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Totally Synthetic by Paul H. Docherty, 31 January 2007

Total Synthesis of Pleocarpenone


M. J. Williams, H. L. Deak, M. L. Snapper, J. Am. Chem. Soc. 2007, 129, 486-487.

DOI: 10.1021/ja0674340

An extraordinary total synthesis of this simple-looking guaiane natural product (along with it’s exo-methylene analogue, pleocarpenene), Marc Snapper has once again used deft control of pericyclic reactions to produce some extremely odd looking intermediates in this synthesis. As regular readers will know, I tend to use a disconnection-based retrosynthesis to explain the synthetic plan, but as you can see, Snapper’s approach makes this a little tricky!

From this retroanalysis, it’s clear that the double ring-expansion is key to this synthesis, but that 3,4,4,5 ring system looks just a little strained to me. Its construction is far from trivial. However, Snapper used some incredibly iron chemistry to build those cyclobutanes, performing a photochemical cyclisation to build the first ring (a cyclobutadiene), and then inserting iron to stabilise it. Functionalisation of the exocyclic ester using fairly standard chemistry (and an oxidation/CBS reduction sequence to introduce asymmetry) left them with a free alkene, which they were able to add to the freed butadiene in one step. This generated the second four-member, along with the cyclopentane, in good yield, and with an reasonable excess of the preferred diastereoisomer.

The final elaboration to produce the rearrangement substrate was cyclopropanation of the butene ring; I thought that this might be a tricky step, but it really didn’t faze them at all:

Copper catalysed elimination of the diazo group left the carbene, which added very efficiently to the butene, generating that amazing 3,4,4,5 ring system, and after oxidation and treatment with methyl grignard, the target substrate. A bit of (somewhat less than gentle) thermal persuasion then snapped those strained rings open, inverted the stereocenter at C1, completed the carbocyclic skeleton. More mundane chemistry was then applied over a couple of steps, completing the total synthesis of the target, and my favourite paper of 2007 so far. :-)

Selected Comments

1 February, 2007 at 2:40, Spiro says:
Does anybody know why they use silver-impregnated silica gel for the separation of compounds 5alpha and 5beta ? See scheme 2, step j. I am clueless!
The answer may be in ref 2 of the supp infos, but I doubt many of us have an easy access to Chrom. News…
By the way, Paul, great blog!
1 February, 2007 at 4:02, aa says:
Although I am not really sure what adding Ag to silica gel columns does to make it a great solid phase, it certainly works well for difficult separations. People in the lab next to mine use it to separate 2-3% of a minor cis isomer from a really long chain trans alkene… Of course it is very annoying since AgNO3 is the silver source and the whole thing has to be wrapped in foil and kept in the dark.
1 February, 2007 at 5:30, synthon says:
Sprio…its called “argentation” chromatography and it can be truly remarkable! Recent review:
1 February, 2007 at 11:47, milkshake says:
I think Ag+ is coordinating to C=C and differentiates alkenes on silica depending on cis/trans and di, tri, tetra-subst
1 February, 2007 at 13:02, Tot. Syn. says:
That’s it exactly. One doesn’t have to use silver, either. Other metals that coordinate well to olefins without undue scrambling work well too, so it’s normally worth experimenting. Sometimes using the argentation chromatography results in adverse affects due to light, but doing the column wrapped in some sort of “black out” stops that from happening. Pesky photochemical effects…