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.