A Stereochemical Surprise at the Late Stage of the Synthesis of Fully N-Differentiated Heparin Oligosaccharides Containing Amino, Acetamido, and N-Sulfonate Groups

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.