The conformational anomeric effect

As we shall see, the conformational anomeric effects can be assigned to stability difference between the various conformers that this ensemble of... 

The conformational anomeric effects design the contrasteric effects observed in acetals which render the more sterically encumbered gauche/ gauche conformers more stable than their anti/gauche and anti/anti conformers. Such effects were first evidenced by Jungins in 1905 and rediscovered by Edward in 1955 and by Lemieux and Chiu in 1958. They observed the higher stability of alkyl a-D-glucopyranosides in comparison with their (3-anomers (Fig. 5).8... 

Consequences of the conformational anomeric effect are largely expressed in monosaccharides and their derivatives. One recognizes the conformational endo-anomeric effect for pyranosides with a polar X group at C(l) (contrasteric electronic stabilization effect Fig. 7A) and conformational exo-anomeric effect for glycosides (acetals) in which the alkyl group of the exocyclic moiety is synclinal (Fig. 7B, C). 

The first interpretation of the conformational anomeric effect, given by Edward,2 invoked more favorable electrostatic interactions in the axial anomers than in the equatorial anomers of carbohydrates (Fig. 8). 

The rationalization of the conformational anomeric effect solely based on electrostatic interactions fails to account for these solvent effects. Another interpretation based on bond polarizability in 1,1-dialkoxyalkyl systems calls electronic transfer from a non bonding electron pair of one oxygen atom to the empty cr c 0 orbital from the other alkoxy substituent (Fig. 10).16... 

A proper analysis of the above results has to take into consideration the particular conformational properties of DFAs, which are governed by stereoelectronic effects. The relatively flexible 1,4-dioxane central ring adopts a chair or boat conformation for dispiro-DFAs having different or identical configuration at the anomeric centers, respectively, in order to place the oxygen substituents in pseu-doaxial orientation, fitting the conformational anomeric effect [47], and the carbon substituents in pseudoequatorial position (Fig. 2). 

Abe H, Shuto S, Matsuda A (2001) Highly a- and P-selective radical C-glycosylation reactions using a controlling anomeric effect based on the conformational restricrion strategy. A study on the conformation - anomeric effect - stereoselectivity relationship in anomeric radical reactions. J Am Chem Soc 123 11870-11882... 

The Ueno-Stork reaction is a radical cyclization of the a-haloacetal of an aUylic alcohol that provides substituted tetrahydrofuran and y-lactone derivatives. The chiral center of the aUylic moiety can control the stereochemical outcome, and the stereoselectivity may also be affected by the conformational anomeric effect. The Ueno-Stork radical cyclization has been applied in the synthesis of (-l-)-eldanolide (Scheme 25.22)," the pheromone of the male African sugarcane stem borer Eldana saccharina, in which bromoacetal 49 evolves to 50. The stereochemical outcome of these reactions is rationalized by a chair-like transition state, in which the adopted conformation maximizes the anomeric effect of the acetal center. 

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. ... 

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. 

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. 

The decrease of the anomeric effect in polar solvents was also supported by quantum mechanics calculations.13 Nevertheless further studies on the anomeric effect demonstrated the limitations of the electrostatic model. In particular, Juaristi et al.14 demonstrated that, at low temperature, the dependence of conformational equilibria of 2-carbomethoxy-l,3-dithiane upon solvent shows an opposite trend to the stronger anomeric effect in less polar media observed at 25 °C (Table 4). 

As conformational anomeric effects represent only a fraction (—1 to —3 kcal/mol) of the global enthalpic anomeric effect or gem-dioxy stabilizing effect (—6 to —17 kcal/mol), additional factors have to be taken into account. Depending on substitution, steric factors can affect the relative stability of acetal conformers. Dubois et al.2S have demonstrated that in furanose pyranose derivatives a bulky substituent at the furanose... 

In a study of the infrared spectra of acetylated and benzoylated gly-copyranosyl fluorides, it was found that, with few exceptions, such compounds exhibit an absorption band at 802-748 cm-1 if the fluorine atom is axial, whereas no such absorption band is observed if the fluorine atom is equatorial therefore, it is necessary to know the conformation of the molecule before the anomeric configuration can thus be determined.45 It is possible that reinterpretation of some of these observed absorptions may be necessary, because some of the conformations of some of the glycopyranosyl fluorides are now known to exist in the conformation opposite to that originally anticipated without proof, because of the strong anomeric effect of a fluorine substituent (see Section III,2e). 

In the conformational equilibrium (Fig. 22) for 5-methyldihydro-l,3,5,-dioxazine (454) the generalized anomeric effect favors the N-Meax conformer 455 and, in addition (relative to jV-Meax piperidine), 455 does not contain the two unfavorable syn-axial interactions involving the axial N-methyl... 

The successive change in position of the N-Mem N-Meeq equilibrium from that in 5-methyldihydro-l,3,5-dioxazine (AG° > 1 kcal mol-1) to 3-methyltetrahydro-l,3-oxazine (AG° 0.10 + 0.05 at — 120°C) to that (AG° —2.7 kcal mol-1) in 1-methylpiperidine results from successive differences of syn-axial interactions involving the axial methyl group and a favoring of the axial methyl conformer by the generalized anomeric effect. 

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