Inverse anomeric effect

D-(+)-galactose (15) is an example of the consecutive numbering of the carbon ring atoms in a monosaccharide (disaccharide see p. 253). Carbohydrates can exist in a cyclic and an acyclic structure. For this reason there is a special position in the structure of a monosaccharide, the carbon atom C-l and so called anomeric center. You can see that there is an equilibrium between er-anomer a-15 and / -anomer /3-15 of D-(+)-glucopyranose over the acyclic aldehyde structure 16. Both are cyclic hemi-acetals. The /Tanomer is the preferred conformation, but there are a few effects, like sterical or stereoelectronical effects (anomeric effect, inverse anomeric effect), which have influence on the a /i rate. 

The first precise evaluation (2A, 25) of both the anomeric and the exo-anomeric effects was obtained by studying 1,7-dioxaspiro[5.5]undecane (9) (Fig. 2). With this system, conformational analysis by low temperature nmr spectroscopy was possible because each conformational change involves a chair inversion which has a relatively high energy barrier. The steric effect could also be easily evaluated, and by adding appropriate alkyl substituents, it was theoretically possible to isolate isomeric compounds which would exist in different conformations. 

Some solvents may form complexes with the oxocarbenium ion intermediates, thereby affecting the anomeric outcome of a glycosylation. For example, diethyl ether is known to increase the a anomeric selectivity. Probably, diethyl ether participates by the formation of diethyl oxonium ion (Scheme 4.9a). The (3 configuration of this intermediate is favoured because of the operation of the reverse anomeric effect (see Chapter 1). Nucleophilic displacement with inversion of configuration will give an a glycoside. Recently, it was shown that a mixture of toluene and dioxane provides a more efficient participating solvent mixture. 

Finally, the simple nucleophilic amine Me2NH attacks the epoxide with inversion of configuration to give methyl mycaminoside. The conformational drawing shows that all substituents are equatorial except the MeO group, which prefers to be axial because of the anomeric effect. 

C-Glycosides.6 Axial C-glycopyranosides are obtained exclusively by photolysis of a mixture of an a-D-glycopyranosyl bromide, acrylonitrile, and tributyltin hydride. The diastereoselectivity may involve an anomeric effect or rapid trapping of the initial radical before inversion can occur. 

In contrast to the equilibrium for 466 and 467, the equilibrium in 2-methylperhydroimidazolo[l,5-a]pyridine (465 R = Me) shifts back towards the trans-conformer (> 98%). This shift must be due to stabilization of the trans-fused conformer by the generalized anomeric effect brought about by N-2 inversion, rather than by N-4 inversion as in 466 and 467. This is supported by the position of equilibrium (83% 480 17% 481) in 465 (R = Me) (87MI2). 

Solvents which are poor donors are commonly used in glycoside synthesis, for instance dichlorometh-ane, cyclohexane or petroleum ether. These solvents favor SN2-type reactions. Solvents which are better donors, for instance ethers (diethyl ether, THF, etc.), acetonitrile, pyridine, nitromethane etc., each result in a typical change in the reaction course due to their different participation in the stabilization of the reaction intermediates. With ethers, acetonitrile and pyridine participation leads to onium-type intermediates (Scheme 5 8 and 9), which eventually provide, via fast equilibration, mainly the -anomer (8), due to their higher thermodynamic stability, based on the inverse anomeric effect .Thus a-product formation is often favored in these solvents (see Section 1.2.3.2.5). Solvents with even higher dielectric constants commonly result in lower diastereocontrol in glycoside synthesis. 

The anomeric effect of halogens is too powerful for a conformation other than 2.23a to be observed in 2-haIooxanes. The evaluation is not based on a conformational equilibrium but rather on an equilibrated chemical reaction (2.6), the inversion of configuration at C-1 of the cis- (2.24c) and trans- (2.24t) 2-halo-4-methyloxanes catalysed by HCl (Anderson and Sepp 1967). 

What are the energy relations in the six-membered ring of pyranoid saccharides The energy difference of the axial and equatorial forms on the anomeric center is low, in the interval of 0-11 kJ.mol", depending on the medium (see Tables II, III, and VII). The interconformational (pseudorota-tional) barrier, AE, in six-membered rings is —42-46 kJ.moI". Some authors assumed an additional increase of the pseudorotational barrier due to the anomeric effect, but, in contrast, data for the ring inversion in... 

During this cyclodehydration, inversion of configuration occurred at CT of 751 to give the /3-D-C-nucleoside 752 rather than its a-anomer because of (i) preference of the protonated bulky heterocycle to occupy the equatorial j8 position in the (envelope) conformation (753) to gain the stabilization of the reverse anomeric effect, and (ii) destabilization of the conformation of the alternative a-anomer (754) by the nonbonded CM-l,3-diaxial interaction between the C3 hydroxyl and the bulky heterocycle (80MI8) (Scheme 195). 

It should be mentioned that the inverse (reverse ) anomeric effect has been postulated (183) recently for propanedinitrile CHjfCN) (95) and its derivatives, based on a synergistic destabilization by two geminal cyano substituents. The authors assumed that the anomeric effect always implies a stabilizing interaction between two substituents at an anomeric center (this assumption is not justified, see Section II.H) and a destabilizing interaction must therefore correspond to an inverse effect. However, such an assumption does not correspond to the definition of the anomeric (and reverse anomeric) effects, which is based on the relation between energies of conformers, not on the energy of interaction between substituents at an anomeric center. 

The electrostatic interpretation of the anomeric effect has generally been regarded as incomplete because it does not lead to quantitative agreement with experiment (188) and does not account for the observed geometries. In particular, dipole-dipole repulsive interactions have been criticized from the theoretical point of view on the basis of ab initio (189) and semiempirical EHMO and CNDO/2 calculations (190) and recently (191) based on the decreased barrier to ring inversion in 2,2-dimethoxyoxane (98, see Section... 

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