Dissertations / Theses on the topic 'Tetrahydroisoquinolines'
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Talk, Ruaa. "Deprotonation-substitution of N-Boc-tetrahydroisoquinolines." Thesis, University of Sheffield, 2017. http://etheses.whiterose.ac.uk/19202/.
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Tetrahydroisoquinolines (THIQs) are found in a wide range of natural products and compounds with biological activity. This thesis describes the methodology of deprotonation‒substitution as an efficient route to 1-substituted THIQs and 3-substituted THIQs. This methodology was developed by using organolithium and organomagnesium chemistry. Firstly, methods were developed for the lithiation–substitution of tetrahydroisoquinolines by carrying out in situ ReactIR spectroscopic monitoring of deprotonation reactions. Moderate to high yields of products were obtained under the optimum reaction conditions. The lithiation‒substitutions of tetrahydroisoquinolines A were carried out. This chemistry was applied to a short synthesis of the alkaloids (±)-dysoxyline and (±)-crispine A. The lithiation–substitution of N-Boc-3-phenyltetrahydroisoquinoline B was also investigated. Lithiation was found to occur with approximately a 2:1 ratio at C-1 to C-3. NMR studies and DFT analysis were carried out in order to calculate the ratio of the two rotamers of B. Investigations have also focused on N-Boc-3-cyanotetrahydroisoquinoline and N-Boc-2-cyanopyrrolidine. High enantioselectivities of the forming products could be obtained from the sequence of deprotonation–substitution of these compounds at –104 ºC using magnesium bases. Altering the solvent was shown to have a large impact on the yield and enantioselectivity of the products.
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Li, Xiabing. "Synthesis of substituted tetrahydroisoquinolines using lithiation-substitution." Thesis, University of Sheffield, 2014. http://etheses.whiterose.ac.uk/6431/.
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Berg, Michael Arthur George. "Studies in the stereoselective synthesis of 1,1-disubstituted 1,2,3,4-tetrahydroisoquinolines." Diss., This resource online, 1992. http://scholar.lib.vt.edu/theses/available/etd-10032007-171522/.
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Strange, Rosalind H. "Studies towards the synthesis of functionalised 1,2,3,4-tetrahydroisoquinolines." Thesis, University of Bath, 1994. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.760650.
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Jones, Michael William Chemistry Faculty of Science UNSW. "Enhancing the cooperative binding properties of 1,1'-bis(1,2,3,4-tetrahydroisoquinolines)." Awarded by:University of New South Wales. School of Chemistry, 2005. http://handle.unsw.edu.au/1959.4/27400.
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The design of partially reduced 1,1'-bisisoquinoline derivatives was investigated with the aim of controlling the conformation about the C1-C1' axis. This would produce ligands with unusual but predictable ligand binding properties, particularly cooperativity. The introduction of ??-aminoalkyl, ??-azidoalkyl, ??-alkynyl and ??-alkenyl groups onto the nitrogens of the reduced bisisoquinoline core was conducted with the intention of broadening the scope of the ligand. Subsequent epoxidation, hydroboration and Huisgen 1,3-dipolar cycloaddition of terminal unsaturated groups and nucleophilic displacement of the chlorine of the corresponding known bischloroacetyl derivative afforded representative examples of new ligand types for future study. 1,1'-Bis(1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline) was found to readily condense with a wide range of aldehydes to give imidazolines and aspects of the rates of condensation were determined. Mono-alkyl bisisoquinolines were obtained efficiently by cleavage of the imidazolines through a newly defined treatment with sodium cyanoborohydride under acidic conditions. A procedure was developed whereby these two steps could be accomplished in a sequential one-pot process. The mono-alkyl compounds were further derivatized through acetylation, alkylation, sulfonylation and reductive alkylation. Synthetic strategies towards ??-excessive N-arenealkyl derivatives were established with the goal to create scaffolds for the coordination of ??-deficient systems, of which the X-ray crystal structures of three N-arenemethyl derivatives were elucidated. These are each closely related in conformation about the C1-C1' axis. Reaction of two examples of the N-arenealkyl compounds with copper(II) and palladium(II) chlorides, furnished the first known examples of this type of highly reduced 1,1'-bisisoquinoline-metal complex. Single crystal X-ray crystallography was used to analyse the structures of these complexes in the solid state. Preliminary physicochemical investigations were conducted with a view to determining the conformation of the molecules about the bisisoquinoline C1-C1' bond. The interaction of intermolecular N-aryl ??-excessive compounds with ??-deficient systems was found to result in minimal spectroscopic changes. Complementary intramolecular ??-excessive/??-deficient systems were found through fluorometric analysis to readily form charge transfer complexes. Finally, it was determined that the conformation of 1,1'-bis[2-(methoxy-18- crown-6)ethanoyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline] could be controlled by the simultaneous coordination of the termini of the diperchlorate salt of 1,3-diaminopropane to the crown ether moieties of the ligand. A range of new N-substituted bisisoquinolines have been synthesised and methods developed for determining interactions between parts of these molecules that through these physicochemical characteristics could allow monitoring of conformational behaviour in future studies. Keywords: 1,1'-bisisoquinoline, conformational analysis, supramolecular chemistry, functional ligands, metal complexes.
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MacLeod, Patricia. "Synthesis of chiral tetrahydroisoquinolines and their applications in asymmetric catalysis." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=86796.
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This thesis describes an investigation on the synthesis of chiral 1,2,3,4-tetrahydroisoquinoline-based amino alcohols (THIQNOLs) and their use as chiral ligands.The synthesis of these structures using an aza-Friedel-Crafts reaction between 3,4-dihydroisoquinoline and naphthols is described in the first part of the thesis. By design, this process occurs without added catalyst and serves as a proof of concept for greener (or self-catalytic) catalysis. The reactions can be carried out either in absence of solvent or by using water as solvent.
The second part of this thesis describes the synthesis of optically enriched THIQNOLs for their use as chiral ligands. The first generation of ligands is a set of tertiary amino alcohols, which were applied to the asymmetric addition of diethylzinc to aldehydes. The second generation of ligands is a set of secondary amino alcohols and these were also applied to the asymmetric addition of diethylzinc to aldehydes, improving on the results achieved with the first generation.
La présente thèse a pour but, l'étude de la synthèse des composés de type 1,2,3,4-tetrahydroisoquinoline portant une fonctionnalité amino-alcool (THIQNOLs). Grâce à cette fonctionnalité, il est possible d'utiliser ces composés comme ligands chiraux en synthèse asymétrique.
La première partie de la thèse décrit la synthèse racémique de ces composés en utilisant la réaction aza-Friedel-Crafts entre les 3,4-dihydroisoquinolines et les naphthols. Ce procédé ne nécessite ni catalyseur, ni réactif stochiométrique. Cette réaction sert de preuve de concept qu'une catatyse plus ''verte'' (ou auto-catalysée) est possible. En général, ces réactions ne nécessitent pas de solvant, bien que l'eau peut être utilisée.
La seconde partie de la thèse décrit la synthèse asymétrique des composés THIQNOLS ainsi que leur utilisation en tant que ligand chiraux pour l'addition asymétrique du diethylzinc aux aldehydes. La première génération des ligands est basée sur les amino-alcool tertiaires, alors que la deuxième génération repose sur les amino-alcool secondaires. Les résultats obtenus pour les ligands de la deuxième génération sont, en général, supérieur à ceux de la première génération.
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Brar, Satjit Singh. "Effects of Smoking and Gender on Tetrahydroisoquinolines and Beta-Carbolines in a Healthy Population and During Alcohol Detoxification." VCU Scholars Compass, 2008. http://hdl.handle.net/10156/1561.
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Frost, Aileen Bernadette. "Aziridines and aziridinium intermediates in the asymmetric synthesis of beta-substituted-alpha-amino acids and 1,2,3,4-tetrahydroisoquinolines." Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:ab3aa702-caab-4d20-9057-028258be5fdb.
