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

Chiral alpha,beta-unsaturated gamma-lactams bearing simple gamma- 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 gamma-substituted a,beta-unsaturated gamma-lactams via a Cu-catalyzed asymmetric boron conjugate addition, which also leads to the efficient synthesis of chiral beta-hydroxy-gamma-lactams with beta,gamma-stereogenic carbon centers. The KR proceeded smoothly with a wide range of gamma-alkyl or aryl substituted substrates including those bearing aromatic heterocycles and different N-protected 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 Cu-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.