Les analogues de nucléosides ont joué, et continuent de jouer, un rôle crucial dans le traitement des maladies virales et cancéreuses. Les travaux de recherche ont permis d’élargir les connaissances sur le mécanisme d’action des analogues de nucléosides. Cependant, certaines zones d’ombre demeurent. Le développement de nouveaux analogues de nucléosides est essentiel à la compréhension de leur mécanisme en vue de synthétiser des analogues beaucoup plus efficaces, moins toxiques, possédant une meilleure biodisponibilité et stabilité métabolique au sein de l’organisme humain. Le laboratoire du Pr Yvan Guindon a développé et breveté plusieurs familles d’analogues de nucléosides à centre quaternaire carboné stéréogénique pour leur utilisation en tant qu’agent antiviral, chimiothérapeutique ou bien dans le contexte de traitement de l’insuffisance cardiaque. Le sujet de ce mémoire présente l’étude de la synthèse d’analogues de nucléosides portant un centre quaternaire C3’ et un groupement hydroxyle en C2’. Pour ce faire, une stratégie de synthèse acyclique est employée afin de contrôler les différents stéréocentres. La réaction énantiosélective de Mukaiyama et la réaction diastéréosélective de transfert d’atomes par catalyse photo-rédox sont des étapes clés de cette voie de synthèse. L’introduction diastéréoselective de la nucléobase sur un précurseur acyclique suivit de la cyclisation intramoléculaire S1’→C4’ permet la formation de l’analogue de nucléoside L-1’,2’-cis-4’-thio. Le développement d’une nouvelle stratégie de synthèse du L-1’,2’-cis-4’-thio est étudié. La réaction radicalaire diastéréosélective de transfert d’atomes développée au laboratoire passe par un intermédiaire oxasilolane bromé qui est peu stable. L’objectif est d’exploiter sa stéréochimie tout en formant le centre quaternaire afin d’obtenir une voie de synthèse beaucoup plus courte et efficace. / Nucleoside analogues have an important role in the treatment of viral and carcinogenic diseases. Although the research has greatly expanded the knowledge of nucleoside analogue synthesis and their mechanisms of action, the development of new analogues remains essential to discovering more effective and less toxic analogues with improved bioavailability and metabolic stability. The laboratory of Professor Yvan Guindon has developed and patented several novel families of nucleoside analogues bearing a stereogenic all-carbon quaternary center for their use as antivirals, chemotherapeutic compounds or in the context of heart failure. The subject of the dissertation is the synthesis of such nucleoside analogues bearing a quaternary center at the C3’ position and a C2’ hydroxyl group. The key steps in the synthetic pathway involve an enantioselective Mukaiyama reaction followed by a diastereoselective group transfer using photoredox catalysis and blue light to generate the stereogenic quaternary center. Diastereoselective introduction of the nucleobase onto an acyclic precursor followed by a subsequent intramolecular S1’-to-C4’ SN2-like cyclization allows for the formation of novel L-1’,2’-cis-4’-thionucleoside analogues. Alternatively, modifications of the key diastereoselective radical atom transfer reaction, typically involving a brominated methylester, have been investigated. Formation and subsequent transformation of a thiolated oxasilolane intermediate will reduce the number of steps to synthesize these novel L-1’,2’-cis-4’-thionucleoside analogues.

