Cette thèse propose une étude théorique des propriétés de transport électronique dans divers réseaux d'une taille nanoscopique, dont la production est devenue possible grâce au progrès récents de la technique de nanofabrication. Les trois types de dispositifs ont été analysés: les nanotubes, les filaments quantiques et les jonctions Josephson. Dans la première partie nous retrouvons, par les méthodes du groupe de renormalisation et de la bosonisation, les diagrammes de phase pour les réseaux réguliers de fils quantiques dans les régimes de faible et forte interaction électronique. Dans la deuxième partie nous nous intéressons aux effets combinés des interférences quantiques dans les réseaux de symétrie Z2 locale en présence d'interaction Coulombienne. Dans le dernière chapitre nous proposons un modèle du spectromètre courant-tension mésurant l'énergie des q-bits, qui peut trouver ses applications dans la théorie de l'information quantique.

Ce mémoire de thèse est composé de deux parties distinctes ayant comme thématique commune, les réactions multicomposants (MCR). Nous nous sommes intéressés dans un premier temps au développement d'une nouvelle MCR conduisant à des dérivés de l'indole, hétérocycle rencontré dans de nombreuses substances naturelles et composés biologiquement actifs. Nous avons ainsi mis au point un nouvelle méthodologie MCR séquentielle, rapide et efficace permettant d'accéder sélectivement, à partir des trois mêmes substrats (un précurseur indolique, un alcyne vrai et un accepteur de Michael) à deux familles de composés : les cyclopent[b]indoles ou les pyrrolo[1,2-a]indoles par une simple inversion de l'ordre des réactions. Puis dans un deuxième temps, nous avons élaboré une nouvelle synthèse totale diastéréosélective de lignanes tétrahydrofuraniques trisubstitués, connus pour leur abondance dans la nature et leurs propriétés biologiques très variées. Cette synthèse courte est composée de trois étapes clés : une réaction de cyclofonctionnalisation multicomposants palladocatalysée, une déméthoxycarboxylation -élimination utilisant des conditions de Krapcho modifiées et une réaction de type Hayashi-Miyaura permettant d'introduire le deuxième groupement aryle. Cette dernière réaction d'addition conjuguée a représenté le défi de cette synthèse et a donc fait l'objet d'une étude particulière sur un substrat modèle.

La présence accrue de la chimie en flux continu dans les publications des dernières années a mené à un développement rapide de cette nouvelle technologie. La transposition de méthodes du ballon réactionnel au réacteur de chimie en flux continu permet au chimiste d’ajouter un outil à son répertoire, afin d’améliorer la productivité et le rendement dans la synthèse de composés d’intérêt. Bien que les réactions de Friedel-Crafts aient été déjà réalisées en chimie en flux continu, aucune méthode homogène robuste n’a été développée pour des composés dérivés du phénol. Les premières parties de ce mémoire portent sur le développement et l’optimisation des conditions réactionnelles de l’acylation de Friedel-Crafts en chimie en flux continu. Tout d’abord, une première méthode a été développée, en utilisant le chlorure d’aluminium et l’anisole. Cependant cette méthode est incompatible avec le phénol. Une deuxième méthode a été développée en utilisant l’acide méthanesulfonique comme acide de Brønsted et solvant réactionnel. Cette méthode est efficace et surtout compatible avec le phénol. Les dernières parties portent sur l’étendue de cette deuxième méthode. La méthode a été employée sur des dérivés du phénol, tels que les di- et tri-hydroxyphénols et des hydroxybicycles. D’autres cycles aromatiques, aussi bien activés que désactivés, contenant une fonction phénol ont aussi été testés. Par la suite, la méthode a été essayée avec des agents acylants différents, afin d’évaluer l’étendue de la réaction. / The increased presence of continuous flow chemistry in recent publications has led to rapid development of the technology. The transposition of methods from round-bottom flask to flow enables chemists to add a tool to their repertoire to improve productivity and yield in the synthesis of compounds of interest. Although Friedel-Crafts reactions have been explored in continuous flow, no robust homogenous method has been developed for phenol derivatives. The initial sections of the work focus on the development and optimization of reaction conditions for continuous flow Friedel-Crafts acylation. First, a method has been developed using aluminum chloride as a catalyst, and anisole for optimization purposes. This method is robust, but proved incompatible with phenols. A second method was then developed using methanesulfonic acid as both catalyst and reaction solvent. The method is effective and, more importantly, compatible with phenols. The final sections address the scope of this second method. The method was applied to various phenol derivates, such as di- and tri-hydroxyphenols and hydroxybicycles. Other aromatic rings, both activated and deactivated, containing a phenol function were also tested. The method was evaluated with different acylating agents, demonstrating the wide range of possibilities it offers.

Chapter one; “(-)-Rhazinilam and (-)-Rhazinal: Alkaloids with Anti-mitotic Properties Derived from Kopsia teoi”, provides the background information behind the motives that initiated this research project. The plant alkaloid (-)-rhazinilam [(-)-1] and its naturally-occurring derivative (-)-rhazinal [(-)-13] both exhibit potent anti-mitotic activities and, as such, are interesting targets for total synthesis. Chapter one is a review of the literature regarding these two compounds and discusses the occurrence, proposed biosynthetic origins, structural elucidation and biological activites of compound (-)-1 and that of its analogues including alkaloid (-)-13. Previous total syntheses of these two compounds are then examined, concluding with the only reported total synthesis of compound (-)-13. Developed within the Banwell research group, this total synthesis produced the racemic modification of alkaloid (-)-13 due to a lack of any stereocontrol in the key intramolecular Michael addition step. This unprecedented key step, involving cyclisation of the C2 of pyrrole onto an N-tethered and ?,?-disubstituted acrylate to produce a quaternary-carbon stereogenic centre, would be of greatly enhanced utility if it could be achieved in a catalytic-enantioselective fashion. The realisation of this goal is the central aim of the research conducted within this thesis. ¶ Chapter two; “Investigating Asymmetric Induction in the Intramolecular Michael Addition of pyrrole to N-Tethered Acrylates and Related Species”, introduces the model study used to direct research towards achieving the goal of asymmetric induction in the title process. The model is a somewhat simplified version of the original process used in the total synthesis of compound (-)-13 involving cyclisation of the C2 of pyrrole onto an N-tethered and ?-monosubstituted Michael acceptor, to produce a tertiary-carbon stereogenic centre. This simplification allows the rapid synthesis of a broad range of potential substrates for use in the title process, thus enabling the investigation of various different approaches to inducing asymmetry therein. High levels of asymmetric induction are observed with the use of chiral substrates or catalysts, facilitating the synthesis of both 6- and 7-membered rings annulated to pyrrole with construction of the relevant tertiary-carbon stereogenic centre in enantio-enriched form. For the reactions producing a 6-membered ring annulated to pyrrole, unambiguous proof of the absolute sense of asymmetric induction observed in the intramolecular Michael addition event is established using a chemical correlation study involving elaboration of a key indolizine-type cyclisation product, to the plant alkaloid of known absolute stereochemistry, (-)-tashiromine [(-)-75]. For the reaction producing a 7-membered ring annulated to pyrrole, the same information is obtained via X-ray crystallographic analyses of a dibrominated derivative of a key pyrroloazepine-type cyclisation product. ¶ Chapter three “An Enantioselective Total Synthesis of the Alkaloid (-)-Rhazinal: An Anti-mitotic Agent Isolated from Kopsia teoi.”, focuses on the application of methodology developed in the previous chapter, to the original goal of inducing asymmetry in the intramolecular Michael addition reaction, involving cyclisation of the C2 of pyrrole onto an N-tethered and ?,?-disubstituted acrylate to produce a quaternary-carbon stereogenic centre. This is ultimately achieved in a catalytic-enantioselective fashion, resulting in the first such total synthesis of the anti-mitotic alkaloid (-)-rhazinal [(-)-13]. ¶ Chapter four “Extending the Reaction Manifold to the Syntheses of Related Natural Products: A Formal Total Synthesis of (+)-Aspidospermidine and Syntheses of (-)-Rhazinilam and (-)-Leuconolam from (-)-Rhazinal”, describes three extensions to the reaction manifold used in the enantioselective total synthesis of alkaloid (-)-13: The acquisition in an enantioselective manner, of an intermediate previously obtained in racemic form, en route to the racemic modification of the natural product (±)-aspidospermidine [(±)-134], constitutes a formal and enantioselective total synthesis of (+)-aspidospermidine [(+)-134]. The direct deformylation of (-)-rhazinal [(-)-13], is carried out, to produce the parent alkaloid (-)-rhazinilam [(-)-1]. The pyrrole ring present in (-)-rhazinilam [(-)-1] is oxidised, to produce the related natural product (-)-Leuconolam [(-)-12] which has not, hitherto, been prepared by total synthesis. ¶Chapter five contains the experimental procedures and characterisation data associated with compounds described in chapters two to four.

