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26 April 2007 9,729 views 31 Comments


Taber, Sikkander, and Storck. JOC, 2007, ASAP. DOI: 10.1021/jo070257g.

A short synthesis and therefore a short post on the synthesis of this secondary metabolite from Laurencia cartilaginea. The family, bromochamigrenes, show selective, potent cytotoxicity in the NCI 60 cell antitumor, and are thus quite deserving of Douglass Taber’s work (who gave a nice lecture here on Tuesday). The key to the synthesis is the carbene insertion, but let’s look at the retro first:


As you can see, the exciting chemistry is happening at a damn congested neo-pentyl centre, so getting anything to happen is quite impressive. The forward shows that they managed this quite efficiently, producing the carbene via deprotonation/loss of bromide. This then inserts into the only available C-H bond (with a small amount of rearrangement product), generating the spirocycle in good yield.

Now, what I found really smart in this work was a “rearrangement” to the 6,6 spirocycle via ozonolysis of the olefin, followed by aldol to give the enone. Nice! I also like the use of hydrobenzoin to protect the ketone and allow resolution… not novel, but nice.

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  • spottospot says:

    Just wondering: what is novel?
    Could you define/articulate novel for the purposes of this blog. For me novel in Org syn is relative to my feelings for that day. But it is never what novel means for chemistry ( ie not org syn), such as mono-primary-C-H bond activation of hexanes by a efficient cheap ($1/g) catalyst!
    So long and thanks for all the platenismycin.

  • Tot. Syn. says:

    I was actually only referring to the protection/resolution – and even then, just cause it’s not novel doesn’t mean it’s not smart! I really like this synthesis.

  • provocateur says:

    y do u kall it a ‘rearragement”!

  • The Canadian Chromatographer says:

    If I may, “provocateur”, TotSyn calls it a “rearrangement” because it takes a methylcyclopentenone unit and turns it into a cyclohexenone by means of bond breakage/bond union. I’m guessing he put quotation marks because this does what a so-called rearrangement does, without being a named rearrangement, such as the Claisen, Cope, Overman, Payne, Brooke, etc. rearrangement.

  • The Canadian Chromatographer says:

    Now, may I exert my sense of criticism. Does anyone agree that performing a resolution (very most likely via chromatography) after a fairly shy-yielding 6-step sequence is not the most efficient way of bringing significant amounts of enantiopure material forward?

    And, in my opinion, the end game was far from elegant. Carrying mixtures of diastereomers for a couple of steps… then suffering a gruesome 19% yield for the final step! Kudos to the grad student who persevered through.

    Nice demonstration of carben C-H insertion, though. It’s just sad its brilliance overshadowed by the former. I must admit that the very structure of the molecule sets the table for a tough assembly puzzle.

    As for the platensimycin story, looking forward to the 2nd generation, then 3rd gen. total synthesis! :)

  • milkshake says:

    I would rather see this piece made from a symmetric precursor, even if racemic – it should be much shorter. The quat dimethyl carbon next to spiro could be made by methylcuprate conjugate addition (if you delete the C=C on the second ring). This is the product of spiro-dearomatization of a phenol with allyl silane. If they need some masked C=C, they can have a chiaral sulfoxide next to carbonyl.This could conveniently provide a chiral auxiliary for directing the cuprate. Hah.

  • pi* says:

    Yeah, brilliant key step…absolute horror of a route to make the precurser…

  • European Chemist says:

    Milkshake, at which University are you going to begin your academic career? Just screening for post-doc possibilities :-D

  • Pete says:

    Now…Correct if I’m wrong…But it seems to me that their synthesis was going reasonably well until the end when, of course, we observed a 19% of that dehydration, allylic oxidation sequence…What troubles me the most is how, or really why they didn’t try any other methods. They even state, “No other methods for allylic oxidation were investigated.” Seems as though maybe a grad student was getting a bit burned out working on this, or maybe the boss was fed up with something, because, I (as well as most chemists) would not have settled on that.

    Overall, I do like how they bring this molecule together…Minus the last step, I would have considered it JACS, or Angewandte “worthy.”

  • Jose says:

    Sorry for a thread hijack, but this is from JACS ASAP today…

    (20) Prof. Baker informed us that their reported (1) absolute stereochemical assignment is in doubt because of erroneous Cahn-Ingold-Prelog prioritization of their Mosher ester derivatives.

    Total Synthesis and Structure Revision of the Marine Metabolite
    Palmerolide A Xin Jiang, Bo Liu, Sylvain Lebreton, and Jef K. De Brabander* JA0715142

  • milkshake says:

    We got Bill Roush here and as you know he is very good (and a rather nice man on personal level).

    I lack the necessary degrees for bossing anyone – I am a medchem cynical technician, in a steady state careerwise, with the beer-induced decline in acuity and motivation.

  • willyoubemine says:

    Canadian is right. Why not resolve? Why do asymmetric synthesis with chiral lignds made from the chiral pool, when you can either resolve, or start from the chiral pool.

  • Tot. Syn. says:

    Bill Roush is amazing. I saw his talk at the Bristol Synthesis meeting, and loved his presentation on Amphidimolide E (http://totallysynthetic.com/blog/?p=390). He seems like a great person to work for.
    Also presenting at that meeting was Dave MacMillan on this SOMO activation/organocatalysis, which is awesome. It’s in Science just now, but I haven’t got access…

  • Tot. Syn. says:

    Jose – I saw that too. I’ll post on it soon…

  • provocateur says:

    hi kanadian
    A rearrangement usually happens in a ‘single’ step.these r two separate steps with basik steps..but i agree its semantik at this point..also a ‘carbene’ need not be invoked for the mechanism.a mechanism kan be drawn from the rearranged alkyne…any thts on it!

