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Taxane Skeleton   

7 December 2011 21,459 views 23 Comments

Baran, Mendoza, Ishihara. Nature Chem., 2011, EarlyView. DOI: 10.1038/nchem.1196 Article PDF  Group Website

Hmm… I’m still not convinced about whether I should really post on this paper, but I’m interested in it, so to hell with the rules!  What we’ve got here is a sort-of meta-synthesis; Baran doesn’t actually make any of the taxane natural products, but demonstrates an extremely neat synthesis of a potential common precursor.  The theory behind the work is related to previous Baran diatribes, where he points out that too many steps in syntheses simply oxidise and reduce the same carbons.  However, in this case Baran describes the Taxanes (which are of course heavily oxidised) as being parented by a simple (almost) un-oxidised ‘precursor’.

This beastie is known as ‘Taxadienone’ – and as the name suggests, it contains a pair of alkene groups and a sole carbonyl as its only oxidation. However, deeming it a ‘precursor’ is perhaps a little ambitious, as to get to taxol or related natural products, a lot of oxidation of unactivated C-H bonds is required.  In the hands of your average chemist, this seems a pretty insurmountable challenge, but with Baran, perhaps…

Baran’s approach to the complex 6,8,6-ring system, as ever, appears fairly simple.  Start with a cyclohexenone, do a pair of carbon-carbon bond formations about the alkene, and then unite these sidechains in a neat cycloaddition.  And the interesting thing is that Baran makes it work just as easily as that.

The first, and more complex, sidechain was appended using an organocopper 1,6 addition.  This combination of diene with dienone looks set to generate a black tar in my hands, but team Baran got a remarkable 86%.  Then using some of Alexakis’ chemistry, they methylated this product in a 1,4 addition to introduce asymmetry.  Using a chiral phosphoramidite ligand, this was achieved in a very reasonable 89% yield and 93% e.e., using pretty low loading of the copper thiophenecarboxylate and ligand.  I really like the simplicity of this approach – keeping the system symmetrical until this point reduces complexity considerably.

Having trapped the product of the methylation as it’s TMS ether, the group then did a Mukaiyama-type aldol coupling with Acrolein.  This was a little awkward, as the group often found the ketone product of desilylation rather than their desired aldol product, even when rigorously excluding water.  Bizarely, adding water helped – and by raking to the back of the Lewis acid cupboard in the lab, they found success with the unusual gadolinium triflate.  These are apparently Kobayashi’s conditions, and gave them a yield of over 85%, but as a 2:1 mixture of diastereomers.  However, they didn’t separate the isomers – rather, they chucked the lot into the Diels-Alder below.

Under more typical reaction conditions, these reaction fairly nicely, giving a reasonable yield of product, but perhaps more importantly (in a sense), the ability to separate the isomers with ease.  They weren’t quite done – a triflation of the cyclohexenone carbonyl at the only acidic methylene position in the molecule generated a enol triflate.  Reaction of this under Negishi conditions with dimethyl zinc provided them with the required methyl cyclohexene moiety – and in a satisfying 84% yield.

Synthesis done, and like me, you may well be wondering what the excitement is about.  However, continue reading the paper into the discussion, and the chemistry takes on a different note, as Baran describes various strategies that were uncooperative.  These included a fail aldol approach to closing the medium ring as a later stage, and a stereochemical nightmare involving a Shapiro reaction.

More importantly, Baran believes that site-selective oxidations of taxadienone are possible, and may lead to a synthesis of taxol form this intermediate.  Now that’s a paper worth getting excited about!

 

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23 Comments

  • TMSOTf says:

    Paul -He does make one taxane, Taxadiene is a natural product…

    BRSM has a great write-up on this — see http://eristocracy.co.uk/brsm/

  • Anon says:

    Sorry, not Nature Chemistry worthy.

  • ginckle says:

    Of course not. Should be in Tett. Lett or lower. Nothing new here or ever in any synthesis. Nature chemistry and JACS should only publish nanotube research or proteomics.

    you people are sick in the head.

  • Anon says:

    @ginckle:

    “Of course not. Should be in Tett. Lett or lower. Nothing new here or ever in any synthesis. Nature chemistry and JACS should only publish nanotube research or proteomics.”

    Couldn’t agree more. Preach it brother (or sister)!

  • Son of Gashira says:

    I think this is important chemistry and I’m glad it gets the attention of a paper like Nature. Maybe it will encourage more people to send their half-time total syntheses to Nature.

    • NAS says:

      Halftime?

      Check me out y’all, PBaran in your area
      About to cause mass hysteria

      I’m a taxol head, I make grams to excite the feds

  • Son of Gashira says:

    Can’t believe the irony didn’t go through to all you poindexters. I was convinced this site gathered intelligent people. This taught me.

  • Son of Gashira says:

    I’m a street rat and I feel offended by this.

  • AK47 says:

    Top Tot Syn of the year?

    Carriera’s Daphnimidin?

    • HPCC says:

      Not that I have a better molecule to propose, but daphmanidin by Carreira was quite linear and rather steppy, so I would vote against… although it’s a beautiful structure.

  • TLC is dead says:

    Love that Shunie.

  • Tom Rovegas says:

    Why was TMS used for protection? When I went to school I used CBJ. It’s easy to remove and provides quick cleavage under slightly elevated temperatures.

    Tip #1: There is taxa but no dienone in the champagne room.

  • Shankar says:

    A very pedestrian approach and certainly not up to his (Prof. Baran) caliber! If I did the same work and submitted to the Nature chemistry, I would have been politely told, try Tetrahedron Letters. The taxol basic skeleton problem was long resolved by many total syntheses and certainly the present strategy does not measure up to the standards established by others. Besides, there is no urgency as the current needs are adequately met by “yew” trees.

    • Lowkey says:

      Ok Shankar, clearly you’re not bitter. Whats the other known way of synthesizing this much enantiopure taxadiene?

      I can’t wait till baran makes Taxol and related :)

  • nord says:

    Stockholm Sweden group already solved taxol synthesis in two steps. what’s your point caller?

  • this is a great blog post, I am going to bookmark it

  • Sid says:

    Use BBr3.EtOH if u want better yields… my yield was 78% with 2:8 ration of BBr3 and BF3 respectively. Also add DHF and magnetically stir it to get the above mentioned yield (78%).

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