Origin of Enantioselectivity in Chiral Phosphoric-Acid-Catalyzed Azlactone Dynamic Kinetic Resolution

Abstract

Theoretical calculations, associated with control experiments, were carried out to gain insights into the mechanism and origin of enantioselectivity in the phosphoric-acid-catalyzed dynamic kinetic resolution of azlactones. The results revealed a Münchnone intermediate as the key species involved in the isomerization of azlactone rings. The developed model was successfully employed in the comprehension and prediction of enantioselectivity under diverse of reaction conditions, including alcoholysis and aminolysis protocols.

Mechanism and Origin of Enantioselectivity in Bifunctional Squaramide‐Catalyzed α‐Thiolation of Azlactones

“…Finally, aiming to increase the accuracy of the predictions and evaluate further possibilities which might lead to lower energy reaction pathways, the reaction involving the formation of a Münchnone‐type intermediate was also evaluated (Step 2C – Scheme 2). This activation mode has been recently described by our research group as the most favorable during chiral phosphoric‐acid catalyzed dynamic kinetic resolution of azlactones by alcoholysis or aminolysis [19] . Notably, the barriers associated to this proposal were considerably lower than the previous models (only 6.74 kcal mol −1 for the R ‐product and 7.91 kcal mol −1 for the S ‐product), making it much more likely to occur.…”

“…This activation mode has been recently described by our research group as the most favorable during chiral phosphoric-acid catalyzed dynamic kinetic resolution of azlactones by alcoholysis or aminolysis. [19] Notably, the barriers associated to this proposal were considerably lower than the previous models (only 6.74 kcal mol À 1 for the R-product and 7.91 kcal mol À 1 for the S-product), making it much more likely to occur. Moreover, the correct enantiomer was predicted as the major product, with ΔΔG � = 1.17 kcal mol À 1 , which results in a theoretical e.e.…”

“…[16][17][18] This kind of activation mode has been proposed as the most plausible mechanism in recent studies involving azlactone ring transformations and has been attracting great interest in the literature. [19,20] Secondary interactions between the squaramide and the succinimide groups are also present in this proposal.…”

“…The last proposal (Step 2C) consists of a less common proposal involving the formation of a key interaction between the azlactone enolate nitrogen atom and the ammonium salt of the catalyst, resulting in a Münchnone‐type activation [16–18] . This kind of activation mode has been proposed as the most plausible mechanism in recent studies involving azlactone ring transformations and has been attracting great interest in the literature [19,20] . Secondary interactions between the squaramide and the succinimide groups are also present in this proposal.…”

“…This level of theory has been successfully employed in the determination of enantioselective transformations involving azlactones. [19] The energies were determined using a temperature of 303.15 K and a pressure of 1 atm, aiming to reproduce the experimental data conditions. [14] A preliminary conformational analysis of the TSs and MCs was carried out considering variations of the most relevant dihedral angles (for full details see the Supporting Information).…”