Chiral beta-phosphonocarbonic esters, processes for their preparation and use

Abstract

The application discloses a kind of chiral β-phosphonocarbonic ester and its preparation method and application, belong to organic synthesis technical field, the structure formula of the chiral β-phosphonocarbonic ester is as shown in following formula, its preparation method is simple and efficient, under hydrogen atmosphere, by hydrogenation precursor, metal ligand complex occurs asymmetric hydrogenation reaction in organic solvent system and is prepared, wherein, the metal ligand complex utilizes metal salt and (S)- t Bu-PHOX is obtained after stirring in methanol and hexafluoroisopropanol solution. This method has mild conditions, high yield, and can obtain the target chiral β-phosphonocarbonic ester with high enantioselectivity. Further, it can be used to synthesize chiral phosphine ligands, which has wide application prospects in the field of asymmetric catalysis.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a chiral beta-phosphoryl carbonate, a preparation method and application thereof. BACKGROUND

[0002] Chirality is a common phenomenon in nature (commonly found in natural products and drugs) and plays an important role in the fields of medicinal chemistry and organic synthesis. Asymmetric catalytic reaction is one of the methods for efficiently and atom-economically synthesizing chiral compounds. For example, a preparation method of optically pure trans-2-(diphenylphosphino)-1-cyclohexanecarboxylic acid is disclosed in Chinese Patent Publication No. CN111484523A. The invention obtains a first intermediate by addition reaction of 1-cyclohexene-1-carboxylate and diphenylphosphine oxide, and then obtains cis-2-(diphenylphosphino)-1-cyclohexanecarboxylic acid methyl ester by reduction of the first intermediate. The trans-2-(diphenylphosphino)-1-cyclohexanecarboxylic acid methyl ester is obtained by adding a flipping agent and a solvent to the cis-2-(diphenylphosphino)-1-cyclohexanecarboxylic acid methyl ester, heating and refluxing, and then extracting and drying. The optically pure trans-2-(diphenylphosphino)-1-cyclohexanecarboxylic acid is obtained by hydrolysis, acidification and re-extraction. Asymmetric catalytic reaction not only solves the problem of chiral control that is difficult to overcome by traditional synthesis methods, but also has less by-product generation, higher raw material utilization rate, and is more in line with the development concept of green chemistry. The key scientific problem is the design and development of chiral ligands.

[0003] Chiral phosphine ligands are an important class of chiral ligands, of which the most representative include the BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) series. BINAP was synthesized by Noyori in 1980, and it has shown good enantioselectivity in chiral catalysis. Catalysts of BINAP and various metals (Ru, Pd, Ag, Rh, Ir, Au) complexes are continuously used in various reactions. For example, Chinese Patent Publication No. CN118106039A discloses a BINAP-coordinated copper cluster catalyst, its preparation method and application. The invention uses BINAP (1,1'-binaphthalene-2,2'-bis-diphenylphosphine), copper salt and amino acid to prepare a BINAP-coordinated copper cluster catalyst, which has a wide application prospect in intramolecular Diels-Alder reaction. Chinese Patent Publication No. CN111450880A discloses a class of sulfonated BINAP and polyether functionalized ionic liquid integrated chiral catalysts. The invention integrates the transition metal complex of chiral bisphosphine ligand BINAP with polyether functionalized ionic liquid to obtain a class of catalysts integrated with phosphine ligand and ionic liquid, which has obvious advantages in asymmetric hydrogenation reaction. Therefore, in order to promote the development of asymmetric catalytic reaction, more chiral phosphine ligands and their precursors need to be developed. SUMMARY

[0004] The present application provides a chiral beta-phosphonocarbonate which can be used as a precursor for synthesizing chiral phosphine ligands, and a preparation method thereof is simple and efficient, has mild conditions, high yield and high enantioselectivity.

[0005] The specific technical solutions are as follows:

[0006] A chiral beta-phosphonocarbonate has a structural formula as shown in formula (I):

[0007]

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

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

[0010] R 3 , R 4 , R 5 are each independently selected from one of hydrogen, methoxy, methyl, halogen or methyl ester, or R 4 and R 5 form a dioxolane structure.

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

[0012] The present application also provides a preparation method of the chiral beta-phosphonocarbonate, comprising:

[0013] The chiral beta-phosphonocarbonate is prepared by asymmetric hydrogenation of a hydrogenated precursor of formula (II) and a metal ligand complex in an organic solvent system under a hydrogen atmosphere;

[0014]

[0015] In formula (I) and formula (II), R 1 , R 2 , R 3 , R 4 , R 5 are defined as above.

[0016] Preferably, the metal ligand complex is prepared by using a metal salt and (S)- tBu-PHOX (commercially available, CAS: 148461-16-9) was obtained by mixing and stirring in methanol and hexafluoroisopropanol solution.

[0017] Further 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 and 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℃, and the reaction time is 24-48h.

[0021] In the above asymmetric hydrogenation reaction, the obtained product is chiral β-phosphoryl carbonate of (S,S) and (R,R) configurations, and the ee value of chiral β-phosphoryl carbonate of (S,S) configuration is >90%.

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

[0023] Method one:

[0024] (S01) The system containing β-tetralone or β-tetralone derivative, carbonate, NaH and tetrahydrofuran is reacted at 0-100℃ for 2-12h, and the first intermediate is prepared by post-treatment;

[0025] (S02) The dichloromethane solution of the first intermediate is cooled to -50–-80℃, then N,N-diisopropyl ethylamine and trifluoromethanesulfonic anhydride are added, and the second intermediate is prepared by post-treatment after reacting for 1-12h;

[0026] (S03) The second intermediate, palladium acetate, 1,4-bis(diphenylphosphine) butane (DPPB) and phosphine oxide compound are mixed, then dimethyl sulfoxide and N,N-diisopropyl ethylamine are added, and the hydrogenation precursor is prepared by post-treatment after reacting at 60-100℃ for 1-5h;

[0027] The structural formula of the β-tetralone derivative is as follows:

[0028]

[0029] Method two:

[0030] (S04) The system containing bromine-substituted β-tetrahydronaphthone, carbonate, NaH and tetrahydrofuran is reacted at 0-100℃ for 2-12h, and the third intermediate is prepared after post-treatment.

[0031] (S05) Cool the dichloromethane solution of the third intermediate to -50–-80℃, then add N,N-diisopropylethylamine and trifluoromethanesulfonic anhydride, react for 1–12 h, and then prepare the fourth intermediate after post-treatment;

[0032] (S06) The fourth intermediate, tris(dibenzylacetone)dipalladium (Pd2(dba)3), DPPB, and phosphine oxide were mixed, and then toluene and N,N-diisopropylethylamine were added. The mixture was reacted at 60-120℃ for 5-20 h, and the fifth intermediate was prepared after post-treatment.

[0033] (S07) Mix the fifth intermediate, cesium carbonate, tris(dibenzylacetone)palladium (Pd2(dba)3), and BrettPhos ligand (which can be purchased directly, CAS: 1070663-78-3), then add toluene and methanol, react at 60-120℃ for 5-10 h, and prepare the hydrogenated precursor after post-processing;

[0034] Method 3:

[0035] The fifth intermediate and tetra(triphenylphosphine)palladium were mixed, and then tetrahydrofuran and AlMe3 were added. The mixture was reacted at 60-120℃ for 5-10 h, and the hydrogenated precursor was prepared after post-treatment.

[0036] Method 4:

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

[0038] The present invention also provides the application of the chiral β-phosphonocarbonate in the synthesis of chiral phosphine ligands.

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

[0040] Specifically, with For example, After recrystallization to achieve 99% optical purity, the compound was reduced by lithium aluminum hydride to introduce a p-toluenesulfonyl group, yielding the compound. Further substitution reactions using lithium diphenylphosphonate and redox reactions with phenylsilanes yielded (S,S)-configured compounds.

[0041] After recrystallization to reach 99% optical purity, isomerization reaction under the thermodynamic condition promoted by bicyclic amidine DBU is carried out to obtain After the reduction reaction of lithium aluminum hydride, p-tolylsulfonyl is introduced, and the substitution reaction of lithium diphenylphosphonate and phenylsilane oxidation-reduction reaction are carried out to obtain (R, S) configuration of

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

[0043] Compared with the prior art, the application has the beneficial effects that:

[0044] The asymmetric hydrogenation method catalyzed by the metal ligand complex has the advantages of mild reaction conditions, high yield, simplicity, high efficiency, and the target chiral β-phosphoryl carbonate can be obtained with high enantioselectivity, the highest yield reaches 99%, the ee value of the product is greater than 90%, and the target chiral β-phosphoryl carbonate can be used as a precursor to synthesize a chiral phosphine ligand, and has wide application prospects in asymmetric catalytic reaction. DETAILED DESCRIPTION

[0045] The application will be further illustrated by the following examples. It should be understood that the examples are only used to illustrate the application, and are not used to limit the scope of the application. The operation methods not specified in the following examples are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturers. The contents not described in detail in the specification belong to the prior art known to those skilled in the art.

