A revisit to proline-catalyzed amination under basic conditions: Insight into the key intermediates and stereocontrolling transition state models for the reversal of enantioselectivity

- We perform SMD/mPW1K study of proline-promoted amination in the presence of DBU.
- TS involving prolinate-DBUH+ can reproduce the reversal of enantioselectivity.
- Activation strain analysis is employed to account for the origin of selectivity.

Density functional calculations have been performed to revisit the reversal of the product enantioselectivity in proline-catalyzed amination between propanal and diethylazodicarboxylate under basic conditions. The efficiencies of three stereodetermining transition state models, involving the key intermediates with different nucleophilic natures e.g. enamine carboxylic acid, enamine carboxylate, and prolinate-DBUH+ to mimic the base-free and basic conditions, are examined at the SMD/mPW1K/6-31+G∗∗ computational level. The activation strain analysis has been employed to explain the stereoselectivity associated with different models. The TS model involving the experimentally validated ion pair intermediate of prolinate-DBUH+ as the key nucleophile in the CN bond formation step exhibits good performance in reproducing the observed reversal of enantioselectivity when switching the conditions from base-free to base-present. The computations support the idea that the simple acid/base manipulation can change the active intermediates and subsequently alter the asymmetric induction strategy in the stereodetermining step.