Kapakahines B and F
Baran, Newhouse, Lewis. JACS, 2009, ASAP. DOI: 10.1021/ja901573x. 
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.
(12 votes, average: 4.08 out of 5)
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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?
JACS publishes overall too many articles. I like reading Angew.
# 100
TNPB,
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.
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???
[...] in mind (chemoselectivity in syntheses) and he used examples from several molecules his team has tackled to drive that point home. I won’t go into all the stories he talked about (others have done a [...]
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!