Nazarov Cyclization Initiated by Peracid
Oxidation: The Total Synthesis of (±)-Rocaglamide
John A. Malona, Kevin Cariou, and Alison J. Frontier
DOI: http://dx.doi.org/10.1021/ja9029736
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:
Scheme 1
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.
Scheme 2
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.
Scheme 3
The mechanism of the key step which builds up 2 adjacent stereocenters diastereoselectively but not enantioselectively looks like this:
Scheme 4
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.
Scheme 5
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…
Filed under: Total Synthesis | Tagged: Allene, Nazarov, Palladium | 1 Comment »