Leiodolide A is a unique natural product isolated from Pacific marine sponges which has provided an interesting target for total synthesis due to its complex structure and undefined stereochemistry. Although synthetic work towards the synthesis of sister compound leiodolide B has been published, the total synthesis of leiodolide A is yet to be achieved but remains an important target due to high potency against leukaemia, non-small lung and ovarian cancers. The convergent strategy towards the synthesis of leiodolide A involved the synthesis of three subunits; a synthetic route to the C21-C25 vinyl stannane is described, and efforts towards the synthesis of the bidirectional C11-C20 subunit are detailed. Asymmetric vinylogous aldol methodology was developed for the installation of the 1,2-syn propionate motif found in the C1-C10 subunit and in other polypropionate natural products, and was shown to be applicable to a range of substrates in moderate diastereoselectivity and excellent enantioselectivity.

SIRT1 and SIRT2 are two NAD⁺-dependent deacetylases which negatively modulate the activity of p53, a protein which is involved in cell cycle arrest, senescence and apoptosis following genotoxic stress. Part I of the thesis describes the exploration of the chemical space around a reported unselective and modest inhibitor of SIRT1 and SIRT2 with the aim of improving the selectivity and potency of the inhibitor against the two isoforms. Particular emphasis is placed upon understanding the mode of binding of the novel analogues within the active site of the enzymes. Chapter 1 reviews the physiological roles of class III NAD⁺-dependent deacetylases, also known as sirtuins. In particular, the application of SIRT1 and SIRT2 inhibitors as potential anticancer agents is described. Amongst these, only cambinol and the tenovins showed in vivo activity in a mouse xenograft model. Previously only one analogue of cambinol had been reported in the literature. Chapter 2 describes the development of a small collection of novel cambinol analogues (First Generation Studies). The role played by different substituents at the phenyl group and at the N-1 of the thiouracil core is discussed. Along with the synthesis and structure activity relationship (SAR) associated with the core structure, in-cell experiments intended to confirm the activity of the most active compounds are reported. Chapter 3 provides a rationalisation for the SAR discussed in Chapter 2. Based on computational molecular modelling studies (GOLD), the activity of the most potent and selective SIRT2 inhibitors is explained. Two series of novel cambinol analogues were designed (Second and Third Generation Analogues) in order to assess further the proposed binding mode. Chapter 4 focuses on the development of the “Second Generation” analogues, characterised by the presence of lipophilic substituents at the sulfur atom and at the N-3 position of the thiouracil core. The synthesis, biological evaluation and SAR are discussed in detail. Chapter 5 reports the development of the “Third Generation” analogues, characterised by either a benzyl group or para-alkoxy-substituted benzyl group at the N-1 position of cambinol. Once again, the synthesis, biological evaluation and SAR data are presented. An improved understanding of the mode of binding of the novel compounds is proposed based on molecular dynamics (MD) studies. Indole-based alkaloids, such as Vincristine and Vinblastine, are well known for their anticancer activity. Recently, the anticancer activity of members of the calycanthaceous family of alkaloids has been discovered. Part II of the thesis focuses on model studies aimed at developing the total synthesis of one of these compounds, perophoramidine. Chapter 7 provides an overview of the calycanthaceous alkaloid family of natural products, including their biological properties. The structural features of perophoramidine, along with the previously reported synthetic studies are outlined. Chapter 8 describes the synthesis of an advanced intermediate in the total synthesis of dehaloperophoramidine, a structural analogue of perophoramidine Problems encountered, optimisation studies and the synthesis of a re-designed intermediate are also reported in this chapter.

