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Citation: Zhi-hao Shang, Lei Luo, Yihao Hu, Ren Lai, Jingjing Wu. Concise synthesis and bioactivity evaluation of 5α,6-dihydroveragranine A, (-)-veragranines A & B, and their analogs[J]. Chinese Chemical Letters, ;2026, 37(10): 112282. doi: 10.1016/j.cclet.2025.112282 shu

Concise synthesis and bioactivity evaluation of 5α,6-dihydroveragranine A, (-)-veragranines A & B, and their analogs

  • a.

    State Key Laboratory of Synergistic Chem-Bio Synthesis, Frontiers Science Center for Transformative Molecules, Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering, Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 200240, China

  • b.

    State Key Laboratory of Genetic Evolution and Animal Models, Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), State Key Laboratory of Genetic Evolution & Animal Models, Sino-African Joint Research Center, and New Cornerstone Science Laboratory, Kunming Institute of Zoology, the Chinese Academy of Sciences, Kunming 650201, China

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  • (-)-Veragranines A and B are two steroidal alkaloids that exhibit potent analgesic activity. Herein, we report a 5-step biomimetic synthesis of 5α,6-dihydroveragranine A form hecogenin acetate, which incorporates two well-designed cascade processes that significantly improve the synthetic efficiency. Based on synthesis, an alternative biosynthetic proposal of veragranines was proposed. Subsequently, we developed the first divergent approach enabling the synthesis of veragranines A and B in 10~12 steps from deoxycholic acid. The synthesis features a photoredox-catalyzed decarboxylative Minisci reaction that achieved good regioselective control and C20 stereochemistry inversion via a radical process. Besides, the strategic use of an A/B cis-fused starting material enabled late-stage introduction of the Δ5(6) double bond, simplifying its installation and providing a valuable strategy for the synthesis of related natural products. Notably, we evaluated a series of synthetic intermediates and derivatives of veragranines to assess their in vitro analgesic activity. We find that compound 16, which is easily accessible and features a saturated pyridine as the F-ring, emerges as a promising lead