Chiral monofluoromalonate substituted allyl compounds, asymmetric catalytic synthesis method and application thereof

Abstract

The application discloses an allyl compound containing chiral monofluoromalonate diester and an asymmetric catalytic synthesis method and application thereof, the compound has the structure shown in the following formula, has potential biological activity and pharmacodynamic activity, provides strong technical support for development of new drugs, and has high practical value; the synthesis method is started from 1,3-diene and a nucleophilic reagent fluoromalonate diester as raw materials, and the chiral monofluoromalonate diester substituted allyl compound is efficiently synthesized through a chiral metal catalyst. The method has the following characteristics: the raw material is cheap and easy to obtain; no base needs to be added, the reaction condition is mild, and the operation is simple; the substrate has a wide application range, excellent enantioselectivity can be obtained, and good to excellent yield is achieved. The product prepared by the application is a useful fluorine-containing building block, and a variety of fluorine-containing compounds can be synthesized through simple chemical conversion.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic compounds, and relates to a chiral monofluoro-malonate substituted allyl compound and an asymmetric catalytic method for synthesizing the compound from a fluoromalonate and a 1,3-diene and application thereof. BACKGROUND

[0002] Fluorine is located in the second period of the periodic table of elements VII main group, and is the element with the largest electronegativity, and the atomic radius is small. Many research results show that introducing fluorine atoms or monofluoroalkyl groups into organic compounds can improve the physical and chemical properties of the corresponding compounds, and also increase the bioavailability, lipophilicity, binding affinity, metabolic stability and membrane permeability of bioactive molecules. For example, the natural product nucleocidin containing fluorine, the drug fluticasone propionate for treating allergic rhinitis or bronchial asthma, and the first-line drug sofosbuvir for treating hepatitis C, the new drug clofarabine for treating acute leukemia, all contain monofluoroalkyl structural units. Therefore, selectively introducing fluorine atoms or monofluoroalkyl groups into known drugs or bioactive molecules is an important means of drug modification and new drug development. Therefore, it is of great significance to develop an efficient synthesis of alpha-chiral monofluoroalkyl-substituted compounds for new drug development.

[0003]

[0004] Some representative monofluoroalkyl-substituted compounds of formula (1) molecules

[0005] In view of the importance of selective hydrofluoroalkylation of olefins in the synthesis of fluorine-containing compounds, and the potential application value in the development of fluorine-containing drugs, through the efforts of researchers, although the anti-Markovnikov hydrofluoroalkylation reaction realized by the addition strategy of fluorine alkyl radical has been widely studied, but compared with it, the branched Markovnikov regioselective hydrofluoroalkylation reaction, especially the asymmetric catalytic hydrofluoroalkylation reaction, has not been reported. Literature research shows that there is only one example of Markovnikov regioselective hydrodifluoroalkylation reaction of olefins through acid-catalyzed carbonium ion process (Nature Communication, 2020, 11, 5500), and the asymmetric hydrofluoroalkylation of olefins has not been realized. Considering that simple olefin raw materials are cheap and easy to obtain, and the potential medicinal value of chiral monofluoroalkyl compounds, therefore, it is of great significance and promoting effect to develop Markovnikov asymmetric hydrofluoroalkylation of olefins to efficiently synthesize such chiral fluorine-containing compounds for the development of new fluorine-containing drugs. SUMMARY

[0006] The present application aims to provide a simple and efficient synthesis method of chiral monofluoro-malonate substituted allyl compounds; the method has good substrate versatility, mild reaction conditions, and the raw materials and catalysts are easy to obtain.

[0007] The chiral monofluoro-malonate substituted allyl compound provided by the present application is shown as formula (I):

[0008]

[0009] 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, heteroaryl; wherein the heteroaryl includes thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, thiazole; R 1 is C1-C10 alkyl and phenyl, C1-C10 alkyl or alkoxy substituted aryl, halogen substituted aryl; the chiral configuration of the allyl group can be (R) configuration or (S) configuration.

