Dynamic Kinetic Resolution of Azlactones with Hydrazines via Negative Catalysis: Synthesis of α‑Chiral Amino Acid Hydrazides and Their Preferential Enrichment Phenomenon

Enantioselective nucleophilic ring-opening reactions of azlactones have been extensively investigated. However, using nitrogen nucleophiles for these reactions remains challenging because of their inherently high reactivity. Herein, we report the catalytic dynamic kinetic resolution of α-chiral azlactones using hydrazines as nucleophiles and bifunctional quinine-thiourea organocatalysts. The reactions proceeded under mild conditions and provided α-chiral amino acid hydrazides with excellent yields (up to 99%) and enantioselectivity (up to 99:1 enantiomeric ratio). Mechanistic studies revealed that the catalyst plays dual roles of enhancing the enantioselectivity and slowing down the reaction by modulating the hydrazine reactivity, which is a rare case of reaction rate suppression in asymmetric catalysis. Computational studies at the M06-2X/TZVP level elucidated the transition-state structures governing the stereocontrol, while independent gradient model analysis highlighted the key noncovalent interactions stabilizing the preferred transition state. Furthermore, a unique preferential enrichment phenomenon was observed during recrystallization, where the solution phase exhibited enhanced optical purity while the crystalline phase formed as a racemate. This work provides new insights into enantioselective negative catalysis and a promising strategy for the synthesis of α-chiral amino acid hydrazides.