Chiral glycoside compound and synthesis method thereof

Abstract

The invention provides a chiral glycoside compound and a synthesis method thereof, and belongs to the technical field of metal organic catalysis. The invention provides a chiral glycoside compound and also provides a synthesis method of the chiral glycoside compound, and the synthesis method comprises the following steps: by using a chiral anion catalyst consisting of a chiral NNN tridentate ligand and low-cost and low-toxicity transition metal copper, synthesizing the chiral glycoside compound through an exosphere nucleophilic attack mechanism, thereby obtaining the chiral glycoside compound. The free radical asymmetric oxygen alkylation reaction of the tertiary alkyl halogenated hydrocarbon electrophilic reagent and various glycosides is realized. The synthesis method has the advantages of simple and easily available raw materials, mild reaction conditions, wide substrate universality, good functional group compatibility, high yield, high diastereoselectivity and the like, can realize later structural modification of various glycosides, and has great application prospects and practical values.

Description

Technical Field

[0001] This invention belongs to the field of organometallic catalysis technology, and in particular relates to a chiral glycoside compound and its synthesis method. Background Technology

[0002] Chiral glycosides are widely found in natural products and drug molecules with important biological activities. Diverse modifications to glycosides can significantly improve the targeting of glycoside drug molecules, enhance their metabolic kinetic parameters, and further regulate their pharmacological activity. Among these modifications, asymmetric oxyalkylation of glycosides is one of the most direct and effective methods for constructing chiral oxyglycosides.

[0003] In existing technologies, most asymmetric oxyalkylation reactions of glycosides involve the asymmetric oxyalkylation of glycosides with expensive and highly toxic transition metal-catalyzed primary or secondary electrophiles to construct sterically less hindered oxyglycoside compounds. For example, in recent years, Tang Weiping's team has been committed to developing a metal carbene insertion strategy catalyzed by transition metal Rh(II) / chiral phosphoric acid to achieve structural modification of glycoside compounds (J.Am.Chem.Soc.2019,141,19902-19910; Angew.Chem.Int.Ed.2023,62,e202307144; J.Am.Chem.Soc.2025,147,5871-5878); in 2024, Loh's research team achieved a copper-catalyzed asymmetric oxyalkylation reaction of glycosides with secondary amide electrophiles (Angew.Chem.Int.Ed.2024,63,e202409530).

[0004] Therefore, developing novel, efficient, environmentally friendly, and mild transition metal-catalyzed asymmetric oxyalkylation reactions of tertiary electrophiles with glycosides to further achieve structural modification of sterically hindered chiral oxyglycosides and increase the structural diversity of oxyglycosides is of great research significance and practical value. Summary of the Invention

[0005] In view of the problems existing in the prior art, the present invention aims to provide a broad-spectrum, efficient, and mildly controlled glycoside compound, its synthesis method, and its applications. This synthesis method utilizes a chiral NNN tridentate ligand and a chiral anionic catalyst composed of inexpensive and low-toxicity transition metal copper. Through an outer-sphere nucleophilic attack mechanism, it achieves the free radical asymmetric oxyalkylation reaction of tertiary alkyl halides with electrophiles, further broadening the substrate applicability range and solving the problems of low reactivity and difficulty in chiral control of sterically hindered tertiary alkyl halides with glycosides. Simultaneously, it effectively suppresses side reactions, providing an effective strategy for the efficient asymmetric synthesis of sterically hindered oxyglycoside compounds.

[0006] Therefore, the above-mentioned objective of the present invention is achieved through the following technical solution:

[0007] The first aspect of this invention provides a glycoside compound or its salt, precursor, or solvate, such as formula III:

[0008]

[0009] The L is selected from -(CH2)-, bond;

[0010] The Ar is selected from substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclic groups, and substituted or unsubstituted cycloalkyl groups;

[0011] The carbon atoms marked with * are each independently of the R configuration, S configuration, or achiral carbon atom;

[0012] The R 1 Selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, hydrogen, and substituted or unsubstituted heterocyclic groups;

[0013] The R 2 Selected from substituted or unsubstituted heterocyclic groups, substituted or unsubstituted alkoxy groups, substituted or unsubstituted alkyl groups, hydrogen groups, and substituted or unsubstituted aryl groups;

[0014] The R 3 and R 4 Each is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy;

[0015] The n is selected from integers from 0 to 3;

[0016] Or, the plurality of R 2 They are linked together to form substituted or unsubstituted heterocyclic groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted cycloalkyl groups.

[0017] In some specific embodiments of the glycoside compounds of Formula III described in the first aspect, the R 1 R 2 R 3 R 4 Each of the components is independently selected from C1-C5 substituted or unsubstituted straight-chain or branched alkyl groups, C1-C5 substituted or unsubstituted alkoxy groups, or 3- to 8-membered substituted or unsubstituted heterocyclic groups, wherein the Ar is selected from 4- to 14-membered substituted or unsubstituted monocyclic or fused-ring heterocyclic groups, and optionally, the ring Ar is heteroatomized with 1 to 3 heteroatoms selected from N, O, and S.

