Fischer, equilibrium glycosidation

This steric preference is a thermodynamic effect and is exhibited in the classic equilibrium glycosidation of Fischer, in which acid-catalyzed reaction of a free sugar with a simple alcohol takes place in a medium of moderate dielectric constant. Under these conditions, the axial anomer is the favored product. This reaction has synthetic limitations, however, for with most sugars the stereoselectivity is not high, and for practical purposes it can only be applied to form simple glycosides. 

The Fischer glycosidation of A-O-deoxy-D-fructos-l-yOaminomethy-lenemalonate (1448) was carried out in a 1.25% solution of hydrogen chloride in methanol at ambient temperature to produce a mixture of fructofuranosides (1449 and 1450) and fructopyranoside (1451). The reaction was complete after 5 hr, but the glycoside equilibrium was attained only after 24 hr (86MI10). 

In the formation of glycosides by the Fischer process (equilibration in the presence of an acid catalyst), fucopyranosides are apparently formed more rapidly than galactopyranosides. In the presence of mineral acids, fucose attains equilibrium in boiling methanol within 6-8 h, whereas a reaction time of 20 h is customary for D-galactose. In reactions catalyzed by cation-exchange resins, maximum pyranoside formation is attained by 8 h for L-fucose,35a whereas D-galactose requires35612-24 h. 

The situation was clarified by the isolation of a, )8, and y isomers of D-glucose by Tanret in 1895. He showed that the a and y isomers mutarotate in opposite directions and, at equilibrium, each have the same rotation as the y3 form. The isomers were also found to have the same molecular weight. Tanret s three isomers of D-glucose were considered to be ring and free aldehyde forms by Lobry de Bruyn and Alberda van Ekenstein in 1895, von Lipp-mann in 1896, and Simon in 1901. Fischer in 1893, and von Lipp-mann pointed out that ring formation would produce a new asymmetric carbon atom, and thus the existence of isomeric sugars, glycosides, and acetates was clarified. 

Although the final equilibrium in the Fischer reaction favors the pyrano-sides, the furanosides appear to be formed first, and they can sometimes be isolated by performing the reaction under mild conditions and arresting it at an early stage. In the same way, advantage can sometimes be taken, at the expense of the yield, of the fact that the a and /3 anomers (furanose or pyranose) may be formed at different rates. If an alcoholic glycoside is refluxed with the alcohol and an acid catalyst, equihbrium between the different forms is re-established. 

At this point we will look at the limits of usefulness of the Fischer method. A large excess of alcohol must be used, preferably as solvent, to displace the equilibrium in the desired direction. Equatorial anomeric alkoxyl anomers are not easily isolated. This reaction cannot be used with phenols, and aryl glycosides are not accessible. 

Cyclization can lead to the a- or (3-furanoside or a- or P-pyranoside. The furanosides are the kinetic products of the Fischer glycosidation and they can be isolated if the reaction is stopped prior to equilibrium. Mechanism 23.2 describes the initial formation of the methyl hemiacetal of D-glucose and its cyclization to a mixture of methyl a-D-glucopyranoside and its P anomer. 

The acetals are converted to the corresponding pyranosides in alcoholic hydrogen chloride (Fischer conditions for preparation of glycosides) and, hence, are in equilibrium with the glycosides, but the equilibrium favors the glycosides. 

Obviously, the presence of a high concentration of alcohol facilitates the synthesis and high concentration of water the hydrolysis. In the Fischer method for the synthesis of the glycosides (Chapter IV), the catalyst is an acid, but, as shown by the excellent work of Bourquelot, H4rissey, and Bridel, enzymes also may be employed with some advantages over the use of acids. When acids are used, all the various isomers are formed, and the equilibrium is very complex although certain constituents predominate under the equilibrium conditions. The enzymes are very much more selective in their catalysis. Almond emulsin catalyzes the sjmthesis and hydroly-... 

The first alkyl glucoside was synthesized and identified in the laboratory by Emil Fischer in 1893 [1], This process is now well known as the Fischer glycosida-tion and comprises an acid-catalyzed reaction of glycoses with alcohols. The structure of ethyl glucoside was defined correctly by Fischer, as may be seen from the historical furanosidic formula proposed ( Fischer projection ). In fact, Fischer glycosidation products are complex, mostly equilibrium mixtures of a/p-anomers and pyranoside/furanoside isomers which also comprise randomly linked glycoside oligomers (Fig. 1) [2]. 

The Fischer glycosidation may be described as a process in which, in a first step, the dextrose reacts relatively quickly and an ohgomer equilibrium is reached. This step is followed by slow degradation of the alkyl polyglycoside. In the course of the degradation, which consists of dealkylation and polymerization steps, the thermodynamically more stable polydextrose is formed substantially irreversibly in increasing concentrations. Reaction mixtures which have exceeded an optimal reaction time may be described as overreacted. ... 

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