Method for synthesizing chiral morpholine from propargyl alcohol ester

Abstract

The invention discloses a method for synthesizing chiral morpholine from propargyl alcohol ester. Chiral morpholine is an important drug molecular skeleton and is widely applied to the aspects of analgesia, anesthesia, tumor resistance, heart treatment and the like as a drug active ingredient, but an efficient synthesis method is lacked. According to the method disclosed by the invention, under the regulation and control of arylboronic acid and a specific chiral ligand, propargyl alcohol ester and an affinity reagent react to obtain optically pure (87-97% ee) morpholine. The method has the characteristics that the catalyst and the ligand are wide in source, and the substrate is cheap and easy to obtain; the chiral morpholine has excellent enantioselectivity and good functional group compatibility, can be suitable for structural modification of bioactive molecules and intermediates, and is a simple and efficient asymmetric catalysis strategy for synthesizing chiral morpholine.

Description

Technical Field

[0001] This invention belongs to the fields of catalytic synthesis technology and fine chemical synthesis, and relates to a method for synthesizing chiral morpholine from propargyl esters. Background Technology

[0002] Chiral morpholines and their derivatives, with their unique molecular structures and physicochemical properties, have become indispensable backbones in medicinal chemistry and molecular design, playing a key role in the development of bioactive molecules and drugs. As active pharmaceutical ingredients, they have wide applications in analgesia, anesthesia, antitumor therapy, and cardiovascular disease treatment, and have also shown potential in the development of drugs for neurodegenerative diseases and anti-infectives. The efficient and green synthesis of optically pure morpholines from simple raw materials has always been a research hotspot in the field of organic synthesis, attracting widespread attention from chemists. Current research on chiral morpholines involves various strategies such as asymmetric catalysis and metal-mediated cyclization, but still has certain limitations. Currently, most methods for synthesizing chiral morpholines are limited to substrate-dependent enantioselectivity, resulting in poor substrate compatibility. Although the allyl metal intermediate route provides a new approach to controlling the chirality of morpholines, its substrate applicability is mostly limited to simple chain alkenes, making it difficult to apply to the construction of complex molecules with multiple functional groups. This restricts its potential for widespread application in innovative drug design and faces challenges such as enantioselectivity instability.

[0003] Transition metal-catalyzed asymmetric substitution reactions of propargyl esters are a powerful tool for synthesizing chiral molecules and have gained widespread favor among chemists in recent years, leading to a series of reaction modes such as asymmetric propargylation, allenylation, and alkenylation. However, compared to the well-developed asymmetric propargylation and allenylation, research on asymmetric alkenylation reactions is relatively scarce, presenting more challenges related to regio, chemo, and stereoselectivity. Existing asymmetric alkenylation strategies have successfully achieved the construction of a series of chiral cyclic allyl molecules; however, the synthesis of acyclic molecules is limited to racemic modes. Therefore, developing novel asymmetric alkenylation strategies for propargyl esters to achieve the synthesis of acyclic chiral allyl compounds and applying them to the efficient and asymmetric construction of chiral morpholines is of great practical significance. This could both expand the reaction mode for propargyl ester alkenylation and develop a new, efficient, and green process for the synthesis of chiral morpholines. The method uses readily available and simple raw materials such as nucleophiles and arylboronic acids, and the required palladium catalysts, ligands, and solvents are widely available and inexpensive. It exhibits excellent enantioselectivity and good functional group compatibility, making it suitable for the structural modification of bioactive molecules and intermediates. It is a simple and efficient asymmetric catalytic strategy for the synthesis of chiral morpholines. Summary of the Invention

[0004] To address the problems existing in the prior art, this invention provides a method for synthesizing chiral morpholines from propargyl esters. This method, through the use of suitable chiral ligands and arylboronic acids, provides a revolutionary pathway for the efficient and selective construction of chiral morpholine skeletons by regio, stereo, and chemiselectivity of internally aliphatic-substituted propargyl esters and nucleophiles. It is not only the first time that the asymmetric alkenylation of propargyl esters to construct acyclic chiral allyl compounds has been achieved, but also the first time that the efficient and rapid conversion of propargyl esters to chiral morpholines has been accomplished. In summary, this invention provides a transition metal-catalyzed asymmetric catalytic mode at unconventional sites for propargyl esters, establishing an efficient, concise, and highly selective catalytic synthesis system for constructing chiral morpholine skeletons.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0006] A method for synthesizing chiral morpholine from propargyl esters, in a solvent, using propargyl esters As a reaction substrate, transition metal palladium (Pd) with a chiral ligand was used in a boronic acid catalytic system and a nucleophile. The reaction proceeds to yield the chiral morpholine product. , where R 1 With R 2 Independently representing alkyl or aryl, OR 3 R represents an ester group. 4 The ligand represents an aryl group, and the chiral ligand represents a chiral phosphine ligand.

[0007] The general formula for the reaction is as follows:

[0008] .

[0009] Preferably, each alkyl substituent is independently selected from hydrogen, C1-C20 alkyl, C1-C20 haloalkyl, C1-C20 alkylcarbonyl, nitro, hydroxyl, ester, alkenyl, ether, amide, silyl, mercapto, amino, or cyano; the aryl group represents a substituent on the benzene ring that is substituted or unsubstituted with C1-C20 alkyl, C1-C20 haloalkyl, C1-C20 alkylcarbonyl, nitro, hydroxyl, ester, alkenyl, ether, amide, silyl, mercapto, amino, or cyano, or biphenyl, naphthyl, anthracene, or a heteroaryl group containing five to thirteen rings of N, O, or S.

[0010] Preferably, OR 3 It is selected from one or more of alkyl sulfonates, aryl sulfonates, amino sulfonates, alkyl carboxylates, aryl carboxylates, amino carboxylates, alkoxy carboxylates, aryloxy carboxylates, alkyl phosphates, aryl phosphates, and arylalkyl phosphates.

[0011] Preferably, R 4 The substituents on the benzene ring are selected from C1-C20 alkyl, C1-C20 halosubstituted alkyl, C1-C20 alkyl carbonyl, nitro, hydroxyl, ester, alkenyl, ether, amide, silyl, mercapto, amino, or cyano-substituted or unsubstituted biphenyl, naphthyl, anthracene, and heteroaryl groups containing N, O, or S in five to thirteen rings.

[0012] Preferably, the chiral ligand includes bidentate chiral N ligands, bidentate chiral P ligands, bidentate chiral NP ligands, monodentate chiral N ligands, monodentate chiral phosphine ligands, tridentate chiral NPN ligands, tridentate chiral NSP ligands, and tridentate chiral N ligands. The types include chiral oxazoline ligands, chiral diamine ligands, chiral monodentate phosphine ligands, chiral phosphorous amide ligands, chiral biphenyl bidentate phosphine ligands, chiral spirocyclic bidentate phosphine ligands, chiral binatidine bidentate phosphine ligands, or chiral sulfinamide-substituted phosphine ligands.

[0013] More preferably, the chiral ligand is a chiral phosphoramidite ligand, a chiral biphenyl bidentate phosphine ligand, a chiral spirocyclic bidentate phosphine ligand, or a chiral binatate bidentate phosphine ligand.

[0014] More preferably, the chiral ligand is a chiral binatate bidentate phosphine ligand, such as (R)-BINAP.

