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Totally Synthetic by Paul H. Docherty, 14 September 2008

Total Synthesis of Allosecurinine


A. B. Leduc, M. A. Kerr, Angew. Chem. Int. Ed. 2008, 47, 7945-7948.

DOI: 10.1002/anie.200803257

The biological activity is limited (a diastereoisomer of Allosecurinine offers GABA receptor antagonism), so let's just focus on the total synthesis. It’s quite a nice looking target, leaving me somewhat surprised that this is its first synthesis:

They used a Mitsunobu reaction to protect the butenol as its PMP ether, which isn't the kind of of reaction one wants at the start of a total synthesis. However, I liked the formation of the cyclopropane - a very smart way to make enantiomerically pure cyclopropanes. Some protecting group transformations were then required to replace the hydroxyl for an hydroxylamine, which they deprotected and cyclised in one pot. In a JACS paper on the methodology, Kerr suggests that one firstly gets formation of an imine, which opens the cyclopropane leaving the stabilised malonate anion and the first ring. The anion then adds to the iminium ion forming the cyclopentane. Nice!

To be fair, there’s quite a lot of work between here and the next intermediate; eight steps isn’t unreasonable though. And I really like the way Kerr finishes the total synthesis of allosecurinine, with two of the more important steps following each other to complete two more rings in direct succession. They actually had a bit of trouble with the order in which to complete these transformations, with the result I’ve shown being the most successful. Deprotections and cyclisation of the remaining ring by displacement of a mesylate then gave the natural product.

Nothing too dramatic, but that methodology is pretty nice!