Chiral beta-phosphonyl carbonate as well as preparation method and application thereof

Abstract

The invention discloses chiral beta-phosphonyl carbonate and a preparation method and application thereof, and belongs to the technical field of organic synthesis, the structural formula of the chiral beta-phosphonyl carbonate is shown in the specification, the preparation method of the chiral beta-phosphonyl carbonate is simple and efficient, and under the hydrogen atmosphere, the chiral beta-phosphonyl carbonate can be used for preparing the chiral beta-phosphonyl carbonate. A hydrogenation precursor and a metal ligand complex are subjected to an asymmetric hydrogenation reaction in an organic solvent system to prepare the catalyst, and the metal ligand complex is obtained by mixing and stirring a metal salt and (S)-tBu-PHOX in methanol and a hexafluoroisopropanol solution. The method is mild in condition and high in yield, target chiral beta-phosphonyl carbonate can be obtained with high enantioselectivity, chiral phosphine ligands can be further synthesized by utilizing the target chiral beta-phosphonyl carbonate, and the method has a wide application prospect in the field of asymmetric catalysis. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a chiral beta-phosphonyl carbonate and a preparation method and application thereof. Background Art

[0002] Chirality is a common phenomenon in nature (common in natural products and drugs), and occupies a pivotal position in the field of medicinal chemistry and organic synthesis. Asymmetric catalytic reaction is one of the methods for synthesizing chiral compounds with high efficiency and high atom economy. For example, Chinese patent document No. CN111484523A discloses a method for preparing optically pure trans-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid, wherein 1-cyclohexene-1-carboxylic acid methyl ester and diphenylphosphine oxide undergo addition reaction to obtain a first intermediate, and then the first intermediate is reduced to obtain cis-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid methyl ester; a flipping agent and a solvent are added to cis-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid methyl ester, and the mixture is heated to reflux, extracted, and dried to obtain trans-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid methyl ester, and then optically pure trans-2-(diphenylphosphine)-1-cyclohexanecarboxylic acid is obtained by hydrolysis, acidification, and re-extraction. Asymmetric catalytic reactions can not only solve the problem of chiral control that is difficult to overcome by traditional synthetic methods, but also produce less by-products and have a higher raw material utilization rate. It is more in line with the development concept of green chemistry. The key scientific issue is the design and development of chiral ligands.

[0003] Chiral phosphine ligands are an important class of chiral ligands, among which the representative ones include the BINAP (2,2'-bis(diphenylphosphine)-1,1'binaphthyl) series. BINAP was first synthesized by Noyori in 1980, and it showed good enantioselectivity in chiral catalysis. Later, catalysts coordinated with BINAP and various metals (Ru, Pd, Ag, Rh, Ir, Au) were continuously used in various reactions. For example, the Chinese patent document with publication number CN118106039A discloses a BINAP coordinated copper cluster catalyst, its preparation method and application. The invention uses BINAP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine), copper salt and amino acid to prepare BINAP coordinated copper cluster catalyst, which has broad application prospects in intramolecular Diels-Alder reaction. The Chinese patent document with publication number CN111450880A discloses a chiral catalyst integrating sulfonated BINAP and polyether functionalized ionic liquid. The invention integrates the transition metal complex of the chiral bisphosphine ligand BINAP with the polyether functionalized ionic liquid to obtain a catalyst integrating phosphine ligand and ionic liquid, which has obvious advantages in asymmetric hydrogenation reaction. Therefore, in order to promote the development of asymmetric catalytic reactions, more chiral phosphine ligands and their precursors need to be developed. Summary of the invention

[0004] The invention provides a chiral beta-phosphonyl carbonate, which can be used as a precursor for synthesizing a chiral phosphine ligand, and the preparation method thereof is simple and efficient, with mild conditions, high yield and high enantioselectivity.

[0005] The specific technical solutions adopted are as follows:

[0006] A chiral β-phosphonocarbonate, the structural formula of which is shown in formula (I):

[0007]

[0008] In formula (I), R 1 Each is independently selected from one of methoxy, furyl, phenyl or substituted phenyl, and further, the substituent in the substituted phenyl is methyl, methoxy, butyl, halogen or phenyl;

[0009] R 2 is at least one of ethyl, propyl, butyl and benzyl;

[0010] R 3 , R 4 , R 5 Each is independently selected from one of hydrogen, methoxy, methyl, halogen, methyl ester, or R 4 and R 5 A dioxolane structure is formed.

[0011] The chiral β-phosphonocarbonate can be an enantiomer, a non-racemic mixture of enantiomers, or a β-phosphonocarbonate with (R,R) configuration.

[0012] The present invention also provides a method for preparing the chiral β-phosphonocarbonate, comprising:

[0013] Under a hydrogen atmosphere, the hydrogenation precursor and the metal ligand complex shown in formula (II) undergo an asymmetric hydrogenation reaction in an organic solvent system to prepare the chiral β-phosphonocarbonate;

[0014]

[0015] Among them, in formula (I) and formula (II), R 1 , R 2 , R 3 , R 4 , R 5 Same definition as above.

[0016] Preferably, the metal ligand complex is a metal salt and (S)- tBu-PHOX (which can be purchased directly, CAS: 148461-16-9) is obtained by mixing and stirring methanol and hexafluoroisopropanol solution.

[0017] More preferably, the metal salt is nickel acetate, nickel acetate and (S)- t The molar ratio of Bu-PHOX is 1:1-2.

[0018] Preferably, the molar ratio of the metal ligand complex to the hydrogenation precursor is 0.03-0.10:1; and the organic solvent is hexafluoroisopropanol.

[0019] Optionally, the organic solvent is hexafluoroisopropanol.

[0020] Specifically, the reaction temperature of the asymmetric hydrogenation reaction is 40-100° C., and the reaction time is 24-48 hours.

[0021] In the above asymmetric hydrogenation reaction, the products obtained are chiral β-phosphonocarbonates of two configurations, (S, S) and (R, R), wherein the ee value of the chiral β-phosphonocarbonate of (S, S) configuration is >90%.

[0022] Furthermore, the preparation method of the hydrogenated precursor is selected from one of the following methods:

[0023] Method 1:

[0024] (S01) reacting a system comprising β-tetralone or a β-tetralone derivative, carbonate, NaH and tetrahydrofuran at 0-100° C. for 2-12 hours, and preparing a first intermediate through post-treatment;

[0025] (S02) cooling the dichloromethane solution of the first intermediate to -50--80°C, then adding N,N-diisopropylethylamine and trifluoromethanesulfonic anhydride, reacting for 1-12 hours, and then post-treating to obtain the second intermediate;

[0026] (S03) mixing the second intermediate, palladium acetate, 1,4-bis(diphenylphosphino)butane (DPPB) and a phosphine oxide compound, adding dimethyl sulfoxide and N,N-diisopropylethylamine, reacting at 60-100° C. for 1-5 hours, and preparing the hydrogenated precursor through post-treatment;

[0027] The structural formula of β-tetralone derivatives is shown below:

[0028]

[0029] Method 2:

[0030] (S04) reacting a system comprising bromine-substituted β-tetralone, carbonate, NaH and tetrahydrofuran at 0-100° C. for 2-12 h, and preparing a third intermediate through post-treatment;

[0031] (S05) cooling the dichloromethane solution of the third intermediate to -50--80°C, then adding N,N-diisopropylethylamine and trifluoromethanesulfonic anhydride, reacting for 1-12 hours, and then post-treating to obtain a fourth intermediate;

[0032] (S06) mixing the fourth intermediate, tri(dibenzylideneacetone)dipalladium (Pd2(dba)3), DPPB, and a phosphine oxide compound, adding toluene and N,N-diisopropylethylamine, reacting at 60-120° C. for 5-20 h, and preparing a fifth intermediate through post-treatment;

[0033] (S07) mixing the fifth intermediate, cesium carbonate, tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), and BrettPhos ligand (which can be purchased directly, CAS: 1070663-78-3), adding toluene and methanol, reacting at 60-120° C. for 5-10 hours, and preparing the hydrogenated precursor through post-treatment;

[0034] Method 3:

[0035] The fifth intermediate and tetrakis(triphenylphosphine)palladium are mixed, and then tetrahydrofuran and AlMe3 are added, and the mixture is reacted at 60-120° C. for 5-10 hours, and the hydrogenated precursor is prepared through post-treatment;

[0036] Method 4:

[0037] The fifth intermediate, palladium acetate, and 1,4-bis(diphenylphosphine)butane (dppp) are mixed, and then N,N-diisopropylethylamine, toluene, and methanol are added, and the mixture is reacted at 60-120° C. for 5-12 hours. After post-treatment, the hydrogenated precursor is prepared.

[0038] The invention also provides application of the chiral β-phosphonyl carbonate in synthesizing chiral phosphine ligands.

[0039] The present invention also provides a chiral phosphine ligand prepared from the chiral β-phosphonocarbonate.

[0040] Specifically, For example, After recrystallization to 99% optical purity, it was reduced by lithium aluminum hydroxide and introduced into the p-toluenesulfonyl group to obtain the compound Further substitution reaction and phenylsilane redox reaction were carried out using lithium diphenylphosphite to obtain (S,S)-configured

[0041] After recrystallization to 99% optical purity, the isomerization reaction was promoted by dicyclic amidine DBU under thermodynamic conditions to obtain Then, after lithium aluminum tetrahydride reduction reaction, p-toluenesulfonyl group was introduced, and lithium diphenylphosphite was used for substitution reaction and phenylsilane redox reaction to obtain (R, S) configuration.

[0042] The invention also provides application of the chiral phosphine ligand in asymmetric catalytic reaction.

[0043] Compared with the prior art, the present invention has the following beneficial effects:

[0044] The method of the invention adopts an asymmetric hydrogenation method catalyzed by a metal ligand complex, has mild conditions, high yield, is simple and efficient, can obtain the target chiral β-phosphonyl carbonate with high enantioselectivity, the highest yield reaches 99%, and the product ee value is greater than 90%. The target chiral β-phosphonyl carbonate can be used as a precursor to synthesize chiral phosphine ligands, and has broad application prospects in asymmetric catalytic reactions. DETAILED DESCRIPTION

[0045] The present invention will be further described below in conjunction with the examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The operating methods in the following examples that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Contents not described in detail in this specification belong to the prior art known to professionals and technicians in this field.

[0046] Specifically, in the following embodiments, the structural formula and code of the hydrogenated precursor are as follows:

[0047]

[0048] The structural formula and code of chiral β-phosphonocarbonate are as follows:

[0049]

[0050] Example 1 Synthesis of hydrogenated precursor

[0051] This embodiment takes the preparation of hydrogenated precursor 1a (the reaction route is shown below) as an example to explain in detail the preparation method of hydrogenated precursors (1a-1o, 1s-1z) of the present invention:

[0052]

[0053] Step 1: Take a 50 mL dry round-bottom flask with a magnetic rod, add NaH (60w%, 324 mg, 8.4 mmol, 2.1 equiv.), dibutyl carbonate (1.9 mL, 16.0 mmol, 4.0 equiv.), tetrahydrofuran (10 mL) under nitrogen atmosphere, stir at 0°C for 5 minutes, slowly add β-tetralone (0.8 M in THF, 4.0 mmol, 1.0 equiv.) solution dropwise, and continue stirring at 0°C for 10 minutes. After the mixture is refluxed at 100°C for 12 hours, the reaction progress is monitored by TLC. After the reaction is completed, saturated ammonium chloride (10 mL) is used to quench the reaction and extract with tert-butyl methyl ether (TBME) (3×20 mL). The combined organic layer is washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain β-ketoester intermediate S2, which is directly used in the next step.

[0054] Step 2: Take a 50 mL dry round-bottom flask with a magnetic rod, add the β-ketoester intermediate S2 obtained in the previous step and dichloromethane DCM (10 mL) under a nitrogen atmosphere, cool to -78 ° C and add DIPEA (0.96 mL, 8.0 mmol, 2.0 equiv.). Slowly add trifluoromethanesulfonic anhydride Tf2O (0.96 mL, 6.0 mmol, 1.5 equiv.) dropwise, and stir at -78 ° C for 4 hours. After the raw material is completely converted, add saturated sodium bicarbonate solution (10 mL) to quench the reaction, extract with dichloromethane (3×10 mL), and combine the organic phases. The organic phase is washed once with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the crude product is separated and purified by column chromatography to obtain the coupling precursor.

[0055] Step 3: The coupling precursor (739 mg, 2.2 mmol, 1.0 equiv), palladium acetate (45.2 mg, 0.2 mmol, 0.05 equiv.), DPPB (85.3 mg, 0.2 mmol, 0.05 equiv.), and diphenylphosphine oxide were placed in a 50 ml round-bottom flask and replaced with nitrogen three times. DMSO (20 mL) and DIPEA (2.16 ml, 18.0 mmol, 4.5 equiv.) were added and stirred at 100°C for 2 hours. Water (40 mL) was added to quench the reaction, and the mixture was extracted with methyl tert-butyl ether (3×20 mL). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated by distillation under reduced pressure. The target hydrogenation precursor was obtained by column chromatography separation and purification.

