CN114106046A - Oxazoline ring 5-substituted chiral spiro oxazoline-aminophosphine ligand and preparation method and application thereof - Google Patents

Oxazoline ring 5-substituted chiral spiro oxazoline-aminophosphine ligand and preparation method and application thereof Download PDF

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CN114106046A
CN114106046A CN202010891792.1A CN202010891792A CN114106046A CN 114106046 A CN114106046 A CN 114106046A CN 202010891792 A CN202010891792 A CN 202010891792A CN 114106046 A CN114106046 A CN 114106046A
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oxazoline
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chiral spiro
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谢建华
顾雪松
王立新
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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Abstract

The invention relates to an oxazoline 5-substituted chiral spiro oxazoline-aminophosphine preparation and a preparation method and application thereof. The chiral spiro oxazoline-aminophosphine ligand is a compound shown in a formula I, or a racemate or an optical isomer thereof, or a catalytically acceptable salt thereof, and is mainly structurally characterized by having a chiral spiro indane skeleton and an oxazoline group substituted at a 5-position. The chiral spiro oxazoline-aminophosphine ligand can be synthesized by taking 7-diaryl/alkyl phosphino-7 '-amino-1, 1' -spiroindane compounds with spiro skeletons as chiral starting materials. After the chiral spiro oxazoline-amino phosphine ligand and transition metal (iridium) salt form a complexCan be used for catalyzing the asymmetric catalytic hydrogenation reaction of alpha-aryloxy substituted lactone compounds. Shows high catalytic activity (TON up to 1000) and enantioselectivity (up to 98% ee), and has practical value.

Description

Oxazoline ring 5-substituted chiral spiro oxazoline-aminophosphine ligand and preparation method and application thereof
Technical Field
The invention belongs to the technical field of organic synthesis, and relates to oxazoline ring 5-substituted chiral spiro oxazoline ring oxazoline-amino phosphine ligands and a preparation method and application thereof, in particular to oxazoline ring 5-substituted chiral spiro oxazoline ring oxazoline-amino phosphine ligands with spiro skeleton, a preparation method thereof and application thereof in asymmetric catalytic hydrogenation of alpha-aryloxy substituted lactone compounds.
Background
The homogeneous catalytic hydrogenation of ester to prepare alcohol is one atom economic, environment friendly, efficient and simple process. As such, homogeneous catalytic hydrogenation of esters has gained widespread interest over the last decade, and many highly efficient catalysts and catalytic systems thereof have been developed and have found widespread application in the large-scale preparation of pharmaceutical molecules and fragrances (Clarke, m.l.cat. sci.technol.2012, 2, 2418-. However, due to the lack of efficient, highly enantioselective chiral catalysts, the success of asymmetric catalytic hydrogenation of ester compounds to chiral alcohols is still rare (Gu, X. -S.; et al. For example, the synthesis of optically active chiral diols by asymmetric catalytic hydrogenation of racemic lactones, the presently successful examples are limited to chiral spiro iridium complex catalyzed racemic α -aryl/alkyl and arylamino substituted lactones of chiral spiro pyridylaminophosphine ligands (Yang, X. -H.; et al. chem. Sci.2017, 8, 1811-116; Gu, X. -S.; et al. org. Lett.2019, 21, 4111-4115). Therefore, the development of novel efficient chiral ligands and catalysts thereof, the realization of the efficient and high enantioselective synthesis of the chiral diols with important applications in chiral drugs and the like, and the important significance and application value are still achieved.
The optically active beta-aryloxy substituted chiral diol is an important chiral raw material or intermediate, and has important application in asymmetric synthesis of chiral drugs and natural products with important physiological activity. For example, the optically active beta-aryloxy 1, 4-diol can be used as a key chiral raw material to synthesize chiral 3-aryloxy substituted tetrahydrofuran and tetrahydropyrrole structural units widely existing in chiral drugs and clinical candidate drug molecules, such as Afatinib (Afatinib), a new drug for treating non-small cell lung cancer and advanced breast cancer, empagliflozin (Empaglifozin), and the like. However, due to the lack of a green, efficient and atom-economical asymmetric synthesis method, chiral drugs containing chiral 3-aryloxy substituted tetrahydrofuran and tetrahydropyrrole structural units, such as afatinib and the like, which are reported in the literature at present are mainly prepared by Mitsunobu reaction of optically active 3-hydroxyfuran with phenol or nucleophilic substitution reaction with fluoro-aromatic hydrocarbon (e.g., Widlicka, D.W.; et al. org. process Res. Dev.2016, 20, 233-. These synthetic methods have disadvantages of poor atom economy, and have limitations on the raw materials for introducing the aryloxy group. Thus, the development of new green, efficient, atom-economical methods for the asymmetric synthesis of chiral β -aryloxy 1, 4-diols would undoubtedly provide new green, efficient, and practical methods for the asymmetric synthesis of these chiral drug molecules.
