| Abstract: | Theoretical calculations were performed to investigate the mechanism and enantioselectivity of cinchonine–thiourea‐catalyzed intramolecular hetero‐Diels–Alder cycloaddition of ethynylphenol derivatives to afford axial chirality naphthalenylpyran products via a vinylidene ortho‐quinone methide (VQM) intermediate. The results show that this transformation occurs through a reaction pathway involving the deprotonation of the naphthol moiety by the quinuclidine base, intramolecular proton transfer in ammonium naphthalenolate, and 4+2] cycloaddition. It is found that the axial chirality of the VQM intermediate is generated by the protonation step, which affects the enantioselectivity of the reaction. The enantioselectivity for the generation of the VQM intermediate is controlled by steric repulsion with the cinchonine framework, which provides an R‐axial chirality VQM as the major intermediate. Moreover, the enantioselectivity for the axial chirality of the naphthopyran product is controlled by the cycloaddition step, in which an extra hydrogen bond between the naphthalenol and cinchonine moieties leads to a favorable configuration for the generation of the S‐axial chirality naphthopyran product. The calculated enantioselectivity and enantiomeric excesses coincide with experimental observations. |
