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Totally Synthetic by Paul H. Docherty, 24 November 2008

Total Synthesis of Cortistatin A


H. M. Lee, C. Nieto-Oberhuber, M. D. Shair, J. Am. Chem. Soc. 2008, 130, 16864-16866.

DOI: 10.1021/ja8071918

A lot of innovative chemistry has been used in the contruction of Cortistatin A already. As a quick reminder, we have covered Phil Baran's total synthesis and the one by Nicolaou and Chen. If you read through Matt Shair's recently published total synthesis, you’ll notice the use of the Hajos-Parrish-Eder-Sauer-Wiechert reaction (HPESW), which has already found application in Nicolaou's total synthesis, reinforcing its application towards steroid synthesis. From the single stereocenter present in the product of the HPESW, Shair first performs a substrate controlled reduction of the ketone to add one stereocenter, and then a few steps later to add a pair by selective hydrogenation, and then Rubottom oxidation. All is very neatly controlled by the substrate.

Removal of the acetal protecting group and a bit of aldol chemistry introduced a cyclohexanone, which was triflated to provide a handle for a slightly unusual palladium mediated coupling. In this case, the nucleophilic partners for the Kumada coupling was a silyl methylene I guess the Kumada process is far faster than the competing Hiyama process . Either way, it’s an interesting way to make the required allylsilanes.

A cyclopropanation of the allyl silanes using dibromocarbene gave them the final functional group required for a rather sweet ring expansion to install the seven membered ring. However, the nature of the silyl group was quite important, as in case of TMS, a process of proton abstraction rather than silyl group elimination competed. Moving to the disiloxane derivative favoured attack of fluoride rather than deprotonation, and removed the competing pathway entirely, resulting in a good yield for the ring expansion.

The remaining bromide was then used as a handle for a Suzuki coupling, appending the remaining carbons for the A ring. Substrate controlled dihydroxylation of the resulting trans olefin left them almost ready an aza-Prins transannular cyclisation, starting with in situ deprotection of the MEM group (which I’ve omitted for clarity) and building several rings in one step.

The isoquinoline moiety was added in the same way as Baran and Nicolaou did, finishing a very interesting total synthesis.