CN112480184A - Method for synthesizing dendronized glycosylamines containing various sugars by utilizing gradient click chemistry - Google Patents

Method for synthesizing dendronized glycosylamines containing various sugars by utilizing gradient click chemistry Download PDF

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CN112480184A
CN112480184A CN202011425507.3A CN202011425507A CN112480184A CN 112480184 A CN112480184 A CN 112480184A CN 202011425507 A CN202011425507 A CN 202011425507A CN 112480184 A CN112480184 A CN 112480184A
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刘美娜
王星又
何琪
王梦彤
周志
杨文璐
孟擂
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Shanghai Institute of Technology
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Abstract

The invention relates to a method for synthesizing dendronized glycosylamine containing various sugars by utilizing gradient click chemistry, which can be used for post-modification of a polymer skeleton containing active ester. The terminal alkyne is then subjected to a gradient CuAAC reaction with an acetyl protected azido sugar, and finally deprotected from the Boc group with trifluoroacetic acid. Compared with the prior art, the method utilizes the advantages of CuAAC click chemistry, provides a simple and quick way for synthesizing the heterogeneous sugar amine containing multiple glycosyl groups, and has important guiding significance for preparing the multifunctional heterogeneous sugar-containing polymer with ordered structure and controllable molecular weight.

Description

Method for synthesizing dendronized glycosylamines containing various sugars by utilizing gradient click chemistry
Technical Field
The invention belongs to the technical field of multifunctional dendronized glucosamine synthesis, and relates to a method for synthesizing dendronized glucosamine containing various sugars by utilizing gradient click chemistry.
Background
The cluster effect of natural saccharides having a multivalent structure can strongly promote the recognition of lectins, and various sugar-containing functional scaffolds, which are easy to synthesize, have been reported to mimic the strong recognition ability of natural polysaccharides, which are difficult to separate and purify. Among them, the sugar-containing polymer has a large adjustable range in the valence of sugar residue on the chain, the function of a connecting group and the whole structure, which has a prominent advantage for systematically researching the influence of the structure of a sugar cluster on the recognition performance. Advantageously, it has been demonstrated that the "hetero-clustering effect" resulting from the introduction of different sugar groups (either recognisable or unrecognizable) into the side chains of the sugar-containing polymers strongly facilitates the recognition of the polymer and lectin with respect to each other. Thus, over the past few years, synthetic sugar-containing polymers have increasingly been used as tools for studying and understanding various parameters governing multivalent interactions between carbohydrates and lectins. However, most synthetic sugar-containing polymers contain only one or two sugars and are not as tunable as the large amount of sugar groups on the surface of glycodendrimers, which prevents further biological applications of sugar-containing polymers. And the strong heterogeneity exhibited by cell surface sugars is far from that exhibited by sugar-containing polymers containing one or both types of sugar groups. It would be highly desirable to develop efficient methods to synthesize novel heterogeneous sugar polymers with multiple sugar motifs in a controlled manner, which would enable exploration of the significance of complex sugar heterogeneity in protein-carbohydrate interactions.
Two main methods for the synthesis of sugar-containing polymers are the direct polymerization of sugar-containing polymerizable monomers and the post-polymerization modification of the polymer backbone with sugar-containing derivatives. Post-polymerization modification is one of the important methods for synthesizing functional saccharide-containing polymers due to high tolerance to various functional groups. The synthesis of heterogeneous saccharide-containing polymers with complex functional, specific side chains, mimicking natural glycoconjugates, is therefore premised on the synthesis of specific saccharide-containing derivatives that can be used for post-polymerization modification.
Click chemistry (click chemistry) is a highly efficient organic reaction proposed by Sharpless, which is a click reaction characterized by modularity, simplicity, high efficiency, no by-product, and the like, and particularly, the CuAAC click reaction, which is the most widely used one, can synthesize not only sugar-containing derivatives (e.g., sugar amine) that are post-modified to polymer scaffolds, but also directly polymerized functional sugar-containing monomers, and has been proven to be an effective way for synthesizing sugar-containing polymers. Prior to the use of click reactions, the synthesis of sugar monomers is cumbersome and the progress of exploring the corresponding functions is hampered by the number of protecting groups and synthesis steps required to ensure chemical and stereoselectivity. However, no literature reports on methods for synthesizing sugar-containing derivatives (e.g., sugar amines) having various sugar groups have been found.
Disclosure of Invention
The invention aims to provide a method for synthesizing dendronized glycosylamine containing multiple saccharides by utilizing gradient click chemistry, provides a simple and quick way for synthesizing heterogeneous sugar amine containing multiple saccharides, and has important guiding significance for preparing multifunctional heterogeneous saccharide-containing polymers with ordered structures and controllable molecular weights.
The three-arm branched carbohydrate-containing derivative disclosed by the invention takes three-arm terminal alkyne as a substrate, utilizes a gradient click strategy and combines three different glycosyl groups to realize the independent functionality of different arms in the three-arm branched carbohydrate-containing derivative, meets different requirements of a symmetrical branch structure and an asymmetrical branch structure, and realizes the accurate arrangement of various glycosyl groups.
The purpose of the invention can be realized by the following technical scheme:
a method for synthesizing a dendrimeric glycosylamine containing multiple sugars using gradient click chemistry, comprising the steps of:
(1) dissolving tris (hydroxymethyl) aminomethane (compound 1) in a mixed solvent of methanol and tert-butyl alcohol, adding a tert-butyl alcohol solution of di-tert-butyl dicarbonate for reaction, and purifying after the reaction is finished to obtain a white powdery product, namely compound 2;
(2) dissolving the compound 2 in N, N-dimethylformamide, dropwise adding 3-bromopropyne, stirring, adding potassium hydroxide powder, continuing to react, and washing, drying and purifying after the reaction is finished to obtain a light yellow oily product, namely a compound 3;
(3) dissolving the compound 3 and azido sugar in a mixed solvent of tert-butyl alcohol and water, adding copper sulfate pentahydrate and sodium ascorbate, uniformly stirring, reacting, filtering after the reaction is finished, and purifying to obtain a colorless viscous product, namely a precursor compound;
(4) and dissolving the precursor compound in a dichloromethane solution, dropwise adding a dichloromethane solution of trifluoroacetic acid in an ice bath, washing after the reaction is finished, drying, filtering and concentrating to obtain a colorless viscous compound, namely the target product.
