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Geigerin   

6 August 2007 10,470 views 48 Comments

geigerin.jpg

Deprés and Carret. ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200702031.

Isolated from the plant colloquially known as the “vomiting bush”, Geigerin is a member of the guaianolide family, represented in the 5,7,5 tricyclic structure. No further mention of the biological activity is noted in this paper, but they do point out that this isn’t the first synthesis of this family, referencing Lee and Bartons works.

The synthesis starts with a bit of chemistry quite familiar to the group, doing a regioselective [2+2] cycloaddition with diphosgene 2,2,2-trichloroacetyl chloride and 7-methylcycloheptatriene. In their previous papers, they had to use a metal to take diphosgene to dichloroketene, but in this case, a bit of ultrasound worked rather well. They then ring-expanded to give the 5,7 motif required.
geigerin_1.jpg

A few steps further along, they used DMDO to generate the hydroxyl group with good substrate control, which formed the lactone under acid conditions. To reuse a phrase I type a lot – not new chemistry, but nice!

geigerin_2.jpg

The lactone product was then subjected to a rather tricky sp2-sp3 Suzuki coupling; the vinyl chloride SM can’t be the best nucleophilic partner, and the methyl boronic acid is also a less than ideal partner. However, using rather standard conditions, they achieved the coupling with a reasonable yield. I’ve only seen one other example of this type of methylation (though I be there are many in the literature), but Evans used the methyl boronate trimer in his synthesis of the FR compounds.

geigerin_3.jpg

My jaw is left fully in place, but I did like this approach to the target, and the use of some smart literature reactions.

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48 Comments

  • Kutti says:

    This is a funny name for a molecule. Could make a new entry for this site: http://www.chm.bris.ac.uk/sillymolecules/sillymols.htm

  • chemist says:

    Diphosgene is CCl3OC=OCl (dimer of phosgene).

  • HPCC says:

    I’ve been a lab colleague of the Ph. D. student who did all this work (S. Carret)… Tot. Synth. may wanna double check the spelling of his last name! :)

  • Spiro says:

    “In their previous papers, they had to use a metal to take diphosgene to dichloroketene, but in this case, a bit of ultrasound worked rather well.”

    Ultra sound avoids the use of activated zinc (ref 14), but you definitely need a metal.
    Maybe I am wrong but there is no supp info available, as often with Angewandte :-(

  • aa says:

    spiro, the supporting info is available at http://www.wiley-vch.de/contents/jc_2002/2007/z702031_s.pdf

    and i think the procedure for the 2+2 is found in their previous methodology paper,referenced in this one.

  • Spiro says:

    aa, thanks for your dedication, but I had read these “supporting information” before writing my discontentment.
    It is just that I do not consider this to be a decent supporting information section, even though the three procedures they show are the most important of the article.
    I do not blame the authors, just the journal. If my boss tells me to write a paper without supp info, I cheer. But this is a bad habit IMHO.
    For example, I am perplex about transformation c in scheme 3, especially when I read ref 19. One way or another there may be something which is missing in the conditions (acid?), and a written procedure could clarify things.

  • carbazole says:

    The lack of supp info in ACIEE is really frustrating. If you’ve done a total synthesis, why can’t the supp info include any procedures for making compounds not already found in the literature? If I’m doing a lit search, and I find a reaction in Org Lett that I can use, I cheer because it will have a procedure most likely. If it’s for ACIEE, I groan, because the supp infos are so spotty.

  • kiwi says:

    Tropylium tetrafluoroborate is the listed starting material – now thats something you don’t see everyday. I sure hope they weren’t buying it…

  • Liquidcarbon says:

    Is it stereocontrolled enolization of methyl propionate that introduces the side-chain stereocenter in the “double conjugate” addition?

