A method for the asymmetric synthesis of chiral secondary phosphine oxides with a conjugated dienyl phosphine center

Abstract

The application discloses a method for synthesizing a chiral secondary phosphine oxide with a conjugated dienyl phosphorus center through desymmetrization. The method is that a primary phosphine oxide reacts with an alkyne to obtain the chiral secondary phosphine oxide with the conjugated dienyl phosphorus center under the joint catalysis of zero-valent nickel and a ligand and the action of an additive. The method realizes the preparation of the chiral secondary phosphine oxide with the conjugated dienyl phosphorus center with high enantioselectivity and specific chemical selectivity through the joint catalysis of the zero-valent nickel and the ligand.

Description

Technical Field

[0001] This invention belongs to the field of asymmetric transition metal catalysis, specifically relating to a method for synthesizing conjugated dienyl phosphine-centered chiral secondary phosphine oxides through desymmetry. Background Technology

[0002] Currently, the synthesis of secondary phosphine oxides with chiral phosphine centers generally involves stereospecific transformation of optically pure starting materials, chiral cofactor induction, or chiral resolution. These methods are generally costly and involve cumbersome synthetic steps. With significant advances in asymmetric catalysis, researchers have developed various strategies for constructing p-chiral phosphine oxides via asymmetric catalysis. In 2020, Zhang Junliang's group reported a Le-Phos-catalyzed kinetic resolution reaction of racemic secondary phosphine oxides, achieving efficient synthesis of chiral phosphine oxides with chiral phosphine centers via allylation. Su Bo's group developed a nickel-catalyzed kinetic resolution reaction of racemic H-phosphine amides with alkyne chlorine, successfully constructing chiral H-phosphine amides. These methods theoretically achieve high enantioselectivity control of secondary phosphine oxides; however, due to the elusive racemization mechanism of secondary phosphine oxides, the optically pure secondary phosphine oxides obtained in practice often have low enantiomeric purity. Furthermore, these methods suffer from low atom economy (wasting at least half of the starting materials), severely limiting their widespread practical application. In addition, Zhang Qingwei's research group reported the enantioselective Marvin hydrophosphineization reaction of nickel-catalyzed primary phosphine oxides and alkynes, and successfully constructed conjugated dienyl phosphine chiral alkenyl secondary phosphine oxides with a broad substrate range and potential application value. However, this strategy is still insufficient for regioselective control of asymmetric internal alkynes. Summary of the Invention

[0003] To address the aforementioned technical problems, this invention provides a method for synthesizing conjugated dienyl phosphine-centered chiral secondary phosphine oxides via desymmetry. This method achieves high enantioselectivity in synthesizing secondary phosphine oxides containing chiral phosphine centers.

[0004] The further technical problem to be solved by the present invention is to provide a method for synthesizing phosphine-centered chiral tertiary phosphine oxides and phosphine-centered chiral compounds with five-membered ring structures, using the aforementioned synthesized secondary phosphine oxides with conjugated diene phosphine chiral centers as raw materials.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] A method for synthesizing conjugated dienylphosphine-centered chiral secondary phosphine oxides via desymmetry involves reacting a primary phosphine oxide with an enyne under the co-catalysis of zero-valent nickel and ligands, and with the aid of additives, to obtain conjugated dienylphosphine-centered chiral secondary phosphine oxides.

[0007] The reaction pathway of this method is shown below:

[0008] .

[0009] Wherein, Ar in the molecular formula of the primary phosphine oxide is a sterically hindered substituted aryl structure; R in the enyne is a different aryl structure or alkyl structure.

[0010] The chemical structural formula of the primary phosphorus oxide is as follows:

[0011] ;

[0012] The chemical structural formula of the alkenyne is as follows:

[0013] .

[0014] Wherein, the zero-valent nickel is Ni(COD)2, and the amount of zero-valent nickel added is 0.005~0.015 mmol; the ligand is (S,S)-BDPP, and the amount of the ligand added is 0.006~0.018 mmol.

[0015] Wherein, the additive is an alkali, and the molar ratio of the additive to primary phosphine oxide is 1:1 to 1:3;

[0016] The molar ratio of the primary phosphine oxide to the enyne is 1:1.5 to 1:2.5.

[0017] The synthesis reaction is carried out in a solvent, namely mesitylene; the temperature of the synthesis reaction is 10~35℃, and the reaction time is 24 hours to 72 hours.

[0018] A conjugated dienyl phosphine-centered chiral secondary phosphine oxide is prepared by the above-described method of synthesizing conjugated dienyl phosphine-centered chiral secondary phosphine oxide via desymmetry.

[0019] The general molecular structural formula of the conjugated diene phosphine-centered chiral secondary phosphine oxide is as follows:

[0020] ;

[0021] Where Ar is a sterically hindered substituted aryl structure; R is a different aryl structure or alkyl structure.

[0022] The molecular structural formula of the conjugated diene phosphine-centered chiral secondary phosphine oxide is as follows:

[0023] ;

[0024] in, for .

[0025] A method for synthesizing a phosphine-centered chiral tertiary phosphine oxide, which is obtained by nucleophilic substitution of the above-mentioned conjugated dienyl phosphine-centered chiral secondary phosphine oxide with an allylating agent or an arylating agent.

[0026] A method for synthesizing a phosphine-centered chiral tertiary phosphine oxide, which is obtained by electrophilic addition of the above-mentioned conjugated dienyl phosphine-centered chiral secondary phosphine oxide with vinylpyridine.

[0027] A method for synthesizing a phosphine-centered chiral compound with a five-membered ring structure is described, which involves introducing an allyl segment into the aforementioned conjugated dienyl phosphine-centered chiral secondary phosphine oxide through nucleophilic substitution, followed by a cyclization reaction with the alkenyl segment inherent in the conjugated dienyl phosphine-centered chiral secondary phosphine oxide itself, under the action of a catalyst.

[0028] The beneficial effects of this invention are as follows:

[0029] (1) This invention achieves the preparation of conjugated diene phosphine-centered chiral secondary phosphine oxides with high enantioselectivity and specific chemoselectivity through the synergistic catalysis of zero-valent nickel and ligands.

[0030] (2) The conjugated diene phosphine-centered chiral secondary phosphine oxide synthesized in this invention is amphiphilic. Attached Figure Description

[0031] Figure 1 This is the NMR spectrum of the conjugated diene phosphine-centered chiral secondary phosphine oxide 3aa prepared in Example 3 of the present invention. Detailed Implementation

[0032] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention. Furthermore, the technical features involved in the various embodiments of this invention described below can be combined with each other as long as they do not conflict with each other.

[0033] The synthesis of the conjugated diene phosphine-centered chiral compound of the present invention specifically involves using a metal catalyst and a ligand as catalysts, adding a base, alkyne, and primary phosphine oxide to a solvent, stirring at a certain temperature, and monitoring the reaction by TLC until completion.

[0034] This invention enables the preparation of conjugated diene phosphine-centered chiral secondary phosphine oxides with high enantioselectivity and specific chemoselectivity through the synergistic regulation of metals and ligands.

[0035] The reaction route for the method of synthesizing conjugated dienyl phosphine-centered chiral secondary phosphine oxides by desymmetry in this invention is shown below:

[0036] .

[0037] In this case, Ar in primary phosphine oxide 1 is a sterically hindered aryl structure; R in enyne 2 is an aryl structure with different substituents or an alkyl structure with different substituents.

[0038] The metal is Ni(COD)₂, added at a rate of 0.005–0.015 mmol, and the ligand is (S,S)-BDPP, added at a rate of 0.006–0.018 mmol. Due to the air sensitivity of zero-valent nickel, the metal and ligand must be added separately to the system in a glove box during the reaction; a catalyst complex cannot be pre-prepared. The mixture is stirred at room temperature for 20 minutes and then frozen at -20°C for 10 minutes. The additive is t-BuCOOK, added at a rate of 1.0–3.0 equivalents (i.e., the molar ratio of the additive to primary phosphine oxide is 1:1–1:3).

