Chiral phosphonate compound and application thereof as agricultural bacteriostatic agent or in preparation of agricultural bacteriostatic agent

Abstract

The invention provides a chiral phosphonate compound, which belongs to the technical field of organic synthesis and pesticide bacteriostatic activity research, and the structural general formula of the chiral phosphonate compound is as shown in formula 1. The compound has remarkable sterilization performance, and has important research significance on further development and utilization of chiral phosphonate compounds. The invention also provides an application of the chiral phosphonate compound as an agricultural bacteriostatic agent or in preparation of the agricultural bacteriostatic agent.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and pesticide antibacterial activity research, and particularly relates to a chiral phosphonate compound and application thereof as or in the preparation of an agricultural antibacterial agent. Background Art

[0002] Phosphorus (V) chiral compounds have been widely used in natural products, drugs and pesticides. At the same time, phosphorus (V) chiral compounds are also used as ligands and organic catalysts. Due to their unique stereostructure, phosphonate compounds have important application value and potential in the fields of medicinal chemistry, organic synthetic chemistry, pesticide science, etc., and are a class of advantageous structures that have received widespread attention. In addition, phosphonate compounds can also be used as prodrugs of many drugs, such as the antiviral drugs adefovir dipivoxil and tenofovir disoproxil fumarate. The methods for constructing phosphonate compounds are usually limited to the addition and desymmetrization of chiral reagents. Despite recent significant progress (Science 2022, 376, 1230-1236; Nat. Chem. 2023, 15, 714-721), it is still a considerable challenge to synthesize phosphonate compounds with high enantioselectivity through catalyst control. At the same time, many pesticide active molecules contain phosphate structural fragments. Therefore, the construction of phosphonate compounds with substrate universality is of great significance for the development of medicines and pesticides. Summary of the invention

[0003] In order to obtain a series of new phosphonate compounds, the present invention provides a chiral phosphonate compound with higher enantioselectivity, which has significant sterilization performance and has important research significance for the further development and utilization of chiral phosphonate compounds.

[0004] The present invention also provides an application of a chiral phosphonate compound as or in the preparation of an agricultural antibacterial agent.

[0005] The present invention is achieved through the following technical solutions:

[0006] The present invention provides a chiral phosphonate compound, and the chiral phosphonate compound has a general structural formula as shown in Formula 1:

[0007]

[0008] In formula 1, the * phosphorus atom is a chiral phosphorus atom;

[0009] X includes O or S;

[0010] In formula 1, the sphere Includes any one of methyl, ethyl, benzyl, cyclopropyl, phenyl and substituted phenyl.

[0011] Based on the same inventive concept, the present invention provides a derivative of a chiral phosphonate compound, the structural formula of the derivative is shown in Formula 4:

[0012]

[0013] Based on the same inventive concept, the present invention provides a method for preparing a chiral phosphonate compound, the preparation method comprising:

[0014] Mixing phenylphosphite, benzoyl chloride, potassium carbonate, chiral catalyst C7 and toluene to obtain a mixture;

[0015] The mixture is reacted at a certain temperature for a period of time to obtain a reaction solution;

[0016] Adding 9-fluorenol to the reaction solution, stirring and reacting for a period of time to obtain a first mixed solution;

[0017] The first mixed solution is subjected to column chromatography and concentrated, and the obtained concentrated product is dissolved in a mixed solution of carbon tetrachloride and dichloromethane to obtain a second mixed solution;

[0018] Adding alcohol and triethylamine to the second mixed solution, reacting at a certain temperature for a period of time, to obtain a third mixed solution;

[0019] Purifying the third mixed solution to obtain a chiral phosphonate compound;

[0020] Wherein, the structural formula of the chiral catalyst C7 is shown in Formula 3:

[0021]

[0022] Further, the step of mixing phenylphosphite, benzoyl chloride, potassium carbonate, chiral catalyst C7 and toluene to obtain a mixture specifically comprises:

[0023] Under an inert atmosphere, phenylphosphite, benzoyl chloride, potassium carbonate, chiral catalyst C7 and toluene are mixed to obtain a mixture;

[0024] Wherein, the molar ratio of the phenylphosphite, the benzoyl chloride and the potassium carbonate is 1:2:2;

[0025] The molar ratio of the chiral catalyst C7 to the phenyl hypophosphorous acid is 15:100.

[0026] Further, the mixture is reacted at a certain temperature for a period of time to obtain a reaction solution, which specifically includes:

[0027] The mixture was stirred at -10°C for 15 min to obtain a reaction solution.

[0028] Further, adding 9-fluorenol to the reaction solution and stirring the reaction for a period of time to obtain a first mixed solution specifically includes:

[0029] Add 9-fluorenol to the reaction solution, and stir the mixture at -10°C for 72 hours to obtain a first mixed solution;

[0030] The molar ratio of the 9-fluorenol to the phenylphosphorous acid is 1.2:1.

[0031] Further, the first mixed solution is subjected to column chromatography and concentrated, and the obtained concentrated product is dissolved in a mixed solution of carbon tetrachloride and dichloromethane to obtain a second mixed solution, which specifically includes:

[0032] Using dichloromethane to perform column chromatography on the first mixed solution, and then concentrating under reduced pressure;

[0033] dissolving the obtained concentrated product in a mixed solution of carbon tetrachloride and dichloromethane to obtain a second mixed solution;

[0034] Wherein, the volume ratio of carbon tetrachloride to dichloromethane in the mixed liquid is 3:1.

[0035] Furthermore, the step of adding alcohol and triethylamine to the second mixed solution and reacting them at a certain temperature for a period of time to obtain a third mixed solution specifically includes:

[0036] Adding alcohol and triethylamine to the second mixed solution, reacting at -50°C for 72 hours, to obtain a third mixed solution;

[0037] The molar ratio of the alcohol, the triethylamine and the phenylphosphorous acid is 2:2:1.

[0038] Furthermore, the third mixed solution is purified to obtain a chiral phosphonate compound, specifically comprising:

[0039] The third mixed solution is purified by silica gel column chromatography to obtain a chiral phosphonate compound.

[0040] Based on the same inventive concept, the present invention provides an application of a chiral phosphonate compound as or in the preparation of an agricultural antibacterial agent.

[0041] Based on the same inventive concept, the present invention provides a use of a chiral phosphonate compound as or in the preparation of an antibacterial agent for the pathogen of rice bacterial blight and / or rice leaf streak disease.

[0042] Based on the same inventive concept, the present invention provides an agricultural antibacterial agent, wherein the active ingredient of the agricultural antibacterial agent includes the above-mentioned chiral phosphonate compound.

[0043] One or more technical solutions in the embodiments of the present invention have at least the following technical effects or advantages:

[0044] 1. The present invention discloses a chiral phosphonate compound, which is constructed by using phenylphosphite and 9-fluorenol. Its derivatives have good universality, excellent enantioselectivity (up to 98:2e.r.) and significant biological activity, and have significant antibacterial activity against rice bacterial blight pathogen and rice streak pathogen, which has important research significance for the further development and utilization of chiral phosphorus compounds.

[0045] 2. The present invention relates to a method for preparing a chiral phosphonate compound. The present invention uses a thiourea small molecule catalyst C7 to achieve highly selective asymmetric condensation of phenylphosphinoic acid with 9-fluorenol, and efficiently prepares chiral phosphonate compounds through the Atherton-Todd reaction. The substrate has good universality, the product yield is as high as 83% and has high enantioselectivity. 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

[0046] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the following briefly introduces the drawings required for use in the description of the embodiments. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0047] Figure 1 The diagram is a synthetic route for the chiral phosphonate compounds of the present invention. DETAILED DESCRIPTION

[0048] The present invention will be described in detail below in conjunction with specific implementations and examples, and the advantages and various effects of the present invention will be more clearly presented. It should be understood by those skilled in the art that these specific implementations and examples are used to illustrate the present invention, rather than to limit the present invention.