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

[0047]

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

[0049]

[0050] Synthesis of hydrogenation precursor in example 1

[0051] This example takes the preparation of hydrogenation precursor 1a(reaction scheme as shown below) as an example to illustrate the preparation method of the hydrogenation precursor (1a-1o, 1s-1z) of the application in detail:

[0052]

[0053] First step: Take a 50 mL dry round bottom flask with a magnetic bar, under nitrogen atmosphere, add NaH (60 w%, 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, then slowly add the solution of β-tetralone (0.8 M in THF, 4.0 mmol, 1.0 equiv.), continue to stir at 0 °C for 10 minutes. After the mixture is refluxed at 100 °C for 12 hours, monitor the reaction progress by TLC. After the reaction is completed, quench the reaction with saturated ammonium chloride (10 mL) and extract with methyl tert-butyl ether TBME (3 x 20 mL). Wash the combined organic layers with brine (10 mL), dry over anhydrous sodium sulfate, filter and concentrate under vacuum to obtain the β-ketoester intermediate S2, which is used directly in the next step.

[0054] Second step: Take a 50 mL dry round bottom flask with a magnetic bar, under nitrogen atmosphere, add the β-ketoester intermediate S2 obtained in the previous step and dichloromethane DCM (10 mL), cool to -78 °C, then add DIPEA (0.96 mL, 8.0 mmol, 2.0 equiv.). Slowly add trifluoromethanesulfonic anhydride Tf20 (0.96 mL, 6.0 mmol, 1.5 equiv.), stir at -78 °C for 4 hours. After the starting material is completely converted, quench the reaction by adding saturated sodium bicarbonate solution (10 mL), extract with dichloromethane (3 x 10 mL), and combine the organic phases. Dry the organic phase over anhydrous sodium sulfate after washing once with saturated sodium chloride (10 mL), filter and concentrate under vacuum, and purify the crude product by column chromatography to obtain the coupling precursor.

[0055] Third step: Put 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 diphenyl phosphine oxide into a 50 mL round bottom flask, and replace with nitrogen three times. Add DMSO (20 mL) and DIPEA (2.16 ml, 18.0 mmol, 4.5 equiv.), stir at 100 °C for 2 hours. Quench the reaction by adding water (40 mL), extract with methyl tert-butyl ether (3 x 20 mL), wash the combined organic phases with saturated sodium chloride (10 mL), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure, and purify the filtrate by column chromatography to obtain the target hydrogenation precursor.

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

[0057]

[0058] When preparing hydrogenation precursor 1n, 1o, 1s, 1t, on the basis of the above step method, the corresponding β-tetralone derivative is used instead of β-tetralone; when preparing hydrogenation precursor 1u-1w, on the basis of the above step method, the corresponding β-tetralone derivative is used instead of β-tetralone, and the corresponding carbonate (diethyl carbonate, dipropyl carbonate, dibenzyl carbonate) is used instead of dibutyl carbonate; when preparing hydrogenation precursor 1x-1z, on the basis of the above step method, the corresponding carbonate (diethyl carbonate, dipropyl carbonate, dibenzyl carbonate) is used instead of dibutyl carbonate, and other conditions remain unchanged.

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

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

[0061] 1 H NMR (600 MHz, CDC13) δ 7.84-7.74 (m, 4H), 7.59-7.53 (m, 2H), 7.51-7.45 (m, 4H), 7.28 (d, J = 7.6 Hz, 1H), 7.26 (s, 1H), 7.25-7.21 (m, 1H), 7.15 (d, J = 7.2 Hz, 1H), 4.05-3.99 (m, 2H), 2.80 (t, J = 7.8 Hz, 2H), 2.39-2.28 (m, 2H), 1.56-1.50 (m, 2H), 1.33-1.23 (m, 3H), 0.85 (t, J = 7.4 Hz, 3H).

[0062] 13 C NMR (150 MHz, CDC13) δ 167.74 (d, J = 7.8 Hz), 144.06 (d, J = 5.8 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, 130.6 (d, J = 12.9 Hz), 129.9, 128.8 (d, J = 95.1 Hz), 128.5 (d, J = 12.1 Hz), 127.5 (d, J = 91.9 Hz), 125.5, 65.58, 30.2, 27.2 (d, J = 6.4 Hz), 24.7 (d, J = 9.6 Hz), 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 (600 MHz, CDC13) δ 7.82 - 7.75 (m, 4H), 7.31 - 7.27 (m, 1H), 7.25 (dd, J = 7.1, 1.7 Hz, 2H), 7.21 - 7.15 (m, 5H), 4.02 (t, J = 6.8 Hz, 2H), 2.81 (t, J = 7.9 Hz, 2H), 2.40 - 2.27 (m, 2H), 1.56 - 1.51 (m, 2H), 1.33 - 1.25 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H).

[0066] 13 C NMR (150 MHz, CDC13) δ 167.6 (d, JC-P = 7.7 Hz), 165.2 (dd, JC-F = 254.4, J = 3.2 Hz), 144.4 (d, J = 6.0 Hz), 136.0 (d, JC-P = 2.2 Hz), 135.0 (dd, J = 11.6, JC-F = 8.7 Hz), 130.3 (d, J = 13.0 Hz), 130.1, 128.1 (J = 386.9), 127.9, 127.6 (d, J = 3.4 Hz), 127.2, 126.9 (d, JC-F = 3.4 Hz), 125.5, 65.7, 30.2, 27.1 (d, J = 6.5 Hz), 24.5 (d, J = 9.6 Hz), 19.1, 13.7.

[0067] 19 F NMR: δ -106.0.

[0068] 31 P NMR δ 26.9.

[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] 1H NMR (600 MHz, CDC13): 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 C NMR (150 MHz, CDC13): 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 P NMR: δ 27.2.

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

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

[0076] 1 H NMR (600 MHz, CDC13): 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 (150MHz, 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,J)C-P = 13.2 Hz), 65.6, 55.4, 30.2, 27.2 (d, J = 6.4 Hz), 24.6 (d, J = 9.4 Hz), 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: 830 mg, 56% yield.

[0091] 1 H NMR (600 MHz, CDC13): δ 7.71 (dd, J = 11.8, 8.2 Hz, 4H), 7.48 (dd, J = 8.4, 2.6 Hz, 4H), 7.26 - 7.20 (m, 4H), 7.14 (d, J = 7.3 Hz, 1H), 3.98 (t, J = 6.8 Hz, 2H), 2.80 (t, J = 7.9 Hz, 2H), 2.35 (q, J = 7.6 Hz, 2H), 1.55 - 1.49 (m, 2H), 1.33 (s, 18H), 1.30 - 1.24 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H).

[0092] 13 C NMR (150 MHz, CDC13): δ 169.6, 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] Hydrogenated 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 19 31 H318O5P [M + H] + : calcd 491.1987, found 491.1996.

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

[0101] 1 H NMR (600 MHz, CDC13): 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 C NMR (150 MHz, CDC13): 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 P NMR: δ 28.9.

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

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

[0106] 1H NMR (600 MHz, CDC13): δ 7.40 - 7.34 (m, 4H), 7.33 - 7.27 (m, 3H), 7.26 - 7.20 (m, 2H), 7.15 (dd, J = 7.4, 1.5 Hz, 1H), 7.10 - 7.05 (m, 2H), 4.03 (t, J = 6.8 Hz, 2H), 3.81 (s, 6H), 2.80 (t, J = 7.9 Hz, 2H), 2.34 (q, J = 7.7 Hz, 2H), 1.57 - 1.47 (m, 2H), 1.31 - 1.22 (m, 3H), 0.85 (t, J = 7.4 Hz, 3H).

[0107] 13 C NMR (150 MHz, CDC13): δ 167.7 (d, J = 7.7 Hz), 159.6 (d, J = 15.0 Hz), 144.0 (d, J = 5.9 Hz), 136.1 (d, J = 2.3 Hz), 133.2, 132.4, 130.6 (d, J = 12.9 Hz), 129.9, 129.6 (d, J = 14.4 Hz), 128.9 (d, J = 95.4 Hz), 127.5 (d, J = 90.6 Hz), 125.5, 124.4 (d, J = 10.2 Hz), 118.4 (d, J = 2.7 Hz), 116.8 (d, J = 11.1 Hz), 65.6, 55.5, 30.2, 27.2 (d, J = 6.4 Hz), 24.8 (d, J = 9.5 Hz), 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] 1H NMR (600 MHz, CDC13): 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 C NMR (150 MHz, CDC13): 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 P NMR: δ 29.1.

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

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

[0116] 1 H NMR (600 MHz, CDC13): 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] 13C NMR (150 MHz, CDC13): 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 P NMR: δ -0.23.

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

[0120] Hydrogenated Precursor 1m: 760 mg, 42% yield.

[0121] 1 H NMR (600 MHz, CDC13): 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 C NMR (150 MHz, CDC13): 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 P NMR: δ 19.2.

