Axial chiral phosphine ligands, processes for their preparation and use

Abstract

The application discloses a new kind of axially chiral phosphine ligand, a preparation method and application thereof. The axially chiral ligand has an axially chiral naphthalene skeleton, and is substituted by trimethylsilyl groups at 3 and 3' positions. The axially chiral phosphine ligand can be used to realize a rhodium catalyzed asymmetric coupling reaction of propargyl alcohol and organic boronic acid with high enantioselectivity, and realize efficient preparation of a tetra-substituted diene compound with high optical activity. The application has wide application prospects.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis and relates to an axially chiral phosphine ligand, its preparation method and application, specifically to a novel axially chiral phosphine ligand and its application in the rhodium-catalyzed asymmetric coupling reaction of propargyl alcohol and organoboronic acid. Background Technology

[0002] Allenes, as the simplest cumulative alkenes containing two carbon-carbon double bonds, are widely found in natural products and active pharmaceutical ingredients. Their unique axial chirality allows chiral compounds containing allene fragments to be used as chiral catalysts or ligands in asymmetric catalytic reactions. Furthermore, due to their diverse reactivity, allenes are increasingly being used in the synthesis of natural products and pharmaceutical molecules (Ref:(a)). A.; Krause, N. Angew. Chem., Int. Ed. 2004, 43, 1196. (b) Rivera-Fuentes, P.; Diederich, F. Angew. Chem., Int. Ed. 2012, 51, 2818.). Allenes have become unique and irreplaceable essential building blocks in organic synthesis, but the efficient synthesis of allenes, especially chiral allenes, has always been a challenge in this field.

[0003] Over the past decade, significant progress has been made in the construction of tetrasubstituted chiral quaternary carbon centers. However, the synthesis of axially chiral tetrasubstituted allenes still faces considerable challenges. The unique cumulative double bond structure of these molecules (composed of two spatially perpendicular carbon-carbon double bonds) results in a distinctive orthorhombic spatial arrangement of the substituents at the 1,3-positions. Compared to central chiral systems, the formation of axial chirality requires a more complex stereoprotective environment: the linear configuration of the cumulative double bonds significantly increases the steric repulsion effect between substituents; the orthorhombicly distributed substituents need to maintain chiral conformational stability during dynamic inversion; and the catalytic system must simultaneously overcome the challenge of balancing the high reactivity of the allene intermediate with the efficiency of axial chirality induction. These structural limitations have limited the currently reported synthetic methods, mainly focusing on transition metal catalysis strategies (such as palladium / rhodium-catalyzed β-elimination reactions) and small organic molecule catalysis systems. Breakthroughs are still needed in areas such as substrate universality, enantioselectivity regulation, and complex molecular modifications. Therefore, developing a method for synthesizing tetrasubstituted axially chiral allenes with high efficiency and high enantioselectivity from readily available starting materials would be a significant breakthrough for existing synthetic methods. Summary of the Invention

[0004] To address the shortcomings of existing technologies, the present invention aims to provide a novel axially chiral phosphine ligand, its preparation method, and its application, and to use it in a rhodium-catalyzed asymmetric coupling reaction of propargyl alcohol and organoboronic acid to generate tetrasubstituted axially chiral, highly optically active allene compounds.

[0005] This invention provides a novel axially chiral phosphine ligand with the structure shown in formula (R)-L or (S)-L:

[0006]

[0007] The present invention also provides a method for preparing the axially chiral phosphine ligand as described above, the method comprising the following steps:

[0008] (1) Using (R) or (S)-axially chiral bisphenol and phosphorus oxychloride as reactants and N-methylpyrrolidone as catalyst, the reaction yields (R) or (S)-axially chiral biaryl phosphorous chloride compounds;

[0009] (2) In a solvent, under the action of n-butyllithium, iminostilbene reacts with the (R) or (S)-axial chiral biaryl phosphorous chloride compound obtained in step (1) to obtain the axial chiral phosphine ligand.

[0010] The reaction formula for the preparation method is as follows:

[0011]

[0012] In this invention, the preparation method specifically includes the following steps:

[0013] Step 1: Add (R) or (S)-axially chiral bisphenol to a dry Shrek tube, purging with argon three times, then add phosphorus trichloride and N-methylpyrrolidone sequentially. The resulting reaction solution is stirred at 70°C under TLC monitoring for 3 hours. After cooling to room temperature, excess phosphorus trichloride is directly dried under vacuum, and residual phosphorus trichloride is removed by azeotropic addition of toluene. Tetrahydrofuran is then added to the resulting (R) or (S)-axially chiral biarylphosphite chloride and used directly in the next step.

[0014]

[0015] Step 2: Iminostilbene was added to a dry Shrek tube, purged with argon three times, and then tetrahydrofuran was added to cool the tube to -78°C. Then, n-butyllithium was added dropwise over 2 minutes, and the mixture was stirred at this temperature for 1 hour. Subsequently, the (R) or (S)-axially chiral biarylphosphine chloride solution prepared in Step 1 was added dropwise over 2 minutes. The resulting reaction solution was brought to room temperature and stirred under TLC monitoring for 14 hours. After the reaction was complete, the solution was directly concentrated. The crude product was purified by silica gel column chromatography to obtain a solid product, namely the axially chiral phosphine ligand (R)-L or (S)-L.

