Palladium-silver dual-mechanism switching carbohydrate hydroxyl region selective sulfonylation method

Abstract

The invention belongs to the field of organic synthesis and carbohydrate chemistry, and particularly discloses a carbohydrate hydroxyl region selective sulfonylation method. According to the method, a reaction mechanism is switched by selectively adding or omitting a palladium catalyst: when the palladium catalyst, a ligand and silver salt coexist, the system selectively sulfonylates equatorial hydroxyl; when a palladium catalyst is not added and only the ligand and the silver salt are retained, the system is selectively sulfonylated into axial or paraaxial hydroxyl. The method is easy and convenient to operate, accurate regulation and control of regioselectivity can be achieved without replacing ligands or additives, and the method has high selectivity and excellent substrate universality and is suitable for various pyranoside substrates and sulfonylation reagents. The obtained sulfonylation product is a key intermediate for synthesizing carbohydrate drugs, natural products and biological probes, and has a wide application prospect.

Description

Technical Field

[0001] This invention belongs to the fields of organic synthesis and carbohydrate chemistry, and specifically relates to a palladium-silver dual-mechanism switching method for regioselective sulfonation of carbohydrate hydroxyl groups. Background Technology

[0002] Unprotected monosaccharide molecules typically contain multiple hydroxyl groups with similar chemical environments, and achieving regioselective functionalization of specific hydroxyl groups has always been a challenge in synthetic chemistry. Current techniques often require the design of custom protecting groups or catalysts for specific substrates, lacking a universal and switchable strategy. In particular, when selectively modifying equatorial bonds or axial hydroxyl groups on the same substrate is required, traditional methods necessitate changing the entire set of reaction conditions, resulting in cumbersome processes and low efficiency. Summary of the Invention

[0003] To address the aforementioned technical problems, this invention proposes a palladium-silver dual-mechanism switching method for regioselective sulfonation of carbohydrate hydroxyl groups, providing a simple, universal, and switchable strategy to achieve regioselective sulfonation of carbohydrate hydroxyl groups.

[0004] The palladium-silver dual-mechanism switching method for regioselective sulfonation of carbohydrate hydroxyl groups of the present invention employs a dual-mechanism catalytic system. By selectively adding or omitting the palladium catalyst, regioselective sulfonation of equatorial or axial hydroxyl groups is achieved, including the following two modes:

[0005] Mode A: In the presence of palladium catalyst, ligand, and silver salt, carbohydrate substrates are reacted with sulfonating agents in an organic solvent under an inert atmosphere to selectively sulfonate equatorial hydroxyl groups;

[0006] Mode B: Without the addition of a palladium catalyst, a ligand and a silver salt are used to react a carbohydrate substrate with a sulfonating agent in an organic solvent to selectively sulfonate axial or paraxial hydroxyl groups.

[0007] The palladium catalyst is (2,2'-bipyridine)palladium(II) chloride, PdCl2, Pd2(dba)3 or Pd(PPh3)4.

[0008] The ligand is 1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, 2,2'-bipyridine, or BINAP.

[0009] The silver salt is Ag2CO3, AgOTf, AgBF4, or AgNO3.

[0010] The sulfonating agent is p-toluenesulfonyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride, p-nitrobenzenesulfonyl chloride, or 2,4,6-triisopropylbenzenesulfonyl chloride.

[0011] The carbohydrate substrate is an unprotected or partially protected pyranoside or furanoside, including mannose, glucose, galactose, rhamnose, fucose, arabinose, or a derivative of sialic acid.

[0012] The organic solvent is anhydrous acetonitrile, anhydrous chloroform, anhydrous THF, or anhydrous dichloromethane.

[0013] The reactions of Mode A and Mode B are carried out under an inert atmosphere at room temperature.

[0014] This invention also proposes a palladium-silver dual-mechanism switching catalytic system for regioselective sulfonation of carbohydrate hydroxyl groups, comprising a silver salt, a ligand, and a palladium catalyst. The regioselectivity of the sulfonation reaction is switched by including or omitting the palladium catalyst.

[0015] The beneficial effects of this invention are:

[0016] Compared with existing technologies, this method employs a unique dual-mechanism catalytic strategy, achieving significantly different regioselectivity simply by selectively adding or omitting the palladium catalyst, without requiring changes to ligands or additives. It is simple to operate and cost-effective. This method exhibits excellent regioselectivity for a variety of pyranoside substrates (including mannose, glucose, galactose, rhamnose, fucose, and arabinose), is applicable to both primary and secondary hydroxyl groups, and has broad substrate compatibility, suitable for various common protecting groups and sulfonyl chloride reagents, laying a solid foundation for subsequent derivatization. Furthermore, the obtained sulfonated products are key intermediates in the synthesis of saccharide drugs, natural products, and biological probes; therefore, this method has excellent industrial application potential and broad application prospects. Attached Figure Description

[0017] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the description of the embodiments are briefly introduced below.

[0018] Figure 1 This is a schematic diagram of two reaction modes of the method of the present invention;

[0019] Figure 2 This is a schematic diagram illustrating the applicability of the method of the present invention to various sulfonyl chloride reagents.

