Submitted by (lucia.rodrigues@ufrpe.br) on 2017-02-15T13:39:52Z No. of bitstreams: 1 Mauro Gomes da Silva.pdf: 2235103 bytes, checksum: 2f7922e62d0e9e6cd2bbc309f61aa8f1 (MD5) / Made available in DSpace on 2017-02-15T13:39:52Z (GMT). No. of bitstreams: 1 Mauro Gomes da Silva.pdf: 2235103 bytes, checksum: 2f7922e62d0e9e6cd2bbc309f61aa8f1 (MD5) Previous issue date: 2012-03-14 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / In the present study ten 2,3-diyne-1,4-naphthoquinone derivatives were synthesized by Sonogashira coupling reaction between the 2,3-dibromo-1,4- naphthoquinone and several functionalized terminal alkynes using a catalytic complex of palladium (II) and CuI. Alkynes are among phenylacetylene, 1-ethyl-4- methoxybenzene, 2-methyl-3-butyn-2-ol, 1-ethynyl-1-cyclohexanol, 4-pentyn-2-ol, 4- pentyn-1-ol, 1-pentyne, 1-hexyne, 1-octyne and 1-decyne. The yields of products obtained ranged 15 to 55%. The enediynes having hydroxyl groups, in their structures such as 2,3-di(3-hydroxy-3-methylbut-1-yn-1-yl)-, 2,3-di[(1- hydroxycyclohexyl)ethynyl]- and 2,3-di(5-hydroxypent-1-yl)-1,4-naphthoquinone were subjected to acetylation reaction using acetic anhydride and montmorillonite clay K- 10 under sonication, thereby obtaining three new enediyne derivatives with yields ranging from 56 to 71%. The compounds were all characterized by 1H NMR and 13C NMR spectra, IR and MS-LC. These compounds containing the 1,4-naphthoquinone nucleus and acetylenic substituents in the quinonoid ring form a enediyne system (Z-3-ene-1,5-diyne) highly reactive, possibly subject to Bergman cycloaromatization, with potential antitumor activity. The enediynes underwent evaluation of the cytotoxic potential against three tumor cell lines, OVCAR-8 (ovarian adenocarcinoma - human), PC-3M (metastatic prostate cancer - human), NCI-H358M (bronchoalveolar lung carcinoma - human), presenting, in general, satisfactory results for inhibition of cell growth. The compound 2,3-di(3-hydroxy-3-methylbut-1-yn-yl)-1,4-naphthoquinone where said among the substances analyzed by presenting a lower IC50 (˂ 2 μg/mL) for three cell lines tested, which is characterized as a potent cytotoxic agent. / No presente trabalho foram obtidos dez derivados 2,3-diino-1,4- naftoquinonas, entre estes sete são inéditos na literatura, empregando a reação de acoplamento de Sonogashira entre o 2,3-dibromo-1,4-naftoquinona e diversos alquinos terminais funcionalizados, utilizando um complexo catalítico de paládio (II) e CuI. Entre os alquinos estão o fenilacetileno, o 4-metoxifenilacetileno, o 2-metil-3- butin-2-ol, o 1-etinil-1-cicloexanol, o 4-pentin-2-ol, o 4-pentin-1-ol, o 1-pentino, o 1- hexino, o 1-octino e o 1-decino. Os rendimentos dos produtos obtidos variaram entre 15-55%. Os enediinos que possuem grupos hidroxilas presentes em suas estruturas, como o 2,3-di(3-hidroxi-3-metilbut-1-in-il)-, o 2,3-di[(1-hidroxicicloexil)etinil]- e o 2,3- di(5-hidroxipent-1-il)-1,4-naftoquinona, foram submetidos à reação de acetilação utilizando anidrido acético e argila montmorillonita K-10 em ultrassom, obtendo assim, três novos derivados enediinos com rendimentos que variaram de 56-71%. Os compostos obtidos foram todos caracterizados por espectros de RMN 1H e RMN 13C, LC-MS e IV. Estes compostos contendo o núcleo 1,4-naftoquinona e substituintes acetilênicos no anel quinônico formam um sistema enediino (Z-3-eno-1,5-diino) altamente reativo, possivelmente sujeito a cicloaromatização de Bergman, com potencial atividade antitumoral. Os enediinos foram submetidos à avaliação do potencial citotóxico em três linhagens de células tumorais, OVCAR-8 (adenocarcinoma de ovário – humano), PC-3M (carcinoma de próstata metastático – humano), NCI-H358M (carcinoma bronquioalveolar de pulmão – humano, apresentando, no geral, resultados satisfatórios para inibição do crescimento celular. O composto 2,3-di(3-hidroxi-3-metilbut-1-in-1-il)-1,4-naftoquinona se destacou dentre as substâncias analisadas por apresentar menor CI50 (˂ 2 μg/mL) para as três linhagens de células testadas, o que o caracteriza como potente agente citotóxico.

