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Aigialomycin D   

11 October 2009 15,563 views 36 Comments

aigialomycin_d

Barrett, Calo, Richardson. Org. Lett., 2009, ASAP. DOI: 10.1021/ol901979x. Article PDF Supporting Information Group Website

Macrolactones?  From Barrett?  It’s not his usual fayre, but as is more normal, there is a twist in the synthesis.  I think most chemists (or at least me…), when presented with a target like aigialomycin, would think about buying-in the aromatic portion, and then trying to bolt on the styrene-type olefin and building around.  However, with his interests in reactive intermediates, Tony Barrett (of IC, London… just down the road), it comes of no real surprise to me that he builds the tetra-substituted phenyl ring late stage.  Before delving into how he went about that, I though a brief retro would be in order.

aigialomycin_d_1

It turns out the buying (much of) the rest of the molecule is quite an easy task.  A chiral, homo allylic alcohol ((S)-(+)-4-penten-2-ol) was easy to buy (though I’d bet pricey), along with the diol, which was bashed out of a sugar (three steps from 2,3-O-isopropylidene-D-erythronolactone).  So with so much material easy to buy, the really interesting bit is how, and what they used to make the phenyl ring.  It went a bit like this:

aigialomycin_d_21

Taking the dioxinone, and heating in toluene allowed a retro-Diels-Alder to occur, leaving a rather open-looking ketene in it’s wake.  Addition of the chiral homo-allylic alcohol bit allowed addition to the ketene, giving them the required ester.  Lastly, addition of a bit of base, followed by a bit of acid allowed cyclisation to give the required resorcinol ring, with the macrolactone precursor chains ready to be RCMd together.  However, there was a small problem with this route, as the synthesis of the starting material was very low yielding.  The first route they used is on the right, and used a lithium enolate addition to a Weinreb amide.  The two steps to build this totalled a 11% efficiency over two steps, so there was definately room for improvement.

A second route involved a Claisen condensation approach; using an acid-chloride analogue of the Weinreb amide above, and a beta-ketoester.  The unnecessary ester moiety was removed easily, as it was allylic, and thus a touch of palladium removed it entirely.

aigialomycin_d_31

At this point, all that remained was the RCM and a bit of deprotection.  Key to this was their use of a secondary olefin in addition to the terminal olefin; two terminal olefins resulted in a 50% yield.  However, using the secondary / terminal olefin combination, the yield was boosted to an altogether more satisfying 81%.  Deprotection with a few protons did the business, and finished the target.  Nice!

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36 Comments

  • gippgig says:

    There is definitely a need for better proofreading (of both entries & comments). The large number of typos & grammatical errors is quite annoying – the sentence starting with “However”, “I though a brief retro…”, the “Commercially Available” ellipse should be slightly larger on the right (including the carbon on the left side of “RCM”), “It turns out the buying…”, “in it’s wake” (There’s a very easy test: just substitute (no catalyst required) “it is” for “it’s”/”its”. If the meaning is the same, it’s “it’s”; if the result is nonsensical, it’s “its”.), “a 11%”, “definately”, the beta-ketoester is missing the O of the ester, & the structure over “LDA” is missing 2 carbon atoms. Ouch!
    I think all the fuss over which journal a paper was published in is rather silly. An interesting synthesis is an interesting synthesis regardless of where it was published (unless it was in the Journal of Irreproducible Results).
    Has anyone compiled a list of structures that can’t be made with current techniques? If not (& I assume it has) it should be worthwhile & thought-provoking.
    One issue that I think deserves some attention is whether a synthesis proves the structure of the product. Offhand, you’d expect that it would, but it seems to be quite common to use reactions that could produce more than 1 product (especially stereochemistry). Converting a product of such a reaction to the desired target obviously wouldn’t prove its structure.
    It might be worthwhile to create a section to report reactions that didn’t work. Again, it should be thought-provoking.
    This is outside my area of knowledge (I’m basically a theory-oriented mad scientist with a general interest in chemistry rather than a specific interest in syntheses) but I get the impression that most of these syntheses are based on clever chemistry using ordinary lab equipment. Is anyone doing or considering doing serious synthesis experiments in a home lab? This sort of thing is possible – there’s a group called AMSAT that’s been building their own communication satellites for ham radio operators for decades for 1/30 the cost of equivalent commercial satellites.
    This is pure speculation, but it occurred to me that some fairly recently discovered compounds (such as HXeCCH) that contain a xenon-acetylenic carbon bond might have unusual properties that could possibly be useful in syntheses. Has this been investigated at all?

