CN117567525A - Method for synthesizing N-glycoside by using unprotected sugar - Google Patents

Method for synthesizing N-glycoside by using unprotected sugar Download PDF

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CN117567525A
CN117567525A CN202311554074.5A CN202311554074A CN117567525A CN 117567525 A CN117567525 A CN 117567525A CN 202311554074 A CN202311554074 A CN 202311554074A CN 117567525 A CN117567525 A CN 117567525A
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water
reaction
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dioxane
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李微
余秋涵
杨旭东
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China Pharmaceutical University
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China Pharmaceutical University
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to the technical field of chemical synthesis, in particular to a method for synthesizing N-glycoside by using unprotected sugar, which is characterized in that unprotected glycosyl donor, acceptor and alkali are dissolved in water or a mixed solvent of water and an organic solvent at the temperature of-78 ℃ to 25 ℃ and an accelerator is added for reaction to obtain corresponding glycoside. The method avoids complex operation of upper and lower protecting groups, has high stereoselectivity of products of glycosylation reaction, and greatly reduces complexity and synthesis cost of glycosylation synthesis operation.

Description

Method for synthesizing N-glycoside by using unprotected sugar
Technical Field
The invention relates to chemical synthesis, in particular to a method for synthesizing N-glycoside by using unprotected sugar.
Background
Sugars, also known as carbohydrates, are associated with proteins, nucleic acids and lipids and are known as four important classes of biological macromolecules during life activities. They are widely distributed in plants, animals, microorganisms and viruses. Saccharides are in the form of monosaccharides, oligosaccharides, polysaccharides and saccharide conjugates. Currently, there are two main methods for in vitro synthesis of sugar: enzymatic synthesis and chemical synthesis. Although enzymatic synthesis has the advantages of mild reaction, good regioselectivity and stereoselectivity, the required glycosyltransferases and glycosidases are relatively expensive, and in addition, the enzyme has poor acceptance of unnatural or abnormal substrates. Thus, chemical synthesis of sugar is indispensable. However, there are a number of drawbacks to the current glycosylation methods. To date, no glycosylation method has been generally applicable to the synthesis of all oligosaccharides. Furthermore, in the existing glycosylation synthesis, a large number of experimental operations involving the upper protecting group and deprotection group are involved, and the prolonged steps of the synthesis operation also increase the complexity of the synthesis. It is therefore of great interest to develop new unprotected sugars for one-pot glycosylation in the aqueous phase.
2-chloro-1, 3-dimethylimidazoline chloride (DMC), developed by Isobe and Ishikawathey in the late 1990's as a dehydration reagent capable of replacing DCC. In 2009, shoda et al introduced DMC for the first time into the carbohydrate domain and revealed its ability to selectively activate unprotected sugar anomeric hydroxyl groups in aqueous solution. Heretofore, DMC has been successfully applied to the synthesis of glycosyloxazolines, the production of 1, 6-anhydrous sugar, the synthesis of glycosylazides, glycosylthiols and the like, but no report has been made on N-glycoside.
Disclosure of Invention
Object of the Invention
In view of the above-mentioned deficiencies of the prior art, it is an object of the present invention to provide a method for the unprotected-sugar synthesis of N-glycosylation mediated by DMC and its analogues.
Technical proposal
A method for synthesizing N-glycoside by using unprotected sugar is characterized in that unprotected glycosyl donor, acceptor and alkali are dissolved in water or a mixed solvent of water and an organic solvent at the temperature of-78 ℃ to 25 ℃, and an accelerator is added to react to obtain the corresponding glycoside, and the reaction general formula is as follows:
the glycosyl donor is pyranose, furanose, disaccharide, polysaccharide or sugar structural analogue;
the receptor is an azacyclic compound or organic ammonia;
the base is triethylamine or DIPEA;
the accelerator is selected from any one of the following structures:
the method is characterized in that,
pyranose is ribose, arabinose or 2-deoxyribose;
the furanose is glucose, galactose, mannose, fucose, xylose, arabinose, N-acetamido glucose or rhamnose;
disaccharides are lactose, maltose or cellobiose;
the sugar structural analogue is tetrahydro-2H-pyran-2-ol.
