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Antheliolide A   

11 October 2006 9,212 views 18 Comments


Corey, Mushti and Kim. JACS, 2006, ASAP. DOI: 10.1021/ja066336b.

Another top synthesis of an interesting polycyclic target, this one with a complex nine-four-six ring system at its core. The structure was determined almost twenty years ago, but the synthesis has apparently slipped through the cracks, along with the absolute stereochemistry. No details on the activity of the target were given in the paper, but I’ve not read the isolation reference yet, so perhaps it does something… however, the synthesis is what we’re interested in :)

After eight steps, the workers achieved a complex cyclisation precursor, full of synthetic handles. Saponification of the ester however, kicks things off, and with salt formation and treatment with tosyl chloride in base, a ketene intermediate is formed. This then performed an intramolecular [2+2], generating the cyclobutane and the useful remaining carbonyl group. This transformation has been somewhat of a Corey favourite, and several references in the paper point to other work containing this style of reaction.
With the carbonyl handle, functionalisation of the cyclobutane was easy, allowing ethylation, and at this point they did a resolution via chiral HPLC. Further functionalisation led them to a β-keto sulfone, with which they did an interesting Pd-catalyzed [2,3]-sigmatropic rearrangement:

Again, this interesting cyclisation left them with a useful synthetic handle, as well as the desired ring (in this case a difficult to form trans-nonene); however, the sulfone was removed via Al-Hg amalgam. Completion of the synthesis was then in sight, via eventual clevage of the five-member ring (using the periodate on silica reagent I mentioned in a previous comment), and formation of the six-rings by stirring in silica:

I know the last transformation is well precendented stuff, but it’s stuff I like :).

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  • movies says:

    I’ve been waiting for this synthesis to show up here!

    My favorite part is that the right-hand portion (the 4,9 fused system) is essentially caryophyllene, another natural product that Corey made over 40 years ago!!

    Check it out: JACS 1964, 86, 485-492.

  • Ashutosh says:

    Why does TBAF deprotect only the TMS and not the TBDPS group? You also must have checked Baran’s Chartelline synthesis from the same ASAP which is also pretty interesting.

  • Ashutosh says:

    Sorry, I meant LiOH, not TBAF

  • Tot. Syn. says:

    Well, the simple answer is that TBDPS is the daddy of Si protecting groups, and takes a fair beating to remove. In an uncrowded hydroxyl, TBAF will remove TBDPS, but you often have to use HF/py.
    TMS is the easiest Si group to remove, and will fall-off in mild base. I’m using KOH in MeOH to do that tomorrow, in the presence of a TBDPS group. Also, the mechanisms can be different – the TMS group is protecting an acetylene, so has a different character to the TBDPS group on an hydroxyl.
    Yep, saw Baran’s sweet synthesis – lots to blog this week :)

  • Tot. Syn. says:

    There’s some useful information about protecting groups here:

    but the best place IMHO is Phil Kocienski’s book.

  • Biotech says:

    Can someone please push some arrows for the last step?

  • WillisWill says:

    Biotech – here’s my take

    a) enamine adds to aldehyde
    b) iminium hydrolysis and dehydration
    c) tethered alkene adds 1,4 to highly activated olefin (two carbonyls, protonated by SiO2)
    d) resulting enolate traps tertiary carbon cation with O

  • Tschoesche says:

    Regarding the mechanism for the last step, Corey claims a [2+4] cycloaddition from the intermediate you receive after Willis step b). Willis take sounds reasonable, but Corey is a nobel laureate…

    I also have two questions:
    i) where does the water for the iminium hydrolysis come from? Is this water created by dehydratation of the emerging alkoxide derived after step a)? But there is no proton left to actually create water… What exactly is the function of SiO2?

    ii) If you take a look at the paper: Why does piperidin react in a Michael addition to the propargyl ester rather than reacting with the aldehyde (step x in the paper)?


