A Stepwise Solvent-Promoted SNi Reaction of α-D-Glucopyranosyl Fluoride: Mechanistic Implications for Retaining Glycosyltransferases

The solvolysis of alpha-D-glucopyranosyl fluoride in hexafluoro-2-propanol gives two products, 1,1,1,3,3,3-hexafluoropropan-2-yl alpha-D- glucopyranoside and 1,6-anhydro-beta-D-glucopyranose. The ratio of these two products is essentially unchanged for reactions that are performed between 56 and 100 degrees C. The activation parameters for the solvolysis reaction are as follows: Delta H-double dagger = 81.4 +/- 1.7 kJ mol(-1), and Delta S-double dagger = -90.3 +/- 4.6 J mol(-1) K-1. To characterize, by use of multiple kinetic isotope effect (KIE) measurements, the TS for the solvolysis reaction in hexafluoro-2-propanol, we synthesized a series of isotopically labeled alpha-D-glucopyranosyl fluorides. The measured KIEs for the C1 deuterium, C2 deuterium, C5 deuterium, anomeric carbon, ring oxygen, O6, and solvent deuterium are 1.185 +/- 0.006, 1.080 +/- 0.010, 0.987 +/- 0.007, 1.008 +/- 0.007, 0.997 +/- 0.006, 1.003 +/- 0.007, and 1.68 +/- 0.07, respectively. The transition state for the solvolysis reaction was modeled computationally using the experimental KIE values as constraints. Taken together, the reported data are consistent with the retained solvolysis product being formed in an S(N)i (D-N(double dagger)*A(Nss)) reaction with a late transition state in which cleavage of the glycosidic bond is coupled to the transfer of a proton from a solvating hexafluoro-2-propanol molecule. In comparison, the inverted product, 1,6-anhydro-beta-D-glucopyranose, is formed by intramolecular capture of a solvent-equilibrated glucopyranosylium ion, which results from dissociation of the solvent-separated ion pair formed in the rate-limiting ionization reaction (D-N(double dagger) + A(N)). The implications that this model reaction have for the mode of action of retaining glycosyltransferases are discussed.