9 research outputs found

    Azidoperfluoroalkany: Syntéza a Aplikace

    Get PDF
    ZavedenĂ­ trifluormethylovĂ© a perfluoralkylovĂ© skupiny do organickĂœch molekul pƙedstavuje jedno z hlavnĂ­ch tĂ©mat syntetickĂ© organofluorovĂ© chemie. Existuje ƙada metod pro zavedenĂ­ CF3 skupiny na atom uhlĂ­ku, kyslĂ­ku a sĂ­ry. Naopak metody pro syntĂ©zu N-trifluor-methylovanĂœch a N-perfluoralkylovanĂœch sloučenin jsou velmi omezenĂ© a vĂœvoj novĂœch pƙístupĆŻ k jejich syntĂ©ze je vysoce ĆŸĂĄdanĂœ. Nedostatek těchto sloučenin nĂĄs vedl k vĂœvoji činidel schopnĂœch pƙenosu perfluoralkylovĂ© skupiny na atom dusĂ­ku, kde jsme jako vhodnĂĄ činidla zvolili azidoperfluoralkany. Tato prĂĄce se zabĂœvĂĄ syntĂ©zou a aplikacĂ­ perfluoralkylazidĆŻ. PrvnĂ­ část popisuje pƙípravu azidoperfluoralkanĆŻ. Po aktivaci fluoridem cesnĂœm mĆŻĆŸe TMSCF3 pƙenĂ©st trifluormethylovou skupinu na elektrofilnĂ­ azid za vzniku ĆŸĂĄdanĂ©ho azidotrifluormethanu. Azidoperfluoralkany s delĆĄĂ­m uhlĂ­katĂœm ƙetězcem byly pƙipraveny podobnĂœm zpĆŻsobem vychĂĄzejĂ­cĂ­m z pƙísluĆĄnĂ©ho organosilanu. RozdĂ­lnĂœ syntetickĂœ pƙístup byl pouĆŸit pro pƙípravu azidoperfluorethanu, kde byl pƙi reakci pentafluorethanu s n BuLi generovĂĄn perfluorethylovĂœ anion, k němuĆŸ byl nĂĄsledně pƙidĂĄn tosylazid. FluorovanĂ© azidy byly izolovĂĄny pomocĂ­ destilace s vhodnĂœm rozpouĆĄtědlem. DruhĂĄ část se zabĂœvĂĄ syntetickĂœm potenciĂĄlem azidoperfluoralkanĆŻ. Tyto azidy vykazovaly velkou reaktivitu v azido-alkynovĂœch...The incorporation of the trifluoromethyl and perfluoroalkyl motifs into organic compounds has been a hot topic in synthetic organofluorine chemistry. There is a plethora of methods for the introduction of the CF3 moiety at carbon, oxygen and sulfur centers. In sharp contrast, methods for synthesizing N-trifluoromethyl and N-perfluoroalkyl compounds are very limited and new approaches are highly sought-after. The scarcity of these compounds prompted us to develop reagents capable of transferring the perfluoroalkyl unit to nitrogen atom. To fulfil this purpose, we have regarded azidoperfluoroalkanes as ideal reagents, therefore, this thesis is concerned with the synthesis and applications of these azides. The first part describes the preparation of azidoperfluoroalkanes. Upon activation by cesium fluoride, TMSCF3 transfers the trifluoromethyl group to an electrophilic azide to produce the desired azidotrifluoromethane. Longer carbon chain azidoperfluoroalkanes were prepared in a similar way, starting from the corresponding organosilane. A different synthetic strategy was applied for the preparation of azidopentafluoroethane where the perfluoroalkyl anion was generated from pentafluoroethane with n BuLi, followed by the addition of tosyl azide. The isolation of these fluorinated azides was...Department of Organic ChemistryKatedra organickĂ© chemieFaculty of SciencePƙírodovědeckĂĄ fakult

    Design, synthesis, pericyclic chemistry and biomedical applications of azopeptides