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This thesis is concerned with the development of methodology for the regioselective ring-opening of aziridines and aziridinium intermediates and its subsequent application to the asymmetric synthesis of β-substituted-α-amino acids and 1,2,3,4-tetrahydroisoquinolines. Chapter 1 introduces methods for the formation of aziridines and aziridinium ions and focusses on their utility as intermediates in synthesis. Chapter 2 describes studies into the synthesis of aziridines from enantiopure α-hydroxy-β-amino esters and their subsequent conversion to the corresponding β-hydroxy-α-amino acids via either a regioselective ring-opening with Cl3CCO2H, or a rearrangement promoted by Cl3CCO2H. Application of this procedure to both syn- and anti-configured substrates enabled the syntheses of (S,S)-allo-threonine, (2R,3S)-threonine, (R,R)-3-hydroxyphenylalanine and (2S,3R)-3-hydroxyphenylalanine. Chapter 3 details attempts to truncate the synthesis described in Chapter 2 by investigating the synthesis of enantiopure anti-β-hydroxy-α-amino acids via the intermediacy of aziridinium ions. These studies culminated in the development of a regioselective and stereospecific one-pot aziridinium formation and ring-opening protocol, leading to the synthesis of a range of C(3)-aryl and C(3)-alkyl substituted anti-β-hydroxy-α-amino acids. Chapter 4 discusses the conversion of enantiopure anti-α-hydroxy-β-amino esters to anti-β-fluoro-α-amino esters via the regioselective and stereospecific ring-opening of an aziridinium intermediates in situ. The subsequent development of a one-pot deprotection strategy leads to a concise and expedient synthesis of anti-β-fluorophenylalanines. The extension of this methodology to access a representative anti-α,β-diamino acid is also demonstrated. Chapter 5 describes the development of a one-pot diastereoselective rearrangement of enantiopure α-hydroxy-β-amino esters to 1,2,3,4-tetrahydroisoquinolines. The substrate scope of this reaction manifold is examined and application to the asymmetric synthesis of enantiopure 1,2,3,4-tetrahydroisoquinolines also discussed. Chapter 6 contains full experimental procedures and characterisation data for all compounds synthesised in Chapters 2, 3, 4 and 5.
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Erdmann, Vanessa [Verfasser], Dörte Akademischer Betreuer] Rother, and Lars Mathias [Akademischer Betreuer] [Blank. "Synthetic enzyme cascades for the synthesis of amino alcohols and tetrahydroisoquinolines / Vanessa Erdmann ; Dörte Rother, Lars Mathias Blank." Aachen : Universitätsbibliothek der RWTH Aachen, 2018. http://d-nb.info/121159081X/34.
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Erdmann, Vanessa Verfasser], Dörte [Akademischer Betreuer] Rother, and Lars Mathias [Akademischer Betreuer] [Blank. "Synthetic enzyme cascades for the synthesis of amino alcohols and tetrahydroisoquinolines / Vanessa Erdmann ; Dörte Rother, Lars Mathias Blank." Aachen : Universitätsbibliothek der RWTH Aachen, 2018. http://d-nb.info/121159081X/34.
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Chiba, Hiroaki. "Total Synthesis of Tetrahydroisoquinoline Alkaloids." 京都大学 (Kyoto University), 2013. http://hdl.handle.net/2433/174544.
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Osuji, Obinna. "Toward the total synthesis of BBIQ alkaloids : the trilobine." Thesis, Bordeaux, 2020. http://www.theses.fr/2020BORD0183.
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Les unités monomériques, benzyltetrahydroisoquinoline, parties de la synthèse totale de la trilobine, sont obtenus par de courtes séquences réactionnelles, à partir de produits commerciaux facilement accessible. Différentes approches ont été développés pour accéder aux composés benzyltetrahydroisoquinoline. Le premier point est la réaction de Pictet-Spengler, très efficace malgré quelques limitations de régiosélectivité.De premiers essais nous ont permis d’accéder, par réaction de Bischler-Napieralski, a des benzyltetrahydroisoquinoline à partir de phénéthylamines halogénées, mais la réaction nécessite des traaux supplémentaires pour optimiser et développer cette réactivité.Par ailleurs, nos efforts pour accéder à la partie sud diarylether par ré action de type Ullmann ont permis l’obtention de résultats encourageants et la préparation de la partie sud de la trilobine, ainsi que celle d’analoguesThe monomeric units, benzyltetrahydroisoquinoline, parts of the total synthesis of trilobine, are obtained by short reaction sequences, from readily available commercial products. Different approaches have been developed to access benzyltetrahydroisoquinoline compounds. The first point is the Pictet-Spengler reaction, which is very efficient despite some limitations in regioselectivity.Initial tests have enabled us to access, by Bischler-Napieralski reaction, benzyltetrahydroisoquinoline from halogenated phenethylamines, but the reaction requires additional work to optimize and develop this reactivity.In addition, our efforts to access the southern part of the diaryl ether by Ullmann-type reaction have yielded encouraging results and the preparation of the southern part of trilobine, as well as that of analogues
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Hedley, Kenneth Andrew. "Aspects of the chemistry of 1, 2, 3, 4-tetrahydroisoquinoline." Thesis, Northumbria University, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245213.
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Willets, Jonathon. "Studies on the potential neurotoxicity of tetrahydroisoquinoline and nicotinamide derivatives." Thesis, University of Leicester, 1995. http://hdl.handle.net/2381/34272.
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The naturally occurring compounds N'-methyl nicotinamide (NMN), 6,7-dihydro-1-methyl-1,2,3,4-tetrahydroisoquinoline (salsolinol) and 1,2,3,4-tetrahydro-2-methyl-4,6,7-isoquinolinetriol (TMIQ) are reported to interact with catecholaminergic systems in vivo and have similar structure to 1-methyl-4-phenylpyridinimuM (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Three cell lines, rat B65, hmuMan IMR32 and SH-SY5Y, were examined to find the most appropriate with which to study such toxins. These data indicate that both B65 and IMR32 cells do not take up catecholamines (2% after one hour), in monolayer culture. In contrast, SH-SY5Y cells take up significant (P 0.05) amounts of both noradrenaline (NA) and dopamine (DA), which can be blocked by uptake1 inhibitors. Furthermore, SH-SY5Y cells store [3H]NA in a releasable pool, which can be stimulated through receptor-occupancy and depolarization. Therefore, the hmuMan SH-SY5Y neuroblastoma cell line was selected for further study. NMN induced cytotoxicity albeit at high concentrations (10mM), in SH-SY5Y cells. Lower concentrations had no significant (P 0.05) effect. Cytotoxicity was inhibited in a dose dependent manner by the addition of a-tocopherol. NMN had little effect upon catecholamine uptake and release. Both salsolinol and TMIQ significantly (P 0.05) inhibited MTT reduction and increased LDH release, at concentrations within the range of MPP+ cytotoxicity, in vitro. Cytotoxicity was not inhibited by the addition of monoamine oxidase inhibitors, antioxidants, or imipramine. TMIQ and salsolinol stimulated catecholamine uptake with EC50 values of 7muM (NA) and 54muM (DA), 17muM (NA) and 11muM (DA), respectively. However, above 100muM, salsolinol inhibited uptake with IC50 values of 411muM and 379muM for NA and DA, respectively. Inhibition of NA uptake by salsolinol, corresponded to the increased displacement of nisoxetine from the uptake1 recognition site, since the Ki (353muM) for displacement was similar to the IC50 values (411 and 379 muM) for uptake. TMIQ also displaced nisoxetine binding with Ki of 71muM. TMIQ and salsolinol stimulated catecholamine uptake does not involve the uptake recognition site, and is not inhibited by elevation of cAMP or cGMP, or the inhibition of PKC. Salsolinol inhibited both carbachol (CCH) and potassium, whilst TMIQ inhibited only potassium evoked [3H]NA release, from SH-SY5Y cells. Thus both TMIQ and salsolinol are cytotoxic to SH-SY5Y cells, although the exact mechanism of toxicity requires further investigation, it appears not to involve bioactivation by MAO, and is not mediated through membrane based free radical damage. NMN is also cytotoxic to neurones, but only at high concentrations, and appears to be membrane directed. The high concentration of NMN required to induce cytotoxicity casts doubt over the relevance of NMN as an in vivo toxin. In contrast, both TMIQ and salsolinol are cytotoxic in vitro and may have a role in neurodegeneration.
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Cullen, Danica Renae. "Development of tetrahydroisoquinoline analogues: Towards a treatment for Human African Trypanosomiasis." Thesis, Curtin University, 2016. http://hdl.handle.net/20.500.11937/52988.
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This research describes the exploration of a new scaffold with the potential to be developed in to a new drug for the treatment of Human African Trypanosomiasis (HAT), a neglected disease endemic in sub-Saharan Africa. Derivatives of an isoquinoline scaffold were synthesised and evaluated for their in vitro activity against T.b.rhodesiense, the causative agent of HAT. Five derivatives were identified with inhibition of T.b.rhodesiense in the sub-micromolar range with good selectivity over mammalian cells.
