Acetals anomeric effect

Keywords Acetal, Anomeric effect, Diastereoselectivity, Glycosylation, Ion pair. Kinetic isotope effect, Stereoelectronic effects... 

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. 

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. 

The trans configuration of the nitrogen lone pair and the Nu fragment in nitroso acetals can be attributed to the anomeric effect of this pair (see Chart 3.23, b). 

Taken from NIST Chemistry Webbook. b Estimated from CH2(CN)2 adding -7 kcal/mol (exchange of a CH2 group by a CHMe group). c Enthalpy difference indicates a destabilization effect for gem-disubstitution with respect to alkanes. d Enthalpy difference shows a stabilization effect for gem-dialkoxy-disubstitution with respect to alkanes. c Enthalpy difference shows increases of enthalpic anomeric effect for tertiary acetals compared to secondary acetals. 

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). 

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... 

Stereoelectronic factors are also important in the conformational dynamics of acyclic acetals [6] (Cosse-Barbi and Dubois, 1986). Here the usual preference for staggered conformations is supplemented by the anomeric effect (Kirby, 1983), which favours the gauche stereochemistry ( = 60°) about both central C-O bonds, mainly because this allows optimal n-rr overlap between an oxygen lone pair and the antibonding (cr ) orbital of the C-0 bond. Thus the pathway for conformational isomerization suggested by... 

Carbohydrates have been included in the wide range of molecules used in the parameterization of MM2 and of MM3. Alcohol and ether parameters have usually been determined from simple alcohols and ethers themselves. However, carbohydrates contain some unusual features in the acetal linkages, and in the many vicinal hydrogen-bonded hydroxyl groups. The "anomeric effect", first discovered by Edward (15) and popularized by Lemieux (16.), is best known in carbohydrates, although, of course, it occurs in other classes of compounds as well. One apparent result of this effect is that an axial alkoxy substituent is often more stable than the corresponding equatorial substituent when attached at the Cl position of a tetrahydropyranyl ring. This effect can be... 

Another anomeric effect is that acetal C-0 bonds, and to a lesser extent, the bonds between acetal carbons and ether oxygens, are shortened or elongated as a function of their associated torsional angles. Jeffrey and Taylor modified MMl to account for these anomeric effects (17) and similar additions were put in the standard 1985 version of MM2 (11). The parameterization of MM3 for anomeric effects is preliminary, with recent (18-20) results being monitored. 

When reacted with an alcohol in the presence of a catalytic amount of a strong acid, 3,4-dihydro-2/f-pyran yields a base-stable 2-alkoxytetrahydropyran (a cyclic acetal) (Scheme 4.13). The reaction is reversed if the acetal is treated with aqueous acid (see Section 3.3.4, page 54), so that this provides a simple way of protecting alcohols in syntheses where a strong base might otherwise deprotonate them. The conformational preferences of 2-alkoxytetrahydopyrans, mediated by the anomeric effect, were commented upon earlier (Section 1.5.3). 

The C1-C15 fragment of spongistatin 1, comprising the AB-spiroacetal 4,10 exhibits an axial-axial disposition of the two acetal oxygen atoms at C7 and hence benefits from two stabilising anomeric effects (Figure 3). Based on this, it was expected that the correct spiroacetal would be... 

It is possible and probably very likely that both types of electronic effects are occurring in the acetal function. In other words, 2 could be more stable than 2 because 2 is stabilized relative to 2 by a partial electron transfer and 2 is destabilized relative to 2 by electronic repulsions. There is presently no experimental technique to differentiate between the two effects. At the present time, many chemists, including myself, prefer to consider the anomeric effect as a stabilizing rather than a destabilizing effect. The main reason is that the concept of stabilization of a system through electronic delocalization is a well established principle in organic chemistry. The resonance theory is indeed based on this principle. I believe that this concept rather than the dipole - dipole or electron pair - electron pair repulsions allows the organic chemist to rationalize his results better. 

As we have seen, the anomeric effect confers a double-bond character to each C—0 bond of conformer D the energy barrier for a C —0 bond rotation in acetals must therefore be higher than that observed in simple alkanes. Borgen and Dale (41) may have provided the first evidence for this point by observing that 1,3,7,9-tetraoxacyclododecane (37) has a much higher conformational barrier (11 kcal/mol) than comparable 12-membered rings such as cyclododecane (7.3 kcal/mol (42) or 1,4,7,10-tetraoxacyclododecane (5.5 and 6.8 kcal/mol (43)). It was also shown that the two 1,3-dioxa groupings in 37 exist in a conformation identical to that of dimethoxymethane, i.e. the conformation D. 

The preceding results demonstrate conclusively that the anomeric effect is important in the case of mono and dithioacetals. The following discussion will show that this effect is equally important in the case of an acetal function having one or two nitrogen atoms. 

Stereoelectronic effects have long been recognized to influence the configuration and the conformation of acetals, particularly in carbohydrates where these effects were first discovered and discussed in terms of the anomeric and the exo-anomeric effects (1-3). The term anomeric effect introduced by Lemieux in 1958 (A) refers to the tendency of an alkoxy group at C-l of a pyranose ring to assume the axial rather than the equatorial orientation despite unfavorable steric interactions, whereas the term exo-anomeric effect also introduced by the same author (5) concerns the preferred orientation of the 0-R bond of the alkoxy group at the anomeric center. 

The first precise evaluation of the anomeric effect was realized by Descotes and co-workers in 1968 (22). These authors have studied the acid catalyzed isomerization of the cis and trans bicyclic acetals 6 and 6 and found that, at equilibrium, the mixture contains 57% ci s and 43% trans at 80°C. The cis isomer is therefore more stable than the trans by 0.17 kcal/mol. The cis isomer 5 has one (stabilizing) anomeric effect whereas the trans isomer 6 has none. Steric interactions in cis acetal 5 were estimated tobel.65 kcal/mol (one gauche form of ri-butane, 0.85 kcal/mol and an OR group axial to cyclohexane, 0.8 kcal/mol). By subtracting an entropy factor (0.42 kcal/ mol at 80°C) caused by the fact that the cis acetal S exists as a mixture of two conformations (cis decalin system), they arrived at a value of 1.4 kcal/mol for the anomeric effect. 

Eliel and Giza (50) have studied the acid equilibration of the isomeric 2-alkylthio 6-methyltetrahydropyrans 59 and 60 (R=CHj and (CH3I3C). They found about 65% of axial isomer 59 indicating that the monothioacetal function possesses an anomeric effect although it is weaker than that of the acetal function. Zefirov and Skekhtman (58) have arrived at a similar conclusion by studying 2-phenylthio and 2-ethylthiotetrahydropyran. 

This last study is quite interesting because it permits an evaluation of the anomeric effect for the nitrogen atom. Conformer 91 with the axial N-methyl group should be less stable than conformer 92 by approximately 1.3 kcal/mol on the basis of steric effects (one gauche form of n-butane, =0.9 kcal/mol and one gauche form of CHj — N - CHj-0, =0.4 kcal/mol). The second anomeric effect caused by the equatorial orientation of the nitrogen electron pair in 91 must compensate for the steric effect. An approximate value of 1.3 kcal/mol must therefore be taken for that electronic effect, a value close to that estimated for the oxygen atom of the acetal function. 

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