Revision of the Unstable Picrotoxinin Hydrolysis Product

• Published in: Angewandte Chemie International Edition 2021-08, Vol.60 (35), p.19113-19116
• Main Authors: Tong, Guanghu, Shenvi, Ryan A.
• Format: Article
• Language: English
• Subjects: Carbon-13 Magnetic Resonance Spectroscopy; Carboxylic Acids - chemical synthesis; Carboxylic Acids - chemistry; Degradation; GABA; Hydrogen-Ion Concentration; Hydrolysis; Metabolites; natural products; Nervous system; NMR spectroscopy; picrotoxin; Picrotoxin - analogs & derivatives; Picrotoxin - chemistry; Proton Magnetic Resonance Spectroscopy; Sesterterpenes; Sodium Hydroxide - chemistry; γ-Aminobutyric acid
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202107785

The plant metabolite picrotoxinin (PXN) is a widely used tool in neuroscience for the identification of GABAergic signaling. Its hydrolysis in weakly alkaline media has been observed for over a century and the structure of the unstable hydrolysis intermediate was assigned by analogy to the degradation product picrotoxic acid. Here we show this assignment to be in error and we revise the structure of the hydrolysis product by spectroscopic characterization in situ. Counterintuitively, hydrolysis occurs at a lactone that remains closed in the major isolable degradation product, which accounts for the longstanding mistake in the literature. The hydrolysis of picrotoxinin (PXN), which is a plant metabolite that is a widely used tool in neuroscience for the identification of GABAergic signaling, in weakly alkaline media gives an unstable hydrolysis intermediate that was initially assigned by analogy to the degradation product picrotoxic acid. This assignment however has been shown to be in error on the basis of the spectroscopic characterization of the hydrolysis product in situ. Counterintuitively, hydrolysis occurs at a lactone that remains closed in the major isolable degradation product, which accounts for the longstanding mistake in the literature.