D-Fructose-6-phosphate Aldolase in Organic Synthesis: Cascade Chemical-Enzymatic Preparation of Sugar-Related Polyhydroxylated Compounds

Authors

  • Alda Lisa Concia,

    1. Biotransformation and Bioactive Molecules Group, Catalonia Institute for Advanced Chemistry-CSIC, Jordi Girona 18–26, 08034 Barcelona (Spain), Fax: (+34)932045904
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  • Carles Lozano Dr.,

    1. Bioglane SLNE, Catalonia Institute for Advanced Chemistry-CSIC, Jordi Girona 18–26, 08034 Barcelona (Spain)
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  • José A. Castillo Dr.,

    1. Biotransformation and Bioactive Molecules Group, Catalonia Institute for Advanced Chemistry-CSIC, Jordi Girona 18–26, 08034 Barcelona (Spain), Fax: (+34)932045904
    2. Present address: Université Blaise Pascal, Laboratoire SEESIB-CNRS UMR 6504-Synthèse et Etude de Systèmes à Intérêt Biologique, 24 avenue des landais, 63177 Aubière, Aubière Cedex (France)
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  • Teodor Parella Dr.,

    1. Servei de Ressonància Magnètica Nuclear, Universitat Autònoma de Barcelona, Bellaterra (Spain)
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  • Jesús Joglar Dr.,

    1. Biotransformation and Bioactive Molecules Group, Catalonia Institute for Advanced Chemistry-CSIC, Jordi Girona 18–26, 08034 Barcelona (Spain), Fax: (+34)932045904
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  • Pere Clapés Dr.

    1. Biotransformation and Bioactive Molecules Group, Catalonia Institute for Advanced Chemistry-CSIC, Jordi Girona 18–26, 08034 Barcelona (Spain), Fax: (+34)932045904
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Abstract

D-Fructose-6-phosphate aldolase (FSA) is a key biocatalyst for the alternative synthetic construction of biologically active products with known therapeutic and research interest or novel structures relevant to drug discovery. Novel aldol addition reactions of dihydroxyacetone and hydroxyacetone to a variety of aldehydes catalyzed by FSA are presented (see scheme).

original image

Novel aldol addition reactions of dihydroxyacetone (DHA) and hydroxyacetone (HA) to a variety of aldehydes catalyzed by D-fructose-6-phosphate aldolase (FSA) are presented. In a chemical-enzymatic cascade reaction approach, 1-deoxynojirimycin and 1-deoxymannojirimycin were synthesized starting from (R)- and (S)-3-(N-Cbz-amino)-2-hydroxypropanal, respectively. Furthermore, 1,4-dideoxy-1,4-imino-D-arabinitol and 1,4,5-trideoxy-1,4-imino-D-arabinitol were prepared from N-Cbz-glycinal. 1-Deoxy-D-xylulose was also synthesized by using HA as the donor and either 2-benzyloxyethanal or 2-hydroxyethanal as acceptors. In both cases the enzymatic aldol addition reaction was fully stereoselective, but with 2-hydroxyethanal 17 % of the epimeric product at C2, 1-deoxy-D-erythro-2-pentulose, was observed due to enolization/epimerization during the isolation steps. It was also observed that D-(−)-threose is a good acceptor substrate for FSA, opening new synthetic possibilities for the preparation of important novel complex carbohydrate-related compounds from aldoses. To illustrate this, 1-deoxy-D-ido-hept-2-ulose was obtained stereoselectively by the addition of HA to D-(−)-threose, catalyzed by FSA. It was found that the reaction performance depended strongly on the donor substrate, HA being the one that gave the best conversions to the aldol adduct. The examples presented in this work show the valuable synthetic potential of FSA for the construction of chiral complex polyhydroxylated sugar-type structures.

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