    Full text link
    Les azapeptides sont des peptidomimĂ©tiques dans lesquels le carbone alpha d'un ou plusieurs acides aminĂ©s a Ă©tĂ© remplacĂ© par un atome d'azote. L'objectif principal de cette Ă©tude doctorale a Ă©tĂ© de dĂ©velopper une nouvelle mĂ©thodologie de synthĂšse d'azapeptides, par l’utilisation d'azopeptides, qui sont des analogues azodicarbonylĂ©s possĂ©dant une fonction imino-urĂ©e. L'oxydation des rĂ©sidus d'aza-glycine s'est avĂ©rĂ©e efficace pour l’obtention d’azopeptides, qui ont ensuite Ă©tĂ© utilisĂ©s pour effectuer des rĂ©action pĂ©ricycliques et examinĂ©s par cristallographie aux rayons X. Les rĂ©actions de Diels-Alder et d'Alder-ene sur les azopeptides ont respectivement permis d'accĂ©der aux rĂ©sidus azapipĂ©colyle et aza-allylglycinyle contraints. L'analyse aux rayons X d'un azopeptide Ă  l'Ă©tat solide a fourni un aperçu de la configuration de l'imino-urĂ©e (Chapitre 2). En employant les produits, issues de la chimie des azopeptides, comme analogues contraints de la valine, des mimes de la sĂ©quence Ala-Val-Pro-Ile de la seconde protĂ©ine activatrice de caspases des mitochondries (Smac) ont Ă©tĂ© synthĂ©tisĂ©s et leur capacitĂ© Ă  induire l'apoptose dans les cellules mammaires cancĂ©reuses a Ă©tĂ© dĂ©montrĂ© (Chapitre 3). Dans le but de poursuivre le dĂ©veloppement des mĂ©thodes pour synthĂ©tiser des azopeptides une approche en phase solide a Ă©tĂ© conçue sur rĂ©sine Rink Amide et pourrais ĂȘtre utiliser pour gĂ©nĂ©rer des chimiothĂšques de composĂ©s en utilisant la chimie combinatoire. Cette Ă©tude a Ă©tĂ© ciblĂ©e sur la synthĂšse d'analogues azapeptides des opioĂŻdes morphiceptine et endomorphine ainsi que le peptide de libĂ©ration de l'hormone de croissance (GHRP-6, HHis- D-Trp-Ala-Trp-D-Phe-Lys-NH2) se liant aux rĂ©cepteur du cluster de diffĂ©renciation 36 (CD36). Les premiers peptides ont Ă©tĂ© examinĂ©s en raison de leur importance en tant qu'agonistes sĂ©lectifs des sous-types de rĂ©cepteurs opioĂŻdes ayant le potentiel de dĂ©velopper de nouveaux analgĂ©siques. Le dernier exemple d’analogue avait pour but de poursuivre le dĂ©veloppement de modulateurs sĂ©lectifs de CD36 ayant un potentiel thĂ©rapeutique pour le traitement de maladies comprenant une inflammation entraĂźnĂ©e par les macrophages, y compris la dĂ©gĂ©nĂ©rescence maculaire liĂ©e Ă  l'Ăąge et l'athĂ©rosclĂ©rose. Douze aza-opioĂŻdes ont Ă©tĂ© synthĂ©tisĂ©s en remplaçant la proline Ă  la position deux des ligands peptidiques respectifs par diffĂ©rents rĂ©sidus d'aza-pipĂ©colate. De mĂȘme, cinq analogues d'aza-pipĂ©colyle GHRP6 ii ont Ă©tĂ© synthĂ©tisĂ©s en utilisant la mĂ©thode en phase solide pour remplacer respectivement les rĂ©sidus Ala3 et Trp4 (chapitre 4). Les aza-opioĂŻdes ont Ă©tĂ© examinĂ© comme inhibiteur des contractions induites Ă©lectriquement sur l'ilĂ©on de cobaye et du canal dĂ©fĂ©rent de souris, et les analogues aza-GHRP-6 pour leurs capacitĂ©s Ă  diminuer la surproduction d'oxyde nitrique induite par CD36 aprĂšs traitement avec l’agoniste lipopeptide fibroblastes des rĂ©cepteurs, tous deux ont dĂ©montrĂ© l'utilitĂ© de la mĂ©thodologie de l'aza-pipĂ©colate pour Ă©tudier l'influence de la conformation sur l'activitĂ© et la sĂ©lectivitĂ© des peptides. Les nouvelles mĂ©thodologies de synthĂšse des azopeptides en solution et sur support solide dĂ©crites dans cette thĂšse sont conçues pour permettre leur utilisation dans des Ă©tudes de relations structure-activitĂ© avec diffĂ©rents peptides biologiquement actifs. A cet Ă©gard, des azopeptides ont Ă©tĂ© utilisĂ©s dans ces recherches pour fabriquer des ligands des facteurs inhibiteurs du mĂ©lanocyte-1 (MIF-1), Smac, opioĂŻde et du rĂ©cepteur CD36. ConsidĂ©rant l'efficacitĂ© des mĂ©thodes de synthĂšse et les applications potentielles des azopeptides, les rĂ©sultats de cette thĂšse offrent un fort potentiel pour l'avancement de la science des peptides dans le contexte de la chimie mĂ©dicinale et de la biologie chimique.The azapeptides are peptide mimics in which the alpha carbon of one or more amino acids has been replaced with a nitrogen atom. The primary goal of this doctorate study was to develop a new method for the synthesis of azapeptides by the application of azopeptides, which are azodicarbonyl analogs that possess an imino urea component. Oxidation of aza-glycine residues proved effective for making azopeptides, which were employed in pericyclic chemistry and examined by X-ray crystallography. Diels−Alder cyclization and Alder−ene reactions on azopeptides enabled respectively access to constrained aza-pipecolyl and azaallylglycinyl residues. X-ray analysis of an azopeptide in the solid state provided insight into imino urea configuration (Chapter 2). Employing the products from azopeptide chemistry as constrained valine analogs, mimics of the Ala-Val-Pro-Ile sequence from the second mitochondria derived activator of caspases (Smac) protein were synthesized and demonstrated ability to induce apoptosis in breast cancer cells (Chapter 3). Following the development of a method to synthesize azopeptides in solution, a solidphase approach was conceived to prepare azopeptides on Rink amide resin and may be amenable to combinatorial chemistry for library generation. This study was targeted on the synthesis of aza-analogs of the opioid peptides morphiceptin and endomorphins as well as the Cluster of Differentiation 36 receptor (CD36) ligand Growth Hormone Releasing Peptide-6 (GHRP-6, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2). The former were examined due to their importance as opioid receptor subtype selective agonists with potential for developing novel analgesics. The latter was targeted in pursuit of selective CD36 modulators with therapeutic potential for treating diseases featuring macrophage-driven inflammation including age-related macular degeneration and atherosclerosis. Twelve aza-opioids were synthesized by replacing proline at the two position of the respective peptide ligands with different aza-pipecolate residues. Similarly, five aza-pipecolyl GHRP-6 analogs were synthesized using the solid-phase method to replace respectively the Ala3 and Trp4 residues (Chapter 4). Examination of the aza-opioids for inhibitory potency on electrically induced contractions of the guinea pig ileum and mouse vas deferens, and the aza-GHRP-6 analogs for capacity to diminish CD36-mediated overproduction of nitric oxide in macrophage cells iv after treatment with the Toll-like receptor-2-agonist fibroblast-stimulating lipopeptide, both demonstrated the utility of the aza-pipecolate methodology for studying the influence of conformation on peptide activity and selectivity. The novel methods for the synthesis of azopeptides in solution and on solid support described in this thesis are designed to enable their use in studies of structure-activity relationships with different biologically active peptides. In this respect, azopeptides have been applied in this research to make ligands of the melanocyte-inhibiting factor-1 (MIF-1), Smac, opioid and CD36 receptors. Considering the effectiveness of the synthetic methods and the potential applications of azopeptides, the findings of this thesis offer strong potential for the advancement of peptide science in the context of medicinal chemistry and chemical biology

    SYNTHESIS OF NITROGEN-CONTAINING COMPOUNDS VIA NITRENE-TRANSFER CATALYSED BY PORPHYRIN COMPLEXES

    Get PDF
    In this Ph.D. thesis several aspects around the topic of metal porphyrins-catalysed nitrene transfer reactions were investigated. It is worth to remark the importance of this sustainable synthetic methodology, it affords valuable nitrogen-containing compounds using cheap starting materials and, if organic azides are employed as nitrene source, molecular nitrogen is the only by-product of the reaction. The scope of ruthenium porphyrin-catalysed amination reaction was extended to the synthesis of important compounds from a biological and pharmaceutical point of view. New strategies to obtain amino acid derivatives and indoles by C-N bond formation were developed. In particular, the reported synthesis of the latter compounds was the first example of intermolecular reaction between an alkyne species and an organic azide affording the indole motif instead of triazoles; thus, it was demonstrated that a great control on the reaction selectivity can be achieved using metal porphyrin catalysts. The optimisation of these transformations was carried out also by studying the mechanism of the catalytic reaction. The generality of a previously performed mechanistic investigation concerning ruthenium porphyrin catalysed allylic amination was assessed. The point of view of Resonance Raman allowed the study of the catalytic system from a different perspective, whilst kinetic and theoretical studies shed some light into the mechanism of ruthenium-porphyrin catalysed aziridination of olefins and benzylic amination to give \u3b1- and \u3b2-aminoesters. The development of new catalysts to improve the catalytic performances and the process sustainability was also considered. Glycoporphyrin complexes, being potentially active compounds in promoting asymmetric synthesis or reactions in aqueous media, seem suitable for the accomplishment of this target. A preliminary study revealed the good catalytic activity in nitrene and carbene transfer reaction of this biocompatible substances, moreover the basis for a catalyst recovery/reuse system were laid