[0124] HRMS (ESI) for: C 17 H 23 O5PNa[M+Na] + : calcd 361.1187, found 361.1177.

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

[0126] 1 H NMR (600 MHz, CDC13): δ 7.82 - 7.74 (m, 4H), 7.57 - 7.52 (m, 2H), 7.50 - 7.44 (m, 4H), 7.19 (t, J = 8.1 Hz, 1H), 6.90 (dd, J = 17.5, 8.0 Hz, 2H), 4.02 (t, J = 6.8 Hz, 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 = 7.4 Hz, 3H).

[0127] 13 C NMR (150 MHz, CDC13): δ 167.9 (d, J = 7.8 Hz), 156.1, 144.1 (d, J = 5.9 Hz), 132.2 (d, J = 10.1 Hz), 132.0 (d, J = 2.8 Hz), 131.5 (d, J = 104.8 Hz), 131.4 (d, J = 12.7 Hz), 128.8 (d, J = 94.5 Hz), 128.5 (d, J = 12.2 Hz), 127.2, 124.3 (d, J = 2.3 Hz), 118.0, 112.2, 65.6, 55.6, 30.2, 24.2 (d, J = 9.4 Hz), 19.3 (d, J = 6.4 Hz), 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 (600 MHz, CDC13): δ 7.83 - 7.75 (m, 4H), 7.58 - 7.53 (m, 2H), 7.51 - 7.44 (m, 4H), 7.06 (d, J = 8.3 Hz, 1H), 6.88 (d, J = 2.6 Hz, 1H), 6.82 (dd, J = 8.2, 2.6 Hz, 1H), 4.05 (t, J = 6.8 Hz, 2H), 3.76 (s, 3H), 2.72 (dd, J = 9.0, 6.7 Hz, 2H), 2.33 - 2.25 (m, 2H), 1.58 - 1.49 (m, 2H), 1.33 - 1.25 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H).

[0132] 13 C NMR (150 MHz, CDC13): δ 167.7 (d, J = 7.8 Hz), 158.6 (d, J = 1.7 Hz), 144.0 (d, J = 5.7 Hz), 132.2 (d, J = 10.1 Hz), 132.1 (d, J = 2.8 Hz), 131.9, 131.3 (d, J = 13.0 Hz), 131.0, 129.4 (d, J = 94.8 Hz), 128.5 (d, J = 12.1 Hz), 128.2 (d, J = 2.3 Hz), 115.4, 111.0, 65.6, 55.4, 30.2, 26.3 (d, J = 6.5 Hz), 25.2 (d, J = 9.5 Hz), 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] 1H NMR (600 MHz, CDC13): 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 C NMR (150 MHz, CDC13): 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 P NMR: δ 28.5.

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

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

[0141] 1H NMR (600 MHz, CDC13): 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 C NMR (150 MHz, CDC13): 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 P NMR: δ 28.4.

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

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

[0146] 1 H NMR (600 MHz, CDC13): 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 (150 MHz, CDC13): δ 167.7 (d, J = 7.7 Hz), 148.6, 146.6, 143.8 (d, J = 6.0 Hz), 132.2 (d, J = 9.9 Hz), 132.0 (d, J = 2.6 Hz), 131.3, 131.3 (d, J = 2.5 Hz), 128.5 (d, J = 12.4 Hz), 126.3 (d, J = 96.9 Hz), 124.2 (d, J = 13.5 Hz), 108.4, 106.0, 101.4, 61.7, 27.6 (d, J = 6.6 Hz), 24.8 (d, J = 9.7 Hz), 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 (600 MHz, CDC13): δ 7.83 - 7.75 (m, 4H), 7.59 - 7.53 (m, 2H), 7.51 - 7.45 (m, 4H), 6.67 (s, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 3.68 - 3.58 (m, 3H), 2.75 (t, J = 7.9 Hz, 2H), 2.26 (q, J = 7.8 Hz, 2H), 2.16 (s, 3H), 1.28 - 1.14 (m, 3H).

[0152] 13 C NMR (150 MHz, CDC13): δ 167.8 (d, J = 7.8 Hz), 156.5 (d, J = 170.8 Hz), 144.0 (d, J = 6.0 Hz), 132.2, 132.2, 132.1 (d, J = 2.7 Hz), 131.9, 131.2, 129.0 (d, J = 13.0 Hz), 128.9, 128.5, 128.5, 128.2, 122.2, 121.4 (d, J = 2.5 Hz), 103.6, 61.6, 60.4, 55.7, 24.8 (d, J = 9.7 Hz), 20.1 (d, J = 6.4 Hz), 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 (600 MHz, CDC13): δ 7.81 - 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 = 7.1 Hz, 2H), 3.89 (s, 3H), 3.83 (s, 3H), 2.73 (dd, J = 9.3, 6.7 Hz, 2H), 2.29 (q, J = 7.7 Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H).

[0157] 13 C NMR (150 MHz, CDC13): δ 167.8 (d, J = 7.6 Hz), 150.2, 147.6, 143.7 (d, J = 6.2 Hz), 132.2, 132.2, 132.1, 132.0 (d, J = 2.7 Hz), 131.4, 129.6 (d, J = 2.5 Hz), 128.5 (d, J = 12.1 Hz), 126.2 (d, J = 96.6 Hz), 123.0 (d, J = 13.3 Hz), 111.0, 108.9, 61.6, 56.0 (d, J = 3.4 Hz), 27.1 (d, J = 6.5 Hz), 24.9 (d, J = 9.7 Hz), 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] 1H NMR (600 MHz, CDC13): 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 C NMR (150 MHz, CDC13): 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 P NMR: δ 28.6.

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

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

[0166] 1 H NMR (600 MHz, CDC13): 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] 13C NMR (150 MHz, CDC13): 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 P NMR: δ 28.6.

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

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

[0171] 1 H NMR (600 MHz, CDC13): 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 C NMR (150 MHz, CDC13): 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 hydrogenation precursor

[0176] The synthetic route for the hydrogenation precursor 1p is shown below:

[0177]

[0178] Take a 50 mL magnetically fitted dry round-bottom flask and, under a nitrogen atmosphere, add NaH (60 w%, 324 mg, 8.4 mmol, 2.1 equiv.), dibutyl carbonate (1.9 mL, 16.0 mmol, 4.0 equiv.), and tetrahydrofuran (10 mL). After stirring at 0 °C for 5 minutes, slowly add a solution of compound S3 (0.8 M in THF, 4.0 mmol, 1.0 equiv.), and continue stirring at 0 °C for 10 minutes. Reflux the mixture at 100 °C and stir for 12 hours, then monitor the reaction progress by TLC. After the reaction is complete, quench the reaction with saturated ammonium chloride (10 mL) and extract with methyl tert-butyl ether (TBME) (3 × 20 mL). Wash the combined organic layers with brine (10 mL), dry to anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain compound S4, which can be used directly in the next step.

[0179] Take a 50 mL magnetically sealed, dry round-bottom flask. Under a nitrogen atmosphere, add compound S4 obtained in the previous step and dichloromethane (DCM) (10 mL). After cooling to -78 °C, 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.), and stir at -78 °C for 4 hours. After complete conversion of the starting material, quench the reaction with saturated sodium bicarbonate solution (10 mL), extract with dichloromethane (3 × 10 mL), and combine the organic phases. Wash the organic phase once with saturated sodium chloride (10 mL), dry it with anhydrous sodium sulfate, filter, and concentrate under vacuum. The crude product is purified by column chromatography to obtain the 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 into a 100 mL round-bottom flask, which was replaced with nitrogen for 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 h. After the raw material was consumed, the reaction solution was concentrated, and the crude product was separated and purified by column chromatography to obtain compound S6 (2.2 g, 80%) as a white solid.

[0181] A 20 mL round-bottom flask was taken, and 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.) were added, which was replaced with nitrogen for three times. Toluene (8 mL) and methanol (1 mL) were added, and the mixture was stirred at 85 °C for 10 h. After being concentrated under reduced pressure, hydrogenation precursor 1p was obtained by column chromatography.

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

[0183] 1 H NMR (500 MHz, CDCl3): δ 7.81-7.74 (m, 4H), 7.57-7.52 (m, 2H), 7.50-7.44 (m, 4H), 7.21 (d, J = 8.6 Hz, 1H), 6.74 (dd, J = 8.6, 2.7 Hz, 1H), 6.69 (d, J = 2.6 Hz, 1H), 3.99 (t, J = 6.8 Hz, 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 = 7.4 Hz, 3H).

[0184] 13C NMR (125 MHz, CDC13): δ 167.9 (d, J = 7.6 Hz), 160.8, 143.8 (d, J = 6.0 Hz), 138.3 (d, J = 2.4 Hz), 132.2 (d, J = 10.2 Hz), 132.0 (d, J = 2.8 Hz), 131.8 (d, J = 104.0 Hz), 128.4 (d, J = 12.1 Hz), 127.1, 125.5 (d, J = 97.5 Hz), 123.7 (d, J = 12.7 Hz), 113.8, 111.8, 65.5, 55.4, 30.2, 27.7 (d, J = 6.6 Hz), 24.6 (d, J = 9.7 Hz), 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.

