C2 Hydroxyl Group Governs the Difference in Hydrolysis Rates of Methyl-α-D-glycero-D-guloseptanoside and Methyl-β-D-glycero-D-guloseptanoside

A computational investigation into the hydrolysis of two methyl septanosides, methyl-alpha-D-glycero-D-guloseptanoside and methyl-beta-D-glycero-D-guloseptanoside was undertaken. These septanosides were chosen as model compounds for comparison to methyl pyranosides and allowed direct comparison of alpha versus beta hydrolysis rates for a specific septanoside isomer. Results suggest that hydrolysis takes place without proceeding through a transition state, an observation that was suggested in previous computational studies on exocyclic bond cleavage of carbohydrates. A conformational analysis of alpha- and beta-anomers 1 and 2 and their corresponding oxocarbenium 3, coupled with relaxed potential energy surface (PES) scans (M06-2X/6-311+G**, implicit methanol), indicated that hydrolysis of the alpha-anomer is favored by 1-2 kcal/mol over the beta-anomer, consistent with experiment. Model systems revealed that the lowest energy conformations of the septanoside ring system destabilize the beta-anomer by 2-3 kcal/mol relative to the alpha-anomer, and the addition of a single hydroxyl group at the C2-position on a minimal oxepane acetal can reproduce the PES for the septanoside 1. These results suggest that the C2 hydroxyl plays a unique role in the hydrolysis mechanism, destabilizing the septanoside via its proximity to the anomeric carbon and also through its interaction with the departing methanol from the alpha-anomer via hydrogen-bonding interactions.