Spurges (Euphorbiaceae) are a rich source of natural products, and parts of the plants have found wide application in traditional folk medicine. Among the active components, ingenanes and related molecules stand out due to their high bioactivity, which led to the FDA approved drug Picato (ingenol mebutate).The diterpenoid (+)-Euphorikanin A, featuring an unprecedented and intriguing structure, was isolated in 2017 from Euphorbia kansui. Its origin and carbon skeleton suggest a biosynthetic relationship to the ingenane family of natural products. In a first-generation synthesis, we were able to access (+)-Euphorikanin A, in 19 steps from (+)-3-carene. This approach features methods which have found little to no prior use in complex molecule preparation. Employment of a chloro-dithiane as an electrophile allows for rapid introduction of an useful C1-building block. In addition, implementation of a ketyl-enoate cyclization cascade, coupled with a solid transition state model, enables the formation of two rings in one step, under high diastereocontrol. This represents the first total synthesis of this challenging natural product. Furthermore, a novel biomimetic route, that is currently investigated in our laboratory, aims to provide a deeper understanding of the biosynthesis of (+)-Euphorikanin A. A major goal of this approach is identification of the missing link to the ingenane diterpenoids, which would provide an unified access to a variety of Euphorbiaceae natural products.

Rearranged euphorbiaceae diterpenoids: Synthetic studies on euphorikanin A

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ACS Fall 2022

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