Les protéines à domaine PDZ, en très grand nombre dans le génome humain, sont impliquées dans des interactions protéine-protéine. Elles participent ainsi à véhiculer des signaux à l'origine de différentes pathologies (cancer, douleur....). L'interruption de l'interaction entre la protéine à domaine PDZ, PSD-95, et le récepteur de la sérotonine, 5-HT2A, entraîne une réduction de l'hyperalgie chez le rat neuropathique. Le développement de molécules capables d'inhiber cette interaction pourrait donc conduire à une nouvelle classe d'antalgiques.Nous avons réalisé, au cours de ces travaux, la synthèse de trois générations de ligands, comportant un noyau indolique, capables d'interagir avec le site S0, site très conservé des protéines à domaines PDZ. Dans un premier temps, nous avons préparé 15 biligands possédant un noyau indolique polysubstitué lié, via un espaceur de longueur variable (2 à 6 atomes de carbone), à différents acides aminés, dans le but d'interagir avec le site S1, montrant beaucoup de diversité en fonction du domaine. Nous avons ensuite, après une étude de relation structure/activité, développé deux autres générations d'indoles polysubstitués présentant notamment des substituants hydrophobes en position 5.Nous avons montré, par RMN HSQC 1H/15N et chromatographie d'affinité, que deux de ces composés sont des inhibiteurs de l'interaction PSD-95/5-HT2A et présentent de fortes interactions avec le site S0 de PSD-95. Ces molécules présentent également des propriétés antalgiques particulièrement intéressantes in vivo. Nous avons également déterminé, par RMN NOESY, la structure du complexe protéine/ligand pour ces deux composés. L'orientation d'une de ces molécules dans le site de la protéine nous permet d'envisager le développement d'une nouvelle génération d'indoles polysubstitués, pouvant interagir avec le site S1 de la protéine et permettant ainsi d'obtenir des inhibiteurs sélectifs de l'interaction PSD-95/5-HT2A.

Malaria continues to threaten human beings, causing a staggering number of more than 400,000 deaths each year. Although effective treatment and prevention methods are available, rapidly emerging resistance towards existing drugs is of great concern, and the need for novel antimalarial compounds are still urgent. The Malaria Box lead molecules MMV008138 and MMV665831 are promising in this regard, due to their apparently novel antimalarial mechanisms of action. The target of MMV008138 is the PfIspD enzyme in the MEP pathway, which is absent in humans. This difference makes the PfIspD a great target. However, while MMV008138 shows potency against Plasmodium falciparum-infected human erythrocytes in vitro, no efficacy was observed in a humanized mouse model or a P. berghei infected mouse in vivo. In order to block potential metabolic spots and to probe for steric demand, a series of analogous featuring C1-deuteration, methyl substitution on B- and C-ring, and an ethylene bridge were prepared. The effect of various substitution on the tetrahydro-β-carboline conformation and D-ring orientation was studied. In the course of preparing the C1-Me analog of MMV008138 featuring 2',4'- dichloro substitution, unexpected ring-expanded azepane products were isolated. Later it was found that the desired product could be isolated when the imine formed was treated with acid at lower temperature. Other intermediates possessing a 2ʹ- substituent were also isolated under the low temperature acid treatment protocol, which upon heating in acid gave the ring-expanded azepane we initially isolated. A mechanism was proposed to account for the formation of the azepane as well as other intermediates. The driving force of the expansion reaction was explored, and the hypothesis that the steric interaction between the 2ʹ-substituent and the C1-Me was supported via DFT calculation and conformational analysis. MMV665831 is another potent hit from the Malaria Box, and it appears to inhibit the hemoglobin endocytosis process of P. falciparum. The structure–activity relationship of MMV665831 was studied with analogues featuring modifications on C2-benzamide, C3-ester, C-7 phenol, as well as the phenolic Mannich base moiety. Modifications at phenolic Mannich base moiety leads to the discovery of an analogue that is twice as potent toward cultured P. falciparum compared to MMV665831. We were worried the phenolic Mannich base moiety might