Synthesis method of glucoside containing chiral quaternary carbon

Abstract

The invention discloses a synthesis method of chiral quaternary carbon glucoside, and belongs to the technical field of organic synthesis. The method disclosed by the invention comprises the following steps: a coupling reagent (aryl bromide, alkenyl bromide, alkynyl bromide, electron-deficient olefin and the like) and glucoside are fully reacted under the irradiation of purple light through catalysis of a photocatalyst or catalysis of the photocatalyst with one or more of a metal catalyst, a ligand and alkali, and the functionalized chiral quaternary carbon-containing glucoside is obtained. According to the invention, synthesis of the glucoside compound containing the chiral quaternary carbon center is realized by utilizing a light / metal concerted catalysis strategy. The method not only is mild in condition and wide in substrate adaptability, but also has the advantages of low cost, high atom utilization rate and economical steps due to the fact that simple and stable glucoside is directly used as a raw material. Through subsequent conversion, synthesis of an anti-cancer drug acetylcholine analogue can also be realized by containing chiral quaternary carbon glycoside, and the chiral quaternary carbon glycoside has a huge synthesis value.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing chiral quaternary carbon glycosides. Background Art

[0002] In the field of modern chemistry, chiral quaternary carbon glycosides have attracted much attention due to their unique structure and wide range of biological activities. The construction of chiral quaternary carbon centers has always been one of the important challenges in organic synthesis, and combining them with glycoside structures with important physiological activities provides broad prospects for the development of new drugs and bioactive molecules. At present, traditional methods for synthesizing chiral quaternary carbon glycosides have many limitations. Some methods have harsh reaction conditions and require high temperature, high pressure or highly corrosive reagents, which not only have high requirements on equipment, but also increase the danger of operation. In addition, the yield of existing methods is often low, and the optical purity of the product is difficult to guarantee, which brings difficulties to subsequent applications. At the same time, the synthesis steps are cumbersome and complicated, involving multiple reaction steps and cumbersome separation and purification processes, resulting in low overall yield and time-consuming and labor-intensive. In order to overcome these problems, it is urgent to develop a new method for synthesizing chiral quaternary carbon glycosides with the advantages of mild reaction conditions, high yield, good optical purity and simple operation to meet the needs of scientific research and industrial production. Summary of the invention

[0003] The object of the present invention is to overcome the shortcomings and deficiencies of the prior art and provide a method for synthesizing chiral quaternary carbon glycosides. The present invention provides a unique solution to the cutting-edge scientific problem of efficient synthesis of chiral quaternary carbon glycosides by exploring and discovering a light / metal coordinated catalytic strategy to site-selectively activate glycoside CH bonds. The method uses aryl bromides, alkenyl bromides, alkynyl bromides, electron-deficient olefins A and glycoside B as raw materials, and directly breaks the carbon-hydrogen bonds of glycoside B to produce glycoside free radicals by using a visible light-promoted hydrogen atom transfer (HAT) process, and then couples with aryl bromides, alkenyl bromides, alkynyl bromides and electron-deficient olefins A under the coordinated catalysis of a metal catalyst to obtain compounds containing chiral quaternary carbon glycosides. The present invention uses a light / metal coordinated catalytic strategy to achieve stereoselective arylation, alkenylation, alkynylation and alkylation of carbon-hydrogen bonds of glycoside B. Through subsequent transformation, chiral quaternary carbon glycosides can also be used to synthesize anticancer drug acetylcholine analogs, which has great synthetic value.

[0004] The purpose of the present invention is achieved through the following technical solutions:

[0005] A method for synthesizing chiral quaternary carbon glycosides comprises the following steps: coupling reagent A and glycoside B react completely under irradiation of ultraviolet light by means of a photocatalyst or a photocatalyst and one or more of a metal catalyst, a ligand, and a base, to obtain a functionalized chiral quaternary carbon glycoside C. The coupling reagent A preferably comprises aryl bromide, alkenyl bromide, alkynyl bromide, electron-deficient olefin, etc., and the corresponding functionalization comprises arylation, alkenylation, alkynylation, alkylation, etc. When the coupling reagent A is an aryl bromide, the aryl bromide and glycoside B need to be catalyzed by a photocatalyst, a metal catalyst, a ligand and a base, and can react completely under ultraviolet light; when the coupling reagent A is an alkenyl bromide, the alkenyl bromide and glycoside B need to be catalyzed by a photocatalyst, a metal catalyst and a base, and can react completely under ultraviolet light; when the coupling reagent A is an alkynyl bromide, the alkynyl bromide and glycoside B need to be catalyzed by a photocatalyst and a base, and can react completely under ultraviolet light; when the coupling reagent A is an electron-deficient olefin, the electron-deficient olefin and glycoside B only need to be catalyzed by a photocatalyst, and can react completely under ultraviolet light. The ultraviolet light is preferably 390nm ultraviolet light, and the reaction conditions are preferably 25°C for 48-60 hours.

[0006] Furthermore, the synthesis method containing chiral quaternary carbon glycoside comprises the following steps: under the protection of inert gas, coupling reagent A, glycoside B and photocatalyst or photocatalyst and one or more of metal catalyst, ligand, photocatalyst and base are added to a solvent, and the reaction is completed under ultraviolet light irradiation to obtain functionalized chiral quaternary carbon glycoside C.

[0007] Preferably, the aryl bromide, alkenyl bromide, alkynyl bromide, and electron-deficient olefin are selected from the following structures:

[0008]

[0009] Preferably, the glycoside B is selected from the following structures:

[0010]

[0011] Preferably, the metal catalyst includes a mixture of one or more of nickel chloride, nickel bromide, nickel chloride dimethyl ether, nickel bromide dimethyl ether, cyclooctadiene nickel, nickel acetylacetonate, nickel perchlorate, nickel iodide, nickel acetate tetrahydrate and ferric dibromide, and is more preferably nickel bromide dimethyl ether or ferric dibromide.

[0012] Preferably, the ligand is selected from the following structures, and D or E is more preferably selected.

[0013]

[0014] Preferably, the photocatalyst is selected from F(TBADT) or G of the following structures.

[0015]

[0016] Preferably, the base includes a mixture of one or more of sodium carbonate, potassium carbonate, potassium phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, sodium bicarbonate, lithium carbonate, cesium carbonate, sodium phosphate and sodium acetate, and more preferably potassium phosphate.

[0017] Preferably, the solvent includes but is not limited to a mixed solvent consisting of one or more of acetonitrile, acetone, water and dimethyl sulfoxide.

[0018] Preferably, when the coupling reagent A is an aryl bromide, the molar ratio of the aryl bromide, glycoside B, metal catalyst, ligand, photocatalyst and base is 1:5:0.1:0.15:0.02:1.2; when the coupling reagent A is an alkenyl bromide, the molar ratio of the alkenyl bromide, glycoside B, metal catalyst, photocatalyst and base is 1:5:0.1:0.02:1.2; when the coupling reagent A is an alkynyl bromide, the molar ratio of the alkynyl bromide, glycoside B, photocatalyst and base is 1:5-10:0.02:0.25; when the coupling reagent A is an electron-deficient olefin, the molar ratio of the electron-deficient olefin, glycoside B, photocatalyst and base is 1:2:0.02; wherein the concentration of the coupling reagent A is 0.1-0.2 mol / L.

[0019] Advantages and beneficial effects of the present invention: The present invention provides a method of directly breaking the carbon-hydrogen bond of glycosides to achieve enantioselective arylation, olefination, alkynylation and alkylation by utilizing photo-promoted hydrogen atom transfer and metal coordinated catalysis strategies, and prepare a series of chiral quaternary carbon glycoside compounds. The method directly uses simple and stable glycosides as raw materials, avoids the use of precious metal catalysts and equivalent redox reagents, and greatly reduces the cost of synthesis. In addition, the method of the present invention has mild reaction conditions, good functional group tolerance, and a wide range of substrate applications. It also has the advantages of low cost, high atom utilization, and step economy. It is an efficient, green, and inexpensive method for synthesizing chiral quaternary carbon glycosides. DETAILED DESCRIPTION

[0020] The following examples will help to understand the present invention, but they are not intended to limit the present invention.

[0021] Example 1

[0022]

[0023] In an inert (argon) atmosphere, nickel bromide glycol dimethyl ether (6.6 mg, 0.02 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine D (8.4 mg, 0.03 mmol), p-bromoacetophenone (39.9 mg, 0.2 mmol), glycoside S1 (158.3 mg, 1.0 mmol), tetrabutylammonium decaprolactone F (13.4 mg, 0.004 mmol), potassium phosphate (51.2 mg, 0.24 mmol), and anhydrous acetonitrile (2.0 mL) were added to a transparent reaction tube equipped with a magnetic electron. The mixture was reacted at 25°C for 60 hours under irradiation with a violet lamp (10 W, 390 nm), concentrated, and subjected to rapid column chromatography to obtain a white solid product 1 (37.1 mg, 67% yield, dr>20 / 1, rr=7 / 1).

[0024] 1 H NMR (600MHz, CDCl3) δ7.99–7.93(m,2H),7.64–7.53(m,2H),4.44(d,J=2.2Hz,1H),4.33(qd,J=6.8,2.1Hz,1H) ,4.07(d,J=10.1Hz,1H),3.88(d,J=10.1Hz,1H),2.60(s,3H),1.63(s,3H),1.40(d,J=6.8Hz,3H),1.27(s,3H); 13 C NMR (151MHz, CDCl3) δ197.6,147.8,136.3,128.5,125.1,114.4,93.2,93.0,82.2,79.3,27.6,26.9,26.6,17.4; HRMS: (ESI)calcd for C 16 H 21 O4 + [M+H] + 277.1434; found 277.1435.

[0025] Example 2

[0026]

[0027] In an inert (argon) atmosphere, 1-(bromoethynyl)-4-(methylsulfonyl)benzene (51.2 mg, 0.2 mmol), glycoside S2 (588.2 mg, 2.0 mmol, α / β=1 / 1.66), tetrabutylammonium decaprolactone F (13.4 mg, 0.004 mmol), potassium phosphate (106.7 mg, 0.5 mmol), and anhydrous acetonitrile (2.0 mL) were added to a transparent reaction tube equipped with a magnetic electron. The mixture was reacted at 25°C for 60 hours under irradiation with a violet lamp (10 W, 390 nm), concentrated, and subjected to rapid column chromatography to obtain a colorless oily product 2 (53.8 mg, 57% yield, α / β=1 / 1).

[0028] 1 H NMR (600MHz, CDCl3) δ8.06(d,J=7.5Hz,2H),8.03(d,J=7.6Hz,2H),7.88(d,J=8.3Hz,2H),7.80(d,J=8.3Hz,2H),7.59(d,J=8.3Hz,2H),7.54 (t,J=7.4Hz,1H),7.44(t,J=7.4Hz,1H),7.38(t,J=7.7Hz,2H),7.33(d,J=8.3Hz,2H),7.25(d,J=7.8Hz,2H),5.63(d,J=11.3Hz,1H,anomeric H),5.46(d,J=5.2Hz,1H,anomeric H),4.96(s,1H),4.94(s,1H),4.76–4.66(m,2H),4.51(t,J=5.9Hz,1H),4.45(dd,J=11.7,5.7Hz,2H),4.41(dd,J=12.0,3.7Hz,1 H),3.91(d,J=11.3Hz,1H),3.48(d,J=5.3Hz,1H),3.05(s,3H),3.05(s,3H),1.62(s,3H),1.60(s,3H),1.58(s,3H),1.56(s,3H); 13C NMR (151MHz, CDCl3) δ166.4,166.2,140.5,140.4,133.4,133.3,132.7,132. 6,129.80,129.77,129.5,129.3,128.52,128.45,127.7,127.4,127.2,127.1 ,115.9,115.1,103.5,102.0,90.1,89.5,88.7,88.2,87.6,86.9,85.4,84.3, 82.2,79.6,65.4,65.1,44.5,44.4,27.0,26.4,26.1,25.3; HRMS: (ESI)calcd for C 24 H 25 8S + [M+H] + 473.1265; found 473.1262.

