Conselho Nacional de Desenvolvimento Científico e Tecnológico / This work reports the synthesis of a series of 4-organoselenyl-isoxazoles (19 examples), prepared via FeCl3/diorganyl diselenides-promoted intramolecular cyclization of alkynone O-metyloximas. In general, the selenyl-isoxazoles were obtained, in 50 to 70% yield. In addition, an alternative method was developed to promote the intramolecular cyclization reaction of o-alkynyl-N,N-dimethyl-anilines, where FeCl3 and substituted diorganyl diselenides were employed as promoter agents to this process. Through this cyclization protocol a series of N-methyl-3-organoselenyl-indoles could be synthesized (20 examples), in yields varying from 36 to 81%, by using room temperature and ambient atmosphere. In order to evaluate the versatility of the obtained compounds as precursors to the synthesis of functionalized isoxazoles and indoles, the 3,5-diphenyl-4-(phenylselenyl)-isoxazole, N-methyl-2-phenyl-3-(phenylselenyl)-1H-indole and N,5-dimethyl-2-phenyl-3-(phenylselenyl)-1H-indole were submitted to PhSe-Lithium exchange reactions, and the corresponding organolithium intermediates, which were generated by treatment with nBuLi, could be trapped with different electrophiles, affording the functionalized isoxazoles (5 examples) and indoles (4 examples) in good yields (45-80%). / Este trabalho relata a síntese de uma série de 4-organoseleno-isoxazóis (19 exemplos), preparados a partir da reação de ciclização intramolecular de O-metiloximas alquinílicas promovidas por FeCl3 e diferentes disselenetos de diorganoíla. Em geral, os derivados de seleno-isoxazóis foram obtidos de maneira satisfatória, em rendimentos de 50 a 70%. Desenvolveu-se também, um método alternativo para promover a reação de ciclização intramolecular de o-alquinil-N,N-dimetil-anilinas, empregando-se FeCl3 e disselenetos de diorganoíla diferentemente substituídos, como agentes promotores da ciclização. Através deste protocolo de ciclização pode-se sintetizar uma série de N-metil-3-organosseleno-indóis (20 exemplos), em rendimentos que variaram de 36 a 81%, utilizando condições de reação brandas, uma vez que os experimentos foram realizados a temperatura e atmosfera ambiente. A fim de avaliar a versatilidade dos compostos obtidos, como precursores para a síntese de isoxazóis e indóis com diferentes funcionalizações, o 3,5-difenil-4-(fenilselenil)-isoxazol e o N-metil-2-fenil-3-(fenilselenil)-1H-indol e N,5-dimetil-2-fenil-3-(fenilselenil)-1H-indol, foram submetidos à reações de troca PhSe-lítio, e o intermediário litiado correspondente, formado a partir de uma reação utilizando n-BuLi, pôde ser capturado com diferentes eletrófilos, obtendo-se como produtos uma série de isoxazóis (5 exemplos) e indóis (4 exemplos) diferentemente funcionalizados em bons rendimentos (45-80%).

No description available.

The complementary value of vibrational spectroscopy and mass spectrometry in obtaining structural information on a range of tricyclic indoles with various ring patterns has been investigated, focusing particularly on whether these heterocycles with a functional group containing oxygen in the third ring should be described as ketoindoles or hydroxindolenines. Parallels between certain fragmentations of ionised indoles and electrophilic substitution in solution have been identified. A mechanistically interesting and analytically useful interesting dimerisation, leading to the formation of [2M-H]+ ions, has been discovered in the positive ion electrospray mass spectra of 3-alkylindoles. This dimerisation, which occurs in the nebuliser of the instrument, offers a potential new route to bisindoles under milder conditions than those employed in classical solution chemistry. Facile formation of C=N bonds by condensation of C=O and H2N has been shown to provide a means of preparing protonated imines and protonated quinoxalines from mixtures of the requisite (di)carbonyl compounds and (di)amines, thus further illustrating how organic synthesis is possible in the droplets in the nebuliser of the instrument. Possible metal catalysed coupling reaction routes to bisindoles have been explored. Acyl transfer reactions from nitrogen to carbon have been investigated in 1-acyl-2-methylindoles and orthogonally protected sulphonamides. These processes have been shown to be intermolecular and intramolecular, respectively. The latter rearrangement, which may be prevented when necessary by choosing the nitrophenylsulphonamide protecting group, offers a route to acyl, carboalkoxy and carboaryloxy aromatic compounds, some of which are difficult to prepare.