[0015] Preferably, the arylboronic acid comprises one or more of 2,8-dimethoxy-10H-dibenzo[b,e][1,4]oxorboran-10-ol, 2,8-ditrifluoromethyl-10H-dibenzo[b,e][1,4]oxorboran-10-ol, 2,8-di-tert-butyl-10H-dibenzo[b,e][1,4]oxorboran-10-ol, 2,8-dimethyl-10H-dibenzo[b,e][1,4]oxorboran-10-ol, 2,8-diethyl-10H-dibenzo[b,e][1,4]oxorboran-10-ol, and 10H-dibenzo[b,e][1,4]oxorboran-10-ol.

[0016] More preferably, the arylboronic acid is 2,8-ditrifluoromethyl-10H-dibenzo[b,e][1,4]oxoborane-10-ol, 2,8-di-tert-butyl-10H-dibenzo[b,e][1,4]oxoborane-10-ol, or 10H-dibenzo[b,e][1,4]oxoborane-10-ol.

[0017] More preferably, the arylboronic acid is 2,8-di-tert-butyl-10H-dibenzo[b,e][1,4]oxoborane-10-ol.

[0018] Preferably, the palladium is selected from palladium chloride, palladium bromide, palladium iodide, palladium acetate, palladium neopentanoate, bis(triphenylphosphine)acetate, 1,2-bis(diphenylphosphine)ethane palladium chloride, (1,1'-bis(diphenylphosphine)ferrocene)dichloride palladium, palladium acetylacetone, bis(hexafluoroacetylacetone)palladium, bis(triphenylphosphine)dichloride palladium, tetra(triphenylphosphine)palladium, bis(tri-tert-butylphosphine)palladium, bis(dibenzylacetone)palladium, chloro(crotonyl)(tricyclohexylphosphine)palladium, and tri(dibenzylacetone)palladium. One or more of the following: dipalladium, tris(dibenzylacetone)dipalladium-chloroform adduct, (1,5-cyclooctadiene)palladium dibromide, palladium trifluoroacetate, tetra(triphenylphosphonium tetraphosphonate)palladium, tetra(tri-o-tolylphosphine)palladium, allyl palladium chloride dimer, (1-methylallyl)palladium chloride dimer, allyl(cyclopentadienyl)palladium, bis(tricyclohexylphosphine)palladium, bis(tri-o-tolylphosphine)palladium, tetra(acetonitrile)tetrafluoroborate, palladium benzoate, or 1,2-bis(benzenesulfinyl)ethyl diacetate palladium.

[0019] More preferably, the palladium is tetra(triphenylphosphine)palladium, bis(tri-tert-butylphosphine)palladium, bis(dibenzylideneacetone)palladium, tri(dibenzylideneacetone)dipalladium, or tri(dibenzylideneacetone)dipalladium-chloroform adduct.

[0020] More preferably, the palladium is bis(dibenzylacetone)palladium.

[0021] Preferably, the organic solvent is selected from one or more of the following: diethyl ether, tert-butyl methyl ether, n-butyl ether, isopropyl ether, diphenyl ether, dimethyl sulfide, cyclopentyl methyl ether, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, acetonitrile, benzonitrile, toluene, trifluorotoluene, acetone, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, ethyl acetate, ethyl formate, propyl formate, 1,4-dioxane, 1,3-dioxolane, tetrahydrofuran, 2-methyltetrahydrofuran, or 1,3-dimethyl-2-imidazolinone.

[0022] More preferably, the organic solvent is selected from isopropyl ether, 1,4-dioxane, 1,3-dioxolane, tetrahydrofuran, cyclopentylmethyl ether, anisole, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether.

[0023] More preferably, the organic solvent is cyclopentylmethyl ether.

[0024] Preferably, the molar ratio of the nucleophile, propargyl ester, palladium, and boric acid is 1:(1-2):(0.01-0.2):(0.1-1).

[0025] Preferably, the reaction is carried out in an inert gas atmosphere at a temperature of 10–50 °C for 8–36 hours.

[0026] Beneficial effects:

[0027] Compared with existing technologies, this invention achieves for the first time the directed conversion of propargyl esters to chiral morpholines. Through the screening and establishment of experimental conditions, chiral morpholines were synthesized via the asymmetric alkenylation of propargyl esters in a chiral palladium catalyst reaction system, realizing the efficient and concise construction of chiral morpholines with high added value. This successfully breaks through the technical barrier of traditional strategies being limited to the construction of cyclic molecules, enriching the application modes and conversion types of propargyl esterification. It is worth emphasizing that the use of appropriate chiral ligands and boric acid is crucial for achieving simultaneous control of regio, chemo, and stereoselectivity during the reaction. It has the following advantages:

[0028] (1) This invention provides a palladium-catalyzed asymmetric alkenylation strategy for propargyl esters. Palladium catalysts are widely available, diverse, and inexpensive. By selecting appropriate chiral ligands and arylboronic acids, regioselectivity, chemoselectivity, and stereoselectivity can be simultaneously controlled to achieve efficient construction of acyclic chiral allyl compounds and to synthesize chiral morpholines.

[0029] (2) This invention is the first to construct chiral morpholines via the asymmetric alkenylation of propargyl esters catalyzed by transition metals. This invention not only avoids the formation of potential, competing allenyl, propargyl, and conjugated dienyl compounds, but also exhibits excellent enantioselectivity. Furthermore, the reaction conditions are simple, safe, environmentally friendly, and convenient to operate, with good substrate functional group compatibility and a wide range of applications. It can be directly used for the structural modification of bioactive molecular intermediates, demonstrating good general applicability and directly yielding chiral morpholine compounds. Under optimized reaction conditions, the target product can be obtained with 87-97% ee, making it a universal, efficient, economical, and convenient method for synthesizing chiral morpholines.

[0030] (3) This invention provides a simple and efficient synthetic strategy for the synthesis of disubstituted chiral morpholine compounds, avoiding the problems of difficult-to-control enantioselectivity and difficult-to-control regioselectivity in the synthesis of dialkyl substituted chiral morpholines by traditional methods.

[0031] (4) The synthesis method of this invention first selects a specific propargyl ester, specifically an aryl alkyl-substituted internal aliphatic propargyl ester rather than a propargyl ester containing terminal alkynes. Unlike the prior art which achieves asymmetric alkenylation of propargyl esters under palladium catalysis, this invention synthesizes chiral morpholine, realizing the synthesis of chiral morpholine from propargyl esters. The chiral morpholine skeleton synthesized by the method of this invention is not only widely found in natural products and bioactive molecules, but is also an important synthon in the field of synthetic chemistry, capable of participating in a series of classical chemical reactions. Detailed Implementation

[0032] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0033] Unless otherwise specified, the experimental methods described in the examples are conventional methods; the reagents and materials, unless otherwise specified, can be obtained commercially or simply prepared using the methods described below. The room temperature is 25°C.

[0034] The initial substrates were synthesized using the following method, and substrates 1a-9a are all known compounds reported in the literature.

[0035]

[0036] One part of anhydrous THF (0.25 M) solution of an acetylene reagent (1.0 equiv) under stirring is placed in a 0 ℃ In a low-temperature reactor, nBuLi (0.25 M in Hexane, 1.0 equiv) was slowly added dropwise, and the compound was kept at 0°C with stirring for 15 minutes. Immediately afterwards, one part of anhydrous THF (1.0 M) solution containing an aldehyde reagent (1.0 equiv) was added dropwise to the above solution, and the mixture was transferred to room temperature and stirred for 1 hour. Then, acyl chloride (R... 3 Cl, 1.5 equiv) or acid anhydride (R 3 OR 3 The aqueous phase was stirred at room temperature for 3 hours (1.5 equiv). Finally, saturated ammonium chloride solution was added for quenching, followed by extraction of the aqueous phase three times with EtOAC (1.0 M). The resulting organic phase was dried over anhydrous Na₂SO₄, filtered to remove Na₂SO₄, and then the solvent was removed using a rotary evaporator. The crude propynyl alcohol ester product was obtained by vacuum concentration. After purification by rapid column chromatography and confirmation of purity by NMR, it was ready for further reaction.

