Advanced Synthetic Strategies toward Ginkgolide Diterpenoids: Total Synthesis of (±)-Ginkgolide C and Formal Syntheses of (±)-Ginkgolides A and B

Abstract

Ginkgolides are highly oxygenated diterpenes isolated from Ginkgo biloba that exhibit potent anti-inflammatory and neuroprotective properties. Their compact hexacyclic architecture—featuring multiple contiguous stereocenters, a spirocyclic core, and a rare tert-butyl group—presents a formidable challenge in synthetic organic chemistry. Herein, we report the first total synthesis of ginkgolide C (3), the most structurally complex member of this family, completed in 26 steps from commercially available materials. The synthesis is guided by a functional group–driven strategy that enables the convergent construction of the polycyclic core through key diastereoselective carbon–carbon bond formations, selective oxidations, and late-stage epoxide-opening lactonizations. In parallel, the formal syntheses of ginkgolides A (1) and B (2) were accomplished via interception of a late-stage intermediate in 17 steps, the shortest route to these targets reported to date. This work provides a unified synthetic platform for accessing the ginkgolide family and offers new opportunities for the synthesis and biological evaluation of related analogues.