Chemoinformatic Catalyst Selection Methods for the Optimization of Copper–Bis(oxazoline)-Mediated, Asymmetric, Vinylogous Mukaiyama Aldol Reactions

Casey L. Olen, Andrew F. Zahrt, Sean W. Reilly, Danielle Schultz, Khateeta Emerson, David Candito, Xiao Wang, Neil A. Strotman, and Scott E. Denmark
ACS Catalysis 2024 14 (4), 2642-2655

DOI: 10.1021/acscatal.3c05903


A catalyst selection method for the optimization of an asymmetric, vinylogous Mukaiyama aldol reaction is described. A large library of commercially available and synthetically accessible copper–bis(oxazoline) catalysts was constructed in silico. Conformer-dependent, grid-based descriptors were calculated for each catalyst, defining a chemical feature space suitable for machine learning. Selection of a diverse subset of catalyst space produced an initial training set of 26 new bis(oxazoline) ligands that were synthesized and tested for stereoselectivity in the copper-catalyzed, vinylogous Mukaiyama aldol reaction for five substrate combinations. One ligand in the training set provided 88% average enantiomeric excess, exceeding the performance of catalysts identified through an initial optimization campaign. Supervised and unsupervised catalyst selection methods, including quantitative structure–selectivity relationship modeling, nearest neighbors analysis, and a focused analogue clustering strategy, were employed to identify an additional 12 new bis(oxazoline) ligands. The selected ligands outperformed the initial training set hit in four out of five product classes and in some cases demonstrated enantiocontrol exceeding 95% ee. The effectiveness of the unsupervised training set selection process is discussed, and the expediency of the nearest neighbor and focused analogue approaches are contrasted with the supervised quantitative structure–selectivity relationship modeling approach.


Example Python code, ligand descriptors, and raw data files can be found in the Git repository: