Cette thèse a pour but de développer de nouveaux procédés catalytiques en combinant de réactifs de l’iode hypervalent avec des complexes de rhodium(II).Le premier chapitre concerne l’observation de l’époxyde comme produit secondaire inatendu dans les conditions de transfert de nitrène catalytique, et le développement d’une nouvelle méthode de préparation d’époxydes qui combine un réactif de l’iode hypervalent(III) et un complexe de dirhodium(II). Le second chapitre vise le développement d’une méthode d’amination C(sp³)–H benzylique intermoléculaire énantiosélective,en utilisant un nouveau complexe de rhodium chiral et un nouveau sulfamate benzylique et l’application de cette méthode à grande échelle et sur des produits complexes.Le dernier chapitre du manuscrit décrit une réaction d’amination régiosélective de liaisons C(sp³)–H non activées d’alcanes par catalyse au rhodium (II), en utilisant une quantité stoechiométrique d’alcanes comme substrats. / This thesis describes the development of new catalytic processes by combining hypervalent iodine reagents with rhodium (II) complexes.The first chapter concerns the observation of the epoxide as a unexpected product under catalytic nitrene transfer conditions, and the development of a new method to promote the epoxidation of alkenes by combining a reagent of hypervalent iodine (III) and a complex of dirhodium (II).The second chapter is centered on the development of a general method forasymmetric intermolecular benzylic C(sp³)–H amination by combining a chiral rhodium (II) catalyst and a benzyl sulfamate, and the application of this method on large scale.The third part of this work show the development of a regioselective C(sp³)–H amination of unactivated alkane by rhodium (II) catalysis, using a stoichiometric amount of alkane as the substrate.

The first step of the synthesis of the hydrocarbon-based chiral surfactant (2) involved the methylation of (S)-leucinol to give (2S)-N-hexadecyl-N,N-dimethyl-(1-hydroxy-4-methyl-1-pentyl)-2-ammonium bromide (2.92g, 67%). The chiral surfactant was synthesized by reacting (2S)-N,N-dimethyl-2-amino-4-methyl-1-pentanol (1) with bromohexadecane (2.06g, 71%). The functionalized styrene for the polymer supported chiral catalyst (6) was synthesized by reacting (1) with 4-vinylbenzyl chloride. The polymerization was carried out with 10% of the functionalized monomer (5) (1.26g, 70.2%), 5% cross-linking agent divinylbenzene, and 85% of styrene with AIBN as the initiator. The structure of each of the products was confirmed by using FTIR and NMR spectroscopy. The activity of the hydrocarbon surfactant and polymeric catalyst were examined by using them as additives in a standard reduction of 2-pentanone with sodium borohydride to yield (R)- and (S)-2-pentanol (3) (4gm, 25%). The resulting alcohol was then esterified with (2S)-methylbutyric acid with iodine as the catalyst and the ester was characterized.

This diploma thesis deals with the use of organocatalysis in an asymmetric allylic substitution reaction of Morita-Baylis-Hillman carbonates by aniline derivatives leading to enantiomerically enriched allylic amines. The first part of the thesis is focused on optimizing the reaction conditions in the organocatalytic reaction with respect to the yields and enantiomeric excesses of the products. In the second part of the thesis prepared enantiomerically enriched allylic amines are used in the cyclization step to give β-lactame cycles that serve as the key intermediates in the total synthesis of Ezetimib as is demonstrated in the final part of the diploma thesis.

This thesis deals with the preparation of enantiomerically and diastereomerically pure spirocompounds using asymmetric organocatalysis. The first part is focused on the enantioselective synthesis of spirocompounds by organocatalytic reaction of α,β-unsaturated aldehydes with sulfur heterocyclic compounds catalysed with secondary amines. It is a domino Michael/Michael/aldol reaction using iminium and enamine activation. The second part is focused on the subsequent transformation of the prepared spirocompounds.

