Multicatalysis-Enabled Multicomponent Reactions Generate a PTP1B Inhibitor.

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Catalysis

Background:

• Multicomponent reactions (MCRs) are vital for drug discovery but often lack selectivity.
• Achieving high chemo-, diastereeo-, and enantioselectivity in MCRs is a significant challenge.

Purpose of the Study:

• To develop a multicatalytic strategy for highly selective MCRs.
• To explore the application of this strategy in discovering novel bioactive molecules.

Main Methods:

• Utilized a cooperative system of rhodium, copper, Brønsted acid, and magnesium catalysts.
• Conducted mechanistic studies combining experimental and computational analyses.
• Employed virtual screening and biological evaluation for drug discovery.

Main Results:

• Achieved excellent chemo-, diastereeo-, and enantioselectivity (up to 99% yield, >20:1 dr, 99% ee).
• Synthesized 50 diverse compounds (CHBOs) with broad substrate generality.
• Discovered a potent PTP1B inhibitor, (S,S)-3ak, with submicromolar IC50, demonstrating the importance of chirality.

Conclusions:

• The developed multicatalytic MCR (MMCR) strategy provides efficient access to enantiopure bioactive molecules.
• This approach facilitates drug discovery, as exemplified by the identification of a novel chiral PTP1B inhibitor.