Selective acylation method of carbohydrate containing 1, 2-cis-diol

Abstract

The present invention relates to a method for the selective acylation of carbohydrates containing 1, 2-cis-diol. Specifically, according to the method, a carbohydrate containing 1.2-cis-diol is used as a reaction substrate, benzoyl fluoride is used as an acylation reagent, DBU is used as a catalyst, and the reaction temperature is-20 DEG C. The method has the advantages of simplicity and high efficiency in operation, wide substrate application range, high regioselectivity, good functional group compatibility and the like, and provides an important methodological basis for synthesis of complex oligosaccharide molecules.

Description

Technical Field

[0001] The present invention relates to the technical field of sugar chemistry, and more particularly to a method for selective acylation of sugar compounds containing 1,2-cis-diol. Background Art

[0002] As one of the four major macromolecules of life, carbohydrates widely regulate key physiological processes such as signal transduction and infection recognition. However, due to the high complexity and microscopic heterogeneity of their structures, it is difficult to obtain sufficient amounts of pure products with defined structures from nature through separation and purification methods for in-depth research. The difficulty in obtaining carbohydrate substances with uniform structure and defined configuration has become a major bottleneck restricting glycobiology research, and chemical synthesis is considered to be an effective way to break through this bottleneck. In the past few decades, chemists have conducted a large number of explorations in the synthesis of carbohydrate compounds, among which how to quickly and massively prepare the required glycosyl modules is a major difficulty.

[0003] To efficiently prepare sugar building blocks, sugar chemists have successfully developed numerous strategies for selectively protecting sugar hydroxyl groups, with acyl, benzyl, and alkyl groups being commonly used. Among these, acyl groups are the most popular due to their ease of introduction and quantitative removal under alkaline conditions. Furthermore, acyl groups undergo acyl migration under alkaline conditions, allowing chemists to exploit this property to synthesize complex oligosaccharides that are difficult to synthesize using conventional methods. This has prompted a growing number of chemists to conduct in-depth research on selective acylation protection. In synthesizing various functional oligosaccharides, researchers have performed various selective hydroxyl protections on monosaccharides. Among these protection reactions, acylation is the most commonly used method for protecting sugar hydroxyl groups.

[0004] Early studies often used organotin reagents for the protection of hydroxyl groups. This method is simple to operate and offers good selectivity. However, these reagents have drawbacks such as high toxicity and poor solubility, necessitating the development of catalysts that could replace alkyltin reagents. Muramatsu et al. reported the selective benzoylation of 1,2- and 1,3-diols catalyzed by dimethyltin dichloride in aqueous phase. Because the reaction is carried out in aqueous phase, the reaction conditions are mild, reducing the use of organic chemical reagents and lowering costs. This environmentally friendly strategy laid the foundation for subsequent selective protection of sugar hydroxyl groups. Taylor et al. first applied the covalent interaction of organoboron reagents with diol substrates to form a reversible borane-oxygen five-membered ring for the selective protection of sugar hydroxyl groups. From a variety of organoboron reagents, they identified organoboron catalysts such as phenylboronic acid, diphenylboronic acid, and diaminoethyl diphenylboronate as highly selective. Using DIPEA as a base, they selectively acylated cis-configured sugar diols. Using different acyl chlorides in the reaction, they achieved good stereoselectivity and yields. It can also achieve selective benzoylation, alkylation and sulfonylation of monosaccharides. The reaction is applicable not only to 1,2-diols, but also to 1,3-diols. Dong Hai's team used organosilicon reagents to achieve selective protection of 1,2- and 1,3-diols. Sauve's team used silver oxide as a catalyst to obtain monosubstituted products of symmetrical diols. Ye Xinshan's team also used silver oxide and potassium iodide to achieve selective protection of the 2,3-hydroxyl groups of glycosides protected by 4,6-benzylidene groups. Miller's team and Tan's team respectively used chiral catalysts to selectively protect the 2,3-hydroxyl groups of mannosides. Although chemists have developed a variety of regioselective acylation strategies, there is still a lack of efficient, simple, green and highly regioselective acylation methods. Summary of the Invention

[0005] The present invention aims to provide a method for selective acylation of saccharide compounds containing 1,2-cis-diol.

[0006] In one aspect, the present invention provides a method for selectively acylating a saccharide compound containing 1,2-cis-diol, comprising reacting the saccharide compound with an acylating agent in the presence of a catalyst, wherein the acylating agent is a fluoride; and the catalyst is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0007] In one embodiment, the acylating agent is benzoyl fluoride. In one embodiment, the acylation is benzoylation.

[0008] In one embodiment, the dosage of the catalyst does not exceed 0.1 equivalent, 0.2 equivalent, 0.3 equivalent, 0.4 equivalent, 0.5 equivalent, 0.6 equivalent, 0.7 equivalent, 0.8 equivalent, or 0.9 equivalent; preferably, the dosage of the catalyst is 0.1 equivalent, 0.15 equivalent, or 0.2 equivalent.

[0009] In one embodiment, the saccharide compound includes a compound with poor solubility, low activity, and an electron-withdrawing group.

[0010] In one embodiment, the carbohydrate compound is selected from galactose or its derivatives, lactose or its derivatives, mannose or its derivatives, fucose or its derivatives, or inositol or its derivatives.

[0011] In one embodiment, the carbohydrate compound is a compound of formula (A), (B), (C) or (D):

[0012] Among them, R 1 、R 2 、R 3 or R 4 is any group; optionally, R 1 、R 2 、R 3 or R 4 Selected from: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, acyl or silanyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, acyl or silanyl is unsubstituted or substituted with one or more substituents selected from halogen, nitro, CN, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl.