[0049] Throughout the specification, unless otherwise specifically stated, the terms used herein should be understood as meanings commonly used in the art. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. In the event of a conflict, the present specification takes precedence.

[0050] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0051] The following is a detailed description of a chiral phosphonate compound of the present application and its application as or in the preparation of an agricultural antibacterial agent in combination with examples and experimental data.

[0052] Example 1

[0053] This embodiment provides a method for preparing a chiral phosphonate compound, and the specific method is as follows:

[0054] like Figure 1 As shown, under nitrogen protection, compound 1a (0.1 mmol, 1.0 equiv.), benzoyl chloride (3a) (0.2 mmol, 2.0 equiv.), potassium carbonate (0.2 mmol, 2.0 equiv.), chiral catalyst C7 (15 mol%) and toluene (1.5 mL) were added to a 4.0 mL vial equipped with a magnetic stirrer. After the reaction mixture was stirred at -10 ° C for 15 minutes, 9-fluorenol (2d) (1.2 equiv.) was added to the system. The reaction was stirred at -10 ° C for 72 hours. Once the starting material was completely consumed by TLC detection, the resulting mixed solution was subjected to column chromatography on a 30.0 mm short silica gel column with dichloromethane (25.0 mL), and then the mixture was concentrated under reduced pressure. The resulting mixture was dissolved in a mixed solution of carbon tetrachloride and dichloromethane (v / v = 3:1), followed by the addition of alcohol or phenol (2.0 equiv.) and triethylamine (2.0 equiv.). The reaction was carried out at -50°C for 72 h. After the starting material was completely consumed, the product 9 was purified by silica gel column chromatography.

[0055] The specific spectrum analysis of product 9 is as follows:

[0056] 9H-Fluoren-9-yl methyl(R)-phenylphosphonate(9a):

[0057]

[0058] 9a, colorless oil; 24.2 mg, 72% yield.

[0059] 1H NMR(400MHz,CDCl3)δ7.91(ddd,J=13.5,8.3,1.4Hz,2H),7.85(dd,J=7.4,1.1Hz,1H),7.68–7.56(m,3H),7.55–7.46(m,2H),7.42(td,J=7.4,1.2Hz,1H),7.35(ddt,J=8.6,7.4,1.1Hz,3H),7.20(td,J=7.5,1.1Hz,1H),6.37(d,J=9.7Hz,1H),3.84(d,J=11.3Hz,3H).

[0060] 13 C NMR(101MHz,CDCl3)δ142.2(d,J=3.0Hz),142.0(d,J=5.1Hz),140.6(d,J=13.1Hz),132.7(d,J=4.0Hz),132.1(d,J=10.1Hz),129.6(d,J=8.1Hz),128.6(d,J=15.2Hz),127.9(d,J=5.1Hz),126.1(d,J=16.2Hz),119.9(d,J=7.1Hz),76.9(d,J=5.1Hz),52.9(d,J=6.1Hz).

[0061] 31 P NMR(162MHz,CDCl3)δ21.9.

[0062] HRMS(ESI,m / z):Calculated for C 20 H 17 NaO3P + [M+Na] + :359.0808,found:359.0808.

[0063] HPLC analysis:97:3e.r.(Chiralcel ODH 40:60i-PrOH / n-Hexane,Flow:1.0mL / min),Rt(major)=8.6min,Rt(minor)=13.0min.

[0064] Ethyl(9H-fluoren-9-yl)(R)-phenylphosphonate(9b):

[0065]

[0066] 9b, colorless oil; 24.2 mg, 69% yield.

[0067] 1 H NMR (400 MHz, CDCl3) δ 7.90 (ddd, J = 13.6, 8.3, 1.4 Hz, 2H), 7.86 (dd, J = 7.5, 1.0 Hz, 1H), 7.65–7.61 (m, 2H), 7.60–7.56 (m, 1H), 7.52–7.46 (m, 2H), 7.42 (td, J = 7.5, 1.3 Hz, 1H), 7.37–7.35 (m, 1H), 7.34–7.32 (m, 2H), 7.19 (td, J = 7.5, 1.1 Hz, 1H), 6.36 (d, J = 9.8 Hz, 1H), 4.29–4.14 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H).

[0068] 13 C NMR (101 MHz, CDCl3) δ 142.4 (d, J = 3.0 Hz), 142.1 (d, J = 5.1 Hz), 140.6 (d, J = 12.1 Hz), 132.6 (d, J = 3.0 Hz), 132.0 (d, J = 10.1 Hz), 129.5 (d, J = 9.1 Hz), 128.5 (d, J = 16.2 Hz), 127.8 (d, J = 14.1 Hz), 126.1 (d, J = 19.2 Hz), 119.9 (d, J = 7.1 Hz), 76.8 (d, J = 6.1 Hz), 62.5 (d, J = 5.1 Hz), 16.4 (d, J = 7.1 Hz).

[0069] 31 P NMR (162 MHz, CDCl3) δ 20.5.

[0070] HRMS (ESI, m / z): Calculated for C 20 H 24 NO4 + [M+Na] + : 373.0964, found: 373.0964.

[0071] HPLC analysis: 96:4 e.r. (Chiralcel ODH 40:60 i-PrOH / n-Hexane, Flow: 1.0 mL / min), Rt (major) = 7.5 min, Rt (minor) = 10.3 min.

[0072] Benzyl(9H-fluoren-9-yl)(R)-phenylphosphonate(9c):

[0073]

[0074] 9c, colorless oil; 29.2 mg, 71% yield.

[0075] 1 H NMR(400MHz,CDCl3)δ7.90(ddd,J=13.6,8.3,1.4Hz,2H),7.75(dd,J=7.5,1.1Hz,1H),7.62(t,J=7.4Hz,2H),7.59–7.54(m,1H),7.49–7.44(m,2H),7.42–7.38(m,2H),7.39–7.37(m,1H),7.36–7.35(m,2H),7.34–7.32(m,2H),7.31–7.27(m,2H),7.20(td,J=7.5,1.1Hz,1H),6.38(d,J=9.8Hz,1H),5.26–5.09(m,2H).

[0076] 13 C NMR(101MHz,CDCl3)δ142.2(d,J=3.0Hz),142.0(d,J=5.1Hz),141.0(d,J=10.1Hz),136.1(d,J=7.1Hz),132.7(d,J=3.0Hz),132.0(d,J=10.1Hz),130.0(d,J=6.1Hz),129.1,128.2(d,J=79.8Hz),128.1(d,J=61.6Hz),128.4(d,J=9.1Hz),127.2,126.2(d,J=12.1Hz),119.9(d,J=5.1Hz),76.9(d,J=6.1Hz),67.8(d,J=5.1Hz).

[0077] 31 P NMR(162MHz,CDCl3)δ20.9.

[0078] HRMS(ESI,m / z):Calculated for C 20 H 24 NO4 + [M+Na] + :435.1121,found:335.1118.

[0079] HPLC analysis: 96:4 e.r. (Chiralcel ODH 40:60 i-PrOH / n-Hexane, Flow: 1.0 mL / min), Rt (major) = 9.2 min, Rt (minor) = 12.4 min.

[0080] Cyclopropyl(9H-fluoren-9-yl)(R)-phenylphosphonate(9d):

[0081]

[0082] 9d, colorless oil; 26.1 mg, 72% yield.

