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1
Bode, Moira Leanne. "Synthetic and spectroscopic studies of indolizine derivatives." Thesis, Rhodes University, 1994. http://hdl.handle.net/10962/d1005050.
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The crystalline compound resulting from thermal cyclization of the Baylis-Hillman product, methyl 3-hydroxy-2-methylene-3-(2-pyridyl)propanoate, has been identified as the indolizine derivative, methyl indolizine-2-carboxylate, and this approach involving the reaction of pyridine-2-carboxaldehydes and acrylate analogues has been established as a general route to 2-substituted indolizines. The ease of cyclization the Baylis-Hillman products to indolizines has been shown to increase by converting the hydroxy group to an acetoxy group, and a range of acetylated Baylis-Hillman products were prepared and cyc1ized to the corresponding 2-substituted indolizines, generally in good overall yield. In the reaction of pyridine-2-carboxaldehyde and methyl vinyl ketone, the intermediate cyclized readily and directly to the corresponding indolizine. One- and two-dimensional ¹H and ¹³C NMR analysis of the 2-substituted indolizine products has permitted complete assignment of all ¹H and ¹³C NMR signals, as well as the measurement of all coupling constants for these compounds. A kinetic and mechanistic study has been conducted on the Baylis-Hillman reaction using ¹H NMR spectroscopy. A range of substrates has been examined and the reaction has been found to be third-order overall. A mechanism involving an addition - elimination sequence is proposed, which fits the kinetic data and accounts for observed substituent effects. Reaction of N,N-dimethylacrylamide with pyridine-2-carboxaldehyde in the presence of the tertiary amine catalyst, DABCO, in chloroform, yielded an unexpected product which has been identified by single crystal X-ray diffraction analysis as 1-(2,2,2-trichloro-1-hydroxyethyl)pyridine. Attempted extension of the general indolizine route to the preparation of chromene systems by reacting salicylaldehyde with methyl acrylate in the presence of DABCO, also led to an unexpected, crystalline material, identified by single crystal X-ray diffraction analysis as the coumarin derivative, 3-[(2-formylphenoxy)methyl]coumarin.A series of chloroquine analogues have been prepared from indolizine-2-carboxylic acid, pyrrolo[I,2-a]quinoline-2-carboxylic acid and imidazo[I,2-a]pyridine-2-carboxylic acid by reaction with suitable amines in the presence of the coupling reagent 1, I' -carbonyldiimidazole. This route has been shown to be a vast improvement on earlier procedures and has provided access to both secondary and tertiary indolizine-2-carboxamides. A range of N,N-dialkylindolizine-2-carboxamides have been prepared by this route, and the influence of substituents on their N-CO rotational energy barriers has been determined using variable temperature ¹H and ¹³C NMR techniques. Intercalation with natural DNA by both chloroquine and the synthesized chloroquine analogues has been examined using UV spectrophotometry, and ¹H and ³¹P NMR spectroscopy. The pyrrolo[I,2-a]quinolines have been shown to be DNA intercalators with binding affinities similar to that of the known antimalarial intercalator, chloroquine. In a preliminary study the synthesis of a short oligonucleotide has been undertaken and changes have been observed in the ¹H and ³¹P NMR spectra of the oligonucleotide on addition of the intercalator, chloroquine.
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Sevrain, Nicolas. "Synthèse de nouveaux systèmes phosphorés à chiralité axiale et leurs applications." Thesis, Montpellier, Ecole nationale supérieure de chimie, 2017. http://www.theses.fr/2017ENCM0019.
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La demande croissante de molécules énantiopures pour la chimie pharmaceutique et agrochimique est l'un des enjeux majeurs actuels de l'industrie chimique. De plus, les nouvelles réglementations environnementales récentes forcent l'émergence de procédés efficaces, rentables et respectueux de l'environnement pour la fabrication de ces nouvelles entités chimiques. Les méthodes impliquant l'utilisation de catalyseurs présentent des avantages évidents par rapport à des méthodes stœchiométriques. À ce titre, les ligands phosphorés ont joué un rôle clé dans l'évolution de la catalyse asymétrique. Leur activité catalytique est une balance entre leurs propriétés électroniques et stériques et il n’existe pas à l’heure actuelle d’inducteur chiral universel. De plus, leur modification est loin d’être triviale au regard des procédures complexes nécessaires pour en modifier la structure.Ces travaux de thèse s’inscrivent dans le développement de nouveaux systèmes phosphorés à chiralité axiale, dont le BINAP en est l’exemple le plus représentatif. Notre premier objectif a été la synthèse et l’étude de systèmes bihétéroaromatiques à 5 chaînons basés sur le motif bis-indolizine, dont le motif hétérocyclique est connu pour la richesse électronique de son noyau aromatique à 10 électrons π. Le second objectif est l’utilisation d’oxydes de bis-triazolylphosphines pour des réactions énantiosélectives d’Abramov, d’allylation d’aldéhydes et pour finir d’aldolisation réductriceThe growing demand of enantiopure molecules for applications in life sciences (pharmaceutical and agrochemical chemistry) or in new fragrances is one of the major issue of the late decades in chemical industry. Moreover, recent environmental regulations pushed the emergence of efficient, cost-effective and environmental-friendly processes for the manufacture of these new chemical entities. The methods involving the use of catalysis have clear advantages over those requiring stoichiometric amounts of reagents and phosphine ligands has played a key role in the evolution of catalysis. However fine tuning of the catalytic activity by modification of the electronic/steric properties of the ligand systems is far from trivial mainly because of the difficulty and cumbersome procedures for structural modification of the ligand scaffolds.This work was focused on the development of new axial chiral phosphorus structures, of which BINAP is the most representative example. The first objective was the synthesis of 5-membered biheteroaromatic systems based on the bis-indolizine scaffold, whose the heterocyclic system is known for the electronic richness of the 10-π electron aromatic core. The second objective was the application of bis-triazolylphosphine oxides in enantioselective Abramov, allylation of aldehydes and finally reductive aldolisation reactions
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Stegarescu-Furdui, Bianca. "Synthèse en série bipyridine. Etude de l'interaction avec l'ADN." Phd thesis, Université Joseph Fourier (Grenoble), 2006. http://tel.archives-ouvertes.fr/tel-00166634.
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Nous avons développé la synthèse d'hétérocycles indoliziniques fonctionnalisés par un cation pyridinium et étudié leur interaction avec L'ADN. L'étape-clé pour accéder aux indolizines est la cycloaddition [3+2]-dipolaire des ylures dérivés des sels quaternaires de la 4,4'-bipyridine avec des dipolarophiles. La synthèse a été effectuée par la voie classique (chauffage en solvant) et par irradiation avec des micro-ondes (“chimie verte”). Nous avons étudié les propriétés acido-basiques des sels diquaternaires et leur activité biologique sur une série de microorganismes. Par ailleurs les propriétés électriques et optiques ainsi que la photoluminescence des indolizines se sont révélées prometteuses pour des applications comme les traceurs biomédicaux. L'interaction des indolizines avec l'ADN a aussi été étudiée. Finalement, nous avons évalué les propriétés antioxydantes des indolizines, qui ont montré une activité inhibitrice de la peroxydation des huiles végétales in vitro.
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Martinez, Thibaut. "Cyclisation de 2-pyridylallènes : vers de nouveaux dérivés d’indolizines et ligands carbéniques chiraux." Thesis, Sorbonne université, 2019. https://accesdistant.sorbonne-universite.fr/login?url=http://theses-intra.upmc.fr/modules/resources/download/theses/2019SORUS273.pdf.
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Les travaux réalisés dans le cadre de cette thèse sont consacrés à l’étude de réactions de cyclisations de 2-pyridylallènes à l’aide de différentes espèces électrophiles. Des 2-pyridylallènes tétrasubstitués ont ainsi été synthétisés et cyclisés en conditions acides, avec différents halogènes électrophiles, des chalcogènes ainsi que de l’or (I) pour donner de nouveaux motifs indoliziniums. Des indolizines 1,3-substitués iodées en position 2 ont également été obtenues permettant une post-fonctionnalisation par couplage croisé. L’utilisation d’or (I) comme électrophile mène à de nouveaux complexes dont les ligands rassemblent les critères structuraux pour être considérés comme des NHCs. Les propriétés électroniques (σ-donation et π-acidité) de ce type de ligand ont été évaluées théoriquement et expérimentalement : si ces composantes électroniques se sont toutes deux révélées très élevées, la σ-donation semble surpasser celle des NHCs décrits dans la littérature. Certains complexes chiraux ont pu être efficacement utilisés en catalyse énantiosélective. Il apparaît clairement que la présence du groupement oxyde de phosphine est nécessaire pour obtenir une énantiosélectivité élevée dans le cas de l’hydroxyalkoxylation intramoléculaire d’un y-allénol. Ainsi, un très bon rapport énantiomérique de 91:9 et un rendement quantitatif ont été obtenusThis PhD work focused on the electrophile-induced cyclisation of 2-pyridylallenes. Various tetrasubstituted 2-pyridylallenes were synthesized and cyclized in acidic conditions, using electrophilic halogens, chalcogens and gold (I) species to afford new indoliziniums scaffolds. The synthesis of 1,3-indolizines bearing an iodine atom in position 2 was also performed, allowing a further late 2-functionnalization step by cross coupling reactions. Using gold (I) as an electrophile gave access to new gold complex bearing NHC type ligands. The electronic properties (σ-donation et π acidity) of this type of ligand were theoretically and experimentally investigated: if both of them were found especially strong, the σ-donation seems to overcome that of the NHCs described since then. Some chiral complexes have been used efficiently in enantioselective catalysis. It appeared clearly that the presence of the phosphine oxyde moiety is necessary to obtain a high enantioselectivity during the intramolecular hydroxyalkoxylation of γ-allenol. An excellent enantiomeric ratio of 91:9 and a quantitative yield were obtained
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Stegarescu-Furdui, Bianca. "Synthèse en série bipyridine. Etude de l'interaction avec l'ADN." Phd thesis, Grenoble 1, 2006. http://www.theses.fr/2006GRE10187.
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Nous avons développé la synthèse d’hétérocycles indoliziniques fonctionnalisés par un cation pyridinium et étudié leur interaction avec L’ADN. L’étape-clé pour accéder aux indolizines est la cycloaddition [3+2]-dipolaire des ylures dérivés des sels quaternaires de la 4,4’-bipyridine avec des dipolarophiles. La synthèse a été effectuée par la voie classique (chauffage en solvant) et par irradiation avec des micro-ondes (“chimie verte”). Nous avons étudié les propriétés acido-basiques des sels diquaternaires et leur activité biologique sur une série de microorganismes. Par ailleurs les propriétés électriques et optiques ainsi que la photoluminescence des indolizines se sont révélées prometteuses pour des applications comme les traceurs biomédicaux. L’interaction des indolizines avec l’ADN a aussi été étudiée. Finalement, nous avons évalué les propriétés antioxydantes des indolizines, qui ont montré une activité inhibitrice de la peroxydation des huiles végétales in vitroWe have developped the synthesis of heterocycles derived from indolizines and carrying a cationic pyridinium substituent, and studied their interaction with DNA. The key-step of the synthesis of the indolizines is a [3+2] dipolar cycloaddition of ylides formed from quaternary 4,4'-bipyridinium salts with dipolarophiles. The synthesis was done either in classical conditions (solvent, temperature) or by microwave irradiation ("green chemistry"). We have studied the acid-base properties of the bipyridinium salts and their biological activities. The electrical and optical properties along with the photolumiscence of theindolizines are promissing for potential applications as biomedical markers. The interaction of indolizines with DNA was also studied. Finally, we have evaluated the antioxidant properties of indolizines, that have shown an inhibition of peroxidation of vegetal oils in vitro
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Beck, Daniel Antony Speedie, and beckautomatic@gmail com. "Stereoselective intramolecular Michael addition reactions of pyrrole and their application to natural product syntheses." The Australian National University. Research School of Chemistry, 2006. http://thesis.anu.edu.au./public/adt-ANU20070130.130009.
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Chapter one; (-)-Rhazinilam and (-)-Rhazinal: Alkaloids with Anti-mitotic Properties Derived from Kopsia teoi, provides the background information behind the motives that initiated this research project. The plant alkaloid (-)-rhazinilam [(-)-1] and its naturally-occurring derivative (-)-rhazinal [(-)-13] both exhibit potent anti-mitotic activities and, as such, are interesting targets for total synthesis. Chapter one is a review of the literature regarding these two compounds and discusses the occurrence, proposed biosynthetic origins, structural elucidation and biological activites of compound (-)-1 and that of its analogues including alkaloid (-)-13. Previous total syntheses of these two compounds are then examined, concluding with the only reported total synthesis of compound (-)-13. Developed within the Banwell research group, this total synthesis produced the racemic modification of alkaloid (-)-13 due to a lack of any stereocontrol in the key intramolecular Michael addition step. This unprecedented key step, involving cyclisation of the C2 of pyrrole onto an N-tethered and ?,?-disubstituted acrylate to produce a quaternary-carbon stereogenic centre, would be of greatly enhanced utility if it could be achieved in a catalytic-enantioselective fashion. The realisation of this goal is the central aim of the research conducted within this thesis.
¶
Chapter two; Investigating Asymmetric Induction in the Intramolecular Michael Addition of pyrrole to N-Tethered Acrylates and Related Species, introduces the model study used to direct research towards achieving the goal of asymmetric induction in the title process. The model is a somewhat simplified version of the original process used in the total synthesis of compound (-)-13 involving cyclisation of the C2 of pyrrole onto an N-tethered and ?-monosubstituted Michael acceptor, to produce a tertiary-carbon stereogenic centre. This simplification allows the rapid synthesis of a broad range of potential substrates for use in the title process, thus enabling the investigation of various different approaches to inducing asymmetry therein. High levels of asymmetric induction are observed with the use of chiral substrates or catalysts, facilitating the synthesis of both 6- and 7-membered rings annulated to pyrrole with construction of the relevant tertiary-carbon stereogenic centre in enantio-enriched form. For the reactions producing a 6-membered ring annulated to pyrrole, unambiguous proof of the absolute sense of asymmetric induction observed in the intramolecular Michael addition event is established using a chemical correlation study involving elaboration of a key indolizine-type cyclisation product, to the plant alkaloid of known absolute stereochemistry, (-)-tashiromine [(-)-75]. For the reaction producing a 7-membered ring annulated to pyrrole, the same information is obtained via X-ray crystallographic analyses of a dibrominated derivative of a key pyrroloazepine-type cyclisation product.
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Chapter three An Enantioselective Total Synthesis of the Alkaloid (-)-Rhazinal: An Anti-mitotic Agent Isolated from Kopsia teoi., focuses on the application of methodology developed in the previous chapter, to the original goal of inducing asymmetry in the intramolecular Michael addition reaction, involving cyclisation of the C2 of pyrrole onto an N-tethered and ?,?-disubstituted acrylate to produce a quaternary-carbon stereogenic centre. This is ultimately achieved in a catalytic-enantioselective fashion, resulting in the first such total synthesis of the anti-mitotic alkaloid (-)-rhazinal [(-)-13].
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Chapter four Extending the Reaction Manifold to the Syntheses of Related Natural Products: A Formal Total Synthesis of (+)-Aspidospermidine and Syntheses of (-)-Rhazinilam and (-)-Leuconolam from (-)-Rhazinal, describes three extensions to the reaction manifold used in the enantioselective total synthesis of alkaloid (-)-13:
The acquisition in an enantioselective manner, of an intermediate previously obtained in racemic form, en route to the racemic modification of the natural product (±)-aspidospermidine [(±)-134], constitutes a formal and enantioselective total synthesis of (+)-aspidospermidine
[(+)-134].
The direct deformylation of (-)-rhazinal [(-)-13], is carried out, to produce the parent alkaloid
(-)-rhazinilam [(-)-1].
The pyrrole ring present in (-)-rhazinilam [(-)-1] is oxidised, to produce the related natural product (-)-Leuconolam [(-)-12] which has not, hitherto, been prepared by total synthesis.
¶Chapter five contains the experimental procedures and characterisation data associated with compounds described in chapters two to four.
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Gizolme, Marie. "Réactions multicomposants et isonitriles." Phd thesis, Ecole Polytechnique X, 2007. http://pastel.archives-ouvertes.fr/pastel-00003258.
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Les couplages de Passerini et de Ugi, réactions multicomposants impliquant des isonitriles, ont suscité un grand intérêt ces dernières années. En effet elles permettent d'obtenir en une étape, avec de bons rendements globaux, des produits complexes et diversifiés. Tout d'abord, une nouvelle méthode de synthèse d'indolizines a été développée à partir d'un couplage entre réaction d'Ugi et cycloaddition [3+2] de sel de pyridinium. Cette étape-clé s'insère dans une cascade Sonogashira/cycloaddition/oxydation qui permet d'accéder de manière rapide à des systèmes hétérocycliques d'une grande complexité structurale, présents dans de nombreux alcaloïdes. Récemment le couplage Ugi-Smiles, équivalent du couplage de Ugi, impliquant un phénol pauvre en électrons comme composé acide, a été développé au laboratoire. Dans ce travail, nous avons étudié la possibilité d'introduire ces composés dans un couplage de Passerini. L'o-nitrophénol ainsi que des phénols hétérocycliques ont été couplés, donnant accès à une grande diversité d'aryloxyamides. Le mécanisme implique un réarrangement de Smiles final – transfert d'aryle d'un atome d'oxygène vers un autre. Nous nous sommes ensuite intéressés à l'introduction de composés soufrés dans le couplage Ugi-Smiles, permettant l'obtention en une étape de thioamides fonctionnalisés. Des produits de couplage avant réarrangement de Smiles ont pu être obtenus à différentes occasions, donnant ainsi un nouvel éclairage au mécanisme de cette réaction. En outre, des hétérocycles soufrés très divers ont été couplés avec succès donnant accès à des composés originaux.
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Tukulula, Matshawandile. "The design and synthesis of novel HIV-1 protease inhibitors." Thesis, Rhodes University, 2009. http://eprints.ru.ac.za/1563/.
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Delattre, François. "Nouveaux senseurs fluorescents à base de β-cyclodextrine incorporant l'unité pyridinoindolizinique : synthèse, détermination structurale et étude de l'inclusion." Littoral, 2003. http://www.theses.fr/2003DUNK0097.
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Ce travail concerne la synthèse et la caractérisation d'une série de nouveaux senseurs fluorescents, à base de β-cyclodextrine, incorporant l'unité pyridinoindolizinique. Ces dispositifs macromoléculaires ont pour caractéristiques d'induire une variation d'intensité de leurs émissions de fluorescence lors de l'inclusion de molécules invitées, à l'intérieur de leur partie macrocyclique. Dans une première partie, nous avons mis au point deux voies de synthèse dont le principe général repose sur des réactions de cycloadditions-1,3 dipolaires, à partir de sels quaternaires de 4,4'-bipyridinium et de dipolarophiles acétyléniques. Les structures des composés synthétisés ont été validées par les méthodes classiques d'analyse élémentaire et d'expériences de spectroscopies de RMN, SM, IR. Dans un second temps, nous avons étudié les phénomènes liés à l'inclusion de dérivés d'adamante et de Composés Organiques Volatils (COV), dans la cavité de la partie cyclodextrine, par spectroscopie de RMN 2D, de Dichroi͏̈sme Circulaire et de fluorescence. Cette étude met en évidence l'influence du positionnement du chromophore, de ces composés, par rapport à leur cavité hydrophobe. Les expériences de complexation ont permis la détermination de la sensitivité de ces capteurs, en solution aqueuse, vis-à-vis de leurs invités et de valider l'aspect "sensitif" de ces composés. Enfin, l'utilisation de la modélisation moléculaire, par des méthodes de Mécaniques Moléculaires et Semi-Empiriques, a contribué à mettre en évidence la structure tridimensionnelle de ces dérivés fluorescentsThe present work concerns the synthesis and characterisation a series of new fluorescent molecular sensors containing β-cyclodextrin and incorporating a pyridinoindolizinic unit. These molecular devices are characterised by their ability to induce a variation of fluorescence intensity when they are incorporated a molecule in the cavity of macrocycle. In a first part, two synthesis methods where developed whose general principle is based on 1,3-cycloaddition reactions from a quaternary salts of 4,4'-bipyridinium and acetylenics dipolarophiles. Structures of the synthesized compounds were validated by the traditional methods elemental analysis and spectroscopic experiments NMR, MS, IR. In the second section, a study was made of the phenomena related to the inclusion of adamante derivatives and Volatils Organics Compounds (VOC), in the cavity of cyclodextrin, by the spectroscopic techniques of 2D NMR, CD and fluorescence. This study highlights the influence of chromophoric positioning, of these compounds, compared to their hydrophobic cavity. The complexation experiments have lead to the determination of sensitivity factors with respect to their guests, in aqueous solution, and to validate the "sensitive" aspect of these compounds. Finally, the use of molecular modeling, by molecular mechanistic and semi-empiricals methods, contributed to highlight the dynamic aspects related to the phenomena of complexation
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Granger, Devin B. "ACENES, HETEROACENES AND ANALOGOUS MOLECULES FOR ORGANIC PHOTOVOLTAIC AND FIELD EFFECT TRANSISTOR APPLICATIONS." UKnowledge, 2017. http://uknowledge.uky.edu/chemistry_etds/76.
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Polycyclic aromatic hydrocarbons composed of benzenoid rings fused in a linear fashion comprise the class of compounds known as acenes. The structures containing three to six ring fusions are brightly colored and possess band gaps and charge transport efficiencies sufficient for semiconductor applications. These molecules have been investigated throughout the past several decades to assess their optoelectronic properties. The absorption, emission and charge transport properties of this series of molecules has been studied extensively to elucidate structure-property relationships. A wide variety of analogous molecules, incorporating heterocycles in place of benzenoid rings, demonstrate similar properties to the parent compounds and have likewise been investigated.
Functionalization of acene compounds by placement of groups around the molecule affects the way in which molecules interact in the solid state, in addition to the energetics of the molecule. The use of electron donating or electron withdrawing groups affects the frontier molecular orbitals and thus affects the optical and electronic gaps of the molecules. The use of bulky side groups such as alkylsilylethynyl groups allows for crystal engineering of molecular aggregates, and changing the volume and dimensions of the alkylsilyl groups affects the intermolecular interactions and thus changes the packing motif.
In chapter 2, a series of tetracene and pentacene molecules with strongly electron withdrawing groups is described. The investigation focuses on the change in energetics of the frontier molecular orbitals between the base acene and the nitrile and dicyanovinyl derivatives as well as the differences between the pentacene and tetracene molecules. The differences in close packing motifs through use of bulky alkylsilylethynyl groups is also discussed in relation to electron acceptor material design and bulk heterojunction organic photovoltaic characteristics.
Chapter 3 focuses on molecular acceptor and donor molecules for bulk heterojunction organic photovoltaics based on anthrathiophene and benzo[1,2-b:4,5-b’]dithiophene central units like literature molecules containing fluorene and dithieno[2,3-b:2’,3’-d]silole cores. The synthetic strategies of developing reduced symmetry benzo[1,2-b:4,5-b’]dithiophene to study the effect of substitution around the central unit is also described. The optical and electronic properties of the donors and acceptors are described along with the performance and characteristics of devices employing these molecules.