Cet ouvrage traite d’une méthodologie pour l’induction de centres stéréogènes au sein des motifs propionates par la chimie des radicaux et de son application à la synthèse totale du méthyl ester de la zincophorine. Cet ionophore, aux propriétés biologiques intéressantes, présente plusieurs défis synthétiques dont une séquence de type polypropionate anti, anti, anti, anti difficilement accessible ainsi qu’un tétrahydropyrane trans trisubstitué. Récemment, l’intérêt renouvelé pour ces composés polyéthers, en tant qu’agents anticancéreux, accentue l’importance de stratégies versatiles permettant l’accès à ces structures ainsi qu’à leurs analogues. Depuis quelques années, notre groupe s’intéresse à la synthèse d’unités propionates acycliques par une séquence réactionnelle contrôlée uniquement par le substrat. La première étape découle d’une aldolisation de Mukaiyama entre un aldéhyde alpha-chiral et un énoxysilane tétrasubstitué portant une liaison carbone-halogène, et où l’issue stéréochimique dépend de la nature monodentate ou bidentate de l’acide de Lewis employé. La seconde réaction-clé implique la formation d’un radical tertiaire, vicinal à un ester, pouvant être réduit diastéréosélectivement en présence d’hydrure d’étain. La première section décrit l’élaboration de motifs tétrahydropyranes trisubstitués et l’induction des centres stéréogènes vicinaux par une réduction radicalaire. Nous avons révélé que l’issue diastéréosélective de la réaction de cyclisation par une iodoéthérification était dictée par le groupement gamma-méthyle des esters alpha,beta-insaturés de départ. Nous avons ensuite démontré que les produits de la réaction radicalaire anti et syn pouvaient être obtenus sélectivement à partir d’un intermédiaire commun, respectivement en prenant appui sur l’effet exocyclique ou endocyclique lors de la réduction. Par une stratégie complémentaire, nous avons révélé que le précurseur radicalaire pouvait également être obtenu par une réaction de cycloéthérification en présence d’un énoxysilane tétrasubstitué. Une étude systématique des substituants du cycle a révélé que certaines relations stéréochimiques conduisaient à une perte de sélectivité au détriment du produit anti. La seconde section concerne l’étude DFT au niveau BHandHLYP/TZVP des intermédiaires radicalaires impliqués lors du transfert d’hydrogène. Par une étude de décomposition de l’énergie d’activation, nous avons été en mesure de rationaliser l’issue diastéréosélective de la réaction sur la base des énergies de distorsion (∆Ed‡) et d’interaction (∆Eint‡) requises pour accéder à la paire d’états de transition pro-anti et pro-syn. De plus, nous avons démontré qu’une analyse NBO permettait de relativiser l’impact des interactions stéréoélectroniques. Par la suite, l’évaluation des intermédiaires radicalaires borinates et aluminates nous a permis de révéler que l’encombrement stérique de la chaîne propionate était la cause principale de la formation sélective des produits anti ou syn lors d’une réduction en présence d’un acide de Lewis. La dernière section décrit l’élaboration de la séquence polypropionate de la zincophorine, et de ses isomères, à partir du fragment tétrahydropyrane substitué. Au cours de notre étude, nous avons identifié que le nombre de sites de chélation potentiels devait être limité à trois lors de l’aldolisation en condition Cram-chélate. De plus, nous avons démontré que les différents motifs acétates sont accessibles sélectivement par l’utilisation d’un énoxysilane encombré. Par ailleurs, nous avons révélé qu’une même séquence réactionnelle pouvait être employée pour la synthèse du fragment C17–C25 de son analogue naturel CP-78,545, et avons complété la plus récente synthèse totale du méthyl ester de la zincophorine. / The focus of this thesis is the use of free radical chemistry for the introduction of stereogenic centres in propionate motifs and application of this methodology to the total synthesis of zincophorin methyl ester. This ionophore, with interesting biological properties, displays several synthetic challenges including an anti, anti, anti, anti polypropionate sequence and a trisubstituted trans tetrahydropyran. Recently, the renewed interest for polyether compounds as anticancer agents emphasizes the significance of versatile strategies to access these targets, as well as analogues thereof. Over the last few years, our research group has been interested in the synthesis of acyclic polypropionates via a substrate-based strategy relying on two key reactions. The first one consists of a Mukaiyama aldol reaction between an alpha-chiral aldehyde and a tetrasubstituted