and carbon dioxide as benign side products. The sp3 C–H functionalization of N-terpenylated cyclic amines was then performed with various terpenaldehydes without side alkene reduction in the presence of arene ruthenium(II) catalyst. These eco-friendly transformations enable the production of a small library of N- and C- terpenylated amines. Some of these terpene alkaloids showed good antibacterial activities. The synthesis of new chiral [Ru(Cp’)] (IV) complexes featuring a N,O chelate were successful, using a chiral ligand derived from commercially available (+)-nopinone, a monoterpene derived from oxidation of β-pinene. The application of these complexes in the asymmetric allylation of cinnamyl carbonate by phenol gave high regioselectivity and satisfactory enantioselectivity.

Lors de ces travaux de thèse, nous nous sommes intéressés au développement de deux voies différentes de cycloaddition dipolaire-1,3 (CD-1,3) asymétrique pour accéder à des acides aminés disubstitués polyfonctionnels nouveaux de façon stéréochimiquement contrôlée.Dans la première partie, nous avons réalisé l’étude de la cycloaddition dipolaire-1,3 diastéréosélective entre différentes nitrones fonctionnelles et différents éthers vinyliques chiraux. La CD-1,3 de la cétonitrone aspartique et de l’éther vinylique du (R) ou (S) stéricol s'opère avec un double contrôle diastéréochimique élevé. Ce contrôle est possible en raison de la stabilité de la nitrone sous une forme (E) qui favorise l’approche exo, facialement contrôlée par le dipolarophile. La N-déprotection chimiosélective de l'adduit fournit une isoxazolidine sous une forme diastéréo- et énantiomériquement pure qui peut être transformée en dérivé d’acide aminé après N-acylation et coupure de la liaison N-O selon un processus dismutatif.Dans la deuxième partie, nous avons réalisé une étude approfondie de la cycloaddition dipolaire-1,3 organocatalysée entre différentes cétonitrones dérivées d’acides aminés vis-à-vis de dipolarophiles pauvres en électrons de type énal ou ynal. Avec le (E)-crotonalldéhyde, de hautes diastéréo- et énantiosélectivités sont obtenues en présence du catalyseur de MacMillan. Cette réaction organocatalysée a été étendue à une variété de d'α-carboxy cétonitrones différemment substituées, ainsi qu'à différents énals β-substitués par un groupement alkyle moyennant une modification de la nature du co-acide. En revanche, les ynals ne montrent aucune réactivité vis à vis des cétonitrones en conditions organocatalytiques. Notre étude a été complétée par l’accès des dérivés d’amino-acides polyhydroxylés par ouverture des adduits obtenus par la voie énantiosélective en utilisant les énals comme dipolarophiles. Cette étude préliminaire permet d’envisager d’accéder à des analogues de la myriocine. / During this thesis, we were interested to develop two different ways of 1,3 dipolar cycloaddition to reach enantiopure disubstituted polyfunctionnal amino acids.We have described in a first part the diastereoselective 1,3-dipolar cycloaddition between an aspartic nitrone and chiral vinyl ethers. The aspartic ketonitrone and vinyl ether of (R) or (S) stericol led to high diastreocontrols. This control is due to the stability of the nitrone under (E) geometry which favors the exo approach, facially controlled by the dipolarophile. The chemoselective N-deprotection of this adduct leads to a diastereo- and enantiomerically pure isoxazolidine which affords the target DAA after N-acylation and N-O ring opening by a dismutative pathway. In a second part, we describe the synthesis of isoxazolidines obtained by organocatalytic enantioselective 1,3-dipolar cycloaddition between an alanine-derived nitrone and an enal or an ynal as the dipolarophile. With enals β-substituted by alkyl groups, good diastereoselectivities and ees were obtained in the presence of the MacMillan catalyst. These organocatalyzed conditions can be applied to a range of carboxy ketonitrones, and to different enals, provided an appropriate choice of the co-acid. Ynals show no reactivity under these organocatalytic conditions, although they lead regioselectively to polyfunctional quaternary isoxazolines under thermal conditions.Our study was achieved by the access of polyhydroxylated amino acids derived from opening adducts obtained by the enantioselective route using enals as dipolarophiles. This study allows to envisage the enantioselective synthesis of analogs of myriocin.

