This paper reports a simple self-assembly strategy towards bowl-shaped carbon-containing hollow particles, as well as an unprecedented potential application for block copolymer vesicles in energy storage. Kippah vesicles (fully collapsed vesicles), formed by solution self-assembly of an amphiphilic polystyrene-block-poly(ethylene oxide) block copolymer, were employed as the template to guide the formation of bowl-shaped nitrogen-doped carbon hollow particles (BNCHPs). As electrode materials of supercapacitors, BNCHPs exhibit superior electrochemical performance. In particular, compared with their spherical counterpart, BNCHPs largely increase their volumetric packing density, leading to much higher volumetric capacitance or volume reduction of electrodes, which is desired for practical supercapacitor devices.

Total synthesis of natural products is of contemporary interest in organic synthesis. One of the useful ways to synthesize the natural products is to originate from inexpensive chiral pool compounds abundantly available in nature. In this context, our research group is actively involved in the use of tartaric acid as the four carbon four hydroxy building block in the synthesis of a number of natural products of therapeutic importance. Our strategy relies on the utility of γ-hydroxy amides derived from tartaric acid involving a controlled addition of Grignard reagents and stereoselective reduction. We were successful in application o f this useful building block for the synthesis of a variety of natural products possessing varied functional groups (Chart-1). derived from tartaric acid in the synthesis of oxylipins such as pinellic acid and diyne containing natural products. Chapter 1 of the thesis describes the total synthesis of (+) pinellic acid 6 and (Z,8S,9S,10R)-8,9,10-trihydroxyoctadec-6-enoic acid 10. Key strategy in the synthesis of pinellic acid is elaboration of the aldehyde 3, derived from the γ-hydroxy amide 2 via Horner-Emmons-Wadsworth reaction to yield the α,β-unsaturated ketone 4. Stereoselective reduction of the ketone with (R)-BINAL-H produced the alcohol with requisite stereochemistry which was further extended to pinellic acid 6 (Scheme 1). Wittig homologation of the aldehyde 8 derived from γ-hydroxy amide 7 is the key step for the synthesis of the (Z,8S,9S,10R)-8,9,10-trihydroxyoctadec-6-enoic acid 10. Second chapter of the thesis deals with total synthesis of diyne containing natural products. In the first part of this chapter enantioselective synthesis of possible diastereomers of heptadeca1-ene-4,6-diyne-3,8,9,10-tetrol, a structure proposed for the natural product isolated from Hydrocotyle leucocephala, is accomplished. The alkyne precursors 13 and 14 were synthesized from the α-hydroxy ester 12 derived from γ-hydroxy amide 11 while the alkyne 17 is synthesized from the masked tetrol 16 derived from lactol 15 which was obtained from D-ribose. yne to assemble the diyne unit which was further elaborated to heptadeca-1-ene-4,6-diyne3,8,9,10-tetrol (Scheme 3). It was found that the NMR spectral data of the putative structure assigned for the natural product did not match with any of the diasteromers that were synthesized. This establishes that the structure proposed for the natural product is wrong and requires revision. OH OH OH 18 OH OH 19 OH OH 20 OH OH Scheme 3: Synthesis of diastereomers of heptadeca-1-ene-4,6-diyne-3,8,9,10-tetrol. [Part of this work is published: Prasad, K. R.; Swain, B. J. Org. Chem. (in press)] Second part of this chapter deals with the synthesis of panaxytriol 26 and panaxydiol 28. Key reaction in the synthesis of panaxytriol and panaxdiol is the coupling of bromoalkynes 25 and 27 with 3-silyloxy pent-1-en-4-yne and further elaboration to the triol and diol. The required alkynes were synthesized from the primary alcohol 24 which was obtained from the γ-hydroxy amide 11 involving a series of simple synthetic operations. (Scheme 4). (For structural formula pl see the abstract file)