The final two data chapters focus on new nitrogen containing polycyclic hydrocarbons containing indolizine and (2.2.2) cyclazine units. The optical, electronic and other physical properties of these molecules are explored, in addition to the synthetic strategies for incorporating the indolizine and cyclazine units. By use of alkylsilylethynyl groups, crystal engineering was investigated for the benzo[2,3-b:5,6-b’]diindolizine chromophore described in chapter 4 to target the 2-D “brick-work” packing motif for application in field effect transistor devices. Optical and electronic properties of the cyclazine end-capped acene molecules described in chapter 5 were investigated and described in relation to the base acene molecules. In both cases, density functional theory calculations were conducted to better understand unexpected optical properties of these molecules, which are like the linear acene series despite the non-linear attachment.
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Cunha, Saraghina Maria Donato da. "A síntese via Adutos de Morita Baylis Hillman dos derivados 2-Indolizina em micro-ondas: novos potenciais moduladores de canais iônicos." Universidade Federal da Paraíba, 2013. http://tede.biblioteca.ufpb.br:8080/handle/tede/7104.
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This work presents microwave irradiation promoting synthetic studies that producing by the first time indolizine-2-carbonitrile (1) and indolizine-2-carboxylate (2) in good to high yields (70% and 81%, respectively) in one step from Morita-Baylis- Hillman adducts (MBHA) 2-(hydroxy(pyridin-2-yl)methyl)acrylonitrile (10) and methyl 2-(hydroxy(pyridin-2-yl)methyl)acrylate (9) respectively. These compounds were subsequently transformed in excellent yields on three 2-indolizine derivatives know in the literature. they are: indolizin-2-yl methanamine (5), 99%, indolizin-2-ylmethanol (6), 100%, indolizine-2-carboxylic acid (3), 100%, in new more three Indolizine, namely : tert-butyl (indolizin-2-ylmethyl) carbonate (7), 99% new, butyl-indolizine-2- carboxylate(4), 94% new, tert-butyl (indolizin-2-ylmethyl)carbamate (8), 86% new. All of the adducts were characterized by infrared physical methods, Gas Chromatography coupled to Mass Spectrometry and Nuclear Magnetic Resonance (1 H NMR and 13 C NMR).All syntheses were developed in this study appropriate industry standards. The reaction activation by microwave irradiation (MO) has been widely used in most synthetic stages of this work, leading to high chemical yields and reduced reaction times. The eight synthesized compounds were in silico designed aiming to present potential selective activities as modulators of ion channels. These activities were suggested by the high score values obtained by using Molinspiration cheminformatics program.
Este trabalho apresenta um estudo sintético promovido por irradiação de micro-ondas, produzindo pela primeira vez a 2-Indolizina-carbonitrila (1) e a 2- Indolizina-carboxilato de metila (2) em bons a altos rendimentos (70% e 81% de rendimentos respectivamente) em uma única etapa, a partir dos Adutos de Morita- Baylis-Hillman (AMBH) 2 (hidroxi(piridin-2-il)metil)acrilonitrila(10) e metil 2- (hidroxi(piridin-2-il)metil)acrilato(9) respectivamente. Estes compostos foram subseqüentemente transformados em excelentes rendimentos em mais três derivados 2-indolizínicos já conhecidos na literatura, a saber: indolizin-2-il metanamina (5), 99%, indolizin-2-il metanol (6), 100%, acido Indolizina-2- carboxílico(3), 100%, e mais três inéditos , a saber: terc-butil (indolizin-2-il metil) carbonato(7), 99% inédito , butil Indolizina-2-carboxilato (4), 94% inédito, e terc-butil (indolizin-2-il metil)carbamato (8), 86% inédito. Todos os Adutos foram caracterizados através dos métodos físicos de Infravermelho, Cromatografia Gasosa acoplada a Espectrometria de Massas e Ressonância Magnética Nuclear (RMN1H e RMN13C). Todas as sínteses neste trabalho foram desenvolvidas em padrões convenientes a indústria. A ativação reacional por irradiação de microondas (MO) foi amplamente utilizada na maioria das etapas sintéticas deste trabalho, conduzindo aos altos rendimentos químicos e aos tempos reacionais reduzidos. Os oito compostos sintetizados foram idealizados in silico objetivando apresentarem potenciais atividades seletivas como moduladores de canais iônicos. Estas atividades foram sugeridas pelos altos valores obtidos de score usando o programa quimioinformático Molinspiration.
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Rasmussen, Martin Ohsten. "Nouvelle approche asymetrique des indolizidines polyhydroxylees : synthese de la (+)-lentiginosine et de la (-)-2-epilentiginosine." Université Joseph Fourier (Grenoble), 2001. http://www.theses.fr/2001GRE10059.
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Les syntheses asymetriques de deux indolizidines dihydroxylees, la (+)-lentiginosine et la ()-2-epilentiginosine, ainsi que celles de deux indolizidines monohydroxylees, la (1r,8as)-1-hydroxyindolizine et la (1s,8as)-1-hydroxyindolizidine ont ete realisees. La strategie de synthese de ces quatre produits naturels est basee sur une cycloaddition de type 2+2 hautement diastereoselective (d. R. =95 : 5) entre le dichlorocetene et un ether d'enol portant un inducteur chiral. Un rearrangement de beckmann des oximes derivant des cyclobutanones ainsi obtenues permet d'introduire la fonction azotee. Ce rearrangement totalement regioselectif a permis d'acceder a des -lactames hautement fonctionnalises avec une tres grande purete stereochimique. L'acces aux deux diastereomeres dihydroxyles cibles a ete effectue par osmylation du lactame insature. La ()-2-epilentiginosine a ete obtenue par reduction du lactame cis dihydroxyle protege, tandis que la (+)-lentiginosine a ete preparee grace a une procedure d'inversion hautement regioselective de ce lactame.
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George, Rosemary. "Synthesis and conformational studies of indolizines." Thesis, Rhodes University, 1994. http://hdl.handle.net/10962/d1005032.
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The present investigation has involved a kinetic and mechanistic study of the thermal cyclization of 3-acetoxy-3-(2-pyridyl)-2-methylenepropanoate esters and related compounds to 2-substituted indolizines. Substrates for the kinetic study were prepared via the Baylis-Hillmann reaction of pyridine-2-carboxaldehydes with acrylate esters, acrylonitrile and methyl vinyl ketone. The resulting hydroxy compounds were then acetylated to afford the acetoxy derivatives, thermal cyclization of which gave the corresponding 2-substituted indolizines. The cyclization reactions was followed using 'H NMR spectroscopy and were shown to follow firstorder kinetics. The influence of the various substituents on the observed first-order rate constants has been examined and variable temperature studies have permitted evaluation of activation parameters for the formation of methyl indolizine-2-carboxylate and ethyl indolizine-2-carboxylate. An alternative route to 2-substituted indolizines via halogenated derivatives was explored and several halogenated 2-pyridyl derivatives were synthesised and their thermal cyclization to indolizines was attempted. Novel 5-methylindolizine-2-carboxamides were prepared as part of this investigation and dynamic NMR spectroscopy was used to study internal rotation about the amide N-CO bond in these compounds.
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González, Soria María José. "Selective synthesis and reactivity of indolizines." Doctoral thesis, Universidad de Alicante, 2018. http://hdl.handle.net/10045/98672.
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Se ha llevado a cabo la síntesis multicomponente de una serie de 1-aminoindolizinas y pirrolo[1,2-a]quinolonas de manera efectiva a partir de derivados de 2-piridincarbaldehído, aminas secundarias y alquinos terminales utilizando CuNPs/C como catalizador en diclorometano a 70 ºC. La metodología se ha aplicado a una variedad de aminas y alquinos, los últimos incluyendo arilacetilenos así como alquilacetilenos, con rendimientos de moderados a altos. Dicho catalizador ha demostrado ser superior a una serie de catalizadores de cobre comerciales. Finalmente, se ha propuesto un mecanismo de reacción basado en la probada participación de aminas propargílicas como intermedios de reacción. Se han sintetizado indolizidinas a través de la hidrogenación catalítica heterogénea de indolizinas usando PtO2 como catalizador en ácido acético como disolvente y a una presión de 3,7 atm. Las indolizidinas se han obtenido con una elevada diastereoselectividad, incluso en el caso de poseer cuatro estereocentros. Se ha demostrado experimentalmente que la hidrogenación de la indolizina se produce a través del intermedio pirrólico 5,6,7,8-tetrahidroindolizina. Además, estas indolizidinas se han podido mono- o di-desbencilar usando un catalizador diferente. Se ha sintetizado una nueva familia de compuestos orgánicos por reacción de las indolizinas en medio ácido. Estos productos son tintes de indolizina de color violeta-rojizos que tienen una estructura D-A-π-A bien definida. La estructura de los tintes de indolizina se ha establecido mediante análisis de rayos X en estado sólido, pero se pueden distinguir dos rotámeros en disolución. Se ha propuesto un mecanismo de reacción en el que la propia indolizina actúa como nucleófilo y electrófilo; en éste, una molécula sufre hidrólisis en medio ácido y la adición Michael de la segunda molécula de indolizina. Un estudio de las características ópticas de estos tintes ha revelado un cambio de color dependiente del tamaño de partícula, un alto poder de coloración y un carácter solvatocrómico (es decir, que el color de la disolución del compuesto depende de la polaridad del disolvente usado), también en materiales plásticos. Finalmente, se ha estudiado la reactividad de las indolizinas con nitrosocompuestos, obteniendo dos productos diferentes según el sustituyente en la posición tres de éstas. En el caso de poseer un sustituyente aromático se obtienen β-enaminonas. Se ha realizado un estudio del alcance de esta metodología cambiando los sustituyentes 1, 3 y 6 de las indolizinas y usando compuestos nitrosoaromáticos con distintos sustituyentes en orto y para, obteniendo las correspondientes β-enaminonas con rendimientos aislados de moderados a buenos. El uso de esta metodología ha demostrado ser el más apropiado para obtener ese tipo de regioisómero, comparado con las metodologías clásicas de condensación de compuestos 1,3-dicarbonilos con aminas que dan el regioisómero opuesto. Para sustituyentes alifáticos, se han obtenido pirroles tetrasustituidos con rendimientos de moderados a buenos, variando los cuatro sustituyentes en la estructura de pirrol. Se han llevado a cabo varios experimentos para elucidar el mecanismo de reacción. Se ha demostrado que proceden vía iónica, no radicalaria. La presencia de agua es beneficiosa para la obtención de β-enaminonas, en cambio, una atmósfera de oxígeno o de argón no lo son. Con todo ello, se ha propuesto un mecanismo para la obtención de éstas en el que participa una estructura de isooxazol como intermedio. En el caso de los pirroles, se ha demostrado que hay una migración de la dibencilamina en la estructura. Tras varios experimentos, enfocados en la obtención de un posible intermedio de reacción, se ha propuesto la secuencia del mecanismo para la obtención de pirroles. En primer lugar, se ha propuesto el ataque nucleófilo al nitrosocompuesto, abriendo la estructura y perdiendo dibencilamina, formando así una cetona α,β-insaturada, seguido del ataque de la dibencialamina y posterior ciclación para la obtención del pirrol.
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Baekelmans, Didier. "Synthèse de benzo-indolizines par cycloaddition 1,3 dipolaire." Doctoral thesis, Universite Libre de Bruxelles, 1998. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/212087.
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Nelson, A. "Synthesis of bioactive indolizidine alkaloids." Thesis, Queen's University Belfast, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.421009.
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Kücükdisli, Murat [Verfasser]. "New synthetic strategies towards indolizines and pyrroles / Murat Kücükdisli." Mainz : Universitätsbibliothek Mainz, 2015. http://d-nb.info/1070409146/34.
