Dissertations / Theses on the topic 'Quinine alkaloids'

Chiral alpha-branched amines are common substructures of bioactive synthetic targets such as alkaloids and amino acids. Direct asymmetric amine synthesis by addition to the C=N bond of carbonyl imino derivatives is promising and efficient to introduce the stereogenic center and carbon-carbon bond in one step. Furthermore, disconnection of either C-C bond at the amine stereogenic center would be the most versatile method to achieve this objective; we could make the choice depending on the different synthetic strategies, such as the availability of precursors and the presence of complicating structural features. In our group, we disclosed that manganese carbonyl mediates stereoselective photolytic radical addition of alkyl iodides to chiral imino acceptors, which is a powerful tool to form a new C-C bond and generate a chiral center. Qualitative mechanistic studies confirm the importance of free radicals, imply that this is a nonchain (or short chain length) free-radical process, and reveal that organomanganese compounds are not a viable source of alkyl radical for the addition reactions under the conditions in our lab. In my thesis, we have extended the application of our methodology. At the beginning of my research, our Mn-mediated addition methodology was first applied to accomplish the couplings of iodides and ketone N-acylhydrazones, generating quaternary carbon stereocenters and offering access to a variety of alpha-alkylated alanine analogs. These radical additions complement enolate alkylation methodologies, as they occur under nonbasic conditions and permit introduction of both primary and secondary alkyl groups with relative ease. The versatility with respect to the iodide is a distinguishing feature of the Mn-mediated coupling that foreshadows application to more complex targets. Secondly, a Mn-mediated radical-ionic annulation strategy was validated as a synthetic route to quinine. Intermolecular radical addition to C=N bonds has rarely been applied as a strategic bond construction in natural product synthesis; this synthesis of quinine offers the strongest demonstration yet of the utility of such reactions in application toward complex multifunctional targets.

Les travaux réalisés pendant cette thèse ont porté sur deux thématiques indépendantes.Les deux premières parties concernent la thématique " alcaloïdes de Vinca ", molécules d'origine naturelle aux propriétés anticancéreuses. Les travaux ont tout d'abord porté sur la synthèse d'analogues oxygénés de la 20,20-difluorocatharanthine, comme précurseurs d'alcaloïdes dimères originaux de Vinca. Bien que les voies de synthèses explorées n'aient pas conduit aux dérivés oxygénés souhaités, les différents résultats obtenus ont cependant permis de montrer que la présence du groupement gem-difluoré sur le squelette de la catharanthine changeait dramatiquement la réactivité du substrat de manière imprévisible. La deuxième partie de ce travail a été dédiée à l'élucidation du mécanisme de fluoration d'alcaloïdes dimères de Vinca en milieu superacide. Le marquage isotopique au deutérium a permis de discriminer deux hypothèses mécanistiques et de valider le mécanisme de fluoration passant par une migration 1,2 d'hydrure dont la contribution minimale est de 20 %. Enfin, la troisième partie de ce travail a été consacrée à la synthèse asymétrique de la (R)-méquitazine. La synthèse de cette dernière s'est basée sur la chiralité déjà " imprimée " dans le squelette d'alcaloïdes de cinchona. La synthèse de la (R)-méquitazine dont les excès énantiomériques finaux sont supérieurs à 99% a été conclue en 8 étapes à partir de la quinine, confirmant le contrôle total du centre asymétrique tout au long de la synthèse.

