DFT/MM modeling of the five-membered ring in 3,6-anhydrogalactose derivatives and its influence on disaccharide adiabatic maps Original Research Article

Different conformations of methyl 3,6-anhydro-4-O-methyl-α-d-galactoside (1) and 3,6-anhydro-4-O-methylgalactitol (2) were studied by molecular mechanics (using the program mm3) and by quantum mechanical (QM) methods at the B3LYP/6-31+G∗∗ and MP2/6-311++G∗∗ levels, with and without solvent emulation. In 2, where the five-membered ring is free to move, two main stable conformations of this ring were found, identified as North (N) and South (S). The latter appears to be more stable, by either calculation, though the energy difference is reduced when emulating solution behavior. In order to find out the possible influence of a glycosidic bond over its shape, and to explain the marked NMR chemical shift displacements observed by opening of the ring, the adiabatic maps of two disaccharides carrying an analog of β-galactoside linked to O-4 of 1 and 2 were generated. It was shown that the characteristics of the 3,6-AnGal terminal influence the characteristics of the map, especially at lower dielectric constants. On the other hand, different glycosidic angles also promote distinct stable conformations of the five-membered ring, changing from N to S, or even variants. Comparison with experimental results leads to the idea of highly flexible disaccharides, with variable values for both the five-membered ring and the glycosidic angles.