Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2014-08-11T14:46:08Z No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Dissertacao River Souza Magalhaes.pdf: 1856967 bytes, checksum: 6da8a950fc3e088ddd4b5b2558c23691 (MD5) / Made available in DSpace on 2014-08-11T14:46:08Z (GMT). No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Dissertacao River Souza Magalhaes.pdf: 1856967 bytes, checksum: 6da8a950fc3e088ddd4b5b2558c23691 (MD5) Previous issue date: 2011-02-25 / This work presents the synthesis of N-[-(4-methylphenyl)]-thiourea, the ligand N-[N'-(2-hydroxyethyll)-(4-methylphenyl)]-guanidine and the copper II complex. The compounds were characterized by infrared spectroscopy,1H NMR and X-ray diffraction. The results of X-ray shows the mode of ligand coordination to the metal ion, in addition to square planar structure, a connection is observed for the trans chromophore CuN2O2. Conformational studies of the molecule the ligand N-[N'-(2-hydroxyethyl)-(4-methylphenyl)]-guanidine and were performed to compare experimental data with calculated data. the computation of ligand molecule N-[N'-(2-hydroxyethyl)-(4-methylphenyl)]-guanidine shows the small energy difference between the threes tautomers, it is not possible to state firmly the most stable. The 1H NMR data show that the solution is more abundant in the tautomer II and III. Calculations of energy transition states for the reaction path. In addition to the calculations of imaginary for the characterization of transition states. / Este trabalho apresenta a síntese da N-[N'-(2-hidroxietil)-(4-metilfenil)]-tioureia, do ligante N-[N'-(2-hidroxietil)-(4-metilfenil)]-guanidina e do complexo de cobre II [Cu(oib)2]. Os compostos foram caracterizados por espectroscopia de infravermelho, RMN de 1H e difração de raios-X. O resultado de DRX mostra o modo de coordenação do ligante ao íon metálico, além da estrutura quadrado planar, é observado uma ligação trans para o cromóforo CuN2O2. Estudos conformacionais da molécula do ligante N-[N'-(2-hidroxietil)-(4-metilfenil)]-guanidina que foram realizados para confrontar dados experimentais com dados calculados. Os cálculos computacionais da molécula do ligante N-[N'-(2-hidroxietil)-(4-metilfenil)]-guanidina mostra uma pequena diferença de energia entre os três tautômeros, não sendo possível afirmar com firmeza o mais estável. Os dados de RMN 1H mostram que o mais abundante em solução é o tautômero II e o III. Cálculos de energia dos estados de transição para o caminho reacional. Além do cálculo das frequências imaginárias para caracterização dos estados de transição.

This thesis deals with the design of ligands for efficientasymmetric catalysis and studies of the conformation of theligands in the catalytically active complexes. All ligandsdeveloped contain chiral oxazoline heterocycles. The conformations of hydroxy- and methoxy-substitutedpyridinooxazolines and bis(oxazolines) during Pd-catalysedallylic alkylations were investigated using crystallography,2D-NMR techniques and DFT calculations. A stabilising OH-Pdinteraction was discovered which might explain the differencein reactivity between the hydroxy- and methoxy-containingligands. The conformational change in the ligands due to thisinteraction may explain the different selectivities observed inthe catalytic reaction. Polymer-bound pyridinooxazolines and bis(oxazolines) weresynthesised and employed in Pd-catalysed allylic alkylationswith results similar to those of monomeric analogues;enantioselectivities up to 95% were obtained. One polymer-boundligand could be re-used several times after removal of Pd(0).The polymer-bound bis(oxazoline) was also used in Zn-catalysedDiels-Alder reactions, but the heterogenised catalyst gavelower selectivities than a monomeric analogue. A series of chiral dendron-containing pyridinooxazolines andbis(oxazolines) were synthesised and evaluated in Pd-catalysedallylic alkylations. The dendrons did not seem to have anyinfluence on the selectivity and little influence on the yieldwhen introduced in the pyridinooxazoline ligands. In thebis(oxazoline) series lower generation dendrimers had a postiveon the selectivity, but the selectivity and the activitydecreased with increasing generation. Crown ether-containing ligands were investigated inpalladium-catalysed alkylations. No evidence of a possibleinteraction between the metal in the crown ether and thenucleophile was discovered. A new type of catalyst, an oxazoline-containing palladacyclewas found to be very active in oxidations of secondary alcoholsto the corresponding aldehydes or ketones. The reactions wereperformed with air as the re-oxidant. Therefore, this is anenviromentally friendly oxidation method. <b>Keywords:</b>asymmetric catalysis, chiral ligand,oxazolines, conformational study, allylic substitution,polymer-bound ligands, dendritic ligands, crown ether,oxidations, palladacycle.