[0016]

[0017] This invention also provides the application of the axially chiral phosphine nitrogen ligand as described above in the generation of tetrasubstituted axially chiral, highly optically active allene compounds in the rhodium-catalyzed asymmetric coupling reaction of propargyl alcohol and organoboronic acid. Specifically, the application is as follows: in an organic solvent, using the compounds shown in Formula 1 and Formula 2 as raw materials, and with the axially chiral phosphine ligand as described above as the ligand, a reaction occurs in the presence of a rhodium catalyst to generate axially chiral, highly optically active allene compounds.

[0018] The reaction equation is shown in reaction equation (1):

[0019]

[0020] in,

[0021] R 1 It is a hydrocarbon group, a hydrocarbon group with a functional group, such as phenyl, aryl, or heterocyclic group;

[0022] R 2 It is a hydrocarbon group, a hydrocarbon group with a functional group, such as phenyl, aryl, or heterocyclic group;

[0023] R 3 It is a hydrocarbon group, a hydrocarbon group with a functional group, such as phenyl, aryl, or heterocyclic group;

[0024] Ar is an aryl group;

[0025] Wherein, the aryl group is a phenyl group with electron-donating or electron-withdrawing substituents at the ortho, meta, or para positions, and the heterocyclic group is a thiophene, furanyl, naphthyl, or pyridyl group, or a thiophene, furanyl, naphthalene, or pyridyl group with electron-donating or electron-withdrawing substituents.

[0026] The palladium catalyst is selected from one or more of the following: hydroxy(1,5-cyclooctadiene)rhodium(I) dimer, (1,5-cyclooctadiene)chlororhodium(I) dimer, acetylacetonyl bis(ethylidene)rhodium(I), acetylacetonyl(1,5-cyclooctadiene)rhodium(I), dicarbonylacetylacetonyl(I), and dicycloocteneacetylacetonyl(I). Preferably, it is dicycloocteneacetylacetonyl(I).

[0027] The organic solvent is selected from any one or more of N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, chlorobenzene, toluene, trifluorotoluene, dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, chloroform, and acetic acid. Preferably, it is 1,4-dioxane.

[0028] The structure of the axial chiral phosphine ligand is shown in formula (R)-L or (S)-L:

[0029]

[0030] Wherein, the molar ratio of the compound of formula 1, the compound of formula 2, the rhodium catalyst, and the axially chiral phosphine ligand is (0.5-2.5):1:(0.03-0.20):(0.03-0.20); preferably, it is 2.1:1:0.05:0.06.

[0031] The reaction temperature is 10-80℃; preferably, it is 60℃.

[0032] The reaction time is 1-15 hours; preferably, the reaction time is determined according to the reactants.

[0033] This invention proposes a novel enantioconvergent reaction mechanism for the rhodium-catalyzed asymmetric coupling reaction of propargyl alcohols and organoboronic acids: the carbon-carbon triple bond of tertiary propargyl alcohol (S)-1a or (R)-1a selectively inserts into a phenyl rhodium group formed by the metallization of Rh(I) catalyst and phenylboronic acid [PhB(OH)2] to obtain alkenyl rhodium intermediates A or B. Subsequently, intermediate A based on tertiary propargyl alcohol (S)-1a preferentially undergoes a bimetallic-assisted trans-β-OH elimination process, while intermediate B based on tertiary propargyl alcohol (R)-1a tends towards a direct cis-β-OH elimination process, ultimately achieving the enantioconvergent synthesis of chiral tetrasubstituted allene (R)-3aa. This invention defines this special asymmetric induced model catalyzed by transition metals as "parallel path enantioconvergent transformations" (PPET). The specific mechanism is shown in the following equation.

[0034]

[0035] The beneficial effects of this invention are as follows: This invention provides a novel axially chiral phosphine ligand. The unique chemical structure of this ligand endows it with high catalytic activity and stereochemical control, exhibiting excellent properties in the rhodium-catalyzed asymmetric coupling reaction of propargyl alcohol and organoboronic acid. These characteristics can be illustrated by the following comparative examples. Detailed Implementation

[0036] The present invention will be further described in detail below with reference to the specific embodiments and reaction formulas. However, the protection of the present invention is not limited to the following embodiments. All variations and advantages that can be conceived by those skilled in the art without departing from the spirit and scope of the inventive concept are included in the present invention and are protected by the appended claims. The processes, conditions, reagents, experimental methods, etc., for carrying out the present invention, except as specifically mentioned below, are all common knowledge and general knowledge in the art, and the present invention does not have any particular limitations. The following embodiments are helpful in understanding the present invention, but do not limit the scope of protection of the present invention.

[0037] The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the invention or its application or use. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without inventive effort are within the scope of protection of this invention.

[0038] In all examples shown and discussed herein, any specific values ​​should be interpreted as merely exemplary and not as limitations. Therefore, other examples of exemplary embodiments may have different values.

