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.