Th. Univ.--Sciences--Paris, 1963. N°: 793. / La date correspond à la date de soutenance. Bibliogr. p. 85-87.

Les hétérocycles sont des motifs présents dans un grand nombre de produits naturels et synthétiques possédant une activité biologique. Le développement de méthodes pour construire ces motifs constitue un axe de recherche important et de nombreuses voies de synthèse ont été et sont encore aujourd'hui étudiées. Au cours de ces travaux de thèse, plusieurs méthodologies ont été développées permettant l'accès à de nouveaux hétérocycles: Une première étude sur l'hydrogénation des indoles et sur l'influence de leur substitution a été réalisée. Ces travaux ont permis de mettre au point une méthode simple et efficace pour obtenir des indoles partiellement ou totalement saturés. Dans un second temps la mise au point de conditions sans solvant et sans métal pour la réaction de cyclisation de Prins a conduit à l'isolation de tetrahydropyranes et à leur utilisation de manière séquentielle avec la réaction de Bartoli. Ces conditions se sont également avérées très efficaces pour la formation de sultames. Enfin, une approche synthétique vers les decytospolides A et B a été réalisée en utilisant comme réaction clé la réaction de cyclisation de Prins / The heterocyclic skeleton is present in many natural and synthetic products with biological activity. The development of methods to build these patterns is an important area of research and many synthetic routes have been and are still being studied. During this work, several methods have been developed allowing access to new heterocyclic compounds: first the hydrogenation of indoles and the influence of their substitution was realised. This work allowed to develop a simple, selective and efficient method to obtain partially or fully saturated indoles. Next the development of neat and metal-free conditions for the Prins cyclization reaction gave tetrahydropyrans and was sequentially used with the Bartoli reaction. These conditions have also proved to be very efficient for sultam synthesis. Finally, a synthetic approach to decytospolides A and B was performed using the Prins cyclization reaction as key step

The importance of fluorinated organic molecules has grown over the last 50 years, particularly in the pharmaceutical and agrochemical industries. Therefore the development of new methods for fluorination is a very attractive research area. In Chapter 1, the properties and impact of the fluorine atom on organic molecules are overviewed. Existing electrophilic and nucleophilic fluorination methods are reviewed, and new developments in asymmetric fluorination are discussed. The emergence of the Prins fluorination reaction as a side product in BF₃.OEt₂ catalysed processes has been investigated as a synthesis method in Chapter 2. Indeed, it is possible to form 4-fluorotetrahydropyrans with some diastereoselectivity from an allylic alcohol and an aldehyde with a stoichiometric amount of BF₃.OEt₂. During this study, formation of 4-fluoropiperidines from N-tosyl-4-butenylamine was achieved. Optimisation of reaction conditions was investigated such as the solvent, the reaction temperature and the influence of substituents on the alcohol and the aldehyde reagents. A ring-opening reaction of 4-fluoro-2-phenyltetrahydropyran was successfully performed. Both oxa-Prins and aza-Prins fluorination reactions were investigated under microwave conditions, allowing reduced reaction times, a process that had a minimum impact on the diastereoselectivity. Attempt to form γ-hydroxy-α-vinylfluorides by the reduction-fluorination of propargylic alcohols with aluminium hydride, or by Horner-Emmons reaction with diethyl (fluoromethyl)phosphonate are reported in Chapter 3. Unfortunately these approaches were unsuccessful in the preparation of γ-hydroxy-α-vinylfluorides. Attempts to fluorinate epoxides by α-lithiation and then treatment with electrophilic fluorination reagents gave encouraging results, but the products could not be purified and characterised due to an apparent instability.