Synthesis method of 3-O-carbohydrate chain betulinic acid aglycone glycoside and 28-COO-carbohydrate chain aglycone glycoside

Abstract

The invention discloses a synthesis method of 3-O-carbohydrate chain betulinic acid aglycone glycoside and 28-COO-carbohydrate chain aglycone glycoside, and belongs to the field of carbohydrate chemistry, and the synthesis method comprises the following steps: # imgabs0 # R1, R2, R3, R6 and R7 are respectively and independently selected from alkyl, aryl, silyl or acyl; r5 is selected from alkanoyl or aroyl; a compound 1 is used as a raw material and is subjected to glycosylation reaction to obtain a compound 7, and the compound 7 is subjected to glycosylation reaction and deprotection reaction to obtain compounds I and II.

Description

Technical Field

[0001] The present invention belongs to the field of glycochemistry, and particularly relates to a synthesis method of 3-O-glycosidic betulinic acid aglycone glycoside and 28-COO-glycosidic aglycone glycoside. Background Art

[0002] Natural products are the source of drug research and development. Betulinic acid is a naturally occurring lupane-type pentacyclic triterpenoid with multiple pharmacological activities. The most remarkable activity is that betulinic acid can inhibit the growth of various cancer cells and it has been found in in vitro experimental studies that it does not affect the growth of normal cells. In addition, the in vivo anti-tumor activity of betulinic acid has also been confirmed. At a dose of 500 mg / kg body weight, no other toxicity was observed in tumour-bearing mice by intraperitoneal injections. Betulinic acid selectively has toxicity to cancer cells and a good therapeutic index, so it is considered a promising anti-tumor drug. However, the further clinical research of betulinic acid has been hindered because it is almost insoluble in water (0.02 micrograms / mL) and it has a high partition coefficient. Introducing sugar chains at its C-3 and C-28 positions can improve its water solubility. Research shows that after introducing L-rhamnose at the C-3 position of betulinic acid, its water solubility and anti-lung cancer activity have been significantly improved.

[0003]

[0004] There are also many triterpenoid saponins in nature with betulinic acid as the aglycone. Compound 1 is a 3-O-glycosidic chain, 28-COO-glycosidic chain betulinic acid triterpenoid saponin, which was isolated from the aerial part of Schefflera rotundifolia. Compound 2 is a 3-O-glycosidic chain betulinic acid natural triterpenoid saponin, which was isolated from the root of Pulsatilla koreana. Research shows that both of these compounds have good water solubility and excellent anti-tumor activity, and are potential research objects for developing into anti-tumor drugs. However, many betulinic acid saponins are obtained by separation and purification. There are many types of naturally occurring triterpenoid saponins with similar structures, which brings great difficulties to separation and purification. Moreover, some betulinic acid saponins have very low contents, and it is even more difficult to obtain enough amounts for activity testing, which has become a bottleneck restricting the in-depth research on the activities of betulinic acid saponin compounds. Chemical synthesis is one of the effective ways to break through this bottleneck. Summary of the Invention

[0005] The purpose of the present invention is to provide a synthesis method of 3-O-glycosidic betulinic acid aglycone glycoside and 28-COO-glycosidic aglycone glycoside.

[0006] For the above purposes, the present invention adopts the following technical solutions:

[0007] A method for synthesizing 3-O-glycosylbetulinic acid aglycone glycoside and 28-COO-glycosyl aglycone glycoside, comprising the following steps:

[0008]

[0009] R 1 、R 2 、R 3 、R 6 、R 7 are each independently selected from alkyl, aryl, silyl or acyl; R 5 is selected from alkanoyl or aroyl;

[0010] Using compound 1 as a raw material, through glycosylation reaction, compound 7 is obtained, and compound 7 undergoes glycosylation reaction and deprotection reaction to obtain compounds I and II.

[0011] Furthermore, the synthesis process of compound 7 is as follows:

[0012]

[0013] R 1 、R 2 、R 3 、R 6 、R 7 are each independently selected from alkyl, aryl, silyl or acyl; R 4 、R 5 is selected from alkanoyl or aroyl; X is selected from substituted or unsubstituted ethynylphenylthio;

[0014] (1) Protect the carboxyl group at the 28th position of compound 1 with a protecting group to obtain compound 2;

[0015] (2) Using compound 2 as an acceptor, carry out glycosylation reaction with glycosyl donor 3 to obtain compound 4;

[0016] (3) Remove the R 4 protecting group from compound 4 to obtain compound 5;

[0017] (4) React compound 5 with glycosyl donor 6 to obtain compound 7.

[0018] Furthermore, the synthesis process of compound I is as follows:

[0019]

[0020] R 1 、R 2 、R 3, R 6 , R 7 , R 8 , R 9 , R 10 Each independently selected from alkyl, aryl, silyl or acyl; R 5 , R 11 Selected from alkanoyl or aroyl; X is selected from substituted or unsubstituted ethynylphenylthio;

[0021] S1. Remove the protecting group of R 2 in compound 7 to obtain compound 8;

[0022] S2. Using compound 8 as the acceptor, perform glycosylation reaction with glycosyl donor 9 to obtain compound 10;

[0023] S3. Remove the protecting group of R 1 in compound 10 to obtain compound 11;

[0024] S4. Finally, remove the protecting groups of R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 to obtain 3-O-glycosylated betulinic acid glycoside 1.

[0025] Furthermore, the synthesis process of compound II is as follows:

[0026]

[0027] R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 10 Each independently selected from alkyl, aryl, silyl or acyl; R 5 , R 11 Selected from alkanoyl or aroyl; X is selected from substituted or unsubstituted ethynylphenylthio;

[0028] a. Remove the protecting group of the carboxyl group in compound 7 to obtain compound 12;

[0029] b. Using compound 12 as the acceptor, perform glycosylation reaction with glycosyl donor 13 to obtain compound 14;

[0030] c. Finally, remove all the protecting groups on compound 14 to obtain 28-COO-glycosylated betulinic acid glycoside II.

[0031] Further, the X 1 is X 2 selected from alkyl, ester group, silyl group, amide group. More preferably, X 2 is selected from tert-butyl, n-butyl, COOMe, COOEt, COPh, TMS or CON(CH 3 ) 2 .

[0032] Further, the glycosylation reaction is carried out with a donor under the action of molecular sieve and a complex of monovalent gold in an organic solvent. The organic solvent is one or more of aromatic solvents, halogenated hydrocarbon solvents, ketone solvents, and ether solvents. The complex of monovalent gold is Ph 3 PAuOTf or Ph 3 PAuNTf 2 , the molecular sieve is molecular sieve; the molar ratio of the donor to the acceptor is (1.3 - 1.1):1, and the molar ratio of the donor to the catalyst is 1:(0.1 - 0.3); based on the donor, the addition amount of the molecular sieve is 3 - 5 g / mmol.

[0033] Further, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 10 are selected from Bz, Ac, CA, Lev, TBDPS, TBS, Ts, All, Nap, Bn or R 2 , R 3 is G represents 1 to 3 identical or different substituents, and each G is independently selected from H, F, Cl, Br, C1 - C4 saturated alkyl, nitro, methoxy, acetoxy. R 4 , R 5 , R 11 are selected from Bz, Ac, Boc, CA or Lev. TBDPS is tert-butyldiphenylsilyl, TBS is tert-butyldimethylsilyl, Ts is p-toluenesulfonyl, All is allyl, Nap is 2-methylnaphthyl, Bn is benzyl, Ac is acetyl, Bz is benzoyl, CA is chloroacetyl, Lev is acetylpropionyl, Boc is tert-butoxycarbonyl.

[0034] Further, the deprotection reaction is mediated by an acid or a base or carried out by reduction with palladium-carbon.

[0035] Preferably, R 1is allyl. The process of step (1) is as follows: Allyl bromide and potassium carbonate are added to the N,N-dimethylformamide solution of betulinic acid, and the mixture is stirred at 50 - 60 °C until the reaction is complete. After post-treatment, compound 2 is obtained. The molar ratio of allyl bromide, potassium carbonate, and betulinic acid is (1 - 2):(2 - 4):1, specifically 2:3:1.

