A Rh(II)-Catalyzed Atropisomer Selective Ring Expansion of 3‑Aryl Indoles to 4‑Aryl Quinolines

Heterocycles containing
stereogenic axes are becoming increasingly
important throughout the drug discovery endeavor, and methodologies
that provide access to pharmaceutically relevant atropisomers are
in high demand. Herein, we report the rhodium(II)-catalyzed atropisomer
selective ring expansion of 3-aryl indoles with α-halodiazoacetates
to furnish 4-aryl quinolines in good yields and enantioselectivity,
with strong correlations between enantioselectivity and steric bulk
observed at different positions of the substrate. Computational studies
suggest that the chemistry proceeds via a Dynamic Kinetic Resolution
(DKR) process wherein the catalyst reacts preferentially with the Ra conformation of the rapidly racemizing 3-aryl
indole starting material to give a cyclopropanated indoline intermediate
that undergoes a Ciamician–Dennstedt-type ring expansion before
the intermediate’s prospective stereogenic axis can epimerize.
The utility of this skeletal transformation is further demonstrated
by the derivatization of enantioenriched products, granting access
to a structurally diverse array of enantioenriched quinolines.