[0029] Example 3

[0030]

[0031] In an inert (argon) atmosphere, nickel bromide glycol dimethyl ether (3.2 mg, 0.01 mmol), 4,4'-di-tert-butyl-2,2'-bipyridyl D (4.2 mg, 0.015 mmol), 1-bromo-4-(methylsulfonyl)benzene (23.3 mg, 0.1 mmol), glycoside S4 (216.1 mg, 0.5 mmol), tetrabutylammonium decaprolactone F (6.8 mg, 0.002 mmol), potassium phosphate (25.3 mg, 0.12 mmol), and anhydrous acetonitrile (1.0 mL) were added to a transparent reaction tube equipped with a magnetic electron. The mixture was reacted at 25°C for 60 hours under irradiation with a violet lamp (10 W, 390 nm), concentrated, and subjected to rapid column chromatography to obtain a colorless oily product 3 (46.9 mg, 80% yield, dr>20 / 1, rr>20 / 1).

[0032] 1 H NMR (600MHz, CDCl3) δ7.64(t,J=7.3Hz,8H),7.57(d,J=8.4Hz,2H),7.48(t,J=7.4Hz,3H),7.41(t,J=7.5Hz, 6H),4.96(d,J=2.4Hz,1H),4.26(q,J=3.6Hz,1H),4.15–4.03(m,4H),2.98(s,3H),1.63(s,3H),1.31(s,3H); 13C NMR (151MHz, CDCl3) δ148.3,139.4,135.5,133.1,130.4,128.1,127.2,126.3,114.7,93.2,89.4,86.6,81.1,64.6,44.4,27.7,27.5; HRMS: (ESI)calcd for C 33 H 35 6SSi + [M+H] + 587.1918; found 587.1923.

[0033] Example 4

[0034]

[0035] In an inert (argon) atmosphere, nickel bromide glycol dimethyl ether (6.6 mg, 0.02 mmol), 4,4'-di-tert-butyl-2,2'-bipyridyl D (8.4 mg, 0.03 mmol), p-bromoacetophenone (39.9 mg, 0.2 mmol), glycoside S5 (216.1 mg, 1.0 mmol), tetrabutylammonium decaprolactone F (13.4 mg, 0.004 mmol), potassium phosphate (51.2 mg, 0.24 mmol), and anhydrous acetonitrile (2.0 mL) were added to a transparent reaction tube equipped with a magnetic electron. The mixture was reacted at 25°C for 60 hours under irradiation with a violet lamp (10 W, 390 nm), concentrated, and subjected to rapid column chromatography to obtain a colorless oily product 4 (50.8 mg, 76% yield, dr>20 / 1, rr=10 / 1).

[0036] 1 H NMR (600MHz, CDCl3) δ7.98–7.94(m,2H),7.64–7.59(m,2H),4.71(d,J=2.4Hz,1H),4.38(td,J=5.4,4.9,2.4Hz,1H),4 .34–4.33(m,2H),4.15(d,J=10.2Hz,1H),3.98(d,J=10.1Hz,1H),2.61(s,3H),2.11(s,3H),1.64(s,3H),1.31(s,3H); 13 C NMR (151MHz, CDCl3) δ197.5,170.6,146.9,136.5,128.5,125.2,114.9,93.1,89.0,83.9,80.2,63.1,27.7,27.2,26.6,20.8; HRMS: (ESI)calcd for C 18 H 23 O6+ [M+H] + 335.1495; found 335.1492.

[0037] Example 5

[0038]

[0039] In an inert (argon) atmosphere, nickel bromide glycol dimethyl ether (6.6 mg, 0.02 mmol), 4,4'-di-tert-butyl-2,2'-bipyridyl D (8.4 mg, 0.03 mmol), p-bromoacetophenone (39.9 mg, 0.2 mmol), glycoside S3 (216.1 mg, 1.0 mmol), tetrabutylammonium decaprolactone F (13.4 mg, 0.004 mmol), potassium phosphate (51.2 mg, 0.24 mmol), and anhydrous acetonitrile (2.0 mL) were added to a transparent reaction tube equipped with a magnetic electron. The mixture was reacted at 25°C for 60 hours under irradiation with a violet lamp (10 W, 390 nm), concentrated, and subjected to rapid column chromatography to obtain a colorless oily product 5 (40.9 mg, 70% yield, dr>20 / 1, rr=10 / 1).

[0040] 1 H NMR (600MHz, CDCl3) δ7.94(d,J=8.4Hz,2H),7.63(d,J=8.4Hz,2H),4.79(d,J=2.7Hz,1H),4.25(td,J=5.1,2.7Hz,1H), 4.16(d,J=10.0Hz,1H),4.00(d,J=10.0Hz,1H),3.92–3.88(m,1H),2.60(s,3H),2.07(s,1H),1.64(s,3H),1.30(s,3H); 13 C NMR (151MHz, CDCl3) δ197.7,147.3,136.4,128.5,125.3,114.7,93.2,88.8,86.6,80.4,62.4,27.8,27.3,26.6; HRMS: (ESI)calcd for C 16 H 21 O5 + [M+H] + 293.1384; found 293.1381.

[0041] Example 6

[0042]

[0043] In an inert (argon) atmosphere, nickel bromide glycol dimethyl ether (6.2 mg, 0.02 mmol), 4,4'-di-tert-butyl-2,2'-bipyridyl D (8.1 mg, 0.03 mmol), p-bromoacetophenone (39.8 mg, 0.2 mmol), glycoside S6 (302.1 mg, 1.0 mmol), tetrabutylammonium decaprolactone F (13.4 mg, 0.004 mmol), potassium phosphate (51.2 mg, 0.24 mmol), and anhydrous acetonitrile (2.0 mL) were added to a transparent reaction tube equipped with a magnetic electron. The mixture was reacted at 25°C for 60 hours under irradiation with a violet lamp (10 W, 390 nm), concentrated, and subjected to rapid column chromatography to obtain a colorless oily product 6 (54.6 mg, 65% yield, dr>20 / 1, rr=9 / 1).

[0044] 1 H NMR (600MHz, CDCl3) δ8.00–7.97(m,2H),7.61–7.57(m,2H),6.44(s,1H),4.59(s,1H),4.36(td,J=6.3,3.7Hz,1H),4.15(d,J=8.0Hz,1 H),3.97(dd,J=8.4,6.2Hz,1H),3.00(t,J=8.3Hz,1H),2.61(s,3H),2.22(s,3H),1.60(s,3H),1.34(s,3H),1.28(s,3H),1.26(s,3H); 13 CNMR (151MHz, CDCl3) δ197.4,168.8,146.2,136.8,128.7,125.4,114.6,109.4,100. 3,93.4,92.0,91.5,75.7,65.0,26.7,26.7,26.5,26.4,25.5,21.3; HRMS: (ESI)calcd for C 22 H 32 O8N + [M+NH4] + 438.2122; found 438.2115.