  • Biotech says:

    Enamine adding to aldehyde would generate an enone. Not sure why the remote double bond would attack the enone under acid catalysis.

  • Hap says:

    The enone would be pretty electron-deficient, particularly protonated (lactone + protonated ketone – like the protonated version of a methylenemalonate, but more electron-deficient), and the pendant olefin is electron-rich and forms a stable carbocation, so it would be reasonable as a stepwise carbocationic mechanism – don’t know if the [4+2] is also good.

    I think silica is readily hydrated, so there is probably some water around – alternatively, the silica has Si-OH groups which might be lost to cyclocondensation in solid phase.

    I haven’t read the paper, but I’m assuming that piperidine is adding to a butynoate to generate the (Z)-piperidinylbutenoate in the penultimate intermediate. Piperidine can’t form an enamine with the aldehyde, so it can’t really do any thing unless there’s acid around – if there’s no acid, the aldehyde probably won’t react, while the propargyl ester is electron-deficient and should add a nucleophile readily. I don’t know why the (Z)-stereo, though.

    Is this reasonable?

  • Chandra says:

    ok guys let me clarify certain things about the synthesis, for the condensation of aldehyde with enamine function of SiO2 is like a acid catalyst and also helps in the dehydration to give the olefin.

    where does water come for the hydrolysis of iminium salt? SiO2 we use for column chromatography usually has good amount water absorbed on it.

    coming to the last step, is it [2+4] or stepwise? if it is step wise with the amount of water around it from silica gel the tertiary cation should lead to the alcohol or acidity should lead to elimination to give olefin but if you look at the yield of the product, it says probably reaction is going via a concerted mechanism.

    why piperidine does not react with aldehyde? kinetics which is more reactive aldehyde or unsaturated ester? and also aldehyde is not enolizable (adjacent center is quartenary) so it can not from enamine which is more stable than the hemi aminal.

  • WillisWill says:

    how do you guys know i don’t have a nobel!?! i’m inclined to beleive corey also, the yield (or more specifically, the lack of alternate products or diastereomers) would suggest a concerted reaction…but maybe we could just call it concerted especially asynchronous and we can both be right!

    you don’t need a ton of water, for instance if acs grade solvent was used instead of anhy. dehydration of the aldol product generates an equivalent of water, no reason that can’t happen before hydrolysis

    chandra – i suspect the pip would not readily react with the aldehyde due to steric hinderance from the adjacent quat center…could get in there, but ester exchange would be faster

  • Chandra says:


    it could to a very less extent react with the aldehyde and the hem aminal will be in equilibrium with the aldehyde (which should predominate the equilibrium).

  • European Chemist says:

    Yeap, aldehyde is encumbered but even if addition does occur, hemiaminal/iminium formation is always reversible whereas if it could form an enamine the thing would be considerably shifted towards product. Further, if the product gets absorbed at the SiO2 surface then the steric issues can get rather enhanced and exacerbated.
    For me, the final cyclisation is simply a 6-Pi-electrocyclisation, quite common in the biosynthetic pathway towards a number of Nat Prod’s.

  • Tschoesche says:

    Well, I didn’t realize, that enamine formation is not possible if pip adds to aldehyde due to quart centre. And, of course, the aldehyde is in sterically highly disfavoured neopentyl position.

    Does anyone have an explanation why piperidine adds in (Z)-fashion to the Michael system? Intuitively, I’d expect it to react from the opposite site of the carbonyl. Maybe due to precoordination of pip’s H to the carbonyl O? Sounds a bit weird to me…

    Thanx for you help, guys!

  • Chandra says:

    the question stereochemistry of enamine is unnecessary because there is no mention of it in the next, if you look at suppo, they didn’t purify any of the intermediates in the steps leading to 1 from 16. I dont know, whether they have put any attention on the stereochemistry of the enamine.

  • […] quite a fascination with this class of natural products, having already completed (amongst others) Antheliolide A back in 2006. However, this work takes a somewhat alternative route to the trans-cyclooctene […]