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Padmanabhan, Padma. "Biosynthetic studies on the indolizidine alkaloid cyclizidine." Thesis, University of Cambridge, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.304387.
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Mitchell, Douglas. "Synthetic studies towards pyrrolizidine and indolizidine alkaloids." Thesis, Sheffield Hallam University, 1992. http://shura.shu.ac.uk/20067/.
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This project was concerned with the synthesis of the pyrrolizidine alkaloids supinidine, trachelanthamidine and isoretronecanol and also synthetic studies towards the indolizidine alkaloid 251D. In all cases, the synthesis began from a cheap, readily-available, simple amino acid, in this case glutamic acid, and proceeded to a suitable monocyclic intermediate which could then undergo an intramolecular Horner-Wittig cyclisation reaction to form the required bicyclic core structure. Subsequent modification reactions then led in the pyrrolizidine series to penultimate precursors of the target alkaloids supinidine, trachelanthamidine and isoretronecanol, and in the indolizidine series to a bicyclic intermediate in the synthesis towards the toxin 251D. The intramolecular Horner-Wittig cyclisation reaction was found to proceed with retention of chirality, thus leading to the enantiospecific synthesis of the pyrrolizidine alkaloids. The use of alternative monocyclic intermediates in the intramolecular Horner-Wittig cyclisation reaction, thus leading to other pyrrolizidine alkaloids is also discussed. One of the major problems encountered in this project was the solubility of the unprotected monocyclic amide intermediates, and this was overcome by the use of N-benzyl and N- carbobenzyloxy protecting groups; in the indolizidine synthesis where the unprotected monocyclic amides were necessary, the reaction work-up for these intermediates usually required continuous solvent extraction. Another major problem was the instability of the bicyclic amide intermediates and some of the monocyclic intermediates,As well as covering a comprehensive background of each class of alkaloid, this report also contains an in-depth discussion of the key intramolecular Horner-Wittig cyclisation reaction and suggestions for its use in the possible synthesis of other classes of alkaloids.
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Pourashraf, Mehrnaz. "Synthèse asymétrique de cyclopentanones et de lactanes : application à la synthèse de la (+)-taonianone et de la (-)-slaframine." Université Joseph Fourier (Grenoble), 1999. http://www.theses.fr/1999GRE10267.
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Au cours de ce travail, nous avons effectue la premiere synthese asymetrique de la (+)-taonianone, representant une nouvelle classe de furanoditerpene marin, et celle de la ()-slaframine, un alcaloide indolizidinique possedant d'importantes proprietes biologiques. Ces deux syntheses font intervenir une cycloaddition asymetrique hautement stereoselective d'un cetene sur un ether d'enol portant un inducteur chiral. Elles se caracterisent de plus par une expansion regio- et stereoselective conduisant a une cyclopentanone ou une lactame hautement fonctionnalisee. La premiere synthese a permis de montrer pour la premiere fois que les alkylcetenes sont aussi efficaces que le dichlorocetene dans cette sequence reactionnelle. La deuxieme synthese, quant a elle, ouvre l'application de cette methodologie a la famille des indolizidines tres repandus dans les structures de produits naturels biologiquement actifs.
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Minassian, Frédéric. "Réactions des [epsilon]-pentadiénylation et réactions intramoléculaires de Diels-Alder : synthèse stéréosélective de composés bicycliques." Université Joseph Fourier (Grenoble), 2000. http://www.theses.fr/2000GRE10117.
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Parmi les differents types de composes presentant des activites biologiques interessantes, les molecules possedant au moins un systeme bicyclique constituent une classe importante. Nous avons etudie une strategie de synthese de ces systemes en une etape basee sur une reaction intramoleculaire de diels-alder (ou reaction imda). Cette reaction met en jeu un precurseur lineaire comportant a ses extremites les entites diene et dienophile necessaires. Nous avons donc etudie des voies d'acces a divers precurseurs de ce type. Nous avons d'abord envisage de former des 4-azabicyclo4. 3. 0nonanes, ou indolizidines, par une strategie combinant une reaction de -pentadienylation d'-aminoaldehydes suivie d'une reaction imda entre un diene carbone et un dienophile de type iminium. Cette methodologie a ete exploitee pour synthetiser des precurseurs des myrmicarines 237 et 663. Ces molecules a structures complexes ont ete recemment isolees des glandes a poison de fourmis de type myrmicinae et sont susceptibles de presenter des activites inhibitrices de glycosidases. Dans le cadre de cette etude, nous avons mis au point les conditions convenables pour l'introduction regio et diastereoselective de l'unite dienique. D'autre part la diastereoselectivite de la reaction imda a ete etudiee de maniere approfondie. Dans un deuxieme temps, nous avons envisage de synthetiser des composes bicycliques comportant un atome de soufre. Nous voulions former des analogues d'antibiotiques comme les cephalosporines ainsi que des thiabicyclo4. 4. 0decanes par une reaction imda entre un dienophile de type thioaldehyde et des dienes respectivement azotes et carbones. Ces deux series de travaux ont en commun l'utilisation de precurseurs thiaethanoanthraceniques des thioaldehydes. Dans la premiere serie, un rearrangement inattendu a conduit a l'obtention d'une thienooxepine pontee. Enfin, une nouvelle methode d'obtention rapide des thiabicyclo4. 4. 0decanes par la cascade alperdada a ete mise au point.
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St-Denis, Yves. "Studies toward the synthesis of hydroxylated indolizidine alkaloids." Thesis, McGill University, 1991. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=70343.
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The formation of the indolizidine ring system was studied. First, the intramolecular electrophilic cyclisation of substituted allylsilanes, vinylsilanes and enol ethers was attempted. Reactions with the allylsilane moiety indeed gave the desired ring system, whereas the vinylsilanes failed to give any cyclisation product. In order to easily introduce oxygen functionalities in the rings, enol ether cyclisations were also attempted but did not produce the expected bicyclic systems.Secondly, the intramolecular nucleophilic cyclisation of free amines bearing suitable leaving groups was attempted, providing an easy method for the formation of the indolizidine system, with an interesting entry into the synthesis of biologically active polyhydroxylated alkaloids Swainsonine and Castanospermine. The synthesis of these two natural compounds, as well as some of their analogues, using the successful nucleophilic methodology was attempted.
Finally, the regioselective and stereoselective introduction of hydroxyl groups into the pyrrolidine ring system was studied in order to prepare mono- and di-hydroxylated pyrrolidines for the synthesis of the aforementioned natural products.
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Kefalas, Panagiotis. "Synthèse d'une indolizidine hydroxylée, analogue de la castanospermine." Paris 11, 1988. http://www.theses.fr/1988PA112340.
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Les alcaloïdes indolizidiniques polyhydroxylés comme la swainsonine et la castanospermine ont une activité remarquable vis-à-vis des glycosidases. Nous nous étions fixés comme but, la synthèse de la castanospermine et de ses épimères. Cet alcaloïde a une activité contre le virus du SIDA in vitro et également contre le virus de la grippe. Ces propriétés biologiques permettraient d'envisager une utilisation comme insecticide. Vu la ressemblance de cet alcaloïde et les sucres, il paraît évident d'utiliser des carbohydrates comme produits du départ. Le D-glucose présente une configuration convenable pour les centres C-6, C-7 et C-8 de l'alcaloïde. Dans une première approche de synthèse, nous avons étudié la formation du noyau à cinq chaînons du système indolizidinique en appliquant la chimie des α-aminonitriles sur l'aldéhyde O-1,2-isopropylidène l-α-D-xylo-pentodialdo-furanose-1,4 –issu du D-glucose - de deux façons: soit par formation de l'a-aminonitrile, N-benzylé suivie de l'introduction des carbones C-2 et C-3 par réaction de Grignard sur le nitrile et cyclisation, soit par préparation de l’a-aminonitrile portant les carbones C-2 et C-3 substitués sur la fonction amine et cyclisation. Les difficultés rencontrées au cours de cette voie nous ont contraints à l'abandonner. Dans une deuxième approche, nous avons étudié la formation du noyau indolizidinique polyhydroxylé à partir des dérivés du D-glucose, du D-xylose et du D-arabinose. On introduit les carbones C-1, C-2 et C-3 et l'oxygène en C-1 sous forme d'éther d'énol par réaction de Wittig. Ensuite, on forme une oxazine-1,2-dihydro-3, 6-2H éthoxy-4 par réaction d'hétéro-Diels-Alder avec un diénophile portant la fonction nitroso. Le dérivé du glucose ne répond pas aux conditions requises pour la suite de la synthèse à cause de la sensibilité du noyau furannique au milieu basique de la réaction de Wittig. Les dérivés du D-xylose et du D·arabinose ne portant pas le noyau furannique permettent la poursuite de cette voie. La cyclisation de l'azote de l’oxazine sur le tosylate en position terminale de la chaine d'arabinose fournit un produit bicyclique portant un hydroxyle libre en β de l'azote. En série xylose une réaction concurrentielle de l'hydroxyle secondaire en a du tosylate fournit aussi l'époxyde; cette différence de comportement est due à des effets stériques. La réduction de la double liaison et de la liaison N-O de l’oxazine en série arabinose donnent un δ-aminoalcool. Nous avons tenté trois méthodes de cyclisation déshydratante de cet aminoalcool en utilisant : i) le système PPh₃; NEt₃; CCI4 ii) le complexe de rhodium RhH (PPh₃)₄ iii) le réactif combiné, diéthylazodicarboxylate-triphénylphosphine (réaction de Mitsunobu). Seule la réaction de Mitsunobu a pu fournir le squelette du produit final en série arabinose, la méthode n'ayant pu aboutir pour des raisons stériques quand elle était appliquée au dérivé bicyclique du xylose. On obtient un seul isomère, la(1R,6R,7R,8R,8aS)-éthoxy-1,hydroxy6;O-7,8 isopropylidène, octahydroindolizidine. La réaction de Mitsunobu s'avère stéréosélective puisque l'hydroxyle libre secondaire du noyau à six n'intervient pas à la réactionSeveral attempts for the synthesis of the indolizidinic alkaloid (1S,6S,7R,8R,8aR)-1,6,7,8 tetrahydroxy-octahydroindolizine (castanospermine), a glucosidase inhibitor and of its epimers are described. The general synthetic approach was undertaken starting from sugars that have an established configuration on the carbon atoms corresponding to the C-6, C-7 and C-8 centres of the indolizidinic ring. Ln a first synthetic route we have studied the formation of the alkaloid five-member ring, through the application of α-aminonitrile chemistry on the aldehyde 1,2-O-isopropylidene-α-D-xylo-pentodialdo-1,4-furanose prepared from D-(+)-Glucose; either by formation of the N-benzyl,α-aminonitrile, followed by the introduction of C-2 and C-3 and cyclization, or by the synthesis of the α-aminonitrile carrying C-2 and C-3 substituted on the amine function and ring closure. The difficulties met during this route obliged us to abandon. In a second approach we have studied the formation of the polyhydroxylated indolizidinic ring starting from D-Glucose, D-Xylose and D-Arabinose derivatives; we introduce C-1, C-2 and C-3 and the oxygen on C-1 in the form of an enol ether, by Wittig reaction. Then we form a 1,2-oxazine-3,6- dihydro-2H; 4 ethoxy by Diels-Alder reaction with a dienophile carrying the nitroso function. The glucose derivative does not meet the requirements for the continuation of the synthesis, due to the sensitivity of the furan ring in the basic medium of the Wittig reaction. Cyclization of the oxazine on the tosylated sugar frame supplies a bicyclic product. Reduction of the double bond and the N-O bond of the arabinose series derivative give a δ-aminoalcohol which leads to the (1S,6S,7R,8R,8aS),1-ethoxy,6-hydroxy;7,8-O- isopropylidene octahydroindolizine(ie. A close analog of castanospermine) by dehydrative cyclization. (Mitsunobu reaction). The same reaction sequence could not be used on the bicyclic xylose derivative; the Mitsunobu reaction being inappropriate for steric reasons
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Agarwal, Sameer. "Transition Metal-Mediated Syntheses of Yohimbane and Indolizidine Alkaloids." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2005. http://nbn-resolving.de/urn:nbn:de:swb:14-1119360417222-39155.
