Research in the field of asymmetric catalysis over the past half century has resulted in landmark advances, enabling the efficient synthesis of chiral building blocks, pharmaceuticals, and natural products. A small number of asymmetric catalytic reactions have been identified that display high selectivity across a broad scope of substrates; not coincidentally, these are the reactions that have the greatest impact on how enantioenriched compounds are synthesized. We postulate that substrate generality in asymmetric catalysis is rare not simply because it is intrinsically difficult to achieve, but also because of the way chiral catalysts are identified and optimized. Typical discovery campaigns rely on a single model substrate, and thus select for high performance in a narrow region of chemical space. Here, we put forth a practical approach for using multiple model substrates to select simultaneously for both enantioselectivity and generality in asymmetric catalysis from the outset. Multisubstrate screening is achieved by conducting high-throughput chiral analyses via supercritical fluid chromatography-mass spectrometry (SFC-MS) with pooled samples. When applied to Pictet–Spengler reactions, the multi-substrate screening approach revealed a promising and unexpected lead for the general enantioselective catalysis of this important transformation.
Additional validation experiments, full experimental protocols, full high-throughput screening results, NMR spectra, and SMILES strings for in silico libraries.