Sugar skeleton polymer and synthesis method thereof

Abstract

The invention belongs to the technical field of polymer materials, and particularly relates to a saccharide skeleton polymer and a synthesis method. A novel sugar skeleton polymer is prepared by utilizing condensation and polymerization methods, and an alcohol-olefin addition reaction is introduced into synthesis of the sugar skeleton polymer to form a brand-new functional sugar main chain alternating polymer in which sugar and aliphatic units are alternately arranged. The method overcomes the defects of high product stereoselectivity control difficulty, low molecular weight, complicated monomer preparation, few types and the like in the existing artificial chemical synthesis method, the molecular weight of the prepared polymer can be up to 71067 g / mol, and the monomer preparation is simple.

Description

Technical Field

[0001] The 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 group itself and the regional isomerism of the glycosidic bond connection 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 existence 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 mechanism of sugar-related life activities from a chemical / physical perspective is 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 product has high polydispersity, and it is difficult to unify the performance between batches. 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 explain the inherent mechanisms of these functions from a chemical level.

[0003] From a structural analysis, the sugar polymers 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 sugar units, its synthesis is still extremely challenging. So far, the extraction 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 obtained products have perfect regularity and stereoselectivity and do not require protecting groups. It has become a promising method for the synthesis of polysaccharides. However, the problem is that 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 is mainly focused on condensation polymerization and ring-opening polymerization. For condensation polymerization: In the chemical preparation process of glycosylation, the formation of oxygen (O) glycosidic bonds is usually activated by 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 a glycosylation donor and acceptor at the same time. Following this idea, 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 for polycondensation in the presence of silver oxide, and finally only obtained oligosaccharides with extremely low yields. Subsequently, many researchers still synthesized different polysaccharides by changing the monomer functional groups and different polymerization conditions, but the results were basically failed due to the low molecular weight of the target polymer and poor stereoselectivity, and this type of polymerization scheme progressed slowly. There are three difficulties in preparing polysaccharides by polycondensation reaction: first, it is difficult to control the selectivity of various hydroxyl spatial conformations, which often have similar reactivity; second, it is difficult to control the stereochemical isomerism of glycosidic bonds; 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. Summary of the invention

[0006] The present invention utilizes a condensation polymerization method to prepare a novel sugar backbone polymer, introduces the addition reaction of alcohol-olefin into the synthesis of the sugar backbone polymer, and forms a new functional sugar backbone alternating polymer in which sugar and aliphatic units are alternately arranged, thereby overcoming the shortcomings of existing artificial chemical synthesis methods such as difficulty in controlling product stereoselectivity, low molecular weight, cumbersome monomer preparation and few types.

[0007] 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.

[0008] Further, the AB structure is selected from any one of the structures shown in (I) and (II) below:

[0009] Where n is a positive integer,

[0010]

[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 at both ends with isopropyl groups.

[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. dissolving acetic anhydride in pyridine and reacting 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. 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;

[0021] 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.

[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.

[0029] Beneficial effects:

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

[0031] Figure 1 is the H-NMR spectrum of the polymer;

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

[0033] In order to make the present invention more clearly understandable, the following is a detailed description in conjunction with the embodiments and drawings. The following description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any form or substance. It should be noted that a person skilled in the art can make several improvements and supplements without departing from the present invention, and these improvements and supplements should also be considered as the protection scope of the present invention.

[0034] Example 1 Synthesis of hexaacetyl trehalose

[0035] 1. Synthesis of 2,2',3,3',4,4'-hexa-O-acetyl-6,6'-di-trityl-trehalose

[0036] Dissolve 10.5g of trehalose in 40ml of pyridine at room temperature, then slowly add 17.0g of triphenylmethane chloride (TrCl) to the reaction bottle and stir overnight at 40°C. Afterwards, take out the reaction bottle and stir in a cold bath at 10°C, dilute 40ml of acetic anhydride with 20ml of pyridine, and slowly add it to the reaction bottle in the cold bath for reaction. Transfer the reaction bottle to a 40°C oil bath and stir overnight. After completion, pour the reaction solution into a 1L ice water bath for precipitation, stir for 2h, filter and transfer the solid product to a beaker again, and continue stirring in 800ml of cold water for 20min. Collect the precipitate, add 150ml of methanol, stir with a glass rod at 60°C for 10min, collect the solid product in methanol by suction filtration, collect and dry in a vacuum oven at 60°C overnight.

[0037] 2. Synthesis of 2,2',3,3',4,4'-hexa-O-acetyl-trehalose (hexaacetyl trehalose)

[0038] The 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 solution and stirred, and then FeCl3·6H2O powder was added and stirred for 1 hour. 150 ml of distilled water was added and continued to stir for half an hour. The reaction solution was transferred to a separatory funnel, the organic phase was collected, and it was 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 product, refluxed to allow the product to be completely dissolved in methanol, and refrigerated in a refrigerator and allowed to stand overnight. Then the triphenylmethanol crystals were removed by suction. The filtrate was collected and concentrated into a syrup, to which 100 ml of tert-butyl methyl ether was added, and the syrup was completely dissolved in tert-butyl methyl ether under reflux, and refrigerated in a refrigerator overnight to crystallize. The collected crystals were hexaacetyl trehalose.

[0039] Its synthetic route is shown as follows (I-A):

[0040]

[0041] Example 2 Synthesis of polysaccharide polymers

[0042] In a dry 25 ml round bottom flask, add 1.189 g of hexaacetyl trehalose synthesized in Example 1 and 10 mg of PPTS. Under argon protection, weigh 0.4045 g of triethylene glycol divinyl ether and dissolve it in 2 ml of anhydrous dichloromethane, transfer it to the reaction bottle, and stir it at room temperature for 24 hours. After the reaction time is over, add 1.2 ml of NaOH solution to quench the reaction, and the polymer is precipitated three times with n-hexane to obtain a 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) spectroscopy was performed using a Bruker 400 MHz instrument, and the deuterated reagent was CDCl3. Chemical shifts were internally referenced to tetramethylsilane (TMS, 0.00 ppm).

[0047] Test results (see Figure 1 ): 1H NMR(400MHz,Chloroform-d)δ5.46(t,J=9.9Hz,2H),5.31–5.20(m,3H),5.07(dd,J=25.5,9.9Hz,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=4.3Hz,6H).

[0048] Example 4 GPC test

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

[0050] Test results (see Figure 2 ): The peak of the product elution is 20.98min. According to the standard curve of polystyrene, the number average molecular weight of the polymer is calculated to be M n =38563 g / 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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