Fischer-Helferich method

The Fischer- Helferich method, as a direct anomeric-oxygen replacement reaction (Scheme 1, path A), has been very successfully applied for syntheses of simple alkyl glycosides. However, because of its reversibility, it has not gained general importance in the synthesis of complex oligosaccharides and glycoconjugates (1). 

Starting with /jemi-acetal 12 the anomeric center has to be protected. Under acidic conditions in methanol the C-l methyl ether is obtained as a mixture of anomers. Therefore the a-anomer is favored because of the anomeric effect (see p. 251). Separation of the two anomers by crystallization is possible. This reaction is connected to the research of E. Fischer (Fischer-Helferich method).13... 

However, another application of the Fischer-Helferich method clearly exhibits its limitations. Long chain alkyl glycosides have gained interest as nonionic surfactants. Their technical synthesis is based on acid catalysis of the reaction between glucose and alcohol. Due to the inherent solubility problems, typical drawbacks of the Fischer-Helferich method are encountered the technical product consists of a mixture of different anomers and, due to the fact that excess alcohol cannot be used for solubilization of the reaction mixture, reaction of glucose with itself is also found. 

Due to the drawbacks of the Fischer-Helferich method it was early recognized that other approaches to glycoside and saccharide synthesis had to be introduced. 

Nucleosides are formed from benzyl ethers of ribose or deoxyribose by replacement of the acetal benzyl groups by bromide and coupling with the mercury salts of nucleic bases. The benzyl ether groups are removed by treatment with ammonia (Fischer-Helferich method not shown). In the case of pyrimidine nucleosides, one usually converts the lactams first to aromatic di-trimethylsilane ethers, which then react in high yields with protected halogenoses (Scheme 8.5.4)... 

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