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Polycyclic nitrogen containing heterocycles form the basic skeleton of numerous alkaloids and physiologically active drugs. Alloyohimbane was obtained from 3,4-dihydro-â-carboline using an iron-mediated [2+2+1] cycloaddition as the key-step. The bis-TMS-diyne was conveniently obtained by the C-alkylation of 3,4-dihydro-â-carboline followed by N-alkylation. Demetalation of the iron-complex followed by hydrogenation, E-ring expansion, and reduction provided alloyohimbane, a structurally and biologically interesting substance, via a linear eight-step sequence in 7% overall yield based on 3,4-dihydro-â-carboline. Another sequence provided (±)-alloyohimbane and (±)-3-epi-alloyohimbane in nine steps. The pyrrole unit occurs in a variety of naturally occurring compounds, pharmaceutical products and polymers. A novel two-step procedure for the synthesis of pyrroles by addition of a propargyl Grignard reagent to a Schiff base and subsequent silver(I)-promoted oxidative cyclization of the resulting homopropargylamine has been developed. The generality of this reaction was proven by the synthesis of a broad variety of substituted pyrroles using silver(I)-promoted cyclization. A three-step synthesis of (±)-harmicine, a natural product isolated from the Malaysian plant Kopsia griffithii having strong anti-leishmania activity, from 3,4-dihydro-â-carboline is achieved by addition of 3-trimethylsilylpropargyl Grignard reagent, Ag(I)-promoted oxidative cyclization to a pyrrole, and chemoselective hydrogenation of pyrrole ring. Total synthesis of anti-tumor active crispine A and biologically active 1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline have been achieved in three steps using silver(I)-promoted oxidative cyclization as key step.
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Kondakal, Vishnu. "The attempted synthesis of indolizidine and pyrrolizidine natural products." Thesis, University of Huddersfield, 2013. http://eprints.hud.ac.uk/id/eprint/19281/.
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Aza-sugars are naturally occurring polyhydroxylated alkaloids in which the ring oxygen is replaced by nitrogen. They are reported to have a wide range of biological properties, most importantly as glycosidase inhibitors; these glycosidases play a key role in various diseases like HIV, cancer and lysosomal storage disorders. This thesis will describe an approach to the synthesis of analogues and precursors of azasugar natural products in the indolizidine (for example castanospermine) and pyrrolizidine (for example hyacinthacine) using cyclopropenones and cyclic imines as key intermediates. This thesis contains work that is an extension of the work pioneered by Eicher and Heimgartner and followed by our group for the reaction of cyclic imines with diphenylcyclopropenone. The methodology was extended towards the synthesis of more complex bicyclic heterocycles like indolizidine and pyrrolizidine aza-sugars and is summarised by the following Scheme. In this thesis, cyclopropenones other than diphenylcyclopropenone were used. This work also extended the range of cyclic imines that can be reacted by using for the first time, the parent aldimines, polyhydroxylated cyclic aldimines synthesised from sugars and other substituted cyclic imines. The reactions gave bicyclic products but always with an extra oxygen at the bridge head postion (X= OH) via aerial oxidation of the initial product (X= H).
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Szeto, Peter. "Recent development in indolizidine alkaloids : a synthesis of (-)-slaframine." Thesis, University of Bristol, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294850.
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Kefalas, Panagiotis. "Synthèse asymétrique d'une indolizidine hydroxylée, analogue de la castanospermine." Grenoble 2 : ANRT, 1988. http://catalogue.bnf.fr/ark:/12148/cb37614731r.
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Farrant, Elizabeth. "A novel approach to the synthesis of polyhydroxylated indolizidine alkaloids." Thesis, University of Reading, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360718.
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Fox, Martin Edward. "Intramolecular cycloaddition reactions of nitrones and hydroxylamines." Thesis, University of Cambridge, 1992. https://www.repository.cam.ac.uk/handle/1810/272243.
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Santarem, Marco. "Synthèse diastéréosélective d’alcaloïdes tricycliques : la (+)-géphyrotoxine et les myrmicarines (-) 217, (+)-215A et (-)-215B." Paris 6, 2010. http://www.theses.fr/2010PA066738.
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Le motif pyrrolidinique est présent dans un grand nombre de composés naturels et (ou) biologiquement actifs. Les stratégies de synthèse stéréosélective de pyrrolidines sont nombreuses, mais il existe très peu de méthodologies permettant d’accéder à des pyrrolidines cis 2,5-disubstituées fonctionnalisées et énantiopures. Au cours de ce travail, nous avons effectué la synthèse totalement diastéréosélective d’une pyrrolidine cis 2,5-disubstituée énantiopure par réduction stéréocontrôlée d’un β-énaminoester oxazolidinique obtenu par condensation du (S)-phénylglycinol sur un ω-oxo-β-cétoester correctement fonctionnalisé. Ceci nous a permis de réaliser une synthèse formelle efficace de la (+) géphyroxine, alcaloïde tricyclique extrait de la peau d’une grenouille colombienne. Nous avons ensuite mis en place des stratégies générales de synthèse de structures indolizidinique et pyrrolizinique fonctionnalisées. À partir de la même pyrrolidine énantiopure cis 2,5-disubstituée, nous avons ainsi pu accéder diastéréosélectivement à un composé tricyclique, intermédiaire clé dans la synthèse totale des myrmicarines (-)-217, (+)215A et (-)-215B, alcaloïdes extraits du venin de fourmis africaines
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Cuthbertson, James D. "New routes to indolizidine alkaloids : the total synthesis of (-)-grandisine B." Thesis, University of York, 2011. http://etheses.whiterose.ac.uk/1970/.
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The plant family Elaeocarpaceae has been the source of a plethora of structurally related alkaloids isolated over the last 50 years. This Thesis describes our synthetic approaches to (−)-grandisine B I, a bioactive indolizidine alkaloid isolated from Elaocarpus grandis in 2005. An overview of alkaloids isolated from the family Elaeocarpaceae is provided and preliminary studies into the synthesis of grandisine B I are described (Chapters 1 and 2). Novel routes to bicyclic lactams II and isoquinuclidinone frameworks III have been developed using aqueous ammonia in a one-pot amination/cyclisation sequence (Chapters 3 and 4). The scope of the developed methodology was initially demonstrated with a concise synthesis of the alkaloid (−)-mearsine V. A biomimetic synthesis of (±)-grandisine B I, using the alkaloid grandisine D IV as a synthetic precursor, is then described in Chapter 5. The development of a formic acid mediated alkyne/acetal cyclisation for the synthesis of heterocyclic scaffolds is also reported. The scope and limitations of the methodology are discussed and applications of the methodology in the synthesis of (−)-grandisine B I and structurally related Elaeocarpus alkaloids are described (Chapter 6).
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Tumidajski, Stephanie. "[4 + 2] cycloadditions of iminoacetonitriles : synthesis of highly substituted tetrahydropyridines and indolizidine alkaloids." Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/84378.
Full textAbstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2013.Cataloged from PDF version of thesis.
Includes bibliographical references.
Iminoacetonitriles participate as activated imino dienophiles in intermolecular and intramolecular aza Diels-Alder reactions affording tetrahydropyridines and indolizidines. The [alpha]-amino nitrile cycloadducts are versatile synthetic intermediates that participate in a variety of stereoselective transformations to further elaborate the six-membered ring. This thesis describes the scope of the intermolecular [4 + 2] cycloaddition of N-benzyliminoacetonitrile with unactivated and activated dienes, as well as, the synthetic elaboration of the cycloadducts. This thesis also describes the worked performed to complete the total syntheses of indolizidines (-)- 235B', (-)-235B", and (+)-235B" using the aza Diels-Alder reaction of an iminoacetonitrile as the key step.
by Stephanie Tumidajski.
Ph.D.
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Albaladejo, Maricó María José. "Síntesis de Aminas Propargílicas, Indolizinas y Chalconas Catalizadas por Nanopartículas de Cobre Soportadas." Doctoral thesis, Universidad de Alicante, 2014. http://hdl.handle.net/10045/83531.
Full textAbstract:
Las nanopartículas de metales de transición han surgido en los últimos años como una nueva familia de catalizadores capaces de promover eficientemente una gran variedad de reacciones de interés en síntesis orgánica1 debido a las características que poseen, en muchos casos los requisitos que hoy en día demanda la llamada Catálisis Verde,2 y especialmente una elevada relación superficie/volumen.3 La síntesis de nanopartículas por reducción de sales metálicas con metales alcalinos activados ha sido ampliamente desarrollada en esta última década en el Departamento de Química Orgánica de la Universidad de Alicante.4 Estas nanopartículas de diferentes metales se han utilizado en diferentes reacciones de interés en química orgánica tanto en suspensión,4d,5 como soportadas sobre soportes inorgánicos.6 Por lo expuesto anteriormente, en la presente tesis se propuso como objetivo la preparación y caracterización de nanopartículas de cobre soportadas sobre diferentes materiales inorgánicos, y su aplicación como catalizadores en distintas reacciones multicomponente. En primer lugar se abordó la síntesis multicomponente de aminas propargílicas a partir de aldehídos, aminas y alquinos terminales. Se prepararon nanopartículas de cobre sobre diferentes soportes inorgánicos, a partir de litio metálico y un areno (como agente de transferencia electrónica), y se probaron en una reacción modelo, con el fin de optimizar las condiciones de reacción y de reutilizar el catalizador. Las condiciones de reacción optimizadas se utilizaron para la generación de una amplia variedad de aminas propargílicas partiendo de distintos sustratos. Se llevaron a cabo estudios mecanísticos, utilizando para ello diversos tipos de test y reacciones de marcaje isotópico. También se estudió la reacción con cetonas en lugar de con aldehídos. Después se estudió la síntesis multicomponente de indolizinas a partir de derivados de piridin-2-carbaldehído, aminas y alquinos terminales. En este caso se siguió una metodología similar a la anterior, se optimizó el catalizador y las condiciones de reacción tratando de conseguir un proceso lo más eficiente posible. Variando el derivado de piridin-2-carbaldehído, amina y alquino, se prepararon una serie de indolizinas con diferentes sustituyentes. Igualmente, se estudió la reactividad de las indolizinas preparadas en este trabajo. Se comenzó por la transformación de indolizinas en indolizidinas a través de métodos de reducción, incluyendo la hidrogenación catalítica homogénea y heterogénea, y la transferencia de hidrógeno. Se obtuvieron diferentes indolizidinas con excesos diastereoméricos a partir de la hidrogenación catalítica en ácido acético de las indolizinas y utilizando PtO2 como catalizador. También se estudió la reactividad de la indolizina en distintos medios ácidos y básicos, obteniendo en esta parte un procedimiento muy novedoso de transformación de indolizinas 1,3-disustituidas en indolizinas 1,3,7-trisustituidas de mayor complejidad estructural que, por su elevada conjugación, absorben radiación en el espectro visible. Por último se llevó a cabo la síntesis de chalconas a partir de alquinos terminales y aldehídos utilizando como catalizador nanopartículas de cobre soportadas. Al igual que en las síntesis anteriores se optimizaron las condiciones de reacción y se obtuvieron diferentes chalconas, heterocíclicas y no heterocíclicas, con modestos rendimientos y estereoquímica E. Se llevaron a cabo diferentes experimentos para estudiar el mecanismo de reacción. Los catalizadores basados en nanopartículas de cobre soportadas sobre diferentes soportes fueron efectivos para la síntesis de diferentes aminas propargílicas, indolizinas y chalconas, en diferentes condiciones de reacción. Además, se obtuvieron indolizidinas e indolizinas trisustituídas a partir de algunas indolizinas obtenidas en este estudio.