No description available.

No description available.

No / The Raman spectrum of scytonin, a novel derivative of the parent scytonemin, is predicted from DFT calculations of the most stable, lowest energy, conformational structure. The diagnostic importance of this study relates to the spectral ability to discriminate between scytonemin and its derivatives alone or in admixture with geological matrices from identified characteristic Raman spectral signatures. The successful interpretation of biosignatures from a wide range of cyanobacterial extremophilic colonization in terrestrial and extraterrestrial scenarios is a fundamental requirement of the evaluation of robotic spectroscopic instrumentation in search for life missions. Scytonemin is produced exclusively by cyanobacterial colonies in environmentally stressed habitats and is widely recognized as a key target biomarker molecule in this enterprise. Here, the detailed theoretical analysis of the structure of scytonin enables a protocol to be established for the recognition of characteristic bands in its Raman spectrum and to accomplish the successful differentiation between scytonin and scytonemin as well as other scytonemin derivatives such as the dimethoxy and tetramethoxy compounds that have been isolated from cyanobacterial colonies but which have not yet been characterized spectroscopically. The results of this study will facilitate an extension of the database capability for miniaturized Raman spectrometers which will be carried on board search for life robotic missions to Mars, Europa, and Titan.

Les alcaloïdes canthin-6-one, 5-méthoxy-canthin-6-one et N-oxyde de canthin-6-one ainsi que l’alkylamide sanshool et trois coumarines ont été identifiés et quantifiés des écorces, feuilles (dans ce cas une étude annuelle a été menée), fruits et racines de Zanthoxylum chiloperone var. angustifolium (Rutaceae) récoltée en Amérique du Sud. Divers analogues de la canthin-6-one ont été obtenus par hémisynthèse en exploitant la réactivité de l’azote pyridinique N-3. De nouveaux analogues ont été synthétisés à partir de différentes tryptamines et anhydrides fonctionnalisés. La mise au point de nouvelles voies de synthèse, permettant leur obtention en 3 ou 4 étapes avec de bons rendements, a permis notamment de retracer toute la voie de biosynthèse de ces alcaloïdes. La stratégie de synthèse a, ensuite, été spécifiquement adaptée à la synthèse de molécules à motifs prénylés. L’activité antituberculeuse, l’activité antiproliférative sur cellules souches cancéreuses, ainsi que plusieurs activités antiparasitaires (maladie de Chagas, paludisme, activité nématicide) ont été étudiées et divers mécanismes d’action proposés. Finalement, nous avons réalisé une étude originale d’électrochimie sur des canthinones ainsi que les premiers essais de formulation galénique avec cette famille d’alcaloïdes. / The alkaloids canthin-6-one, 5-methoxy-canthin-6-one and canthin-6-one Noxide,as well as the alkylamide sanshool and three known coumarines were identified and quantified from stem bark, leaves (in this case an annual analysis was conducted), fruits and roots of Zanthoxylum chiloperone var. angustifolium (Rutaceae) collected in South America. Some canthin-6-one derivates were prepared by hemisynthesis by exploring the N-3 reactivity of the pyridine nitrogen. Other new derivates were prepared from different tryptamines and some functionalized anhydrides by an efficient new synthetic route (3 or 4 steps) in good overall yields. The biosynthetic pathway of the canthin-6-one was also chemically explored.Furthermore, this work has prompted us to explore the reactivity of some prenylated derivates of canthin-6-one and serotonin. The antitubercular activity, the antiproliferative activity on cancer stem cells and several antiparasitic activities (Chagas disease, malaria, nematicidal activity) were studied and various mechanisms of action proposed. Finally, an original study of the electrochemical behaviour of canthinones has been investigated and a pharmaceutical formulation was achieved.

