Sugar backbone polymers and methods of synthesis

Abstract

The application belongs to the technical field of polymer materials, and particularly relates to a sugar skeleton polymer and a synthesis method. The application utilizes condensation and polymerization methods to prepare a new sugar skeleton polymer, introduces alcohol-olefin addition reaction into the synthesis of the sugar skeleton polymer, forms a brand new functional sugar main chain alternating polymer with sugar and aliphatic units arranged alternately, overcomes the shortcomings of the existing artificial chemical synthesis method, such as difficulty in controlling stereoselectivity of a product, low molecular weight, complicated monomer preparation, and few types of monomers, and the prepared polymer has a highest molecular weight of 71067 g / mol and simple monomer preparation.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of polymer materials, and particularly relates to a sugar skeleton polymer and a synthesis method. BACKGROUND

[0002] Nature is the source of inspiration for new ideas and perspectives. For decades, chemists have been trying to mimic nature to simulate complex systems that can perform advanced functions. In this regard, scientists have constructed many chemical structures by assembling different building units in various ways. Sugar is one of the most widely distributed biological macromolecules in nature, with a wide variety of structures, spatial orientations of hydroxyl groups, and regions of glycosidic bond connections. The number of sugar chains formed by combination is as high as 10 12 . These sugar chains maintain various life activities in a normal and orderly manner in vivo, and the form of the sugar chains is an important carrier of their functions, which is difficult to predict through the structure of small molecules alone. Therefore, it is of great significance to study the relationship between the structure and function of sugar macromolecules and to reveal the mechanism of sugar-related life activities from the chemical / physical perspective, in order to obtain biological medical materials with complex structures, intelligent responses, and wide adaptability. However, the extraction of natural polysaccharides is not only complex, but also the products have high polydispersity, and the performance between batches is difficult to unify. Developing efficient synthesis methods for polysaccharides has been one of the main research areas of sugar science. Due to the complexity and polydispersity of polysaccharides in structure, even with the help of a large number of various analytical techniques that have been developed, it is still difficult to clearly define the roles played by various polysaccharides in physiological processes and to elucidate the intrinsic mechanisms of these functions from a chemical perspective.

[0003] From the structural point of view, the sugar polymers reported so far can be divided into two categories. The first category is sugar-containing polymers with sugar units as side chains and polymers or polypeptides as main chains. This type of material benefits from the rapid development of click chemistry and controlled radical polymerization, and its synthesis and structure become more controllable. The rich sugar groups enable the polymer to simulate the ubiquitous sugar-sugar / sugar-protein multi-site binding phenomenon in various life activities (such as cell-to-cell signaling, immune response, etc.), so that the self-assembled body can specifically bind to certain cells or proteins, achieving targeted drug delivery or immune behavior regulation. The second category is polysaccharides with sugar rings as the main chain. Compared with the former, its structure is closer to that of natural sugar chains, but due to the high density of similar functional groups and complex spatial chemical structures of the sugar units, its synthesis is still extremely challenging. So far, the extraction of polysaccharides from natural products is complex, the products have high polydispersity, and the performance between batches is difficult to unify.

[0004] Polysaccharide synthesis methods can be divided into biosynthesis and chemical synthesis. Biosynthesis typically employs enzymatic glycosylation, yielding products with perfect regularity and stereoselectivity without the need for protecting groups, making it a promising method for polysaccharide synthesis. However, due to the high specificity of enzymes, only a limited number of enzymes can be used for polysaccharide synthesis, which greatly restricts the application of enzymatic methods to specific substrates or reactions. Furthermore, the high cost of enzymes is a major obstacle to polysaccharide synthesis and further commercialization. Chemical synthesis of polysaccharide polymers mainly focuses on condensation polymerization and ring-opening polymerization. For condensation polymerization: in the chemical preparation process of glycosylation, the formation of the oxygen (O) glycosidic bond usually occurs under the activation of a suitable catalyst. The hydroxyl group of the glycosylation acceptor electrophilically replaces the leaving group on the anodic carbon, which acts as a glycosylation donor. When the sugar molecule contains both an anodic carbon leaving group and an unprotected hydroxyl group, it can simultaneously function as both a glycosylation donor and acceptor. Following this line of thought, Haq et al. reported the synthesis of linear polysaccharides via self-condensation in 1956. They used 2,3,4-tris-O-acetyl-α-pyranoyl glucoyl bromoamide as the reactant monomer in the presence of silver oxide, ultimately obtaining oligosaccharides in extremely low yields. Subsequently, many researchers attempted to synthesize different polysaccharides by changing the monomer functional groups and different polymerization conditions, but these efforts generally failed due to the low molecular weight of the target polymer and poor stereoselectivity, resulting in slow progress in this type of polymerization. The difficulties in preparing polysaccharides via condensation reactions are threefold: first, it is difficult to control the selectivity of the spatial conformations of various hydroxyl groups, which often have similar reactivity; second, it is difficult to control the stereochemical isomerism of glycosidic bonds; and third, it is difficult to obtain high molecular weight polysaccharides.

