Gold compounds have been used in medicine dating back as early as 2500 BC. Over the years gold(I) and gold(III) compounds have been used and designed to target rheumatoid arthritis, cancer, and viral diseases. New drug targets have been found for gold compounds that give insight into their mechanisms of action. Here we focus on the synthesis of Au(III) compounds designed to selectively target zinc finger (ZF) proteins. ZF proteins exhibit a variety of functions, including transcription, DNA repair, and apoptosis. Displacement of the central zinc ion, along with mutation of coordinated amino acids can result in a loss of biological function. Synthesis of complexes that selectively target zinc finger proteins, in turn inhibiting DNA/ZF interactions and therefore resulting in loss of protein function, is of great interest. Of particular interest here is the Cys3His (Cys = cysteine, His = histidine) HIV nucleocapsid zinc finger protein, NCp7. NCp7 is involved in multiple steps of the HIV life cycle, thus making it a desirable drug target. Previous studies from our group show platinated nucleobases such as [Pt(dien)(9-EtG)]2+ (dien = diethylenetriamine; 9-EtG = 9-ethylguanine) to stack effectively in a non-covalent manner with tryptophan of the C-terminal finger of HIV Nucleocapsid, NCp7(F2), a key residue involved in nucleic acid recognition. Due to the isoelectronic and isostructural relationship of Au(III) to Pt(II), we have expanded this system to Au(III)-(nucleobase/N-heterocycle) compounds. Novel Au(III)(dien)(N-heterocycle) compounds, including the first Au(III)N3(N-purine) examples, were synthesized. As previously reported for [AuCl(dien)]Cl2, these compounds exhibit pH dependency of the 1H NMR chemical shifts of the dien ligand. The acidity of the dien ligand is affected by the nature of the fourth ligand as a leaving group. The presence of an inert nitrogen donor, compared to that of the more labile Cl-, as the leaving group stabilizes the Au(III) metal center towards reduction, resulting in significant enhancement of π−π stacking interactions with tryptophan relative to platinum(II) and palladium(II) compounds. The presence of a more inert N-donor as the leaving group slows down the reaction with the sulfur-containing amino acid N-Acetylmethionine (N-AcMet); essentially no reaction was observed for the Au(III)-N-heterocycle compounds. All compounds react readily with N-Acetylcysteine (N-AcCys), however lack of N-heterocycle ligand dissociation indicates, to our knowledge, the first long-lived N-heterocycle-Au-S species in solution. Electrospray ionization mass spectrometry (ESI-MS) studies with NCp7(F2) indicate [Au(dien)(DMAP)]3+ (DMAP = 4-dimethylaminopyridine) to be the least reactive of the Au(III) compounds studied, showing the presence of intact NCp7(F2) zinc finger at initial reaction times. Reactivity of the Au-compounds was compared with that of Sp1(F3), a Cys2His2 ZF; in contrast, no intact ZF was observed for any of the compounds studied, suggesting the mode of action of these compounds is dependent on the nature of the zinc binding core. ESI-MS studies were expanded to that of the full HIV NCp7 zinc finger. [Au(dien)(9-EtG)]3+ reacts quickly with NCp7, resulting in immediate zinc ejection and replacement with up to three gold ions. Unlike with [Au(dien)(DMAP)]3+, no intact NCp7 was observed. Addition of [Au(dien)(9-EtG)]3+ to preformed NC-SL2 complex results in release of free RNA; based on EMSA (electrophoretic mobility shift assay) studies, [Au(dien)(9-EtG)]3+ disrupts the NCp7-RNA complex with an IC50 of ~450 µM. It is possible that this HIV nucleocapsid-nucleic acid antagonism may result in a loss of viral activity.