[0083] 1 H NMR(400 MHz, CDCl3) δ 7.90 (ddd, J = 13.6, 8.3, 1.4 Hz, 2H), 7.85 (dd, J = 7.5, 1.0 Hz, 1H), 7.66–7.62 (m, 2H), 7.61–7.58 (m, 1H), 7.51–7.46 (m, 2H), 7.42 (td, J = 7.5, 1.3 Hz, 1H), 7.38–7.36 (m, 2H), 7.35–7.33 (m, 1H), 7.19 (td, J = 7.5, 1.1 Hz, 1H), 6.40 (d, J = 9.7 Hz, 1H), 4.04 (tt, J = 6.0, 3.0 Hz, 1H), 0.91–0.78 (m, 2H), 0.63–0.56 (m, 2H).

[0084] 13 C NMR(101 MHz, CDCl3) δ 142.3 (d, J = 4.0 Hz), 142.0 (d, J = 5.1 Hz), 140.6 (d, J = 12.1 Hz), 132.7 (d, J = 3.0 Hz), 132.0 (d, J = 10.1 Hz), 129.6 (d, J = 8.1 Hz), 128.5 (d, J = 15.2 Hz), 127.8 (d, J = 9.1 Hz), 126.2 (d, J = 18.2 Hz), 120.0 (d, J = 6.1 Hz), 76.9, 50.7 (d, J = 5.1 Hz), 5.73 (dd, J = 5.1, 4.0 Hz).

[0085] 31 P NMR(162 MHz, CDCl3) δ 20.8.

[0086] HRMS(ESI, m / z): Calculated for C 20 H24 NO4 + [M+Na] + :385.0964, found: 385.0948.

[0087] HPLC analysis: 96:4 e.r. (Chiralcel ODH 40:60 i-PrOH / n-Hexane, Flow: 1.0 mL / min), Rt (major) = 7.6 min, Rt (minor) = 10.2 min.

[0088] R-Ethyl O-(9H-Fluoren-9-yl)(S)-phenylphosphonothioate(9e):

[0089]

[0090] 9e, colorless oil; 22.3 mg, 61% yield.

[0091] 1 H NMR (400 MHz, CDCl3) δ 7.92 (ddt, J = 14.0, 7.0, 1.4 Hz, 2H), 7.79 (d, J = 7.4 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.64 (dd, J = 11.8, 7.5 Hz, 2H), 7.56–7.51 (m, 1H), 7.48–7.43 (m, 2H), 7.42–7.37 (m, 2H), 7.36–7.31 (m, 1H), 7.29–7.25 (m, 1H), 6.53 (d, J = 12.0 Hz, 1H). 3.02–2.85 (m, 2H), 1.33 (t, J = 7.4 Hz, 3H).

[0092] 13 C NMR (101 MHz, CDCl3) δ 142.0 (d, J = 3.0 Hz), 141.9 (d, J = 5.1 Hz), 140.7 (d, J = 35.4 Hz), 133.0 (d, J = 3.0 Hz), 132.6 (d, J = 3.0 Hz), 131.3 (d, J = 11.1 Hz), 129.6 (d, J = 13.1 Hz), 128.5 (d, J = 15.2 Hz), 127.9 (d, J = 18.2 Hz), 126.4 (d, J = 64.6 Hz), 120.0 (d, J = 21.2 Hz), 25.4 (d, J = 3.0 Hz), 16.3 (d, J = 6.1 Hz).

[0093] 3131P NMR (162 MHz, CDCl3) δ 47.2.

[0094] HRMS (ESI, m / z): Calculated for C 21 H 19 NaO2P5 + [M + Na] + : 389.0736, found: 389.0732.

[0095] HPLC analysis: 78:22 e.r. (Chiralcel ODH 40:60 i-PrOH / n-Hexane, Flow: 1.0 mL / min), Rt (major) = 8.6 min, Rt (minor) = 12.8 min.

[0096] 9H-Fluoren-9-yl phenyl (S)-phenylphosphonate (9f):

[0097]

[0098] 9f, colorless oil; 33.0 mg, 83% yield.

[0099] 1 1H NMR (400 MHz, CDCl3) δ 7.95 (ddd, J = 13.8, 8.3, 1.4 Hz, 2H), 7.63 (dd, J = 7.6, 4.9 Hz, 2H), 7.56 (td, J = 7.6, 1.4 Hz, 2H), 7.50–7.45 (m, 3H), 7.38 (dtd, J = 12.4, 7.5, 1.2 Hz, 2H), 7.34–7.25 (m, 3H), 7.24–7.22 (m, 2H), 7.21–7.12 (m, 2H), 6.52 (d, J = 9.8 Hz, 1H).

[0100] 13C NMR(101MHz,CDCl3)δ150.6(d,J08.1Hz),141.8(d,J4.0Hz),141.9 (d,J4.0Hz),140.6(d,J6.1Hz),132.9(d,J3.0Hz),132.2(d,J10). .1Hz),129.7,129.6(d,J3.0Hz),128.6(d,J615.2Hz),127.9(d,J6). 6.1Hz),126.2,125.0,120.8(d,J4.0Hz),120.0.77.6(d,J6.1Hz).

[0101] 31 P NMR(162MHz,CDCl3)δ17.2.

[0102] HRMS(ESI,m / z):Calcd 20 H 24 NO4 + [M+Na] + :421.0964,found:421.0958.

[0103] HPLC analysis:96:4e.r.(Chiralcel ODH 75:25i-PrOH / n-Hexane,Flow:1.0mL / min),Rt(major)E16.1min,Rt(minor)E14.6min.

[0104] Benzo[d][1,3]dioxol-5-yl(9H-fluoren-9-yl)(S)-phenylphosphonate(9g):

[0105]

[0106] 9g,prescription drug:34.0mg,77% price.

[0107] 1H NMR(400MHz,CDCl3)δ7.93(ddd,J=13.8,8.3,1.4Hz,2H),7.63(ddd,J=7.3,4.0,2.7Hz,3H),7.61–7.56(m,1H),7.51–7.45(m,2H),7.45–7.42(m,1H),7.38(ddd,J=16.5,7.5,1.1Hz,2H),7.29(td,J=7.5,1.1Hz,1H),7.21(td,J=7.5,1.1Hz,1H),6.74(d,J=1.4Hz,1H),6.67(d,J=1.3Hz,2H),6.50(d,J=9.7Hz,1H),5.93(s,2H).

[0108] 13 C NMR(101MHz,CDCl3)δ148.1,144.8,144.9,141.9(d,J=4.0Hz),141.8(d,J=4.0Hz),140.6(d,J=7.1Hz),133.0(d,J=4.0Hz),132.2(d,J=10.1Hz),129.7(d,J=4.0Hz),128.6(d,J=16.2Hz),127.9(d,J=5.1Hz),126.2(d,J=6.1Hz),120.0(d,J=2.0Hz),113.2(d,J=5.1Hz),108.0(d,J=1.0Hz),103.3(d,J=4.0Hz),101.6,77.5(d,J=6.1Hz).

[0109] 31 P NMR(162MHz,CDCl3)δ17.6.

[0110] HRMS(ESI,m / z):Calculated for C 26 H 19 NaO5P + [M+Na] + :465.0862,found:465.0645.

[0111] HPLC analysis:96:4e.r.(Chiralcel ODH 40:60i-PrOH / n-Hexane,Flow:1.0mL / min),Rt(major)=7.1min,Rt(minor)=8.6min.

[0112] 9H-Fluoren-9-yl(4-methyl-2-oxo-2H-chromen-7-yl)(S)-phenylphosphonate(9h):

[0113]

[0114] 9h, colorless oil; 37.4 mg, 71% yield.

[0115] 1 H NMR(400 MHz, CDCl3) δ 7.98–7.92(m, 2H), 7.70(dq, J = 7.5, 0.9 Hz, 1H), 7.66–7.64(m, 1H), 7.63–7.59(m, 2H), 7.53–7.50(m, 2H), 7.49–7.45(m, 2H), 7.40(dtd, J = 13.6, 7.6, 1.1 Hz, 2H), 7.29(td, J = 7.5, 1.1 Hz, 1H), 7.26–7.24(m, 1H), 7.23–7.21(m, 1H), 7.15–7.14(m, 1H), 6.52(d, J = 9.8 Hz, 1H), 6.22(d, J = 1.4 Hz, 1H), 2.39(d, J = 1.3 Hz, 3H).

[0116] 13 C NMR(101 MHz, CDCl3) δ 160.5, 154.3, 153.0(d, J = 7.1 Hz), 151.9, 141.5(d, J = 4.0 Hz), 141.4(d, J = 5.1 Hz), 140.7(d, J = 14.1 Hz), 133.4(d, J = 3.0 Hz), 132.2(d, J = 11.1 Hz), 129.9(d, J = 6.1 Hz), 128.8(d, J = 6.1 Hz), 127.9(d, J = 3.0 Hz), 126.2, 125.7, 120.1(d, J = 7.1 Hz), 117.2, 117.1, 114.1, 109.3(d, J = 5.1 Hz), 77.9(d, J = 6.1 Hz), 18.7.

[0117] 31 P NMR(162 MHz, CDCl3) δ 17.6.

[0118] HRMS(ESI, m / z): Calculated for C 29 H 21 NaO5P + [M+Na] +:503.1090, found:503.1010.

[0119] HPLC analysis: 94:6 e.r. (Chiralcel ODH 30:70 i-PrOH / n-Hexane, Flow: 1.0 mL / min), Rt (major) = 11.6 min, Rt (minor) = 32.9 min.

[0120] 9H-Fluoren-9-yl(2-methyl-4-oxo-4H-pyran-3-yl)(S)-phenylphosphonate(9i):

[0121]

[0122] 9i, colorless oil; 33.5 mg, 78% yield.

[0123] 1 H NMR(400 MHz, CDCl3) δ 8.03–7.98 (m, 2H), 7.89 (dq, J = 7.4, 0.9 Hz, 1H), 7.69–7.64 (m, 2H), 7.63–7.60 (m, 2H), 7.59–7.54 (m, 1H), 7.50–7.44 (m, 2H), 7.41 (td, J = 7.5, 1.2 Hz, 1H), 7.37–7.31 (m, 2H), 7.23 (td, J = 7.5, 1.1 Hz, 1H), 6.96 (d, J = 10.2 Hz, 1H), 6.39 (d, J = 5.7 Hz, 1H). 3.22 (d, J = 1.6 Hz, 3H).

[0124] 13 C NMR(101 MHz, CDCl3) δ 172.8, 158.8 (d, J = 5.1 Hz), 153.7, 142.3 (d, J = 5.1 Hz), 142.1 (d, J = 3.0 Hz), 140.7 (d, J = 22.2 Hz), 139.5 (d, J = 9.1 Hz), 132.8 (d, J = 3.0 Hz), 132.0 (d, J = 10.1 Hz), 129.5 (d, J = 8.1 Hz), 128.4 (d, J = 16.2 Hz), 127.9 (d, J = 1.0 Hz), 126.5 (d, J = 27.3 Hz), 119.9 (d, J = 12.1 Hz), 116.9, 78.0 (d, J = 6.1 Hz), 15.7.

[0125] 31P NMR (162 MHz, CDCl3) δ 18.6.

[0126] HRMS (ESI, m / z): Calculated for C 25 H 19 NaO5P + [M + Na] + : 453.0862, found: 453.0858.

[0127] HPLC analysis: 95:5 e.r. (Chiralcel ODH 20:80 i-PrOH / n-Hexane, Flow: 1.0 mL / min), Rt (major) = 14.5 min, Rt (minor) = 16.4 min.

[0128] 5-Acetyl-2-methoxyphenyl(9H-fluoren-9-yl)(S)-phenylphosphonate(9j):

[0129]

[0130] 9j, colorless oil; 35.3 mg, 75% yield.

[0131] 1 H NMR (400 MHz, CDCl3) δ 7.94–7.88 (m, 2H), 7.70–7.68 (m, 1H), 7.59–7.53 (m, 3H), 7.52–7.47 (m, 2H), 7.43–7.39 (m, 2H), 7.38–7.33 (m, 2H), 7.33–7.28 (m, 2H), 7.25–7.21 (m, 1H), 7.19–7.15 (m, 1H), 6.55 (d, J = 10.2 Hz, 1H), 3.71 (s, 3H), 2.50 (s, 3H).

[0132] 1313C NMR (101 MHz, CDCl3) δ 196.9, 151.2 (d, J = 5.1 Hz), 144.0 (d, J = 7.1 Hz), 141.9 (d, J = 4.0 Hz), 141.8 (d, J = 4.0 Hz), 140.7 (d, J = 19.2 Hz), 134.7, 133.0 (d, J = 3.0 Hz), 132.2 (d, J = 11.1 Hz), 129.7 (d, J = 5.1 Hz), 128.5 (d, J = 16.2 Hz), 127.9 (d, J = 5.1 Hz), 126.3 (d, J = 18.2 Hz), 122.2 (d, J = 1.0 Hz), 121.3 (d, J = 3.0 Hz), 119.9 (d, J = 7.1 Hz), 111.6, 77.5 (d, J = 7.1 Hz), 55.9, 26.5.

[0133] 31 31P NMR (162 MHz, CDCl3) δ 17.7.

[0134] HRMS (ESI, m / z): Calculated for C 20 H 24 NO4 + [M+Na] + : 493.1175, found: 493.1175.

[0135] HPLC analysis: 97:3 e.r. (Chiralcel ODH 40:60 i-PrOH / n-Hexane, Flow: 1.0 mL / min), Rt (major) = 7.2 min, Rt (minor) = 11.1 min.

[0136] 4-Allyl-2-methoxyphenyl(9H-fluoren-9-yl)(S)-phenylphosphonate (9k):

[0137]

[0138] 9k, colorless oil; 35.1 mg, 75% yield.

[0139] 1H NMR(400MHz,CDCl3)δ7.98(ddd,J=13.9,8.3,1.4Hz,2H),7.69–7.66(m,1H),7.65–7.60(m,3H),7.59–7.52(m,1H),7.48–7.43(m,2H),7.38(dtd,J=15.0,7.6,1.0Hz,2H),7.28(td,J=7.5,1.1Hz,1H),7.25–7.21(m,1H),7.18(dd,J=8.1,1.6Hz,1H),6.73(d,J=2.0Hz,1H),6.69(dd,J=8.1,2.0Hz,1H),6.64(d,J=10.1Hz,1H),5.98–5.88(m,1H),5.11–5.08(m,1H),5.06(t,J=1.5Hz,1H),3.69(s,3H),3.34(d,J=6.7Hz,2H).

[0140] 13 C NMR(101MHz,CDCl3)δ150.8(d,J=3.4Hz),142.2(d,J=5.1Hz),142.1(d,J=4.0Hz),140.6(d,J=16.2Hz),138.2(d,J=8.1Hz),137.8(d,J=2.0Hz),137.1,132.7(d,J=3.0Hz),132.2(d,J=11.1Hz),129.5(d,J=2.0Hz),128.3(d,J=16.2Hz),127.8(d,J=5.1Hz),126.4(d,J=17.2Hz),121.5(d,J=4.0Hz),120.7(d,J=1.0Hz),119.9(d,J=4.0Hz),116.0,113.1,77.2(d,J=6.1Hz),55.7,39.9.

