A method for the synthesis of unprotected s-glycosides or se-glycosides

Abstract

The application relates to a synthesis method of unprotected S-glycoside or Se-glycoside. The synthesis method takes an unprotected fluorosugar compound as a glycosylation donor, reacts with a compound R-X-X-R shown in formula I under the action of a reducing agent and an activating agent in a solvent environment, and synthesizes the unprotected S-glycoside or Se-glycoside; in formula I, X is S or Se; R is selected from any one of C 1‑10 alkyl, C 1‑10 substituted alkyl, C 6‑20 aryl, C 6‑20 substituted aryl, wherein any H atom in the substituted alkyl, the substituted aryl is independently substituted by C 1‑6 alkyl, C 1‑6 alkoxy, halogen, aryl, heterocyclyl. Compared with the prior art, the application avoids the limitation of too many protecting groups on the substrate sugar and the use of large-odor and unstable thiol and selenol compounds, simultaneously uses a cheap green solvent system, an activating agent and a reducing agent, the condition operation is simple, and atomic utilization rate and reaction efficiency are high.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for synthesizing unprotected S-glycosides or Se-glycosides. Background Technology

[0002] S-glycosides and Se-glycosides possess unique biological activities, including but not limited to antitumor activity, immunomodulation, and hypoglycemic activity. Furthermore, their relatively stable structures make them excellent donors for glycosylation reactions.

[0003] However, directly converting natural sugars into complex glycosides remains a significant challenge. Traditional glycosylation reactions inevitably involve cumbersome upprotection-deprotection steps, and even require changing different leaving groups to adapt to different reactivity levels in order to improve substrate activity. These steps are highly complex and lack atom economy.

[0004] Existing research has begun to bypass the cumbersome upprotection-deprotection process through ingenious chemical design, enabling the successful preparation of unprotected S-glycosides or Se-glycosides. For example, existing research (Direct radical functionalization of native sugars. Nature, 2024, 631(8020), 319-327.) utilizes DMC (2-chloro-1,3-dimethylimidazoline chloride) to selectively activate the anomeric hydroxyl group, generating a transient 2,3,5,6-tetrafluoropyridine-4-thioglycoside intermediate. Subsequently, under photoinduced free radical cross-coupling, it reacts with diselenide or disulfide to directly obtain unprotected Se-glycosides and S-glycosides. For example, existing research (Protecting-group-free S-glycosylation towards thioglycosides and thioglycopeptides in water) successfully prepared high-yield S-linked glycopeptides using glycosyl fluoride as a donor, thiol-modified methyl glycosides as acceptors, and Ca(OH)₂ as a promoter, under aqueous phase and room temperature conditions. However, the above techniques are only effective for water-soluble acceptor nucleophiles, and their reaction effect is poor for poorly water-soluble thiol compounds. Furthermore, they have not yet been applied to selenium-containing acceptor nucleophiles. At the same time, many existing small-molecule sulfur and selenium nucleophiles are highly toxic, have unpleasant odors, and low boiling points, making them unsuitable for direct use. In addition, the above methods typically require 3 equivalents of fluoroglycoside substrate to ensure a high reaction yield.

[0005] Therefore, there is an urgent need to develop a novel preparation method that can avoid the cumbersome protection-deprotection steps, directly synthesize unprotected S-glycosides or Se-glycosides, and is suitable for acceptor nucleophiles with poor water solubility, has little odor, is easy to operate, and uses a small amount of fluoroglycosides. Summary of the Invention

[0006] The purpose of this invention is to overcome the defects of the prior art and provide a method for synthesizing unprotected S-glycosides or Se-glycosides.

[0007] The objective of this invention can be achieved through the following technical solutions: This invention provides a method for synthesizing unprotected S-glycosides or Se-glycosides. The method uses an unprotected fluoroglycoside as a glycosylation donor and reacts it with compound RXXR of Formula I in a solvent environment under the action of a reducing agent and an activating agent to synthesize unprotected S-glycosides or Se-glycosides. In Formula I, X is S or Se; R is selected from C 1-10 Alkyl, C 1-10 Substituted alkyl, C 6-20 Aryl, C 6-20 Any of the substituted aryl groups, wherein any H atom in the substituted alkyl or substituted aryl group is independently C 1-6 Alkyl, C 1-6 Alkoxy, halogen, aryl, heterocyclic substitution.

[0008] Furthermore, the unprotected fluorinated glycoside is an unprotected monosaccharide or disaccharide.

