Chiral phosphonate compound and derivative, preparation method, pesticide bacteriostatic agent and application thereof

Abstract

The invention relates to the technical field of organic synthesis and pesticide bacteriostatic activity research, in particular to a chiral phosphonate compound, a derivative thereof, a preparation method, a pesticide bacteriostatic agent and application. The structural general formula of the chiral phosphonate compound is as shown in formula 1. The chiral P (V) phosphonate compound is constructed by catalyzing phosphonate and 1-naphthol through N-heterocyclic carbene, and the chiral P (V) phosphonate compound is high in yield (85%), excellent in enantioselectivity (97: 3e.r.) and remarkable in biological activity. The compound has remarkable bacteriostatic activity on rice bacterial leaf blight germs and rice leaf streak germs, and has important research significance on further development and utilization of chiral phosphine compounds.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis and pesticide antibacterial activity research, and in particular to a chiral phosphonate compound and its derivatives, a preparation method, a pesticide antibacterial agent and application. Background Art

[0002] The chiral P(V) skeleton is widely present in biomolecules, drugs and other functional molecules with its diverse biological activities and catalytic functions, and has shown wide application value in many fields such as medicine, pesticides and materials. The enantioselective construction of chiral P(V) phosphonate compounds has received more and more attention. So far, the acquisition of chiral phosphonate compounds mainly relies on the use of chiral resolution, chiral auxiliary agents and diastereoselective synthesis. In recent years, asymmetric catalytic methods have also been developed (Nature 2024, 6032, 1052-1059.; Nat. Chem. 2023, 15, 714-721), but the catalyst control directly on the phosphorus atom through the formation of PO or PN bonds still has certain limitations. At the same time, in the pesticide molecules that have been developed, phosphonate is a common structural fragment, so the development of a chiral phosphonate compound synthesis method with good substrate universality is of great significance for exploring the development of drug active structures. Summary of the invention

[0003] In order to solve the above problems, the present invention provides a chiral phosphonate compound and its derivatives, a preparation method, a pesticide antibacterial agent and application. The present invention provides a chiral P(V) phosphonate compound with high yield and high enantioselectivity. The compound has significant sterilization efficacy and has important research significance for the further development and utilization of chiral phosphonate compounds.

[0004] In order to achieve the above object, the present invention provides the following technical solutions:

[0005] The present invention provides a chiral phosphonate compound, and the chiral P(V) phosphonate compound has a general structural formula as shown in Formula 1:

[0006]

[0007] Wherein, P* is a chiral phosphorus atom;

[0008] R 1 including phenyl, 4-methylphenyl, 4-n-butylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 4-phenylphenyl, 4-chlorophenyl, 3-methylphenyl, 2-methylphenyl, 2-chlorophenyl or methyl;

[0009] Ar' includes 2-methyl-6-nitrophenyl;

[0010] Ar includes naphthyl, 4-methylnaphthyl, 4-chloronaphthyl, 4-bromonaphthyl, 1-hydroxypyrenyl, 2,4-dimethoxyphenyl, 2-methylacetophenone, methyl 2-methoxybenzoate, 2-methoxy-4-allylphenyl, ethyl 2-methoxycinnamate or N-(2,3-dichlorophenyl)-1-methylcyclohexanecarboxamide.

[0011] The present invention also provides a derivative of the chiral phosphonate compound described in the above technical solution, and the general structural formula of the derivative is shown in Formula 2:

[0012]

[0013] Wherein, P* is a chiral phosphorus atom;

[0014] X includes O or S;

[0015] R 2 The alkyl radicals include methyl, deuterated methyl, ethyl, isopropyl, benzyl, 2',3'-isopropylureido, 2',3'-isopropylidene adenosyl, methyl-2,3-O-isopropylidene-D-ribofuranoside, menthol, cholesterol, androsterone, pregnenolone or dodecyl.

[0016] The present invention also provides a derivative of the chiral phosphonate compound described in the above technical solution, and the general structural formula of the derivative is shown in Formula 3:

[0017]

[0018] Wherein, P* is a chiral phosphorus atom;

[0019] X includes N;

[0020] R 3 These include phenyl, benzyl, benzo[d][1,3]dioxolane-5-amino-2-ethylfuran, 4,4′-diaminodiphenylsulfone or 4-phenylcarboxylic acid ethyl ester.

[0021] The present invention also provides a derivative of the chiral P(V) phosphonate compound described in the above technical solution, and the general structural formula of the derivative is shown in Formula 4:

[0022]

[0023] Wherein, P* is a chiral phosphorus atom;

[0024] R 4 including methyl, ethyl, 4-methylphenyl or 2-methoxyphenyl;

[0025] R 5 These include ethoxy or 2-methoxyphenyl.

[0026] The present invention also provides a method for preparing the chiral phosphonate compound described in the above technical solution, comprising the following steps:

[0027] 1) mixing and reacting a phosphonate, a carbonate, an azacarbene and fluorobenzene to obtain a reaction solution;

[0028] The structural formula of the chiral azacarbene is shown in Formula 5:

[0029]

[0030] 2) mixing the reaction solution obtained in step 1) with 1-naphthol, stirring and reacting to obtain a stirred reaction solution;

[0031] 3) Purifying the stirred reaction solution obtained in step 2) to obtain a chiral P(V) phosphonate compound.

[0032] Preferably, in step 1), the volume ratio of the mole of phosphonate, the mole of carbonate, the mole of azacarbene and fluorobenzene is 0.1 mmol: 0.15 mmol: 0.02 mmol: 4 mL;

[0033] The carbonate includes cesium carbonate and / or rubidium carbonate;

[0034] The reaction conditions include: temperature of 0°C and time of 1 h.

[0035] Preferably, in step 2), the molar ratio of 1-naphthol to phosphonate is 0.11:0.1;

[0036] The stirring reaction conditions include: temperature of -30°C and time of 24h.

[0037] The present invention also provides the use of the chiral phosphonate compounds described in the above technical solution or the derivatives described in the above technical solution in preventing and controlling plant diseases.

[0038] Preferably, the plant diseases include rice bacterial blight and / or rice leaf streak disease.

[0039] The present invention also provides an antibacterial agent for preventing and controlling plant diseases, wherein the antibacterial agent comprises one or more of the chiral phosphonate compounds described in the above technical solution and the derivatives described in the above technical solution.

[0040] The present invention also provides the use of the antibacterial agent described in the above technical solution in preventing and controlling plant diseases, wherein the plant diseases include rice bacterial blight and / or rice leaf streak disease.

[0041] Beneficial effects of the present invention:

[0042] 1. The present invention provides a chiral P(V) phosphonate compound, which is constructed by using phosphonate and 1-naphthol, and has a high yield (85%) and excellent enantioselectivity (97:3e.r.) and a chiral P(V) phosphonate compound with significant biological activity. It has significant antibacterial activity against rice bacterial blight pathogens and rice leaf streak pathogens, and has important research significance for the further development and utilization of chiral phosphorus compounds.

[0043] 2. The present invention provides a method for preparing a chiral phosphonate compound. The present invention provides a new covalent organic catalytic mode, wherein nitrogen heterocyclic carbene (NHC C) is added to a symmetrical phosphonate that is easily stably activated, and the enantioselectivity of the chiral phosphorus skeleton is constructed through a new PO bond formation. The reaction substrate has good universality, the product yield is as high as 85% and has high enantioselectivity, and the obtained product has significant antibacterial activity. The development of chiral phosphonate compounds provides a useful skeleton structure for future exploration of crop protection drugs, especially agricultural chemicals with antibacterial and antifungal activities, and has important research significance for the further development and utilization of chiral phosphonate compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required to be used in the embodiments are briefly introduced below.

[0045] Figure 1 The diagram is a synthetic route for the chiral phosphonate compounds of the present invention. DETAILED DESCRIPTION

[0046] The present invention provides a chiral phosphonate compound, and the chiral phosphonate compound has a general structural formula as shown in Formula 1:

[0047]

[0048] Where P* is a chiral phosphorus atom; R 1 Ar includes phenyl, 4-methylphenyl, 4-n-butylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 4-phenylphenyl, 4-chlorophenyl, 3-methylphenyl, 2-methylphenyl, 2-chlorophenyl or methyl; Ar' includes 2-methyl-6-nitrophenyl or 4-nitrophenyl; Ar includes naphthyl, 4-methylnaphthyl, 4-chloronaphthyl, 4-bromonaphthyl, 1-hydroxypyrene, 2,4-dimethoxyphenyl, 2-methylacetophenone, methyl 2-methoxybenzoate, 2-methoxy-4-allylphenyl, ethyl 2-methoxycinnamate or N-(2,3-dichlorophenyl)-1-methylcyclohexanecarboxamide.

[0049] The present invention provides a method for preparing the chiral phosphonate compound described in the above technical solution, comprising the following steps:

[0050] 1) mixing and reacting a phosphonate, a carbonate, an azacarbene and fluorobenzene to obtain a reaction solution;

[0051] The structural formula of the chiral azacarbene is shown in Formula 5:

[0052]

[0053] 2) mixing the reaction solution obtained in step 1) with 1-naphthol, stirring and reacting to obtain a stirred reaction solution;

[0054] 3) Purifying the stirred reaction solution obtained in step 2) to obtain a chiral P(V) phosphonate compound.

[0055] In the present invention, the preparation of the chiral P(V) phosphonate compounds is preferably carried out under nitrogen protection. In the present invention, the volume ratio of the mole of the phosphonate, the mole of the carbonate, the mole of the azacarbene and the fluorobenzene is preferably 0.1mmol:0.15mmol:0.02mmol:4mL. In the present invention, the carbonate preferably includes cesium carbonate or rubidium carbonate. In the present invention, the conditions of the azacyclic carbene activation process preferably include: temperature of 0°C and time of 1h. In the present invention, the molar ratio of 1-naphthol to phosphonate is preferably 0.11:0.1, and in the present invention, the conditions of the phosphonate desymmetrization process preferably include: temperature of -30°C and time of 24h. The present invention does not specifically limit the purification conditions, and those skilled in the art can use conventional purification methods.

[0056] The present invention also provides a derivative of the chiral P(V) phosphonate compound described in the above technical solution, and the general structural formula of the derivative is shown in Formula 2:

[0057]

[0058] Wherein, P* is a chiral phosphorus atom; X includes O or S; R 2 The alkyl radicals include methyl, deuterated methyl, ethyl, isopropyl, benzyl, 2',3'-isopropylureido, 2',3'-isopropylidene adenosyl, methyl-2,3-O-isopropylidene-D-ribofuranoside, menthol, cholesterol, androsterone, pregnenolone or dodecyl.

[0059] In the present invention, the preparation method of the above derivative preferably comprises the following steps: mixing a nucleophile with tetrahydrofuran, tert-butyl magnesium chloride (t-BuMgCl), and the chiral P(V) phosphonate compound described in the above technical solution, stirring at room temperature, and purifying to obtain a derivative after the chiral P(V) phosphonate compound is consumed. In the present invention, the derivative is preferably prepared under a nitrogen atmosphere. In the present invention, the nucleophile is R-OH, and R preferably includes methyl, deuterated methyl, ethyl, isopropyl, benzyl, 2',3'-isopropylurea, 2',3'-isopropylidene adenosyl, methyl-2,3-O-isopropylidene-D-furanosyl, menthol, cholesterol, androsterone, pregnenolone or dodecyl. In the present invention, the molar ratio of the nucleophilic reagent to the volume of tetrahydrofuran, the molar ratio of t-BuMgCl, and the molar ratio of the chiral P(V) phosphonate compound is 0.15mmol:2ML:0.15mmol:0.1mmol. The present invention does not specifically limit the purification method, and those skilled in the art can use conventional methods.

[0060] The present invention also provides a derivative of the chiral phosphonate compound described in the above technical solution, and the general structural formula of the derivative is shown in Formula 3:

[0061]

[0062] Wherein, P* is a chiral phosphorus atom; X includes N; R 3 Including phenyl, benzyl, benzo[d][1,3]dioxolane-5-amino, 2-ethylfuranyl, 4,4′-diaminodiphenylsulfone or 4-phenylcarboxylic acid ethyl ester.

[0063] In the present invention, the preparation method of the above derivative preferably comprises the following steps: mixing a nucleophile with tetrahydrofuran, n-butyl lithium, and the chiral P(V) phosphonate compound described in the above technical scheme, stirring at -78°C, and purifying to obtain a derivative after the chiral P(V) phosphonate compound is consumed. In the present invention, the derivative is preferably prepared under a nitrogen atmosphere. In the present invention, the nucleophile is R-OH, and R preferably includes phenyl, benzyl, benzo[d][1,3]dioxolane-5-amine, 2-ethylfuranyl, 4,4′-diaminodiphenylsulfone or 4-phenylformic acid ethyl ester. In the present invention, the molar ratio of the nucleophile to the volume of tetrahydrofuran, the molar ratio of n-butyl lithium, and the chiral P(V) phosphonate compound is 0.15mmol:2ML:0.15mmol:0.1mmol. The present invention does not specifically limit the purification method, and those skilled in the art can use conventional methods.

[0064] The present invention also provides a derivative of the chiral phosphonate compound described in the above technical solution, and the general structural formula of the derivative is shown in Formula 4:

[0065]

[0066] Among them, R 4 Including methyl, ethyl, 4-methylphenyl or 2-methoxyphenyl; R 5 These include ethoxy or 2-methoxyphenyl.

[0067] The present invention also provides the use of the chiral phosphonate compounds or derivatives described in the above technical solution in preventing and controlling plant diseases. In the present invention, the plant diseases preferably include rice bacterial blight and / or rice leaf streak disease.

[0068] The present invention also provides an antibacterial agent for preventing and controlling plant diseases, the antibacterial agent comprising one or more of the chiral phosphonate compounds and the derivatives described in the above technical solution. The present invention has no special limitation on the preparation method of the antibacterial agent, and those skilled in the art can prepare it by conventional preparation methods.

[0069] The present invention also provides the use of the antibacterial agent described in the above technical solution in preventing and controlling plant diseases, wherein the plant diseases include rice bacterial blight and / or rice leaf streak disease.

