Anomeric equilibrium

Ha S, J Gao, B Tidor, J W Brady and M Karplus 1991. Solvent Effect on the Anomeric Equilibrium in d Glucose A Free Eneigy Simulation Analysis. Journal of the American Chemical Sod. ty 113 1553-1557... 

It IS not possible to tell by inspection whether the a or p pyranose form of a par ticular carbohydrate predominates at equilibrium As just described the p pyranose form IS the major species present m an aqueous solution of d glucose whereas the a pyranose form predominates m a solution of d mannose (Problem 25 8) The relative abundance of a and p pyranose forms m solution depends on two factors The first is solvation of the anomeric hydroxyl group An equatorial OH is less crowded and better solvated by water than an axial one This effect stabilizes the p pyranose form m aqueous solution The other factor called the anomeric effect, involves an electronic interaction between the nng oxygen and the anomeric substituent and preferentially stabilizes the axial OH of the a pyranose form Because the two effects operate m different directions but are com parable m magnitude m aqueous solution the a pyranose form is more abundant for some carbohydrates and the p pyranose form for others... 

The magnitude of the anomeric effect depends on the nature of the substituent and decreases with increasing dielectric constant of the medium. The effect of the substituent can be seen by comparing the related 2-chloro- and 2-methoxy-substituted tetrahydropy-rans in entries 2 apd 3. The 2-chloro compound exhibits a significantly greater preference for the axial orientation than the 2-methoxy compound. Entry 3 also provides data relative to the effect of solvent polarity it is observed that the equilibrium constant is larger in carbon tetrachloride (e = 2.2) than in acetonitrile (e = 37.5). 

Compounds in which conformational, rather than configurational, equilibria are influenced by the anomeric effect are depicted in entries 4—6. Single-crystal X-ray dilfiaction studies have unambiguously established that all the chlorine atoms of trans, cis, ira j-2,3,5,6-tetrachloro-l,4-dioxane occupy axial sites in the crystal. Each chlorine in die molecule is bonded to an anomeric carbon and is subject to the anomeric effect. Equally striking is the observation that all the substituents of the tri-0-acetyl-/ -D-xylopyranosyl chloride shown in entry 5 are in the axial orientation in solution. Here, no special crystal packing forces can be invoked to rationalize the preferred conformation. The anomeric effect of a single chlorine is sufficient to drive the equilibrium in favor of the conformation that puts the three acetoxy groups in axial positions. 

In cyclic systems such as 1, the dominant conformation is the one with the maximum anomeric effect. In the case of 1, only conformation lA provides the preferred antiperiplanar geometry for both oxygens. Antiperiplanar relationships are indicated by including lone pairs in the oxygen orbitals. Other effects, such as torsional strain and nonbonded repulsion, contribute to the conformational equilibrium, of course. Normally, a value of about 1.5 kcal/mol is assigned to the stabilization due to an optimum anomeric interaction in an acetal. 

The distribution between the a and p anomeric fonns at equilibrium is readily calculated from the optical rotations of the pure isomers and the final optical rotation of the solution, and is deter-mined to be 36% a to 64% p. Independent measurements have established that only the pyranose fonns of D-glucose are present in significant quantities at equilibrium. 

Maltose and cellobiose are both reducing sugars because the anomeric carbons on the right-hand glucopyranose units have hemiacetal groups and are in equilibrium with aldehyde forms. For a similar reason, both maltose and cellobiose exhibit mutaiotation of a and /3 anomers of the glucopyranose unit on the right. 

Hall et al.1 s estimated the conformational equilibrium for the structural units in the polymer of 2 using the numerical parameters determined for carbohydrates16. For a frans-l,3-tetrahydropyranoside, conformer 8 is calculated to be more stable than 7 by 9.2 kJmol-1 and would therefore occur almost exclusively (ca. 98%) at equilibrium. For a m-1,3-tetrahydropyranoside unit, the anomeric effect favors con-former 9, but its severe syn-axial interaction between alkoxy and alkyl groups would highly favor 10 (ca. 99%). 

