La catalyse représente une thématique incontournable de la chimie moderne. Elle occupe une place stratégique dans la recherche de procédés de synthèse plus écologiques et plus économiques en atomes et en énergie. Notre travail réside, d’une part, dans la valorisation d’un biocatalyseur original et, d’autre part, dans la synthèse pallado-catalysée de nouveaux dérivés pyridopyrimidiniques. Dans la première partie, l’utilisation d’un nouveau support naturel préparé à base d’os animal (Animal Bone Meal : ABM) en catalyse hétérogène a été mise en oeuvre, ce qui représente une voie nouvelle et originale, permettant de remplacer les différents catalyseurs solides minéraux connus actuellement et ce, dans diverses réactions classiques de la synthèse organique. Outre les excellents rendements obtenus, les aspects positifs de l’ABM résident dans sa grande stabilité, sa facilité de manipulation et de régénération ainsi que dans l’absence de dangers sur l'environnement. Dans la deuxième partie, une nouvelle stratégie de synthèse simple et efficace de 2,4-di(hét)aryl-pyrido[2,3-d]pyrimidines via un couplage de Suzuki-Miyaura catalysée par le palladium a été développée. Nous avons ensuite étudié la réactivité de diverses 2,4,6-trihalogénopyrido[2,3-d]pyrimidines vis-à-vis des couplages de Suzuki. Cette étude a été étendue à la synthèse de nouvelles 2,4,6-tri(hét)arylpyrido[2,3-d]pyrimidines. / Catalysis is an essential theme of modern chemistry. It occupies a strategic position in the search process more environmentally friendly and more economical energy to atoms and synthesis. Our work lies, on one hand, the development of an original biocatalyst and, secondly, in the pallado-catalyzed synthesis of new derivatives pyridopyrimidiniques. In the first part, the use of a new natural media prepared animal bone (Animal Bone Meal: ABM) based in heterogeneous catalysis has been implemented, which is a new and original way, to replace different solid catalysts currently known minerals and that, in several classical reactions in organic synthesis. In addition to the excellent yields, the positive aspects of ABM lies in its stability, ease of handling and regeneration as well as in the absence of environmental hazards. In the second part, a new strategy for simple and efficient synthesis of 2,4-di(het)aryl-pyrido[2,3-d]pyrimidine via a Suzuki- Miyaura coupling catalyzed by palladium has been developed. We then studied the reactivity of various 2,4,6- trihalogénopyrido[2,3-d]pyrimidine via Suzuki couplings. This study was extended to the synthesis of new 2,4,6- tri(het)arylpyrido[2,3-d]pyrimidine.

La formation de cancers est liée à des dérèglements de la progression du cycle cellulaire ou de l’apoptose. L’identification des acteurs cellulaires mis en jeu dans la maladie et l’élucidation des mécanismes responsables de ces dysfonctionnements sont à la base de nouveaux traitements anticancéreux. Ainsi, en vue du développement de thérapies ciblées, les kinases Pim et les protéines anti-apoptotiques de la famille des Bcl-2, surexprimées dans de nombreux types de cancers et associées à des phénomènes de chimiorésistance, constituent des cibles pertinentes. Les kinases Pim (Pim-1,-2 et -3) sont une famille de sérine / thréonine kinases qui jouent un rôle fondamental dans les processus de survie, de prolifération ou de différenciation cellulaire. Bien qu’elles possèdent un substrat commun avec les autres protéines kinases, l’ATP, des différences structurales permettent de les différencier et de les inhiber sélectivement. En tenant compte de ces spécificités, nous nous sommes intéressés à la synthèse de nouveaux inhibiteurs sélectifs des kinases Pim, compétitifs de l’ATP. Parmi les autres agents impliqués dans la formation de tumeurs, les protéines de la famille des Bcl-2, responsables du phénomène d’apoptose ou mort cellulaire programmée, font l’objet d’un domaine d’étude récent. Elles se classent en deux familles selon leur fonction : les protéines pro-apoptotiques et les protéines anti-apoptotiques dont la surexpression est observée dans de nombreux cancers. Nous avons poursuivi l’étude de relations structure-activité initiée au laboratoire à partir de trimères