The unstable Ginkgo biloba metabolite bilobalide (BB) antagonizes gamma-aminobutyric acid A receptors (GABAAR) and rescues cognitive deficits in mouse models of Down syndrome. Prior syntheses gradually increase oxidation state and require lengthy redox strategies to mitigate competing reactivity between functional groups. Here we show 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 of (–)-BB. Asymmetry is imparted by an unusual catalytic enantioselective Reformatsky reaction. A custom silane reagent allows the discovery of solvent-dependence in stereoselective radical hydration, and a parallel kinetic resolution guides the diastereoselective formation of a remarkably acid-stable oxetane acetal, which proves crucial to relay stereochemical information.

Eleven-step synthesis of (–)-bilobalide

2019 Fall National Meeting

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