The Ginkgo biloba metabolite bilobalide (BB) antagonizes gamma-aminobutyric acid A receptors (GABAAR) and rescues cognitive dysfunction in Ts65Dn mice, models of Down syndrome in which GABAergic inhibition is overactive. However, BB decomposes in weakly basic media, obstructing its derivatization; and structure modification by total synthesis is frustrated by its stereochemically-rich and congested architecture. Here, we report an 11-step synthesis of (–)-bilobalide that relies on the pseudosymmetry of its core. Stereochemistry is relayed from an unusual Reformatsky reaction to a solvent-dependent radical hydration and a stereoselective oxetane acetalization. Facile skeletal rearrangement enables a late-stage ‘inside-out’ oxidation of a deep C-H bond. Rapid access to BB provides the opportunity to stabilize the core while maintaining its unique GABAAR antagonist profile.

11-step catalytic asymmetric synthesis of (–)-bilobalide

2019 Fall National Meeting

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