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Totally Synthetic by Paul H. Docherty, 21 November 2006

Total Synthesis of Polyanthellin A, Cladiella-6,11-dien-3-ol, Deacetoxyalcyonin Acetate


H. Kim, H. Lee, J. Kim, S. Kim, D. Kim, J. Am. Chem. Soc. 2006, 128, 15851-15855.

DOI: 10.1021/ja065782w

Not one, two, or even three; four total syntheses in this paper, all of medium ring diterpenes, generally with a 9-member ether present in the target. Of course, all originate from a common precursor, and in Kim’s route, from his intramolecular amide enolate alkylation (IAEA) methodology. The original methodology paper was published in 2003 in JACS, followed by a paper in Org. Lett. describing their total synthesis of laurencin.

As can be seen with the example above, their methodology is exceptional at producing that medium ring, and with an E double bond in it! This was isolated as a single diastereoisomer - really impressive. Some relatively straight-forward chemistry took them to a Diels-Alder (DA) substrate; reduction of the amide, followed by Corey olefination with lithio TMS-aldimine and methylenation. The DA itself has been done before, by my mate Ryan, and also by Crimmins, but is still a sweet piece of chemistry:

With the bulk of the natural product carbocyclic skeleton complete, they only needed five steps to finish. Notable was the conversion of the methyl ester to an isopropyl group by addition of MeLi with CeCl3 to produce a tertiary acetate. This was then removed by dissolving metal reduction.

Target natural product done, they then set their ambitious sights on three more, manipulating that Z-olefin:

First mercuric acetate - three different transformations in one pot, including a sequential oxy-mercuration to complete polyanthellin A in one step. A dihydroxylation with osmium tetroxide delivered a diol to the correct face to complete (-)-cladiell-11-ene-3,6,7-triol, leaving the more complex (-)-deacetoxyalcyonin acetate to be finished in four steps including a nice Burgess salt promoted elimination to give the exocyclic double bond.

A top total synthesis, and one of my favourite reads this month.