Les polyesters insaturés sont des résines thermodurcissables particulièrement appréciées pour leur facilité de mise en œuvre et leur coût modéré. Cependant, comme tous les polymères organiques ils ont une réaction au feu médiocre, ce qui est critique dans un certains nombres de d'applications. L'objectif de cette thèse était d'élaborer de nouvelles formulations de résines ayant un comportement au feu amélioré. La première stratégie développée a été le greffage de monomères phosponés dans la matrice polyester. Des monomères méthacryliques et styrénique ont été synthétisés et utilisés pour remplacer une partie du styrène dans la résine. La stabilité thermique des résines modifiées est diminuée, mais leur comportement au feu est globalement meilleur. Des effets du phosphore en phase gazeuse et en phase condensée ont pu être mis en évidence.Dans une seconde partie, une sélection de particules se distinguant par leur nature, leur taille et leur facteur de forme a été testée. Si l'impact des ces charges est assez limité lorsqu'elles sont utilisées individuellement, des tests calorimétriques ont révélé que certaines combinaisons de particules pouvaient améliorer significativement la réaction au feu des résines. Enfin, des associations d'additifs phosphorés et de particules submicroniques ont été investiguées. Le polyphosphate d'ammonium se distingue des autres additifs par un impact très important sur le comportement au feu et particulièrement par le charbonnement important qu'il engendre, cependant sa combinaison avec des charges inorganiques ne s'est pas révélée probante. / Unsaturated polyesters are thermoset resins particularly appreciated for their low cost and easy processing. Nevertheless one of their main drawbacks is their poor fire resistance. The aim of this PhD thesis was to prepare new resin formulations with an improved fire behaviour. The first part of this work was dedicated to the grafting of phosphorous monomers in the polyester matrix. Methacrylic and styrenic monomers were synthesized and used to replace of part of the styrene in the resin. Resin thermal stability was decreased, but on the whole their fire behaviour was improved. Condensed phase and gas phase effects of phosphorus were highlighted.In a second part, a screening of various kinds of particles with different sizes was performed. Calorimetric tests revealed that, while the effect of these particles used alone is limited, a decrease of resin flammability could be achieved with specific combinations. Finally, commercial phosphorous additives were associated with submicronic fillers. From all the additives tested, ammonium polyphosphate stands out, with a powerful impact on the resin fire reaction and especially a much increased charring. However, its combination with inorganic particles was not conclusive.

La maladie d’Alzheimer (MA) est une pathologie neurodégénérative lente, progressive et irréversible. Elle est principalement caractérisée par deux lésions histopathologiques : les dégénérescences neurofibrillaires, causées par l’accumulation intraneuronale d'agrégats de protéines Tau hyper- et anormalement phosphorylées ; et les dépôts amyloïdes parenchymateux, constitués d’agrégats de peptides amyloïdes (Aβ) issus du clivage de la protéine précurseur du peptide amyloïde (APP). À ces deux lésions s'ajoute entre autres une dérégulation de l'homéostasie protéique et des systèmes de dégradation des protéines : protéasome, autophagie et voie endosome/lysosome qui sont les mécanismes principaux mis en jeu pour l'élimination des agrégats protéiques. Plusieurs études suggèrent que la surproduction et l'agrégation des peptides Aβ sont les causes principales de la MA. Ainsi, la réduction de leur production et/ou l’amélioration de leur clairance représentent des stratégies potentielles pour le développement de traitement contre la MA. Les objectifs de mes travaux de thèse furent d’étudier de façon plus approfondie l’implication respective des voies de dégradation de l’APP et de ses métabolites ; de déterminer le mode d’action biologique de dérivés chimiques de la chloroquine sur le métabolisme de l’APP en relation avec la Valosin-Containing protéine (VCP), supposée être la cible de ces molécules, et par la même occasion d’étudier la relation existante entre l’APP et VCP. Dans un premier temps, nous avons pu démontrer que l’APP et ses fragments carboxyterminaux (APP-CTFs) étaient principalement dégradés par deux voies : la g-sécrétase et la voie endolysosome. Ensuite, nous avons démontré que VCP régulait le trafic intracellulaire de l’APP. Enfin, nous avons découvert que l’action des molécules était indépendante de la protéine VCP et qu’il s’agissait de modulateurs indirects de l’activité β-sécrétase permettant ainsi de réduire