Origin and Stabilization of Axial Chirality on the Construction of Naphthyl C2 Indoles: A DFT Study

The origin and maintenance of axial chirality on the construction of naphthyl-C2-indoles via the asymmetric annulation of ortho-alkynylaniline catalyzed by a chiral Bronsted base (cinchonine-thiourea) have been systematically explored by density functional theory (DFT). Several key processes are included in the general mechanism of this kind of reaction, i.e. hydrogen bond adsorption of the ortho-alkynylaniline by catalyst, proton transfer for forming ortho-quinone methide (VQM) intermediate, intramolecular cyclization, release of catalyst to generate R- or S-axial-chiral aryl-C2-indole skeletons. The stereoselectivity-determining steps were identified, and the calculated results show that the pathway associated with the R-configurational isomer has the lower energy barrier, so the corresponding product should be the main one. Non-covalent interaction and atom-in-molecule analyses indicate that the N-H⋯O, C-H⋯π and π⋯π interactions paly the important roles in controlling the stereoselectivity. Multiple processes and different substituents were employed to compute the energy barriers for transformation between R- and S-configurational isomers, which discloses that the volume of the substituents would be the key for maintaince of the high axial chirality. The obtained insights on the origin for generating and stabilizing the high axial chirality would be valuable for the rational design of more efficient organocatalytic reactions.