A method for electrochemically mediated cross-coupling of glycosyl thiols with 4-hydroxycoumarin derivatives to form thioglycosides

Abstract

The application discloses a method for electrochemically mediating glycosyl mercaptan and 4-hydroxyl coumarin derivative cross-coupling to form thioglycoside, which uses an organic solution containing glycosyl mercaptan, 4-hydroxyl coumarin derivative and electrolyte salt as an electrolyte, places an anode and a cathode in the electrolyte, and passes direct current to perform electrochemical reaction to obtain a thioglycoside compound. The method can efficiently obtain a single configuration thioglycoside product in an air environment without adding additional metal catalysts, oxidants / reducing agents, acids / alkalis and the like, and the electrochemical reaction is compatible with different protecting group monosaccharides, disaccharides, 4-hydroxyl coumarin, quinolinone and other substrates, and has the advantages of high efficiency, environmental protection, high atom economy, stereo-keeping and the like.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing thioglycosides, and 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 pharmaceutical intermediate synthesis. Background Art

[0002] 4-Hydroxycoumarin and its derivatives possess excellent biological activity and nonlinear optical properties, and have broad applications in pharmaceutical engineering, organic optoelectronic materials, dyes, and other fields. They are commonly used in anti-AIDS, anti-vascular sclerosis, and antibacterial applications. For example, phenprocoumon and 3-phenylcoumarin exhibit excellent anti-HIV activity; dicoumarol, neoformanserin, and warfarin are all commonly used anticoagulants for thrombosis prevention in medicine; and neoformanserin sodium exhibits excellent antibacterial and bactericidal activity. These drug molecules demonstrate the enormous potential of 4-hydroxycoumarin and its derivatives. Therefore, the design and synthesis of more coumarin derivatives for further pharmacological research is of great significance. Regarding thioglycosides, as components of cell surface molecules, they participate in various important cell signaling pathways. They play a regulatory role in physiological processes such as cell adhesion, apoptosis, and cell proliferation. Furthermore, thioglycosides are closely associated with cellular immunoregulation and inflammatory responses, playing a vital role in maintaining the normal function of the immune system.

[0003]

[0004] Currently, the modification of 4-hydroxycoumarin mainly involves the introduction of different aglycones at position 3 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 (II)-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 aryl 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 aPhotosensitizer. 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, a paper (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 in the presence of an inorganic base. However, this method inevitably involves environmentally unfriendly conditions such as high temperatures, metal catalysts, and oxidants.

[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 catalyzed construction of aromatic thioglycosides. This method used electro / nickel synergistic catalysis to successfully allow 1-glycosyl thiols to undergo Migita coupling with aryl, 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 an electrochemically catalyzed dehydrogenative cross-coupling reaction of glycosylthiols with xanthene and its derivatives to construct C-S 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 or reducing agents are required. 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 hazardous or toxic chemicals. Compared with traditional chemical synthesis, it greatly reduces pollution. The mild conditions are more in line with the concept of green chemistry. Summary of the Invention

[0006] To solve the technical problems existing in the prior art, the present invention provides a method for synthesizing thioglycosides by electrochemically mediated cross-coupling of glycosyl thiols and 4-hydroxycoumarin derivatives. 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. It 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, and stereo preservation, 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. The method uses an organic solution containing glycosyl thiols, 4-hydroxycoumarin derivatives and electrolyte salts as an electrolyte, places an anode and a cathode in the electrolyte, and passes direct current to carry out an 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. Preferably, the polyvalent sugar ring is a two-membered sugar ring. Six-membered sugar rings include glucose rings, while five-membered sugar rings include fructose and ribose. The hydroxyl groups on the five-membered sugar ring, six-membered sugar ring, or polyvalent sugar ring in the glycosyl thiol of the present invention are etherified or acylated. For example, the acylated group may 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, chlorine, bromine, 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, and the molar ratio of the glycosyl thiol to the 4-hydroxycoumarin derivative is more preferably 1.0:1.5.

