Chiral monophosphine ligands, processes for their preparation and use in asymmetric synthesis

Abstract

This invention discloses a chiral monophosphine ligand, its preparation method, and its application in asymmetric synthesis. The ligand preparation method involves mixing an N,N',1,2-tetrasubstituted ethane-1,2-diamine compound, phosphorus trichloride, triethylamine, and solvent under a nitrogen or argon atmosphere at -80 to -70°C, and reacting at 60 to 80°C for 6 to 8 hours. The resulting reaction mixture is then cooled to room temperature, and an alcohol, phenol, or Grignard reagent is added dropwise, reacting at 60 to 80°C for 8 to 12 hours. The resulting mixture is then post-treated to obtain the chiral monophosphine ligand. The application involves stirring a nickel catalyst, a chiral monophosphine ligand, a solvent, a diene, and an aldehyde under an argon or nitrogen atmosphere at a specified temperature for 12 to 15 hours. The mixture is then post-treated to obtain the target product. This method utilizes widely available and inexpensive raw materials, and the operation is simple, achieving high stereoselectivity and enantioselectivity in the synthesis of alcohol compounds containing chiral conjugated dienes through a one-step reaction.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis, specifically to a chiral monophosphine ligand, its preparation method, and its application in asymmetric synthesis. Background Technology

[0002] Chiral conjugated dienols have attracted much attention due to their unique dienyl skeleton and allyl chiral center, and this structural segment is widely found in various natural products and drug molecules. Besides their important biological significance, these compounds are also versatile synthetic building blocks in organic synthesis, facilitating the rapid construction of complex molecular structures. Given their dual importance, developing universal and efficient synthetic methods has always been a key research goal in the field of chemical synthesis.

[0003] In the synthesis of chiral conjugated dienols, traditional methods often employ multi-step synthetic strategies. Typical synthetic routes fall into two main categories: one combines successive Widtig reactions with asymmetric reduction reactions (P. He, X. Liu, H. Zheng, W. Li, L. Lin, X. Feng, Org. Lett. 2012, 14, 5134–5137; C. Li, W. Lu, B. Lu, W. Li, X. Xie, Z. Zhang, J. Org. Chem. 2019, 84, 16086–16094.), and the other employs a cross-coupling strategy. While these traditional methods can synthesize the target product, they have significant limitations—they typically require simple starting materials and multiple reaction steps to complete the synthesis, which greatly restricts their synthetic efficiency and practical application value.

[0004]

[0005] Among the reported synthetic methods, the direct addition of alkenyl nucleophiles to aldehydes is particularly attractive. This transformation reaction can utilize readily available and readily available synthetic building blocks to construct new carbon-carbon bonds, demonstrating significant advantages in terms of synthetic efficiency, cost-effectiveness, and procedural economy. This type of direct synthetic strategy can construct structurally diverse chiral conjugated dienols through a single reaction step (K. Aikawa, Y. Hioki, K. Mikami, J. Am. Chem. Soc. 2009, 131, 13922–13923; S.-Z. Tan, P. Chen, L. Zhu, M.-Q. Gan, Q. Ouyang, W. Du, Y.-C. Chen, J. Am. Chem. Soc. 2022, 144, 22689–22697; P. Zhang, JP Morken, J. Am. Chem. Soc. 2009, 131, 12550–12551.).

[0006]

[0007] However, the above methods rely on pre-prepared alkenyl metal reagents, which are typically prepared from alkenyl halides using stoichiometric excesses of metal—a challenge in terms of reagent stability, waste generation, and practical applicability. To address these limitations, alternative methods employ reductive coupling reactions, in the presence of an external reducing agent, from alkenyl halides (Y. Gao, DE Hill, W. Hao, BJ McNicholas, JC Vantourout, RGHadt, SE Reisman, DG Blackmond, PS Baran, J. Am. Chem. Soc. 2021, 143, 9478–9488; P. Gu, L. Ding, X. Fang, J. Zhu, S. Kang, B. Wu, J. Zhang, Y. Zhao, Z. Shi, Angew. Chem. Int. Ed. 2024, 63, e202408195; J. Chen, L. Wu, Z. Song, Y. Wang, Z. Li, Y. Wang, S. Zhu, J. Am. Chem. Soc. 2024, 146, 26223–26232; C. Lin, J. Zhang, Z. Sun, Y. Guo, Q. Chong, Z. Zhang, F. Meng, Angew.Chem. Int. Ed. 2024, 63, e202405290; T. Xia, X.-Z. Shu, JS Zhou, Y. Chen,CCS Chem. 2025, Just Accepted. DOI: 10.31635 / ccschem.025.202506433.) or alkynes (KM Miller, EA Colby, KS Woodin, TF Jamison, Adv. Synth. Catal. 2005,347, 1533–1536; JR Kong, MJ Krische, J. Am. Chem. Soc. 2006, 128, 16040–16041; V. Komanduri, MJ Krische, J. Am. Chem. Soc. 2006, 128, 16448–16449; RL Patman, MR Chaulagain, VM Williams, MJKrische, J. Am. Chem. Soc. 2009, 131, 2066–2067; H. Wang, G. Lu, GJ Sormunen, HA Malik, P. Liu, J. Montgomery, J. Am. Chem. Soc. 2017, 139, 9317–9324; W. Fu, M. Nie, A. Wang, Z. Cao, W. Tang, Angew. Chem. Int. Ed. 2015, 54, 2520–2524; Y.-L. Li, S.-Q. Zhang, J. Chen, J.-B. Xia, J. Am. Chem. Soc. 2021, 143, 7306–7313; Int. Ed. 2020, (59, 1562–1566.) In-situ generation of alkenyl metal species. Although these methods avoid the use of isolated alkenyl metal reagents, they still suffer from problems such as complex reaction procedures and limited atom economy.

[0008]

[0009] A highly attractive but underexplored strategy is to directly use simple 1,3-dienes (rather than pre-prepared alkenyl metal reagents) as nucleophiles to induce addition reactions with aldehydes. This method is inherently atom-economical and holds promise for the efficient preparation of chiral conjugated dienols with various structures. However, direct addition reactions of alkenes with aldehydes remain relatively rare, and the lack of suitable electron-rich chiral monophosphine ligands hinders the progress in developing enantioselective versions of the direct addition reactions of 1,3-dienes with aldehydes. Therefore, there is an urgent need in the field to develop a novel chiral monophosphine ligand for the enantioselective direct addition reaction of 1,3-dienes with aldehydes, to prepare chiral conjugated dienols with excellent enantioselectivity, regioselectivity, and E / Z selectivity, thus overcoming existing technical challenges. Summary of the Invention

[0010] To address the problems existing in the prior art, one objective of this invention is to provide a chiral monophosphine ligand derived from a chiral diamine that is easily modified; another objective of this invention is to provide a simple and efficient method for synthesizing this chiral monophosphine ligand; yet another objective of this invention is to provide an application of this type of ligand in asymmetric catalytic reactions, enabling the asymmetric direct addition reaction of 1,3-diene to aldehydes without the use of alkenyl metal reagents, thereby achieving the efficient synthesis of chiral conjugated dienols with high regioselectivity and high enantioselectivity.

[0011] Therefore, the present invention adopts the following technical solution:

[0012] A chiral monophosphine ligand has the following structural formula:

[0013] ,

[0014] Among them, R 1 It is aryl; R 2 It is an alkyl, aryl, or substituted aryl group; R 3 It can be alkoxy, phenoloxy, aryl, or alkyl.

[0015] Preferably, for R 1 The aryl group is a substituted phenyl or naphthyl group, wherein the substituted phenyl group is 3,5-dimethylphenyl, o-methylphenyl, or 3,5-dimethoxyphenyl; for R 2 The alkyl group is cycloalkyl, benzyl, or neopentyl, wherein the cycloalkyl group is cyclopentyl, cyclohexyl, or cycloheptyl; the aryl group is naphthyl; the substituted aryl group is 3,5-di-tert-butylphenyl, 3,5-di-tert-butyl-4-methoxyphenyl, 2,4,6-trimethylphenyl, or p-tert-butylphenyl; for R 3 The alkoxy group is isopropoxy, methoxy, or (S)-1-phenylethoxy; the alkyl group is isopropyl, cycloalkyl, or benzyl, wherein the cycloalkyl group is cyclobutyl, cyclopentyl, or cyclohexyl; and the aryl group is a substituted phenyl group.

[0016] More preferably: for R 1 The aryl group is phenyl; for R 2 The substituted aryl group is 3,5-di-tert-butylphenyl or 3,5-di-tert-butyl-4-methoxyphenyl; for R 3 The alkoxy group is (S)-1-phenylethoxy.

[0017] A method for preparing the above-mentioned chiral monophosphine ligand includes the following steps:

[0018] S1, In a nitrogen or argon atmosphere, at -80 to -70°C, N,N',1,2-tetrasubstituted ethane-1,2-diamine compounds, phosphorus trichloride, triethylamine and solvent are mixed, and the temperature is slowly raised to 60 to 80°C. The reaction is carried out for 6 to 8 hours to obtain a reaction mixture containing intermediates.

