One-Pot Multisubstrate Screening for Asymmetric Catalysis Enabled by ¹⁹F NMR-Based Simultaneous Chiral Analysis

Exploring a diverse chemical space is essential for advancing asymmetric synthesis. The complexity of the chirality-determining processes often requires resource-intensive optimization campaigns across multiple substrates. Although one-pot multisubstrate screening offers a promising solution for high-throughput screening (HTS), a persistent challenge lies in the accurate and efficient analysis of complex reaction mixtures, which has traditionally relied on chromatography-based techniques with limited resolution. In this work, we present a rapid multisubstrate screening workflow that utilizes ¹⁹F NMR spectroscopy for simultaneous chiral analysis. By employing an NMR-shifting cobalt reagent, we accurately determined both yields and enantiomeric excesses for up to 21 different substrates in a single reaction mixture during the ruthenium-catalyzed asymmetric reductive amination of ketones. This method facilitates precise chiral analysis through dynamic peak shifts and splitting in ¹⁹F NMR spectra induced by the shift reagent. This approach accelerates the evaluation of structure-selectivity relationships, offering valuable mechanistic insights into enantio-determining processes.