[0013] In one embodiment, In the compound of formula (A), R 1 is aglycone, such as Mp, STol, Me, , SEt, SPh, Ac or All; R 2 and R 3 is a cyclic group, such as a cycloalkyl group, an aryl group, a heterocyclic group or a silyl group, preferably TBS, TIPS, TMS, Bn, Bz or TBDPS; In the compound of formula (B), R 1 is aglycone, such as Mp, STol, Me, , SEt, SPh, Ac or All; R 2 and R 3 is a cyclic group, such as a cycloalkyl group, an aryl group, a heterocyclic group, a silyl group or R 2 and R 3Cyclic, preferably TBS, TIPS, TMS, Bn, Bz or TBDPS; In the compound of formula (C), R 1 is aglycone, such as AII, Mp, STol, , Me, SEt, SPh or Ac; R 2 is a cyclic group, such as a cycloalkyl group, an aryl group, a heterocyclic group or a silyl group, preferably TBS, TIPS, TMS, Bn, Bz or TBDPS; In the compound of formula (D), R 1 、R 2 、R 3 or R 4 is a cyclic group, such as a cycloalkyl group, an aryl group, a heterocyclic group or a silyl group, preferably TBS, TIPS, TMS, Bn, Bz or TBDPS.

[0014] In one embodiment, the carbohydrate compound is any one or more compounds represented by formula (I)-(XIII): .

[0015] In one embodiment, the carbohydrate compound is a compound of formula (A), and the reaction product is a 4-hydroxyacylated compound; Or, the carbohydrate compound is a compound of formula (B), and the reaction product is a 2-hydroxyacylated compound; Or, the carbohydrate compound is a compound of formula (C), and the reaction product is a 4-hydroxyacylated compound; Alternatively, the carbohydrate compound is a compound of formula (D), and the reaction product is a 2-hydroxy acylated compound.

[0016] In one embodiment, the selective acylation refers to acylation of one hydroxyl group in the 1,2-cis-diol of the saccharide compound containing 1,2-cis-diol, while the other hydroxyl group remains unacylated. Preferably, the selective acylation refers to acylation of the axial hydroxyl group in the 1,2-cis-diol of the saccharide compound containing 1,2-cis-diol, while the equatorial hydroxyl group remains unacylated.

[0017] In one embodiment, the method is capable of selectively acylating the axial hydroxyl groups of 1,2-cis diols.

[0018] In one embodiment, one hydroxyl group of the 1,2-cis diol is acylated and the other hydroxyl group is not acylated.

[0019] In one embodiment, the axial hydroxyl groups in the 1,2-cis diol are acylated, and the non-axial hydroxyl groups are not acylated.

[0020] In one embodiment, one hydroxyl group of the 1,2-cis diol is acylated to a benzoyl group, and the other hydroxyl group is not acylated.

[0021] In one embodiment, the carbohydrate compound is any one or more compounds represented by formula (I)-(XIII), and corresponding to the compounds represented by formula (I)-(XIII), the (main) reaction products thereof are the compounds represented by (1a)-(13a) below: .

[0022] In one embodiment, the reaction solvent is dichloromethane or a dichloromethane / acetonitrile mixed solution.

[0023] In one embodiment, the reaction temperature is no higher than -20°C, no higher than -10°C, or no higher than 0°C.

[0024] In one embodiment, the reaction temperature is -80°C to -0°C; preferably, the reaction temperature is -20±10°C, -20±5°C, -20±2°C, or -20±1°C. More preferably, the reaction temperature is -20°C.

[0025] In one embodiment, the reaction time is not less than 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h or 22h.

[0026] In one embodiment, the reaction time is 3.5 h, 4.5 h, 5 h, 9 h, 10 h, 10.5 h, 11 h, 16.5 h or 22 h. Preferably, the reaction time is 3.5 h to 22 h.

[0027] In one embodiment, 4Å molecular sieves are added to the reaction flask of the reaction.

[0028] In one embodiment, the reaction is carried out under argon.

[0029] In one embodiment, the method further comprises the step of monitoring the extent of the reaction using thin layer chromatography (TLC).

[0030] In one embodiment, the method further includes the following steps of isolating and purifying the product: adding ammonium chloride solution to quench the reaction, diluting with dichloromethane, filtering off the molecular sieve with diatomaceous earth, washing the reaction solution with 1N HCl solution, saturated sodium bicarbonate, and sodium chloride solution in sequence, then drying with anhydrous sodium sulfate, filtering, concentrating, and separating and purifying by column chromatography (petroleum ether / ethyl acetate = 3:1).

[0031] In one embodiment, the yield of the selective acylated product obtained by the method is not less than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%. Beneficial effects

[0032] The present invention provides a method for selectively acylating a saccharide compound containing 1,2-cis-diol. The method uses benzoyl fluoride as an acylation reagent and DBU as a catalyst. The method has the advantages of simple and efficient operation, a wide range of substrate applicability, high regioselectivity, good functional group compatibility, and high yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 .NMR spectrum of compound 1a.

[0034] Figure 2 .NMR spectrum of compound 2a.

[0035] Figure 3 (A)-(D). NMR spectra of compound 3a.

[0036] Figure 4 .NMR spectrum of compound 4a.

[0037] Figure 5 .NMR spectrum of compound 5a.

[0038] Figure 6 .NMR spectrum of compound 6a.