Further, in the step (1), the molar ratio of the trihydroxymethylaminomethane to the di-tert-butyl dicarbonate is 1: 1.3;
the reaction process is as follows: the reaction was carried out at room temperature for 18 h.
Further, in the step (2), the molar ratio of the compound 2, the 3-bromopropyne and the potassium hydroxide is 1.0:3.1: 3.1;
the reaction process is as follows: dropwise adding 3-bromopropyne under the condition of keeping the temperature of 0 ℃ in an ice bath, stirring to react for 10min, adding potassium hydroxide powder, reacting for 30min at the temperature of 0 ℃, and continuing to react for 18h at room temperature.
Further, in the step (2), the washing process adopts ethyl acetate/water washing, wherein the volume ratio of the N, N-dimethylformamide to the ethyl acetate to the water is 1:2.5:2.5, meanwhile, the anhydrous sodium sulfate is adopted for drying, the molar ratio of the anhydrous sodium sulfate to the ethyl acetate is 11:1, and column chromatography is adopted for purification.
Further, in the step (3), the molar ratio of the compound 3, the azido sugar, the copper sulfate pentahydrate and the sodium ascorbate is (1.0-1.5): (1.0-2.1): 0.4-0.5): 0.8-1.0. Specifically, the molar amount of addition varies depending on the azido sugar and the reaction substrate (i.e., compound 3, etc.).
Further, in the step (3), the azido sugar is R-OAc-N3Wherein, R is one or more of alpha Man-, beta Glu-or beta Gal-. Specifically, alpha Man-OAc-N3(A)、βGal-OAc-N3(B) And beta Glu-OAc-N3(C) Are respectively as
Figure BDA0002824637800000021
Furthermore, the obtained colorless viscous product also replaces the compound 3 to repeat the reaction in the step (3) to obtain a precursor compound, so as to obtain different kinds of heterogeneous sugar amines containing multiple sugar groups. Specifically, the reaction process of step (3) is divided into the following cases according to the different raw materials used, and different precursor compounds are obtained:
as in 1) directly to prepare compound 3 and α Man-OAc-N3(A) Dissolving in a mixed solvent of tert-butyl alcohol and water, adding copper sulfate pentahydrate and sodium ascorbate, stirring uniformly, reacting, filtering after the reaction is finished, and purifying to obtain colorless viscous products, namely Boc-alpha Man-OAc (AAA precursor), Boc-alpha Man-yne-OAc (AAX precursor) and Boc-alpha Man-yne-OAc (AXX precursor);
or 2) to prepare the obtained compound AAX precursor and beta Gal-OAc-N3(B) Dissolving in a mixed solvent of tert-butyl alcohol and water, adding copper sulfate pentahydrate and sodium ascorbate, stirring uniformly, reacting, filtering after the reaction is finished, and purifying to obtain a colorless viscous product, namely a compound Boc-alpha Man-beta Gal-OAc (AAB precursor);
or 3) preparing the obtained AA precursor X and beta Glu-OAc-N of the compound3(C) Dissolving in a mixed solvent of tert-butyl alcohol and water, adding copper sulfate pentahydrate and sodium ascorbate, stirring uniformly, reacting, filtering after the reaction is finished, and purifying to obtain a colorless viscous product, namely a compound Boc-alpha Man-beta Glu-OAc (AAC precursor);
or 4) preparing the obtained compound AXX precursor and beta Gal-OAc-N3(B) Dissolving in mixed solvent of tert-butyl alcohol and water, adding copper sulfate pentahydrate and sodium ascorbate, stirring, reacting, filtering, and purifying to obtain colorless viscous product, i.e. compound Boc-alpha Man-beta Gal-X-OAc (ABX precursor) and Boc-alpha Man-beta Gal-OAc (ABB precursor)A driver);
or 5) to prepare the resulting compounds AXX and β Glu-OAc-N3(C) Dissolving in a mixed solvent of tert-butyl alcohol and water, adding copper sulfate pentahydrate and sodium ascorbate, stirring uniformly, reacting, filtering after the reaction is finished, and purifying to obtain a colorless viscous product, namely a compound Boc-alpha Man-beta Glu-OAc (ACC precursor);
or 6) preparing the obtained ABX precursor and beta Glu-OAc-N3(C) Dissolving in a mixed solvent of tert-butyl alcohol and water, adding copper sulfate pentahydrate and sodium ascorbate, stirring uniformly, reacting, filtering after the reaction is finished, and purifying to obtain a colorless viscous product, namely the compound Boc-alpha Man-beta Gal-beta Glu-OAc (ABC precursor).
Further, in the step (3), the reaction is carried out at room temperature for 3 hours.
Further, in step (4), 2mL of trifluoroacetic acid was added for every 1mmol of precursor compound.
Further, in the step (4), the reaction process specifically comprises: stirring was carried out at 0 ℃ for 1h, and then the reaction was continued at room temperature for 3 h.
