Totally Synthetic by Paul H. Docherty, 9 November 2006
Total Synthesis of Acutiphycin
R. M. Moslin, T. F. Jamison, J. Am. Chem. Soc. 2006, 128, 15106-15107.
An exceptionally convergent synthesis, this paper from Jamison at MIT shows interesting coupling techniques and use of novel methodology. Here is the retroanalysis:
Hopefully you are already wondering what's going on here, so I’ll start with the first major coupling reaction, based on work by Wipf (1, 2). He published this hydrozirconation-transmetallation-stereoselective carbonyl addition in a couple of papers in the late 90’s. And this is a great way to build up complexity, especially the trisubstituted alkene.
An interesting Reformatsky reaction with samarium diiodide allows coupling of the next two fragments - a relatively unused procedure in the intermolecular sense, generally because of side reactions of the enolate. However, they state in the paper that the alpha gem-dimethyl may prevent much of this behaviour, and account for the impressive yield.
With a few functional group transformations, they were ready for their macrolactonisation; adding the lithium anion derived from ethoxyethyne into the lactone provided the hemiketal functionality, and they were set. Addition of the starting materials into a refluxing solution of Bu3N in xylene performed a retro-ene reaction, extruding ethene from the molecule to create a ketene, which then added to the hydroxyl (noteably, as they point out, the most remote) to complete the macrocycle in 90% yield. An amazing synthesis!
Four further steps (basically to do a selective oxidation) then returned the natural product in 18 steps (longest linear from commercial SM), and a particularly nice paper :).