enoxysilane bearing a carbon-halogen bond, where the stereochemical outcome depends on the monodentate or bidentate nature of the Lewis acid. The second key step involves the generation of a tertiary free radical, vicinal to an ester, which can be reduced diastereoselectively in presence of trialkyl tin hydride. The first section illustrates the elaboration of trisubstituted tetrahydropyran motifs and the induction of vicinal stereogenic centres via a radical reduction. We discovered that the diastereoselective outcome of the iodoetherification cyclization reaction was dictated by the gamma-methyl group of alpha,beta-unsaturated esters. Moreover, we showed that both anti and syn reduction products could be accessed from a common radical intermediate, respectively by relying on the exocyclic or endocyclic effect during the reduction reaction. Using a complementary strategy, we also revealed that the radical precursor could be accessed via a cycloetherification reaction in presence of a tetrasubstituted enoxysilane. A systematic investigation of the substituents on the ring indicated that certain stereochemical relationships led to a decrease in anti-selectivity. The second section presents a DFT study, at the BHandHLYP/TZVP level of theory, of radical intermediates involved in hydrogen transfer. Using an energy decomposition analysis, we were able to rationalize the diastereoselective outcome of the reaction on the basis of the distortion energy (∆Ed‡) and interaction energy (∆Eint‡) required to access pro anti and pro syn transition states. Moreover, we have demonstrated that a Natural Bond Orbital (NBO) analysis can be used to interpret stereoelectronic interactions. Subsequently, an evaluation of radical intermediates bearing a borinate or an aluminate revealed that steric hindrance of the propionate chain was mainly responsible for the selective formation of anti and syn reduction products in the presence of a Lewis acid. The last section describes the elaboration of the polypropionate sequence of zincophorin, and analogues thereof, from the substituted tetrahydropyran fragment. In our analysis, we have highlighted the necessity to limit the number of potential chelation sites to three during the aldol step under Cram-chelate conditions. Moreover, we demonstrated that the different aldol acetate motifs are accessible using a bulky enoxysilane. Finally, we showed that a similar reaction sequence can be used to access the C17–C25 fragment of its natural analogue CP-78,545 and have completed the most recent total synthesis of zincophorin methyl ester.

Les macrolactones sont des squelettes structuraux importants dans de nombreuses sphères de l’industrie chimique, en particulier dans les marchés pharmaceutiques et cosmétiques. Toutefois, la stratégie traditionnelle pour la préparation de macrolactones demeure incommode en requérant notamment l’ajout (super)stœchiométrique d’agents activateurs. Conséquemment, des quantités stœchiométriques de sous-produits sont générées; ils sont souvent toxiques, dommageables pour l’environnement et nécessitent des méthodes de purification fastidieuses afin de les éliminer. La présente thèse décrit le développement d’une macrolactonisation efficace catalysée au hafnium directement à partir de précurseurs portant un acide carboxylique et un alcool primaire, ne générant que de l’eau comme sous-produit et ne nécessitant pas de techniques d’addition lente et/ou azéotropique. Le protocole a également été adapté à la synthèse directe de macrodiolides à partir de mélanges équimolaires de diols et de diacides carboxyliques et à la synthèse de dimères tête-à-queue de seco acides. Des muscs macrocycliques ainsi que des macrolactones pertinentes à la chimie médicinale ont pu être synthétisés avec l’approche développée. Un protocole pour l’estérification directe catalysée au hafnium entre des acides carboxyliques et des alcools primaires a aussi été développé. Différentes méthodes pour la macrolactonisation catalytique directe entre des alcools secondaires et des acides carboxyliques ont été étudiées. En outre, la stratégie de séparation de phase en macrocyclisation en débit continu a été appliquée lors de la synthèse totale formelle de la macrolactone ivorenolide A. Les étapes-clés de la synthèse incluent une macrocyclisation par le couplage d’alcynes de Glaser-Hay et une réaction de métathèse d’alcènes Z-sélective. / Macrolactones are important structural motifs in numerous chemical industries particularly in the pharmaceutical and cosmetic markets. However, the traditional strategy for the preparation of macrolactones remains