    • Safety conscious says:

      “Is anyone doing or considering doing serious synthesis experiments in a home lab? This sort of thing is possible….”

      Yes, this sort of thing is possible in a home lab. If you’re prepared to deal with routine procedures involving noxious fumes, toxic and pyrophoric materials, strong acids and bases…to say nothing of the requirement to have available large volumes of flammable solvents (which in most jurisdictions will require specialist storage in flame-retardant cupboards). You will also need an inert gas line, specialist glassware at pressurisation specification, the ability to generate high vacuum on demand, analytical equipment cooled using liquid helium, other analytical equipment run with medium-pressure pumps, large amounts of computing power to efficiently process the data obtained from said instruments, high-precision glass syringes….

      I am aware that part of your arguement concerns “…1/30 the cost of equivalent commercial [materials]“. However synthesis concerns chemical substances of unknown toxicity. Even outside of newly prepared materials, I’d be extremely unhappy to think of people trying to evaporate diethyl ether on top of their gas stove, or generating amounts of methanethiol in their living areas. Also, my local council is rather choosy about what I do with my waste (or do you suggest these home labs tip their phosphate buffers, their chromium and palladium wastes, their concentrated bases, down the domestic drain?)

      Once you resolve these safety concerns, I’d debate whether there is an actual difference between your home lab and a commercial venture.

      • C. Bailey says:

        yeah, organic chemistry labwork is not the same as fussing with electronics in your garage…

      • gippgig says:

        I absolutely agree that this is not stovetop chemistry. This is for the person who knows how to handle dangerous chemicals (I assume many of the readers of this blog do) and has sufficient interest to expend the effort necessary to make a good quality lab (some might).

        • Knut Jacksworthy says:

          Well, there was this guy named JJ La Clair who did a 32-step total synthesis in a refurbished yoga loft with the help of five technicians and without an in-house NMR…

    • nitrosonium says:

      compiling “a list of structures that can’t be made with current techniques” is slightly less useful than your comment, gippgig

    • mary says:

      Dude, gippgig, please either get a clue or be quiet. You acknowledge that synthesis is not your purview, and indeed, your observations/speculations underscore that fact.
      Too, your complaints about typos, etc., are sorta ridiculous.

    • gippgig says:

      Correction: substitute “it is” should be substitute “it is” or “it has”.

    • Mediator says:

      I don’t think this is such a bad post. I’m a grad student interested in synthesis, and I don’t think it’s bad if someone from another field is interested in synthesis also. We have a lot to learn from each other. Ease up everyone, this shouldn’t provoke such a negative response.

      Chill…

      • Safety conscious says:

        I’m not commenting on the quality of the post, or the quality of the comment. I am honestly, deeply concerned by the suggestion that cutting-edge research chemistry be conducted in the domestic environment without the proper safety controls. Safety controls include the effect on people around you (in the form of wastes). Readily available, constantly serviced safety cabinets, fire extinguishers are only the start of it….I just don’t see a domestic set-up being sufficient, or sensible.

        I wouldn’t want to be living in the same apartment building as the guy who is stewing reactions all day. Heck, I’ve know people go crazy at the mere smell of frying onions, and that isn’t exactly noxious!

        As you say, there is nothing wrong with people having an interest, I welcome the interested. But there has to be an understanding that what we do is >dangerous<. Even to the highly trained. And that is always worth reminding people.

      • mary says:

        Okay, Mediator, you’re right. I shouldn’t have gone off on gpp..whatever his name is, and I’m sorry. I think what bugs me is that our man TotSyn goes to the trouble of posting this stuff so that we might be intrigued, enlightened, whatever. So, when he’s taken to task for, like, the number of little dots in an ellipsis…well, that gets my Irish up.

      • z says:

        I think it is good to encourage questions and comments from people who are not specialists in our field, no matter how naive those questions and comments may be. I also believe that if someone wants to be arrogant and condescending, then that is his/her (it’s?) prerogative. But the two really do not mix well, and I think that is gippgig’s major problem–coming in like a know-it-all trying to enlighten us with a long list of ridiculous suggestions.

