Synthesis and Comparative Glycosidase Inhibitory Properties of Reducing Castanospermine Analogues

The feasibility of the intramolecular nucleophilic addition of the nitrogen atom in cyclic (thio)carbamates with a pseudo‐C‐nucleoside structure to the masked carbonyl group in aldose precursors in the synthesis of reducing (i.e., 5‐hydroxy)6‐oxaindolizidine frameworks is illustrated by the preparation of the 6‐epi, 7‐epi, 8‐epi and 6,8a‐di‐epi diastereomers of the potent glycosidase inhibitor (+)‐castanospermine. In all cases, the increased anomeric effect caused by the high sp2 character of the pseudoamide‐type nitrogen atom resulted in the pseudoanomeric hydroxy group being anchored in an axial orientation in aqueous solution, as in the aglycons in α‐glycosides. These analogs of the natural alkaloid showed a higher selectivity in the inhibition of α‐glucosidases. Structure/glycosidase inhibitory activity studies indicated that inversion of any hydroxy group resulted in a dramatic decrease in the inhibition potency, confirming the critical importance of a correct hydroxylation profile. In the case of (+)‐8‐epi‐6‐oxacastanospermine derivatives, with a hydroxylation profile with a structural complementarity to that of D‐galactose, a moderate but very selective inhibition of α‐galactosidase was observed, supporting the importance of a defined configuration at pseudoanomeric centres for anomeric specificity. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)