Spirobarbituric acid-epoxyhexane compound as well as synthesis method and application thereof

Abstract

The invention provides a spirobarbituric acid-epoxyhexane compound as well as a synthesis method and application thereof. The structural formula of the compound is # imgabs0, a group R2 is C1-6 alkyl, C1-6 alkoxy, hydrogen, halogen, halogenated C1-6 alkyl, nitro or naphthyl, and a group R3 is C1-6 alkyl, C1-6 alkoxy, hydrogen, halogen or naphthyl; and the group R4 is C1-6 alkyl or benzyl. The invention also provides a synthesis method of the compound, which comprises the following steps: by taking an alkenyl barbituric acid compound and a 1, 2-substituted allyl carbonate compound as raw materials, carrying out asymmetric cycloaddition reaction under the action of a palladium catalyst, a chiral ligand and alkali to synthesize a series of spirobarbituric acid-epoxyhexane compounds. The synthesis method has the advantages of mild reaction conditions, simplicity and convenience in operation, wide substrate application range, high yield, good stereoselectivity and the like. Tests show that the compound has certain anti-tumor activity. The invention provides an application of the compound in preparation of antitumor drugs.

Description

Technical Field

[0001] The invention relates to the field of organic chemical synthesis, and in particular to a spirobarbituric acid-epoxyhexane compound and a synthesis method and application thereof. Background Art

[0002] Spirobarbiturates are barbituric acid derivatives. These compounds are difunctionalized at the C-5 position of barbituric acid to obtain a unique spirocyclic structure. Studies have shown that spirobarbituric acid compounds have important application prospects in the biomedical field, especially spirocyclic compounds composed of barbituric acid and a six-membered ring. Spirobarbituric acid-cyclohexane compounds have significant anti-tumor activity (J. Med. Chem., 1964, 7, 695); spirobarbituric acid-azacycloalanine compounds are used as anticonvulsant drugs (Pharm. Chem. J., 2009, 43, 315); spirobarbituric acid-pyrimidone compounds have strong urease inhibitory activity (Iran. J. Pharm. Res., 2015, 14, 1105); spirobarbituric acid-cyclohexanone compounds show HIV-1 inhibitor activity (Org. Biomol. Chem., 2011, 9, 7282). Therefore, the development of a new functional group synthesis method 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 process of barbituric acid compounds, and metal catalysts can affect the structure of the compounds. Therefore, the development of new metal catalysts is conducive to further enriching spirobarbituric acid compounds. Summary of the invention

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

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

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

[0006]

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

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

[0009] Preferably, the palladium catalyst is Pd2(dba)3·CHCl3, Pd2(dba)3, Pd(dba)2 or Pd(PPh3)4, and the molar ratio of the palladium catalyst to 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, and can be an inorganic base or an organic base, wherein the inorganic base can be cesium carbonate, sodium carbonate, sodium bicarbonate, sodium tert-butoxide, potassium phosphate or potassium carbonate, etc., and the organic base can be 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), DBU, 1,4-diaminobicyclo[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, chloroform, toluene, acetonitrile, etc.

[0012] The 1-phosphanorbornene-dimethyloxanthene chiral ligand is a novel chiral phosphine ligand. By introducing a rigid skeleton, three completely bound PC bonds are formed, which successfully solves the scientific problem that the phosphorus chiral center is easy to racemize. Such phosphorus chiral ligands can be widely used in asymmetric reactions such as metal-catalyzed asymmetric cyclization, and can prepare spirobarbituric acid-epoxyhexane compounds, which have the characteristics of good stereoselectivity and high reaction yield. Therefore, in the process of synthesizing spirobarbituric acid-epoxyhexane compounds, the main function of the 1-phosphanorbornene-dimethyloxanthene chiral ligand is to regulate the stereo configuration of the product, and the molar ratio of the 1-phosphanorbornene-dimethyloxanthene chiral ligand to compound II is preferably 0.05 to 0.3:1. The structural formula of the chiral ligand is shown in the following formulas III and III':

[0013]

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

[0015] Among them, in the present invention, the "C 1-6 Alkyl", "C 1-6 Alkoxy", "C 1-6 "Alkenyl" refers to alkyl, alkoxy, and alkenyl groups containing 1 to 6 carbon atoms. 1-6 The "alkyl" includes aliphatic alkyl and cycloalkyl. The number of substituents in the various "substituted phenyl" groups 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, R 1 It is hydrogen or tert-butyl.

