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

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journal contribution
posted on 17.04.2018, 00:00 by Bren Jordan P. Atienza, Lionel D. Jensen, Sarah L. Noton, Anil Kumar Victoria Ansalem, Tom Hobman, Rachel Fearns, David J. Marchant, F. G. West
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.

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