la sécrétion de peptides Aβ. En conclusion, ces travaux ont permis de contribuer à une meilleure compréhension du métabolisme de l’APP et de ses processus de dégradation ainsi que de caractériser l’effet biologique de nouveaux inhibiteurs indirects de la β-sécrétase. / Alzheimer's disease (AD) is a slow, progressive and irreversible neurodegenerative disease. There are two histopathological hallmarks found in AD brains: neurofibrillary tangles, caused by the intraneuronal accumulation of Tau protein aggregates in a hyper- and abnormally phosphorylated form; and amyloid deposits in the brain parenchyma which are mainly composed of amyloid peptides (Aβ) aggregates derived from the cleavage of the amyloid precursor protein (APP). AD physiopathology also includes a deregulation of protein homeostasis and degradation systems: proteasome, autophagy and the endosome/lysosome pathway, which are the main processes involved in the elimination of protein aggregates. Many evidences suggest that overproduction and aggregation of Aβ peptides are the main causes of AD and that strategies aiming to reduce their production and/or improve their clearance represent attractive approaches for AD therapeutics. Thus, this thesis aimed to study the respective contribution of g-secretase, proteasome and lysosomes in APP degradation; to determine the biological mode of action of chloroquine derivatives on APP metabolism in relationship with the Valosin-Containing Protein (VCP), supposed to be the target of these molecules, and at the same time, to study the relationship between APP and VCP. First, we have demonstrated that APP and its carboxy-terminal fragments (APP-CTFs) were mainly degraded by two pathways: g-secretase and the endosome/lysosome pathway. Next, we showed that VCP was involved in APP trafficking and processing. Finally, we have discovered that the action of our molecules does not depend on VCP but that they are indirect modulators of the β-secretase activity, reducing Aβ peptides secretion. In conclusion, this work contributed to a better understanding of APP metabolism and its degradation processes but also to characterize the biological effects of new indirect β-secretase inhibitors.

[pt] O Ácido Húmico (AH) é uma fração orgânica obtida em solos, corpos hídricos bem como em matrizes carbonáceas. Nos últimos anos o interesse associado a esta substância vem crescendo progressivamente à medida que novas aplicações são descobertas, tais como: fertilizantes, recuperação de áreas degradadas e tratamento de efluentes contaminados com metais. As principais características dos AH são dependentes do método de extração e da matriz escolhida, posto que se pode extraí-lo de uma ampla gama de matérias primas, assim como por meio de diferentes métodos. Dentro deste contexto, o objetivo principal do presente trabalho pretende avaliar o potencial de extração de ácido húmico a partir de diferentes precursores carbonáceos. Foram utilizadas três matrizes carbonáceas distintas: rejeito de carvão mineral (RCM), coque mineral (CM) e coque verde de petróleo (CVP). Além deste estudo experimental foram apresentados alguns resultados de estudo semelhante disponível na literatura. O método de extração utilizado foi adaptado de Trompowski et al (2005), e a caracterização foi feita utilizando-se técnicas de ICP-OES, CNHS, MEV/EDS, FTIR e Difração de Raio-X. A eficiência da extração, em termos de recuperação em massa, variou, significativamente, em função do método adotado, sendo os melhores resultados associados ao rejeito de carvão mineral (17,0 porcento), ao passo que a menor eficiência está relacionada ao coque verde de petróleo, após destilação (0,2 porcento). A extração a partir do coque verde de petróleo, como recebido, é inviável em função da sua imiscibilidade com a solução de ácido nítrico. Os resultados obtidos a partir do FTIR foram satisfatórios para todos os AH analisados, apresentando bandas características de AH e compatíveis com o indicado na literatura. Os resultados da análise de ICP-OES apresentaram baixa presença de metais e elementos traços para o AH oriundo do coque mineral. No que diz respeito ao ácido húmico extraído do rejeito de carvão mineral, que apresentou a maior concentração inicial de metais, principalmente ferro, foi implementado, com sucesso, uma purificação utilizando ácido nítrico. Com base nos resultados