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Dichotomy in regioselectivity of Pd-catalyzed direct C-H arylation of protected uracils
Čerňová, Miroslava ; Hocek, Michal
Uracil bases and nucleosides bearing aryl groups in positions 5 or 6 are an important class of compounds and display wide range of biological activities1. In addition, arylation in position 5 is often used for labeling of nucleotides, oligonucleotides and DNA for applications in bioanalysis or chemical biology2. The 5- or 6-aryluracils can be prepared by heterocyclization or by cross-coupling reactions of halouracils with arylboronic acids or stannanes or metallated uracils with aryl halides. Direct C–H arylation of uracil is an alternative to classical cross-couplings where the preparation of reactive organometallic reagent is avoided. Recently, we have developed regioselective Pd-catalyzed and/or Cu-mediated direct C–H arylations of 1,3-dimethyluracil as a model compound for pyrimidine bases to position C-5 or C-6 3.
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Modular synthesis of 5-substituted thiophene and furan C-nucleosides and their analogues
Bárta, Jan ; Hocek, Michal
A new modular and efficient methodology for the preparation of 5-substituted thiophen-2-yl and 5-substituted furan-2-yl C-nucleosides was developed. A Friedel–Crafts-type of C-glycosidation of 2-bromothiophene or 2-bromofuran with bis-toluoyl protected methyl- 2′-deoxyribofuranoside in presence of Lewis acid gave the desired bis-toluoyl protected 5-bromothiophne and 5-bromofuran C-nucleosides in good yields. They were used as key intermediates for Stille or Suzuki coupling whith (hetero)arylstannanes or boronic acids to afford a series of 5-(hetero)aryl thiophene and 5-(heteroaryl)furan C-nucleosides.
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Hetaryl derivatives of 7-deazapurine ribonucleosides: potent cytostatic agents
Perlíková, Pavla ; Nauš, Petr ; Bourderioux, Aurelie ; Hocek, Michal
A series of novel 7-deazapurine ribonucleosides substituted with aryl and hetaryl groups has been prepared. Suzuki or Stille cross-coupling reactions with 6-chloro-7-deazapurine ribonucleosides substituted with H, F of Cl atom in position 7 were used in the key step of the synthesis. Either cross-coupling of protected ribonucleoside with appropriate (het)arylboronic acid or stannane followed by deprotection, or single-step aqueous-phase Suzuki cross-coupling reaction of unprotected 7-deazapurine ribonucleoside with boronic acid provided target (het)aryl-7-deazapurine ribonucleosides. 6-Furyl- and 6-thienyl-7-deazapurine ribonucleosides showed cytostatic effect in multiple cancer cell lines in nanomolar range. Application of cyclosaligenyl and alanyl-ester phosphoramidate prodrugs did not improved cytostatic activity of parent nucleosides.
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Development of a general and modular approach to C-nucleosides
Kubelka, Tomáš ; Štefko, Martin ; Bárta, Jan ; Joubert, Nicolas ; Urban, Milan ; Chapuis, Hubert Jean ; Hocek, Michal
Highly efficient and modular approach was developed for the synthesis of various types of new (het)aryl C-nucleosides. This protocol consists of the synthesis of haloaryl-C-nucleoside intermediates, followed by a functional group transformation to introduce various substituents. Using this approach protected 2′-deoxy-C-nucleosides bearing halogenated benzene, pyridine, thiophene, furane and pyrimidine were prepared. These intermediates were then submitted to a wide range of palladium-catalyzed reactions. The same approach was also used for preparation of C-nucleosides bearing ribofuranose moiety. Functional ribofuranosides bearing diverse substituted pyridine and benzene nucleobases were prepared in this way.
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Cyclic and acyclic phosphonate tyrosine ester prodrugs of acyclic nucleoside phosphonates
Williams, M. ; Krylov, I. S. ; Zakharova, V. M. ; Serpi, M. ; Peterson, L. W. ; Krečmerová, Marcela ; Kashemirov, B. A. ; McKenna, Ch. E.
A series of P-O ester derivatives of HPMPA, HPMPC, PMEA a (R)-PMPDAP was synthesized as potential anti-malarial prodrugs.
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