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Totally Synthetic by Paul H. Docherty, 27 January 2007

Total Synthesis of Fusicoauritone


D. R. Williams, L. A. Robinson, C. R. Nevill, J. P. Reddy, Angew. Chem. Int. Ed. 2007, 46, 915-918.

DOI: 10.1002/anie.200603853

Another appearance for the Nazarov rearrangement in this smart total synthesis of Fusicoauritone, an interesting terpene with a dicyclopenta[a,d]cyclooctane ring system. Of course, many related structures have been made before, but this appears to be the first synthesis of this molecule. Williams et al. have used a partially-biomimetic approach to the ring system, first creating an eleven-member ring, then closing to form a 5,8-system. However, the cyclisation precursor is hardly non-trivial, so lets look at that first:

The total synthesis of that beast begins with a Johnson-Claisen ortho-ester rearrangement, used again a few steps later. This, in conjunction with a nice hydroboration/oxidation/alkylation sequence allows facile construction of this precursor.

The eleven-member ring was then formed via a modified Julia condensation. This reaction is closely related to both the Julia olefination and the aldol condensation, and worked rather well. However, subsequent dehydroelimination of the sulfonyl group failed, so the group had to think again.

Success, however, was had with a phenylselenation of the sulfonyl ketone, allowing elimination to give the divinyl ketone, and then perform that cracking Nazarov rearrangement.

Now, in what must be a biomimetic step, an air oxidation allowed transformation of this via a putative enolisation and capture of the conjugated enol by dissolved oxygen. This returned the hydroperoxide of the natural product in a good yield, but needed more than three days. The hydroperoxide was then reduced to the alcohol (and to the target) in a high yielding step. However, the air oxidation takes three days, so a faster alternative was direct conversion with tert-butylhypochlorite.