We found in the previous period that iridium catalyst (Xie, J. -H.; Zhou, Q. -L.; et al, Angew. chem. int. Ed.2011, 50, 7329-, High enantioselectivity asymmetric catalytic hydrogenation is carried out to synthesize optically active beta-aryloxy substituted 1, 4-and 1, 5-diol. Although the oxazoline ring 4-substituted chiral spiro oxazoline-aminophosphine ligand has been reported in the literature (Zhang, f. -h.; et al. adv. synth. cal. cat. 2019, 361, 2832-2835), the iridium complex of the oxazoline ring 5-substituted chiral spiro oxazoline-aminophosphine ligand gives more excellent enantioselectivity in the asymmetric catalytic hydrogenation of the ester. Therefore, the oxazoline ring 5-substituted chiral spiro oxazoline-aminophosphine ligand and the iridium complex thereof are highly efficient and highly enantioselective asymmetric hydrogenation synthesis of optically active beta-aryloxy substituted 1, 4-and 1, 5-diol from racemic alpha-aryloxy substituted lactone, and provide a highly efficient and highly enantioselective chiral ligand and catalyst, and also provide important chiral raw materials and methods for asymmetric synthesis of oxygen-containing and nitrogen-containing heterocycles such as chiral 3-aryloxy substituted tetrahydrofuran, tetrahydropyrrole and the like. The synthesis method has the advantages of environmental protection, atom economy, mild reaction conditions, simple operation and suitability for industrial production, and has very good application prospect and value.
Disclosure of Invention
The invention aims to provide an oxazoline ring 5-substituted chiral spiro oxazoline-amino phosphine ligand and a preparation method and application thereof. The invention develops a new chiral spiro oxazoline-aminophosphine ligand by introducing a 5-substituted oxazoline ring on a chiral spiro aminophosphine ligand SpiroAP (Xie, J. -B.; et al, J. Am. chem. Soc.2010, 132, 4538-containing 4539; Zhongqi, Xijianhua, Xixijiabo, Wanglixin CN101671365A), the iridium complex of the chiral ligand can efficiently catalyze the asymmetric catalytic hydrogenation of racemic alpha-aryloxy substituted lactone, and the good yield (more than 95%) and the ee enantioselectivity up to 96% are obtained, thereby providing a new efficient chiral ligand and a catalyst for the asymmetric catalytic hydrogenation of ester, and also providing a green, efficient, high-performance, high-purity chiral ligand and a catalyst for the asymmetric synthesis of optically active beta-aryloxy substituted 1, 4-and 1, 5-diol, and 3-aryloxy substituted tetrahydrofuran and tetrahydropyrrole, A novel synthesis method with economical atoms and simple operation.
The oxazoline ring 5-substituted chiral spiro oxazoline-aminophosphine ligand provided by the invention is a compound with a formula I or an enantiomer and a racemate of the compound, or a catalytically acceptable salt thereof.
Figure BSA0000217432520000031
Wherein R is1The aryl group is selected from C1-C10 alkyl, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl or benzyl, wherein the substituent on the phenyl is C1-C10 alkyl or alkoxy, the number of the substituents is 1-5, and the heteroaryl is furyl, thienyl or pyridyl;
R2、R3respectively 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 alkyl and alkoxy, the number of the substituents is 1-5, and the heteroaryl is furyl, thienyl or pyridyl; or C1-C10 alkoxy; r2、R3May be the same or different;
the oxazoline ring 5-substituted chiral spiro oxazoline-aminophosphine ligand provided by the invention is selected from enantiomers, racemates or catalytically acceptable salts of the following compounds:
Figure BSA0000217432520000032
the invention provides a preparation method of oxazoline ring 5-substituted chiral spiro oxazoline-aminophosphine ligand, which is characterized in that the invention is prepared by taking racemic or optically active 7-diaryl/alkyl phosphino-7 '-amino-1, 1' -spiroindane compound shown in formula II with chiral spiroindane skeleton as the starting material through the following reaction formula:
wherein R in the formulae II, III, IV and V1、R2、R3The meaning of (A) is identical to that described above. Compounds of formula II having a chiral spiroindane skeleton are prepared according to literature procedures (Jianan-Bo Xie, Jianan-Hua Xie, Xiao-Yan Liu, Wei-Ling Kong, Shen Li, Qi-Lin Zhou, J.am.chem.Soc.2010, 132, 4538; Zhongqilin, Xiejian, Xixibo, Wanglixin, CN 101671365A).