[0039] Figure 7 (A)-(D). NMR spectra of compound 7a.

[0040] Figure 8 (A)-(D). NMR spectra of compound 8a.

[0041] Figure 9 .NMR spectrum of compound 9a.

[0042] Figure 10 .NMR spectrum of compound 10a.

[0043] Figure 11 .NMR spectrum of compound 11a.

[0044] Figure 12 .NMR spectrum of compound 12a.

[0045] Figure 13 (A)-(B). NMR spectra of compound 13a. DETAILED DESCRIPTION

[0046] The present invention will be further described below with reference to the following embodiments. The following description is merely a preferred embodiment of the present invention and does not limit the present invention in any other form. Any person skilled in the art may utilize the above disclosed technical content to make equivalent embodiments with equivalent variations. Any simple modification or equivalent variation of the following embodiments made in accordance with the technical essence of the present invention without departing from the content of the present invention shall fall within the scope of protection of the present invention.

[0047]

[0048] A dry two-necked flask was filled with 4Å molecular sieves and vacuum-baked three times. After cooling to room temperature and purging with argon, substrate 1 (50.0 mg, 107.3 μmol) was added and dissolved in 1.6 mL of freshly distilled dichloromethane. BzF (13.0 µL, 117.7 μmol) was then added. The reaction mixture was cooled to -20°C and DBU (1.6 µL, 10.7 μmol) was added. The reaction was stirred at this temperature for 10 hours. After thin-layer chromatography (TLC) monitoring indicated the reaction was complete, ammonium chloride solution was added to quench the reaction, the mixture was diluted with dichloromethane, and the molecular sieves were removed by filtration through celite. The reaction solution was washed sequentially with 1N HCl solution, saturated sodium bicarbonate solution, and sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 1a (57.3 mg, 94%) as a white solid. The NMR spectrum of compound 1a is shown in Figure 1. Figure 1 As shown, 1 H NMR (400 MHz, CDCl3) δ 8.00 (d, J =7.7 Hz, 2H, Ar H ), 7.51 (t, J = 7.4 Hz, 1H, Ar H ), 7.35-7.39 (m, 2H, Ar H ), 7.11- 7.29 (m, 10H, Ar H ), 7.00 (d, J = 8.5 Hz, 2H, Ar H ), 6.74 (d, J = 8.6 Hz, 2H,Ar H ), 5.58 (d, J = 3.3 Hz, 1H, 4-H), 5.00 (d, J = 11.1 Hz, 1H, PhC H 2 ), 4.88(d, J= 7.5 Hz, 1H, 1-H), 4.72 (d, J = 11.1 Hz, 1H, PhC H 2 ), 4.42 (d, J = 11.7Hz, 1H, PhC H 2 ), 4.35 (d, J = 11.6 Hz, 1H, PhC H 2 ), 3.85 - 3.91 (m, 2H, 5-H, 3-H), 3.79 (t, J = 8.6 Hz, 1H, 2-H), 3.69 (s, 3H, O Me ), 3.57 - 3.58 (m, 2H, 6-H, 6'-H), 2.56 (br, 1H, O H ).

[0049]

[0050] A dry two-necked flask was filled with 4Å molecular sieves and vacuum-baked three times. After cooling to room temperature and purging with argon, substrate 2 (50.0 mg, 107.3 μmol) was added and dissolved in 1.6 mL of freshly distilled dichloromethane. BzF (13.0 µL, 117.7 μmol) was then added. The reaction mixture was cooled to -20°C and DBU (1.6 µL, 10.7 μmol) was added. The reaction was stirred at this temperature for 16.5 hours. After thin-layer chromatography (TLC) monitoring indicated the reaction was complete, ammonium chloride solution was added to quench the reaction, the mixture was diluted with dichloromethane, and the molecular sieves were removed by filtration through celite. The reaction solution was washed sequentially with 1N HCl solution, saturated sodium bicarbonate solution, and sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 2a (55.5 mg, 91%) as a white solid. The NMR spectrum of compound 2a is shown in Figure 2. Figure 2 As shown, 1 H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 7.8 Hz, 2H, Ar H ), 7.53 - 7.61 (m, 3H, Ar H ), 7.18 - 7.48 (m, 17H, Ar H ), 7.10(d, J = 7.7 Hz, 2H, Ar H), 5.61 (d, J = 3.3 Hz, 1H, 4-H), 4.90 (d, J = 10.7Hz, 1H, PhC H 2 ), 4.60 - 4.68 (m, 2H, PhC H 2 , 1-H), 4.49 (d, J = 11.5 Hz, 1H,PhC H 2 ), 4.40 (d, J = 11.8 Hz, 1H, PhC H 2 ), 3.86 - 3.93 (m, 2H, 3-H, 5-H), 3.56- 3.67 (m, 3H, 2-H, 6-H, 6'-H), 2.35 (s, 3H, Ph Me ).

