Orientador: Fernando Antonio Santos Coelho / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-09T04:17:59Z (GMT). No. of bitstreams: 1 Ganzella_Valeria_M.pdf: 1487234 bytes, checksum: fdd7f8b301fc75fbc0d2d835e22e56cc (MD5) Previous issue date: 2006 / Resumo: Entre os metabólitos, recentemente isolados de algas vermelhas tropicais, da espécie Vidalia sp, podemos destacar a Vidalenolona, uma 1,2-dicetona que apresenta em sua estrutura um centro quaternário. No extrato bruto, do qual se isolou a Vidalenolona outros dois fenóis já conhecidos, também foram encontrados. As três substâncias, juntas, apresentaram atividade inibitória sobre interações protéicas SH2, relacionadas ao desenvolvimento de alguns tipos de tumores malignos. Apesar de apresentar um carbono estereogênico, a estereoquímica absoluta da Vidalenolona não foi determinada pelos pesquisadores que a isolaram. Esse trabalho teve como objetivo propor uma estratégia sintética assimétrica visando preparar os dois possíveis enantiômeros da Vidalenolona e confirmar a estereoquímica do produto natural explorando a potencialidade sintética de adutos de Morita-Bayllis-Hillman, como matéria-prima simples, de fácil obtenção, baixo custo e elevada versatilidade. Os resultados alcançados, que levaram à síntese de um intermediário avançado, que pode ser utilizado tanto na síntese racêmica quanto assimétrica da Vidalenolona, estão resumidos no Esquema 1: A reação de Morita Baylis-Hillman entre a 2-ciclopentenona (29) e o 4- oxipivaloil-benzaldeído (34) forneceu um aduto (33) no qual todo o esqueleto de carbono do produto natural já estava incorporado. Reação de acetilação da hidroxila secundária do aduto, seguido de uma migração de dupla ligação e uma redução da carbonila mediada pelo uso de NaBH4, levou à formação de um álcool alílico (43), que foi utilizado como substrato para uma reação de epoxidação na presença de ácido m-cloroperbenzóico (AMCPB). O epóxido racêmico usado como modelo, foi clivado regioseletivamente na presença de hidrogênio para fornecer o diol 45, intermediário avançado na estratégia de síntese proposta. Esse último deverá ser utilizado para finalizar a primeira síntese racêmica da Vidalenolona. A mesma via sintética poderá ser utilizada na síntese assimétrica desse produto natural, bastando para isso realizar a etapa de epoxidação utilizando a metodologia de epoxidação assimétrica de Sharpless. O intermediário avançado 45 foi preparado em 5 etapas com um rendimento global de 15%, a partir de ciclopentenona comercial / Abstract: Among the secondary metabolites, recently isolated from tropical red algas from Vidalia spp, we cite Vidalenolone (12), a 1,2-diketone which bears a oxygenated quaternary center in its structure. Besides Vidalenolone, two other phenolic derivatives has also been isolated from the crude extract. The three substances together have shown a inhibitory activity against SH2 proteic interactions, which are attached to the development of certain malign tumors. Despite of the presence of chiral quaternary center in the structure of Vidalenolone, the absolute stereochemistry of this stereogenic center was not determined by the authors who isolated this marine natural product.This work had as proposal the development of an asymmetric synthetic strategy in order to prepare the both enantiomers of the natural products, confirming its absolute stereochemistry and exploring the synthetic versatility of the Morita Baylis-Hillman adducts. These adducts are simples, easily available, cheap and show a great versatility. The results achieved in this synthetic study, which led to the synthesis of an advanced intermediate for the racemic and asymmetric total syntheses of Vidalenolone, are depicted in scheme below. A Morita-Baylis-Hillman reaction between cyclopenten-2-one (29) and 4- oxypivaloyl-benzaldehyde (34) gave the adduct 33, in 88% yield. All the carbon skeleton of Vidalenolone are already incorporated in the structure of 33. An acetylation reaction of 33, followed by the treatment of the acetylated iintermediate with NaBH4 in methanol led to the double bond migration accompanied by the carbonyl reduction to furnish the allylic alcohol 43, in 52% for the two steps. The later was the substrate for an epoxidation using m-chlorperbenzoic acid (MCPBA) as oxidizing agent, which furnish the epoxide 44 in 59% yield. The racemic epoxide was regioselectivity opened in the presence of hydrogen and Pd/C to afford the diol 45, which is an advanced intermediate for the racemic total synthesis of the marine natural product. The diol 45 will be used to finish the first racemic total synthesis of Vidalenolone. The same synthetic strategy will be used for the asymmetric synthesis of this natural product, however in the epoxidation step the MCPBA will be replaced by a Sharpless asymmetric epoxidation. The advanced intermediate 45 was prepared in 5 steps with an overall yield of 15%, from commercial cyclopenten- 2-one / Mestrado / Quimica Organica / Mestre em Química

