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1
Ostric, Adrian. "Hydroxyethylene isosters of Xaa-Pro dipeptides: synthetic approaches and new HIV-PR inhibitors." Doctoral thesis, Università degli studi di Trieste, 2011. http://hdl.handle.net/10077/4576.
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2009/2010The aspartic protease (HIV-Pr) of the human immunodeficiency virus, responsible agent for AIDS, is surely one of the most studied enzymes in terms of structure and activity. HIV-Pr is responsible for cleaving the viral polyprotein precursor into structural proteins and enzymes and plays an essential role in the viral replication and maturation. HIV-Pr has thus become the target of numerous efforts to design antiviral therapeutic agents suitable for the treatment of AIDS. In the field of organic chemistry, the search for effective HIV-Pr inhibitors has boosted the development of new methodologies for the stereoselective synthesis of compounds containing multiple chiral centers, on which reversible inhibitors are generally based. HIV-Pr shows peculiar characteristics as it is able, unlike any other eukaryotic aspartic protease, to hydrolyze amide bonds with proline as the N-terminal residue. Moreover, it is active in a dimeric form, possessing C2 symmetry, in which each monomer contributes a catalytic aspartate. The first part of the present doctoral work described in Chapter 2, has been dedicated to the synthesis of hydroxyethylene Phe-Pro isosters in which the pyrrolidine ring is expanded by a condensed aromatic ring in order to provide a better fit to the enzyme’s catalytic site. During the synthesis of the isoster a novel reaction was discovered in which enaminones are directly formed by treatment of α,β-unsaturated ketones with trimethylsilylazide and fluoride. Phe-Pro isosters based on the enaminone structure showed moderate activity as HIV-Pr inhibitors. The direct amination of α,β-unsaturated ketones is the subject of Chapter 3. This reaction is demonstrated to be general for enones containing a β-hydrogen. A mechanism based on azide activation via formation of a pentacoordinated silicon species followed by a 1,3-dipolar cycloaddition is proposed and supported by experimental results and calculations. In Chapter 4 is reported the synthesis of a library of triazole inhibitors by a combinatorial approach based on click chemistry. The library was screened for HIV-Pr inhibition and deconvoluted. A set of promising members from the library was synthesized as single, enantiomerically pure compounds that confirmed to be active HIV-Pr inhibitors. Finally, in Chapter 5 the development of an alternative approach to dipeptide isosters, based on the ring closing metathesis of aminoacid-derived allylamines, is described. Building of the four carbon atom backbone of the isosteres is obtained after mounting the olefins on designed linkers that allow selectivity in the cross metathesis, and easy final cleavage. Carbamate linkers will also allow also protection of the amino groups during the next steps of the synthesis leading to the desired di- and monohydroxyethylene isosters.
La proteasi aspartica (HIV-PR) del virus della immunodeficienza umana, l'agente responsabile dell'AIDS, è sicuramente uno degli enzimi più studiati in termini di struttura e di attività. HIV-Pr è responsabile della scissione della poliproteina virale in proteine strutturali ed enzimi e svolge un ruolo essenziale nella replicazione e maturazione del virus. HIV-Pr è così diventato il bersaglio di numerosi studi mirati alla progettazione di agenti terapeutici antivirali adatti per il trattamento dell'AIDS. Nel campo della chimica organica, la ricerca di efficaci inibitori dell'HIV-Pr ha stimolato lo sviluppo di nuove metodologie per la sintesi stereoselettiva di composti contenenti più centri chirali, che costituiscono la base strutturale della maggior parte degli inibitori reversibili. HIV-Pr presenta caratteristiche peculiari in quanto è in grado, unica tra le proteasi aspartiche da eucarioti, di idrolizzare legami ammidici con la prolina come residuo N-terminale. Inoltre, l’enzima è attivo in una forma dimerica, con simmetria C2, in cui ogni monomero contribuisce con un residuo catalitico di acido aspartico. La prima parte del presente lavoro di dottorato, descritta nel capitolo 2, è stata dedicata alla sintesi di isosteri idrossietilenici del dipeptide Phe-Pro, contenenti un anello pirrolidinico espanso al fine di migliorare le interazioni con il sito catalitico dell'enzima. Durante la sintesi dell’ isostere è stata scoperta una nuova reazione di formazione di enaminoni per trattamento di chetoni α,β-insaturi con trimethylsilylazide e fluoruro. Alcuni isosteri Phe-Pro basati sulla struttura enaminonica hanno mostrato una moderata attività come inibitori della HIV-PR. L'amminazione diretta di chetoni -insaturi è il soggetto del capitolo 3. Questa reazione si è dimostrata essere generale per enoni contenente un idrogeno in posizione β. Un meccanismo basato sulla attivazione della azide attraverso la formazione di una specie pentacoordinata di silicio seguita da una cicloaddizione 1,3-dipolare viene proposto sulla base dei risultati sperimentali e di calcoli teorici. Nel capitolo 4 è riportata la sintesi di una libreria di inibitori triazolici ottenuti con un approccio combinatoriale. La libreria è stato analizzata per l'inibizione di HIV-Pr e deconvoluta. Alcuni membri promettenti della biblioteca sono stati sintetizzati come composti singoli, in forma enantiomericamente pura, confermandosi attivi inibitori della HIV-PR. Infine, nel capitolo 5, é descritto lo sviluppo di un approccio alternativo a isosteri di dipeptidi, basato sulla “ring closing methatesis” di allilamine derivate da aminoacidi. La costruzione dello scheletro degli isosteres si ottiene dopo l’assemblaggio delle olefine su un nuovo linker che consente una cross-metatesi selettività nonché un facile distacco del prodotto. Il linker può anche essere utilizzato come gruppo proteggente nella successiva elaborazione sintetica dei prodotti.
XXIII Ciclo
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Sinibaldi, Marie-Eve. "Nouveaux intermediaires pour la synthese d'alcaloides pentacycliques : synthese totale de la desethyl-20 acetyl-20 aspidospermidine." Clermont-Ferrand 2, 1988. http://www.theses.fr/1988CLF21144.
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Pereira, Fernando Luiz Cardoso. "Aplicações sintéticas de β-enamino ésteres." Universidade de São Paulo, 2002. http://www.teses.usp.br/teses/disponiveis/46/46135/tde-19112015-162222/.
