(6Z)- and (6E)-Cladiellin Diterpenes
Kim, Kim, Lee and Kim. JACS, 2006, ASAP. 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 an Org. Lett. in 2005 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 quite impressive. Some relatively straight-forward chemistry took them to a Diels-Alder substrate; reduction of the amide, followed by Corey olefination with Î±-lithio TMS-aldimine and methylenation. The DA itself has been done before, by my mate Ryan, and also by Crimmins (whoever he is… ), 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 binned by dissolving metal reduction.
Target natural product done, they then set their ambitious sights on three more, manipulating that Z-olefin to death:
First, buckets of mercuric acetate – three different transformations in one pot, including a sequential oxy-mercuration to complete polyanthellin A in one step. A dihydroxylation with osmium tet 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.
Top stuff, and one of my favourite reads this month.