N[BOND]O Bond as a Glycosidic-Bond Surrogate: Synthetic Studies Toward Polyhydroxylated N-Alkoxypiperidines

Authors

  • Dr. Gaëlle Malik,

    1. Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette (France)
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  • Angélique Ferry,

    1. Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette (France)
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  • Dr. Xavier Guinchard,

    1. Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette (France)
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  • Dr. Thierry Cresteil,

    1. Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette (France)
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  • Prof. Dr. David Crich

    Corresponding author
    1. Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette (France)
    2. Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202 (USA), Fax: (+1) 313-577-8822
    • Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette (France)
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Abstract

A series of novel polyhydroxylated N-alkoxypiperidines has been synthesized by ring-closing double reductive amination (DRA) of highly functionalized 1,5-dialdehydes with various hydroxylamines. The required saccharide-based dialdehydes were prepared efficiently from sodium cyclopentadienylide in seven steps. A two-step protocol has been developed for the DRA; it led, after deprotection, to isofagomine, 3-deoxyisofagomine, and numerous other N-alkoxy analogues. The barrier to inversion in these polyhydroxylated N-alkoxypiperidine derivatives was found by variable-temperature NMR methods to be approximately 15 kcal mol−1. With the exception of N-hydroxyisofagomine itself, none of the compounds prepared showed significant inhibitory activity against sweet almond β-glucosidase.

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