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Uma série de β-enamino ésteres foi submetida a reações de iodociclização ou lactonização mediada por iodo, fornecendo como produtos iodo-β-enamino ésteres cíclicos ou β-enamino lactonas, respectivamente. Os iodo-β-enamino ésteres cíclicos obtidos foram submetidos a reações de desidroiodação, fornecendo os correspondentes produtos de eliminação de HI a partir de iodociclos de cinco membros, e ciclopentanos trissubstituídos, a partir de anéis de seis membros. Esta última reação ocorreu por substituição nucleofílica intramolecular, em vez da esperada reação de desidroiodação. O efeito do N-substituinte, nestas reações, foi estudado para uma série de N-alquil e N-aril derivados, fornecendo dados que possibilitaram uma melhor compreensão dos mecanismos envolvidos. As β-enamino lactonas foram obtidas em baixos rendimentos, devido à formação de subprodutos decorrentes da poliiodação do substrato, e mostraram-se resistentes à redução da dupla ligação carbono-carbono por uma série de métodos testados. Um estudo de análise conformacional dos compostos bicíclicos nitrogenados também foi efetuado, através de dados espectroscópicos de RMN-1H e RMN-13C, com o auxílio de cálculos de mecânica molecular e semi-empíricos. Concluiu-se que em função do N-substituinte os biciclos adotam diferentes conformações preferenciais, o que altera significativamente seus perfis espectroscópicos.A series of acyclic β-enamino esters was submitted to iodocyclization reactions or to iodine-mediated lactonization, leading to the corresponding cyclic iodo-β-enamino esters or β-enamino lactones. Dehydroiodination of the five-membered ring enamino esters furnished pyrrole, tetrahydroindole and hexahydroindole derivatives, under basic or neutral conditions. The six-membered ring enamino esters, when submitled to treatment with triethylamine, gave rise to trisubstituted cyclopentanes. This transformation occurred through an intramolecular nucleophilic substitution, instead of the expected dehydroiodination reaction. The effect of the N-substituent in these reactions was studied for a series for N-alkyl and N-aryl derivatives. The β-enamino lactones were obtained in poor yields, due to the poliiodination of the substrates, and showed to be resistent to reduction of the carbon-carbon double bond under several conditions. A study of conformational analysis of the bicyclic β-enamino esters was undertaken, using 1H-NMR and13C-NMR data, molecular mechanics and semi-empirical methods. From this study, it was observed that the bicyclic compounds adopt different conformations depending upon the N-substituent.
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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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Throup, Adam Eric. "Synthetic methodology and application of enamine [2+2] cyclisations for cyclobutane synthesis : development of integrin antagonists as anticancer therapeutics towards a total synthesis of providencin." Thesis, University of Bradford, 2015. http://hdl.handle.net/10454/14411.
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Cyclobutanes represent an underutilised structural feature in medicinal chemistry, partially due to difficulties in forming them in an easy and controlled manner. Herein is described their application to a drug discovery project and development of the enamine [2+2] cyclisation; a straightforward synthesis of functionalised cyclobutanes. A library of 30 cyclobutane based integrin antagonists have been designed and synthesised to explore the SAR around the hit dual β3 integrin antagonist ICT9055. Several of which were shown to be highly potent antagonists inhibiting cancer cell adhesion, migration and invasion while remaining non-toxic. ICT9072 had comparable β3 activity to hit compound ICT9055 but also had activity against αvβ5 and therefore showed greater inhibition of migration of DLD-1 cells. This showed the ability to modify this scaffold for multi integrin antagonism and potential benefit of this. Synthetic studies towards the marine natural product providencin has led to the development of a previously unknown intramolecular enamine [2+2] cyclisation which has been shown to proceed in a diastereoselective manner. This reaction has been applied to the synthesis of a highly functionalised enatiopure cyclobutene suitable for inclusion into the total synthesis. A model furyl cyclobutane has also been synthesised to exemplify the route from the enantiopure cyclobutene through to the furyl cyclobutane fragment of providencin.
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Throup, Adam E. "Synthetic Methodology and Application of Enamine [2+2] Cyclisations for Cyclobutane Synthesis. Development of Integrin Antagonists as Anticancer Therapeutics Towards a Total Synthesis of Providencin." Thesis, University of Bradford, 2015. http://hdl.handle.net/10454/14411.
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DELBECQ, PHILIPPE. "Nouvelles voies d'acces aux beta-enaminones cycliques. Application a la synthese de la six-methylpelletierine." Paris 6, 1990. http://www.theses.fr/1990PA066472.
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La decarboxylation de beta-enaminocetoesters cycliques par thermolyse en presence d'acide orthoborique permet d'acceder a des beta-enaminones variees. La desacylation de beta-enaminodicetones par le methylate de sodium conduit a des resultats analogues. La reduction de la liaison ethylenique de beta-enaminones cycliques mene a des alcaloides cycliques comme la six-methylpelletierine
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Sevenich, Adrian Manuel [Verfasser]. "Entwicklung und Anwendung photochemischer Reaktionen zur Synthese und Modifikation von Heterocyclen : Synthese von (−)-Hexahydrofurofuranol; Synthese und Funktionalisierung von Enaminonen / Adrian Manuel Sevenich." Mainz : Universitätsbibliothek der Johannes Gutenberg-Universität Mainz, 2021. http://d-nb.info/122704853X/34.
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Taylor, Jane M. "The design and synthesis of acylated enamino esters as potential inhibitors of serine proteases." Thesis, University of Canterbury. Chemistry, 1993. http://hdl.handle.net/10092/8000.
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This thesis examines the synthesis of bromo acylatad enamino asters, of the type (4.01), and protio acylatad enamino esters, of the type (4.02), designed as a new class of potential mechanism-based inactivators and alternate substrata inhibitors, respectively, of chymotrypsin.
[Diagram]
Chapter 1 describes the synthesis of succinic-, glutaric- and phthalic-basad, bromo and chloro enollactones (1.11-1.15, 1.17) via a new reaction involving halo enollactonization of keto acid phosphoranes (1.06-1.10). The phthalic bromo enollactones (1.17) are also synthesized via the reaction of Ph₃P=CBrCO₂Et with 4,5-dichlorophthalic anhydride. The reactions are extensions of the SCOOPY and Wittig anhydride carbonyl olefination reactions.
Chapter 2 describes the synthesis of simple succinimide- and phthallmide-based protio and chloro enamino asters (2.09, 2.63-2.75, 2.93, 2.95, 2.98) via a versatile new reaction in which an enollactone (2.33, 1.11, 2.115) and amine react to form an isolable keto-amide (2.37-2.47, 2.94, 2.96, 2.116) and/or hydroxy lactam (2.48-2.50, 2.97) intermediate. Subsequent elimination of H₂O on heating gives the enamino aster via an overall insertion process.
Chapter 3 describes the synthesis of simple succinimide-basad protio and bromo enamino asters (2.66, 2.71, 3.02-3.03) from the reaction of β-keto ester (3.01), via an isolable enamine intermediate (3.07-3.10). The synthesis of α 3-substituted enamino aster (3.04) via the insertion and β-keto ester routes is also described.
Chapter 4 describes the synthesis of the target 3,3-disubstituted enamino esters (4.01-4.07) via the insertion reaction and a TiCl₄ mediated β-keto ester reaction. The benzyl group at position 3, required for recognition by chymotrypsin, is introduced stereoselectively using methodology developed largely by Seebach and coworkers for the asymmetric synthesis of α,α;-disubstituted amino acids. By changing this residue other serine proteases can be targeted. The proposed inhibitors (4.01-4.07) are designed to be incorporated into an oligopeptide having optimum interaction with the target enzyme. Preliminary testing of enamino esters and enollactones (2.71, 3.04, 4.01- 4.02, 4.03, 4.06, 4.42, 4.43) for chymotrypsin Inhibition is also described.
Chapter 5 examines trends in the ¹³CNMR, ³¹PNMR and FAB mass spectra of keto acid and keto ester phosphoranes (4.15, 4.26, 4.40-4.41, 5.04-5.06); key intermediates to enamino esters and enollactones (eg 4.01-4.06, 4.42, 4.43).
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Deng, Yongming. "Asymmetric cyclization reactions through an enamine/acid cooperative approach. Synthesis of unsymmetrically functionalized benzoporphyrins." Miami University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=miami1406213121.
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Lallemand, Marie-Christine. "Etude de la réactivité de la 2-cyano-6-phényloxazolopipéridine et de ses dérivés 2-alkyles précurseurs d'énamines." Paris 11, 1996. http://www.theses.fr/1996PA114806.
