α‑Geminal Dihydroxymethyl Piperidine and Pyrrolidine Iminosugars: Synthesis, Conformational Analysis, Glycosidase Inhibitory Activity, and Molecular Docking Studies
2012-09-21T00:00:00Z (GMT) by
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 <b>7a</b>–<b>c</b> 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 <b>2a</b>–<b>c</b>. Alternatively, removal of protecting groups in <b>7b</b> and <b>7c</b> and chopping of C1-anomeric carbon gave C2-aldehyde that on intramolecular reductive aminocyclization with C5-amino gave 4C-dihydroxymethyl pyrrolidine iminosugars <b>1b</b> and <b>1c</b>, respectively. On the basis of the <sup>1</sup>H NMR studies, the conformations of <b>2a</b>/<b>2b</b> were assigned as <sup><b>4</b></sup><i><b>C</b></i><sub><b>1</b></sub> and that of <b>2c</b> as <sup><b>1</b></sup><i><b>C</b></i><sub><b>4</b></sub>. The glycosidase inhibitory activities of all five iminosugars were studied with various glycosidase enzymes and compared with natural d-<i>gluco</i>-1-deoxynojirimycin (DNJ). All the five compounds were found to be potent inhibitors of rice α-glucosidase with <i>K</i><sub>i</sub> and IC<sub>50</sub> values in the nanomolar concentration range. Iminosugars <b>2b</b> and <b>1b</b> were found to be more potent inhibitors than their parent iminosugar. These results were substantiated by in silico molecular docking studies.