Reengineered BI-DIME Ligand Core Based on Computer Modeling to Increase Selectivity in Asymmetric Suzuki-Miyaura Coupling for the Challenging Axially Chiral HIV Integrase Inhibitor

Through a computer-guided approach, new series of monophosphine ligands were designed and developed for asymmetric Suzuki-Miyaura couplings of challenging heterocyclic substrates. Computer modeling pointed to a tunable, yet unexplored quadrant in BI-DIME, leading to the discovery of the 3',5'-dimethyl-substituted ligand which improved the atropisomeric selectivity of the Suzuki-Miyaura reaction from the previously reported 5: 1 dr to 15: 1 dr for the synthesis of a challenging HIV integrase intermediate, and up to 24: 1 dr with various other quinoline substrates.