Method for synthesizing thioglycoside through cross coupling of electrochemically mediated glycosyl mercaptan and 4-hydroxycoumarin derivative

Abstract

The invention discloses a method for synthesizing thioglycoside through electrochemical-mediated cross coupling of glycosyl mercaptan and 4-hydroxycoumarin derivatives, which comprises the following steps: by taking an organic solution containing glycosyl mercaptan, 4-hydroxycoumarin derivatives and electrolyte salt as electrolyte, placing an anode and a cathode in the electrolyte, and introducing direct current for electrochemical reaction to obtain the thioglycoside compound. According to the method, a single-configuration thioglycoside product can be efficiently obtained in an air environment without adding an additional metal catalyst, an oxidizing agent / reducing agent, acid / alkali and the like, the electrochemical reaction is compatible with substrates such as monosaccharide, disaccharide, 4-hydroxycoumarin and quinolinone with different protecting groups, and the method has the advantages of high efficiency, environmental protection, high atom economy, three-dimensional maintenance and the like.

Description

Technical Field

[0001] The invention relates to a method for synthesizing thioglycoside, in particular to a method for synthesizing thioglycoside compounds by cross-dehydrogenation coupling of glycosyl thiol and 4-hydroxycoumarin derivatives under the action of direct current, belonging to the technical field of drug intermediate synthesis. Background Art

[0002] 4-Hydroxycoumarin and its derivatives have excellent biological activity and nonlinear optical properties, and have wide application value in pharmaceutical engineering, organic optoelectronic materials, dyes and other fields. They are often used in anti-AIDS, anti-vascular sclerosis, antibacterial, etc. For example, phenprocoumon and 3-phenylcoumarin have excellent anti-HIV activity; dicoumarol, new anticoagulant, warfarin, etc. are all anticoagulants commonly used in medicine to prevent thrombosis, and neomycin sodium has excellent antibacterial and sterilization activities. The above drug molecules show that 4-hydroxycoumarin and its derivatives have extremely strong application prospects. Therefore, it is of great significance to design and synthesize more coumarin derivatives for subsequent pharmacological research. For thioglycosides, as a component of cell surface molecules, thioglycosides participate in a variety of important cell signaling pathways in terms of cell signal transduction. It plays a regulatory role in physiological processes such as cell adhesion, cell apoptosis, and cell proliferation. In addition, thioglycosides are also closely related to cellular immunoregulation and inflammatory response, which is of great significance for maintaining the normal function of the immune system.

[0003]

[0004] At present, the modification of 4-hydroxycoumarin is mainly to introduce different aglycones at its 3rd position to obtain a series of 4-hydroxycoumarin derivatives. In 2016, the literature (Paul, S.; Shrestha, R.; Edison, TNJI; Lee, YR; Kim, SH, Copper (I) Bromide-Dimethyl Sulfide-Catalyzed Direct Sulfanylation of 4-Hydroxycoumarins and 4-Hydroxy quinolinones with Arylsulfonylhydrazides and Selective Fluorescence Switch-On Sensing of Cadmium (II) Ion in Water. Advanced Synthesis & Catalysis 2016, 358, 3050-3056.) disclosed a copper-catalyzed sulfinylation reaction of benzenesulfonylhydrazide with 4-hydroxycoumarin and its derivatives. In 2019, the document (Das, D.; Mukherjee, P.; Das, AR, Magnetically Recyclable Nano Nickel Ferrite Catalyzed One-pot Chalcogenation of Bioactive Heterocycles Under Aerobic Condition. Chemistry Select 2019, 4, 1971-1978) disclosed a metal nickel-catalyzed sulfination reaction of aromatic iodides with 4-hydroxycoumarin and its derivatives. In 2021, the literature (Brahmachari, G.; Bhowmick, A.; Karmakar, I., Visible Light-Driven and Singlet Oxygen-Mediated Photochemical Cross-Dehydrogenative C(3)-HSulfenylation of 4-Hydroxycoumarins with Thiols Using Rose Bengal as a Photosensitizer. J. Org. Chem. 2021, 86, 9658-9669.) reported a visible light-mediated dehydrogenative cross-coupling reaction of alkyl thiols with 4-hydroxycoumarin and its derivatives.In 2022, the literature (Lapcinska, S.; Dimitrijevs, P.; Arsenyan, P., Nonyl Acridine Orange as a Prospective Photocatalyst in Chalcogenylation of Coumarins and Quinolinones. J Org Chem 2022, 87, 15261-15272.) reported a visible light-mediated reaction of sulfur / selenium electrophiles with 4-hydroxycoumarin and its derivatives to construct CS / C-Se bonds. In 2023, the literature (Yang, D.; Li, S.; Wu, X.; Wang, W.; Cai, Z.; Ma, C., Synthesis, Optical Properties, and Applications of Luminescent Benzothiazole: Base Promoted Intramolecular C–S Bond Formation. The Journal of Organic Chemistry 2023, 88, 11581-11589.) reported a method for synthesizing benzothiazole compounds from 7-diethylamino-4-hydroxycoumarin and 2-iodophenylthiocyanate under the catalysis of an inorganic base. However, the above method inevitably uses high temperature, metal catalysts, oxidants and other conditions that are not environmentally friendly.

