Carbohydrates hydroxyl group nucleophilicity

If the carbonyl and the hydroxyl group are in the same molecule, an intramolecular nucleophilic addition can take place, leading to the formation of a cyclic hemiacetal. Five- and six-membered cyclic hemiacetals are relatively strain-free and particularly stable, and many carbohydrates therefore exist in an equilibrium between open-chain and cyclic forms. Glucose, for instance, exists in aqueous solution primarily in the six-membered, pyranose form resulting from intramolecular nucleophilic addition of the -OH group at C5 to the Cl carbonyl group (Figure 25.4). The name pyranose is derived from pyran, the name of the unsaturated six-membered cyclic ether. 

Another potential site of reactivity for anhydrides in protein molecules is modification of any attached carbohydrate chains. In addition to amino group modification in the polypeptide chain, glycoproteins may be modified at their polysaccharide hydroxyl groups to form ester derivatives. Esterification of carbohydrates by acetic anhydride, especially cellulose, is a major industrial application for this compound. In aqueous solutions, however, esterification may be a minor product, since the oxygen of water is about as strong a nucleophile as the hydroxyls of sugar residues. 

Benzyl and triphenylmethyl ethers of carbohydrates are preferred over methyl ethers when selective removal of protecting groups is important. The relatively high nucleophilic activity of the 5-hydroxyl group in glycosides and 1,2-O-alkylidene derivatives of 4 permits its benzylation and triphenylmethylation under mild conditions. Thus, treatment of 33 (Ref. 34) and 36 (Ref. 57) with benzyl bromide and... 

The reaction of sulfuryl chloride with carbohydrates to give chloro-deoxy derivatives has been reviewed briefly in this Series.98 The reaction of sulfuryl chloride with monosaccharides has been shown to afford products in which the secondary hydroxyl groups are replaced by chlorine with inversion of configuration.68-75 Jones and coworkers reported that the reaction of methyl a-D-glucopyranoside with sulfuryl chloride and pyridine in chloroform at room temperature proceeds by way of the 4,6-bis(chlorosulfate) by an Sn2 process, with chloride as the nucleophile, to give methyl 4,6-dichloro-4,6-dideoxy-a-D-galactopyranoside 2,3-bis(chlorosulfate).74... 

The value of the sulphonate esters in carbohydrate chemistry lies in their ability to undergo cleavage by reaction with nucleophiles in one of two possible ways, (i) cleavage of the S—O bond with regeneration of the hydroxyl group as a result of SN2 attack at the sulphur atom, and (ii) cleavage of the C—O bond as a result of SN2 attack at the carbon atom. 

M. Miljkovic, D. Miljkovic, A. Jokic, V. Andrejevic, and E. A. Davidson, Neighboring group participation in carbohydrate chemistry. 3. Neighboring group participation of the 6-hydroxyl group in a nucleophilic displacement of a 5-p-toluenesulfonate, J. Org. Chem., 37 (1972) 2536-2540. 

Ogawa, T, Matsui, M, Approach to synthesis of glycosides enhancement of nucleophilicity of hydroxyl-groups by trialkylstannylation, Carbohydr. Res., 51, C13-C18, 1976. 

Many natural compounds include heterocyclic systems constructed by hemiacetal formation between a hydroxyl group and a keto group of the chain in a 1,4- or 1,5-relative disposition. It is advantageous in a retrosynthetic analysis to take this point into account and to devise a disconnection next to the carbonyl group. Moreover, the synthetic connection does not involve chiral center formation. An obvious translation of this principle in carbohydrate chemistry is the formation of a carbon-carbon bond at the anomeric center by nucleophilic addition to lactones. However, other methods have also been devised to reach this goal. 

Carbohydrates are excellent substrates to test nucleophilic displacement reactions with a variety of heteroatom-based nucleophiles. These reactions can be tried on primary and secondary hydroxyl groups at different sites of the sugar ring, and with different steric or stereoelectronic dispositions [1]. 

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