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

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Catalysis

Background:

• The 2-(3-indolyl)indolin-3-one scaffold is a key structural motif in the antiviral natural product isatisine A.
• Developing efficient synthetic routes to complex bis(indole) structures is crucial for drug discovery.

Purpose of the Study:

• To establish a novel, modular, and procedurally simple method for synthesizing the 2-(3-indolyl)indolin-3-one scaffold.
• To explore the potential of the synthesized bis(indole) libraries for anti-infective applications.

Main Methods:

• A dual catalytic sequence involving aryl azides and indole nucleophiles at room temperature.
• Utilizing a copper(II) triflate (Cu(OTf)2) precatalyst that undergoes redox activation by indole to generate a catalytically active copper(I) species.
• Employing a Brønsted acid generated in situ for the C-C bond-forming indole addition step.

Main Results:

• Successful generation of indolenones with a reactive C-acylimine moiety from aryl azides and ortho-metallocarbene intermediates.
• Efficient formation of the 2-(3-indolyl)indolin-3-one scaffold through the reaction with indole nucleophiles.
• Rapid assembly of diverse bis(indole) libraries.

Conclusions:

• The developed dual catalytic method provides a straightforward route to complex bis(indole) structures.
• Several synthesized bis(indole) compounds demonstrated anti-infective activity against respiratory syncytial virus (RSV) and Zika virus.
• This approach facilitates the rapid exploration of chemical space for novel antiviral agents.