It is widely accepted that palladium is one of the most useful catalysts in organic chemistry, and many palladium(0)-catalysed carbon–carbon bond-forming reactions have been developed over the years. In addition, the ever-growing need for more environmentally benign processes in the chemical industry has driven scientists to look for greener options while developing new methodologies for organic synthesis. This thesis describes a series of studies on Suzuki and Heck coupling reactions in water and the application of palladium(0) catalysis to the development of new HIV-1 integrase inhibitors. The previously described 'transition-metal-free Suzuki-type coupling' reaction was shown to take place due to sub-ppm levels of palladium contaminants present in the commercially available sodium carbonate base. Based on this finding, a new, microwave-assisted Suzuki protocol utilizing ppb/ppm levels of palladium in water was developed. This methodology was adapted to terminal Heck coupling, although the scope of the protocol was found to be rather limited. Finally, both Suzuki and Heck reaction processes were successfully scaled up to 100 mmol using an automated batch stop-flow microwave apparatus. As the methodologies utilizing ultralow palladium concentrations were not applicable to aryl chlorides, attention was shifted towards palladium on carbon. This simple catalyst, together with microwave heating employing simultaneous cooling, was found to be beneficial in the Suzuki coupling of aryl chlorides with phenylboronic acid in water. Ligand-controlled internal arylation of ethylene glycol vinyl ether with aryl halides was shown to be possible in water alone without any additives. Reactions were run under air, using conventional heating and the products formed were isolated as aryl methyl ketones in good to excellent yields. The electron-rich (dippp)2Pd complex was shown to be beneficial for the microwave-assisted internal arylation of some aryl chlorides. Furthermore, the active role of the hydroxyl group of ethylene glycol vinyl ether in the formation of a cationic intermediate leading to internal Heck coupling product was elucidated. Finally, to demonstrate the usefulness of palladium(0) catalysis in the development of new pharmaceutical entities, a series of HIV-1 integrase inhibitors was synthesised and evaluated in strand transfer assays and in vitro. Based on the results and docking studies performed, valuable information related to the structure–activity relationship was obtained.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The catalytic activity of hierarchical hybrid structures, formed by metal nanoparticles, M-NPs (AuNPs and PdNPs), synthesized and stabilized by block copolymers, is reported in this present work. The catalytic activity was investigated by the study of nanoparticle size and chemical nature of the block copolymer overlaying the M-NP. To evaluate the chemical structure effect of the polymer on catalytic properties of the hybrid systems, a series of eight distinct polymers was used: poly(ethylene oxide)113-b-poly(glycerol monomethacrylate)30-b-poly [2-(diisopropylamino)ethyl methacrylate]50 (PEO113-b-PG2MA30-b-PDPA50), poly(ethylene oxide)113-b-poly[2-(diethylamino)ethyl methacrylate]50 (PEO113-b-PDEA50) , poly(2- methacryloyloxyethyl phosphorylcholine)30-b- poly(2-(diisopropylamino) ethyl methacrylate)60 (PMPC30-b-PDPA60), poly(ethylene oxide)100-b-poly(propylene oxide)65-b-poly(ethylene oxide)100 (PEO100-b-PPO65-b-PEO100 or F127), α-carboxylic ω-thiol poly(N-isopropyl acrylamide)137 (HS-PNIPAM137-COOH), poly(4-vinylpyridine)137-b-(ethylene oxide)45 (PEO45-b-P4VP137), poly(N-vinyl caprolactam)94 (PNVCL94) and poly(N-vinyl caprolactam)53 (PNVCL53). The size of M-NPs was determined by dynamic light scattering (DLS) and their morphology was confirmed by transmission electron microscopy (TEM). Subsequently, was tested the catalyst efficiency, by the reduction of p-nitrophenol to p-aminophenol, the catalyst could be regenerated about 6 times, proving that system (AuNPs and PdNPs) as capacity for regeneration and can be an effective catalyst. The PdNPs were tested like catalyst in reactions of Suzuki coupling. / A atividade