[0056] When preparing hydrogenated precursors 1b-1m, based on the above steps, the following corresponding phosphine oxide compounds are used as raw materials, and other conditions remain unchanged:

[0057]

[0058] When preparing hydrogenated precursors 1n, 1o, 1s, and 1t, on the basis of the above steps and methods, the corresponding β-tetralone derivatives are used instead of β-tetralone; when preparing hydrogenated precursors 1u-1w, on the basis of the above steps and methods, the corresponding β-tetralone derivatives are used instead of β-tetralone, and the corresponding carbonates (diethyl carbonate, dipropyl carbonate, dibenzyl carbonate) are used instead of dibutyl carbonate; when preparing hydrogenated precursors 1x-1z, on the basis of the above steps and methods, the corresponding carbonates (diethyl carbonate, dipropyl carbonate, dibenzyl carbonate) are used instead of dibutyl carbonate, and other conditions remain unchanged.

[0059] The yields and characterization data of the hydrogenated precursors 1a-1o, 1s-1z prepared in this example are as follows:

[0060] Hydrogenated precursor 1a: 1.6 g, 74% yield.

[0061] 1 H NMR (600MHz, CDCl3) δ7.84–7.74(m,4H),7.59–7.53(m,2H),7.51–7.45(m,4H),7.28(d,J=7.6Hz,1H),7.26(s,1H),7.25–7.21(m,1H),7.15 (d,J=7.2Hz,1H),4.05–3.99(m,2H),2.80(t,J=7.8Hz,2H),2.39–2.28(m,2H),1.56–1.50(m,2H),1.33–1.23(m,3H),0.85(t,J=7.4Hz,3H).

[0062] 13 C NMR (150MHz, CDCl3) δ167.74(d,J=7.8Hz), 144.06(d,J=5.8Hz), 136.1(d,J =2.3Hz),132.2(d,J=10.1Hz),132.1(d,J=2.8Hz),131.9,131.1,130.6(d,J =12.9Hz), 129.9, 128.8 (d, J = 95.1Hz), 128.5 (d, J = 12.1Hz), 127.5 (d, J = 91. 9Hz), 125.5, 65.58, 30.2, 27.2 (d, J = 6.4Hz), 24.7 (d, J = 9.6Hz), 19.2, 13.7.

[0063] HRMS(ESI)C 19 H 24BrO6[M+H]+:calcd 427.0756, found 427.0760.

[0064] Hydrogenated precursor 1b: 510 mg, 50% yield.

[0065] 1 H NMR (600MHz, CDCl3) δ7.82–7.75(m,4H),7.31–7.27(m,1H),7.25(dd,J=7.1,1.7Hz,2H),7.21–7.15(m,5H),4.02(t, J=6.8Hz,2H),2.81(t,J=7.9Hz,2H),2.40–2.27(m,2H),1.56–1.51(m,2H),1.33–1.25(m,2H),0.87(t,J=7.4Hz,3H).

[0066] 13 C NMR (150MHz, CDCl3) δ167.6 (d, JC-P=7.7Hz), 165.2 (dd, JC-F=254.4, J=3.2Hz), 14 4.4(d,J=6.0Hz),136.0(d,JC-P=2.2Hz),135.0(dd,J=11.6,JC-F=8.7Hz),130.3(d ,J=13.0Hz),130.1,128.1(J=386.9),127.9,127.6(d,J=3.4Hz),127.2,126.9(d, JC-F=3.4Hz),125.5,65.7,30.2,27.1(d,J=6.5Hz),24.5(d,J=9.6Hz),19.1,13.7.

[0067] 19 F NMR: δ-106.0.

[0068] 31 P NMRδ26.9.

[0069] HRMS(ESI)for:C 27 H 26 F2O3P[M+H]+:calcd 467.1588, found 467.1591.

[0070] Hydrogenated precursor 1c: 583 mg, 68% yield.

[0071] 11H NMR (600 MHz, CDCl3): δ 7.74–7.67 (m, 4H), 7.50–7.45 (m, 4H), 7.33–7.27 (m, 1H), 7.25 (dd, J=6.6, 1.6 Hz, 2H), 7.17 (d, J=7.3 Hz, 1H), 4.00 (t, J=6.8 Hz, 2H), 2.80 (t, J=7.9 Hz, 2H), 2.38–2.27 (m, 2H), 1.56–1.49 (m, 2H), 1.34–1.23 (m, 3H), 0.87 (t, J=7.4 Hz, 3H).

[0072] 13 13C NMR (150 MHz, CDCl3): 167.9 (d, J=7.5 Hz), 143.6 (d, JC-P=5.8 Hz), 142.5 (d, JC-P=2.8 Hz), 136.1 (d, J=2.2 Hz), 132.3 (d, JC-P=10.5 Hz), 130.7 (d, JC-P=12.7 Hz), 129.4 (d, J=113.4 Hz), 129.7, 129.2 (d, JC-P=12.7 Hz), 128.4 (d, JC-P=107.1 Hz), 127.8, 127.1, 125.4, 65.6, 30.2, 27.2 (d, JC-P=6.4 Hz), 24.7 (d, JC-P=9.5 Hz), 21.6, 19.2, 13.7.

[0073] 31 31P NMR: δ 27.2.

[0074] HRMS (ESI) for: C 27 H 26 Cl2O3P [M+H] + : calcd 499.0997, found 499.1022.

[0075] Hydrogenation precursor 1d: 830 mg, 75% yield.

[0076] 1 1H NMR (600 MHz, CDCl3): δ 7.65 (dd, J=16.5, 7.7 Hz, 4H), 7.46 (t, J=7.6 Hz, 2H), 7.36 (t, J=7.4 Hz, 1H), 7.21 (d, J=7.8 Hz, 2H), 6.73 (s, 1H), 6.32 (s, 1H), 5.90 (s, 2H), 3.50 (s, 3H), 2.84 (dd, J=9.6, 6.5 Hz, 2H), 2.70 (dd, J=9.7, 6.4 Hz, 2H).

[0077] 13 C NMR (150MHz, CDCl3): δ 167.8, 144.9, 144.1, 140.0, 136.1, 132.8, 130.6, 130.1 (d, J = 87.7Hz), 129.9, 129.0, 129.0, 128.9 (d, J = 79. 1Hz), 128.2, 127.5 (d, J = 91.5Hz), 127.3, 127.2 (d, J = 10.2Hz), 125.5, 65.7, 30.3, 27.3 (d, J = 6.5Hz), 24.7 (d, J = 9.6Hz), 19.2, 13.7.

[0078] 31 P NMR: δ 28.3.

[0079] HRMS(ESI)for:C 39 H 36 O3P[M+H] + :calcd 583.2407, found 583.2417.

[0080] Hydrogenated precursor 1e: 570 mg, 77% yield.

[0081] 1 H NMR (600MHz, CDCl3): δ7.80–7.58(m,4H),7.34–7.20(m,7H),7.19–7.10(m,1H),4.11–3.95(m,2H),2.78(t, J=7.9Hz,2H),2.39–2.25(m,2H),1.64–1.48(m,2H),1.29(dtd,J=14.9,7.4,5.5Hz,2H),0.94–0.82(m,3H).

[0082] 13 C NMR (150 MHz, CDCl3): 167.9 (d, J C-P =7.7Hz),143.5(d,J C-P =5.6Hz),143.5(d,J C-P =5.6Hz),142.4(d,J C-P =2.8Hz),136.09(d,J C-P =2.4Hz),136.1(d,J C-P =2.4Hz),132.3(d,J C-P =10.3Hz), 130.7(d,J C-P=12.9Hz),129.8,129.7,129.2(d,J C-P =12.6Hz),128.4(d,J C-P =107.0Hz),127.4(d,J C-P =90.1Hz),65.6,30.2,27.2(d,J C-P =6.4Hz),24.7(d,J C-P =9.5Hz),21.6,19.2,13.7.

[0083] 31 P NMR: δ 28.4.

[0084] HRMS(ESI)for:C 29 H 32 O3P[M+H] + :calcd 459.2089, found 459.2094.

[0085] Hydrogenated precursor 1f: 700 mg, 60% yield.

[0086] 1 H NMR (600MHz, CDCl3): δ7.74–7.66(m,4H),7.25–7.20(m,2H),7.14(dd,J=7.5,1.6Hz,1H),7.00–6.95(m,4H),4.03(t,J=6. 8Hz,2H),3.85(s,6H),2.81–2.74(m,2H),2.36–2.28(m,2H),1.56–1.51(m,2H),1.34–1.24(m,2H),0.87(t,J=7.4Hz,3H).

[0087] 13 C NMR (150MHz, CDCl3): δ168.0(d,J C-P =7.8Hz),162.5(d,J C-P =2.8Hz),143.2(d,J C-P =6.0Hz),136.1(d,J C-P =2.3Hz),134.2(d,J C-P =11.5Hz),130.7(d,J C-P =12.8Hz),130.1,129.7,129.4,127.4(d,J C-P =94.7Hz),125.3,122.9(d,J C-P =111.2Hz),114.0(d,JC-P =13.2Hz), 65.6, 55.4, 30.2, 27.2 (d, J = 6.4Hz), 24.6 (d, J = 9.4Hz), 19.2, 13.7.

[0088] 31 P NMR: δ 27.9.

[0089] HRMS(ESI)for:C 29 H 32 O5P[M+H] + :calcd 491.1987, found 491.1993.

[0090] Hydrogenated precursor 1g: 830mg, 56% yield.

[0091] 1 H NMR (600MHz, CDCl3): δ7.71(dd,J=11.8,8.2Hz,4H),7.48(dd,J=8.4,2.6Hz,4H),7.26–7.20(m,4H),7.14(d,J=7.3Hz,1H),3.98(t,J =6.8Hz,2H),2.80(t,J=7.9Hz,2H),2.35(q,J=7.6Hz,2H),1.55–1.49(m,2H),1.33(s,18H),1.30–1.24(m,2H),0.85(t,J=7.4Hz,3H).

[0092] 13 C NMR (150MHz, CDCl3): δ169.6,147.5,146.0,145.5,141.6,136.6,132.2,129.6 ,128.5,128.1,125.2,108.8,108.0,101.0,51.2,37.8,28.4,25.5,24.4,13.8.

[0093] 31 P NMR: δ 28.3.

[0094] HRMS(ESI)for:C 35 H 44 O3P[M+H] + :calcd 543.3028, found 543.3024.

[0095] Hydrogenation precursor 1h: 620 mg, 63% yield.

[0096] 11H NMR (600 MHz, CDCl3): δ 7.62 (dd, J = 14.3, 7.6 Hz, 2H), 7.53–7.46 (m, 2H), 7.25–7.17 (m, 3H), 7.14 (d, J = 7.5 Hz, 1H), 7.06–6.99 (m, 2H), 6.92 (dd, J = 8.3, 5.2 Hz, 2H), 4.20 (t, J = 7.0 Hz, 2H), 3.71 (s, 6H), 2.78 (t, J = 7.8 Hz, 2H), 2.40 (q, J = 8.3 Hz, 2H), 1.58–1.45 (m, 2H), 1.35–1.22 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H).

[0097] 13 13C NMR (150 MHz, CDCl3): δ 168.2 (d, J C-P = 7.9 Hz), 161.1 (d, J C-P = 2.7 Hz), 142.2 (d, J C-P = 6.2 Hz), 136.6 (d, J C-P = 2.5 Hz), 134.3 (d, J C-P = 8.3 Hz), 133.5 (d, J C-P = 2.2 Hz), 132.2 (d, J C-P = 100.4 Hz), 131.6, 131.5, 129.0, 127.1 (d, J C-P = 77.5 Hz), 125.3, 120.7 (d, J C-P = 12.3 Hz), 120.5 (d, J C-P = 107.0 Hz), 110.8 (d, J C-P = 6.4 Hz), 65.3, 55.4, 30.2, 27.8 (d, J C-P = 6.9 Hz), 25.0 (d, J C-P = 10.7 Hz), 19.2, 13.8.

[0098] 31 31P NMR: δ 24.8.

[0099] HRMS (ESI) for: C 29 H 31 O5P [M + H] + : calcd 491.1987, found 491.1996.

[0100] Hydrogenation precursor 1i: 872 mg, 81% yield.

[0101] 1 1H NMR (600 MHz, CDCl3): δ 7.67 (d, J = 12.5 Hz, 2H), 7.54–7.48 (m, 2H), 7.38–7.31 (m, 4H), 7.30 (dd, J = 7.5, 1.6 Hz, 1H), 7.27–7.20 (m, 2H), 7.14 (dd, J = 7.3, 1.6 Hz, 1H), 4.06 (t, J = 6.8 Hz, 2H), 2.79 (t, J = 7.9 Hz, 2H), 2.38 (s, 6H), 2.32 (q, J = 7.6 Hz, 2H), 1.55 (m, 2H), 1.32–1.24 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H).

[0102] 13 13C NMR (150 MHz, CDCl3): δ 167.8 (d, J = 7.6 Hz), 143.8 (d, J = 5.6 Hz), 138.4 (d, J = 12.0 Hz), 136.1 (d, J = 2.3 Hz), 132.9 (d, J = 2.7 Hz), 132.6 (d, J = 9.8 Hz), 131.4 (d, J = 104.6 Hz), 130.6 (d, J = 12.9 Hz), 129.8, 129.2 (d, J = 10.3 Hz), 129.1 (d, J = 95.1 Hz), 128.3 (d, J = 13.0 Hz), 127.8, 127.1, 125.4, 65.5, 30.2, 27.20 (d, J = 6.3 Hz), 24.8 (d, J = 9.7 Hz), 21.4, 19.2, 13.7.

[0103] 31 31P NMR: δ 28.9.

[0104] HRMS (ESI) for: C 29 H 32 O3P [M + H]: calcd 459.2089, found 459.2092.