[0017] The method for synthesizing the chiral ligand comprises taking a 9,9-dimethylxanthene compound and a 1-phosphanorbornene amine compound as raw materials, and generating the above-mentioned 1-phosphanorbornene-dimethylxanthene chiral ligand through H[1,5] migration and phospha-DA reaction, wherein the structural formula of the 9,9-dimethylxanthene compound is shown in the following formula I, and the structural formula of the 1-phosphanorbornene amine compound is shown in the following formula II and II'; the reaction formula is shown as follows:

[0018]

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

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

[0021] The main function of the desiccant is to dry the byproduct water generated during the reaction, and the desiccant may be anhydrous magnesium sulfate, anhydrous sodium sulfate, etc. The amount of the desiccant used is preferably 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 amount of the reducing agent is preferably 1 to 1.2 equivalents.

[0023] The above-mentioned synthesis method specifically includes: taking the 9,9-dimethyloxanthene compound and the 1-phosphanorbornene amine compound in a first Schlenk bottle of a certain volume, adding the first organic solvent and the desiccant, and heating and refluxing 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-dimethyloxanthene chiral ligand. Preferably, the heating reflux time is 1-3h to ensure that compounds I and II react completely. The reaction time in the ice water bath is preferably 2-4h.

[0024] Furthermore, after the chiral ligand is synthesized, it is extracted with ethyl acetate, the organic layers are combined, dried with MgSO4, filtered, the solvent is evaporated under reduced pressure, and separated by column chromatography; the corresponding product is obtained with a yield of 50-78%.

[0025] The synthesis method of the compound I comprises the following steps:

[0026] Synthesis of compound I-2: First, compound I-1 and n-butyl lithium are used as raw materials to undergo lithiation reaction in an ice-water bath, and then iodine is added to react at room temperature to synthesize compound I-2. The reaction formula is as follows:

[0027]

[0028] Synthesis of compound I: First, the compound I-2 and n-butyl lithium are reacted at low temperature as raw materials, diphenylphosphine chloride is added to react, and then n-butyl lithium is added to react under alkaline conditions to synthesize the compound I. The reaction formula is as follows:

[0029]

[0030] The steps of synthesizing compound I-2 specifically include: first adding compound I-1 into a second Schlenk flask, after replacing N2, dissolving it with anhydrous ether, placing it in an ice-water bath, and then adding an alkaline substance, slowly adding n-butyl lithium, removing the ice-water bath, and placing the Schlenk flask at 30-50°C for reaction for 3-5 hours; cooling to 0°C, slowly adding iodine dissolved in tetrahydrofuran, warming to room temperature, reacting overnight, and after TLC detection of the complete reaction, treating the unreacted iodine with a saturated sodium thiosulfate solution, extracting with ethyl acetate, combining the organic phases and drying with anhydrous magnesium sulfate, filtering, concentrating under reduced pressure, and separating by column chromatography to obtain compound I-2.

[0031] The steps of synthesizing compound I specifically include: placing the compound I-2 in a third Schlenk bottle, dissolving it with anhydrous tetrahydrofuran after replacing nitrogen, and cooling it at -78°C, then slowly dropping n-butyl lithium therein, reacting at -78°C for 1 to 2 hours, slowly dropping diphenylphosphine chloride, continuing the reaction for 0.5 to 1.5 hours, then adding n-butyl lithium therein, reacting for 1 to 2 hours, adding alkaline substances, reacting at -78°C for 1.5 to 2.5 hours, then slowly warming to room temperature, reacting overnight, after the reaction is completed by TLC detection, adding water to quench the reaction, 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 the compound I.

[0032] The synthesis method of the 1-phosphanorbornene amine compound comprises the following steps:

[0033] Synthesis of compound II-4: Compound II-3, tert-butylsulfenamide and tetraisopropyl titanate are used as raw materials to undergo a condensation reaction to generate compound II-4. The reaction formula is as follows:

[0034]

[0035] Synthesis of compounds II-5 and II-5': Compound II-4 and Grignard reagent RMgBr were used as raw materials, and compounds II-5 and II-5' were synthesized in an ice-water bath. The reaction formula is as follows:

[0036]

