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ent-Clavilactone B   

15 October 2006 6,819 views 16 Comments

clavilactone.jpg

Barrett, Larrosa, Silva, Gómez, Hannen, Ko, Lenger, Linke, White and Wilton. JACS, 2006, ASAP. DOI: 10.1021/ja0662671.

A nice, and short synthesis of this antibiotic/antifungal agent, using an interesting three-component-coupling strategy. First, the retro:

clavilactone_2.jpg

The larger substrate for this tranformation was assembled quickly, and the coupling completed by addition of methyl allyl grignard to the benzyne. The grignard generated in situ was then reacted with the aldehyde partner, completing the coupling.
clavilactone_3.jpg

The required diastereoisomer was recieved along with 21% of the undesired, but this was recycled using the aluminium species shown below. I’ve no idea how this reaction works (does the Al species simply act as a lewis acid, breaking the C-O bond, and then allowing to reform as the thermodynamically more stable product?), but one of the synthesis team now works at Cambridge, so I’ll ask :).

clavilactone_4.jpg

Nice work, and completed in ten steps.

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16 Comments

  • OCD Chemist says:

    10 steps, 10 authors. That’s an interesting ratio.

  • European Chemist says:

    A very elegant synthesis indeed. Although there was a firm precedent for this type of benzyne coupling since the work of Albert Meyers, we all know that such chemistry can be rather difficult to resume to practice.

    I would be inclined to say the same as you – C-O bond fission is induced by the Al species and probably (?) intermediately trapped by one of the nucleophilic oxygens of the Lewis Acid. Maybe that’s why BF3 and TiCl(OiPr) derivatives failed in this reaction… I would say that a “naked” benzylic carbocation in the presence of all those double bonds would be up to no good! :-)
    Anyway, an inventive solution to a tricky problem (he could as well have opened the lactone, oxidised the resulting benzylic alcohol with MnO2 and simply used a powerful reducing agent to rectify the stereochemical issue – haven’t we seen this before somewhere? :-P)…

    PS: to stirr opinions around there, have you seen the number of names on this paper?…. :-D

  • Mbombok says:

    Do you need ten people to complete a 10 steps synthesis???

  • ddd says:

    ya, 1 step each, although they are from inductry (part of them) so it is excusable

  • yepyep says:

    New union rules, Mbombok. Can’t force people to do more than one step.

    Nice and concise synthesis. I like that 3-component coupling.

  • ddd says:

    unions…mwahaha :))) lololo yea, it could be

  • WillisWill says:

    yepyep,

    if it was a union synthesis, they’re be three chemists doing the work, 5 chemists “supervising” and 2 just sitting around in case one of the supervisers calls in sick

    at least, that’s how it works here in new york

  • Tot. Syn. says:

    I know for a fact that at least one of the names on the list was an undergraduate project student, so props to Barrett for putting the names on there.

  • European Chemist says:

    I have a personal tenet about this kind of synthetic work: “the shorter the synthesis and the smaller the molecule, the trickier it can get and the longer it can take to finish it” because you’ll tend to hand it to a single student at a time since it looks so “deceptfully simple”….

  • pH says:

    Organometallic to benzyne.. awesome!

  • TWYI says:

    More good stuff out of Imperial

  • p k samy says:

    It is a nice synthesis. Many people commenting about 10 people. Even a few people really worked, as a supervisor he want to motivate others and as a group-team they won the match.

  • David says:

    4 postdocs, 1 PhD, 3 undergrads, 1 crystallographer, 1 supervisor.

    Larrosa – postdoc who completed the work
    de Silva – long-suffering PhD
    Gomez – postdoc
    Hannen – postdoc
    Ko – Undergrad
    Lenger – postdoc
    Linke – undergrad
    White – crystallographer
    Wilton – undergrad
    Barrett – supervisor

    All except Tony did benchwork. The whole (current) group celebrated with champagne at the publication (me included).

  • Marianne says:

    Well, well well, I would agree with the last person… I am actually the long suffering PhD.. To the critics, I did spend 4 years of my life trying to work out this molecule. and I can also add that the one person who came up with the idea of the benzyne step is actually NOT on the paper. It’s true there are a lot of people on this paper, some of them having done more work than others that’s for sure.
    It does look incredibly simple as a molecule, but trust me, it’s NOT!!!!!!!!1

  • I was searching for ‘antibiotic reaction’ at google and got this your post (‘lavilactone B at TotallySynthetic.com’) in search results. Not very relevant result, but still interesting to read :)

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