Figure BSA0000217432520000041
The preparation method of the oxazoline ring 5-substituted chiral spiro oxazoline-aminophosphine ligand is described as follows: reacting a compound shown as a formula II with ethyl glyoxylate in a reactor for 2-24 hours in the presence of an organic solvent and a reducing agent to prepare a compound shown as a formula III; carrying out alkaline hydrolysis on the compound shown in the formula III to obtain a compound shown in a formula IV; in an organic solvent, condensing a compound shown in a formula IV and various substituted amino alcohols under the action of a carboxylic acid activating reagent to obtain a compound shown in a formula V; and (3) the compound shown in the formula V is subjected to ring closing under the activation of methylsulfonyl chloride to obtain the compound shown in the formula I.
In the above synthesis method, the organic solvent may be one or a mixture of methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, toluene, xylene, methyl tert-butyl ether, diethyl ether, dioxane, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, and 1, 2-dichloroethane; the reducing reagent can be lithium aluminum hydride, sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride; the base comprises organic base and inorganic base, wherein the organic base can be pyridine, triethylamine, tributylamine, N-methylmorpholine and N, N-diethylisopropylamine; the inorganic base can be sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; the carboxyl activating reagent is ethyl chloroformate, isopropyl chloroformate, N' -dicyclohexylcarbodiimide and carbonyldiimidazole.
The application of the oxazoline ring 5-substituted chiral spiro oxazoline-aminophosphine ligand disclosed by the invention is characterized in that the ligand and transition metal (iridium) metal salt form a complex in situ, and the iridium complex (which can be directly insoluble or can be prepared into a storable solid after being insoluble) is used as an iridium catalyst and is used for catalyzing the asymmetric catalytic hydrogenation reaction of an alpha-aryloxy substituted lactone compound.
Figure BSA0000217432520000051
As a preferential scheme, the chiral spiro-ring oxazoline-amino phosphine ligand substituted at the 5-position of the oxazoline ring forms a complex with transition metal salt, and then is used for the asymmetric catalytic hydrogenation reaction of the alpha-aryloxy substituted lactone compound.
As a preferential scheme, under the inert gas atmosphere, adding the chiral spiro oxazoline-aminophosphine ligand and the transition metal salt into an organic solvent, and reacting for 0.5 to 4 hours under the reaction condition of 25 ℃; and then stirring and reacting for 1-3 hours in a hydrogen atmosphere of 0.1-20 atm to prepare the complex formed by the chiral spiro phosphine oxazoline-aminophosphine ligand and the transition metal salt. As a further preferred scheme, the molar ratio of the chiral spiro oxazoline-aminophosphine ligand to the transition metal salt is 1: 1-2: 1, and the optimal molar ratio is 1.2: 1-1.8: 1.
More preferably, the transition metal salt is a metal salt of iridium. The iridium metal salt is [ Ir (COD) Cl]2(COD-cyclooctadiene), [ Ir (COD)2]BF4、[Ir(COD)2]PF6、[Ir(COD)2]SbF6Or [ Ir (COD)2]OTf。
The asymmetric catalytic hydrogenation reaction for catalyzing alpha-aryloxy substituted lactone provided by the invention comprises the following steps:
as a further priority scheme, adding alpha-aryloxy substituted lactone and alkali into the prepared complex solution, and carrying out hydrogenation reaction under the conditions of 0.1-100 atm of hydrogen atmosphere and 0-80 ℃; the molar ratio of the alpha-aryloxy substituted lactone to the complex is 100: 1-50000: 1. The concentration of the substrate is 0.001-10.0M, and the concentration of the alkali is 0.005-1.0M; the alkali 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.
As a further preferable mode, the organic solvent is one or a mixture of methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, N-dimethylformamide and dimethylsulfoxide.
The oxazoline ring 5-substituted chiral spiro oxazoline-aminophosphine ligand provided by the invention has the main structural characteristics of having a chiral spiroindane skeleton and having an oxazoline group, and can be used as a chiral ligand for an iridium-catalyzed asymmetric catalytic hydrogenation reaction of alpha-aryloxy substituted racemic gamma-and delta-lactone, thereby giving good yield and enantioselectivity of up to 96% ee. This is the first report of an asymmetric catalytic hydrogenation of an alpha-aryloxy substituted racemic lactone. The asymmetric catalytic hydrogenation reaction can also be carried out on a gram scale with 0.1 mol% of catalyst and provides a new method for the asymmetric synthesis of chiral alpha-aryloxy substituted tetrahydrofuran and tetrahydropyrrole.
Detailed Description
The present invention will be described in more detail and fully hereinafter with reference to the following examples, which are set forth to provide an understanding of the present invention and are not intended to limit the scope of the present invention.
