Chiral spirocyclic oxazoline-aminophosphine ligand substituted at 5-position of oxazoline ring and preparation method and application thereof

Abstract

The present invention relates to a chiral spirocyclic oxazoline-aminophosphine ligand substituted at 5-position of oxazoline and its preparation method and application. The chiral spirocyclic oxazoline-aminophosphine ligand is a compound shown in Formula I, or a racemate or optical isomer thereof, or a catalytically acceptable salt thereof, and the main structural feature is a chiral spirodihydroindane skeleton and an oxazoline group substituted at 5-position. The chiral spirocyclic oxazoline-aminophosphine ligand can be synthesized as a chiral starting material by using 7-diaryl / alkylphosphino-7′-amino-1,1′-spirodihydroindane compounds having a spirocyclic skeleton. After the chiral spirocyclic oxazoline-aminophosphine ligand forms a complex with a transition metal (iridium) salt, it can be used to catalyze the asymmetric catalytic hydrogenation reaction of α-aryloxy substituted lactone compounds. It exhibits very high catalytic activity (TON reaches 1000) and enantioselectivity (up to 98%ee), and has practical value.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and relates to a type of chiral spirocyclic oxazoline-aminophosphine ligand substituted at the 5-position of an oxazoline ring, and a preparation method and application thereof, and specifically relates to a type of chiral spirocyclic oxazoline-aminophosphine ligand substituted at the 5-position of an oxazoline ring with a spirocyclic skeleton, and a preparation method thereof, and application thereof in the asymmetric catalytic hydrogenation reaction of α-aryloxy substituted lactone compounds. Background Art

[0002] Homogeneous catalytic hydrogenation of esters to prepare alcohols is an atom-economical, environmentally friendly, most efficient and simple method. For this reason, the homogeneous catalytic hydrogenation of esters has received widespread attention in the past decade, and many efficient catalysts and catalytic systems have been developed, and have been widely used in the large-scale preparation of drug molecules and spices (Clarke, ML Catal. Sci. Technol. 2012, 2, 2418-2423; Magano, J.; Dunetz, JR Org. Process Res. Dev. 2012, 16, 1156-1184). However, due to the lack of efficient and highly enantioselective chiral catalysts, the successful examples of asymmetric catalytic hydrogenation of ester compounds to synthesize chiral alcohols are still rare (Gu, X.-S.; et al. Acta Chim. Sinica 2019, 77, 598-612). For example, the synthesis of optically active chiral diols by asymmetric catalytic hydrogenation of racemic lactones, the current successful examples are limited to the asymmetric hydrogenation of racemic α-aryl / alkyl and arylamine substituted lactones catalyzed by chiral spirocyclic iridium complexes of chiral spirocyclic pyridine aminophosphine ligands (Yang, X.-H.; et al. Chem. Sci. 2017, 8, 1811-1814; Gu, X.-S.; et al. Org. Lett. 2019, 21, 4111-4115). Therefore, the development of new and efficient chiral ligands and catalysts thereof to achieve efficient and highly enantioselective synthesis of diverse chiral diols that have important uses in chiral drugs and the like still has very important significance and application value.

[0003] Optically active β-aryloxy substituted chiral diols are an important class of chiral raw materials or intermediates, and are of great use in the asymmetric synthesis of chiral drugs and natural products with important physiological activities. For example, optically active β-aryloxy 1,4-diols can be used as key chiral raw materials to synthesize chiral 3-aryloxy substituted tetrahydrofuran and tetrahydropyrrole structural units that are widely present in chiral drugs and clinical candidate drug molecules, such as afatinib, an anticancer drug for the clinical treatment of non-small cell lung cancer and advanced breast cancer, and empaglifozin, a new drug for the treatment of type 2 diabetes. However, due to the lack of green, efficient, and atom-economic asymmetric synthesis methods, the chiral drugs such as afatinib containing chiral 3-aryloxy-substituted tetrahydrofuran and tetrahydropyrrole structural units reported in the literature are mainly prepared by Mitsunobu reaction of optically active 3-hydroxyfuran and phenol or nucleophilic substitution reaction with fluoroaromatic hydrocarbons (such as: Widlicka, DW; et al. Org. Process Res. Dev. 2016, 20, 233-241; Wang, X.-J.; et al, Org. Lett. 2014, 16, 4090-4093). In addition to the disadvantage of poor atom economy, these synthesis methods also have certain limitations on the raw materials introduced by the aryloxy group. Therefore, the development of a green, efficient, and atom-economic new method for the asymmetric synthesis of chiral β-aryloxy 1,4-diols will undoubtedly provide a green, efficient, and practical new method for the asymmetric synthesis of these chiral drug molecules.

[0004] Based on our previous discovery that chiral spirocyclic pyridine aminophosphine ligand iridium catalyst (Xie, J.-H.; Zhou, Q.-L.; et al., Angew. Chem. Int. Ed. 2011, 50, 7329-9332; Zhou Qilin et al. CN102040625A) can efficiently and highly enantioselectively catalyze the asymmetric hydrogenation of racemic α-aryl / alkyl substituted valerolactones (Yang, X.-H.; et al. Chem. Sci. 2017, 8, 1811-1814) and α-arylamine substituted butyrolactone and valerolactone (Gu, X.-S.; et al. Org. Lett. 2019, 21, 4111-4115; Xie Jianhua et al., CN201910366247) to synthesize the corresponding chiral diols, we further targeted the optically active chiral β- Asymmetric synthesis of aryloxy-substituted diols. A class of chiral spirocyclic oxazoline-aminophosphine ligands substituted at the 5-position of the oxazoline ring was designed and developed, and its iridium complex was used to achieve efficient and highly enantioselective asymmetric catalytic hydrogenation of racemic α-aryloxy-substituted lactones to synthesize optically active β-aryloxy-substituted 1,4- and 1,5-diols. Although there are literature reports on chiral spirocyclic oxazoline-aminophosphine ligands substituted at the 4-position of the oxazoline ring (Zhang, F.-H.; et al. Adv. Synth. Catal. 2019, 361, 2832-2835), the iridium complex of the chiral spirocyclic oxazoline-aminophosphine ligand substituted at the 5-position of the oxazoline ring gives better enantioselectivity in the asymmetric catalytic hydrogenation reaction of the ester. Therefore, the chiral spirocyclic oxazoline-aminophosphine ligand substituted at the 5-position of the oxazoline ring and its iridium complex provide efficient and highly enantioselective chiral ligands and catalysts for the efficient and highly enantioselective asymmetric hydrogenation of racemic α-aryloxy substituted lactones to synthesize optically active β-aryloxy substituted 1,4- and 1,5-diols, and also provide important chiral raw materials and methods for the asymmetric synthesis of chiral 3-aryloxy substituted tetrahydrofuran and tetrahydropyrrole and other oxygen-containing and nitrogen-containing heterocycles. The synthesis method has the advantages of being green, atom-economical, mild reaction conditions, simple operation, and suitable for industrial production, and has very good application prospects and value. Summary of the invention

[0005] The purpose of the present invention is to provide a type of chiral spirocyclic oxazoline-aminophosphine ligand substituted at the 5-position of the oxazoline ring, and a preparation method and application thereof. The invention develops a new type of chiral spirocyclic oxazoline-aminophosphine ligand by introducing a 5-substituted oxazoline ring into a chiral spirocyclic aminophosphine ligand SpiroAP (Xie, J.-B.; et al, J.Am.Chem.Soc. 2010, 132, 4538-4539; Zhou Qilin, Xie Jianhua, Xie Jianbo, Wang Lixin CN CN101671365A). The iridium complex of the chiral ligand can efficiently catalyze the asymmetric catalytic hydrogenation of racemic α-aryloxy substituted lactone, and achieves a good yield (greater than 95%) and up to 96% ee enantioselectivity, thereby providing a new high-efficiency chiral ligand and catalyst for the asymmetric catalytic hydrogenation of esters, and also providing a green, efficient, atom-economical and simple-to-operate new synthesis method for the asymmetric synthesis of optically active β-aryloxy substituted 1,4- and 1,5-diols and 3-aryloxy substituted tetrahydrofuran and tetrahydropyrrole.

[0006] The chiral spirocyclic oxazoline-aminophosphine ligand substituted at the 5-position of the oxazoline ring provided by the present invention is a compound having formula I or an enantiomer, a racemate of the compound, or a catalytically acceptable salt thereof.

