title: A stereochemical surprise at the late stage of the synthesis of fully N-differentiated heparin oligosaccharides containing amino, acetamido, and N-sulfonate groups.
abstract: The glucosamine residues in heparin-like glycosaminoglycans have been found to exist as amines, acetamides, and N-sulfonates. To develop a completely general, modular synthesis of heparin, three degrees of orthogonal nitrogen protection are required. Reported herein is a strategy for the synthesis of fully N-differentiated heparin oligosaccharides in the context of target octasaccharide 1, which contains an N-acetate, N-sulfonates, and a free amine. The protecting group scheme used in the synthesis blocked the N-acetate as a N-diacetate, the N-sulfonates as azido groups, and the amine as a N-CBz; free hydroxyls were masked as benzyl ethers and O-sulfonates as acetate esters. Disaccharide and tetrasaccharide modules were synthesized using this strategy; however, the union of tetrasaccharide trichloroacetimidate 4 with disaccharide acceptor 5 unexpectedly formed the undesired beta-linked glycoside in addition to the alpha-linkage anticipated for iduronic acid nucleophiles, resulting in an inseparable 6:1 alpha/beta mixture of products. Detailed studies into the basis for this unexpected result were conducted and are also reported.
authors.affiliation: Massachusetts Institute of Technology, 77 Massachusetts Avenue 18-292, Cambridge, Massachusetts 02139, USA.
authors.forename: Gregory J S
authors.initials: GJ
authors.lastname: Lohman
authors.forename: Peter H
authors.initials: PH
authors.lastname: Seeberger
mesh_terms: D002236:Carbohydrate Conformation; D006493:Heparin / Q000138:chemical synthesis* / Q000737:chemistry; D009844:Oligosaccharides / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D009844:Oligosaccharides; D006493:Heparin