[0039] This invention discloses a novel axially chiral phosphine ligand, its preparation method, and its applications. This axially chiral ligand possesses the axial chirality of a naphthyl skeleton, with trimethylsilyl groups substituted at the 3 and 3' positions. Using the axially chiral phosphine ligand described in this invention, the rhodium-catalyzed asymmetric coupling reaction of propargyl alcohols and organoboronic acids can be achieved with high enantioselectivity, enabling the efficient preparation of highly optically active tetrasubstituted allene compounds. This invention has broad application prospects.

[0040] Unless otherwise specified, the experimental materials used in the examples are all conventional biochemical reagents.

[0041] Note: In the reaction formulas of the comparative examples and examples below, equiv means equivalent amount; mol means mole; Ar means argon; ligand means ligand; THF means tetrahydrofuran; Dioxane means 1,4-dioxane; recovery means recovery; NMR yield means NMR yield; ee means enantiomer excess; dr means diastereomeric proportion.

[0042] Example 1: Preparation of axial chiral phosphine ligand (S)-L

[0043] Step 1: Add (S)-axially chiral bisphenol to a dry Shrek tube, purging with argon three times, then add phosphorus trichloride and N-methylpyrrolidone sequentially. The resulting reaction solution is stirred at 70°C under TLC monitoring for 3 hours. After cooling to room temperature, excess phosphorus trichloride is directly dried under vacuum, and residual phosphorus trichloride is removed by azeotropic addition of toluene. Tetrahydrofuran is then added to the resulting (S)-axially chiral biarylphosphine chloride and used directly in the next step.

[0044]

[0045] Step 2: Iminostilbene was added to a dry Shrek tube, purged with argon three times, and then tetrahydrofuran was added to cool the tube to -78°C. Then, n-butyllithium was added dropwise over 2 minutes, and the mixture was stirred at this temperature for 1 hour. Subsequently, the (S)-axial chiral biaryl phosphorous chloride solution prepared in Step 1 was added dropwise over 2 minutes. The resulting reaction solution was brought to room temperature and stirred under TLC monitoring for 14 hours. After the reaction was complete, the solution was directly concentrated.

[0046] The crude product was purified by silica gel column chromatography to obtain the solid product, the axially chiral phosphine ligand (S)-L.

[0047]

[0048] Example 2: Preparation of axial chiral phosphine ligand (R)-L

[0049] The operating steps are the same as in Embodiment 1 of this invention.

[0050] In the first step, (S)-axially chiral bisphenol A was added to a dry Shrek tube, and argon gas was purged three times. Then, phosphorus trichloride and N-methylpyrrolidone were added sequentially. The resulting reaction solution was stirred at 70°C under TLC monitoring for 3 hours. After cooling to room temperature, excess phosphorus trichloride was directly dried under vacuum, and residual phosphorus trichloride was removed by azeotropic addition of toluene. Tetrahydrofuran was then added to the resulting (S)-axially chiral biarylphosphite chloride and used directly in the next step.

[0051]

[0052] Step 2: Iminostilbene was added to a dry Shrek tube, purged with argon three times, and then tetrahydrofuran was added to cool the tube to -78°C. Then, n-butyllithium was added dropwise over 2 minutes, and the mixture was stirred at this temperature for 1 hour. Subsequently, the (S)-axial chiral biaryl phosphorous chloride solution prepared in Step 1 was added dropwise over 2 minutes. The resulting reaction solution was brought to room temperature and stirred under TLC monitoring for 14 hours. After the reaction was complete, the solution was directly concentrated.

[0053] The crude product was purified by silica gel column chromatography to obtain the solid product, the axially chiral phosphine ligand (S)-L.

[0054]

[0055] Example 3

[0056]

[0057] Chiral ligand (S)-L (19.6 mg, 0.03 mmol) was added to a dry Schlenk tube. After transferring to a glove box, Rh(COE)2(acac) (10.6 mg, 0.025 mmol) was added. The tube was then removed from the glove box, and the mixture was purged with argon three times. 1,4-Dioxane (2.5 mL) was added, and the mixture was pre-stirred at room temperature for 30 minutes. Then, phenylboronic acid 2a (61.0 mg, 0.5 mmol) and rac-1a (212.6 mg, 1.05 mmol) / 1,4-dioxane (2.5 mL) were added sequentially. The resulting reaction solution was stirred by TLC at 60 °C in an oil bath for 5 hours. The solution was diluted with ethyl acetate (5 mL), filtered through a short silica gel column (3 cm), eluted with ethyl acetate (20 mL), and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether (150 mL)) to give an oily liquid product (R)-3aa (106.1 mg, 81%): 95:5er (HPLC conditions: OJ-H column, hexane / i-PrOH = 99.5 / 0.5, 0.7 mL / min, λ = 214 nm, t R (major) = 6.3 min, t R (minor) = 7.8min); [α] D 26 =-295.0(c=1.04,CHCl3)[Previous:98%ee,[α] D 27 =-326.1 (c=1.17, CHCl3)]; 1 H NMR (400MHz, CDCl3): δ = 7.43 (t, J = 7.4Hz, 4H, Ar-H), 7.36-7.26 (m, 4H, Ar-H), 7.24-7.15 (m, 2H, Ar-H), 2.61-2.48 (m,2H,CH2),2.20(s,3H,CH3),1.57(quint,J=7.4Hz,2H,CH2),1.48-1.34(m,2H,CH2),0.91(t,J=7.2Hz,3H,CH3); 13C NMR (100MHz, CDCl3): δ=205.5,137.2,137.0,128.41,128.37,126.7,126.6,126.1,125.6,107.8,103.6,30.1,30.0,22.6,16.8,14.0.

