Ru-Catalyzed Asymmetric Hydrogenation of α,β-Unsaturated γ-Lactams

作者：Zheng‐Dong Ding, Yicong Luo, Qianjia Yuan, Guangjie Wang, Zhenpeng Yu, Min Zhao, Delong Liu, Wanbin Zhang · 发表于：Journal of the American Chemical Society · 年份：2024 · DOI：10.1021/jacs.4c09794 · 被引用次数：32 · 研究领域：Asymmetric Hydrogenation and Catalysis、Carbon dioxide utilization in catalysis、Catalysis for Biomass Conversion

A highly efficient Ru-catalyzed asymmetric hydrogenation of α,β-unsaturated γ-lactams has been developed by using a C 2 -symmetric ruthenocenyl phosphine-oxazoline as the chiral ligand. This method achieves the enantioselective synthesis of chiral β-substituted γ-lactams in high yields and with excellent enantioselectivities (up to 99% yield with 99% ee). Mechanistic studies based on detailed control experiments and computational investigation revealed that the cationic Ru-complex acts as the active catalytic species; the protonation process of the oxa-π-allyl-Ru complex, which is formed by the migratory insertion of the C=C double bond to the Ru–H bond (the stereocontrolling step) followed by an isomerization process, is the rate-determining step, and the existence of PPh 3 is crucial for the highly efficient catalytic behavior. The protocol provides a straightforward and practical pathway for the synthesis of key intermediates for several chiral drugs and bioactive compounds, particularly for the 150 kg-scale industrial production of Brivaracetam, an antiepileptic drug that shows 13-fold more potent binding to the synaptic vesicle protein 2A compared with the well-known Levetiracetam.