Chiral monofluorobis(arylsulfonyl)methyl / (deuterated)monofluoromethyl substituted chiral allylic compounds and methods of synthesis thereof

Abstract

The present application relates to a kind of chiral monofluoro bis (aryl sulfonyl) methyl or (deuterated) monofluoromethyl substituted chiral allyl compound and its asymmetric catalytic synthesis method and application.The compound has potential biological activity and pharmacodynamic activity, and can provide strong technical support for fluorine-containing new drug research and development.The synthesis method is: under the condition of chiral catalyst, with 1,3-diene and fluorinated bis aryl sulfonyl methane as raw material, by asymmetric hydrogen monofluoroalkylation reaction or asymmetric hydrogen monofluoroalkylation reaction / reduction de-fouling base series reaction, high stereoselectivity synthesis the chiral monofluoro bis (phenylsulfonyl) methyl or (deuterated) monofluoromethyl substituted chiral allyl compound, and the specific reaction process is as shown in reaction formula (A).The raw material is cheap and easy to obtain;Reaction condition is mild, and operation is simple;Substrate structure is rich and varied, can obtain good to excellent yield and enantioselectivity etc., with wide application prospect.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis methods, and relates to a class of chiral monofluorobis(arylsulfonyl)methyl and / or (deuterated) monofluoromethyl substituted chiral allyl compounds, as well as an asymmetric catalytic method for synthesizing such compounds from 1,3-diene and fluorobisarylsulfonylmethane. Background Technology

[0002] Fluorine atoms possess the strongest electronegativity and a small atomic radius. Based on the unique properties of fluorine atoms, introducing them into organic compounds can alter their physical, chemical, and physiological properties. Therefore, selectively introducing fluorine atoms or fluorine-containing groups into known drugs or bioactive molecules is an important method for drug modification and new drug development. As shown in formula (1), methyl monofluorinated ibuprofen exhibits increased analgesic activity and reduces gastric damage compared to ibuprofen; monofluoromethyl dihydroxyphenylalanine can inhibit dopa deacidase in vivo; monofluoromethyl histidine can inhibit histidine decarboxylase in vivo; and sofosbuvir, a drug containing a monofluoroalkyl structural unit, is a first-line drug for treating hepatitis C. All of the above compounds contain a monofluoromethyl structural unit. Therefore, the selective introduction of monofluoromethyl groups into compounds is of great significance for new drug development. Thus, developing a method for the efficient synthesis of chiral monofluoromethyl-substituted allyl compounds capable of diverse transformations has significant application value for the development of fluorine-containing drugs.

[0003]

[0004] Given this, despite the tireless efforts of chemists, numerous methods for constructing corresponding fluoroalkyl compounds through trifluoro, perfluoro, and difluoroalkylation have been developed. However, the selective introduction of monofluoromethyl groups into bioactive molecules, particularly into chiral centers, remains very limited. This is partly due to the scarcity of commercially available monofluoromethylating reagents, and partly due to the unique characteristics of fluorinated compounds, which render conventional methods for non-fluorinated substrates unsuitable for reactions involving fluorinated substrates. Nevertheless, fluorobis(aryl)sulfonylmethanes are considered effective equivalences of monofluoromethylating reagents and have seen initial applications in asymmetric catalytic reactions in recent years. Meanwhile, regioselective hydrofluoroalkylation of alkenes has become an effective strategy for synthesizing fluoroalkyl compounds. However, almost all current reports focus on anti-Markovnikov regioselective hydrofluoroalkylation reactions for constructing linear, non-chiral fluoroalkyl compounds. Only one example of racemic difluoroalkylation of Markovnikov regioselective alkenes has been reported, and no reports have yet documented Markovnikov regioselective asymmetric fluoromonomethylation for constructing chiral monofluoromethyl groups. Because olefin raw materials are inexpensive and readily available, and because chiral monofluoromethyl substituted allyl compounds have significant potential applications in new drug development, it is of great importance to develop efficient synthetic compounds of this type. Summary of the Invention

[0005] The purpose of this invention is to provide a simple, efficient and highly selective method for synthesizing chiral deuterated monofluoromethyl or monofluoromethyl or monofluorobis(arylsulfonyl)methyl substituted allyl compounds. The method of this invention has good substrate versatility, mild reaction conditions, and readily available raw materials and catalysts.

[0006] Another objective of this invention is to provide a series of chiral monofluorobis(arylsulfonyl)methyl and (deuterated) monofluoromethyl substituted allyl compounds with potential biological and pharmaceutical activity, providing effective technical support for new drug development.

[0007] This invention provides a method for synthesizing chiral monofluorobis(arylsulfonyl)methyl and / or monofluoromethyl and / or deuterated monofluoromethyl substituted allyl compounds. In solvent 1, 1,3-diene and fluorobisarylsulfonylmethane undergo an asymmetric hydrogen monofluoroalkylation reaction under the action of a chiral catalyst, and the resulting compound (I) can be isolated and purified. Further, in solvent 2, compound (I) can undergo a reductive desulfonation tandem reaction to generate chiral monofluoromethyl olefin compound (II) or deuterated chiral monofluoromethyl olefin compound (III).

[0008] The synthesis method of this invention is shown in the following reaction formula (A):

[0009]

[0010] Wherein, R is selected from C1-C20 alkyl, C1-C20 alkenyl, phenyl, C1-C10 alkyl-substituted aryl, halogen-substituted aryl, C1-C10 alkoxy-substituted aryl, and heteroaryl; wherein, the heteroaryl includes thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, and thiazole; R 1 It is a phenyl, a C1-C20 alkyl-substituted aryl, a halogen-substituted aryl, or a C1-C20 alkoxy-substituted aryl; wherein the chiral configuration at the allyl position can be either (R) or (S).

[0011] Specifically, the synthesis method of the present invention includes the following steps:

[0012] A catalyst, 1,3-diene, and fluorobis(arylsulfonyl)methane are added sequentially to a reaction vessel, followed by the addition of solvent. The reaction is stirred until TLC shows that the fluorobis(arylsulfonyl)methane has completely disappeared or remains almost unchanged, at which point the reaction is stopped. The solvent is removed by rotary evaporation, and the crude product is rapidly concentrated using a short column to obtain the crude product. Direct column chromatography purification yields chiral monofluorobis(arylsulfonyl)methyl-substituted allyl compounds of formula I. If solvent and reducing agent are added to this crude product, and the reaction is continued until TLC shows that intermediate I has completely disappeared or remains almost unchanged, column chromatography can be used to separate monofluoromethyl-substituted allyl compounds of formula II or III. The enantioselectivity (ee value) of formulas I, II, and III can be determined by high-performance liquid chromatography (HPLC).

[0013] In this invention, the chiral catalyst is a complex of a transition metal and a chiral ligand, wherein the transition metal is selected from one or more of iron, copper, nickel, palladium, rhodium, cobalt, and iridium; preferably, the transition metal is one or more of Ni(COD)2, Ni(OAc)2, Pd2(dba)3, and Pd(OAc)2.

[0014] In this invention, the chiral ligand is selected from one or more of chiral bioxazoline (pyridine) ligand, Salen ligand, Binap ligand, Josiphos ligand, PHOX ligand, QuinoxP ligand, and Segphos ligand; preferably, the chiral ligand is one or more of chiral bioxazoline ligand, Binap ligand, Josiphos ligand, PHOX ligand, and QuinoxP ligand.

[0015] In this invention, the reducing agent is a reducing metal, partially selected from one or more of iron, manganese, zinc, magnesium, and lithium; preferably, the metal reducing agent is one or more of iron, manganese, zinc, and magnesium.

[0016] In this invention, the amount of the chiral catalyst is based on the amount of fluorobis(aryl)sulfonylmethane, and is 0.1-50 mol%; preferably, it is 5 mol%, 10 mol%, or 20 mol%.

[0017] In this invention, the amount of reducing agent used is based on the amount of fluorobisbenzenesulfonylmethane, which is 1 to 50 equivalents; preferably, it is 10 to 30 equivalents.

[0018] In this invention, solvent 1 is selected from one or more of toluene, dichloromethane, ethyl acetate, tetrahydrofuran, acetone, acetonitrile, ethanol, methanol, isopropanol, tert-butanol, trifluoroethanol, etc.; preferably, it is toluene, tetrahydrofuran, or ethanol.

[0019] In this invention, the solvent 2 is selected from one or more of ethanol, methanol, deuterated methanol, isopropanol, tert-butanol, and trifluoroethanol; preferably, it is methanol or deuterated methanol.

[0020] In this invention, the amount of solvent 1 used is from 0.1 mL to 50 mL per millimole of fluorobis(aryl)sulfonylmethane; preferably, it is 5 mL and 10 mL.

[0021] In this invention, the amount of solvent 2 used is 0.1 mL to 50 mL per millimole of fluorobisbenzenesulfonylmethane; preferably, it is 5 mL and 10 mL.

[0022] In this invention, the molar ratio of the 1,3-diene to the fluorobis(arylsulfonylmethane) is (1-10):1; preferably, it is 1.5:1 or 2:1.