d’alkoxyquinoléines, inhibiteurs micromolaires des protéines anti-apoptotiques Bcl-2 et Bcl-xL, en préparant de nouveaux analogues. / Cancer development is associated with dysfunctions in cell cycle progression or apoptosis. The identification of cellular agents involved in this disease, and the elucidation of mechanisms responsible for these dysfunctions provide the basis for the development of novel anti-cancer drugs.Thus, Pim kinases and Bcl-2 anti-apoptotic proteins which are overexpressed in many malignancies and contribute significantly to chemoresistance are of great interest for the development of targeted cancer therapy. Pim kinases (Pim-1,-2 and -3) belong to a family of serine / threonine kinases which play a key role in cell survival, proliferation and differenciation. Although all protein kinases share ATP as a common substrate, the structure of the ATP-binding pocket of Pim kinases is unique and offers an opportunity for a selective inhibition. Taking account of these specificities, we were interested in the synthesis of novel selective ATP competitive Pim kinase inhibitors. Among the other agents involved in tumorigenesis, Bcl-2 family proteins, which govern apoptosis (or programmed cell death), are subject of a recent interest. These proteins are divided in two classes depending on their function : pro-apoptotic and anti-apoptotic members that are overexpressed in a variety of cancers. In a preliminary work in the laboratory, alkoxyquinoline trimers have demonstrated micromolar inhibition against antiapoptotic proteins Bcl-2 and Bcl-xL. Therefore, we carried on this structure-activity relationship study with the synthesis of novel analogues.

Nesta monografia foram desenvolvidas metodologias sintéticas para a funcionalização das 2-(S)-isopropil-5-iodo-pirimidinonas, utilizando a reação de acoplamento cruzado de Suzuki-Miyaura e a reação de cicloadição azida-acetileno com cobre, através de estratégias simples e eficientes que permitiram a preparação de uma série de compostos com grande diversidade estrutural. Inicialmente descreve-se a síntese da 2-(S)-isopropil-5-iodo-pirimidinona (S)- 3, a partir da (S)-asparagina enantiomericamente pura 1, um aminoácido barato e de fácil acesso, produzindo na primeira etapa o 2-(S)-isopropil-peridropirimidinona-6- ácido carboxílico (2S,6S)-2, que reagindo com diacetoxiiodo benzeno/iodo e BF3.OEt2, gera a pirimidinona (S)-3. Em seguida, preparou-se uma série de 2-(S)-isopropil-5-aril-pirimidinonas (S)- 6a-q e 2-(S)-isopropil-5-alquinil-pirimidinonas (S)-7a-q, através da reação de acoplamento cruzado de Suzuki-Miyaura, sob catálise de paládio, utilizando aril- (4aq) e alquiniltrifluoroboratos de potássio (5a-q), respectivamente. Desta forma sintetizou-se uma variedade de pirimidinonas com alterações programadas de substituintes na posição 5 do anel, com rendimentos de 15% a 95%. Ainda a fim de obter algumas pirimidinonas com substituintes acetilênicos alquílicos 9a-f, utilizou-se a metodologia de acoplamento de Sonogashira. Em todos os casos obtiveram-se bons rendimentos. Dando sequência ao projeto, sintetizou-se as 2-(S)-isopropil-pirimidinonas funcionalizadas na posição C5 com anéis triazólicos substituídos na posição N1 (S)- 11a-k, através da reação de cicloadição azida-acetileno utilizando CuI como fonte de cobre e ondas ultra-sônicas como fonte de energia. Preparou-se diversos compostos, todos com rendimentos variando de 79% a 87% em 5 minutos de reação. Por último, através da redução da dupla ligação endocíclica dos compostos (S)-6a, 6b, 6g, 6l e 6n e posterior hidrólise utilizando radiação microondas proporcionou a obtenção de α-aril β-aminoácidos altamente enantioenriquecidos. / This monograph shows the development of a synthetic methodology for the functionalization of 2-(S)-isopropyl-5-iodo-pyrimidinones using either Suzuki-Miyaura cross-coupling reactions or cycloaddition reactions of azide-acetylenes with copper, through a simple and efficient pathway enabling the preparation of a series of structurally diverse compounds. This paper begins by describing the synthesis of 2-(S)-isopropyl-5-iodopyrimidinones (S)-3, from enantiomerically pure (S)-asparagine 1. This inexpensive