[0010] Preferably, formula (I) is:

[0011]

[0012] The present application provides a method for synthesizing chiral monofluoro-malonate substituted allyl compounds, in which olefins and fluorinated malonate undergo Markovnikov regioselective asymmetric hydrofluoroalkylation under the action of a chiral metal catalyst in a solvent to generate the target compound formula (I). The method is shown in the following reaction formula (A):

[0013]

[0014] 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, heteroaryl; wherein the heteroaryl includes thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, thiazole; R 1 is C1-C10 alkyl and phenyl, C1-C10 alkyl or alkoxy substituted aryl, halogen substituted aryl; the chiral configuration of the allyl group can be (R) configuration or (S) configuration.

[0015] Specifically, the synthetic method of the present application comprises the following steps: adding a catalyst and a chiral ligand into a reaction container, then sequentially adding a 1,3-diene, a fluorinated malonate, a solvent, stirring for 5 minutes at room temperature, continuing the reaction at a corresponding temperature until the reaction is stopped after TLC shows that the fluorinated malonate completely disappears or hardly changes, spinning off the solvent, separating the product by column chromatography, and determining the enantioselectivity (ee value) of the product by a high-performance liquid chromatograph (HPLC).

[0016] In the present application, the catalyst is a transition metal acetylacetone nickel, a cyclooctadiene nickel, a nickel acetate, a palladium acetate, etc.; the chiral ligand is selected from a chiral Box, a Py-Box ligand, a FOXAPL ligand, a Binap ligand, a Josiphos ligand, a PHOX ligand, a QuinoxP ligand, and a Segphos ligand; preferably, the chiral ligand is a chiral bisoxazoline ligand, a Binap ligand, a Josiphos ligand, a PHOX ligand, and a QuinoxP ligand.

[0017] In the present application, the amount of the chiral catalyst is 0.1-50 mol% based on the amount of the malonate; preferably, 5 mol% and 10 mol%.

[0018] In the present application, the solvent is selected from one or more of ethyl acetate, dichloromethane, toluene, tetrahydrofuran, chloroform, 1,2-dichloroethane, diethyl ether, ethanol, methanol, and isopropanol; preferably, methanol, ethanol, and isopropanol.

[0019] In the present application, the amount of the solvent is 0.1 mL to 50 mL per mmol of the olefin; preferably, 5 mL and 10 mL.

[0020] In the present application, the molar ratio of the fluorinated malonate to the olefin is 1:(0.1-20); preferably, 1:1.5.

[0021] In the present application, the reaction temperature is -10-100℃; preferably, 25℃, 40℃, 50℃, and 60℃.

[0022] In the present application, the reaction time is 1-120 h.

[0023] In the present application, the olefin refers to 1,3-diene with different aryl or alkyl substitution, which can be conveniently synthesized according to the literature method [(a) J.S. Marcum, T.N. Cervarich, R.S. Manan, C.C. Roberts, S.J. Meek, ACS Catal. 2019, 9, 5881. (b) A. Bhowmik, R.A. Fernandes, Org. Lett. 2019, 21, 9203. The structure is shown in the following formula (a):

[0024]

[0025] 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, heteroaryl; wherein the heteroaryl includes thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, thiazole; preferably, R is phenyl, naphthyl, thiophene, furan, p-methylphenyl, p-fluorophenyl, p-chlorophenyl, p-methoxyphenyl, n-pentyl, cyclohexyl, phenethyl.

[0026] In the present application, the fluorinated malonate has the structure shown in the following formula (b):

[0027]

[0028] R of formula (b) 1 are independently selected from C1-C10 alkyl and phenyl, C1-C10 alkyl or alkoxy substituted aryl, halogen substituted aryl alkyl; preferably, R 1 is C1-C10 alkyl, aryl.

[0029] In the synthesis method of the present application, the chiral monofluoromalonate diester substituted allyl compound is efficiently synthesized by a cheap nickel catalyst. At present, the synthesis method of the chiral monofluoromalonate diester substituted allyl compound is mainly realized by substitution reaction of an allyl compound containing a leaving group under the catalysis of a noble metal palladium. This method usually needs to add an equivalent of base and will produce stoichiometric waste, and the olefin needs to be pre-functionalized. The method of the present application has the characteristics of: raw materials are cheap and easy to obtain; no pre-functionalization is needed; no base is needed, the reaction condition is mild, the operation is simple; the substrate has a wide application range, and excellent enantioselectivity and good to excellent yield can be obtained. The product prepared by the present application is a useful fluorine-containing building block, which can be used to synthesize various fluorine-containing compounds through simple chemical conversion.

