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

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