[0105] Hydrogenation precursor 1j: 680 mg, 64% yield.

[0106] 1H NMR (600MHz, CDCl3): δ7.40–7.34(m,4H),7.33–7.27(m,3H),7.26–7.20(m,2H),7.15(dd,J=7.4,1.5Hz,1H),7.10–7.05(m,2H),4.03(t ,J=6.8Hz,2H),3.81(s,6H),2.80(t,J=7.9Hz,2H),2.34(q,J=7.7Hz,2H),1.57–1.47(m,2H),1.31–1.22(m,3H),0.85(t,J=7.4Hz,3H).

[0107] 13 C NMR (150MHz, CDCl3): δ167.7 (d, J = 7.7Hz), 159.6 (d, J = 15.0Hz), 144.0 (d, J = 5.9Hz), 13 6.1(d,J=2.3Hz),133.2,132.4,130.6(d,J=12.9Hz),129.9,129.6(d,J=14.4Hz),128.9 (d,J=95.4Hz),127.5(d,J=90.6Hz),125.5,124.4(d,J=10.2Hz),118.4(d,J=2.7Hz),1 16.8(d,J=11.1Hz),65.6,55.5,30.2,27.2(d,J=6.4Hz),24.8(d,J=9.5Hz),19.2,13.7.

[0108] 31 P NMR: δ 28.9.

[0109] HRMS(ESI)for:C 29 H 32 O5P[M+H] + :calcd 491.1987, found 491.1996.

[0110] Hydrogenated precursor 1k: 210 mg, 36% yield.

[0111] 11H NMR (600 MHz, CDCl3): δ 7.38 (dd, J = 12.4, 1.7 Hz, 4H), 7.32–7.27 (m, 1H), 7.26–7.20 (m, 2H), 7.19–7.12 (m, 3H), 4.06 (t, J = 6.8 Hz, 2H), 2.79 (dd, J = 9.1, 6.6 Hz, 2H), 2.33 (m, 14H), 1.59–1.50 (m, 2H), 1.32–1.26 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H).

[0112] 13 13C NMR (150 MHz, CDCl3): δ 167.9 (d, J = 7.7 Hz), 143.5 (d, J = 5.8 Hz), 138.1 (d, J = 12.7 Hz), 136.1 (d, J = 2.3 Hz), 133.7 (d, J = 2.8 Hz), 131.3 (d, J = 103.9 Hz), 130.8 (d, J = 12.8 Hz), 129.8, 129.7, 129.7, 129.0, 127.4 (d, J = 90.7 Hz), 125.4, 65.5, 30.3, 27.3 (d, J = 6.4 Hz), 24.8 (d, J = 9.5 Hz), 21.3, 19.2, 13.7.

[0113] 31 31P NMR: δ 29.1.

[0114] HRMS (ESI) for: C 31 H 36 O3P [M + H] + : calcd 487.2402, found 487.2405.

[0115] Hydrogenation precursor 1l: 550 mg, 71% yield.

[0116] 1 1H NMR (600 MHz, CDCl3): δ 7.71 (s, 2H), 7.32 (d, J = 7.6 Hz, 1H), 7.27–7.21 (m, 2H), 7.20–7.13 (m, 3H), 6.57–6.51 (m, 2H), 4.33 (t, J = 6.9 Hz, 2H), 2.85–2.73 (m, 2H), 2.45–2.31 (m, 2H), 1.74–1.62 (m, 2H), 1.45–1.32 (m, 2H), 0.91 (t, J = 7.5 Hz, 3H).

[0117] 1313C NMR (150 MHz, CDCl3): δ 167.6 (d, J = 8.5 Hz), 148.4 (d, J = 7.9 Hz), 146.8 (d, J = 147.6 Hz), 145.4 (d, J = 6.5 Hz), 136.3 (d, J = 2.4 Hz), 130.3 (d, J = 14.2 Hz), 130.1, 127.9, 127.1, 126.3, 125.5, 125.4, 123.2 (d, J = 20.6 Hz), 65.8, 30.3, 27.14 (d, J = 7.3 Hz), 23.22 (d, J = 11.2 Hz), 19.2, 13.7.

[0118] 31 31P NMR: δ -0.23.

[0119] HRMS (ESI) for: C 23 H 24 O5P [M + H] + : calcd 411.1361, found 411.1358.

[0120] Hydrogenation precursor 1m: 760 mg, 42% yield.

[0121] 1 1H NMR (600 MHz, CDCl3): δ 7.29 (t, J = 7.3 Hz, 1H), 7.25–7.16 (m, 3H), 4.35 (t, J = 6.9 Hz, 2H), 3.77 (s, 3H), 3.75 (s, 3H), 2.85 (t, J = 8.0 Hz, 2H), 2.50 (q, J = 8.1 Hz, 2H), 1.78–1.71 (m, 2H), 1.48–1.40 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H).

[0122] 13 13C NMR (150 MHz, CDCl3): δ 168.0 (d, J = 9.3 Hz), 144.9 (d, J = 10.3 Hz), 136.4 (d, J = 2.7 Hz), 130.0, 129.9 (d, J = 17.5 Hz), 128.0, 127.1, 125.7, 122.9 (d, J = 183.0 Hz), 65.8, 52.6 (d, J = 5.3 Hz), 30.4, 27.0 (d, J = 7.3 Hz), 23.4 (d, J = 7.7 Hz), 19.2, 13.7.

[0123] 31 31P NMR: δ 19.2.

[0124] HRMS(ESI)for:C 17 H 23 O5PNa[M+Na] + :calcd 361.1187,found361.1177.

[0125] Hydrogenated precursor 1n: 1200 mg, 52% yield.

[0126] 1 H NMR (600MHz, CDCl3): δ7.82–7.74(m,4H),7.57–7.52(m,2H),7.50–7.44(m,4H),7.19(t,J=8.1Hz,1H),6.90(dd,J=17.5,8.0Hz,2H ),4.02(t,J=6.8Hz,2H),3.81(s,3H),2.79(t,2H),2.33–2.25(m,2H),1.58–1.49(m,2H),1.32–1.24(m,2H),0.85(t,J=7.4Hz,3H).

[0127] 13 C NMR (150MHz, CDCl3): δ167.9 (d, J = 7.8Hz), 156.1, 144.1 (d, J = 5.9Hz), 132. 2(d,J=10.1Hz),132.0(d,J=2.8Hz),131.5(d,J=104.8Hz),131.4(d,J=12.7 Hz),128.8(d,J=94.5Hz),128.5(d,J=12.2Hz),127.2,124.3(d,J=2.3Hz), 118.0,112.2,65.6,55.6,30.2,24.2(d,J=9.4Hz),19.3(d,J=6.4Hz),13.7.

[0128] 31 P NMR: δ 28.7.

[0129] HRMS(ESI)for:C 28 H 30 O4P[M+H] + :calcd 461.1882,found 461.1888.

[0130] Hydrogenated precursor 1o: 370 mg, 80% yield.

[0131] 1H NMR (600MHz, CDCl3): δ7.83–7.75(m,4H),7.58–7.53(m,2H),7.51–7.44(m,4H),7.06(d,J=8.3Hz,1H),6.88(d,J=2.6Hz,1H),6.82(dd,J=8.2,2.6Hz, 1H),4.05(t,J=6.8Hz,2H),3.76(s,3H),2.72(dd,J=9.0,6.7Hz,2H),2.33 –2.25(m,2H),1.58–1.49(m,2H),1.33–1.25(m,2H),0.85(t,J=7.4Hz,3H).

[0132] 13 C NMR (150MHz, CDCl3): δ167.7(d,J=7.8Hz), 158.6(d,J=1.7Hz), 144.0(d,J=5 .7Hz),132.2(d,J=10.1Hz),132.1(d,J=2.8Hz),131.9,131.3(d,J=13.0Hz) ,131.0,129.4(d,J=94.8Hz),128.5(d,J=12.1Hz),128.2(d,J=2.3Hz),115. 4,111.0,65.6,55.4,30.2,26.3(d,J=6.5Hz),25.2(d,J=9.5Hz),19.2,13.7.

[0133] 31 P NMR: δ 28.7.

[0134] HRMS(ESI)for:C 28 H 30 O4P[M+H] + :calcd 461.1882, found 461.1888.

[0135] Hydrogenated precursor 1s: 460 mg, 25% yield.

[0136] 11H NMR (600 MHz, CDCl3): δ 7.78 (dd, J = 12.2, 7.6 Hz, 4H), 7.56 (t, J = 7.5 Hz, 2H), 7.52–7.41 (m, 4H), 7.33–7.26 (m, 1H), 6.96–6.82 (m, 2H), 4.03 (t, J = 6.8 Hz, 2H), 2.78 (t, J = 7.9 Hz, 2H), 2.31 (q, J = 7.8 Hz, 2H), 1.52 (q, J = 7.2 Hz, 2H), 1.28 (s, 2H), 0.85 (t, J = 7.4 Hz, 3H).

[0137] 13 13C NMR (150 MHz, CDCl3): δ 167.6 (d, J = 7.5 Hz), 163.3 (d, J = 251.0 Hz), 143.2 (d, J = 6.0 Hz), 139.0 (dd, J = 8.2, 2.3 Hz), 132.2, 132.2 (d, J = 10.0 Hz), 131.3 (d, J = 104.9 Hz), 128.6 (d, J = 12.1 Hz), 128.0 (dd, J = 95.6, 2.4 Hz), 127.5 (d, J = 8.9 Hz), 126.8 (dd, J = 13.0, 3.1 Hz), 115.0 (d, J = 22.0 Hz), 113.9 (d, J = 21.6 Hz), 65.7, 30.2, 27.4 (d, J = 6.7 Hz), 24.4 (d, J = 9.7 Hz), 19.1, 13.7.

[0138] 1 31P NMR: δ 28.5.

[0139] HRMS (ESI) for: C 28 H 30 O3P [M + H] + : calcd 445.1933, found 445.1938.

[0140] Hydrogenation precursor 1t: 960 mg, 70% yield.

[0141] 11H NMR (600 MHz, CDCl3): δ 7.77 (dd, J = 12.0, 7.5 Hz, 4H), 7.57 (dd, J = 8.1, 6.4 Hz, 2H), 7.51–7.44 (m, 4H), 7.24–7.18 (m, 2H), 7.15 (s, 1H), 4.02 (t, J = 6.8 Hz, 2H), 2.77 (t, J = 7.9 Hz, 2H), 2.31 (q, J = 7.7 Hz, 2H), 1.55–1.48 (m, 2H), 1.27 (q, J = 7.5 Hz, 2H), 0.85 (t, J = 7.4 Hz, 3H).

[0142] 13 13C NMR (150 MHz, CDCl3): δ 167.4 (d, J = 7.5 Hz), 143.1 (d, J = 5.9 Hz), 137.9 (d, J = 2.3 Hz), 135.4, 132.2, 132.2 (d, J = 10.1 Hz), 131.3 (d, J = 104.9 Hz), 129.8, 129.1 (d, J = 5.9 Hz), 129.0, 128.5 (d, J = 12.2 Hz), 127.5 (d, J = 91.6 Hz), 126.7, 65.7, 30.1, 27.1 (d, J = 6.6 Hz), 24.5 (d, J = 9.7 Hz), 19.1, 13.7.

[0143] 31 31P NMR: δ 28.4.

[0144] HRMS (ESI) for: C 27 H 27 O3FP [M + H] + : calcd 449.1682, found 449.1684.

[0145] Hydrogenation precursor 1u: 470 mg, 67% yield.

[0146] 1 1H NMR (600 MHz, CDCl3): δ 7.81–7.73 (m, 4H), 7.58–7.52 (m, 2H), 7.51–7.44 (m, 4H), 6.82 (s, 1H), 6.64 (s, 1H), 5.95 (s, 2H), 4.07 (q, J = 7.2 Hz, 2H), 2.69 (dd, J = 9.4, 6.7 Hz, 2H), 2.30–2.23 (m, 2H), 1.18 (t, J = 7.2 Hz, 3H).

[0147] 13C NMR (150MHz, CDCl3): δ167.7 (d, J = 7.7Hz), 148.6, 146.6, 143.8 (d, J = 6.0Hz), 132.2 (d, J = 9.9Hz), 132.0 (d, J = 2.6Hz), 131.3, 131.3 (d, J = 2.5 Hz), 128.5 (d, J = 12.4Hz), 126.3 (d, J = 96.9Hz), 124.2 (d, J = 13.5Hz), 108.4, 106.0, 101.4, 61.7, 27.6 (d, J = 6.6Hz), 24.8 (d, J = 9.7Hz), 13.8.

[0148] 31 P NMR: δ 28.7.

[0149] HRMS(ESI)for:C 26 H 24 O5P[M+H] + :calcd 447.1361,found 447.1362.

[0150] Hydrogenated precursor 1v: 1100 mg, 90% yield.

[0151] 1 H NMR (600MHz, CDCl3): δ7.83–7.75(m,4H),7.59–7.53(m,2H),7.51–7.45(m,4H),6.67(s,1H),4.12(q,J=7.1Hz,2 H),3.78(s,3H),3.68–3.58(m,3H),2.75(t,J=7.9Hz,2H),2.26(q,J=7.8Hz,2H),2.16(s,3H),1.28–1.14(m,3H).

