Danishefsky and Yu, JACS, 2008, ASAP. DOI:
I found this short synthesis remarkable for taking a modern twist on some resolutely old-school chemistry. I haven’t come across this particular family of natural products before, and Danishefsky doesn’t tell us too much about their properties, other than mentioning “varying degrees of antibiotic and antitumor activity”. I guess this means that we’re in for the chemistry, which involves one hell of a challenging Diels-Alder. I’m not going into the methodology here (but there is some discussion of it in the paper) – I’ll just point out it works, and is remarkable in that fact.
Just consider the regiochemical control that this reaction displays (and perhaps be lenient on the enantioselectivity) – and also bear in mind the propensity for vinylindene species to polymerise in this situation. Top stuff. However, with three stereocenters in the bag, it’s interesting to see that not one of thoses stereocenters is present in the target! So whilst the carbocyclic skeleton in now complete, there’s still quite some work to do…
First-off was an epimerisation of the more-acidic bridgehead stereocenter, converting from a psuedo-cis geometry to a pseudo-trans. This was done to provide control for the substrate controlled reduction of the cyclohexenone moiety in the following step, which was completed with ease.
This substrate was then subjected to a nucleophillic epoxidation, again substrate-controlled to provide the “up” epoxide only. Now they had the stereocentres required for the target, it was time to strip-out the excess. First, the remaining olefin was dihydroxylated, and the secondary alcohol oxidised to an alpha-hydroxy ketone. The tertiary alcohol was dehydrated along the 5,6-ring junction, and the allylic/benzylic position oxidised to provide the desired indenone system. Lastly, aerobic/basic conditions resulted in oxidation to a fluorenone, which only required deprotection to yield product.