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Totally Synthetic by Paul H. Docherty, 19 February 2008

Total Synthesis of Coraxeniolide A


O. V. Larionov, E. J. Corey, J. Am. Chem. Soc. 2008, 130, 2954-2955.

DOI: 10.1021/ja8003705

This article contains some quite remarkable chemistry. Corey himself has had quite a fascination with this class of natural products, having already completed Antheliolide A back in 2006. However, this work takes a somewhat alternative route to the trans-cyclooctene moiety, starting with an primordial (a very early) example of organocatalysis - the Hajos-Parrish-Eder-Sauer-Wiechert reaction (see Org. Syn.). Not only is this a nominee for the longest named reaction, it’s probably also the first enantioselective organocatalytic reaction. The result of the reaction, a hydroxy dione, was reduced with sodium triacetoxyborohydride, achieving excellent selectivity. What was required next was a selective elimination of the secondary alcohol; this was achieved by Mitsunobu activation in a transformation I personally haven’t seen before. Nice result!

However, a stereoselective reduction of the remaining ketone was then required, but sodium borohydride was found to be nonselective. After completing the reduction using CBS catalyst and borane disulfide, and a tosylation, it was time for the pièce de résistance. An elimination of the tosylate group via carbonyl formation and loss of the bicyclic bond left the desired trans-trisubstituted olefin. Most interestingly, this relatively simple molecule is actually chiral, as demonstrated by its optical activity. In fact, many trans-substituted medium rings can be isolated in enaniomerically pure form by both resolution and synthesis. (Both the papers linked to are worth a read!)

The group then took both this material and the enantiomer (produced separately) forward through to two natural products, coraxeniolide A and caryophyllene. The former was produced using some smart transformations - starting with a trityl perchlorate mediated conjugate addition of a silyl ketene acetal. Nice! Next was a selective enolisation using sodium tert-pentoxide, trapping with formaldehyde and ring closure gave the required lactone with the desired trans ring junction.

The natural product was complete shortly thereafter using only a few more steps. However, installation of the exocyclic methylene was troublesome as some standard conditions were ineffective. Fortunately, salt-free methylenetriphenylphosphorane did the job, which they attributed to enhanced reactivity of the salt-free ylid. After this, the sidechain was appended by a relatively simple alkylation. Unfortunately, the undesired epimer was favoured. This selectivity was overturned by treatment of the product mixture with Schwesinger phosphazene P2-Et - an organic, non-ionic super base.

A really nice total synthesis, which also demonstrates that the Corey lab is the place to find obscure reagents…