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Synthetic, Mechanistic, and Biological Interrogation of Ginkgo biloba Chemical Space En Route to (−)-Bilobalide

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    Synthetic, Mechanistic, and Biological Interrogation of Ginkgo biloba Chemical Space En Route to (−)-Bilobalide
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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2020, 142, 43, 18599–18618
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    https://doi.org/10.1021/jacs.0c08231
    Published September 29, 2020
    Copyright © 2020 American Chemical Society
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    Abstract

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    Here we interrogate the structurally dense (1.64 mcbits/Å3) GABAA receptor antagonist bilobalide, intermediates en route to its synthesis, and related mechanistic questions. 13C isotope labeling identifies an unexpected bromine migration en route to an α-selective, catalytic asymmetric Reformatsky reaction, ruling out an asymmetric allylation pathway. Experiment and computation converge on the driving forces behind two surprising observations. First, an oxetane acetal persists in concentrated mineral acid (1.5 M DCl in THF-d8/D2O); its longevity is correlated to destabilizing steric clash between substituents upon ring-opening. Second, a regioselective oxidation of des-hydroxybilobalide is found to rely on lactone acidification through lone-pair delocalization, which leads to extremely rapid intermolecular enolate equilibration. We also establish equivalent effects of (−)-bilobalide and the nonconvulsive sesquiterpene (−)-jiadifenolide on action potential-independent inhibitory currents at GABAergic synapses, using (+)-bilobalide as a negative control. The high information density of bilobalide distinguishes it from other scaffolds and may characterize natural product (NP) space more generally. Therefore, we also include a Python script to quickly (ca. 132 000 molecules/min) calculate information content (Böttcher scores), which may prove helpful to identify important features of NP space.

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    • Part I: Experimental materials and methods (PDF)

    • Part II: Electrophysiology (PDF)

    • Python script that annotates molecules with Böttcher scores (ZIP)

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    • Crystallographic data for compounds in this manuscript (CIF)

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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2020, 142, 43, 18599–18618
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jacs.0c08231
    Published September 29, 2020
    Copyright © 2020 American Chemical Society
    Request reuse permissions

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