[0023] In this invention, the reaction temperature 1 is -10℃ to 100℃, and the reaction time is 0.5-96 hours; preferably, the reaction temperature 1 is 0℃ or 25℃, and the reaction time is 12 hours or 24 hours.

[0024] In this invention, the reaction temperature 2 is 0℃~100℃, and the reaction time is 1-7 days; preferably, the reaction temperature 2 is 25℃ or 50℃, and the reaction time is 12 hours or 24 hours.

[0025] In this invention, the 1,3-diene has the structure shown in formula (a):

[0026]

[0027] Wherein, R is selected from C1-C20 alkyl, C1-C20 alkenyl, phenyl, C1-C10 alkyl-substituted aryl, halogen-substituted aryl, C1-C10 alkoxy-substituted aryl, and heteroaryl; wherein, the heteroaryl includes thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, and thiazole;

[0028] Preferably, R is phenyl, naphthyl, thiophene, furan, p-methylphenyl, p-fluorophenyl, p-chlorophenyl, p-methoxyphenyl, n-pentyl, cyclohexyl, or phenethyl.

[0029] In this invention, the fluorobisarylsulfonylmethane has the structure shown in formula (b):

[0030]

[0031] Among them, R 1 It can be phenyl, C1-C20 alkyl-substituted aryl, halogen-substituted aryl, or C1-C20 alkoxy-substituted aryl;

[0032] Preferably, the fluorophenyl, naphthyl, p-methylphenyl, p-fluorophenyl, p-chlorophenyl, or p-methoxyphenyl. This type of fluorobis(benzenesulfonyl)methane can be conveniently synthesized according to literature methods [(a) U. Sankar, S. Mahalakshmi, KK Balasubramanian, Synlett 2013, 24, 1533; (b) M. Urban, M. Franc, M. Hofmanová, I. J. Org. Biomol. Chem. 2017, 15, 9071]

[0033] The synthetic method of this invention features mild reaction conditions and a broad substrate range, applicable not only to aryl-substituted alkenes but also to chain-alkyl-substituted alkenes. Furthermore, unlike the radical mechanism of traditional photocatalytic hydrofluoric acid alkylation reactions, it avoids the use of strong oxidants. In addition, the sulfone group is easily removed, allowing for a simple one-step synthesis of monofluoromethyl alkenes. The reaction can also proceed smoothly by tandem hydrofluoric acid alkylation and sulfone removal, providing a novel synthetic strategy for monofluoromethyl compounds.

[0034] The present invention also provides a chiral monofluorobis(arylsulfonyl)methyl-substituted allyl compound, the structural formula of which is shown in formula (I) below:

[0035]

[0036] in,

[0037] R is selected from C1-C20 alkyl, C1-C20 alkenyl, phenyl, C1-C10 alkyl-substituted aryl, halogen-substituted aryl, C1-C10 alkoxy-substituted aryl, and heteroaryl; wherein the heteroaryl includes thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, and thiazole.

[0038] R 1It can be phenyl, C1-C20 alkyl-substituted aryl, halogen-substituted aryl, or C1-C20 alkoxy-substituted aryl; the chiral configuration at the allyl position can be either (R) or (S).

[0039] Preferably, R is a C1-C10 alkyl, phenyl, C1-C10 alkyl-substituted phenyl, halogen-substituted phenyl, C1-C10 alkoxy-substituted phenyl, thiophene, furan, or pyridine;

[0040] R 1 It is a phenyl, a C1-C10 alkyl-substituted phenyl, a halogen-substituted phenyl, or a C1-C10 alkoxy-substituted phenyl.

[0041] More preferably, R is phenyl, naphthyl, thiophene, furan, p-methylphenyl, p-fluorophenyl, p-chlorophenyl, p-methoxyphenyl, n-pentyl, cyclohexyl, or phenethyl;

[0042] R 1 It can be phenyl, naphthyl, p-methylphenyl, p-fluorophenyl, p-chlorophenyl, or p-methoxyphenyl.

[0043] Preferably, the structure of formula (I) is as follows:

[0044]

[0045] The present invention also provides a chiral monofluoromethyl-substituted allyl compound, the structural formula of which is shown in formula (II) below:

[0046]

[0047] in,

[0048] R is selected from C1-C20 alkyl, C1-C20 alkenyl, phenyl, C1-C10 alkyl-substituted aryl, halogen-substituted aryl, C1-C10 alkoxy-substituted aryl, and heteroaryl; wherein the heteroaryl includes thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, and thiazole.

[0049] The chiral configuration at the allyl position can be either (R) or (S).

[0050] Preferably, R is a C1-C10 alkyl, phenyl, C1-C10 alkyl-substituted phenyl, halogen-substituted phenyl, C1-C10 alkoxy-substituted phenyl, thiophene, furan, or pyridine;

[0051] More preferably, R is phenyl, naphthyl, thiophene, furan, p-methylphenyl, p-fluorophenyl, p-chlorophenyl, p-methoxyphenyl, n-pentyl, cyclohexyl, or phenethyl.

[0052] More preferably, the structure of formula (II) is as follows:

[0053] The invention also provides a chiral deuterated monofluoromethyl substituted allyl compound, the structural formula of which is shown in formula (Ⅲ) below:

[0054]

[0055] in,

[0056] R is selected from C1-C20 alkyl, C1-C20 alkenyl, phenyl, C1-C10 alkyl-substituted aryl, halogen-substituted aryl, C1-C10 alkoxy-substituted aryl, and heteroaryl; wherein the heteroaryl includes thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, and thiazole.

[0057] The chiral configuration at the allyl position can be either (R) or (S).

[0058] Preferably, R is a C1-C10 alkyl, phenyl, C1-C10 alkyl-substituted phenyl, halogen-substituted phenyl, C1-C10 alkoxy-substituted phenyl, thiophene, furan, or pyridine;

[0059] More preferably, R is phenyl, naphthyl, thiophene, furan, p-methylphenyl, p-fluorophenyl, p-chlorophenyl, p-methoxyphenyl, n-pentyl, cyclohexyl, or phenethyl.

[0060] More preferably, the structure of formula (III) is as follows:

[0061]

[0062] This invention also proposes the application of the chiral monofluorobis(arylsulfonyl)methyl and / or monofluoromethyl substituted allyl compounds in the preparation of drug molecules. Monofluoromethyl dihydroxyphenylalanine can inhibit dopa deacidase in vivo; monofluoromethyl histidine can inhibit histidine decarboxylase in vivo; sofosbuvir, a drug containing a monofluoroalkyl structural unit, is a first-line drug for the treatment of hepatitis C; florfenicol reduces the drug resistance of some bacteria by introducing a monofluoromethyl group.

[0063] The present invention provides a class of chiral monofluoroalkyl(methyl)-substituted allyl compounds and their asymmetric catalytic synthesis method, which has high practical value. At the same time, the method has significant beneficial effects: the raw materials are inexpensive and readily available; the reaction conditions are mild and the operation is simple and convenient; the substrates have a wide range of applicability, and all can achieve good yields and good to excellent enantioselectivity (up to 99% yield and 99% ee value); chiral monofluorobis(arylsulfonyl)methyl and monofluoromethyl-substituted allyl compounds have important potential pharmaceutical value. Detailed Implementation

[0064] The present invention is further described in detail below with reference to the embodiments shown. These embodiments illustrate different aspects of the invention, but the scope of protection of the invention is not limited to these embodiments. Variations and advantages that can be conceived by those skilled in the art without departing from the spirit and scope of the inventive concept are included in the invention and are protected by the appended claims. The processes, conditions, reagents, experimental methods, etc., used to implement the invention, except as specifically mentioned below, are all common knowledge and general knowledge in the art, and the invention does not have any particular limitations. The data given in the following embodiments include the operation and reaction conditions and products of asymmetric synthesis. Enantioselectivity (ee value) was determined by HPLC.

[0065] Example: Synthesis of chiral monofluorobis(arylsulfonyl)methyl-substituted allyl compounds III-1 to III-16

[0066] Example 1

[0067]

[0068] In a glove box, Ni(COD)₂ (3.4 mg, 0.0125 mmol), chiral ligand (S,S)-QuinoxP* (4.6 mg, 0.01375 mmol), 1,3-diene II-1 (48.8 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at room temperature for 3 days under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and column chromatography was performed using petroleum ether / ethyl acetate as eluent (8:1). 95.6 mg of a white solid, III-1, was obtained in 86% yield. HPLC analysis (Chiralcel OX-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major) = 17.12 min, t r (minor)=19.18min gave the isomeric composition of the product:96%ee; [α] D 20 = -56.0 (c = 0.04, CHCl3); 11H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 7.6 Hz, 2H), 7.81 (d, J = 7.2 Hz, 2H), 7.70 (t, J = 7.6 Hz, 1H), 7.60 - 7.57 (m, 1H), 7.55 - 7.51 (m, 2H), 7.44 - 7.40 (m, 2H), 7.30 - 7.21 (m, 5H), 6.31 - 6.22 (m, 2H), 3.53 - 3.45 (m, 1H), 1.68 (d, J = 7.2 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 136.5, 136.4, 136.0, 135.0, 134.8, 133.7 (d, J = 2.0 Hz), 131.0 (d, J = 2.0 Hz), 130.8 (d, J = 2.0 Hz), 128.8, 128.7, 128.4, 127.8, 126.5, 125.5 (d, J = 5.0 Hz), 116.2 (d, J = 264.0 Hz), 41.5 (d, J = 18.0 Hz), 15.0 (d, J = 5.0 Hz); 19 19F NMR (376 MHz, CDCl3): δ -130.17 (s, 1F); IR (neat): 1448, 1344, 1169, 1151, 1076, 970, 752, 723, 685, 588, 572 cm -1 ; HRMS (ESI): Exact mass calcd for C 23 H 21 FnaO4S2 [M+Na] + : 467.0758, Found: 467.0769.