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Zhao, Qiang. "Development of New Synthetic Transformations of N-Sulfony1-1,2,3-triazoles." Kyoto University, 2019. http://hdl.handle.net/2433/242534.
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DAKA, PHILIAS. "ENAMINE-METAL LEWIS ACID BIFUNCTIONAL CATALYSTS FOR ASYMMETRIC ALDOL REACTIONS. DESIGN AND SYNTHESIS OF STAT3 INHIBITORS." Miami University / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=miami1374852476.
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DePizzo, Ashley. "Synthesis of bis(2,2,2-trifluoroethyl) β-ketophosphonates from bis(2,2,2-trifluoroethyl) 1-alkynylphosphonates via enamine vinyl phosphonates." Youngstown State University / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ysu1287586787.
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LACROIX, ERIC. "Syntheses cyclopropeniques de polyquinanes." Université Louis Pasteur (Strasbourg) (1971-2008), 1988. http://www.theses.fr/1988STR13123.
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L'addition d'enamines sur des cyclopropenes electrophiles gem-dimethyles conduits aux cetones alpha -cyclopropylees attendues mais aussi a des produits de cycloaddition. Ces cycloadduits conduisent par traitement acide a des cyclopentenes gem-dimethyles. L'obtention et la reactivite de ces composes ont ete etudiees pour modeliser l'acces a des triquinanes naturele. Ainsi l'hirsutene et le silphinene ont ete synthetises. Les syntheses d'autres triquinanes naturels (acide pentalenique, pentalene et corioline) ont ete ebauchees
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Dohe, Janis [Verfasser], Thomas J. J. [Akademischer Betreuer] Müller, and Klaus [Gutachter] Schaper. "Synthese von festkörperlumineszenten Bordifluorid Enaminon Komplexen auf Basis einer Palladium-katalysierten Multikomponentenreaktion / Janis Dohe ; Gutachter: Klaus Schaper ; Betreuer: Thomas J. J. Müller." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2018. http://d-nb.info/1150477466/34.
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Zhang, Yang. "Dynamic Systems : Enzymatic Synthesis, Exchange Reactions and Applications in Materials Science." Doctoral thesis, KTH, Organisk kemi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-173480.
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This thesis is divided into three parts, revolving around the developments of dynamic systems utilized in dynamic kinetic resolution (DKR) and constitutional dynamic chemistry (CDC). The first section gives an introduction to constitutional dynamics, the core concept of this thesis. Constitutional dynamics can be tuned through reversible interactions. Then, the basic principles of constitutional dynamics in DKR and CDC are discussed, along with their applications. The second section explores the asymmetric synthesis of oxazolidinone derivatives using lipase catalysis through kinetic resolution (KR) and dynamic kinetic resolution. In the first example, synthetic protocol to enantioenriched 5-phenyloxazolidin-2-ones is described, where a kinetically controlled carbamation is followed by lipase-catalyzed cyclization. In contrast to the 5-substituted species, the synthesis of 3-phenyloxazolidin-2-one derivatives could be achieved through lipase-catalyzed cascade O- and N- alkoxycarbonylations in one pot. Furthermore, this KR system could be coupled to a ruthenium-catalyzed racemization process of 1,2-aminoalcohols, thus providing an efficient DKR methodology for asymmetric transformations. The third section focuses on dynamic systems built through reversible covalent reactions. In the first example, a selective gelation process is described, and employed to resolve dynamic imine systems consisting of gelator candidates. In the second example, reversible reactions with aldehyde enamines are presented, including enamine formation and exchange reactions. In particular, Bi(III) and Sc(III) were discovered to accelerate the enamine exchange reactions by 50-400 times, in which the equilibria could be reached within hours. The last example describes reversible nitroaldol reactions in aqueous media, where rapid and efficient equilibration was identified for selected structures in neutral phosphate buffer.QC 20150911
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Charlton, Andrew. "Towards the development of direct methodology to enantioenriched α-alkylated aldehydes." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:bcfe43bb-1497-4f94-bcc7-6f7c2ae0b3a1.
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Enantiopure α-alkyl-substituted aldehydes are widely recognised as important building blocks in synthesis. Despite this, methods to prepare such substrates are limited. Strategically, asymmetric intermolecular SN2 α-alkylation represents a highly straightforward transformation, but still remains an elusive feat. This thesis describes efforts to address this challenge, with attempted access to enantioenriched α-alkyl aldehydes by way of C-alkylation of chiral, non-racemic, hindered aldenamines using simple alkyl halides. Enamines derived from four types of auxiliary (a tropane, an oxazolidine, a pyrrolidine and a homotropane) have been prepared, and their alkylation profile examined. While the desired levels of asymmetric induction were not attained, use of the tropane and homotropane auxiliaries, which differ only by a single methylene group, interestingly, gave complimentary diastereocontrol during alkylation with EtI. The observed stereoselectivity is supported by density functional studies performed for ethylation of both enamines. Additionally, in the course of preparing the homotropane a highly efficient asymmetric synthesis of a homotropinone bearing gem-α-substitution has been developed.
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HAMMAMI, HEDI. "Reaction de beta-enamino esters chiraux avec les olefines electrophiles : synthese asymetrique de beta-ceto esters alpha, alpha-disubstitues, applications synthetiques." Paris 6, 1993. http://www.theses.fr/1993PA066380.
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Nous presentons dans le preambule un apercu des differentes methodes de synthese asymetriques de beta-ceto esters alpha, alpha-disubstitues parues dans la litterature. Dans le premier chapitre nous exposons l'addition de michael des beta-enaminoesters alpha-disubstitues avec divers accepteurs de michael (enones, acrylates, acrylonitrile). Elle conduit, avec de bons exces enantiomeriques et bons rendements chimiques, a des beta-ceto esters alpha, alpha-disubstitues. Ce motif est frequemment rencontre, soit sous sa forme premiere, soit sous des formes derivees dans de nombreux produits biologiquement actifs. Cette reaction a ete catalysee par des acides de lewis et par l'application de hautes pressions. Une etude detaillee de la reactivite de cette addition en fonction de la temperature, du solvant et de la nature de l'acide de lewis a ete realisee. Une interpretation de l'etat de transition, a partir des observations experimentales et des analyses spectrales est proposee. Dans le deuxieme chapitre nous appliquons cette reaction de michael a la synthese enantioselective de lactames spirocycliques, precurseurs directs d'alcaloides: la (+)-isonitramine et la ()-nitramine. Dans le troisieme chapitre nous traitons les differentes approches du pisiferol
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Würtz, Sebastian. "Palladium-Katalyse Synthese und Anwendung neuartiger chiraler und achiraler N-heterocyclischer Carbene (NHC) in Palladium-katalysierten Kreuzkupplungen und Palladium-katalysierte oxidative Cyclisierung von N-Aryl-Enaminen zur Synthese hochfunktionalisierter Indole." Lichtenberg (Odw.) Harland Media, 2008. http://d-nb.info/992466458/04.
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Xie, Sheng. "Perfluroaryl azides : Reactivities, Unique Reactions and their Applications in the Synthesis of Theranostic Agents." Doctoral thesis, KTH, Organisk kemi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-172950.
