Part I: Compounds of the type benzo(group VI)azole (I) were treated with diborane using standard vacuum line techniques. The group VI elements were oxygen. sulfur. and selenium. Initially. an insoluble borane adduct formed which spontaneously reduced and replaced carbon in the hetero-ring by boron via an unstable intermediate either (II) or (III). For example. benzoxazole reacted to produce 2-H-3-methyl-l.3.2- benzoxazaborole (IV). The 2-H-3-alkyl-l,3.2-benzo(group VI)azaboroles (V) were easily purified. produced in high yield, and upon methanolysis yielded N-alkyl-2-(group VI)anilines (VI). These boroles were characterized by IR, H-l and B-ll NMR spectra, and mass spectroscopy. Part II: Kinetics of the polymerization of imidazole-borane in the presence of diborane was followed by monitoring hydrogen production at 30°C. Pseudo first-order kinetics was observed at all ratios of diborane to irnidazole-borane, and the observed rate constant increased linearly with excess diborane. A mechanism is proposed in which the diborane acts as a catalyst. Half the hydrogen molecule comes from the diborane, while the other half comes from the nitrogen-bonded hydrogen on imidazole-borane. Hydrogen is formed when diborane reacts with imidazole-borane in a slow step. followed by fast coupling with another imidazole-borane and regeneration of diborane. The structure of the polymer is shown below (VII). and the average size of the polyme1 was 32-38 units.

Imidazo[1,5-a]pyridines are an important and versatile class of N-heterocyclic compounds due to their stability, unique biological, and photochemical properties. Due to the conjugation and charged structure, their properties are extended to conducting electricity and also have electronic properties. They can be used for chelating transition metals especially heavy metals that can be harmful to living things (including human). The aim of this research was to develop more useful imidazo[1,5-a]pyridines which are stable in both free and complexed state. A variety of imidazo[1,5-a]pyridyl compounds was synthesized following three useful methods namely (i) The first route includes the isolation of imine intermediates which were then treated with phosphorus oxychloride in one case and hydrochloric acid in another case as catalysts. Both cases resulted in the yield of the same imidazo[1,5-a]pyridyl compounds. (ii) The second route was the development on the first route for those imine intermediates that could not be isolated and only hydrochloric acid catalyst was used. In both the first and second routes, paraformaldehyde was used for the ringclosure step of the reaction. The last route for the formation of imidazo[1,5-a]pyridyl compounds did not involve the use of the paraformaldehyde reagent. The suitable routes were followed depending on the nature of the targeted products and the reaction yields were moderate to excellent. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg,2010.

Nature provides fascinating and complicated molecular structures which offer synthetic organic chemists amazing opportunities for the design of new strategies for natural product synthesis. Among these, nitrogen containing aza-heterocycles are of unparalleled importance in natural product, bioorganic, and medicinal chemistry. Pyridine and its derivatives in particular are the most common aza-heterocycles encountered in natural products, medicinal and materials chemistry. Pyridine derivatives also serve as precursors to functionalized piperidines, which are likewise common structural motifs in bioactive and functionalized materials. Thus, developing synthetic methods suitable for the manipulation of pyridine ring systems remains an important objective in synthetic organic chemistry. The functionalization of pyridine derivatives via manipulation at the benzylic position has been investigated. First, the nucleophilicity of the benzylic position of the 4-alkyl pyridine substrates was used to engage in Brønsted acid-catalyzed aldol-like cyclizations with attached carbonyl electrophiles. These conditions afforded substituted pyridines with functionalized lactams. These substrates underwent an unusual dehydration/oxidation reaction when treated with thionyl chloride. In a similar study, 1,2-dialkylimidazoles afforded nucleophilic 2-alkylidene imidazolines upon treatment with an electrophilic activating group such as Boc2O. Positioning a ketone electrophile with in an N1-alkyl side chain results in cyclization at the imidazole 2-position to afford fused ring imidazoles through an aldol-like cyclization reaction. The stereoselective synthesis of a tricyclic analogue of the bis(piperidine) alkaloid xestoproxamine C was also investigated. Dearomatization of a tricyclic pyridine derivative afforded an alkylidene dihydropyridine (anhydrobase) intermediate which was subjected to catalytic heterogeneous hydrogenation to install the correct relative stereochemistry about the bis(piperidine) ring system. Other key features of these model studies included development of an efficient ring-closing metathesis procedure to prepare macrocyclic derivatives of 3,4-disusbstituted pyridines, intramolecular cyclizations of alkylidene dihydropyridines to establish pyridine-substituted pyrrolidines and piperidines, successful homologation of pyridine-4-carboxaldehydes using formaldehyde dimethyl thioacetal monoxide (FAMSO), and application of B-alkyl Suzuki coupling to assemble substituted pyridines. Lastly, a study was done to assess the feasibility of synthesizing one of the two chiral precursors needed for the asymmetric synthesis of xestoproxamine C via enzyme catalyzed transesterification of symmetric 1,3-diols. This resulted in successful transesterification of a symmetric 1,3-diol substrate with high enantioselectivity.

