CN112794858B - Preparation method of compound with 3,4-trans-3, 6-anhydro-hexofuranose structure - Google Patents

Preparation method of compound with 3,4-trans-3, 6-anhydro-hexofuranose structure Download PDF

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CN112794858B
CN112794858B CN202110398950.4A CN202110398950A CN112794858B CN 112794858 B CN112794858 B CN 112794858B CN 202110398950 A CN202110398950 A CN 202110398950A CN 112794858 B CN112794858 B CN 112794858B
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arabinofuranose
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谢唯佳
王志梅
陶文祥
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China Pharmaceutical University
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Abstract

The invention discloses a liquid crystal display with 3,4-transA preparation method of a compound with an (E) -3, 6-anhydro-hexofuranose structure. The method initiates intramolecular hemiacetalization reaction while removing benzyl through multi-step reaction and hydrogenation by taking palladium-carbon as a catalyst to obtain the 3,4-trans-3, 6-anhydrohexofuranose structural compounds.

Description

Preparation method of compound with 3,4-trans-3, 6-anhydro-hexofuranose structure
Technical Field
The invention belongs to the field of chemical synthesis, and relates to a preparation method of a compound with 3,4-transA preparation method of a compound with an (E) -3, 6-anhydro-hexofuranose structure.
Background
Sauropounol E is prepared from sauropuo sauropus spathulaSauropus spatusifolius BeilleThe natural active components extracted from the plant are found to have nature by analyzing the structureExtremely rare 3,4-trans-3, 6-anhydrohexose furanose backbone structure.
Found through literature research, the 3,4-transNo chemical synthesis method of the-3, 6-anhydro-furan hexose skeleton is reported. Foster et al in 1954 reported the synthesis of methyl-3, 6-anhydro-2-deoxy-alpha-D-glucopyranoside and methyl 3, 6-anhydro-2-deoxy-alpha-D-galactopyranoside and the corresponding 4-methyl ether derivatives. When methyl-2-deoxy-alpha-D-galactopyranoside was explored, it was found that only dimethylacetal compounds could be formed, since the 3-and 4-positions are in the trans configuration (R)trans) Therefore, 3, 4-trans-bifuran ring cannot be directly formed. Kasireddy et al discovered in 1996 when they explored the Wacker oxidation reaction of a carbohydrate compound,trans-3-hydroxy-4-ethoxycarbonylfuranoside cannot undergo lactosylation. In 2001, Lowary et al synthesized a brown algae source from the coast of south australiaNotheia anomalaWhen the extracted marine natural product is separated, the hydroxyl and chain aldehyde groups with ortho-trans configuration can not carry out ring closure reaction through intramolecular hemiacetalization.
Disclosure of Invention
The purpose of the invention is as follows: the present invention provides a liquid crystal display device having 3,4-transA preparation method of a compound with an (E) -3, 6-anhydro-furanose hexose structure, which is used for solving the problem of 3,4-trans-3, 6-anhydrohexose compounds, such as the natural product sauropunol E.
The technical scheme is as follows: the invention relates to a liquid crystal display device with 3,4-trans-a process for the preparation of a compound of the structure 3, 6-anhydrohexofuranose comprising the steps of:
（1）（2S，3S，4S) Synthesis of (3, 4-bis (benzyloxy) -5-methoxytetrahydrofuran-2-carbaldehyde (compound No. 5) by Wittig reaction of aldehyde groupS，4R，5R) -3, 4-bis (benzyloxy) -2-methoxy-5-vinyltetrahydrofuran (compound No. 6); the reaction solvent of the Wittig reaction is tetrahydrofuran, dichloromethane and acetonitrile, the reaction reagents are n-butyllithium and methyl triphenyl phosphonium bromide, the reaction temperature is-20 ℃ to 30 ℃, and the reaction time is 1 to 10 hours;
（2）（3S，4R，5R) Synthesis of (2) from (E) -3, 4-bis (benzyloxy) -2-methoxy-5-vinyltetrahydrofuran (Compound No. 6) by demethoxylation at the 2-positionR，3R，4R) -3, 4-bis (benzyloxy) -2-vinyltetrahydrofuran (compound No. 7); the demethoxylation reaction is carried out by taking dichloromethane, acetonitrile or tetrahydrofuran as a reaction solvent, taking triethylsilane and boron trifluoride diethyl etherate as a reaction reagent, and reacting at-10-30 ℃ for 4-16 hours;
（3）（2R，3R，4R) Synthesis of 2- ((2) from (E) -3, 4-bis (benzyloxy) -2-vinyltetrahydrofuran (Compound No. 7) by Oxidation of an olefinR，3R，4R) -3, 4-bis (benzyloxy) tetrahydrofuran-2-yl) ethan-1-ol (compound No. 8); the reaction solvent of the olefin oxidation reaction can be tetrahydrofuran, acetonitrile or dichloromethane, the reaction reagents are borane, sodium hydroxide and hydrogen peroxide, the reaction temperature is-10-30 ℃, and the reaction time is 4-16 hours;
（4）2-（（2R，3R，4R) Synthesis of 2- ((2) by oxyhydroxide reaction of (E) -3, 4-bis (benzyloxy) tetrahydrofuran-2-yl) ethan-1-ol (Compound No. 8)R，3R，4R) -3, 4-bis (benzyloxy) tetrahydrofuran-2-yl) acetaldehyde (compound No. 9); the hydroxyl oxidation reaction is Dess-Martin oxidation reaction, Jones oxidation reaction, Swern oxidation reaction, Ley oxidation reaction, Tempo oxidation reaction or IBX oxidation reaction, the reaction solvent is dichloromethane, acetonitrile or DMSO, the reaction reagent is dessimidine reagent, Jones reagent, IBX reagent or TPAP reagent, the reaction temperature is-10 ℃ to 30 ℃, and the reaction time is 1 to 10 hours;
（5）2-（（2R，3R，4R) The (3 a) is obtained by the palladium mediated trans lactonization of (E) -3, 4-bis (benzyloxy) tetrahydrofuran-2-yl) acetaldehyde (compound No. 9) after the debenzylation reaction at the 3, 4-positionR，6R，6aS) -hexahydrofuro [3, 2-beta ]]Furan-2, 6-diol (compound No. 10);
（6）（3aR，6R，6aS) -hexahydrofuro [3, 2-beta ]]The 6-position hydroxyl of furan-2, 6-diol (compound NO. 10) is subjected to glycosylation reaction to obtain a compound with a structure shown in formula (I) or formula (II); the reaction solvent of the glycosylation reaction is methanol, ethanol, isopropanol or n-butanol; the reaction reagent of the glycosylation reaction is concentrated hydrochloric acid, acetyl chloride or sulfuric acid; the reaction temperature is-10 ℃ to 30 ℃, and the reaction time is 1 to 10 hours;
Figure 406109DEST_PATH_IMAGE001
and R is selected from methyl, ethyl, isopropyl or n-butyl.