L'utilisation de méthodologies de synthèse toujours plus performantes et respectueuses de l'environnement est un axe de recherche majeur de la chimie moderne. L'apport de la catalyse, avec l'utilisation de superacides de Lewis, a permis d'améliorer de nombreux processus synthétiques. Nous avons pu développer dans ce manuscrit des réactions de cycloisomérisation de type réaction de Friedel-Crafts qui donnent accès à un ensemble de structures polycycliques intéressantes avec de bons rendements et sélectivités. L'utilisation d'une quantité catalytique, entre 1 et 10 mol% de Bi(OTf)3, permet l'activation d'oléfines et d'allènes non activés ainsi que de systèmes 1,3-diéniques. Ce type de méthodologie, à économie d'atomes maximale, a permis de limiter la formation de sous-produits, le catalyseur pouvant être recyclé et réutilisé sans perte d'activité. Des approches intra- et intermoléculaires, des réactions cascades et tandems ainsi qu'une étude mécanistique ont été effectuées afin de mieux comprendre la réactivité et ses limitations, et ainsi atteindre une plus large gamme de structures. Les méthodologies développées ont été appliquées au domaine des arômes et parfums pour la synthèse d'analogues de la Calone 1951®, de chromanes, d'indanes et de tétralines fonctionnalisés, posant les bases de travaux futurs pour une meilleur compréhension des relations structures-odeurs

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Carbo- and heterocyclic compounds are of great interest to chemists. Intramolecular cyclization strategies of donor-acceptor (D-A) cyclopropanes and alkylidene malonate monoamides have excellent potential for synthesis as they offer easy access to structurally-diverse compounds. The work described in this thesis accesses the scope of the In(OTf)3-catalyzed cyclization reaction of cyclopropanes and alkylidene malonate monoamides. In(OTf)3-catalyzed reactions of alkenyl and heteroaryl cyclopropyl ketones were examined in the synthesis of functionalized cyclohexenone-based derivatives (Chapter 2). Subsequent efforts to utilize a tandem cyclopropane ring-opening/Friedel-Crafts alkylation sequence of methyl 1-(1H-indolecarbonyl)-1-cyclopropanecarboxylates to prepare functionalized hydropyrido[1,2-a]indole-6(7H)-ones is discussed in Chapter 3. The extension of this tandem protocol towards the total synthesis of (±)-deethyleburnamonine is the subject of Chapter 6. Intramolecular Friedel-Crafts alkylation of N-indolyl alkylidene malonate monoamides was also examined. An In(OTf)3-catalyzed cyclization of substituted methyl 2-(1H-indole-1-carbonyl) acrylates afforded a series of 1H-pyrrolo[1,2-a]indole-3(2H)-ones (Chapter 4), whereas substrates with the indole 2-position blocked provided access to substituted 4H-pyrrolo[3,2,1-ij]quinolin-4-ones (Chapter 5).

Doctor Educationis / The research focused on the synthesis, characterisation and activity of zeolite supported metal catalysts for the Friedel-Crafts alkylation of benzene with t-butyl chloride. Alkyl benzenes are traditionally produced via systems that employ the use of Lewis acids or strong mineral acids. There have been widespread concerns over these approaches based on their environmental impacts and separation difficulties. Recent approaches have endeavoured the much to use more environmentally eco-friendly systems and zeolites have proved to be versatile support materials. The use of zeolites has also shown to greatly improve product selectivity as well as easing separation constraints. However the adoption of zeolites on large scale Friedel-Crafts alkylation has been hampered by the high cost of zeolite production from commercial sources. On the other hand fly ash has been found to be a viable starting material for zeolite synthesis. Apart from that South Africa is faced with fly disposal challenges and there is continual accumulation of fly ash at the coal fired power stations, which provide about 77 % of the power produced in the country. In this light the use of fly ash will help to reduce the disposal constraints as well as providing a cheap starting material for zeolite synthesis. In this study the hierarchical Zeolite X has been successfully synthesised from fly ash via a hydrothermal treatment. The zeolite was then loaded with Fe/Mn via two approaches namely liquid phase ion exchange and incipient wetness impregnation. For comparison purposes seasoned commercial support materials namely HBEA and MCM- 41 were also loaded with the same metals and