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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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Design and synthesis of a potential orexin receptor OX2R modulator with the use of in silico methods
Kárová, Barbora ; Doležal, Rafael (advisor) ; Kolář, Karel (referee)
Orexinergic nervous system is a complex of neurons playing a significant role in managing sleep cycle and food intake. Orexin neurons situated in the lateral hypothalamus produce orexin neuropeptides A and B, which interact with two orexin receptors in a broad range of neurons in the brain. A reduced production of these neuropeptides due to the loss of orexin neurons is the cause of a specific and rare disease narcolepsy, which is currently incurable. A significant milestone in terms of drug research and development against narcolepsy is a study of Takashi Nagaraha's scientific group (2015), which was the first one to synthesize a non-peptidic agonist of the orexin 2 receptor (OX2R) that has inspired further design of new drug candidates with an increased chance to reach the clinical practice. This Bachelor Thesis is focused on the design and organic synthesis of a novel OX2R agonist with a 2-deoxystreptamine substructure and follows the Nagahara's study using rational and computer-aided drug design. The theoretical part is dedicated to the literature review of this issue, the practical part focuses on the design of 11 ligands using in silico and medicinal chemistry methods. The organic synthesis was then proposed, based on a retrosynthetic analysis, for the final candidate with the optimal...
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Development of a synthetic methodology for the preparation of advanced cycloarenes and their analogues
Bambas, Daniel ; Stará, Irena (advisor) ; Míšek, Jiří (referee)
This Bachelor's Thesis deals with a design and preparation attempts leading to building blocks suitable for macrocycle construction with further utilization in cycloarene synthesis. In Theoretical Background methods for preparation of [n]circulenes and kekulene-like structures are summarized with focus on the final ring-closing steps. In Results and Discussion chapter efforts to prepare the selected advanced building block as a starting compound for macrocyle construction whose transformation using [2+2+2] cyclotrimerization as a ring-forming reaction might provide the selected cycloarene are described. Part Proposed alternatives of synthesis and discussion of further approach is about future possible development of this study. Experimental Part provides practical information about undertaken experiments and characterizations of the prepared compounds.
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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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Enantioselective allylation of dienals and their application in tiacumicin synthesis
Koukal, Petr ; Kotora, Martin (advisor) ; Cibulka, Radek (referee) ; Pour, Milan (referee)
The current methodologies of catalytic enantioselective allylation of aldehydes were studied on conjugated dienals and later on haloacrylaldehydes as the substrates. The resulting enantioenriched homoallylalcohols were prepared by reactions promoted either by commercial Brønsted acid catalysts or by Lewis base catalysts developed by our group, often with high enantio- and diastereoselectivities. Subsequently, the methodology was expanded on catalytic enantioselective crotylation and pentenylation reactions, practically unknown not only with these substrates. The applicability of this synthetic approach was demonstrated on preparation of several natural products or their intermediates.
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Synthesis of new carborane and metallacarborane bulding blocks appliable in design of biologically active compounds
Nekvinda, Jan ; Grüner, Bohumír (advisor) ; Janoušek, Zbyněk (referee)
Compounds with carboxylic and amidic functions belong to basic structural blocks, which are used for construction of functional molecules in organic, organometallic and also in carborane chemistry. However, considering cobalt bis(dicarbollide)(1-) ion, the synthetic ways to these derivatives have been virtually unknown. A published procedure on lithiation in THF and reaction with CO2 leading to mono- and dicarboxylic acids had failed in our hands. Nevertheless, a detailed revision of the experimental conditions provided finally good yields of mixture of both acids, which could be separated by chromatography and crystallization, and compound of general formulation [(1-HOOC-1,2-C2B9H10)(1',2'-C2B9H10)-3,3'-Co(III)]- and stereoisomeric mixture of [(HOOC)2-(1,2-C2B9H10)2-3,3'-Co(III)]- were characterized for the first time by combination of NMR, MS and HPLC. Also, the carboxylic acid derivatives with methylene and ethylene connectors of the general formula [(1-HOOC-(CH2)n-1,2- C2B9H10)(1',2'-C2B9H10)-3,3'-Co(III)]- were prepared by lithiation of Cs1 in DME at low temperatures followed by reaction with BrCH2COOEt and subsequent hydrolysis of the resulting ester or by oxidation of the respective propylhydroxy derivative. The acids were converted to reactive p-nitrophenyl esters...
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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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Synthesis of selaginpulvilins
Beytlerová, Nela ; Kotora, Martin (advisor) ; Hájíček, Josef (referee)
This bachelor thesis is focused on the application of [2+2+2] cyclotrimerization in the total synthesis of natural fluorene derivate, selaginpulvilin D, which was isolated from the plant Selaginella pulvinata. The plant is used in the traditional Chinese medicine for treatment of asthma and traumatic injuries. The study is focused on development of the catalytic cyclotrimerization reaction that is used to prepare the key intermediate. The integral part of the project is a study how various catalysts and catalytic systems, solvents and reaction temperatures affect the course of the reaction. Synthesis of the suitable cyclotrimerization precursor was achieved from benzaldehyde and the formal synthesis of selaginpulvilin D was completed by conversion of cyclotrimerization product to the known intermediate of the selaginpulvilin D synthesis. Key words: [2+2+2] cyclotrimerization, selaginpulvilin D, natural compound, fluorene core
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Enantioselective allylation of dienals and their application in tiacumicin synthesis
Koukal, Petr ; Kotora, Martin (advisor) ; Cibulka, Radek (referee) ; Pour, Milan (referee)
The current methodologies of catalytic enantioselective allylation of aldehydes were studied on conjugated dienals and later on haloacrylaldehydes as the substrates. The resulting enantioenriched homoallylalcohols were prepared by reactions promoted either by commercial Brønsted acid catalysts or by Lewis base catalysts developed by our group, often with high enantio- and diastereoselectivities. Subsequently, the methodology was expanded on catalytic enantioselective crotylation and pentenylation reactions, practically unknown not only with these substrates. The applicability of this synthetic approach was demonstrated on preparation of several natural products or their intermediates.
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