Example 1:
Figure BSA0000217432520000061
to a 250mL dry two-neck round bottom flask fitted with a reflux condenser was added II (1.5g, 2.4mmol), replaced with an argon atmosphere, and 60mL dry methanol (insoluble) was added. Ethyl glyoxylate (1.2g, 6mmol, 50% w/w in toluene) and glacial acetic acid (345. mu.L, 6mmol) were added successively. The reaction was carried out at 40 ℃ for 6 hours until the solid was completely dissolved. Adding NaBH in one time3CN (495mg, 7.8mmol) was reacted at 40 ℃ for 6 hours until the starting material disappeared. After the reaction is finished, cooling to room temperature, removing the solvent under reduced pressure, adding ethyl acetate for dissolving, and quenching by a saturated sodium bicarbonate solution. Extraction was carried out with ethyl acetate (5 mL. times.3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered with suction and the solvent was removed under reduced pressure. Chromatography of the residue on a silica gel column (30: 1. RTM. petroleum ether: ethyl acetate) gave 1.4g of white solid III in 86% yield. Melting point: 157 ℃ at 159 ℃ to the reaction temperature of 157-,
Figure BSA0000217432520000062
(c 0.1，CHCl3)。1H NMR(400MHz，CDCl3)δ：7.36(d，J＝7.2Hz，1H)，7.32(s，1H)，7.24-7.21(m， 2H)，7.17-7.05(m，2H)，6.93(d，J＝8.0Hz，2H)，6.74(d，J＝7.2Hz，1H)，6.68(d，J＝7.2Hz，2H)， 5.91(d，J＝8.0Hz，1H)，4.12-3.97(m，2H)，3.65(d，J＝5.0Hz，1H)，3.39(dd，J＝17.6，7.2Hz， 1H)，3.16-3.04(m，2H)，3.01-2.87(m，2H)，2.81(dd，J＝17.6，2.4Hz，1H)，2.49-2.23(m，3H)， 2.20-2.12(m，1H)，1.22(s，18H)，1.16(s，18H).13C NMR(101MHz，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)，60.7，45.0，39.2，39.1，35.7，34.7，34.6，31.4，31.3，31.2，30.8，14.0.31P NMR(162MHz，CDCl3)δ：-19.43.Calcd for C49H64NO2P[M+H]+：730.4747；Found：730.4752.
example 2:
Figure BSA0000217432520000063
in a 100mL sealed tube with a magnetic stirrer were added spirocyclic chiral glycine ethyl ester III (900mg, 1.3mmol), lithium hydroxide monohydrate (259mg, 6.5mmol), tetrahydrofuran and water, 7mL each. Degassed four times and placed in an oil bath at 80 ℃ for reaction for 12 hours. After the reaction, the reaction mixture was cooled to room temperature, and the reaction system was acidified to a pH of 2.0 to 3.0 with 4N dilute hydrochloric acid. Extraction was carried out with ethyl acetate (5 mL. times.3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered with suction and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate: 3: 1) to give 780mg of a white solid IV in a yield of 90% and a melting point of 111-,
Figure BSA0000217432520000071
(c 0.1，CHCl3)。1H 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).13C 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)，31.36，31.3.31P NMR(162MHz，CDCl3)δ：-18.35.HRMS(MALDI) Calcd for C47H60NO2P[M+H]+：702.4435；Found：702.4439.
example 3:
Figure BSA0000217432520000072
to a 100mL dry Schlenk flask equipped with a magnetic stirrer were added IV (200mg, 0.3mmol), (S) -phenylglycinol (148mg, 0.9mmol), HOBt (193mg, 1.5mmol), EDCI-HCl (274mg, 1.5mmol) in that order, replaced with argon atmosphere, and 25mL of anhydrous dichloromethane and triethylamine (396. mu.L, 3.0mmol) were added via syringe. The reaction was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column (petroleum ether: ethyl acetate: 10: 1) to give 216mg of Va as a white solid in 88% yield and a melting point of 96-98 deg.C,
Figure BSA0000217432520000073
(c 0.1，CHCl3).1H 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).13C 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)，46.4，46.2，36.8，36.7，34.9，33.5，33.4，30.1，30.0，29.5，29.3.31P NMR(162MHz，CDCl3) δ：-16.67.HRMS(ESI)Calcd for C50H70N2O2P([M+H]+)：821.5169；Found：821.5174.
example 4:
Figure BSA0000217432520000081
the procedure is as in example 3. Vb: 216mg of white solid, 88% of yield, 96-98 ℃ of melting point,
Figure BSA0000217432520000082
(c 0.1，CHCl3).。1H 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).13C 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， 33.8，33.7，30.4，30.3，29.8，29.6.31P NMR(162MHz，CDCl3)δ：-16.35.HRMS(ESI)Calcd for C50H70N2O2P([M+H]+)：821.5169；Found：821.5174.
example 5:
Figure BSA0000217432520000083
the procedure is as in example 3. Vc: white solid, 186mg, yield: 82%, melting point: 101-102 deg.c,
Figure BSA0000217432520000084
(c 0.1，CHCl3).1H 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).13C 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)，36.2，34.8，34.7，31.4，31.3，30.7，30.5，20.3.31P NMR(162MHz，CDCl3)δ：-15.9.HRMS(ESI)Calcd for C50H68N2O2P([M+H]+)： 759.5013；Found：759.5022.
example 6:
Figure BSA0000217432520000091
the procedure was as in example 3. Vd: white solid, 175mg, yield: 74%, melting point: 94-96 ℃.