[0007]

[0008] Among them, R 1 A group selected from C1-C10 hydrocarbon groups, phenyl groups, substituted phenyl groups, 1-naphthyl groups, 2-naphthyl groups, heteroaryl groups or benzyl groups, wherein the substituents on the phenyl groups are C1-C10 hydrocarbon groups or alkoxy groups, the number of substituents is 1-5, and the heteroaryl group is furyl group, thienyl group or pyridyl group;

[0009] R 2 , R 3 are selected from H, C1-C10 alkyl, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl or benzyl, wherein the substituent on the phenyl is C1-C10 hydrocarbon or alkoxy, the number of substituents is 1-5, and the heteroaryl is furyl, thienyl or pyridyl; or C1-C10 alkoxy; R 2 , R 3 It can be the same or different;

[0010] The chiral spirocyclic oxazoline-aminophosphine ligand substituted at the 5-position of the oxazoline ring provided by the present invention is selected from the enantiomers, racemates or catalytically acceptable salts thereof of the following compounds:

[0011]

[0012] The present invention provides a method for preparing a chiral spirocyclic oxazoline-aminophosphine ligand substituted at the 5-position of the oxazoline ring, which is characterized in that a racemic or optically active 7-diaryl / alkylphosphino-7′-amino-1,1′-spirodihydroindane compound represented by formula II having a chiral spirodihydroindane skeleton is used as a starting material and prepared by the following reaction formula:

[0013] Wherein, R 1 , R 2 , R 3 The meaning is consistent with the above. The compound represented by formula II having a chiral spirodihydroindane skeleton is prepared according to the literature method (Jian-Bo Xie, Jian-Hua Xie, Xiao-Yan Liu, Wei-Ling Kong, Shen Li, Qi-Lin Zhou, J. Am. Chem. Soc. 2010, 132, 4538; Zhou Qilin, Xie Jianhua, Xie Jianbo, Wang Lixin, CN 101671365A).

[0014]

[0015] The preparation method of the chiral spirocyclic oxazoline-aminophosphine ligand substituted at the 5-position of the oxazoline ring is described as follows: a compound represented by formula II is first reacted with ethyl glyoxylate in the presence of an organic solvent and a reducing agent in a reactor for 2 to 24 hours to prepare a compound represented by formula III; the compound represented by formula III is then hydrolyzed with an alkali to obtain a compound represented by formula IV; in an organic solvent, the compound represented by formula IV is condensed with various substituted amino alcohols in the presence of a carboxylic acid activating agent to obtain a compound represented by formula V; the compound represented by formula V is ring-closed under the activation of methylsulfonyl chloride to obtain a compound represented by formula I.

[0016] In the above synthesis method, the organic solvent can be one of methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, toluene, xylene, methyl tert-butyl ether, ether, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane or a mixed solvent of several thereof; the reducing agent can be lithium aluminum hydride, sodium borohydride, sodium triacetoxyborohydride, sodium nitrile borohydride; the base includes an organic base and an inorganic base, wherein the organic base can be pyridine, triethylamine, tributylamine, N-methylmorpholine, N,N-diethylisopropylamine; the inorganic base can be sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate; the carboxyl activation agent can be ethyl chloroformate, isopropyl chloroformate, N,N′-dicyclohexylcarbodiimide, carbonyldiimidazole.

[0017] The present invention discloses an application of a chiral spirocyclic oxazoline-aminophosphine ligand substituted at the 5-position of the oxazoline ring, wherein the ligand forms a complex in situ with a transition metal (iridium) metal salt, and the iridium complex (which can be directly prepared into a storable solid without desolventizing or after desolventizing) is used as an iridium catalyst to catalyze the asymmetric catalytic hydrogenation reaction of α-aryloxy substituted lactone compounds.

[0018]

[0019] As a preferred solution, the chiral spirocyclic oxazoline-aminophosphine ligand substituted at the 5-position of the oxazoline ring is firstly made to form a complex with a transition metal salt, and then used for the asymmetric catalytic hydrogenation reaction of α-aryloxy substituted lactone compounds.

[0020] As a preferred solution, in an inert gas atmosphere, the chiral spirocyclic oxazoline-aminophosphine ligand and the transition metal salt are added to an organic solvent, and reacted at 25°C for 0.5 to 4 hours; then stirred and reacted in a 0.1 to 20 atm hydrogen atmosphere for 1 to 3 hours to prepare a complex formed by the chiral spirocyclic phosphine oxazoline-aminophosphine ligand and the transition metal salt. As a further preferred solution, the molar ratio of the chiral spirocyclic oxazoline-aminophosphine ligand to the transition metal salt is 1:1 to 2:1, and 1.2:1 to 1.8:1 is the best.

[0021] As a more preferred solution, the transition metal salt is a metal salt of iridium, and the iridium metal salt is [Ir(COD)Cl]2 (COD = cyclooctadiene), [Ir(COD)2]BF4, [Ir(COD)2]PF6, [Ir(COD)2]SbF6 or [Ir(COD)2]OTf.

[0022] The asymmetric catalytic hydrogenation reaction for catalyzing α-aryloxy substituted lactone provided by the present invention comprises the following steps:

[0023] As a further preferred scheme, α-aryloxy substituted lactone and base are added to the prepared complex solution, and hydrogenation reaction is carried out under 0.1-100 atm hydrogen atmosphere and 0-80° C.; the molar ratio of the α-aryloxy substituted lactone to the complex is 100:1-50000:1. The substrate concentration is 0.001-10.0 M, and the base concentration is 0.005 M-1.0 M; the base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, triethylamine, tributylamine or N-methylmorpholine.

[0024] As a further preferred solution, the organic solvent is one of methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, or a mixed solvent of several thereof.

[0025] The chiral spirocyclic oxazoline-aminophosphine ligand substituted at the 5-position of the oxazoline ring provided by the present invention has the main structural characteristics of having a chiral spirodihydroindane skeleton and an oxazoline group, and can be used as a chiral ligand in the asymmetric catalytic hydrogenation reaction of α-aryloxy substituted racemic γ- and δ-lactones catalyzed by iridium to give a good yield and an enantioselectivity of up to 96%ee. This is the first report of the asymmetric catalytic hydrogenation reaction of α-aryloxy substituted racemic lactone. The asymmetric catalytic hydrogenation reaction can also be carried out on a gram scale at a catalyst dosage of 0.1 mol%, and provides a new method for the asymmetric synthesis of tetrahydrofuran and tetrahydropyrrole substituted with chiral α-aryloxy. DETAILED DESCRIPTION

[0026] The present invention will be further described in detail and completely below in conjunction with the examples. The examples listed will help to understand the present invention, but they cannot limit the contents of the present invention.

[0027] Embodiment 1:

[0028]

[0029] Add II (1.5 g, 2.4 mmol) to a 250 mL dry two-necked round-bottom flask connected to a condenser reflux tube, replace the atmosphere with argon, and add 60 mL of anhydrous methanol (insoluble). Add ethyl glyoxylate (1.2 g, 6 mmol, 50% w / w toluene solution) and glacial acetic acid (345 μL, 6 mmol) in sequence. React at 40°C for 6 hours until all the solids are dissolved. Add NaBH3CN (495 mg, 7.8 mmol) at one time and continue to react at 40°C for 6 hours until the raw material disappears. After the reaction is completed, cool to room temperature, remove the solvent under reduced pressure, add ethyl acetate to dissolve, and quench with saturated sodium bicarbonate solution. Extract with ethyl acetate (5 mL × 3), combine the organic phases, dry the organic phases with anhydrous magnesium sulfate, filter, and remove the solvent under reduced pressure. The residue is chromatographed on a silica gel column (petroleum ether: ethyl acetate = 30: 1) to obtain 1.4 g of white solid III with a yield of 86%. Melting point: 157-159°C, (c 0.1, CHCl3). 1HNMR (400 MHz, CDCl3) δ: 7.36 (d, J = 7.2 Hz, 1H), 7.32 (s, 1H), 7.24 - 7.21 (m, 2H), 7.17 - 7.05 (m, 2H), 6.93 (d, J = 8.0 Hz, 2H), 6.74 (d, J = 7.2 Hz, 1H), 6.68 (d, J = 7.2 Hz, 2H), 5.91 (d, J = 8.0 Hz, 1H), 4.12 - 3.97 (m, 2H), 3.65 (d, J = 5.0 Hz, 1H), 3.39 (dd, J = 17.6, 7.2 Hz, 1H), 3.16 - 3.04 (m, 2H), 3.01 - 2.87 (m, 2H), 2.81 (dd, J = 17.6, 2.4 Hz, 1H), 2.49 - 2.23 (m, 3H), 2.20 - 2.12 (m, 1H), 1.22 (s, 18H), 1.16 (s, 18H). 13 C NMR (101 MHz, CDCl3) δ: 170.4, 152.7, 152.5, 149.9, 149.8, 149.7, 149.68, 144.5, 144.4, 144.0, 143.9, 142.8, 142.7, 138.8, 138.7, 135.9, 135.8, 134.5, 134.2, 134.1 (d), 133.0, 132.9, 128.3, 128.2, 127.9, 127.5, 127.4, 127.1, 125.8, 122.3, 121.1, 114.2, 108.1, 61.5 (d), 60.7, 45.0, 39.2, 39.1, 35.7, 34.7, 34.6, 31.4, 31.3, 31.2, 30.8, 14.0. 31 P NMR (162 MHz, CDCl3) δ: -19.43. Calcd for C 49 H 64 NO2P [M + H] + : 730.4747; Found: 730.4752.

