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Phorboxazole A   

24 November 2006 8,526 views 17 Comments


White, Kuntiyong and Lee. Org. Lett., 2006, ASAP. DOI: 10.1021/ol062530r.

White, Lee and Kuntiyong. Org. Lett., 2006, ASAP. DOI: 10.1021/ol062531j.

I was damn surprised to see a total synthesis of a beast like this ‘un in Org. Lett. today, but I’m afraid that after reading the papers, I’m less so. Obviously, the target has been around for years, and has been pretty popular, with syntheses by Forsyth, Smith, Williams, and Pattenden in the bag. Unsurprising given that tasty-hot cytotoxicity! Anyway, on with another, and the retro:

As you can see, we’re not looking at anything particularly novel, but it’s certainly a well designed synthesis, with plenty convergency. The interesting reaction(s – there’s two of them) are the alkoxycarbonylations. This reaction was first investigated by Semmelhack in 1989, using stoichiometric palladium to effect the transformation. The White group used this as in the literature to create the A-ring as shown below.

However, White noted that the carbon monoxide was reducing the Palladium to Pd(0), explaining the need for a stoichiometric “catalyst”. Thus, adding an oxidant (excess p-benzoquinone), catalytic palladium dichloride bis(acetonitrile) was able to effect a similar transformation to create the B-ring in a similar fashion, though in only 58%.Without any directly comparable examples, it’s difficult to judge this methodology properly; palladium acetate is expensive, but binning a significant proportion of the SM is also expensive (they did recover 15-20%)…

Anyway, that’s all I’m discussing about these papers… did I miss anything interesting?

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  • European Chemist says:

    Once again a very good post Tot. Syn. but I’m afraid the synthesis is less than “exciting”… I downloaded the papers and after a quick read came to the same conclusion, the only “interesting/unusual” stuff were those alkoxycarbonylations. No new methodology apart from that… snif

    It’s funny that you comment on this being on JACS or Org. Lett. I personally find it funny the thought that “just because it’s a big molecule it should go to JACS or ACIE”. I’d tell you more, IMHO if this was REALLY a good synthesis with lots of kinky chemistry and elegance, it would get to JACS even if there were 50 previous syntheses!

    That’s why I say small molecule synthesis can be all the much trickier: ’cause it’s small, you can’t fool people with 30 protection and deprotection + oxidation steps. :-P You have to do it quick and elegant, otherwise some else has already done better than you in some 1970 JOC :-D

    PS: The final plan used a Julia-Kociensky disconnection rather than the asymmetric allylboration for the left-hand part, cf. the second paper.

  • Tot. Syn. says:

    Yeah, I saw “Phorboxazole A” in Org. Lett., and after reading the papers, I wasn’t surprised it was there. Initially, I thought a JOC article would have been more suitable, but nah… But the idea of splitting an “article” into two “communications” is just bizarre. Perhaps a full paper in Euro JOC would have been more appropriate??

  • European Chemist says:

    No idea… anyway, you should know that Americans don’t read Euro JOC :-), so that’s automatically out of question. As for the splitting, it’s characteristically Nicolaou’s way of doing things.
    I’m personally not opposed to back-to-back communications, and it seems kind of warranted in such cases where you build intermediates and then couple them, or when you describe new methodology and then apply it to a “more-or-less-complex” total synthesis.
    Did you notice that Julia coupling, BTW?

  • An interesting piece here about the mechanism of action, which contains a link to some hardcore biology in JACS performed in collaboration with……..JJ La Clair at the Xenobe Institute. It’s a small world isn’t it.


    FWIW it doesn’t appear to be a cytotoxic – rather a cytostatic agent acting on Cdk4.

  • American Chemist says:

    Dear European Chemist:

    Large molecule synthesis is not a joke. Small molecule syntheses could indeed be tricky. However, you have a luxury of an easy re-design and conclusive model studies (and relatively easy analysis of what is going on!). With a large molecule synthesis everything is more complicated. You spend two years getting your fragments just to find out that you have not selected a correct protecting group and need to go 20 steps back. When you do so you find that with the new protecting group your previous route doesn’t work and you need to spend additional 6 month to find the right way to repeat everything.