[0036] Preferably, the structure of donor 3 is The process of step (2) is as follows: Under nitrogen protection, donor 3, acceptor 2 and molecular sieve are added to dry CH 2 Cl 2 and pre-mixed for 10 - 40 min. Under nitrogen protection, PPh 3 AuNTf 2 is added at room temperature, and the mixture is stirred until the reaction is complete. After post-treatment, compound 4 is obtained.

[0037] Preferably, the process of step (3) is as follows: Compound 4 is dissolved in a mixed solvent of MeOH / THF / H 2 O, and the volume ratio of MeOH / THF / H 2 O is (1 - 2):(3 - 4):(1 - 2), more preferably 1:(1 - 3):1. Sodium hydroxide is added, and the reaction is carried out at 35 - 45 °C until complete. After post-treatment, compound 5 is obtained. The molar ratio of compound 4 to sodium hydroxide is 1:(10 - 20).

[0038] Preferably, the structure of donor 6 is: The process of step (4) is as follows: Under nitrogen protection, donor 6, acceptor 5 and molecular sieve are added to dry CH 2 Cl 2 and pre-mixed for 10 - 40 min. Under nitrogen protection, PPh 3 AuNTf 2 is added at room temperature, and the mixture is stirred until the reaction is complete. After post-treatment, compound 7 is obtained.

[0039] Preferably, the specific process of step S1 is: A mixture of compound 7, Pd(PPh 3 ) 4 , and 1,3-dimethylbarbituric acid is added to dry THF. Under nitrogen protection, the mixture is stirred at 85 - 95 °C until the reaction is complete. After post-treatment, compound 8 is obtained. The molar ratio of compound 7, Pd(PPh 3 ) 4 to 1,3-dimethylbarbituric acid is 1:(0.03 - 0.08):(1.5 - 2.5).

[0040] Preferably, the structural formula of donor 9 is The specific process of step S2 is: Under nitrogen protection, acceptor 8 and The molecular sieve is dissolved in dry trifluorotoluene and premixed at room temperature for 20 - 40 min, then PPh 3 AuNTf 2 is added, and the mixture is stirred for 30 min. Then, a solution of donor 9 in trifluorotoluene is added dropwise to the system at intervals of 10 - 20 min, with each addition being (0.1 - 0.2 mL) until the addition is complete. After stirring the reaction to completion, the product is obtained through post-treatment to give compound 10. The concentration of donor 9 in trifluorotoluene is 0.03 - 0.05 mmol / mL.

[0041] Preferably, the specific process of step S3 is as follows: Compound 10 is dissolved in an aqueous solution of AcOH with a mass fraction of 75 - 85%, and the mixture is stirred at 75 - 85 °C until the reaction is complete. After post-treatment, compound 11 is obtained. The concentration of compound 10 in the aqueous solution of AcOH with a mass fraction of 75 - 85% is 0.02 - 0.04 mmol / mL.

[0042] Preferably, the specific process of step S4 is as follows: Compound 11 and sodium hydroxide are dissolved in a mixed solvent of H 2 O / THF / MeOH, and the volume ratio of H 2 O / THF / MeOH is (1 - 2):(3 - 4):(1 - 2). The mixture is stirred at room temperature until the reaction is complete, and then neutralized to pH = 4 - 5 with a cationic weakly acidic resin (Purolite C104E Plus). After filtration, evaporation, and column chromatography, compound I is obtained. The molar ratio of compound 11 to sodium hydroxide is 1:(10 - 30).

[0043] Preferably, the specific process of step a is as follows: Compound 7 is dissolved in an aqueous solution of AcOH with a mass fraction of 75 - 85%, and the mixture is stirred at 75 - 85 °C until the reaction is complete. After post-treatment, compound 12 is obtained. The concentration of compound 7 in the aqueous solution of AcOH with a mass fraction of 75 - 85% is 0.08 - 0.1 mmol / mL.

[0044] Preferably, the structure of donor 13 is: The specific process of step b is as follows: Compound 12 and Bu 2 SnO are dissolved in dry toluene, and the mixture is heated under reflux to separate water. It is stirred at a constant temperature for 5 - 8 h, then CsF is added. After evaporation, dry DMF, Bu 4 NI, and allyl bromide are added, and the mixture is stirred at room temperature until the reaction is complete. After post-treatment, the intermediate receptor is obtained. The molar ratio of compound 12, Bu 2 SnO, CsF, Bu 4 NI, and allyl bromide is 1:1:(1 - 3):(0.1 - 0.3):(1 - 3).

[0045] Under nitrogen protection, donor 13, the receptor prepared in the previous step, and The molecular sieve was premixed in dry dichloromethane for 20 - 40 min, and then PPh was added at room temperature under nitrogen protection. 3 AuNTf 2 , and the mixture was stirred until the reaction was complete. After work-up, the compound 14 with allyl protection at C28 was obtained. The compound 14 with allyl protection at C28 and PdCl 2 were dissolved in a mixed solvent of dichloromethane / methanol (volume ratio 1:2 - 4). The mixture was stirred at -5°C to 5°C for 5 - 15 min, and then stirred at 30°C to 40°C until the reaction was complete. After work-up, compound 14 was obtained. The molar ratio of the compound 14 with allyl protection at C28 to PdCl 2 was 1:(1 - 2).

[0046] Preferably, the specific process of step c is as follows: Compound 14 and sodium hydroxide were dissolved in a mixed solvent of H 2 O / THF / MeOH. The volume ratio of H 2 O / THF / MeOH was (1 - 2):(3 - 4):(1 - 2). The mixture was stirred at room temperature until the reaction was complete, and then neutralized to pH = 4 - 5 with a cationic weakly acidic resin (Purolite C104E Plus). After filtration, rotary evaporation, and column chromatography, compound II was obtained. The molar ratio of compound 14 to sodium hydroxide was 1:(10 - 30).

[0047] The present invention uses commercially available compound 1 as a raw material and prepares 3 - O - glycopeptide betulinic acid aglycone glycoside and 28 - COO - glycopeptide aglycone glycoside through multiple steps. The method has mild conditions, can be synthesized in large quantities, is easy to operate, and has a high yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 is the 1 1H NMR spectrum of compound I of the present invention;

[0049] Figure 2 is the 13 13C NMR spectrum of compound I of the present invention;

[0050] Figure 3 is the 1 1H NMR spectrum of compound II of the present invention;

[0051] Figure 4 is the 13 13C NMR spectrum of compound II of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0052] The present invention can be better understood according to the following embodiments. However, those skilled in the art can easily understand that the content described in the embodiments is only used to illustrate the present invention and should not and will not limit the present invention described in detail in the claims. Synthesis of Key Intermediate Compound 7 in Example 1

[0053] Preparation of Compound 2:

[0054]

[0055] Allyl bromide (0.88 mL, 10.19 mmol) and potassium carbonate (2.10 g, 15.17 mmol) were added to a solution of betulinic acid (2.32 g, 5.09 mmol) in N,N-dimethylformamide (32.4 mL). The reaction mixture was stirred at 55 °C overnight. After cooling to room temperature, it was diluted with ethyl acetate, and the organic phase was extracted with 1N HCl. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed three times with saturated sodium bicarbonate solution, twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and purified by column chromatography (petroleum ether / ethyl acetate = 8:1) to obtain white product 2 (2.6145 g, 99%). 1 H NMR (600 MHz, Chloroform-d) δ 5.92 (ddt, J = 16.4, 10.9, 5.7 Hz, 1H), 5.33 (dd, J = 17.2, 2.0 Hz, 1H), 5.23 (d, J = 10.4 Hz, 1H), 4.73 (d, J = 2.3 Hz, 1H), 4.62 - 4.57 (m, 2H), 4.54 (dd, J = 13.3, 5.7 Hz, 1H), 4.22 - 4.15 (m, 3H), 4.05 (dd, J = 7.6, 5.7 Hz, 1H), 3.77 - 3.73 (m, 1H), 3.62 (t, J = 7.7 Hz, 1H), 3.09 (dd, J = 11.5, 4.5 Hz, 1H), 3.00 (td, J = 11.1, 4.8 Hz, 1H), 2.31 (q, J = 7.4 Hz, 1H), 2.26 (dd, J = 8.9, 3.2 Hz, 1H), 2.23 - 2.18 (m, 1H), 1.90 (td, J = 8.5, 5.5 Hz, 2H), 1.81 - 1.76 (m, 1H), 1.53 (s, 3H), 1.36 (s, 3H), 1.14 (dd, J = 10.2, 3.1 Hz, 1H), 0.95 (d, J = 7.3 Hz, 6H), 0.89 (s, 3H), 0.81 (s, 3H), 0.79 (s, 3H).