Plasmachemical processes are one of the methods used for wastewater treatment. Sewage and household wastewaters include a variety of organic substances that must be removed to reuse water in industry or households. The aim of this diploma thesisisthe observation of alkaloids decomposition by plasma chemical process. The theoretical part is focused on plasma generation in liquids and characterization of selected alkaloids. The decomposition of caffeine and quinine in direct current electrical discharge in liquid with diaphragm configuration is investigated in this work. The experiments were carried out in a batch reactor divided into two parts by a diaphragm made from ceramic material ShapalTM-M (thickness 3.0 mm, pin-hole diameter 1.0 mm). The stainless steel electrodes of 5×12 cm size were used. The mean electric power was set to 135 W for an operation time of 60 minutes in each experiment. Caffeine solutions (total volume of 4 L) were prepared in concentrations of 10, 25 and 50 ppm, quinine solutions in concentrations of 5, 10 and 15 ppm. The initial conductivity was adjusted by sodium chloride at three different values – 400, 750 or 1000 µS•cm-1. The experimental part consisted also of using analytical methods necessary for compound quantification. Hydrogen peroxide formation during the electrical discharge was determined by colorimetric method based on generation of yellow complex with titanium(IV) sulfate reagent. The caffeine concentration was measured by UV spectrometric method at wavelength 273 nmand thenHPLC/MS analysis was performed. Quinine degradation was monitored by UV-VIS spectrometry and fluorescent measurements. The plasma generation in water solutions induces formation of hydroxyl radical, hydrogen peroxide, oxygen, hydrogen and other reactive species. Hydrogen peroxide is produced and then utilized in degradation of organic compounds and thus lower concentration of H2O2was measured in solution with caffeine and quinine than in solution without alkaloids. However, the situation is different between cathode chamber and anode chamber. There is only negligible amount of H2O2used on degradation in cathode chamber. In contrary, the considerable degradation of caffeine and quinine and diminished concentration of H2O2 was observed in anode chamber.

Thesis (Ph. D.)--West Virginia University, 2005.
Title from document title page. Document formatted into pages; contains xvii, 207 p. : ill. Includes abstract. Includes bibliographical references (p. 97-101).

Die Ziele dieser Arbeit waren die Darstellung der Naturstoffe Murrayachinon-B–E und Pyrayachinon-A–C, sowie die Synthese einiger nicht natürlicher, potentiell anti-Tuberkulose-aktiver Carbazole und Carbazolchinone. Für die Darstellung der aus der Pflanze Murraya euchrestifolia Hayata isolierten Naturstoffe wurden verschiedene synthetische Herangehensweisen untersucht: Die Transformation eines 7 Hydroxycarbazolchinons in die Zielverbindungen gelang nicht, ebenso wie die Syntheseroute über eine trioxygenierte Vorstufe. 7-Methoxy-3-methyl-1-tosyloxycarbazol (A) ließ sich jedoch in einer Ausbeute von 76 % über drei Stufen darstellen. Ausgehend von A konnten die Zielverbindungen regioselektiv in fünf bis sieben Stufen in Gesamtausbeuten von 10 % bis 46 % synthetisiert werden. Der Pyranring in Pyrayachinon-A wurde dabei über eine Sequenz aus Bromierung, Prenylierung, Cyclisierung und Oxidation aufgebaut. Die Anellierung der Pyranringe in Pyrayachinon-B und –C erfolgte, nach Methyletherspaltung an A in zwei Stufen. Die Einführung der Prenyl- und Geranylgruppen für die Synthese der Murrayachinone gelang durch reduktive Pyranringöffnung bzw. über eine Sequenz aus Methyletherspaltung, Propargylierung, partieller Hydrierung und Umlagerung. Außerdem wurde für Murrayafolin-B, Bismurrayafolin-B und -D über diese Syntheseroute ein Zugang geschaffen. Diese Verbindungen konnten, ausgehend von A, in sechs bzw. sieben Stufen in Gesamtausbeuten von 39 % bis 53 % dargestellt werden. Im Vergleich zu den bislang beschriebenen Synthesen dieser Verbindungen konnten alle Gesamtausbeuten signifikant gesteigert werden. Besonders hervorzuheben sind die Synthesen von Murrayafolin-B (bislang: 0.4 %, in dieser Arbeit: 40.0 %) und Pyrayachinon-A (bislang: 3.0 %, in dieser Arbeit: 22.1 %). Überdies wurde erstmalig die palladiumkatalysierte oxidative Cyclisierung eines O-tosylgeschützten Diarylamins zu einem Carbazol beschrieben. In Fortführung vorangegangener Arbeiten wurden zehn bislang nicht beschriebene Derivate des anti-Tuberkulose-aktiven 3-Methoxy-2-methylcarbazol-1,4-chinons dargestellt, darunter neun Carbazolchinone und ein Carbazol. Die Synthese der Carbazolchinone gelang palladiumkatalysiert in je vier bis sechs Stufen. Das Carbazol wurde eisenvermittelt über fünf Stufen dargestellt. Die Untersuchung der Aktivität gegenüber Mycobacterium tuberculosis steht noch aus.