O presente trabalho consiste no estudo do papel da simetrial quiral no potencial nucleon-nucleon devido à troca de dois píons. Para o calculo do potencial foi levada em consideração a troca de dois píons não-correlacionados, envolvendo contribuicões com até um loop. A simetria quiral é introduzida no potencial através da sua realização não-linear, utilizando-se a Lagrangiana fenomenológica quiral de Weinberg. Os diagramas de Feynman construidos com os vértices dessa Lagragiana são ordenadas segundo potencias crescentes do momento, e calculados covariantemente. Os diagramas divergentes são regularizados covariantemente. Partindo do formalismo da equação de Bethe-Salpeter, relacionamos, em uma primeira etapa, as amplitudes de transição covariantes com o potencial, através do princípio da unitariedade elástica. O potencial, covariante e relativístico, e obtido no espaço dos momentos e é não-local e dependente da energia. Em uma segunda etapa, efetuamos a redução não-relativística do potencial e sua transformada de Fourier, obtendo um potencial local e independente da energia, que pode ser usado na equação de Schrödinger. O potencial obtido possui contribuições central, spin-orbita, tensorial e spin-spin. A parte dependente de isospin e semelhante à do potencial de Lemon e Partovi, sendo que as maiores modificações aparecem na parte isoescalar, principalmente no canal central, onde um substancial aumento de atração na região de 1.2 a 2.0 fm é observada. A fim de compararmos nosso potencial com a literatura, fixamos o valor de A como sendo 50 GeV, fazendo com que os efeitos do parâmetro de corte fiquem restritos à região r 0.5 fm. Os resultados obtidos foram comparados com o potencial fenomenológico de Argonne e revelaram razoável compatibilidade na maioria dos canais. Entretanto, existem discrepâncias importantes, possivelmente devidas a efeitos não estudados neste trabalho, tais como os devidos às ressonâncias A e p. / This work is devoted to the study of the role of chiral symmetry in the two pion exchange nucleon-nucleon potential. We consider only non-correlated two pion exchanges due to one loop contributions. Chiral symmetry is implemented in the potential through its non-linear realization, given by Weinberg\'s phenomenological Lagrangian. Feynman diagrams derived from this Lagrangian are arranged according to increasing powers of the momentum, and calculated covariantly. Divergent diagrams are regularizated covariantly. Starting from the Bethe-Salpeter equation, we relate the covariant transition amplitudes with the potential, using the elastic unitarity principle. The potential in momentum space is covariant, relativistic, non-local and energy dependent. Next, we perform its nonrelativistic reduction and Fourier transform, obtaining a potential which is local, energy independent and that can be used in the Schrödinger equation. This potential has central, spin-orbit, tensor and spin-spin components. The isospin dependent part is similar to that of the Lomon and Partovi potential, but important differences appear in the isoscalar part, especially in the central channel, where a substantial increase of attraction in the 1.2 to 2.0 fm region is observed. In order to compare our potential with the literature, we fixed the cutoff parameter at A = 50 GeV, restricting its effects to the r 0.5 fm region. Our results are compared with Argonne phenomenological potential, and a reasonable compatibility in most of the channels is found. However, there are also important discrepancies which may be due to effects not considered in this work, such as those due to A and the p ressonances.