[0009] Further, the unprotected fluorinated glycosides are α-1-fluoro-D-glucose pyranopyranose, α-1-fluoro-D-galactopyranose, α-1-fluoro-D-mannopyranose, α-1-fluoro-D-frucopyranose, α-1-fluoro-L-rhamnopyranose, α-1-fluoro-D-fucopyranose, α-1-fluoro-D-ribofuranosaccharide, α-1-fluoro-2-deoxy-D-ribofuranosaccharide, etc. Any one of α-1-fluoro-D-xylpyranose, α-1-fluoro-L-arabinopyranose, α-1-fluoro-D-arabinopyranose, α-1-fluoro-D-maltopyranose, α-1-fluoro-D-cellobiose, α-1-fluoro-D-sucrose, α-1-fluoro-D-lactose, α-1-fluoro-D-trehalose, and α-1-fluoro-D-gentiobiose.

[0010] Further, the unprotected fluorinated glycosyl compound is preferably α-1-fluoro-D-glucose pyranose, α-1-fluoro-D-galactopyranose, or α-1-fluoro-D-mannopyranose, with the following structural formulas: , , .

[0011] Furthermore, the compound RXXR shown in Formula I is specifically selected from the following structural formulas: , , , , , .

[0012] Furthermore, the molar ratio of the unprotected fluoroglycoside compound to the compound shown in Formula I is (0.5~6):1.

[0013] Furthermore, the molar ratio of the unprotected fluorinated glycoside compound, the reducing agent, and the activator is (1~2): 1:(1~2).

[0014] Furthermore, the reducing agent is an organic reducing agent or an inorganic reducing agent.

[0015] Furthermore, the organic reducing agent is any one or more of trimethylphosphine, tri-n-butylphosphine, tri-n-hexylphosphine, tri-n-octylphosphine, triphenylphosphine, and diphenylphosphine, preferably an organophosphine reagent, and more preferably diphenylphosphine.

[0016] Furthermore, the inorganic reducing agent is any one or more of zinc, sodium borohydride, phosphite, sodium dithionite, and hydrazine.

[0017] Furthermore, the activator is a metal hydroxide or a mixture of metal ions and an alkali.

[0018] Furthermore, the metal hydroxide is preferably calcium hydroxide.

[0019] Furthermore, the mixture of metal ions and alkali is preferably a mixture of calcium chloride and triethylamine, and the molar ratio of calcium ions to alkali is 3:1 to 1:3, preferably 1:1.

[0020] Furthermore, the solvent is water or a mixture of water and an organic solvent.

[0021] Furthermore, the organic solvent is any one or a combination of methanol, ethanol, propanol, isopropanol, and triethylene glycol.

[0022] Furthermore, the volume ratio of the organic solvent to water is (2-5):1.

[0023] Furthermore, the reaction temperature is 25-50 °C.

[0024] Furthermore, the reaction time is 4-10 h.

[0025] Compared with the prior art, the present invention has the following technical advantages: (1) This invention uses relatively stable fluorinated sugars as glycosylation donors and stable, low-odor disulfide and diselenide compounds as acceptor precursors. Under the action of activators and reducing agents, a variety of unprotected S-glycosides or Se-glycosides are prepared simply and efficiently through a "one-pot method".

[0026] (2) The present invention uses unprotected fluoroglycosides for the reaction, avoiding the cumbersome steps of protection-deprotection, shortening the synthetic route and improving the reaction efficiency.

[0027] (3) The present invention uses diphenylphosphine to reduce thioether and selenide to generate nucleophilic reagents, avoiding the use of thiols or selenols with strong odor, instability and high toxicity as glycosylation acceptors, embodying the concept of green chemistry synthesis, and is suitable for industrial production.

[0028] (4) The present invention uses a cheap and green water / methanol green solvent system, which is simple to operate and the activator and reducing agent are cheap; at the same time, the atom utilization rate and reaction efficiency are high, and glycosylated products with β configuration can be obtained. Attached Figure Description

[0029] Figure 1 The product of Example 1 1 H NMR spectrum.

[0030] Figure 2 The product of Example 1 13 C NMR spectrum.

[0031] Figure 3 The product of Example 2 1 H NMR spectrum.

[0032] Figure 4 The product of Example 2 13 C NMR spectrum.

[0033] Figure 5 The product of Example 3 1 H NMR spectrum.