Said (2)S，3S，4S) -3, 4-bis (benzyloxy) -5-methoxytetrahydrofuran-2-carbaldehyde (compound No. 5) was synthesized by the following method: by 1-O-methyl-2, 3-OOxidation reaction of the 5-hydroxy group of (E) -dibenzyl-D-arabinofuranose (Compound No. 4) to give (2)S，3S，4S) -3, 4-bis (benzyloxy) -5-methoxytetrahydrofuran-2-carbaldehyde (compound No. 5).
The 1-O-methyl-2, 3-O-dibenzyl-D-arabinofuranose (compound No. 4) was synthesized by the following method: 1-O-methyl-2, 3-O-dibenzyl-5-OThe 5-hydroxyl of the- (dimethyl tert-butyl silyl) -D-arabinofuranose (compound No. 3) is subjected to deprotection reaction to obtain 1-O-methyl-2, 3-O-dibenzyl-D-arabinofuranose (compound No. 4).
The 1-O-methyl-2, 3-O-dibenzyl-5-OAnd (2) carrying out deprotection reaction on 5-site hydroxyl of the- (dimethyl tert-butyl silyl) -D-arabinofuranose (compound No. 3), wherein a reaction solvent is tetrahydrofuran, N-dimethylformamide or acetonitrile, a reaction reagent is a fluorination reagent, the fluorination reagent is tetrabutylammonium fluoride, a pyridine solution of hydrofluoric acid or an acetic acid solution of hydrogen fluoride, the reaction temperature is-10-30 ℃, and the reaction time is 4-16 hours.
The 1-O-methyl-2, 3-O-dibenzylGroup-5-O- (dimethyl-tert-butylsilyl) -D-arabinofuranose (Compound No. 3) was synthesized by the following method: 1-O-methyl-5-OBenzyl protection reaction of 2, 3-hydroxy of- (dimethyl tert-butyl silyl) -D-arabinofuranose (compound No. 2).
The 1-O-methyl-5-O- (dimethyl-tert-butylsilyl) -D-arabinofuranose (Compound No. 2) was synthesized by the following method: 1-OThe 5-silyl ether protection reaction of the (1) -methyl-D-arabinofuranose to obtain 1-O-methyl-5-O- (dimethyl-tert-butylsilyl) -D-arabinofuranose (Compound No. 2).
The 1-O-methyl-D-arabinofuranose was synthesized by the following method: the 1-hydroxymethylation of D-arabinose to obtain 1-O-methyl-D-arabinofuranose (compound No. 1).
The 1-hydroxy methylation of the D-arabinose is carried out, a reaction solvent is methanol, a reaction reagent is acetyl chloride, the reaction temperature is-10 ℃ to 30 ℃, and the reaction time is 1 to 10 hours.
The 1-O-methyl-2, 3-OThe 5-hydroxy oxidation reaction of the dibenzyl-D-arabinofuranose (compound NO. 4) is Dess-Martin reaction, Jones oxidation reaction, Swern oxidation reaction, Ley oxidation reaction, Tempo oxidation reaction or IBX oxidation reaction, the reaction solvent is dichloromethane, acetonitrile or DMSO, the reaction reagent is a dessimutan reagent, a Jones reagent, an IBX reagent or a TPAP reagent, the reaction temperature is-10 ℃ to 30 ℃, and the reaction time is 1 to 10 hours.
The 1-O-methyl-5- O Protecting 2, 3-hydroxy of- (dimethyl tert-butyl silyl) -D-arabinofuranose (compound No. 2) by using benzyl for reaction, wherein a reaction solvent is N, N-dimethylformamide, tetrahydrofuran or acetonitrile, a reaction reagent is benzyl bromide, an alkali is sodium hydride, imidazole, potassium hydroxide or sodium hydroxide, the reaction temperature is-10-30 ℃, and the reaction time is 1-10 hours.
In the step (5), the 2- ((2)R，3R，4R) Debenzylation of 3, 4-bis (benzyloxy) tetrahydrofuran-2-yl) acetaldehyde (Compound No. 9)And a palladium-mediated trans-lactonization reaction, wherein the reaction solvent is 95% of acetic acid, tetrahydrofuran, dioxane, methanol or dichloromethane, the reaction temperature is 30-80 ℃, the reaction time is 10-36 hours, and the reaction reagent is palladium carbon or platinum carbon.
The 1-OCarrying out a 5-site silyl ether protection reaction on the-methyl-D-arabinofuranose (compound NO. 1), wherein a reaction solvent is tetrahydrofuran, N-dimethylformamide, 1, 4-dioxane or acetonitrile, a reaction reagent is tert-butyldimethylchlorosilane, triphenylchlorosilane or trityldimethylchlorosilane, an alkali can be imidazole or pyridine, the reaction temperature is-10-30 ℃, and the reaction time is 1-10 hours.
Has the advantages that: (1) the invention completes the first time of having 3,4-transSynthesis of-3, 6-anhydro-furanose hexose structure, such as the natural product sauropunol E, by hydrodebenzylation mediated lactonization reaction using noble metal catalyst for the first time constructed 3,4- trans The 3, 6-anhydro-furan hexose skeleton lays a foundation for synthesizing natural products containing the structural fragment and pharmaceutically active molecules; (2) the invention also synthesizes saruropodenol E and derivatives thereof, and proves the anti-inflammatory activity of the derivatives of the saruropodenol E, thereby enriching the structure-activity relationship research of the compounds; (3) the invention can also take D-arabinose as a raw material, and oxidize 5-site naked hydroxyl into aldehyde group through selective hydroxyl protection. Then, a carbon chain is lengthened through a Wittig reaction, then primary alcohol for prolonging the carbon chain is obtained through hydroboration and oxidation, and then aldehyde derivatives are obtained through oxidation again. The obtained aldehyde is hydrogenated and debenzylated under the catalysis of palladium-carbon, lactonization is carried out, and methylation reaction is carried out under the catalysis of acid to obtain a final product, namely, sauropunol E and a derivative thereof, so that the problem of the source of raw materials is solved.
Drawings
FIG. 1 is the structural formula of sauropunol E;
FIG. 2 is a scheme for the synthesis of saruropounol E and its derivatives;
FIG. 3 shows the results of the anti-inflammatory activity of saruropounol E and its derivatives.
Detailed Description
The following specific examples illustrate the invention in more detail, but are not intended to limit the invention in any way.
First, sample preparation
Example 1: d-arabinose (10 g, 66.7 mmol) was dissolved in dry 50mL of methanol, chloroacetyl (0.01 mL, 0.14 mmol) was slowly added dropwise under ice bath conditions, the mixture was stirred and naturally warmed to room temperature, then stirring was continued for 4 hours, sodium bicarbonate powder was added to the reaction solution to adjust the pH to 7, and the mixture was filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography (dichloromethane: methanol volume ratio: 50: 1) to obtain compound No.1 (10.5 g, 64.0mmol, 96%).
Dissolving Compound No.1 in driedN,N150mL of Dimethylformamide (DMF), stirring, cooling in ice at 0 ℃ for 30min, sequentially adding imidazole (11 g, 172 mmol) and tert-butyldimethylsilyl chloride (TBSCl, 12g, 80 mmol), stirring for 10h, adding ice water, quenching, and adding CH2Cl2(dichloromethane) extraction three times, followed by washing with ice water 5 times, saturated sodium chloride three times, concentration under reduced pressure, and silica gel column chromatography (petroleum ether: ethyl acetate =10: 1) to give compound No.2 as a colorless oil.
Alpha-anomer of compound No. 2: [ alpha ] to]D 25= -0.53 (c = 0.21 in CHCl3); 1H-NMR (300 MHz, CDCl3): δ 4.91 (s, 1H), 4.23 – 4.15 (m, 2H), 3.98 (dd, J = 20.9, 11.3 Hz, 2H), 3.86 (qd, J = 11.2, 2.0 Hz, 2H), 3.42 (s, 3H), 0.93 (s, 9H), 0.14 (s, 6H). 13C-NMR (75 MHz, CDCl3): δ 109.5,87.5, 78.2, 77.9, 63.3, 54.8, 25.8, 18.4, -5.6, -5.7; HRMS (ESI) m/z Calcd. for C12H26NaO5Si [M+Na]+: 301.1508, found: 301.1506.
Beta-anomer of compound No. 2: [ alpha ] to]D 25= -0.62(c = 0.25 in CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.83 – 4.70 (m, 1H), 4.09 – 3.96 (m, 2H), 3.85 – 3.77 (m, 1H), 3.68 (d, J = 5.1 Hz, 2H), 3.38 (s, 3H), 0.88 (s, 9H), 0.05 (s, 6H).13C NMR (75 MHz, CDCl3) δ 101.92, 82.12, 77.89, 77.49, 77.07, 76.74, 76.64, 64.87, 55.27, 25.87, 25.66, 18.34, -5.42. HRMS (ESI) m/z Calcd. for C12H26NaO5Si [M+Na]+: 301.1509, found: 301.1507.
Example 2: compound No.2 (8.7 g, 31.3 mmol) was dissolved in 80 mL of N, N-dimethylformamide, sodium hydride (60%, 3.8g, 93.9 mmol) was added under ice-water bath conditions, and stirred under these conditions for 30min, benzyl bromide (8.2 mL, 9 mmol) was added, and after naturally warming to room temperature, stirring was carried out for 5 h. After the reaction is finished, adding ice water for quenching, and adding ethyl acetate: the mixture solvent of petroleum ether =1:1 was extracted 3 times, the organic phases were combined, washed three times with ice water and three times with saturated sodium chloride solution, and concentrated under reduced pressure to conduct silica gel column chromatography (petroleum ether: ethyl acetate =50: 1) to obtain compound No.3 (13.2 g, 92.3%) as a yellow oil.
α -anomer: [ alpha ] to]D 25 = -28(c = 2.1 in CHCl3); 1H-NMR (300 MHz, CDCl3): δ 7.51 – 7.25 (m, 10H), 4.79 – 4.53 (m, 5H), 4.25 – 4.10 (m, 2H), 4.10 – 3.98 (m, 1H), 3.86 – 3.67 (m, 2H), 3.43 (d, J = 9.2 Hz, 3H), 0.97 (d, J = 2.6 Hz, 9H), 0.14 (d, J = 3.0 Hz, 6H).;13C-NMR (75 MHz, CDCl3): δ 137.5, 128.6, 127.8, 127.4, 110.2, 84.0, 82.0, 81.2, 73.3, 63.6, 55.8, 30.6, 25.9, -2.3; HRMS (ESI) m/z Calcd. for C26H38NaO5Si [M+Na]+: 481.2507, found:481.2508.
Example 3: compound No.3 (13.2 g, 28.8 mmol) was dissolved in 30mL of tetrahydrofuran, 1M tetrabutylammonium fluoride (9.1 g, 28.8 mmol) was added thereto, and the mixture was stirred at room temperature for 8 hours, after completion of the reaction, methanol was added thereto for quenching, and the mixture was concentrated under reduced pressure and subjected to silica gel column chromatography (petroleum ether: ethyl acetate =50:1-10: 1) to give Compound No.4 (8.92 g, 90%) as a colorless oily compound.
