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Pseudo-brevenal   

11 July 2006 6,901 views 8 Comments

Brevenal.jpg

Sasaki, Fuwa, and Ebine. JACS, 2006, ASAP. DOI: 10.1021/ja062524q.

Yup, another poly-ether, though with some interesting biological activity; this one seems to have positive effects, increasing tracheal mucus velocity, and thus potentially of use in respiritory disorders. Also, it appears to be a brevetoxin antagonist in vivo. As discussed in the comments surrounding the previous post (ciguatoxin), much of the work relating to ladder-type poly-ethers has been published before, so I’ll stick to the main disconnections.

Firstly, a Suzuki-Miyaura coupling of the main A,B and D,E fragments, building part of the C ring. This was completed using Sasaki’s own methodology involving enol-phosphates:

Brevenal_2.jpg

Completing this coupling in over 84% (quoted over two steps), including a stereoselective hydroboration, they set themselves up nicely to complete the C-ring. Once delivered, they then had to couple the left-hand sidechain, containing a devilsome tetra-substituded olefin. Impressively, they were able to constuct this using a Stille coupling, in its Cu-TC form.
Brevenal_3.jpg

With relatively simple modifications required to complete the right-hand sidechain, they soon delivered the proposed structure for the natural product, but were confronted by ill-matching spectra when compared to the isolated substance. They propose that they have simply made the C-26 epimer of the natural product (the right-most hydroxyl-bearing carbon), so I’m sure we’ll see the complete specimen shortly.

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8 Comments

  • Atompusher says:

    “This was completed using Sasaki’s own methodology involving enol-phosphates”

    I though this was Nicolaou methodology? Who is stealing from whom?
    J. Am. Chem. Soc.; (Communication); 1997; 119(23); 5467-5468.

  • Tot. Syn. says:

    Nicolaou: http://dx.doi.org/10.1021/ja970619+ 1997 (as you said)

    Sasaki: http://dx.doi.org/10.1016/S0040-4039(98)02025-5 (1998, Tet Lett.)

    http://dx.doi.org/10.1021/ol990885n (1999, Org Lett.)

    Hmm. Both use Pd mediated processes to elaborate a ketene acetal phosphate, but Nicolaou didn’t (in that paper) use it to couple to large fragments. However, the implication is clearly there, and I’m sure he used in that way in a later paper. The Tet Lett Sasaki published feels a bit “shit, they’ve scooped us”, but it’s always hard to tell. Remember the Taxol debacle with Nicolaou?
    Perhaps they both came upon the idea at the same time (cough, cough); or perhaps they both stole it from Corey.

  • ddd says:

    my question is this:

    why nicolaou’s taxol synth. was published in nature, while Holton’s synth. which came up earlier was not?

  • secret milkshake says:

    The two polyene appendages at both ends of the molecule – it seems like an untied shoelaces. One is drawn into performing a RCM in the end, to tie the molecule into one happy macrocycle…

  • Tot. Syn. says:

    Must…stop…RCM…arghh… Shrock!!! (in my best William Shatner)

  • Hap says:

    I thought that KCN published in Nature because their time to publication was shorter than JACS or ACIEE – I think he knew (though I don’t know either for sure or firsthand) that Holton’s paper was in process and so he wanted to publish first. I assume that Holton submitted to JACS, and didn’t really think about Nature as a place to publish his synthesis. I thought that a lot of people went “Huh?” when KCN published in Nature.

  • [...] So the structure has been confirmed. And using a nice total synthesis too. So do we know if La Clair has lied? Not conclusively; someone would have to follow his synthesis exactly, and try to see where the discprepancies creap in [1]. However, it’s very difficult to see any element of honesty in his work, and what’s more annoying is why. Aferall, had he gone after the original target, completed the synthesis and then discovered that the spectral data didn’t match, it would hardly be the first example. This happens often enough, and he could simply have postulated his thoughts on the discrepancy, as the authors of this paper did with their synthesis of pseudo-brevinal. But no, he seems to have lied. What does this mean for us? [...]