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Totally Synthetic by Paul H. Docherty, 26 April 2007

Total Synthesis of Majusculone


D. F. Taber, M. I. Sikkander, P. H. Storck, J. Org. Chem. 2007, 4098-4101.

DOI: 10.1021/jo070257g

A short synthesis and therefore a short post on the total synthesis of this secondary metabolite from Laurencia cartilaginea. The family, bromochamigrenes, show selective, potent cytotoxicity in the NCI 60 cell antitumor, and are thus quite deserving of Douglass Taber’s work. The key to the synthesis is the carbene insertion, but let’s look at the retrosynthesis first:

As you can see, the exciting chemistry is happening at a very congested neopentyl centre, so getting anything to happen is quite impressive. The forward synthesis shows that they managed this quite efficiently, producing the carbene via deprotonation/loss of bromide. This then inserts into the only available C-H bond (with a small amount of rearrangement product), generating the spirocycle in good yield.

Now, what I found really smart in this work was a “rearrangement” to the 6,6-spirocycle via ozonolysis of the olefin, followed by aldol condensation to give the enone. A nice total synthesis! I also like the use of hydrobenzoin to protect the ketone and allow resolution… not novel, but nice.