[0070] In order to further illustrate the present invention, the present invention is described in detail below in conjunction with embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0071] Example 1

[0072] This embodiment provides a method for preparing a chiral P(V) phosphonate compound, and the specific method is as follows:

[0073] Under N2 conditions, phosphonate 1 (0.1 mmol, 1.0 equiv.), azacarbene (NHC C) (0.02 mmol, 20 mol%), Cs2CO3 (0.15 mmol, 1.5 equiv.), and PhF (4.0 mL) were added to a 4.0 mL vial equipped with a magnetic stirrer. After stirring at 0 °C for 1 hour, the reaction solution was cooled to -30 °C and nucleophile 2 (1-naphthol, 4-methyl-1-naphthol, 4-chloro-1-naphthol, 4-bromonaphthol, 1-hydroxypyrene, 2,4-dimethylphenol, 2,4-dimethoxyphenol, 4-hydroxy-3-methylacetophenone, methyl vanillate, eugenol, ethyl ferulate or fenhexamid) (0.11 mmol, 1.1 equiv.) was added until the substrate was completely consumed (TLC monitoring). Hydrogen chloride-dioxane solution (0.2 mL) was slowly added dropwise to the reaction system to terminate the reaction. The residue was dried under reduced pressure and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=10:1) to obtain the title chiral compound 3.

[0074] The specific spectrum analysis of product 3 is as follows:

[0075] 2-Methyl-6-nitrophenylnaphthalen-1-yl (S)-phenylphosphonate (3a):

[0076]

[0077] Prepared according to general procedure E. Flash column chromatography (PE / EtOAc=10:1) yielded the title compound 3a, white solid (35.65mg, 85% yield); R f 0.50 (PE / EtOAc=4:1); mp100.1-102.0℃.

[0078] 1 H NMR (400MHz, CDCl3) δ8.13-8.02(m,2H),8.04-7.97(m,1H),7.81-7.77(m,1H),7.74(dd,J=8.1,1.7Hz, 1H),7.66-7.56(m,2H),7.55-7.43(m,5H),7.32(dt,J=7.7,1.4Hz,1H),7.30-7.19(m,2H),2.45(s,3H).

[0079] 13C NMR(101MHz,CDCl3)146.2(d,J7.0Hz),143.5,141.0(d,J10.0Hz),136.0(d,J1.9). Hz),134.7,134.4(d,JC3.5Hz),133.6(d,JS3.3Hz),132.3(d,JC10.9Hz),128.7(d,J6). 16.4Hz),127.7,126.6(d),126.3(d,JS6.1Hz),125.8(d,JS196.0Hz),125.4(d,JS2.0). Hz), 125.3(d,JC1.5Hz),125.1,123.3(d,JC1.6Hz),121.4,115.4(d,JC3.3Hz),17.4.

[0080] 31 PNMR(162MHz,CDCl3)δ13.66.

[0081] HRMS (ESI, m / z): calculated for C 23 H 18 NO5PNa + [M+Na] + :442.0815,found:4

[0082]

[0083] HPLC analysis:97:3e.r.(Chiralcel ID,30:70i-PrOH / n-Hexane,1.0mL / min),40°C,Rt(minor)E10.7min,Rt(major)E12.0min.

[0084] 2-substitute-6-substitute(S)-substitute complex(4-substitute-1-substitute)(3b):

[0085]

[0086] Prepared according to general procedure E.Flash column chromatography (PE / EtOAc10:1) yielded the title compound 3b6

[0087] oil(29.5mg.68% yield)R f 0.50(PE / EtOAc4:1).

[0088] 1 H NMR (400MHz, CDCl3) δ8.14-7.99(m,3H),7.96-7.86(m,1H),7.74(dd,J=8.1,1.7Hz,1H),7.66-7.57( m,1H),7.56-7.44(m,5H),7.25-7.18(m,2H),7.08(dd,J=7.8,1.1Hz,1H),2.58(s,3H),2.46(s,3H).

[0089] 13 C NMR (101MHz, CDCl3) δ144.7 (d, J = 7.0Hz), 143.6, 141.0 (d, J = 10.1Hz), 136.0 (d, J = 1.9 Hz),134.4(d,J=3.6Hz),133.6(d,J=2.6Hz),132.4(d,J=10.9Hz),131.5,128.7(d,J=1 6.3Hz), 126.4, 126.3 (d, J = 5.9Hz), 126.0, 125.96 (d, J = 195.0Hz), 125.7 (d, J = 1.6Hz), 125.3(d,J=2.0Hz),124.2,123.3(d,J=1.8Hz),121.9,114.9(d,J=3.2Hz),19.0,17.4.

[0090] 31 PNMR (162MHz,CDCl3)δ13.67.

[0091] HRMS(ESI,m / z):calculated for C 24 H 20 NO5PNa + [M+Na] + :456.0972,found:456.0971.

[0092]

[0093] HPLC analysis: 96:4e.r. (Chiralcel ID, 30:70i-PrOH / n-Hexane, 1.0mL / min), 40°C, Rt (minor) = 10.9min, Rt (major) = 14.4min.

[0094] 4-Chloronaphthalen-1-yl (2-methyl-6-nitrophenyl) (S)-phenylphosphonate (3c):

[0095]

[0096] Prepared according to general procedure E.Flash column chromatography(PE / EtOAc=10:1)yielded the title compound 3c,oil(40.4mg,89%yield);R f 0.50(PE / EtOAc=4:1).

[0097] 1 H NMR(400MHz,CDCl3)δ8.23-8.14(m,1H),8.11-8.01(m,3H),7.74(dd,J=8.2,1.7Hz,1H),7.65-7.53(m,3H),7.53-7.47(m,3H),7.35(d,J=8.3Hz,1H),7.29-7.21(m,2H),2.45(s,3H).

[0098] 13 C NMR(101MHz,CDCl3)δ145.2(d,J=6.8Hz),143.5(d,J=3.7Hz),140.8(d,J=10.2Hz),136.1(d,J=1.9Hz),134.3(d,J=3.5Hz),133.8(d,J=3.2Hz),132.3(d,J=10.9Hz),131.6,128.8(d,J=16.2Hz),128.4(d,J=1.5Hz),127.7,127.3(d,J=6.1Hz),127.2,125.52(d,J=195.0Hz),125.50(d,J=1.9Hz),125.4(d,J=1.5Hz),124.6(d,J=2.7Hz),123.4(d,J=1.8Hz),121.9,115.4(d,J=3.2Hz),17.4.

[0099] 31 PNMR(162MHz,DCM)δ13.84.

[0100] HRMS(ESI,m / z):calculated for C 23 H 17 ClNO5PNa + [M+Na] + :476.0426,found:476.0425.

[0101]

[0102] HPLC analysis: 98.5:1.5 e.r. (Chiralcel ID, 30:70 i-PrOH / n-Hexane, 1.0 mL / min), 40 °C, Rt (minor) = 9.6 min, Rt (major) = 12.8 min.

[0103] (4-Bromonaphthalen-1-yl)(2-methyl-6-nitrophenyl)(S)-phenylphosphonate (3d):

[0104]

[0105] Prepared according to general procedure E. Flash column chromatography (PE / EtOAc = 10:1) yielded the title compound 3d, white solid (44.8 mg, 90% yield); R f 0.50 (PE / EtOAc = 4:1); m.p. 128.0 - 129.8 °C.

[0106] 1 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.3 Hz, 1H), 8.12 - 7.95 (m, 3H), 7.76 (dd, J = 8.1, 1.7 Hz, 1H), 7.68 - 7.47 (m, 7H), 7.29 - 7.20 (m, 2H), 2.46 (s, 3H).

[0107] 13 13C NMR (101 MHz, CDCl3) δ 145.9 (d, J = 6.7 Hz), 143.5 (d, J = 3.8 Hz), 140.9 (d, J = 10.2 Hz), 136.1 (d, J = 1.9 Hz), 134.3 (d, J = 3.5 Hz), 133.8 (d, J = 3.3 Hz), 132.9, 132.3 (d, J = 10.9 Hz), 129.1 (d, J = 1.5 Hz), 128.8 (d, J = 16.3 Hz), 128.0, 127.5 (d, J = 6.1 Hz), 127.3, 125.52 (d, J = 1.9 Hz), 125.51 (d, J = 194.9 Hz), 123.4 (d, J = 1.8 Hz), 122.0, 118.8 (d, J = 1.7 Hz), 115.9 (d, J = 3.3 Hz), 17.4.

[0108] 31 PNMR (162MHz,CDCl3)δ13.73.

[0109] HRMS(ESI,m / z):calculated for C 23 H 17 BrNO5PNa + [M+Na] + :519.9920,found:519.9920.

[0110]

[0111] HPLC analysis: 92:8e.r. (Chiralcel ID, 30:70i-PrOH / n-Hexane, 1.0mL / min), 40°C, Rt (minor) = 10.1min, Rt (major) = 14.1min.

[0112] 2-Methyl-6-nitrophenylpyran-1-yl (S)-phenylphosphonate (3e):

[0113]

[0114] Prepared according to general procedure E. Flash column chromatography (PE / EtOAc=10:1) yielded the title compound 3e, oil (40.1 mg, 81% yield); R f 0.50 (PE / EtOAc=4:1).

[0115] 1 H NMR (400MHz, CDCl3) δ8.20(d,J=9.1Hz,1H),8.17-8.08(m,4H),8.06(d,J=9.2Hz,1H),8.02-7.93(m,4H),7.93- 7.89(m,1H),7.76(dd,J=8.1,1.7Hz,1H),7.62-7.56(m,1H),7.54-7.45(m,3H),7.28-7.21(m,1H),2.47(s,3H).

[0116] 13C NMR (101MHz, CDCl3) δ143.9 (d, J = 7.2Hz), 143.6, 141.0 (d, J = 10.1Hz), 136.0, 134.5 (d,J=3.5Hz),133.7(d,J=3.3Hz),132.4(d,J=10.9Hz),131.1(d,J=13.1Hz),128.7 (d),128.1,126.9(d),126.4,125.5(d),125.1(d,J=6.4Hz),125.9(d,J=200.0Hz), 125.0(d,J=135.3Hz),123.4,122.5(d,J=6.3Hz),120.4,117.6(d,J=2.8Hz),17.5.

[0117] 31 P NMR (162MHz,CDCl3)δ13.89.

[0118] HRMS(ESI,m / z):calculated for C 29 H 20 NO5PNa + [M+Na] + :516.0972,found:516.0971.

[0119]

[0120] HPLC analysis: 96:4e.r. (Chiralcel ID, 30:70i-PrOH / n-Hexane, 1.0mL / min), 40°C, Rt (minor) = 15.3min, Rt (major) = 31.5min.

[0121] 2,4-Dimethylphenyl (S)-phenylphosphonate (2-methyl-6-nitrophenyl) (3f):

[0122]

[0123] Prepared according to general procedure E. Flash column chromatography (PE / EtOAc=10:1) yielded the title compound 3f, oil (27.0 mg, 68% yield); R f 0.50 (PE / EtOAc=4:1)

[0124] 1H NMR (400MHz, CDCl3) δ8.11-7.99(m,2H),7.72(dd,J=8.1,1.7Hz,1H),7.69-7.61(m,1H),7.58-7.49(m,2H),7.47(d,J=7.6 ,1H),7.22(td,J=7.9,1.3Hz,1H),6.94-6.84(m,2H),6.79(dd,J=8.4,2.2Hz,1H),2.44(s,3H),2.21(s,3H),2.06(s,3H).

[0125] HRMS(ESI,m / z):calculated for C 21 H 20 NO5PNa + [M+Na] + :420.0972,found:420.0971.

[0126]

[0127] HPLC analysis: 94.5:5.5er (Chiralcel ID, 30:70i-PrOH / n-Hexane, 1.0mL / min), 40°C, Rt (minor) = 9.2min, Rt (major) = 13.1min.

[0128] 2,4-Dimethoxyphenyl (2-methyl-6-nitrophenyl) (R)-phenylphosphonate (3g):

[0129]

[0130] Prepared according to general procedure E. Flash column chromatography (PE / EtOAc=10:1) yielded the title compound 3g, oil (21.5mg, 50% yield); R f 0.50 (PE / EtOAc=4:1).

[0131] 1H NMR(400MHz,CDCl3)δ8.14-8.04(m,2H),7.76(dd,J=8.1,1.7Hz,1H),7.66-7.60(m,1H),7.57-7.49(m,2H),7.48(d,J=7.6,1H),7.22(td,J=7.9,1.3Hz,1H),6.85(dd,J=8.9,1.6Hz,1H),6.36(d,J=2.8Hz,1H),6.25(dd,J=8.9,2.8Hz,1H),3.69(s,3H),3.53(s,3H),2.48(s,3H).

[0132] 13 C NMR(101MHz,CDCl3)δ157.6(d,J=1.5Hz),151.1(d,J=4.0Hz),143.7(d,J=3.6Hz),141.0(d,J=10.6Hz),135.7(d,J=1.9Hz),134.6(d,J=3.5Hz),133.5(d,J=7.7Hz),133.1(d,J=3.3Hz),132.3(d,J=10.8Hz),128.3(d,J=16.4Hz),126.8.(d,J=196.0Hz),125.1(d,J=1.9Hz),123.1(d,J=1.7Hz),121.3(d,J=3.5Hz),103.8(d,J=1.4Hz),102.3-96.8(m),55.5(d,J=7.3Hz),17.3.

[0133] 31 PNMR(162MHz,CDCl3)δ14.45.

[0134] HRMS(ESI,m / z):calculated for C 21 H 20 NO7PNa + [M+Na] + :452.0870,found:452.0870.

[0135]

[0136] HPLC analysis:96:4e.r.(Chiralcel ID,30:70i-PrOH / n-Hexane,1.0mL / min),40℃,Rt(minor)=20.1min,Rt(major)=27.3min.

