Rhodium/Bisphosphine-Thiourea System Catalyzed Asymmetric Hydrogenation of α,β-Unsaturated γ-Lactams

Chiral γ-lactams represent an important class of five-membered nitrogen-containing heterocyclic scaffolds, widely found in natural products and bioactive drug molecules. Although multiple strategies exist for constructing this scaffold, asymmetric catalytic hydrogenation is regarded as the most direct and efficient approach owing to its atom economy and step simplicity. Here, we report a Rh/bisphosphine-thiourea catalytic system successfully applied to the asymmetric hydrogenation of various N-substituted α,β-unsaturated γ-lactams, including chiral amino acid derivatives. Excellent enantioselectivity (up to 99% ee and 99:1 dr) and exceptionally high turnover numbers (TON up to 3000) were achieved. The method has been successfully applied to the gram-scale synthesis of key intermediates for pharmaceutically relevant compounds, including brivaracetam, (R)-pregabalin, and (R)-baclofen, demonstrating its potential for application in pharmaceutical manufacture.