act as the precursor of toxic quinone methide intermediates, and designed two analogs to block this potential toxicophore. Although the modification resulted in reduced potency, this result proved that the potency of MMV665831 does not stem from the formation of quinone methides. Unfortunately, MMV665831 did not reduce parasitemia in P. berghei- infected mice. Fast hepatocyte metabolism was observed for MMV665831, and the loss of in vivo efficacy was discussed in comparison with other phenolic Mannich bases with similar hepatocyte stability. / Doctor of Philosophy / In the fight against malaria, one concerning issue is the rapidly emerging resistance towards existing drugs. The continuous development of antimalarials with novel mechanism of action is greatly needed. To accelerate the development of novel antimalarials, an open access ensemble of 400 compounds that are toxic to the malaria parasite known as the Malaria Box, has been made available. My work involves the optimization of two compounds from this ensemble, MMV008138 and MMV665831. MMV008138 kills the malaria parasite by inhibiting an enzyme named PfIspD, which is absent in human. In the parasite an enzyme called PfIspD is responsible for the biosynthesis of IPP and DMAPP, two chemical building blocks that are essential for all cells. It is unlikely that MMV008138 will interrupt with the biosynthesis of IPP and DMAPP in human, since we use another enzyme to synthesize them. Although MMV008138 shows great in vitro potency, but did not protect a live mouse from malaria infection. The lack of in vivo efficacy could stem from the rapid metabolism of MMV008138, and analogs aimed to prevent metabolism were designed and prepared. While preparing analogs featuring 2ʹ-substitution, the desired product was not found, but other unexpected by-products were isolated. The conditions that leads to both the desired products and the by-products were found, and the mechanistics detail of this unexpected reaction were studied. During the blood-stage, which causes malaria symptoms in human, the Plasmodium falciparum parasite invades and feeds on human red blood cells (erythrocytes). The parasite destroys human hemoglobin through a multistep process that begins by transporting the hemoglobin from the red blood cell into itself, a process called endocytosis. MMV665831 appears to interfere with this endocytosis process of P. falciparum, thus starving the parasite of its food. Analogs of MMV665831 were prepared to probe for the effect on potency, and one compound that is twice as potent in cultured parasites was found. The structure of MMV665831 contains a potentially unstable moiety, which might lead to toxicity in humans. Two analogs with the problematic moiety removed were designed and prepared, and one still shows antimalarial activity, showing that the reactivity of the potentially unstable moiety is not the reason for the antimalarial activity of MMV665831. However, MMV665831did not protect P. berghei-infected mice (murine malaria) in vivo, and the reason for the loss of efficacy was discussed.

Les alcaloïdes canthin-6-one, 5-méthoxy-canthin-6-one et N-oxyde de canthin-6-one ainsi que l'alkylamide sanshool et trois coumarines ont été identifiés et quantifiés des écorces, feuilles (dans ce cas une étude annuelle a été menée), fruits et racines de Zanthoxylum chiloperone var. angustifolium (Rutaceae) récoltée en Amérique du Sud. Divers analogues de la canthin-6-one ont été obtenus par hémisynthèse en exploitant la réactivité de l'azote pyridinique N-3. De nouveaux analogues ont été synthétisés à partir de différentes tryptamines et anhydrides fonctionnalisés. La mise au point de nouvelles voies de synthèse, permettant leur obtention en 3 ou 4 étapes avec de bons rendements, a permis notamment de retracer toute la voie de biosynthèse de ces alcaloïdes. La stratégie de synthèse a, ensuite, été spécifiquement adaptée à la synthèse de molécules à motifs prénylés. L'activité antituberculeuse, l'activité antiproliférative sur cellules souches cancéreuses, ainsi que plusieurs activités antiparasitaires (maladie de Chagas, paludisme, activité nématicide) ont été étudiées et divers mécanismes d'action proposés. Finalement, nous avons réalisé une étude originale d'électrochimie sur des canthinones ainsi que les premiers essais de formulation galénique avec cette famille d'alcaloïdes.