[0005] The best approach is to find novel and controllable synthetic methods to obtain entirely new sugar polymers that mimic the structure and function of natural polysaccharides. Controlling the polymer structure and physicochemical properties at the molecular level to endow materials with new functions and characteristics is an important direction for future development. Summary of the Invention

[0006] This invention utilizes condensation polymerization to prepare a novel sugar backbone polymer. By introducing the addition reaction of alcohol-olefin into the synthesis of sugar backbone polymers, a novel functional sugar backbone alternating polymer with alternating sugar and aliphatic units is formed. This overcomes the shortcomings of existing artificial chemical synthesis methods, such as difficulty in controlling the stereoselectivity of products, low molecular weight, and cumbersome and limited monomer preparation.

[0007] In a first aspect, the present invention provides a glycoskeletal polymer, wherein the basic structural unit of the glycoskeletal polymer is an AB structure, wherein A is a pyranose or a furanose, and B is any one of alkyl, alkoxy, phenyl, benzyl, m-benzyl, aryl, amino acid, or polypeptide.

[0008] Further, the A-B structure is selected from any one of the structures shown in (I) and (II) as follows:

[0009] wherein n is a positive integer,

[0010]

[0011] wherein the basic structural unit of the sugar backbone polymer is composed of two parts, the first part structural unit A is a sugar ring, including pyranose as shown in (I) and furanose as shown in (II), and the side group direction of the sugar ring can be perpendicular to the sugar ring upward or downward; the second part structural unit is any one of aliphatic, aromatic, amino acid, polypeptide connected by isopropyl at both ends.

[0012] Further, in the first part structural unit A of the sugar backbone polymer, R is selected from any one of methyl, ethyl, acetyl, n-propyl, isopropyl, propenyl, n-butyl, sec-butyl, isoamyl, benzyl;

[0013] Further, in the second part structural unit B of the sugar backbone polymer, X is selected from any one of alkyl, alkoxy, phenyl, benzyl, m-benzyl, aryl, amino acid, polypeptide.

[0014] Further, in the basic structural unit A of the sugar backbone polymer, R is preferably acetyl; and in the second part structural unit B, X is preferably alkoxy.

[0015] In a second aspect, the present application provides a preparation method of a sugar backbone polymer, which comprises the following steps:

[0016] S1. Dissolve trehalose in pyridine, and then react with triphenylmethyl chloride;

[0017] S2. Dissolve acetic anhydride in pyridine and react with the reaction system in step S1;

[0018] S3. Precipitate the reaction solution obtained in step S2 in a water bath, collect the precipitate by suction filtration, and add methanol to collect the solid product;

[0019] S4. Dissolve the solid product obtained in step S3 in dichloromethane, add FeCl3 powder, and then transfer to a separatory funnel, collect, filter, and concentrate to obtain an organic phase;

[0020] S5. Dissolve the organic phase obtained in step S4 in methanol, remove triphenylmethanol crystals by suction filtration, and add tert-butyl methyl ether to the filtrate to generate crystals, and the crystals are hexaacetyl trehalose;

[0021] S6. The crystal obtained in step S5 is dissolved in dichloromethane with a catalyst and triethylene glycol divinyl ether, and the obtained polymer is precipitated again by n-hexane to obtain the sugar skeleton polymer of the present application.

[0022] Further, the trehalose is preferably anhydrous trehalose.

[0023] Further, step S1 is performed in an ice bath.