[0005] In 2020, the literature (Zhu, M.; Alami, M.; Messaoudi, S., Electrochemical nickel-catalyzed Migita cross-coupling of 1-thiosugars with aryl, alkenyl and alkynylbromides. Chem. Commun. 2020, 56, 4464-4467.) reported for the first time a method for electrochemically catalyzing the construction of aromatic thioglycosides. This method used electro / nickel synergistic catalysis to successfully allow 1-glycosyl thiols to undergo Migita coupling with aromatic, alkynyl, and alkenyl bromides to synthesize aromatic thioglycosides. In 2023, the literature (Wang, R.-Q.; Jiang, Q.-H.; Wang, H.-X.; Zhang, X.-W.; Yan, N., Electrochemically Mediated S-Glycosylation of 1-Thiosugars with Xanthene Derivatives. Org. Lett. 2023, 25, 4252-4257.) reported a reaction of electrochemically catalyzed dehydrogenative cross-coupling of glycosylthiols with xanthene and its derivatives to construct CS bonds. Organic electrochemical synthesis is an emerging interdisciplinary subject. Researchers have cleverly applied non-toxic (or low-toxic) electrochemical technology to organic synthesis. At present, the field of organic electrosynthesis has developed rapidly and has been widely used in pharmaceuticals, chemicals, pesticides and other fields. Compared with traditional organic synthetic chemistry, it has its own unique advantages, such as (1) controlling the reaction rate and the termination and start-up of the reaction by controlling the current / voltage, which greatly increases the safety of chemical reactions in industry, which is not possible in traditional synthesis methods. (2) No oxidants and reductants need to be added. In the electrochemical system, the oxidation and reduction reactions occurring at the anode and cathode can replace them, which greatly improves the economic benefits of the reaction. (3) It can be carried out at room temperature and pressure without the addition of highly dangerous and toxic chemicals. Compared with traditional chemical synthesis, it greatly reduces pollution, and the mild conditions are more in line with the concept of green chemistry. Summary of the invention

[0006] In order to solve the technical problems existing in the prior art, the present invention provides a method for synthesizing thioglycosides by cross-coupling of glycosyl thiols and 4-hydroxycoumarin derivatives mediated by electrochemical reaction. The reaction replaces the oxidant with electrochemical oxidation, and the by-product is hydrogen. It is clean and efficient, conforms to the concept of green chemistry, and is applicable to a variety of different substrates, and is compatible with monosaccharides, disaccharides, quinolinones and 4-hydroxycoumarin derivatives. At the same time, it has the advantages of high efficiency, environmental protection, high atom economy, stereo retention, etc., which is conducive to the construction of new thioglycoside compounds.

[0007] In order to achieve the above technical objectives, the present invention provides a method for synthesizing thioglycosides by electrochemically mediated cross-coupling of glycosyl thiols and 4-hydroxycoumarin derivatives, wherein an organic solution containing glycosyl thiols, 4-hydroxycoumarin derivatives and electrolyte salts is used as an electrolyte, an anode and a cathode are placed in the electrolyte, and direct current is passed through for electrochemical reaction to obtain thioglycoside compounds.