[0039] The reaction is carried out in a solvent, namely mesitylene.

[0040] The amount of primary phosphine oxide 1 added is 1.0 equivalent, and the amount of enyne 2 added is 1.5 to 2.5 equivalent.

[0041] The reaction was carried out at 10~35℃ for 24~72 hours.

[0042] The equipment used in this embodiment is as follows:

[0043] Bruker 400M NMR spectrometer, Bruker 500M NMR spectrometer, Agilent high performance liquid chromatograph, high resolution mass spectrometer, and polarimeter.

[0044] Example 1

[0045] This embodiment prepares racemic conjugated diene-based secondary phosphine oxides.

[0046] The synthesis route in this embodiment is shown in the figure below:

[0047] .

[0048] Under a nitrogen atmosphere, Ni(COD)₂ (0.0025–0.0075 mmol, 5–15% mol), DPPP (0.003–0.009 mmol, 6–18% mol), and mesitylene (0.25–0.5 mL) were added to a 4 mL reaction flask equipped with a magnetic stir bar. The mixture was then stirred at room temperature for 10 minutes, followed by the addition of K₃PO₄ (1.0–3.0 equivalents, 0.05–0.15 mmol), primary phosphine oxide 1 (1.0 equivalent, 0.05 mmol), and enyne 2 (1.5–2.5 equivalents, 0.075–0.125 mmol). The flask was capped, and the sample vial was removed from the glove box and stirred overnight at 10–35 °C. The reaction system was purified by silica gel plate separation using petroleum ether:ethyl acetate = 1:1 as the developing solvent to obtain the corresponding product rac-3.

[0049] Example 2

[0050] This embodiment prepares chiral conjugated diene-based secondary phosphine oxides.

[0051] The synthetic route is shown below:

[0052] .

[0053] Under a nitrogen atmosphere, Ni(COD)₂ (0.005–0.015 mmol, 5–15 mol%), (S,S)-BDPP (0.006–0.018 mmol, 6–18 mol%), and mesitylene (0.5–1.0 mL) were added to a 4 mL reaction flask equipped with a magnetic stir bar. The mixture was stirred at room temperature for 20 minutes, then cooled to -20 °C in a glove box. Potassium neopentate (0.1–0.3 mmol), primary phosphine oxide 1 (0.1 mmol), and enyne 2 (0.15–0.25 mmol) were then added. The reaction flask was quickly capped and sealed, removed from the glove box, and the reaction system was stirred at 10–35 °C for 24–72 hours. The reaction system was purified by silica gel agar plate separation using petroleum ether:ethyl acetate = 1:1 as the developing solvent to obtain the corresponding product 3.

[0054] Specifically, Ar in primary phosphine oxide 1 is... In enyne 2, R represents an aryl structure with different substituents. The structural formulas, product yields, and enantioselectivity (ee) of the synthetic reactions of primary phosphine oxide 1 and different enynes 2 are as follows:

[0055] .

[0056] Specifically, Ar in primary phosphine oxide 1 is a sterically hindered aryl structure, and enyne 2 is... The structural formulas, product yields, and enantioselectivity of different primary phosphine oxides 1 and enyne 2 obtained by synthetic reactions are as follows:

[0057] .

[0058] As can be seen from the enantioselectivity data of the above products, the method of the present invention can synthesize phosphine-centered chiral secondary phosphine oxides with high enantioselectivity.

[0059] Example 3

[0060] This embodiment represents a scale-up of conjugated diene phosphine-centered chiral secondary phosphine oxides.

[0061] The synthesis route is shown below:

[0062] .

