Infoscience

Journal article

Synthesis of C-linked imino disaccharides (=aza-C-disaccharides) with a pyrrolidine-3,4-diol moiety attached at C(3) of galactose via a hydroxymethylene linker and of a 7-(1,2,3-trihydroxypropyl)-octahydroxyindolizine-1,2,6,8-tetrol

The lithium enolate of(+/-)-6-endo-chloro-5-exo-(phenylseleno)-7-oxabicyclo[2.2.1]heptan-2-o ne (16) added to furan-2-carboxaldehyde giving a single aldol 19 (Schemes 1 and 2) that was converted with high stereoselectivity into (+/-)-(1RS, 3SR,4SR,5RS,6SR)-5-exo-{(RS)-[(tert-butyl)dimethylsilyloxy](furan-2-yl)m ethyl}-6-endo-(methoxymethoxy)-2-oxo-7-oxabicyclo[2.2.1]hept-3-exo-yl 4-bromobenzenesulfonate (46). Highly regioselective Baeyer-Villiger oxidation of 46 provided the corresponding beta-DL-altrofuranurono-6,1-lactone 49, the methanolysis of which gave (+/-)-methyl 1,5-anhydro-3-{(SR)-[(tert-butyl)dimethyldilyloxy](furan-2-yl)methyl}-3- deoxy-2-O-(methoxymethyl)-alpha-DL-galactofuranuronate (51). Reduction of 51 followed by protection furnished (+/-)-1,4-anhydro-3-{(SR)-[(tert-butyl)dimethylsilyloxy](furan-2-yl)meth yl}-3-deoxy-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 pyrroles such as (+/-)-1,4-anhydro-3-{(SR)-[(tert-butyl)dimethylsilyloxy](1-benzyl-1H-pyr rol-2-yl)methyl}-3-deoxy-2,6-bis-O-(methoxymethyl)-alpha-DL-galactopyran ose (58; Scheme 5), or into pyrrolidin-3,4-diols by dihydroxylation of (+/-)-1,4-anhydro-3-{(1'RS,2'RS,Z)-1'-[(tert-butyl)-dimethylsilyloxy]-2' ,5'-bis[(methylsulfonyl)oxy]pent-3'-enyl}-3-deoxy-2,6-bis-O-(methoxymeth yl)-alpha-DL-galactopyranose (70; Schemes 6 and 7). After adequate protection (--> 70), selective displacement of one of the mesylate moieties with LiN3, followed by hydrogenation of the corresponding primary azide and intramolecular substitution, led to four protected, stereoisomeric C-linked imino disaccharides (Scheme 7); the latter were deprotected under acidic conditions to give (+/-)-3-deoxy-3-[(1'SR)-2',5'-dideoxy-2',5'-imino-alpha-LD-ribitol-1'-C- yl]-DL-galactose (3), (+/-)-3-deoxy-3-[(1'SR)-2',5'-dideoxy-2',5'-imino-alpha-DL-arabintol-1'- C-yl]-DL-galactose (4); (+/-)-3-deoxy-3[(1'SR)-2',5'-dideoxy-2',5'-imino-beta-DL-ribitol-1'-C-yl ]-DL-galactose (5), and (+/-)-3-deoxy-3-[(1 'SR)-2',5'-dideoxy-2',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, followed by NaBH4 reduction, gave (+/-)-(1RS,2SR,6SR,7RS,8RS,8aSR)-1,2,3,5,6,7,8,8a-octahydro-7-[(1SR,2SR) -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, such as (+/-)-methyl 3-deoxy-3-[(1'SR)-2',5'-dideoxy-2',5'-imino-alpha-LD-ribitol-1'-C-yl]-be ta-DL-galactofuranoside (7), (+/-)-methyl 3-deoxy-3-[(1 'SR)-2', 5'-dideoxy-2', 5'-imino-beta-LD-arabinitol-1'-C-yl]-beta-DL-galactofuranoside (8) and -alpha-DL-galactopyranoside (9), (+/-)-methyl 3-deoxy-3-[(1'SR)-2',5'-dideoxy-2',5'-imino-alpha-DL-arabinitol-1'-C-yI] -beta-DL-galactofuranoside (11) and -alpha-DL-galactopyranoside (10), and (+/-)-methyl 3-deoxy-3-[(1'SR)-2', 5'-dideoxy-2',5'-imino-beta-DL-ribitol-1'-C-yl]-beta-DL-galactofuranosid e (13) and -alpha-DL-galactopyranoside (12). All these new C-linked imino disaccharides can be obtained in their enantiomerically pure form either starting with enantiomerically pure 7-oxabicyclo[2.2.1]heptan-2-one derivatives ('naked sugars of the first generation') or using the method of Johnson and Zeller applied to the racemic protected aldol 3-exo-{[(tert-butyl)dimethylsilyloxy](furan-2-yl)methyl}-6-endo-chloro-5 -exo-(phenylseleno)-7-oxabicyclo[2.2.1]heptan-2-one (22; see Scheme 2). The unprotected C-linked imino disaccharides 3-13 and octahydroindolizineletrol 14 were tested for their inhibitory activity toward 25 commercially available glycohydrolases. Only compound 3 which mimics the mannopyranosyl-cation intermediate during the hydrolysis of an alpha-mannopyranosyl-(1-->3)-galactose has a weak, but specific a-mannosidase inhibitory activity.

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