Totally Synthetic by Paul H. Docherty, 11 October 2006
Total Synthesis of Antheliolide A
C. S. Mushti, J.-H. Kim, E. J. Corey, J. Am. Chem. Soc. 2006, 128, 14050-14052.
Another top total synthesis of an interesting polycyclic target, this one features a complex nine-four-six ring system at its core. The structure was determined almost twenty years ago, but the synthesis has apparently slipped through, along with the absolute stereochemistry. No details on the activity of the compound were given in the paper, but I haven't read the isolation reference yet, so perhaps it shows some activity… However, the synthesis is what we’re interested in!
After eight steps, the workers achieved a complex cyclisation precursor, full of synthetic handles. After saponification of the ester however, salt formation and treatment with tosyl chloride in base, a ketene intermediate is formed. This then performed an intramolecular [2+2] cycloaddition, generating the cyclobutane and the useful remaining carbonyl group. This transformation has been somewhat of a Corey favourite, and several references in the paper point to other work containing this style of reaction.
With the carbonyl handle, functionalisation of the cyclobutane was easy, allowing ethylation, and at this point they did a resolution via chiral HPLC. Further functionalisation led them to a β-keto sulfone, with which they did an interesting Pd catalysed [2,3]-sigmatropic rearrangement:
Again, this interesting cyclisation left them with a useful synthetic handle, as well as the desired ring (in this case a difficult to form trans-nonene); however, the sulfone was removed using Al-Hg amalgam. Completion of the synthesis was then in sight, via eventual clevage of the five-member ring (using a periodate on silica reagent), and formation of some six-member rings by stirring in silica: