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

Abstract

AbstractChiral 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 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 CuI‐catalyzed mechanism is the likely pathway in the catalytic reaction.