[0051]

[0052] A dry two-necked flask was filled with 4Å molecular sieves and vacuum-baked three times. After cooling to room temperature and purging with argon, substrate 3 (50.0 mg, 133.7 μmol) was added and dissolved in 1.9 mL of freshly distilled dichloromethane. BzF (16.0 µL, 147.1 μmol) was then added. The reaction mixture was cooled to -20°C, and DBU (2.0 µL, 13.4 μmol) was added. The reaction was stirred at this temperature for 9 hours. After thin-layer chromatography (TLC) monitoring indicated the reaction was complete, ammonium chloride solution was added to quench the reaction, the mixture was diluted with dichloromethane, and the molecular sieves were removed by filtration through celite. The reaction solution was washed sequentially with 1N HCl solution, saturated sodium bicarbonate, and sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain 3a (56.9 mg, 89%) as a white solid. The NMR spectra of compound 3a are shown in Figures 3(A)-(D). 1 H NMR (400 MHz, CDCl3) δ 7.94(d, J = 7.7 Hz, 2H, Ar H ), 7.52 (t, J = 7.4 Hz, 1H, Ar H ), 7.37 (t, J = 7.7 Hz,2H, Ar H), 7.21 - 7.30 (m, 4H, Ar H ), 7.11 - 7.18 (m, 5H, Ar H ), 5.59 (d, J =3.5 Hz, 1H, 4-H), 4.74 (d, J = 3.4 Hz, 1H, 1-H), 4.66 (d, J = 11.9 Hz, 1H,PhC H 2 ), 4.60 (d, J = 12.0 Hz, 1H, PhC H 2 ), 4.42 (d, J = 11.8 Hz, 1H, PhC H 2 ),4.33 (d, J = 11.9 Hz, 1H, PhC H 2 ), 4.20 (dd, J = 10.2, 3.4 Hz, 1H, 3-H), 4.10(t, J = 6.3 Hz, 1H, 5-H), 3.74 (dd, J = 9.8, 3.4 Hz, 1H, 2-H), 3.48 (d, J =6.3 Hz, 2H, 6-H, 6’-H), 3.33 (s, 3H, O Me ). 13 C{ 1 H}NMR (100 MHz, CDCl3) δ166.3, 137.9, 137.7, 133.1, 129.9, 129.8, 128.6, 128.5, 128.4, 128.3, 128.1,128.0, 127.6, 127.5, 98.1, 76.6, 73.5, 73.0, 71.3, 68.8, 68.4, 68.0, 55.5.HRMS (ESI-TOF) m / z: [M + K] + Calcd for C 28 H 30 O7K: 517.1624; Found: 517.1661。

[0053]

[0054] A dry two-necked flask was filled with 4Å molecular sieves and vacuum-baked three times. After cooling to room temperature and purging with argon, substrate 3 (50.0 mg, 81.4 μmol) was added and dissolved in 1.2 mL of freshly distilled dichloromethane. BzF (9.7 µL, 89.5 μmol) was then added. The reaction mixture was cooled to -20°C and DBU (1.2 µL, 8.1 μmol) was added. The reaction was stirred at this temperature for 9 hours. After thin-layer chromatography (TLC) monitoring indicated the reaction was complete, ammonium chloride solution was added to quench the reaction, the mixture was diluted with dichloromethane, and the molecular sieves were removed by filtration through celite. The reaction solution was washed sequentially with 1N HCl solution, saturated sodium bicarbonate solution, and sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 4a (52.6 mg, 90%) as a colorless, transparent semisolid. The NMR spectrum of compound 4a is shown in Figure 4. Figure 4 As shown, 1 H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.8 Hz, 2H, Ar H ), 7.53 (t, J = 7.4 Hz, 3H, Ar H ), 7.44 (d, J = 7.4 Hz, 2H,Ar H ), 7.18 - 7.39 (m, 11H, Ar H ), 7.08 (t, J = 7.4 Hz, 2H, Ar H ), 6.97 (d, J =8.5 Hz, 2H, Ar H ), 6.72 (d, J = 8.5 Hz, 2H, Ar H ), 5.66 (d, J = 3.3 Hz, 1H, 4-H), 4.99 (d, J = 11.1 Hz, 1H, PhC H 2 ), 4.86 (d, J = 7.7 Hz, 1H, 1-H), 4.72 (d, J = 11.2 Hz, 1H, PhC H 2), 3.88 - 3.92 (m, 1H, 3-H), 3.72 - 3.82 (m, 4H, 2-H,5-H, 6-H, 6'-H), 3.69 (s, 3H, O Me ), 2.43 (br, 1H, O H ), 0.94 (s, 9H, tert- Butyl ).

[0055]

[0056] A dry two-necked flask was filled with 4Å molecular sieves and vacuum-baked three times. After cooling to room temperature and purging with argon, substrate 5 (50.0 mg, 101.2 μmol) was added and dissolved in 10 mL of dichloromethane / acetonitrile (2:1). BzF (12.0 µL, 110.0 μmol) was then added. The reaction mixture was cooled to -20°C, and DBU (1.5 µL, 10.1 μmol) was added. The reaction was stirred at this temperature for 5 hours. After completion of the reaction as monitored by thin-layer chromatography (TLC), ammonium chloride solution was added to quench the reaction, the mixture was diluted with dichloromethane, and the molecular sieves were removed by filtration through celite. The reaction solution was washed sequentially with 1N HCl solution, saturated sodium bicarbonate, and sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain 5a (45.1 mg, 75%) as a white solid. The NMR spectrum of compound 5a is shown in Figure 2. Figure 5 As shown, 1 H NMR (400 MHz, CDCl3) δ 8.17 - 8.19(d, J = 7.7 Hz, 2H, Ar H ), 8.06 (d, J = 7.7 Hz, 4H, Ar H ), 7.57 - 7.64 (m, 3H,Ar H ), 7.43 - 7.51 (m, 6H, Ar H ), 6.98 (d, J = 8.4 Hz, 2H, Ar H ), 6.67 (d, J =8.5 Hz, 2H, Ar H ), 5.80 (d, J = 4.0 Hz, 1H, 4-H), 5.61 (t, J = 8.9 Hz, 1H, 2-H), 5.14 (d, J= 7.9 Hz, 1H, 1-H), 4.52 - 4.61 (m, 2H, 6-H, 6'-H), 4.27 (t, J = 6.5 Hz, 1H, 5-H), 4.22 (dd, J = 10.0, 3.4 Hz, 1H, 3-H), 3.72 (s, 3H, O Me ),2.94 (br, 1H, O H ).