[0037] Some of the initial nucleophiles were synthesized using the following method. Nucleophiles 1b-3b and 6b-8b are known compounds reported in the literature, and nucleophiles 4b-5b were synthesized using the method described below.

[0038]

[0039] Cuprous iodide (0.2 equiv) and L-proline (0.4 equiv) were placed in a nitrogen-filled flask equipped with a magnetic stirrer. Aryl iodine (1.0 equiv) and DMSO (0.5 M) were added to the flask. After stirring for five minutes, the solution turned blue. Ethanolamine (2.0 equiv) was added, and the reaction was carried out at room temperature for 12 h. Finally, the reaction was quenched with saturated ammonium chloride solution, extracted with EtOAC and water, and dried over anhydrous Na₂SO₄. After filtering to remove Na₂SO₄, the solvent was removed by rotary evaporation, and the crude product was obtained by vacuum concentration. The crude product was purified by rapid column chromatography, and its purity was confirmed by NMR before being used in the reaction. The reactant for nucleophile 4b was p-benzyloxyiodobenzene, and the reactant for nucleophile 5b was 2,2-difluoro-5-iodobenzo[d][1,3]dioxane.

[0040] Nucleophile 4b: . 1 H NMR (400 MHz, CDCl3) δ 7.50 – 7.27(m, 5H), 6.89 – 6.82 (m, 2H), 6.68 – 6.59 (m, 2H), 5.00 (s, 2H), 3.81 (t, J =5.3 Hz, 2H), 3.26 (t, J = 5.2, 2H). 13 C NMR (101 MHz, CDCl3) δ 151.71, 137.52,128.52, 127.82, 127.51, 116.15, 114.63, 70.83, 61.35, 47.07. HRMS (ESI):Calcd 244.1332 for C 15 H 18 NO2 [M+H]+; Found: 243.1326.

[0041] Nucleophile 5b: . 1 H NMR (400 MHz, CDCl3) δ 6.85 (d, J = 8.6 Hz, 1H), 6.42 (d, J = 2.3 Hz, 1H), 6.28 (dd, J = 8.6, 2.2 Hz, 1H), 3.85(t, J = 5.1 Hz, 2H), 3.25 (t, J = 5.0, 2H).13 C NMR (101 MHz, CDCl3) δ 145.24,144.70, 136.15, 131.71 (t, J = 253.3), 109.75, 107.02, 95.75, 61.07, 46.66. 19 F NMR (376 MHz, CDCl3) δ -50.47. HRMS (ESI): Calcd 218.0623 for C9H 10 F2NO3 [M+H]+; Found: 218.0620.

[0042] The chiral ligand L used in the embodiments is (R)-BINAP, CAS number 76189-55-4, which is commercially available. The specific structural formula is as follows: .

[0043] The specific structures of all substrates and products in the embodiments are shown in Table 1.

[0044] Example 1: Synthesis of Compound 1

[0045] Under nitrogen atmosphere, propargyl ester 1a (0.15 mmol), nucleophile 1b (0.1 mmol), bis(dibenzylacetone)palladium (0.01 mmol), (R)-BINAP (0.011 mmol), arylboronic acid (0.02 mmol), and cyclopentyl methyl ether (2.0 mL) were added sequentially to a 10 mL reaction flask equipped with a magnetic stir bar. The flask was sealed and the reaction was allowed to proceed at room temperature for 24 h. The reaction was then slowly brought back to room temperature and quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (4.0 mL x 3) and the organic phases were combined. After removing the solvent by rotary evaporation, the product compound 1 was separated by rapid column chromatography (eluent: petroleum ether:ethyl acetate V / V = 30:1) to obtain the product compound 1 (70% yield, 92% ee). 1 H NMR (400 MHz, CDCl3) δ 7.75 (d, J =16.0 Hz, 2H), 7.66 – 7.60 (m, 3H), 7.44 – 7.40 (m, 4H), 7.28 (dd, J = 8.6, 7.5 Hz, 2H), 7.10 (d, J = 16.0 Hz, 2H), 6.84 – 6.71 (m, 5H), 6.32 (t, J= 2.3Hz, 1H), 5.36 (s, 1H), 4.52 – 4.47 (m, 1H), 4.30 – 4.26 (m, 1H), 4.00 (dt, J = 8.7, 4.4 Hz, 1H), 3.80 (s, 6H), 3.52 – 3.38 (m, 2H), 1.88 – 1.73 (m, 2H), 1.47 – 1.32 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ170.18, 144.17, 143.55, 128.93, 120.45, 118.89, 103.11, 99.89, 65.12, 57.22,51.09, 33.40, 26.99, 22.61, 14.03. HRMS (ESI): Calcd 368.2220 for C 23 H 29 NO3 [M+H] + ; Found: 368.2195. HPLC analysis: The enantiomeric excess was determined on a CHIRALPAK IC column (5% i PrOH in hexane, 0.5 mL / min, 35 ℃, λ = 220 nm),t R (major) = 28.27 min, t R (minor) = 23.16 min. [α] D 25 = 31.3° ( c = 1.0, CHCl3).

[0046] Example 2 Synthesis of Compound 2

[0047] Under nitrogen atmosphere, propargyl ester 2a (0.15 mmol), nucleophile 2b (0.1 mmol), bis(dibenzylacetone)palladium (0.01 mmol), (R)-BINAP (0.011 mmol), arylboronic acid (0.02 mmol), and cyclopentyl methyl ether (2.0 mL) were added sequentially to a 10 mL reaction flask equipped with a magnetic stir bar. The flask was sealed and the reaction was allowed to proceed at room temperature for 24 h. The reaction was then slowly brought back to room temperature and quenched with saturated ammonium chloride solution. The product compound 2 was obtained by extraction with ethyl acetate (4.0 mL x 3) and the organic phases were combined. After removing the solvent by rotary evaporation, the product compound 2 was separated by rapid column chromatography (eluent: petroleum ether:ethyl acetate V / V = 10:1) to obtain the product compound 2 (64% yield, 90% ee). 1 H NMR (400 MHz, CDCl3) δ 8.32 (d, J =2.3 Hz, 1H), 8.01 – 7.95 (m, 1H), 6.93 – 6.86 (m, 2H), 6.81 – 6.76 (m, 2H), 6.73 (t, J = 10.2 Hz, 1H), 5.41 (s, 1H), 4.46 – 4.38 (m, 1H), 4.22 – 4.18 (m,1H), 3.95 (d, J = 2.6 Hz, 3H), 3.80 (s, 3H), 3.52 – 3.46 (m, 1H), 3.28 (m,1H), 1.68 (dd, J = 9.5, 3.8 Hz, 2H), 1.50 – 1.32 (m, 4H), 0.89 (t, J = 6.7Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 162.11, 152.71, 151.22, 146.31, 143.29,138.39, 125.17, 115.55, 114.82, 110.17, 104.26, 66.40, 61.96, 55.71, 53.38,43.39, 30.86, 28.95, 22.54, 14.11. HRMS (ESI): Calcd 369.2173 for C 22 H 29 N₂O₃ [M+H] +; Found: 369.2166. HPLC analysis: The enantiomeric excess was determined on a CHIRALPAK IC-H column (5% i PrOH in hexane, 0.5 mL / min, 35 ℃, λ = 220nm), t R (major) = 29.99 min, t R (minor) = 20.46 min. [α] D 25 = 89.1° ( c = 0.2,CHCl3).