Triquentrinas A são produtos naturais marinhos com atividade biológica e alta complexidade estrutural. Estes fatores tornam estes alcaloides e compostos análogos, como os herbindóis, alvos para a síntese total e plataforma para o desenvolvimento de novas metodologias sintéticas. Nesta Dissertação de Mestrado, procurou-se completar a síntese estereosseletiva da (+)-cis-triquentrina A empregando-se intermediários sintéticos protegidos com o grupo benzila que poderão ser usados para a futura prospecção de novos compostos com atividade biológica. A rota proposta baseia-se na obtenção do ácido (S)-3-(1-benzil-4-etil-1H-indol-7-il)butanóico, um intermediário-chave já descrito por Silva e colaboradores no percurso da síntese total da (+)-trans-triquentrina A, e da finalização da síntese de acordo com a abordagem proposta pelo grupo de RajanBabu para conversão do análogo protegido com grupo tosila à (+)-cis-triquentrina A. A resolução enzimática do intermediário-chave com lipase de Pseudomonas cepacia imobilizada em terra diatomácea foi otimizada, resultando em rendimentos de 32% e 99% ee na metade do tempo descrito anteriormente. Na etapa-chave da síntese, o (S)-ácido foi submetido a uma acilação de Friedel-Crafts intramolecular na presença de anidrido trifluoroacético que produziu o produto de ciclização desejado com 40% de rendimento. Na etapa final da síntese, o intermediário sintético protegido com grupo benzila não pode ser convertido à (+)-cis-triquentrina A, empregando-se a metodologia desenvolvida para a redução do composto análogo tosilado, dada a diferença de reatividade imposta pela troca do grupo protetor. As etapas realizadas até o penúltimo intermediário sintético (S)-8, consta com 10 etapas e rendimento global de 1,3%. viii As diferenças eletrônicas e estruturais relacionadas a diferentes grupos protetores poderão ser refletidas em variações na atividade antiproliferativa de indóis relacionados a triquentrinas. Ainda no interesse de preparar moléculas para envio à análises de atividade antiproliferativa preparou-se um composto relacionado à síntese da trans-triquentrina A tendo como etapa-chave uma contração de anel mediada por I(III) em 21% de rendimento, cujo trabalho foi incluído nos anexos. / Trikentrins A are marine natural products with biological activity and high structural complexity. These factors make these alkaloids and analogous compounds, such as herbidoles, targets for total synthesis and platform for the development of new synthetic methodologies. In this Master\'s Dissertation, we attempted to complete the stereoselective synthesis of (+)-cis-trikentrin A using synthetic intermediates protected with the benzyl group that could be used for the future prospection of new compounds with biological activity. The proposed route is based on the preparation of (S)-3-(1-benzyl-4-ethyl-1H-indol-7-yl) butanoic acid, a key intermediate already described by Silva et al., in the course of total synthesis (+)-trans-triquentrin A, and the final part of the synthesis according to the approach proposed by the RajanBabus group for conversion of the protected analogue with tosyl group to (+)-cis-trikentrin A. The enzymatic resolution of the key intermediate with Pseudomonas cepacia lipase immobilized on diatomaceous earth was optimized, resulting in 32% yield and 99% ee in half the time described above. In the key step of the synthesis, the (S)-acid was subjected to an intramolecular Friedel-Crafts acylation in the presence of trifluoroacetic anhydride which yielded the desired cyclization product in 40% yield. In the final step of the synthesis, the synthetic intermediate protected with benzyl group couldnt be converted to (+)-cis-trikentrin A, employing the methodology developed for the reduction of the tosylated analogous compound, given the difference of reactivity imposed by exchange of the protective group. The steps carried out up to the synthetic intermediate (S)-8, consists of 10 steps and overall yield of 1.3%. Electronic and structural differences related to different protective groups may be reflected in variations in the antiproliferative activity of indoles related to trikentrins. A compound related to the synthesis of trans-triquentrin A having as its key step an I(III) mediated ring contraction in 21% yield was also prepared in the interest of preparing molecules for antiproliferative activity analysis, whose work was included in the appendix.

