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.