The method is characterized in that when the receptor is an azacyclic compound, the receptor is selected from any of the following compounds:
wherein R is 1 Is hydrogen, fluorine, chlorine, bromine, iodine, amino, acetoacetyl, azobenzoyl, NHBoc or N (Boc) 2 ；R 2 In the hydrogen, fluorine, chlorine, bromine, iodine, amino, acetoacetyl, azobenzoyl, NHBoc or N (Boc) 2 ；R 3 Hydrogen, hydroxy, carboxy, methyl formate, nitro, amino, fluoro, chloro, bromo or iodo; r is R 4 Hydrogen, hydroxy, carboxy, methyl formate, nitro, amino, fluoro, chloro, bromo or iodo;
when the acceptor is organic ammonia, the acceptor comprises straight-chain ammonia and aromatic ammonia, wherein the straight-chain ammonia is n-butylamine, and the aromatic ammonia is aniline, p-methylaniline or p-methoxyaniline.
The method is characterized in that the mixed solvent of water and an organic solvent is any one of mixed reagent of water and tetrahydrofuran, mixed reagent of water and 1, 4-dioxane, mixed reagent of water and acetonitrile, mixed reagent of water and DMF, mixed reagent of water and DMSO and mixed reagent of water and acetone.
The method is characterized in that:
the molar ratio of the glycosyl donor to the acceptor is 1:1.1-1:10; the molar ratio of the glycosyl donor to the accelerator is 1:1.5-1:5; the molar ratio of the glycosyl donor to the alkali is 1:5-1:20.
The method is characterized in that: the volume ratio of the mixed solvent of the reaction solvents is 1:0-1:5.
The method is characterized in that: the temperature is-10 ℃.
In some embodiments of the invention, the molar ratio of glycosyl donor to acceptor is 1:1.1 to 1:10, preferably 1:5; the molar ratio of the glycosyl donor to the accelerator is 1:1.5-1:5, preferably 1:3; the molar ratio of the glycosyl donor to the alkali is 1:5-1:20, preferably 1:5-1:10, and most preferably 1:10;
in some embodiments of the present invention, the reaction solvent is any one of water, a mixed reagent of water and tetrahydrofuran, a mixed reagent of water and 1, 4-dioxane, a mixed reagent of water and acetonitrile, a mixed reagent of water and DMF, a mixed reagent of water and DMSO, a mixed reagent of water and acetone, preferably a mixed reagent of water and tetrahydrofuran or a mixed reagent of water and 1, 4-dioxane.
In some embodiments of the present invention, the mixing ratio (volume ratio) of the reaction solvent is preferably V Water and its preparation method ：V Organic reagent =1:0 to 1:1, most preferably V Water and its preparation method ：V Organic reagent ＝1:1；
In some embodiments of the invention, the aqueous phase glycosylation product is subjected to an acetylation step, in view of the ease of subsequent isolation and purification and structural rigidity, characterized in that: dissolving the aqueous phase glycosylation product in anhydrous pyridine at 0 ℃, slowly adding acetic anhydride, reacting overnight at room temperature, washing the reaction liquid with 1N diluted hydrochloric acid, extracting the reaction liquid with EA for three times, combining organic phases, washing the organic phases with water, washing with saturated sodium bicarbonate, washing with brine, drying with anhydrous sodium sulfate, filtering, and purifying by column chromatography.
Further, the molar ratio of the aqueous phase glycosylation product to pyridine is 1:5-1: 30, preferably 1:10; the molar ratio of the aqueous phase glycosylation product to acetic anhydride is 1:4 to 1:20, preferably 1:5.