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

[0031] As a preferred solution, 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 embodiment, the electrolyte uses DMF and / or DMSO as a solvent. The electrochemical reaction between the glycosyl thiol and 4-hydroxycoumarin is affected by the solvent in the electrolyte. For example, when acetonitrile is used as the solvent, the yield of the target product is relatively low, while when DMF or DMSO is used as the solvent, the yield of the target product is significantly improved, and the best effect is achieved when DMF is used as the solvent.

[0033] As a preferred embodiment, 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 a carbon rod electrode as the anode and a carbon rod electrode as the cathode. Different electrode combinations have a significant impact on the electrochemical reaction between glycosyl thiols and 4-hydroxycoumarin. When carbon rod electrodes are used as both the anode and cathode, a high yield of the target product can be achieved.

[0034] As a preferred embodiment, the electrochemical reaction conditions are: a direct current current of 5 to 15 mA, a temperature of 60 to 70° C., and a reaction time of 40 to 50 minutes in air or a protective atmosphere. Examples of protective atmospheres include nitrogen or an inert atmosphere, such as argon. Air is a more preferred reaction atmosphere, as the reaction is insensitive to oxygen and does not require a protective atmosphere. The direct current current significantly affects the electrochemical reaction between the glycosyl thiol and the 4-hydroxycoumarin derivative. As the current increases, the yield of the target product initially increases and then levels off. Therefore, a further preferred current is 10 to 15 mA.

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

[0036] 1. Add glycosylthiol (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 at 60°C;

[0037] 2. Two carbon rod electrodes serve 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, dissolve the glycosyl thiol in 1 mL of DMF solution, then add it dropwise into the above-mentioned electroreaction system within 30 minutes. After the addition is completed, react for another 10 minutes.

[0039] 4. Monitor the reaction by TLC. After the reaction of glycosyl thiol is complete, extract with ethyl acetate 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 existing technology, 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] Figure 9 For compound 5 1 H NMR.

[0053] Figure 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] Unless otherwise specified in the following specific examples, the reaction raw materials are all conventional commercial reagents.

[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 (0.2 mmol) was used as the electrolyte, and two platinum electrodes (15 mm × 15 mm × 0.1 mm) were selected as the anode and cathode. A 5 mA direct current was applied at room temperature (25°C) for 40 min. Unfortunately, the target compound (3a) was not found, but 99% of the disulfide compound was isolated. The inventors speculated that this was mainly because the activity of 4-hydroxycoumarin was too low to couple with the sulfhydryl radical to obtain the glycosylated product. Therefore, an attempt was made to increase the temperature to see if it would improve the reactivity of 4-hydroxycoumarin.

[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 in Table 1, the reaction temperature was gradually increased. 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: On 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 the optimal reaction conditions screened are used 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 served as the anode and cathode of an electrochemical cell. A 10 mA current was applied. Simultaneously, the glycosyl thiol was dissolved in 1 mL of DMF and added dropwise to the electrochemical reaction system over 30 minutes. After the addition was complete, the reaction was allowed to proceed for an additional 10 minutes. The reaction was monitored by TLC. After complete reaction of the glycosyl thiol, the mixture was extracted five times with ethyl acetate. 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] The 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 The reaction can proceed when Bu4NPF6 and the like are used as electrolyte salts, but the effect is far worse than that of NaI. The best electrolyte salt is NaI.

[0074] Experimental groups 1 and 5-6 in the table above investigated the effects of different current sizes on the electrochemical reaction. The experiments showed that the current size had a certain effect. 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 table above investigated the effects of different solvents on the electrochemical reaction. The experiments showed that the solvent had a certain influence on the reaction. The reaction could proceed smoothly when acetonitrile, DMSO and DMF were used as solvents, but the effect was better when DMSO and DMF were used as solvents, and the best reaction solvent was DMF.