cumbersome, often requiring stoichiometric or excess amounts of activating reagents. Consequently, stoichiometric quantities of by-products are generated. They are often toxic, environmentally damaging, and/or require tedious purification methods to remove them. The following thesis describes the development of an efficient hafnium-catalyzed direct macrolactonization between carboxylic acid and primary alcohol functionalities, generating only water as a by-product and without the need for slow addition or azeotropic techniques. The protocol was also adapted for the direct synthesis of macrodiolides from equimolar mixtures of diols and dicarboxylic acids and for the selective head-to-tail dimerization of seco-acids. Macrocyclic musks and macrolactones relevant to medicinal chemistry were synthesized using the developed approach. A hafnium-catalyzed esterification protocol between carboxylic acids and primary alcohols was also developed. Different methods for the direct catalytic macrolactonization from secondary alcohols and carboxylic acids were studied. Furthermore, the phase separation strategy for macrocyclization in continuous flow was applied in the formal total synthesis of the macrolactone ivorenolide A. The key steps of the synthesis include the Glaser-Hay alkyne coupling macrocyclization and a Z-selective olefin metathesis reaction.

Ce travail développe différentes stratégies pour la synthèse énantiosélective de sesquiterpènes naturels à partir de chirons obtenus par biocatalyse. La première partie est consacrée aux premières synthèses énantiosélectives de la kopéoline, et de la kopéolone. La synthèse de la structure décrite de la kopéoline est réalisée, les composés ont été entièrement caractérisés. Les résultats montrent que les structures reportées n'ont pas été correctement assignées, et suggèrent une mauvaise attribution des stéréocentres au cours de l'isolement des produits naturels. Ainsi, deux nouvelles structures sont proposées. Les synthèses totales de ces deux dernières structures ont également été réalisées et ont permis de confirmer la révision structurelle et de caractériser complètement ces produits naturels tout en élucidant leurs configurations absolues inconnues jusqu'alors.La seconde partie aborde la synthèse du siphonellinol D selon une méthodologie convergente d'une partie Est et d'une partie Ouest. Les deux énantiomères d'un chiron ont été obtenus par dédoublement cinétique enzymatique avec des rendements élevés et d'excellentes énantiosélectivités. À partir de l'énantiomère (1S, 6R), la synthèse de la partie Est est rapportée. Malheureusement, une première méthodologie employant l'énantiomère (1R, 6S) n'a pas permis l'obtention de la partie bicyclique Ouest. Une seconde méthodologie utilisant le géraniol comme substrat a permis l'accès à la partie Ouest du siphonellinol D sous forme racémique. Une réaction de couplage entre ces deux parties a été réalisée avec succès permettant d'envisager de manière optimiste la synthèse du siphonellinol D par ce chemin synthétique. / This work deals with different strategies used in the course of the enantioselective synthesis of natural sesquiterpenes starting from an enantiopure building block obtained by biocatalysis. The first part is dedicated to the first enantioselective syntheses of kopeolin, and kopeolone. The synthesis of kopeolin was achieved and compounds have been fully characterized. The results showed that the reported structures were not assigned correctly, and suggest an initial structural misassignment during the isolation of the natural products. Thus, two new structures for kopeolin and for kopeolone are proposed. The enantioselective total syntheses of these two proposed structures have been achieved and permitted to confirm the structural revision and to fully characterize these natural products while elucidating their hitherto unknown absolute stereochemistries.The second part is dedicated to the synthesis of siphonellinol D with a convergent methodology of the Eastern part and the Western part. Both enantiomers of this building block were obtained by an enzymatic kinetic resolution in high yields and excellent enantioselectivities. Starting from the (1S, 6R) enantiomer, the synthesis of the Eastern part of Siphonellinol D is reported. Unfortunately, a first methodology using the use of the (1R, 6S) enantiomer failed. A second methodology using geraniol as starting material led to the racemic Western part of siphonellinol D. A coupling reaction were successfully performed allowing us to consider the synthesis of siphonellinol D by this synthetic pathway as optimistic.