[0034] Figure 6 The product of Example 3 13 C NMR spectrum.

[0035] Figure 7 The product of Example 4 1 H NMR spectrum.

[0036] Figure 8 The product of Example 4 13C NMR spectrum.

[0037] Figure 9 The product of Example 5 1 H NMR spectrum.

[0038] Figure 10 The product of Example 5 13 C NMR spectrum.

[0039] Figure 11 The product of Example 6 1 H NMR spectrum.

[0040] Figure 12 The product of Example 6 13 C NMR spectrum.

[0041] Figure 13 The product of Example 7 1 H NMR spectrum.

[0042] Figure 14 The product of Example 7 13 C NMR spectrum.

[0043] Figure 15 The product of Example 8 1 H NMR spectrum.

[0044] Figure 16 The product of Example 8 13 C NMR spectrum.

[0045] Figure 17 The product of Example 9 1 H NMR spectrum.

[0046] Figure 18 The product of Example 9 13 C NMR spectrum.

[0047] Figure 19 The product of Example 10 1 H NMR spectrum.

[0048] Figure 20 The product of Example 10 13 C NMR spectrum. Detailed Implementation

[0049] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments. These embodiments are based on the technical solution of the present invention and provide detailed implementation methods and specific operating procedures. However, the scope of protection of the present invention is not limited to the following embodiments.

[0050] Unless otherwise specified, the reagents, methods, instruments, and equipment used in this invention are conventional in the art. Unless otherwise specified, the reagents and materials used in the following examples are all commercially available.

[0051] This invention provides a method for synthesizing unprotected S-glycosides or Se-glycosides. Using relatively stable unprotected α-fluoroglycosides as glycosylation donors, the unprotected S-glycosides or Se-glycosides undergo a nucleophilic reaction with disulfide or diselenide in a solvent environment under the action of reducing agents and activators to synthesize unprotected S-glycosides or Se-glycosides.

[0052] The reaction formula of this invention can be referred to as follows: .

[0053] RXXR refers to disulfides or diselenides, specifically dialkyl disulfides (referring to SP). 3 Carbon bonded to sulfur atoms), dialkyl diselenyl ether (referring to sp...) 3 Carbon bonded to selenium atom), diaryl disulfide (referring to sp...) 2 Carbon bonded to sulfur atom), diaryl diselenide (referring to sp...) 2 Carbon bonds to selenium atoms.

[0054] Specifically, the R group is a substituted or unsubstituted alkyl or aryl group. The alkyl group includes, but is not limited to, straight-chain alkyl, branched-chain amino, and cycloalkyl groups; the aryl group includes, but is not limited to, phenyl, naphthyl, anthraceneyl, and phenanthreneyl groups; any H atom in the substituted alkyl or substituted aryl group is independently C 1-6 Alkyl, C 1-6 Alkoxy, halogen, aryl, and heterocyclic group substitutions. Those skilled in the art can design disulfides or diselenides with corresponding structures based on the molecular structure of the final product.

[0055] Specifically, diphenylphosphine is preferred as the reducing agent. Diphenylphosphine has the advantages of being inexpensive, requiring mild reduction conditions, and having a fast reduction rate; it can rapidly convert disulfides and diselenes into two equivalents of thiols or selenols at room temperature.

[0056] Specifically, the solvent is a methanol / water mixture with a volume ratio of 5:1. The advantage is that it has good solubility for various organic and inorganic raw materials and can inhibit the hydrolysis and alcoholysis reactions of fluoroglycoside raw materials.

[0057] Specifically, calcium hydroxide is preferred as the activator. Its advantages include optimal solubility in mixed solvents, maintaining a relatively low concentration of the activated fluoroglycoside molecules and suppressing side reactions; and the presence of both the activating calcium ion and the hydroxide ion, which serves as the necessary base in the reaction.

[0058] This invention selects RXXR disulfide or diselenide as the acceptor precursor. Compared with their corresponding thiols and selenols, the molecular weight is almost twice as large, the boiling point is high, the illicitity is low, and the unpleasant odor is significantly reduced. At the same time, organic disulfides and organic diselenides have higher oxidative stability than their corresponding thiols and enols, are easy to operate, and do not require strict anaerobic conditions. They can rapidly release the required thiols and selenophiles in the presence of a reducing agent.

[0059] Example 1: This embodiment provides a method for synthesizing unprotected S-glycosides, as detailed below: .

