Novel Approaches for the Synthesis of C-5 Modified Pyrimidine Nucleosides

The antiviral or anticancer activities of C-5 modified pyrimidine nucleoside analogues validate the need for the development of their syntheses. In the first half of this dissertation, I explore the Pd-catalyzed cross-coupling reaction of allylphenylgermanes with aryl halides in the presence of SbF5/TBAF to give various biaryls by transferring multiple phenyl groups, which has also been applied to the 5-halo pyrimidine nucleosides for the synthesis of 5-aryl derivatives. To avoid the use of organometallic reagents, I developed Pd-catalyzed direct arylation of 5-halo pyrimidine nucleosides. It was discovered that 5-aryl pyrimidine nucleosides could be synthesized by Pd-catalyzed direct arylation of N3-free 5-halo uracil and uracil nucleosides with simple arenes or heteroaromatics in the presence of TBAF within 1 h. Both N3-protected and N3-free uracil and uracil nucleosides could undergo base-promoted Pd-catalyzed direct arylation, but only with electron rich heteroaromatics. In the second half of this dissertation, 5-acetylenic uracil and uracil nucleosides have been employed to investigate the hydrogermylation, hydrosulfonylation as well as hydroazidation for the synthesis of various functionalized 5-vinyl pyrimidine nucleosides. Hydrogermylation of 5-alkynyl uracil analogues with trialkylgermane or tris(trimethylsilyl)germane hydride gave the corresponding vinyl trialkylgermane, or tris(trimethylsilyl)germane uracil derivatives. During the hydrogermylation with triphenylgermane, besides the vinyl triphenylgermane uracil derivatives, 5-[2-(triphenylgermyl)acetyl]uracil was also isolated and characterized and the origin of the acetyl oxygen was clarified. Tris(trimethylsilyl)germane uracil derivatives were coupled to aryl halides but with decent yield. Iron-mediated regio- and stereoselective hydrosulfonylation of the 5-ethynyl pyrimidine analogues with sulfonyl chloride or sulfonyl hydrazine to give 5-(1-halo-2-tosyl)vinyluracil nucleoside derivatives has been developed. Nucleophilic substitution of the 5-(β-halovinyl)sulfonyl nucleosides with various nucleophiles have been performed to give highly functionalized 5-vinyl pyrimidine nucleosides via the addition-elimination mechanism. The 5-(β-keto)sulfonyluracil derivative has also been synthesized via the aerobic difunctionalization of 5-ethynyluracil analogue with sulfinic acid in the presence of catalytic amount of pyridine. Silver catalyzed hydroazidation of protected 2'-deoxy-5-ethynyluridine with TMSN3 in the presence of catalytic amount of water to give 5-(α-azidovinyl)uracil nucleoside derivatives was developed. Strain promoted Click reaction of the 5-(α-azidovinyl)uracil with cyclooctyne provide the corresponding fully conjugated triazole product.

THE DESIGN AND SYNTHESIS OF SILOXANE PRECURSORS FOR CHIRAL PERIODIC MESOPOROUS ORGANOSILICA MATERIALS

The development of cost-effective and reliable methods for the synthesis and separation of asymmetric compounds is paramount in helping to meet society’s ever-growing demand for chiral small molecules. Of these methods, chiral heterogeneous supports are particularly appealing as they allow for the reuse of the chiral source. One such support, based on the synergy between chiral organic units and structurally stable inorganic silicon scaffolds are periodic mesoporous organosilicas (PMOs). In the work described herein, I examine some of the factors governing the transmission of chirality between chiral dopants and prochiral bulk phases in chiral PMO materials. In particular, the exploration of 1,1’-binaphthalene-bridged chiral dopants with a focus on the point of attachment into the materials. Moreover, the effects of ordering in the materials are examined and reveal that chirality transfer is more facile in materials with molecular-scale order then those containing amorphous walls. Secondly, the issues surrounding the synthesis and purification of aryl-triethoxysilanes as siloxane precursors are addressed. Both the introduction of a two-carbon linker and the direct attachment of allyl and mixed allyldiethoxysilane species are explored. This work demonstrates that allyldiethoxysilanes are ideal, in that they are stable enough to permit facile synthesis, while still being able to hydrolyze completely to produce well-ordered materials. Lastly, the production of new bulk phases for chiral PMO materials is examined by introducing new prochiral nitrogen-containing siloxane precursors. Biphenyldiamine and bipyridine-bridged siloxane precursors are readily synthesized on reasonable scales. Their use as the bulk siloxane precursor in the production of PMO materials however, is precluded by insufficient gelation and additional siloxane precursors are necessary for the production of ordered materials. In addition to the research detailed above that forms the body of this thesis, two short works are appended. The first details the production of polythiophene assemblies mediated through coordination nanospaces, while the second explores the production of N-heterocyclic carbene functionalized gold nanoparticles through ligand exchange.

