Iminosugars are polyhydroxylated alkaloids, and can be generally defined as sugar mimetics in which the endocyclic oxygen atom has been replaced with a basic nitrogen. A common affect of this atomic substitution is to bestow these compounds with the ability to inhibit various sugarprocessing enzymes; most significantly the glycosidases (glycoside hydrolases) which areintimately involved in a huge array of biological functions. Compounds which inhibit these enzymes concordantly possess much potential as medicinal agents for the treatment of a variety of diseases. Several iminosugars have already achieved market approval as drugs, and many more are promising candidates in the late stages of clinical development. As such there remains considerable interest in this class of compound, both in terms of the exploration of novel iminosugar structures, as well as the continual development of more efficient general methodology for their synthesis. The densely-packed functionality and stereochemical information present in iminosugars makes them challenging targets for asymmetric chemical synthesis, whereas carbohydrates are clearly very attractive as chiral-pool starting materials for this purpose. Indeed, the majority of the most successful syntheses of iminosugars use the latter approach, and such is the focus of this thesis. Chapter 1 presents a relatively brief introduction to iminosugars, including their types of structure, natural occurrence and biological mode of action. The rationale behind their use as therapeutic agents for the treatment of some significant disease targets is also discussed. Chapter 2 is concerned with the preparation of a number of novel polyhydroxylated azetidines, and their evaluation as glycosidase inhibitors. Such compounds represent an almost entirely neglected class of iminosugars within the literature. An overview of natural and synthetic products incorporating an azetidine motif is given, as well as a brief review of preparative methods and known azetidine iminosugars. A highly efficient and flexible method for the key azetidine ring formation is demonstrated by the cyclisations of 3,5-di-O-triflates of pentoses and hexoses, and of a 2,4-di-O-triflate of glucose, with various primary amines. In this manner, many azetidine triols and tetrols were prepared in good yield. Furthermore, this process is readily adaptable to the installation of added functionality to the azetidine scaffold, as demonstrated by the preparation of 1-acetamido analogues. The initial biological screening of these compounds showed a promising array of glycosidase inhibition, including that of selective inhibition of fungal enzymes. Chapter 3 describes a strategy with which to prepare all sixteen stereoisomers of a known piperidine iminosugar, alpha-homonojirimycin (alpha-HNJ), in a highly divergent manner from just four of the possible thirty-two 6-azidoheptitols using traditional chemical synthesis in tandem with biotechnological transformations. One half of the execution of this strategy is described in this thesis. Two 6-azidoheptitols were prepared from D-mannose, thereby providing access to four 6-azidoketoheptoses through a combination of microbial oxidation and enzymatic epimerisation. Catalytic hydrogenation of these 6-azidoketoheptoses furnished four diastereomeric mixtures of 2,6-iminoheptitols, with varying degrees of stereoselectivity. Purification of these mixtures allowed six 2,6-iminoheptitols to be isolated, two of which have never previously been tested for glycosidase inhibition. Significantly, one of them was found to be a potent and highly selectiveinhibitor of alpha-galactosidases, and may therefore be of interest in the treatment of Fabry disease.

This thesis centres on the synthesis of taxol analogues via late-stage hydroxylation with P450 enzymes. To accomplish this, the taxane core, specifically taxa-4(5),11(12)-dien-2-one, was synthesised by classical synthetic methods, and subsequently oxidised using P450_BM3 mutants. Chapter 1 introduces enzymatic catalysis, and the advantages and disadvantages of its application to organic synthesis. Additionally, an overview of taxol, including its discovery, mode of action, biosynthesis and large-scale production, and a summary of the previously reported approaches to the taxane core are described. Chapter 2 details the problems encountered and solutions implemented when reproducing Baran's route to taxa-4(5),11(12)-dien-2-one. Furthermore, approaches to some of its intermediates and an alternative route to taxa-4(5),11(12)-dien-2-one, which is based on Baran's, are discussed. Chapter 3 describes the development of a new, practical and short synthetic route to taxa-4(5),11(12)-dien-2-one which, ultimately, led to 1,3-di-epi-taxa-4(5),11(12)-dien-2-one. Additionally, the application of this route to the synthesis of a model compound and attempts to convert this racemic synthesis into an enantioselective route are reported. Finally, the enzymatic oxidation of taxa-4(5),11(12)-dien-2-one and related molecules using P450_BM3 mutants is explored in Chapter 4. A preliminary study to determine the substrate enantioselectivity of the mutants is also described, along with the biological assays of the oxidised compounds produced during the study.