[0060] To a 10 mL Schlenk tube, p-toluene disulfide (123 mg, 0.5 mmol), calcium hydroxide (74 mg, 1.0 mmol, 2.0 eq), and diphenylphosphine (92 mg, 0.5 mmol, 1.0 eq) were added and dissolved in a 5 / 1 (v / v) methanol / water mixture (6 mL). After stirring at room temperature for 10 minutes, α-D-glucopyranosyl fluoride (CAS: 2106-10-7, 182 mg, 1.0 mmol, 2.0 eq) was added, and the mixture was reacted at 35 °C with stirring for 6 hours.

[0061] After the reaction was completed, the reaction solution was evaporated and concentrated. The reactants were adsorbed onto silica gel and purified by silica gel column chromatography to obtain the corresponding β-configuration coupling product (229 mg, 80% yield). 1 1H NMR analysis of product purity.

[0062] Nuclear magnetic resonance characterization is shown in Figure 1-2 The data is as follows: 1 H NMR (600 MHz, Methanol- d 4) δ 7.48–7.43 (m, 2H), 7.12 (d, J = 7.8Hz, 2H), 4.50 (d, J = 9.8 Hz, 1H), 3.85 (dd, J = 12.1, 1.9 Hz, 1H), 3.65 (dd, J = 12.0, 5.1 Hz, 1H), 3.36 (t, J = 8.4 Hz, 1H), 3.29 – 3.24 (m, 2H), 3.20 –3.14 (m, 1H), 2.31 (s, 3H). 13 C NMR (151 MHz, Methanol- d 4) δ 138.8, 133.5, 131.2, 130.5, 89.6, 82.0, 79.7, 73.7, 71.4, 62.9, 21.1.

[0063] Example 2: This embodiment provides a method for synthesizing unprotected S-glycosides, as detailed below: .

[0064] Difurfuryl disulfide (113 mg, 0.5 mmol), calcium hydroxide (74 mg, 1.0 mmol, 2.0 eq), and diphenylphosphine (92 mg, 0.5 mmol, 1.0 eq) were added to a 10 mL Schlenk tube and dissolved in a 5 / 1 methanol / water mixture (6 mL). After stirring at room temperature for 10 minutes, α-fluorosaccharide (182 mg, 1.0 mmol, 2.0 eq) was added, and the mixture was reacted at 35 °C with stirring for 6 hours.

[0065] After the reaction was complete, the reaction solution was evaporated and concentrated. The reactants were adsorbed onto silica gel and purified by silica gel column chromatography to obtain the corresponding β-configuration coupling product (155 mg, 56% yield). 1 1H NMR analysis of product purity.

[0066] Nuclear magnetic resonance characterization is shown in Figure 3-4 The data is as follows: 1 H NMR (600 MHz, Methanol-) d 4) δ 7.41 (d, J = 1.8 Hz, 1H), 6.33 (t, J =2.4 Hz, 1H), 6.27 (d, J = 3.2 Hz, 1H), 4.33 (d, J = 9.7 Hz, 1H), 4.09 (d, J =14.5 Hz, 1H), 3.91 –3.82 (m, 2H), 3.67 (dd, J = 12.1, 5.9 Hz, 1H), 3.33 –3.30 (m, 2H), 3.27 – 3.22 (m, 2H). 13 C NMR (151 MHz, Methanol-d 4) δ 152.6, 143.3, 111.4, 108.8, 85.5,81.9, 79.6, 74.3, 71.4, 62.8, 26.4.

[0067] Example 3: This embodiment provides a method for synthesizing unprotected S-glycosides, as detailed below: .

[0068] Isopropyl disulfide (75 mg, 0.5 mmol), calcium hydroxide (74 mg, 1.0 mmol, 2.0 eq), and diphenylphosphine (92 mg, 0.5 mmol, 1.0 eq) were added to a 10 mL Schlenk tube and dissolved in a 5 / 1 methanol / water mixture (6 mL). After stirring at room temperature for 10 minutes, α-fluorosaccharide (182 mg, 1.0 mmol, 2.0 eq) was added, and the mixture was reacted at 35 °C with stirring for 6 hours.

[0069] After the reaction was complete, the reaction solution was evaporated and concentrated. The reactants were adsorbed onto silica gel and purified by silica gel column chromatography to obtain the corresponding β-configuration coupling product (155 mg, 65% yield). 1 1H NMR analysis of product purity.