This thesis describes, in detail, the synthesis of novel heterobidentate ligands. These ligands were subsequently used in palladium catalysed allylic substitution reactions to synthesise enantiomerically enriched alkylated products. The thesis also describes novel approaches to asymmetric catalysis, in particular asymmetric epoxidation derived from Katsuki-Sharpless methodology. Chapter 1 - This chapter reviews the literature, discussing the significant synthetic advancements in asymmetric catalysis in the past 10-15 years. Chapter 2 - This chapter describes in detail the synthesis of new heterobidentate ligands containing nitrogen and phosphorus ligating atoms. These ligands are based on imines containing enantiomerically pure asymmetric centres in an alpha position to the nitrogen moiety. Other ligands that were synthesised were derived from C2- symmetric diamines, also containing an asymmetric centre alpha position to the nitrogen, that produce ligands with the nitrogen functionality contained in a ring. Chapter 3 - This chapter describes the use of the novel ligands synthesised in Chapter 2 in palladium catalysed allylic substitution reactions. The racemic substrate, 1 ,3-diphenyl-3-acetoxy-1-propene, was alkylated to produce an enantiomeric enriched alkylated product. The alkylated product was obtained with up to 77 % enantiomeric excess. The reaction was conducted with a palladium catalyst in the presence of a novel ligand using dimethyl malonate as a nucleophile. The development and optimisation of these ligands within this reaction is discussed. Chapter 4 - This chapter discusses some novel approaches to asymmetric epoxidation. The epoxidation is based on methodology developed by Katsuki and Sharpless. This epoxidation relies on the substrate containing an up-unsaturated alcohol. The chapter discusses the use of a reversible nucleophile in the form of cyanide. The nucleophile is designed to react with a substrate to provide an upunsaturated cyanohydrin, suitable to undergo a Katsuki-Sharpless epoxidation. Once the asymmetric epoxidation is complete, the nucleophile would be removed. This chapter describes the attempts to develop the principle further. An improvement to the system would be to provide an environment capable of sustaining a dynamic kinetic resolution. Chapter 5 - This chapter contains the experimental which provides the exact details of the reactions reported in the thesis.