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Muller, Sabine. "Régiochimie de l'attaque de l'indolizine par des réactifs électrophiles :les indolizines portant un groupe capteur en position 2." Doctoral thesis, Universite Libre de Bruxelles, 1997. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/212133.
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Rached, Abdelouahed. "Hétérocycles dérivés de la théophylline, des indolizines, du thiazole, du benzothiazole et du benzimidazole : synthèse et étude pharmacologique." Toulouse, INPT, 1992. http://www.theses.fr/1992INPT055G.
Full textAbstract:
Apres une etude bibliographique des proprietes pharmacologiques et des methodes de synthese de la theophylline, l'auteur dans une premiere partie decrit une douzaine de theophylline originales substituees en 8 le plus souvent par des heterocycles oxygenes. L'etude pharmacologique in vitro a montre pour certains derives une activite superieure a celle de la theophylline. Une etude de modelisation permet d'envisager des composes encore plus actifs. Dans la deuxieme partie, l'auteur s'interesse a des phosphonates a visee inhibitrice calcique a structure voisine d'une theophylline de la premiere partie. Apres une etude bibliograpique de la pharmacomodulation du fostedil, phosphonate inhibiteur calcique, il a obtenu une douzaine de phosphonate originaux greffes sur des structures heterocycliques dont certaines rappellent des nematodicides, comme le levamisole. L'etude pharmacologique de ces composes n'a pas mis en evidence des proprietes inhibitrices calciques par contre certains d'entre eux et notamment les structures tricycliques ont montre une activite non negligeable vis-a-vis des deux nematodes etudies
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Katavic, Peter L., and n/a. "Chemical Investigations of the Alkaloids from the Plants of the Family Elaeocarpaceae." Griffith University. School of Science, 2006. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20070710.160928.
Full textAbstract:
A phytochemical survey to detect alkaloids was performed on extracts of 339 discrete plants parts from a total of 77 species from five genera of Elaeocarpaceae, including 30 species from Queensland, 38 from PNG, and nine from China. An alkaloid detecting reagent, bismuth (III) tetraiodide (Dragendorff's reagent) was used in a preliminary test for alkaloids, with positive ESIMS used to confirm the presence of alkaloids. A total of 35 extracts of various plant parts produced positive results with Dragendorff's reagent. Positive ESIMS detected alkaloids in only 13 of these extracts. Bismuth (III) tetraiodide was demonstrated to produce false positive results with the new non-alkaloidal poly-oxygenated compounds 112 and 113, which were purified from the extract of Sloanea tieghemii. Two new alkaloid producing species, Elaeocarpus habbeniensis, and E. fuscoides were detected from the survey. These species were chemically investigated for the first time. Two other previously investigated species, E. grandis and Peripentadenia mearsii, were also studied. A total of 16 alkaloids, 11 of which are new, were purified from the extracts of these four species. The novel pyrrolidine alkaloids habbenine (114) and peripentonine (123), were isolated from the leaves of E. habbeniensis and Peripentadenia mearsii, respectively. Both of these compounds were purified as inseparable mixtures of diastereomers. The new pyrrolidine alkaloid mearsamine 1 (124), and the novel amino alkaloid mearsamine 2 (125), were also purified from the leaves of P. mearsii. The known pyrrolidine alkaloid peripentadenine (81), was purified from the bark of P. mearsii. Peripentonine (123) was reduced to peripentadenine (81) upon reaction with Pd/C. Four aromatic indolizidine alkaloids were isolated from the extract of the leaves of E. fuscoides. One new compound, elaeocarpenine (122), was isolated from this New Guinean plant. Three known Elaeocarpus alkaloids, isoelaeocarpicine (62), elaeocarpine (60) and isoelaeocarpine (61) were also purified from E. fuscoides. Elaeocarpenine (122) was demonstrated to produce the epimeric compounds elaeocarpine and isoelaeocarpine via reaction with ammonia. The chemical investigation of the Queensland plant E. grandis by two separate purification procedures was performed. An SCX/C18 isolation protocol was used to purify the new indolizidine alkaloids grandisine C (127), D (126), and E (128), in conjunction with the known tetracyclic indolizidine isoelaeocarpiline (63). The second purification of E. grandis was achieved with the use of ammonia in an acid/base partitioning protocol. Grandisine F (129) and G (130), and compounds 131a and b were purified by this procedure, as were 63, 126 and 127. Grandisine F and G were proposed to be ammonia adducts of grandisine D (126). Compound 131a and b were isolated as a mixture of diastereomers. The reduction of grandisine D (126) with Pd/C yielded a mixture of isoelaeocarpine (61) and elaeocarpine (60), whereas the reduction of isoelaeocarpiline (63) produced isoelaeocarpine (61). All of the alkaloids isolated from the Elaeocarpaceae, except grandisine E (128) and 131a and b, were evaluated for binding affinity against the human ? opioid receptor. Every compound except mearsamine 2 (125) possessed a binding affinity of less than 100 ?M. The most active compounds were grandisine F (129), D (126), C (127), elaeocarpenine (122), isoelaeocarpine (61), isoelaeocarpiline (63) and peripentadenine (81). The IC50 values for these compounds were 1.55, 1.65, 14.6, 2.74, 13.6, 9.86 and 11.4 ?M, respectively. The SAR of the active compounds was compared. These observations indicated that the indolizidine alkaloids were more active than the pyrrolidine alkaloids, and a phenol or ketone at position C-12 of the indolizidine alkaloids produced better binding affinity. All of these alkaloids, except 129, were proposed to interact with two of the three binding domains of the ? opioid receptor. Grandisine F (129) was proposed to have a different mode of action than the other alkaloids in the series. Synthetic modifications to isoelaeocarpine (61) and peripentadenine (81) were investigated in an attempt to incorporate an extra aromatic group into these molecules. An extra aromatic group was proposed to provide increased binding affinity to the ? opioid receptor by interaction with the third binding domain of the receptor. Two different aromatic amines were successfully attached to peripentadenine (81) by a reductive amination reaction using NaBH(OAc)3 and a titanium catalyst. The reductive amination of the ketone in isoelaecarpine (61) with various amines and NaBH(OAc)3 or NaBH4 proved unsuccessful.
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González, Rodríguez Julio César. "Síntesis de nuevos alcaloides derivados de Indolizinas análogos de moléculas inhibidoras de microtúbulos en células cancerígenas." Tesis de maestría, Universidad Autónoma del Estado de México, 2020. http://hdl.handle.net/20.500.11799/105463.
Full textAbstract:
Tesis de Grado de MaestríaEl presente trabajo de investigación presenta la síntesis de nuevas moléculas alcaloides derivadas de indolizinas análogas de moléculas inhibidoras de microtúbulos en células cancerígenas, dichos derivados de indolizina fueron obtenidos e identificados como un par de isómeros estructurales en una relación equimolar. El proceso de síntesis del núcleo de la indolizina se llevó a cabo a través de un novedoso proceso tándem aza-Wittig - condensación intramoleculas de imina y substitución electrofílica aromática, a partir del uso de intermediarios iminofosforanos y su reacción con dialdehídos heteroarílicos como el 2,3-tiofendicarboxaldehído. Por su parte, los derivados iminofosforanos fueron obtenidos a partir de la reacción de Staudinger de la correspondiente azida orgánica y su reacción con trifenilfosfina. Finalmente, las azidas orgánicas (materiales de partida), se obtuvieron por una reacción de condensación aldólica entre el azidoacetato de etilo y aldehídos heteroarilicos como el 3-tiofencarboxaldehído, 2-furanocarboxaldehido, 4-bromotiofen-2-carboxaldehido, 4-metiltiofen-2-carboxaldehido, 4-feniltiofen-2-carboxaldehido, 5-feniltiofen-2-carboxaldehido, 5-fenilfuran-2-carboxaldehido y 1-metilpirrol-2-carboxaldehido
Secretaria de Investigación y Estudios Avanzados de la UAEMex, bajo el proyecto No. 4734/2019CIB
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Fellah, Mouloud. "Synthèses diastéréosélectives de l’indolizidine (+)-223A, de la (-)-lasubine II et de la quinolizidine (-)-217A." Paris 6, 2009. http://www.theses.fr/2010PA066034.
Full textAbstract:
Les cycles indolizidiniques et quinolizidiniques sont présents dans de nombreux alcaloïdes ainsi que dans des molécules possédant des activités biologiques intéressantes. La recherche de nouvelles voies d’accès à ce type de composés est donc un enjeu important, le travail effectué au cours de cette thèse s’inscrit dans cette thématique. Notre stratégie de synthèse repose sur les intermédiaires clefs β-énaminoesters pyrrolidiniques et pipéridiniques chiraux dont les réductions diastéréosélectives conduisent respectivement à des pyrrolidines et à des pipéridines fonctionnalisées énantiopures comprenant les premiers centres stéréogènes des alcaloïdes cibles. Les derniers centres asymétriques sont, quant à eux, obtenus par hydrogénation diastéréosélective après aménagement fonctionnel. Cette méthodologie a été adaptée en fonction des alcaloïdes cibles et a ainsi permis de préparer avec de bons rendements et de façon énantiopure trois alcaloïdes : l’indolizidine (+)-223A, (-)-lasubine II et la quinolizidine ( ) 217A
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Katavic, Peter L. "Chemical Investigations of the Alkaloids from the Plants of the Family Elaeocarpaceae." Thesis, Griffith University, 2006. http://hdl.handle.net/10072/367380.
