DFT‐assisted rational design of salan ligands for highly enantioselective Zr–salan‐catalyzed hydroxylation of cyclic β ‐keto esters

Abstract In this work, a structurally simple, inexpensive, and readily accessible Zr–salan catalytic system was designed and developed with the aid of density functional theory (DFT) calculations. Density functional theory studies revealed that stereocontrol arises primarily from the steric shielding and noncovalent interactions of the salan ligand, rather than diaryl structural motifs, enabling the rational design of an economically efficient ligand framework. This strategy eliminates the reliance on Suzuki–Miyaura coupling by employing a commercially available sterically hindered ligand intermediate. The resulting Zr–salan catalyst exhibits excellent asymmetric catalytic performance, delivering yields of up to 99% and enantiomeric excesses (ee) of 99% across a broad substrate scope of 44 examples, including β ‐keto esters derived from 1‐indanone and 1‐tetralone. Further DFT investigations indicate that weak noncovalent interactions (C–H···C–H) between the Zr catalyst and the substrate play a crucial role in the reaction mechanism, providing insight into the origin of the high enantioselectivity. The synthetic practicality of this method was demonstrated through gram‐scale reactions, catalyst recyclability over five cycles, and product derivatization.