Radical reaction enables protecting group-free sugar chemistry

Sugar molecules are ubiquitous in the natural world, inspiring researchers to study their many interesting biological activities. But making and modifying sugars in the lab is no easy feat. They’re chock-full of tricky stereocenters and hydroxyl groups that are prone to side reactions, which often require chemists to use tedious protection and deprotection steps to get to the products they want.

Now, a team of researchers co-led by Ming Joo Koh and Benjamin Davis has devised a method for forming chemical attachments to natural sugars without using any protecting groups (Nature 2024, DOI: 10.1038/s41586-024-07548-0). Being able to carry out chemical glycosylation without protection is “as close as we’re ever going to get to the beautiful way that nature does it,” says Davis, a chemical biologist at the University of Oxford and the Rosalind Franklin Institute.

In 2022, Koh and his team at the National University of Singapore published a radical reaction for making C-glycosides from glycosyl sulfones. The new method uses the same light-activated chemistry, but the glycosyl radical is generated from a redox-active thioglycoside that can be created in one easy step from the natural sugar, as opposed to four steps to make the sulfone. The thioglycoside is bench stable, but it doesn’t have to be purified before the coupling step, so the whole protocol can be carried out in a single flask. “We just found a sweet spot,” says Koh.

The researchers tested the reaction on a variety of mono-, di-, and trisaccharides with alky, aryl, sulfur, and selenium-based coupling partners. Regardless of the stereochemistry of the starting sugar, the radical reaction selectively makes products with an α configuration. By using a water-friendly boron-based reductant, the researchers were also able to create C-glycoside links with proteins that had been modified with a dehydroalanine residue.

Ming-Yu Ngai, an organic chemist at Purdue University who researches photoredox catalysis and carbohydrate synthesis, says this work is a notable advance toward bypassing major bottlenecks in glycosylation chemistry. He adds that the ultimate impact will likely depend on how well the method scales up from the bench.

Koh says he and Davis have filed patents and hope eventually to commercialize the bench-stable thioglycosides. They’re particularly excited about applying the chemistry to biological systems, including attaching sugars to nucleotides and grafting sugars from one protein onto another or to cell surfaces. “We can basically just clip bits out of biology and drop them into a new context,” says Davis.