[0030] Example 2:

[0031]

[0032] Add chiral spirocyclic glycine ethyl ester III (900 mg, 1.3 mmol) and lithium hydroxide monohydrate (259 mg, 6.5 mmol), 7 mL of tetrahydrofuran and water to a 100 mL sealed tube with a magnetic stirrer. Degas four times and place in an oil bath at 80°C for 12 hours. After the reaction is completed, cool to room temperature and acidify the reaction system to a pH of 2.0 to 3.0 using 4N dilute hydrochloric acid. Extract with ethyl acetate (5 mL × 3), combine the organic phases, dry the organic phases with anhydrous magnesium sulfate, filter, and remove the solvent under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 3:1) to obtain 780 mg of white solid IV with a yield of 90% and a melting point of 111-113°C. (c 0.1, CHCl3). 1 H NMR (400MHz, CDCl3) δ: 7.40-7.28 (m, 2H), 7.25-7.16 (m, 2H), 7.16-7.05 (m, 2H), 6.96 (d, J=8.0Hz, 2H), 6.75 (d, J= 7.2Hz, 1H), 6.68 (d, J=7.6Hz, 2H), 5.97 (d, J=8.0Hz, 1H), 3.23 (d, J=18.0Hz, 1H), 3.18-2.75 (m, 5H), 2.26-2.15 (m, 4H), 1.19 (d, J=23.5Hz, 36H). 13 C NMR (101MHz, CDCl3) δ: 174.4, 152.3, 152.0, 150.2(d), 149.8(d), 144.8(d), 144.0(d), 142.5(d), 138.1(d), 135.4(d), 134.5(d), 134.0, 133.1(d), 128.4(d), 128.1, 127.6(d), 127.2, 125.9, 122.6, 121.4, 115.2, 108.5, 61.5(d), 45.4, 38.8(d), 36.2, 34.7(d), 31.36, 31.3. 31 P NMR (162MHz, CDCl3) δ: -18.35.HRMS (MALDI) Calcd for C 47 H 60 NO2P[M+H] + :702.4435; Found:702.4439.

[0033] Embodiment 3:

[0034]

[0035] IV (200 mg, 0.3 mmol), (S)-phenylglycinol (148 mg, 0.9 mmol), HOBt (193 mg, 1.5 mmol), EDCI-HCl (274 mg, 1.5 mmol) were added to a 100 mL dry Schlenk bottle equipped with a magnetic stirrer. The atmosphere was replaced with argon gas, and 25 mL of anhydrous dichloromethane and triethylamine (396 μL, 3.0 mmol) were added by syringe. The reaction was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 216 mg of white solid Va, with a yield of 88% and a melting point of 96-98°C. (c 0.1, CHCl3). 1 H NMR (400MHz, CDCl) δ: 7.42-7.36 (m, 1H), 7.35-7.30 (m, 2H), 7.25-7.18 (m, 4H), 7.17-7.10 (m, 2H), 7.09-7.03 (m, 2H), 6.87 (d, J=7.6Hz, 2H), 6.77-6.66 (m, 3H), 6.04 (d, J=8.0Hz, 1H), 4.60-4.54 (m, 1H), 3 .77-3.70(m, 1H), 3.42-3.25(m, 2H), 3.17(d, J=3.6Hz, 1H), 3.13-2.96(m, 4H), 2.91-2.81(m, 1H), 2.66-2.58(m, 1H), 2.28-2.16(m, 1H), 2.15-2.03(m, 2H), 2.01-1.91(m, 1H), 1.19(s, 18H), 1.15(s, 18H). 13 C NMR (101MHz, CDCl3) δ: 170.8, 150.6, 150.3, 149.2, 149.1, 148.9(d), 143.8(d), 142.8, 142.7, 141.8(d), 140.1, 135.3, 135.2, 134.0, 133.9, 132.8, 132.6, 132.0, 130.8(d), 127.1, 126.9, 126.8, 126.6, 126.5, 126.3, 126.1, 126.0, 124.9, 124.3, 121.3, 120.7, 114.4, 107.1, 72.3, 60.3(d), 46.4, 46.2, 36.8, 36.7, 34.9, 33.5, 33.4, 30.1, 30.0, 29.5, 29.3. 31 P NMR(162MHz, CDCl3) δ: -16.67.HRMS(ESI)Calcd forC50 H 70 N2O2P([M+H] + ): 821.5169; Found: 821.5174.

[0036] Embodiment 4:

[0037]

[0038] The operation process is the same as that of Example 3.Vb: white solid, 216 mg, yield 88%, melting point 96-98°C, (c 0.1, CHCl3). 1 H NMR (400MHz, CDCl3) δ: 7.58-7.51 (m, 1H), 7.39-7.30 (m, 3H), 7.30-7.24 (m, 3H), 7.21-7.11 (m, 4H), 6.92 (d, J=8.0Hz, 2H), 6.78 (dd, J=17.6, 8.0Hz, 3H), 6.07 (d, J= 8.0Hz, 1H), 4.72-4.65 (m, 1H), 3.86-3.79 (m, 1H), 3.53-3.44 (m, 1H), 3.37 (dd, J=17.8, 6.4Hz, 1H), 3.29-3.21(m, 1H), 3.16-3.13(m, 1H), 3.12-3.00(m, 2H), 2.94-2.83(m, 2H), 2.68-2.58(m, 1H), 2.30-2.18(m, 1H), 2.15-2.04(m, 2H), 1.97-1.85(m, 1H), 1.24(s, 18H), 1.21(s, 18H). 13 C NMR (101MHz, CDCl3) δ: 170.9, 150.8, 150.6, 149.4(d), 149.2, 149.1, 144.1, 143.1, 143.0, 142.1(d), 140.5, 135.4, 135.3, 134.4, 134.3, 133.2, 133.0, 132.2, 130.9(d), 127.4(d), 127.2(d), 126.7, 126.5, 126.4, 126.3, 125.1, 124.7, 121.5, 121.0, 114.6, 107.2, 72.3, 60.7, 60.6, 46.7, 46.3, 36.9, 35.2, 33.8, 33.7, 30.4, 30.3, 29.8, 29.6. 31 P NMR(162MHz, CDCl3)δ: -16.35.HRMS(ESI)Calcd for C50 H 70 N2O2P([M+H] + ): 821.5169; Found: 821.5174.

