Vorbrüggen glycosylation

What is Vorbrüggen glycosylation?

The Vorbrüggen glycosylation, an extension of the Hilbert-Johnson reaction used to prepare N-glycosides, was first reported in 1970 by Niedballa and Vorbrüggen (Research Laboratories of Schering A.G.). This reaction involves treating a mixture of peracylated sugar and silylated heterocyclic base with a Lewis acid. It is also known as Vorbrüggen reaction, Vorbrüggen glycosidation, or Vorbrüggen coupling.

Vorbrüggen glycosylation - general reaction scheme - Vorbrüggen reaction - Vorbrüggen glycosidation - Vorbrüggen coupling
Vorbrüggen glycosylation

R = CH3CO, PhCO (see list of acronyms)

The reaction is typically carried out in MeCN or dichloroethane using a Lewis acid such as TMSOTf or SnCl4. Sugar peracetates react more readily than the corresponding benzoylated sugar donors, and silylated pyrimidine heterocycles usually lead to nucleosides with N-glycosylation occurring at the N1 position. Silylated purine heterocycles give lower yields and a mixture of regioisomers. The configuration of nucleosides at the anomeric site is controlled by the C2 directing group.

The reaction yields can be enhanced by performing the reaction at a higher temperature instead of room temperature. The silylated heterocycles can be prepared by treating purine or pyrimidine heterocycles with hexamethyldisilazane and pyridine. The reaction can also be performed with unprotected riboses, which may be persilylated before the reaction with a heterocyclic base.

References

Niedballa, U. and Vorbrüggen, H. (1970), A General Synthesis of Pyrimidine Nucleosides. Angew. Chem. Int. Ed. Engl., 9: 461-462. https://doi.org/10.1002/anie.197004612

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