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Totally Synthetic by Paul H. Docherty, 12 February 2008

Total Synthesis of Fluostatin C


M. Yu, S. J. Danishefsky, J. Am. Chem. Soc. 2008, 130, 2783-2785.

DOI: 10.1021/ja7113757

I found this short synthesis remarkable for taking a modern twist on some 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”. This means that we’re in for the chemistry, which involves a really challenging Diels-Alder reaction. I’m not going into details (as the reaction is discussed in the paper) - I just point out it works, and is remarkable in that fact.

Just consider the regiochemical control that this reaction displays and also bear in mind the propensity for vinylindene species to polymerise in this situation. A very interesting synthetic step! However, it’s interesting to see that not one of the stereocenters generated is present in the target! So whilst the carbocyclic skeleton is now complete, there’s still quite a lot of 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 stereocenters required for the target. The remaining olefin was then dihydroxylated, and the secondary alcohol oxidised to an α-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.