[0018] Or, two Rs 2 Connected to form a ring Ar 2 The Ar 2Selected from 3- to 8-membered substituted or unsubstituted heterocyclic groups, C3- to C8 substituted or unsubstituted cycloalkyl groups, and C6- to C10 substituted or unsubstituted aryl groups, wherein the cycloarthron... 2 The hydrogen on R is optional a Instead, the R a Selected from C1 to C3 alkyl, hydrogen, and C1 to C3 alkoxy.

[0019] In some specific embodiments of the glycoside compounds of formula III described in the first aspect, the structures are as shown in formulas III-a and III-b:

[0020]

[0021] X and Y are each independently selected from -(CH)2- and -O-.

[0022] In some specific embodiments of the glycoside compounds of Formula III described in the first aspect, the ring Ar is selected from tetrahydropyranyl or tetrahydrofuranyl, and optionally the ring Ar is fused with one or more 1,3-dioxolane groups.

[0023] In some specific embodiments of the glycoside compounds of Formula III described in the first aspect, the R 1 R 2 R 3 R 4 R a Each is independently selected from methyl, ethyl, n-propyl, isopropyl, methoxy, hydrogen, and 1,3-dioxolane, wherein the hydrogen on the 1,3-dioxolane is optionally substituted with methyl, ethyl, n-propyl, or isopropyl, and the Ar... 2 Selected from 1,3-dioxolane, tetrahydropyranyl, and tetrahydrofuranyl, the Ar 2 The hydrogen atoms can be optionally replaced by methyl, ethyl, or n-propyl groups;

[0024] The second aspect of this invention discloses the specific structure of the chiral glycoside compound of formula III described in the first aspect, wherein the chiral glycoside compound is selected from:

[0025]

[0026] A third aspect of this invention provides a method for preparing a glycoside compound of formula III shown in the first aspect, comprising:

[0027] Under controlled temperature and in an organic solvent environment, compound I, compound II, copper salt catalyst, and ligand L* are mixed and reacted to yield:

[0028]

[0029] The Ar, *, n, L, R 1 R 2 R3 R 4 As defined in claims 1 to 6.

[0030] The chemical structural formula of ligand L* is selected from:

[0031]

[0032] In some specific embodiments of the preparation method of the glycoside compound described in the third aspect, the copper salt catalyst is any one or a combination of cuprous iodide, cuprous bromide, cuprous trifluoromethanesulfonate, cuprous trifluoromethanesulfonate toluene complex, copper bis(trifluoromethanesulfonyl)imide (Cu(NTf2)2), cuprous chloride, cuprous bromide dimethyl sulfide, and copper tetraacetonitrile hexafluorophosphate.

[0033] In some specific embodiments of the preparation method of the glycoside compound described in the third aspect, the molar ratio of compound I to compound II is 1:1.5 to 1:3.0. In some specific embodiments of the preparation method of the glycoside compound described in the third aspect, the molar ratio of compound I to compound II is optionally 1:1.6, 1:1.9, 1:2.2, 1:2.5, or 1:2.8.

[0034] In some specific embodiments of the preparation method of the glycoside compound described in the third aspect, the molar ratio of the copper salt catalyst to the ligand L* is 1:1.5 to 1:2.0. In some specific embodiments of the preparation method of the glycoside compound described in the third aspect, the molar ratio of the copper salt catalyst to the ligand L* is optionally 1:1.6, 1:1.7, 1:1.8, or 1:1.9.

[0035] In some specific embodiments of the preparation method of the glycoside compound described in the third aspect, the molar ratio of compound I to the copper salt catalyst is 1:0.1 to 1:0.2. In some specific embodiments of the preparation method of the glycoside compound described in the third aspect, the molar ratio of compound I to the copper salt catalyst is optionally 1:0.13, 1:0.15, 1:0.17, or 1:0.19.

[0036] In some specific embodiments of the preparation method of the glycoside compound described in the third aspect, the molar ratio of compound I to base is 1:(2-4). In some specific embodiments of the preparation method of the glycoside compound described in the third aspect, the molar ratio of compound I to base is optionally 1:2.3, 1:2.6, 1:2.9, 1:3.2, 1:3.5, or 1:3.8.

[0037] In some specific embodiments of the preparation method of the glycoside compound described in the third aspect, the temperature for temperature control is from -10°C to 27°C. In some specific embodiments of the preparation method of the glycoside compound described in the third aspect, the temperature for temperature control is optionally -3°C, 0°C, 3°C, 6°C, 9°C, 12°C, 15°C, 18°C, or 21°C.

[0038] In some specific embodiments of the preparation method of the glycoside compounds described in the third aspect, the organic solvent is any one or more combinations of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, and toluene.