        (Of course, I think he was trolling, but I’m a sucker and try to give people the benefit of the doubt and take them at face value).

  • Eric M says:

    I love it when the complaint is longer than the original post.

  • Tom says:

    gippgig-

    Not cool.

  • pi* says:

    what a douch

  • Kai says:

    missing an oxygen atom there at the allyl ester?!

  • Kai says:

    Re: gippgig
    gotta love those theorists. we had a physics postdoc in our lab who wanted to hang out with me for a week or so while I was doing synthesis to “see how it’s done”, I guess to start making his own molecules…

    • gippgig says:

      There’s a joke that anytime a theoretical physicist goes in a lab the equipment breaks. As the story goes, one day a really important piece of equipment failed – and the researchers realized that a world-class theoretician had just gotten off the train at the local station.
      The missing oxygen has been fixed.

      • stfu says:

        You definitely have some issues my friend. There are increasingly more and more useless comments like this on this blog. My favorite one is this “nice synthesis”.

        • milkshake says:

          where is the moderator (Paul) when we need him… I once got a pompous douche trolling my web site and desperately trying to plug his green chemistry expertise in like 1000+ word comments, completely off-topic with dramatic spacing, various funny colored fonts (even imbeciles can learn HTML) and plenty of exclamation marks. After first warning I deleted his further comments and since that did not seem to stop him I got the spam filter to divert his drivel and that eventually did the trick. It felt great, too.

  • LW says:

    As I was once told, a theoretical physicist (usually the ones sitting in front of the ‘supercomputers’, generally perving on Facebook and looking for an even bigger external hard drive on Amazon to store all those television series they’ve downloaded from Piratebay) spend about 10 minutes on an experiment, and then 3 years trying to find out what the hell happened. I challenge gippgig to do a simple titration of t-Buli in the bathroom sink.

    With regards to HXeCCH, yeah I’ll try it in a Sonogashira. I’ll do it in the kitchen whilst I make myself a cheese toastie, and I’ll get you to do the computational stuff afterwards. We’ll publish it together and we can send it to Nature in 2012. Trust me, it’ll get in because of the computational stuff.

  • Pilky01 says:

    Do you think he could have made this molecule with his Grignard addition to benzyne and CO2 trapping methodology?

  • Will says:

    There already is a journal where people report reactions that don’t work – it’s called Tetrahedron Letters

    I’ll be here all night…

    • krest17 says:

      Will – not cool, keep such comments please.

      Not everybody is able to publish in JACS, especially when you are working outside USA – it is a real problem. Not all procedures from JACS/Org. Lett. are reproducible also – D.Sames and etc.
      I have papers in Tetrahedron and Tet. Lett. – and not because chemistry did not work.
      BTW, Corey himself published a lot in Tet. Lett.

      • milkshake says:

        yea but it was way back when coal was still swaying its branches in the breeze and steam co-distillation was the cutting-edge purification technique. OL took up lots of decent stuff that would go to TL before.

      • mary says:

        C’mon, krest, Will’s joke was funny!
        And I think the problem is not whether one is in- or outside the U.S., but whether one is communicating good science.

        • DC says:

          I guess you are from the US then, mary? It’s common knowledge outside the US that it’s generally much harder for non-US researchers to publish in JACS. But it’s the ACS after all.

    • Atom Recession says:

      I guess TL;DR has a very different meaning in chemistry blogs than on other sites on the web…

  • TWYI says:

    Just skimmed this months issue of Tett Lett – papers from Danishefsky, Burgess, John Wood, Nakamura, Dave Knight..

    not bad for a crap journal.

    • krest17 says:

      TWYI – Thank you :-) anyway let’s stop discussions about journals and mistakes in English please, enough. TS-blog is not about it I guess.

  • Piperidine-Longstockings says:

    Most amusing! I would have thought gippgig’s post would have gotten deleted much quicker, after all it IS completely useless. Way to spark some anonymity between theoretics and synthetics he he! He is right you know, it is possible to do this sort of thing in a home lab. In fact they’re quite common, although illegal, because of what’s usually manufactured there :) Thanx for the laugh though!!!

  • Piperidine-Longstockings says:

    Serves me right for clicking on the spell check ! :)