Ferrocene skeleton chiral bisphosphine compounds containing adamantyl phosphine and applications thereof

Abstract

The application discloses a diamond alkyl phosphine-containing ferrocene skeleton chiral bisphosphine compound and application thereof, and particularly discloses a compound of formula A, a preparation method thereof and application of the compound in catalyzing asymmetric substitution reaction. The compound provided by the application shows excellent stereoselectivity control effect.

Description

Technical Field

[0001] This invention relates to chiral bisphosphine compounds with adamantylphosphine-containing ferrocene framework and their applications. Background Technology

[0002] JosiPhos chiral ligands are a widely used and advantageous type of ligand with excellent performance in asymmetric transformations catalyzed by many transition metals, such as palladium, iridium, rhodium, and copper, and many have been commercialized. Topics in Catalysis , 2002, 19 , 1; Helv. Chim. Acta 2021, 104 (e2000192). The preparation of this type of ligand is relatively simple, and the steric hindrance and electronic properties of the substituents at different phosphorus atom centers can be independently controlled, thereby obtaining a variety of chiral ligands of this type.

[0003] However, most of the structures of these ligands currently use common aryl substitutions, with only a few reports of arylphosphine-adamantylphosphine-substituted JosiPhos ligands, which have not shown good reactivity in related transformations. Summary of the Invention

[0004] The technical problem this invention aims to solve is the insufficient variety of chiral bisphosphine ligands with a ferrocene framework and the limited stereoselectivity. This invention provides a chiral bisphosphine compound with a ferrocene framework containing adamantylphosphine and its applications. The compound provided by this invention exhibits excellent stereoselectivity control.

[0005] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0006] This invention provides a compound of formula A: ; Among them, R 1 C 1-6 Alkyl or C 3-10 cycloalkyl; R 2 It is an adamantyl group.

[0007] In some implementation schemes, R 1 C 1-6 alkyl.

[0008] In some implementation schemes, R 1 In, the C 1-6 The alkyl group is ethyl, n-propyl, isopropyl, tert-butyl, sec-butyl, or neopentyl, preferably tert-butyl.

[0009] In some implementation schemes, R 1 In, the C3-10 The cycloalkyl group is cyclopentyl, cyclohexyl, cyclooctyl or cycloheptyl, preferably cyclohexyl.

[0010] In some implementation schemes, R 2 In this context, the adamantyl group is 1-adamantyl.

[0011] In some implementation schemes, R 1 It is tert-butyl or cyclohexyl, preferably tert-butyl.

[0012] In some embodiments, the compound of formula A is a compound of formula A-1 or formula A-2: , ; Among them, R 1 and R 2 The definition is as described in any embodiment of this invention.

[0013] In some embodiments, the compound of formula A-1 is any of the following compounds: or , where Ad is 1-adamantyl.

[0014] In some embodiments, the compound of formula A-2 is any of the following compounds: or , where Ad is 1-adamantyl.

[0015] The present invention also provides a method for preparing compound A of the above formula, which includes the following steps: In the presence of a solvent, compound B undergoes a nucleophilic substitution reaction with compound III as shown below to give compound A; ; Among them, R 1 and R 2 The definition is as described in any embodiment of this invention.

[0016] In some embodiments, the compound of formula B is a compound of formula B-1 or formula B-2: , .

[0017] In some embodiments, the compound of formula B is a compound of formula B-1. The corresponding compound of formula A is compound of formula A-1. .

[0018] In some embodiments, the compound of formula B is a compound of formula B-2. The corresponding compound of formula A is compound of formula A-2. .

[0019] In some embodiments, the nucleophilic substitution reaction is carried out in a nitrogen atmosphere.

[0020] In some embodiments, the compound of formula III is bis(1-adamantyl)phosphine hydrogen.

[0021] In some embodiments, the molar ratio of the compound of formula III to the compound of formula B is (0.1-5):1, preferably (0.5-2):1, for example (1.4-1.6):1.

[0022] In some embodiments, the solvent is acetic anhydride or acetic acid.

[0023] In some embodiments, the molar volume ratio of the compound of formula B to the solvent is 0.1-5 mol / L, preferably 0.1-1.0 mol / L, and more preferably 0.45-0.75 mol / L.

[0024] In some embodiments, when the solvent is acetic anhydride, the reaction is further carried out in hexafluoroisopropanol, wherein the volume ratio of the acetic anhydride to the hexafluoroisopropanol is (1.5-2.5):1.

[0025] In some embodiments, the nucleophilic substitution reaction is carried out at a temperature of 50°C-110°C, for example, the nucleophilic substitution reaction is carried out first at 60°C and then at 100°C.

[0026] In some embodiments, the progress of the nucleophilic substitution reaction can be monitored using conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR), with the reaction endpoint typically defined as the disappearance of the starting material or the cessation of the reaction. The preferred reaction time for the nucleophilic substitution reaction is 12-13 hours.

[0027] In some embodiments, the reaction reactants consist of the following substances: the compound of formula B, the solvent, the compound of formula III, and the hexafluoroisopropanol; Alternatively, the compound of formula B, the solvent, and the compound of formula III.

[0028] In some embodiments, the method for preparing the compound of formula A further includes the following steps: In an organic solvent, in the presence of an alkyllithium reagent, compound I reacts with compound II as shown below to give compound B; .

[0029] In some embodiments, the compound of formula I is a compound of formula I-1 or formula I-2: , .

[0030] In some embodiments, the compound of formula I is a compound of formula I-1. The corresponding compound B is compound B-1. .

[0031] In some embodiments, the compound of formula I is a compound of formula I-1. The corresponding compound B is compound B-1. .

[0032] In some implementations, the reaction is carried out in a nitrogen atmosphere.

[0033] In some embodiments, the compound of formula II is t Bu2PCl or Cy2PCl, preferably t Bu2PCl.

[0034] In some embodiments, the compound of formula II is added in the form of a solution of compound of formula II, preferably in the form of a solution of compound of formula II in diethyl ether. The concentration of compound of formula II in the solution of compound of formula II is preferably 2 mol / L.

[0035] In some embodiments, the molar ratio of the compound of formula II to the compound of formula I is (0.1-5):1, preferably (0.5-2):1, for example 1:1.

[0036] In some embodiments, the organic solvent is an ether solvent, preferably diethyl ether.

[0037] In some embodiments, the molar volume ratio of the compound of formula I to the organic solvent is 0.05-3 mol / L, preferably 0.1-0.5 mol / L, for example 0.3 mol / L.

[0038] In some embodiments, the alkyllithium reagent is a butyllithium reagent, preferably sec-butyllithium.

[0039] In some embodiments, the alkyllithium reagent is added in the form of an alkyllithium solution, preferably in the form of an alkyllithium tetrahydrofuran solution. The concentration of the alkyllithium reagent in the alkyllithium solution is preferably 1.3 mol / L.

[0040] In some embodiments, the molar ratio of the alkyllithium reagent to the compound of formula I is (0.1-5):1, preferably (0.5-2):1, for example (1-1.5):1.

[0041] In some embodiments, the reaction temperature is -80°C to room temperature.

[0042] In some embodiments, the reaction progress can be detected using conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR), with the reaction endpoint generally defined as the disappearance of the starting material or the cessation of the reaction.

[0043] In some embodiments, the reactants consist of the following substances: the organic solvent, the compound of formula I, the alkyllithium reagent, and the compound of formula II.

[0044] The present invention also provides the application of compound A as described in any embodiment of the present invention in catalytic asymmetric substitution reactions.

[0045] In some embodiments, the asymmetric substitution reaction is an asymmetric propyne substitution reaction.