[0069] Example 2

[0070]

[0071] In a glove box, Ni(COD)₂ (3.4 mg, 0.0125 mmol), chiral ligand (R,R)-QuinoxP* (4.6 mg, 0.01375 mmol), 1,3-diene II-1 (48.8 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at room temperature for 2 days under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and column chromatography was performed using petroleum ether / ethyl acetate as eluent (8:1). 94.5 mg of a white solid product III-2 was obtained in 85% yield. HPLC analysis (Chiralcel OX-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major) = 19.18 min, t r (minor)=17.12min gave the isomeric composition of the product:97%ee; [α] D 20 = +56.0 (c = 0.04, CHCl3); 1 H NMR (400MHz, CDCl3): δ7.93(d,J=7.6Hz,2H),7.81(d,J=7.2Hz,2H),7.70(t,J=7.6Hz,1H),7.60-7.57(m,1H),7.5 5-7.51(m,2H),7.44-7.40(m,2H),7.30-7.21(m,5H),6.31-6.22(m,2H),3.53-3.45(m,1H),1.68(d,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3): δ136.5, 136.4, 136.0, 135.0, 134.8, 133.7 (d, J = 2.0Hz), 131.0 (d, J = 2.0Hz), 130.8 (d, J = 2.0Hz) ,128.8,128.7,128.4,127.8,126.5,125.5(d,J=5.0Hz),116.2(d,J=264.0Hz),41.5(d,J=18.0Hz),15.0(d,J=5.0Hz); 19 F NMR (376MHz, CDCl3): δ-130.17 (s, 1F).

[0072] Example 3

[0073]

[0074] In a glove box, Ni(COD)₂ (13.8 mg, 0.05 mmol) and chiral ligand (S,S) were added sequentially to a 25.0 mL Schlenk tube. p Phosferrox (22.4 mg, 0.055 mmol), 1,3-diene II-2 (54.1 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added. The reaction tube was then removed from the glove box, and the reaction was carried out at room temperature for 4 days under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and column chromatography was performed using petroleum ether / ethyl acetate as eluent (8:1). 113.5 mg of a white solid product III-3 was obtained in 99% yield. HPLC analysis (Chiralcel OX-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major) = 18.43 min, t r (minor)=20.76min gave the isomeric composition of the product:94%ee.[α] D 20 = -70.9 (c = 0.04, CHCl3); 1 H NMR (400MHz, CDCl3): δ7.93(d,J=8.0Hz,2H),7.80(d,J=8.0Hz,2H),7.69(t,J=7.2Hz,1H),7.58(t,J=7.6Hz,1H),7.52(t,J=7 .6Hz,2H),7.41(t,J=7.6Hz,2H),7.14-7.07(m,4H),6.21-6.20(m,2H),3.51-3.43(m,1H),2.32(s,3H),1.67(d,J=7.2Hz,3H); 13C NMR (100MHz, CDCl3): δ137.6, 136.5, 136.0, 135.0, 134.8, 133.62, 133.60, 131.0 (d, J = 1.8Hz), 130.7 (d, J = 1.8Hz), 129.1, 128.8, 128.7, 126.4, 124.4 (d, J = 5.6Hz), 116.2 (d, J = 264.5Hz), 41.5 (d, J = 17.8Hz), 21.1, 15.0 (d, J = 5.0Hz); 19 F NMR (376MHz, CDCl3): δ-129.94 (s, 1F); IR (neat): 1448,1339,1149,1072,970,800,723,683,580,571cm -1 ;HRMS(ESI):Exact mass calcd for C 24 H 23 FnaO4S2[M+Na] + :481.0914,Found:481.0919.

[0075] Example 4

[0076]

[0077] In a glove box, Ni(COD)₂ (13.8 mg, 0.05 mmol), chiral ligand (S)-PhPHOX (28.0 mg, 0.055 mmol), 1,3-diene II-3 (60.1 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at room temperature for 5 days under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and column chromatography was performed using petroleum ether / ethyl acetate as eluent (8:1). 115.1 mg of the yellow liquid product III-4 was obtained in 97% yield. HPLC analysis (ChiralcelOX-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major) = 30.87 min, t r (minor)=33.36min gave the isomeric composition of the product:97%ee.[α] D 20=-161.8 (c = 0.1, CHCl3); 1 1H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.69 (t, J = 7.2 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.52 (t, J = 8.0 Hz, 2H), 7.41 (t, J = 8.0 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 6.19 (d, J = 15.6 Hz, 1H), 6.09 (dd, J = 15.6, 7.6 Hz, 1H), 3.80 (s, 3H), 3.52 - 3.43 (m, 1H), 1.67 (d, J = 7.2 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 159.3, 136.5, 135.9, 135.0, 134.7, 133.1 (d, J = 1.4 Hz), 131.0 (d, J = 1.8 Hz), 130.69 (d, J = 1.8 Hz), 129.1, 128.8, 128.6, 127.6, 123.1 (d, J = 5.7 Hz), 116.2 (d, J = 264.3 Hz), 113.8, 55.2, 41.5 (d, J = 17.8 Hz), 15.0 (d, J = 5.0 Hz); 19 19F NMR (376 MHz, CDCl3): δ -129.95 (s, 1F); IR (neat): 1510, 1448, 1339, 1252, 1167, 1149, 1076, 972, 910, 754, 723, 683, 553 cm -1 ; HRMS (ESI): Exact mass calcd for C 23 H + FnaO5S2 [M+Na] i : 497.0863, Found: 497.0871.

[0078] Example 5

[0079]

[0080] In a glove box, Ni(COD)₂ (6.9 mg, 0.025 mmol), chiral ligand (S)-PhPHOX (14.5 mg, 0.0275 mmol), 1,3-diene II-4 (74.3 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at room temperature for 2 days under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and column chromatography was performed using petroleum ether / ethyl acetate as eluent (8:1). 119.2 mg of a white solid product III-5 was obtained in 93% yield. HPLC analysis (ChiralcelOX-H, i PrOH / hexane=15 / 85,1.0mL / min,254nm; t r (major) = 15.36 min, t r (minor)=17.13min gave the isomeric composition of the product:97%ee.[α] D 20 = -104.6 (c = 0.08, CHCl3); 1 H NMR (400MHz, CDCl3): δ7.91(d,J=7.6Hz,2H),7.80(d,J=7.6Hz,2H),7.70(t,J=7.6Hz,1H),7.61(t,J=7.6Hz,1H),7.55-7.51(m,4H),7. 43(t,J=7.6Hz,2H),7.37(d,J=8.0Hz,2H),6.46(dd,J=16,7.6Hz,1H),6.32(d,J=15.6Hz,1H),3.58-3.49(m,1H),1.68(d,J=6.8Hz,3H); 13 C NMR (100MHz, CDCl3): δ139.9,136.3,135.8,135.1,134.9,132.3,131.0(d,J=1.7Hz),130.7(d,J=1.9Hz),129.6(q,J=24.0Hz),128.9,1 28.8, 128.4 (d, J = 5.9Hz), 126.7, 125.4 (q, J = 3.8Hz), 124.1 (q, J = 270.1Hz) 115.9 (d, J = 265.1Hz), 41.5 (d, J = 17.9Hz), 14.8 (d, J = 5.2Hz); 19F NMR (376MHz, CDCl3): δ-62.47 (s, 3F), -130.79 (s, 1F); IR (neat): 1614,1448,1325,1167,1066,974,816,754,685,574cm -1 ;HRMS(ESI):Exact mass calcd for C 24 H 20 F4NaO4S2[M+Na] + :535.0631,Found:535.0639.

[0081] Example 6

[0082]

[0083] In a glove box, Ni(COD)₂ (6.9 mg, 0.025 mmol) and chiral ligands (R, S) were added sequentially to a 25.0 mL Schlenk tube. p Josiphos (16.3 mg, 0.0275 mmol), 1,3-diene II-5 (61.7 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added. The reaction tube was then removed from the glove box, and the reaction was carried out at room temperature for 5 days under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and column chromatography was performed using petroleum ether / ethyl acetate as eluent (8:1). 104.2 mg of a white solid product III-6 was obtained in 87% yield. HPLC analysis (Chiralcel OX-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major) = 17.47 min, t r (minor)=20.04min gave the isomeric composition of the product:97%ee.[α] D 20 =-90.7 (c=0.06, CHCl3); 11H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H), 7.69 (t, J = 7.6 Hz, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 6.32 - 6.20 (m, 2H), 3.54 - 3.46 (m, 1H), 1.67 (d, J = 7.2 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 136.3, 135.8, 135.1, 134.90, 134.86, 133.4, 132.4 (d, J = 1.5 Hz), 130.9 (d, J = 1.8 Hz), 130.7 (d, J = 1.9 Hz), 128.8, 128.7, 128.5, 127.7, 126.2 (d, J = 5.7 Hz), 116.0 (d, J = 264.7 Hz), 41.4 (d, J = 17.9 Hz), 14.8 (d, J = 5.1 Hz); 19 19F NMR (376 MHz, CDCl3): δ -130.46 (s, 1F); IR (neat): 1497, 1448, 1337, 1167, 1088, 972, 752, 682, 586, 532 cm -1 ; HRMS (ESI): Exact mass calcd for C 23 H 20 ClFNaO4S2 [M + Na] + : 501.0368, Found: 501.0365.

