γ-Hydroxyethyl piperidine iminosugar and N-alkylated derivatives: A study of their activity as glycosidase inhibitors and as immunosuppressive agents

An efficient and practical strategy for the synthesis of (3R, 4s, 5S)-4-(2-hydroxyethyl) piperidine-3,4,5-triol and its N-alkyl derivatives 8a-f, starting from the D-glucose, is reported. The chiral pool methodology involves preparation of the C-3-allyl-alpha-D-ribofuranodialdose 10, which was converted to the C-5-amino derivative 11 by reductive amination. The presence of C-3-allyl group gives an easy access to the requisite hydroxyethyl substituted compound 13. Intramolecular reductive aminocyclization of C-5 amino group with C-1 aldehyde provided the gamma-hydroxyethyl substituted piperidine iminosugar 8a that was N-alkylated to get N-alkyl derivatives 8b-f. Iminosugars 8a-f were screened against glycosidase enzymes. Amongst synthetic N-alkylated iminosugars, 8b and 8c were found to be a-galactosidase inhibitors while 8d and 8e were selective and moderate alpha-mannosidase inhibitors. In addition, immunomodulatory activity of compounds 8a-f was examined. These results were substantiated by molecular docking studies using AUTODOCK 4.2 programme. (C) 2014 Elsevier Ltd. All rights reserved.