<p>This thesis deals with the design of ligands for efficientasymmetric catalysis and studies of the conformation of theligands in the catalytically active complexes. All ligandsdeveloped contain chiral oxazoline heterocycles.</p><p>The conformations of hydroxy- and methoxy-substitutedpyridinooxazolines and bis(oxazolines) during Pd-catalysedallylic alkylations were investigated using crystallography,2D-NMR techniques and DFT calculations. A stabilising OH-Pdinteraction was discovered which might explain the differencein reactivity between the hydroxy- and methoxy-containingligands. The conformational change in the ligands due to thisinteraction may explain the different selectivities observed inthe catalytic reaction.</p><p>Polymer-bound pyridinooxazolines and bis(oxazolines) weresynthesised and employed in Pd-catalysed allylic alkylationswith results similar to those of monomeric analogues;enantioselectivities up to 95% were obtained. One polymer-boundligand could be re-used several times after removal of Pd(0).The polymer-bound bis(oxazoline) was also used in Zn-catalysedDiels-Alder reactions, but the heterogenised catalyst gavelower selectivities than a monomeric analogue.</p><p>A series of chiral dendron-containing pyridinooxazolines andbis(oxazolines) were synthesised and evaluated in Pd-catalysedallylic alkylations. The dendrons did not seem to have anyinfluence on the selectivity and little influence on the yieldwhen introduced in the pyridinooxazoline ligands. In thebis(oxazoline) series lower generation dendrimers had a postiveon the selectivity, but the selectivity and the activitydecreased with increasing generation.</p><p>Crown ether-containing ligands were investigated inpalladium-catalysed alkylations. No evidence of a possibleinteraction between the metal in the crown ether and thenucleophile was discovered.</p><p>A new type of catalyst, an oxazoline-containing palladacyclewas found to be very active in oxidations of secondary alcoholsto the corresponding aldehydes or ketones. The reactions wereperformed with air as the re-oxidant. Therefore, this is anenviromentally friendly oxidation method.</p><p><b>Keywords:</b>asymmetric catalysis, chiral ligand,oxazolines, conformational study, allylic substitution,polymer-bound ligands, dendritic ligands, crown ether,oxidations, palladacycle.</p>

Made available in DSpace on 2015-07-22T20:49:20Z (GMT). No. of bitstreams: 0 Previous issue date: 2012-02-29. Added 1 bitstream(s) on 2015-08-11T03:26:18Z : No. of bitstreams: 1 Publico-13280.pdf: 1828173 bytes, checksum: df8fb9928c37e920c5f9a2281ba9c092 (MD5) / O presente trabalho trata do estudo conformacional de S-nitrosotióis com potencial atividade biológica, 2–acetamido-3-metil-3-nitrosossulfanil-N-arilbutanamidas, e de seus tióis precursores, 2–acetamido-3-mercapto-3-metil-N-arilbutanamidas. As conformações de menor energia dos S-nitrosotióis e tióis em estudo são estabilizadas por ligações de hidrogênio intramoleculares que promovem uma maior estabilidade dos confôrmeros. A análise geométrica do grupo R-SNO mostra que esses compostos preferem a conformação trans. O cálculo das interações orbitalares pelo método NBO (Natural Bond Orbital) para as 2–acetamido-3-mercapto-3-metil-N-arilbutanamidas mostrou que as mesmas são estabilizadas pelas seguintes interações: no (N2) → &#61552;&#61482; (C3-O4) e no(N10) → (C11-O12). Os resultados de NBO para os S-nitrosotíois mostraram que a interação hiperconjugativa é bastante efetiva nas conformações estáveis desses compostos, enfraquecendo a ligação que resulta no aumento do comprimento da ligação S-N em S-Nitrosotióis. A forte delocalização , induz caráter parcial a ligação S-N. A fraca ligação S-N indica uma forte delocalização do par de elétrons do O(NO) devido a interação, que é responsável pelo alongamento da ligação S-N, aumentando e a potencial capacidade do óxido nítrico ser liberado. / We carried out a conformational study on the S-nitrosothiols (R-SNO), 2-acetamido-3-methyl-3-(nitrososulfanyl)-N-arylbutanamides