<p>Peptide secondary structure mimetics are important tools in medicinal chemistry, as they provide analogues of endogeneous peptides with new physicochemical and pharmacological properties. The <i>β</i>-hairpin motif has been shown to be involved in numerous physiological processes, among others in regulation of eucariotic gene transcription. This thesis addresses the design, synthesis and conformational analysis of photoswitchable <i>β</i>-hairpin mimetics.</p><p>The developmental work included the establishment of an improved procedure for cross coupling of aryl halides with terminal alkynes. Microwave mediated Sonogashira couplings in closed vessels were optimized under homogeneous and solid-phase conditions furnishing excellent yields for a large variety of substrates within 5 – 25 minutes. In addition, microwave heating was shown not to have any non-conventional effect on the reaction rate.</p><p>Furthermore, the most important factors affecting <i>β</i>-hairpin stability were evaluated. Studies of tetrapeptide and decapeptide analogues revealed the essential role of the <i>β</i>-turn in initiation of hairpin folding. Moreover, hydrogen bonding was shown to be the main interchain stabilizing force, whereas hydrophobic interactions were found to be relatively weak. Nevertheless, hydrophobic packing appears to provide an important contribution to the thermodynamic stability of <i>β</i>-hairpins.</p><p>Photoswitchable peptidomimetics were prepared by incorporation of various stilbene moieties into tetra- and decapeptides. Synthesis, photochemical isomerisation and spectroscopic conformational analysis of the compounds were performed.</p>

Peptide secondary structure mimetics are important tools in medicinal chemistry, as they provide analogues of endogeneous peptides with new physicochemical and pharmacological properties. The β-hairpin motif has been shown to be involved in numerous physiological processes, among others in regulation of eucariotic gene transcription. This thesis addresses the design, synthesis and conformational analysis of photoswitchable β-hairpin mimetics. The developmental work included the establishment of an improved procedure for cross coupling of aryl halides with terminal alkynes. Microwave mediated Sonogashira couplings in closed vessels were optimized under homogeneous and solid-phase conditions furnishing excellent yields for a large variety of substrates within 5 – 25 minutes. In addition, microwave heating was shown not to have any non-conventional effect on the reaction rate. Furthermore, the most important factors affecting β-hairpin stability were evaluated. Studies of tetrapeptide and decapeptide analogues revealed the essential role of the β-turn in initiation of hairpin folding. Moreover, hydrogen bonding was shown to be the main interchain stabilizing force, whereas hydrophobic interactions were found to be relatively weak. Nevertheless, hydrophobic packing appears to provide an important contribution to the thermodynamic stability of β-hairpins. Photoswitchable peptidomimetics were prepared by incorporation of various stilbene moieties into tetra- and decapeptides. Synthesis, photochemical isomerisation and spectroscopic conformational analysis of the compounds were performed.

The demand for protection of eyes and various types of optical sensors from laser-beam pulses has resulted in the search for optical limiting devices that have the property of being transparent at low intensity of light (normal light), but non-transparent towards high intensity (laser) light. This type of protection may be obtained by using an organic material that displays nonlinear optical (NLO) properties. Examples of NLO effects that can be used for optical limiting are reverse saturable absorption (RSA), two-photon absorption (TPA) and nonlinear refraction. The advantage of using compounds that show such NLO effects is that they can have very fast response and are self-activating, that is, there is no need for externally controlled switching to obtain optical limiting. In this work, several dialkynyl substituted thiophenes and some thiophenyl-alkynyl-platinum(II)-complexes were synthesized and tested for nonlinear absorption of light. A palladium-copper mediated coupling (Sonogashira coupling) was utilized for all reactions between terminal alkynes and aryl halides. Molecular orbital calculations were used in order to screen for suitable properties, such as the second hyperpolarizability, in compounds of interest. A quantitative structure-activity relationship (QSPR) study using a PLS approach were performed in order to identify important molecular electronic variables for optical limiting of organic compounds.