[0046] In some embodiments, the asymmetric propargyl substitution reaction includes the following steps: In an organic solvent, in the presence of a catalyst, a ligand, and a base, compound 4 undergoes a substitution reaction with dimethyl malonate to give compound 6. ; Among them, in compound formula 6, the label " The carbon atom in the symbol is a chiral carbon atom; R is C 1-12 Alkyl, C 6-14 Aryl, 4-10 membered heterocyclic alkyl, with one or more R a Replacement C 6-14 aryl, with one or more R b Substituted 4-10 membered heterocyclic alkyl groups or substituted with one or more R c Replacement C 1-12 alkyl; R a For CN, C 1-6 Haloalkyl, C 1-6 Alkoxy, , or ; R b -COOC 1-6 alkyl; R c C 6-14 Aryl, halogen, -OBn or ; R' is C 1-6 Alkyl or H; The ligand is either compound A-1 or compound A-2 as described above.

[0047] In some embodiments, the ligand is a compound of formula A-1. The corresponding compound of formula 6 is .

[0048] In some embodiments, the ligand is a compound of formula A-2. The corresponding compound of formula 6 is .

[0049] In some implementations, the ligand is or Preferred , where Ad is 1-adamantyl.

[0050] In some embodiments, the molar percentage of the Formula 4 compound to the ligand is 1.0-10.0 mol%, preferably 5.5 mol%.

[0051] In some embodiments, the organic solvent is a nitrile solvent, preferably acetonitrile.

[0052] In some embodiments, the molar volume ratio of the compound of Formula 4 to the organic solvent is (0.1-5) mol / L, preferably (0.8-1.2) mol / L, for example 1 mol / L.

[0053] In some embodiments, the catalyst is a palladium catalyst, preferably [Pd(allyl)Cl]2.

[0054] In some embodiments, the catalyst has a molar percentage of 1.0-10.0 mol% to the compound of Formula 4, preferably 2.5 mol%.

[0055] In some embodiments, the base is an organic aliphatic base, preferably triethylamine.

[0056] In some embodiments, the molar ratio of the base to the compound of formula 4 is (1-5):1, preferably 3:1.

[0057] In some embodiments, the molar ratio of the dimethyl malonate to the compound of formula 4 is (1-5):1, preferably 2:1.

[0058] In some embodiments, the substitution reaction is carried out under nitrogen protection.

[0059] In some embodiments, the substitution reaction is carried out at a temperature of room temperature to 80°C, for example, the substitution reaction is carried out first at -78°C and then at room temperature.

[0060] In some embodiments, the reaction progress of the substitution reaction can be monitored using conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR), generally with the disappearance of the starting material or the cessation of the reaction as the reaction endpoint. The preferred reaction time for the substitution reaction is 72-96 hours.

[0061] In some embodiments, the reaction raw materials for the substitution reaction consist of the organic solvent, the ligand, the catalyst, the base, the compound of formula 4, and dimethyl malonate.

[0062] In some implementations, R is phenyl, , , , , , , , , , , , , , or .

[0063] In some implementations, R' is methyl or H.

[0064] In some embodiments, the compound of formula 6 is any of the following compounds; , , , , , , , , , , , , , , or .

[0065] The present invention also provides a method for preparing a compound of formula 6, comprising the following steps: In an organic solvent, in the presence of a catalyst, a ligand, and a base, compound 4 undergoes a substitution reaction with dimethyl malonate to give compound 6. ; Among them, in compound formula 6, the label " The carbon atom in the symbol is a chiral carbon atom; The ligand is a compound of formula A-1 or a compound of formula A-2; The definitions of R and R', as well as the reaction conditions and operations, are as described in any embodiment of the present invention.

[0066] In this invention, "room temperature" refers to 15-35℃.

[0067] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0068] The reagents and raw materials used in this invention are all commercially available.

[0069] The significant advantages of this invention are as follows: the value and benefits of the ferrocene-based chiral bisphosphine compound containing adamantylphosphine have been demonstrated through its application in previously unreported non-classical propargyl substitution reactions, exhibiting significantly superior stereoselectivity control compared to known commercial ligands. This compound is simple to synthesize, easy to prepare, and holds promise for applications in a wider range of asymmetric catalytic transformations. Detailed Implementation

[0070] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0071] Example 1: Synthesis of ligand Cy-AJPhos

[0072] Under nitrogen protection, add ( S Ugi's amine 1 (0.78 g, 3.0 mmol), dry diethyl ether (10 mL), and the reaction was carried out at -78°C. Then, the following was added dropwise to the reaction mixture. sBuLi (1.3 M in THF, 2.3 mL, 3.0 mmol). The reaction was then carried out at -78°C for half an hour, followed by reaction at room temperature for 1 hour. The reaction solution was then placed at -78°C, and Cy2PCl (2.0 M in Et2O, 1.5 mL) was added. The mixture was stirred overnight at room temperature. Afterward, saturated ammonium chloride aqueous solution (20 mL) was added, followed by extraction with ethyl acetate (15 mL × 3), washing with brine, drying over anhydrous sodium sulfate, filtration, concentration, and column chromatography to obtain intermediate 2 in 50% yield. In a separate 50 mL Shrek tube, under nitrogen protection, intermediate 2 (0.68 g, 1.5 mmol), acetic acid (2.0 mL), and bis(1-adamantyl)phosphine hydrogen (0.50 g, 2.3 mmol) were added. The reaction was carried out at 100°C for 12 hours. The reaction was then quenched with saturated NaHCO3 aqueous solution until the pH of the reaction solution was > 7. Next, the compound was extracted with ethyl acetate (15 mL × 3), washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography. The obtained compound was then recrystallized from ethanol / toluene to obtain the high-purity chiral ligand Cy-AJPhos.

[0073] Orange solid, 18% yield. [α] D 25 +104.3 (c 0.2, CHCl3). 1 H NMR (400 MHz, CDCl3)δ 4.42 (s, 1H), 4.20 (s, 1H), 4.15 - 4.07 (m, 6H), 3.34 - 3.15 (m, 1H), 2.39- 2.27 (m, 2H), 2.06 - 1.12 (m, 55H). 31 P NMR (162 MHz, CDCl3) δ 98.3 (d, J =12.2 Hz), 37.3 (d, J = 12.2 Hz). 13 C NMR (126 MHz, CDCl3) δ 102.3 (t, J = 22.3Hz), 78.2 (dd, J = 21.1, 3.3 Hz), 70.7 (dd, J = 7.1, 3.7 Hz), 70.1 (d, J =4.0 Hz), 69.5, 66.9, 42.4 (d, J = 11.6 Hz), 42.3 (d,J = 11.1 Hz), 39.3 (d, J = 34.6 Hz), 38.5 (d, J = 29.9 Hz), 37.2 (d, J = 2.7 Hz), 36.8 (d, J = 12.5Hz), 36.7 (d, J = 12.6 Hz), 35.9 (d, J = 13.5 Hz), 33.6 (d, J = 23.0 Hz), 32.0 (dd, J = 15.7, 2.8 Hz), 31.0 (d, J = 6.2 Hz), 29.5 (d, J = 6.5 Hz), 29.1(d, J = 8.3 Hz), 29.0 (d, J = 8.5 Hz), 28.3 (d, J = 14.4 Hz), 28.1 (d, J =12.5 Hz), 28.0 (d, J = 6.9 Hz), 27.8 (dd, J = 26.5, 6.6 Hz), 26.7 (d, J =21.9 Hz), 21.2 (d, J = 2.9 Hz). HRMS (ESI): [M+H] + C 44 H 65 P2Fe + Calculated value: 711.3906; Measured value: 711.3898.

