Spirobarbituric acid-epoxyhexane compounds, synthesis method and application thereof

Abstract

The application provides a spiro-barbituric acid-epoxyhexane compound and a synthesis method and application thereof. A structural formula of the compound is as follows: wherein, a group R 2 is C 1‑6 alkyl, C 1‑6 alkoxy, hydrogen, halogen, halogenated C 1‑6 alkyl, nitro or naphthyl, a group R 3 is C 1‑6 alkyl, C 1‑6 alkoxy, hydrogen, halogen or naphthyl; and a group R 4 is C 1‑6 alkyl or benzyl. The application further provides a synthesis method of the compound, which comprises using an alkenyl barbituric acid compound and a 1,2-substituted allyl carbonate compound as raw materials, and under the action of a palladium catalyst, a chiral ligand and a base, asymmetric cycloaddition reaction is generated to synthesize a series of spiro-barbituric acid-epoxyhexane compounds. The synthesis method has the advantages of mild reaction condition, simple operation, wide applicable range of substrates, high yield and good stereoselectivity. It is tested that the compound has certain antitumor activity. The application provides an application of the compound in preparation of an antitumor drug.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis, specifically to a spirobarbituric acid-epoxyhexane compound, its synthesis method, and its application. Background Technology

[0002] Spirobarbiturates are barbituric acid derivatives. These compounds undergo bifunctionalization at the C-5 position of barbituric acid, resulting in unique spirocyclic structures. Studies have shown that spirobarbiturates, especially spirocyclic compounds composed of barbituric acid and a six-membered ring, have significant potential applications in the biomedical field. Spirobarbiturate-cyclohexane compounds exhibit significant antitumor activity (J. Med. Chem., 1964, 7, 695); spirobarbiturate-azacycloalanine compounds have been used as anticonvulsants (Pharm. Chem. J., 2009, 43, 315); spirobarbiturate-pyrimidinone compounds possess strong urease inhibitory activity (Iran. J. Pharm. Res., 2015, 14, 1105); and spirobarbiturate-cyclohexanone compounds show HIV-1 inhibitory activity (Org. Biomol. Chem., 2011, 9, 7282). Therefore, developing new functionalization synthesis methods for spirobarbituric acid will further enrich the structural diversity of spirobarbituric acid compounds and promote further development in this field. Metal catalysts are commonly used in the synthesis of barbituric acid compounds, and metal catalysts can affect the structure of compounds. Therefore, developing new metal catalysts is beneficial to further enrich the spirobarbituric acid compound range. Summary of the Invention

[0003] In view of this, one object of the present invention is to provide a spirobarbituric acid-epoxyhexane compound. Among them, group R 2 C 1-6 Alkyl, C 1-6 Alkoxy, hydrogen, halogen, halogenated C 1-6 Alkyl, nitro, or naphthyl groups, R 3 C 1-6 Alkyl, C 1-6 Alkoxy, hydrogen, halogen, or naphthyl groups; group R 4 C 1-6 Alkyl or benzyl.

[0004] Preferably, the group R 2 The radicals can be methyl, isopropyl, tert-butyl, methoxy, hydrogen, fluorine, chlorine, bromine, trifluoromethyl, nitro, or naphthyl, etc.; the radical R is also present. 3 It can be methyl, methoxy, hydrogen, chlorine, fluorine, or naphthyl, etc.; the group R 4 It can be methyl, ethyl, or benzyl, etc.

[0005] A second objective of this invention is to provide a method for synthesizing the above-mentioned spirobarbituric acid-epoxyhexane compounds, comprising: using a 1,2-substituted allyl carbonate compound as shown in compound XX1 and an alkenyl barbituric acid compound as shown in compound XX2 as raw materials, and conducting an asymmetric cycloaddition reaction under the action of a palladium catalyst, a 1-phosphanorbornene-dimethyloxanthracene chiral ligand, and a base to synthesize the above-mentioned spirobarbituric acid-epoxyhexane compounds. The reaction formula is shown below:

[0006]

[0007] Specifically, the synthesis method of the above-mentioned spirobarbituric acid-epoxyhexane compounds includes: mixing the palladium catalyst, chiral ligand, base, and second organic solvent under a nitrogen atmosphere to obtain a mixed system; then adding the compounds XX1 and XX2 to the mixed system; and conducting a 4+2 asymmetric cycloaddition reaction at 0–25°C for 20–28 h; after the reaction is completed, concentrating and purifying to obtain spirobarbituric acid-epoxyhexane compound P.

[0008] The preferred molar ratio of compound XX1 to compound XX2 is 1 to 2:1 to improve reaction efficiency.

[0009] Preferably, the palladium catalyst is Pd2(dba)3·CHCl3, Pd2(dba)3, Pd(dba)2 or Pd(PPh3)4, and its molar ratio with compound II is preferably 0.05 to 0.2:1.

[0010] The main function of the base is to promote hydrogen transfer during the reaction. It can be an inorganic or organic base. The inorganic base can be cesium carbonate, sodium carbonate, sodium bicarbonate, sodium tert-butoxide, potassium phosphate, or potassium carbonate, etc., while the organic base can be 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), DBU, 1,4-diammazirobenzyl[2.2.2]octane (DABCO), or triethylamine, etc. The molar ratio of the base to compound II is preferably 0.3 to 4:1 to improve the reaction yield.

[0011] The second organic solvent is mainly used to dissolve the reaction raw materials, and can be ethyl acetate, tetrahydrofuran, dichloromethane, trichloromethane, toluene, acetonitrile, etc.

[0012] The 1-phosphonobornene-dimethyloxanthracene chiral ligand, as a novel type of chiral phosphine ligand, successfully solves the scientific problem of easy racemization of the chiral phosphorus center by introducing a rigid skeleton to form three fully bound PC bonds. This type of chiral phosphorus ligand can be widely used in asymmetric reactions such as metal-catalyzed asymmetric cyclization, and can be used to prepare spirobarbituric acid-epoxyhexane compounds, exhibiting good stereoselectivity and high reaction yield. Therefore, in the synthesis of spirobarbituric acid-epoxyhexane compounds, the main role of the 1-phosphonobornene-dimethyloxanthracene chiral ligand is to regulate the stereoconfiguration of the product, and its molar ratio with compound II is preferably 0.05–0.3:1. The structural formulas of the chiral ligand are shown in formulas III and III' below:

[0013]

[0014] In the above structural formula, group R is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkenyl, phenyl, halophenyl, C 1-6 Alkyl-substituted phenyl or C 1-6 Alkoxy-substituted phenyl, group R 1 C 1-6 alkyl.

[0015] In this invention, the "C" 1-6 Alkyl", C 1-6 Alkoxy, C 1-6 "Alkenyl" refers to alkyl, alkoxy, and alkenyl groups containing 1-6 carbon atoms, respectively. 1-6 "Alkyl" includes aliphatic alkyl and cycloalkyl, and the number of substituents in the various "substituted phenyl" can be one, two or three, preferably one substituent.

[0016] Preferably, R is methyl, ethyl, propyl, butyl, allyl, phenyl, benzyl, 4-tert-butylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-cyclohexylphenyl, 2-methylphenyl, 3-methylphenyl, 3-chlorophenyl, or 3,5-dimethylphenyl. 1 It is hydrogen-based or tert-butyl-based.

[0017] The method for synthesizing the chiral ligand includes using 9,9-dimethyloxanthracene and 1-phosphanorbornene as raw materials, and generating the above-mentioned 1-phosphanorbornene-dimethyloxanthracene chiral ligand via H[1,5] migration and phosphadaDA reaction. The structural formula of the 9,9-dimethyloxanthracene is shown in Formula I below, and the structural formulas of the 1-phosphanorbornene are shown in Formulas II and II' below. The reaction formula is shown below:

[0018]

[0019] To improve reaction efficiency, the molar ratio of compound I to compound II is preferably 1:1-1.5.

[0020] The main function of the first organic solvent is to dissolve the reaction raw materials, and it can be anhydrous methanol, ethanol, dichloromethane, tetrahydrofuran, etc.

[0021] The main function of the desiccant is to dry the water, a byproduct generated during the reaction, and it can be anhydrous magnesium sulfate, anhydrous sodium sulfate, etc. The preferred amount of the desiccant is 5 to 10 equivalents.

[0022] The reducing agent is mainly used to reduce the generated imine intermediate, and can be sodium borohydride, sodium cyanoborohydride, etc. The preferred amount of the reducing agent is 1 to 1.2 equivalents.

[0023] The above-mentioned synthesis method specifically includes: placing the 9,9-dimethyloxanthracene compound and the 1-phosphanorbornene compound into a first Schlenk flask of a certain volume, adding the first organic solvent and a drying agent, and heating under reflux at 60-80°C until the reaction is complete; placing the reaction system in an ice-water bath, adding the reducing agent, and then continuing the reaction in the ice-water bath until the reaction is complete, quenching the reaction, and synthesizing the above-mentioned 1-phosphanorbornene-dimethyloxanthracene chiral ligand. Preferably, the heating under reflux time is 1-3 hours to ensure that compounds I and II react completely. The reaction time in the ice-water bath is preferably 2-4 hours.

[0024] Further, after synthesizing the above chiral ligands, the mixture was extracted with ethyl acetate, the organic layers were combined, dried with MgSO4, filtered, the solvent was removed by vacuum distillation, and the mixture was separated by column chromatography to obtain the corresponding products in yields of 50–78%.

[0025] The method for synthesizing compound I includes the following steps:

[0026] Synthesis of compound I-2: First, compound I-1 and n-butyllithium were used as raw materials to undergo a lithiation reaction in an ice-water bath. Then, elemental iodine was added and reacted at room temperature to synthesize compound I-2. The reaction formula is as follows:

[0027]

[0028] Synthesis of Compound I: First, Compound I-2 and n-butyllithium are reacted at low temperature, then diphenylphosphine chloride is added and reacted, followed by the addition of n-butyllithium under alkaline conditions to synthesize Compound I. The reaction formula is as follows:

[0029]

[0030] The specific steps for synthesizing compound I-2 include: first, adding compound I-1 to a second Schlenk flask, replacing the nitrogen with N2, dissolving it in anhydrous diethyl ether, placing it in an ice-water bath, adding an alkaline substance, slowly adding n-butyllithium, removing the ice-water bath, and placing the Schlenk flask at 30–50°C for 3–5 hours; then cooling to 0°C, slowly adding iodine dissolved in tetrahydrofuran, raising the temperature to room temperature, reacting overnight, and detecting complete reaction by TLC. The unreacted iodine was then treated with saturated sodium thiosulfate solution, extracted with ethyl acetate, the organic phases were combined and dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain compound I-2.