[0030] The present application has the advantages that the chiral monofluoro malonate substituted allyl compound and the synthesis method thereof have high practical value, and the synthesis method has the following remarkable features: the raw materials are cheap and easy to obtain, the reaction conditions are mild, no other additives are needed, and the operation is simple and convenient; the substrate has a wide application range, and good yield and good to excellent enantioselectivity (up to 98% yield and 99% ee value) can be obtained; and the chiral monofluoro malonate substituted allyl compound has potential important medicinal value.

[0031] In addition, the chiral monofluoro malonate substituted allyl compound can be converted into a variety of fluorine-containing compounds through simple chemical conversion, such as the compound shown in the following formula (B), and has wide application prospects.

[0032] DETAILED DESCRIPTION

[0033] The present application will be further described in detail in combination with the following examples, and the following examples show different aspects of the present application, but the protection scope of the present application is not limited to the following examples. Changes and advantages that can be thought of by those skilled in the art without departing from the spirit and scope of the present application are included in the present application, and the protection scope is limited by the appended claims. The process, conditions, reagents, experimental methods, etc. for implementing the present application are the general knowledge and common sense in the art, and the present application has no special limitation. The data given in the following examples include the operation and reaction conditions of asymmetric synthesis and the products. The enantioselectivity (ee value) is determined by HPLC.

[0034] Example 1

[0035] Synthesis of chiral monofluoro malonate substituted allyl compound III-1:

[0036]

[0037] In a 10.0 mL sealed tube, cyclooctadiene nickel (3.5 mg, 0.0125 mmol), chiral ligand (S, S)-QuinoxP* (4.6 mg, 0.01375 mmol), 1,3-diene I-1 (48.8 mg, 0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg, 0.25 mmol), anhydrous ethanol (2.5 mL) were added in turn, and the reaction solution was stirred at 50°C for 15 h. TLC detection showed that the raw material was basically reacted, and the reaction was stopped. After rotary evaporation, column chromatography was performed, and the eluent was petroleum ether / ethyl acetate (1 / 20) to obtain the product III-1 as a colorless liquid 66.3 mg, yield 97%. [α] D 20= -84.7 (c = 0.51, CHCI3); 96% ee. (Chiralcel AD-H column, 98:2 n-hexane: isopropanol) 1 H NMR (400 MHz, CDCI3): δ 7.29-7.17 (m, 5H), 6.46 (d, J = 16.0 Hz, 1H), 6.07 (dd, J = 15.6, 9.2 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 4.20 - 4.15 (m, 2H), 3.42 - 3.29 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H), 1.19 - 1.15 (m, 6H); 13 C NMR (100 MHz, CDCI3): δ 165.56 (d, J = 25.3 Hz), 165.55 (d, J = 25.7 Hz), 136.67, 133.09, 128.51, 127.67, 126.85 (d, J = 2.7 Hz), 126.36, 97.08 (d, J = 203.9 Hz), 62.65, 62.48, 42.73 (d, J = 20.4 Hz), 14.70 (d, J = 4.4 Hz), 14.06, 14.03; 19 F NMR (376 MHz, CDCI3): δ -178.21 (s, 1F). IR (ATR): 1747, 1369, 1232, 1097, 968, 858, 746, 694 cm"1; HRMS (ESI): Exact mass calcd for C 17 H 21 FNaO4[M + Na] + : 331.1316, Found: 331.1309.

