Synthetic, Mechanistic, and Biological Interrogation of Ginkgo biloba Chemical Space En Route to (-)-Bilobalide
- 15 October 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 142 (43), 18599-18618
- https://doi.org/10.1021/jacs.0c08231
Abstract
Here we interrogate the structurally dense (1.64 mcbits/angstrom(3)) GABA(A) receptor antagonist bilobalide, intermediates en route to its synthesis, and related mechanistic questions. C-13 isotope labeling identifies an unexpected bromine migration en route to an alpha-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 DCI in THF-d(8)/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 (Biittcher scores), which may prove helpful to identify important features of NP space.Funding Information
- Division of Chemistry (CHE 1764328, CHE 1955922)
- Office of Cyberinfrastructure (OCI 1053575)
- National Institute of General Medical Sciences (R35 GM122606)
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