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Crisamicin A   

22 June 2008 33,101 views 70 Comments

Wang, Yang, Li, Gao, Tang, Dai, Wang. Org. Lett., 2008, ASAP. DOI: 10.1021/ol800977n. Article PDF Supporting Information ResearchBlogging.org

Another top paper in from somewhere in China (there’s quite a few insitutions mentioned… and I got lost yet again trying to find a homepage… help?), this is certainly a different class of natural product, and one with quite a biological clout.  To quote the paper, we’re talking about ‘activity against B16 murine melanoma cells, the herpes simplex, and vesicular stomatitis viruses’ – a pretty diverse CV.  Hopefully you’ve all notice one intriguing structural feature – C2 symmertry.  Generally there are two ways to take advantage of that facet: two directional synthesis, or dimerisation.  In this case, the symmetry was centred on a biaryl linkage, so they made the more logical dimerisation disconnection.  Retro:

So with the molecule bisected, the two main transformations to be considered were a Diels-Alder to build the 1,4-naphthoquinone, and an impressive bit of Pd-juggling to build the 6,5-fused pyran system.  On with the forward:

Now that’s what I like!  I’ve always had a thing about lactonisations (I think you know why) – and that’s some pretty hot stuff.  It’s quite a witch’s brew, though, so let’s look at the ingredients and rationale.  Perhaps the most important additive was that of a thiourea ligand; normally, sulfur ligands eat Pd catalysts for breakfast, but in this case it was required to mediate the Lewis acidity of palladium acetate.  This stemmed from a concern that by itself, the Pd(OAc)2 would chew-up the benzylic ether.

The copper chloride is there to aid catalytic turn-over of the palladium (used as 10 mol%), but in their screening, presented a complication, as the free chloride had an annoying habit of attacking the pi-allyl palladium complex.  This is where the propylene oxide steps in; five equivalents were sacrificed to mop-up the chloride. Finally, the ammonium acetate was there for the carbonylation step – I quote ‘Our earlier work suggested acetates to be a beneficial additive in the Pd-catalyzed carbonylations’.  In effect, it seems to boost the d.r. of the ring fusion to completely cis-, rising from a 6.5:1 d.r. in it’s absence.  Excellent stuff.

After doing a rather nice Diels Alder / oxidation sequence to provide the naphthoquinone core, a triflation and Pd-mediated borylation provided the substrate for the dimerisation.  Again with the sulfur ligands!  However, this bad-boy wasn’t developed in-house – rather it’s the work of one Kristin Bowman-James.  (Or at least the authors reckon it is, but it’s not actually in the cited paper…)  The yield for the dimerisation is great, but a little confusing – y’see the authors claim that it’s an ‘87% yield over two steps’, but the previous step also has a yield attached to is – 76%.  This kills the maths (so to speak) – what gives?!  (The SI also states 87% over two steps and excises any mention of a yield for the borylation)

Anyway, dodgy maths aside, this is a cracking synthesis demonstrating exquisite control of those Pd atoms.

Li, Z., Gao, Y., Tang, Y., Dai, M., Wang, G., Wang, Z., Yang, Z. (2008). Total Synthesis of Crisamicin A. Organic Letters DOI: 10.1021/ol800977n

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  • TWYI says:

    Pretty amazing that no referee picked up on the total basence of any NOe data. It may or may not have helped but they surely must have irradiated the aromatic OMe.

  • PKR says:

    I also read the paper from Kraus. The two diene is so different from each other. Yes, when you just consider the electronic effect, they should give the same result in the DA reaction. This is why I don’t believe the electronic effect dominate this reaction. However, from the view of steric effect, they are quite different, especially when you think the DA reaction occured in an endo fashion (the explaination in Kraus paper). In the endo DA, you should consider the interaction between the diene and the pyran and the lactone moiety. With the diene in Kraus paper, the endo DA is reasonable, since the TMSO is on the 1-position. In this work, the endo DA is almost impossible, since there is always steric hindrance between the diene and methyl or the lactone (from top or below). So, although the dienophile is quite similar, with different diene, the DA occured by different fashion to give different result, no surprise.
    I believe both of them are right, and the problem is, they don’t show enough proof, this is why so many people argue about this.

  • furrowstatin says:

    Re: Tot. Syn
    As I know, half of those authors were undergrads at the time they finished this job and right now they almost finished their PhDs. I feel respected to Prof.Yang primarily b/c he never hesitate to recommend his great students to Big groups in US when they finish their undergrads or even not, like transfer~~Actually I don’t think producing papers is his primary concern.

    If you pay little attentions to look at Chinese grad students from Baran, Nicolaou, Danishefsky, Trost, Schreiber group etc., you will see they were almost exclusively came from Yang’s group.

  • Mugu gai ba dan says:


    diastereomeric mixture….toothpaste….pet food….



  • antiaromatic says:

    In all honesty, I’m not terribly surprised by the change due to sterics, especially given the bulk of the diene (which itself probably doesn’t adopt an s-cis with much ease). In a similar vein to this topic, there’s the new Corey org. lett. that has a pretty impressive DA given that this is a long-standing problem in steroid synthesis.

  • Bill says:

    I think it has S2 symmetry

  • GYA says:

    Why don’t you move on to Stoltz’s cyanthiwigin in Nature. I’m tired of all the complaining about this synthesis!

  • antiaromatic says:


    S2 symmetry is by definition simply Ci (i.e. contains only an inversion center). There is no center of inversion in this molecule. The molecule certainly has C2 symmetry, and if it were of the S2 symmetric group, then the molecule would not be chiral.

  • Anti-Anomeric says:

    GYA – Man, forget that hype. Let’s talk about Trauner’s Rubioncolin B.

  • GYA says:

    Why? Isn’t that approach obvious–its probably even suggested in the isolation paper I’m guessing?

  • ,,, says:

    To furrowstatin

    What does all this have to do with the topic?

  • Avi says:

    Hey Tot Syn.,

    When you say that the Pd will eat away the Benzyl ethers, do you mean that it will deprotect the Phenols?

  • Sorkiller says:

    I agree with PKR’s analysis, the steric effect of the diene in this paper is completely different from that of Kraus, it should make something different. From the computational chemistry point of view, the electronic difference is pretty slight for the two carbon in the dienophile.

  • PJ says:

    Has anything come of this? Corrections/Errata published …

    Or are the ACS sweeping it under the carpet?

  • TWYI says:

    The methodology for the lactone sythesis is now out in Org. Lett., not that is sheds any light on the anomolies discussed above

  • Martyn says:

    They rather disingenuously claim that this previously required stoichiometric palladium, when it was published using 10% palladium acetate 25 years ago (JACS 1983, 2034). The yields are no better now either.

  • Totally Natural says:

    There is something very fishy about this work. Did anybody check the spectra for compounds 29, 30 and 1 in the SI?

    The homocouplig of racemic 27 should give a roughly 1:1 mixture of racemic 29 and its meso isomer. An isolated yield of 87% for 27 (after 2 steps!) is clearly out of the question. I wonder what the referees were smoking when reviewing this article…

  • […] TotallySynthetic com Blog Archive Crisamicin A Posted by root 22 hours ago (http://totallysynthetic.com) The methodology for the lactone sythesis is now out in org lett not that is sheds any light on the anomolies discussed above reply to this comment Discuss  |  Bury |  News | totallysynthetic com blog archive crisamicin a […]

  • French Women says:

    melanoma can really kill people in such a very short time specially if the immune system is compromised ;”‘

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