La synthèse tout-en-un de 4-quinolones et d'indoxyles a été réalisée par couplage de Sonogashira carbonylant suivi d'une cyclisation. Une étude en catalyse homogène a révélé que les catalyseurs présents contrôlaient la sélectivité vers l'un ou l'autre des composés. Si la première étape est pallado-catalysée, l'étape de cyclisation est catalysée par des nucléophiles organiques. Ainsi, des 4-quinolones ont été préparées par multi-catalyse {[Pd]+amine} et des indoxyles par catalyse tandem {[Pd]/phosphine}. Les systèmes catalytiques ont été hétérogénéisés par fonctionnalisation de silices mésoporeuses de type SBA. Deux stratégies ont été utilisées pour contrôler la localisation de la fonctionnalité. Différents complexes de Pd ont été intégrés dans les pores du matériau par greffage post-synthétique ou dans les murs par synthèse directe. Plusieurs amines et une phosphine ont été immobilisées par greffage post-synthétique donnant ainsi des catalyseurs nucléophiles fonctionnalisés dans leurs pores. Les activités catalytiques de ces matériaux ont été évaluées dans la synthèse de la 2-phényl-4-quinolone et du 2-benzylidène-indoxyle. La première a été préparée dans de bons rendements et le système {[Pd]@SBA+amine@SBA} est recyclable sur 3 cycles. Tous les matériaux ont montré une lixiviation du Pd mais leur utilisation permet de diminuer la contamination en Pd du produit final comparé à un complexe homogène. L'indoxyle a été obtenu avec un système semi-hétérogène {[Pd]@SBA/PPh3}, l'utilisation de la phosphine greffée conduisant à la transformation de l'indoxyle vers le 2-benzylindole. La formation d'α-céto-amides en catalyse hétérogène via double carbonylation a aussi été étudiée

Please note that the structures do not display correctly in the pdf document. Therefore the original manuscript in MSWord has also been uploaded. Please contact us email if you cannot view these files. / Sonogashira cross-coupling of 2-aryl-4-chloro-3-iodoquinoline derivatives with stoichiometric amount of terminal alkynes in the presence of bis(triphenylphosphine)palladium(II)chloride and copper iodide in triethylamine afforded the 3-(alkynyl)-2-aryl-4-chloroquinoline, exclusively. On the other hand, the 2-aryl-4-chloro-3-iodoquinolines with excess (2.5 equiv.) of terminal alkynes in the presence of PdCl2(PPh3)2-CuI catalyst mixture and NEt3 in dioxane-water (3:1 v/v) afforded the 2-aryl-3,4-bis(alkynyl)quinoline derivatives in a one-step operation. Further transformation of the 2-aryl-3-(alkynyl)-4-chloroquinoline via Suzuki cross-coupling reaction with boronic acid derivatives in the presence of tetrakis(triphenylphosphine)palladium and tricyclohexylphosphine as a ligand in dioxane-water (3:1 v/v) afforded the 2,4-diaryl-3-(alkynyl)quinolines in moderate to high yields. The 2-aryl-3-(alkynyl)-4-chloroquinolines were also transformed to the corresponding 2-aryl-4-(methylamino)-3-(alkynyl)quinoline derivatives using methylamine in ethanol under reflux. / Chemistry / M.Sc.