Na primeira parte da tese foram abordadas diversas rotas sintéticas para a preparação dos fragmentos nordeste e sudoeste do alcaloide bisindólico Raputindol D, cuja síntese total nunca foi descrita. A proposta inicial era obter o fragmento nordeste em 13 etapas a partir do composto comercial 3-metil-4-nitrofenol, utilizando como etapas-chave uma reação de Diels-Alder, uma abertura redutiva de anel e uma contração de anel com iodo(III). Empregando uma reação de Diels-Alder regiosseletiva de um intermediário silil substituído, a construção de uma unidade tricíclica linear foi alcançada com a obtenção de um único regioisômero. Entretanto, todas as tentativas de abertura de anel do alqueno oxabicíclico resultaram apenas no regioisômero não desejado, apesar dos estudos prévios com compostos modelo terem revelado que essa proposta era viável. Assim, foi possível acessar um intermediário avançado em 13 etapas e 12% de rendimento global. O fragmento sudoeste foi obtido em 3 etapas a partir do 5-bromoindol comercial, em rendimento global de 47% e empregando como etapas principais uma reação de Sonogashira e uma reação de acoplamento com 1-hidróxibenziodoxolone. Na segunda parte da tese são apresentados os resultados referentes ao estudo da etapa-chave para a conexão dos fragmentos nordeste e sudoeste, através do desenvolvimento de uma nova metodologia de α-alquinilação eletrofílica de compostos carbonílicos aromáticos não-ativados com o iodo hipervalente TMS-EBX. Empregando tBuOK como base e TBAF como agente ativante, cetonas mono- e dialquiniladas foram obtidas em ótimos rendimentos. A utilização de aldeídos como substratos também se mostrou viável, o que permitiu acessar derivados de álcoois homopropargílicos em rendimentos moderados após a redução dos produtos com NaBH4 in situ. Finalmente, a aplicação da metodologia desenvolvida foi demonstrada através da preparação de um intermediário de alquinilação avançado. A atividade antiproliferativa desse composto foi investigada, mostrando-se apenas fracamente ativo com uma atividade mais pronunciada para células de carcinoma de ovário e leucemia. / In the first part of the thesis several synthetic routes for the preparation of the northeast and southwest fragments of the bisindolic alkaloid Raputindole D, whose total synthesis has never been described, were approached. The initial proposal was to obtain the northeast fragment in 13 steps from the commercial compound 3-methyl-4-nitrophenol, using as key steps a Diels-Alder reaction, a reductive ring opening and a ring contraction with iodine(III). Employing a regioselective Diels-Alder reaction of a silyl substituted intermediate, the construction of a linear tricyclic unit was achieved with the obtainment of a single regioisomer. However, all attempts to ring opening of the oxabicyclic alkene only resulted in the undesired regioisomer, although previous studies with model compounds revealed that this proposal was feasible. Thus, it was possible to access an advanced intermediary in 13 steps and 12% overall yield. The southwest fragment was obtained in 3 steps from commercial 5- bromoindole in 47% overall yield and employing as main steps a Sonogashira reaction and a coupling with 1-hydroxybenziodoxolone. In the second part of the thesis are presented the results regarding the study of the key step for the connection of the northeast and southwest fragments, through the development of a new methodology for the electrophilic α-alkynylation of non-activated aromatic carbonyl compounds with the hypervalent iodine TMS- EBX. Employing t-BuOK as a base and TBAF as an activating agent, mono- and dialkynylated ketones were obtained in good yields. The use of aldehydes as substrates also proved to be possible, allowing to access homopropargylic alcohols derivatives in moderate yields after reduction in situ using NaBH4. Finally, the application of the developed methodology was demonstrated by the preparation of an advanced alkynylation intermediate. The antiproliferative activity of this compound was investigated, showing only weakly active with a more pronounced activity for ovarian carcinoma and leukemia cells.

