Sugar backbone polymer and synthesis method

Abstract

A polymer material, specifically a sugar backbone polymer and a synthesis method. A new type of sugar backbone polymer is prepared using a condensation and polymerization method. An addition reaction of alcohol-olefin is introduced into the synthesis of the sugar backbone polymer, to form a new functional primary sugar chain alternating polymer having alternating sugar and aliphatic units. It overcomes shortcomings of existing artificial chemical synthesis methods such as difficulty in controlling the stereoselectivity of the product, low molecular weight, cumbersome monomer preparation and few types. The molecular weight of the prepared polymer can reach 71,067 g / mol, and monomer preparation is simple.

Description

Sugar skeleton polymer and synthesis method Technical Field

[0001] The present invention belongs to the technical field of polymer materials, and specifically relates to a sugar skeleton polymer and a synthesis method. Background Art

[0002] Nature is a 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 blocks in various ways. Sugar is one of the most widely distributed biomacromolecules in nature. Its structure is diverse, and the spatial orientation of the hydroxyl groups themselves and the regional isomerism of the glycosidic bonds can form as many as 10 sugar chains. 12 These sugar chains carry out various life activities normally and orderly in the body, and the form of sugar chains is an important carrier of their functions, which is difficult to predict only by the structure of small molecules. Therefore, studying the relationship between the structure and function of sugar macromolecules and revealing the life activity mechanism of sugars from the perspective of chemistry / physics are of great significance for obtaining biomedical materials with complex structures, intelligent responses and wide adaptability. However, the extraction of natural polysaccharides is not only complicated, but also the products are highly polydisperse, and the performance between batches is difficult to unify. The development of efficient synthesis methods for polysaccharides has always been one of the main research areas of glycoscience. Due to the structural complexity and polydispersity of polysaccharides, even with the help of a large number of developed analytical techniques, it is still difficult for us to clearly define the roles played by various polysaccharides in physiological processes and to elucidate the intrinsic mechanisms of these functions from a chemical level.

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

[0004] The synthesis methods of polysaccharides can be divided into biosynthesis and chemical synthesis. The biosynthesis method usually uses enzymatic glycosylation, and the products obtained have perfect regularity and stereoselectivity and do not require protecting groups. It has become a promising method for polysaccharide synthesis. However, due to the high specificity of enzymes, only a few enzymes can be used for polysaccharide synthesis, which greatly limits the enzymatic synthesis or reaction of specific substrates. In addition, the high cost of enzymes is also a major obstacle to the realization of polysaccharide synthesis and further commercialization. The chemical synthesis method 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 oxygen (O) glycosidic bond is usually under the activation of a suitable catalyst, and the glycosylation acceptor hydroxyl group electrophilically replaces the leaving group on the anomeric carbon as the glycosylation donor. When the sugar molecule contains an anomeric carbon leaving group and an unprotected hydroxyl group, it can act as both a glycosylation donor and an acceptor. Following this line of thought, Haq et al. reported the synthesis of linear polysaccharides by self-condensation as early as 1956. He used 2,3,4-tri-O-acetyl-α-pyranose glucoside bromide as a reaction monomer and carried out polycondensation in the presence of silver oxide, ultimately obtaining oligosaccharides with extremely low yields. Subsequently, many researchers continued to synthesize different polysaccharides by changing the monomer functional groups and different polymerization conditions, but the results were basically unsuccessful due to the low molecular weight of the target polymer and poor stereoselectivity, and this type of polymerization scheme made slow progress. The difficulties in preparing polysaccharides by polycondensation reactions are as follows: 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 the glycosidic bond; and third, it is difficult to obtain high molecular weight polysaccharides.

[0005] The best solution is to find new controllable synthesis methods to obtain new sugar polymers that simulate the structure and function of natural polysaccharides. Regulating the polymer structure and physical and chemical properties at the molecular level and giving the materials new functions and characteristics is an important direction for future development.

[0006] Summary of the Invention

[0007] The present invention utilizes a condensation polymerization method to prepare a novel sugar backbone polymer, introducing the alcohol-olefin addition reaction into the synthesis of the sugar backbone polymer to form a novel functional sugar backbone alternating polymer in which sugar and aliphatic units are alternately arranged. This overcomes the shortcomings of existing artificial chemical synthesis methods, such as the difficulty in controlling product stereoselectivity, low molecular weight, cumbersome monomer preparation, and limited variety.

[0008] In a first aspect, the present invention provides a sugar backbone polymer, wherein the basic structural unit of the sugar backbone polymer is an AB structure, wherein A is pyranose or furanose, and B is any one of an alkyl group, an alkoxy group, a phenyl group, a benzyl group, a meta-benzyl group, an aryl group, an amino acid, and a polypeptide.