  • Gilgerto says:

    I totally agree with you carbazole, I cannot conceive that in 2007, a supp. info for a total synthesis includes only 2 procedures and 4 nmr. It is clearly a lack of rigour from Angew…

  • aa says:

    spiro- right, sorry about that. yes, the lack of SI in ACIE is pretty terrible. i especially hate when their a reaction in a tot syn that you would like to try and can’t get a detailed procedure.

    liquidcarbon- yes, its the enolization that gives you control of that stereocentre… i believe Ireland has a paper (JOC, 1990 or 1991) detailing conditions and bases for generating propionyl silyl ketene acetals with high E/Z selectivity.

  • willyoubemine says:

    Supporting Info is all that really matters in these papers anyway right? I mean its nice that someone made something, but its irrelevant if irreproducible bc of spotty SI.

  • HPCC says:

    12: The ultimate best example was last year’s synthesis by James La Clair… Deoxoudol, or the molecule-that-shall-change-name-upon-criticism-of-its-synthesis!

  • organic chemist says:

    Hijack topic – Can anyone please tell me how to make a stable -100 degree celcious bath?

  • HPCC says:

    14: Go to this great website: http://chem.chem.rochester.edu/~nvd/

    Click on “cooling baths”, and you might have to click further to reach “Hoveyda website”… if -92 ºC is not cold enough for ya! ;-)

  • JamesB says:

    Isn’t an author obliged to provide experimental detail/spectral data on request for published reactions? My ex-boss certainly behaves like it – and believe me, the hours I put into scanning spectra and compiling supp. info means the SI isn’t “spotty” in the slightest.

  • benchmonkey says:

    “The lactone product was then subjected to a rather tricky sp2-sp3 Suzuki coupling; the vinyl chloride SM can’t be the best nucleophilic partner, and the methyl boronic acid is also a less than ideal partner. However, using rather standard conditions, they achieved the coupling with a reasonable yield. I’ve only seen one other example of this type of methylation (though I be there are many in the literature)”

    Right, Fu has done a lot of work on sp3-alkyl Suzuki couplings includinga very recent JACS communication on an alkyl-alkyl coupling with a Ni catalyst. It seems extremely neat and useful chemistry and yet I’ve seen it used almost not at all. Some of the initial stuff was published back in 2000 and there’s still no real sitation in total synthesis, any thoughts why?

  • willyoubemine says:

    is that a trick question? a problem for tot synth readers to slove perhaps?

  • willyoubemine says:

    is that a trick question? a problem for tot synth readers to slove perhaps?

  • Gilgerto says:

    benchmonkey: It seems that fu’s Suziki coupling is not very tolerant in terms of fonctionnal group. Other than that I don’t see any reason for poeple to avoid this chemistry, maybe chemists don’t have this strategy in mind.

  • TheEdge says:

    benchmonkey: There was a paper a couple months back (in JACS, I think) where they used Fu’s chemistry to couple two fairly complicated bits together in ~50-60% yield, but when they made the system even more complicated to improve convergency, they saw no reactivity at all. There really didn’t seem to be any difference between the systems (to me) other than the size of the fragments. I’ll see if I can find it. It may be a while, so no one hold their breath.

    For the guy who wanted a -100 bath: use liquid nitrogen and toluene (-110) or ether (-95). Add the liq N2 until the bath freezes, then add just a little more liquid and mash it all together. Everytime the toluene or ether solid starts to melt, add some more liq N2 to freeze the surface and then mix it into the bath. Make sure you cover the bath with an insulating blanket (I use tin foil and cotton). I’ve kept a 3L flask at -95 that way for 2 hrs during an addition. It’s labor intensive, but you wouldn’t be trying to hit that temp if you weren’t desperate, and desperate times call for desperate measures. God help you if you’re somewhere humid.

  • Jose says:

    Why the heck didn’t they just do a Stille? That 58% would have been at least 90%. Tetramethyltin isn’t *that* scary….

