Totally Synthetic by Paul H. Docherty, 1 November 2007
Total Synthesis of Amphidinolide H & G
A. Fürstner, L. C. Bouchez, J.-A. Funel, V. Liepins, F.-H. Porée, R. Gilmour, F. Beaufils, D. Laurich, M. Tamiya, Angew. Chem. Int. Ed. 2007, 46, 9265-9270.
As with a lot of macrolide syntheses, there’s plenty of leg-work to get the fragments together, and a degree of familiarity due to the type of chemistry used to make them, but there’s still some pretty smart stuff in the total synthesis of amphidinolide H & G:
Looking at the retrosynthesis, there’s that degree of familiarity I mentioned. They used metathesis to close the macrolactone, after using the 1,4-anti aldol reaction to unite the two largest fragments. The ester was formed using DCC/DMAP, rather than the more complex systems I’m used to reading, and a Stille-type coupling was used to make the diene. This is where things get interesting for me, as the “Stille” wasn’t mediated by palladium, and wasn’t catalytic either. They used copper chemistry in the form of copper thiophene-2-carboxylate (CuTC) instead. This reagent is often employed in situations where the normal Stille conditions fail, and worked really quite well for them (82%).
The fragment synthesis also interested me, as they needed to hydrostannylate to form the internal stannane. Tricky reaction, but they overcame this using the commercial Bu3SnSiMe3, and a bit of palladium catalyst. The silylstannation went well, and following removal of the TMS (and TBS) groups, left the desired internal stannane.
Another interesting reaction in the synthesis of the fragments was the use of a Reetz hydrogenation. Although this is quite well known, the result is sweet and worth highlighting. The use of such a small amount of phosphite ligand and metal precatalyst is awesome!
I haven’t highlighted the trouble they had with some of the final deprotections, which is such a bad luck, but switching protecting groups in the fragments allowed completion of the synthesis. Nice work…