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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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Synthesis of New Types of Biologically Active Substances Using the Organometallic Compounds
Korotvička, Aleš ; Kotora, Martin (advisor) ; Dvořák, Dalimil (referee) ; Starý, Ivo (referee)
This work consists of four separate chapters. Although they are seemingly different projects, they have a common feature - the application of organometallic chemistry. 1. Lusianthridin and denbinobin, the phenanthrene derivatives, can be found in plants of the family Orchidaceae. They exhibit cytostatic activity against cancer of human lung and ovarian and against promyelocytic leukemia. Therefore, new synthetic methods for these substances may be applied in research and development of new bioactive compounds. I prepared 9,10- disubstituted phenanthrenes through reactions of biphenylene with alkynes, which were catalyzed by iridium complexes. Phenanthridine derivatives are found naturally in the group benzo[c]phenanthridine alkaloids. The most famous of these include sanguinarine and chelerythrine. Sanguinarine selectively induces apoptosis (planned cell death) of human cancer cells and, therefore, is investigated as a potential antitumor agent. Chelerythrine selectively inhibits protein kinase C, leading again to apoptosis. I have studied reactions of biphenylene with nitriles catalyzed by rhodium complexes that have not been described yet. By this, I prepared a series of 6-substituted phenanthridines. 2. Carboranes are artificially prepared organic compounds of boron, which are not represented in...
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Synthesis of Specifically Substituted Heterocycles via Catalytic Reactions
Kratochvíl, Jiří ; Pour, Milan (advisor) ; Kotora, Martin (referee) ; Dvořák, Dalimil (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate Mgr. Jiří Kratochvíl Supervisor prof. RNDr. Milan Pour, Ph.D. Title of Doctoral Thesis Synthesis of Specifically Substituted Heterocycles via Catalytic Reactions This Ph.D. thesis deals with the synthesis of γ-alkylidene-α,β-unsaturated δ-lactones and lactams. Migita- Stille cross-coupling served as the key step in their preparation. Catalysis with palladium black was applied to the synthesis of the lactones and we demonstrated that it doesn't act as heterogeneous catalyst. Instead, it's only a precursor for catalytically active species, which is generated in situ and its true nature is unknown. The palladium nanoparticles are most likely responsible for the catalysis, although involvement of complexed atomic palladium cannot be excluded. Palladium black catalysis was also successfully applied to the synthesis of a series of structurally different substrates, which demonstrates its versatility and it was also proved that the catalyst can be easily recycled by simple filtration. An unusual Tsuji-Trost reaction then enabled transfer of the alkylidene substituent of the lactones to C5 furnishing polysubstituted heterocycles.
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I. Synthesis and Application of N-Silyloxy Enamines II. Helquats: Synthesis and Properties
Sonawane, Manoj Rambhau ; Teplý, Filip (advisor) ; Dvořák, Dalimil (referee) ; Veselý, Jan (referee)
1. Abstract The work reported in this thesis is divided into two parts. In the first part, the chemistry of N-silyloxy enamine is discussed. The introductory section contains a brief overview of enamines, N,N-bis(silyloxy)enamines and N-silyloxy enamines, including their preparation, reactivity as well as comparison of their nucleophilicity with enolates and silyl enol ethers. Enamines in aldol reactions and synthetic challenges of asymmetric cross-aldol reactions are briefly discussed. The results and discussion section describes the synthesis of N-silyloxy enamines derived from aldehydes and use of N-(trimethylsilyloxy)enamines as new aldehyde enolate synthons for general, efficient and diastereoselective aldol-type reaction with dimethyl acetals and ketals. Also the syn-diastereoselectivity in β-methoxy nitrone products and their conversion to respective β-methoxy aldehydes is mentioned. Furthermore, synthesis of N-methyl-N-(trimethylsilyloxy)enamines from ketones is reported. In the second part, synthesis of new symmetric and non-symmetric helquats is reported. In the introductory section a brief overview of N-heteroaromatic cations including their natural occurrence and synthetic aspects as well as their applications in organocatalysis, molecular biology is discussed. Helicenes, viologens,...
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Total Synthesis of (-) - Methoxyestrone
Betík, Robert ; Kotora, Martin (advisor) ; Dvořák, Dalimil (referee) ; Jahn, Ullrich (referee)
English Abstract The new diastereoselective synthesis of estrone precursor and enantioselective synthesis of (-)-methoxyestrone are described in this work. The diastereoselective synthesis was based on 2 Bu2ZrCp2 mediated reactions followed by Pauson-Khand cyclocarbonylation. The sequence of reactions yielded 16-keto-17-methylestratetraene, compound with tetracyclic steroid framework, with excellent diastereoselectivity. Synthesis was finished with chemoselective reduction of the keto group in 16-keto-17-methylestratetraene to furnish 17- methylestratetraene, which is known precursor of estrone. The enantioselective synthesis was based on a conjugate addition of vinylmagnesium bromide to aldimine formed from 1-formyl- 3,4-dihydro-6-methoxynaphthalene and (L)-t-leucine t-butyl ester, which afforded crucial chiral intermediate 1-formyl-3,4-dihydro-6-methoxy-2-vinyl-naphthalene with very high ee > 98 %. Further transformations led to the construction of alkyl side chain containing triple bond and finally, the Pauson-Khand cyclocarbonylation followed by chemoselective reduction of carbonyl group gave estrone precursor, which was converted to (-)- methoxyestrone according known procedure.