[0037] Synthesis of compound II: The compound II-5 or II-5' is first subjected to a reduction reaction under nickel catalysis, and then reacted with dilute hydrochloric acid to remove the sulfinyl group, thereby synthesizing the 1-phosphanorborneneamine compound II or II'. The reaction formula is as follows:

[0038]

[0039] The steps of synthesizing compound II-4 specifically include: placing compound II-3, tert-butylsulfenamide and tetraisopropyl titanate in a fourth Schlenk flask of a certain volume, dissolving them with dry tetrahydrofuran after replacing N2, the reaction temperature is 60-80°C, and after reacting for 2-4 hours, the reaction is monitored by TCL. After the reaction is detected to be complete, ethyl acetate is added thereto for extraction, the organic phase is dried and filtered with anhydrous magnesium sulfate, rotary evaporated, and then subjected to column silica gel chromatography to obtain the diastereoisomer compound II-4.

[0040] The steps of synthesizing compounds II-5 and II-5' include: placing the compound II-4 in a fifth Schlenk flask, dissolving it with tetrahydrofuran after replacing N2, placing it in an ice-water bath, slowly adding the Grignard reagent RMgBr at 0°C, reacting at 0°C for 0.5 to 1.5 hours, and after TLC detection of the reaction being complete, adding water to quench the reaction, and then extracting with ethyl acetate; combining the organic phases, drying with anhydrous magnesium sulfate, filtering and spin-drying; separating through a silica gel column to obtain compounds II-5 and II-5'.

[0041] The step of synthesizing the 1-phosphanorbornene amine compound comprises: placing Raney nickel in a sixth Schlenk bottle after nitrogen has been evacuated, washing the Raney nickel with ethanol, then adding the compound II-5 or II-5', filtering out the Raney nickel, and rotating the remaining reaction liquid to dryness, dissolving the obtained solid with methanol, adding dilute hydrochloric acid, reacting at room temperature for 1 to 3 hours, and detecting the reaction by TLC. After the reaction is complete, extracting with saturated sodium bicarbonate and ethyl acetate, combining the organic phases, drying with anhydrous magnesium sulfate, filtering, rotating to dryness, and filtering with a silica gel column to obtain the 1-phosphanorbornene amine compound II or II'.

[0042] The third object of the present invention is to provide a use of the above-mentioned spirobarbituric acid-epoxyhexane compounds in the preparation of anti-tumor 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 the present invention have anti-tumor activity and are expected to be used as anti-tumor drugs;

[0045] 2) The method for synthesizing spirobarbituric acid-epoxyhexane compounds provided by the present invention uses 1-phosphanorbornene-dimethyloxanthene chiral compounds as ligands, alkenylbarbituric acid as electron-deficient olefins, and phenyl-substituted 2-hydroxyallyl carbonate tert-butyl ester under palladium catalysis to undergo an asymmetric (4+2) cycloaddition reaction for synthesis, thereby overcoming the defect that effective stereoinduction cannot be achieved when using traditional chiral ligands; and the method for synthesizing spirobarbituric acid-epoxyhexane compounds provided by the present invention has the characteristics of mild reaction conditions, simple and safe operation, cheap and easy-to-obtain raw materials, high reaction yield, etc., and the reaction yield can reach 50-96%, and the diastereoselectivity of the spirobarbituric acid-epoxyhexane compounds is greater than 20:1 and / or the stereoselectivity is greater than 98%.

[0046] 3) In the synthesis process of the above-mentioned spirobarbituric acid-epoxyhexane compounds provided by the present invention, the synthesis method of 1-phosphanorbornene-dimethyloxanthene chiral ligands used is simple, feasible, and has high yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of 1-phosphanorbornene-dimethylxanthene chiral ligand III-8;

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

[0049] Figure 3 This is a graph showing the results of an in vitro antitumor activity test of the spirobarbituric acid-epoxyhexane compound P10. DETAILED DESCRIPTION

[0050] The technical solution of the present invention is further described in detail below through specific implementation methods.

[0051] Unless otherwise specified, the terms used in the present invention are all commonly used terms in the relevant field. The technical means used in the examples, such as preparation processes, testing methods, etc., are all conventional means well known to those skilled in the art; the raw materials used in the examples are all commercially available.

