Bioinspired Total Syntheses of Skeletally Diverse Lycopodium Alkaloids.

Authors

Yu-Fei Ou, Yuan Jin, Zai-Feng Yuan, Jin He, Xiao-Nian Li, Qin-Shi Zhao

Published in

Journal of the American Chemical Society. Oct 23, 2025. Epub Oct 23, 2025.

Abstract

The phlegmarine skeleton is widely recognized as a key biogenetic intermediate in Lycopodium alkaloids. On this basis, we designed a phlegmarine-derived common intermediate that enables the collective, asymmetric total syntheses of 12 Lycopodium alkaloids with five distinct carbon skeletons. This intermediate was prepared on a decagram scale using commercially available (R)-pulegone in an eight-step sequence, with a stereoselective Michael addition as a key transformation. Subsequent selective carbon-carbon bond formation of this pivotal intermediate─(C4-C10, C4-C12, C1-C14, and C4-C13)─along with a skeletal rearrangement, delivered five frameworks: the huperzimine, lycodine, lycopodine, and phlegmarine classes, which were represented by (-)-hupserrine A, (-)-β-obscurine, (-)-lycopodine, (-)-cermizine B, and the lyconadin C diastereomer, respectively. Furthermore, we developed the first asymmetric total synthesis of (-)-hupserrine A, which bears a complex [6/6/5/6/7] pentacyclic cage structure and inhibits the 5-HT3A receptor (IC₅₀ = 10.6 μM).

PMID:
41129742
Bibliographic data and abstract were imported from PubMed on 24 Oct 2025.

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