Palladium Catalysis Featuring Attractive Noncovalent Interactions Enabled Highly Enantioselective Access to β-Quaternary δ-Lactams

Abstract

Described herein is a highly enantioselective route to β-quaternary δ-lactams by palladium/pyridine-dihydroisoquinoline (PyDHIQ)-catalyzed conjugate arylations. Notably, the effect of π-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. © 2022 American Chemical Society. All rights reserved.