[0024] Further, step S2 further comprises transferring the reaction system to an oil bath.

[0025] Further, the water bath in step S2 is preferably a water bath with a temperature of 5-15℃.

[0026] Further, the catalyst used in step S6 is preferably pyridine p-toluenesulfonate (PPTS).

[0027] Further, the FeCl3 is preferably FeCl3·6H2O.

[0028] Further, the organic phase is dried with anhydrous magnesium sulfate.

[0029] Beneficial effects:

[0030] The polymer provided by the present application is a new type of polysaccharide structure connected by aliphatic units, which has significantly improved stability and is a potential biocompatible sugar-based macromolecular material. The polymer obtained by the "Markovnikov addition reaction" has high stereoselectivity, and the molecular weight can be up to 71067 g / mol, and the monomer is simple to prepare. BRIEF DESCRIPTION OF DRAWINGS

[0031] Figure 1 The nuclear magnetic hydrogen spectrum of the polymer;

[0032] Figure 2 The GPC curve of the polymer under THF mobile phase. DETAILED DESCRIPTION

[0033] In order to make the present application more obvious and easy to understand, the following will be described in detail in combination with the embodiments and the drawings. The following description is only a preferred embodiment of the present application, and is not a limitation on the form and substance of the present application. It should be pointed out that, for ordinary skilled in the art, without departing from the present application, a number of improvements and supplements can also be made, which should be regarded as the protection scope of the present application.

[0034] Example 1 Synthesis of hexaacetyl trehalose

[0035] 1.2,2',3,3',4,4'-hexa-O-acetyl-6,6'-di-trityl-trehalose synthesis

[0036] Dissolve 10.5 g of trehalose in 40 ml of pyridine at room temperature, then slowly add 17.0 g of triphenylmethyl chloride (TrCl) to the reaction flask, and stir overnight at 40 °C. Thereafter, remove the reaction flask from the cold bath at 10 °C, and stir while adding 40 ml of acetic anhydride diluted with 20 ml of pyridine slowly to the reaction flask in the cold bath. Transfer the reaction flask to an oil bath at 40 °C, and stir overnight. After completion, pour the reaction solution into a 1 L ice water bath to precipitate, and stir for 2 h. After filtration, transfer the solid product to a beaker, and continue stirring in 800 ml of cold water for 20 min. Collect the precipitate, add 150 ml of methanol, and stir with a glass rod at 60 °C for 10 min. Collect the solid product in methanol by filtration, and dry in a vacuum oven at 60 °C overnight.

[0037] 2.2,2',3,3',4,4'-Hexa-O-acetyl-trehalose (Hexa-acetyl trehalose) synthesis

[0038] Dissolve 10.5 g of trehalose in 40 ml of pyridine at room temperature, then slowly add 17.0 g of triphenylmethyl chloride (TrCl) to the reaction flask, and stir overnight at 40 °C. Thereafter, remove the reaction flask from the cold bath at 10 °C, and stir while adding 40 ml of acetic anhydride diluted with 20 ml of pyridine slowly to the reaction flask in the cold bath. Transfer the reaction flask to an oil bath at 40 °C, and stir overnight. After completion, pour the reaction solution into a 1 L ice water bath to precipitate, and stir for 2 h. After filtration, transfer the solid product to a beaker, and continue stirring in 800 ml of cold water for 20 min. Collect the precipitate, add 150 ml of methanol, and stir with a glass rod at 60 °C for 10 min. Collect the solid product in methanol by filtration, and dry in a vacuum oven at 60 °C overnight.

[0039] The synthesis route is shown below (I-A):

[0040]

[0041] Example 2 Synthesis of polysaccharide polymer

[0042] In a dry 25 ml round bottom flask, add 1.189 g of hexa-acetyl trehalose synthesized in Example 1 and 10 mg of PPTS. Under argon protection, weigh 0.4045 g of triethylene glycol divinyl ether into 2 ml of anhydrous dichloromethane, and transfer to the reaction flask, and stir at room temperature for 24 h. After the reaction time is up, add 1.2 ml of NaOH solution to quench the reaction, and precipitate the polymer with n-hexane three times to obtain white polymer, which is dried in a vacuum oven at 50 °C overnight.

