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Totally Synthetic by Paul H. Docherty, 13 August 2008

Total Synthesis of Exiguamine A & B

Trauner, Andersen

M. Volgraf, J.-P. Lumb, H. C. Brastianos, G. Carr, M. K. W. Chung, M. Münzel, A. G. Mauk, R. J. Andersen, D. Trauner, Nat. Chem. Biol. 2008, 4, 535-537.

DOI: 10.1038/nchembio.107

Dirk Trauner has just published the total synthesis of another polyaromatic beast in Nature Chem. Bio. Although there is a degree of biomimetic synthesis in the paper, the focus on chemistry is excellent.

So what about the target? Well, Exiguamine isolated from a marine sponge inhibits 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 allowing the conditions mimicking biology to proceed. In this the intermediate was built by a Stille-like biaryl coupling, and Henry reaction / reduction to install 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.

Next up was the true biological mimicking - after a quick enolate addition to the para-quinone, and global deprotection. After the construction of the dimethyl hydantoin group, an oxidation with 10 equivalents of silver oxide gave the desired target, Exiguamine A. However, in attempting to improve the yield of this transformation, they increased the excess of oxidant, and found that a further oxidised derivative predominated (the C17-hydroxy analog). They then found that the hydroxy analog is also present in the sponge and decided to call this natural product Exiguamine B instead of Trauneramine.

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 biomimetic synthesis (and the mechanism for these reactions) must diverge. A postulated mechanism is given in the supporting information.

Interesting work from many perspectives…