[0070] Nuclear magnetic resonance characterization is shown in Figure 5-6 The data is as follows: 1 H NMR (600 MHz, Methanol-) d 4) δ 4.43 (d, J = 9.8 Hz, 1H), 3.84 (dd,12.0, 2.1 Hz, 1H), 3.64 (dd, J = 12.0, 5.5 Hz, 1H), 3.35 (t, J = 8.5 Hz, 1H),3.31–3.19 (m, 3H), 3.15 (dd, J = 9.8, 8.6 Hz, 1H), 1.30 (dd, J = 8.8, 6.7 Hz, 6H). 13 C NMR (151 MHz, Methanol- d 4) δ 86.5, 81.9, 79.7, 74.6, 71.5, 62.9, 35.7, 24.3, 24.3.

[0071] Example 4: This embodiment provides a method for synthesizing unprotected Se-glycosides, as detailed below: .

[0072] Diphenylselenoether (118 mg, 5 mmol), calcium hydroxide (74 mg, 1.0 mmol, 2.0 eq), and diphenylphosphine (92 mg, 0.5 mmol, 1.0 eq) were added to a 10 mL Schlenk tube and dissolved in a 5 / 1 methanol / water mixture (6 mL). After stirring at room temperature for 10 minutes, α-fluorosaccharide (182 mg, 1.0 mmol, 2.0 eq) was added, and the mixture was reacted at 35 °C with stirring for 6 hours.

[0073] After the reaction was completed, the reaction solution was evaporated and concentrated. The reactants were adsorbed onto silica gel and purified by silica gel column chromatography to obtain the corresponding β-configuration coupling product (263 mg, 82% yield). 1 1H NMR analysis of product purity.

[0074] Nuclear magnetic resonance characterization is shown in Figure 7-8 The data is as follows: 1 H NMR (600 MHz, Methanol- d 4) δ 7.71 – 7.64 (m, 2H), 7.30 –7.25 (m, 3H), 4.81 (d, J = 9.8 Hz, 1H), 3.85 (dd, J = 12.0, 1.6 Hz, 1H), 3.67 – 3.62(m, 1H), 3.37 – 3.33 (m, 1H), 3.29 – 3.22 (m, 3H). 13 C NMR (151 MHz, Methanol- d 4) δ 135.3, 129.9, 129.8, 128.7, 86.0, 83.1, 79.5, 74.4, 71.3, 62.8.

[0075] Example 5: This embodiment provides a method for synthesizing unprotected Se-glycosides, as detailed below: .

[0076] Cyclohexyldiselelenide (162 mg, 0.5 mmol), calcium hydroxide (74 mg, 1.0 mmol, 2.0 eq), and diphenylphosphine (92 mg, 0.5 mmol, 1.0 eq) were added to a 10 mL Schlenk tube and dissolved in a 5 / 1 methanol / water mixture (6 mL). After stirring at room temperature for 10 minutes, α-fluorosaccharide (182 mg, 1.0 mmol, 2.0 eq) was added, and the mixture was reacted at 35 °C with stirring for 6 hours.

[0077] After the reaction was completed, the reaction solution was evaporated and concentrated. The reactants were adsorbed onto silica gel and purified by silica gel column chromatography to obtain the corresponding β-configuration coupling product (198 mg, 61% yield). 1 1H NMR analysis of product purity.

[0078] Nuclear magnetic resonance characterization is shown in Figure 9-10 The data is as follows: 1 H NMR (600 MHz, Methanol- d 4) δ 4.66 (d, J = 9.7 Hz, 1H), 3.79 (dd, J = 12.1, 2.2 Hz, 1H), 3.58 (dd, J = 12.1, 5.7 Hz, 1H), 3.28 – 3.26 (m, 1H), 3.24 – 3.18 (m, 3H), 2.09 – 1.94 (m, 2H), 1.73–1.64 (m, 2H), 1.59 – 1.47 (m, 3H), 1.39 – 1.20 (m, 4H). 13 C NMR (151 MHz, Methanol- d 4) δ 83.2, 81.9, 79.6, 75.5, 71.5, 62.9, 40.1, 36.2, 35.9, 27.8, 27.7, 27.0.

[0079] Example 6: This embodiment provides a method for synthesizing unprotected Se-glycosides, as detailed below: .