The following steps were used for screening for further inventors:
1. screening for alkali
Wherein the sugar is D-glucose, the acceptor is 6-chloropurine, the promoter is 1-1, the solvent is water and 1, 4-dioxane (V) Water and its preparation method ：V Organic reagent For example, =1:1) and at-10 ℃, common bases were screened for the following reaction formula:
the alkali type screening results are shown in Table 1.
TABLE 1 alkali species screening
Note that: trace is a yield of less than 5%.
2. Screening the promoter
With sugar as D-glucose, 6-chloropurine as acceptor, triethylamine as base, water and 1, 4-dioxane (V) as reaction solvent at-10deg.C Water and its preparation method ：V Organic reagent For example, =1:1), the accelerators were screened and the reaction formula was as follows:
the screening results are shown in Table 2.
TABLE 2 promoter screening
3. Screening the solvent and the solvent proportion
Taking D-glucose as sugar, 6-chloropurine as acceptor, 1-1 as promoter, triethylamine as base and-10deg.C as examples, selecting solvent and solvent ratio, and reacting with the following formula:
the screening results are shown in Table 3.
TABLE 3 solvent screening
4. Screening the conditions of the reaction temperature
In some embodiments of the invention, the temperature is from-78 ℃ to 25 ℃, preferably from-40 ℃ to-10 ℃, most preferably-10 ℃. Sugar is D-glucose, acceptor is 6-chloropurine, accelerator is compound 1-1, base is triethylamine, and solvent is water and 1, 4-dioxane (V) Water and its preparation method ：V Organic reagent For example, =1:1), the conditions were selected for the reaction temperature, and the reaction formula was as follows:
the screening results are shown in Table 4.
TABLE 4 temperature screening
The beneficial effects are that:
1. the prior art shows that DMC has been successfully applied to the synthesis of glycosyloxazolines, the production of 1, 6-anhydrous sugar, the synthesis of glycosylazides, glycosylthiols and the like, but no literature report of N-glycoside is seen, and particularly the receptor is a nucleotide base. For example, receptors such as purines, where there are multiple sites N, but specific binding to a particular site such as position 9, without the need for protecting groups, is a constant technical difficulty in the art. The invention discovers that DMC can mediate the synthesis of N-glycoside (nucleotide) by unprotected sugar under specific conditions of temperature and alkali for the first time, wherein attention is required to be paid to the fact that N at 9-position of a receptor can be selectively bound instead of N at other positions, and the above-mentioned non-literature report is provided.
2. The invention synthesizes a series of analogues of DMC, which are not reported in literature, belong to novel compounds, can mediate unprotected glycosylation of receptor as base, and can specifically bind to 9-position N of receptor. The method avoids complex operation of upper and lower protecting groups, has high stereoselectivity of products of glycosylation reaction, and greatly reduces complexity and synthesis cost of glycosylation synthesis operation.
Abbreviation form
Boc Boc-group
Bz Benzoyl group
Ac Acetyl group
DCM Dichloromethane (dichloromethane)
PE Petroleum ether
EA Acetic acid ethyl ester
THF Tetrahydrofuran (THF)
DMF N, N-dimethylformamide
DMSO Dimethyl sulfoxide
Dioxane 1, 4-Dioxahexacyclic ring
MeOH Methanol
DBU 1, 8-diazabicyclo [5.4.0]Undec-7-ene
DIPEA Diisopropylethylamine
DABCO Triethylene diamine
TEA Triethylamine
DMC 2-chloro-1, 3-dimethylchlorinated imidazolines
CDMBI 2-chloro-1, 3-dimethyl-1H-benzimidazole-3-chloride
NaOH Sodium hydroxide
R.T. Room temperature
MeCN Acetonitrile
Terminology and description
In the present invention, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art. Meanwhile, in order to better understand the present invention, definitions and explanations of related terms are provided below.
All ranges recited herein include those endpoints that list ranges between the two values. All values recited herein, whether or not stated, include the degree of expected experimental error, technical error, and instrumental error for a given technique for measuring the value.