and readily available amino acid forms 2-(S)-isopropyl-perhidropyrimidinone-6- carboxylic acid (2S, 6S)-2, which is reacted with DIB / iodine and BF3·OEt2 to form pyrimidinone (S)-3. Using palladium-catalyzed Suzuki-Miyaura cross-coupling reactions, a series of 2-(S)-isopropyl-5-arylpyrimidinones (S)-6a-q and 2-(S)-isopropyl-5- alkynylpyrimidinones (S)-7a-q were prepared using potassium aryl- (4a-q) and alkynyltrifluoroborates (5a-q), respectively. With this reaction, a variety of pyrimidinones with different substituents at position 5 of the ring were synthesized, with yields ranging from 15% to 95%. The Sonogashira coupling reaction was used to prepare pyrimidinones with alkyl acetylenic substituents (S)-9a-f, giving good yields in all cases. 2-(S)-Isopropylpyrimidinones were then functionalized in the C5 position with N1 (S)-11a-k substituted triazole rings. These functionalizations were performed by the cycloaddition of azide-acetylenes using CuI and ultrasonic waves, which provided enough energy to reduce the reaction time to only five minutes. Several different variations of this compound were prepared, all with yields between 78% and 87%. Finally, the endocyclic double bonds in compounds (S)-6a, 6b, 6g, 6l and 6n were reduced, followed by a hydrolysis using microwave radiation to afford the highly enantioenriched α-aryl β-amino acids.

Des nouveaux catalyseurs bimétalliques à base de palladium et de cuivre ont été développés. Deux voies de préparation ont été testées : l'imprégnation successive (TSI) et la co-imprégnation (CI) en utilisant la zéolithe 4Å (4A) et l'oxyde mixte MgAlxOy comme support. Les catalyseurs ont été caractérisés à l'état frais et testés dans la réaction de couplage Suzuki–Miyaura afin de comparer leurs activités, sélectivités et stabilités. L'étude de stabilité nous a montré que le catalyseur Cu-Pd-4A-TSI restait actif pendant six cycles alors que l'activité du catalyseur Cu-Pd-4A-CI diminuait. Sur le support MgAlxOy, le catalyseur CI était stable pendant six cycles contrairement au catalyseur TSI. Nous avons montré que le point clé pour l'obtention d'une bonne activité et stabilité est la présence de la phase active correspondant à l'alliage Cu/Pd 1/1 identifiée grâce à la caractérisation des catalyseurs et ce quelle que soit la méthode de préparation des catalyseurs. Une différence cruciale existe entre les catalyseurs supportés sur MgAlxOy et 4A : le catalyseur Cu–Pd supporté sur MgAlxOy permet de réduire le temps de réaction de moitié pour une même conversion par rapport à Cu-Pd-4A-TSI. De plus, l'utilisation d'un support plus basique permet, dans une certaine mesure, la diminution de la quantité de la base ajoutée durant la réaction. La réaction Petasis-borono Mannich a été aussi effectuée avec succès sur ces catalyseurs. / New bimetallic palladium/copper catalysts were developed by successive impregnation (TSI) and co-impregnation (CI) on 4Å molecular sieve (4A) and MgAlO mixed oxides supports. The fresh catalysts were characterised and tested in the Suzuki–Miyaura reaction to test their activity, selectivity and stability. It was observed that while the Cu-Pd-4A-TSI catalyst kept its activity during six cycles that of the Cu-Pd-4A-CI dropped. On MgAlO support the catalyst prepared with CI proved to be stable even for six runs contrary to TSI. The active phase of the reaction – namely the Cu–Pd alloy with atomic ratio 1:1 - was determined with the help of catalyst characterisation of the recovered catalysts. This observation confirms that whatever the way of preparation or the support is, the key-point is the presence of Pd-Cu 1:1 particles to enhance the catalytic performances. A crucial difference between the MgAlO and 4A supported catalyst was found in the reaction time necessary for the Suzuki–Miyaura reaction. With the Cu-Pd-MgAl-CI catalyst the reaction time could be reduced to thirty minutes contrary to one hour with Cu-Pd-4A-TSI. Moreover it was concluded that with a more basic support the reduction of the quantity of the base was possible however it brought slightly decreasing yield. The Petasis-borono Mannich reaction was also performed in the presence of each mono-and bimetallic catalysts.

