Here we interrogate the structurally dense (1.63 mcbits/Å 3 ) GABA A receptor antagonist bilobalide, intermediates en route to its synthesis and related mechanistic questions. 13 C 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-d 8 /D 2 O); 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/minute) calculate information content (Böttcher scores), which may prove helpful to identify important features of NP space.

The Ginkgo biloba metabolite bilobalide is widely ingested by humans but its effect on the mammalian central nervous system is not fully understood 1,2,3,4. Antagonism of gammaaminobutyric acid A receptors (GABA A Rs) by bilobalide has been tied to rescue of cognitive deficits in mouse models of Down syndrome 5. A lack of convulsant activity coupled with these neuroprotective effects have led some to postulate an alternative, unidentified target. 4 However, steric congestion and the instability of 1 1,2,6 have prevented pulldown of biological targets other than the GABA A Rs. A concise and flexible synthesis of 1 would provide a platform to generate probes for identification of potential new targets; analogs with differential selectivity between insect and human GABA A Rs; and stabilized analogs with enhanced serum half-life 7. Here we exploit the unusual reactivity of bilobalide to affect a late-stage oxidation that symmetrizes the molecular core and allows oxidation states to be embedded in the starting material. The same overall strategy disclosed here may be applicable to G. biloba congeners including the ginkgolides, some of which are glycine receptor (GlyR)-selective antagonists 8. The therapeutic potential of bilobalide and its incompletely understood effects can now be interrogated through chemical synthesis.

Neuroactive metabolites from the bark of Galbulimima belgraveana occur in variable distributions among trees and are not easily accessible through chemical synthesis because of elaborate bond networks and dense stereochemistry. Previous syntheses of complex congeners such as himgaline have relied on iterative, stepwise installation of multiple methine stereocenters. We decreased the synthetic burden of himgaline chemical space to nearly one-third of the prior best (7 to 9 versus 19 to 31 steps) by cross-coupling high fraction aromatic building blocks (high F sp 2) followed by complete, stereoselective reduction to high fraction sp 3 products (high F sp 3). This short entry into Galbulimima alkaloid space should facilitate extensive chemical exploration and biological interrogation.