catalítica de estruturas hierárquicas híbridas formadas por nanopartículas metálicas, M-NPs (AuNPs e PdNPs), sintetizadas e estabilizadas por copolímeros em bloco é relatada neste trabalho. A atividade catalítica foi investigada em função da natureza química do copolímero em bloco que as revestem. Uma série de 08 (oito) polímeros estruturalmente relacionados foi utilizada: poli(óxido de etileno)113-b-poli(metacrilato de 2,3-diidroxipropila)30-b-poli(metacrilato de 2-(diisopropilamino)etila)50 (PEO113-b-PG2MA30-b-PDPA50), Poli(óxido de etileno)113-poli [ metacrilato de 2-(dietilamino)etil]50 (PEO113-b-PDEA50), poli(2-metacriloiloxietil fosforilcolina)30-b-poli[metacrilato de 2-(diisopropilamino)etil]60 (PMPC30-b-PDPA60), poli(óxido de etileno)100-b-poli(óxido de propileno)65-b-poli(óxido de etileno)100 (PEO100-b-PPO55-b-PEO100 ou F127), α-tiol-ω-ácido carboxílico poli(N-isopropil acrilamida)113 (HS-PNIPAM113-COOH), poli(oxido de etileno)137-b- poli(4-vinil piridina)45 (PEO137-b-P4VP43) poli(N-vinil caprolactana)94 (PNVCL94) e poli(N-vinil caprolactana)53 (PNVCL53). O tamanho das M-NPs foi determinado por espalhamento de luz (DLS) e sua morfologia comprovada através de análise de microscopia de transmissão (TEM). Sua eficiência foi posteriormente testada na catálise da redução do p-nitrofenol a p-aminofenol. Comprovou-se, mediante á ciclos reacionais, que ambos os sistemas (AuNPs e PdNPs) apresentaram capacidade de regeneração, sendo regenerado 6 vezes, provando ser um catalisador eficiente. As PdNPs foram testadas em reações de acoplamento de Suzuki.

The war between human and malaria has never stopped, and the development and application of antimalarial drugs has not eradicated this terrible disease. To fight drug-resistant malaria, many leads have been studied over the years. (1S,3R)-MMV008138 and MMV1803522 are two compounds that have been studied in the Carlier Group. My research focused on the structural variation of each of these compounds, in the hope that greater potency could be realized. Chapter 2 describes my work on (1S,3R)-MMV008138, which inhibits the enzyme PfIspD in the methylerythritol phosphate (MEP) pathway. This compound shows good in vitro potency against the drug resistant Dd2 strain of Plasmodium falciparum. However, this lead showed no activity in mouse models. This lack of activity may be due to poor metabolic stability of the compound. However, a significant increase in in vitro potency could also improve in vivo activity. Towards that end, I focused on further variation of the D-ring and A-rings. With the regard to the D-ring, we made five analogs of MMV008138 that replaced the 2,4-dichlorophenyl ring with dihalogenated thiophen-3-yl and thiophen-2-yl rings. We also explored the effect of installing a cyano group on the A-ring of MMV008138. Unfortunately, none of these new compounds were potent growth inhibitors of Dd2 strain P. falciparum. We conclude that the lead goes into a well-defined pocket within the PfIspD enzyme that only accommodates 2,4-dihalogenated phenyl D-rings. This pocket also cannot accept any substitution larger than F on the A-ring. Interestingly, the crystal structure of 5-cyano-substituted MMV008138 was obtained ((±)-2-50c). This is the first compound out of more than 100 analogs of MMV008138 family to be amenable to crystallization. The solid state conformation of the (±)-2-50c revealed that the C3-carboxyl group was in a pseudoequatorial orientation, and the C1-aryl group was thus in a pseudoaxial orientation. 1H NMR spectroscopic studies in CD3OD-D2O were carried out to determine the solution conformation. As expected from previous studies of ester derivatives of MMV008138, these studies indicated that in solution, 2-5 would adopt both the C3-carboxyl pseudoequatorial and pseudoaxial conformations. In Chapter 3, I describe the synthesis of analogs of the antimalarial drug candidate MMV1803522. This β-carboline-3-carboxamide shows good in vitro growth inhibition potency of Dd2 strain P. falciparum, operating by a still unknown mechanism. To investigate the pharmacophore of this lead, I first sought to determine whether the pyridine N (i.e. N2) of the β-carboline was important for in vitro potency. I