[0137] 4-Acetyl-2-methoxyphenyl (2-methyl-6-nitrophenyl) (R)-phenylphosphonate (3h):

[0138]

[0139] Prepared according to general procedure E. Flash column chromatography (PE / EtOAc=10:1) yielded the title compound 3h, oil (37.5mg, 85% yield); R f 0.50 (PE / EtOAc=4:1).

[0140] 1 H NMR (400MHz, CDCl3) δ8.11-8.00(m,2H),7.79-7.71(m,2H),7.71-7.65(m,1H),7.63(dd,J=8.5,2.3Hz,1H),7.60-7.53(m ,2H),7.51-7.49(m,1H),7.26(td,J=7.9,1.3Hz,1H),7.14(dd,J=8.5,1.3Hz,1H),2.51(s,3H),2.44(s,3H),2.17(s,3H).

[0141] 13 C NMR (101MHz, CDCl3) δ197.0, 152.5 (d, J = 7.1Hz), 143.5 (d, J = 3.7Hz), 140.7 (d, J = 10.4Hz ),136.0(d,J=1.9Hz),134.3(d,J=3.5Hz),134.0(d),133.9(d,J=3.3Hz),132.3(d,J=10 .9Hz),131.6,129.8(d,J=6.2Hz),128.9(d,J=16.4Hz),127.7(d,J=1.1Hz),125.8(d,J= 195.0Hz),125.6(d,J=1.9Hz),123.3(d,J=1.7Hz),119.9(d,J=2.8Hz),26.5,17.4,16.4.

[0142] 31 P NMR (162MHz,CDCl3)δ13.22.

[0143] HRMS(ESI,m / z):calculated for C 22 H 20NO7PNa + [M+Na] + :464.0870,found:464.0869.

[0144]

[0145] HPLC analysis: 99:1e.r. (Chiralcel ID, 30:70i-PrOH / n-Hexane, 1.0mL / min), 40°C, Rt (minor) = 21.1min, Rt (major) = 29.7min.

[0146] Methyl (R)-3-methoxy-4-(((2-methyl-6-nitrophenoxy)(phenyl)phosphonic acid)oxy)benzoate (3i):

[0147]

[0148] Prepared according to general procedure E. Flash column chromatography (PE / EtOAc=10:1) yielded the title compound 3i, oil (33.4 mg, 73% yield); R f 0.50 (PE / EtOAc=4:1).

[0149] 1 H NMR(400MHz, CDCl3)δ8.19-7.96(m,2H),7.79(dd,J=8.1,1.7Hz,1H),7.72-7.61(m,1H),7.60-7.50(m,2H) ,7.53-7.44(m,3H),7.31-7.20(m,1H),7.02(dd,J=8.9,1.5Hz,1H),3.85(s,3H),3.63(s,3H),2.49(s,3H).

[0150] 13C NMR (101MHz, CDCl3) δ166.2, 150.2 (d, J = 4.4Hz), 143.6 (d, J = 3.6Hz), 143.3 (d, J = 7. 5Hz),140.8(d,J=10.8Hz),135.9(d,J=2.1Hz),134.5(d,J=3.5Hz),133.5(d,J=3.3H z),132.3(d,J=11.1Hz),128.5(d,J=16.6Hz),127.7,126.3(d,J=198.0Hz),125.3(d ,J=1.9Hz),123.2(d,J=1.9Hz),122.6,121.0(d,J=3.6Hz),113.6,55.6,52.2,17.3.

[0151] 31 P NMR (162MHz,CDCl3)δ13.98.

[0152] HRMS(ESI,m / z):calculated for C 22 H 20 NO8PNa + [M+Na] + :480.0819,found:480.0819.

[0153]

[0154] HPLC analysis:96:4e.r.(Chiralcel ODH,10:90i-PrOH / n-Hexane,0.5mL / min),40℃,Rt(major)=25.2min,Rt(minor)=28.4min,

[0155] 4-Allyl-2-methoxyphenyl (2-methyl-6-nitrophenyl) (R)-phenylphosphonate (3j):

[0156]

[0157] Prepared according to general procedure E. Flash column chromatography (PE / EtOAc=10:1) yielded the title compound 3j, oil (35.2mg, 80% yield); R f 0.50 (PE / EtOAc=4:1).

[0158] 1 H NMR(400MHz,CDCl3)δ8.20-7.97(m,2H),7.77(dd,J=8.2,1.7Hz,1H),7.69-7.61(m,1H),7.58-7.51(m,2H),7.50-7.43(m,1H),7.22(dd,J=7.9,1.3Hz,1H),6.84(dd,J=8.1,1.5Hz,1H),6.62(d,J=2.0Hz,1H),6.58(dd,J=8.1,2.0Hz,1H),5.91-5.81(m,1H),5.23-4.69(m,2H),3.54(s,3H),3.26(d,J=6.7Hz,2H),2.49(s,3H).

[0159] 13 C NMR(101MHz,CDCl3)δ150.2(d,J=4.1Hz),143.8,141.0(d,J=10.6Hz),137.9(d,J=1.8Hz),137.8,137.0,135.8(d,J=1.9Hz),134.7(d,J=3.3Hz),133.2(d,J=3.3Hz),132.3(d,J=11.0Hz),128.4(d,J=16.5Hz),126.8(d,J=200.0Hz),125.1(d,J=1.8Hz),123.1(d,J=1.8Hz),121.0(d,J=3.6Hz),120.6,116.0,113.0,55.4,39.8,17.4.

[0160] 31 PNMR(162MHz,CDCl3)δ14.18.

[0161] HRMS(ESI,m / z):calculated for C 23 H 22 NO6PNa + [M+Na] + :462.1077,found:462.1077.

[0162]

[0163] HPLC analysis:95:5e.r.(Chiralcel ODH,5:95i-PrOH / n-Hexane,0.3mL / min),40℃,Rt(major)=41.8min,Rt(minor)=45.1min.

[0164] Ethyl (R,E)-3-(3-methoxy-4-(((2-methyl-6-nitrophenoxy)(phenyl)phosphono)oxy)phenyl)acrylate (3k):

[0165]

[0166] Prepared according to general procedure E. Flash column chromatography (PE / EtOAc=10:1) yielded the title compound 3k, oil (41.9mg, 87% yield); R f 0.50 (EtOAc / hexane = 4:1).

[0167] 1 H NMR (400MHz, CDCl3) δ8.10 (ddd, J=14.7, 8.3, 1.3Hz, 2H), 7.79 (dd, J=8.1, 1.7Hz, 1H), 7.70-7.62 (m, 1H), 7.59-7.48 (m, 4H), 7.29 -7.22(m,1H),7.00-6.91(m,3H),6.28(d,J=16.0Hz,1H),4.23(q,J=7.1Hz,2H),3.59(s,3H),2.49(s,3H),1.31(t,J=7.1Hz,3H).

[0168] 13 C NMR (101MHz, CDCl3) δ166.7, 150.7 (d, J = 4.3Hz), 143.6, 141.1 (d, J = 7.7Hz), 140.8 (d, J = 10 .8Hz),135.9(d,J=1.9Hz),134.6(d,J=3.4Hz),133.4(d,J=3.2Hz),132.4(d,J=1.6Hz),13 2.3(d,J=11.0Hz),128.5(d,J=16.5Hz),126.5(d,J=199.0Hz),125.3(d,J=1.9Hz),123.2( d,J=1.7Hz),121.6(d,J=3.7Hz),121.2(d,J=1.7Hz),118.3,111.4,60.5,55.5,17.3,14.2.

[0169] 31 P NMR (162MHz,CDCl3)δ14.13.

[0170] HRMS(ESI,m / z):calculated for C 25 H 24 NO8PNa + [M+Na] + :520.1132,found:520.1132.

[0171]

[0172] HPLC analysis: 96:4e.r. (Chiralcel ODH, 10:90i-PrOH / n-Hexane, 0.5mL / min), 40°C, Rt (major) = 38.1min, Rt (minor) = 43.9min.

[0173] 2-Methoxy-4-(1-methylcyclohexane-1-carboxamide)phenyl(2-methyl-6-nitrophenyl)(R)-phenylphosphonate (31):

[0174]

[0175] Prepared according to general procedure E. Flash column chromatography (PE / EtOAc=10:1) yielded the title compound 3l, oil (28.9mg, 50% yield); R f 0.50 (EtOAc / hexane = 4:1).

[0176] 1 H NMR (400MHz, CDCl3) δ8.20 (d, J = 9.3Hz, 1H), 8.13-7.98 (m, 2H), 7.90 (s, 1H ),7.77(d,J=8.1,1H),7.73-7.62(m,1H),7.61-7.52(m,2H),7.49(d,J=7. 6,1H),7.25(td,J=7.9,1.3Hz,1H),7.11(dd,J=9.3,1.4Hz,1H),2.47(s,3 H),2.01-1.96(m,2H),1.61-1.57(m,2H),1.51-1.39(m,6H),1.23(s,3H).

[0177] 13C NMR (101MHz, CDCl3) δ176.0, 143.5 (d, J = 3.7Hz), 142.7 (d, J = 5.9Hz), 140.7 (d, J = 1 0.6Hz),136.1(d,J=1.8Hz),134.3(d,J=3.5Hz),134.0(d,J=3.3Hz),133.4,132.5( d, J=11.2Hz), 128.8 (d, J=16.5Hz), 125.6 (d, J=1.8Hz), 125.2 (d, J=196.0Hz), 124. 9(d,J=6.8Hz),123.4(d,J=1.8Hz),120.5-118.6(m),44.2,35.6,25.6,22.8,17.3.

[0178] 31 P NMR (162MHz,CDCl3)δ14.25.

[0179] HRMS(ESI,m / z):calculated for C 28 H 31 N2O7PNa + [M+Na] + :561.1762,found:561.1761.

[0180]

[0181] HPLC analysis: 96:4e.r. (Chiralcel ID, 30:70i-PrOH / n-Hexane, 1.0mL / min), 40°C, Rt(minor)=25.9min, Rt(major)=36.2min.

[0182] 2-Methyl-6-nitrophenylnaphthalen-1-yl (S)-p-tolylphosphonate (3m):

[0183]

[0184] Prepared according to general procedure E. Flash column chromatography (PE / EtOAc=10:1) yielded the title compound 3m, oil (30.3mg, 70% yield); R f 0.50 (EtOAc / hexane = 4:1).

[0185] 1H NMR (400MHz, CDCl3) δ8.06-7.99(m,1H),8.00-7.90(m,2H),7.80-7.75(m,1H),7.72(d,J=8.1Hz,1H),7. 57(d,J=8.2Hz,1H),7.53-7.41(m,3H),7.36-7.25(m,3H),7.27-7.16(m,2H),2.44(s,3H),2.38(s,3H).

[0186] 13 C NMR (101MHz, CDCl3) δ 146.2 (d, J = 6.7Hz), 144.5 (d, J = 3.3Hz), 143.5 (d, J = 3.9Hz), 141. 0(d,J=10.1Hz),135.9(d,J=1.8Hz),134.7,134.3(d,J=3.3Hz),132.3(d,J=11.4Hz),12 9.5,127.7,126.4(d,J=15.2Hz),126.3(d,J=5.9Hz),125.3(d,J=1.5Hz),125.0,124.3( d, J=192.0Hz), 123.2 (d, J=1.7Hz), 121.4, 115.2 (d, J=3.3Hz), 21.7 (d, J=1.6Hz), 17.4.

[0187] 31 PNMR (162MHz,CDCl3)δ14.54.

[0188] HRMS(ESI,m / z):calculated for C 24 H 20 NO5PNa + [M+Na] + :456.0972,found:456.0971.

[0189]

[0190] HPLC analysis: 96:4e.r. (Chiralcel ID, 30:70i-PrOH / n-Hexane, 1.0mL / min), 40°C, Rt (minor) = 10.6min, Rt (major) = 11.8min.

[0191] 2-Methyl-6-nitrophenylnaphthalen-1-yl (S)-(4-butylphenyl)phosphonate (3n):

[0192]

[0193] Prepared according to general procedure E.Flash column chromatography(PE / EtOAc=10:1)yielded the title compound 3n,oil(40.0mg,85%yield);R f 0.50(PE / EtOAc=4:1).

[0194] 1 H NMR(400MHz,CDCl3)δ8.10-7.87(m,3H),7.84-7.67(m,2H),7.59(d,J=8.1Hz,1H),7.54-7.40(m,3H),7.37-7.16(m,5H),2.66(t,J=7.8Hz,2H),2.46(s,3H),1.66-1.56(m,3H),1.39-1.30(m,2H),0.92(t,J=7.3Hz,3H).

[0195] 13 C NMR(101MHz,CDCl3)δ149.4(d,J=3.3Hz),146.3(d,J=6.9Hz),143.6(d,J=3.6Hz),141.0(d,J=10.2Hz),136.0(d,J=2.0Hz),134.7,134.4(d,J=3.5Hz),132.4(d,J=11.4Hz),128.9(d,J=16.7Hz),127.7,126.5(d,J=16.4Hz),126.3(d,J=7.1Hz),125.34(d,J=1.4Hz),125.30(d,J=2.1Hz),125.0,123.6,123.3(d,J=1.7Hz),122.6(d,J=198.0Hz),121.5,115.3(d,J=3.4Hz),35.8,33.0,22.2,17.4,13.8.

[0196] 31 PNMR(162MHz,CDCl3)δ14.52.

[0197] HRMS(ESI,m / z):calculated for C 27 H 26 NO5PNa + [M+Na] +:498.1441,found:498.1441.

[0198]

[0199] HPLC analysis: 96:4e.r. (Chiralcel ID, 30:70i-PrOH / n-Hexane, 1.0mL / min), 40°C, Rt (minor) = 9.4min, Rt (major) = 10.1min.

[0200] 2-Methyl-6-nitrophenylnaphthalen-1-yl (S)-(4-isopropylphenyl)phosphonate (3o):

[0201]

[0202] Prepared according to general procedure E. Flash column chromatography (PE / EtOAc=10:1) yielded the title compound 3o, oil (36.0 mg, 78% yield); R f 0.50 (PE / EtOAc=4:1).