In the present invention,% is weight/weight (w/w) percent unless otherwise indicated.
In the present invention, room temperature is 20 to 30 ℃, for example: 20 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 ℃.
Unless otherwise indicated, any numerical values, such as concentrations or ranges of concentrations described herein, are to be understood as being modified in all instances by the term "about. Thus, a numerical value typically includes ±10% of the value.
"alkyl" refers to saturated aliphatic hydrocarbon groups, straight and branched chain groups comprising 1 to 10 carbon atoms, preferably comprising 1 to 6 carbon atoms. Non-limiting examples of alkyl groups in the present invention include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo. In some preferred embodiments of the invention, alkyl is methyl or ethyl.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of the compound 1aa obtained in example 1.
Detailed Description
The invention will now be described in further detail with reference to the following examples, it being understood that the following description is illustrative only and is not limiting in any way. The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the examples described below, unless otherwise specified, were purchased from conventional biochemical reagent stores.
Example 1:
synthesis of 1 a:
d-glucose(45 mg,0.25 mmol) and 1-1 (228 mg,0.75 mmol) were dissolved in a mixture of water and 1, 4-dioxane (1 ml, V total) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, p-6-chloropurine (192.5 mg,1.25 mmol) was added. The reaction was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound 1a in 58% yield.
Example 2:
synthesis of 1 aa:
dissolving 1a in anhydrous pyridine at 0 ℃, slowly adding acetic anhydride, reacting overnight at room temperature, washing the reaction liquid with 1N diluted hydrochloric acid, performing EA extraction reaction for three times, combining organic phases, washing the organic phases with water, washing with saturated sodium bicarbonate, washing with brine, drying with anhydrous sodium sulfate, and purifying by column chromatography. The nuclear magnetic spectrum is shown as S1, and is consistent with the result of the spectrum in the existing report.
1 H NMR(300MHz,Chloroform-d)δ8.78(s,1H),8.34(s,1H),5.96(d,J＝9.5Hz,1H),5.68(t,J＝9.4Hz,1H),5.48(t,J＝9.4Hz,1H),5.31(t,J＝9.7Hz,1H),4.30(dd,J＝12.6,4.8Hz,1H),4.19–4.00(m,2H),2.08(s,3H),2.07(s,3H),2.04(s,3H),1.78(s,3H).
Example 3:
synthesis of 1 a:
d-glucose (45 mg,0.25 mmol) and CDMBI (165 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, p-6-chloropurine (192.5 mg,1.25 mmol) was added. The reaction was kept at-10℃and monitored by TLC. After the reaction, the reaction solution is dried by spinning, and purified by column chromatography (the eluent adopts ethyl acetate: methanol=10:1) to obtain the targeted productCompound 1a, 49% yield.
Example 4:
synthesis of 1 a:
d-glucose (45 mg,0.25 mmol) and 1-4 (127.5 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, p-6-chloropurine (192.5 mg,1.25 mmol) was added. The temperature was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound 1a in 17% yield.
Example 5:
synthesis of 1 a:
d-glucose (45 mg,0.25 mmol) and 1-5 (137.6 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, p-6-chloropurine (192.5 mg,1.25 mmol) was added. The reaction was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound 1a in 30% yield.
Example 6:
synthesis of 1 a:
d-glucose (45 mg,0.25 mmol) and 1-6 (167.3 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane =1:1), pre-cooled triethylamine 350ul is added at-10 ℃, and reaction is carried out for 5min at-10 ℃ and then6-chloropurine (192.5 mg,1.25 mmol) was added. The temperature was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound 1a in 32% yield.
Example 7:
/>
synthesis of 1 a:
d-glucose (45 mg,0.25 mmol) and 1-7 (188.2 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, p-6-chloropurine (192.5 mg,1.25 mmol) was added. The reaction was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound 1a in 32% yield.