Na primeira parte da tese foram abordadas diversas rotas sintéticas para a preparação dos fragmentos nordeste e sudoeste do alcaloide bisindólico Raputindol D, cuja síntese total nunca foi descrita. A proposta inicial era obter o fragmento nordeste em 13 etapas a partir do composto comercial 3-metil-4-nitrofenol, utilizando como etapas-chave uma reação de Diels-Alder, uma abertura redutiva de anel e uma contração de anel com iodo(III). Empregando uma reação de Diels-Alder regiosseletiva de um intermediário silil substituído, a construção de uma unidade tricíclica linear foi alcançada com a obtenção de um único regioisômero. Entretanto, todas as tentativas de abertura de anel do alqueno oxabicíclico resultaram apenas no regioisômero não desejado, apesar dos estudos prévios com compostos modelo terem revelado que essa proposta era viável. Assim, foi possível acessar um intermediário avançado em 13 etapas e 12% de rendimento global. O fragmento sudoeste foi obtido em 3 etapas a partir do 5-bromoindol comercial, em rendimento global de 47% e empregando como etapas principais uma reação de Sonogashira e uma reação de acoplamento com 1-hidróxibenziodoxolone. Na segunda parte da tese são apresentados os resultados referentes ao estudo da etapa-chave para a conexão dos fragmentos nordeste e sudoeste, através do desenvolvimento de uma nova metodologia de α-alquinilação eletrofílica de compostos carbonílicos aromáticos não-ativados com o iodo hipervalente TMS-EBX. Empregando tBuOK como base e TBAF como agente ativante, cetonas mono- e dialquiniladas foram obtidas em ótimos rendimentos. A utilização de aldeídos como substratos também se mostrou viável, o que permitiu acessar derivados de álcoois homopropargílicos em rendimentos moderados após a redução dos produtos com NaBH4 in situ. Finalmente, a aplicação da metodologia desenvolvida foi demonstrada através da preparação de um intermediário de alquinilação avançado. A atividade antiproliferativa desse composto foi investigada, mostrando-se apenas fracamente ativo com uma atividade mais pronunciada para células de carcinoma de ovário e leucemia. / In the first part of the thesis several synthetic routes for the preparation of the northeast and southwest fragments of the bisindolic alkaloid Raputindole D, whose total synthesis has never been described, were approached. The initial proposal was to obtain the northeast fragment in 13 steps from the commercial compound 3-methyl-4-nitrophenol, using as key steps a Diels-Alder reaction, a reductive ring opening and a ring contraction with iodine(III). Employing a regioselective Diels-Alder reaction of a silyl substituted intermediate, the construction of a linear tricyclic unit was achieved with the obtainment of a single regioisomer. However, all attempts to ring opening of the oxabicyclic alkene only resulted in the undesired regioisomer, although previous studies with model compounds revealed that this proposal was feasible. Thus, it was possible to access an advanced intermediary in 13 steps and 12% overall yield. The southwest fragment was obtained in 3 steps from commercial 5- bromoindole in 47% overall yield and employing as main steps a Sonogashira reaction and a coupling with 1-hydroxybenziodoxolone. In the second part of the thesis are presented the results regarding the study of the key step for the connection of the northeast and southwest fragments, through the development of a new methodology for the electrophilic α-alkynylation of non-activated aromatic carbonyl compounds with the hypervalent iodine TMS- EBX. Employing t-BuOK as a base and TBAF as an activating agent, mono- and dialkynylated ketones were obtained in good yields. The use of aldehydes as substrates also proved to be possible, allowing to access homopropargylic alcohols derivatives in moderate yields after reduction in situ using NaBH4. Finally, the application of the developed methodology was demonstrated by the preparation of an advanced alkynylation intermediate. The antiproliferative activity of this compound was investigated, showing only weakly active with a more pronounced activity for ovarian carcinoma and leukemia cells.

