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Synthesis

Simple synthesis for shapeshifting molecules

Bullvalene’s constant metamorphosis could be exploited in sensing applications

by Mark Peplow, special to C&EN
February 28, 2020

20200228lnp4-bullvalene.jpg

Bullvalene is a restless molecule. Its bonds ebb and flow in a perpetual series of rearrangements, so that each of its 10 carbon atoms endlessly swaps places with the others. The bizarre consequence is that bullvalene is a stable organic molecule without any permanent carbon-carbon bonds.

Although bullvalene (C10H10) was first synthesized in 1963, there are relatively few methods for making derivatives of the cage-like compound. “It’s a molecule with a really interesting scaffold that hasn’t really been explored,” says Thomas Fallon at the University of Adelaide.

He and his colleagues have now developed a straightforward method to make bullvalene derivatives that carry up to three boronate ester groups (J. Am. Chem. Soc. 2020, DOI: 10.1021/jacs.9b12930). Since these can easily be replaced by a wide range of other substituents, the compounds could provide a way to probe bullvalene’s chemistry in more detail, and may lead to applications in sensing or drug discovery.

Credit: Thomas Fallon
This shape-shifting bullvalene derivative, which carries three boronate ester substituents (green), exists as a collection of interconverting isomers (blue = carbon, white = hydrogen).

Fallon’s team reported the shortest route for making bullvalene a few years ago (Angew. Chem. Int. Ed. 2018, DOI: 10.1002/anie.201712157), and they adapted this to make the boronate ester bullvalenes.

The method uses a cobalt-catalyzed reaction to combine cyclooctatetraene (C8H8) with an alkyne bearing one or two pinacol boronate esters (Bpin). A rearrangement driven by ultraviolet light then produced mono- or di-substituted bullvalenes. By starting with cyclooctatetraene that already carried a Bpin group, the team even created a tri-substituted bullvalene. Palladium-catalyzed cross-coupling reactions could then replace these boronate esters with a wide range of aryl groups.

Fallon’s team also created a bullvalene bearing two different boronate esters — Bpin and N-methyliminodiacetic acid boronate ester (BMIDA) — which could undergo two separate coupling reactions to add two different substituents.

“I think it’s fantastic,” says Jeffrey W. Bode at ETH Zurich. “These shapeshifting molecules are still underexploited, so having a much shorter route to these fascinating structures will be really great for the field.”

Each substituent always remains attached to the same carbon atom in the bullvalene skeleton. But the incessant game of musical chairs going on in the core means that the substituents spontaneously explore every single position in the structure. That means a single bullvalene derivative can act as a collection of dozens or hundreds of different, interconverting isomers.

Bode had previously exploited this constant metamorphosis in a boronic acid-substituted bullvalene that acted as a sensor for polyols such as carbohydrates and flavanols (J. Am. Chem. Soc. 2013, DOI: 10.1021/ja404981q). He found that each polyol would selectively bind to a specific set of bullvalene structures, shifting the equilibrium of the population of isomers in a way that created a characteristic NMR pattern that identified the binding partner.

Fallon is keen to explore similar sensing applications with his boronate ester bullvalenes, and also wants to make druglike molecules that contain the shape-shifting structure. In principle, a drug target such as an enzyme would preferentially bind a subset of the possible bullvalene-based isomers, which may provide clues about the shape of the enzyme’s active site. “If you can analyze that, get a crystal structure, it might inspire the design of a static molecule that would be perfect for that target,” Fallon says.

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