Modular synthesis of heparin oligosaccharides.
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.
Orgueira
Hernán A
HA
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Bartolozzi
Alessandra
A
Schell
Peter
P
Litjens
Remy E J N
RE
Palmacci
Emma R
ER
Seeberger
Peter H
PH
D000990:Antithrombin III / Q000378:metabolism; D001671:Biochemistry / Q000379:methods*; D002240:Carbohydrate Sequence; D004187:Disaccharides / Q000138:chemical synthesis; D006025:Glycosaminoglycans / Q000737:chemistry / Q000378:metabolism; D006031:Glycosylation; D006493:Heparin / Q000737:chemistry*; D008969:Molecular Sequence Data; D009844:Oligosaccharides / Q000138:chemical synthesis* / Q000378:metabolism; D013237:Stereoisomerism
D004187:Disaccharides; D006025:Glycosaminoglycans; D009844:Oligosaccharides; C020341:glucosaminoglycans; D000990:Antithrombin III; D006493:Heparin