Looking glass inhibitors: scalable syntheses of DNJ, DMDP, and (3R)-3-hydroxy-l-bulgecinine from d-glucuronolactone and of l-DNJ, l-DMDP, and (3S)-3-hydroxy-d-bulgecinine from l-glucuronolactone. DMDP inhibits β-glucosidases and β-galactosidases whereas l-DMDP is a potent and specific inhibitor of α-glucosidases

Abstract

A convenient large-scale synthesis of 1-deoxynojirimyin (DNJ) from d-glucuronolactone involves introduction of azide at C-5 with retention of configuration to give 5-azido-5-deoxy-1,2-O-isopropylidene-α-d-glucofuranose as a key intermediate in an overall yield of up to 72%; the same intermediate can be transformed into DMDP [(2R,3R,4R,5R)-2,5-bis(hydroxymethyl)pyrrolidine-3,4-diol] and (3R)-3-hydroxy-l-bulgecinine [(2S,3R,4R,5R)-3,4-dihydroxy-5-hydroxymethyl-l-proline]. l-Glucuronolactone, a readily available l-sugar chiron, may similarly be used to access the enantiomers l-DNJ, l-DMDP, and (3S)-3-hydroxy-d-bulgecinine. A comparison of glycosidase inhibition by DMDP (an inhibitor of β-glucosidases and β-galactosidases) and l-DMDP (a potent and specific α-glucosidase inhibitor) with the corresponding enantiomeric hydroxybulgecinines is reported; DMDP and (3R)-3-hydroxy-l-bulgecinine show weak inhibition of glycogen phosphorylase.