[0052] 1. 1-phosphanorbornene-dimethylxanthene chiral ligand and its synthesis method

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

[0054]

[0055] Take a 250mL Schlenk bottle, add 2.1g (10mmol) of 9,9'dimethylxanthene, dissolve it with anhydrous ether, place it in an ice-water bath, add 2.2eq. of TMEDA, slowly add 3.0eq. of n-butyllithium, remove the ice-water bath, place the reaction bottle at 40°C, react for 4h, cool to 0°C, slowly add iodine dissolved in tetrahydrofuran, warm to room temperature, react overnight, after TLC detection of the reaction is complete, 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 2 by column chromatography as a white solid.

[0056]

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

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

[0059]

[0060] Take a 50mL Schlenk bottle, put compound 3, 1.2 equivalents of tert-butylsulfenamide, and 2 equivalents of tetraisopropyl titanate in it, and dissolve it in dry tetrahydrofuran after replacing N2. The reaction temperature is 70°C. After 3 hours of reaction, TCL monitors the reaction. After the reaction is detected to be complete, ethyl acetate is added to it for extraction. The organic phase is dried and filtered with anhydrous magnesium sulfate and evaporated to dryness. Then, column silica gel chromatography is used to obtain a pair of diastereomers 4.

[0061]

[0062] The diastereomer 4 obtained in the previous step was placed in a 25 mL Schlenk bottle, and after replacing N2, it was dissolved in tetrahydrofuran, placed in an ice-water bath, and 2 equivalents of Grignard reagent were slowly added dropwise at 0°C. The reaction was allowed to react for 1 hour at 0°C. After TLC detection, the reaction was complete, water was added to quench the reaction, and then extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and dried. Compounds 5 and 5' were separated by passing through a silica gel column.

[0063]

[0064] Take a 25mL Schlenk bottle, replace nitrogen, add an appropriate amount of Raney nickel, wash the Raney nickel three times with ethanol, and then wash it three times with tetrahydrofuran, then add compound II-5 or II-5' dissolved in tetrahydrofuran, and detect the reaction by TLC. After the reaction is complete, filter out the Raney nickel, and spin dry the remaining reaction liquid. After dissolving the obtained solid with methanol, add 2 equivalents of dilute hydrochloric acid, react at room temperature for 2 hours, and detect 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, spin dry, and filter with a silica gel column to obtain compound II or II'.

[0065] Example 3 The synthesis method of compounds III-1 to III'-16, the steps are as follows:

[0066]

[0067] Compound I and compound II or II' were respectively placed in a Schlenk bottle, anhydrous methanol was added, and then anhydrous magnesium sulfate was added, and the mixture was heated to reflux at 70°C for 2 hours. TLC was used to detect the progress of the reaction. 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 the reaction was complete, and then water was added to quench the reaction. The mixture was extracted with ethyl acetate, the organic layers were combined, dried with MgSO4, filtered, the solvent was evaporated under reduced pressure, and separated by column chromatography; the corresponding products III-1 to III-16 or their corresponding isomers were obtained with a yield 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] 2. Application: Synthesis of spirobarbituric acid-epoxyhexane compounds

[0105] Example P1

[0106] The synthesis method of the compound P1 comprises: adding 0.005 mmol of Pd2(dba)3, 0.008 mmol of 1-phosphanorbornene-dimethylxanthene chiral ligand, and 0.08 mmol of DBN to a 10 mL reaction bottle under a nitrogen atmosphere, stirring at room temperature for 0.5 hours, and then adding 0.2 mmol of 2-hydroxymethyl-1-phenylallyl carbonate tert-butyl ester and 0.1 mmol of 5-benzylidene-1,3-dimethylbarbituric acid at 5°C. After the reaction is completed, the solvent is removed by extraction, drying, and rotary evaporation, and the residue is separated by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1), and the yield of the final product is 85%.

[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 an important influence on it; the ligand shown in Table 1 is used to replace the 1-phosphanorbornene-dimethyloxanthene ligand III-8 used in this example to synthesize compound P1, and the other methods and parameters are the same. The yield and enantiomeric excess of synthesized P1 are shown in Table 1.

