A non-classical c-glycoside, its stereospecific synthesis and use

Abstract

The application provides a non-classical C-glycoside and a stereospecific synthesis method and application thereof, and the synthesis method comprises the following steps: taking a non-classical sugar-based stannane as a nucleophilic reagent, taking a halogenated hydrocarbon as an electrophilic reagent, and performing a Stille cross-coupling reaction to obtain the non-classical C-glycoside. The non-classical C-glycoside and the stereospecific synthesis method and application thereof provided by the application have the advantages that the synthesis method is simple in process, convenient in operation, high in yield, good in functional group tolerance, strong in stereospecificity, wide in sugar substrate range, and compatible with unprotected sugar and an aqueous phase system; furthermore, the obtained non-classical C-glycoside not only has better antibacterial activity, but also can be used as an active pharmaceutical material, and promotes the technological progress of the pharmaceutical synthesis industry and the pharmaceutical industry.

Description

Technical Field

[0001] This invention belongs to the field of glycoside synthesis technology, and particularly relates to a non-classical C-glycoside and its stereospecific synthesis method and application. Background Technology

[0002] C-glycosides are widely found in a variety of physiologically active natural products and commercially available drugs. Classical C-glycosides have a substituent at the C-1 position of the sugar ring, while atypical C-glycosides have a substituent at the C-5 position of the pyranose or the C-4 position of the furanose. Due to their unique glycosidic bond linkage mode, atypical C-glycosides have shown promise as anticancer drugs, antibiotics, or diabetes inhibitors, such as soggliflozin. However, the limited synthetic methods for atypical C-glycosides severely hinder broader research into their structural characteristics and mechanisms of action. Therefore, the synthesis of atypical C-glycosides has significant theoretical and industrial value.

[0003] Currently, methods for synthesizing non-classical C-glycosides include:

[0004] Method 1: Synthesize nonclassical aryl or heteroaryl carbon glycosides by cis-selective addition reaction of ZnBr2-mediated aryl zinc reagent with 4α-epoxypyranoside.

[0005]

[0006] The limitations of this method are that the resulting non-classical C-glycosides have only cis selectivity, a narrow range of sugar substrates, and poor functional group tolerance, which is not conducive to industrial production.

[0007] Method 2: Selective [4+2] cycloaddition reaction between aromatic aldehydes and Danishefsky dienes to construct the core structure of non-classical aryl C-glycosides.

[0008]

[0009] The drawbacks of this method are that the obtained non-classical C-glycosides only have cis selectivity, diene raw materials are difficult to synthesize, and the reaction has poor modularity, which is not conducive to industrial production.

[0010] Method 3: The glycosyl radical intermediate formed by uronic acid undergoes a Minisci reaction with N-heteroaryl hydrocarbons to construct non-classical heteroaryl C-glycosides.

[0011]

[0012] The limitations of this method are that it requires stoichiometric amounts of oxidants and free radical initiators to facilitate the reaction, and the stereoconfiguration of the glycosidic bond is controlled by the substrate, which is not conducive to industrial production.

[0013] Method 4: The glycosyl radical intermediate formed by α-alkoxyacyl telluride undergoes a Minisci reaction with N-heteroaryl hydrocarbons to construct non-classical heteroaryl C-glycosides.

[0014]

[0015] The limitations of this method are also that it requires stoichiometric amounts of oxidants and free radical initiators to facilitate the reaction, and the stereoconfiguration of the glycosidic bond is controlled by the substrate, which is not conducive to industrial production.

[0016] Method 5: Non-classical glycosyl-DHP reagents and aryl or heteroaryl bromides are reacted with nickel photocatalysis to form glycosyl radical intermediates, which then undergo coupling reactions to achieve the efficient synthesis of non-classical aryl C-glycosides.

[0017]

[0018] The limitation of this method is that both sugar and aromatic backbones are closely related to stereochemical processes, making it difficult to obtain α and β isomers simultaneously with high stereospecificity, which is not conducive to separation and purification, and is not conducive to industrial production.

[0019] Method 6: Non-classical glycosyl-DHP reagents are used to synthesize non-classical heteroaryl C-glycosides by diastereoselective Minisci-type glycosylation with N-heteroaryl hydrocarbons under visible light irradiation.

[0020]

[0021] The limitations of this method are that it is difficult to obtain α and β isomers simultaneously with high stereospecificity, which is not conducive to separation and purification, and is not conducive to industrial production.

[0022] Method 7: Synthesize nonclassical vinyl C-glycosides by using nonclassical glycosyl-DHP reagents and VBX or VBO through photo-oxidation-reduction catalysis to achieve coupling reaction between nonclassical glycosyl free radicals and vinyl groups.

[0023]

[0024] The limitations of this method are also that it is difficult to obtain α and β isomers simultaneously with high stereospecificity, which is not conducive to separation and purification, and is not conducive to industrial production.

[0025] In summary, although there are various methods for synthesizing non-classical C-glycosides, a series of problems still exist, such as difficulty in obtaining raw materials, narrow sugar range, poor functional group tolerance, and poor stereospecificity. Summary of the Invention

[0026] To address the aforementioned technical problems, this invention provides a non-classical C-glycoside and its stereospecific synthetic method and application. The synthetic method is not only simple, convenient, and yield-efficient, but also exhibits good functional group tolerance and strong stereospecificity. Furthermore, it has a broad range of sugar substrates and is compatible with unprotected sugars and aqueous systems. Moreover, the resulting non-classical C-glycoside not only possesses superior antibacterial activity but can also serve as a raw material for active pharmaceutical ingredients, thus promoting technological advancements in the pharmaceutical synthesis and medical industries.

[0027] The present invention proposes a stereospecific synthesis method for non-classical C-glycosides, comprising: using non-classical glycosylstanane as a nucleophile and haloalkanes as an electrophile, performing a Stille cross-coupling reaction to obtain non-classical C-glycosides as shown in structural formula III.

[0028]

[0029] Wherein, R1 is hydrogen or alkyl, R2 is hydrogen, hydroxyl, alkyl, alkoxy, alkenyl, aryl, ester carbonyl, amino, NH-acyl, azide, mercapto, alkyl mercapto, or -OP, R3 and R4 are hydrogen, hydroxyl, amino, glycosyl, NH-acyl, azide, mercapto, alkyl mercapto, or -OP, R5 is hydrogen, alkyl, or P, P is a hydroxyl protecting group on a glycosyl group, R is alkenyl or aryl, and X is a halogen.

[0030] Preferably, P is Bn, Ac, TBS, TIPS, Piv, Bz, Boc, TBDPS, TMS, TES, TBDMS, PMB, Tr, MMT, DMT, MOM, BOM, MTM, THP, MEM, PMBOM, Cbz, or Fmoc; R1 is Bu; X is Br or I.

[0031] Preferably, the C-1 substituent on the sugar ring of the non-classical glycosylstanane shown in structural formula I or the non-classical C-glycoside shown in structural formula III is an alkoxy group, preferably β or α-methoxy, and the C-5 and C-4 substituents are in trans or cis configuration.

[0032] Preferably, the Stille cross-coupling reaction is carried out under reaction conditions of palladium catalyst, phosphorus ligand, cuprous salt and solvent;

[0033] Preferably, the palladium catalyst is at least one selected from PdCl2, Pd(OAc)2, Pd(TFA)2, Pd2(Dba)3, Pd(PPh3)4, Pd(acac)2, (Ph3P)2PdCl2 or allyl palladium chloride dimer, preferably Pd2(Dba)3.

[0034] The phosphorus ligand is at least one of PPh3, PCy3, Dppp, Dppb, Dppf, Binap, Jackiephos, Xantphos, Xu-Phos, X-Phos or tBuBrettphos, preferably Jackiephos;

[0035] The cuprous salt is at least one of CuI, CuCl, CuBr, CuTc or (CuOTf)2·PhCH3, preferably CuCl;

[0036] The solvent is at least one of 1,4-dioxane, tert-butanol, N,N-dimethylformamide, toluene, diethylene glycol dimethyl ether, or water, preferably a mixed solvent of 1,4-dioxane and tert-butanol in a volume ratio of 1:1.

[0037] Preferably, the reaction conditions further include silver salt;

[0038] Preferably, the silver salt is at least one of AgNO3, Ag2CO3, Ag2O, AgF or Ag2SO4, and is preferably AgF.

[0039] Preferably, the molar ratio of the non-classical saccharidane shown in structural formula I to the haloalkanes shown in structural formula II is 0.5-3:1; more preferably 2:1.

[0040] The molar ratio of the palladium catalyst to the haloalkane shown in structural formula II is 0.01-0.05:1, preferably 0.025:1;

[0041] The molar ratio of the phosphorus ligand to the haloalkane shown in structural formula II is 0.05-0.2:1, preferably 0.1:1;

[0042] The molar ratio of the cuprous salt to the halohydrocarbon shown in structural formula II is 0.5-2:1, preferably 1:1;

[0043] The molar ratio of the silver salt to the halohydrocarbon shown in structural formula II is 1-3:1, preferably 2:1.

[0044] Preferably, the Stille cross-coupling reaction temperature is 50-110℃, more preferably 70℃, and the time is 48-72h, more preferably 48h.

[0045] Preferably, the method for synthesizing the non-classical glycosylstanane shown in structural formula I includes:

[0046] Using the glycoene shown in structural formula IV as a raw material, an alkenyl oxidation reaction is carried out to obtain the epoxidized glycoside shown in structural formula V; then, using the epoxidized glycoside shown in structural formula V as an electrophile and the alkyltin metal reagent shown in structural formula VI as a nucleophile, an epoxide ring-opening reaction is carried out, followed by hydrolysis or hydroxylation protection reaction to obtain the nonclassical glycosyltinane shown in structural formula I.

