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Ligands are essential for controlling the reactivity and selectivity of transition metal-catalyzed reactions. Access to large phosphine ligand libraries has become an essential tool for the application of metal-catalyzed reactions industrially, but these existing libraries are not well suited to new catalytic methods based on non-precious metals (i.e., Ni, Cu, Fe). The development of the requisite nitrogen- and oxygen-based ligand libraries lags far behind phosphines and the development of new libraries is anticipated to be time consuming. Here we show that this process can be dramatically accelerated by mining a typical pharmaceutical compound library that is rich in heterocycles for new ligands. Using this approach, we were able to screen a structurally diverse set of compounds with minimal synthetic effort and identify several new ligand classes for nickel-catalyzed cross-electrophile coupling. These new ligands gave improved yields for challenging cross-couplings of pharmaceutically relevant substrates compared to previously published ligands.

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A practical synthesis of SGLT2 inhibitor candidate ertugliflozin (1) has been developed for potential commercial application. The highly telescoped process involves only three intermediate isolations over a 12-step sequence. The dioxabicyclo[3.2.1]octane motif is prepared from commercially available 2,3,4,6-tetra-O-benzyl-D-glucose, with nucleophilic hydroxymethylation of a 5-ketogluconamide intermediate as a key step. The aglycone moiety is introduced via aryl anion addition to a methylpiperazine amide. High chemical purity of the API is assured through isolation of the crystalline penultimate intermediate, tetraacetate 39. A cocrystalline complex of the amorphous solid 1 with L-pyroglutamic acid has been prepared in order to improve the physical properties for manufacture and to ensure robust API quality.