[0074] Example 2: Ligand t Synthesis of Bu-AJPhos

[0075] Under nitrogen protection, add ( S Ugi's amine 1 (3.1 g, 12 mmol), dry diethyl ether (40 mL), and the reaction was carried out at -78°C. Then, the following solution was added dropwise to the reaction mixture. sBuLi (1.3 M in THF, 14 mL, 18 mmol). The reaction was then carried out at -78°C for half an hour, followed by reaction at room temperature for 1 hour. The reaction solution was then placed at -78°C and [the following was added]... t Bu2PCl (2.0 M in Et2O, 6.0 mL). Stirring continued overnight at room temperature. Then, saturated ammonium chloride aqueous solution (20 mL) was added, followed by extraction with ethyl acetate (15 mL × 3), washing with brine, drying to anhydrous sodium sulfate, filtration, concentration, and column chromatography to obtain intermediate 3 in 53% yield. In a separate 50 mL Shrek tube, 3 (2.6 g, 6.4 mmol) and acetic anhydride (13 mL) were added under nitrogen protection, and the reaction was carried out at 60 °C for 1 hour. The reaction was then quenched with saturated NaHCO3 aqueous solution until the pH of the reaction solution was > 7. Extraction was then carried out with ethyl acetate (15 mL × 3), washing with brine, drying to anhydrous sodium sulfate, filtration, concentration, and column chromatography. The obtained compound was dissolved in hexafluoroisopropanol (7.0 mL) under nitrogen protection, and bis(1-adamantyl)phosphine hydrogen (1.7 g, 5.6 mmol) was added. The reaction was carried out at 100 °C for 12 hours. The reaction solution was concentrated and subjected to column chromatography. The resulting compound was then recrystallized from ethanol / toluene to obtain high-purity chiral ligands. t Bu-AJPhos.

[0076] Orange solid, 29% yield. [α] D 25 +189.1 (c 0.2, CHCl3). 1 H NMR (400 MHz, CDCl3)δ 4.72 (t, J = 3.0 Hz, 1H), 4.33 (t, J = 2.6 Hz, 1H), 4.25 - 4.22 (m, 1H), 4.16 (s, 5H), 3.18 - 3.10 (m, 1H), 2.23 - 2.18 (m, 6H), 2.05 - 1.94 (m, 15H), 1.84 - 1.71 (m, 12H), 1.50 (d, J = 12.0 Hz, 9H), 0.92 (d, J = 11.2 Hz, 9H). 13 C NMR (126 MHz, CDCl3) δ 106.4 (t, J = 26.5 Hz), 77.0 (d, J = 5.0 Hz), 72.0 (dd,J = 16.0, 4.5 Hz), 71.3 (d, J = 5.4 Hz), 69.8, 67.6, 42.4 (d, J = 11.8Hz), 42.3 (d, J = 10.9 Hz), 38.6 (d, J = 24.8 Hz), 38.2 (d, J = 32.1 Hz), 37.2 (d, J = 18.8 Hz), 33.1 (d, J = 22.1 Hz), 31.7 (d, J = 20.4 Hz), 30.8 (dd, J = 13.8, 2.0 Hz), 30.6 (d, J = 14.8 Hz), 29.1 (d, J = 7.9 Hz), 28.9 (d, J = 7.9 Hz), 26.2 (dd, J = 30.7, 12.8 Hz), 25.0 (dd, J = 5.3, 2.5 Hz). 31 P NMR (162 MHz, CDCl3) δ 44.6 (d, J = 10.7 Hz, 1P), 12.7 (d, J = 10.7 Hz, 1P). HRMS(ESI): [M+H] + C 40 H 61 P2Fe + Calculated value: 659.3593; Measured value: 659.3585.

[0077] Application Example 1: Non-classical asymmetric propargyl substitution

[0078] (1) Preparation of compound 4

[0079] Under nitrogen protection, 7 (5.0 mmol) was added to a Shrek tube, and 10 mL of dried tetrahydrofuran was added. The reaction was then placed at -78°C. LiHMDS (1.0 M in THF, 5.0 mL, 5.0 mmol) was then added dropwise to the reaction mixture. The reaction was then placed at -78°C for half an hour, followed by the addition of 8 (6.0 mmol). The reaction was continued at -78°C for three hours. Afterward, the mixture was quenched with saturated ammonium chloride aqueous solution (5.0 mL), extracted with ethyl acetate (15 mL × 3), washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain intermediate 9. In a separate 50 mL reaction flask, 9 (4.0 mmol), DMAP (0.45 g, 4.0 mmol), triethylamine (0.50 g, 5.0 mmol), and 10 mL of tetrahydrofuran were added, followed by the dropwise addition of (Boc)₂O (5.0 mmol). The reaction was then carried out at room temperature for 6 hours, followed by column chromatography to obtain pure compound 4.

[0080] Compound 4a: Known substance ( ACS Catal. 2024, 14 , 574–584)

[0081] Compound 4b: white solid, 47% yield, >95% purity. 1 H NMR (400 MHz, CDCl3) δ 7.58(d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 1.77 (s, 6H), 1.50 (s, 9H). 13 CNMR (101 MHz, CDCl3) δ 151.4, 132.3, 132.0, 127.7, 118.5, 111.8, 94.5, 82.7,82.4, 73.4, 28.8, 27.9. HRMS (ESI): [M+Na] + C 17 H 19 NO3Na + Calculated value: 308.1257; Measured value: 308.1257.

[0082] Compound 4c: white solid, 58% yield, >95% purity. 1 H NMR (400 MHz, CDCl3) δ 7.57– 7.50 (m, 4H), 1.78 (s, 6H), 1.51 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 151.4,132.0, 130.2 (q, J = 32.6 Hz), 126.6, 125.2 (q, J = 3.9 Hz), 92.5, 82.9,82.3, 73.6, 28.9, 27.9. 19 F NMR (376 MHz, CDCl3) δ -62.95 (s, 3F). HRMS (ESI): [M+Na] + C 17 H 19 O3F3Na + Calculated value: 351.1179; Measured value: 351.1184.

[0083] Compound 4d: Yellow oil, 62% yield, >95% purity. 1 H NMR (400 MHz, CDCl3) δ 7.38- 7.33 (m, 2H), 6.83 - 6.79 (m, 2H), 3.80 (s, 3H), 1.77 (s, 6H), 1.50 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 159.7, 151.5, 133.3, 114.8, 113.9, 88.6, 84.1,82.0, 74.2, 55.3, 29.2, 27.9. HRMS (FI): [M] + C 17 H 22 O4 + Calculated value: 290.1513; Measured value: 290.1509.

[0084] Compound 4e: colorless oil, 25% yield, >95% purity. 1 H NMR (400 MHz, CDCl3) δ 7.30- 7.26 (m, 2H), 7.21 - 7.17 (m, 3H), 2.72 (t, J = 7.5 Hz, 2H), 2.22 (t, J =6.9 Hz, 2H), 1.84 - 1.78 (m, 2H), 1.68 (s, 6H), 1.49 (s, 9H). 13C NMR (101MHz, CDCl3) δ 151.5, 141.8, 128.7, 128.4, 125.9, 84.4, 81.85, 81.83, 73.9,34.6, 30.2, 29.4, 27.9, 18.1. HRMS (FI): [M] + C 19 H 26 O3 + Calculated value: 302.1876; Measured value: 302.1871.