Orientador: Aldo Eloizo Job / Banca: Marcos Augusto de Lima Nobre / Banca: Marcelo Ornaghi Orlandi / O Programa de Pós-Graduação em Ciência e Tecnologia de Materiais, PosMat, tem caráter institucional e integra as atividades de pesquisa em materiais de diversos campi da Unesp / Resumo: O objetivo deste trabalho foi estudar "efeitos de escala e tamanho" através de medidas de permissividade dielétrica de partículas nanométricas e/ou nanoestruturadas do óxido policátion niobato de potássio dopado com estrôncio (K'Sr IND. 2' N'b IND. 5' 'O IND. 15'), um óxido ferroelétrico da família tetragonal tungstênio bronze (TTB). A determinação da constante dielétrica de nanopartículas foi realizada através da técnica de mistura. Nesta técnica, nanopartículas de permissividade dielétrica desconhecidas são dispersas em um meio de permissividade dielétrica conhecida. A partir da resposta dielétrica da mistura a permissividade dielétrica das nanopartículas foram calculadas utilizando modelagem numérica via circuitos elétricos equivalentes. A fase K'Sr IND. 2' N'b IND. 5' 'O IND. 15, foi preparada por rota química (método poliol modificado), a temperatura de calcinação necessária à obtenção de nanopartículas foi otimizada e partículas nanoestruturadas de K'Sr IND. 2' N'b IND. 5' 'O IND. 15' monofásico foram avaliadas. A caracterização estrutural foi realizada utilizando as técnicas de difratometrica de raiox x (DRX), espectroscopia vibracional de absorção na região do infravermelho (FTIR) e ultravioleta visível (UV/vis) a partir das quais se avaliaram os parâmetros de rede, cristalinidade relativa, tamanho médio de cristalito, volume da cela unitária e energia de gap. Utilizando a técnica de espectroscopia de impedância entre 5 Hz e 3 MHz foram estudadas as propriedades dielétricas das amostras através de medidas de permissividade confirmando a existência de ferroeletricidade nas amostras e foi identificado o efeito de tamanho nas propriedades dielétricas das nanopartículas. / Abstract: This work aimed the study of "size effect" through permittivity measurements of nanometric particles and/or nanostructured of niobate oxide K'Sr IND. 2' N'b IND. 5' 'O IND. 15', a ferroelectric oxide belonging to the tetragonal tungsten bronze family (TTB). Determination of nanoparticles dielectric constant was done using the mixture technique. In this technique, nanoparticles of unknown dielectric permittivity are dispersed in a medium of know dielectric permittivity. From the dielectric response of the mixture, the dielectric permittivity of the nanoparticles is calculated using numerical modeling by means of equivalent circuits. The K'Sr IND. 2' N'b IND. 5' 'O IND. 15' phase was prepared using a chemical route (polyol modified method) and the optmization of the temperature calcination was performed aiming to obtain nanoparticles and the resulting nanostructured particles were evaluated. The structural characterization was carried out by X-ray diffraction (XRD), infrared absorption spectroscopy (FTIR) and UV-Vis spectroscopy allowing the evaluation of cell parameters, relative crystallinity and crystallite size, unitary cell volume and gap energy. The impedance spectroscopy technique in the range from 5 Hz to 3 MHz to study dielectric properties of samples was used. The presence of ferroelectric phase in samples was confirmed and the size effect was identified on nanoparticles. / Mestre