and their thiol precursors 2-acetamido-3-mercapto-3-methyl-N-arylbutanamides. The lowest energy conformation for both compounds is stabilized by intramolecular hydrogen bonds. Trans conformation was determined as the predominant conformation after geometrical analysis of R-SNO. Orbital interactions for 2-acetamido-3-mercapto-3-methyl-N-arylbutanamides were calculated using Natural Bond Orbital (NBO) methodology. Calculations indicated that orbital interactions for these compounds are stabilized by the following interactions: no (N2) → &#61552;&#61482; (C3-O4) and no(N10) → (C11-O12). NBO results showed that the hyperconjugative interaction is very effective, weakening the σ bond and resulting in increasing length of the S-N bond in R-SNO. The strong delocalization induces partial character to the S-N bond. The bond S-N indicates a strong delocalization of the electron pair of O(NO) due to interaction. This interaction is responsible for the elongation of the S-N bond which increases the ability of the compound to release nitric oxide (NO). Based on the enhanced capacity to release NO by these compounds, our findings suggest that both compounds may display biological activity. / TEDE / BV UNIFESP: Teses e dissertações

Dans notre groupe, nous nous intéressons au développement de peptides contenant des acides γ-aminés. Comme d’autres peptides contenant des acides aminés non naturels, ils ont montré leur capacité à posséder des conformations stables et/ou des propriétés biologiques intéressantes. De plus, ces peptides sont généralement résistant à la protéolyse. Dans l’objectif de synthétiser des acides -diaminés sous la forme d’un seul stéréoisomère, nous avons développé une voie de synthèse reposant sur une réaction de Blaise suivie d’une réduction diastéréosélective. En appliquant cette méthode, nous avons synthétisé des acides β,γ-diaminés dérivés de la D-phénylalanine et de l’acide L-glutamique. Le premier a été utilisé pour concevoir des analogues d’un peptide antimicrobien, la gramicidine S. Comparé à la molécule parent, les analogues ont montré une cytotoxicité beaucoup moins importante pour les cellules hôtes tout en conservant une activité antibactérienne intéressante. Cette étude nous a donné de meilleures connaissances pour développer d’autres analogues de la gramicidine S ainsi que d’autres peptides antimicrobiens. Nous avons également effectué de nombreuses optimisations pour synthétiser de façon efficace des acides β,γ-diaminés cycliques à partir de l’acide L-glutamique. Les oligomères incorporant ces acides β,γ-diaminés et des acides α-aminés ont montré un fort potentiel pour l’adoption de conformations stables. Ces études vont être poursuivies. / In our group, we are interested in developing peptides containing β,γ-diamino acids . Along with many other peptides containing unnatural amino acids, they have shown the ability to possess stable conformations and/or interesting biological activities. Moreover, those peptides are usually more resistant to proteolysis. In order to synthesize stereopure γ-amino acids, we have developed a synthetic route using Blaise reaction and subsequent diastereoselective reduction as key reactions. Through applying this method, we have synthesized β,γ-diamino acids derived from D-phenylalanine and L-glutamic acid. The former β,γ-diamino acid was used for designing antimicrobial peptide gramicidin S analogues. Compared with mother molecule, the analogues exerted much less host cell cytotoxicity while remaining interesting antibacterial activity. Meanwhile, it gave us more knowledge for further developing analogues of gramicidin S as well as other antimicrobial peptides. We also paid lots of effort to efficiently synthesize cyclic β,γ-diamino acids starting from L-glutamic acid. Interestingly, when oligomers incorporating this β,γ-diamino acids and α-amino acids, they have shown the potential to adopt stable conformations. The following studies will be continuously investigated.