[0152] 13 C NMR (150MHz, CDCl3): δ167.8 (d, J = 7.8Hz), 156.5 (d, J = 170.8Hz), 144.0 (d, J = 6.0Hz), 132.2, 132.2, 132.1 (d, J = 2.7Hz), 131.9, 131.2, 129.0 (d ,J=13.0Hz),128.9,128.5,128.5,128.2,122.2,121.4(d,J=2.5Hz),10 3.6, 61.6, 60.4, 55.7, 24.8 (d, J = 9.7Hz), 20.1 (d, J = 6.4Hz), 13.9, 9.3.

[0153] 31 P NMR: δ 28.7.

[0154] HRMS(ESI)for:C 28 H 30 O5P[M+H] + :calcd 477.1831, found 477.1833.

[0155] Hydrogenated precursor 1w: 550 mg, 70% yield.

[0156] 1 H NMR (600MHz, CDCl3): δ7.81–7.75(m,4H),7.58–7.53(m,2H),7.51–7.45(m,4H),6.88(s,1H),6.67(s,1H),4.09(q, J=7.1Hz,2H),3.89(s,3H),3.83(s,3H),2.73(dd,J=9.3,6.7Hz,2H),2.29(q,J=7.7Hz,2H),1.18(t,J=7.1Hz,3H).

[0157] 13 C NMR (150MHz, CDCl3): δ167.8 (d, J = 7.6Hz), 150.2, 147.6, 143.7 (d, J = 6.2Hz), 132.2, 132.2, 132.1, 132.0 (d, J = 2.7Hz), 131.4, 129.6 (d, J = 2.5Hz), 128.5(d,J=12.1Hz),126.2(d,J=96.6Hz),123.0(d,J=13.3Hz),111.0,10 8.9, 61.6, 56.0 (d, J = 3.4Hz), 27.1 (d, J = 6.5Hz), 24.9 (d, J = 9.7Hz), 13.8.

[0158] 31 P NMR: δ 28.8.

[0159] HRMS(ESI)for:C 27 H 28 O5P[M+H] + :calcd 463.1674, found 463.1679.

[0160] Hydrogenated precursor 1x: 2100 mg, 92% yield.

[0161] 11H NMR (600 MHz, CDCl3): δ 7.82–7.76 (m, 4H), 7.58–7.53 (m, 2H), 7.51–7.45 (m, 4H), 7.28 (td, J = 7.8, 1.5 Hz, 2H), 7.23 (td, J = 7.5, 1.5 Hz, 1H), 7.17–7.13 (m, 1H), 4.08 (q, J = 7.2 Hz, 2H), 2.80 (t, J = 7.8 Hz, 2H), 2.37–2.30 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H).

[0162] 13 13C NMR (150 MHz, CDCl3): δ 167.6 (d, J = 7.5 Hz), 143.9 (d, J = 5.9 Hz), 136.1 (d, J = 2.3 Hz), 132.2 (d, J = 10.1 Hz), 132.1 (d, J = 2.8 Hz), 131.9, 131.1, 130.5 (d, J = 12.9 Hz), 129.9, 129.3, 128.6, 128.5, 127.8, 127.1, 125.4, 61.6, 27.2 (d, J = 6.5 Hz), 24.7 (d, J = 9.6 Hz), 13.8.

[0163] 31 31P NMR: δ 28.6.

[0164] HRMS (ESI) for: for: C 25 H 24 O3P [M + H] + : calcd 403.1463, found 403.1468.

[0165] Hydrogenation precursor 1y: 300 mg, 73% yield.

[0166] 1 1H NMR (600 MHz, CDCl3): δ 7.83–7.75 (m, 4H), 7.56 (td, J = 7.3, 1.4 Hz, 2H), 7.48 (dt, J = 7.6, 3.8 Hz, 4H), 7.28 (d, J = 7.8 Hz, 2H), 7.25–7.21 (m, 1H), 7.15 (d, J = 7.2 Hz, 1H), 3.98 (t, J = 6.8 Hz, 2H), 2.80 (t, J = 7.8 Hz, 2H), 2.34 (q, J = 7.6 Hz, 2H), 1.61–1.56 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H).

[0167] 1313C NMR (150 MHz, CDCl3): δ 167.8 (d, J = 7.8 Hz), 144.1 (d, J = 5.7 Hz), 136.1 (d, J = 2.3 Hz), 132.2 (d, J = 10.1 Hz), 132.1 (d, J = 2.7 Hz), 131.9, 131.0, 130.6 (d, J = 12.9 Hz), 129.9, 129.1, 128.5 (d, J = 12.1 Hz), 128.4, 127.8, 127.1, 125.5, 67.3, 27.2 (d, J = 6.4 Hz), 24.7 (d, J = 9.6 Hz), 21.6, 10.4.

[0168] 31 31P NMR: δ 28.6.

[0169] HRMS (ESI) for: for: C 26 H 26 O3P [M + H] + : calcd 417.1619, found 417.1613.

[0170] Hydrogenation precursor 1z: 1100 mg, 49% yield.

[0171] 1 1H NMR (600 MHz, CDCl3): δ 7.82–7.75 (m, 4H), 7.55 (td, J = 7.4, 1.6 Hz, 2H), 7.46 (td, J = 7.6, 2.8 Hz, 4H), 7.31–7.26 (m, 5H), 7.25–7.20 (m, 2H), 7.16 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 7.4 Hz, 1H), 5.12 (s, 2H), 2.77 (t, J = 8.0 Hz, 2H), 2.30 (q, J = 7.7 Hz, 2H).

[0172] 13 13C NMR (150 MHz, CDCl3): δ 167.6 (d, J = 7.8 Hz), 143.9 (d, J = 5.5 Hz), 135.9 (d, J = 2.3 Hz), 135.4, 132.3, 132.2, 132.1, 132.1, 131.7, 130.9, 130.4 (d, J = 12.8 Hz), 129.9, 129.4, 128.8, 128.6, 128.5, 128.3, 128.1, 127.8, 127.1, 125.5, 67.6, 27.1 (d, J = 6.5 Hz), 24.7 (d, J = 9.7 Hz).

[0173] 31 P NMR: δ 28.5.

[0174] HRMS(ESI)for:for:C 30 H 26 O3P[M+H] + :calcd 465.1619,found465.1622.

[0175] Example 2 Synthesis of hydrogenated precursor

[0176] The synthetic route of the hydrogenated precursor 1p is as follows:

[0177]

[0178] Take a 50 mL dry round-bottom flask with a magnetic rod, under a nitrogen atmosphere, add NaH (60w%, 324 mg, 8.4 mmol, 2.1 equiv.), dibutyl carbonate (1.9 mL, 16.0 mmol, 4.0 equiv.), tetrahydrofuran (10 mL), stir at 0 ° C for 5 minutes, slowly add compound S3 (0.8M in THF, 4.0 mmol, 1.0 equiv.) solution, and continue stirring at 0 ° C for 10 minutes. After the mixture is refluxed at 100 ° C and stirred for 12 hours, the reaction progress is monitored by TLC. After the reaction is completed, saturated ammonium chloride (10 mL) is used to quench the reaction and extract with methyl tert-butyl ether TBME (3×20 mL). The combined organic layer is washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain compound S4, which is directly used in the next step.

[0179] Take a 50 mL dry round-bottom flask with a magnetic rod, add compound S4 obtained in the previous step and dichloromethane DCM (10 mL) under a nitrogen atmosphere, cool to -78 ° C and add DIPEA (0.96 mL, 8.0 mmol, 2.0 equiv.). Slowly add trifluoromethanesulfonic anhydride Tf2O (0.96 mL, 6.0 mmol, 1.5 equiv.) dropwise, and stir at -78 ° C for 4 hours. After the raw material is completely converted, add saturated sodium bicarbonate solution (10 mL) to quench the reaction, extract with dichloromethane (3×10 mL), and combine the organic phases. The organic phase is washed once with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the crude product is separated and purified by column chromatography to obtain coupling precursor S5.

[0180] Compound S5 (2.5 g, 5.5 mmol, 1.0 equiv.), Pd2(dba)3 (125 mg, 0.14 mmol, 0.025 equiv.), DPPB (113 mg, 0.27 mmol, 0.05 equiv.), diphenylphosphine oxide (1.43 g, 7.1 mmol, 1.3 equiv.) were added to a 100 mL round-bottom flask, and the atmosphere was replaced with nitrogen three times. Toluene (45 mL) and DIPEA (1.3 mL, 10.4 mmol, 2.0 equiv.) were added, and the mixture was stirred at 110° C. for 20 hours. After the raw materials were consumed, the reaction solution was concentrated, and the crude product was separated and purified by column chromatography to obtain a white solid compound S6 (2.2 g, 80%).

[0181] Take a 20 mL round-bottom flask, add compound S6 (400 mg, 0.8 mmol, 1.0 equiv.), cesium carbonate (392 mg, 1.2 mmol, 1.5 equiv.), Pd2(dba)3 (12 mg, 0.013 mmol, 0.016 equiv.), BrettPhos ligand (18 mg, 0.034 mmol, 0.042 equiv.), replace with nitrogen three times. Add toluene (8 mL) and methanol (1 mL), stir at 85 ° C for 10 hours. After reduced pressure concentration, separate and purify by column chromatography to obtain hydrogenated precursor 1p.

[0182] Hydrogenated precursor 1p: 370 mg, 80% yield.

[0183] 1 H NMR (500MHz, CDCl3): δ7.81–7.74(m,4H),7.57–7.52(m,2H),7.50–7.44(m,4H),7.21(d,J=8.6Hz,1H),6.74(dd,J=8.6,2.7Hz,1H),6.69(d,J =2.6Hz,1H),3.99(t,J=6.8Hz,2H),3.81(s,3H),2.77(t,2H),2.35–2. 26(m,2H),1.57–1.46(m,2H),1.34–1.23(m,2H),0.85(t,J=7.4Hz,3H).

[0184] 13C NMR (125MHz, CDCl3): δ167.9 (d, J = 7.6Hz), 160.8, 143.8 (d, J = 6.0Hz), 138.3 (d,J=2.4Hz),132.2(d,J=10.2Hz),132.0(d,J=2.8Hz),131.8(d,J=104.0Hz) ,128.4(d,J=12.1Hz),127.1,125.5(d,J=97.5Hz),123.7(d,J=12.7Hz),113. 8,111.8,65.5,55.4,30.2,27.7(d,J=6.6Hz),24.6(d,J=9.7Hz),19.2,13.7.

[0185] 31 P NMR: δ 28.7.

[0186] HRMS(ESI)for:C 29 H 32 O5P[M+H]+: calcd 491.1987, found 491.1996. Example 3 Synthesis of hydrogenated precursor

[0187] The synthetic route of hydrogenated precursor 1q is as follows:

[0188]

[0189] A 50 mL round-bottom flask was added with compound S6 (550 mg, 1.1 mmol, 1.0 equiv.) synthesized in Example 2, Pd(PPh)4 (132 mg, 0.11 mmol, 0.1 equiv.), nitrogen was replaced three times, THF (20 mL) and AlMe3 (1.0 M in hexane, 1.5 mL, 1.5 mmol, 1.5 equiv.) were added, and stirred at 80°C for 6 hours. Saturated ammonium chloride solution was slowly added dropwise under ice bath to quench (5 mL), then acidified with 2N hydrochloric acid (10 mL), and extracted with ethyl acetate (3×10 mL). The organic phase was washed with saturated sodium chloride (10 mL) and dried with sodium sulfate. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain hydrogenated precursor 1q.

[0190] Hydrogenated precursor 1q: 410 mg, 84%.

[0191] 1H NMR(500MHz, CDCl3):7.82–7.75(m,4H),7.57–7.52(m,2H),7.50–7.44(m,4H),7.16(dd,J=7.9,1.5Hz,1H),7.03(d,J=8.0Hz,1H),6.9 7(s,1H),3.99(t,J=6.8Hz,2H),2.75(t,J=7.9Hz,2H),2.35–2.28(m,5H),1.56–1.48(m,2H),1.33–1.22(m,2H),0.85(t,J=7.4Hz,3H).

[0192] 13 C NMR (125MHz, CDCl3): δ 167.8 (d, J = 7.5Hz), 144.1 (d, J = 5.9Hz), 140.2, 136.1 (d, J = 2.2Hz), 132.2 (d, J = 10.0Hz), 132.0 (d, J = 2.5Hz), 131 .3,128.6,128.5,128.4,128.0(d,J=13.2Hz),127.7,127.1,125.5,65.5,30.2,27.3(d,J=6.4Hz),24.7(d,J=9.6Hz),21.4,19.1,13.7.

[0193] 31 P NMR: δ 28.3.

[0194] HRMS(ESI)for:C 28 H 30 O3P[M+H] + :calcd 445.1933, found 445.1938. Example 4 Synthesis of hydrogenated precursor

[0195] The synthetic route of substrate 1r is as follows:

[0196]

[0197] A 50 mL round-bottom flask was added with compound S6 (400 mg, 0.8 mmol, 1.0 equiv.) synthesized in Example 2, Pd(OAc)2 (54 mg, 0.24 mmol, 0.3 equiv.), dppp ligand (115 mg, 0.28 mmol, 0.35 equiv.), and carbon monoxide gas was replaced three times. DIPEA (0.6 mL, 3.52 mmol, 4.4 equiv.), toluene (8 mL) and methanol (8 mL) were added, and stirred at 100° C. for 12 hours. After reduced pressure concentration, the mixture was separated and purified by column chromatography to obtain hydrogenated precursor 1r.