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Made available in DSpace on 2015-03-26T13:42:30Z (GMT). No. of bitstreams: 1 texto completo.pdf: 897621 bytes, checksum: e2a579de88f1b70bef922be819992a6c (MD5) Previous issue date: 2013-03-19 / Fundação de Amparo a Pesquisa do Estado de Minas Gerais / The fluorescente in situ hybridization advent introducted the cytogenetics in molecular era, with methodological advances that enable the investigation of chromosome science at different levels. Among these advances, it stands out the unequivocally identification of homologous chromosomes pairs, the specific sequences location, the direct prospecting of chromosomal abnormalities, besides providing high-resolution information on the structure and organization of chromosomes. Within the strategies of molecular cytogenetics, microdissection and DOP-PCR techniques have been widely used in the chromosome-specific probes construction. However, the absence of well-established and reproducible protocols, besides the need for relatively large number of chromosomes for micromanipulation, this technique has been limited. The present study aimed to standard a methodology for chromosome-specific probes construction, involving micromanipulation and DOP-PCR techniques. Human lymphocyte cultures were carried out to obtain metaphases, both male and female origin. In situ amplification (PRINS) reaction was performed on a slide containing metaphase, applying 50 μL of reaction mix with Platinun® Taq DNA Polymerase High Fidelity 1 U, enzime reaction buffer, MgSO4 2 mM, dNTPs 200 μM and primer 4 μM. Then, ten X chromosomes fragments were microdissected using microneedles coupled to a phase contrast microscope and transferred to a tube containing 0.2 μL proteinase K, where deproteinizated at 37 °C for 24 hours. The material was amplified by DOP-PCR in 15 μL of reaction, and marked with Tetramethyl-rhodamine-5-dUTP. The probe was denatured for 10 minutes at 99 °C in 35 μL of hybridization mix containing: formamide 50 %, SSC 2X, Dextran Sulfate 10 %, 1 mg of Cot-1 and 200 ng of labeled probe. This mix was applied on the slide, which was denatured at 75 ºC for 8 minutes and then subjected to hybridization at 37 °C for 20 hours. After hybridization, stringency washes and counter-staining with DAPI were performed, and the material was analyzed with a fluorescence microscope coupled to an image capture system. A subcentromeric X chromosome specific probe was obtained, with an unique mark in male metaphase and two marks in female metaphases, with one or two fluorescent signals in interphase nuclei. / Com o advento da hibridização in situ fluorescente, a citogenética foi introduzida na era molecular, com avanços metodológicos que possibilitaram a investigação em vários níveis da ciência dos cromossomos. Destaca-se entre esses avanços a identificação de pares de cromossomos homólogos de forma inequívoca, a localização de sequências específicas, a prospecção direta de anormalidades cromossômicas, além de proporcionar informações de alta-resolução sobre a estrutura e organização dos cromossomos. Dentro das estratégias da citogenética molecular, as técnicas de microdissecção e de DOP-PCR têm sido muito utilizadas na construção de sondas cromossomo-específicas. Entretanto, a ausência de protocolos bem estabelecidos e reprodutíveis, além da necessidade de captura por micromanipulação de um número relativamente grande de cromossomos, essa técnica tem sido limitada quanto à sua aplicação mais ampla. O presente trabalho teve como objetivo padronizar uma metodologia para construção de sondas cromossomo-específicas, associando as técnicas de micromanipulação e DOP-PCR. Culturas de linfócitos humanos foram realizadas para a obtenção de lâminas contendo metáfases, tanto de origem masculina quanto feminina. A reação de amplificação in situ (PRINS) foi realizada sobre uma lâmina contendo metáfases, aplicando uma mistura de 50 μl de reação, contendo 1,0 U de Platinun® Taq DNA Polymerase High Fidelity, tampão de reação da enzima, 2 mM de MgSO4, 200 μM de dNTPs e 4 μM de primer. Em seguida, dez fragmentos de cromossomos X foram microdissectados utilizando microagulhas acopladas a um microscópio de contraste de fase e transferidos para um tubo de 0,2mL contendo proteinase K, de onde seguiu para a desproteinização a 37 ºC por 24 horas. O material foi amplificado por DOP-PCR em 15 μl de reação, e marcado com Tetramethyl-rhodamine-5-dUTP. A sonda foi desnaturada por 10 minutos a 99 ºC em 35 μL de uma mistura de hibridização contendo: 50 % Formamida, 2X SSC, 10 % Dextran Sulfato, 1 μg de Cot-1 e 200 ng da sonda marcada. Essa mistura foi aplicada na lâmina, que foi desnatura a 75 ºC por 8 minutos e depois foi submetida à hibridização a 37 ºC por 20 horas. Após a hibridização, foram realizadas as lavagens de estringência, contra-coloração com DAPI, e visualização do material em microscópio de fluorescência acoplado a um sistema de captura de imagens. Uma sonda específica para a região subcentromérica do cromossomo X foi obtida, apresentando uma marcação em metáfases de indivíduos masculinos e duas marcações em metáfases de indivíduos femininos, além de um ou dois sinais fluorescentes nos núcleos interfásicos.

