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Catalytic and photochemical cycloadditions of alkynes
Fadeev, Aleksandr ; Kotora, Martin (advisor) ; Pour, Milan (referee) ; Parkan, Kamil (referee)
Novel approaches to utilizing alkynes in transition metal-catalyzed [2+2+2] cycloadditions and photochemical [2+2] cycloadditions were investigated with respect to the potential applications of these transformations. First, a chemo- and regioselective fully intermolecular cocyclotrimerization of internal alkynes with a commercially available ethynyl boronate was developed using Ru-catalysis and its mechanism was examined using DFT calculations. The established method allows for a straightforward preparation of various 1,4-diborylated benzenes, which can serve as multifunctional building blocks in organic synthesis. In particular, the products can be used in cross-coupling, carbonylation and oxidation reactions to access a broad variety of contiguously substituted arenes, such as natural products mirandamycin and violaceoid C. Second, a comparative study of catalytic and uncatalyzed photocycloadditions between alkynes and quinones was undertaken. Contrary to the recent reports, irradiation with visible light alone is sufficient to obtain not only the [2+2] cycloaddition products, but also several products of cascade transformations. Thus, depending on the structure of the quinone used, either carbo- or heterocycloaddition pathway is mainly realized, giving rise either to annulated cyclobutenes or...
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Novel quinazoline derivatives with biological activity
Brožová, Zuzana Rania ; Pour, Milan (advisor) ; Miletín, Miroslav (referee) ; Soural, Miroslav (referee)
Faculty of Pharmacy in Hradec Králové, Charles University Department of Organic and Bioorganic Chemistry Candidate: Mgr. Zuzana Rania Brožová Supervisor: prof. RNDr. Milan Pour, Ph.D. Title of Doctoral Thesis: Novel quinazoline derivatives with biological activity This thesis is divided into two parts, both dealing with the synthesis of novel quinazoline derivatives and evaluation of their biological activity. The first part is focused on the synthesis of bronchodilatory active derivatives derived from vasicinone as a lead compound and 3-[3-(piperidin-1-yl)-propyl]-3,4- dihydroquinazoline-4-one and 4-[3-(piperidin-1-yl)-propylsulfanyl]-3,4-dihydroquinazoline-4- one, the most active derivatives from our previous work. The derivatives were subsequently tested on isolated rat trachea and their bronchodilatory activity was evaluated. Their toxicity, in vivo activity, mechanism of action and the relationships between structure and activity (SAR) were also investigated. The second part deals with the synthesis of novel derivatives of 2,4-disubstituted quinazoline and their testing for affinity to nuclear constitutive androstane receptor (CAR). This work follows up on the previous random discovery that 2-(3-methoxyphenyl)quinazoline- 4-ol is a promising CAR agonist which own activity comparable to that of...
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Synthesis and reactivity of selected [3]dendralene derivatives
Štemberová, Marie ; Pour, Milan (advisor) ; Matouš, Petr (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Candidate: Marie Štemberová Supervisor: prof. RNDr. Milan Pour, Ph.D. Supervisor - specialist: PharmDr. Zbyněk Brůža, Ph.D. Title of Diploma Thesis: Synthesis and reactivity of chosen derivates of [3]dendralenes This diploma thesis is focused on the preparation of derivates of [3]dendralenes containing electron-withdrawing ester groups. The synthesis is based on a palladium- catalyzed Migita-Stille coupling between stannylated esters and iodinated acrylate which are prepared from methyl-propiolates. Subsequently these dendralenes undergo Dien-transmissive Diels-Alder reaction with electron-deficient dienophile N-phenylmaleimide, resulting in formation of polycyclic structures.
