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Azadirachtin Pt. II   

1 August 2007 9,619 views 23 Comments

azadirachtin.jpg

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

In this part of the discussion, I’m going to cover the synthesis of the more complex fragment from the retrosynthesis given in the previous post, that of the decalin fragment. The subunit is certainly a challenge all by itself, containing ten contiguous stereocenters, and complex oxygenation. Most of the work on this fragment was referenced back to previous papers by the group, and from what I read, most of the information is in this Perkin 1, and this Tetrahedron paper.
azadirachtin_3.jpg

Their synthesis of this portion is well envisaged, starting with generation of four stereocenters from an IMDA. Importantly, the endo/exo control comes from their use of a silane precursor, which gave them the endo product in a 5:2 ratio. Without this functional group, the ratio was reduced to 1:7, so was fairly important.

azadirachtin_4.jpg

It was also the control element in the next transformation, an intramolecular aldol, which created a further three stereocenters with good control. The desired diastereoisomer was received in a reasonable yield, along with a further 10% of the methyl ketal, which was converted to the hemiketal easily. The silyl group was transformed into the required hydroxyl with retention of stereochemistry using mercuridesilylation, (a modified Tamao-Flemming oxidation) – a reaction on my brown-trousers shortlist…

Also noteworthy in the Perkin 1 paper was the chain reduction of an aldehyde by formation of the corresponding silyl enol-ether and ozonolysis. Such a simple method, it must have been done before – but this is the first time I’ve seen it.

In the same paper, they then took this advance racemic intermediate and did a resolution to get the desired enantiomer – but I can’t tell if this is what they did to complete the total synthesis – any ideas?

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23 Comments

  • Liquidcarbon says:

    Something wrong with IMDA…

  • Tot. Syn. says:

    yep, that shouldn’t be a lactone at the top of the fragment – they Tebbe’d it…

  • apropos says:

    Also the trans olefin couldn’t have given the cis product in the IMDA

  • cheyanimal says:

    i think that they said they could also obtain this piece through degradation in the paper. so perhaps there was no large scale resolution needed. the synthesis of this piece seems a lot better than the other piece, though not enantioselective. The mesylate synthesis made me cringe.

  • TMTCl says:

    can anyone recall a Barton quote which is something along the lines of : it’s very easy to accidentally develop new methodology, but very difficult to do so purposefully.
    i have googled until I could google no more but i need to find it on my supervisors orders.

  • spottospot says:

    16 comments on the big synthesis. I guess it isn’t big news.
    Relay is weak. Relay is oldschool. Did he start this before the invention of NMR? Maybe you can make a synthesis more impressive if you just use IR, UV and EA to analysis the synthetic products. Another brevitoxin.
    They tell me it isn’t the size that counts its the way you make it.

  • orgoboy says:

    It’s not about how big it is but how you use it!

    hehehehe

  • Jose says:

    Tiny thread hijack- I’ve heard rumours that David Gin ran an obscene number of reactions in two yrs when working on Ect 743 at Harvard. Does anyone have ballpark numbers? We’re busy playing “How productive is productive?”

  • .... says:

    it’s my understanding that Andy Myers was working alongside Dave Gin (i.e. the neighboring fumehood) during his PhD. That would certainly motivate me to spend a good portion of the day working. Can’t say much for his time with Corey but nailing down Et743 during a post-doctoral fellowship (compared to the efforts of other groups) certainly indicates that work ethic was one of Gin’s strengths.

  • GYA says:

    David Gin actually did his PhD with Myers working on the tunicamycin antibiotics before heading to the Corey group.
    Interesting article about him and his development:
    http://www.mskcc.org/mskcc/html/73091.cfm

  • jimbo says:

    spottospot: It’s big news but there isn’t much to say. If you think relay is lame, then you haven’t worked on, nor known anyone who’s worked on azadirachtin. I’d rather see a relay synthesis than know that some chump postdoc/grad student had to spend all of their time in the lab working on the kilogram scale just to get to the end with a few hundred micrograms of material.

    This is kind of my point in the previous thread… you can get your hands on kilos of azadirachtin… the only argument -for- it’s synthesis is that it’s really bloody hard to make. There’s nothing brevitoxin about it… brevitoxin is about size. Azadirachtin is about extraordinarily dense functionality… and out of this work has come a handful of different approaches at constructing extremely hindered junctions.

    And for the record, Ley’s synthesis of azadirachtin is dead sexy. This could very well have been a Nature or Science paper.

    on David Gin– I had lunch with the bloke and he couldn’t stop talking about how many reactions he would run. That dude is full of energy.

  • GYA says:

    Nature or Science solely for the conquest not for the synthetic design. Nature or Science require something more.

  • synthon says:

    When Gin was at IL (and I was a grad student) the rumor was the number of reactions run during his time with Corey was ~1700. Who cares…the et743 synthesis is spectacular!

  • Jose says:

    TMTCl-
    You should look for a Tetrahedron Perpectives paper (mid to late ’80’s?) by Barton, called something like “Inventing New Reactions.” I’l try and dig it out of my files if time permits.

    Thanks all, for the David Gin info!

  • regularchem says:

    “can anyone recall a Barton quote which is something along the lines of : it’s very easy to accidentally develop new methodology, but very difficult to do so purposefully.
    i have googled until I could google no more but i need to find it on my supervisors orders”
    I believe it is “chances always favor the prepared mind”, something like that.

  • anaon..... says:

    Angewandte Chemie, International Edition (2007), 46(9), 1512-1516…what do you think about this route…which on is more creative?

  • sjb says:

    “chances always favor the prepared mind” (or the equivalent) was Pasteur, I think

  • HPCC says:

    I still prefer Ley’s route to Watanabe’s, for the following reason. In order to build the decalin, although Watanabe’s C-C bond forming reactions are clever and allow for the incorporation of many if not most of the oxygenations of the AB rings – sorry, I forgot the minute details, as I read that paper so loooong ago! – Watanabe’s strategy also requires one to break C-C bonds in order to finalise the construction of the rest of the cyclic appendages.

    Must be said, both Watanabe’s and Ley’s key steps for the construction of the evil C8-C14 bond are masterpieces.

  • jerry says:

    I am a beginner for total synthesis,May I ask a very simple question: What does “relay route” mean?

    Thanks very much

  • Jose says:

    Relays are when you take natural material and degrade it to one of your synthetic intermediates. Assuming the natural material is easily available and reasonably cheap, this saves time and money in not always moving material forward in order to advance the synthesis. Not very common anymore (most new NP are isolated in low mg quantities) but old school alkaloid chemists were the masters of this technique.

  • Spiro says:

    Routine blablabla in Nature :
    Nature 448, 630-631 (9 August 2007) | doi:10.1038/448630a

    The article is so informative that they do not even bother to provide a structure of Azadirachtin to their readers…

  • Derek Lowe says:

    Why do they always quote me?

    I am so awesome.

  • Derek Lowe says:

    I’ll defer comment on my awesomeness for now, and just note that comment 22 isn’t actually from me.

    As for getting quoted, it’s like all of these things – you get called for quotes after you’ve been called for quotes. The hard part is getting called the first time or two.