Nordihydroguaiaretic acid (NDGA), is a naturally-occurring lignan isolated from the creosote bush (Larrea tridentata). The aqueous extract of this shrub, commonly referred to as Chaparral tea, was listed in the American pharmacopeia as an ethnobotanical used to treat tuberculosis, arthritis and cancer. Other documented traditional applications of creosote bush extract include treatment for infertility, rheumatism, arthritis, diabetes, gallbladder and kidney stones, pain and inflammation among many others. In spite of the numerous pharmacological properties, NDGA use has been associated with toxicities including hepatotoxicity in humans. Previous studies in our group showed that oxidative cyclization of NDGA (a di-catechol) at physiological pH forms a dibenzocyclooctadiene that may have therapeutic benefits whilst oxidation to ortho-quinone likely mediates toxicological properties. In order to investigate the structural features responsible for pharmacological and toxicological properties, a series of NDGA analogues were designed, synthesized and characterized for the purpose of studying their oxidative metabolism. Literature procedures were modified to successfully prepare seven lignan analogues via multi-step synthesis. In our effort to understand the mechanisms of NDGA intramolecular cyclization, the prepared analogues were incubated under previously established conditions where NDGA autoxidized to yield the dibenzocyclooctadiene derivative. We also evaluated the stability of the analogues under the conditions of this study. Furthermore, we evaluated bioactivation potential of the prepared analogues with a goal of eliminating reactive metabolite liability through rational structural modification. We incubated NDGA and its analogues in rat liver microsomes (RLM) in the presence of glutathione as a nucleophilic trapping agent. Standards for comparison were generated by performing glutathione trapping experiments with chemical and enzyme oxidation systems. The potential of the dibenzocyclooctadiene lignan 2 derived from NDGA under physiological conditions to contribute to toxicological properties via reactive metabolite formation was also evaluated. Glutathione conjugates were detected by electrospray ionization-mass spectrometry (ESI-MS) scanning for neutral loss (NL) 129 Da or 307 Da in positive ion mode or precursor ion (PI) scanning for 272 Da in negative ion mode and further characterized by liquid chromatography–tandem mass spectrometry (LC–MS/MS) or in a single LC-MS run using multiple reactions monitoring (MRM) as a survey scan to trigger acquisition of enhanced product ion (EPI) data. We determined that NDGA autoxidation at pH 7.4 is dependent on substituents and/or substitution pattern on the two aromatic rings. In particular, spontaneous intramolecular cyclization to a dibenzocyclooctadiene required a di-catechol lignan, raising the possibility that o-Q formation may not be necessary for cyclization to occur. Cyclization was significantly inhibited in the presence of excess GSH which supports the involvement of free radicals as opposed to o-Q in the intramolecular cyclization process. The mono-catechol analogues A1 and A4 underwent oxidation to o-Q but no evidence of cyclization was found implying that electrophilic substitution cannot account for NDGA cyclization. The phenol-type analogues were oxidatively more stable in comparison with the catechol-type analogues at pH 7.4. The results demonstrate that electrophilic substitution makes no contribution to the intramolecular cyclization process and that a radical mediated process accurately describes the situation for NDGA. Oxidative metabolism and bioactivation studies on NDGA and its analogues revealed that reactive metabolites formation is dependent on substitution and/or substitution pattern of the aromatic rings. Cytochrome P450-mediated oxidation of NDGA and its catechol-type analogues yielded electrophilic intermediates which reacted with GSH. The GSH mono-conjugates were identified as ring adducts derived from o-Q although the position at which the GSH binds to the aromatic rings could not be determined. We also found that NL 129 or 307 scanning in positive ionization mode has potential diagnostic utility in distinguishing between aromatic and benzylic GSH conjugates although further studies may be required for validation. We found no evidence of p-QM either directly or via isomerization of o-Q intermediates suggesting that o-Q is the major reactive toxicophore responsible for reactive metabolite mediated toxicities associated with NDGA use. In addition, we demonstrated that the NDGA-derived dibenzycyclooctadiene lignan (cNDGA 2) undergoes P450-mediated oxidation to a reactive metabolite which might have toxicological implications. There was no evidence of P450-mediated oxidation to reactive metabolites for the phenol-type NDGA analogues. It is concluded that structural modification efforts should focus on phenol-type analogues to potentially enhance the safety profile of NDGA.

Depuis la découverte du Virus de l'Immunodéficience Humaine (VIH) au début des années 80, la recherche de nouvelles molécules anti-VIH demeure un challenge important pour la communauté scientifique. Les effets secondaires liés à l'usage d'inhibiteurs de la réplication virale, la découverte des récepteurs et la compréhension du mécanisme d'entrée du virus dans la cellule hôte ont encouragé la recherche sur de nouveaux inhibiteurs ciblant l'entrée virale. A ce jour, l'Enfuvirtide est le seul inhibiteur d'entrée approuvé en tant qu'inhibiteur de fusion. Bien que ce composé soit un antiviral puissant, il présente néanmoins de sérieuses limitations, son mode d'administration (injection sous cutanée deux fois par jour) et l'émergence de résistances, le classent en agent rétroviral de seconde classe. Une approche alternative est la génération de D-peptides inhibiteurs de fusion, résistants aux protéases et prometteurs pour le développement et l'identification d'une nouvelle classe de médicaments anti-VIH. Basée sur cette dernière approche, cette thèse est consacrée à la synthèse et à l'étude d'analogues peptidiques en tant qu'inhibiteurs de fusion du VIH. Tout d'abord, des études de modélisation associées à la synthèse d'analogues peptidiques ont permis de mettre en évidence et de comprendre les caractéristiques essentielles responsables de l'activité des D-peptides. Ensuite, des études de relations structure-activité, à partir de séquences modifiées, ont conduit à l'obtention de nouveaux analogues peptidiques inhibiteurs de fusion actifs. Enfin, dans le but de réduire la nature peptidique et par conséquent d'améliorer les propriétés pharmaceutiques, des macrocycles peptidiques ont été conçus, et une nouvelle stratégie de synthèse de peptides cycliques a été développée. / Since the discovery of the Human Immunodeficiency Virus (HIV) at the beginning of the 1980's, the search for new anti-HIV molecules remains an important challenge for the scientific community. Secondary effects associated with viral replication inhibitors, the discovery of receptors and the understanding of the mechanism of the viral entry makes HIV viral entry one of the most promising target for HIV drug development. To date, Enfurvitide is the only approved entry inhibitor as HIV fusion inhibitor. Although highly effective, Enfurvirtide has several serious limitations including high dosing requirements, the administration by injection, and the emergence of resistant strains. An alternative approach that has shown considerable potential is the generation of new D-peptides HIV fusion inhibitors expected to be resistant to proteolytic degradation and useful for the development and the identification of a new class of anti-HIV drugs with improv ed bioavailability.Based on this approach, the present work is dedicated to the synthesis and the study of peptide analogs as HIV fusion inhibitors. First, modeling studies and the synthesis of peptide analogs were devoted to point out and to understand the key elements responsible for the activity of the reference D-peptides. Then, structure activity relationship studies based on different modifications sequences led to the discovery of active peptide analogues as HIV fusion inhibitors. In another approach, in order to decrease peptide nature and consequently to improve the pharmaceutical properties, reduced cyclic peptides were designed. Finally, a novel strategy for cyclic peptide synthesis was developed.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Cette thèse décrit le développement et la méthodologie pour la synthèse de 2-pyrazolo[1,5-a]pyridines à partir d’ylures de N-iminopyridinium et d’halogénures de styryle. Des dérivés de chaque ylure de N-iminopyridinium et d’halogénures de styryle ont été utilisés pour la synthèse de plusieurs composés avec un intérêt pharmaceutique. Le premier chapitre présente les précédents littéraires pour la synthèse de pyrazolopyridines. Spécifiquement trois types différents de synthèse seront présentés en détail. L’importance biologique de ces composés sera discutée. La vue d’ensemble des travaux développés dans notre groupe de recherche pour la synthèse des produits de départ sera présentée brièvement. Finalement, la science intéressante qui a apporté cette idée de recherche sera révélée. Le deuxième chapitre décrit les résultats des optimisations étudiées pour la synthèse des 2-phénylpyrazolo[1,5-a]pyridines à partir d’ylures de N-benzoyl-iminopyridinium et d’iodure de styryle. Chaque substrat de la réaction a été étudié individuellement afin d’être optimisé; les ratios, les solvants, la température du milieu réactionnel et le temps optimal de la réaction ont aussi été explorés. Le troisième chapitre présente l’étendue de la synthèse des pyrazolopyridines. L’étendue de la réaction inclut les dérivés des halogénures de styryle. L’étendue de la réaction a été élargie aux dérivés d’ylures de N-iminopyridinium et ils incluent des groupements donneurs d’électrons ainsi que des groupements pauvres en électrons. Des groupements exotiques d’iodure et de bromure de vinyle ont aussi été explorés. Le quatrième chapitre démontre les études mécanistiques que l’on a faites pour mieux comprendre les cycles catalytiques qui ont lieu durant la réaction. Des études de cyclisation avec les ylures de N-iminopyridinium ont été explorées pour les produits de départ suivants : iodure de styryle et phényl acetylène. / This thesis describes the development of a methodology for the one-pot synthesis of 2-pyrazolo[1,5-a]pyridines from N-iminopyridinium ylide and styryl-halide starting materials. Both N-iminopyridinium ylide derivatives and styryl-halide derivatives were employed for the synthesis of various pharmaceutically interesting pyrazolo[1,5-a]pyridines. The first chapter presents the literature precedents for the synthesis of pyrazolopyridines. More specifically, three different types of syntheses will be shown in detail. Furthermore, the biological importance of these compounds will be discussed. An overview of the developed methodologies previously carried out in our research group for the synthesis of the starting materials will be presented. Finally, the copper-catalyzed direct alkenylation of N-iminopyridinium ylides that brought about this research idea will be discussed. The second chapter describes the results of the optimization studies for the synthesis of 2-phenyl pyrazolo[1,5-a]pyridines from N-benzoyliminopyridinium ylides and styryl iodides. Each component of the reaction was individually screened and the loading ratios were optimized: e.g., solvent and temperature. The third chapter presents the scope of the pyrazolopyridine synthesis. The scope includes styryl iodide, –bromide and –chloride derivatives. The scope of the reaction was extended to N-iminopyridinium ylide derivatives and included electron donating and electron withdrawing groups. Substituted vinyl iodides and bromides were also investigated. The fourth chapter demonstrates the mechanistic studies conducted in order to obtain an accurate understanding of the catalytic cycles taking place during the reaction. Cyclization studies were explored for both styryl iodides and phenyl acetylene starting materials reacted with N-iminopyridinium ylides.

