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Actinophyllic Acid   

27 May 2008 12,023 views 30 Comments

Overman, Martin and Rohde. JACS, 2008, ASAP. DOI: 10.1021/ja803158y. Article PDF Supporting Information Group Website ResearchBlogging.org

Can a target scream ‘Overman’ any more?! And, yet again, his approach to this little beastie is as smart and unique as ever. But before we get into the synthesis, let’s find out if it’s go well with the morning aspirin… Turn’s out it’s ‘…an inhibitor of carboxypeptidase U (CPU)…’; this is interesting, as CPU itself inhibits the removal of fibrin clots, so one might expect actinophyllic acid to favour the fibrinolysis process. Certainly more interesting than the usual ‘cytotoxic…’.

Synthesis-wise, Overman’s taken an unusual approach too – building the key eight-membered ring via an amazing intramolecular oxidative coupling of the malonate with the enolate of the piperidone… And with quite a strange metal oxidant; the cited papers are here and here, but there’s not an abundance of detail. However, other papers cited show that both Paquette and Baran have managed this type of chemistry with slightly less exotic reagents. Nice result!

If you thought that was good… After a bit of vinyl-Grignard, removal of the Boc group (and saponification / mono-decarboxylation of the t-butyl esters) left the basic nitrogen ready for a bit of action. Formaldehyde gave the iminium ion, which immediately did the [3+3] thing to give ten-membered ring interemediate. This was then set to do the Mannich part of the aza-Cope−Mannich.

Only two further steps were required to get to product in this short, but very sweet paper. Top banana!


Martin, C.L., Overman, L.E., Rohde, J.M. (2008). Total Sythesis of (±)-Actinophyllic Acid. Journal of the American Chemical Society DOI: 10.1021/ja803158y

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30 Comments

  • J says:

    Interesting intramolecular coupling reaction. Is the iron cluster commercially available or is it made in situ (from FeCl3, maybe?)? The spectroscopy would’ve given me a headache.

  • gilgerto says:

    Is there any single molecule Overman can’t make using aza-cope/ Mannich??? May be C 60…

    Nice application by the way.

  • ... says:

    I saw Overman talk on this subject recently. He described the iron oxidant as the solid that crashes out when you add FeCl3 to DMF.

  • antiaromatic says:

    An interesting thing to note about Overman is that you never really see him doing the “biomimetic” thing. I think overall, he’s just more interested in using cool chemistry to make cool molecules. In some ways, I think this can require more creativity. He may not always be the first guy to make a molecule, but quite often, it’s pretty impressive when he finishes one.

  • Ribeye says:

    Has anyone heard rumours of this guy retiring soon?

    I hope he’s still around when I start my PhD in a few yrs…

  • Game over... man! says:

    Talk about putting a mean looking molecule in its place! Wow! Overman is an elegant magician. This is my favorite synthesis of the year.

    And he requires basically just TFA, LDA, HCl, and paraformaldehyde (with a pinch of ‘strange iron’) to man-handle this beast. Superb! With all due respect to AF, this IS VOODOO.

  • DRG says:

    Indeed, truly awesome work. Overman is one of a handful of guys whose papers I drop everything to read when they show up on asap.

    Nitpick: Shouldn’t the [3+3] really be [3, 3]?

  • Jose says:

    Anyone else notice this?

    We thank Professor Phil Baran for discussion and
    samples of metal salts…

  • SMILES says:

    It’s always a pleasure to read from professor Overman.

    This coupling with “ate” complexe is really impressive even if closely related to Baran’s previous work.

    But does anyone know why in case of iron catalyst an amid such as DMF or NMP can be helpful??

    Have you noticed the small mistake in the Title….?

  • gilgerto says:

    Well done, reviewers…

  • InfMP says:

    yeah I caught a missing letter in the title of one of my proofs!

    I notice on the Overman website that he often puts his name in a place other than 1st or last. the only supervisor I’ve seen do this when it isn’t a multiple corresponding author paper.

    Any ideas why?

  • TWYI says:

    What does he do when the paper only has two names?

  • gilgerto says:

    Overman uses alphabetical order for authors… I believe it is a very bad way of ranking authors, since first names usually mean bigger contribution to the work…

  • Madforit says:

    Hy guys,what about Leo A. Paquette syntheses of Formannosina?

  • Ribeye: rumors of Overman hanging up the Dockers + Sweater-vests and pulling down the hood sashes for good are greatly exaggerated. Spoke to him recently and it was clear he’s taking students this year and will be continuing to for some time. His group is now ~60% post-docs, 40% grads.

