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18 June 2007 7,477 views 15 Comments


Grainger and Welsh. ACIEE, 2007, Early View. DOI: 10.1002/anie.200701055.

I’ll apologise immediately for overlooking this paper; last week was a little busy – I’ve been teaching myself the art of the Evans Aldol. I guess another reason I didn’t blog this paper is the deceptive simplicity of the target. Only two stereocentre; how difficult can that be. Look closer, and you notice the quaternary centre and the stereodefined tertiary amine, and it starts getting a bit more complex…


So how did they start? With a little induction of stereochemistry from Ellman’s sulfinamide auxiliary to set the amine centre, using a Grignard attack into the imine. An explanation for this result comes directly from Ellman’s model, something I hadn’t previously considered. They then methylated the amine, did a particularly nice RCM with Grubbs II, and removed the auxiluary to leave the desired enantiomer of the amino cyclohexene derivative in high e.e. and yield.


Now for the most interesting reaction (IMHO) – a sweet 5-exo-trig cyclisation to generate the quaternary sterocenter from a dithiocarbamates (reminicent of Barton’s seminal work in this area). The regiochemistry of this reaction is explained nicely in a model in the actual paper (but suffice to say that 6-endo-trig cyclisations are considerably less favourable). Neatly, the cleaved dithiocarbamate then trapped to provide a third stereocentre, which was ultimately binned to introduce the phenolic ring.


This portion of the synthesis involved a couple of old-school reactions that I was happlily reacquainted with – a bit of Dale Boger’s chemistry to introduce the pyrone ring, and then an IED DA reaction dimethoxyethylene ketal followed by loss of CO2 and MeOH to give the phenol. Nice work (and cred to Boger where it’s due…). This then led them to an advance intermediate and a formal synthesis of a tricky little target, using some smart chemistry.

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  • milkshake says:

    If I had to make aphanorphine on process scale I think I would try to use protected D-Tyrosine. (There is a paper from Pavel Majer on sequence: aminoacid activation + coupling with Meldrum’s acid + in situ borohydride reduction folloved by thermolytic cyclization/decarboxylation that provides N-protected 5-subtituted pyrrolidinone with preserved stereochemistry.)

  • spottospot says:

    Or any other resonable sequence.

  • Spiro says:

    3 cheesy rings + one quat center = 15 steps too many steps

  • Tot. Syn. says:

    It is a bit steppy, but some of those reactions are really nice. Plus, I’m obsessed with radical cyclisations…

  • pi* says:

    the synthesis of that zanthate thingy doesnt impress me, but after that its a real beauty.
    i wiwh I could remember all the ways of adding an aromatic ring to a compound like they do here at the end. I know you can do it but its not something thats easy to look up.

  • Hap says:

    Why is the pendant olefin a cis-olefin with an ethyl group at the terminus? Why didn’t they use a terminal olefin or a (E)-olefin instead? (I figure the sulfinamide is polar enough to keep the substrate from going away quickly; it could undergo Cope rearrangement that the ethyl group might hinder but I wouldn’t figure that the Cope rearrangement product is as happy as the sulfinimine).

  • milkshake says:

    What they do with Ellmans methodology followed by RCM I would scale up instead with isoprene Diels-Alder with Ts-acetylene followed by addition of N-Me alpha phenethyl amine and sepaeration of diastereomers. (I bet you can get close to 83:17 dr reported with Ellman). Then Na in liq. NH3 and you are done, you don’t have to mess with Grobbs.

  • WillisWill says:

    @ Hap

    I bet it’s because the cis heptenal is commercially available from aldrich, whereas the pentenal is not

  • Spiro says:

    Using Boger’s pyrone chemistry is total nonsense.

    There are so many short and efficient ways to convert the cyclohexanone to the final betanaphtol.

    For example the annelation of cpd 16 could be done with 3-(phenylthio)-3-buten-2-one in just 2 steps.
    JOC 47 (1982), 1200. http://pubs.acs.org/cgi-bin/searchRedirect.cgi/joceah/1982/47/i07/pdf/jo00346a012.pdf

    The methods of ref 26 are lame.

  • pi* says:

    spiro: nice catch

  • huxley says:

    I don’t see what you’re getting at spiro. You seem to be advocating an even crappier method – Robinson ring annulation / aromatization followed by phenolic methylation with something like dimethyl sulfate, yay :/ I like the way they did it and their yields aren’t too bad either.

  • huxley says:

    Oh my mistake, Ignore that comment. I was looking at the wrong target.

  • kiwi says:

    #6, #9: It will be to fight the competing formation of the sym dimer around that olefin in the GII step – those 1,1 disub’d olefins are pretty sluggishly reactive, and if you don’t slow the dimerisation step you can get stuck with a dead-end dimer, where the internal olefin is too hindered to recruit catalyst to backbite product out of the dimer. A real pain

  • Mukund says:

    What’s the mechanism for desulphonation

  • chemist_in_the_making says:

    Its more like an SN2. protonate the amine of sulfinamide resulting in the ammmonium species. Cl FROM HCl attacks the electron poor sulfur displacing the ammonium.