prepared series of carbazole analogs of MMV1803522, which replace N2 with a CH. These compounds potently inhibited the growth of Dd2 strain P. falciparum. These results suggest that N2 of MMV1803522 is not involved in any energetically significant interactions with its target protein. To further identify the pharmacophore, we prepared truncated analogs lacking the A- and B- rings (biphenyl analogs), and tricyclic analogs that feature a reversed indole moiety. Unfortunately, the biphenyl analogs and reversed indole analogs show no growth inhibition at 10,000 nM the highest concentration tested. Lastly, I describe analogs of MMV1803522 in which the 3,4-dichlorophenyl ring of MMV1803522 was replaced with halogenated thiophene. This substitution was tolerated, but compounds were roughly half as potent as MMV1803522. / Doctor of Philosophy / Malaria, mainly caused by the infection of P. falciparum, is a serious worldwide disease. In 2020, there were 241 million cases of malaria infections and over 600,000 deaths from malaria. Combinations of commercially available antimalarial compounds, such as chloroquine, mefloquine and artemisinin, are commonly used as combination therapies to treat malaria. Since different antimalarial compounds have different mechanisms of action, this combination strategy can greatly slow down the spread of drug-resistant parasites. However, multiple drug-resistant strains of P. falciparum have been reported. Therefore, there is an urgent need for new antimalarial compounds with novel mechanisms of action. This dissertation involves my research on the investigation and optimization of two novel antimalarial compounds, MMV008138 and MMV1803522. MMV008138 is an inhibitor of the MEP pathway, which is an essential metabolic pathway and attractive target for antimalarial therapies, in malaria parasites. The parasites cannot survive, with the MEP pathway inhibited. Since the MEP pathway is not present in human, the MMV008138 molecule is unlikely to have toxicity to human. The MMV008138 molecule has been demonstrated to have great in vitro performance of inhibiting the MEP pathway in several studies, however, the in vivo performance in mouse models is yet to improve. This may be due to the poor metabolic stability of this compound. The compound decomposes in the mouse body before it takes effect. To enhance the metabolic stability and potency, I performed chemical modifications on the A- and D-rings of the MMV008138 compound. An X-ray crystal structure was obtained to help elucidate the conformer distribution of MMV008138. This crystal structure can be used to guide our understanding of the docking of this compound to the target enzyme in the future. MMV1803522 is another compound that shows great potency in vitro and in vivo. This compound is fully oxidized and contains four aromatic rings. However, the target enzyme and the mechanism of action of MMV1803522 is yet to be discovered, and the structure-activity relationship between the chemical structure and the biological activity of this molecule is still unknown. Therefore, I have developed synthetic methods to synthesize a series of compounds that are structurally similar to the MMV1803522 and found that potency of this molecule is not due to the nitrogen on the C-ring. Also, the number and size of the ring structures in the MMV1803522 may be crucial for this molecule to exhibit great potency in vitro and in vivo.

L'objet de ce travail de thèse concerne la synthèse par réaction cascade pallado-catalysé d'une nouvelle famille de chromophores pentacycliques azotés dont les propriétés de fluorescence peuvent être modulées en fonction des groupements fonctionnels présents dans la molécule. Ces chromophores sont obtenus par réaction one-pot entre des acides 2-formyl boroniques et des 2,5-dihalopyridines. Le processus cascade est initié par un couplage de Suzuki suivi par deux cyclisations successives. La première se fait sur l'azote de la pyridine et la seconde se produit de façon régio-sélective sur le carbone adjacent à l'azote. Les structures cristallines et le calcul théorique DFT ont montré la régio et la stéréo-sélectivité de la réaction. De plus, des études préliminaires ont