[0031] The specific steps for synthesizing compound I include: placing compound I-2 in a third Schlenk flask, purging with nitrogen, dissolving it in anhydrous tetrahydrofuran, cooling it at -78°C, then slowly adding n-butyllithium dropwise, reacting at -78°C for 1–2 h, then slowly adding diphenylphosphine chloride dropwise, continuing the reaction for 0.5–1.5 h, then adding n-butyllithium again, reacting for 1–2 h, adding an alkaline substance, reacting at -78°C for 1.5–2.5 h, then slowly raising the temperature to room temperature, reacting overnight, and after the reaction is detected by TLC, quenching the reaction with water, extracting with ethyl acetate, combining the organic phases, drying with anhydrous magnesium sulfate, filtering, concentrating under reduced pressure, and separating by column chromatography to obtain compound I.

[0032] The method for synthesizing the 1-phosphanorbornene compound includes the following steps:

[0033] Synthesis of compound II-4: Using compound II-3, tert-butylsulfonamide, and tetraisopropyl titanate as starting materials, a condensation reaction occurs to generate compound II-4, as shown in the following reaction formula:

[0034]

[0035] Synthesis of compounds II-5 and II-5': Using compound II-4 and Grignard reagent RMgBr as starting materials, compounds II-5 and II-5' were synthesized under ice-water bath conditions, as shown in the following reaction formula:

[0036]

[0037] Synthesis of Compound II: Compound II-5 or II-5' is first reduced under nickel catalysis, and then reacted with dilute hydrochloric acid to remove the sulfinyl group, thus synthesizing the 1-phosphanorbornene compound II or II', as shown in the following reaction formula:

[0038]

[0039] The specific steps for synthesizing compound II-4 include: placing compound II-3, tert-butylsulfinamide, and tetraisopropyl titanate in a fourth Schlenk flask of a certain volume, replacing the nitrogen with N2, dissolving it in dry tetrahydrofuran, reacting at 60-80°C, reacting for 2-4 hours, monitoring the reaction with a TCL, and after detecting that the reaction is complete, adding ethyl acetate for extraction, drying the organic phase with anhydrous magnesium sulfate, filtering, evaporating by rotary evaporation, and then passing it through a silica gel column to obtain the diastereomeric compound II-4.

[0040] The steps for synthesizing compounds II-5 and II-5' include: placing compound II-4 in a fifth Schlenk flask, replacing it with N2, dissolving it in tetrahydrofuran, placing it in an ice-water bath, slowly adding Grignard reagent RMgBr at 0°C, reacting at 0°C for 0.5–1.5 h, detecting the completeness of the reaction by TLC, quenching it with water, and extracting with ethyl acetate; combining the organic phases, drying them with anhydrous magnesium sulfate, filtering, and evaporating to dryness; separating them by silica gel column chromatography to obtain compounds II-5 and II-5'.

[0041] The steps for synthesizing the 1-phosphanorbornenamine compound include: placing Raney nickel in a sixth Schlenk flask that has been purged with nitrogen, washing the Raney nickel with ethanol, then adding the compound II-5 or II-5', filtering out the Raney nickel, evaporating the remaining reaction solution, dissolving the obtained solid in methanol, adding dilute hydrochloric acid, reacting at room temperature for 1-3 hours, detecting the reaction by TLC, and after the reaction is complete, extracting with saturated sodium bicarbonate and ethyl acetate, combining the organic phases, drying with anhydrous magnesium sulfate, filtering, evaporating, and filtering with a silica gel column to obtain the 1-phosphanorbornenamine compound II or II'.

[0042] A third objective of this invention is to provide an application of the above-mentioned spirobarbituric acid-epoxyhexane compounds in the preparation of antitumor drugs.

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

[0044] 1) It has been verified that the spirobarbituric acid-epoxyhexane compounds provided by this invention have antitumor activity and are expected to be used as antitumor drugs;

[0045] 2) The method for synthesizing spirobarbituric acid-epoxyhexane compounds provided by this invention uses 1-phosphanorbornene-dimethyloxanthracene chiral compounds as ligands and alkenyl barbituric acid as an electron-deficient olefin. The spirobarbituric acid reacts with phenyl-substituted 2-hydroxyallyl tert-butyl carbonate under palladium catalysis via an asymmetric (4+2) cycloaddition reaction. This overcomes the limitation of traditional chiral ligands in achieving effective stereoinduction. Furthermore, the method for synthesizing spirobarbituric acid-epoxyhexane compounds provided by this invention features mild reaction conditions, simple and safe operation, readily available and inexpensive raw materials, and high reaction yield, with a yield reaching 50-96%. The diastereoselectivity of the spirobarbituric acid-epoxyhexane compounds is greater than 20:1 and / or the stereoselectivity is greater than 98%.

[0046] 3) The synthesis method of 1-phosphanorbornene-dimethyloxanthracene chiral ligands used in the synthesis process of the above-mentioned spirobarbituric acid-epoxyhexane compounds provided by the present invention is simple, feasible, and has a high yield. Attached Figure Description

[0047] Figure 1 The 1H NMR spectrum of 1-phosphanorbornene-dimethyloxanthracene chiral ligand III-8;

[0048] Figure 2 The 1H NMR spectrum of spirobarbituric acid-epoxyhexane compound P10;

[0049] Figure 3 The figure shows the results of the in vitro antitumor activity assay of spirobarbituric acid-epoxyhexane compound P10. Detailed Implementation

[0050] The technical solution of the present invention will be further described in detail below through specific embodiments.

[0051] Unless otherwise specified, the terminology used in this invention is a common term in the relevant field, and the technical means used in the embodiments, such as preparation processes and testing methods, are all conventional means well known to those skilled in the art; the raw materials used in the embodiments are all commercially available products.

[0052] I. 1-Phospazorbornene-dimethyloxanthracene chiral ligands and their synthesis methods

[0053] Example 1: The synthesis method of compound I is as follows:

[0054]

[0055] Take a 250 mL Schlenk flask and add 2.1 g (10 mmol) of 9,9'-dimethyloxanthracene. After replacing the nitrogen with N2, dissolve the flask in anhydrous diethyl ether and place it in an ice-water bath. Add 2.2 eq. of TMEDA and then slowly add 3.0 eq. of n-butyllithium. Remove the ice-water bath and place the reaction flask at 40 °C. After reacting for 4 h, cool down to 0 °C and slowly add iodine dissolved in tetrahydrofuran. After warming up to room temperature, react overnight. After the reaction is complete as detected by TLC, treat the unreacted iodine with saturated sodium thiosulfate solution, extract with ethyl acetate, combine the organic phases and dry with anhydrous magnesium sulfate. Filter, concentrate under reduced pressure, and separate the iodine by column chromatography as a white solid.

[0056]

[0057] Take a 50 mL Schlenk flask, add the separated 2 to it, replace the nitrogen gas, dissolve it with anhydrous tetrahydrofuran, and place it at -78 °C. After cooling for 10 minutes, slowly add 1.0 eq. of n-butyllithium and react at -78 °C for 1.5 h. Then slowly add 1.0 eq. of diphenylphosphine chloride and continue reacting for 1 h. Add 2.0 eq. of n-butyllithium and react for 1.5 h. Add 2.0 eq. of DMF and react at -78 °C for 2.0 h. Then slowly raise the temperature to room temperature and react overnight. After the reaction is completed by TLC, add water to quench the reaction, extract with ethyl acetate, combine the organic phases, dry with anhydrous magnesium sulfate, filter, concentrate under reduced pressure, and pass through a column chromatography column (petroleum ether: ethyl acetate = 20:1) to obtain I, a white solid.

[0058] Example 2: The synthesis method of compound II is as follows:

[0059]

[0060] A 50 mL Schlenk flask was used to contain compound 3, 1.2 equivalents of tert-butylsulfinamide, and 2 equivalents of tetraisopropyl titanate. After purging with nitrogen, the compound was dissolved in dry tetrahydrofuran. The reaction was carried out at 70 °C for 3 hours, and the reaction was monitored by TCL. Once the reaction was confirmed to be complete, ethyl acetate was added for extraction. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness by rotary evaporation. The resulting product was then subjected to silica gel column chromatography to obtain a pair of diastereomers, 4.

[0061]

[0062] The diastereomer 4 obtained in the previous step was placed in a 25 mL Schlenk flask, dissolved in tetrahydrofuran after purging with N2, and placed in an ice-water bath. Two equivalents of Grignard reagent were slowly added dropwise at 0°C, and the reaction was carried out at 0°C for 1 hour. After the reaction was confirmed to be complete by TLC, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. Compounds 5 and 5' were separated by silica gel column chromatography.

[0063]

[0064] Take a 25 mL Schlenk flask, purge it with nitrogen, add an appropriate amount of Raney nickel, wash the Raney nickel three times with ethanol, then wash it three times with tetrahydrofuran. Then add compound II-5 or II-5' dissolved in tetrahydrofuran, monitor the reaction by TLC, and after the reaction is complete, filter out the Raney nickel, evaporate the remaining reaction solution to dryness, dissolve the obtained solid in methanol, add 2 equivalents of dilute hydrochloric acid, react at room temperature for 2 h, monitor the reaction by TLC, after the reaction is complete, extract with saturated sodium bicarbonate and ethyl acetate, combine the organic phases, dry with anhydrous magnesium sulfate, filter, evaporate to dryness, and filter with silica gel column to obtain compound II or II'.

[0065] Example 3 describes the synthesis of compounds III-1 to III'-16, with the following steps:

[0066]

[0067] Compound I and compound II or II' were placed in Schlenk flasks, respectively. Anhydrous methanol was added, followed by anhydrous magnesium sulfate. The mixture was heated to reflux at 70°C for 2 hours. The reaction progress was monitored by TLC. When the reaction was complete, the reaction system was placed in an ice-water bath, and 1.1 equivalents of sodium borohydride were slowly added. The reaction was continued at this temperature for 3 hours until complete. The reaction was then quenched with water, extracted with ethyl acetate, and the organic layers were combined, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was then separated by column chromatography to obtain the corresponding products III-1 to III-16 or their corresponding isomers, in yields of 50-78%.