THE IMPORTANCE OF MHC-INDEPENDENT NATURAL KILLER CELL RECEPTORS IN THE IMMUNOREGULATION OF MURINE PREGNANCY

Numerous leukocyte populations are essential for pregnancy success. Uterine natural killer (uNK) cells are chief amongst these leukocytes and represent a unique lineage with limited cytotoxicity but abundant angiokine production. They possess a distinct phenotype of activating and inhibitory receptors that recognize major histocompatibility complex (MHC) molecules, such as the killer immunoglobulin like receptors (KIRs; mouse Ly49), and MHC-independent activating receptors, including the aryl hydrocarbon receptor (AHR) and natural cytotoxicity receptor 1 (NCR1). While the roles of MHC-dependent receptors are widely addressed in pregnancy, MHC-independent receptors are relatively unstudied. This thesis investigated the roles of MHC-independent receptors in promotion of mouse pregnancy and characterized early leukocyte interactions in the presence and absence of NCR1. It was hypothesized that loss of MHC-independent receptors impairs uNK cell development resulting in aberrations in leukocyte function and decidual vasculature. Implantation sites from Ahr-/- and Ncr1Gfp/Gfp mice were assessed using whole mount in situ immunohistochemistry (WM-IHC) and histochemical techniques. Leukocyte interactions identified during preliminary WM-IHC studies were confirmed as immune synapses. The novel identification of immune synapses in early mouse pregnancy compelled further examination of leukocyte conjugates in wildtype C57BL/6 and Ncr1Gfp/Gfp mice. In Ahr-/- and Ncr1Gfp/Gfp mice, receptor loss resulted in reduced uNK cell diameters, impaired decidual vasculature, and failures in spiral artery remodeling. Ahr-/- mice had severe fertility deficits whereas Ncr1Gfp/Gfp mice had increased fetal resorption indicating differing receptor requirements in pregnancy success. NCR1 loss primarily affected uNK cell maturation and function as identified by alterations in granule ultrastructure, lytic protein expression, and angiokine production. Leukocyte conjugates were frequent in early C57BL/6 decidua basalis and included uNK cells conjugating first with antigen presenting cells and then with T cells. Overall conjugate formation was reduced in the absence of NCR1, but specific uNK cell conjugations were unaffected by receptor loss. While KIR-MHC interactions are associated with numerous pregnancy complications in humans, the role of other uNK cell receptors are not well characterized. These results illustrate the importance of MHC-independent receptors in uNK cell activation during early pregnancy in mice and encourage further studies of pregnancy complications that may occur independently of maternal KIR-MHC contributions.

