Chiral phosphine oxide compound containing pyrrole group, preparation method and application of chiral phosphine oxide compound as antitumor drug

Abstract

The invention belongs to the technical field of organic compounds, and discloses a chiral phosphine oxide compound containing a pyrrole group, a preparation method and application of the chiral phosphine oxide compound as an antitumor drug. According to the preparation method of the chiral phosphine oxide compound containing the pyrrole group, the novel P-chiral phosphine oxide compound containing the pyrrole group is constructed through [3 + 2] cycloaddition reaction of alkyne and isocyano acetate catalyzed by silver salt or cuprous salt and a chiral ligand, the reaction process is simple, the reaction condition is mild, the substrate application range is wide, and the method is suitable for industrial production. The chiral phosphine oxide containing the pyrrole group in the target product has better yield and enantioselectivity, so that the technical problems of narrower substrate application range, harsh reaction conditions and low yield of the target product in the prior art for preparing the chiral phosphine oxide by a desymmetry and kinetic resolution method are solved; meanwhile, the prepared pyrrolyl-containing phosphine oxide compound is further subjected to an anti-tumor activity test, and a relatively good tumor cell proliferation inhibition effect is shown.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic compounds, and in particular relates to a chiral phosphine oxide compound containing a pyrrole group, a preparation method thereof, and an application thereof as an anti-tumor drug. Background Art

[0002] Traditional methods for preparing chiral phosphine oxides require the use of stoichiometric amounts of chiral starting materials or reagents. Therefore, asymmetric catalytic desymmetrization strategies hold greater promise. Currently used asymmetric catalytic desymmetrization methods for preparing chiral phosphine oxides include 2+2+2 coupling cyclization and aromatization with other alkynes to yield polyaromatic rings; addition of O or N nucleophiles to yield alkenyl groups; intramolecular metathesis with alkenes; and reaction with azides to yield triazoles. In recent years, chemists have explored asymmetric catalytic approaches to construct chiral phosphine oxides, with major research efforts focusing on noble metal (palladium, rhodium, iridium)-catalyzed asymmetric CH / NH functionalization reactions, CP cross-coupling reactions, and organocatalyzed nucleophilic substitution reactions. Research on the de novo formation of nitrogen heteroarenes to construct phosphorus-containing chiral centers remains incomplete, with significant limitations in terms of reaction diversity and substrate scope. Summary of the Invention

[0003] This study exploits the de novo formation of N-heteroarenes from alkynylphosphine oxides with isocyanoacetates, developing the first universal and facile catalytic asymmetric method for the synthesis of a wide range of highly enantiomerically enriched pyrrole-based chiral phosphine oxides via desymmetrization and kinetic resolution. Furthermore, structure-based screening of the compound library for antitumor activity highlights the importance of chiral phosphine oxides and substituents in drug discovery and development.

[0004] The purpose of the present invention is achieved by at least one of the following technical solutions.

[0005] The present invention provides a chiral phosphate and phosphoramide compound containing a pyrrole group, the structure of which is as follows:

[0006]

[0007] Among the compounds I, II, III and IV,

[0008] R 1 is H, C1-C10 aliphatic group, C1-C10 alkyl group, benzyl group;

[0009] R 2 C1-C10 aliphatic group, C1-C10 alkyl group, benzyl group;

[0010] Moreover, R 1 and R 2 It can be different;

[0011] R 3 is H, C1-C10 aliphatic group, thienyl, pyridyl, C1-C10 alkyl, ester group, alkoxy group, phenyl group and phenyl group containing substituents, wherein the substituent is an electron-withdrawing or electron-donating protecting group, the electron-withdrawing protecting group is halogen, nitro, trifluoromethyl and ester substituent; the electron-donating protecting group is methyl, ethyl, tert-butyl, phenyl, phenolic hydroxyl and methoxy; wherein the ester substituent is methyl ester, ethyl ester and benzyl ester;

[0012] R 4 is p-toluenesulfonyl, an ester group, wherein the ester group is methyl ester, ethyl ester, isopropyl ester, tert-butyl ester, or benzyl ester;

[0013] R 5 phenyl, naphthyl, C1-C10 aliphatic group, thienyl, C1-C10 alkyl, C1-C10 alkoxy, phenoxy, phenyl containing a substituent, and amino containing a substituent, wherein the substituent of the phenyl group is at least one of halogen, C1-C10 alkyl, and C1-C10 alkoxy, and the substituent of the amino group is at least one of C1-C10 aliphatic group, C1-C10 alkyl, phenyl, and benzyl;

[0014] R 6 The alkyl group may be a C1-C10 aliphatic group, a C1-C10 alkyl group, a phenyl group, a phenyl group containing a substituent, a benzyl group, a benzyl group containing a substituent, a β-D-glucopyranosyl group, an α-D-galactopyranosyl group, a β-D-mannopyranosyl group or the like.

[0015] The present invention provides a method for preparing a chiral phosphoramide compound I containing a pyrrole group, the preparation method comprising the steps of:

[0016] In a solvent, diacetylenic phosphoramide and isocyanoacetate are used as reaction raw materials, and under the action of metal salt and chiral ligand, the chiral phosphine oxide compound I is obtained by reaction. The reaction process is shown in the following reaction formula (1):

[0017]

[0018] Reaction formula (1);

[0019] in,

[0020] R 1 is H, C1-C10 aliphatic group, C1-C10 alkyl group, benzyl group;

[0021] R 2 C1-C10 aliphatic group, C1-C10 alkyl group, benzyl group;

[0022] R 3is H, C1-C10 aliphatic group, thienyl, pyridyl, C1-C10 alkyl, ester group, alkoxy group, phenyl group and phenyl group containing substituents, wherein the substituent is an electron-withdrawing or electron-donating protecting group, the electron-withdrawing protecting group is halogen, nitro, trifluoromethyl and ester substituent; the electron-donating protecting group is methyl, ethyl, tert-butyl, phenyl, phenolic hydroxyl and methoxy; wherein the ester substituent is methyl ester, ethyl ester and benzyl ester;

[0023] R 4 is p-toluenesulfonyl, an ester group, wherein the ester group is methyl ester, ethyl ester, isopropyl ester, tert-butyl ester, or benzyl ester;

[0024] Moreover, R 1 、R 2 It can be different;

[0025] Preferably, R 1 、R 2 is H, isopropyl, ethyl, cyclohexyl, allyl, benzyl; R 3 is H, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethylphenyl, p-cyanophenyl, 2-naphthyl, m-chlorophenyl, m-cyanophenyl, 2-thienyl, 2-pyridyl, 2-quinolyl, cyclopropyl, n-butyl, or 1-cyclohexenyl; R 4 are methyl formate, ethyl formate, isopropyl formate, tert-butyl formate, benzyl formate;

[0026] Wherein, the reactant isocyanoacetate is 1-2 equivalents of the phosphine oxide structure alkyne, that is, the molar ratio of the diyne to isocyanoacetate is 1:(1-2); preferably, 1:2;

[0027] The solvent is one or more of toluene, dichloromethane, chloroform, ether, ethyl acetate, tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, dioxane, and methanol; preferably, acetonitrile:ethyl acetate = 1:1; the amount of the solvent is 1 mL-100 mL (based on the two digits of the diyne), preferably, the concentration is 0.1 M.

[0028] The additive is one or more of an acid, a base, and a molecular sieve; the acid is trifluoroacetic acid or benzoic acid; the base is potassium carbonate, potassium phosphate, potassium fluoride, or sodium acetate; and the molecular sieve is a spherical or powdered molecular sieve; preferably, potassium carbonate.

[0029] The catalyst is AgX 1 or CuX 2 Other metals, including X 1 F - 、Cl - Br - 、OAc -、OTf - 、BF4 - 、SbF6 - 、NO3 - 、CO3 2- 、SO4 2- CF3COO - , O 2- , where X 2 Cl - Br - , I - 、CN - PF6 - , O 2- ; Preferably Ag2O.