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The work centersaround perfluoroaryl azides (PFAAs), and theirability to undergo certain fast and robusttransformations. The chemistry was furtherappliedfor biomedical applications. The first section focuses on the azide-aldehyde-amine cycloaddition using PFAAs. Experimental and computational investigations uncovered a fast azide-enamine cycloaddition to form triazolines, which spontaneously rearrange into stable amidine products. In addition, this transformation was explored in the formulation of pure nanodrugs. Because this reaction can introduce a phenyl and a perfluoroaryl moiety enabling supramolecular interactions near the antibiotic drug, the resulting ciprofloxacin derivatives formed nano-sized aggregates by precipitation, which displayed aggregation-induced emission for bacterial imaging as well as enhanced size-dependent antibacterial efficacy. In the second section, the high electrophilicity of PFAAs was explored to transform azides to aryl amides. The reactivity of PFAAs in the thioacid/azide reaction was studied. In addition, PFAAs were discovered to react with phenylacetaldehyde to form aryl amidesviaan azide-enol cycloaddition, similar tothe perfluoroaryl azide-aldehyde-amine reaction.This strategyof amide synthesiswas furthermoregeneralized through a combination of base-catalyzed azide-enolate cycloaddition reaction and acid-or heat-promoted rearrangement of triazolines. The last section describes a type of azide fluorogens whose fluorescence can be switched on by alight-initiated intramolecular nitrene insertion intoa C-H bond in the neighboring aromaticring. These fluorogenic structures were efficiently accessed via the direct nucleophilic aromatic substitution of PFAAs.QC 20150903
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Léger, Frédéric. "Additions d'énamines β-lithiées sur des esters α, β-éthyléniques. Nouvelles propriétés des énamines β-halogénées." Rouen, 1996. http://www.theses.fr/1996ROUES051.
Full textAbstract:
Les énamines β-lithiées sont obtenues par bromation des énamines puis échange halogène-métal et réagissent directement avec les esters α, β-éthyléniques exclusivement en 1,4 conduisant après hydrolyse aux énaminoesters correspondants. Ces composés sont obtenus avec de bons rendements et présentent une rétention de configuration par rapport aux énamines β-bromées de départ. L'énolate intermédiairement formé a été condensé sur l'iodure de méthyle conduisant à la création d'un carbone stéréogénique supplémentaire. Dans ce cas les nouveaux énaminoesters sont obtenus avec une excellente diastéréosélectivité. L'hydrolyse des énaminoesters conduit, selon les conditions utilisées, aux cétoesters ou aux cétoacides correspondants avec en général une très bonne diastéréosélectivité. En utilisant des énamines β-lithiées achirales sur des esters α, β-éthyléniques d'alcool chiral, les excès diastéréoisomériques ont été moyens. Par contre la réaction de Michael entre une énamine β-lithiée chirale et le crotonate de tertiobutyle conduit a une complète diastéréoselectivité au niveau de l'énaminoester. Dans les conditions de réaction de Heck (Pd(OAc)2, PPh3, NEt#3, CH3CN), les énamines beta-halogénées ont été réduites en amines tertiaires avec des rendements corrects. L'utilisation d'énamines β-halogénées à reste aminé chiral conduit aux amines tertiaires chirales correspondantes. L'agent de réduction est vraisemblablement la triéthylamine. La deracémisation d'aldéhydes α-substitués par l'intermédiaire d'énamines β-substituées chirales conduit à des aldéhydes α-substitués optiquement actifs. Les différents paramètres de la réaction ont été étudiés et ont permis d'atteindre des excès énantiomériques de 60%.
23
Barth, Francis. "Synthese de squelettes mono et sesquiterpeniques au depart de cyclopropenes et cyclobutenes electrophiles." Université Louis Pasteur (Strasbourg) (1971-2008), 1988. http://www.theses.fr/1988STR13167.
Full textAbstract:
Preparation des structures du titre grace a des reactions de cycloaddition. Une nouvelle synthese non photochimique de systemes bicyclo (2. 2. 0) hexaniques a partir de cyclobutenes et d'enamines est ainsi effectuee. La reaction de diels alder de cyclopropenes electrophiles avec des dienes heterosubstitues permet l'obtention de systemes careniques. Enfin, une synthese de la dihydro-2,3 illudine m est realisee
24
CUSSERNE, BARDOU ANITA. "Etude de la reduction et de l'alkylation des -enamino esters cycliques. Application a la synthese hautement enantioselective de trois alcaloides de venins d'amphibiens : les (-) (5r, 8r, 8as) indolizidines 181b, 209b et 223i." Paris 6, 1997. http://www.theses.fr/1997PA066293.
Full textAbstract:
La these presentee porte sur la mise au point d'une nouvelle synthese hautement enantioselective de trois indolizidines naturelles disubstituees en positions 5 et 8. Le travail est base sur les proprietes inductrices d'une copule chirale bien connue : l'-methylbenzylamine. Le point de depart de la synthese consiste en la preparation d'un -enamino ester trisubstitue chiral qui est d'abord reduit de maniere hautement diastereoselective, puis alkyle pour introduire l'un des substituants present dans ces alcaloides. Ce second centre asymetrique est lui aussi obtenu avec un tres bon exces diastereoisomerique. L'excellente diastereoselectivite obtenue lors de l'introduction d'un groupe methyle a permis d'etendre cette reaction a la preparation -amino esters chiraux divers. L'apport du second substituant a ensuite ete rendu possible grace a la synthese d'un ylure stabilise approprie qui a, par la suite, ete condense sur un amino aldehyde obtenu par reduction partielle d'un des -amino esters precedents. La derniere partie du travail a consiste a mettre au point des conditions d'annelation par amination reductrice qui ont conduit a l'isolement des trois alcaloides-cibles. Une etude structurale par rmn a haut champ a enfin permis de confirmer pour l'un d'entre-eux et d'etablir pour les deux autres les structures tridimensionnelles de ces produits naturels. Cette strategie est donc suffisamment generale pour que la preparation de toute indolizidine naturelle disubstituee en positions 5 et 8 soit envisagee de maniere hautement enantioselective.
25
Al, Badri Hashim. "Synthèse et réactivité d'énamines phosphoniques fonctionnelles et de phosphonates allyliques. Applications à la synthèse de diènes fonctionnels utilisés dans la réaction de Diels-Alder." Rouen, 1996. http://www.theses.fr/1996ROUES054.
Full textAbstract:
Dans ce travail, de nouvelles applications des énamines phosphoniques et des phosphonates allyliques fonctionnels ou non ont été étudiées. La première partie du travail concerne l'étude de la réactivité des énamines 2-phosphoniques 2-fonctionnelles N, N'-diméthylées vis-à-vis de différents nucléophiles. Cette étude a permis l'accès à des phosphonates allyliques 2-fonctionnels qui ont été utilisés dans la synthèse de nouveaux butadiènes 2-carboxylates diversement substitués. Par ailleurs une voie d'accès particulièrement simple aux énamines 2-phosphoniques 2-fonctionnelles N-arylées a été mise au point. La deuxième partie de ce mémoire s'intéresse à la synthèse de différents phosphonates insaturés fonctionnels. La réaction des carbanions issus des phosphonates allyliques non fonctionnels vis-à-vis de différents électrophiles conduit à des nouveaux phosphonobutadiènes diversements substitués, à des (1-E)-2-phosphonobutadiénols ou à des diénoxyphosphonates acétylés et silylés ainsi qu'à des phosphonates allyliques 2-silylés. La réaction des carbanions des phosphonates allyliques 2-silylés permet également l'accès à d'autres types de composés organophosphorés intéressants, en particulier à des phosphonates 2, 3-insaturés 3-fonctionnels aptes à subir des transformations chimiques ultérieures par exemple dans la chimie des rétinoïdes, ainsi que des butadiènes phosphoniques, des phosphonolactones et des alkoxydiènes phosphoniques. Enfin, les diènes obtenus ont permis de synthétiser selon la réaction de Diels-Alder de nouveaux composés carbocycliques et hétérocycliques, difficiles d'accès.