Modulation of CYP1A1 by PKC Inhibitors and TPA Pre-Treatments in MH1C1 Rat Hepatoma Cells Exposed to 3 -Methylcholanthrene

Cytochrome P4501A1 (CYP1A1), an enzyme known to metabolize polycyclic aromatic hydrocarbons, is regulated by the aryl hydrocarbon receptor (AhR). The involvement of protein kinase C (PKC) in the regulation of AhR signal transduction pathway, has been widely studied but the role of specific PKC isoform(s) involved in this process it is not well clarified. To study which PKC isoform(s) is implicated in the regulation of CYP1A1, in the poorly tumorigenic MH1C1 rat hepatoma cells, we examined the effects of some PKC pharmacological inhibitors, Calphostin C (CAL), Staurosporine (STA) and H7, and of 12-0-tetradecanoyl phorbol 13-acetate (TPA), a PKC activator, on basal and 3- methylcholanthrene (MC)-induced CYP1A1 protein expression and mediated ethoxyresorufin O-deethylation (EROD) activity. In parallel, the activities of PKC-α, -βI, -δ and -ε isoforms, the most expressed in MH1C1 cells, were monitored. After pre-treatment with CAL, STA and H7, the MC-induced CYP1A1 protein and EROD activity were rapidly reduced with temporal profile similar to the profile of the activity of α and β1 PKC isoforms. Moreover, TPA pre-treatment induced a biphasic effect on EROD activity, and a decline of PKC -βI and -α, in first instance, and -δ and -ε activities later on. These findings clearly show that, in MH1C1 cells, PKC is involved in CYP1A1 regulation and that α and βI classic PKC isoforms play an active role in modulating this process.

Characterising granuloma regression and liver recovery in a murine model of schistosomiasis japonica

For hepatic schistosomiasis the egg-induced granulomatous response and the development of extensive fibrosis are the main pathologies. We used a Schistosoma japonicum-infected mouse model to characterise the multi-cellular pathways associated with the recovery from hepatic fibrosis following clearance of the infection with the anti-schistosomal drug, praziquantel. In the recovering liver splenomegaly, granuloma density and liver fibrosis were all reduced. Inflammatory cell infiltration into the liver was evident, and the numbers of neutrophils, eosinophils and macrophages were significantly decreased. Transcriptomic analysis revealed the up-regulation of fatty acid metabolism genes and the identification of Peroxisome proliferator activated receptor alpha as the upstream regulator of liver recovery. The aryl hydrocarbon receptor signalling pathway which regulates xenobiotic metabolism was also differentially up-regulated. These findings provide a better understanding of the mechanisms associated with the regression of hepatic schistosomiasis.

A Theoretical and Synthetic Investigation of New Donors for Organic Electro-Optic Chromophores: Understanding the Effects of Structure and Substituents on Donor Strength

Thesis (Ph.D.)--University of Washington, 2016-08

Studies on the Catalytic Asymmetric Fischer Indolization

This work describes further developments and applications of the catalytic asymmetric Fischer indolization. In the first part of this thesis, the development of an organocatalytic asymmetric synthesis of helicenes via a Fischer indolization is discussed. The application of a novel SPINOL-derived phosphoric acid, featuring extended π-surfaces as 3,3‘-substituents which can potentially participate in π-interactions with the polyaromatic intermediate, afforded the corresponding products in high yields and enantioselectivities. The second part of this work describes the development of a catalytic asymmetric dearomatizing synthesis of 1,4-diketones via an interrupted Fischer indolization. Employing aryl hydrazines with α-substituents next to the hydrazine group prevents the rearomatization which takes place in common Fischer indole syntheses, thus enabling the hydrolysis of the generated diimine species. In the presence of STRIP as catalyst, a variety of different 1,4-diketones could be obtained in generally high yields, diastereo- and enantioselectivities. The last part of this thesis deals with the development of an organocatalytic asymmetric stereodivergent synthesis of novel 3H- and 2H-pyrroles, applying an interrupted Fischer indolization and for the 2H-pyrroles a subsequent stereospecific [1,5]-alkyl shift. Employing STRIP as catalyst afforded the corresponding products in good to excellent yields and enantioselectivities. Preliminary biological investigations of these novel structure motifs in cell-based assays, monitoring biological signal transduction pathways showed an inhibition of the Hedgehog signaling pathway in a μM range.