[0085] Compound 4f: colorless oil, 82% yield, >95% purity. 1 H NMR (500 MHz, CDCl3) δ 3.65(t, J = 6.4 Hz, 2H), 2.39 (t, J = 6.7 Hz, 2H), 1.97 - 1.88 (m, 2H), 1.64 (s, 6H), 1.47 (s, 9H). 13 C NMR (126 MHz, CDCl3) δ 151.5, 82.8, 82.3, 81.9, 73.7,43.6, 31.3, 29.2, 27.9, 16.2. HRMS (ESI): [M+Na] + C 13 H 21 O3ClNa + Calculated value: 283.1071; Measured value: 283.1074.

[0086] Compound 4g: colorless oil, 58% yield, >95% purity. 1 H NMR (500 MHz, CDCl3) δ 3.85- 3.77 (m, 2H), 3.50 - 3.42 (m, 2H), 2.67 - 2.58 (m, 1H), 1.79 - 1.70 (m,2H), 1.61 (s, 6H), 1.60 - 1.52 (m, 2H), 1.43 (s, 9H). 13 C NMR (126 MHz, CDCl3)δ 151.3, 86.6, 82.5, 81.7, 73.7, 65.9, 31.9, 29.2, 27.8, 25.7. HRMS (ESI): [M+Na] + C 15 H24 O4Na + Calculated value: 291.1567; Measured value: 291.1569.

[0087] Compound 4h: colorless oil, 87% yield, >95% purity. 1 H NMR (500 MHz, CDCl3) δ 3.98(t, J = 8.5 Hz, 2H), 3.75 (dd, J = 8.2, 6.3 Hz, 2H), 3.26 - 3.17 (m, 1H), 1.53 (s, 6H), 1.36 (s, 9H), 1.30 (s, 9H). 13 C NMR (126 MHz, CDCl3) δ 155.7,151.2, 84.1, 84.0, 81.7, 79.4, 73.2, 28.8, 28.2, 27.6, 19.0. HRMS (ESI): [M+Na] + C 18 H 29 NO5Na + Calculated value: 362.1937; Measured value: 362.1943.

[0088] Compound 4i: white solid, 86% yield, >95% purity. 1 H NMR (400 MHz, CDCl3) δ 8.11(d, J = 2.3 Hz, 1H), 8.02 (dd, J = 8.9, 2.3 Hz, 1H), 6.97 (d, J = 8.9 Hz, 1H), 4.34 (t, J = 6.2 Hz, 2H), 3.86 (d, J = 6.5 Hz, 2H), 2.70 (s, 3H), 2.36(t, J = 6.9 Hz, 2H), 2.21 - 2.08 (m, 1H), 1.98 - 1.85 (m, 2H), 1.62 (s, 6H), 1.44 (s, 9H), 1.04 (d, J = 6.7 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 167.1,162.4, 161.8, 161.1, 151.3, 132.5, 131.9, 125.9, 121.6, 115.3, 112.6, 102.8,82.9, 82.1, 81.8, 75.6, 73.6, 63.8, 29.1, 28.1, 27.8, 27.6, 19.0, 17.4, 15.5.HRMS (ESI): [M+H] + C 29 H 37 O6N2S + Calculated value: 541.2367; Measured value: 541.2373.

[0089] Compound 4j: colorless oil, 81% yield, >95% purity. 1 H NMR (400 MHz, CDCl3) δ 7.40(d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 6.99 (d, J = 7.4 Hz, 1H), 6.65(d, J = 7.6 Hz, 1H), 6.59 (s, 1H), 5.08 (s, 2H), 3.88 (t, J = 5.5 Hz, 2H),2.30 (s, 3H), 2.15 (s, 3H), 1.77 (s, 6H), 1.75 - 1.66 (m, 4H), 1.50 (s, 9H),1.23 (s, 6H). 13 C NMR (126 MHz, CDCl3) δ 177.5, 156.9, 151.4, 136.5, 136.5,131.9, 130.3, 127.7, 123.6, 122.5, 120.7, 111.9, 90.4, 83.8, 82.1, 73.9,67.9, 65.7, 42.2, 37.1, 29.0, 27.9, 25.20, 25.17, 21.5, 15.8. HRMS (ESI): [M+Na] + C 32 H 42 O6Na + Calculated value: 545.2874; Measured value: 545.2874.

[0090] Compound 4K: colorless oil, 82% yield, >95% purity. 1 H NMR (500 MHz, CDCl3) δ 7.64- 7.58 (m, 2H), 7.57 - 7.51 (m, 2H), 7.40 - 7.29 (m, 8H), 7.26 (d, J = 8.2Hz, 2H), 5.14 (s, 2H), 3.20 (t, J = 7.4 Hz, 2H), 2.97 (t, J = 7.4 Hz, 2H), 1.78 (s, 6H), 1.50 (s, 9H). 13 C NMR (126 MHz, CDCl3) δ 171.8, 161.6, 151.4,145.4, 136.0, 135.1, 132.4, 131.9, 128.9, 128.7, 128.6, 128.5, 128.1, 127.9,126.5, 122.6, 90.4, 83.7, 82.1, 73.8, 66.1, 31.1, 29.0, 27.8, 23.5. HRMS(ESI): [M+Na] + C 35 H 35 O6NNa + Calculated value: 588.2357; Measured value: 588.2363.

[0091] Compound 4l: white solid, 76% yield, >95% purity. 1 H NMR (500 MHz, CDCl3) δ 8.12(d, J = 2.4 Hz, 1H), 7.88 (dd, J = 7.7, 1.4 Hz, 1H), 7.57 - 7.54 (m, 1H), 7.49 - 7.46 (m, 1H), 7.42 - 7.39 (m, 3H), 7.36 (dd, J = 7.6, 1.3 Hz, 1H), 7.26 (dd, J = 7.9 (1.5 Hz, 2H), 7.02 (d, J =8.4 Hz, 1H), 5.18 (s, 2H), 5.11 (s, 2H), 3.69 (s, 2H), 1.78 (s, 6H), 1.51 (s, 9H). 13 C NMR (126 MHz, CDCl3) δ190.8, 171.2, 160.5, 151.4, 140.5, 136.4, 135.9, 135.5, 132.8, 132.5, 131.9,129.5, 129.3, 128.0, 127.9, 127.6, 125.1, 122.7, 121.1, 90.5, 83.7, 82.1,73.8, 73.6, 66.3, 40.2, 29.0, 27.9. HRMS (ESI): [M+Na] + C 33 H 32 O7Na + Calculated value: 563.2040; Measured value: 563.2042.

[0092] Compound 4M: colorless oil, 67% yield, >95% purity. 1 H NMR (400 MHz, CDCl3) δ 7.12(d, J = 8.8 Hz, 2H), 6.73 - 6.66 (m, 2H), 4.18 (t, J = 6.3 Hz, 2H), 2.11 (t, J = 6.9 Hz, 2H), 1.72 (p, J = 6.6 Hz, 2H), 1.57 (s, 6H), 1.50 (s, 6H), 1.40 (s, 9H). 13 C NMR (101Hz, CDCl3) δ 173.6, 154.0, 151.3, 129.0, 127.0, 120.1,82.7, 82.1, 81.6, 79.3, 73.4, 63.8, 29.0, 27.7, 27.3, 25.2, 15.1. HRMS (FI):[M] + C 23 H 31 ClO6 + Calculated value: 438.1609; Measured value: 438.1615.

[0093] Compound 4n: Yellow oil, 63% yield, >95% purity.1 H NMR (500 MHz, CDCl3) δ 7.38- 7.31 (m, 4H), 7.31 - 7.25 (m, 1H), 5.30 - 5.21 (m, 1H), 4.50 (s, 2H), 3.46(t, J = 6.6 Hz, 2H), 2.19 (td, J = 7.1, 1.9 Hz, 2H), 1.64 - 1.58 (m, 2H), 1.50 - 1.47 (m, 14H), 1.40 - 1.35 (m, 4H). 13 C NMR (126 MHz, CDCl3) δ 152.6,138.7, 128.4, 127.7, 127.5, 86.0, 82.4, 78.4, 72.9, 70.4, 63.8, 29.7, 28.6,28.4, 27.8, 25.7, 21.9, 18.7. HRMS (FI): [M] + C 22 H 32 O4 + Calculated value: 360.2295; Measured value: 360.2289.

