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Synthesis of tricyclic hydrocarbon derivatives
Tuzova, Uliana ; Hrdina, Radim (advisor) ; Rýček, Lukáš (referee)
This bachelor thesis deals with the preparation of enantiopure Binol-derived phosphoric acids with different substituents at the 3,3'-position, which are typically used as Brønsted acids in enantioselective non-covalent organocatalysis. The prepared 3,3'-adamantane substituted Binol-derived phosphoric acids are planned to be used as organocatalysts. Bulky alkyl substituents at the 3,3' position have been introduced in order to compare their properties with those of phenyl substituents at the 3,3' position. The different dispersion forces between substrate and catalyst are expected when aryl and alkyl substituents are incorporated into the catalyst structure. Keywords Organocatalysis, asymmetric synthesis, Brønsted acids.
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Synthesis of Adamantane Derivatives
Todd, Matthew Zagorey ; Hrdina, Radim (advisor) ; Rýček, Lukáš (referee)
Undirected functionalization of adamantane by electrophilic oxidation proceeds mainly at the tertiary positions, owing to the higher reactivity of its C-H bonds and stability of electron deficient species, relative to the secondary positions. Ring contraction and expansion methods have been shown as a powerful tool to prepare such derivatives avoiding the reactivity constraints of undirected electrophilic oxidation reactions. Previous ring contraction methods proceeded under harsh conditions limiting their scope to simple alkyl substituents. In this work a new ring contraction method for the preparation of noradamantane derivatives from adamantane under mild conditions has been developed, enabling the presence of additional functional groups during the process. The new method utilizes the commercially available Burgess reagent for mild dehydration conditions of the starting material leading to 1,3- and 3,7-disubstituted (3-noradamantyl)methylene aldehydes, that were previously hard to obtain, if not unobtainable, and post functionalized to their corresponding protected amino-alcohols and diols. The method was also applied for the synthesis of protoadaman-4-one that is mainly synthesized through the deamination of 2-aminoadamantan-1-ol. The deamination method was also optimized for the preparation...
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Design and Synthesis of Prodrugs of 6-Diazo-5-oxo-L-norleucine; Potential Treatment for Glioblastoma
Novotná, Kateřina ; Majer, Pavel (advisor) ; Rýček, Lukáš (referee)
6-Diazo-5-oxo-L-norleucine (DON, 1) is a non-standard amino acid with proven antitumor activity found in soil bacteria of the genus Streptomyces. However, due to the considerable systemic toxicity manifested mainly in the gastrointestinal tract, DON alone is not a suitable clinical candidate for the treatment of cancer. One of the ways to solve the problem of its toxicity is the reversible structural modification of this molecule by protecting both its amino group and carboxyl functional group, by preparing the so-called prodrug of DON. The prepared prodrug may suitably alter the distribution of DON in the body and at the same time increase its permeability to brain tissue. Due to this structural modification, its side effects can be eliminated and a substance for the treatment of brain tumors, such as glioblastoma multiforme (GBM), can potentially be formed. In my dissertation, five strategies for the specific delivery of DON to the brain using different types of its prodrugs are discussed. The new prodrugs are designed to be either capable of spontaneous penetration across the blood-brain barrier or of being a substrate for one of its influx transporters. At the same time, these prodrugs should be stable in other metabolically active organs and blood plasma in order to sufficiently reduce the...
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Synthesis of chemical constituents from the Selaginellaceae family
Mulenga, Mutale Jane ; Rýček, Lukáš (advisor) ; Hrdina, Radim (referee)
The genus Selaginella belongs to the family Selaginellaceae. There have been about 30 selaginellins reported with possession of biological activities such as antimicrobial, cytotoxic, antioxidant, and phosphodiesterase-4 (PDE4) inhibitory properties. This master's thesis will focus on the synthesis of the natural product selaginellin T, containing the isobenzofuran- 1(3H)-one core in its structure. The first attempts to create the core were attempted via partially intramolecular [2+2+2] cyclotrimerization from the corresponding diyne connected by an ester linker and external alkyne. This strategy failed, as the formation of the stating ester was not feasible. The alternative strategy relying on [4+2] cycloaddition was evaluated, however, without any success. Finally, the isobenzofuran-1(3H)-one core was formed via [2+2+2] cyclotrimerization of the corresponding diyne connected by ether linker, leading to the corresponding 1,3-dihydroisobenzofuran, which was further oxidized to the desired lactone. The difficulties with the removal of the protecting groups were encountered at the later stage of the synthesis, and therefore, the use of alternative protecting groups is proposed. Key words: Selaginellaceae, selaginella, cyclotrimerization, metal catalysis.
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Synthesis of selagibenzophenone C and derivatives for confirmation of the stucture of the natural product.