Les travaux exposés dans ce manuscrit s’articulent autour de l’élaboration de nouvelles plateformes pyridylalkylamines polyfonctionelles et chirales afin de permettre le développement d’un nouveau processus de réactions catalysées en cascade. La première partie de ce document décrit la synthèse de plateformes pyridylméthylamines (pma) portant des motifs chiraux et (thio)urées. La seconde partie traite de leur utilisation dans des réactions d’organocatalyse et de métallocatalyse asymétriques, puis dans des réactions catalysées en cascade séquencée. La troisième partie porte sur la synthèse de plateformes pyridyléthylamines (pea) via l’utilisation d’une réaction d’amination électrophile organocatalysée et une réaction de cyclisation de Prins. / The works described in this manuscript is dealing with the construction of new polyfunctional chiral pyridylmethylamine (pma) platforms in order to allow the development of new one-pot catalytic reaction sequences. The first part of this document focuses on the synthesis of pyridylméthylamine platforms carrying chiral motifs and (thio)ureas. The second part reports their use in asymmetric organocatalysis and metallocatalysis and then in catalyzed cascade reaction sequences. The third part deals with the synthesis of pyridyléthylamine (pea) platforms through an organocatalyzed electrophilic reaction followed by a Prins cyclisation.

Les tétrahydropyranes et les pipéridines sont des motifs que l'on retrouve dans de nombreuses molécules naturelles bioactives. L'intérêt pour ces familles de composés ne cesse de croître. En effet le noyau pipéridine est le troisième motif cyclique le plus retrouvé dans les molécules thérapeutiques après les noyaux phényle et pyridine alors que le tétrahydropyrane prend lui la 6ème place. Il apparaît donc opportun de développer des voies d'accès simples et efficaces afin d'obtenir de façon stéréosélective (diastéréo et/ou énantiosélective) ces motifs structuraux. Les travaux de recherche présentés dans ce manuscrit concernent le développement de deux nouvelles méthodologies de la cyclisation d'aza-Prins. La cyclisation d'aza-Prins permet par la réaction entre une amine homoallylique et un aldéhyde en présence d'un acide (Lewis ou Brønsted) la formation de pipéridine. La première a été développée pour pallier à l'absence dans la littérature de méthodologie applicable à tous types d'amines homoallyliques. Cette nouvelle méthodologie repose sur la promotion de la réaction par un effet synergétique entre un acide de Lewis (TiCl4 1 éq.) et un acide de Brønsted (p-TSA 0.1 éq.). Cette méthodologie a permis l'obtention de pipéridine avec de bons rendements et une excellente diastéréosélectivité a été obtenue selon la nature de l'amine homoallylique utilisé. La deuxième méthodologie qui a été développée permet l'aminolyse de pipéridine-lactone. Ces pipéridine-lactones, obtenues par une réaction d'aza-Prins, sont ainsi aminolysées par un acide aminé en présence d'un promoteur puissant LiNTf2. Ces deux méthodologies combinées nous ont permis d'obtenir divers motifs pipéridines. Un certain nombre de ces pipéridines synthétisées seront testées afin de mettre en évidence une éventuelle activité biologique. / Tetrahydropyrans and piperidines are cyclic motifs found in numerous bioactive natural products. Interest in these families of compounds is continuously growing. Indeed, piperidine is the 3rd most common cyclic motif found in therapeutic molecules after phenyl and pyridine structures, while the tetrahydropyran takes the 6th place. Thus the development of simple and effective methodologies to obtain these structures stereoselectively (diastereo and/or enantioselectively) is of great interest. The research presented in this manuscript concerns the development of two new methodologies for aza-Prins cyclization. These reactions involve condensation of homoallylic amines with aldehydes in the presence of a Lewis or Brønsted acid to give piperidine compounds. The first method was promoted by a synergistic combination of a Lewis acid and a Brønsted acid and employs N-alkyl, N-aryl, and unprotected homoallylamines to efficiently form piperidines with good yields and excellent diastereoselectivity, which was controlled by the nature homoallylamine. The second method allows piperidine-lactone aminolysis in presence of aminoacids with the help of a powerful promoter LiNTf2. These two combined methodologies allowed us to obtain a library of piperidine structures, some of which will be tested in order to assess their possible biological activity.

