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Totally Synthetic by Paul H. Docherty, 8 September 2007

Total Synthesis of Artochamin F, H, I, J


K. C. Nicolaou, T. Lister, R. M. Denton, C. F. Gelin, Angew. Chem. Int. Ed. 2007, 46, 7501-7505.

DOI: 10.1002/anie.200702363

Recently isolated in an attempt to find the bioactive ingredients in some folk-medicines, the artochamins haven’t actually got that much biological activity. They are described as being weakly cytotoxic, so let’s focus on the interesting ring system as our reason for synthesis. However, before leaping into the chemistry, an interesting note is that the natural product is isolated as a racemic mixture, which suggests a non-enzymatic biosynthesis.

The key substrate for this reaction is actually a symmetrical molecule, created very quickly from two small subunits. The ether bonds were put in using copper(II) chloride and a propargyl carbonate. The terminal acetylene moieties were then reduced to the olefins using Lindlar conditions. The stillbene moiety was then created using a Julia-Kocienski olefination. However, it’s important to point out at this stage that a Wittig coupling was also attempted…

With the precurosor complete, it was time to perform some sigmatropic rearrangements according to Woodward-Hoffman! (Don’t forget that the thermal decomposition of Boc groups is also a sigmatropic rearrangement…)

Nice!! Straight through to a precursor for the natural product family! However, I’ll bet I’m not the only one who wondered about what the triphenyl phosphine oxide was doing… I quote from the paper:

The effect of Ph3PO was recognized when stilbene 5a derived from the Julia-Kocienski olefination failed to perform well in this process, whilst the same substrate 5a derived from a Wittig reaction (and therefore assumed to contain trace amounts of Ph3PO) went through the cascade sequence smoothly; further investigations into the precise role of the Ph3PO are currently underway and full details will be reported in due course.

Interesting. Further, those of you up on your Corey rules will also remember that thermal [2+2] cycloadditions are required to go through a suprafacial-antarafacial sense. An example of this is the addition of ketene, in which the orthogonal set of p orbitals allows the reaction to proceed via a crossed transition state. However, unless I’m mistaken, this isn’t possible in this case. In other words, this is more likely to involve a diradical or ionic mechanism. The authors postulate as much:

“We must also consider two further mechanistic alternatives for the microwave-promoted reactions. The first, and least probable, involves a [2+2] cycloaddition. The second involves a stepwise diradical mechanism in which formation of the five membered ring precedes diradical recombination. Preliminary experiments with (E)- and (Z)-5a indicate that the formal cycloaddition reaction is not stereospecific with respect to the alkene geometry. On the basis of this observation a stepwise radical mechanism, in which bond rotation occurs to some extent before recombination of the diradical, or the redox mechanism shown in Scheme 6 are currently favored. These possibilities are under investigation and full details will be disclosed in due course.”

So, again we must wait for another paper. However, given that this is a reasonably short paper, couldn’t we have waited a little longer? They postulate a mechanism, involving autooxidation of the catechol moiety to give a ketone, to which the olefin adds in a conjugate manner, but nothing is proven.