α-Geminal disubstituted pyrrolidine iminosugars and their C-4-fluoro analogues: Synthesis, glycosidase inhibition and molecular docking studies

A simple strategy for the synthesis of alpha-geminal disubstituted pyrrolidine iminosugars 3a-c and their C-4 fluorinated derivatives 4a-c has been described from D-glucose. The methodology involves the Corey-Link and Jocic-Reeve reaction with 3-oxo-alpha-D-glucofuranose and nucleophilic displacement reaction to get the furanose fused pyrrolidine ring skeleton with requisite CH2OH/CO2H functionalities at C-3. The fluorine substituent in target molecules was introduced by nucleophilic displacement of -OTf in 9a/9c with CsF. Appropriate manipulation of the anomeric carbon in the furanose fused pyrrolidine ring skeleton afforded alpha-geminal disubstituted pyrrolidine iminosugars 3a-c and C-4 fluoro derivatives 4a-c. The pyrrolidine iminosugars 3a and 3c were found to be potent inhibitors of alpha-galactosidase while, the fluoro derivatives 4a and 4b showed strong inhibition of beta-glucosidase and beta-galactosidase, respectively. These results were substantiated by in silico molecular docking studies. (C) 2017 Elsevier Ltd. All rights reserved.