Le mycothiazole-4,19-diol, découvert en 2006, est une molécule naturelle isolée de l’éponge marine cacospongia mycofijiensis, dont il n’existe à ce jour aucune synthèse. La structure originale, combinée à la faible abondance naturelle et à une activité biologique potentielle du mycothiazole-4,19-diol font de cette molécule une cible synthétique attractive pour le chimiste organicien et constitue l’objectif de ces travaux de thèse. Le principal enjeu de cette synthèse est la construction du motif diol-1,2 allylique. Au total, quatre déconnections ont été étudiées. Pour chacune d’entre elles, plusieurs approches ont été effectuées afin de construire de manière efficace et élégante le mycothiazole-4,19-diol. Une étude sur l’utilisation du palladium en synthèse organique a également été effectuée au cours cette thèse. Parmi les nombreux systèmes catalytiques dans lesquels ce métal intervient, nous nous sommes intéressés à l’oxydation aérobique des alcools en leurs dérivés carbonylés. Nous avons élaboré un nouveau système permettant l’oxydation sélective des alcools allyliques. Les résultats obtenus sur la haute chimiosélectivité intramoléculaire font de cette méthode un outil puissant et efficace et a été mis à profit dans le cadre des approches du mycothiazole-4,19-diol. Une étude supplémentaire réalisée sur l’utilisation du palladium en réactions séquentielles a également été menée avec l’élaboration d’un processus oxydation aérobique-formation de liaison C-C par couplage de Heck. L’originalité de la méthodologie développée est que le catalyseur intervient dans deux réactions totalement différentes permettant ainsi la synthèse rapide de molécules relativement complexes à partir de substrats simples. / Mycothiazole-4,19-diol is a natural compound isolated in 2006 from a marine sponge cacospongia mycofijiensis which has never been synthesized. Its unique structure, its weak abundance and its potential biological activity make mycothiazole-4,19-diol an attractive target in organic chemistry. The challenge is the building of allylic diol-1,2 moiety. In order to make a concise and elegant synthesis of this molecule, four disconnections and many approaches have been studied. A study about the use of palladium in organic synthesis has also been done. Among all the catalytic systems in which this metal is involved, we were first interested in the aerobic oxidation of alcohols into their corresponding carbonyl compounds. We have elaborated a new catalytic system which enables the selective oxidation of allylic alcohols. This methodology has been applied in the different synthetic approaches towards the mycothiazole-4,19-diol. A second study has been done about the use of palladium in sequential processes. We have elaborated a new catalyzed process with two sequential different steps: allylic alcohol oxidation-Heck reaction. The originality of this system is that the catalyst is involved in both reactions which makes an easy access to functionalized α,β-unsaturated ketones from allylic alcohols.

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Submitted by ANA KARLA PEREIRA RODRIGUES (anakarla_@hotmail.com) on 2017-08-01T12:29:24Z No. of bitstreams: 1 arquivototal.pdf: 4942842 bytes, checksum: f0ad011fa73c8b3eb2a49c98e8ca9de4 (MD5) / Made available in DSpace on 2017-08-01T12:29:24Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 4942842 bytes, checksum: f0ad011fa73c8b3eb2a49c98e8ca9de4 (MD5) Previous issue date: 2017-02-15 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Currently several works have been developed in order to provide alternative routes for the synthesis of several organic compounds. These new protocols are generally aimed at obtaining softer and more eco-friendly reactive conditions, better yields and / or reactional times, and mechanistic studies, among others. This