[0047]

[0048] Wherein, MX is a metal, a metal salt, or an alkyl metal.

[0049] This invention proposes a non-classical C-glycoside, which is a non-classical C-glycoside or a derivative thereof synthesized by the above-mentioned synthetic method.

[0050] Preferably, the non-classical C-glycoside is a compound with the structure shown below:

[0051]

[0052] This invention also proposes an application of the above-mentioned non-classical C-glycosides in antibacterial products.

[0053] This invention proposes a stereospecific synthetic method for non-classical C-glycosides. By using readily synthesized non-classical styrosine compounds as substrates, a glycosyl cross-coupling reaction is carried out with aryl or vinyl halides, resulting in the highly stereospecific synthesis of non-classical C-glycosides. Compared with other existing synthetic methods, this invention offers several advantages. First, it can highly stereospecifically control the configuration of two non-classical end-group isomers derived from various sugars, exhibiting a broad substrate range, excellent functional group tolerance, and consistently high chemoselectivity and stereospecificity. Furthermore, it is compatible with various non-classical styrosines, electrophilic reagents, and sugars with exposed hydroxyl groups. Second, the entire process is characterized by mild conditions, a broad substrate range, excellent product stereoselectivity, high product yield, and environmental friendliness, making it suitable for industrial production. The resulting non-classical C-glycosides can be widely applied in pharmaceutical synthesis and the total synthesis of natural products in both industrial and academic fields. Attached Figure Description

[0054] Figure 1 The 1H NMR spectrum of methyl 4-((2R,3R,4S,5R,6R)-4,5-bis(benzyloxy)-3-hydroxy-6-methoxytetrahydro-2H-pyran-2-yl)benzoate described in Example 1;

[0055] Figure 2 The carbon NMR spectrum of methyl 4-((2R,3R,4S,5R,6R)-4,5-bis(benzyloxy)-3-hydroxy-6-methoxytetrahydro-2H-pyran-2-yl)benzoate described in Example 1. Detailed Implementation

[0056] In this invention, "non-classical styrosine" has the meaning commonly understood by those skilled in the art, such as compounds in which a tin alkyl group is attached at the C-5 position of a pyranose.

[0057] In this invention, JackiePhos and tris(dibenzylacetone)palladium were purchased from Shanghai Haohong Biomedical Technology Co., Ltd.; cuprous chloride was purchased from Sigma-Aldrich (Shanghai) Trading Co., Ltd., a subsidiary of Merck; silver fluoride, silver carbonate, and 4-bromobiphenyl were purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.; anhydrous 1,4-dioxane and anhydrous tert-butanol were purchased from Shanghai Adamas Reagent Co., Ltd.; all other reagents used were commercially available, and the raw materials used were easy to synthesize and purify.

[0058] 1 H NMR and 13 All C NMR measurements were performed using a Bruker Avance 400 / 500 spectrometer; the test temperature was room temperature, and the solvent was deuterated chloroform (CDCl3). Reference values ​​were selected as follows: 1 1H NMR: CDCl3 was 7.26 ppm; 13 C NMR: CHCl3 was 77.16 ppm.

[0059] The present invention will now be described in detail through specific embodiments. However, these embodiments are clearly provided for illustrative purposes and are not intended to limit the scope of the present invention.

[0060] First, the synthesis conditions for non-classical C-glycosides were optimized to determine the optimal catalytic reaction conditions. Specifically, the synthesis of (2R,3R,4S,5R,6R)-2-([1,1'-biphenyl]-4-yl)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran was used as an example, and the procedure is as follows:

[0061] The general synthetic methods for (2R,3R,4S,5R,6R)-2-([1,1'-biphenyl]-4-yl)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran include:

[0062]

[0063] As shown in the above reaction formula, in a dry 4 mL vial that has been repeatedly purged with nitrogen three times, the reactants shown in structural formula 1 (0.20 mmol), the reactants shown in structural formula 2 (0.10 mmol), tris(dibenzylacetone)palladium (5 mol%), ligand (20 mol%), copper salt (1.0 equivalent), and silver salt (1.0 or 2.0 equivalent) and solvent were added sequentially. After heating and stirring, the mixture was cooled to room temperature, filtered with diatomaceous earth, concentrated to obtain a crude product, and further purified by column chromatography using petroleum ether and ethyl acetate in a 3:1 ratio as the eluent to obtain the target product shown in structural formula 3 and the byproduct shown in structural formula 4.

[0064] Following the above method, 29 parallel experimental groups were set up, using different ligands, copper salts, silver salts, solvents, and different molar equivalents of the reactants shown in structural formulas 1 and 2, while simultaneously changing the reaction temperature and time. The NMR yields of the target product shown in structural formula 3 and the byproduct shown in structural formula 4 are shown in Table 1 below:

[0065] Table 1. Yield comparison of target product under different reaction conditions a

[0066]

[0067]

[0068] [a] Typical reaction conditions: 1 (0.20 mmol), 2 (0.10 mmol), tris(dibenzylacetone)palladium (5 mol%), ligand (20 mol%), copper salt (1.0 equivalent), silver salt (1.0 or 2.0 equivalent), solvent (2.00 mL); by purifying the crude reaction mixture... 1 H NMR analysis confirmed the stereochemical results; [b] The NMR yield was determined using an internal standard (CHBr3); [c] NMR yields were based on compound 1; [d] Cuprous chloride (3.0 equivalents), potassium fluoride (2.0 equivalents); [e] Tris(dibenzylacetone)palladium (2.5 mol%), ligand L1 (10 mol%); [f] NMR yield was 97%, and separation yield was 93%. [g] 4-Chlorobiphenyl was used as an electrophilic reagent; [h] 4-Iodobiphenyl was used as an electrophilic reagent; [i] 4-Biphenyl trifluoromethanesulfonic acid was used as the electrophilic reagent.

[0069] As shown in Table 1 above, the tris(dibenzylacetone)dipalladium / Jackiephos method, traditionally used in the synthesis of classic aryl C-glycosides, can be directly employed. When L1 was used as the catalytic system, the NMR yield of the target product was only 68%, while the NMR yield of the byproduct was as high as 98% (Table 1, No. 1). Surprisingly, by omitting the addition of potassium fluoride and adding silver carbonate, the yield of the target product could be increased to 80%, and the yield of the byproduct could be reduced to only 9% (Table 1, No. 2). This shows that silver salt makes an important contribution to solving the competitive elimination of the C-4 oxygen group in the glycosyl group and reducing the yield of the byproduct. Changing the molar equivalent ratio of the reactants shown in structural formulas 1 and 2 had little effect on the yield of the target product (Table 1, No. 3). Furthermore, lowering the reaction temperature showed that the byproduct was almost completely suppressed (Table 1, No. 4). This shows that lowering the reaction temperature is also beneficial to solving the competitive elimination of the C-4 oxygen group in the glycosyl group. Using toluene, N,N-dimethylformamide, and acetonitrile to replace L1, L2, and N2 respectively... When 1,4-dioxane was used as the solvent, the yield of the target product decreased significantly (Table 1, No. 5-7). However, when tert-butanol was used as the solvent, the yield increased slightly (Table 1, No. 8). Finally, after selecting 1,4-dioxane / tert-butanol = 1:1 as the solvent, the yield of the target product could be further improved (Table 1, No. 9). It can be seen that 1,4-dioxane / tert-butanol = 1:1 is the best solvent for the reaction. Shortening the reaction time and changing the molar equivalent ratio of the reactants shown in structural formulas 1 and 2 had little effect on the yield of the target product (Table 1, No. 10-12). It can be seen that extending the reaction time does not contribute to the yield of the target product. Replacing L1 with L2, L3, and L4 as ligands, however, reduced the yield of the target product to varying degrees and increased the yield of by-products (Table 1, No. 13-15). It can be seen that jackiphs L1 is superior to other test ligands; replacing cuprous chloride with cuprous bromide and cuprous iodide reduces the yield of the target product to varying degrees (Table 1, No. 16-17), indicating that copper salts and their anions significantly affect the reaction results; however, omitting the addition of cuprous chloride makes the target product almost undetectable (Table 1, No. 20), showing that cuprous salts are essential additives for the reaction; replacing silver carbonate with silver oxide slightly increases the yield of the target product, while replacing silver carbonate with silver fluoride increases the yield of the target product but also increases the yield of byproducts (Table 1, No. 18-19). Of course, omitting the addition of silver carbonate also reduces the yield of the target product (Table 1, No. 21); however, surprisingly, replacing silver carbonate with silver fluoride and gradually decreasing the reaction temperature gradually increases the yield of the target product and decreases the yield of byproducts. However, if the reaction temperature is too low, the yield of the target product also decreases (Table 1, No. 21).(22-23); Finally, by reducing the amounts of tris(dibenzylacetone)palladium and ligand L1, and by using silver fluoride instead of silver carbonate as an additive, the yield of the target product could be increased to 97% (Table 1, No. 24), thus determining the optimal reaction conditions; when using common aryl electrophiles such as 4-chlorobiphenyl, 4-iodobiphenyl, and 4-biphenyl trifluoromethanesulfonate as electrophiles, only the use of 4-iodobiphenyl resulted in the highest yield of the target product (Table 1, No. 25-27); Surprisingly, the reaction could also be carried out in a solvent of 1,4-dioxane / water = 1:1, and the yield of the target product could still be maintained at a high level (Table 1, No. 28-29), which provides potential for the diversification of late-stage sugars in water-soluble biomacromolecules.

