Lycosquarrines A–R, <i>Lycopodium</i> Alkaloids from <i>Phlegmariurus squarrosus</i>

Eighteen new Lycopodium alkaloids, lycosquarrines A–R (1–18), and eight known alkaloids were isolated from the aerial parts of Phlegmariurus squarrosus. Compounds 1–5 and 19, identified from natural sources for the first time, are uncommon lycopodine-type alkaloids with β-oriented H-4. Pentacyclic 4 and 5 represent the first examples of 5,12- and 5,11-epoxy Lycopodium alkaloids, respectively, and an epoxide-opening cyclization reaction is suggested to be a key step in their biosynthesis. Compound 18 possesses the same carbon skeleton as carinatine A (22), which was previously reported as a unique Lycopodium alkaloid with a 5/6/6/6 ring system. X-ray crystallographic data analysis was used to determine the absolute configuration of 18, leading to the establishment of the absolute configuration of 22 by comparison of the ECD spectra. An anti-acetylcholinesterase activity assay showed that 11 and 20 exhibited inhibitory activities with IC50 values of 4.2 and 2.1 μM, respectively.