(−)-Huperzine A (1) is a tricyclic alkaloid that is produced in low yield by the Chinese herb Huperzia serrata. There is intense contemporary interest in clinical application of (−)-huperzine A (1) for treating neurodegenerative diseases and protecting against the lethal effects of chemical warfare agents, such as sarin and VX. We report a robust, scalable, and efficient synthesis of (−)-huperzine A (1) from (R)-4-methyl-cyclohex-2-ene-1-one (5). Our route proceeds in 35–45% overall yield, delivers (−)-huperzine A (1) in only eight steps from cyclohexenone5, requires only three chromatographic purifications, and can provide gram quantities of the target. This route represents a critical, enabling advance toward detailed evaluation of (−)-huperzine A (1) in clinical settings.
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