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Gramm, Katharina. "Nachweis und Bedeutung von Tetrahydroisoquinolinen im Urin von Patienten mit Aufmerksamkeits-Defizit-Hyperaktivitätsstörung." Lübeck Zentrale Hochschulbibliothek Lübeck, 2010. http://d-nb.info/1001809645/34.
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Di, Xiaohui. "Zéolithes dopées au cuivre(I) comme catalyseurs verts pour la synthèse organique." Electronic Thesis or Diss., Strasbourg, 2024. http://www.theses.fr/2024STRAF012.
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Les motifs aryliques sont présents dans de nombreux composés biologiquement actifs. Nombre d’entre eux se retrouvent sous forme de biaryles, de phénols et de tétrahydroisoquinoléines, systèmes que l’on trouve dans de nombreux produits naturels et certains intermédiaires synthétiques importants. Au cours des dernières décennies, diverses réactions de couplage catalysées par des métaux (de transition) ont émergé pour synthétiser de tels motifs ou molécules en formant des liaisons carbone-carbone ou des liaisons carbone-hétéroatome. Cependant, la plupart de ces réactions ont été réalisée dans des conditions homogènes avec des conditions de réaction non satisfaisantes, telles que des températures élevées, des solvants toxiques et des bases et ligands supplémentaires. Afin de rendre ces conditions plus vertes et plus durables, le potentiel des zéolithes dopées au cuivre en tant que catalyseurs hétérogènes et recyclables a été évalué pour la synthèse de biaryles, de phénols et de dérivés de tétrahydroisoquinoléine au travers de plusieurs réactions de couplage, telles que les réactions de type homocouplage, les réactions de couplage croisé de type Chan-Lam-Evans et les réactions de couplage déhydrogénatif croisé. Plusieurs procédés catalytiques efficaces et économiques ont été développés dans des conditions plus vertes et plus douces, sans avoir besoin d’un ligand ni d’une base supplémentaire.De plus, l’application des motifs biaryles ainsi obtenus a également été explorée dans des réactions de Diels-Alder pour la construction d’hétérocycles d’intérêt avec des économies d’atomes élevéesAryl rings are a predominant feature in numerous biologically active compounds. Most of them can exist as biaryl, phenol, and tetrahydroisoquinoline moieties, which are encountered in many natural products and in various important synthetic intermediates. In the last few decades, various (transition) metal-catalyzed coupling reactions have emerged to synthesize such motifs or molecules via the formation of carbon-carbon bonds or carbon-heteroatom bonds. However, most of them were performed under homogeneous conditions with unsatisfactory reaction conditions, such as high temperatures, toxic solvents, and additional bases and ligands. To improve the greenness and sustainability of these processes, the potential of copper-doped zeolites as heterogeneous and recyclable catalysts was evaluated for the synthesis of biaryls, phenols, and tetrahydroisoquinoline derivatives through the study of several coupling reactions, such as homocoupling-type reactions, Chan-Lam-Evans-type cross-coupling and cross-dehydrogenative coupling reactions. Several efficient and economical catalytic procedures were developed under greener and milder conditions without the need for any additional ligand and base.Furthermore, the application of the so-obtained important biaryl motifs has also been explored in Diels–Alder reactions for the construction of heterocycles of interest with high atom economies
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Gramm, Katharina [Verfasser]. "Nachweis und Bedeutung von Tetrahydroisoquinolinen im Urin von Patienten mit Aufmerksamkeits-Defizit-Hyperaktivitätsstörung / Katharina Gramm." Lübeck : Zentrale Hochschulbibliothek Lübeck, 2010. http://d-nb.info/1001809645/34.
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Dushing, M. P. "“Target cum flexibility": towards the synthesis of spirocyclic nucleosides, carbapenems and tri-/tetracyclic tetrahydroisoquinoline alkaloids." Thesis(Ph.D.), CSIR-National Chemical Laboratory, Pune, 2013. http://dspace.ncl.res.in:8080/xmlui/handle/20.500.12252/2205.
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Patel, Krishnakant. "Approaches Toward the Inhibition of Mycobacterium tuberculosis enzyme MshC using Substrate Analogues and Natural Products." University of Toledo / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=toledo151327611162838.
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Chen, Chiliu. "Efforts toward the first enantioselective total synthesis of praziquantel and synthetic model studies on ecteinascidin 743 by novel aromatic C-H insertion methodology." [Tampa, Fla.] : University of South Florida, 2004. http://purl.fcla.edu/fcla/etd/SFE0000266.
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Silva, Luiz André de Araújo. "Novos derivados sintéticos de alcaloides tetrahidroisoquinolínicos." Universidade Federal da Paraíba, 2016. http://tede.biblioteca.ufpb.br:8080/handle/tede/9080.
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Alkaloids are secondary metabolites of great medical importance, covering a diverse group of nitrogen containing molecules in its structure, the number of alkaloid containing the tetrahidroisoquinolínico skeleton 1-substituted is extensive and impressive pharmacological versatility of this class arouses interest in experimental pharmacologists, the importance. This work has as objective, the synthesis of tetrahydroisoquinolines and provide material for future pharmacological studies both in-vivo and in-vitro. For the synthesis of phenyltetrahydroisoquinolinics alkaloids, benzyltetrahydroisoquinilinic and phenyltetrahydro-β-carboline the Pictet-Spengler reaction was aplicated. With the aim of expanding the pharmacological studies of the alkaloid (1-(3-dimethoxy-4-hydroxyphenyl)-7-methoxy-1,2,3,4,-tetrahydroisoquinoline (MTHP) your synthesis was repeated. 4 alkaloids were obtained, 2 phenyltetrahydroisoquinolinic (1-(3,5-dimethoxy-4-hydroxyphenyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline (73%) and 1-(2-hydroxyphenyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline (54%)), 1 phenyltetrahydro-β-carboline (1-(3,5-dimethoxy-4-hydroxyphenyl)-1,2,3,4,-tetrahydro-β-carboline (38%)) and 1 benzyltetrhydroisoquinilínic (1-(1-ethyl-3,4-metilenodioxidofenil)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (87%)). From the material available for the pharmacological MTHP tests showed low toxicity without genotoxicity, its immunomodulatory mechanism in asthma is related to regulation of TH2 profile.
Alcaloides são metabólitos secundários de grande importância medicinal, abrangendo um grupo diverso de moléculas contendo nitrogênio na sua estrutura. O número de alcaloides que contém o esqueleto tetrahidroisoquinolínico 1-substituído é extenso e a impressionante versatilidade farmacológica desta classe desperta o interesse nos farmacologistas experimentais. Visto a importância dos alcaloides isoquinolínicos, o nosso trabalho tem como objetivo a síntese de derivados tetrahidroisoquinolínicos e fornecer material para futuros estudos farmacológicos tanto in-vivo como in-vitro. Para a síntese dos alcaloides feniltetrahidroisoquinolínicos, benziltratrahidroisoquinilínicos e feniltetrahidro-β-carbolínicos foi utilizado a reação de Pictet-Spengler. Com o objetivo de ampliar os estudos farmacológicos a respeito do alcaloide (1-(3-dimetoxi-4-hidroxifenil)-7-metoxi-1,2,3,4,-tetrahidro isoquinolina (MTHP) refizemos a sua síntese como descrito na literatura. Obtivemos 4 alcaloides, sendo 2 deles feniltetrahidroisoquinolínicos (1-(3,5-dimetoxi-4-hidroxifenil)-7-metoxi-1,2,3,4,-tetrahidro isoquinolina (73%) e 1-(2-hidroxifenil)-7-metoxi-1,2,3,4,-tetrahidro isoquinolina (54%)), 1 feniltetrahidro-β-carbolínicos (1-(3,5-dimetoxi-4-hidroxifenil)-1,2,3,4,-tetrahidro-β-carbolina (38%)) e 1 benziltratrahidroisoquinilínicos (1-(1-etil-3,4-metilenodioxidofenil)-6,7-dimetoxi-1,2,3,4,-tetrahidro isoquinolina(87%)). A partir da disponibilização de material para os testes farmacológicos do MTHP, apresentou baixa toxicidade sem genotoxicidade, seu mecanismo imunomodulador na asma está relacionado a regulação do perfil TH2.
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CODY, WAYNE LIVINGSTON. "SYNTHESIS, BIOLOGICAL ACTIVITY AND CONFORMATIONAL ANALYSIS OF FRAGMENT ANALOGUES OF ALPHA-MELANOTROPIN (PEPTIDE, STRUCTURE-FUNCTION, PHENYLGLYCINE, NMR, TETRAHYDROISOQUINOLINE-3-CARBOXYLATE)." Diss., The University of Arizona, 1985. http://hdl.handle.net/10150/188044.
