Mapping the Reactivity and Selectivity of 2-Azidofucosyl Donors for the Assembly of N-Acetylfucosamine-Containing Bacterial Oligosaccharides

[Image: see text] The synthesis of complex oligosaccharides is often hindered by a lack of knowledge on the reactivity and selectivity of their constituent building blocks. We investigated the reactivity and selectivity of 2-azidofucosyl (FucN(3)) donors, valuable synthons in the synthesis of 2-acetamido-2-deoxyfucose (FucNAc) containing oligosaccharides. Six FucN(3) donors, bearing benzyl, benzoyl, or tert-butyldimethylsilyl protecting groups at the C3-O and C4-O positions, were synthesized, and their reactivity was assessed in a series of glycosylations using acceptors of varying nucleophilicity and size. It was found that more reactive nucleophiles and electron-withdrawing benzoyl groups on the donor favor the formation of β-glycosides, while poorly reactive nucleophiles and electron-donating protecting groups on the donor favor α-glycosidic bond formation. Low-temperature NMR activation studies of Bn- and Bz-protected donors revealed the formation of covalent FucN(3) triflates and oxosulfonium triflates. From these results, a mechanistic explanation is offered in which more reactive acceptors preferentially react via an S(N)2-like pathway, while less reactive acceptors react via an S(N)1-like pathway. The knowledge obtained in this reactivity study was then applied in the construction of α-FucN(3) linkages relevant to bacterial saccharides. Finally, a modular synthesis of the Staphylococcus aureus type 5 capsular polysaccharide repeating unit, a trisaccharide consisting of two FucNAc units, is described.