[0043] The synthetic route is shown below (II-B):

[0044]

[0045] Example 3 1 H-NMR test

[0046] Nuclear magnetic resonance (1H-NMR) spectra were recorded using a Bruker 400 MHz instrument with deuterated reagent CDCl3. Chemical shifts were referenced to tetramethylsilane (TMS, 0.00 ppm) as internal standard.

[0047] Test results (see Figure 1 ): 1H NMR (400 MHz, Chloroform-d) δ 5.46 (t, J = 9.9 Hz, 2H), 5.31 - 5.20 (m, 3H), 5.07 (dd, J = 25.5, 9.9 Hz, 4H), 4.78 - 4.64 (m, 2H), 4.03 (s, 2H), 3.75 - 3.63 (m, 4H), 3.63 - 3.50 (m, 13H), 2.12 - 2.00 (m, 18H), 1.26 (d, J = 4.3 Hz, 6H).

[0048] Example 4 GPC test

[0049] Gel permeation chromatography (GPC) analysis was performed using an Agilent / Wyatt model 1260 instrument. DMF containing 0.5 M LiBr was used as eluent at a flow rate of 1 mL / min and a detection temperature of 35 °C. The detector was a refractive index detector (RI) and the calibration standard was polystyrene (PS).

[0050] Test results (see Figure 2 ): The product eluted with a peak top at 20.98 min and the number average molecular weight of the polymer was calculated to be M n = 38563 g / mol, the number average molecular weight was M W = 71067 g / mol and the polymer dispersity index PDI was 1.84.

Claims

1. A saccharide backbone polymer, wherein a basic structural unit of the saccharide backbone polymer is an A-B structure selected from any one of the following structures (I) and (II) : （I）； (II); wherein The basic structural unit of the saccharide backbone polymer is composed of two parts, wherein a first part structural unit A is a sugar ring including a pyranose as shown in (I) and a furanose as shown in (II), and a side group direction of the sugar ring can be perpendicular to the sugar ring upward or downward; and a second part structural unit is any one of aliphatic, aromatic, amino acid, and polypeptide connected by isopropyl at both ends; R in the first part structural unit of the saccharide backbone polymer is selected from any one of methyl, ethyl, acetyl, n-propyl, isopropyl, propenyl, n-butyl, sec-butyl, isoamyl, and benzyl; X in the second part structural unit of the saccharide backbone polymer is selected from any one of alkyl, alkoxy, benzyl, m-benzyl, aryl, amino acid, and polypeptide; and n is a positive integer.

2. The glycoform polymer of claim 1, wherein R in the basic structural unit A of the saccharide backbone polymer is acetyl; and X in the second part structural unit B is alkoxy. 3.A preparation method of a saccharide backbone polymer, the method comprising the following steps: S1. dissolving trehalose in pyridine, and then reacting with triphenylmethyl chloride; S2. dissolving acetic anhydride in pyridine, and then reacting with the reaction system in step S1; S3. precipitating the reaction solution obtained in step S2 in a water bath, collecting the precipitate by suction filtration, adding methanol, and collecting the solid product; S4. dissolving the solid product obtained in step S3 in dichloromethane, adding FeCl3 powder, and then transferring to a separatory funnel, collecting, filtering, and concentrating to obtain an organic phase; S5. dissolving the organic phase obtained in step S4 in methanol, removing triphenylmethanol crystals by suction filtration, adding tert-butyl methyl ether in the filtrate, and reacting to generate crystals, wherein the crystals are hexaacetyl trehalose; S6. dissolving the crystals obtained in step S5, a catalyst, and triethylene glycol divinyl ether in dichloromethane, and fully reacting to obtain a polymer, and then precipitating the polymer again by using n-hexane to obtain the saccharide backbone polymer.

4. The method for preparing a glycoform polymer according to claim 3, wherein The trehalose is selected from anhydrous trehalose.

5. The method for preparing a glycoform polymer according to claim 3, wherein The water bath in step S2 is selected from a water bath with a temperature of 5-15℃.

6. The method for preparing a glycoform polymer according to claim 3, wherein The FeCl3 is selected from FeCl3·6H2O.

7. The method for preparing a glycoform polymer according to claim 3, wherein The organic phase is dried by using anhydrous magnesium sulfate.

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