[0058] Example 4

[0059]

[0060] The operating procedure is the same as in Example 3 of this invention. 4-Ethylphenylboronic acid 2b (75.0 mg, 0.5 mmol), rac-1a (212.4 mg, 1.05 mmol), Rh(COE)2(acac) (10.6 mg, 0.025 mmol), and chiral ligand (S)-L (19.6 mg, 0.03 mmol) were reacted in 1,4-dioxane (5 mL) to give an oily liquid product (R)-3ab (94.7 mg, 65%) (eluent: petroleum ether (140 mL)): 97:3er (HPLC conditions: OJ-H column, hexane / i-PrOH = 99.5 / 0.5, 0.7 mL / min, λ = 214 nm, t R (major) = 6.3 min, t R (minor) = 7.8min); [α] D 24 = -336.1 (c = 1.09, CHCl3); 1 H NMR (400MHz, CDCl3): δ = 7.44 (d, J = 7.6Hz, 2H, Ar-H), 7.38-7.26 (m, 4H, Ar-H), 7.22-7.16(m,1H,Ar-H),7.14(d,J=8.0Hz,2H,Ar-H),2.62(q,J=7.6Hz,2H,CH 2),2.57-2.47(m,2H,CH2),2.19(s,3H,CH3),1.56(quint,J=7.4Hz,2H,CH2), 1.48-1.35(m,2H,CH2),1.22(t,J=7.4Hz,3H,CH3),0.90(t,J=7.2Hz,3H,CH3); 13C NMR (100MHz, CDCl3): δ=205.4,142.8,137.4,134.3,128.4,127.9,126.5,126.0,125.6,107.6,103.4,30. 1,30.0,28.5,22.6,16.9,15.6,14.0; IR(neat):v=2962,2924,1934,1902,1795,1510,1492,1460,1025cm -1 MS (70eV, EI) m / z (%): 291 (M + +1,8.85),290(M + ,34.90),247(100); HRMS(EI)calcd for C 22 H 26 [M + ]:290.2029,found:290.2031.

[0061] Example 5

[0062]

[0063] The operating procedure is the same as in Example 3 of this invention. 4-Trimethylsilylphenylboronic acid 2c (102.2 mg, 0.5 mmol, purity: 95%), rac-1a (212.6 mg, 1.05 mmol), Rh(COE)2(acac) (10.6 mg, 0.025 mmol), and chiral ligand (S)-L (19.7 mg, 0.03 mmol) were reacted in 1,4-dioxane (5 mL) to give an oily liquid product (R)-3ac (132.8 mg, 79%) (eluent: petroleum ether (120 mL)): 93:7er (HPLC conditions: OJ-3 (3.0 mm ID*150 mm) column, CO2 / MeOH = 98 / 2, 1.0 mL / min, λ = 214 nm, t R (major) = 2.6 min, t R (minor) = 3.2min); [α] D 26 = -294.4 (c = 1.00, CHCl3); 1H NMR (400MHz, CDCl3): δ=7.50-7.37(m,6H,Ar-H),7.30(t,J=7.8Hz,2H,Ar-H),7.22-7.16(m,1H,Ar-H),2.55(t,J=7.6Hz,2H ,Ar-H),2.20(s,3H,CH3),1.57(quint,J=7.4Hz,2H,CH2),1.48-1.37(m,2H,CH2),0.90(t,J=7.2Hz,3H,CH3),0.25(s,9H,3x CH3); 13 C NMR (100MHz, CDCl3): δ=205.8,138.7,137.5,137.2,133.5,128.4,126.6,125.6,125.4,107.8,1 03.7,30.1,29.8,22.6,16.8,14.0,-1.1; IR(neat):v=2952,1933,1801,1595,1493,1248,1113cm -1 MS (70eV, EI) m / z (%): 334 (M + ,3.61),73(100);HRMS(EI)calcd for C 23 H 30 Si[M + ]:334.2111,found:334.2113.

