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Amphidimolide E   

1 December 2006 7,376 views 27 Comments

amphidinolide_e_8.jpg
Roush and Va. JACS, 2006, ASAP. DOI: 10.1021/ja066663j.

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:

amphidinolide_e_9.jpg

As you can see, some of the disconnections are more obvious than others, but I assure you, their methodology isn’t “shoe-horned” in… The top-half of the molecule was discussed first, preparing the substrates for that funky [3+2], which is where I found my interest piqued initially. They did a silylallylboration of the aldehyde, referencing their earlier work on that procedure, which returned the product allylsilane in fantastic yield and d.r.
amphidinolide_e_5.jpg

TES protection of this compound left them ready to perform the [3+2]. They used 2.5eq of the alkyne, achieving a reasonable yield of the product, and with great diastereomeric control. They mention that they recover the excess of alkyne, but the remaining aldehyde cyclotrimerises under the reaction conditions.

amphidinolide_e_6.jpg

With this fragment in hand, they were ready to couple the next fragment. This might appear to be a relatively simple esterification, and that Yamaguchi conditions would have this done before breakfast tea, but apparently not. They found that under all conditions attempted, the diene-acid isomerised to the more conjugated material, leaving with a tricky problem. However, their solution is super-smart – protect the diene!! They used the iron complex shown to hold the diene unit in place, performed the modified Yamaguchi in great yield, and then oxidised the iron off.
amphidinolide_e_7.jpg

RCM completed the macrocycle, leaving them with only the side-chain to append. A great synthesis of this rather popular molecule.

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27 Comments

  • Rof5 says:

    European Chemist,as you said, now here it is!

  • European Chemist says:

    Indeed. It’s a pity that the 3+2 reaction – rather spiffy when you consider it in mechanistic terms, far from obvious! – doesn’t give a better yield. Of course, the requisite for excess alkyne is also a drawback, even if you can recover it at the end because it will essentially make up for a trickier chromatography.
    The diene protection trick is indeed quite “elegant” (if you know what I mean :-D) and is the kind of thing you want to see when you read total synthesis papers.

    Of course, could you imagine a total synthesis by Roush without an asymmetric allylboration? LOL

  • pendejo says:

    You forgot to draw the oxygens in the silylallyboration reagent

  • cabronations says:

    Very buena synthesis!

  • pendejo says:

    I hear there’s a another paper coming out concerning what happens when you use the other acid diastereomer ;)

  • culonito says:

    I can’t wait for the next paper…I hope it gets here before breakfast tea!

  • Andrei says:

    check the spelling in the title please

  • Chemist of Sorts says:

    Enough already with the macrolide syntheses! How about some “real” synthetic work (deliver us from aldol hell). Remember: real chemists make alkaloids. Just kidding, but seriously its time for some variety.

  • ddd says:

    I agree, time to put some Fukuyama molecules here, I love his syntheses, there is always something in them. CP made by KCN consisted 2 back to back papers with 8 people. Fukuyama 2 page communication with 2 people.

  • Lurker says:

    A suggestion to profile, though it isn’t strictly a synthesis:
    http://dx.doi.org/10.1021/ol062520q

    I wonder where the idea to protect the diene came from – that’s pretty good stuff.

  • European Chemist says:

    I’ve noticed that Org Lett by Braddock too – always nice when you can publish papers without doing any experimental work. Makes you remember the 1930′s…

    As for variety, I suppose what Tot. Syn. looks for is not the type of reaction involved or the class of molecule but rather wether there is interesting chemistry to be discussed and learned. For example, I hope everyone who asks for “deliverance from the aldol hell” LOL would have thought of protecting the diene by forming an iron complex… ;-)

  • synthon says:

    The iron complex to protect dienes has been known for some time. Some seriously beautiful diterpene work by P. Kocienski about 5 years ago if memory serves.

    On a related note, Kocienski’s protecting group book has been updated with a new addition as has the old standby Green and Wuts. I see another new version of March is due in January as well. To many books these days!

