Fischer-Helferich synthesis

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). 

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. 

Almost thirty years passed before Todd and coworkers applied the Fischer-Helferich procedure to the synthesis of the natural purine nucleosides, adenosine (l)i and guanosine (2). Condensation of tri-O-acetyl-D-ribofuranosyl chloride, prepared from 5-0-benzyl-D-ribose by way of tetra-0-acetyl-D-ribofuranose,i 2 with the silver salt of 2,8-dichloroadenine... 

After his doctoral graduation, Helferich became Emil Fischer s personal assistant for two years, and, from 1913 onwards, a teaching assistant. Together with Fischer, he published a series of papers on glycoside synthesis during this period. His scientific career was then interrupted by the First World War, in which he served as an officer throughout. 

An alternative sequence consists in connecting the sugar to a carboxymethyl residue instead of an allyl one. Fischer and Helferich reported the synthesis... 

Johnson and Bergmann, as well as Helferich and Kosche, noted the possibility that the glycosyl ureides might be utilized as intermediates for an improved method of synthesis of pyrimidine nucleosides. Fischer s method was used for obtaining 1-n-glucosylurea as well as 1-n-arabinosyl-urea and 1,3-di-n-xylosylurea. 

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