[0038] Example 2

[0039] Synthesis of chiral monofluoromalonate substituted allylic compounds III-2:

[0040]

[0041] In a 10.0 mL vial, cyclooctadiene nickel (6.9 mg, 0.0125 mmol), chiral ligand (R,R)-QuinoxP* (4.6 mg, 0.01375 mmol), 1,3-diene I-1 (48.8 mg, 0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg, 0.25 mmol), anhydrous ethanol (2.5 mL) were added successively. The reaction was stirred at 50 °C for 15 h. TLC detection showed that the starting material was almost completely reacted, and the reaction was stopped. After drying, column chromatography was performed, and the eluent was petroleum ether / ethyl acetate (1 / 20) to obtain the product III-2 as a colorless liquid 66.3 mg, yield 97%.[α] D 20 = +84.7 (c = 0.51, CHCI3); -96% ee. (Chiralcel AD-H column, 98:2 n-hexane: isopropanol) 1 H NMR (400 MHz, CDCI3): δ 7.29-7.17 (m, 5H), 6.46 (d, J = 16.0 Hz, 1H), 6.07 (dd, J = 15.6, 9.2 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 4.20-4.15 (m, 2H), 3.42-3.29 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H), 1.19-1.15 (m, 6H); 13 C NMR (100 MHz, CDCI3): δ 165.56 (d, J = 25.3 Hz), 165.55 (d, J = 25.7 Hz), 136.67, 133.09, 128.51, 127.67, 126.85 (d, J = 2.7 Hz), 126.36, 97.08 (d, J = 203.9 Hz), 62.65, 62.48, 42.73 (d, J = 20.4 Hz), 14.70 (d, J = 4.4 Hz), 14.06, 14.03; 19 F NMR (376 MHz, CDCI3): δ -178.21 (s, 1F). IR (ATR): 1747, 1369, 1232, 1097, 968, 858, 746, 694 cm"1; HRMS (ESI): Exact mass calcd for C 17 H 21 FNaO4[M + Na] + : 331.1316, Found: 331.1309.

[0042] Example 3

[0043] Synthesis of chiral monofluoro malonate substituted allyl compound III-3:

[0044]

[0045] In a 10.0 mL vial, nickel acetate (2.2 mg, 0.0125 mmol), chiral ligand (S)-PyBox (5.1 mg, 0.01375 mmol), 1,3-diene I-2 (55.6 mg, 0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg, 0.25 mmol), anhydrous ethanol (2.5 mL) were added successively. The reaction was stirred at 50 °C for 24 h. TLC detection showed that the starting material was almost completely reacted, and the reaction was stopped. After drying, column chromatography was performed, and the eluent was petroleum ether / ethyl acetate (1 / 20). The product III-3 was obtained as a colorless liquid 66.9 mg, yield 82%.[α] D 20 = -28.4 (c = 0.50, CHCl3); 97% ee. (Chiralcel AD-H column, 98:2 n-hexane: isopropanol) 1 H NMR (400 MHz, CDCl3): δ 7.31-7.28 (m, 2H), 7.00-6.96 (m, 2H) 6.47 (d, J = 15.6 Hz, 1H), 6.04 (dd, J = 16.4, 9.2 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 3.44-3.30 (m, 1H), 1.33 (t, J = 7.2 Hz, 3H), 1.24-1.20 (m, 6H); 13 C NMR (100 MHz, CDCl3): δ 165.54 (d, J = 25.5 Hz, 2C), 162.37 (d, J = 245.5 Hz), 132.82 (d, J = 3.3 Hz), 131.87, 127.85 (d, J = 7.9 Hz), 126.64 (t, J = 2.4 Hz), 97.03 (d, J = 204.1 Hz), 62.66, 62.47, 42.65 (d, J = 20.3 Hz), 14.66 (d, J = 4.3 Hz), 14.06, 14.02; 19 F NMR (376 MHz, CDCl3): δ -178.21 (s, IF), -114.33 (s, IF); IR (ATR): 1747, 1369, 1226, 1159, 1097, 970, 858, 821 cm-1; HRMS (ESI): Exact mass calcd for C17H20F2NaO4 [M + Na]+: 349.1222, Found: 349.1219

[0046] Example 4

[0047] Synthesis of chiral monofluoro-malonate substituted allyl compound III-4:

[0048]

