J-Coupling Analysis as a Means for Stereochemical Assignments in Furanosides

The widespread use of 1H NMR coupling constant information for stereochemical assignment in pyranosides is based on the conformationally rigid six-membered ring they contain, allowing an easy discrimination between the large axial-axial couplings and the small axial-equatorial and equatorial-equatorial couplings. This is not the case for furanosides, where the flexibility of the five-membered ring (leading to the so called pseudorotation) causes large variations in coupling constants of vicinal protons between conformers, so that coupling constants are considered uninformative. As a consequence, stereochemical elucidation of furanosides is usually based on NOESY/ROESY correlations and/or chemical degradation. This is the approach we usually in the structural elucidation of glycolipids. However, during the elucidation of the structure of vesparioside B (a complex glycosphingolipid from the marine sponge Speciospongia vesparia) ROESY correlations were not enough to define the stereochemistry of the inner furanose sugar. In contrast, some of the coupling constants between vicinal protons of this sugar showed unusually small values. We undertook an in-depth computational study of coupling constants of furanosides: we calculated systematically the dependence of the vicinal proton-proton coupling constants on the pseudorotation angle (the parameter used to describe the conformation of the five-membered rings) for each of the eight diasteromeric pentofuranosides using quantum mechanical methods (Gaussian 03 program at the mPW1PW91/6-31G(d) level and the 6-311G+(d,p) basis set). Looking at the results, it was apparent that coupling constants between trans vicinal protons vary over a very broad range of values (0–8 Hz), but coupling constants between cis vicinal protons are never smaller than 2.5 Hz. This happens because in furanose rings dihedral angles which are geometrically accessible to cis vicinal protons (from –45° to +45°) are never close to 90° (which would imply small coupling constants), while those allowed fortrans vicinal proton are in the range between 85° and 165° (so that both very large and very small couplings can be observed). Therefore, whenever a vicinal coupling constant in a furanoside is < 2 Hz (for H-1/H-2 or H-3/H-4) or < 3.5 Hz (for H-2/H-3), the relevant protons must be trans oriented (as H-1/H-2 and H-2/H-3 are in vesparioside B). Unfortunately, this rule does not work the other way round, and a coupling above the threshold (as for H-3/H-4) does not provide any information about the stereochemistry of the coupled protons.