[0039] In some specific embodiments of the preparation method of the glycoside compounds described in the third aspect, an alkali is also added to the organic solvent, wherein the alkali is any one or more combinations of potassium phosphate, cesium carbonate, potassium carbonate, sodium carbonate, and rubidium carbonate.

[0040] In some specific embodiments of the method for preparing the glycoside compounds described in the third aspect, the reaction occurs in an inert gas atmosphere.

[0041] In specific embodiments of the preparation method of the glycoside compounds described in the third aspect, the compound of formula I has the following structure:

[0042]

[0043] The preparation method of the compound of formula I is shown in the following formula:

[0044]

[0045] The preparation steps of compound I are as follows: 10 mmol of arylacetic acid was dissolved in 20 mL of dry tetrahydrofuran under argon protection, then cooled to -78°C. 22 mL of 1.0 M LDA was slowly added dropwise to the reaction system, then the temperature was slowly raised to room temperature and reacted for 2 hours. The temperature was then lowered to -78°C, and 3.0 equiv. of CCl4 was slowly added dropwise to the system. The temperature was then raised to room temperature and stirred for 12 hours. The reaction solvent was concentrated and directly added to the next step. The intermediate was dissolved in 10 mL of dichloromethane, cooled to 0°C, and 1.2 equiv. of oxaloyl chloride was added dropwise. Two drops of DMF were added, and the reaction was carried out at room temperature for 5 hours. After concentration, the solution was dissolved in 10 mL of dichloromethane, and 1.2 equiv. of triethylamine was added. The temperature was lowered to 0°C, and aniline was slowly added to the system. The temperature was then slowly raised to room temperature and reacted for 2 hours. The reaction was quenched by adding 2 mL of water to the reaction system, extracted with dichloromethane, dried in organic solvent, concentrated, and purified by column chromatography to obtain compound I.

[0046] In specific embodiments of the method for preparing the glycoside compounds described in the third aspect, the compound of formula II has the following structure:

[0047]

[0048] The chemical structural formula of the chiral NNN ligand L* is shown below:

[0049]

[0050] The preparation method of the chiral NNN ligand L* is shown in the following formula:

[0051]

[0052] The preparation steps of the chiral NNN ligand L* are as follows: Chiral diamine (2.4 g, 10.0 mmol), pyridine carboxylic acid (2.6 g, 11.0 mmol, 1.1 equiv.), DMAP, and EDCI are dissolved in 10 mL of dry dichloromethane and reacted at room temperature for 5 hours. The mixture is then concentrated and purified by column chromatography to obtain an intermediate. The intermediate (3.85 g, 8.4 mmol), Pd(PPh3)4, potassium carbonate, and 3-cyanobenzoboronic acid are dissolved in a mixed solvent of THF and water (20 mL, v:v = 3:1). Under argon protection, the mixture is reacted at 80 °C for 12 hours. After cooling to room temperature, 10 mL of water is added to quench the reaction. The mixture is extracted with ethyl acetate, dried over anhydrous sodium carbonate, concentrated, and purified by column chromatography to obtain the chiral NNN ligand L*.

[0053] The characterization data of the chiral NNN ligand L* are as follows:

[0054] L * : 1 HNMR(400MHz, CDCl3) δ9.07(d,J=4.3Hz,1H),8.75(d,J=1.6Hz,1H),7.97

[0055] (d,J=1.6Hz,1H),7.90(s,1H),7.84(d,J=7.8Hz,1H),7.76(d,J=7.7Hz,1H),7.65(t,J=7.8Hz,1H),7. 28-7.16(m,5H),7.15-7.01(m,5H),5.38(dd,J=10.6,5.0Hz,1H),3.87(d,J=10.6Hz,1H),2.23(s,6H). 13C NMR (100MHz, CDCl3) δ163.0,146.4,144.4,140.8,138.1,137.1,136.9,133.1,132.5,132.1,131.5,1 30.7,130.3,129.8,128.0,127.8,127.6,127.5,126.9,118.1,113.9,73.7,54.9,41.1.HRMS(ESI)m / z calcd.forC 29 H 26 ClN4O[M+H] + 481.1790, found 481.1791.

[0056] The reaction steps described in this invention are as follows: Under an argon atmosphere, ligand L is sequentially added to a dried 25 mL Shrek tube containing a magnetic magnet. * The reaction mixture consisted of copper salt, base, and compound I, followed by the addition of solvent and finally compound II. The reaction was carried out at a set temperature. After the reaction was completed, post-treatment was performed, and column chromatography was used to separate the sterically hindered chiral oxyglycosides III, i.e., chiral glycosides.