Example 8:
synthesis of 1 a:
d-glucose (45 mg,0.25 mmol) and 1-8 (240.8 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, p-6-chloropurine (192.5 mg,1.25 mmol) was added. The reaction was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound 1a in 37% yield.
Example 9:
synthesis of 1 a:
d-glucose (45 mg,0.25 mmol) and 1-9 (208.9 mg,0.75 mmol) were dissolvedIn a mixed system of water and 1, 4-dioxane (1 ml, V in total) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, p-6-chloropurine (192.5 mg,1.25 mmol) was added. The reaction was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound 1a in 50% yield.
Example 10:
synthesis of 1 a:
d-glucose (45 mg,0.25 mmol) and 1-10 (165.2 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, p-6-chloropurine (192.5 mg,1.25 mmol) was added. The reaction was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound 1a in 43% yield.
Example 11:
synthesis of 1 a:
d-glucose (45 mg,0.25 mmol) and 1-11 (183.9 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, p-6-chloropurine (192.5 mg,1.25 mmol) was added. The reaction was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound 1a in 50% yield.
Example 12:
synthesis of 1 a:
d-glucose (45 mg,0.25 mmol) and 1-12 (245.0 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, p-6-chloropurine (192.5 mg,1.25 mmol) was added. The reaction was maintained at-10 ℃ overnight, the aqueous layer was extracted with DCM, the aqueous layer was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the title compound 1a in 40% yield.
Example 13:
synthesis of 1 a:
d-glucose (45 mg,0.25 mmol) and 1-13 (204.7 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, p-6-chloropurine (192.5 mg,1.25 mmol) was added. The reaction was maintained at-10 ℃ overnight, the aqueous layer was extracted with DCM, the aqueous layer was dried by spin-drying, and purified by column chromatography (eluent ethyl acetate: methanol=10:1) to give the title compound 1a in 39% yield.
Example 14:
synthesis of 1 a:
d-glucose (45 mg,0.25 mmol) and DMC (127 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (1 ml total, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, p-6-chloropurine (192.5 mg,1.25 mmol) was added. The reaction was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound 1a in 47 yield％。
Example 15:
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1b synthesis:
d-glucose (45 mg,0.25 mmol) and 1-1 (228 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, p-2-chloropurine (192.5 mg,1.25 mmol) was added. The reaction was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound 1b in 29% yield.
Example 16:
1c synthesis:
d-glucose (45 mg,0.25 mmol) and 1-1 (228 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, para-6-methoxypurine (187.5 mg,1.25 mmol) was added. The temperature was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound 1c in 46% yield.
Example 17:
1d synthesis:
d-glucose (45 mg,0.25 mmol) and 1-1 (228 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane =1:1), pre-cooled triethylamine 350ul was added at-10 ℃, and p-purine (15) was added after reaction at-10 ℃ for 5min0.4mg,1.25 mmol). The reaction was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound 1d in 36% yield.
Example 18:
1e synthesis:
d-glucose (45 mg,0.25 mmol) and 1-1 (228 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ in =1:1), 350ul of pre-cooled triethylamine was added, and after 5min of reaction at-10 ℃, pair 1-18 (262.5 mg,1.25 mmol) was added. The reaction was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound 1e in 35% yield.
Example 19:
1f synthesis:
d-glucose (45 mg,0.25 mmol) and 1-1 (228 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ in =1:1), 350ul of pre-cooled triethylamine was added, and after 5min of reaction at-10 ℃, pair 1-19 (337 mg,1.25 mmol) was added. The reaction was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=20:1 as eluent) to give the objective compound 1f in 56% yield.
Example 20:
synthesis of 1 g:
d-glucose (45 mg,0.25 mmol) and 1-1 (228 mg,0.75 mmol) were dissolved in a mixture of water and 1, 4-dioxaneSystemium (1 ml, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, p-6-bromopurine (248.7 mg,1.25 mmol) was added. The reaction was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give 1g of the objective compound in 45% yield.