[0039] Embodiment 5:

[0040]

[0041] The operation process is the same as that of Example 3. Vc: white solid, 186 mg, yield: 82%, melting point: 101-102°C, (c 0.1, CHCl3). 1 H NMR (400MHz, CDCl3) δ: 7.60-7.51 (m, 1H), 7.35-7.29 (m, 2H), 7.22-7.08 (m, 3H), 6.88 (dd, J=7.8, 1.8Hz, 2H), 6.76 (dd, J=8.4, 2.0Hz, 2H), 6.70 (d, J=7.4Hz, 1H), 6.11 (d, J=8.0Hz, 1H), 3.88-3.79(m, 1H), 3.77-3.68(m, 1H), 3.45-3.32(m, 2H), 3.20-3.11(m, 1H), 3.09-2.94(m, 2H), 2.88-2.70(m, 2H), 2.60-2.42(m, 2H), 2.34-2.21(m, 1H), 2.13-1.99(m, 2H), 1.89-1.77 (m, 1H), 1.20 (s, 18H), 1.17 (s, 18H), 0.96 (d, J=6.3Hz, 3H). 13 C NMR (101MHz, CDCl3) δ: 171.9, 151.7, 151.5, 150.4, 150.4, 150.2, 150.1, 145.1(d), 144.1, 144.0, 143.1(d), 136.1, 136.0, 135.3, 135.2, 134.1, 133.9, 133.1, 131.6(d), 128.5, 128.4, 128.3, 127.7, 127.5, 127.3, 126.1, 122.4, 122.2, 115.6, 108.3, 67.3, 61.7, 61.6, 47.7, 46.7, 37.7(d), 36.2, 34.8, 34.7, 31.4, 31.3, 30.7, 30.5, 20.3. 31 PNMR(162MHz, CDCl3)δ: -15.9.HRMS(ESI)Calcd for C 50 H 68N2O2P([M+H] + ): 759.5013; Found: 759.5022.

[0042] Embodiment 6:

[0043]

[0044] The operation process is the same as that of Example 3. Vd: white solid, 175 mg, yield: 74%, melting point: 94-96°C. (c 0.1, CHCl3). 1 H NMR (400MHz, CDCl3) δ: 7.65-7.57 (m, 1H), 7.34-7.28 (m, 3H), 7.24-7.12 (m, 3H), 6 .86-6.75(m, 4H), 6.70(d, J=7.4Hz, 1H), 6.13(d, J=8.0Hz, 1H), 3.91-3.84(m, 1H), 3.46 (dd, J=18.0, 6.0Hz, 1H), 3.42-3.35 (m, 1H), 3.26 (dd, J=18.0, 5.0Hz, 1H), 3.19-3.14 (m, 1H), 3.10-2.93(m, 2H), 2.85-2.73(m, 2H), 2.55-2.41(m, 2H), 2.31-2.20(m, 1H), 2.11-1.94(m, 2H), 1.77-1.66 (m, 1H), 1.56-1.47 (m, 1H), 1.18 (d, J=3.8Hz, 36H), 0.82 (d, J=6.8Hz, 3H), 0.63 (d, J=6.8Hz, 3H). 13 C NMR (101MHz, CDCl3) δ: 172.2(d), 151.8, 151.5, 150.5, 150.4(d), 150.3, 145.3, 145.2, 144.2, 144.1, 143.3(d), 135.9, 135.8, 135.6, 135.5, 134.2, 134.0, 132.9, 131.3(d), 128.8, 128.6, 128.4, 127.6, 127.4(d), 126.3, 122.5, 122.3, 115.6, 108.4, 76.4, 61.8(d), 47.8, 43.4, 37.7, 37.6, 36.3, 34.9, 34.8, 31.6, 31.5, 31.4, 30.8, 30.6, 18.8, 18.0. 31 P NMR(162MHz, CDCl3)δ: -15.07.HRMS(ESI)Calcd for C52 H 72 N2O2P([M+H] + ):787.5326; Found:787.5328

[0045] Embodiment 7:

[0046]

[0047] The operation process is the same as that of Example 3. Ve: white solid, 199 mg, yield: 78%, melting point: 100-102°C, (c 0.1, CHCl3). 1 H NMR (400MHz, CDCl3) δ: 7.50-7.43 (m, 1H), 7.36-7.26 (m, 3H), 7.24-7.19 (m, 1H), 7.17-7.08 (m, 2H), 7.07-7.02 (m, 2H), 6.91-6.85 (m, 2H), 6.79-6.70 (m, 5H), 6.02 (d, J= 8.0Hz, 1H), 4.65-4.55(m, 1H), 3.81-3.71(m, 4H), 3.43-3.35(m, 1H), 3.30(dd, J=17.8, 6.8Hz, 1H), 3.11-2.92(m, 4H), 2.91-2.79(m, 2H), 2.61(dd, J=16.0, 9.2Hz, 1H), 2.26-2.15(m, 1H), 2.11-2.00(m, 2H), 1.98-1.87(m, 1H), 1.20(s, 18H), 1.16(s, 18H). 13 C NMR(101MHz, CDCl3)δ: 171.7, 158.9, 151.9, 151.6, 150.4, 150.6, 150.2, 150.1, 145.1, 145.1, 144.1, 144.0, 143.1, 143.0, 136.5, 136.4, 135.3, 135.2, 134.2, 134.0, 133.7, 133.3, 132.0(d), 128.4, 128.3, 128.1, 127.6(d), 127.3, 127.0, 126.2, 122.5, 122.0, 115.6, 113.6, 108.2, 72.8, 61.6, 55.2, 47.7, 47.2, 38.0, 37.9, 36.1, 34.8, 34.7, 31.4, 31.3, 30.8, 30.6. 31 P NMR(162MHz, CDCl3)δ: -16.71.HRMS(ESI)Calcd for C56 H 72 N2O3P([M+H] + ): 851.5275; Found: 851.5270.

[0048] Embodiment 8:

[0049]

[0050] The operation process is the same as that of Example 3. Vf: white solid, 240 mg, yield: 90%, melting point: 110-111°C, (c 0.1, CHCl3). 1 H NMR (400MHz, CDCl3) δ: 7.72-7.60 (m, 1H), 7.46 (d, J=8.0Hz, 2H), 7.35-7.28 (m, 3H), 7.24-7.13 (m, 3H), 7.11-7.05 (m, 1H), 6.87 (d, J=7.6Hz, 2H), 6.79 (d, J=8.4 Hz, 2H), 6.71 (d, J=7.6Hz, 1H), 6.01 (d, J=8.0Hz, 1H), 4.70 (d, J=7.8Hz, 1H), 3.96-3.81 (m, 1H), 3.61 (s, 1H), 3.48-3.33 (m, 2H), 3.19 (dd, J=18.0, 4.4Hz, 1H), 3.08-2.92 (m, 2H), 2.88-2.71 (m, 2H), 2.58-2.48 (m, 1H), 2.23-2.11 (m, 1H), 2.08-1.97 (m, 2H), 1.84-1.75 (m, 1H), 1.18 (s, 36H). 13 C NMR (101MHz, CDCl3) δ: 172.2, 151.7, 151.5, 150.5, 150.5, 150.4, 150.3, 145.6, 145.4, 144.1, 144.1, 143.0, 143.0, 135.9, 135.8, 135.5, 135.4, 134.0, 133.8, 133.0, 131.6, 131.6, 129.7, 129.4, 128.6, 128.4, 127.6, 127.4, 126.2, 126.1, 125.5, 125.2, 125.1, 122.8, 122.4, 122.3, 115.8, 107.9, 72.7, 61.7(d), 47.6, 47.3, 37.7, 36.2, 34.9, 34.8, 31.4, 31.3, 30.8, 30.5. 31P NMR(162MHz, CDCl3)δ: -15.36.HRMS(ESI)Calcd for C 58 H 69 F3N2O2P([M+H] + ): 889.5043; Found: 889.5046.

[0051] Embodiment 9:

[0052]

[0053] The operation process is the same as that of Example 3. Vg: white solid, 200 mg, yield: 78%, melting point: 99-100°C, (c 0.1, CHCl3). 1 H NMR (400MHz, CDCl3) δ: 7.45 (s, 1H), 7.35-7.29 (m, 2H), 7.24-7.18 (m, 1H), 7.15-7.08 (m, 2H), 6.89 (d, J=8.0Hz, 2H), 6.86-6.79 (m, 3H), 6.75 (dd, J=14.4, 7.8Hz, 3H), 6.06 (d, J=8.0Hz, 1H), 4.60 (d, J=8.6Hz, 1H), 3.81-3.74 (m, 1H), 3.51-3.43 (m, 1H), 3.31 (dd, J=17.8, 6.8Hz, 1H), 3.12-2.78 (m, 6H), 2.68-2.50 (m, 2H), 2.22 (s, 6H), 2.12-2.04 (m, 2H), 1.99-1.90 (m, 1H), 1.19 (s, 18H), 1.16 (s, 18H). 13 C NMR (101MHz, CDCl3) δ: 171.8, 151.9, 151.7, 150.5, 150.4, 150.2(d), 145.2, 145.1, 144.1, 144.0, 143.2(d), 141.5, 137.8, 136.6(d), 135.3, 135.2, 134.4, 134.2, 133.4, 132.2(d), 129.1, 128.4, 128.3, 128.1, 127.9, 127.7, 127.4, 126.2, 123.5, 122.6, 122.0, 115.7, 108.3, 73.3, 61.7(d), 47.9, 47.3, 46.2, 38.0, 38.0, 36.2, 34.9, 34.8, 31.4, 31.3, 30.9, 30.6, 21.3. 31P NMR(162MHz, CDCl3)δ: -17.02.HRMS(ESI)Calcd for C 57 H 74 N2O2P ([M+H] + ): 849.5482; Found: 849.5479.