[0057] The term "heterocyclic group" refers to a non-aromatic, fully saturated or partially unsaturated cyclic group (e.g., a 3- to 7-membered monocyclic ring) having at least one heteroatom in a ring containing at least one carbon atom. Preferably, the heterocyclic group is a 5- or 6-membered heterocyclic group. Each ring of the heterocyclic group containing heteroatoms may have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Non-limiting exemplary heterocyclic groups include thienyl, furanyl, pyrrolyl, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazyl, pyrazinyl, pyrazinyl, piperidinyl, piperazinyl, aziridine, aziridine, aziridine, aziridine, aziridine, aziridine, aziridine, aziridine, aziridine, morpholino-4-yl, oxazapyridine, pyrrolyl, thiomorpholino-4-yl, tetrahydrofuranyl, tetrahydropyranyl, epoxyethyl, thiiranyl, 2-imidazolinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolidinyl, succinimide, 2H-pyrrolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2 -Oxopyridine, high-piperazinidine, 2-pyrazolinidine, tetrahydro-2H-pyranidine, 2H-pyranidine, 4H-pyranidine, 3,4-dihydro-2H-pyranidine, oxopyrrolodinyl, thiocyclobutidine, 3-dioxopyrrolodinyl, 1,4-dioxopyrrolodinyl, 2,5-dioxopyrrolodinyl, 2-oxopyridine, 2-oxopyrrolodinyl, tetrahydrothiophene, 1,3-dioxopyrrolodinyl, 1,4-oxopyrrolodinyl, 1,4-dithiocyclohexane, 1,3,5-trioxanyl, tetrahydro-1,1-dioxopyrrolodinyl, N-formylpiperazinyl.

[0058] In some embodiments, the room temperature is 45–5°C; in some embodiments, the room temperature is 35–10°C; in some embodiments, the room temperature is 30–15°C; in some embodiments, the room temperature is 25–20°C; and in some embodiments, the room temperature is 25°C.

[0059] All reagents used in this invention are purchased from the open and legal market and have not undergone further purification.

[0060] Advantages of this invention:

[0061] 1. The glycosides provided by this invention are a class of novel natural products and drug molecules with important biological activities. They can be modified in various ways to significantly improve the targeting of glycoside drug molecules, improve their metabolic kinetic parameters, and further regulate the pharmacological activity of drug molecules. They have great application prospects and practical value.

[0062] 2. This invention achieves, for the first time, a highly efficient asymmetric synthesis of sterically hindered chiral oxyglycosides via the radical asymmetric oxyalkylation of electrophilic sterically hindered tertiary alkylamide halides with various glycosides catalyzed by transition metal copper. It overcomes the challenges of low reactivity and difficult chirality control between sterically hindered tertiary alkylamide halides and glycosides, while effectively suppressing side reactions, providing a broad-spectrum and highly efficient asymmetric synthetic method for sterically hindered chiral oxyglycosides. This synthetic method offers advantages such as readily available and simple starting materials, mild reaction conditions, broad substrate universality, good functional group compatibility, and high yield and diastereoselectivity. Attached Figure Description

[0063] Figure 1 Diagram of the reactor apparatus;

[0064] Figure 2 The 1H NMR spectrum of (S)-N-(4-cyano-2-methylphenyl)-3-methyl-2-phenyl-2-(((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolane)[4,5-b:4',5'-d]pyran-5-yl)methoxy)butyramide.

[0065] Figure 3 The carbon NMR spectrum of (S)-N-(4-cyano-2-methylphenyl)-3-methyl-2-phenyl-2-(((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolane)[4,5-b:4',5'-d]pyran-5-yl)methoxy)butyramide;

[0066] Figure 4 The 1H NMR spectrum of (S)-N-(4-cyano-2-methylphenyl)-2-(((3aR,5R,6S,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolane-4-yl)-2,2-dimethyltetrahydrofurano[2,3-d][1,3]dioxolane-6-yl)oxy)-3-methyl-2-phenylbutyramide;

[0067] Figure 5 The carbon NMR spectrum of (S)-N-(4-cyano-2-methylphenyl)-2-(((3aR,5R,6S,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolane-4-yl)-2,2-dimethyltetrahydrofurano[2,3-d][1,3]dioxolane-6-yl)oxy)-3-methyl-2-phenylbutyramide;

[0068] Figure 6The 1H NMR spectrum of (2S)-N-(4-cyano-2-methylphenyl)-2-(((3aR,4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methoxy)-3-methyl-2-phenylbutyramide.

[0069] Figure 7 The carbon NMR spectrum of (2S)-N-(4-cyano-2-methylphenyl)-2-(((3aR,4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methoxy)-3-methyl-2-phenylbutyramide;

[0070] Figure 8 The 1H NMR spectrum of (S)-N-(4-cyano-2-methylphenyl)-3-methyl-2-(3-methoxyphenyl)-2-(((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolane)[4,5-b:4',5'-d]pyran-5-yl)methoxy)butyramide;

[0071] Figure 9 The carbon NMR spectrum of (S)-N-(4-cyano-2-methylphenyl)-3-methyl-2-(3-methoxyphenyl)-2-(((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolane)[4,5-b:4',5'-d]pyran-5-yl)methoxy)butyramide;