According to the invention, through the characteristics of gradient CuAAC click chemistry, simplicity and high efficiency, diversified target glycosamine can be realized, and meanwhile, the glycosamine can be utilized to synthesize the glycosamine with controllable molecular weight, and the glycosyl components have definite density and order on the whole framework, so that the factors influencing the specificity recognition of the carbohydrate-containing polymer can be researched in a targeted manner. The method is simple, efficient and convenient to operate, and provides a method for preparing the dendronized glycosylamine capable of being used for post-polymerization modification by simultaneously introducing three glycosyl groups on the terminal alkyne.
In the invention, di-tert-butyl dicarbonate (Diboc) is firstly used for reacting with Trihydroxymethylaminomethane (THAM), tertiary butyloxycarbonyl is used for protecting amino in the Trihydroxymethylaminomethane (THAM), and then Williamson ether-forming reaction is used for introducing alkyne with three ends at the end of the compound. Then the terminal alkyne and acetyl protected azido sugar are subjected to gradient CuAAC reaction, and finally trifluoroacetic acid is used for removing Boc group protection, so that the reaction can be effectively carried out in each step, the post-treatment is easy, high yield is obtained, and each reaction step needs to be carried out according to the process condition of the reaction process. The method utilizes the advantages of CuAAC click chemistry, provides a simple and quick way for synthesizing the heterogeneous sugar amine containing multiple glycosyl groups, and has important guiding significance for preparing the multifunctional heterogeneous sugar-containing polymer with ordered structure and controllable molecular weight.
Compared with the prior art, the invention has the following advantages:
1. the method utilizes the gradient CuAAC reaction for the first time, and prepares the dendronized glycosylamine containing three glycosyl groups simply and efficiently.
2. The dendronized glycosylamine synthesized by the invention is suitable for post-modification of a polymer skeleton containing pentafluorophenol ester to prepare a biological functional polymer, and can also be used for post-modification of other polymers containing active lipid groups.
3. The method for preparing the dendronized glucosamine can also be suitable for preparing other functional materials, such as silicon-containing materials, fluorine-containing materials and the like.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of the compound Boc- α Man- α Man-OAc (4, AAA precursor);
FIG. 2 is a nuclear magnetic carbon spectrum of the compound Boc- α Man- α Man-OAc (4, AAA precursor);
FIG. 3 is a nuclear magnetic hydrogen spectrum of the compound Boc- α Man- α Man-yne-OAc (5, AAX precursor);
FIG. 4 is a nuclear magnetic carbon spectrum of the compound Boc- α Man- α Man-yne-OAc (5, AAX precursor);
FIG. 5 is a nuclear magnetic hydrogen spectrum of the compound Boc- α Man-yne-yne-OAc (6, AXX precursor);
FIG. 6 is a nuclear magnetic carbon spectrum of the compound Boc- α Man-yne-yne-OAc (6, AXX precursor);
FIG. 7 is a nuclear magnetic hydrogen spectrum of the compound Boc- α Man- α Man- β Gal-OAc (7, AAB precursor);
FIG. 8 is a nuclear magnetic carbon spectrum of the compound Boc- α Man- α Man- β Gal-OAc (7, AAB precursor);
FIG. 9 is a nuclear magnetic hydrogen spectrum of the compound Boc- α Man- α Man- β Glu-OAc (8, AAC precursor);
FIG. 10 is a nuclear magnetic carbon spectrum of the compound Boc- α Man- α Man- β Glu-OAc (8, AAC precursor);
FIG. 11 is a nuclear magnetic hydrogen spectrum of the compound Boc- α Man- β Gal-X-OAc (9, ABX precursor);
FIG. 12 is a nuclear magnetic carbon spectrum of the compound Boc- α Man- β Gal-X-OAc (9, ABX precursor);
FIG. 13 is a nuclear magnetic hydrogen spectrum of the compound Boc- α Man- β Gal- β Gal-OAc (11, ABB precursor);
FIG. 14 is a nuclear magnetic carbon spectrum of the compound Boc- α Man- β Gal- β Gal-OAc (11, ABB precursor);
FIG. 15 is a nuclear magnetic hydrogen spectrum of the compound Boc- α Man- β Gal- β Glu-OAc (10, ABC precursor);
FIG. 16 is a nuclear magnetic carbon spectrum of the compound Boc- α Man- β Gal- β Glu-OAc (10, ABC precursor);
FIG. 17 is a nuclear magnetic hydrogen spectrum of the compound Boc- α Man- β Glu- β Glu-OAc (12, ACC precursor);
FIG. 18 is a nuclear magnetic carbon spectrum of the compound Boc- α Man- β Glu- β Glu-OAc (12, ACC precursor);
FIG. 19 is compound NH2-nuclear magnetic hydrogen spectrum of α Man-OAc (13, AAA);
FIG. 20 is Compound NH2-nuclear magnetic carbon spectrum of α Man-OAc (13, AAA);
FIG. 21 is Compound NH2-nuclear magnetic hydrogen spectrum of α Man- β Gal-OAc (14, AAB);
FIG. 22 is Compound NH2-nuclear magnetic carbon spectrum of α Man- β Gal-OAc (14, AAB);
FIG. 23 is compound NH2-nuclear magnetic hydrogen spectrum of α Man- β Glu-OAc (15, AAC);
FIG. 24 is compound NH2-nuclear magnetic carbon spectrum of α Man- β Glu-OAc (15, AAC);
FIG. 25 is Compound NH2-nuclear magnetic hydrogen spectrum of α Man- β Gal-OAc (16, ABB);
FIG. 26 is Compound NH2-nuclear magnetic carbon spectrum of α Man- β Gal-OAc (16, ABB);
FIG. 27 is Compound NH2-αMan-βGlu-βNuclear magnetic hydrogen spectrum of Glu-OAc (17, ACC);
FIG. 28 is Compound NH2-nuclear magnetic carbon spectrum of α Man- β Glu-OAc (17, ACC);
FIG. 29 is Compound NH2-nuclear magnetic hydrogen spectrum of α Man- β Gal- β Glu-OAc (18, ABC);
FIG. 30 is Compound NH2-nuclear magnetic carbon spectrum of α Man- β Gal- β Glu-OAc (18, ABC);
FIG. 31 is compound NH2-nuclear magnetic hydrogen spectrum of α Man-yne-OAc (19, AAX);
FIG. 32 is compound NH2-nuclear magnetic carbon spectrum of α Man-yne-OAc (19, AAX);
FIG. 33 is Compound NH2-nuclear magnetic hydrogen spectrum of α Man-yne-yne-OAc (20, AXX);
FIG. 34 is Compound NH2-nuclear magnetic carbon spectrum of α Man-yne-yne-OAc (20, AXX);
FIG. 35 is a flow chart of a process for preparing a precursor compound;
FIG. 36 is a process diagram for the preparation of dendrimeric glycosylamines with multiple sugars.