[0187] The synthesis route of hydrogenation precursor 1q is shown below:

[0188]

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

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

[0191] 1H NMR (500 MHz, CDC13): 7.82-7.75 (m, 4H), 7.57-7.52 (m, 2H), 7.50-7.44 (m, 4H), 7.16 (dd, J = 7.9, 1.5 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.97 (s, 1H), 3.99 (t, J = 6.8 Hz, 2H), 2.75 (t, J = 7.9 Hz, 2H), 2.35-2.28 (m, 5H), 1.56-1.48 (m, 2H), 1.33-1.22 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H).

[0192] 13 C NMR (125 MHz, CDC13): 167.8 (d, J = 7.5 Hz), 144.1 (d, J = 5.9 Hz), 140.2, 136.1 (d, J = 2.2 Hz), 132.2 (d, J = 10.0 Hz), 132.0 (d, J = 2.5 Hz), 131.3, 128.6, 128.5, 128.4, 128.0 (d, J = 13.2 Hz), 127.7, 127.1, 125.5, 65.5, 30.2, 27.3 (d, J = 6.4 Hz), 24.7 (d, J = 9.6 Hz), 21.4, 19.1, 13.7.

[0193] 31 P NMR: 28.3.

[0194] HRMS (ESI) for: C 28 H 30 O3P[M+H] + : calcd 445.1933, found 445.1938.

[0195] The synthesis route of substrate 1r is shown below:

[0196]

[0197] A 50 mL round-bottom flask was charged 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 the mixture was stirred at 100 °C for 12 h. After concentration under reduced pressure, the hydrogenation precursor 1r was isolated and purified by column chromatography.

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

[0199] 1 H NMR (500 MHz, Chloroform-d): δ 7.90 (dd, J = 8.1, 1.8 Hz, 1H), 7.84 - 7.75 (m, 5H), 7.61 - 7.54 (m, 2H), 7.53 - 7.45 (m, 4H), 7.37 (d, J = 8.2 Hz, 1H), 4.07 (t, J = 6.8 Hz, 2H), 3.91 (s, 3H), 2.85 (t, J = 7.9 Hz, 2H), 2.35 (q, J = 7.6 Hz, 2H), 1.58 - 1.50 (m, 2H), 1.33 - 1.22 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H).

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

[0203] The corresponding chiral β- phosphonocarbonates were synthesized using the hydrogenation precursors prepared in Examples 1-4 as substrates, respectively:

[0204] Take 10 mL reaction tube, add anhydrous nickel acetate (21.2 mg, 0.120 mmol) successively, (S)- tBu-PHOX (55.8 mg, 0.144 mmol), super dry methanol (270 μί), HFIP (2.45 mL), deep red liquid (0.04 M) was obtained after stirring at room temperature in glovebox for 18 h. 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 into dry quartz tube sequentially. After transferring the quartz tube into a high pressure reactor, the reactor was purged with hydrogen three times and the hydrogen pressure was controlled at 40 Bar while the temperature was controlled at 70 °C. The reaction was stirred vigorously for 48 h. The reaction mixture was concentrated at room temperature under reduced pressure. The hydrogenation product chiral β- phosphorocarbonates 2a-2z were isolated and purified by column chromatography.

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

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

[0207] 1 H NMR (600 MHz, CDC13): δ 7.84 - 7.74 (m, 4H), 7.59 - 7.53 (m, 2H), 7.51 - 7.45 (m, 4H), 7.28 (d, J = 7.6 Hz, 1H), 7.26 (s, 1H), 7.25 - 7.21 (m, 1H), 7.15 (d, J = 7.2 Hz, 1H), 4.05 - 3.99 (m, 2H), 2.80 (t, J = 7.9 Hz, 2H), 2.39 - 2.28 (m, 2H), 1.56 - 1.50 (m, 2H), 1.33 - 1.23 (m, 3H), 0.85 (t, J = 7.4 Hz, 3H).

[0208] 13 C NMR (125 MHz, CDC13): δ 167.7 (d, J = 7.8 Hz), 144.1 (d, J = 5.8 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, 130.6 (d, J = 12.9 Hz), 129.9, 128.8 (d, J = 95.1 Hz), 128.5 (d, J = 12.1 Hz), 127.5 (d, J = 91.9 Hz), 125.5, 65.6, 30.2, 27.2 (d, J = 6.4 Hz), 24.7 (d, J = 9.6 Hz), 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 synthesis, HFIP volume 0.35 mL, catalyst 0.10 equiv.).

[0212] 1 H NMR (600 MHz, CDC13): δ 7.87 - 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 = 3.9 Hz, 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 = 7.4 Hz, 3H).

[0213] 13 C NMR (125 MHz, CDC13): δ 171.9 (d, J = 3.3 Hz), 166.0 (t, J = 2.9 Hz), 164.0 (t, J = 3.1 Hz), 136.0, 134.08 - 132.53 (m), 129.8, 128.6, 128.4 (d, J = 3.4 Hz), 127.9 (d, J = 3.3 Hz), 127.6, 127.1 (d, J = 3.5 Hz), 126.0, 116.3 (d, J = 3.1 Hz), 116.2 (d, J = 3.0 Hz), 116.2 (d, J = 3.1 Hz), 116.1 (d, J = 3.2 Hz), 65.0, 43.4 (d, J = 1.8 Hz), 38.3 (d, J = 73.9 Hz), 30.4, 28.5 (d, J = 13.3 Hz), 19.1, 18.0, 13.7.

[0214] 31 P NMR: δ 31.5.

[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 synthesis, HFIP volume 0.35 mL, catalyst 0.10 equiv.).

[0217] 1 H NMR (600 MHz, CDC13): δ 7.80 - 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 = 3.9 Hz, 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 = 7.4 Hz, 3H).

[0218] 13 C NMR (125 MHz, CDC13): δ 171.8 (d, J = 3.3 Hz), 138.7, 138.7 (d, J = 3.2 Hz), 135.9, 133.3 (d, J = 12.3 Hz), 132.5 (d, J = 9.5 Hz), 132.4 (d, J = 9.6 Hz), 130.6 (d, J = 56.4 Hz), 129.8, 129.8 (d, J = 57.2 Hz), 129.2 (d, J = 2.9 Hz), 129.1 (d, J = 2.6 Hz), 128.7, 127.6, 126.0, 65.1, 43.4 (d, J = 1.8 Hz), 38.0 (d, J = 73.7 Hz), 30.4, 28.5 (d, J = 13.2 Hz), 19.1, 17.9, 13.7.

[0219] 31 P NMR: δ 30.4.

[0220] HRMS (ESI) for: C 27 H 28 Cl203P [M + H] + : calcd 501.1153, found 501.1148.

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

[0222] 1H NMR (600 MHz, CDC13): δ 8.03 - 7.91 (m, 4H), 7.80 - 7.70 (m, 4H), 7.61 (t, J = 8.0 Hz, 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, 1.8 Hz, 2H), 4.07 (t, J = 6.8 Hz, 2H), 4.01 (d, J = 4.0 Hz, 1H), 3.15 - 3.03 (m, 1H), 2.96 - 2.77 (m, 3H), 1.98 (dd, J = 10.0, 5.0 Hz, 1H), 1.68 - 1.51 (m, 2H), 1.29 (h, J = 7.5 Hz, 2H), 0.88 (t, J = 7.4 Hz, 3H).

[0223] 13 C NMR (125 MHz, CDC13): δ 172.1 (d, J = 3.2 Hz), 144.6 (d, J = 2.6 Hz), 144.6 (d, J = 2.7 Hz), 139.9 (d, J = 7.2 Hz), 136.2, 133.8 (d, J = 12.3 Hz), 131.7 (d, J = 8.8 Hz), 131.6 (d, J = 9.0 Hz), 131.0 (d, J = 53.1 Hz), 130.2 (d, J = 54.2 Hz), 129.4 (d, J = 140.2 Hz), 129.0, 128.2, 127.5, 127.4 (d, J = 11.7 Hz), 127.3 (d, J = 2.9 Hz), 126.0, 65.1, 43.5 (d, J = 1.7 Hz), 38.2 (d, J = 73.0 Hz), 30.4, 28.6 (d, J = 13.0 Hz), 19.2, 17.9, 13.8.

[0224] 31 P NMR: δ 31.1.

[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 (600 MHz, CDC13): δ 7.76 - 7.68 (m, 4H), 7.29 (dd, J = 8.1, 2.6 Hz, 4H), 7.19 - 7.11 (m, 2H), 7.09 - 7.05 (m, 2H), 4.02 (t, J = 6.9 Hz, 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 = 8.0 Hz, 6H), 1.88 (t, J = 7.5 Hz, 1H), 1.62 - 1.54 (m, 2H), 1.31 - 1.25 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H).

