SYNTHESIS OF 1-DEOXYNOJIRIMYCIN-CONTAINING DISACCHARIDES

Abstract

1-Deoxynojirimycin (DNJ) is one of the simplest natural carbohydrate mimics. Its biological activity revolves primarily around the fact that it is a glycosidase inhibitor and one of its most important biological activities is an inhibiting enzyme responsible for glycoprotein processing. The work undertaken is to study the synthesis of DNJ-containing disaccharides particularly those in which DNJ is ?-glycosidically linked to D-glucose, D-galactose and D-mannose, since ?-glycosidase inhibitors might be effective against virus disease. DNJ was prepared from L-sorbose via the intermediate 6-azido-6-deoxy-2,3-O isopropylidene-?-L-sorbofuranose. For synthesis of 1?2 linked disaccharides, 4,6-O-benzylidene-N- benzyloxycarbonyl-3-O-chloroacetyl-1,5-dideoxy-1 ,5-imino-D-glucitol was prepared by selective chloroacetylation of 4,6-O-benzylidence-O-benzyloxycarbonyl- 1 ,5- dideoxy- 1 ,5-imino-D-glucitol. When 2-OH glycosyl acceptor was reacted with benzylated ?-D-gluco- or manno-pyranosyl trichloroacetimidate in the presence of trimethylsilyl triflate, 1?2 ?-linked disaccharides were obtained in good yields. Glycosylation using benzylated phenyl 1-thio-?-D-galactopyranoside as the glycosyl donor and a combination of mercury (II) chloride and mercury (II) sulfate as promoter also gave 1?2 ?-linked disaccharide but required a longer reaction time. For synthesis of 1?3 linked disaccharides, the C-2 hydroxyl group of 4,6-O- benzylidene-N-benzyloxycarbonyl-1,5-didexy- 1 ,5-imino-D-glucitol was also regioselectively functionalized by activation with di-n-butyltin oxide, followed by reaction of the resulting stannylene with benzoyl chloride to give 2-O-benzoyl-4,6-O benzylidene-N-benzyloxycarbonyl-1,5-dideoxy-imino-D-glucitol. When 3-OH glycosyl acceptor was reacted with benzylated ?-D-gluco- or manno-pyranosyl glycosyl acceptor was reacted with benzylated ?-D-gluco- or manno-pyranosyl trichloroacetimidate in the presence of trimethylsilyl triflate to give 1?3 ?-linked disaccharides in good yields. Glycosylation using benzylated phenyl 1-thio-?-D galactopyranoside as the glycosyl donor and a combination of mercury (II) chloride and mercury (II) sulfate as promoter also gave 1?3 ?-linked disaccharide. For synthesis of 1?4 linked disaccharides, 4,6-O-benzylidene-N- benzyloxycarbonyl-1,5-dideoxy-1 ,5-imino-D-glucitol was initially converted to the 2,3-di-O-benzyl derivative, and then reduced to 2,3,6-tri-O-benzyl-N benzyloxycarbonyl-l,5-dideoxy-1 ,5-imino-D-glucitol. When 4-OH glycosyl acceptor was reacted with benzylated ?-D-gluco- or manno-pyranosyl trichloroacetimdate in the presence of trimethylsilyl triflate, only 1?4 ?-linked gluco series disaccharide was obtained in good yield. Glycosylation using benzylated phenyl 1-thio-?-D galactopyranoside as the glycosyl donor and a combination of mercury (II) and mercury (II) sulfate as promoter also gave 1?4 ?-linked disaccharide after a longer reaction time. For synthesis of 1?6 linked disaccharides, the C-6 hydroxyl group of N- benzyloxycarbonyl-1,5-dideoxy-1,5-imino-D-glucitol was first protected using tert- butyldiphenylsilyl chloride in pyridine. The remaining hydroxyl groups were then acetylated. Removal of the 6-O-tert-butyldiphenylsilyl group then gave 2,3,4-tri-O acetyl-N-benzyloxycarbonyl-l,5-dideoxy-l ,5-imino-D-glucitol. Reaction of the 6-OH glycosyl acceptor with benzylated ?-D-gluco- or manno-pyranosyl trichloroacetimidate in the presence of trimethylsilyl triflate gave good yields of 1?6 ?-linked disaccharides. Glycosylation using benzylated phenyl 1-thio-?-D galactopyranoside as the glycosyl donor and a combination of mercury (II) chloride and mercury (II) sulfate as promoter also gave 1?6 ?-linked disaccharide after a longer reaction time.