[0057]

[0058] A dry two-necked flask was filled with 4Å molecular sieves and vacuum-baked three times. After cooling to room temperature and purging with argon, substrate 5 (50.0 mg, 101.2 μmol) was added and dissolved in 10 mL of dichloromethane / acetonitrile (2:1). BzF (12.0 µL, 110.0 μmol) was then added. The reaction mixture was cooled to -20°C, and DBU (1.5 µL, 10.1 μmol) was added. The reaction was stirred at this temperature for 3.5 hours. After thin-layer chromatography (TLC) monitoring indicated the reaction was complete, ammonium chloride solution was added to quench the reaction, the mixture was diluted with dichloromethane, and the molecular sieves were removed by filtration through Celite. The reaction solution was washed sequentially with 1N HCl solution, saturated sodium bicarbonate, and sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 6a (43.7 mg, 72%) as a white solid. The NMR spectrum of compound 6a is shown in Figure 2. Figure 6 As shown, 1 H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.8 Hz, 2H, Ar H ), 8.04 (d, J = 7.8 Hz, 2H, Ar H ), 7.97 (d, J = 7.8 Hz, 2H,Ar H ), 7.56 - 7.66 (m, 4H, Ar H ), 7.41 - 7.53 (m, 9H, ArH), 7.02 (d, J = 7.8Hz, 2H, Ar H ), 5.77 (d, J = 3.3 Hz, 1H, 4-H), 5.30 (t, J = 9.7 Hz, 1H, 2-H),4.87 (d,J = 9.8 Hz, 1H, 1-H), 4.57 (dd, J = 11.6, 7.1 Hz, 1H, 6-H), 4.44(dd, J = 11.7, 5.2 Hz, 1H, 6'-H), 4.13 - 4.19 (m, 2H, 3-H, 5-H), 3.04 (br,1H, O H ) 2.34 (s, 3H, Ph Me ).

[0059]

[0060] A dry two-necked flask was filled with 4Å molecular sieves and vacuum-baked three times. After cooling to room temperature and purging with argon, substrate 7 (50.0 mg, 55.7 μmol) was added and dissolved in 5.6 mL of dichloromethane / acetonitrile (2 / 1). BzF (6.7 µL, 61.2 μmol) was then added. The reaction mixture was cooled to -20°C, and DBU (0.8 µL, 5.6 μmol) was added. The reaction was stirred at this temperature for 10.5 hours. After thin-layer chromatography (TLC) monitoring indicated the reaction was complete, ammonium chloride solution was added to quench the reaction, the mixture was diluted with dichloromethane, and the molecular sieves were removed by filtration through Celite. The reaction solution was washed sequentially with 1N HCl solution, saturated sodium bicarbonate solution, and sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain 2 g (47.0 mg, 84%) of a white solid 7a. The NMR spectra of compound 7a are shown in Figures 7(A)-(D). 1 H NMR (600 MHz, CDCl3) δ8.00 - 8.01 (m, 2H, Ar H ), 7.55 - 7.58 (m, 1H, Ar H ), 7.40 - 7.42 (m, 2H, Ar H ),7.28 - 7.38 (m, 17H, Ar H ), 7.16 - 7.21 (m, 6H, Ar H ), 7.11 - 7.13 (m, 2H,Ar H ), 7.05 - 7.07 (m 2H, Ar H ), 6.83 - 6.84 (m, 2H, Ar H ), 5.63 (d, J = 3.4 Hz,1H, 4a-H), 5.14 (d,J = 10.7 Hz, 1H, PhC H 2 ), 5.02 (d, J = 10.9 Hz, 1H, PhC H 2 ),4.90 - 4.91 (m, 1H, 1b-H), 4.84 - 4.86 (m, 3H, PhC H 2 ×3), 4.73 (d, J = 11.3Hz, 1H, PhC H 2 ), 4.58 - 4.62 (m, 2H, PhC H 2 , 1a-H), 4.43 - 4.48 (m, 2H, PhC H 2 ×2), 4.25 (d, J = 11.9 Hz, 1H, PhC H 2 ), 4.10 - 4.13 (m, 1H, 3b-H), 3.85 - 3.86(m, 2H, 6b-H, 6b’-H), 3.81 (s, 4H, 3a-H, O Me ), 3.69 - 3.72 (m, 3H, 2b-H, 5a-H, 4b-H), 3.53 - 3.58 (m, 2H, 2a-H, 5b-H), 3.44 - 3.47 (m, 2H, 6a-H, 6a’-H). 13 C{ 1H}NMR (150 MHz, CDCl3) δ 166.4, 155.3, 151.6, 138.9, 138.4, 138.1, 137.8,133.2, 129.8, 129.7, 128.5, 128.4, 128.3, 128.3, 128.1, 128.1, 127.9, 127.9,127.8, 127.7, 127.6, 127.6, 127.6, 127.3, 118.5, 114.5, 102.9, 102.6, 82.8,81.5, 80.2, 75.5, 75.3, 75.2, 73.5, 73.3, 72.8, 72.4, 70.2, 68.2, 67.4, 55.6.HRMS (ESI-TOF) m / z: [M + NH4] + Calcd for C 61 H 66 NO 13 1020.4529; Found: 1020.4529.

