Design and Application of a Screening Set for Monophosphine Ligands in Cross-Coupling

In reaction discovery, the search space of discrete reaction parameters such as catalyst structure is often not explored systematically. We have developed a tool set to aid the search of optimal catalysts in the context of phosphine ligands. A virtual library, kraken, which is representative of the monodentate P­(III)-ligand chemical space, was utilized as the basis to represent the discrete ligands as continuous variables. Using dimensionality reduction and clustering techniques, we suggested a Phosphine Optimization Screening Set (PHOSS) of 32 commercially available ligands that samples this chemical space completely and evenly. We present the application of this screening set in the identification of active catalysts for various cross-coupling reactions and show how well-distributed sampling of the chemical space facilitates identification of active catalysts. Furthermore, we demonstrate how proximity in ligand space can be a useful guide to further explore ligands when very few active catalysts are known.