    Design of functional polymer architectures by RAFT polymerization

    Get PDF
    Die vorliegende Dissertation behandelt die definierte MakromolekĂŒlsynthese maßgeschneiderter Strukturen und FunktionalitĂ€ten, sowie die Möglichkeit der PrĂ€paration von Nanostrukturen durch Selbstorganisation oder NanofĂ€llung. In diesem Zusammenhang wurden verschiedene Strategien zum Aufbau solcher MakromolekĂŒle intensiv untersucht. Neben dem Einbau funktionaler Monomere in das PolymerrĂŒckgrat, erfolgte die Synthese von Blockcopolymersegmenten unterschiedlicher BlocklĂ€nge. Die vorliegende Forschungsarbeit behandelt im speziellen die RAFT-(Co)Polymerisation von Methacrylaten und Styrol-Bausteinen fĂŒr den Aufbau hochfunktionalisierter Polymere mit definierten photophysikalischen Eigenschaften bzw. „stimuli-responsivem“ Verhalten

    Collected publications, 1982-1997

    Get PDF

    The synthesis and thermal and photochemical transformations of 1, 3-dipolar cycloadducts derived from 1, 2,3-triazolium-N-imides

    Get PDF
    The cycloadducts formed on addition of triazolium-l-imides to a variety of dipolarophiles were originally assigned as pyrazolotriazoles. Subsequent re-examination in the 1980’s led to the discovery of a tandem cycloaddition - sigmatropic rearrangement mechanism leading to pyrrolotriazoles. These pyrrolotriazoles contain an azimine function as part of the ring system and the thermal and photochemical transformations of these compounds are of interest because of the wide structural variety found among the products. In the current work on cycloaddition reactions leading to pyrrolotriazoles a number of side products, including triazoles and substituted anilines are identified The acid catalyzed epimerization of the cycloadduct was also observed. A range of new cycloadducts have been synthesized. The thermal reaction of hexahydropyrrolo[2,3-i/]triazoles led to fragmentation to substituted triazoles The tetrahydro-analogues, however underwent a 1,3-sigmatropic rearrangement followed by electrocyclic ring expansion to substituted 2,5-dihydro-l,2,3- triazines in high yield, and the structure was confirmed by x-ray crystallography. The importance of the unsaturation was confirmed as hexahydro derivatives were oxidized and found to produce the triazines in high yield. The photochemical rearrangements of these species were found to depend on both the degree of unsaturation and the bridgehead substituents. For the 3a,6a-diaryl hexahydroderivatives, irradiation led to a disrotatory ring expansion to the new 2,5,6,7-tetrahydro- 1.2.3.5-tetrazocines, the structure of which was confirmed by x-ray crystallographic determination. The tetrahydro-analogues, on ring opening to 2,5-dihydro-l,2,3,5- tetrazocine underwent a transannular ring contraction followed by a 1,4-sigmatropic rearrangement to imidazo[4,5-c]pyrazoles The proposed intermediacy of 2,5-dihydro- 1.2.3.5-tetrazocine in the rearrangement of 3a,6a,-diaryl tetrahydropyrrolotriazoles was confirmed. Irradiation of 3a,6a-dimethyl hexahydropyrrolo[2,3-i/] 1,2,3-triazole led to pyrrolo[3,2- 6 ]indole via a complex series of sequential transformations. The pathway was investigated by isolation of the intermediates and was found to consist of an initial epimerization, a 1,2-phenyl migration and an eliminative rearrangement followed by 5-exotrig closure to pyrrolo[3,2-6]indole. Two intermediates were characterized by x-ray crystallographic analyses. Irradiation of the tetrahydro-analogues led to the formation of substituted pyrroles and azobenzene

    Methodologies for the synthesis of novel modified nucleosides with therapeutic potential

    Get PDF
    1 v.This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legalsThesis (D.Sc.)--University of Adelaide, Faculty of Science, 199

    The development of new procedures for heterocycle synthesis under metal-free conditions

    Get PDF
    This thesis mainly describes recent development in the synthesis of N- and O-containing heterocycles, which were conducted under transition-metal-free condition. A series of heterocycles like quinazolinones, quinazolinimines, quinazolinamines, aminoisoquinoline and dibenzoxazepinamines etc. were synthesized under transition-metal-free condition as presented in this thesis, which aims to provide a green, convenient and efficient methodology for the construction of the compounds bearing these units.Diese Arbeit beschreibt vorwiegend die aktuellen Entwicklungen auf dem Gebiet der ĂŒbergangsmetallfreien Synthese von stickstoff- und sauerstoffhaltigen Heterozyklen. Somit wurden unterschiedliche Heterozyklen wie Quinazolinone, Quinazolinimine, Quinazolinamine, Aminoisoquinoline, Dibenzoxazepinamine und weitere unter ĂŒbergangsmetall-freien Bedingungen synthetisiert. Die entwickelten Methoden könnten grĂŒne, gĂŒnstige und effiziente Alternativen fĂŒr die Herstellung von Substanzen mit diesen genannten Struktureinheiten darstellen
    corecore