work consists of the study of synthesis routes of cyanohydrins and tetrahydropyrans, using lanthanide catalysts and ionic liquids, respectively. As cyanohydrins are products that can be transformed into important organic intermediates. They are obtained by the cyanosilylation of aldehydes reaction, which is synthetically viable only in the presence of a Lewis acid. In this work, the MOF [Eu2 (MELL)(H2O)6] was used as a heterogeneous catalyst in the cyanosilylation of aldehydes reaction. The catalytic assays were optimized using a thermally activated MOF in acetonitrile. Different aldehydes several structurally provided their respective cyanohydrins ranging from 1 to 6 hours and yields of 62 to 100%. The MOF was recycled in the addition reaction of TMSCN to 2-furfuraldehyde without loss of activity for five cycles. Tetrahydropyran rings (THP) are common in many natural products, so various strategies are being developed to synthesize them. In this work we also describe the study to obtain 2,4,6-trisubstituted tetrahydropyrans in a single step promoted by the ionic liquid (IL) BMIM][PF6] between the allyl bromide and aldehydes, through the Barbier-Prins reaction. The tests were performed under different conditions and optimized using 1: 4 benzaldehyde and allyl bromide. The use of IL [BMIM][PF6] provided THPs of various aldehydes in good yields ranging from 40% to 75% in 8 hours of reaction. In addition, IL [BMIM][PF6] was recovered and reused in the preparation of 4-bromo-2,6-diphenyl-tetrahydro-2H-pyran by up to 5 times without significant loss of yield of that product. The influence of the PF6- anion on the reaction between benzaldehyde and allyl bromide under the Barbier reaction conditions was investigated, as well as the influence of SnBr2 salt on the Prins cyclization reaction between homoallylic alcohol and benzaldehyde. The results show evidence that PF6- acts by accelerating the Barbier reaction and the excess of SnBr2 acts as Lewis acid in the Prins cyclization reaction. Subsequently, the use of KI in the reaction between benzaldehyde and allyl bromide was investigated, and it was found that depending on the ratio used between KI and SnBr2, the preferential formation of homoalyl alcohol or THP compound could occur. / Atualmente vários trabalhos têm sido desenvolvidos no intuito de possibilitar rotas alternativas para a síntese de diversos compostos orgânicos. Esses novos protocolos visam geralmente a obtenção de condições reacionais mais brandas e eco-amigáveis, melhores rendimentos e/ou tempos reacionais, estudos mecanísticos entre outros. Este trabalho consiste no estudo de rotas de síntese de cianoidrinas e tetraidropiranos, utilizando catalisadores de lantanídeos e líquidos iônicos, respectivamente. As cianoidrinas são substâncias que podem ser transformadas em intermediários orgânicos importantes. São geralmente obtidas através da reação de cianossililação de aldeídos, que é sinteticamente viável apenas na presença de um ácido de Lewis. Nesse trabalho, a MOF [Eu2(MELL)(H2O)6] foi utilizada como catalisador heterogêneo na reação de cianossililação de aldeídos. Os ensaios catalíticos foram otimizados utilizando a MOF ativada termicamente em acetonitrila. Diversos aldeídos estruturalmente diferentes forneceram suas respectivas cianoidrinas variando de 1 a 6 horas e com rendimentos de 62 a 100%. A MOF foi reciclada na reação de adição de TMSCN à 2-furfuraldeído sem perda de atividade durante cinco ciclos. Anéis tetraidropirânicos (THP) são comuns em vários produtos naturais, portanto várias estratégias estão sendo desenvolvidas para sintetizá-los. Nesse trabalho descrevemos também o estudo para a obtenção de tetraidropiranos 2,4,6-trissubstituídos meso em uma única etapa promovida pelo líquido iônico (LI) BMIM][PF6] entre o brometo de alila e aldeídos, através da reação Barbier-Prins. Os