Le cadre industriel de ce projet est de trouver une alternative à la résine phénol-formaldéhyde (RFP) et à son durcisseur, utilisée actuellement en pneumatique pour améliorer les performances aussi bien des compositions de caoutchouc que celles des produits semi-finis. Un des aspects essentiels de la pneumatique est d’augmenter la rigidité à faible déformation des pneus sans augmenter l'hystérésis des élastomères durcis chargés de noir de carbone. Ainsi, l'objectif de ce travail de thèse est de proposer un système thermodurcissable alternatif aux résines RFP actuelles. Ce nouveau système doit être riche en carbone renouvelable et doit être chimiquement modifié au moyen de procédés écologiques. La lignine a été choisie comme source de carbone renouvelable. Une étude préliminaire a souligné les potentialités d'une classe de lignines époxy pour l'application visée. Notre approche consiste en la conception de lignines modifiées par des époxy par une méthode originale évitant l'utilisation de l'épichlorhydrine suivie de son durcissement par des agents de réticulation appropriés. Des tests préliminaires avec un composé modèle de lignine ont donné la gamme des composés époxy et les conditions à tester pour la réaction avec la lignine. Les expériences avec la lignine ont alors confirmé le potentiel de l’ester diglycidylique de l’acide 4, 5-époxytetrahydrophthalique, un composé époxy contenant à la fois un groupement cycloaliphatique et deux types de groupements époxy glycidyliques, comme alternative à l'épichlorohydrine pour la préparation de lignines modifiées. Dans les conditions que nous avons définies, la réaction donne des prépolymères de type lignine-époxy sous forme de poudre avec un niveau d’époxydation de 1,2 mol/kg déterminé par spectroscopie FTIR. La série de tests effectuée sur des mélanges de caoutchouc a montré que la nouvelle lignine époxy associée à la p-xylylènediamine peut être mélangée avec succès avec le caoutchouc naturel et peut atteindre les propriétés de notre mix de référence. / The industrial framework of this project is the substitution of phenol formaldehyde resin (RFP) and its methyl donor hardener currently used for improving the performances of rubber compositions of tires or semi-finished products for tires. A critical aspect is the need for an increase of rigidity at low deformation without enhancement of the hysteresis of the cured elastomers filled with carbon black. The specific aim of this PhD work was to propose an alternative thermosetting system to the current RFP resins. This new system should be rich in renewable carbon and chemically modified by environmentally friendly processes. Lignin was chosen as the source of the renewable carbon. A preliminary study emphasized the potentialities of a class of epoxy-modified lignins for the targeted application. The main approach was the design of epoxy modified lignin to be obtained by an original method avoiding the use of epichlorohydrine and to be subsequently cured by appropriate cross-linkers. A preliminary screening with a lignin model compound gave the range of the epoxy compounds and the conditions to be tested for the reaction with lignin. Then various experiments with lignin confirmed the potential of 4, 5-epoxytetrahydrophthalic acid diglycidylester, an epoxy compound containing both one cycloaliphatic and two glycidyl type of epoxy groups, as an alternative for epichlorohydrine for the preparation of modified lignin. In the conditions we have defined, the reaction yielded epoxy lignin-based prepolymers as a powder with epoxy level as high as 1,2 mol/kg determined by FTIR spectroscopy. The series of evaluation campaigns in rubber blends showed that the new epoxy-modified lignin associated with p-xylylenediamine can be successfully mixed with natural rubber and enable to reach the properties of our reference mix.

L'objectif de ce travail est de développer un système catalytique hétérogène pour l'époxydation en utilisant directement O2 de l'air plutôt que H2O2 commercial. La stratégie adoptée a été de coupler la production in situ de H2O2, catalysée par la glucose oxydase (GOx), avec un catalyseur à base de Ti. La GOx a été immobilisée de manière covalente sur une mousse silicique mesocellulaire (MCF) amino-fonctionnalisée puis la stabilité thermique et aux solvants organiques de MCF-NH2-GOx a été étudiée. L'approche visant à ancrer Ti puis la GOx sur le même support n’a pas abouti à un catalyseur tandem efficace du fait d'un recouvrement de Ti par –NH2. L’hydrophilie de MCF apparaît, de plus, défavoriser l'oxydation d'alcènes organosolubles. Une option a consisté à utiliser la zéolithe TS-1 hydrophobe et réputée fonctionner en milieu aqueux mais dont les micropores ne peuvent loger la GOx. Cette dernière, associée à MCF-NH2-GOx en mélange mécanique, s’est montrée performante pour l'oxydation du cyclohexène dans MeOH/tampon acétate 50:50 à 35°C (rendement de 50% en époxyde et ses dérivés). D’encore meilleurs résultats ont été obtenus pour le prop-2-ène-1-ol en milieu aqueux à 40°C (rendement de 87% en glycérol). L’attaque basique de TS-1 crée une porosité suffisante pour loger la GOx, mais endommage son activité. En revanche, le recouvrement de MCF par un film de TS-1 a eu un effet bénéfique sur l’oxydation du prop-2-ène-1-ol dans l’eau par H2O2. Enfin, la porphyrine Mn-TCPP s’est montrée efficace comme catalyseur d'oxydation en tandem avec la GOx en solution mais, en cas d’immobilisation sur le support silicique MCF, la formation d’un précipité inhibe son activité. / The objective of this work was to develop an heterogeneous catalyst system supplied by dioxygen, rather than commercial H2O2, in order to carry out epoxidation reactions. Our strategy was to couple the in situ production of H2O2, catalyzed by glucose oxidase (GOx), with a Ti-based catalyst. The enzyme was covalently grafted onto a silicic mesocellular foam (MCF) functionalized by aminopropyle groups, then the thermal stability and behavior in organic solvents of the resulting material were investigated. The approach aiming at anchoring Ti, then GOx on the same support did not result in an effective tandem catalyst because of a too high –NH2 surface coverage. Hydrophilicity of MCF makes the oxidation of organosoluble alkenes unefficient. An alternative approach consisted in using the hydrophobic TS-1 zeolite known to operate in aqueous medium but whose micropores do not allow GOx hosting. However, TS-1 combined in a mechanical mixture with GOX immobilized on MCF turned out to be effective for the oxidation of cyclohexene in MeOH/acetate buffer 50:50 at 35°C (50% yield of epoxide and its derivatives). Even better performances were obtained for prop-2-ene-1-ol oxidation in aqueous medium at 40°C (87 % yield of glycerol). The basic attack of TS-1 has created mesoporosity to host GOx but damaged active Ti sites. On the other hand, TS-1 coated MCF appeared to be a good option having a beneficial effect on the oxidation of prop-2-en-1-ol in water by H2O2. Finally, a manganese porphyrin, Mn-TCPP, was also tested successfully as alkene oxidation catalyst in combination with GOx but, in case of immobilization, the presence of the silicate support lead to a deactivated catalyst.