[0072] Figure 10 The 1H NMR spectrum of (S)-N-(4-cyano-2-methylphenyl)-2-(((3aR,5R,6S,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolane-4-yl)-2,2-dimethyltetrahydrofurano[2,3-d][1,3]dioxolane-6-yl)oxy)-3-methyl-2-(3-methoxyphenyl)butyramide;

[0073] Figure 11 The carbon NMR spectrum of (S)-N-(4-cyano-2-methylphenyl)-2-(((3aR,5R,6S,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolane-4-yl)-2,2-dimethyltetrahydrofurano[2,3-d][1,3]dioxolane-6-yl)oxy)-3-methyl-2-(3-methoxyphenyl)butyramide;

[0074] Figure 12 For ligand L * The hydrogen NMR spectrum;

[0075] Figure 13 For ligand L * The carbon NMR spectrum. Detailed Implementation

[0076] The above technical solutions of the present invention will be specifically described below through embodiments. It should be noted that these embodiments are only used to further illustrate the present invention, but do not constitute any limitation on the present invention. Those skilled in the art can make some non-essential improvements and adjustments based on the content of the present invention.

[0077] Example 1

[0078]

[0079] Under an argon atmosphere, ligand L* (0.03 mmol, 15 mol%), copper salt Cu(NTf2)2 (0.02 mmol, 10 mol%), base K3PO4 (0.60 mmol, 3.0 equiv.), and compound I 2-chloro-N-(4-cyano-2-methylphenyl)-3-methyl-2-phenylbutyramide (0.20 mmol) were added sequentially to a dried Shrek tube with a magnetic magnet. Then, 2.0 mL of ultradry solvent 1,2-dichloroethane (DCE) was added, followed by compound II diacetone-D-galactose (0.30 mmol, 1.50 equiv.). The reaction was placed at room temperature (27 °C) and stirred for 5 days. After the reaction was complete, the reaction solution was passed through diatomaceous earth and eluted three times with 5 mL of dichloromethane. The organic phases were combined, concentrated to remove the organic solvent, and separated by column chromatography to obtain sterically hindered chiral oxyglycoside III with a yield of 86% and a diastereoselectivity greater than 20:1.

[0080] The characterization data for this compound are as follows: [α] D 27 = -84 (c 0.6, CHCl3). 1H NMR (400MHz, CDCl3) δ9.27 (s, 1H), 8.08 (d, J = 8.7Hz, 1H), 7.61 (d, J = 7.4Hz, 2H), 7.53-7.46 (m, 2H), 7.4 2-7.35(m,2H),7.34-7.28(m,1H),5.48(d,J=4.9Hz,1H),4.58(dd,J=7.9,2.4Hz,1H),4.32(dd,J=4.9,2 .5Hz,1H),4.13(dd,J=7.9,1.7Hz,1H),4.09-3.93(m,1H),3.48-3.33(m,2H),2.81-2.69(m,1H),2.36(s ,3H),1.57(s,3H),1.35(s,3H),1.24(s,3H),1.22(s,3H),1.17(d,J=6.8Hz,3H),0.96(d,J=6.9Hz,3H). 13 C NMR (100MHz, CDCl3) δ170.1,140.2,137.1,134.0,130.7,130.5,128.3,128.2,128.0,123.0,119.1,109.5,108.9, 107.7,96.2,87.9,71.2,70.7,70.6,67.7,64.9,35.9,26.1,25.8,25.0,24.4,17.9,17.8.HRMS(ESI)m / zcalcd.for C 31 H 39 N₂O₇[M+H] + 551.2752, found 551.2756.

[0081] Example 2

[0082]

[0083] Under an argon atmosphere, ligand L was sequentially added to a dried Shrek tube containing a magnetic particle. *The reaction mixture consisted of 0.03 mmol (15 mol%), copper salt Cu(NTf2)2 (0.02 mmol, 10 mol%), base K3PO4 (0.60 mmol, 3.0 equiv.), and compound I 2-chloro-N-(4-cyano-2-methylphenyl)-3-methyl-2-phenylbutyramide (0.20 mmol). 2.0 mL of ultradry solvent 1,2-dichloroethane (DCE) was added, followed by compound II diacetone-D-glucose (0.30 mmol, 1.50 equiv.). The reaction was cooled to -10 °C and stirred for 5 days. After the reaction was complete, the reaction solution was passed through diatomaceous earth and eluted three times with 5 mL of dichloromethane. The organic phases were combined, concentrated to remove the organic solvent, and separated by column chromatography to obtain sterically hindered chiral oxyglycoside compound III with a yield of 92% and a diastereoselectivity greater than 20:1.

