Corey and Larionov. JACS, 2008, ASAP. DOI: 10.1021/ja8003705.
This article was mentioned in the comments for the previous post, and contains some quite remarkable chemistry. Corey himself has had quite a fascination with this class of natural products, having already completed (amongst others) Antheliolide A back in 2006. However, this work takes a somewhat alternative route to the trans-cyclooctene moiety, starting with a bit of primordeal organocatalysis – the Hajos-Parrish-Eder-Sauer-Wiechert reaction (see the Org. Syn. too)! Not only is this a nominee for the longest named reaction, it’s also (probably) the first enantioselective organocatalytic reaction. The result of the reaction, a hydroxy dione, was reduced selectively with triacetoxy sodiumborohydride, 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 spot of trouble was had next – a stereoselective reduction of the remaining ketone was required, but sodium borohydride was found to be “nonselective”. Interesting how a subtle change in functionalisation of the 5,6-ring system has overturned the previous selective approach of the reducing agent.
After completing the reduction using CBS catalyst (I bet the group have an entire fridge of them!), and tosylating, it was time for the piÃ¨ce de rÃ©sistance. 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 are endowed with this feature, and have been isolated 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 (that old gem…?!!), 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, but again there’s quite a bit to consider. Installation of the exo-cyclic methylene was slightly troublesome as some standard conditions were ineffective; however, salt-free methylenetriphenylphosphorane did the job, which they attributed to enhanced reactivity of the salt-free ylid. (I wonder if Tebbe’s or Petasis’ reagent worked? Perhaps they knackered the lactone…). After this, the sidechain was appended by a relatively simple alkylation; unfortunately, the undesired epimer was favoured. This selectivity was overturned by treating the product mixture with Schwesinger phosphazene P2-Et – again, not a reagent I’m familiar with, but is basically an organic, non-ionic super base
A really nice synthesis, which also demonstrates that the Corey lab is the place to steal obscure reagents…