[0056] Preparation of Compound 5:

[0057]

[0058] Under nitrogen protection, donor 3 (0.6961 mg, 1.5 mmol), acceptor 2 (0.61875 mg, 1.25 mmol), and MS (5.0 g) were added to dry CH 2 Cl 2 (50 mL) and pre-mixed for 30 min. Under nitrogen protection, PPh 3 AuNTf 2 (219.5 mg, 0.3 mmol) was added at room temperature, and the reaction was stirred for 2 h. Triethylamine was added to quench the reaction. The mixture was filtered, concentrated, and purified by column chromatography (toluene / EA = 40:1) to obtain crude product 4. 1 1H NMR (400 MHz, Chloroform-d) δ 8.07 - 7.99 (m, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 5.90 (ddt, J = 16.4, 11.0, 5.7 Hz, 1H), 5.36 - 5.28 (m, 2H), 5.21 (dd, J = 10.3, 1.5 Hz, 1H), 4.72 (d, J = 2.4 Hz, 1H), 4.61 - 4.47 (m, 4H), 4.30 (d, J = 5.5 Hz, 2H), 4.22 (dd, J = 13.1, 2.4 Hz, 1H), 3.81 (dd, J = 13.0, 2.9 Hz, 1H), 2.99 (dp, J = 11.9, 3.5 Hz, 2H), 2.31 - 2.11 (m, 2H), 1.89 (dt, J = 9.1, 2.9 Hz, 2H), 1.67 (s, 4H), 1.26 (d, J = 6.6 Hz, 3H), 1.20 (d, J = 2.6 Hz, 2H), 0.92 (s, 3H), 0.85 (s, 3H), 0.76 (s, 3H), 0.69 (s, 3H), 0.59 (s, 4H). 13 13C NMR (101 MHz, CDCl3) δ 175.76, 165.34, 150.66, 132.65, 130.17, 129.91, 118.21, 110.60, 109.67, 102.43, 76.58, 73.90, 73.07, 64.67, 56.66, 55.74, 49.61, 47.03, 42.46, 40.84, 39.06, 38.84, 38.33, 37.11, 37.00, 34.39, 32.24, 30.72, 29.72, 27.87, 27.76, 26.34, 26.08, 25.67, 21.00, 19.52, 18.20, 16.16, 16.09, 16.04, 14.76.

[0059] Dissolve the compound 4 from the previous step in a system of MeOH / THF / H 2 O = 1:2:1 (21 mL:42 mL:21 mL), add sodium hydroxide (1.00 g, 25 mmol), stir and react at 40 °C for 6 h, and monitor the completion of the reaction by TLC. Cool the reaction system to room temperature, neutralize it with 1N HCl to pH = 4 - 5, extract the aqueous phase three times with ethyl acetate, combine the organic phases, wash twice with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate, and perform column chromatography (petroleum ether / ethyl acetate = 8:1) to obtain a white foamy substance 5 (0.586 g, 70%). 1 1H NMR (600 MHz, CDCl3) δ 5.86 (ddt, J = 16.4, 10.9, 5.7 Hz, 1H), 5.27 (dd, J = 17.2, 2.0 Hz, 1H), 5.16 (d, J = 10.4 Hz, 1H), 4.66 (d, J = 2.3 Hz, 1H), 4.55 - 4.51 (m, 2H), 4.48 (dd, J = 13.3, 5.7 Hz, 1H), 4.16 - 4.09 (m, 3H), 3.99 (dd, J = 7.6, 5.7 Hz, 1H), 3.71 - 3.66 (m, 1H), 3.56 (t, J = 7.7 Hz, 1H), 3.03 (dd, J = 11.5, 4.5 Hz, 1H), 2.94 (td, J = 11.1, 4.8 Hz, 1H), 2.25 (q, J = 7.4 Hz, 1H), 2.20 (dd, J = 8.9, 3.2 Hz, 1H), 2.17 - 2.12 (m, 1H), 1.83 (td, J = 8.5, 5.5 Hz, 2H), 1.75 - 1.70 (m, 1H), 1.47 (s, 3H), 1.29 (s, 3H), 1.07 (dd, J = 10.2, 3.1 Hz, 1H), 0.89 (d, J = 7.3 Hz, 6H), 0.83 (s, 3H), 0.75 (s, 3H), 0.73 (s, 3H), 0.63 - 0.59 (m, 1H).

[0060] Preparation of Compound 7:

[0061]

[0062] Under nitrogen protection, premix the donor 6 (829.8 mg, 1.79 mmol), the acceptor 5 (1 g, 1.49 mmol) and MS (5.90 g) in dry dichloromethane (59 mL) for 30 min, and add PPh 3 AuNTf 2(150 mg, 0.2 mmol), stirred until the reaction was complete, quenched with triethylamine, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 6:1) to obtain white foamy substance 7 (1.3935 g, 99%). 1 H NMR (400 MHz, Chloroform-d) δ 5.90 (ddt, J = 16.4, 10.4, 5.7 Hz, 1H), 5.36 - 5.28 (m, 4H), 5.21 (dt, J = 10.4, 1.4 Hz, 1H), 5.02 (t, J = 9.9 Hz, 1H), 4.71 (d, J = 2.4 Hz, 1H), 4.62 - 4.49 (m, 3H), 4.33 (d, J = 7.5 Hz, 1H), 4.21 - 4.07 (m, 4H), 3.73 (dt, J = 13.1, 5.4 Hz, 2H), 3.05 (dd, J = 11.4, 4.5 Hz, 1H), 3.01 - 2.94 (m, 1H), 2.13 (s, 3H), 1.99 (s, 3H), 1.94 (s, 3H), 1.17 (d, J = 6.2 Hz, 3H), 1.01 (s, 3H), 0.93 (s, 3H), 0.87 (s, 4H), 0.79 (d, J = 8.7 Hz, 6H), 0.67 (d, J = 9.2 Hz, 1H). 13 C NMR (151 MHz, Chloroform-d) δ 175.79, 170.25, 170.08, 170.01, 150.67, 132.63, 118.20, 110.41, 109.68, 103.24, 95.18, 89.19, 79.26, 75.00, 73.48, 71.28, 69.61, 69.12, 66.22, 64.66, 62.72, 56.64, 56.03, 50.62, 49.53, 47.00, 42.44, 40.82, 39.24, 39.05, 38.28, 37.08, 36.97, 34.33, 32.19, 30.66, 29.70, 27.98, 27.86, 26.35, 26.20, 25.60, 21.08, 20.96, 20.90, 20.83, 19.48, 18.26, 17.43, 16.31, 16.26, 16.03, 14.73. HRMS (ESI) m / z calcd for C 53 H 80 O 14 [M + Na]+: 963.54403, found: 963.54403.