[0198] Hydrogenated precursor 1r: 310 mg, 64%.

[0199] 1 H NMR (500MHz, Chloroform-d): δ7.90(dd,J=8.1,1.8Hz,1H),7.84–7.75(m,5H),7.61–7.54(m,2H),7.53–7.45(m,4H),7.37(d,J=8.2Hz,1H),4 .07(t,J=6.8Hz,2H),3.91(s,3H),2.85(t,J=7.9Hz,2H),2.35(q,J=7.6Hz,2H),1.58–1.50(m,2H),1.33–1.22(m,2H),0.86(t,J=7.4Hz,3H).

[0200] 13 C NMR (125MHz, Chloroform-d): δ 167.4 (d, J = 7.5Hz), 166.5, 143.2 (d, J = 5.9Hz), 136.1 (d, J = 2.2Hz), 134.5 (d, J = 12.7Hz), 132.3, 132.2 (d, J = 10.1Hz), 132.1 (d,J=36.4Hz),131.6,130.8,130.7,128.6(d,J=12.3Hz),128.6(d,J=43.7Hz ),125.4,65.8,52.3,30.2,27.0(d,J=6.3Hz),24.7(d,J=9.4Hz),19.1,13.7.

[0201] 31 P NMR: δ 28.3.

[0202] HRMS(ESI)for:C 29 H 30 O5P[M+H] + :calcd 489.1931, found 489.1839. Example 5 Synthesis of chiral β-phosphonocarbonate

[0203] The corresponding chiral β-phosphonocarbonate was synthesized using the hydrogenated precursors prepared in Examples 1-4 as substrates:

[0204] Take a 10mL reaction tube and add anhydrous nickel acetate (21.2mg, 0.120mmol), (S)- tBu-PHOX (55.8 mg, 0.144 mmol), ultra-dry methanol (270 μL), HFIP (2.45 mL), stirred at room temperature in a glove box for 18 hours to obtain a dark red liquid (0.04 M) for use. The hydrogenation precursor (0.1 mmol), HFIP (0.35-0.45 mL) and catalyst solution (0.003-0.010 mmol, 0.03-0.10 equiv.) were added to a dry quartz tube in sequence. After the quartz tube was transferred to a high-pressure reactor, the air in the autoclave was replaced with hydrogen. After three replacements, the hydrogen pressure was controlled at 40 Bar, and the temperature was controlled to 70 ° C. Stirring vigorously for 48 hours. The reaction solution was concentrated under reduced pressure at room temperature, and the hydrogenation product chiral β-phosphonocarbonate 2a-2z was separated and purified by column chromatography.

[0205] The characterization data of chiral β-phosphonocarbonates 2a-2z are shown below:

[0206] Chiral β-phosphonocarbonate 2a: 99% yield, 96% ee. (During the synthesis, HFIP volume was 0.35 mL, catalyst was 0.10 equiv.).

[0207] 1 H NMR (600MHz, CDCl3): δ7.84–7.74(m,4H),7.59–7.53(m,2H),7.51–7.45(m,4H),7.28(d,J=7.6Hz,1H),7.26(s,1H),7.25–7.21(m,1H),7.15 (d,J=7.2Hz,1H),4.05–3.99(m,2H),2.80(t,J=7.9Hz,2H),2.39–2.28(m,2H),1.56–1.50(m,2H),1.33–1.23(m,3H),0.85(t,J=7.4Hz,3H).

[0208] 13 C NMR (125MHz, CDCl3): δ167.7(d,J=7.8Hz), 144.1(d,J=5.8Hz), 136.1(d,J= 2.3Hz),132.2(d,J=10.1Hz),132.1(d,J=2.8Hz),131.9,131.1,130.6(d,J= 12.9Hz), 129.9, 128.8 (d, J = 95.1Hz), 128.5 (d, J = 12.1Hz), 127.5 (d, J = 91. 9Hz), 125.5, 65.6, 30.2, 27.2 (d, J = 6.4Hz), 24.7 (d, J = 9.6Hz), 19.15, 13.7.

[0209] 31 P NMR: δ 28.6.

[0210] HRMS(ESI)for:C 27 H 30 O3P[M+H] + :calcd 433.1933, found 433.1935.

[0211] Chiral β-phosphonocarbonate 2b: 90% yield, 94% ee. (During the synthesis, HFIP volume was 0.35 mL, catalyst was 0.10 equiv.).

[0212] 1 H NMR (600MHz, CDCl3): δ7.87–7.79(m,4H),7.24–7.12(m,6H),7.12–7.06(m,2H),4.08–3.98(m,2H),3.90(t,J=3.9Hz,1H),3 .10–3.01(m,1H),2.89–2.76(m,2H),2.75–2.68(m,1H),1.87(m,1H),1.60–1.50(m,2H),1.28(m,2H),0.88(t,J=7.4Hz,3H).

[0213] 13 C NMR (125MHz, CDCl3): δ171.9 (d, J = 3.3Hz), 166.0 (t, J = 2.9Hz), 164.0 (t, J = 3.1Hz), 136.0, 1 34.08–132.53(m),129.8,128.6,128.4(d,J=3.4Hz),127.9(d,J=3.3Hz),127.6,127.1(d,J= 3.5Hz),126.0,116.3(d,J=3.1Hz),116.2(d,J=3.0Hz),116.2(d,J=3.1Hz),116.1(d,J=3.2H z), 65.0, 43.4 (d, J = 1.8Hz), 38.3 (d, J = 73.9Hz), 30.4, 28.5 (d, J = 13.3Hz), 19.1, 18.0, 13.7.

[0214] 31 P NMR: δ31.5.

[0215] HRMS(ESI)for:C 27 H 28 F2O3P[M+H] + :calcd 469.1745, found 469.1749.

[0216] Chiral β-phosphonocarbonate 2c: 99% yield, 94% ee. (During the synthesis, HFIP volume was 0.35 mL, catalyst was 0.10 equiv.).

[0217] 1 H NMR (600MHz, CDCl3): δ7.80–7.71(m,4H),7.53–7.46(m,4H),7.21–7.06(m,4H),4.08–3.97(m,2H),3.90(t,J=3.9Hz,1H ),3.11–3.00(m,1H),2.91–2.67(m,3H),1.93–1.81(m,1H),1.60–1.52(m,2H),1.31–1.23(m,2H),0.88(t,J=7.4Hz,3H).

[0218] 13 C NMR (125MHz, CDCl3): δ171.8 (d, J = 3.3Hz), 138.7, 138.7 (d, J = 3.2Hz), 135.9, 133.3 ( d,J=12.3Hz),132.5(d,J=9.5Hz),132.4(d,J=9.6Hz),130.6(d,J=56.4Hz),129.8,12 9.8(d,J=57.2Hz),129.2(d,J=2.9Hz),129.1(d,J=2.6Hz),128.7,127.6,126.0,65. 1, 43.4 (d, J = 1.8Hz), 38.0 (d, J = 73.7Hz), 30.4, 28.5 (d, J = 13.2Hz), 19.1, 17.9, 13.7.

[0219] 31 P NMR: δ 30.4.

[0220] HRMS(ESI)for:C 27 H 28 Cl2O3P[M+H] + :calcd 501.1153,found 501.1148.

[0221] Chiral β-phosphonocarbonate 2d: 95% yield, 93% ee. (During the synthesis, HFIP volume was 0.45 mL, catalyst was 0.03 equiv.).

[0222] 1H NMR (600MHz, CDCl3): δ8.03–7.91(m,4H),7.80–7.70(m,4H),7.61(t,J=8.0Hz,4H),7. 53–7.43(m,4H),7.42–7.36(m,2H),7.20–7.13(m,2H),7.10(dd,J=6.6,1.8Hz,2H),4.0 7(t,J=6.8Hz,2H),4.01(d,J=4.0Hz,1H),3.15–3.03(m,1H),2.96–2.77(m,3H),1.98(d d,J=10.0,5.0Hz,1H),1.68–1.51(m,2H),1.29(h,J=7.5Hz,2H),0.88(t,J=7.4Hz,3H).

[0223] 13 C NMR (125MHz, CDCl3): δ172.1(d,J=3.2Hz), 144.6(d,J=2.6Hz), 144.6(d,J=2.7Hz), 139.9(d,J=7.2 Hz), 136.2, 133.8 (d, J = 12.3Hz), 131.7 (d, J = 8.8Hz), 131.6 (d, J = 9.0Hz), 131.0 (d, J = 53.1Hz), 130. 2(d,J=54.2Hz),129.4(d,J=140.2Hz),129.0,128.2,127.5,127.4(d,J=11.7Hz),127.3(d,J=2.9H z), 126.0, 65.1, 43.5 (d, J = 1.7Hz), 38.2 (d, J = 73.0Hz), 30.4, 28.6 (d, J = 13.0Hz), 19.2, 17.9, 13.8.

[0224] 31 P NMR: δ31.1.

[0225] HRMS(ESI)for:C 39 H 38 O3P[M+H] + :calcd 585.2559, found 585.2552.

[0226] Chiral β-phosphonocarbonate 2e: 87% yield, 94% ee. (During the synthesis, HFIP volume 0.40, catalyst 0.06 equiv.).

[0227] 1H NMR (600MHz, CDCl3): δ7.76–7.68 (m, 4H), 7.29 (dd, J = 8.1, 2.6Hz, 4H), 7.19–7 .11(m,2H),7.09–7.05(m,2H),4.02(t,J=6.9Hz,2H),3.95–3.90(m,1H),3.08– 3.00(m,1H),2.87–2.75(m,2H),2.75–2.68(m,1H),2.40(d,J=8.0Hz,6H),1.88 (t,J=7.5Hz,1H),1.62–1.54(m,2H),1.31–1.25(m,2H),0.88(t,J=7.4Hz,3H).

[0228] 13 C NMR (125MHz, CDCl3): δ172.1(d,J=3.3Hz), 142.1(d,J=2.7Hz), 142.0(d,J=2.7Hz), 136 .3,133.9(d,J=12.0Hz), 131.1(d,J=8.9Hz), 131.0(d,J=9.1Hz), 129.4(d,J=11.6Hz), 129.4(d,J=56.3Hz),129.2(d,J=141.4Hz),128.6(d,J=57.1Hz),127.4,125.8,64.9,4 3.5, 38.2 (d, J = 73.0Hz), 30.4, 28.6 (d, J = 13.0Hz), 21.6 (d, J = 5.6Hz), 19.2, 17.9, 13.8.

[0229] 31 P NMR: δ 31.2.

[0230] HRMS(ESI)for:C 29 H 33 O3PNa[M+Na] + :calcd 483.2065,found483.2070.

[0231] Chiral β-phosphonocarbonate 2f: 97% yield, 95% ee. (During the synthesis, HFIP volume 0.45, catalyst 0.10 equiv.).

[0232] 1H NMR (600MHz, CDCl3): δ7.77–7.71(m,4H),7.18–7.12(m,2H),7.10–7.06(m, 2H),7.02–6.97(m,4H),4.04–3.99(m,2H),3.94–3.91(m,1H),3.85(d,J=5. 9Hz,6H),3.08–2.97(m,1H),2.87–2.74(m,2H),2.71–2.61(m,1H),1.89(d, J=6.4Hz,1H),1.62–1.53(m,2H),1.32–1.24(m,2H),0.88(t,J=7.4Hz,3H).

[0233] 13 C NMR (125MHz, CDCl3): δ172.1 (d, J = 3.3Hz), 162.2 (d, J = 2.8Hz), 136.3, 134.0 (d, J=12.0Hz),133.0(d,J=10.0Hz),132.8(d,J=10.1Hz),129.7,128.6,127.4,125. 8,123.8(d,J=83.2Hz),123.0(d,J=84.2Hz),114.2(d,J=12.4Hz),64.9,55.3,43 .5(d,J=1.7Hz),38.5(d,J=73.6Hz),30.4,28.7(d,J=13.0Hz),19.2,18.0,13.8.

[0234] 31 P NMR: δ 31.2.

[0235] HRMS(ESI)for:C 29 H 34 O5P[M+H] + :calcd 493.2144, found 493.2152.

[0236] Chiral β-phosphonocarbonate 2g: 92% yield, 94% ee. (During the synthesis, HFIP volume 0.40mL, catalyst 0.06equiv.).

[0237] 1H NMR (600MHz, CDCl3): δ7.80–7.73(m,4H),7.53–7.46(m,4H),7.18–7.11(m,2H),7.11–7.05(m,2H),4.04–3.97(m,2H),3.95(t,J=3.7Hz,1H),3.0 8–2.99(m,1H),2.89–2.69(m,3H),1.96–1.87(m,1H),1.60–1.51(m,2H) ,1.33(s,9H),1.32(s,9H),1.26(q,J=7.5Hz,2H),0.87(t,J=7.3Hz,3H).

[0238] 13 C NMR (125MHz, CDCl3): δ172.2 (d, J = 3.2Hz), 155.0 (d, J = 2.6Hz), 136.3, 134.0 (d, J = 12 .0Hz), 131.0 (d, J = 8.9Hz), 130.9 (d, J = 9.2Hz), 129.2 (d, J = 69.6Hz), 129.2 (d, J = 139. 9Hz),128.4(d,J=70.0Hz),127.4,125.8,125.7(d,J=2.5Hz),125.6(d,J=2.6Hz),64 .9,43.4,38.3(d,J=72.7Hz),35.0,31.1,30.4,28.7(d,J=13.0Hz),19.2,17.9,13.8.

