Concise asymmetric synthesis of (−)-bilobalide

Abstract

The Ginkgo biloba metabolite bilobalide is widely ingested by humans but its effect on the mammalian central nervous system is not fully understood1,2,3,4. Antagonism of γ-aminobutyric acid A receptors (GABAARs) by bilobalide has been linked to the rescue of cognitive deficits in mouse models of Down syndrome5. A lack of convulsant activity coupled with neuroprotective effects have led some to postulate an alternative, unidentified target4; however, steric congestion and the instability of bilobalide1,2,6 have prevented pull-down of biological targets other than the GABAΑRs. A concise and flexible synthesis of bilobalide would facilitate the development of probes for the identification of potential new targets, analogues with differential selectivity between insect and human GABAΑRs, and stabilized analogues with an enhanced serum half-life7. Here we exploit the unusual reactivity of bilobalide to enable a late-stage deep oxidation that symmetrizes the molecular core and enables oxidation states to be embedded in the starting materials. The same overall strategy may be applicable to G. biloba congeners, including the ginkgolides—some of which are glycine-receptor-selective antagonists8. A chemical synthesis of bilobalide should facilitate the investigation of its biological effects and its therapeutic potential.

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Fig. 1: Congeners and design considerations.
Fig. 2: Synthesis of (−)-bilobalide.
Fig. 3: Late-stage, regio- and stereoselective oxidation of C10 over C1.

Data availability

All data is available in the text of this Article or its Supplementary Information. Structural parameters are available from the Cambridge Crystallographic Data Centre (CCDC) under the following reference numbers: (−)-5, CCDC 1911131; (−)-8, CCDC 1911128; 12, CCDC 1911129; and 16c, CCDC 1911127.

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Acknowledgements

We thank P. Baran and K. Engle for conversations, and the Engle laboratory for donations of chiral phosphoric acids, including (−)-B. A. Rheingold, C. Moore and M. Gembicky are acknowledged for X-ray crystallographic analysis. We thank J. Chen and B. Sanchez in the Scripps Research Automated Synthesis Facility for purification assistance and for analysis of chiral non-racemic compounds. Support was provided by the National Institutes of Health (R35 GM122606) and the Uehara Memorial Foundation; additional support was provided by Eli Lilly, Novartis, Bristol-Myers Squibb, Amgen, Boehringer-Ingelheim, the Sloan Foundation and the Baxter Foundation.

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R.A.S., M.A.B., R.M.D. and M.O. conceived the project. R.A.S. directed the research, and R.A.S., M.O., M.A.B. and R.M.D. composed the manuscript and the Supporting Information section. M.O., M.A.B. and R.M.D. completed a first-generation synthesis of rac-1. M.A.B. conceived and developed the catalytic asymmetric synthesis of (−)-7. M.A.B. observed, designed and optimized the parallel kinetic resolution of rac-9. M.O. and R.M.D. screened and optimized conditions for the alkyne oxidation of rac-12 and (+)-12. R.M.D. developed the hydration of rac-8 and (−)-8 and optimized scale-up campaigns of rac-5 and (−)-5. M.A.B. and R.M.D. conducted large-scale syntheses of rac-5 and (−)-5. M.A.B. and R.M.D. investigated the rearrangement of rac-5 and (−)-5 to 16ac. M.O. discovered an oxidation of rac-5 to rac-1. M.A.B. investigated the rearrangement of rac-5 and (−)-5 to 16b and 16c, and discovered conditions that were utilized for the oxidation of rac-5 and (−)-5 to rac-1 and (−)-1; M.A.B. and R.M.D. both optimized this process.

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Correspondence to Masaki Ohtawa or Ryan A. Shenvi.

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Supplementary Information

The Supplementary Information contains detailed procedures, additional supporting figures, as well as the required spectral data for publication

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Baker, M.A., Demoret, R.M., Ohtawa, M. et al. Concise asymmetric synthesis of (−)-bilobalide. Nature 575, 643–646 (2019). https://doi.org/10.1038/s41586-019-1690-5

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