Como objetivo general de este trabajo se estudiarán heteropolioxometalatos con estructura Keggin confinados en microesferas mesoporosas de sílice, obtenidas a partir del método sol-gel, como catalizadores en reacciones multicomponente de síntesis de compuestos heterocíclicos con potencial actividad biológica. Se propone, así, reemplazar los catalizadores líquidos convencionales por los heteropolioxometalatos, así como usar catalizadores soportados por su fácil recuperación, llevar a cabo las reacciones en ausencia de solvente, como principales variantes. Esto debe permitir obtener compuestos pertenecientes a la familia de los imidazoles tri y tetra sustituidos, a través de reacciones multicomponente.

Thesis (M.Sc.). / Written for the Dept. of Neurology and Neurosurgery. Title from title page of PDF (viewed 2008/05/14). Includes bibliographical references.

D.Phil. / Porphyrazines like porphyrins and phthalocyanines have unique physical, chemical and spectral properties. This allows them to have many impressive applications. They are less studied than phthalocyanines because of the absence of convenient methods for their synthesis. However, recent studies, including this one, have made these compounds more accessible. The palladium-imidazolium salt systems have proved to be one of the most successful catalysts for the Heck and Suzuki coupling reactions. Substituents on nitrogen atoms of imidazolium significantly influence the catalytic activities of the corresponding palladiumimidazolium salt systems in the Heck and Suzuki coupling. The synthesis of the imidazolium salts is discussed in this study. The synthesis of the imidazoles started from diamines. A new route for the synthesis of 4,5-diaminophthalonitrile is discussed here and so far it is the most convenient and less tedious route with higher yields. The catalytic activities on different substrates have also been extensively investigated and gave impressive results, on the Heck and Suzuki reaction. The catalysis study was first performed using the dicyanoimidazolium salts and then with the imidazolium salts of the porphyrazines. The results indicate that both these systems are active ligands for Suzuki and Heck reactions. Two complexes, [1’,1’’-dibutyl-3’,3’’-(4,5-(1,2-dicyanobenzene))diimidazolium dibromide] and [2,3-benzo(2’,3’-(3’’,3’’’-dibutyldiimidazolium-2’,2’’-diylidene)palladium(II)- dibromide)-7,8,12,13,17,18-hexapropyl,porphyrazine] were synthesised successfully in good yields and used for Suzuki and Heck catalysis reactions. Catalyst recovery in homogeneous catalysis is always a major problem; this led this study to make use of porphyrazines in biphasic catalysis because of their high extinction coefficient which comes from their very intense colour. The reactions were performed in a combination of water with toluene and also water with ionic liquid. Both this systems gave results which proved that it is possible to separate the catalyst and the products once the reaction is complete. Two aminoporphyrazines and phthalonitriles were also synthesised in multistep synthesis. The synthesis involved a lot of protection and deprotection steps. These compounds are starting materials to aminophosphine ligands which have a wide variety of catalysis applications.

Some compounds, analogous to those found in naturally occurring systems, are found to possess chemotherapeutic activity. Some, in the form of their nucleoside or nucleotide derivatives, are valuable antimetabolites in that they may block normal RNA or DNA polymerisation, or may be incorporated into nucleic acids to form fraudulent, but not necessarily defective, polymers. Modification of natural ring systems, with a view to promoting chemotherapeutic activity is therefore of considerable interest; variation in the position and nature of the modification or ring substituent having a marked effect on chemotherapeutic activity. It is the purpose of this thesis to suggest methods for the facile synthesis of various uracils, pyrazoles and pyrazolo [3,4-d] - pyrimidines with alkyl, aryl and glycosyl substituents such that the nature of the ring substituents is easily varied. To this end a number of ethoxymethylene reagents were prepared which, by reaction with primary amines and hydrazines, would give acyclic intermediates capable of easy cyclisation into the uracil, pyrazole and pyrazolo [3,4-d] pyrimidine ring systems. Variation in the nature of specific substituents being determined by the choice of amine or hydrazine, other substituents being varied by modification of the original reagent. / S.R.G.

Ferroptosis is an iron-dependent form of cell death driven by peroxidation of phospholipids with polyunsaturated fatty acyl (PUFA) tails. Dietary factors, such as fatty acids and iron, regulate ferroptosis. Moreover, the incidence and progression of several cancers is correlated with diet; models of lymphoma have shown sensitivity to ferroptosis. We investigated the effects of altering dietary factors linked to ferroptosis on diffuse large B cell lymphomas (DLBCL). We found that DLBCL cells undergo ferroptosis in response to iron and PUFA treatments in vitro, and that their growth in xenograft models is substantially reduced. We observed that monounsaturated fatty acids (MUFAs), in contrast, suppress ferroptosis and promote growth in DLBCL cell and animal models. The inhibitory effect of the ferroptosis inducer imidazole ketone erastin (IKE) on DLBCL xenograft growth was lessened by dietary MUFA. Ferroptosis linked fatty acids and iron thus impact the growth and response to ferroptosis treatment of DLBCL tumors.

