Modulating Stereoselectivity through Electrostatic Interactions in a SPINOL-Phosphoric Acid-Catalyzed Synthesis of 2,3-Dihydroquinazolinones

Chiral phosphoric acids have received considerable attention because of their excellent performance in many asymmetric catalytic reactions. However, the full breadth of means by which the stereoselectivity of these catalysts can be tuned has not been fully elucidated. Herein, the origin of enantioselectivity in a catalytic asymmetric synthesis of 2,3-dihydroquinazolinones using SPINOL-derived chiral phosphoric acids (ACS Catal. 2013, 3, 2244) is explored using density functional theory computations. We show that the enantioselectivity of this reaction is determined during the intramolecular amine addition step of an organocascade sequence and is modulated by differential noncovalent interactions of the substrate with the aryl groups of the catalyst as well as CH···O and NH···O interactions with the phosphate core of the catalyst. Most notably, we demonstrate that the strength of these latter interactions is modulated by their position within the electrostatic environment created by the catalyst. This provides clear evidence of the ability to precisely control the selectivity of an organocatalyzed reaction through the tuning of electrostatic interactions.