Les hétérocycles azotés chiraux représentent une classe importante de composés biologiquement actifs. L’hydroamination asymétrique intramoléculaire correspond parfaitement au concept d’économie d’atomes et permet l’accès direct à la formation de nouvelles liaisons carbone-azote. Le développement de catalyseurs pour la formation de pyrrolidines et piperidines reste cependant une tâche importante. Le thème de cette thèse est l’étude de nouveaux complexes chiraux binaphthylamide d’yttrium facilement accessibles et leur application pour promouvoir la réaction d’hydroamination/cyclisation des amines primaires liées à des alcènes stériquement encombrés.Des complexes chiraux binaphthylamidure alkyl ate d’yttrium ont été développés. Ces systèmes catalytiques ont été préparés in situ par une réaction simple stœchiométrique en présence d’un précurseur d’yttrium [Li(THF)4][Y(CH2SiMe3)4] connu et d’une variété de ligands chiraux binaphthyldiamine substitués. Les complexes chiraux hétéroleptiques obtenus se sont révélés actifs et énantiosélectifs pour la réaction d’hydroamination asymétrique intramoléculaire des aminoalcènes 1,2-disubstitués conduisant à la formation d’hétérocycles azotés avec cinq et six châinons. Les catalyseurs d’yttrium préparés à partir du ligand (R)-N-anthrylmethyl-binaphthylamine H2L13 et des ligands (R)-benzyl N-para-substitués H2L4 or H2L6 se sont révélés les plus énantiosélectifs à 70-110°C pour la réaction d’hydroamination/cyclisation des aminoalcènes encombrés. Un excès énantiomérique de 77% a été obtenu comme valeur la plus élevée décrite jusqu’à présent pour l’hydroamination asymétrique intramoléculaire des amines comportant des alcènes 1,2-disubstitués. Les premiers exemples de la réaction d’hydroamination intramoléculaire asymétrique des aminoalcènes 1,1,2-trisubstitués ont été rapportés. Les complexes ate alkyl d’yttrium ont fourni les produits hétérocycliques avec des centres quaternaires énantiomériquement enrichis dans des conditions réactionelles plus sévères que la cyclisation des aminoalcènes 1,2-disubstitués et avec des énantiosélectivités prometteuses atteignant 55%. Les complexes alkyl d’yttrium contenant une molécule de chlorure de lithium [{(R)-C20H12(NSiMe3)2}Y{CH2SiMe3}{LiCl(THF)2}] and [{(R)-C20H12(NC5H9)2}Y{CH2SiMe3}{LiCl(THF)2}] ont été préparés et comparés aux mêmes complexes sans LiCl. Ils se sont révélés être des catalyseurs efficaces pour la réaction d’hydroamination intramoléculaire des aminoalcènes terminaux. / Chiral nitrogen-containing heterocycles represent an important class of biologically active compounds. The asymmetric intramolecular hydroamination perfectly matches the concept of sustainable chemistry and allows the formation of new nitrogen-carbon bonds in an ideal atom efficiency and economy, starting from non activated substrates. The development of catalysts for formation of enantioenriched pyrrolidines and piperidines derivatives remains however a challenging task. The topic of this dissertation is the study of new easily accessible chiral yttrium binaphthylamide complexes and their application for promoting the hydroamination/cyclisation of primary amines tethered to sterically demanding alkenes. Chiral binaphthylamido alkyl ate yttrium complexes have been investigated. These catalytic systems have been prepared by a facile in situ stoichiometric reaction of a well-known yttrium precursor [Li(THF)4][Y(CH2SiMe3)4] with a variety of chiral substituted (R)-binaphthylamine ligands. These chiral heteroleptic complexes are shown to be efficient catalysts for the enantioselective intramolecular hydroamination of 1,2-disubstituted aminoalkenes leading to the formation of five and six-membered N-heterocycles. Yttrium catalysts prepared from (R)-N-anthrylmethyl-binaphthylamine ligand H2L13 and (R)-N-para-substituted benzyl ligands H2L4 or H2L6 proved to be the most enantioselective catalysts at 70-110°C for the hydroamination/cyclisation of challenging aminoalkenes. An enantiomeric excess value of 77 % was indeed disclosed as the highest value reported so far for the asymmetric intramolecular hydroamination of amines tethered to 1,2-disubstituted alkenes. The first examples of asymmetric intramolecular hydroamination of 1,1,2-tri-substituted aminoalkenes have been reported. The alkyl ate yttrium complexes produced the heterocyclic compounds with enantioenriched quaternary centres under harsher reaction conditions than the cyclisation of the corresponding 1,2-disubstituted alkenes, and with promising enantioselectivities of up to 55 %.The neutral alkyl yttrium complexes containing one molecule of lithium chloride [{(R)-C20H12(NSiMe3)2}Y{CH2SiMe3}{LiCl(THF)2}] and [{(R)-C20H12(NC5H9)2}Y{CH2SiMe3}{LiCl(THF)2}] have been prepared and compared with the same complexes lacking LiCl. They have been revealed as efficient catalysts for intramolecular hydroamination of terminal aminoalkenes.

