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.

轴手性吲哚类骨架（axially chiral indole-based frameworks）广泛存在于天然产物、生物活性分子以及手性配体中。因此，开发用于全新构建此类骨架的催化不对称阻转选择性（atroposelective）方法，具有极高的应用价值。
本文报道了一种阻转选择性有机/金属联合双催化策略，用于全新构建高价值轴手性吲哚类骨架。该催化体系采用1 mol%的两种手性磷酸与1 mol%的硝酸银（AgNO3）组合而成，并基于我们近期报道的C-炔基N,O-缩醛（C-alkynyl N,O-acetals）与2-萘胺（2-naphthylamines）之间尚未见诸报道的分子间环加成-异构化反应。
研究成功以良好的收率和对映选择性，得到了一类此前难以获取的重要C-N轴型轴手性吲哚化合物。
所得轴手性吲哚还可作为平台分子，用于催化剂控制下的双C-N轴轴手性吲哚的阻转选择性合成——此类化合物通过现有合成方法极难获得。
本研究同时也是2-萘胺作为1,3-双亲核试剂以及环加成反应中三原子CCN合成子（CCN synthons）应用的典型范例。