[0094] Compound 4o: colorless oil, 67% yield, >95% purity. 1 H NMR (500 MHz, CDCl3) δ 5.24(qt, J = 6.6, 1.9 Hz, 1H), 2.18 (td, J = 7.1, 1.9 Hz, 2H), 1.49 - 1.47 (m,15H), 1.37 - 1.32 (m, 2H), 1.28 - 1.24 (m, 7H), 0.87 (t, J = 6.8 Hz, 3H). 13 CNMR (126 MHz, CDCl3) δ 152.7, 86.2, 82.4, 78.3, 63.8, 31.9, 29.2, 29.1, 28.8,28.5, 27.8, 22.7, 21.9, 18.7, 14.2. HRMS (FI): [M+H] + C 17 H 31 O3 + Calculated value: 283.2268; Measured value: 283.2266.

[0095] Compound 4p: colorless oil, 91% yield, >95% purity. 1 H NMR (400 MHz, CDCl3) δ 5.24(qt, J = 6.8, 2.0 Hz, 1H), 2.18 (td, J = 7.1, 2.1 Hz, 2H), 1.53 - 1.45 (m,15H), 1.35 - 1.22 (m, 15H), 0.87 (t, J = 6.5 Hz, 3H). 13 C NMR (126 MHz, CDCl3)δ 152.7, 86.2, 82.4, 78.3, 63.8, 32.0, 29.7, 29.6, 29.4, 29.2, 28.9, 28.5,27.8, 22.8, 21.9, 18.7, 14.2. HRMS (FI): [M+H] + C 20 H 37 O3 + Calculated value: 325.2737; Measured value: 325.2733.

[0096] (2) Asymmetric propargyl substitution reaction

[0097] In a nitrogen-protected glove box, [Pd(allyl)Cl]₂ (0.0025 mmol, 2.5 mol%), a chiral ligand, was added to a 4 mL reaction flask. t Bu-AJPhos or Cy-AJPhos (0.0055 mmol, 5.5 mol%) and MeCN (0.10 mL). After stirring at 80 °C for 10 min, add substrate 4 (0.10 mmol), dimethyl malonate 5 (26 mg, 0.20 mmol), and triethylamine. (42 μL, 0.30 mmol). The reaction was continued at room temperature with stirring for three days. After the reaction was completed, the reaction solution was directly concentrated and then subjected to rapid column chromatography (petroleum ether and ethyl acetate as eluents) to obtain the corresponding product 6. The substrates and structures of products 6a-6i are shown in Table 1.

