A True Reverse Anomeric Effect Does Exist After All: A Hydrogen Bonding Stereocontrolling Effect in 2-Iminoaldoses

J Org Chem. 2024 May 16. doi: 10.1021/acs.joc.4c00562. Online ahead of print.

Abstract

The reverse anomeric effect is usually associated with the equatorial preference of nitrogen substituents at the anomeric center. Once postulated as another anomeric effect with explanations ranging from electrostatic interactions to delocalization effects, it is now firmly considered to be essentially steric in nature. Through an extensive research on aryl imines from 2-amino-2-deoxyaldoses, spanning nearly two decades, we realized that such substances often show an anomalous anomeric behavior that cannot easily be rationalized on the basis of purely steric grounds. The apparent preference, or stabilization, of the β-anomer takes place to an extent that not only neutralizes but also overcomes the normal anomeric effect. Calculations indicate that there is no stereoelectronic effect opposing the anomeric effect, resulting from the repulsion between electron lone pairs on the imine nitrogen and the endocyclic oxygen. Such data and compelling structural evidence unravel why the exoanomeric effect is largely inhibited. We are now confident, as witnessed by 2-iminoaldoses, that elimination of the exo-anomeric effect in the α-anomer is due to the formation of an intramolecular hydrogen bond between the anomeric hydroxyl and the iminic nitrogen, thereby accounting for a true electronic effect. In addition, discrete solvation may help justify the observed preference for the β-anomer.