α -anomer: [ alpha ] to]D 25 = +19.6 (c = 1.5 in CHCl3); 1H-NMR (300 MHz, CDCl3):δ 7.35 (dd, J = 5.5, 2.3 Hz, 10H), 4.96 (s, 1H), 4.65 – 4.49 (m, 4H), 4.16 (dt, J = 6.6, 3.2 Hz, 1H), 4.01 (dt, J = 8.8, 2.7 Hz, 2H), 3.85 (dd, J = 12.0, 2.9 Hz, 1H), 3.66 (dd, J = 11.6, 3.5 Hz, 1H), 3.40 (s, 3H); 13C-NMR (75 MHz, CDCl3): δ138.5, 127.6, 127.7, 127.4, 110.2, 84.0, 82.0, 81.2, 73.3, 63.6, 55.8,, 26.3, 25.8; HRMS(ESI) m/z Calcd. for C25H32NaO8 [M+Na]+: 367.1603, found 367.1605.
Beta-anomer: [ alpha ] to]D 25 = -28 (c = 2.1 in CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.32 (dt, J = 14.1, 3.9 Hz, 10H), 4.73 – 4.54 (m, 5H), 4.22 (dd, J = 7.1, 5.8 Hz, 1H), 4.04 (ddd, J = 8.8, 6.2, 4.0 Hz, 2H), 3.69 – 3.50 (m, 2H), 3.37 (s, 3H).13C NMR (75 MHz, CDCl3) δ 138.05, 137.60, 128.47, 128.44, 128.19, 128.01, 127.80, 101.86, 84.40, 82.28, 81.38, 72.67, 72.55, 64.19, 55.61. HRMS(ESI) m/ z Calcd. for C25H32NaO8 [M+Na]+: 367.1603, found 367.1605.
Example 4: compound No.4 (8.92 g, 25.9 mmol) was dissolved in 15mL of dichloromethane, and dess-Martin oxidant (C) was added13H13IO813.2g, 31.1mmol) at 0 ℃, adding 50mL of n-hexane after 2 hours of complete reaction, continuing stirring to separate out a solid, filtering, concentrating under reduced pressure, pulping with petroleum ether, filtering, concentrating under reduced pressure, washing with saturated sodium thiosulfate for three times, concentrating under reduced pressure, and performing silica gel column chromatographic separation (petroleum ether: ethyl acetate =50: 1) to obtain a pale yellow oily compound No.5(7.27g, 82%), methyl triphenyl phosphonium bromide (6.2 g, 17.4 mmol) is weighed and dissolved in 20mL of dry tetrahydrofuran, 2.5mol/L n-butyl lithium tetrahydrofuran (7 mL, 17.5 mmol) is added at 0 ℃ under nitrogen protection, after warming to room temperature and stirring for 2.5h, a tetrahydrofuran solution of a compound No.5 (2 g, 5.8 mmol) is added, stirring is performed at room temperature, after the reaction is finished, methanol is added to quench, and after reduced pressure concentration, silica gel column chromatography separation is performed (petroleum ether: ethyl acetate = 60: 1, obtaining a yellow oily compound, and carrying out the third step in the same wayAfter that time, Compound No.6 (4.35 g, 61%) was obtained.
[α]D 25= +18.7 (c = 1.1 in CHCl3); 1H-NMR (300 MHz, CDCl3): 1H NMR (300 MHz, CDCl3) δ 7.48 – 7.24 (m, 10H), 4.93 (s, 1H), 4.67 – 4.47 (m, 4H), 4.16 (td, J = 7.0, 5.6 Hz, 1H), 4.01 (dd, J = 3.2, 1.2 Hz, 1H), 3.85 – 3.72 (m, 3H), 3.39 (s, 3H), 1.94 (qd, J = 5.7, 2.5 Hz, 2H).13C-NMR (75 MHz, CDCl3):δ 137.48, 137.34, 128.51, 128.47, 128.01, 127.99, 127.95, 106.99, 88.20, 87.14, 79.93, 72.36, 72.20, 60.54, 54.82, 35.49 ; HRMS(ESI) m/z Calcd. for C21H24NaO3[M+Na]+: 363.1747, found: 363.1744.
Example 5: compound No.6 (5.9 g, 17.35 mmol) was dissolved in dry 30mL of dichloromethane, cooled to 0 ℃, triethylsilane (8.2 mL, 52.1 mmol) and a catalytic amount of trifluoromethanesulfonic acid (0.02 mL, 0.2 mmol) were added, and after stirring for 30min, boron trifluoride diethyl etherate (8.7 mL, 69.2 mmol) was added, the temperature was naturally raised to room temperature, stirring was carried out for 15h, triethylamine was added, the reaction solution was adjusted to pH =7, and the mixture was concentrated under reduced pressure to conduct silica gel column separation (petroleum ether: ethyl acetate =50: 1), whereby Compound No.7(3.5g, 65%) was obtained as a yellow oily compound.
[α]D 25 = +15.3(c =0.8 in CHCl3); 1H-NMR (300 MHz, CDCl3): 1H NMR (300 MHz, CDCl3) δ 7.50 – 7.26 (m, 10H), 6.03 (ddd, J = 17.3, 10.4, 7.1 Hz, 1H), 5.48 – 5.18 (m, 2H), 4.71 – 4.48 (m, 4H), 4.32 (dd, J = 7.0, 4.4 Hz, 1H), 4.21 – 4.06 (m, 2H), 4.06 – 3.91 (m, 2H).;13C-NMR (75 MHz, CDCl3): 13C NMR (75 MHz, CDCl3) δ 137.82, 137.72, 136.63, 128.49, 128.02, 127.90, 127.84, 127.74, 127.65, 117.08, 87.99, 84.91, 83.63, 83.56, 72.02, 71.52, 71.45, 71.39, 71.32.HRMS(ESI) m/z Calcd. for C20H22NaO3 [M+Na]+: 333.1615, found: 333.1616.