Detailed Description
The invention is described in detail below with reference to the figures and specific embodiments. The present embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation manner and a specific operation process are given, but the scope of the present invention is not limited to the following embodiments.
In the following examples, the reagents used are as follows:
three azido sugars (. alpha.Man-OAc-N)3、βGal-OAc-N3、βGlu-OAc-N3) Synthesized according to the methods of the following two documents; tris (hydroxymethyl) aminomethane, a product of Hakka Adama reagent, Inc.; di-tert-butyl dicarbonate, a product of Hakka Adama reagents, Inc.; propargyl bromide, a product of Hakka Adama reagent, Inc.; copper sulfate pentahydrate, product of Hainan Hadamard reagent, Inc; sodium ascorbate, a product of Hakka Adama reagents, Inc.; potassium hydroxide, a product of shanghai hadamard reagents ltd; d-glucose, USAProducts of Aldrich company; d-mannose, a product of Aldrich, USA; d-galactose, a product of Aldrich, USA; all other raw materials are commercially available analytical reagents, wherein anhydrous methanol, anhydrous Dichloromethane (DCM) and anhydrous N, N-Dimethylformamide (DMF) (containing molecular sieve, water content is less than or equal to 0.05%) are all purchased from Shanghai Michelin Biochemical Co., Ltd. Among them, reference 1 is a. bianchiand a. bernardi, j.org.chem.,2006,71, 4565-; document 2 is V.Percec, P.Leowanawat, H.J.Sun, O.Kulikov, C.D.Nusbaum, T.M.Tran, A.Bertin, D.A.Wilson, M.Peterca, S.Zhang, N.P.Kamat, K.Vargo, D.Moock, E.D.Johnston, D.A.Hammer, D.J.Pochan, Y.Chen, Y.M.Charre, T.C.Shiao, M.Bergeron-Brlek, S.Andre, R.Roy, H.J.Gabius and P.A.Heiney, J.Am.Chem.Soc.,2013,135, 55.9077.9077.
The preparation of dendrimeric sugar amines containing multiple sugars is carried out according to the preparation process schemes as shown in fig. 35 and 36.
Example 1
1. Synthesis of Compound 2
A solution of di-tert-butyl dicarbonate (23.4g,107.3mmol) in t-BuOH (100mL) was added to a solution of tris (hydroxymethyl) aminomethane (i.e., Compound 1, 10.0g, 82.6mmol) in MeOH/t-BuOH (MeOH,75 mL; t-BuOH,75mL) at room temperature, followed by reaction for 18h at room temperature. The solvent was removed by rotary evaporation of the reaction solution, and the residue was recrystallized from ethyl acetate, vacuum filtered and dried to obtain a white powdery product (16.4g, yield 90%) protected with Boc group, which was Compound 2.
1H NMR(500MHz,DMSO-d6):δ＝5.71(s,1H),4.55(s,3H,OH),3.46(s,6H),1.31(s,9H).
2. Synthesis of Compound 3
The product compound 2(10.0g,45.2mmol) was dissolved in 50mL of DMF and stirred at 0 deg.C for 10min, 3-bromopropyne (11.0mL,140.1mmol) was added dropwise, followed by powdered potassium hydroxide (7.9g,140.1mmol) and stirring continued at 0 deg.C for 1 h. The reaction was then allowed to warm to room temperature for 18 h. TLC (PE: EA: 6:1, R)f0.55), the reaction mixture was diluted with 100mL of ethyl acetate and washed with water (3 × 50 mL). Drying the organic phase with anhydrous sodium sulfate, filtering, removing the solvent by rotary evaporation,the product was obtained as a yellow oil (9.9g, yield 65%) by silica gel column chromatography (PE: EA ═ 9:1), which was compound 3.
1H NMR(500MHz,CDCl3):δ＝4.89(s,1H),4.11(d,J＝2.0Hz,6H),3.74(s,6H),2.41(t,J＝2.0Hz,3H),1.39(s,9H).
3. Synthesis of Compounds Boc- α Man- α Man- α Man-OAc (i.e., Compound 4, AAA), Boc- α Man- α Man-yne-OAc (i.e., Compound 5, AAX) and Boc- α Man-yne-yne-OAc (i.e., Compound 6, AXX)
Compound 3(4.4g,13.1mmol) and azidomannose (. alpha.Man-OAc-N)3I.e., azido sugar A) (4.9g,13.1mmol) was dissolved in t-BuOH/H2O (60mL,1:1v/v), and copper sulfate pentahydrate (1.3g,5.3mmol) and sodium ascorbate (2.1g,10.5mmol) were added sequentially. The reaction was stirred at room temperature for 3h, TLC (PE: EA: 1:2, Compound 11R)f0.5; compound 12, Rf0.25; compound 13, Rf= 0.7) and after completion of the reaction, dichloromethane 100mL was added to dilute the reaction solution, and the reaction solution was washed with water (2 × 50mL) and saturated brine (2 × 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was removed by rotary evaporation, and the colorless oily products Boc- α Man-OAc (compound 4, AAA precursor) (2.7g, 42%), Boc- α Man-yne-OAc (compound 5, AAX precursor) (2.2g, 30%) and Boc- α Man-yne-yne-OAc (compound 6, AXX precursor) (1.6g, 17%) were obtained by silica gel column chromatography (PE: EA ═ 6:1-1: 4).
