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Ambiguine H   

24 March 2007 6,508 views 14 Comments

hapalindole-u.jpg

Baran, Maimone and Richter. Nature, 2007, 446, 404-408. DOI: 10.1038/nature05569.

If you read this blog, and you haven’t hassled me about a post on this paper, you’re actually in the minority. It’s from what appears to be a bit of a special on chemistry – or at least I’m not used to seeing quite this much in Nature. In the commentary, we’ve got a highlight by John Porco on this paper, a piece on C-H activation, and a review by F. Dean Toste on relativistic effects in gold catalysis. And as pointed out in a previous comment, I’m in it too…:)

Anyway on with the synthesis:

hapalindole-u_1.jpg

Nice. They actually investigated the coupling with plain indole, but even though they got a good yield, the subsequent 6-exo-trig cyclisation went best with the bromide in-place. Interestingly, radical cyclisation conditions went via a 7-endo-trig route, which I wouldn’t have thought to be so facile.

I’ve missed out the next few steps, primarily because they are a little less novel, but also because if I transcribed them, I’ve have done the whole synthesis… Anyway, with Hapuindole U done, all that was required was to install the tert-prenyl unit onto C2 of the indole – but direct methods weren’t compatible with that funky isonitrile. However, following a Danishefsky protocol, they formed the pentacyclic chloroimidate by addition of prenyl-9-BBN.

hapalindole-u_2.jpg

Now things get rather tasty – a Norrish-type 1 (I think) cleavage of the chloroimidate, followed by the usual hydrogen abstraction allowed deborylation and reduction back to the indole with the prenyl group in place – top banana!
hapalindole-u_3.jpg

Sweet synthesis, over in six steps! I can’t believe how good that last sequence is… Anyway, we’ll look at welwitindolinone A and fischerindole I in a couple of days…

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14 Comments

  • The end game of ambiguine is brilliant. What a perfect way to take advantage of an isonitrile group.

  • monkey want a phd too! says:

    I’m pretty sure that carvone-ish looking ketone with the alpha-quaternary carbon stereocenter isn’t purchased from Aldrich Chemical in enantio enriched form. Although carvone probably is, so the six steps is from known, not $$. If its made in a similar way to the intermediate Baran used in the welwit A syn, then I seem to recall the yield in setting the quat center isn’t so hot. But hey, carvone’s cheap, just buy more.

    That said, this is a damn sweet synthesis, and a nice summary totalsyn. I’m surprised tBuOCl didn’t tear their indole a new one. By plan or desperation, the entire imidoyl chloride sequence is a bold move – and it sure paid off.

    Nitpick – I’d draw in the stereochemistry of the tertiary center in that ketone as well because its looks important for the dr of the Cu(II) chemistry.

  • lucagh says:

    ummm… can someone please pick up my jaw. it just fell out after reading this paper.

  • provocateur says:

    seriously….how do u plan these syntheses????

  • milkshake says:

    Maybe the isonitrile participation was not exactly what they had in mind – though when it happened they found a way to restore the isonitrile in the end. (Which would not change the fact that lots of nifty stuff was combined in this high-risk scheme, and put to practice with a synthetic bravado).

  • .... says:

    The thing that I love about this paper (on top of its staggering beauty), is the references included (Classics 1/2, “atom economy”, “step economy”, Fu/Evans/Hoveyda directing groups, etc.). Sure it’s all salesmanship, but he includes every reference that a contemporary synthetic chemist should know about. Someone who knows nothing about total synthesis could consult this paper and come out knowing quite a bit. This is of course the responsibility of anyone publishing in Nature, but it is done here with exceptional style and taste.

    Provocateur: I’ve heard Baran say at a conference that they plan their syntheses quite loosely, allowing them to take advantage of serendipitous discoveries along the way….but I guess that’s common sense.

  • That cyclization looks liek it could be a mess, i wonder how hard it is to pull it off in the lab.

  • WestCoast85 says:

    Phil Baran is an emergent researcher like Andrew Myers from Harvard for example. The next Nicolaou ?

  • Rof5 says:

    You can say it again, WestCoast85. Corey said once, “I am convinced that Phil Baran is and will be, the most outstanding synthetic chemist of his generation.” (C&EN Jan 1 ,2007, P30) Most of all, he is at the age of 29.
    Let’s just wait and see!

  • willyoubemine says:

    is it me, or has he done this work almost exactly as before in a JACS paper…why si this a NATURE?

    not puttng down the work, just surprised that this is a NATURE.

  • ddd says:

    NATURE requires a solid literature precedent lol….Can you guess what would be the next step to beat Baran’s strategy?

  • Darksyde says:

    Not to shit in the pool. I really like these syntheses, have a lot of respect for Baran, and think they *should* be in nature, those smug biologists need to understand that academic chemists do relevant things — but, I have to say the label “protecting group free” is a bit misleading. I believe in the synthesis, the isonitrile group is being protected by a chlorine atom.

  • KS says:

    It looks like it should be published on Org. Lett or JACS not in Nature

  • pi* says:

    It is a damn good synthesis. Probably one of the nicest in some time, better that the Jacs standard (which is usually pretty high).
    Nature hardly ever has any chemistry, let alown synthesis. The entire issue was primarily chemistry. I think that the issue (and to include the synthesis) was kind of a hats off to synthesis and chemistry in general.
    Yeah it isn’t going to change anything, you didn’t discover anything new. but certainly at the top of the game in a very difficult field.
    The paper on breaking bonds using mechanical strain is pretty typical nature fair, and I’m sure would have gotten in even without a special chemistry issue…this will open up a new field of chemistry.