Chloroperoxidase (CPO) is a heme-thiolate protein with exceptional versatility and great potential as a biocatalyst. The CPO reactive species, Compound I ( Cpd I) is of particular interest, as well as the Cytochrome P450 (P450) -type monoxygenase catalytic activity, which has significant biotechnological potential. Proximal hydrogen bonding of the axial sulfur with the backbone amides (NH•••S) is a conserved feature of heme-thiolate enzymes. In CPO, the effect of NH•••S bonds is amplified by the dipole moment of the proximal helix. The role of the proximal region has been disputed as to whether it simply protects the axial sulfur, or whether it additionally influences catalysis via modulation of the push effect. The objective of the research presented herein is two-fold. First, the influence of the NH•••S bonds on Cpd I formation is determined by obtaining the reaction coordinate, starting from a peroxide bound heme, for two model systems (one with proximal residues providing NH•••S bonds and one without) and comparing the results. Secondly, the influence of the proximal region on the epoxidation of Cis-β-methylsterene is obtained. This is performed similarly to the first objective however, the reaction coordinate begins with a Cpd I-CBMS complex and the proximal contribution is extended to include the influence of the proximal helix dipole. Our findings show that the proximal region stabilizes Cpd 0 relative to all other minima and reduces the barrier for Cpd 0’s formation. The stability of protonated Compound 0 is reduced, favoring a hybrid homo-heterolytic relative to a classic heterolytic mechanism for O-O bond scission. Additionally, the proximal region significantly enhances CPO’s reactivity; the Cβ-O bond barrier is stabilized, while Cα-O-Cβ ring closure becomes barrierless. The stabilization of the reaction barrier correlates with increased electron density transfer to residues of the proximal pocket and involves a change in the electron transfer mechanism. These results can be traced to a reduction in the pKa of the heme-bound substrate and an increase in oxidation potential, a result of the proximal region reducing the “push effect”.

No description available.