[0070] Based on the optimal catalytic reaction conditions determined above, the present invention further expands the range of substrates suitable for the reaction, as detailed below:

[0071] Example 1

[0072] Synthesis of methyl 4-((2R,3R,4S,5R,6R)-4,5-bis(benzyloxy)-3-hydroxy-6-methoxytetrahydro-2H-pyran-2-yl)benzoate

[0073] At room temperature, in a dry 4 mL vial that has been repeatedly purged with nitrogen three times, add sequentially the following: (2R,3S,4S,5R,6R)-4,5-bis(benzyloxy)-6-methoxy-2-(tributylmethyltinyl)tetrahydro-2H-pyran-3-ol (126.7 mg, 0.200 mmol), methyl p-bromobenzoate (21.5 mg, 0.100 mmol), tris(dibenzylacetone)dipalladium (2.30 mg, 0.0025 mmol), and JackiePhos (8.00 mg, 0.00 mmol). The reaction mixture was prepared with 0.010 mg of cuprous chloride (9.90 mg, 0.100 mmol), 25.4 mg of silver fluoride (0.200 mmol), 1,4-dioxane (1.0 mL), and tert-butanol (1.0 mL). The mixture was stirred at 70 °C for 48 h. After the reaction was completed, the mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated to obtain the crude product, and further purified by column chromatography using petroleum ether and ethyl acetate in a 3:1 ratio as the eluent. The target product was obtained in a yield of 47.6 mg, which was 99%.

[0074] Characterization data of the target product methyl 4-((2R,3R,4S,5R,6R)-4,5-bis(benzyloxy)-3-hydroxy-6-methoxytetrahydro-2H-pyran-2-yl)benzoate: 1H NMR(400MHz, CDCl3)δ8.04(d,J=8.4Hz,2H),7.51(d,J=8.4Hz,2H),7.42–7.29(m,10H),5.00–4.96(m,2H),4 .78–4.75(m,2H),4.50(d,J=7.3Hz,1H),4.25(d,J=9.0Hz,1H),3.91(s,3H),3.63–3.53(m,6H),2.15(s,1H); 13 C NMR (101MHz, CDCl3) δ166.9,143.3,138.6,138.5,130.1,129.7,128.7,128.5,128.3,128 .0(2),127.9,127.4,105.2,84.0,82.1,77.2,75.5,75.0,74.8,57.4,52.2; HRMS(ESI)m / z calcd for C 28 H 30 O7Na[M+Na] + 501.1884, found 501.1891.

[0075] Example 2

[0076] Synthesis of methyl 4-((2S,3S,4S,5R,6S)-4,5-bis(benzyloxy)-3-hydroxy-6-methoxytetrahydro-2H-pyran-2-yl)benzoate

[0077] Following the method described in Example 1, except that (2S,3R,4S,5R,6S)-4,5-bis(benzyloxy)-6-methoxy-2-(tributylmethanetinyl)tetrahydro-2H-pyran-3-ol (126.7 mg, 0.200 mmol) was used as the substrate, 33.9 mg of the target product was obtained, with a yield of 71%.

[0078] Characterization data of the target product, methyl 4-((2S,3S,4S,5R,6S)-4,5-bis(benzyloxy)-3-hydroxy-6-methoxytetrahydro-2H-pyran-2-yl)benzoate: 1H NMR(400MHz, CDCl3)δ8.03(d,J=8.6Hz,2H),7.57(d,J=8.1Hz,2H),7.40–7.31(m,8H) ,7.25–7.23(m,2H),4.94(d,J=12.5Hz,1H),4.83(d,J=1.2Hz,1H),4.63(d,J=12.6Hz, 1H),4.56(d,J=4.4Hz,1H),4.54(d,J=2.6Hz,1H),4.43(d,J=11.6Hz,1H),3.92–3.89 (m,4H),3.79(t,J=3.5Hz,1H),3.76(dd,J=3.7,1.2Hz,1H),3.53(s,3H),2.05(s,1H); 13 C NMR (101MHz, CDCl3) δ167.1,144.4,138.3,137.5,129.8,129.6,128.8,128.6,128.4,128.2 ,128.1,128.0,127.7,100.9,77.9,76.6,74.0,73.9,73.3,69.6,57.5,52.2; HRMS(ESI)m / z calcd forC 28 H 30 O7Na[M+Na] + 501.1884, found 501.1893.

[0079] Example 3

[0080] Synthesis of methyl 4-((2R,3R,4S,5R,6S)-4,5-bis(benzyloxy)-3-hydroxy-6-methoxytetrahydro-2H-pyran-2-yl)benzoate

[0081] Following the method described in Example 1, except that (2R,3S,4S,5R,6S)-4,5-bis(benzyloxy)-6-methoxy-2-(tributylmethanetinyl)tetrahydro-2H-pyran-3-ol (126.7 mg, 0.200 mmol) was used as the substrate, 40.3 mg of the target product was obtained, with a yield of 84%.

[0082] Characterization data of the target product methyl 4-((2R,3R,4S,5R,6S)-4,5-bis(benzyloxy)-3-hydroxy-6-methoxytetrahydro-2H-pyran-2-yl)benzoate: 1H NMR (400MHz, CDCl3) δ8.02(d,J=8.4Hz,2H),7.46(d,J=8.4Hz,2H),7.43–7.28(m,10H),5.04(d,J=11.4Hz,1H),4.84(d,J=12.0Hz,1H),4 .79–4.71(m,3H),4.56(d,J=9.7Hz,1H),3.96–3.89(m,4H),3.68(dd,J=9.6,3.6Hz,1H),3.53(t,J=9.3Hz,1H),3.42(s,3H),2.17(s,1H); 13 C NMR (101MHz, CDCl3) δ166.9,143.6,138.7,138.1,130.1,129.7,128.7,128.6,128.2,128.1 ,128.0(2),127.6,98.7,81.4,79.8,75.6,75.0,73.4,72.8,55.7,52.2; HRMS(ESI)m / zcalcd for C 28 H 30 O7Na[M+Na] + 501.1884, found 501.1896.

[0083] Example 4

[0084] Synthesis of methyl 4-((2R,3R,4S,5S,6S)-4,5-bis(benzyloxy)-3-hydroxy-6-methoxytetrahydro-2H-pyran-2-yl)benzoate

[0085] Following the method described in Example 1, except that (2R,3S,4S,5S,6S)-4,5-bis(benzyloxy)-6-methoxy-2-(tributylmtinyl)tetrahydro-2H-pyran-3-ol (126.7 mg, 0.200 mmol) was used as the substrate, 30.8 mg of the target product was obtained, with a yield of 64%.

[0086] Characterization data of the target product methyl 4-((2R,3R,4S,5S,6S)-4,5-bis(benzyloxy)-3-hydroxy-6-methoxytetrahydro-2H-pyran-2-yl)benzoate: 1H NMR(400MHz, CDCl3) δ8.05(d,J=8.4Hz,2H),7.57(d,J=8.4Hz,2H),7.42–7. 28(m,10H),4.88(d,J=1.8Hz,1H),4.77–4.70(m,2H),4.63(d,J=11.7Hz,1H ),4.55–4.51(m,2H),4.10(t,J=9.5Hz,1H),3.91(s,3H),3.89(dd,J=3.2,1 .8Hz,1H),3.85(dd,J=9.4,3.1Hz,1H),3.38(s,3H),2.23(d,J=2.6Hz,1H); 13 C NMR (101MHz, CDCl3) δ167.0,144.1,138.3,138.2,130.1,129.7,128.6,128.5,128.0, 127.9(3),127.8,99.8,79.6,74.4,74.2,72.8,71.9,71.2,55.3,52.2; HRMS(ESI)m / z calcd for C 28 H 30 O7Na[M+Na] + 501.1884, found 501.1889.

[0087] Example 5

[0088] Synthesis of methyl 4-((2S,3R,5R,6S)-5-(benzyloxy)-3-hydroxy-6-methoxytetrahydro-2H-pyran-2-yl)benzoate

[0089] Following the method described in Example 1, except that (2S,3R,5R,6S)-5-(benzyloxy)-6-methoxy-2-(tributylmtinyl)tetrahydro-2H-pyran-3-ol (105.5 mg, 0.200 mmol) was used as the substrate, 22.3 mg of the target product was obtained, with a yield of 60%.

[0090] Characterization data of the target product methyl 4-((2S,3R,5R,6S)-5-(benzyloxy)-3-hydroxy-6-methoxytetrahydro-2H-pyran-2-yl)benzoate: 1H NMR (400MHz, CDCl3) δ8.03(d,J=8.2Hz,2H),7.58(d,J=8.3Hz,2H),7.42–7.28(m,5H),4.87(d,J=12.7Hz,1H),4.70(d,J=12.6Hz, 1H),4.55(s,1H),4.22(d,J=9.2Hz,1H),3.96–3.90(m,4H),3.79–3.77(m,1H),3.53(s,3H),2.38–2.33(m,1H),1.70–1.61(m,2H); 13 C NMR (101MHz, CDCl3) δ167.0,144.0,138.8,130.1,129.8,128.4,127.8,127.7,127.6,103.9,82.4,73.8,72.6,67.8,57.4,52.3,36.1; HRMS (ESI) m / z calcd for C 21 H 24 O6Na[M+Na] + 395.1465, found 395.1469.

[0091] Example 6

[0092] Synthesis of methyl 4-((2R,3S,4R,6R)-4-(benzyloxy)-3-hydroxy-6-methoxytetrahydro-2H-pyran-2-yl)benzoate

[0093] Following the method described in Example 1, except that (2R,3S,4R,6R)-4-(benzyloxy)-6-methoxy-2-(tributyltinyl)tetrahydro-2H-pyran-3-ol (105.5 mg, 0.200 mmol) was used as the substrate, 24.1 mg of the target product was obtained, with a yield of 65%.