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Delipment of a new synthetic approach for synthesis of isoquinoline alkaloids
Pašek, Dominik ; Kotora, Martin (advisor) ; Pour, Milan (referee)
This bachelor work is focused on synthesis of a specifically substituted isoquinoline core which is the fundamental structure of natural isoquinoline alkaloids. The main aim is development of a new method for a synthesis of molecules with the isoquinoline framework which could lead to a more efficient way of total synthesis of these important natural substances. The main subject of interest is a cyclization providing a substituted piperidine ring condensed with the tetrahydroisoquinoline core. Zirconocene-based chemistry is used as the crucial synthetic step. Following the development of this new synthetic method, the goal was to study possibilities of cyclization of substituted 1,7-dienes by using the Negishi's reagent. Effects of temperature, reaction time, amount of Negishi's reagent on the course of the reaction as well as stereochemistry of the cyclization were studied. Key words: alkaloid, isoquinoline, synthesis, cyclization, zirconocene, Negishi's reagent
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Synthesis of modified and labeled acylceramides
Havrišák, Tomáš ; Opálka, Lukáš (advisor) ; Pour, Milan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Candidate: Tomáš Havrišák Supervisor: PharmDr. Lukáš Opálka, Ph.D Title of diploma thesis: Synthesis of modified and labeled acylceramides Upper most layer of skin, stratum corneum is providing effective barrier which protects us from impact of environment. Extracellular lipids of stratum corneum are mostly composed of ceramides, free atty acids and cholesterol. Earlier it was suggested that these lipids are highly rigid, which enables sufficient barrier function. But presently, it is known that some structural parts of these lipids are more fluid. So far, ultralong ceramides (also known as acylceramides), lipids which are necessary for correct barrier function still remain partly unexplored. Mobility of sphingosine part and linoleic ester have already been studied, but mobility of the ultralong chain is speculative. Obtaining information about mobility of particular parts of acylceramides is difficult because of their unavailability with required labelling. Our aim was to prepare acylceramides with deuterium-labelled half of their ultralong chain between carbons C17 - C32 from commercially available perdeuterated compounds. From available options we chose 1,12-dibromodocecane and...
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Synthetic studies of 3,5-disubstituted gamma-lactams
Coufalová, Klára ; Pour, Milan (advisor) ; Kuneš, Jiří (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate: Klára Coufalová Consultant: Prof. RNDr. Milan Pour, PhD. Title of Thesis: Synthetic studies of 3,5-disubstituted gamma-lactams The aim of my thesis was to synthesize lactam analogues of hydrolytically and enzymatically unstable 3,5-disubstituted five-membered lactone rings possessing an antifungal effect. I have tried to develop the preparation of 5-(acyloxymethyl)- -3-(4-methoxyfenyl)-1H-2,5-dihydropyrrol-2-one, however, even application of two reaction pathways did not (for now) successfully lead to the desired five-membered lactam ring.
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Synthesis and Utilization of Selected Nitrogen Heterocycles
Mikušek, Jiří ; Pour, Milan (advisor) ; Veselý, Jan (referee) ; Bureš, Filip (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate: Mgr. Jiří Mikušek Supervisor: prof. RNDr. Milan Pour, PhD. Title of Doctoral Thesis: Synthesis and Utilization of Selected Nitrogen Heterocycles The thesis is divided into two parts, both dealing with the synthesis of pyridine and pyrimidine derivatives. The first one is focused on the cyclization of enynes with gold(I) catalysts. Main attention is paid to the synthesis of various acyclic precursors starting from propargylamines, their addition to propiolates and Sonogashira cross-coupling. The mechanism of the cyclization with (TFP)AuCl is then discussed in detail. Prepared dihydropyridines were converted to pyridines or tetrahydropyridines. A precursor of the antidepressant drug paroxetine was prepared. The second part deals with quinazoline alkaloids with pyrimidine moiety and their structural variations towards potential organocatalysts and biologically active compounds. Therein new types of organocatalysts based on the structure of vasicine were prepared and screened on model aldolization and addition reactions. Prepared compounds were tested for bronchodilator activity.