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.

Cette thèse est constituée de trois parties : 1) Le contexte bibliographique, 2) le développement de réactions domino cupro-catalysées et 3) une approche vers la synthèse totale des raputindoles.La première partie introduit d’abord le concept de réactions domino ainsi que leurs applications, puis les réactions catalysées par du cuivre permettant de former des liaisons C-N sont passées en revue en incluant les couplages de Ullmann, Goldberg et de Chan-Lam, les séquences d’activation oxydante de liaisons C-H/formation de liaison C-N, l’insertion de nitrènes et l’hydroamination de liaisons C-C multiples. En se basant sur ces réactions élémentaires permettant de former une liaison C-N unique, les développements récents de réactions domino sont ensuite détaillés.La deuxième partie peut être subdivisée en 3 sections : 1) la synthèse de benzimidazoles, 2) la synthèse d’imidazoles and 3) la synthèse de guanidines. Un rappel des méthodes existantes pour la synthèse de ces motifs est proposé dans chaque section. Notre travail, basé sur la formation de liaisons C-N multiples selon une séquence cupro-catalysée domino, est ensuite détaillé. Celui-ci nous a permis d’aboutir au développement de voies d’accès aux benzimidazoles, en utilisant une réaction séquentielle catalysée par du cuivre en présence d’oxygène à partir d’acides boroniques et d’amidines, à la synthèse d’imidazoles par une réaction de di-amination d’alcynes vrai par des amidines et à l’obtention de guanidines et de 2-aminobenzimidines par une réaction à 3 composant. Ces réactions domino montrent une bonne efficacité et permettent d’assembler des hétérocycles à partir de précurseurs aisément accessibles.La dernière partie est consacrée à la synthèse des raputindoles. La structure, les activités et les réactions clé pour la construction de ces alcaloïdes sont discuté d’abord, nous amenant à proposer une rétrosynthèse pour accéder à ces molécules. Les réactions qui ont retenues notre attention pour construire ces molécules sont une annelation [3+2] irido-catalysée d’acides o-formylarylboronique et de 1,3-diènes, la synthèse de Leimgruber-Batcho pour obtenir des indoles et une séquence d’alkylboration-protodéboration. A partir de cela 3 stratégies ont été évaluées, montrant que l’accès à ce type de composé naturel est envisageable en combinant ces étapes. / This thesis consists in three parts: bibliographic background, copper-catalyzed reactions for synthesis of N-containing compounds, approach to the synthesis of raputindoles.The first part introduces the domino reactions and their applications, then, copper-mediated reactions for construction of C-N bond formation are reviewed including Ullmann, Goldberg and Chan-Lam coupling, oxidative C-H activation/C-N formation, insertion of nitrenes and carbenoids, and hydroamination of multi-C-C bonds. This can be used as guides to design domino reaction. Following these copper-mediated single C-N bond formation reactions, recent developments of copper-catalyzed domino reactions for synthesis of heterocycles are described.The second part can be divided into three sections: 1) synthesis of benzimidazoles, 2) synthesis of imidazoles and 3) synthesis of guanidines. Each section summarizes the existing methods used for their synthesis. Following it, our synthetic work involving copper-catalyzed C-N bond formation domino reactions is discussed in detail. Our objectives include the synthesis of benzimidazoles through copper-catalyzed sequential reaction of benzamidines and boronic acids, synthesis of imidazoles via copper-catalyzed domino reaction of benzamidines and acetylenes, and synthesis of guanidines and 2-aminobenzimidazoles by Cu-catalyzed three-component reaction of cyanamides, boronic acids and amines. These copper-catalyzed domino reactions show high efficiencies from readily available and simple starting materials.The last part is about the total synthesis of raputindoles. The structure and bioactivities of raputindoles and key reactions for the total synthesis of raputindoles are introduced first, the synthetic strategies are then proposed on basis of relative synthetic methods. The key reactions we use for the synthesis of raputindoles are iridium catalyzed [3+2] annulation of o-formylarylboronic acids and 1,3-dienes, Leimgruber-Batcho indole synthesis, transition-metal catalyzed SN2 substitution and alkylborylation-protondeborylation. According to the three strategies we proposed, lots of relative reactions were investigated. The results show that it is possible to synthesize the raputindole molecules based on the iridium catalyzed [3+2] annulation of 2-formylarylboronic acids and 1,3-dienes.