La maladie d'Alzheimer représente un défi mondial pour la société. Il n'y a pas à ce jour de traitement efficace pour traiter ou ralentir les symptômes de la maladie d'Alzheimer. Cette maladie est caractérisée par une perte de synapses, une augmentation du nombre de plaques extracellulaires d'Abêta et une augmentation de Tau hyperphosphorylée agrégée intracellulaire (neurodégénérescence fibrillaire). Il est communément admis que la maladie d'Alzheimer est principalement liée à l’oligomérisation et à la fibrillation de peptides amyloïdes bêta, et que les oligomères Abêta solubles et les fibres sont des espèces neurotoxiques. Une stratégie pour réduire la présence de ces espèces toxiques de Abêta est l'utilisation de peptides ou de peptidomimétiques pour inhiber l'agrégation de Abêta, soit par interaction avec les oligomères d'Abêta pour empêcher davantage son agrégation en fibres ou en stabilisant les conformations hélicoïdales transitoires de Abêta pour empêcher sa transition vers des structures en feuillets bêta. Dans un premier temps, sur la base des résultats encourageants de glycopeptides contenant un élément polaire casseur de feuillets bêta pour moduler l'agrégation du peptide Abêta, et des propriétés uniques du groupe trifluoromethylhydroxyle, nous avons conçu et synthétisé des mimes de pentapeptides contenant la séquence (Boc) Ala-Val-X-Val-Leu-OMe (X = Ser, Thr, (2S, 3R)-CF3 Thr et (2S, 3S)-CF3 Thr), pour interagir avec le site de nucléation du peptide Abêta dans sa forme monomérique ou oligomérique de manière à perturber l'auto-assemblage en oligomères toxiques. Des études conformationnelles par RMN 2D et par modélisation moléculaire ont indiqué que ces peptides adoptent des conformations étendues dans des solvants polaires (eau et méthanol). Nous avons constaté expérimentalement et théoriquement que les pentapeptides contenant l’acide aminé non naturel (2S, 3S)-CF3-thréonine sont plus étendus que les pentapeptides contenant les acides aminés naturels L-sérine et L-thréonine. Nous avons également observé que les pentapeptides (2S, 3S)-CF3-Thr ont une propension à s’auto-associer en formant des brins bêta intermoléculaires. La capacité de ces pentapeptides à inhiber la formation de fibres amyloïdes a été évaluée sur les peptides Abêta 1-42 et IAPP (impliqué dans le diabète de type II) par des essais de fluorescence à la thioflavine T (ThT). Il a été constaté qu'aucun de ces pentapeptides ont un effet d'inhibition de l'agrégation des peptides Abêta 1-42 et IAPP. Au contraire, certains composés ont montré un effet d'accélération de l'agrégation de IAPP. Accélérer l'agrégation est moins intuitif mais cette stratégie a plus récemment suscité un intérêt. Il pourrait être intéressant d'étudier plus en détail l’intérêt de cette accélération de l'agrégation de IAPP par des techniques complémentaires.Dans une deuxième partie de cette thèse, nous avons assemblé une unité amino acide basée sur un motif CF3-1,4 disubstituted-1,2,3-triazole en homo-oligomères (trimères et tétramères) et en peptidomimétiques. Des études conformationnelles de ces oligomères fluorés ont été menées par RMN 2D et par des simulations de modélisation moléculaire. Nos études préliminaires de modélisation moléculaire prévoient des structures hélicoïdales avec des trimères et des tétramères d'acides aminés à base de ces CF3-triazoles. L'analyse par RMN 2D du tétramère affiche des corrélations NOE très intéressantes, ce qui indique une structure repliée. La capacité de ces oligomères fluorés à moduler la formation de fibres amyloïdes des peptides Abêta 1-42 et IAPP a été évaluée par test de fluorescence à la ThT. Nous avons