L’importance des produits naturels dans le développement de nouveaux médicaments est indéniable. Malheureusement, l’isolation et la purification de ces produits de leurs sources naturelles procure normalement de très faibles quantités de molécules biologiquement actives. Ce problème a grandement limité l’accès à des études biologiques approfondies et/ou à une distribution sur une grande échelle du composé actif. Par exemple, la famille des pipéridines contient plusieurs composés bioactifs isolés de sources naturelles en très faible quantité (de l’ordre du milligramme). Pour pallier à ce problème, nous avons développé trois nouvelles approches synthétiques divergentes vers des pipéridines polysubstituées contenant une séquence d’activation/désaromatisation d’un sel de pyridinium chiral et énantioenrichi. La première approche vise la synthèse de pipéridines 2,5-disubstituées par l’utilisation d’une réaction d’arylation intermoléculaire sur des 1,2,3,4-tétrahydropyridines 2-substituées. Nous avons ensuite développé une méthode de synthèse d’indolizidines et de quinolizidines par l’utilisation d’amides secondaires. Cette deuxième approche permet ainsi la synthèse formelle d’alcaloïdes non-naturels à la suite d’une addition/cyclisation diastéréosélective et régiosélective sur un intermédiaire pyridinium commun. Finalement, nous avons développé une nouvelle approche pour la synthèse de pipéridines 2,6-disubstituées par l’utilisation d’une réaction de lithiation dirigée suivie d’un couplage croisé de Negishi ou d’un parachèvement avec un réactif électrophile. Le développement de transformations chimiosélectives et versatiles est un enjeu crucial et actuel pour les chimistes organiciens. Nous avons émis l’hypothèse qu’il serait possible d’appliquer le concept de chimiosélectivité à la fonctionnalisation d’amides, un des groupements le plus souvent rencontrés dans la structure des molécules naturelles. Dans le cadre précis de cette thèse, des transformations chimiosélectives ont été réalisées sur des amides secondaires fonctionnalisés. La méthode repose sur l’activation de la fonction carbonyle par l’anhydride triflique en présence d’une base faible. Dans un premier temps, l’amide ainsi activé a été réduit sélectivement en fonction imine, aldéhyde ou amine en présence d’hydrures peu nucléophiles. Alternativement, un nucléophile carboné a été employé afin de permettre la synthèse de cétones ou des cétimines. D’autre part, en combinant un amide et un dérivé de pyridine, une réaction de cyclisation/déshydratation permet d’obtenir les d’imidazo[1,5-a]pyridines polysubstituées. De plus, nous avons brièvement appliqué ces conditions d’activation au réarrangement interrompu de type Beckmann sur des cétoximes. Une nouvelle voie synthétique pour la synthèse d’iodures d’alcyne a finalement été développée en utilisant une réaction d’homologation/élimination en un seul pot à partir de bromures benzyliques et allyliques commercialement disponibles. La présente méthode se distincte des autres méthodes disponibles dans la littérature par la simplicité des procédures réactionnelles qui ont été optimisées afin d’être applicable sur grande échelle. / The importance of natural products in the development of new drugs is undeniable. Unfortunately, the isolation and purification of those products from their natural sources provides normally very small amounts of the desired bioactive molecules. Consequently there is largely limited access to in-depth biological studies and/or to the large scale distribution of the bioactive compound. For example, the piperidine family contains a large diversity of bioactive compounds isolated from natural sources in very limited quantities (on the order of milligram scale). To address the issue, we have developed three new divergent synthetic approaches towards polysubstituted piperidines containing an activation/dearomatization sequence from a chiral and enantioenchired pyridinium salt. The first approach aims towards the synthesis of 2,5-disubstituted piperidines by the use of an intermolecular arylation reaction on 2-substituted 