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

• Published in: Journal of organic chemistry Vol. 83; no. 13; pp. 6829 - 6842
• Main Authors: Atienza, Bren Jordan P, Jensen, Lionel D, Noton, Sarah L, Ansalem, Anil Kumar Victoria, Hobman, Tom, Fearns, Rachel, Marchant, David J, West, F. G
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 06-07-2018
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.8b00222

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.