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

preprint
submitted on 04.06.2019 and posted on 05.06.2019 by Robert Godfrey, Nicholas Green, Gary Nichol, Andrew Lawrence

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.

Funding

Gram-Scale Synthesis of Brevianamide Alkaloids.

Engineering and Physical Sciences Research Council

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Practical Organic Synthesis Inspired by Nature

European Commission

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History

Email Address of Submitting Author

a.lawrence@ed.ac.uk

Institution

University of Edinburgh

Country

UK

ORCID For Submitting Author

0000-0002-9573-5637

Declaration of Conflict of Interest

no conflict of interest

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