[0030] The molar ratio of the metal salt catalyst to the ligand is preferably 1:1

[0031] The amount of the catalyst is x mol%, where x is 1-50, and x mol% refers to the molar percentage of the co-catalyst in the entire reaction system; preferably, x is 20.

[0032] Wherein, the reaction temperature is -30°C to 50°C; preferably, it is 25°C.

[0033] The reaction time is 12-96 hours, preferably 72 hours.

[0034] The ligand is selected from L1-L16, preferably, L14.

[0035]

[0036] The present invention provides a method for preparing a chiral phosphoramide compound II containing a pyrrole group, the preparation method comprising the steps of:

[0037] In a solvent, monoalkynyl phosphoramide and isocyanoacetate are used as reaction raw materials, and under the action of metal salt and chiral ligand, the chiral phosphine oxide compound II is reacted. The reaction process is shown in the following reaction formula (2):

[0038]

[0039] Reaction formula (2):

[0040] in,

[0041] R 1 is H, C1-C10 aliphatic group, C1-C10 alkyl group, benzyl group;

[0042] R 2 C1-C10 aliphatic group, C1-C10 alkyl group, benzyl group;

[0043] R 3 is H, C1-C10 aliphatic group, thienyl, pyridyl, C1-C10 alkyl, ester group, alkoxy group, phenyl group and phenyl group containing substituents, wherein the substituent is an electron-withdrawing or electron-donating protecting group, the electron-withdrawing protecting group is halogen, nitro, trifluoromethyl and ester substituent; the electron-donating protecting group is methyl, ethyl, tert-butyl, phenyl, phenolic hydroxyl and methoxy; wherein the ester substituent is methyl ester, ethyl ester and benzyl ester;

[0044] R 4 is p-toluenesulfonyl, an ester group, wherein the ester group is methyl ester, ethyl ester, isopropyl ester, tert-butyl ester, or benzyl ester;

[0045] R 5 phenyl, naphthyl, C1-C10 aliphatic group, thienyl, C1-C10 alkyl, C1-C10 alkoxy, phenoxy, phenyl containing a substituent, and amino containing a substituent, wherein the substituent of the phenyl group is at least one of halogen, C1-C10 alkyl, and C1-C10 alkoxy, and the substituent of the amino group is at least one of C1-C10 aliphatic group, C1-C10 alkyl, phenyl, and benzyl;

[0046] Moreover, R 1 、R 2 It can be different;

[0047] Preferably, R 1 、R 2 is H, isopropyl, ethyl, cyclohexyl, allyl, benzyl; R 3 is H, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethylphenyl, p-cyanophenyl, 2-naphthyl, m-chlorophenyl, m-cyanophenyl, 2-thienyl, 2-pyridyl, 2-quinolyl, cyclopropyl, n-butyl, or 1-cyclohexenyl; R 4 is methyl formate, ethyl formate, isopropyl formate, tert-butyl formate, benzyl formate; R 5 is phenyl, methyl, methoxy;

[0048] Wherein, the equivalent of the reactant phosphine oxide structure alkyne is 1-2 of isocyanoacetate, that is, the molar ratio of the diyne to isocyanoacetate is (1-2):1; preferably, 2:1;

[0049] The solvent is one or more of toluene, dichloromethane, chloroform, ether, ethyl acetate, tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, dioxane, methanol, and trifluorotoluene; preferably, trifluorotoluene; the amount of the solvent is 1 mL-100 mL (based on the two digits of the diyne), preferably, the concentration is 0.1 M.

[0050] The additive is one or more of an acid, a base, and a molecular sieve; the acid is trifluoroacetic acid or benzoic acid; the base is potassium carbonate, potassium phosphate, potassium fluoride, or sodium acetate; and the molecular sieve is a spherical or powdered molecular sieve; preferably, potassium phosphate.

[0051] The catalyst is selected from AgX 1 or CuX 2 Other metals, including X 1 F - 、Cl - Br - 、OAc - 、OTf - 、BF4 - 、SbF6 - 、NO3 - 、CO3 2- 、SO4 2- CF3COO - , O 2- , where X 2 Cl - Br - , I - 、CN - PF6 - , O 2- ; Preferably Ag2O.

[0052] The molar ratio of the metal salt catalyst to the ligand is preferably 1:1.

[0053] The amount of the catalyst is x mol%, where x is 1-50, and x mol% refers to the molar percentage of the co-catalyst in the entire reaction system; preferably, x is 20.

[0054] Wherein, the reaction temperature is -30°C to 50°C; preferably, it is 25°C.

[0055] The reaction time is 12-96 hours, preferably 72 hours.

[0056] The ligand is selected from L1-L16, preferably, L10.

[0057]

[0058] The present invention provides a method for preparing a chiral phosphate compound III containing a pyrrole group, the preparation method comprising the steps of:

[0059] In a solvent, diacetylene phosphate and isocyanate are used as the reaction raw materials, and in the presence of metal salt and chiral complex

[0060]

[0061] Under the action of the body, the chiral phosphine oxide compound III is obtained by reaction, and the reaction process is shown in the following reaction formula (3):

[0062] Reaction formula (3):

[0063] in,

[0064] R 3 is H, C1-C10 aliphatic group, thienyl, pyridyl, C1-C10 alkyl, ester group, alkoxy group, phenyl group and phenyl group containing substituents, wherein the substituent is an electron-withdrawing or electron-donating protecting group, the electron-withdrawing protecting group is halogen, nitro, trifluoromethyl and ester substituent; the electron-donating protecting group is methyl, ethyl, tert-butyl, phenyl, phenolic hydroxyl and methoxy; wherein the ester substituent is methyl ester, ethyl ester and benzyl ester;

[0065] R 4 is p-toluenesulfonyl, an ester group, wherein the ester group is methyl ester, ethyl ester, isopropyl ester, tert-butyl ester, or benzyl ester;

[0066] R 6 The alkyl group may be a C1-C10 aliphatic group, a C1-C10 alkyl group, a phenyl group, a phenyl group containing a substituent, a benzyl group, a benzyl group containing a substituent, a β-D-glucopyranosyl group, an α-D-galactopyranosyl group, a β-D-mannopyranosyl group or the like.

[0067] Preferably, R 3 is H, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethylphenyl, p-cyanophenyl, 2-naphthyl, m-chlorophenyl, m-cyanophenyl, 2-thienyl, 2-pyridyl, 2-quinolyl, cyclopropyl, n-butyl, or 1-cyclohexenyl; R 4 is methyl formate, ethyl formate, isopropyl formate, tert-butyl formate, benzyl formate; R 6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl;

[0068] Wherein, the reactant isocyanoacetate is 1-2 times the equivalent of the phosphine oxide structure alkyne, that is, the molar ratio of the diyne to isocyanoacetate is 1:(1-2); preferably, 1:1;

[0069] The solvent is one or more of toluene, dichloromethane, chloroform, ether, ethyl acetate, tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, dioxane, and methanol; preferably, toluene; the amount of the solvent is 1 mL-100 mL (based on the two digits of the diyne), and preferably, the concentration is 0.1 M.

[0070] The catalyst is selected from AgX 1 or CuX 2Other metals, including X 1 F - 、Cl - Br - 、OAc - 、OTf - 、BF4 - 、SbF6 - 、NO3 - 、CO3 2- 、SO4 2- CF3COO - , O 2- , where X 2 Cl - Br - , I - 、CN - PF6 - , O 2- ; Preferably Ag2O.

[0071] The molar ratio of the metal salt catalyst to the ligand is preferably 1:1.

[0072] The amount of the catalyst is x mol%, where x is 1-50, and x mol% refers to the molar percentage of the co-catalyst in the entire reaction system; preferably, x is 20.

[0073] Wherein, the reaction temperature is -30°C to 50°C; preferably, 0°C.

[0074] The reaction time is 12-96 hours, preferably 72 hours.