[0019] S2, the reaction mixture containing the intermediate is cooled to room temperature, and then alcohol, phenol or Grignard reagent is added dropwise. The temperature is slowly raised to 60-80°C and reacted for 8-12 hours. The reaction mixture is then filtered through diatomaceous earth, the filtrate is concentrated under reduced pressure to remove the solvent, and the residue is purified by rapid column chromatography to obtain the chiral monophosphine ligand.

[0020] Preferably, the N,N',1,2-tetrasubstituted ethane-1,2-diamine compound is (1R,2R)-N¹,N²,1,2-tetraphenylethane-1,2-diamine, (1R,2R)-N¹,N²-bis(3,5-di-tert-butylphenyl)-1,2-diphenylethane-1,2-diamine, or (1R,2R)-N¹,N²-bis(3,5-di-tert-butyl-4-methoxyphenyl)-1,2-diphenylethane-1,2-diamine; the solvent is tetrahydrofuran, and the amount used is 1 mmol for each N,N',1,2-tetrasubstituted ethane-1,2-diamine compound. ml; the alcohol is isopropanol or (S)-1-phenylethanol; the phenol is phenol; the Grignard reagent is an aryl Grignard reagent or an alkyl Grignard reagent; preferably, the aryl Grignard reagent is phenyl magnesium bromide, and the alkyl Grignard reagent is cyclohexyl magnesium bromide, isopropyl magnesium bromide, or benzyl magnesium bromide; the equivalent ratio of the diamine, phosphorus trichloride, triethylamine, and the (alcohol, phenol, or Grignard reagent) is 1:(1.1-1.3):(8.0-12.0):(1.0-2.0).

[0021] An application of the above-mentioned chiral monophosphine ligand in the nickel-catalyzed asymmetric addition reaction of dienes to aldehydes is described below:

[0022]

[0023] Under an argon or nitrogen atmosphere and with stirring, a nickel catalyst, the chiral monophosphine ligand, solvent, diene, and aldehyde are added to a reaction flask. The mixture is stirred at a specified temperature for 12-15 hours. After the reaction is complete, the mixture is filtered through a short silica gel pad. The solvent is removed from the filtrate under reduced pressure. The residue is then separated by column chromatography to obtain the target product, wherein:

[0024] In the structural formula of the aldehyde, R 4 The alkyl group is alkyl or aryl, preferably cycloalkyl, tert-butyl or phenylpropyl, and the aryl group is benzofuran-3-yl or p-fluorophenyl; more preferably, the cycloalkyl group is a C4-C7 cycloalkyl group.

[0025] In the structural formula of the diene, R 5 The alkyl group is aryl or alkyl, preferably 6-methoxynaphthio-2-yl, benzothiophene-2-yl, 3,5-dimethylphenyl, 4-chloro-phenyl or 4-dimethylamino-phenyl, and the alkyl group is cyclohexyl;

[0026] The nickel catalyst is Ni(COD)2 or Ni(tBustb)3;

[0027] The solvent is a mixture of methanol and acetonitrile, with a volume ratio of (4~50):1; the amount of solvent used is 0.2-0.3 ml per 1 mmol aldehyde.

[0028] The specified temperature is 25-30 °C.

[0029] Preferably, the chiral monophosphine ligand is:

[0030] or ,

[0031] The amount of chiral monophosphine ligand used is 8–24 mol of the aldehyde.

[0032] Preferably, the chiral monophosphine ligand is L2; ​​the amount of nickel catalyst is 7-20 mol% of the aldehyde; and the amount of diene is 1.5 equivalents of the aldehyde.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] 1. This invention achieves highly stereoselective and enantioselective synthesis of chiral conjugated dienol compounds simply by using a nickel catalyst in combination with a novel chiral monophosphine ligand.

[0035] 2. The reagents used in this invention are commercially available, the raw materials are widely available and inexpensive, and all reagents are stable at room temperature and pressure, making them easy to handle and requiring no special treatment.

[0036] 3. The present invention successfully synthesized a pharmaceutically active molecule (Example 10) and a natural product molecule analog (Example 17).

[0037] 4. This invention is simple to operate, and the target product can be obtained in one step. It avoids the dangerous reagents such as alkyl metal reagents that are extremely sensitive to air and water involved in previous methods. There are also no special requirements for post-processing, which greatly reduces the production cost of synthesizing this type of compound. Detailed Implementation

[0038] The following detailed description of the ligands, their preparation methods, and applications of the present invention is provided in conjunction with the embodiments. However, it should be emphasized that the present invention is by no means limited to the contents shown in the following embodiments.

[0039] Example 1

[0040] Preparation of (4R,5R)-2-isopropoxy-1,3-dineopentyl-4,5-diphenyl-1,3,2-diazaphosphacyclopentane (L1):

[0041]

[0042] (1R,2R)-N was added to a Schlenk flask under a nitrogen atmosphere and at -78 °C. 1 N 2-Dineoptiyl-1,2-diphenylethylenediamine (1.0 mmol, 1.0 equivalent), freshly distilled phosphorus trichloride (1.2 mmol, 1.2 equivalent), triethylamine (8.0 mmol, 8.0 equivalent), and tetrahydrofuran (10 mL). The reaction mixture was heated to 60 °C for 6 h, cooled to room temperature, and then isopropanol (iPrOH, 2.0 mmol, 2.0 equivalent) was added dropwise. The reaction mixture was then heated to 60 °C for another 10 h. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth (Celite), and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography using petroleum ether / ethyl acetate (PE / EA = 20:1) as the eluent to give a white solid, which was ligand L1, in 54% yield. The detection data for ligand L1 are as follows:

[0043] 1 H NMR (600 MHz, CDCl3) δ 7.31 (d, J = 7.4 Hz, 3H), 7.26 (d, J = 8.2Hz, 3H), 7.24 – 7.07 (m, 4H), 4.39 (t, J = 6.9 Hz, 1H), 4.34 – 4.27 (m, 1H), 4.22 (d, J = 6.7 Hz, 1H), 2.76 (t, J = 14.9 Hz, 1H), 2.68 (t, J = 15.0 Hz, 1H), 2.44 (t, J = 13.9 Hz, 1H), 2.21 (dd, J = 18.7, 13.7 Hz, 1H), 1.34 (d, J= 6.1 Hz, 3H), 1.31 (d, J = 6.2 Hz, 3H), 0.84 (d, J = 21.5 Hz, 18H). 13 C NMR(151 MHz, CDCl3) δ 142.2, 142.1, 128.8, 128.8, 128.2, 128.1, 127.5, 127.0,78.2, 78.1, 76.0, 75.9, 67.0, 66.8, 57.3, 57.2, 56.1, 56.0, 34.5, 34.5, 32.8,29.2, 29.1, 28.8, 28.8, 25.9, 25.8, 25.1, 25.0. 31 P NMR (243 MHz, CDCl3) δ139.5. HRMS (ESI) calcd. for [C 27 H 41N2OP, M+H] + : 441.3029, found: 441.3031.[α] D 30 = +61.6 (c 0.50, CHCl3). mp: 72–73 ℃.

[0044] Example 2

[0045] Preparation of (4R,5R)-1,3-bis(3,5-di-tert-butylphenyl)-4,5-diphenyl-2-((S)-1-phenethoxy)-1,3,2-diazaphosphacyclopentane (L2):

[0046]

[0047] (1R,2R)-N was added to a Schlenk flask under a nitrogen atmosphere and at -78°C. 1 N 2 -Bis(3,5-di-tert-butylphenyl)-1,2-diphenylethylenediamine (1.0 mmol, 1.0 equivalent), freshly distilled phosphorus trichloride (1.2 mmol, 1.2 equivalent), triethylamine (8.0 mmol, 8.0 equivalent), and tetrahydrofuran (10 mL). The mixture was heated to 70 °C and stirred for 6 h. The reaction mixture was then cooled to room temperature, and (S)-1-phenylethanol (2.0 mmol, 2.0 equivalent) was added dropwise. The mixture was then heated to 70 °C and stirred for 12 h. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by rapid column chromatography using petroleum ether / ethyl acetate (PE / EA = 20:1) as the eluent. The target component was collected and concentrated under reduced pressure to obtain a white solid, which was ligand L2, in 57% yield. The detection data for ligand L2 are as follows:

[0048] 1H NMR (600 MHz, CDCl3) δ 7.25 (s, 1H), 7.22 – 7.18 (m, 3H), 7.16 (t,J = 7.7 Hz, 3H), 7.12 (d, J = 6.8 Hz, 1H), 7.08 (d, J = 7.5 Hz, 2H), 7.02 (s,3H), 6.96 (s, 2H), 6.80 (d, J = 7.3 Hz, 3H), 6.72 (s, 1H), 6.69 (s, 2H), 5.28– 5.20 (m, 1H), 5.12 (d, J = 8.2 Hz, 1H), 4.88 (d, J = 8.3 Hz, 1H), 1.51 (d,J = 6.5 Hz, 3H), 1.15 (s, 18H), 1.01 (s, 18H). 13 C NMR (151 MHz, CDCl3) δ151.1, 150.8, 144.5, 144.5, 143.7, 143.5, 142.2, 142.1, 140.8, 140.1, 140.0,128.5, 128.1, 127.9, 127.9, 127.4, 127.4, 126.8, 125.4, 122.5115.7, 115.6,115.08, 115.1, 114.2, 111.5, 111.4, 73.8, 73.8, 73.3, 73.1, 72.1, 72.0, 35.1, 34.8, 31.6, 31.5, 31.4, 25.9, 25.9. 31 P NMR (243 MHz, CDCl3) δ 127.1. HRMS(ESI) calcd. for [C 50 H 63 N2OP, M+Na] + : 761.4571, found: 761.4570. [α] D 30 = +62.4(c 0.50, CHCl3). mp: 80–81 ℃.