Example 21:
synthesizing for 1 h:
d-glucose (45 mg,0.25 mmol) and 1-1 (228 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, para-6-methylpurine (167.5 mg,1.25 mmol) was added. The reaction was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound in 48% yield for 1 h.
Example 22:
2a synthesis:
d-mannose (45 mg,0.25 mmol) and 1-1 (228 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, p-6-chloropurine (192.5 mg,1.25 mmol) was added. The temperature was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound 2a in 40% yield.
Example 23:
/>
2b synthesis:
d-mannose (45 mg,0.25 mmol) and 1-1 (228 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, p-6-bromopurine (248.7 mg,1.25 mmol) was added. The temperature was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound 2b in 35% yield.
Example 24:
2c synthesis:
d-mannose (45 mg,0.25 mmol) and 1-1 (228 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ in =1:1), 350ul of pre-cooled triethylamine was added, and after 5min of reaction at-10 ℃, pair 1-24 (418.8 mg,1.25 mmol) was added. The temperature was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=20:1 as eluent) to give the objective compound 2c in 31% yield.
Example 25:
synthesis of 3 a:
d-xylose (38 mg,0.25 mmol) and 1-1 (228 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, p-6-chloropurine (192.5 mg,1.25 mmol) was added. The temperature was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound 3a in 31% yield.
Example 26
4a synthesis:
l-rhamnose (41 mg,0.25 mmol) and 1-1 (228 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (1 ml total, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, p-6-chloropurine (192.5 mg,1.25 mmol) was added. The temperature was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound 4a in 27% yield.
Example 27:
synthesis of 5 a:
d-galactose (45 mg,0.25 mmol) and 1-1 (228 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, p-6-bromopurine (248.7 mg,1.25 mmol) was added. The reaction was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound 5a in 26% yield.
Example 28:
6a synthesis:
cellobiose (85.5 mg,0.25 mmol) and 1-1 (308.2 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, p-6-chloropurine (192.5 mg,1.25 mmol) was added. The temperature was kept at-10℃and monitored by TLC. After the reaction, spin-drying the reaction solutionColumn chromatography purification (eluent ethyl acetate: methanol=8:1) afforded the title compound 6a in 29% yield.
Example 29
7a synthesis:
lactose (85.5 mg,0.25 mmol) and 1-1 (308.2 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, p-6-chloropurine (192.5 mg,1.25 mmol) was added. The temperature was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=8:1 as eluent) to give the objective compound 7a in 30% yield.
Example 29
8a synthesis:
n-acetylglucosamine (55 mg,0.25 mmol) and 1-1 (228 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and after 5min of reaction at-10 ℃, p-6-chloropurine (192.5 mg,1.25 mmol) was added. The reaction was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound 8a in 42% yield.
Example 31:
9a synthesis:
d-glucose (45 mg,0.25 mmol) and 1-1 (228 mg,0.75 mmol) were dissolved in a mixed system of water and tetrahydrofuran (total 1ml, V) Water and its preparation method ：V THF =1:1), -10350ul of pre-cooled triethylamine was added at-10℃and after 5min of reaction, n-butylamine (91.2 mg,1.25 mmol) was added. The temperature was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound 9a in 36% yield.
Example 32:
synthesis of 10 a:
d-glucose (45 mg,0.25 mmol) and 1-1 (228 mg,0.75 mmol) were dissolved in a mixed system of water and 1, 4-dioxane (total 1ml, V) Water and its preparation method ：V Dioxane To-10 ℃ was added 350ul of pre-cooled triethylamine, and p-aniline (116.4 mg,1.25 mmol) was added after reaction at-10 ℃ for 30 min. The temperature was kept at-10℃and monitored by TLC. After the reaction, the reaction mixture was dried by spin-drying, and purified by column chromatography (ethyl acetate: methanol=10:1 as eluent) to give the objective compound 10a (β: α=3:1) in 78% yield.
