Dual Catalytic Synthesis of Antiviral Compounds Based on Metallocarbene-Azide Cascade Chemistry

Aryl azides trap ortho-metallocarbene intermediates to generate indolenones possessing a reactive C-acylimine moiety, which can react with added indole nucleophiles to afford the 2-(3-indolyl)indolin-3-one scaffold found in the antiviral natural product isatisine A. This overall process occurs through a dual catalytic sequence at room temperature. Redox activation of the Cu(OTf)₂ precatalyst by indole results in catalytically competent Cu(I) required for azide-metallocarbene coupling. The Brønsted acid that is also formed from Cu(OTf)₂ reduction is responsible for catalysis of the C-C bond-forming indole addition step. This modular, procedurally simple method allows for rapid assembly of bis(indole) libraries, several of which proved to have anti-infective activity against respiratory syncytial virus and Zika virus.