montré que ces composés polycycliques possèdent d'excellentes propriétés de fluorescence ainsi qu'une activité biologique qui devraient nous permettre d'étendre le champ d'application de ces nouveaux chromophores vers le domaine médical et l'électronique moléculaire / The aim of this work concerns the synthesis of a new family of aza-pentacyclic chromophore whose fluorescence properties can be modulated according to the functional groups present in the molecule. These chromophores were obtained through a cascade process between 2-formylbenzene boronic acid and 2,5-dihalopyridines. The cascade process is initiated by a palladium-catalyzed cross-coupling reaction and is followed by two successive nucleophilic cyclizations; the first cyclization performed on the pyridine nitrogen and the second occurred regioselectively on the adjacent carbon atom. This new cascade reaction allowed the formation of a pentacycle as a single regioisomer with four new bonds and two contiguous stereocenters with trans relationships. In addition, preliminary studies have shown that these polycyclic compounds have excellent fluorescence properties as well as biological properties that should enable us to extend the scope of these new chromophores to the medical field and molecular electronics

Ce mémoire est subdivise en deux parties. La première partie concerne la synthèse de pyrazoles présentant un intérêt sur le plan agrochimique. En effet, le noyau pyrazole est présent dans de nombreux composes ayant des activités biologiques diverses et en particulier antifongique. Au cours de ce travail, nous avons développé diverses approches convergentes de pyrazoles diversement substitués au moyen de réactions de couplages croisés pallado-catalyses sélectifs et séquentiels à partir de pyrazoles possédant différents points d’encrages. Dans la deuxième partie, nous nous sommes intéressés à la synthèse de diverses furopyridones en tant qu’analogues de produits naturels possédant une activité antifongique, et notamment le Cladobotryal. Dans ce but, diverses alcynylpyridones ont été synthétisées et mises en jeu dans divers processus de cyclisation pour atteindre de manière divergente une série de furo[3,2-c]pyridin-4-ones, furo[3,2-c]pyridin-6-ones et furo[2,3-b]pyridin-4-ones / This thesis is subdivided into two principal parts. The first part is focussed on the synthesis of pyrazole derivatives of agrochemical relevance. Indeed, the pyrazole nucleus is found in numerous compounds possessing interesting biological properties, and notably antifungal activities. Various convergent approaches to diversely substituted pyrazoles have therefore been developed by means of site-selective palladium-catalyzed cross-coupling reactions conducted sequentially on pyrazole scaffolds. In the second part, we have been involved in the synthesis of furopyridones as simplified analogues of natural compounds possessing antifungal activities such as Cladobotryal. Toward this end, various alkynylpyridones have been synthesizes and involved in diverse cyclization processes to access a series of furo[3,2-c]pyridin-4-ones, furo[3,2-c]pyridin-6-ones, and furo[2,3-b]pyridin-4-ones

In this study, organic and polymeric fluorophores based on 2,4,6-triphenylpyridiene (TPP) structure were found to have the novel aggregation-induced emission enhancement (AIEE) property. For the small-mass fluorophores, TPP and cyano-functionalized TPP (TPP-CN) were prepared from the facile Chichibabin reaction and their AIEE properties were characterized by the emission behavior in solvent/nonsolvent pair. Solid samples of TPP and TPP-CN exhibit enhanced emission with increasing annealing time under solvent vapors, thus, both compounds have the characters of crystallization-induced emission enhancement (CIEE) behavior. For polymeric system, copolymers PTPPF containing alternative TPP and 9,9-dioctylfluorene units were prepared through Suzuki coupling and study on its fluorescence behavior also reveals its AIEE feature. The rigid polymer possesses high emission intensity in its dilute solution state and remains almost unchanged with increasing nonsolvent fraction. The solid sample was found to have a high quantum yield (ФF) of 70 %.

