New route to lycopodium alkaloids

The lycopodium alkaloids are a large and extensively studied alkaloid family. Huperzine A (1), the medicinally most significant lycopodine alkaloid as a potential treatment for Alzheimer’s disease, functions as an acetylcholinesterase inhibitor but may have other roles as has been addressed in several recent reviews.  Sauroine (2, 7,8-dihydroxylycopodine), from Huperzia saururus, was reported in 2004 and shown in 2009 to improve memory retention in the step-down test in male Wistar rats, significantly increasing hippocampal plasticity. 7-Hydroxylycopodine (3), from Huperzia serrata, was also reported in 2004 and may have related biological activity.

In their recent Organic Letters paper entitled the Synthesis of (±)-7-Hydroxylycopodine, the Snider lab at Brandeis developed a new general route to these bridgehead hydroxylated lycopodines. They reported a practical six-step synthesis of 7-hydroxylycopodine which makes it readily available for further biological evaluation. The key step of the synthesis is the treatment of bicyclic enol ether 4 with 60% sulfuric acid that affords tricyclic amino alcohol 5, which is further elaborated to 7-hydroxylycopodine (3) in three steps. The application of this route to the synthesis of sauroine (2) is now under investigation.

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