Wherein, the nuclear magnetic hydrogen spectrogram and the nuclear magnetic carbon spectrogram of the prepared compound 4, compound 5 and compound 6 are respectively shown in figures 1 to 6.
Boc- α Man- α Man- α Man-OAc (Compound 4, AAA precursor)1H NMR(500MHz,CDCl3):δ＝7.80(s,3H),6.05(d,J＝2.5Hz,3H),5.94–5.90(m,6H),5.38(t,J＝9.0Hz,3H),5.01(s,1H),4.63(d,J＝3.5Hz,6H),4.35(dd,J＝12.5,5.0Hz,3H),4.06(dd,J＝12.5,2.5Hz,3H),3.92–3.88(m,3H),3.76(s,6H),2.17(s,9H),2.07(s,9H),2.05(s,9H),2.03(s,9H),1.39(s,9H).13C NMR(125MHz,CDCl3):δ＝170.77,170.19,169.37,169.33,169.17,145.08,123.18,83.34,71.68,68.88,68.60,67.85,65.64,64.11,61.31,60.01,58.15,28.01,20.63,20.31,20.18,13.85.HRMS(ESI):m/z calc.for C60H82N10O32Na[M+Na]+:1477.49888；found:1477.49884.
Boc- α Man- α Man-yne-OAc (Compound 5, AAX precursor)1H NMR(500MHz,CDCl3):δ＝7.77(d,J＝2.5Hz,2H),6.02(s,2H),5.95–5.90(m,4H),5.38(t,J＝8.5Hz,2H),4.97(s,1H),4.67(s,4H),4.36(dd,J＝12.5,5.0Hz,2H),4.12(d,J＝2.0Hz,2H),4.06(dd,J＝12.5,2.5Hz,2H),3.93–3.88(m,2H),3.77(d,J＝7.5Hz,6H),2.46(t,J＝2.5Hz,1H),2.17(s,6H),2.08(s,6H),2.05(s,6H),2.03(s,6H),1.40(s,9H).13C NMR(125MHz,CDCl3):δ＝170.29,169.47,169.22,154.56,145.40,123.03,83.39,79.47,79.04,74.89,71.84,69.12,68.66,68.02,65.79,64.41,61.38,60.13,58.36,58.11,28.14,20.79,20.46,20.34,13.99.HRMS(ESI):m/z calc.for C46H63N7O23Na[M+Na]+:1104.38675；found:1104.38669.
Boc-alpha Man-yne-yne-OAc (Compound 6, AXX precursor)1H NMR(500MHz,CDCl3):δ＝7.76(s,1H),5.99(d,J＝2.0Hz,1H),5.96–5.91(m,2H),5.37(t,J＝9.0Hz,1H),4.94(s,1H),4.70(s,2H),4.36(dd,J＝12.5,5.0Hz,1H),4.14–4.12(m,4H),4.06(dd,J＝12.5,2.5Hz,1H),3.93–3.88(m,1H),3.78(d,J＝3.9Hz,6H),2.44(s,2H),2.18(s,3H),2.08(s,3H),2.05(s,3H),2.04(s,3H),1.41(s,9H).13C NMR(125MHz,CDCl3):δ＝170.43,169.63,169.59,169.29,154.68,145.82,122.91,83.48,79.57,79.22,74.85,72.02,69.36,68.75,68.25,65.94,64.75,61.47,58.54,58.11,28.28,20.62,20.51.HRMS(ESI):m/z calc.for C32H44N4O14Na[M+Na]+:731.27462；found:731.27458.
Example 2
1. Compounds 2-6 were synthesized as in example 1;
2. synthesis of Compound Boc- α Man- α Man- β Gal-OAc (Compound 7, AAB precursor)
With compound 5(0.5g,0.4mmol) and azidogalactose (. beta. Gal-OAc-N3I.e., azido sugar B) (0.2g,0.5mmol) was synthesized in the same manner as in compounds 4, 5 and 6 (except for AAX precursor,. beta.Gal-OAc-N3The mole ratio of the copper sulfate pentahydrate to the sodium ascorbateExample roughly adjusted to 1.0:1.1:0.5:1.0) Boc- α Man- β Gal-OAc (compound 7, AAB precursor) (0.58g, 91%) was prepared as a colorless oil by silica gel column chromatography (PE: EA ═ 1:3) (PE: EA ═ 1:4, R: 1.0)f＝0.47)。
The nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum of the obtained compound 7 are shown in FIGS. 7 and 8.
1H NMR(500MHz,CDCl3):δ＝7.86(s,1H),7.81(d,J＝6.0Hz,2H),6.09(s,2H),5.94(d,J＝6.5Hz,4H),5.89(d,J＝9.5Hz,1H),5.58(t,J＝10.0Hz,1H),5.54(d,J＝3.0Hz,1H),5.40(t,J＝9.0Hz,2H),5.31–5.28(m,1H),5.00(s,1H),4.64(t,J＝6.5Hz,6H),4.35(dd,J＝12.5,5.0Hz,2H),4.28(d,J＝6.5Hz,1H),4.17–4.10(m,2H),4.06(d,J＝12.5Hz,2H),3.93–3.91(m,2H),3.81–3.74(m,4H),3.67(dd,J＝24.0,9.0Hz,2H),2.20(d,J＝10.0Hz,9H),2.08(s,7H),2.05(s,6H),2.03(s,7H),2.02(s,3H),2.00(s,4H),1.40(s,9H).13C NMR(125MHz,CDCl3):δ＝170.32,170.15,169.93,169.59,169.54,169.49,169.30,168.99,154.61,145.37,144.89,123.19,121.63,85.67,83.53,79.02,73.65,71.83,70.61,69.20,68.76,68.14,67.70,66.95,65.75,64.45,64.08,61.47,61.13,58.27,53.52,28.19,20.57,20.49,20.45,20.38,20.31,19.93.HRMS(ESI):m/z calc.for C60H82N10O32Na[M+Na]+:1477.49888；found:1477.49883.
