Effect, anomeric

FIGURE 1.10 The anomeric effect, (a) The n-o interaction stabilizes the a anomer. (b) The P anomer experiences unfavorable dipole-dipole interaction that is reduced in the a anomer. (c) Greater electrostatic repulsion between the lone-pair electrons of the endocyclic oxygen and the electronegative anomeric substituent in the (1 anomer. 

To see the relationship between the Bohlmann effect and the anomeric effect we can look at the valence bond stractures for methylamine and dimethoxymethane. Structure 4  

As one of a number of such examples, the a-form of d-glucose (36%) is more abundant with respect to the fi-form (64%) than expectations based on substituents in cyclohexane would indicate. This unexpected abundance of the a-form is known as the anomeric effect, 

Both 42 and 44 have been isolated as separate compounds. The a-anomer 42 has [a]D = +112.2 and the p-anomer 44 has [a]D = + 18.7. When either anomer is dissolved in water, it is slowly converted into the equilibrium mixture of anomers which has [a]D = +52.6. With this information it is possible to determine the ratios of a- and p-anomers at equilibrium. If is the percentage of a-anomer, one can write x x 112.2 + (100 - x) x 18.7 = 100 x 52.6. Solving for x gives x = 36.2%. With the justified assumption that the concentration of the open-chain form is ca. 0%, it follows that the amounts of the cyclic forms present at equilibrium are 42 (a-form) 36.2% and 44 (P-form) 63.8%. 

Similar behaviour, again mediated by an open-chain aldehyde form, has been observed with the related sugar D-mannose, in which the cc-anomer 45 (69%) now predominates over the (3-anomer 46 (31%). 

A further example is provided by the methyl mannosides 47 and 48. In 1% methanolic HC1, equilibration of the anomers was achieved and the ratio a 3 = 94 6 (see Senderowitz et al.5). 

In these and other examples, the percentage occupancy of the axial position by OH, OMe, OCOMe and Cl significantly exceeds expectations based on the corresponding cyclohexyl derivatives (see Table 6.2 for a list of substituent A values). This excess population of the axial position, first observed with sugars, is known as the anomeric effect it is exhibited only by electronegative substituents. 

Kuchitsu, M. Nakata, and S. Yamamoto, in Stereochemical Applications of Gas-Phase Electron Diffraction , eds. I. Hargittai and M. Hargittai, VCH, New York, 1988, pp. 227-263. 

L nczos, Applied Analysis , Prentice-Hall, Englewood Cliffs, NJ, 1956. 

Potential Energy Hypersurfaces , Elsevier, New York, 1987. 

Bartell, D. J. Romenesko, and T. C. Wong, in Specialist Periodical Reports. Molecular Structure by Diffraction Methods , Chemical Society, London, 1975, Vol. 3. 

Teukolsky, W. T. Vetterling, and B. P. Flannery, Numerical Recipes , Cambridge Academic Press, New York, 1994, 2nd. edn. 

---

The anomeric effect is best explained by a molecular or bital analysis that is beyond the scope of this text... 

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... 

Anomeric effect (Section 25 8) The preference for an elec tronegative substituent especially a hydroxyl group to oc cupy an axial orientation when bonded to the anomeric carbon m the pyranose form of a carbohydrate Anti (Section 3 1) Term describing relative position of two substituents on adjacent atoms when the angle between their bonds is on the order of 180° Atoms X and Y m the structure shown are anti to each other... 

An electronegative substituent adjacent to a ring oxygen atom also shows a preference for an axial orientation. This is known as the anomeric effect , and is particularly significant to the conformations of carbohydrates (B-71MI20100, B-83MI20100). 

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. 

Several structural factors have been considered as possible causes of the anomeric effect. In localized valence bond terminology, it can be recognized that there will be a dipole-dipole repulsion between the polar bonds at the anomeric carbon in the equatorial conformation. This dipole-dipole interaction is reduced in the axial conformation, and this factor probably contributes to the solvent dependence of the anomeric effect. 

The anomeric effect is also present in acyclic systems and stabilizes conformations that allow antiperiplanar (ap) alignment of the C—X bond with a lone-pair orbital of the heteroatom. Anomeric effects are prominent in determining the conformation of acetals and a-alkoxyamines, as well as a-haloethers. MO calculations (4-3IG) have found 4kcal/mol as the difference between the two conformations shown below for methoxy-methyl chloride. ... 

