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Cortistatin A   

20 May 2008 27,429 views 53 Comments

Baran, Shenvi, Guerrero, Shi and Li. JACS, 2008, ASAP. DOI: 10.1021/ja8023466. Article PDF Supporting Information Group Website ResearchBlogging.org

Wow, a bit of steriod chemistry! A blast-from-the-past or what? And, in certain respects, the chemistry Baran has used to complete what is effectively a semi-synthesis is pretty old-school too. That does him a lot of credit in this situation, as many a chemist has learned that the subtleties of steroid architecture to be worked with, not against.

So what does this steroid do, and would Dwayne Chambers like some? It’s actually got some pretty odd activity (to my eye, at least); ‘[it] inhibits the proliferation of human umbilical vein endothelial cells…’. Hmm. However, biological studies pointed to other activity that was worth investigating, for which a chunk of synthetic compound would have been helpful. Enter the Baran group.

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 good chunk 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 somewhat capricious-looking bromo-cyclopropane. Capricious it is – a bit of your favourite samarium regent opens the cyclopropane to give a cycloheptene ring. Note the new position of the bromide – the mechanism postulated by Baran suggests that the Sm does it’s thing with the ketone to radically open the cyclopropane and then eliminate a bromine atom (Br-dot) to give an extended enolate. This is then trapped by bromine [Br+] released from the TBCHD. Interesting stuff!

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 a alkenyl iodide. Coupling of this (with a fair-old lump of palladium) gave the penultimate compound, which was chemoselectively reduced to the natural product.

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

Shenvi, R.A., Guerrero, C.A., Shi, J., Li, C., Baran, P.S. (2008). Synthesis of (+)-Cortistatin A. Journal of the American Chemical Society DOI: 10.1021/ja8023466

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