A maioria dos agentes terapêuticos, freqüentemente prescritos, são formulados e comercializados sob a forma racêmica, embora para alguns deles, já tenha sido demonstrado que os efeitos farmacológicos e/ou tóxicos estejam relacionados apenas a um dos enantiômeros. Além disso, é conhecido o fato de que os enantiômeros podem apresentar perfis farmacocinéticos e farmacodinâmicos diferentes. Neste trabalho foram selecionados fármacos que fazem parte de dois grupos importantes no uso clínico. São fármacos freqüentemente prescritos, como os β-bloqueadores (atenolol, metoprolol, pindolol, betaxolol e nadolol) e os antiinflamatórios não-esteróides (ibuprofeno e flurbiprofeno ). Existem na literatura científica várias citações que descrevem o uso da cromatografia líquida de alta eficiência com fases estacionárias quirais (CLAE-FEQ) em estudos farmacológicos, mas não na análise quantitativa dos enantiômeros em preparações farmacêuticas. É conhecido o fato de que o método CLAE-FEQs oferece vantagens sobre as técnicas clássicas de separação e análise de estereoisômeros, especialmente para os enantiômeros. As separações enantioméricas diretas do atenolol, metoprolol, nadolol e betaxolol foram obtidas utilizando-se FEQ Chiralcel OD®. Os enantiômeros do pindolol foram separados com FEQ α-Burke 2® e os do ibuprofeno e do flurbiprofeno com FEQ do tipo WheIk-O 1®. Neste trabalho são apresentados métodos rápidos e sensíveis para determinação estereoespecífica do atenolol (AT), do metoprolol (MT) e do flurbiprofeno (FLU) em formulações farmacêuticas. A determinação quantitativa dos enantiômeros do atenolol e do metoprolol nos comprimidos foi realizada através de método cromatográfico validado. As condições analíticas foram padronizadas através do sistema de cromatografia líquida de alta eficiência, usando coluna do tipo carbamato de celulose tris-3,5-dimetilfenil, Chiralcel OD®, (250x4.6 mm, 10µm) como FEQ. As amostras foram cromatografadas à temperatura ambiente, com um volume de injeção de 20µ L. A detecção foi efetuada em 276 nm. Para o atenolol a fase móvel foi constituída de hexano:etanol:dietilamina:ácido acético (60:40:0,2:0,2 v/v/v/v), com vazão de 1,0 rnL/min. As curvas padrões do R-AT e do S-AT apresentaram boa linearidade entre 50,0-130,0µg/rnL, com coeficiente de correlação de 0,9991 e 0,9980 respectivamente. As amostras comerciais A, B, C e D referentes a R-AT analisadas, apresentaram coeficiente de variação e percentual de recuperação de 1,15% e 101,06%; 0,74% e 99,25%; 1,05% e 102,57%; 0,84% e 101,57% respectivamente, já o coeficiente de variação e percentual de recuperação do S- AT nas amostras A, B, C e D foram 1,33% e 98,87%; 0,99% e 100,76%; 1,17% e 101,69%; 1,26% e 100,39%, respectivamente. Para o metoprolol a fase móvel foi constituída de hexano:etanol:dietilamina:ácido acético (40:60:0,2:0,2 v/v/v/v), com vazão de 0,8 rnL/min. As curvas padrões do R-MT e do S-MT apresentaram boa linearidade entre 30,0-110,0µg/rnL, com coeficiente de correlação de 0,9988 e 0,9990 respectivamente. A amostra comercial analisada, apresentou coeficiente de variação e percentual de recuperação de 0,86% e 98,62% para R-MT e de 1,40% e 99,39% para S-MT. Um método cromatográfico foi desenvolvido e validado para separação e quantificação enantiomérica do FLU na forma farmacêutica. As condições analíticas foram padronizadas através do sistema de cromatografia líquida de alta eficiência, usando coluna do tipo Whelk-O 1® (250x4,6 mm, 5,0 µm) como FEQ. As amostras foram cromatografadas à temperatura ambiente, com um volume de injeção de 20µ L. A detecção foi efetuada em 246 nm. A fase móvel foi constituída de hexano:etanol:ácido acético (95:05:0,2 v/v/v), com vazão de 0,9 rnL/min. A curva padrão do S-FLU apresentou boa linearidade entre 2,0-18,0 µg/mL, com coeficiente de correlação de 0,9993. A amostra comercial analisada apresentou coeficiente de variação e percentual de recuperação de 0,16% e 100,1% para R_FLU e 0,14% e 100,4% para S-FLU, respectivamente. Os métodos propostos permitam a separação quantitativa dos enantiômeros de AT, MT e FLU contidos nas formas farmacêuticas analisadas, com precisão e exatidão e que podem ser aplicados no controle de qualidade enantiomérico destes fármacos. / The majority of the therapeutic agents, frequently prescribed, are formulated and commercialized as racemic mixture, even so for some of them, it has been demonstrated that the pharmacological and/or toxic effect are confined only to one of the enantiomer. Besides, it is well known that the enantiomers can present different pharmacokinetic and pharmacodynamic profiles. In the present work we selected drugs belonging to two classes of clínical importance. These pharmaceuticals are widely prescribed in clinical practice such as, the beta-blockers (atenolol, metoprolol, pindoloI, betaxolol and nadolol) and the non-steroid anti-inflammatorydrugs (ibuprofen and flurbiprofen). Several references could be found in scientific literature that describes the use of high performance liquid chromatography with chiral stationary phase (HPLC-CSP) in pharmacological studies, seldom in the quantitative determination of