[0228] 13 C NMR (125 MHz, CDC13): δ 172.1 (d, J = 3.3 Hz), 142.1 (d, J = 2.7 Hz), 142.0 (d, J = 2.7 Hz), 136.3, 133.9 (d, J = 12.0 Hz), 131.1 (d, J = 8.9 Hz), 131.0 (d, J = 9.1 Hz), 129.4 (d, J = 11.6 Hz), 129.4 (d, J = 56.3 Hz), 129.2 (d, J = 141.4 Hz), 128.6 (d, J = 57.1 Hz), 127.4, 125.8, 64.9, 43.5, 38.2 (d, J = 73.0 Hz), 30.4, 28.6 (d, J = 13.0 Hz), 21.6 (d, J = 5.6 Hz), 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, found 483.2070.

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

[0232] 1H NMR (600 MHz, CDC13): δ 7.77 - 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 = 5.9 Hz, 6H), 3.08 - 2.97 (m, 1H), 2.87 - 2.74 (m, 2H), 2.71 - 2.61 (m, 1H), 1.89 (d, J = 6.4 Hz, 1H), 1.62 - 1.53 (m, 2H), 1.32 - 1.24 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H).

[0233] 13 C NMR (125 MHz, CDC13): δ 172.1 (d, J = 3.3 Hz), 162.2 (d, J = 2.8 Hz), 136.3, 134.0 (d, J = 12.0 Hz), 133.0 (d, J = 10.0 Hz), 132.8 (d, J = 10.1 Hz), 129.7, 128.6, 127.4, 125.8, 123.8 (d, J = 83.2 Hz), 123.0 (d, J = 84.2 Hz), 114.2 (d, J = 12.4 Hz), 64.9, 55.3, 43.5 (d, J = 1.7 Hz), 38.5 (d, J = 73.6 Hz), 30.4, 28.7 (d, J = 13.0 Hz), 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 0.40 mL, catalyst 0.06 equiv.).

[0237] 1H NMR (600 MHz, CDC13): δ 7.80 - 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 = 3.7 Hz, 1H), 3.08 - 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 = 7.5 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H).

[0238] 13 C NMR (125 MHz, CDC13): δ 172.2 (d, J = 3.2 Hz), 155.0 (d, J = 2.6 Hz), 136.3, 134.0 (d, J = 12.0 Hz), 131.0 (d, J = 8.9 Hz), 130.9 (d, J = 9.2 Hz), 129.2 (d, J = 69.6 Hz), 129.2 (d, J = 139.9 Hz), 128.4 (d, J = 70.0 Hz), 127.4, 125.8, 125.7 (d, J = 2.5 Hz), 125.6 (d, J = 2.6 Hz), 64.9, 43.4, 38.3 (d, J = 72.7 Hz), 35.0, 31.1, 30.4, 28.7 (d, J = 13.0 Hz), 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 synthesis, HFIP volume 0.35 mL, catalyst 0.06 equiv.).

[0242] 1H NMR (600 MHz, CDC13): δ 7.94 - 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 = 4.1 Hz, 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 = 7.4 Hz, 3H).

[0243] 13 C NMR (125 MHz, CDC13): δ 172.5 (d, J = 3.6 Hz), 160.1 (dd, J = 10.8, 4.0 Hz), 136.8 (d, J = 1.5 Hz), 134.9 (d, J = 6.1 Hz), 134.9, 134.8 (d, J = 6.3 Hz), 134.7, 133.3 (d, J = 2.2 Hz), 133.2 (d, J = 2.1 Hz), 129.7, 128.72, 127.1, 125.7, 121.5 (d, J = 20.6 Hz), 120.9, 120.8 (d, J = 6.3 Hz), 120.7 (d, J = 5.8 Hz), 110.7 (d, J = 6.7 Hz), 110.6 (d, J = 6.7 Hz), 64.6, 55.3 (d, J = 19.9 Hz), 43.9 (d, J = 1.7 Hz), 38.18 (d, J = 75.9 Hz), 30.3, 29.5 (d, J = 14.4 Hz), 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 0.45 mL, catalyst 0.06 equiv.).

[0247] 1H NMR (600 MHz, CDC13): δ 7.76 - 7.69 (m, 2H), 7.63 - 7.53 (m, 2H), 7.41 - 7.30 (m, 4H), 7.20 - 7.13 (m, 2H), 7.12 - 7.04 (m, 2H), 4.05 (t, J = 6.9 Hz, 2H), 3.90 (t, J = 3.4 Hz, 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 = 7.4 Hz, 3H).

[0248] 13 C NMR (125 MHz, CDC13): δ 172.1 (d, J = 3.4 Hz), 138.6, 138.6 (d, J = 22.9 Hz), 136.3, 133.9 (d, J = 12.2 Hz), 132.6 (d, J = 2.9 Hz), 132.5, 132.5 (d, J = 3.1 Hz), 132.2, 131.9 (d, J = 8.0 Hz), 131.7 (d, J = 8.4 Hz), 131.6 (d, J = 37.7 Hz), 129.8, 128.6, 128.5 (d, J = 11.9 Hz), 127.8 (d, J = 9.1 Hz), 127.7 (d, J = 8.9 Hz), 127.5, 125.9, 65.0, 43.4, 37.9 (d, J = 72.5 Hz), 30.4, 28.6 (d, J = 13.0 Hz), 21.5 (d, J = 3.2 Hz), 19.2, 17.8, 13.8.

[0249] 31 P NMR: δ 31.0. HRMS (ESI) for: C 29 H 34 O3P[M+H] + : calcd 461.2245, found 461.2244.

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

[0251] 1H NMR (600 MHz, CDC13): δ 7.46 (dd, J = 12.5, 2.8 Hz, 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 = 3.4 Hz, 1H), 3.88 - 3.79 (m, 6H), 3.05 (d, J = 12.5 Hz, 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 (125 MHz, CDC13): δ 169.7 (d, J = 3.2 Hz), 157.3 (d, J = 2.7 Hz), 157.2 (d, J = 2.8 Hz), 133.8, 131.4 (d, J = 19.2 Hz), 131.2 (d, J = 13.6 Hz), 130.6 (d, J = 45.9 Hz), 127.5, 127.3, 126.2, 125.0, 123.5, 120.3 (d, J = 5.6 Hz), 120.3 (d, J = 5.4 Hz), 115.7 (d, J = 2.6 Hz), 115.3 (d, J = 2.7 Hz), 113.9 (d, J = 9.5 Hz), 113.6 (d, J = 9.1 Hz), 62.6, 53.0 (d, J = 2.2 Hz), 40.9 (d, J = 1.8 Hz), 35.6 (d, J = 73.0 Hz), 28.0, 26.1 (d, J = 13.0 Hz), 16.7, 15.4, 11.3.

[0253] 31 P NMR: δ 31.3.

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

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

[0256] 1H NMR (600 MHz, CDC13): δ 7.48 - 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 = 3.4 Hz, 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 = 7.5 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H).

[0257] 13 C NMR (125 MHz, CDC13): δ 170.2 (d, J = 3.1 Hz), 136.4 (d, J = 9.6 Hz), 136.4 (d, J = 9.6 Hz), 134.5, 132.2 (d, J = 12.1 Hz), 131.6 (d, J = 2.9 Hz), 131.5 (d, J = 2.8 Hz), 130.4 (d, J = 17.9 Hz), 129.7 (d, J = 19.1 Hz), 127.3 (d, J = 141.2 Hz), 126.7 (d, J = 3.9 Hz), 126.6 (d, J = 4.2 Hz), 124.7 (d, J = 200.5 Hz), 63.1, 41.5 (d, J = 1.7 Hz), 35.9 (d, J = 72.3 Hz), 28.5, 26.7 (d, J = 13.0 Hz), 19.5 (d, J = 2.1 Hz), 17.3, 15.8, 11.9.

[0258] 31 P NMR: δ 31.1.

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

[0260] Chiral β- phosphonocarbonate 21 : 98% yield, 96% ee. (During the synthesis, HFIP volume 0.35 mL, catalyst 0.10 equiv.).

[0261] 1H NMR (600 MHz, CDC13): δ 7.72 (dt, J = 7.4, 2.2 Hz, 2H), 7.27 (d, J = 2.0 Hz, 1H), 7.21 - 7.16 (m, 2H), 7.14 - 7.10 (m, 3H), 6.56 - 6.53 (m, 2H), 4.09 (d, J = 4.0 Hz, 1H), 3.98 (t, J = 6.8 Hz, 2H), 3.03 (dt, J = 16.8, 5.0 Hz, 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 = 7.4 Hz, 3H).

[0262] 13 C NMR (125 MHz, CDC13): δ 171.8 (d, J = 3.8 Hz), 148.22 (d, J = 7.4 Hz), 148.0 (d, J = 7.5 Hz), 147.7, 146.6 (d, J = 7.9 Hz), 145.5, 136.1, 133.2 (d, J = 13.3 Hz), 129.7, 128.9, 127.5, 125.9, 123.5 (d, J = 18.3 Hz), 122.6 (d, J = 18.4 Hz), 111.7 - 109.7 (m), 65.0, 43.0, 38.6 (d, J = 82.7 Hz), 30.4, 28.5 (d, J = 14.7 Hz), 19.1, 17.7, 13.7.

