The acidity of β-phosphoglucomutase monofluoromethylenephosphonate ligands probed by NMR spectroscopy and quantum mechanical methods

We recently described the binding of 1-β-phosphonomethylene-1-deoxy-d-glucopyranose, (S)-1-β-phosphonofluoromethylene-1-deoxy-D-glucopyranose (βG1CFSP), and (R)-1-β-phosphonofluoromethylene-1-deoxy-d-glucopyranose (βG1CFRP) to the enzyme β-phosphoglucomutase as transition state analogues of phosphoryl transfer through formation of stable MgF3− and AlF4− complexes (Proc. Natl. Acad. Sci. U.S.A. 2014, 111, 12384). Herein, we describe in detail the five-fold difference in acidity (pKa2) for the (S)- and (R)-configured diastereomeric fluorophosphonates through a series of NMR spectroscopy experiments. The differences in acidity were corroborated using computational quantum mechanical calculations to determine structures of lowest energy conformers and provide insight into why the (S) isomer is substantially more acidic.