[0064] Example 6

[0065]

[0066] The operating steps are the same as in Example 3 of this invention. (E)-(4-(3-ethoxy-3-oxoprop-1-en-1-yl)phenyl)boronic acid 2d (110.0 mg, 0.5 mmol), rac-1a (212.6 mg, 1.05 mmol), Rh(COE)2(acac) (10.6 mg, 0.025 mmol), and chiral ligand (S)-L (19.6 mg, 0.03 mmol) were reacted in 1,4-dioxane (5 mL) to give the solid product (R)-3ad (87.1 mg, 48%). (Silica gel was pretreated with 5% (v / v) triethylamine in petroleum ether solution; eluent: petroleum ether / acetone = 300:1 (150 mL)): 94:6er (HPLC conditions: AD-H column, hexane / i-PrOH = 95 / 5, 1.0 mL / min, λ = 214 nm, t R(major) = 4.8 min, t R (minor) = 6.3min); [α] D 26 = -524.6 (c = 1.13, CHCl3); mp 68.8-69.6℃ (dichloromethane / methanol); 1 H NMR (400MHz, CDCl3): δ = 7.66 (d, J = 16.0Hz, 1H, = CH), 7.51-7.38 (m, 6H, Ar-H), 7.32 (t ,J=7.8Hz,2H,Ar-H),7.25-7.18(m,1H,Ar-H),6.40(d,J=16.0Hz,1H,=CH),4.25(q,J =7.1Hz,2H,CH2),2.61-2.47(m,2H,CH2),2.21(s,3H,CH3),1.56(quint,J=7.4Hz,2H ,CH2),1.48-1.37(m,2H,CH2),1.33(t,J=7.0Hz,3H,CH3),0.91(t,J=7.4Hz,3H,CH3); 13 C NMR (100MHz, CDCl3): δ=206.4,167.1,144.2,139.2,136.8,132.8,128.4,128.2,126.8,126.4,125.6,117.5,107.5,10 4.1,60.4,30.0,29.8,22.6,16.7,14.3,13.9; IR(neat):v=2922,1929,1705,1632,1601,1314,1259,1211,1174,1032cm -1 MS (70eV, EI) m / z (%): 361 (M + +1,8.43),360(M + ,27.83),229(100);Anal.Calcd.for C 25 H 28 O2:C 83.29,H 7.83;found:C 83.19,H 7.92.

[0067] Example 7

[0068]

[0069] The operating steps are the same as in Example 3 of this invention. Phenylboronic acid 2a (61.1 mg, 0.5 mmol), rac-1b (227.2 mg, 1.05 mmol), Rh(COE)2(acac) (10.6 mg, 0.025 mmol), and chiral ligand (S)-L (19.6 mg, 0.03 mmol) were reacted in 1,4-dioxane (5 mL) to give an oily liquid product (R)-3ba (122.1 mg, 88%) (eluent: petroleum ether (130 mL)): 91:9er (HPLC conditions: OJ-H column, hexane / i-PrOH = 99.5 / 0.5, 0.7 mL / min, λ = 214 nm, t R (major) = 6.2 min, t R (minor) = 7.2min); [α] D 27 = -297.0 (c = 1.05, CHCl3); 1 H NMR (400MHz, CDCl3): δ = 7.42 (d, J = 7.6Hz, 2H, Ar-H), 7.36-7.24 (m, 4H, Ar-H), 7.22-7.15 (m, 1H, Ar-H), 7.12 (d, J = 8.0Hz, 2H, Ar-H), 2.61- 2.45(m,2H,CH2),2.33(s,3H,CH3),2.18(s,3H,CH3),1.56(quint,J=7.4Hz,2H,CH2),1.48-1.35(m,2H,CH2),0.90(t,J=7.2Hz,3H,CH3); 13 C NMR (100MHz, CDCl3): δ=205.3,137.2,136.4,134.3,129.1,128.4,126.6,126.0,125.5,107.6,1 03.5,30.1,30.0,22.6,21.0,16.9,14.0; IR(neat):v=2925,1932,1796,1510,1492,1445,1062cm -1 MS (70eV, EI) m / z (%): 277 (M + +1,1.68),276(M + ,7.02),219(100); HRMS(EI)calcd for C 21 H 24 [M + ]:276.1873,found:276.1873.

[0070] Example 8

[0071]

[0072] The operating steps are the same as in Example 3 of this invention. Phenylboronic acid 2a (60.9 mg, 0.5 mmol), rac-1c (231.5 mg, 1.05 mmol), Rh(COE)2(acac) (10.5 mg, 0.025 mmol), and chiral ligand (S)-L (19.6 mg, 0.03 mmol) were reacted in 1,4-dioxane (5 mL) to give an oily liquid product (R)-3ca (105.9 mg, 76%) (eluent: petroleum ether (100 mL)): 95:5er (HPLC conditions: OJ-H column, hexane / i-PrOH = 99.5 / 0.5, 0.7 mL / min, λ = 214 nm, t R (major) = 6.0 min, t R (minor) = 7.9min); [α] D 25 = -250.8 (c = 1.07, CHCl3); 1 H NMR (400MHz, CDCl3): δ=7.46-7.34(m,4H,Ar-H),7.31(t,J=7.8Hz,2H,Ar-H),7.23-7.17(m,1H,Ar-H),7.04-6.94(m,2H,Ar- H),2.54(t,J=7.6Hz,2H,CH2),2.18(s,3H,CH3),1.62-1.49(m,2H,CH2),1.48-1.35(m,2H,CH2),0.91(t,J=7.2Hz,3H,CH3); 13 C NMR (100MHz, CDCl3): δ=205.2 (d, J=1.6Hz), 161.8 (d, J=244.1Hz), 136.9, 133.2 (d, J=3.1Hz), 128.4 ,127.1(d,J=7.9Hz),126.8,126.0,115.2(d,J=21.3Hz),108.0,102.8,30.1,30.0,22.6,17.0,14.0; 19 F NMR (376MHz, CDCl3): δ = -116.8; IR (neat): v = 2934, 2048, 1935, 1886, 1801, 1599, 1505, 1445, 1227, 1158, 1061cm -1 MS (70eV, EI) m / z (%): 281 (M ++1,2.11),280(M + ,6.98),223(100);HRMS(EI)calcd for C 20 H 21 F[M + ]:280.1622,found:280.1625.