[0063] Synthesis of Compound I in Example 2

[0064] Preparation of Compound 8:

[0065]

[0066] A mixture of Compound 7 (50 mg, 0.053 mmol) and Pd(PPh 3 ) 4 (3.06 mg, 0.003 mmol), 1,3-dimethylbarbituric acid (16.55 mg, 0.106 mmol) was added to dry THF, heated to 90 °C under nitrogen protection, stirred overnight, the reaction system was poured into saturated sodium carbonate solution, the aqueous phase was extracted twice with ethyl acetate, washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain a pale yellow solid 8 (39.3 mg, 83%). 1 H NMR (600 MHz, Chloroform-d) δ 5.36 - 5.29 (m, 3H), 5.04 (t, J = 9.9 Hz, 1H), 4.73 (s, 1H), 4.60 (s, 1H), 4.35 (d, J = 7.5 Hz, 1H), 4.22 - 4.09 (m, 4H), 3.80 - 3.72 (m, 2H), 3.09 - 2.94 (m, 2H), 2.25 (dt, J = 13.2, 3.6 Hz, 1H), 2.14 (s, 3H), 2.00 (s, 3H), 1.95 (s, 4H), 1.19 (d, J = 6.1 Hz, 4H), 0.81 (s, 3H), 0.78 (s, 3H), 0.69 (d, J = 10.0 Hz, 1H). 1313C NMR (151 MHz, Chloroform-d) δ 174.29, 170.86, 170.74, 170.46, 170.29, 169.60, 169.54, 169.41, 169.13, 150.35, 137.39, 134.88, 129.13, 128.40, 126.08, 117.86, 109.88, 104.48, 101.23, 100.18, 91.19, 90.89, 81.98, 81.65, 74.25, 73.41, 73.00, 72.66, 72.09, 71.75, 69.99, 68.93, 68.48, 68.11, 65.83, 62.12, 61.62, 56.94, 55.84, 50.62, 49.25, 46.87, 42.53, 40.80, 39.40, 38.83, 38.28, 37.00, 36.60, 34.54, 31.82, 30.51, 29.83, 29.80, 29.45, 27.71, 26.32, 25.63, 22.83, 21.01, 20.96, 20.91, 20.84, 20.78, 20.75, 20.73, 19.54, 18.25, 16.21, 16.15, 16.13, 14.78. HRMS (ESI) m / z calcd for C 50 H 76 O 14 [M+Na] + : 923.51273, found: 923.51273.

[0067] Preparation of Compound 10:

[0068]

[0069] Under nitrogen protection, receptor 8 (50 mg, 0.055 mmol) and MS (250 mg) were dissolved in dry trifluorotoluene (0.5 mL), pre-mixed at room temperature for 30 min, PPh 3 AuNTf 2 (7.5 mg, 0.01 mmol) was added, and the mixture was stirred for 30 min. Then, a solution of donor 9 (34.7 mg, 0.067 mmol) in trifluorotoluene (2 mL) was added dropwise to the system. The donor (2.67 mg, 0.154 mL) was added every 15 min for 3 h. After 1 h, TLC showed that the reaction was complete. Triethylamine was added to quench the reaction, and the mixture was filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate:dichloromethane = 2:1:1) to obtain white foam product 10 (60.3 mg, 89%). 11H NMR (400 MHz, Chloroform-d) δ 5.67 (d, J = 8.1 Hz, 1H), 5.32 - 5.10 (m, 6H), 5.01 (t, J = 9.8 Hz, 1H), 4.71 (d, J = 2.0 Hz, 1H), 4.57 (t, J = 1.9 Hz, 1H), 4.34 - 4.26 (m, 2H), 4.20 - 4.00 (m, 5H), 3.80 (ddd, J = 10.0, 4.4, 2.4 Hz, 1H), 3.77 - 3.67 (m, 2H), 3.03 (dd, J = 11.4, 4.5 Hz, 1H), 2.91 (td, J = 10.9, 4.5 Hz, 1H), 2.12 (s, 4H), 1.50 (s, 3H), 1.30 (s, 3H), 0.65 (d, J = 10.0 Hz, 1H). 13 13C NMR (101 MHz, Chloroform-d) δ 170.65, 170.22, 169.98, 150.22, 110.42, 109.87, 103.24, 95.20, 91.12, 89.09, 79.23, 75.06, 73.47, 72.97, 72.60, 71.33, 69.98, 69.66, 69.13, 68.06, 66.24, 62.71, 61.58, 56.90, 55.99, 50.58, 49.22, 46.85, 42.48, 40.76, 39.25, 39.04, 38.28, 36.98, 36.56, 34.43, 31.81, 30.48, 29.76, 27.98, 27.85, 26.34, 26.18, 25.56, 21.04, 20.95, 20.87, 20.78, 20.76, 20.65, 20.62, 19.49, 18.28, 17.42, 16.29, 16.25, 16.06, 14.74. HRMS (ESI) m / z calcd for C 64 H 94 O 23 [M + Na] + : 1253.60781, found: 1253.60781.

[0070] Preparation of Compound 11:

[0071]

[0072] Compound 10 (100 mg, 0.08 mmol), 80% aqueous AcOH solution (2.4 mL acetic acid, 0.6 mL water) were placed in a 10 mL round-bottom flask and stirred at 80 °C for 30 min. The system changed from turbid to clear. The reaction was monitored to completion by TLC. The system was poured into a beaker, and saturated sodium bicarbonate solution was added until no more bubbles were produced. Then it was washed three times with saturated sodium bicarbonate solution to further remove the acid, washed twice with water, extracted once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to obtain white product 11 (73.4 mg, 77%). 1 H NMR (400 MHz, Chloroform-d) δ 5.66 (d, J = 8.2 Hz, 1H), 5.27 - 5.20 (m, 3H), 5.14 (dt, J = 21.2, 9.0 Hz, 2H), 5.03 (d, J = 9.6 Hz, 2H), 4.70 (d, J = 2.3 Hz, 1H), 4.62 (d, J = 3.3 Hz, 1H), 4.56 (s, 1H), 4.28 (dd, J = 12.5, 4.3 Hz, 1H), 4.01 (ddd, J = 16.5, 11.2, 4.2 Hz, 2H), 3.90–3.76 (m, 4H), 3.72 (dd, J = 11.8, 7.7 Hz, 1H), 3.55 (dd, J = 11.8, 4.0 Hz, 1H), 3.36 (d, J = 8.9 Hz, 1H), 3.04 (dd, J = 11.6, 4.6 Hz, 1H), 2.90 (td, J = 11.0, 4.5 Hz, 1H), 2.55 (d, J = 8.5 Hz, 1H). 1313C NMR (101 MHz, Chloroform-d) δ 174.22, 170.62, 170.19, 170.12, 170.06, 170.02, 169.45, 168.99, 150.16, 109.87, 102.13, 98.07, 91.11, 90.23, 75.89, 72.93, 72.57, 70.95, 70.83, 69.98, 69.77, 68.98, 68.05, 66.95, 65.63, 61.57, 61.34, 56.85, 55.64, 50.55, 49.18, 46.81, 42.46, 40.71, 39.23, 38.83, 38.22, 36.94, 36.53, 34.39, 31.77, 30.43, 29.73, 28.00, 25.99, 25.51, 20.93, 20.84, 20.76, 20.73, 20.62, 20.60, 19.45, 18.27, 17.36, 16.22, 16.19, 16.03, 14.72. HRMS (ESI) m / z calcd for C 61 H 90 O 23 [M+Na] + : 1213.57651, found: 1213.57651.