Mass spectrometry was used to study two disparate transformations: in an applied project, the supposed degradation of perfluorooctanesulfonate (PFOS); and in a fundamental study, the Suzuki-Miyaura (SM) reaction was investigated in detail. The first investigation revealed that published methods to degrade PFOS were ineffectual, with apparent decreases being associated with adsorption onto available surfaces. In the Suzuki-Miyaura reaction, a dynamic series of equilibria were observed, and there is no direct evidence of a single pathway. Instead, there appear to be two mechanisms which are active in different conditions (one fluoride, one aqueous). Studies were initiated into the related SM polycondensation reaction and the hydrolysis of aryltrifluoroborates, the former indicating a step-growth mechanism, and the latter indicating a dynamic series of equilibria which are very sensitive to experimental conditions. Processing and interpretation of mass spectrometric data was a significant part of all of these projects, so a python framework was developed to assist in these tasks and its features are also documented herein. / Graduate / 0488 / 0486 / larsy@uvic.ca

Face à l’apparition grandissante de souches bactériennes multi-résistantes à l’arsenal d’antibiotiques actuels, les thiopeptides antibiotiques, bien que connus depuis plus de 60 ans, suscitent actuellement un fort regain d’intérêt. En effet, cette classe de molécules présente une forte activité antibiotique contre des souches bactériennes résistantes et multirésistantes, et met en œuvre deux modes d’inhibition originaux de la synthèse protéique encore inexploités en thérapie antibiotique humaine. Leur développement pharmacologique est en particulier freiné par la difficulté de préparation de ces molécules très complexes. L'élaboration d'une stratégie innovante de synthèse de la partie la plus complexe de ces molécules, le cœur hétérocyclique est étudiée dans ce travail. Cette approche repose sur l'étude et la valorisation de nouvelles méthodologies de fonctionnalisation directe des liaisons C-H et C-X de mono- et bis-thiazoles avec une large gamme d’hétéroaromatiques. Sa viabilité est démontrée par la préparation du cœur hétérocyclique commun aux amythiamicines. / Due to the emergence of multiresistant bacterial strains to standard antibacterial treatments, thiopeptides antibiotics are actually highly considered, though they are known for 60 years. They show an excellent antibiotic activity against multiresistant bacterial strains, and implement two originals inhibition mechanisms of protein synthesis, still unemployed in human therapy. However, the difficulty to prepare these complex macromolecules limits their pharmacological development. The development of a new strategy to synthetize the most complicated part of these macromolecules, their heterocyclic core, is studied here in. This approach is based on the study and the exploitation of novel direct C-H and C-X transition-metal-catalyzed couplings of mono- and bithiazoles units with a broad panel of heteroaromatics. Its viability is here demonstrated trough the multi-step synthesis of the common heterocyclic core of amythiamicins.

Cette thèse est consacrée à l’étude de mécanismes de réactions catalysées par des métaux ainsi qu’au développement de nouveaux outils pour la rationalisation et la prévision du comportement catalytique. L’étape de transmétallation entre le bore et le nickel a été étudiée en détail à l’aide de méthodes expérimentales variées (electrochimie, RMN, cinétiques) et par DFT, permettant d’expliquer certaines limitations rencontrées par les experimentateurs. La seconde partie de cette thèse est dédiée à la rationalisation du comportement d’une famille d’acides de Lewis : les sels de triflate et de triflimidate. Leur comportement a été étudié sur des réactions modèles d’amination et d’oxidation et une nouvelle échelle théorique d’acidité de Lewis basée sur l’estimation du transfert de charge vers l’acide à permis de reproduire et prévoir l’activité catalytique. / In this thesis mechanistic studies of metal-catalyzed reactions as well as development of new tools to predict and rationalize the catalytic properties are presented. The boron-tonickel transmetalation step was thoroughly studied by experimental technics (electrochemistry, NMR, kinetics) and DFT calculations, allowing us to solve some of the limitation encountered by the synthetic chemists. In the second part of this thesis the behavior of a family of Lewis acids (triflates and triflimides) is rationalize. Two model reactions (SN and redox) were studied and a new theoretical scale of Lewis acidity was developed based on the charge transferred to the acid allowing us to reproduce and predict the catalytic activity of these salts.