[0073] Example 9

[0074]

[0075] The operating steps are the same as in Example 3 of this invention. Phenylboronic acid 2a (61.0 mg, 0.5 mmol), rac-1d (295.5 mg, 1.05 mmol), Rh(COE)2(acac) (10.6 mg, 0.025 mmol), and chiral ligand (S)-L (19.6 mg, 0.03 mmol) were reacted in 1,4-dioxane (5 mL) to give an oily liquid product (R)-3da (115.2 mg, 67%) (eluent: petroleum ether (100 mL)): 95:5er (HPLC conditions: OJ-H column, hexane / i-PrOH = 99.5 / 0.5, 0.7 mL / min, λ = 214 nm, t R (major) = 7.0 min, t R (minor) = 9.5min); [α] D 27 = -311.4 (c = 0.96, CHCl3); 1 H NMR (400MHz, CDCl3): δ=7.46-7.36(m,4H,Ar-H),7.34-7.26(m,4H,Ar-H),7.24-7.17(m,1H,Ar-H),2.54(t,J= 7.6Hz,2H,CH2),2.17(s,3H,CH3),1.59-1.48(m,2H,CH2),1.47-1.35(m,2H,CH2),0.90(t,J=7.4Hz,3H,CH3); 13 C NMR (100MHz, CDCl3): δ=205.6,136.6,136.3,131.4,128.5,127.2,126.9,126.1,120.5,108.3,102. 9,30.1,29.9,22.6,16.8,14.0; IR(neat):v=2926,1930,1887,1594,1485,1447,1371,1075,1006cm -1MS (70eV, EI) m / z (%): 342 (M + ( 81 Br), 3.53), 340(M + ( 79 Br),3.52),219(100); HRMS(EI)calcdfor C 20 H 21 79 Br[M + ]:340.0821,found:340.0824.

[0076] Example 10

[0077]

[0078] The operating steps are the same as in Example 3 of this invention. Phenylboronic acid 2a (61.0 mg, 0.5 mmol), rac-1e (224.2 mg, 1.05 mmol), Rh(COE)2(acac) (10.5 mg, 0.025 mmol), and chiral ligand (S)-L (19.6 mg, 0.03 mmol) were reacted in 1,4-dioxane (5 mL) to give an oily liquid product (R)-3ea (109.2 mg, 80%) (eluent: petroleum ether / ethyl acetate = 30:1 (310 mL)): 93:7er (HPLC conditions: OJ-H column, hexane / i-PrOH = 80 / 20, 1.0 mL / min, λ = 214 nm, t R (major) = 11.1 min, t R (minor) = 17.8 min); [α] D 26 = -252.7 (c = 1.03, CHCl3); 1 H NMR (400MHz, CDCl3): δ = 7.42 (d, J = 7.6Hz, 4H, Ar-H), 7.33 (t, J = 7.6Hz, 4H, Ar-H), 7.27-7.19 (m, 2H, Ar -H),2.71(t,J=7.2Hz,2H,CH2),2.41(t,J=7.2Hz,2H,CH2),2.23(s,3H,CH3),2.01-1.87(m,2H,CH2); 13C NMR (100MHz, CDCl3): δ=205.0,136.5,136.0,128.6,128.5,127.15,127.10,125.9,125.6,119.5,106 .1,105.0,28.9,23.7,16.9,16.7; IR(neat):v=3028,2245,1932,1877,1805,1596,1491,1444,1027cm -1 MS (70eV, EI) m / z (%): 274 (M + +1,3.30),273(M + ,15.20),205(100); HRMS(EI)calcd for C 20 H 19 N[M + ]:273.1512,found:273.1515.

[0079] Example 11

[0080]