Kunák, Dominik ; Rýček, Lukáš (advisor) ; Matoušová, Eliška (referee)
5 Abstract This bachelor's thesis deals with the preparation of selagibenzophenone C. The natural product was prepared in a six-step synthesis, where subsequent analysis and comparison of the spectrum of the synthetic substance with the spectra described for the isolated product verified whether the structure of the isolated natural product was deciphered correctly. Furthermore, it was verified that intermediates in the synthesis of selagibenzophenone C can undergo cyclization reactions to form a fluorene core. Analogous cyclization is the main step in the biosynthesis of selaginpulvilins from the corresponding selaginellins. The obtained fluorene derivatives will therefore be used as standards in the following studies to determine whether these substances obtained by us are also natural compounds. Key words Total synthesis, natural product, polyphenols, natural fluorene derivates, selagibenzophenones
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Synthesis of Cationic Helical N-Heterocycles
Hrubý, Samuel ; Kotora, Martin (advisor) ; Rýček, Lukáš (referee)
Diploma thesis concerns synthesis of hitherto unknown cationic helical heterocyclic compounds by catalytic processes from simple building blocks. The focus was on the utilization of a catalytic C-C bond cleavage in biphenylene followed by annulation with nitriles, a method that was developed in our research group. As an alternative approach was applied Suzuki- Miyaura cross-coupling. The prepared phenanthridines were used in catalytic C-H bond activation followed by annulation with alkynes giving rise to cationic helical heterocycles. These compounds have potential application in various fields of material chemistry. Key words: C-C bond activation, C-H bond activation, Suzuki-Miyaura cross-coupling, heterocycles, helical compounds, catalysis
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Enantioselective synthesis of spirooxindoles
Vopálenská, Andrea ; Veselý, Jan (advisor) ; Rýček, Lukáš (referee)
This diploma thesis is focused on the enantioselective synthesis of spiro[cyclopentane- oxindoles] from 3-alkylideneoxindoles and 1-bromo-3-nitropropane catalyzed by chiral bifunctional organocatalysts. The first part of this work is devoted to the preparation of the proposed starting 3-alkylideneoxindoles and 1-bromo-3-nitropropane. In the second part, the reaction conditions of the enantioselective synthesis of chiral spirooxindoles were optimized, and then the scope of the method's use on selected substrates was studied under the optimized conditions.
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Synthesis of Azafluoranthene Derivatives via C-H Activation/Annulation Process.
Hladík, Ondřej ; Nečas, David (advisor) ; Rýček, Lukáš (referee)
The azafluoranthenes are a small group of natural substances, occuring in tropical vines from Menispermaceae family. They display promising medicinal effects (such as anti-HIV, cytotoxic activity) and other biological activities have been predicted. This bachelor thesis is focused on the synthesis of azafluoranthene core via directed C-H activation/annulation process. Firstly, required starting compounds have been prepared. In the next step, suitable catalytical conditions enabling the crucial transformation have been found and optimized. Finally, the applicability of the developed methodology has been confirmed by the synthesis of several new 1-azafluoranthene derivatives. Keywords: C-H activation, annulation, 1-azafluorathene, rhodium
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Enantioselective Synthesis of Chiral Cyclohexenones Using NHC Catalysis
Lóška, Ladislav ; Veselý, Jan (advisor) ; Rýček, Lukáš (referee)
This work deals with the enantioselective synthesis of chiral cyclohexenones from substituted 4-nitroisoxazoles and α-bromo-α,β-unsaturated aldehydes using of N-heterocyclic carbenes (NHC) as organocatalysts. The work includes the preparation of commercially unavailable NHC-precursors and the synthesis of starting materials, substituted 4-nitroisoxazoles and α-bromo-α,β-unsaturated aldehydes. The second part of the work deals with the optimization of reaction conditions of the enantioselective synthesis of chiral cyclohexenones, proceeding via an azolium dienolate intermediate, and the detailed substrate scope screening.
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Preparation, synthesis and activity of new inhibitors of cystein proteases from Porphyromonas gingivalis
Gistrová, Tereza ; Konvalinka, Jan (advisor) ; Rýček, Lukáš (referee)
This bachelor thesis deals with modification of known inhibitor KYT-36 specific for the Porphyromonas gingivalis protease called gingipain (Kgp).1 Proposed modification with an oligoethylenglycole linker in suitable position will enable the use of the derivative in the iBodies concept.2 These polyfunctional macromolecules based on a polymer backbone are capable of replacing antibodies in biochemical experiments in the study of enzymes. The main aim of the thesis is to propose and perform an effective synthetic strategy. This thesis includes an analysis of a crystal structure of enzyme Kgp with the inhibitor KYT-36 (PDB ID: 6I9A).3 The analysis enabled a choice of an appropriate modification site. A suitable functional group was added to the selected fragment allowing attachment of the linker. The linker's design was based on requirements for the intended use within the iBodies concept. One of them being a suitable functional group at the end of the chain ensuring an effortless conjugation with polymer backbone. Based on a retrosynthetic analysis, a synthetic strategy of the inhibitor core was proposed. This strategy builds upon the Passerini reaction. Key words: Porphyromonas gingivalis, gingipain, inhibitor, KYT-36, iBodies, Passerini
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