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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

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journal contribution
posted on 16.05.2014, 00:00 by Aloysius Siriwardena, Dhiraj P. Sonawane, Omprakash P. Bande, Pramod R. Markad, Sayuri Yonekawa, Michael B. Tropak, Sougata Ghosh, Balu A. Chopade, Don J. Mahuran, Dilip D. Dhavale
We report herein a newly developed domino reaction that facilitates the synthesis of new 1,5-dideoxy-1,5-iminoribitol iminosugar C-glycosides 7ae 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 10ae in a “one-pot” protocol. The iminoribitol C-glycosides 7ae and 8 were found to be modest β-galactosidase (bGal) inhibitors. However, compounds 7c and 7e showed “pharmacological chaperone” activity for mutant lysosomal bGal activity and facilitated its recovery in GM1 gangliosidosis patient fibroblasts by 2–6-fold.