[0063] Under a nitrogen atmosphere, Ni(COD)₂ (0.05–0.15 mmol, 5–15 mol%), (S,S)-BDPP (0.06–0.18 mmol, 6–18 mol%), and mesitylene (5.0–10.0 mL) were added to a 20 mL reaction flask equipped with a magnetic stir bar. The mixture was stirred at room temperature for 20 minutes, then cooled to -20 °C in a glove box. Potassium neopentate (1.0–3.0 mmol), primary phosphine oxide 1 (1.0 mmol), and enyne 2 (1.5–2.5 mmol) were then added. The reaction flask was quickly capped and sealed, removed from the glove box, and the reaction system was stirred at 10–35 °C for 24–72 hours. The reaction system was separated and purified using silica gel plates with petroleum ether:ethyl acetate as the developing solvent to obtain the corresponding product 3aa (yellow oily liquid, 265.7 mg, 82% yield, 94% ee value).

[0064] Figure 1 This is the NMR spectrum of the conjugated dienyl phosphine-centered chiral secondary phosphine oxide 3aa prepared in Example 3 of the present invention. Specifically, the NMR data, HPLC, and high-resolution characterization of the phosphine-centered chiral secondary phosphine oxide 3aa are as follows:

[0065] 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 484.3 Hz, 1H), 7.52 (d, J =20.9 Hz, 1H), 7.45-7.43 (m, 2H), 7.41-7.33 (m, 3H), 6.71-6.59 (m, 1H), 5.21-5.17 (m, 1H), 5.11 (dd, J = 18.1, 2.1 Hz, 1H), 2.52 (s, 6H), 2.28 (s, 3H), 2.21 (s, 6H).

[0066] 13 C NMR (101 MHz, CDCl3) δ 142.87 (d, J = 8.3 Hz), 140.10 (d, J = 2.9Hz), 137.22 (d, J = 9.8 Hz), 135.55 (d, J = 17.2 Hz), 133.95 (d, J = 11.2Hz), 132.28, 131.39, 131.03 (d, J = 11.1 Hz), 129.90, 128.87, 128.44, 126.77,125.71, 119.41 (d, J = 7.7 Hz), 18.83 (d, J = 10.2 Hz), 17.55, 16.45 (d, J =1.8 Hz).

[0067] 31 P NMR (162 MHz, Chloroform-d) δ 12.11.

[0068] HRMS (ESI) calcd for C 21 H 26 OP + [M+H] + 325.1716, Found 325.1722.

[0069] HPLC: Daicel Chiralcel OD-H (95% ee), n-hexane / isopropanol = 90 / 10, 1 mL / min, λ = 254 nm, t (major) = 13.73 min, t (minor) = 18.86 min. = -73.1 (c = 0.10, acetone).

[0070] Example 4

[0071] This embodiment describes the application of conjugated dienyl phosphine-centered chiral secondary phosphine oxides. Specifically, it describes the synthesis of phosphine-centered chiral tertiary phosphine oxides using conjugated dienyl phosphine-centered chiral secondary phosphine oxides. In this embodiment, the conjugated dienyl phosphine-centered chiral secondary phosphine oxide undergoes nucleophilic substitution with an arylating agent to generate phosphine-centered chiral tertiary phosphine oxides.

[0072] The synthetic route is shown below:

[0073] .

[0074] Under a nitrogen atmosphere, a magnetic flask was added to a 4 mL reaction flask, followed by the sequential addition of 3aa (32.4 mg, 0.10 mmol, 94% ee), iodine diphenyltrifluoromethanesulfonate (55.9 mg, 0.13 mmol), CuCl (1.5 mg, 15 mol%), Et3N (10.1 mg, 0.1 mmol), and DCM (1.0 mL, 0.1 M). The mixture was stirred at room temperature until the 3aa was completely consumed. Subsequently, the reaction system was purified by silica gel agar plate separation using petroleum ether:ethyl acetate (1:1) as the developing solvent, yielding the target product 4 (colorless oily liquid, 36.0 mg, 90% yield, 80% ee value).

