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Azadirachtin Pt. I   

31 July 2007 9,427 views 18 Comments

azadirachtin.jpg

Ley, Veitch, Beckmann, Burke, Boyer and Maslen. ACIEE, 2007, Early View. DOIs: 10.1002/anie.200703027, 10.1002/anie.200703028.

The completion of Azadirachtin, like Rapamycin (blogged back in December), marks the conclusion of a lengthy chapter in the Ley group, and having been a student at Cambridge for a few years, the progress on these molecules was frequently subject to rumour. It seemed that everyone knew someone who had worked on either, going back years to the early work. It must be very odd to have them complete, published and no longer a hot topic in the lab… Also, props to Alastair and and everyone else I know on this paper.

Anyway, many of you will also have met this molecule in publications leading up to the total synthesis, but for those who haven’t, it’s a complex in biologically interesting insect antifeedant. Basically, it causes and growth-disruption and antifeedation (sp?) in insect species which are detrimental to the plant in which it is found, but not to insects which aid the plant, such as lady-birds and bees. Interesting, but to us organic chemists, the more attractive (or terrifying) aspect of the target are the sixteen contiguous stereogenic centers!

I promised a retro, and here it is: the main disconnection between the two largest fragments are discussed in this post.
azadirachtin_5.jpg

Their plan (which hasn’t changed too much over the years) was to split it into two large fragments – the “Decalin” component and the “Pyran” component. The decalin fragment has been the focus of several papers by the group over the years, and is covered in the following post, with the pyran unit was made with apparent ease from a galactose derivative.

azadirachtin_6.jpg

To me, however, the most impressive transformation was the synthesis of the bicyclic ether via a radical cyclisation onto an allene. First, of course, they had to make the allene, which they did using a rather tasty Claisen rearrangement:

azadirachtin_1.jpg

I find it interesting and useful that they give two sets of conditions for this reaction, and also slightly surprised that the results are identical, but the conditions couldn’t be more different. The gold chemistry references a Toste paper (no suprises! – and, as an aside, the Boss always refers to gold as being “A big proton”, which explains to me how this works), and a previous Ley paper (with my previous supervisor). Either way, the chirality transfer goes well, and they have the desired allene. Now, to generate the radical, they use some Barton/Motherwell chemistry (old-school), forming the xanthate ester from a free alcohol, and were set to cyclise:

azadirachtin_2.jpg

Now that’s a nice cyclisation! (Though I am somewhat predisposed to like a good radical cyclisation…) The methodology might not be new, but the yield goes to show how useful a well-planned radical cyclisation can be.

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18 Comments

  • ZZZZZ says:

    Congrats to the Ley Group, a tour-de-force to complete this molecule. Very impressive.

  • HPCC says:

    Especially when the group has been working on this for 20+ years… How many times have students felt like giving up on this thing?

    Anyone notice the fairly brutal conditions and poor yield for the crucial epoxidation? That attests how crowded the environment of that double bond really is!

  • Spiro says:

    Great job! This beast makes other molecules look very humble ;-)

    Does anyone know of other beasts like this one, that have generated many and many synthesis attempts, and have not been completed yet?
    I can only think of maitotoxin, that is going to generate a zillion of articles, even tough I would rather put maito in the iterative-type synthesis category.

  • Liquidcarbon says:

    Claisen stole one methyl!..

  • jimbo says:

    If there were ever a total synthesis analogy to a Rube-Goldberg machine, this would be it. Like a Rube-Goldberg device, you stand back and think, “Wow, that’s really impressive! All that work must lead to something important… oh… it kills bugs.”

    That said, it’s nice to confirm that, indeed, with enough effort and (wo)man hours any natural product can be synthesized. Formally, anyway.

    Kudos to everyone involved… I would have jumped off of the tallest thing at Cambridge had this been my PhD project.

  • HPCC says:

    “Kudos to everyone involved… I would have jumped off of the tallest thing at Cambridge had this been my PhD project.”

    I would have attempted double-suicide in Jimbo’s company, needless to say, if I had been on this project…

  • Spiro says:

    “All that work must lead to something important… oh… it kills bugs.”