Figure BSA0000217432520000092
(c 0.1，CHCl3)。1H 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).13C 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， 43.4，37.7，37.6，36.3，34.9，34.8，31.6，31.5，31.4，30.8，30.6，18.8，18.0.31P NMR(162MHz， CDCl3)δ：-15.07.HRMS(ESI)Calcd for C52H72N2O2P([M+H]+)：787.5326；Found：787.5328
Example 7:
Figure BSA0000217432520000093
the procedure is as in example 3. Ve: white solid, 199mg, yield: 78%, melting point: 100-102 deg.c,
Figure BSA0000217432520000094
(c 0.1，CHCl3).1H 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).13C 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， 34.8，34.7，31.4，31.3，30.8，30.6.31P NMR(162MHz，CDCl3)δ：-16.71.HRMS(ESI)Calcd for C56H72N2O3P([M+H]+)：851.5275；Found：851.5270.
example 8:
Figure BSA0000217432520000101
the procedure was as in example 3. Vf: white solid, 240mg, yield: 90%, melting point: 110-111 deg.c,
Figure BSA0000217432520000102
(c 0.1，CHCl3)。1H 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).13C 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 C58H69F3N2O2P([M+H]+)：889.5043；Found：889.5046.
example 9:
Figure BSA0000217432520000103
the procedure is as in example 3. Vg: white solid, 200mg, yield: 78%, melting point: the temperature of the mixture is 99-100 ℃,
Figure BSA0000217432520000104
(c 0.1，CHCl3)。1H 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).13C 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 C57H74N2O2P ([M+H]+)：849.5482；Found：849.5479.
example 10:
Figure BSA0000217432520000111
the procedure is as in example 3. Vh: white solid, 140mg, yield: 52%, melting point: 114-115 deg.c,
Figure BSA0000217432520000112
(c 0.1，CHCl3).1H 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).13C 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 C61H74N2O2P([M+H]+)：897.5482 Found：897.5492
example 11:
Figure BSA0000217432520000113
the procedure was as in example 3. Vi: white solid, 165mg, yield: 66%, melting point: 117 at a temperature of 118 c,
Figure BSA0000217432520000114
(c 0.1，CHCl3)。1H 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).13C 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 C56H70N2O2P([M+H]+)：833.5169； Found：833.5178
example 12:
Figure BSA0000217432520000121
va (164mg, 0.2mmol) and DMAP (6.0mg, 0.04mmol) were added to a 50mL dry Schlenk tube equipped with a magnetic stir bar, replaced with an argon atmosphere, and triethylamine (260. mu.L, 1.6mmol) and 10mL dry dichloromethane were added via syringe. The reaction system was cooled to below 0 ℃ in an ice salt bath, and MsCl (20. mu.L, 0.22mmol) was slowly added dropwise to the reaction system. The reaction was stirred at room temperature for 12 hours. After the reaction is finished, the solvent is removed from the system by using a rotary evaporator. The residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate: 30: 1) to give 128mg of Ia as a white solid in yield: 80%, melting point: at the temperature of between 77 and 78 ℃,
Figure BSA0000217432520000122
(c 0.1，CHCl3)。1H NMR(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， 144.5，144.4，144.0，143.9，143.4(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)，35.8，34.9，34.8，31.5，31.4，31.3，30.9.31P NMR(162 MHz，CDCl3)δ：-19.79.HRMS(ESI)Calcd for C55H68N2OP([M+H]+)：803.5064；Found： 803.5053.
example 13:
Figure BSA0000217432520000131
the procedure is as in example 12. Ib: white solid, 107mg, yield 80%, melting point 77-78 deg.C,
Figure BSA0000217432520000132
(c 0.1，CHCl3)。1H 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，5H)，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)，36.1，34.9，34.8，31.6，31.4，31.3，30.9，29.8，29.8.31P NMR(162MHz，CDCl3)δ：-19.46. HRMS(ESI)Calcd for C55H68N2OP([M+H]+)：803.5064；Found：803.5068.
example 14:
Figure BSA0000217432520000133
the procedure was as in example 12. Ic: white solid, 107mg, yield: 72%, melting point: the temperature of the mixture is between 83 and 84 ℃,
Figure BSA0000217432520000134
(c 0.1，CHCl3)。1H 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)，34.9，33.7，33.6，30.4，30.3，30.2，29.8，28.7，19.9.31P NMR(162MHz， CDCl3)δ：-19.18.HRMS(ESI)Calcd for C50H66N2OP([M+H]+)：741.4907；Found：741.4916.