[0045] Example 7

[0046]

[0047] In an inert (argon) atmosphere, nickel bromide glycol dimethyl ether (6.2 mg, 0.02 mmol), 4,4'-di-tert-butyl-2,2'-bipyridyl D (8.3 mg, 0.03 mmol), p-bromoacetophenone (39.8 mg, 0.2 mmol), glycoside S7 (302.1 mg, 1.0 mmol), tetrabutylammonium decaprolactone F (13.4 mg, 0.004 mmol), potassium phosphate (51.2 mg, 0.24 mmol), and anhydrous acetonitrile (2.0 mL) were added to a transparent reaction tube equipped with a magnetic electron. The mixture was reacted at 25°C for 60 hours under irradiation with a violet lamp (10 W, 390 nm), concentrated, and subjected to rapid column chromatography to obtain a white solid product 7 (47.9 mg, 57% yield, dr>20 / 1, rr=10 / 1).

[0048] 1 H NMR (600MHz, CDCl3) δ7.97–7.94(m,2H),7.63–7.58(m,2H),6.30(s,1H),4.68(s,1H),4.36(td,J=6.3,3.7Hz,1H),4.15(d,J=6.6Hz,1H ),4.07(dd,J=9.0,3.7Hz,1H),4.03(dd,J=9.0,6.1Hz,1H),2.60(s,3H),2.22(s,3H),1.60(s,3H),1.22(d,J=8.6Hz,6H),0.85(s,3H); 13 C NMR (151MHz, CDCl3) δ197.6,169.1,146.9,136.3,128.3,125.7,114.2,109.0,100.0 ,92.7,92.2,88.9,73.5,66.3,26.7,26.6,26.3,26.1,25.3,21.3; HRMS: (ESI)calcd for C 22 H 32 O8N + [M+NH4] + 438.2122; found 438.2113.

[0049] Example 8

[0050]

[0051] In an inert (argon) atmosphere, nickel bromide glycol dimethyl ether (6.4 mg, 0.02 mmol), 4,4'-di-tert-butyl-2,2'-bipyridyl D (8.0 mg, 0.03 mmol), p-bromoacetophenone (40.0 mg, 0.2 mmol), glycoside S8 (230.0 mg, 1.0 mmol), tetrabutylammonium decaprolactone F (13.3 mg, 0.004 mmol), potassium phosphate (51.2 mg, 0.24 mmol), and anhydrous acetonitrile (2.0 mL) were added to a transparent reaction tube equipped with a magnetic electron. The mixture was reacted at 25°C for 60 hours under irradiation with a violet lamp (10 W, 390 nm), concentrated, and subjected to rapid column chromatography to obtain a white solid product 8 (35.5 mg, 51% yield, dr>20 / 1, rr>20 / 1).

[0052] 1 H NMR (600MHz, CDCl3) δ7.98–7.94(m,2H),7.73–7.68(m,2H),5.65(d,J=5.1Hz,1H),4.63(d,J=2.5Hz,1H),4.48(dd,J=5.1,2 .5Hz,1H),3.64(d,J=12.7Hz,1H),3.55(d,J=12.7Hz,1H),2.61(s,3H),1.62(s,3H),1.58(s,3H),1.43(s,3H),1.18(s,3H); 13 C NMR (151MHz, CDCl3) δ197.8,147.9,136.4,128.3,126.3,109.3,109.3,95.8,81.6,76.5,70.3,66.2,26.7,26.4,25.9,25.4,25.1; HRMS: (ESI)calcd for C 19 H 25 O6 + [M+H] + 349.1646; found 369.1641.

[0053] Example 9

[0054]

[0055] In an inert (argon) atmosphere, 3-(bromoethynyl)pyridine (36.2 mg, 0.2 mmol), glycoside S9 (244.0 mg, 1.0 mmol), tetrabutylammonium decaprolactone F (13.3 mg, 0.004 mmol), potassium phosphate (102.4 mg, 0.5 mmol), and anhydrous acetonitrile (2.0 mL) were added to a transparent reaction tube equipped with a magnetic electron. The mixture was reacted at 25°C for 60 hours under irradiation with a violet lamp (10 W, 390 nm), concentrated, and subjected to rapid column chromatography to obtain a colorless oily product 9 (56.6 mg, 82% yield, dr>20 / 1, rr=5 / 1).

[0056] 1 H NMR (600MHz, CDCl3) δ8.68–8.64(m,1H),8.57(dd,J=4.9,1.6Hz,1H),7.72(dt, J=7.9,1.8Hz,1H),7.30–7.25(m,1H),4.36–4.31(m,2H),4.00–3.96(m,1H),3. 91(d,J=13.0Hz,1H),3.84(dd,J=10.1,7.8Hz,1H),3.75(t,J=10.5Hz,1H),3.2 8(td,J=10.1,5.6Hz,1H),1.70(s,3H),1.61(s,3H),1.53(s,3H),1.45(s,3H); 13 C NMR (151MHz, CDCl3) δ152.1,149.2,138.5,123.0,99.7,91.2,83.3,81.8,76.1,72.4,71.6,69.8,61.9,29.0,28.9,27.8,18.7; HRMS: (ESI)calcd for C 19 H 24 NO5 + [M+H] + 346.1649; found 346.1640.

[0057] Example 10

[0058]

[0059] In an inert (argon) atmosphere, 1-(bromoethynyl)-4-(methylsulfonyl)benzene (51.2 mg, 0.2 mmol), glycoside S11 (230.0 mg, 1.0 mmol), tetrabutylammonium decaprolactone F (13.4 mg, 0.004 mmol), potassium phosphate (106.7 mg, 0.5 mmol), and anhydrous acetonitrile (2.0 mL) were added to a transparent reaction tube equipped with a magnetic electron. The mixture was reacted at 25°C for 60 hours under irradiation with a violet lamp (10 W, 390 nm), concentrated, and subjected to rapid column chromatography to obtain a white solid product 10 (66.9 mg, 82% yield, dr>20 / 1, rr=4 / 1).

[0060] 1 H NMR (600MHz, CDCl3) δ7.93–7.88(m,2H),7.62–7.54(m,2H),4.94(dd,J=7.1,6.1Hz,1H),4.42(d,J=6.0Hz,1H),4.22(d,J=13.0H z,1H),3.81(d,J=13.0Hz,1H),3.53(p,J=6.5Hz,1H),3.05(s,3H),2.11(s,3H),1.62(s,3H),1.60(s,3H),1.28(d,J=6.4Hz,3H); 13 CNMR (151MHz, CDCl3) δ169.9,140.4,132.5,127.7,127.5,112.1,91.7,84.5, 81.3,75.3,74.1,72.9,70.7,44.4,27.8,27.1,21.0,18.5; HRMS:(ESI)calcd for C 20 H 25 7S + [M+H] + 409.1321; found 409.1322.

[0061] Embodiment 11

[0062]

[0063] In an inert (argon) atmosphere, nickel bromide glycol dimethyl ether (6.6 mg, 0.02 mmol), 4,4'-di-tert-butyl-2,2'-bipyridyl D (8.4 mg, 0.03 mmol), p-bromoacetophenone (39.9 mg, 0.2 mmol), glycoside S15 (260.2 mg, 1.0 mmol), tetrabutylammonium decaprolactone F (13.4 mg, 0.004 mmol), potassium phosphate (51.2 mg, 0.24 mmol), and anhydrous acetonitrile (2.0 mL) were added to a transparent reaction tube equipped with a magnetic electron. The mixture was reacted at 25°C for 60 hours under irradiation with a violet lamp (10 W, 390 nm), concentrated, and subjected to rapid column chromatography to obtain a colorless oily product 11 (34.0 mg, 45% yield, rr>20 / 1, dr>20 / 1).

[0064] 1 H NMR (600MHz, CDCl3) δ7.99–7.94(m,2H),7.75–7.70(m,2H),4.68(d,J=2.7Hz,1H),4.51(d,J=2.7Hz,1H),3.81–3.76(m,2H),3.72(d, J=12.7Hz,1H),3.64(d,J=12.7Hz,1H),2.61(s,3H),2.15(dd,J=7.9,4.9Hz,1H),1.63(s,3H),1.58(s,3H),1.50(s,3H),1.16(s,3H); 13 C NMR (151MHz, CDCl3) δ197.8,147.6,136.5,128.3,126.3,109.33,109.27,103. 2,81.6,76.7,70.7,67.3,65.5,26.7,26.3,26.1,25.6,25.1; HRMS: (ESI)calcd for C 20 H 27 O7 + [M+H] + 379.1751; found 379.1751.

[0065] Example 12

[0066]

[0067] In an inert (argon) atmosphere, 1-(bromoethynyl)-4-(methylsulfonyl)benzene (52.0 mg, 0.2 mmol), glycoside S11 (288.0 mg, 1.0 mmol), tetrabutylammonium decaprolactone F (13.4 mg, 0.004 mmol), potassium phosphate (102.4 mg, 0.5 mmol), and anhydrous acetonitrile (2.0 mL) were added to a transparent reaction tube equipped with a magnetic pole. The mixture was reacted at 25°C for 60 hours under irradiation with a violet lamp (10 W, 390 nm). After the reaction, the mixture was hydrolyzed with LiOH / H2O / THF, concentrated, and subjected to rapid column chromatography to obtain a colorless oily product 12 (42.8 mg, 56% yield, dr>20 / 1, rr=14 / 1).

[0068] 1 H NMR (600MHz, CDCl3) δ7.90(d,J=8.4Hz,2H),7.60(d,J=8.4Hz,2H),4.41(d,J=5.6Hz,1H),4.16(dd,J=11.7,5.4Hz,1H ),4.06–3.95(m,4H),3.53(dd,J=11.7,6.9Hz,1H),3.05(s,3H),2.37(s,1H),2.22(s,1H),1.62(s,3H),1.53(s,3H); 13 C NMR (151MHz, CDCl3) δ140.4,132.4,127.6,127.4,112.4,92.2,84.7,84.1,79.4,76.2,68.3,67.5,62.3,44.4,28.0,26.9; HRMS: (ESI)calcd for C 18 H 23 7S + [M+H] + 383.1159; found 383.1162.

[0069] Embodiment 13

[0070]

[0071] In an inert (argon) atmosphere, 1-(bromoethynyl)-4-(methylsulfonyl)benzene (51.8 mg, 0.2 mmol), glycoside S12 (244.0 mg, 1.0 mmol), tetrabutylammonium decaprolactone F (13.3 mg, 0.004 mmol), potassium phosphate (102.4 mg, 0.5 mmol), and anhydrous acetonitrile (2.0 mL) were added to a transparent reaction tube equipped with a magnetic pole. The mixture was reacted at 25°C for 60 hours under irradiation with a violet lamp (10 W, 390 nm). The mixture was concentrated and subjected to rapid column chromatography to obtain a colorless oily product 13 (65.8 mg, 78% yield, dr>20 / 1, rr=6 / 1).

[0072] 1 H NMR (600MHz, CDCl3) δ7.92–7.88(m,2H),7.68–7.62(m,2H),5.44–5.41(m,1H),5.04–5.01(m,1H),4.67–4.64(m,1H),4.37– 4.30(m,1H),4.09(dd,J=7.5,1.3Hz,1H),3.83(dd,J=7.5,6.1Hz,1H),3.05(s,3H),2.17(s,3H),1.57(s,3H),1.47(s,3H); 13 C NMR (151MHz, CDCl3) δ170.0,140.4,132.8,127.4,111.7,101.3,90.4,84.5,79.2,73.4,73.3,69.8,65.1,44.5,25.7,25.7,21.1; HRMS: (ESI)calcd for C 20 H 23 8S + [M+H] + 423.1114; found 423.1120.

[0073] Embodiment 14

[0074]

[0075] In an inert (argon) atmosphere, nickel bromide glycol dimethyl ether (6.6 mg, 0.02 mmol), 4,4'-di-tert-butyl-2,2'-bipyridyl D (8.4 mg, 0.03 mmol), 1-bromo-4-(methylsulfonyl)benzene (46.6 mg, 0.2 mmol), glycoside S13 (274.4 mg, 1.0 mmol), tetrabutylammonium decaprolactone F (13.4 mg, 0.004 mmol), potassium phosphate (51.2 mg, 0.24 mmol), and anhydrous acetonitrile (2.0 mL) were added to a transparent reaction tube equipped with a magnetic electron. The mixture was reacted at 25°C for 60 hours under irradiation with a violet lamp (10 W, 390 nm), concentrated, and subjected to rapid column chromatography to obtain a colorless oily product 14 (44.5 mg, 52% yield, dr>20 / 1).

