NOVEL REGIOSELECTIVE AND STEREOSELECTIVE O-6-DESULFATION OF THE GLUCOSAMINE MOIETY OF HEPARIN WITH N-METHYLPYRROLIDINONE-WATER OR N,N-DIMETHYLFORMAMIDE-WATER MIXTURES

The degree of completeness and selectivity of the solvolytic O-6-desul fation reactions of the glucosamine moiety adjacent to the 2-O-sulfoid uronic acid group of heparin was systematically studied. Using solutio ns of various ammonium salts of heparin (salts of tributylamine, quino line and pyridine) in mixtures of 9:1 aprotic solvents and water (solv ents of medium polarity, in order of decreasing polarity: Me2SO > Me2N CHO > Me2NAc > N-methylpyrrolidinone), the influence of different reac tion conditions were studied. The ammonium salt of heparin with a stro ng base (e.g., tributylamine) in Me2SO showed almost no desulfation, w hile in Me2NCHO a relatively low degree of completeness of O-6-desulfa tion (30%) with moderate selectivity (15% [I-2(OS)]-desulfation) was o bserved. Weak bases like quinoline or pyridine in Me2SO-water resulted in nearly complete [A-6(OS)]-desulfation (95 and 94%, respectively) w ith low selectivity [I-2(OS)]-desulfation (49 and 35%, respectively). The heparin pyridinium salt in Me2NCHO-water showed both a relatively high degree of completeness and high selectivity (72% [A-6(0S)]- and 8 % [I-2(OS)]-desulfation). The highest regioselectivity (i.e., a, high degree of completeness accompanied by high selectivity) was achieved u sing an N-methylpyrrolidinone-water mixture (88% [A-6(OS)]-desulfation and 10% [I-2(OS)]-desulfation). A nearly complete O-6-desulfation (95 %), accompanied by a lower selectivity (18% [I-2(OS)]-desulfation), wa s achieved when the reaction was carried out twice. Lower temperature improved selectivity(5% [I-2(OS)]-desulfation) but reduced the complet eness of [A-6(OS)]-desulfation (72%). In comparison with the variety o f O-6-desulfations reported to date, the novel reactions presented in this article led to remarkable increase in completeness and regioselec tivity of the reactions that were investigated. (C) 1998 Elsevier Scie nce Ltd. All rights reserved.