No description available.

Triquentrinas A são produtos naturais marinhos com atividade biológica e alta complexidade estrutural. Estes fatores tornam estes alcaloides e compostos análogos, como os herbindóis, alvos para a síntese total e plataforma para o desenvolvimento de novas metodologias sintéticas. Nesta Dissertação de Mestrado, procurou-se completar a síntese estereosseletiva da (+)-cis-triquentrina A empregando-se intermediários sintéticos protegidos com o grupo benzila que poderão ser usados para a futura prospecção de novos compostos com atividade biológica. A rota proposta baseia-se na obtenção do ácido (S)-3-(1-benzil-4-etil-1H-indol-7-il)butanóico, um intermediário-chave já descrito por Silva e colaboradores no percurso da síntese total da (+)-trans-triquentrina A, e da finalização da síntese de acordo com a abordagem proposta pelo grupo de RajanBabu para conversão do análogo protegido com grupo tosila à (+)-cis-triquentrina A. A resolução enzimática do intermediário-chave com lipase de Pseudomonas cepacia imobilizada em terra diatomácea foi otimizada, resultando em rendimentos de 32% e 99% ee na metade do tempo descrito anteriormente. Na etapa-chave da síntese, o (S)-ácido foi submetido a uma acilação de Friedel-Crafts intramolecular na presença de anidrido trifluoroacético que produziu o produto de ciclização desejado com 40% de rendimento. Na etapa final da síntese, o intermediário sintético protegido com grupo benzila não pode ser convertido à (+)-cis-triquentrina A, empregando-se a metodologia desenvolvida para a redução do composto análogo tosilado, dada a diferença de reatividade imposta pela troca do grupo protetor. As etapas realizadas até o penúltimo intermediário sintético (S)-8, consta com 10 etapas e rendimento global de 1,3%. viii As diferenças eletrônicas e estruturais relacionadas a diferentes grupos protetores poderão ser refletidas em variações na atividade antiproliferativa de indóis relacionados a triquentrinas. Ainda no interesse de preparar moléculas para envio à análises de atividade antiproliferativa preparou-se um composto relacionado à síntese da trans-triquentrina A tendo como etapa-chave uma contração de anel mediada por I(III) em 21% de rendimento, cujo trabalho foi incluído nos anexos. / Trikentrins A are marine natural products with biological activity and high structural complexity. These factors make these alkaloids and analogous compounds, such as herbidoles, targets for total synthesis and platform for the development of new synthetic methodologies. In this Master\'s Dissertation, we attempted to complete the stereoselective synthesis of (+)-cis-trikentrin A using synthetic intermediates protected with the benzyl group that could be used for the future prospection of new compounds with biological activity. The proposed route is based on the preparation of (S)-3-(1-benzyl-4-ethyl-1H-indol-7-yl) butanoic acid, a key intermediate already described by Silva et al., in the course of total synthesis (+)-trans-triquentrin A, and the final part of the synthesis according to the approach proposed by the RajanBabus group for conversion of the protected analogue with tosyl group to (+)-cis-trikentrin A. The enzymatic resolution of the key intermediate with Pseudomonas cepacia lipase immobilized on diatomaceous earth was optimized, resulting in 32% yield and 99% ee in half the time described above. In the key step of the synthesis, the (S)-acid was subjected to an intramolecular Friedel-Crafts acylation in the presence of trifluoroacetic anhydride which yielded the desired cyclization product in 40% yield. In the final step of the synthesis, the synthetic intermediate protected with benzyl group couldnt be converted to (+)-cis-trikentrin A, employing the methodology developed for the reduction of the tosylated analogous compound, given the difference of reactivity imposed by exchange of the protective group. The steps carried out up to the synthetic intermediate (S)-8, consists of 10 steps and overall yield of 1.3%. Electronic and structural differences related to different protective groups may be reflected in variations in the antiproliferative activity of indoles related to trikentrins. A compound related to the synthesis of trans-triquentrin A having as its key step an I(III) mediated ring contraction in 21% yield was also prepared in the interest of preparing molecules for antiproliferative activity analysis, whose work was included in the appendix.

