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Synthesis and cytostatic activity of 3,5-disubstituted pentenolides analogous to gelastatin
Pavlík, Jan ; Pour, Milan (advisor) ; Starý, Ivo (referee) ; Dvořák, Dalimil (referee)
Within the framework of this thesis, a large series of 5-(acyloxymethyl)-3-aryl-5,6- dihydro-2H-pyran-2-ones was prepared and their cytostatic activity investigated. The key steps in the preparation of the compounds were alkylation of esters of substituted phenylacetic acids with 2-iodomethyl-5,5-dimethyl-1,3-dioxane, followed by cyclization to furnish a saturated lactone into which a double bond was introduced in the next step. Some of the target compounds displayed interesting cytostatic activity (IC50 < 10 µmol/L) against a panel of standard cell lines including both leukemic cells and those derived from solid tumours. The activity against colorectal carcinoma HT29 cell line, which is otherwise resistant against the standard combination of cytostatic agents used in the treatment of these tumours is especially remarkable. In the next part, the development of the synthesis of the 5-alkylidene analogues of these compounds, which are also analogous to bioactive natural products, such as the gelastatins and CR377, is described. Successful strategy is based on the use of 2-iodo allylic alcohols as the starting materials, which are converted into the target 3-substituted-5-alkylidene pentenolides via an array of Pd-catalyzed reactions, including Sonogashira coupling with methyl propiolate,...
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The synthesis of thiamacrocycles and the study of their properties
Nejedlý, Jindřich ; Kroutil, Jiří (referee) ; Starý, Ivo (advisor)
The aim of this work is the study of a simple method of preparing macrocyclic ligands for complexation of fullerenes. Necessary attribute of those ligands is their construction of electron-rich building blocks, which are prerequisite for π-π interactions with electron- deficiency fullerene spherical systems. Tetrathiafulvalene (TTF) is a known electron-rich system and for this reason, 2,3-bis(butylthio)-6,7-bis(2-kyanoethylthio)- tetrathiafulvalene was chosen as a basic building block. The protecting cyanoethyl group in this derivative can be removed by the acting of a base and thus generated thiolate function group is used in alkylation reactions of bis(bromomethyl)aryls. In reactions of these two components of bifunctional alkylation reactions was produced (in addition to the prevalent oligomeric products) a mixture of macrocycles with different sizes, the number of included building units was marked as [2 +2], [3 +3] and [4 +4] macrocycles. Reactions of TTF derivative with 4,4'- bis(bromomethyl)biphenyl and 4,4'-bis(bromomethyl)diphenylether have been performed. Column chromatography fractions of cyclic products were in both cases analyzed by gel permeation chromatography, NMR spectroscopy. The performed study has shown, that an equipoise to the simplicity of the synthetic protocol are low yields of...
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The synthesis of functionalised electron donors and acceptors and the study of their interaction
Rejchrtová, Blanka ; Betík, Robert (referee) ; Starý, Ivo (advisor)
This work is focused on the stepwise preparation of model dimer, containing tetrathiafulvalene as electron donor unit. Main method used in the synthesis was Sonogashira coupling. Theoretical part deals with current state of research in the field of nanoscience and nanotechnology and molecular electronics. It is focused on noncovalent interactions, especially of the electron donor - electron acceptor (CT complexes). Properties of tetrathiafulvalene and its derivatives are described in detail as well as mechanism of Sonogashira coupling. In the part devoted to the results and discussion is described preparation of monomeric precursor from known TTF alcohol and new iodobenzylbromide with protected acetylene function. Stepwise synthesis utilizing Sonogashira coupling leads to the preparation of model dimer in moderate yield. All new compounds were characterized by spectral methods (NMR, MS, FTIR) and by elemental analysis, eventually HR-MS.
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Reactions of Alkenes Iniciated by Transition Metals Alkyls and Hydrides
Nečas, David ; Kotora, Martin (advisor) ; Jindřich, Jindřich (referee) ; Starý, Ivo (referee) ; Mazal, Ctibor (referee)
l0 5. Conclusion 1) The first and practical catalýic method for smooth deallylation of 2-substituted-2-allylmalonates to 2-substituted malonates via selective cleavage of the C-C bond under mild reaction conditions has been developed' The reaction seems to be general with respect to the transition-metal complexes; however, the comparison of Ru and Ni catalysts indicates considerable differences in their specific activity and selectiviý. Last but not least, the smooth deallylation offers an opportuniý to use the allyl group as an effective protective group for acidic hydrogen of malonic esters. 2) It has been shown that it is possible to re-route the course of the reaction from c{ bond cleavage (deallylation) to c{ bond formation (cyclization) in Ni hydride cataryzed, reactions by a change in the amount of organoaluminium. It proceeded in high yields even in cases where deallylation could compete with cyclization (e.g. diallylmalonate, etc.) in high selectiviý. In addition, generation of Ni hydride species in sinr provides an effective means for fast and selective cyclization of variously substituted 1,6- heptadienes to cyclopentanes. Moreover, it is possible exert certain level of control for the preferential formation of methylidene(methyl)cyclopentanes or cyclopentenes by the appropriate choice of thb...