26
Léon, Patrick. "Alkylation d'amines par les sels de sulfonium, reaction de type gabriel et synthese de polyamines." Paris 6, 1987. http://www.theses.fr/1987PA066488.
Full text
27
Puchot, Catherine. "Contribution à l'étude des synthèses asymétriques catalysées par les acides aminés." Paris 6, 1986. http://www.theses.fr/1986PA066136.
Full text
28
Marabout, Benoît. "Synthèse totale de la ( + ou - ) perhydrohistrionicotoxine." Rouen, 1988. http://www.theses.fr/1988ROUES019.
Full text
29
Scalzullo, Stefania Margherita. "Synthesis of lamellarin alkaloid analogues from enaminone precursors." Thesis, 2014.
Find full textAbstract:
The synthesis of alkaloids from enaminones has been used extensively in the University of the Witwatersrand’s organic chemistry laboratories. In this thesis enaminone precursors are one of the main ways of accessing lamellarin analogues. The lamellarin alkaloids are an important family of marine alkaloids, owing to their vast biological properties. A brief background to marine alkaloids and their general potential is given, followed by a review of lamellarin alkaloids, their structural and biological properties and some of the major syntheses carried out over the past few years.
Two novel features form the basis of the synthetic methods described in the thesis. The first is an approach to forming the lamellarin alkaloids from enaminone precursors, which are prepared through the Eschenmoser sulphide contraction. The second method uses a novel pyrrole formation, which was initially conceptualized by Garreth L. Morgans in his PhD thesis (2008). The main target of the investigation was lamellarin G trimethyl ether.
In Chapter 3, the syntheses of a range of mono-, di- and tetra-substituted phenacyl halides are discussed. The phenacyl halides were used in the preparation of various enaminone precursors. The tetrasubstituted phenacyl halide 2-bromo-1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone 3.17 is required for the synthesis of our target lamellarin G trimethyl ether. The phenacyl halides are important in both the model synthesis described in Chapter 4 and the synthesis toward lamellarins in Chapter 5.
Chapter 4 deals mainly with the synthesis of pyrrolizine systems. Methodology is described for the preparation of a variety of enaminones, pyrroles and tetracyclic lamellarin analogues. The closest pyrrolizine system to lamellarin G trimethyl ether, 11-(3,4-dimethoxyphenyl)-2,3-dimethoxy-9,10-dihydrochromeno[4,3-b]pyrrolizin-6(8H)-one 4.52, was the final and most complex tetracyclic model structure analogous to lamellarin G trimethyl ether. Indolizine and pyrroloazepine adaptations were also demonstrated and tetracyclic systems 10,11-dihydro-8H-chromeno[3,2-a]indolizin-12(9H)-one 4.39 and 9,10,11,12-tetrahydrochromeno[3',2':3,4]pyrrolo[1,2-a]azepin-6(8H)-one 4.40 were successfully prepared, even though the pyrrole formed in an unexpected way.
Finally in Chapter 5, the methodology established in the model study was used in the attempted synthesis of lamellarin G trimethyl ether. A second method was also investigated. Thus, various N-alkylated and N-H enaminones were successfully synthesized, from which novel and unexpected pyrrole-containing products 8-(3,4-dimethoxyphenyl)-2,3-dimethoxy-5H-chromeno[3',2':3,4]pyrrolo[2,1]isoquinolin-14(6H)-one 5.28 and (3-ethoxy-8,9-dimethoxy-2-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-1-yl)(phenyl)methanone 5.37 were formed, even though our desired product lamellarin G trimethyl ether could not be attained from either method.
30
Sultan, Saleem Syed. "The synthesis of 8-substituted indolizidines from enaminone precursors." Thesis, 2012. http://hdl.handle.net/10539/11615.
Full textAbstract:
Indolizidine alkaloids are found in several natural sources such as higher plants, fungi and
bacteria as well as vertebrates and invertebrates from both marine and terrestrial sources. This
dissertation describes investigations aimed at preparing indolizidines bearing carbon or
heteroatomic substituents at C-8 as model systems for various classes of alkaloids. In addition,
we intend to synthesise tricyclic benzo-fused indolizidine derivatives and attempt to introduce
similar substituents into these compounds. Key intermediates in our approach are enaminones,
which can show both electrophilic and nucleophilic behaviour. A convenient way to prepare
them is to proceed via thiolactams, which allows for the Eschenmoser sulfide contraction with a-
halocarbonyl compounds to make the enaminone intermediates.
The simple bicyclic enaminone 2,3,5,6-tetrahydroindolizidin-7(1H)-one (54) was prepared in
five steps and 22% overall yield. This was achieved by thionating pyrrolidin-2-one to pyrrolidin-
2-thione with phosphorus pentasulfide, followed by N-alkylation with acrylate esters, then
Eschenmoser sulfide contraction with ethyl bromoacetate to give enaminones (vinylogous
urethanes) in which the double bond was exocyclic to the pyrrolidine ring. The products were
then cyclised to give ethyl 7-oxo-1,2,3,5,6,7-hexahydroindolizine-8-carboxylate (55), which was
hydrolysed and decarboxylated to give compound 54. Several addition and substitution reactions
were then attempted on this compound, including acylation at C-8 with acryloyl chloride,
alkylation with 1,4-dibromobutane, as well as oxygenation attempts with sodium percarbonate
and meta-chloroperbenzoic acid, and amination with a diazonium salt.
To extend our methodology to tricyclic benzo-fused analogues, ethyl 5-oxo-1,2,3,5-
tetrahydropyrrolo[1,2-a]quinoline-4-carboxylate (49) and 4-ethyl 9-methyl 5-oxo-1,2,3,5-
tetrahydropyrrolo[1,2-a]quinoline-4,9-dicarboxylate (101) were synthesised from methyl
anthranilate. Synthesis of these compounds proved to be slightly more difficult, resulting in
interesting side-products such as methyl 2-(methylamino)benzoate (91), methyl 2-{4-[2-
(methoxycarbonyl)phenylamino]butanamido}benzoate (92) and 3a-methyl-3,3a-dihydro-1Hbenzo[
d]pyrrolo[2,1-b][1,3]oxazin-5(2H)-one (98)
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Riley, Darren Lyall. "Synthesis of amphibean indolizidine alkaloids and related compounds from enaminone precursors." Thesis, 2008. http://hdl.handle.net/10539/4967.
Full textAbstract:
The work discussed in this thesis is centered on the synthetic protocol developed for the
synthesis of alkaloids in the organic chemistry laboratories at the University of the
Witwatersrand. The alkaloids of interest in this thesis are the 5,8-disubstituted indolizidines
(-)-209I [185] and (-)-223V [174], the piperidine alkaloid (±)-thalictroidine [257] as well as
several 5-monosubstituted indolizidines including (±)-tashiromine [330a] and (±)-5-epitashiromine
[330b]. The work is put into perspective in two parts. The first part is a review of
all the classes of alkaloids that have currently been isolated and identified from the skin
extracts of amphibians, in particular the Dendrobatidae family of neotropical frogs. The
second part gives a chronological review of all previous racemic and enantioselective
syntheses of the 5,8-disubstituted indolizidines. This is followed by an overview of the
general synthetic approach used in the syntheses of alkaloids in the “Wits” laboratories.
