Fluorinated and Conformationally Fixed Derivatives of l‑HomoDMDP: Synthesis and Glycosidase Inhibition

Abstract

Fluorinated and conformationally fixed derivatives of l-homoDMDP, i.e., 2,5-dideoxy-2,5-imino-dl-<i>glycero</i>-l-<i>manno</i>-heptitol, have been synthesized from d-xylose-derived cyclic nitrone <b>10</b> with oxazolidinone <b>19</b> or <b>28</b> and oxazinanone <b>22</b> or <b>32</b> as key intermediates. An evaluation of glycosidase inhibition showed replacement of the C-6 hydroxyl groups with fluoride in l-homoDMDP and its C-6 epimer did not have a significant influence on α-glucosidase inhibition by these iminosugars, while replacement of an amino group with a cyclic carbamate group in most conformationally fixed derivatives led to a sharp decrease in the level of glycosidase inhibition, revealing the importance of the free amino group in interaction of enzymes with these molecules