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Totally Synthetic by Paul H. Docherty, 9 November 2006

Total Synthesis of Acutiphycin

Jamison

R. M. Moslin, T. F. Jamison, J. Am. Chem. Soc. 2006, 128, 15106-15107.

DOI: 10.1021/ja0670660

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 :).

Selected Comments

10 November, 2006 at 15:06, Tot. Syn. says:
Ryan (or anyone else who knows the answer…), why did you use tributylamine? Is it just because it’s less volatile than triethylamine (especially at 150C), or is there something more specific?
10 November, 2006 at 18:49, Ryan says:
Tertiary amines catalyse the addition of alcohols to ketenes. Bu3N was simply the first amine tested and was chosen based on some earlier work. Funk used NEt3 in his system, but that was conducted at a lower temperature, since he used tert-butyloxyalkyne as his ketene precursor. Different (more substituted) alkoxyalkynes will allow for lower temperatures and there is a wonderful theoretical paper on the thermal decomposition of alkoxyalkynes (JOC, 1987, 52, 5532). I chose ethoxyethyne because it’s commercial and can be made in situ. I should’ve done a more complete screen, but I’m out of time with my PhD.