1,2,3,4-tetrahydropyridines. Then, we have developed a synthetic method for indolizidines and quinolizidines starting from secondary amides. The second approach leads to the formal synthesis of non-natural alkaloids via a highly diastereoselective and regioselective addition/cyclization from a common pyridinium intermediate. Finally, we have found a new approach for the synthesis of 2,6-disubstituted piperidines by the use of a directed lithiation sequence followed by either a Negishi cross-coupling reaction or a quench with an electrophilic reagent. The development of highly chemoselective and versatile transformations are crucial to organic chemists. We have issued the hypothesis that it could be possible to apply the chemoselectivity concept towards the functionalization of amides, one of the most encountered subunits in the structures of natural products. In the specific context of the thesis, the highly chemoselective transformations are realized on functionalized secondary amides. The method relies on the activation of the carbonyl function of the amide by triflic anhydride in presence of a weak base. Firstly, the activated amide can be selectively reduced to imine, aldehyde, or amine oxidation state in the presence of a poorly nucleophilic hydride source. Alternatively, a carbon nucleophile could also be employed in order to allow the synthesis of ketones or ketimines. By combining an amide with a pyridine derivative a cyclization/dehydration reaction was used for the synthesis of polysubstituted imidazo[1,5-a]pyridines. Moreover, we have briefly applied the activation conditions to the interrupted Beckmann rearrangement of ketoximes. We have finally developed a new synthetic pathway for iodoalkynes by using a one-pot homologation/elimination reaction from commercially available benzylic and allylic bromides. The present method is distinctively different from literature precedents by the simplicity of the reaction procedures and purifications which were optimized in order to be applied to large scale synthesis

O tratamento mais comumente utilizado na inflamação é o uso de agentes antiinflamatórios não-esteróides (AINE). Estes fármacos, por sua vez, inibem as cicloxigenases, enzima responsável pela transformação do ácido araquidônico em prostaglandinas flogísticas, pela ação da fosfolipase A2. A síntese de compostos antiinflamatórios contendo núcleo pirrólico em suas estruturas vêm sendo um tópico muito atrativo e bastante estudado. O conhecimento do sítio de interação do fármaco ao receptor possibilita o planejamento de estruturas de novas substâncias candidatas a protótipos de novos fármacos. Portanto, esse trabalho consiste na síntese de derivados, contendo núcleo pirrólico, com potencial atividade antiinflamatória, com base na indometacina, protótipo da classe dos derivados arilalcanóicos. Os compostos foram obtidos, inicialmente via ciclização de β-enaminoésteres, entretanto devido à complexidade da rota sintética e alto custo de determinados reagentes, propôs-se a metodologia de Hantzsch, descrita por Roomi e McDonald (1970). Esta metodologia consiste na formação de derivados pirrólicos à partir da condensação de &#945-halocetonas e compostos 1,3-dicarbonílicos na presença de amônia. Com base nesta metodologia, foram sintetizados compostos contendo núcleo pirrólico em suas estruturas, partindo de β-enaminoésteres já sintetizados em nosso laboratório, como apresentado de maneira resumida no esquema 1 abaixo. (Veja arquivo em PDF). / Non-steroidal anti-inflammatory drugs (NSAIDs) have successfully been employed in the treatment of inflammation. These drugs are potent and highly selective as cyclo-oxigenase (COX-2) inhibitors. Recently, several pyrroles have been synthesized and evaluated for selective COX-1 / COX-2 enzyme inhibition. This is an extremely attractive topic. Thus, these recent findings have led us to design new pyrroles from &#946-enaminoesters and α-halo ketonas (scheme 1). (See PDF file)