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α-MSH (α-melanotropin) is a naturally occurring linear tridecapeptide (Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH₂) that is primarily known for its ability to stimulate integumental melanocytes and more recently has been implicated in a variety of physiological and neurological processes. It has been shown that substitution of D-phenylalanine in the seven position of this hormone led to an analogue with increased potency and prolonged biological activity. Furthermore, cyclization between the four and ten positions via a cystine bridge led to analogues with enhanced potency. In this regard, a series of conformationally restricted linear and cyclic fragment analogues of α-MSH have been prepared and carefully analyzed by both biological and biophysical methods. Conformational restriction was incorporated in α-MSH fragment analogues, by: (1) substitution of sterically restricted amino acids into the native sequence; or (2) cyclization of the peptide via a disulfide bridge. Due to the biological differences observed for these synthetic α-MSH fragment analogues, a complete conformational analysis by both proton and carbon-13 NMR was performed. The conformational preferences of the backbone were examined by analyzing: (1) the alpha proton chemical shifts; (2) the amide proton chemical shifts; (3) the amide proton coupling constants; and (4) the amide proton temperature dependencies. The data suggests that the peptide backbone in both linear and cyclic analogues possesses a great amount of conformational flexibility with no hydrogen-bonded stabilization. The three-dimensional orientations of individual amino acid side chains have been examined by analyzing: (1) the chemical shifts of the side chain protons; (2) the alpha-beta coupling constants (corresponding rotamer populations); and (3) the carbon-13 spin lattice relaxation times (T₁). A careful examination a the chemical shifts of the side chains of individual amino acids in linear α-MSH fragments reveals that incorporation of an aromatic D-amino acid in the seven position results in an interaction of the side chains of the six, seven and eight positions. In addition, the low carbon-13 spin-lattice relaxation times for the β-carbons of the 5-9 sequence for both Ac-[Nle⁴]-α-MSH₄₋₁₁-NH₂ and Ac-[Nle⁴, D-Phe⁷]-α-MSH₄₋₁₁-NH₂, provides further evidence for an interaction of these side chains. Similar shielding patterns have been observed for the cyclic α-MSH fragment analogues depending upon whether L- or D-phenylalanine is incorporated in the seven position. Considering the differences in biological potency and the similarities in the NMR parameters between the linear and cyclic homologs, it can be concluded that the conformational properties that determine biological potency are too subtle to be measured by present NMR methodology. Furthermore, the similarity of the NMR shielding patterns suggests that a 23-membered ring is too large to impart significant conformational constraints on the peptide backbone or amino acid side chains.
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Mottinelli, Marco. "Targeting estrogen biosynthesis and hormone receptor pathways for the treatment of cancer." Thesis, University of Bath, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.642016.
Full textAbstract:
The tetrahydroisoquinoline (THIQ) core structure is explored as a steroidomimetic nucleus with attractive pharmaceutical properties. A library was synthesised employing Pomeranz-Fritsch, Pictet-Spengler, Bischler-Napieralski strategies yielding 77 final targets, substituted at every position, for biological evaluation. Complementary strategies overcame synthetic difficulties, sometimes yielding two products in a single cyclisation. Three compounds were initially tested against a panel of 19 nuclear receptors (NRs) and exhibited broad substitution-dependent activity. 2-(4-Chlorophenyl)-1-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-ol fully inhibited every NR at 100 µM, confirming the THIQ as a lead for optimisation. Compounds were evaluated for cytotoxicity against 60 cell lines by the NCI (USA), exhibiting moderate to insignificant cytotoxicity. Three compounds showed ca. 30-90% of average growth inhibition and were selected for a five dose test. Off-target evaluation highlighted compounds with activity against glucagon-like peptide 1 secretion, calcitonin gene-related peptide receptor antagonism and with >100% inhibition against the metabotropic glutamate receptor 2. Estrogen receptor-related receptor α (ERRα), a constitutively active orphan NR, is a hormone-dependent cancer target and diethylstilboestrol (DES), a known inverse agonist, possesses similarities to THIQs. THIQs tested against ERRα revealed no general SAR rules, but showed a lower degree of efficacy in a commercial TR-FRET assay, with 1-benzyl-2-(4-chlorophenyl)-4-methyl-1,2,3,4-tetrahydroisoquinolin-6-ol showing 79% efficacy at 100 µM as an inverse agonist, being more active than DES (64% at 100 µM). Inhibition of steroidogenic enzymes like 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is an emerging approach for the treatment of HDBC, compared to other current clinical strategies. THIQs evaluated against 17β-HSD1 showed good activity in both whole cell and cell lysate assays, with the best inhibitor, 2-(4-chlorophenyl)-4-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-ol, possessing an IC50 value of 336 nM. The value of THIQ as a drug-like steroidomimetic scaffold is thus established and this work reveals straightforward strategies to optimise potency and selectivity for a range of potential targets by structural and stereochemical iteration.
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Bonetti, A. "BETA-AMINO ACIDS AS TOOL FOR THE PREPARATION OF FOLDAMERS AND NANOMATERIALS." Doctoral thesis, Università degli Studi di Milano, 2015. http://hdl.handle.net/2434/250238.
Full textAbstract:
beta-Amino acids are analogues of alpha-amino acids (AAs) in which the amino group is linked to the beta-carbon instead of the alpha-carbon. In this thesis are reported different approces to beta amino acids both from the synthetic and applicative points of view.
Beta-2,3-diaryl-beta amino acids: Development of diastero- and enantioselective synthesis of variously substituted 2,3-Diaryl amino esters using a TiCl4 catalyzed Mannich-like reation. Preparation of -Hybrid peptides containing 2,3-Diaryl amino acids and Alanine. Structural characterization of -hybrid using NMR analysis and X-Ray diffraction to understand if their strong aromatic component affect the secondary structure of these peptide. Studies on the self assembly of these derivatives in order to obtain sopramolecular architectures.
Tetrahydroisoquinoline-4-carboxylic acid (TIC): Development of a simple and scalable synthesis of tetrahydroisoquinoline 4-carboxylic acid, solving the problems encountered using the literature synthetic protocol. Bio-enzymatic resolution of TIC. Preparation of model peptides in in order to study TIC conformational behavior.
Rhodium catalyzed transformation of diazobarbonyl-piperidine derived from beta amino acids n efficient preparation of three different classes of -diazocarbonylpiperidine compounds derived from -AAs, including the simple Nipecotic acid, its benzocondensate, i.e. TIC, and TIC derivatives in which a further aryl moiety is present at position 3. Generation of rhodium carbenes starting from diazocarbonyl derivatives and rhodium-(II) dimer catalysts to give intramolecular carbene insertion.Search of the best catalyst and the optimal reaction conditions to drive the chemoselectivity of the insertion reaction. NMR characterization of the polycyclic compounds obtained by intramolecular carbene insertions.
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Neves, dos Santos Ana Rita. "Exploration of [2+2+2] cyclotrimerisation reactions of alkynes : a new methodology for the synthesis of small molecules to probe biological systems." Thesis, University of Bradford, 2013. http://hdl.handle.net/10454/6311.
Full textAbstract:
The generation of new chemical entities (NCEs) for use in chemical biology and drug discovery is of wide interest to both academia and the pharmaceutical industry. In order to generate NCEs, this project focused on development of new synthetic methodologies using transition-metal mediated [2+2+2] cyclotrimerisation of alkynes and unsaturated molecules to form bi- and tricyclic heterocyclic derivatives, some with structural resemblance to the quinocarcin family of natural products. Three different dialkynes (1,5-di(prop-2-yn-1-yl)pyrrolidin-2-one 2.117a, 1,6-di(prop-2-yn-1-yl)piperidin-2-one 2.118a and 4-benzyl-1,6-di(prop-2-yn-1-yl)piperazin-2-one 2.120a) were successfully synthesised. Several cyclotrimerisations were attempted, with the best yields being obtained when diethylacetylene dicarboxylate 2.113a was used as the monoalkyne and Cp*Ru(cod)Cl as the catalyst in refluxing toluene. New heterocyclic compounds with potential for diversification were synthesised using a diversity-oriented synthesis approach; specifically the build/couple/pair strategy for the synthesis of small molecules. Racemic nitrogen and oxygen building blocks were coupled with acrylonitrile, bromoacetonitrile and acyl chlorides. The pair step involved the intramolecular ring closure using transition-metal catalysed [2+2+2] cyclotrimerisations using microwave assisted radiation. The best catalyst for this approach was found to be CpCo(CO)2 at 150 ºC (300 W) in chlorobenzene. This provided a new methodology with potential for synthesising a diverse set of small molecules for biological testing. 20 compounds were subjected to chemosensitivity testing using the MTT assay. Several compounds were shown to possess activity in bladder (RT112) and breast (MCF-7) cancer cell lines. As these two cell lines are known to express extra-hepatic cytochromes P450 enzymes, it is possible that these are involved in generating cytotoxic metabolites that may damage DNA.