[0075] The ligand is selected from L1-L16, preferably, L15.

[0076]

[0077] The present invention provides a method for preparing a chiral phosphate compound IV containing a pyrrole group, the preparation method comprising the steps of:

[0078] In a solvent, monoalkyne phosphate and isocyanoacetate are used as reaction raw materials, and under the action of metal salt and chiral ligand, the chiral phosphine oxide compound IV is obtained by reaction. The reaction process is shown in the following reaction formula (4):

[0079]

[0080] As shown:

[0081] Reaction formula (4):

[0082] in,

[0083] R 3is H, C1-C10 aliphatic group, thienyl, pyridyl, C1-C10 alkyl, ester group, alkoxy group, phenyl group and phenyl group containing substituents, wherein the substituent is an electron-withdrawing or electron-donating protecting group, the electron-withdrawing protecting group is halogen, nitro, trifluoromethyl and ester substituent; the electron-donating protecting group is methyl, ethyl, tert-butyl, phenyl, phenolic hydroxyl and methoxy; wherein the ester substituent is methyl ester, ethyl ester and benzyl ester;

[0084] R 4 is p-toluenesulfonyl, an ester group, wherein the ester group is methyl ester, ethyl ester, isopropyl ester, tert-butyl ester, or benzyl ester;

[0085] R 5 phenyl, naphthyl, C1-C10 aliphatic group, thienyl, C1-C10 alkyl, C1-C10 alkoxy, phenoxy, phenyl containing a substituent, and amino containing a substituent, wherein the substituent of the phenyl group is at least one of halogen, C1-C10 alkyl, and C1-C10 alkoxy, and the substituent of the amino group is at least one of C1-C10 aliphatic group, C1-C10 alkyl, phenyl, and benzyl;

[0086] R 6 The alkyl group may be a C1-C10 aliphatic group, a C1-C10 alkyl group, a phenyl group, a phenyl group containing a substituent, a benzyl group, a benzyl group containing a substituent, a β-D-glucopyranosyl group, an α-D-galactopyranosyl group, a β-D-mannopyranosyl group or the like.

[0087] Preferably, R 3 is H, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethylphenyl, p-cyanophenyl, 2-naphthyl, m-chlorophenyl, m-cyanophenyl, 2-thienyl, 2-pyridyl, 2-quinolyl, cyclopropyl, n-butyl, or 1-cyclohexenyl; R 4 is methyl formate, ethyl formate, isopropyl formate, tert-butyl formate, benzyl formate; R 5 is phenyl, methyl, or diethylamino; R 6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl;

[0088] Wherein, the reactant phosphine oxide structure alkyne equivalent is 1-2 of isocyanoacetate, that is, the molar ratio of mono- to isocyanoacetate is (1-2):1; preferably, 2:1;

[0089] The solvent is one or more of toluene, dichloromethane, chloroform, ether, ethyl acetate, tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, dioxane, methanol, and trifluorotoluene; preferably, trifluorotoluene; the amount of the solvent is 1 mL-100 mL (based on the two digits of the diyne), preferably, the concentration is 0.1 M.

[0090] The additive is one or more of an acid, a base, and a molecular sieve; the acid is trifluoroacetic acid or benzoic acid; the base is potassium carbonate, potassium phosphate, potassium fluoride, or sodium acetate; and the molecular sieve is a spherical or powdered molecular sieve; preferably, potassium phosphate.

[0091] The catalyst is selected from AgX 1 or CuX 2 Other metals, including X 1 F - 、Cl - Br - 、OAc - 、OTf - 、BF4 - 、SbF6 - 、NO3 - 、CO3 2- 、SO4 2- CF3COO - , O 2- , where X 2 Cl - Br - , I - 、CN - PF6 - , O 2- ; Preferably Ag2O.

[0092] The molar ratio of the metal salt catalyst to the ligand is preferably 1:1.

[0093] The amount of the catalyst is x mol%, where x is 1-50, and x mol% refers to the molar percentage of the co-catalyst in the entire reaction system; preferably, x is 20.

[0094] Wherein, the reaction temperature is -30°C to 50°C; preferably, it is 25°C.

[0095] The reaction time is 12-96 hours, preferably 72 hours.

[0096] The ligand is selected from L1-L16, preferably, L10.

[0097]

[0098] The present invention provides an application of a chiral phosphine oxide compound containing a pyrrole group;

[0099] The applications are specifically applications in catalysts, active molecules of anti-tumor drugs, and molecules that can be connected to biological macromolecules.

[0100] The advantages of the present invention are: the present invention provides a chiral phosphine oxide compound containing a pyrrole group, a preparation method and an application thereof, wherein the preparation method of the chiral phosphine oxide compound containing a pyrrole group comprises adding a solvent to a silver salt or a monovalent copper salt and a chiral ligand, stirring at room temperature, adding a dialkynyl phosphine oxide compound and isocyanoacetate to react at -30°C to 50°C, and obtaining a chiral phosphine oxide compound containing a pyrrole group after purification. The reaction principle is to construct a novel chiral phosphine oxide compound containing a pyrrole group by a [3+2] cycloaddition reaction of alkyne and isocyanoacetate catalyzed by the silver salt or the monovalent copper salt and the chiral ligand. The invention discloses a P-chiral phosphine oxide compound containing a pyrrole group, which has a simple reaction process, mild reaction conditions, a wide range of substrate applications, and a target product containing a pyrrole group in a chiral phosphine oxide compound with good yield and enantioselectivity, thereby solving the technical problems of a narrow substrate application range, harsh reaction conditions, and low yield of the target product in the prior art of preparing chiral phosphine oxide compounds by a desymmetrization method. At the same time, the invention provides a chiral phosphine oxide compound containing a pyrrole group, which has the potential for application in catalysts, active molecules of anti-tumor drugs, and catalysis and medicinal chemistry connected to biomacromolecules. BRIEF DESCRIPTION OF THE DRAWINGS

[0101] Figure 1 The hydrogen spectrum of the chiral phosphine oxide compound containing pyrrole group provided in Example 1 of the present invention is shown in FIG. 1 H NMR spectrum of 3aa (400MHz, CDCl3);

[0102] Figure 2 The phosphorus spectrum of the chiral phosphine oxide compound containing pyrrole group provided in Example 1 of the present invention is as follows: 31 P NMR spectrum of 3aa (162MHz, CDCl3);

[0103] Figure 3 The carbon spectrum of the chiral phosphine oxide compound containing a pyrrole group provided in Example 1 of the present invention; 13 C NMR spectrum of 3aa (101MHz, CDCl3);

[0104] Figure 4 The results of the proliferation activity test of HepG2 liver cancer cells for the phosphine oxide compound library prepared by the present invention; Figure 5 Several compounds were tested for their antiproliferative activity as shown by IC50 values. DETAILED DESCRIPTION

[0105] The technical solution of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts shall fall within the scope of protection of the present invention.

[0106] Example 1

[0107]

[0108] Desymmetric synthesis of chiral phosphoramide compound 3aa.

[0109] In a 10 mL reaction tube, Ag2O (0.01 mmol), ligand L14 (0.02 mmol), 0.5 mL of anhydrous acetonitrile, and 0.5 mL of anhydrous ethyl acetate were added sequentially and reacted at room temperature for about 15 min. Then, 1a (0.1 mmol), potassium carbonate (0.2 mmol), and 2a (0.2 mmol) were added sequentially. After reacting for 72 h, the mixture was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to give 3aa (white solid, 44.3 mg, 99% yield, 99% ee).

[0110] The data of hydrogen, carbon and phosphorus nuclear magnetic resonance spectra, mass spectrometry and liquid chromatography are as follows:

[0111] 1 H NMR(400MHz, CDCl3) δ10.06(s,1H),7.66(d,J=6.5Hz,3H),7.40(dd,J=23.6,7.2Hz,3H),7.35–7.2 6(m,5H),3.68(s,3H),3.32(dp,J=20.0,6.6Hz,2H),1.23(d,J=6.7Hz,6H),0.92(d,J=6.7Hz,6H).