[0048] Example 3 Synthesis of Compound 3

[0049] Under nitrogen atmosphere, propargyl ester 3a (0.15 mmol), nucleophile 2b (0.1 mmol), bis(dibenzylacetone)palladium (0.01 mmol), (R)-BINAP (0.011 mmol), arylboronic acid (0.02 mmol), and cyclopentyl methyl ether (2.0 mL) were added sequentially to a 10 mL reaction flask equipped with a magnetic stir bar. The flask was sealed and the reaction was allowed to proceed at room temperature for 24 h. The reaction was then slowly brought back to room temperature and quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (4.0 mL x 3) and the organic phases were combined. After removing the solvent by rotary evaporation, the product compound 3 was separated by rapid column chromatography (eluent: petroleum ether:ethyl acetate V / V = 30:1) to obtain the product compound 3 (72% yield, 94% ee). 1 H NMR (400 MHz, CDCl3) δ 7.56 (t, J =10.4 Hz, 2H), 7.39 – 7.29 (m, 4H), 6.80 (dd, J = 19.1, 7.7 Hz, 3H), 5.44 (s,1H), 4.56 – 4. 48 (m, 1H), 4.35 – 4.24 (m, 1H), 4.16 – 3.99 (m, 1H), 3.55 –3.37 (m, 2H), 1.48 – 1.39 (m, 2H), 1.38 (d, J = 12.5 Hz, 2H), 1.34 (s, 9H), 1.29 (d, J = 3.8 Hz, 2H), 0.91 (t,J = 6.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ150.38, 148.82, 148.57, 132.86, 129.38, 128.02, 125.11, 117.72, 112.69,107.35, 65.80, 61.09, 43.19, 34.48, 32.80, 31.33, 28.75, 22.58, 14.14. HRMS(ESI): Calcd 386.2454 for C 25 H 33 NONa [M+Na] + ; Found: 386.2440. HPLC analysis:The enantiomeric excess was determined on a CHIRALPAK OD-H column (1% i PrOHin hexane, 0.5 mL / min, 35 ℃, λ = 250 nm), t R (major) = 12.66 min, t R (minor) = 11.87 min. [α] D 25 = 68.3° ( c = 0.5, CHCl3).

[0050] Example 4 Synthesis of Compound 4

[0051] Under nitrogen atmosphere, propargyl ester 4a (0.15 mmol), nucleophile 2b (0.1 mmol), bis(dibenzylacetone)palladium (0.01 mmol), (R)-BINAP (0.011 mmol), arylboronic acid (0.02 mmol), and cyclopentyl methyl ether (2.0 mL) were added sequentially to a 10 mL reaction flask equipped with a magnetic stir bar. The flask was sealed and the reaction was allowed to proceed at room temperature for 24 h. The reaction was then slowly brought back to room temperature and quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (4.0 mL x 3) and the organic phases were combined. After removing the solvent by rotary evaporation, the product compound 4 was separated by rapid column chromatography (eluent: petroleum ether:ethyl acetate V / V = 30:1) to obtain the product compound 4 (62% yield, 88% ee). 1H NMR (400 MHz, CDCl3) δ 7.59 – 7.49(m, 2H), 7.27 – 7.23 (m, 2H), 6.95 – 6.69 (m, 4H), 5.41 (s, 1H), 4.48 – 4.40(m, 1H), 4.25 – 4.15 (m, 1H), 3.96 – 3.86 (m, 1H), 3.78 (d, J = 4.3 Hz, 3H),3.53 – 3.20 (m, 2H), 1.86 – 1.64 (m, 2H), 1.47 – 1.28 (m, 4H), 0.86 (t, J =6.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 152.67, 152.00, 143.27, 134.17,131.19, 129.55, 128.24, 115.34, 114.84, 106.76, 66.30, 62.07, 55.73, 43.49,31.44, 28.91, 22.55, 14.11. HRMS (ESI): Calcd 372.1725 for C 22 H 26 ClNO2 [M+H] + ;Found: 372.1621. HPLC analysis: The enantiomeric excess was determined on aCHIRALPAK OD-H column (10% i PrOH in hexane, 0.5 mL / min, 35 ℃, λ = 220 nm),t R (major) = 15.41 min, t R (minor) = 14.61 min. [α] D 25 = 49.0° ( c = 0.4, CHCl3).

[0052] Example 5 Synthesis of Compound 5

[0053] Under nitrogen atmosphere, propargyl ester 5a (0.15 mmol), nucleophile 2b (0.1 mmol), bis(dibenzylacetone)palladium (0.01 mmol), (R)-BINAP (0.011 mmol), arylboronic acid (0.02 mmol), and cyclopentyl methyl ether (2.0 mL) were added sequentially to a 10 mL reaction flask equipped with a magnetic stir bar. The flask was sealed and the reaction was allowed to proceed at room temperature for 24 h. The reaction was then slowly brought back to room temperature and quenched with saturated ammonium chloride solution. The product compound 5 was obtained by extraction with ethyl acetate (4.0 mL x 3) and the organic phases were combined. After removing the solvent by rotary evaporation, the product compound 5 was separated by rapid column chromatography (eluent: petroleum ether:ethyl acetate V / V = 30:1) to obtain the product compound 5 (57% yield, 92% ee). 1 H NMR (400 MHz, CDCl3) δ 7.69 (d, J =8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 6.4 Hz, 2H), 6.77 (d, J =9.1 Hz, 2H), 5.44 (s, 1H), 4.55 – 4.48 (m, 1H), 4.35 – 4.25 (m, 1H), 3.96(dd, J = 10.1, 4.3 Hz, 1H), 3.85 – 3.74 (m, 3H), 3.58 – 3.47 (m, 1H), 3.37 –3.29 (m, 1H), 1.92 – 1.71 (m, 2H), 1.47 – 1.34 (m, 4H), 0.90 (t, J = 6.2 Hz, 3H). 1313C NMR (101 MHz, CDCl3) δ 160.52 (s), 151.21 (s), 147.09 (s), 143.37(s), 137.28 (s), 134.79 (s), 130.53 (s), 129.19 (s), 128.98 (s), 128.41 (s),125.42 (s), 122.61 (s), 113.80 (s), 107.54 (s), 106.52 (s), 98.40 (s), 77.35(s), 77.03 (s), 76.71 (s), 65.58 (s), 61.14 (s), 55.29 (s), 43.33 (s), 32.99(s), 28.71 (s), 22.55 (s), 14.10 (s).HRMS (ESI): Calcd 363.2067 for C 23 H 27 N2O2[M+H] + ; Found: 363.2055 HPLC analysis: The enantiomeric excess was determinedon a CHIRALPAK OD-H column (5% i PrOH in hexane, 0.5 mL / min, 25 ℃, λ = 220nm), t R (major) = 32.69 min, t R (minor) = 31.49 min. [α] D 25 = 23.9° ( c = 0.5,CHCl3).