characterised with various techniques namely; HRSEM, EDS, HRTEM, XRD, SAED, ICP-OES and N2 adsorption analysis, It was found from the characterisation undertaken that the integrity of the respective supports was generally retained upon metal loading. Both the ICP-OES and the EDS proved that the desired metals were successfully introduced onto the zeolitic support materials. The calculated percentage metal loading for the catalysts prepared via incipient wetness impregnation was closely related to the actual values obtained from the ICP-OES analysis for both the monometallic and the bimetallic catalysts (Fe/Mn). It was observed that the amount of metal that can be introduced on a zeolite via liquid phase ion exchange is largely dependent on the cation exchange capacity of the zeolite Supported metal catalysts for FC alkylation Page v and of the catalysts prepared using 0.25 M Fe solution it was found that Zeolite X had the highest Fe wt% loading of 11.4 %, with the lowest loading of 2.2 % obtained with the MCM-41 supported catalyst. The XRD patterns for the both HBEA and the MCM-41 supported metal catalysts resembled the patterns of the respective prestine support materials except in the case of catalysts with anFe wt % of more than 10, which exhibited peaks due to the Fe2O3 crystallites. In the case of the hierarchical Zeolite X, the metal loaded support had a significant reduction in the XRD peak intensities. The prepared catalysts were tested for the alkylation of benzene with t-butyl chloride. The benzene was also used as the solvent. The alkylation reaction was carried out in a round bottomed flask under reflux conditions and stirring at a temperature of 45 oC over a period of 5 h. A total of 18 catalysts was tested and the highest percentage conversion of 100 % was obtained with the 10%FeH after a reaction time of 2 h. The general trend obtained with the majority of the catalysts was characterised with a rapid initial increase and then steady state was achieved. Generally after a reaction time of 3 h almost all the catalysts had reached steady state in terms of the percentage conversion obtained. The outcomes reflect that the inclusion of Mn does not enhance the conversion but rather decreases it. It was also found that the Mn was not active in the alkylation of benzene as shown by the inactivity of the 10%MnM, where 10% by weight Mn was loaded on MCM-41. However the other monometallic catalysts containing Mn supported on Zeolite X and HBEA were found to be active. The activity is attributed to the presence of Brønsted acid sites in these zeolites which are not present in MCM-41. The selectivity studies reflect that the inclusion of Mn does slightly improve the selectivity towards the formation of the monoalkylated product (t-butyl benzene). The highest selectivity of 91.1 % was obtained with the 10%FeMnM after a reaction time of 4 h. MCM-41 supported catalysts had a relatively higher selectivity compared to the other supports. Considering the Fe monometallic catalysts tested it generally can be said that the yield were in the order HBEA > MCM-41 > Zeolite X. It however should be noted that the percentage yield is calculated from the conversion and selectivity percentages, this implies that the factors affecting these parameters will consequently affect the percentage yield obtained. Supported metal catalysts for FC alkylation Page vi The alkylation reaction was found to be characterised by the formation of two intermediate products which could not be identified. These products were formed during the transient start up stages of the reaction and would disappear from the reaction mixture with longer reaction times, and after 3 h in almost all the reactions studied the intermediates were not detected in the reaction mixture. The main products found were the monoalkylated product (desired product) and the para isomer (1,4-t-di-butyl benzene). There were no other dialkylated isomers or trialkylated products detected. The formation of the para isomer was usually after a reaction time of 2 h in most reactions. The research managed to show that the hierarchical Zeolites X can be synthesised from fly ash and ion exchange and incipient wetness impregnation are appropriate approaches that can be used to introduce Fe/Mn onto the support materials studied. The catalysts prepared were active to varying degrees in the Friedel-Crafts alkylation of benzene with t-butylchloride, with the exception of the 10%MnM which was found to be inactive.