[0075] The NMR, HPLC, and high-resolution characterization data of target product 4 are as follows:

[0076] 1 H NMR (500 MHz, CDCl3) δ 7.76-7.72 (m, 2H), 7.48-7.45 (m, 1H), 7.42-7.37 (m, 2H), 7.38-7.32 (m, 4H), 7.30-7.27 (m, 1H), 7.20 (d, J = 21.1 Hz, 1H), 6.69-6.59 (m, 1H), 5.52 (d, J = 17.9 Hz, 1H), 5.24 (dd, J = 11.5, 2.1Hz, 1H), 2.32 (s, 6H), 2.29 (s, 3H), 2.18 (s, 6H).

[0077] 13C NMR (126 MHz, CDCl3) δ 140.66 (d, J = 10.7 Hz), 139.08 (d, J = 2.8Hz), 138.73 (d, J = 9.7 Hz), 137.12, 136.31 (d, J = 18.8 Hz), 136.02 (d, J =17.7 Hz), 135.44, 133.98 (d, J = 11.5 Hz), 131.60 (d, J = 9.4 Hz), 131.06,130.98 (d, J = 3.0 Hz), 129.77, 128.43, 128.29 (d, J = 4.4 Hz), 128.21,121.51, 21.42 (d, J = 6.4 Hz), 17.34, 16.41 (d, J = 1.6 Hz).

[0078] 31 P NMR (202 MHz, CDCl3) δ 32.73.

[0079] HRMS (ESI) calcd for C 27 H 30 OP + [M+H] + 401.2029, Found 401.2038.

[0080] HPLC: Daicel Chiralcel IM (80% ee), n-hexane / isopropanol = 80 / 20, 1 mL / min, λ = 254 nm, t (minor) = 9.69 min, t (major) = 12.51 min. = 8.9 (c = 0.65, chloroform).

[0081] Example 5

[0082] This embodiment describes the application of conjugated dienyl phosphine-centered chiral secondary phosphine oxides. Specifically, it describes the synthesis of phosphine-centered chiral tertiary phosphine oxides using conjugated dienyl phosphine-centered chiral secondary phosphine oxides. In this embodiment, the conjugated dienyl phosphine-centered chiral secondary phosphine oxide undergoes nucleophilic substitution with an arylating agent to generate phosphine-centered chiral tertiary phosphine oxides.

[0083] The synthesis route is shown below:

[0084] .

[0085] Under a nitrogen atmosphere, Pd2(dba)3 (4.6 mg, 5 mol%), rac-BINAP (7.5 mg, 12 mol%), and THF (0.1 mL, 0.1 M) were added sequentially to a 4 mL reaction flask equipped with a magnetic stir bar. After stirring at room temperature for 10 minutes, 3aa (32.4 mg, 0.1 mmol, 94% ee) and tert-butyl cinnamon carbonate (46.8 mg, 0.2 mmol) were added sequentially. The flask was capped and stirred at room temperature until the 3aa was completely consumed. The reaction system was then purified by silica gel plate separation using petroleum ether:ethyl acetate (1:1) as the developing solvent. The purified product was 5 (39.2 mg of colorless oily liquid, 89% yield, 92% ee).

[0086] The NMR, HPLC, and high-resolution characterization data of target product 5 are as follows:

[0087] 1 H NMR (500 MHz, CDCl3) δ 7.33-7.27 (m, 6H), 7.23-7.22 (m, 4H), 7.19-7.15 (m, 1H), 6.69-6.59 (m, 1H), 6.42-6.38 (m, 1H), 6.22-6.15 (m, 1H), 5.34-5.30 (m, 1H), 5.25-5.2 (m, 1H), 3.37 -3.21 (m, 2H), 2.54 (s, 6H), 2.28 (s,3H), 2.20 (s, 6H).