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Direct Activation of the C-H Bond in Tetrazoles
Lubojacký, Richard ; Pour, Milan (advisor) ; Hrabálek, Alexandr (referee)
Direct activation of C-H bond in tetrazoles Richard Lubojacký, 5th grade Supervisor: Prof. RNDr. Milan Pour, Ph.D. Department of Inorganic and Organic Chemistry, Faculty of Pharmacy in Hradec Králové Within the framework of this diploma thesis, direct arylation and alkenylation of 1- substituted tetrazoles at C5 was developed and optimized. An economical preparation of a range of 1,5-disubstituted tetrazoles was thus made possible. In these reactions, Pd-catalysis in the presence of CuI and Cs2CO3 was found as optimal. Contrary to similar reactions of imidazoles and purines, it was necessary to incorporate phosphine ligands in order to stabilize Pd - intermediates and prevent them from a premature decomposition into cyanamides. A library of 1,5-disubstituted tetrazoles with very promising yields has been prepared using this method.
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Synthesis and Biological Evaluation of Selected Polysubstituted Furanones
Kratochvíl, Jiří ; Pour, Milan (advisor) ; Opletalová, Veronika (referee)
The aim of this thesis was to prepare 5-(benzyloxymethyl)-3-(4-bromophenyl)-2,5- dihydrofuran-2-one derived from cytostatically active 5-alkoxymethyl-3-(4-bromophenyl)- 2,5-dihydrofuran-2-ones. However, none of the three proposed synthetic procedures led to the target molecule. Next we focused on the preparation of a series of 5-bis(acetyloxymethyl)-3- aryl-4-phenyl-2,5-dihydrofuran-2-ones with different aryl substitution derived from the antibacterially, antifungally and cytostatically active 5-bis(acetyloxymethyl)-3- (4-bromophenyl)-4-phenyl-2,5-dihydrofuran-2-one. The aim was to explore a relationship between aryl substitution in position 3 and biological activity of the compounds. The spectrum of products was also enriched by 5-acetyloxymethyl-3-aryl-4-phenyl-2,5-dihydrofuran-2-ones. In conclusion aryl substitution leads to a significant decrease or vanishing of the antibacterial, antifungal and cytostatic effects with the exception of 5-acetyloxymethyl-3-aryl-4-phenyl-2,5- dihydrofuran-2-ones, in which marginal antifungal (Absidia corymbifera), antibacterial (Staphycoccus aureus a Staphylococcus epidermidis) and significant cytostatic (L1210, HeLa S3, CCRF-CEM, IC50 < 5 µmol.l-1 ) activities were found.
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Development of new pathways for syntheses of sesquiterpenoids
Topolovčan, Nikola ; Kotora, Martin (advisor) ; Dvořák, Dalimil (referee) ; Pour, Milan (referee)
This work consists of four consecutive parts, each dealing with syntheses of structurally diverse compounds. The syntheses were based on the methods within the domain of transition-metal catalyzed and/or mediated reactions with particular emaphasis on the application of organozirconium chemistry. 1. A method for synthesis of tricyclic condensed hydrocarbons possessing 5(6)-7-6(aryl) framework was developed. It is based on reaction of bicyclic zirconacyclopentenes, prepared by oxidative dimerization of enynes on a low-valent zirconocene species (Negishi's reagent), with ortho-halobenzaldehydes in the presence of various additives. The presence of two different centers of reactivity - the sp2 C-Zr and sp3 C-Zr bond - allowed sequential functionalization of each bond. Thanks to its higher nucleophilicity, the sp3 C-Zr bond reacted preferentially with the carbonyl carbon of the aldehyde yielding an oxazirconacycloheptene. The subsequent transmetallation of the remaining sp2 C-Zr bond with CuCl in the presence of other additives (catalysts) enabled an intramolecular cross-coupling reaction with the aryl halide moiety furnishing the desired tricyclic products in reasonable yields. The scope of the reaction with respect to differently functionalized reactants was assessed, as well as its mechanistic...
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