Enantioselective and Protecting Group-Free Synthesis of I-Deoxythionojirimycin, 1-Deoxythiomannojirimycin, and 1-Deoxythiotalonojirimycin (original) (raw)
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Tetrahedron: Asymmetry, 2000
Alkaloids mimicking the structures of monosaccharides are now believed to be widespread in plants and microorganisms, and these sugar mimics inhibit glycosidases because of a structural resemblance to the sugar moiety of the natural substrate. Naturally occurring sugar mimics with a nitrogen in the ring are classi®ed into ®ve structural classes: polyhydroxylated piperidines, pyrrolidines, indolizidines, pyrrolizidines and nortropanes. Glycosidases are involved in a wide range of important biological processes, such as intestinal digestion, post-translational processing of glycoproteins and the lysosomal catabolism of glycoconjugates. The realization that alkaloidal sugar mimics might have enormous therapeutic potential in many diseases such as viral infection, cancer and diabetes has led to increasing interest and demand for these compounds. Most of these eects can be shown to result from the direct or indirect inhibition of glycosidases. The glycosphingolipid (GSL) storage diseases are relatively rare hereditary disorders that are severe in nature and frequently fatal. Possible strategies for the treatment of these lysosomal storage diseases include enzyme replacement therapy, gene therapy and substrate deprivation. Recently, quite a new therapy for lysosomal storage diseases has been reported, namely a`chemical chaperone therapy' for Fabry disease. In this report, the structural basis for the speci®city of inhibition of alkaloidal sugar mimics and their current and potential application to biomedical problems will be reviewed. #
Helvetica Chimica Acta, 2006
The racemic 2-azabicyclo[3.2.2]nonanes 5 and 18 were synthesized and tested as b-glycosidase inhibitors. The intramolecular Diels-Alder reaction of the masked o-benzoquinone generated from 2-(allyloxy)phenol (6) gave the a-keto acetal 7 which was reduced with SmI 2 to the hydroxy ketone 8. Dihydroxylation, isopropylidenation (! 12), and Beckmann rearrangement provided lactam 15. N-Benzylation of this lactam, reduction to the amine 17, and deprotection provided the amino triol 19 which was debenzylated to the secondary amine 5. Both 5 and 19 proved weak inhibitors of snail b-mannosidase (IC 50 > 10 mM), Caldocellum saccharolyticum b-glucosidase (IC 50 > 10 mM), sweet almond b-glucosidase (IC 50 > 10 mM), yeast a-glucosidase (5: IC 50 > 10 mM; 19: IC 50 = 1.2 mM), and Jack bean a-mannosidase (no inhibition detected).