Synthesis of 1,5-dideoxy-1,5-iminoribitol C-glycosides through a nitrone-olefin cycloaddition domino strategy: identification of pharmacological chaperones of mutant human lysosomal β-galactosidase.

[gm1 gangliosidosis]

We report herein a newly developed domino reaction that facilitates the synthesis of new 1 ,5 -dideoxy-1 ,5 -iminoribitol iminosugar C-glycosides 7 a-e and 8 . The key intermediate in this approach is a six -membered cyclic sugar nitrone that is generated in situ and trapped by an alkene dipolarophile via a [2 + 3 ] cycloaddition reaction to give the corresponding isooxazolidines 10 a-e in a "one -pot " protocol . The iminoribitol C-glycosides 7 a-e and 8 were found to be modest β-galactosidase (bGal ) inhibitors . However , compounds 7 c and 7 e showed "pharmacological chaperone " activity for mutant lysosomal bGal activity and facilitated its recovery in GM 1 gangliosidosis patient fibroblasts by 2 -6 -fold .