testes foram realizados sob diferentes condições e foi otimizado utilizando-se o benzaldeído e brometo de alila na proporção 1:4. A utilização LI [BMIM][PF6] forneceu produtos THPs de vários aldeídos com bons rendimentos variando-se de 40% a 75% em 8 horas de reação. Adicionalmente o LI [BMIM][PF6] foi recuperado e reutilizado na preparação do 4-bromo-2,6-difenil-tetraidro-2H-pirano em até 5 vezes sem perda significativa dos rendimentos desse produto. Foi investigado a influência isolada do ânion PF6- na reação entre o benzaldeído e o brometo de alila nas condições reacionais de Barbier, assim como a influência do sal SnBr2 na reação de ciclização de Prins entre o álcool homoalílico e o benzaldeído. Os resultados mostram evidências que o PF6- atua acelerando a reação de Barbier e o excesso de SnBr2 atua como ácido de Lewis na reação de ciclização de Prins. Posteriormente foi investigado a utilização do KI na reação entre o benzaldeído e o brometo de alila, e verificou-se que dependendo da proporção utilizada entre o KI e o SnBr2 pode ocorrer a formação preferencial do álcool homoalílico ou do composto THP.Atualmente vários trabalhos têm sido desenvolvidos no intuito de possibilitar rotas alternativas para a síntese de diversos compostos orgânicos. Esses novos protocolos visam geralmente a obtenção de condições reacionais mais brandas e eco-amigáveis, melhores rendimentos e/ou tempos reacionais, estudos mecanísticos entre outros. Este trabalho consiste no estudo de rotas de síntese de cianoidrinas e tetraidropiranos, utilizando catalisadores de lantanídeos e líquidos iônicos, respectivamente. As cianoidrinas são substâncias que podem ser transformadas em intermediários orgânicos importantes. São geralmente obtidas através da reação de cianossililação de aldeídos, que é sinteticamente viável apenas na presença de um ácido de Lewis. Nesse trabalho, a MOF [Eu2(MELL)(H2O)6] foi utilizada como catalisador heterogêneo na reação de cianossililação de aldeídos. Os ensaios catalíticos foram otimizados utilizando a MOF ativada termicamente em acetonitrila. Diversos aldeídos estruturalmente diferentes forneceram suas respectivas cianoidrinas variando de 1 a 6 horas e com rendimentos de 62 a 100%. A MOF foi reciclada na reação de adição de TMSCN à 2-furfuraldeído sem perda de atividade durante cinco ciclos. Anéis tetraidropirânicos (THP) são comuns em vários produtos naturais, portanto várias estratégias estão sendo desenvolvidas para sintetizá-los. Nesse trabalho descrevemos também o estudo para a obtenção de tetraidropiranos 2,4,6-trissubstituídos meso em uma única etapa promovida pelo líquido iônico (LI) BMIM][PF6] entre o brometo de alila e aldeídos, através da reação Barbier-Prins. Os testes foram realizados sob diferentes condições e foi otimizado utilizando-se o benzaldeído e brometo de alila na proporção 1:4. A utilização LI [BMIM][PF6] forneceu produtos THPs de vários aldeídos com bons rendimentos variando-se de 40% a 75% em 8 horas de reação. Adicionalmente o LI [BMIM][PF6] foi recuperado e reutilizado na preparação do 4-bromo-2,6-difenil-tetraidro-2H-pirano em até 5 vezes sem perda significativa dos rendimentos desse produto. Foi investigado a influência isolada do ânion PF6- na reação entre o benzaldeído e o brometo de alila nas condições reacionais de Barbier, assim como a influência do sal SnBr2 na reação de ciclização de Prins entre o álcool homoalílico e o benzaldeído. Os resultados mostram evidências que o PF6- atua acelerando a reação de Barbier e o excesso de SnBr2 atua como ácido de Lewis na reação de ciclização de Prins. Posteriormente foi investigado a utilização do KI na reação entre o benzaldeído e o brometo de alila, e verificou-se que dependendo da proporção utilizada entre o KI e o SnBr2 pode ocorrer a formação preferencial do álcool homoalílico ou do composto THP.

