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5-epi-vibsanin E   

20 May 2009 13,905 views 22 Comments


Davies, Williams, Schwartz, Denton, Lian. JACS, 2009, ASAP. DOI: 10.1021/ja9019484. Article PDF Supporting Information Group Website Group Website

Now that’s a substituted ring…  done and dusted by Huw Davies and Craig Williams as a collaborative effort (I’d quite like to know how this worked, as the two groups are quite removed), with Davies weighing in with some smart chemistry for building seven-membered rings.  This clearly critical to the synthesis of such a molecule, but the challenge is the heavy substitution, which has thwarted several groups (including individual efforts).  Whilst this paper doesn’t complete the parent molecule, vibsanin E, the C-5 epimer is also a natural product, so they get the badge for this impressive work.


It’s that neat cycloheptadiene-forming chemistry that kicks this synthesis off, using a vinyldiazoester and a triene (derived from Geraniol) to form a cyclopropane.  This was done enantio- and diastereoselectivly using Davies rhodium chemistry, and a catalyst containing a very bulky ligand (that Ad is adamantyl).  However, diasteroselectivity was unnecessary, as that cyclopropane snapped-open in a [4+3] to generate the requred seven-ring, and a quaternary centre in cracking e.e. and decent yield.  Considering the complexity of the system, that’s quite a success – but it took a bit of optimisation, which I’ll leave in the paper.


With one ring firmly in-place, the next two followed very quickly by completing a Lewis-acid promoted hetero-Diels-Alder.  One new stereocenter followed, along with both rings, in excellent yield.  Things started to get a bit more difficult here, as functionalising the ring isn’t particularly easy.  Medium rings, like this bad-boy, often have unique conformations, which can play-havoc with stereoselective reactions.  Davies and Williams approach was use a Claisen rearrangement to impart one of the more tricky stereocenters, but this was problematic, as they first had to generate an enolate with the correct regiochemistry.  Silylation, followed by allylation of the ketone (developing the correct regiochemistry) was quite effective though, and microwave assisted rearrangement gave the desired product in a reasonable yield and decent d.r. (again, considering the system).


Completion of the synthesis required only a few more steps – deprotection, oxidation and olefination of the primary hydroxyl using Williams chemistry (an Anders–Gaßner modification).  Although this olefination doesn’t look particularly traumatic, the trans-vinylacetate moiety seems to be particularly difficult to install.

This is a nice piece of work, showcasing work gleened from both groups, making a pretty recalcitrant molecule.

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  • John Wood says:

    Anyone know why thy used MeLi to remove the TMS over the traditional flouride ion, if that’s not why they used it, then why did they use it? and lastly, what about attack at the Carbonyl?

    • milkshake says:

      1. MeLi clips off the TMS and generates the corresponding Li enolate cleanly and at low temp. To do this with fluoride you would have to use strictly anhydrous soluble source like TASF with the electrophile present and do the work at around 0 C – lots of bad things could happen including the enolate isomerization etc.
      2. there is no carbonyl attack because there is no carbonyl anywhere. MeLi attacks TMSO on silicone, the product is Me4Si and Li-enolate.
      3. Flouride is best saved for the nucular pastry experts.

  • John Wood says:

    ahhm, got it
    guess I shoulda glanced at the paper first

  • UBChem says:

    To Tot. Synth. _ I refer you to the 2005 Org. Lett. of epi,epi-vibsanine. The Davies lab has been trying to make the vibsanine natural products since they developed the formal [4+3] reaction (approx. 1991). The methodology is incredibly powerful in building the core in rapid fashion. Functionalizing the core is the problem, hence epi,epi. My take on the collaboration is that Williams was treading too close to home and a collaboration was better than being scooped. Honestly, there is no better way to make the core.

  • KiddieKhem says:

    Davies is at it again with Ru CH activation, Step I is what has me

    • chemical waste says:

      The first step of the reaction is a cyclopropanation, not C-H activation.

      The second step is a Cope rearrangement, not a [4+3] like in the text above!

      I feel a little duped by the title of this paper – the reaction is a formal [4+3] cycloaddition, as described in their previous papers. Cyclopropanation/Cope, while powerful, is much less cool – I guess they realize that as well :)

    • EUChem says:

      Did I miss something? I do not see Ru or C-H activation/insertion anywhere in this paper?

  • UBChem says:

    I’m sure it was a typo and misunderstanding. The importance for the formal [3+4] is the generation of the cis divinyl cyclopropane, which the Davies methodology provides flawlessly. But if you want to see awesome utilization of divinyl cyclopropane rearrangements, check out Takeda’s approach to the cyathane core. DOI: 10.1021/ol0059753

    • EUChem says:

      Good call, thanks.

      I am always a sucker for the utilization of a Brook rearrangement. I love the Johnson group’s synthesis of zaragozic acid C (DOI: 10.1021/ja808347q) as well as all the NHC catalyzed stuff that is out there.

      • UBChem says:

        Yeah, Johnson’s application of their acyl-anion chemistry is pretty excellent. For a diazo-cycloaddition ‘wetdream’ I refer you back to Zaragozic acid by Hashimoto, actually blogged here (Zaragozic Acid (Part II)). I thought is was pretty freaking awesome.

  • Nienn says:

    I ehhhhh, nope… got nothing smug. you is all to smarts for me

  • European Chemist says:

    Nice synthesis, but some of the previous comments here tell the story.

    To Tot. Syn.,

    I think you should probably consider editing the sentence “However, diasteroselectivity was unnecessary, as that cyclopropane snapped-open in a [4+3] to generate the requred seven-ring, and a quaternary centre in cracking e.e. and decent yield.”, since

    a) you NEED a cis-divinyl cyclopropane for the Cope-rearrangement to occur. Trans-disubstituted divinylcyclopropanes simply cannot do it as the two olefin moieties are geometrically unable to reach each other. Diastereoselectivity was therefore far from “unnecessary”…
    b) as pointed above by chemical waste, this is really NOT a [4+3] cycloaddition – only formally in terms of starting materials and end product.

    Nice synthesis nevertheless – and a great post once again (as you have got us used to in this blog).

    • Tot. Syn. says:

      Will do. Thanks for the clarification; I clearly missunderstood the original article. I’m on holiday just now in Switzerland, so I’ll change it when I get back.

    • paul wender's moustache says:

      What about it makes it not a [4+3] — that it’s not pericyclic, or that there’s a discrete intermediate at rt? These two features are actually not requirements for a cycloaddition, am i correct?

  • Christine says:

    Totally random question for all you synthetic geniuses:

    So I’m trying to stereoselectively make the MOM-enol ether of basically ethyl acetoacetate. I’ve tried tons of base/temperature combinations, but can’t even get the MOM to go on. Could it be a problem with the MOMCl I’m using (we make our own)? K, thnx!

    • antiaromatic says:

      If you want to know for sure if it is your MOMCl or something else that’s causing the problem, you can always try it with TBSCl instead, workup with bicarb, and check your crude. That’s always been a good test for enolization for me. If you do it with NaHMDS in THF, you can usually tell immediately if it is working b/c the NaCl precipitates from the reaction.

  • Christine says:

    Thank you antiaromatic! Appreciate it.

  • bandit says:

    blah blah blah…..

    Fukuyama / Tokuyama finished haplophytine (angewandte vip)

  • Sydney says:

    In table3 why catalyzed by [Rh2(S-DOSP)4] in only 5%(entry3)??What’s the effect of t-Bu??