    As far as fooling people with 30 protection/deprotection steps is concerned, I have seen a number of large molecule syntheses that failed at the very last step because the late stage deprotections were not regarded as something serious. Confronting these small issues dealing with protection/deprotection/oxidation, etc. is as challenging as optimizing some Pd reaction or a cycloaddition. That’s, probably, the reason why a number of quite serious scientists such as J. D. White spend their time developing new precedents and generalizing the old methods. Who knows, maybe in 20 years making polyketides and carbohydrates will be as easy as making peptides today.

  • regularchem says:

    I am sure they sent it to JACS and got rejected. The reason it appeared in OL , not ACIE, probably has something to do with the professor’s personal preference. I know several american prfessors who never publsihed in ACIE. Keep in mind, even H.C.Brown one time was against publishing in JACS.

    • James D. White says:

      Not true! This work was never submitted to JACS. Far more synthetic organic chemists read Org Lett these days than read JACS, especially graduate students. Org Lett is rigid about the four page max but Amos Smith strongly encouraged back-to-backs in this case.

  • Irregular Chemist says:

    It’s a fine enough synthesis and I doubt that it got rejected from JACS. OL’s all the rage these days, and they are very good about publishing things fast. (does JACS even publish synthetic organic chemistry anymore?) While the two communication thing does seem like cheating at first (can’t fit it in 4 pages? How about 8!), it is a big molecule. I don’t think that the White group has published anything on phorboxazole since a 2001 communication on the Semmelhack alkoxy carbonylation for the C20-C26 ring, so there’s quite a bit to talk about.

    For a really efficient synthesis of phorboxazole (B), you have to like the Evans route. (also told in back to back communications….angew, i think.)

  • ddd says:

    my communication was published in 4 weeks, and it was accepted in JACS after 1 week we sent it. it was 2004.

    P.S. Phorboxazole is done done done. Stop making it, Amos makes gram quantities already. This structure is beaten to death. Macrolides do have a limited number of carbons – meaning there are LIMITED numbers of efficient syntheses exist.

  • Gram quantities is nowhere near enough for pre-clinical toxicology/pharmacokinetic studies, where you are probably looking for 1kg minimum (obviously depends on intended dose/regimen to some extent).

  • movies says:

    I bet they submitted this to JACS as a full paper (ca. 8 pages) but it got bounced so they sent it to OL where it was a sure thing to get in.

    I don’t think this a poor synthesis by any means. Also the fact that it has been made before shouldn’t affect its importance. Take longifolene as an example, it’s been made about 10 times using all kinds of different approaches and a bunch of really interesting chemistry has come out of those pursuits. You can learn a lot by making a molecule in different ways!

  • ddd says:

    if you remember discodermolide story, 60g is enough for preclinical (or clinical I am not sure), check Org Pros Res Dev

    • James D. White says:

      This work was never submitted to JACS either as a full paper (which I have yet to publish) or in Communication form.

  • European Chemist says:

    Dear American Chemist

    I did not, by any means, pretend to say that “large molecule synthesis is a joke”. If you recall, the comment was intended at the suggestion that all syntheses of large molecules should, “per se”, justify a place in JACS or ACIE. The case in hand is one in which, though the work is highly commendable and was surely faced with many difficulties, there is nothing particularly novel, original or “better” than previously described work. Sure, it is a huge piece of work. But that doesn’t make it “extraordinary” work, if you get what I mean.

    I totally agree with you on the issues of protecting groups and correct ordering of steps in lengthy sequences, in which a false step can prove deadly to the whole strategy. And in the risk of building advanced fragments only to find out they can’t be coupled the way you expected them to. But, as far as the graduate student is concerned, advanced fragments that are synthesized ALWAYS mean at least one or two publications assured (“synthesis of the C1000-C985899 fragment of Yourfavoritemacrolide”), whereas 1 year of lost work in a seemingly simple transformation for a small molecule (and I have seen many such cases here) will yield… nothing.

  • arrived here from facebook. Your column has become a little contentious. Might want to participate there so they can get to know you easier and you can meet better web denizens.

  • lovesorganometallics says:

    zzzz. Talk about boring and tiresome!! I mean, its a perfectly beautiful beast of a molecule, and you have such obvious chemistry. It kinda reminds me of Nicolaou’s syntheses – they are long or huge or whatever but there is not so much novelty many times.

    I wanna ask something here. When people know that their papers are GOING to be quite simple like this, why not do better work, or try interesting transforms? I mean, the alkoxycarbonylation is also quite simple, but its Transition metal catalyzed and hey! its unorthodox and elegant.

    I just don’t understand why people bust their heads into stabilizing procedures into something they know will just get an OL?! -___-