Elucidating the mechanism and origin of stereoselectivity in C-C bond formation under isothiourea and amine cooperative catalysis

Cooperative catalysis integrating chiral amine and isothiourea organocatalysts offers a promising yet underexplored strategy for stereodivergent C–C bond formation. However, the interplay of their orthogonal activation modes and the origins of stereoselectivity remain poorly understood. This study deciphers the cooperative interplay of chiral amine and isothiourea catalysts in stereodivergent Michael additions through DFT analysis. Activation of the α,β-unsaturated aldehyde forms an iminium intermediate and activation of an ester forms an ammonium enolate. Notably, the in situ generated C6F5OH plays a key role in facilitating dehydrolysis to form the iminium intermediate. Noncovalent interaction and AIM analyses demonstrate that Si-Re addition pathway dominates due to stabilizing noncovalent interactions (i.e., C-H···π and π···π interactions), favoring the RS-configured product. Furthermore, the FMO analysis identify that the implication of an amine with α,β-unsaturated aldehyde can largely lower the energy barrier of C-C bond formation step by lowering the LUMO energy of α,β-unsaturated aldehyde.