Ce travail de thèse porte sur l'étude d'un procédé d'époxydation et de carbonatation par CO₂ des huiles végétales ce qui permet de valoriser à la fois les huiles et le CO₂ .Un modèle cinétique passant par la formation in situ de l'acide performique est construit pour l'époxydation de l'acide oléique et de l'huile de coton, en couplant les bilans de matière et d'énergie. Une stratégie permettant de réduire le nombre de paramètre à estimer est adoptée. Ce modèle est potentiellement transposable aux autres huiles ayant une structure similaire, car la réactivité de chaque type d'acide gras est déterminée. Pour la réaction de carbonatation, une étude cinétique est réalisée, et la solubilité et le coefficient de transfert de matière du CO₂ dans la phase liquide sont mesurés en tenant compte de la non idéalité des conditions à l'aide de l'équation d'état de Peng-Robinson. L'utilisation du carbonate obtenu est enfin examinée dans la synthèse de polyuréthanes sans isocyanates (NIPUs). / This thesis focuses on the process aspect of the first two steps in the synthesis of non-isocyanates polyurethanes (NIPUs) from vegetable oils, i.e. epoxidation and carbonation reaction. This process adds value to both vegetable oil and CO₂. A kinetic model by using performic acid formed in-situ is built for epoxidation of oleic acid and cottonseed oil, by coupling the mass balance and energy balance. This model is potentially transferable to other oils with similar structure as the reactivity of each type of fatty acid is determined. For the carbonation reaction, a kinetic study is carried out, and the solubility and the CO₂ mass transfer coefficient in the liquid phase is measured under non-ideal condition using the Peng-Robinson equation of state.

No description available.

Lyconadin A is a pentacyclic Lycopodium alkaloid isolated from the club moss Lycopodium companatum with anticancer activity. Our approach sought to incorporate a 7-exo–6-exo acyl radical cyclization cascade to access the bicyclo[5.4.0]undecane framework of lyconadin A. Our studies created methodology for the synthesis of 5-alkyl and 3,5-dialkyl-6-carbomethoxy-2-pyridones and sterically demanding epoxide substrates. These epoxide substrates underwent an unanticipated Payne rearrangement.Cranomycin is a potent antibiotic with antiprotozoal activity. Structurally it is a cyclopentane ring system with substitution at each carbon in the ring. Another interesting structural aspect is the existence of three contiguous quaternary stereocenters including two tertiary alcohols and a tert-alkylamine. Our strategy led to the development of a highly diastereoselective synthesis of vicinal tertiary diol systems. We have successfully synthesized the cyclopentenone system shown above, from which we hope to assemble cranomycin.

The main objectives of this study were to develop an effective process to produce modified pea starch with enhanced enzyme resistance property (RS) for food applications. The work compares a non-chemical method (heat moisture treatment) versus a chemical method (crosslinking). One type of commercial pea starch (Nutri-Pea) was used exclusively as the raw material in this study. A number of methods were used to characterize the properties of the modified pea starches: water solubility index (WSI), titration (conversion, iodine value), intrinsic viscosity, infrared spectroscopy (FT-IR), Englyst digestion method, total starch content, and rapid visco analysis (RVA). The effects of heat-moisture treatment on native pea starch and enzyme treated pea starch were examined. The results showed that the produced samples with both native starch and enzyme treated starch exhibited a sharp increase in intrinsic viscosity. Overall, this method was deemed undesirable and not extensively examined past preliminary evaluations. The main focus of the study was on a citric acid crosslinking reaction, chosen for its food compliancy. A temperature of 120 oC was considered ideal for the reaction. FT-IR confirmed the presence of the citric acid incorporation in the starch samples. To improve the extent of reaction, Butanetetracarboxylic acid (BTCA) was considered as a replacement for citric acid and its treated samples showed higher conversion and lower water solubility index than that of the citric acid treated samples. Sodium propionate (NaP) was also considered in the reaction, this time as a food-grade catalyst and found to have minor benefit in cross-linking. BTCA/NaP treated sample reached the highest conversion of the study (96.8±2.3 %) and the lowest WSI (13.1±2.0 %), which increased the RS fraction of the starch from 18% to 32%. The RVA pasting profiles examined were too low to compare due to the high degree of cross-linking. Further improvements to RS were sought by debranching the starch before acid crosslinking. A BTCA/NaP treated sample with enzyme treatment showed a low WSI (31.7±2.3 %) yet substantially higher RS fraction (80.81±0.18 %). Similar to the non-debranched acid modified samples, there were no significant RVA pasting results because of the high cross-linking. Finally, crosslinking with an epoxidized oil was tested to continue looking at food-grade solution yet possible increase the rate of the crosslinking reaction. The results of WSI indicated that this method had little influence on cross-linking, possibly due to the low epoxidation efficiency of vegetable oils, as determined by iodine value. / Thesis / Master of Applied Science (MASc)