Synthetic method of a (3R)-3-thiosaccharide

Abstract

The present invention provides a method for synthesizing (3 R )-3-thiosugar. 6-phosphonate-3,4- O -carbonate galactal, a thiol nucleophile, a catalyst, a ligand, and zinc powder are added to an organic solvent, and the reaction is carried out under stirring. The reaction process is monitored by TLC. When the starting material spot of 6-phosphonate-3,4- O -carbonate galactal disappears, the reaction is stopped. After extraction, vacuum distillation, and column chromatography, (3 R )-3-thiosugar is obtained. The present invention uses a nickel metal catalyst to form a metal complex and introduces a phosphonate as a directing group, which can synthesize (3 R )-3-thiosugar with high selectivity.

Description

Technical Field

[0001] The present method relates to a method for synthesizing (3R)-3-thiosugar, belonging to the technical field of organic synthesis. Technical Background

[0002] Carbohydrate compounds are important energy sources in living organisms and are involved in numerous life activities. Thiosaccharide substances play an even more crucial role, having very positive significance both in the biological field and the chemical field. Some natural thiosaccharide substances themselves serve as surface substances on the cell surface that can be recognized by antigens and play important roles in enzymatic reactions. In the chemical field, as analogs of numerous natural oxosugars, natural products modified with thiosugars not only retain the biological activity and pharmaceutical activity of oxosugars but also, to a certain extent, improve chemical stability compared to natural oxosugars and are more stable under enzymatic hydrolysis. In addition, some thiosaccharide structures are already well-established commercially available drugs, such as clindamycin, auranofin, etc., which play important roles in the fields of anti-inflammation and anti-rheumatism. However, the significance of thiosaccharides is not limited to this. For example, after replacing β-1,3-gluco-oligosaccharide with thio-β-1,3-gluco-oligosaccharide, its immunomodulatory and anti-tumor activities are significantly improved. In addition, some active molecules of thiosaccharides are being further developed and have attracted attention in multiple fields such as antioxidant and anti-cancer.

[0003] Compared with oxosugars that are widely present and applied, the synthesis methods of thiosugars are relatively few. The highly regioselective and highly stereoselective synthesis of thiosaccharide compounds at the 1-position and 3-position is particularly important. Generally, in the synthesis of glycoside compounds, glycosyl donors, solvents, ligand catalysts, directing groups, etc. play crucial roles in the glycosylation reaction. The present invention is committed to developing a method for obtaining R-type thiosugar at the 3-position with regioselectivity and stereoselectivity by using galactalene sugar with a phosphonate group introduced at the C6 position as a directing group and catalyzed by a nickel catalyst. Summary of the Invention

[0004] 6-phosphonate-3,4-O-carbonate galactalene sugar, a thiol nucleophile, a catalyst, a ligand, and zinc powder are added to an organic solvent and stirred at 80 - 100 °C, and the reaction process is detected by TLC. When the raw material spot of 6-phosphonate-3,4-O-carbonate galactalene sugar disappears, the reaction is stopped, the reaction solution is extracted, the organic phases are collected and combined, the solvent is removed by distillation under reduced pressure to obtain a crude product, and the crude product is column chromatographed using petroleum ether / ethyl acetate / dichloromethane as the mobile phase to obtain (3R)-3-thiosugar.

[0005] The thiol nucleophile described above includes any one of benzenethiol, pyridinethiol, and thiophene thiol.

[0006] The mercapto nucleophile also includes any one of substituted benzenethiol, substituted pyridinethiol, and substituted thiophenethiol.

[0007] The substituent is a substituent on phenyl, pyridyl, or thiophenyl, including any one of C1-C4 alkyl, methoxy, ethoxy, fluorine, chlorine, and bromine; the position of the substituent on phenyl, pyridyl, or thiophenyl is not fixed.

[0008] The catalyst includes any one of NiBr2, NiCl2, Ni(cod)2, and Ni[P(Cy)3]2Cl2.

[0009] The ligand includes any one of PPh3, xantphos, DPPB, DPPP, and DPPF.

[0010] The solvent is acetonitrile.

