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Totally Synthetic by Paul H. Docherty, 2 September 2007

Total Synthesis of Fawcettimine


X. Linghu, J. J. Kennedy-Smith, F. D. Toste, Angew. Chem. Int. Ed. 2007, 46, 7671-7673.

DOI: 10.1002/anie.200702695

Not much room for maneuver in this tightly packed little alkaloid, and that makes the synthetic challenge all the more attractive. Toste’s approach somewhat unsurprisingly uses gold catalysis in the key transformation, but there’s lots of other cool chemistry here. As ever with this type of chemistry, the first goal was a successful synthesis of the key substrate:

This is the first reaction that interested me. Toste references this silyl triflate promoted allene addition to Haruta, and it works like a gem, giving a decent yield and impressive control of stereochemistry. A bit of silver nitrate and iodine gave the haloalkene, completing the synthesis of the cyclisation substrate. The gold does its job reasonably well, but over the three steps from the cyclohexenone, the yield is relatively poor.

However, a far more efficient route was found with a terminal olefin on the sidechain. No explanation for this boost in yield is given… The starting material was made using a neat organocatalytic Robinson annulation, which they state was efficient even on a ten-gram scale. Good stuff.

The rest of the synthesis used more routine chemistry - a sp2-sp3 Suzuki coupling on the vinyl iodide gave the required amine-containing chain. The alkene was then hydroborated and the alcohol oxidised to the ketone. Conversion of the terminal olefin to an iodide then allowed displacement by the pendant amine to give the nine-member ring. Treatment of this substrate with TFA released the free amine to cyclise onto the desired ketone, giving the natural product in good yield. Nice work!