[0094] Characterization data of the target product, methyl 4-((2R,3S,4R,6R)-4-(benzyloxy)-3-hydroxy-6-methoxytetrahydro-2H-pyran-2-yl)benzoate: 1H NMR(500MHz, CDCl3)δ8.04(d,J=8.2Hz,2H),7.53(d,J=8.4Hz,2H),7.38–7.29( m,5H),4.73(d,J=11.7Hz,1H),4.58(d,J=11.7Hz,1H),4.54(dd,J=9.8,2.1Hz,1 H),4.20(d,J=9.2Hz,1H),3.91(s,3H),3.64–3.58(m,1H),3.54–3.52(m,1H),3 .49(s,3H),2.42(ddd,J=12.5,4.7,2.1Hz,1H),2.35(s,1H),1.75–1.69(m,1H); 13 C NMR (126MHz, CDCl3) δ167.0,143.7,138.1,130.1,129.7,128.7,128.1,127.9,127.6,101.4,78.6,77.6,75.4,71.4,56.9,52.3,36.2; HRMS (ESI) m / z calcdfor C 21 H 24 O6Na[M+Na] + 395.1465, found 395.1472.

[0095] Example 7

[0096] Synthesis of methyl 4-((2S,3S,4S,5R,6R)-5-(benzyloxy)-3,4-dihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)benzoate

[0097] Following the method described in Example 1, except that (2S,3S,4S,5R,6R)-4,5-bis(benzyloxy)-6-methoxy-2-(tributylmethanetinyl)tetrahydro-2H-pyran-3-ol (126.7 mg, 0.200 mmol) was used as the substrate, 30.3 mg of the target product was obtained, with a yield of 63%.

[0098] Characterization data of the target product, methyl 4-((2S,3S,4S,5R,6R)-5-(benzyloxy)-3,4-dihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)benzoate: 1H NMR(500MHz, CDCl3)δ8.02(d,J=8.5Hz,2H),7.47(d,J=8.4Hz,2H),7.40–7.31(m,8H),7.29–7.27(m,2H),5.23(s,1H),4.95(s,1H),4.71(d, J=12.5Hz,1H),4.62–4.54(m,3H),3.91–3.88(m,4H),3.79(dd,J=11.4,3.4Hz,1H),3.63–3.62(m,1H),3.43(s,3H),3.22(d,J=11.4Hz,1H); 13 C NMR (126MHz, CDCl3) δ167.2,144.4,138.0,136.9,129.5,129.2,128.7(2),128.4,128.1 (2),128.0,126.7,100.7,74.0,73.3,72.6,72.2,69.8,68.2,55.9,52.2; HRMS(ESI)m / z calcdfor C 28 H 30 O7Na[M+Na] + 501.1884, found 501.1896.

[0099] Example 8

[0100] Synthesis of methyl 4-((2R,3R,4R,5R,6R)-4-(benzyloxy)-5-(dibenzylamino)-3-hydroxy-6-methoxytetrahydro-2H-pyran-2-yl)benzoate

[0101] Following the method described in Example 1, except that (2R,3S,4R,5R,6R)-4-(benzyloxy)-5-(dibenzylamino)-6-methoxy-2-(tributylmtinyl)tetrahydro-2H-pyran-3-ol (144.5 mg, 0.200 mmol) was used as the substrate, 46.6 mg of the target product was obtained, with a yield of 82%.

[0102] Characterization data of the target product, methyl 4-((2R,3R,4R,5R,6R)-4-(benzyloxy)-5-(dibenzylamino)-3-hydroxy-6-methoxytetrahydro-2H-pyran-2-yl)benzoate: 1H NMR(500MHz, CDCl3)δ8.01(d,J=8.4Hz,2H),7.48–7.47(m,6H),7.41–7.37(m,4H), 7.34–7.23(m,7H),5.01(d,J=11.3Hz,1H),4.80(d,J=11.1Hz,1H),4.65(d,J=8.4Hz ,1H),4.17(d,J=9.6Hz,1H),4.09(d,J=13.7Hz,2H),3.95(d,J=13.7Hz,2H),3.90(s ,3H),3.77(t,J=9.4Hz,1H),3.57–3.53(m,4H),3.07(t,J=9.3Hz,1H),2.10(s,1H); 13 C NMR (126MHz, CDCl3) δ167.0,143.5,139.9,138.9,130.0,129.7,129.1,128.6,128.3,12 7.8,127.5,127.0,104.1,80.9,77.3,76.0,74.0,63.1,56.6,55.2,52.2; HRMS(ESI)m / z calcd forC 35 H 37 O6NNa[M+Na] + 590.2513, found 590.2520.

[0103] Example 9

[0104] Synthesis of methyl 4-((2R,3R,4S,5R,6R)-5-(benzyloxy)-3-hydroxy-6-methoxy-4-((triisopropylsilyl)oxy)tetrahydro-2H-pyran-2-yl)benzoate

[0105] Following the method described in Example 1, except that (2R,3S,4S,5R,6R)-5-(benzyloxy)-6-methoxy-2-(tributyltinyl)-4-((triisopropylsilyl)oxy)tetrahydro-2H-pyran-3-ol (139.90 mg, 0.200 mmol) was used as the substrate, 41.1 mg of the target product was obtained, with a yield of 75%.

[0106] Characterization data of the target product, methyl 4-((2R,3R,4S,5R,6R)-5-(benzyloxy)-3-hydroxy-6-methoxy-4-((triisopropylsilyl)oxy)tetrahydro-2H-pyran-2-yl)benzoate: 1H NMR(500MHz, CDCl3)δ8.05(d,J=8.4Hz,2H),7.54(d,J=8.4Hz,2H),7.36–7.2 7(m,5H),5.04(d,J=11.3Hz,1H),4.64(d,J=11.1Hz,1H),4.45(d,J=7.6Hz,1 H),4.26(d,J=9.6Hz,1H),3.91(s,3H),3.88(t,J=8.7Hz,1H),3.51–3.47(m, 4H),3.39(dd,J=8.9,7.8Hz,1H),2.11(d,J=3.1Hz,1H),1.15–1.02(m,21H); 13 C NMR (126MHz, CDCl3) δ167.0,143.6,139.2,130.1,129.8,128.2,127.5,127.4(2) ,105.6,82.6,77.8,77.0,76.6,74.2,57.3,52.3,18.4,18.3,13.0; HRMS(ESI)m / z calcd forC 30 H 44 O7SiNa[M+Na] + 567.2749, found 567.2759.

[0107] Example 10

[0108] Synthesis of methyl 4-((2R,3R,4S,5R,6R)-5-(benzyloxy)-6-methoxy-3,4-bis(naphthyl-2-ylmethoxy)tetrahydro-2H-pyran-2-yl)benzoate

[0109] Following the method described in Example 1, except that ((2R,3S,4R,5R,6R)-5-(benzyloxy)-6-methoxy-3,4-bis(naphthyl-2-ylmethoxy)tetrahydro-2H-pyran-2-yl)tributyltinane (164.7 mg, 0.200 mmol) was used as the substrate, 59.6 mg of the target product was obtained, with a yield of 89%.

[0110] Characterization data of the target product, methyl 4-((2R,3R,4S,5R,6R)-5-(benzyloxy)-6-methoxy-3,4-bis(naphthyl-2-ylmethoxy)tetrahydro-2H-pyran-2-yl)benzoate: 1H NMR(500MHz, CDCl3)δ8.06(d,J=8.2Hz,2H),7.86–7.74(m,5H),7.65–7.58(m,4H),7.51–7.43( m,7H),7.37–7.31(m,4H),7.03(d,J=8.4Hz,1H),5.17(d,J=11.3Hz,1H),5.07–5.03(m,2H),4.8 5(d,J=11.0Hz,1H),4.64(d,J=10.7Hz,1H),4.55(d,J=7.8Hz,1H),4.39(d,J=9.5Hz,1H),4.09( d,J=10.7Hz,1H),3.96(s,3H),3.89(t,J=9.1Hz,1H),3.68(t,J=8.5Hz,1H),3.64–3.60(m,4H); 13 C NMR (126MHz, CDCl3) δ166.9,143.8,138.6,136.1,135.0,133.4,133.2,133.1,133.0,130.1,129.7,128.5,128.2(2),128.1,128.0(2),1 27.8(2),127.7(2),127.1,126.6,126.1(3),126.0(2),125.9,105.1,84.4,83.6,82.4,77.0,76.0,75.2,75.0,57.5,52.2; HRMS(ESI)m / z calcd for C 43 H 40 O7Na[M+Na] + 691.2666, found691.2668.

[0111] Example 11

[0112] Synthesis of methyl 4-((2R,3S,4S,5R,6R)-5-(benzyloxy)-3,4-dihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)benzoate

[0113] Following the method described in Example 1, except that (2R,3S,4S,5R,6R)-5-(benzyloxy)-6-methoxy-2-(tributyltinyl)tetrahydro-2H-pyran-3,4-diol (108.7 mg, 0.200 mmol) was used as the substrate, 20.8 mg of the target product was obtained, with a yield of 54%.

[0114] Characterization data of the target product, methyl 4-((2R,3S,4S,5R,6R)-5-(benzyloxy)-3,4-dihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)benzoate: 1 H NMR (500MHz, CDCl3) δ8.04(d,J=8.4Hz,2H),7.50(d,J=8.4Hz,2H),7.39–7.30(m,5H),4.98(d,J=11.4Hz,1H),4.69(d,J=11.4Hz,1H),4.47(d,J=7.8H z,1H),4.25(d,J=9.5Hz,1H),3.91(s,3H),3.67(t,J=9.2Hz,1H),3.55(s,3 H),3.48(t,J=9.2Hz,1H),3.36(t,J=8.5Hz,1H),2.79(s,1H),2.48(s,1H); 13 C NMR (126MHz, CDCl3) δ167.0,143.1,138.4,130.2,129.8,128.7,128.3,128.1,127.5,104.9,81.1,77.3,76.0,74.9,74.5,57.4,52.3; HRMS (ESI) m / z calcdfor C 21 H 24 O7Na[M+Na] + 411.1414, found 411.1418.

