RESUMO
A general, modular strategy for the first completely stereoselective synthesis of defined heparin oligosaccharides is described. Six monosaccharide building blocks (four differentially protected glucosamines, one glucuronic and one iduronic acid) were utilized to prepare di- and trisaccharide modules in a fully selective fashion. Installation of the alpha-glucosamine linkage was controlled by placing a conformational constraint on the uronic acid glycosyl acceptors thereby establishing a new concept for stereochemical control. Combination of disaccharide modules to form trans-uronic acid linkages was completely selective by virtue of C2 participating groups. Coupling reactions between disaccharide modules exhibited sequence dependence. While the union of many glucosamine uronic acid disaccharide modules did not meet any problems, certain sequences proved not accessible. Elaboration of glucosamine uronic acid disaccharide building blocks to trisaccharide modules by addition of either one additional glucosamine or uronic acid allowed for stereoselective access to oligosaccharides as demonstrated on the example of a hexasaccharide resembling the ATIII-binding sequence. Final deprotection and sulfation yielded the fully synthetic heparin oligosaccharides.
Assuntos
Bioquímica/métodos , Heparina/química , Oligossacarídeos/síntese química , Antitrombina III/metabolismo , Sequência de Carboidratos , Dissacarídeos/síntese química , Glicosaminoglicanos/química , Glicosaminoglicanos/metabolismo , Glicosilação , Dados de Sequência Molecular , Oligossacarídeos/metabolismo , EstereoisomerismoRESUMO
[reaction: see text] A short, high-yielding synthesis of the C-glucoside 8,10-di-O-methylbergenin is reported. Key elements of the synthesis are a stereoselective installation of a beta-C-aryl linkage, a palladium(0)-catalyzed aryl carbonylation, and a regioselective lactonization reaction. This pathway should allow access to a host of bergenin analogues.