La chimie des hétérocycles est un des domaines les plus importants en chimie organique. En effet, 65% de la littérature en chimie organique traite des hétérocycles. Ils sont largement présents dans la nature, essentiels à la vie et leurs applications sont infinies. Parmi eux, les structures dites privilégiées, attirent une attention particulière. Ces structures privilégiées, dont font partie les quinoléines et les indoles, jouent un rôle central dans la chimie médicinale, pour la production de librairies de cibles thérapeutiques. De ce fait, le développement de nouvelles méthodes de synthèse de structures privilégiées, simples, efficaces et sensibles à l’impact environnemental reste un défi pour les chimistes. De nombreuses méthodes de synthèse requièrent l’emploi de dérivés d’anilines acylées en position ortho, mais ces substrats sont peu disponibles. La réaction d’addition en cascade, catalysée au cuivre, d’un réactif de Grignard sur l’anthranilate de méthyle permet l’obtention d’une aniline acylée en position ortho, jamais reportée au préalable, avec un rendement quantitatif. Cette dernière servira alors de substrat de départ pour la synthèse de plusieurs hétérocycles privilégiés dont les quinoléines et les indoles. La réaction de Friedlander est utilisée depuis plusieurs siècles mais souffre de l’emploi de conditions réactionnelles extrêmes et nocives pour l’environnement. Elle a donc été modernisée pour donner accès à une série de huit quinoléines trisubstituées, sans solvant, ni acide fort, ni hautes températures. Par ailleurs, le procédé de Heumann consiste en la synthèse d’indoles substitués en position par alkylation d’anilines acylées en position ortho, suivie d’une étape de saponification et de cyclisation intramoléculaire. Breveté par l’entreprise B.A.S.F., en 1895, ce procédé est rapidement devenu obsolète dû à de faibles rendements et des conditions réactionnelles difficiles. La chimie en flux continu a alors permis la renaissance de ce procédé grâce à l’élaboration d’un protocole plus efficace et plus sécuritaire. Somme toute, les travaux présentés dans cette thèse contribuent au développement de méthodologies simples, efficaces, sensibles aux enjeux environnementaux et menant à des structures plus complexes. / The heterocycle chemistry is one of the most important fields in organic chemistry. Indeed, 65% of the literature in organic chemistry is about heterocycles. They are widely present in nature, essential to life and their applications are endless. Among them, the so-called privileged structures, attract particular attention. Privileged structures, of which quinolines and indoles are a part, play a crucial role in medicinal chemistry, for the production of libraries of therapeutic targets. Therefore, the development of new synthetic methods, simple, efficient and sensitive to environmental impact remains a challenge for chemists. Many synthetic methods require the use of o-acylated anilines, but these substrates are not easily available. The copper catalyzed addition reaction of a Grignard reagent on methyl anthranilate allows to form an o-acylated aniline, never reported before, with a quantitative yield. The latter will then serve as starting material for the synthesis of several privileged heterocycles including quinolines and indoles. The Friedlander reaction has been used for several centuries but suffers from the use of extreme reaction conditions which are harmful to the environment. It has therefore been modernized to give access to a series of eight trisubstituted quinolines, without solvent, strong acid or high temperatures. Furthermore, Heumann's process consists of the synthesis of indoles substituted in position by o-acylated anilines alkylation, followed by saponification and intramolecular cyclization steps. Patented by B.A.S.F. in 1895, this process quickly became obsolete due to low yields and difficult reaction conditions. Continuous flow chemistry has resurrected this process through the development of a more efficient and safer protocol. All in all, the work presented in this thesis contributes to the development of simple, effective methodologies, sensitive to environmental issues and leading to increasingly complex structures.