[0115] Example 12

[0116] Synthesis of methyl 4-((2R,3R,4S,5R,6R)-4,5-bis(benzyloxy)-3-(((2R,3S,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-hydroxytetrahydro-2H-pyran-2-yl)oxy)-6-methoxytetrahydro-2H-pyran-2-yl)benzoate

[0117] Following the method described in Example 1, except that (2R,3S,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(((2R,3S,4R,5R,6R)-4,5-bis(benzyloxy)-6-methoxy-2-(tributylmethyltinyl)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3-ol (213.2 mg, 0.200 mmol) was used as the substrate, 46.6 mg of the target product was obtained, with a yield of 51%.

[0118] Characterization data of the target product, methyl 4-((2R,3R,4S,5R,6R)-4,5-bis(benzyloxy)-3-(((2R,3S,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-hydroxytetrahydro-2H-pyran-2-yl)oxy)-6-methoxytetrahydro-2H-pyran-2-yl)benzoate: 1 H NMR(500MHz, CDCl3) δ7.99(d,J=8.2Hz,2H),7.44(d,J=8.2Hz,2H),7.39–7.22(m,23H),7.09(d,J=7.3Hz,2H),5. 37(s,1H),4.99–4.97(m,2H),4.75(d,J=10.8Hz,1H),4.69–4.64(m,2H),4.60(s,2H),4.51–4.47(m,2H),4.33(d, J=11.4Hz,1H),4.24(d,J=12.2Hz,1H),4.20(d,J=9.5Hz,1H),3.85–3.82(m,4H),3.75–3.68(m,3H),3.60(t,J=8. 5Hz,1H),3.55(s,3H),3.46(dd,J=9.3,3.4Hz,1H),3.07(dd,J=11.0,3.1Hz,1H),2.78(d,J=10.7Hz,1H),1.97(br s,1H),1.84(d,J=9.8Hz,1H); 13 C NMR (126MHz, CDCl3) δ166.6,143.5,139.0,138.4,138.2(2),138.0,130.3,129.9,128.6(2),128.5,128.4,128.3(2),128.2,128.0,127.9(3 ),127.5,127.3(2),105.2,99.9,84.7,82.7,79.3,77.8,77.1,75.7,74.9,74.5,73.5(2),71.9,71.1,68.7,68.0,57.4,52.2; HRMS(ESI)m / z calcd for C 55 H 58 O 12 Na[M+Na] + 933.3820, found 933.3837.

[0119] Example 13

[0120] Synthesis of (2R,3R,4S,5S,6R)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6R)-4,5-bis(benzyloxy)-6-methoxy-2-(4-(methoxycarbonyl)phenyl)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetic acid triester

[0121] Following the method described in Example 1, except that (2R,3R,4S,5S,6R)-2-(acetoxymethyl)-6-(((2R,3S,4R,5R,6R)-4,5-bis(benzyloxy)-6-methoxy-2-(tributylmethyltinyl)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetic acid triester (192.7 mg, 0.200 mmol) was used as the substrate, 72.4 mg of the target product was obtained, with a yield of 90%.

[0122] Characterization data of the target product (2R,3R,4S,5S,6R)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6R)-4,5-bis(benzyloxy)-6-methoxy-2-(4-(methoxycarbonyl)phenyl)tetrahydro-2H-pyran-3-yl)oxy)tetrahydro-2H-pyran-3,4,5-triacetic acid triester): 1 H NMR(500MHz, CDCl3)δ8.07(d,J=8.4Hz,2H),7.55(d,J=8.4Hz,2H),7.36–7.27(m,5H),7.25–7.23(m,3H),7.17–7.15 (m,2H),5.34(d,J=1.8Hz,1H),5.19(dd,J=3.1,1.8Hz,1H),5.01–4.90(m,4H),4.73(d,J=11.0Hz,1H),4.59(d,J=11. 0Hz,1H),4.50(d,J=7.8Hz,1H),4.32(d,J=9.5Hz,1H),3.90(s,3H),3.80(t,J=9.0Hz,1H),3.71(t,J=9.2Hz,1H),3.6 1–3.54(m,5H),3.33(dd,J=12.4,2.5Hz,1H),2.01(s,3H),1.95(s,3H),1.94(s,3H),1.93(s,3H),1.66–1.63(m,1H); 13C NMR (126MHz, CDCl3) δ170.5,170.2,169.8,169.6,166.6,143.8,138.2,137.9,130.4,130.1,128.6,128.4,128.2,127.9(2),127.7 ,105.2,97.0,84.8,82.5,76.5,76.4,75.5,74.8,69.1,68.8,67.9,65.0,61.7,57.5,52.3,20.8(3),20.4; HRMS(ESI)m / zcalcdfor C 42 H 48 O 16 Na[M+Na] + 831.2835, found 831.2848.

[0123] Example 14

[0124] Synthesis of (2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-2-methoxy-6-(4-methoxyphenyl)tetrahydro-2H-pyran

[0125] Following the method described in Example 1, except that tributyl((2R,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)stanane (145 mg, 0.200 mmol) and 4-bromoanisole (18.7 mg, 0.100 mmol) were used as substrates, 50.3 mg of the target product was obtained, with a yield of 93%.

[0126] Characterization data of the target product (2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-2-methoxy-6-(4-methoxyphenyl)tetrahydro-2H-pyran: 1 H NMR(400MHz, CDCl3)δ7.44–7.30(m,12H),7.26–7.23(m,3H),7.00–6.95(m,4H),5 .00(d,J=11.1Hz,1H),4.96(d,J=10.8Hz,1H),4.88(d,J=10.8Hz,1H),4.81(d,J=1 1.0Hz,1H),4.49(d,J=7.8Hz,1H),4.44(d,J=10.2Hz,1H),4.25(d,J=9.6Hz,1H),3 .89–3.86(m,4H),3.77(t,J=9.1Hz,1H),3.62–3.58(m,4H),3.53(t,J=9.3Hz,1H); 13C NMR (101MHz, CDCl3) δ159.7,138.8,138.7,137.8,130.9,128.9,128.5(2),128.3(2),128.2,128.0, 127.8(2),127.7,113.8,105.0,84.3,84.1,82.5,77.2,76.0,75.1,75.0,57.4,55.4; HRMS(ESI)m / z calcd for C 34 H 36 O6Na[M+Na] + 563.2404, found 563.2411.

[0127] Example 15

[0128] Synthesis of methyl 4-((2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)benzoate

[0129] Following the method described in Example 1, except that tributyl((2R,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)stanane (145 mg, 0.200 mmol) was used as the substrate, 55.7 mg of the target product was obtained, with a yield of 98%.

[0130] Characterization data of the target product methyl 4-((2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)benzoate: 1 H NMR(400MHz, CDCl3)δ8.08(d,J=8.2Hz,2H),7.57(d,J=8.1Hz,2H),7.42–7.30(m,10H),7.2 4–7.19(m,3H),6.95–6.93(m,2H),5.00–4.95(m,2H),4.87(d,J=10.9Hz,1H),4.79(d,J=11 .0Hz,1H),4.49(d,J=7.8Hz,1H),4.46(d,J=10.3Hz,1H),4.34(d,J=9.5Hz,1H),3.96(s,3H ),3.83(d,J=10.3Hz,1H),3.78(t,J=9.0Hz,1H),3.62–3.57(m,4H),3.50(t,J=9.3Hz,1H); 13C NMR (101MHz, CDCl3) δ167.0,143.8,138.6,138.5,137.4,130.1,129.7,128.5,128.4,128.3,128.2,128 .0,127.9,127.8(2),127.7,105.1,84.4,83.6,82.4,76.9,76.0,75.2,75.0,57.5,52.3; HRMS(ESI)m / z calcd for C 35 H 36 O7Na[M+Na] + 591.2353, found 591.2364.

[0131] Example 16

[0132] Synthesis of (4-((2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)phenyl)methanol

[0133] Following the method described in Example 1, except that tributyl((2R,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)stanane (145 mg, 0.200 mmol) and 4-bromobenzyl alcohol (18.7 mg, 0.100 mmol) were used as substrates, 49.6 mg of the target product was obtained, with a yield of 92%.

[0134] Characterization data of the target product (4-((2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)phenyl)methanol): 1 H NMR (400MHz, CDCl3) δ7.48 (d, J = 8.1Hz, 2H), 7.39–7.29 (m, 12H), 7.22–7.18 (m, 3H), 6.95–6. 92(m,2H),4.96(d,J=11.0Hz,1H),4.92(d,J=10.9Hz,1H),4.83(d,J=10.9Hz,1H),4.77(d,J =11.0Hz,1H),4.73(s,2H),4.46(d,J=7.7Hz,1H),4.41(d,J=10.4Hz,1H),4.26(d,J=9.5Hz, 1H),3.83(d,J=10.4Hz,1H),3.74(t,J=9.1Hz,1H),3.59–3.54(m,4H),3.51(t,J=9.3Hz,1H); 13CNMR(101MHz, CDCl3)δ141.2,138.7,138.6,138.1,137.7,128.5(2),128.3(2),128.2,128.0,127 .9,127.8,127.7,126.9,105.0,84.3,83.9,82.5,77.2,76.0,75.0(2),65.0,57.4; HRMS(ESI)m / z calcd for C 34 H 36 O6Na[M+Na] + 563.2404, found 563.2407.

[0135] Example 17

[0136] Synthesis of (2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-2-methoxy-6-(o-tolyl)tetrahydro-2H-pyran

[0137] Following the method described in Example 1, except that tributyl((2R,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)stanane (145 mg, 0.200 mmol) and 2-bromotoluene (17.1 mg, 0.100 mmol) were used as substrates, 41.8 mg of the target product was obtained, with a yield of 80%.

