Synthesis and conformational analysis of an analogue of the antithrombin‐binding region of heparin: The role of the carboxylate function of α‐L‐idopyranuronate

Abstract

Abstract An analogue of the antithrombin‐III‐binding region of heparin has been synthesized. This analogue [GlcNSO 3 (6‐OSO 3 )‐GlcU‐GlcNSO 3 (3,6‐OSO 3 )‐ Xyl(2‐OSO 3 ) ‐GlcNSO 3 (6‐OSO 3 ), i.e. compound 11 ] lacks the carboxylate function of the α‐L‐iduronic acid moiety, which implies that the 2‐ O ‐sulphated α‐L‐idopyranuronate unit is replaced by 2‐ O ‐sulphated β‐D‐xylopyranose. Compound 11 was prepared from fully protected pentasaccharide 10a , which was synthesized from two disaccharides ( 7 and 6b ) and a monosaccharide ( 9 ). Synthesis of disaccharide 6b required preparation of a new, suitably protected xylopyranose‐building block: 2‐ O ‐acetyl‐ or 2‐ O ‐benzoyl‐3‐ O ‐benzyl‐4‐ O ‐levulinoyl‐α‐D‐xylopyranosyl fluoride 4a,b. High‐field NMR spectroscopy of compound 11 afforded a complete set of interproton coupling data and Nuclear Overhauser Enhancement data, which have been used for conformational analysis. It appears that β‐D‐xylopyranose in compound 11 adopts exclusively the 4 C 1 conformation, whereas it is known that α‐L‐idopyranuronate in the naturally occurring heparin fragment exhibits 2 S 0 and 1 C 4 conformations. Thus, the carboxylate function of α‐L‐idopyranuronate in the heparin fragment is an important conformational drive. Since neither compound 11 nor another analogue containing L‐idose (with similar conformational properties as the natural fragment) elicit AT‐III‐mediated activity, it is proposed that the carboxylate of idopyranuronate interacts with AT‐III to bring about the active conformation of the protease inhibitor.