Les alcaloïdes sont, en général, une famille de composés hétérocycliquesd'origine végétale qui intègrent des atomes d'azote dans leur structure complexe.Leur intérêt réside dans les activités biologiques intéressantes qu'ils présentent, etpour cette raison, ils sont largement utilisés par l'industrie pharmaceutique. Enparticulier, les anneaux de pyrrolidine et de pipéridine se trouvent comme basefondamentale dans un grand nombre de telles structures. D'autre part, l'un desprincipaux objectifs de la chimie synthétique est d'obtenir ces types de moléculesd'une manière asymétrique. Entre autres, la catalyse métallique s'est révélée trèsutile à cet effet. Par exemple, les ligands de type ferrocényle précédemmentdéveloppés dans notre groupe donnent naissance à des pyrrolidines énantiopuréesdensément substituées. De même, ces types de ligands ont été évalués dansdifférents types de réactions de cycloaddition, ce qui a entraîné la formationasymétrique de structures tricycliques d'intérêt biologique. D'autre part, une synthèseracémique collective de composés tétracycliques de la famille Securinega a étédéveloppée. Cette synthèse permet d'accéder à différents produits naturels de lafamille en raison de la polyvalence de l'intermédiaire lactone bicyclique. / Alkaloids are, in general, a family of heterocyclic compounds of vegetal originthat incorporate nitrogen atoms in their complex structure. Their interest lies in theoutstanding biological activities they present, and for this reason they are widely usedby the pharmaceutical industry. In particular, pyrrolidine and piperidine rings arefundamental scaffolds found in a large number of such structures. On the other hand,one of the main objectives of synthetic chemistry is to obtain these types ofmolecules in an asymmetric way. Among others, metal catalysis has proven to bevery useful for this purpose. For example, ferrocenyl proline ligands previouslydeveloped in our group gave rise to densely substituted enantiopure pyrrolidines.Likewise, these types of ligands have been evaluated in different types ofcycloaddition reactions, which have resulted in the asymmetric formation of tricyclicstructures of biological interest. In contrast, a collective racemic synthesis oftetracyclic compounds of the Securinega family has been developed. This synthesisprovides an access to different natural products of the family due to the divergencegiven by a bicyclic lactone intermediate.

No description available.

Le tripeptide GPE possède une activité neuroprotectrice intéressante in-vitro et in-vivo pour différents types de dommage neuronaux. L'objectif de cette thèse est de mettre au point des méthodes de couplage peptidique pour les acides aminés trifluorométhylés et de réaliser des analogues trifluorométhylés du GPE.Au cours de cette thèse, la synthèse d'acides aminés trifluorométhylés cycliques énantiopurs (proline, pseudoproline) a été réalisée à l'échelle du gramme.Ensuite, une étude méthodologique de l'incorporation de ces acides aminés trifluorométhylés dans des peptides a été effectuée.Des expériences RMN ont été menées pour étudier la conformation cis/trans de la liaison amide de ces peptides trifluorométhylés.Enfin, des analogues du tripeptides GPE ont été synthétisé en remplaçant le motif proline par une proline ou pseudoproline trifluorométhylé. Des tests biologiques sont actuellement en cours pour évaluer leur activité sur divers troubles neuronaux.

Orientador: Carlos Roque Duarte Correia / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-16T16:31:07Z (GMT). No. of bitstreams: 1 Godoi_MarlaNarciso_D.pdf: 10035986 bytes, checksum: 6deb65c44c4239f0ee6985fb972c18b1 (MD5) Previous issue date: 2010 / Resumo: Este trabalho de tese visou desenvolver rotas sintéticas eficientes para síntese de prolinas ariladas utilizando como etapa-chave a reação de arilação de Heck-Matsuda. Além disso, os aminoácidos arilados tiveram seu potencial organocatalítico avaliado frente a reações aldólicas e Mannich multicomponente. No primeiro capítulo serão apresentados resultados referentes à síntese de 5-arilprolinas. A preparação estereosseletiva destes compostos teve como etapa-chave uma das reações de arilação de Heck-Matsuda e envolveu um enecarbamato derivado do ácido piroglutâmico. Após foi realizada a avaliação organocatalítica destes aminoácidos, e constatamos que seu desempenho não superou a L-prolina. Diante disso, partimos para síntese e investigação do desempenho organocatalítico de derivados da prolina arilados em C-4. Iniciamos o segundo capítulo com resultados sobre o desempenho organocatalítico do arilcainóide 61, arilado em C-4. Este aminoácido foi inicialmente testado em uma reação aldólica e apresentou um desempenho catalítico um pouco superior ao da L-prolina. Desta forma, partimos para síntese de 4-arilprolinas, explorando uma segunda reação de arilação de Heck- Matsuda que utiliza L-desidroprolinas como olefinas. Nesta etapa do trabalho, realizamos um estudo metodológico para obtenção de enecarbamatos monoarilados. O uso de microondas na reação de arilação proporcionou uma redução bastante significativa nos tempos reacionais. A partir da eliminação estereosseletiva com hidreto de silano e BF3.Et2O dos intermediários 2- metoxiprolinas 4-arilados foi possível a obtenção de cis-4-arilprolinas em apenas 3 etapas. / Abstract: This work aimed at the development of efficient routes for the synthesis of aryl prolines with the Heck-Matsuda reaction as key step. The potential of these arylated amino acids as organocatalysts was evaluated through aldol and multicomponent Mannich reactions. In the first chapter results will be presented concerning the synthesis of 5-aryl prolines. The stereoselective preparation of these compounds employed the Heck-Matsuda reaction as key step and involved an enecarbamate derived from piroglutamic acid. The organocatalytic behavior of these amino acids was evaluated and one noted that its performance was inferior to that of L-proline. Due to this observation, derivatives of prolines arylated in C-4 were synthesized and tested as organocatalysts. The second chapter begins with studies on the performance of the C-4- arylated aryl kainoid xx as organocatalyst. This amino acid was initially tested in aldol reactions and presented an organocatalytic performance slightly superior to that of L-proline itself. Hence, 4-arylprolines were synthesized, exploring the Heck-Matsuda reaction with L-dehydroprolines as olefins, and their potential as organocatalysts was also investigated. In this moment of the work, a methodologic study concerning the preparation of monoarylated enecarbamates was performed. Employ of microwaves-based heating on the arylation reactions allowed significant reduction of reaction times. From a stereoselective methanol elimination from 4-arylated 2-methoxy-prolines, employing silane hydrides and BF3.Et2O, one could obtain cis-4-aryl-prolines in only three steps. / Doutorado / Quimica Organica / Doutor em Ciências

Orientador: Carlos Roque Duarte Correia / Acompanha Anexo denominado V.2. Paginação continua / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-12T12:04:47Z (GMT). No. of bitstreams: 1 Garcia_ArielLazaroLlanes_D.pdf: 15520800 bytes, checksum: 2744757a92f3045d187a1c68320729d5 (MD5) Previous issue date: 2008 / Resumo: A reação de arilação de Heck-Matsuda é um procedimento sintético valioso e extremamente versátil para a formação de ligações carbono-carbono, baseada no acoplamento de uma olefina com um sal de arenodiazônio na presença de uma espécie organometálica de paládio zerovalente. Recentemente, a utilização desta reação tem ganhado espaço na arte de sínteses totais, demonstrando a viabilidade da mesma. Neste trabalho, apresentamos o desenvolvimento de metodologias novas e flexíveis para a síntese eficiente de vários produtos naturais e sintéticos com propriedades farmacológicas importantes, utilizando a reação de arilação de Heck-Matsuda como etapa chave. No total, foram sintetizados 21 compostos finais, incluindo: prolinas e pirrolidinas poliidroxiladas racêmicas e quirais, Radicamina B e outros a-C-ariliminociclitóis quirais análogos das Radicaminas A e B, Rolipram, ácidos b-aril-g-aminobutíricos análogos do Baclofeno, e um precursor chave de Prepolicitrina A e Policitrina A. Os compostos sintetizados, assim como seus respectivos intermediários de reação, foram plenamente caracterizados e os resultados obtidos foram comparados com aqueles reportados na literatura quando aplicável. Dados analíticos e espectroscópicos satisfatórios foram obtidos em todos os casos. / Abstract: The Heck-Matsuda arylation reaction is a valuable and extremely versatile synthetic procedure for carbon-carbon bond formation, based on the coupling of an olefin with an arenediazonium salt in the presence of a zerovalent palladium organometallic specie. Recently, the use of this reaction has been gaining space in total syntheses, demonstrating its viability. In this work, we presented the development of new and flexible methodologies for the efficient synthesis of several natural and synthetic products with important pharmacologic properties, using the Heck-Matsuda arylation reaction as a key stage. Totally, a set of 21 final compounds were synthesized, including: racemic and chiral polyhydroxylated prolines and pyrrolidines, Radicamine B and other chiral C-aryl-iminocyclitols analogues of Radicamines A and B, Rolipram and b-aryl-g-aminobutyric acids analogues of Baclofen, and a key precursor of Prepolycitrin A and Polycitrin A. The synthesized compounds, as well as their respective reaction intermediates, were entirely characterized and the obtained results were compared with those reported in the literature when applicable. Satisfactory analytical and spectral data were obtained in all cases. / Doutorado / Quimica Organica / Doutor em Ciências

Le tripeptide GPE possède une activité neuroprotectrice intéressante in-vitro et in-vivo pour différents types de dommage neuronaux. L'objectif de cette thèse est de mettre au point des méthodes de couplage peptidique pour les acides aminés trifluorométhylés et de réaliser des analogues trifluorométhylés du GPE.Au cours de cette thèse, la synthèse d'acides aminés trifluorométhylés cycliques énantiopurs (proline, pseudoproline) a été réalisée à l'échelle du gramme.Ensuite, une étude méthodologique de l'incorporation de ces acides aminés trifluorométhylés dans des peptides a été effectuée.Des expériences RMN ont été menées pour étudier la conformation cis/trans de la liaison amide de ces peptides trifluorométhylés.Enfin, des analogues du tripeptides GPE ont été synthétisé en remplaçant le motif proline par une proline ou pseudoproline trifluorométhylé. Des tests biologiques sont actuellement en cours pour évaluer leur activité sur divers troubles neuronaux. / GPE is a tripeptide with neuroprotecting activity both in-vitro and in-vivo for various neuronal dammage. The goal of this thesis was to work out peptide coupling methods for trifluoromethylated amino acids and the synthesis of trifluoromethylated analogs of GPE.During this thesis, the synthesis of enantiopure cyclic trifluoromethylated amino acids (proline and pseudoprolines) was performed successfully on grams scale.Then, methodological study of their incorporation in peptide was performed.NMR experiments were made to investigate the cis/trans conformation of the amide bound of trifluoromethylated peptide. At last, analogs of the tripeptide GPE were made with trifluoromethylated proline and pseudoprolines instead of the proline. Biological tests are currently under progress to evaluate their activity on various neuronal disorders.

No description available.