[0138] Characterization data of the target product (2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-2-methoxy-6-(o-tolyl)tetrahydro-2H-pyran: 1 H NMR (400MHz, CDCl3) δ7.53–7.50(m,1H),7.39–7.29(m,10H),7.25–7.23(m,2H),7.20–7.16(m,4 H),6.91–6.88(m,2H),4.97(d,J=11.1Hz,1H),4.92(d,J=10.8Hz,1H),4.85(d,J=10.9Hz,1H),4. 78(d,J=11.1Hz,1H),4.57(d,J=9.5Hz,1H),4.47(d,J=7.7Hz,1H),4.38(d,J=10.4Hz,1H),3.81 (d,J=10.4Hz,1H),3.75(t,J=9.1Hz,1H),3.62(t,J=9.2Hz,1H),3.59–3.56(m,4H),2.39(s,3H); 13C NMR (101MHz, CDCl3) δ138.9,138.8,138.0,137.4,136.7,130.4,128.5,128.3(2),128.2,128.1,128 .0,127.7(2),127.4,126.4,105.3,84.6(2),82.7,76.0,75.1,74.9,73.6,57.4,20.0; HRMS(ESI)m / z calcd for C 34 H 36 O5Na[M+Na] + 547.2455, found 547.2457.

[0139] Example 18

[0140] Synthesis of (2R,3R,4S,5R,6R)-4,5-bis(benzyloxy)-2-(1H-inden-2-yl)-6-methoxytetrahydro-2H-pyran-3-ol

[0141] Following the method described in Example 1, except that 2-indene bromide (19.5 mg, 0.100 mmol) was used as the substrate, 22.7 mg of the target product was obtained, with a yield of 50%.

[0142] Characterization data of the target product (2R,3R,4S,5R,6R)-4,5-bis(benzyloxy)-2-(1H-inden-2-yl)-6-methoxytetrahydro-2H-pyran-3-ol: 1 H NMR (400MHz, CDCl3) δ7.46–7.27(m,13H),7.21–7.17(m,1H),6.92(s,1H),5.00–4.97(m,2H),4.77(d, J=11.5Hz,2H),4.47(d,J=7.3Hz,1H),4.21(d,J=9.2Hz,1H),3.65–3.47(m,8H),2.15(d,J=2.3Hz,1H); 13 C NMR (101MHz, CDCl3) δ145.0,144.2,143.5,138.6(2),130.5,128.7,128.5,128.3,128.1,128.0,127 .9,126.5,125.0,123.9,121.3,105.0,84.1,82.1,75.5,74.8,74.5,73.5,57.3,38.2; HRMS(ESI)m / z calcd for C 29 H 30 O5Na[M+Na] +481.1985, found 481.1991.

[0143] Example 19

[0144] Synthesis of methyl((S)-2-((tert-butoxycarbonyl)amino)-3-(4-((2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)phenyl)propionyl)-L-phenylalanine ester

[0145] Following the method described in Example 1, except that tributyl((2R,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)stanane (145 mg, 0.200 mmol) and ((S)-3-(4-bromophenyl)-2-((tert-butoxycarbonyl)amino)propionyl)-L-phenylalanine methyl ester (50.5 mg, 0.100 mmol) were used as substrates, 76.3 mg of the target product was obtained, with a yield of 89%.

[0146] Characterization data of the target product methyl((S)-2-((tert-butoxycarbonyl)amino)-3-(4-((2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)phenyl)propionyl)-L-phenylalanine ester: 1 H NMR (400MHz, CDCl3) δ7.43–7.27(m,14H),7.25–7.20(m,6H),7.03–7.01(m,2 H),6.96–6.93(m,2H),6.41(d,J=7.6Hz,1H),4.99–4.92(m,3H),4.87–4.77(m ,3H),4.46(d,J=7.8Hz,1H),4.41–4.38(m,2H),4.25(d,J=9.5Hz,1H),3.82– 3.73(m,2H),3.69(s,3H),3.59–3.47(m,5H),3.17–3.00(m,4H),1.39(s,9H); 13C NMR (101MHz, CDCl3) δ171.5,170.8,155.4,138.7,138.6,137.7,137.5,136.7,135.7,129.4,129.3,128.7,128.5,128.4,128.3(2),128.2,128 .0(2),127.8(2),127.7,127.2,105.0,84.3,83.9,82.5,80.3,77.2,76 .0,75.0,74.9,57.3,55.6,53.4,52.4,38.0,37.9,28.3; HRMS(ESI)m / z calcd for C 51 H 58 O 10 N₂Na[M+Na] + 881.3984, found 881.3982.

[0147] Example 20

[0148] Synthesis of methyl 2-(5-methoxy-2-methyl-1-(4-((2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2)-yl)benzoyl)-1H-indole-3-yl)acetate

[0149] Following the method described in Example 1, except that tributyl((2R,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)stanane (145 mg, 0.200 mmol) and methyl 2-(1-(4-bromobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate (41.6 mg, 0.100 mmol) were used as substrates, 72.1 mg of the target product was obtained, with a yield of 94%.

[0150] Characterization data of the target product, methyl 2-(5-methoxy-2-methyl-1-(4-((2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-methoxytetrahydro-2H-pyran-2)-yl)benzoyl)-1H-indole-3-yl)acetate: 1H NMR(400MHz, CDCl3) δ7.76(d,J=8.3Hz,2H),7.64(d,J=8.3Hz,2H),7.42–7.30(m,10H),7.25–7.23(m, 3H),7.03–6.98(m,3H),6.91(d,J=9.0Hz,1H),6.54(dd,J=9.0,2.6Hz,1H),5.01–4.96(m,2H),4.87(d, J=11.0Hz,1H),4.80(d,J=11.1Hz,1H),4.56–4.52(m,2H),4.39(d,J=9.5Hz,1H),3.97(d,J=10.4Hz,1H ),3.83–3.79(m,4H),3.73(s,3H),3.69(s,2H),3.64–3.60(m,4H),3.54(t,J=9.2Hz,1H),2.41(s,3H); 13 C NMR (101MHz, CDCl3) δ171.5,169.2,156.0,143.9,138.6(2),137.5,136.1,135.6,131.1,130.7,129.8,128.5(2),128.2,128.1,128.0,127 .9,127.8,127.7,115.1,112.3,111.5,105.1,101.5,84.4,83.6,82.4,76.8,76.0,75.2,75.0,57.5,55.8,52.2,30.3,13.4; HRMS(ESI)m / z calcd for C 47 H 47 O9NNa[M+Na] + 792.3143, found 792.3143.

[0151] The substrates, target products, and yields in Examples 1-20 are listed in Table 2 below:

[0152] Table 2 Comparison of target products and yields in Examples 1-20

[0153]

[0154]

[0155]

[0156] As shown in Table 2 above, using commercially available tris(dibenzylacetone)dipalladium as a palladium catalyst, Jackiephos as a ligand, and cuprous chloride and silver fluoride as additives, various non-classical styrosine alkyl groups can be stereospecifically synthesized by Stille coupling reactions with aryl or alkenyl halides. This synthetic method exhibits a broad substrate range, excellent functional group tolerance, and consistently high chemoselectivity and stereospecificity. Furthermore, it is compatible with various saccharide types of non-classical styrosine alkyl groups, non-classical styrosine alkyl groups with exposed hydroxyl groups, aryl or alkenyl halides, and halides of bioactive molecules. It is a mild and simple general synthetic method for non-classical aryl or alkenyl C-glycosides.

[0157] For the non-classical glycosylstananes with the 4,5-trans configuration in Examples 1-20, the general synthetic method includes:

[0158] 4-Deoxypentenyl glycoside (1.0 equivalent) was dissolved in a mixed solution of dichloromethane, acetone, and saturated sodium bicarbonate. The mixture was stirred vigorously under ice bath conditions until homogeneous. Potassium peroxide monosulfonate was then added dropwise to the system over 15 minutes. A 4.0 equivalent aqueous solution was added to the reaction mixture. The resulting reaction mixture was stirred at 0°C for 0.5 h, then stirred at room temperature for 2 h. The mixture was extracted with dichloromethane, the organic phase was collected, dried, filtered, and concentrated to obtain an epoxide. The obtained epoxide was dissolved in anhydrous and degassed tetrahydrofuran without separation, cooled to -15°C, and then a tetrahydrofuran solution containing tri-n-butyltin methyl magnesium (1.5 equivalents) was added to the system. The resulting reaction mixture was stirred at -15°C for 1.5 h, then heated to -10°C and stirred for another 1 h. The reaction was quenched with water, filtered, extracted with dichloromethane, the organic phase was collected, dried, filtered, concentrated, and subjected to silica gel column chromatography to obtain the non-classical glycosyltinane.

