Construction of Axially Chiral Indoles by Cycloaddition-Isomerization via Atroposelective Phosphoric Acid and Silver Sequential Catalysis

Axially chiral indole-based frameworks occur in natural products, bioactive molecules, and chiral ligands. Thus, the development of catalytic asymmetric atroposelective approaches for de novo construction of these frameworks is highly valuable. Here, the atroposelective organo/metal combined dual catalysis strategy for de novo construction of valuable axially chiral indole frameworks has been developed. This protocol utilized a catalyst system of two chiral phosphoric acids (1 mol %) in combination with AgNO3 (1 mol %) and was based on the unreported intermolecular cycloaddition-isomerization reaction of our recently introduced C-alkynyl N,O-acetals and 2-naphthylamines. An important class of hitherto inaccessible axially chiral indoles with a C-N axis were obtained in good yields and enantioselectivities. The axially chiral indoles obtained also provided a platform for the catalyst-controlled atroposelective synthesis of axially chiral indoles bearing two C-N axes, which are difficult to access by the existing methods. This work is also an example of 2-naphthylamines used as 1,3-dinucleophiles and three-atom (CCN) synthons in cycloadditions.