[0109] Table 1 Effect of ligand on the yield and enantiomeric excess of compound P1

[0110] Ligand Yield Enantiomeric excess Ligand Yield Enantiomeric excess Commercially available 1 -- -- III-3 36％ 70％ Commercially available 2 -- -- III-4 39％ 76％ Commercially available 3 -- -- 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 represented by 1-3 in Table 1 are (S)-(-)-(6,6'-dimethoxybiphenyl-2,2'-yl)bis(diphenylphosphine); (S)-(-)-5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxadiazole; (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 conditions of starting reactants, catalyst, solvent and reaction temperature, the spirobarbituric acid-epoxyhexane compound P1 cannot be synthesized using the commercially available compound 1-3 as a ligand; among the 1-phosphanorbornene-dimethyloxanthene ligand compounds III-1 to III-8 synthesized in Examples 1-8, the yield and enantiomeric excess of the synthesized spirobarbituric acid-epoxyhexane compound P1 are the highest when the 1-phosphanorbornene-dimethyloxanthene ligand compound III-8 is used as a ligand.

[0113] Example P2

[0114] The synthesis method of the compound P2 comprises: adding 0.005 mmol of Pd2(dba)3, 0.008 mmol of 1-phosphanorbornene-dimethylxanthene chiral ligand compound III-8, and 0.08 mmol of DBN to a 10 mL reaction bottle under a nitrogen atmosphere, stirring at room temperature for 0.5 hours, and then adding 0.2 mmol of 2-hydroxymethyl-1-phenylallyl carbonate tert-butyl ester and 0.1 mmol of 1,3-dibenzyl-5-benzylidenebarbituric acid at 5°C. After the reaction is completed, the solvent is removed by extraction, drying, and rotary evaporation, and the residue is separated by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1), and the yield of the final product is 59%.

[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 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 method of the compound P3 comprises: adding Pd2(dba)3 0.005mmol, 1-phosphanorbornene-dimethylxanthene chiral ligand compound III-8 0.008mmol, DBN 0.08mmol in a 10mL reaction bottle under a nitrogen atmosphere, stirring at room temperature for 0.5 hours, and then adding 2-hydroxymethyl-1-(4-chlorophenyl)allyl carbonate tert-butyl ester 0.2mmol, 1,3-dibenzyl-5-benzylidenebarbituric acid 0.1mmol at 5°C. After the reaction is completed, the solvent is removed by extraction, drying, and rotary evaporation, and the residue is separated by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1), and the yield of the final product is 64%.

[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 for C 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 method of the compound P4 comprises: adding 0.005 mmol of Pd2(dba)3, 0.008 mmol of 1-phosphanorbornene-dimethylxanthene chiral ligand compound III-8, and 0.08 mmol of DBN to a 10 mL reaction bottle under a nitrogen atmosphere, stirring at room temperature for 0.5 hours, and then adding 0.2 mmol of 2-hydroxymethyl-1-(4-methylphenyl)allyl carbonate tert-butyl ester and 0.1 mmol of 1,3-dibenzyl-5-benzylidenebarbituric acid at 5°C. After the reaction is completed, the solvent is removed by extraction, drying, and rotary evaporation, and the residue is separated by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1), and the yield of the final product is 59%.

[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] Embodiment P5

[0123] The synthesis method of the compound P5 comprises: adding 0.005 mmol of Pd2(dba)3, 0.008 mmol of 1-phosphanorbornene-dimethylxanthene chiral ligand compound III-8, and 0.08 mmol of DBN to a 10 mL reaction bottle under a nitrogen atmosphere, stirring at room temperature for 0.5 hours, and then adding 0.2 mmol of 2-hydroxymethyl-1-(4-fluorophenyl)allyl carbonate tert-butyl ester and 0.1 mmol of 1,3-dibenzyl-5-benzylidenebarbituric acid at 5°C. After the reaction is completed, the solvent is removed by extraction, drying, and rotary evaporation, and the residue is separated by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1), and the yield of the final product is 52%.

[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 method of the compound P6 comprises: adding 0.005 mmol of Pd2(dba)3, 0.008 mmol of 1-phosphanorbornene-dimethylxanthene chiral ligand compound III-8, and 0.08 mmol of DBN to a 10 mL reaction bottle under a nitrogen atmosphere, stirring at room temperature for 0.5 hours, and then adding 0.2 mmol of 2-hydroxymethyl-1-(1-naphthyl)allyl carbonate tert-butyl ester and 0.1 mmol of 1,3-dibenzyl-5-benzylidenebarbituric acid at 5°C. After the reaction is completed, the solvent is removed by extraction, drying, and rotary evaporation, and the residue is separated by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1), and the yield of the final product is 76%.

[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 =9.020min,11.719min.