[0008] As a preferred embodiment, the glycosyl thiol has a structure of Formula 1:

[0009] R1-SH

[0010] Formula 1

[0011] in,

[0012] R1 is a five-membered sugar ring, a six-membered sugar ring or a polyvalent sugar ring.

[0013] The polyvalent sugar ring in the glycosyl thiol of the present invention is composed of two or more five-membered sugar rings or six-membered sugar rings bonded together, and the preferred polyvalent sugar ring is a two-membered sugar ring. The six-membered sugar ring is a glucose ring, and the five-membered sugar ring is fructose and ribose. The hydroxyl groups on the five-membered sugar ring, the six-membered sugar ring or the polyvalent sugar ring in the glycosyl thiol of the present invention are etherified or acylated, for example, the acylated group can be an acetyl group, a benzoyl group or a pivaloyl group.

[0014] As a preferred embodiment, the 4-hydroxycoumarin derivative has a structure of Formula 2:

[0015]

[0016] in,

[0017] R is hydrogen, a halogen substituent, a hydroxyl group, a C1-C5 alkyl group, or a C1-C5 alkoxy group;

[0018] X is O, S or NH.

[0019] In the 4-hydroxycoumarin derivatives of the present invention, the halogen substituents may be fluorine substituents, chlorine substituents, bromine substituents, etc. C1-C5 alkyl groups include methyl, ethyl, butyl, etc. C1-C5 alkoxy groups include methoxy, ethoxy, etc.

[0020] As a preferred embodiment, the thioglycoside compound has a structure of Formula 3:

[0021]

[0022] in,

[0023] R1 is a five-membered sugar ring, a six-membered sugar ring or a polyvalent sugar ring;

[0024] R is hydrogen, fluoride ion, hydroxyl, C1-C5 alkyl or C1-C5 alkoxy;

[0025] X is O, S or NH.

[0026] The preferred thioglycoside compounds of the present invention have the following structure:

[0027]

[0028] The thioglycoside compounds of the present invention can be used as drug synthesis intermediates and as glycosyl donors for synthesizing oligosaccharides and glycoconjugates.

[0029] As a preferred embodiment, the molar ratio of the glycosyl thiol to the 4-hydroxycoumarin derivative is 1:1.5 to 2.0. The molar ratio of the glycosyl thiol to the 4-hydroxycoumarin derivative is more preferably 1.0:1.5.

[0030] As a preferred embodiment, the molar ratio of the glycosyl thiol to the electrolyte salt is 1.0:1.0-1.5.

[0031] As a preferred embodiment, the electrolyte salt is sodium iodide, NH4I, n Bu4NBF4, n At least one of Bu4NPF6. These electrolyte salts all have a certain promoting effect on the electrochemical reaction between glycosyl thiol and 4-hydroxycoumarin, and can obtain a better yield of the target product. When sodium iodide is selected as the electrolyte salt, it can bring better effects than other electrolyte salts.

[0032] As a preferred solution, the electrolyte uses DMF and / or DMSO as a solvent. The electrochemical reaction between glycosyl mercaptan and 4-hydroxycoumarin is affected by the solvent in the electrolyte. For example, when acetonitrile is selected as the solvent, the yield of the target product is relatively low, while when DMF or DMSO is selected as the solvent, the yield of the target product is significantly improved, especially when DMF is selected as the solvent, the effect is the best.

[0033] As a preferred solution, the anode is a carbon rod electrode or a platinum sheet electrode; the cathode is a carbon rod electrode or a platinum sheet electrode. The most preferred electrode combination is that the anode is a carbon rod electrode and the cathode is a carbon rod electrode. Different electrode combinations have a significant effect on the electrochemical reaction between glycosyl thiol and 4-hydroxycoumarin. When carbon rod electrodes are selected as anode and cathode, a high yield of the target product can be ensured.

[0034] As a preferred solution, the conditions of the electrochemical reaction are: under air or protective atmosphere, the current of direct current is 5-15 mA, the temperature is 60-70 ° C, and the time is 40-50 minutes. The protective atmosphere is, for example, nitrogen or an inert atmosphere, and the inert atmosphere is, for example, argon. The reaction atmosphere is more preferably air, and the reaction is insensitive to oxygen, so there is no need to use a protective atmosphere. The current of direct current has a significant effect on the electrochemical reaction between glycosyl thiol and 4-hydroxycoumarin derivatives. As the current increases, the yield of the target product increases first and then tends to be flat, so the further preferred current size is 10-15 mA.