Développement de la polymérisation par (hétéro)arylation directe pour l’électronique organique

L’électronique organique suscite un intérêt grandissant en recherche grâce aux nouvelles possibilités qu’elle offre pour faciliter l’intégration de dispositifs électroniques dans nos vies. Grâce à elle, il est possible d’envisager des produits légers, flexibles et peu coûteux à produire. Les classes majeures de dispositifs étudiées sont les cellules photovoltaïques organiques (CPO) et les transistors organiques à effet de champ (TOEC). Dans les dernières années, une attention particulière a été portée sur les méthodes de polymérisation des matériaux organiques entrant dans la fabrication de ces dispositifs. La polymérisation par (hétéro)arylation directe (PHAD) catalysée au Pd offre une synthèse sans dérivé organométallique utilisant simplement un lien C-H aromatique, ce qui facilite la purification, diminue le nombre d’étapes et rend possible la production de matériaux à plus faible coût. De plus, la PHAD permet la préparation de matériaux qui était difficile, voire impossible, à obtenir auparavant. Cependant, l’inconvénient majeur de la PHAD reste sa limitation à certaines classes de polymères possédant des monomères ayant des positions bloquées favorisant qu’une seule paire de liaisons C-H. Dans le cadre de ces travaux de doctorat, l’objectif général est d’étudier la polymérisation par PHAD afin d’accéder à des classes de monomères qui n’étaient pas envisageables auparavant et à étendre l’application de cet outil dans le domaine des polymères conjugués. Plus spécifiquement, nous avons étudié l’utilisation de groupements protecteurs et partants sur des unités de benzodithiophènes et de bithiophène-silylés. Suivant ces résultats, nos travaux ont porté sur la polymérisation de dérivés de bithiophènes avec des bromo(aryle)s, une classe de polymères fréquemment utilisée en électronique organique mais qui était jugée impossible à polymériser par PHAD auparavant. Cette étude a montré l’importance de contrôler la PHAD afin d’obtenir le polymère souhaité. Finalement, nous avons étudié l’effet du système catalytique sur le taux de β−ramifications lors de la synthèse de polymères à base de thiophènes. Dans cette dernière étude, nous avons démontré l’importance d’utiliser des outils de caractérisation adéquats afin de confirmer la qualité des polymères obtenus.

Ferulates and lignin structural composition in cork

The structure of lignin and suberin, and ferulic acid (FA) content in cork from Quercus suber L. were studied. Extractive-free cork (Cork), suberin, desuberized cork (Cork(sap)), and milled-cork lignins (MCL) from Cork and Cork(sap) were isolated. Suberin composition was determined by GC-MS/FID, whereas the polymers structure in Cork, Corksap, and MCL was studied by Py-TMAH and 2D-HSQC-NMR. Suberin contained 94.4% of aliphatics and 3.2% of phenolics, with 90% of omega-hydroxyacids and alpha,omega-diacids. FA represented 2.7% of the suberin monomers, overwhelmingly esterified to the cork matrix. Py-TMAH revealed significant FA amounts in all samples, with about 3% and 6% in cork and cork lignins, respectively. Py-TMAH and 2D-HSQC-NMR demonstrated that cork lignin is a G-lignin (>96% G units), with a structure dominated by beta-O-4' alkyl-aryl ether linkages (80% and 77% of all linkages in MCL and MCLsap, respectively), followed by phenylcoumarans (18% and 20% in MCL and MCLsap, respectively), and smaller amounts of resinols (ca. 2%) and dibenzodioxocins (1%). HSQC also revealed that cork lignin is heavily acylated (ca. 50%) exclusively at the side-chain gamma-position. Ferulates possibly have an important function in the chemical assembly of cork cell walls with a cross-linking role between suberin, lignin and carbohydrates.