[0128] Example P7

[0129] The synthesis method of the compound P7 comprises: adding 0.005 mmol of Pd2(dba)3, 0.008 mmol of 1-phosphanorbornene-dimethylxanthene chiral ligand compound III-8, and 0.08 mmol of DBN to a 10 mL reaction bottle under a nitrogen atmosphere, stirring at room temperature for 0.5 hours, and then adding 0.2 mmol of 2-hydroxymethyl-1-phenylallyl carbonate tert-butyl ester and 0.1 mmol of 5-(4-phenylbenzylidene)-1,3-dimethylbarbituric acid at 5° C. After the reaction is completed, the solvent is removed by extraction, drying, and rotary evaporation, and the residue is separated by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1), and the yield of the final product is 96%.

[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 =11.372min,15.922min.

[0131] Example P8

[0132] The synthesis method of the compound P8 comprises: adding 0.005 mmol of Pd2(dba)3, 0.008 mmol of 1-phosphanorbornene-dimethylxanthene chiral ligand compound III-8, and 0.08 mmol of DBN to a 10 mL reaction bottle under a nitrogen atmosphere, stirring at room temperature for 0.5 hours, and then adding 0.2 mmol of 2-hydroxymethyl-1-phenylallyl carbonate tert-butyl ester and 0.1 mmol of 5-(4-fluorobenzylidene)-1,3-dimethylbarbituric acid at 5°C. After the reaction is completed, the solvent is removed by extraction, drying, and rotary evaporation, and the residue is separated by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1), and the yield of the final product is 74%.

[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 method of the compound P9 comprises: adding 0.005 mmol of Pd2(dba)3, 0.008 mmol of 1-phosphanorbornene-dimethylxanthene chiral ligand compound III-8, and 0.08 mmol of DBN to a 10 mL reaction bottle under a nitrogen atmosphere, stirring at room temperature for 0.5 hours, and then adding 0.2 mmol of 2-hydroxymethyl-1-phenylallyl carbonate tert-butyl ester and 0.1 mmol of 5-(2,4-difluorobenzylidene)-1,3-dimethylbarbituric acid at 5°C. After the reaction is completed, the solvent is removed by extraction, drying, and rotary evaporation, and the residue is separated by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1), and the yield of the final product is 71%.

[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 =33.712min,36.197min.

[0137] Example P10

[0138] The synthesis method of the compound P10 comprises: adding 0.005 mmol of Pd2(dba)3, 0.008 mmol of 1-phosphanorbornene-dimethylxanthene ligand compound III-8, and 0.08 mmol of DBN to a 10 mL reaction bottle under a nitrogen atmosphere, stirring at room temperature for 0.5 hours, and then adding 0.2 mmol of 2-hydroxymethyl-1-phenylallyl carbonate tert-butyl ester and 0.1 mmol of 5-(4-trifluoromethylbenzylidene)-1,3-dimethylbarbituric acid at 5° C. After the reaction is completed, the solvent is removed by extraction, drying, and rotary evaporation, and the residue is separated by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1), and the yield of the final product is 66%.

[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 method was used to perform cytotoxicity analysis on the compounds P1-P10 synthesized in Examples P1-P10. The specific test method is as follows: HeLa tumor cells were inoculated in a 96-well plate, and three replicate wells were set for each concentration. After the cells adhered to the wall and grew, the cells were treated with drugs of different concentrations for 24 hours. After the drug effect ended, MTT solution was added (MTT mother solution was 5 mg / mL, 10 μL per well), and the cells were placed in an incubator and continued to be cultured for ~4 hours. After the culture was terminated, the culture medium was carefully aspirated, DMSO (100 μL per well) was added using a spray gun, and the cells were shaken on a shaker in the dark for 10 minutes to ensure that the purple formazan crystals formed could be completely dissolved. Place in a microplate reader and read the optical density OD value at 490 nm. The cell viability was calculated according to the formula and the fluorescence intensity of the blank control group, and then the IC of the compounds synthesized in Examples P1-P10 was calculated. 50 Values, as shown in Table 2 and Figure 3 shown.

[0142] Table 2 IC 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 half-inhibitory concentration of the spirobarbituric acid-epoxyhexane compound synthesized in the embodiment of the present invention is low for tumor cells, which shows that the spirobarbituric acid-epoxyhexane compound has good anti-tumor activity and is expected to be used as an anti-tumor drug. In addition, the synthesis method provided in the embodiment of the present invention can make the yield of the spirobarbituric acid-epoxyhexane compound reach 96%, the diastereoselectivity is greater than 20:1, and the stereoselectivity is greater than 98%.