example 15:
Figure BSA0000217432520000135
the procedure is as in example 12. Id: white solid, 100mg, yield: 65%, melting point: the temperature of the mixture is between 78 and 79 ℃,
Figure BSA0000217432520000141
(c 0.1，CHCl3)。1H 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， 35.9，34.8，34.7，32.5，31.4，31.3，31.2，30.9，17.9，17.5.31P NMR(162MHz，CDCl3)δ：-19.34. HRMS(ESI)Calcd for C52H70N2OP([M+H]+)：769.5220；Found：769.5226
example 16:
Figure BSA0000217432520000142
the procedure is as in example 12. Ie: white solid, 199mg, yield: 20%, melting point: the temperature of the mixture is between 78 and 79 ℃,
Figure BSA0000217432520000143
(c 0.1，CHCl3)。1H 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. 31P NMR(162MHz，CDCl3)δ：-19.45.HRMS(ESI)Calcd for C56H70N2O2P([M+H]+)：833.5169； Found：833.5176.
example 17:
Figure BSA0000217432520000144
the procedure was as in example 12. If: white solid, 110mg, yield: 66%, melting point: the temperature of the mixture is between 90 and 91 ℃,
Figure BSA0000217432520000151
(c 0.1，CHCl3)。1H 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， 39.7，37.9，37.8，34.8，33.6，33.5，30.2，30.1，30.0，29.6.31P NMR(162MHz，CDCl3)δ：-19.52. HRMS(ESI)Calcd for C58H67F3N2OP([M+H]+)：871.4938；Found：871.4944.
example 18:
Figure BSA0000217432520000152
example 12. Ig: white solid, 91mg, yield: 55%, melting point: 179-180 deg.c,
Figure BSA0000217432520000153
(c 0.1，CHCl3)。1H 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)，34.9，33.8，33.7，30.4，30.3，30.2，29.8，25.9，20.2.31P NMR(162MHz，CDCl3)δ：-19.62. HRMS(ESI)Calcd for C57H72N2OP([M+H]+)：831.5377；Found：831.5381.
example 19:
Figure BSA0000217432520000154
the procedure was as in example 12. Ih: white solid, 96.7mg, yield: 55%, melting point: the temperature of the mixture is 82-84 ℃,
Figure BSA0000217432520000161
(c 0.1，CHCl3)。1H 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. 31P NMR(162MHz，CDCl3)δ：-19.51.HRMS(ESI)Calcd for C61H72N2OP([M+H]+)：879.5377 Found：879.5379.
example 20:
Figure BSA0000217432520000162
the procedure was as in example 12. Ii: white solid, 81mg, yield: 50%, melting point: the temperature of the mixture is 99-100 ℃,
Figure BSA0000217432520000163
(c 0.1，CHCl3)。1H 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)，30.9.31P NMR(162MHz， CDCl3)δ：-19.43.HRMS(ESI)Calcd for C56H68N2OP([M+H]+)：815.5064；Found：815.5072.
example 21:
asymmetric catalytic hydrogenation reaction of chiral spiro oxazoline-aminophosphine ligand iridium catalyzed p-alpha-phenoxy substituted butyrolactone compound
Figure BSA0000217432520000171
Weighing the ligand (S) in a glove boxaS) -I (3.2. mu. mol) and [ Ir (COD) Cl]2(1.0mg, 1.5. mu. mol) were placed in a dry, clean 10mL Schlenk tube equipped with a magnetic stir bar and sealed until needed. After the reaction mixture was taken out, 6mL of anhydrous n-propanol was added thereto, and the mixture was stirred at room temperature for 0.5 hour. Under the protection of nitrogen, the solution is added into a hydrogenation reaction kettle provided with a glass inner tube and a magnetic stirring bar by a syringe, the gas in the reaction kettle is quickly replaced by hydrogen for three times, the pressure of the hydrogen is adjusted to 10atm, and after stirring reaction is carried out for 0.5 hour at room temperature, the hydrogen in the reaction kettle is slowly released. Taking with a syringe under the protection of nitrogenThen, 4mL of the solution was added to an autoclave containing 1.0 to 10mmol of the substrate and 0.05 to 25mmol of potassium tert-butoxide in n-propanol (0.5mL (0.1mmol/mL) to 25mL (1 mmol/mL)). And (3) rapidly replacing the gas in the reaction kettle with hydrogen for three times, finally adjusting the hydrogen pressure to 8-30 atm, and stirring and reacting at room temperature until the hydrogen pressure is not reduced any more. Slowly releasing hydrogen in the reaction kettle, and removing the solvent by a rotary evaporator to obtain a crude product. After the catalyst was removed by filtration through a short silica gel column, the conversion 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, and the results of the hydrogenation experiments are shown in table 1.