[0073] Preparation of Compound I:

[0074]

[0075] Compound 11 (57.5 mg, 0.048 mmol) and sodium hydroxide (38.4 mg, 0.96 mmol) were dissolved in H 2 O:THF:MeOH = 1:2:1 (0.85 mL: 1.7 mL: 0.85 mL), stirred at room temperature for 3 h. After the reaction was complete, a cationic weakly acidic resin (Purolite C104E Plus) was added to neutralize to pH = 4 - 5. Filtered and concentrated by rotary evaporation, then purified by column chromatography (chloroform / methanol =

[0076] 10:1) to obtain white product I (46.9 mg, 83%). The 1 1H NMR spectrum and 13 13C NMR spectrum of Compound I are shown in detail in Figure 1 and Figure 2 , 1 1H NMR (400 MHz, Methanol-d 4)δ5.50 (d, J = 8.1 Hz, 1H), 5.12 (s, 1H), 4.74 - 4.71 (m, 1H), 4.61 (s, 1H), 4.53 (d, J = 4.2 Hz, 1H), 3.92 - 3.89 (m, 1H), 3.78 (dddd, J = 25.7, 22.6, 12.3, 3.8 Hz, 10H), 3.53 - 3.37 (m, 6H), 3.32 (d, J = 7.8 Hz, 2H), 3.09 (dd, J = 11.6, 4.5 Hz, 1H), 3.01 (td, J = 11.0, 4.6 Hz, 1H), 2.39 - 2.30 (m, 2H), 1.23 (d, J = 6.2 Hz, 3H), 1.00 (d, J = 4.4 Hz, 6H), 0.87 (s, 3H), 0.82 (s, 3H), 0.74 (d, J = 9.2 Hz, 1H). 13 C NMR (101 MHz, Methanol - d 4 )δ176.10, 151.73, 110.33, 104.74, 101.96, 95.18, 90.56, 78.67, 78.30, 76.76, 74.01, 73.81, 72.98, 72.08, 71.10, 70.16, 68.32, 63.73, 57.86, 57.12, 51.98, 50.58, 48.29, 43.54, 42.00, 40.35, 40.17, 39.32, 38.06, 37.47, 35.48, 32.78, 31.42, 30.76, 28.53, 27.16, 26.83, 22.07, 19.60, 19.29, 17.99, 16.87, 16.64, 15.26. Synthesis of Compound II in Example 3

[0077] Preparation of Compound 12:

[0078]

[0079] Compound 7 (849.9 mg, 0.903 mmol) was dissolved in 80% (by mass) AcOH solution (7.8 mL of acetic acid and 1.8 mL of water) and stirred at 80 °C for 1 h. The reaction was monitored by TLC and was found to be complete when the system changed from turbid to clear. The reaction was monitored by TLC until completion. The reaction mixture was poured into a beaker, and saturated sodium bicarbonate solution was added until no more bubbles were produced. Then, it was washed three more times with saturated sodium bicarbonate solution to further remove the acid, extracted twice with water, once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain white product 12 (73.4 mg, 67%). 11H NMR (400 MHz, Chloroform-d) δ 5.93 (ddt, J = 16.4, 10.8, 5.7 Hz, 1H), 5.36 - 5.21 (m, 4H), 5.10–5.02 (m, 2H), 4.73 (d, J = 5.6 Hz, 2H), 4.58 (dd, J = 12.4, 5.0 Hz, 3H), 4.01 (dt, J = 9.9, 6.0 Hz, 1H), 3.94–3.84 (m, 3H), 3.74 (t, J = 10.0 Hz, 1H), 3.61 (dd, J = 11.7, 4.4 Hz, 1H), 3.09 (dd, J = 11.6, 4.5 Hz, 1H), 3.01 (dt, J = 12.3, 6.4 Hz, 1H), 2.14 (s, 3H), 2.04 (s, 3H), 1.98 (s, 3H), 1.68 (s, 6H), 0.95 (s, 6H), 0.90 (s, 3H), 0.82 (s, 3H), 0.77 (s, 3H), 0.69 (d, J = 8.6 Hz, 1H).

[0080] Preparation of Compound 14:

[0081]

[0082] Compound 12 (737.8 mg, 0.82 mmol) and Bu 2 SnO (203.5 mg, 0.82 mmol) were dissolved in dry toluene (12.9 mL), heated under reflux to separate water, and reacted at a constant temperature for 6 h. CsF (254 mg, 1.67 mmol) was added, and then the solvent was evaporated under reduced pressure. Dry DMF (6.68 mL), Bu 4 NI (30.77 mg, 0.083 mmol), and allyl bromide (0.144 mL, 1.66 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction was monitored by TLC and was found to be complete. The reaction mixture was diluted with dichloromethane, washed five times with water and twice with saturated sodium chloride solution. The organic phase was dried, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 2:1) gave a white foamy product (740.1 mg, 79%).

[0083] Under nitrogen protection, donor 13 (135.6 mg, 0.176 mmol), the acceptor obtained in the previous step (137.9 mg, 0.147 mmol), and MS (590 mg) were premixed in dry dichloromethane (5.9 mL) for 30 min, and then PPh 3 AuNTf 2(38.8 mg, 0.053 mmol), stir until the reaction is complete, add triethylamine to quench the reaction, filter, concentrate, and perform column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain a white foamy product.

[0084] Under nitrogen protection, the white product (200 mg, 0.132 mmol) and PdCl 2 (35.11 mg, 0.198 mg) were dissolved in a solution of dichloromethane / methanol = 1:3 (1 mL:3 mL). After stirring at 0 °C for 10 min, the reaction was stirred at 35 °C for 6 h. TLC detected that the reaction was complete. The reaction was cooled to room temperature, filtered, concentrated, and column chromatography (petroleum ether / ethyl acetate = 1:1) was performed to obtain white foamy product 14 (0.2256 g, 95%), and the total yield of the three steps was 53%. 1 H NMR (600 MHz, Chloroform-d) δ 8.02 (d, J = 7.7 Hz, 2H), 7.95 (d, J = 7.8 Hz, 2H), 7.89 (d, J = 7.8 Hz, 2H), 7.83 (d, J = 7.8 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.52 - 7.46 (m, 2H), 7.42 (dd, J = 9.7, 7.5 Hz, 3H), 7.38 - 7.32 (m, 4H), 7.29 (d, J = 7.7 Hz, 2H), 5.91 (t, J = 9.7 Hz, 1H), 5.68 (t, J = 9.7 Hz, 1H), 5.55 (dd, J = 9.8, 7.8 Hz, 1H), 5.27 (dd, J = 10.2, 3.5 Hz, 1H), 5.24 - 5.21 (m, 1H), 5.08 - 5.00 (m, 2H), 4.95 (s, 1H), 4.74 (s, 1H), 4.68 (dd, J = 12.2, 3.3 Hz, 1H), 4.63 - 4.54 (m, 2H), 4.49 (dd, J = 12.1, 4.9 Hz, 1H), 4.20 (dt, J = 9.0, 4.2 Hz, 1H), 4.06 - 3.93 (m, 3H), 3.79 (s, 1H), 3.76 - 3.70 (m, 1H), 3.63 (dd, J = 11.9, 3.7 Hz, 1H), 3.03 - 2.91 (m, 3H), 2.22 (dtd, J = 28.6, 11.9, 11.2, 3.6 Hz, 3H), 2.12 (s, 3H), 2.03 (s, 3H), 1.98 (s, 4H), 1.69 (s, 5H), 0.79 (s, 3H), 0.72 (s, 3H), 0.65 (d, J = 9.6 Hz, 1H). 1313C NMR (151 MHz, Chloroform-d) δ 170.03, 170.01, 166.10, 165.79, 165.32, 165.16, 150.41, 133.44, 133.24, 133.11, 129.87, 129.80, 129.79, 129.61, 129.15, 128.81, 128.79, 128.42, 128.39, 128.31, 109.73, 102.20, 101.74, 97.79, 90.22, 75.84, 75.70, 72.80, 72.28, 72.07, 70.94, 70.18, 69.71, 69.55, 68.98, 66.72, 62.96, 60.15, 56.26, 55.71, 50.53, 49.25, 46.85, 42.42, 40.70, 39.17, 38.83, 38.31, 37.04, 36.89, 34.28, 32.14, 30.55, 29.71, 29.68, 29.34, 27.99, 25.91, 25.51, 20.92, 20.86, 20.82, 20.75, 19.41, 18.21, 17.29, 16.16, 15.96, 14.65. HRMS (ESI) m / z calcd for C 81 H 98 O 23 [M+Na] + : 1461.63911, found: 1461.63911. Preparation of Compound II:

[0085]