[0011] The input ratio of 6-phosphonate-3,4-O-carbonate galactal, mercapto nucleophile, catalyst, zinc powder, and ligand is 1:(1.0-1.1):(0.1-0.15):(0.1-0.15):(0.2-0.3).

[0012] The reaction temperature is 80-100 °C.

[0013] The (3R)-3-thiosugar obtained after extraction, vacuum distillation, and column chromatography in the present invention refers to the post-treatment using the extraction process, conventional vacuum distillation method, and conventional column chromatography well-known to those skilled in the art.

[0014] The core key step of the present invention uses a nickel metal catalyst to form a metal complex and introduces a phosphonate as a directing group, which can synthesize (3R)-3-thiosugar with high selectivity. The high selectivity refers to obtaining a product with a unique stereoselectivity. The yield of the (3R)-3-thiosugar is higher than 45%, further preferably the selectivity is higher than 50%, further preferably the selectivity is higher than 55%, further preferably the selectivity is higher than 60%, further preferably the selectivity is higher than 65%, and further preferably the selectivity is higher than 70%. Description of the Drawings

[0015] Figure 1 1H NMR spectrum of p-toluenethiol (3R)-3-thiosugar 1 H NMR spectrum.

[0016] Figure 2 13C NMR spectrum of p-toluenethiol (3R)-3-thiosugar 13 C NMR spectrum. Detailed Embodiments

[0017] The reagents used in this embodiment are as follows:

[0018] Dichloromethane (analytical grade, Tianjin Kemiou Chemical Reagent Co., Ltd.), petroleum ether (boiling range 60 - 90 °C, Tianjin Hengxing Chemical Reagent Manufacturing Co., Ltd.), ethyl acetate (analytical grade, Tianjin Kemiou Chemical Reagent Co., Ltd.), anhydrous sodium sulfate (analytical grade, Sinopharm Chemical Reagent Co., Ltd.), deuterated chloroform (deuterium atom content 99.8%, TMS content 0.03% V / V, 10 * 0.5 mL / box, ARMAR Company, Switzerland); NMR tube (5 mm 100 / pk 2ST500 - 8, Norell Company, USA).

[0019] The experimental instruments used in this embodiment are as follows:

[0020] ZXZ - 4 rotary vane vacuum pump (Linhai Tanshi Vacuum Equipment Co., Ltd.), SHB - IIIA circulating water multi - purpose vacuum pump (Shanghai Yukang Scientific and Educational Instrument Equipment Co., Ltd.), CL - 4 flat magnetic stirrer (Zhengzhou Great Wall Scientific and Industrial Co., Ltd.), EYELA SB - 1100 rotary evaporator (Shanghai Ailan Instrument Co., Ltd.), FA2104B analytical balance (Shanghai Yueping Scientific Instrument Co., Ltd.), XRC - 1 micro melting point detector (Sichuan University Scientific Instrument Factory), DF - 101S collecting - type constant temperature heating magnetic stirrer (Gongyi Yingyu Yuhua Instrument Factory), GZX - 9240MBE digital display forced - air drying oven (Shanghai Boxun Industry Co., Ltd., Medical Equipment Factory), ZF - 6 three - purpose ultraviolet analyzer (Shanghai Jiapeng Technology Co., Ltd.), Ultrashied 400MHzPlus nuclear magnetic resonance spectrometer (Bruker Company, Switzerland).

[0021] Example 1

[0022] The method for preparing (3R) - 3 - thioglycoside using 6 - phosphonate - 3,4 - O - carbonate galactal as a raw material is as follows:

[0023]

[0024] Mix 6 - phosphonate - 3,4 - O - carbonate galactal, NiBr2, xantphos and zinc powder, and use dichloromethane as the solvent. Stir at 35 °C, and detect the reaction process by TLC. Stop the reaction when the raw material spot of 6 - phosphonate - 3,4 - O - carbonate galactal disappears. Extract the reaction solution, collect and combine the organic phase, and remove the solvent by vacuum distillation to obtain a crude product. The crude product is subjected to column chromatography using petroleum ether / ethyl acetate / dichloromethane as the mobile phase to obtain (3R) - 3 - thioglycoside. The (3R) - 3 - thioglycoside is the only stereoselective product, and the following (3R) - 3 - thioglycoside substrate compound products are also the only stereoselective products.