[0098] Table 1

[0099] Compound 6a: Using ligands t Bu-AJPhos: Colorless oil, 96% yield, >20:1 ratio, >95% purity. [α] D 25 +209.9 ( c 0.9, CHCl3) for 95:5 er; 1 H NMR (400 MHz, CDCl3) δ 7.30 - 7.25 (m,2H), 7.23 - 7.14 (m, 3H), 6.12 (h, J = 3.1 Hz, 1H), 3.70 (s, 3H), 3.61 (dd, J = 8.8, 6.1 Hz, 1H), 3.42 (s, 3H), 2.82 - 2.70 (m, 1H), 2.67 - 2.56 (m, 1H), 1.86 (d, J = 2.9 Hz, 3H). 13 C10 NMR (101 MHz, CDCl3) δ 201.6, 169.6, 169.3, 135.0, 128.5, 127.0, 126.9, 101.6, 96.6, 52.7, 52.4, 50.1, 32.7, 19.3. HPLC analysis: Chiracel AD-H column; detection at 254 nm, 25 o C; i PrOH : n-hexane = 20 : 80; Flow rate = 1.0 mL / min; Retention time: 6.0 min. The ligand used was Cy-AJPhos: a colorless oil, 45% yield, >20:1 rr, >95% purity. [α] D 25 +209.9 (c 0.9, CHCl3) for 80:20 er. Compound 6b: colorless oil, 81% yield, >20:1 ratio, >95% purity. [α] D 25 +190.4 (c1.3, CHCl3) for 95:5 er. 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 6.13 (h, J = 3.1 Hz, 1H), 3.71 (s, 3H), 3.57 (dd, J= 8.9, 6.1 Hz, 1H), 3.44 (s, 3H), 2.81 - 2.60 (m, 2H), 1.87 (d, J = 2.8 Hz, 3H). 13 HRMS (ESI): [M+Na] + C 17 H 17 NO4Na + Calculated value: 322.1050; Measured value: 322.1053. HPLC analysis: Chiracel AD-H column; detection at 210 nm, 25 °C. o C; i PrOH : n-hexane = 5 : 95; Flow rate = 1.0 mL / min; Retention time: 19.4 min. Compound 6c: Yellow oil, 80% yield, >20:1 ratio, >95% purity. [α] D 25 +159.2 (c1.3, CHCl3) for 95:5 er. 1 H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 6.15 (q, J = 3.2 Hz, 1H), 3.71 (s, 3H), 3.59 (dd, J= 8.8, 6.2 Hz, 1H), 3.44 (s, 3H), 2.81 - 2.60 (m, 2H), 1.88 (d, J = 2.8 Hz,3H). 13C NMR (126 MHz, CDCl3) δ 202.7, 169.5, 169.2, 138.9, 128.8 (q, J = 32.5Hz), 126.9, 125.5 (q, J = 3.9 Hz), 102.5, 95.7, 52.8, 52.5, 50.0, 32.5, 19.1. 19 F NMR (376 MHz, chloroform-d) δ -10.27 (s, 1F). HRMS (ESI): [M+Na] + C 17 H 17 O4F3Na + Calculated value: 365.0971; Measured value: 365.0975. HPLC analysis: Chiracel AD-H column; detection at 210 nm, 25 °C. o C; i PrOH : n-hexane = 5 : 95; Flow rate = 1.0 mL / min; Retention time: 5.6 min. Compound 6d: colorless oil, 70% yield, >20:1 rr, >95% purity. [α] D 25 +155.8 (c1.2, CHCl3) for 92:8 er. 1 H NMR (500 MHz, CDCl3) δ 7.14 - 7.10 (m, 2H), 6.84 -6.81 (m, 2H), 6.10 - 6.06 (m, 1H), 3.79 (s, 3H), 3.70 (s, 3H), 3.61 (dd, J =8.9, 6.0 Hz, 1H), 3.43 (s, 3H), 2.78 - 2.72 (m, 1H), 2.63 - 2.57 (m, 1H), 1.84 (d, J = 2.9 Hz, 3H). 13 HRMS (FI): [M] + C 17 H 20 O5 +Calculated value: 304.1305; Measured value: 304.1310. HPLC analysis: Chiracel AD-H column; detection at 254 nm, 25 o C; i PrOH : n-hexane = 10 : 90; Flow rate = 1.0 mL / min; Retention time: 7.1 min. Compound 6e: colorless oil, 92% yield, >20:1 ratio, >95% purity. [α] D 25 +50.8 (c 1.3,CHCl3) for 94:6er; 1 H NMR (400 MHz, CDCl3) δ 7.30 - 7.25 (m, 2H), 7.20 - 7.16(m, 3H), 5.17 - 5.06 (m, 1H), 3.70 (s, 3H), 3.68 (s, 3H), 3.56 (t, J = 7.5Hz, 1H), 2.63 (t, J = 7.7 Hz, 2H), 2.58 - 2.50 (m, 2H), 1.99 - 1.93 (m, 2H), 1.72 (d, J = 2.8 Hz, 3H), 1.71 - 1.64 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ200.5, 169.7, 169.6, 142.4, 128.5, 128.3, 125.8, 97.2, 92.7, 52.6, 50.4,35.4, 32.6, 30.8, 28.8, 19.7. HRMS (FI): [M] + C 19 H 24 O4 + Calculated value: 316.1669; Measured value: 316.1666. HPLC analysis: Chiracel IG-3 column; detection at 210 nm, 25 °C. o C; i PrOH : n-hexane = 3 : 97; Flow rate = 1.0 mL / min; Retention time: 7.7 min. Compound 6f: Yellow oil, 90% yield, >20:1 ratio, >95% purity. [α] D 25 +52.1 (c 0.7,CHCl3) for 95:5 er.1 H NMR (500 MHz, CDCl3) δ 5.11 - 5.05 (m, 1H), 3.73 (d, J= 2.8 Hz, 6H), 3.57 - 3.53 (m, 3H), 2.55 - 2.49 (m, 2H), 2.07 (q, J = 7.2 Hz, 2H), 1.86 - 1.80 (m, 2H), 1.71 (d, J = 2.9 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ200.7, 169.7, 169.6, 97.9, 91.5, 52.7, 52.7, 50.4, 44.5, 32.5, 31.7, 26.4,19.6. HRMS (ESI): [M+Na] + C 13 H 19 O4ClNa + Calculated value: 297.0864; Measured value: 297.0868. HPLC analysis: Chiracel OD-H column; detection at 210 nm, 25 °C. o C; i PrOH : n-hexane = 1 : 99; Flow rate = 1.0 mL / min; Retention time: 11.0 min. Compound 6g: Yellow oil, 83% yield, >20:1 ratio, >95% purity. [α] D 25 +58.4 (c 0.5,CHCl3) for 91:9 er. 1 H NMR (400 MHz, CDCl3) δ 5.11 - 5.05 (m, 1H), 3.95 - 3.90(m, 2H), 3.72 (d, J = 2.5 Hz, 6H), 3.54 (t, J = 7.5 Hz, 1H), 3.42 - 3.35 (m,2H), 2.53 (dd, J = 7.4, 3.4 Hz, 2H), 2.16 - 2.08 (m, 1H), 1.71 (d, J = 2.9Hz, 3H), 1.63 - 1.57 (m, 2H), 1.43 - 1.33 (m, 2H). 13C NMR (101 MHz, CDCl3) δ199.3, 169.63, 169.58, 98.9, 97.8, 67.7, 52.7, 52.6, 50.4, 34.8, 32.60,32.58, 32.5, 19.8. HRMS (ESI): [M+Na] + C 15 H 22 O5Na + Calculated value: 305.1359; Measured value: 305.1358. HPLC analysis: Chiracel OD-H column; detection at 210 nm, 25 °C. o C; i PrOH : n-hexane = 1 : 99; Flow rate = 1.0 mL / min; Retention time: 18.8 min. Compound 6h: Yellow oil, 61% yield, >20:1 rr, >95% purity. [α] D 25 +42.4 (c 1.1,CHCl3) for 95:5 er. 1 H NMR (500 MHz, CDCl3) δ 5.28 - 5.23 (m, 1H), 4.05 - 3.99(m, 2H), 3.71 (d, J = 4.6 Hz, 6H), 3.65 (dd, J = 8.5, 5.9 Hz, 2H), 3.50 (t, J= 7.5 Hz, 1H), 3.04 - 2.97 (m, 1H), 2.54 (dd, J = 7.6, 3.3 Hz, 2H), 1.72 (d,J = 2.8 Hz, 3H), 1.41 (s, 9H). 13 C NMR (126 MHz, CDCl3) δ 199.9, 169.5, 169.3,156.4, 99.9, 94.6, 79.4, 52.66, 52.65, 50.3, 32.4, 28.4, 28.2, 19.5. HRMS(ESI): [M+Na] + C 18 H 27 NO6Na + Calculated value: 376.1730; Measured value: 376.1729. HPLC analysis: Chiracel OD-H column; detection at 210 nm, 25 °C. o C;i PrOH : n-hexane = 5 : 95; Flow rate = 1.0 mL / min; Retention time: 10.0 min. Compound 6i: Yellow oil, 96% yield, >20:1 ratio, >95% purity. [α] D 25 +26.8 (c 1.8,CHCl3) for 95:5 er. 