[0054] Embodiment 10:

[0055]

[0056] The operation process is the same as that of Example 3. Vh: white solid, 140 mg, yield: 52%, melting point: 114-115°C, (c 0.1, CHCl3). 1 H NMR (400MHz, CDCl3) δ: 7.44-7.32 (m, 2H), 7.31-7.26 (m, 1H), 7.25-7.16 (m, 5H), 7.16-7.01 (m, 6H), 7.00-6.88 (m, 6H), 6.83 (d, J=7.2Hz, 1H), 6.61 (d, J=7.2Hz, 2H), 5.89 (d, J=8.0Hz, 1H), 5.02 (dd, J=8.0, 4.8Hz, 1H), 4.74 (d, J=4.8Hz, 1H), 3.51-3.41 (m, 1H), 3.18-2.92(m, 4H), 2.80(dd, J=17.6, 7.2Hz, 1H), 2.62(dd, J=17.6, 3.6Hz, 1H), 2.41-2.27(m, 3H), 2.23-2.12(m, 1H), 1.2(s, 18H), 1.1(s, 18H). 13 C NMR (101MHz, CDCl3) δ: 171.0, 152.6, 152.4, 150.5(d), 150.0, 149.9, 144.6(d), 144.1, 144.0, 142.7(d), 140.3, 139.2, 138.5, 138.4, 135.0, 134.9, 134.7, 134.5, 134.4(d), 133.9, 133.8, 128.6, 128.4, 128.3(d), 128.0, 127.6, 127.5, 127.4(d), 127.3, 127.2, 126.3, 123.2, 121.3, 116.1, 109.5, 77.2, 61.8, 61.7, 59.2, 47.6, 39.1(d), 36.1, 34.9, 34.7, 31.5, 31.3, 31.2, 30.9. 31P NMR(162MHz, CDCl3)δ: -20.15.HRMS(ESI)Calcd for C 61 H 74 N2O2P([M+H] + ):897.5482 Found:897.5492

[0057] Embodiment 11:

[0058]

[0059] The operation process is the same as that of Example 3. Vi: white solid, 165 mg, yield: 66%, melting point: 117-118°C, (c 0.1, CHCl3). 1 H NMR (400MHz, CDCl3) δ: 7.40 (s, 1H), 7.29-7.26 (m, 1H), 7.21-7.05 (m, 7H), 6.96 (d, J = 8.2Hz, 2H), 6.84 (d, J = 7.2Hz, 1H), 6.78 (d, J =7.4Hz, 1H), 6.62 (d, J = 7.6Hz, 2H), 6.08 (d, J = 7.6Hz, 1H), 5.28-5.17 (m, 1H), 4.58-4.47 (m, 1H), 3.60-3.49 (m, 1H), 3.16-2.83 (m, 7H), 2.81-2.68(m, 1H), 2.35-2.12(m, 3H), 2.07-1.97(m, 1H), 1.76(d, J=5.2Hz, 1H), 1.25(s, 18H), 1.13(s, 18H). 13 C NMR (101MHz, CDCl3) δ: 170.5, 151.5, 151.2, 149.5, 149.4, 148.9(d), 143.6(d), 143.1, 143.0, 141.8(d), 139.3, 138.6, 137.4, 137.2, 134.1, 134.0, 133.7, 133.4, 133.3(d), 132.7(d), 127.3(d), 127.1, 127.0, 126.5, 126.3, 126.2, 126.1, 125.1, 124.1, 123.2, 122.0, 120.3, 114.9, 108.2, 72.7, 60.6(d), 56.4, 46.9, 38.7, 37.8(d), 35.0, 33.9, 33.7, 30.5, 30.3, 30.0, 29.7. 31P NMR(162MHz, CDCl3)δ: -20.11.HRMS(ESI)Calcd for C 56 H 70 N2O2P([M+H] + ): 833.5169; Found: 833.5178

[0060] Embodiment 12:

[0061]

[0062] Va (164 mg, 0.2 mmol) and DMAP (6.0 mg, 0.04 mmol) were added to a 50 mL dry Schlenk tube equipped with a magnetic stirrer, and the atmosphere was replaced with argon. Triethylamine (260 μL, 1.6 mmol) and 10 mL of anhydrous dichloromethane were added by syringe. The reaction system was cooled to below 0°C in an ice-salt bath, and MsCl (20 μL, 0.22 mmol) was slowly added dropwise to the reaction system. The reaction was stirred at room temperature for 12 hours. After the reaction was completed, the system was desolventized by a rotary evaporator. The residue was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 30: 1) to obtain 128 mg of white solid Ia, with a yield of 80%, a melting point of 77-78°C, (c 0.1, CHCl3). 1 HNMR (400MHz, CDCl) δ: 7.51-7.27(m, 5H), 7.20-7.15(m, 1H), 7.14-6.99(m, 5H), 6.98-6.93 (m, 2H), 6.89 (d, J=7.2Hz, 1H), 6.73 (d, J=7.2Hz, 1H), 6.66 (dd, J=7.4, 2.0Hz, 2H), 6.12 (d, J=8.0Hz, 1H), 5.25 (dd, J=10.2, 7.2Hz, 1H), 4.23-4.02 (m, 1H), 3.75-3.58 (m, 2H), 3.54-3.43(m, 1H), 3.04-2.74(m, 5H), 2.41-2.14(m, 3H), 2.08-1.97(m, 1H), 1.21(s, 18H), 1.13(s, 18H). 13C NMR (101MHz, CDCl3) δ: 165.0, 152.8, 152.5, 150.1, 150.0, 149.9, 149.8, 144.5, 144.4, 1 44.0, 143.9, 143.4(d), 141.1, 138.9, 138.8, 136.0, 135.9, 134.6, 134.4, 134.2, 134.2, 133.5(d), 128.7, 128.5, 128.4, 128.2(d), 127.7, 127.5, 126.9, 125.9, 125.6, 122.6, 121.3, 114.6, 108.9, 80.7, 62.7, 61.6(d), 41.0, 39.3(d), 35.8, 34.9, 34.8, 31.5, 31.4, 31.3, 30.9. 31 P NMR(162 MHz, CDCl3)δ: -19.79.HRMS(ESI)Calcd for C 55 H 68 N2OP([M+H] + ): 803.5064; Found: 803.5053.

[0063] Embodiment 13:

[0064]

[0065] The operation process is the same as that of Example 12.Ib: white solid, 107 mg, yield 80%, melting point 77-78°C, (c 0.1, CHCl3). 1 H NMR (400MHz, CDCl3) δ: 7.34-7.26 (m, 4H), 7.24-7.18 (m, 2H), 7.16-7.06 (m, 5H), 6.95 (dd, J=8.2, 1.8Hz, 2H), 6.77-6.64 (m, 3H), 6.14 (d, J=8.0Hz, 1H), 5.38-5.25 (m, 1H), 4.15-4.02(m, 1H), 3.73-3.59(m, 2H), 3.32(dd, J=16.4, 6.0Hz, 1H), 3.15-2.85(m, 5 H), 2.47-2.34(m, 1H), 2.29-2.19(m, 2H), 2.16-2.06(m, 1H), 1.22(s, 18H), 1.14(s, 18H). 13C NMR (101MHz, CDCl3) δ: 165.2, 152.8, 152.5, 150.1, 150.0, 149.9, 149.8, 144.5, 144.5, 144.1(d), 143.5(d), 140.8, 138.9138.7, 136.1, 136.0, 134.7, 134.5, 134.2(d), 133.0, 133.0, 128.8, 128.4, 128.3, 128.2, 127.8, 127.6, 127.0, 125.9, 125.8, 122.5, 121.3, 114.4, 108.6, 81.1, 62.5, 61.6, 61.6, 41.0, 39.3(d), 36.1, 34.9, 34.8, 31.6, 31.4, 31.3, 30.9, 29.8, 29.8. 31 P NMR(162MHz, CDCl3)δ: -19.46. HRMS(ESI)Calcd for C 55 H 68 N2OP([M+H] + ): 803.5064; Found: 803.5068.