[0084] Example 7

[0085]

[0086] In a glove box, Ni(COD)₂ (6.9 mg, 0.025 mmol), chiral ligand (S)-Tol-Binap (18.7 mg, 0.0275 mmol), 1,3-diene II-6 (55.6 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at room temperature for 1 day under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and column chromatography was performed using petroleum ether / ethyl acetate as eluent (8:1). 85.6 mg of the white solid product III-7 was obtained in 74% yield. HPLC analysis (Chiralcel OX-H, i PrOH / hexane=20 / 80,1.0mL / min,205nm; t r (major) = 19.55 min, t r (minor)=22.49min gave the isomeric composition of the product:99%ee.[α] D 20 = -38.5 (c = 0.03, CHCl3); 1 H NMR (400MHz, CDCl3): δ7.92(d,J=8.0Hz,2H),7.81(d,J=8.0Hz,2H),7.70(t,J=7.6Hz,1H),7.60(t,J=7.6Hz,1H),7.53(t,J=7.6Hz,2H),7.4 3(t,J=7.6Hz,2H),7.27-7.21(m,1H),7.03(d,J=7.6Hz,1H),6.94-6.91(m,2H),6.33-6.21(m,2H),3.55-3.47(m,1H),1.68(d,J=7.2Hz,3H); 13C NMR (100MHz, CDCl3): δ162.3 (d, J = 245.7Hz), 135.3, 135.8, 135.0, 134.8, 132 .5(d,J=3.3Hz),132.4,130.9(d,J=1.8Hz),130.7(d,J=2.0Hz),128.7(d,J=1 2.3Hz),128.0(d,J=8.0Hz),125.24(d,J=2.3Hz),125.18(d,J=2.3Hz),116.0 (d, J = 264.5Hz), 115.3 (d, J = 21.5Hz), 41.4 (d, J = 17.9Hz), 14.9 (d, J = 5.1Hz); 19 F NMR (376MHz, CDCl3): δ-113.95 (s, 1F), -130.40 (s, 1F); IR (neat): 1508,1448,1344,1229,1151,1078,1074,972,754,723,684,638,582cm -1 ;HRMS(ESI):Exactmass calcd for C 23 H 20 F2NaO4S2[M+Na] + :485.0663,Found:485.0672.

[0087] Example 8

[0088]

[0089] In a glove box, Ni(COD)₂ (6.9 mg, 0.025 mmol), chiral ligand I-DTBM-Seghos (32.4 mg, 0.0275 mmol), 1,3-diene II-7 (67.6 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at room temperature for 2 days under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and column chromatography was performed using petroleum ether / ethyl acetate as eluent (8:1). 119.9 mg of the white solid product III-8 was obtained in 97% yield. HPLC analysis (Chiralcel OX-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major) = 24.44 min, t r(minor) = 27.99 min gave the isomeric composition of the product: 99% ee. [α] D 20 = -81.7 (c = 0.04, CHCl3); 1 1H NMR (400 MHz, CDCl3): δ 7.95 (d, J = 7.6 Hz, 2H), 7.83 - 7.73 (m, 5H), 7.69 (t, J = 8.0 Hz, 1H), 7.59 (s, 1H), 7.57 - 7.51 (m, 3H), 7.47 - 7.37 (m, 5H), 6.44 - 6.34 (m, 2H), 3.61 - 3.52 (m, 1H), 1.73 (d, J = 6.8 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 136.6, 136.1, 135.0, 134.8, 133.9, 133.8 (d, J = 2.0 Hz), 133.4, 133.1, 131.1 (d, J = 2.0 Hz), 130.8 (d, J = 2.0 Hz), 128.8, 128.7, 128.1, 127.9, 127.6, 126.4, 126.3, 125.96, 125.89 (d, J = 5.0 Hz), 123.7, 116.3 (d, J = 264.0 Hz), 41.6 (d, J = 18.0 Hz), 15.0 (d, J = 5.0 Hz); 19 19F NMR (376 MHz, CDCl3): δ -130.09 (s, 1F); IR (neat): 1448, 1346, 1169, 1151, 1078, 812, 752, 684, 584, 571, 546 cm -1 ; HRMS (ESI): Exact mass calcd for C 27 H 23 FNaO4S2 [M + Na] + : 517.0914, Found: 517.0927.

[0090] Example 9

[0091]

[0092] In a glove box, Ni(COD)₂ (6.9 mg, 0.025 mmol), chiral ligand (S,S)-Ph-Box (9.2 mg, 0.0275 mmol), 1,3-diene II-8 (45.0 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at room temperature for 1 day under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and column chromatography was performed using petroleum ether / ethyl acetate as eluent (8:1). 92.3 mg of the yellow solid product III-9 was obtained in 85% yield. HPLC analysis (Chiralcel OX-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major) = 21.03 min, t r (minor)=24.41min gave the isomeric composition of the product:93%ee.[α] D 20 = -84.2 (c = 0.07, CHCl3); 1 H NMR (400MHz, CDCl3): δ7.94(d,J=8.0Hz,2H),7.78(d,J=7.6Hz,2H),7.70(t,J=7.2Hz,1H),7.60-7.51(m,3H)7.39(t,J=8.0Hz ,2H),7.29(s,1H),6.33-6.32(m,1H),6.15(d,J=3.2Hz,1H),6.08(d,J=3.2Hz,2H),3.52-3.45(m,1H),1.69(d,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3): δ151.9, 142.0, 136.5, 136.0, 135.0, 134.6, 131.1 (d, J = 2.0Hz), 130.7 (d, J = 2.0Hz), 128.8, 128. 6,124.0(d,J=5.8Hz),121.9(d,J=1.5Hz),116.2(d,J=264.2Hz),111.2,108.3,40.9(d,J=17.6Hz),14.5(d,J=5.3Hz); 19F NMR (376MHz, CDCl3): δ-130.13 (s, 1F); IR (neat): 1448,1339,1169,1151,1078,966,754,685,690,576cm -1 ;HRMS(ESI):Exact mass calcd for C 21 H 19 FNaO5S2[M+Na] + :457.0550,Found:457.0553.

[0093] Example 10

[0094]

[0095] In a glove box, Ni(COD)₂ (6.9 mg, 0.025 mmol), chiral ligand (S,S)-Ph-Box (9.2 mg, 0.0275 mmol), 1,3-diene II-9 (51.1 mg, 0.375 mmol), fluorobis(benzenesulfonyl)methane I-1 (78.6 mg, 0.25 mmol), and anhydrous methanol (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at 50 °C for 6 days under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and column chromatography was performed using petroleum ether / ethyl acetate as eluent (8:1). 110.4 mg of a yellow solid, III-10, was obtained in 98% yield. HPLC analysis (Chiralcel OX-H, i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major) = 22.49 min, t r (minor)=25.71min gave the isomeric composition of the product:98%ee.[α] D 20 = -59.1 (c = 0.07, CHCl3); 11H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.70 (t, J = 7.2 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.53 (t, J = 7.6 Hz, 2H), 7.42 (t, J = 8.0 Hz, 2H), 7.14 (d, J = 5.2 Hz, 1H), 6.92 (t, J = 3.6 Hz, 1H), 6.86 (d, J = 3.6 Hz, 1H), 6.36 (d, J = 7.6 Hz, 1H), 5.98 (dd, J = 15.6, 7.6 Hz, 1H), 3.54 - 3.45 (m, 1H), 1.69 (d, J = 7.2 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 141.3, 136.4, 135.8, 135.0, 134.8, 131.1 (d, J = 1.8 Hz), 130.6 (d, J = 1.9 Hz), 128.8, 128.7, 127.2, 126.9 (d, J = 1.5 Hz), 125.9, 124.8 (d, J = 5.6 Hz), 124.6, 116.1 (d, J = 264.3 Hz), 41.1 (d, J = 17.5 Hz), 14.7 (d, J = 5.0 Hz); 19 19F NMR (376 MHz, CDCl3): δ -129.83 (s, 1F); IR (neat): 1583, 1448, 1344, 1151, 1078, 960, 754, 684, 570 cm -1 ; HRMS (ESI): Exact mass calcd for C 21 H 19 19FNaO4S3 [M + Na] + : 473.0322, Found: 473.0321.