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

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

[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 substituent groups 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 custom-made reaction vessel. Two carbon rod electrodes served as the anode and cathode of an integrated electrochemical cell. A 10 mA current was applied. 1a was dissolved in 1 mL of DMF and added dropwise to the electrochemical reaction system over 30 minutes. After the addition was complete, the reaction was allowed to proceed for an additional 10 minutes. The reaction was monitored by TLC. After complete reaction of the glycosyl thiol, the mixture was extracted with ethyl acetate four to five 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 custom-made reaction vessel. Two carbon rod electrodes served as the anode and cathode of an integrated electrochemical cell. A 10 mA current was applied. Simultaneously, 1b was dissolved in 1 mL of DMF and added dropwise to the electrochemical reaction system over 30 minutes. After the addition was complete, the reaction was allowed to proceed for an additional 10 minutes. The reaction was monitored by TLC. After complete reaction of the glycosyl thiol, the mixture was extracted with ethyl acetate 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 custom-made reaction vessel. Two carbon rod electrodes served as the anode and cathode of an integrated electrochemical cell. A 10 mA current was applied. Simultaneously, 2c was dissolved in 1 mL of DMF and added dropwise to the electrochemical reaction system over 30 minutes. After the addition was complete, the reaction was allowed to proceed for an additional 10 minutes. The reaction was monitored by TLC. After complete reaction of the glycosyl thiol, the mixture was extracted with ethyl acetate 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 custom-made reaction vessel. Two carbon rod electrodes served as the anode and cathode of an integrated electrochemical cell. A 10 mA current was applied. Simultaneously, 2a was dissolved in 1 mL of DMF and added dropwise to the electrochemical reaction system over 30 minutes. After the addition was complete, the reaction was allowed to proceed for an additional 10 minutes. The reaction was monitored by TLC. After complete reaction of the glycosyl thiol, the mixture was extracted with ethyl acetate four to five 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=8.4Hz,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,

[0109] 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). 13 C NMR(101MHz,DMSO-d6)δ169.79,169.49,169.32,169.22,167.77,160.70,

[0110] 150.85,134.33,133.57,123.62,116.18,115.17,93.34,82.57,74.33,72.93,70.61,67.97,61.82,20.46,20.37,20.33,20.28,20.13.

[0111] Example 5

[0112] At 60°C, 2c (0.3 mmol, 1.5 equiv), NaI (0.2 mmol, 1.0 equiv), and DMF (3 mL) were added to a custom-made reaction vessel. Two carbon rod electrodes served as the anode and cathode of an integrated electrochemical cell. A 10 mA current was applied. Simultaneously, 2a was dissolved in 1 mL of DMF and added dropwise to the electrochemical reaction system over 30 minutes. After the addition was complete, the reaction was allowed to proceed for an additional 10 minutes. The reaction was monitored by TLC. Upon complete reaction of the glycosyl thiol, the product was extracted with ethyl acetate 4-5 times. The organic phases were combined, dried over anhydrous NaSO₄, concentrated under reduced pressure, and separated by column chromatography. Column chromatography afforded the target compound 3 (83.2 mg) in a 75% yield.

[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 a glycosyl thiol, a 4-hydroxycoumarin derivative, and an electrolyte salt is used as an electrolyte, an anode and a cathode are placed in the electrolyte, and a direct current is passed through to perform an electrochemical reaction to obtain a thioglycoside compound; The glycosyl thiol has a structure of Formula 1: Formula 1 in, R1 is a five-membered sugar ring, a six-membered sugar ring or a polyvalent sugar ring; The 4-hydroxycoumarin derivative has a structure of Formula 2: 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; The electrochemical reaction conditions are: in air or protective atmosphere, a direct current of 5 to 15 mA, a temperature of 60 to 70° C., and a reaction time of 40 to 50 minutes.

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 thioglycoside compound has a structure of formula 3: 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.

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

0.

4. The method for synthesizing thioglycosides by electrochemically mediated cross-coupling of glycosyl thiols and 4-hydroxycoumarin derivatives according to any one of claims 1 to 2, characterized in that: The molar ratio of the glycosyl thiol to the electrolyte salt is 1.0:1.0~1.

5.

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

6. The method for synthesizing thioglycosides by electrochemically mediated cross-coupling of glycosyl thiols and 4-hydroxycoumarin derivatives according to any one of claims 1 to 2, characterized in that: The electrolyte uses DMF and / or DMSO as solvent.

7. The method for synthesizing thioglycosides by electrochemically mediated cross-coupling of glycosyl thiols and 4-hydroxycoumarin derivatives according to any one of claims 1 to 2, 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.

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