[0263] 31 P NMR: δ 13.6.

[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 synthesis, HFIP volume 0.45 mL, catalyst 0.06 equiv.).

[0266] 1H NMR (600 MHz, CDC13): δ 7.23 - 7.16 (m, 2H), 7.16 - 7.09 (m, 2H), 4.10 - 4.03 (m, 3H), 3.79 (dd, J = 10.7, 5.8 Hz, 6H), 3.06 - 2.98 (m, 1H), 2.90 - 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 = 7.4 Hz, 3H).

[0267] 13 C NMR (125 MHz, CDC13): δ 172.4 (d, J = 3.8 Hz), 136.0, 132.9 (d, J = 15.3 Hz), 129.8, 128.8, 127.47, 125.9, 64.85, 53.0 (d, J = 6.6 Hz), 52.8 (d, J = 6.9 Hz), 43.9 (d, J = 2.8 Hz), 35.6 (d, J = 146.4 Hz), 30.5, 28.5 (d, J = 16.2 Hz), 19.1, 18.4 (d, J = 2.7 Hz), 13.7.

[0268] 31 P NMR: δ 31.7.

[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 0.35 mL, catalyst 0.10 equiv.).

[0271] 1H NMR (600 MHz, CDC13): δ 7.90 - 7.80 (m, 4H), 7.57 - 7.45 (m, 6H), 7.07 (t, J = 7.9 Hz, 1H), 6.70 (t, J = 8.8 Hz, 2H), 4.08 - 3.97 (m, 2H), 3.92 (d, J = 3.8 Hz, 1H), 3.80 (s, 3H), 3.03 (dd, J = 17.0, 4.9 Hz, 1H), 2.80 - 2.69 (m, 2H), 2.61 - 2.51 (m, 1H), 1.97 - 1.89 (m, 1H), 1.58 (q, J = 7.2 Hz, 2H), 1.34 - 1.23 (m, 3H), 0.88 (t, J = 7.4 Hz, 3H).

[0272] 13 C NMR (125 MHz, CDC13): δ 172.0, 157.7, 134.9 (d, J = 11.6 Hz), 132.5 (d, J = 61.4 Hz), 131.8, 131.7 (d, J = 62.1 Hz), 131.2 (d, J = 9.0 Hz), 131.0 (d, J = 8.1 Hz), 128.7 (d, J = 11.6 Hz), 126.3, 125.4, 120.7, 108.5, 65.0, 55.3, 43.2, 37.7 (d, J = 72.8 Hz), 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 0.35 mL, catalyst 0.06 equiv.).

[0276] 1H NMR (600 MHz, CDC13): δ 7.90 - 7.80 (m, 4H), 7.57 - 7.46 (m, 6H), 7.05 (d, J = 8.5 Hz, 1H), 6.75 (dd, J = 8.4, 2.7 Hz, 1H), 6.60 (d, J = 2.7 Hz, 1H), 4.08 - 3.98 (m, 2H), 3.88 (t, J = 3.4 Hz, 1H), 3.72 (s, 3H), 2.97 (d, J = 12.1 Hz, 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 = 7.4 Hz, 3H).

[0277] 13 C NMR (125 MHz, CDC13): δ 172.0, 157.6, 134.5 (d, J = 12.7 Hz), 132.6, 132.2, 131.8 (d, J = 10.4 Hz), 131.4, 131.2 (d, J = 8.8 Hz), 131.0 (d, J = 7.9 Hz), 130.7, 128.7 (d, J = 11.5 Hz), 128.1, 114.4, 112.8, 65.0, 55.3, 43.7, 38.1 (d, J = 72.6 Hz), 30.4, 27.9 (d, J = 13.2 Hz), 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 synthesis, HFIP volume 0.45 mL, catalyst 0.06 equiv.).

[0281] 1H NMR (600 MHz, CDC13): δ 7.88 - 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 = 3.7 Hz, 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 = 7.4 Hz, 3H).

[0282] 13 C NMR (125 MHz, CDC13): δ 172.3 (d, J = 3.2 Hz), 158.8, 137.5, 132.5 (d, J = 52.0 Hz), 131.8 (d, J = 3.1 Hz), 131.7 (d, J = 52.9 Hz), 131.7 (d, J = 2.7 Hz), 131.2 (d, J = 8.4 Hz), 131.0 (d, J = 8.8 Hz), 129.6, 128.7 (d, J = 11.5 Hz), 126.1 (d, J = 12.4 Hz), 113.2 (d, J = 202.1 Hz), 64.9, 55.3, 42.7, 38.3 (d, J = 72.6 Hz), 30.4, 28.9 (d, J = 13.2 Hz), 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 0.45 mL, catalyst 0.06 equiv.).

[0286] 1H NMR (600 MHz, CDC13): δ 7.89 - 7.80 (m, 4H), 7.57 - 7.43 (m, 7H), 6.98 - 6.94 (m, 2H), 6.90 (dd, J = 7.9, 1.9 Hz, 1H), 4.07 - 3.97 (m, 2H), 3.89 (t, J = 3.7 Hz, 1H), 3.00 (qd, J = 11.2, 10.2, 5.5 Hz, 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 = 7.4 Hz, 3H).

[0287] 13 C NMR (125 MHz, CDC13): δ 172.2 (d, J = 3.2 Hz), 137.1, 135.91, 132.7, 132.3, 131.7 (d, J = 2.7 Hz), 131.7 (d, J = 54.1 Hz), 131.7 (d, J = 2.8 Hz), 131.2 (d, J = 8.6 Hz), 131.0 (d, J = 8.8 Hz), 130.8 (d, J = 12.1 Hz), 130.2, 128.6 (d, J = 11.4 Hz), 127.6 (d, J = 207.8 Hz), 64.9, 43.0 (d, J = 1.8 Hz), 38.2 (d, J = 72.9 Hz), 30.4, 28.6 (d, J = 13.2 Hz), 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 0.45 mL, catalyst 0.06 equiv.).

[0291] 1H NMR (600 MHz, CDC13): δ 7.89 - 7.80 (m, 4H), 7.57 - 7.43 (m, 7H), 6.98 - 6.94 (m, 2H), 6.90 (dd, J = 7.9, 1.9 Hz, 1H), 4.07 - 3.97 (m, 2H), 3.89 (t, J = 3.7 Hz, 1H), 3.00 (qd, J = 11.2, 10.2, 5.5 Hz, 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 = 7.4 Hz, 3H).

[0292] 13 C NMR (125 MHz, CDC13): δ 171.7 (d, J = 3.4 Hz), 138.1, 133.1, 132.5, 132.3, 132.2, 132.0, 131.9 (d, J = 2.8 Hz), 131.8 (d, J = 2.7 Hz), 131.7, 131.2, 131.2 (d, J = 8.7 Hz), 131.0 (d, J = 8.8 Hz), 129.9, 129.5, 128.8 (d, J = 4.1 Hz), 128.7 (d, J = 4.1 Hz), 126.2, 65.12, 43.0, 38.0 (d, J = 72.7 Hz), 30.4, 28.5 (d, J = 13.0 Hz), 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 0.45 mL, catalyst 0.06 equiv.).

[0296] 1H NMR (600 MHz, CDC13): δ 7.89 - 7.80 (m, 4H), 7.58 - 7.44 (m, 6H), 6.58 (s, 1H), 6.53 (s, 1H), 5.88 (d, J = 1.4 Hz, 1H), 5.85 (d, J = 1.5 Hz, 1H), 4.14 - 4.04 (m, 2H), 3.80 (d, J = 3.5 Hz, 1H), 2.97 - 2.88 (m, 1H), 2.82 - 2.68 (m, 3H), 1.87 - 1.81 (m, 1H), 1.23 (t, J = 7.1 Hz, 3H).

[0297] 13 C NMR (125 MHz, CDC13): δ 172.1 (d, J = 3.2 Hz), 147.1, 145.9, 132.7, 132.2, 131.9, 131.8 (d, J = 2.7 Hz), 131.7 (d, J = 2.5 Hz), 131.4, 131.1 (d, J = 8.5 Hz), 131.0 (d, J = 8.8 Hz), 129.6, 128.7 (d, J = 3.5 Hz), 128.6 (d, J = 3.4 Hz), 126.5 (d, J = 12.7 Hz), 109.1, 108.2, 100.9, 61.1, 43.3 (d, J = 1.7 Hz), 38.2 (d, J = 72.7 Hz), 28.9 (d, J = 13.3 Hz), 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 0.45 mL, catalyst 0.06 equiv.).