[0009] Furthermore, the AB structure is selected from any one of the structures shown in (I) and (II) below:

[0010] Where n is a positive integer,

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

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

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

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

[0015] In a second aspect, the present invention provides a method for preparing a sugar backbone polymer, the method comprising the following steps:

[0016] S1. dissolving trehalose in pyridine and then reacting with triphenylmethane;

[0017] S2. acetic anhydride is dissolved in pyridine and reacted with the reaction system in step S1;

[0018] S3. The reaction solution obtained in step S2 was precipitated in a water bath, the precipitate was collected by filtration and methanol was added to collect the solid product;

[0019] S4. The solid product obtained in step S3 was dissolved in dichloromethane, FeCl3 powder was added, and then transferred to a separatory funnel, collected, filtered, and concentrated to obtain an organic phase;

[0020] S5. The organic phase obtained in step S4 is dissolved in methanol, the triphenylmethanol crystals are removed by filtration, tert-butyl methyl ether is added to the filtrate, and the reaction generates crystals, wherein the crystals are hexaacetyl trehalose;

[0021] S6. The crystals obtained in step S5 are dissolved together with the catalyst and triethylene glycol divinyl ether in dichloromethane and reacted sufficiently. The obtained polymer is precipitated again with n-hexane to obtain the sugar backbone polymer of the present invention.

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

[0023] Furthermore, step S1 is carried out in an ice bath.

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

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

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

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

[0028] Furthermore, the organic phase is dried over anhydrous magnesium sulfate. Beneficial effects:

[0029] The polymers provided by this invention represent a novel polysaccharide structure composed of linked aliphatic units. These polysaccharide polymers exhibit significantly improved stability and represent a promising class of biocompatible glycosyl macromolecular materials. The polymers obtained through the Markovnikov addition reaction exhibit high stereoselectivity, molecular weights up to 71,067 g / mol, and simple monomer preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 is the H NMR spectrum of the polymer;

[0031] Figure 2 is the GPC curve of the polymer under THF mobile phase. DETAILED DESCRIPTION

[0032] To make the present invention more clearly understood, the following is a detailed description with reference to the following embodiments and accompanying drawings. The following description is merely a preferred embodiment of the present invention and does not constitute any formal or substantial limitation to the present invention. It should be noted that those skilled in the art may make various improvements and supplements without departing from the present invention, and such improvements and supplements should also be considered within the scope of protection of the present invention.

[0033] Example 1 Synthesis of Hexaacetyl Trehalose

[0034] 1. Synthesis of 2,2',3,3',4,4'-hexa-O-acetyl-6,6'-di-trityl-trehalose

[0035] Dissolve 10.5g of trehalose in 40ml of pyridine at room temperature. Then slowly add 17.0g of triphenylmethane (TrCl) to the reaction flask and stir overnight at 40°C. Afterwards, remove the reaction flask from the heat and stir in a 10°C cold bath. Dilute 40ml of acetic anhydride with 20ml of pyridine and slowly add it to the cold bath. Transfer the reaction flask to a 40°C oil bath and stir overnight. Upon completion, pour the reaction solution into a 1L ice-water bath for precipitation. After stirring for 2 hours, filter the solution with suction and transfer the solid product back to a beaker. Stir in 800ml of cold water for another 20 minutes. Collect the precipitate, add 150ml of methanol, and stir at 60°C with a glass rod for 10 minutes. Collect the solid product in the methanol by suction filtration and dry it in a vacuum oven at 60°C overnight.

[0036] 2. Synthesis of 2,2',3,3',4,4'-hexa-O-acetyl-trehalose (hexaacetyl trehalose)

[0037] 2,2',3,3',4,4'-hexa-O-acetyl-6,6'-2-trityl-trehalose (29 g, 27 mmol) synthesized in the first step of Example 1 was dissolved in 150 ml of dichloromethane and stirred. FeCl3·6H2O powder was then added and stirred for 1 hour. 150 ml of distilled water was added and stirring continued for half an hour. The reaction mixture was transferred to a separatory funnel, and the organic phase was collected and rinsed with additional distilled water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated. 90 ml of methanol was added to the concentrated paste, and the mixture was refluxed to completely dissolve the product in the methanol. The mixture was then refrigerated and allowed to stand overnight. Triphenylmethanol crystals were then removed by filtration. The filtrate was collected and concentrated to a syrup, to which 100 ml of tert-butyl methyl ether was added. The syrup was completely dissolved in the tert-butyl methyl ether under reflux, and refrigerated overnight to allow crystallization. The collected crystals were hexaacetyl trehalose.