The focus of these studies has been toward the development of new synthetic methods and procedures for the synthesis of novel compounds with unique biological properties. This research has led to the development of two new synthetic strategies for the construction of two novel amphibian alkaloids. In addition, the efforts have led to the large-scale process for the preparation of a novel analgesic compound. The regioselective ring opening of lactones (δ-valerolactone and γ-butyrolactone) with aryllithium reagents is reported for the construction of a series of δ-hydroxyarylketones and γ-hydroxyarylketones. Both the R and S enantiomers of the amphibian alkaloid noranabasamine were prepared in >30% overall yield with 80% ee and 86% ee, respectively. An enantioselective iridium-catalyzed N-heterocyclization reaction with either (R)- or (S)-1-phenylethylamine and 1-(5-methoxypyridin-3-yl)-1, 5-pentanediol was employed to generate the 2-(pyridin-3-yl)-piperidine ring system in 69-72% yield. A cis-2, 5-disubstitued pyrrolidine building block derived from (-)-Cocaine•HCl was prepared. We utilized this compound as a chiral building block for the formal synthesis of (+)-gephyrotoxin. Using this pyrrolidine building block, Kishi's intermediate was obtained enantiospecifically in 15 steps and 9.4% overall yield. A large-scale process for the preparation of the analgesic compounds SCP-123 and its sodium salt, SCP-123ss•monohydrate has been developed. The process for the preparation of SCP-123 required three synthetic steps with no chromatography, while the process for the preparation of SCP-123ss required four synthetic steps and no chromatography. The overall yields for both SCP-123 and SCP-123ss were 47% and 46%, respectively, and both compounds were obtained in exceptionally high purity (>99%).

Les molécules chirales représentent environ 60% des médicaments présents sur le marché pharmaceutique et plus de 80% des médicaments en développement avec plus de 150 milliards de dollars de chiffre d’affaire pour l’année 2002. Les intermédiaires chiraux sont fortement demandés dans l’industrie pharmaceutique atteignant 15 milliards de dollars de chiffre d’affaire en 2009. D’autres domaines en sont demandeurs avec une répartition d’environ 15% dans l’agrochimie et 5% pour la parfumerie. L’obtention de composés d’intérêt pharmaceutique de façon asymétrique est un réel défi et une réelle nécessité. Ces molécules possèdent une architecture spatiale qui entraîne des interactions spécifiques et des affinités particulières avec les enzymes ou des récepteurs biologiques chiraux. L’utilisation de catalyseurs pour accéder à des composés organiques chiraux et plus précisément l’oxydation d’alcanes prochiraux ou d’oléfines constitue un domaine en essor ces dernières décennies. Pour parvenir à synthétiser des molécules chirales, l’industrie pharmaceutique s’est tournée vers l’utilisation de biocatalyseurs en partie pour réaliser différentes réactions stéréo-contrôlées avec la nécessité de séparer les mélanges racémiques par résolution enzymatique. Cependant, les biocatalyseurs présentent un inconvénient majeur qui est généralement le faible rendement en composé chiral recherché et nécessite un savoir faire pour la manipulation de ces enzymes. Les métalloporphyrines sont des catalyseurs comportant un macrocycle tétrapyrrolique et différentes fonctionnalisations en positions méso. Ces molécules ont fait l’objet de nombreuses études qui ont conduit à la synthèse de métalloporphyrines chirales très complexes. Malheureusement, leur synthèse est souvent longue avec de faibles rendements et leur application à un nombre limité de substrats ne permet pas leur généralisation. Ce travail de thèse, développé pour la première fois au laboratoire, s’inscrit dans le cadre d'un contrat CIFRE, dans le but de parvenir à la synthèse de porphyrines chirales facilement accessibles, applicables dans des réactions d’oxydation énantiosélectives efficacement (stabilité). Le premier objectif visé est la synthèse de porphyrines chirales dont la structure ciblée comporte des groupements hétérocycliques azotés chiraux en position méso, reliés par une liaison carbone-hétéroatome (C-N). Nous avons pu atteindre 4 séries de porphyrines qui ont été évaluées dans des réactions d’oxydation énantiosélectives (époxydation, hydroxylation). Le deuxième objectif visé est d’exploiter les propriétés électroniques particulières des porphyrines permettant l’application des porphyrines en tant que photosensibilisant après photoactivation en thérapie anticancéreuse. L’étude des paramètres physiques est primordiale pour déterminer la longueur d’onde d’activation et le rendement quantique. Nous avons souhaité utiliser nos porphyrines et leurs précurseurs en tant qu’agents antiparasitaires, sans photoactivation dans un premier temps, conduisant à la découverte d’activités très intéressantes sur certaines espèce de leishmanies. Enfin, leur application sur P. falciparum nous a permis d’isoler une molécule avec une activité très intéressante. Dans les deux cas, des manipulations avec photoactivation sont en cours. / Chiral molecules represent about 60% of drugs in pharmaceutical market and over 80% of drugs in development with more than 150 billion dollars in 2002. Chiral intermediates are in high demand in the pharmaceutical industry producing a turnover of 15 billion dollars in 2009. Other areas are seekers of chiral molecules with a distribution