CONFORMATIONAL-ANALYSIS OF 4,1',6'-TRICHLORO-4,1',6'-TRIDEOXY-GALACTO-SUCROSE (SUCRALOSE) BY A COMBINED MOLECULAR-MODELING AND NMR-SPECTROSCOPY APPROACH

Sucralose, a trichlorinated derivative of sucrose 1',6'-trichloro-4,1' ,6'-trideoxy-galacto-sucrose), is approximately 650 times sweeter than sugar on a mass basis. It has a sucrose-like taste profile, with no u npleasant aftertaste, while being noncaloric and noncariogenic. This s weetener is emerging as the most commercially useful compound in the f ield of sucrochemistry. The conformational behavior of aqueous sucralo se was studied by NMR and computerized molecular modeling. Steady-stat e NOEs at 400.13 MHz and transient NOEs at both 250.13 and 400.13 MHz have been measured. Long-range C-13-H-1 coupling constants are also re ported. In parallel, the complete conformational analysis of the disac charide has been achieved with two different molecular mechanics metho ds. The conformation of the pyranose ring is confirmed by the excellen t agreement between the experimental and theoretical intracyclic scala r coupling constants. The furanoid ring is shown to exhibit some flexi bility, covering the four adjacent 3E, 4T3, 4E, and 4T5 shapes. Within the potential energy surfaces calculated for the disaccharide, four f amilies of stable conformers can be identified. One of these correspon ds closely to the crystalline conformation of sucralose not only in te rms of conformation about the glycosidic linkage but also in terms of orientation of the chloromethyl groups and occurrence of the interresi due hydrogen bond. The 3J(C-H) coupling constant about the glycosidic linkage was calculated using an equation suitable for COCH segments. T he data do not support a single conformational model, and only conform ational averaging can provide agreement between theoretical and experi mental parameters. The theoretical NMR relaxation data were calculated taking into account all the accessible conformations and using the av eraging methods appropriate for both slow and fast internal motions. I n agreement with a recent solution dynamics simulation of beta-maltose , the relaxation data suggest that the large-amplitude interglycosidic torsional motions of sucralose are occurring on a time scale similar to that of molecular reorientation. This extensive molecular-modeling investigation provides a good description of the conformational behavi or of both aqueous and crystalline sucralose.