Example 6: dissolving compound No.7(3.5g, 11.3mmol) in 20mL of dry tetrahydrofuran, adding 2mol/L of borane (17 mL, 34 mmol) under the condition of ice-water bath under the protection of nitrogen, stirring for 5h at room temperature, adding 3mol/L of aqueous sodium hydroxide solution (5.7 mL, 17 mmol) and 30% hydrogen peroxide solution (5.7 mL, 56.5 mmol) under the condition of ice-water bath, reacting for 12h, adding ice water for quenching, extracting with dichloromethane three times, washing with saturated sodium chloride once, adding anhydrous sodium sulfate for drying, filtering, concentrating under reduced pressure, and performing column chromatography (petroleum ether: ethyl acetate =50: 1-20: 1) to obtain compound No.8(2.3g, 62.2%) as colorless oil.
[α]D 25 = +28.3 (c = 0.55 in CHCl3); 1H-NMR (300 MHz, CDCl3): δ 7.36-7.26(m, 10H),4.60-4.48 (m, 4H), 4.09-4.03 (m, 2H), 4.00-3.94 (m, 1H), 3.91-3.88 (m, 2H), 3.82-3.76 (m, 2H), 1.98-1.88 (m,1H); 13C-NMR (75 MHz, CDCl3): δ137.1, 128.0, 127.4, 127.5, 87.3, 82.7, 82.4, 76.6, 76.2, 60.2, 34.9.; HRMS(ESI) m/z Calcd. for C20H24NaO4 [M+Na]+:351.1710,found351.1709.
Example 7: dissolving compound No.8(2.3g, 7.0 mmol) in 12mL of dried dichloromethane, adding dess-martin oxidant (3.6 g, 8 mmol) under ice water bath, reacting for 5h, adding 20mL of n-hexane, stirring, filtering after solid precipitation is completed, concentrating under reduced pressure, adding petroleum ether, pulping, filtering, washing with saturated sodium thiosulfate three times, concentrating under reduced pressure, and separating by silica gel column chromatography (petroleum ether: ethyl acetate =50: 1) to obtain compound No.9 (2.1 g, 6.5 mmol).
[α]D 25 =+23.1(c= 0.41 in CHCl3);1H NMR (300 MHz, CDCl3) δ 9.79 (s, 1H), 7.36 (q, J = 6.8, 6.4 Hz, 10H), 4.67 – 4.43 (m, 4H), 4.37 (ddd, J = 7.5, 5.6, 3.4 Hz, 1H), 4.17 – 4.02 (m, 2H), 3.97 (dd, J = 10.1, 4.2 Hz, 1H), 3.87 (d, J= 3.4 Hz, 1H), 2.99 – 2.63 (m, 2H).;13C-NMR (75 MHz, CDCl3): δ 200.65, 137.58, 128.56, 128.00, 127.97, 127.81, 127.76, 127.67, 86.76, 82.95, 78.41, 71.93, 71.58, 71.53, 71.42, 47.29.; HRMS(ESI) m/z Calcd. for C20H22NaO4 [M+Na]+:349.1510, found: 349.1506.
Example 8: dissolving a compound NO.9 (2.1 g, 6.5 mmol) in an acetic acid aqueous solution (the mass concentration is 95 percent and 15 mL), adding palladium carbon (0.21 g), replacing hydrogen, carrying out catalytic hydrogenation in an oil bath at 50 ℃ to react for 10 hours to obtain a target compound NO.10, dissolving the obtained compound NO.10 in methanol (15 mL), adding concentrated hydrochloric acid (100 uL), detecting the reaction completion by TCL, adding sodium bicarbonate to neutralize, filtering, and concentrating an organic solution under reduced pressure to obtain sauropunol E (0.62 g).
[ɑ]D 20= +5.33 ( c = 0.21 in CHCl3 ); 1H NMR (300 MHz, CDCl3) δ 5.19 – 4.85 (m, 2H), 4.40 (dd, J = 40.5, 3.9 Hz, 2H), 3.86 (dt, J = 13.3, 10.2 Hz, 2H), 3.34 (s, 3H), 2.30 – 2.19 (m, 1H), 2.07 (ddd, J = 14.5, 5.3, 3.1 Hz, 1H).; 13C-NMR (75 MHz, CDCl3): δ 106.19, 87.00, 81.27, 77.45, 77.02, 76.60, 75.74, 72.73, 54.95, 40.07.; HRMS (ESI) m/z Calcd. for C7H12NaO4 [M+Na]+183.1711, found183.1708.
Example 9: dissolving compound No.9 (2.1 g, 6.5 mmol) in acetic acid aqueous solution (mass concentration 95%, 15 mL), adding palladium carbon (0.21 g), replacing with hydrogen, carrying out catalytic hydrogenation in 50 ℃ oil bath, reacting for 10 hours to obtain target compound No.10, dissolving obtained compound No.10 in ethanol (15 mL), adding concentrated hydrochloric acid (100 uL), detecting the reaction completion by TCL, adding sodium bicarbonate to neutralize, filtering, and concentrating the organic solution under reduced pressure to obtain Etsau (0.48 g) and Et' sau (0.22 g).
Etsau :[α] D 20 = -77.83 (c = 0.5 in CDCl3); 1H NMR (300 MHz, CDCl3)δ5.24 (dd, J = 5.4, 1.9 Hz, 1H), 5.05 – 4.91 (m, 1H), 4.50 (d, J = 4.6 Hz, 1H), 4.33 (s, 1H), 3.98 – 3.67 (m, 3H), 3.46 (m, J = 9.6, 7.2 Hz, 1H), 2.26 (ddd, J = 14.5, 7.2, 2.0 Hz, 1H), 2.09 (ddd, J = 14.4, 5.3, 3.1 Hz, 1H), 1.22 (t, J = 7.1 Hz, 3H).13C NMR (75 MHz, CDCl3)δ 104.9, 87.0, 81.4, 75.7, 72.8, 63.2, 40.2, 15.1. HRMS (ESI) m/z calcd for [M+Na]+197.0790, found 197.0791.
Et’sau: [α] D 25 = -18.47 (c = 0.30 in CHCl3); 1H NMR (300 MHz, CDCl3) δ5.18 (dd, J = 4.9, 1.6 Hz, 1H), 5.03 – 4.84 (m, 1H), 4.56 (d, J = 5.0 Hz, 1H), 4.36 (m, 2H), 3.97 – 3.65 (m, 3H), 3.58 – 3.42 (m, 1H), 2.27 – 2.08 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H).13C NMR (75 MHz, CDCl3) δ105.1, 90.2, 81.3, 73.6, 63.5, 40.6, 15.0. HRMS (ESI) m/z calcd for [M+Na]+ 197.0790, found 197.0789.