[0066] Embodiment 14:

[0067]

[0068] The operation process is the same as that of Example 12.Ic: white solid, 107 mg, yield: 72%, melting point: 83-84°C, (c 0.1, CHCl3). 1 H NMR (400MHz, CDCl3) δ: 7.35-7.26 (m, 2H), 7.20-7.05 (m, 4H), 6.95-6.87 (m, 2H), 6.75-6.64 (m, 3H), 6.07 (d, J=8.0Hz, 1H), 4.55- 4.37(m, 1H), 3.80-3.69(m, 1H), 3.66-3.57(m, 1H), 3.33-3.18(m, 2H), 3.09-2.82(m, 5H), 2.45-2.34(m, 1H), 2.29-2.17(m, 2H), 2.15-2.07(m, 1H), 1.23-1.10(m, 39H). 13C NMR (101MHz, CDCl3) δ: 163.8, 151.6, 151.3, 148.9, 148.8, 148.7(d), 143.3(d), 143.0(d), 142.4(d), 137.6, 137.5, 134.9, 134.8, 133.6, 133.4, 133.0, 132.9, 131.7(d), 127.3, 127.2, 127.0, 126.7, 126.5, 125.8, 124.7, 121.3, 120.2, 113.1, 107.3, 75.1, 60.5, 60.4, 59.9, 39.9, 38.0(d), 34.9, 33.7, 33.6, 30.4, 30.3, 30.2, 29.8, 28.7, 19.9. 31 P NMR(162MHz, CDCl3)δ: -19.18.HRMS(ESI)Calcd for C 50 H 66 N2OP([M+H] + ): 741.4907; Found: 741.4916.

[0069] Embodiment 15:

[0070]

[0071] The operation process is the same as that of Example 12. Id: white solid, 100 mg, yield: 65%, melting point: 78-79°C, (c 0.1, CHCl3). 1 H NMR (400MHz, CDCl3) δ: 7.33-7.24(m, 2H), 7.20-7.13(m, 2H), 7.12-7.04(m, 2H), 6 .93(d, J=8.1Hz, 2H), 6.72-6.64(m, 3H), 6.07(d, J=8.0Hz, 1H), 4.13-4.03(m, 1H), 3.70-3.54(m, 2H), 3.43-3.31(m, 1H), 3.24-3.16(m, 1H), 3.10-2.82(m, 5H), 2.47-2.34(m, 1H), 2.30-2.18(m, 2H), 2.15-2.06(m, 1H), 1.70-1.59(m, 1H), 1.21(s, 18H), 1.14(s, 18H), 0.81(dd, J =14.4, 6.4Hz, 6H). 13C NMR (101MHz, CDCl3) δ: 165.3, 152.7, 152.5, 150.0, 149.9, 149.8, 149.7, 144.4(d), 144.0(d), 143.5(d), 138.7, 138.6, 136.0, 135.9, 134.7, 134.4, 134.1, 134.0, 132.8(d), 128.3, 128.0, 127.7, 127.5, 126.9, 125.8, 122.3, 121.2, 114.2, 108.5, 85.0, 61.5(d), 57.1, 40.9, 39.2, 39.1, 35.9, 34.8, 34.7, 32.5, 31.4, 31.3, 31.2, 30.9, 17.9, 17.5. 31 P NMR(162MHz, CDCl3)δ: -19.34. HRMS(ESI)Calcd forC 52 H 70 N2OP([M+H] + ): 769.5220; Found: 769.5226

[0072] Embodiment 16:

[0073]

[0074] The operation process is the same as that of Example 12.Ie: white solid, 199 mg, yield: 20%, melting point: 78-79°C, (c 0.1, CHCl3). 1 H NMR (400MHz, CDCl3) δ: 7.33-7.28 (m, 1H), 7.25-7.17 (m, 2H), 7.15-7.03 (m, 5H), 6. 94 (dd, J=8.0, 2.0Hz, 2H), 6.88-6.81 (m, 2H), 6.74-6.63 (m, 3H), 6.12 (d, J=8.0Hz, 1H), 5.37-5.18(m, 1H), 4.04(dd, J=14.4, 10.0Hz, 1H), 3.79(s, 3H), 3.68-3.59(m, 2H), 3.29(dd, J=16.2, 6.0Hz, 1H), 3.13-2.84(m, 5H), 2.45-2.34(m, 1H), 2.31-2.19(m, 2H), 2.15-2.08(m, 1H), 1.21(s, 18H), 1.13(s, 18H). 13C NMR (101MHz, CDCl3) δ: 163.2, 157.7, 150.7, 150.5, 148.0 (d), 147.9, 147.8, 142.5(d), 142.1, 142.0, 141.5(d), 136.8, 136.7, 134.1, 134.0, 132.7, 132.5, 132.1, 132.1, 131.0, 130.9, 130.7, 126.3, 126.3, 126.1, 125.8, 125.6(d), 125.0, 123.9, 120.4, 119.3, 112.3, 112.1, 106.6, 79.1, 60.1, 59.6, 59.6, 53.4, 38.95, 38.0, 37.2, 34.0, 32.9, 32.8, 29.5, 29.4, 29.5, 28.9. 31 P NMR(162MHz, CDCl3)δ: -19.45.HRMS(ESI)Calcd for C 56 H 70 N2O2P([M+H] + ): 833.5169; Found: 833.5176.

[0075] Embodiment 17:

[0076]

[0077] The operation process is the same as that of Example 12. If: white solid, 110 mg, yield: 66%, melting point: 90-91°C, (c 0.1, CHCl3). 1 H NMR (400MHz, CDCl3) δ: 7.57 (d, J=8.1Hz, 2H), 7.38-7.32 (m, 1H), 7.26-7.21 (m, 3H), 7.19-7.08 (m, 3H), 6.99 (dd, J=8.0, 1.6Hz, 2H), 6.79-6.68 (m, 3H), 6.18 (d, J=8.0 Hz, 1H), 5.38 (dd, J=10.0, 8.0 Hz, 1H), 4.21-4.10 (m, 1H), 3.74-3.59 (m, 2H), 3.38 (dd, J= 16.4, 6.4Hz, 1H), 3.19 (dd, J=16.4, 4.8Hz, 1H), 3.11-2.85 (m, 4H), 2.46-2.34 (m, 1H), 2.30-2.20 (m, 2H), 2.18-2.11 (m, 1H), 1.24 (s, 18H), 1.17 (s, 18H). 13C NMR (101MHz, CDCl3) δ: 163.9, 151.4, 151.1, 148.8, 148.7, 148.6(d), 143.5, 143.3(d), 142.9, 142.8, 142.2, 142.1, 137.3, 137.2, 134.9, 134.8, 133.5, 133.2, 132.9, 132.8, 131.8(d), 129.2, 128.9, 127.1, 126.9, 126.8, 126.5, 126.3, 125.7, 124.6, 124.5(d), 124.4(d), 124.1121.4, 121.2, 120.1, 113.3, 107.3, 78.8, 61.2, 60.4, 60.3, 39.7, 37.9, 37.8, 34.8, 33.6, 33.5, 30.2, 30.1, 30.0, 29.6. 31 P NMR(162MHz, CDCl3)δ: -19.52. HRMS(ESI)Calcd for C 58 H 67 F3N2OP([M+H] + ): 871.4938; Found: 871.4944.