[0068]

[0069] White solid.Yield:70%.MP:125-126.5℃.[α] D =-111(c=0.1,CH2Cl) 2, 29.4℃). 31 P NMR(121MHz, CDCl3)δ-16.98(s),-20.27(s)ppm. 1H NMR(300MHz,CDCl3)δ7.50-7.29(m,13H),7.26-7.13(m,8H),7.09-6.92(m,8H),6.56-6.52(m,1H),3.98(dd,J=10.0,5.5Hz,1H),3.33-3.19(m,2H),2.93(d,J=6.9Hz,1H),2.82(t,J=6.0Hz,1H),2.41(s,1H),1.67(s,3H),1.63(s,3H),1.54(s,3H),1.47-1.41(m,1H),1.39(s,9H),1.18(s,3H),0.84(t,J=10.6Hz,1H)ppm. 13 C NMR(75MHz,CDCl3)δ152.91(s),151.54(d,J=15.6Hz),149.85(s),148.19(s),142.29(s),142.20(s),142.07(s),139.25(s),139.06(d,J=2.8Hz),138.97(s),136.39(d,J=10.6Hz),135.81(d,J=10.1Hz),134.43(s),134.17(s),133.93(s),133.66(s),131.26(s),129.66(d,J=1.2Hz),129.32(s),129.18(s),128.76(s),128.65(s),128.59(s),128.54(s),128.44(s),128.41(s),128.32(s),128.25(s),128.18(s),127.86(s),127.76(s),126.78(s),126.31(s),126.18(s),125.01(d,J=14.1Hz),124.88(s),124.23(s),123.20(s),122.76(s),65.33(d,J=10.1Hz),63.82(d,J=4.9Hz),55.27(d,J=18.0Hz),55.03(d,J=2.1Hz),48.53(d,J=4.1Hz),47.07(s),34.53(s),34.15(d,J=1.1Hz),32.46(s),32.27(s),31.56(s),20.79(s),16.56(s)ppm.HRMS(ESI)(m / z)[M+H] + Calcd for C 59 H 60 NOP2 +860.4145;found 860.4172.

[0070]

[0071] III-1’.White solid.Yield:0.30g,68%. 31 P NMR(121MHz,CDCl3)δ-17.66(s),-20.94(s)ppm. 1 H NMR(300MHz,CDCl3)δ7.45-7.32(m,10H),7.25-7.09(m,10H),7.05-6.87(m,9H),6.52-6.46(m,1H),3.92(dd,J=9.7,5.4Hz,1H),3.29-3.13(m,2H),2.88(d,J=6.8Hz,1H),2.79-2.73(m,1H),1.63(s,3H),1.59(s,3H),1.49(s,3H),1.45-1.41(m,1H),1.34(s,9H),1.13(s,3H),0.79(t,J=10.5Hz,1H)ppm. 13C NMR(75MHz,CDCl3)δ152.88(s),151.53(d,J=15.3Hz),149.82(s),148.16(s),142.27(s),142.18(s),142.05(s),139.06(dd,J=11.6,9.1Hz),139.03(d,J=2.5Hz),136.37(d,J=10.6Hz),135.81(d,J=10.4Hz),134.40(s),134.14(s),133.91(s),133.64(s),131.23(s),129.65(s),129.30(s),129.15(s),128.73(s),128.62(s),128.56(s),128.50(s),128.41(s),128.38(s),128.29(s),128.15(s),127.82(s),127.73(s),126.74(s),126.27(s),126.14(s),125.00(d,J=13.9 Hz),124.84(s),124.19(s),123.16(s),122.72(s),65.31(d,J=10.3 Hz),63.81(d,J=4.9 Hz),55.27(d,J=18.3 Hz),55.01(d,J=2.3 Hz),48.52(d,J=3.8 Hz),47.02(s),34.50(s),34.14(s),32.42(s),32.23(s),31.53(s),20.76(s),16.52(s)ppm.

[0072]

[0073] White solid.Yield:0.28 g,66%. 31 P NMR(121 MHz,CDCl3)δ-17.00(s),-20.62(s)ppm. 1H NMR(300 MHz,CDCl3)δ7.58-7.52(m,5H),7.51-7.47(m,16H),7.15–6.99(m,8H),6.67-6.61(m,1H),4.05(dd,J=9.5,5.3 Hz,1H),3.33(dd,J=27.4,13.2 Hz,2H),3.06-2.94(m,2H),2.65(s,1H),2.49(s,3H),1.75(s,3H),1.69(s,3H),1.64(s,3H),1.57-1.49(m,1H),1.27(s,3H),0.96(t,J=10.4 Hz,1H)ppm. 13 C NMR(75 MHz,CDCl3)δ152.98(s),151.67(d,J=15.7 Hz),148.42(s),142.43(s),142.26(s),142.21(s),139.35(s),139.07(s),136.69(s),136.54(d,J=10.8 Hz),135.89(d,J=10.0 Hz),134.57(s),134.30(s),133.94(s),133.68(s),131.42(s),129.79(s),129.47(s),129.32(s),128.97(s),128.90(s),128.81(s),128.72(s),128.68(s),128.58(s),128.54(s),128.44(s),128.29(s),128.13(s),127.94(s),126.92(s),126.51(s),126.30(s),125.00(d,J=13.7 Hz),124.43(s),123.37(s),122.91(s),65.81(d,J=9.8 Hz),63.99(d,J=5.0 Hz),55.53(s),55.29(s),53.65(s),48.68(s),47.43(s),34.25(s),32.54(s),32.32(s),21.44(s),20.88(s),16.73(s).

[0074]

[0075] White solid.Yield:66%.MP:69.0-69.7℃.[α] D =+109(c=0.1,CH2Cl 2, 28.0℃).31 P NMR(121 MHz,CDCl3)δ-16.86(s),-20.42(s)ppm. 1 H NMR(300 MHz,CDCl3)δ7.42-7.37(m,5H),7.35-7.26(m,6H),7.23-7.11(m,11H),7.03-6.81(m,8H),6.50-6.46(m,1H),3.87(dd,J=10.1,5.8 Hz,1H),3.15(q,J=13.3 Hz,2H),2.87(d,J=6.9 Hz,1H),2.77(t,J=6.2 Hz,1H),2.38(s,3H),1.62(s,3H),1.57(s,3H),1.49(s,3H),1.38-1.34(m,1H),1.13(s,3H),0.85-0.75(m,1H)ppm. 13 C NMR(101 MHz,CDCl3)δ152.86(s),151.59(d,J=15.5 Hz),148.24(s),142.26(s),142.16(s),142.09(s),139.27(s),139.00(s),136.52(s),136.40(s),135.85(d,J=10.5 Hz),134.37(s),134.17(s),133.82(s),133.62(s),131.25(s),129.71(s),129.35(s),129.16(s),128.77(s),128.69(s),128.65(s),128.61(s),128.57(s),128.54(s),128.48(s),128.41(s),128.35(s),128.28(s),128.12(s),127.87(s),127.76(s),126.70(s),126.30(s),126.10(s),124.93(d,J=14.0Hz),124.16(s),123.15(s),122.69(s),65.68(d,J=10.2 Hz),63.88(d,J=4.9 Hz),55.41(s),55.19(s),48.50(s),47.09(s),34.13(s),32.32(s),32.13(s),21.22(s),20.70(s),16.48(s)ppm.HRMS(ESI)(m / z)[M+H] + Calcd for C 56 H 54NOP2 + 818.3675;found818.3602.

[0076]

[0077] White solid.Yield:71%.MP:88.2-89.3℃.[α] D =-284(c=0.1,CH2Cl 2, 23.4℃). 31 P NMR(121 MHz,CDCl3)δ-16.76(s),-19.52(s)ppm. 1 H NMR(300 MHz,CDCl3)δ7.49 -7.46(m,3H),7.41-7.35(m,5H),7.28-7.28(m,6H),7.19-7.16(m,5H),7.13-7.06(m,3H),7.06-6.98(m,3H),6.96-6.95(m,3H),6.60-6.56(m,1H),3.93(dd,J=8.8,6.6 Hz,1H),3.28(q,J=13.4 Hz,2H),3.03(d,J=6.7 Hz,1H),2.83(t,J=6.3 Hz,1H),2.40(s,6H),1.68(s,3H),1.65(s,3H),1.56(s,3H),1.50-1.47(m,1H),1.23(s,3H),1.07(t,J=10.5Hz,1H)ppm. 13C NMR(101 MHz,CDCl3)δ152.83(s),151.69(d,J=15.7 Hz),148.26(s),142.53(d,J=2.5 Hz),142.46(s),142.38(s),142.29(s),139.25(d,J=20.9 Hz),137.30(s),136.54(d,J=10.9 Hz),136.01(d,J=10.5 Hz),134.45(s),134.25(s),133.92(s),133.72(s),131.33(s),129.82(s),129.41(s),129.18(s),128.80(s),128.77(s),128.66(s),128.58(s),128.51(s),128.46(s),128.39(d,J=1.5 Hz),128.21(s),127.93(s),127.78(s),126.79(s),126.47(d,J=3.1 Hz),126.31(s),126.17(s),125.06(d,J=14.0Hz),124.23(s),123.26(s),122.76(s),77.42(d,J=11.4 Hz),77.16(s),76.84(s),66.33(d,J=11.2 Hz),64.15(d,J=4.9 Hz),55.55(s),55.22(d,J=17.8 Hz),48.64(d,J=4.7Hz),47.27(s),34.21(s),32.36(s),32.26(s),29.80(s),21.59(s),20.85(s),16.58(s)ppm.HRMS(ESI)(m / z)[M+H] + Calcd for C 57 H 56 NOP2 + 832.3832;found832.3759.

