The bicyclo[2.2.2]diazaoctane alkaloids are a vast group of natural products which have been the focus of attention from the scientific community for several decades. This interest stems from their broad...
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<p>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.
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The bicyclo[2.2.2]diazaoctane alkaloids are a vast group of natural products which have been the focus of attention from the scientific community for several decades. This interest stems from their broad range of biological activities, their diverse biosynthetic origins, and their topologically complex structures, which combined make them enticing targets for chemical synthesis. In this article, full details of our synthetic studies into the chemical feasibility of a proposed network of biosynthetic pathways towards the brevianamide family of bicyclo[2.2.2]diazaoctane alkaloids are disclosed. Insights into issues of reactivity and selectivity in the biosynthesis of these structures have aided the development of a unified biomimetic synthetic strategy, which has resulted in the total synthesis of all known bicyclo[2.2.2]diazaoctane brevianamides and the anticipation of an as-yet-undiscovered congener.
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