[0159] The following are specific synthetic methods for (2R,3S,4S,5R,6R)-4,5-bis(benzyloxy)-6-methoxy-2-(tributylmethanesulfonyl)tetrahydro-2H-pyran-3-ol, a non-classical glycosylstanane:

[0160] Synthesis of (2R,3S,4S,5R,6R)-4,5-bis(benzyloxy)-6-methoxy-2-(tributylmethanesulfonic acid)tetrahydro-2H-pyran-3-ol

[0161]

[0162] At room temperature, (2R,3R,4S)-3,4-bis(benzyloxy)-2-methoxy-3,4-dihydro-2H-pyran (5.03 g, 15.4 mmol), dichloromethane (128 mL), saturated sodium bicarbonate solution (214 mL), and acetone (26 mL) were added to a 1 L round-bottom flask. The mixture was stirred vigorously in an ice bath until homogeneous. Potassium peroxymonosulfonate (37.9 g, 61.7 mmol) was dissolved in water (150 mL), and the resulting aqueous solution was added dropwise to the reaction system over 15 min. The resulting reaction mixture was stirred at 0 °C for 0.5 h, and then stirred at room temperature for 2 h. After the reaction was completed, the mixture was extracted with dichloromethane (2 × 50 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The epoxide compound was concentrated to obtain an epoxy compound. Without separation, the obtained epoxide compound was dissolved in anhydrous and degassed tetrahydrofuran (30 mL), cooled to -15 °C, and then a tetrahydrofuran solution containing tri-n-butyltin methyl magnesium (7.62 g, 23.1 mmol) was added to the resulting reaction system. The reaction mixture was stirred at -15 °C for 1.5 h, then heated to -10 °C and stirred for another 1 h. After the reaction was complete, water (30 mL) was added to quench the reaction, filtered, and extracted with dichloromethane (3 × 30 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated to obtain a crude product, and further purified by column chromatography using petroleum ether and ethyl acetate in a 15:1 eluent, yielding 2.61 g of product, with a yield of 27%.

[0163] Characterization data of the product (2R,3S,4S,5R,6R)-4,5-bis(benzyloxy)-6-methoxy-2-(tributylmethanesulfonyl)tetrahydro-2H-pyran-3-ol: 1 H NMR (400MHz, CDCl3) δ7.39–7.27(m,10H),4.99–4.93(m,2H),4.71–4.64(m,2H),4.15(d,J=7.3Hz,1H),3.70(ddd,J=11.0,8.2 ,2.8Hz,1H),3.54(s,3H),3.43–3.30(m,3H),2.15(d,J=2.8Hz,1H),1.56–1.44(m,6H),1.36–1.26(m,6H),1.04–0.87(m,15H); 13C NMR (101MHz, CDCl3) δ138.8,138.7,128.7,128.5,128.3,128.2,128.0,127.8,108.2 ,86.4,82.6,75.5,74.7,73.5,69.9,57.0,29.2,27.6,13.9,9.0; HRMS(ESI)m / zcalcd for C 32 H 50 O5SnNa[M+Na] + 657.2572, found 657.2582.

[0164] For the non-classical glycosyltinanes with the 4,5-cis configuration in Examples 1-20, the general synthetic method is to use zinc bromide and tri-n-butyltin methyllithium instead of tri-n-butyltin methyl magnesium as reactants in the epoxide ring-opening step.

[0165] The following are specific synthetic methods for (2S,3S,4S,5R,6R)-4,5-bis(benzyloxy)-6-methoxy-2-(tributylmethanesulfonyl)tetrahydro-2H-pyran-3-ol, a non-classical styrosine:

[0166]

[0167] At room temperature, (2R,3R,4S)-3,4-bis(benzyloxy)-2-methoxy-3,4-dihydro-2H-pyran (1.41 g, 4.33 mmol), dichloromethane (36 mL), saturated sodium bicarbonate solution (60 mL), and acetone (7.2 mL) were added to a 250 mL round-bottom flask. The mixture was stirred vigorously in an ice bath until homogeneous. Potassium peroxymonosulfonate (10.6 g, 17.2 mmol) was dissolved in water (42 mL), and the resulting aqueous solution was added dropwise to the aforementioned reaction system over 15 min. The resulting reaction mixture was stirred at 0 °C for 0.5 h, and then stirred at room temperature for 2 h. After the reaction was completed, the mixture was extracted with dichloromethane (2 × 30 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain an epoxide compound. Under nitrogen protection, zinc bromide (6.83 g, ...) was added to a flame-dried 100 mL round-bottom flask. 30.3 mmol) and anhydrous tetrahydrofuran (21 mL) were added to the reaction system and cooled to -78 °C. Then, a tetrahydrofuran solution containing tri-n-butyltin methyllithium (7.72 g, 26.0 mmol) was added to the resulting reaction system. The reaction system was heated to 0 °C and stirred at 0 °C for 30 min. Then, it was cooled to -78 °C again. Anhydrous tetrahydrofuran solution containing the above epoxide (11 mL) was added dropwise to the above reaction system at -78 °C. The temperature was slowly raised to -30 °C and then stirred at -30 °C for 16 h. After the reaction was completed, water (10 mL) was added to the reaction system to quench the reaction. The mixture was filtered and extracted with dichloromethane (3 × 30 mL). The organic phase was collected, dried with anhydrous sodium sulfate, filtered, concentrated to obtain crude product, and further purified by column chromatography with petroleum ether and ethyl acetate in a ratio of 12:1 as eluent. 274.3 mg of product was obtained, with a yield of 10%.

[0168] Characterization data of the product (2S,3S,4S,5R,6R)-4,5-bis(benzyloxy)-6-methoxy-2-(tributylmethanesulfonyl)tetrahydro-2H-pyran-3-ol: 1 H NMR(500MHz, CDCl3)δ7.36–7.27(m,10H),4.72(d,J=12.2Hz,1H),4.62–4.53(m,5H),3.63–3.55(m,2H),3.47 –3.45(m,1H),3.41(s,3H),3.04(d,J=8.9Hz,1H),1.58–1.46(m,6H),1.35–1.28(m,6H),0.97–0.88(m,15H); 13C NMR (126MHz, CDCl3) δ138.5,137.8,128.6(2),128.0,127.9(2),101.3,76.6,76.1,72.9,72.8,71.7,67.2,55.7,29.3,27.6,13.9,9.7; HRMS(ESI) m / z calcd forC 32 H 50 O5SnNa[M+Na] + 657.2572, found 657.2577.

[0169] Biological evaluation was performed on the non-classical C-glycoside—mannosyl-indomethacin derivative—synthesized by the methods described in the above embodiments. The specific process is as follows:

[0170] (1) Synthesis of the non-classical mannose-indomethacin derivative 2-(5-methoxy-2-methyl-1-(4-((2R,3S,4S,5S,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)benzoyl)-1H-indo-3-yl)acetic acid:

[0171]

[0172] At room temperature, in a dry 4 mL vial that has been repeatedly purged with nitrogen three times, add sequentially the following: (2R,3S,4S,5R,6R)-4,5-bis(benzyloxy)-6-methoxy-2-(tributylmethyltinyl)tetrahydro-2H-pyran-3-ol (126.7 mg, 0.200 mmol), methyl 1-(4-bromobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetate (41.6 mg, 0.100 mmol), tris(dibenzylacetone)dipalladium (2.30 mg, 0.0025 mmol), and Jackie... Phos (8.00 mg, 0.010 mmol), cuprous chloride (9.90 mg, 0.100 mmol), silver fluoride (25.4 mg, 0.200 mmol), 1,4-dioxane (1.0 mL), and tert-butanol (1.0 mL) were stirred at 70 °C for 48 h. After the reaction was completed, the mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated to obtain crude product, and further purified by column chromatography using petroleum ether and ethyl acetate in a 3:1 ratio to obtain intermediate A36.7 mg of non-classical C-glycoside, with a yield of 54%.

[0173] Intermediate A (83.1 mg, 0.122 mmol) of the above-mentioned non-classical C-glycoside was dissolved in tetrahydrofuran / isopropanol (3:1, 2.4 mL). 10% Pd / C (39.0 mg, 0.037 mmol) and 10% Pd(OH)2 / C (25.8 mg, 0.037 mmol) were added to the resulting solution. The mixture was stirred at 50 °C for 13 h to remove the benzyl protecting group. After the reaction was completed, the mixture was cooled to room temperature, filtered with diatomaceous earth, concentrated to obtain the crude product, and further purified by column chromatography using dichloromethane and ethyl acetate in a 1:3 ratio as the eluent to obtain 52.9 mg of intermediate compound B of the non-classical C-glycoside, with a yield of 87%.

[0174] Under nitrogen atmosphere, intermediate B (26.5 mg, 0.0530 mmol), 1,2-dichloroethane (1.1 mL), and trimethyltin hydroxide (28.8 mg, 0.159 mmol) of the above-mentioned non-classical C-glycoside were added to a Schlenk tube. The reaction was heated at 80 °C for 4 h to reduce the ester group to the carboxyl group. After the reaction was completed, the mixture was cooled to room temperature, filtered with diatomaceous earth, concentrated to obtain the crude product, and further purified by column chromatography using dichloromethane and methanol in a ratio of 8:1 to obtain 21.0 mg of the target product of the non-classical mannosyl-indomethacin derivative, with a yield of 82%.

[0175] Characterization data of the target product, a non-classical mannosyl-indomethacin derivative, namely 2-(5-methoxy-2-methyl-1-(4-((2R,3S,4S,5S,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)benzoyl)-1H-indole-3-yl)acetic acid: 1 H NMR (500MHz, CD3OD) δ7.67–7.64(m,4H),7.00(d,J=2.9Hz,1H),6.92(d,J=9.0Hz,1H),6.62(dd,J=9.0,2.7Hz,1H),4.77(s,1H),4.49(d,J=9. 5Hz,1H),3.93(dd,J=3.4,1.5Hz,1H),3.83(dd,J=9.5,3.5Hz,1H),3.79(s,3H),3.75(t,J=9.5Hz,1H),3.66(s,2H),3.40(s,3H),2.30(s,3H); 13C NMR (126MHz, CD3OD) δ171.0,157.4,146.2,136.8,136.5,132.4,132.2,130.4,129.6,115. 9,112.5,103.3,102.4,75.8,73.1,72.6,72.1,56.1,55.5,49.9,31.2,13.5; HRMS(ESI)m / z calcd forC 25 H 27 O9NNa[M+Na] + 508.1578, found 508.1587.