[0078]

[0079] White solid.Yield:85%.MP:133.7-135.2℃.[α] D =-114(c=0.1,CH2Cl 2, 28.7℃). 31 PNMR(162 MHz,CDCl3)δ-14.02(s),-16.42(s)ppm. 1H NMR(400 MHz,CDCl3)δ7.46-7.37(m,5H),7.37-7.30(m,10H),7.24-7.22(m,2H),7.11(m,5H),7.02-6.89(m,3H),6.55(m,1H),3.57(s,2H),2.92(d,J=6.4 Hz,1H),2.85-2.77(m,1H),2.37(t,J=5.7 Hz,1H),1.87(t,J=10.4 Hz,1H),1.65(s,3H),1.62(m,1H),1.59(s,3H),1.48(s,3H),1.37(m,2H),1.28(s,3H),1.08-0.81(m,4H),0.60(t,J=7.1 Hz,3H)ppm. 13 C NMR(101 MHz,CDCl3)δ152.83(s),151.89(d,J=16.0 Hz),148.14(s),143.13(s),142.54(d,J=16.0 Hz),139.37(s),139.17(s),136.55(d,J=4.6 Hz),136.43(d,J=4.4 Hz),134.26(s),134.14(s),134.06(s),133.94(s),131.32(s),129.95(s),129.55(s),128.91(s),128.80(s),128.65(s),128.60(s),128.58(s),128.53(s),128.49(s),128.27(s),127.69(s),126.67(s),126.19(s),126.05(s),125.06(d,J=14.4 Hz),123.89(s),123.27(s),122.61(s),64.61(d,J=4.7 Hz),60.07(d,J=12.4 Hz),54.20(s),51.89(d,J=16.2 Hz),49.19(d,J=3.6 Hz),46.44(s),34.27(s),34.16(s),32.58(s),31.57(s),28.04(s),22.76(s),20.95(s),16.39(s),13.96(s).HRMS(ESI)(m / z)[M+H] + Calcd forC 53 H 56 NOP2 + 784.3846;found 784.3759.

[0080]

[0081] White solid.Yield:75%.MP:115.7-117.8℃.[α] D =-105(c=0.1,CH2Cl 2, 31.3℃). 31 PNMR(121 MHz,CDCl3)δ-17.76(s),-21.28(s)ppm. 1 H NMR(300 MHz,CDCl3)δ7.87(d,J=7.2 Hz,1H),7.45(dd,J=18.6,8.1 Hz,10H),7.32-7.20(m,12H),7.11-7.02(m,4H),6.93(dd,J=16.9,7.2 Hz,2H),6.67-6.61(m,1H),4.38(t,J=7.2 Hz,1H),3.42(d,J=13.5 Hz,1H),3.24(d,J=13.5 Hz,1H),3.02(d,J=6.3 Hz,1H),2.93(t,J=6.3 Hz,1H),2.42(s,3H),1.69(s,3H),1.66(s,3H),1.54(s,3H),1.38(d,J=15.3 Hz,2H),1.30(s,3H)ppm. 13C NMR(75 MHz,CDCl3)δ152.82(s),151.82(d,J=15.5 Hz),148.35(s),142.30(s),142.26(s),142.08(s),141.39(d,J=1.8 Hz),139.29(s),139.01(s),136.64(d,J=11.0Hz),136.45(s),136.05(d,J=10.4 Hz),134.47(s),134.20(s),133.93(s),133.66(s),131.41(s),130.04(s),129.90(s),129.47(s),129.12(s),128.89(s),128.69(s),128.65(s),128.59(s),128.54(s),128.45(s),128.33(s),128.25(s),127.85(s),127.73(s),126.83(s),126.60(s),126.30(s),126.22(s),124.99(d,J=14.2 Hz),124.24(s),123.37(s),122.88(s),64.57(d,J=4.6 Hz),55.55(s),55.37(s),49.10(d,J=5.2 Hz),47.06(s),34.25(s),32.30(s),32.12(s),20.94(s),20.57(s),20.53(s),16.55(s)ppm.HRMS(ESI)(m / z)[M+H] + Calcd for C 56 H 54 NOP2 + 818.3677;found 818.3602.

[0082]

[0083] White solid.Yield:67%.MP:91.3-92.5℃.[α] D =-75(c=0.1,CH2Cl 2, 24.4C). 31 P NMR(121 MHz,CDCl3)δ-16.78(s),-19.89(s)ppm. 1H NMR(300 MHz,CDCl3)δ7.45-7.38(m,3H),7.36-7.29(m,6H),7.26-7.16(m,9H),7.13-7.06(m,3H),7.04-6.87(m,8H),6.52-6.48(m,1H),3.88(dd,J=9.5,6.1 Hz,1H),3.19(q,J=13.4 Hz,2H),2.91(d,J=6.9 Hz,1H),2.76(t,J=6.4 Hz,1H),2.38(s,3H),1.62(s,3H),1.59(s,3H),1.49(s,3H),1.44-1.38(m,1H),1.15(s,3H),0.93-0.86(m,1H)ppm. 13 C NMR(101 MHz,CDCl3)δ152.84(s),151.59(d,J=16.0 Hz),148.20(s),142.39(s),142.28(s),142.20(s),142.12(s),139.22(s),139.01(s),137.47(s),136.44(d,J=11.0 Hz),135.88(d,J=10.1 Hz),134.37(s),134.17(s),133.84(s),133.64(s),131.26(s),129.72(s),129.36(s),129.22(s),129.19(s),129.11(s),128.72(s),128.62(s),128.57(s),128.54(s),128.49(s),128.42(s),128.37(s),128.30(s),128.26(s),128.14(s),127.84(s),127.73(s),126.72(s),126.28(s),125.82(d,J=3.2 Hz),124.95(d,J=14.1 Hz),124.19(s),123.17(s),122.69(s),66.07(d,J=10.7 Hz),63.99(d,J=4.9 Hz),55.30(d,J=6.9Hz),55.08(s),48.55(d,J=4.7 Hz),47.14(s),34.13(s),32.27(s),32.19(s),21.63(s),20.73(s),16.48(s).HRMS(ESI)(m / z)[M+H] + Calcd for C 56 H 54NOP2 + 818.3678;found 818.3602.

[0084]

[0085] White solid.Yield:78%.MP:107.6–110.1℃.[α] D =-96(c=0.1,CH2Cl 2, 32.0℃). 31 PNMR(121 MHz,CDCl3)δ-16.34(s),-16.49(s)ppm. 1 H NMR(300 MHz,CDCl3)δ7.45(m,7H),7.37-7.32(m,10H),7.30(m,2H),7.13(m,4H),7.03(m,1H),6.93(s,1H),6.58(m,1H),3.56(d,J=14.3 Hz,1H),3.41(d,J=14.3 Hz,1H),2.96-2.89(m,2H),2.35(t,J=6.8 Hz,1H),1.67(s,3H),1.65(s,3H),1.51(s,3H),1.33(m,1H),1.31(s,3H),1.23(d,J=6.2 Hz,3H),0.94(m,1H)ppm. 13C NMR(75 MHz,CDCl3)δ152.54(s),151.79(d,J=15.6 Hz),147.91(s),142.75(s),139.12(d,J=21.0 Hz),136.52(s),136.37(s),136.21(s),134.21(s),134.14(s),133.94(s),133.87(s),131.39(s),129.83(s),129.42(s),128.86(s),128.81(s),128.76(s),128.63(s),128.59(s),128.57(s),128.54(s),128.48(s),128.43(s),128.27(s),127.80(s),127.17(s),126.77(s),126.24(s),126.20(s),124.91(d,J=14.3Hz),123.99(s),123.30(s),122.74(s),64.73(d,J=4.8 Hz),56.83(d,J=13.7 Hz),55.54(s),54.69(d,J=16.4 Hz),49.02(d,J=3.9 Hz),45.87(s),34.21(s),32.54(s),31.86(s),22.71(s),20.89(s),16.39(s)ppm.HRMS(ESI)(m / z)[M+H] + Calcd for C 50 H 50 NOP2 + 742.3358;found 742.3289.

[0086]

[0087] White solid.Yield:72%%.MP:121.3-124.1℃.[α] D =-125(c=0.1,CH2Cl 2, 32.2℃). 31 PNMR(121 MHz,CDCl3)δ-14.09(s),-16.34(s)ppm. 1H NMR(400 MHz,CDCl3)δ7.49-7.44(m,6H),7.43-7.35(m,11H),7.31-7.29(m,3H),7.22-7.12(m,6H),7.07-6.97(m,3H),6.62-6.57(m,1H),3.65-3.53(m,2H),2.99(d,J=6.0 Hz,1H),2.84-2.77(m,1H),2.42-2.38(m,1H),1.90(t,J=10.4 Hz,1H),1.71(s,3H),1.63(s,3H),1.52(s,3H),1.33(s,3H),0.95-0.93(m,2H),0.92-0.90(m,1H),0.63(t,J=7.2 Hz,3H)ppm. 13 C NMR(101MHz,CDCl3)δ152.91(s),151.85(d,J=15.8 Hz),148.02(s),143.18(s),142.32(d,J=15.7 Hz),139.24(d,J=20.1 Hz),136.55(s),136.46(s),136.36(s),134.23(s),134.16(s),134.03(s),133.96(s),131.36(s),129.91(s),129.49(s),128.87(s),128.80(s),128.62(s),128.57(s),128.55(s),128.51(s),128.29(s),127.72(s),127.49(s),126.73(s),126.21(s),126.07(s),124.98(d,J=14.2 Hz),123.89(s),123.29(s),122.61(s),64.74(d,J=4.6 Hz),61.85(d,J=12.7 Hz),54.47(s),51.47(d,J=16.6 Hz),49.01(d,J=3.6 Hz),46.25(s),34.26(s),32.83(s),31.43(s),26.85(d,J=8.6 Hz),20.95(s),16.40(s),10.00(s)ppm.HRMS(ESI)(m / z)[M+H] + Calcd forC 51 H 52 NOP2 + 756.3535;found756.3446.

[0088]

[0089] White solid.Yield:50%.MP:96.5-97.1℃.[α] D =-87(c=0.1,CH2Cl 2, 29.8℃). 31 P NMR(162 MHz,CDCl3)δ-14.04(s),-16.33(s)ppm. 1 H NMR(400 MHz,CDCl3)δ7.50(t,J=7.4Hz,3H),7.47-7.45(m,2H),7.43-7.41(m,5H),7.39-7.36(m,5H),7.32-7.29(m,2H),7.23-7.13(m,5H),7.08-7.03(m,2H),6.99(t,J=7.6 Hz,1H),6.63-6.59(m,1H),3.70-3.59(m,2H),2.98(d,J=6.4 Hz,1H),2.89(p,J=5.8 Hz,1H),2.41(t,J=5.7 Hz,1H),1.98-1.90(m,1H),1.72(s,3H),1.71-1.67(m,1H),1.64(s,3H),1.54(s,3H),1.44-1.37(m,2H),1.35(s,3H),1.13(ddd,J=12.9,11.4,5.8 Hz,1H),0.98-0.91(m,1H),0.63(t,J=7.3Hz,3H)ppm. 13C NMR(101 MHz,CDCl3)δ152.91(s),151.91(d,J=15.4 Hz),148.19(s),143.18(s),142.49(d,J=15.9 Hz),139.37(s),139.16(s),136.55(d,J=5.6 Hz),136.44(d,J=5.2 Hz),134.32(s),134.12(s),133.92(s),131.34(s),129.97(s),129.58(s),128.90(s),128.83(s),128.69(s),128.63(s),128.61(s),128.56(s),128.53(s),128.31(s),127.73(s),126.69(s),126.15(d,J=16.5 Hz),125.04(d,J=14.6 Hz),123.92(s),123.31(s),122.63(s),64.63(d,J=4.9 Hz),59.54(d,J=12.5 Hz),54.19(d,J=2.6Hz),52.07(d,J=16.2 Hz),49.11(d,J=3.7Hz),46.43(s),36.84(d,J=9.9 Hz),34.29(d,J=1.2 Hz),32.86(s),31.25(s),20.99(s),19.00(s),16.41(s),14.12(s)ppm.HRMS(ESI)(m / z)[M+H] + Calcd for C 52 H 54 NOP2 + 770.3682;found 770.3602.

