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

The treatment of benzyl 2,3-O-isopropylidene-beta-L-Xylopyranoside with N-hydroxyphthalimide under Mitsunobu conditions, followed by protecting-group interchange, gave benzyl 4-O-[(tert-butoxycarbonyl)aminol-2,3-O-isopropylidene-alpha-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 H-5(6) 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 beta-glucosidases (K-i = 27 and 35 muM). Benzyl 2,3-O-isopropylidene-beta-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-alpha-D-arabinoside. Treatment of this amine with hydrogen and palladium-on-carbon gave isofagomine.