A novel bis-phosphonyl C-glycoside: the first synthesis of C-(1,6-deoxy-β-d-glucopyranosyl)dimethylphosphonate, a stable bisphosphonate to probe the mechanism of β-phosphoglucomutase†

Abstract

β-Phosphoglucomutase (β-PGM) catalyzes the interconversion of β-D-glucose-1-phosphate and β-D-glucose-6-phosphate sequentially utilizing a transient aspartyl-phospho enzyme and a β-D-glucose-1,6-bisphosphate intermediate. Herein, we report the first synthesis of the isosteric, cleavage resistant, phosphonate analogue C-(1,6-deoxy-β-D-glucopyranosyl)dimethylphosphonate, to aid in mechanistic and structural investigations of β-PGM and its phosphate transfer process. The introduction of the ‘pseudo anomeric’ phosphonate was accomplished through methylenephosphonate anion addition to gluconolactone, whilst the second phosphonate was installed at C-6 of the β-D-glucopyranosyl moiety using a Horner–Wadsworth–Emmons (HWE) reaction on the C-6 aldehyde. The synthesis was completed in 10 steps with 8% overall yield.