of about 15% in agrochemicals and 5% for the perfume. Asymmetrically production of compounds of pharmaceutical interest is a real challenge. These molecules have a spatial architecture that results in specific interactions and affinity with the enzymes or biological chiral receptors. The use of catalysts to synthesis chiral organic compounds, and more specifically to oxidize alkenes and alkanes having prochiral positions, is a very important area extensively studied in recent decades with few positive results. To achieve the synthesis of chiral molecules, the pharmaceutical industry has turned to the use of biocatalysts, in part, to perform various stereo-controlled reactions with systematically followed by separation of the different isomers by different methodes. However, biocatalysts have a major disadvantage relative to low yields of chiral compound and requires expertise for handling these enzymes. Metalloporphyrins are tetrapyrrolic macrocyle substituted in meso position with various functional groups and incorporating metals (Fe, Mn, Co, Ru). These molecules have been extensively studied and led to the synthesis of many complex chiral metalloporphyrins. Unfortunately, their synthesis is often long with low yields and their application to a limited number of substrates is a major drawback. The first objective of this work is the synthesis of original chiral porphyrins. The targeted structure contains chiral heterocyclic nitrogen groups in two meso positions, connected by a carbon-heteoatom bond (C-N). We were able to reach 4 porphyrins-series that have been evaluated as catalyst in oxidation reactions (epoxidation, hydroxylation). The second objective is to take advantage of specific electronic properties of porphyrins for applications as photosensitizer after photoactivation for cancer by photodynamic therapy. The use of this therapy increased during last decades but poor specificity and solubility of the different porphyrins used in clinic against many cancers prompt us to investigate this area. The study of the physical parameters is essential to determine wavelength activation and quantum yield of a photosensitizer. We wanted to use our porphyrins and their precursors as antiparasitic agents, with and without photoactivation against L. donovani, L. major, T. brucei brucei. Malaria is caused by a protist of the genus of Plasmodium. This parasite has an iron deficiency on one hand and cannot biosynthesize certain amino acids. Strucure analogy of porphyrins with heme led us to evaluate antimalarial activity of several porphyrins against P. falciparum.

Ce travail porte sur l’étude de la réaction de Povarov, une réaction de type aza-Diels-Alder à demande inverse d’électrons entre un diène de type 2-aza-diène (généralement une imine dérivée d’une aniline) et un diénophile tel qu’une oléfine riche en électrons, aboutissant ainsi à la formation de tétrahydroquinoléines. Nous sommes parvenus à réaliser cette réaction dans sa version multicomposants, c’est-à-dire en formant in situ l’imine à partir de l’aldéhyde et de l’aniline correspondants. De plus, cette réaction multicomposants a pu être effectuée de manière énantiosélective, en utilisant comme catalyseur des organocatalyseurs de type acides phosphoriques chiraux, et en choisissant judicieusement comme diénophile des ène-carbamates, qui possèdent une liaison N-H capable d’interagir avec l’acide phosphorique. Cette méthodologie a ainsi permis la synthèse de 4-amino-tétrahydroquinoléines avec une diastéréosélectivité totale, de bons rendements, et d’excellents excès énantiomériques. L’utilisation de diénophiles de type ène-thiourées a permis selon la même stratégie d’accéder à des composés hexahydropyrroloquinoléines avec des sélectivités similaires.Nous nous sommes également intéressés au mécanisme de cette réaction de Povarov, qui s’est révélé se dérouler en deux étapes distinctes, l’intermédiaire immonium pouvant être piégé, soit de manière intermoléculaire par l’éthanol, conduisant après réduction à des 1,3-diamines chirales, soit de manière intramoléculaire dans le cas particulier de l’utilisation du phénylacétaldéhyde, conduisant alors à des 1,3-diaminotétralines. / This work deals with the Povarov reaction, an inverse electron-demanding Diels-Alder reaction between 2-aza-dienes (generally an N-aryl-imine) and a dienophile such as an electron-rich olefin, leading to the formation of tetrahydroquinolines. We were able to perform this reaction in a multicomponent way, ie by the in situ formation of the imine from the corresponding aldehyde and aniline. Moreover, this multicomponent reaction was also énantiosélective, by using chiral phosphoric acids as catalysts, and by choosing enecarbamates as diénophiles, which could interact with the catalyst thanks to their N-H bond. This methodology allowed to synthesize 4-amino-tetrahydroquinolines in good yields with total diastereoselectivities and excellent enantioselectivities. The use of ene-thioureas as dienophiles also allowed to synthesize hexahydropyrroloquinolines with the same selectivities, following the same method.We also studied the mechanism of this Povarov reaction. We proved that it is a stepwise mechanism, by trapping the iminium intermediate, either via an intermolecular reaction with ethanol leading to chiral 1,3-diamines, or via an intramolecular reaction in the particular case of phenylacetaldehyde, then leading to 1,3-diaminotetralins.

