Synthesis of Acyclic α-Quaternary Chiral Nitriles via Ni-Catalyzed Asymmetric Markovnikov Hydrocyanation of 1,1-Disubstituted and Trisubstituted Alkenes

The catalytic asymmetric Markovnikov hydrofunctionalization of minimally functionalized, multisubstituted alkenes to construct quaternary stereocenters in acyclic compounds represents a longstanding synthetic challenge in synthetic organic chemistry, primarily due to the high steric hindrance and limited spatial differentiation among substituents. To overcome this challenge, we develop a Ni-catalyzed asymmetric hydrocyanation of 1,1-disubstituted and <i>E</i>/<i>Z</i>-mixed trisubstituted alkenes by using a novel 3,3'- and 7,7'-binaphthol-based diphosphite, which delivers enantioenriched α-quaternary nitriles with high yields (up to 92%) and excellent enantioselectivity (up to 99:1 <i>er</i>). The transformation exhibits broad functional group tolerance and enables enantiodivergent synthesis by altering the C═C double bond positioning along the carbon chain in the substrate. The synthetic utility of this methodology is highlighted through the streamlined preparation of pharmaceutical intermediates and bioactive molecules, including a serotonin antagonist, underscoring its potential in drug discovery and stereoselective synthesis. In addition, computational studies reveal that catalytic environment is dictated by ligand dihedral angles modulated via noncovalent interactions, offering valuable insights for ligand design.