[0112] 13C NMR (101MHz, CDCl3) δ161.23 (d, J = 1.8Hz), 133.80 (d, J = 11.2Hz), 132.95, 132.14 (d, J=1.8Hz),131.55,130.63(d,J=23.7Hz),129.97,128.57,127.58,127.31,121.72(d ,J=12.9Hz),121.11(d,J=4.4Hz),117.99(d,J=177.0Hz),99.08(d,J=34.0Hz),87.4 9(d,J=184.5Hz), 51.62, 46.84(d,J=5.6Hz), 23.27(d,J=2.8Hz), 21.51(d,J=2.0Hz).

[0113] 31 P NMR (162 MHz, CDCl3) δ 0.14.

[0114] HRMS(ESI)calcd for C 26 H 30 N2O3Pm / z[M+H] + :449.1989; found:449.1984.

[0115] HPLC (Daicel Chiralpak AD-H, i-PrOH / hexane=20 / 80, flow rate 1.0mL / min, λ=254nm): t1=4.643min, t2=11.934min.

[0116] Example 2

[0117]

[0118] Desymmetric synthesis of chiral phosphoramide compound 3f'a.

[0119] In a 10 mL reaction tube, Ag2O (0.01 mmol), ligand L14 (0.02 mmol), 0.5 mL of anhydrous acetonitrile and 0.5 mL of anhydrous ethyl acetate were added in sequence and reacted at room temperature for about 15 min. Then, 1f' (0.1 mmol), potassium carbonate (0.2 mmol) and 2a (0.2 mmol) were added in sequence. After reacting for 72 h, the mixture was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to give 3f'a (colorless viscous liquid, 44.3 mg, 99% yield, 99% ee).

[0120] The data of hydrogen, carbon and phosphorus nuclear magnetic resonance spectra, mass spectrometry and liquid chromatography are as follows:

[0121] 1 1H NMR (400 MHz, CDCl3) δ 10.93 (s, 1H), 7.66–7.58 (m, 1H), 7.47 (t, J = 3.6 Hz, 1H), 7.33–7.26 (m, 3H), 7.25–7.18 (m, 3H), 7.08–6.94 (m, 7H), 3.50 (s, 3H), 2.31 (s, 3H).

[0122] 13 13C NMR (101 MHz, CDCl3) δ 161.1 (d, J = 1.8 Hz), 141.0 (d, J = 11.2 Hz), 134.0 (d, J = 12.4 Hz), 133.1 (d, J = 11.7 Hz), 132.9 (d, J = 1.4 Hz), 132.4 (d, J = 1.8 Hz), 132.2 (d, J = 9.8 Hz), 132.0 (d, J = 2.7 Hz), 131.2 (d, J = 12.0 Hz), 130.4, 130.3, 130.2 (d, J = 125.6 Hz), 129.7 (d, J = 20.3 Hz), 128.6 (d, J = 12.1 Hz), 128.5, 127.3, 127.2, 125.4 (d, J = 13.7 Hz), 121.6 (d, J = 12.3 Hz), 120.3 (d, J = 4.0 Hz), 116.7 (d, J = 142.7 Hz), 103.6 (d, J = 31.6 Hz), 83.8 (d, J = 175.3 Hz), 51.5, 21.0 (d, J = 5.4 Hz).

[0123] 31 31P NMR (162 MHz, CDCl3) δ -0.80.

[0124] HRMS (ESI) calcd for C 30 H 28 N2O3P m / z [M + H] + : 495.1833; found: 495.1829.

[0125] HPLC (Daicel Chiralpak IBN-3, i-PrOH / hexane = 20 / 80, flow rate 1.0 mL / min, λ = 254 nm): t1 = 6.787 min, t2 = 7.917 min.

[0126] Example 3

[0127]

[0128] Desymmetric synthesis of chiral phosphoramide compound 3c'a.

[0129] In a 10 mL reaction tube, Ag2O (0.01 mmol), ligand L14 (0.02 mmol), 0.5 mL of anhydrous acetonitrile, and 0.5 mL of anhydrous ethyl acetate were added in sequence and reacted at room temperature for about 15 min. Then, 1c' (0.1 mmol), potassium carbonate (0.2 mmol), and 2a (0.2 mmol) were added in sequence. After reacting for 72 h, the mixture was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to give 3c'a (colorless viscous liquid, 31.9 mg, 70% yield, 76% ee).

[0130] The data of hydrogen, carbon and phosphorus nuclear magnetic resonance spectra, mass spectrometry and liquid chromatography are as follows:

[0131] 1 H NMR (400MHz, CDCl3) δ10.93 (s, 1H), 7.66–7.58 (m, 1H), 7.47 (t, J = 3.6Hz, 1H), 7. 33–7.26(m,3H),7.25–7.18(m,3H),7.08–6.94(m,7H),3.50(s,3H),2.31(s,3H).

[0132] 13 C NMR (101MHz, CDCl3) δ161.1 (d, J = 1.8Hz), 141.0 (d, J = 11.2Hz), 134.0 (d, J = 12.4Hz), 133.1 (d, J = 11.7Hz), 132.9 (d, J=1.4Hz),132.4(d,J=1.8Hz),132.2(d,J=9.8Hz),132.0(d,J=2.7Hz),131.2(d,J=12.0Hz),130.4,130.3,130.2(d ,J=125.6Hz),129.7(d,J=20.3Hz),128.6(d,J=12.1Hz),128.5,127.3,127.2,125.4(d,J=13.7Hz),121.6(d,J=12. 3Hz), 120.3 (d, J = 4.0Hz), 116.7 (d, J = 142.7Hz), 103.6 (d, J = 31.6Hz), 83.8 (d, J = 175.3Hz), 51.5, 21.0 (d, J = 5.4Hz).

[0133] 31 P NMR (162 MHz, CDCl3) δ-0.80.

[0134] HRMS(ESI)calcd for C 26 H 25 N2O3Pm / z[M+H] + :445.1676; found:445.1674.

[0135] HPLC (Daicel Chiralpak IBN-3, i-PrOH / hexane=20 / 80, flow rate 1.0mL / min, λ=254nm): t1=6.391min, t2=7.123min.

[0136] Example 4

[0137] Desymmetric synthesis of chiral phosphoramide compound 3ya.

[0138]

[0139] In a 10 mL reaction tube, Ag2O (0.01 mmol), ligand L10 (0.02 mmol), 0.5 mL of anhydrous acetonitrile, and 0.5 mL of anhydrous ethyl acetate were added in sequence and reacted at room temperature for about 15 min. Then, 1y (0.1 mmol), potassium carbonate (0.2 mmol), and 2a (0.2 mmol) were added in sequence. After reacting for 72 h, the mixture was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to give 3ya (white solid, 23.7 mg, 80% yield, 72% ee).

[0140] The data of hydrogen, carbon and phosphorus nuclear magnetic resonance spectra, mass spectrometry and liquid chromatography are as follows:

[0141] 1 H NMR (500MHz, CDCl3) δ10.41(s,1H),7.35(td,J=3.5,1.6Hz,1H),7.18(dd,J=4.8,2.8Hz,1H),3.85(s,3 H), 3.46 (dp, J = 20.1, 6.8Hz, 2H), 3.06 (d, J = 10.0Hz, 1H), 1.35 (d, J = 6.8Hz, 6H), 1.24 (d, J = 6.8Hz, 6H).

[0142] 13 C NMR (126MHz, CDCl3) δ128.90, 128.71, 117.27 (d, J = 12.7Hz), 88.11 (d, J = 32.7Hz), 51.75, 46.47 (d, J = 6.0Hz), 23.28 (d, J = 2.6Hz), 21.55.

[0143] 31 P NMR (203 MHz, CDCl3) δ 1.12.

