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31 January 2007 78,386 views 18 Comments


Snapper, Williams and Deak. JACS, 2007, 129, 486. DOI: 10.1021/ja0674340.

An extraordinary 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 retro, it’s clear that the double ring-expansion (is that the correct term?) is key to this synthesis, but that 3,4,4,5 ring system looks just a little strained to me, and to my eyes, it’s construction is far from trivial. However, Snapper used some incredibly funky 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 a 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 stereocentre at C1, completed the carbocyclic skeleton. More mundane chemistry was then applied over a couple of steps, completing the synthesis of the target, and my favourite paper of 2007 so far. :)

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  • Zinc says:

    While the fragmentation reaction is pretty cool, it seems like alot of work to make a 5,7 system. The point of the synthesis may be to showcase the key reaction, not to simply make the molecule, but a target that was more in need of such a solution would have made a more interesting read.

  • Chemist of Sorts says:

    I have to agree. Some interesting chemistry, but, from a target oriented view, the synthesis feels over-engineered.

  • middle lab says:

    Nice synthesis, but I bet the author doesn’t have The Belt!

  • 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!

  • 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.

  • synthon says:

    Sprio…its called “argentation” chromatography and it can be truly remarkable! Recent review: http://dx.doi.org/10.1016/S0040-4020(00)00927-3

  • milkshake says:

    I think Ag+ is coordinating to C=C and differentiates alkenes on silica depending on cis/trans and di, tri, tetra-subst

  • 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…

  • sheriff says:

    theh doi doesnt work

  • earth23 says:

    RCM = ring closing metathesis, seems like their use of Grubbs 2nd gen is intermolecular.

  • Spiro says:

    The doi works fine for me.

    The technique is really interesting from an analytical point of view, but I am not convinced of its preparative use $$$ They must have run one column for publication purpose…

    Big thanks to synthon!

  • synthon says:

    Re: $$$ – the silica does have the potential to be recycled as your compound is likely already rather pure from the initial chromatography. It really is super helpful with small non-polar hydrocarbons such as the compound described here. I used it to remove a small amount of dimeric material from my compound following a Cu-catalyzed alkylation with iospropenyl magnesium bromide.

  • European Chemist says:

    In my opinion, this paper is a nice demonstration of interesting methodology applied to the wrong target. Seems to have made it to JACS, nonetheless. Anyway, building a hyper-strained tetracycle only to break two of the rings seems like going to all the way China to buy “instant-noodles”.

    And a further highlight of the deficiencies in current Organic Chemistry, most of them in the first synthetic scheme:
    a) Why the hell don’t someone find a useful and efficient way to reduce esters to aldehydes without having to spend two steps???
    b) Why is it that the best way to introduce asymmetry at a “quasi”-benzilic carbon is to oxidise to the ketone and then make an asymmetric reduction?

    Just some thoughts…

  • Vikrant says:

    Oops… typo detected. Its not RCM its CM (cross metathesis)

  • Dan says:

    What’s the rationalization of the inversion of stereochemistry at C1 in the rearrangement?

  • middle lab says:

    Check their prior paper on the methodology applied to this system. You can actually retain stereochemistry through a lewis acid mediated version:

    Acid mediated fragmentation:

  • Nanaji says:

    simply super,i like the DBU catalyzed reaction.