Nicolaou, Chen, Guduru, Sun, and Banerji. ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200702243.
I didn’t manage the macrolide spectacular I promised in the last post, but here’s a gem I missed in the ASAPs from a few weeks back. The target is a landmark for several reasons, but the more aware of chemical politics will have noticed that this is the first (of many I imagine) 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 (Hi, Frankie!). As an aside, it’s also interesting to note that David Chen did
a post-doc his PhD (probably) for Ian Paterson, so certainly knows his macrolides!
Anyway, enough politics – 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 it’s 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 stereocentres 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.
[However, this brings me to a point of consideration – why are Stille coupling more common in academic publications, and Suzuki more so in an industrial/commercial context? When it came time for me to make some dienes, I decide to use Suzuki chemistry, and found that disiamyl borane did the hydrometallation very nicely, and that the coupling was quite straight forward, but perhaps I was rather lucky…]
And now to a bit more catalysis, and some Buchwald chemistry (who gave an excellent talk here earlier this year). This time we’re working with catalytic copper (I’ve heard that copper (I) iodide can be a bit of a pain to work with due to disproportionation – anyone want to clarify?), achieving an impressive coupling, ableit is 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)!