L'objectif principal de ce travail était l'étude systématique de plusieurs groupes de matériaux conducteurs protoniques: Gd₃₋ₓMeₓGaO₆₋₅ (Me = Ca²+, Sr²+), Ba₂Nb₁₋ₓY₁₊ₓO₆₋₅, et BaZr₀.₈₅Y₀.₁₅O₃₋₅ (BZY15). Nous avons développé une voie de synthèse pour chaque groupe de matériaux tels que le procédé de combustion sol-gel, la synthèse lyophilisation et le procédé de complexation de citrate-EDTA modifié des nanopoudres pures et des céramiques denses ont été obtenus après ces synthèses suives d'un processus de frittage classique. La structure et la composition des produits obtenues ont été caractérisées par diffraction des rayons X (XRD) et microscopie électronique à balayage (MEB). La variation de la conductivité en fonction de la température a été étudiée par spectroscopie d'impédance, ainsi que la dépendance en fonction de pO₂ et pH₂O. Pour la famille de Gd₃₋ₓMeₓGaO₆₋₅ (Me = Ca²+, Sr²+), nous avons étudié l'influence de la nature et la quantité de dopant sur les propriétés structurales et électriques. Les résultats indiquent une solution solide possible jusqu'à 10% de taux du substituant. Selon les observations au MEB, la taille des grains est augmente le taux de substitution. En ce qui concerne les propriétés électriques, nous avons constaté une augmentation de la conduction avec le taux de substitution. Tous les composés présentent une bonne stabilité en milieu humide, sous hydrogène et CO₂. Dans le cas des matériaux Ba₂Y₁₊ₓNb₁₋ₓO₆₋₅, les propriétés physico-chimiques des matériaux synthétisés ont été caractérisées par la diffraction des rayons X et par MEB. La taille moyenne des grains a considérablement augmenté avec l'augmentation du taux de Y³⁺. Les propriétés de conduction ont été légèrement améliorées avec la substitution partielle de niobium par l'yttrium. La stabilité de Ba₂Y₁₊ₓNb₁₋ₓO₆₋₅ composés a été étudiée sous différentes atmosphères et conditions. Les propriétés de conduction ionique restent modestes ce qui a été explique par des simulations de dynamique moléculaire. Enfin, nous avons étudié l'influence d'emploi d'un additif ZnO et NiO lors de la synthèse de BZY15, les adjuvants de frittage pouvant être utilisés pour abaisser la température de frittage. L'oxyde de zinc comme un adjuvant de frittage permet de diminuer de 300 °C la température de frittage et d'augmenter légèrement la conduction ionique. / The main objective of the present work was the systematic study of several groups of materials: Gd₃₋ₓMeₓGaO₆₋₅ (Me = Ca²+, Sr²+), Ba₂Nb₁₋ₓY₁₊ₓO₆₋₅, and BaZr₀.₈₅Y₀.₁₅O₃₋₅ (BZY15) as proton conductors. We developed a synthesis route for each group of materials such as sol-gel combustion method, freeze-drying synthesis and modified citrate-EDTA complexing method. Pure nanopowders and dense ceramics were obtained after these syntheses plus a classical sintering process. The structure and composition of the obtained products were characterized by X-ray diffraction (XRD) and scanning electron microscope (SEM). The temperature dependences of the conductivity were investigated by impedance spectroscopy as a function of pO₂ and pH₂O. For the family of Gd₃₋ₓMeₓGaO₆₋₅ (Me = Ca²+, Sr²+), we studied the influence of dopant nature and content on the structural and electrical properties. Results indicate that the substitution possible till 10 % of doping content. According to the SEM observations, the grain size is increased with increasing dopant content. Concerning electrical properties, we found an increase of conduction with increasing dopant content. All compounds present a good stability in humid, hydrogen and CO₂ containing atmosphere. In case of Ba₂Y₁₊ₓNb₁₋ₓO₆₋₅ materials, the physico-chemical properties of synthesized materials have been characterized by the XRD and SEM techniques. The average grain size increased significantly with increasing amount of Y³⁺. Conduction properties were slightly improved with the partial substitution of niobium by yttrium. The stability of Ba₂Y₁₊ₓNb₁₋ₓO₆₋₅ compounds was investigated under different atmospheres and conditions. The ionic conduction in this case is quite low, which has been explained by futher molecular dynamics simulations. Finally, we studied the influence of an ZnO and NiO additives on the sintering of BZY15, being these sintering aids used to lower the sintering temperature. Zinc oxide as a sintering aid lowers the sintering temperature by 300 °C and slightly increases the bulk and total conductivity of BZY15.

