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Papulacandin D   

19 February 2007 7,709 views 24 Comments


Denmark, Regens and Kobayashi. JACS, 2007, ASAP. DOI: 10.1021/ja070071z.

Definitely a target of split personalities, or at least lipophillicities, papulacandin D and the rest of the family represent an interesting synthetic challange, as well as a powerful antifungal treatment. The first and only synthesis of this natural product was completed by Tony Barrett, back in ’96, using not entirely different disconnection, but I guess that is no surprise. However, the implementation of the chemistry used by Denmark is quite a different beast, using his own chemistry twice, and in a useful manner.


The retro-synthetic analysis perhaps doesn’t give too much away, other that the rather nice allylation chemistry. Incidentally, I wasn’t sure how to represent it on a retro, but the C14” stereocentre was introduced via a asymmetric hydrogenation, meaning that they could construct the bulk of that lipophillic sidechain from geraniol. They were able to extend the sidechain with a bit ozonolysis, and then a Wittig to put in the more removed diene. The oxygen functionality was then reduced/oxidised to the aldehyde, with which they did a rather interesting allylation, providing a decent amount of diastereomeric control.


The key transformations, at least for me, were those assembling the spiroketal. Just a few steps, leading to impressive complexity. So, starting with a chiral THP (referenced to a Methods. Carbohydr. Chem. paper, so I’ll assume some gross sugar-bashing), protected differentially, but with three siyl groups, they were able to oxidise the free silane to the silanol using a ruthenium catalyst and water. This gave them a synthetic handle, allowing a Hiyama-type coupling to the aryl iodide. With this inplace, they removed the pivolyl protecting group, and performed a tandem epoxidation/opening on the THP, returing the desired spiroketal in an impressive 77% yield. Good work!!


Completion of the target then required some careful protecting group manipulations, and a Yamaguchi esterification to unify the two fragments, and finish this top paper.

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  • Rumor says:

    I just heard an interesting rumor and was curious if anybody had heard anything. I was told that Baran has completed Palau’amine, the assigned structure is wrong, and the paper is submitted. Comments? If true, it would be utterly amazing.

  • excimer says:

    Not to sound mean to Baran, but I know someone working on Palau’amine and so I hope Baran’s is wrong so he doesn’t get scooped.

    (Actually I also know the guy who did this work. Super guy, great chemist, great group in general.)

  • .... says:

    Kinnel (who was an author of the original palau’amine isolation paper) notes on his website that they have submitted a paper entitled “Absolute Stereochemistry of (-)-Palauamine” to Organic Letters but it is not yet in print.

    I overheard a conversation with Baran at a conference where he said that he was not working on palau’amine but had doubts about the proposed structure.

  • The Canadian Chromatographer says:

    Well, well, there was a talk recently “where I do my post-doc” by Prof. Köck (Matthias, I believe), who was presenting NMR data against the actual proposed structure of Palau’amine, indeed. But I was not at the dinner where Phil Baran most likely was, so I could not say if (a) Baran is working on it and/or close to finishing it or (b) the structure is right or wrong. The Köck guy actually mentioned their data had been refused for publication…

    So in a nutshell, maybe that’s how the story got distorted in post #1 by “Rumor”.

  • The Canadian Chromatographer says:

    Back to today’s synthesis. The spiroketalisation goes against the usual rules for stereoelectronic control, am I wrong? Why is that?…

    I know that Chemistry remains an experimental science, and thus, what takes place in the flask vs. what classroom told you should happen are often two very distinct things!

  • ranfiddler says:

    Is that paper about Palau’amine in Nature (in press)? Baran mentioned it in his website. hoho…

  • ranfiddler says:

    yeah…I am thinking some aldol reaction can construct the right part. The List or Trost’s chemistry might work… Denmark’s method is good. But, here, they clearly paied a lot to do the right piece.

  • TheEdge says:

    D-glucanal is commercially available, and the fully acylated version they start with is only two steps/one purification from glucose according to the reference they cite. Hard to argue w/glucose as a starting material.
    The aldol is really tempting, but once you have that many oxygenated stereocenters, your protecting group strategy becomes overwhelmingly important, both in terms of order of deprotection and influence on diastereoselective reactions. Denmark’s disconnection and PG scheme seem to be pretty straightforward and efficient.
    To CC: I bet the ketal formation is through the oxonium species. I think that would give the observed product.