[0081] The operating steps are the same as in Example 3 of this invention. Phenylboronic acid 2a (61.0 mg, 0.5 mmol), rac-1f (227.1 mg, 1.05 mmol), Rh(COE)2(acac) (10.6 mg, 0.025 mmol), and chiral ligand (S)-L (19.6 mg, 0.03 mmol) were reacted in 1,4-dioxane (5 mL) to give an oily liquid product (R)-3fa (103.7 mg, 75%) (eluent: petroleum ether (200 mL)): 95:5er (HPLC conditions: OJ-H column, hexane / i-PrOH = 99.5 / 0.5, 0.7 mL / min, λ = 214 nm, t R (major) = 5.6 min, t R (minor) = 6.8min); [α] D 23 = -245.0 (c = 0.98, CHCl3); 1H NMR (400MHz, CDCl3): δ=7.51-7.37(m,4H,Ar-H),7.35-7.24(m,4H,Ar-H),7.22-7.15(m,2H,Ar-H),2.66-2.48(m,4H,2x CH2),1.66-1.52(m,2H,CH2),1.48-1.37(m,2H,CH2),1.18(t,J=7.4Hz,3H,CH3),0.91(t,J=7.2Hz,3H,CH3); 13 C NMR (100MHz, CDCl3): δ=204.9,137.1,137.0,128.4,126.6,125.9,125.8,110.7,109.9,3 0.3,30.1,23.3,22.8,14.0,12.6;IR(neat):v=2955,2927,1930,1596,1492,1446,1029cm -1 MS (70eV, EI) m / z (%): 276 (M + ,3.43),205(100); HRMS(EI)calcd for C 21 H 24 [M + ]:276.1873,found:276.1871.

[0082] Example 12

[0083]

[0084] The operating steps are the same as in Example 3 of this invention. Phenylboronic acid 2a (18.3 mg, 0.15 mmol), rac-1g (119.8 mg, 0.315 mmol), Rh(COE)2(acac) (3.2 mg, 0.0075 mmol), and chiral ligand (S)-L (5.9 mg, 0.009 mmol) were reacted in 1,4-dioxane (1.5 mL) to give an oily liquid product (R)-3ga (41.4 mg, 63%) (eluent: petroleum ether / dichloromethane = 4:1 (200 mL)): 95:5dr (HPLC conditions: AD-H column, hexane / i-PrOH = 98 / 2, 1.0 mL / min, λ = 214 nm, t R (major) = 5.3 min, t R (minor) = 8.5min); [α] D 25 = -303.6 (c = 1.23, CHCl3); 11H NMR (400 MHz, CDCl3): δ = 8.00 (d, J = 8.4 Hz, 2H, Ar-H), 7.49 (d, J = 8.4 Hz, 2H, Ar-H), 7.44-7.37 (m, 2H, Ar-H), 7.31 (t, J = 7.6 Hz, 2H, Ar-H), 7.25-7.18 (m, 1H, Ar-H), 5.83 (s, 1H, =CH), 4.77-4.64 (m, 4H, 2×=CH and CH2), 2.56 (t, J = 7.4 Hz, 2H, CH2), 2.27-2.08 (m, 7H, CH3 and 2× CH2), 2.05-1.93 (m, 1H, CH), 1.90-1.81 (m, 1H, CH), 1.74 (s, 3H, CH3), 1.62-1.48 (m, 3H, CH2 and CH), 1.48-1.36 (m, 2H, CH2), 0.91 (t, J = 7.4 Hz, 3H, CH3); 13 13C NMR (100 MHz, CDCl3): δ = 206.7, 166.3, 149.6, 142.2, 136.4, 132.7, 129.7, 128.5, 128.3, 126.9, 126.1, 125.4, 108.8, 108.3, 103.3, 68.6, 40.8, 30.4, 30.0, 29.9, 27.3, 26.4, 22.6, 20.7, 16.7, 13.9; IR (neat): v = 2918, 1932, 1715, 1603, 1266, 1179, 1101 cm -1 ; MS (ESI) m / z: 441 (M+H + ); HRMS (ESI) calcd for C 31 H 37 O2[M+H + : 441.2788, found: 441.2774.

[0085] Example 13

[0086]

[0087] The operating steps are the same as in Example 3 of this invention. Phenylboronic acid 2a (61.0 mg, 0.5 mmol), rac-1a (212.4 mg, 1.05 mmol), Rh(COE)2(acac) (10.6 mg, 0.025 mmol), and chiral ligand (R)-L (19.6 mg, 0.03 mmol) were reacted in 1,4-dioxane (5 mL) to give an oily liquid product (S)-3aa (92.1 mg, 63%) (eluent: petroleum ether (140 mL)): 95:5er (HPLC conditions: OJ-H column, hexane / i-PrOH = 99.5 / 0.5, 0.7 mL / min, λ = 214 nm, t R (major) = 7.7 min, t R (minor) = 6.1 min); [α] D 26 = +290.4 (c = 1.03, CHCl3); 1 H NMR (400MHz, CDCl3): δ = 7.43 (t, J = 7.4Hz, 4H, Ar-H), 7.36-7.26 (m, 4H, Ar-H), 7.24-7.15 (m, 2H, Ar-H), 2.61-2.48 (m,2H,CH2),2.20(s,3H,CH3),1.57(quint,J=7.4Hz,2H,CH2),1.48-1.34(m,2H,CH2),0.91(t,J=7.2Hz,3H,CH3); 13 C NMR (100MHz, CDCl3): δ=205.5,137.2,137.0,128.41,128.37,126.7,126.6,126.1,125.6,107.8,103.6,30.1,30.0,22.6,16.8,14.0.