Le but de ce travail de thèse, effectué dans le cadre du programme Européen IRSES « Nanolicom », était d’étudier l’influence de la nanostructuration sur les propriétés de transport de deux matériaux conducteurs par les ions lithium, la pérovskite LLTO (Li0.3La0.57TiO3) et le nasicon LATPO (Li1.3Al0.3Ti1.7(PO4)3).Une première partie importante de cette thèse a été consacrée à l’exploration et au développement de méthodes de synthèse par chimie douce plus favorables à la préparation de poudres nanométriques : la voie sol-gel, la voie des complexes polymérisables, la synthèse hydro-solvothermale et la réalisation de microémulsions. Les matériaux obtenusont ensuite été caractérisés par diffraction des rayons X, analyses thermiques et microscopies électroniques.La mise en forme des échantillons ainsi que leur densification ont également fait l’objet d’une étude approfondie. En effet, la détermination des propriétés de transport des matériaux nécessite l’utilisation de céramiques denses mais il est difficile de conserver le caractère nanostructuré des poudres lors de l’étape de frittage. Finalement, les mesures de conductivitésioniques ont été réalisées par spectroscopie d’impédance. L’ensemble des résultats obtenus a ensuite été comparé à ce qui a déjà été observé et reporté dans la littérature pour les composés microstructurés de même formulation. / The aim of this thesis, which has been carried out within the European program « Nanolicom », was to study the influence of the nanostructuration on the transport properties of two lithium ionic conductors, the perovskite LLTO (Li0.3La0.57TiO3) and the nasicon LATPO (Li1.3Al0.3Ti1.7(PO4)3).The first part of this thesis is devoted to the exploration and to the optimization of the best soft chemistry route in order to get nanometric powders: sol-gel route, hydro-solvothermal synthesis, reversed microemulsion method and complex polymerizable Pechini method. The obtained materials were characterized by X-ray diffraction, thermal analysis andelectronic microscopy. Shaping and sintering of the samples were also thoroughly studied. Indeed, the determination of transport properties of the materials requires the use of dense ceramics but it is difficult to preserve the nanostructured character of the powders during the sintering step. Finally, the ionic conductivity measurements were carried out by compleximpedance spectroscopy. All results were then compared to what has been observed and reported in the literature for microstructured compounds of the same formulation.

