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Enantioselective resolution of side-chain modified gem-difluorinated alcohols catalysed by Candida antarctica lipase B and monitored by capillary electrophoresis

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    SYSNO ASEP0503710
    Document TypeJ - Journal Article
    R&D Document TypeJournal Article
    Subsidiary JČlánek ve WOS
    TitleEnantioselective resolution of side-chain modified gem-difluorinated alcohols catalysed by Candida antarctica lipase B and monitored by capillary electrophoresis
    Author(s) Pomeisl, Karel (UOCHB-X) RID
    Lamatová, Nikola (UOCHB-X)
    Šolínová, Veronika (UOCHB-X) RID, ORCID
    Pohl, Radek (UOCHB-X) RID, ORCID
    Brabcová, Jana (UOCHB-X) RID
    Kašička, Václav (UOCHB-X) RID, ORCID
    Krečmerová, Marcela (UOCHB-X) RID, ORCID
    Source TitleBioorganic & Medicinal Chemistry. - : Elsevier - ISSN 0968-0896
    Roč. 27, č. 7 (2019), s. 1246-1253
    Number of pages8 s.
    Languageeng - English
    CountryGB - United Kingdom
    Keywordsacyclic nucleoside phosphonates ; Candida antarctica lipase ; capillary electrophoresis ; enantioselective resolution ; enzyme catalysis ; gem-difluorinated alcohols ; isomerisation ; transesterification
    Subject RIVCC - Organic Chemistry
    OECD categoryOrganic chemistry
    R&D ProjectsGA14-00522S GA ČR - Czech Science Foundation (CSF)
    GA17-10832S GA ČR - Czech Science Foundation (CSF)
    GA18-02597S GA ČR - Czech Science Foundation (CSF)
    Method of publishingLimited access
    Institutional supportUOCHB-X - RVO:61388963
    UT WOS000461168400007
    EID SCOPUS85061619987
    DOI10.1016/j.bmc.2019.02.022
    AnnotationAn enzymatic alternative to the chemical synthesis of chiral gem-difluorinated alcohols has been developed. The method is highly effective and stereoselective, feasible at laboratory temperature, avoiding the use of toxic heavy metal catalysts which is an important benefit in medicinal chemistry including the synthesis of drugs and drug precursors. Candida antarctica lipases A and B were applied for the enantioselective resolution of side-chain modified gem-difluorinated alcohols, (R)- and (S)-3-benzyloxy-1,1-difluoropropan-2-ols (1a and 1b), compounds serving as chiral building blocks in the synthesis of various bioactive molecules bearing a gem-difluorinated grouping. The catalytic activity of these lipases was investigated for the chiral acetylation of 1a and 1b in non-polar solvents using vinyl acetate as an acetyl donor. The dependence of the reaction course on various substrate and enzyme concentrations, reaction time, and temperature was monitored by chiral capillary electrophoresis (CE) using sulfobutyl ether beta-cyclodextrin as a stereoselective additive of the aqueous background electrolyte. The application of CE, NMR, and MS methods has proved that the complex enzyme effect of Candida antarctica lipase B leads to the thermodynamically stable (S)-enantiomer 1b instead of the expected acetylated derivatives. In contrast, the enantioselective acetylation of racemic alcohol 1 was observed as a kinetically controlled process, where (R)-enantiomer 1a was formed as the main product. This process was followed by enzymatic hydrolysis and chiral isomerisation. Finally, single pure enantiomers 1a and 1b were isolated and their absolute configurations were assigned from NMR analysis after esterification with Mosher's acids.
    WorkplaceInstitute of Organic Chemistry and Biochemistry
    Contactasep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434
    Year of Publishing2020
    Electronic addresshttps://www.sciencedirect.com/science/article/pii/S0968089618318169?via%3Dihub
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