[0076] 1 H NMR(600MHz, CDCl3) δ7.98(d,J=8.5Hz,2H),7.72(d,J=8.5Hz,2H),6.36(s,1H),4.70(s,1H ,H2),4.31–4.20(m,3H),3.07(s,3H),2.22(s,3H),1.91(s,3H),1.59(s,3H),1.23(s,3H); 13 C NMR (151MHz, CDCl3) δ170.5,168.9,146.8,140.3,127.7,126.2,114.7,100.1,92.2,91.8,86.7,61.7,44.4,26.6,26.5,21.2,20.6; HRMS: (ESI)calcd forC 19 H 24 oeLh + [M+Na] + 451.1033; found 451.1020.

[0077] Embodiment 15

[0078]

[0079] Under an inert (argon) atmosphere, add ferric dibromide (2.2 mg, 0.01 mmol), (E)-1-(2-bromovinyl)-4-(methylsulfonyl)benzene (26.0 mg, 0.1 mmol), glycoside S13 (137.7 mg, 0.5 mmol), tetrabutylammonium decaprolactone F (6.7 mg, 0.002 mmol), potassium phosphate (26.0 mg, 0.12 mmol), and anhydrous acetonitrile (1.0 mL) to a transparent reaction tube equipped with a magnetic pole. The mixture was reacted at 25°C for 60 hours under irradiation with a violet lamp (10 W, 390 nm), concentrated, and subjected to rapid column chromatography to obtain a colorless liquid product 15 (19.0 mg, 42% yield, dr>20 / 1, E / Z>20:1).

[0080] 1 H NMR (600MHz, CDCl3) δ7.92(d,J=8.4Hz,2H),7.59(d,J=8.3Hz,2H),6.91(d,J=15.8Hz,1H),6.47(d,J=15.8Hz,1H),6.27(s,1H),4.56(s,1H),4.37( dd,J=12.1,3.3Hz,1H),4.29(dd,J=7.6,3.2Hz,1H),4.20(dd,J=12.1,7.6 Hz,1H),3.06(s,3H),2.16(s,3H),2.03(s,3H),1.55(s,3H),1.41(s,3H); 13 C NMR (151MHz, CDCl3) δ170.8,169.2,141.2,139.7,131.8,129.3,127.9,127.4,114 .7,100.4,90.8,90.1,83.1,62.4,44.5,26.9,26.8,21.1,20.8; HRMS: (ESI)calcd for C 21 H 26 oeLh + [M+Na] + 477.1189; found 477.1181.

[0081] Example 16

[0082]

[0083] In an inert (argon) atmosphere, 1-(bromoethynyl)-4-(methylsulfonyl)benzene (52.2 mg, 0.2 mmol), glycoside S13 (274.4 mg, 1.0 mmol), tetrabutylammonium decaprolactone F (13.4 mg, 0.004 mmol), potassium phosphate (102.4 mg, 0.5 mmol), and anhydrous acetonitrile (2.0 mL) were added to a transparent reaction tube equipped with a magnetic electron. The mixture was reacted at 25°C for 60 hours under irradiation with a violet lamp (10 W, 390 nm). The mixture was concentrated and subjected to rapid column chromatography to obtain a colorless oily product 16 (61.5 mg, 68% yield, dr>20 / 1).

[0084] 1 H NMR(600MHz, CDCl3)δ7.93(d,J=8.4Hz,2H),7.65(d,J=8.4Hz,2H),6.20(s,1H),4.84(s,1H),4.55–4.46 (m,2H),4.30(dd,J=11.8,7.1Hz,1H),3.06(s,3H),2.14(s,3H),2.09(s,3H),1.55(s,3H),1.51(s,3H); 13 C NMR (151MHz, CDCl3) δ170.7,169.3,140.6,132.6,127.5,127.4,115.5,100.3,91 .4,89.8,85.4,83.9,82.3,61.9,44.4,26.3,25.5,21.1,20.9; HRMS: (ESI)calcd for C 21 H 28 9n + [M+NH4] + 470.1479; found 470.1481.

[0085] Embodiment 17

[0086]

[0087] In an inert (argon) atmosphere, acrylonitrile (11.2 mg, 0.2 mmol), glycoside S13 (109.6 mg, 0.4 mmol), tetrabutylammonium decaprolactone F (13.5 mg, 0.004 mmol), acetonitrile (1.0 mL), and H2O (100 uL) were added to a transparent reaction tube equipped with a magnet. The mixture was reacted at 25°C for 60 hours under irradiation with a violet lamp (10 W, 390 nm), concentrated, and subjected to rapid column chromatography to obtain a colorless liquid product 17 (55.6 mg, 85% yield, dr>20 / 1).

[0088] 1H NMR (600MHz, CDCl3) δ6.17(s,1H),4.42(s,1H),4.39–4.34(m,1H),4.10–4.05(m,2H),2.65–2.47( m,2H),2.19(dddd,J=49.7,14.3,9.8,6.0Hz,2H),2.08(d,J=0.7Hz,6H),1.45(s,3H),1.40(s,3H); 13 C NMR (151MHz, CDCl3) δ170.7,169.0,118.9,114.6,99.6,89.5,88.8,82.9,62.9,32.1,27.3,27.1,20.9,20.8,12.7; HRMS: (ESI)calcd forC 15 H 21 NONa + [M+Na] + 350.1210; found 350.1206.

[0089] Embodiment 18

[0090]

[0091] In an inert (argon) atmosphere, nickel bromide glycol dimethyl ether (6.6 mg, 0.02 mmol), 4,4'-di-tert-butyl-2,2'-bipyridyl D (8.4 mg, 0.03 mmol), p-bromoacetophenone (39.9 mg, 0.2 mmol), glycoside S16 (399.1 mg, 1.0 mmol), tetrabutylammonium decaprolactone F (13.4 mg, 0.004 mmol), potassium phosphate (51.2 mg, 0.24 mmol), and anhydrous acetonitrile (2.0 mL) were added to a transparent reaction tube equipped with a magnetic electron. The mixture was reacted at 25°C for 48 hours under irradiation with a violet lamp (10 W, 390 nm), concentrated, and subjected to rapid column chromatography to obtain a colorless oily product 18 (69% yield, dr>20 / 1).

