Practical Rh–ZhangPhos Catalyzed Asymmetric Hydrogenation of Enamides: From Scalable Access to Mechanistic Insight

Herein, we report a simple, one-pot, scalable process for the preparation of a series of enamides, which were subsequently hydrogenated with high efficiency and excellent enantioselectivity to the corresponding chiral amides using the Rh-ZhangPhos catalyst. This methodology is practical and facilitates easy postreaction handling, with the hydrogenation providing nearly perfect stereoselectivity. DFT studies uncovered distinct rate-determining steps for competing enantiomeric pathways: migrational insertion for the major product and reductive elimination for the minor product, challenging conventional assumptions of a unified mechanistic origin. Noncovalent interaction analysis, particularly steric repulsion in the reductive elimination step, offers a theoretical rationale for long-standing empirical strategies in bisphosphine ligand design, bridging experiment, and computation in asymmetric hydrogenation.