[0080] Add p-methoxyphenyl disulfide (186 mg, 0.5 mmol), calcium hydroxide (74 mg, 1.0 mmol, 2.0 eq), and diphenylphosphine (92 mg, 0.5 mmol, 1.0 eq) to a 10 mL Schlenk tube, then dissolve in a 5 / 1 methanol / water mixture (6 mL). Stir at room temperature for 10 minutes, then add α-fluorosaccharide (182 mg, 1.0 mmol, 2.0 eq), and react at 35 °C with stirring for 6 hours.

[0081] After the reaction was completed, the reaction solution was evaporated and concentrated. The reactants were adsorbed onto silica gel and purified by silica gel column chromatography to obtain the corresponding β-configuration coupling product (282 mg, 81% yield). 1 1H NMR analysis of product purity.

[0082] Nuclear magnetic resonance characterization is shown in Figure 11-12 The data is as follows: 1 H NMR (600 MHz, Methanol- d 4) δ 7.59 – 7.54 (m, 2H), 6.83 – 6.77 (m, 2H), 4.60 (d, J = 9.8 Hz, 1H), 3.78 (dd, J = 12.1, 1.9 Hz, 1H), 3.73 (s, 3H), 3.57 (dd, J = 12.0, 5.2 Hz, 1H), 3.27 (t, J = 8.4 Hz, 1H), 3.21 – 3.14 (m,2H), 3.10 (t, J = 9.3 Hz, 1H). 13 C NMR (151 MHz, Methanol- d 4) δ 161.5, 138.3, 118.8, 115.5, 86.0, 83.1, 79.5, 74.3, 71.4, 62.9, 55.7.

[0083] Example 7: This embodiment provides a method for synthesizing unprotected S-glycosides, as detailed below: .

[0084] Add p-toluene disulfide (123 mg, 0.5 mmol), calcium hydroxide (74 mg, 1.0 mmol, 2.0 eq), and diphenylphosphine (92 mg, 0.5 mmol, 1.0 eq) to a 10 mL Schlenk tube, then dissolve in a 5 / 1 methanol / water mixture (6 mL). Stir at room temperature for 10 minutes, then add fluorosaccharides (182 mg, 1.0 mmol, 2.0 eq) and react at 35 °C with stirring for 6 hours.

[0085] After the reaction was complete, the reaction solution was evaporated and concentrated. The reactants were adsorbed onto silica gel and purified by silica gel column chromatography to obtain the corresponding β-configuration coupling product (228 mg, 80% yield). 1 1H NMR analysis of product purity.

[0086] Nuclear magnetic resonance characterization is shown in Figure 13-14 The data is as follows: 1 H NMR (600 MHz, Methanol- d 4) δ 7.45 (d, J = 7.8 Hz, 2H), 7.11 (d, J =7.9 Hz, 2H), 4.51 (d, J = 9.6 Hz, 1H), 3.89 (d, J = 3.3 Hz, 1H), 3.78 – 3.68(m, 2H), 3.58 (t, J = 9.4 Hz, 1H), 3.53 (t, J = 6.1 Hz, 1H), 3.49 (dd, J =9.2, 3.3 Hz, 1H), 2.30 (s, 3H). 13 C NMR (151 MHz, Methanol- d 4) δ 138.4, 132.9, 132.1, 130.5, 90.6, 80.5, 76.3, 71.0, 70.4, 62.6, 21.1.

[0087] Example 8: This embodiment provides a method for synthesizing unprotected Se-glycosides, as detailed below: .

[0088] Diphenyldiselenoether (118 mg, 0.5 mmol), calcium hydroxide (74 mg, 1.0 mmol, 2.0 eq), and diphenylphosphine (92 mg, 0.5 mmol, 1.0 eq) were added to a 10 mL Schlenk tube and dissolved in a 5 / 1 methanol / water mixture (6 mL). After stirring at room temperature for 10 minutes, fluorosaccharides (182 mg, 1.0 mmol, 2.0 eq) were added, and the mixture was reacted at 35 °C with stirring for 6 hours.

[0089] After the reaction was completed, the reaction solution was evaporated and concentrated. The reactants were adsorbed onto silica gel and purified by silica gel column chromatography to obtain the corresponding β-configuration coupling product (269 mg, 84% yield). 1 1H NMR analysis of product purity.

