α?Geminal Dihydroxymethyl Piperidine and Pyrrolidine Iminosugars: Synthesis, Conformational Analysis, Glycosidase Inhibitory Activity, and Molecular Docking Studies

摘要

The Jocic−Reeve and Corey−Link type reaction of dichloromethyllithium with suitably protected 5-ketohexofuranosesnfollowed by treatment with sodium azide and sodium borohydride reduction gave 5-azido-5-hydroxylmethylnsubstituted hexofuranoses 7a−c with required geminal dihydroxymethyl group. Removal of protecting groups and converting thenC-1 anomeric carbon into free hemiacetal followed by intramolecular reductive aminocyclization with in situ generated C5-aminonfunctionality afforded corresponding 5C-dihydroxymethyl piperidine iminosugars 2a−c. Alternatively, removal of protectingngroups in 7b and 7c and chopping of C1-anomeric carbon gave C2-aldehyde that on intramolecular reductive aminocyclizationnwith C5-amino gave 4C-dihydroxymethyl pyrrolidine iminosugars 1b and 1c, respectively. On the basis of the 1H NMR studies,nthe conformations of 2a/2b were assigned as 4C1 and that of 2c as 1C4. The glycosidase inhibitory activities of all five iminosugarsnwere studied with various glycosidase enzymes and compared with natural D-gluco-1-deoxynojirimycin (DNJ). All the fivencompounds were found to be potent inhibitors of rice α-glucosidase with Ki and IC50 values in the nanomolar concentrationnrange. Iminosugars 2b and 1b were found to be more potent inhibitors than their parent iminosugar. These results werensubstantiated by in silico molecular docking studies.