Precise synthesis of natural polysaccharides through active polymerization strategies

On April 27, 2023, the Niu Jia team from Boston College published a research paper entitled “Precision native polysaccharides from living polymerization of anhydrosugars” in the journal Nature Chemistry.

The study enabled the active cationic polymerization of 1,6-dehydrate sugar, a biomass-derived monomer, providing a new method for the precise synthesis of a variety of natural polysaccharides, including α-D-1,6-glucan, α-D-1,6-mannan, and a rare α-L-1,6-glucan. At the same time, the obtained glycan material also exhibits excellent chemical recyclability and controllable thermal and mechanical properties.

The corresponding author of the paper is Professor Niu Jia; The first author is Wu Lianqian.

As one of the most abundant biopolymers on Earth, polysaccharides have a wide range of uses in biology, renewable energy, and sustainable materials. However, the complex structural properties of polysaccharides make it extremely challenging to synthesize a sufficient number of accurate polysaccharides, which greatly hinders the research progress on the structure-function relationship of polysaccharides. Therefore, how to achieve the precise synthesis of polysaccharides, that is, to control the composition, sequence, length and connection type of glycosidic bonds of polysaccharides, has always been the focus and difficulty of research in the field of glycoscience.

Polysaccharides can be separated from abundant biological resources, but the resulting polysaccharides are often heterogeneous, which greatly limits the use of polysaccharides. In addition, enzyme-catalyzed synthesis has become an efficient polysaccharide synthesis method due to the excellent regional and stereoselectivity of enzyme-catalyzed glycosylation reactions. However, since only a few biological enzymes can be used to catalyze polysaccharide synthesis, and considering the high specificity of enzymes, enzyme-catalyzed synthesis methods can only be limited to specific substrates or reactions. Recently, iterative assembly strategies based on chemical synthesis have provided new methods for the preparation of polysaccharides with precise sequences and lengths. At the same time, by combining solid-phase synthesis, the automated polysaccharide assembly technology also greatly improves the synthesis efficiency of complex polysaccharides. Chemical polymerization has been widely used in the preparation of polysaccharides or polysaccharide analogues as an efficient and large-scale synthesis strategy. However, how to control these polymerization processes and thus achieve the precise synthesis of polysaccharides is still a difficult challenge.

Using the synergy of glycosyl donor initiator and Lewis acid catalyst, the Niu Jia team at Boston College realized the active cationic ring-opening polymerization of 1,6-dehydrated sugar for the first time, and synthesized a series of precise polysaccharides with adjustable molecular weight, low dispersion and regular stereotype. When a glycosyl fluoride initiator and a boron trifluoride ether catalyst are used, ring-opening polymerization of methyl-protected 1,6-dehydrated glucose monomer occurs smoothly, and the conversion rate of the monomer is as high as 90%. The polymerization reaction also showed good control, with a molecular weight of 5.8 kDa, a dispersion of 1.23, and an end-group fidelity of 90%. In addition, the chain structure of glycans was characterized by 1H NMR and MALDI-TOF-MS, in which α-terminal groups, omega-terminal groups, and glucosyl repeat units were confirmed. More importantly, a single carbon signal at 96.34 ppm and a specific optical rotation value of up to 201.3° further confirmed the stereostructured structure of the glycan. Polymerization also exhibits numerous characteristics of active polymerization, including first-order reaction kinetics, linear increase in molecular weight with conversion rate, controllable molecular weight, and low dispersion. In addition, using this active polymerization strategy, the researchers also synthesized a complex diblock copolysaccharide. Finally, through the chain end group modification strategy, carbon-carbon double bonds and carbon-carbon triple bond functional groups can also be introduced into polysaccharides, which opens up a new path for post-modification of polysaccharide polymers.

Next, this novel polymerization method was also used to synthesize a series of important natural polysaccharides. Allyl protected 1,6-dehydrated glucose monomer is first actively polymerized to obtain glycosaccharides with good molecular weight control (Mn = 3.2 kDa,= 1.24)。 Through the subsequent palladium-catalyzed deprotection strategy, α-D-1,6-glucan with a well-defined structure was synthesized. The synthesized dextran has the same hydrogen and carbon spectral signals as the natural dextran, further indicating the excellent regional and stereoselectivity of this polymerization method. In addition, this strategy can also be used in the synthesis of α-D-1,6-mannan, a polysaccharide widely present in the cell wall of Mycobacterium tuberculosis. Finally, when L-1,6-dehydrated glucose monomer is used, this method can also be used to synthesize a rare α-L-1,6-glucan.

In addition to the synthesis of natural polysaccharides, this method is also suitable for the preparation of a range of novel glycan materials. First of all, the polymer has excellent chemical stability, and when the glycan is treated with excess Lewis acid or Lewis base, its molecular weight remains essentially unchanged at room temperature. Secondly, the glycan also exhibits excellent thermodynamic stability, with thermogravimetric analysis showing a decomposition temperature of up to 345 °C. In addition, the morphology and thermal properties of glycans can be regulated by changing the side chain substituents. Methyl-protected polysaccharides have a high crystallinity and a melting point of 284 °C. Polysaccharides with other long-chain alkyl groups show amorphous morphology. When the protective group is extended from ethyl to n-pentyl, the glass transition temperature is reduced from 67 °C to -23 °C. Finally, the glycan material also shows excellent chemical recyclability. When the catalytic amount of boron trifluoride ether catalyst is added and the temperature is increased to 80 °C, the glycans can be depolymerized efficiently, and the initial monomer can be recovered with a yield of 86%. In addition, the recovered monomers can also be reused for polymerization to obtain glycans with similar material properties.

The precise synthesis of natural polysaccharides was achieved by using an active cationic polymerization strategy. Polymerization reactions feature precise molecular weight control, excellent chain end group fidelity, and good regional and stereoselective control. In addition, the prepared glycan materials also show excellent chemical recyclability and adjustable thermal and mechanical properties. Therefore, this new strategy for polysaccharide synthesis will have a significant impact on applications in the fields of materials science and bioengineering. (Source: Science Network)

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