[0086] Compound 14 (69.10 mg, 0.048 mmol) and sodium hydroxide (38.4 mg, 0.96 mmol) were dissolved in a mixed solvent of H 2 O / THF / MeOH (0.85 mL: 1.7 mL: 0.85 mL) with a volume ratio of 1:2:1, and stirred at room temperature for 3 h until the reaction was complete. Then, a cationic weakly acidic resin (Purolite C104E Plus) was added to neutralize to pH = 4 - 5. After filtration and evaporation to dryness, the residue was loaded onto a column and eluted by column chromatography (chloroform / methanol = 5:1) to obtain white product II (31.2 mg, 72%). The 1 1H NMR spectrum and 13 13C NMR spectrum of Compound II are shown in detail in Figure 3 and Figure 4 , 1 1H NMR (400 MHz, Pyridine-d 5)δ6.23(s,1H),5.18(d,J=7.8Hz,1H),4.95(d,J=2.6Hz,1H),4.81 - 4.75(m,3H),4.66(dq,J=8.8,4.8,3.2Hz,2H),4.57 - 4.51(m,2H),4.41(dd,J=11.9,4.6Hz,2H),4.35(d,J=9.2Hz,1H),4.31 - 4.19(m,4H),4.07(t,J=8.4Hz,1H),3.96 - 3.90(m,1H),3.81(d,J=12.0Hz,1H),3.55(s,1H),3.27 - 3.21(m,1H),2.70(dd,J=43.1,11.4Hz,2H),2.27(d,J=12.7Hz,2H),2.15 - 2.05(m,2H),1.94(s,1H),1.86(s,1H),1.79(s,3H),1.76(d,J=5.4Hz,1H),1.66(d,J=6.1Hz,3H),1.20(s,3H),1.11(d,J=2.3Hz,6H),1.01(d,J=10.5Hz,3H),0.79(d,J=9.3Hz,3H),0.73(d,J=11.2Hz,1H). 13 C NMR(151MHz,Pyridine - d 5 )δ179.25,151.60,110.23,106.79,105.35,102.13,89.12,80.13,79.14,78.86,76.70,75.80,74.55,74.37,72.77,72.64,71.51,70.12,64.96,62.79,56.92,56.37,51.09,50.03,48.07,43.12,41.34,39.91,39.43,38.84,37.88,37.44,35.00,33.16,31.49,30.56,28.24,27.13,26.35,21.45,19.73,18.99,18.78,17.14,16.73,15.13.

[0087] Synthesis of Donors 3, 6, 9 and 13 in Example 4

[0088] Preparation of Donor 3:

[0089]

[0090] L - arabinose (10 g, 66.6 mmol) and dimethylaminopyridine (80 mg, 0.7 mmol) were dissolved in anhydrous pyridine (153 mL) until the solids were completely dissolved. Subsequently, benzoyl chloride (50 mL, 430 mmol) was added under an ice bath, and the mixture was stirred for 30 min. Then the ice bath was removed, and the reaction was continued with stirring at room temperature for 2 h. The reaction was monitored by TLC and was found to be complete. The mixture was diluted with ethyl acetate and extracted 10 times with a large amount of water (1 times the volume after dilution with ethyl acetate), and then extracted 10 times with a large amount of 1N HCl (1 times the volume after dilution with ethyl acetate) until the smell of pyridine disappeared. The mixture was washed three times with saturated sodium bicarbonate solution and extracted twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of compound 3a, which was directly used in the next step.

[0091] Compound 3a was dissolved in redistilled dichloromethane (159.6 mL). Under an ice - water bath, 33% HBr / HOAc (36 mL) was added and the mixture was stirred for 30 min. Then it was transferred to room temperature and stirred for 4 h. The reaction was monitored by TLC and was found to be complete. The reaction system was poured into an ice - water bath and stirred, and saturated sodium bicarbonate solution was added until no more bubbles were generated or the pH reached 7. Subsequently, it was washed three times with saturated sodium bicarbonate solution, extracted twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product 3a - 1, which was directly used in the next step.

[0092] Under nitrogen protection, potassium carbonate (11.03 g, 79.92 mmol) and o - bromothiophenol (9.57 mL, 79.92 mmol) were placed in a round - bottom flask. Acetone (109 mL) was added to the flask, and the mixture was stirred at 40 °C for 30 min. The crude product 3a - 1 dissolved in dry toluene (109 mL) was added, and the reaction was continued with stirring at 40 °C for 10 h. The reaction was monitored by TLC and was found to be complete. The mixture was diluted with dichloromethane, washed three times with water, washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product 3b, which was directly used in the next step.

[0093] 3b and sodium methoxide (359.78 mg, 6.66 mmol) were placed in a round - bottom flask. Methanol (200 mL) was added to the flask, and the reaction was carried out at room temperature until the reaction was monitored by TLC and found to be complete. Acidic resin (Amberlite IR120) was added to neutralize and stirred overnight until the pH reached 7. It was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 15:1) to obtain the crude product 3c (15.1875 g, 47.29 mmol, 71%).

[0094] The crude product 3c (6 g, 18.68 mmol) and p-toluenesulfonic acid (289.4 mg, 1.68 mmol) were placed in a round-bottom flask, and dry N,N-dimethylformamide (51.88 mL) was added. After the solid was completely dissolved, 2,2-dimethoxypropane (5.99 mL, 48.71 mmol) was added. The reaction was stirred at room temperature. After 4 h of reaction, TLC detected that the reaction was complete. Then, triethylamine was added to quench the reaction, and it was diluted with ethyl acetate. It was washed with water five times successively, with saturated sodium bicarbonate solution three times, and with saturated sodium chloride solution twice, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product 3c-1, which was directly used for the next step.

[0095] The crude product 3c-1 was placed in a round-bottom flask, and anhydrous pyridine (180.68 mL) was added. After the solid dissolved, benzoyl chloride (3.25 mL, 28.02 mmol) was added dropwise under an ice-water bath. After stirring in the ice-water bath for 30 min, the ice bath was removed and the reaction was stirred at room temperature for 3 h. TLC detected that the reaction was complete. The system was diluted with ethyl acetate, extracted with a large amount of water 10 times, and extracted with a large amount of 1N HCl 10 times until the smell of pyridine disappeared. It was washed with saturated sodium bicarbonate solution three times, extracted with saturated sodium chloride solution twice, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatographed (petroleum ether / ethyl acetate = 10:1) to obtain the white foamy product 3d.

[0096] (7.5405 g, 16.2 mmol, 87% over two steps). From L-arabinose to the obtained product 3d, a total of 6 steps were passed through, with an overall yield of 62%. 1 H NMR (400 MHz, Chloroform-d) δ 8.11 - 8.02 (m, 2H), 7.63 - 7.48 (m, 3H), 7.43 (t, J = 7.7 Hz, 2H), 7.27 - 7.21 (m, 1H), 7.07 (td, J = 7.7, 1.6 Hz, 1H), 5.53 (t, J = 5.8 Hz, 1H), 5.18 (d, J = 6.4 Hz, 1H), 4.39 (dq, J = 15.7, 5.4 Hz, 2H), 4.30 (dd, J = 12.8, 5.2 Hz, 1H), 3.87 (dd, J = 12.8, 4.5 Hz, 1H), 1.65 (s, 3H), 1.39 (s, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 165.16, 135.80, 133.41, 133.08, 132.11, 129.94, 129.45, 128.51, 128.42, 127.96, 125.78, 110.66, 84.67, 75.03, 71.57, 71.34, 63.65, 27.79, 26.35. HRMS (ESI) m / z calcd for C21 H 21 BrO 5 S[M

[0097] +Na] + :487.01853, found: 487.01853.

