Multi-substrate Screening for Asymmetric Catalysis Enabled by 19F NMR-based Simultaneous Chiral Analysis

Exploring a broad chemical space is essential for advancing asymmetric catalysis, but the intricate nature of chiral catalysts demands highly resource-intensive optimization processes. Multi-substrate screening offers a promising solution for high-throughput screening (HTS). However, analyzing complex mixtures remains challenging and typically relies on chromatography-based methods. This study introduces ¹⁹F NMR spectroscopy for simultaneous chiral analysis, enabling accurate determination of yield and enantiomeric excess in multi-substrate screening. Applied to the ruthenium-catalyzed asymmetric reductive amination of ammonia with twenty-one distinct ketones, this method enables precise simultaneous chiral analysis through NMR shift reagent-induced dynamic peak shifts and splitting in ¹⁹F NMR spectra. This approach enhances HTS by simplifying the analysis of complex mixtures, providing a powerful tool to accelerate the discovery of chiral catalysts and optimize asymmetric reactions.