Method for stereoselectively synthesizing β-oxyglucoside by using 3-O-quinaldate enose donor

Abstract

A method for stereoselectively synthesizing β - oxygen glycosides based on 3 - O -quinolinate enose donors comprises the following steps: using 3 - O -quinolinate glucal as the enose donor, adding a catalyst, a ligand, triethylamine, a sugar acceptor and an organic solvent, stirring at 50 - 70 °C, monitoring the reaction progress by TLC. When the 3 - O -quinolinate glucal raw material completely disappears, terminate the reaction to obtain β - 2,3 - unsaturated oxygen glycoside. In the technical solution of the present invention, the quinolinate at the C - 3 position of the enose donor is a good leaving group and can easily form a π - allylpalladium intermediate under palladium catalysis. Subsequently, the acceptor attacks the anomeric carbon from the β - face to obtain a β - 2,3 - unsaturated glycoside oxygen product without the generation of rearrangement by - products. Triethylamine is added to the reaction system to make the reaction solution weakly alkaline, and the obtained β - 2,3 - unsaturated glycoside oxygen product is not easily hydrolyzed.

Description

Summary of the Invention

[0001] The present invention provides a method for stereoselectively synthesizing β-oxy-glycosides based on 3-O-quinaldate glycal donors, belonging to the technical field of organic synthesis. Background Art

[0002] Carbohydrate compounds not only serve as an energy source for human life activities but also play a crucial role in various life activities. They have extensive applications in the development of natural products and new drug research. Many glycoside compounds have important biological activities and medicinal values. For example, the O-glycoside compound ginsenoside CK has pharmacological effects of inhibiting the growth of tumor cells and inducing apoptosis of cancer cells; the main active ingredient of the traditional Chinese medicine Rhodiola rosea, salidroside, has effects such as enhancing human immunity and anti-fatigue.

[0003] The difference in the α,β-configurations of glycosidic bonds has a profound impact on the properties and biological functions of carbohydrate compounds. For example, cellulose and starch are polysaccharides composed of β-D-glucose residues and α-D-glucose residues linked by 1,4-bonds respectively. However, due to the different stereoconfigurations, the former is a structural component of wood, while the latter is a substance that provides energy for life activities in food. Therefore, in glycosylation reactions, stereoselectively constructing glycosidic bonds is crucial. However, the traditional glycosylation reaction has poor stereoselectivity and usually yields a mixture of diastereoisomers. Therefore, achieving efficient stereoselective synthesis of glycoside compounds still poses great challenges. Many sugar chemists at home and abroad have developed many highly efficient stereoselective glycosylation methods using various saturated sugars as glycal donors. Compared with saturated sugars, glycals have fewer protecting groups and are more convenient in the synthesis of glycal donors. However, due to the absence of the 2-position of the sugar ring, they cannot utilize the neighboring group participation effect to control stereoselectivity as well as saturated sugars. Before the development of transition metal-catalyzed glycosylation reactions, triacetylated glycals were usually used to synthesize α-configured glycosides through the Lewis acid-catalyzed Ferrier rearrangement reaction. However, this method is usually difficult to be used for synthesizing disaccharide substrates and has poor stereoselectivity, greatly limiting the application of glycosylation reactions. And there are also many difficulties in using glycal donors to synthesize β-configured glycoside compounds: the reaction activity of glycals is low, the required nucleophiles need to be softened by zinc reagents, there may be rearrangement by-products, and the reaction operation is complex, etc. Summary of the Invention

[0005] In view of the above technical problems, the present invention has developed a highly efficient glycosylation reaction with excellent β-stereoselectivity and a wide substrate scope using highly active 3-O-quinaldate glycal donors. The specific technical solutions are as follows:

[0006] A method for stereoselectively synthesizing β-oxygen glycosides based on 3-O-quinaldic acid ester glycal donors, comprising the following steps: Using 3-O-quinaldic acid ester glucal as a glycal donor, adding a catalyst, a ligand, triethylamine, a sugar acceptor and an organic solvent, stirring at 50-70 °C, monitoring the reaction progress by TLC, and terminating the reaction when the 3-O-quinaldic acid ester glucal raw material completely disappears, then β-2,3-unsaturated oxygen glycosides can be obtained. The reaction formula is as follows:

[0007]

[0008] The structural formula of the sugar acceptor is ROH, where the structural formula of R includes alkyl groups (methyl, ethyl, propyl, isopropyl, cyclohexyl, tert-butyl, etc.), monosaccharides (diacetone-D-galactose, diacetone-D-glucose, 2,3,4-tribenzyl-methyl-α-D-pyranose, etc.), amino acids (serine, etc.).

