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Fluostatin C   

12 February 2008 6,797 views 16 Comments

Danishefsky and Yu, JACS, 2008, ASAP. DOI: 10.1021/ja7113757. Article PDF Supporting Information Group Website

I found this short synthesis remarkable for taking a modern twist on some resolutely old-school chemistry. I haven’t come across this particular family of natural products before, and Danishefsky doesn’t tell us too much about their properties, other than mentioning “varying degrees of antibiotic and antitumor activity”. I guess this means that we’re in for the chemistry, which involves one hell of a challenging Diels-Alder. I’m not going into the methodology here (but there is some discussion of it in the paper) – I’ll just point out it works, and is remarkable in that fact.

Just consider the regiochemical control that this reaction displays (and perhaps be lenient on the enantioselectivity) – and also bear in mind the propensity for vinylindene species to polymerise in this situation. Top stuff. However, with three stereocenters in the bag, it’s interesting to see that not one of thoses stereocenters is present in the target! So whilst the carbocyclic skeleton in now complete, there’s still quite some work to do…

First-off was an epimerisation of the more-acidic bridgehead stereocenter, converting from a psuedo-cis geometry to a pseudo-trans. This was done to provide control for the substrate controlled reduction of the cyclohexenone moiety in the following step, which was completed with ease.

This substrate was then subjected to a nucleophillic epoxidation, again substrate-controlled to provide the “up” epoxide only. Now they had the stereocentres required for the target, it was time to strip-out the excess. First, the remaining olefin was dihydroxylated, and the secondary alcohol oxidised to an alpha-hydroxy ketone. The tertiary alcohol was dehydrated along the 5,6-ring junction, and the allylic/benzylic position oxidised to provide the desired indenone system. Lastly, aerobic/basic conditions resulted in oxidation to a fluorenone, which only required deprotection to yield product.

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16 Comments

  • GiVi says:

    nice work!

    the DOI is correct but the link leads to the quinine of last week…

  • antiaromatic says:

    So I’ve talked Danishefsky about this paper. The heart of this work wasn’t so much about the natural product, as Tot. Syn. has mentioned. This work stems, at least in part, from the old days of steroid chemistry when many attempts were made to access the C-D ring system through a Diels-Alder with unsymmetrical para-quinones on similar vinylidene species (only a few, meaning ~2-3, were actually successful). It’s sort of an unsolved problem that has always been on Danishefsky’s mind. Great work, though.

  • Tot. Syn. says:

    Problem with links fixed.

  • Malcolm says:

    I know that a lot of big-name chemists write their names first, but any idea why Danishefsky, who usually stays last, put his first this timeÉ Do they do that because they came up with all the ideasÉ

  • antiaromatic says:

    Malcom,

    Danishefsky didn’t put his first this time. I think it’s a Tot. Syn. convention to put the big name first, but in general, a lot of the big names put their names first because when people screen through journal TOC, you can see whose paper it is quickly. Also, I know a couple of the big names actually write the papers.

  • pari says:

    hi,

    can anyone give me pointer or bash for selectively how to do hydrolysis of methyl vinyl ether without using HCl also i have base sensitive group?
    thanks in advance
    pari

  • Andrei says:

    PPTS

  • Retread says:

    It’s great to see that Sam is still alive and kicking — he was very overweight when I knew him from ’60 – ’62 in grad school. He’s either lost a lot of weight or he has a very strong constitution (speaking as a retired MD — able to retire early because of the massive medical complications of the massivity of massive people). He was a very nice guy then and probably still is.

    This is the blog that got me started back reading organic chemistry — with the structure of Lyconadin B last spring. I posted on ChemBark as Rip Van Winkle (nom de plume Retread. Sadly, ChemBark has been in a slumber for the past 3 months. Just started posting on The Skeptical Chymist under “Chemiotics” still as Retread. The comments people posted on Rip Van Winkle were fascinating and were more interesting (to me)than what I wrote. Feel free to do so on Chemiotics. The first post went up yesterday. There should be a very interesting new one on the 18th.

  • Malcolm says:

    antiaromatic thanks for the info. yeah I later noticed danish. was last. But I am reading the Corey JACS that came out today,…..And his name is last!! How rare. I always wonder if this means that the entire synthesis was carried out without the knowledge of the supervisor, or if it is just that it impressed Corey so much.

    -Malcolm

  • Big_C says:

    For both professors I’ve worked under, it’s been convention to put their names last. And as for Corey’s latest ASAP… I looks as though most of his publications past 2006 have him authored last, so it’s actually quite ordinary for him.

  • Reverend J says:

    Maybe I’m missing something on the first step with the DA giving a 65% ee, what exactly are they referring to? I haven’t had a chance to read the paper so maybe I’m missing something but the low ee of a Lewis-Acid catalyzed DA doesn’t strike me as special. However I’m not Danishefsky so I’m assuming I’m not seeing something here, anyone help me here?

  • Madforit says:

    Please could you give us further explanations about the epimerisation
    step? We are not able to see the need to provide stereochemical control
    for the following reduction. If Danishefsky had directly carried out
    the reduction on the Diels-Alder product (skipping the epimerisation
    step), he would have obtained the desired stereochemistry (hydroxyl
    group down, equatorial), as the hydride donor would have attacked from
    the less hindered side of the pseudo cis-decaline system. Maybe the
    reason why the 6,6 ring junction must be trans is in the last step,
    which is basically an elimination reaction with the hydride ion playing
    the role of leaving group (with a little help of oxygen): a trans
    diaxial relationship between the two Hs which are to be eliminated
    makes the aromatisation easier. Thanks in advance

  • milkshake says:

    EJ started putting himself last on the author list back in 90s, with projects where the main idea was not his own. I remember Hening Steinhagen, a bright German postdoc who did just one year in the group and got very boring asignment originally – a synthesis of quinoline benzylic bromides, to be used for quarternising cinchona alcaloids to be used as chiral phase transfer catalysts. Instead Henning proposed a novel heterodiels-alder scheme to build dihydro and tetrahydroquinolines quickly and with a good stereocontrol, and then he proceeded to a small natural product with 2 stereocenters, using this methodology. All done in one year.

  • Malcolm says:

    cool story!

  • Retread says:

    Stretch your brains a bit and look at the latest Chemiotics post “We had to destroy the village to save it” on the Skeptical Chymist. Leave comments — the box for comments on the site is tiny unfortunately. I’ve spoken to them about it, but getting things changed in a bureaucracy is never easy as we all know.

  • [...] to blogging another synthesis, but this kinda thing interests me. Y’see, after blogging the Danishefsky synthesis last week, and the Corey synthesis on Monday, I was intregued by the differences in graphical [...]