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Cortistatins A (J, K and L) Pt. IV   

7 August 2010 19,881 views 15 Comments

Myers, Flyer, Si. Nat. Chem., 2010, AOP. DOI: 10.1038/nchem.794 Article PDF Supporting Information Group Website

Cortistatin is one of those targets like platensimycin that has attracted an almost unhealthy synthetic lust in the last few years, with three previous appearances in these interwebs (Baran, Nicolaou, Shair).  The reasons for both are the same – both have remarkable biological profiles, and both are of challenging complexity.  However, both are now what I’d call mature targets – in that the best disconnections have been tried, and that there are unavoidable methods that feature in most routes.  However, that doesn’t mean that the science is over – now it’s time to refine the chemistry to the nth degree, and allow for maximum flexibility.  And that’s more-or-less what Andy Myers has got going on here – a synthesis of four family members from a common intermediate – 5 – shown below.

Myers’ route to 5 is all about contruction of the 7-member B ring – using  metathesis to close it, and a metal-coupling to build the acyclic intermediate.  This leaves a relatively simple A ring intermediate, and the more complex C,D ring fragment.  Myers’ doesn’t take this compound back to the Aldrich bottle, but starts instead with a literature compound containing much of the complexity.  Keen organocatalysers will probably recognise this compound’s heritage in the Hajos–Parrish enedione, with several steps required for elaboration.  I really like these few steps leading to the coupling component – a neat conjugate addition of triphenylphosphine and protection in the first step, then the world’s smallest Wittig coupling in the second.  The third step is something I didn’t even know was possible in one step – a concomitant deprotection / triflation sequence.  Nice stuff!

As I said, this triflate was coupled with the A ring fragment, and the the exocyclic alkene RCM-ed to form the seven member ring.  An epoxidation installs the free hydroxyl shown in my next scheme, with a fairly forcing hydrogenation taking care of the styrene unsaturation.  Then it’s time for an oxidative cyclisation (also used, and credited to, Sarpong), dearomatising the phenol and installing the oxo-bridge.  Three more steps were required to get to 5 – firstly a neatly selective hydrosilyation / reduction to reduce the less substituted alkene.  A bromination with NBS diastereoselectively installed a bromine, which was displaced by the desired azide in excellent yield.  Reduction of the ketone was more problematic, though, as typical substrate-controlled methods were unselective, or leant towards the wrong diastereomer.  A bit of CBS reduction did the trick, though – which some might frown at as ‘cheating’.  I’d take the good yield and go to the pub, though…

From this intermediate Myers goes on to make four Cortistatins – two for the first time.  I’m not going into the details, ’cause I don’t find the chemistry quite as appealing.  However, I’ve summarised the route effiency below – and it’s hard not to be impressed with the flexibility of his route.  Nice stuff, and a must-read paper!

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15 Comments

  • Ryecatcher says:

    smart job!

  • tamboys says:

    Good job!

  • cascade says:

    Hate to hijack the thread so early…but….got a bit woooried after a chat with the campus interview guys. Wonder if there would be enough organic chemistry jobs in the near future? Maybe its time to move back to Europe?

    • HPCC says:

      Hate being pessimistic, but here’s my 2 cents.

      There are jobs. They are scarce, and they are precarious. Be prepared not to settle down anywhere for much more than 3 years. You’ll be lucky to work 10-15 years for the same place, something that used to be commonplace not so long ago.

      It is now a privilege to do research in the field we love, especially in industry. This is what the job market looks like, to me, in 2010.

      • Bzzz says:

        The job market is terrible since most chemistry has been outsourced, reminds me of physics in the 90′s…
        good luck if you get smth, MA & CA r the ‘hot spots’…
        to encourage you: the pharma industry is going down the drain…

  • InfMP says:

    Anyone know if there are any other nobel laureates speaking in Boston next week at ACS other than Schrock?

  • Anon says:

    I believe Christina White is Tuesday, but Ley is Monday.

  • rhino says:

    I agree about the vinyl triflate. i really could have used that once before, but i didn’t know it was possible either.

  • geng says:

    full of metal! from this paper, demonstrated myers is only a craftsman. I wonder why this paper accepted by nature chemistry?

  • Andrea says:

    A recent ChemComm article “An Expeditious Asymmetric Synthesis of the Pentacyclic Core of the Cortistatins by an Intramolecular (4+3) Cycloaddition” by Pauline Chiu is currently featured on the ChemComm blog pages and the article is free to access from there until 28th March. To see the blog post follow the link below

    http://blogs.rsc.org/cc/2011/02/28/intramolecular-cycloaddition-leads-to-the-pentacyclic-core-of-cortistatins/

  • Nanaji says:

    excellent,i would like to do again………..