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Harfouche, Abha. "Isolement de composés d’intérêt chimique et biologique dans des mélanges complexes." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS043.
Full textAbstract:
Cette thèse est fondée sur le développement de nouvelles méthodes de criblage et d’analyse appliquées aux extraits naturels. Le premier axe de ce travail a consisté à isoler une molécule très minoritaire dans un mélange réactionnel de synthèse biomimétique en utilisant entre autre la chromatographie de partage centrifuge (CPC) en mode pH-zone refining. Nous avons pu isoler la nitrarine avec un rendement de 0,04% en permettant de valider le mécanisme proposé pour sa synthèse biomimétique.Le deuxième axe de ce projet est consacré à l’identification par fractionnement bioguidé, dans les graines de Mucuna pruriens (une plante de la pharmacopée traditionnelle indienne), des molécules responsables de la synergie thérapeutique antiparkinsonienne mise en évidence dans la littérature par des essais in vivo et cliniques. L’extrait hydro-alcoolique de graines de Mucuna pruriens a été fractionné par chromatographie sur colonne de gel de silice, puis les fractions obtenues ont été évaluée in vitro sur plusieurs cibles biologiques : enzymes de dégradation de la dopamine (MAO, COMT), et une enzyme de sa synthèse endogène (DDC). Nous avons développé une méthodes de détection d’une activité d’inhibition de ces enzymes par spectrométrie de masse. À partir des fractions identifiées comme étant actives, nous avons isolé et identifié une vingtaine de molécules, parmi lesquelles une dizaine sont nouvellement décrites. Il a été nécessaire de synthétiser certaines d'entre elles en raison de la quantité nécessaire aux essais biologiques. Certaines de ces molécules ont montré une activité inhibitrice intéressante sur la COMTThis thesis is based on the development of new methods of screening and analysis applied to natural extracts.The first axis of this work consisted in isolating a minoritary molecule in a reaction mixture of a biomimetic synthesis using different techniques including centrifugal partition chromatography (CPC) in pH-zone refining mode. We were able to isolate the nitrarine with a yield of 0.04%, thus allowing to validate the proposed mechanism of its biomimetic synthesis.The second axis of this project is dedicated to the identification in the seeds of Mucuna pruriens (a plant of Indian traditional pharmacopoeia), by bioguided fractionation, the molecules responsible for the antiparkinsonian synergy demonstrated by in vivo studies and clinical trials. For this purpose, the hydroalcoholic extract of M. pruriens seeds was fractionated by chromatography on a silica gel column and the obtained fractions were evaluated in vitro on various biological targets: the dopamine-degrading enzymes (MAO, COMT) and an enzyme implicated in its endogenous synthesis (DDC). Moreover, we have developed a method to detect by mass spectrometry fractions or compounds having an inhibitory activity on these enzymes. From fractions identified as active, we isolated and identified about twenty molecules, from which a dozen are newly described. On the other hand, it was necessary to synthetize some of them due to the amount required by bioassays. Some of these molecules have shown an interesting inhibitory activity against the COMT enzyme
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Mandel, Jérémie. "Approches synthétiques de tétrahydroisoquinoléines par cyclisation Pallado-Catalysée & synthèse de composés spirocétaliques par RRM." Phd thesis, Université de Haute Alsace - Mulhouse, 2010. http://tel.archives-ouvertes.fr/tel-00717736.
Full textAbstract:
Après avoir exposé les enjeux de ce travail en présentant dans le chapitre 1 les produits naturels possédant le motif tétrahydroisoquinoléinique, leurs intérêts pharmacologiques et leur unique voie d'accès via la réaction de Pictet Spengler, nous avons présenté la synthèse énantiosélective de tétrahydroisoquinoléine 1,3-disubstituées et différentes tentatives d'obtention des motifs pentacycliques de différents alcaloïdes d'intérêt biologique. La synthèse énantiosélective de tétrahydroisoquinoléines 1,3-disubstituées a été effectuée en 6 étapes utilisant deux étapes clés. Une alkylation catalysée par transfert de phase permet de créer un centre asymétrique et une cyclisation pallado-catalysée permet d'accéder au motif tétrahydroisoquinoléinique. Dans la suite, les différentes voies d'accès testées permettant d'accéder au motif pentacyclique n'ont pas été couronnées de succès. Dans un second temps ont été exposées les différentes sources de composés possédant un motif spirocétalique, leurs propriétés électroniques et conformationnelles. Les différentes voies de synthèse de spirocétals ont été présentées. Les différentes voies de synthèse d'a-hétérofuranes ont été introduites en se concentrant sur les dérivés soufrés, azotés et oxygénés. L'utilisation des a alcoxyfuranes en réaction de cycloaddition a ensuite été présentée ainsi que l'utilisation des adduits. Enfin la réaction de RRM a été étudiée en se focalisant sur les réactifs à forte tension de cycle. Différentes voies de synthèse des a-alcoxyfuranes ont été exposées. Une voie d'accès générale a été développée par réaction d'addition/élimination sur le 2,5-diméthoxy-2,5-dihydro-2-furanoate de méthyle. La séquence cycloaddition [4+2] ou [4+3]1 RRM a été ensuite présentée permettant d'accéder aux spirocétals (5,6) et (6,6). L'application de cette méthodologie à la synthèse des aculéatines et des aculéatols, est étudiée.
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Al-Horani, Rami. "Designing Direct and Indirect Factor Xa Inhibitors." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/329.
Full textAbstract:
Anticoagulants are the basis for treatment and prevention of thrombotic diseases. The currently available medicines are associated with a wide range of adverse reactions that mandates developing new anticoagulants. Several lines of evidence support the superiority of factor Xa (FXa) as a promising target to develop novel anticoagulants. This work focuses on the design of direct and indirect FXa inhibitors using an interdisciplinary approach. As indirect FXa inhibitors, a focused library of tetrasulfated N–arylacyl tetrahydroisoquinoline (THIQ) nonsaccharide allosteric antithrombin activators was designed, synthesized, and biochemically evaluated to establish their structure–activity relationship (SAR). An N–arylacyl THIQ analog having carboxylate at position–3, two sulfate groups at positions–5 and –8 of THIQ moiety, butanoyl linker, and two sulfate groups at positions–2 and –5 of the phenolic monocyclic moiety was identified as the most promising nonsaccharide antithrombin activator with KD of 1322 ± 237 μM and acceleration potential of 80–fold. Its biochemical profile indicates a strong possibility that it activates antithrombin by the pre–equilibrium pathway rather than the induced–fit mechanism utilized by heparin analogs. A similar interdisciplinary approach was exploited to design direct FXa inhibitors that possess high selectivity and are potentially orally bioavailable. Structurally, the designed direct FXa inhibitors are neutral THIQ dicarboxamides. THIQ dicarboxamide is a privileged structure with a semi–rigid character, a structural feature that potentially offers high selectivity for targeting FXa over other coagulation and digestive proteases. It can also be thought of as an amino acid–like structure, which affords accessibility to a large number of compounds using well established peptide chemistry. Mechanistically, the designed inhibitors were expected to bind to FXa in the active site and function as orthosteric inhibitors. These direct FXa active site inhibitors are also likely to inhibit clot–bound enzyme. Nearly 60 THIQ dicarboxamides were synthesized and biochemically evaluated. Through detailed SAR analysis, the most potent analog was designed and found to exhibit an IC50 of 270 nM (Ki = 135 nM), an improvement of more than 207–fold over the first inhibitor synthesized in the study. The most potent inhibitor displayed at least 1887–fold selectivity for FXa over other coagulation enzymes and a selectivity index of at least 279–fold over the digestive serine proteases. This analog doubled plasma clotting times at 17–20 μM, which are comparable to those of agents being currently studied in clinical trials. Overall, allosteric and orthosteric approaches led to the design of indirect and direct small molecule inhibitors of FXa based on the THIQ scaffold. This work introduces two promising molecules, a tetrasulfated N–arylacyl THIQ analog as a heparin mimetic and a neutral THIQ dicarboxamide as a potent, selective, and potentially bioavailable peptidomimetic, for further advanced medicinal chemistry studies.