Cette thèse vise à développer de nouvelles méthodes efficaces pour incorporer des isotopes de l’hydrogène dans les molécules organiques complexes, après une introduction portant sur les applications et la synthèse des molécules marquées par le deutérium et tritium. Les méthodes permettant le marquage, par échange isotopique direct, d’hétérocycles azotés par des isotopes de l’hydrogène restent perfectibles, voire inexistantes dans certains cas, malgré la récurrence de ce type de sous-structures dans les molécules d’intérêt pharmacologique. Pour cette raison, la majeure partie de ce travail a consisté au développement de nouvelles méthodes d’incorporation d’atomes de deutérium et de tritium sur des hétérocycles azotés catalysées par des nanoparticules métalliques. Dans un premier chapitre, la mise au point, le champ d’application d’une méthode de marquage mettant en jeu l’utilisation de nanocatalyseurs de ruthénium seront discutés. Dans ce cadre, des calculs théoriques ont permis de rationaliser les regiosélectivités obtenues expérimentalement et d’identifier notamment des intermédiaires clefs inédits. D’un point de vue applicatif, cette méthode a permis de synthétiser des étalons internes deutérés pour la quantification LC-MS mais aussi des molécules complexes tritiées ayant des activités spécifiques élevées en une étape de synthèse. Dans un autre chapitre, la synthèse et la réactivité de nouveaux nanocatalyseurs de nickel permettant de réaliser des échanges isotopiques sélectifs seront discutés. / This PhD thesis deals with the development of new efficient methods for the incorporation of hydrogen isotopes into organic molecules, which represents a serious issue especially for drug discovery and drug development processes. After giving an introduction about hydrogen isotopes and their applications in organic molecules, the course will proceed to an overview of different chemical transformations for establishing deuterium or tritium labels on molecular frameworks. The possibilities to label N-heterocycles by hydrogen isotopes through hydrogen isotope exchange (HIE) are still very restricted and even impossible for some representatives despite the strong recurrence of these substructures in numerous biologically active molecules. For this reason, the emphasis of the practical part will lie on the development of new methods for the incorporation of deuterium and tritium on N-heterocycles through metal nanoparticle catalysis. In the first chapter, HIE through ruthenium nanocatalysts will be optimized and the application range will be demonstrated. In this context, DFT-based calculations allowed to explain experimental regioselectivities and to identify new keyintermediates. In terms of application, it was shown that the ruthenium-catalyzed method is useful for the synthesis of deuterium labelled internal standards for LC-MS quantifications and for the tritiation of complex molecules displaying satisfying specific activities. In the next chapter, the synthesis of new nickel nanoparticles and their potential to catalyze selective HIE on N-heterocyclic derivatives will be discussed.

Les hétérocycles azotés occupent une place importante en chimie organique et médicinale et, à ce titre, constituent des cibles de choix pour le développement de réactions toujours plus efficaces et faciles d’emploi. Les travaux antérieurs, réalisés au laboratoire URCOM sur l’accès aux γ-lactames, ont servi de base pour développer une méthodologie impliquant des conditions douces qui ont mis en évidence les propriétés spécifiques des N-alkoxy amides pour accéder aux γ- et δ-lactames hautement fonctionnalisés de manière hautement diastéréosélective selon un processus domino. Cette méthodologie a aussi pu être étendue aux hydantoïnes, 2-imino-thiazolidin-4-ones et thiazinan-4-ones qui constituent également des molécules étudiées en chimie médicinale. En parallèle, une comparaison de réactivité entre N-alkoxy amides et N-alkyl amides a montré la meilleure réactivité des composés N-alkoxylés pour l’obtention de ces différents hétérocycles azotés. Cette différence de réactivité a été attribuée à la possible chélation du contre anion alcalins des bases minérales utilisées dans notre approche par les N-alkoxy amides. Les conditions douces ont permis d’envisager des versions organocatalysées énantiosélectives ou multicomposantes des réactions précédentes conduisant à des résultats préliminaires intéressants. / Nitrogen-containing heterocycles are key compounds in organic and medicinal chemistry and continue to attract synthetic effort for the development of more efficient and convenient reaction. Previous work carried out at the URCOM laboratory for the access to γ-lactams has provided the basis for developing a highly diastereoselective methodology under mild conditions that has demonstrated the specific properties of N-alkoxy amides, allowing the access to γ- and δ-lactams following a domino process. This methodology also allowed the access to hydantoïns, 2-imino thiazolidin-4-ones and thiazinan-4-ones which are compounds of importance in medicinal chemistry. In parallel, a comparison of reactivity between N-alkoxy and N-alkyl amides was carried out in order to demonstrate the better reactivity of the N-alkoxy amide compounds. This better reactivity was attributed to a possible chelation of the alkali metal counter anion of the mineral bases used in our conditions by the N-alkoxy amides. These mild conditions allowed organocatalyzed enantioselective or multicomponents approaches providing interesting preliminary results.

