Kahne glycosylation

What is Kahne glycosylation?

In 1989, Kahne reported a reaction that has come to be known as the Kahne glycosylation. This reaction involves the use of glycosyl phenyl sulfoxide as the glycosyl donor and a glycosylation promoter in the synthesis of glycosides, disaccharides, and oligosaccharides.

Kahne glycosylation - general reaction scheme
Kahne glycosylation
  • P, P’ = protecting group
  • Promoter = Tf2O, TMSOTf, or TfOH (see list of acronyms)
  • Acid scavenger = di-t-butyl-methylpyridine, etc.

The reaction has several advantages, including mild reaction conditions, good to excellent anomeric stereocontrol, compatibility with both solution and solid-phase glycosylation, and high reactivity of the glycosyl donor. As a result, it has been widely used in the synthesis of oligosaccharides, especially for unreactive acceptors and hindered alcohols.

The Kahne glycosylation has been used to prepare a variety of compounds, including glycosides of acetamide, hindered bile acids, hydroxylamines, hydroxylated amino acids, phenols, tertiary alcohols, and carbohydrates. To enhance the nucleophilicity of acceptors, alcohols have sometimes been converted into their tributylstannyl ether derivatives before mixing with glycosyl sulfoxides.

The promoters for this reaction include triflic anhydride Tf2O, trimethylsilyl triflate TMSOTf, and triflic acid TfOH. It is often carried out in a nonpolar solvent at low temperature and in the presence of an acid scavenger. However, the choice of promoter, solvent, and scavenger can affect the stereochemical outcome of the reaction.

The protecting groups on sulfinil glycosides have an apparent effect on the stereochemistry of glycosides. For example, pivalate-protected glucosyl phenyl sulfoxide always gives β-glycosides, while the corresponding perbenzyl derivatives result in a mixture of α- and β-anomers. The mixing sequence of a promoter and acceptor can also influence the stereochemical outcome of the reaction.

To ensure optimal selectivity, it is generally recommended to activate the sulfoxide donor with triflic anhydride Tf2O before adding the glycosyl acceptor. Additionally, glycosyl alkyl sulfoxides and sulfimides are suitable glycosyl donors as well.

References

Kahne, D., Walker, S., Cheng, Y., and Van Engen, D. (1989). Glycosylation of unreactive substrates. Journal of the American Chemical Society, 111(17), 6881-6882
DOI: 10.1021/ja00199a081

Shares