2-Alkoxytetrahydropyrans, anomeric effect

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 greater stability of the axial conformer of 2-alkoxytetrahydropyrans, ascribed to the anomeric effect, has been confirmed by a combined NMR and dipole moment investigation (69T3365). Additionally, out of the six conformers which in principle can arise from rotational isomerism about the exocyclic C—OR bond, two were shown to predominate in the equilibrium mixture. 

The very marked anomeric effect shown by 2-alkoxytetrahydropyran-3-ones (199) has been interpreted in terms of stabilizing orbital interactions (77NJC79). The influence of the heteroatom and the carbonyl group on the stabilization of the conformer in which the alkoxy group is axial is apparent. 

On the basis of the above results and discussion, the glycosides can now be considered. Efforts have been made previously to evaluate the magnitude of the anomeric effect by undertaking equilibration studies between equatorial and axial isomers at the anomeric center in carbohydrates (48), in monosubstituted 2-alkoxytetrahydropyrans (49, 50) and in more rigid systems (51). The anomeric effect has been evaluated to be of the order of 1.2 to 1.8 kcal/mol from these studies. In these evaluations, the conformation of the OR group in the axial and in the equatorial isomer was not considered the influence of the exo-anomeric effect was therefore neglected (3). Nevertheless, these studies demonstrated the importance of the anomeric effect. 

In some sugars, e.g. D-glucose, and 2-alkoxytetrahydropyrans, the axial form is populated to a greater extent than the axial population of the corresponding cyclohexane would suggest. This is known as the anomeric effect and two possible contributory factors were discussed. 

Finally, it must be noted that the conformational behavior characteristic of the exo anomeric effect could be reproduced not only by MO calculations but also using molecular mechanics methods, as was shown by Navio and Molina (105) for twelve 2-alkoxytetrahydropyran derivatives 38 (Figure 6) (see Section III.A.6). 

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