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.

Automated summary

In this study, we developed a tool set to aid the search for optimal catalysts and represented discrete ligands as continuous variables using the virtual library kraken. By using dimensionality reduction and clustering techniques, we proposed a Phosphine Optimization Screening Set (PHOSS) consisting of 32 commercially available ligands, which completely and evenly samples the chemical space. We demonstrated the application of this screening set in identifying active catalysts for different cross-coupling reactions and showed how evenly sampling the chemical space facilitates the identification of active catalysts.