[0049] Example 3

[0050] Preparation of (4R,5R)-1,3-bis(3,5-di-tert-butyl-4-methoxyphenyl)-4,5-diphenyl-2-((S)-1-phenethoxy)-1,3,2-diazaphosphacyclopentane (L3):

[0051]

[0052] (1R,2R)-N was added to a Schlenk flask under an argon atmosphere and at -78°C. 1 N 2 -Bis(3,5-di-tert-butyl-4-methoxyphenyl)-1,2-diphenylethylenediamine (1.0 mmol, 1.0 equivalent), freshly distilled phosphorus trichloride (1.2 mmol, 1.2 equivalent), triethylamine (8.0 mmol, 8.0 equivalent), and tetrahydrofuran (10 mL). The mixture was heated to 60 °C and stirred for 8 h. The reaction mixture was then cooled to room temperature, and (S)-1-phenylethanol (2.0 mmol, 2.0 equivalent) was added dropwise. The mixture was then heated to 60 °C and stirred for another 8 h. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by rapid column chromatography using petroleum ether / ethyl acetate (PE / EA = 20:1) as the eluent. The target component was collected and concentrated under reduced pressure to give a white solid, which was ligand L3, in 75% yield. The detection data for ligand L3 are as follows:

[0053] 1 H NMR (600 MHz, CDCl3) δ 7.30 – 7.25 (m, 5H), 7.23 – 7.16 (m, 4H), 7.13 – 7.07 (m, 4H), 7.06 (d, J = 7.6 Hz, 2H), 6.82 (s, 2H), 6.75 – 6.64 (m,2H), 5.23 (dq, J = 12.9, 6.8 Hz, 1H), 5.07 (d, J = 8.5 Hz, 1H), 4.83 (d, J =8.4 Hz, 1H), 3.60 (s, 3H), 3.48 (s, 3H), 1.56 (d, J = 6.5 Hz, 3H), 1.29 (s, 18H), 1.14 (s, 18H). 13C NMR (151 MHz, CDCl3) δ 153.7, 153.2, 144.7, 143.6,143.2, 140.8, 139.8, 139.0, 138.9, 137.3, 137.2, 128.6, 128.5, 128.2, 128.0,127.5, 127.5, 126.9, 125.4, 119.5, 119.4, 115.2, 115.1, 74.1, 74.0, 73.3,73.1, 72.2, 72.1, 64.2, 64.1, 36.1, 35.8, 32.2, 32.1, 26.4, 26.3. 31 P NMR (243MHz, CDCl3) δ 127.1. HRMS (ESI) calcd. for [C 52 H 67 [N₂O₃P, M+Na] + : 821.4782, found: 821.4781. [α] D 29 = +46.9 (c 0.5, CHCl3). mp: 85–86 ℃.

[0054] Example 4

[0055] Preparation of (4R,5R)-2-isopropoxy-1,3-dimestrimethyl-4,5-diphenyl-1,3,2-diazaphosphacyclopentane (L4):

[0056]

[0057] Under an argon atmosphere and at -78°C, (1R,2R)-N,N'-dimethyltrimethyl-1,2-diphenylethylenediamine (1.0 mmol, 1.0 equivalent), freshly distilled phosphorus trichloride (1.2 mmol, 1.2 equivalent), triethylamine (8.0 mmol, 8.0 equivalent), and tetrahydrofuran (10 mL) were added to a Schlenk flask. The mixture was heated to 60°C and stirred for 8 h. The reaction mixture was then cooled to room temperature, and isopropanol (2.0 mmol, 2.0 equivalent) was added dropwise. The mixture was then heated to 60°C and stirred for another 8 h. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by rapid column chromatography using petroleum ether / ethyl acetate (PE / EA = 20:1) as the eluent. The target component was collected and concentrated under reduced pressure to obtain a white solid, which was ligand L4, in 55% yield. The detection data for ligand L4 are as follows:

[0058] 1 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H), 7.25 (d, J = 2.9 Hz, 1H), 7.18– 7.14 (m, 3H), 7.12 – 7.08 (m, 2H), 7.07 – 7.02 (m, 3H), 6.86 (d, J = 2.2Hz, 1H), 6.79 (d, J = 2.2 Hz, 1H), 6.65 – 6.58 (m, 2H), 5.74 (d, 1H), 4.54(dd, J = 9.7, 1.5 Hz, 1H), 4.10 – 3.94 (m, 1H), 2.68 (s, 3H), 2.62 (s, 3H),2.51 (d, J = 1.6 Hz, 3H), 2.16 (dd, J = 13.2, 1.6 Hz, 6H), 2.04 (s, 3H), 1.14(d, J = 6.2 Hz, 3H), 0.83 (d, J = 6.2 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ139.4, 139.3, 138.0, 137.4, 136.6, 136.4, 135.7, 134.3, 134.3, 130.5, 130.5,129.8, 129.6, 129.4, 129.2, 128.0, 127.8, 127.8, 127.6, 127.4, 77.8, 77.8,73.1, 73.0, 68.4, 68.1, 25.0, 25.0, 24.8, 24.8, 21.7, 21.0, 20.9, 20.9, 20.8,19.6, 19.5. 31 31P NMR (162 MHz, CDCl3) δ 129.9. HRMS (ESI) calcd. for[C 35 H 41 N2OP, M+H] + : 537.3029, found: 537.3037. [α] D 30 = +232.1 (c 0.50, CHCl3).m.p.: 137 – 138 ℃

[0059] Example 5

[0060] Preparation of (4R,5R)-4,5-bis(3,5-dimethylphenyl)-2-isopropoxy-1,3-diphenyl-1,3,2-diazaphosphacyclopentane (L5)

[0061]

[0062] Under an argon atmosphere and at -78°C, (1R,2R)-1,2-bis(3,5-dimethylphenyl)-N¹,N²-diphenylethylenediamine (1.0 mmol, 1.0 equivalent), freshly distilled phosphorus trichloride (1.2 mmol, 1.2 equivalent), triethylamine (8.0 mmol, 8.0 equivalent), and tetrahydrofuran (10 mL) were added to a Schlenk flask. The mixture was heated to 60°C and stirred for 8 h. The reaction mixture was then cooled to room temperature, and isopropanol (2.0 mmol, 2.0 equivalent) was added dropwise. The mixture was then heated to 60°C and stirred for another 8 h. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by rapid column chromatography using petroleum ether / ethyl acetate (PE / EA = 20:1) as the eluent. The target fraction was collected and concentrated under reduced pressure to give a white solid, which was ligand L3, in 84% yield. The detection data for ligand L5 are as follows:

[0063] 1 H NMR (600 MHz, CDCl3) δ 7.11 (dt, J = 13.7, 7.7 Hz, 4H), 6.99 (dd, J= 12.3, 8.1 Hz, 4H), 6.95 (s, 2H), 6.89 – 6.72 (m, 6H), 5.00 (d, J = 6.9 Hz, 1H), 4.77 (dd, J = 7.1, 3.1 Hz, 1H), 4.45 (tq, J = 12.7, 6.4 Hz, 1H), 2.23 (d, J = 19.9 Hz, 12H), 1.23 (d, J = 6.2 Hz, 3H), 0.97 (d, J = 6.1 Hz, 3H). 13CNMR (151 MHz, CDCl3) δ 144.9, 144.7, 143.4, 143.3, 140.6, 140.3, 140.3,137.8, 137.6, 129.2, 129.0, 128.8, 128.7, 125.3, 125.0, 120.7, 120.3, 120.3,119.6, 116.4, 116.3, 73.1, 73.0, 71.7, 71.6, 68.5, 68.4, 24.8, 24.8, 24.5,24.5, 21.4, 21.4. 31 P NMR (243 MHz, CDCl3) δ 125.4.

[0064] Example 6: Preparation of (4R,5R)-1,2,3,4,5-pentaphenyl-1,3,2-diazaphosphacyclopentane (L6):

[0065]

[0066] Under a nitrogen atmosphere and at -78°C, the following reactants were added to a Schlenk flask: (1R,2R)-N¹,N²,1,2-tetraphenylethylenediamine (1.0 mmol, 1.0 equivalent), phosphorus trichloride (10 mmol, 10.0 equivalent), triethylamine (15.0 mmol, 15.0 equivalent), and tetrahydrofuran (10 mL). The mixture was heated to 60°C and reacted for 6 h. The reaction solution was then cooled to room temperature, filtered under positive nitrogen pressure, and the filtrate was desolvated. The resulting solid was redissolved in tetrahydrofuran (10 mL). After cooling to -78°C, phenyl magnesium bromide (1.5 mmol, 1.5 equivalent) was added dropwise. The mixture was heated to 60°C and reacted for 10 h. Subsequently, a borane-tetrahydrofuran complex (10.0 mmol, 10.0 equivalent) was added to the reaction solution at 0°C, and the mixture was stirred at room temperature for 12 h. The reaction was quenched slowly with water at 0°C, followed by extraction with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to give the intermediate.

[0067] Under a nitrogen atmosphere, triethylenediamine (5.0 mmol, 5.0 equivalent), toluene (2 mL), and the intermediate (1.0 mmol, 1.0 equivalent) were added to a sealed tube. The mixture was heated to 90 °C and reacted for 12 h. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by rapid column chromatography on a neutral alumina column under an argon atmosphere (eluent: n-hexane / ethyl acetate = 20:1) to give a white solid, which was ligand L6, in 41% yield. The detection data of ligand L6 are as follows:

[0068] 1 H NMR (400 MHz, CDCl3) δ 7.45 (t, J = 6.3 Hz, 2H), 7.35 – 7.27 (m,3H), 7.21 (dd, J = 5.3, 1.8 Hz, 3H), 7.19 – 7.10 (m, 7H), 7.03 (t, J = 7.5Hz, 4H), 6.93 (d, J = 8.1 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 6.81 (t, J = 7.3Hz, 1H), 6.74 (t, J = 7.3 Hz, 1H), 5.01 (s, 2H). 13 C NMR (101 MHz, CDCl3) δ146.8, 146.6, 143.3, 142.7, 142.2, 139.2, 139.0, 130.5, 130.3, 129.5, 128.9,128.8, 128.8, 128.6, 128.2, 128.2, 128.1, 127.8, 127.7, 127.5, 127.4, 121.0,120.9, 120.5, 120.5, 119.4, 116.7, 116.5, 74.3, 74.2, 72.0, 71.9. 31 P NMR (162MHz, CDCl3) δ 105.1. HRMS (EI) calcd. for [C 32 H 27 N2P, M] + : 470.1912, found:470.1903. [α] D 30 = +116.8 (c 0.24, CHCl3). mp: 127–128 ℃.

[0069] Example 7

[0070] Preparation of (4R,5R)-1,2,3,4,5-pentaphenyl-1,3,2-diazaphosphacyclopentane (L7):

[0071]

[0072] Under a nitrogen atmosphere and at -78°C, the following reactants were added to a Schlenk flask: (1R,2R)-N¹,N²,1,2-tetraphenylethylenediamine (1.0 mmol, 1.0 equivalent), phosphorus trichloride (10 mmol, 10.0 equivalent), triethylamine (15.0 mmol, 15.0 equivalent), and tetrahydrofuran (10 mL). The mixture was heated to 60°C and reacted for 6 h. The reaction solution was then cooled to room temperature, filtered under positive nitrogen pressure, and the filtrate was desolvated. The resulting solid was redissolved in tetrahydrofuran (10 mL). After cooling to -78°C, benzyl magnesium bromide (1.5 mmol, 1.5 equivalent) was added dropwise. The mixture was heated to 60°C and reacted for 10 h. Subsequently, a borane-tetrahydrofuran complex (10.0 mmol, 10.0 equivalent) was added to the reaction solution at 0°C, and the mixture was stirred at room temperature for 12 h. The reaction was quenched slowly with water at 0°C, followed by extraction with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to give the intermediate.

[0073] Under a nitrogen atmosphere, triethylenediamine (5.0 mmol, 5.0 equivalent), toluene (2 mL), and the intermediate (1.0 mmol, 1.0 equivalent) were added to a sealed tube. The mixture was heated to 90 °C and reacted for 12 h. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by rapid column chromatography on a neutral alumina column under an argon atmosphere (eluent: n-hexane / ethyl acetate = 20:1) to give a white solid, which was ligand L7, in 45% yield. The detection data for ligand L7 are as follows:

[0074] 1 H NMR (400 MHz, CDCl3) δ 7.33 – 7.12 (m, 15H), 7.06 (t, J = 7.8 Hz,2H), 6.95 (q, J = 8.6 Hz, 4H), 6.78 (t, J = 7.4 Hz, 1H), 6.70 (t, J = 7.3 Hz,1H), 6.46 (d, J = 8.1 Hz, 2H), 5.00 (d, J = 8.6 Hz, 1H), 4.91 (d, J = 8.6 Hz,1H), 3.35 (d, J = 13.3 Hz, 1H), 3.08 (dd, J = 13.3, 7.5 Hz, 1H). 13C NMR 13CNMR (101 MHz, CDCl3) δ 146.24, 146.02, 143.25, 139.52, 138.42, 136.07,135.97, 129.59, 129.54, 128.96, 128.76, 128.58, 128.50, 128.22, 127.94,127.78, 125.73, 121.56, 121.14, 119.35, 116.48, 74.49, 71.74, 40.44, 40.00. 31 PNMR (162 MHz, CDCl3) δ 125.0.

[0075] Example 8

[0076] Synthesis of (S,2E,4E)-1-cyclohexyl-5-phenylpenta-2,4-dien-1-ol (P1):

[0077]

[0078] In an argon-filled glove box, a stir bar was added to a dried, sealed tube, followed by Ni(COD)₂ (2.8 mg, 0.01 mmol), L₂ (8.9 mg, 0.012 mmol), methanol (200 μL), acetonitrile (50 μL), 2a (19.5 mg, 0.15 mmol), and 1a (11.2 mg, 0.1 mmol). After stirring for 5 minutes, the tube was sealed and removed from the glove box. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was filtered through a short silica gel liner. The filtrate was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 6:1) to give 17.4 mg of a colorless oily product P1, in 72% yield (EE / ZE = 11:1).

[0079] 11H NMR (600 MHz, CDCl3) δ 7.39 (d, J = 7.7 Hz, 2H), 7.31 (t, J = 7.7Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 6.78 (dd, J = 15.7, 10.5 Hz, 1H), 6.54 (d,J = 15.7 Hz, 1H), 6.36 (dd, J = 15.2, 10.5 Hz, 1H), 5.83 (dd, J = 15.2, 7.2Hz, 1H), 3.95 (t, J = 6.8 Hz, 1H), 1.88 (d, J = 13.1 Hz, 1H), 1.79 – 1.65 (m,4H), 1.50 – 1.42 (m, 1H), 1.28 – 1.20 (m, 2H), 1.19 – 1.13 (m, 1H), 1.06 –0.96 (m, 2H). 13 13C NMR (151 MHz, CDCl3) δ 137.3, 135. 6, 132.6, 131.7, 128.8,128.7, 128.5, 127.67, 126.5, 44.1, 29.0, 28.7, 26.6, 26.3, 26.2. HRMS (ESI)calcd. for [C 17 17 12 H + 16 D 28 O, M+H] ® : 243.1744, found: 243.1743. [α] R 20 R = +20.2 (c 0.50,CHCl3). HPLC analysis: The ee (91%) was determined using a Chiralpak

[0080] Example 9

[0081] Synthesis of (R,4E,6E)-2,2-dimethyl-7-phenylhepta-4,6-dien-3-ol (P2):

[0082]

[0083] In an argon-filled glove box, a stir bar was added to a dried, sealed tube, followed by Ni(COD)₂ (96 mg, 0.35 mmol), L₂ (296 mg, 0.4 mmol), methanol (10 mL), acetonitrile (2.5 mL), 2a (975 mg, 7.5 mmol), and 1b (430 mg, 5.0 mmol). After stirring for 5 minutes, the tube was sealed and removed from the glove box. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was filtered through a short silica gel liner. The filtrate was concentrated under reduced pressure to obtain the crude product. The residue was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 6:1) to give 670 mg of yellow solid product P₂, in 62% yield (EE / ZE = 9:1).

[0084] 1 H NMR (600 MHz, CDCl3) δ 7.39 (d, J = 7.7 Hz, 2H), 7.31 (t, J = 7.6Hz, 2H), 7.22 (t, J = 7.3 Hz, 1H), 6.78 (dd, J = 15.6, 10.5 Hz, 1H), 6.55 (d,J = 15.7 Hz, 1H), 6.39 (dd, J = 15.2, 10.5 Hz, 1H), 5.89 (dd, J = 15.2, 7.3Hz, 1H), 3.85 (d, J = 7.3 Hz, 1H), 1.53 (s, 1H), 0.94 (s, 9H). 13 C NMR (151MHz, CDCl3) δ 137.3, 134.0, 132.6, 132.4, 128.8, 128.7, 128.6, 127.7, 126.5,80.8, 35.4, 25.9, 25.7. HRMS (ESI) calcd. for [C 15 H 20 O, M+H] + : 217.1587, found:217.1576. [α] D 29= +27.5 (c 0.50, CHCl3). mp = 42–43 ℃. HPLC analysis: Theee (93%) was determined using a Chiralpak ® OD-H column, hexane / 2-propanol =90:10, flow rate = 1.0 mL / min, 280 nm UV detector, t R (minor) = 5.91 min, t R (major) = 9.40 min.

