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Fawcettimine   

17 June 2010 11,903 views 11 Comments

Jung, Chang, Org. Lett., 2010, ASAP DOI: 10.1021/ol1009762. Article PDF Supporting Information Group Website

Although the number of actual steps in a formal synthesis is (or at least should be) smaller than in a full total-synthesis, I often feel that the actual work is harder.  Afterall, one is directly comparing ones work with that of another researcher, and in this case Michael Jung has got his work cut-out.  There aren’t many professors whose work is truly that daunting, but Clayton Heathcock is one of them. Jung’s work intercepts the Heathcock synthesis eight steps from then end of the total synthesis, so is certainly a very worthy addition to the literature – and does things asymmetrically, which is  notably absent from the former paper.  However, the overall strategy is shared between the papers – using cycloaddition/alkene chemistry to build that complex ring-system, starting with the 6,5-bicycle.

Jung’s approach was to use some rather novel cyclopropane chemistry to trigger a cycloaddition – but first he had to build his cyclopropane fragment.  The difficult thing here is that it needed to be a single enantiomer, so he chose to use a modified chiral auxiliary to get going.  A Corey-Chaykovsky reaction was used to install the three-member-ring, leaving the group with only a simple hydrolysis in methanol to complete the malonate group and free the cyclopropane.

This fragment was put to work immediately in a tasty Michael addition into a known cyclohexenone, promoted by triflimide. Not only did this reaction form a carbon-carbon bond, but a new stereocenter was installed, and the required silyl enol ether was formed too.  Following this, a methylenation of the ketone (which looks to be a tetchy reaction) provided the substrate for the key cyclopropane chemistry.  Treating this loaded intermediate with a bit of Lewis acid promoted a Mukaiyama-like collapse of the silyl enol ether, which adds into the cyclopropane, thereby completing the 6,5-system and providing a pair of stereocenters.

Importantly, it also provides a useful functional handle (in the form of the malonate), allowing the group to quickly converge with Heathcock after a microwave-assisted decarboxylation.  Rather than just concluding here, I thought I’d have a look back at the Heathcock paper:

Heathcock, Blumenkopf, Smith, J. Org. Chem., 198954, 1548. DOI: 10.1021/jo00268a015Article PDF Supporting Information Group Website

Heathcock set the precedent, working with a molecule very similar to that of Jung.  A little Wittig chemistry creates a diene, which undergoes a 5-exo-trig cyclisation to build the cyclopentane, featuring the same exocyclic methylene as Jung.  The catch here is the ester side-chain – Jung’s innovative route places this one methylene group further away from the ring system.  This is key, as Heathcock then needs four more steps to do the same thing (effectively a Arnt-Eistart homologation).

This is where the routes converge, but for Heathcock, targeting the first total synthesis, the work was a long way from done.  Completing a larger nine-member cyclic amine was next on the agenda, using nothing too spectacular to achieve this.  However, the final cyclisation to complete the molecule really is very neat, so here it is in its fineness:

Impressive work by all involved, and due praise to Jung for bringing some neat chemistry to this tasty natural product.

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11 Comments

  • Heiko says:

    yeah, indeed nice work… interesting to see the Baldwin rules in action in the ring closing step of the cyclopentane ring (5-exo-tet vs. 5-endo-trig)…

    the synthesis of the cyclopropane key intermediate is really powerful… seems that cyclopropanes have some more potential in total synthesis than i thought ;)

    thx for presenting this stuff

    Heiko

  • anon says:

    I very much doubt that cyclisation has much to do with the Baldwin rules – it’s probably pseudo-cationic, with the regioselectivity being dictated by the ability of the alkene to stabilise the buildup of positive charge at the adjacent carbon.

    Nice synthesis.

    • chemist_in_the_making says:

      Michael Kerr will agree with that clarification.

      • ba says:

        Pseudocationic? Under sodium ethoxide conditions? Hmmm, wouldn’t make that suggestion myself, but I’ve been wrong before…

        If you take a look at the Heathcock paper, he shows that the corresponding intermolecular reaction undergoes selective 1,6-addition.

        • snarky snarklton says:

          I think they were referring to the Sc(OTf)3-promoted cyclization in the discussion above.

  • kc says:

    JONAH CHANG IS SMART

    • chemist_in_the_making says:

      Trust me, he is dumb. I have known him since 2005 (Indiana University Bloomington).

      • Zakar214 says:

        Very nice work. I always like how random people talk trash when they probably have not done anything worth noting in their own careers. Regardless of who the author is, they put in the hard work and got a publication out of it. By the way, way to call out someone you used to know by calling him dumb. Very professional.

        • chemist_in_the_making says:

          relax dude, it wasn’t something serious. By the way, why does it offend you? Whatever I said doesn’t concern you anyways. It will only concern you if you are Jonah Chang and if I know him correctly then, he will have a laugh about it. Jonah had the highest grade in the synthesis courses and he was the smartest in the class of 2005. So my calling him dumb doesn’t make him dumb.:)

          Some facts now:
          Just putting in the hard work doesn’t always mean that its a great work. I never commented on the quality of the work. But, now that you have brought it up, all I have to say is that this work is okay. Intercepting a Heathcock’s intermediate eight steps into the synthesis by doing a Michael addition between a cyclohexenone derivative (substrate 25, same in Heathcock’s synthesis) with a cyclopropane derivative doesn’t make it a eyecatching work. If you have time, go through Kerr’s work on cyclopropane diester synthesis and its application in a number of syntheses. A number of syntheses of fawcettimine and related lycopodium molecules have been reported so far. I am aware of 5 syntheses of fawcettimine with the lastest one appearing in the JOC (Mukai, 2010, 75, 3420. total syntheses of (+)-Fawcettimine and (+)-lycoposerramine)-yes, its a total synthesis and not formal synthesis. So, i will call this work okay.

          Random comment about some “Jonah Chang” being smart on a public website is not professional either.

          Your random quote and assumtion about others not having any research worth nothing is highly imaginative, biased, and unprofessional.

  • SciLiar says:

    No love for the Toste group on this thread, eh?
    http://www.organic-chemistry.org/Highlights/2008/01September.shtm

  • Sheep says:

    My personal favourite is this elegant synthesis (which will give fawcettimine if formaldehyde is excluded in the last step) which came out a couple of days from the Mulzer group:

    http://pubs.acs.org/doi/abs/10.1021/ja107533m