A Novel Approach to Indoloditerpenes by Nazarov Photocyclization: Synthesis and Biological Investigations of Terpendole E Analogues

A Novel Approach to Indoloditerpenes by Nazarov Photocyclization: Synthesis and Biological Investigations of Terpendole E Analogues

Fa´tima Churruca, Manolis Fousteris, Yuichi Ishikawa, Margarete von Wantoch Rekowski, Candide Hounsou, Thomas Surrey, and Athanassios Giannis

DOI: http://dx.doi.org/10.1021/ol100579w

As the title suggests it’s time for some sunlight chemistry… Ok only one step but the rest of the synthesis is also worth reading. The Terpendoles are a family of indoleterpenes which show weak activity as acyl-CoA:cholesterol acyltransferase inhibitors. Recently it was discovered that the terpendoles inhibit the kinesin spindle protein (KSP).

In this paper the synthesis of one member of this class is described. The retro is rather short as the paper is, too. We’re starting with some FGI and cut the molecule into two halves by using the above mentioned Nazarov cyclization strategy. As can easily be seen, the molecule should be accessible directly from the known Wieland-Miescher-ketone.


So here we go:

The scheme starts with a selective protection of the unconjugated carbonyl. Phenylthiomethylation (search for Kirk-Petrow-reaction for further information) which was followed by a SET reduction under Birch conditions and subsequent trapping of the anion with allylbromide then yields the allylated/methylated ketone. LAH reduction of the remaining ketone, boronation of the terminal olefin and oxidation results in lactone formation. Oxidation of the ketone lactone to an α-β-unsatured one was achieved under more or less unconventional conditions. Epoxidation with H2O2, epoxide opening with phenylselenide and protection of the resulting alcohol as the MOM ether closes the first scheme.

Scheme 1

Because the phenylthiomethylation looks a bit odd, here is the mechanism:

Mechanism 1

The first few steps should be clear. The Birch reduction step might involve an intermediate radical anion which is trapped by allylbromide and reprotonated under thermodynamic control.

Furthermore the dehydration dehydrogenation step with this to me unknown reagent:

Mechanism 2

This is only a proposal of what I think the mechanism might be… I’m open for better ideas or corrections.

With the blue intermediate in hand we can move on. Selective reduction of the lactone was achieved with DIBAL-H and the aldehyde olefinated. Epoxidation of the alkene with mCPBA was followed by Sc(III) mediated pyran formation, oxidation and epimerization of the isomeric ethers to give one single pyran ring. Grignard reaction with methylmagnesium chloride, PG interconversion and acetal cleavage sets the stage for the final few steps.

Scheme 2

The first step involves an aldol condensation/hydrogenation to link both halves of the molecule together. Methylation of the ketone, benzylic oxidation with DDQ, dehydration of the tertiary alcohol with Burgess reagent to the exocyclic alkene and isomerization of the latter one to the endocyclic alkene prepares the key intermediate for the Nazarov cyclization. This [2+2] cyclization was mediated by UV light and closes the ring in a disrotatory manner.

Scheme 3

Protecting group removal and complete reduction of the ketone then yields Terpendole E.

Scheme 4

Overall a nice synthesis but I would have preferred a bit more details in the paper. The authors only give the used reagents without any more information like conditions or eq’s. Nevertheless nice chemistry but there’s a little mistake in the published paper. Maybe you find it too…

Any comments?


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


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…