[0020] Figure 3 This is a schematic diagram showing the results of regioselective sulfonation of various carbohydrate substrates using the method of the present invention. Detailed Implementation

[0021] To enable those skilled in the art to better understand the technical solution of the present invention, the present invention will be further described in detail below with reference to the accompanying drawings.

[0022] Example 1

[0023] like Figure 1 As shown, the palladium-silver dual-mechanism switching method for regioselective sulfonation of carbohydrate hydroxyl groups achieves regioselective sulfonation of equatorial or axial hydroxyl groups by selectively adding or omitting the palladium catalyst, including the following two modes:

[0024] Substrate: 2,3-O-unprotected methyl α- D -Mannopyranoside 1a.

[0025] Mode A: Under an argon atmosphere, a dried 10 mL Schlenk tube with a magnetic stir bar was filled with the following additives in sequence: (2,2'-bipyridine)palladium(II) dichloride 3.3 mg (0.010 mmol, 10 mol%), 1,10-phenanthroline 3.3 mg (0.010 mmol, 10 mol%), Ag₂CO₃ 27.5 mg (0.10 mmol, 1.0 equiv.), substrate 1a 28.2 mg (0.10 mmol), and p-toluenesulfonyl chloride (TsCl) 22.8 mg (0.12 mmol, 1.2 equiv.). After purging with argon three times, 2.0 mL of anhydrous acetonitrile was injected, and the mixture was stirred at room temperature (25 °C) for 48 h. TLC (petroleum ether / ethyl acetate 2:1) showed the disappearance of the starting material. The reaction solution was filtered through diatomaceous earth, concentrated, and subjected to silica gel column chromatography (petroleum ether / ethyl acetate 3:1 → 1:1) to give a colorless oily substance, 3-O-p-toluenesulfonyl-methyl α- D -Mannopyranoside 3a;

[0026] Mode B: The procedure is the same as in Mode A, except that (2,2'-bipyridine)palladium(II) dichloride is omitted. Stir at room temperature for 48 h. Post-treatment and purification are the same, yielding a white solid 2-O-p-toluenesulfonyl-methyl α- D -Mannopyranoside 4a.

[0027] Example 2 Sulfonation Reagent Extension

[0028] like Figure 2 As shown, subsequent studies on various sulfonyl chloride compounds demonstrate that this reaction exhibits significant tolerance to a variety of substituents (2b–2m) with different electronic effects or steric hindrance effects. Notably, the compatibility with commonly used organic synthesis reagents such as benzenesulfonyl chloride (BsCl in 2b), p-nitrobenzenesulfonyl chloride (p-NsCl in 2f), methanesulfonyl chloride (MsCl in 2g), and 2,4,6-triisopropylbenzenesulfonyl chloride (TIPBsCl in 2m) is of significant value, laying a solid foundation for subsequent general chemical transformations. Meanwhile, the sulfonyl group has extremely wide applications in drug molecule design, and can be introduced into molecules as a bioisostere to enhance biological activity, regulate solubility, prolong bioavailability, and improve pharmacokinetic properties.

[0029] Example 3 Substrate Expansion

[0030] like Figure 3 As shown, the substrate scope of carbohydrate derivatives was further evaluated. This catalytic system can be widely applied to monosaccharide compounds containing primary or secondary hydroxyl groups. α- D -Thiomannopyranoside also exhibits excellent selectivity and high yield in the sulfonation reaction at position 3 (5c). Due to the steric hindrance effect of the TBS group, which hinders the coordination of the metal with 4,6-di-tert-butyldimethylsilylmannopyranoside diol, the yield drops sharply in mode A at 5d, while only the 2-OTS product is generated at 6d in mode B. D-galactose containing 1,2-cis-diol, L Rhamnose and D-galactosyl-azidoformose yielded equatorially substituted products 5e, 5f, and 5g, respectively, in high yields under mode A. Furthermore, under mode B, the corresponding products with axial substitution, 6e, 6f, and 6g, were mainly obtained.

[0031] Catalytic mode A also exhibited significant catalytic activity for pyranose substrates containing 1,3-diol. While mode B yielded the same product as mode A, the yield was significantly lower. Therefore, using unprotected glycosides at positions 4 and 6 as substrates ultimately yielded the 6-monosulfonated product 5h-5k in 91-98% yield.

[0032] Subsequently, selective p-toluenesulfonation was performed on polyhydroxy carbohydrate derivatives containing cis-vicinal diol structures, including 6-O-TIPS protected pyranoside derivatives: galactose (5l), mannose (5m), and commercially available derivatives rhamnose (5n), fucose (5o), and arabinose (5p, 5q). The results showed that the selective p-toluenesulfonation of the equatorial O3 group yielded excellent results, ranging from 74% to 98%. For glycoside substrates containing both cis-vicinal diols and 1,3-diols (such as free methyl galactoside and mannoside), there was no or poor selectivity between the equatorial O3 group and the primary hydroxyl group in the reaction, thus generating 34% and 44% of 3,6-OTs (5r1) galactoside and 38% of 3,6-OTs mannoside (5s), respectively. For free methyl glucoside and sialic acid, since there is no cis-diol competing with 1,3-diol in the sulfonation reaction, the primary alcohol sulfonation products 5t and 5u were generated in yields of 45% and 46%, respectively. The lower yields of 5t and 5u may be due to the poor solubility of the substrate in acetonitrile.

