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Totally Synthetic by Paul H. Docherty, 16 October 2008

Total Synthesis of Aspidophytine


K. C. Nicolaou, S. M. Dalby, U. Majumder, J. Am. Chem. Soc. 2008, 130, 14942-14943.

DOI: 10.1021/ja806176w

Not only a natural product but aspidophytine is also a building block on the way towards haplophytine - a very challenging natural product. You can read more about it in a Corey paper from two years back. Aspidophytine is one half of the larger target, with Nicolaou’s approach towards the other half published last year, so it can’t be long until we see the finished product. But let’s look at this fairly short paper first.

It’s basically a tale of getting the cyclisations to go in the right order, so Nicolaou separated the molecule into an indole system, and a fragment based on a piperidinone. These two units were united by a Suzuki coupling, with asymmetry in the piperidinone generated through a distereoselective alkylation. This took them very quickly to a precursor for the first cyclisation (nine steps), a Vilsmeier-Haack reaction (using triflic anhydride in-place of the more common POCl3).

A nice, diastereoselective reduction then gave the desired cis ring junction. Only a couple of steps were required to get to the next reaction, a radical cyclisation using a xanthate to control the source of radical generation. The reaction went in a astonishing yield, but gave a 3:1 mixture of allyl-radical reduction regioisomers, of which the desired was isolated in 58% yield, generating two new stereocenters.

They only had a couple of steps left, but they mangage to do everything in one pot, using interesting conditions. Unbuffered TBAF removed the TMSE protecting group, leaving the carboxylate anion to do a oxidative lactonization using potassium ferricyanide. This process isn’t dissimilar to that used by Corey in his total synthesis of aspidophytine, back in ’99, where he suggests that the oxidation goes via an iminium ion, which is attacked by the carboxylate group (bear in mind that unbuffered TBAF is pretty basic). Also notable from the Corey paper is the use of a common substrate in the form of the indole…

Nice total synthesis! I look forward to the haplophytine paper!