Cette thèse est constituée de trois parties : 1) Le contexte bibliographique, 2) le développement de réactions domino cupro-catalysées et 3) une approche vers la synthèse totale des raputindoles.La première partie introduit d’abord le concept de réactions domino ainsi que leurs applications, puis les réactions catalysées par du cuivre permettant de former des liaisons C-N sont passées en revue en incluant les couplages de Ullmann, Goldberg et de Chan-Lam, les séquences d’activation oxydante de liaisons C-H/formation de liaison C-N, l’insertion de nitrènes et l’hydroamination de liaisons C-C multiples. En se basant sur ces réactions élémentaires permettant de former une liaison C-N unique, les développements récents de réactions domino sont ensuite détaillés.La deuxième partie peut être subdivisée en 3 sections : 1) la synthèse de benzimidazoles, 2) la synthèse d’imidazoles and 3) la synthèse de guanidines. Un rappel des méthodes existantes pour la synthèse de ces motifs est proposé dans chaque section. Notre travail, basé sur la formation de liaisons C-N multiples selon une séquence cupro-catalysée domino, est ensuite détaillé. Celui-ci nous a permis d’aboutir au développement de voies d’accès aux benzimidazoles, en utilisant une réaction séquentielle catalysée par du cuivre en présence d’oxygène à partir d’acides boroniques et d’amidines, à la synthèse d’imidazoles par une réaction de di-amination d’alcynes vrai par des amidines et à l’obtention de guanidines et de 2-aminobenzimidines par une réaction à 3 composant. Ces réactions domino montrent une bonne efficacité et permettent d’assembler des hétérocycles à partir de précurseurs aisément accessibles.La dernière partie est consacrée à la synthèse des raputindoles. La structure, les activités et les réactions clé pour la construction de ces alcaloïdes sont discuté d’abord, nous amenant à proposer une rétrosynthèse pour accéder à ces molécules. Les réactions qui ont retenues notre attention pour construire ces molécules sont une annelation [3+2] irido-catalysée d’acides o-formylarylboronique et de 1,3-diènes, la synthèse de Leimgruber-Batcho pour obtenir des indoles et une séquence d’alkylboration-protodéboration. A partir de cela 3 stratégies ont été évaluées, montrant que l’accès à ce type de composé naturel est envisageable en combinant ces étapes. / This thesis consists in three parts: bibliographic background, copper-catalyzed reactions for synthesis of N-containing compounds, approach to the synthesis of raputindoles.The first part introduces the domino reactions and their applications, then, copper-mediated reactions for construction of C-N bond formation are reviewed including Ullmann, Goldberg and Chan-Lam coupling, oxidative C-H activation/C-N formation, insertion of nitrenes and carbenoids, and hydroamination of multi-C-C bonds. This can be used as guides to design domino reaction. Following these copper-mediated single C-N bond formation reactions, recent developments of copper-catalyzed domino reactions for synthesis of heterocycles are described.The second part can be divided into three sections: 1) synthesis of benzimidazoles, 2) synthesis of imidazoles and 3) synthesis of guanidines. Each section summarizes the existing methods used for their synthesis. Following it, our synthetic work involving copper-catalyzed C-N bond formation domino reactions is discussed in detail. Our objectives include the synthesis of benzimidazoles through copper-catalyzed sequential reaction of benzamidines and boronic acids, synthesis of imidazoles via copper-catalyzed domino reaction of benzamidines and acetylenes, and synthesis of guanidines and 2-aminobenzimidazoles by Cu-catalyzed three-component reaction of cyanamides, boronic acids and amines. These copper-catalyzed domino reactions show high efficiencies from readily available and simple starting materials.The last part is about the total synthesis of raputindoles. The structure and bioactivities of raputindoles and key reactions for the total synthesis of raputindoles are introduced first, the synthetic strategies are then proposed on basis of relative synthetic methods. The key reactions we use for the synthesis of raputindoles are iridium catalyzed [3+2] annulation of o-formylarylboronic acids and 1,3-dienes, Leimgruber-Batcho indole synthesis, transition-metal catalyzed SN2 substitution and alkylborylation-protondeborylation. According to the three strategies we proposed, lots of relative reactions were investigated. The results show that it is possible to synthesize the raputindole molecules based on the iridium catalyzed [3+2] annulation of 2-formylarylboronic acids and 1,3-dienes.