  • TheEdge says:

    hmm, the Hoveyda list claims I’ve reversed toluene and ether. My source, who/which shall remain unnamed, must have erred. I apologize for the error.

  • kiwi says:

    #21 also a paper in Org Lett recently (last 2-3 months, Andy Phelps i think) which had a Fu/Suzuki sp3-sp3 coupling in it, as a late stage step to converge two pieces together. It seemed to work for them.

  • TheEdge says:

    Kiwi and I are both half right, assuming this is the paper he was thinking of. It may not be. DOI: 10.1021/ol070517g

  • carbazole says:

    Sure, being required to provide spectra/procedures on request is fine, but why can’t it be included online at the time of publication? Are their servers running low on hard disk space? It was different before online publication obviously, journal pages were precious. Why should I have to email someone for something that really should be provided in the first place?

  • ZZZZZ says:

    zzzzzzz

    Carbazole says good stuff, me agree…

    zzzzzzz

  • Jose says:

    It makes me wonder if that might be why so often high level papers get sent to Angew over JACS by certain groups in particular….

  • kiwi says:

    Nope my one is by Andy Phillips, DOI: 10.1021/ol0710111.

  • TheEdge says:

    Ah, I remember reading that now. Thank you, kiwi. I think the earlier paper stuck with me because of their scope problems. The Phillips certainly contains some nicer chemistry.

  • willyoubemine says:

    Jose is onto something.

    Anyone see baran’s SI for Chartelline in JACS. It was immaculate, the way SI should be.

    And thanks to TOT SYNTH for being just about the only blog on the planet not to have an entry for Barry Bonds 756*

  • PG says:

    You’re right, the lack of entry about Barry Bonds is a relief. But then again, who cares about steroid chemistry any more?

  • ArrowPushingMonster says:

    Er £9.7 billion on Steroidal contraceptives and £2.3 billion on heart disease Steroidal drugs per annum not mention hydrocortisone studies etc etc (rant rant rant) … (My PhD’s in Steroid chemistry)

  • tom says:

    Most of the time when I email someone for supporting info I don’t get it.. I emailed one of sharpless’s underlings for SI on allyic azide precursors and got not a single response.

  • Tot. Syn. says:

    I’ve got no friggin’ idea who or what “Barry Bonds” is… though I have a notion it’s to with an American sport… hmm… Rugby season starts again soon…

  • benchmonkey says:

    Thanks for the response on the Fu Suzuki question, the Philips paper’s really quite nice, 79% for the Suzuki in presence of a spiroketal.

  • willyoubemine says:

    yeah, sorry for a near thread hijack…i forgot you might be a baseball ignorant brit. Anyways, I thought all things American were world news, didnt the BBC cover Bonds?

  • milkshake says:

    My name is Bonds. Barry Bonds.

  • kiwi says:

    #35 ready for 1x crushing at the hands of the mighty ABs this year? that is, assuming you make it out of pool A ;-)

  • TWYI says:

    I like the Corey paper!

  • Klug says:

    Does anyone know which JACS paper deployed the Fu Suzuki reaction? That would be really helpful.

  • Liquidcarbon says:

    Check J. Am. Chem. Soc. 2006, 128, 5360-5361, it might cite a few earlier papers.

  • TWYI says:

    I know you’re probably really busy Paul, but your forum has been spammed big time.

    back to Angewandte papers, do they all have to have witty titles before the abstract. ‘Geiger counter’ in this example

  • PG says:

    The ‘witty titles’ in the Angewandte table of content are made up by the brains at Angew HQ, not by the authors.
    There’re trying to follow a tend set by the bio journals (the guys at Cell love this kind of stuff… “The Microtubules Dance and the Spindle Poles Swing”).

  • Tot. Syn. says:

    TWYI:
    I’m actually not in Oxford just now – back home in Edinburgh visiting the folks. I’ll heave through the sh*te on my return later this week. Cheers.

  • Brandon Cash says:

    i like the 2+2 ):