Dynamic Kinetic Resolution of Carboxylic Esters Catalyzed by Chiral PPY N‑Oxides: Synthesis of Nonsteroidal Anti-Inflammatory Drugs and Mechanistic Insights

Bifunctional chiral 4-pyrrolidinopyridine (PPY) N-oxides catalyzing the dynamic kinetic resolution of racemic carboxylic esters was reported to construct chiral α-aryl α-alkyl carboxylic esters in up to 93% yield and 99% ee. Several esters of nonsteroidal anti-inflammatory drugs (NSAIDs), including (S)-ibuprofen ester, (S)-ketoprofen ester, (S)-fenaprofen ester, and (S)-flurbinprofen ester, were obtained. Additionally, the drug molecule (S)-naproxen could be achieved by hydrogenation of (S)-naproxen ester. The (S)-naproxen ester was prepared on a gram scale in 87% yield and 94% ee. The catalyst was recyclable and reusable. Mechanistic studies were conducted by control experiments, HRMS analysis, 1H NMR spectral detection, stereochemical experiments, racemization studies, competitive experiments, a linearity relationship determination, a kinetic order analysis, and a DFT computational study. The obtained results suggested that in PPY N-oxides the oxygen atom served as the nucleophilic site and N–H bond acted as the H-bond donor, resulting in a synergistic effect. In comparison with previous works using nitrogen or carbon as the nucleophilic sites, we found that chiral PPY N-oxides with oxygen as the nucleophilic site could also catalyze such reactions.