A synthesis of strychnine by a longest linear sequence of six steps

A synthesis of strychnine by a longest linear sequence of six steps

David B. C. Martin and Christopher D. Vanderwal*

Department of Chemistry, University of California, Irvine

Chemical Science, Advanced Article

Strychnine, a crystalline alkaloid known to most as a powerful toxin used in pesticides, has long been a target of interest for synthetic organic chemists.  Boasting six contiguous stereocenters, five of which are located on a central saturated six-membered ring, and a total of seven rings, strychnine is arguably the most complex natural product for its size.  The first total synthesis of the compound was reported in 1954 by Nobel Laureate R.B. Woodward and has been followed by more than ten alternative approaches.  The most recent synthesis, currently an advanced article in Chemical Science by Martin and Vanderwal from University of California, Irvine, completes the synthesis in a longest linear sequence of six steps, making it the shortest to date. ­­­­

The starting materials consist of the inexpensive compounds 1,4-butynediol, pyridine, and tryptamine.  The impressively short synthesis is accomplished by quickly forming a Zincke aldehyde (a 5-amino-2,4-pentadienal) with proper functional group locations and correct oxidation states.   The Zincke aldehyde then undergoes an intramolecular Diels-Alder reaction, quickly producing two of the fused rings. By utilizing a ruthenium-catalyzed hydrosilylation of 1,4-butynediol and placing the product as a side chain on the skeleton, the researchers quickly obtained the clever precursor 4.  A Brook rearrangement with transmetalation to copper instead of proton extraction followed by an intramolecular conjugate addition yielded the Wieland-Gumlich aldehyde, which can be converted quickly and efficiently to strychnine.

Such a short synthesis did not come without a price.  In designing organic syntheses, it is often best to place low-yielding reactions towards the beginning of the synthesis, but the penultimate step with the Brooke rearrangement took place in only 5 – 10% yield.  The authors believe that this conversion “is self-limiting in the sense that the presence of acidic protons in the substrate and/or product leads to quenching of the key reactive organometallic reagent.”  Despite its relatively low overall yield, the quick synthesis is nonetheless very impressive.  Future work focuses on improving the synthesis’ overall yield even if it demands a longer sequence.

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