TABLE 1 Iridium catalyzed asymmetric catalytic hydrogenation of alpha-phenoxy substituted butyrolactone Compounds with chiral Spiro-oxazoline-aminophosphine ligands
Serial number I S/C Reaction time (h) Yield (%) ee(％)
1 (Sa，S)-Ia 500 20 43 68
2 (Sa，S)-Ib 500 6 94 91
3 (Sa，S)-Ic 500 20 66 90
4 (Sa，S)-Id 500 20 66 90
5 (Sa，S)-Ie 500 20 93 86
6 (Sa，S)-If 500 20 93 86
7 (Sa，S)-Ig 500 20 92 90
8 (Sa，R，S)-Ih 500 20 94 89
9 (Sa，S，S)-Ii 500 20 95 64
Example 22:
the chiral spiro oxazoline-aminophosphine ligand iridium catalyst is applied to asymmetric catalytic hydrogenation reaction of alpha-aryloxy substituted lactone compounds.
Figure BSA0000217432520000181
The procedure was as in example 21. After the catalyst was removed by filtration through a short silica gel column, the yield of the reaction was analyzed by thin layer chromatography or nuclear magnetic resonance, the optical purity of the product was analyzed by high performance liquid chromatography, and the results of the hydrogenation experiments are shown in Table 2.
TABLE 2 asymmetric catalytic hydrogenation of racemic α -aryloxy substituted lactones
Figure BSA0000217432520000182
Figure BSA0000217432520000191
Example 23:
experiment of dynamic kinetic resolution high conversion number of asymmetric catalytic hydrogenation of alpha-aryloxy substituted lactone (S/C1000)
Under the protection of argon, 10mmol of alpha-phenoxy-gamma-butyrolactone, 0.1 mol% of chiral spiro oxazoline catalyst, 2mmol of potassium tert-butoxide and 20mL of n-propanol are sequentially added into a hydrogenation reaction inner tube. Sealing the reaction kettle, quickly replacing gas in the reaction kettle with hydrogen for three times, adjusting the pressure of the hydrogen to 10atm, and stirring and reacting for 12 hours at room temperature. After the reaction is finished, slowly releasing hydrogen in the reaction kettle, and removing the solvent by a rotary evaporator to obtain a crude product. Column chromatography gave 1.6g of the hydrogenated product, 88% yield and 94% ee.
Example 24:
Figure BSA0000217432520000201
to a 10mL stoppered tube were added (S) -2-phenoxy-1, 4-butanediol (182mg, 1.0mmol), and anhydrous p-toluenesulfonic acid (86mg, 0.5mmol) in that order. Dry toluene (2mL) was added under argon and the tube was tightened. The reaction was carried out at 110 ℃ for 24 h. Cooled to room temperature, added with water, and extracted three times with ethyl acetate (2 mL. times.3). Drying with anhydrous magnesium sulfate, suction filtering, and removing solvent under reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography (5: 1 petroleum ether: ethyl acetate) to give 156mg of a yellow liquid in 95% yield.
Figure BSA0000217432520000202
(c 0.5，CHCl3)。1H 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).13C NMR(101MHz，CDCl3)δ157.40，129.57，120.95，115.37，77.19，73.15， 67.23，33.05.
Example 25: synthesis of (S) -3-aryloxy tetrahydropyrrole compound
Figure BSA0000217432520000203
Add the hydrogenation substrate (S) -2-phenoxy-1, 4-butanediol (236.6mg, 1.3mmol) to a 25mL Schleck tube, displacing the argon. Cool to below 0 deg.C, add dry triethylamine (525.2mg, 5.2mmol), and slowly add methanesulfonyl chloride (592.8mg, 5.2mmol) dropwise. After 2 hours of reaction, the solvent was removed directly under reduced pressure, dissolved by addition of acetonitrile (2mL) and refluxed with a solution of methylamine in methanol (2M, 4.0mL) for 24 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solution was removed under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (5: 1 petroleum ether: ethyl acetate) to give 138mg of a yellow liquid in 60% yield.
Figure BSA0000217432520000204
(c 0.5，EtOH)1H 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). 13C 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 C11H16NO([M+H]+)：178.1226；Found：178.1227。

Claims (10)

1. The oxazoline 5-substituted chiral spiro oxazoline-aminophosphine ligand provided by the invention is a compound with a formula I or an enantiomer, a racemate or a catalytically acceptable salt thereof:
Figure FSA0000217432510000011
wherein R is1Selected from C1-C10 alkyl, phenyl and substitutedThe aryl group comprises phenyl, 1-naphthyl, 2-naphthyl, heteroaryl or benzyl, wherein the substituent on the phenyl is C1-C10 alkyl or alkoxy, the number of the substituents is 1-5, and the heteroaryl is furyl, thienyl or pyridyl;
R2、R3the aryl group is 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 alkyl and alkoxy, the number of the substituents is 1-5, and the heteroaryl is furyl, thienyl or pyridyl; or C1-C10 alkoxy.