[0061]

[0062] A dry two-necked flask was filled with 4Å molecular sieves and vacuum-baked three times. After cooling to room temperature and purging with argon, substrate 8 (40.0 mg, 44.5 µmol) was added and dissolved in 4.5 mL of dichloromethane / acetonitrile (2:1). BzF (4.8 µL, 44.7 µmol) was then added. The reaction mixture was cooled to -20°C, and DBU (0.7 µL, 4.5 µmol) was added. The reaction was stirred at this temperature for 11 hours. After thin-layer chromatography (TLC) monitoring indicated the reaction was complete, ammonium chloride solution was added to quench the reaction, the mixture was diluted with dichloromethane, and the molecular sieves were removed by filtration through Celite. The reaction solution was washed sequentially with 1N HCl solution, saturated sodium bicarbonate, and sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 8a (36.1 mg, 80%) as a white solid. The NMR spectra of compound 8a are shown in Figures 8(A)-(D). 1 H NMR (400 MHz, CDCl3) δ 7.91(d, J = 7.7 Hz, 2H, Ar H ), 7.45 (t, J = 7.5 Hz, 1H, Ar H ), 7.36 (d, J = 7.4 Hz,2H, ArH ), 6.97 - 7.28 (m, 29H, Ar H ), 6.74 (d, J = 8.4 Hz, 2H, Ar H ), 5.49 (d, J = 3.2 Hz, 1H, 4a-H), 5.23 (d, J = 3.6 Hz, 1H, 1b-H), 5.07 (d, J = 10.5 Hz,1H, PhC H 2 ), 4.69 - 4.82 (m, 4H, PhC H 2 ×4), 4.50 - 4.63 (m, 4H, PhC H 2 ×4), 4.35(t, J = 8.8 Hz, 2H, 1a-H, PhC H 2 ), 4.27 (d, J = 12.0 Hz, 1H, PhC H 2 ), 4.13 (d, J = 12.0 Hz, 1H, PhC H 2 ), 3.97 - 4.05 (m, 2H, 3b-H, 5a-H), 3.77 (d, J = 9.9 Hz,2H, 6a-H, 4b-H), 3.70 (s, 3H, OMe), 3.50 - 3.58 (m, 3H, 3a-H, 2b-H, 5b-H),3.44 (d, J = 9.3 Hz, 2H, 2a-H, 6a’-H), 3.36 (d, J = 6.8 Hz, 2H, 6b-H, 6b’-H). 13 C{ 1H}NMR (100 MHz, CDCl3) δ 166.4, 155.0, 151.0, 139.2, 138.2, 138.1, 137.8,137.8, 133.1, 129.8, 129.6, 128.4, 128.3, 128.2, 128.0, 127.9, 127.9, 127.8,127.7, 127.7, 127.6, 127.5, 127.2, 118.2, 114.5, 102.5, 96.8, 80.1, 80.0,78.8, 76.5, 75.5, 75.1, 73.5, 73.4, 73.2, 72.6, 72.4, 70.7, 70.2, 67.8, 67.4,55.6. HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 61 H 62 O 13 Na: 1025.4083; Found1025.4094.

[0063]

[0064] A dry two-necked flask was filled with 4Å molecular sieves and vacuum-baked three times. After cooling to room temperature and purging with argon, substrate 9 (30.0 mg, 80.2 μmol) was added and dissolved in 1.1 mL of freshly distilled dichloromethane. BzF (9.6 µL, 88.2 μmol) was then added. The reaction mixture was cooled to -20°C and DBU (1.2 µL, 8.0 μmol) was added. The reaction was stirred at this temperature for 4.5 hours. After thin-layer chromatography (TLC) monitoring indicated the reaction was complete, ammonium chloride solution was added to quench the reaction, the mixture was diluted with dichloromethane, and the molecular sieves were removed by filtration through celite. The reaction solution was washed sequentially with 1N HCl solution, saturated sodium bicarbonate solution, and sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain 9a (33.7 mg, 88%) as a white solid. The NMR spectrum of compound 9a is shown in Figure 2. Figure 9 As shown, 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.6 Hz, 2H, Ar H ), 7.56 (t, J = 7.4 Hz, 1H, Ar H ), 7.25 - 7.44 (m, 15H, Ar H),5.3 (d, J = 3.2 Hz, 1H, 2-H), 4.85 (s, 1H, 1-H), 4.74 - 4.82 (m, 2H, PhC H 2 ),4.53 - 4.65 (m, 2H, PhC H 2 ), 4.25 (dd, J = 9.4, 3.2 Hz, 1H, 3-H), 3.99 (t, J =9.6 Hz, 1H, 4-H), 3.91 (dd, J = 11.0, 3.9 Hz, 1H, 6-H), 3.78 - 3.83 (m, 2H,5-H, 6'-H), 3.40 (s, 3H, O Me ), 2.20 (br, 1H, O H ).

