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Amphidinolide E   

14 November 2006 6,551 views 13 Comments

amphidinolide_e.jpg
Lee, Kim, An, Shin, Yu, Woo and Jung. ACIEE, 2006, Early View. DOI: 10.1002/anie.200603363.

Another amphidinolide in the bag, this time Amphidinolide E, completed by Eun Lee’s group at Seoul National University. Their approach is very convergent, with an interesting choice of disconnections, some which are obvious, others less so.

amphidinolide_e_2.jpg

So, to the forward synthesis; starting with a known chiral triol, protection with a PMP acetal and reduction of a an ester to the aldehyde gave the starting material for the first interesting transformation, a Roush crotylation. Many of you will have seen this before, but the result (86%, 16:1 d.r.) goes to re-enforce the utility of this transformation.
amphidinolide_e_3.jpg

Transformation of this product into the starting material shown below was accomplished easily, firstly by protection of the free alcohol, deprotection of the acetal and selective tosylation of the primary alcohol. The free alcohol was then free for functionalisation with an olefin and the tosylate converted to an iodide via a Finklestein reaction. Cyclisation onto the alkene via radical generation ((TMS)3SiH) returned the THF in rather decent 92%. However, they had a problem, in that they required homologation of the olefin to the acetylene shown. The tried using an NHK, Wittig sequence, but this gave them rather low yields, so they resorted to using diazophosphonate on the aldehyde. Again, not novel chemistry, but a nice implementation in 83% overall.

amphidinolide_e_4.jpg

Metathesis of the acetylene with 1,4-pentadiene completed most of the top-half, requiring functional group transformation to deliver the Julia-Kocienski substrate. Coupling with the lower fragment (produced relatively quickly), deprotection and macrolactonisation then completed the target.

I’ll be honest and say that whilst this is all well done, this paper didn’t grab me, generally because it’s lacking in novel methodology. However, it’s a complex target, and the first total synthesis, so I guess it’s still worthy…

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13 Comments

  • Canuck Chemist says:

    You really love the macrocycles, man! For us nuts-n-bolts practioners of organic chem., this stuff can have some practical value, but I’m having trouble seeing the academic value in these sorts of syntheses. Unless you’re bringing something substantially new to the table, why make these things?

  • ddd says:

    Answers why:

    1. good training for student, and mentor…Good overall training in chemistry and chemical reactions. Pro-fighters train all the time to be in shape, although there is nothing new in punches or kicks they throw, however they can come up with some new useful combinations.

    2. Material supply and analog synthesis (if bacteria which coexisted with the sponge one time, suddenly disappear, case of leucascandrolide A) or case of bryostatins and their much simpler versions called “bryologs”. Well synthesis of spongistatins on 1g scale is a formidable challenge too

    3. Synthesis of fluorescent and biotinilated analogs to figure mechanism of action in the cell.

    4. New methodology which can arise from the off shoot reactions.

    Ideally when you make a molecule you should combain all 1-4 in your synthesis.

  • Rof5 says:

    Any idea on why the authors choose Roush crotylation to get the homoallylic alcohol? What about the Leighton reagent?

  • ddd says:

    why bother to be in shape for chemist?

    So that when there will be Tamiflu supply problem we could design an easy and quickly scalable synthetic scheme to save people’s lives.

  • European Chemist says:

    I’d risk saying that the “training” part should be more than a mere technical training…
    OK, so you’ve never run a Dess-Martin oxidation before. Is there something substantially useful in doing that in the frame of “good training”?….
    I would personally prefer “intellectual” training, where the student has to come up with new solutions and propose inventive and fast ways to solve (his!) synthetic problems.
    All in all, this kind of project might have some utility for the beggining Ph.D. student, but if you’re in your 3rd year and this is all your supervisor has to throw at you, I wouldn’t be that excited….

    Tot. Syn.: experience seems to show that even underneath the most trivial synthetic work there are useful lessons to be learned. The question is wether those lessons are apparent from the discussion presented by the authors in the paper or not….

  • Tot. Syn. says:

    EC:
    Very good point. Especially in these short papers, the full extent of the work is generally not apparent, and who knows what else they tried? Even basic chemistry teaches every student something the first time they do it… that first Swern Oxidation – everybody learns something! The first time you do a LAH reduction on more than 10g – you learn the smell of fear…

    In this paper, the students had to use TlOEt in the Suzuki coupling for the bottom fragment. I’d imagine the chemists in question learnt a lot there… also disappointment at the yield.

    BTW, I try not to have a macrolide bias, but I can’t not present Amphidinolide E…!

  • ddd says:

    training part is obviously less important than 2-4, but essential part. training included intellectual part also – “intellectual training” as you said – “where the student has to come up with new solutions and propose inventive and fast ways to solve (his!) synthetic problems.”

    As Dess-Martin is concerned. Mitsunobu reaction looks gr8 on paper, but only after do you run it you see that O=PPh3 is a problem, esp. on the large scale. Only after do you run reaction at -100 you will really see that yes…-100C is a bit problematic. Also running just Dess-Martin reaction is not stimulating, but when you have 10 step sequence and you have to pick right protective groups, have to decide WHEN do you your Dess-martin oxidation : on your second or seventh step, that is a good training. But overall I agree intellectual training is much more important.

  • yepyep says:

    Sometimes the problem with these letters or communications is that the number of pages is so limited that the authors can’t really go through all the stuff that didn’t work but that might explain why they chose a certain synthetic pathway.

    For example, the compound I’m working on at the moment contains a functionality that on paper doesn’t look labile at all but in reality it pretty much dictates what reagents I can use. I could of course get rid of that functionality to make things easier for me but then I would have to add more steps to the synthesis, and because I’m such a elegantophile, I just can’t do that :)

  • Observer says:

    Question for ddd: Has Tamiflu ever been proven to save lives? Has it ever been proven to be effective in treating avian influenza?

  • ddd says:

    tamiflu no, but penicillin yes..

  • josef says:

    what is NHK, Wittig sequence?

  • Tot. Syn. says:

    A Nozaki-Hiyama-Kishi reaction, followed by a Wittig olefination.
    http://www.organic-chemistry.org/namedreactions/nozaki-hiyama-coupling.shtm

  • […] Nope, this isn’t déjà vu (or the film), this really is another synthesis of amphidinolide E, the second this month (the first was by Lee in Korea). This time it’s Bill Roush from Scripps, using some their own methodology to construct that THF. So, first the retro: […]