JACS Au· 2026Q1
A Pathway-Economical Synthesis Enabling Systematic Evaluation: Enantiodivergent Access to Aspidosperma Alkaloids Unlocks Divergent Antitumor Mechanisms
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- Q1SCImago
- 2026year
Short summary
A new synthesis provides enantiodivergent access to ten Aspidosperma alkaloids, revealing that enantiomers exhibit distinct antitumor mechanisms: one acts via direct cytotoxicity, the other via immune-dependent T cell exhaustion reversal.
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Key points
- A novel synthesis allows access to both enantiomers of ten Aspidosperma alkaloids from common starting materials.
- The synthesis relies on an intermolecular enantioselective cycloaddition/retro-aza-Michael addition/skeletal reorganization cascade.
- Enantiomers of vincadifformine display divergent antitumor mechanisms: direct cytotoxicity vs. T cell exhaustion reversal.
- (+)-Vincadifformine is identified as a promising lead for cancer immunotherapy due to its immune-dependent mechanism.
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Abstract
Abstract The difficulty in efficiently accessing to both enantiomers has long hampered the systematic evaluation of how chirality governs the bioactivity of natural products. We report a pathway-economical synthesis that addresses this challenge, unlocking enantiodivergent access to ten Aspidosperma alkaloids. The highlight of our strategy lies in an intermolecular enantioselective cycloaddition/retro-aza-Michael addition/DDQ-mediated skeletal reorganization cascade induced by Evans’ auxiliary, which enables access to either enantiomeric series of the tetracyclic core from common starting materials simply by modulating the solvent. This synthesis enabled a comparative biological evaluation, uncovering starkly divergent antitumor mechanisms between enantiomers: (−)-vincadifformine acts through direct cytotoxicity, whereas its (+)-antipode is noncytotoxic but potently reverses T cell exhaustion via an immune-dependent mechanism. This work not only solves a longstanding supply problem of the two enantiomers of Aspidosperma alkaloids, but, by decoupling cytotoxicity from immunostimulation, identifies (+)-vincadifformine as a promising lead for cancer immunotherapy.
The authors' abstract, as published at the source. JACS Au, 2026 · DOI ↗
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