[0301] 1H NMR (600 MHz, CDC13): δ 7.90 - 7.81 (m, 4H), 7.58 - 7.46 (m, 6H), 6.36 (s, 1H), 4.15 - 4.07 (m, 2H), 3.85 (t, J = 3.2 Hz, 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 = 7.2 Hz, 3H).

[0302] 13 C NMR (125 MHz, CDC13): δ 172.0, 157.0 (d, J = 84.6 Hz), 132.6 (d, J = 55.5 Hz), 132.0 (d, J = 4.2 Hz), 131.8 (d, J = 64.6 Hz), 131.7 (d, J = 2.8 Hz), 131.7 (d, J = 2.7 Hz), 131.1 (d, J = 6.8 Hz), 131.0 (d, J = 7.0 Hz), 128.7 (d, J = 11.4 Hz), 121.9, 119.1, 105.9, 61.1, 59.8, 55.6, 43.6, 38.0 (d, J = 72.8 Hz), 22.9 (d, J = 12.9 Hz), 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 0.35 mL, catalyst 0.10 equiv.).

[0306] 1H NMR (600 MHz, CDC13): δ 7.91 - 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 = 3.9 Hz, 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 = 7.1 Hz, 3H).

[0307] 13 C NMR (125 MHz, CDC13): δ 172.2 (d, J = 3.2 Hz), 148.5, 147.3, 132.5 (d, J = 44.5 Hz), 131.8 (d, J = 2.8 Hz), 131.8 (d, J = 45.7 Hz), 131.7 (d, J = 2.8 Hz), 131.1 (d, J = 5.5 Hz), 131.0 (d, J = 5.8 Hz), 128.7 (d, J = 11.4 Hz), 128.2, 125.4 (d, J = 12.7 Hz), 111.4 (d, J = 120.0 Hz), 61.1, 55.9 (d, J = 9.8 Hz), 43.1 (d, J = 1.7 Hz), 38.1 (d, J = 72.8 Hz), 28.3 (d, J = 13.2 Hz), 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 0.35 mL, catalyst 0.10 equiv.).

[0311] 1H NMR (600 MHz, CDC13): δ 7.90 - 7.82 (m, 4H), 7.58 - 7.47 (m, 6H), 7.19 - 7.13 (m, 2H), 7.08 (dd, J = 5.5, 1.8 Hz, 2H), 4.09 (qd, J = 7.1, 1.2 Hz, 2H), 3.92 (t, J = 3.6 Hz, 1H), 3.10 - 3.01 (m, 1H), 2.89 - 2.73 (m, 3H), 1.93 - 1.85 (m, 1H), 1.22 (t, J = 7.1 Hz, 3H).

[0312] 13 C NMR (125 MHz, CDC13): δ 172.0 (d, J = 3.3 Hz), 136.2, 133.7 (d, J = 12.1 Hz), 132.6, 132.2, 131.9, 131.8 (d, J = 2.7 Hz), 131.7 (d, J = 2.7 Hz), 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 = 72.8 Hz), 28.6 (d, J = 13.0 Hz), 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, found 405.1615.

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

[0316] 1 H NMR (600 MHz, CDC13): δ 7.85 (dtt, J = 11.0, 7.7, 1.5 Hz, 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 = 7.4 Hz, 3H).

[0317] 13 C NMR (125 MHz, CDC13): δ 172.0 (d, J = 3.3 Hz), 136.2, 133.8 (d, J = 12.1 Hz), 132.6, 132.1, 131.9, 131.8 (d, J = 2.7 Hz), 131.7 (d, J = 2.8 Hz), 131.5, 131.2, 131.1, 131.1, 131.0, 129.8, 128.7 (d, J = 2.3 Hz), 128.7, 128.6, 127.5, 125.9, 66.7, 43.4, 38.0 (d, J = 72.9 Hz), 28.6 (d, J = 13.0 Hz), 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, found 419.1785.

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

[0321] 1 H NMR (600 MHz, CDC13): δ 7.90 - 7.77 (m, 4H), 7.50 (qd, J = 8.5, 7.8, 5.8 Hz, 4H), 7.39 (td, J = 7.7, 2.8 Hz, 2H), 7.36 - 7.27 (m, 5H), 7.20 - 7.12 (m, 2H), 7.06 (h, J = 6.4, 5.8 Hz, 2H), 5.10 (q, J = 12.5 Hz, 2H), 3.97 (t, J = 3.7 Hz, 1H), 3.06 (d, J = 11.9 Hz, 1H), 2.90 - 2.74 (m, 3H).

[0322] 13C NMR (125 MHz, CDC13): δ 171.7 (d, J = 3.3 Hz), 136.2, 136.0, 133.4 (d, J = 12.0 Hz), 132.3 (d, J = 15.5 Hz), 131.7 (d, J = 2.7 Hz), 131.5 (d, J = 16.8 Hz), 131.0 (d, J = 7.4 Hz), 130.9, 129.8, 128.7 (d, J = 4.6 Hz), 128.6 (d, J = 4.0 Hz), 128.6, 128.3 (d, J = 3.1 Hz), 127.8, 127.5, 125.9, 66.9, 43.3 (d, J = 1.8 Hz), 38.0 (d, J = 72.6 Hz), 28.5 (d, J = 13.0 Hz), 17.8.

[0323] 31 P NMR: δ 31.0.

[0324] HRMS (ESI) for: for: C 27 H 30 O3P[M+H] + : calcd 467.1776, found 467.1778.

[0325] Application Example 1 Synthesis of chiral phosphine ligand

[0326] Take 100 mL round bottom flask, add lithium aluminum hydride (217 mg, 5.7 mmol, 0.98 equiv.), 38 mL tetrahydrofuran. Slowly drop the chiral β-phosphoryl carbonate 2a (2.0 g, 5.8 mmol, 1.0 equiv.) prepared in Example 5 in tetrahydrofuran solution at zero degrees. After stirring at room temperature for 4 hours, ice water bath cooling, slowly add 217 microliters of water, 217 microliters of 15% sodium hydroxide, 660 microliters of water in turn. After stirring at room temperature for 30 minutes, add 3 grams of magnesium sulfate and stir for 10 minutes. The filtrate was rotary dried to obtain the crude product.

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

[0328] 1H NMR (500 MHz, CDC13) δ 7.80 (dd, J = 10.8, 7.8 Hz, 2H), 7.72 (dd, J = 11.0, 7.7 Hz, 2H), 7.62 - 7.41 (m, 8H), 7.26 - 7.22 (m, 3H), 7.17 (t, J = 7.3 Hz, 1H), 7.07 (q, J = 8.1 Hz, 3H), 4.92 (dd, J = 10.2, 3.8 Hz, 1H), 4.09 (t, J = 9.9 Hz, 1H), 3.18 (dd, J = 9.5, 4.4 Hz, 1H), 2.90 (dd, J = 17.5, 7.4 Hz, 1H), 2.80 (dt, J = 17.7, 9.0 Hz, 1H), 2.73 - 2.65 (m, 1H), 2.43 (s, 3H), 2.20 - 2.06 (m, 1H), 1.88 (dt, J = 14.8, 7.4 Hz, 1H).

[0329] 13 C NMR (125 MHz, CDC13) δ 144.4, 135.9 (d, J = 12.5 Hz), 135.0, 132.7, 132.0 (d, J = 2.6 Hz), 131.9 (d, J = 2.6 Hz), 131.3 (d, J = 59.1 Hz), 130.8 (d, J = 1.8 Hz), 130.7, 130.6, 129.7, 129.3, 129.0, 128.9 (d, J = 3.0 Hz), 128.8, 128.0, 127.4, 125.6, 71.4 (d, J = 2.0 Hz), 38.5 (d, J = 1.9 Hz), 37.1 (d, J = 71.5 Hz), 27.8 (d, J = 12.3 Hz), 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, found 517.1605.

[0332] A dry 50 mL round bottom flask was purged with nitrogen three times. HPPh2 (0.6 mL, 3.45 mmol, 2.5 equiv.), n-hexane (8.8 mL), was added and cooled to 0 °C. n-Butyllithium (2.4 M, 1.16 mL, 2.0 equiv.) was added slowly and stirred at 0 °C for 10 minutes. The reaction was dissolved in tetrahydrofuran (8.8 mL) and added to the flask. The reaction was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The reaction was stirred for 1 hour and then quenched with water. The reaction was extracted with ethyl acetate and the organic layer was dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (ethyl acetate / hexanes, 1 :9) to give the product. (700 mg, 1.36 mmol, 1.0 equiv.) was added slowly to the above prepared LiPPh2solution. Stirring was continued for one hour at 0 °C, after the addition of H2O2(30% wt, 1.7 mL) stirring was continued for one hour. After the addition of 20 mL water extraction was performed using TBME (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate, after concentration the crude product was isolated and purified using column chromatography to yield a white solid (600 mg, 81%). Its characterization data are:

[0333] 1 H NMR (500 MHz, CDC13) δ 7.80 - 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 = 7.7 Hz, 1H), 7.01 - 6.97 (m, 1H), 6.95 (d, J = 7.5 Hz, 1H), 6.81 (t, J = 7.4 Hz, 1H), 3.91 (dd, J = 15.4, 12.1 Hz, 1H), 3.77 (s, 1H), 3.03 - 2.94 (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 (125 MHz, CDC13) δ 139.3 (d, J = 12.9 Hz), 134.4, 134.0 (d, J = 23.8 Hz), 133.2 (d, J = 23.9 Hz), 132.8, 132.0 (d, J = 6.5 Hz), 132.0 (d, J = 2.7 Hz), 131.7 (d, J = 2.8 Hz), 131.3 (d, J = 2.7 Hz), 131.3, 131.0 (d, J = 2.7 Hz), 130.9 (d, J = 2.2 Hz), 130.8, 130.6, 130.6 (d, J = 1.7 Hz), 130.5, 129.9, 129.1 (d, J = 11.5 Hz), 128.9 (d, J = 3.5 Hz), 128.8, 128.5 (d, J = 11.8 Hz), 128.2 (d, J = 11.7 Hz), 127.2, 125.2, 38.3 (dd, J = 71.6, 12.4 Hz), 33.8 (t, J = 2.7 Hz), 31.4 (d, J = 72.1 Hz), 26.7 (d, J = 12.4 Hz), 16.8.

