Cortistatin Pt. III
Shair, Lee, and Nieto-Oberhuber, JACS, 2008, ASAP. DOI: 10.1021/ja8071918.
A third showing for everybodies favourite androstane, this offering from Matt Shair adds to the quantity of inovative chemistry used in it’s contruction. As a quick reminder, first up was Phil Baran, back in May; then came Nicolaou and Chen in August – along with several ‘studies towards papers’. However, rather than my going through it all again, have a look at this excellent review by Stefan Bräse which was in ACIEE last month.
If you read it through, you’ll notice Nicolaou’s use of the Hajos-Parrish ketone (the synthesis of which I discussed in my post on that work); Shair does likewise, reinforcing it’s application towards steroid synthesis. From the single stereocenter present in that SM, Shair first does a substrate-controlled reduction of the ketone to add one stereocenter, and then a few steps later adds a pair by selective hydrogenation, and then Rubottom oxidation. Nothing new here, but it is all 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 (or at least I found it a bit special…). In this case, the nucleophilic partners for the Kumada coupling was a silyl methylene Grignard – an interesting substrate, as I’m sure there could be a competing Hiyama process, but I guess the Kumada process is far faster. Either way, it’s a neat way to make the required allyl-silanes.
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 a) (where TMS was used), 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 dihydroxylaion of the resulting trans olefin left them almost ready for the pièce de résistance, 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. I must admit that I had trouble visualising the freed hydroxyl ‘reaching’ over to the olefin, but building a model relieved my fears.
Completion of the molecule (and appendage of the isoquinoline) was done much in the same way as Baran and Nicolaou did, finishing a pretty tasty synthesis. However, one criticism has to be the number of yields which were quoted over multiple steps. Most were admittedly very good, but it’s always nice to know if, say, a 65% over two steps was [65% + 100%] or [80% + 81%].