obtidos é possível afirmar que a utilização de diferente precursores carbonosos permitiu a extração de AH com características semelhantes aqueles citados na literatura e extraídos de outras fontes. / [en] The humic acid (HA) is an organic fraction that can be found in soil and watercourses as well as in carbonaceous matrices. In recent years the interest associated with this substance has been growing steadily as new applications are discovered, such as fertilizers, remediation of degraded areas and treatment of wastewater contaminated with metals. The main features of HA are dependent on the method of extraction and the chosen matrix, since it can be extract from a wide range of raw materials, as well as by different methods. Within this context, the main objective of this work is related to an assessment of the potential of extracting humic acid from different carbonaceous precursors. three different carbonaceous matrices were used: coal tailings (RCM), coke (CM) and green petroleum coke (CVP). Besides this experimental study some results of a similar study available in the literature were presented. The extraction method used was adapted from Trompowski et al, and the characterization was done using ICP- OES techniques, CNHS, MEV / EDS and FTIR. The extraction efficiency, in terms of mass recovery, significantly varied depending on the method used, the best results being associated with coal tailings (17.0 percent), while lower efficiency relates to the calcinated petrocoke after distillation (0.2 percent). The extraction from green petroleum coke, as received, is unfeasible due to its immiscibility with the nitric acid solution. The results obtained from FTIR were satisfactory for all the HA analyzed, displaying bands consistent with those from HA and compatible with bands shown in the literature. The results of the analysis of ICP-OES showed a low presence of metals and trace elements coming from the HA for coke. With respect to the extracted humic acid from coal tailings, which showed the highest initial concentration of metals, particularly iron, was successfully implemented, a purification with nitric acid. Based on the results obtained it can be stated that the use of different carbonaceous precursors allowed the extraction of humic acid with similar characteristics as cited in the literature and those obtained from other sources.

The diffusion behavior of guest molecules introduced in porous materials has been studied. Diffusion studies in such porous materials may help for elucidating the structural properties, transport mechanism and/or surface barriers of the zeolite structure. The focus of this work is on diffusion in nanoporous materials with complex pore spaces. First a short introduction in the basics of diffusion and the PFG NMR technique (Pulsed Field Gradient Nuclear Magnetic Resonance) is described. In the following two chapters the diffusion in hierarchical pore spaces or, to be more precise, zeolites with generated mesopores, which traverse the microporous bulk phase, are investigated. The hierarchical pore spaces consists in the first case of micro- and mesopores and in the second case of micro-, meso- and macropores. The diffusion behavior in these materials has been investigated revealing diffusion acceleration in the mesoporous samples, as compared to the purely microporous material. In the next chapter the diffusion behavior in glass samples with different porosity and their complementary pore space is investigated. Diffusion with full loaded pore spaces and surface diffusion, where the molecules were only able to diffuse along the pore walls, has been explored. The aim was to find out to what extent the diffusion in two complementary pore spaces is correlated. In the last chapter, the effect of an inorganic binder on the transport in zeolite pellets has been studied. First the diffusion behavior in binderless zeolite beads in comparison with the zeolite powder employed for their production has been explored. The particular interest was to find out up to which extent the diffusion patterns observed with the powder samples could again be recognized in the beads. In a second study the transport characteristics within binderless molecular sieves have been investigated, with the purpose to reveal differences in the diffusion behavior in comparison with their binder-containing counterparts.