Figure 588829DEST_PATH_IMAGE002
Example 10: dissolving a compound NO.9 (2.1 g, 6.5 mmol) in an acetic acid aqueous solution (the mass concentration is 95 percent and 15 mL), adding palladium carbon (0.21 g), replacing by hydrogen, carrying out catalytic hydrogenation in an oil bath at 50 ℃ to react for 10 hours to obtain a target compound NO.10, dissolving the obtained compound NO.10 in isopropanol (15 mL), adding concentrated hydrochloric acid (100 uL), detecting the completion of the reaction by TCL, adding sodium bicarbonate to neutralize, filtering, and concentrating an organic solution under reduced pressure to obtain Prsau (0.52 g) and Pr' sau (0.21 g).
Prsau :[α] D 25 = -18.47 (c = 0.30 in CHCl3); 1H NMR (300 MHz, CDCl3)δ5.18 (dd, J = 4.9, 1.6 Hz, 1H), 5.03 – 4.84 (m, 1H), 4.56 (d, J = 5.0 Hz, 1H), 4.36 (m, 2H), 3.97 – 3.65 (m, 3H), 3.58 – 3.42 (m, 1H), 2.27 – 2.08 (m, 2H), 1.23 (m, 3H).13C NMR (75 MHz, CDCl3) δ105.1, 86.9, 81.4, 75.8, 72.8, 69.4, 40.1, 22.84, 10.6. HRMS (ESI) m/z calcd for [M+Na]+211.0946, found 211.0944.
Pr’sau :[α] D 20 = -13.53 (c = 0.23 in CHCl3); 1H NMR (300 MHz, CDCl3) δ5.20 (ddd, J = 17.3, 5.1, 1.8 Hz, 2H), 5.09 – 4.85 (m, 2H), 4.53 (m, 2H), 4.38 (dt, J = 6.1, 3.5 Hz, 4H), 3.92 (dt, J = 10.1, 3.5 Hz, 1H), 3.87 – 3.72 (m, 3H), 3.72 – 3.58 (m, 2H), 3.52 – 3.34 (m, 2H), 2.23 – 2.14 (m, 3H), 1.62 (m, 9H), 0.96 (s, 6H), 0.11 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 105.5, 90.2, 81.3, 77.2, 73.5, 70.0, 40.6, 29.7, 22.8. HRMS (ESI) m/z calcd for [M+Na]+211.0946, found 211.0952.
Figure 634145DEST_PATH_IMAGE003
Example 11: dissolving a compound NO.9 (2.1 g, 6.5 mmol) in an acetic acid aqueous solution (the mass concentration is 95 percent and 15 mL), adding palladium carbon (0.21 g), performing hydrogen replacement, performing catalytic hydrogenation in an oil bath at 50 ℃ to obtain a target compound NO.10 after reaction for 10 hours, dissolving the obtained compound NO.10 in n-butanol (15 mL), adding concentrated hydrochloric acid (100 uL), detecting the reaction completion by TCL, adding sodium bicarbonate to neutralize, filtering, and concentrating an organic solution under reduced pressure to obtain Busau (0.57 g) and Bu' sau (0.23 g).
Busau: [α] D 20 = -53.99 (c = 0.97 in CDCl3); 1H NMR (600 MHz, CDCl3) δ5.25 – 5.21 (m, 1H), 4.69 (t, J = 5.8 Hz, 1H), 4.62 – 4.56 (m, 1H), 4.17 (q, J = 5.4 Hz, 1H), 3.86 (dd, J = 9.4, 5.1 Hz, 1H), 3.81 – 3.72 (m, 2H), 3.47 (dt, J = 9.4, 6.8 Hz, 1H), 2.23 – 2.15 (m, 2H), 1.63 – 1.54 (m, 2H), 1.41 – 1.31 (m, 2H), 0.91 (s, 3H). 13C NMR (150 MHz, CDCl3) δ106.5, 84.5, 81.9, 73.5, 71.4, 69.2, 40.4, 31.6, 19.3, 13.8. HRMS (ESI) m/z calcd for [M+Na]+225.1103, found 225.1101.
Bu’sau :[α] D 20= +37.28 (c = 0.33 in CDCl3); 1H NMR (600 MHz, CDCl3) δ5.32 (dd, J = 5.2, 2.2 Hz, 1H), 4.75 (ddd, J = 7.3, 5.2, 3.3 Hz, 1H), 4.54 (t, J = 5.2 Hz, 1H), 4.21 (dt, J = 6.5, 5.7 Hz, 1H), 3.84 (dd, J = 9.3, 5.7 Hz, 1H), 3.69 (dt, J = 9.6, 6.6 Hz, 1H), 3.57 (dd, J = 9.3, 6.6 Hz, 1H), 3.39 (dt, J = 9.6, 6.6 Hz, 1H), 2.24 (ddd, J = 14.2, 7.3, 2.2 Hz, 1H), 2.12 (ddd,J = 14.2, 5.3, 3.3 Hz, 1H), 1.57 – 1.49 (m, 2H), 1.40 – 1.30 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H).13C NMR (150 MHz, CDCl3) δ 106.3, 82.0, 80.5, 72.1, 71.7, 67.9, 40.8, 31.6, 19.3, 13.8 . HRMS (ESI) m/z calcd for [M+Na]+ 225.1103, found 225.1102.
Figure 685147DEST_PATH_IMAGE004
Second, anti-inflammatory Activity assay
2.1 Experimental drugs: TPA (phorbol ester) (Sigma Aldrich), indomethacin (Sigma Aldrich), Sauropunol E, Etsau, Et ' sau, Prsau, Pr ' sau, Busau, Bu ' sau.
2.2 Experimental animals: male ICR mice (shanghai jestie laboratory animals ltd), purchased mice were randomly grouped into 6 mice each. The weight average of the body is between 20 and 25 g. The animal experiment process conforms to the animal experiment feeding management and use guide and is approved by the animal ethics committee of the Chinese pharmaceutical university.
