Conformational analysis of synthetic heparin‐like oligosaccharides containing α‐L‐idopyranosyluronic acid

High‐field NMR spectroscopy of synthetic heparin‐like di‐ and trisaccharides has afforded a complete set of inter‐proton‐coupling data on α‐L‐idopyranosyluronic acid, which have been used for conformational analysis. These data lead to the conclusion that α‐L‐iduronic acid may display considerable conformational freedom including ¹C₄, ⁴C₁ and ²S₀ (e.g. compound 1) conformers. The 2‐O‐sulphate substituent at iduronic acid tends to stabilize the ¹C₄ conformation (e.g. compounds 2 and 4). In addition carbohydrate substituents at position 4 hinder the ⁴C₁ conformation (e.g. compound 3a,b versus 1). Furthermore, the conformation of α‐L‐idopyranosyluronic acid 2‐sulphate is affected seriously by the substituent at position 2 of the non‐reducing glucosamine residue. Thus the presence of an ammonium group (i.e. compound 7) leads to unexpected deformation of the ¹C₄ form of iduronic acid, whereas a sulphamino substituent at this position (e.g. compound 5a,b) brings about the ²S₀ skew boat conformation. The iduronic acid moiety of a trisaccharide (compound 6), which represents a part of the anti‐thrombin III‐binding site of heparin, shows conformational preference for the ²S₀ form in aqueous solution under low ionic conditions. However, increasing the ionic strength (e.g. 3 M NaCl) causes the conformational equilibrium to incline towards the ¹C₄ chair conformer. This feature may be indicative for the mechanism of conformational control as exerted by the AT‐III protein upon heparin binding. Several molecular models of preferred conformers have been constructed; Nuclear Overhauser Enhancement data, exo‐anomeric effect and Van der Waals interactions have been taken into account.