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Chamaecypanone C   

19 January 2009 8,146 views 20 Comments

Porco, Dong, Hamel, Bai, Covell, and Beutler. ACIEE, 2009, EarlyView. DOI: 10.1002/anie.200804883. Article PDF Supporting Information Group Website

It’s not often I’m surprised by the origin of natural products, afterall ocean trenches, acidic pits and frozen wastelands have all revealed ‘tartan TLC-plates’, but I didn’t consider tree heartwoods as likely targets. On second thought, why not? Loads of trees yield interesting isolates, but there’s something about heartwood that makes me think ‘woody’, and not much else… I mean, I’m currently resting my forearms on a lump of beech – and I’ve never considered it as source of tubulin polymerisation inhibitors. It’s probably not, but Chamaecyparis obtusa (some sorta cypress tree) is.

If your screw your eyes up a bit (I’m pretty sure that’s the technique Nobel-prize winners use to concoct retrosyntheses), you might see a hint of dimerisation, and perhaps a bit of Diels-Alder. However, whilst the approach used by Porco contains these elements, the overall strategy is pretty special. A test case for the methodology use turned up in JACS last year, with a bit of oxidative dimerisation, using sparteine to engender asymmetry. The yield and e.e. is definitely awesome, but I must say that the use of 2.3 equivs of sparteine is quite high. However, it’s pretty cheap, and I’m sure that they can recover is at the end of the reaction.

Now comes the really interesting bit; heat the crap out of the dimer, and it retro-Diels-Alders to give the hydroxy-cyclohexadienone, which can go on to Diels-Alder with an alternate dienophile. In a test scenario, they used N-phenylmaleimide, which worked fantastically – a 99% yield of the cycloadduct, presumably with complete control of diastereoselectivity.

After an initial foray went astray, synthesis of the target used exactly the same retro-Diels-Alder/Diels-Alder cascade, with some impressive selectivity. It’s pretty obivious that all that needed to do at this point was demethylate, and job done – tribromoborane did the task nicely.

However, we’re not quite done yet, as the eagle-eyed will have noticed that our hydroxy-cyclohexadienone intermediate has flipped configuration, which presents a problem. This quandry is that (+)-sparteine is very hard to come-by, and correspondingly expensive. A useful workaround is Peter O’Brien’s surrogate – which would be interesting to try in this situation. However, Porco came up with a fantastic alternative – make a similar hydroxy-cyclohexadienone enantiomer is before, and use an α-ketol rearrangement (a pinacol-like 1,2 Wagner-Meerwein shift – check that JACS again) to rearrange into the desired enantiomer. Damn fine paper…

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20 Comments

  • Liquidcarbon says:

    They should try doing it water (add some base to dissolve phenol) with CuSO4 and sodium ascorbate :)

  • Liquidcarbon says:

    *in water

    It’s interesting that they get all kinds of oxidized phenols, including catechols which I would expect to easily oxidize further…

  • LW says:

    nice paper, good to see some good come out of some methodology, as well as some biology in the same paper rather than belstein-ing the structure of a molecule you got from a total synthesis project that didn’t give you the compound you were actually hunting for.

  • advil says:

    This was nice but the Snyder paper on JACS ASAPs this morning really blew me away! Another home run from that group!

  • Madforit says:

    hi guys,Can someone suggest me a good rersearch group for a PhD in synthesis in UK?! P.S. really nice methodology!!

  • Tot. Syn. says:

    I’ll suggest just a few people that I can personally recommend, not just for their publications, but for their attitude and friendliness:

    Burton (obviously), Donohoe, Ed Anderson, Dixon & Willis @ Oxford.
    Paterson, Spring & Gaunt @ Cambridge.
    Bruker-Milburn & Aggarwal @ Bristol.
    Craig, Braddock & Spivey @ Imperial College
    Taylor @ York, Clark @ Glasgow, Motherwell @ UCl.

    Anything specific in mind?!

  • Martyn says:

    Assuming we’re just talking total synthesis, I’d add Phil Kocienski at Leeds and Chris Moody at Nottingham to that list. If you’re looking for an, erm, *intense* experience you could try Andrew Evans (Liverpool) or Tony Barrett (Imperial). Like Tot.Syn. says, we could do with some clues about your interests.

  • UBChem says:

    I’ve been really impressed the work coming out of the Harrity lab at Sheffield. I’ve also worked with one of his former students and I have to say he was one of the best chemists I’ve ever met.

  • John Wood says:

    Any picks/suggestions for the United states?(assymetric organocatalysis/ tot. syn.)

  • stork naked says:

    i agree, that harrity post-doc was phenomenal. top notch chemist and could make a dynamite curry

  • Chemistree says:

    How about up and comers; not Corey, Trost, Danishefsky, Nicolau, etc (for the US that is).

  • ZZZZZ says:

    zzzzz

    …please, no more nonsense about ‘hot up-and-comer profs’ and ‘profs-who-are-nice-but-may-slave-drive-you’… it’s too repetitive and it makes me, well, sleepy…

    zzzzz

  • Madforit says:

    Thank you so much guys..my interest are in the field of methodology(thesis work:vinilogous aldol) directed towards the synthesis of natural/biogically active product.The main thing is that i would really like to improve my chemistry knowledge and my english!!i thought about UK because prerequisite in US are impossible…

  • madbrat says:

    doi link is for Ishikawa oseltamivir paper

  • Catharanthus says:

    Tot. Syn. and Martyn,

    Handy list. I’ll be looking soon for a postdoc in UK. How about Coldham @ Sheffield, Clayden @ Manchester and Greaney @ Edinburgh? Can you recommend anyone in Ireland?

  • Next Phil Baran says:

    Porco’s work with “dimerized” natural products is well documented, as well as, his use of Diels-Alder chemistry to complete the dimerization. Is this a biomimicry methodology for this paper? Is he just good at selecting his targets? Who knows. So who is the best “mimicre”[sic]? Porco or Sorenson?

  • Martyn says:

    Catharanthus: of those three, Clayden is probably publishing the best work, but they’re all good chemists. If you’re looking at Edinburgh, I’d recommend that you consider Hon Wai Lam too.

    Not sure about anyone in Ireland, Karl Hale at Queen’s Belfast maybe?

  • Catharanthus says:

    Martyn,

    Thanks a lot! I appreciate your reply. I’m just hoping that they are not the “intense experience” type…. :)

  • ... says:

    Steve Connon at Trinity College Dublin

  • John Wood says:

    What about Chris Vanderwal at UC Irvine?