En la presente tesis se desarrolla el empleo de alcoholes fluorados, en concreto, el hexafluoroisopropano, como disolventes para el desarrollo de metodologías alternativas para las reacciones de oxidación y ciclación. De este modo, en el primer capítulo, síntesis de tetrahidrofuradons substituidos mediante la apertura cíclica de epóxidos con alquenos ricos en electrones promovida por HFIP, se ha desarrollado un método directo para la síntesis de tetrahidrofuranos a través de la adición de alquenos ricos en electrones a epóxidos empleando alcoholes fluorados, en particular el 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), como disolventes y promotores de la reacción. El procedimiento descrito da lugar a la obtención de nuevos espiro compuestos basados en tetrahidrofuranos, así como derivados de tetrahidrobenzofuranos en rendimientos moderados y bajo condiciones de reacción suaves siendo, de este modo, una metodología medioambientalmente benigna debido a su economía atómica y la disponibilidad de los reactivos. Por otro lado, en el segundo capítulo, oxidación de arenos ricos en electrones empleando sistemas HFIP-UHP, se ha descrito la oxidación directa de arenos ricos en electrones empleando el aducto de urea-peróxido de hidrógeno (UHP) como fuente oxidante y el 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) como disolvente y promotor de la reacción. Así pues, se obtuvieron una gran variedad de quinonas en rendimientos de moderados a excelentes mediante un proceso de reacción considerado como sostenible, quedando de este modo demostrado que no es necesaria la utilización de metales para dar lugar al proceso oxidativo. Dentro del tercer capítulo, síntesis directa de N,N-formamidas disubstituidas mediante la oxidación de iminas empleando sistemas de HFIP-UHP, se describe la síntesis directa de formamidas N,N-disustituidas mediante la combinación de 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) como disolvente y el aducto de urea-peróxido de hidrógeno (UHP) como fuente oxidante. Se obtuvieron de este modo una gran variedad de formamidas con unos rendimientos de buenos a excelentes bajo unas condiciones suaves de reacción, siendo también posible su síntesis a través de una secuencia de un paso. Este protocolo medioambientalmente benigno fue aplicado para la síntesis a gran escala de la N,N-difenilformamida. En el capítulo 4, ruptura oxidativa de indoles mediante el empleo de UHP o H2O2 en disolventes polares, se ha llevado a cabo la ruptura oxidativa de indoles, conocida como oxidación de Witkop, mediante el empleo de disolventes polares con una fuente oxidativa como el agua oxigenada o el aducto de urea-peróxido de hidrógeno (UHP). En efecto, el uso del HFIP, de entre los disolventes utilizados, fue seleccionado como el más recomendable para la obtención de las 2-cetoacetanilidas con altos rendimientos. Además de los indoles, este protocolo de reacción se amplió para la ruptura de los derivados de pirrol y furanos. Además, se demostró que dicho procedimiento era factible a mayor escala, pudiendo recuperar y reutilizar el disolvente hasta cuatro ciclos, dando lugar a una metodología sostenible. Finalmente, dentro del último capítulo que encontramos en la tesis, deshidrogenación de compuestos N-heterocíclicos empleando H2O2 y mediada por disolventes polares, se expone una deshidrogenación oxidativa alternativa de compuestos N-heterocíclicos mediada por una fuente oxidativa más verde, como es el agua oxigenada, en combinación con disolventes polares como el HFIP o el agua. Aunque se obtuvieron buenos resultados al emplear el agua como disolvente, se lograron alcanzar rendimientos más altos para los derivados heteroaromáticos cuando se utilizó el HFIP debido a la activación electrofílica del H2O2. Junto con la amplia gama de tetrahidroquinolinas seleccionadas, diferentes compuestos N-heterocíclicos como las tetrahidroisoquinolinas o las indolinas, también se llevaron a estudio obteniendo los correspondientes productos con bajos rendimientos. Además de esto, es importante señalar que le metodología descrita fue también implementada en gran escala, reciclando de este modo el disolvente hasta cinco veces con una ligera erosión en la conversión después de cada ciclo. Con ello, se han desarrollado metodologías alternativas donde se reduce el uso de metales como catalizadores o condiciones extremas de reacción, ya bien sea por las elevadas temperaturas o presiones. Por otro lado, se ha propuesto en todos los capítulos un mecanismo de reacción para cada uno de los procedimientos descritos, así como el reciclaje y reutilización de disolvente, o la síntesis a gran escala, demostrándose la aplicabilidad de los procesos y demostrando la sostenibilidad del proceso.

