Totally Synthetic by Paul H. Docherty, 11 July 2007
Total Synthesis of Palmerolide A
K. C. Nicolaou, R. Guduru, Y.-P. Sun, B. Banerji, D. Y. K. Chen, Angew. Chem. Int. Ed. 2007, 5896-5900.
Palmerolide A is a landmark for several reasons, but the more aware of chemical politics will have noticed that this is the first publication from the Nicolaou/Chen labs at the A*star institute, Singapore. This venture is one that has captured a lot of interest, and I think many of us know people involved in this. As an aside, it’s also interesting to note that David Chen did his PhD for Ian Paterson, so certainly knows his macrolides!
Anyway, more chemistry! Many of you will recognise the target, even though this is only the second synthesis (the first being that by De Brabander), as quite a bit of noise was made on its isolation. This is because of its impressive biological profile, as well as its geographical location in the Antarctic! As I mentioned in the last post, the retrosynthesis of this type of target gives away much of the game, and in this case, provide few surprises. I guess the enamide coupling will have raised some eyebrows - we’ll discuss that shortly. Otherwise, RCM/Yamaguchi/Stille are fairly par for the course.
The synthesis of the partners for the Stille coupling is what first caught my attention, where they used an interesting allylation reaction to impart two stereocenters in good enantio- and distereoselectivity from a diisopinocampheylborane species. The carbamate was then formed, and they were set to hydrostanylate the free acetylene. Although they don’t discuss their reasons, they use some neat chemistry by Gerry Pattenden to do this. Presumably, the silver nitrate is basic enough to deprotonate the acetylene and cause bromination. This bromo acetylene can then be stereo- and regioselectively hydrostannylated using catalytic palladium and tributyltin hydride. Neat.
And now to reaction conditions developed by Buchwald. This time with catalytic copper, achieving an impressive coupling, albeit in somewhat modest yield. Importantly, however, most of that mass balance is returned starting material - an important consideration in such an advanced reaction! That’s it - job done well (including a stereochemical reassignment I didn’t mention)!