En la presente Memoria se recogen los resultados del estudio de las reacciones de adición nucleofílica de sistemas propargílicos y de nitrocompuestos a N-tercbutanosulfinil iminas, así como sus aplicaciones sintéticas, abordando la preparación de diferentes moléculas polifuncionalizadas. Es por ello que la tesis ha sido dividida en dos grandes bloques: - Propargilación diastereoselectiva y aplicaciones sintéticas. La reacción de 3-bromo-1-trimetilsililpropino con N-terc-butanosulfinil iminas en presencia de indio, THF como disolvente, bajo irradiación de ultrasonidos, dio lugar a los correspondientes productos de propargilación de manera regioselectiva, con una alta diastereoselectividad, sobre todo en el caso de las iminas derivadas de metil cetonas alifáticas. Los productos de propargilación fueron utilizados como precursores en la síntesis de derivados policíclicos de tetrahidro-1H-pirido[4,3-b]- benzofurano e indol, después de varios pasos de reacción que incluían un acoplamiento de Sonogashira con orto-yodofenol u orto-yodoanilina, respectivamente, ciclación intramolecular con formación de un anillo heteroaromático de cinco eslabones y finalmente una condensación de Pictet-Spengler. Por otro lado, la reacción de metátesis de cierre de anillo con el catalizador de Grubbs de segunda generación en diferentes derivados de homoalil amina N-terc-butanosulfinil sustituidas, que además portan en su estructura un anillo aromático orto-alquinil sustituido, condujo a la formación de los correspondientes sistemas 1,3-diénicos cíclicos, con buenos rendimientos en general. - Acoplamiento diastereoselectivo con nitroalcanos y aplicaciones sintéticas. La reacción de nitrometano y nitroetano con N-terc-butanosulfinil iminas en presencia de bicarbonato de sodio dio lugar a la formación de derivados de β-nitroamina con rendimientos y diastereoselectividades de moderados a buenos. Estos productos de reacción fueron transformados bajo condiciones de reacción tipo Nef en derivados de α-aminoácidos, en el caso del nitrometano, y de α-aminocetonas, los que se obtuvieron a partir de nitroetano. El acoplamiento entre de 4-nitrobutanoatos de metilo y etilo y Nterc-butanosulfinil iminas en presencia de una cantidad subestequiométrica de hidróxido de sodio transcurrió con rendimientos moderados y una elevada diastereoselectividad facial, siendo trasformados los productos de reacción obtenidos en piperidina-2,5-dionas sustituidas en la posición 6. Por último se intentó llevar a cabo la síntesis del producto natural (+)-desoxoprosofillina utilizando dos estrategias diferentes. El paso clave en la primera de ellas fue el acoplamiento de 1-nitrohexadecan-4-ona con la N-terc-butanosulfinil imina derivada del hidroxiacetaldehído, obteniéndose el producto de reacción esperado con rendimiento moderado y alta diastereoselectividad. En la segunda estrategia, los pasos clave fueron una alilación diastereoselectiva de la imina derivada del hidroxiacetaldehído y una reacción de metátesis cruzada entre el producto de alilación y pentadec-1-en-3-ona con el catalizador de Hoveyda-Grubbs de segunda generación. El producto de reacción obtenido tras la metátesis contenía todo el esqueleto hidrocarbonado presente en la molécula objetivo. Desafortunadamente ninguna de las dos estrategias nos permitió de momento sintetizar el producto natural (+)-desoxoprosofillina deseado, siendo esperanzadores los resultados obtenidos en el segundo de los casos.