Styrene production by a (FlDAB)PdII(TFA)(η2-C2H4) complex was modeled using density functional theory (DFT). Benzene C-H activation by this complex was studied via five mechanisms: oxidative addition/reductive elimination, sigma-bond metathesis, concerted metalation deprotonation (CMD), CMD activation of ethylene, and benzene substitution of ethylene followed by CMD of the ligated benzene. Calculations provided evidence that conversion of benzene and ethylene to styrene was initiated by the fifth pathway, arylation via CMD of coordinated benzene, followed by ethylene insertion into the Ru-Ph bond, and then β-hydrogen elimination. Also, monomer (active species)/dimer equilibrium concentrations were analyzed. The results obtained from present study were compared with that of a recently reported RhI complex to help identify more suitable catalysts for the direct production of styrene from ethylene and benzene. Second, theoretical studies of heterobimetallic {Ag–Fe(CO)5}+ fragments were performed in conjunction with experiments. The computational models suggested that for this first example of a heterodinuclear, metal-only FeAg Lewis pair (MOLP) that Fe(CO)5 acts as a Lewis base and AgI as a Lewis acid. The ῡCO bands of the studied molecules showed a blue shift relative to those measured for free Fe(CO)5, which indicated a reduction in Fe→CO backbonding upon coordination to silver(I). Electrostatic interaction is predicted via DFT as the dominant mode of Fe—Ag bonding augmented by a modest amount of charge transfer between Ag+ and Fe(CO)5. Third, computational analyses of hypothetical transition metal-terminal boride [MB(PNPR)] complexes were reported. DFT, natural orbital analysis (NBO), and multiconfiguration self-consistent field (MCSCF) calculations were employed to investigate the structure and bonding of terminal boride complexes, in particular the extent of metal dπ - boron pπ bonding. Comparison of metal-boride, -borylene and –boryl bond lengths confirms the presence of metal-boron π bonds, albeit the modest shortening (~ 3%) of the metal-boron bond suggests that the π-bonding is weak. Their instabilities, as measured by free energies of H2 addition to make the corresponding boryl complexes, indicate terminal boride complexes to be thermodynamically weak. It is concluded that for the boride complexes studied, covering a range of 4d and 5d metals, that the metal-boride bond consisted of a reasonably covalent σ and two very polarized π metal-boron bonds. High polarization of the boron to metal π-bonds indicated that a terminal boride is an acceptor or Z type ligand. Finally, anti-Markovnikov addition of water to olefins has been a long-standing goal in catalysis. The [Rh(COD)(DPEphos)]+ complex was found as a general and regioselective group 9 catalyst for intermolecular hydroamination of alkenes. The reaction mechanism was adapted for intermolecular hydration of alkenes catalyzed by a [Rh(DPEphos)]+ catalyst and studied by DFT calculations. Olefin hydration pathways were analyzed for anti-Markovnikov and Markovnikov regioselectivity. On the basis of the DFT results, the operating mechanism can be summarized as follows: styrene activation through nucleophilic attack by OHδ− of water to alkene with simultaneous Hδ+ transfer to the Rh; this is then followed by formation of primary alcohol via reductive elimination. The competitive formation of phenylethane was studied via a β-elimination pathway followed by hydrogenation. The origin of the regioselectivity (Markovnikov vs anti-Markovnikov) was analyzed by means of studying the molecular orbitals, plus natural atomic charges, and shown to be primarily orbital-driven rather than charge-driven.

Regulation of gene expression comprises a wide range of mechanisms that control the abundance of gene products in response to environmental and developmental changes. These biological processes can be modulated by posttranslational modifications including arginine methylation. Among the enzymes that catalyze the methylation, protein arginine methyltransferase 7 (PRMT7) is known to modify histones to repress gene expression. Jumonji domain-containing protein 6 (JMJD6) is a putative arginine demethylase that potentially antagonize PRMT7. However, the biological significance of these enzymes is not well understood. This thesis summarizes the investigation of both PRMT7 and JMJD6 in cell culture models for adipocyte differentiation. The results suggest that PRMT7 is not required for the differentiation, whereas JMJD6 is necessary for the differentiation by promoting the expression of the lineage determining transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancerbinding proteins (C/EBPs). The underlying mechanisms by which JMJD6 regulate differentiation involve transcriptional and post-transcriptional control of gene expression. Unexpectedly, the adipogenic function of JMJD6 is independent of its enzymatic activity. Collectively, the present research reveals a novel role of JMJD6 in gene regulation during the differentiation of adipocytes.