[pt] As doenças negligenciadas são causadas por agentes infecciosos ou parasitas, gerando altas taxas de morbidade e mortalidade em todo o mundo. Os investimentos dos países desenvolvidos em pesquisa, produção de medicamentos e controle dessas enfermidades são muito reduzidos, pois elas afetam, majoritariamente, as populações com baixo Índice de Desenvolvimento Humano. Uma dessas enfermidades é a Doença de Chagas, causada pelo Trypanosoma cruzi. Apresenta-se na forma de uma infecção parasitária crônica e altamente debilitante, acometendo mais de 6 milhões de pessoas na América Latina e este número pode ter um incremento, de aproximadamente 25 por cento nos próximos anos. O fármaco referência para o tratamento da Doença de Chagas disponível no Brasil é o benznidazol, extremamente eficaz na fase aguda da doença, mas sua eficácia na fase crônica é limitada, o que torna essencial a busca por novos compostos que atuem também nesta fase. No presente trabalho, foram descritas rotas sintéticas para uma série de 12 derivados de tiazol, destes 8 são inéditos. Posteriormente, 10 deles foram avaliados quanto a sua atividade tripanocida e toxicidade em modelos in vitro. Os compostos possuindo o anel tiazólico foram estruturalmente planejados, a partir do levantamento bibliográfico, onde verificou-se que certos compostos com um centro tiazólico apresentam propriedade tripanocida. Nas sínteses, a 4-bromoacetofenona (55) foi utilizada como material de partida para a obtenção dos intermediários tiazólicos 4-(4-bromofenil)-2- metiltiazol (56) e 4-(4-bromofenil)-2-aminotiazol (57). A partir desses, diversas modificações foram feitas para se chegar às moléculas alvo. A elucidação estrutural dos compostos foi realizada por RMN de 1H e RMN de 13C. A avaliação preliminar da atividade tripanocida foi realizada na forma amastigota intracelular da Cepa Tulahuen e a toxicidade aguda (LC50) foi feita in vitro em células hospedeiras de mamíferos (linhagem celular L929). Dentre os compostos sintetizados, a maioria apresentou baixa toxicidade, com valores de LC50 maiores que 400 (micro)mol.L-1. O composto tiazólico piridil-substituído 59c apresentou os melhores resultados em termos de atividade tripanocida, tendo reduzido 76 por cento da infecção. em células hospedeiras em concentração de 20 (micro)mol.L-1 Esse composto servirá como base para otimizações estruturais visando a melhoria da atividade tripanocida. / [en] Neglected diseases are mainly caused by infectious agents or parasites, generating high morbidity and mortality rates worldwide. The investments from developed countries in research, production of drugs/medicines and control of these diseases are small, since they mainly affect populations with low Human Development Index. One of these illnesses is Chagas disease, caused by Trypanosoma cruzi. It presents as a chronic and highly debilitating parasitic infection, affecting more than 6 million people only in Latin America with a perspective of increasing approximately 25 percent in few years. The reference drug for the treatment of Chagas disease in Brazil is benznidazole, which is extremely effective in the acute phase of the disease, but its efficacy in the chronic phase is limited, which makes essential the search for new compounds that also act in this phase. In the present work, synthetic routes were developed for a series of 12 thiazole derivatives, from which eight have been described for the first time. These molecules had their preliminary trypanocidal activity and toxicity evaluated in in vitro models. The compounds with the thiazole ring were structurally planned, based on the bibliographic review, where it was found that certain compounds with this heterocycle display trypanocidal properties. In the synthesis, 1-(4- bromophenyl)ethenone (54) was used as a starting material to obtain the thiazole intermediates 4-(4-bromophenyl)-2-methylthiazole (56) and 4-(4-bromophenyl)thiazol-2- amine (57). Several modifications were performed on these intermediates to produce the target molecules. The structural elucidation of the compounds was performed by 1H NMR and 13C NMR. Preliminary evaluation of trypanocidal activity was performed in the amastigotes intracellular form of the Tulahuen strain and the acute toxicity (LC50) was tested in vitro in mammalian host cells (cell line L929). Among the synthesized compounds, most of them presented low toxicity, with LC50 values greater than 400 (micro)mol/mol.L-1. The thiazole compound pyridil-substituted 59c showed the best results in terms of trypanocidal activity, reducing 76 percent of the infection in host cells in a concentration of 20 (micro)mol/mol.L-1. This thia\ole derivative will be used as a lead compound for structural optimizations aiming at improving trypanocidal activity.

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