Glycoside Koenigs-Knorr reaction

Although the Koenigs-Knorr reaction appears to involve a simple backside S 2 displacement of bromide ion by alkoxide ion, the situation is actually more complex. Both a and /3 anomers of tetraacetyl-o-glucopyranosyl bromide give the same /3-glycoside product, implying that they react by a common pathway. 

Koenigs-Knorr reaction (Section 25.6) A method for the synthesis of glycosides by reaction of an alcohol with a pyranosyl bromide. 

The synthesis93 of N-(2,4-dinitrophenyl)-3-0-(tetra-0-acetyl-/ -D-glu-copyranosyl)-L-threonine methyl ester (131) involved a two-step procedure. First, formation of the intermediate, L-threonine orthoester 130 was achieved by treatment of tetra-O-acetyl-a-D-glucopyranosyl bromide (128) with the methyl ester of N-(2,4-dinitrophenyl)-L-threonine94 (129) under the conditions of the Koenigs-Knorr reaction (see next paragraph), and this was then converted into the L-threonine glycoside 131. 

A number of glycosides were available to Fischer by way of the Koenigs-Knorr reaction and his own glycoside synthesis, which involves treatment of... 

A second method is based on the abnormal course of the Koenigs-Knorr reaction with fluoroalkyl alcohols. Indeed, when there are two or three methylenes between the Rf group and the hydroxyl, the reaction does not lead to substitution of the anomeric bromide but instead affords an orthoester. In the presence of mercuric bromide, this orthoester can undergo a rearrangement into an (9-fluoroalkyl glycoside (Figure 6.47). 

Koenigs-Knorr reaction is carried out using simple, liquid aglycons (methanol or ethanol, for example), the alcohol also serves as the solvent for the halide, and is frequently present in large excess. In such cases, the halide is rapidly converted into glycoside, and the water formed in the secondary reaction between the liberated hydrogen halide and silver carbonate is seldom cause for concern. 

The above, indirect, procedure for glycoside synthesis is the Koenigs-Knorr method. Glycosidation may be effected from monosaccharides directly by treatment with an alcohol in the presence of a mineral acid catalyst. For example, when a-D-galactose (13) is heated in methanolic solution containing 2 per cent of hydrogen chloride the thermodymanically more stable methyl a-D-galacto-pyranoside (14) (Expt 5.113) is formed preferentially, and may be isolated from the reaction product by crystallisation as the monohydrate. The less abundant /i-anomer may be recovered from the mother-liquors. 

The Koenigs-Knorr reaction will yield exclusively 1,2-trans glycosides, especially when insoluble silver salts are used as promoters. 

Despite its wide application in glycoside synthesis, the Koenigs-Knorr reaction suffers from several disadvantages (i) the glycosyl halides are unstable, (ii) excess toxic heavy metals are needed to activate the donor, and (iii) a desiccant (to absorb any liberated water) and an acid acceptor (to absorb the liberated hydrogen halide and can be a promoter itself) are often needed to increase the yield and suppress side reactions. 

Methyl /3-Iactoside monohydrate is prepared by treating hepta-O-acetyl-a-lactosyl chloride (or, preferably, the bromide) with methanol in the presence of silver carbonate (the Koenigs-Knorr reaction), followed by saponification with a trace of sodium methoxide in methanol. The unacetyl-ated glycoside can be obtained directly from the bromide derivative by the use of magnesium ethoxide in methanol. ... 

---