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6 September 2009 18,179 views 31 Comments


MacMillan, Jones, Simmons. JACS, 2009, ASAP. DOI: 10.1021/ja9052366. Article PDF Supporting Information Group Website

Now this is a popular target; I’ve covered syntheses by both Qin and Overman (with a related synthesis of vincorine by Qin too), both of which contain some really nice chemistry, and aren’t exactly lengthy.  However, this approach by MacMillan is incredibly concise, containing only nine steps, and starting with a commercially available indole.  To get to the key cyclisation precursor, a process of carbonylating the C-2 position by lithiation and addition of DMF, followed by a Horner-Wadsworth-Emmons olefination provided the required diene ophile.


Diene ophile?  Well that lets the cat out of the bag, so to speak.  Yep, it’s [4+2] time, using propargyl aldehyde and a imidazolidinone catalyst.  The catalyst and aldehyde do the rather expected imine formation (this is organocatalysis after all), and then the acetylene does the Diels-Alder thing, generating (as this is an alkyene) an enamine intermediate.  This is of course in tautomeric equilibrium with an indolinium imine ion, trapped-out by addition of that conveniently situated  pendant amine.  Snaps that ring shut, giving them the product – two new rings and two stereocenters to the better.  Both a cracking yield and example of stereochemical control. (BTW, TBA is tribromoaceticacid.  Why’s it better than TFA?)


Completion of the target took another five steps (that’s called maths…) – a bit of protecting group shennanigans and a reductive amination provided the remaining carbon.  The approach here was kinda interesting; they had two sulfides, one of which was propargylic.  Treatment with t-butyl tin hydride (the bulk is important, apparently) promoted radical formation on the cyclohexene, and addition to the alkyene in a 6-exo-dig manner, loosing the extraneous thiol to give an allene.  Not a bad yield, but that’s quite a chunk of initiator – 50 mol% relative to product.

Completion of the target from here required only loss of the protecting groups and a reduction of the allene – providing a bit of a selectivity headache there.  However, simply dumping in a bit of palladium on carbon with a hydrogen atmosphere did a regioselective and diastereoselective reduction, providing the require exocyclic trans-ethylidene in over 90%, 20:1 d.r.  There’s no discussion of this result, so I’m happy for them, but kinda bemused.  However, it’s a rather fitting result to complete this sweet synthesis.

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  • GYA says:

    Impressive application of orgnaocatalysis! MacMillan’s best synthetic work thus far.

  • Medchem says:

    ya its impressive one..

  • milkshake says:

    you have a typo there: the MeS-vinyl indole is actually a diene (not a dienophile).

    The Pd-C selective hydrogenation of the allene was done at -15C. They must have tried few conditions obviously.

    One weird detail in the supplementary is the lithiation/DMF quench of the Boc-tryptamine. They do it in neat 1,2-dimethoxyethane as a solvent at -78C. It turns out the melting point of glyme is -58C, even with eutectic mp lowering effect, the reactin would have been frozen solid at -78C. Maybe they have made a typo also.

  • WestCoast85 says:

    Great synthesis

    A good mixture between green chemistry (organocatalysis) and tin chemistry (3 equivalents…)

  • InfMP says:

    nice call on the mp inconsistency.

    I am having trouble seeing the baldwin. can someone help me see what’s going on there?

  • Martyn says:

    The final hydrogenation is impressive, but easy enough to rationalise – the allene reduces first at the unsubstituted end which is much less hindered. The orbitals of that double bond are parallel to the piperidine ring, with the approach from the left side (as you’ve drawn it) blocked by the bridged ring system, so H2 comes in from the right hand side, giving the correct stuff.

    I bet it took a few attempts before they could get 90% though.

  • bob says:


    Sarpong just published a sweet alkaloid synthesis in JACS last week. Just in case you’re looking for a new subject.

  • sls says:

    Nowadays, there are a lot of beautiful synthesis for natural product such as De Brabander, Smith, Sarpong and so on..
    But this is the most impressive research paper ever I’ve met nowadays.
    Good job Dave!!

    For mp, I couldn’t catch it. I’ll think about it :)

  • FRNicolaou says:

    This is very nice, elegant and very modern synthesis. It’s kind of funny that during the optimization of the key-step (organocatalytic cycloaddition) authors say that catalyst 14 (with TBA) is better than catalyst 7 (with TFA), though the yields differ only by 3%. Could they loose some of the material during the work-up or purrification??? And, yet, why would the catalyst 14 give better result than the catalyst 7?
    Beside the key step, I really like the end-game (radical cyclization). I haven’t seen the use of t-Bu3SnH instead of n-Bu3SnH (TBTH), at least, not in a successful way! Why is that? Anyway, I am impressed!
    McMillan, keep publishing nice syntheses like this one!!!

    • faba says:

      87% with 14 is isolated yield, 83% NMR yield and the ee is much higher with 14. They claim, 14 is better, because the shielding effect of naphtyl in transition state is higher

      • FRNicolaou says:

        It does make sense, but as long as a naphtyl system is closer and not connected by a very flexible linker. But, as this one, a lot of other facts cannot be explained or, at least, are not intuitive at the first glance! However, this does not diminish the beauty of the synthesis; I am just wondering what is the rationale behind it (quantitative one and more solid explanation).

  • Remev says:

    Why only make 10 mgs if it’s so short? Overman route made >50 mgs…

    • jasdou says:

      Why would you need more than 10 mg? I mean, as long as you’ve got enough material to get a nice 1H and 13C NMR, IR, MS and optical rotation…

    • GYA says:

      I agree. I think a short and efficient synthesis should be showcased by providing access to more significant quantities. The approach and the amount synthesized don’t match up.

      • Tok says:

        I disagree. Unless they’re going to do something like animal studies that require multigram quantities, scale up is a waste of time and resources. Especially when you’re a grad student wanting to get the paper out as quickly as possible, or a PI working on getting tenure.

  • jack says:

    nice synthesis! but it is actually ten steps long :)

  • Joe says:

    Why the NaBH4/CeCl3 in the organocatalytic Diels-Alder cascade step?

  • bob says:

    The amount they made isn’t important, especially for a communication. Would you want to hold up on publishing just to bring up more material and maybe get scooped in the meantime?

    That being said, if a group does do that extra effort my hat is off to them. Sometimes you don’t iron all the wrinkles out til you’ve done the steps on larger scale.

  • sandra742 says:

    Hi! I was surfing and found your blog post… nice! I love your blog. :) Cheers! Sandra. R.

  • redox says:

    Nicolaous&Chen`s Haplophytine synthesis is early-view now!..
    interestingly, the same introduction as Fukuyama`s paper..

  • ian says:

    this is pretty awesome stuff

    where can I find the lit. on the use of the naphthalene substituted catalyst…?

  • HPCC says:

    xoeve’s post is SPAM SPAM SPAM!!! It’s a copy-paste of Jones’ earlier post. And the html link under his “name”, my company network won’t allow… :P