[0090] Nuclear magnetic resonance characterization is shown in Figure 15-16 The data is as follows: 1 H NMR (600 MHz, Methanol- d 4) δ 7.67 (dd, J = 6.6, 2.9 Hz, 2H), 7.29– 7.23 (m, 3H), 4.81 (d, J = 9.9 Hz, 1H), 3.91 (d, J = 3.3 Hz, 1H), 3.76 (dd, J = 11.5, 6.8 Hz, 1H), 3.73 – 3.65 (m, 2H), 3.52 (t, J = 6.1 Hz, 1H), 3.47(dd, J = 9.2, 3.3 Hz, 1H). 13 C NMR (151 MHz, Methanol- d 4) δ 134.8, 130.7, 129.9, 128.4, 87.2, 81.8, 76.2, 71.8, 70.5, 62.6.

[0091] Example 9: This embodiment provides a method for synthesizing unprotected S-glycosides, as detailed below: .

[0092] Add p-toluene disulfide (123 mg, 0.5 mmol), calcium hydroxide (74 mg, 1.0 mmol, 2.0 eq), and diphenylphosphine (92 mg, 0.5 mmol, 1.0 eq) to a 10 mL Schlenk tube, then dissolve in a 5 / 1 methanol / water mixture (6 mL). Stir at room temperature for 10 minutes, then add fluorosaccharides (182 mg, 1.0 mmol, 2.0 eq) and react at 35 °C with stirring for 6 hours.

[0093] After the reaction was complete, the reaction solution was evaporated and concentrated. The reactants were adsorbed onto silica gel and purified by silica gel column chromatography to obtain the corresponding β-configuration coupling product (228 mg, 80% yield). 1 1H NMR analysis of product purity.

[0094] Nuclear magnetic resonance characterization is shown in Figure 17-18 The data is as follows: 1 H NMR (600 MHz, Methanol- d 4) δ 7.44 – 7.38 (m, 2H), 7.13 (d, J = 7.9Hz, 2H), 5.35 (d, J = 1.6 Hz, 1H), 4.07 (dd, J = 3.2, 1.6 Hz, 1H), 4.04 (ddd, J = 9.2, 5.4, 2.4 Hz, 1H), 3.81 (dd, J = 12.0, 2.5 Hz, 1H), 3.78 – 3.65 (m,3H), 2.31 (s, 3H). 13 C NMR (151 MHz, Methanol- d 4) δ 138.9, 133.5, 132.1, 130.7, 90.8,75.5, 73.7, 73.1, 68.7, 62.6, 21.1.

[0095] Example 10: This embodiment provides a method for synthesizing unprotected Se-glycosides, as detailed below: .

[0096] Diphenyldiselenoether (118 mg, 0.5 mmol), calcium hydroxide (74 mg, 1.0 mmol, 2.0 eq), and diphenylphosphine (92 mg, 0.5 mmol, 1.0 eq) were added to a 10 mL Schlenk tube and dissolved in a 5 / 1 methanol / water mixture (6 mL). After stirring at room temperature for 10 minutes, fluorosaccharides (182 mg, 1.0 mmol, 2.0 eq) were added, and the mixture was reacted at 35 °C with stirring for 6 hours.

[0097] After the reaction was completed, the reaction solution was evaporated and concentrated. The reactants were adsorbed onto silica gel and purified by silica gel column chromatography to obtain the corresponding β-configuration coupling product (260 mg, 81% yield). 1 1H NMR analysis of product purity.

[0098] Nuclear magnetic resonance characterization is shown in Figures 19-20 The data is as follows: 1 H NMR (600 MHz, Methanol- d 4) δ 7.66 – 7.60 (m, 2H), 7.29 (dd, J =5.1, 1.9 Hz, 3H), 5.73 (d, J = 1.5 Hz, 1H), 4.19 (dd, J = 3.3, 1.5 Hz, 1H),4.00 – 3.92 (m, 1H), 3.84 (dd, J = 12.0, 2.5 Hz, 1H), 3.82 – 3.72 (m, 2H), 3.70 (dd, J = 9.5, 3.2 Hz, 1H). 13 C NMR (151 MHz, Methanol- d 4) δ 135.1, 131.0, 130.2, 128.7, 88.6,77.4, 74.3, 73.5, 68.5, 62.5.

[0099] In summary, this invention utilizes relatively stable α-fluoroglycosides as glycosylation donors and stable, odorless disulfide and diselenoside compounds as acceptor precursors. Under the action of activators and reducing agents, it achieves the simple and efficient preparation of various S-glycoside and Se-glycoside compounds. This invention avoids the limitation of requiring excessive protecting groups on the substrate sugar and also avoids the use of odorous and unstable thiols and selenools. It employs inexpensive and environmentally friendly solvent systems, activators, and reducing agents, and is easy to operate. Furthermore, it boasts high atom utilization and reaction efficiency, primarily yielding β-configured products, thus possessing significant social and economic benefits.