Abordaram-se diversos aspectos da reação de contração de álcoois homoalílicos promovida por trinitrato de tálio (TTN). A configuração relativa do indano obtido como produto foi estabelecida graças a uma difratometria de raio-x de seu derivado sólido, possibilitando a elaboração de um mecanismo detalhado desta transformação. As reações de contração de anel de alquenóis secundários e terciários com TTN produzem indanos em 33-65%. Por outro lado, os 3-alquenóis terciários que possuem uma metila a mais em posição alílica conduzem a produtos oriundos de uma reação de fragmentação em 51-69%, com a perda de uma molécula de acetona. Álcoois homoalílicos primários, ao reagirem com iodo ou iodo hipervalente, sofrem uma reação de fragmentação, formando formaldeído, que sofre uma ciclização de Prins com o substrato, produzindo hexahidro- benzo-isocromenos em 26-48%. No caso da reação com iodo, parte do substrato sofre também uma ciclização 5-endo-trig seguida de aromatização, levando a um di-hidro-naftofurano em até 30% de rendimento. A ciclização de Prins de 3-alquenóis primário, secundário ou terciário com quantidades equimolares de aldeídos - aromáticos ou alifáticos - ou cetonas alifáticas catalisada por 5 mol% de iodo pode ser alcançada em rendimentos de 54-82%. Estas reações foram efetuadas em condições brandas e não anidras. Esta metodologia foi expandida para a preparação de uma hexa-hidro-benzo-isoquinolina à partir de uma tosilamida homoalílica, em 60% de rendimento. Um método simples e eficiente para a 2,2-dicloração de 1-tetralonas, da indanona e da benzosuberona foi desenvolvido utilizando-se água de cloro e metanol (5:1), à temperatura ambiente, em 61-90% de rendimento. A caramboxina é uma neurotoxina extraída da carambola. Sua síntese seria desejável para a confirmar sua estrutura e realizar novos ensaios biológicos. A rota sintética estudada possui, como etapa-chave, uma reação de Diels-Alder seguida de uma retro-Diels-Alder entre um éster clorotetrólico e um ciclo-hexadieno derivado da dimedona. No entanto, a síntese não pode ser concluída e um análogo ciclizado da caramboxina, uma isoquinolona, foi obtido em um rendimento global de 7%, em 10 etapas, à partir da dimedona. / Several aspects concerning the reaction of homoallylic alcohols and thallium trinitrate were addressed. The relative configuration of the indan obtained as product was established based on an x-ray diffration analysis of its solid derivative. With this information a more detailed mechanism was proposed. The ring contraction reactions of secondary and tertiary alkenols with TTN produced indans in 33-65% yield. Nevertheless, 3-alkenols bearing a methyl group on the allylic position lead to fragmentation products in 51- 69% yield, with the loss of a molecule of acetone. Treatment of primary homoallylic alcohols with iodine or hypervalent iodine leads to hexahydrobenzoisochromenes in 26-48% yield via a fragmentation reaction where formaldehyde is produced and reacts with the substrate on a Prins cyclization reaction. When iodine is used, dihydronaphtofuranes are also produced in up to 30% yield through a 5-endo-trig cyclization followed by an aromatization reaction. The Prins cyclization of 3-alkenols primary, secondary or tertiary with equimolar amounts of aldehydes - aromatic or aliphatic or aliphatic ketones catalysed by 5 mol% of iodine was accomplished in 54- 82% yield. These reactions were performed in mild and non-anhydrous conditions.This methodology was also used for the preparation of a hexahydrobenzoisoquinoline from a homoallylic tosylamide, in 60% yield. An easy and efficient method to the 2,2-dichlorination of 1-tetralones, indanone and benzosuberone was developed using household bleach and methanol (5:1), at room temperature in 61-90% Caramboxin is a neurotoxin isolated from star fruit. Its synthesis was desired to confirm its structure and perform new biological tests. The key step of the synthetic path is a Diels Alder followed by a retro-Diels Alder between a chlorotetrolic ester and a cyclohexene derived from dimedone. Unfortunately the synthesis was not concluded and a cyclized analogous of caramboxin, an isoquinoline, was obtained in 7% global yield, in 10 steps, from dimedone.