[0035] The method for synthesizing thioglycosides of the present invention comprises the following specific steps:

[0036] 1. At 60°C, add glycosyl thiol (0.2 mmol), 4-hydroxycoumarin derivative (0.3 mmol, 1.5 equiv), NaI (0.2 mmol, 1.0 equiv), and DMF (3 mL) into a reaction vessel;

[0037] 2. Two carbon rod electrodes are used as the anode and cathode of the electrochemical integrated cell, and a current of 10 mA is passed through;

[0038] 3. At the same time, the glycosyl thiol was dissolved in 1 mL of DMF solution, and then added dropwise into the above-mentioned electroreaction system within 30 minutes. After the addition was completed, the reaction was continued for another 10 minutes.

[0039] 4. Monitor the reaction by TLC. When the glycosyl thiol reacts completely, extract with ethyl acetate for 4 to 5 times. Combine the organic phases, dry over anhydrous NaSO4, concentrate under reduced pressure, and separate by column chromatography.

[0040] Compared with the prior art, the technical solution of the present invention brings the following beneficial technical effects:

[0041] 1. This method is simple to operate, mild in conditions, clean and efficient.

[0042] 2. No need to use transition metal catalysts, oxidants, reducing agents and other chemical reagents.

[0043] 3. It should have good universality and good tolerance to different substrate functional groups. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 For compound 1 1 H NMR.

[0045] Figure 2 For compound 1 13 C NMR.

[0046] Figure 3 For compound 2 1H NMR.

[0047] Figure 4 For compound 2 13 C NMR.

[0048] Figure 5 For compound 3 1 H NMR.

[0049] Figure 6 For compound 3 13 C NMR.

[0050] Figure 7 For compound 4 1 H NMR.

[0051] Figure 8 For compound 4 13 C NMR.

[0052] Fig. 9 For compound 5 1 H NMR.

[0053] Fig.10 For compound 5 13 C NMR. DETAILED DESCRIPTION

[0054] The following specific examples are intended to further illustrate the present invention rather than to limit the scope of protection of the claims.

[0055] In the following specific examples, unless otherwise specified, the reaction raw materials are all conventional commercial pharmaceutical agents.

[0056] Condition optimization experiment 1:

[0057] First, fully acetyl-protected 1-thioglucose (1, 0.2 mmol) and 4-hydroxycoumarin (2, 0.3 mmol) were used as substrates and acetonitrile (4 mL) as solvent. n Bu4NBF4 (0.2mmol) was used as the electrolyte, and two platinum electrodes (15mm×15mm×0.1mm) were selected as the anode and cathode. A 5mA direct current was passed at room temperature (25°C) for 40min. Unfortunately, the target compound (3a) was not found, but 99% of the disulfide compound was separated. The inventors inferred that this was mainly because the activity of 4-hydroxycoumarin was too low to couple with the sulfur free radical to obtain the glycosylation product. Therefore, an attempt was made to increase the temperature to observe whether the reaction activity of 4-hydroxycoumarin was improved.

[0058]

[0059] Table 1 Effect of different temperatures on the reaction

[0060]

[0061]

[0062] Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2 (0.3 mmol, 1.5 equiv), n Bu4NBF4(0.2

[0063] mmol, 1.0 equiv), Pt(+)|Pt(-)I=5mA, CH3CN(4mL).

[0064] As can be seen from Table 1, the reaction temperature was increased step by step. When the reaction temperature was increased to 40°C (experimental group 1), the target compound was still not obtained. Therefore, the temperature was further increased. When the temperature reached 60°C, it was found that the glucosidation product could be harvested with a yield of 27% (experimental group 2). When the temperature was further increased to 70°C, the yield did not change significantly (experimental group 3). Therefore, 60°C is the optimal temperature.

[0065] Condition optimization experiment 2: Under the premise of screening out the optimal reaction temperature, optimize other reaction conditions:

[0066] The present invention is specifically described by taking the reaction of synthesizing thioglycoside compounds by electrochemical reaction of glycosyl thiol and 4-hydroxycoumarin as an example, and taking the screened optimal reaction conditions as standard reaction conditions. The specific reaction formula is as follows:

[0067]

[0068] At 60°C, glycosyl thiol (1a, 0.2 mmol), 2a (0.3 mmol, 1.5 equiv), NaI (0.2 mmol, 1.0 equiv), and DMF (3 mL) were added to a reaction vessel. Two carbon rod electrodes were used as the anode and cathode of the electrochemical integrated cell. A 10 mA current was passed through. At the same time, the glycosyl thiol was dissolved in a 1 mL DMF solution and then added dropwise into the above-mentioned electroreaction system within 30 min. After the addition was completed, the reaction was continued for 10 min. The reaction was monitored by TLC. After the glycosyl thiol reaction was complete, it was extracted with ethyl acetate 5 times, the organic phases were combined, dried over anhydrous NaSO4, concentrated under reduced pressure, and separated by column chromatography.

[0069] The following control experimental groups 1 to 11 are based on standard reaction conditions for comparison and explanation:

[0070]

[0071]

[0072] Reaction conditions: 1a (0.2 mmol, 1 equiv), 2a (0.3 mmol, 1.5 equiv), NaI (0.2 mmol, 1.0 equiv), C(+)|C(-)I=10 mA, DMF (4 mL), 60°C.

[0073] Experimental groups 1 to 4 in the table above investigated the effects of different electrolyte salts on the electrochemical reaction. The experiments showed that electrolyte salts had a certain influence on the reaction. n Bu4NBF4, n Bu4NPF6 and the like are used as electrolyte salts, and the reaction can proceed, but the effect is far inferior to NaI. The best electrolyte salt is NaI.

[0074] Experimental groups 1 and 5-6 in the above table investigated the effects of different current sizes on the electrochemical reaction. The experiments showed that the current size had a certain influence. As the current increased, the yield of the target product showed a trend of first increasing and then decreasing or tending to be flat. Therefore, the preferred current was 10-15 mA, and the optimal current was 10 mA.

[0075] Experimental groups 1 and 7-8 in the above table investigated the effects of different solvents on the electrochemical reactions. The experiments showed that the solvent had a certain influence on the reaction. When acetonitrile, DMSO and DMF were used as solvents, the reactions could proceed smoothly. However, when DMSO and DMF were used as solvents, the effects were better, and DMF was the best reaction solvent.

[0076] Experimental groups 1 and 9 in the above table investigated the effects of different electrode pairs on electrochemical reactions. The experiments showed that the electrode pairs had a certain influence on the reactions. The reactions could proceed smoothly when either platinum electrodes or carbon rod electrodes were used, but the best electrode pair was when both the cathode and the anode were carbon rod electrodes.

[0077] Experimental groups 1 and 10 in the above table investigated the effect of nitrogen atmosphere on the electrochemical reaction. The experiments showed that nitrogen had little effect on the reaction. Since it is convenient and easy to operate under air conditions, the best reaction condition is air atmosphere.

[0078] Experimental groups 1 and 11 in the table above investigated the effect of direct current on electrochemical reactions. If direct current is not applied, the reaction cannot proceed smoothly.

[0079] The following examples are intended to investigate the effects of different substituents on the reaction.

[0080] Example 1

[0081]

[0082] At 60°C, 2a (0.3 mmol, 1.5 equiv), NaI (0.2 mmol, 1.0 equiv), and DMF (3 mL) were added to a special reaction vessel. Two carbon rod electrodes were used as the anode and cathode of the electrochemical integrated cell. A 10 mA current was passed through. At the same time, 1a was dissolved in a 1 mL DMF solution and then added dropwise into the above-mentioned electroreaction system within 30 min. After the addition was completed, the reaction was continued for 10 min. The reaction was monitored by TLC. After the glycosylthiol reaction was complete, it was extracted with ethyl acetate for 4-5 times, the organic phases were combined, dried over anhydrous NaSO4, concentrated under reduced pressure, and separated by column chromatography.

[0083] The target compound 1 (90 mg) was obtained by column chromatography with a yield of 86%.

