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 identified 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 is shown to persist in concentrated mineral acid (1.5 M DCl in THF-d8/D2O), and its longevity is correlated to destabilizing steric clashes between substituents. 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. In addition, we describe multiple pitfalls, puzzles and unexpected reactions that ultimately uncovered a concise total synthesis. These problems arose from the high information density of bilobalide that 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 be helpful to identify important features of NP space.
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