[0054] Example 6 Synthesis of Compound 6

[0055] Under nitrogen atmosphere, propargyl ester 5a (0.15 mmol), nucleophile 2b (0.1 mmol), bis(dibenzylacetone)palladium (0.01 mmol), (R)-BINAP (0.011 mmol), arylboronic acid (0.02 mmol), and cyclopentyl methyl ether (2.0 mL) were added sequentially to a 10 mL reaction flask equipped with a magnetic stir bar. The flask was sealed and the reaction was allowed to proceed at room temperature for 24 h. The reaction was then slowly brought back to room temperature and quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (4.0 mL x 3) and the organic phases were combined. After removing the solvent by rotary evaporation, the product compound 6 was separated by rapid column chromatography (eluent: petroleum ether:ethyl acetate V / V = 30:1) to obtain the product compound 6 (60% yield, 94% ee). 1 H NMR (400 MHz, CDCl3) δ 7.69 (d, J =8.2 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H), 6.80 – 6.70(d, 2H), 5.47 (s, 1H), 4.57 – 4.41 (m, 1H), 4.28 – 4.20 (m, 1H), 3.94 (dd, J 0.89 (t, J = 6.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 208.60, 138.60, 132.53, 130.51, 118.71, 111.47, 76.75, 44.61, 33.72, 31.68, 24.60, 22.60, 14.10. 19 F NMR (376 MHz, CDCl3) δ -60.06.HRMS (ESI): Calcd 406.1989 for C 23 H 27 F3NO2 [MH] +; Found: 406.1981. HPLCanalysis: The enantiomeric excess was determined on a CHIRALPAK OD-H column(5% i PrOH in hexane, 0.5 mL / min, 35 ℃, λ = 220 nm), t R (major) = 17.07 min,t R (minor) = 13.68 min. [α] D 25 = 17.9° ( c = 0.3, CHCl3).

[0056] Example 7 Synthesis of Compound 7

[0057] Under nitrogen atmosphere, propargyl ester 7a (0.15 mmol), nucleophile 2b (0.1 mmol), bis(dibenzylacetone)palladium (0.01 mmol), (R)-BINAP (0.011 mmol), arylboronic acid (0.02 mmol), and cyclopentyl methyl ether (2.0 mL) were added sequentially to a 10 mL reaction flask equipped with a magnetic stir bar. The flask was sealed and the reaction was allowed to proceed at room temperature for 24 h. The reaction was then slowly brought back to room temperature and quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (4.0 mL x 3) and the organic phases were combined. After removing the solvent by rotary evaporation, the product compound 7 was separated by rapid column chromatography (eluent: petroleum ether:ethyl acetate V / V = 30:1) to obtain the product compound 7 (61% yield, 96% ee). 1 H NMR (400 MHz, CDCl3) δ 7.41 (d, J =2.0 Hz, 2H), 7.23 – 7.16 (m, 1H), 6.98 (d, J = 7.4 Hz, 1H), 6.87 (dd, J =9.8, 2.8 Hz, 2H), 6.77 (t, J= 6.3 Hz, 2H), 5.44 (s, 1H), 4.47 – 4.37 (m,1H), 4.21 – 4.15 (m, 1H), 3.96 – 3.88 (m, 1H), 3.78 (s, 3H), 3.52 – 3.44 (m,1H), 3.30 – 3.25 (m, 1H), 2.34 (s, 3H), 1.89 – 1.77 (m, 1H), 1.69 – 1.58 (m,1H), 1.43 – 1.29 (m, 4H), 0.87 (t, J = 6.6 Hz, 3H). 13 C NMR (100 MHz, CDCl3)152.60 (s), 151.20, 143.40, 137.63, 129.02, 128.10, 126.76, 125.50, 115.37,114.83, 108.18, 77.34, 77.02, 76.70, 66.32, 62.12, 55.73, 43.47, 31.17,29.72, 28.92, 22.56, 21.56, 14.11. HRMS (ESI): Calcd 374.2090 for C 23 H 29 NO2Na[M+Na] + ; Found: 374.2068. HPLC analysis: The enantiomeric excess was determined on a CHIRALPAK OD-H column (5% i PrOH in hexane, 0.5 mL / min, 35 ℃, λ = 220 nm), t R (major) = 25.30 min, t R (minor) = 23.90 min. [α] D 25 = 2.8° ( c =1.0, CHCl3).

[0058] Example 8 Synthesis of Compound 8

[0059] Under nitrogen atmosphere, propargyl ester 3a (0.15 mmol), nucleophile 2b (0.1 mmol), bis(dibenzylacetone)palladium (0.01 mmol), (R)-BINAP (0.011 mmol), arylboronic acid (0.02 mmol), and cyclopentyl methyl ether (2.0 mL) were added sequentially to a 10 mL reaction flask equipped with a magnetic stir bar. The flask was sealed and the reaction was allowed to proceed at room temperature for 24 h. The reaction was then slowly brought back to room temperature and quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (4.0 mL x 3) and the organic phases were combined. After removing the solvent by rotary evaporation, the product compound 8 was separated by rapid column chromatography (eluent: petroleum ether:ethyl acetate V / V = 30:1) to obtain product compound 8 (70% yield, 97% ee). 1 H NMR (400 MHz, CDCl3) δ 7.40 (t, J =10.4 Hz, 2H), 7.24 – 7.16 (m, 1H), 6.98 (d, J = 7.4 Hz, 1H), 6.87 (dd, J =9.8, 2.8 Hz, 2H), 6.77 (t, J = 6.3 Hz, 2H), 5.44 (s, 1H), 4.50 – 4.34 (m,1H), 4.25 – 4.14 (m, 1H), 3.98 – 3.85 (m, 1H), 3.78 (s, 3H), 3.49 – 3.43 (m,1H), 3.30 –3.24(m, 1H), 2.34 (s, 3H), 1.83 – 1.70 (m, 2H), 1.44 – 1.30 (m,4H), 0.87 (t, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 152.60, 151.20,143.40, 137.63, 135.58, 129.02, 128.10, 126.76, 125.50, 115.37, 114.83,108.18, 66.32, 62.12, 55.73, 43.47, 31.17, 29.72, 28.92, 22.56, 21.56, 14.11. 19 F NMR (376 MHz, CDCl3) δ -121.67. HRMS (ESI): Calcd 356.2021 for C 22H 27 FNO2 [M+H] + ; Found: 356.2008. HPLC analysis: The enantiomeric excess was determined on a CHIRALPAK OD-H column (5% i PrOH in hexane, 0.4 mL / min, 35 ℃, λ = 220nm), t R (major) = 14.04 min, t R (minor) = 13.58 min. [α] D 25 = 29.1° ( c = 0.4, CHCl3).

[0060] Example 9 Synthesis of Compound 9

[0061] Under nitrogen atmosphere, propargyl ester 9a (0.15 mmol), nucleophile 2b (0.1 mmol), bis(dibenzylacetone)palladium (0.01 mmol), (R)-BINAP (0.011 mmol), arylboronic acid (0.02 mmol), and cyclopentyl methyl ether (2.0 mL) were added sequentially to a 10 mL reaction flask equipped with a magnetic stir bar. The flask was sealed and the reaction was allowed to proceed at room temperature for 24 h. The reaction was then slowly brought back to room temperature and quenched with saturated ammonium chloride solution. The product compound 9 was obtained by extraction with ethyl acetate (4.0 mL x 3) and the organic phases were combined. After removing the solvent by rotary evaporation, the product compound 9 was separated by rapid column chromatography (eluent: petroleum ether:ethyl acetate V / V = 30:1) to obtain the product compound 9 (75% yield, 97% ee). 1 H NMR (400 MHz, CDCl3) δ 7.65 – 7.59(m, 2H), 7.36 – 7.28 (m, 2H), 7.21 – 7.13 (m, 1H), 6.93 – 6.85 (m, 2H), 6.80– 6.76 (m, 2H), 5.48 (s, 1H), 4.48 – 4.40 (m, 1H), 4.25 – 4.15 (m, 1H), 3.98 – 3.91 (m, 1H), 3.79 (s, 3H), 3.53 – 3.46 (m, 1H), 3.30 – 3.26 (m, 1H), 1.75– 1.55 (m, 2H), 1.44 – 1.31 (m, 4H), 0.89 (t,J = 6.8, 3H). 13 C NMR (101 MHz, CDCl3) δ 152.63, 151.41, 143.39, 135.71, 128.37, 128.19, 125.93, 115.41,114.84, 108.07, 77.37, 77.05, 76.73, 66.32, 62.11, 55.73, 43.48, 31.21,28.93, 22.57, 14.13. HRMS (ESI): Calcd 338.2115 for C 22 H 28 NO2 [M+H] + ; Found:338.2113. HPLC analysis: The enantiomeric excess was determined on aCHIRALPAK OD-H column (5% i PrOH in hexane, 0.5 mL / min, 35 ℃, λ = 254 nm), t R (major) = 12.18 min, t R (minor) = 11.54 min. [α] D 25 = 92.5° ( c = 0.3, CHCl3).