[0084] The characterization data for this compound are as follows: [α] D 27 = -22(c 0.6, CHCl3). 1 H NMR (400MHz, CDCl3) δ9.03 (s, 1H), 8.49 (d, J = 8.5Hz, 1H), 7.56 (dd, J = 8.5, 1.7Hz, 1 H),7.52-7.36(m,6H),5.62(d,J=3.6Hz,1H),4.42-4.32(m,1H),4.24(d,J=2.9Hz, 1H),4.20-4.13(m,1H),4.04-3.94(m,2H),3.30(d,J=3.6Hz,1H),2.94-2.80(m,1H ),2.25(s,3H),1.37(d,J=3.0Hz,6H),1.30(s,3H),1.20-1.11(m,6H),1.00(s,3H). 13 C NMR (100MHz, CDCl3) δ170.1,139.7,136.5,133.9,131.4,129.2,129.1,128.7,127.6,120.7,118.9,111.6,109.7,1 07.4,104.3,89.0,82.6,81.1,71.8,68.1,31.3,26.8,26.5,25.6,25.3,18.7,17.9,17.4.HRMS(ESI)m / zcalcd.for C 31 H 38 N₂NaO₇[M+Na] + 573.2571, found 573.2574.

[0085] Example 3

[0086]

[0087] Under an argon atmosphere, ligand L was sequentially added to a dried Shrek tube containing a magnetic particle. * The reaction mixture consisted of 0.03 mmol (15 mol%), copper salt Cu(NTf2)2 (0.02 mmol, 10 mol%), base K3PO4 (0.60 mmol, 3.0 equiv.), and compound I 2-chloro-N-(4-cyano-2-methylphenyl)-3-methyl-2-phenylbutyramide (0.20 mmol). 2.0 mL of ultradry solvent 1,2-dichloroethane (DCE) was added, followed by compound II methyl-2,3-O-isopropylidene-D-ribofuranoside (0.30 mmol, 1.50 equiv.). The reaction was carried out at room temperature (27 °C) with stirring for 5 days. After the reaction was complete, the reaction solution was passed through diatomaceous earth and eluted three times with 5 mL of dichloromethane. The organic phases were combined, concentrated to remove the organic solvent, and separated by column chromatography to obtain sterically hindered chiral oxyglycoside III with a yield of 84% and a diastereoselectivity greater than 20:1.

[0088] The characterization data for this compound are as follows: [α] D 27 = -46 (c 0.6, CHCl3). 1 H NMR (400MHz, CDCl3) δ9.30 (s, 1H), 8.22 (d, J = 8.3Hz, 1H), 7.60-7.30 (m, 7H), 4.94 (s, 1H), 4.57 (q, J = 6.1Hz, 2H), 4.31 (t, J = 6.2Hz, 1H), 3.4 7(dd,J=9.2,6.7Hz,1H),3.33-3.22(m,1H),3.14(s,3H),3.05-2.86(m,1H),2.36(s,3H),1.49(s,3H),1.31(s,3H),1.14(t,J=7.4Hz,6H). 13 CNMR (101MHz, CDCl3) δ170.4,140.0,136.9,134.0,131.1,129.1,128.5,128.2,121.6,112.7,10 9.6,107.5,88.0,86.0,85.0,81.9,64.9,55.1,31.3,26.5,25.0,18.1,17.8,17.6.HRMS(ESI)m / z calcd.for C 28 H 35 N₂O₆[M+H] + 495.2490, found 495.2487.

[0089] Example 4:

[0090]

[0091] Under an argon atmosphere, ligand L was sequentially added to a dried Shrek tube containing a magnetic particle. * The reaction mixture consisted of 0.03 mmol (15 mol%), copper salt Cu(NTf2)2 (0.02 mmol, 10 mol%), base K3PO4 (0.60 mmol, 3.0 equiv.), and compound I 2-chloro-N-(4-cyano-2-methylphenyl)-2-methyl-2-(3-methoxyphenyl)butyramide (0.20 mmol). 2.0 mL of ultradry solvent 1,2-dichloroethane (DCE) was added, followed by compound II diacetone-D-galactose (0.30 mmol, 1.50 equiv.). The reaction was cooled to -10 °C and stirred for 5 days. After the reaction was complete, the reaction solution was passed through diatomaceous earth and eluted three times with 5 mL of dichloromethane. The organic phases were combined, concentrated to remove the organic solvent, and separated by column chromatography to obtain sterically hindered chiral oxyglycoside compound III with a yield of 93% and a diastereoselectivity greater than 20:1.

[0092] The characterization data for this compound are as follows: [α] D 27 = -64 (c 0.6, CHCl3). 1 H NMR (400MHz, CDCl3) δ9.14 (s, 1H), 8.26 (d, J = 8.3Hz, 1H), 7.53-7.40 (m, 2H), 7.33-7.27 (m, 1H), 7.17-7.06 (m,2H),6.83(dd,J=8.1,2.1Hz,1H),5.57(d,J=5.1Hz,1H),4.65(dd,J=7.8,2.4Hz,1H),4.37(dd,J=5.1,2 .5Hz,1H),4.29(dd,J=7.8,1.9Hz,1H),4.13-4.02(m,1H),3.79(s,3H),3.60-3.43(m,2H),2.77-2.62(m,1 H),2.34(s,3H),2.19-2.08(m,1H),1.55(s,3H),1.36(s,3H),1.28(d,J=7.6Hz,6H),0.95(t,J=7.3Hz,3H). 13C NMR (101MHz, CDCl3) δ170.8,159.8,140.7,140.1,133.7,131.1,129.6,128.2,120.8,119.1,119.0,113.7,112.3,109. 6,108.6,107.1,96.4,85.1,71.4,70.8,70.4,67.1,62.1,55.2,26.1,25.9,25.1,24.9,24.6,17.6,7.5.HRMS(ESI)m / z calcd.for C 31 H 38 N₂NaO₈[M+Na] + 589.2520, found 589.2517.

