Bradshaw, Bonjoch, Etxebarria-Jard?´. JACS, 2010, ASAP. DOI: 10.1021/ja101994q.
It’s been a while since I wrote about a synthesis from Spain, so it’s nice to return with a rather sweet synthesis from the labs of Josep Bonjoch and his compatriot, Ben Bradshaw. Their efforts have been focused towards a sub-set of diterpenoids produced by Aspergillus, in which the decalin ring junction contains a pair of quaternary carbons. That’s a pretty significant challenge by itself, but the rest of the decalin in subsituted in an all cis- arrangement, making for a pretty tricky system. Perhaps this is why there have been no reported syntheses!
The Spanish team’s approach hinges on a rather tasty piece of methodology executed in the first few steps of the campaign. Using a rather complex-looking proline/BINOL derivative, they were able to perform an asymmetric Robinson annulation, requiring only 1 mol% base catalyst. This produced the Wieland-Miescher ketone product in an excellent yield and enantiomeric excess, allowing them to proceed directly to a conjugate addition. Using the usual cuperate conditions, they completed quaternarisation of the decalin in only three steps and in impressive yield.
A selective ketone protection / methylenation / deprotection sequence later, they were ready to functionalise the decalin. A key synthetic handle was enone-functionality, installed using Nicolaou’s hypervalent-iodine prep. This might not be a stunning yield, but in terms of route-efficiency, you can’t beat it. However, IBX at 70C is somewhat of a concern…
A futher methyl group was appended using an interesting approach of enolisation followed by Eschenmoser’s salt. Reduction then provided the desired methyl group in the correct orientation. Rather neatly, they then moved the oxygenation around the ring by reducing the ketone and displacing with an aryl-selenide. Treatment of this with mCPBA allowed the usual sigmatropic rearrangement to occur, where the conformation of the ring allowed for a nicely diastereoselective reaction. Interestingly, this reaction only performed well when the solvent was wet…
Even-more selenium chemistry was used to install a further enone (I feel sorry for the other workers in this lab – I hope the fume-hoods were up to the task!!), leaving them perfectly set for addition of the indole moiety. The group admit that they did a screen of Lewis-acids in the lab, and that for no-reason-in-particular, zirconium tetrachloride was the winner. This lead to the all-cis arrangement required in the target – with an interesting deprotection of the pendant acetate using KF in ethanol. Anyone done that chemistry before?
Getting to the target took a futher four steps – oxidation of the primary alcohol and methylenation provided a handle for metathesis to complete the prenyl group, followed by deprotection of the remaining TES group.
All things considered, this is a really neat synthesis and a cracking implementation of some powerful methodology. The best thing is that their methodology fits pretty much perfectly – it isn’t shoe-horned into the synthesis like we see in many other papers. The only catch is that the route is entirely linear – something that I think is unavoidable with this target, so of no real consequence.