Magister Scientiae - MSc (Chemistry) / This work involves the synthesis of copper telluride-polypropylenimine tetra(5-(2-thienyl) salicylaldimine) (CuTe@PPI) and copper antimonide-polypropylenimine tetra(5-(2-thienyl) salicylaldimine) (CuSb@PPI) core-shell nanoparticles (NPs), using two-pots and one-pot synthesis methods, respectively. Their morphology was studied by X-ray diffraction spectroscopy (XRD), high resolution transmission electron microscopy (HRTEM) and high resolution scanning electron microscopy (HRSEM); while their structures were characterized by Fourier transform infrared spectroscopy (FTIR) and elemental analysis. Photophysical properties of the core-shell NPs were determined from ultraviolet-visible absorption spectroscopy (UV-Vis) and photoluminescence spectroscopy (PL). For core-shell NPs produced via two-pots method only CuTe@PPI exhibited ? ? ?* and n ? ?* which indicate that CuSb@PPI produced via two-pots method was unsuccessfully synthesized. The ? ? ?* and n ? ?* transitions indicate the presence of polypropylenimine tetra(5-(2-thienyl) salicylaldimine) (PPI) on the surface of CuTe NPs and CuSb NPs. FTIR confirmed coordination of PPI on the surface of CuTe NPs and CuSb NPs by showing a shift in wavenumber of C=N group bands from PPI. HR-TEM showed that the CuTe@PPI synthesized via one-pot method have a wide particles sizes distribution with an average particles size of 13.60 nm while for CuTe@PPI synthesized via two-pots it was impossible to determine the particles size due to aggregation. CuSb@PPI synthesized via twopots method and one-pot method has a wide particles sizes distribution with an average size of 7.98 nm and 11.61 nm respectively. The average particles sizes determined by HR-SEM were found to be 35.24 nm (CuTe@PPI two-pots method), 33.90 nm (CuTe@PPI one-pot method), 18.30 nm (CuSb@PPI two-pots method), and 16.18 nm (CuSb@PPI one pot method). / 2021-08-31

There are two kinds of protein aggregates associated with Alzheimer’s disease: amyloid-beta and tau aggregates. Protein ligands are molecules with the ability to bind to these pathologicalprotein accumulations, and if the ligands are fluorescent, they can be used to detect the aggregates they’re bound to. The ligands can be selective and only bind to one kind of protein aggregate, or they can be general and bind to both kinds. PI-2620 is a ligand selective for tau aggregates, and in this thesis, three analogues of PI-2620 were synthesized and determined to be functional fluorescent protein ligands. Two of them, designated A1 and B1, were selective for amyloid-beta aggregates, while the third ligand, A2, obtained by ester-hydrolysis of A1, would bind to both tau and amyloid-beta aggregates. This finding suggests that introducing a charge to a ligand lowers its selectivity, since the staining experiments were carried out in a buffered solution at pH 7.4, where ligand A2 might be partially charged.

Metallfluoride sind dank ihrer hohen chemischen und thermischen Stabilität, insbesondere bei Reaktionen unter Beteiligung von hoch korrosiven Gasen (HF, HCl, Cl2, F2) den entsprechenden Oxiden überlegen. Über den Sol-Gel Prozess synthetisierte Produkte weisen oft spezifische, zum Teil sehr unterschiedliche Eigenschaften im Vergleich zu klassisch hergestellten Verbindungen auf. In dieser Arbeit wurde der Sol-Gel Prozess zur Herstellung von binären Fluoriden (AlF3, MgF2, CaF2, CuF2 und FeF3) genutzt und zum Teil weiter entwickelt sowie das Synthesepotential dieser Methode als Zugang für komplexe Fluoride (KMgF3, K3AlF6), für Metallfluorid-geträgerte „nano Edelmetall-Systeme (Pd/AlF3, Pt/AlF3, Pd/CaF2, Pd/MgF2) und für Gast–Wirt–Metallfluorid-Systeme (CuF2/AlF3, FeF3/AlF3) untersucht. Die Eigenschaften der als kompakte Materialien hergestellten Metallfluorid Systeme wurden mit Hilfe spektroskopischer Methoden untersucht und dabei insbesondere deren Oberflächeneigenschaften bestimmt. Die neuen Materialien wurden für die Nutzung akademisch und industriell bedeutsamer Katalysereaktionen evaluiert und mit klassischen Katalysatoren verglichen. Es konnte gezeigt werden, dass der Sol-Gel Prozess für Fluoride zu neuartigen Materialien mit außergewöhnlichen Eigenschaften führt. Insbesondere infolge der Synthese-bedingten Vergrößerung der spezifischen Oberflächen um einen bis zu 20-fachen Faktor im Vergleich zu klassisch hergestellten Fluoriden konnten auch eine Reihe von katalytisch interessanten Metallen (Pd, Pt) in die nanoskopischen Festkörperfluoride eingebracht werden. Die TEM Aufnahmen zeigen, dass z. B. 2-5 nm große Palladiumpartikel sehr homogen in ca. 80 nm große CaF2- bzw. 20 nm große AlF3-Matrices in nur einem einzigen Reaktionsschritt eingeführt werden können. Die neuen Materialien wurden in verschiedenen katalytischen Reaktionen getestet und zeigten sich in mehreren Fällen den „Standard Katalysatoren“ überlegen. / Because of their high chemical and thermal