[0144] HRMS(ESI)calcd for C 14 H 21 N2O3Pm / z[M+H] + :198.1043; found:198.1048.

[0145] HPLC (Daicel Chiralpak IA-3, i-PrOH / hexane=10 / 90, flow rate 1.0mL / min, λ=254nm): t1=12.895min, t2=15.131min.

[0146] Example 5

[0147] Kinetic resolution and synthesis of chiral phosphoramide compound 3'ia.

[0148]

[0149] To a 10 mL reaction tube, Ag2O (0.01 mmol), ligand L10 (0.02 mmol) and 1 mL of trifluorotoluene were added in sequence and reacted at room temperature for about 15 min. Then, 1'i (0.2 mmol) and 2e (0.1 mmol) were added. After reacting for 72 h, the mixture was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to give 3'ie (gray solid, 40.8 mg, 96% yield, 90% ee).

[0150] The data of hydrogen, carbon and phosphorus nuclear magnetic resonance spectra, mass spectrometry and liquid chromatography are as follows:

[0151] 1 H NMR(500MHz, CDCl3)δ10.91(s,1H),8.40(d,J=5.0Hz,1H),7.65–7.50(m,3H),7.42(t,J=7.9Hz,1H),7.30–7.14(m ,4H),7.03–6.95(m,1H),3.52(s,3H),3.45(dp,J=19.9,6.6Hz,2H),1.19(d,J=6.7Hz,6H),1.03(d,J=6.7Hz,6H).

[0152] 13C NMR (126MHz, CDCl3) δ160.75, 152.75, 147.92 (d, J = 4.9Hz), 135.46 (d, J = 123. 8Hz),135.20,133.10(d,J=11.0Hz),131.39(d,J=10.2Hz),130.42(d,J=2.9Hz ),128.87(d,J=18.2Hz),127.59(d,J=12.6Hz),122.58(d,J=11.8Hz),121.83, 117.37(d,J=144.0Hz), 51.40, 46.81(d,J=5.4Hz), 23.48(d,J=2.2Hz), 22.50.

[0153] 31 P NMR (203MHz,CDCl3)δ25.58.

[0154] HRMS(ESI)calcd for C 23 H 29 N3O3Pm / z[M+H] + :426.1942; found:426.1928.

[0155] HPLC (Daicel Chiralpak IA-3, i-PrOH / hexane=20 / 80, flow rate 1.0mL / min, λ=262.8nm): t1=7.631min, t2=11.945min.

[0156] Example 6

[0157] Desymmetric synthesis of chiral phosphate compound 12aa

[0158]

[0159] In a 10 mL reaction tube, Ag2O (0.01 mmol), ligand L15 (0.02 mmol) and 1 mL of toluene were added in sequence and reacted at room temperature for about 15 min. Then, 10a (0.1 mmol) was added, and the mixture was cooled at 0°C for 10 min. Then, the corresponding 2a (0.11 mmol) was added. After reacting at 0°C for 72 h, the mixture was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to give 12aa (yellow viscous liquid, 50.0 mg, 97% yield, 81% ee).

[0160] The data of hydrogen, carbon and phosphorus nuclear magnetic resonance spectra, mass spectrometry and liquid chromatography are as follows:

[0161] 1H NMR (500MHz, CDCl3) δ10.89 (s, 1H), 7.67 (d, J = 3.5Hz, 1H), 7.60 (s, 4H), 7.58 (s ,1H),7.56(s,1H),7.36(d,J=8.1Hz,2H),3.77(d,J=12.8Hz,3H),3.69(s,3H).

[0162] 13 C NMR (126MHz, CDCl3) δ160.81 (d, J = 2.2Hz), 137.19, 132.81 (d, J = 2.1Hz), 132.4 8,132.30–131.83(m),131.09,130.46(d,J=21.2Hz),129.77(d,J=32.3Hz),12 5.50(d,J=3.8Hz),124.38(d,J=3.9Hz),122.03(d,J=14.2Hz),113.85(d,J=19 3.8Hz), 98.93 (d, J = 40.8Hz), 83.63 (d, J = 222.0Hz), 52.21 (d, J = 6.3Hz), 51.82.

[0163] 31 P NMR (203 MHz, CDCl3) δ 4.85.

[0164] 19 F NMR (471MHz, CDCl3) δ-62.53,-63.25.

[0165] HRMS(ESI)calcd for C 23 H 16 F6NO4Pm / z[M+Na] + :538.0613; found:538.0607.

[0166] HPLC (Daicel Chiralpak IBN-3, i-PrOH / hexane=20 / 80, flow rate 1.0mL / min, λ=254nm): t1=6.959min, t2=9.562min.

[0167] Example 7

[0168] Desymmetric synthesis of chiral phosphate compound 12be

[0169]

[0170] Ag2O (0.01 mmol), ligand L15 (0.02 mmol) and 1 mL of toluene were added in sequence to a 10 mL reaction tube. The mixture was reacted at room temperature for about 15 min, and then 10b (0.1 mmol) was added. The mixture was cooled at 0°C for 10 min, and then 2e (0.11 mmol) was added. The mixture was reacted at 0°C for 72 h and concentrated in vacuo. The mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to give 12be (colorless viscous liquid, 54.9 mg, 93% yield, 90% ee).

[0171] The data of hydrogen, carbon and phosphorus nuclear magnetic resonance spectra, mass spectrometry and liquid chromatography are as follows:

[0172] 1 H NMR (500MHz, CDCl3) δ11.10(s,1H),7.69(s,1H),7.53(dd,J=19.4,7.0Hz,6H),7.34(d,J=8.0H z,2H),7.22(d,J=7.4Hz,3H),6.97(d,J=7.2Hz,2H),5.18–5.05(m,2H),3.73(d,J=12.7Hz,3H).

[0173] 13 C NMR (126MHz, CDCl3) δ109.75 (d, J = 2.2Hz), 86.63, 84.20, 82.06, 81.56 (d, J = 32. 9Hz),81.27(d,J=13.3Hz),80.40,80.02(d,J=21.1Hz),78.94(d,J=32.3Hz),77 .74,77.63,77.16,72.46(d,J=5.2Hz),71.72,71.54(d,J=14.0Hz),63.01(d,J= 193.9Hz), 48.16 (d, J = 41.1Hz), 32.96 (d, J = 222.3Hz), 15.96, 1.46 (d, J = 6.3Hz).

[0174] 31 P NMR (203 MHz, CDCl3) δ 4.81.

[0175] 19 F NMR(471MHz, CDCl3)δ-62.42,-63.22.

[0176] HRMS(ESI)calcd for C 29 H 20 F6NO4Pm / z[M+Na]+:614.0926; found:614.0920.

[0177] HPLC (Daicel Chiralpak IBN-3, i-PrOH / hexane=20 / 80, flow rate 1.0mL / min, λ=254nm): t1=12.341min, t2=20.413min.

[0178] Example 8

[0179] Desymmetric synthesis of chiral phosphate ester 12ca

[0180]

[0181] In a 10 mL reaction tube, Ag2O (0.01 mmol), ligand L15 (0.02 mmol) and 1 mL of toluene were added in sequence and reacted at room temperature for about 15 min. Then, 10c (0.1 mmol) was added and the mixture was cooled at 0°C for 10 min. Then, 2a (0.11 mmol) was added and the mixture was reacted at 0°C for 72 h. The mixture was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to give 12ca (colorless viscous liquid, 19.6 mg, 86% yield, 43% ee).

[0182] The data of hydrogen, carbon and phosphorus nuclear magnetic resonance spectra, mass spectrometry and liquid chromatography are as follows:

[0183] 1 H NMR (500MHz, CDCl3) δ10.60 (s, 1H), 7.55–7.47 (m, 1H), 7.19 (dt, J = 5.2, 2.0Hz, 1H), 3.95–3.80 (m, 6H), 3.08 (d, J = 11.1Hz, 1H).

