Aza-C-disaccharide

Figure 10.31 Synthetic route to oxygenated pyrrolizidine alkaloids, and an aza-C-disaccharide as glycosidase inhibitors.

Vogel, P. et al. Stereoselective Synthesis ofC-Disaccharides, Aza-C-Disaccharides and C-Glycosides of Carbapyranoses Using the "Naked Sugars 1998 [97]... 

Consequently, a dihydroxylated azidodialdehyde was examined next which indeed behaved as anticipated. When generated from the racemic allylic azide 37 [109], FruA catalysis effected a smooth tandem addition to the dialdehyde to provide a diastereoisomerically pure bipyranoid azido C-disaccharide 38, from which the pyrrolidine type aza sugar 39 was highly stereoselectively produced by standard reductive amination [108]. Model considerations suggest a close resemblance of the protonated aza C-disaccharide to transition states of saccha-rase or maltase. Indeed, several of the glycosidases tested were inhibited by 39 at concentrations below 1 mM. 

Scheme 8. Synthetic entry to aza C-disaccharides based on tandem enzymatic aldolizations...

The procedure has been used in a variety of syntheses of natural products [143, 144] for example, in the synthesis of dihydroxyserrulatic acid (Scheme 2-50) [145], the aggregation pheromone of Cathartus quadricollis (quadrilure) [146], and aza-C-disaccharides [147]. 

A. Baudat and P. Vogel, Aza-C-disaccharides Synthesis of 6-deoxyglalctono-jirimycin (3-C-(l->3) linked with D-altrofuranosides and D-galactose, J. Org. Chem., 62 (1997) 6252-6260. 

C.-F. Valenza, S. Picasso, A. Goti, and A. Brandi, Straight-forward synthesis of (l->-2)-linked pseudo and aza-C-disaccharides by the novel cycloaddition of enantiopure cyclic nitrones to glycals, J. Org. Chem., 63 (1998) 7311-7318. 

Stereoselective cycloaddition between functionalized six-membered cyclic nitrone 166 derived from o-lyxose and sugar alkenes was employed for the synthesis of aza-C-disaccharides [72]. Reaction of nitrone 166 and alkene 167 prepared from methyl a-o-mannopyranoside in toluene at reflux led to the isolation of a crystalline cycloadduct 168 in 84% yield. The isoxazohdine 168 was acetylated and cleaved using Mo(CO)6. This was followed by deoxygenation and routine deprotection to give the aza-C-disaccharide 169, isolated as its hydrochloride (44% overall from 168). 

Johnson and coworkers [47] have synthesized (l->6)-, (l->4)-, and (1->1)-linked aza-C-disaccharides D-azaMan- -Jl->6)-D-Man(8), D-azaMan-(3-(1->6)-d-G1c(9), D-azaMan-(3-(l->4)-D-Talo(10) and D-azaMan-P-(l-> 1)-D-P-Glc(ll). The polyhydroxylated piperidine ring is constructed employing vinylbromide, (3R,4R,5S,6S)-3-[(N-benzyloxycarbonyl)amino]-l-bromo-4-[(tert-butyldimethylsilyl)oxy]-5,6-(0-isopropylidenedioxy)cyclohex-l-ene(12), as a common intermediate for these sugars. Vinylbromide (12) required for Suzuki coupling is synthesized de novo from 3-bromocyclohex-3,5-dien-l,2-diol as outlined in Scheme 31.12 [47]. 

Stereoisomers of 249 can be obtained readily, for instance, by exo-dihydroxylation of (+)-170. As seen in Scheme 29, trans- and c -aminohydroxylated derivatives can be prepared also with high stereo- and regioselectivity, thus permitting, in principle, the synthesis of aza-C-disaccharides containing amino-iminopentitols. 

---