Palladium Catalysis Featuring Attractive Noncovalent Interactions Enabled Highly Enantioselective Access to fl-Quaternary ?-Lactams

Described herein is a highly enantioselective route to beta-quaternary (5-lactams by palladium/pyridine-dihydroisoquinoline (PyDHIQ)-catalyzed conjugate arylations. Notably, the effect of pi-interactions on the high enantioselectivity was elucidated by DFT calculations and noncovalent interaction (NCI) analysis. The skeleton of the PyDHIQ ligand plays a key role in the formation of attractive noncovalent interactions with substrates in an enantioselectivity-determining step. The developed methodology was successfully applied to the asymmetric formal synthesis of (-)-picenadol.

Automated summary

A highly enantioselective route to beta-quaternary (5-lactams) was described using palladium/pyridine-dihydroisoquinoline (PyDHIQ)-catalyzed conjugate arylations. The effect of pi-interactions on the enantioselectivity was elucidated, and the PyDHIQ ligand was found to play a crucial role in determining the enantioselectivity through attractive noncovalent interactions with substrates. The methodology was successfully applied to the asymmetric formal synthesis of (-)-picenadol.