[0239] 31 P NMR: δ 31.0.

[0240] HRMS(ESI)for:C 35 H 46 O3P[M+H] + :calcd 545.3185,found 545.3182.

[0241] Chiral β-phosphonocarbonate 2h: 99% yield, 90% ee. (During the synthesis, HFIP volume was 0.35 mL, catalyst was 0.06 equiv.).

[0242] 1H NMR (600MHz, CDCl3): δ7.94–7.86(m,1H),7.84–7.77(m,1H),7.51–7.42(m,2H),7.20 –7.01(m,6H),6.91–6.84(m,2H),4.04(t,J=4.1Hz,1H),3.97–3.90(m,1H),3.79–3.75 (m,1H),3.74(s,3H),3.68(s,3H),3.45–3.37(m,1H),3.12–3.01(m,1H),2.96–2.82(m ,2H),2.08–2.00(m,1H),1.50–1.42(m,2H),1.26–1.18(m,2H),0.83(t,J=7.4Hz,3H).

[0243] 13 C NMR (125MHz, CDCl3): δ172.5(d,J=3.6Hz), 160.1(dd,J=10.8,4.0Hz), 136.8(d,J=1.5Hz), 134.9(d,J=6.1Hz ),134.9,134.8(d,J=6.3Hz),134.7,133.3(d,J=2.2Hz),133.2(d,J=2.1Hz),129.7,128.72,127.1,125.7,12 1.5(d,J=20.6Hz),120.9,120.8(d,J=6.3Hz),120.7(d,J=5.8Hz),110.7(d,J=6.7Hz),110.6(d,J=6.7Hz),6 4.6, 55.3 (d, J = 19.9Hz), 43.9 (d, J = 1.7Hz), 38.18 (d, J = 75.9Hz), 30.3, 29.5 (d, J = 14.4Hz), 19.1, 18.8, 13.8.

[0244] 31 P NMR: δ 39.7.

[0245] HRMS(ESI)for:C 29 H 34 O5P[M+H] + :calcd 493.2145, found 493.2141.

[0246] Chiral β-phosphonocarbonate 2i: 90% yield, 95% ee. (During the synthesis, HFIP volume was 0.45 mL, catalyst was 0.06 equiv.).

[0247] 1H NMR (600MHz, CDCl3): δ7.76–7.69(m,2H),7.63–7.53(m,2H),7.41–7.30(m,4 H),7.20–7.13(m,2H),7.12–7.04(m,2H),4.05(t,J=6.9Hz,2H),3.90(t,J=3. 4Hz,1H),3.13–2.97(m,1H),2.93–2.70(m,3H),2.41(s,3H),2.39(s,3H),1. 96–1.82(m,1H),1.65–1.51(m,2H),1.37–1.22(m,2H),0.89(t,J=7.4Hz,3H).

[0248] 13 C NMR (125MHz, CDCl3): δ172.1 (d, J = 3.4Hz), 138.6, 138.6 (d, J = 22.9Hz), 136.3, 133.9 (d, J = 12.2Hz), 132.6(d,J=2.9Hz),132.5,132.5(d,J=3.1Hz),132.2,131.9(d,J=8.0Hz),131.7(d,J=8.4Hz),131.6 (d,J=37.7Hz),129.8,128.6,128.5(d,J=11.9Hz),127.8(d,J=9.1Hz),127.7(d,J=8.9Hz),127.5,1 25.9, 65.0, 43.4, 37.9 (d, J = 72.5Hz), 30.4, 28.6 (d, J = 13.0Hz), 21.5 (d, J = 3.2Hz), 19.2, 17.8, 13.8.

[0249] 31 P NMR: δ31.0. HRMS (ESI) for: C 29 H 34 O3P[M+H] + :calcd 461.2245,found461.2244.

[0250] Chiral β-phosphonocarbonate 2j: 96% yield, 90% ee. (During the synthesis, HFIP volume was 0.35 mL, catalyst was 0.10 equiv.).

[0251] 1H NMR (600MHz, CDCl3): δ7.46 (dd, J=12.5, 2.8Hz, 2H), 7.43–7.29 (m, 4H), 7.20 –7.12(m,2H),7.10–7.02(m,4H),4.12–3.99(m,2H),3.93(q,J=3.4Hz,1H),3. 88–3.79(m,6H),3.05(d,J=12.5Hz,1H),2.89–2.76(m,2H),2.76–2.67(m,1H) ,1.94–1.84(m,1H),1.63–1.53(m,2H),1.34–1.23(m,2H),0.92–0.84(m,3H).

[0252] 13 C NMR (125MHz, CDCl3): δ169.7 (d, J = 3.2Hz), 157.3 (d, J = 2.7Hz), 157.2 (d, J = 2.8Hz), 133.8, 131.4 (d, J = 19 .2Hz),131.2(d,J=13.6Hz),130.6(d,J=45.9Hz),127.5,127.3,126.2,125.0,123.5,120.3(d,J=5.6Hz) ,120.3(d,J=5.4Hz),115.7(d,J=2.6Hz),115.3(d,J=2.7Hz),113.9(d,J=9.5Hz),113.6(d,J=9.1Hz),62 .6,53.0(d,J=2.2Hz),40.9(d,J=1.8Hz),35.6(d,J=73.0Hz),28.0,26.1(d,J=13.0Hz),16.7,15.4,11.3.

[0253] 31 P NMR: δ31.3.

[0254] HRMS(ESI)for:C 29 H 33 O5PNa[M+Na] + :calcd 515.1964,found515.1964.

[0255] Chiral β-phosphonocarbonate 2k: 99% yield, 96% ee. (During the synthesis, HFIP volume was 0.45 mL, catalyst was 0.06 equiv.).

[0256] 1H NMR (600MHz, CDCl3): δ7.48–7.42(m,4H),7.19–7.12(m,4H),7.11–7.03(m,2H),4.10–4.03(m,2H),3.88(t,J=3.4Hz,1H),3.11–3.01(m ,1H),2.89–2.68(m,3H),2.36(s,6H),2.34(s,6H),1.91–1.83(m,1H),1.63–1.55(m,2H),1.30(q,J=7.5Hz,2H),0.89(t,J=7.4Hz,3H).

[0257] 13 C NMR (125MHz, CDCl3): δ170.2 (d, J = 3.1Hz), 136.4 (d, J = 9.6Hz), 136.4 (d, J = 9.6Hz), 134.5, 132.2 (d,J=12.1Hz),131.6(d,J=2.9Hz),131.5(d,J=2.8Hz),130.4(d,J=17.9Hz),129.7(d,J=19.1Hz) ,127.3(d,J=141.2Hz),126.7(d,J=3.9Hz),126.6(d,J=4.2Hz),124.7(d,J=200.5Hz),63.1,41.5 (d,J=1.7Hz),35.9(d,J=72.3Hz),28.5,26.7(d,J=13.0Hz),19.5(d,J=2.1Hz),17.3,15.8,11.9.

[0258] 31 P NMR: δ31.1.

[0259] HRMS(ESI)for:C 31 H 38 O3P[M+H] + :calcd 489.2559,found 489.2552.

[0260] Chiral β-phosphonocarbonate 2l: 98% yield, 96% ee. (During the synthesis, HFIP volume was 0.35 mL, catalyst was 0.10 equiv.).

[0261] 1H NMR (600MHz, CDCl3): δ7.72 (dt, J=7.4, 2.2Hz, 2H), 7.27 (d, J=2.0Hz, 1H), 7.21–7 .16(m,2H),7.14–7.10(m,3H),6.56–6.53(m,2H),4.09(d,J=4.0Hz,1H),3.98(t, J=6.8Hz,2H),3.03(dt,J=16.8,5.0Hz,1H),2.90–2.84(m,2H),2.78–2.70(m,1H) ,2.01–1.92(m,1H),1.59–1.52(m,2H),1.30–1.28(m,2H),0.88(t,J=7.4Hz,3H).

[0262] 13 C NMR (125MHz, CDCl3): δ171.8(d,J=3.8Hz), 148.22(d,J=7.4Hz), 148.0(d,J=7 .5Hz),147.7,146.6(d,J=7.9Hz),145.5,136.1,133.2(d,J=13.3Hz),129.7,1 28.9,127.5,125.9,123.5(d,J=18.3Hz),122.6(d,J=18.4Hz),111.7–109.7(m ),65.0,43.0,38.6(d,J=82.7Hz),30.4,28.5(d,J=14.7Hz),19.1,17.7,13.7.

[0263] 31 P NMR: δ13.6.

[0264] HRMS(ESI)for:C 23 H 26 O5P[M+H] + :calcd 413.1522, found 413.1524.

[0265] Chiral β-phosphonocarbonate 2m: 99% yield, 99% ee. (During the synthesis, HFIP volume was 0.45 mL, catalyst was 0.06 equiv.).

[0266] 1H NMR (600MHz, CDCl3): δ7.23–7.16(m,2H),7.16–7.09(m,2H),4.10–4.03(m,3H),3.79(dd,J=10.7,5.8Hz,6H),3.06–2.98(m,1H),2.9 0–2.81(m,1H),2.70–2.59(m,1H),2.38–2.28(m,1H),2.22–2.13(m,1H),1.63–1.58(m,2H),1.38–1.32(m,2H),0.90(t,J=7.4Hz,3H).

[0267] 13 C NMR (125MHz, CDCl3): δ172.4 (d, J = 3.8Hz), 136.0, 132.9 (d, J = 15.3Hz), 129.8, 128.8, 127.47, 125.9, 64.85, 53.0 (d, J = 6. 6Hz), 52.8 (d, J = 6.9Hz), 43.9 (d, J = 2.8Hz), 35.6 (d, J = 146.4Hz), 30.5, 28.5 (d, J = 16.2Hz), 19.1, 18.4 (d, J = 2.7Hz), 13.7.

[0268] 31 P NMR: δ31.7.

[0269] HRMS(ESI)for:C 17 H 26 O5PNa[M+H] + :calcd 341.1522,found 341.1517.

[0270] Chiral β-phosphonocarbonate 2n: 99% yield, 95% ee. (During the synthesis, HFIP volume was 0.35 mL, catalyst was 0.10 equiv.).

[0271] 1H NMR (600MHz, CDCl3): δ7.90–7.80(m,4H),7.57–7.45(m,6H),7.07(t,J=7.9Hz ,1H),6.70(t,J=8.8Hz,2H),4.08–3.97(m,2H),3.92(d,J=3.8Hz,1H),3.80(s, 3H),3.03(dd,J=17.0,4.9Hz,1H),2.80–2.69(m,2H),2.61–2.51(m,1H),1.97 –1.89(m,1H),1.58(q,J=7.2Hz,2H),1.34–1.23(m,3H),0.88(t,J=7.4Hz,3H).

[0272] 13 C NMR (125MHz, CDCl3): δ172.0, 157.7, 134.9 (d, J = 11.6Hz), 132.5 (d, J = 61.4Hz), 131.8, 131.7 (d, J = 62.1Hz), 131.2 (d, J = 9 .0Hz), 131.0 (d, J = 8.1Hz), 128.7 (d, J = 11.6Hz), 126.3, 125.4, 120.7, 108.5, 65.0, 55.3, 43.2, 37.7 (d, J = 72.8Hz), 30.4.

[0273] 31 P NMR: δ 31.0.

[0274] HRMS(ESI)for:C 28 H 32 O4P[M+H] + :calcd 463.2038, found 463.2042.

[0275] Chiral β-phosphonocarbonate 2o: 99% yield, 95% ee. (During the synthesis, HFIP volume was 0.35 mL, catalyst was 0.06 equiv.).

[0276] 1H NMR (600MHz, CDCl3): δ7.90–7.80(m,4H),7.57–7.46(m,6H),7.05(d,J=8.5Hz ,1H),6.75(dd,J=8.4,2.7Hz,1H),6.60(d,J=2.7Hz,1H),4.08–3.98(m,2H),3. 88(t,J=3.4Hz,1H),3.72(s,3H),2.97(d,J=12.1Hz,1H),2.83–2.71(m,3H),1 .93–1.85(m,1H),1.61–1.53(m,2H),1.31–1.25(m,2H),0.88(t,J=7.4Hz,3H).

[0277] 13 C NMR (125MHz, CDCl3): δ172.0, 157.6, 134.5 (d, J = 12.7Hz), 132.6, 132.2, 131.8 (d, J = 10.4Hz), 131.4, 131.2 (d, J = 8.8Hz), 131.0 (d, J = 7.9 Hz), 130.7, 128.7 (d, J = 11.5Hz), 128.1, 114.4, 112.8, 65.0, 55.3, 43.7, 38.1 (d, J = 72.6Hz), 30.4, 27.9 (d, J = 13.2Hz), 19.2, 18.1, 13.8.

[0278] 31 P NMR: δ 31.0.

[0279] HRMS(ESI)for:C 28 H 32 O4P[M+H] + :calcd 463.2038, found 463.2047.

[0280] Chiral β-phosphonocarbonate 2p: 95% yield, 95% ee. (During the synthesis, HFIP volume was 0.45 mL, catalyst was 0.06 equiv.).

[0281] 1H NMR (600MHz, CDCl3): δ7.88–7.81(m,4H),7.58–7.46(m,6H),7.00–6.97(m,1H),6.68–6.64(m,2H),4.05–3.97(m,2H),3.87(t,J=3.7Hz, 1H),3.75(s,3H),3.06–2.96(m,1H),2.86–2.71(m,3H),1.90–1.85(m,1H),1.59–1.52(m,2H),1.31–1.25(m,2H),0.88(t,J=7.4Hz,3H).

