Glycosylation Koenigs - Knorr method

In the Koenigs-Knorr method and in the Helferich or Zemplen modifications thereof, a glycosyl halide (bromide or chloride iodides can be produced in situ by the addition of tetraalkylammonium iodide) is allowed to react with a hydrox-ylic compound in the presence of a heavy-metal promoter such as silver oxide, carbonate, perchlorate, or mercuric bromide and/or oxide,19-21 or by silver triflu-oromethanesulfonate22 (AgOTf). Related to this is the use of glycosyl fluoride donors,23 which normally are prepared from thioglycosides.24... 

From a historic perspective glycosyl chlorides and bromides introduced, respectively, by Michael [2] and Koenigs and Knorr [3] were the most widely used donors in the saccharide synthesis for a very long time. The introduction of 1,2-orthoesters in 1964 [4] was the first important attempt to find an alternative to the Koenigs-Knorr method. However, Paulsen in his 1990 review of reliable donors for glycosyl... 

Other anomeric-oxygen exchange reactions have been recently investigated quite extensively. Closely related to the Koenigs-Knorr method is the introduction offluorine as the leaving group (Scheme 1, path B) (6,9-13). Because of the difference in halophilicity of this element as compared with bromine and chlorine, additional promoter systems besides silver salts were found useful as activators for glycosylation reactions (14-16). However,... 

Since 1965, a number of attempts for obtaining sialyl glycosides have been achieved [15,16], mainly by the classic Koenigs-Knorr method using Al-acetylneuraminyl halides 2 as glycosyl donors. However, the yield and stereoselectivity of the glycosides with sugar... 

The plication of these observations has also led to many excellent results in V-glycoside synthesis. (The discussion of the special aspects of N- and C-glycoside synthesis is beyond the scope of this chapter.) However, severe, partly inherent disadvantages of the Koenigs-Knorr method could not be overcome. These include the low thermal stability and the sensitivity to hydrolysis of many glycosyl halides, and the use of at least equimolar amounts of heavy metal salts as catalysts , which are partly toxic or even explosive, to mention only a few aspects. This had led to an increased search for improved methods applicable also to large scale preparations. 

As a representative example, Paulsen and Von Reessen used a sialyl bromide to apply the Koenigs-Knorr method to the synthesis of an a-2,3-linked disaccharide (Scheme 8) [7b]. Glycosylation of the galactose acceptor 19 with sialyl bromide 18 led to the desired disaccharide 20, although with poor stereoselectivity (ca. 1 1 a j8). The low yields of Koenigs-Knorr glycosylations with secondary alcohols are partly due to elimination of the sialyl halide and formation of the 2,3-dehydro derivative 21. 

In the Koenigs-Knorr method, glycosyl halides are the glycosyl donors. The procedure consists of the treatment of glycosyl bromides or chlorides, easily obtained as pure a anomers [3], with alcoholic or phenolic acceptors in the presence of an excess of a heavy metal salt [92], Silver carbonate or silver oxide were originally used, but at present silver triflate or mercury (II) salts are the most frequently promoters employed [93]. 

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