O miclobutanil é fungicida quiral da família dos triazóis, comercializado como mistura racêmica. Apesar dos enantiômeros apresentarem as mesmas propriedades físico-químicas, estes podem diferir em termos de atividade, metabolismo, excreção e toxicidade. No presente trabalho, foram realizados estudos in vitro enantiosseletivos de metabolismo empregando microssomas hepáticos de humanos cujos objetivos foram determinar os parâmetros cinéticos das enzimas do citocromo P450 (CYP450) após metabolismo do miclobutanil (na forma de racemato e enantiômeros isolados), determinar quais isoformas do CYP450 são responsáveis pelo metabolismo do praguicida e também a capacidade deste praguicida em inibir as principais enzimas do CYP450. Os estudos foram realizados empregando a mistura racêmica e também os enantiômeros isolados. Para tanto, foi desenvolvido e validado um método para análise enantiosseletiva do miclobutanil em meio microssomal empregando a cromatografia líquida de alta eficiência acoplada a espectrometria de massas. A separação dos enantiômeros foi realizada na coluna Chiralpak AD® empregando metanol (100%) como fase móvel. Após a validação do método, os parâmetros cinéticos foram determinados, com valores de Vmáx, Km e CLint de 66,06 + 4,59 nmol min-1 mg-1, 3,61 + 0,88 ?mol L-1 e 18,30 mL min-1 mg-1 respectivamente, quando o substrato foi o racemato e de 305,50 + 18,39 nmol min-1 mg-1, 6,85 + 1,29 ?mol L-1 e 44,60 mL min-1 mg-1 respectivamente, quando o (+)-miclobutanil foi empregado como substrato. O (?)-miclobutanil não foi metabolizado pelas enzimas presentes nos microssomas hepáticos de humanos. As isoformas responsáveis pelo metabolismo do miclobutanil foram a CYP2C19 e a CYP3A4. Os estudos in vitro de inibição mostraram que o miclobutanil é um inibidor moderado das enzimas CYP2D6 e CYP2C9 um inibidor forte das enzimas CYP3A4/5 e CYP2C19. / Myclobutanil is a chiral triazole fungicide, sold as a racemic mixture. Although the enantiomers have the same physico-chemical properties, they may exhibit different bioactivity, metabolism, excretion and toxicity. In the present work, in vitro enantioselective metabolism studies were carried out by using human liver microsomes, aiming to determine the kinetic parameters of cytochrome P450 (CYP450) enzymes after myclobutanil metabolism and the main CYP450 isoforms involved in the metabolism. In addition, the myclobutanil inhibition capacity over the main CYP450 enzymes was evaluated. The studies were carried out with rac-myclobutanil as well as with the isolated enantiomers. To accomplish that, an enantioselective method for myclobutanil analysis was developed and validated by using high performance liquid chromatography coupled with mass spectrometry. The separation of enantiomers was realized on a Chiralpak AD® column and methanol (100%) was used as mobile phase. The enzymatic kinetics, Vmáx, Km and CLint, were: 66.06 + 4.59 nmol min-1 mg-1, 3.61 + 0.88 ?mol L-1 and 18.30 mL min-1 mg-1, respectively, for rac-myclobutanil and 305.50 + 18.39 nmol min-1 mg-1, 6.85 + 1.29 ?mol L-1 and 44.60 mL min-1 mg-1, respectively, for the (+)-myclobutanil. The (?)-myclobutanil was not metabolized by CYP450 enzymes. The isoforms involved in myclobutanil metabolism were CYP2C19 and CYP3A4. In vitro inhibition studies showed that myclobutanil is a medium inhibitor of CYP2D6 and CYP2C9 enzymes and a strong inhibitor of CYP3A4/A5 and CYP2C19 enzymes.