This thesis deconstructs the gender symbolism evident in the opera Faust (1859) by Gounod. The objective is to determine the gendered authenticity, originality and contributing nature of the work, acknowledging the Catholic nineteenth-century French context in which it was written. The study aims to establish the nature of the gender constructs portrayed (whether representative of their conservative milieu, or suggestive of unconventionality, liberalism and innovation) and how these portrayals were executed by Gounod and his librettists. An exploration of the construction of Faust and a comparison with Goethe’s Faust: Der Tragödie Erster Teil (1808), on which the Gounodian creation is loosely based, initiates the study. The theory of performativity by Judith Butler (1990), together with other general gender hypotheses on, for instance, masculine and feminine personalities and perversity, follows. Hereafter, gender in the context of artistic performances, and gender constructs in Christianity are investigated. These general, performance-based and theological theories and ideas are then compared to the gendered characters in Faust. The secular and Catholic gender norms that governed men and women in nineteenth-century France inevitably had an influence on how gender is represented in the opera. Hence, contextual aspects, as well as Gounod’s own interaction with, and exhibition of gender are analysed in order to establish their influential extent on Faust. A deconstruction of the opera as three different texts – libretto, score and DVD productions of three Faust performances – is applied since this contributes to holistic and objective conclusions. The aspects investigated in the study have brought to light that Faust shamelessly highlights the destructive consequences of social, cultural and religious gender stereotypes governing nineteenth-century Catholic France, whilst simultaneously proposing liberated gender identities. Gounod is innovative in presenting a female protagonist through the role of Marguerite. She is an intricate, developing character representative of multiple perplexed femininities, many of which are conquering and symbolic of female empowerment. Siébel serves as a source of great gender ambiguity and contradiction. These aspects are fuelled by an ironic female identity – hence, the notion of performativity is ingeniously incorporated into this character. Both femininity and masculinity is advocated in the portrayals of Méphistophèles and the Christian God, while interesting and unexpected masculinities are embodied through Faust and Valentin. By using the above methodology, I suggest that Gounod’s Faust is an authentic and pioneering work representing ambivalent, controversial, contradictory and empowering gender constructs, making it a composition of considerable worth, both musically and historically. NB: Additional information available on a CD stored at the Merensky Library front Counter. / Dissertation (MMus)--University of Pretoria, Pretoria, 2013. / 5 CDs available with the study. Kept at the Open Scholarship Office in the Embargo room. / Music / unrestricted

Le mycothiazole-4,19-diol, découvert en 2006, est une molécule naturelle isolée de l'éponge marine cacospongia mycofijiensis, dont il n'existe à ce jour aucune synthèse. La structure originale, combinée à la faible abondance naturelle et à une activité biologique potentielle du mycothiazole-4,19-diol font de cette molécule une cible synthétique attractive pour le chimiste organicien et constitue l'objectif de ces travaux de thèse. Le principal enjeu de cette synthèse est la construction du motif diol-1,2 allylique. Au total, quatre déconnections ont été étudiées. Pour chacune d'entre elles, plusieurs approches ont été effectuées afin de construire de manière efficace et élégante le mycothiazole-4,19-diol. Une étude sur l'utilisation du palladium en synthèse organique a également été effectuée au cours cette thèse. Parmi les nombreux systèmes catalytiques dans lesquels ce métal intervient, nous nous sommes intéressés à l'oxydation aérobique des alcools en leurs dérivés carbonylés. Nous avons élaboré un nouveau système permettant l'oxydation sélective des alcools allyliques. Les résultats obtenus sur la haute chimiosélectivité intramoléculaire font de cette méthode un outil puissant et efficace et a été mis à profit dans le cadre des approches du mycothiazole-4,19-diol. Une étude supplémentaire réalisée sur l'utilisation du palladium en réactions séquentielles a également été menée avec l'élaboration d'un processus oxydation aérobique-formation de liaison C-C par couplage de Heck. L'originalité de la méthodologie développée est que le catalyseur intervient dans deux réactions totalement différentes permettant ainsi la synthèse rapide de molécules relativement complexes à partir de substrats simples.