[0092] 1H NMR (600MHz, CDCl3) δ7.99–7.94(m,2H),7.72–7.67(m,2H),5.12(s,2H),4.68(d,J=2.7Hz,1H),4.47(d,J=2.7Hz,1H),4.43(d,J=10.8Hz,1H ),4.33(d,J=10.8Hz,1H),3.71(d,J=12.7Hz,1H),3.64(d,J=12.7Hz,1H),2.61(s,3H),1.63(s,3H),1.58(s,3H),1.52(s,3H),1.16(s,3H); 13 C NMR (151MHz, CDCl3) δ197.8,147.2,136.5,128.4,126.3,110.2,109.5,101.0 ,81.3,76.5,71.1,70.3,67.2,26.7,26.3,26.1,25.3,25.1; HRMS: (ESI)calcd for C 20 H 28 NO9S + [M+H] + 458.1479; found 458.1476.

[0093] Embodiment 19

[0094]

[0095] In an inert (argon) atmosphere, 1-(bromoethynyl)-4-(methylsulfonyl)benzene (52.2 mg, 0.2 mmol), glycoside S16 (339.1 mg, 1.0 mmol), tetrabutylammonium decaprolactone F (13.4 mg, 0.004 mmol), potassium phosphate (102.4 mg, 0.5 mmol), and anhydrous acetonitrile (2.0 mL) were added to a transparent reaction tube equipped with a magnetic pole. The mixture was reacted at 25°C for 48 hours under irradiation with a violet lamp (10 W, 390 nm). The mixture was concentrated and subjected to rapid column chromatography to obtain a colorless oily product 19 (63.1 mg, 61% yield, dr>20 / 1).

[0096] 1H NMR (600MHz, CDCl3) δ7.90(d,J=8.4Hz,2H),7.61(d,J=8.4Hz,2H),5.00(s,2H),4.79(d,J=2.7Hz,1H),4.41(d,J=2.7Hz,1H),4.35(d,J=10.9Hz ,1H),4.24(d,J=10.9Hz,1H),4.00(d,J=12.6Hz,1H),3.90(d,J=12.6Hz ,1H),3.05(s,3H),1.61(s,3H),1.55(s,3H),1.51(s,3H),1.46(s,3H); 13 C NMR (151MHz, CDCl3) δ140.4,132.6,127.7,127.4,110.8,110.0,100.8,91.3,84 .6,76.6,72.4,70.8,70.4,64.9,44.4,26.3,26.0,25.1,24.3; HRMS: (ESI)calcd for C 21 H 31 N2O 10 S2 + [M+NH4] + 535.1415; found 535.1416.

[0097] Example 20: Synthesis of Anticancer Drug Acetylcholine Analogs

[0098]

[0099] In an inert (argon) atmosphere, 1-(bromoethynyl)-4-(methylsulfonyl)benzene (52.2 mg, 0.2 mmol), glycoside S14 (336.2 mg, 1.0 mmol), tetrabutylammonium decaprolactone F (13.4 mg, 0.004 mmol), potassium phosphate (102.4 mg, 0.5 mmol), and anhydrous acetonitrile (2.0 mL) were added to a transparent reaction tube equipped with a magnetic pole. The mixture was reacted at 25°C for 48 hours under irradiation with a violet lamp (10 W, 390 nm). The mixture was concentrated and subjected to rapid column chromatography to obtain a colorless oily product 20 (69.9 mg, 68% yield, dr>20 / 1).

[0100] 1H NMR (600MHz, CDCl3) δ8.10–8.05(m,2H),7.88–7.84(m,2H),7.55–7.50(m,3H),7.38–7.33(m,2H),6.22(s,1H),4 .86(s,1H),4.71(dd,J=10.4,4.8Hz,1H),4.65–4.59(m,2H),3.04(s,3H),2.13(s,3H),1.57(s,3H),1.54(s,3H); 13 C NMR (151MHz, CDCl3) δ169.3,166.2,140.5,133.2,132.6,129.9,129.7,128.4,127.5,127.4 ,115.5,100.4,91.5,90.2,85.4,83.6,82.3,61.7,44.4,26.4,25.7,21.1; HRMS: (ESI)calcd for C 26 H 27 9S + [M+H] + 515.1376; found 515.1372.

[0101]

[0102] 20 (256.7 mg, 0.5 mmol) and trifluoroacetic acid / H2O (8 / 2, 5 mL) were added to the reaction flask, and the mixture was stirred at room temperature for 24 hours. After the reaction was completed, saturated NaHCO3 was used to quench the mixture, and the mixture was extracted three times with CH2Cl2, and the organic layers were combined. The combined organic layers were washed with brine, then dried and concentrated over anhydrous Na2SO4. Subsequently, pyridine (2 mL), DMAP (6.1 mg, 0.05 mmol) and Ac2O (0.5 mL) were added to the crude product. After stirring at room temperature for 4 hours, the reaction solution was directly concentrated under reduced pressure. Rapid column chromatography gave a white solid product 23 (201.3 mg, 72% yield, dr>20 / 1).

[0103] 1H NMR (600MHz, CDCl3) δ8.09–8.04(m,2H),7.89–7.84(m,2H),7.59–7.54(m,3H),7.43–7.39(m,2H),6.27(d,J=2.0Hz,1H),5.88(d,J=2.0Hz,1H) ,4.95(dd,J=6.5,4.9Hz,1H),4.81(dd,J=11.9,4.9Hz,1H),4.62(dd,J=11.9,6.5Hz,1H),3.05(s,3H),2.17(s,3H),2.13(s,3H),2.09(s,3H); 13 C NMR (151MHz, CDCl3) δ169.3,168.7,168.2,166.0,140.6,133.4,132.8,132.6,129.8,129.7,129.5,12 8.4,127.3,127.2,99.0,87.3,86.7,84.4,79.8,76.3,62.0,44.3,21.0,20.9,20.4.HRMS:(ESI)calcd for C 27 H 27 NO 11 S + [M+NH4] + 576.1543; found 576.1516.

