Concise asymmetric synthesis of (-)-bilobalide.
Meghan A Baker1, Robert M Demoret1, Masaki Ohtawa2,3
1Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
Nature
|October 17, 2019
Summary
Bilobalide, a Ginkgo biloba compound, has its central nervous system effects investigated. A new synthesis allows for the creation of probes to identify new targets and develop therapeutic analogs.
Area of Science:
- Neuroscience
- Organic Chemistry
- Pharmacology
Background:
- Bilobalide, a Ginkgo biloba metabolite, is ingested by humans, but its effects on the mammalian central nervous system remain unclear.
- Bilobalide antagonizes gamma-aminobutyric acid A receptors (GABAARs), showing potential in rescuing cognitive deficits in mouse models of Down syndrome.
- Previous research faced challenges in identifying bilobalide's targets due to its steric hindrance and instability, limiting exploration beyond GABAARs.
Purpose of the Study:
- To develop a concise and flexible synthesis of bilobalide.
- To facilitate the creation of chemical probes for identifying novel biological targets.
- To enable the development of bilobalide analogues with enhanced selectivity and stability for therapeutic applications.
Main Methods:
- Exploited the unique reactivity of bilobalide for a late-stage deep oxidation strategy.
- Symmetrized the molecular core through oxidation, allowing for the embedding of oxidation states in starting materials.
- Developed a synthetic route applicable to related Ginkgo biloba compounds like ginkgolides.
Main Results:
- Achieved a novel chemical synthesis of bilobalide.
- The synthetic strategy allows for the introduction of varied oxidation states.
- The approach may be extendable to other Ginkgo biloba metabolites, such as ginkgolides.
Conclusions:
- The developed synthesis of bilobalide is crucial for further investigation of its biological activities.
- This work paves the way for identifying new therapeutic targets and developing novel drug candidates.
- The synthetic methodology holds promise for exploring the pharmacology of related natural products.
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