Efficient synthesis of 2,6,7,8-tetrahydroxyindolizidines (castanospermine analogues) via the dipolar cycloadditions of N-benzyl-C-(tetrofuranos-4-yl)nitrones to methyl acrylate

Abstract The dipolar cycloaddition of ( Z )- N -benzyl-(3- O -benzyl-1,2- O -isopropylidene-α- d -ribofuranos-5-ylidene)amine N-oxide to methyl acrylate gives a 53:16:26:5 diastereomeric mixture of isoxazolidine derivatives. The dipolar cycloaddition of the xylo analogue to methyl acrylate is more diastereoselective, producing a 44:13:43 mixture of only three diastereomers. The ribo-configured adducts have been converted (4 steps only) into the new (2 R ,6 S ,7 S ,8 R ,8a R )-, (2 S ,6 S ,7 S ,8 R ,8a R )-, (2 S ,6 S ,7 S ,8 R ,8a S )- and (2 R ,6 S ,7 S ,8 R ,8a S )-2,6,7,8-tetrahydroxyindolizidines. Similarly, the two xylo-configured major isoxazolidine derivatives were converted into the known derivatives (2 R ,6 S ,7 R ,8 R ,8a S )- and (2 S ,6 S ,7 R ,8 R ,8a R )-2,6,7,8-tetrahydroxyindolizidines. The six isomeric indolizidine derivatives obtained have been evaluated for their inhibiting activities towards 15 glycosidases. Only the (2 R ,6 S ,7 S ,8 R ,8a R )-configured isomer is a selective inhibitor of amyloglucosidases from Aspergillus niger (IC 50  = 350 μM) and from Rhizopus mold (IC 50  = 90 μM, K i  = 195 μM, non-competitive), the other indolizidines show very little inhibitory activity at 1 mM concentration.