[0096] Example 11

[0097]

[0098] In a glove box, Ni(COD)₂ (3.4 mg, 0.0125 mmol), chiral ligand (S,S)-QuinoxP* (4.6 mg, 0.01375 mmol), conjugated triene II-10 (78.1 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at room temperature for 3 days under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and column chromatography was performed using petroleum ether / ethyl acetate as eluent (8:1). 116.5 mg of colorless liquid product III-11 was obtained in 99% yield. HPLC analysis (Chiralcel AD-H) was performed. i PrOH / hexane=20 / 80,1.0mL / min,254nm; t r (major) = 19.29 min, t r (minor)=22.40min gave the isomeric composition of the product:97%ee.[α] D 20 = -69.7 (c = 0.06, CHCl3); 1 H NMR (400MHz, CDCl3): δ7.91(d,J=8.0Hz,2H),7.82(d,J=7.6Hz,2H),7.69(t,J=7.2Hz,1H ),7.63(t,J=8.0Hz,1H),7.53(t,J=8.0Hz,2H),7.47(t,J=7.6Hz,2H),7.37-7.29(m,4H) ,7.24-7.21(m,1H),6.63(dd,J=15.6,10.4Hz,1H),6.45(d,J=15.6Hz,1H),6.07(dd,J=1 5.6,10.4Hz,1H),5.90(dd,J=14.8,8.0Hz,1H),3.46-3.37(m,1H),1.64(d,J=7.2Hz,3H); 13C NMR (100MHz, CDCl3): δ136.9, 136.4, 135.9, 135.0, 134.8, 134.2, 132.8, 131.0 (d, J = 1.8Hz), 130.8 (d, J = 2.0Hz), 129.3 (d,J=5.7Hz),128.8,128.7,128.6,128.1,127.6,126.3,116.1(d,J=264.6Hz),41.3(d,J=17.9Hz),14.9(d,J=4.9Hz); 19 F NMR (376MHz, CDCl3): δ-130.18 (s, 1F); IR (neat): 1448,1340,1169,1151,1080,991,750,685,580,569cm -1 ;HRMS(ESI):Exact mass calcd forC 25 H 23 FNaO4S2[M+Na] + :493.0914,Found:493.0916.

[0099] Example 12

[0100]

[0101] In a glove box, Ni(OAc)₂ (2.2 mg, 0.0125 mmol), chiral ligand (S,S)-QuinoxP* (4.6 mg, 0.01375 mmol), 1,3-diene II-11 (46.6 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at room temperature for 3 days under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and column chromatography was performed using petroleum ether / ethyl acetate as eluent (8:1). 73.5 mg of the yellow liquid product III-12 was obtained in 67% yield. HPLC analysis (Chiralcel OD-H, i PrOH / hexane=10 / 90,1.0mL / min,230nm; t r (major) = 10.72 min, t r (minor)=11.41min gave the isomeric composition of the product:93%ee.[α] D 20=-7.2 (c = 0.06, CHCl3); 1 1H NMR (400 MHz, CDCl3): δ 7.90 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.71 - 7.64 (m, 2H), 7.54 - 7.47 (m, 4H), 5.54 - 5.48 (m, 1H), 5.39 - 5.32 (m, 1H), 3.31 - 3.22 (m, 1H), 1.93 - 1.87 (m, 2H), 1.56 (d, J = 6.4 Hz, 3H), 1.30 - 1.22 (m, 6H), 0.88 (t, J = 6.8 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 136.7, 136.0, 135.7 (d, J = 1.4 Hz), 134.9, 134.7, 130.9 (d, J = 1.9 Hz), 130.7 (d, J = 2.1 Hz), 128.7, 128.6, 125.4 (d, J = 5.6 Hz), 116.2 (d, J = 263.9 Hz), 41.3 (d, J = 17.8 Hz), 32.3, 31.2, 28.5, 22.4, 15.2 (d, J = 5.1 Hz), 14.0; 19 19F NMR (376 MHz, CDCl3): δ -129.78 (s, 1F); IR (neat): 2922, 1583, 1448, 1336, 1151, 972, 754, 723, 682, 570 cm -1 ; HRMS (ESI): Exact mass calcd for C 22 H 27 FNaO4S2 [M + Na] + : 461.1227, Found: 461.1236.

[0102] Example 13

[0103]

[0104] In a glove box, Pd(OAc)₂ (2.8 mg, 0.0125 mmol), chiral ligand (S,S)-QuinoxP* (4.6 mg, 0.01375 mmol), 1,3-diene II-11 (59.3 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at 70°C for 2 days under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and column chromatography was performed using petroleum ether / ethyl acetate as eluent (8:1). 95.7 mg of a white solid product III-13 was obtained in 81% yield. HPLC analysis (Chiralcel OD-H, i PrOH / hexane=20 / 80,1.0mL / min,205nm; t r (major) = 15.14 min, t r (minor)=17.59min gave the isomeric composition of the product:90%ee.[α] D 20 =-19.9 (c=0.1, CHCl3); 1 H NMR (400MHz, CDCl3): δ7.89(d,J=8.0Hz,2H),7.80(d,J=8.0Hz,2H),7.70-7.63(m,2H),7.53-7.45(m,4H),7.29-7.25(m,2H),7.20-7.12(m,3H) ,5.57(dd,J=15.6,8.0Hz,1H),5.41(dt,J=15.2,6.4Hz,1H),3.30-3.21 (m,1H),2.59(t,J=7.6Hz,2H),2.26-2.20(m,2H),1.54(d,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3): δ141.5, 136.6, 136.0, 134.9, 134.8, 134.5 (d, J = 1.5Hz), 130.9 (d, J = 1.9Hz), 130.7 (d, J = 2.0Hz), 128. 7,128.6,128.4,128.2,126.3(d,J=5.6Hz),125.8,116.1(d,J=264.2Hz),41.3(d,J=17.9Hz),35.3,34.0,15.2(d,J=5.2Hz); 19F NMR (376MHz, CDCl3): δ-129.93 (s, 1F); IR (neat): 1448,1339,1166,1149,1078,972,752,683,576,561cm -1 ;HRMS(ESI):Exactmass calcd forC 25 H 25 FNaO4S2[M+Na] + :495.1071,Found:495.1072.

[0105] Example 14

[0106]

[0107] In a glove box, Pd(OAc)₂ (2.8 mg, 0.0125 mmol), chiral ligand (S,S)-QuinoxP* (4.6 mg, 0.01375 mmol), 1,3-diene II-13 (66.9 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous toluene (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at 40°C for 5 days under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and column chromatography was performed using petroleum ether / ethyl acetate as eluent (8:1). 51.7 mg of the colorless liquid product III-14 was obtained in 42% yield. HPLC analysis (Chiralcel OD-H, i PrOH / hexane=20 / 80,1.0mL / min,205nm; t r (major) = 15.14 min, t r (minor)=17.59min gave the isomeric composition of the product:90%ee.[α] D 20 =-19.9 (c=0.1, CHCl3); 11H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H), 7.70 - 7.63 (m, 2H), 7.53 - 7.45 (m, 4H), 7.29 - 7.25 (m, 2H), 7.20 - 7.12 (m, 3H), 5.57 (dd, J = 15.6, 8.0 Hz, 1H), 5.41 (dt, J = 15.2, 6.4 Hz, 1H), 3.30 - 3.21 (m, 1H), 2.59 (t, J = 7.6 Hz, 2H), 2.26 - 2.20 (m, 2H), 1.54 (d, J = 7.2 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 141.5, 136.6, 136.0, 134.9, 134.8, 134.5 (d, J = 1.5 Hz), 130.9 (d, J = 1.9 Hz), 130.7 (d, J = 2.0 Hz), 128.7, 128.6, 128.4, 128.2, 126.3 (d, J = 5.6 Hz), 125.8, 116.1 (d, J = 264.2 Hz), 41.3 (d, J = 17.9 Hz), 35.3, 34.0, 15.2 (d, J = 5.2 Hz); 19 19F NMR (376 MHz, CDCl3): δ -129.93 (s, 1F); IR (neat): 1448, 1339, 1166, 1149, 1078, 972, 752, 683, 576, 561 cm -1 ; HRMS (ESI): Exact mass calcd for C 25 H 25 19FNaO4S2 [M + Na] + : 495.1071, Found: 495.1072.

