Synthesis of a novel fluorinated phosphonyl C-glycoside, (3-deoxy-3-fluoro-ß-d-glucopyranosyl)methylphosphonate, a potential inhibitor of ß-phosphoglucomutase.

ABSTRACT

ß-phosphoglucomutase (ßPGM) catalyzes the conversion of ß-glucose 1-phosphate (ßG1P) to glucose-6-phosphate (G6P), a universal source of cellular energy, in a two-step process. Transition state analogue (TSA) complexes formed from substrate analogues and a metal fluoride (MgF3- and AlF4-) enable analysis of each of these enzymatic steps independently. Novel substrate analogues incorporating fluorine offer opportunities to interrogate the enzyme mechanism using 19F NMR spectroscopy. Herein, the synthesis of a novel fluorinated phosphonyl C-glycoside (3-deoxy-3-fluoro-ß-d-glucopyranosyl)methylphosphonate (1), in 12 steps (0.85 % overall yield) is disclosed. A four-stage synthetic strategy was employed, involving 1) fluorine addition to the monosaccharide, 2) selective anomeric deprotection, 3) phosphonylation of the anomeric centre, and 4) global deprotection. Analysis of ßPGM and 1 will be reported in due course.