[EN] Heterogeneous catalysis is one of the most important tools in the advancement of green chemistry, understood it as one that efficiently uses (preferably renewable) raw materials, eliminate waste and avoids the use of toxic and/or dangerous reagents and solvents in chemicals production and application. In this thesis we have investigated the reaction mechanisms and the nature of the active centers in C-C, C-N and N-N bond forming reactions over cerium oxide and over gold nanoparticles supported on cerium oxide heterogeneous catalysts. As C-C bond formation reaction, we had been studied Sonogashira reaction catalyzed by a heterogeneous Au/CeO2 catalyst, wherein the CeO2 nanoparticle is about 5 nm in diameter. The second part of the thesis comprises the study of C-N bonds formation during carbamoylation reaction between diaminotoluene and dimethyl carbonate, catalyzed by cerium oxide, studying the effect over the reaction of the crystal planes available for reactants adsorption. In a third part, the N-N bond formation in the reductive coupling reaction of nitrocompounds to obtain azocompounds was studied, using Au/CeO2 as heterogeneous catalyst. Also in this section we report, by first time, an active and selective heterogeneous catalyst for the Mills reaction between nitroso compounds and anilines to obtain symmetric and asymmetric azocompounds. / [ES] La catálisis heterogénea es una de las más importantes herramientas para el desarrollo de la Química Sostenible, entendida como aquella que utiliza eficientemente las materias primas (preferiblemente renovables), elimina los desechos y evita el uso de reactivos y solventes tóxicos y/o peligrosos en la manufactura y aplicación de los productos químicos. En esta tesis doctoral se han investigado los mecanismos de reacción y la naturaleza de los centros activos, en reacciones de formación de enlaces C-C, C-N, y N-N sobre catalizadores heterogéneos de óxido de cerio y de nanopartículas de oro soportadas en óxido de cerio. Como reacción de formación de enlaces C-C se ha estudiado la reacción de Sonogashira catalizada con un catalizador heterogéneo de Au/CeO2, en donde el CeO2 está en forma de nanopartículas de cerca de 5nm de diámetro. En la segunda parte de la tesis se profundiza en el estudio de la formación de enlaces C-N durante la reacción de carbamoilación del diaminotolueno con dimetilcarbonato catalizada por el óxido de cerio, estudiando el efecto que tiene sobre la reacción la naturaleza de los planos cristalinos disponibles para la adsorción de los reactivos. En una tercera parte se estudia la formación de enlaces N-N en la reacción de acoplamiento reductivo de nitrocompuestos para obtener azocompuestos en presencia de un catalizador heterogéneo de Au/CeO2. Es este mismo apartado se reporta por primera vez un catalizador heterogéneo de alta actividad y selectividad para la Reacción de Mills entre un nitrosocompuesto y una anilina para obtener azocompuestos simétricos y asimétricos. / [CAT] La catàlisi heterogènia és una de les ferramentes més importants per al desenvolupament de la Química Sostenible, entesa com aquella que utilitza eficientment les matèries pimes (preferiblement renovables), elimina els rebutjos i evita l'ús de reactius i dissolvents tòxics i/o perillosos en la manufactura i aplicació dels productes químics. En esta tesi doctoral s'han investigat els mecanismes de reacció i la natura dels centres actius, en reaccions de formació d'enllaços C-C, C-N i N-N sobre catalitzadors heterogenis d'òxid de ceri i nanopartícules d'or suportades en òxid de ceri. Com reacció de formació d'enllaços C-C s'ha estudiat la reacció de Sonogashira catalitzada amb un catalitzador heterogeni d'Au/CeO2, on el CeO2 està en forma de nanopartícules amb un diàmetre proper als 5nm. En la segona part de la tesi s'aprofundeix en l'estudi de la formació d'enllaços C-N durant la reacció de carbamilació del diaminotoluè amb dimetilcarbonat catalitzada per l'òxid de ceri, estudiant l'efecte que té sobre la reacció la natura dels plans cristal·lins disponibles per a l'adsorció dels reactius. En una tercera part s'estudia la formació d'enllaços N-N en la reacció d'acoblament reductiu de nitrocompostos per a obtenir azocompostos en presència d'un catalitzador heterogeni d'Au/CeO2. En aquest mateix apartat es reporta per primera vegada un catalitzador heterogeni d'alta activitat i selectivitat per a la Reacció de Mills entre un nitrocompost i una anilina per a obtenir azocompostos simètrics i asimètrics. / Cómbita Merchán, DF. (2016). Formación de enlaces C-C, C-N y N-N con catalizadores de óxido de cerio y de oro/óxido de cerio [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/62780 / TESIS

Project I. Cinchona alkaloid-derived quaternary ammonium salts have been successfully used as phase-transfer catalysts, particularly in asymmetric alkylations. Our group applied this type of catalyst in the synthesis of β-hydroxy α-amino acids via aldol reactions and discovered that the Park-Jew catalyst afforded good yields and good enantiomeric excess of the syn diasteromers, but negligible diastereoselectivity. This project was therefore focused on the synthesis of novel cinchonidine-derived catalysts with the Park-Jew catalyst as the lead structure. The C3 position of cinchonidine nucleus was modified to achieve dimers and catalysts possessing electron-deficient alkyne and alkene moieties. Synthesized catalysts were tested in the asymmetric aldol reactions, with some of them yielding improvements relative to the Park-Jew catalyst. Project II. Celogentin C is a natural product that was isolated from the seeds of Celosia argentea by Kobayashi in 2001. It is the most potent inhibitor of the polymerization of tubulin from among the celogentin family. The novel bicyclic octapeptide structure contains unusual linkages between leucine β-carbon and indole C-6 of tryptophan and between tryptophan indole C-2 and imidazole N-1 of histidine. The project culminated in the first total synthesis of celogentin C. Reaction conditions were developed by synthesizing the left-hand ring and the right-hand ring separately, and the total synthesis was accomplished via a left to right strategy. Key transformations in the construction included intermolecular Knoevenagel condensation, radical conjugate addition, macrolactamization, and oxidative coupling.

No description available.