Ce travail s’inscrit dans le cadre du développement de nouvelles stratégies d’anti-contrefaçon. Des marqueurs oligouréthanes à séquences définies ont été étudiés comme nouvelles stratégies dans la traçabilité et la lutte contre la contrefaçon. Ces oligouréthanes à séquence définie ont été préparés par chimie itérative en phase solide. Leur synthèse est basée sur l'utilisation de deux étapes chimiosélectives successives; la formation d'un carbonate activé et sa réaction sélective avec la fonction amine primaire d'un aminoalcool. L'utilisation de différents blocs constitutifs d'aminoalcools avec différents groupes latéraux comme de monomères de base permet la synthèse de polymères codés en séquence. Par conséquent, chaque oligouréthane a une séquence de monomère unique qui constitue une identité exclusive du produit. Dans ce travail, les marqueurs oligouréthanes ont été incorporés dans différents types de matériaux hôtes, tels que des films plastiques, des implants biomédicaux et du bois. L'extraction des marqueurs, par spectrométrie de masse en tandem (MS / MS) ont été étudiées en collaboration avec un laboratoire de spectrométrie de masse. Pour tous les matériaux étudiés, les différents marqueurs ont été extraits efficacement et leurs séquences ont été décryptées par MS/MS, démontrant ainsi la robustesse et la polyvalence de la stratégie de marquage basée sur l’utilisation de oligouréthanes à séquence-définie. Dans ce travail, il a été également démontré que ces marqueurs peuvent être stockés avec succès et utilisés in vivo. Sur la base de ces résultats forts prometteurs, des stratégies de marquage plus perfectionnées (donc plus sécurisées) ont également été étudiées dans ce travail. Par exemple, le développement de marqueurs codés en séquence 2D et l’intégration de manière covalente des marqueurs aux réseaux de polymères sont également décrits dans cette thèse. / This PhD thesis deals with the development of a new anti-counterfeiting strategy. Sequence-defined oligourethane taggants were studied herein as a novel option for anti-counterfeit and traceability applications. These oligomers were prepared by iterative solid-phase chemistry. Their synthesis is based on the use of two successive chemoselective steps; the formation of an activated carbonate and its selective reaction with the primary amine function of an amino alcohol. The use of different amino alcohol building-blocks with different side-groups allows synthesis of sequence-coded polymers. Therefore, each oligourethane has a unique monomer sequence, which constitutes an exclusive product identity. In this work, oligourethane taggants were included in different types of host materials such as model commodity plastic films, biomedical implants and wood. The extraction and detection of the taggants by tandem mass spectrometry (MS/MS) was studied in a collaboration with a mass spectrometry laboratory. In all cases, the coded oligourethanes were efficiently extracted from the host materials and their sequences were deciphered by MS/MS, thus evidencing the robustness and versatility of the taggant strategy. For instance, it was even demonstrated in this thesis that the taggants can be successfully stored and used in vivo. Based on these successful results, more complex (thus more secure) tagging strategies were also studied in this work. For instance, the development of 2D-sequence-coded taggants and the covalent attachment of the taggants to polymer networks are also described in this thesis.

Les travaux exposés dans ce manuscrit ont pour objectif d’étudier des séquences réactionnelles organocatalysées permettant la formation stéréosélective de liaisons carbone-carbone ou carbone-hétéroatome. Plusieurs stratégies ont été développées pour la préparation d’architectures cycliques chirales dont la synthèse représente un enjeu important en raison de leur présence dans un grand nombre de molécules d’intérêt biologique. Le manuscrit débute par une introduction sur le principe de l’organocatalyse en se focalisant sur les différents modes d’activation en aminocatalyse.Le premier chapitre traite de la synthèse, sans solvant, régio- et diastéréosélective de bicycles comportant une hydrazine cyclique. Le deuxième chapitre combine la désaromatisation ou la désymétrisation à une séquence aminocatalysée, pour former des polycycles tridimensionnels énantio-enrichis à partir d’aldéhydes insaturés. Enfin, le troisième chapitre se concentre sur la synthèse de sulfamides non symétriques et leur utilisation comme substrats en aminocatalyse. / The work presented in this manuscript aims to study organocatalytic reaction sequences enabling the stereoselective formation of carbon-carbon and carbon-heteroatom bonds. Various strategies have been developped for the preparation of chiral cyclic architectures, which represents an important challenge due to their presence in a vast number of biologically active compounds. This manuscript starts off by introducing the principal of organocatalysis, and more specifically the different activation means used in aminocatalysis.The first chapter focuses on the regio- and diastereoselective synthesis of cyclic hydrazine-containing bicycles in a solvent-free way. The second chapter merges de-aromatization or desymetrization with an aminocatalytic reaction sequence, to yield tridimensional enantioenriched polycycles from unsaturated aldehydes. Lastly, the third chapter concentrates on the synthesis of unsymmetrical sulfamides and their uses as substrates in aminocatalysis.