[0203] 1 H NMR (400MHz, CDCl3) δ8.05-7.95(m,3H),7.82-7.75(m,1H),7.74(d,J=9.9Hz,1H),7.59(d,J=8.2Hz,1H),7.52 -7.44(m,3H),7.40-7.31(m,3H),7.30-7.19(m,2H),2.96(p,J=6.9Hz,1H),2.46(s,3H),1.26(d,J=6.9Hz,6H).

[0204] 13C NMR (101MHz, CDCl3) δ155.2(d,J=3.2Hz), 146.3(d,J=6.9Hz), 143.6(d,J=3.8Hz), 141.0(d,J= 10.2Hz),136.0(d,J=1.9Hz),134.7,134.4(d,J=3.5Hz),132.5(d,J=11.3Hz),127.7,127.1,12 6.9,126.5,126.4,126.3(d,J=6.1Hz),125.35(d,J=1.0Hz),125.30(d,J=1.9Hz),125.0,123.3 (d, J=1.8Hz), 122.7 (d, J=198.0Hz), 121.5, 115.3 (d, J=3.3Hz), 34.3, 23.5 (d, J=2.7Hz), 17.4.

[0205] 31 PNMR (162MHz,CDCl3)δ14.42.

[0206] HRMS(ESI,m / z):calculated for C 26 H 24 NO5PNa + [M+Na] + :484.1285,found:484.1284.

[0207]

[0208] HPLC analysis: 97:3e.r. (Chiralcel ID, 30:70i-PrOH / n-Hexane, 1.0mL / min), 40°C, Rt (minor) = 9.0min, Rt (major) = 9.8min.

[0209] 2-Methyl-6-nitrophenylnaphthalen-1-yl (S)-(4-(tert-butyl)phenyl)phosphonate (3p):

[0210]

[0211] Prepared according to general procedure E. Flash column chromatography (PE / EtOAc=10:1) yielded the title compound 3p, oil (43.3mg, 91% yield); R f 0.50 (PE / EtOAc=4:1).

[0212] 1 H NMR (400MHz, CDCl3) δ8.06-7.97(m,3H),7.80-7.78(m,1H),7.74(d,J=8.1Hz,1H),7.59(d,J=8.2Hz ,1H),7.57-7.45(m,5H),7.35(dt,J=7.8,1.4Hz,1H),7.29-7.20(m,2H),2.47(s,3H),1.33(s,9H).

[0213] 13 C NMR (101MHz, CDCl3) δ157.4 (d, J = 3.4Hz), 146.3 (d, J = 6.9Hz), 143.6 (d, J = 3.9Hz), 141.0 (d ,J=10.2Hz),136.0(d,J=1.9Hz),134.7,134.4(d,J=3.4Hz),132.3(d,J=11.4Hz),127.7,12 6.5(d,J=16.6Hz),126.3,125.8(d,J=16.4Hz),125.4(d,J=1.4Hz),125.3(d,J=1.9Hz),124 .9,123.3(d,J=1.7Hz),122.4(d,J=197.0Hz),121.5,115.2(d,J=3.2Hz),35.2,31.0,17.4.

[0214] 31 PNMR (162MHz,CDCl3)δ14.40.

[0215] HRMS(ESI,m / z):calculated for C 27 H 26 NO5PNa + [M+Na] + :498.1441found:498.1441.

[0216]

[0217] HPLC analysis: 97:3e.r. (Chiralcel ODH, 20:80i-PrOH / n-Hexane, 1.0mL / min), 40°C, Rt (minor) = 15.6min, Rt (major) = 16.4min.

[0218] 2-Methyl-6-nitrophenylnaphthalen-1-yl (S)-(4-methoxyphenyl)phosphonate (3q):

[0219]

[0220] Prepared according to general procedure E.Flash column chromatography(PE / EtOAc=10:1)yielded the title compound 3q,oil(31.5mg,70%yield);R f 0.50(PE / EtOAc=4:1).

[0221] 1 H NMR(400MHz,CDCl3)δ8.10-7.91(m,3H),7.78-7.76(m,1H),7.73(d,J=8.1Hz,1H),7.57(d,J=8.4Hz,1H),7.52-7.42(m,3H),7.30(dt,J=7.7,1.4Hz,1H),7.27-7.16(m,2H),7.04-6.88(m,2H),3.82(s,3H),2.46(s,3H).

[0222] 13 C NMR(101MHz,CDCl3)δ163.8(d,J=3.6Hz),146.3(d,J=6.5Hz),143.6,141.1(d,J=10.0Hz),136.0(d,J=1.9Hz),134.7,134.6,134.5(d,J=4.0Hz),134.4,127.7,126.5(d,J=14.5Hz),126.4(d,J=8.1Hz),125.33,125.28(d,J=2.0Hz),125.0,123.3(d,J=1.7Hz),121.5,116.7(d,J=202.3Hz),115.3(d,J=3.3Hz),114.3(d,J=17.4Hz),55.4,17.5.

[0223] 31 PNMR(162MHz,CDCl3)δ14.74.

[0224] HRMS(ESI,m / z):calculated for C 24 H 20 NO5PNa + [M+Na] + :472.0921,found:472.0920.

[0225]

[0226] HPLC analysis: 95:5e.r. (Chiralcel ID, 30:70i-PrOH / n-Hexane, 1.0mL / min), 40°C, Rt (minor) = 13.1min, Rt (major) = 14.1min.

[0227] 2-Methyl-6-nitrophenylnaphthalen-1-yl (S)-[1,1'-biphenyl]-4-ylphosphonate (3r):

[0228]

[0229] Prepared according to general procedure E. Flash column chromatography (PE / EtOAc=10:1) yielded the title compound 3r, oil (43.1 mg, 87% yield); R f 0.50 (PE / EtOAc=4:1).

[0230] 1 H NMR (400MHz, CDCl3) δ8.15-8.06(m,2H),8.05-7.98(m,1H),7.75(ddd,J=9.9,7.6,1.5Hz,2H),7.71-7 .66(m,2H),7.60-7.54(m,3H),7.50-7.41(m,5H),7.39-7.32(m,2H),7.25-7.19(m,2H),2.46(s,3H).

[0231] 1313C NMR (101 MHz, CDCl3) δ 146.4 (d, J = 3.4 Hz), 146.2 (d, J = 6.9 Hz), 143.5, 141.0 (d, J = 10.1 Hz), 139.5, 136.1 (d, J = 1.9 Hz), 134.7, 134.4 (d, J = 3.5 Hz), 132.9 (d, J = 11.3 Hz), 129.0, 128.4, 127.7, 127.5, 127.3 (d, J = 1.5 Hz), 126.5 (d, J = 13.5 Hz), 126.3 (d, J = 6.1 Hz), 125.4 (d, J = 6.1 Hz), 125.1, 124.2 (d, J = 198.0 Hz), 123.4 (d, J = 1.7 Hz), 121.4, 115.3 (d, J = 3.3 Hz), 17.5.

[0232] 31 31P NMR (162 MHz, CDCl3) δ 13.94.

[0233] HRMS (ESI, m / z): calculated for C 29 H 22 NO5PNa + [M + Na] + : 518.1128, found: 518.1128.

[0234]

[0235] HPLC analysis: 97:3 e.r. (Chiralcel ID, 30:70 i-PrOH / n-Hexane, 1.0 mL / min), 40 °C, Rt (minor) = 13.7 min, Rt (major) = 14.7 min.

[0236] (S)-2-Methyl-6-nitrophenyl 1-naphthyl (4-chlorophenyl)phosphonate (3s):

[0237]

[0238] Prepared according to general procedure E. Flash column chromatography (PE / EtOAc = 10:1) yielded the title compound 3s, oil (39.9 mg, 88% yield); R f 0.50 (PE / EtOAc = 4:1).

[0239] 1 H NMR (400MHz, CDCl3) δ8.07-7.92(m,3H),7.83-7.74(m,2H),7.60(d,J=8.5Hz,1H),7.55-7.41(m,5H),7.33-7.22(m,3H),2.46(s,3H).

[0240] 13 C NMR (101MHz, CDCl3) δ146.0 (d, J = 6.8Hz), 143.3, 140.9 (d, J = 10.0Hz), 140.4 (d, J = 4 .3Hz),136.1(d,J=1.9Hz),134.7,134.3(d,J=3.5Hz),133.8(d,J=11.9Hz),129.2( d,J=16.9Hz),127.8,126.6(d,J=11.0Hz),126.2(d,J=5.9Hz),125.6(d,J=1.8Hz), 125.3, 124.3 (d, J = 197.0Hz), 123.4 (d, J = 1.7Hz), 121.2, 115.3 (d, J = 3.3Hz), 17.4.

[0241] 31 P NMR (162MHz,CDCl3)δ12.51.

[0242] HRMS(ESI,m / z):calculated for C 23 H 17 ClNO5PNa + [M+Na] + :476.0426,found:476.0425.

[0243]

[0244] HPLC analysis: 97:3e.r. (Chiralcel ID, 30:70i-PrOH / n-Hexane, 1.0mL / min), 40°C, Rt(minor)=8.9min, Rt(major)=9.9min.

[0245] 2-Methyl-6-nitrophenylnaphthalen-1-yl (S)-p-tolylphosphonate (3t):

[0246]

[0247] Prepared according to general procedure E.Flash column chromatography(PE / EtOAc=10:1)yielded the title compound 3t,oil(40.3mg,93%yield);R f 0.50(PE / EtOAc=4:1).

[0248] 1 H NMR(400MHz,CDCl3)δ8.06-7.97(m,1H),7.93-7.83(m,2H),7.81-7.77(m,1H),7.75(dd,J=8.1,1.7Hz,1H),7.59(d,J=7.4Hz,1H),7.53-7.45(m,3H),7.41(dt,J=7.6,5.3Hz,2H),7.35-7.28(m,1H),7.30-7.20(m,2H),2.46(s,3H),2.39(s,3H).

[0249] 13 C NMR(101MHz,CDCl3)δ146.2(d,J=6.9Hz),143.6,141.0(d,J=10.2Hz),138.7(d,J=16.3Hz),136.0(d,J=2.0Hz),134.7,134.5(d,J=3.3Hz),134.4(d,J=3.6Hz),132.8(d,J=11.1Hz),129.4(d,J=10.6Hz),128.7(d,J=17.1Hz),127.7,126.6,126.4,126.3(d,J=8.1Hz),125.6(d,J=193.9Hz),125.3(d),125.0(d),123.3(d,J=1.5Hz),121.5,115.4(d,J=3.3Hz),21.3,17.4.

[0250] 31 PNMR(162MHz,CDCl3)δ14.21.

[0251] HRMS(ESI,m / z):calculated for C 24 H 20 NO5PNa + [M+Na] + :456.0972,found:456.0971.

[0252]

[0253] HPLC analysis: 97:3e.r. (Chiralcel ID, 30:70i-PrOH / n-Hexane, 1.0mL / min), 40°C, Rt (minor) = 9.3min, Rt (major) = 10.3min.

[0254] 2-Methyl-6-nitrophenylnaphthalen-1-yl (S)-o-tolylphosphonate (3u):

[0255]

[0256] Prepared according to general procedure E. Flash column chromatography (PE / EtOAc=10:1) yielded the title compound 3u, oil (26.0mg, 60% yield); R f 0.50 (PE / EtOAc=4:1).

[0257] 1 H NMR(400MHz, CDCl3)δ8.18(ddd,J=15.5,7.8,1.5Hz,1H),8.13-8.00(m,1H),7.88-7.77(m,1H),7.75(d,J=8.1,1H), 7.59(d,J=7.9Hz,1H),7.56-7.42(m,4H),7.39-7.27(m,3H),7.27-7.20(m,2H),2.74(d,J=1.8Hz,3H),2.41(s,3H).

[0258] 13C NMR(101MHz,CDCl3)δ146.3(d,J6.8Hz),143.5,142.3(d,J11.4Hz),141.2(d,J610.0H). z),135.9(d,JC1.8Hz),134.7,134.4(d,JC11.2Hz),134.2(d,JC3.7Hz),133.6(d,JC3.2H). z), 131.6(d,J16.4Hz),127.7,126.6,126.4,126.2(d,J6.4Hz),125.8(d,J616.0Hz), 125.3,125.1(d,J189.9Hz),124.8,123.3(d,J1.8Hz),121.5,21.7(d,J3.5Hz),17.4.

[0259] 31 PNMR(162MHz,CDCl3)δ14.87.

[0260] HRMS (ESI, m / z): calculated for C 24 H 20 NO5PNa + [M+Na] + :456.0972,found:456.0971.

[0261]

[0262] HPLC analysis:99:1e.r.(Chiralcel ID,30:70i-PrOH / n-Hexane,1.0mL / min),40°C,Rt(minor)E11.8min,Rt(major)E13.2min.

[0263] 2-shell-6-shell-shell-1-shell(S)-(2-shell-shell)speed(3v):

[0264]

[0265] Prepared according to general procedure E.Flash column chromatography(PE / EtOAc(10:1)yielded the title compound 3v,white solid(38.6mg,85% yield)R f 0.50(PE / EtOAc4:1).

[0266] 1 H NMR (400MHz, CDCl3) δ8.47-8.09(m,2H),7.99-7.67(m,2H),7.61(d,J=8.2Hz,1H),7.58-7.38(m,7H),7.33-7.12(m,2H),2.39(s,3H).

[0267] 13 C NMR (101MHz, CDCl3) δ146.3(d,J=7.0Hz), 143.0(d,J=3.9Hz), 141.3(d,J=9.6Hz), 136.7(d,J =2.5Hz), 136.5 (d, J = 9.4Hz), 136.0 (d, J = 2.0Hz), 134.7, 134.6 (d, J = 2.7Hz), 134.0 (d, J = 3.9 Hz),131.0(d,J=11.2Hz),127.6,127.0(d,J=202.0Hz),126.8,126.6,126.4,126.2(d,J=7.1 Hz), 125.3 (d, J = 1.8Hz), 125.3, 125.0, 123.4 (d, J = 1.6Hz), 121.9, 114.7 (d, J = 3.4Hz), 17.2.

[0268] 31 P NMR (162MHz,CDCl3)δ9.95.