stabilities, metal fluorides have found to be advantageous over metal oxides in such cases where reactions involving generation of corrosive acids like HCl and HF are concerned. The Sol-gel method is known for the synthesis of materials with considerably different properties to those prepared by classical routes. In this work, sol-gel route has been employed for the synthesis of binary fluorides (AlF3, MgF2, CaF2, CuF2 and FeF3), hydroxyfluorides [AlF3-x(OH)x, MgF2-x(OH)x] complex fluorides (KMgF3, K3AlF6), metal fluoride supported nanoscopic noble metals (Pd, Pt) and host-guest fluoride systems (CuF2/AlF3, FeF3/AlF3). Besides the successful synthesis of metal fluorides described above, the present thesis deals with investigation of their bulk and surface properties using various analytical and spectroscopic methods (XRD, BET, NH3-TPD FTIR-pyridine adsorption, XPS, microscopic studies) as well as with their catalytic properties for the reactions of academic and industrial interest. Metal fluorides prepared via sol-gel method have shown to possess extraordinary surface properties in terms of surface area, particle size, porosity, Lewis acidity and distortion in their structures as compared to those of classical methods like aqueous synthesis or impregnations. A homogeneous dispersion of Pd nanoparticles supported on high surface area metal fluoride prepared by this method was confirmed by XRD, XPS and TEM imaging. Catalytic properties of these materials have been investigated for dehydrofluorination of hydrofluorocarbons, isomerization of citronellal, hydrodehalogenation of chlorodifluoromethane, Suzuki cross coupling and oxidative fluorination of benzene.

Les réactions pallado-catalysées permettant la formation de liaisons carbone-carbone trouvent de nombreuses applications en synthèse organique et constituent l’étape clé de la synthèse d’un grand nombre de molécules. La première partie de cette thèse décrit la préparation et l’étude de catalyseurs hétérogènes et réutilisables comportant du palladium supporté sur un polymère portant des groupements phosphinés, polymère dérivé soit d'une résine de Merrifield soit d’une résine Rasta. De très bons résultats ont été obtenus pour leur utilisation dans les couplages croisés de Hiyama, Heck et Suzuki et dans chaque cas la possibilité de réutilisation jusqu’à 4 fois du catalyseur a été vérifiée. Notre travail constitue une des premières utilisations d’un catalyseur réutilisable dans le couplage de Hiyama. Nous avons aussi mis au point des conditions permettant d’effectuer le couplage de Heck en présence d’une quantité infime de palladium. Notre étude sur les résines Rasta constitue la première application de ces supports en pallado-catalyse. La deuxième partie de la thèse décrit l’étude de la préparation de catalyseurs où le palladium serait supporté sur des nanoparticules superparamagnétiques et qui pourraient donc être récupérés de tout milieu réactionnel grâce à un champ magnétique externe. Des nanoparticules de cobalt ont été préparées puis recouvertes de pyrocarbone par dépôt chimique en phase vapeur. Des groupements organiques ont été fixés sur la coque de carbone, ce qui permet l’introduction de ligands phosphinés. La structure de ces particules a été étudiée par microscopie électronique en transmission et leur préparation optimisée en fonction des résultats structuraux. / Palladium-catalyzed reactions forming carbon-carbon bonds have found widespread applications in organic synthesis as they represent the key step of many important syntheses in various domains. The first part of this work describes the preparation and study of heterogeneous, reusable, catalysts containing palladium supported on a polymer bearing phosphino groups derived from either a Merrifield resin or a Rasta resin. Very good results have been obtained for the use of these catalysts in Hiyama, Heck and Suzuki cross-couplings and, in each case, the possibility of reuse of the catalyst at least 4 times has been verified. Our work constitutes one of the first use of a reusable catalyst in a Hiyama coupling. We have also found experimental conditions allowing to run the Heck coupling in the presence of only a minimal amount of palladium. Our work constitutes the first use of Rasta resins to prepare heterogeneous palladium catalysts. The second part of the thesis describes the study of the preparation of catalysts where palladium would be supported on superparamagnetic nanoparticles and which could therefore be recovered from any reaction medium by using a magnetic field. Cobalt nanoparticles were prepared and then covered by pyrocarbon by Chemical Vapor Deposition. Organic groups, allowing the subsequent introduction of phosphino ligands, were then grafted on the carbon shells. The structure of the particles was determined by Transmission Electron Microscopy and their preparation optimized according to these structural results.