[0088] 13C NMR (126 MHz, CDCl3) δ 140.65 (d, J = 9.3 Hz), 138.87 (d, J = 3.2Hz), 138.08 (d, J = 9.8 Hz), 137.28 (d, J = 3.0 Hz), 136.47, 135.93, 135.78,134.23 (d, J = 12.7 Hz), 134.05 (d, J = 11.5 Hz), 131.23 (d, J = 8.4 Hz), 129.77, 128.41 (d, J = 3.7 Hz), 128.26, 127.23, 126.22 (d, J = 1.7 Hz),120.83, 120.75, 120.27 (d, J = 4.8 Hz), 37.41 (d, J = 67.5 Hz), 20.82 (d, J =5.2 Hz), 17.34, 16.44.

[0089] 31 P NMR (202 MHz, CDCl3) δ 38.16.

[0090] HRMS (ESI) calcd for C 30 H 34 OP + [M+H] + 441.2342, Found 441.2339.

[0091] HPLC: Daicel Chiralcel OD-H (92% ee), n-hexane / isopropanol = 90 / 10, 1 mL / min, λ = 254 nm, t (minor) = 14.32 min, t (major) = 26.08 min. = -34.4 (c = 0.21, chloroform).

[0092] Example 6

[0093] This embodiment describes the application of a conjugated dienyl phosphine-centered chiral secondary phosphine oxide. Specifically, a phosphine-centered chiral tertiary phosphine oxide is synthesized using a conjugated dienyl phosphine-centered chiral secondary phosphine oxide. In this embodiment, the conjugated dienyl phosphine-centered chiral secondary phosphine oxide undergoes electrophilic addition with vinylpyridine to generate a phosphine-centered chiral tertiary phosphine oxide.

[0094] The synthetic route is shown below:

[0095] .

[0096] Under a nitrogen atmosphere, 3aa (32.4 mg, 94% ee), 2-vinylpyridine (12.6 mg, 0.12 mmol), (PhO)₂P(O)OH (5 mg, 20 mol%), and toluene (1.0 mL, 0.1 M) were added sequentially to a 4 mL reaction flask equipped with a magnetic stir bar. The reaction mixture was stirred at room temperature until 3aa was completely consumed. The reaction mixture was then purified using silica gel agar plates with petroleum ether:ethyl acetate (1:1) as the developing solvent. The purified product yielded the target product 6 (colorless oily liquid, 39.9 mg, 93% yield, 95% ee).

[0097] The NMR, HPLC, and high-resolution characterization data of target product 6 are as follows:

[0098] 1 H NMR (500 MHz, CDCl3) δ 8.48-8.44 (m, 1H), 7.53-7.49 (m, 1H), 7.41-7.39 (m, 2H), 7.37-7.33 (m, 2H), 7.32-7.28 (m, 1H), 7.25 (d, J = 19.5 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 7.06 (ddd, J = 7.6, 4.9, 1.1 Hz, 1H), 6.73-6.63 (m, 1H), 5.60-5.55 (m, 1H), 5.33-5.29 (m, 1H), 3.17-3.09 (m, 1H), 3.02-2.94 (m, 1H), 2.79-2.73 (m, 2H), 2.56 (s, 6H), 2.27 (s, 3H), 2.19 (s, 6H).

[0099] 13C NMR (126 MHz, CDCl3) δ 161.09 (d, J = 14.7 Hz), 149.18, 140.02 (d, J = 10.4 Hz), 138.80 (d, J = 2.9 Hz), 138.41 (d, J = 9.7 Hz), 136.32, 136.12(d, J = 60.7 Hz), 135.71 (d, J = 9.5 Hz), 134.11 (d, J = 11.5 Hz), 131.18 (d,J = 8.4 Hz), 129.93, 128.53, 126.79 (d, J = 97.6 Hz), 123.02, 121.20, 120.71(d, J = 5.0 Hz), 31.39, 30.91-30.82 (m), 20.63 (d, J = 5.2 Hz), 17.37, 16.49(d, J = 1.5 Hz).