3. Synthesis of Compound Boc-alpha Man-beta Glu-OAc (Compound 8, AAC precursor)
With compound 5(0.5g,0.4mmol) and azidoglucose (. beta.Glu-OAc-N)3) (C) (0.2g,0.5mmol) in the same manner as in Compounds 4, 5 and 6 (except for AAX precursor,. beta.Glu-OAc-N)3The molar ratio of copper sulfate pentahydrate to sodium ascorbate was adjusted to approximately 1.0:1.1:0.5:1.0) and Boc- α Man- β Glu-OAc (compound 8, AAC precursor) (0.63g, 92%) was obtained as a colorless oil by silica gel column chromatography (PE: EA ═ 1:3) (PE: EA ═ 1:4, R ═ 1:4)f＝0.47)。
The nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum of the obtained compound 8 are shown in FIGS. 9 and 10.
1H NMR(500MHz,CDCl3):δ＝7.83(s,1H),7.81(d,J＝6.0Hz,2H),6.08(t,J＝2.5Hz,2H),5.96–5.90(m,5H),5.48(dd,J＝19.5,9.5Hz,2H),5.40(t,J＝9.0Hz,2H),5.24(t,J＝9.5Hz,1H),4.99(s,1H),4.68–4.59(m,6H),4.35(dd,J＝12.5,5.0Hz,2H),4.29(dd,J＝12.5,5.0Hz,1H),4.14(d,J＝13.0Hz,1H),4.06(d,J＝11.0Hz,3H),3.93–3.90(m,2H),3.80–3.73(m,8H),3.68(dd,J＝18.0,9.0Hz,2H),2.19(s,6H),2.08–2.01(m,30H),1.39(s,9H).13C NMR(125MHz,CDCl3):δ＝170.38,169.77,169.60,169.54,169.34,169.29,168.89,154.65,145.42,145.08,123.16,121.58,85.25,83.58,79.10,74.73,72.51,71.88,70.09,69.24,68.78,68.18,67.67,65.80,64.47,64.15,61.51,58.29,53.53,28.23,20.62,20.54,20.43,20.37,19.89.HRMS(ESI):m/z calc.for C60H82N10O32Na[M+Na]+:1477.49888；found:1477.49886.
Example 3
1. Compounds 2-6 were synthesized as in example 1.
2. Synthesis of Compounds Boc- α Man- β Gal-yne-OAc (Compound 9, AAB precursor) and Boc- α Man- β Gal- β Gal-OAc (Compound 11, ABB precursor)
With compound 6(0.8g,1.1mmol) and azidogalactose (. beta. Gal-OAc-N3) (B) (0.3g,0.8mmol) in the same manner as in the case of the compounds 4, 5 and 6 (AXX precursor,. beta.Gal-OAc-N)3(B) The molar ratio of copper sulfate pentahydrate to sodium ascorbate was adjusted to approximately 1.5:1.0:0.5:1.0) and Boc- α Man- β Gal-OAc (compound 11, ABB precursor) (0.21g, 39%) was prepared as colorless oils by silica gel column chromatography (PE: EA ═ 1:4) to yield Boc- α Man- β Gal-yne-OAc (compound 9, ABX precursor) (0.47g, 58%) and Boc- α Man- β Gal-OAc (compound 11, ABB precursor) (PE: EA ═ 1:2, compound 9, R ═ 1:2, compound 9, and R ═ 1:4)f0.4; compound 11, Rf＝0.12)。
The nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum of the prepared compound 9 and compound 11 are shown in fig. 11 to 14.
Boc-alpha Man-beta Gal-yne-OAc (Compound 9, ABX precursor)1H NMR(500MHz,CDCl3):δ＝7.85(d,J＝4.0Hz,1H),7.81(s,1H),6.07(d,J＝8.5Hz,1H),5.98–5.94(m,2H),5.86(d,J＝9.0Hz,1H),5.60–5.54(m,2H),5.40(t,J＝9.0Hz,1H),5.27(dd,J＝10.0,3.0Hz,1H),4.98(s,1H),4.68–4.62(m,4H),4.35(dd,J＝12.5,5.0Hz,1H),4.26(t,J＝6.5Hz,1H),4.21–4.14(m,2H),4.14–4.12(m,2H),4.06(d,J＝12.5Hz,1H),3.93(d,J＝9.0Hz,1H),3.76(m,6H),2.46(d,J＝2.5Hz,1H),2.21(d,J＝10.0Hz,6H),2.09(s,3H),2.06–2.03(m,12H),2.00(s,3H),1.41(s,9H).13C NMR(125MHz,CDCl3):δ＝170.49,170.31,170.02,169.76,169.64,169.42,169.11,154.76,145.70,145.37,123.18,121.40,85.99,83.64,79.68,79.22,74.87,73.91,71.99,70.76,69.49,68.86,68.36,67.82,67.01,65.90,64.73,64.47,61.59,61.24,58.53,58.29,53.56,29.61,28.33,20.75,20.65,20.61,20.55,20.46,20.13.HRMS(ESI):m/z calc.for C46H63N7O23Na[M+Na]+:1104.38675；found:1104.38671.