O trabalho da tese apresentada é focado na aplicação de diazocetonas como intermediários avançados na síntese de sistemas N-heterocíclicos. No primeiro capítulo foi avaliada a reação de aza-Michael sobre as diazocetonas α,β-insaturadas, com o emprego de hidrazinas e hidroxilaminas como nucleófilos. Essa abordagem leva a formação de adutos de aza-Michael, que quando submetidos as reações de inserção N-H ou o rearranjo fotoquímico de Wolff, permitem o acesso aos núcleos de hexaidropiridazinas e 1,2-oxazinanas. Esses núcleos são encontrados em uma série de produtos naturais, apresentando diferentes tipos de atividades biológicas. Tendo isso em vista, foi planejada a aplicação da metodologia desenvolvida nesse capítulo na síntese da 1-(-)-Azafagomina e análogos. O capítulo 2 é focado na síntese de N-heterocíclos bicíclicos a partir de diazocetonas como blocos de construção, sendo esse capítulo foi dividido em duas partes. Na primeira parte foi avaliada à aplicação de diazocetonas α,β-insaturadas N-terminais na síntese de diferentes classes de núcleos N-heterocíclos, como as indolizidinas e pirrolizidinas. A estratégia sintética aplicada nesse tópico foi baseada na remoção de um grupo protetor de nitrogênio, a realização de uma reação de adição de aza-Michael intramolecular, e um rearranjo de Wolff fotoquímico para a construção da unidade bicíclica. Essa abordagem permitiu a obtenção de um escopo variado de núcleos indolizidínicos e pirrolizidínicos em bons rendimentos, e para alguns casos boa diastereosseletividade. A segunda parte desse capitulo teve como foco a síntese de núcleos [1,2,3]-triazólicos bicíclicos fundidos a partir de α-amino diazocetonas. A estratégia empregada para a construção da unidade bicíclica tem como etapa principal a formação in situ de um intermediário α-diazo imina, que via uma ciclização do tipo 5-endo-dig forma o núcleo triazólico bicíclico. A partir dessa abordagem foi possível a sintetizar um escopo variado de triazóis bicíclicos em bons rendimentos. / This work is focused on the application of diazoketones as advanced intermediates in the synthesis of N-heterocyclic systems. In the first chapter the aza-Michael reaction was evaluated on α,β-unsaturated diazoketones with the use of hydrazines and hydroxylamines as nucleophiles. This approach leads to the formation of aza-Michael adducts, which upon submission to the N-H insertion or the photochemical Wolff rearrangement, allows the access to hexahydropyridazine and 1,2-oxazinane cores. These units are found in a variety of natural products with different types of biological activities. Considering that we aimed the application of the developed methodology in the synthesis of the 1-(-)-Azafagomine and their analogues. The Chapter 2 is focused on the synthesis of bicyclic N-heterocyclic from diazoketones as building blocks. This chapter is divided in two parts. In the first part, the α,β-unsaturated N-terminal diazoketones were evaluated in the synthesis of different classes of N-heterocycles, such as indolizidines and pyrrolizidines. The methodology is based on the removal of a nitrogen protecting group, an intramolecular aza-Michael addition, and a photochemical Wolff rearrangement for the construction of the bicyclic unit. This approach not only allowed the synthesis of a broad scope of indolizidines and pyrrolizidines in good yields, but also good diastereoselectivity in some examples. The second part of this chapter was focused on the synthesis of bicyclic [1,2,3] triazolic cores from α-amino diazoketones. The strategy employed for the construction of the bicyclic unit is based on the in situ formation of a α-diazo imine intermediate, which upon a 5-endo-dig cyclization provide the bicyclic triazole core. The developed methodology allowed the synthesis of a varied scope of bicyclic triazoles in good yields.

Fossils fuels are highly demanded in everyday life domestically or industrially. Fossil fuels are finite resources and they are rapidly depleting, as such alternative renewable feedstocks are sought to replace fossil fuels. Tall oil from paper processing and cashew nut shell liquid from the cashew nut industry are the two major renewable sources we studied, they are both waste byproducts, and have the potential to be converted into value-added materials. Tall oil from the paper industry mainly contained tall oil fatty acid, and under isomerising methoxycarbonylation with palladium catalyst, dimethyl 1,19-dimethyl nonadecanedioate can be obtained. This difunctional ester, dimethyl 1,19-dimethyl nonadecanedioate, is converted to diols, secondary and primary diamines by a hydrogenation reaction with ruthenium complexes of 1,1,1-tris(diphenylphosphinometyl)ethane (triphos) as catalysts in the presence of water, amine or aqueous ammonia respectively. In the case of aqueous ammonia it is necessary to use a two step reaction via diol to obtain 1,19-diaminononadecane. Diesters, diols and diamines are useful precursors for the synthesis of polyesters and polyamides. Difunctional substrates with 8-19 carbon chains are all tolerated under the reaction conditions and are successfully converted to the corresponding diols and diamines in high yields. Under similar hydrogenation conditions with the same ruthenium catalyst, cyclic products were predominantly produced with decreased chain length. N-heterocycles, which are important building blocks for the synthesis of drug molecules, were formed from the hydrogenation of diesters with 4-7 carbon chains in the presence of an amine. Another polymer precursor, ε-caprolactam, which is the precursor for Nylon 6, is obtained in a reasonable yield from both adipic acid and adipate esters together with aqueous ammonia in the presence of ruthenium catalyst. Cashew nut shell liquid was also converted into useful medical drugs, such as norfenefrine, rac-phenylephrine, etilefrine and fenoprofene in reasonable yields. Most of these drug molecules have been formed from 3-vinylphenol by catalytic hydroxyamination followed by methylation or ethylation. 3-Vinylphenol was synthesised from cardanol by ethenolysis to 3-non-8-enylphenol followed by isomerising ethenolysis, whilst the N-alkylation reactions used methyl or ethyl triflate to avoid dialkylation. Fenoprofene was formed by firstly O-phenylating cardanol then ethenolysis followed by isomerising ethenolysis to form 1-phenoxy-3-vinylbenzene. Methoxycarbonyation followed by hydrolysis formed the final product in good yield. Our methods start from renewable waste materials and avoid unpleasant reagents in the original stoichiometric synthesis of those drugs, for example, cyanide is no longer essential for the synthesis of fenoprofene.

La présence importante des hétérocycles azotés en chimie organique et médicinale explique le grand intérêt et les très nombreuses recherches dont ils font l’objet. Parmi tous ces motifs, les pyrrolidines ainsi que les γ- et δ-lactames bicycliques ont tout particulièrement focalisé notre attention. En se basant sur des résultats antérieurs obtenus au laboratoire nous avons mis au point deux nouvelles voies d’accès rapides et innovantes pour accéder diastéréosélectivement à ces motifs. D’une part une réaction tandem aza-MIRC (Michael Induced Ring Closure) a permis de former des pyrrolidines polysubstituées et d’autre part une séquence domino oxa-Michael/aza-MIRC a donné accès à de très nombreux γ- et δ-lactames bicycliques. Ces deux méthodes ont, en outre, été appliquées à la synthèse de composés d’intérêts connus pour leurs activités biologiques. La séquence aza-MIRC a été utilisée pour les synthèses totale et formelle respectivement des alcaloïdes Coerulescine et Martinelline, tandis que le processus oxa-Michael/aza-MIRC a été employé pour accéder de manière stéréosélective à des composés spirooxindoliques énantioenrichis. En parallèle du développement de ces deux méthodes, une étude mécanistique poussée de la séquence oxa-Michael/aza-MIRC a été réalisée au moyen de calculs théoriques. Cette étude a permis d’expliquer la majeure partie des résultats obtenus en fournissant un outil puissant capable d’anticiper, dans une certaine mesure, la réactivité de la séquence domino oxa-Michael/aza-MIRC. / N-heterocycle scaffolds are found in many synthetic and medicinal chemical compounds explaining the high interest for developing efficient synthetic methodologies to reach such structures. In that field, our group has developed over the years innovative routes to y-lactams and bicyclic γ- and δ-lactams using tandem and domino reactions. Based on those previous works, we have developed two new methods to synthesize N-heterocycles. A tandem aza-MIRC (Michael Induced Ring Closure) sequence have been investigated to access pyrrolidines whereas the bicyclique scaffold of bislactames have been obtained using a domino oxa-Michael/aza-MIRC pathway. These two new methods have been then applied to the syntheses of more complexes and thus challenging backbones. The aza-MIRC tandem process have been used for the total and formal synthesis of alkaloids Coerulescine and Martinelline, respectively, whereas the domino oxa-Michael/aza-MIRC sequence has proved to be a powerful tool for stereoselective access to enantioenriched spirooxindolic compounds. DFT calculations studies have allowed elucidation of the diastereoselectivity and double chirality transfer of the domino reaction therefore could be used in the future to develop efficient total syntheses.

No description available.