São apresentados nesta tese os resultados dos estudos visando a síntese total assimétrica do populeno D, um produto natural extraído do troco da árvore Thespesia populnea. A proposta sintética era obter a molécula alvo em 14 etapas, entretanto, não foi possível finalizar a síntese. Foi obtido o último intermediário da síntese em 13 etapas em um rendimento global de 8%, a partir do L-lactato de etila, comercialmente disponível. A rota sintética proposta tem como etapa chave uma reação de ciclização de Prins catalisada por iodo molecular. Tal metodologia foi utilizada para sintetizar quatro análogos do populeno D, compostos inéditos que foram caracterizados e enviados para ensaios de atividade biológica. Dois destes quatro compostos apresentaram bons resultados contra linhagens celulares do ovário com fenótipo de resistência a múltiplos fármacos. Apresenta-se também uma metodologia de meta-alquilação de N-aril-2- aminopirimidinas com haletos secundários catalisada por rutênio. No total, foram obtidos vinte compostos inéditos que foram completamente caracterizados. / Studies aiming the asymmetric total synthesis of populene D are presented in this thesis. Populene D is a natural product extracted from Thespesia populnea tree trunk. Synthetic proposal for the target molecule comprised 14 steps, however, total synthesis was not achieved. Last intermediate of the proposed route was obtained, in 13 steps and 8% global yield, starting from commercially available ethyl L-lactate. An iodine-catalyzed Prins cyclization reaction is the key step of proposed synthesis. This methodology was applied to synthesize four analogues of populene D, all unknown compounds which were fully characterized, and submitted to biological activity tests. Among these four compounds, two of them have shown good results against ovary cell lines with with multidrug resistance phenotype. A new protocol of ruthenium-catalyzed site-selective alkylation of N-aryl-2- aminopyrimidines is also presented in this thesis. 20 unknown compounds were obtained using this protocol and they were fully characterized as well.

São apresentados nesta tese os resultados dos estudos visando a síntese total assimétrica do populeno D, um produto natural extraído do troco da árvore Thespesia populnea. A proposta sintética era obter a molécula alvo em 14 etapas, entretanto, não foi possível finalizar a síntese. Foi obtido o último intermediário da síntese em 13 etapas em um rendimento global de 8%, a partir do L-lactato de etila, comercialmente disponível. A rota sintética proposta tem como etapa chave uma reação de ciclização de Prins catalisada por iodo molecular. Tal metodologia foi utilizada para sintetizar quatro análogos do populeno D, compostos inéditos que foram caracterizados e enviados para ensaios de atividade biológica. Dois destes quatro compostos apresentaram bons resultados contra linhagens celulares do ovário com fenótipo de resistência a múltiplos fármacos. Apresenta-se também uma metodologia de meta-alquilação de N-aril-2- aminopirimidinas com haletos secundários catalisada por rutênio. No total, foram obtidos vinte compostos inéditos que foram completamente caracterizados. / Studies aiming the asymmetric total synthesis of populene D are presented in this thesis. Populene D is a natural product extracted from Thespesia populnea tree trunk. Synthetic proposal for the target molecule comprised 14 steps, however, total synthesis was not achieved. Last intermediate of the proposed route was obtained, in 13 steps and 8% global yield, starting from commercially available ethyl L-lactate. An iodine-catalyzed Prins cyclization reaction is the key step of proposed synthesis. This methodology was applied to synthesize four analogues of populene D, all unknown compounds which were fully characterized, and submitted to biological activity tests. Among these four compounds, two of them have shown good results against ovary cell lines with with multidrug resistance phenotype. A new protocol of ruthenium-catalyzed site-selective alkylation of N-aryl-2- aminopyrimidines is also presented in this thesis. 20 unknown compounds were obtained using this protocol and they were fully characterized as well.