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On Azahelicenes: Synthesis, Resolution, Properties and Applications
Míšek, Jiří ; Starý, Ivo (advisor) ; Kroutil, Jiří (referee) ; Macháček, Vladimír (referee) ; Závada, Jiří (referee)
1 Abstract A novel and modular approach to azahelicenes has been developed. Using 12+2+2) cyclotrimerisation of appropriate triyne as a key step, azahelicenes 83, 84 and 85 have been prepared (Scheme 1). &83 84 Scheme 1. Aza[6]he|icenes 84 and 85 have shown to be sufÍicienl|y conÍigurationa||y stable and have been resolve inlo individual enantiomers by the diastereoisomeric sa|t crysta|isation and chira| HPLC. This a||owed to determine exact Va|ues oÍ racemisation barriers Íorboth aza[6]he|icenes 84 and 85. In general' both hexacyclic derivatives 84 and 85 are stable enough to be used in asymmetric transÍormations or chira| sensing. The abi|ity oÍ aza[6]he|icenes 84 and 85 to serve as chira| ligands íortransition meta|s has been proven by the preparation and X. ray analysis ol corresponding si|ver comp|exes. lnteresting chira| selÍ.recogniton properties oÍaza[6]he|icenes 84 in gas phase have been described using mass spectrometry techniques. |n order to comp|ement inÍormation about azahelicenes basicilies, gas phase proton afÍinities oÍ derivatives 84 and 85 and so|ution phase dissociation constants oÍ azahe|icenes 83. 84 and 85 have been determined. Eventua||y, the Íirst uti|ization oÍ azahe|icene in asymmetric catalysis has been demonstrated by the successÍu| use oÍ optical|y pure aza[6]he|icene...
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Synthesis of helical molecules and their application in enantioselective catalysis
Krausová, Zuzana ; Starý, Ivo (advisor) ; Kotora, Martin (referee) ; Kvíčala, Jaroslav (referee) ; Hájíček, Josef (referee)
9. Summary We have prepared a set of helical compounds using a modular approach based on 12+2+21 cycloisomerisation of aromatic triynes under cobalt (l) catalysis. [7]helicene-like compound (P,S)-(+)-10, which represents a new structural type of possible liquid crystalline materials, was obtained in an optically pure form on a preparative scale. We have explored the diastereoselective synthesis as a general methodology for the preparation of functionalised helical compounds. A series of methoxy- and bromo-substituted helicene derivatives was successfully prepared with diastereoisomer ratios up to 100:0. ln addition, we have developed a practical synthesis of racemic heptahelicene rac-87. Optically pure heptahelicene (M)-(-)-87 and optically highly enriched (P)-(+)-87 were obtained by resolution of rac-87 by semipreparative HPLC on a chiral column. we have developed an original approach to the synthesis of phosphite ligands bearing helically chiral moieties, which were subsequently used in enantioselective catalysis, namely in hydroformylation reactions and allylic aminations. A series of hydroformylations of styrene, 4-chlorostyrene and vinyl acetate performed with Rh(acac)(co)2 under various conditions revealed that all helically chiral ligands under study afforded good to excellent regioselectivities....
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Investigation of acid-based properties of mono- and diaza[5]helicenes by non-aqueous capillary electrophoresis and quantum chemical calculations
Šolínová, Veronika ; Štěpánová, Sille ; Jančařík, Andrej ; Klívar, Jiří ; Šámal, Michal ; Stará, Irena G. ; Vacek Chocholoušová, Jana ; Vacek, Jaroslav ; Starý, Ivo ; Kašička, Václav
Non-aqueous capillary electrophoresis (NACE) using methanol (MeOH) as a solvent of the background electrolytes was used to determine the thermodynamic acidity (ionization) constants (pKa) of a series of monoaza[5]helicenes and diaza[5]helicenes protonated to the first degree in MeOH and water. Depending on the number and position of the nitrogen atoms in their molecules, the analyzed aza[5]helicenes were found to be weak to moderate bases with methanolic pKa,MeOH in the range 3.90-8.75 and with aqueous pKa,H2O in the range 3.53-8.28.
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