No / The identification of an agent that is selectively activated by a cytochrome P450 (CYP) has the potential for tissue specific dose intensification as a means of significantly improving its therapeutic value. Towards this goal, we disclose evidence for the pathway of activation of a duocarmycin analogue, ICT2700, which targets CYP1A1 for biological activity.

La fonctionnalisation de liaisons C-H réputées peu réactives ouvre de nouvelles perspectives en synthèse organique. La catalyse par un métal de transition comme le palladium représente une solution particulièrement efficace à ce problème. Les travaux de thèse présentés dans ce mémoire s’inscrivent dans ce contexte. Dans un premier temps, la réaction étudiée, catalysée par le palladium, a visé à étendre une méthodologie mise au point au laboratoire pour la synthèse de carbocycles et d’hétérocycles à cinq chaînons par activation intramoléculaire de liaisons C(sp3)-H à partir de chlorures d’aryles. Ces derniers sont en effet plus disponibles et moins onéreux que les bromures d’aryle correspondants. Des études d’optimisation ont été effectuées pour la mise au point d'une réaction diastéréosélective et régiosélective. Plusieurs substrats ont été synthétisés pour être ensuite placés dans les conditions optimales de la réaction d’activation C(sp3)-H, et ont conduit à une grande diversité de cycles à cinq chaînons fusionnés. Dans un deuxième temps, nos travaux ont consisté à étendre l’activation C(sp3)-H pallado-catalysée à des précurseurs non aromatiques cycliques ou acycliques. Pour des raisons d'accessibilité, nos études se sont alors portées sur la préparation de bromures vinyliques azotés pouvant conduire après activation C-H à des motifs hexahydroindoles ou pyrrolidines. De nouvelles conditions d’activation CH ont alors été trouvées pour cette famille de substrats, et ont conduit aux hétérocycles cibles de manière diastéréosélective et régiosélective. Après extension de la réaction à divers précurseurs, nous nous sommes intéressés à la synthèse d’un intermédiaire poly-fonctionnalisé permettant d'accéder aux aéruginosines, famille de produits naturels bioactifs. / The direct functionalization of unactivated C-H bonds represents an atom- and step-economical alternative to more traditional synthetic methods based on functional group transformation, which often require multi-step sequences. In particular, transition-metal catalysis has recently emerged as a owerful tool to functionalize otherwise unreactive C-H bonds. In this context, we first investigated the extension of a methodology that has been developed in our laboratory for the synthesis of fused five-membered rings via palladium-catalyzed C(sp3)-H activation from aryl chlorides. Optimization studies were conducted and reaction conditions leading to a regioand diastereoselective process were found. These optimal conditions were applied to various ubstrates, giving rise to a variety of fused five-membered carbocycles and heterocycles. Next, our work was devoted to the extension of the palladium-catalyzed C(sp3)-H activation to cyclic and acyclic non aromatic precursors. Our studies focused on the preparation of the more accessible nitrogen-containing bromoalkene substrates, leading to interesting hexahydroindole or pyrrolidine motifs by C-H activation. New C-H activation conditions were adapted to this family of substrates and led to the synthesis of the target heterocycles in a regio- and diastereoselective manner. As a more complex application of this method, we investigated the synthesis of a polyfunctionalized intermediate allowing the access to the aeruginosin family of bioactive natural products.