Boc- α Man- β Gal- β Gal-OAc (Compound 11, ABB precursor)1H NMR(500MHz,CDCl3):δ＝7.87(d,J＝6.0Hz,2H),7.84(s,1H),6.12(s,1H),5.98–5.95(m,2H),5.90(dd,J＝9.5,4.0Hz,2H),5.60(td,J＝10.0,3.5Hz,2H),5.55(d,J＝3.0Hz,2H),5.43(t,J＝9.5Hz,1H),5.29(dt,J＝10.5,3.5Hz,2H),5.02(s,1H),4.67–4.60(m,6H),4.37–4.33(m,1H),4.28(d,J＝6.0Hz,2H),4.20–4.14(m 4H),4.07(d,J＝12.5Hz,1H),3.95–3.92(m,1H),3.80–3.70(m,6H),2.21(d,J＝6.0Hz,9H),2.10–1.99(m,29H),1.41(s,9H).13C NMR(125MHz,CDCl3):δ＝170.61,170.43,170.16,169.92,169.87,169.75,169.59,169.15,154.90,145.66,145.37,123.45,121.74,121.68,86.06,83.85,73.94,72.04,70.90,69.67,69.28,69.03,68.51,67.95,67.05,65.95,64.77,64.56,61.74,61.25,58.52,28.45,20.74,20.64,20.57,20.22,20.19.HRMS(ESI):m/z calc.for C60H82N10O32Na[M+Na]+:1477.49888；found:1477.49885.
3. Synthesis of compound Boc-alpha Man-beta Gal-beta Glu-OAc (Compound 10, ABC precursor)
Using compound 9(0.3g,0.3mmol) and azidoglucose (. beta.Glu-OAc-N3) (c) (0.1g,0.3mmol), the same procedures as those for compounds 4, 5 and 6 were followed (except for ABX precursor and. beta.Glu-OAc-N)3(C) The molar ratio of copper sulfate pentahydrate to sodium ascorbate was adjusted to approximately 1.0:1.1:0.5:1.0) and Boc- α Man- β Ga was prepared as a colorless oil by silica gel column chromatography (PE: EA ═ 1: 2-1: 3)l- β Glu-OAc (compound 10, ABC precursor) (0.35g, 87%) (PE: EA ═ 1:4, Rf ═ 0.45).
The nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum of the prepared compound 10 are shown in fig. 15 and fig. 16.
1H NMR(500MHz,CDCl3):δ＝7.91(s,1H),7.86(d,J＝4.5Hz,1H),7.82(s,1H),6.11(s,1H),5.94(m,4H),5.60(td,J＝10.0,3.0Hz,1H),5.55(s,1H),5.52(d,J＝9.5Hz,1H),5.46–5.41(m,2H),5.33–5.28(m,2H),4.99(s,1H),4.66–4.60(m,6H),4.38–4.33(m,1H),4.32–4.29(m,2H),4.21–4.12(m,3H),4.07(dd,J＝12.5,2.0Hz,2H),3.95–3.91(m,1H),3.83–3.79(m,1H),3.73(dd,J＝18.5,9.0Hz,5H),2.21(d,J＝7.0Hz,6H),2.10–2.00(m,30H),1.40(s,9H).13C NMR(125MHz,CDCl3):δ＝170.64,170.46,170.19,170.08,169.94,169.89,169.79,169.59,169.24,169.00,154.94,145.76,145.69,145.65,145.42,123.38,121.66,86.09,85.69,83.88,75.12,73.96,72.87,72.09,70.94,70.38,69.71,69.46,69.05,68.54,67.92,67.11,66.02,64.83,64.54,61.77,61.26,58.56,28.48,20.91,20.78,20.68,20.62,20.26,20.24,20.19,20.16.HRMS(ESI):m/z calc.for C60H82N10O32Na[M+Na]+:1477.49888；found:1477.49881.
Example 4
1. Compounds 2-6 were synthesized as in example 1.
2. Synthesis of Compound Boc- α Man- β Glu- β Glu-OAc (Compound 12, ACC precursor)
With compound 6(0.5g,0.4mmol) and azidoglucose (. beta.Glu-OAc-N)3) (c) (0.2g,0.5mmol) in the same manner as in Compounds 4, 5 and 6 (except for AXX precursor,. beta.Glu-OAc-N3(C) Copper sulfate pentahydrate and sodium ascorbate in a molar ratio of 1.0:2.1:0.5:1.0) were subjected to silica gel column chromatography (PE: EA ═ 1:4) to give Boc- α Man- β Glu-OAc (compound 12, ACC precursor) (0.6g, 91%) as a colorless oil (PE: EA ═ 1:4, R ═ 1 ═ 91%) (PE: EA ═ 1:4, R%f＝0.47)。
The nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum of the prepared compound 12 are shown in figures 17 and 18.
1H NMR(500MHz,CDCl3):δ＝7.86(s,1H),7.81(d,J＝6.0Hz,2H),6.09(s,2H),5.94(d,J＝6.5Hz,4H),5.89(d,J＝9.5Hz,1H),5.58(t,J＝10.0Hz,1H),5.54(d,J＝3.0Hz,1H),5.40(t,J＝9.0Hz,2H),5.31–5.28(m,1H),5.00(s,1H),4.64(t,J＝6.5Hz,6H),4.35(dd,J＝12.5,5.0Hz,2H),4.28(d,J＝6.5Hz,1H),4.17–4.10(m,2H),4.06(d,J＝12.5Hz,2H),3.93–3.91(m,2H),3.81–3.74(m,4H),3.67(dd,J＝24.0,9.0Hz,2H),2.20(d,J＝10.0Hz,9H),2.08(s,7H),2.05(s,6H),2.03(s,7H),2.02(s,3H),2.00(s,4H),1.40(s,9H).13C NMR(125MHz,CDCl3):δ＝170.32,170.15,169.93,169.59,169.54,169.49,169.30,168.99,154.61,145.37,144.89,123.19,121.63,85.67,83.53,79.02,73.65,71.83,70.61,69.20,68.76,68.14,67.70,66.95,65.75,64.45,64.08,61.47,61.13,58.27,53.52,28.19,20.57,20.49,20.45,20.38,20.31,19.93.HRMS(ESI):m/z calc.for C60H82N10O32Na[M+Na]+:1477.49888；found:1477.49883.
