Anomerisation

Simmerling C, T Fox and P A Kollman 1998. Use of LocaUy Enhanced Sampling in Free Energ Calculations Testing and Application to the o —> /3 Anomerisation of Glucose. Journal of tl American Chemical Society 120 5771-5782. 

Deoxy-a-D-ribosyl-l-phosphate 20, a key substrate in the preparation of 2 -deoxynucleosides, was stereoselectively prepared by crystallization-induced asymmetric transformation in the presence of an excess of ortho-phosphoric acid and tri( -butyl)amine under strictly anhydrous conditions (Scheme 2).7 Initial Sn2 displacement of Cl in ot-glycosyl chloride 16 by phosphoric acid resulted in a 1 1 a/p anomeric mixture of 17 and 18 due to the rapid anomerisation of the a-chloride in polar solvents. Under acidic conditions, in the presence of an excess of H3P04, an equilibration between the a and p anomers gradually changed in favour of the thermodynamically more stable a-counterpart. By selective crystallization of the mono tri( -butyl)ammonium salt of the a-phosphate from the mixture, the equilibrium could be shifted towards the desired a-D-ribosyl phosphate 18 (oc/p = 98.5 1.5), which was isolated as bis-cyclohexylammonium salt 19 and deprotected to furnish compound 20. 

On the grounds that furanosides anomerise and hydrolyse very much more readily than do the corresponding pyranosides. Bishop eind Cooper assumed that the first step in the glycosidation process is the methanol-ysis of the furanose form of the free sugar, and they visualised, without evidence, a unimolecular process proceeding by way of a stabilised cyclic ion (1). In support of this they observed 5) that for xylose, lyxose and ribose the furanoside formation rates (3,1,12 respectively) correlated with the furanoside contents at equilibrium (see Table 3) and hence, presum-... 

Newer Observations on the Synthesis of O-Glycosides 2. Anomerisation of Furanosides... 

After anomerisation and before initiation of the ring-expansion process, the a-and p-glucofuranosides were found to be present in a -equilibrium in the ratio 1 1.7 which agrees with the value obtained by radiochemical methods and with that observed by Bishop and Cooper for the methyl xylofuranosides 4). However, the ratio for the xylosides was found in the isotope work to be 1 1.2 (1 1.3 for ethyl xylofuranosides) regardless of whether they were derived from xylose or either of its methyl furanosides. A further relevant observation made with these furanosides was that acetal was formed during their anomerisation indicating that pathways (C) and (E) (Scheme 3) are open. 

From their kinetic results Bishop and collaborators >8) calculated the velocity constants of the furanoside anomerisations of their seven aldoses (Table 1), and rationalised them in terms of ring conformations and group interactions. Thus, for example, in the extreme cases methyl a-D-arabinofuranoside (4), having the fewest non-bonded steric interactions, is the most stable pentofuranoside, while methyl p-o-lyxofurano-side (5), having the least stable ring, reacts most rapidly. 

Table 1. First order rate constants for methyl furanoside anomerisations (2% solution in 0.01% methanolic hydrogen chloride at 35 °C)...

Bishop and his colleagues were again able to calculate the relative reactivities of the various methyl aldopjnranosides in anomerisations, and to obtain equilibrimn values for anomers, but they did not siscertain the mechanisms of the reactions involved other experiments have however helped to make this the best understood step in the glycosidation process. As with the furanosides, the reaction can proceed by way of... 

Aryl glycosides of 2-amino-2-deoxy sugars, as might be expected, can be prepared by similar techniques as was illustrated by the synthesis of phenyl 3,4,6-tri-0-acetyl-2-acetamido-2-deoxy-p-D-glucoside and -D-galactoside by toluene -sulphonic acid catalysed reactions between phenol and the hexosamine penta-acetates These products were then anomerised using zinc chloride as catalyst to provide means of obtaining -anomers. 

Several means are available for the synthesis of glycosides by application of modifications to accessible compounds. Here, only those reactions involving changes at C-1 — anomerisations and transglycosidations, will be considered. 

An interesting and unusual case of anomerisation occurring under basic conditions has been reported by Lindberg who showed that 2,4-dinitrophenyl p-D-glucopyranoside gave the a-anomer on treatment with sodium hydroxide in dry pyridine. Neither mononitro nor unsubstituted phenyl p-glycosides, however, were reactive under these conditions 76). The mechanism of the isomerisation has not been elucidated but would appear to involve the imusual abstraction of a proton from C-1, and the... 

A major breakthrough in a-glycosidic bond synthesis came with the introduction of the in situ anomerisation procedure.1 Lemieux and coworkers observed that a rapid equilibrium can be established between a and (3 halides by the addition of tetra-w-butyl ammonium bromide (Scheme 4.6). The anomerisation is believed to proceed through several intermediates. At equilibrium, there is a shift towards the a bromide since this compound is stabilised by an endoanomeric effect. Because, the p bromide is much more reactive towards nucleophilic attack by an alcohol,... 

Scheme 4.6 ot-Glycosidic bond synthesis by in situ anomerisation. 

It is essential that the in situ anomerisation is performed in a solvent of low polarity. In polar solvents, the reaction proceeds via an oxocarbenium ion and the anomeric selectivity is reduced. 

The efficacy of the in situ anomerisation procedure was demonstrated by the condensation of a fucosyl bromide with a glycosyl acceptor in the presence of tetra-n-butyl ammonium bromide to give a trisaccharide mainly as the a anomer (Scheme 4.6). 

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