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Amphidinolide H and G   

1 November 2007 7,980 views 14 Comments

Fürstner, Bouchez, Funel, Liepins, Porée, Gilmour, Beaufils, Laurich and Tamiya. ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200704024. Article PDF Supporting Information Group Website

Apologies for the lack of blogging – turns out this writing-the-thesis thing is quite time consuming. Feel free to talk amongst yourselves… Anyway, normal service has been resumed for today, with another Amphidinolide in the bag (actually a pair – Amphidinolide H & G). As with a lot of macrolide syntheses, there’s plenty of leg-work to get the fragments together, and a degree of familiarity due to the type of chemistry used to make ‘em, but there’s still some pretty smart stuff here…

Looking at the retrosynthesis, there’s that degree of familiarity I mentioned. They used metathesis to close the macrolactone, after using the 1,4-anti aldol to unite the two largest fragments. The ester was formed using using DCC/DMAP, rather than the more complex systems I’m used to reading, and a Stille-type coupling was used to make the diene. This is where things get interesting for me, as the “Stille” wasn’t mediated by palladium, and wasn’t catalytic either. Nope, they used copper chemistry in the form of copper thiophene-2-carboxylate, or CuTC to you and me. This reagent is often employed in situations when the normal Stille conditions fail, and worked really quite well for them (82%).

The fragment synthesis also interested me, as they needed to hydrostannylate to form the internal stannane. Tricky reaction, but they overcame this using the commercial Bu3SnSiMe3, and a bit of palladium catalyst. The silylstannation went well, and following removal of the TMS (and TBS) groups, left the desired internal stannane. Now, the interesting bit for me is the regioselectivity of the silylstannation – why did it go that way? It’s probably in the references – I’ll read them and annotate this later.

Another intersting reaction in the synthesis of the fragments was the use of a Reetz hydrodgenation. Although this is quite well known, the result is sweet and worth highlighting. The use of such a small amount of phosphite ligand and metal precatalyst is awesome!

I haven’t highlighted the trouble they had – the final deprotections screwed the advanced material over, which is such appalling luck, but switching protecting groups in the fragments allowed completion of the synthesis. Nice work…

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14 Comments

  • accurate says:

    For me, Fuerstner’s chemistry was much more interesting at the beginning of his career when he was developing/improving new methodologies as for example new coupling reactions or alkyne metathesis. On the other hand, we need some total synthesis groups in Europe and this one is doing just great in this field.

  • TWYI says:

    I just can’t get into these macrolide syntheses. I’ve tried.

  • willyoubemine says:

    I agree with accurate, his work on the Epothilones, Nakadomarin, and especially Roseophilin are really nice syntheses, all before 2000? i think. And all utilizing appropriately his metathesis work.

  • Jose says:

    If memory serves, the stannyl component always goes to the more substituted position in hydrostannylations, stannylcuprations and the like.

  • Tot. Syn. says:

    I spoke with a collegue about this and the suggestion was that a palladostannylation must be first, with bulk of the palladium directed to the terminal end, leaving the tin in the internal positions. Then Pd-Si exchange dumps the silicon in the terminal position.

  • Amphi-buff says:

    Your retrosynthesis has an alpha-ketolactone. It should be a methyl substituted enoate instead. This is a high impact synthesis considering all the effort directed at achieving any of the members of this subclass of the amphidinolides (see Refs. 5 and 6).

  • Kefi says:

    Macrolides are so boring… You just use the right tools from the box and set your synthesis in a make-sense order and you getting your molecule (who said peptides?).
    I am sorry, this chemistry should move to a new journal called “Journal of Macrolides Chemistry”.

  • TWYI says:

    Agreed Kefi.

    Mention Aldol, Wittig/HWE, Sharpless, RCM, and esterification and you have covered 80% of the steps in most macrolide syntheses

  • lemi says:

    a interestng phenomenon– many famous European total synthesis groups pay more attention to macrolides,Paterson(U.K),Cossy(France),Fürstner(Germany)… maybe just because macrolides mean good papers(except for potent possibility of being drugs), once you finish the total synthesis, it means JACS or Angew., or OL even if you just finish a fragment,i still remember Leucascandrolide A, after twenties Angew/JACS/OL on it, Cossy group reported a formal synthesis just some monthes ago in OL, God save me…

  • lemi says:

    about Leucascandrolide A, current issue in Angew. published a interesting synthesis of Leucascandrolide A Macrolactone, using a electron-transfer-initiated cyclization method, different and really interesting…
    http://www3.interscience.wiley.com/cgi-bin/abstract/116323977/ABSTRACT

  • aaaa says:

    This is not just a macrolactone. Look back – many groups in the world are trying to make Amphidinolides for ages. First papers with advanced fragments appeared in the 80′s, then, in the 90′s Pattenden was 1 step from finishing it, but…nothing. And so on. The particularity of this molecule is the extremely strange (and non-existent in other molecules) diene structure, the sensitive vinyl-epoxide etc. Exactly the diene system is what causes the headache for nearly all groups trying to make these things. Very nice work.

  • Moz says:

    This molecule is more challenging than it looks, and personally I think it looks like a bitch. Just because something has a macrolactone doesn’t mean it’s a simple synthesis, sure you can close the ring but you’ve still got to get to the seco acid. Plus what’s wrong with lactonizations? I had a synthesis where I did a transesterification then tried to close the ring with a Reformatsky, it didn’t work. But doing the Reformatsky followed by the macrolactonization worked well and shortend the synthesis by 1-2 steps. Why’s that less elegant?

  • ZZZZZ says:

    zzzzz

    TWYI makes a good point; at first glance all macrolides look the same, ie. boring as hell. Only after reading the papers more closely can I judge how novel/difficult the syntheses at hand really are…

    zzzzz

  • FFFF says:

    Fuerstner’s work looks like very good, but its retrosynthetic analysis was almost resemble with that in eariler publication. the Stille coupling catalyzed by CuTc was also used by ***group in synthetic studies on amphidinolide B.so I can not see any novelty in this paper.