[0090]

[0091] White solid.Yield:64%.MP:115.3-117.1℃.[α] D =-37(c=0.1,CH2Cl 2, 27.7℃). 31 P NMR(162 MHz,CDCl3)δ-13.31(s),-16.11(s)ppm. 1H NMR(400 MHz,CDCl3)δ7.45-7.44(m,1H),7.39-7.35(m,9H),7.34-7.31(m,5H),7.26-7.24(m,2H),7.14-7.10(m,3H),7.04-6.99(m,6H),6.96-6.92(m,2H),6.80-6.80(m,2H),6.58-6.58(m,1H),3.57(q,J=15.0 Hz,2H),3.18(p,J=6.1 Hz,1H),3.04(d,J=6.5 Hz 1H),2.85-2.73(m,2H),2.26(t,J=6.0Hz,1H),1.91(t,J=10.5 Hz,1H),1.71-1.67(m,1H),1.64(s,3H),1.62(s,3H),1.47(s,3H),1.30(s,3H),0.93(t,J=6.7 Hz,1H)ppm. 13C NMR(101 MHz,CDCl3)δ152.87(s),151.70(d,J=15.5 Hz),147.87(s),142.88(s),142.28(d,J=15.8 Hz),139.24(s),139.01(s),136.55(s),136.43(s),136.33(s),134.22(s),134.11(s),134.02(s),133.91(s),131.22(s),129.76(d,J=1.2Hz),129.48(s),129.33(s),129.04(s),128.79(s),128.74(s),128.63(s),128.59(s),128.56(s),128.52(s),128.45(s),128.20(s),127.80(s),127.67(s),127.33(s),126.64(s),126.10(d,J=10.3 Hz),125.54(s),125.01(d,J=14.4 Hz),123.83(s),123.19(s),122.51(s),64.68(d,J=4.6Hz),61.92(d,J=13.7 Hz),54.38(d,J=3.2 Hz),51.10(d,J=16.3 Hz),49.13(d,J=3.7 Hz),45.85 (s), 40.07(d, J = 11.2 Hz), 34.18 (d, J = 1.1 Hz), 32.30 (s), 31.97 (s), 20.94 (s),16.33 (s)ppm.HRMS(ESI)(m / z)[M+H] + Calcd for C 56 H 54 NOP2 + 818.3678;found 818.3602.

[0092]

[0093] White solid.Yield:57%.MP:87.3-89.1℃.[α] D =-103(c=0.1,CH2Cl 2, 32.6℃). 31 P NMR(121 MHz,CDCl3)δ-14.51(s),-16.55(s). 1H NMR(300 MHz,CDCl3)δ7.46-7.40(m,6H),7.37-7.3(m,12H),7.29-7.26(m,2H),7.17-7.11(m,3H),7.05-7.01(m,2H),6.58-6.54(m,1H),5.60-5.46(m,1H),4.79(dd,J=21.6,13.6 Hz,2H),3.60(d,J=14.6 Hz,1H),3.49(d,J=14.8 Hz,1H),3.01-2.87(m,2H),2.40-2.23(m,3H),1.84(t,J=10.5 Hz,1H),1.66(s,3H),1.63(s,3H),1.48(s,3H),1.30(s,3H),0.89(d,J=2.9 Hz,1H). 13 C NMR(101MHz,CDCl3)δ152.88(s),151.81(d,J=16.1 Hz),147.93(s),142.93(s),142.22(d,J=15.9 Hz),139.22(d,J=21.0 Hz),136.55(s),136.45(s),136.35(s),135.45(s),134.19(s),134.17(s),133.98(s),131.34(s),129.85(s),129.44(s),128.96(s),128.79(s),128.60(s),128.56(s),128.48(s),128.25(s),127.68(s),127.29(s),126.71(s),126.18(s),126.07(s),124.99(d,J=14.8 Hz),123.88(s),123.25(s),122.61(s),117.07(s),64.81(d,J=4.8 Hz),60.82(d,J=13.6 Hz),54.68(s),51.58(d,J=16.8 Hz),48.99(s),46.06(s),38.48(d,J=10.8 Hz),34.24(s),32.54(s),31.75(s),20.92(s),16.38(s).HRMS(ESI)(m / z)[M+H] + Calcd for C 52 H 52 NOP2 + 768.3512;found 768.3446.

[0094]

[0095] White solid.Yield:60%.MP:102.3-103.4℃.[α] D =-6(c=0.1,CH2Cl 2, 29.1℃). 31 P NMR(121 MHz,CDCl3)δ-5.92(s),-19.68(s)ppm. 1 H NMR(300 MHz,CDCl3)δ7.50(dd,J=9.0,1.5 Hz,1H),7.39-7.35(m,15H),7.32-7.18(m,8H),7.11-7.00(m,5H),6.95(d,J=8.3 Hz,1H),3.92-3.83(m,1H),3.65(d,J=13.5 Hz,1H),3.49(d,J=13.5 Hz,1H),2.75(d,J=6.8 Hz,1H),2.59(t,J=6.6 Hz,1H),1.53(s,3H),1.51(s,3H),1.47(s,3H),1.35(s,9H),1.29-1.27(m,1H),1.15(s,3H),1.02-0.94(m,1H)ppm. 13C NMR(101 MHz,CDCl3)δ152.92(s),151.30(s),150.02(s),148.93(s),142.12(s),141.78(d,J=15.9 Hz),138.96(s),138.75(s),137.84(d,J=10.8 Hz),133.58(s),133.39(s),132.86(dd,J=21.6,6.8Hz),130.38(s),130.29(s),130.21(s),129.56(s),128.81(s),128.60(s),128.57(s),128.53(s),128.50(s),128.46(s),128.23(s),127.84(s),127.70(d,J=3.3 Hz),127.27(s),126.33(d,J=12.3 Hz),125.66(s),125.05(s),116.78(d,J=6.2 Hz),116.10(s),64.66(d,J=12.1 Hz),64.21(d,J=5.0 Hz),55.51(d,J=2.5Hz),55.09(d,J=17.4 Hz),50.94(s),48.57(d,J=4.2 Hz),34.51(s),34.06(s),32.45(s),32.39(s),31.46(s),20.76(s),16.38(s)ppm.HRMS(ESI)(m / z)[M+H] + Calcd for C 59 H 60 NOP2 + 860.4150;found860.4072.

[0096]

[0097] White solid.Yield:71%.MP:132.3-134.1℃.[α] D =-95(c=0.1,CH2Cl 2, 28.4℃). 31 P NMR(121 MHz,CDCl3)δ-16.84(s),-20.28(s)ppm. 1H NMR(300 MHz,CDCl3)δ7.46-7.41(m,5H),7.38-7.29(m,4H),7.28-7.13(m,12H),7.05-6.91(m,8H),6.53-6.48(m,1H),3.93(dd,J=10.1,5.6 Hz,1H),3.22(s,2H),2.89(d,J=7.0 Hz,1H),2.78(t,J=6.1 Hz,1H),2.53(t,J=9.2 Hz,1H),1.96-1.84(m,4H),1.81-1.78(m,1H),1.65(s,3H),1.60(s,3H),1.52(s,3H),1.48(s,3H),1.15(s,3H),1.04–0.98(m,1H),0.95-0.88(m,2H),0.83-0.76(m,1H). 13 CNMR(101 MHz,CDCl3)δ152.86(s),151.56(d,J=15.8 Hz),148.16(s),146.84(s),142.27(s),142.20(s),142.11(s),139.44(d,J=2.1 Hz),139.22(s),139.02(s),136.40(d,J=10.9 Hz),135.87(d,J=10.2 Hz),134.37(s),134.17(s),133.91(s),133.71(s),131.22(s),129.69(s),129.32(s),129.16(s),128.69(s),128.62(s),128.55(s),128.47(s),128.40(s),128.36(s),128.29(s),128.15(s),127.75(s),126.71(s),126.43(s),126.29(s),126.14(s),125.05(d,J=14.5 Hz),124.15(s),123.15(s),122.71(s),65.44(d,J=10.1 Hz),63.84(d,J=4.9 Hz),55.32(d,J=18.5 Hz),55.14(s),48.51(d,J=4.6 Hz),46.91(s),44.30(s),34.60(d,J=6.6 Hz),34.14(s),32.38(s),32.20(s),27.03(s),26.30(s),20.74(s),16.50(s).HRMS(ESI)(m / z)[M+H] +Calcd forC 61 H 62 NOP2 + 886.4306;found 886.4228.

[0098]

[0099] White solid.Yield:69%.MP:103.8-104.9℃.[α] D =-122(c=0.1,CH2Cl 2, 26.6℃). 31 PNMR(162 MHz,CDCl3)δ-16.81(s),-20.52(s)ppm. 1 H NMR(400 MHz,CDCl3)δ7.42-7.36(m,5H),7.32-7.22(m,5H),7.22-7.07(m,9H),7.00-6.80(m,10H),6.47-6.44(m,1H),3.81(s,1H),3.14(dd,J=33.5,13.4 Hz,2H),2.81(d,J=6.9 Hz,1H),2.73(t,J=6.2 Hz,1H),1.60(s,3H),1.54(s,3H),1.47(s,3H),1.43(s,1H),1.38-1.33(m,1H),1.10(s,3H),0.81-0.74(m,1H)ppm. 13C NMR(101 MHz,CDCl3)δ158.68(s),152.87(s),151.54(d,J=16.3Hz),148.25(s),142.19(s),142.11(s),142.02(s),139.07(d,J=21.0 Hz),136.42(d,J=11.1 Hz),135.79(d,J=10.1 Hz),134.37(s),134.17(s),133.78(s),133.59(s),131.25(s),129.66(s),129.34(s),129.15(s),128.71(s),128.67(s),128.58(s),128.54(s),128.48(s),128.42(s),128.35(s),128.27(s),128.22(s),128.13(s),127.90(s),127.77(s),126.73(s),126.33(s),126.12(s),124.87(d,J=13.8 Hz),124.22(s),123.16(s),122.70(s),113.40(s),65.19(d,J=9.9 Hz),63.88(s),55.41(s),55.22(s),48.49(s),47.14(s),34.12(s),32.40(s),32.10(s),26.94(s),20.69(s),16.50(s).HRMS(ESI)(m / z)[M+H] + Calcd for C 56 H 53 NO2P2 + 834.3641;found834.3552.

