Enantioselective Ruthenium-Catalyzed Hydrogenation of Substituted 3-Acylamino Pyridinium Salts

Chiral amino-substituted piperidines are prevalent and privileged structural motifs in pharmaceuticals and bioactive compounds. Nevertheless, practical, atom-economical, and concise synthetic methods toward enantioenriched amino-substituted piperidines are still lacking. In this study, a highly efficient and enantioselective ruthenium-catalyzed asymmetric hydrogenation of readily available amino-substituted pyridinium salts is developed, providing a series of synthetically challenging chiral cis-3-amino-4-alkyl-substituted piperidines in good yields and enantioselectivities. The development of a sterically bulky AdP-tBuO-BIBOP ligand is crucial for the success of this transformation. Mechanistic study revealed that the hydrogenation proceeds through initial formation of 4-methylene-1,4-dihydropyridine intermediate, followed by tautomerization to form acylimine species, asymmetric reduction of acylimine, and finally diastereoselective hydrogenation. The method has enabled concise and practical syntheses of JAK inhibitors tofacitinib and ASP3627, as well as the key chiral piperidine intermediate of ent-ritlecitinib.