    InfMP & gilgerto, Re: Alphabetical listing – learn to live without the ego. I guess if it really bugs you, then on your CV/resume, you could just put a little note pointing out that author names were ordered alphabetical. I didn’t bother. Overman writes great, fair, and descriptive letters of rec, so your contributions are well-defined in other aspects of your application for jobs out of his group. Do well by him and you’ll be in great shape. Notice his students and post-docs do quite well on the job market – industry or academia. I’ll testify on that score whenever you like.

    i best get back to work.

  • gilgerto says:

    Re: Chris Douglas

    I understand your point. Of course, when you’re out of Overman’s lab, you have no problem finding a job, no matter if your name was first or last on publications. But when your applying for a followship, I believe it does matter. Also, when you’re in a smaller group with a less impressive background/reputation, you also want your publications to tell, at least qualitatively, the amount of work you’ve done. It’s not an ego question, it’s just to get the recognition you deserve…

  • long live totalsynthesis says:

    The inaugural JACS Virtual Issue (http://pubs.acs.org/JACSbeta/JVI/index.html) focuses on
    the total synthesis of natural products. This topic was selected since a significant number of
    the most highly viewed papers published in JACS concern the synthesis of natural
    productssreflecting the continued vitality and broad interest in this important field of research.

  • sulfur says:

    gilgerto

    don’t you think reviewers are aware of different name arrangements, your recognition does not only depend on order

  • InfMP says:

    Chris thanks for your input. I guess you are right, and perhaps it is a certain amount of ego that makes me want to be high in the author list. That being said, if I were a prof, I would never put mine first.
    I think the alphabetical thing is a bit confusing. It doesn’t make sense to me, but I believe what you say is true concerning recommendations.

    PS nice PNAS paper, if only Jason Altom had seen it, maybe it would have saved his life

  • TWYI says:

    Chris Douglas, how do you go about getting 8 publications from a BS project?

  • TWYI says:

    How long is the practical portion of an American BS? Has Hsung been giving away publications or does he acknowledge miniscule amounts of work on a project? Much to Douglas’ benefit obviously.

    How many of those 8 publications counted towards him getting a decent grad school supervisor and post doc?

  • TheEdge says:

    TWYI-
    Chris’s undergrad institution, Minnesota, strongly encourages undergraduate research. It’s one of the reasons I chose to go there, and one of the reasons that the best students there can go to grad school anywhere they want to. The honors students can start in lab as early as the second semester of their first year, and the university (and the chemistry department) provides a lot of money for summer research. FWIW, I don’t think this is typical of american institutions.
    My understanding of the Hsung lab was that Richard was willing to throw bodies at table filling in order to get things out the door, especially before he got tenure, and that most grad students in started in the lab by filling other people’s tables. That leads to pharma style author lists, of course, where you get one or two first author papers in front of a number of co-authors. I don’t think that this is a bad thing. The more authors on a methodology paper, the more likely it is to acutally work for somebody other than the lead author, and the more likely it is to have a diverse table of substrates.

  • GYA says:

    InfMP–what PNAS paper are you referring to? I seriously doubt the appearance of any paper would have influenced Jason in anyway–and to infer so is poor judgement.

  • HPCC says:

    GYA: I, too, doubt there is anything in this, albeit nice, review of methods to form all-carbon quat centres that could have led to haplophytine rather than cyanide ingestion…

  • ZZZZZ says:

    ZZZZZ

    …bringing up Jason is in really bad taste – and this is coming from someone who usually has some of the worst manners…

    ZZZZZ

  • HPCC says:

    Hey, zzzz, nice to see you come out of your slumber. :)

  • InfMP says:

    he was trying to secure a quat center which is difficult.

    sorry about that guys

  • milkshake says:

    if you ask me, what he needed most was to take his project and his career less seriously. Three weeks in Hawaii with someone close alongside would have made all the difference.

  • SiO2lungs says:

    that dienolate coupling was amazing! Have you noticed that if the stereochemistry at the substituted alpha C to the ketone were set then they’d get the optically active Actinophyllic acid… any ideas on how to set it??

  • The structure representation you have is visually correct but I am struggling to get the right structure defined to generate a full InChi. The depiction you have gives “InChI=1/C19H20N2O4/c22-17(23)18-9-25-19(24)11-5-7-21(8-6-13(18)19)15(11)14-10-3-1-2-4-12(10)20-16(14)18/h1-4,11,13,15,20,24H,5-9H2,(H,22,23)/t11?,13?,15?,18-,19?/m0/s1/f/h22H” Notice the question marks. DO you know the stereo center definitions? Please send to me at antonyDOTwilliamsATchemspiderDOTcom