[0100]

[0101] White solid.Yield:74%.MP:115.4-117.1℃.[α] D =-107(c=0.1,CH2Cl 2, 28.3℃). 31 PNMR(162 MHz,CDCl3)δ-16.64(s),-19.49(s)ppm. 1H NMR(400 MHz,CDCl3)δ7.53(s,1H),7.49-7.43(m,3H),7.41-7.35(m,6H),7.31-7.27(m,4H),7.27-7.23(m,4H),7.15-6.88(m,11H),6.57-6.55(m,1H),3.96(dd,J=8.1,6.6 Hz,1H),3.30(d,J=13.5 Hz,1H),3.19(d,J=13.5 Hz,1H),2.93(d,J=6.8 Hz,1H),2.77(t,J=6.3 Hz,1H),2.46(s,1H),1.68(s,3H),1.64(s,3H),1.54(s,3H),1.50-1.48(m,1H),1.23(s,3H),1.08(t,J=10.7 Hz,1H)ppm. 13 C NMR(101 MHz,CDCl3)δ152.97(s),151.55(d,J=15.5 Hz),148.22(s),145.09(d,J=3.1 Hz),141.95(s),141.90(s),139.02(s),138.81(s),136.36(d,J=10.4 Hz),135.82(d,J=10.2 Hz),134.40(s),134.20(s),134.04(s),133.83(s),133.63(s),131.34(s),129.72(s),129.49(s),129.33(s),129.03(s),128.84(s),128.70(s),128.66(s),128.59(s),128.53(s),128.48(s),128.41(s),128.25(s),127.91(s),127.86(s),127.82(s),127.26(s),126.84(s),126.76(d,J=3.7Hz),126.42(s),126.29(s),124.85(d,J=13.7Hz),124.45(s),123.32(s),122.80(s),65.77(d,J=11.6 Hz),64.19(d,J=4.9 Hz),55.27(s),55.08(d,J=17.5 Hz),48.69(d,J=5.5 Hz),47.24(s),34.18(s),32.37(s),32.24(s),20.78(s),16.57(s)ppm.HRMS(ESI)(m / z)[M+H] +Calcdfor C 55 H 51 ClNOP2 + 838.3141;found 838.3056.

[0102]

[0103] White solid.Yield:55%.MP:95.8-96.4℃.[α] D =-46(c=0.1,CH2Cl 2, 25.7℃). 31 P NMR(121 MHz,CDCl3)δ-13.43(s),-15.15(s). 1 H NMR(300 MHz,CDCl3)δ7.21-7.44(m,5H),7.39-7.37(m,10H),7.32-7.27(m,2H),7.19-7.12(m,6H),6.58-6.56(m,1H),3.56(dd,J=38.6,14.5 Hz,2H),3.02(d,J=6.2 Hz,1H),2.89-2.80(m,1H),2.44(t,J=6.1 Hz,1H),1.94(t,J=10.4 Hz,1H),1.74(s,3H),1.68(s,3H),1.62-1.55(m,1H),1.51(s,3H),1.34(s,9H),1.34-1.33(m,3H),1.33-1.32(m,2H),1.20(s,9H),0.67(t,J=7.2 Hz,3H). 13CNMR (75 MHz, CDCl3) δ152.90 (s), 149.84 (d, J = 15.7 Hz), 145.91 (s), 145.24 (s), 144.85 (s), 143.14 (s), 142.31 (d, J = 16.3 Hz),139.43(s),139.15(s),136.88(d,J=4.6 Hz),136.73(d,J=4.6 Hz),134.25(s),134.19(s),133.98(s),133.92(s),128.92(s),128.9 0(s),128.80(s),128.69(s),128.63(s),128.53(s),128.49(s),128. 45(s),128.39(s),128.36(s),128.29(s),127.88(s),127.76(s),126 .20(s),126.07(s),124.44(s),123.84(d,J=14.0Hz),123.31(s),120. 44(s),64.84(d,J=4.9Hz),62.23(d,J=12.9Hz),54.34(d,J=2.8Hz),51.13(d,J=16.5Hz),49.05(d,J=2.4Hz),46.47(s),34.67(d,J=1.4Hz) ,34.58(s),34.51(s),32.88(s),31.88(s),31.66(s),31.40(s),26.79(d,J=11.2Hz),20.95(s),16.40(s),10.03(s).HRMS(ESI)(m / z)[M+H] + Calcd for C 59 H 68 NOP2 + 868.4781; found 868.4698.

[0104] II. Application: Synthesis of spirobarbituric acid-epoxyhexane compounds

[0105] Example P1

[0106] The synthesis of compound P1 involved the following steps: In a 10 mL reaction flask under a nitrogen atmosphere, 0.005 mmol of Pd2(dba)3, 0.008 mmol of 1-phosphanorbornene-dimethyloxanthracene chiral ligand, and 0.08 mmol of DBN were added to 2 mL of ethyl acetate solution. The mixture was stirred at room temperature for 0.5 hours. Subsequently, 0.2 mmol of 2-hydroxymethyl-1-phenylallyl tert-butyl carbonate and 0.1 mmol of 5-benzyl-1,3-dimethylbarbituric acid were added at 5 °C. After the reaction was complete, the mixture was extracted, dried, and the solvent was removed by rotary evaporation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1), yielding a final product in 85% yield.

[0107] Yellow oil.Yield:85%yield.[α] D =+191(c=0.055, CH2Cl2, 33.5℃). 1 H NMR(600MHz, CDCl3)δ7.35(t,J=7.5Hz,2H),7.31–7.27(m,2H),7.27–7.24(m,2H,overlapped with the peak of chloroform),7.22(d,J=7.5Hz,2H),7.07(d,J=7.1Hz,2H),6.49(s,1H),5.19(d,J=13.6Hz,1H),4.89(s ,1H),4.48(d,J=13.5Hz,1H),3.59(d,J=14.8Hz,1H),3.10(s,3H),2.96(s,3H),2.84(d,J=14.9Hz,1H). 13 C NMR (151MHz, CDCl3) δ169.4,167.3,150.2,136.4,135.8,131.0,129.4,129.0,128.3,128.2,127.0 126.8,125.6,85.1,68.5,58.1,38.2,28.5,27.9.HRMS(ESI)(m / z)[M+H] + Calcd for C 23 H 23 N2O4 + 391.1652; found391.1650.HPLC:The product was analyzed by HPLC to determine the enantiomericexcess:94%ee(Chiralpak AD-H,n-hexane / i-propanol=70 / 30,1mL / min,254nm)tR = 6.576min, 8.126min.

[0108] In the synthesis of spirobarbituric acid-epoxyhexane compound P1, the ligand used has a significant impact on its yield. Compound P1 was synthesized by replacing the 1-phosphanorbornene-dimethyloxanthracene ligand III-8 used in this example with the ligands shown in Table 1. Other methods and parameters were the same. The yield and enantiomeric excess values ​​of P1 are shown in Table 1.

[0109] Table 1. Effects of ligands on the yield and enantiomeric excess of compound P1.

[0110] ligands yield Enantiomer excess value ligands yield Enantiomer excess value Commercially available 1 -- -- III-3 36％ 70％ Commercially available 2 -- -- III-4 39％ 76％ 3 commercially available -- -- III-5 36％ 74％ III-1 42％ 64％ III-6 78％ 74％ III-2 42％ 51％ III-7 76％ 50％

[0111] Among them, the commercially available compounds 1-3 in Table 1 represent (S)-(-)-(6,6'-dimethoxybiphenyl-2,2'-yl)bis(diphenylphosphine); (S)-(-)-5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxane; and (S,R,R)-(+)-(3,5-dioxa-4-phosphacycloheptadien[2,1-a:3,4-a′]dinaphth-4-yl)di(1-phenylethyl)amine.

[0112] Under the same starting reactants, catalyst, solvent, and reaction temperature conditions, spirobarbituric acid-epoxyhexane compounds P1 could not be synthesized using commercially available compounds 1-3 as ligands. Among the 1-phosphonobornene-dimethyloxanthracene ligand compounds III-1 to III-8 synthesized in Examples 1-8, the highest yield and enantiomeric excess of spirobarbituric acid-epoxyhexane compounds P1 were achieved when 1-phosphonobornene-dimethyloxanthracene ligand compound III-8 was used as the ligand.

[0113] Example P2

[0114] The synthesis of compound P2 involved the following steps: In a 10 mL reaction flask under a nitrogen atmosphere, 0.005 mmol of Pd2(dba)3, 0.008 mmol of 1-phosphanorbornene-dimethyloxanthracene chiral ligand III-8, and 0.08 mmol of DBN were added to 2 mL of ethyl acetate solution. The mixture was stirred at room temperature for 0.5 hours. Subsequently, 0.2 mmol of 2-hydroxymethyl-1-phenylallyl tert-butyl carbonate and 0.1 mmol of 1,3-dibenzyl-5-benzylidene barbiturate were added at 5 °C. After the reaction was complete, the mixture was extracted, dried, and the solvent was removed by rotary evaporation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1), yielding a final product in 59% yield.