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Synthesis of novel types of annulated deazapurine nucleosides with potential biological activity
Tichý, Michal ; Hocek, Michal (advisor) ; Dvořák, Dalimil (referee) ; Hlaváč, Jan (referee)
This thesis reports the syntheses and biological activities of benzo- and thieno-fused 7-deazapurine ribonucleosides, which were designed as extended analogues of potent cytostatic 6-hetaryl-7-deazapurine or 6-amino-7-hetaryl-7-deazapurine ribonucleosides. First of all, multigram syntheses of (di)chloro-9H-pyrimido[4,5-b]indoles from simple chloro- nitrobenzenes were developed. Pyrimidoindoles were successfully glycosylated and used for the synthesis of 4-hetaryl-6-chloro-, 4,6-bis(hetaryl)-, 4-amino-6-hetaryl-, 4-amino-5-hetaryl- and 4-susbtituted pyrimido[4,5-b]indole ribonucleosides. Hetaryl groups were introduced by Suzuki or Stille cross-coupling reaction. Standard catalysts and conditions were used for reaction in position 4. To observe some reactivity of unreactive chlorine in position 6, modification of standard protocol was necessary. Screening of several ligands had been done and Buchwald ligand X-Phos was found to be optimal. As chlorine in position 4 is activated for nucleophilic substitution, amino and dimethylamino derivatives were prepared by reaction with aqueous ammonia and dimethylamine, respectively. 4-Alkyl derivatives were synthesized by palladium-catalyzed alkylation with trialkylaluminium or by Negishi coupling in case of cyclopropyl derivative. Desired free nucleosides were...
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Novel modified nucleosides with antiviral or cytostatic activity
Tokarenko, Anna ; Hocek, Michal (advisor) ; Rádl, Stanislav (referee) ; Dvořák, Dalimil (referee)
A general and modular synthetic approach to 4-substituted phenyl, 2-substituted pyridin- 5-yl and 5-substituted pyridin-2-yl 2′-C-methyl-C-ribonucleosides as potential anti-HCV agents was developed. Addition of halo(het)aryllithium reagents to benzylated 2-C-methyl-D- ribonolactone gave the corresponding hemiketals, which were subsequently converted to the β-anomeric benzyl-protected bromo(het)aryl-C-nucleosides via either direct reduction (in the case of phenyl derivative) or acetylation followed by reduction of the resulting hemiketal acetates (in the case of pyridyl derivatives). The key halogenated (het)aryl-C-nucleoside intermediates were further transformed by Pd-catalyzed cross-coupling, hydroxylation and amination reactions affording series of protected C-nucleosides with small hydrophilic and hydrophobic substituents. The final protecting group removal was rather problematic, and different debenzylation methods, such as hydrogenation on Pd/C or treatment with BCl3, had to be optimized for each derivative to minimize the formation of side-products. The final C- nucleosides were also converted into their 5′-O-triphosphates, and biological activity screenings revealed that none of the free C-nucleosides possesses any antiviral activity in the HCV replicon assay, and none of their NTPs...
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Development of new syntheses of condensed aromatic compounds
Kaiser, Reinhard Peter ; Kotora, Martin (advisor) ; Starý, Ivo (referee) ; Dvořák, Dalimil (referee)
This work is divided into two parts that are focused on the synthesis and assessment of photophysical properties of two structurally related compounds: (i) 9,9'-spirobifluorenes (SBFs) and (ii) dispiroindeno[2,1-c]fluorenes (DS-IFs). (i) In the first part, a five-step synthetic approach to SBFs was developed and as the crucial step was used an intermolecular [2+2+2] cyclotrimerization of symmetrically or unsymmetrically substituted diynols with alkynes catalyzed by Rh-complexes. Catalyst screening showed that Wilkinson's catalyst (RhCl(PPh3)3) had the highest efficiency in yielding 1,2,3,4-substituted fluorenols - the key intermediates. The fluorenols were then converted into SBFs bearing various electron-donating and -withdrawing groups, aromatic substituents, and -extended aromatic hydrocarbon moieties (PAHs). Altogether 19 different SBFs were prepared and their photophysical properties screened. The fluorescent emission maxima em were in the range of 315-389 nm with excellent quantum yields s (up to 1.00). As far as the substituent effect is concerned the presence of electron-withdrawing substituents on the SBF scaffold results in the red-shift of the emission maxima. (ii) In the second part, a similar synthetic strategy was applied for synthesis DS-IFs. In this instance was utilized again the...
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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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