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George, Nicolas. "Étude de la synthèse totale de tétrahydroisoquinoléines naturelles : quinocarcine, Tétrazomine et Lémonomycine. : rapide accés aux α-amidosulfures et leur utilisation en tant que précurseurs de N-acylimines dans la réaction de Friedel-Crafts." Phd thesis, Université Paris Sud - Paris XI, 2011. http://tel.archives-ouvertes.fr/tel-00980348.
Full textAbstract:
La quinocarcine, la tétrazomine et la lémonomycine constituent une sous-famille appartenant à la famille des tétrahydroisquinoléines trisubstituées naturelles. Ce sont des puissants agents cytotoxiques et possèdent de nombreuses activités biologiques telles qu'antitumorales et antibiotiques. Leur complexité structurale, leurs intérêts biologiques ainsi que leur faible rendement d'extraction du milieu naturel font de ces molécules des cibles attrayantes pour les chimistes de synthèse.Ces trois molécules sont constituées d'une tétrahydroisoquinoléine différemment substitué fusionnée avec un diazabicycle[3.2.1]octane commun. Le but de ce projet était de mettre au point une stratégie commune à cette sous-famille et divergente grâce à la synthèse du diazabicyclooctane en premier. Une première stratégie faisant intervenir une aziridine n'a pas permis de construire le bicycle. Cet objectif a été réalisé grâce à une seconde stratégie. Elle repose sur une première cyclisation d'un hémiaminal puis d'une cyclisation par addition nucléophile d'un éther d'énol silylé sur un N-acylimmonium formé in situ au départ d'un N,S-acétal.Parallèlement à cette étude synthétique, nous avons mis au point une réaction multicomposant séquentielle qui permet l'accès rapide et général aux a-amidosulfures, comblant un manque dans la littérature. Ensuite nous avons étudié la réactivité de ces composés en tant que précurseurs simples de N-acylimines en conditions acides douces. Trois conditions réactionnelles, nous ont permis d'accéder à cette objectif : l'utilisation stœchiométrique d'acétate d'argent, catalytique d'acide phosphorique ainsi que le NIS en quantité stœchiométrique et catalytique. Cette dernière réaction est très attrayante. En effet, ce réactif doux et neutre permet l'élimination efficace du thiol formant la N-acylimine puis son activation pour se faire piéger in situ par un nucléophile. Les rendements atteints sont très hauts en moins de 5 minutes.
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Zungu, Vezekile Princess. "Enantioselective synthesis of 1-substituted tetrahydroisoquinolines." Thesis, 2014. http://hdl.handle.net/10413/11217.
Full textAbstract:
Many organic compounds are chiral and they are useful because of the biological
activities associated with them. The biological activities of chiral compounds are often
linked to absolute configuration, i.e. a compound and its mirror image can have different
biological activities. For example, one enantiomer can be toxic whereas the other
enantiomer is non-toxic. Enantioselective synthesis plays a significant role in the
synthesis of biologically active compounds. The activity of tetrahydroisoquinolines
prompted us to investigate the stereoselective synthesis of selected 1-substituted
tetrahydroisoquinolines.
The objectives of this project were to investigate stereoselective synthesis of some 1-
substituted tetrahydroisoquinolines and compare different chiral auxiliaries used in the
Bischler-Napieralski and Pictet-Spengler reactions and finally to optimize the number of
steps needed to prepare the target compounds. The main challenge encountered in the
Pictet-Spengler method was the decomposition of the phenylacetaldehyde. The
successfully used method was the Bischler-Napieralski reaction because it does not
involve the use of a phenylacetaldehyde.
Using the Bischler-Napieralski method, non-stereoselective and stereoselective syntheses
of tetrahydroisoquinolines have been achieved. The racemic tetrahydroisoquinolines have
been synthesized in a three-step procedure starting from 3,4-dimethoxyphenylethylamine
whereas the chiral tetrahydroisoquinolines were synthesized from vanillin in a seven-step
reaction procedure. The R and S enantiomers of α-methylbenzylamine were successfully
employed in the synthesis of 1-benzyltetrahydroisoquinolines. However, the Renantiomer
of 1,2,3,4-tetrahydro-1-naphthylamine could be used to form a chiral
phenylethylamine, while ring closure in a Biscler-Napieralski reaction was not successful
under similar reaction conditions.
The diastereoselectivity of the reactions to form the chiral tetrahydroisoquinolines was
determined using NMR spectroscopy and was found to be 96% and 90% de for the (R)-
and (S)-1-benzyl-6,7-dimethoxy-N-(1-phenylethyl)-1,2,3,4-tetrahydroisoquinoline, respectively. The stereochemistry of the final products was found to be similar to that of
the chiral auxiliary starting material for each of the synthesized chiral
tetrahydroisoquinolines. Yields for the precursors were good to moderate, especially on
the final stages of the synthesis.Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2014.
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Matthews, Kenneth Stanley Magnus Philip Douglas. "The total synthesis of (±)-renieramycin g and studies toward the synthesis of (±)-lemonomycin and (±)-saframycin b." 2005. http://repositories.lib.utexas.edu/bitstream/handle/2152/1996/matthewsk14313.pdf.
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Chan, Benjamin Kin Heng Chemistry Faculty of Science UNSW. "Seeking new understanding and applications of 1,1' -Bisisoquinolines." 2007. http://handle.unsw.edu.au/1959.4/40830.
Full textAbstract:
This thesis has two parts. The first deals with the conformational behaviour of Nsubstituted and N-unsubstituted bis-tetrahydroisoquinoline derivatives under neutral and acidic conditions and the second describes the design, synthesis and structural characterization of a new class of N-ureidyl bis-tetrahydroisoquinoline derivatives, potential catch and release agents. Four N-alkyl derivatives, two of which were new, were studied in detail for their conformational behaviour and their spectroscopic properties compared extensively with N-unsubstituted compounds. NMR chemical shift changes and vicinal spin couplings were measured and related to conformational change within the heterocyclic rings and about the central C1-C1' axis. The basicity of the amines were determined through pKa measurements, and differences between the behaviour of secondary and tertiary amine examples discussed. Analysis of titration results revealed the formation of discrete 1:1 and 1:2 complexes between the secondary examples and added carboxylic acids, but only 1:1 complexes in the case of tertiary amine complexes. Monitoring of changes in conformation with incremental addition of acid provided new understanding about modes of binding. A new class of nine ureidyl bis-tetrahydroisoquinoline derivatives has been prepared. These contain N'-aryl and N'-adamantyl urea groups attached to the bisisoquinoline core through alkyl linker groups with varying length. The conformation of these derivatives were heavily dependent upon the linker length while the nature of the urea group (in one case a thiourea) played a small role in the preferred conformation of the bis-tetrahydroisoquinoline. Three non-isoquinoline derived model ureidyl amine systems were also synthesized for comparative studies. Four partner ureidyl acids were prepared and their pKa values in DMSO were measured. Studies of the interaction of the ureidyl acids with the ureidyl amines revealed that the chain length of the ureidyl bistetrahydroisoquinoline linker played a small role while the remote aryl and adamantyl groups of both acids and amines played a more important role. DMSO was found to interfere with the normal conformations of the ureidyl bis-tetrahydroisoquinolines and with the interaction of the ureidyl bis-tetrahydroisoquinolines with their partner ureidyl acids in deuterochloroform. The latter studies will provide the basis for future design of catch-and-release agents derived from bis-tetrahydroisoquinolines.
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Matthews, Kenneth Stanley. "The total synthesis of (±)-renieramycin g and studies toward the synthesis of (±)-lemonomycin and (±)-saframycin b." Thesis, 2005. http://hdl.handle.net/2152/1996.
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Shih, Yu-Wei, and 施郁偉. "Study on the Synthesis of Oxazolo[2,3-a]tetrahydroisoquinolines via Tandem Reaction." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/929d5v.
Full textAbstract:
碩士國立暨南國際大學
應用化學系
105
1,3-Oxazolidine frameworks were found in natural products and pharmaceutical compounds. In this research, addition of -hydroxy-,-unsaturated ketones 30 with 3,4-dihydroisoquinolines 49 provided oxazolo[2,3-a]tetrahydroisoquinoline 50 derivatives via tandem reaction involving nucleophilic addition and aza-Michael addition. The reaction proceeded under mild condition without catalyst and finished in 15 minutes, giving the various products with good to excellent yields (85-98%) and high diastereoselectivity (up to 25:1 dr). The relative stereo-structure of the products were confirmed by NMR technique and X-ray crystallography. This synthetic strategy corresponded with “green chemistry” and atomic economy.