Particular emphasis is placed on the enantioselective synthetic strategies, developed by
Gravestock, for the synthesis of 5,8-disubstituted indolizidine alkaloids. The aims and
strategies to be used in the present project are then introduced.
The racemic synthesis of (±)-thalictroidine [257], used in model studies in order to practice
fundamental functional group transformations for the preparation of piperidine systems is
reported. The key reactions introduced in this section were the preparation of
bromoacetamides, thiolactams and enaminones, the latter by the application of Eschenmoser’s
sulfide contraction, as well as the reduction of exocyclic carbon-carbon double bonds in six
membered vinylogous urethanes. The synthesis of (±)-thalictroidine [257], is the first reported
synthesis of the natural product, and spectroscopic and crystallographic data are in agreement
with the structure proposed by Kennelly et al.125
The synthesis of several 5-monosubstituted indolizidines, used in model studies in order to
establish fundamental skeletal and functional group transformations for 5,8-disubstituted
indolizidines are then shown. Key reactions include the preparation of several enaminones
including a vinylogous urethane [312] and a Weinreb amide [314] from thiolactam [304].
These enaminones were cyclised under alkylative conditions to afford 5-substituted
indolizidines [320] and [322] respectively. The synthetic utility of the Weinreb amide for the
introduction of unbranched alkyl substituents at the 5-position is introduced, and the utility of the vinylogous urethane [320] is shown by a three step conversion into (±)-tashiromine [330a]
and (±)-5-epi-tashiromine [330b].
The formal enantioselective synthesis of indolizidine (-)-209I [185] is reported. In order to
begin the enantioselective synthesis of (-)-209I [185], methodology developed by Gravestock
was adapted to the preparation and utilization of vinylogous ureas containing the Weinreb
amide functionality. Conjugate addition of the secondary amine N-benzyl-N-(1R)-1-
phenylethylamine [243] to tert-butyl (2E)-2-hexenoate [267] gave optically pure tertiary
amine [268]. Debenzylation of this amine gave primary amine [336]. Subsequent lactam
formation, thionation and sulfide contraction with N-methoxy-N-methyl-2-bromoacetamide
[271] yielded vinylogous urea [272]. The reduction of tert-butyl ester [272] to liberate alcohol
[273] was low yielding and an alternative method was used, which involved the reduction of
the tert-butyl ester at an early stage of the synthesis, protecting it as a silyl ether, and then
liberating the free alcohol at an appropriate stage in the synthesis. The silyl ether was not
compatible with the thionation step and was swapped at the lactam stage for an acetate
protecting group. Subsequent reactions included an acylative cyclisation to form the
indolizidine skeleton and a stereoselective reduction of the carbon-carbon double bond to
yield (5R,8S,8aS)-N-methoxy-N-methyl-5-propyloctahydro-8-indolizinecarboxamide [275].
Mono-alkylation of the Weinreb amide functionality and epimerization to 1-[(5R,8R,8aS)-5-
propyloctahydro-8-indolizinyl]-1-propanone [191] represented a formal synthesis of
indolizidine (-)-209I [185].
Approaches towards the synthesis of a late stage common intermediate [259] which could
have the substituents at both the 5- and 8-positions modified independent of each other at or
near the end of the synthesis are discussed. Finally an alternative synthetic approach negating
the need for several of the protection and deprotection steps is shown with regards to the
synthesis of the structurally related 1,4-disubstituted quinolizidines
32
Mthembu, Siyanda Thabani. "Enaminone-based approaches to the synthesis of alkaloids possessing the pyrrolo[1,2-a]azepine core." Thesis, 2018. https://hdl.handle.net/10539/26053.
Full textAbstract:
A thesis submitted to the Faculty of Science, University of the
Witwatersrand, Johannesburg.
In fulfilment of the requirements for the Degree of Doctor of Philosophy
February 2018.This thesis illustrate strides taken toward the construction of the pyrrolo[1,2-a]azepine 4 nucleus via enaminone chemistry developed in this University for creating pyrrolizidine 1, indolizidine 2 and quinolizidine 3 alkaloids. The pyrrolo[1,2-a]azepine 4 core is a fused pyrrolidine and azepine system found in lehmizidine, Stemona, Cephalotaxus alkaloids and other alkaloids. A concise background is given on the nature of enaminones, how they are accessed with strong emphasis on the Eschenmoser sulphide contraction reaction and their versatile reactivity, followed by literature review of this University background on synthesis of alkaloids containing 1, 2 and 3 nuclei. The aims and strategies presented are preceded by literature review of lehmizidine, Stemona, Cephalotaxus alkaloids and some reported synthesis. A range of attempts and successes are reported in chapter 2 for making four-carbon chain length enaminones (via N-alkylation, condensation, thionation, Eschenmoser sulphide contraction and tandem acylation/Michael addition reactions) crucial in creating azepane onto pyrrolidine in an acylation or alkylation ring closing steps yielding lehmizidine like compounds (E)-ethyl 8-oxo- 2,3,5,6,7,8-hexahydro-1H-pyrrolo[1,2-a]azepine-9-carboxylate 144 and (E)-ethyl 2,3,5,6,7,8- hexahydro-1H-pyrrolo[1,2-a]azepine-9-carboxylate 147. Vice versa, the synthesis of two carbon chain length N-alkyl vinylogous amides is demonstrated leading to the formation of pyrroles, ethyl 2-phenyl-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylate 222, ethyl 2-(4-nitrophenyl)- 6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylate 223 and ethyl 2-(4-methoxyphenyl)- 6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-3-carboxylate 224 in Knoevenagel condensation reactions similar to those described by Garreth Morgans and Stefania Scalzullo in their PhD theses. The synthesis of 1-benzoyl-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-2,3-dione 233 and 1-(4-methoxybenzoyl)-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-2,3-dione 235 in a double acylation reaction between NH vinylogous amides and oxalyl chloride is also demonstrated. In chapter 3, the synthesis of vinylogous urethanes for making the Cephalotaxus core via Nalkylation, condensation, thionation, Eschenmoser sulphide contraction and tandem acylation/Michael addition reactions are described. A variety of attempts of the arylation reaction on vinylogous urethanes are demonstrated leading to a comparison study to ascertain carbon chain length dependency of the step. The synthesis of pyrido[1,2-a]azonine nucleus of Sessilifoliamide alkaloids, which are a subset of the Stemona alkaloids demonstrated in chapter 4 is in line with our fascination with bigger ringed alkaloids. The synthetic route is presented leading the formation of compounds 1-benzoyl-3- methyl-2,3,7,8,9,10,11,12-octahydropyrido[1,2-a]azonin-4(6H)-one 337, 3-methyl-1-(4- nitrobenzoyl)-2,3,7,8,9,10,11,12-octahydropyrido[1,2-a]azonin-4(6H)-one 338 and 1-(4- methoxybenzoyl)-3-methyl-2,3,7,8,9,10,11,12-octahydropyrido[1,2-a]azonin-4(6H)-one 339.
LG2018
33
Mthembu, Siyanda Thabani. "Enaminones in the synthesis of azabicyclic models for alkaloids." Thesis, 2008. http://hdl.handle.net/10539/5725.
Full textAbstract:
The purpose of this project was to investigate whether methodology developed in
these laboratories for preparing 5/6 and 6/6 azabicyclic systems with bridged
head nitrogen can be extended to 7/6, 8/6, 9/6 and 13/6 azabicyclic systems. The
methodology entails the use of enaminones as central to the formation of the
azabicyclic systems.
The synthetic route adopted began with the Beckmann rearrangement reaction
and/or the Schmidt reaction of cyclic ketones to make lactams, which were then
thionated by Curphy or Brillon procedures. The Michael reaction of NH
thiolactams with tert-butyl acrylate was followed by Eschenmoser sulfide
contraction to afford the enaminones 132 which were utilised in the ring-closing
step. This involved hydrolysis of the tert-butyl ester and cyclisation via a mixed
anhydride. Ethyl 7-oxo-1,2,3,5,6,7-hexahydroindolizine-8-carboxylate 170b, 1-(4-
nitrobenzoyl)-3,4,6,7,8,9-hexahydroquinolizin-2-one 172a, 1-benzoyl-
3,4,7,8,9,10-hexahydropyrido[1,2-a]azepin-2(6H)-one 173d, 1-(4-nitrobenzoyl)-
3,4,6,7,8,9,10,11-octahydropyrido[1,2-a]azocin-2-one 174a, and 1-(4-
nitrobenzoyl)-3,4,7,8,9,10,11,12,13,14,17,16-dodecahydropyrido[1,2-a]azacyclotridecin-
2(6H)-one 176a were synthesised in good yields, but yields of 8-(4-
nitrobenzoyl)-2,3,5,6-tetrahydroindolizin-7(1H)-one 171a and 1-(4-nitrobenzoyl)-
3,4,7,8,9,10,11,12-octahydropyrido[1,2-a]azonin-2(6H)-one 175a were not
satisfactory. In a much shorter synthetic route that involves enaminone chemistry as well, NH
vinylogous amides were synthesised by the Eschenmoser sulfide contraction and
used in the aza-annulation reaction with acryloyl chloride. Structural isomers (to
compounds mentioned above) 8-(4-nitrobenzoyl)-2,3,6,7-tetrahydroindolizin-
5(1H)-one 178a, 1-(4-nitrobenzoyl)-2,3,7,8,9,10-hexahydropyrido[1,2-a]azepin-
4(6H)-one 180a, 1-benzoyl-2,3,7,8,9,10-hexahydropyrido[1,2-a]azepin-4(6H)-one
180b, 1-(4-nitrobenzoyl)-2,3,6,7,8,9,10,11-octahydropyrido[1,2-a]azocin-4-one 181a, 1-(4-nitrobenzoyl)-2,3,7,8,9,10,11,12-octahydropyrido[1,2-a]azonin-4(6H)-
one 182a and 1-(4-nitrobenzoyl)-2,6,7,8,9,10,11,12,13,14,15,16-
dodecahydropyrido[1,2-a]azacyclo-tridecin-4(3H)-one 183a were synthesised in
good yields. 1-(4-Nitrobenzoyl)-2,3,6,7,8,9-hexahydroquinolizin-4-one 179a was
obtained in low yield, and apparently as two conformational isomers.
34
Morgans, Garreth Llewellyn. "New routes to arylated azabicyclic systems from enaminones, and applications to alkaloid synthesis." Thesis, 2009. http://hdl.handle.net/10539/6887.
Full textAbstract:
This thesis describes the application of enaminones towards the construction
of azabicyclic systems. After a brief survey of indolizidine alkaloids bearing
aromatic substituents an overview of the general strategies developed in
laboratories at this University for the synthesis of alkaloids is given in Chapter
1. More specifically, the use of the Eschenmoser sulfide contraction for the
construction of vinylogous amides is central to the work presented in this
thesis.
Syntheses of nitrile containing indolizidine systems are described in chapter 2.
Preliminary reactions towards this goal included the preparation of the
vinylogous amide 3-{2-[(E)-2-oxo-2-phenylethylidene]-1-pyrrolidinyl}propanenitrile
[157] by application of Eschenmoser’s sulfide contraction reaction
to the appropriate thiolactam 3-(2-thioxo-1-pyrrolidinyl)propanenitrile [168A].
In addition, the vinylogous amide was reduced to afford the key amino-ketone
3-[2-(2-oxo-2-phenylethyl)-1-pyrrolidinyl]propanenitrile [160]. Cyclization of
this intermediate afforded the vinylogous amides rel-(7R,8aS)-7-phenyl-
1,2,3,7,8,8a-hexahydro-6-indolizinecarbonitrile [179A] and rel-(7R,8aR)-7-
phenyl-1,2,3,7,8,8a-hexahydro-6-indolizinecarbonitrile [179B] under specific
reaction conditions. By altering the reaction conditions, an additional three
products were isolated and characterized; a result that allowed for a step-bystep
elucidation of the reaction mechanism for conversion of the aminoketone
3-{2-[(E)-2-oxo-2-phenylethylidene]-1-pyrrolidinyl}propanenitrile [157] into the vinylogous amides rel-(7R,8aS)-7-phenyl-1,2,3,7,8,8a-hexahydro-6-
indolizinecarbonitrile [179A] and rel-(7R,8aR)-7-phenyl-1,2,3,7,8,8a-hexahydro-
6-indolizinecarbonitrile [179B]. In addition, approaches to sulfonecontaining
indolizidine systems were explored.
Approaches to the syntheses of the pyrrolidine 2-[1-(2-oxo-2-phenylethyl)-2-
pyrrolidinyl]-1-phenyl-1-ethanone [172A], a key precursor for the construction Chapter 3. In trying to achieve this strategy, we found that synthesis of the
intermediate pyrrolidine 2-[1-(2-oxo-2-phenylethyl)-2-pyrrolidinyl]-1-phenyl-1-
ethanone [172A] proved to be non-trivial. Therefore the timing of reaction
sequences and assembly of the N-alkyl chain was a necessary part of the
strategy. A serendipitous discovery during this part of the research was the
facile acid-induced cyclization of the vinylogous amides with an N-phenacyl
group which lead to the formation of the pyrrolizine system.
Therefore, Chapter 4 describes some of the approaches that were attempted
in constructing this class of nitrogen-containing compound. More specifically,
we explored the ambident nucleophilicity and electrophilicity of vinylogous
amides towards the construction of the pyrrolizine system. The chapter ends
by extending this approach towards the potential synthesis of the lamellarin
class of alkaloids by application of this novel cyclization strategy.
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Throup, Adam, Laurence H. Patterson, and Helen M. Sheldrake. "Intramolecular thermal stepwise [2 + 2] cycloadditions: investigation of a stereoselective synthesis of [n.2.0]-bicyclolactones." 2016. http://hdl.handle.net/10454/9488.
Full textAbstract:
YesFused cyclobutanes are found in a range of natural products and formation of these motifs in a straightforward and easy manner represents an interesting synthetic challenge. To this end we investigated an intramolecular variant of the thermal enamine [2 + 2] cyclisation, developing a diastereoselective intramolecular enamine [2 + 2] cyclisation furnishing δ lactone and lactam fused cyclobutenes in good yield and excellent diastereoselectivity.