  • TWYI says:

    We need papers like this every now and then to stop JOC going completely down the pan.

  • TheEdge says:

    er, what’s the mechanism from the alkyne? Reactions like this are generally thought to go through the carbene, and the alkyne thought to be a dead end. If you could really get to the product from the alkyne, you would be able to push the reaction to completion, right? And you would see, by TLC, that the alkyne formed first, and then went on to product. You also wouldn’t need to go through the (significantly more difficult to synthesize) bromoolefin.

    Now, you probably can get the alkyne-carbene rearrangement to go backwards, but that still means the mechanism involves the carbene. It also probably involves really high temps and/or crazy lewis acids.

  • provocateur says:

    you can form an allene from the alkyne with the help of the base…y does not lithium exchange take place in these cases…bekos for the carbene to form hydrogen abstraction shd take place first.I know xplaining it thru the carbene is konvenient.

  • TheEdge says:

    #18- Lithium exchange doesn’t happen because the procedure involves KHMDS. They use pretty standard conditions for generating a carbene from a mono-bromoolefin. You use Li-halogen exchange to a make a carbene from a di-bromoolefin, ala the Corey-Fuchs reaction.

    I’ll give you that you can make an allene from an internal alkyne via deprotonation, although you normally run that reaction with the KAPPA reagent. I still don’t see how you get to their product from that intermediate. How do you make the C-C bond?

  • TheEdge says:

    yet more for #18- I don’t mean to sound like an angry troll, but I’m sure young chemists come here to learn. If you’re going to propose a non-standard mechanism, you should provide a full description to prevent confusion, and then explain why it fits the observed data better than the standard mech.

  • Tot. Syn. says:

    provocateur: I can see how one might arrive at the allene, but that doesn’t explain the insertion into a C-H bond. I can imagine it’s possible via a metal-mediated process (Pd, Rh or similar), but this doesn’t seem possible here. If you have a mechanism in mind, do send a chemdraw to the usual email address.

    Also, and this is a personal request – please stick to standard English (UKian if possible :)) – I can’t abide the thought of 1337 speak here!

  • Spiro says:

    About alkylidene carbene rearrangement : dx.doi.org/10.1021/cr9601324
    The alkyne is a dead end.

    OK to convert a terminal alkyne to an allene, but in this case it is a methyl alkyne, and it won’t go to the allene (it is the allene that will convert to the methyl alkyne IMHO).

    The carbene insertion is daring in this deactivated-hindered environment. Great way to make 5-membered rings spiro cpds.
    As for the methylcyclopentene-cyclohexanone trick, it has been known and used for half a century.

  • milkshake says:

    right you are, in steroid total synthesis for example, to make the A ring

  • Tot. Syn. says:

    Spiro: thanks for your mechanistic insight; I’d suspected as much, but didn’t know it was a named reaction.
    You’re right that the “methylcyclopentene-cyclohexanone trick” is an oldie, but it’s also a goodie :). We all saw this for the first time somewhere!

  • neo says:

    I am really going crazy over this C-H bond activation..need some serious help

  • neo says:

    Maybe I am getting ahead of myself but I think that the only reason that the carbene (by the…way I strongly believe in a carbene intermediate..) and the rather hindered CH bond react is because of the ease of formation of 5 membered ring which is a thermodynamically favoured outcome.

  • spottospot says:

    The 5 membered ring formation is a kinetic product. Remember, “highly” reactive intermediates normally proceed via the kinetic not the thermodynamic pathway. Cyclizations to give the five membered ring are the fastest of all cyclizations. It is ~1000 TIMES FASTER than the six membered ring ie a yield of 99.9% five membered ring and .1% of six membered ring (5>6>3>7>4>8-10 rates of ring cyclization, Carey and Sunberg). Note that there are 7 other C-H insertions reasonably possible to make a 7 membered ring.
    Also, the carbene that is formed in this reaction is a singlet so that would imply that this is “really” an insertion reaction. Compare that to a triplet carbene that would react via a hydrogen abstraction.
    Grab yourself a physical organic text and the Logic of Total Synthesis then enjoy.

  • Spiro says:


    There is no C-H activation of any kind, just a simple carbene insertion.
    The reason for the 5-membered ring is… well… the carbene has little choice : it loves to react with a bond (preferably pi rather than sigma) or a lone pair (as in C=O for example). If it cannot do it intra or intermolecularly, then the alkylidene carbene rearranges to the alkyne. It is what happens here to a little extent : a carbene in a non-reactive environment.
    But the carbene here chooses mainly to go for the 5-membered ring C-H insertion. The 6-membered ring C-H insertion is precluded here, but a 5-membered ring would prevail over a 6 in a similar environment.
    No thermodynamic is involved, just the kinetic, irreversible reaction of an unstable carbene.

    Again, the answer is here: http://dx.doi.org/10.1021/cr9601324

  • neo says:

    Thanks spottospot and Spiro.

  • kiwi says:

    thanks for awesome explanation spottospot, a few surprises hidden in that order of rates for ring closure

  • Dylan says: