Transition metal–catalyzed cross-couplings have great potential to furnish complex ethers; however, challenges in the C(sp3)–O functionalization step have precluded general methods. Here, we describe computationally guided transition metal–ligand design … Transition metal–catalyzed cross-couplings have great potential to furnish complex ethers; however, challenges in the C(sp3)–O functionalization step have precluded general methods. Here, we describe computationally guided transition metal–ligand design … Science