constaté que le trimère est un faible inhibiteur de l'agrégation de Abêta 1-42, mais aussi un promoteur d'agrégation de IAPP. Le tétramère a été trouvé capable de moduler l'agrégation de Abêta 1-42 et de IAPP, mais non d'une manière classique d'inhibition ou de promotion. / It has been widely recognized that Alzheimer’s disease (AD) represents an unsettling, worldwide challenge for society. By far, there has been no effective cure for AD. Pathologically, AD is characterized by a loss of synapses, an increase in the number of extracellular Abeta plaques and an increase in intracellular aggregated hyperphosphorylated Tau (neurofibrillary tangles). It is commonly believed that AD is primarily linked to oligomerization and fibrillization of amyloid beta peptides, and the soluble Abeta oligomers and fibrils are neurotoxic species.One strategy to reduce the Abeta fibrils is the use of peptides or peptidomimetics to inhibit the Abeta aggregation either by interaction with the Abeta oligomers to prevent its further aggregation into fibrils, or by stabilizing the transient Abeta α-helical conformations to prevent its transition to beta-sheet structures.In the first direction, based on the encouraging results of the glycopeptides containing the polar sugar beta-sheet breaker element to modulate Abeta peptide aggregation and the unique properties of trifluoromethylhydroxyl group, we designed and synthesized pentapeptide mimics with the sequence (Boc) Ala-Val-X-Val-Leu-OMe (X = Ser, Thr, (2S, 3R)-CF3-Thr and (2S, 3S)-CF3-Thr) to interact with the nucleation site of Abeta peptide in its monomeric or oligomeric form so as to disrupt the self-assembly into toxic oligomeric form. Both 2D NMR and molecular modelling studies indicated that these peptides in polar solvent (water and methanol) adopt mainly extended backbone conformations. It is found both experimentally and theoretically that, the (2S, 3S)-CF3-threonine-containing pentapeptides are more extended than the L-serine- and L- threonine-containing pentapeptides. It is also observed that the (2S, 3S)-CF3-Thr pentapeptides have a propensity to self-associate of by forming intermolecular beta-strand contacts. The ability of these pentapeptides to inhibit amyloid fibril formation was evaluated on Abeta1-42 and IAPP peptides by ThT fluorescence assay. It was found that none of these pentapeptides have any inhibition effect in Abeta1-42 peptide and IAPP aggregation. On the contrary, some compounds showed an acceleration effect in IAPP aggregation. Accelerating the aggregation pathways is less intuitive but this strategy has more recently aroused interest. It could be interesting to further study the effect of accelerating IAPP aggregation by complementary techniques.In the other direction, we have assembled novel a CF3-1,4-triazole-based amino acid mimic into homo-oligomers (trimer and tetramer) and peptidomimetics. The fluorinated oligomers were investigated both by NMR conformational studies and molecular modelling simulations. Our preliminary modelling studies predict helical structures with trimer and tetramers of CF3-1,4-disubstituted- 1,2,3- triazole-based amino acid. NMR analysis of tetramer displayed very interesting NOE correlations, indicating a folded structure. The ability of these fluorinated oligomers to modulate the amyloid fibril formation of Abeta1-42 and IAPP peptides were evaluated by ThT fluorescence assay. It was found that trimer was a weak inhibitor of Abeta1-42 aggregation but also a promoter of IAPP aggregation. The tetramer was found able to modulate the aggregation of Abeta1-42 and IAPP but not in a classical inhibition or promotion manner.