[0085] Example 10 (Synthesis of active pharmaceutical molecules)

[0086] Synthesis of (S,4E,6E)-1,7-diphenylhepta-4,6-dien-3-ol (ASPP 049) (P3):

[0087]

[0088] In an argon-filled glove box, a stir bar was added to a dried, sealed tube, followed by Ni(COD)₂ (2.8 mg, 0.01 mmol), L₂ (8.9 mg, 0.012 mmol), methanol (250 μL), acetonitrile (5 μL), 2a (19.5 mg, 0.15 mmol), and 1c (13.4 mg, 0.1 mmol). After stirring for 5 minutes, the tube was sealed and removed from the glove box. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was filtered through a short silica gel liner. The filtrate was concentrated under reduced pressure to obtain the crude product. The residue was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 6:1) to give 15.6 mg of a colorless oily product P₃, in 58% yield (EE / ZE = 9:1).

[0089] 11H NMR (600 MHz, CDCl3) δ 7.40 (d, J = 7.6 Hz, 2H), 7.30 (dt, J = 14.7, 7.4 Hz, 4H), 7.25 – 7.14 (m, 4H), 6.77 (dd, J = 15.7, 10.5 Hz, 1H), 6.56 (d, J = 15.6 Hz, 1H), 6.39 (dd, J = 15.2, 10.5 Hz, 1H), 5.85 (dd, J = 15.3, 6.8 Hz, 1H), 4.29 – 4.13 (m, 1H), 2.84 – 2.63 (m, 2H), 2.03 – 1.77 (m, 2H). 13 13C NMR (151 MHz, CDCl3) δ 141.9, 137.2, 136.4, 133.0, 131.2, 128.8, 128.6, 128.6, 128.3, 127.8, 126.5, 126.0, 72.2, 38.9, 31.9. HRMS (ESI) calcd. for 19 C 20 H + O, M+Na] [α] D 29 = +14.2 (c 025, EtOH). HPLC analysis: The ee (90%) was determined using a Chiralpak ® OD-H column, hexane / 2-propanol = 90:10, flow rate = 1.0 mL / min, 280 nm UV detector, t R (minor) = 31.84 min, t R (major) = 34.45 min.

[0090] Example 11

[0091] Synthesis of (1R,2E,4E)-1-((1s,3S)-adamantan-1-yl)-5-phenylpenta-2,4-dien-1-ol (P4):

[0092]

[0093] In an argon-filled glove box, a stir bar was added to a dried, sealed tube, followed by Ni(COD)₂ (2.8 mg, 0.01 mmol), L₂ (8.9 mg, 0.012 mmol), methanol (200 μL), acetonitrile (50 μL), 2a (19.5 mg, 0.15 mmol), and 1d (16.4 mg, 0.1 mmol). After stirring for 5 minutes, the tube was sealed and removed from the glove box. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was filtered through a short silica gel liner. The filtrate was concentrated under reduced pressure to obtain the crude product. The residue was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 7:1) to give 20.6 mg of colorless oily product P₄, in 70% yield (EE / ZE = 10:1).

[0094] 1 H NMR (600 MHz, CDCl3) δ 7.39 (d, J = 7.7 Hz, 2H), 7.31 (t, J = 7.7Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 6.79 (dd, J = 15.7, 10.5 Hz, 1H), 6.54 (d,J = 15.7 Hz, 1H), 6.36 (dd, J = 15.4, 10.6 Hz, 1H), 5.90 (dd, J = 15.3, 7.4Hz, 1H), 3.67 (d, J = 7.4 Hz, 1H), 2.00 (s, 3H), 1.72 (d, J = 12.4 Hz, 3H),1.67 – 1.60 (m, 6H), 1.56 (d, J = 12.4 Hz, 3H), 1.49 (s, 1H). 13 C NMR (151MHz, CDCl3) δ 137.4, 133.3, 132.6, 132.5, 128.7, 128.6, 127.7, 126.5, 81.2,38.3, 37.3, 28.5. HRMS (ESI) calcd. for [C 21 H 26 O, M+H] + : 295.2056, found:295.2049. [α] D 31= +27.5 (c 0.50, CHCl3). HPLC analysis: The ee (90%) was determined using a Chiralpak ® OD-H column, hexane / 2-propanol = 95:5, flow rate= 1.0 mL / min, 280 nm UV detector, t R (minor) = 13.17 min, t R (major) = 22.77min.

[0095] Example 12

[0096] Synthesis of tert-butyl-4-((S,2E,4E)-1-hydroxy-5-phenylpenta-2,4-dien-1-yl)piperidine-1-carboxylate (P5):

[0097]

[0098] In an argon-filled glove box, a stir bar was added to a dried, sealed tube, followed by Ni(COD)₂ (2.8 mg, 0.01 mmol), L₂ (8.9 mg, 0.012 mmol), methanol (200 μL), acetonitrile (50 μL), 2a (19.5 mg, 0.15 mmol), and 1e (21.3 mg, 0.1 mmol). After stirring for 5 minutes, the tube was sealed and removed from the glove box. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was filtered through a short silica gel liner. The filtrate was concentrated under reduced pressure to obtain the crude product. The residue was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2:1) to give 23.5 mg of colorless oily product P5, in 69% yield (EE / ZE = 11:1).

[0099] 11H NMR (600 MHz, CDCl3) δ 7.39 (d, J = 7.8 Hz, 2H), 7.32 (t, J = 7.7 Hz, 2H), 7.23 (t, J = 7.4 Hz, 1H), 6.76 (dd, J = 15.7, 10.5 Hz, 1H), 6.55 (d, J = 15.7 Hz, 1H), 6.37 (dd, J = 15.2, 10.5 Hz, 1H), 5.80 (dd, J = 15.2, 7.4 Hz, 1H), 4.14 (s, 2H), 3.97 (t, J = 7.0 Hz, 1H), 2.67 (s, 2H), 1.86 (d, J = 13.3 Hz, 1H), 1.74 – 1.62 (m, 2H), 1.45 (s, 9H), 1.24 – 1.18 (m, 2H). 13 13C NMR(151 MHz, CDCl3) δ 155.0, 137.1, 134.6, 133.2, 132.3, 128.8, 128.1, 127.8, 126.5, 79.5, 76.6, 42.4, 28.6, 28.1. HRMS (ESI) calcd. for [C 21 H 29 NO3, M+Na] + : 366.2040, found: 366. 2035. [α] D 29 = +41.2 (c 0.50, CHCl3). HPLC analysis: Theee (90%) was determined using a Chiralpak ® OD-H column, hexane / 2-propanol = 90:10, flow rate = 1.0 mL / min, 280 nm UV detector, t R (minor) = 11.97 min, t R (major) = 25.02 min.

[0100] Example 13

[0101] (R,2E,4E)-1-(benzofuran-3-yl)-5-phenylpenta-2,4-dien-1-ol (P6) Synthesis:

[0102]

[0103] In an argon-filled glove box, a stir bar was added to a dried, sealed tube, followed by Ni(COD)₂ (2.8 mg, 0.01 mmol), L₃ (9.6 mg, 0.012 mmol), methanol (200 μL), acetonitrile (50 μL), 2a (19.5 mg, 0.15 mmol), and 1f (14.6 mg, 0.1 mmol). After stirring for 5 minutes, the tube was sealed and removed from the glove box. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was filtered through a short silica gel liner. The filtrate was concentrated under reduced pressure to obtain the crude product. The residue was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 7:1) to give 9.6 mg of colorless oily product P₆, in 35% yield (EE / ZE = 6:1).

[0104] 1 H NMR (600 MHz, CDCl3) δ 7.68 (d, J = 7.8 Hz, 1H), 7.62 (s, 1H), 7.49(d, J = 8.2 Hz, 1H), 7.40 (d, J = 7.6 Hz, 2H), 7.32 (t, J = 7.8 Hz, 3H), 7.24(d, J = 7.2 Hz, 2H), 6.82 (dd, J = 15.7, 10.6 Hz, 1H), 6.64 – 6.56 (m, 2H), 6.14 (dd, J = 15.5, 6.6 Hz, 1H), 5.58 (d, J = 6.5 Hz, 1H), 2.02 (s, 1H). 13 CNMR (151 MHz, CDCl3) δ 156.0, 142.0, 137.1, 133.9, 133.7, 132.2, 128.8,128.0, 127.9, 126.6, 126.1, 124.8, 122.9, 122.7, 120.8, 111.8, 68.0. HRMS(ESI) calcd. for [C 19 H 18 O2, M+H] + : 277.1224, found: 277.1215. [α] D 28= -4.0 (c0.50, CHCl3). HPLC analysis: The ee (84%) was determined using a Chiralpak ® OD-H column, hexane / 2-propanol = 90:10, flow rate = 1.0 mL / min, 280 nm UVdetector, t R (minor) = 17.35 min, t R (major) = 24.32 min.

