Total synthesis of brevianamide A

Area of Science:

• Natural Product Chemistry
• Organic Synthesis
• Chemical Biology

Background:

• Fungal-derived bicyclo[2.2.2]diazaoctane alkaloids exhibit potent biological activities.
• The insecticidal alkaloid (+)-brevianamide A is a synthetically challenging natural product.
• Previous synthetic strategies have been hindered by reactivity and selectivity issues.

Purpose of the Study:

• To report the first successful chemical synthesis of (+)-brevianamide A.
• To develop a novel synthetic route overcoming long-standing challenges.
• To provide a scalable method for producing (+)-brevianamide A.

Main Methods:

• A bioinspired cascade transformation was employed.
• The synthesis started from (-)-dehydrobrevianamide E.
• The strategy involved a seven-step sequence.

Main Results:

• (+)-brevianamide A was synthesized in seven steps with a 7.2% overall yield.
• A 750 mg scale synthesis was achieved.
• A topologically complex bridged-spiro-fused structure was successfully constructed.

Conclusions:

• The developed synthetic route effectively addresses the challenges in accessing (+)-brevianamide A.
• This synthesis provides a foundation for exploring the biological activities and biogenesis of this alkaloid.
• The methodology may be applicable to other complex fungal alkaloids.