Made available in DSpace on 2015-05-14T13:21:21Z (GMT). No. of bitstreams: 1 ArquivoTotal.pdf: 14314411 bytes, checksum: 28743a0226eb51126ce933c575333208 (MD5) Previous issue date: 2013-08-02 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / This work is described the synthesis of ten new tetrahydropyran derivatives (compounds 42-51) designed from (±)-Naproxen structure utilizing the Prins reaction of cyclization as the key step to building shaped diastereoselective 2,4- cis and 2,4,6-cis rings tetrahydropyran, with overall yields between 62 - 65%. These new tetrahydropyran derivatives were in vivo bioevaluated on antinociceptive effect in the acetic acid-induced abdominal writhing test, the tail flick test, the rota-rod performance and open field tests, and all these new compounds showed greater antinociceptive activity compared to compound (±)- 1a, highlighting high activity tetraidropirânico derivative (±)-49, which showed 87.5% of inhibition, whereas compound (±)-1a gave only 14% inhibition in in the acetic acid-induced abdominal writhing test. Moreover, the (tail-flick test) indicated compounds (±)-46 and (±)-49 as the most actives, and all compounds showed antinociceptive activity (except compound (±) -51) without harming the motor impairment and without showing toxicity in mice. In continuation to this work, there was the synthesis of new hybrid molecules based on the structure of six non-steroidal anti-inflammatory drugs with a portion tetrahydropyran using molecular hybridization strategy. These new hybrid tetrahydropyran (74 - 79) were obtained in yields between (70 - 93%). Preliminary studies antinociceptive effect in the acetic acid-induced abdominal writhing test in the compounds (74 - 79) showed that all tetrahydropyran derivatives were more efficacious (lower ED50) and their precursors drugs and no sign of intoxication were observed in the animals. / Neste trabalho, é descrito a síntese de 10 novos derivados tetraidropirânicos compostos (42 51) planejados a partir da estrutura do (±)-Naproxeno, utilizando a reação de ciclização de Prins como etapa chave para a construção em forma diastereosseletiva 2,4-cis e 2,4,6-cis de anéis tetraidropirânicos, com rendimentos globais entre 62 65%. Estes novos derivados tetraidropirânicos foram bioavaliados in vivo em testes de contorções abdominais, retirada de cauda, desempenho no rota-rod e campo aberto, sendo que todos estes compostos apresentaram uma maior atividade antinociceptiva em relação ao composto (±)-1a, com destaque para a alta atividade do derivado tetraidropirânico (±)-49, que apresentou 87,5% de inibição, enquanto que o composto (±)-1a apresentou apenas 14% de inibição no teste de contorções abdominais induzida por ácido acético. Além disso, os testes de retirada de cauda indicaram os compostos (±)-46 e (±)-49 como os mais ativos, sendo que todos os compostos apresentaram atividade antinociceptiva (exceto composto (±)-51) sem prejudicar o comprometimento motor e sem demonstrar toxicidades em camundongos. Em continuação ao nosso trabalho, realizou-se a síntese de moléculas híbridas inéditas baseadas na estrutura de seis fármacos antiinflamatórios não esteroidais com uma porção tetraidropirânica utilizando a estratégia de hibridização molecular. Estes novos derivados tetraidropirânicos híbridos (74 79) foram obtidos em rendimentos entre 70 93%. Estudos preliminares realizados em teste contorções abdominais induzidas por ácido acético realizados nos compostos (74 79) revelaram que todos os derivados tetraidropirânicos foram mais eficazes (DE50 menor) que os seus fármacos percusores e nenhum sintoma de intoxicação foi observado nos animais.