Sequential biocatalytic aldol reactions in multistep asymmetric synthesis: Pipecolic acid, piperidine and pyrrolidine (homo)iminocyclitol derivatives from achiral building blocks

Anna Soler, Xavier Garrabou, Karel Hernández, Mariana L. Gutiérrez, Eduardo Busto, Jordi Bujons, Teodor Parella, Jesús Joglar, Pere Clapés

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    23 Citations (Scopus)

    Abstract

    © 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. A multistep chemoenzymatic synthesis for stereodiverse polyhydroxypipecolic acid analogues, homoiminocyclitols and polyhydroxylated piperidine and pyrrolidine derivatives combining glycine-dependent aldolases and both d-fructose-6-phosphate aldolase (FSA) or dihydroxyacetone phosphate (DHAP)-dependent aldolases is presented. The methodology allowed the preparation of known and innovative imine-derived molecules with a great structural diversity from simple achiral substrates. The strategy consisted of two key aldol addition steps: a first aldol addition of glycine to dimethoxyacetaldehyde catalyzed by L- and D-glycine aldolases and a second aldol addition of DHAP, dihydroxyacetone, hydroxyacetone or glycolaldehyde using FSA or DHAP-dependent aldolases as catalysts to a conveniently transformed aldol adduct from the first aldol addition. Catalytic reductive amination on the aldol adducts rendered the polyhydroxypipecolic acid analogues, (homo)iminocyclitols and polyhydroxylated pyrrolidine iminocyclitols. The reported strategy is thus designed to create up to five new stereogenic centers in three steps, four of them being controlled in two enzymatic reactions. Moreover, it allowed the installation of diverse functionalities in the molecules. This was possible by taking the full advantage of using aldolases in a multistep approach by virtue of their stereocomplementarity, stereoselectivity and broad substrate tolerance.
    Original languageEnglish
    Pages (from-to)3007-3024
    JournalAdvanced Synthesis and Catalysis
    Volume356
    Issue number14-15
    DOIs
    Publication statusPublished - 1 Oct 2014

    Keywords

    • Aldol reaction
    • Amino acids
    • Amino aldehydes
    • Azasugars
    • Diversity-oriented synthesis
    • Enzyme catalysis
    • Pipecolic acids

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