Synthesis of benzyl protected β-d-GlcA-(1 → 2)-α-d-Man thioglycoside building blocks for construction of Cryptococcus neoformans capsular polysaccharide structures

•The ‘nitrile effect’ with benzylated glucuronic acid donors has been investigated.•Alternative routes to benzyl protected β-linked glucuronides have been investigated.•Efficient β-selective glycosylations with benzylated GlcA donors are described.•Pathways developed are reproducible and can be performed on a large scale.

In a project targeting the synthesis of large oligosaccharide structures corresponding to the Cryptococcus neoformans GXM capsular polysaccharide, an easy access to thiodisaccharide building blocks comprising a β-linked glucuronic acid moiety and a 6-O-acetyl group was required. Several pathways to such building blocks have been investigated, addressing the problem of constructing a β-linked glucuronic acid residue protected with groups that are orthogonal to a primary acetyl group. Two efficient routes have been developed, one using benzoylated glucosyl donors to form the β-linkage followed by a change of protecting groups to benzyls and subsequent introduction of the carboxyl function and the acetyl group. The second route explored the possibility to achieve β-selectivity using glucuronyl donors without acyl protecting groups. BF3-etherate promoted glycosylations with benzyl (2,3,4-tri-O-benzyl-α-d-glucupyranosyl)uronate trichloroacetimidate in the presence of nitrile solvents and at low temperatures reproducibly gave good yields of disaccharides with high β-selectivity. Furthermore, the use of recently reported glucuronyl thioglycoside donors protected with a cyclic 2,4-silylene acetal was found to represent another efficient and completely β-selective way to desired disaccharide building blocks.

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