Ce travail vise à comprendre l’effet de la chiralité sur la structure et la photoréactivité de biomolécules, isolées en phase gazeuse. Pour cela, nous combinons des méthodes de spectroscopie laser couplées à la spectrométrie de masse avec des calculs de chimie quantique. La comparaison entre spectres expérimentaux et simulés permet de déterminer la structure des espèces étudiées et de comprendre leur photoréactivité. La première partie étudie la différence de structure entre les deux diastéréoisomères d’un dipeptide cyclique (cyclo Tyr-Tyr). Une seule forme est observée quand les deux résidus tyrosine n’ont pas la même chiralité. Dans cette structure, un des cycles aromatiques est replié sur le cycle peptidique et l’autre est étendu à l’extérieur. Dans le stéréoisomère où les deux résidus ont la même chiralité, cette forme coexiste avec une autre, dans laquelle les deux cycles aromatiques interagissent par une liaison hydrogène. La deuxième partie concerne la structure et la nature des états excités de complexes d’alcaloïdes dérivés de la quinine avec l’acide sulfurique. Les complexes sont formés par l’ajout de l’ion bisulfate sur l’alcaloïde doublement protoné. L’ion bisulfate protège l’alcaloïde de la photodissociation UV grâce à un effet de cage, qui est identique pour la quinine et son pseudoénantiomère la quinidine
This thesis aims at understanding chirality effects on the structure and photoreactivity of biomolecules in the gas phase by combining laser spectroscopy coupled to mass spectrometry and quantum chemical calculations. Comparison between experimental and simulated spectra allows determining the structure of the species under study and understanding their photoreactivity. The first part of this work focuses on the structural differences between the two diastereoisomers of a cyclic dipeptide, cyclo Tyr-Tyr. Only one form is observed when the two residues have different chirality. In this form, one of the aromatic rings is folded over the dipeptide ring and the other one is extended outwards. For the diastereomer with residues of identical chirality, this form coexists with a structure in which the two aromatic rings are in a stacked position, stabilized by hydrogen bond formation. The second part of this thesis deals with the structure and the nature of the excited states of complexes of cinchona alkaloids with sulfuric acid. An important finding is that the complexes are formed by adding the bisulfate ions to doubly-protonated alkaloid. The presence of the bisulfate ion has a protective effect towards photodissociation thanks to the cage effect, which is identical for quinine and its pseudo enantiomer quinidine

The work described in this thesis deals with the development of the asymmetric organocatalytic conjugate addition reaction of 1,3-dicarbonyl compounds to ortho-quinone methides. Due to their instability, these synthetically appealing intermediates have not been fully exploited in catalytic asymmetric settings. In this work, the instability of ortho-quinone methides is overcome by their generation in situ under mild basic conditions, starting from the corresponding sulfonyl derivatives. The bifunctional catalysts used are able to activate both substrates for the reaction, by means of a synergic action of the two catalytic sites, inducing at the same time high enantioselection in the addition step. The reaction leads to the generation of a 2-alkylphenolic framework, featuring a chiral centre at the benzylic position. In particular, the employment of acetylacetone and Meldrum acid as nucleophiles has allowed the obtainment of 4H-chromenes and chroman-2-ones in good yields and generally excellent enantioselectivities. These compounds are synthetic precursors of several natural products, some of which showing interesting biological activity, and of some active pharmaceutical ingredients used in commercial drugs.