[0065]

[0066] A dry two-necked flask was filled with 4Å molecular sieves and vacuum-baked three times. After cooling to room temperature and purging with argon, substrate 10 (50.0 mg, 177.3 μmol) was added and dissolved in 17.7 mL of dichloromethane / acetonitrile (2:1). BzF (21.0 µL, 195.0 μmol) was then added. The reaction mixture was cooled to -20°C, and DBU (2.7 µL, 17.7 μmol) was added. The reaction was stirred at this temperature for 11 hours. After thin-layer chromatography (TLC) monitoring indicated the reaction was complete, ammonium chloride solution was added to quench the reaction, the mixture was diluted with dichloromethane, and the molecular sieves were removed by filtration through Celite. The reaction solution was washed sequentially with 1N HCl solution, saturated sodium bicarbonate, and sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 10a (52.5 mg, 77%) as a white solid. The NMR spectrum of compound 10a is shown in Figure 2. Figure 10 As shown, 1 H NMR (400 MHz, CDCl3) δ 8.10(d, J = 7.7 Hz, 2H, Ar H ), 7.60 (t, J = 7.4 Hz, 1H, Ar H ), 7.46 - 7.53 (m, 4H,Ar H ), 7.34 - 7.43 (m, 3H, ArH ), 5.66 (s, 1H, PhC H 2 ), 5.46 (dd, J = 3.5, 1.6Hz, 1H, 2-H), 4.84 (s, 1H, 1-H), 4.29 - 4.36 (m, 2H, 4-H, 6-H), 3.99 - 4.08(m, 1H, 5-H), 3.86 - 3.94 (m, 2H, 3-H, 6'-H), 3.43 (s, 3H, O M e).

[0067]

[0068] A dry two-necked flask was filled with 4Å molecular sieves and vacuum-baked three times. After cooling to room temperature and purging with argon, substrate 11 (50.0 mg, 133.7 μmol) was added and dissolved in 13.4 mL of dichloromethane / acetonitrile (2:1). BzF (16.0 µL, 147.4 μmol) was then added. The reaction mixture was cooled to -20°C, and DBU (2.0 µL, 13.4 μmol) was added. The reaction was stirred at this temperature for 11 hours. After thin-layer chromatography (TLC) monitoring indicated the reaction was complete, ammonium chloride solution was added to quench the reaction, the mixture was diluted with dichloromethane, and the molecular sieves were removed by filtration through Celite. The reaction solution was washed sequentially with 1N HCl solution, saturated sodium bicarbonate, and sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 11a (51.1 mg, 80%) as a white solid. The NMR spectrum of compound 11a is shown in Figure 1. Figure 11 As shown, 1 H NMR (400 MHz, CDCl3) δ 8.13(d, J = 7.7 Hz, 2H, Ar H ), 7.62 (t, J = 7.4 Hz, 1H, Ar H ), 7.48 - 7.57 (m, 4H,Ar H ), 7.38 - 7.41 (m, 3H, Ar H ), 7.00 - 7.04 (m, 2H, Ar H ), 6.84 - 6.87 (m, 2H,Ar H ), 5.68 (s, 1H, PhC H 2), 5.65 - 5.66 (m, 1H, 2-H), 5.56 (s, 1H, 1-H), 4.53- 4.56 (m, 1H, 4-H), 4.28 (dd, J = 10.1, 3.7 Hz, 1H, 5-H), 4.07 - 4.15 (m,2H, 3-H, 6-H), 3.87 (t, J = 9.7 Hz, 1H, 6'-H), 3.78 (s, 3H, O Me ).

[0069]

[0070] A dry two-necked flask was filled with 4Å molecular sieves and vacuum-baked three times. After cooling to room temperature and purging with argon, substrate 12 (53.0 mg, 180.0 μmol) was added and dissolved in 2.0 mL of dichloromethane. BzF (22.0 µL, 198.0 μmol) was then added. The reaction mixture was cooled to -20°C and DBU (2.7 µL, 18.0 μmol) was added. The reaction was stirred at this temperature for 22 hours. After thin-layer chromatography (TLC) monitoring indicated the reaction was complete, ammonium chloride solution was added to quench the reaction, the mixture was diluted with dichloromethane, and the molecular sieves were removed by filtration through celite. The reaction solution was washed sequentially with 1N HCl solution, saturated sodium bicarbonate, and sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain 12a (60.0 mg, 84%) as a white solid. The NMR spectrum of compound 12a is shown in Figure 1. Figure 12 As shown, 1 H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 7.8Hz, 2H, Ar H ), 7.59 (t, J = 7.4 Hz, 1H, Ar H ), 7.47 (t, J = 7.6 Hz, 2H, Ar H ),7.26 - 7.38 (m, 5H, Ar H ), 6.01 (ddt, J = 16.5, 10.9, 5.6 Hz, 1H, OCH2 CH =CH2),5.36 - 5.43 (m, 2H, 4-H, OCH2 CH =CH2), 5.25 (d, J = 10.4 Hz, 1H, OCH2 CH =CH2),5.03 (d, J = 11.2 Hz, 1H, PhC H 2 ), 4.71 (d, J = 11.2 Hz, 1H, PhC H 2 ), 4.46 -4.50 (m, 2H, 1-H, OCH2 CH =CH2), 4.15 - 4.20 (m, 1H, OCH2 CH =CH2), 3.86 (dd, J =9.7, 3.5 Hz, 1H, 3-H), 3.79 - 3.82 (m, 1H, 5-H), 3.63 (t, J = 8.7 Hz, 1H, 2-H), 1.26 (d, J = 6.1 Hz, 3H, Me ).