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 2.3 Hz, 1H), 8.08 (dd, J = 8.8, 2.3 Hz, 1H), 7.00 (d, J = 8.9 Hz, 1H), 5.16 - 5.09 (m, 1H), 4.31 (t, J = 6.5 Hz, 2H), 3.89 (d, J = 6.5 Hz, 2H), 3.72 (s, 6H), 3.55 (t, J= 7.6 Hz, 1H), 2.75 (s, 3H), 2.57 - 2.50 (m, 2H), 2.23 - 2.16 (m, 1H), 2.06(q, J = 7.1 Hz, 2H), 1.86 - 1.77 (m, 2H), 1.71 (d, J = 2.9 Hz, 3H), 1.08 (d,J = 6.7 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 200.6, 169.6, 169.5, 167.3, 162.5,162.1, 161.2, 132.6, 132.1, 126.0, 121.8, 115.4, 112.7, 103.0, 98.0, 91.8,75.7, 64.7, 52.6, 50.4, 32.5, 28.2, 28.0, 25.7, 19.6, 19.1, 17.5. HRMS (ESI):[M+Na] + C 29 H 34 N2O7NaS + Calculated value: 577.1979; Measured value: 577.1970. HPLC analysis: Chiracel AD-H column; detection at 254 nm, 25 o C; iPrOH : n-hexane = 10 : 90; Flow rate = 1.0 mL / min; Retention time: 23.6 min. Compound 6j: Yellow oil, 81% yield, >20:1 ratio, >95% purity. [α] D 25 +105.7 (c1.8, CHCl3) for 94:6 er. 1 H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 8.2 Hz, 2H), 7.00 (d, J = 7.4 Hz, 1H), 6.66 (d, J = 8.3 Hz, 1H), 6.60 (s, 1H), 6.12 (h, J = 3.1 Hz, 1H), 5.07 (s, 2H), 3.91 - 3.87 (m, 2H), 3.71 (s, 3H), 3.61 (dd, J = 8.7, 6.2 Hz, 1H), 3.43 (s, 3H), 2.80 - 2.73 (m,1H), 2.67 - 2.59 (m,1H), 2.31 (s, 3H), 2.16 (s, 3H), 1.86 (d, J = 2.8 Hz,3H), 1.75 - 1.71 (m, 4H), 1.23 (s, 6H). 13 C NMR (126 MHz, CDCl3) δ 201.8,177.6, 169.6, 169.3, 157.0, 136.5, 135.0, 134.9, 130.3, 128.2, 126.9, 123.6,120.7, 111.9, 101.8, 96.2, 67.9, 66.0, 52.7, 52.4, 50.1, 42.2, 37.1, 32.6,25.20, 25.19, 21.5, 19.2, 15.8. HRMS (ESI): [M+Na] + C 32 H 40 O7Na + Calculated value: 559.2666; Measured value: 559.2672. HPLC analysis: Chiracel AD-H + ​​AD-H column; detection at 210 nm, 25 °C. o C; iPrOH : n-hexane = 5 : 95; Flow rate = 1.0 mL / min; Retention time: 24.3 min. Compound 6K: Yellow oil, 79% yield, >20:1 rr, >95% purity. [α] D 25 +103.3 (c2.1, CHCl3) for 94:6 er. 1 H NMR (400 MHz, CDCl3) δ 7.64 - 7.60 (m, 2H), 7.57 -7.54 (m, 2H), 7.38 - 7.31 (m, 6H), 7.26 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.1Hz, 2H), 6.10 (h, J = 3.1 Hz, 1H), 5.13 (s, 2H), 3.70 (s, 3H), 3.59 (dd, J =8.5, 6.3 Hz, 1H), 3.45 (s, 3H), 3.20 (t, J = 7.4 Hz, 2H), 2.96 (t, J = 7.4Hz, 2H), 2.80 - 2.72 (m, 1H), 2.66 - 2.58 (m, 1H), 1.85 (d, J = 2.9 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 201.9, 171.9, 169.6, 169.3, 161.7, 145.4, 135.13,135.09, 134.4, 132.5, 129.0, 128.7, 128.6, 128.50, 128.48, 128.1, 127.9,127.0, 126.5, 101.8, 96.2, 66.4, 52.7, 52.5, 50.1, 32.6, 31.2, 23.5, 19.2.HRMS (ESI): [M+Na] + C 35 H 33 NO7Na + Calculated value: 602.2149; Measured value: 602.2144. HPLC analysis: Chiracel OD-H + ​​OD-H column; detection at 250 nm, 25 o C; iPrOH : n-hexane = 20 : 80; Flow rate = 1.0 mL / min; Retention time: 26.1 min. Compound 6l: Yellow oil, 69% yield, >20:1 ratio, >95% purity. [α] D 25 +92.1 (c 2.0,CHCl3) for 94:6 er. 1 H NMR (500 MHz, CDCl3) δ 8.12 (d, J = 2.4 Hz, 1H), 7.89 (dd, J = 7.6, 1.4 Hz, 1H), 7.56 (td, J = 7.5, 1.4 Hz, 1H), 7.47 (td, J = 7.6,1.3 Hz, 1H), 7.42 (dd, J = 8.4, 2.4 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.26(d, J = 8.7 Hz, 2H), 7.21 - 7.17 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 6.12 (h,J = 3.1 Hz, 1H), 5.19 (s, 2H), 5.10 (s, 2H), 3.71 (s, 3H), 3.68 (s, 2H), 3.60 (dd, J = 8.6, 6.3 Hz, 1H), 3.44 (s, 3H), 2.79 - 2.71 (m, 1H), 2.66 - 2.59 (m,1H), 1.86 (d, J = 2.8 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 201.9, 190.9, 171.3,169.6, 169.3, 160.5, 140.5, 136.4, 135.6, 135.2, 134.3, 132.8, 132.6, HRMS (ESI): [M+Na] + C 33 H 30 O8Na +Calculated value: 577.1833; Measured value: 577.1831. HPLC analysis: Chiracel AD-H column; detection at 210 nm, 25 °C. o C; i PrOH : n-hexane = 20 : 80; Flow rate = 1.0 mL / min; Retention time: 37.3 min. Compound 6M: Yellow oil, 83% yield, >20:1 ratio, >95% purity. [α] D 25 +33.9 (c 1.5,CHCl3) for 95:5 er. 1 H NMR (400 MHz, CDCl3) δ 7.19 - 7.16 (m, 2H), 6.77 - 6.75(m, 2H), 5.07 - 5.00 (m, 1H), 4.16 (t, J = 6.5 Hz, 2H), 3.70 (d, J = 5.5 Hz, 6H), 3.52 (t, J = 7.5 Hz, 1H), 2.55 - 2.48 (m, 2H), 1.90 - 1.84 (m, 2H), 1.71- 1.64 (m, 5H), 1.57 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 200.5, 174.1, 169.6,169.5, 154.1, 129.2, 127.2, 120.3, 98.0, 91.7, 79.5, 65.0, 52.62, 52.61,50.4, 32.5, 27.7, 25.4, 25.3, 19.6. HRMS (FI): [M] + C 23 H 29 O7Cl + Calculated value: 452.1596, Measured value: 452.1603. HPLC analysis: Chiracel AD-H + ​​AD-H column; Detection at 210 nm, 25 °C. o C; i PrOH : n-hexane = 1 : 99; Flow rate = 1.0 mL / min; Retention time: 60.2 min. Compound 6n: Known compound (Nat. Commun. 2015, 10, 507), colorless oil, 80% yield, >95% purity. [α] D25 +39.7 (c 1.3, CHCl3). 1 H NMR (500 MHz, CDCl3) δ 7.37 - 7.31 (m,4H), 7.30 - 7.26 (m, 1H), 5.18 - 5.06 (m, 2H), 4.50 (s, 2H), 3.73 (s, 6H), 3.50 (t, J = 7.6 Hz, 1H), 3.46 (t, J = 6.6 Hz, 2H), 2.61 - 2.54 (m, 2H), 1.94 (qd, J = 6.8, 3.0 Hz, 2H), 1.63 - 1.60 (m, 2H), 1.41 - 1.31 (m, 6H). Compound 6o: Known compound (Org. Chem. Front. 2015, 2, 688), colorless oil, 62% yield, >20:1 rr, >95% purity. [α] D 25 +57.2 (c 0.5, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 5.21- 5.04 (m, 2H), 3.73 (s, 6H), 3.50 (t, J = 7.5 Hz, 1H), 2.62 - 2.52 (m, 2H), 1.94 (qd, J = 6.8, 3.0 Hz, 2H), 1.38 - 1.26 (m, 12H), 0.87 (t, J = 6.7 Hz, 3H). Compound 6p: Known (Eur. J. Org. Chem. 2015, 7, 1596), colorless oil, 79% yield, >20:1 rr, >95% purity. [α] D 25 +46.4 (c 1.5, CHCl3); 1 H NMR (400 MHz, CDCl3)δ 5.31 - 4.97 (m, 2H), 3.73 (s, 6H), 3.50 (t, J = 7.5 Hz, 1H), 2.66 - 2.52(m, 2H), 2.00 - 1.87 (m, 2H), 1.38 - 1.21 (m, 18H), 0.87 (t, J = 6.7 Hz, 3H).