While the molecular defect that cause sickle cell disease has well been established, the cause of vaso-occlusive crisis remains elusive and largely debated upon. Majority of studies have linked the painful episodes to polymerization of sickle hemoglobin following its deoxygenation. The variability of the disease symptoms among patients, compounds efforts for a holistic therapy. Hydroxyurea, a stimulator of Hb F induction and a widely used treatment, has ameliorated the complication of SCD but it is only effective in 50% of the patients. Expression of Hb F lowers the content of Hb S in blood and hence reduces oxidative stress caused by Hb S denaturation. Sickle cell disease severity depends on several factors. Most importantly, the ability of red cell to sickle dominates all other determinants. While deoxygenation of sickle hemoglobin may be inevitable, the duration with which the red cell remains in the deoxygenated state can be manipulated. Deoxygenation is a transient process that when compared to the time taken to develop the long filaments of deoxyhemoglobin to causes severe sickling, the red cell would have been cycled back to the lungs and re-oxygenated to restore the healthy conditions of the cell. In fact, if sickle cells would flow as fast as healthy erythrocytes, the detrimental impacts of sickling such as vaso-occlusive crisis, would not be a concern for this disease. Unfortunately, the unstable sickle hemoglobin undergoes denaturation through auto-oxidation, which imposes oxidative stress to the cells. The oxidative stress inhibits erythrocytes tyrosine phosphatases, a course which subsequently impair their constitutive action against the tyrosine kinases. In the end, a net tyrosine phosphorylation state in the red cell membrane proteins, most notably the transmembrane protein band 3, succeeds. Band 3 tyrosine phosphorylation abrogates the protein’s interaction with ankyrin and spectrin-actin cytoskeleton, hence the cytoskeleton loses its major anchorage to the membrane thus engendering membrane destabilization. A destabilized erythrocyte sheds membrane fragments in form of microvesicles/microparticles and discharges free hemoglobin into the extra cellular matrix. In consequence, the microparticles power initiation of coagulation cascade through activation of thrombin, while free Hb inflicts inflammation, scavenges nitric oxide which is necessary for vasodilation and induces further oxidative stress within the microvasculature, and activates expression of adhesion receptors on the endothelium. Taken together, these events culminate in entrapment of red cells (not naming leucocytes and platelets) in the microvasculature, blockade of blood vessels and further damage of erythrocytes through prolonged deoxygenated state thus terminating in tissue injury, strokes, and organ damage, amid vaso-occlusive episodes which always require hospitalization and extensive medical care for survival. Band 3 tyrosine phosphorylation and membrane weakening is not unique just to SCD, but also a druggable target for malaria. Malaria, a disease that is touted as the evolutionary cause of sickle cell disease, surprisingly thrives through the same mechanism. Briefly, malaria parasite consumes hemoglobin for its DNA synthesis, and in the process generate reactive oxygen species from denatured hemoglobin that feeds into the oxidative stress which triggers band 3 tyrosine phosphorylation. In this case however, a destabilized membrane offers perfect conditions for merozoites’ (malaria daughter parasites) egress/exit out of the cell to begin infecting other red cells. Ultimately, the ensuing anemia and organ dysfunction leads to patient’s death. Treatment of diseased cells with imatinib and other Syk inhibitors effectively reversed membrane weakening. A stabilized membrane not only survives longer in circulation to alleviate SCD symptoms but also traps and starves malaria parasite leading to termination of the parasitic infection. With band 3 tyrosine phosphorylation at center stage, this dissertation explores the above events in an effort to unveil a novel therapy for sickle cell and malaria diseases. First, the therapeutic strategy regarding SCD is discussed in detail beginning with non-transfused patients and ending in additional mechanistic study on inactivation of the principal erythrocyte’s protein tyrosine phosphatase 1 B, PTP1B. The dissertation then provides an initial proof of concept on efficacy of imatinib in treatment of malaria as a monotherapy and its efficacy when used in a triple combination therapy with the standard of care treatment. Finally, I outline an alternative possible mechanism of action of quinine against malaria.

Cylindricines A-K [1-11], lepadifonnine [12] and fasicularin [13] are tricyclic ascidian alkaloids exhibiting the perhydropyrrolo[2,1 :j]quinoline and perhydropyrido[2,1-j]quinoline ring systems. The structural features and biological activity of these alkaloids make them ideal targets for total synthesis. The first aim of this project was to construct the azabicycles [111] and [112] that resemble the spirocyclic core of these alkaloids. The synthesis began with the C ring intact and the attempted construction of the B ring using Diels-Alder methodology. A key step was the Eschenmoser coupling reaction between thiolactams [105] and [106] to give the vinylogous amides [107] and [108]. All attempts to convert the vinylogous amides to the corresponding dienes proved to be unsuccessful, due to the fact that the preferred site for deprotonation was ~ to nitrogen and not a to the carbonyl group. Due to time constraints we moved to our second aim, the enantioselective synthesis of the B and C rings offasicularin [13]. Significant progress was made towards our second goal. (5S)-5-Hydroxytetrahydro2(lH)pyridinone [127], which represents the C ring of fasicularin, was successfully synthesized in 5 steps from L-glutamic acid [113]. This lactam was O-protected with tertbutyldiphenylsilyl group to afford (5S)-5-tert-butyldiphenylsilyloxy-2-piperidinone [114]. Thionation of lactam [114] gave the thiolactam [160]. Conjugate addition of this thiolactam to methyl acrylate gave methyl 3-[(5S)-5- {[tert-butyl(diphenyl)silyl]oxy}-2-thioxotetrahydro1(2H)-pyridinyl ]propanoate [163], which underwent a Eschenmoser coupling reaction with bromoacetone to gIve methyl 3-[(5S)-5-{ [tert-butyl(diphenyl)-silyl]oxy} 2-[(£)-2oxopropylidine] tetrahydro-2(1H)-pyridinyl]propanoate [164]. Unfortunately conversion of [164] into the corresponding diene using KHMDS and TBSCI was unsuccessful. The reaction conditions caused the cleavage of the methyl acrylate protecting group on nitrogen, affording the secondary E-vinylogous amide [167]. This constituted an important serendipitous discovery - methyl acrylate can be used to protect the nitrogen atom of enaminones and can be removed by KHMDS to access secondary E-enaminones that are otherwise difficult to synthesise. Another route pursued was to introduce the hexyl chain in the A ring of fasicularin by means of an SN2 reaction between lactam [114] and mesylate [116]. The stereodefined (lR)1-(2-{[tert-butyl-(dimethyl)sily]oxy}ethyl)heptyl methanesulfonate [116] was successfully x synthesized in 5 steps from l-octyne [115]. Unfortunately the subsequent SN2 reaction with lactam [114] failed when we using t-BuOK and THF and time constraints prevented us from attempting this coupling reaction using alternative conditions.
Thesis (M.Sc.)-University of Natal, Pietermaritzburg, 2002.