[0009] The molar ratio of 3-O-quinaldic acid ester glucal to the sugar acceptor is 1:1.0 - 3.0.

[0010] The PG includes any one of 4,6-O-p-methoxybenzylidene, 4,6-O-benzylidene, 4,6-O-cyclohexylidene, 4,6-O-isopropylidene, 4,6-O-di-tert-butylmethylsilylene, 4,6-O-dibenzyl, 4,6-O-di-p-methoxybenzyl.

[0011] The catalyst includes any one of Pd(PPh3)4, Pd2(dba)3, Pd(dba)2, Pd(OAc)2, Pd(acac)2, PdCl2, Pd(PPh3)2Cl2, Pd(MeCN)2Cl2, White catalyst, and the addition amount of the catalyst is 1 - 20% of the molar amount of 3-O-quinaldic acid ester glucal.

[0012] The ligand includes any one of xantphos, DPEPhos, DPPB, DPPE, DPPF, BINAP, dppbz, PPh3, P(OMe)3, X-Phos, S-Phos, JohnPhos, tBuXPhos, and the addition amount of the ligand is 5 - 30% of the molar amount of 3-O-quinaldic acid ester glucal.

[0013] The solvent includes any one of tetrahydrofuran, dichloromethane, 1,4-dioxane, toluene, acetonitrile, and the concentration of the glycal donor in the solvent is between 0.1M and 10.0M.

[0014] As a preferred scheme, the reaction temperature for synthesizing β-2,3-unsaturated oxygen glycosides is 60 °C.

[0015] In the technical solution of the present invention, the quinolinic acid ester at the C-3 position of the glycose donor is a good leaving group and can easily form a π-allylpalladium intermediate under palladium catalysis. Subsequently, the acceptor attacks the anomeric carbon from the β-face to obtain a β-2,3-unsaturated glycoside product, and there is no by-product of rearrangement. Triethylamine is added to the reaction system to make the reaction solution weakly basic, and the obtained β-2,3-unsaturated glycoside product is not easily hydrolyzed. Description of the Drawings

[0016] Figure 1 1H NMR spectrum of the compound prepared in Example 1.

[0017] Figure 2 13C NMR spectrum of the compound prepared in Example 1. Detailed Embodiments

[0018] The experimental reagents used in this example are as follows:

[0019] Tetrakis(triphenylphosphine)palladium (Jiangsu Xinnuoke Catalyst 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 Co., Switzerland); NMR tube (5 mm 100 / pk 2ST500-8, Norell Co., USA).

[0020] Experimental Instruments

[0021] ZXZ-4 rotary vane vacuum pump (Linhai Tanshi Vacuum Equipment Co., Ltd.), DZF-6020 vacuum drying oven (Shanghai Xinmiao Medical Instrument Manufacturing 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 Ailang 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 heating magnetic stirrer with heat collection and constant temperature (Yuhua Instrument Factory, Yingyu, Gongyi City), 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 400MHz Plus nuclear magnetic resonance spectrometer (Bruker Co., Switzerland), API 4000 LC-MS / MS mass spectrometer (Bruker Daltonics Co., Germany)

[0022] Example 1

[0023] Taking 3-O-quinaldate glucono-1,5-lactone as an example, optimization experimental schemes with different catalysts, ligands and solvents were adopted, which are specifically as follows:

[0024]

[0025]

[0026]

[0027] Note: All experiments were carried out with 0.1 mmol of 3-O-quinaldate glucono-1,5-lactone, 0.2 mmol of benzyl alcohol, 10 mol% Pd catalyst, 15 mol% phosphine ligand, 0.22 mmol of triethylamine stirred and reacted in 2 mL of solvent at 60 °C; separation yield; DPEPhos: bis(2-diphenylphosphino)phenyl ether, DPPB: 1,4-bis(diphenylphosphino)butane, DPPF: 1,1'-bis(diphenylphosphino)ferrocene, (R)-BINAP: R-(+)-1,1'-binaphthalene-2,2'-diphenylphosphine.