In solution, most simple sugars and many of their derivatives occur as equilibrium mixtures of tautomers. The presence of a mixture of two anomers of the same ring size may be indicated in the name by the notation a,P-, e.g. a,P-D-gIucose. In formulae, the same situation can be expressed by separating the representation of the ligands at the anomeric centre from the a and P bonds [see examples (a) and (c)], or by use of a wavy line [(b) and (d)] (particularly if hydrogen atoms are omitted). 

The ratio of the different isomeric products was found to vary with time, temperature, and initial concentration. This suggested that some kind of equilibration was occurring between isomers. I3C NMR spectroscopy of a reaction mixture showed, upon cooling, the reversible formation of a pair of signals in the anomeric region. These signals were ascribed to the anomeric carbon atoms of fructofuranosyl fluorides (10), which were presumed to be in equilibrium with the reactive fructofuranosyl cation, 11. 

The reversible reactions are initiated by an equilibrium between neutral and ionized forms of the monosaccharides (see Fig. 6). The oxyanion at the anomeric carbon weakens the ring C-O bond and allows mutarotation and isomerization via an acyclic enediol intermediate. This reaction is responsible for the sometimes reported occurrence of D-mannose in alkaline mixtures of sucrose and invert sugar, the three reducing sugars are in equilibrium via the enediol intermediate. The mechanism of isomerization, known as the Lobry de Bruyn-... 

The problems of anomeric equilibrium may be avoided by investigating 2-ketoses. Both a hydroxyl group and a hydroxymethyl group are attached to the anomeric carbon atom in such sugars, and the bulky hydroxymethyl group favors the equatorial position. These authors measured c.d. spectra for three ketoses, the 2-(hydroxymethyl) derivatives of a-L-xylose, a-D-xylose, and a-D-mannose, in aqueous solution. 

Acetamido-2-deoxy-D-galactopyranose (—), and 2-Acetamido-2-deoxy-D-mannopyranose ( ) at Anomeric Equilibrium in Aqueous Solution (redrawn from Ref. 28), and 2-Acetamido-2-deoxy-D-glucopyranose (- -) at Anomeric Equilibrium in Aqueous Solution. (Redrawn from Ref. 29.)... 

However, workers do not agree as to the shape of the c.d. spectrum for these sugars at shorter wavelengths, as Fig. 15 demonstrates. The correct spectrum still remains an open question, but the intense c.d. band expected at 190 nm for the amide mr c.d. bands are of opposite sign for the two anomers and nearly cancel in the equilibrium mixture. Thus, differences in the anomeric mixtures could explain differences in the c.d. spectra. The amide irir c.d. band is obvious for the anomeric mixture from 2-acetamido-... 

Hultiple products are frequently observed for the separation of TMS-sugar derivatives. At equilibrium reducing sugars can exist in more than one isomeric form known as anomers. Formation of their THS derivatives followed by gas chromatography will result in multiple peaks corresponding in composition to the equilibriue anomeric mixture [436]. 

The authors also evidenced an increase of the percentages of a-talo-pyranose and a-ia/ofuranose upon 2H substitution at C(l) concomitantly with a decrease of the percentages of (l-conformers. This observed shift on the talopyranose anomeric equilibrium was attributed to the preference of the shorter C-2H bond (relative to the C l l bond) to assume an equatorial orientation. 

In the case of 2-hydroxytetrahydropyran, the axial conformer 22 is calculated to be more stable than its equatorial conformer 23 in vacuum (Fig. 12). Solvent effects change the equilibrium constant and the equatorial form 23 is favored in aqueous solution, in agreement with data. The magnitude of the conformational endo-anomeric effect in 22 is estimated to 2.0 kcal/mol (gas phase stereoelectronic effects overwhelming the steric... 

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. 

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