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

Abstract

Abstract 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 1 C 4 , 4 C 1 and 2 S 0 (e.g. compound 1 ) conformers. The 2‐ O ‐sulphate substituent at iduronic acid tends to stabilize the 1 C 4 conformation ( e.g. compounds 2 and 4 ). In addition carbohydrate substituents at position 4 hinder the 4 C 1 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 1 C 4 form of iduronic acid, whereas a sulphamino substituent at this position ( e.g. compound 5a,b ) brings about the 2 S 0 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 2 S 0 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 1 C 4 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.