[0115] Yellow oil.Yield:59%yield.[α]D = +121 (c = 0.120, CH2Cl2, 34.3 °C). 1 1H NMR (600 MHz, CDCl3) δ 7.37–7.34 (m, 4H), 7.33–7.31 (m, 3H), 7.30–7.28 (m, 2H), 7.28–7.24 (m, 4H, overlapped with the peak of chloroform), 7.22 (d, J = 7.5 Hz, 2H), 7.11–7.07 (m, 1H), 6.82 (d, J = 4.5 Hz, 4H), 6.43 (s, 1H), 5.18 (d, J = 13.5 Hz, 1H), 4.91 (d, J = 15.1 Hz, 2H), 4.83–4.75 (m, 2H), 4.65 (d, J = 13.9 Hz, 1H), 4.46 (d, J = 13.5 Hz, 1H), 3.49 (d, J = 14.6 Hz, 1H), 2.84 (d, J = 14.7 Hz, 1H). 13 13C NMR (151 MHz, CDCl3) δ 169.5, 166.9, 150.3, 136.3, 136.0, 135.7, 135.4, 130.7, 129.6, 129.5, 129.1, 128.7, 128.5, 128.4, 128.3, 128.2, 128.0, 127.8, 127.2, 127.1, 126.0, 84.4, 68.4, 57.6, 45.5, 45.0, 39.6. HRMS (ESI) (m / z) [M+H] + Calcd for C<{ 35 [[ID=*]]H 31 N2O4 + 543.2278; found 543.2270. HPLC: The product was analyzed by HPLC to determine the enantiomeric excess: 88% ee (Chiralpak AD-H, n-hexane / i-propanol = 95 / 5, 1 mL / min, 254 nm) t R = 14.148 min, 15.610 min.

[0116] Example P3

[0117] The synthesis of compound P3 involved the following steps: In a 10 mL reaction flask under a nitrogen atmosphere, 0.005 mmol of Pd2(dba)3, 0.008 mmol of 1-phosphanorbornene-dimethyloxanthracene chiral ligand III-8, and 0.08 mmol of DBN were added to 2 mL of ethyl acetate solution. The mixture was stirred at room temperature for 0.5 hours. Subsequently, 0.2 mmol of 2-hydroxymethyl-1-(4-chlorophenyl)allyl tert-butyl carbonate and 0.1 mmol of 1,3-dibenzyl-5-benzylidene barbiturate were added at 5 °C. After the reaction was complete, the mixture was extracted, dried, and the solvent was removed by rotary evaporation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1), yielding a final product in 64% yield.

[0118] White solid.Yield:64%yield.MP:155.4–155.8℃.[α] D =+113(c=0.108, CH2Cl2, 28.3℃). 1 H NMR(600MHz, CDCl3)δ7.36(t,J=7.6Hz,2H),7.30–7.25(m,4H,overlapped with the peak of chloroform),7.22(d,J=7.6Hz,2H),7.07(d,J=7.0Hz,2H),6.49(s,1H),5.19(d,J=13.5Hz,1H),4.90(s ,1H),4.48(d,J=13.5Hz,1H),3.59(d,J=14.9Hz,1H),3.10(s,3H),2.96(s,3H),2.84(d,J=14.9Hz,1H). 13 C NMR (151MHz, CDCl3) δ169.4,167.4,150.2,136.4,135.7,131.0,129.4,129.0,128.3, 128.2,127.0,126.8,125.6,85.1,68.5,58.1,38.2,28.5,28.0.HRMS(ESI)(m / z)[M+H] + Calcd forC 23 H 21 ClN2NaO4 +447.1082; found 447.1076.HPLC:The product was analyzed by HPLC to determine the enantiomeric excess:92%ee(Chiralpak AD-H,n-hexane / i-propanol=70 / 30,1mL / min,254nm)t R = 6.520min, 7.995min.

[0119] Example P4

[0120] The synthesis of compound P4 involved the following steps: In a 10 mL reaction flask under a nitrogen atmosphere, 0.005 mmol of Pd2(dba)3, 0.008 mmol of 1-phosphanorbornene-dimethyloxanthracene chiral ligand III-8, and 0.08 mmol of DBN were added to 2 mL of ethyl acetate solution. The mixture was stirred at room temperature for 0.5 hours. Subsequently, 0.2 mmol of 2-hydroxymethyl-1-(4-methylphenyl)allyl tert-butyl carbonate and 0.1 mmol of 1,3-dibenzyl-5-benzylidene barbiturate were added at 5 °C. After the reaction was complete, the mixture was extracted, dried, and the solvent was removed by rotary evaporation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1), yielding a final product in 59% yield.

[0121] White oil.Yield:59%yield.[α] D =+70(c=0.160, CH2Cl2, 29.5℃). 1 H NMR(600MHz,CDCl3)δ7.30–7.24(m,3H,overlapped with the peak of chloroform),7.16(d,J=7.8Hz,2H),7.11(d,J=7.8Hz,2H),7.06(d,J=7.2Hz,2H),6.45(s,1H),5.19(d,J=13.5Hz,1H),4. 89(s,1H),4.48(d,J=13.5Hz,1H),3.57(d,J=14.9Hz,1H),3.10(s,3H),2.96(s,3H),2.83(d,J=14.9Hz,1H),2.35(s,3H). 13C NMR (151MHz, CDCl3) δ169.5,167.4,150.2,136.7,135.8,133.5,130.2,129.4,129.0,129 .0,128.2,126.8,125.6,85.1,68.6,58.2,38.2,28.5,27.9,21.2.HRMS(ESI)(m / z)[M+H] + Calcd for C 24 H 24 N2NaO4 + 427.1628; found 427.1624.HPLC:The product was analyzed by HPLC to determine theenantiomeric excess:92%ee(Chiralpak AD-H,n-hexane / i-propanol=70 / 30,1mL / min,254nm)t R =7.877min, 10.468min.

[0122] Example P5

[0123] The synthesis of compound P5 involved the following steps: In a 10 mL reaction flask under a nitrogen atmosphere, 0.005 mmol of Pd2(dba)3, 0.008 mmol of 1-phosphanorbornene-dimethyloxanthracene chiral ligand III-8, and 0.08 mmol of DBN were added to 2 mL of ethyl acetate solution. The mixture was stirred at room temperature for 0.5 hours. Subsequently, 0.2 mmol of 2-hydroxymethyl-1-(4-fluorophenyl)allyl tert-butyl carbonate and 0.1 mmol of 1,3-dibenzyl-5-benzylidene barbiturate were added at 5 °C. After the reaction was complete, the mixture was extracted, dried, and the solvent was removed by rotary evaporation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1), yielding a final product in 52% yield.

[0124] Yellow oil.Yield:52%yield.[α] D =+73(c=0.080, CH2Cl2, 33.5℃). 11H NMR (600 MHz, CDCl3) δ 7.30–7.25 (m, 3H, overlapped with the peak of chloroform), 7.21–7.17 (m, 2H), 7.09–7.02 (m, 4H), 6.44 (s, 1H), 5.13 (d, J = 13.5 Hz, 1H), 4.89 (s, 1H), 4.46 (d, J = 13.5 Hz, 1H), 3.58 (d, J = 14.9 Hz, 1H), 3.10 (s, 3H), 2.97 (s, 3H), 2.82 (d, J = 14.9 Hz, 1H). 13 13C NMR (151 MHz, CDCl3) δ 169.3, 167.4, 161.8 (d, J = 246.6 Hz), 150.1, 135.6, 132.4 (d, J = 3.3 Hz), 131.1, 130.7, 130.6, 129.5, 128.2, 125.7, 125.6, 115.3, 115.2, 85.1, 68.3, 58.1, 38.1, 28.5, 27.9. HRMS (ESI) (m / z) [M+H] + Calcd for C 23 H 22 FN2O4 + 409.1558; found 409.1557. HPLC: The product was analyzed by HPLC to determine the enantiomeric excess: 89% ee (Chiralpak AD-H, n-hexane / i-propanol = 70 / 30, 1 mL / min, 254 nm) t R = 7.434 min, 9.561 min.

[0125] Example P6

[0126] The synthesis of compound P6 involved the following steps: In a 10 mL reaction flask under a nitrogen atmosphere, 0.005 mmol of Pd2(dba)3, 0.008 mmol of 1-phosphanorbornene-dimethyloxanthracene chiral ligand III-8, and 0.08 mmol of DBN were added to 2 mL of ethyl acetate solution. The mixture was stirred at room temperature for 0.5 hours. Subsequently, 0.2 mmol of 2-hydroxymethyl-1-(1-naphthyl)allyl tert-butyl carbonate and 0.1 mmol of 1,3-dibenzyl-5-benzylidene barbiturate were added at 5 °C. After the reaction was complete, the mixture was extracted, dried, and the solvent was removed by rotary evaporation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1), yielding a final product in 76% yield.

[0127] Yellow oil.Yield:76%yield.[α] D =-56 (c=0.080, CH2Cl2, 27.5℃). 1 H NMR (600MHz, CDCl3) δ7.84–7.80(m,3H),7.65(s,1H),7.49–7.44(m,2H),7.40–7.37(m,1H),7.32–7.24(m,3H, overlapped with the peak of chloroform),7.10–7.05(m,2H),6.63(s,1H),5.28(d,J=13.5Hz,1H),4.92(s,1H),4.56(d ,J=13.6Hz,1H),3.64(d,J=14.9Hz,1H),3.12(s,3H),2.98(s,3H),2.90(d,J=14.9Hz,1H). 13 C NMR (151MHz, CDCl3) δ169.4,167.4,150.2,135.8,133.9,133.3,132.4,131.5,129.4,128.2,128.0,127.9, 127.8,127.7,127.3,126.8,126.2,125.9,125.6,85.1,68.6,58.2,38.3,28.5,28.0.HRMS(ESI)(m / z)[M+H] + Calcd for C 27 H 25 N2O4 +441.1809; found 441.1831.HPLC:The product wasanalyzed by HPLC to determine the enantiomeric excess:92%ee(Chiralpak AD-H,n-hexane / i-propanol=85 / 15,1mL / min,254nm)t R = 9.020 min, 11.719 min.

[0128] Example P7

[0129] The synthesis of compound P7 involved the following steps: In a 10 mL reaction flask under a nitrogen atmosphere, 0.005 mmol of Pd₂(dba)₃, 0.008 mmol of 1-phosphanorbornene-dimethyloxanthracene chiral ligand III-8, and 0.08 mmol of DBN were added to 2 mL of ethyl acetate solution. The mixture was stirred at room temperature for 0.5 hours. Subsequently, 0.2 mmol of 2-hydroxymethyl-1-phenylallyl tert-butyl carbonate and 0.1 mmol of 5-(4-phenylbenzylene)-1,3-dimethylbarbituric acid were added at 5 °C. After the reaction was complete, the mixture was extracted, dried, and the solvent was removed by rotary evaporation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1), yielding a final product in 96% yield.

