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

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.本研究针对结构致密（1.64 兆比特每立方埃，1.64 mcbits/ų）的γ-氨基丁酸A型受体（GABAA receptor）拮抗剂白果内酯（bilobalide）、其合成路线中的中间体及相关机制问题展开探究。通过13C同位素标记实验，我们发现了一条通往α选择性催化不对称瑞福马斯基反应（Reformatsky reaction）的意外溴迁移路径，从而排除了不对称烯丙基化反应通路的可能性。实验与计算结果共同揭示了两项令人意外的观测结果背后的驱动力：其一，氧杂环丁烷缩醛（oxetane acetal）在1.5 M DCl（氘代氯化氢）溶于THF-d8（四氢呋喃-d8）与D2O（重水）的混合溶剂中仍能稳定存在；其稳定性与开环过程中取代基间产生的去稳定化空间位阻冲突密切相关。其二，研究发现脱羟基白果内酯的区域选择性氧化反应，其机制依赖于通过孤对电子离域实现的内酯酸化过程，该过程可引发极快的分子间烯醇负离子（enolate）平衡。本研究以(+)-白果内酯作为阴性对照，证实了(−)-白果内酯与非惊厥性倍半萜（sesquiterpene）(−)-贾第内酯（jiadifenolide）对γ-氨基丁酸能突触（GABAergic synapses）处不依赖动作电位的抑制性电流具有等效调控效应。白果内酯极高的信息密度使其区别于其他分子骨架，且这一特征或可普遍适用于天然产物（natural product, NP）空间。为此，本研究还提供了一段Python脚本，可快速（约132000个分子/分钟）计算信息含量（伯特歇尔评分，Böttcher scores），该工具或有助于挖掘天然产物空间的关键特征。