[0078] Embodiment 18:

[0079]

[0080] The operation process is the same as that of Example 12. Ig: white solid, 91 mg, yield: 55%, melting point: 179-180°C, (c 0.1, CHCl3). 1 H NMR (400MHz CDCl3) δ: 7.31 (s, 1H), 7.26-7.17 (m, 2H), 7.15-7.06 (m, 3H), 6.98-6.90 (m, 3H), 6.78 (s, 2H), 6.73-6.66 (m, 3H), 6.14 (d, J=8.0 Hz, 1H), 5.24 (t, J=8.8Hz, 1H), 4.08-3.97 (m, 1H), 3.69-3.59 (m, 2H), 3.28 (dd, J=16.4, 6.0Hz, 1H), 3.13-2.89 (m, 5H), 2.46-2.34(m, 1H), 2.31-2.20(m, 8H), 2.16-2.08(m, 1H), 1.22(s, 18H), 1.14(s, 18H). 13C NMR (101MHz, CDCl3) δ: 164.1, 151.7, 151.4, 148.9(d), 148.7(d), 143.4, 143.3, 143.0, 142.9, 142.3(d), 139.6, 137.7, 137.6, 137.3, 135.0, 134.9, 133.6, 133.4, 133.1, 133.0, 131.9, 131.8, 128.8, 127.2, 127.0, 126.6, 126.4, 125.9, 124.8, 122.5, 121.3, 120.1, 113.2, 107.5, 80.2, 61.3, 60.5(d), 39.8, 38.2(d), 34.9, 33.8, 33.7, 30.4, 30.3, 30.2, 29.8, 25.9, 20.2. 31 P NMR(162MHz, CDCl3)δ: -19.62. HRMS(ESI)Calcdfor C 57 H 72 N2OP([M+H] + ): 831.5377; Found: 831.5381.

[0081] Embodiment 19:

[0082]

[0083] The operation process is the same as that of Example 12.Ih: white solid, 96.7 mg, yield: 55%, melting point: 82-84°C, (c 0.1, CHCl3). 1 H NMR (400MHz, CDCl3) δ: 7.33 (s, 1H), 7.21-7.12 (m, 2H), 7.10-6.92 (m, 12H), 6.78-6 .67 (m, 7H), 6.21 (d, J = 8.0Hz, 1H), 5.67 (d, J = 10.0Hz, 1H), 5.35 (d, J = 10.1Hz, 1H), 3.92-3.85 (m, 1H), 3.56 (dd, J=16.0, 6.4Hz, 1H), 3.28-3.20 (m, 1H), 3.09-2.90 (m, 4H), 2.53-2.43 (m, 1H), 2.39-2.31 (m, 1H), 2.28-2.22 (m, 1H), 2.17-2.09 (m, 1H), 1.24 (s, 19H), 1.14 (s, 19H). 13C NMR (101MHz, CDCl3) δ: 166.3, 152.7, 152.4, 149.9, 149.8, 149.8, 149.7, 144.5, 144.4, 144.0, 143.9, 143.4(d), 138.8, 138.7(d), 136.3, 136.2, 136.0, 134.5, 134.3, 134.2, 134.2, 133.4, 133.4, 128.3, 128.1, 127.7, 127.7, 127.6, 127.5, 127.4, 127.3, 127.0, 126.7, 126.5, 125.9, 122.4, 121.2, 114.3, 108.6, 85.6, 73.4, 61.6(d), 40.9, 39.4(d), 36.1, 34.9, 34.7, 31.5, 31.3, 30.9, 29.7. 31 P NMR(162MHz, CDCl3)δ: -19.51.HRMS(ESI)Calcd for C 61 H 72 N2OP([M+H] + ): 879.5377 Found: 879.5379.

[0084] Embodiment 20:

[0085]

[0086] The operation process is the same as that of Example 12.Ii: white solid, 81 mg, yield: 50%, melting point: 99-100°C, (c 0.1, CHCl3). 1 H NMR (400MHz, CDCl3) δ: 7.40-7.29 (m, 2H), 7.26 (s, 1H), 7.23-7.14 (m, 5H), 7.08-7.00 (m, 2H), 6.85 (dd, J=8.4, 1.6Hz, 2H), 6.71-6.61 (m, 3H), 5.90 (d, J=7.6Hz, 1H), 5.38 (d, J=8.0Hz, 1H), 5.17-5.08 (m, 1H), 3.55 (dd, J=7.4, 3.2Hz, 1H), 3.37-3.26 (m, 2H), 3.14-2.86(m, 5H), 2.84-2.77(m, 1H), 2.43-2.28(m, 2H), 2.26-2.19(m, 1H), 2.14-2.05(m, 1H), 1.15-1.10(m, 36H). 13C NMR (101MHz, CDCl3) δ: 164.9, 152.8, 152.5, 149.8, 149.7, 149.7, 144.3(d), 144.0(d), 143.2(d), 141.7, 139.5, 138.8, 138.7, 135.7, 135.5, 134.7, 134.4, 134.1(d), 133.0, 133.0, 128.3(d), 128.1, 127.9, 127.6, 127.4, 127.2, 126.9, 125.7, 125.6, 125.1, 122.4, 121.1, 114.0, 108.2, 83.1, 76.3, 61.5, 61.4, 40.5, 39.5, 39.3(d), 35.9, 34.7, 31.3(d), 30.9. 31 P NMR(162MHz, CDCl3)δ: -19.43.HRMS(ESI)Calcd for C 56 H 68 N2OP([M+H] + ): 815.5064; Found: 815.5072.

[0087] Embodiment 21:

[0088] Asymmetric Hydrogenation of α-Phenoxy-Substituted Butyrolactones Catalyzed by Iridium Spirocyclic Oxazoline-Aminophosphine Ligands

[0089]

[0090] In the glove box, weigh the ligand (S a, S)-I (3.2 μmol) and [Ir(COD)Cl]2 (1.0 mg, 1.5 μmol) were placed in a dry and clean 10 mL Schlenk tube equipped with a magnetic stirrer and sealed for later use. After taking out, 6 mL of anhydrous n-propanol was added and stirred at room temperature for 0.5 hours. Under nitrogen protection, the solution was added to a hydrogenation reactor equipped with a glass inner tube and a magnetic stirrer with a syringe, and the gas in the reactor was quickly replaced with hydrogen three times. The hydrogen pressure was adjusted to 10 atm. After stirring and reacting at room temperature for 0.5 hours, the hydrogen in the reactor was slowly released. Under nitrogen protection, 4 mL was taken out with a syringe and added to a reactor containing 1.0 to 10 mmol substrate and 0.05 to 25 mmol potassium tert-butoxide in n-propanol solution (0.5 mL (0.1 mmol / mL) to 25 mL (1 mmol / mL)). The gas in the reactor was quickly replaced with hydrogen three times, and the hydrogen pressure was finally adjusted to 8-30 atm. The reaction was stirred at room temperature until the hydrogen pressure no longer decreased. The hydrogen in the reactor was slowly released, and the solvent was removed by rotary evaporator to obtain a crude product. After filtering the catalyst through a short silica gel column, the conversion rate and yield of the reaction were analyzed by thin layer chromatography or nuclear magnetic resonance, and the optical purity of the product was analyzed by high performance liquid chromatography. The obtained hydrogenation experimental results are shown in Table 1.

[0091] Table 1. Asymmetric catalytic hydrogenation of α-phenoxy-substituted butyrolactone compounds catalyzed by chiral spirocyclic oxazoline-aminophosphine ligand iridium

[0092] Serial number I S / C Reaction time (h) Yield (%) ee(%) 1 <![CDATA[(S a ,S)-It]]> 500 20 43 68 2 <![CDATA[(S a ,S)-Ib]]> 500 6 94 91 3 <![CDATA[(S a ,S)-Ic]]> 500 20 66 90 4 <![CDATA[(S a ,S)-Id]]> 500 20 66 90 5 <![CDATA[(S a ,S)-Ie]]> 500 20 93 86 6 <![CDATA[(S a ,S)-If]]> 500 20 93 86 7 <![CDATA[(S a ,S)-Ig]]> 500 20 92 90 8 <![CDATA[(S a ,R,S)-Ih]]> 500 20 94 89 9 <![CDATA[(S a ,S,S)-Ii]]> 500 20 95 64

[0093] Embodiment 22:

[0094] Application of chiral spirocyclic oxazoline-aminophosphine ligand iridium catalysis in the asymmetric catalytic hydrogenation of α-aryloxy substituted lactone compounds.

[0095]

[0096] The operation process is the same as that of Example 21. After the catalyst is removed by filtration through a short silica gel column, the yield of the reaction is analyzed by thin layer chromatography or nuclear magnetic resonance, and the optical purity of the product is analyzed by high performance liquid chromatography. The hydrogenation experimental results are shown in Table 2.