    To ddd: Fukuyama is indeed the man and there is always methodology to be found in his natural product synthesis (cf. vinblastine – one of my personaly favorites) – and don’t forget his modification of the Mitsunobu reaction.

    Cheers

  • Tot. Syn. says:

    I blog the stuff that’s published! If everyone wants to make macrolides, that’s what’s going to get blogged. If you want post on other classes of molecules, go make some! Personally, my total synthesis isn’t a macrolide either… though it could be…

  • ddd says:

    I heard Kishi was bringing lunches to Fukuyama, so that He would not bother going away from the hood :))). His other famous phrase (fukuyama): “Once you’ve started you have to complete”, I will remember this for the rest of my life :)

  • yepyep says:

    I’m not a big fan of macrolides but that Fe(CO)3 as a protecting group is rather nice. I like to think that I would have tried something similar in the end but it’s more likely that I would have given up and started planning another synthetic route :) An elegant (that word again!) solution to a problem is always nice to see, no matter what target.

  • HOMO-LUMO says:

    Hey that emphasis about Fukuyama is great, his synthesis are just art works. Thanks for the Mitsonobu tip. I’d like to add, that japanese chemists are great at developing reactions, even not the very well known ones.

    A synthesis that wasnt highlighted here this year was (-)-sordarin by Narasaka, a really good one. To tell you about the approach, the skeleton is a guanacastepene type, and then it gets complicated. Another name I really would like to see here is Raymond Funk, to me a very innovative academic, but these are
    just personal preferences.

    To conclude, macrolides are really important as synthetic targets not only because their biological activity, but
    the synthetic innovations discovered in their synthesis many times can be applied to other important fields as macromolecular chemistry. (Altought are not my prefered molecules)

  • .... says:

    It’s my understanding that sordarin appeared here on May 6th – 2006. I believe this was the first totallysynthetic post I read and have fond memories of subsequently reading the paper in print on the grass outside the chemistry building.

  • ranfiddler says:

    many people don’t like macrolides because aldol, RCM and Yamaguchi are mostly seen. it’s nice that Roush applied the protected diene in the esterification. one thing to reminder, people more like to see a synthesis of polycyclic skeleton because it looks really good. :)

  • OCD Chemist says:

    To beat a dead horse, the Fe(CO)3 group to protect 1,3-dienes has been known for some time now (>20 years). Although it’s not by any means new, Roush did use it nicely here, IMO.

  • HOMO-LUMO says:

    Ouch, sorry.

    What about R. Funk?

  • ranfiddler says:

    Funk published some nice syntheses in OL lately.

  • European Chemist says:

    Nobody pretended the use of Fe(CO)3 to protect dienes was “new”. But as OCD Chemist says, it was a nice application in this particular case. I stress once again, it is far fom obvious that we (me included) would have thought of this. It’s not because it’s known for 100 years that everyone immediately thinks about it to solve problems, for heaven’s sake!

    I don’t think that it is reasonable to demand that truely “new” chemistry be in every total synthesis. I, for instance, like syntheses which refresh my memory like this one by Roush. An “elegant” (…) solution like the diene protection is enough to make me feel my time has been put to good use in browsing through that paper. Discovering some methodology I didn’t know about before is always useful, too. For those of you who found this to be so obvious and so blatantly clear, I hope to see you some years from now at Stockholm collecting your Nobel prizes! :-D

  • OCD Chemist says:

    I wasn’t trying to insult anyone, I was just clarifying that the method is well known (I have OCD, as you know). As I said, it is well used by the scientists in this synthesis. Best wishes to all…

  • JK says:

    yea.. just another total synthesis……

  • Ernestinho says:

    A question concerning the configuraton of the methyl-group at C-19. Why doesn’t it change it’s absolut configuration during the [3+2]annulation step? Both the protecting groups closely positioned do so. Is there a reasonable explanation?

  • Rof5 says:

    Wow, Va and Roush had another paper of Amphidinolide E & Amphidinolide E stereoisomers on Tetrahedron 2007, 63, 5768-5796. 28 pages, nice!