[0098] Transfer the above-obtained product to a sealed tube, evacuate with an air pump for 30 min, and then add (PPh 3 ) 2 PdCl 2 (1.142 g, 1.62 mmol), CuI (1.242 g, 6.52 mmol), PPh 3 (1.7112 g, 6.52 mmol) into the sealed tube, evacuate at -78 °C, start the first nitrogen replacement (hereinafter referred to as gas replacement) after 15 min, after evacuating and replacing the gas three times, continue to evacuate for 5 min, and then replace the gas every 5 min for a total of three times. After replacing the gas three times, add N,N-dimethylformamide (16.6 mL) and diisopropylamine (33.1 mL), seal at -78 °C for 10 min (the purpose is to cool the newly added solvent to -78 °C to avoid the solvent being pumped away during subsequent evacuation), evacuate and replace the gas three times again, add 3,3-dimethyl-1-butyne (5.71 mL, 46.37 mmol), and seal the system. Transfer the system to room temperature, wait for it to slowly return to room temperature, then place it in a 90 °C oil bath and start stirring the reaction. After 18 h of reaction, quench the system with saturated ammonium chloride solution, filter four layers (diatomaceous earth, silica gel, diatomaceous earth, silica gel), dilute with dichloromethane, wash three times with saturated ammonium chloride aqueous solution, wash three times with saturated sodium bicarbonate aqueous solution, wash twice with saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate, filter, concentrate, and obtain a dark yellow product by column chromatography (petroleum ether / ethyl acetate = 15:1). Subsequently, a pale yellow product 3 (6.806 g, 86%) can be obtained by secondary column chromatography (petroleum ether / ethyl acetate = 18:1). This donor is obtained in 7 steps and finally with a yield of 53%. 1 H NMR (400 MHz, Chloroform-d) δ 8.10 - 8.04 (m, 2H), 7.61 - 7.55 (m, 1H), 7.52 - 7.42 (m, 3H), 7.35 (dd, J = 7.6, 1.6 Hz, 1H), 7.22 (td, J = 7.7, 1.6 Hz, 1H), 7.14 (td, J = 7.5, 1.3 Hz, 1H), 5.59 - 5.53 (m, 1H), 5.29 (d, J = 6.6 Hz, 1H), 4.44 (q, J = 4.9 Hz, 1H), 4.41 - 4.34 (m, 2H), 3.92 (dd, J = 12.6, 4.4 Hz, 1H), 1.68 (s, 3H), 1.42 (s, 3H), 1.23 (s, 9H).13 C NMR (101 MHz, Chloroform-d) δ 165.28, 137.64, 133.39, 132.38, 130.10, 129.73, 129.20, 128.47, 128.14, 126.35, 124.80, 110.73, 105.23, 83.89, 75.32, 71.90, 71.66, 63.71, 30.86, 28.29, 27.94, 26.48. HRMS (ESI) m / z calcd for C 27 H 30 BrO 5 S [M+Na]+: 489.17061, found: 489.17061.

[0099] Preparation of Donor 6:

[0100]

[0101] Dissolve L-rhamnose (10 g, 60.9 mmol) directly in acetic anhydride (105.6 mL) and pyridine (105.6 mL), stir the reaction at room temperature for 2 h, monitor the reaction by TLC until completion, quench with methanol under ice bath (methanol destroys the excess acetic anhydride) until no more bubbles are generated. Wash with water three times, wash with saturated sodium bicarbonate solution three times, extract with saturated sodium chloride solution three times, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product 6a, which is directly used in the next step.

[0102] Dissolve compound 6a in redistilled dichloromethane (132 mL), add 33% HBr / HOAc (30.04 mL) under ice-water bath, stir for 30 min, transfer to room temperature and stir the reaction overnight, monitor the reaction by TLC until completion, pour the reaction system into ice-water bath and stir, add saturated sodium bicarbonate solution until no more bubbles are generated or pH = 7, then wash with saturated sodium bicarbonate solution three times, extract with saturated sodium chloride solution twice, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product 6a-1 as a green foam, which is directly used in the next step.

[0103] Under nitrogen protection, potassium carbonate (9.115 g, 66.03 mmol) and o-bromothiophenol (7.9 mL, 66.03 mmol) are placed in a round-bottom flask, add acetone (109.2 mL) to the flask, stir at 40 °C for 30 min. Add the crude product 6a-1 dissolved in dry toluene (109.2 mL), continue to stir the reaction at 40 °C for 10 h, monitor the reaction by TLC until completion. Dilute with dichloromethane, wash with water three times, wash with saturated sodium chloride solution three times, dry over anhydrous sodium sulfate, filter, and perform column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the white product 6b (15.3433 g, 61% for three steps).

[0104] 6b (13.6756 g, 29.64 mmol), (PPh 3 ) 2 PdCl 2 (2.083 g, 2.96 mmol), CuI (2.265 g, 11.87 mmol), PPh 3 (3.1779 g, 11.87 mmol) were placed in a sealed tube, evacuated at -78 °C. After 15 min, the first nitrogen replacement (hereinafter referred to as gas replacement) was started. After three times of evacuation and gas replacement, evacuation was continued for 5 min, and then gas replacement was carried out every 5 min for a total of three times. After three times of gas replacement, N,N-dimethylformamide (30 mL) and diisopropylamine (60 mL) were added. After sealing at -78 °C for 10 min (the purpose is to cool the newly added solvent to -78 °C to avoid the solvent being pumped away during subsequent evacuation), after evacuating and replacing the gas three times again, 3,3-dimethyl-1-butyne (10.23 mL, 83.07 mmol) was added, and the system was sealed. The system was transferred to room temperature. After slowly returning to room temperature, it was placed in an oil bath at 90 °C and stirred for reaction. After 18 h of reaction, the reaction was quenched with saturated ammonium chloride solution, filtered through four layers (diatomaceous earth, silica gel, diatomaceous earth, silica gel), diluted with dichloromethane, washed three times with saturated ammonium chloride aqueous solution, three times with saturated sodium bicarbonate aqueous solution, twice with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was carried out to obtain a dark yellow product (petroleum ether / ethyl acetate = 18:1). A pale yellow product 6 (10.7518 g, 78%) could be obtained after subsequent secondary column chromatography (petroleum ether / ethyl acetate = 20:1). This donor was obtained in 4 steps with a final yield of 48%. 1 1H NMR (600 MHz, Chloroform-d) δ 7.46 - 7.43 (m, 1H), 7.40 - 7.38 (m, 1H), 7.20 (qt, J = 7.5, 3.6 Hz, 2H), 5.67 (dd, J = 3.6, 1.2 Hz, 1H), 5.12 (t, J = 9.8 Hz, 1H), 5.09 (d, J = 1.3 Hz, 1H), 5.04 (dd, J = 10.1, 3.6 Hz, 1H), 3.57 (dq, J = 9.5, 6.2 Hz, 1H), 2.21 (s, 3H), 2.04 (s, 3H), 1.98 (s, 3H), 1.33 (s, 9H), 1.28 (d, J = 6.2 Hz, 3H). 1313C NMR (151 MHz, Chloroform-d) δ 170.25, 170.22, 170.21, 169.97, 169.96, 135.51, 132.66, 130.96, 128.17, 127.43, 126.02, 126.01, 105.61, 83.62, 74.94, 71.90, 71.18, 70.41, 70.40, 30.93, 28.42, 20.93, 20.92, 20.73, 20.72, 17.84. HRMS (ESI) m / z calcd for C 24 H 37 O 9 S [M+Na] + : 485.16044, found: 485.16044.

[0105] Preparation of Donor 9:

[0106]

[0107] Method 1: The preparation of Donor 9 is the same as that of 6a to prepare 6, so it will not be introduced again. This donor was obtained as a yellow donor 9 in a 4-step 56% yield. 1 1H NMR (400 MHz, Chloroform-d) δ 7.45 - 7.41 (m, 1H), 7.35 (dd, J = 7.4, 1.7 Hz, 1H), 7.20 (td, J = 7.6, 1.7 Hz, 1H), 7.14 (td, J = 7.5, 1.3 Hz, 1H), 5.26 (t, J = 9.3 Hz, 1H), 5.13 (dt, J = 17.4, 9.7 Hz, 2H), 4.95 (d, J = 10.0 Hz, 1H), 4.24 (dd, J = 12.3, 5.8 Hz, 1H), 4.13 (dd, J = 12.3, 2.3 Hz, 1H), 3.80 (ddd, J = 10.0, 5.8, 2.3 Hz, 1H), 2.03 (dd, J = 12.8, 10.0 Hz, 12H), 1.32 (s, 9H). 13 13C NMR (101 MHz, Chloroform-d) δ 170.66, 170.28, 169.53, 169.24, 136.39, 132.39, 128.79, 128.17, 126.66, 124.66, 105.67, 84.48, 75.85, 74.01, 69.97, 68.54, 62.44, 30.96, 28.39, 20.82, 20.73, 20.71. HRMS (ESI) m / z calcd for C 26 H 32 O9 S[M+Na] + : 543.16592, found: 543.16592.

