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Dehydroaltenuene B   

16 August 2008 8,769 views 10 Comments

Barrett, Soorukram and Qu. Org. Lett, 2008, ASAP. DOI: 10.1021/ol8015435. Article PDF Supporting Information Group Website ResearchBlogging.org

This is the second example of Barrett’s benzyne centred three-component-coupling I’ve featured on the blog, and it’s still looking like a damned smart way of constructing heavily substituted aromatic systems.  The first was ent-clavilactone B, back in 2006, which shares a further couple feature with todays target – lack of an established absolute stereochemistry, and bacteria-bashing activity.  For those that didn’t cover benzynes in their schooling, there’s one key feature of their reactivity that is key to this strategy – an electrophilic nature.  The means that attack of a benzyne with an anion results in the generation of a second adduct anion, which one can trap, building an ortho-substituted system.  That’s the meat and veg of this approach, so let’s see it in action:

Okay, so what’s going on here is the initial deprotonation of either of the protons betwixt the fluorine and methoxy groups.  The fluorine then eliminates, generating the intermediate benzyne.  We’ve then got a regio-controlled addition of the alkyl-Grignard into the benzyne, generating an aryl Grignard.  This is then treated with carbon-dioxide, leading to a magnesium benzoate salt.  A bit of iodine then forms an iodonium ion, which iodolactonates to complete the lactone and give the iodide product as a single diastereoisomer.  Considering how much has happened, that’s an absolutely cracking yield.

To get to the target, they needed to do quite a bit of work on the cyclohexane.  However, I really enjoyed their strategy of oxidation and functionalisation, moving unsaturation around the ring, so I’ve drawn an abbreviated route:

Most interesting was the oxidation of the enone to give a dienone using a benzeneseleninic anhydride.  Barrett states that this reaction was far better than the more common enolate formation and trapping with selanide and oxidation/elimination.  He links to a Barton paper from the early 90s, which is well worth a read (and also an earlier paper I found here). Also noteworthy was the selectivity acheived with final reduction using Stryker’s reagent; Barrett ascribes this purely to the relaxed sterics on that olefin.  The last oxgenation was a stereocontrolled enolate trapping of Davies Davis oxaziridine, attributing the control to preffered cyclohexenone geometry (pseudo-chair over twist-boat).  Nice work, and a good application of this strategy.


Soorukram, D., Qu, T., Barrett, A.G. (2008). Four-Component Benzyne Coupling Reactions: A Concise Total Synthesis of Dehydroaltenuene B. Organic Letters DOI: 10.1021/ol8015435

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10 Comments

  • Tex says:

    I believe it is Davis and not Davies oxaziridine.

    Tex

  • Tot. Syn. says:

    Nope, it’s definitely Davies, after Steve Davies at my former Uni:
    http://www.chem.ox.ac.uk/researchguide/sgdavies.html

  • Tex says:

    TS:

    Sorry, but you are incorrect – it is Franklin A. Davis of Temple University (formerly at Drexel). Check ref 19.

    Tex

  • Tot. Syn. says:

    Damn!! I’d thought it was Steve Davies for sodding years!! At least I never asked him anything about it… that would have been good!

  • milkshake says:

    This benzyne generation/addition with Grignard/trapping with electrophile was popularized by Buchwald – this is how he makes his ortho-subst biaryl phosphines, although I think the reaction is not his discovery, it just something that came very handy.

    I am always delighted when I see a good methodology-driven tot synthesis paper like this one, something on a molecule that can be made within a reasonable timeframe/by a limited number of authors – small enough to be used to make sensible-looking drug candidates. Very sweet paper.

  • ale says:

    very nice paper, great methodology I’d say, this kind of benzyne coupling was developed by Albert Meyers, if I well remember.

  • [...] was a bit more complicated.  First up was formation of an dienone – something we also saw in Barretts paper I blogged yesterday.  Also shunning the traditional enolate-formation / selanide trapping / oxidation – elimination [...]

  • InfMP says:

    Yeah, this is like a more complicated version of the Buchwald phosphane synthesis, but I really like how this one came out. I would have enjoyed seeing it in JACS instead.

  • mevans says:

    They don’t draw enough attention to benzyne chemistry here in the States, if you ask me. Who needs nucleophilic aromatic substitution when you’ve got stuff like this?

  • Wanderer says:

    i cannot find the difference between “using benzeneseleninic anhydride and camphorsulfonic acid” and “enolate phenylselenylation and selenoxide elimination”,even after reading the ref. 17 that is given in the paper.can anybody tell me exactly the differences and give me some relative references?thank you very much!