[0033] Next, sulfonation of glycosyl derivatives containing trans-1,2-diol structures was carried out under Mode B. These conditions favor the sulfonation of the hydroxyl group adjacent to the axial alkoxy substituent in the equatorial trans-diol. When these conditions were applied to 2,3-O-unprotected α-D-glucopyranoside with different 4,6-O-protecting groups (PhCH, NaphCH, tBu2Si, [(iPr)2Si]2O), the corresponding 2-O-sulfonated products 6zb-6ze were obtained in good to excellent yields with the assistance of the axial methoxy group. Similarly, 2,3-O-unprotected β-D-galactopyranoside reacted selectively at the C3-OH site, yielding product 6zf-6zh in excellent yields with the promotion of the axial C4-O-substituent. 2,3-O-unprotected α- D 2,6-O-galactopyranoside primarily yields the C3-OTs product (6zi). Notably, the sulfonation of unprotected 2,6-O-galactopyranoside exhibits unexpected regiochemical results: contrary to the typically higher reactivity of primary alcohols, the C2-OH preferentially undergoes sulfonation over the C6-OH, yielding 6zi. This selectivity is attributed to the significant influence of the adjacent axial methoxy group.

[0034] The foregoing has only described certain exemplary embodiments of the present invention by way of illustration. Undoubtedly, those skilled in the art can modify the described embodiments in various ways without departing from the spirit and scope of the present invention. Therefore, the foregoing drawings and descriptions are illustrative in nature and should not be construed as limiting the scope of protection of the claims of the present invention.

Claims

1. A method for regioselective sulfonation of carbohydrate hydroxyl groups using a palladium-silver dual-mechanism switching approach, characterized in that, A dual-mechanism catalytic system is employed to achieve regioselective sulfonation of equatorial or axial hydroxyl groups by selectively adding or omitting palladium catalysts, including the following two modes: Mode A: In the presence of palladium catalyst, ligand, and silver salt, carbohydrate substrates are reacted with sulfonating agents in an organic solvent under an inert atmosphere to selectively sulfonate equatorial hydroxyl groups; Mode B: Without the addition of a palladium catalyst, a ligand and a silver salt are used to react a carbohydrate substrate with a sulfonating agent in an organic solvent to selectively sulfonate axial or paraxial hydroxyl groups.

2. The palladium-silver dual-mechanism switching method for regioselective sulfonation of carbohydrate hydroxyl groups according to claim 1, characterized in that, The palladium catalyst is (2,2'-bipyridine)palladium(II) chloride, PdCl2, Pd2(dba)3 or Pd(PPh3)4.

3. The palladium-silver dual-mechanism switching method for regioselective sulfonation of carbohydrate hydroxyl groups according to claim 2, characterized in that, The ligand is 1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, 2,2'-bipyridine, or BINAP.

4. The palladium-silver dual-mechanism switching method for regioselective sulfonation of carbohydrate hydroxyl groups according to claim 3, characterized in that, The silver salt is Ag2CO3, AgOTf, AgBF4, or AgNO3.

5. The palladium-silver dual-mechanism switching method for regioselective sulfonation of carbohydrate hydroxyl groups according to claim 4, characterized in that... The sulfonating agent is p-toluenesulfonyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride, p-nitrobenzenesulfonyl chloride, or 2,4,6-triisopropylbenzenesulfonyl chloride.

6. The palladium-silver dual-mechanism switching method for regioselective sulfonation of carbohydrate hydroxyl groups according to claim 5, characterized in that, The carbohydrate substrate is an unprotected or partially protected pyranoside or furanoside, including mannose, glucose, galactose, rhamnose, fucose, arabinose, or a derivative of sialic acid.

7. The palladium-silver dual-mechanism switching method for regioselective sulfonation of carbohydrate hydroxyl groups according to claim 6, characterized in that, The organic solvent is anhydrous acetonitrile, anhydrous DMF, anhydrous THF, or anhydrous dichloromethane.

8. The palladium-silver dual-mechanism switching method for regioselective sulfonation of carbohydrate hydroxyl groups according to claim 1, characterized in that, The reactions of Mode A and Mode B are carried out under an inert atmosphere at room temperature.

9. A palladium-silver dual-mechanism switching regioselective sulfonation catalytic system for carbohydrate hydroxyl groups, characterized in that, The system includes silver salts, ligands, and palladium catalysts, and the regioselectivity of the sulfonation reaction is switched by including or omitting the palladium catalyst.

10. The use of sulfonated carbohydrate derivatives prepared by any one of the methods described in claims 1-8 in synthetic drugs, natural products or biological probes.

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