Polyhydroxylated azetidine iminosugars: Synthesis, glycosidase inhibitory activity and molecular docking studies

Abstract An efficient and practical strategy for the synthesis of unknown azetidine iminosugars (2 S ,3 R ,4 S )-2-(( R )-1,2-dihydroxyethyl)-3-hydroxy-4-(hydroxymethyl)azetidine 2 , (2 S ,3 r ,4 R )-3-hydroxy-2,4-bis(hydroxymethyl)azetidine 3 and (2 S ,3 R ,4 S )-3-hydroxy-4-(hydroxymethyl)- N -methylazetidine-2-carboxylic acid 4 , starting from the d -glucose has been reported. The methodology involves preparation of the 3-amino- N -benzyloxycarbonyl-3-deoxy-6- O - tert -butyldimethylsillyl-1,2- O -isopropylidene- α - d -glucofuranose 9 , which was converted to the C-5- OMs derivative 11 . Intramolecular nucleophilic displacement of the C-5- OMs group with in situ generated 3-amino functionality provided the required key azetidine ring skeletons 10 with additional hydroxymethyl group. Removal of 1,2-acetonide protection, followed by reduction and hydrogenolysis afforded azetidine iminosugar 2 . Alternatively, removal of 1,2-acetonide group and chopping of C1-anomeric carbon gave C2-aldehyde that on reduction or oxidation followed by hydrogenolysis gave 2,4-bis(hydroxymethyl) azetidine iminosugars 3 and N -methylazetidine-2-carboxylic acid 4 respectively. The glycosidase inhibitory activity of 2 – 4 iminosugars was screened against various glycosidase enzymes and compared with a standard miglitol. Amongst synthesized targets, the compound 2 was found to be more potent amyloglucosidase inhibitor than miglitol. These results were supported by molecular docking studies.