enantiomers in pharmaceutical formulations. It is well known that the HPLC-CSP methods offer distinct advantages over classical techniques of isomeric separation and analysis, especially for the enantiomeric separation. The direct enantiomeric separation of atenolol metoprolol nadolol and betaxolol were obtained using CSP Chiralcel OD®.The enantiomers of pindolol were separate utilizing CSP α-Burke 2® and those of ibuprofen and the flurbiprofen with CSP Whelk-O 1®. In this work are presented efficient and sensitive methods for stereospecific determination of atenolol (AT), metoprolol (MT) and flurbiprofen (FLU) in pharmaceutical formulations. The stereoselective determination of atenolol and metoprolol in pharmaceuticals was performed through validated chromatographic method. The validation of liquid chromatographic methods was done utilizing a cellulose tris- 3,5-dimethylphenyl carbamate, Chiralcel OD®, (250x4.6 mm, 10µm)as CSP. The samples were analyzed at room temperature with injection volume of 20µL and UV detection was made at 276nm. In case of atenolol, the mobile phase was constituted of hexane:ethanol:diethylamine:acetic acid (60:40:0.2:0.2 v/v), with a flow rate of 1.0 mL/min. Separate standard curve for R-AT and S-AT showed good linearity over a concentration range from 50-130 µg/mL, with coefficient of correlation of 0.9991 and 0.998, respectively. The coefficient of variation and average recovery for R-AT in the samples A, B, C, and D were 1.15% and 101.06%; 0.74% and 99.25%; 1.05% and 102.57%; 0.84% and 101.57% respectively. The coefficient of variation and average recovery for S-AT in samples A, B, C and D were 1.33% and 98.87%; 0.99% and 100.76%; 1.17% and 101.69%; 1.26% and 100.39%, respectively. In case of metoprolol, the mobile phase was constituted of hexane:ethanol:diethylamine:acetic acid (40:60:0.2:0.2 v/v), with a flow rate of 0.8 m L/min. Separate standard curve for R-MT and S-MT showed good linearity over a concentration range fIom 30-110 µg/mL, with coefficient of correlation of 0.9988 and 0.9990, respectively. The coefficient of variation and average recovery for R-MT in sample analyzed was 0.86% and 98.62% and for S-MT was 1.40% and 99.39%, respectively. A high performance liquid chromatographic method is developed and validated for enantiomeric separation and quantitative determination of FLU in pharmaceutical preparation. A WheIk-O 1® column (250x4.6 mm, 5µm)was used as chiral stationary phase (CSP). The mobile phase was constituted of hexane:ethanol:acetic acid (95:05:0.2 v/v/v), at a flow rate of 0.9 rnL/min and UV detection at 246nm. All experiments were done at ambient temperature. The S-FLU standard curve showed linearity over a concentration range from 2-18µg/mL, (R2 = 0.9993). The coefficient of variation and average recovery of R-FLU were 0.16% and 100.13% and for S-FLU were 0.14% and 100.4%; respectively. The proposed methods permits quantitative separation of AT, MT and FLU enantiomers in pharmaceutical formulations studied with precision and accuracy. The proposed validated methods can be used in the enantiomeric quality controI of referred pharmaceutical drugs.

O objetivo deste texto é apresentar uma classe de módulos para álgebra de Lie de campos vetoriais em um toro N -dimensional, Vect( T N ). O caso N = 1 nos dá a famosa álgebra de Witt (sua extensão central é álgebra de Virasoro). A álgebra Vect( T N ) apresenta um classe de módulos parametrizada por módulos de dimensão finita da álgebra gl N . Nosso objeto central de estudo são módulos induzidos dos módulos tensoriais de Vect( T N ) para Vect( T N +1 ). Estes módulos apresentam um quociente irredutível com espaços de peso de dimensão finita. A álgebra Vect( T N ) apresenta como subálgebra sl N +1 . Com a restrição da ação de Vect( T N ) a esta subálgebra obtemos o carácter deste quociente. Para obter um critério de irredutibilidade e construir sua realização de campo livre, consideramos uma classe de módulos para 1 (T N +1 )/ d 0 (T N +1 ) o Vect (T N ) , construída a partir de álgebras de vértice. Quando restritos a Vect (T N ) estes módulos continuam irredutíveis a menos que apareçam no chiral de De Rham. / The goal of this text is to present a class of modules for the Lie algebra of vector fields in a N -dimensional torus, Vect (T N ) . The case N = 1 give us the famous Witt algebra (its central extension is the Virasoro algebra). The algebra Vect( T N ) has a class of modules parametrized by finite dimensional gl N -modules. The central object of our study are modules induced from tensor modules for Vect( T N ) to Vect( T N +1 ). Those modules have an irreducible quotient such that every weight space has finite dimension. The algebra Vect( T N ) has as subalgebra sl N +1 . Restricting the action of Vect( T N ) to this subálgebra we have the character of this quotient. To obtain a irreducible critreria and construct a free field reazilation, we consider a class of modules for 1 (T N +1 )/ d 0 (T N +1 ) o Vect (T N ) , constructed from vertex algebras. When restricted to Vect (T N ) thesse modules remain irreducible, unless they belongs to the chiral De Rham complex.