[0100] 31 P NMR (202 MHz, CDCl3) δ 41.74.

[0101] HRMS (ESI) calcd for C 28 H 33 NOP + [M+H] + 430.2294, Found 430.2297.

[0102] HPLC: Daicel Chiralcel AD-H (95% ee), n-hexane / isopropanol = 80 / 20, 1 mL / min, λ = 254 nm, t (minor) = 18.15 min, t (major) = 28.01 min. = -59.9 (c = 0.62, chloroform).

[0103] Example 7

[0104] This embodiment describes the application of conjugated dienylphosphine-centered chiral secondary phosphine oxides. Specifically, conjugated dienylphosphine-centered chiral secondary phosphine oxides are used to synthesize phosphine-centered chiral compounds with a five-membered ring structure. In this embodiment, the conjugated dienylphosphine-centered chiral secondary phosphine oxide, after introducing an allyl segment through nucleophilic substitution, can undergo a cyclization reaction with the alkenyl segment inherent in the conjugated dienylphosphine-centered chiral secondary phosphine oxide itself under the action of a catalyst, forming a phosphine-centered chiral compound with a five-membered ring structure.

[0105] The synthesis route is shown below:

[0106] .

[0107] Under a nitrogen atmosphere, 3aa (16.2 mg, 94% ee), allyl iodine (10.0 mg, 0.06 mmol), Cs₂CO₃ (32.5 mg, 0.1 mmol), and MeCN (0.5 mL) were added sequentially to a 4 mL reaction flask equipped with a magnetic stir bar. The reaction was stirred at room temperature until 3aa was completely converted. Subsequently, the acetonitrile solvent was removed by vacuum distillation. Under a nitrogen atmosphere, Hoveyda-Grubbs II catalyst (1.5 mg, 0.00025 mmol) and toluene (0.05 mL) were added, and the mixture was stirred at room temperature until the target product was completely formed. The reaction system was purified by silica gel agar plate separation using petroleum ether:ethyl acetate = 1:1 as the developing solvent to give target product 7 (colorless oily liquid, 68% yield, 75% ee value).

[0108] The NMR, HPLC, and high-resolution characterization of target product 7 are as follows:

[0109] 1 H NMR (500 MHz, CDCl3) δ 7.41-7.35 (m, 4H), 7.31-7.28 (m, 1H), 7.28-7.19 (m, 1H), 6.84 (d, J = 18.7 Hz, 1H), 6.41-6.34 (m, 1H), 2.91-2.87 (m,2H), 2.45 (s, 6H), 2.29 (s, 3H), 2.21 (s, 6H).

[0110] 13C NMR (126 MHz, CDCl3) δ 140.41 (d, J = 95.5 Hz), 139.39 (d, J =3.1 Hz), 139.05 (d, J = 10.5 Hz), 136.90 (d, J = 17.1 Hz), 134.37 (d, J =11.7 Hz), 132.94 (d, J = 10.2 Hz), 132.29 (d, J = 6.3 Hz), 130.61 (d, J =29.5 Hz), 128.90, 128.60, 128.32, 125.51 (d, J = 95.3 Hz), 35.57 (d, J = 68.9Hz), 20.07 (d, J = 5.6 Hz), 17.48, 16.53 (d, J = 1.7 Hz).

[0111] 31P NMR (202 MHz, CDCl3) δ 48.85.

[0112] HRMS (ESI) calcd for C22H26OP+ [M+H]+ 337.1716, Found 337.1717.

[0113] HPLC: Daicel Chiralcel AD-H (75% ee), n-hexane / isopropanol = 95 / 5, 1 mL / min, λ = 254 nm, t (minor) = 42.70 min, t (major) = 50.68 min. = 210 (c = 0.26, chloroform).

[0114] Those skilled in the art will readily understand that the above description is merely a preferred embodiment of the present invention. The above embodiments are provided only for the purpose of describing the present invention and are not intended to limit the present invention. Parts not described in detail in this specification are well-known in the art and are not intended to limit the scope of the present invention. The scope of the present invention is defined by the appended claims. All equivalent substitutions and modifications made without departing from the spirit and principle of the present invention should be covered within the scope of the present invention.

