Optimizing Phosphine Ligands for Ruthenium Catalysts in Asymmetric Hydrogenation of β-Keto Esters: The Role of Water in Activity and Selectivity

This study presents the development of ruthenium complexes with chiral phosphine ligands for the efficient asymmetric hydrogenation of β-keto esters in a continuous-flow reactor. By employing Bayesian optimization for multi-parameter screening, we identified the optimal Segphos-Ru catalyst and reaction conditions in just 48 experiments, enabling the preparation of the desired chiral alcohols in under 20 minutes. In addition, three catalysts from the Segphos-Ru catalyst were synthesized using various preparation methods, revealing distinct trends in activity and enantioselectivity with varying water content. Notably, the Ru@Seg III catalyst achieved the highest enantioselectivity (95%) at a water/substrate equivalency (v/v) of 0.2. Finally, the possible pathways of asymmetric hydrogenation catalyzed by the ionic hydrogenation catalyst in low-water organic media were elucidated using experimental data and density functional theory computations.