[0184] 13 C NMR (126MHz, CDCl3) δ161.10 (d, J = 2.0Hz), 129.80 (d, J = 23.6Hz), 125.21 (d, J = 15.7Hz), 117 .62(d,J=13.6Hz), 113.36(d,J=196.0Hz), 89.69(d,J=39.5Hz), 52.44(d,J=6.2Hz), 52.02.

[0185] 31 P NMR (203 MHz, CDCl3) δ 5.25.

[0186] HRMS (ESI) calculation for C9H 10 NO4Pm / z[M+H] +:228.0420;found:228.0418.

[0187] HPLC (Daicel Chiralpak IA-3, i-PrOH / hexane=5 / 95, flow rate 1.0mL / min, λ=254nm): t1=41.024min, t2=44.759min.

[0188] Example 9

[0189] Desymmetric synthesis of chiral phosphate compound 12da

[0190]

[0191] In a 10 mL reaction tube, Ag2O (0.01 mmol), ligand L15 (0.02 mmol) and 1 mL of toluene were added in sequence and reacted at room temperature for about 15 min. Then, 10d (0.1 mmol) was added and cooled at 0°C for 10 min. Then, 2a (0.11 mmol) was added and reacted at 0°C for 72 h. The mixture was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to give 12da (colorless viscous liquid, 30.7 mg, 78% yield, 66% ee).

[0192] The data of hydrogen, carbon and phosphorus nuclear magnetic resonance spectra, mass spectrometry and liquid chromatography are as follows:

[0193] 1 H NMR (500MHz, CDCl3) δ9.82 (s, 1H), 7.64 (t, J = 3.5Hz, 1H), 7.52–7.45 (m, 2H), 7.45–7.29(m,8H),4.05(p,J=7.3Hz,2H),3.69(s,3H),1.18(t,J=7.0Hz,3H).

[0194] 13 C NMR (126MHz, CDCl3) δ161.14,133.84(d,J=12.5Hz),133.26,130.68,130.49,130.08(d,J=22.0Hz),128.49,127.72,127.41,121.60(d,J=14.2 Hz), 120.06 (d, J = 4.8Hz), 115.33 (d, J = 192.6Hz), 100.48 (d, J = 41.7Hz), 82.69 (d, J = 224.3Hz), 62.00 (d, J = 6.3Hz), 51.75, 16.13 (d, J = 7.5Hz).

[0195] 31 P NMR (203 MHz, CDCl3) δ 2.95.

[0196] HRMS(ESI)calcd for C 22 H 20 NO4Pm / z[M+H] + :394.1203; found:394.1198.

[0197] HPLC (Daicel Chiralpak IBN3, i-PrOH / hexane=20 / 80, flow rate 1.0mL / min, λ=254nm): t1=11.199min, t2=13.141min.

[0198] Example 10

[0199] Given that existing phosphine compounds with carbon, axial, spiro, or planar chirality suffer from limitations in catalysis and diverse modification compared to phosphorus-chiral phosphine compounds, the chiral phosphine oxide compounds containing pyrrole groups provided by the present invention can be modified in a wider range of ways by varying the phosphorus atom substituents. For example, alkynyl groups can be reduced, or alkynyl groups can be linked to amino acids, sugars, or nucleosides via CuAAC reactions for further attachment to biomacromolecules. These modifications hold promise for catalysis and medicinal chemistry.

[0200] This embodiment is shown in Formula 5-7:

[0201]

[0202] Reaction formula 5;

[0203]

[0204] Reaction formula 6;

[0205]

[0206] Reaction formula 7;

[0207] In formula 5-7, X is O or N;

[0208] R 1 is H, C1-C10 aliphatic group, C1-C10 alkyl group or benzyl group;

[0209] R 2 is a C1-C10 aliphatic group, a C1-C10 alkyl group or a benzyl group;

[0210] R 3is H, C1-C10 aliphatic group, thienyl, pyridyl, C1-C10 alkyl, ester group, alkoxy group, phenyl group or phenyl group containing a substituent; the substituent is an electron-withdrawing or electron-donating protecting group, the electron-withdrawing protecting group is a halogen, nitro, trifluoromethyl or ester substituent; the electron-donating protecting group is a methyl, ethyl, tert-butyl, phenyl, phenolic hydroxyl or methoxy group; the ester substituent is a methyl ester, ethyl ester or benzyl ester;

[0211] R 4 is a p-toluenesulfonyl group or an ester group, wherein the ester group is a methyl ester, an ethyl ester, an isopropyl ester, a tert-butyl ester or a benzyl ester;

[0212] R 7 It is an amino acid group, a sugar group, a nucleoside group, a benzyl group or a benzyl group containing a substituent; the substituent is an electron-withdrawing or electron-donating protecting group, the electron-withdrawing protecting group is a halogen, nitro, trifluoromethyl or ester substituent; the electron-donating protecting group is a methyl, ethyl, phenolic hydroxyl or methoxy group; wherein the ester substituent is a methyl ester, an ethyl ester or a benzyl ester, etc.

[0213] Moreover, R 1 、R 2 It can be different;

[0214] In formula 5, the conditions for the hydrogenation reaction are conventional reaction conditions;

[0215] In formula 6, the conditions for grubbs cyclization are conventional reaction conditions;

[0216] In formula 7, the conditions of the CuAAC reaction are conventional reaction conditions;

[0217] To further illustrate that the chiral phosphine oxide compound containing a pyrrole group described in Example 6 can be modified in various ways, the present invention provides further derivatization methods and chiral phosphine compounds as shown in Examples 8-10.

[0218] Example 10

[0219] Example 1: Reduction of chiral phosphine oxide 3aa to prepare chiral phosphine oxide 7

[0220]

[0221] 3aa (0.1 mmol, 99% ee), methanol (1 mL) and 10% Pd / C (10 mg) were added sequentially to a high-pressure hydrogen reactor. The reaction mixture was stirred at room temperature overnight under a hydrogen atmosphere pressure of 0.2 MPa. After thin-layer chromatography (TLC) analysis confirmed the complete consumption of 3aa, the reaction mixture was filtered and washed with methanol. The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography using petroleum ether / ethyl acetate (1 / 1.5, volume ratio) as eluent to obtain the desired product 7 (39.2 mg, 85% yield, 99% ee).

[0222] The data of hydrogen, carbon and phosphorus nuclear magnetic resonance spectra, mass spectrometry and liquid chromatography are as follows:

[0223] 1 H NMR(400MHz, CDCl3)δ10.65(s,1H),7.48–7.42(m,1H),7.37–7.30(m,1H),7.24–7.19(m,1H),7.18–7.12(m,1H),7.02–6.97 (m,2H),3.63(s,2H),3.42–3.24(m,2H),2.92–2.71(m,1H),2.00–1.76(m,2H),1.16(d,J=6.8Hz,5H),1.09(d,J=6.7Hz,5H).

[0224] 13 C NMR(101MHz, CDCl3)δ161.27,142.03(d,J=17.7Hz),134.32,133.13,130.86,129.43(d,J=16.9Hz),128.50,128.13,127 .68,127.51,126.05,121.49(d,J=11.5Hz),51.47,46.26(d,J=5.0Hz),32.93,32.22,28.32,23.51(d,J=1.9Hz),23.01.

[0225] 31 P NMR (162MHz,CDCl3)δ33.56.

[0226] HRMS(ESI)calcd for C 26 H 34 N2O3Pm / z[M+H] + :453.1567; found:453.1567.

[0227] HPLC (Daicel Chiralpak IBN-3, i-PrOH / hexane=20 / 80, flow rate 1.0mL / min, λ=254nm): t1=5.581min, t2=13.422min.