The work was funded by Yorkshire Cancer Research
36
Zheng-YanLu and 呂政彥. "Synthesis of Quinolines from Enamine Derivatives via Copper-catalyzed Oxidation Reaction." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/9stfk2.
Full textAbstract:
碩士國立成功大學
化學系
102
In organic synthesis, transition metals as the catalysts have been widely using in industrial or research purpose. Using copper salts as a catalyst compared with other transition metal salts (Ex. Pd(II)、Pd(IV)、Au(III) or Ag(II)), copper salts have relatively inexpensive and environmental friendly characters, etc. Also, copper catalysts in the radical oxidation reaction are great tool for forming the carbon-carbon bond, therefore, The thesis is focus on this study.
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Lin, Pin-Chun, and 林品君. "Double Michael Addition in the synthesis of α-2-Deoxy-Ulosides from β-enamino Ketone." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/92471348350965285743.
Full textAbstract:
碩士中國醫藥大學
藥物化學研究所碩士班
101
Hex-1-en-3-one that had been prepared by oxidation reactions of D-glucals or D-galactals were subjected to Michael addition15 with 3.0 equiv of primary amines (including benzylamine, n-butylamine, and n-octylamine) in MeOH for 2 h. The products,β-Enamino ketone 26, were obtained in 87-95% with high diastereoselective Z-geometry due to the intramolecular hydrogen bonding. β-Enamino kentone 26a reacted with n-hexanol under basic conditions. Several Lewis acids (3.0 equiv), solvents and temperatures were examined. Among these reaction shown that 12N HCl (3.0 equiv) at 100 W/60 oC for 10 min was found to provide the desired product n-hexyl-2-deoxy-α-deoxyulosides (27) with the highest isolated yield (88%) and stereoselectivity (ratio of α/β-amomers: 95/5). α-2-Deoxyglycosides were synthesized in good yields by microware-assisted reaction of β-enamino ketone with various O- and S-nucleophiles in the presence of 3.0 equiv of hydrogen chloride. These glycosyl additions were throgh the double Michael reaction and occurred high α-stereoselectivity and were complete in 10 min in 51-93% yield. The palladium complex were synthesized in good yields by reacting β-enamino ketone with palladium(II) acetate in the presence of 5.0 equiv of sodium bicarbonate and 1.0 equiv of tetrabutylamino bromide in DMF at room temperature for 3 h.
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Pei-JuTsai and 蔡佩如. "Synthesis of Quinolines by Manganese(III) Acetate Mediated Oxidative Free Radical Reaction of Enamine Derivatives." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/15704327191823358554.
Full textAbstract:
碩士國立成功大學
化學系碩博士班
101
Free radical reactions have been recognized as a great tool for forming carbon-carbon bond in organic chemistry; especially the free radical cyclizations of alkenes to become polycyclic compounds. But the reactions are usually terminated by hydrogen atom transfer. In recent decades, oxidative free radical reactions with transition metal salts (Mn(III), Ce(IV), Ag(II) and Pb(IV) etc.) have been taken serious. Because the reactions are terminated by oxidation of the free radical to a carbocation, that can become various products. This thesis is divided into three parts: (1)Quinolines can be synthesized by the oxidative free radical reaction of N-(2’-stilbenyl)enamine derivatives with excess manganese(III) acetate under oxygen. (2)The oxidative free radical reaction of N-(2’-stilbenyl)enamine derivatives with catalytic amount manganese(III) acetate, excess cobalt(II) acetate and oxygen produce quinolines. (3)4-Acylquinolines can be synthesized by the oxidative free radical reaction of ethyl 3-(2-alkynylaniline)-3-benzylacrylate derivatives with excess manganese(III) acetate under oxygen and catalytic manganese(III) acetate combined with excess cobalt(II) acetate and oxygen respectively.
39
Arend, Michael. "Regio- und stereoselektive Synthese von Mannich-Basen durch Addition von Enaminen und Iminen an Iminiumsalze /." 1996. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=007410505&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Tsai, Chia-Chung, and 蔡嘉忠. "一、New, Simple, and Practical Enamine Cyclopropanation Using CH2Cl2二、TiCl4-Mg Promoted Direct Coupling of CHCl3 to Aldehydes, Ketones, and Enamines.三、Asymmetric Synthesis of (+)-Valienamine." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/40513439465041150540.
Full textAbstract:
博士中興大學
化學系所
95
一、New, Simple, and Practical Enamine Cyclopropanation Using CH2Cl2 Abstract： Dichloromethane serves as a novel electrophilic carbene equivalent which adds to an enamine double bond. The presence of other alkenes moieties in the enamine partner is well tolerated. Even enamines derived from sterically hindered ketones react readily with dichloromethane promoted by TiCl4-Mg. 二、TiCl4-Mg Promoted Direct Coupling of CHCl3 to Aldehydes, Ketones, and Enamines. Abstract： Direct oxidative addition of CHCl3 to the Mg-TiCl4 bimetallic species resulted in the generation of an ambiphilic chloromethylenetitanium complex, which not only effected nucleophilic addition to aldehydes and ketones to provide vinyl chlorides but also served as an electrophilic carbene complex to effect enamine-cyclopropanation to give chlorocyclopropanes. 三、Asymmetric Synthesis of (+)-Valienamine Abstract： (+)-valienamine, a potent glycosidase, has a cyclohexene framework containing one amino and three hydroxyl groups on four stereogenic carbons. A new strategy toward enantiopure O-isopropylidene-protected valienamine evolved from controlled construction of a C2 chiral O-isopropylidene-protected cyclohexenediol via ruthenium-catalyzed ring closing metathesis of a C2 chiral O-isopropylidene-protected octadienediol. Regiocontrolled introduction of the hydroxymethyl unit via palladium-promoted carbonylation of vinyl triflate followed by stereocontrolled installation of the amino unit via a displacement of hydroxyl group with net inversion of configuration led efficiently to isopropylidene-protected valienamine. The requisite C2 chiral octadienediol was readily prepared from the (+)-tartaric acid via a three-step protocol: (a) conventional one-pot elaboration of tartaric acid into O-isopropylidene-protected diamide, (b) coupling of diamide with vinylmagnesium bromide, and (c) stereocontrolled reduction of dienedione. The total asymmetric synthesis of O-isopropylidene-protected valienamine was thus realized in fourteen steps with an overall yield of 10.5%. The present route also indicates several shortcomings of current methodology that, once resolved, will provide further efficiency of this route to (+)-valienamine.
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Limbach, Michael. "Ein Baukastensystem zum universellen Aufbau kleiner rigidifizierter Peptidomimetika und spirocyclopropanierter Wirkstoffanaloga." Doctoral thesis, 2004. http://hdl.handle.net/11858/00-1735-0000-0006-B0C3-0.
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Klapa, Katharina Anna. "Untersuchungen zur Synthese von Yohimban- und Campthoteca-Alkaloiden durch Domino-Knoevenagel-Hetero-Diels-Alder-Reaktion." Doctoral thesis, 2007. http://hdl.handle.net/11858/00-1735-0000-0006-AC9C-5.
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Wu, Yao-Ting. "β-Aminosubstituted α,β-Unsaturated Fischer Carbene Complexes as Precursors for Complex Oligocyclic Molecules - Basics and Applications." Doctoral thesis, 2003. http://hdl.handle.net/11858/00-1735-0000-0006-B61B-7.
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