[0105] Example 14

[0106] Synthesis of (R,1E,3E)-9-(2,5-dimethylphenoxy)-6,6-dimethyl-1-phenylnona-1,3-dien-5-ol (P7):

[0107]

[0108] In an argon-filled glove box, a stir bar was added to a dried, sealed tube, followed by Ni(COD)₂ (2.8 mg, 0.01 mmol), L₂ (8.9 mg, 0.012 mmol), methanol (200 μL), acetonitrile (50 μL), 2a (19.5 mg, 0.15 mmol), and 1 g (23.4 mg, 0.1 mmol). After stirring for 5 minutes, the tube was sealed and removed from the glove box. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was filtered through a short silica gel liner. The filtrate was concentrated under reduced pressure to obtain the crude product. The residue was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 7:1) to give 22.2 mg of colorless oily product P7, in 61% yield (EE / ZE = 12:1).

[0109] 1H NMR (600 MHz, CDCl3) δ 7.39 (d, J = 7.7 Hz, 2H), 7.31 (t, J = 7.6Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.83 – 6.73 (m,1H), 6.65 (d, J = 7.6 Hz, 1H), 6.62 (s, 1H), 6.55 (d, J = 15.7 Hz, 1H), 6.40(dd, J = 15.2, 10.5 Hz, 1H), 5.91 (dd, J = 15.2, 7.3 Hz, 1H), 3.97 (d, J =7.4 Hz, 1H), 3.93 (t, J = 6.7 Hz, 2H), 2.30 (s, 3H), 2.18 (s, 3H), 1.88 –1.76 (m, 2H), 1.56 – 1.49 (m, 1H), 1.46 – 1.38 (m, 1H), 0.97 (s, 3H), 0.94(s, 3H). 13 C NMR (151 MHz, CDCl3) δ 157.2, 137.3, 136.6, 133.6, 132.7, 132.6,130.4, 128.7, 128.5, 127.7, 126.5, 123.7, 120.7, 112.1, 79.6, 68.7, 37.7,35.2, 24.1, 23.0, 22.9, 21.5, 15.9. HRMS (ESI) calcd. for [C 25 H 32 O2, M+Na] + :387.2295, found: 387.2289. [α] D 28 = +23.4 (c 0.50, CHCl3). HPLC analysis: Theee (90%) was determined using a Chiralpak ® AD-3 column, hexane / 2-propanol =95:5, flow rate = 1.0 mL / min, 280 nm UV detector, t R (minor) = 21.58 min, tR (major) = 18.03 min.

[0110] Example 15

[0111] Synthesis of (1E,3E,7S)-7,11-dimethyl-1-phenyldodeca-1,3,10-trien-5-ol (P8):

[0112]

[0113] In an argon-filled glove box, a stir bar was added to a dried, sealed tube, followed by Ni(COD)₂ (2.8 mg, 0.01 mmol), L₂ (8.9 mg, 0.012 mmol), methanol (250 μL), acetonitrile (5 μL), 2a (19.5 mg, 0.15 mmol), and 1h (15.4 mg, 0.1 mmol). After stirring for 5 minutes, the tube was sealed and removed from the glove box. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was filtered through a short silica gel liner. The filtrate was concentrated under reduced pressure to obtain the crude product. The residue was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 7:1) to give 20.4 mg of a white solid product P8, in 72% yield (EE / ZE = 10:1).

[0114] 1 H NMR (600 MHz, CDCl3) δ 7.39 (d, J = 7.7 Hz, 2H), 7.31 (t, J = 8.6Hz, 2H), 7.25 – 7.20 (m, 1H), 6.83 – 6.69 (m, 1H), 6.55 (d, J = 15.6 Hz, 1H), 6.43 – 6.32 (m, 1H), 5.79 (dd, J = 15.7, 6.9 Hz, 1H), 5.11 (d, J = 7.5 Hz, 1H), 4.33 – 4.26 (m, 1H), 2.06 – 1.90 (m, 2H), 1.68 (s, 3H), 1.60 (s, 3H),1.55 – 1.45 (m, 3H), 1.45 – 1.35 (m, 1H), 1.23 – 1.13 (m, 1H), 0.99 – 0.89 (m, 3H). 1313C NMR (151 MHz, CDCl3) δ 137.3, 136.9, 132.8, 131.4, 130.9, 128.7, 128.4, 127.7, 126.5, 124.8, 71.3, 44.7, 37.2, 29.3, 25.8, 25.5, 20.1, 17.8. HRMS (ESI) calcd. for [C 20 H 28 O, M+H] + : 285.2213, found: 285.2209. [α] D 31 = -10.5(c 0.50, CHCl3). m.p. = 47–48 ℃. HPLC analysis: The dr (94:6) was determined using a Chiralpak ® AD-3 column, hexane / 2-propanol = 95:5, flow rate = 1.0 mL / min, 280 nm UV detector, t R (minor) = 10.29 min, t R (major) = 9.08 min.

[0115] Example 16

[0116] (3R,5S,7S,8R,9S,10S,13R,14S,17R)-17-((2R,5S,6E,8E)-5-hydroxy-9-phenylnona-6,8-dien-2-yl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3,7-diol (P9) synthesis:

[0117]

[0118] In an argon-filled glove box, a stir bar was added to a dried, sealed tube, followed by Ni(COD)₂ (2.8 mg, 0.01 mmol), L₂ (8.9 mg, 0.012 mmol), methanol (250 μL), acetonitrile (5 μL), 2a (19.5 mg, 0.15 mmol), and 1i (37.7 mg, 0.1 mmol). After stirring for 5 minutes, the tube was sealed and removed from the glove box. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was filtered through a short silica gel liner. The filtrate was concentrated under reduced pressure to obtain the crude product. The residue was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to give 22.2 mg of colorless oily product P9, in 44% yield (EE / ZE = 7:1).

[0119] 1 H NMR (600 MHz, CDCl3) δ 7.40 (d, J = 7.8 Hz, 2H), 7.32 (t, J = 7.6Hz, 2H), 7.23 (t, J = 7.4 Hz, 1H), 6.77 (dd, J = 15.6, 10.5 Hz, 1H), 6.55 (d,J = 15.6 Hz, 1H), 6.38 (dd, J = 15.2, 10.6 Hz, 1H), 5.81 (dd, J = 15.3, 6.9Hz, 1H), 4.15 (q, J = 6.6 Hz, 1H), 3.63 – 3.52 (m, 2H), 2.00 (d, J = 12.7 Hz,1H), 1.92 – 1.84 (m, 1H), 1.82 – 1.75 (m, 3H), 1.61 – 1.39 (m, 14H), 1.34 – 1.27 (m, 2H), 1.24 – 1.19 (m, 1H), 1.15 – 0.99 (m, 4H), 0.94 (t, J = 3.3 Hz, 6H), 0.68 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 137.3, 136.8, 132.8, 131.0,128.8, 128.4, 127.7, 126.5, 73.5, 71.6, 71.6, 55.8, 55.1, 43.9, 43.9, for [C 34 H 50 O3, M+Na] + : 529.3652, found:529.3641. [α] D 30 = +27.9 (c 0.50, CHCl3). HPLC analysis: The dr (95:5) was determined using a Chiralpak ® AD-3 column, hexane / 2-propanol = 95:5, flow rate= 1.0 mL / min, 280 nm UV detector, t R (minor) = 46.02 min, t R (major) = 49.31min.

[0120] Example 17 (Synthesis of natural product molecular analogs)

[0121] Synthesis of tert-butyl(R)-2-((S,3E,5E)-2-hydroxy-6-phenylhexa-3,5-dien-1-yl)pyrrolidine-1-carboxylate (P10):

[0122]

[0123] In an argon-filled glove box, a stir bar was added to a dried, sealed tube, followed by Ni(COD)₂ (2.8 mg, 0.01 mmol), L₂ (8.9 mg, 0.012 mmol), methanol (250 μL), acetonitrile (5 μL), 2a (19.5 mg, 0.15 mmol), and 1j (21.3 mg, 0.1 mmol). After stirring for 5 minutes, the tube was sealed and removed from the glove box. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was filtered through a short silica gel pad. The filtrate was concentrated under reduced pressure to obtain the crude product. The residue was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 7:1) to give 23.1 mg of colorless oily product P10, in 68% yield (diastereomer ratio dr > 99:1).