Claims

1. A method for synthesizing conjugated dienylphosphine-centered chiral secondary phosphine oxides via desymmetry, characterized in that, This method involves reacting primary phosphine oxides with enyne under the co-catalysis of zero-valent nickel and ligands, and with the help of additives, to obtain conjugated dienylphosphine-centered chiral secondary phosphine oxides. The reaction pathway of this method is shown below: ； Wherein, Ar in the molecular formula of the primary phosphine oxide is a sterically hindered substituted aryl structure; R in the enyne is a different aryl structure or alkyl structure.

2. The method for synthesizing conjugated diene phosphine-centered chiral secondary phosphine oxides via desymmetry according to claim 1, characterized in that, The chemical structural formula of the primary phosphorus oxide is as follows: ； The chemical structural formula of the alkenyne is as follows: 。 3. The method for synthesizing conjugated diene phosphine-centered chiral secondary phosphine oxides via desymmetry according to claim 1, characterized in that, The zero-valent nickel is Ni(COD)2, and the amount of zero-valent nickel added is 0.005~0.015 mmol; the ligand is (S,S)-BDPP, and the amount of the ligand added is 0.006~0.018 mmol.

4. The method for synthesizing conjugated diene phosphine-centered chiral secondary phosphine oxides by desymmetry according to claim 1, characterized in that, The additive is an alkali, and the molar ratio of the additive to primary phosphine oxide is 1:1 to 1:3; The molar ratio of the primary phosphine oxide to the enyne is 1:1.5 to 1:2.

5.

5. The method for synthesizing conjugated diene phosphine-centered chiral secondary phosphine oxides by desymmetry according to any one of claims 1 to 4, characterized in that, The synthesis reaction is carried out in a solvent, namely mesitylene; the temperature of the synthesis reaction is 10~35℃, and the reaction time is 24 hours to 72 hours.

6. A conjugated dienylphosphine-centered chiral secondary phosphine oxide, characterized in that, The conjugated diene phosphine-centered chiral secondary phosphine oxide is prepared by the method described in any one of claims 1 to 5, which involves desymmetry synthesis of the conjugated diene phosphine-centered chiral secondary phosphine oxide. The general molecular structural formula of the conjugated diene phosphine-centered chiral secondary phosphine oxide is as follows: ； In this context, Ar represents a sterically hindered aryl structure, and R represents different aryl or alkyl structures.

7. The conjugated diene-based phosphine-centered chiral secondary phosphine oxide according to claim 6, characterized in that, The molecular structure of the conjugated diene phosphine-centered chiral secondary phosphine oxide is as follows: ； in, for .

8. A method for synthesizing a phosphine-centered chiral tertiary phosphine oxide, characterized in that, The phosphine-centered chiral tertiary phosphine oxide is obtained by nucleophilic substitution of the conjugated dienyl phosphine-centered chiral secondary phosphine oxide as described in claim 6 or 7 with an allylating or arylating agent.

9. A method for synthesizing a phosphine-centered chiral tertiary phosphine oxide, characterized in that, The phosphine-centered chiral tertiary phosphine oxide is obtained by electrophilic addition of the conjugated diene-centered chiral secondary phosphine oxide as described in claim 6 or 7 with vinylpyridine.

10. A method for synthesizing a phosphine-centered chiral compound having a five-membered ring structure, characterized in that, The phosphine-centered chiral compound with a five-membered ring structure is formed by the introduction of an allyl segment into the conjugated dienyl phosphine-centered chiral secondary phosphine oxide as described in claim 6 or 7 through nucleophilic substitution, followed by a cyclization reaction with the alkenyl segment inherent in the conjugated dienyl phosphine-centered chiral secondary phosphine oxide itself, under the action of a catalyst.

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