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Kapakahines B and F   

18 April 2009 29,104 views 102 Comments


Baran, Newhouse, Lewis. JACS, 2009, ASAP. DOI: 10.1021/ja901573x. Article PDF Supporting Information Group Website

It’s always nice to be surprised by a synthesis dropping from nowhere… even though the commenting team here at Tot. Syn. mentioned an impeding Baran synthesis of an Indole-containing natural product.  And here it is, breaking a unmentioned Tot. Syn. rule – I don’t do peptides.  I’ve never mentioned this before, and no one has ever complained, so I guess I’m not the only one!  Kapakahine B gets out of this quandry by also featuring a rather tasty tetracyclic indole centered moiety, and a selectivity issue built into the macrocycle.


The synthesis starts with a rather nice bit of Knochel, allowing addition of an alkyne to the primary iodides without disturbing the acidic chiral center.  What’s going on here is firstly an insertion of a copper/zinc complex into the alkyliodide, and then attack into the haloacetylene.  Nice, as this acetylene leaves them perfectly set for a bit of indole building later.

The next bit of chemistry is distinctly reminiscent of work done by Baran and Newhouse last year, working towards psychotrimine.  As I said in that previous post, “their key reaction … involved an oxidative coupling of an indole with an aniline, and then cyclisation of the resulting imine with a pendant amide to form the aminal centre”.  And this trick works as well as in the previous synthesis, with a similar yield, and in this case, with impressive induction of stereochemistry.


After doing a Larock indole-formation with both the fragments above, the group had the right-had intermediate shown below.  The group’s bet was that under amide-forming conditions, the aminal center will equibrilate between the two forms on the top of the figure.  The key point is that one has a free, primary amine, whilst the other has a secondary amide (with the nitrogen lone-pair tied-up into the pi-system).  This means that although the 6,5,6 system is less favoured, it reacts in the cyclisation reaction far faster, pulling the equilibrium towards it.


And damn, their bet paid-off.  A 70% yield, with the majority in their favour is a fantastic success, using non-too-special reagents.  (BTW, HOAt = 1-Hydroxy-7-Azabenzotriazole).  What more can be said?  The rest of the synthesis is peptide-bashing, allowing completion of two family members in 12 and 14 steps.  Top banana.

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  • Totally Natural says:

    There we go again. Nobody has to fall in love with a synthesis to make it JACS worthy. Look at what else goes to JACS, especially in the nano-bio arena, not to mention “new methodology” where a group or catalyst X is replaced by Y in a well known, often name reaction, and oops JACS commun after filling a Table with whatever works well. How many of these methods actually solve some serious synthesis problem? And how many represent even a minor improvement over existing methods?

  • InfMP says:

    JACS publishes overall too many articles. I like reading Angew.

  • PC says:

    # 100


    I just want to make it to 100… Seems you don’t like Baran’s chemistry… This is the first synthesis of Kapakahines B and F (in gram scale). It may also be the most efficient synthesis for the next 5 or 10 years. Must be a JACS paper.

  • Kyoto says:

    This is absolutely a nice total synthesis and the approach solves almost all problems associated with its large scale synthesis. Also, it provides a facile synthetic route for modifying the prime core of the target; which may allow determination and improvement of any biological activities possible for analogous compounds. JACS is fine for it. One question: I read here that some papers are not fit for JACS. Can someone tell me what we expect in JACS???

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  • John says:

    Interesting peptide chemistry indeed – not often published in JACS. You would be surprised at how many un-natural amino acids (protected and unprotected) can just be bought today. You can take a look at http://www.peptideresource.com/ – they have a peptide synthesis reagent supplier list. They are also a lot of vendors listing specialty coupling reagents and peptide synthesis grade sovlents. Long live peptide synthesis chemistry!

  • On the other hand, with all the recent growth in numerous technologies in the aspects of peptide synthesis, screening, stability, and modifications, peptides at the moment are acknowledged as lead molecules for therapeutics.