[0124] 1 H NMR (600 MHz, CDCl3) δ 7.38 (d, J = 7.6 Hz, 2H), 7.30 (t, J = 7.6Hz, 2H), 7.20 (t, J = 7.5 Hz, 1H), 6.77 (dd, J = 15.6, 10.6 Hz, 1H), 6.58 –6.42 (m, 2H), 5.86 (dd, J = 15.3, 5.4 Hz, 1H), 5.25 (s, 1H), 4.20 (p, J = 8.1Hz, 2H), 3.35 (t, J = 6.9 Hz, 2H), 2.00 (p, J = 9.4 Hz, 1H), 1.93 – 1.85 (m,2H), 1.62 – 1.54 (m, 2H), 1.48 (s, 9H). 13 C NMR (151 MHz, CDCl3) δ 156.7,137.4, 136.3, 131.8, 129.4, 128.8, 128.5, 127.3, 126.3, 80.1, 77.2, 77.0,76.8, 68.1, 53.6, 46.6, 43.9, 31.2, 28.4, 23.6.HRMS (ESI) calcd. for[C 21 H 29 NO3, M+Na] + : 366.2040, found: 366.2035. [α] D 29= + 41.9 (c 0.50, CHCl3).HPLC analysis: The dr (>99:1) was determined using a Chiralpak ® OD-H column, hexane / 2-propanol = 95:5, flow rate = 1.0 mL / min, 280 nm UV detector, t R (major) = 18.56 min.

[0125] Example 18

[0126] Synthesis of (S,2E,4E)-1-cyclohexyl-5-(4-(dimethylamino)phenyl)penta-2,4-dien-1-ol(P11):

[0127]

[0128] In an argon-filled glove box, a stir bar was added to a dried, sealed tube, followed by Ni(COD)₂ (2.8 mg, 0.01 mmol), L₂ (8.9 mg, 0.012 mmol), methanol (250 μL), acetonitrile (5 μL), 2b (26.0 mg, 0.15 mmol), and 1a (11.2 mg, 0.1 mmol). After stirring for 5 minutes, the tube was sealed and removed from the glove box. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was filtered through a short silica gel liner. The filtrate was concentrated under reduced pressure to obtain the crude product. The residue was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 7:1) to give 16.5 mg of colorless oily product P11, in 58% yield (EE / ZE = 16:1).

[0129] 11H NMR (600 MHz, CDCl3) δ 7.28 (d, J = 8.3 Hz, 2H), 6.67 (d, J = 8.3Hz, 2H), 6.59 (dd, J = 15.7, 10.5 Hz, 1H), 6.46 (d, J = 15.6 Hz, 1H), 6.31(dd, J = 15.1, 10.4 Hz, 1H), 5.71 (dd, J = 15.3, 7.5 Hz, 1H), 3.90 (t, J =7.1 Hz, 1H), 2.96 (s, 6H), 1.88 (d, J = 13.1 Hz, 1H), 1.74 (t, J = 17.3 Hz,2H), 1.70 – 1.62 (m, 2H), 1.48 – 1.39 (m, 1H), 1.29 – 1.19 (m, 2H), 1.18 –1.10 (m, 1H), 1.00 (q, J = 12.8 Hz, 2H). 13 13C NMR (151 MHz, CDCl3) δ 150.2,132.9, 132.9, 132.6, 127.6, 125.8, 124.3, 112.5, 112.5, 77.7, 44.1, 40.6,29.0, 28.8, 26.7, 26.3, 26.2. HRMS (ESI) calcd. for [C 19 17 27 H + 13 D 30 NO, M+H] : 286.2165,found: 286.2162. [α] ® 20D R = +19.5 (c 0.25, CHCl3). R HPLC analysis: The ee (93%)was determined using a Chiralpak

[0130] Example 19

[0131] Synthesis of (S,2E,4E)-1-cyclohexyl-5-(3,5-dimethylphenyl)penta-2,4-dien-1-ol(P12):

[0132]

[0133] In an argon-filled glove box, a stir bar was added to a dried, sealed tube, followed by Ni(COD)₂ (2.8 mg, 0.01 mmol), L₂ (8.9 mg, 0.012 mmol), methanol (250 μL), acetonitrile (5 μL), 2c (23.7 mg, 0.15 mmol), and 1a (11.2 mg, 0.1 mmol). After stirring for 5 minutes, the tube was sealed and removed from the glove box. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was filtered through a short silica gel liner. The filtrate was concentrated under reduced pressure to obtain the crude product. The residue was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 6:1) to give 22.1 mg of a colorless oily product P₁₂, in 82% yield (EE / ZE = 14:1).

[0134] 1 H NMR (600 MHz, CDCl3) δ 7.02 (s, 2H), 6.88 (s, 1H), 6.76 (dd, J =15.8, 10.7 Hz, 1H), 6.48 (d, J = 15.6 Hz, 1H), 6.35 (dd, J = 15.2, 10.6 Hz,1H), 5.81 (dd, J = 15.3, 7.2 Hz, 1H), 3.94 (t, J = 6.9 Hz, 1H), 2.31 (s, 6H),1.88 (d, J = 13.1 Hz, 1H), 1.77 (t, J = 13.9 Hz, 2H), 1.69 (t, J = 16.4 Hz,2H), 1.50 – 1.41 (m, 1H), 1.27 – 1.21 (m, 2H), 1.16 (t, J = 12.9 Hz, 1H), 1.07 – 0.97 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 138.2, 137.2, 135.1, 132.8,131.8, 129.5, 128.1, 124.4, 77.4, 44.1, 29.0, 28.7, 26.6, 26.3, 26.2,21.4.HRMS (ESI) calcd. for [C 19 H 26 O, M+H] + : 271.2056, found: 271.2048. [α] D 30 =+17.9 (c 0.50, CHCl3). HPLC analysis: The ee (92%) was determined using aChiralpak ® IN column, hexane / 2-propanol = 95:5, flow rate = 1.0 mL / min, 280 nmUV detector, t R (minor) = 12.37 min, t R (major) = 10.22 min.

[0135] Example 20

[0136] Synthesis of (S,2E,4E)-1-cyclohexyl-4-methyl-5-phenylpenta-2,4-dien-1-ol (P13):

[0137]

[0138] In an argon-filled glove box, a stir bar was added to a dried, sealed tube, followed by Ni(COD)₂ (5.6 mg, 0.02 mmol), L₂ (17.8 mg, 0.024 mmol), methanol (200 μL), acetonitrile (50 μL), 2d (21.6 mg, 0.15 mmol), and 1a (11.2 mg, 0.1 mmol). After stirring for 5 minutes, the tube was sealed and removed from the glove box. The reaction mixture was stirred at 25 °C for 12 hours. After the reaction was complete, the mixture was filtered through a short silica gel pad. The filtrate was concentrated under reduced pressure to obtain the crude product. The residue was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 6:1) to give 12.3 mg of a colorless oily product P13, in 48% yield (EE / ZE > 20:1).

[0139] 1 1H NMR (600 MHz, CDCl3) δ 7.37 – 7.32 (m, 2H), 7.31 – 7.27 (m, 2H), 7.24 – 7.20 (m, 1H), 6.52 (s, 1H), 6.39 (d, J = 15.4 Hz, 1H), 5.86 – 5.74 (m, 1H), 4.00 – 3.94 (m, 1H), 2.01 (s, 3H), 1.91 (d, J = 13.0 Hz, 1H), 1.80 – 1.65 (m, 4H), 1.55 – 1.42 (m, 2H), 1.26 (s, 2H), 1.20 – 1.13 (m, 1H), 1.09 – 0.97 (m, 2H). 13 13C NMR (151 MHz, CDCl3) δ 137.9, 136.8, 135.3, 131.6, 130.6, 129.3, 128.3, 126.7, 77.9, 44.2, 29.1, 28.8, 26.7, 26.3, 26.2, 14.1. HRMS(ESI) calcd. for [C 18 H 24 O, M+H] + : 257.1900, found: 257.1901. [α] D 30 = +10.6 (c 0.50, CHCl3). HPLC analysis: The ee (88%) was determined using a Chiralpak ® AD-3 column, hexane / 2-propanol = 95:5, flow rate = 1.0 mL / min, 280 nm UV detector, t R (minor) = 12.39 min, t R (major) = 10.84 min.

[0140] Example 21

[0141] (S,2E,4E)-5-(benzo[b]thiophen-2-yl)-1-cyclohexylpenta-2,4-dien-1-ol (P14) synthesis:

[0142]

[0143] In an argon-filled glove box, a stir bar was added to a dried, sealed tube, followed by Ni(COD)₂ (2.8 mg, 0.01 mmol), L₂ (8.9 mg, 0.012 mmol), methanol (200 μL), acetonitrile (50 μL), 2e (27.9 mg, 0.15 mmol), and 1a (11.2 mg, 0.1 mmol). After stirring for 5 minutes, the tube was sealed and removed from the glove box. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was filtered through a short silica gel liner. The filtrate was concentrated under reduced pressure to obtain the crude product. The residue was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 6:1) to give 21.1 mg of the yellow solid product P14, in 71% yield (EE / ZE = 17:1).