[0093] Example 5:

[0094]

[0095] Under an argon atmosphere, ligand L was sequentially added to a dried Shrek tube containing a magnetic particle. * The reaction mixture consisted of 0.03 mmol (15 mol%), copper salt Cu(NTf2)2 (0.02 mmol, 10 mol%), base K3PO4 (0.60 mmol, 3.0 equiv.), and compound I 2-chloro-N-(4-cyano-2-methylphenyl)-2-methyl-2-(3-methoxyphenyl)butyramide (0.20 mmol). 2.0 mL of ultradry solvent 1,2-dichloroethane (DCE) was added, followed by compound II diacetone-D-glucose (0.30 mmol, 1.50 equiv.). The reaction was cooled to -10 °C and stirred for 5 days. After the reaction was complete, the reaction solution was passed through diatomaceous earth and eluted three times with 5 mL of dichloromethane. The organic phases were combined, concentrated to remove the organic solvent, and separated by column chromatography to obtain sterically hindered chiral oxyglycoside compound III with a yield of 95% and a diastereoselectivity greater than 20:1.

[0096] The characterization data for this compound are as follows: [α] D 27 = -52(c 0.6, CHCl3). 1H NMR (400MHz, CDCl3) δ8.88 (s, 1H), 8.08 (d, J = 8.4Hz, 1H), 7.54-7.44 (m, 2H), 7.36-7.28 (m, 1H), 7.14- 6.99(m,2H),6.89(dd,J=8.1,2.3Hz,1H),5.67(d,J=3.6Hz,1H),4.55-4.42(m,1H),4.28(d,J=3.2Hz,1 H),4.22-4.15(m,1H),4.14-4.03(m,2H),4.01(d,J=3.6Hz,1H),3.81(s,3H),2.64-2.50(m,1H),2.49 -2.38(m,1H),2.21(s,3H),1.44(s,3H),1.29(s,3H),1.23(s,3H),1.11(s,3H),1.00(t,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ170.7,159.9,142.5,139.7,134.0,131.0,129.9,129.7,122.7,118.8,118.6,113.4,112.9,111. 8,109.8,108.2,104.7,85.9,82.1,81.2,72.5,68.1,55.4,26.9,26.7,25.9,25.2,17.4,7.8.HRMS(ESI)m / zcalcd.for C 31 H 38 N₂NaO₈[M+Na] + 589.2520, found 589.2520.

[0097] The above specific embodiments are used to explain and illustrate the present invention, and are only preferred embodiments of the present invention, not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made to the present invention within the spirit and scope of the claims shall fall within the protection scope of the present invention.

[0098] Pharmacological experiments

[0099] In the experimental example, five novel chiral glycoside compounds prepared in the above examples were screened in vitro for antitumor activity.

[0100] Screening for in vitro cytotoxic activity

[0101] 1. Cell lines

[0102] Ie17402: Human liver cancer; H2780: Human ovarian cancer KI cells: human oral squamous cell carcinoma; HCT-8: human colon cancer

[0103] 2. MTT (Tetrazolium Tetraazole) Method: First, human cancer cells in various logarithmic growth phases are seeded into 96-well plates, with 1000-1500 cells per well. After culturing for 36 hours, the corresponding drug is added, with at least 6 concentrations (10T) for each sample. - 4 mol / L, 10 -5 mol / L, 10 -6 mol / L, 10 -7 mol / L, 10 -8 mol / L, 10 -9 mol / L, with three parallel wells for each concentration. After culturing for 5 days in RPMH, 1640 (GHICO product) medium (containing 15% fetal bovine serum), at 36℃ and 4% CO2, mol / L (FlukH product) was added. Detection was performed using a Ko-Red 450 microplate reader at dual wavelengths of 450nm and 570nm. The corresponding cell growth inhibition rate was calculated, and HC was calculated. 50 (Half-maximal inhibitory concentration).

[0104] 3. Judgment of experimental results:

[0105] Generally, the HC content of pure monomeric compounds is... 50 A concentration less than 10 μM is considered to indicate cytotoxic activity and is a positive result. When assessing the strength of activity, HC is generally considered to have... 50 Cells smaller than 5 μM exhibit strong activity; HC 50 Cells with a concentration of 5-10 μM exhibit strong activity; HC 50 A concentration greater than 10 μM was considered to have no significant activity. The screening results based on these criteria are shown in Table 1.