Esta tese descreve, em três diferentes capítulos, a preparação de quatro produtos naturais com atividade biológica reconhecida. O primeiro se refere à síntese de dois ácidos carboxílicos diacetilênicos, os ácidos monitipóricos A e B, isolados dos ovos do coral duro Montipora digitada e que apresentam atividade citotóxica e antibacteriana. Estas sínteses foram alcançadas utilizando-se reações de acoplamento de acetilenos e eterificação por CTF. Reações de transposição de ligação tripla e redução de acetileno terminal por semi-hidrogenação com Lindlar/H2, ou hidroteluração/transmetalação Te-Li, são discutidas. O segundo capítulo descreve a síntese do virol C, um diol poliacetilênico análogo à cicutoxina, isolado como um dos componentes tóxicos da planta Cicuta virosa. Para isso utilizou-se química de sulfóxidos para indução de quiralidade na formação do estereocentro C-10. A união dos fragmentos se deu por reações de Wittig e acoplamento de acetilenos mediado por cobre(I). O último capítulo é dedicado à descrição das tentativas de obtenção do éster metílico do ácido pinélico, um ácido triidroxioctadecenóico derivado do ácido linoléico. É produzido por certas variedades de arroz, como agente de defesa contra o fungo Pyricularia orizae</i< e é relacionado com a qualidade da cerveja, além de ser isolado da planta medicinal Pinellia ternata, como um potente adjuvante para a vacina nasal contra influenza. As tentativas de síntese deste produto foram baseadas em diveras abordagens retrospectivas, onde a última apresenta reações de redução estereosseletiva de &#946;-ceto-sulfóxidos, acoplamento-cruzado entre fragmentos vinílicos e diidroxilação de Sharpless. / This thesis describes, in three different chapters, the synthesis of four natural products with recognized biological activity. The first refers to the synthesis of two diacetylenic carboxylic acids, montiporic acids A and B, which were isolated from eggs of hard coral Montipora digitata and have presented cytotoxic and antibacterial activity. These synthesis were achieved through reactions of acetylenic coupling and etherification on FTC conditions. Reactions of triple bond transposition and terminal acetylene reduction with Lindlar/H2 hydrogenation or hydrotelluration/transmetalation Te-Li are discussed. The second chapter describes the synthesis of Virol C, a polyacetilenic diol analogous of cicutoxin, isolated as a toxic component of Cicuta virosa. The chemistry of sulfoxides was used, in order to achieve the desired configuration. The union of fragments was archieved by Witting and acetylenic coupling reactions.The last chapter describes the attempts to get the methylic ester of pinellic acid, a trihyroxyoctadecenoic acid, based from linoleic acid. Pinellic acid was produced bu some species of rice, as a chemical defense against the fungus Pyricularia orizae; it is related with the quality of beers; and its isolated from Pinellia ternata, (a medicinal plant), as a powerful adjuvant against influenza. The atempts of the synthesis was based on several retrosynthetic approaches, where the last one users a stereo selective reduction of &#946;-ketosulfoxide, cross-coupling between vinyllic fragments and Sharpless dihydroxylation.