[0108] Example 15

[0109]

[0110] In a glove box, Pd2(dba)3 (11.4 mg, 0.0125 mmol), chiral ligand (S,S)-QuinoxP* (4.6 mg, 0.01375 mmol), 1,3-diene II-1 (48.8 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-2 (95.3 mg, 0.25 mmol), and tetrahydrofuran (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at 50 °C for 5 days under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and column chromatography was performed using petroleum ether / ethyl acetate as eluent (8:1). 120.6 mg of a yellow solid, product III-15, was obtained in 94% yield. HPLC analysis (Chiralcel AD-H) was performed. i PrOH / hexane=15 / 85,1.0mL / min,254nm; t r (major) = 18.17 min, t r (minor)=18.95min gave the isomeric composition of the product:97%ee.[α] D 20 = -45.5 (c = 0.04, CHCl3); 1 H NMR (400MHz, CDCl3): δ7.89(d,J=8.4Hz,2H),7.73(d,J=8.0Hz,2H),7.53(d,J=8.4Hz,2H),7.38(d,J=8.4Hz,2H),7.33-7.29(m,2H), 7.26-7.25(m,1H),7.22-7.20(m,2H),6.27(d,J=16.0Hz,1H),6.13(dd,J=16.0,7.6Hz,1H),3.54-3.45(m,1H),1.68(d,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3): δ142.3, 142.2, 136.1, 134.8, 134.3, 133.9 (d, J = 1.5Hz), 132.5 (d, J = 1.9Hz), 132.1 (d, J = 2.1Hz) ,129.2,129.1,128.6,128.0,126.4,124.9(d,J=5.4Hz),116.3(d,J=264.1Hz),41.2(d,J=17.5Hz),14.7(d,J=5.2Hz); 19F NMR (376MHz, CDCl3): δ-130.52 (s, 1F); IR (neat): 2361,2341,1576,1475,1344,1168,1153,1091,970,824,752,694,567cm -1 ;HRMS(ESI):Exact mass calcdforC 23 H 19 Cl2FNaO4S2[M+Na] + :534.9978,Found:534.9973.

[0111] Example 16

[0112]

[0113] In a glove box, Pd2(dba)3 (11.4 mg, 0.0125 mmol), chiral ligand (S,S)-QuinoxP* (4.6 mg, 0.01375 mmol), 1,3-diene II-1 (48.8 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-3 (103.6 mg, 0.25 mmol), and tetrahydrofuran (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at 50 °C for 5 days under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and column chromatography was performed using petroleum ether / ethyl acetate as eluent (8:1). 134.8 mg of a yellow solid, product III-16, was obtained in 99% yield. HPLC analysis (Chiralcel AD-H) was performed. i PrOH / hexane=40 / 60,1.0mL / min,254nm; t r (major) = 19.23 min, t r (minor)=27.98min gave the isomeric composition of the product:95%ee.[α] D 20 = -52.2 (c = 0.05, CHCl3); 1H NMR (400MHz, CDCl3): δ8.42(s,1H),8.24(s,1H),7.82-7.76(m,4H),7.72(d,J=8.0Hz,1H),7.67-7.53(m,6 H),7.47(t,J=7.6Hz,1H),7.21-7.16(m,5H),6.40-6.30(m,2H),3.75-3.67(m,1H),1.79(d,J=6.8Hz,3H); 13 C NMR (100MHz, CDCl3): δ136.4,135.7,135.6,133.7,133.4,133.2,133.0,132 .8,131.6,131.5,129.9,129.8,129.6,129.5,128.7(d,J=5.6Hz),128.4,127 .8,127.7,127.6,127.5,126.4,125.7(d,J=5.6Hz),124.7(d,J=2.6Hz),124. 4(d,J=3.2Hz), 116.6(d,J=264.2Hz), 41.5(d,J=17.8Hz), 15.2(d,J=5.0Hz); 19 F NMR (376MHz, CDCl3): δ-130.00 (s, 1F); IR (neat): 1340,1167,1130,1067,968,864,815,748,636,571cm -1 ;HRMS(ESI):Exact mass calcdforC 31 H 25 FNaO4S2[M+Na] + :567.1071,Found:567.1065.

[0114] Example: Synthesis of chiral monofluoromethyl-substituted allyl compounds IV-1 to IV-5

[0115] Example 17

[0116]

[0117] In a glove box, Ni(COD)₂ (6.9 mg, 0.025 mmol), chiral ligand (S,S)-QuinoxP* (9.2 mg, 0.0275 mmol), 1,3-diene II-1 (48.8 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at room temperature for 3 days under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and the crude product was rapidly passed through a short column and evaporated to dryness. Under a nitrogen atmosphere, methanol (2.5 mL) and active magnesium powder (120 mg, 5 mmol) were added sequentially to the crude product, and the reaction was carried out at 0°C for 12 hours. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. Water (3 mL) was added to the reaction system, the reaction was quenched with dilute hydrochloric acid (3 mL, 2 M), and the mixture was extracted with dichloromethane (2 × 15 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Column chromatography was performed, eluent (petroleum ether). 34.9 mg of colorless liquid product IV-1 was given in 85% yield. HPLC analysis (Chiralcel OD-H, i PrOH / hexane=0 / 100,1.0mL / min,254nm; t r (major) = 17.71 min, t r (minor)=13.90min gave theisomeric composition of the product:96%ee;[α] D 20 =-1.3 (c=0.02, CHCl3); 1 H NMR (400MHz, CDCl3): δ7.37-7.35(m,2H),7.32-7.28(m,2H),7.25-7.20(m,1H),6.58(d,J=16.0Hz,1H),6. 13(dd,J=16.0,7.6Hz,1H),4.46-4.44(m,1H),4.34-4.24(m,1H),2.81-2.67(m,1H),1.16(d,J=6.8Hz,3H); 13 C NMR (100MHz, CDCl3): δ137.2, 130.7, 130.5 (d, J = 6.6Hz), 128.5, 127.3, 126.1, 87.3 (d, J = 171.3Hz), 37.9 (d, J = 18.9Hz), 15.8 (d, J = 6.1Hz); 19F NMR (376MHz, CDCl3): δ-219.64 (s, 1F); IR (neat): 2966,1490,1215,1047,966,752,721,692,678,669cm -1 ;HRMS(ESI):Exact mass calcd forC 11 H 14 F[M+H] + :165.1080,Found:165.1079.

[0118] Example 18

[0119]

[0120] In a glove box, Ni(COD)₂ (6.9 mg, 0.025 mmol), chiral ligand (R,R)-QuinoxP* (9.2 mg, 0.0275 mmol), 1,3-diene II-1 (48.8 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at room temperature for 2 days under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and the crude product was rapidly passed through a short column and evaporated to dryness. Under a nitrogen atmosphere, methanol (2.5 mL) and activated magnesium powder (120 mg, 5 mmol) were added sequentially to the crude product, and the reaction was carried out at 0°C for 12 hours. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. Water (3 mL) was added to the reaction system, the reaction was quenched with dilute hydrochloric acid (3 mL, 2 M), and the mixture was extracted with dichloromethane (2 × 15 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Column chromatography was performed, eluent (petroleum ether). 36.1 mg of colorless liquid product IV-2 was given in 88% yield. HPLC analysis (Chiralcel OD-H, i PrOH / hexane=0 / 100,1.0mL / min,254nm; t r (major) = 13.90 min, t r (minor)=17.71min,gave theisomeric composition of the product:97%ee; [α] D 20 = +1.4 (c = 0.02, CHCl3); 1H NMR (400MHz, CDCl3): δ7.37-7.35(m,2H),7.32-7.28(m,2H),7.25-7.20(m,1H),6.58(d,J=16.0Hz,1H),6. 13(dd,J=16.0,7.6Hz,1H),4.46-4.44(m,1H),4.34-4.24(m,1H),2.81-2.67(m,1H),1.16(d,J=6.8Hz,3H); 13 C NMR (100MHz, CDCl3): δ137.2, 130.7, 130.5 (d, J = 6.6Hz), 128.5, 127.3, 126.1, 87.3 (d, J = 171.3Hz), 37.9 (d, J = 18.9Hz), 15.8 (d, J = 6.1Hz); 19 F NMR (376MHz, CDCl3): δ-219.64 (s, 1F).

[0121] Example 19

[0122]

[0123] In a glove box, Ni(COD)₂ (6.9 mg, 0.025 mmol), chiral ligand (S)-Tol-Binap (18.7 mg, 0.0275 mmol), 1,3-diene II-3 (60.1 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at room temperature for 1 day under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and the crude product was rapidly passed through a short column and evaporated to dryness. Under a nitrogen atmosphere, methanol (2.5 mL) and activated magnesium powder (120 mg, 5 mmol) were added sequentially to the crude product, and the reaction was carried out at room temperature for 12 hours. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. Water (3 mL) was added to the reaction system, the reaction was quenched with dilute hydrochloric acid (3 mL, 2 M), and extracted with dichloromethane (2 × 15 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Column chromatography was performed, using petroleum ether / dichloromethane = 10:1 as eluent. 42.7 mg of the colorless liquid product IV-3 was given in 88% yield. HPLC analysis (Chiralcel OD-H, i PrOH / hexane=0.1 / 99.9,1.0mL / min,254nm; t r (major) = 18.29 min, t r(minor) = 17.22 min gave the isomeric composition of the product: 96% ee. [α] D 20 = -8.3 (c = 0.06, CHCl3); 1 1H NMR (400 MHz, CDCl3): δ 7.31 - 7.24 (m, 2H), 6.86 - 6.82 (m, 2H), 6.41 (d, J = 16.0 Hz, 1H), 5.97 (dd, J = 16.0, 7.2 Hz, 1H), 4.44 - 4.34 (m, 1H), 4.32 - 4.22 (m, 1H), 3.79 (s, 3H), 2.78 - 2.63 (m, 1H), 1.15 (dd, J = 6.8, 1.2 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 158.9, 130.1, 130.0, 128.2 (d, J = 6.7 Hz), 127.2, 113.9, 87.4 (d, J = 171.1 Hz), 55.2, 37.8 (d, J = 18.9 Hz), 15.9 (d, J = 5.9 Hz); 19 19F NMR (376 MHz, CDCl3): δ -219.34 (s, 1F); IR (neat): 2964, 1606, 1510, 1246, 1033, 966, 910, 806, 750, 669, 532 cm -1 ; HRMS (ESI): Exact mass calcd for C 12 H 16 OF [M + H] + : 195.1185, Found: 195.1179.