Made available in DSpace on 2015-05-14T13:21:22Z (GMT). No. of bitstreams: 1 ArquivoTotal.pdf: 18195512 bytes, checksum: 6229ab5e9f367190d5f7b4336c07dfec (MD5) Previous issue date: 2013-08-30 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / This study was designed based on the concept of achiral / meso compound. The importance of preparing achiral compounds is based on their structural simplification, leading to new molecules which require no further investigations pharmacodynamics and pharmacokinetics of the enantiomers. Therefore, it is proposed to the synthesis of analogues tetrahydropyrans achiral/meso using the Prins cyclization reaction. The homoallylic alcohols synthesized in this work were derived from the Barbier reaction obtained in great yields, wherein these products are used as a synthesis intermediate for the preparation of tetrahydropyrans proposed. The Prins cyclization reaction is an efficient method for the preparation of tetrahydropyrans therefore proved to be a powerful tool for synthesis and versatile for the preparation of substituted tetrahydropyrans to give all the compounds synthesized in satisfactory yields. Through spectroscopic and crystallographic studies were possible to determine in detail the relative configuration of the molecules 40a, 41a, 44a, 45a, 46a, 46b and 48b. Furthermore, a theoretical study was developed using the density functional theory to obtain the molecular geometries optimized in the gas phase, making it possible to compare these preferred conformations with geometries defined by crystals. The tetrahydropyrans bioevaluated were synthesized in the leukemic cell line K562 and two types of normal L929 cells and PBMC. The results were very promising in cancer in vitro assays, highlighting the hydrazones 42a-c and the 43a-c aminoguanidines they were the only compounds that were active against resistant cell line K562, highlighting the tetrahydropyran 42c which showed higher activity series counterpart (present value of IC50 7.59 μM) and the tetrahydropyran 42b with an excellent IC50 (8.97 μM) value and a good selectivity index (2.2 in L929 and 1.6 in PBMC). / Este trabalho foi idealizado baseado no conceito de compostos aquirais/meso. A importância da preparação de compostos aquirais está baseada na sua simplificação estrutural, conduzindo a novas moléculas que não necessitam de posteriores investigações farmacodinâmicas e farmacocinéticas dos enantiômeros. Sendo assim, propomos neste trabalho a síntese de análogos tetraidropirânicos aquirais/meso utilizando a reação de ciclização de Prins. Os álcoois homoalílicos sintetizados foram provenientes da reação de Barbier obtidos em ótimos rendimentos, no qual estes produtos foram utilizados como intermediário de síntese para a preparação dos tetraidropiranos propostos. A reação de ciclização de Prins é um método eficiente na preparação dos tetraidropiranos, pois mostrou-se ser uma ferramenta de síntese poderosa e versátil para a preparação dos tetraidropiranos substituídos, obtendo-se todos os compostos sintetizados em rendimentos satisfatórios. Através de estudos espectroscópicos e cristalográficos foi possível determinar detalhadamente a configuração relativa das moléculas 40a, 41a, 44a, 45a, 46a, 46b e 48b. Além disso, foi desenvolvido um estudo teórico utilizando a teoria do funcional densidade para se obter as geometrias moleculares otimizadas em fase gasosa, tornando possível comparar estas conformações preferenciais com as geometrias definidas pelos cristais. Os tetraidropiranos sintetizados foram bioavaliados na linhagem de células leucêmicas K562 e dois tipos de células normais L929 e PBMC. Os resultados em câncer foram bastante promissores nos ensaios in vitro, dando destaque para as hidrazonas 42a-c e as aminoguanidinas 43a-c que foram os únicos compostos que se mostraram ativos contra a linhagem celular resistente K562, destacando-se o tetraidropirano 42c que apresentou maior atividade da série congênere (apresentando valor de CI50 7.59 μM) e o tetraidropirano 42b que apresentou excelente valor de IC50 (8.97 μM) e um bom índice de seletividade (2.2 em L929 e 1.6 em PBMC).

M.A. / This dissertation explores On The Contrary by Andre P. Brink against the backdrop of creative reading with emphasis on interpretation of the text as a process rather than as a product. The title On The Contrary is already indicative of the author's intention to unlock a myriad of interpretative possibilities in stead of tangibilitating a conclusion. The title also illuminates the principle that what is written is not necessarily what is said, that none of the content is cast in concrete and that the work concerns itself with the offering of contrasts: truth and untruth, imagination and reality, guilt and innocence. A symbiosis of dualism and parallelism is portrayed in order to enrich the potential for multiple text interpretations. Various texts are incorporated into the text of On The Contrary on an inter-textual