Home » Still In The RBF

Pestalotiopsin A   

30 March 2008 8,199 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

InChiKey dump

PCHMZVVQOYLBCH-XTKRSHFYBH OOQMBQPGFMHLCL-UHFFFAOYAF WWFUGKCPYBZQPD-UHFFFAOYAJ AVHMDXVXGLLQPM-UHFFFAOYAW VWCJRPXNFDMILF-VIFPVBQEBX HCSJULWSWURSKM-PSASIEDQBW OKMHBGNYJQGAMT-QYNIQEEDBL BPNGIIAUHCCNBX-DTWKUNHWBR

1 Star2 Stars3 Stars4 Stars5 Stars (1 votes, average: 3.00 out of 5)
Loading ... Loading ...

16 Comments

  • 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)

  • Tot. Syn. says:

    Hope you all like the new theme. It’s take a lot of customisation… and way too much php/css… One thing that is missing is a “Recent Comments” list. I’ll try to code that back in asap.

  • milkhake says:

    Please gimme back the old-time theme. It was good enough for me.

  • gilgerto says:

    I like this one. Specially if u can add a “Recent Comments” list. Great job, looks good!

  • HPCC says:

    I LOVE the new theme! Keep it! :)

  • Tot. Syn. says:

    There were a few bugs that I’ve just sorted – links to some images were broken, so things definitely didn’t look right. Fixed now. Let me know if you find any other bugs.

  • sjb says:

    I know it’s not good(tm) to be using MSIE7, but on a standard install, standard font sizes here, the boxes for comments do not align with the description.

    Another vote for the old timey style, btw, what’s with the revamp? Gotten tired of thesis writing already? :)

  • Tot. Syn. says:

    I’ll see if I can fix that some time soon…

    The theme was changed along with a wordpress upgrade (to 2.5) because the old theme was *really* badly coded. This one is far more simple, so perhaps more resilient. We’ll see.

  • dione says:

    Nice work ! I like this look, great work.

  • Hap says:

    I don’t mind it. MS Exploder doesn’t do anything peculiar here.

  • InfMP says:

    yeah this theme looks awesome. continually, a site that stands apart.

  • sjh9 says:

    Great new look!
    With all of the great reviews for ACIE papers, I’m very tempted to get my own subscription. $yikes!$