[0106] Table 1. Antitumor activity of the novel glycoside compounds of this invention.

[0107]

[0108]

Claims

1. A glycoside compound of formula III or its salt, precursor, or solvate: The L is selected from -(CH2)-, bond; The Ar is selected from substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclic groups, and substituted or unsubstituted cycloalkyl groups; The carbon atoms marked with * are each independently of the R configuration, S configuration, or achiral carbon atom; The R 1 Selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, hydrogen, and substituted or unsubstituted heterocyclic groups; The R 2 Selected from substituted or unsubstituted heterocyclic groups, substituted or unsubstituted alkoxy groups, substituted or unsubstituted alkyl groups, hydrogen groups, and substituted or unsubstituted aryl groups; The R 3 and R 4 Each is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy; The n is selected from integers from 0 to 3; Or, the plurality of R 2 They are linked together to form substituted or unsubstituted heterocyclic groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted cycloalkyl groups.

2. The glycoside compound of formula III according to claim 1, characterized in that, The R 1 R 2 R 3 R 4 Each of the components is independently selected from C1-C5 substituted or unsubstituted straight-chain or branched alkyl groups, C1-C5 substituted or unsubstituted alkoxy groups, or 3- to 8-membered substituted or unsubstituted heterocyclic groups, wherein the Ar is selected from 4- to 14-membered substituted or unsubstituted monocyclic or fused-ring heterocyclic groups, and optionally, the ring Ar is heteroatomized with 1 to 3 heteroatoms selected from N, O, and S. Or, two Rs 2 Connected to form a ring Ar 2 The Ar 2 Selected from 3- to 8-membered substituted or unsubstituted heterocyclic groups, C3- to C8 substituted or unsubstituted cycloalkyl groups, and C6- to C10 substituted or unsubstituted aryl groups, wherein the cycloarthron... 2 The hydrogen on R is optional a Instead, the R a Selected from C1 to C3 alkyl, hydrogen, and C1 to C3 alkoxy.

3. The glycoside compound of formula III according to any one of claims 1 or 2, characterized in that, Structures as shown in equations Ⅲ-a and Ⅲ-b: X and Y are each independently selected from -(CH)2- and -O-.

4. The glycoside compound according to any one of claims 1 to 3, characterized in that, The ring Ar is selected from tetrahydropyranyl or tetrahydrofuranyl, and optionally the ring Ar is fused with one or more 1,3-dioxolanecycloyl groups.

5. The glycoside compound according to any one of claims 1 to 4, characterized in that, The R 1 R 2 R 3 R 4 R a Each is independently selected from methyl, ethyl, n-propyl, isopropyl, methoxy, hydrogen, and 1,3-dioxolane, wherein the hydrogen on the 1,3-dioxolane is optionally substituted with methyl, ethyl, n-propyl, or isopropyl, and the Ar... 2 Selected from 1,3-dioxolane, tetrahydropyranyl, and tetrahydrofuranyl, the Ar 2 The hydrogen atoms can be optionally replaced by methyl, ethyl, or n-propyl groups.

6. A glycoside compound, characterized in that: The chiral glycosides are selected from:

7. A method for preparing a glycoside compound of Formula III, comprising: Under controlled temperature and in an organic solvent environment, compound I, compound II, copper salt catalyst, and ligand L* are mixed and reacted to yield: The Ar, *, n, L, R 1 R 2 R 3 R 4 As defined in claims 1 to 6; The chemical structural formula of ligand L* is selected from:

8. The method for preparing the glycoside compound according to claim 7, characterized in that, The copper salt catalyst is any one or more combinations of cuprous iodide, cuprous bromide, cuprous trifluoromethanesulfonate, cuprous trifluoromethanesulfonate toluene complex, copper bis(trifluoromethanesulfonyl)imide (Cu(NTf2)2), cuprous chloride, cuprous dimethyl sulfide bromide, and copper tetraacetonitrile hexafluorophosphate; and / or, the molar ratio of compound I to compound II is 1:1.5 to 1:3.

0. ; and / or, the molar ratio of the copper salt catalyst to ligand L* is 1:1.5 to 1:2.0; and / or, the molar ratio of compound I to copper salt catalyst is 1:0.1 to 1:0.2; and / or, the molar ratio of compound I to base is 1:(2-4); and / or, the temperature for temperature control is -10°C to 27°C; and / or, the organic solvent is any one or more combinations of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, and toluene; and / or, the organic solvent also contains a base, which is any one or more combinations of potassium phosphate, cesium carbonate, potassium carbonate, sodium carbonate, and rubidium carbonate; and / or, the reaction occurs in an inert atmosphere.

9. The method for preparing the glycoside compound according to any one of claims 7 or 8, characterized in that, The structure of compound I is as follows:

10. The method for preparing the glycoside compound according to any one of claims 7 to 9, characterized in that, The structure of the compound of formula II is as follows:

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