EXCITON ENGINEERING THROUGH TUNALBLE FLUORESCENT QUANTUM DEFECTS

This thesis demonstrates exciton engineering in semiconducting single-walled carbon nanotubes through tunable fluorescent quantum defects. By introducing different functional moieties on the sp2 lattice of carbon nanotubes, the nanotube photoluminescence is systematically tuned over 68 meV in the second near-infrared window. This new class of quantum emitters is enabled by a new chemistry that allows covalent attachment of alkyl/aryl functional groups from their iodide precursors in aqueous solution. Using aminoaryl quantum defects, we show that the pH and temperature of complex fluids can be optically measured through defect photoluminescence that encodes the local environment information. Furthermore, defect-bound trions, which are electron-hole-electron tri-carrier quasi-particles, are observed in alkylated single-walled carbon nanotubes at room temperature with surprisingly high photoluminescence brightness. Collectively, the emission from defect-bound excitons and trions in (6,5)-single walled carbon nanotubes is 18-fold brighter than that of the native exciton. These findings pave the way to chemical tailoring of the electronic and optical properties of carbon nanostructures with fluorescent quantum defects and may find applications in optoelectronics and bioimaging.

Novel Anti-Campylobacter Compounds Identified Using High Throughput Screening of a Pre-selected Enriched Small Molecules Library

Campylobacter is a leading cause of foodborne bacterial gastroenteritis worldwide and infections can be fatal. The emergence of antibiotic-resistant Campylobacter spp. necessitates the development of new antimicrobials. We identified novel anti-Campylobacter small molecule inhibitors using a high throughput growth inhibition assay. To expedite screening, we made use of a “bioactive” library of 4,182 compounds that we have previously shown to be active against diverse microbes. Screening for growth inhibition of Campylobacter jejuni, identified 781 compounds that were either bactericidal or bacteriostatic at a concentration of 200 µM. Seventy nine of the bactericidal compounds were prioritized for secondary screening based on their physico-chemical properties. Based on the minimum inhibitory concentration against a diverse range of C. jejuni and a lack of effect on gut microbes, we selected 12 compounds. No resistance was observed to any of these 12 lead compounds when C. jejuni was cultured with lethal or sub-lethal concentrations suggesting that C. jejuni is less likely to develop resistance to these compounds. Top 12 compounds also possessed low cytotoxicity to human intestinal epithelial cells (Caco-2 cells) and no hemolytic activity against sheep red blood cells. Next, these 12 compounds were evaluated for ability to clear C. jejuni in vitro. A total of 10 compounds had an anti-C. jejuni effect in Caco-2 cells with some effective even at 25 µM concentrations. These novel 12 compounds belong to five established antimicrobial chemical classes; piperazines, aryl amines, piperidines, sulfonamide and pyridazinone. Exploitation of analogues of these chemical classes may provide Campylobacter specific drugs that can be applied in both human and animal medicine.

Développement et caractérisation de dérivés dipyrrométhène pour des applications dans le domaine du photovoltaïque