[0269] HRMS(ESI,m / z):calculated for C 23 H 17 ClNO5PNa+[M+Na] + :476.0426,found:476.0425.

[0270]

[0271] HPLC analysis: 98:2e.r. (Chiralcel ID, 30:70i-PrOH / n-Hexane, 1.0mL / min), 40°C, Rt (minor) = 11.7min, Rt (major) = 13.1min.

[0272] 2-Methyl-6-nitrophenylnaphthalen-1-yl (S)-methylphosphonate (3w):

[0273]

[0274] Prepared according to general procedure E.Flash column chromatography(PE / EtOAc=10:1)yielded the title compound 3w,white solid(32.2mg,90%yield);R f 0.50(PE / EtOAc=4:1).

[0275] 1 H NMR(400MHz,CDCl3)δ8.17-8.05(m,1H),7.91-7.81(m,1H),7.80(dd,J=8.2,1.7Hz,1H),7.67(dd,J=8.3,1.1Hz,1H),7.61-7.46(m,2H),7.50-7.40(m,2H),7.40-7.31(m,1H),7.22(td,J=7.9,1.2Hz,1H),2.39(s,3H),1.97(d,J=17.8Hz,3H).

[0276] 13 C NMR(101MHz,CDCl3)δ146.0(d,J=7.6Hz),142.7(d,J=4.1Hz),141.5(d,J=10.2Hz),136.2(d,J=1.9Hz),134.8,134.0(d,J=3.3Hz),127.8(d,J=5.0Hz),127.1(d,J=138.4Hz),126.7(d,J=10.9Hz),126.3(d,J=5.8Hz),125.5(d,J=1.6Hz),125.2(d,J=1.4Hz),123.4(d,J=1.8Hz),121.2,115.7(d,J=3.5Hz),115.4(d,J=3.2Hz),17.2,11.9(d,J=143.8Hz).

[0277] 31 PNMR(162MHz,CDCl3)δ26.75.

[0278] HRMS(ESI,m / z):calculated for C 18 H 16 NO5PNa + [M+Na] + :380.0659,found:380.0658.

[0279]

[0280] HPLC analysis: 77:23e.r. (Chiralcel ID, 30:70i-PrOH / n-Hexane, 1.0mL / min), 40°C, Rt (major) = 10.7min, Rt (minor) = 11.9min.

[0281] Example 2

[0282] This embodiment provides a method for preparing a derivative 5 of a chiral P(V) phosphonate compound, comprising the following steps:

[0283]

[0284] Under nitrogen protection, nucleophile 4 (0.15 mmol, 1.5 equiv.) and tetrahydrofuran were added to a 10 ml Shrek bottle equipped with a magnetic stirrer. Nucleophile 4 was R-OH, and R-OH included methyl, deuterated methyl, ethyl, isopropyl, benzyl, 2',3'-isopropylurea, 2',3'-isopropylidene adenosyl, methyl-2,3-O-isopropylidene-D-furanosyl, menthol, cholesterol, androsterone, pregnenolone or dodecyl. t-BuMgCl (1.7 M in ) was added at 0 °C. THF, 0.15mmol, 1.5equiv.), after 20 minutes, compound 3a (0.1mmol, 1.0equiv.) was added dropwise, after the addition was completed, the mixture was stirred at room temperature, 3a was consumed (monitored by thin layer chromatography TLC), saturated ammonium chloride solution (2.0mL) was added, and the aqueous phase was extracted with ethyl acetate (3x1.5mL). The combined organic phase was dried over anhydrous sodium sulfate, all volatiles were removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=8:1) to obtain the target compound 5.

[0285] Shape and spectrum analysis of compound 5:

[0286] Methylnaphthyl-1-yl (S)-phenylphosphonate (5a):

[0287]

[0288] Prepared according to general procedure F. Flash column chromatography (PE / EtOAc=10:1) yielded the title compound 5a, white solid (17.9 mg, 60% yield); R f0.50 (PE / EtOAc = 4:1).

[0289] 1 1H NMR (400 MHz, CDCl3) δ 8.19 - 8.08 (m, 1H), 8.03 - 7.91 (m, 2H), 7.88 - 7.78 (m, 1H), 7.63 (dd, J = 8.3, 1.1 Hz, 1H), 7.63 - 7.54 (m, 1H), 7.54 - 7.42 (m, 5H), 7.36 (t, J = 7.9 Hz, 1H), 3.90 (d, J = 11.3 Hz, 3H).

[0290] 13 13C NMR (101 MHz, CDCl3) δ 146.5 (d, J = 7.7 Hz), 134.8, 133.0 (d, J = 3.2 Hz), 132.0 (d, J = 10.2 Hz), 128.6 (d, J = 15.5 Hz), 127.7, 127.0 (d, J = 192.9 Hz), 126.54 (d, J = 5.1 Hz), 126.53, 126.2, 125.5 (d, J = 1.7 Hz), 124.7 (d, J = 1.3 Hz), 121.7, 115.4 (d, J = 3.3 Hz), 53.3 (d, J = 5.9 Hz).

[0291] 31 31P NMR (162 MHz, CDCl3) δ 17.14.

[0292] HRMS (ESI, m / z): calculated for C 17 H 16 O3P + [M + H] + : 299.0832, found: 299.0830

[0293]

[0294] HPLC analysis: 97:3 e.r. (Chiralcel ID, 30:70 i-PrOH / n-Hexane, 1.0 mL / min), 40 °C, Rt (minor) = 6.8 min, Rt (major) = 7.2 min.

[0295] Methyl-D3 naphthalen-1-yl (S)-phenylphosphonate (5b):

[0296]

[0297] Prepared according to general procedure F. Flash column chromatography (PE / EtOAc=10:1) yielded the title compound 5b, oil (18.5mg, 62% yield); R f 0.50 (PE / EtOAc=4:1).

[0298] 1 1H NMR (400MHz, CDCl3) δ8.20 - 8.08 (m, 1H), 8.04 - 7.91 (m, 2H), 7.90 - 7.77 (m, 1H), 7.63 (d, J=7.7Hz, 1H), 7.61 - 7.55 (m, 1H), 7.54 - 7.42 (m, 5H), 7.36 (t, J=7.9Hz, 1H).

[0299] 13 13C NMR (101MHz, CDCl3) δ146.5 (d, J=7.7Hz), 134.8, 133.0 (d, J=3.2Hz), 132.0 (d, J=10.2Hz), 128.6 (d, J=15.4Hz), 127.7, 127.0 (d, J=191.9Hz), 126.6 (d, J=4.0Hz), 126.5, 126.2, 125.5 (d, J=1.6Hz), 124.7, 121.7, 115.4 (d, J=3.3Hz).

[0300] 31 31P NMR (162MHz, CDCl3) δ17.16.

[0301] HRMS (ESI, m / z): calculated for C 17 H 13 D3O3P+ [M+H] + : 302.1020, found: 302.1019.

[0302]

[0303] HPLC analysis: 98:2 e.r. (Chiralcel ID, 30:70 i-PrOH / n-Hexane, 1.0mL / min), 40℃, Rt(minor)=6.8min, Rt(major)=7.2min.

[0304] (S)-Phenyl 1-naphthylphosphonate (5c):

[0305]

[0306] Prepared according to general procedure F.Flash column chromatography(PE / EtOAc=10:1)yielded the title compound 5c,oil(23.4mg,75%yield);R f 0.50(PE / EtOAc=4:1).

[0307] 1 H NMR(400MHz,CDCl3)δ8.19-8.08(m,1H),8.05-7.91(m,2H),7.89-7.75(m,1H),7.62(d,J=7.2Hz,1H),7.61-7.52(m,1H),7.53-7.43(m,5H),7.35(t,J=7.9Hz,1H),4.33-4.26(m,2H),1.34(t,J=7.1Hz,3H).

[0308] 13 C NMR(101MHz,CDCl3)δ146.6(d,J=7.7Hz),134.7,132.8(d,J=3.2Hz),131.9(d,J=10.2Hz),128.5(d,J=15.4Hz),127.71(d,J=192.9Hz),127.68,126.6(d,J=5.7Hz),126.5,126.1,125.5(d,J=1.5Hz),124.6(d,J=1.3Hz),121.7,115.3(d,J=3.4Hz),63.1(d,J=5.9Hz),16.3(d,J=6.4Hz).

[0309] 31 PNMR(162MHz,CDCl3)δ15.72.

[0310] HRMS(ESI,m / z):calculated for C 18 H 17 O3PNa + [M+Na] + :335.0808,found:335.0807.

[0311]

[0312] HPLC analysis: 97:3 e.r. (Chiralcel ODH, 20:80 i-PrOH / n-Hexane, 0.5 mL / min), 40 °C, Rt (minor) = 9.6 min, Rt (major) = 10.4 min.

[0313] Isopropylnaphthalen-1-yl (S)-phenylphosphonate (5d):

[0314]

[0315] Prepared according to general procedure F. Flash column chromatography (PE / EtOAc = 10:1) yielded the title compound 5d, oil (27.7 mg, 85% yield); R f 0.50 (PE / EtOAc = 4:1).

[0316] 1 1H NMR (400 MHz, CDCl3) δ 8.17 - 8.09 (m, 1H), 8.04 - 7.89 (m, 2H), 7.87 - 7.74 (m, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.59 - 7.50 (m, 1H), 7.52 - 7.41 (m, 5H), 7.35 (t, J = 7.9 Hz, 1H), 4.98 - 4.90 (m, 1H), 1.33 (dd, J = 6.2, 1.7 Hz, 6H).

[0317] 13 13C NMR (101 MHz, CDCl3) δ 146.6 (d, J = 7.9 Hz), 134.7, 132.6 (d, J = 3.2 Hz), 131.8 (d, J = 10.1 Hz), 128.46 (d, J = 15.5 Hz), 128.45 (d, J = 192.9 Hz), 127.6, 126.6 (d, J = 5.6 Hz), 126.4, 126.0, 125.5 (d, J = 1.5 Hz), 124.4 (d, J = 1.2 Hz), 121.8, 115.4 (d, J = 3.4 Hz), 72.2 (d, J = 6.1 Hz), 23.9 (d, J = 4.7 Hz).

[0318] 31 31P NMR (162 MHz, CDCl3) δ 14.62.

[0319] HRMS(ESI,m / z):calculated for C 19 H 19 O3PNa + [M+Na] + :349.0965,found:349.0962.

[0320]

[0321] HPLC analysis:97:3 e.r.(Chiralcel ODH,20:80 i-PrOH / n-Hexane,0.5 mL / min),40 °C,Rt(minor)=10.4 min,Rt(major)=11.6 min.

[0322] Benzyl naphthalen-1-yl (S)-phenylphosphonate (5e):

[0323]

[0324] Prepared according to general procedure F.Flash column chromatography(PE / EtOAc=10:1)yielded the title compound 5e,oil(27.33 mg,55% yield);R f 0.50(PE / EtOAc=4:1).

[0325] 1 H NMR(400 MHz,CDCl3)δ8.14 - 8.03(m,1H),8.03 - 7.90(m,2H),7.87 - 7.77(m,1H),7.62(d,J=8.2 Hz,1H),7.61 - 7.52(m,1H),7.51 - 7.44(m,5H),7.38 - 7.27(m,6H),5.38 - 5.14(m,2H).

[0326] 13C NMR (101MHz, CDCl3) δ146.5 (d, J = 8.0Hz), 135.8 (d, J = 6.9Hz), 134.7, 132.9 (d, J = 3.1Hz), 131.9 (d, J = 10.3Hz), 128.7, 128.5, 128.4, 1 27.9, 127.7, 126.6 (d, J = 5.7Hz), 126.5, 126.2, 125.5 (d, J = 1.5Hz), 124.7 (d, J = 1.3Hz), 121.8, 115.4 (d, J = 3.5Hz), 68.3 (d, J = 5.6Hz).

[0327] 31 P NMR (162MHz,CDCl3)δ16.21.

[0328] HRMS(ESI,m / z):calculated for C 23 H 19 O3PNa + [M+Na] + :397.0965,found:397.0958.

[0329]

[0330] HPLC analysis: 97:3e.r. (Chiralcel ID, 30:70i-PrOH / n-Hexane, 1.0mL / min), 40°C, Rt(minor)=8.6min, Rt(major)=9.4min.

[0331] ((3aR,4R,6R,6aR)-6-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxan-4-yl)methylnaphthol-1-yl (S)-phenylphosphonate (5f):

[0332]

[0333] Prepared according to general procedure F.3a(0.1mmol,1.0equiv.)wasused as phosphonate,2 ′ ,3 ′-O-Isopropylideneuridine(0.15mmol,1.5equiv.)used asnucleophile and t-BuMgCl(1.7M in THF,0.3mmol,3.0equiv.)as base in THF at roomtemperature for 10h.Flash column chromatography(CH2Cl2 / MeOH=95:5)yieldedthetitle compound 5f,Colourless oil(29.2mg,53%yield);R f 0.50(CH2Cl2 / MeOH=20:1).

[0334] 1 H NMR(400MHz,CDCl3)δ8.90(s,1H),8.16-8.05(m,1H),8.02-7.90(m,2H),7.89-7.77(m,1H),7.68-7.60(m,1H),7.64-7.55(m,1H),7.55-7.41(m,5H),7.34(t,J=7.9Hz,1H),7.18(d,J=8.1Hz,1H),5.68(d,J=2.6Hz,1H),5.49(dd,J=8.1,2.1Hz,1H),4.78(dd,J=6.4,3.5Hz,1H),4.65(dd,J=6.4,2.6Hz,1H),4.45-4.38(m,2H),4.38-4.35(m,1H),1.53(s,3H),1.30(s,3H).

[0335] 13 C NMR(101MHz,CDCl3)δ163.0,149.8,146.1(d,J=7.8Hz),141.3,134.8,133.4(d,J=3.2Hz),132.0(d,J=10.4Hz),128.8(d,J=15.6Hz),127.9,126.7,126.5(d,J=192.0Hz),126.4(d,J=6.1Hz),,126.38,125.5,125.0,121.5,115.5(d,J=3.5Hz),114.6,102.5,93.6,85.3(d,J=6.9Hz),84.3,80.5,66.1(d,J=5.4Hz),27.0,25.2.

[0336] 31PNMR (162MHz,CDCl3)δ16.56.

[0337] HRMS(ESI,m / z):calculated for C 28 H 27 N2O8PNa + [M+Na] + :573.1398,found:573.1392.

[0338]

[0339] ((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxan-4-yl)methylnaphthol-1-yl (S)-phenylphosphonate (5 g):

[0340]

[0341] Prepared according to general general procedure F.3a(0.1mmol,1.0equiv.)was used as phosphonate,2',3'-isopropylideneadenosine(0.15mmol,1.5equiv.)used as nucleophile and t-BuMgCl(1.7M in THF,0.30mmol,3.0equiv.)asbase in THF at room temperature for 10h.Flash column chromatography (CH2Cl2 / MeOH=95:5) yielded the title compound 5g, Colourless oil (22.9mg, 40% yield); R f 0.50(CH2Cl2 / MeOH=20:1).

[0342] 1H NMR(400MHz, CDCl3)δ8.20(s,1H),8.10-8.03(m,1H),7.84(s,1H),7.83-7.75(m,3H),7.61(d ,J=8.3Hz,1H),7.54-7.45(m,3H),7.40(dt,J=7.7,1.4Hz,1H),7.38-7.32(m,2H),7.30(d,J=7 .8Hz,1H),6.03(d,J=2.3Hz,1H),5.73(s,2H),5.24(dd,J=6.3,2.3Hz,1H),5.03(dd,J=6.3,2 .9Hz,1H),4.52(td,J=5.1,2.9Hz,1H),4.40(dd,J=6.9,5.1Hz,2H),1.58(s,3H),1.34(s,3H).

[0343] 13 C NMR (101MHz, CDCl3) δ155.4, 153.1, 149.1, 146.2 (d, J = 7.7Hz), 139.5, 134.7, 133. 1(d,J=3.0Hz),131.8(d,J=10.3Hz),128.5(d,J=15.7Hz),127.7,126.6,126.4(d,J =5.7Hz),126.39(d,J=191.9Hz),126.29,125.4,124.9,121.6,120.2,115.5(d,J= 3.6Hz),114.5,91.3,85.6(d,J=7.5Hz),84.2,81.5,65.9(d,J=5.5Hz),27.1,25.3.

[0344] 31 P NMR (162MHz,CDCl3)δ16.55.

[0345] HRMS(ESI,m / z):calculated for C 29 H 29 N5O6P + [M+H] + :574.1850,found:574.1830.

[0346]

[0347] ((3aR,4R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxan-4-yl)methylnaphth-1-yl (S)-phenylphosphonate (5h):

[0348]

[0349] Prepared according to general procedure F.Flash column chromatography(PE / EtOAc=10:1)yielded the title compound 5h,Colourless oil(32.9mg,70%yield);R f 0.50(PE / EtOAc=4:1).

[0350] 1 H NMR(400MHz,CDCl3)δ8.17-8.08(m,1H),8.03-7.94(m,2H),7.85-7.78(m,1H),7.63(d,J=8.2Hz,1H),7.61-7.55(m,1H),7.54-7.41(m,5H),7.36(t,J=7.9Hz,1H),4.92(s,1H),4.62(dd,J=6.0,1.0Hz,1H),4.49(d,J=5.9Hz,1H),4.44-4.29(m,1H),4.22-4.08(m,2H),3.22(s,3H),1.45(s,3H),1.26(s,3H).

[0351] 13 C NMR(101MHz,CDCl3)δ146.3(d,J=8.0Hz),134.8,133.1(d,J=3.1Hz),132.0(d,J=10.3Hz),128.6(d,J=15.6Hz),127.7,126.5(d,J=6.1Hz),127.0(d,J=192.9Hz),126.5,126.3,125.5(d,J=1.7Hz),124.8(d,J=1.3Hz),121.7,115.6(d,J=3.5Hz),112.4,109.3,84.9,84.7(d,J=8.5Hz),81.4,66.2(d,J=6.0Hz),54.9,26.3,24.8.

[0352] 31 PNMR(162MHz,CDCl3)δ16.11.

[0353] HRMS(ESI,m / z):calculated for C 25 H 27 O7PNa+ [M+Na] + :493.1387,found:493.1390.

[0354]

[0355] (1R,2S,5R)-2-Isopropyl-5-methylcyclohexylnaphth-1-yl (S)-phenylphosphonate (5i):

[0356]

[0357] Prepared according to general procedure F. Flash column chromatography (PE / EtOAc=10:1) yielded the title compound 5i, oil (36.3 mg, 86% yield); R f 0.50 (PE / EtOAc=4:1).

[0358] 1 H NMR (400MHz, CDCl3) δ8.18-8.03(m,1H),8.04-7.90(m,2H),7.89-7.74(m,1H),7.60(d,J=8.2 Hz,1H),7.59-7.48(m,2H),7.52-7.40(m,4H),7.34(t,J=7.9Hz,1H),5.34-3.94(m,1H),2.25- 2.12(m,1H),2.03-1.86(m,1H),1.76-1.55(m,2H),1.50-1.31(m,2H),1.15(td,J=12.1,10.9H z,1H),1.06-0.91(m,1H),0.85(d,J=6.6Hz,4H),0.74(d,J=7.0Hz,3H),0.61(d,J=6.9Hz,3H).

[0359] 13C NMR (101MHz, CDCl3) δ146.7 (d, J = 7.6Hz), 134.7, 132.5 (d, J = 3.2Hz), 131.7 (d, J = 1 0.2Hz),129.14(d,J=193.9Hz),128.4(d,J=15.4Hz),127.6,126.7(d,J=5.8Hz),12 6.3,125.9,125.5(d,J=1.6Hz),124.4(d,J=1.2Hz),121.8,115.6(d,J=3.3Hz),79 .5(d,J=7.2Hz),48.5(d,J=6.5Hz),43.0,34.0,31.5,25.3,22.7,21.8,20.8,15.4.

[0360] 31 PNMR (162MHz, CDCl3) δ14.92 (minor), 14.35 (major).

[0361] HRMS(ESI,m / z):calculated for C 26 H 31 O3PNa + [M+Na] + :445.1904,found:445.1904.

[0362]

[0363] (3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptane-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-ylnaphthalen-1-yl (S)-phenylphosphonate (5j):

[0364]

[0365] Prepared according to general procedure F. Flash column chromatography (PE / EtOAc=10:1) yielded the title compound 5j, oil (58.8mg, 90% yield); R f 0.50 (PE / EtOAc=4:1).

[0366] 1H NMR(400MHz,CDCl3)δ8.17-8.07(m,1H),8.04-7.88(m,2H),7.85-7.76(m,1H),7.61(d,J=8.4Hz,1H),7.59-7.51(m,1H),7.53-7.41(m,5H),7.35(t,J=7.9Hz,1H),5.38-5.01(m,1H),4.66-4.35(m,1H),2.55-2.29(m,2H),2.08-1.88(m,3H),1.88-1.75(m,2H),1.74-1.65(m,1H),1.61-1.37(m,6H),1.40-1.20(m,5H),1.19-1.05(m,6H),1.04-0.94(m,5H),0.94-0.79(m,10H),0.66(s,3H).

[0367] 13 C NMR(101MHz,CDCl3)δ146.6(d,J=8.4Hz),139.3,134.7,132.6(d,J=3.7Hz),131.8(d,J=9.0Hz),128.53(d,J=193.9),128.48(d,J=15.5Hz),127.6,126.6(d,J=5.8Hz),126.4,126.1,125.5,124.4,123.0,121.9,115.4(d,J=4.1Hz),77.9(d,J=6.5Hz),56.3(d,J=52.4Hz),49.9,42.3(d,J=3.1Hz),40.2(d,J=5.0Hz),39.6(d,J=16.0Hz),36.9,36.2(d,J=18.5Hz),35.7,31.8(d,J=6.0Hz),29.8,28.1(d,J=21.4Hz),24.0(d,J=42.8Hz),22.7(d,J=26.6Hz),21.0,18.9(d,J=57.3Hz),11.8.

[0368] 31 PNMR(162MHz,CDCl3)δ14.56.

[0369] HRMS(ESI,m / z):calculated for C 43 H 57 O3PNa + [M+Na] + :675.3938,found:675.3938.

[0370]

[0371] (3S,5S,8R,9S,10S,13S,14S)-10,13-Dimethyl-17-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-3-ylnaphthol-1-yl (S)-phenylphosphonate (5k):

[0372]

[0373] Prepared according to general procedure F. Flash column chromatography (PE / EtOAc=10:1) yielded the title compound 5k, oil (49.5mg, 89% yield); R f 0.50 (PE / EtOAc=4:1).

[0374] 1 H NMR (400MHz, CDCl3) δ8.26-8.08(m,1H),8.08-7.93(m,2H),7.90-7.74(m,1H),7.64(dd,J=8.3,1.2Hz,1H) ,7.63-7.54(m,1H),7.56-7.44(m,5H),7.37(t,J=7.9Hz,1H),5.00-4.73(m,1H),2.44(dd,J=19.2,8.8Hz,1 H),2.09(dt,J=19.3,9.0Hz,1H),2.00-1.86(m,1H),1.77(dd,J=8.7,2.6Hz,1H),1.66-1.51(m,3H),1.50-1 .30(m,5H),1.28-1.12(m,5H),1.11-0.95(m,2H),0.82-0.76(m,4H),0.71-0.61(m,4H),0.54-0.39(m,1H).

[0375] 13C NMR (101MHz, CDCl3) δ221.4,146.5(d,J=8.7Hz),134.7,132.6(d,J=3.1Hz),131.7(d,J=1 0.0Hz),129.7,128.8(d,J=193.9Hz),127.7,127.0(d,J=5.0Hz),126.4,126.1,125.5,12 4.7,122.1,116.2(d,J=3.4Hz),74.7(d,J=6.2Hz),53.9,51.4,47.7,39.0,35.8,35.6,34 .8,34.4(d,J=2.5Hz),32.2,31.5,30.3,27.8(d,J=5.7Hz),27.5,21.7,19.9,13.7,11.2.

[0376] 31 PNMR (162MHz, CDCl3) δ15.00 (major), 14.75 (minor).

[0377] HRMS(ESI,m / z):calculated for C 35 H 41 O4PNa + [M+Na] + :579.2635,found:579.2633.

[0378]

[0379] (3R,8S,9S,10R,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-ylnaphth-1-yl (S)-phenylphosphonate (51):

[0380]

[0381] Prepared according to general procedure F. Flash column chromatography (PE / EtOAc=10:1) yielded the title compound 5l, oil (52.4mg, 90% yield); R f 0.50 (PE / EtOAc=4:1).

[0382] 1H NMR (400MHz, CDCl3) δ8.19-8.05(m,1H),8.02-7.88(m,2H),7.86-7.76(m,1H),7.70-7.57(m,1H ),7.60-7.51(m,1H),7.53-7.41(m,5H),7.34(t,J=7.9Hz,1H),5.47-4.98(m,1H),4.76-4.27(m ,1H),2.60-2.32(m,3H),2.11(s,4H),2.06-1.90(m,3H),1.88-1.74(m,1H),1.77-1.59(m,4H), 1.62-1.50(m,1H),1.52-1.40(m,2H),1.41(s,1H),1.30-1.02(m,4H),0.98(s,3H),0.61(s,3H).

[0383] 13 C NMR (101MHz, CDCl3) δ209.5,146.6(d,J=7.8Hz),139.3,134.7,132.7(d,J=3.0Hz),131.8(d,J=10 .2Hz),128.5(d,J=15.4Hz),128.4(d,J=193.0Hz),127.7,126.6(d,J=5.7Hz),126.4,126.1,125.5 ,124.5,122.7,121.9,115.4(d,J=3.4Hz),77.8(d,J=6.3Hz),63.6,56.7,49.7,43.9,40.1(d,J=4 .6Hz),38.7,36.9,36.4,31.7(d,J=4.9Hz),31.5,29.8(d,J=3.6Hz),24.4,22.8,21.0,19.2,13.2.

[0384] 31 PNMR (162MHz,CDCl3)δ14.66.

[0385] HRMS(ESI,m / z):calculated for C 37 H 43 O4PNa + [M+Na] + :605.2792,found:605.2786.

[0386]

[0387] S-Dodecyl-O-(naphthalen-1-yl)(R)-phenylphosphonothioate (5m):

[0388]

[0389] Flash column chromatography(PE / EtOAc=15:1)yielded the title compound5m,yellow oil(18.7mg,40%yield);R f 0.60

[0390] (PE / EtOAc=4:1).

[0391] 1 H NMR(400MHz,CDCl3)δ8.17-8.07(m,3H),7.96-7.76(m,1H),7.71-7.57(m,3H),7.60-7.46(m,4H),7.40(t,J=7.9Hz,1H),2.83-2.76(m,2H),1.49-1.41(m,2H),1.35-0.93(m,18H),0.88(t,J=6.9Hz,3H).

[0392] 13 C NMR(101MHz,CDCl3)δ146.7(d,J=10.1Hz),134.8,132.9(d,J=3.3Hz),132.6(d,J=150.5Hz),131.3(d,J=11.2Hz),128.7(d,J=15.1Hz),127.8,126.7(d,J=5.4Hz),126.6,126.3,125.6(d,J=1.6Hz),125.0(d,J=1.5Hz),121.7,116.3(d,J=4.4Hz),31.9,30.8(d,J=2.7Hz),30.5(d,J=5.3Hz),29.6,29.5,29.3,28.8,28.3,22.7,14.1.

[0393] 31 PNMR(162MHz,CDCl3)δ44.09.

[0394] HRMS(ESI,m / z):calculated for C 28 H 37 O2PSNa + [M+Na] + :491.2145,found:491.2140.

[0395]

[0396] HPLC analysis: 96:4e.r. (Chiralcel ID, 2:98i-PrOH / n-Hexane, 0.5mL / min), 40°C, Rt (minor) = 52.8min, Rt (major) = 55.9min.

[0397] Example 3

[0398] This embodiment provides a method for preparing a derivative 5 of a chiral phosphonate compound, comprising the following steps:

[0399]

[0400] Under nitrogen protection, a 10 ml Shrek bottle equipped with a magnetic stirrer was added with nucleophile 4 (0.15 mmol, 1.5 equiv.) and tetrahydrofuran, wherein the nucleophile was R-OH, and R included phenyl, benzyl, benzo[d][1,3]dioxolane-5-amine, 2-ethylfuran, 4,4′-diaminodiphenylsulfone or 4-phenylformic acid ethyl ester. n-Butyl lithium (2.5 M inhexane, 0.15 mmol, 1.5 equiv.) was added at -78°C, and after 20 minutes, compound 3a (0.1 mmol, 1.0 equiv.) was added dropwise. After the addition was completed, the mixture was stirred at room temperature. When 3a was consumed (monitored by thin layer chromatography TLC), saturated ammonium chloride solution (2.0 mL) was added, and the aqueous phase was extracted with ethyl acetate (3 x 1.5 mL). The combined organic phases were dried over anhydrous sodium sulfate, all volatiles were removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1) to obtain the target compound 5.

[0401] Shape and spectrum analysis of compound 5:

[0402] Naphthalene-1-yl (R)-N,P-diphenylphosphinamide (5n):

[0403]

[0404] Prepared according to general procedure G.Flash column chromatography (PE / EtOAc=2:1) ​​yielded the title compound 5n, white solid (32.7mg, 91% yield); R f 0.60 (PE / EtOAc=2:1).

[0405] 1H NMR (400MHz, CDCl3) δ8.17-8.06(m,1H),8.06-7.91(m,2H),7.86-7.69(m,1H),7.61-7.37(m,7H),7. 23(t,J=8.0Hz,1H),7.12-7.01(m,2H),6.93-6.85(m,2H),6.87-6.78(m,1H),6.10(d,J=6.6Hz,1H).

[0406] 13 C NMR (101MHz, CDCl3) δ146.3 (d, J = 8.4Hz), 139.3, 134.8, 132.8 (d, J = 3.2Hz), 129.6 (d, J = 178.8Hz), 129.3, 128.8 (d, J = 1 5.2Hz), 127.8, 126.7 (d, J = 5.6Hz), 126.5, 126.3, 125.6, 124.8, 122.2, 121.6, 118.4 (d, J = 6.5Hz), 115.4 (d, J = 4.0Hz).

[0407] 31 P NMR (162MHz,CDCl3)δ14.98.

[0408] HRMS(ESI,m / z):calculated for C 22 H 18 NO2PNa + [M+Na] + :382.0967,found:382.0961.

[0409]

[0410] HPLC analysis: 5:95e.r. (Chiralcel ID, 30:70i-PrOH / n-Hexane, 1.0mL / min), 40°C, Rt(minor)=9.0min, Rt(major)=10.3min.

[0411] Naphthalene-1-yl (R)-N-benzyl-phosphine-phenylphosphineamide (5o):

[0412]

[0413] Prepared according to general procedure G.Flash column chromatography(PE / EtOAc=2:1)yielded the title compound 5o,oil(33.6mg,90%yield);R f 0.60(PE / EtOAc=2:1).

[0414] 1 H NMR(400MHz,CDCl3)δ8.16-8.06(m,1H),8.07-7.95(m,2H),7.87-7.79(m,1H),7.63(d,J=8.0Hz,2H),7.62-7.52(m,1H),7.54-7.43(m,4H),7.36(t,J=8.0Hz,1H),7.26-7.16(m,3H),7.12(m,2H),4.16(dd,J=8.9,6.9Hz,2H),3.39(m,1H).

[0415] 13 C NMR(101MHz,CDCl3)δ146.8(d,J=8.1Hz),139.0(d,J=6.9Hz),134.8,132.4(d,J=3.0Hz),131.5(d,J=10.1Hz),130.2(d,J=177.0Hz),128.7(d,J=14.8Hz),128.5,127.9,127.3,126.6(d,J=5.9Hz),126.4,126.2,125.7,124.3,121.5,115.3(d,J=4.0Hz),45.1.

[0416] 31 PNMR(162MHz,CDCl3)δ20.38.

[0417] HRMS(ESI,m / z):calculated for C 23 H 20 NO2PNa + [M+Na] + :396.1124,found:396.1115.

[0418]

[0419] HPLC analysis: 6:94e.r. (Chiralcel ODH, 30:70i-PrOH / n-Hexane, 1.0mL / min), 40℃, Rt(minor)=6.1min, Rt(major)=8.2min.

[0420] Naphthalene-1-yl (R)-N-(furan-2-ylmethyl)-phosphine-phenylphosphonamidate (5p):

[0421]

[0422] Prepared according to general procedure G.Flash column chromatography (PE / EtOAc=2:1) ​​yielded the title compound 5p, oil (32.3mg, 89% yield); R f 0.65 (PE / EtOAc=2:1).

[0423] 1 H NMR (400MHz, CDCl3) δ8.15-8.08(m,1H),7.98(m,2H),7.89-7.77(m,1H),7.61(m,2H),7.55(m,1H),7.48(m,4H),7.35(t,J=8.0Hz ,1H),7.21(d,J=1.8Hz,1H),6.17(dd,J=3.3,1.8Hz,1H),5.96(d,J=3.2Hz,1H),4.14(dd,J=10.1,6.7Hz,2H),3.66-3.50(m,1H).

[0424] 13 C NMR (101MHz, CDCl3) δ152.2 (d, J = 6.5Hz), 146.7 (d, J = 8.3Hz), 142.0, 134.7, 132.3 (d, J = 3.1Hz), 131.5 (d, J = 10.2Hz), 130.1 (d, J = 178.2Hz) ,128.6(d,J=14.9Hz),127.8,126.6(d,J=5.9Hz),126.4,126.1,125.7(d,J=1.2Hz),124.3,121.5,115.3(d,J=4.0Hz),110.2,106.9,38.0.

[0425] 31 PNMR (162MHz,CDCl3)δ20.40.

[0426] HRMS(ESI,m / z):calculated for C 21 H 19 NO3PH + [M+H] + :364.1097,found:364.1097.

[0427]

[0428] HPLC analysis: 4:96e.r. (Chiralcel ODH, 30:70i-PrOH / n-Hexane, 1.0mL / min), 40°C, Rt (minor) = 5.7min, Rt (major) = 7.5min.

[0429] Naphthalene-1-yl (R)-N-(benzo[d][1,3]dioxol-5-yl)-phosphine-phenylphosphonamide ester (5q):

[0430]

[0431] Prepared according to general procedure G.Flash column chromatography (PE / EtOAc=2:1) ​​yielded the title compound 5q, oil (33.1mg, 82% yield); R f 0.65 (PE / EtOAc=2:1).

[0432] 1 H NMR(400MHz, CDCl3)δ8.15(dt,J=8.4,3.0Hz,1H),8.06-7.91(m,2H),7.88-7.76(m,1H),7.62(d,J=8.3Hz,1H),7.61 -7.52(m,2H),7.54-7.43(m,4H),7.29(t,J=8.0Hz,1H),6.61-6.45(m,2H),6.35(dd,J=8.3,2.2Hz,1H),5.81(s,2H).

[0433] 13C NMR (101MHz, CDCl3) δ148.0, 146.3 (d, J = 8.6Hz), 143.0, 134.8, 133.5, 132. 6(d,J=3.1Hz), 131.6(d,J=10.5Hz), 129.66(d,J=191.9Hz), 128.8(d,J=15. 2Hz),127.8,126.7(d,J=5.6Hz),126.4(d,J=25.4Hz),125.6,124.7,121.7 ,115.3(d,J=4.0Hz),112.0(d,J=6.6Hz),108.3,101.8(d,J=6.2Hz),101.0.

[0434] 31 P NMR (162MHz,CDCl3)δ15.56.

[0435] HRMS(ESI,m / z):calculated for C 23 H 19 NO4P+[M+H] + :404.1046,found:404.1042

[0436]

[0437] HPLC analysis: 5:95e.r. (Chiralcel ODH, 30:70i-PrOH / n-Hexane, 1.0mL / min), 40°C, Rt (minor) = 7.3min, Rt (major) = 13.2min.

[0438] Naphthalene-1-yl (R)-N-(4-((4-aminophenyl)sulfonyl)phenyl)-phosphine-phenylphosphonamidate (5r):

[0439]

[0440] Prepared according to general procedure G.Flash column chromatography (PE / EtOAc=1:1) yielded the title compound 5r, oil (36.0mg, 70% yield); R f 0.45 (PE / EtOAc=1:1).

[0441] 1H NMR (400MHz, CDCl3) δ8.21-8.06(m,1H),8.05-7.89(m,2H),7.88-7.68(m,1H),7.68-7.41(m,10H),7.36( dt,J=7.8,1.3Hz,1H),7.30(d,J=6.2Hz,1H),7.21(t,J=7.9Hz,1H),6.96-6.80(m,2H),6.68-6.42(m,2H).

[0442] 13 C NMR(101MHz, CDCl3)δ150.7,145.8(d,J=8.8Hz),143.8,135.5,134.8,133.2,131.5(d,J=10.8Hz),130.0,129.6,129.1(d,J=15.3Hz), 128.7, 127.9, 127.2 (d, J = 119.2Hz), 126.6 (d, J = 19.9Hz), 125.3 (d, J = 24.9Hz), 121.4, 117.6 (d, J = 7.0Hz), 115.4 (d, J = 4.0Hz), 114.1.

[0443] 31 PNMR (162MHz,CDCl3)δ14.56.

[0444] HRMS(ESI,m / z):calculated for C 28 H 23 N2O4PSNa + [M+Na] + :537.1008,found:537.1010.

[0445]

[0446] HPLC analysis: 5:95e.r. (Chiralcel IB, 30:70i-PrOH / n-Hexane, 1.0mL / min), 40°C, Rt (minor) = 26.8min, Rt (major) = 36.0min.

[0447] (R)-4-(((Naphthalene-1-oxy)(phenyl)phosphonic acid)amino)benzoic acid ethyl ester (5s):

[0448]

[0449] Prepared according to general procedure G.Flash column chromatography(PE / EtOAc=2:1)yielded the title compound 5s,oil(32.4mg,75%yield);R f 0.60(PE / EtOAc=2:1).

[0450] 1 H NMR(400MHz,CDCl3)δ8.20(m,1H),8.09-7.97(m,2H),7.87-7.78(m,1H),7.76(d,J=8.4Hz,2H),7.68-7.55(m,2H),7.51(m,4H),7.44(d,J=7.7Hz,1H),7.25(m,1H),6.91(d,J=8.7Hz,2H),4.28(q,J=7.1Hz,2H),1.32(t,J=7.1Hz,3H).

[0451] 13 C NMR(101MHz,CDCl3)δ166.2,146.0(d,J=8.8Hz),144.0,134.9,133.0(d,J=3.1Hz),131.6(d,J=10.7Hz),131.1,129.9(d,J=179.8Hz),129.0(d,J=15.3Hz),127.9,126.7,126.6,126.5,125.5,125.1,123.8,121.6,117.1(d,J=7.0Hz),115.4(d,J=4.0Hz),60.6,14.3.

[0452] 31 PNMR(162MHz,CDCl3)δ14.34.

[0453] HRMS(ESI,m / z):calculated for C 25 H 22 NO4PNa + [M+Na] + :454.1179,found:454.1178.

[0454]

[0455] HPLC analysis: 5:95e.r. (Chiralcel IE, 30:70i-PrOH / n-Hexane, 1.0mL / min), 40°C, Rt (minor) = 13.9min, Rt (major) = 16.0min.

[0456] Example 4

[0457] This embodiment provides a method for preparing a derivative 6 of a chiral phosphonate compound, comprising the following steps:

[0458]

[0459] Under nitrogen protection, 5c (0.1 mmol, 1.0 equiv.) and tetrahydrofuran were added to a 10 ml Shrek bottle equipped with a magnetic stirrer. An appropriate Grignard reagent solution (0.15 mmol, 1.5 equiv.) was added dropwise at 0°C. The Grignard reagent was R-MgBr, and R included methyl, ethyl, 4-methylphenyl or 2-methoxyphenyl. After the addition was completed, the mixture was stirred at room temperature. When 5c was consumed (monitored by thin layer chromatography TLC), a saturated ammonium chloride solution (2.0 mL) was added, and the aqueous phase was extracted with ethyl acetate (3 x 1.5 mL). The combined organic phases were dried over anhydrous sodium sulfate and dried under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1) to obtain the title chiral compound 6.

[0460] Shape and spectrum analysis of compound 6:

[0461] Ethyl (S)-methyl (phenyl) phosphonate (6a):

[0462]

[0463] Prepared according to general procedure H.Flash column chromatography(CH2Cl2 / MeOH=25:1)yielded the title compound

[0464] 6a, white solid (9.6mg, 52% yield); R f 0.50 (PE / EtOAc=1:1)

[0465] 11H NMR (400 MHz, CDCl3) δ 7.79 (m, 2H), 7.60 - 7.51 (m, 1H), 7.48 (m, 2H), 4.22 - 3.98 (m, 1H), 3.83 (m, 1H), 1.67 (d, J = 14.6 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[0466] HRMS (ESI, m / z): calculated for C9H 13 O2PNa + [M+Na] + : 207.0546, found: 207.0541.

[0467]

[0468] HPLC analysis: 96:4 e.r. (Chiralcel IC, 20:80 i-PrOH / n-Hexane, 0.5 mL / min), rt, Rt(minor) = 34.2 min, Rt(major) = 36.3 min.

[0469] Ethyl (S)-ethyl(phenyl)phosphonate (6b):

[0470]

[0471] Prepared according to general procedure H. Flash column chromatography (CH2Cl2 / MeOH = 25:1) yielded the title compound

[0472] 6b, white solid (13.9 mg, 70% yield); R f 0.50 (PE / EtOAc = 1:1)

[0473] 1 1H NMR (400 MHz, CDCl3) δ 7.81 - 7.68 (m, 2H), 7.60 - 7.50 (m, 1H), 7.51 - 7.41 (m, 2H), 4.07 (m, 1H), 3.85 (m, 1H), 1.99 - 1.77 (m, 2H), 1.28 (t, J = 7.0 Hz, 3H), 1.09 (dt, J = 18.8, 7.7 Hz, 3H).

[0474] 1313C NMR (101 MHz, CDCl3) δ 132.1 (d, J = 2.4 Hz), 131.7 (d, J = 9.6 Hz), 128.5 (d, J = 12.1 Hz), 60.5 (d, J = 6.2 Hz), 22.7 (d, J = 102.0 Hz), 16.4 (d, J = 6.3 Hz), 5.8 (d, J = 4.4 Hz).

[0475] 31 31P NMR (162 MHz, CDCl3) δ 46.36.

[0476] HRMS (ESI, m / z): calculated for C 10 H 15 O2PNa + [M+Na] + : 221.0702, found: 221.0699.

[0477]

[0478] HPLC analysis: 96:4 e.r. (Chiralcel IC, 10:90 i-PrOH / n-Hexane, 0.5 mL / min), rt, Rt(minor) = 59.1 min, Rt(major) = 61.9 min.

[0479] Ethyl (R)-phenyl(4-tolyl)phosphonate (6c):

[0480]

[0481] Prepared according to general procedure H. Flash column chromatography (CH2Cl2 / MeOH = 30:1) yielded the title compound

[0482] 6c, white solid (16.9 mg, 65% yield); R f 0.50 (PE / EtOAc = 2:1)

[0483] 1H NMR (400MHz, CDCl3) δ7.86-7.75(m,2H),7.75-7.64(m,2H),7.54-7.45(m,1H),7.43( m,2H),7.30-7.14(m,2H),4.09(p,J=7.1Hz,2H),2.37(s,3H),1.35(t,J=7.1Hz,3H).

[0484] 13 C NMR (101MHz, CDCl3) δ142.6(d,J=2.9Hz), 132.0(d,J=137.36Hz), 131.9(d,J=2.8Hz), 131.7(d,J=10.5Hz), 131.5(d,J= 10.0Hz), 129.2 (d, J = 13.4Hz), 128.4 (d, J = 13.1Hz), 128.3 (d, J = 139.4Hz), 61.0 (d, J = 5.8Hz), 21.6, 16.5 (d, J = 6.6Hz).

[0485] 31 P NMR (162MHz,CDCl3)δ31.85.

[0486] HRMS(ESI,m / z):calculated for C 15 H 17 O2PNa + [M+Na] + :283.0859,found:283.0853.

[0487]

[0488] HPLC analysis: 95:5e.r. (Chiralcel IC, 20:80i-PrOH / n-Hexane, 0.7mL / min), 40°C, Rt (minor) = 28.0min, Rt (major) = 29.9min.

[0489] (R)-2-Methoxyphenyl(methyl)(phenyl)phosphine oxide (7a):

[0490]

[0491] Flash column chromatography (CH2Cl2 / MeOH=30:1) yielded the title compound 7a, white solid (18.5mg, 75% yield); R f

[0492] 0.40 (PE / EtOAc=1:1)

[0493] 1 H NMR (400MHz, CDCl3) δ8.06-7.89(m,1H),7.81-7.66(m,2H),7.63-7.35(m,4H),7. 18-7.03(m,1H),6.89(dd,J=8.4,5.3Hz,1H),3.73(s,3H),2.08(d,J=14.0Hz,3H).

[0494] 13 C NMR (101MHz, CDCl3) δ159.9 (d, J = 4.2Hz), 133.9 (d, J = 5.6Hz), 133.9 (d, J = 2.2Hz), 131.3 (d, J = 2.7Hz), 130 .2(d,J=10.1Hz),128.2(d,J=12.1Hz),121.0(d,J=11.1Hz),110.9(d,J=6.8Hz),55.3,16.1(d,J=75.4Hz).

[0495] 31 P NMR (162MHz,CDCl3)δ28.51.

[0496]

[0497] HPLC analysis: 95:5e.r. (Chiralcel IC, 30:70i-PrOH / n-Hexane, 1.0mL / min), 40°C, Rt(major)=21.9min, Rt(minor)=24.5min.

[0498] Example 5

[0499] This example provides antibacterial activity tests of related compounds:

[0500] (1) Test method

[0501] ① The turbidity method was used to test the inhibitory activity of some target compounds against Xanthomonas oryzaepv.oryzae (Xoo) and Xanthomonas oryzaepv.oryzicola (Xoc), the pathogen of rice leaf blight. Thiophanate-copper and chlorothalonil were used as positive controls. The specific operation steps are as follows:

[0502] 8.0 mg of the compound was dissolved in 320.0 μL of dimethyl sulfoxide and diluted with 0.1% (V / V) Tween-20 to prepare a solution with a concentration of 500 μg / mL. 1.0 mL of the above solution was added to a non-toxic nutrient broth (NB: 1.5 g beef extract, 2.5 g peptone, 0.5 g yeast powder, 5.0 g glucose and 500 mL distilled water, pH = 7.0-7.2) liquid culture medium in a 4.0 mL test tube (compound concentration is 100 μg / mL). Then, 40.0 μL of NB solution containing Xoo or Xoc was added to 5.0 mL of NB solution containing the test compound. The inoculated test tube was incubated at (28±1)°C by measuring the optical density (OD) at 595 nm. 595 ) to monitor culture growth and expressed as corrected turbidity. The relative inhibition rate was calculated as follows:

[0503] I(%)=(Ctur-Ttur) / Ctur×100%

[0504] Ctur: Corrected turbidity value for bacterial growth on untreated NB;

[0505] Ttur: turbidity value corrected for bacterial growth on treated NB;

[0506] I: relative inhibition rate.

[0507] Table 1. Test results of the target compound series (100 μg / mL) against rice bacterial blight (inhibition rate %). [a]

[0508] Compound Xoo inhibition rate (%) Compound Xoo inhibition rate (%) (S)-3a 26.46±1.10 (S)-3v 83.69±1.53 (S)-3b 74.34±1.40 (S)-3k 0 (S)-3c 27.90±2.90 (S)-5c 78.65±2.01 (S)-3d 29.97±2.10 (S)-5f 68.46±2.11 (S)-3e 21.90±1.82 (S)-5g 71.12±1.32 (R)-3g 32.53±2.81 (S)-5h 58.29±1.52 (R)-3i 53.16±1.94 (S)-5i 55.40±2.42 (R)-3j 57.71±2.63 (S)-5j 0 (R)-3l 48.04±2.10 (S)-5l 0 (R)-3m 42.85±2.07 BT[b] 57.74±1.28 (R)-3q 52.28±1.58 TC[c] 42.23±1.811

[0509] In Table 1: [a] average of three tests; [b] the inhibitory activity of the commercial drug chlorpyrifos was used as a positive control. [c] the inhibitory activity of the commercial drug thiophanate-methyl was used as a positive control.

[0510] Table 2 Test results of the target compound series (100 μg / mL) against rice leaf streak pathogen (inhibition rate %). [a]

[0511] compound Xo inhibition rate (%) compound Xo inhibition rate (%) (S)-3a 30.78±1.98 (S)-3v 36.37±1.55 (S)-3b 61.12±1.70 (S)-3k 0 (S)-3c 54.28±2.75 (S)-5c 56.59±2.92 (S)-3d 38.84±1.71 (S)-5f 62.43±1.66 (S)-3e 24.47±2.21 (S)-5g 64.23±1.66 (R)-3g 62.61±1.92 (S)-5h 40.00±1.71 (R)-3i 24.38±2.75 (S)-5i 0 (R)-3j 38.09±1.94 (S)-5j 57.63±2.27 (R)-3l 40.28±1.62 (S)-5l 0 (S)-3m 0 BT[b] 69.11±0.51 (S)-3q 73.95±1.84 TC[c] 60.82±2.75

[0512] In Table 2: [a] average of three tests; [b] the inhibitory activity of the commercial drug chlorpyrifos was used as a positive control; [c] the inhibitory activity of the commercial drug thiophanate-methyl was used as a positive control.

[0513] The antibacterial activity of the obtained chiral products was preliminarily studied. In particular, compounds (S)-3v and (S)-5c showed higher activity against Xanthomonas oryzae (Xoo) at a concentration of 100 μg / mL than the positive control commercial fungicides chlorothalonil (BT) and thiophanate-methyl (TC). Meanwhile, the phosphonate (S)-3q showed a higher inhibition rate (87.36%) against Xanthomonas oryzae (Xoc) than thiophanate-methyl (69.11%) and thiophanate-methyl (60.82%).

[0514] The different configurations of compounds 3b, 3g, 3q, 3v and 5c were studied for their antibacterial effects (Table 3). The configuration of compound 3b had no significant effect on the inhibitory effect of Xoo, and compounds 3b and 5c had no significant inhibitory effect on Xoc. It is worth noting that the inhibitory activity of racemic compounds 3g, 3q and 3v on Xoo or Xoc was slightly lower than that of their (S)-isomer products.

[0515] Table 3 Study on the antibacterial effect of different configurations of compounds 3b, 3g, 3q, 3v, and 5c (100 μg / mL) [a]

[0516] Compounds Xoo inhibition rate (%) Xo inhibition rate (%) (S)-3b 75.47±2.60 65.03±2.00 (±)-3b 74.81±2.24 63.70±1.58 (R)-3g 49.23±1.21 71.21±1.56 (±)-3g 34.49±2.14 64.23±1.27 (S)-3q 59.72±2.20 87.36±1.94 (±)-3q 52.81±1.64 77.77±1.25 (S)-3v 92.60±2.32 55.58±1.20 (±)-3v 86.51±1.69 36.73±1.35 (S)-5c 86.56±1.94 56.46±0.87 (±)-5c 73.23±1.16 55.63±1.26 <![CDATA[BT b ]]> 57.74±1.28 69.11±0.51 <![CDATA[TC c ]]> 42.23±1.81 60.82±2.75

[0517] In Table 3: [a] average of three tests; [b] the inhibitory activity of the commercial drug chlorpyrifos was used as a positive control; [c] the inhibitory activity of the commercial drug thiophanate-methyl was used as a positive control.

[0518] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. People can also obtain other embodiments based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A chiral phosphonate compound, characterized in that: The general structural formula of the chiral phosphonate compound is shown in Formula 1: Wherein, P* is a chiral phosphorus atom; R 1 including phenyl, 4-methylphenyl, 4-n-butylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 4-phenylphenyl, 4-chlorophenyl, 3-methylphenyl, 2-methylphenyl, 2-chlorophenyl or methyl; Ar' includes 2-methyl-6-nitrophenyl Ar includes naphthyl, 4-methylnaphthyl, 4-chloronaphthyl, 4-bromonaphthyl, 1-hydroxypyrenyl, 2,4-dimethoxyphenyl, 2-methylacetophenone, methyl 2-methoxybenzoate, 2-methoxy-4-allylphenyl, ethyl 2-methoxycinnamate or N-(2,3-dichlorophenyl)-1-methylcyclohexanecarboxamide.

2. A derivative of the chiral phosphonate compound according to claim 1, characterized in that: The general structural formula of the derivative is shown in Formula 2: Wherein, P* is a chiral phosphorus atom; X includes O or S; R 2 The alkyl radicals include methyl, deuterated methyl, ethyl, isopropyl, benzyl, 2',3'-isopropylureido, 2',3'-isopropylidene adenosyl, methyl-2,3-O-isopropylidene-D-ribofuranoside, menthol, cholesterol, androsterone, pregnenolone or dodecyl.

3. A derivative of the chiral phosphonate compound according to claim 1, characterized in that: The general structural formula of the derivative is shown in Formula 3: Wherein, P* is a chiral phosphorus atom; X includes N; R 3 Including phenyl, benzyl, benzo[d][1,3]dioxolane-5-amine, 2-ethylfuran, 4,4'-diaminodiphenylsulfone or 4-phenylcarboxylic acid ethyl ester.

4. A derivative of the chiral phosphonate compound according to claim 1, characterized in that: The general structural formula of the derivative is shown in Formula 4: Wherein, P* is a chiral phosphorus atom; R 4 including methyl, ethyl, 4-methylphenyl or 2-methoxyphenyl; R 5 These include ethoxy or 2-methoxyphenyl.

5. A method for preparing the chiral phosphonate compound according to claim 1, characterized in that: The following steps are involved: 1) mixing and reacting a phosphonate, a carbonate, an azacarbene and fluorobenzene to obtain a reaction solution; The structural formula of the chiral azacarbene is shown in Formula 5: 2) mixing the reaction solution obtained in step 1) with 1-naphthol, stirring and reacting to obtain a stirred reaction solution; 3) Purifying the stirred reaction solution obtained in step 2) to obtain a chiral P(V) phosphonate compound.

6. The preparation method according to claim 5, characterized in that: In the step 1), the volume ratio of the mole of phosphonate, the mole of carbonate, the mole of azacarbene and fluorobenzene is 0.1 mmol: 0.15 mmol: 0.02 mmol: 4 mL; The carbonate includes cesium carbonate or rubidium carbonate; The reaction conditions include: temperature of 0°C and time of 1 h.

7. The preparation method according to claim 5, characterized in that: In the step 2), the molar ratio of 1-naphthol to phosphonate is 0.11:0.1; The stirring reaction conditions include: temperature of -30°C and time of 24h.

8. Use of the chiral phosphonate compound according to claim 1 or the derivative according to any one of claims 2 to 3 in preventing and controlling plant diseases.

9. The use according to claim 8, characterized in that: The plant diseases include rice bacterial blight and / or rice leaf streak disease.

10. An antibacterial agent for preventing and controlling plant diseases, characterized in that: The antibacterial agent comprises one or more of the chiral phosphonate compound according to claim 1 and the derivatives according to any one of claims 2 to 3; The plant diseases include rice bacterial blight and / or rice leaf streak disease.

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