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Totally Synthetic by Paul H. Docherty, 13 January 2009

Total Synthesis of Chamaecypanone C


S. Dong, E. Hamel, R. Bai, D. G. Covell, J. A. Beutler, J. A. Porco, Angew. Chem. Int. Ed. 2009, 48, 1494-1497.

DOI: 10.1002/anie.200805486

I’m surprised, that the heartwood of Chamaecyparis obtusa (Japanese cypress) is the origin of Chamaecypanone C, which is a tubulin polymerisation inhibitor. Well, loads of trees yield interesting isolates, but for me  heartwood is more or less wooden…

If  you have a look at the target, you maybe recognize a dimerisation, and perhaps a Diels-Alder reaction. However, whilst the approach used by Porco contains these elements, the overall strategy is pretty special. A test case for the methodology was published in JACS one year ago, with an oxidative dimerisation, using sparteine to induce asymmetry. The yield and e.e. is definitely awesome, but the use of 2.3 equivs of sparteine is quite high. However, this additive is very cheap, and I’m sure that they can recover it at the end of the reaction.

Now comes the really interesting part; prolonged heating leads to a retro-Diels-Alder reaction to give the hydroxy cyclohexadienone, which can perform a Diels-Alder reaction with an alternate dienophile. In a test scenario, they used N-phenylmaleimide, which worked fantastically - a 99% yield of the cycloadduct, presumably with complete control of diastereoselectivity.

The total synthesis of Chamaecypanone C used exactly the same retro-Diels-Alder/Diels-Alder cascade, with some impressive selectivity. It’s obivious that only a demethylation step is required, and job done - tribromoborane did the task nicely.

However, we’re not quite done yet, as the eagle-eyed readers will have noticed that our hydroxy cyclohexadienone intermediate has flipped configuration, which presents a problem. This problem is that (+)-sparteine is very expensive. A useful workaround is Peter O’Brien’s surrogate - which would be interesting to try in this situation. However, Porco came up with a fantastic alternative - a similar hydroxy cyclohexadienone enantiomer is used in an α-ketol rearrangement (a pinacol-like 1,2 Wagner-Meerwein shift - check that JACS again) to rearrange into the desired enantiomer. A very fine total synthesis…