[0038] Its synthetic route is shown below (I-A):

[0039] Example 2 Synthesis of polysaccharide polymer

[0040] To a dry 25ml round-bottom flask, add 1.189g of hexaacetyl trehalose synthesized in Example 1 and 10mg of PPTS. Under argon, dissolve 0.4045g of triethylene glycol divinyl ether in 2ml of anhydrous dichloromethane. Transfer the mixture to a reaction flask and stir at room temperature for 24 hours. After the reaction, quench the reaction by adding 1.2ml of NaOH solution. The polymer was precipitated three times with n-hexane to obtain a white polymer, which was dried in a vacuum oven at 50°C overnight.

[0041] The synthetic route is shown below (II-B):

[0042] Example 3 1 H-NMR test

[0043] Nuclear magnetic resonance (1H-NMR) spectroscopy was performed using a Bruker 400 MHz instrument with CDCl3 as the deuterated reagent. Chemical shifts were internally referenced to tetramethylsilane (TMS, 0.00 ppm).

[0044] 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).

[0045] Example 4 GPC test

[0046] Gel permeation chromatography (GPC) analysis was performed using an Agilent / Wyatt 1260 instrument. DMF containing 0.5 M LiBr was used as the eluent at a flow rate of 1 mL / min and a detection temperature of 35°C. A differential refractive index (RI) detector was used, and polystyrene (PS) was used as the calibration standard.

[0047] Test results (see Figure 2): The peak of the product elution is at 20.98 min, and the number average molecular weight of the polymer is calculated based on the polystyrene standard curve to be M n =38563g / mol, number average molecular weight is M W =71067 g / mol, and the polymer dispersibility index PDI is 1.84.

Claims

1. A sugar backbone polymer, wherein the basic structural unit of the sugar backbone polymer is an AB structure, wherein A is pyranose or furanose, and B is any one of an alkyl group, an alkoxy group, a phenyl group, a benzyl group, a meta-benzyl group, an aryl group, an amino acid, and a polypeptide.

2. The sugar backbone polymer according to claim 1, characterized in that The AB structure is selected from any one of the structures shown in (I) and (II) below: Where n is a positive integer, Among them, the basic structural unit of the sugar backbone polymer is composed of two parts. The first structural unit A is a sugar ring, including pyranose as shown in (I) and furanose as shown in (II), and the direction of the side group of the sugar ring can be perpendicular to the sugar ring upward or perpendicular to the sugar ring downward; the second structural unit is any one of an aliphatic, aromatic, amino acid, or polypeptide connected at both ends with isopropyl groups.

3. The sugar backbone polymer according to claim 1, characterized in that In the first 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, isopentyl and benzyl; 4. The sugar backbone polymer according to claim 1, characterized in that In the second structural unit B of the sugar backbone polymer, X is selected from any one of alkyl, alkoxy, phenyl, benzyl, m-benzyl, aryl, amino acid and polypeptide.

5. The sugar backbone polymer according to claim 1, characterized in that In the basic structural unit A of the sugar backbone polymer, R is selected from acetyl; and in the second structural unit B, X is selected from alkoxy.

6. A method for preparing a sugar backbone polymer, the method comprising the following steps: S1. dissolving trehalose in pyridine and then reacting with triphenylmethane; S2. dissolving acetic anhydride in pyridine and reacting with the reaction system in step S1; S3. The reaction solution obtained in step S2 was precipitated in a water bath, the precipitate was collected by filtration and methanol was added to collect the solid product; S4. The solid product obtained in step S3 was dissolved in dichloromethane, FeCl3 powder was added, and then transferred to a separatory funnel, collected, filtered, and concentrated to obtain an organic phase; S5. dissolving the organic phase obtained in step S4 in methanol, removing the triphenylmethanol crystals by suction filtration, adding tert-butyl methyl ether to the filtrate, and reacting to generate crystals, wherein the crystals are hexaacetyl trehalose; S6. The crystals obtained in step S5 are dissolved together with the catalyst and triethylene glycol divinyl ether in dichloromethane, and the mixture is fully reacted. The obtained polymer is precipitated again with n-hexane to obtain the sugar backbone polymer of the present invention.

7. The method for preparing a sugar backbone polymer according to claim 6, characterized in that: The trehalose is selected from anhydrous trehalose.

8. The method for preparing a sugar backbone polymer according to claim 6, characterized in that: The water bath in step S2 is selected from a water bath with a temperature of 5-15°C.

9. The method for preparing a sugar backbone polymer according to claim 6, characterized in that: The FeCl3 is selected from FeCl3·6H2O.

10. The method for preparing a sugar backbone polymer according to claim 6, characterized in that: The organic phase was dried over anhydrous magnesium sulfate.

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