Cu‐Catalyzed Asymmetric Kinetic Boron Conjugate Addition of γ‐Substituted α,β‐Unsaturated γ‐Lactams

Abstract

Chiral α,β-unsaturated γ-lactams bearing simple γ-substituents are found in biologically active molecules and natural products, however, their synthesis still remains difficult. Herein, we report an efficient kinetic resolution (KR) of γ-substituted α,β-unsaturated γ-lactams via a Cu-catalyzed asymmetric boron conjugate addition, which also leads to the efficient synthesis of chiral β-hydroxy-γ-lactams with β,γ-stereogenic carbon centers. The KR proceeded smoothly with a wide range of γ-alkyl or aryl substituted substrates including those bearing aromatic heterocycles and different Nprotected substrates in up to 347 of s value. Their highly versatile transformations, synthetic utility in biologically active molecules, and inhibitory activities against cisplatin-sensitive ovarian cancer cell A2780 have also been demonstrated. Differing from the well-known mechanism involving CuÀ B species in Cu-catalyzed boron conjugate additions, our mechanistic studies using density functional theory (DFT) calculations and experiments indicate that a Lewis acid Cu I -catalyzed mechanism is the likely pathway in the catalytic reaction.