[0104]

[0105] 23 (111.1 mg, 1.0 mmol), N, O-bis (trimethylsilyl) acetamide BSA (406.1 mg, 2.0 mmol) were added to the reaction flask and refluxed in a solution in anhydrous MeCN (10 mL) for 1 hour. 21 (201.3 mg, 0.36 mmol) and TMSOTf (333.4 mg, 1.5 mmol) were subsequently added. After stirring at 60 ° C for 24 hours, the reaction mixture was quenched with saturated NaHCO3 aqueous solution and extracted three times with EA, and the organic layers were combined. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and then concentrated. Rapid column chromatography gave a white solid product 24 (212.6 mg, 97% yield, dr>20 / 1).

[0106] 1H NMR(600MHz, CDCl3)δ8.31(s,1H),8.03–7.97(m,2H),7.77(d,J=8.1Hz,2H),7.52–7.47(m,1H),7.43(d, J=8.1Hz,2H),7.38(d,J=7.5Hz,1H),7.34(t,J=7.8Hz,2H),6.69(s,1H),6.27(d,J=4.4Hz,1H,anomeric H),5.83(d,J=7.4Hz,1H),5.80(d,J=4.5Hz,1H),5.28(t,J=5.9Hz,1H),4.62(d,J=5.9Hz,2H),2.99(s,3H),2.14(s,3H),2.02(s,3H); 13 C NMR (151MHz, CDCl3) δ168.9,168.2,166.3,166.2,155.8,141.9,140.5,133.4,132.7,129.8,129.4,12 8.5,127.2,126.9,95.9,91.8,87.4,86.8,84.3,77.9,76.3,62.2,44.3,21.1,20.6.HRMS:(ESI)calcd for C 29 H 28 N3O 10 S + [M+H] + 610.1490; found 610.1485.

[0107]

[0108] 24 (212.6 mg, 0.35 mmol) was dissolved in saturated methanolic ammonia (5 mL) and stirred at room temperature for 24 hours. The reaction solution was spin-dried to obtain a crude product, which was then washed and purified with an appropriate EA solution to obtain the anticancer drug acetylcholine analog 22 (144.4 mg, 98% yield, dr>20 / 1).

[0109] 1 H NMR (600MHz, CD3OD) δ7.87–7.82(m,2H),7.65(d,J=7.4Hz,1H),7.62–7.57(m,2H),5.70(d,J=6.2Hz,1H),4.69 (d,J=6.2Hz,2H),4.57–4.44(m,6H),3.86(dd,J=12.2,3.3Hz,1H),3.78(dd,J=12.2,6.9Hz,1H),3.04(s,3H); 13C NMR (151MHz, CD3OD) δ143.1,140.5,132.2,129.5,129.4,127.8,127.2,92.6,90.8,86.2,83.5,79.8,73.2,65.3,60.6,42.8.HRMS: (ESI)calcd for C 18 H 20 N3O7S + [M+H] + 422.1017; found 422.1015.

[0110] Comparative Example

[0111] According to the method in Example 1, when the ligand or photocatalyst in Example 1 is replaced with the following structure, the target product cannot be successfully obtained.

[0112]

[0113] The above examples are only some specific embodiments of the present invention. Obviously, the present invention is not limited to the above embodiments, but may have many variations. All variations that can be directly derived or indirectly associated with the contents disclosed by a person skilled in the art should be considered to be within the protection scope of the present invention.

Claims

1. A method for synthesizing a chiral quaternary carbon glycoside, characterized in that: The following steps are involved: The coupling reagent and the glycoside are fully reacted under the catalysis of a photocatalyst or a photocatalyst and one or more of a metal catalyst, a ligand, and a base under ultraviolet light irradiation to obtain a functionalized chiral quaternary carbon glycoside; the coupling reagent includes aryl bromide, alkenyl bromide, alkynyl bromide, and electron-deficient olefin, and the functionalization includes arylation, alkenylation, alkynylation, and alkylation.

2. The synthesis method according to claim 1, characterized in that: When the coupling reagent is an aryl bromide, the aryl bromide and the glycoside react completely under the catalysis of a photocatalyst, a metal catalyst, a ligand and a base under the irradiation of ultraviolet light; when the coupling reagent is an alkenyl bromide, the alkenyl bromide and the glycoside react completely under the catalysis of a photocatalyst, a metal catalyst and a base under the irradiation of ultraviolet light; when the coupling reagent is an alkynyl bromide, the alkynyl bromide and the glycoside react completely under the catalysis of a photocatalyst and a base under the irradiation of ultraviolet light; when the coupling reagent is an electron-deficient olefin, the electron-deficient olefin and the glycoside react completely under the catalysis of a photocatalyst under the irradiation of ultraviolet light.

3. The synthesis method according to claim 1, characterized in that The following steps are involved: Under the protection of inert gas, a coupling reagent, glycoside and photocatalyst or one or more of the photocatalyst and metal catalyst, ligand and base are added to a solvent, and the reaction is completed under ultraviolet light irradiation to obtain a functionalized chiral quaternary carbon glycoside.

4. The synthesis method according to any one of claims 1 to 3, characterized in that: The aryl bromide, alkenyl bromide, alkynyl bromide, and electron-deficient olefin are selected from the following structures:

5. The synthesis method according to any one of claims 1 to 3, characterized in that: The glycoside is selected from the following structures:

6. The synthesis method according to any one of claims 1 to 3, characterized in that: The metal catalyst comprises a mixture of one or more of nickel chloride, nickel bromide, nickel chloride dimethyl ether, nickel bromide dimethyl ether, cyclooctadiene nickel, nickel acetylacetonate, nickel perchlorate, nickel iodide, nickel acetate tetrahydrate and ferric dibromide.

7. The synthesis method according to any one of claims 1 to 3, characterized in that: The ligand is selected from the following structures:

8. The synthesis method according to any one of claims 1 to 3, characterized in that: The photocatalyst is selected from the following structures:

9. The synthesis method according to any one of claims 1 to 3, characterized in that: The base used includes a mixture of one or more of sodium carbonate, potassium carbonate, potassium phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, sodium bicarbonate, lithium carbonate, cesium carbonate, sodium phosphate and sodium acetate.

10. The synthesis method according to any one of claims 1 to 3, characterized in that: The solvent includes a mixed solvent composed of one or more of acetonitrile, acetone, water and dimethyl sulfoxide.

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