basis, for the purpose of facilitating the interpretative process in an explicit and/or implicit manner. This study investigates and discusses the following three specific texts: • Don Quijote by Cervantes. Several explicit references are made to this canonised novel of Western literature, but it is the subtle, implied similarities between the lives of the characters Estienne Barbier and Don Quojote that serve as interpretative keys. • Jeanne d' Arc and her history. • The life history of Estienne Barbier, the historical 18 th century Cape figure. Remarkable documented similarities between the historical characters, Barbier and Jeanne d'Arc invite the analytical reader to try and establish the extent and purpose of incorporating the Jeanne d'Arc text into On The Contrary. Through the process of creative reading, the reader's assessment and understanding of Estienne Barbier, as a character in the novel, is moulded and formed by the life story and philosophy of Jeanne d'Arc. Barbier is constructed from a compound of historical facts and fictitious incidents. Historical "gaps" in the life of Estienne Barbier are compensated for through the introduction of elements from the life history and philosophy of Jeanne d'Arc. To that extent Barbier is a consequential character whose life and philosophy inextricably reflects examples derived from Jeanne d'Arc. The inter-textual process imbues a linear Estienne Barbier with depth in regard to the events that effect him and allows him to grow in the eyes of the reader, through fruitful application of parallels between the histories of Jeanne d'Arc and Estienne Barbier. The use of Jeanne d'Arc inter-textually and the virtual "retelling" of Jeanne, profoundly tell the story of a rebellious Barbier's "crusade" in pursuit of righteousness. In similar fashion the historical character Estienne Barbier is "told" into the romantic character Barbier in an attempt to transcend from imagination to reality. The reinterpretation of history, with the view of arriving at an alternative historical interpretation, becomes possible through the use of fiction. In primary instance this study investigates the manner in which the abovementioned three texts are incorporated inter-textually in the novel On The Contrary. Secondly an attempt is made to identify the narrative strategies that are used to arrive at a possible interpretation of the text and lastly it indulges in an exploration of the healing effect that the process of (imaginary) storytelling has in the lives of characters such as Don Quijote and Estienne Barbier.

Cette thèse se compose en deux parties: Première Partie: La conception et la synthèse d’analogues pyrrolidiniques, utilisés comme agents anticancéreux, dérivés du FTY720. FTY720 est actuellement commercialisé comme médicament (GilenyaTM) pour le traitement de la sclérose en plaques rémittente-récurrente. Il agit comme immunosuppresseur en raison de son effet sur les récepteurs de la sphingosine-1-phosphate. A fortes doses, FTY720 présente un effet antinéoplasique. Cependant, à de telles doses, un des effets secondaires observé est la bradycardie dû à l’activation des récepteurs S1P1 et S1P3. Ceci limite son potentiel d’utilisation lors de chimiothérapie. Nos précédentes études ont montré que des analogues pyrrolidiniques dérivés du FTY720 présentaient une activité anticancéreuse mais aucune sur les récepteurs S1P1 et S1P3. Nous avons soumis l’idée qu’une étude relation structure-activité (SARs) pourrait nous conduire à la découverte de nouveaux agents anti tumoraux. Ainsi, deux séries de composés pyrrolidiniques (O-arylmethyl substitué et C-arylmethyl substitué) ont pu être envisagés et synthétisés (Chapitre 1). Ces analogues ont montré d’excellentes activités cytotoxiques contre diverses cellules cancéreuses humaines (prostate, colon, sein, pancréas et leucémie), plus particulièrement les analogues actifs qui ne peuvent pas être phosphorylés par SphK, présentent un plus grand potentiel pour le traitement du cancer sans effet secondaire comme la bradycardie. Les études mécanistiques suggèrent que ces analogues de déclencheurs de régulation négative sur les transporteurs de nutriments induisent une crise bioénergétique en affamant les cellules cancéreuses. Afin d’approfondir nos connaissances sur les récepteurs cibles, nous avons conçu et synthétisé des sondes diazirine basées sur le marquage d’affinité aux photons (méthode PAL: Photo-Affinity Labeling) (Chapitre 2). En s’appuyant sur la méthode PAL, il est possible de récolter des informations sur les récepteurs cibles à travers l’analyse LC/MS/MS de la protéine. Ces tests sont en cours et les résultats sont prometteurs. Deuxième partie: Coordination métallique et catalyse di fonctionnelle de dérivés β-hydroxy cétones tertiaires. Les réactions de Barbier et de Grignard sont des méthodes classiques pour former des liaisons carbone-carbone, et généralement utilisées pour la préparation d’alcools secondaires et tertiaires. En