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

Abstract

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.

Pseudo Natural Products—Chemical Evolution of Natural Product Structure

“…From this perspective, NP‐derived fragments consist of connected informational units similar to DNA or RNA and represent individual genotypes. Their chemical information is densely packed and encompasses high fractions of sp 3 ‐hybridized atoms, high stereogenic content, high heteroatom content, and low aromaticity [62, 63] . Each genotype determines a three‐dimensional structure with specific physico‐chemical and biochemical characteristics, that is, the genotype is expressed as a phenotype.…”

“…Their chemical information is densely packed and encompasses high fractions of sp 3 -hybridized atoms,high stereogenic content, high heteroatom content, and low aromaticity. [62,63] Each genotype determines athree-dimensional structure with specific physico-chemical and biochemical characteristics, that is,t he genotype is expressed as ap henotype.T he phenotype,i nt urn, can form complementary interactions with other molecules and, consequently,serve as the target of selection and evolutionary optimisation. Asimilar genotypephenotype dichotomy is known for RNA.…”

Change the channel: CysLoop receptor antagonists from nature

“…(−)‐Bilobalide represents a challenging target due to its steric congestion and bowl‐shaped topology; the only prior asymmetric synthesis required 24 steps. Our group identified simple L‐type bisoxazoline (indabox) ligands to catalyze an asymmetric Reformatsky addition to a hindered aldehyde fragment 122,123 . A series of radical reactions then delivered the hindered, polysubtituted cyclopentane core of bilobalide, including the distinctive tert ‐butyl substituent.…”

Aza-Yang Cyclization—Buchner Aromatic Ring Expansion: Collective Synthesis of Cycloheptatriene-containing Azetidine Lactones

“…In addition to structural complexity, the "information density" of molecules, a notion recently introduced by Shenvi and Forli, 5 may also help to define choices among different sequential steps in a non-targeted synthesis even more concisely. Information specified by the structure of one member from a group of isomeric molecules can be considered high.…”