11-Step Asymmetric Synthesis of (–)-Bilobalide

The Ginkgo biloba metabolite bilobalide (BB) is widely ingested but poorly understood. However, its antagonism of gamma-aminobutyric acid A receptors (GABA_AR) has been tied to rescue of cognitive deficits in mouse models of Down syndrome. Prior syntheses required multistep redox strategies to mitigate competing reactions of functional groups—emergent properties of the BB scaffold that cause unexpected reactivity. Here we exploit the unusual reactivity of bilobalide to affect a late-stage ‘inside-out’ oxidation that symmetrizes the molecular core and allows oxidation states to be embedded in the starting material, resulting in an 11-step synthesis. The stereochemically dense scaffold is accessed in asymmetric fashion through a novel catalytic enantioselective Reformatsky reaction and a solvent-dependent radical hydration. Steric compression and a parallel kinetic resolution result in the diastereoselective formation of a remarkably acid-stable oxetane acetal that proves crucial to relay stereochemical information.