Example 5
1. Synthesis of Compounds 2-6 as in example 1, and Compounds 7, 8, 10-12 as in examples 2-4.
2. Synthesis of Compounds 4-8 and 10-12
Trifluoroacetic acid (0.6mL) in DCM (0.6mL) was added dropwise to a solution of compounds 4-8 and 10-12(0.3mmol) in DCM (1mL) at 0 ℃ and stirred, the reaction was stirred at 0 ℃ for 1h, then continued at room temperature for 3h, the reaction was concentrated to dryness after TLC (DCM/MeOH ═ 10:1) detection of completion, the residue was redissolved in DCM (20mL) and saturated NaHCO was used3The solution (2 × 20mL) was washed then with H2Wash with O (2 × 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the solvent removed by rotary evaporation to yield the desired product compound 13-20 (94% -98% yield).
The nuclear magnetic hydrogen spectra and nuclear magnetic carbon spectra of compounds 13 to 20 are shown in fig. 19 to 34, respectively.
The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.

Claims (10)

1. A method for synthesizing dendronized glycosylamines containing multiple sugars by utilizing gradient click chemistry is characterized by comprising the following steps of:
(1) dissolving tris (hydroxymethyl) aminomethane in a mixed solvent of methanol and tert-butyl alcohol, adding a tert-butyl alcohol solution of di-tert-butyl dicarbonate for reaction, and purifying after the reaction is finished to obtain a white powdery product, namely a compound 2;
(2) dissolving the compound 2 in N, N-dimethylformamide, dropwise adding 3-bromopropyne, stirring, adding potassium hydroxide powder, continuing to react, and washing, drying and purifying after the reaction is finished to obtain a light yellow oily product, namely a compound 3;
(3) dissolving the compound 3 and azido sugar in a mixed solvent of tert-butyl alcohol and water, adding copper sulfate pentahydrate and sodium ascorbate, uniformly stirring, reacting, filtering after the reaction is finished, and purifying to obtain a colorless viscous product, namely a precursor compound;
(4) and dissolving the precursor compound in a dichloromethane solution, dropwise adding a dichloromethane solution of trifluoroacetic acid in an ice bath, washing after the reaction is finished, drying, filtering and concentrating to obtain a colorless viscous compound, namely the target product.
2. The method for synthesizing the branched sugar amine containing multiple sugars by using the gradient click chemistry as claimed in claim 1, wherein in the step (1), the molar ratio of the tris (hydroxymethyl) aminomethane to the di-tert-butyl dicarbonate is 1: 1.3;
the reaction process is as follows: the reaction was carried out at room temperature for 18 h.
3. The method for synthesizing the dendrimeric glycoamines containing a plurality of sugars according to the claim 1, wherein in the step (2), the molar ratio of the compound 2, the 3-bromopropyne and the potassium hydroxide is 1.0:3.1: 3.1;
the reaction process is as follows: dropwise adding 3-bromopropyne under the condition of keeping the temperature of 0 ℃ in an ice bath, stirring to react for 10min, adding potassium hydroxide powder, reacting for 30min at the temperature of 0 ℃, and continuing to react for 18h at room temperature.
4. The method for synthesizing branched glycosylamines with multiple sugars by using gradient click chemistry as claimed in claim 1, wherein in step (2), the washing process is performed by using ethyl acetate/water, wherein the volume ratio of N, N-dimethylformamide to ethyl acetate to water is 1:2.5:2.5, and simultaneously, the drying process is performed by using anhydrous sodium sulfate, the molar ratio of anhydrous sodium sulfate to ethyl acetate is 11:1, and the purification process is performed by using column chromatography.
5. The method for synthesizing branched glycosylamines with multiple sugars using gradient click chemistry as claimed in claim 1, wherein in step (3), the molar ratio of compound 3, azido sugar, copper sulfate pentahydrate and sodium ascorbate is (1.0-1.5): (1.0-2.1): (0.4-0.5): (0.8-1.0).
6. The method for synthesizing dendrimeric sugar amines containing multiple sugars according to the claim 1, wherein in the step (3), the azido sugar is R-OAc-N3Wherein, R is one or more of alpha Man-, beta Glu-or beta Gal-.
7. The method for synthesizing dendrimeric sugar amines containing multiple sugars according to the claim 6, wherein the obtained colorless viscous product is further substituted for the compound 3 to repeat the reaction in the step (3) to obtain the precursor compound.
8. The method for synthesizing branched glycosylamines containing multiple sugars according to claim 1, wherein the reaction in step (3) is performed at room temperature for 3 h.
9. The method for synthesizing branched glycosylamines with multiple sugars using gradient click chemistry as claimed in claim 1, wherein 2mL of trifluoroacetic acid is added for every 1mmol of precursor compound in step (4).
10. The method for synthesizing the dendrimeric glycoamines containing a plurality of sugars by using the gradient click chemistry as claimed in claim 1, wherein in the step (4), the reaction process specifically comprises: stirring was carried out at 0 ℃ for 1h, and then the reaction was continued at room temperature for 3 h.
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Application publication date: 20210312