SYNTHESIS OF C-LINKED IMINO DISACCHARIDES (=AZA-C-DISACCHARIDES) WITHA PYRROLIDINE-3,4-DIOL MOIETY ATTACHED AT C(3) OF GALACTOSE VIA A HYDROXYMETHYLENE LINKER AND OF A YDROXYPROPYL)-OCTAHYDROXYINDOLIZINE-1,2,6,8-TETROL

The lithium enolate exo-(phenylseleno)-7-oxabicyclo[2.2.1]heptan-2-one (16) added to furan-2-carboxaldehyde giving a single aldol 19 (Scheme s 1 and 2) that was converted with high stereoselectivity into (+/-)-( 1RS, oxymethoxy)-2-oxo-7-oxabicyclo[2.2.1]hept-3-exo-yl 4-bromobenzene sulfonate (46). Highly regioselective Baeyer-Villiger oxidation of 46 provided the corresponding beta-DL-altrofuranurono-6,1-lactone 49, the methanolysis of which gave (+/-)-methyl y-2-O-(methoxymethyl)-alpha-D L-galactofuranuronate (51). Reduction of 51 followed by protection fur nished 2,6-bis-O-(methoxymethyl)-alpha-DL-galactopyranose (54). Clean oxidation of the furan unit in 54 was possible with dimethyldioxirane, giving the corresponding (Z)-4-oxoenal 59 that was converted into pyr roles such as 2,6-bis-O-(methoxymethyl)-alpha-DL-galactopyranose (58; Scheme 5), or into pyrrolidin-3,4-diols by dihydroxylation of 2,6-bis- O-(methoxymethyl)-alpha-DL-galactopyranose (70; Schemes 6 and 7). Afte r adequate protection (--> 70), selective displacement of one of the m esylate moieties with LiN3, followed by hydrogenation of the correspon ding primary azide and intramolecular substitution, led to four protec ted, stereoisomeric C-linked imino disaccharides (Scheme 7); the latte r were deprotected under acidic conditions to give 2',5'-imino-alpha-L D-ribitol-1'-C-yl]-DL-galactose (3), ,5'-imino-alpha-DL-arabintol-1'-C -yl]-DL-galactose (4); -2',5'-imino-beta-DL-ribitol-1'-C-yl]-DL-galact ose (5), and (+/-)-3-deoxy-3-[(1 ,5'-imino-beta-LD-arabinitol-1'-C-yl] -DL-galactose (6). These unprotected C-linked imino disaccharides were more stable as ammonium chlorides in H2O. Neutralization of 4.HCl, fo llowed by NaBH4 reduction, gave )-1,2,3-trihydroxypropyl]indolizine-1, 2,6,8-tetrol (14), a new octahydroindolizinepolyol (Scheme 8). Methyl glycosides of C-linked imino disaccharides 3-6 were also obtained, suc h as (+/-)-methyl lpha-LD-ribitol-1'-C-yl]-beta-DL-galactofuranoside ( 7), (+/-)-methyl 3-deoxy-3-[(1 'SR)-2', 5'-dideoxy-2', a-LD-arabinitol -1'-C-yl]-beta-DL-galactofuranoside (8) and -alpha-DL-galactopyranosid e (9), (+/-)-methyl a-DL-arabinitol-1'-C-yI]-beta-DL-galactofuranoside (11) and -alpha-DL-galactopyranoside (10), and (+/-)-methyl 3-deoxy-3 -[(1'SR)-2', beta-DL-ribitol-1'-C-yl]-beta-DL-galactofuranoside (13) a nd -alpha-DL-galactopyranoside (12). All these new C-linked imino disa ccharides can be obtained in their enantiomerically pure form either s tarting with enantiomerically pure 7-oxabicyclo[2.2.1]heptan-2-one der ivatives ('naked sugars of the first generation') or using the method of Johnson and Zeller applied to the racemic protected aldol exo-(phen ylseleno)-7-oxabicyclo[2.2.1]heptan-2-one (22; see Scheme 2). The unpr otected C-linked imino disaccharides 3-13 and octahydroindolizineletro l 14 were tested for their inhibitory activity toward 25 commercially available glycohydrolases. Only compound 3 which mimics the mannopyran osyl-cation intermediate during the hydrolysis of an alpha-mannopyrano syl-(1-->3)-galactose has a weak, but specific a-mannosidase inhibitor y activity.