Die Ziele dieser Arbeit waren die Darstellung der Naturstoffe Murrayachinon-B–E und Pyrayachinon-A–C, sowie die Synthese einiger nicht natürlicher, potentiell anti-Tuberkulose-aktiver Carbazole und Carbazolchinone. Für die Darstellung der aus der Pflanze Murraya euchrestifolia Hayata isolierten Naturstoffe wurden verschiedene synthetische Herangehensweisen untersucht: Die Transformation eines 7 Hydroxycarbazolchinons in die Zielverbindungen gelang nicht, ebenso wie die Syntheseroute über eine trioxygenierte Vorstufe. 7-Methoxy-3-methyl-1-tosyloxycarbazol (A) ließ sich jedoch in einer Ausbeute von 76 % über drei Stufen darstellen. Ausgehend von A konnten die Zielverbindungen regioselektiv in fünf bis sieben Stufen in Gesamtausbeuten von 10 % bis 46 % synthetisiert werden. Der Pyranring in Pyrayachinon-A wurde dabei über eine Sequenz aus Bromierung, Prenylierung, Cyclisierung und Oxidation aufgebaut. Die Anellierung der Pyranringe in Pyrayachinon-B und –C erfolgte, nach Methyletherspaltung an A in zwei Stufen. Die Einführung der Prenyl- und Geranylgruppen für die Synthese der Murrayachinone gelang durch reduktive Pyranringöffnung bzw. über eine Sequenz aus Methyletherspaltung, Propargylierung, partieller Hydrierung und Umlagerung. Außerdem wurde für Murrayafolin-B, Bismurrayafolin-B und -D über diese Syntheseroute ein Zugang geschaffen. Diese Verbindungen konnten, ausgehend von A, in sechs bzw. sieben Stufen in Gesamtausbeuten von 39 % bis 53 % dargestellt werden. Im Vergleich zu den bislang beschriebenen Synthesen dieser Verbindungen konnten alle Gesamtausbeuten signifikant gesteigert werden. Besonders hervorzuheben sind die Synthesen von Murrayafolin-B (bislang: 0.4 %, in dieser Arbeit: 40.0 %) und Pyrayachinon-A (bislang: 3.0 %, in dieser Arbeit: 22.1 %). Überdies wurde erstmalig die palladiumkatalysierte oxidative Cyclisierung eines O-tosylgeschützten Diarylamins zu einem Carbazol beschrieben. In Fortführung vorangegangener Arbeiten wurden zehn bislang nicht beschriebene Derivate des anti-Tuberkulose-aktiven 3-Methoxy-2-methylcarbazol-1,4-chinons dargestellt, darunter neun Carbazolchinone und ein Carbazol. Die Synthese der Carbazolchinone gelang palladiumkatalysiert in je vier bis sechs Stufen. Das Carbazol wurde eisenvermittelt über fünf Stufen dargestellt. Die Untersuchung der Aktivität gegenüber Mycobacterium tuberculosis steht noch aus.