[0071]

[0072] A dry two-necked flask was filled with 4Å molecular sieves and vacuum-baked three times. After cooling to room temperature and purging with argon, substrate 13 (40 mg, 74.0 µmol) was added and dissolved in 1.1 mL of freshly distilled dichloromethane. BzF (8.3 µL, 77.7 µmol) was then added. The reaction mixture was cooled to -20°C and DBU (1.1 µL, 7.4 µmol) was added. The reaction was stirred at this temperature for 11 hours. After thin-layer chromatography (TLC) monitoring indicated completion of the reaction, ammonium chloride solution was added to quench the reaction, the mixture was diluted with dichloromethane, and the molecular sieves were removed by filtration through Celite. The reaction solution was washed sequentially with 1N HCl solution, saturated sodium bicarbonate solution, and sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain 13a (34.3 mg, 72%) as a white solid. The NMR spectra of compound 13a are shown in Figures 13(A)-(B). 1 H NMR (400 MHz, CDCl3) δ 7.97 - 7.99(m, 2H, Ar H ), 7.51 - 7.54 (m, 1H, Ar H ), 7.41 (t, J = 7.8 Hz, 2H, Ar H ), 7.17 -7.27 (m, 19H, Ar H), 5.88 (t, J = 2.8 Hz, 1H, 2-H), 4.89 - 4.94 (m, 2H, PhC H 2 ×2), 4.86 (d, J = 10.7 Hz, 1H, PhC H 2 ), 4.79 (d, J = 10.5 Hz, 1H, PhC H 2 ), 4.75(dd, J = 11.1, 8.4 Hz, 2H, PhC H 2 ×2), 4.69 (d, J = 11.2 Hz, 1H, PhC H 2 ), 4.48(d, J = 11.4 Hz, 1H, PhC H 2 ), 3.92 (t, J = 9.5 Hz, 1H, 4-H), 3.82 (t, J = 9.6Hz, 1H, 6-H), 3.64 (dd, J = 9.9, 2.8 Hz, 1H, 1-H), 3.57 (dd, J = 9.7, 2.9 Hz,1H, 3-H), 3.53 (t, J = 9.4 Hz, 1H, H-5).

[0073] In the present invention, other commonly used acylating agents, such as BzCl and Bz2O, were also tried. BzCl and Bz2O were able to acylate the above-mentioned substrates, but could not achieve high regioselectivity. Other catalysts, such as triethylamine, quinine, and quinidine, were also tried. These catalysts could not react at low temperatures (-20°C). When the reaction temperature was increased, acylation could be achieved, but regioselective acylation could not be achieved, and the conversion rate was very low (less than 40%), that is, they could not effectively catalyze the reaction. In addition, the reaction temperature was optimal at -20°C. Increasing the reaction temperature resulted in poor regioselectivity of the acylation, while decreasing the reaction temperature resulted in low product conversion.

[0074] Although the specific embodiments of the present invention have been described in detail, those skilled in the art will understand that various modifications and changes can be made to the details based on all the teachings published, and these changes are all within the scope of protection of the present invention. The entire invention is given by the appended claims and any equivalents thereof.

Claims

1. A method for selectively acylating a saccharide compound containing 1,2-cis-diol, comprising reacting the saccharide compound with an acylating agent in the presence of a catalyst, wherein: The acylating agent is benzoyl fluoride, and the catalyst is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

2. The method according to claim 1, characterized in that The method can selectively acylate the axial hydroxyl groups in 1,2-cis diols.

3. The method according to claim 1, characterized in that The carbohydrate compound is selected from galactose or its derivatives, lactose or its derivatives, mannose or its derivatives, fucose or its derivatives or inositol or its derivatives.

4. The method according to claim 1, wherein The carbohydrate compound is a compound of formula (A), (B), (C) or (D): Among them, R 1 、R 2 、R 3 or R 4 is any group, optionally, R 1 、R 2 、R 3 or R 4 Selected from: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, acyl or silane.

5. The method according to claim 4, characterized in that In the compound of formula (A), R 1 is aglycone, such as Mp, STol, Me, , SEt, SPh, Ac or All; R 2 and R 3 is a cyclic group, such as a cycloalkyl group, an aryl group, a heterocyclic group or a silyl group; In the compound of formula (B), R 1 is aglycone, such as Mp, STol, Me, , SEt, SPh, Ac or All; R 2 and R 3 is a cyclic group, such as a cycloalkyl group, an aryl group, a heterocyclic group, a silyl group or R 2 and R 3 Ringing; In the compound of formula (C), R 1 is aglycone, such as AII, Mp, STol, , Me, SEt, SPh or Ac; R 2 is a cyclic group, such as a cycloalkyl group, an aryl group, a heterocyclic group or a silyl group; In the compound of formula (D), R 1 、R 2 、R 3 or R 4 is a cyclic group, such as a cycloalkyl group, an aryl group, a heterocyclic group or a silyl group.

6. The method according to claim 5, characterized in that The carbohydrate compound is any one or more compounds represented by the following formulas (I) to (XIII): 。 7. The method according to claim 4, characterized in that The carbohydrate compound is a compound of formula (A), and the reaction product is a 4-hydroxy acylated compound; Or, the carbohydrate compound is a compound of formula (B), and the reaction product is a 2-hydroxyacylated compound; Or, the carbohydrate compound is a compound of formula (C), and the reaction product is a 4-hydroxyacylated compound; Alternatively, the carbohydrate compound is a compound of formula (D), and the reaction product is a 2-hydroxy acylated compound.

8. The method according to claim 1, characterized in that The reaction solvent is dichloromethane or a dichloromethane / acetonitrile mixed solution.

9. The method according to claim 1, characterized in that The reaction temperature is -20±5°C.

10. The method according to claim 1, characterized in that The reaction time is not less than 3.5 hours.

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