The preference for the gauche arrangement is an example of the anomeric effect. An oxygen lone pair is anti to fluorine in the stable conformation but not in the unstable conformation. 

Even molecules as simple as dimethoxymethane give evidence of anomeric effects. The preferred conformation of dimethoxymethane aligns each C—O bond with a lone-pair orbital of the adjacent oxygen. ... 

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. 

Many examples of reactivity effects that are due to the anomeric effect have been identified. For example, Cr03 can oxidize some pyranose acetals, leading eventually to ketoesters. 

Gluconolactone shows no exchange. The reason is that the tetrahedral intermediate is formed and breaks down stereoselectively. Even though proton exchange can occur in the tetrahedral intermediate, the anomeric effect leads to preferential loss of the axial oxygen. 

E. Juaristi and G. Cuevas, The Anomeric Effect, CRC Press, Boca Raton, Florida, 1995. 

A. J. Kirby, The Anomeric Effect and Related Stereoelectronic Effects at Oxygen, Springer-Verlag, New %rk, 1983. 

Anomeric effect (Section 25.8) The preference for an electronegative substituent, especially a hydroxyl group, to occupy an axial orientation when bonded to the anomeric carbon in the pyranose form of a carbohydrate. 

The six-membered rings 8.12a and 8.12b adopt chair conformations with all three halogen atoms in axial positions. This arrangement is stabilized by the delocalization of the nitrogen lone pair into an S-X a bond (the anomeric effect) All the S-N distances are equal within experimental error [ld(S-N)l = 1.60 (8.12a)/ 1.59 A (8.12b) ]. 

Anomeric effect of monosaccharides and their derivatives insights from the new QVBMM (quantized valence bond molecular mechanisms) molecular mechanics force field 98H(48)2389. 

Reaction of 3-amino-1-propanol and 5-bromo-5-deoxy-D-furanoxylose (25) in D2O was monitored by NMR (Scheme 4). The a-anomer of trihydroxypyridoPd-f l-LbSloxazine 26 formed 20 times faster, but the /3-anomer 27 was more stable (A / 7.3). The faster formation of the Q -anomer is a consequence of a kinetic anomeric effect that destabilizes the transition state for equatorial A -alkylation and formation of the /3-anomer 27 (OOJOC889). 

The general features of the monensin synthesis conducted by Kishi et al. are outlined, in retrosynthetic format, in Scheme 1. It was decided to delay the construction of monensin s spiroketal substructure, the l,6-dioxaspiro[4.5]decane framework, to a very late stage in the synthesis (see Scheme 1). It seemed reasonable to expect that exposure of the keto triol resulting from the hydrogen-olysis of the C-5 benzyl ether in 2 to an acidic medium could, under equilibrating conditions, result in the formation of the spiroketal in 1. This proposition was based on the reasonable assumption that the configuration of the spiroketal carbon (C-9) in monensin corresponds to the thermodynamically most stable form, as is the case for most spiroketal-containing natural products.19 Spiro-ketals found in nature usually adopt conformations in which steric effects are minimized and anomeric effects are maximized. 

For oxathiane 1, lone pair selectivity is controlled by steric interactions of the gem-dimethyl group and an anomeric effect, which renders the equatorial lone pair less nucleophilic than the axial lone pair. Of the resulting ylide conformations, 25a will be strongly preferred and will react on the more open Re face, since the Si face is blocked by the gem-dimethyl group (Scheme 1.9) [3, 15]. 

Donation from Lone-Pairs into Adjacent Antibonding Bond Orbitals, Anomeric Effect... 

It is interesting to speculate that asymmetric induction may be the consequence of the exo anomeric effect, a stereoelectronic effect that favors the conformation 5 that places the aglycone O-C bond antiperiplanar to the pyran C(1) —C(2) bond7fi. Related asymmetric induction has also been observed in aldehyde addition reactions of the related, but racemic, pinacol (Z)-y-(tetrahydropyranyloxy)allylboronate49. As indicated in the examples above, however, the level of diastereoselectivity is modest and the only application in asymmetric synthesis is Wuts exo-brevicomin synthesis75. 

---