Ce projet de recherche mené en collaboration industrielle avec St-Jean Photochimie Inc. / PCAS Canada vise le développement et la caractérisation de dérivés dipyrrométhène pour des applications dans le domaine du photovoltaïque. La quête du récoltage des photons se situant dans le proche-infrarouge a été au centre des modifications structurales explorées afin d’augmenter l’efficacité de conversion des cellules solaires de type organique et à pigments photosensibles. Trois familles de composés intégrant le motif dipyrrométhène ont été synthétisées et caractérisées du point de vue spectroscopique, électrochimique, structural ainsi que par modélisation moléculaire afin d’établir des relations structures-propriétés. La première famille comporte six azadipyrrométhènes au potentiel de coordination tétradentate sur des centres métalliques. Le développement d’une nouvelle voie synthétique asymétrique combinée à l’utilisation d’une voie symétrique classique ont permis d’obtenir l’ensemble des combinaisons de substituants possibles sur les aryles proximaux incluant les noyaux 2-hydroxyphényle, 2-méthoxyphényle et 2- pyridyle. La modulation du maximum d’absorption dans le rouge a pu être faite entre 598 et 619 nm. De même, la présence de groupements méthoxyle ou hydroxyle augmente l’absorption dans le violet (~410 nm) tel que démontré par modélisation. La caractérisation électrochimique a montré que les dérivés tétradentates étaient en général moins stables aux processus redox que leur contre-parti bidentate. La deuxième famille comporte dix dérivés BODIPY fusionnés de façon asymétrique en position [b]. L’aryle proximal a été modifié de façon systématique afin de mieux comprendre l’impact des substituents riches en électron et de la fusion de cycles aromatiques. De plus, ces dérivés ont été mis en relation avec une vaste série de composés analogues. Les résultats empiriques ont montré que les propriétés optoélectroniques de la plateforme sont régies par le degré de communication électronique entre l’aryle proximal, le pyrrole sur lequel il est attaché et le noyau indolique adjacent à ce dernier. Les maximums d’absorption dans le rouge sont modulables entre 547 et 628 nm et la fluorescence des composés se situe dans le proche- infrarouge. L’un des composé s’est révélé souhaitable pour une utilisation en photovoltaïque ainsi qu’à titre de sonde à pH. La troisième famille comporte cinq complexes neutres de RuII basés sur des polypyridines et portant un ligand azadipyrrométhène cyclométalé. Les composés ont montré une forte absorption de photons dans la région de 600 à 800 nm (rouge à proche- infrarouge) et qui a pu être étendue au-delà de 1100 nm dans le cas des dérivés portant un ligand terpyridine. L’analyse des propriétés optoélectroniques de façon empirique et théorique a montré un impact significatif de la cyclométalation et ouvert la voie pour leur étude en tant que photosensibilisateurs en OPV et en DSSC. La capacité d’un des complexes à photo-injecter un électron dans la bande de conduction du semi-conducteur TiO2 a été démontré en collaboration avec le groupe du Pr Gerald J. Meyer à University of North Carolina at Chapel Hill, premier pas vers une utilisation dans les cellules solaires à pigments photosensibles. La stabilité des complexes en solution s’est toutefois avérée problématique et des pistes de solutions sont suggérées basées sur les connaissances acquises dans le cadre de cette thèse.

Síntese de ligantes Bis-amida e aplicação em reações de acoplamento Suzuki

As amidas constituem uma classe de moléculas com amplo perfil farmacológico e que despertam atenção também pela capacidade de coordenar metais de transição. Esta proposta de trabalho compreende, inicialmente, a síntese de 3 ligantes bis-amidas simétricas tendo como reagentes de partida etilenodiamina, orto-fenilenodiamina, salicilato de metila e cloreto de benzoíla. Esses compostos foram caracterizados por espectroscopia no infravermelho (IV), ressonância magnética nuclear de hidrogênio (RMN 1H) e difração de raios X em monocristal (DRX). Após sintetizar e caracterizar esses compostos, a outra etapa do trabalho foi a utilização dessas bis-amidas como ligante na reação catalítica de acoplamento Suzuki. O sistema catalítico otimizado à base destes ligantes na presença de paládio, foi capaz de promover a formação de bifenilas com rendimentos superiores a 90% à temperatura de 50 °C e tempo reacional de 1 h. Este sistema se mostrou eficiente para reagentes com diversos grupos substituintes (eletroretiradores e eletrodoadores) nos anéis aromáticos dos haletos de arila e ácidos arilborônicos.