Claims

1. A compound of formula A: ； in, R 1 C 1-6 Alkyl or C 3-10 cycloalkyl; R 2 It is an adamantyl group.

2. The compound of formula A as claimed in claim 1, characterized in that, R 1 C 1-6 alkyl.

3. The compound of formula A as described in claim 1, characterized in that, It meets one or more of the following conditions: (1) R 1 In, the C 1-6 The alkyl group is ethyl, n-propyl, isopropyl, tert-butyl, sec-butyl, or neopentyl, preferably tert-butyl; (2) R 1 In, the C 3-10 The cycloalkyl group is cyclopentyl, cyclohexyl, cyclooctyl or cycloheptyl, preferably cyclohexyl; (3) R 2 In this context, the adamantyl group is 1-adamantyl.

4. The compound of formula A according to any one of claims 1-3, characterized in that, The compound of formula A is a compound of formula A-1 or formula A-2: 、 ； Preferably, the compound of formula A-1 is any of the following compounds: or Where Ad is 1-adamantyl; The compound of formula A-2 is any of the following compounds: or , where Ad is 1-adamantyl.

5. A method for preparing compound A according to any one of claims 1-4, characterized in that, It includes the following steps: In the presence of a solvent, compound B undergoes a nucleophilic substitution reaction with compound III as shown below to give compound A; ； Preferably, the compound of formula B is a compound of formula B-1 or formula B-2: 、 。 6. The preparation method according to claim 5, characterized in that, It meets one or more of the following conditions: (1) The compound of formula B is a compound of formula B-1. The corresponding compound of formula A is compound of formula A-1. ; (2) The compound of formula B is compound of formula B-2. The corresponding compound of formula A is compound of formula A-2. ; (3) The nucleophilic substitution reaction is carried out in a nitrogen atmosphere; (4) The compound of formula III is bis(1-adamantyl)phosphine hydrogen; (5) The molar ratio of the compound of formula III to the compound of formula B is (0.1-5):1; (6) The solvent is acetic anhydride or acetic acid; (7) The molar volume ratio of the compound of formula B to the solvent is 0.1-5 mol / L; (8) The temperature for the nucleophilic substitution reaction is 50℃-110℃; (9) The reaction time for the nucleophilic substitution reaction is 12-13 h; Preferably, it satisfies one or more of the following conditions: (1) The molar ratio of the compound of formula III to the compound of formula B is (0.5-2):1; (2) The molar volume ratio of the compound of formula B to the solvent is 0.1-1.0 mol / L; (3) When the solvent is acetic anhydride, the reaction is also carried out in hexafluoroisopropanol, wherein the volume ratio of acetic anhydride to hexafluoroisopropanol is (1.5-2.5):1; (4) The nucleophilic substitution reaction is first carried out at 60°C and then at 100°C; More preferably, it satisfies one or two of the following conditions: (1) The molar ratio of the compound of formula III to the compound of formula B is (1.4-1.6):1; (2) The molar volume ratio of the compound of formula B to the solvent is 0.45-0.75 mol / L; More preferably, the reaction raw materials consist of the following substances: the compound of formula B, the solvent, the compound of formula III, and the hexafluoroisopropanol; Alternatively, the reaction reactants consist of the following substances: the compound of formula B, the solvent, and the compound of formula III.

7. The preparation method according to claim 5, characterized in that, It also includes the following steps: In an organic solvent, in the presence of an alkyllithium reagent, compound I reacts with compound II as shown below to give compound B; ； Preferably, the compound of formula I is a compound of formula I-1 or formula I-2: 、 。 8. The preparation method according to claim 7, characterized in that, It meets one or more of the following conditions: (1) The compound of formula I is a compound of formula I-1. The corresponding compound B is compound B-1. ; (2) The compound of formula I is a compound of formula I-1. The corresponding compound B is compound B-1. ; (3) The reaction is carried out in a nitrogen atmosphere; (4) The compound of formula II is t Bu2PCl or Cy2PCl; (5) The compound of formula II is added in the form of a solution of compound of formula II; (6) The molar ratio of the compound of formula II to the compound of formula I is (0.1-5):1; (7) The organic solvent is an ether solvent; (8) The molar volume ratio of the compound of formula I to the organic solvent is 0.05-3 mol / L; (9) The alkyllithium reagent is a butyllithium reagent; (10) The alkyllithium reagent is added in the form of an alkyllithium solution; (11) The molar ratio of the alkyllithium reagent to the compound of formula I is (0.1-5):1; (12) The reaction temperature is -80℃ to room temperature; Preferably, one or more of the following conditions are met: (1) The compound of formula II is t Bu2PCl; (2) The compound of formula II is added in the form of an ether solution of the compound of formula II; (3) The concentration of compound II in the solution of compound II is 2 mol / L; (4) The molar ratio of the compound of formula II to the compound of formula I is (0.5-2):1; (5) The organic solvent is diethyl ether; (6) The molar volume ratio of the compound of formula I to the organic solvent is 0.1-0.5 mol / L; (7) The alkyl lithium reagent is sec-butyllithium; (8) The alkyllithium reagent is added in the form of an alkyllithium tetrahydrofuran solution; (9) The concentration of the alkyllithium reagent in the alkyllithium solution is 1.3 mol / L; (10) The molar ratio of the alkyllithium reagent to the compound of formula I is (0.5-2):1; More preferably, it satisfies one or more of the following conditions: (1) The molar ratio of the compound of formula II to the compound of formula I is 1:1; (2) The molar volume ratio of the compound of formula I to the organic solvent is 0.3 mol / L; (3) The molar ratio of the alkyllithium reagent to the compound of formula I is (1-1.5):1; More preferably, the reactants consist of the following substances: the organic solvent, the compound of formula I, the alkyllithium reagent, and the compound of formula II.

9. The use of a compound of formula A as described in any one of claims 1-4 in a catalytic asymmetric substitution reaction; Preferably, the asymmetric substitution reaction is an asymmetric propyne substitution reaction; More preferably, the asymmetric propargyl substitution reaction includes the following steps: In an organic solvent, in the presence of a catalyst, a ligand, and a base, compound 4 undergoes a substitution reaction with dimethyl malonate to give compound 6. Among them, in compound formula 6, the label " The carbon atom in the symbol is a chiral carbon atom; R is C 1-12 Alkyl, C 6-14 Aryl, 4-10 membered heterocyclic alkyl, with one or more R a Replacement C 6-14 aryl, with one or more R b Substituted 4-10 membered heterocyclic alkyl groups or substituted with one or more R c Replacement C 1-12 alkyl; R a For CN, C 1-6 Haloalkyl, C 1-6 Alkoxy, , or ; R b -COOC 1-6 alkyl; R c C 6-14 Aryl, halogen, -OBn or ; R' is C 1-6 Alkyl or H; The ligand is a compound of formula A-1 or formula A-2 as described in claim 4.

10. The application as described in claim 9, characterized in that, The asymmetric propargyl substitution reaction satisfies one or more of the following conditions: (1) The ligand is a compound of formula A-1. The corresponding compound of formula 6 is ; (2) The ligand is a compound of formula A-2. The corresponding compound of formula 6 is ; (3) The ligand is or Where Ad is 1-adamantyl; (4) The molar percentage of the compound of formula 4 and the ligand is 1.0-10.0 mol% (5) The organic solvent is a nitrile solvent; (6) The molar volume ratio of the compound of formula 4 to the organic solvent is (0.1-5) mol / L; (7) The catalyst is a palladium catalyst; (8) The molar percentage of the catalyst to the compound of Formula 4 is 1.0-10.0 mol% (9) The base is an organic aliphatic base; (10) The molar ratio of the base to the compound of formula 4 is (1-5):1; (11) The molar ratio of the dimethyl malonate to the compound of formula 4 is (1-5):1; (12) The substitution reaction is carried out under nitrogen protection; (13) The reaction temperature of the substitution reaction is room temperature to 80°C; (14) The reaction time of the substitution reaction is 72-96 h; (15) R is phenyl, , , , , , , , , , , , , , or ; (16) R' is methyl or H; Preferably, the asymmetric propyne substitution reaction satisfies one or more of the following conditions: (1) The ligand is Where Ad is 1-adamantyl; (2) The molar percentage of the compound of Formula 4 to the ligand is 5.5 mol%; (3) The organic solvent is acetonitrile; (4) The molar volume ratio of the compound of formula 4 to the organic solvent is (0.8-1.2) mol / L; (5) The catalyst is [Pd(allyl)Cl]2; (6) The molar percentage of the catalyst to the compound of formula 4 is 2.5 mol% (7) The base is triethylamine; (8) The molar ratio of the base to the compound of formula 4 is 3:1; (9) The molar ratio of the dimethyl malonate to the compound of formula 4 is 2:1; (10) The substitution reaction is first carried out at -78°C and then at room temperature; (11) The compound of Formula 6 is any of the following compounds; , , , , , , , , , , , , , , or ; More preferably, the reaction raw materials for the substitution reaction consist of the following substances: the organic solvent, the ligand, the catalyst, the base, the compound of formula 4, and dimethyl malonate.

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