[0084]

[0085] (2R,3R,4R,5R,6S)-2-(acetoxymethyl)-6-((4-hydroxy-2-oxo-2H-chromen-3-yl)thio)tetrahydro-2H-pyran-3,4,5-triyl triacetate.

[0086] Yield: 86%

[0087] The characterization data of the compound are as follows: 1 H NMR (400MHz, DMSO-d6) δ7.88(d,J=7.7Hz,1H),7.62(t,J=7.3Hz,1H),7.32(t,J=7.9Hz,2H),5.28(t,J=9.4Hz,1H),5.08(d,J =10.0Hz,1H),4.98-4.84(m,2H),4.16-4.06(m,1H),3.97-3.79(m,2H),2.00(s,3H),1.96(s,3H),1.93(s,3H),1.82(s,3H). 13 C NMR(101MHz,DMSO-d6)δ169.84,169.50,169.32,169.23,169.03,161.19,152.86,132.86,124.31,12 3.75,117.01,116.20,91.68,82.82,74.30,73.06,70.77,68.01,61.82,20.50,20.38,20.30,20.20.

[0088] Example 2

[0089] At 60°C, 2a (0.3 mmol, 1.5 equiv), NaI (0.2 mmol, 1.0 equiv), and DMF (3 mL) were added to a special reaction vessel. Two carbon rod electrodes were used as the anode and cathode of the electrochemical integrated cell. A 10 mA current was passed through. At the same time, 1b was dissolved in a 1 mL DMF solution and then added dropwise into the above-mentioned electroreaction system within 30 min. After the addition was completed, the reaction was continued for 10 min. The reaction was monitored by TLC. After the glycosylthiol reaction was complete, it was extracted with ethyl acetate for 4-5 times, the organic phases were combined, dried over anhydrous NaSO4, concentrated under reduced pressure, and separated by column chromatography.

[0090] The target compound 2 (90 mg) was obtained by column chromatography with a yield of 86%.

[0091]

[0092] (2R,3S,4R,5R,6S)-2-(acetoxymethyl)-6-((4-hydroxy-2-oxo-2H-chromen-3-yl)thio)tetrahydro-2H-pyran-3,4,5-triyl triacetate.

[0093] Yield: 86%.

[0094] The characterization data of the compound are as follows: 1 H NMR (400MHz, DMSO-d6) δ7.90(d,J=7.8Hz,1H),7.68(t,J=7.2Hz,1H),7.47-7.31(m,2H),5.31-5.19(m,2H),5.15-5.09(m,1H),5.06(d,J=9. 9Hz,1H),4.18-4.11(m,1H),3.99(dd,J=11.2,7.5Hz,1H),3.89(dd,J=11.3,5.2Hz,1H),2.11(s,3H),2.05(s,3H),1.92(s,3H),1.71(s,3H). 13 C NMR(101MHz,DMSO-d6)δ169.88,169.62,169.51,169.38,167.57,160.54,152.66,133.46,124.29,12 4.06,116.40,115.55,93.81,83.29,73.62,70.94,67.90,67.58,61.30,20.57,20.44,20.35,20.03.

[0095] Example 3

[0096] At 60°C, 2a (0.3 mmol, 1.5 equiv), NaI (0.2 mmol, 1.0 equiv), and DMF (3 mL) were added to a special reaction vessel. Two carbon rod electrodes were used as the anode and cathode of the electrochemical integrated cell. A 10 mA current was passed through. At the same time, 2c was dissolved in a 1 mL DMF solution and then added dropwise into the above-mentioned electroreaction system within 30 min. After the addition was completed, the reaction was continued for 10 min. The reaction was monitored by TLC. After the glycosylthiol reaction was complete, it was extracted with ethyl acetate for 4-5 times, the organic phases were combined, dried over anhydrous NaSO4, concentrated under reduced pressure, and separated by column chromatography.

[0097] The target compound 3 (57 mg) was obtained by column chromatography with a yield of 61%.

[0098]

[0099] (2R,3S,4S,5R,6R)-2-((4-hydroxy-2-oxo-2H-chromen-3-yl)thio)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate.