[0062] Example 10 Synthesis of Compound 10

[0063] Under nitrogen atmosphere, propargyl ester 9a (0.15 mmol), nucleophile (0.1 mmol), bis(benzylacetone)palladium (0.01 mmol), (R)-BINAP (0.011 mmol), arylboronic acid (0.02 mmol), and cyclopentyl methyl ether (2.0 mL) were added sequentially to a 10 mL reaction flask equipped with a magnetic stir bar. The flask was sealed and the reaction was allowed to proceed at room temperature for 24 h. The reaction was then slowly brought back to room temperature and quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (4.0 mL x 3) and the organic phases were combined. After removing the solvent by rotary evaporation, the product compound 10 was separated by rapid column chromatography (eluent: petroleum ether:ethyl acetate V / V = 30:1) to obtain the product compound 10 (68% yield, 87% ee). 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J =7.5 Hz, 2H), 7.31 (t, J = 7.7 Hz, 2H), 7.24 – 7.14 (m, 2H), 6.42 – 6.28 (m,3H), 5.43 (s, 1H), 4.55 – 4.47 (m, 1H), 4.30 – 4.24 (m, 1H), 4.09 – 3.97 (m,1H), 3.81 (d, J = 7.9 Hz, 3H), 3.53 – 3.35 (m, 2H), 1.89 – 1.75 (m, 2H), 1.49– 1.32 (m, 4H), 0.91 (t, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.88,150.89, 149.93, 135.69, 130.09, 128.30,128.19, 125.88, 107.38, 105.66,102.35, 99.34, 77.36, 77.04, 76.72, 65.66, 61.10, 55.20, 43.39, 33.18, 28.74,22.58, 14.14. HRMS (ESI): Calcd 338.2115 for C 22 H 28 NO2 [M+H] + ; Found: 338.2111.HPLC analysis: The enantiomeric excess was determined on a CHIRALPAK IC-Hcolumn (5% i PrOH in hexane, 0.5 mL / min, 35 ℃, λ = 220 nm), t R (major) = 14.02 min, t R (minor) = 13.81 min. [α] D 25 = 128.1° ( c = 0.3, CHCl3).

[0064] Example 11 Synthesis of Compound 11

[0065] Under nitrogen atmosphere, propargyl ester 1a (0.15 mmol), nucleophile 4b (0.1 mmol), bis(dibenzylacetone)palladium (0.01 mmol), (R)-BINAP (0.011 mmol), arylboronic acid (0.02 mmol), and cyclopentyl methyl ether (2.0 mL) were added sequentially to a 10 mL reaction flask equipped with a magnetic stir bar. The flask was sealed and the reaction was allowed to proceed at room temperature for 24 h. The reaction was then slowly brought back to room temperature and quenched with saturated ammonium chloride solution. The product compound 11 (71% yield, 95% ee) was obtained by extraction with ethyl acetate (4.0 mL x 3) and combination of organic phases. After solvent removal by rotary evaporation, the product compound 11 was separated by rapid column chromatography (eluent: petroleum ether:ethyl acetate V / V = 30:1) to obtain the product compound 11. 1 H NMR (400 MHz, CDCl3) δ 7.49 – 7.28(m, 6H), 6.94 (d, J = 9.0 Hz, 2H), 6.81 (d, J = 2.3 Hz, 2H), 6.74 (d, J = 9.1Hz, 2H), 5.38 (d, J = 8.9 Hz, 1H), 5.02 (s, 2H), 4.47 – 4.41 (m, 1H), 4.25 –4.18 (m, 1H), 3.95 – 3.87 (m, 1H), 3.80 (s, 6H), 3.51 – 3.42 (m, 1H), 3.31 –3.24 (m, 1H), 1.86 – 1.64 (m, 2H), 1.43 – 1.30 (m, 4H), 0.88 (t, J = 6.9 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 160.51, 151.96, 151.75, 143.54, 137.48,128.55, 127.85, 127.50, 116.04, 115.06, 107.85, 106.52, 98.38, 77.36, 77.05,76.73, 70.71, 66.24, 62.07, 55.29, 43.51, 31.74, 28.88, 22.58, 14.13. HRMS(ESI): Calcd 496.2458 for C 30 H 35 NO4Na [M+Na] +; Found: 496.2451. HPLC analysis:The enantiomeric excess was determined on a CHIRALPAK OD-H column (5% i PrOHin hexane, 0.5 mL / min, 35 ℃, λ = 220 nm), t R (major) = 23.90 min, t R (minor) = 23.11 min. [α] D 25 = 78.2° ( c = 0.7, CHCl3).

[0066] Example 12 Synthesis of Compound 12

[0067] Under nitrogen atmosphere, propargyl ester 1a (0.15 mmol), nucleophile 5b (0.1 mmol), bis(dibenzylacetone)palladium (0.01 mmol), (R)-BINAP (0.011 mmol), arylboronic acid (0.02 mmol), and cyclopentyl methyl ether (2.0 mL) were added sequentially to a 10 mL reaction flask equipped with a magnetic stir bar. The flask was sealed and the reaction was allowed to proceed at room temperature for 24 h. The reaction was then slowly brought back to room temperature and quenched with saturated ammonium chloride solution. The product compound 12 (75% yield, 93% ee) was obtained by extraction with ethyl acetate (4.0 mL x 3) and combination of organic phases. After solvent removal by rotary evaporation, the product compound 12 was separated by rapid column chromatography (eluent: petroleum ether:ethyl acetate V / V = 30:1) to obtain the product compound 12. 1 H NMR (400 MHz, CDCl3) δ 6.94 (d, J= 8.8 Hz, 1H), 6.82 (t, J = 3.5 Hz, 2H), 6.52 (dd, J = 6.8, 2.4 Hz, 1H), 6.40– 6.32 (m, 2H), 5.39 (s, 1H), 4.51 – 4.44 (m, 1H), 4.29 – 4.20 (m, 1H), 3.93– 3.85 (m, 1H), 3.80 (s, 6H), 3.48 – 3.38 (m, 1H), 3.35 – 3.27 (m, 1H), 1.88 – 1.67 (m, 2H), 1.47 – 1.32 (m, 4H), 0.90 (t, J= 6.9 Hz, 3H). 13 C NMR (101MHz, CDCl3) δ 160.55, 151.12, 146.07, 144.92, 137.20, 136.24, 133.37, 130.59,122.16, 117.70, 109.72, 107.87, 107.18, 106.58, 98.48, 96.04, 77.37, 77.06,76.74, 65.64, 62.08, 55.29, 43.83, 32.50, 28.76, 22.55, 14.09. 19 F NMR (376MHz, CDCl3) δ -50.33. HRMS (ESI): Calcd 448.1930 for C 22 H 28 F2NO5[M+H] + ; Found:448.1925. HPLC analysis: The enantiomeric excess was determined on aCHIRALPAK OD-H column (1% i PrOH in hexane, 0.5 mL / min, 35 ℃, λ = 220 nm), t R (major) = 15.95 min, t R (minor) = 14.46 min. [α] D 25 = 68.8° ( c = 1.0, CHCl3).