[0100] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A method for synthesizing an unprotected S-glycoside or Se-glycoside, characterized in that, This synthetic method uses unprotected fluorinated glycosyl compounds as glycosylation donors, and reacts them with compound RXXR shown in Formula I in a solvent environment under the action of reducing agents and activators to synthesize unprotected S-glycosides or Se-glycosides. In Formula I, X is S or Se; R is selected from C 1-10 Alkyl, C 1-10 Substituted alkyl, C 6-20 Aryl, C 6-20 Any of the substituted aryl groups, wherein any H atom in the substituted alkyl or substituted aryl group is independently C 1-6 Alkyl, C 1-6 Alkoxy, halogen, aryl, heterocyclic substitution.

2. The method for synthesizing an unprotected S-glycoside or Se-glycoside according to claim 1, characterized in that, The unprotected fluorinated glycosides are unprotected monosaccharides or disaccharides; The unprotected fluoroglycosyl compounds are α-1-fluoro-D-glucose pyranopyranose, α-1-fluoro-D-galactopyranose, α-1-fluoro-D-mannopyranose, α-1-fluoro-D-frucopyranose, α-1-fluoro-L-rhamnopyranose, α-1-fluoro-D-furanose, α-1-fluoro-D-ribofuranosaccharide, α-1-fluoro-2-deoxy-D-ribofuranosaccharide, α-1 Any one of the following: α-fluoro-D-xylpyranose, α-1-fluoro-L-arabinopyranose, α-1-fluoro-D-arabinopyranose, α-1-fluoro-D-malpyranose, α-1-fluoro-D-cellobiose, α-1-fluoro-D-sucrose, α-1-fluoro-D-lactopyranose, α-1-fluoro-D-trehalose, and α-1-fluoro-D-gentiobiose.

3. The method for synthesizing an unprotected S-glycoside or Se-glycoside according to claim 1, characterized in that, The unprotected fluoroglycosyl compound is preferably α-1-fluoro-D-glucose pyranose, α-1-fluoro-D-galactopyranose, or α-1-fluoro-D-mannopyranose, with the following structural formulas: ， ， 。 4. The method for synthesizing an unprotected S-glycoside or Se-glycoside according to claim 1, characterized in that, The compound RXXR shown in Formula I is specifically selected from the following structural formulas: ， ， ， ， ， 。 5. The method for synthesizing an unprotected S-glycoside or Se-glycoside according to claim 1, characterized in that, The molar ratio of the unprotected fluoroglycoside compound to the compound shown in Formula I is (0.5~6): 1; The molar ratio of the unprotected fluorinated glycoside compound, the reducing agent, and the activator is (1~2): 1: (1~2).

6. The method for synthesizing an unprotected S-glycoside or Se-glycoside according to claim 1, characterized in that, The reducing agent is an organic reducing agent or an inorganic reducing agent; The organic reducing agent is any one or more of trimethylphosphine, tri-n-butylphosphine, tri-n-hexylphosphine, tri-n-octylphosphine, triphenylphosphine, and diphenylphosphine; The inorganic reducing agent is any one or more of zinc, sodium borohydride, phosphite, sodium dithionite, and hydrazine.

7. The method for synthesizing an unprotected S-glycoside or Se-glycoside according to claim 1, characterized in that, The activator is a metal hydroxide or a mixture of metal ions and an alkali.

8. The method for synthesizing an unprotected S-glycoside or Se-glycoside according to claim 7, characterized in that, The metal hydroxide is preferably calcium hydroxide; The mixture of metal ions and alkali is preferably a mixture of calcium chloride and triethylamine, and the molar ratio of calcium ions to alkali is 3:1 to 1:

3.

9. The method for synthesizing an unprotected S-glycoside or Se-glycoside according to claim 1, characterized in that, The solvent is water or a mixture of water and an organic solvent; The organic solvent is any one or a combination of methanol, ethanol, propanol, isopropanol, and triethylene glycol, and the volume ratio of the organic solvent to water is (2-5):

1.

10. The method for synthesizing an unprotected S-glycoside or Se-glycoside according to claim 1, characterized in that, The reaction temperature is 25-50 °C, and the reaction time is 4-10 h.

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