2.3 Experimental methods
Establishing and dosing a mouse auricle swelling model: by topical application, the right ear of each mouse was inflamed by application of 0.5 μ g TPA (dissolved in 20 μ L acetone); the experimental groups were treated 30min before TPA with indomethacin, Sauropounol E, Etsau, Et ' sau, Prsau, Pr ' sau, Busau, Bu ' sau (2 mg per ear in 20. mu.L acetone) and the model groups were treated with 20. mu.L acetone.
Mouse ear thickness determination: after 6 hours of topical application of TPA, the ear thickness of the mice was determined using a digital vernier caliper, and all measurement experiments were performed by the same person in order to reduce the measurement error.
The experimental results are as follows: all anti-inflammatory activity profile data are expressed as mean ± s.e.m, and by t-test, p <0.05 was considered as statistically insignificant difference (. p <0.05,. p < 0.01).
2.4 anti-inflammatory Activity results of Sauropenol E and its derivatives
TABLE 1 blank set of experimental data
Figure 30677DEST_PATH_IMAGE005
Table 2 model set experimental data
Figure 118719DEST_PATH_IMAGE007
TABLE 3 anti-inflammatory Activity data for Indometacin
Figure 526698DEST_PATH_IMAGE008
TABLE 4 anti-inflammatory Activity data for sau E
Figure 256756DEST_PATH_IMAGE009
TABLE 5 anti-inflammatory Activity data of Etsau
Figure 191214DEST_PATH_IMAGE010
TABLE 6 anti-inflammatory Activity data for Et' sau
Figure 574791DEST_PATH_IMAGE011
Table 7 anti-inflammatory activity data for Prsau
Figure 860279DEST_PATH_IMAGE012
TABLE 8 anti-inflammatory Activity data for Pr' sau
Figure 3815DEST_PATH_IMAGE013
TABLE 9 anti-inflammatory Activity data of Busau
Figure 792780DEST_PATH_IMAGE014
TABLE 10 anti-inflammatory Activity data for Bu' sau
Figure 753783DEST_PATH_IMAGE015
The final statistical results are shown in fig. 3, and it can be seen from the results that the blank group was not administered any drug, and was not inflamed by TPA, and there was no significant difference in the thickness of the left and right ears; the model group is given acetone as a blank control, the left ear is not inflamed, the right ear is inflamed by TPA, and the thickness of the ears on the two sides is obviously different; the indomethacin group was used as a positive control, the drugs used in the experimental groups were saruropounol E, Etsau, Et ' sau, Prsau, Pr ' sau, Busau, Bu ' sau, respectively, and the degree of decrease in the thickness of the right ear in all experimental groups compared to the model group represents the level of anti-inflammatory activity.
From experimental data, saruropounol E and its derivatives all have varying degrees of anti-inflammatory activity, with the propyl-substituted compound Prsau having the strongest anti-inflammatory activity; the different enantiomers have a large influence on the anti-inflammatory activity, and the β -anomer shows a stronger anti-inflammatory activity than the α -anomer.

Claims (9)

1. Has 3,4-transPreparation method of compound with (E) -3, 6-anhydro-hexofuranose structureThe method is characterized by comprising the following steps:
（1）（2S，3S，4S) Synthesizing (3, 4-bis (benzyloxy) -5-methoxytetrahydrofuran-2-formaldehyde through Wittig reaction of aldehyde groupS，4R，5R) -3, 4-bis (benzyloxy) -2-methoxy-5-vinyltetrahydrofuran; the reaction solvent of the Wittig reaction is tetrahydrofuran, dichloromethane or acetonitrile, the reaction reagents are n-butyllithium and methyl triphenyl phosphonium bromide, the reaction temperature is-20 ℃ to 30 ℃, and the reaction time is 1 to 10 hours;
（2）（3S，4R，5R) Synthesis of (2) from (E) -3, 4-bis (benzyloxy) -2-methoxy-5-vinyltetrahydrofuran by demethoxylation at the 2-positionR，3R，4R) -3, 4-bis (benzyloxy) -2-vinyltetrahydrofuran; the reaction solvent of the demethoxylation reaction is dichloromethane, acetonitrile or tetrahydrofuran, the reaction reagents are triethylsilane and boron trifluoride diethyl etherate, and the reaction temperature is
The reaction time is 4-16 hours at the temperature of minus 10-30 ℃;
（3）（2R，3R，4R) Synthesis of 2- ((2) from (E) -3, 4-bis (benzyloxy) -2-vinyltetrahydrofuran by olefin oxidationR，3R，4R) -3, 4-bis (benzyloxy) tetrahydrofuran-2-yl) ethan-1-ol; the reaction solvent of the olefin oxidation reaction is tetrahydrofuran, acetonitrile or dichloromethane, the reaction reagents are borane, sodium hydroxide and hydrogen peroxide, the reaction temperature is-10 ℃ to 30 ℃, and the reaction time is 4 to 16 hours;
（4）2-（（2R，3R，4R) Synthesis of 2- ((2) by oxyhydroxide reaction of (E) -3, 4-bis (benzyloxy) tetrahydrofuran-2-yl) ethan-1-olR，3R，4R) -3, 4-bis (benzyloxy) tetrahydrofuran-2-yl) acetaldehyde; the hydroxyl oxidation reaction is Dess-Martin oxidation reaction, Jones oxidation reaction, Swern oxidation reaction, Ley oxidation reaction, Tempo oxidation reaction or IBX oxidation reaction, the reaction solvent is dichloromethane, acetonitrile or DMSO, the reaction reagent is dessimidine reagent, Jones reagent, IBX reagent or TPAP reagent, the reaction temperature is-10 ℃ to 30 ℃,the reaction time is 1-10 hours;
（5）2-（（2R，3R，4R) The (3 a) is obtained by the palladium mediated trans lactonization reaction of (E) -3, 4-bis (benzyloxy) tetrahydrofuran-2-yl) acetaldehyde after the 3, 4-debenzylation reactionR，6R，6aS) -hexahydrofuran [3,2-β]Furan-2, 6-diol; the 2- ((2)R，3R，4R) -3, 4-debenzylation of 3, 4-bis (benzyloxy) tetrahydrofuran-2-yl) acetaldehyde and palladium-mediated trans-lactonization, wherein the reaction solvent is 95% acetic acid, tetrahydrofuran, dioxane, methanol or dichloromethane, the reaction temperature is 30-80 ℃, the reaction time is 10-36 hours, and the reaction reagent is palladium carbon or platinum carbon;
（6）（3aR，6R，6aS) -hexahydrofuran [3,2-β]The 6-hydroxyl of furan-2, 6-diol is reacted by glycosylation to obtain a compound with a structure shown in formula (I) or formula (II); the reaction solvent of the glycosylation reaction is methanol, ethanol, isopropanol or n-butanol; the reaction reagent of the glycosylation reaction is concentrated hydrochloric acid, acetyl chloride or sulfuric acid; the reaction temperature is-10 ℃ to 30 ℃, and the reaction time is 1 to 10 hours;
Figure 833013DEST_PATH_IMAGE001
Figure 568888DEST_PATH_IMAGE002
（Ⅰ） （Ⅱ）
and R is selected from methyl, ethyl, isopropyl or n-butyl.
