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‐one ( 16 ) added to furan‐2‐carboxaldehyde giving a single aldol 19 ( Schemes 1 and 2 ) that was converted with high stereoselectivity into (±)‐(1 RS ,3 SR ,4 SR ,5 RS ,6 SR )‐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 LiN 3 , 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 H 2 O. Neutralization of 4 · HCl, followed by NaBH 4 reduction, gave (±)‐(1 RS ,2 SR ,6 SR ,7 RS ,8 RS ,8a SR )‐1,2,3,5,6,7,8,8a‐octahydro‐7‐[(1 SR ,2 SR )‐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.