Synthesis and conformational analysis of (alpha-D-galactosyl)phenylmethane and alpha-,beta-difluoromethane analogues: interactions with the plant lectin viscumin.

(Alpha-D-galactosyl)phenylmethane (1), (alpha- and beta-D-galactosyl)(difluoro)phenylmethane (2 and 3) have been prepared and their conformations in solution were described by using a combination of force-field calculations and NMR spectroscopic studies. Galactoside 1 adopts a (4)C(1) chair conformation and an exo anomeric orientation, as is the case for natural alpha-galactosides. The X-ray crystal structure of its difluoromethylene derivative 2 similarly shows a (4)C(1) chair conformation. Surprisingly, compound 2 exhibits a different equilibrium between (1)C(4) chair and (1)S(3) skew boat conformations and significant flexibility around the pseudoglycosidic linkage when in solution. The beta-stereoisomer 3 adopts a major (4)C(1) chair conformation. Interestingly, C-galactosides 1, 2, and 3 bind to viscumin (VAA), a galactoside-specific lectin, which is confirmed by NMR experiments and docking calculations.