Nazarov Cyclization Initiated by Peracid Oxidation: The Total Synthesis of (±)-Rocaglamide

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

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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

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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

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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

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The mechanism of the key step which builds up 2 adjacent stereocenters diastereoselectively but not enantioselectively looks like this:

Scheme 4

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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

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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…