[0335] 31 P NMR , δ 33.6, 30.1.

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

[0337] Take 10 ml sealed tube, add substrate (300 mg, 0.6 mmol) and replace with nitrogen three times. Add phenylsilane (3 mL) and react at 130 °C for 12 hours. Purify by column chromatography, directly load the reaction mixture, elute with petroleum ether to remove excess phenylsilane, then elute with petroleum ether / ethyl acetate system to obtain white target chiral phosphine ligand of (S, S) configuration (160 mg, 57%). Its characterization data are as follows:

[0338] 1 H NMR (500 MHz, CDC13) δ 7.53 - 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 = 7.4 Hz, 1H), 7.00 (t, J = 7.4 Hz, 1H), 6.88 (d, J = 7.6 Hz, 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 NMR δ -15.51 (d, J = 10.1 Hz), -20.69 (d, J = 10.0 Hz).

[0340] 13C NMR (125 MHz, CDC13) δ 140.7 (dd, J = 5.5, 2.8 Hz), 139.7 (d, J = 13.6 Hz), 137.5 (d, J = 14.3 Hz), 137.2 (d, J = 13.6 Hz), 136.1 (d, J = 12.4 Hz), 135.6, 133.9 (d, J = 20.7 Hz), 133.6 (d, J = 19.7 Hz), 133.4 (d, J = 19.4 Hz), 132.5 (d, J = 18.5 Hz), 130.0 (d, J = 7.1 Hz), 129.2, 129.0, 128.6, 128.6 (d, J = 2.3 Hz), 128.4 (d, J = 2.4 Hz), 128.4, 128.1 (d, J = 6.5 Hz), 128.0, 126.6, 124.8, 38.0 (dd, J = 9.6, 6.5 Hz), 37.4 (dd, J = 13.1, 10.3 Hz), 31.8 - 31.4 (m), 27.9 (d, J = 10.1 Hz), 20.3 (d, J = 17.3 Hz).

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

[0342] Take 100 mL round bottom flask, add chiral β- phosphonocarbonic ester 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.) successively, stir at 85°C for 24 hours. Dilute with TBME (20 mL), wash with 2N hydrochloric acid (3 x 20 mL), saturated sodium chloride (1 x 20 mL) successively. Evaporate to concentrate, the crude product obtained is dissolved in TBME (3 mL), white solid is precipitated under ultrasonic (760 mg, 54% yield, >99% ee, >99% de). Evaporate to concentrate the mother liquor, add toluene (20 mL), DBU (1.35 mL), stir at 85°C for 24 hours, repeat the above operation to obtain (R, S) configuration (370 mg, 27% yield, >99% ee, >99% de).

[0343] The characterization data of are as follows:

[0344] 1H NMR (500 MHz, CDC13) δ 7.94 - 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, 2.3 Hz, 1H), 4.26 (dd, J = 16.1, 8.0 Hz, 1H), 3.77 (dt, J = 10.8, 6.8 Hz, 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 = 7.4 Hz, 3H).

[0345] 31 P NMR δ 33.6.

[0346] 13 C NMR (125 MHz, CDC13) δ 174.0 (d, J = 3.5 Hz), 137.45, 132.2 (d, J = 2.0 Hz), 132.0 (d, J = 29.9 Hz), 131.8 (d, J = 2.7 Hz), 131.8 (d, J = 2.7 Hz), 131.7, 131.6, 131.3 (d, J = 37.7 Hz), 131.1, 131.1, 128.9, 128.8, 128.7, 128.6, 128.5, 128.4, 127.0, 126.4, 65.1, 43.4, 36.3 (d, J = 72.0 Hz), 30.3, 29.2 (d, J = 12.5 Hz), 21.8 (d, J = 2.1 Hz), 19.1, 13.7.

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

[0348] Five 5 mL quartz tubes were charged with catalyst Rh(COD)2BArF (2.4 mg, 0.00125 mmol, 4 mol%), corresponding ligand (compound 11 1.05 mg, chiral phosphine ligand 4 1.24 mg, synthesized in application example 1, chiral phosphine ligand 6 1.24 mg, 0.0015 mmol, 4.8 mol%) and super dry CH2Cl2(0.3 mL). After stirring at room temperature for 30 min in the glove box, orange liquid was obtained. Hydrogenation precursor 9 (20.5 mg, 0.1 mmol, 1.0 equiv.), super dry CH2Cl2(0.3 mL) were added to the above orange catalyst solution successively. After transferring the quartz tube to the high pressure reactor, the reactor was purged with hydrogen three times and the hydrogen pressure was controlled at 40 Bar, while the temperature was controlled at 40 °C. The reaction was stirred vigorously for 36 h. The reaction solution was concentrated at room temperature under reduced pressure. The hydrogenation product was separated and purified by column chromatography. The ee value of the product was determined by HPLC. Both chiral phosphine ligand 4 and 6 exhibited good reactivity. The yield of compound 11, chiral phosphine ligand 4 and chiral phosphine ligand 6 was 98%, 99%, 95% respectively, and the ee value was 11% ee, 36% ee, 33% ee respectively.

[0349]

[0350] The characterization data of 11 are as follows:

[0351] 1 H NMR (500 MHz, CDC13) δ 7.37 - 7.28 (m, 4H), 7.27 - 7.22 (m, 1H), 3.65 (s, 3H), 3.15 (d, J = 10.6 Hz, 1H), 2.45 - 2.23 (m, 1H), 1.03 (d, J = 6.4 Hz, 3H), 0.70 (d, J = 6.8 Hz, 3H).

[0352] 13 C NMR (125 MHz, CDC13) δ 174.48, 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 above embodiments of the present application are described in detail, it should be understood that the above described are only specific embodiments of the present application, and are not intended to limit the present application, any modification, supplement or similar way of substitution made within the principle range of the present application, should be included in the protection scope of the present application.

Claims

1. A chiral β- phosphonocarbonate, characterized in that, The structural formula is shown as formula (I): ； In formula (I), R 1 each independently is selected from one of methoxy, furanyl, phenyl, or substituted phenyl; the substituent of substituted phenyl is methyl, methoxy, butyl, halogen, or phenyl; R 2 is at least one of ethyl, propyl, butyl, benzyl; R 3 , R 4 , R 5 each independently is selected from one of hydrogen, methoxy, methyl, halogen, methoxycarbonyl; or R 3 is one of hydrogen, methoxy, methyl, halogen, carboxymethyl, R 4 and R 5 form a dioxolane structure.

2. The process for the preparation of chiral β- phosphonocarbonic acid esters according to claim 1, characterized in that, The application relates to a method for preparing a chiral beta-phosphonocarbonate by asymmetric hydrogenation of a hydrogenated precursor shown as formula (II) in an organic solvent system under a hydrogen atmosphere. The molar ratio of the metal ligand complex and the hydrogenated precursor is 0.03-0.10:1; the organic solvent is hexafluoroisopropanol. ; wherein, in the formula (I) and the formula (II), R 1 , R 2 , R 3 , R 4 , R 5 are the same as defined in claim 1; The metal ligand complex utilizes a metal salt and S t Bu-PHOX was obtained after mixing and stirring in methanol and hexafluoroisopropanol solution; the metal salt was nickel acetate.​ 3. The process for the preparation of chiral β- phosphonocarbonic acid esters according to claim 2, characterized in that, nickel acetate and S t The molar ratio of Bu-PHOX is 1 : 1-2.​ 4. The process for the preparation of chiral β- phosphonocarbonic acid esters according to claim 2, characterized in that, The reaction temperature of the asymmetric hydrogenation reaction is 40-100 DEG C, and the reaction time is 24-48 h.

5. The process for the preparation of chiral β- phosphonocarbonic acid esters according to claim 2, characterized in that, ​

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