Generalized anomeric effect in action: Synthesis and evaluation of stable reducing indolizidine glycomimetics as glycosidase inhibitors

A series of aminoketalic castanospermine analogues incorporating a stereoel ectronically anchored axial hydroxy group at the pseudoanomeric stereocente r (C-5) have been synthesized to satisfy the need for glucosidase inhibitor s that are highly selective for alpha-glucosidases. The polyhydroxylated bi cyclic system was built from readily available hexofuranose derivatives thr ough a synthetic scheme that involved (i) the construction of a five-member ed cyclic (thio)carbamate or (thio)urea moiety at the nonreducing end and ( ii) the intramolecular nucleophilic addition of the heterocyclic thiocarbam ic nitrogen atom to the masked aldehyde group of the monosaccharide. A biol ogical screening of the resulting reducing 2-oxa- and 8-azaindolizidines ag ainst several glycosidase enzymes is reported.