Grâce à leurs fortes acidités, les milieux superacides permettent d’accéder par polyprotonation à des intermédiaires superélectrophiles polycationiques, capables d’être piégés par des nucléophiles très faibles. Ces espèces très réactives ont permis de développer des méthodologies de synthèse sans équivalent en conditions « classiques ».Dans la première partie de ce travail, le comportement de composés organophosphorés dans le milieu HF/SbF5 a été évalué et les sites de protonation de différentes fonctions phosphorées ont pu être observés par RMN in situ à basse température. La réactivité d’oxydes de phosphines insaturés a également été évaluée et des composés organophosphorés cycliques et/ou fluorés ont été synthétisés avec de bons rendements. Des expériences de RMN in situ à basse température ont permis de mettre en évidence un intermédiaire superélectrophile de type phosphonium-carbénium inédit dont l’implication a été confirmée par des calculs théoriques.La deuxième partie est consacrée à l’exploitation de la contrainte benzylique d’espèces superélectrophiles. A partir d’éphédrines tosylées, des benzosultames cycliques ont été obtenus par cyclisation intramoléculaire diastéréospécifique dans l’acide trifluorométhanesulfonique. L’analyse des intermédiaires réactionnels par RMN a permis de révéler l’implication d’une contrainte benzylique contrôlant la spécificité de la réaction. Les benzosultames chiraux N-F obtenus après fluoration ont été utilisés comme réactifs de fluoration électrophile énantiosélective et la synthèse de dioxydes de méthanodibenzothiazocines chiraux inédits a également été envisagée. / Thanks to their exceptional acidity, superacid allow access to polycationic superelectrophiles by polyprotonation. These highly reactive species are capable of being trapped by very weak nucleophiles and can be used to develop new synthetic methodologies without equivalents under “classical” conditions. In the first part of this work, the behavior of organophosphorus compounds in HF/SbF5 was evaluated and the protonation sites of different phosphorus functions have been observed by low temperature NMR spectroscopy. The reactivity of unsaturated phosphine oxides has also been evaluated and cyclic and/or fluorinated organophosphorus compounds have been synthetized in good yields. In situ low-temperature NMR experiments revealed a phosphonium-carbenium superelectrophilic intermediate whose implication was confirmed by theoretical calculations. The second part deals with the study of the benzylic strain applied to superelectrophilic species. From tosylated ephedrines, cyclic benzosultams were obtained by diastereospecific intramolecular process in trifluoromethanesulfonic acid. Analysis of the reaction intermediates by NMR revealed the implication of a benzylic strain controlling the specificity of the reaction. After fluorination, the obtained N-F chiral benzosultams were used as enantioselective electrophilic fluorination reagents and the synthesis of new chiral methanodibenzothiazocine dioxides was also considered.