[0028] The technical solution of the present invention screened and optimized the reaction conditions. First, the influence of palladium catalysts on the reaction was explored (entries 1-7). All seven palladium catalysts could obtain the oxygen glycoside product mainly in the β configuration. The best one was Pd(PPh3)4, and the target product 2b was obtained with a yield of 75% and a stereoselectivity of β:α greater than 30:1 (entry 3). Then different phosphine ligands were screened. When (R)-BINAP was used, the target product 2b was obtained with a relatively high yield and selectivity (entry 19). Subsequently, the reaction solvent was screened. When acetonitrile was used, the yield of the reaction could be increased from 80% to 90%, and there was still excellent β stereoselectivity (entry 23). When N,N-dimethylformamide was used, no product was detected. When isobutyronitrile was used as the solvent, the stereoselectivity and yield of the reaction were not high. Finally, the optimal reaction conditions for synthesizing β-2,3-unsaturated oxygen glycosides were determined as follows: Pd(PPh3)4 as the catalyst, (R)-BINAP as the ligand, reacting in acetonitrile at 60 °C for 24 hours, with a yield of 90%; Summarizing the experimental results, the optimal conditions for synthesizing α-2,3-unsaturated oxygen glycosides based on 3-O-quinaldate glucono-1,5-lactone donor were: Pd(PPh3)4 as the catalyst, (R)-BINAP as the ligand, reacting in acetonitrile at 60 °C for 24 hours, the stereoselectivity of the product was β:α greater than 30:1, and the yield was 90%.

[0029] In the case of the above route, the present invention also prepared β-benzyl-2,3-unsaturated oxygen glycosides using 3-O-quinaldate gluconoenose as a raw material, and the technical route is as follows:

[0030]

[0031] Add 3-O-quinaldate gluconoenose (0.1 mmol, 41.9 mg), sugar acceptor (benzyl alcohol) (0.2 mmol, 21.6 mg), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 11.6 mg, 0.01 mmol), and R-(+)-1,1'-binaphthalene-2,2'-diphenylphosphine ((R)-BINAP, 9.3 mg, 0.015 mmol) to 2 mL of acetonitrile, stir at 60 °C, monitor the reaction progress by TLC. After the enose raw material has completely reacted, quench the reaction, extract and collect the organic phase, remove the solvent by distillation under reduced pressure to obtain the crude product, and then perform column chromatography using a petroleum ether / ethyl acetate solution as the mobile phase to obtain β-benzyl-2,3-unsaturated oxygen glycoside (yield: 90%).

[0032] Substrate scope

[0033] The preparation of β-2,3-unsaturated gluconoenose oxygen glycoside substrates refers to the conditions of Example 1.

[0034]

[0035]

[0036] Spectral data

[0037] Benzyl 2,3-dideoxy-4,6-O-(p-methoxybenzylidene)-β-D-erythro-hex-2-enopyranoside

[0038]

[0039] 11H NMR (400 MHz, CDCl3) δ 7.47 - 7.40 (m, 2H), 7.40 - 7.27 (m, 5H), 6.98 - 6.78 (m, 2H), 6.16 (d, J = 10.3 Hz, 1H), 5.73 (ddd, J = 10.3, 2.6, 1.5 Hz, 1H), 5.59 (s, 1H), 5.49 - 5.41 (m, 1H), 4.86 (d, J = 11.7 Hz, 1H), 4.65 (d, J = 11.7 Hz, 1H), 4.39 - 4.34 (m, 1H), 4.32 (dd, J = 10.2, 4.5 Hz, 1H), 3.90 (t, J = 10.3 Hz, 1H), 3.81 (s, 4H).; 13 13C NMR (100 MHz, CDCl3) δ 160.1, 137.3, 131.5, 129.8, 128.4, 128.2, 127.9, 127.8, 127.5, 113.7, 102.0, 97.7, 75.0, 70.5, 69.4, 69.0, 55.3.

Claims

1. A method for stereoselectively synthesizing β-glycosides based on 3- O quinolinic acid ester glycal donors, characterized in that, The reaction equation is as follows: Dissolve 0.1 mmol of 3- O -quinolinate glucoenose, 0.2 mmol of the sugar receptor benzyl alcohol, 0.01 mmol of tetrakis(triphenylphosphine)palladium, R 0.015 mmol of (-)-(+)-1,1'-binaphthalene-2,2'-diphenylphosphine, and 0.22 mmol of triethylamine in 2 mL of acetonitrile, stir at 60 °C, monitor the reaction progress by TLC. After the glucoenose raw material has completely reacted, quench the reaction, extract and collect the organic phase, remove the solvent by distillation under reduced pressure to obtain the crude product, and then perform column chromatography using a petroleum ether / ethyl acetate solution as the mobile phase to obtain β-benzyl-2,3-unsaturated oxygen glycoside.

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