[0228] Example 11

[0229] Example 3: Reduction of chiral phosphine oxide 3c'a to prepare chiral phosphine oxide 8

[0230]

[0231] A 10 mL Shrek tube dried in an oven and equipped with a magnetic stirrer was charged with 3c'a (0.07 mmol), Grubbs' catalyst (0.01 mmol), and dichloromethane (1 mL) under a nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 24 hours. After confirming complete consumption of 5 by thin layer chromatography (TLC), the reaction solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to give 8 (29.3 mg, 75% yield, 76% ee) as a viscous oil.

[0232] The data of hydrogen, carbon and phosphorus nuclear magnetic resonance spectra, mass spectrometry and liquid chromatography are as follows:

[0233] 1 H NMR (400MHz, CDCl3) δ9.90 (s, 1H), 7.65 (t, J = 3.5Hz, 1H), 7.48–7.39 (m, 5H) ,7.36–7.24(m,6H),5.56(d,J=2.2Hz,2H),3.89–3.72(m,4H),3.68(s,3H).

[0234] 13 C NMR (101MHz, CDCl3) δ161.19,133.55,132.48,130.93(d,J=16.5Hz),130.29(d,J=4.1Hz),128.54,127.57,127.35,125 .88(d,J=9.7Hz),121.70,120.46(d,J=4.1Hz),100.98(d,J=37.7Hz),83.54(d,J=205.0Hz),53.54(d,J=7.4Hz),51.64.

[0235] 31 P NMR (162MHz,CDCl3)δ-3.30.

[0236] HRMS(ESI)calcd for C 21 H 19 O2N4PNa m / z[M+H] + :417.1466; found:417.1467.

[0237] HPLC (Daicel Chiralpak AD-H, i-PrOH / hexane=20 / 80, flow rate 1.0mL / min, λ=265nm): t1=18.365min, t2=34.444min.

[0238] Example 12

[0239]

[0240] Example 4: Reduction of chiral phosphine oxide 3ya to prepare chiral phosphine oxide 9

[0241] To a solution of 3ya (0.1 mmol), CuSO4·5H2O (0.01 mmol) and sodium ascorbate (0.01 mmol) in dichloromethane (0.5 mL) and water (0.5 mL) was added Fmoc-Lys(N3)-OH (0.1 mmol). The reaction mixture was vigorously stirred at room temperature for 24 hours. After separation of the organic layer, the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate and evaporated. The crude product was dissolved in 5 mL (80% acetonitrile / water), filtered through a 0.22 μm filter and purified by reverse phase high performance liquid chromatography (RP-HPLC). The pure fractions were combined and then lyophilized to obtain the product 9 as a white solid (58.7 mg, 85% yield).

[0242] The nuclear magnetic resonance hydrogen spectrum, carbon spectrum, phosphorus spectrum and mass spectrum data are as follows:

[0243] 1H NMR (500MHz, CDCl3) δ10.52–10.17(m,1H),8.30(s,1H),7.71(d,J=7.5Hz,2H),7.57–7.44(m,2H),7 .33(d,J=7.8Hz,2H),7.30–7.06(m,7H),5.93(dd,J=18.8,7.9Hz,1H),4.44–4.30(m,4H),4.14(t,J= 7.0Hz,1H),3.77(d,J=5.7Hz,3H),3.58(dp,J=20.4,6.8Hz,2H),1.94–1.81(m,2H),1.79–1.69(m,1H ),1.37(tt,J=14.4,6.9Hz,1H),1.28(d,J=6.5Hz,1H),1.20(d,J=6.7Hz,6H),1.15(d,J=6.7Hz,6H).

[0244] 13 C NMR (126MHz, CDCl3) δ161.22,156.21,143.92,143.77,141.25,141.23,127.68,127.07,125.16,124.65,124.54,119.93,118. 11,118.01,66.96,53.70,51.79,49.86,47.27,47.14,47.04,46.99,31.93,29.70,23.32,22.70,22.36,18.93,14.19,14.12.

[0245] 31 P NMR (203MHz,CDCl3)δ-13.72.

[0246] HRMS(ESI)calcd for C 35 H 43 N6O7Pm / z[M+H] + :691.3004; found:691.3005.

[0247] Example 14

[0248] In this example, a compound library was screened for anti-tumor activity based on structure.

[0249] MTT cell proliferation assay for phosphine oxide compounds: When the liver cancer cells HepG2 grow to the confluent state, the cell density is adjusted to 1.5×10 4Cells were seeded at a density of 200 μL / well (3,000 cells / well) in 96-well flat-bottom culture plates. After overnight growth and attachment, cells were starved for 6-8 hours using serum-free medium. Different concentrations of drug were then added, with triplicate wells containing 200 μL / well of each drug concentration, resulting in final concentrations of 12.5, 25, 50, 100, and 200 μM. A control group (negative control) was also established without drug. Cells were cultured in a 37°C, 5% CO2 humidified incubator for 24, 48, and 72 hours. Then, 5 mg / mL MTT was added at 20 μL / well. Culture was continued for another 4 hours, after which the supernatant was discarded and 150 μL / well of DMSO was added to dissolve the formazan complex (phosphine oxide library). The absorbance (OD490) of each well was measured using a microplate reader. Chiral phosphoramide 3aa exhibited significantly greater antiproliferative activity compared to the racemic (±)-3aa. The activity of N-methylated product 4, phosphinate analogue 5, and hydrogenated products 7 and 9 was reduced. These results suggest that the amino and alkynyl moieties may be the determining factors for achieving better biological activity. Importantly, the activity of racemate (±)-3aa was significantly higher than that of racemate (±)-1'a, which strongly suggests the potential role of pyrrole. The test results are attached. Figure 4 Subsequently, the antiproliferative activity of several compounds was further tested by IC50 values ​​(see attached for test results). Figure 5 ).

[0250] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application.

Claims

1. A chiral phosphine oxide compound containing a pyrrole group, characterized in that: It includes a pyrrole ring-containing phosphoramide compound and a pyrrole ring-containing phosphate compound; the structural formula of the pyrrole ring-containing phosphoramide compound is shown in Formula I and II, and the structural formula of the pyrrole ring-containing phosphate compound is shown in Formula II and IV: Among them, R 1 is H, C1-C10 aliphatic group, C1-C10 alkyl group or benzyl group; R 2 is a C1-C10 aliphatic group, a C1-C10 alkyl group or a benzyl group; R 3 is H, C1-C10 aliphatic group, thienyl, pyridyl, C1-C10 alkyl, ester group, alkoxy group, phenyl group and phenyl group containing substituents; the substituents are electron-withdrawing or electron-donating protecting groups, the electron-withdrawing protecting groups are halogen, nitro, trifluoromethyl and ester substituents; the electron-donating protecting groups are methyl, ethyl, tert-butyl, phenyl, phenolic hydroxyl or methoxy; the ester substituents are methyl ester, ethyl ester or benzyl ester; R 4 is p-toluenesulfonyl or an ester group; the ester group is methyl ester, ethyl ester, isopropyl ester, tert-butyl ester or benzyl ester; R 5 is phenyl, naphthyl, C1-C10 aliphatic group, thienyl, C1-C10 alkyl, C1-C10 alkoxy, phenoxy, phenyl containing a substituent, or amino containing a substituent; the substituent of the phenyl group is at least one of halogen, C1-C10 alkyl, and C1-C10 alkoxy; the substituent of the amino group is at least one of C1-C10 aliphatic group, C1-C10 alkyl, phenyl, and benzyl; R 6 It is a C1-C10 aliphatic group, a C1-C10 alkyl group, a phenyl group, a phenyl group containing a substituent, a benzyl group, a benzyl group containing a substituent, a β-D-glucopyranosyl group, an α-D-galactopyranosyl group or a β-D-mannopyranosyl group.