Les benzofuroindolines forment une famille de composés qui se retrouvent sous deux formes : les benzofuro[2,3-b]indolines ou les benzofuro[3,2-b]indolines. Ce motif se retrouve dans de nombreuses molécules naturelles comme la bipleiophylline, la voacalgine A, le diazonamide A et la phalarine ce qui a mené à de nombreuses recherches pour leur synthèse. La biogénèse postulée est le couplage oxydant d'un indole et d'un phénol. Nous avons développé plusieurs voies d'accès à ces motifs en utilisant le noyau indolique. La première étude a consisté en un couplage oxydant direct entre un N-acétylindole et un phénol en présence de FeCl₃ et de DDQ. La méthodologie a montré sa généralité sur des dérivés d'indoles N-acétylés pour former en une seule étape des benzofuro[3,2-b]indolines. Dans certains cas, la benzofuro[2,3-b]indoline est obtenue si les groupements fonctionnels en position 2 et 3 sur l'indole sont identiques. Dans un but de synthétiser la phalarine, unique molécule naturelle contenant un motif benzofuro[3,2-b]indoline, nous avons réalisé une étape de C2-arylation d'un indole par un phénol à l'aide d'un couplage pallado-catalysé. La cyclisation à l'aide de NIS permet d'obtenir la benzofuro[3,2-b]indoline. L'ajout du carbone manquant de l'un des cycles est en cours d'étude par ajout d'un nucléophile monocarboné possédant un groupement partant. Par ailleurs, une dernière voie d'accès aux benzofuro[3,2-b]indolines a pu été mise au point par une réaction de Fischer interrompue. La réaction entre des benzofuran-3-ones et des arylhydrazines dans des conditions acides conduit aux benzofuroindolines souhaitées sous forme d'hémiacétals. La méthode a montré sa généralité et sa robustesse. Finalement, réaliser l'Umpolung de l'indole est un défi intéressant pour additionner des nucléophiles en position 3 de l'indole. Pour cela, des N-hydroxyindoles ont été synthétisés et l'utilisation de sels de biaryliodonium triflate a permis de réaliser une O-arylation. Le produit formé étant instable, il subit un réarrangement sigmatropique [3,3] pour conduire aux benzofuro[2,3-b]indolines désirées. / Benzofuroindolines are a family of compounds which can be found in two regioisomeric forms: benzofuro[2,3-b]indolines or benzofuro[3,2-b]indolines. This core is present in several natural products such as bipleiophylline, voacalgine A, diazonamide A or phalarine which have been the subject of intensive efforts towards their syntheses. The postulated biogenesis is the oxidative coupling of an indole and a phenol. We developed four pathways to access these structures using the indole nucleus.The first part consisted in a direct oxidative coupling between a N-acetylindole and a phenol in presence of FeCl₃ and DDQ. This strategy showed its generality on N-acetylindoles derivatives to form in only one step the benzofuro[3,2-b]indoline core. In some cases, the benzofuro[2,3-b]indoline is obtained if the substitution in the C-2 and C-3 position is the same. In order to synthesize the phalarine, the unique natural product to possess a benzofuro[3,2-b]indoline core, we designed a C-2 arylation of an indole with a phenol using a palladium-catalyzed coupling. The cyclization steps using NIS led to the benzofuro[3,2-b]indoline core. The insertion of the missing carbon of one of the rings is under study by adding a nucleophile which contains only one carbon and a leaving group. The last strategy to access to benzofuro[3,2-b]indolines has been focused on an interrupted Fischer indolization. The reaction between benzofuran-3-ones and arylhydrazines in acidic conditions led to the desired benzofuro[3,2-b]indolines. This methodology is general and robust. Another part of the project was to achieve the Umpolung of the indole to add nucleophiles in C-3 position of the indole nucleus. N-hydroxyindoles were synthesized and the use of biaryliodonium triflate salts allowed an O-arylation reaction. The product being unstable, a [3,3] sigmatropic rearrangement can take place to afford the desired benzofuro[2,3-b]indolines.

Yang, Yaling. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 187-207). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts also in Chinese.