[0124] Example 20

[0125]

[0126] In a glove box, Ni(COD)₂ (6.9 mg, 0.025 mmol), chiral ligand (R)-DTBM-Seghos (32.4 mg, 0.0275 mmol), 1,3-diene II-8 (45.0 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at room temperature for 24 hours under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and the crude product was rapidly passed through a short column and evaporated to dryness. Under a nitrogen atmosphere, methanol (2.5 mL) and activated magnesium powder (120 mg, 5 mmol) were added sequentially to the crude product, and the reaction was carried out at room temperature for 1 day. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. Water (3 mL) was added to the reaction system, the reaction was quenched with dilute hydrochloric acid (3 mL, 2 M), and the mixture was extracted with dichloromethane (2 × 15 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Column chromatography was performed, eluent (petroleum ether). 15.0 mg of colorless liquid product IV-4 was given in 39% yield. HPLC analysis (Chiralcel OD-H, i PrOH / hexane=0 / 100,1.0mL / min,254nm; t r (major) = 8.96 min, t r (minor)=8.36min)gave theisomeric composition of the product:96%ee.[α] D 20 = -3.2 (c = 0.03, CHCl3); 1 H NMR (400MHz, CDCl3): δ7.32 (d, J = 2.0Hz, 1H), 6.36-6.35 (m, 1H), 6.32-6.28 (m, 1H), 6.19 (d, J = 3.2Hz, 1H),6.08(dd,J=16.0,0.8Hz,1H),4.44-4.22(m,2H),2.76-2.65(m,1H),1.69(dd,J=6.8,0.8Hz,3H); 13 C NMR (100MHz, CDCl3): δ152.7, 141.6, 129.3 (d, J = 7.0Hz), 119.3, 111.2, 107.1, 84.1 (d, J = 117.0Hz), 37.6 (d, J = 19.0Hz), 15.7 (d, J = 6.0Hz); 19FNMR (376MHz, CDCl3): δ-219.35 (s, 1F); IR (neat): 2933,1215,1115,981,962,883,796,667,594cm -1 ;HRMS(ESI):Exact mass calcd for C9H 12 F[M+H] + :155.0872,Found:155.0866.

[0127] Example 21

[0128]

[0129] In a glove box, Ni(COD)₂ (6.9 mg, 0.025 mmol), chiral ligand (S,S)-Ph-Box (9.2 mg, 0.0275 mmol), 1,3-diene II-11 (59.3 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at room temperature for 3 days under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and the crude product was rapidly passed through a short column and evaporated to dryness. Under a nitrogen atmosphere, methanol (2.5 mL) and activated magnesium powder (120 mg, 5 mmol) were added sequentially to the crude product, and the reaction was carried out at room temperature for 12 hours. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. Water (3 mL) was added to the reaction system, the reaction was quenched with dilute hydrochloric acid (3 mL, 2 M), and the mixture was extracted with dichloromethane (2 × 15 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Column chromatography was performed, using petroleum ether as eluent. 41.3 mg of the colorless liquid product IV-5 was given in 86% yield. HPLC analysis (Chiralcel OD-H+OD-H, i PrOH / hexane=0 / 100,1.0mL / min,205nm; t r (major) = 18.81 min, t r (minor)=20.60mingave the isomeric composition of the product:93%ee.[α] D 20 = -4.4 (c = 0.06, CHCl3); 1H NMR (400MHz, CDCl3): δ7.30-7.26(m,2H),7.20-7.16(m,3H),5.60-5.52(m,1H),5.36-5.29(m,1H),4. 32-4.09(m,2H),2.69-2.65(m,2H),2.56-2.45(m,1H),2.35-2.29(m,2H),1.01(dd,J=6.8,1.2Hz,3H); 13 C NMR (100MHz, CDCl3): δ 141.8, 131.0 (d, J = 6.9Hz), 130.7, 128.5, 128.2, 125.7, 87.6 (d, J = 170.5Hz), 37.4 (d, J = 18.8Hz), 35.9, 34.5, 15.9 (d, J = 5.9Hz); 19 F NMR (376MHz, CDCl3): δ-219.30 (s, 1F); IR (neat): 2927,1454,1388,1215,1006,970,908,750,698,667,570cm -1 Exact mass calcd for C 13 H 18 F[M+H] + :193.1393,Found:193.1392.

[0130] Example: Synthesis of chiral deuterated monofluoromethyl substituted allyl compounds V-1 to V-5

[0131] Example 22

[0132]

[0133] In a glove box, Ni(COD)₂ (6.9 mg, 0.025 mmol), chiral ligand (S,S)-QuinoxP* (9.2 mg, 0.0275 mmol), 1,3-diene II-1 (48.8 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at room temperature for 3 days under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and the crude product was rapidly passed through a short column and evaporated to dryness. Under a nitrogen atmosphere, deuterated methanol (2.5 mL) and active magnesium powder (120 mg, 5 mmol) were added sequentially to the crude product, and the reaction was carried out at 0°C for 12 hours. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. Water (3 mL) was added to the reaction system, the reaction was quenched with dilute hydrochloric acid (3 mL, 2 M), and the mixture was extracted with dichloromethane (2 × 15 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Column chromatography was performed, eluent (petroleum ether). 34.9 mg of colorless liquid product V-1 was given in 85% yield. HPLC analysis (Chiralcel OD-H, i PrOH / hexane=0 / 100,1.0mL / min,254nm; t r (major) = 17.71 min, t r (minor)=13.90min gave theisomeric composition of the product:96%ee;[α] D 20 =-1.3 (c=0.02, CHCl3); 1 H NMR (400MHz, CDCl3): δ7.37-7.35(m,2H),7.32-7.28(m,2H),7.25-7.20(m,1H),6.58(d ,J=16.0Hz,1H),6.13(dd,J=16.0,7.6Hz,1H),2.81-2.67(m,1H),1.16(d,J=6.8Hz,3H); 13 CNMR (100MHz, CDCl3): δ137.2, 130.7, 130.5 (d, J = 6.6Hz), 128.5, 127.3, 126.1, 87.3 (d, J = 171.3Hz), 37.9 (d, J = 18.9Hz), 15.8 (d, J = 6.1Hz); 19F NMR (376MHz, CDCl3): δ-219.64 (s, 1F); IR (neat): 2966,1490,1215,1047,966,752,721,692,678,669cm -1 ;HRMS(ESI):Exactmass calcd for C 11 H 14 F[M+H] + :165.1080,Found:165.1079.

[0134] Example 23

[0135]

[0136] In a glove box, Ni(COD)₂ (6.9 mg, 0.025 mmol), chiral ligand (R,R)-QuinoxP* (9.2 mg, 0.0275 mmol), 1,3-diene II-1 (48.8 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at room temperature for 2 days under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and the crude product was rapidly passed through a short column and evaporated to dryness. Under a nitrogen atmosphere, deuterated methanol (2.5 mL) and active magnesium powder (120 mg, 5 mmol) were added sequentially to the crude product, and the reaction was carried out at 0°C for 12 hours. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. Water (3 mL) was added to the reaction system, the reaction was quenched with dilute hydrochloric acid (3 mL, 2 M), and the mixture was extracted with dichloromethane (2 × 15 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Column chromatography was performed, eluent (petroleum ether). 36.1 mg of colorless liquid product V-2 was given in 88% yield. HPLC analysis (Chiralcel OD-H, i PrOH / hexane=0 / 100,1.0mL / min,254nm; t r (major) = 13.90 min, t r (minor)=17.71min,gave theisomeric composition of the product:97%ee; [α] D 20 = +1.4 (c = 0.02, CHCl3); 1H NMR (400MHz, CDCl3): δ7.37-7.35(m,2H),7.32-7.28(m,2H),7.25-7.20(m,1H),6.58(d ,J=16.0Hz,1H),6.13(dd,J=16.0,7.6Hz,1H),2.81-2.67(m,1H),1.16(d,J=6.8Hz,3H); 13 CNMR (100MHz, CDCl3): δ137.2, 130.7, 130.5 (d, J = 6.6Hz), 128.5, 127.3, 126.1, 87.3 (d, J = 171.3Hz), 37.9 (d, J = 18.9Hz), 15.8 (d, J = 6.1Hz); 19 F NMR (376MHz, CDCl3): δ-219.64 (s, 1F).

