From the TotallySynthetic.com Blog by Paul Docherty

Exiguamines A & B

Trauner, Andersen, Volgraf, Lumb, Brastianos, Carr, Chung, Münzel and Mauk. Nat. Chem. Bio., 2008, ASAP. DOI: 10.1038/nchembio.107.

Starting to look like the king of biomimetic synthesis, Dirk Trauner 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.  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 they decided to call  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