A new directed-halogenation reaction has enabled the synthesis of a rare marine natural product and paves the way for a thorough investigation of its biological activity
There are a number of good reasons to embark on a natural-product synthesis: it can be used to test out a new reaction methodology, or the compound in question may have interesting biological activity. Alternatively, it may be for the sheer challenge of making a complex molecular structure in the laboratory, with the expectation that new chemistry may be developed along the way. The combination of these aims in a single total synthesis is particularly noteworthy.
(+)-Cortistatin A certainly displays some interesting biological activity, such as inhibiting the formation of blood vessels — a property desirable in some classes of new drugs — but is only available from natural sources in very small amounts. Now, Phil Baran and co-workers from the Scripps Research Institute in California have achieved1 the synthesis of (+)-cortistatin A from an inexpensive commercial starting material, the steroid prednisone. The team identified the oxidation of a methyl group as a key step in the synthesis, but known methods did not work for this system. To overcome this problem, they chose an alcohol-directed radical dibromination as the starting point for a cascade resulting in ring expansion to give the seven-membered ring at the core of cortistatin.
Unusually, the compound could not be compared to a natural sample, because doing this would impede ongoing biological studies — so small is the stock of naturally derived compound. The completed synthesis provides (+)-cortistatin A in an overall 3% yield, from a starting material available in kilogram quantities, and using a route that will enable easy investigation of the properties of related structures.
References
Shenvi, R. A., Guerrero, C. N., Shi, J., Li, C.-C. & Baran, P. S. Synthesis of (+)-cortistatin A. J. Am. Chem. Soc. 10.1021/ja8023466 (2008).
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Davey, S. Radical rescue. Nature Chem (2008). https://doi.org/10.1038/nchem.14
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DOI: https://doi.org/10.1038/nchem.14