On June 17, 2024, the team of Dawen Niu from Sichuan University and Academician Yundong Wu from Peking University published a research paper titled "Catalytic Glycosylation for Minimally Protected Donors and Acceptors" in Nature. The study reports a Glycosylation platform that enables selective coupling between unprotected or minimally protected donor sugars and acceptor sugars to produce 1,2-cis-O-glycosides in a catalyst-controlled site-selective manner.
Free radical activation of allyl glycosyl sulfones forms glycosyl bromides. A designed aminoboronic acid catalyst brings this active intermediate close to the acceptor through a network of non-covalent hydrogen bonds and reversible covalent B-O bond interactions, thereby achieving precise glycosyl transfer. Different aminoboronic acid catalysts can change the glycosylation site by affecting how they interact with the substrate. The method can accommodate a wide range of sugar types and is suitable for the preparation of naturally occurring sugar chains and pentasaccharides containing 11 free hydroxyl groups. Experimental and computational studies provide insights into the origin of the selective results.
The assembly of oligosaccharides involves the formation of stereocontrolled C-O bonds between a carbon center and one of the numerous hydroxyl groups, which is an outstanding challenge in chemistry. Given the number of free hydroxyl groups present in both reactants and taking into account the two possible configurations (α/β) of the resulting anomeric (glycosidic) center, the reaction between glycosyl donor and acceptor may produce a total of (m+n+1)*2 disaccharide products. In order to efficiently obtain one of them, methods are required to simultaneously deal with the problems of site selectivity, stereoselectivity, and chemoselectivity. For more than a century, chemists have mostly adopted protecting groups to address these challenges.
In fact, the roles of some "protecting" groups include blocking unwanted reaction sites and controlling stereoselectivity. Remarkable achievements have been made, making the preparation of complex oligosaccharides possible. Regardless, overthrowing the dominance of protecting groups remains one of the most actively pursued goals. Progress in this direction could not only simplify the synthesis of oligosaccharides, but also avoid potential problems associated with deprotection of the final products. More importantly, it may open up new horizons for selectivity control, providing products that are difficult to obtain through traditional, protecting group-based methods.
In this regard, milestone advances include methods from Aoyama, Taylor, and Toshima, methods using boron/boronic acid catalysts, methods utilizing double urea catalysts, methods exploring Ca2+/sucrose complexation, methods utilizing various non-covalent interactions, and other methods for selective modification of sugars. However, these reported methods still require fully protected glycosyl donors or show limited substrate scope. A generally applicable selective glycosylation platform coupling minimally protected donors and acceptors remains elusive. Even more demanding is the ability to change the selectivity of products through catalyst control.
Fig. 1 Oligosaccharide synthesis. (Dang, et al., 2024)
Their approach was validated using a glucose-derived donor and a fucose-derived acceptor as model substrates to generate disaccharide products. Both reactants were minimally protected and contained a total of five free hydroxyl groups. The sulfone donor was successfully converted to the brominated glycosyl by visible light irradiation in the presence of fac-Ir(ppy)3 and BrCF2CO2Et. The general structure of the catalyst contains a boronic acid molecule and an amine molecule connected via a C-N bond, designed to host the acceptor and the brominated glycosyl. These catalysts were optimized, and aminoboronic acid catalysts were determined to effectively promote the reaction. The reaction was carried out in ethyl acetate at room temperature under near-neutral conditions, and the products generated were highly stereo- and site-selective.
The versatility of the method was explored by testing a variety of donors and acceptors. Monosaccharide donors such as Glucose, Galactose, fucose, and arabinose as well as more complex disaccharide donors were successfully used. The method was effective in constructing 1,2-cis-α-glycosidic bonds and 1,2-cis-β-glycosidic bonds. The method was applicable to a variety of acceptors, including those containing cis-1,2-diol units, phenolic O-glycosides, and S-glycosides. The glycosyl units were installed onto the axial hydroxyl groups of the acceptors with good site selectivity. The method was also extended to non-sugar acceptors such as shikimate, demonstrating its broad applicability. Complex oligosaccharides, including tetrasaccharides and pentasaccharides, were synthesized using this approach.
The versatility of the method was explored by testing a variety of donors and acceptors. Monosaccharide donors such as glucose, galactose, fucose, and arabinose as well as more complex disaccharide donors were successfully used. The method was effective in constructing 1,2-cis-α-glycosidic bonds and 1,2-cis-β-glycosidic bonds. The method was applicable to a variety of acceptors, including those containing cis-1,2-diol units, phenolic O-glycosides, and S-glycosides. The glycosyl units were installed onto the axial hydroxyl groups of the acceptors with good site selectivity. The method was also extended to non-sugar acceptors such as shikimate, demonstrating its broad applicability. Complex oligosaccharides, including tetrasaccharides and pentasaccharides, were synthesized using this approach.
The platform allows for catalyst-controlled O-glycosylation at different sites. This site variability was demonstrated using a variety of acceptors and donors, highlighting the flexibility of the method in achieving site-selective glycosylation. The method was also applied to prepare naturally occurring oligosaccharide chains such as the core trisaccharide unit of globulins and the repeating unit in Klebsiella K20. These examples highlight the utility of this approach for the Synthesis of biologically relevant oligosaccharides.
Control experiments using donors and acceptors with modified structures showed that the unprotected C2-OH group in the donor plays a crucial role in the reaction efficiency. The in situ formed glycosyl bromide was identified as the key reaction intermediate. Upon addition of the acceptor, the NMR spectrum of the catalyst changed, indicating that the formation of the complex enhanced the nucleophilicity of the acceptor. DFT calculations further revealed the catalytic mechanism. The key transition structure showed that the aminoboronic acid catalyst brings the donor and acceptor into proximity, allowing the C2-OH in the donor to coordinate with the boron atom in the catalyst, thereby promoting 1,2-cis glycosyl transfer. The non-covalent hydrogen bonding interaction between the catalyst and the reactant is crucial for the observed selectivity.
A general platform has been developed to accomplish site-, stereo-, and chemoselective O-glycosylation between minimally protected donors and acceptors. The strategy operates on a radical-based donor activation system that generates electrophilic glycosyl bromides under mild conditions, which allows the application of designed aminoboronic acid catalysts to control the trajectory of subsequent glycosyl transfer to the acceptor. Experimental and computational studies show that the role of the catalyst is to organize the donor and acceptor together through reversible covalent B-O bonding and non-covalent H-bond interactions.
The approach provides challenging cis-O-glycosidic bonds in a position-switchable manner: the reaction site can be switched by changing the structure of the catalyst. In the developed reactions, most acceptors contain a cis-1,2-diol unit (chelated to the boron atom in the catalyst), and 1,2-cis glycosylation occurs within the unit. The versatility and potential utility of this strategy are demonstrated in the synthesis of complex oligosaccharides and naturally occurring sugar chains. This study demonstrates a straightforward stage for designing protecting group-independent, catalyst-controlled glycosylation reactions, which will ultimately simplify the synthesis of Oligosaccharides and facilitate the exploration of carbohydrate functionalities.
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