Chemical Synthesis of (+)-Brevianamide a Supports a Diels–Alderase-Free Biosynthesis

05 June 2019, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


The fungal-derived bicyclo[2.2.2]diazaoctane alkaloids are of significant interest to the scientific community for their potent and varied biological activities. Within this large and diverse family of natural products the insecticidal metabolite (+)-brevianamide A is particularly noteworthy for its synthetic intractability and inexplicable biogenesis. Despite five decades of research, this alkaloid has never succumbed to chemical synthesis. It has been suggested that a proposed Diels–Alder reaction in the biosynthesis of (+)-brevianamide A requires a Diels–Alderase enzyme. We herein report the first chemical synthesis of (+)-brevianamide A (7 steps, 8.0% overall yield, 750 mg scale), which provides compelling evidence in support of a Diels–Alderase-free biosynthesis; a significant departure from the established biosynthesis of related alkaloids.


biomimetic synthesis
total synthesis

Supplementary materials

Brevianamide A - SI


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