A 3,4-metilenodioximetanfetamina (MDMA, ecstasy), derivada da anfetamina, é uma droga largamente utilizada para fins recreacionais devido à sensação de euforia, energia e desejo de socialização. Apesar de ter a reputação de ser uma droga segura, um número crescente de relatos clínicos e estudos experimentais indica que a MDMA pode produzir toxicidade no SNC, rim, fígado e coração. Embora esteja contida nos comprimidos de ecstasy como racemato (uma mistura de 50% de seus enantiômeros), sua biotransformação é enantioseletiva; em ratos, o enantiômero R é biotransformado mais rapidamente que o S. Como a biotransformação de MDMA é capaz de produzir metabólitos reativos, muito provavelmente, a forma R tenha um maior potencial para gerar ERO/ERN e dano oxidativo nos tecidos do que a forma S. Nos seres humanos ocorre o inverso. Portanto, o presente trabalho teve como objetivo avaliar a contribuição individual de cada enantiômero da MDMA isoladamente, tendo como referência a mistura racêmica, no estresse oxidativo hepático renal e estriatal de ratos. Ratos Wistar machos adultos (180-220g) foram divididos em quatro grupos: controle (salina), MDMA racêmico, R-MDMA e S-MDMA. (2 doses consecutivas de 10 mg/kg no intervalo de 24h, gavage). Parâmetros de estresse oxidativo serão utilizados como a medida da formação de malonaldeído, a determinação de níveis de glutationa reduzida e a atividade da glutationa-S-transferase. Os enantiômeros da MDMA racêmica foram separados por meio da cromatografia em fase líquida de alta eficiência em fase estacionária quiral. Os enantiômeros obtidos mostraram um alto grau de pureza e um bom rendimento. Nossos resultados mostraram que o conteúdo hepático de glutationa total dos ratos do grupo R,S-MDMA e do grupo R-MDMA, foi significativamente menor do que os do controle e os do S-MDMA, revelando que é o enantiômero R que contribui para a depleção de glutationa hepática induzida pela mistura racêmica. A alta reatividade do enantiômero R no fígado também pode ser constatada nos animais tratados apenas com R-MMDA, uma vez que houve uma produção significativamente aumentada de MDA, comparativamente aos outros grupos tratados e o controle. O conteúdo renal de glutationa total foi significantemente menor para todos os grupos tratados quando comparados com o controle. Com relação ao estriado, apenas os animais tratados com o isômero S isoladamente mostraram uma queda significativa da atividade da GST em comparação aos demais grupos tratados e controle. Tomando todos esses dados em conjunto, esse trabalho mostrou que os enantiômeros isolados da MDMA podem atuar de formas distintas no que se refere ao estado redox, principalmente no fígado, uma vez que o isômero R foi o que mais contribuiu para um dano oxidativo. / MDMA (3,4-methylenedioxymethamphetamine) is an amphetamine derivate that is largely used for recreational purpose due to its feeling of euphoria, energy and the desire to socialize. Although MDMA has the reputation of being safe, a growing number of clinical reports and experimental studies indicate that MDMA can produce toxicity in the CNS, kidney, liver and heart.Although MDMA is present in ecstasy tablets as a racemate (a 50% mixture of its enantiomer) it has an enantioselective metabolism; in rats, the S-enantiomer is metabolized faster than the R-enantiomer and it is the more active pharmacological form. As the MDMA biotransformation can produce reactive metabolites, probably the R form has a greater potential to generate ROS / ERN and oxidative damage in tissues than the S. In humans, the opposite occurs. Therefore, this aim of the present study was to evaluate the individual contribution of single MDMA enantiomers, compared to racemic mixture in liver, kidney and striatal rats oxidative stress. Adult male Wistar rats (180- 220g) will be divided into four groups: control treatment (saline), racemic MDMA, R-MDMA and S-MDMA (two consecutive doses 24h apart with 10mg/kg, gavage). Oxidative stress status parameters will be used to measure malondialdehyde formation, the reduced glutathione levels determination and the glutathione-S-transferase activity. The enantiomers of racemic MDMA were separated by liquid chromatography high-efficiency chiral stationary phase. The enantiomers showed a high degree of purity and a good recovery. Our results showed that the total glutathione content in liver of rats in R,S-MDMA and R-MDMA group was significantly lower than the control and S-MDMA, revealing that the R-enantiomer that contributes to hepatic glutathione depletion induced by the racemic mixture. The high reactivity of the R enantiomer in the liver can also be observed in animals treated with R-MMDA, since there was a significantly increased production of MDA, compared with other treated and control groups. The total glutathione content in kidney was significantly lower for all treated groups compared with control. With respect to the striatum, only animals treated with the S isomer alone showed a significant decrease in GST activity compared to other treatment and control groups. Taking all these data together, this study shows that the isolated enantiomers of MDMA can act differently with regard to the redox state, mainly in the liver, since the R isomer was the largest contributor to oxidative damage.