Disclosing the Intra‐Catalyst Non‐Covalent Interactions in Tetrahydropyran‐Based Dipeptidic Catalysts

Herein, we describe how minor structural modifications to our bifunctional organocatalysts based on sugar amino acids (SAAs) can alter the network of non‐covalent interactions (NCIs) within the catalyst, leading to significant changes in their catalytic activity. This is attributed to the intra‐catalyst NCIs, which induce conformational changes that are reflected in the transition state of the rate‐determining step of the Michael addition of aldehydes to trans‐β‐nitrostyrenes. Through kinetic experiments, conformational analysis, and DFT calculations, we found that the presence of a methoxy group at the C4 position of the tetrahydropyran ring reduces the catalytic activity by a factor of five compared to the catalyst without the methoxy group. Additionally, we have identified the different intra‐catalyst NCIs, both attractive and repulsive, that drive the conformational changes, ultimately modifying the energy levels of the transition states of the rate‐ and enantioselectivity‐determining step of the reaction.