[0097] Table 2. Asymmetric catalytic hydrogenation of racemic α-aryloxy substituted lactones

[0098]

[0099]

[0100] Implementation Case 23:

[0101] Dynamic Kinetic Resolution of Asymmetric Hydrogenation of α-Aryloxy-Substituted Lactones with High Conversion Numbers (S / C=1000)

[0102] Under argon protection, 10mmol α-phenoxy-γ-butyrolactone, 0.1mol% chiral spirocyclic oxazoline catalyst, 2mmol potassium tert-butoxide, and 20mL n-propanol were added to the inner tube of the hydrogenation reaction. The reactor was sealed, and the gas in the reactor was quickly replaced with hydrogen three times. The hydrogen pressure was adjusted to 10atm, and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the hydrogen in the reactor was slowly released, and the solvent was removed by rotary evaporator to obtain a crude product. Column chromatography gave 1.6g of hydrogenated product with a yield of 88% and 94%ee.

[0103] Implementation Case 24:

[0104]

[0105] Add (S)-2-phenoxy-1,4-butanediol (182 mg, 1.0 mmol) and anhydrous p-toluenesulfonic acid (86 mg, 0.5 mmol) to a 10 mL sealed tube with a branch. Add dry toluene (2 mL) under argon protection and tighten the sealed tube. React at 110 ° C for 24 h. Cool to room temperature, add water, and extract with ethyl acetate three times (2 mL × 3). Dry with anhydrous magnesium sulfate, filter, and remove the solvent under reduced pressure to obtain a crude product. The crude product is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain 156 mg of yellow liquid with a yield of 95%. (c 0.5, CHCl3). 1 H NMR (400MHz, CDCl3) δ7.33-7.24(m, 2H), 6.98-6.92(m, 1H), 6.88-6.82(m, 2H), 4.96-4.84(m, 1H), 4.03-3.93(m, 3H), 3.92-3.85(m, 1H), 2.23-2.09(m,2H). 13 C NMR (101MHz, CDCl3) δ157.40, 129.57, 120.95, 115.37, 77.19, 73.15, 67.23, 33.05.

[0106] Example 25: Synthesis of (S)-3-aryloxytetrahydropyrrole compounds

[0107]

[0108] Add the hydrogenation substrate (S)-2-phenoxy-1,4-butanediol (236.6 mg, 1.3 mmol) to a 25 mL Schleck tube and replace the argon. Cool to below 0°C, add dry triethylamine (525.2 mg, 5.2 mmol), and slowly drop methanesulfonyl chloride (592.8 mg, 5.2 mmol). After reacting for 2 hours, directly remove the solvent under reduced pressure, add acetonitrile (2 mL) to dissolve, and reflux the methanol solution of methylamine (2M, 4.0 mL) for 24 hours. After the reaction is completed, cool to room temperature, remove the solvent under reduced pressure to obtain a crude product. The crude product is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain 138 mg of a yellow liquid with a yield of 60%. (c 0.5, EtOH) 1 H NMR (400MHz, CDCl3) δ7.31-7.23 (m, 2H), 6.96-6.90 (m, 1H), 6.87-6.82 (m, 2H), 4.87-4.79 (m, 1H), 2.91-2.78 (m, 3H), 2.55-2.47 (m, 1H), 2.41 (s, 3H), 2.36-2.25 (m, 1H), 2.06-1.95 (m, 1H). 13 C NMR (101MHz, CDCl3) δ157.63, 129.46, 120.61, 115.27, 76.78, 62.36, 55.13, 42.15, 32.86. HRMS (ESI) Calcd for C 11 H 16 NO([M+H] + ): 178.1226; Found: 178.1227.

Claims

1. A chiral spirocyclic oxazoline-aminophosphine ligand:

2. The method for preparing the chiral spirocyclic oxazoline-aminophosphine ligand according to claim 1, characterized in that The optically active compound represented by formula II having a chiral spirodihydroindane skeleton is used as the starting material to prepare the product through the following reaction formula: The specific steps are: In the presence of an organic solvent and a reducing agent, a compound represented by formula II is first reacted with ethyl glyoxylate in a reactor for 2 to 24 hours to prepare a compound represented by formula III; the compound represented by formula III is then hydrolyzed with an alkali to obtain a compound represented by formula IV; in an organic solvent, the compound represented by formula IV is condensed with a substituted amino alcohol under the action of a carboxylic acid activating agent to obtain a compound represented by formula V; the compound represented by formula V is ring-closed under the activation of methanesulfonyl chloride to obtain a compound represented by formula I; The organic solvent is one of methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, toluene, xylene, methyl tert-butyl ether, ethyl ether, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, or a mixed solvent of several thereof; The reducing agent is lithium aluminum hydride, sodium borohydride, sodium triacetoxyborohydride, sodium nitrile borohydride; the base is an organic base and an inorganic base, wherein the organic base can be pyridine, triethylamine, tributylamine, N-methylmorpholine, N,N-diethylisopropylamine; the inorganic base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate; The carboxyl activation reagent is ethyl chloroformate, isopropyl chloroformate, N,N′-dicyclohexylcarbodiimide, carbonyldiimidazole; Wherein, the chiral spirocyclic oxazoline-aminophosphine ligand compound I is as described in claim 1.

3. The use of the chiral spirocyclic oxazoline aminophosphine ligand according to claim 1, characterized in that The ligand and the iridium metal salt in situ form an iridium complex as an iridium catalyst for catalyzing the asymmetric catalytic hydrogenation reaction of alpha-aryloxy substituted lactone compounds.

4. The use according to claim 3, characterized in that The in-situ preparation method of iridium complex comprises the following steps: In an organic solvent and under reaction conditions of 25 to 120° C., the chiral spirocyclic oxazoline-aminophosphine ligand is first reacted with an iridium catalyst precursor for 0.5 to 4 hours, and then stirred in a 0.1 to 50 atm hydrogen atmosphere for 0.1 to 3 hours to obtain the chiral spirocyclic oxazoline-aminophosphine ligand iridium catalyst required for the hydrogenation reaction; The molar ratio of the chiral spirocyclic oxazoline-aminophosphine ligand to the iridium catalyst precursor is 1:1 to 2:1; The iridium catalyst precursor is [Ir(COD)Cl]2, [Ir(COD)2]BF4, [Ir(COD)2]PF6, [Ir(COD)2]SbF6 or [Ir(COD)2]OTf.

5. The use according to claim 3, characterized in that The in-situ preparation of the iridium complex is to add the chiral spirocyclic oxazoline-aminophosphine ligand and the iridium catalyst precursor into an organic solvent under an inert gas atmosphere, and react at 25° C. for 0.5 to 4 hours; then stir and react in a hydrogen atmosphere of 0.1 to 20 atm for 1 to 3 hours to prepare a complex formed by the chiral spirocyclic oxazoline-aminophosphine ligand and the iridium catalyst precursor; The molar ratio of the chiral spirocyclic oxazoline-aminophosphine ligand to the transition metal salt is 1.2:1 to 1.8:

1.

6. The use according to claim 3, characterized in that The asymmetric catalytic hydrogenation reaction for catalyzing α-aryloxy substituted lactone compounds comprises the following steps: Under nitrogen protection, a chiral spirocyclic oxazoline-aminophosphine ligand iridium catalyst is added to the organic solvent of a hydrogenation reactor, and an α-aryloxy substituted lactone compound and a base are added, and the reaction is stirred in a hydrogen atmosphere of 0.1 to 100 atm for 0.1 to 80 hours, and the solvent and catalyst are removed by a rotary evaporator, and the conversion rate and yield of the reaction are analyzed by thin layer chromatography or nuclear magnetic resonance.

7. The use according to claim 6, characterized in that The molar ratio of the α-aryloxy substituted lactone substrate to the catalyst is 10:1-5000:1, and the substrate concentration is 0.001-10.0M.

8. The use according to claim 6, characterized in that The base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, triethylamine, tributylamine or N-methylmorpholine; The alkali concentration is 0.005M~1.0M; the reaction temperature is 0~80℃.

9. The use according to claim 6, characterized in that The organic solvent is one of methanol, ethanol, n-propanol, isopropanol, butanol, tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, N,N-dimethylformamide, dimethyl sulfoxide or a mixed solvent of several thereof.

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