2. The chiral spiro oxazoline-aminophosphine ligand of claim 1 is selected from the group consisting of enantiomers, racemates or catalytically acceptable salts of the following compounds:
Figure FSA0000217432510000012
3. the method for preparing chiral spiro oxazoline-aminophosphine ligand of claim 1, which is characterized in that the chiral spiro indane skeleton-containing racemic or optically active 7-diaryl/alkyl phosphino-7 '-amino-1, 1' -spiro indane compound shown in formula II is prepared by the following reaction formula as a starting material:
Figure FSA0000217432510000021
the method comprises the following specific steps:
under the condition of the existence of an organic solvent and a reducing agent, firstly, reacting a compound shown as a formula II with ethyl glyoxylate in a reactor for 2-24 hours under the condition of the existence of the organic solvent and the reducing agent to prepare a compound shown as a formula III; carrying out alkaline hydrolysis on the compound shown in the formula III to obtain a compound shown in a formula IV; in an organic solvent, condensing a compound shown in a formula IV and various substituted amino alcohols under the action of a carboxylic acid activating reagent to obtain a compound shown in a formula V; the compound shown in the formula V is subjected to ring closing under the activation of methylsulfonyl chloride to obtain a compound shown in a formula I;
the organic solvent can be one or a mixture of methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, toluene, xylene, methyl tert-butyl ether, diethyl ether, dioxane, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform and 1, 2-dichloroethane;
the reducing reagent can be lithium aluminum hydride, sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride; the base comprises organic base and inorganic base, wherein the organic base can be pyridine, triethylamine, tributylamine, N-methylmorpholine and N, N-diethylisopropylamine; the inorganic base can be sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate;
the carboxyl activating reagent is ethyl chloroformate, isopropyl chloroformate, N' -dicyclohexylcarbodiimide and carbonyldiimidazole.
4. The application of the chiral spiro oxazoline aminophosphine ligand as claimed in claim 1 or 2, characterized in that the ligand and iridium metal salt form an iridium complex in situ as an iridium catalyst for catalyzing the asymmetric catalytic hydrogenation reaction of an alpha-aryloxy substituted lactone compound.
5. The use according to claim 4, characterized in that the in situ preparation process of the iridium complex comprises the following steps:
under the reaction conditions of an organic solvent and 25-120 ℃, the chiral spiro oxazoline-aminophosphine ligand firstly reacts with the iridium catalyst precursor for 0.5-4 hours, and then the mixture is stirred and reacts for 0.1-3 hours in a hydrogen atmosphere of 0.1-50 atm to obtain the chiral spiro oxazoline-aminophosphine ligand iridium catalyst required by hydrogenation reaction;
the molar ratio of the chiral spiro oxazoline-aminophosphine ligand to the iridium catalyst precursor is 1: 1-2: 1;
the iridium catalyst precursor is [ Ir (COD) Cl]2(COD-cyclooctadiene), [ Ir (COD)2]BF4、[Ir(COD)2]PF6、[Ir(COD)2]SbF6Or [ Ir (COD)2]OTf。
6. The application of the iridium complex as claimed in claim 4, wherein the in-situ preparation of the iridium complex is carried out by adding the chiral spiro oxazoline-aminophosphine ligand and the iridium catalyst precursor into an organic solvent under an inert gas atmosphere, and reacting for 0.5-4 hours under a reaction condition of 25 ℃; then stirring and reacting for 1-3 hours in a hydrogen atmosphere of 0.1-20 atm to prepare a complex formed by the chiral spiro oxazoline-aminophosphine ligand and an iridium catalyst precursor;
the molar ratio of the chiral spiro oxazoline-aminophosphine ligand to the transition metal salt is 1.2: 1-1.8: 1.
7. The use according to claim 4, wherein said asymmetric catalytic hydrogenation for catalyzing α -aryloxy substituted lactone compounds comprises the steps of:
under the protection of nitrogen, adding a chiral spiro oxazoline-aminophosphine ligand iridium catalyst into an organic solvent of a hydrogenation reactor, adding an alpha-aryloxy substituted lactone compound and alkali, stirring and reacting for 0.1-80 hours in a hydrogen atmosphere of 0.1-100 atm, removing the solvent and the catalyst by a rotary evaporator, and analyzing the conversion rate and the yield of the reaction by thin layer chromatography or nuclear magnetic resonance.
8. The use according to claim 7, wherein the molar ratio of the α -aryloxy substituted lactone substrate to the catalyst is 10: 1 to 5000: 1, i.e. the amount of the catalyst is 0.1 to 0.02 mol%; the substrate concentration is 0.001-10.0M.
9. The use according to claim 7, wherein 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 ℃.
10. The use according to claim 7, wherein the organic solvent is one or more of methanol, ethanol, N-propanol, isopropanol, butanol, tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, N-dimethylformamide, and dimethylsulfoxide.
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