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Keywords:

  • carbohydrates;
  • glycosidases;
  • iminosugars;
  • nitrogen heterocycles;
  • reductive amination

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.