[0176] (2) Synthesis of the classic mannosyl-indomethacin derivative 2-(5-methoxy-2-methyl-1-(4-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzoyl)-1H-indo-3-yl)acetic acid:

[0177]

[0178] At room temperature, in a dry 4 mL vial that has been repeatedly purged with nitrogen three times, add 2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl bromide (123 mg, 0.300 mmol), methyl 1-(4-bromobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetate (41.6 mg, 0.100 mmol), Hantzsch ester (76.0 mg, 0.300 mmol), and MgCl2 (19.0 mg, 0.200 mmol); in another 4 mL vial, add NiBr2·DME (3.1 mg, 0.010 mmol), dtbbpy (4.00 mg, 0.0150 mmol), and acetonitrile (2.0 mL). Transfer the resulting mixed solution to the first vial and add DIPEA (77.5 mg,

[0179] The mixture was purged with nitrogen and stirred at 28°C for 16 h under an 18W purple LED lamp. After the reaction was completed, the mixture was filtered with diatomaceous earth, concentrated to obtain crude product, and further purified by column chromatography with petroleum ether and ethyl acetate in a ratio of 4:3 as eluent to obtain 46.1 mg of the classic C-glycoside intermediate C, with a yield of 69%.

[0180] Under nitrogen atmosphere, intermediate C (148.9 mg, 0.223 mmol) of the above-mentioned classical C-glycoside, 1,2-dichloroethane (4.5 mL), and trimethyltin hydroxide (604.9 mg, 3.35 mmol) were added to a Schlenk tube. The reaction was heated at 80 °C for 17 h. After the reaction was completed, the mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated to obtain the crude product, and further purified by column chromatography using dichloromethane and methanol in a 5:1 eluent to obtain 43.1 mg of the target product of the classical mannosyl-indomethacin derivative, with a yield of 40%.

[0181] Characterization data of the target product, a classic mannosyl-indomethacin derivative, namely 2-(5-methoxy-2-methyl-1-(4-((2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzoyl)-1H-indol-3-yl)acetic acid: = +29.4 (c = 0.50, MeOH); 1 H NMR (500MHz, CD3OD) δ7.70–7.65(m,4H),7.01(d,J=2.6Hz,1H),6.92(d,J=9.0Hz,1H),6.62(dd,J=9.0,2.4Hz,1H),5.04(d,J=4.6Hz,1H),4.39(dd,J=4 .5,3.1Hz,1H),3.92(dd,J=11.9,6.9Hz,1H),3.85–3.80(m,2H),3.79(s,3H ),3.64(dd,J=7.4,3.1Hz,1H),3.62(s,2H),3.60–3.56(m,1H),2.27(s,3H); 13 CNMR(126MHz,CD3OD)δ170.9,157.4,145.3,136.5,136.3,132.4(2),130.8,128.4,115.9,11 5.6,112.4,102.5,78.5,77.5,72.7,71.6,69.8,62.6,56.1,32.0,13.6; HRMS(ESI)m / zcalcd for C 25 H 27 O9NNa[M+Na] + 508.1578, found 508.1588.

[0182] (3) The antibacterial activity of the synthesized non-classical mannosyl-indomethacin derivative and the classical mannosyl-indomethacin derivative against wild type M. smegmatis MC2155 was tested. The specific experimental steps for testing the minimum inhibitory concentration of the non-classical and classical mannosyl-indomethacin derivatives against M. smegmatis included:

[0183] The antibacterial activity of the compound was determined by measuring the minimum inhibitory concentration (MIC) using the broth microdilution assay. 100 μL of 7H9 medium (BD Biosciences) was added to each well, with an initial cell density of 1-5 × 10⁵ CFU / ml of *Mycobacterium smegmatis* wild type M. smegmatis MC2155 (Msm), followed by the addition of 20 μL of... 0.1 mg / ml resazurin solution was added to 96-well plates (YB-96U, Yueyi Biotechnology), followed by 100 μL of 7H9 medium containing a series of dilutions with final concentrations of 0, 1, 2, 4, 8, 16, 32, 64, and 128 μg / ml of the test compound, including non-classical mannosyl-indomethacin derivatives, classical mannosyl-indomethacin derivatives, and indomethacin. Rifampin was used as a positive control, and negative controls, resazurin control, and DMSO control were also added. After incubation at 37°C for two days, the color change of the 96-well plates was observed, and the MIC was quantitatively analyzed. The color of resazurin changed from blue in the oxidized state to pink in the reduced state, indicating bacterial growth. The specific antibacterial effects are shown in Table 3 below.

[0184] Table 3 Comparison of antibacterial activities between non-classical and classic mannosyl-indomethacin derivatives

[0185]

[0186] As shown in Table 3 above, a systematic evaluation of the antibacterial activity of non-classical mannosyl-indomethacin derivatives and classical mannosyl-indomethacin derivatives against *M. smegmatis* MC2 155 was conducted, determining the impact of different substitution site sugar modifications on the bioactivity of indomethacin derivatives. Table 1 shows that, compared to the C-1-sugar-modified classical mannosyl-indomethacin derivative which showed no perceptible activity at a concentration of 128 μg / ml, the C-5-sugar-modified non-classical mannosyl-indomethacin derivative exhibited significant anti-mycobacterial activity, with a MIC (minimum inhibitory concentration) of 16 μg / ml, comparable to that of indomethacin (16 μg / ml). This result indicates that non-classical glycosylation modification has broad potential in drug development and will be a promising emerging field.

[0187] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A stereospecific synthesis method for non-classical C-glycosides, characterized in that, include: Using the non-classical glycosyl stanane shown in structural formula I as a nucleophile and the haloalkane shown in structural formula II as an electrophile, a Stille cross-coupling reaction was carried out to obtain the non-classical C-glycoside shown in structural formula III. Wherein, R1 is an alkyl group, R2 is an alkoxy group or -OP, and R3 and R4 are hydrogen, hydroxyl, or hydrogen. Acyl or -OP, R5 is hydrogen, alkyl, glycosyl or P, P is a hydroxyl protecting group on the glycosyl group, R is alkenyl or aryl, X is Br or I; The Stille cross-coupling reaction was carried out under the reaction conditions of palladium catalyst, phosphorus ligand, cuprous salt and solvent; The palladium catalyst is Pd2(Dba)3; the phosphorus ligand is at least one of Jackiephos or Xu-Phos; the cuprous salt is at least one of CuCl or CuBr; the solvent is at least one of 1,4-dioxane, tert-butanol or toluene, or the solvent is a mixture of 1,4-dioxane and water. The reaction conditions also include a silver salt; the silver salt is... , or At least one of them; The Stille cross-coupling reaction was carried out at a temperature of 50-110 °C for 48-72 h.

2. The stereospecific synthesis method for non-classical C-glycosides according to claim 1, characterized in that, P is Bn, Ac, TBS, TIPS, Piv, Bz, Boc, TBDPS, TMS, TES, TBDMS, PMB, Tr, MMT, DMT, MOM, BOM, MTM, THP, MEM, PMBOM, Cbz, or Fmoc; R1 is Bu.

3. The stereospecific synthesis method for non-classical C-glycosides according to claim 1, characterized in that, The non-classical glycosylstanane shown in structural formula I or the non-classical C-glycoside shown in structural formula III has a β- or α-methoxy substituent at the C-1 position on the sugar ring, and a trans or cis configuration at the C-5 and C-4 positions.

4. The method for stereospecific synthesis of non-classical C-glycosides according to any one of claims 1-3, characterized in that, The palladium catalyst is Pd2(Dba)3; the phosphorus ligand is Jackiephos; the cuprous salt is CuCl; the solvent is a mixed solvent of 1,4-dioxane and tert-butanol in a volume ratio of 1:1; and the silver salt is AgF.

5. The method for stereospecific synthesis of non-classical C-glycosides according to any one of claims 1-3, characterized in that, The molar ratio of the non-classical sucralose stanane shown in structural formula I to the haloalkane shown in structural formula II is 0.5-3:1; the molar ratio of the palladium catalyst to the haloalkane shown in structural formula II is 0.01-0.05:1; the molar ratio of the phosphorus ligand to the haloalkane shown in structural formula II is 0.05-0.2:1; the molar ratio of the cuprous salt to the haloalkane shown in structural formula II is 0.5-2:1; and the molar ratio of the silver salt to the haloalkane shown in structural formula II is 1-3:

1.

6. The method for stereospecific synthesis of non-classical C-glycosides according to claim 5, characterized in that, The molar ratio of the non-classical sucralose stanane shown in structural formula I to the haloalkane shown in structural formula II is 2:1; the molar ratio of the palladium catalyst to the haloalkane shown in structural formula II is 0.025:1; the molar ratio of the phosphorus ligand to the haloalkane shown in structural formula II is 0.1:1; the molar ratio of the cuprous salt to the haloalkane shown in structural formula II is 1:1; and the molar ratio of the silver salt to the haloalkane shown in structural formula II is 2:

1.

7. The method for stereospecific synthesis of non-classical C-glycosides according to any one of claims 1-3, characterized in that, The Stille cross-coupling reaction was carried out at a temperature of 70 °C for 48 h.

8. The method for stereospecific synthesis of non-classical C-glycosides according to any one of claims 1-3, characterized in that, The synthetic methods for the non-classical glycosyl stananes shown in structural formula I include: Using the glycoene shown in structural formula IV as a raw material, an alkenyl oxidation reaction is carried out to obtain the epoxidized glycoside shown in structural formula V; then, using the epoxidized glycoside shown in structural formula V as an electrophile and the alkyltin metal reagent shown in structural formula VI as a nucleophile, an epoxide ring-opening reaction is carried out, followed by hydrolysis or hydroxylation protection reaction to obtain the nonclassical glycosyltinane shown in structural formula I. Wherein, MX is a metal, a metal salt, or an alkyl metal.

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