[0145] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, ordinary technicians in the field should understand that the specific implementation methods of the present invention can still be modified or some technical features can be replaced by equivalents without departing from the spirit of the technical solution of the present invention, which should be included in the scope of the technical solution for protection of the present invention.

Claims

1. A spirobarbituric acid-epoxyethane compound, characterized in that: The structural formula is shown below: Among them, the group R 2 C 1-6 Alkyl, C 1-6 Alkoxy, hydrogen, halogen, halo 1-6 Alkyl, nitro or naphthyl, group R 3 C 1-6 Alkyl, C 1-6 Alkoxy, hydrogen, halo or naphthyl; the group R 4 C 1-6 Alkyl, or benzyl.

2. The spirobarbituric acid-epoxyhexane compound according to claim 1, characterized in that: The group R 2 is methyl, isopropyl, tert-butyl, methoxy, hydrogen, fluorine, chlorine, bromine, trifluoromethyl, nitro or naphthyl, the group R 3 is methyl, methoxy, hydrogen, chlorine, fluorine or naphthyl; the group R 4 It is methyl, ethyl or benzyl.

3. The spirobarbituric acid-epoxyhexane compound according to claim 1, characterized in that: It is one of the following structural formulas:

4. A method for synthesizing the spirobarbituric acid-epoxyhexane compound according to any one of claims 1 to 3, comprising: Using alkenyl barbituric acid represented by compound XX1 and compound XX2 as raw materials, an asymmetric cycloaddition reaction occurs under the action of a palladium catalyst, a chiral ligand and a base to synthesize the spirobarbituric acid-epoxyhexane compound. The reaction formula is shown below: Wherein, the chiral ligand is a 1-phosphanorbornene-dimethylxanthene chiral ligand, and the structural formula is shown in the following formula III or III': Wherein, in the structural formula III or III', the group R is C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkenyl, phenyl, halogenated phenyl, C 1-6 Alkyl substituted phenyl or C 1-6 Alkoxy substituted phenyl group, group R 1 C 1-6 alkyl.

5. The synthesis method according to claim 4, characterized in that Under a nitrogen atmosphere, the palladium catalyst, the chiral ligand, the base and the second organic solvent are mixed to obtain a mixed system, and then the compound XX1 and the compound XX2 are added to the mixed system, and the mixture is reacted at 0-25° C. for 20-28 hours. After the reaction is completed, the mixture is concentrated and purified to obtain spirobarbituric acid-epoxyhexane compounds; wherein the molar ratio of the compound XX1 to the compound XX2 is 1-2:1, the molar ratio of the palladium catalyst to the compound XX2 is 0.05-0.2:1, the molar ratio of the chiral ligand to the compound XX2 is 0.05-0.3:1, and the molar ratio of the base to the compound II is 0.3-4:

1.

6. The synthesis method according to claim 5, characterized in that In the structural formula III and III' shown in the chiral ligand, the group 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, and the group R 1 It is hydrogen or tert-butyl.

7. The synthesis method according to claim 6, characterized in that The chiral ligand is one of the following structural formulas:

8. The synthesis method according to any one of claims 4 to 7, characterized in that: The method comprises using 9,9-dimethyloxanthene compounds and 1-phosphanorbornene amine compounds as raw materials, and generating the chiral ligand through H[1,5] migration and phosphanorbornene DA reaction, wherein the structural formula of the 9,9-dimethyloxanthene compounds is shown in the following formula I, and the structural formula of the 1-phosphanorbornene amine compounds is shown in the following formula II or II'; the reaction formula is shown as follows:

9. The synthesis method according to any one of claims 4 to 7, characterized in that: The palladium catalyst is Pd2(dba)3·CHCl3, Pd2(dba)3, Pd(dba)2 or Pd(PPh3)4, and the base is cesium carbonate, sodium carbonate, sodium bicarbonate, sodium tert-butoxide, potassium phosphate, potassium carbonate, 1,5-diazabicyclo[4.3.0]non-5-ene, DBU or 1,4-diaminobicyclo[2.2.2]octane or triethylamine.

10. Use of the spirobarbituric acid-epoxyhexane compound according to any one of claims 1 to 3 in the preparation of anti-tumor drugs.

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