Diversity in Catalytic Reactions of Propargylic Diazoesters

Abstract Title of Document: Diversity in Catalytic Reactions of Propargylic Diazoesters Huang Qiu, Doctor of Philosophy, 2016 Directed By: Professor Michael P. Doyle, Department of Chemistry and Biochemistry Propargylic aryldiazoesters, which possess multiple reactive functional groups in a single molecule, were expected to undergo divergent reaction pathways as a function of catalysts. A variety of transition metal complexes including rhodium(II), palladium(II), silver(I), mercury(II), copper(I and II), and cationic gold (I) complexes have been examined to be effective in the catalytic domino reactions of propargylic aryldiazoesters. An unexpected Lewis acid catalyzed pathway was also discovered by using FeCl3 as the catalyst. Under the catalysis of selected gold catalysts, propargylic aryldiazoesters exist in equilibrium with 1-aryl-1,2-dien-1-yl diazoacetate allenes that are rapidly formed at room temperature through 1,3-acyloxy migration. The newly formed allenes further undergo a metal-free rearrangement in which the terminal nitrogen of the diazo functional group adds to the central carbon of the allene initiating a sequence of bond forming reactions resulting in the production of 1,5-dihydro-4H-pyrazol-4-ones in good yields. These 1,5-dihydro-4H-pyrazol-4-ones undergo intramolecular 1,3-acyl migration to form an equilibrium mixture or quantitatively transfer the acyl group to an external nucleophile with formation of 4-hydroxypyrazoles. In the presence of a pyridine-N-oxide, both E- and Z-1,3-dienyl aryldiazoacetates are formed in high combined yields by Au(I)-catalyzed rearrangement of propargyl arylyldiazoacetates at short reaction times. Under thermal reactions the E-isomers form the products from intramolecular [4+2]-cycloaddition with H‡298 = 15.6 kcal/mol and S‡298= -27.3 cal/ (mol•degree). The Z-isomer is inert to [4+2]-cycloaddition under these conditions. The Hammett relationships from aryl-substituted diazo esters ( = +0.89) and aryl-substituted dienes ( = -1.65) are consistent with the dipolar nature of this transformation. An unexpected reaction for the synthesis of seven-membered conjugated 1,4-diketones from propargylic diazoesters with unsaturated imines was disclosed. To undergo this process vinyl gold carbene intermediates generated by 1,2-acyloxy migration of propargylic aryldiazoesters undergo a formal [4+3]-cycloaddition, and the resulting aryldiazoesters tethered dihydroazepines undergo an intricate metal-free process to form observed seven-membered conjugated 1,4-diketones with moderate to high yields.

Estudos de vias sintéticas catalíticas para benzociclo-alcanois e análogos: potenciais fármacos para doença de Alzhjeimer

A doença de Alzheimer constitui uma ameaça significativa a nível mundial. Estima-se que, mundialmente existam cerca de 35 milhões de pessoas afetadas por este tipo de demência. Os compostos contendo um esqueleto benzocicloalcanol (que incluem benzofuranos e di-hidrobenzofuranóis) mostram atividades biológicas significativas e possuem muito potencial no tratamento das doenças neurodegenerativas. Nos últimos anos têm havido avanços significativos no campo das reações catalisadas por metais. As reações de adição nucleófila intramolecular e a de Heck intramolecular constituem metodologias importantes para a síntese de benzocicloalcanóis. No âmbito deste trabalho, pretendia-se sintetizar uma biblioteca de compostos contendo um esqueleto benzocicloalcanol. A estratégia adotada para a síntese de dihidrobenzofuranóis envolveu um método de ciclização catalítica de cetonas aril-éteres e para a síntese de benzofuranos, um método de ciclização catalítico de enoatos e enamidas (amidas de Weinreb). Várias condições foram estudadas; Abstract: Studies on Synthetic Catalytic Pathways to Benzocycloalkanols and Derivatives – Potential Drugs for Alzheimer’s Disease Alzheimer's disease constitutes a significant threat worldwide. It is estimated that are about 35 million people worldwide suffering from this type of dementia. The compounds containing a benzocycloalkanol scaffold (including benzofurans and dihydrobenzofurans) show significant biological activity and have great potential in the treatment of neurodegenerative diseases. In recent years there have been many advances in the field of catalyzed reactions by transition-metals. The intramolecular nucleophilic addition and the intramolecular Heck reactions constitute important methods for the synthesis of benzocycloalkanols. Within this work, the main goal was to synthesize a library of compounds containing a benzocycloalkanol scaffold. The adopted strategy for the synthesis of dihydrobenzofurans was the catalytic cyclization of aryl ether ketones and for the synthesis of benzofurans, the catalytic cyclization of enoates and enamides (Weinreb amides). Several conditions were studied