[0144] 1 H NMR (600 MHz, CDCl3) δ 7.73 (d, J = 7.5 Hz, 1H), 7.65 (d, J = 7.6Hz, 1H), 7.37 – 7.25 (m, 2H), 7.13 (s, 1H), 6.75 (d, J = 15.4 Hz, 1H), 6.68 –6.60 (m, 1H), 6.34 (dd, J = 15.2, 10.4 Hz, 1H), 5.87 (dd, J = 15.2, 7.0 Hz, 1H), 3.95 (t, J = 6.7 Hz, 1H), 1.87 (d, J = 13.1 Hz, 1H), 1.80 – 1.67 (m,4H), 1.50 – 1.42 (m, 1H), 1.29 – 1.19 (m, 2H), 1.19 – 1.13 (m, 1H), 1.08 –0.97 (m, 2H). 13 C NMR (151 MHz, CDCl3) δ 142.8, 140.3, 139.1, 136.8, 130.7,125.9, 124.8, 124.6, 123.5, 123.1, 122.3, 77.2, 44.1, 29.0, 28.7, 26.6, 26.3,26.2. HRMS (ESI) calcd. for [C 19 H 22 OS, M+Na] +321.1284, found: 321.1279.

[0145] [α] D 30 = +20.64 (c 0.50, CHCl3). mp = 94 – 95 ℃. HPLC analysis: Theee (90%) was determined using a Chiralpak ® IN column, hexane / 2-propanol = 90:10, flow rate = 1.0 mL / min, 320 nm UV detector, t R (minor) = 15.29 min, t R (major) = 12.32 min.

[0146] Example 22

[0147] Synthesis of (S,2E,4E)-1,5-dicyclohexylpenta-2,4-dien-1-ol (P15):

[0148]

[0149] In an argon-filled glove box, a stir bar was added to a dried, sealed tube, followed by Ni(COD)₂ (5.6 mg, 0.02 mmol), L₂ (17.8 mg, 0.024 mmol), methanol (250 μL), acetonitrile (5 μL), 2f (20.4 mg, 0.15 mmol), and 1a (11.2 mg, 0.1 mmol). After stirring for 5 minutes, the tube was sealed and removed from the glove box. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture was filtered through a short silica gel pad. The filtrate was concentrated under reduced pressure to obtain the crude product. The residue was purified by rapid silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to give 4.9 mg of a colorless oily product P15, in 20% yield (EE / ZE = 3:1).

[0150] 1H NMR (600 MHz, CDCl3) δ 6.19 – 6.12 (m, 1H), 6.00 (dd, J = 15.3,10.4 Hz, 1H), 5.65 (dd, J = 15.4, 6.9 Hz, 1H), 5.59 (dd, J = 15.2, 7.4 Hz,1H), 3.84 (t, J = 7.1 Hz, 1H), 1.99 (q, J = 9.9 Hz, 1H), 1.86 (d, J = 13.3Hz, 1H), 1.79 – 1.69 (m, 5H), 1.68 – 1.62 (m, 5H), 1.46 – 1.37 (m, 2H), 1.29(d, J = 10.0 Hz, 1H), 1.16 – 1.07 (m, 5H), 0.98 (q, J = 12.2 Hz, 2H). 13 C NMR(151 MHz, CDCl3) δ 141.1, 132.3, 132.2, 126.9, 77.5, 43.8, 40.7, 32.7, 28.8,28.6, 26.5, 26.1, 26.1, 26.0. HRMS (ESI) calcd. for [C 17 H 28 O, M+Na] + : 249.2214,found: 249.2213. [α] D 29 = +17.9 (c 0.29, CHCl3). HPLC analysis: The ee (74%)was determined using a Chiralpak ® IN column, hexane / 2-propanol = 99:1, flowrate = 0.5 mL / min, 230 nm UV detector, t R (minor) = 23.33 min, t R (major) =20.20 min.

Claims

1. A chiral monophosphine ligand, characterized in that, The structural formula is as follows: ， Among them, R 1 It is aryl; R 2 It is an alkyl, aryl, or substituted aryl group; R 3 It can be alkoxy, phenoloxy, aryl, or alkyl.

2. The chiral monophosphine ligand according to claim 1, characterized in that: For R 1 The aryl group is a substituted phenyl or naphthyl group, wherein the substituted phenyl group is 3,5-dimethylphenyl, o-methylphenyl, or 3,5-dimethoxyphenyl; For R 2 The alkyl group is cycloalkyl, benzyl, or neopentyl, wherein the cycloalkyl group is cyclopentyl, cyclohexyl, or cycloheptyl; the aryl group is naphthyl; and the substituted aryl group is 3,5-di-tert-butylphenyl, 3,5-di-tert-butyl-4-methoxyphenyl, 2,4,6-trimethylphenyl, or p-tert-butylphenyl. For R 3 The alkoxy group is isopropoxy, methoxy, or (S)-1-phenylethoxy; the alkyl group is isopropyl, cycloalkyl, or benzyl, wherein the cycloalkyl group is cyclobutyl, cyclopentyl, or cyclohexyl; and the aryl group is a substituted phenyl group.

3. The chiral monophosphine ligand according to claim 2, characterized in that: For R 1 The aryl group is phenyl; For R 2 The substituted aryl group is 3,5-di-tert-butylphenyl or 3,5-di-tert-butyl-4-methoxyphenyl; For R 3 The alkoxy group is (S)-1-phenylethoxy.

4. A method for preparing the chiral monophosphine ligand according to any one of claims 1-3, characterized in that, The steps are as follows: S1, In a nitrogen or argon atmosphere, at -80 to -70°C, N,N',1,2-tetrasubstituted ethane-1,2-diamine compounds, phosphorus trichloride, triethylamine and solvent are mixed, and the temperature is slowly raised to 60 to 80°C. The reaction is carried out for 6 to 8 hours to obtain the intermediate. S2, the reaction mixture containing the intermediate is cooled to room temperature, and then an alcohol, phenol or Grignard reagent is added dropwise. The temperature is slowly raised to 60-80°C and reacted for 8-12 hours. The reaction mixture is then filtered through diatomaceous earth, the filtrate is concentrated under reduced pressure to remove the solvent, and the residue is purified by rapid column chromatography to obtain the chiral monophosphine ligand.

5. The preparation method according to claim 4, characterized in that: The N,N',1,2-tetrasubstituted ethane-1,2-diamine compounds are (1R,2R)-N¹,N²,1,2-tetraphenylethane-1,2-diamine, (1R,2R)-N1,N2-bis(3,5-di-tert-butylphenyl)-1,2-diphenylethane-1,2-diamine, and (1R,2R)-N1,N2-bis(3,5-di-tert-butyl-4-methoxyphenyl)-1,2-diphenylethane-1,2-diamine; The solvent is tetrahydrofuran, and the amount used is 10-15 ml for 1 mmol of N,N',1,2-tetrasubstituted ethane-1,2-diamine compounds. The alcohol is isopropanol or (S)-1-phenylethanol; The phenol is phenol; The Grignard reagent is an aryl Grignard reagent or an alkyl Grignard reagent; preferably, the aryl Grignard reagent is phenyl magnesium bromide, and the alkyl Grignard reagent is cyclohexyl magnesium bromide, isopropyl magnesium bromide, or benzyl magnesium bromide. The equivalent ratio of the diamine, phosphorus trichloride, triethylamine to the (alcohol, phenol or Grignard reagent) is 1:(1.1-1.3):(8.0-12.0):(1.0-2.0).

6. The application of the chiral monophosphine ligand according to claim 1 in the nickel-catalyzed asymmetric addition reaction of dienes to aldehydes, characterized in that, The method is as follows: ， Under an argon or nitrogen atmosphere and with stirring, a nickel catalyst, the chiral monophosphine ligand, solvent, diene, and aldehyde are added to a reaction flask. The mixture is stirred at a specified temperature for 12-15 hours. After the reaction is complete, the mixture is filtered through a short silica gel pad. The solvent is removed from the filtrate under reduced pressure. The residue is then separated by column chromatography to obtain the target product, wherein: In the structural formula of the aldehyde, R 4 The alkyl group is alkyl or aryl, preferably cycloalkyl, tert-butyl or phenylpropyl, and the aryl group is benzofuran-3-yl or p-fluorophenyl; more preferably, the cycloalkyl group is a C4-C7 cycloalkyl group. In the structural formula of the diene, R 5 The alkyl group is aryl or alkyl, preferably 6-methoxynaphthio-2-yl, benzothiophene-2-yl, 3,5-dimethylphenyl, 4-chloro-phenyl or 4-dimethylamino-phenyl, and the alkyl group is cyclohexyl; The nickel catalyst is Ni(COD)2 or Ni(tBustb)3; The solvent is a mixture of methanol and acetonitrile, with a volume ratio of (4~50):1; the amount of solvent used is 0.2-0.3 ml per 1 mmol aldehyde. The specified temperature is 25-30 °C.

7. The application according to claim 6, characterized in that, The chiral monophosphine ligand is: or , The amount of chiral monophosphine ligand used is 8–24 mol of the aldehyde.

8. The application according to claim 6, characterized in that, The chiral monophosphine ligand is L2.

9. The application according to claim 6, characterized in that: The amount of nickel catalyst used is 7 to 20 mol of the aldehyde.

10. The application according to claim 6, characterized in that: The amount of diene used is 1.5 equivalents of the aldehyde.

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