Nazarov Cyclization Initiated by Peracid
Oxidation: The Total Synthesis of (±)-Rocaglamide
John A. Malona, Kevin Cariou, and Alison J. Frontier
Ok, here I am back again and this time with a nice old fashioned reaction: the Nazarov cyclization .
The target is not that challenging but shows some interesting biological effects for example various cytotoxic activity against human cancer cells (as usual…) with an IC50 of 8 to 9 which is of course pretty good.
That’s it for the biology so far, let’s take a look on the synthesis.
They started with a rather unusual Hoesch reaction , in fact some sort of Friedel Crafts acylation) and protected the resulting benzofuranone with MeI:
The protocol dates back to a 1992 published unstereoselective synthesis of the same product. If you are interested in further information click here (http://www.rsc.org/publishing/journals/P1/article.asp?doi=p19920002657).
Next they introduced the formylgroup with a vinylgrignard which was oxidatively cleaved with OsO4/NaIO4.
Alkylation with phenylacetylene was followed by protection of the resulting alcohol as a PMB ether while when protecting it as an ethyl ether they were not able to further functionalize the molecule in the ongoing synthesis.
Now comes the interesting part of the synthesis:
First an allenylstannane was prepared by deprotonating the ethinyl-residue and quenching the resulting anion with tributylstannylchloride. The allenyl-PMB-enol ether was epoxidised in with mCPBA, like in the Rubottom-oxidation, and opened under the acidic reaction conditions to give the expected Nazarov cyclised product.
After PMB removal and a rare DDQ mediated oxygenation of the enol they had the almost functionalized diosphenol in hand.
The mechanism of the key step which builds up 2 adjacent stereocenters diastereoselectively but not enantioselectively looks like this:
Maybe they should have tried to epoxidise the enol ether enantioselectively by a Shi or Jacobsen epoxidation to get access to only one enantiomer (?).
Afterwards the enol was converted into a triflate and carbonylated using a bit of CO and MeOH to give the methyl ester in good yield.
The double bond was hydrogenated with PtO2 to give a single diastereomer which was used for the stereoselective reduction of the ketone.
At least the ester was converted into a dimetyhlamide to give (+/-)-Rocaglamide in an overall acceptable yield (Y=NMe2). They also prepared the free acid (Y=OH, rocagloic acid) and the methyl ester (Y=OMe, aglafolin).
In my opinion this synthesis is really an interesting piece, the Nazarov cyclisation as the key step very powerful but at least not enantioselective enough to be a good alternative to a more linear but stereoselective approach. Hopefully they will extend their methodology.
That’s it again and maybe you have some comments or suggestions?
I know the paper is outdated (but cool) but I was busy the last days…