[0141] 31 P NMR(162MHz,CDCl3)δ17.7.

[0142] HRMS(ESI,m / z):Calculated for C 29 H 25 NaO4P + [M+Na] + :491.1383,found:491.1377.

[0143] HPLC analysis: 94:6 e.r. (Chiralcel IG 40:60 i-PrOH / n-Hexane, Flow: 1.0 mL / min), Rt (major) = 21.4 min, Rt (minor) = 12.6 min.

[0144] 4-(4-Chlorobenzoyl)phenyl(9H-fluoren-9-yl)(S)-phenylphosphonate(9l):

[0145]

[0146] 9l, colorless oil; 38.1 mg, 71% yield.

[0147] 1 H NMR (400 MHz, CDCl3) δ 8.00–7.94 (m, 2H), 7.76–7.73 (m, 2H), 7.72–7.69 (m, 2H), 7.67–7.64 (m, 2H), 7.63–7.60 (m, 2H), 7.54–7.48 (m, 2H), 7.47–7.44 (m, 3H), 7.42–7.36 (m, 2H), 7.37–7.33 (m, 2H), 7.34 (t, J = 1.7 Hz, 1H), 7.30 (ddd, J = 7.7, 4.1, 1.1 Hz, 1H), 7.23 (td, J = 7.5, 1.1 Hz, 1H).

[0148] 13 C NMR (101 MHz, CDCl3) δ 194.2, 154.1 (d, J = 7.1 Hz), 141.6 (d, J = 4.0 Hz), 141.5 (d, J = 5.1 Hz), 140.7 (d, J = 14.1 Hz), 138.9, 135.7, 133.9, 133.3 (d, J = 3.0 Hz), 132.2 (d, J = 11.1 Hz), 132.0, 131.3, 129.8 (d, J = 6.1 Hz), 128.8, 128.7, 127.9 (d, J = 1.0 Hz), 126.3 (d, J = 3.0 Hz), 120.7 (d, J = 5.1 Hz), 120.1 (d, J = 6.1 Hz), 77.8 (d, J = 7.1 Hz).

[0149] 31 P NMR (162 MHz, CDCl3) δ 17.4.

[0150] HRMS (ESI, m / z): Calculated for C32 H 22 ClNaO4P + [M+Na] + :559.0836, found:559.0825.

[0151] HPLC analysis: 95:5 e.r. (Chiralcel IC 40:60 i-PrOH / n-Hexane, Flow: 1.0 mL / min), Rt (major) = 14.2 min, Rt (minor) = 10.3 min.

[0152] 9H-Fluoren-9-yl(4-(4-oxo-4H-chromen-2-yl)phenyl)(S)-phenylphosphonate(9m):

[0153]

[0154] 9m, colorless oil; 41.2 mg, 76% yield.

[0155] 1 H NMR(400 MHz, CDCl3) δ 8.29(dd, J = 8.0, 1.7 Hz, 1H), 7.86(dq, J = 7.4, 1.0 Hz, 1H), 7.76(dd, J = 7.2, 1.6 Hz, 2H), 7.72–7.67(m, 2H), 7.66–7.63(m, 3H), 7.61(dd, J = 7.5, 1.0 Hz, 1H), 7.53(dd, J = 8.5, 1.0 Hz, 1H), 7.44–7.39(m, 3H), 7.33(ddd, J = 13.8, 7.4, 1.2 Hz, 2H), 7.28–7.26(m, 1H), 7.25–7.24(m, 1H), 7.23–7.21(m, 1H), 7.19–7.14(m, 3H), 7.09(d, J = 10.0 Hz, 1H).

[0156] 1313C NMR (101 MHz, CDCl3) δ 173.3, 156.2 (d, J = 6.1 Hz), 155.5, 142.4 (d, J = 5.1 Hz), 142.3 (d, J = 3.0 Hz), 140.7 (d, J = 21.2 Hz), 134.7 (d, J = 9.1 Hz), 133.8, 132.2 (d, J = 3.0 Hz), 131.6 (d, J = 10.1 Hz), 130.8, 130.0 (d, J = 3.0 Hz), 129.4 (d, J = 8.1 Hz), 128.9, 128.2, 128.0 (d, J = 16.2 Hz), 127.8 (d, J = 3.0 Hz), 126.8, 126.5 (d, J = 16.2 Hz), 125.0, 123.8, 119.8 (d, J = 13.1 Hz), 118.0, 77.9 (d, J = 6.1 Hz).

[0157] 31 31P NMR (162 MHz, CDCl3) δ 18.3.

[0158] HRMS (ESI, m / z): Calculated for C 34 H 23 NaO5P + [M+Na] + : 565.1175, found: 565.1150.

[0159] HPLC analysis: 98:2 e.r. (Chiralcel ID 40:60 i-PrOH / n-Hexane, Flow: 1.0 mL / min), Rt (major) = 20.4 min, Rt (minor) = 18.0 min.

[0160] Methyl (S,E)-3-(4-((((9H-fluoren-9-yl)oxy)(phenyl)phosphoryl)oxy)-3-methoxyphenyl)acrylate (9n):

[0161]

[0162] 9n, colorless oil; 37.9 mg, 74% yield.

[0163] 1H NMR(400MHz,CDCl3)δ7.93–7.87(m,2H),7.65(dt,J=7.5,1.0Hz,1H),7.58–7.55(m,2H),7.54(d,J=0.9Hz,1H),7.52(dd,J=2.3,1.4Hz,1H),7.51–7.47(m,1H),7.42–7.37(m,2H),7.31(dtd,J=15.1,7.5,1.1Hz,2H),7.23–7.19(m,2H),7.16(td,J=7.5,1.1Hz,1H),6.99–6.96(m,2H),6.55(d,J=10.1Hz,1H),6.27(d,J=15.9Hz,1H),3.69(d,J=22.9Hz,6H).

[0164] 13 C NMR(101MHz,CDCl3)δ167.3,151.3(d,J=5.1Hz),144.1,142.0(d,J=5.1Hz),141.9(d,J=4.0Hz),141.6(d,J=7.1Hz),140.6(d,J=18.2Hz),132.9(d,J=3.0Hz),132.2(d,J=11.1Hz),129.6(d,J=4.0Hz),128.4(d,J=16.2Hz),127.8(d,J=194.9Hz),127.9(d,J=5.1Hz),126.3(d,J=18.2Hz),122.0(d,J=4.0Hz),121.3(d,J=2.0Hz),119.9(d,J=6.1Hz),117.7,111.5,77.3(d,J=18.2Hz),55.7,51.7.

[0165] 31 P NMR(162MHz,CDCl3)δ17.8.

[0166] HRMS(ESI,m / z):Calculated for C 30 H 25 NaO6P + [M+Na] + :535.1281,found:535.1276.

[0167] HPLC analysis: 95:5 e.r. (Chiralcel ODH 40:60 i-PrOH / n-Hexane, Flow: 1.0 mL / min), Rt (major) = 8.7 min, Rt (minor) = 12.4 min.

[0168] (E)-4-(3,5-Dimethoxystyryl)phenyl(9H-fluoren-9-yl)(S)-phenylphosphonate (9o):

[0169]

[0170] 9o, colorless oil; 39.2 mg, 70% yield.

[0171] 1 H NMR (400 MHz, CDCl3) δ 7.99–7.93 (m, 2H), 7.66–7.63 (m, 2H), 7.61–7.56 (m, 2H), 7.62–7.57 (m, 2H), 7.52–7.47 (m, 2H), 7.45–7.39 (m, 2H), 7.38–7.35 (m, 1H), 7.27 (dd, J = 7.5, 1.1 Hz, 1H), 7.25–7.21 (m, 3H), 7.05–6.92 (m, 2H), 6.65 (d, J = 2.2 Hz, 2H), 6.53 (d, J = 9.8 Hz, 1H), 6.40 (t, J = 2.2 Hz, 1H), 3.83 (s, 6H).