[0108] Method 2: Donor 13 (1 g, 1.35 mmol) and sodium methoxide (73.1 mg, 0.135 mmol) were dissolved in methanol (13.5 mL), and the mixture was stirred at room temperature for 5 h. After the reaction was completed as detected by TLC, it was neutralized to pH = 7 with acidic resin (Amberlite IR120), filtered, and concentrated to obtain crude product 13a, which was directly used for the next step.

[0109] The crude product 13a was dissolved in acetic anhydride (2.59 mL) and pyridine (2.59 mL), and the mixture was stirred at room temperature overnight. After the reaction was completed as detected by TLC, it was quenched with methanol (methanol destroyed the excess acetic anhydride) in an ice bath until no more bubbles were generated. It was washed three times with water, three times with saturated sodium bicarbonate solution, extracted three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain a pale yellow product 9 (0.5357 g, 76% for two steps).

[0110] Preparation of donor 13:

[0111]

[0112] The preparation of donor 13 was the same as that of 9 and will not be introduced again. This donor was obtained from D-glucose as a raw material with a yield of 64% in 4 steps to obtain a pale yellow donor 13. 1 H NMR (400 MHz, Chloroform-d) δ 8.06 (d, J = 7.7 Hz, 2H), 7.97 (d, J = 7.7 Hz, 4H), 7.85 (d, J = 7.7 Hz, 2H), 7.64 - 7.34 (m, 12H), 7.09 (t, J = 7.5 Hz, 1H), 6.94 (t, J = 7.7 Hz, 1H), 6.04 (t, J = 9.5 Hz, 1H), 5.73 (dt, J = 14.3, 9.8 Hz, 2H), 5.33 (d, J = 10.1 Hz, 1H), 4.72 (dd, J = 12.3, 2.6 Hz, 1H), 4.53 (dd, J = 12.1, 6.9 Hz, 1H), 4.35 (ddd, J = 9.7, 7.0, 2.6 Hz, 1H), 1.14 (s, 9H). 1313C NMR (101 MHz, Chloroform-d) δ 166.18, 165.88, 165.40, 165.16, 136.86, 134.09, 133.67, 133.40, 133.34, 132.09, 130.07, 130.00, 129.92, 129.84, 129.66, 129.11, 128.83, 128.75, 128.67, 128.58, 128.52, 128.42, 128.15, 126.47, 124.52, 105.71, 84.94, 76.45, 74.18, 70.56, 69.74, 63.66, 30.68, 28.20. HRMS (ESI) m / z calcd for C 46 H 40 O 9 S [M+Na] + : 791.22852, found: 791.22852。

Claims

1. A method for synthesizing 3-O-sugar chain betulinic acid aglycone glycoside and 28-COO-sugar chain aglycone glycoside, characterized in that: The steps include: R1, R2, R3, R6, R7 are each independently selected from an alkyl group, an aryl group, a silane group or an acyl group; R5 is selected from an alkanoyl group or an aroyl group; Compound 1 is used as a raw material, and compound 7 is obtained through glycosylation reaction. Compound 7 is subjected to glycosylation reaction and deprotection reaction to obtain compounds I and II.

2. The method for synthesizing 3-O-sugar chain betulinic acid aglycone glycoside and 28-COO-sugar chain aglycone glycoside according to claim 1, characterized in that: The synthesis process of compound 7 is as follows: R1, R2, R3, R6, R7 are each independently selected from alkyl, aryl, silane or acyl; R4, R5 are selected from alkanoyl or aroyl; X1 is selected from substituted or unsubstituted acetylenic phenylthio; (1) protecting the carboxyl group at position 28 in compound 1 with a protecting group to obtain compound 2; (2) Compound 2 acts as an acceptor and undergoes glycosylation reaction with glycosyl donor 3 to obtain compound 4; (3) removing the R4 protecting group in compound 4 to obtain compound 5; (4) Compound 5 reacts with glycosyl donor 6 to obtain compound 7.

3. The method for synthesizing 3-O-sugar chain betulinic acid aglycone glycoside and 28-COO-sugar chain aglycone glycoside according to claim 1, characterized in that: The synthesis process of compound I is as follows: R1, R2, R3, R6, R7, R8, R9, R 10 Each is independently selected from an alkyl group, an aryl group, a silane group or an acyl group; R5, R 11 is selected from alkanoyl or aroyl; X1 is selected from substituted or unsubstituted alkynylphenylthio; S1, removing the R2 protecting group in compound 7 to obtain compound 8; S2, compound 8 as an acceptor, and glycosylation reaction with glycosyl donor 9 to obtain compound 10; S3, removing the R1 protecting group in compound 10 to obtain compound 11; S4, finally, R3, R5, R6, R7, R8, R9, R 10 , R 11 The protecting group can be removed to obtain 3-O-glycosylated betulinic acid glycoside 1.

4. The method for synthesizing 3-O-sugar chain betulinic acid aglycone glycoside and 28-COO-sugar chain aglycone glycoside according to claim 1, characterized in that: The synthesis process of compound II is as follows: R1, R2, R3, R6, R7, R8, R9, R 10 Each is independently selected from an alkyl group, an aryl group, a silane group or an acyl group; R5, R 11 is selected from alkanoyl or aroyl; X1 is selected from substituted or unsubstituted alkynylphenylthio; a. removing the protecting group of the carboxyl group in compound 7 to obtain compound 12; b. Compound 12 is used as an acceptor and undergoes glycosylation reaction with glycosyl donor 13 to obtain compound 14; c. Finally, the protecting groups on compound 14 are removed to obtain 28-COO-sugar chain betulinic acid glycoside II.

5. The method for synthesizing 3-O-sugar chain betulinic acid aglycone glycoside and 28-COO-sugar chain aglycone glycoside according to any one of claims 2 to 4, characterized in that: The X1 is X2 is selected from an alkyl group, an ester group, a silicon group or an amide group.

6. The method for synthesizing 3-O-sugar chain betulinic acid aglycone glycoside and 28-COO-sugar chain aglycone glycoside according to any one of claims 2 to 4, characterized in that: The glycosidation reaction is carried out in an organic solvent under the action of a molecular sieve and a monovalent gold complex with a donor, the organic solvent is one or more of an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, a ketone solvent, and an ether solvent, the monovalent gold complex is Ph3PAuOTf or Ph3PAuNTf2, and the molecular sieve is Molecular sieve; the molar ratio of donor to acceptor is (1.3-1.1):1, the molar ratio of donor to catalyst is 1:(0.1-0.3); based on the donor, the added amount of molecular sieve is 3-5 g / mmol.

7. The method for synthesizing 3-O-sugar chain betulinic acid aglycone glycoside and 28-COO-sugar chain aglycone glycoside according to any one of claims 1 to 4, characterized in that: R1, R2, R3, R6, R7, R8, R9, R 10 is selected from Bz, Ac, CA, Lev, TBDPS, TBS, Ts, All, Nap, Bn or R2, R3 is G represents 1 to 3 identical or different substituents, and each G is independently selected from H, F, Cl, Br, C1-C4 saturated alkyl, nitro, methoxy, acetoxy, R4, R5, R 11 Selected from Bz, Ac, Boc, CA or Lev, TBDPS is tert-butyldiphenylsilyl, TBS is tert-butyldimethylsilyl, Ts is p-toluenesulfonyl, All is allyl, Nap is 2-methylnaphthyl, Bn is benzyl, Ac is acetyl, Bz is benzoyl, CA is chloroacetyl, Lev is levulinyl, and Boc is tert-butyloxycarbonyl.

8. The method for synthesizing 3-O-sugar chain betulinic acid aglycone glycoside and 28-COO-sugar chain aglycone glycoside according to any one of claims 2 to 4, wherein the deprotection reaction is carried out under the mediation of acid or base or by palladium carbon reduction.

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