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Totally Synthetic by Paul H. Docherty, 20 May 2008

Total Synthesis of Cortistatin A


R. A. Shenvi, C. A. Guerrero, J. Shi, C.-C. Li, P. S. Baran, J. Am. Chem. Soc. 2008, 130, 7241-7243.

DOI: 10.1021/ja8023466

This steroid offers some pretty odd biological activity; ‘[it] inhibits the proliferation of human umbilical vein endothelial cells…’. However, biological studies pointed to other activity that was worth investigating, for which the synthetic compound would have been helpful. This is where the Baran group comes in.

As in many steroid syntheses, starting from scratch and building the steroid architecture ab initio is a bit of a waste of time, as many steroids are commercially available, and are pretty cheap too. In this case, they started with prednisone, which contains a part of the carbon skeleton and is pretty cheap. Now comes the tricky bit from my perspective - deciding which reactions to mention in this post. In this paper, it’s phenomenally tough as so much of this chemistry is of merit. I can easily see this type of synthesis turning up in a final-year undergrad exam at Cambridge or Oxford…

Anyway, first up is a startling oxidative bis-halogenation of an axial methyl group. In this reaction the active reagent is acetoxy hypobromite, generated in situ, which is coordinated towards the methyl group by the free hydroxyl. Why this doesn’t then displace the bromide to form a THF is discussed in detail in the paper, where Baran suggests that the carbon-bromine sigma anti-bonding orbital is of too small a coefficient to react in an SN2 manner.

Treatment of the gem-dibromide with TMSCl then protected the free hydroxyl, allowing a safe enolisation of the ketone to form the bromocyclopropane. Samarium diiodide opens the cyclopropane to give a cycloheptene ring. Note the new position of the bromide - the mechanism postulated by Baran suggests that the Sm reacts with the ketone to radically open the cyclopropane and then eliminate a bromine atom (Br) to give an extended enolate. This is then trapped by bromine [Br+] released from the TBCHD. An interesting reaction!

The next reaction I was intrigued by was a modified Stille coupling of cortistatinone (the core of the natural product) with an aryl stannane. Baran did this by first forming the hydrazone, and then treating this with triethylamine and iodine to give an alkenyl iodide. Pd-catalysed coupling gave the penultimate compound, which was chemoselectively reduced to the natural product.

A remarkable total synthesis and read - and one that’s free - no JACS subscription required here!