2. The composition of claim 1 having 3,4-transA process for producing a compound having a structure of (2) 3, 6-anhydrohexofuranose, which comprisesS，3S，4S) -3, 4-bis (benzyloxy) -5-methoxytetrahydrofuran-2-carbaldehyde was synthesized by the following method: by 1-O-methyl-2, 3-O-dibenzylOxidation of the 5-hydroxy group of (E) -D-arabinofuranose to give (2)S，3S，4S) -3, 4-bis (benzyloxy) -5-methoxytetrahydrofuran-2-carbaldehyde.
3. The composition of claim 2 having 3,4-transA process for producing a compound having an (E) -3, 6-anhydrohexofuranose structure, which comprises reacting a compound having an (E) -1-membered heterocyclic ring with a compound having an (E) -3, 6-anhydrohexofuranose structureO-methyl-2, 3-O-dibenzyl-D-arabinofuranose was synthesized by the following method: 1-O-methyl-2, 3-O-dibenzyl-5-OThe 5-hydroxyl of the- (dimethyl tertiary butyl silicon) -D-arabinofuranose is subjected to deprotection reaction to obtain 1-O-methyl-2, 3-O-dibenzyl-D-arabinofuranose.
4. The composition of claim 3 having 3,4-transA process for producing a compound having an (E) -3, 6-anhydrohexofuranose structure, which comprises reacting a compound having an (E) -1-membered heterocyclic ring with a compound having an (E) -3, 6-anhydrohexofuranose structureO-methyl-2, 3-O-dibenzyl-5-O(dimethyl tert-butyl silyl) -D-arabinofuranose via 1-O-methyl-5-OBenzyl protection reaction of 2, 3-hydroxyl of- (dimethyl tertiary butyl silicon) -D-arabinofuranose.
5. The composition of claim 4 having 3,4-transA process for producing a compound having an (E) -3, 6-anhydrohexofuranose structure, which comprises reacting a compound having an (E) -1-membered heterocyclic ring with a compound having an (E) -3, 6-anhydrohexofuranose structureO-methyl-5-OThe- (dimethyl tert-butyl silyl) -D-arabinofuranose is synthesized by the following method: 1-OThe 5-silyl ether protection reaction of the-methyl-D-arabinofuranose to obtain 1-O-methyl-5-O- (dimethyl tert-butyl silyl) -D-arabinofuranose.
6. The composition of claim 5 having 3,4-transA process for producing a compound having an (E) -3, 6-anhydrohexofuranose structure, which comprises reacting a compound having an (E) -1-membered heterocyclic ring with a compound having an (E) -3, 6-anhydrohexofuranose structureO-methyl-D-arabinofuranose was synthesized by the following method: the 1-hydroxymethylation of D-arabinose to obtain 1-O-methyl-D-arabinofuranose.
7. The composition of claim 2 having 3,4-transA process for producing a compound having an (E) -3, 6-anhydrohexofuranose structure, which comprises reacting a compound having an (E) -1-membered heterocyclic ring with a compound having an (E) -3, 6-anhydrohexofuranose structureO-methyl-2, 3-OThe 5-hydroxy oxidation reaction of the-dibenzyl-D-arabinofuranose is Dess-Martin oxidation reaction, Jones oxidation reaction, Swern oxidation reaction, Ley oxidation reaction, Tempo oxidation reaction or IBX oxidation reaction, the reaction solvent is dichloromethane, acetonitrile or DMSO, the reaction reagent is a dessimidine reagent, a Jones reagent, an IBX reagent or a TPAP reagent, the reaction temperature is-10-30 ℃, and the reaction time is 1-10 hours.
8. The composition of claim 4 having 3,4-transA process for producing a compound having an (E) -3, 6-anhydrohexofuranose structure, which comprises reacting a compound having an (E) -1-membered heterocyclic ring with a compound having an (E) -3, 6-anhydrohexofuranose structureO-methyl-5-OProtecting 2, 3-hydroxy of the- (dimethyl tert-butyl silyl) -D-arabinofuranose by using benzyl for reaction, wherein a reaction solvent is N, N-dimethylformamide, tetrahydrofuran or acetonitrile, a reaction reagent is benzyl bromide, an alkali is sodium hydride, imidazole, potassium hydroxide or sodium hydroxide, the reaction temperature is-10-30 ℃, and the reaction time is 1-10 hours.
9. The composition of claim 5 having 3,4-transA process for producing a compound having an (E) -3, 6-anhydrohexofuranose structure, which comprises reacting a compound having an (E) -1-membered heterocyclic ring with a compound having an (E) -3, 6-anhydrohexofuranose structureOProtecting 5-site silyl ether of-methyl-D-arabinofuranose, wherein a reaction solvent is tetrahydrofuran, N-dimethylformamide, 1, 4-dioxane or acetonitrile, a reaction reagent is tert-butyldimethylchlorosilane, triphenylchlorosilane or trityldimethylchlorosilane, an alkali is imidazole or pyridine, the reaction temperature is-10-30 ℃, and the reaction time is 1-10 hours.
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