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
Authors: Kraehenbuehl Karin , Picasso Sylviane , Vogel Pierre 
Published: December 2004

The lithium enolate of (±)‐6‐endo‐chloro‐5‐exo‐(phenylseleno)‐7‐oxabicyclo[2.2.1]heptan‐2‐one (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)methyl}‐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 β‐DL‐altrofuranurono‐6,1‐lactone 49, the methanolysis of which gave (±)‐methyl 1,5‐anhydro‐3‐{(SR)‐[(tert‐butyl)dimethylsiloxy](furan‐2‐yl)methyl}‐3‐deoxy‐2‐O‐(methoxymethyl)‐α‐DL‐galactofuranuronate (51). Reduction of 51 followed by protection furnished (±)‐1,4‐anhydro‐3‐{(SR)‐[(tert‐butyl)dimethylsilyoxy](furan‐2‐yl)methyl}‐3‐deoxy‐2,6‐bis‐O‐(methoxymethyl)‐α‐DL‐galactopyranose (54). Clean oxidation of the furan unit in (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‐1 H‐pyrrol‐2‐yl)methyl}‐3‐deoxy‐2,6‐bis‐O‐(methoxymethyl)‐α‐DL‐galactopyranose (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‐(methoxymethyl)‐α‐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‐α‐LD‐ribitol‐1′‐C‐yl]‐DL‐galactose (3), (±)‐3‐deoxy‐3‐[(1′SR)‐2′,5′‐dideoxy‐2′,5′‐imino‐α‐DL‐arabinitol‐1′‐C‐yl]‐DL‐galactose (4), (±)‐3‐deoxy‐3‐[(1′SR)‐2′,5′‐dideoxy‐2′,5′‐imino‐β‐DL‐ribitol‐1′‐C‐yl]‐DL‐galactose (5), and (±)‐3‐deoxy‐3‐[(1′SR)‐2′,5′‐dideoxy‐2′,5′‐imino‐β‐DL‐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‐α‐LD‐ribitol‐1′‐C‐yl]‐β‐DL‐galactofuranoside (7), (±)‐methyl 3‐deoxy‐3‐[(1′SR)‐2′,5′‐dideoxy‐2′,5′‐imino‐β‐LD‐arabinitol‐1′‐C‐yl]‐β‐DL‐galactofuranoside (8) and ‐α‐DL‐galactofuranoside (9), (±)‐methyl 3‐deoxy‐3‐[(1′SR)‐2′,5′‐dideoxy‐2′,5′‐imino‐α‐DL‐arabinitol‐1′‐C‐yl]‐β‐DL‐galactofuranoside (11) and ‐α‐DL‐galactopyranoside (10), and (±)‐methyl 3‐deoxy‐3‐[(1′SR)‐2′,5′‐dideoxy‐2′,5′‐imino‐β‐DL‐ribitol‐1′‐C‐yl]‐β‐DL‐galactofuranoside (13) and ‐α‐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]heptain‐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)dimethylsiloxy](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 octahydroindolzinetetrol 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 α‐mannopyranosyl‐(1 → 3)‐galactose has a weak, but specific α‐mannosidase inhibitory activity.