O tratamento mais comumente utilizado na inflamação é o uso de agentes antiinflamatórios não-esteróides (AINE). Estes fármacos, por sua vez, inibem as cicloxigenases, enzima responsável pela transformação do ácido araquidônico em prostaglandinas flogísticas, pela ação da fosfolipase A2. A síntese de compostos antiinflamatórios contendo núcleo pirrólico em suas estruturas vêm sendo um tópico muito atrativo e bastante estudado. O conhecimento do sítio de interação do fármaco ao receptor possibilita o planejamento de estruturas de novas substâncias candidatas a protótipos de novos fármacos. Portanto, esse trabalho consiste na síntese de derivados, contendo núcleo pirrólico, com potencial atividade antiinflamatória, com base na indometacina, protótipo da classe dos derivados arilalcanóicos. Os compostos foram obtidos, inicialmente via ciclização de β-enaminoésteres, entretanto devido à complexidade da rota sintética e alto custo de determinados reagentes, propôs-se a metodologia de Hantzsch, descrita por Roomi e McDonald (1970). Esta metodologia consiste na formação de derivados pirrólicos à partir da condensação de &#945-halocetonas e compostos 1,3-dicarbonílicos na presença de amônia. Com base nesta metodologia, foram sintetizados compostos contendo núcleo pirrólico em suas estruturas, partindo de β-enaminoésteres já sintetizados em nosso laboratório, como apresentado de maneira resumida no esquema 1 abaixo. (Veja arquivo em PDF). / Non-steroidal anti-inflammatory drugs (NSAIDs) have successfully been employed in the treatment of inflammation. These drugs are potent and highly selective as cyclo-oxigenase (COX-2) inhibitors. Recently, several pyrroles have been synthesized and evaluated for selective COX-1 / COX-2 enzyme inhibition. This is an extremely attractive topic. Thus, these recent findings have led us to design new pyrroles from &#946-enaminoesters and α-halo ketonas (scheme 1). (See PDF file)

Le motif 3-hydroxyoxindole est présent dans de nombreuses molécules biologiquement actives, qu’elles soient d’origine naturelle ou synthétique. Dans le cadre de cette thèse nous nous sommes intéressés aux différents aspects de la chimie associée à ce motif. Dans un premier temps, nous avons développé une nouvelle méthodologie très générale donnant accès à cet hétérocycle. En effet, une réaction de Friedel-Crafts cyclisante promue par l’acide trifluoroacétique permet d’obtenir des 3-hydroxy, 3-amino et 3-spirooxindoles diversement substitués à partir de cétoanilides non préfonctionnalisés. Dans un deuxième temps, nous avons commencé l’étude vers la synthèse de l’azonazine, qui fait intervenir un intermédiaire 3-hydroxyoxindole. L’étape clé de cette synthèse est la réaction de Friedel-Crafts cyclisante, développée dans la première partie. Le 3-hydroxyoxindole intermédiaire a été obtenu avec un bon rendement, illustrant notre méthodologie. Finalement, nous avons poursuivi l’étude vers la synthèse du TMC-95A, qui contient le motif 3-hydroxyoxindole, initiée précédemment dans notre laboratoire. Nous avons développé la voie de synthèse permettant d’accéder à la partie Nord, 3-hydroxyoxindole hautement fonctionnalisé de la molécule. L’étape clé est la synthèse du motif 3-hydroxoxindole à partir d’une isatine par addition d’un acide alcénylboronique catalysée au rhodium(I). / The 3-hydroxyoxindole motif can be found in many biologically active compounds, natural or man-made. In the context of this work, we got interested in the different aspects of the chemistry associated with this motif. First, we developed a new and very general methodology to access this heterocycle. Indeed, a cyclizing reaction of Friedel-Crafts promoted by trifluoroacetic acid gave us access to variously substituted 3-hydroxy, 3-amino and 3-spirooxindoles from non prefunctionalized ketoanilides. Then, we started studies towards the synthesis of azonazine, which involves a 3-hydroxyoxindole intermediate.The key step of this synthesis is the cyclizing reaction of Friedel-Crafts developed in the first part. The 3-hydroxyoxindole intermediate was obtained with a good yield, thus illustrating our methodology. Finally, we continued the studies towards the synthesis of TMC-95A, which contains the 3-hydroxyoxindole motif. We developed the synthetic pathway enabling us to access the Northern part of the molecule, a highly functionalized 3-hydroxyoxindole. The key step is the synthesis of the 3-hydroxyoxindole from an isatin by a rhodium(I)-catalyzed addition of an alkenylboronic acid.