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Totally Synthetic by Paul H. Docherty, 18 April 2009

Total Synthesis of Kapakahine B & F


T. Newhouse, C. A. Lewis, P. S. Baran, J. Am. Chem. Soc. 2009, 131, 6360-6361.

DOI: 10.1021/ja901573x

I normally do not bother about peptides. However, Kapakahine B features a very interesting tetracyclic indole centered moiety, and a selectivity issue built into the macrocycle.

The synthesis starts with a rather nice method developed by Knochel, allowing addition of an alkyne to a primary iodide without disturbing an acidic chiral center. In this reaction, an insertion of a copper/zinc complex into the alkyliodide is followed by an attack into the haloacetylene. This acetylene leaves them perfectly set for the later construction of the indole.

The next step resembles work done by Baran and Newhouse last year, towards psychotrimine. 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 in the synthesis of Kapakahine B as well as, with a similar yield and with impressive induction of stereochemistry.

A Larock indole formation with both fragments shown above gave the right-hand intermediate shown below. The group thought, that under the conditions used for forming the amide, the aminal center will perhaps 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 features a secondary amide (with the nitrogen lone-pair tied up into the π-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 their idea was great. A 70% yield is a fantastic success, using standard chemicals (BTW, HOAt = 1-Hydroxy-7-Azabenzotriazole). What more can be said? The rest of the total synthesis consists of peptide bond formations, allowing completion of two family members in 12 and 14 steps. A top total synthesis!