A new approach inspired by nature stimulates stable sugar synthesis

Researchers at the National University of Singapore (NUS) have developed a new biomimetic concept to convert natural sugars into various classes of stable glycosides and glycoproteins without relying on protecting group chemistry. This innovation promises to accelerate carbohydrate synthesis and post-translational modification of proteins, with potential applications for the pharmaceutical, cosmetics and biotechnology sectors.

The research team was led by Associate Professor Koh Ming Joo from the Department of Chemistry at NUS, in collaboration with Professor Benjamin G. Davis from the Rosalind Franklin Institute and the University of Oxford, UK. Their scientific advance was published in the prestigious scientific journal Nature on June 19, 2024.

Carbohydrates play an indispensable role in biological processes, and the simple attachment of a glycosyl moiety often adds desirable functions. Due to their importance, considerable effort has been devoted to synthesizing these carbohydrates and their derivatives to better understand their properties and functions, as well as to develop sugar-based medicines, skin care ingredients and other valuable products. In particular, C-glycosyl compounds have gained importance as mimics of metabolically stable and often more biologically potent O-glycosides.

However, the chemical synthesis of C-glycosyl compounds is traditionally hampered by the need for multistep protecting group strategies and harsh conditions, which generate excessive waste. This is because native sugars contain several hydroxyl groups of similar reactivity, making it difficult to selectively react with them without using protecting groups. For many years, the practical inefficiencies of these approaches have limited their use in synthetic glycochemistry and in conditions requiring high biocompatibility.

Professor Koh said: “Many research groups, including ours, have worked tirelessly to design a protecting group-free chemical glycosylation approach that can directly transform native sugars into desired glycosides through selective functionalization at the anomeric position. . be extremely difficult.

“Cap and glycosylate” technology inspired by nature

Enzymes known as glycosyltransferases are highly proficient in mediating selective glycosylations at the anomeric carbon without having to protect the remaining hydroxyl groups. Researchers took inspiration from nature by designing a biomimetic chemical approach that preferentially activates and replaces the anomeric hydroxyl group of a native sugar with a nucleophilic thiol (a process called capping). This generates a temporary thioglycoside intermediate which, under photoinduced conditions, undergoes stereocontrolled desulfurative cross-coupling with an appropriate reagent (a process called glycosylation). Similar to nature, this “cap and glycosylate” strategy converts native sugars to glycosides in a single operation.

To demonstrate the broad applicability of this technology, researchers synthesized densely functionalized C-glycosyl, S-glycosyl, Se-glycosyl, and O-glycosyl compounds. Beyond the glycosylation of small molecules, the method can be extended to complex biomolecules. Previously, posttranslational chemical glycosylation of proteins by direct anomeric functionalization of native sugars was challenging and largely unexplored. In the new work, C-glycosylation of four proteins of different sizes and folds was successfully achieved, highlighting the power of the “cap and glycosylate” approach.