Dake and Kozak. ACIEE, 2008, EarlyView. 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 it’s cousin, drawing a retrosynthesis onto the structure is quite tricky with such tight constraints, 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 (nice cuperate addition…), so I’m not covering it here…
The annulation itself was sweet – cracking yield, and apparently only one diastereoisomer. They suggest that they were concerned about the thiocarbamate group – specifically that sulfur atom’s propensity to knacker palladium platinum (technical term), but encountered no such problems. (They did mention that at low catalyst loadings, the reaction was slow – I wonder if the reaction is faster with a carbamate analogue?)
An allylic oxidation later, and they were ready for the next cyclisation – conjugate addition of a freshly liberate thiolate. This delivered the eight membered ring in great yield, but I’m a bit confused about the stereochemistry, as their figure is inaccurate. (I’ve drawn what I think they made below.) 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-BÃ¤cklund 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, so I bet they were chuffed (and rather relived) when Chan’s one-pot procedure did the business. One reduction later – natural product.
Kozak, J.A., Dake, G.R. (2008). Total Synthesis of (+)-Fawcettidine. Angewandte Chemie International Edition DOI: 10.1002/anie.200800522
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