Les interactions protéine-protéine (IPPs) contrôlent de nombreux processus physiologiques importantsdans les cellules humaines. Une caractéristique des cancers est l'échappement des cellules àl'apoptose, qui est souvent associé à la surexpression de protéines anti-apoptotiques, membres de lafamille de protéines Bcl-2. Cette famille comprend des membres anti-apoptotiques (Bcl-2, Bcl-xL,Mcl-1) et pro-apoptotiques. Dans de nombreux cancers dont les cancers de l’ovaire chimiorésistants,l'équilibre entre les membres pro- et anti-apoptotiques de la famille de protéines Bcl-2 est altéré etconduit à la survie des cellules cancéreuses. Une des stratégies envisagées pour surmonter cettechimiorésistance est rétablir l’apoptose par l’inhibition concomitante des protéines Mcl-1 et Bcl-xL.L’objectif est de concevoir des inhibiteurs à dualité d’action visant les protéines Mcl-1 et Bcl-xL.Les travaux antérieurs du laboratoire ont permis la découverte d’un inhibiteur sélectif de la protéineMcl-1, appelé Pyridoclax. Par une approche combinant les méthodes de Fragment-Based Drug Designet Structure-Based Drug Design, à partir de la structure du Pyridoclax, la conception de dual inhibiteurs,leur synthèse et leur évaluation biologique, sont rapportées dans cette thèse. L’exploration de nouveauxespaces chimiques et biologiques est ainsi rendue possible par la mise en oeuvre de cette approche ausein de laquelle le développement de nouvelles méthodologies de synthèse dans le but de concevoirdes fragments tridimensionnels originaux sera présenté.Ces travaux de thèse ont permis de concevoir, synthétiser et caractériser plus de 90 molécules.Certaines ont montré une activité pro-apoptotique intéressante en inhibant les protéines Mcl-1 et Bcl-xLnotamment. / Protein-protein interactions (PPIs) control many important physiological processes within human cells.A hallmark of cancers is the escape of cells from apoptosis, which is often associated with theoverexpression of the anti-apoptotic proteins of the Bcl-2 family. This family comprises pro-survival(Bcl-2, Bcl-xL, Mcl-1) and pro-apoptotic members. In many cancers and, in particular, chemoresistantovarian cancers, the balance between the pro- and anti-apoptotic Bcl-2 family members is alteredleading to the survival of cancerous cells. One of the strategies used to overcome chemoresistance isto re-establish apoptosis by the concomitant inhibition of Mcl-1 and Bcl-xL proteins. Therefore, theobjective is to design dual Mcl-1/Bcl-xL inhibitors.Our groups previous work allowed the discovery of a selective Mcl-1 inhibitor, named Pyridoclax. UsingFragment-Based Drug Design and Structure-Based Drug Design approaches, from the structure ofPyridoclax, the design, synthesis and biological evaluation of dual inhibitors are reported in this thesis.The exploration of novel chemical and biological space is possible by the implementation of thisapproach. The development of synthetic methodologies for the design of new 3-dimensional fragmentswill be presented.In this work, around 90 molecules were synthesized using an approach which combined Fragment-Based Drug Design and Structure-Based Drug Design methods. Some showed a pro-apoptotic activityby inhibiting Mcl-1 and Bcl-xL proteins.

Carbene ligands over these years have become a heavily utilizes and effective ligand for catalysis. The diamino carbene class of ligands are slightly less understood. The effects of bis(carbene) ligand structures of palladium (II) catalysts were investigated using the ETS-NOCV method. The results showed that the amount of π-backbonding played a major role in the rate of the reaction for these NHC complexes. The amount of pi acceptance from the ligand increased in correlation to the length of the methylene linkage in the ligand back bone resulting in increased catalytic activity. The ETS-NOCV method was used to determine the deformation densities that had a contribution to this interaction based on visual interpretation. The percent contribution of pi interactions provided a linear correlation to the natural log of the initial reaction rate, indicating that π-backbonding plays a crucial role in the overall catalytic activity of the palladium complexes. Gold (I) bis acyclic diamino carbenes (ADCs) were investigated for the possibility to be strong hydrogen bond catalysts. The ligand motif of the gold (I) bisADCs were found to be analogous thiourea compounds. Based on NBO analysis there were some improvements to hydrogen bond donicity in comparison to thioureas with the same functional group. The complexes were analyzed for hydrogen bond interactions and polarizations interactions between simple nitroolefin substrate and the catalyst using ETS-NOCV. Results showed that the compounds can form a stable hydrogen bonding system and activate the substrate. This capability is tunable by changing the electron withdrawing properties of the ligase motif, providing the idea that gold (I) bisADCs have potential to be good hydrogen bond catalysts. New thiourea-like gold (I) catalysts utilizing the acyclic diamino carbene motif that were hypothesized were synthesized using a one pot synthesis approach utilizing a metal templated synthesis method. The synthesis, characterization, and application prove these complexes with their cationic centers and bisADCs ligand motif can be utilized for Friedel-Crafts alkylation of indoles, resulting in the production of three new compounds to literature. This research also provided a new application for this specific ligand class and further proved the robustness of ADC ligands.