vue d’améliorer la réaction de Grignard avec le 1-iodobutane dans les conditions « one-pot » de Barbier, nous avons obtenu comme produit majoritaire la β-hydroxy cétone provenant de l’auto aldolisation de la 5-hexen-2-one, plutôt que le produit attendu d’addition de l’alcool (Chapitre 3). La formation inattendue de la β-hydroxy cétone a également été observée en utilisant d’autres dérivés méthyl cétone. Étonnement dans la réaction intramoléculaire d’une tricétone, connue pour former la cétone Hajos-Parrish, le produit majoritaire est rarement la β-hydroxy cétone présentant la fonction alcool en position axiale. Intrigué par ces résultats et après l’étude systématique des conditions de réaction, nous avons développé deux nouvelles méthodes à travers la synthèse sélective et catalytique de β-hydroxy cétones spécifiques par cyclisation intramoléculaire avec des rendements élevés (Chapitre 4). La réaction peut être catalysée soit par une base adaptée et du bromure de lithium comme additif en passant par un état de transition coordonné au lithium, ou bien soit à l’aide d’un catalyseur TBD di fonctionnel, via un état de transition médiée par une coordination bidenté au TBD. Les mécanismes proposés ont été corroborés par calcul DFT. Ces réactions catalytiques ont également été appliquées à d’autres substrats comme les tricétones et les dicétones. Bien que les efforts préliminaires afin d’obtenir une enantioselectivité se sont révélés sans succès, la synthèse et la recherche de nouveaux catalyseurs chiraux sont en cours. / This thesis consists of two parts: Part 1: Design and synthesis of constrained azacyclic pyrrolidine analogues of FTY720 as anticancer agents FTY720 is presently marketed as a drug (GilenyaTM) for the treatment of relapsing-remitting multiple sclerosis. It functions as an immunosuppressant due to its effect on sphingosine-1-phosphate (S1P) receptors. At higher doses, FTY720 also has antineoplastic actions. However, at such doses it induces bradycardia due to the activation of the S1P1 and S1P3 receptors. This limits its potentical to be used as a cancer therapy in humans. Our previous studies have shown that some constrained pyrrolidine analogues of FTY720 have anticancer activity but no activity toward S1P1 and S1P3 receptors. We reasoned that a study of the structure-activity relationships (SARs) could lead to the discovery of new effective antitumor agents. Thus, two series of constrained analogues (O-arylmethyl-substituted pyrrolidines and C-aryl-substituted pyrrolidines) were designed and synthesized (Chapter 1). These analogues showed excellent cytotoxic activity against various human cancer cells (prostate, colon, breast, pancreas and leukemia). Especially, several active analogues, which cannot be phosphorylated by SphK, have the potency to be further studied in the treatment of cancer without inducing bradycardia. Mechanistic studies suggest that these constrained analogues trigger down-regulation of nutrient transporters, which induce a bioenergetic crisis and the cancer cells starve to death. To further investigate their target receptors, we have designed and synthesized diazirine based photo-affinity labeling (PAL) probes (Chapter 2). Aided by the PAL technique, information regarding the target receptor could be obtained through LC/MS/MS protein analysis. These tests are in progress and the preliminary results appear promising. Part 2: Metal coordination-controlled and bifunctional catalysis toward tertiary β-ketols The Barbier and Grignard reactions are classical methods to form carbon-carbon bonds, and generally used to prepare secondary or tertiary alcohols. In an attempt to perform a Grignard reaction with n-butyl iodide under Barbier one-pot conditions, we obtained major product β-hydroxyl ketol from the self-aldol reaction of 5-hexen-2-one, rather than the expected addition alcohol product (Chapter 3). The unusual β-ketol formation was also observed using other methyl ketone substrates. Interestingly, in an intramolecular reaction of a triketone substrate, which is well known to give the Hajos-Parrish ketone, the favored product was a rarely studied β-ketol with the hydroxyl group at axial position. Intrigued by these results, after systematic reaction condition studies, we developed two new methods toward the catalytic synthesis of specific β-ketols by intramolecular cylcization in high yield and selectivity (Chapter 4). The reaction can be catalyzed either by a suitable base and lithium bromide as the additive, through a lithium pre-organized transition state or by a bifunctional catalyst TBD (triazabicyclodecene), through a TBD mediated bidentate transition state. The proposed mechanisms were corroborated by DFT computation. These catalytic reactions were also extended to other triketone and diketone substrates. Although the initial efforts to achieve enantioselectivity were not successful, they merit further study of the synthesis and investigation of new chiral catalysts.