[0100] Yield: 61%

[0101] The characterization data of the compound are as follows: 1 H NMR (400MHz, DMSO-d6) δ7.93(d,J=7.6Hz,1H),7.67(t,J=7.3Hz,1H),7.37(t,J=8.2Hz,2H),5.43(s,1H),5.40(d,J=3.5Hz,1H),5.25(dd ,J=10.3,3.5Hz,1H),4.92(t,J=10.0Hz,1H),4.44(dq,J=12.1,6.1Hz,1H),2.11(s,3H),2.08(s,3H),1.95(s,3H),1.00(d,J=6.2Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ169.70,169.58,168.32,161.29,152.78,133.31,124.22,124.11 ,116.38,116.15,92.64,81.98,70.11,69.63,69.01,67.81,20.59,20.55,20.43,16.99.

[0102] Example 4

[0103] At 60°C, 2b (0.3 mmol, 1.5 equiv), NaI (0.2 mmol, 1.0 equiv), and DMF (3 mL) were added to a specially prepared reaction vessel. Two carbon rod electrodes were used as the anode and cathode of the electrochemical integrated cell. A 10 mA current was passed through. At the same time, 2a was dissolved in a 1 mL DMF solution and then added dropwise into the above-mentioned electroreaction system within 30 min. After the addition was completed, the reaction was continued for 10 min. The reaction was monitored by TLC. After the glycosylthiol reaction was complete, it was extracted with ethyl acetate for 4-5 times, the organic phases were combined, dried over anhydrous NaSO4, concentrated under reduced pressure, and separated by column chromatography.

[0104] The target compound 3 (94.8 mg) was obtained by column chromatography with a yield of 88%.

[0105]

[0106] (2R,3R,4R,5R,6S)-2-(acetoxymethyl)-6-((4-hydroxy-6-methyl-2-oxo-2H-chromen-3-yl)thio)tetrahydro-2H-pyran-3,4,5-triyl triacetate.

[0107] Yield: 88%

[0108] The characterization data of the compound are as follows: 1 H NMR(400MHz, DMSO-d6)δ7.68(s,1H),7.49(dd,J=8.5,1.9Hz,1H),7.30(d,J=8.4H z,1H),5.32(t,J=9.4Hz,1H),5.11(d,J=10.0Hz,1H),4.90(dt,J=17.5,9.7Hz,2H ),4.11(dd,J=12.2,5.6Hz,1H),3.95(ddd,J=9.8,5.6,2.1Hz,1H),3.86(dd,J=12 .1,1.9Hz,1H),2.37(s,3H),2.01(s,3H),1.96(s,3H),1.93(s,3H),1.80(s,3H). 13C NMR(101MHz,DMSO-d6)δ169.79,169.49,169.32,169.22,167.77,160.70,150.85,134.33,133.57,123.6 2,116.18,115.17,93.34,82.57,74.33,72.93,70.61,67.97,61.82,20.46,20.37,20.33,20.28,20.13.

[0111] Example 5

[0112] At 60°C, 2c (0.3mmol, 1.5equiv), NaI (0.2mmol, 1.0equiv), and DMF (3mL) were added to a special reaction container. Two carbon rod electrodes were used as the anode and cathode of the electrochemical integrated cell. A 10mA current was passed through. At the same time, 2a was dissolved in a 1mL DMF solution and then added dropwise into the above-mentioned electroreaction system within 30min. After the addition was completed, the reaction was continued for 10min. The reaction was monitored by TLC. After the glycosylthiol reaction was complete, it was extracted with ethyl acetate for 4-5 times, the organic phases were combined, dried over anhydrous NaSO4, concentrated under reduced pressure, and separated by column chromatography. The target compound 3 (83.2mg) was obtained by column chromatography with a yield of 75%.

[0113]

[0114] (2R,3R,4R,5R,6S)-2-(acetoxymethyl)-6-((4-hydroxy-6-methoxy-2-oxo-2H-chromen-3-yl)thio)tetrahydro-2H-pyran-3,4,5-triyl triacetate.