[0282] 13 C NMR (125MHz, CDCl3): δ172.3 (d, J = 3.2Hz), 158.8, 137.5, 132.5 (d, J = 52.0Hz), 131. 8(d,J=3.1Hz),131.7(d,J=52.9Hz),131.7(d,J=2.7Hz),131.2(d,J=8.4Hz),131.0( d,J=8.8Hz),129.6,128.7(d,J=11.5Hz),126.1(d,J=12.4Hz),113.2(d,J=202.1Hz ),64.9,55.3,42.7,38.3(d,J=72.6Hz),30.4,28.9(d,J=13.2Hz),19.2,17.8,13.8.

[0283] 31 P NMR: δ 31.0.

[0284] HRMS(ESI)for:C 29 H 34 O5P[M+H] + :calcd 463.2038, found 463.2038.

[0285] Chiral β-phosphonocarbonate 2q: 98% yield, 93% ee. (During the synthesis, HFIP volume was 0.45 mL, catalyst was 0.06 equiv.).

[0286] 1H NMR (600MHz, CDCl3): δ7.89–7.80(m,4H),7.57–7.43(m,7H),6.98–6.94(m ,2H),6.90(dd,J=7.9,1.9Hz,1H),4.07–3.97(m,2H),3.89(t,J=3.7Hz,1H) ,3.00(qd,J=11.2,10.2,5.5Hz,1H),2.85–2.70(m,3H),2.26(s,3H),1.93 –1.85(m,1H),1.62–1.52(m,2H),1.31–1.26(m,2H),0.88(t,J=7.4Hz,3H).

[0287] 13 C NMR (125MHz, CDCl3): δ172.2(d,J=3.2Hz),137.1,135.91,132.7,132.3,131.7(d,J=2 .7Hz),131.7(d,J=54.1Hz),131.7(d,J=2.8Hz),131.2(d,J=8.6Hz),131.0(d,J=8.8H z), 130.8 (d, J = 12.1Hz), 130.2, 128.6 (d, J = 11.4Hz), 127.6 (d, J = 207.8Hz), 64.9, 43. 0(d,J=1.8Hz),38.2(d,J=72.9Hz),30.4,28.6(d,J=13.2Hz),21.0,19.1,17.9,13.7.

[0288] 31 P NMR: δ 31.0.

[0289] HRMS(ESI)for:C 28 H 32 O3P[M+H] + :calcd 447.2089, found 447.2087.

[0290] Chiral β-phosphonocarbonate 2t: 99% yield, 96% ee. (During the synthesis, HFIP volume was 0.45 mL, catalyst was 0.06 equiv.).

[0291] 1H NMR (600MHz, CDCl3): δ7.89–7.80(m,4H),7.57–7.43(m,7H),6.98–6.94(m ,2H),6.90(dd,J=7.9,1.9Hz,1H),4.07–3.97(m,2H),3.89(t,J=3.7Hz,1H) ,3.00(qd,J=11.2,10.2,5.5Hz,1H),2.85–2.70(m,3H),2.26(s,3H),1.93 –1.85(m,1H),1.62–1.52(m,2H),1.31–1.26(m,2H),0.88(t,J=7.4Hz,3H).

[0292] 13 C NMR (125MHz, CDCl3): δ171.7 (d, J = 3.4Hz), 138.1, 133.1, 132.5, 132.3, 132.2, 1 32.0,131.9(d,J=2.8Hz),131.8(d,J=2.7Hz),131.7,131.2,131.2(d,J=8.7Hz) ,131.0(d,J=8.8Hz),129.9,129.5,128.8(d,J=4.1Hz),128.7(d,J=4.1Hz),126 .2,65.12,43.0,38.0(d,J=72.7Hz),30.4,28.5(d,J=13.0Hz),19.1,17.6,13.7.

[0293] 31 P NMR: δ 30.8.

[0294] HRMS(ESI)for:C 27 H 29 ClO3P[M+H] + :calcd 467.1543, found 467.1554.

[0295] Chiral β-phosphonocarbonate 2u: 95% yield, 94% ee. (During the synthesis, HFIP volume was 0.45 mL, catalyst was 0.06 equiv.).

[0296] 1H NMR (600MHz, CDCl3): δ7.89–7.80(m,4H),7.58–7.44(m,6H),6.58(s,1H),6.53(s,1H),5.88(d,J=1.4Hz,1H),5.85(d,J=1.5Hz ,1H),4.14–4.04(m,2H),3.80(d,J=3.5Hz,1H),2.97–2.88(m,1H),2.82–2.68(m,3H),1.87–1.81(m,1H),1.23(t,J=7.1Hz,3H).

[0297] 13 C NMR (125MHz, CDCl3): δ172.1 (d, J=3.2Hz), 147.1, 145.9, 132.7, 132.2, 131.9, 131. 8(d,J=2.7Hz),131.7(d,J=2.5Hz),131.4,131.1(d,J=8.5Hz),131.0(d,J=8.8Hz), 129.6,128.7(d,J=3.5Hz),128.6(d,J=3.4Hz),126.5(d,J=12.7Hz),109.1,108.2, 100.9, 61.1, 43.3 (d, J = 1.7Hz), 38.2 (d, J = 72.7Hz), 28.9 (d, J = 13.3Hz), 18.0, 14.0.

[0298] 31 P NMR: δ 30.9.

[0299] HRMS(ESI)for:C 26 H 26 O5P[M+H] + :calcd 449.1518, found 449.1524.

[0300] Chiral β-phosphonocarbonate 2v: 98% yield, 94% ee. (During the synthesis, HFIP volume was 0.45 mL, catalyst was 0.06 equiv.).

[0301] 1H NMR (600MHz, CDCl3): δ7.90–7.81(m,4H),7.58–7.46(m,6H),6.36(s,1H),4.15–4.07(m,2H),3.85(t,J=3.2Hz,1H),3.72(s,3H) ),3.69(s,3H),3.09–3.00(m,1H),2.79–2.68(m,2H),2.66–2.54(m,1H),2.10(s,3H),1.96–1.89(m,1H),1.23(t,J=7.2Hz,3H).

[0302] 13 C NMR (125MHz, CDCl3): δ172.0, 157.0 (d, J = 84.6Hz), 132.6 (d, J = 55.5Hz), 132.0 ( d,J=4.2Hz),131.8(d,J=64.6Hz),131.7(d,J=2.8Hz),131.7(d,J=2.7Hz),131. 1(d,J=6.8Hz),131.0(d,J=7.0Hz),128.7(d,J=11.4Hz),121.9,119.1,105.9,6 1.1,59.8,55.6,43.6,38.0(d,J=72.8Hz),22.9(d,J=12.9Hz),17.6,14.0,9.0.

[0303] 31 P NMR: 30.8.

[0304] HRMS(ESI)for:C 28 H 30 O5P[M+H] + :calcd 479.1987, found 479.1987.

[0305] Chiral β-phosphonocarbonate 2w: 99% yield, 95% ee. (During the synthesis, HFIP volume was 0.35 mL, catalyst was 0.10 equiv.).

[0306] 1H NMR (600MHz, CDCl3): δ7.91–7.81(m,4H),7.60–7.46(m,6H),6.61(s,1H),6.54(s,1H),4.18–4.05(m,2H),3.83(s,3H ),3.81(d,J=3.9Hz,1H),3.77(s,3H),2.99–2.90(m,1H),2.83–2.71(m,3H),1.93–1.85(m,1H),1.23(t,J=7.1Hz,3H).

[0307] 13 C NMR (125MHz, CDCl3): δ172.2 (d, J = 3.2Hz), 148.5, 147.3, 132.5 (d, J = 44.5Hz), 131.8 (d ,J=2.8Hz),131.8(d,J=45.7Hz),131.7(d,J=2.8Hz),131.1(d,J=5.5Hz),131.0(d,J=5. 8Hz),128.7(d,J=11.4Hz),128.2,125.4(d,J=12.7Hz),111.4(d,J=120.0Hz),61.1,55 .9(d,J=9.8Hz),43.1(d,J=1.7Hz),38.1(d,J=72.8Hz),28.3(d,J=13.2Hz),17.9,14.0.

[0308] 31 P NMR: δ 30.9.

[0309] HRMS(ESI)for:C 27 H 30 O5P[M+H] + :calcd 465.1831, found 465.1832.

[0310] Chiral β-phosphonocarbonate 2x: 99% yield, 92% ee. (During the synthesis, HFIP volume was 0.35 mL, catalyst was 0.10 equiv.).

[0311] 1H NMR (600MHz, CDCl3): δ7.90–7.82(m,4H),7.58–7.47(m,6H),7.19–7.13(m,2H),7.08(dd,J=5.5,1.8Hz,2H),4.09(qd,J =7.1,1.2Hz,2H),3.92(t,J=3.6Hz,1H),3.10–3.01(m,1H),2.89–2.73(m,3H),1.93–1.85(m,1H),1.22(t,J=7.1Hz,3H).

[0312] 13 C NMR (125MHz, CDCl3): δ 172.0 (d, J = 3.3Hz), 136.2, 133.7 (d, J = 12.1Hz), 132.6, 132.2, 131.9, 131.8 (d, J = 2.7Hz), 131.7 (d, J = 2.7Hz), 131. 5,131.1,131.1,131.0,131.0,129.8,128.7,128.7,128.7,127.5,125.9,61.1,43.4,38.1(d,J=72.8Hz),28.6(d,J=13.0Hz),17.9,14.0.

[0313] 31 P NMR: δ 30.9.

[0314] HRMS(ESI)for:for:C 25 H 26 O3P[M+H] + :calcd 405.1619,found405.1615.

[0315] Chiral β-phosphonocarbonate 2y: 99% yield, 90% ee. (During the synthesis, HFIP volume was 0.35 mL, catalyst was 0.10 equiv.).

[0316] 1 H NMR(600MHz, CDCl3): δ7.85(dtt,J=11.0,7.7,1.5Hz,4H),7.57–7.46(m,6H),7.19–7.12(m,2H),7.10–7.06(m,2H),4.01–3.96 (m,2H),3.95–3.91(m,1H),3.10–3.01(m,1H),2.90–2.73(m,3H),1.94–1.86(m,1H),1.68–1.56(m,2H),0.85(t,J=7.4Hz,3H).

[0317] 13 C NMR (125MHz, CDCl3): δ172.0 (d, J = 3.3Hz), 136.2, 133.8 (d, J = 12.1Hz), 132.6, 132.1, 131.9, 131.8 (d, J = 2.7Hz), 131.7 (d, J = 2.8Hz), 131.5, 131.2, 131.1,131.1,131.0,129.8,128.7(d,J=2.3Hz),128.7,128.6,127.5,125 .9,66.7,43.4,38.0(d,J=72.9Hz),28.6(d,J=13.0Hz),21.8,17.9,10.4.

[0318] 31 P NMR: δ 30.9.

[0319] HRMS(ESI)for:for:C 26 H 28 O3P[M+H] + :calcd 419.1776,found419.1785.

[0320] Chiral β-phosphonocarbonate 2z: 99% yield, 93% ee. (During the synthesis, HFIP volume was 0.35 mL, catalyst was 0.10 equiv.).

[0321] 1 H NMR (600MHz, CDCl3): δ7.90–7.77(m,4H),7.50(qd,J=8.5,7.8,5.8Hz,4H),7.39(td,J=7.7,2.8Hz,2H),7.36–7.27(m,5H),7.20– 7.12(m,2H),7.06(h,J=6.4,5.8Hz,2H),5.10(q,J=12.5Hz,2H),3.97(t,J=3.7Hz,1H),3.06(d,J=11.9Hz,1H),2.90–2.74(m,3H).

[0322] 13C NMR (125MHz, CDCl3): δ171.7 (d, J = 3.3Hz), 136.2, 136.0, 133.4 (d, J = 12.0Hz), 132. 3(d,J=15.5Hz),131.7(d,J=2.7Hz),131.5(d,J=16.8Hz),131.0(d,J=7.4Hz),130.9 ,129.8,128.7(d,J=4.6Hz),128.6(d,J=4.0Hz),128.6,128.3(d,J=3.1Hz),127.8,1 27.5, 125.9, 66.9, 43.3 (d, J = 1.8Hz), 38.0 (d, J = 72.6Hz), 28.5 (d, J = 13.0Hz), 17.8.

[0323] 31 P NMR: δ 31.0.

[0324] HRMS(ESI)for:for:C 27 H 30 O3P[M+H] + :calcd 467.1776,found467.1778.

[0325] Application Example 1 Synthesis of Chiral Phosphine Ligands

[0326] Take a 100 ml dry round-bottom flask, add lithium aluminum tetrahydride (217 mg, 5.7 mmol, 0.98 equiv.) and 38 ml tetrahydrofuran. Slowly drop the tetrahydrofuran solution of chiral β-phosphonocarbonate 2a (2.0 g, 5.8 mmol, 1.0 equiv.) prepared in Example 5 at zero degrees. Stir at room temperature for 4 hours and cool in an ice-water bath, then slowly add 217 μl of water, 217 μl of 15% sodium hydroxide, and 660 μl of water. Stir at room temperature for 30 minutes, then add 3 g of magnesium sulfate and stir for 10 minutes. The filtrate is spun dry to obtain a crude product.