Reference is made to:
[1]Tanaka T,Nagai H,Noguchi M,et al.One-step conversion of unprotected sugars to b-glycosyl azides using 2-chloroimidazolinium salt in aqueous solution[J].Chemical communications-royal society of chemistry,2009(23):3378；
[2]Tomonari,Tanaka,Takeshi,et al.Direct Transformation of Unprotected Sugars to Aryl1-Thio-β-glycosides in Aqueous Media Using 2-Chloro-1,3-dimethylimidazolinium Chloride[J].Chemistry Letters,2009,38(5):458-459；
[3]M.Sc,Sebastian,et al.One-Pot Synthesis of Unprotected Anomeric Glycosyl Thiols in Water for Glycan Ligation Reactions with Highly Functionalized Sugars[J].
Angewandte Chemie International Edition,2016；[4]Qiu X,Fairbanks AJ.Direct Synthesis of para-Nitrophenyl Glycosides from Reducing Sugars in Water[J].Organic Letters,2020,22(6).

Claims (7)

1. a method for synthesizing N-glycoside by using unprotected sugar is characterized in that unprotected glycosyl donor, acceptor and alkali are dissolved in water or a mixed solvent of water and an organic solvent at the temperature of-78 ℃ to 25 ℃, and an accelerator is added to react to obtain the corresponding glycoside, and the reaction general formula is as follows:
wherein: r is a structure corresponding to a receptor;
the glycosyl donor is pyranose, furanose, disaccharide, polysaccharide or sugar structural analogue;
the receptor is an azacyclic compound or organic ammonia;
the base is triethylamine or DIPEA;
the accelerator is selected from any one of the following structures:
2. the method of claim 1, wherein the step of determining the position of the substrate comprises,
pyranose is ribose, arabinose or 2-deoxyribose;
the furanose is glucose, galactose, mannose, fucose, xylose, arabinose, N-acetamido glucose or rhamnose;
disaccharides are lactose, maltose or cellobiose;
the sugar structural analogue is tetrahydro-2H-pyran-2-ol.
3. The method of claim 1, wherein when the acceptor is an azacyclic compound, the acceptor is selected from any of the structural compounds shown below:
wherein R is 1 Is hydrogen, fluorine, chlorine, bromine, iodine, amino, acetoacetyl, azobenzoyl, NHBoc or N (Boc) 2； R 2 In the hydrogen, fluorine, chlorine, bromine, iodine, amino, acetoacetyl, azobenzoyl, NHBoc or N (Boc) 2； R 3 Hydrogen, hydroxy, carboxy, methyl formate, nitro, amino, fluoro, chloro, bromo or iodo; r is R 4 Hydrogen, hydroxy, carboxy, methyl formate, nitro, amino, fluoro, chloro, bromo or iodo;
when the acceptor is organic ammonia, the acceptor comprises linear ammonia and aromatic ammonia, wherein the linear ammonia is n-butylamine, and the aromatic ammonia is aniline, p-methylaniline or p-methoxyaniline.
4. The method according to claim 1, wherein the mixed solvent of water and an organic solvent is any one of a mixed reagent of water and tetrahydrofuran, a mixed reagent of water and 1, 4-dioxane, a mixed reagent of water and acetonitrile, a mixed reagent of water and DMF, a mixed reagent of water and DMSO, and a mixed reagent of water and acetone.
5. The method according to claim 4, wherein: the volume ratio of the mixed solvent of the reaction solvents is 1:0-1:5.
6. The method according to claim 1, characterized in that:
the molar ratio of the glycosyl donor to the acceptor is 1:1.1-1:10; the molar ratio of the glycosyl donor to the accelerator is 1:1.5-1:5; the molar ratio of the glycosyl donor to the alkali is 1:5-1:20.
7. The method according to claim 1, characterized in that: the temperature is-10 ℃.
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