Ce manuscrit décrit des approches synthétiques de la benzosceptrine, pyrrole-2-aminoimidazole (P-2-AI) d'origine marine, via la création de liaisons C-N et une photodimérisation [2+2]. La synthèse totale de cette molécule originale et unique présente plusieurs challenges : la construction du motif benzo-bis-2-aminoimidazole et la synthèse régio- et stéréo-sélective du motif benzocyclobutanique. C’est dans ce but qu’une nouvelle méthodologie de diamination de 2-cyclohexènones par la 2-aminopyrimidine en présence du système catalytique fer/diiode/dioxygène a été mise au point et étendue aux 2-aminopyridines, chalcones et la chromone. L’application de cette méthode a permis d’achever la synthèse du motif benzo-bis-2-aminoimidazole de la benzosceptrine via l’installation de 4 liaisons C-N, en 6 étapes avec un rendement global de 28 % ; et d’explorer la réactivité de ce motif. La deuxième partie cyclobutanique a pu être réalisée grâce au développement d’une photodimérisation stéréo- et régio- sélective d’un acide (E)-3-(imidazo[1,2-a]pyrimidin-2-yl)acrylique. Bien que la synthèse totale de la benzosceptrine n’ait pas été achevée, ce travail nous a permis de préparer une chimiothèque de 50 dérivés simplifiés destinée aux évaluations biologiques. Ces évaluations en inhibition de kinases et en cytotoxicité ont mis en évidence un produit cytotoxique original et intéressant. Ce travail de recherche a donc permis d’avancer la synthèse de la benzosceptrine, de mettre au point une nouvelle méthode de diamination et de créer une chimiothèque de dérivés simplifiés d’un produit naturel. / This manuscript describes synthetic approaches of benzosceptrin, a pyrrole-2-aminoimidazole (P-2-AI) isolated from a marine sponge, via C-N bond formation and a [2+2] photodimerization. Its synthesis presents the challenges of the benzo-bis-2-aminoimidazole moiety construction and the regio- and stereoselective synthesis of the benzocyclobutanic motif. With this objective, a new methodology of diamination of 2-cyclohexenones by 2-aminopyrimidine and 2-aminopyridines in the presence of the very simple iron/iodine/dioxygen catalytic system has been developed. It was also extended to chalcones and chromone. The application of this method allowed the synthesis of the benzo-bis-2-aminoimidazole moiety of benzosceptrin via the formation of 4 C-N bonds, in 6 steps in an overall yield of 28 % and to explore the reactivity of some intermediates. The second cyclobutanic moiety has been completed thanks to the development of a stereo- and regioselective photodimerization [2+2] of a (E)-3-(imidazo[1,2-a]pyrimidin-2-yl)acrylic acid. Although the total synthesis of benzosceptrin was not achieved, this work allowed the preparation of a chemical library of 50 simplified derivatives for biological evaluations. Those evaluations in kinases inhibition and cytotoxicity helped to highlight an original and interesting cytotoxic product. This research permitted to progress the synthesis of benzosceptrin, to develop a new method of diamination and to create a chemical library of simplified derivatives of a natural product.

Les bicycles imidazo-imidazoles constituent une classe de composés hétérocycliques intéressants tant sur le plan chimique que pharmaceutique. Ils jouent un rôle très important dans la synthèse et la fonctionnalisation des composés à visé thérapeutique. Dans le cadre de la recherche de nouveaux candidats inhibiteurs de kinases, nous avons développé une voie de synthèse des imidazo[1,2-a]imidazoles mono- et bifonctionnalisés. Par la suite, nous avons mis au point une stratégie de synthèse rapide et efficace de bicycles imidazo[1,5-a]imidazolin-2-one et imidazo[1,5-a]imidazole. En outre, nous avons développé deux stratégies de fonctionnalisation via des réactions de couplage pallado-catalysées. Finalement nous avons synthétisé le motif imidazo[1,5-a]imidazole via la réaction de Groebke-Blackburn-Bienaymé (GBB). La potentialité de cette réaction a été exploitée dans des réactions decyclisation intramoléculaire! afin de préparer une nouvelle chimiothèque de composés polyhétérocycliques azotés. / The imidazo-imidazoles bicycles have received special attention among other nitrogen cycles due to their biologically interesting properties exploited in the medicine manufacturing. The imidazo-imidazole scaffold is one of the most representative nitrogen containing heterocycle, as it plays a significant role and possesses a major interest in drug synthesis and functionalization. In this work we report firstly a synthetic pathway to novel imidazo[1,2-a]imidazoles candidates for CKD inhibitors. Secondly we develop two strategies to prepareimidazo[1,5-a]imidazoles and their reactivity via pallado-catalyzed reactions. Finally, we disclose a fast and an efficient access to imidazo[1,5-a]imidazoles by using the Groebke-Blackburn-Bienaymé reaction (GBB), followed by a palladium catalysed intramolecular cyclization, affording thus new tetracyclic products with an elevated degree of molecular diversity.