Home » Still In The RBF

Exiguamines A & B   

13 August 2008 10,909 views 16 Comments

Trauner, Andersen, Volgraf, Lumb, Brastianos, Carr, Chung, Münzel and Mauk. Nat. Chem. Bio., 2008, ASAP. DOI: 10.1038/nchembio.107. Article PDF Supporting Information Group Website Group Website ResearchBlogging.org

Starting to look like the king of biomimetic synthesis, Dirk Trauner (soon to be moving to Munich – the TUM I believe LMU - I stand sit corrected) has dropped the synthesis of another polyaromatic beast, this time into Nature Chem. Bio.  This isn’t too uncommon – Kozmin showed his take on Leucascandrolide earlier this year (though I’m bored to tears with that macrolide).  Although there is a degree of ‘bio-padding’ to the paper, the focus on chemistry is excellent.

So what about the target?  Well, it turns-out it loves smacking-down indoleamine-2,3-dioxygenase, which in turn metabolises tryptophan.  Now tryptophan appears to be important in the immune response – to quote: ‘solid tumours evade the immune response by decreasing local concentrations of the amino acid’.  So there are definitely interesting biological mechanisms at play – but how to build it?

As usual for a biomimetic synthesis, it’s all about making a key intermediate by hook-or-by-crook, and then letting the biological-type conditions do their thing.  In this the intermediate was built by a biaryl coupling Stille-style, and Henry reaction / reduction to put on the pendant amine.  Treatment of the phenol with Salcomine (a reversible binder of dioxygen) did an oxidation to provide a pair of isomeric quinones, with the undesired ortho-quinone unfortunately predominating.  No reference was given for this step – so any takers on a mechanism?

Next-up was the true biological mimicking – after a quick enolate addition to the para-quinone, and global deprotection.  With the dimethyl hydantoin group bolted-on, a bit of oxidation with 10 equivalents of silver oxide gave the desired target, Exiguamine A.  However, in attempting to boost the yield of this transformation, they upped the excess of oxidant, and found that a further-oxidised derivative predominated (the C17-hydroxy analog).  They then went back to the isolation gunk and found that the same substance was also present, which the decided to call Trauneramine Exiguamine B.

Even more interesting was the fact that they couldn’t oxidise Exiguamine A to Exiguamine B – suggesting that A isn’t part of the biosynthesis of B, and thus that their biosynthesis (and the mechanism for these reactions) must diverge.  A postulated mechanism is given in the SI, but as that is avaliable to all and sundry, I’ll save my ChemDraw fingers for now (though I could redraw it if pushed).

Interesting work from many perspectives…

Volgraf, M., Lumb, J., Brastianos, H.C., Carr, G., Chung, M.K., Münzel, M., Mauk, A.G., Andersen, R.J., Trauner, D. (2008). Biomimetic synthesis of the IDO inhibitors exiguamine A and B. Nature Chemical Biology DOI: 10.1038/nchembio.107

1 Star2 Stars3 Stars4 Stars5 Stars (No Ratings Yet)


  • Kutti says:

    Acutally, he has already arrived in Munich but his group belongs to the LMU (Ludwigs-Maximilians-Universität) and not to the TUM ;-)

    By the way: the synthesis is really sweet!

  • Tot. Syn. says:

    Ah… I knew I’d guess wrong. I saw him present this work at BOSS, and it was awesome. Interestingly enough, he cited the his new institution as being far more willing to part with cash. I wouldn’t have thought of Berkley as being ‘tight’… Best of luck to him – I’ve been to Munich many times and thought it was a fantastic city.

  • PhN2Ph says:

    That Matt Volgraf looks like a real whiz-kid. In addition to this great work, he was a major player in Trauner’s light-gated ion channel project.

  • GYA says:

    How much of a contribution can one author have on a paper which has eight authors (in addition to the advisor)? Anyway, there really is only one noteworthy step here.

  • @Berkeley says:


    Volgraf was really the driver of this project. if you read the abstract more closely you will see that there were only three people involved in the synthesis (not including advisor), and one of those people was a visiting student. Before you make comments like that, do your homework.

    As far as Berkeley money goes… it is a public school in the chronically broke state of California. So it is probably mo’ po’ than many people expect.

  • @Berkeley says:

    Also, how many syntheses of this length have more than one “noteworthy step”? I think the idea of cyclization by oxidation is a nice one, if not totally unexpected, and the execution of steps on the indoloquinone core is also interesting as these compounds are likely quite unstable.

  • GYA says:

    Three people is a lot for a synthesis of this length with only one noteworthy step. Pretty mundane chemistry until cmpd. 19 is oxidized (which proceeds with poor selectivity) and that’s simply an oxidation to a quinone (haven’t seen that before!). Also, if you were educated in considerations about biosynthesis, you also may have developed this same approach to the molecule. It really isn’t a heroically creative idea (its nice don’t get me wrong).
    Also, “syntheses of this length”–I’m guessing means you think its really short (its actually still 20 steps from cmpd 12)–not that short when you buy 3 of the rings. Plenty of syntheses of this length (and shorter) have more noteworthy transformations.

  • TWYI says:

    Salcomine is usually petty reliable, even with both ortho-positions to the phenol free. Has to be due to the indole-Boc

    Fremys? Maybe would hit the anisole tho’…

  • PhN2Ph says:

    The exiguamines were just reported in Dec. of ’06, which makes this really rapid turn-around for synthetic work; that’s very important for a biologically relevant molecule currently pursued by numerous groups (as this one is). My guess is the Trauner group and collaborators will now produce the lion’s share of discoveries associated with the exiguamines.
    That should put the contributions of Volgraf et al in a better light for the benefit of readership like GYA.

  • frisco says:

    Hey Tot. Syn.,

    Did you see this highly oxidized beast that was finished by the Floreancig group?


    There’s a few particularly thoughtful transformations in that route.

  • anon says:

    I’ll take a stab at the salcomine mechanism, I guess…

    1) Reversible O2 binding implies an equilibrium between the Co(II) species drawn and a Co(III) superoxide complex, Co(III)-O-O, with an unpaired electron on the terminal oxygen
    2) The Co(III) superoxide abstracts the phenolic hydrogen to generate the phenoxy radical and a Co(III) peroxide complex
    3) The phenoxy radical reacts with O2 at the ortho or para position to generate a cyclohexadienone with a peroxide radical at the ‘methylene’ carbon; this rearomatises to restore the phenol
    4) The phenol/peroxy radical abstracts the proton from the Co(III) peroxide complex, regenerating the Co(III) superoxide complex and forming a phenol with a peroxide at the para or ortho position
    5) The lone pair on the phenol oxygen pushes down through the aromatic ring, the O-O bond is cleaved to kick out water and form the quinone.

  • ale says:

    I agree with your mechanism hipothesis for the oxidation step with Co(salen).

  • GYA says:

    In the end, the major contribution here is the biosynthetic idea. Hard to know who had it (Trauner or one of his students). Not something in the abstratct!

  • @Berkeley says:


    I agree that the synthesis clearly falls out from biosynthetic considerations and also that it isn’t a mind-blowingly difficult one to propose. My main point is that there were really only two people working on the molecule for much of the time, not eight. Volgraf deserves a lot of credit for this work, even if it isn’t crammed with new chemistry.

  • GYA says:

    Fair enough.

  • desichemist says:

    Why is this paper in Nature again?