[0088] Comparative Example

[0089] The reactivity and enantioselectivity of the known ligands L1-L13 in the prior art with the axial chiral phosphine ligands of the present invention in the rhodium-catalyzed asymmetric coupling reaction of propargyl alcohol and organoboronic acid are compared as follows:

[0090]

[0091] The L1-L13 in the table above (where ligand L13 is ligand 34) are commercially available ligands that are relatively common in the field. These ligands have poor control over reactivity and enantioselectivity in the rhodium-catalyzed asymmetric coupling reaction of propargyl alcohol and organoboronic acid, which further demonstrates the unique advantages of the axial chiral phosphine ligand L proposed in this invention.

[0092] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0093] As used in this invention, the term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention but does not exclude other aspects.

[0094] The above embodiments are merely illustrative of the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made based on the essence of the content of the present invention are covered within the scope of protection of the present invention.

Claims

1. An axially chiral phosphine ligand, characterized in that, Its structure is shown in equation (R)-L or (S)-L:

2. The method for preparing the axially chiral phosphine ligand as described in claim 1, characterized in that, The preparation method includes the following steps: (1) Using (R) or (S)-axially chiral bisphenol and phosphorus oxychloride as reactants and N-methylpyrrolidone as catalyst, the reaction yields (R) or (S)-axially chiral biaryl phosphorous chloride compounds; (2) In a solvent, under the action of n-butyllithium, iminostilbene reacts with the (R) or (S)-axial chiral biaryl phosphorous chloride compound obtained in step (1) to obtain the axial chiral phosphine ligand; The reaction formula for the preparation method is as follows:

3. The preparation method according to claim 2, characterized in that, The specific steps of the first step are as follows: Step 1: Add (R) or (S)-axial chiral bisphenol to a dry Shrek tube, purging the tube with argon three times. Then add phosphorus trichloride and N-methylpyrrolidone in sequence. Stir the resulting reaction solution at 70°C under TLC monitoring for 3 hours. After cooling to room temperature, remove excess phosphorus trichloride directly under vacuum. Remove residual phosphorus trichloride by azeotropic addition of toluene. Then add tetrahydrofuran to the obtained (R) or (S)-axial chiral biarylphosphite chloride and use it directly in the next step.

4. The preparation method according to claim 2, characterized in that, The specific steps of the second step are as follows: Step 2: Add iminostilbene to a dry Shrek tube, replace with argon three times, add tetrahydrofuran ice to cool to -78°C, then add n-butyllithium dropwise over 2 minutes and stir at this temperature for 1 hour. Subsequently, add the (R) or (S)-axial chiral biaryl phosphorous chloride solution prepared in Step 1 dropwise over 2 minutes. The resulting reaction solution is heated to room temperature and stirred under TLC monitoring for 14 hours. After the reaction is completed, the solution is directly concentrated, and the crude product is purified by silica gel column chromatography to obtain a solid product, namely the axial chiral phosphine ligand (R)-L or (S)-L.

5. The application of the axially chiral phosphine ligand as described in claim 1 in the generation of highly optically active allene compounds with axial chirality in the rhodium-catalyzed asymmetric coupling reaction of propargyl alcohol and organoboronic acid, characterized in that... In an organic solvent, using the compounds shown in Formula 1 and Formula 2 as raw materials, and with the axially chiral phosphine ligand as described in claim 1 as the ligand, a reaction occurs in the presence of a rhodium catalyst to generate an axially chiral, highly optically active allene compound. The reaction equation is shown in reaction equation (1): in, R 1 It is a hydrocarbon group, a hydrocarbon group with a functional group, such as phenyl, aryl, or heterocyclic group; R 2 It is a hydrocarbon group, a hydrocarbon group with a functional group, such as phenyl, aryl, or heterocyclic group; R 3 It is a hydrocarbon group, a hydrocarbon group with a functional group, such as phenyl, aryl, or heterocyclic group; Ar is an aryl group; among which... The aryl group is a phenyl group with electron-donating or electron-withdrawing substituents at the ortho, meta, or para positions, and the heterocyclic group is a thiophene, furanyl, naphthyl, or pyridyl group, or a thiophene, furanyl, naphthalene, or pyridyl group with electron-donating or electron-withdrawing substituents.

6. The application as described in claim 5, characterized in that, The rhodium catalyst is selected from any one or more of the following: hydroxy(1,5-cyclooctadiene)rhodium(I) dimer, (1,5-cyclooctadiene)chlororhodium(I) dimer, acetylacetonyl bis(ethylene) rhodium(I), acetylacetonyl (1,5-cyclooctadiene) rhodium(I), dicarbonyl acetylacetonyl (I), and dicyclooctene acetylacetonyl (I).

7. The application as described in claim 5, characterized in that, The organic solvent is selected from any one or more of N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, chlorobenzene, toluene, trifluorotoluene, dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, chloroform, and acetic acid.

8. The application as described in claim 5, characterized in that, The structure of the axially chiral phosphine ligand is shown as that of formula (R)-L or (S)-L:

9. The application as described in claim 5, characterized in that, The molar ratio of the compound of formula 1, the compound of formula 2, the rhodium catalyst, and the axially chiral phosphine ligand is (0.5-2.5):1:(0.03-0.20):(0.03-0.20).

10. The application as described in claim 5, characterized in that, The reaction temperature is 10-80℃.

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