2. A method for preparing a chiral phosphine oxide compound containing a pyrrole group as claimed in claim 1, characterized in that: The preparation method comprises the steps of: In a solvent, diacetylenic phosphoramide and isocyanoacetate are used as reaction raw materials, and under the action of metal salt and chiral ligand, the chiral phosphine oxide compound I is obtained by reaction. The reaction process is shown in the following reaction formula (1): Reaction formula (1): in, R 1 is H, C1-C10 aliphatic group, C1-C10 alkyl group or benzyl group; R 2 is a C1-C10 aliphatic group, a C1-C10 alkyl group or a benzyl group; R 3 is H, C1-C10 aliphatic group, thienyl, pyridyl, C1-C10 alkyl, ester group, alkoxy group, phenyl group or phenyl group containing a substituent; the substituent is an electron-withdrawing or electron-donating protecting group, the electron-withdrawing protecting group is a halogen, nitro, trifluoromethyl or ester substituent; the electron-donating protecting group is a methyl, ethyl, tert-butyl, phenyl, phenolic hydroxyl or methoxy group; wherein the ester substituent is a methyl ester, an ethyl ester or a benzyl ester; R 4 is p-toluenesulfonyl or an ester group; the ester group is methyl ester, ethyl ester, isopropyl ester, tert-butyl ester or benzyl ester; The molar ratio of the dialkynylphosphine oxide to the isocyanoacetate is 1:1-5.

3. A method for preparing a chiral phosphine oxide compound containing a pyrrole group as claimed in claim 1, characterized in that: The preparation method comprises the steps of: In a solvent, monoalkynyl phosphoramide and isocyanoacetate are used as reaction raw materials, and under the action of metal salt and chiral ligand, the chiral phosphine oxide compound II is reacted. The reaction process is shown in the following reaction formula (2): Reaction formula (2): in, R 1 is H, C1-C10 aliphatic group, C1-C10 alkyl group or benzyl group; R 2 is a C1-C10 aliphatic group, a C1-C10 alkyl group or a benzyl group; R 3 is H, C1-C10 aliphatic group, thienyl, pyridyl, C1-C10 alkyl, ester group, alkoxy group, phenyl group or phenyl group containing a substituent; the substituent is an electron-withdrawing or electron-donating protecting group, the electron-withdrawing protecting group is a halogen, nitro, trifluoromethyl or ester substituent; the electron-donating protecting group is a methyl, ethyl, tert-butyl, phenyl, phenolic hydroxyl or methoxy group; wherein the ester substituent is a methyl ester, an ethyl ester or a benzyl ester; R 4 is p-toluenesulfonyl, an ester group, wherein the ester group is methyl ester, ethyl ester, isopropyl ester, tert-butyl ester or benzyl ester; R 5 is phenyl, naphthyl, C1-C10 aliphatic group, thienyl, C1-C10 alkyl, C1-C10 alkoxy, phenoxy, phenyl containing a substituent, or amino containing a substituent; the substituent of the phenyl group is at least one of halogen, C1-C10 alkyl, and C1-C10 alkoxy; the substituent of the amino group is at least one of C1-C10 aliphatic group, C1-C10 alkyl, phenyl, and benzyl; The molar ratio of the monoalkynyl phosphoramide to the isocyanoacetate is 2:1-5.

4. A method for preparing a chiral phosphine oxide compound containing a pyrrole group as claimed in claim 1, characterized in that: The preparation method comprises the steps of: In a solvent, dialkynyl phosphate and isocyanoacetate are used as reaction raw materials, and under the action of metal salt and chiral ligand, the chiral phosphine oxide compound III is obtained by reaction. The reaction process is shown in the following reaction formula (3): Reaction formula (3): in, R 3 is H, C1-C10 aliphatic group, thienyl, pyridyl, C1-C10 alkyl, ester group, alkoxy group, phenyl group or phenyl group with substituents; the substituent is an electron-withdrawing or electron-donating protecting group, the electron-withdrawing protecting group is a halogen, nitro, trifluoromethyl or ester substituent; the electron-donating protecting group is a methyl, ethyl, tert-butyl, phenyl, phenolic hydroxyl or methoxy group; wherein the ester substituent is a methyl ester, an ethyl ester or a benzyl ester; R 4 is p-toluenesulfonyl or an ester group; the ester group is methyl ester, ethyl ester, isopropyl ester, tert-butyl ester or benzyl ester; R 6 is a C1-C10 aliphatic group, a C1-C10 alkyl group, a phenyl group, a phenyl group containing a substituent, a benzyl group, a benzyl group containing a substituent, a β-D-glucopyranosyl group, an α-D-galactopyranosyl group or a β-D-mannopyranosyl group; The molar ratio of the dialkynylphosphine oxide to the isocyanoacetate is 1:1-5.

5. A method for preparing a chiral phosphine oxide compound containing a pyrrole group as claimed in claim 1, characterized in that: The preparation method comprises the steps of: In a solvent, monoalkyne phosphate and isocyanoacetate are used as reaction raw materials, and under the action of metal salt and chiral ligand, the chiral phosphine oxide compound IV is obtained by reaction. The reaction process is shown in the following reaction formula (4): Reaction formula (4): in, R 3 is H, C1-C10 aliphatic group, thienyl, pyridyl, C1-C10 alkyl, ester group, alkoxy group, phenyl group or phenyl group with substituents; the substituent is an electron-withdrawing or electron-donating protecting group, the electron-withdrawing protecting group is a halogen, nitro, trifluoromethyl or ester substituent; the electron-donating protecting group is a methyl, ethyl, tert-butyl, phenyl, phenolic hydroxyl or methoxy group; the ester substituent is a methyl ester, ethyl ester or benzyl ester; R 4 is p-toluenesulfonyl or an ester group; the ester group is methyl ester, ethyl ester, isopropyl ester, tert-butyl ester or benzyl ester; R 5 phenyl, naphthyl, C1-C10 aliphatic group, thienyl, C1-C10 alkyl, C1-C10 alkoxy, phenoxy, phenyl containing a substituent, and amino containing a substituent, wherein the substituent of the phenyl group is at least one of halogen, C1-C10 alkyl, and C1-C10 alkoxy, and the substituent of the amino group is at least one of C1-C10 aliphatic group, C1-C10 alkyl, phenyl, and benzyl; R 6 is a C1-C10 aliphatic group, a C1-C10 alkyl group, a phenyl group, a phenyl group containing a substituent, a benzyl group, a benzyl group containing a substituent, a β-D-glucopyranosyl group, an α-D-galactopyranosyl group or a β-D-mannopyranosyl group; The molar ratio of the monoalkynyl phosphoramide to the isocyanoacetate is 2:1-5.

6. The method according to any one of claims 2 to 5, wherein: The solvent is selected from at least one of toluene, dichloromethane, chloroform, ether, ethyl acetate, tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, dioxane, methanol, and trifluorotoluene; The catalyst is AgX 1 or CuX 2 Other metals, including X 1 F - 、Cl - Br - 、OAc - ,OTf - 、BF4 - 、SbF6 - 、NO3 - 、CO3 2- 、SO4 2- CF3COO - or O 2- , where X 2 Cl - Br - , I - 、CN - PF6 - or O 2- ; The molar ratio of the metal salt catalyst to the ligand is 1:1-5.

7. The method according to any one of claims 2 to 5, characterized in that: The reaction temperature is -30°C to 50°C; The structure of the chiral ligand is shown below: The additive is at least one of an acid, a base and a molecular sieve; the molecular sieve is selected from spherical or powdered molecular sieves; the acid is selected from trifluoroacetic acid or benzoic acid, and the base is selected from potassium carbonate, potassium phosphate, potassium fluoride or sodium acetate.

8. The use of the chiral phosphine oxide compound containing a pyrrole group according to claim 1, characterized in that: Applications include catalysts, active molecules of anti-tumor drugs, or catalysts and drugs connected to biological macromolecules.

9. A molecule having anti-tumor activity, characterized in that The active ingredient is a series of pyrrole-containing phosphine oxide compounds as claimed in claim 1.

10. The molecule having anti-tumor activity according to claim 9, characterized in that For anti-tumor use, the tumor is a liver cancer tumor, and the anti-tumor effect is to inhibit the proliferation of tumor cells.

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