Die Ziele dieser Arbeit waren die Darstellung der Naturstoffe Murrayachinon-B–E und Pyrayachinon-A–C, sowie die Synthese einiger nicht natürlicher, potentiell anti-Tuberkulose-aktiver Carbazole und Carbazolchinone. Für die Darstellung der aus der Pflanze Murraya euchrestifolia Hayata isolierten Naturstoffe wurden verschiedene synthetische Herangehensweisen untersucht: Die Transformation eines 7 Hydroxycarbazolchinons in die Zielverbindungen gelang nicht, ebenso wie die Syntheseroute über eine trioxygenierte Vorstufe. 7-Methoxy-3-methyl-1-tosyloxycarbazol (A) ließ sich jedoch in einer Ausbeute von 76 % über drei Stufen darstellen. Ausgehend von A konnten die Zielverbindungen regioselektiv in fünf bis sieben Stufen in Gesamtausbeuten von 10 % bis 46 % synthetisiert werden. Der Pyranring in Pyrayachinon-A wurde dabei über eine Sequenz aus Bromierung, Prenylierung, Cyclisierung und Oxidation aufgebaut. Die Anellierung der Pyranringe in Pyrayachinon-B und –C erfolgte, nach Methyletherspaltung an A in zwei Stufen. Die Einführung der Prenyl- und Geranylgruppen für die Synthese der Murrayachinone gelang durch reduktive Pyranringöffnung bzw. über eine Sequenz aus Methyletherspaltung, Propargylierung, partieller Hydrierung und Umlagerung. Außerdem wurde für Murrayafolin-B, Bismurrayafolin-B und -D über diese Syntheseroute ein Zugang geschaffen. Diese Verbindungen konnten, ausgehend von A, in sechs bzw. sieben Stufen in Gesamtausbeuten von 39 % bis 53 % dargestellt werden. Im Vergleich zu den bislang beschriebenen Synthesen dieser Verbindungen konnten alle Gesamtausbeuten signifikant gesteigert werden. Besonders hervorzuheben sind die Synthesen von Murrayafolin-B (bislang: 0.4 %, in dieser Arbeit: 40.0 %) und Pyrayachinon-A (bislang: 3.0 %, in dieser Arbeit: 22.1 %). Überdies wurde erstmalig die palladiumkatalysierte oxidative Cyclisierung eines O-tosylgeschützten Diarylamins zu einem Carbazol beschrieben. In Fortführung vorangegangener Arbeiten wurden zehn bislang nicht beschriebene Derivate des anti-Tuberkulose-aktiven 3-Methoxy-2-methylcarbazol-1,4-chinons dargestellt, darunter neun Carbazolchinone und ein Carbazol. Die Synthese der Carbazolchinone gelang palladiumkatalysiert in je vier bis sechs Stufen. Das Carbazol wurde eisenvermittelt über fünf Stufen dargestellt. Die Untersuchung der Aktivität gegenüber Mycobacterium tuberculosis steht noch aus.

This thesis describes the development of nitro-Mannich/hydroamination cascade reactions for the synthesis of N-heterocycles, which are important motifs found in a variety of biologically active natural products and pharmaceuticals, such as atorvastatin (Lipitor®). Chapter 2 outlines the development of an efficient synthesis of 2,5-disubstituted pyrroles using a nitro-Mannich/hydroamination cascade. Starting from easily prepared N-protected imines and nitroalkyne substrates, a compatible combination of KOtBu (10 mol%) and AuCl3 (5 mol%) was used to afford the desired pyrrole products, after an alkene isomerisation/HNO2 elimination reaction sequence. Chapter 3 describes the extension of this methodology to the diastereo- and enantioselective synthesis of 1,2,3,4-tetrahydropyridine derivatives using a nitroalkyne substrate with an extended carbon chain. The sequential addition of a bifunctional Brønsted base/H-bond donor organocatalyst and a gold complex was found to facilitate the desired cascade reaction affording substituted 1,2,3,4-tetrahydropyridine products. We then established that highly substituted pyrrolidine compounds could be prepared by replacing the nitroalkyne substrate with a nitroallene substrate (Chapter 4). The combination of KOtBu (5 mol%) and a gold catalyst derived from Au(PPh3)Cl (10 mol%) and AgSbF6 (20 mol%) was found to give an efficient diastereoselective synthesis of pyrrolidine derivatives after an additional nitro group epimerisation step. In addition, the nitro-Mannich/hydroamination cascade using nitroallene substrates was developed into an enantioselective variant using the previously employed bifunctional Brønsted base/H-bond donor organocatalyst. This afforded enantioenriched pyrrolidine derivatives.

