Totally Synthetic by Paul H. Docherty, 4 August 2008
Total Synthesis of Pinnatoxin A
S. Nakamura, J. Inagaki, T. Sugimoto, M. Kudo, M. Nakajima, S. Hashimoto, Org. Lett. 2001, 3, 4075-4078.
S. Nakamura, F. Kikuchi, S. Hashimoto, Angew. Chem. Int. Ed. 2008, 47, 7091-7094.
A second total synthesis of this very complex moleculy (the first being Zakarian's). Pinnatoxin A is ‘reported to activate Ca2+ channels’, so I guess that counts as a reason to produce more and discover further biological activities…
With a target of this size, it’s all about the retrosynthesis - and to be fair, the main disconnections are quite different to what we might be used to. The key to this was the separation of two fragments, with one fragment mostly developed in a paper in Org. Lett. from 2001. The polyketal would be constructed as usual from an acyclic polyketone.
Construction of that intermediate went rather smoothly, deploying a sugar derivative for the bottom tetraol, and constructing the rest of the molecule with typical unification protocols. However, it’s the cyclisation that you’ve got to love: acid, then base and three rings and three stereocenters are generated.
A few steps later, and it’s time to perform an interesting Diels-Alder reaction modified by Roush. Unfortunately, they had to use a massive excess of the dienophile at a very elevated temperature. The result wasn’t amazing either, with a 45:27:18:10 mixture of products that had to be separated by prep TLC. However, the reaction provides the A ring.
They then used a reacetion developed by Trost to complete the macrocycle in an impressive yield, considering the complexity of the substrate. There’s not much discussion of this reaction, or what happened to the other 21%, but that can be forgiven if one considers how much of challenge this must have been with only 12mg of material to work with.
Completion of the target from here took eleven steps (all high yielding) and they isolated Pinnatoxin A as a nice white solid! This total synthesis is an amazing achievement, although somewhat lacking in new chemistry.