A second synthesis of this beast (the first being Zakarians) and, it’s not looking any less complex.Â I had a look back at the Zakarian post, and I was surprised to see that I didn’t mention any biological activity.Â However, Hashimoto and Nakamura only mention ‘…reported to activate Ca2+ channels…’, so I guess that counts as a reason to make more and discover what else it does.
With a target 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.Â The key to this was a separation of the ‘northern and southern hemispheres’ (to use typical Tot. Syn. parlance), with the southern fragment mostly developed in the Org. Lett. from 2001.Â This poly-ketal would be constructed as usual from an acyclic poly-ketone, and hope that nature was kind…
Construction of that intermediate went rather smoothly, grabbing some sugar-type of thing for the bottom tetraol, and constructing the rest of the molecule with typical unification protocols.Â (Interesting proc for the dithane removal: NCS, AgNO3, Î³-collidine, CH3CN-H2O, 87%).Â However, it’s the cyclisation that you’ve got to love – a bit of acid, a bit of base and we’re up three rings and three stereocentres.
A few (okay, quite a few) steps later, and it’s time to do that tasty Roush Diels-Alder.Â Unfortunately, they had to use a massive excess of the dienophile, and at that temperature, I wouldn’t rate their chances of recovering the remainder (they don’t mention it in either the paper or the SI).Â The result wasn’t amazing either, with a 45:27:18:10 mixture of products that had to be separated by prep TLC.Â However, it does provide the A ring and leaves them with suitable functionality for the G ring, so it was time to move on.
They used a rather tasty piece of Trost chemistry to complete the macrocycle, and in an impressive yield, considering the complexity of the substrate.Â 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 a not-inconsiderable eleven steps (all high-yielding), but they isolated it as a nice white solid!Â However, I guess many of your will have realised from my tone that I wasn’t set-on-fire by this synthesis.Â I dunno why – it’s an amazing achievement, but still somewhat lacking in new chemistry.Â Is that just me?
Nakamura, S., Kikuchi, F., Hashimoto, S. (2008). Total Synthesis of Pinnatoxin A. Angewandte Chemie International Edition DOI: 10.1002/anie.200802729