Iminosugars, carbohydrate analogues in which nitrogen replaces the endocyclic oxygen, have attracted much interest due to their biological activity. Iminosugars inhibit carbohydrate-processing enzymes, thereby affecting many biological processes. Several iminosugars are licensed drugs, with many more compounds undergoing clinical trials. The main subject of this thesis is the synthesis and evaluation of novel iminosugars, particularly the effects of structural modifications on the biological activity of these compounds. Chapter 1 describes the role of carbohydrate-processing enzymes in the body, and explores the therapeutic applications of iminosugars that arise from their activity against these enzymes. Examples of substituted iminosugars are reviewed, and the effects of substituents on enzyme inhibition are described. Chapter 2 concerns methyl-branched swainsonine derivatives. Swainsonine has shown potential as a cancer treatment through its inhibition of α-mannosidase. The synthesis of (6R)- and (6S)-C-methyl D-swainsonine is described; both compounds were potent and selective α-mannosidase inhibitors (IC₅₀ 3.8 μM, 14 μM). Although less active than the parent compound, their selectivity for Golgi mannosidase over lysosomal mannosidase may be more important than the absolute value against the model enzyme. Chapter 3 describes the synthesis of a 2-C-methyl L-fucose derivative. A diastereoselective Kiliani reaction allowed the formation of a single lactone bearing a new quaternary centre. The utility of this intermediate in accessing di-branched iminosugars was explored; however, attempts to introduce nitrogen to the lactone lacked the necessary stereoselectivity. Chapter 4 relates to the synthesis of pyrrolidine iminosugars, specifically methyl amides. Two enantiomeric dihydroxyproline amides were synthesised; the D-proline derivative was a potent β-N-acetylhexosaminidase inhibitor (IC₅₀ values of up to 3.6 μM), but the L-enantiomer was completely inactive. Inhibition of N-acetylhexosaminidases is relevant to the treatment of cancer and lysosomal storage diseases, and this work contributed to a wider project investigating the effects of altered stereochemistry on the biological activity of pyrrolidine amides.

The 2-aryl-6,8-dibromoquinazolin-4(3H)-ones were prepared in a single-pot operation by condensing 6,8-dibromoanthranilamide and aryl aldehydes in the presence of molecular iodine in ethanol. Treatment of the 2-aryl-6,8-dibromoquinazolin-4(3H)-ones with thionylchloride in the presence of dimethylformamide afforded the corresponding 2-aryl-4-chloro-6,8-dibromoquinazolines. Palladium(0)-copper iodide catalysed Sonogashira cross-coupling reaction of 2-aryl-4-chloro-6,8-dibromoquinazolines with terminal alkynes at room temperature afforded series of 2-aryl-6,8-dibromo-4-(alkynyl)quinazolines. Further transformation of the 2-aryl-6,8-dibromo-4-(phenylethynyl)quinazolines via Suzuki-Miyaura cross-coupling with arylboronic acids occurred without selectivity to afford the corresponding 2,6,8-triaryl-4-(phenylethynyl)quinazolines. The compounds were characterized using a combination of NMR (1H and 13C) and IR spectroscopic techniques as well as mass spectrometry. The absorption and emission properties of 2,6,8-triaryl-4-(phenylethynyl)quinazolines were determined in solution. / Chemistry / M.Sc. (Chemistry)

Doped ZnO nanoparticles were synthesized by three different methods – electrochemical deposition under oxidizing conditions (EDOC) , combustion method and wet chemical synthesis – for investigating the oxygen gas sensing response. Ga-doped ZnO was mostly synthesized but also In-doped ZnO was made. The samples were analyzed by XRD, SEM, EDX and TEM. Gas response curves are given alongside with Langmuir fitted curves and data for pure ZnO and Ga-doped ZnO. DFT quantum chemical investigation of cluster models ZnO nanoparticles were performed to evaluate defect effects and oxygen and nitrogen dioxide reactions with the ZnO surface. Defects were investigated by DOS and HOMO-LUMO plots , and are oxygen vacancy, zinc vacancy, zinc interstitial and gallium doping by replacing zinc with gallium. Oxygen and nitrogen dioxide reactions were investigated by computing Mulliken charges, bond lengths, DOS spectra and HOMO-LUMO plots.