Cortistatin A

I haven’t been doing any retrosynthetic analyses for a long time that my retrosynthesis skills are slowly deteriorating. Also, the number of visitors to this blog have dropped since I stopped Friday Night Retrosynthesis posts. So, to keep myself in good form and to keep this blog more or less interesting a quick retrosynthesis post is exactly what is needed.

After this brief introduction from a renowned group’s web-page:

Cortistatin A. In 2006, the unique natural product cortistatin A was reported as an extremely potent inhibitor of the migration and proliferation of HUVECs (Human Umbilical Vascular Endothelial Cells); IC50 = 180 pM (VEGF-stimulated HUVECs proliferation). It was also shown that cortistatin A is 3000 times more potent at inhibiting the proliferation of HUVECs versus other cancer and normal cell lines, suggesting that cortistatin A may be a highly selective angiogenesis inhibitor. Cortistatin A has an unprecedented structure, with a particularly challenging [3.2.1]oxabicyclooctene ring system.

…on with the retrosynthesis:

UPDATE: I agree with Greg that it is almost not possible to predict which c=c bond will cyclopropanate first. But what I wanted to say is that the core structure could (in principle) be built in this way. Here is the proposed mechanism of the key step:

UPDATE II:

… isomerization step:

BTW, (maybe) the problematic isopropyl group stereochemistry of Guanacastapen A could be installed in this manner, too. But that should be a topic of another retrosynthesis post…

Solution

So, here is the solution of the last mechanism problem:

The only answer came from an anonymous anon and his answer was absolutely right.

P.S. In fact people do this reaction in two steps: first they condense acetone and hydrazine an then it is heated in the presence of ZnCl2. Sorry if I confused some of you by not writing the details of this reaction.

Another mechanism problem

Well, my previous problem was answered very quickly by Greg over at Carbon Tet who published the solution in a very understabdable way.

Another one for those who love solving mechanism problems:

You will have to determine the structure of the product and propose a plausible mechanism for this wonderful transformation.

Hope that this one will be answered as quickly as the previous one.

Just a Mechanism

Try to figure out a plausible mechanism of the following transformation. Note that this problem was taken from the ICho 39 (International Chemistry Olympiad among Highschool Students) Preparatory Problems which will be held at Moscow State University in July. So, shame on you if you can’t solve it!

P.S. Friday Night Retrosynthesis Categoryis renamed to Chalk Talk. Since I am quite busy with my Diploma Project I don’t have much time to do retrosyntheses and post this kind of stuff lately. However,  you can expect to see new retrosynthesis posts from time to time.

INTERNATIONAL JOURNAL FOR PHILOSOPHY OF CHEMISTRY

Never knew about existence of such a journal. Found about it while reading an article in Angewandte Chemie.  You can read it free of charge at www.hyle.org .