Efficient synthesis of a library of heparin tri- and tetrasaccharides relevant to the substrate of heparanase

Abstract

The glycosylation reaction for construction of the challenging α-GlcN–(1→4)-GlcA/IdoA linkages has been investigated carefully. A standard protocol was thus fixed that employed 2-azido-glucopyranosyl N-phenyl trifluoroacetimidates as donors, TMSOTf as a catalyst, toluene as a solvent, and −30 °C as the working temperature. With this protocol, a variety of mono- and disaccharide donors and acceptors were condensed reliably to provide the corresponding coupled tri- and tetrasaccharides in satisfactory yields and α-selectivity, whereas a remote protecting group or a sugar unit in either the donor or the acceptor did affect considerably the outcome. The resulting tri- and tetrasaccharides bearing orthogonal protecting groups were then converted efficiently into the corresponding heparin tri- and tetrasaccharides via a robust approach involving saponification, O-sulfation, azide reduction, N-sulfation/N-acetylation, and global debenzylation. These heparin tri- and tetrasaccharides are structurally relevant to ΔHexA(2S)–GlcN(NS,6S)–GlcA–GlcN(NS,6S), a reported substrate of heparanase, and therefore could be exploited to examine the substrate specificity of this important enzyme.