The topic of this thesis is the design and synthesis of biaryl-based self adaptableligands for asymmetric metal catalysis. The results discussed in papers I-III are covered, together with some unpublished results concerning substrate-adaptable catalysts. A general survey of self-adaptable catalysts is presented first. The second chapter of this thesis starts with a survey of inversion barriers in biphenyl-based ligands and catalysts. Thereafter, the determination of barriers to conformational adaptation in dibenzoazepines and dibenzophosphepines is described. Palladium complexes with a diphosphine ligand or a diamine ligand, as well as the free diamine ligand, were studied. Entropies and enthalpies of activation were determined with variable temperature NMR spectroscopy. The mechanism of conformational change in the metal complexes was elucidated. The third chapter describes the synthesis of semiflexible and rigid phosphinite ligands, as well as their application in rhodium-catalysed asymmetric hydrogenation. Modest enantioselectivities (up to 63% ee) were obtained. The semiflexible ligand was found to behave like the most active rigid diastereomer. The fourth chapter describes the behaviour of amine and phosphoramidite ligands in model complexes relevant to the palladium-catalysed asymmetricallylic alkylation of benchmark substrates. Diphosphoramidite and aminephosphoramiditeligands were designed and synthesised. Pd(olefin) complexesof diamine and diphosphoramidite ligands were studied, and their symmetry determined. It was found that both types of ligands are able to adapt their conformation to the substrate. / QC20100630

This thesis deals with the design and synthesis of ligands for asymmetric catalysis: palladium catalyzed allylic alkylations, and rho-dium and iridium catalyzed hydrogenations of olefins. Chirally flexible phosphepine ligands based on biphenyl were synthesized and their properties were studied. The rotation barrier for configurationally flexible phosphepines was determined by NMR spectroscopy. The ratio of the atropisomers was shown to depend on the group bound to phosphorus. Only complexes with two homochiral ligands bound to the metal center were observed upon complexation with Rh(I). It was shown that one diastereomer of the flexible ligand exhibits higher activity but lower selectivity than its diastereomer in the rhodium catalyzed hydrogenation of methyl alfa-acetamidocinnamate. These ligands were also tested in nickel catalyzed silabora-tions. Chiral P,N-ligands with pseudo-C2 and pseudo-CS symmetry based on pyrrolidines-phospholanes or azepines-phosphepines were synthesized and studied in palladium catalyzed allylic alkylations. Semi-flexible azepine-phosphepine based ligands were prepared and their ability to adopt pseudo-C2 or pseudo-CS symmetry depending on the substrate in allylic alkylations was studied. It was shown on model allyl systems with flexible N,N-ligands that the ligand prefers CS-symmetry in compexes with anti-anti as well as syn-syn allyl moieties, but that for the latter type of complexes, according to computations, the configuration of the ligand is R*,R* in the olefin complexes formed after addition of a nucleophile to the allylic group. A preliminary investigation of the possibilities to use a su-pramolecular approach for the preparation of P,N-ligands with pseudo-C2 and pseudo-S symmetry was made. An N,N-ligand with C2 symmetry was prepared and its activity in palladium catalyzed ally-lic alkylation was studied. Pyridine-based P,N-ligands were tested in iridium catalyzed hy-drogenations of unfunctionalized olefins with good activities and se-lectivities. In order to attempt to improve the selectivity, ligands with a chirally flexible phosphepine fragment were prepared and applied in catalysis with promising results. / QC 20100929