Full textAbstract:
A phytochemical survey to detect alkaloids was performed on extracts of 339 discrete plants parts from a total of 77 species from five genera of Elaeocarpaceae, including 30 species from Queensland, 38 from PNG, and nine from China. An alkaloid detecting reagent, bismuth (III) tetraiodide (Dragendorff's reagent) was used in a preliminary test for alkaloids, with positive ESIMS used to confirm the presence of alkaloids. A total of 35 extracts of various plant parts produced positive results with Dragendorff's reagent. Positive ESIMS detected alkaloids in only 13 of these extracts. Bismuth (III) tetraiodide was demonstrated to produce false positive results with the new non-alkaloidal poly-oxygenated compounds 112 and 113, which were purified from the extract of Sloanea tieghemii. Two new alkaloid producing species, Elaeocarpus habbeniensis, and E. fuscoides were detected from the survey. These species were chemically investigated for the first time. Two other previously investigated species, E. grandis and Peripentadenia mearsii, were also studied. A total of 16 alkaloids, 11 of which are new, were purified from the extracts of these four species. The novel pyrrolidine alkaloids habbenine (114) and peripentonine (123), were isolated from the leaves of E. habbeniensis and Peripentadenia mearsii, respectively. Both of these compounds were purified as inseparable mixtures of diastereomers. The new pyrrolidine alkaloid mearsamine 1 (124), and the novel amino alkaloid mearsamine 2 (125), were also purified from the leaves of P. mearsii. The known pyrrolidine alkaloid peripentadenine (81), was purified from the bark of P. mearsii. Peripentonine (123) was reduced to peripentadenine (81) upon reaction with Pd/C. Four aromatic indolizidine alkaloids were isolated from the extract of the leaves of E. fuscoides. One new compound, elaeocarpenine (122), was isolated from this New Guinean plant. Three known Elaeocarpus alkaloids, isoelaeocarpicine (62), elaeocarpine (60) and isoelaeocarpine (61) were also purified from E. fuscoides. Elaeocarpenine (122) was demonstrated to produce the epimeric compounds elaeocarpine and isoelaeocarpine via reaction with ammonia. The chemical investigation of the Queensland plant E. grandis by two separate purification procedures was performed. An SCX/C18 isolation protocol was used to purify the new indolizidine alkaloids grandisine C (127), D (126), and E (128), in conjunction with the known tetracyclic indolizidine isoelaeocarpiline (63). The second purification of E. grandis was achieved with the use of ammonia in an acid/base partitioning protocol. Grandisine F (129) and G (130), and compounds 131a and b were purified by this procedure, as were 63, 126 and 127. Grandisine F and G were proposed to be ammonia adducts of grandisine D (126). Compound 131a and b were isolated as a mixture of diastereomers. The reduction of grandisine D (126) with Pd/C yielded a mixture of isoelaeocarpine (61) and elaeocarpine (60), whereas the reduction of isoelaeocarpiline (63) produced isoelaeocarpine (61). All of the alkaloids isolated from the Elaeocarpaceae, except grandisine E (128) and 131a and b, were evaluated for binding affinity against the human ? opioid receptor. Every compound except mearsamine 2 (125) possessed a binding affinity of less than 100 ?M. The most active compounds were grandisine F (129), D (126), C (127), elaeocarpenine (122), isoelaeocarpine (61), isoelaeocarpiline (63) and peripentadenine (81). The IC50 values for these compounds were 1.55, 1.65, 14.6, 2.74, 13.6, 9.86 and 11.4 ?M, respectively. The SAR of the active compounds was compared. These observations indicated that the indolizidine alkaloids were more active than the pyrrolidine alkaloids, and a phenol or ketone at position C-12 of the indolizidine alkaloids produced better binding affinity. All of these alkaloids, except 129, were proposed to interact with two of the three binding domains of the ? opioid receptor. Grandisine F (129) was proposed to have a different mode of action than the other alkaloids in the series. Synthetic modifications to isoelaeocarpine (61) and peripentadenine (81) were investigated in an attempt to incorporate an extra aromatic group into these molecules. An extra aromatic group was proposed to provide increased binding affinity to the ? opioid receptor by interaction with the third binding domain of the receptor. Two different aromatic amines were successfully attached to peripentadenine (81) by a reductive amination reaction using NaBH(OAc)3 and a titanium catalyst. The reductive amination of the ketone in isoelaecarpine (61) with various amines and NaBH(OAc)3 or NaBH4 proved unsuccessful.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Science
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Lu, Yuanyuan. "Indolizidine and quinolizidine motifs for the synthesis of conformationally constrained smac mimetics and chloroquine conjugates." Doctoral thesis, Universitat Autònoma de Barcelona, 2014. http://hdl.handle.net/10803/283725.
Full textAbstract:
L’esquelet d’indolizidina o quinolizidina és present a molts productes naturals i sintètics, alguns del quals presenten activitats biològiques diverses. Aquesta tesi es centra en la preparació estereoselectiva de derivats quirals d’indolizidina i quinolizidina amb un doble propòsit: i) com a precursors de peptidomimètics d’Smac conformacionalment limitats i ii) per formar conjugats amb residus de cloroquina a la recerca de nous fàrmacs antimalàrics contra soques resistents.
Pel primer propòsit, s’ha aplicat una aproximació prèviament desenvolupada en el nostre grup per a la síntesi estèreo-controlada d’indolizidines i quinolizidines N-substituïdes. La primera etapa clau de la seqüència és l’al·lilació enantioselectiva de succinimida i glutarimida amb monòxid de butadiè racèmic catalitzada per pal·ladi, on la configuració absoluta del producte al·lilat ve marcada pel sentit de quiralitat del lligand del pal·ladi. Les etapes restants fins als azabicicles fusionats inclogueren la reducció regioselectiva de la imida, una al·lilació nucleòfila i una metàtesi de tancament d’anell (RCM). Eventualment, les configuracions dels intermedis i productes es varen establir mitjançant anàlisi per difracció de raigs X.
Posteriorment, aquesta estratègia es va estendre a substrats del tipus α-amino succinimida i glutarimida. Per a derivats d’indolizidina, la nova seqüència va partir de l’àcid L-aspàrtic, que es convertí en pocs passos en (3S)-3-amino-2,5-pirrolidinodiona. L’al·lilació asimètrica sobre aquest substrat va resultar satisfactòria, conduint a un únic estereoisòmer. S’aconseguí la reducció regioselectiva clau utilitzant DIBAL-H i l’al·lilació nucleòfila i RCM consecutives van portar a l’α-aminoindolizidina esperada, com a una barreja equilibrada de dos epímers, la configuració relativa dels quals es va establir mitjançant experiments de RMN, incloent espectres COSY i NOSY. Els estudis per a obtenir els peptidomimètics d’indolizidina s’estan desenvolupant actualment. Pels anàlegs de tipus α-aminoquinolizidina, es va explorar una seqüència paral·lela a partir de l’àcid L-glutàmic. Malauradament, l’al·lilació asimètrica no va portar al producte esperat i la substitució del lligand del pal·ladi per PPh3 no va resultar prou resolutiva. Els resultats d’alguns intents realitzats amb diferents grups protectors de l’àtom de nitrogen també van ser negatius i s’examinaran més detalladament en un futur.
Pel segon propòsit, es varen considerar dues aproximacions alternatives depenent del caràcter nucleòfil o electròfil de cada reactiu. A tal fi, es van preparar varis azabicicles i derivats de cloroquina nucleòfils i electròfils. Lamentablement, en les reaccions explorades fins ara, els conjugats esperats no van ser mai detectats.The indolizidine and quinolizidine framework is present in many natural and synthetic compounds, some of which display diverse bioactivities. This thesis focuses on the stereoselective preparation of chiral indolizidine and quinolizidine derivatives with a double purpose: i) as precursors of conformationally constrained Smac peptidomimetics and ii) to form conjugates with chloroquine residues, in the search for new antimalarial drugs against resistant strains. For the first purpose, it has been applied an approach previously developed in our group for the stereocontrolled synthesis of N-substituted indolizidines and quinolizidines. The first key step of the sequence is the palladium-catalyzed enantioselective allylation of succinimide and glutarimide with racemic butadiene monoxide, wherein the absolute configuration of the allylated products is controlled by the sense of chirality of the palladium ligand. The next steps to the fused azabicyclic compounds included regioselective reduction of the imide, followed by nucleophilic allylation and then ring closing metathesis (RCM). In the event, the configurations of the intermediates and products were established by X-ray diffraction analysis. This strategy was later on extended to α-amino succinimide and glutarimide substrates. The new sequence for the indolizidine derivatives started from L-aspartic acid, which was converted into a protected (3S)-3-amino-2,5-pyrrolidinedione in a few steps. The asymmetric allylation worked well on this substrate, providing a unique stereoisomer. The key regioselective reduction was achieved by using DIBAL-H, and the subsequent nucleophilic allylation and RCM furnished the expected α-aminoindolizidine as a balanced mixture of two epimers. Their relative and absolute configuration was inferred from NMR experiments, including COSY and NOESY spectra. The conversion of these intermediates into the targeted indolizidine peptidomimetics is currently in progress. For the α-aminoquinolizidine analogs, a parallel sequence starting from L-glutamic acid was explored. Unfortunately, in this case the asymmetric allylation did not furnish the expected product and the replacement of the palladium ligand by PPh3 showed limited assistance. Several attempts with a different nitrogen protection were also negative and will be re-examined in the future. For the second purpose, two alternative approaches were considered depending of the nucleophilic or electrophilic character of each reaction partner. With this aim, several nucleophilic and electrophilic azabicycles and chloroquine derivatives were prepared. Unluckily, in the different reactions explored up to now, the expected conjugate was never detected.
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Bur, Scott Kenneth. "Studies on the vinylogous Mannich reaction and its application to the synthesis of indolizidine natural products /." Digital version:, 2000. http://wwwlib.umi.com/cr/utexas/fullcit?p9992758.
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Bertonha, Ariane Fernandes. "Construção do esqueleto 6-aril indolizidínico a partir de α-clorocetonas derivadas da (S)-prolina: síntese da (S)-desoxiipalbidina." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/75/75133/tde-03072014-144521/.
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A estrutura básica dos alcaloides indolizidínicos é formada por anéis bicíclicos de cinco e seis membros contendo um átomo de nitrogênio compartilhado na posição 4. Esse sistema de anéis possui grande destaque dentre os alcaloides, pois está presente em um grande número de compostos e apresenta um interessante perfil biológico. A ipalbidina, por exemplo, é um alcaloide indolizidínico com propriedades analgésicas e antioxidantes. Este composto possui estrutura química relativamente simples, entretanto, poucas são as rotas que apresentam sínteses curtas e divergentes, sendo apenas quatro delas enantiosseletivas. Assim, este trabalho de dissertação visa o estudo de uma nova estratégia sintética que permite a preparação da (+)-ipalbidina, bem como de outros alcaloides que possuem o sistema 4-azabiciclo[4.3.0]-non-3-eno com um substituinte fenólico na posição 3. Uma rota promitente para a síntese desses alcaloides (objetivo deste trabalho) é a obtenção do esqueleto indolizidínico a partir da reação de ciclização de uma α-clorocetona funcionalizada derivada do (S)-prolinal protegido (Boc e Cbz). As etapas chaves dessa estratégia são: uma reação de olefinação (Wittig), a preparação de α-clorocetonas, adição do grupo aril a α-clorocetona e a conversão destas no esqueleto indolizidínico por uma reação de ciclização. A α-clorocetona pode ser preparada com rendimentos globais de 56% (Cbz) e 81% (Boc) a partir do (S)-prolinal protegido em apenas 3 etapas: reação de olefinação, seguida de uma reação de redução da olefina obtida e a preparação da α-cloroacetona a partir do éster. A adição do grupo aril a α-clorocetona foi obtida tanto para o grupo Boc (40%) quanto para o grupo Cbz (42%). O α-cloroálcool protegido com Boc foi convertido no esqueleto indolizidínico por meio de uma reação \"one-pot\" de desproteção seguida de ciclização (80%). O produto de ciclização, por sua vez, foi convertido ao análogo inédito da (+)-ipalbidina, a (S)-desoxiipalbidina (30%). Essa estratégia levou a síntese da (S)-desoxiipalbidina em 6 etapas e com rendimento global de 8%. Cabe ressaltar que este tipo de abordagem utilizando α-clorocetonas nunca foi empregado na síntese de alcaloides indolizidínicos, sendo que esta estratégia também poderá ser aplicada a síntese total da (+)-ipalbidina e de outros alcaloides indolizidínicos tais como as fenantroindolizidinas.The basic structure of indolizidine alkaloids is formed by a five and sixmembered bicyclic ring containing one nitrogen atom shared at the 4 position. This ring system has great prominence among the alkaloids, it is present in a large number of compounds and possess interesting biological profiles. Ipalbidine, for example, is an indolizidine alkaloid with analgesic and anti-oxidant properties. Although this compound has a relatively simple chemical structure, only four enantioselective synthesis are described for this compound. Thus, this dissertation aims to study a new synthetic strategy that allows the preparation of (+)-ipalbidine, as well as other alkaloids having the system 4- azabicyclo[4.3.0]non-3-ene with a phenolic substituent in position 3. A possible interesting route for the synthesis of these alkaloids is to obtain the indolizidine skeleton from a cyclization reaction using a functionalized α-chloroketone (derivative of protected (S)-prolinal (Boc and Cbz)). The key steps of this strategy are: an olefination reaction (Wittig), the preparation of α-chloroketones, addition of aryl group to the α-chloroketones and converting them into the indolizidine skeleton by a cyclization reaction. The α-chloroketones were prepared with overall yields varying from 56 % (Cbz) to 81% (Boc) starting from protected (S)-prolinal in just three steps: olefination reaction , followed by a reduction reaction of the obtained olefin and preparation of the α-chloroketone from an ester . The addition step of the aryl group to α-chloroketone was obtained for both Boc (40%) and Cbz (42%) groups. The Boc-protected α-chloroalcohol was converted to indolizidine skeleton through an \"one-pot\" deprotection reaction, followed by a cyclization reaction (80 %). The cyclization product, in turn, was converted to the novel (+)-ipalbidine analog, (S)-desoxyipalbidine (30 %). This strategy led to the synthesis of (S)-desoxyipalbidine in 6 steps and overall yield of 8 %. It is noteworthy that this type of approach using α-chloroketones was never employed in the synthesis of indolizidine alkaloids, and that strategy can be applied also to the total synthesis of (+)-ipalbidine and other indolizidine alkaloids such as phenanthroindolizidine.
