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

Publication date: 1 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
Author(s): Kishor S. Gavale, Shrawan R. Chavan, Navanath Kumbhar, Sonali Kawade, Pooja Doshi, Ayesha Khan, Dilip D. Dhavale
A simple strategy for the synthesis of α-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-α-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 α-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 α-galactosidase while, the fluoro derivatives 4a and 4b showed strong inhibition of β-glucosidase and β-galactosidase, respectively. These results were substantiated by in silico molecular docking studies.

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