Highly tunable artificial Suzukiase catalyzes the atroposelective synthesis of N -heterobiaryls

Enantiopure N -heterobiaryls are valuable motifs in medicinal chemistry and asymmetric catalysis. Yet, their atroposelective synthesis via Pd-catalyzed Suzuki–Miyaura cross-coupling remains challenging as Lewis-basic heterocycles can coordinate to the Pd catalyst and inhibit catalysis. Herein, we report an artificial Suzukiase based on a biotinylated dialkylbiarylphosphine-Pd cofactor embedded within a streptavidin scaffold (Sav). Anchoring of the Pd cofactor minimizes unproductive coordination by N -heterocycles, enabling atroposelective cross-coupling of otherwise challenging heteroaryl substrates. Chemo-genetic optimization was achieved by screening six biotinylated dialkylbiarylphosphine ligands combined with a 400-member double-site saturation Sav library. The resulting Suzukiases catalyze the atroposelective synthesis of diverse axially chiral N -heterobiaryls, including (iso)quinoline, pyridine, pyrimidine, and other pharmaceutically-relevant heterocyclic scaffolds. Stereodivergent access to either atropisomer was achieved through variation of the protein scaffold and the Pd cofactor. This study highlights how an engineered protein environment can minimize substrate-induced catalyst deactivation while providing tunable stereocontrol in asymmetric Pd-catalyzed cross-coupling.