[0327] Take a 100 ml round-bottom flask, add the crude product obtained in the previous step, DMPA (254 mg, 2.08 mmol, 0.36 equiv.), TsCl (1.98 g, 10.25 mmol, 1.77 equiv.), dichloromethane (61 mL) in sequence, and cool in an ice-water bath. Add triethylamine (1.22 mL, 10.1 mmol, 1.74 equiv.). Stir at room temperature for 12 hours, concentrate the reaction solution and purify it by column chromatography to obtain a white solid. (1.56g, 57%), its characterization data are:

[0328] 1H NMR(500MHz, CDCl3)δ7.80(dd,J=10.8,7.8Hz,2H),7.72(dd,J=11.0,7.7Hz,2H),7.62–7.41(m,8 H),7.26–7.22(m,3H),7.17(t,J=7.3Hz,1H),7.07(q,J=8.1Hz,3H),4.92(dd,J=10.2,3.8Hz,1H) ,4.09(t,J=9.9Hz,1H),3.18(dd,J=9.5,4.4Hz,1H),2.90(dd,J=17.5,7.4Hz,1H),2.80(dt,J=17 .7,9.0Hz,1H),2.73–2.65(m,1H),2.43(s,3H),2.20–2.06(m,1H),1.88(dt,J=14.8,7.4Hz,1H).

[0329] 13 C NMR (125MHz, CDCl3) δ144.4,135.9(d,J=12.5Hz),135.0,132.7,132.0(d,J=2.6 Hz),131.9(d,J=2.6Hz),131.3(d,J=59.1Hz),130.8(d,J=1.8Hz),130.7,130.6, 129.7,129.3,129.0,128.9(d,J=3.0Hz),128.8,128.0,127.4,125.6,71.4(d,J =2.0Hz),38.5(d,J=1.9Hz),37.1(d,J=71.5Hz),27.8(d,J=12.3Hz),21.7,17.7.

[0330] 31 P NMR δ 31.9.

[0331] HRMS(ESI)for:for:C 30 H 30 O4PS[M+H] + :calcd 517.1602,found517.1605.

[0332] Take a dry 50 ml round bottom flask and replace it with nitrogen three times. Add HPPh2 (0.6 mL, 3.45 mmol, 2.5 equiv.) and n-hexane (8.8 mL) in sequence and cool to 0°C. Slowly add n-butyl lithium (2.4 M, 1.16 mL, 2.0 equiv.) and stir at 0°C for 10 minutes. Dissolve the reactant in tetrahydrofuran (8.8 mL) (700 mg, 1.36 mmol, 1.0 equiv.) was slowly added to the LiPPh2 solution prepared above. Stirring was continued at 0°C for one hour. After adding H2O2 (30% wt, 1.7 mL), stirring was continued for one hour. After adding 20 mL of water, TBME was used for extraction (3×10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was separated and purified by column chromatography to obtain a white solid. (600 mg, 81%). Its characterization data are:

[0333] 1 H NMR(500MHz, CDCl3)δ7.80–7.65(m,5H),7.56–7.42(m,6H),7.40–7.27(m,4H), 7.25–7.21(m,1H),7.07(d,J=7.7Hz,1H),7.01–6.97(m,1H),6.95(d,J=7.5Hz,1 H),6.81(t,J=7.4Hz,1H),3.91(dd,J=15.4,12.1Hz,1H),3.77(s,1H),3.03–2.9 4(m,1H),2.85–2.76(m,1H),2.67–2.59(m,1H),2.56–2.39(m,2H),1.86(s,1H).

[0334] 13 C NMR (125MHz, CDCl3) δ139.3 (d, J = 12.9Hz), 134.4, 134.0 (d, J = 23.8Hz), 133.2 (d, J = 23.9Hz), 132.8, 132.0 (d, J = 6.5Hz) ,132.0(d,J=2.7Hz),131.7(d,J=2.8Hz),131.3(d,J=2.7Hz),131.3,131.0(d,J=2.7Hz),130.9(d,J=2.2Hz),130.8,13 0.6,130.6(d,J=1.7Hz),130.5,129.9,129.1(d,J=11.5Hz),128.9(d,J=3.5Hz),128.8,128.5(d,J=11.8Hz),128.2(d, J=11.7Hz),127.2,125.2,38.3(dd,J=71.6,12.4Hz),33.8(t,J=2.7Hz),31.4(d,J=72.1Hz),26.7(d,J=12.4Hz),16.8.

[0335] 31 P NMR , δ33.6,30.1.

[0336] HRMS(ESI)for:C 35 H 33 P2O2[M+H] + :calcd 547.1955,found 547.1957.

[0337] Take 10 ml of sealed tube and add substrate (300 mg, 0.6 mmol) was replaced with nitrogen three times. Phenylsilane (3 mL) was added and reacted at 130 ° C for 12 hours. Column chromatography was used for purification. The reaction solution was directly loaded and eluted with petroleum ether to remove excess phenylsilane. Then, the white target (S, S) chiral phosphine ligand was obtained by elution with petroleum ether and ethyl acetate system. (160 mg, 57%). Its characterization data are:

[0338] 1 H NMR (500MHz, CDCl3) δ7.53–7.45(m,4H),7.38–7.32(m,3H),7.32–7.26(m,5H),7.23–7.07(m,9H),7.05(d,J=7.4Hz,1H),7.00(t,J =7.4Hz,1H),6.88(d,J=7.6Hz,1H),3.12–3.05(m,1H),3.05–2.90(m,2H),2.87–2.74(m,2H),2.19–2.05(m,2H),1.69–1.59(m,1H).

[0339] 31 P NMRδ-15.51(d,J=10.1Hz),-20.69(d,J=10.0Hz).

[0340] 13C NMR (125MHz, CDCl3) δ140.7(dd,J=5.5,2.8Hz),139.7(d,J=13.6Hz),137.5(d,J=14.3Hz),137.2(d,J=13.6Hz),136 .1(d,J=12.4Hz),135.6,133.9(d,J=20.7Hz),133.6(d,J=19.7Hz),133.4(d,J=19.4Hz),132.5(d,J=18.5Hz),130.0 (d,J=7.1Hz),129.2,129.0,128.6,128.6(d,J=2.3Hz),128.4(d,J=2.4Hz),128.4,128.1(d,J=6.5Hz),128.0,126.6 ,124.8,38.0(dd,J=9.6,6.5Hz),37.4(dd,J=13.1,10.3Hz),31.8–31.4(m),27.9(d,J=10.1Hz),20.3(d,J=17.3Hz).

[0341] HRMS(ESI)for:C 35 H 33 P2[M+H] + :calcd 515.2057, found 515.2052.

[0342] Take a 100 ml round-bottom flask, add the chiral β-phosphonocarbonate 2a (1.4 g, 3.6 mmol, 1.0 equiv.) prepared in Example 5, toluene (36 mL) and DBU (2.7 mL, 18.0 mmol, 5.0 equiv.) in sequence, and stir at 85 ° C for 24 hours. Add TBME (20 mL) to dilute, and wash with 2N hydrochloric acid (3×20 mL) and saturated sodium chloride (1×20 mL) in sequence. The crude product obtained after evaporation and concentration was dissolved in TBME (3 mL), and a white solid was precipitated under ultrasound. (760 mg, 54% yield, >99% ee, >99% de). After evaporation and concentration of the mother liquor, toluene (20 mL) and DBU (1.35 mL) were added and stirred at 85°C for 24 hours. The above operation was repeated to obtain (R, S)-configured (370mg, 27% yield, >99%ee, >99%de).

[0343] The characterization data are:

[0344] 1H NMR (500MHz, CDCl3) δ7.94–7.81(m,4H),7.56–7.41(m,6H),7.28–7.22(m,1H),7 .14–7.06(m,2H),7.05(dd,J=6.7,2.3Hz,1H),4.26(dd,J=16.1,8.0Hz,1H),3.77 (dt,J=10.8,6.8Hz,1H),3.51–3.42(m,2H),2.88–2.73(m,2H),2.10–2.01(m,1H) ,1.89–1.77(m,1H),1.42–1.33(m,2H),1.26–1.17(m,2H),0.85(t,J=7.4Hz,3H).

[0345] 31 P NMR δ 33.6.

[0346] 13 C NMR (125MHz, CDCl3) δ174.0 (d, J=3.5Hz), 137.45, 132.2 (d, J=2.0Hz), 132.0 (d, J= 29.9Hz),131.8(d,J=2.7Hz),131.8(d,J=2.7Hz),131.7,131.6,131.3(d,J=37.7H z),131.1,131.1,128.9,128.8,128.7,128.6,128.5,128.4,127.0,126.4,65.1,4 3.4, 36.3 (d, J = 72.0Hz), 30.3, 29.2 (d, J = 12.5Hz), 21.8 (d, J = 2.1Hz), 19.1, 13.7.

[0347] HRMS(ESI)for:C 27 H 30 O3P[M+H] + :calcd 443.1932,found 443.1935. Application Example 2 Application of chiral phosphine ligands

[0348] Take five 5mL quartz tubes, add catalyst Rh(COD)2BArF (2.4mg, 0.00125mmol, 4mol%), corresponding ligand (compound 11 1.05mg, chiral phosphine ligand 4 synthesized in Application Example 1 1.24mg, chiral phosphine ligand 6 synthesized in Application Example 1 1.24mg, 0.0015mmol, 4.8mol%) and ultra-dry CH2Cl2 (0.3mL), stir at room temperature in the glove box for 30 minutes to obtain an orange liquid. Hydrogenation precursor 9 (20.5mg, 0.1mmol, 1.0equiv.) and ultra-dry CH2Cl2 (0.3mL) are added to the above orange catalyst solution in sequence. After transferring the quartz tube to a high-pressure reactor, hydrogen is used to replace the air in the autoclave. After three replacements, the hydrogen pressure is controlled at 40Bar, and the temperature is controlled to 40°C, and stirred vigorously for 36 hours. The reaction solution was concentrated under reduced pressure at room temperature, and the hydrogenation product was separated and purified by column chromatography, and the product ee value was determined by HPLC. The chiral phosphine ligands 4 and 6 both showed good reactivity, and the yields of compound 11, chiral phosphine ligand 4, and chiral phosphine ligand 6 were 98%, 99%, and 95%, respectively, and the ee values ​​were 11% ee, 36% ee, and 33% ee, respectively.

[0349]

[0350] The characterization data are:

[0351] 1 H NMR (500MHz, CDCl3) δ7.37–7.28(m,4H),7.27–7.22(m,1H),3.65(s,3H),3.15(d ,J=10.6Hz,1H),2.45–2.23(m,1H),1.03(d,J=6.4Hz,3H),0.70(d,J=6.8Hz,3H).

[0352] 13 C NMR (125MHz, CDCl3) δ174.48,138.35,128.49,128.47,127.24,60.00,51.75,31.93,21.50,20.21.

[0353] HRMS(ESI)for:C 13 H 19 O2[M+H] + :calcd 207.1385, found 207.1381.

[0354] The embodiments described above provide a detailed description of the technical solutions of the present invention. It should be understood that the above are only specific embodiments of the present invention and are not intended to limit the present invention. Any modifications, supplements or similar substitutions made within the scope of the principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A chiral β-phosphonocarbonate, characterized in that: The structural formula is shown in formula (I): In formula (I), R 1 Each is independently selected from one of methoxy, furyl, phenyl or substituted phenyl; R 2 is at least one of ethyl, propyl, butyl and benzyl; R 3 , R 4 , R 5 Each is independently selected from one of hydrogen, methoxy, methyl, halogen, methyl ester, or R 4 and R 5 A dioxolane structure is formed.

2. The chiral β-phosphonocarbonate according to claim 1, characterized in that R 1 In the above, the substituent in the substituted phenyl group is methyl, methoxy, butyl, halogen or phenyl.

3. The method for preparing a chiral β-phosphonocarbonate according to claim 1 or 2, characterized in that: include: Under a hydrogen atmosphere, the hydrogenation precursor and the metal ligand complex shown in formula (II) undergo an asymmetric hydrogenation reaction in an organic solvent system to prepare the chiral β-phosphonocarbonate; Among them, in formula (II), R 1 , R 2 , R 3 , R 4 , R 5 The definition of is the same as that of formula (I).

4. The method for preparing a chiral β-phosphonocarbonate according to claim 3, characterized in that: The metal ligand complex is a metal salt and (S)- t Bu-PHOX is obtained by mixing and stirring methanol and hexafluoroisopropanol solutions.

5. The method for preparing a chiral β-phosphonocarbonate according to claim 4, characterized in that: The metal salt is nickel acetate, nickel acetate and (S)- t The molar ratio of Bu-PHOX is 1:1-2.

6. The method for preparing a chiral β-phosphonocarbonate according to claim 3, characterized in that: The molar ratio of the metal ligand complex to the hydrogenation precursor is 0.03-0.10:1; and the organic solvent is hexafluoroisopropanol.

7. The method for preparing a chiral β-phosphonocarbonate according to claim 3, characterized in that: The reaction temperature of the asymmetric hydrogenation reaction is 40-100°C and the reaction time is 24-48h.

8. Use of the chiral β-phosphonocarbonate according to claim 1 in the synthesis of chiral phosphine ligands.

9. A chiral phosphine ligand, characterized in that: The chiral β-phosphonocarbonate is prepared from the chiral β-phosphonocarbonate according to claim 1 or 2.

10. Use of the chiral phosphine ligand according to claim 9 in an asymmetric catalytic reaction.

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