[0172] 13 C NMR (101 MHz, CDCl3) δ 161.0, 150.0 (d, J = 8.1 Hz), 141.8 (d, J = 5.1 Hz), 141.9 (d, J = 4.0 Hz), 140.6 (d, J = 6.1 Hz), 139.2, 134.2, 133.0 (d, J = 3.0 Hz), 132.2 (d, J = 10.1 Hz), 129.7 (d, J = 3.0 Hz), 128.7 (d, J = 3.0 Hz), 128.5, 128.1, 127.9 (d, J = 8.1 Hz), 127.8, 126.2 (d, J = 3.0 Hz), 121.1 (d, J = 4.0 Hz), 120.0, 104.5, 100.0, 77.6 (d, J = 6.1 Hz), 55.37.

[0173] 31 P NMR (162 MHz, CDCl3) δ 17.3.

[0174] HRMS(ESI, m / z): Calculated for C 35 H 29 NaO5P + [M + Na] + : 583.1645, found: 583.1626.

[0175] HPLC analysis: 95:5 e.r. (Chiralcel ODH 40:60 i-PrOH / n-Hexane, Flow: 1.0 mL / min), Rt(major) = 16.7 min, Rt(minor) = 24.0 min.

[0176] 2-Morpholinoethyl (S,E)-6-(4-((((9H-fluoren-9-yl)oxy)(phenyl)phosphoryl)oxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoate (9p):

[0177]

[0178] 9p, colorless oil; 58.0 mg, 61% yield.

[0179] 1 H NMR (400 MHz, CDCl3) δ 8.15 (ddd, J = 14.2, 8.3, 1.4 Hz, 2H), 7.64–7.58 (m, 3H), 7.52 (ddd, J = 8.6, 6.8, 4.7 Hz, 2H), 7.40–7.36 (m, 1H), 7.35–7.32 (m, 3H), 7.17 (td, J = 7.5, 1.1 Hz, 1H), 7.11 (td, J = 7.5, 1.1 Hz, 1H), 6.63 (d, J = 9.1 Hz, 1H), 5.05 (s, 2H), 4.96 (d, J = 15.1 Hz, 2H), 4.12 (t, J = 5.9 Hz, 2H), 3.76 (s, 3H), 3.71–3.63 (m, 4H), 3.38 (d, J = 6.7 Hz, 2H)., 2.53 (t, J = 5.9 Hz, 2H), 2.44 (t, J = 4.7 Hz, 4H), 2.34–2.24 (m, 2H), 2.21 (d, J = 1.3 Hz, 3H), 2.20–2.12 (m, 2H), 1.59 (d, J = 1.3 Hz, 3H).

[0180] 13 C NMR(101MHz,CDCl3)δ173.2,167.9,162.9(d,J=3.0Hz),146.4(d,J=1.0Hz),145.1(d,J=10.1Hz),142.0(d,J=4.0Hz),141.8(d,J=5.1Hz),140.6(d,J=34.3Hz),134.1,133.0(d,J=3.0Hz),132.6(d,J=10.1Hz),129.9(d,J=4.0Hz),129.4(d,J=13.1Hz),128.4(d,J=16.2Hz),127.6(d,J=46.5Hz),126.2(d,J=14.1Hz),122.6,122.3(d,J=1.0Hz),119.8(d,J=2.0Hz),114.3(d,J=3.0Hz),78.1(d,J=6.1Hz),67.8,66.9,61.4,61.0,57.0,53.8,33.6(d,J=146.5Hz),29.5(d,J=38.4Hz),24.0,16.2,11.7.

[0181] 31 P NMR(162MHz,CDCl3)δ17.2.

[0182] HRMS(ESI,m / z):Calculated for C 42 H 45 NO9P + [M+H] + :738.2826,found:738.2805.

[0183] HPLC analysis:83:17e.r.(Chiralcel IG 40:60i-PrOH / n-Hexane,Flow:1.0mL / min),Rt(major)=47.7min,Rt(minor)=36.4min.

[0184] Methyl(S)-3-(4-(((R)-((9H-fluoren-9-yl)oxy)(phenyl)phosphoryl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate(9q):

[0185]

[0186] 9q, colorless oil; 44.9 mg, 75% yield.

[0187] 1 1H NMR (400 MHz, CDCl3) δ 7.94 (ddd, J = 13.8, 8.3, 1.4 Hz, 2H), 7.64–7.61 (m, 2H), 7.60–7.56 (m, 2H), 7.55–7.46 (m, 2H), 7.45–7.43 (m, 1H), 7.42–7.34 (m, 2H), 7.29 (td, J = 7.5, 1.1 Hz, 1H), 7.21 (td, J = 7.5, 1.1 Hz, 1H), 7.18–7.15 (m, 2H), 7.06–7.04 (m, 2H), 6.50 (d, J = 9.8 Hz, 1H), 4.98 (d, J = 8.3 Hz, 1H), 4.55 (q, J = 6.6 Hz, 1H), 3.66 (s, 3H), 3.04 (qd, J = 13.8, 5.9 Hz, 2H), 1.41 (s, 9H).

[0188] 13 13C NMR (101 MHz, CDCl3) δ 172.1, 155.0, 149.6 (d, J = 8.1 Hz), 141.8 (d, J = 4.0 Hz), 141.7 (d, J = 5.1 Hz), 140.6 (d, J = 8.1 Hz), 133.0 (d, J = 4.0 Hz), 132.1 (d, J = 11.1 Hz), 130.5, 129.7 (d, J = 5.1 Hz), 128.6 (d, J = 16.2 Hz), 127.9 (d, J = 9.1 Hz), 126.1, 120.8 (d, J = 5.1 Hz), 119.9 (d, J = 3.0 Hz), 80.0, 77.5 (d, J = 7.1 Hz), 54.3, 52.2, 37.5, 28.2.

[0189] 31 31P NMR (162 MHz, CDCl3) δ 17.2.

[0190] HRMS (ESI, m / z): Calculated for C 42 H 45 NO9P + [M+Na] + : 622.1965, found: 622.1976. >20:1 d.r. (determined by 1 1H NMR).

[0191] 4-(Tert-butyl)1-methyl(S)-2-(4-(((S)-((9H-fluoren-9-yl)oxy)(phenyl)phosphor-yl)oxy)phenyl)succinate(9r):

[0192]

[0193] 9r, colorless oil; 43.2 mg, 74% yield.

[0194] 1 H NMR(400MHz,CDCl3)δ7.86(ddd,J=13.9,8.2,1.4Hz,2H),7.55–7.52(m,2H),7.50–7.48(m,1H),7.45–7.40(m,2H),7.39–7.35(m,2H),7.33–7.25(m,2H),7.24–7.18(m,3H),7.15(dd,J=3.7,1.1Hz,2H),7.14–7.12(m,1H),6.41(d,J=9.8Hz,1H),5.49(d,J=7.6Hz,1H),5.22(d,J=7.5Hz,1H),3.62(s,3H),1.34(s,9H),1.26–1.20(m,1H).7.45–7.40(m,2H).

[0195] 13 C NMR(101MHz,CDCl3)δ171.3,154.7,150.5(d,J=7.1Hz),141.7(d,J=5.1Hz),141.6(d,J=4.0Hz),140.6(d,J=8.1Hz),133.7,133.0(d,J=3.0Hz),132.1(d,J=10.1Hz),129.7(d,J=4.0Hz),128.7,128.5,127.8(d,J=7.1Hz),126.1,121.2(d,J=5.1Hz),120.0(d,J=3.0Hz),80.2,77.5(d,J=6.1Hz),56.9,52.7,28.2.

