Synthetic, Mechanistic and Biological Interrogation of Ginkgo biloba Chemical Space en route to (-)-Bilobalide

Here we interrogate the structurally dense (1.63 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 concen-trated 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 in-hibitory currents at GABAergic synapses, using (+)-bilobalide as a negative control. The high information density of bilob-alide 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/ minute) calculate information content (Böttcher scores), which may prove helpful to identify important features of NP space.