    Malaria causes 400–900 million cases of fever and one to three million deaths annually. I personnally think killing bugs is more important matter than curing ED.

  • jimbo says:

    Most drugs on the market aren’t for ED. http://www.drugs.com/top200.html

    You can isolate azadiractin from the neem tree by the kilo and nobody is going to do a med chem project on it (because it isn’t really a drug). It’s pretty unlikely that the total synthesis will be of any value, and it certainly isn’t going to improve the availability of the compound in tropical regions. The argument for making the natural product is that it’s hard, which is a perfectly good reason if you can get funding.

    It’s all a great training exercise, and I’m sure the countless students who have dedicated several years to this beast have become great chemists and we should all be proud of them. You can’t really argue that this total synthesis is important otherwise. It’s all just a pissing match amongst the academic elite, and the poor students involved are all downwind.

  • milkshake says:

    The first thing to cross my mind (when looking at this beautifully tailored synthesis) is the relief that upon the completion and final deprotection step, the natural compound did not turned out wrongly asigned on one stereocenter…

  • pi* says:

    your right, fine radical cyclization

  • Greg says:

    That is a great radical cyclization. Very nifty. I am fond of sigmatropic rearrangements too.

  • Liquidcarbon says:

    Surprise re-visit! :)
    I’m doing an assignment on this and had a quick thought that the complications from undefined C-23 methyl acetal could be avoided by using a bulkier protecting group for the nearby alcohol (they had benzyl). That could help push the methoxy group trans from this substituent (instead of dealing with 1:1 mixture which had to be separated).

    Overall, it’s fucking hell… 22-year-long effort towards naturally abundant substance… the other paper describes total synthesis of azadirachtin from azadirachtin…

  • Liquidcarbon says:

    And yes, their decalin fragment was clearly derived from natural product. 1992 JCSPT1 paper describes the synthesis of a compound without C8-Me. A very ugly one, I should say. 38 steps from 3,3-diethoxy-1-propyne, 2-TBSOacetaldehyde, and a three-carbon dithiane. Horrible mixtures at half of the steps and a late-stage resolution of diastereomeric camphanate esters by prep. HPLC

  • Tot. Syn. says:

    Liquidcarbon: I like your idea of using a bigger protecting group, but do you have any conformational evidence for it’s effect other than an on-paper representation? I did a couple of rather rough molecular-dynamics / minimisations to look at the effect of switching to a TBDPS group (fairly big, I’d say), and it seems to me that the PG is too far away to influence things very much.

    I know a few of the people who worked on this project in it’s closing phases, so I’ll try to find-out what they think of your suggestion.

    However, I’ve got to say that Ley’s approach to this target (and it’s ‘cousin’ in the Wiffen Lab, rapamycin) was completely difficult to that of, say, Nicolaou or Furstner. For Ley, it was all about the journey, and the discoveries made on the way, rather than just getting there. I know plenty of people who’d argue against me on this one, but I for one am a fan.

  • Martyn says:

    So, there are 46 names (by my count) on the full paper in Chem. Eur. J. – is that a record?

    As an aside, I think maybe you’re being a little harsh on Furstner there. There’s plenty of good methodology coming out of his lab.

  • Tot. Syn. says:

    Harsh? Not a bit of it. I think Furstner’s work is fantastic; probably the best in Europe just now. But that wasn’t my point. What I’m trying (and possibly failing) to constrast is their modus operandi. If everyone took 25 years about their syntheses, we’d be in a fine state… but it does make for a change!

    I don’t think that 46 is a record in the literature in general, but it *might* be in organic synthesis. However, some of thoses names are very significiant in modern chemistry and industry – Tony Wood, for instance, is VP of Pfizer, and my former superviser, Chris Spilling, is HoD at UMSL. I very nearly did my PhD for Don Craig…

    For a huge number of authors, check out a genetics paper, like this: http://dx.doi.org/10.1038%2F35057062

  • TWYI says:

    Woodward’s erythromycin was over 40 authors I think..

  • antiaromatic says:

    The discovery of the Top quark at Fermi Lab had somewhere around 200 authors on the paper. It’s a shame because the Nobel committee couldn’t award the prize for its discovery because too many scientists were involved.