[0130] White solid.Yield:96%yield.MP:64.8–65.2℃.[α] D =+39(c=0.200, CH2Cl2, 34.2℃). 1 H NMR (600MHz, CDCl3) δ7.52(d,J=7.6Hz,2H),7.49(d,J=7.6Hz,2H),7.42(t,J=7.3Hz,2H),7.36(t,J=7.8Hz,3H),7.28–7.21(m,3H, overlapped with the peak ofchloroform),7.14(d,J=7.7Hz,2H),6.49(s,1H),5.21(d,J=13.5Hz,1H),4.95(s,1H),4.4 9(d,J=13.5Hz,1H),3.59(d,J=14.8Hz,1H),3.14(s,3H),2.99(s,3H),2.86(d,J=14.8Hz,1H). 13C NMR (151MHz, CDCl3) δ169.5,167.4,150.1,142.3,140.2,136.4,134.8,131.0,129.1,128.8,128.3, 127.7,127.2,127.0,126.9,126.9,126.1,84.8,68.5,58.1,38.3,28.6,28.0.HRMS(ESI)(m / z)[M+H] + Calcd for C 29 H 27 N2O4 + 467.1965; found467.1961.HPLC: The product was analyzed by HPLC to determine the enantiomericexcess:91%ee(Chiralpak AD-H,n-hexane / i-propanol=85 / 15,1mL / min,254nm)t R = 11.372 min, 15.922 min.

[0131] Example P8

[0132] The synthesis of compound P8 involved the following steps: In a 10 mL reaction flask under a nitrogen atmosphere, 0.005 mmol of Pd₂(dba)₃, 0.008 mmol of 1-phosphanorbornene-dimethyloxanthracene chiral ligand III-8, and 0.08 mmol of DBN were added to 2 mL of ethyl acetate solution. The mixture was stirred at room temperature for 0.5 hours. Subsequently, 0.2 mmol of 2-hydroxymethyl-1-phenylallyl tert-butyl carbonate and 0.1 mmol of 5-(4-fluorobenzyl)-1,3-dimethylbarbituric acid were added at 5 °C. After the reaction was complete, the mixture was extracted, dried, and the solvent was removed by rotary evaporation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1), yielding a final product in 74% yield.

[0133] White solid.Yield:74%yield.MP:146.6–147.2℃.[α] D =+156(c=0.059, CH2Cl2, 25.3℃). 11H NMR (600 MHz, CDCl3) δ 7.36 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 9.1 Hz, 2H), 7.22 (d, J = 7.5 Hz, 2H), 7.09–7.05 (m, 1H, overlapped with the peak of chloroform), 6.96 (t, J = 8.6 Hz, 2H), 6.48 (s, 1H), 5.18 (d, J = 13.5 Hz, 1H), 4.90 (s, 1H), 4.47 (d, J = 13.5 Hz, 1H), 3.57 (d, J = 14.8 Hz, 1H), 3.13 (s, 3H), 3.00 (s, 3H), 2.83 (d, J = 14.9 Hz, 1H). 13 13C NMR (151 MHz, CDCl3) δ 169.4, 167.2, 163.0 (d, J C-F = 248.8 Hz), 150.1, 136.3, 131.8 (d, J C-F = 3.3 Hz), 130.7, 127.5, 127.5, 127.1 (d, J C-F = 8.2 Hz), 115.3 (d, J C-F = 21.6 Hz), 84.2, 68.5, 58.0, 38.4, 28.6, 28.0. HRMS (ESI) (m / z) [M + H] + Calcd for C 23 H 22 FN2O4 + 409.1558; found 409.1556. HPLC: The product was analyzed by HPLC to determine the enantiomeric excess: 94% ee (Chiralpak AD-H, n-hexane / i-propanol = 85 / 15, 1 mL / min, 254 nm) t R = 10.595 min, 11.809 min. <\

[0134] Example P9

[0135] The synthesis of compound P9 involved the following steps: In a 10 mL reaction flask under a nitrogen atmosphere, 0.005 mmol of Pd₂(dba)₃, 0.008 mmol of 1-phosphanorbornene-dimethyloxanthracene chiral ligand III-8, and 0.08 mmol of DBN were added to 2 mL of ethyl acetate solution. The mixture was stirred at room temperature for 0.5 hours. Subsequently, 0.2 mmol of 2-hydroxymethyl-1-phenylallyl tert-butyl carbonate and 0.1 mmol of 5-(2,4-difluorobenzyl)-1,3-dimethylbarbituric acid were added at 5 °C. After the reaction was complete, the mixture was extracted, dried, and the solvent was removed by rotary evaporation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1), yielding a final product in 71% yield.

[0136] White solid.Yield:71%yield.MP:188.8–189.2℃.[α] D =+118(c=0.055, CH2Cl2, 31.8℃). 1 H NMR(600MHz, CDCl3)δ7.36(t,J=7.6Hz,2H),7.28–7.24(m,3H,overlapped with the peak of chloroform),7.21(d,J=7.5Hz,2H),6.86–6.82(m,1H),6.77–6.72(m,1H),6.52(s,1H),5.17–5.13(m, 2H), 4.49 (d, J = 13.6Hz, 1H), 3.58 (d, J = 14.9Hz, 1H), 3.19 (s, 2H), 2.98 (s, 2H), 2.93 (d, J = 15.0Hz, 1H). 13 C NMR(151MHz,CDCl3)δ168.3,167.5,163.2(dd,J C-F =255.2Hz), 158.9(dd,J C-F =250.7Hz),150.3,136.3,130.7,129.2(q,J C-F =9.3Hz),129.0,128.3,127.1(d,J C-F =11.5Hz), 119.5(dd,J C-F =13.6Hz), 111.7(dd,J C-F =18.2Hz), 103.4, 103.39 (d, J) C-F =26.7Hz),68.8,57.8,37.5,29.7,28.8,28.1.HRMS(ESI)(m / z)[M+H] +Calcd for C 23 H 20 F2N2NaO4 + 449.1283; found 449.1276.HPLC:The product was analyzed by HPLC to determine the enantiomeric excess:94%ee(Chiralpak AD-H,n-hexane / i-propanol=98 / 2,1mL / min,254nm)t R = 33.712 min, 36.197 min.

[0137] Example P10

[0138] The synthesis of compound P10 involved the following steps: In a 10 mL reaction flask under a nitrogen atmosphere, 0.005 mmol of Pd2(dba)3, 0.008 mmol of 1-phosphanorbornene-dimethyloxanthracene ligand III-8, and 0.08 mmol of DBN were added to 2 mL of ethyl acetate solution. The mixture was stirred at room temperature for 0.5 hours. Subsequently, 0.2 mmol of 2-hydroxymethyl-1-phenylallyl tert-butyl carbonate and 0.1 mmol of 5-(4-trifluoromethylbenzylene)-1,3-dimethylbarbituric acid were added at 5 °C. After the reaction was complete, the mixture was extracted, dried, and the solvent was removed by rotary evaporation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1), yielding a final product in 66% yield.

[0139] White solid.Yield:66%yield.MP:100.5–100.9℃.[α] D =+197(c=0.070, CH2Cl2, 25.3℃). Figure 2 shown 1 H NMR(600MHz, CDCl3)δ7.53(d,J=8.0Hz,2H),7.38–7.34(m,2H),7.29–7.25(m,1H,overlapped with the peak of chloroform),7.25–7.20(m,4H),6.49(s,1H),5.19(d,J=13.5Hz,1H),5.01(s,1H),4.48(d ,J=13.5Hz,1H),3.56(d,J=14.7Hz,1H),3.15(s,3H),2.97(s,3H),2.86(d,J=14.8Hz,1H). 13C NMR (151MHz, CDCl3) δ169.3,166.9,150.0,140.1,136.2,131.5(q,J C-F =32.9Hz),130.3,129.0,128.4,127.4,127.2,125.2(d,J C-F =3.4Hz), 123.7(q,J C-F =272.5Hz),83.8,68.4,57.7,38.8,28.6,28.0.HRMS(ESI)(m / z)[M+H] + Calcd for C 24 H 22 F3N2O4 + 459.1526; found459.1527.HPLC: The product was analyzed by HPLC to determine the enantiomeric excess: 90%ee (Chiralpak IA-H, n-hexane / i-propanol=95 / 5, 1mL / min, 254nm)t R =17.308min, 20.796min.

[0140] Cell viability test

[0141] The classic MTT assay was used to analyze the cytotoxicity of compounds P1-P10 synthesized in Examples P1-P10. The specific testing method was as follows: HeLa tumor cells were seeded in 96-well plates, with three replicates for each concentration. After cell adhesion and growth, cells were treated with different concentrations of the drug for 24 hours. After drug treatment, MTT solution (5 mg / mL MTT stock solution, 10 μL per well) was added, and the cells were incubated for another 4 hours. After terminating the culture, the culture medium was carefully aspirated, and DMSO (100 μL per well) was added using a pipette. The plates were shaken in the dark for 10 minutes to ensure complete dissolution of the formed purple formazan crystals. The optical density (OD) value at 490 nm was read using a microplate reader. Cell viability was calculated based on the formula and the fluorescence intensity of the blank control group, and the IC50 of the compounds synthesized in Examples P1-P10 was then calculated. 50 Values, as shown in Table 2 and Figure 3 As shown.

[0142] Table 2 IC50 of spirobarbituric acid-epoxyhexane compounds 50 Value table

[0143] Example <![CDATA[IC 50 (μmol / L)]]> Example <![CDATA[IC 50 (μmol / L)]]> Example <![CDATA[IC 50 (μmol / L)]]> P1 2.1 P5 3.4 P9 4.2 P2 1.6 P6 2.5 P10 6.86 P3 2.3 P7 3.8 P4 0.9 P8 1.3

[0144] Therefore, the spirobarbituric acid-epoxyhexane compounds synthesized in the embodiments of the present invention exhibit a low half-maximal inhibitory concentration (WMC) against tumor cells, demonstrating that spirobarbituric acid-epoxyhexane compounds possess good antitumor activity and are promising candidates for antitumor drugs. Furthermore, the synthesis method provided in the embodiments of the present invention enables the spirobarbituric acid-epoxyhexane compounds to achieve a yield of 96%, a diastereoselectivity greater than 20:1, and a stereoselectivity greater than 98%.

[0145] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them; although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications can still be made to the specific implementation of the present invention or equivalent substitutions can be made to some technical features without departing from the spirit of the technical solutions of the present invention, and all such modifications and substitutions should be covered within the scope of the technical solutions claimed in the present invention.

Claims

1. The application of a spirobarbituric acid-epoxyhexane compound in the preparation of an anti-HeLa tumor cell drug, wherein, The spirobarbituric acid-epoxyhexane compound is 。

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