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Du, Wen-Pine, and 杜文平. "Synthesis of Tetrahydroisoquinolines via Intramolecular Diels-Alder Reaction of Furans with Allenylamines." Thesis, 2002. http://ndltd.ncl.edu.tw/handle/97352479916973130849.
Full textAbstract:
碩士國立交通大學
應用化學系
90
Synthesis of Tetrahydroisoquinolines via Intramolecular Diels-Alder Reaction of Furans with Allenylamine Student : Du, Wen-Pine Advisor : Dr. Wu, Hsien-Jen Institute of Applied Chemistry National Chiao Tung University Abstract The skeleton of tetrahydroisoquinoline 11, 13, 16 via intramolecular Diels-Alder reaction of furan diene with propargyl amine was synthesized, successfully. And we also study the influence of hetroatom to intramolecular Diels- Alder reaction. In the series of nitrogen, when the substituent is hydrogen or methyl group, we can isolate the cycloadduct 6 and 23, directly. In the series of nitrogen and oxygen, when the substituent is methylthio group we all isolate ring opening product 35, 42, 54, directly, and we don’t obtain the cycloadduct. In here, we propose a proper machanism of intramolecular Diels-Alder reaction product, and use methylsulfonyl and methylsulfinyl group, 62 and 67 to prove the machanism. But we don’t obtain the positive evidence. We only obtain the elimination product.
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Cui, Jianwen. "Progress towards enantioselective total synthesis of the bisbenzyltetrahydroisoquinoline alkaloid (-)- cycleanine and a new approach to the syntheses of some isoquinolones /." 2003.
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Zhou, Ningzhang. "Further progress towards enantioselective total synthesis of the bisbenzyltetrahydroisoquinoline alkaloid (-)-cycleanine /." 2004.
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Naicker, Tricia. "Synthesis and evaluation of novel tetrahydroisoquinoline organocatalysts in asymmetric catalysis." Thesis, 2012. http://hdl.handle.net/10413/5365.
Full textAbstract:
Organocatalysis has rapidly expanded in the last decade to encompass a wide variety of small
organic molecules that are capable of either activating substrates or transforming them into
more reactive forms. The aim of this study was to develop novel chiral organocatalysts based
on the tetrahydroisoquinoline backbone and evaluate them on asymmetric reactions. Three
organocatalytic modes of activation have been investigated for C-C bond forming
asymmetric reactions. In chapter 2, for the first time organocatalysts bearing a secondary
nitrogen within a cyclohexane ring were evaluated in the asymmetric Diels–Alder reaction.
These catalysts were tested over a range of dienes and dienophiles and displayed promising
chemical conversions of up to 100 % with up to 64 % ee when triflic acid was employed as
the cocatalyst. Density functional theory computational studies and 2D NMR spectroscopy
were used to determine the structure of the intermediate iminium ion formed between the
most efficient catalyst and cinnamaldehyde. Chapter 3 includes a series of novel
tetrahydroisoquinoline chiral N-oxide organocatalysts and their evaluation in the asymmetric
allylation reaction of aromatic and α-β-unsaturated aldehydes with allyltrichlorosilane. The
chiral homoallyl products were obtained with good chemical efficiency (up to 93 % yield)
and high enantioselectivity (up to 91 % ee) under mild reaction conditions (23 °C). Chapter 4
is the simple and practical microwave-assisted synthesis of new tetrahydroisquinoline
guanidine organocatalysts and their evaluation in the asymmetric Michael addition reaction
of malonates and β-ketoesters with nitro-olefins. In addition, a novel microwave assisted
procedure of introducing the guanidine unit onto amino amide derivatives is reported. The
chiral products were obtained with quantitative chemical efficiency (up to 99 % yield) and
excellent enantioselectivity (up to 97 % ee). Chapter 5 is a collection of all X-ray crystal
structures that were published from novel compounds synthesized pertaining to Chapters 2-4,
it contains 15 published crystal structures while Chapters 3-4 contain 3 other X-ray crystal
structures.
It should be noted that with the exception of the introduction and Chapter 4 (submitted for
publication), the remaining chapters of this thesis have been published in international peer
reviewed journals. In the next section (DECLARATION 2 – PUBLICATIONS) a precise
description of my contribution to each of the publications/chapters is provided.Thesis (Ph.D.)-University of KwaZulu-Natal, Westville, 2012.
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Chakka, Sai Kumar. "Synthesis of tetrahydroisoquinoline (TIQ) ligands and their applications in ayymmetric catalysis." Thesis, 2010. http://hdl.handle.net/10413/6190.
Full textAbstract:
A series of 88 novel tetrahydroisoquinoline (TIQ) compounds have been synthesised for
applications in asymmetric catalysis. Several chiral TIQ ligands, possessing N,O and N,N
donor atoms, have been prepared and evaluated for the catalytic asymmetric transfer
hydrogenation (ATH) of pro-chiral ketones. The highest selectivity obtained for the
asymmetric transfer hydrogenation of acetophenone with the N,O donor atom ligands was
>99 % ee at low temperatures in iso-propanol with [Ru(p-cymene)Cl2]2 as a pre-catalyst. The
observed enantioselectivity was supported by theoretical calculations using the Jaguar
interphase program (Paper I). An enantioselectivity of 70 % was obtained with the ligands
possessing the N,N donor atoms with the observation that water played a significant role in
the enantioselectivity of the ATH reaction of acetophenone (Paper II).
An investigation into the usefulness of the TIQ scaffold with other donor atoms was also
undertaken. A series of novel P,N oxazoline ligands were synthesised and coordinated to
Iridium BArF. These complexes were screened as chiral catalysts for the high pressure
asymmetric hydrogenation of unsymmetrical olefins. The reactions proceeded readily at
ambient temperature and provided selectivities of up to >91 % ee with excellent conversion
rates (>99 %) for the benchmark reactions. Based upon these favorable results, the ligands
providing the best results were further screened on a variety of functionalized and unfunctionalised
olefins (Paper III).
The success of the TIQ backbone in ATH reactions prompted an investigation into its
applications in carbon-carbon (C-C) bond forming reactions. The Henry (nitroaldol) reaction
is an important C-C bond forming reaction with the chiral oxazoline class of ligands being
widely utilised. A series of novel, chiral TIQ oxazoline ligands were synthesised and
complexed to various metals (Cu, Sc, Co, Zn, Ni and Mn). These complexes were screened
as chiral catalysts in the asymmetric Henry reaction. The highest enantioselectivity (>77 %)
was obtained when Cu(OAc)2was employed as a pre-catalyst and iso-propanol as a solvent
(Paper IV).
The final chapter deals with carbon-sulphur bond formations facilitated by the conjugate
addition of thioglycolate to various chalcones. A series of novel, chiral TIQ N-oxide ligands
were synthesised and complexed to lanthanum. The complexes were screened for activity
against the benchmark reaction and an enantioselectivity of 81 % was obtained.Thesis (Ph.D.)-University of KwaZulu-Natal, Westville, 2010.
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Huang, Jia-Yun, and 黃佳筠. "(I) Synthesis of Thio(seleno)hydantoin-fused tetrahydroisoquinolines and diketopiperazine-fused tetrahydroisoquinolines (II) One-pot Synthesis of Chiral 2-imino thia(selena)zole derivatives and 2-thio(seleno)xoimidazolin-4-ones." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/b2757e.
Full textAbstract:
碩士國立交通大學
應用化學系碩博士班
107
The first part deals with the diastereoselective synthesis of thio(seleno)-hydantoin-fused tetrahydroisoquinolines and diketopiperazine-fused tetrahydro-isoquinolines via the molecular hybridization synthetic strategy. The second part describes the one-pot regioselective synthesis of chiral 2-iminothia(selena)zole derivatives and 2-thio(seleno)xoimidazolin-4-ones through multi-component reactions.
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Peters, Byron Kennedy. "Synthesis of novel tetrahydroisoquinoline chiral ligands for application in asymmetric transfer hydrogenation." Thesis, 2010. http://hdl.handle.net/10413/5428.
