The synthesis of a carbohydrate-like dihydrooxazine and tetrahydrooxazine as putative inhibitors of glycoside hydrolases: A direct synthesis of isofagomine

Abstract

The treatment of benzyl 2,3-O-isopropylidene-β-L-xylopyranoside with N-hydroxyphthalimide under Mitsunobu conditions, followed by protecting-group interchange, gave benzyl 4-O-[(tert-butoxycarbonyl)amino]-2,3- O-isopropylidene-α-D-arabinoside. Mild acid hydrolysis and catalytic hydrogenolysis afforded 4-O-[(tert-butoxycarbonyl)amino]-D-arabinose that, upon heating in water, gave the dihydrooxazine [(4R,5S,6R)-5,6-dihydro-4,5-dihydroxy-6-hydroxymethyl-4H-1,2-oxazine] as a crystalline solid. A single-crystal structure determination of this solid showed it to exist in the 5H6 conformation. Reduction of the dihydrooxazine gave the tetrahydrooxazine [(4R,5S,6R)-4,5-dihydroxy-6-hydroxymethyl-3,4,5,6-tetrahydro-2H-1,2-oxazine]. The dihydrooxazine was an effective inhibitor of two β-glucosidases (Ki = 27 and 35 µM). Benzyl 2,3-O-isopropylidene-β-L-xylopyranoside, via the derived imidazylate, was converted into a nitrile that, upon reduction and protecting-group manipulations, gave benzyl 4-C-aminomethyl-4-deoxy-α-D-arabinoside. Treatment of this amine with hydrogen and palladium-on-carbon gave isofagomine.Key words: dihydrooxazine, tetrahydrooxazine, isofagomine, iminosugars, glycosidase inhibitors.