[0137] Example 24

[0138]

[0139] In a glove box, Ni(COD)₂ (6.9 mg, 0.025 mmol), chiral ligand (S)-Tol-Binap (18.7 mg, 0.0275 mmol), 1,3-diene II-3 (60.1 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at room temperature for 1 day under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and the crude product was rapidly passed through a short column and evaporated to dryness. Under a nitrogen atmosphere, deuterated methanol (2.5 mL) and active magnesium powder (120 mg, 5 mmol) were added sequentially to the crude product, and the reaction was carried out at room temperature for 12 hours. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. Water (3 mL) was added to the reaction system, the reaction was quenched with dilute hydrochloric acid (3 mL, 2 M), and extracted with dichloromethane (2 × 15 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Column chromatography was performed, using petroleum ether / dichloromethane = 10:1 as eluent. 42.7 mg of colorless liquid product V-3 was given in 88% yield. HPLC analysis (Chiralcel OD-H, i PrOH / hexane=0.1 / 99.9,1.0mL / min,254nm; t r (major) = 18.29 min, t r(minor) = 17.22 min gave the isomeric composition of the product: 96% ee. [α] D 20 = -8.3 (c = 0.06, CHCl3); 1 1H NMR (400 MHz, CDCl3): δ 7.31 - 7.24 (m, 2H), 6.86 - 6.82 (m, 2H), 6.41 (d, J = 16.0 Hz, 1H), 5.97 (dd, J = 16.0, 7.2 Hz, 1H), 3.79 (s, 3H), 2.78 - 2.63 (m, 1H), 1.15 (dd, J = 6.8, 1.2 Hz, 3H); 13 13C NMR (100 MHz, CDCl3): δ 158.9, 130.1, 130.0, 128.2 (d, J = 6.7 Hz), 127.2, 113.9, 87.4 (d, J = 171.1 Hz), 55.2, 37.8 (d, J = 18.9 Hz), 15.9 (d, J = 5.9 Hz); 19 19F NMR (376 MHz, CDCl3): δ -219.34 (s, 1F); IR (neat): 2964, 1606, 1510 1246, 1033, 966, 910, 806, 750, 669, 532 cm -1 ; HRMS (ESI): Exact mass calcd for C 12 H 16 OF [M + H] + : 195.1185, Found: 195.1179.

[0140] Example 25

[0141]

[0142] In a glove box, Ni(COD)₂ (6.9 mg, 0.025 mmol), chiral ligand (R)-DTBM-Seghos (32.4 mg, 0.0275 mmol), 1,3-diene II-8 (45.0 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at room temperature for 24 hours under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and the crude product was rapidly passed through a short column and evaporated to dryness. Under a nitrogen atmosphere, deuterated methanol (2.5 mL) and active magnesium powder (120 mg, 5 mmol) were added sequentially to the crude product, and the reaction was carried out at room temperature for 1 day. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. Water (3 mL) was added to the reaction system, the reaction was quenched with dilute hydrochloric acid (3 mL, 2 M), and the mixture was extracted with dichloromethane (2 × 15 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Column chromatography was performed, eluent (petroleum ether). 15.0 mg of colorless liquid product V-4 was given in 39% yield. HPLC analysis (Chiralcel OD-H, i PrOH / hexane=0 / 100,1.0mL / min,254nm; t r (major) = 8.96 min, t r (minor)=8.36min)gave the isomeric composition of the product:96%ee.[α] D 20 = -3.2 (c = 0.03, CHCl3); 1 HNMR (400MHz, CDCl3): δ7.32(d,J=2.0Hz,1H),6.36-6.35(m,1H),6.32-6.28(m,1H),6.19(d ,J=3.2Hz,1H),6.08(dd,J=16.0,0.8Hz,1H),2.76-2.65(m,1H),1.69(dd,J=6.8,0.8Hz,3H); 13 C NMR (100MHz, CDCl3): δ152.7, 141.6, 129.3 (d, J = 7.0Hz), 119.3, 111.2, 107.1, 84.1 (d, J = 117.0Hz), 37.6 (d, J = 19.0Hz), 15.7 (d, J = 6.0Hz); 19F NMR (376MHz, CDCl3): δ-219.35 (s, 1F); IR (neat): 2933,1215,1115,981,962,883,796,667,594cm -1 ;HRMS(ESI):Exact mass calcd for C9H 12 F[M+H] + :155.0872,Found:155.0866.

[0143] Example 26

[0144]

[0145] In a glove box, Ni(COD)₂ (6.9 mg, 0.025 mmol), chiral ligand (S,S)-Ph-Box (9.2 mg, 0.0275 mmol), 1,3-diene II-11 (59.3 mg, 0.375 mmol), fluorobis(benzenesulfonylmethane) I-1 (78.6 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added sequentially to a 25.0 mL Schlenk tube. The reaction tube was then removed from the glove box, and the reaction was carried out at room temperature for 3 days under nitrogen protection. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. The reaction solution was concentrated, and the crude product was rapidly passed through a short column and evaporated to dryness. Under a nitrogen atmosphere, deuterated methanol (2.5 mL) and active magnesium powder (120 mg, 5 mmol) were added sequentially to the crude product, and the reaction was carried out at room temperature for 12 hours. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. Water (3 mL) was added to the reaction system, the reaction was quenched with dilute hydrochloric acid (3 mL, 2 M), and extracted with dichloromethane (2 × 15 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Column chromatography was performed, eluent (petroleum ether). 41.3 mg of colorless liquid product V-5 was given in 86% yield. HPLC analysis (Chiralcel OD-H+OD-H, i PrOH / hexane=0 / 100,1.0mL / min,205nm; t r (major) = 18.81 min, t r (minor)=20.60mingave the isomeric composition of the product:93%ee.[α] D 20 = -4.4 (c = 0.06, CHCl3); 1H NMR (400MHz, CDCl3): δ7.30-7.26(m,2H),7.20-7.16(m,3H),5.60-5.52(m,1H),5.36-5.29( m,1H),2.69-2.65(m,2H),2.56-2.45(m,1H),2.35-2.29(m,2H),1.01(dd,J=6.8,1.2Hz,3H); 13 C NMR (100MHz, CDCl3): δ 141.8, 131.0 (d, J = 6.9Hz), 130.7, 128.5, 128.2, 125.7, 87.6 (d, J = 170.5Hz), 37.4 (d, J = 18.8Hz), 35.9, 34.5, 15.9 (d, J = 5.9Hz); 19 F NMR (376MHz, CDCl3): δ-219.30 (s, 1F); IR (neat): 2927,1454,1388,1215,1006,970,908,750,698,667,570cm -1 Exact mass calcd for C 13 H 18 F[M+H] + :193.1393,Found:193.1392.

[0146] The above embodiments are merely illustrative of the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made based on the essence of the content of the present invention are covered within the scope of protection of the present invention.

Claims

1. A method for synthesizing a chiral monofluorobis(arylsulfonyl)methyl and / or monofluoromethyl substituted allylic compound and / or a deuterated monofluoromethyl substituted allylic compound, characterized in that, In solvent 1, 1,3-diene and fluorinated bis-aryl sulfonyl methane undergo asymmetric monofluoroalkylation under the action of a chiral catalyst to obtain compound formula (I) which can be separated and purified; and / or, in solvent 2, the compound formula (I) can further undergo reductive defluorination tandem reaction to generate chiral monofluoromethyl olefin compound formula (II) or deuterated chiral monofluoromethyl olefin compound formula (III); The method is shown in the following reaction formula (A): wherein R is selected from the group consisting of C1-C20 alkyl, C1-C20 alkenyl, phenyl, C1-C10 alkyl substituted aryl, halogen substituted aryl, C1-C10 alkoxy substituted aryl, heteroaryl; wherein the heteroaryl includes thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, thiazole; R 1 is phenyl, C1-C20 alkyl substituted aryl, halogen substituted aryl, C1-C20 alkoxy substituted aryl; wherein the chiral configuration of the allyl group can be either (R) configuration or (S) configuration; The chiral catalyst is a complex of transition metal and chiral ligand; wherein the transition metal is selected from one or more of iron, copper, nickel, palladium, rhodium, cobalt, iridium; the chiral ligand is selected from one or more of chiral bis-oxazoline (pyridine) ligand, Salen ligand, Binap ligand, Josiphos ligand, PHOX ligand, QuinoxP ligand, Segphos ligand.

2. The method of synthesis of claim 1, wherein, The amount of the chiral catalyst is 0.1-50 mol% based on the amount of the fluorinated bis-aryl sulfonyl methane.

3. The method of synthesis of claim 1, wherein, The reducing agent is a reducing metal selected from one or more of iron, manganese, zinc, magnesium, lithium.

4. The method of synthesis of claim 1, wherein, The solvent 1 is selected from one or more of toluene, dichloromethane, ethyl acetate, tetrahydrofuran, acetone, acetonitrile, ethanol, methanol, isopropanol, tert-butanol, trifluoroethanol; the amount thereof is 0.1 mL to 50 mL per mmol of fluorinated bis-phenyl sulfonyl methane.

5. The method of synthesis of claim 1, wherein, The molar ratio of the amount of 1,3-diene to the amount of fluorinated bis-aryl sulfonyl methane is (1-10):

1.

6. The method of synthesis of claim 1, wherein, The solvent 2 is selected from one or more of ethanol, methanol, isopropanol, tert-butanol, trifluoroethanol, deuterated methanol; the amount thereof is 0.1 mL to 50 mL per mmol of product formula (I).

7. The method of synthesis of claim 1, wherein, The temperature 1 is -10℃ to 100℃; the temperature 2 is 0℃ to 80℃.

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