Full textAbstract:
Several tetrahydroisoquinoline (TIQ) diamine derivatives were prepared for use as ligands in asymmetric transfer hydrogenation (ATH) of acetophenone of which 17 intermediates and the eight target ligands were novel compounds. The initial design followed that of Noyori, who presented the efficiency of his monotosylated diamine in ATH. A series of eight novel secondary amine derivatives (78a-g and 88) were prepared with substituents that influenced the electronics and the sterics of and around the nitrogen donor. Ligand 71 was shown to have no activity for the ATH of acetophenone. It was apparent from experimental observations that a balance between the electronic and steric characteristics of the substituent was necessary to facilitate activity. It was found that ligand 78d possessing a benzyl group, had the greatest
activity (81 % conv.). The greatest selectivity was obtained with ligand 78f (77 % ee) having a chiral phenylmethyl substituent. It was discovered in the case of the active diamine ligands that an optimised 1500 equivalents of water was required in order to demonstrate any enantioselectivity. The exact role of the water has never been ascertained, although there are many publications in which the effect of water has been examined. The most active metal
precursor was also investigated and [RhCl2(Cp*)]2 was found to be the best for these TIQ diamine ligands in the specified model reactions. This work has recently been accepted for publication and has established criteria for further rational design on this system.Thesis (M.Sc.)-University of KwaZulu-Natal, Westville, 2010.
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郭銘翔. "Reaction mechanism and synthesis of oxo-/sulfo- tetrahydroisoquinolines and oxo-/sulfo-/seleno-hydrantion fused tetrahydro-β-carbolines." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/36217579360099121337.
Full text
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N, Archith, and S. Sharada D. "A Facile One-Pot Protocol for the Synthesis of Tetrazolyl Tetrahydroisoquinolines via novel Domino Intramolecular Cyclization/Azide-Ugi Sequence." Thesis, 2014. http://raiith.iith.ac.in/97/1/CY12M1005.pdf.
Full textAbstract:
A facile one pot, four component domino reaction between 2-(2-
bromoethyl)benzaldehyde, isocyanide, amine and sodium azide has been developed for the
synthesis of novel tetrazolyl tetrahydroisoquinoline derivatives. The domino sequence involves
intramolecular replacement of halide by iminium nitrogen followed by azide-ugi reaction. The
developed reactions proceeded cleanly in a rapid manner to afford the corresponding tetrazolyl
tetrahydroisoquinoline scaffolds with high to excellent yields.
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Turcotte-Savard, Marc-Olivier. "Synthesis of Highly Functionalized Tetrahydroisoquinolines by a Palladium-catalyzed Domino ortho-Alkylation/Heck Reaction Sequence and Diastereoselective Aryne Diels-Alder Reactions." Thesis, 2009. http://hdl.handle.net/1807/17449.
Full textAbstract:
We report a palladium-catalyzed, norbornene mediated synthesis of tetrahydroisoquinolines via a domino ortho-alkylation/Heck reaction sequence. The desired products are obtained in moderate to excellent yields starting from readily available aryl iodides. The reaction conditions can be extended to the formation of tetrahydroisoquinolinones and tetrahydrobenzo[c]azepines. The reaction allows for sequential intermolecular and intramolecular ortho-alkylations. However, the product yields are higher with ortho-blocked aryl iodides, which simplify the domino process to one intramolecular ortho-alkylation and a Heck reaction.
The Lautens group has previously reported diastereoselective aryne Diels-Alder reactions of benzyne with dienes supporting a chiral auxiliary at its terminal carbon. In an effort to extend this work and allow access to a wider variety of 1,4-dihydronaphthalenes, we attempted the synthesis of dienes supporting a chiral auxiliary at a central carbon. Chiral pyridyne precursors were also synthesized, in an attempt to vary the source of chirality in diastereoselective cycloadditions.
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Chaudhuri, Ansuman Ray. "Interactions Involving Organics Fluorine In Crystal Engineering : Insights From Crystal Packing And Polymorphism." Thesis, 2004. https://etd.iisc.ac.in/handle/2005/1352.
Full text
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Chaudhuri, Ansuman Ray. "Interactions Involving Organics Fluorine In Crystal Engineering : Insights From Crystal Packing And Polymorphism." Thesis, 2004. http://etd.iisc.ernet.in/handle/2005/1352.
Full text
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Huang, Sheng-Han, and 黃聖涵. "1. Total Synthesis of (+)-Antrocin 2. Study and Synthesis of Thionated Perylene Diimides for N-Channel Organic Field Effect Transistors3. Thiazo[2,3-a]tetrahydroisoquinolines from Addition Reaction of 3,4-Dihydroisoquinolines with (E)-4-Mercapto-2-butenoic Ester." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/05116601965888128991.
Full textAbstract:
博士國立暨南國際大學
應用化學系
105
Part 1: This thesis three parts. The frist total synthesis of (+)-antrocin, which was need to clarify the absolute structure of the natural sesquiterpenoid (-)-antrocin. Special transformations in this synthetic route include highly stereoselective intramolecular Diels-Alder reaction (IMDA) of camphanate triene intermediate and highly efficient selective hydrogenation with two different catalysts. We explain the key intramolecular Diels-Alder reaction mechanism by density functional theory calculation. Overall the (+)-anrtocin was synthesized starting from commercial available 2,2-dimethyl cyclohexanone in 15 steps and the total yield was 7.3 %. Part 2: We designed and synthesized a new series of thionated perylene diimides (PDTI), which could be used for N-channel organic field effect transistor. The PDTI were synthesized in the five steps strating from commercial available 4-Bromo-1,8-naphthalic Anhydride. Electrochemical and photophysical properties of PDTI were different and special from Perylene Diimide analogs. Significantly, the thionated compounds had narrower energy gaps and lower lowest unoccupied molecular orbital (LUMO) levels than those of their corresponding imide analogs. Part 3: A green and highly efficient method for the building of a variety of thiazo[2,3,-a]tetrahydroisoquinolines by tandem addition [Micheal / nucleophilic addition] of 3,4-dihydro- isoquinolines with (E)-4-mercapto-2-butenoic ester in green solvent. The adventages of using environmental friendly solvent, catalyst-free, ligand-free, atom-ecomonic,and having wide functional group are described. The yields of thiazo[2,3,-a]tetrahydroisoquinolines ranged from 60% to 83%.
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Santos, Ana R. N., Helen M. Sheldrake, Ali I. M. Ibrahim, Chhanda C. Danta, D. Bonanni, M. Daga, s. Oliaro-Bosso, D. Boschi, M. L. Lolli, and Klaus Pors. "Exploration of [2 + 2 + 2] cyclotrimerisation methodology to prepare tetrahydroisoquinoline-based compounds with potential aldo-keto reductase 1C3 target affinity." 2019. http://hdl.handle.net/10454/17252.
Full textAbstract:
YesTetrahydroisoquinoline (THIQ) is a key structural component in many biologically active molecules including natural products and synthetic pharmaceuticals. Here, we report on the use of transition-metal mediated [2 + 2 + 2] cyclotrimerisation of alkynes to generate tricyclic THIQs with potential to selectively inhibit AKR1C3.
Fundação para a Ciência, a Tecnologia (PhD studentship ARNS SFRH/BD/46871/2008), EPSRC (RCUK Academic Fellowship HMS), UniTO grant Ricerca Locale 2015 (grant number LOLM_RILO_17_01) and Fondazione Cassa di Risparmio di Torino (grant BOSD_CRT_17_2).
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Sun, Tsung-Hsien, and 孫宗賢. "Design of Anticancer Agents Based on the Tetrahydroisoquinoline Alkaloids." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/h795p6.
Full textAbstract:
博士國立中山大學
化學系研究所
96
The tetrahydroisoquinoline alkaloids have been studied thoroughly about their biological and chemical significance over the past 30 years. These natural products show great biological activity, especially ET-743 and saframycin A, makes them promising therapeutics, while their structural complexity and particularity provide challenging synthetic targets. These alkaloids or derivatives show interesting biological activity, but the most important drawback as potential market therapeutics is the minute amount of them available from nature, and the synthetic methods published are inconvenient, difficult, and hard to handle. Herein is described our researches about the tetrahydroisoquinoline alkaloids. Chapter 1 describes relevant background related to the biological significance of these alkaloids, and the currently synthetic studies toward these natural products. Chapter 2 describes our design and synthesis of the analogues based on the anticancer mechanism of the tetrahydroisoquinoline alkaloids, and the biological activities of these analogues. Chapter 3 describes a rapid synthetic route for the common structure of the bis-tetrahydroisoquinoline alkaloids via a controlled mono-Pictet-Spengler cyclization.