Anomeric effect nature

Mo, Y. (2010). Computational evidence that hyperconjugative interactions are not responsible for the anomeric effect. Nature Chemistry, 2, 666-671. 

Assessment of the anomeric effect natural orbital analysis... 

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). 

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. 

Numerous literature references104 attest to the fact that the naturally occurring spiroketals and many synthetic products adopt conformations in which the anomeric effects are maximized and the steric effects are minimized. However, in some such compounds, the steric effects of bulky substituents and diaxial interactions can result in a conformation in which the anomeric effect cannot operate. 

New synthetic methods are the lifeblood of organic chemistry. Synthetic efforts toward natural products often provide the impetus for the development of novel methodology. Reactive synthons derived from 1,3-dioxanes have proven to be valuable intermediates for both syn- and anfz-1,3-diols found in many complex natural products. Coupling reactions at the 4-position of 1,3-dioxanes exploit anomeric effects to generate syu-1,3-diols (cyanohydrin acetonides), autz-1,3-diols (4-acetoxy-1,3-dioxanes), and either syn- or azztz-1,3-diols (4-lithio-1,3-dioxanes). In the future, as biologically active polyol-containing natural products continue to be discovered, the methods described above should see much use. 

In addition to solvolysis and nitrenium ion formation, Af-aLkoxy-A-chloroamides (2) also undergo bimolecular reactions with nucleophiles at nitrogen. Not only is the configuration destabilized by the anomeric effect, it also parallels that of a-halo ketones, where halogen on an sp carbon is activated towards reactions by the adjacent carbonyl. This rate-enhancing effect on 8 /2 processes at carbon is well-known, and has been attributed to conjugation of the p-orbital on carbon with the carbonyl jr-bond in the S 2 transition state stabilization of ionic character at the central carbon as outlined by Pross as weU as electrostatic attraction to the carbonyl carbon. The transition states are also affected by the nature of the nucleophile. ... 

The nature of the anomeric effect in the bicyclic /ra r-fused octahydro-l-methyl-l//-2,l-benzothiazine 2,2-dioxide 37 has been examined by single crystal X-ray structure analysis (Figure 5) <1998CJC164>. The crystal structure of 37 shows that the A -Me group assumes an axial position in the solid state. The authors suggest that this conformation is also the most stable in solution and propose that this hyperconjugation effect is >2.0 kcal mol . ... 

A number of fundamental studies of the nature of the anomeric effect have been undertaken, probed via kinetics and exo-/endo-regioselectivities. 

The presence of particular substituents and the nature of the solvent appear to have an effect on the equilibrium composition of particular monosaccharides. As already discussed, the anomeric effect is stronger in... 

An unambiguous success of the n-a overlap model of the anomeric effect is its ability to rationalise 35C1 nuclear quadrupole resonance frequencies in axial and equatorial glycopyranosyl chlorides (David, 1979). The axial chlorides invariably resonate at lower frequency, in accord with the more ionic nature of the C—Cl bond and hence the more spherically symmetrical distribution of electrons around the chlorine nucleus. 

There are many good ways to draw these conformations and yet more not quite so good. Make sure ou have each acetal oxygen atom axial on the other ring to enjoy the full anomeric effect op. 1128-31). We show three ways to draw each compound. The natural products are, in fact, the impounds in the frames according to R. Baker et al, ]. Chem. Soc., Chem. Commun., 1982, 601. 

Although the origin and nature of the anomeric and exo-anomeric effects appear well appreciated, the importance of these effects on conformational equilibria, especially with regard to the influence of the exo-anomeric effect on the conformational preferences about glycosidic linkages, is not well appreciated. This paper is concerned with experimental investigations which were designed to help clarify this situation. 

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