[0115] Yield: 75%

[0116] The characterization data of the compound are as follows: 1 H NMR(400MHz,DMSO-d6)δ7.36(d,J=8.9Hz,

[0117] 1H),7.31(d,J=2.9Hz,1H),7.27(dd,J=8.9,3.0Hz,1H),5.32(t,J=9.4Hz,1H),5.12(d,J=10.0Hz,1H),4.96-4.91(m,1H),4.90-4.84(m,1H),4.12(dd,J=12.3,5.5Hz,1H),3.95(ddd,J=10.0,5.5,2.3Hz,1H),3.87(dd,J=12.2,2.3Hz,1H),3.81(s,3H),2.01(s,3H),1.97(s,3H),1.94(s,3H),1.82(s,3H). 13 C NMR(101MHz,DMSO-d6)δ169.80,169.50,169.32,169.23,167.48,160.70,155.45,147.09,121.32,117.74,115.94,105.67,93.76,82.58,74.33,72.93,70.62,67.96,61.78,55.76,55.73,20.46,20.38,20.29,20.18。

Claims

1. A method for synthesizing thioglycosides by electrochemically mediated cross-coupling of glycosyl thiols and 4-hydroxycoumarin derivatives, characterized in that: An organic solution containing glycosyl mercaptan, 4-hydroxycoumarin derivatives and electrolyte salt is used as an electrolyte, an anode and a cathode are placed in the electrolyte, and direct current is passed through to perform an electrochemical reaction to obtain a thioglycoside compound.

2. The method for synthesizing thioglycosides by electrochemically mediated cross-coupling of glycosyl thiols and 4-hydroxycoumarin derivatives according to claim 1, characterized in that: The glycosyl thiol has a structure of Formula 1: R1 Formula 1 in, R1 is a five-membered sugar ring, a six-membered sugar ring or a polyvalent sugar ring.

3. The method for synthesizing thioglycosides by electrochemically mediated cross-coupling of glycosyl thiols and 4-hydroxycoumarin derivatives according to claim 1, characterized in that: The 4-hydroxycoumarin derivative has a structure of Formula 2: in, R is hydrogen, a halogen substituent, a hydroxyl group, a C1-C5 alkyl group, or a C1-C5 alkoxy group; X is O, S or NH.

4. The method for synthesizing thioglycosides by electrochemically mediated cross-coupling of glycosyl thiols and 4-hydroxycoumarin derivatives according to claim 1, characterized in that: The thioglycoside compound has a structure of Formula 3: in, R1 is a five-membered sugar ring, a six-membered sugar ring or a polyvalent sugar ring; R is hydrogen, a halogen substituent, a hydroxyl group, a C1-C5 alkyl group, or a C1-C5 alkoxy group; X is O, S or NH.

5. A method for synthesizing thioglycosides by electrochemically mediated cross-coupling of glycosyl thiols and 4-hydroxycoumarin derivatives according to any one of claims 1 to 4, characterized in that: The molar ratio of the glycosyl thiol to the 4-hydroxycoumarin derivative is 1:1.5-2.

0.

6. A method for synthesizing thioglycosides by electrochemically mediated cross-coupling of glycosyl thiols and 4-hydroxycoumarin derivatives according to any one of claims 1 to 4, characterized in that: The molar ratio of the glycosyl thiol to the electrolyte salt is 1.0:1.0-1.

5.

7. The method for synthesizing thioglycosides by electrochemically mediated cross-coupling of glycosyl thiols and 4-hydroxycoumarin derivatives according to claim 6, characterized in that: The electrolyte salt is sodium iodide, NH4I, n Bu4NBF4, n At least one of Bu4NPF6.

8. A method for synthesizing thioglycosides by electrochemically mediated cross-coupling of glycosyl thiols and 4-hydroxycoumarin derivatives according to any one of claims 1 to 4, characterized in that: The electrolyte uses DMF and / or DMSO as solvent.

9. A method for synthesizing thioglycosides by electrochemically mediated cross-coupling of glycosyl thiols and 4-hydroxycoumarin derivatives according to any one of claims 1 to 4, characterized in that: The anode is a carbon rod electrode or a platinum sheet electrode; the cathode is a carbon rod electrode or a platinum sheet electrode.

10. A method for synthesizing thioglycosides by electrochemically mediated cross-coupling of glycosyl thiols and 4-hydroxycoumarin derivatives according to any one of claims 1 to 4, characterized in that: The conditions of the electrochemical reaction are: in air or protective atmosphere, the direct current is 5-15 mA, the temperature is 60-70° C., and the time is 40-50 minutes.

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