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Synthesis of Purine - Amino Acid Conjugates
Čapek, Petr ; Hocek, Michal (advisor) ; Kotora, Martin (referee) ; Dvořák, Dalimil (referee) ; Mazal, Ctibor (referee)
4. Conclusions A simple and efficient approach to the synthesis of (purin-6-yl)alanines based on Negishi cross-coupling reactions of 6-iodopurines and iodozinc- alanines applicable to the synthesis of both racemic and optically pure compounds was developed. Though analogous reactions were used before for the synthesis of some simple aryl- or hetarylaranines, this was the first successful use in the functionalization ofprotected nucleobases and nucleosides. A practical method for synthesis of enantiomerically pure (purin-6_ yl)phenylalanines by palladium catalyzeď, copper mediated Stille cross-coupling reactions ofprotected 4-(trimethylstanyl)phenylalanines and 6-iodopurines was developed. This method was used in the synthesis of series of (purin_6_ yl)phenylalanines (bases and nucleosides) varying in substitution in position 9 of purine scaffold and in absolute configuration on o-carbon ofphenylalanine. The shaughnessy method for the Suzuki cross-coupling reactions in aqueous media was further optimized and applied to the single-step synthesis of novel optically pure (adenin-8-yl)phenylalanines and (purine_6_yl)phenyl_ alanines. wide tolerance of this methodology towards variety of functionalities and its applicability to 1abile systems was demonstrated particularly by the very first examples of couplings...
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Synthesis of axially chiral pyridin N-oxides and their application in organocatalysis
Hrdina, Radim ; Kotora, Martin (advisor) ; Černý, Miloslav (referee) ; Dvořák, Dalimil (referee) ; Starý, Ivo (referee)
o\ =Í Ě=Eíš$;*e.s Ei3E'1a?i l=;iěa ÉiE.Eé gžiž|; E=ž:g 7ElĚ.; zĚi;i žÉÉiĚě:-'7i,ž 1.!:;s .iÉeEi,Éři{É -;E'-žEš;1;;ítEšÉ .Ě=-Ě!:, ?:íiťŠš:;Ě;'b'jÉ3Ěi.í=-íš;EašÉ€ ={=.á .1 ==ž,+ai g=*ŤÉ É E'! : ::Ě,'!žiE Éí; g := : 9 ?EE =N:jÉ i;i,PE' ii;eÚÉs2 É.e.t sš:áE7 €šÉ-;:ň'ÉÉ |i. ":;šiÉ"EEÉ';Eč=;=.sz;==iaú - !Á..-= "i eať= 'É ď., -'á'.š L >q) N =t ú\r EÉiF T2yEĚ "?*;;> á ''j Ě .| : |, ? - a ^ l p Á ž 2 z: i i i i : i -, Ž .i, É? E=-,+; i Ě siiEĚ Éi;ž4i lEEř:Eí5iř iEE?5:E Ě;tžEizE== l;7;": :;ee-_?Ezii i;+ir+? -ž3;š: zďii; EiUÍEE =.=E=? "€:ž= š:ž=FE,?;EE= iěi;i í! 3,:- .'|:€ F1E.= a o3;Ezi _ =. l'z 'Ú ž ii.- Ě:c5-i= '=2E;šl +:É?49 1i;,í.i ÉE3E;E-€šls*iŤ+z\ ^EE E-oŤ ž.E:š.=ts €šrš EÉEii L EĚIE:Í;E5 oi BaEEE c.,B*Bcá (, I Q Ý
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Synthesis of polysubstituted pyrimidines with potential anti-inflammatory properties
Kalčic, Filip ; Janeba, Zlatko (advisor) ; Dvořák, Dalimil (referee)
This thesis is engaged in the synthesis of polysubstituted pyrimidines with anti- inflammatory properties. Such molecules can inhibit production of prostaglandin E2 (PGE2). The aim of this study was to enhance water-solubility and anti-inflammatory efficacy of such derivatives via structural modifications of the lead scaffold. Among applied synthetic tools, the Suzuki-Miyaura cross-coupling was the prevalent reaction, however, many other synthetic procedures (Heck reaction, condensation, borylation, ozonolysis, nucleophilic substitution, etc.) were utilized as well. Overall, 43 final products were prepared. The anti-inflammatory efficacy (inhibition of PGE2 production) was successfully increased as the most potent compound achieved three orders of magnitude higher activity compared to the current lead structure WQE-134. Furthermore, no general influence of the length of the substituent in the C5 position of pyrimidine (C5pyr) on the anti-inflammatory efficacy of synthesized compounds was observed. Significant bioavailability obstacle in future development of the current lead WQE-134 is its poor solubility which was successfully enhanced by introduction of heteroatom bearing moieties to C5pyr. The most water-soluble compound achieved two orders of magnitude higher solubility than WQE-134 while...
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Functionalization of pyrimidine nucleobases by direct C-H arylations.
Čerňová, Miroslava ; Hocek, Michal (advisor) ; Dvořák, Dalimil (referee) ; Rádl, Stanislav (referee)
Within presented dissertation thesis Pd-catalyzed direct C-H arylation of 1,3-dimethyluracil to position 5 or 6 was developed. An interesting dichotomy in the regioselectivity and mechanism of reactions were observed. A reaction of 1,3-dimethyluracil with diverse aryl halides performed in the absence of CuI led preferentially to 5-aryl-1,3-dimethyluracils, while with the addition of CuI 6-aryl-1,3-dimethyluracils were formed as the major products. Reactions mediated only in the presence of copper(I) iodide (in the absence of a Pd-catalyst) proceeded with lower yields but led exclusively to 6-arylated derivatives. In order to prepare free 5- and 6 arylated uracils for biological activity screening, the developed methodologies for the direct C-H arylations were applied to various 1,3-protected uracils. Benzyl-protected uracil was selected as the best candidate both in terms of stability during the arylations, as well as facile cleavage of the benzyl groups during deprotection of arylated uracils. Synthesis of various substituted 5- and 6-aryl-1,3-dibenzyluracils proceeded with the same regioselectivity as with the model compound 1,3-dimethyluracil. For deprotection of synthesized derivatives either transfer hydrogenolysis over Pd/C or treatment with BBr3 in case of uracils bearing bulky aromatic...
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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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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 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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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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