[0068] Example 13 Synthesis of Compound 13

[0069] Under nitrogen atmosphere, propargyl ester 1a (0.15 mmol), nucleophile 6b (0.1 mmol), bis(dibenzylacetone)palladium (0.01 mmol), (R)-BINAP (0.011 mmol), arylboronic acid (0.02 mmol), and cyclopentyl methyl ether (2.0 mL) were added sequentially to a 10 mL reaction flask equipped with a magnetic stir bar. The flask was sealed and the reaction was allowed to proceed at room temperature for 24 h. The reaction was then slowly brought back to room temperature and quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (4.0 mL x 3) and the organic phases were combined. After removing the solvent by rotary evaporation, the product compound 13 was separated by rapid column chromatography (eluent: petroleum ether:ethyl acetate V / V = 30:1) to obtain the product compound 13 (69% yield, 92% ee). 1 H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 7.9 Hz, 2H), 7.11 (s, 1H), 6.80 (s, 2H), 6.65 (d, J = 7.7 Hz, 2H), 5.36 (s,1H), 4.49 (t, J = 8.4 Hz, 1H), 4.34 – 4.22 (m, 1H), 3.94 (dd, J = 10.3, 3.6Hz, 1H), 3.83 – 3.76 (m, 6H), 3.45 (d, J = 12.1 Hz, 1H), 3.41 – 3.32 (m, 1H), 1.86 – 1.71 (m, 2H), 1.40 – 1.29 (m, 4H), 0.90 (t, J = 6.1 Hz, 3H). 13 C NMR(100 MHz, CDCl3) δ 160.52, 151.21, 147.09, 143.37, 137.28, 134.79, 130.53,129.19, 128.98, 128.41, 125.42, 122.61, HRMS(ESI): Calcd 402.1831 for C 23 H 29 ClNO3 [M+H]+ ; Found: 402.1822. HPLC analysis:The enantiomeric excess was determined on a CHIRALPAK OD-H column (5% i PrOHin hexane, 0.5 mL / min, 25 ℃, λ = 220 nm), t R (major) = 34.01 min, t R (minor) = 32.24 min. [α] D 25 = 23.9° ( c = 0.5, CHCl3).

[0070] Example 14 Synthesis of Compound 14

[0071] Under nitrogen atmosphere, propargyl ester 1a (0.15 mmol), nucleophile 7b (0.1 mmol), bis(dibenzylacetone)palladium (0.01 mmol), (R)-BINAP (0.011 mmol), arylboronic acid (0.02 mmol), and cyclopentyl methyl ether (2.0 mL) were added sequentially to a 10 mL reaction flask equipped with a magnetic stir bar. The flask was sealed and the reaction was allowed to proceed at room temperature for 24 h. The reaction was then slowly brought back to room temperature and quenched with saturated ammonium chloride solution. The product compound 14 was obtained by extraction with ethyl acetate (4.0 mL x 3) and the organic phases were combined. After removing the solvent by rotary evaporation, the product compound 14 was separated by rapid column chromatography (eluent: petroleum ether:ethyl acetate V / V = 30:1) to obtain the product compound 14 (69% yield, 92% ee). 1 H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 1.8 Hz, 2H), 6.70 (d, J = 8.6 Hz, 2H), 6.31 (t, J = 1.9 Hz, 1H), 5.33 (s, 1H), 4.55 – 4.48 (m, 1H), 4.34 – 4.22 (m, 1H), 3.97(dd, J = 9.0, 5.4 Hz, 1H), 3.81 (d, J = 8.4 Hz, 6H), 3.50 – 3.40 (m, 2H), 1.79 (t,J = 11.4 Hz, 2H), 1.49 – 1.36 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H). 13 CNMR (100 MHz, CDCl3) δ 160.49, 151.74, 146.23, 140.42, 137.55, 126.18,112.23, 107.17, 106.44, 98.27, 77.35, 77.03, 76.72, 65.83, 61.28, 55.29,43.38, 33.85, 33.43, 31.52, 28.74, 22.60, 14.15. HRMS (ESI): Calcd 484.2846for C 27 H 38 NO3 [M+H] + ; Found: 424.2836. HPLC analysis: The enantiomeric excess was determined on a CHIRALPAK OD-H column (5% i PrOH in hexane, 0.5 mL / min, 35℃, λ = 250 nm), t R (major) = 21.98 min, t R (minor) = 15.46 min. [α] D 25 = 12.6° ( c = 0.8, CHCl3).

[0072] Example 15 Synthesis of Compound 15

[0073] Under nitrogen atmosphere, propargyl ester 1a (0.15 mmol), nucleophile 8b (0.1 mmol), bis(dibenzylacetone)palladium (0.01 mmol), (R)-BINAP (0.011 mmol), arylboronic acid (0.02 mmol), and cyclopentyl methyl ether (2.0 mL) were added sequentially to a 10 mL reaction flask equipped with a magnetic stir bar. The flask was sealed and the reaction was allowed to proceed at room temperature for 24 h. The reaction was then slowly brought back to room temperature and quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (4.0 mL x 3) and the organic phases were combined. After removing the solvent by rotary evaporation, the product compound 15 was separated by rapid column chromatography (eluent: petroleum ether:ethyl acetate V / V = 30:1) to obtain the product compound 15 (50% yield, 97% ee). 1 H NMR (400 MHz, CDCl3) δ 7.03 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 2.2 Hz, 2H), 6.59 – 6.49 (m, 2H), 6.32 (t, J =2.2 Hz, 1H), 5.37 (s, 1H), 4.52 – 4.44 (m, 1H), 4.32 – 4.19 (m, 1H), 3.97(dd, J = 10.3, 4.1 Hz, 1H), 3.80 (s, 6H), 3.54 – 3.31 (m, 3H), 2.25 (s, 3H), 2.19 (s, 3H), 1.85 – 1.73 (m, 2H), 1.47 – 1.33 (m, 4H), 0.89 (t, J = 6.5 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 160.49, 151.90, 146.93, 137.56,137.39, 130.40,126.06, 114.75, 110.65, 107.47, 106.47, 98.30, 66.05, 61.35, 55.28, 43.27,32.49, 28.80, 22.55, 20.43, 18.67, 14.13. HRMS (ESI): Calcd 396.2533 forC 25 H 34 NO3 [M+H] +; Found: 396.2528. HPLC analysis: The enantiomeric excess was determined on a CHIRALPAK OD-H column (5% i PrOH in hexane, 0.5 mL / min, 35 ℃, λ = 220 nm), t R (major) = 36.81 min, t R (minor) = 19.76 min. [α] D 25 = 37.3° ( c = 0.2, CHCl3).

[0074] Table 1. Structural formulas of raw materials and products in Examples 1-15 and corresponding experimental results.

[0075]

[0076]

[0077] Comparative Example 1

[0078] Comparative Example 1 uses the same method as Example 1, except that no palladium catalyst is added and the yield of the target product is 0.

