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Physostigmine & Convolutamydine E   

8 June 2009 13,314 views 27 Comments

physostigmine

Barbas, Bui, Syed. JACS, 2009, ASAP. DOI: 10.1021/ja903520c. Article PDF Supporting Information Group Website

Now, this is a bit of a fib already. I’m not entirely sure of Barbas’ reason for calling this paper a ‘formal total-synthesis of physostigimine’, as, whilst it is a formal synthesis, he actually stops at another natural product, esermethole.  Now, this is fine – and it’s still a formal synthesis of physostigimine, but it is moreso a total synthesis of esermethole.  Why he felt the need to call this a formal synthesis I don’t know.

It’s a shame to dwell on this, though, as the synthesis is pretty sweet.  Starting with a lightly-functionalised indolinone, he is able to demonstrate a pretty wide variety of Michael additions to nitro-olefins.  Not only were these reactions highly enantioselective, he was also able to demonstrate good diastereoselectivity in the case of non-terminal nitro-olefins.  This was done in conjuction with a fair-old catalyst screen, turning up Takamoto’s thiourea catalyst as the winner.  Other thiourea-based catalysts were also active, but the difference between >90% e.e. and <10% e.e. was remarkable WRT catalyst design.

physostigmine_1

So with the addition done, and a quaternary center in place, completion of the synthesis only took a few more steps. Reduction and ‘protection’ of the nitro group allowed a reductive cyclisation to to complete the cis-ring junction, with somewhat unsurprising diastereoselectivity (making the trans- fused analogues is tough).  This completes esermethole, with a reference to Overman’s work converging the syntheses.  All that’s required is a deprotection followed by addition into an isocyanate to give the carbamate – so no real sweat (though it’s worth examing Overman’s yield-issues in the original paper…).

physostigmine_2

Interestingly, this a similar piece of work turned up in Chemistry – A European Journal this week too…

Nakamura, Hara, Shibata, Takeshi. Chem. Eur. J, 2009, EarlyView. DOI: 10.1002/chem.200900944. Article PDF Supporting Information Group Website

convolutamydine_e1

So the compound we’re making here is distinctly less complex, using a different approach to create a similar benzylic stereocenter (an aldol in this case).  There’s even a similarity to the catalysts used in each synthesis.  The limitation here is the scope of the paper (which is only a Chem. Eur. J. communication) – the addition chemistry is only demonstrated using acetaldehyde, something the authors seem quite happy about.

It’s be interesting to see how both of these reactions are adopted over the coming years.  Nice work all around.

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27 Comments

  • Martyn says:

    Will have to have a look at the Chem. Eur. J paper. It seems that using acetaldehyde in these organocatalytic reactions is quite a challenge – Ben List got a paper in Nature out of it, and I seem to remember another similar high-impact paper from around the same time.

    List’s paper: Nature, 452, pp453-455; doi:10.1038/nature06740

    • Old Timer says:

      That List paper in Nature belongs in Synlett – the numbers are pathetic. Acetaldehyde isn’t that difficult to use in organocatalytic reactions (I have for a variety of catalysts), but most people don’t use it in their screens for some reason.

      • LW says:

        As far as I understand the only difference between the failed attempts to the successfull results published in Nature by List was that he used an excess of acetaldehyde. He realised that this may have been the problem whilst on a jog, before apparently putting together a four person team. Wow. I’m just waiting for the organocatalytic bubble to really burst!

  • freetown-IU says:

    takamoto or takemoto (in Kyoto)?

  • stir_bar says:

    Is the Boc in the natural product? I’m not at school right now but that seems odd…

  • milkshake says:

    there is typo: LAH takes Boc down to methyl. Physostigmine has methyl. The renewed interest in physostigmine (in the last 20 years) was because at one point it looked like a good drug to treat Alzheimer symptoms. Thats probably why you forgot to change the Boc to methyl.

    Also there is Pavel Kocovsky (Glasgow uni) method for doing organocatalytic addition of acetone to isatins, with simple valinol aminoalcohol as the catalyst. the system gives good ees but it works well only for acetone.

  • Liquidcarbon says:

    convoluteamidyne is kinda dumb name

  • Kyoto says:

    Takemoto, it should be.
    Some nice chemistry for demonstration of reaction application.
    Hope that the starting materials are cheap enough.
    I read the JACS, but did not kknow about the Eur. Chem. paper.

  • Farmer oleg says:

    Organocatalysis = a big sad joke

  • Elias J. Woodward says:

    Shouldn’t be in JACS…….

  • ee says:

    The method is more valuable than the total synthesis. Definately a JACS-worthy method!

  • loging says:

    if i see one more nucleophile adding to vinyl nitro appear in jacs or aciee I am going to puke (again).

  • LW says:

    A lot of organocatalysts are substrate specific. If you can be arsed to have a library of catalysts stored up, and screen all of them then so be it. With a lot of organocatalysts, other than the usual suspects like Macmillan’s,Joergensen’s etc, it seems difficult to rationally predict whether they will actually do the trick or not.

  • Colors! says:

    “JACS worthy?” What a tired old conversation…I don’t know about the rest of you, but I am always thrilled to see some synthetic work in JACS as opposed to something like this: http://pubs.acs.org/doi/abs/10.1021/ja903694d

    • Organic says:

      Yes! Thank you.
      All of the most read JACS papers are synthetic, but papers like that one are taking up pages in the journal and makes it tough for synthetic papers to get in.
      Why do reviewers so quick to reject organic manuscripts?
      Here’s a concept for JACS reviewers: If you reject a good paper that is from somebody that is working in a related area to yourself, you’ve just lowered the impact of your own work.

  • Cascade says:

    Sorry to interrupt, but has anyone here faced an interagency review when applying for a J1 visa? What are the typical waiting times from Canada

  • Knut Jacksworthy says:

    Cascade, you can get a TN at the border with your diploma and the right letter of offer.

  • ytuerty says:

    Rule 8: Work on the Important
    Problems in Your Field

  • Cascade says:

    Thanks Liquidcarbon and Knut!

  • Orgcat says:

    Prof. Hayashi and co-workers report the synthesis of convolutamydine and CPC-1 through the reaction of isatin with acetaldehyde using thier organocatalysts. The enantioselectivity and yield is excellent.
    http://pubs.acs.org/doi/abs/10.1021/ol901432a