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Blue-light special offers sweeter route to 𝐶-glycosides

Glycosyl sulfones need no catalyst for light-triggered radical coupling

by Mark Peplow, special to C&EN
September 28, 2022 | A version of this story appeared in Volume 100, Issue 35


Reaction scheme showing an unprotected pyridyl glycosyl sulfone reacting with blue light and an α,β-unsaturated amide to form a C-glycoamino acid derivative
Credit: M.J. Koh
Blue light and a Hantzsch ester team up to trigger a radical reaction that couples an unprotected pyridyl glycosyl sulfone with an α,β-unsaturated amide. The reaction forms a C-glycoamino acid derivative that could be useful in the development of glycopeptide or glycoprotein drugs.

For medicinal chemists, C-glycosides hit something of a sweet spot. These molecules contain a sugar and a nonsugar group tied together by a carbon-carbon bond that is sturdier than the carbon-oxygen linkage found in many natural glycosides. That bond makes them more resistant to breakdown by enzymes in the body. Several C-glycosides are already used to treat type II diabetes, with others showing promise against malaria and Chagas disease.

Researchers have now developed a method that literally makes light work of C-glycoside synthesis (Nat. Synth. 2022, DOI: 10.1038/s44160-022-00162-w). Starting from glycosyl sulfones, the reaction happens at room temperature, needs no catalyst, and is triggered by blue light. I think this is one of the most general ways of making a broad range of C-glycosides,” says M.J. Koh of the National University of Singapore, who led the work.

Although there are many methods for making C-glycosides (Chem. Rev. 2017, DOI: 10.1021/acs.chemrev.7b00234), they have various drawbacks. For example, one approach relies on generating a glycosyl radical that couples to a nonsugar partner. But the sugar’s hydroxy groups often need to be covered by protecting groups to avoid unwanted side reactions, which adds steps to the synthesis. It can also be tricky to control the stereochemistry of the newly formed carbon-carbon bond, and the methods don’t work well for bulky sugars.

Koh had previously developed an iron-catalyzed method to improve C-glycoside synthesis (Nat. Synth. 2022, DOI: 10.1038/s44160-022-00024-5) but found that some of the glycosyl halide starting materials used in that reaction were unstable to air or moisture, making them difficult to handle.

So his team turned to pyridyl glycosyl sulfones, stable solids that can be prepared at gram scale from sugars of all shapes and sizes. The new method turns these into glycosyl radicals that react with alkenes, alkynes, and other partners, all bearing an array of different functional groups. Koh’s team cranked through more than 60 examples to show the versatility of the reaction, which generally gives C-glycosides in 70-90% yields, even without protecting the sugar’s hydroxy groups. In most cases, it also produces a single diastereomer of the C-glycoside. “The reaction is exceptionally diastereoselective,” Koh says.

The secret sauce in the reaction is a reagent known as a Hantzsch ester. The team thinks that when this ester is exposed to blue light, it helps cleave the starting material’s pyridyl sulfone group to generate the glycosyl radical.

“It’s a nice piece of work,” says Wei Wang, a drug discovery researcher at the University of Arizona, who was not involved in the research. “I think it will attract great interest” among sugar chemists, he adds, because “it’s a really straightforward method.” Wang previously used a Hantzsch ester and blue light to form C-glycoamino acids, although he says that method relied on a different reaction mechanism (Org. Lett. 2019, DOI: 10.1021/acs.orglett.9b00724).

Koh is now in talks with reagent vendors such as Sigma-Aldrich to explore whether some of the glycosyl sulfone precursors could be made commercially available. “If you can buy these off the shelf, it will truly empower chemical users, especially companies who are involved in carbohydrate applications,” Koh says.


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