[0196] 31 P NMR(162MHz,CDCl3)δ17.3.

[0197] HRMS(ESI,m / z):Calculated for C 42 H 45 NO9P + [M+H]+ : 738.2826, found: 738.2805. [α] 2 D 5 = -28.536 (c = 1.0 in CHCl3), >20:1 d.r. (determined by 1 H NMR).

[0198] (2aR,3R,5aS,9S,11aR)-2a,5a,8,8-tetramethyl-3-((R)-6-methylhept-5-en-2-yl)tetradecahydro-1H,12H-cyclopenta[a]cyclopropa[e]phenanthren-9-yl (E)-3-(4-(((R)-((9H-fluoren-9-yl)oxy)(phenyl)phosphoryl)oxy)-3-methoxyphenyl)acrylate (9s):

[0199]

[0200] 9s, colorless oil; 58.0 mg, 64% yield.

[0201] 1H NMR(400MHz,CDCl3)δ7.98(ddd,J=14.0,8.3,1.4Hz,2H),7.73(dd,J=7.5,1.0Hz,1H),7.67–7.61(m,3H),7.60–7.55(m,2H),7.49–7.44(m,2H),7.39(dtd,J=15.2,7.5,1.1Hz,2H),7.29(ddt,J=7.4,3.8,1.4Hz,2H),7.23(dd,J=7.5,1.1Hz,1H),7.06–7.03(m,2H),6.62(d,J=10.1Hz,1H),6.36(d,J=15.9Hz,1H),4.74–4.66(m,2H),3.75(s,3H),2.29–2.10(m,1H),2.05–1.96(m,2H),1.95–1.84(m,3H),1.75–1.67(m,3H),1.65–1.63(m,2H),1.61(d,J=1.2Hz,2H),1.59–1.51(m,3H),1.48–1.42(m,2H),1.41–1.34(m,2H),1.20–1.13(m,2H),1.12–1.06(m,2H),1.03(dd,J=6.9,2.3Hz,3H),0.97(s,6H),0.92–0.90(m,3H),0.89(s,6H),0.86–0.81(m,2H),0.80–0.77(m,1H),0.60(d,J=4.2Hz,1H),0.37(d,J=4.1Hz,1H).

[0202] 13C NMR(101MHz,CDCl3)δ166.6,156.9,151.2(d,J=4.0Hz),143.5,142.0(d,J=4.0Hz),141.9(d,J=4.0Hz),141.5(d,J=7.1Hz),140.6(d,J=17.2Hz),132.9(d,J=3.0Hz),132.3(d,J=2.0Hz),132.2(d,J=11.1Hz),130.9,129.6(d,J=4.0Hz),128.4(d,J=15.2Hz),127.9(d,J=3.0Hz),126.3(d,J=18.2Hz),125.2,122.0(d,J=3.0Hz),121.3,119.9(d,J=6.1Hz),118.8,111.4,105.9,80.8,77.3(d,J=20.2Hz),55.8,52.2(d,J=2.0Hz),48.8,47.5(d,J=64.6Hz),45.3(d,J=2.0Hz),39.7,36.2,36.0(d,J=24.2Hz),35.5,35.0,33.8,33.3(d,J=94.9Hz),31.5(d,J=31.3Hz),28.9(d,J=165.6Hz),26.7(d,J=41.4Hz),25.8(d,J=9.1Hz),25.7(d,J=48.5Hz),24.9,21.9(d,J=14.1Hz),20.9,20.2,19.3(d,J=2.0Hz),18.3(d,J=7.1Hz),18.0,17.6,15.3.

[0203] 31 P NMR(162MHz,CDCl3)δ17.7.

[0204] HRMS(ESI,m / z):Calculated for C 59 H 71 NaO6P + [M+Na] + :929.4880,found:829.4869. >20:1d.r.(determinedby 1 H NMR).

[0205] 6 - ((((R)-((9H - Fluoren - 9 - yl)oxy)(phenyl)phosphoryl)oxy)methyl)tetrahydro - 2H - pyran - 2,3,4,5 - tetrayltetraacetate(9t):

[0206]

[0207] 9t, colorless oil; 45.0 mg, 71% yield.

[0208] 1 H NMR(400 MHz, CDCl3) δ 7.97–7.89(m, 2H), 7.88–7.86(m, 1H), 7.65–7.60(m, 2H), 7.59–7.57(m, 1H), 7.53–7.48(m, 2H), 7.43(td, J = 7.5, 1.4 Hz, 1H), 7.40–7.33(m, 3H), 7.20(td, J = 7.5, 1.1 Hz, 1H), 6.33(d, J = 9.8 Hz, 1H), 5.68(d, J = 8.2 Hz, 1H), 5.21–5.19(m, 2H), 5.08–5.03(m, 1H), 4.28–4.25(m, 2H), 3.84–3.80(m, 1H), 2.01(d, J = 3.9 Hz, 6H), 1.98(s, 3H), 1.76(s, 3H).

[0209] 13 C NMR(101 MHz, CDCl3) δ 170.1, 169.2(d, J = 8.1 Hz), 168.8, 142.1(d, J = 4.0 Hz), 141.9(d, J = 5.1 Hz), 140.5(d, J = 13.1 Hz), 132.9(d, J = 3.0 Hz), 132.3(d, J = 10.1 Hz), 129.6(d, J = 13.1 Hz), 128.5(d, J = 15.2 Hz), 127.9(d, J = 25.3 Hz), 126.2(d, J = 16.2 Hz), 119.9(d, J = 12.1 Hz), 91.6, 73.14(d, J = 7.1 Hz), 72.8, 70.1, 67.4, 63.4(d, J = 5.1 Hz), 20.6, 20.5(d, J = 2.0 Hz), 20.2.

[0210] 31 P NMR(162 MHz, CDCl3) δ 21.3.

[0211] HRMS(ESI,m / z):Calculated for C 20 H 24 NO4 + [M+Na] + :675.1602,found:675.1598. >20:1d.r.(determined by 1 H NMR).

[0212] Example 2

[0213] This embodiment provides a method for preparing a derivative 10 of a chiral phosphonate compound, comprising the following steps:

[0214]

[0215] Under nitrogen protection, p-methoxymagnesium bromide (1.2 equiv.) and tetrahydrofuran (0.5 mL) were added to a 4.0 mL vial equipped with a magnetic stirrer, and the mixture was then cooled to -78 °C. Compound 9a (0.1 mmol, 1.0 equiv.) was dissolved in 0.5 mL of tetrahydrofuran and then slowly added dropwise to the reaction solution using a syringe. The reaction solution was slowly returned to room temperature and stirred for 12 h. After 9a was consumed (monitored by thin layer chromatography TLC), the reaction solution was quenched with saturated ammonium chloride solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel (dichloromethane / methanol = 100:1-50:1) gave pure product 10 as a colorless oil (14.9 mg, 57% yield, 94:6 e.r.).

[0216] Shape and spectrum analysis of compound 10:

[0217] Colorless oil;

[0218] (Methyl(S)-(4-methoxyphenyl)(phenyl)phosphinate(10):

[0219]

[0220] 1 H NMR (400MHz, CDCl3) δ7.81–7.71(m,4H),7.53–7.48(m,1H),7.46–7.41(m,2H),6.96(dd,J=8.8,2.7Hz,2H),3.83(s,3H),3.74(d,J=11.1Hz,3H).

[0221] 31P NMR (162 MHz, CDCl3) δ 33.7.