[0079] Comparative Example 2

[0080] Comparative Example 2 uses the same method as Example 1, except that the chiral ligand (R)-BINAP is not added and the target product has an ee value of 0.

[0081] Comparative Example 3

[0082] Comparative Example 3 uses the same method as Example 1, except that boric acid is not added and the yield of the target product is 20%.

[0083] Comparative Example 4

[0084] Comparative Example 4 uses the same method as Example 1, except that the reaction time is shortened to 4 hours and the target product has an ee value of 50.

[0085] Comparative Example 5

[0086] Comparative Example 5 uses the same method as Example 1, except that the ligand (R)-BINAP is replaced with other chiral ligands, such as (R,R)-DACH-pyridyl Trost ligand, Ph-Chiraphite, (R)-1-{(Sp)-2-[bis[2-(methoxy)phenyl]phosphine]ferrocene}ethyl di-tert-butylphosphine, (R)-Me-iPr-INDOLPhos, and (R)-[1,1'-binaphthyl]-2-yldiphenylphosphine, with a target product ee value of 0.

[0087] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the invention. The various palladium catalysts in the present invention can theoretically undergo oxidative addition with propargyl esters, thereby facilitating the smooth progress of the reaction. Modification of substituents only affects the reaction to a certain extent and does not play a decisive role in the occurrence of the reaction. Anyone skilled in the art will readily understand that, without departing from the scope of the present invention, variations or modifications can be made to obtain corresponding embodiments. For example, the substituents can be replaced, changed, or modified within the scope of the present invention to achieve the method of the present invention. Any modifications, alterations, or equivalent changes made to the above embodiments based on the present invention without departing from the spirit of the present invention are still within the scope of the present invention.

Claims

1. A method for synthesizing chiral morpholine from propargyl esters, characterized in that, In a solvent, propargyl ester As a reaction substrate, transition metal palladium (Pd) with chiral ligands in an arylboronic acid catalytic system and nucleophiles were used. The reaction proceeds to yield the chiral morpholine product. , where R 1 With R 2 Independently representing alkyl or aryl, OR 3 R represents an ester group. 4 The ligand represents an aryl group, and the chiral ligand represents a chiral phosphine ligand.

2. The method for synthesizing chiral morpholine from propargyl esters according to claim 1, characterized in that, Each alkyl substituent is independently selected from hydrogen, C1-C20 alkyl, C1-C20 haloalkyl, C1-C20 alkylcarbonyl, nitro, hydroxyl, ester, alkenyl, ether, amide, silyl, mercapto, amino, or cyano; its aryl group represents the substituent on the benzene ring, which is selected from C1-C20 alkyl, C1-C20 haloalkyl, C1-C20 alkylcarbonyl, nitro, hydroxyl, ester, alkenyl, ether, amide, silyl, mercapto, amino, or cyano-substituted or unsubstituted biphenyl, naphthyl, anthracene, or heteroaryl containing N, O, or S rings of five to thirteen rings.

3. The method for synthesizing chiral morpholine from propargyl esters according to claim 1, characterized in that, OR 3 It is selected from one or more of alkyl sulfonates, aryl sulfonates, amino sulfonates, alkyl carboxylates, aryl carboxylates, amino carboxylates, alkoxy carboxylates, aryloxy carboxylates, alkyl phosphates, aryl phosphates, and arylalkyl phosphates.

4. The method for synthesizing chiral morpholine from propargyl esters according to claim 1, characterized in that, R 4 The substituents on the benzene ring are selected from C1-C20 alkyl, C1-C20 halosubstituted alkyl, C1-C20 alkyl carbonyl, nitro, hydroxyl, ester, alkenyl, ether, amide, silyl, mercapto, amino, or cyano-substituted or unsubstituted biphenyl, naphthyl, anthracene, and heteroaryl groups containing N, O, or S in five to thirteen rings.

5. The method for synthesizing chiral morpholine from propargyl esters according to claim 1, characterized in that, The chiral ligands include bidentate chiral N ligands, bidentate chiral P ligands, bidentate chiral NP ligands, monodentate chiral N ligands, monodentate chiral phosphine ligands, tridentate chiral NPN ligands, tridentate chiral NSP ligands, and tridentate chiral N ligands. Their types include chiral oxazoline ligands, chiral diamine ligands, chiral monodentate phosphine ligands, chiral phosphorous amide ligands, chiral biphenyl bidentate phosphine ligands, chiral spirocyclic bidentate phosphine ligands, chiral binatidine bidentate phosphine ligands, or chiral sulfinamide-substituted phosphine ligands.

6. The method for synthesizing chiral morpholine from propargyl esters according to claim 1, characterized in that, The arylboronic acid is selected from one or more of 2,8-dimethoxy-10H-dibenzo[b,e][1,4]oxorboran-10-ol, 2,8-ditrifluoromethyl-10H-dibenzo[b,e][1,4]oxorboran-10-ol, 2,8-di-tert-butyl-10H-dibenzo[b,e][1,4]oxorboran-10-ol, 2,8-dimethyl-10H-dibenzo[b,e][1,4]oxorboran-10-ol, 2,8-diethyl-10H-dibenzo[b,e][1,4]oxorboran-10-ol, and 10H-dibenzo[b,e][1,4]oxorboran-10-ol.

7. The method for synthesizing chiral morpholine from propargyl esters according to claim 1, characterized in that, The palladium is selected from palladium chloride, palladium bromide, palladium iodide, (1,1'-bis(diphenylphosphine)ferrocene)palladium dichloride, palladium acetylacetonate, bis(hexafluoroacetylacetonate)palladium, bis(triphenylphosphine)palladium dichloride, tetra(triphenylphosphine)palladium, bis(tri-tert-butylphosphine)palladium, bis(dibenzylacetone)palladium, chloro(crotonyl)(tricyclohexylphosphine)palladium, tri(dibenzylacetone)dipalladium, tri(dibenzylacetone)dipalladium-chloroform adduct, (1,5-cyclooctyl) Palladium dibromide (diene), palladium trifluoroacetate, tetra(triphenyl phosphonite) palladium, tetra(tri-o-tolylphosphine) palladium, allyl palladium chloride dimer, (1-methylallyl) palladium chloride dimer, allyl(cyclopentadienyl) palladium, bis(tricyclohexylphosphine) palladium, bis(tri-o-tolylphosphine) palladium, tetra(acetonitrile) tetrafluoroborate, palladium benzoate, or one or more of 1,2-bis(benzenesulfinyl)ethyl diacetate palladium.

8. The method for synthesizing chiral morpholine from propargyl esters according to claim 1, characterized in that, The organic solvent is selected from one or more of the following: diethyl ether, tert-butyl methyl ether, n-butyl ether, isopropyl ether, diphenyl ether, dimethyl sulfide, cyclopentyl methyl ether, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, acetonitrile, benzonitrile, benzene, toluene, trifluorotoluene, acetone, dichloromethane, chloroform, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, ethyl acetate, ethyl formate, propyl formate, 1,4-dioxane, 1,3-dioxolane, tetrahydrofuran, 2-methyltetrahydrofuran, or 1,3-dimethyl-2-imidazolinone.

9. The method for synthesizing chiral morpholine from propargyl esters according to claim 1, characterized in that, The molar ratio of the nucleophile, propargyl ester, palladium, and boric acid is 1:(1-2):(0.01-0.2):(0.1-1).

10. The method for synthesizing chiral morpholine from propargyl esters according to claim 1, characterized in that, The reaction needs to be carried out in an inert gas atmosphere, at a temperature of 10~50 ℃, for a time of 8~36 hours.

Images