The Ginkgo tree’s metabolite, bilobalide, is widely ingested by humans despite its effect on the mammalian central nervous system not being well understood. Although there are many hypotheses, it has been difficult to study the mechanism due to the instability of bilobalide and steric congestion.
New research has invented an efficient method for making a synthetic version of bilobalide which could provide a platform to identify potential new targets.
The method, published in Nature in a paper titled “Concise asymmetric synthesis of (−)-bilobalide,” allows chemists to make and study bilobalide and related compounds relatively easily and much more affordably than previously possible.
“This process demonstrates how inventing the right new chemical reactions allows quick access to complex natural compounds,” said Ryan Shenvi, PhD, professor in the department of chemistry at the Scripps Research Institute. “Now we can access bilobalide and the chemical space around it, much of which might have even better properties.”
The ginkgo tree (Ginkgo biloba) is considered a living fossil. Closely related species lived on Earth 270 million years ago, before dinosaurs, and managed to survive subsequent global cataclysms that extinguished the dinosaurs as well as most other kinds of plant and animal.
Unsurprisingly, given that legacy, individual ginkgo trees today are unusually hardy and long-lived; some specimens are said to be thousands of years old. Traditional Chinese medicine includes the use of ginkgo extracts for a variety of ailments, and even the leaves are said to have been used in ancient times as bookmarks to protect against paper-eating insects like silverfish.
A likely factor in G. biloba‘s longevity is the set of insecticidal compounds found in its leaves and nuts. These include ginkgolide compounds, which can cause dangerous bleeding in humans who ingest them at high enough doses, but also the less well-known bilobalide, which has powerful effects on insects but appears to be essentially nontoxic to people. Bilobalide also breaks down quickly in the environment, adding to its attributes for a “green” insecticide.
However, bilobalide has a complex carbon-skeleton structure with eight oxygen atoms that makes it inherently tricky to synthesize. Previously published methods were lengthy, in part because of the difficulty of getting all those oxygen atoms into the proper positions.
“We tried a different approach,” Shenvi said. “Rather than chiseling away at the structure by putting oxygen atoms in one-by-one, we started with large, oxygen-containing fragments, and then pieced them together, like assembling Ikea furniture.”
The new synthesis method, developed principally by graduate students Meghan Baker and Robert Demoret, as well as postdoc Masaki Ohtawa, PhD, culminated with a procedure in which the bowl-like molecular architecture was opened and a final oxygen atom was placed at a precise location inside it.
“Figuring out how to do the last part was a monumental effort,” Shenvi said.
The synthesis, on the whole, involves far less time and effort compared to prior methods, and its development means that chemists now have a practical organic-synthesis method for making not only bilobalide but also derivative compounds, in order to investigate their properties as insecticides or even as potential pharmaceuticals.
“We were first interested in bilobalide because of its potential relevance for human neuroscience,” Shenvi said. “However, since word has spread about the new synthesis, we’ve had the strongest expression of interest from the agrochemical industry, because of bilobalide’s good characteristics as an insecticide and its safety profile.”
Shenvi and his colleagues plan to use their new method to make bilobalide analogs and explore their properties.
