Fischer-Helferich glycosylation

What is Fischer-Helferich glycosylation?

The Fischer-Helferich glycosylation, also known as Helferich glycosylation, is a reaction that was first reported by Fischer in 1893 and later modified by Helferich. This method involves using mineral acids such as H2SO4 or HCl as a catalyst to prepare O- or S-alkyl glycosides from unprotected carbohydrates and alcohols or thiols.

Fischer-Helferich glycosylation - general reaction scheme
Fischer-Helferich glycosylation

The reaction results in the formation of oxocarbenium ion or its reactive equivalent, and has been successfully used to prepare various glycosides including methyl, benzyl, and allyl glycosides. However, it should be noted that solid alcohol or sugar derivatives are not suitable for this reaction. Different acids, including Lewis acids, have been used as promoters for this reaction. Unfortunately, this method always produces a mixture of both pyranosides and furanosides, along with their anomeric mixtures.