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Fetching fluoride with hydrogen bonding

Catalyst spurs insoluble salts into action as nucleophiles for enantioselective reactions

by Bethany Halford
May 11, 2018 | A version of this story appeared in Volume 96, Issue 20


Reaction shows a β-bromosulfide transformed by cesium fluoride and a chiral bis-urea catalyst into a β-fluorosulfide.
Enantioselective nucleophilic fluorination reaction takes place with retention of configuration via double displacement—first by sulfur to form a symmetrical episulfonium-ion intermediate and then by fluoride guided to one side of that ion.

As fantastic a nucleophile as fluoride is, when it’s tied up in an inorganic salt, such as CsF or KF, the anion becomes a recalcitrant reagent for organic synthesis because these salts are insoluble in many organic solvents. Chemists at the University of Oxford have now found a way to release fluoride from these salty bonds so that these inexpensive salts can provide nucleophiles for enantioselective reactions.

The key to the achievement, says Véronique Gouverneur, who spearheaded the project, was to marry phase-transfer catalysis—in which a molecule shepherds a reagent from one phase to another so it can react—with a hydrogen-bond donor catalyst that plucks the fluoride from its salt and guides its reactivity in solution.

Chemists often use crown ethers to sequester the cation of an inorganic salt so that its anion becomes more reactive, Gouverneur explains. “Here we do the opposite. We use a hydrogen-bond donor to bind fluoride,” she says. “The fundamental difference between the two is that in the case of fluoride binding, if you pick your hydrogen-bond donor properly, you can control fluoride’s reactivity.”

Gouverneur’s team used experimental and computational studies to figure out the optimal hydrogen-bond donor for the transformation, settling on a chiral bis-urea catalyst. This catalyst brings the fluoride from the undissolved salt into solution and directs the nucleophile to one carbon on a symmetrical episulfonium-ion intermediate that forms from a β-bromosulfide starting material. In this way, the chemists transform a racemic mixture of β-bromosulfide into a single enantiomer of β-fluorosulfide product (Science 2018, DOI: 10.1126/science.aar7941).

Although the reported reactions use only β-bromosulfide substrates, Gouverneur says the reaction is not limited to that starting material, and her group is working on expanding the substrate scope.

“Gouverneur and coworkers have accomplished a very impressive feat by applying chiral hydrogen-bonding catalysis to fluorination chemistry,” says Eric N. Jacobsen, whose lab at Harvard University uses hydrogen-bonding catalysts.

F. Dean Toste, an organic synthesis expert at the University of California, Berkeley, adds that such enantioselective nucleophilic substitutions with fluoride are rare, “but perhaps more importantly, the concept of hydrogen-bonding phase-transfer catalysts could have application beyond delivery of fluoride.”

Gouverneur says her lab is exploring this possibility. “We want to harness the reactivity of nucleophiles other than fluoride, inexpensive inorganic nucleophiles that are currently not used,” she says.


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