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

Abstract

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 the Si-Re addition pathway dominates due to stabilizing noncovalent interactions (i.e., C–H⋯π and π⋯π interactions), favoring the SR-configured product. Furthermore, the FMO analysis identifies that the involvement of an amine with an α,β-unsaturated aldehyde can largely lower the energy barrier of the C–C bond formation step by lowering the LUMO energy of the α,β-unsaturated aldehyde.