[0025] Taking the process and conditions of Example 1 as the conditions for the following examples, the synthesis preparations of different substrates were screened, and the substrate ranges and yields of the fifth were as follows:

[0026] (3R)-3-Thiosugar substrate ranges and yields are as follows:

[0027]

[0028] Nuclear magnetic resonance spectroscopy data

[0029] ((2R,3S)-3-hydroxy-4-(p-tolylthio)-3,4-dihydro-2H-pyran-2-yl)methyldiphenylphosphinate

[0030]

[0031] 1 H NMR(400 MHz,CDCl3)δ7.87–7.76(m,2H),7.79–7.68(m,2H),7.61–7.50(m,2H),7.52–7.39(m,4H),7.28–7.24(m,2H),7.05–6.98(m,2H),6.50(d,J=5.9 Hz,1H),4.92(dd,J=7.5,5.4 Hz,1H),4.57–4.48(m,1H),4.28(dd,J=10.1,2.5 Hz,1H),4.16(dd,J=10.5,2.6 Hz,1H),4.06–4.00(m,1H),3.71(s,1H),3.66(dd,J=5.4,1.6 Hz,1H),2.30(s,3H).

[0032] 13 C NMR(100 MHz,CDCl3)δ145.4,137.7,132.6(d,J C-P =2.8 Hz),132.5(d,J C-P =2.8 Hz),132.4,131.9(d,J C-P =10.2 Hz),131.4(d,J C-P =10.4 Hz),131.1(d,J C-P =47.5Hz),130.2,129.9,129.8(d,J C-P =42.0 Hz),128.8(d,J C-P =13.0 Hz),128.6(d,J C-P= 13.4 Hz), 98.1, 71.2 (d, J C-P = 5.6 Hz), 65.5, 62.7 (d, J C-P = 5.7 Hz), 45.0, 21.1。

Claims

1. A method for synthesizing a (3 R )-3-thiosaccharide, characterized in that It includes the following steps: 6-Phosphonate-3,4- O -carbonate galactal, a thiol nucleophile, a catalyst, a ligand and zinc powder are added to an organic solvent, and the reaction is carried out under stirring. The reaction process is monitored by TLC. When the starting material spot of 6-phosphonate-3,4- O -carbonate galactal disappears, the reaction is stopped. After extraction, distillation under reduced pressure and column chromatography, (3 R )-3-thiosugar is obtained. The catalyst is any one of NiBr2, NiCl2, Ni(cod)2, Ni[P(Cy)3]2Cl2. The thiol nucleophile is any one of benzenethiol, pyridinethiol, thiophenethiol. The ligand is any one of PPh3, xantphos, DPPB, DPPP, DPPF.

2. The synthesis method of the (3 R )-3-thiosugar according to claim 1, characterized in that The mercapto nucleophile is also any one of substituted benzenethiol, substituted pyridinethiol, and substituted thiophenethiol. The substituent is a substituent on phenyl, pyridyl, or thiophenyl, and is any one of C1-C4 alkyl, methoxy, ethoxy, fluorine, chlorine, and bromine; the position of the substituent on phenyl, pyridyl, or thiophenyl is not fixed.

3. The synthesis method of the (3 R )-3-thiosugar according to claim 1, characterized in that The solvent is any one of acetonitrile, toluene, and tetrahydrofuran.

4. The synthesis method of the (3 R )-3-thiosugar according to claim 1, characterized in that 6-Phosphonate-3,4- O The input ratio of -carbonate galactoenose, thiol nucleophile, catalyst, zinc powder and ligand is 1:(1.0 - 1.1):(0.1 - 0.15):(0.1 - 0.15):(0.2 - 0.3).

5. The synthesis method of the (3 R )-3-thiosaccharide according to claim 1, characterized in that The reaction temperature is 80-100 °C.

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