This thesis deals with the design and syntheses of chiral,enantiopure pyridinecontaining ligands and their applicationsin asymmetric catalyis. Chiral pyridyl pyrrolidine ligands and pyridyl oxazolineligands were synthesized and employed in thepalladium-catalysed allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate. Theinfluence of the steric properties of the ligands wereinvestigated. Ditopic ligands, containing crown ether units as structuralelements, were synthesized and some of the ligands were used asligands in the palladiumcatalysed allylic alkylation of1,3-diphenyl-2-propenyl acetate with dimethyl malonate. A smallrate enhancement was observed, compared with analogous ligandslacking the crown ether unit, when these ditopic ligands wereused in dilute systems. A modular approach was used to synthesize chiralenantiomerically pure pyridyl alcohols and C2-symmetric2,2’-bipyridines, with the chirality originating from thechiral pool. Electronic and steric properties of the compoundswere varied and they were used as ligands in theenantioselective addition of diethylzinc to benzaldehyde. Thesense of asymmetric induction was found to be determined by theabsolute configuration of the carbinol carbon atom. Theelectronic properties of the ligands had a minor influence onthe levels of enantioselectivity induced by the ligands. Chiral pyridyl phosphinite ligands and pyridyl phosphiteligands were synthesized from the pyridyl alcohols andevaluated as ligands in palladiumcatalysed allylic alkylations.With the phosphinite ligands, the sense of chiral induction wasfound to be determined by the absolute configuration of theformer carbinol carbon atom. A kinetic resolution of theracemic starting material was observed with one of thephosphite ligands. Moderate enantioselectivities wereachieved. <b>Kewords:</b>asymmetric catalysis, chiral ligand, chiralpool, oxazoline, crownether, ditopic receptor, bipyridine,pyridyl alcohol, modular approach, P,Nligand, diethylzinc,allylic alkylation.

The development and application of unnatural amino alcohols,prepared via hetero-Diels-Alder reactions,in synthesis and catalysis is described.The studies are concerned with the [i]scope of the hetero-Diels-Alder reaction and preparation of important intermediates in the synthesis of antiviral agents,[ii ]application of amino alcohols in the ruthenium transfer hydrogenation of ketones,[iii ]use of similar precursors in the in situ generation of oxazaborolidines for reduction of ketones,and [iv] development and application of new chiral auxiliaries for dialkylzinc additions to activated imines, respectively. [i ]The use of chiral exo -2-azanorbornyl-3-carboxylates in the preparation of enantiopure cyclopentyl-amines is described.At the same time the scope of the hetero-Diels-Alder reaction,used in their preparation,is extended by manipulations of the dienophiles. [ii ]Application of 2-azanorbornyl-3-methanol as a very efficient ligand in the ruthenium-catalysed asymmetric transfer hydrogenation of aromatic ketones.This ligand (2 mol%)in combination with [RuCl2(p -cymene)]2 (0.25 mol%)gave rise to a very fast reaction (1.5 h)leading to the reduced products in excellent yields and enantioselectivities (up to 97%ee ). [iii ]Preparation of α-disubstituded 2-azanorbornyl-3-methanols,in situ generation of the corresponding oxazaborolidines,and use of the latter in reduction of aromatic ketones.Concentration, solvent,and temperature effects on the reaction outcome are described. [iv ]Development of two generations of chiral auxiliaries for the addition of dialkylzinc reagents to N - (diphenylphosphinoyl)imines.Studies using density functional computations allowed the rationalisation of the reaction mechanism and the development of a second generation of ligands that improved the previously reported results.Up to 98%ee could be obtained with these new ligands. Solvent effects on the outcome of the reaction and extension of the work to a larger variety of N - (diphenylphosphinoyl)imines are described.