  • sufuric says:

    Don’t forget that the product from the ketalization is the anomerically stablized alpha anomer. And as TheEdge says, it probably goes through the oxonium species.

  • synthon says:

    CC: The axial orienation of the anomeric oxygen is expected due to stereoelectronic considerations. If memory serves however, the hydroxyl group should direct the substituent to the beta postion through anchimeric assistance. I don’t have the conditions in front of me, but sounds like this is the thermodynamic product from which the stereoelectronic argument is derived.

  • .... says:


    I see no reference to a Nature paper on Baran’s website. Was that sarcasm?

  • ranfiddler says:

    this one is coming from the faculty profile at scripps:

    Baran, P. S.; Maimone, T. J.; Richter, J. M. Total Synthesis of Marine Natural Products Without Using Protecting Groups, Nature 2007, in press.


  • The Canadian Chromatographer says:

    Thanks. Due to your readership being overwhelmingly awake, it was made pretty clear that epoxide formation was directed opposite to the existing OTES chiral centre. Then, oxonium formation following epoxide opening gives the observed product.

    The CC-guy thanks you for enlightening discussions. :-)

  • The Canadian Chromatographer says:

    And while we’re at it, has anybody got an easy mnemotechnic devce to remember who’s alpha and who’s beta? This sugar nomenclature always confuses me – isn’t “up” and “down” a tad simpler? This is just me blabbering.

  • JamesB says:

    Well, depending on how you draw the ring “up” or “down” could be either alpha or beta. The only way I manage it (we do a LOT of carbohydrate chemistry) is to look for the orbital overlap. Overlap? Yes=alpha, No=beta.

    Corrections on a postcard please.

  • Tex says:

    I seem to recall (it’s been a long time), in carbohydrates that(in hexoses) it has to do with the relative orientation of the anomeric substituent and the substituent on C5. Other uses, in non-carbohydrate systems are dependent on how you draw the molecule.


  • stockholmare says:

    you can remember that *beta* is *above* the plane of the ring, because “b” is the second letter of *above*.

    of course, this only holds true for your ‘usual set’ of sugars if you draw them in the usual way, but it is nevertheless my favourite mnemonic. hope this helps.

  • buyproduct says:

    The above trick only works for D pyranose sugars. I do a lot of carbohydrate chemistry and this is how I tell the difference. I figure out the R-S configuration at the anomeric carbon. Next I figure out the R-S configuration at the first stereogenic carbon closest to the in ring oxygen (C5 or C4). If they match then the sugar is alpha. If they are a mismatch then the sugar is Beta.

  • WillisWill says:

    I always did it based on relative stereochemistry of the 1 and 5 substituents. If they are cis, the sugar is beta, if they are trans, the sugar is alpha. this works for pyranose and furanose derivs.

  • .... says:

    A paper appears in today’s (Feb 22) J. Org. Chem. ASAPS detailing the isolation of new palau’amine related products – the stylissadines – and reassigning the structure of palau’amine.

    In this paper, the new structure of palau’amine is assigned as having a trans-fused bicyclo[3.3.0]octane. I’m not sure that I buy this. Does anyone know of other natural products bearing trans-fused 5,5 rings?

  • Tex says:

    A similar paper also came out in latest issue of TL indicating a revision of the palau’amine stereochemistry. I too, am somewhat surprised by the trans fusion of the bicyclic system. These are not completely unknown – there was a total synthesis of a terpene (the name escapes me) by Schreiber, Jamieson and one other author which contains a trans fused [3.3.0] system. Again if I recall correctly, it contained an oxygen atom, and it may be in these systems that the presence of a heteroatom reduces some of the torsional and non-bonded strain. It is highly unusual though.


  • Dude McDude says:

    Calling Rychnovsky and disciples: maybe this would be a good opportunity to use that NMR prediction software – on palau’amine.

  • The Canadian Chromatographer says:

    Today in Angewandte Early View, there is a paper (which the author came to present at Scripps) on the palau’amine structural revision. Could Tot Synth please put this link? DOI: 10.1002/anie.200604076. This is the paper I was talking about in post #4 on this blog entry.

    Cross-referencing myself. That increases my citation number!

  • Hap says:

    21) That’s epoxydictymene – it has an 8.5.5 core with the three core rings trans-fused to another. The eight-membered ring probably has something to do with it, though.