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Mamouni, Aïcha. "Synthèse et réactivité de pyrrolo(ou pyrido)thiéno[2]azépine diversement fonctionnalisées." Le Havre, 1996. http://www.theses.fr/1996LEHA0010.
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Lors de ce travail, nous avons synthétisé des N-thiénylméthylsuccinimides (ou tétraméthylsuccinimides) dont nous avons étudié la réactivité. Leur réduction conduit aux hydroxylactames qui donnent deux types de réaction selon que le milieu acide est ou basique. Dans le premier cas, nous assistons à la formation d'ions N-acyliminiums ou d'énamidones (formés par réarrangement de Meyer-Schuster). Dans le second cas, nous avons formation du carbonyle masqué qui donne lieu à des réactions de type Wittig. Les produits précédents ont été utilisés dans diverses réactions de cyclisation telles que : 1) - L'attaque d'un ion N-acyliminium sur un système π (aromatique ou oléfinique) ; 2) - le couplage entre un système π (aromatique ou oléfinique) et un dérivé halogéné en présence de palladium (0) ou (II) ; 3) - une réaction de type Friedel et Crafts appliquée aux acides acétiques (ou thioglycoliques) substitués. Les réarrangements de Schmidt et Beckmann, appliqués à nos azépinones et oximes fusionneées à la succinimide, conduisent sélectivement à des dérivées des pyrrolothiéno[1,3]azocines. Par ailleurs, nous avons synthétisé des pyridothiénoazépinones (ou thiénoazocinones) par traitement dans l'acide polyphosphorique à partir des acides N-alkylpipéridine-2-acétiques (ou 2-propanoïques). Nous avons ainsi formé des structures polycycliques incluant le motif pyrrolidinone ou pipéridine fusionné au thiophène par l'intermédiaire d'un cycle comportant 6 à 8 chaînons (azépine, azocine, indolizine, oxazocine, thiazocine,. . . ), avec des hétéroatomes tels que l'oxygène, le soufre et l'azote.
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Sol-Rolland, José. "Les sulfone indolizines : caractérisation et purification de leur site de liaison associé au canal calcique lent voltage-dépendant du muscle squelettique de babouin." Montpellier 2, 1991. http://www.theses.fr/1991MON20097.
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Les sulfone indolizines constituent une nouvelle famille d'antagonistes du calcium destines au traitement des pathologies cardiovasculaires. Le sr trente trois mille cinq cent cinquante sept appartient a cette famille. L'utilisation de ce produit tritie nous a permis de caracteriser son site de liaison sur les membranes de muscle squelettique de babouin. Le choix de cet animal a ete motive par le fait, qu'apparemment, aucun travail concernant les recepteurs chez le babouin n'a ete publie, alors que cette espece est largement utilisee dans les etudes de securite des medicaments. Nous avons montre que le sr trente trois mille cinq cent cinquante sept tritie se lie specifiquement avec une tres haute affinite a un site associe au canal calcique lent voltage-dependant. Ce site est distinct de ceux des trois principales familles d'antagonistes du calcium connues et est couple allosteriquement a leurs recepteurs. Il existe dans un rapport stchiometrique un sur un avec chacun d'eux. Nous avons egalement montre que le canal calcique de type l du muscle squelettique de babouin purifie sur wga-sepharose et heparine-sepharose possede quatre sous-unites dont les poids moleculaires sont proches de ceux des monomeres alpha un, alpha deux, beta et gamma du canal calcique lent des especes animales etudiees par d'autres auteurs. Sa purification devrait permettre d'elucider sa structure primaire
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Outin, Johanne. "Synthèse de composés polycycliques azotés par cyclisation de Vilsmeier-Haack et cyclisation de Mannich organocatalysée en séquence." Thèse, Université de Sherbrooke, 2017. http://hdl.handle.net/11143/10979.
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Les recherches présentées dans cette thèse découlent de problématiques rencontrées lors de précédents travaux effectués dans notre groupe au sujet de cyclisations séquentielles de Vilsmeier-Haack et de Mannich par une activation chimiosélective d’amides. Deux limitations avaient été soulevées : une faible réactivité lors de la seconde cyclisation de Mannich et aucune possibilité d’obtention de produit de double cyclisation de façon énantiosélective.
Au chapitre un, une étude de double cyclisation de Vilsmeier-Haack et de Mannich est présentée, tout d’abord sur des substrats allylsilane-aldéhyde puis vératrol-aldéhyde. Une étude mécanistique est détaillée dans le but d’améliorer le rendement de la réaction. Les bases de notre méthodologie avec l’aldéhyde sont établies dans ce premier chapitre.
Au chapitre deux, une étude de double cyclisation de Vilsmeier-Haack et de Mannich en présence d’une cétone est exposée. Les conditions de première cyclisation sont rapidement déterminées tandis que pour la seconde étape, les divers paramètres pouvant influencer la réaction sont examinés. Aussi, une tentative de formation de centres quaternaires produisant des squelettes carbonés de type quinolizidine et spirocyclique est présentée, ainsi qu’une variation de tailles de cycles formés.
Au chapitre trois, l’étendue de notre méthodologie est étudiée et celle-ci est appliquée sur divers substrats. Les nucléophiles de type indole, pyrrole, éther d’énol et allylsilane sont couverts et la variation de taille de cycle est également testée.
Au chapitre quatre, une étude sur le développement catalytique et un effort vers une version non racémique de notre méthodologie sera présentée. Diverses amines secondaires chirales sont investiguées et les excès énantiomériques mesurés.
Le chapitre cinq propose des suites au projet de thèse, incluant des pistes au sujet de l’induction asymétrique en s’appuyant sur des exemples concrets de la littérature.
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Davis, Jonathan C. "Section one : photochemical methodologies towards the pyrrolizidine and indolizidine alkaloid skeleta; section two; synthesis of novel leukotriene photoaffinity labels." Thesis, University of Reading, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360717.
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CHALARD, PIERRE. "Cyclisation d'allylsilanes chiraux sur des ions n-acyliminium. Syntheses totales enantioselectives des ()-lasubines i et ii, (+)-subcosine ii et ()-indolizidine 167b." Clermont-Ferrand 2, 1999. http://www.theses.fr/1999CLF22093.
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Les alcaloides bicycliques a squelettes quinolizidine et indolizidine constituent une classe de composes tres importante, qui presentent pour la plupart de nombreuses activites biologiques. Nous avons developpe une nouvelle methode de synthese asymetrique de ces alcaloides basee sur la cyclisation intramoleculaire d'un allylsilane sur un ion n-acyliminium chiral. Les synthons de depart sont des -aminoesters chiraux obtenus par une reaction de michael enantioselective du lithien de l'-methylbenzylbenzylamine sur un ester ,-ethylenique. Ces synthons sont condenses sur l'anhydride glutarique ou succinique qui servent a edifier le premier cycle du squelette. L'allylsilane est prepare in situ a partir de la fonction ester. Sa cyclisation sur l'ion n-acyliminium conduit aux squelettes quinolizidine et indolizidine avec une bonne diastereoselectivite. Les amenagements fonctionnels ulterieurs permettent la synthese des quinolizidines et indolizidines naturelles. Cette methode a ete appliquee a la synthese de trois alcaloides a squelette quinolizidine : les ()-lasubines i et ii, obtenues en 6 etapes avec des rendements respectifs de 7% et 14%, et la (+)-subcosine ii, obtenue en 7 etapes avec un rendement global de 9%. Ce sont les premieres syntheses asymetriques de la ()-lasubine ii et de la (+)-subcosine ii decrites a ce jour. Nous avons egalement prepare un alcaloide a squelette indolizidine, la ()-indolizidine 167b, en 7 etapes avec un rendement global de 17%. Les alcaloides sont obtenus avec des exces enantiomeriques superieurs a 90%. Cette methode est suffisamment generale pour etre appliquee a la synthese d'une grande variete d'alcaloides bicycliques.
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Kauloorkar, S. V. "Synthetic studies towards biologically active compounds containing indolizidine , pyrrolizidine quinolizidine and lactone moieties employing asymmetric dihdroxylation and proline catalyzed organic transformations." Thesis(Ph.D.), CSIR-National Chemical Laboratory, Pune, 2016. http://dspace.ncl.res.in:8080/xmlui/handle/20.500.12252/5967.
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Kauloorkar, S. V. "Synthetic studies towards biologically active compounds containing indolizidine , pyrrolizidine quinolizidine and lactone moieties employing asymmetric dihdroxylation and proline catalyzed organic transformations." Thesis(Ph.D.), CSIR-National Chemical Laboratory, Pune, 2016. http://dspace.ncl.res.in:8080/xmlui/handle/20.500.12252/2081.
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Pinho, Vagner Dantas. "Abordagens divergentes na preparação de alcaloides indolizidínicos." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/75/75133/tde-30072013-093827/.
Full textAbstract:
O presente trabalho descreve 3 abordagens divergentes para obtenção do esqueleto bicíclico presente nos alcaloides indolizidínicos. A primeira abordagem consiste no desenvolvimento de um novo método de preparação de diazocetonas α,β-insaturadas a partir da reação de Horner-Wadsworth-Emmons (HWE) entre diazofosfonato e aldeídos. As dizocetonas α,β-insaturadas obtidas foram utilizadas como bloco de construção do esqueleto cabocíclico indolizidínico, onde o intermediário chave foi obtido através do rearranjo de Wolff. A segunda estratégia consiste no desenvolvimento do acoplamento redutivo entre derivados α-aminocarbonílicos e acrilato de metila mediado por SmI2, onde em apenas duas etapas foram obtidos os intermediários avançados da síntese da (-)-pumiliotoxina 251D e da (+/-)-epiquinamida. A terceira estratégia utiliza como etapa chave a reação de Wittig/HWE intramolecular para preparação do intermediário bicíclico contendo o sistema α,β-insaturado que pode ser utilizado na síntese divergente dessas substâncias.Herein were described three diverted oriented approaches for the construction of the bicyclic scaffold of indolizidines alkaloids, that figures between one of the most important classes of natural products. In the first approach, a new method to prepare α,β - unsaturated diazoketones was described using the Horner-Wadsworth-Emmons (HWE) reaction between diazophosphonate and aldehydes. The unsaturated diazoketones were used as powerful plataforms to construct the indolizidine carbocyclic scaffold, enploying the Wolff rearrangement as the key step. The second approach was the development of a reductive coupling between α-aminocarbonyl derivatives and methyl acrylate, mediate by SmI2, from this approach, the well-known advanced intermediate for the synthesis of (-)-pumiliotoxin 251D e of the (+/-)-epiquinamide was obtained in only two steps. The third approach uses the intermolecular Wittig/HWE reaction as the key step in the construction of a bicyclic intermediate containing an α,β -unsaturated moiety that could be used for a diverted oriented approach in the indolizidine alkaloids synthesis.