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Totally Synthetic by Paul H. Docherty, 29 April 2008

Total Synthesis of Fawcettidine


J. A. Kozak, G. R. Dake, Angew. Chem. Int. Ed. 2008, 47, 4221-4223.

DOI: 10.1002/anie.200800522

A complex little target, this natural product is related to fawcettimine, which we looked at last year. However, fawcettidine has attracted far less synthetic attention than the latter, and this synthesis constitutes the first. Like its cousin, drawing a retroanalysis is difficult, so we’ll go straight into the forward synthesis.

The key reaction, developed from some of the groups methodology (in this Org. Lett.), was a palladium mediated enamide annulation. Of course, they had to build the starting material first, which conveniently came in enantioenriched form - natural pulegone. The elaboration of this into the desired precursor was smart and efficient, but uses routine chemistry…

The annulation itself was sweet - very high yield, and apparently only one diastereoisomer. They suggest that they were concerned about the thiocarbamate group - specifically that sulfur atom’s propensity to deactivate the platinum catalyst, but encountered no such problems.

An allylic oxidation later, and they were ready for the next cyclisation - conjugate addition of a freshly liberated thiolate. This delivered the eight membered ring in great yield. Still, I’m impressed with the yield, considering the ring size and potential for competing processes.

Then comes a reaction I was very pleased to see - a Ramberg-Bäcklund reaction. This little beauty extrudes sulfur dioxide from the eight-membered ring to give the desired ring contraction as an olefin. The two step process (involving formation of a three-membered cyclic sulfone and then a separate decomposition step) failed. However, I bet they were happy when Chan’s one-pot procedure did the business. One reduction later, the total synthesis of the natural product was finished.