[0222] HPLC analysis: 94: 6e.r. (Chiralcel IC 40: 60i-PrOH / n-Hexane, Flow: 1.0mL / min), Rt (major) = 15.0min, Rt (minor) = 16.5min.

[0223] Product matched literature characterization data (Daili, F. etal. Nickel-catalyzed electrosynthesis of aryl and vinyl phosphinates. Eur. J. Org. Chem. 2020, 3452–3455 (2020).

[0224] Example 3

[0225] This example provides antibacterial activity tests of related compounds:

[0226] (1) Test method

[0227] ① The turbidity method was used to test the inhibitory activity of some target compounds against Xanthomonas oryzae pv.oryzae (Xoo) and Xanthomonas oryzae pv.oryzicola (Xoc), with thiophanate-methyl and chlorothiazol as positive controls. The specific operation steps are as follows:

[0228] The compound was dissolved in 150.0 μL dimethylformamide and diluted with 0.1% (V / V) Tween-20 to prepare a solution with a concentration of 25 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. 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:

[0229] I(%)=(Ctur-Ttur) / Ctur×100%

[0230] Ctur: Corrected turbidity value for bacterial growth on untreated NB;

[0231] Ttur: turbidity value corrected for bacterial growth on treated NB;

[0232] I: relative inhibition rate.

[0233] Table 1. In vitro antibacterial activity of the target compounds against Xoo and Xoc. [a]

[0234]

[0235]

[0236] 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.

[0237] The inhibitory activity of the target compounds against Xanthoceras oryzae (Xoo) was tested by turbidity method with commercial agents thiophanate-methyl and chlorothiazol as positive controls at test concentrations of 100 and 50 μg / mL (see Table 1). The bioassay results showed that most products were very effective in inhibiting Xoo. It is worth noting that at a relatively low concentration of 50 μg / mL, compounds 9a, 9j, and 9m showed significant inhibitory effects, and the inhibition rate was significantly better than that of the commercial fungicide chlorothiazol (BT). At the same time, the inhibitory effect of this class of compounds on Xoc was also promising. At a concentration of 50 μg / mL, the inhibition rates of most test compounds were comparable to or slightly higher than those of commercial drugs. The inhibition rates of compound 9a were 98.52% (100 μg / mL) and 97.83% (50 μg / mL), respectively, which significantly exceeded the inhibitory effect of TC as a positive control.

[0238] Table 2. Study on the antibacterial effects of different configurations of compounds 9a and 9j [a]

[0239]

[0240] 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.

[0241] We studied the effects of different configurations of compounds 9a and 9j on the antibacterial activity of Xoo at different concentrations (see Table 2). It is noteworthy that (S)-9j has a significantly better inhibitory effect on Xoo than their racemic isomer (±)-9j.

[0242] At the same time, we studied the effects of different configurations of compounds 9a and 9j on the antibacterial effect of Xoc at different concentrations (see Table 2). It is worth noting that (R)-9a and (S)-9j showed significantly high inhibition rates against Xoc (97.83% and 76.25%, respectively, at 50 μg / mL), which were superior to their racemates (±)-9a and (±)-9j.

[0243] Finally, it should be noted that the terms "comprises," "includes," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that includes a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements that are inherent to such process, method, article, or apparatus.

[0244] Although the preferred embodiments of the present invention have been described, those skilled in the art may make additional changes and modifications to these embodiments once they have learned the basic creative concept. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

[0245] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A chiral phosphonate compound, characterized in that: The general structural formula of the chiral phosphonate compound is shown in Formula 1: Formula 1; In formula 1, the * phosphorus atom is a chiral phosphorus atom; X includes O or S; In formula 1, the sphere Includes any one of methyl, ethyl, benzyl, cyclopropyl, phenyl and substituted phenyl.

2. A chiral phosphonate derivative, characterized in that: The structural formula of the derivative is shown in Formula 4:

3. The method for preparing a chiral phosphonate compound according to claim 1, characterized in that: The preparation method comprises: Mixing phenylphosphite, benzoyl chloride, potassium carbonate, chiral catalyst C7 and toluene to obtain a mixture; The mixture is reacted at a certain temperature for a period of time to obtain a reaction solution; Adding 9-fluorenol to the reaction solution, stirring and reacting for a period of time to obtain a first mixed solution; The first mixed solution is subjected to column chromatography and concentrated, and the obtained concentrated product is dissolved in a mixed solution of carbon tetrachloride and dichloromethane to obtain a second mixed solution; Adding alcohol and triethylamine to the second mixed solution, reacting at a certain temperature for a period of time, to obtain a third mixed solution; Purifying the third mixed solution to obtain a chiral phosphonate compound; Wherein, the structural formula of the chiral catalyst C7 is shown in Formula 3:

4. The method for preparing a chiral phosphonate compound according to claim 3, characterized in that: The step of mixing phenylphosphite, benzoyl chloride, potassium carbonate, chiral catalyst C7 and toluene to obtain a mixture specifically comprises: Under an inert atmosphere, phenylphosphite, benzoyl chloride, potassium carbonate, chiral catalyst C7 and toluene are mixed to obtain a mixture; Wherein, the molar ratio of the phenylphosphite, the benzoyl chloride and the potassium carbonate is 1:2:2; The molar ratio of the chiral catalyst C7 to the phenyl hypophosphorous acid is 15:

100.

5. The method for preparing a chiral phosphonate compound according to claim 3, characterized in that: The mixture is reacted at a certain temperature for a period of time to obtain a reaction solution, which specifically comprises: The mixture was stirred at -10°C for 15 min to obtain a reaction solution.

6. The method for preparing a chiral phosphonate compound according to claim 3, characterized in that: The step of adding 9-fluorenol to the reaction solution and stirring the reaction solution for a period of time to obtain a first mixed solution specifically comprises: Add 9-fluorenol to the reaction solution, and stir the mixture at -10°C for 72 hours to obtain a first mixed solution; The molar ratio of the 9-fluorenol to the phenylphosphorous acid is 1.2:

1.

7. The method for preparing a chiral phosphonate compound according to claim 3, characterized in that: The first mixed solution is subjected to column chromatography and concentrated, and the obtained concentrated product is dissolved in a mixed solution of carbon tetrachloride and dichloromethane to obtain a second mixed solution, which specifically includes: Using dichloromethane to perform column chromatography on the first mixed solution, and then concentrating under reduced pressure; dissolving the obtained concentrated product in a mixed solution of carbon tetrachloride and dichloromethane to obtain a second mixed solution; Wherein, the volume ratio of carbon tetrachloride to dichloromethane in the mixed liquid is 3:

1.

8. The method for preparing a chiral phosphonate compound according to claim 3, characterized in that: The step of adding alcohol and triethylamine to the second mixed solution and reacting them at a certain temperature for a period of time to obtain a third mixed solution specifically comprises: Adding alcohol and triethylamine to the second mixed solution, reacting at -50°C for 72 hours, to obtain a third mixed solution; The molar ratio of the alcohol, the triethylamine and the phenylphosphorous acid is 2:2:

1.

9. The method for preparing a chiral phosphonate compound according to claim 3, characterized in that: Purifying the third mixed solution to obtain a chiral phosphonate compound specifically includes: The third mixed solution is purified by silica gel column chromatography to obtain a chiral phosphonate compound.

10. Use of a chiral phosphonate compound as claimed in claim 1 as or in the preparation of an agricultural antibacterial agent.

11. Use of a chiral phosphonate compound according to claim 1 as or in the preparation of an antibacterial agent for bacterial blight of rice and / or rice leaf streak disease.

12. An agricultural antibacterial agent, characterized in that: The active ingredient of the agricultural antibacterial agent includes the chiral phosphonate compound according to claim 1.

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