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Pestalotiopsin A   

30 March 2008 8,559 views 16 Comments

Tadano, Takao, Hayakawa, Yamada, Yamaguchi, Morita and Kawasaki, ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200800253. Article PDF Supporting Information Group Website ResearchBlogging.org

Mentioned in the comments, this tidy little synthesis features one hell of a tightly functionalised ring system, with seven contiguous stereocentres and a trans- trisubstituted olefin in a ten-membered ring. The biological activity seems impressive too: cytotoxicity and immunosuppressive activity, but the potency isn’t mentioned in this paper. This is actually the first synthesis of pestalotiopsin A, even though it’s recieved plenty of attention from the Procter and Paquette groups. Retro time:

Circumventing the metathesis problems of Paquette by using a NHK coupling to put in the medium ring and a [2+2] to create the cyclobutane, there’s plenty of interesting chemistry to examine. Lets start with the [2+2] – using Oppolzer’s camphorsultam chrial auxilliary to control the following reductive step. However, a closer look at the cycloaddition reveals impressive regioselectivity – but only after almost a week on the stove…

Without going into too much detail, the elaboration of this core is neat, with cleavage of the ketal allowing a substrate contolled addition of vinyl Grignard, and displacement of a tosylate with cyanide providing the one-carbon homologate. A little aqueous acid hydrolysed the nitrile and allowed cyclisation of provide the desired gamma lactone.

However, it’s their synthesis of an enantiomerically enriched propargyl alcohol that I liked most. This prep was developed by Takano in the 80’s, and it’s utillity stems from the ease of synthesis of the starting materials, β-cholo epoxides, which are of course easily prepared using an SAE. Treatment of the chloro-epoxide with three equivalents of butyl lithium results first in opening of the epoxide to give the allylic alchol. A second deprotonation and elimination provides the required terminal acetylene which was promptly deprotonated itself. A spot of methyl iodide then left the desired product, quickly and easily. Nice.

There’s a lot more nice chemistry in this paper, including that nice (and high-yielding) NHK, but also a bit of a protecting group dance. Smart work.

Takao, K., Hayakawa, N., Yamada, R., Yamaguchi, T., Morita, U., Kawasaki, S., Tadano, K. (2008). Total Synthesis of (−)-Pestalotiopsin A. Angewandte Chemie International Edition DOI: 10.1002/anie.200800253

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  • ZAL says:

    I hope this is not a stupisd observation, but if the Grignard addition to the four-membered cyclic ketone is substrate-controlled, I would assume the -OH group to coordinate magnesium, and so the addition should occur on the same side of the ring relative to the hydroxymethylene group, not on the opposite side as you drawed it. Am I missing something horribly obvious?
    I haven’t read the paper yet, so I apologize if the answer is already there.

  • Tot. Syn. says:

    Apologies – I’ve not been chronological when I discussed those transformations. The cyanide displacement of the sulfonate takes place before the Grignard, so there’s no (or at least very little) coordination going on.

  • milkshake says:

    I would be perfectly happy with thermal 2 2 at the start of the synthesis – even if it took a week to complete. Photochemistry is usually hard to scale up.

    I dont ike the acetonide piece synthesis though – there must be some more direct way from glyceraldehyde acetonide (which is just one step from D-mannitol diacetonide)even if one had to column off the undesired diastereomer

  • Eraser says:

    Hi Milkshake

    I second that, The Carreira Zinc acetylide addition should do the trick. The method works well even against substrate selectivity as here.

    Chelation control might also be used here. There is some precedence (I’ll se if I can dig out the link later).

  • ... says:

    Says in the paper they make the chloro epoxide from glyceraldehyde acetonide, I would imagine they must have tried the direct additions first. BTW I believe that chealation-controlled additions into that aldehyde can go w/ around 4:1 dr (that I’ve seen at least)

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