[0049] In a 10.0 mL sealed tube, nickel acetylacetonate (3.2 mg, 0.0125 mmol), chiral ligand (R,R)-QuinoxP* (4.6 mg, 0.01375 mmol), 1,3-diene I-3 (61.7 mg, 0.375 mmol), diethyl fluoro-malonate II-1 (44.5 mg, 0.25 mmol), anhydrous methanol (2.5 mL) were added successively. The reaction was stirred at 50 °C for 20 h. TLC detection showed that the starting material was almost completely reacted, and the reaction was stopped. After rotary evaporation, column chromatography was performed, and the eluent was petroleum ether / ethyl acetate (1 / 20) to obtain product III-4 as a colorless liquid 74.6 mg, yield 83%.[α] D 20 = -40.0 (c = 0.52, CHCI3); 95% ee. (Chiralcel AD-H column, 98:2 n-hexane: isopropanol) 1 H NMR (400 MHz, CDCI3): δ 7.26 (s, 4H), 6.45 (d, J = 16.0 Hz, 1H), 6.10 (dd, J = 16.0, 9.2 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 3.45 - 3.32 (m, 1H), 1.33 (t, J = 7.2 Hz, 3H), 1.23 - 1.20 (m, 6H); 13 C NMR: (100 MHz, CDCI3): δ 165.51 (d, J = 25.6 Hz), 165.49 (d, J = 25.3 Hz), 135.14, 133.35, 131.87, 128.69, 127.60 (d, J = 1.8 Hz), 127.56, 96.96 (d, J = 204.2 Hz), 62.71, 62.51, 42.66 (d, J = 20.3 Hz), 14.61 (d, J = 4.3 Hz), 14.07, 14.03; 19 F NMR (376 MHz, CDCI3): δ -178.19 (s, IF); IR (ATR): 1747, 1369, 1232, 1163, 1093, 1039, 970, 810 cm -1 ; HRMS (ESI): Exact mass calcd for C 17 H 20 ClFNaO4[M + Na] +:365.0926, Found: 365.0920.

[0050] Example 5

[0051] Synthesis of chiral monofluoromalonate substituted allyl compound III-5:

[0052]

[0053] In a 10.0 mL sealed tube, palladium acetate (2.8 mg, 0.0125 mmol), chiral ligand (S)-BINAP (8.6 mg, 0.01375 mmol), 1,3-diene I-4 (74.3 mg, 0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg, 0.25 mmol), anhydrous ethanol (2.5 mL) were added successively. The reaction was stirred at 40 °C for 24 h. TLC detection showed that the starting material was almost completely reacted, and the reaction was stopped. After drying, column chromatography was performed, and the eluent was petroleum ether / ethyl acetate (1 / 20) to obtain the product III-5 as a colorless liquid 90.7 mg, yield 96%. -47.4 (c = 0.71, CHCl3); 93% ee. (Chiralcel AD-H column, 98:2 n-hexane: isopropanol). 1 H NMR (400 MHz, CDCl3): δ 7.55 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 6.54 (d, J = 15.6 Hz, 1H), 6.23 (dd, J = 16.0, 9.2 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 4.23 (q, J = 7.2 Hz, 2H), 3.49 - 3.34 (m, 1H), 1.33 (t, J = 7.2 Hz, 3H), 1.24 - 1.20 (m, 6H); 13 C NMR (100 MHz, CDCl3): δ 165.40 (d, J = 25.8 Hz), 165.35 (d, J = 25.4 Hz), 140.08, 131.73, 129.72 (d, J = 2.6 Hz), 129.45 (q, J = 32.1 Hz), 126.48, 125.44 (q, J = 3.5 Hz), 124.07 (q, J = 270.1 Hz), 96.78 (d, J = 204.2 Hz), 62.69, 62.50, 42.55 (d, J = 20.5 Hz), 14.47 (d, J = 3.7 Hz), 13.99, 13.94; 19FNMR (376 MHz, CDC13): δ -177.95 (s, IF), -62.55 (s, 3F); IR (ATR): 1749, 1616, 1323, 1234, 1163, 1066, 824, 737 cm -1 ; HRMS (ESI): Exact mass calcd for C 18 H 20 F4NaO4[M+Na] + : 399.1190, Found: 399.1181.

[0054] Example 6

[0055] Synthesis of chiral monofluoro malonate substituted allyl compound III-6:

[0056]

[0057] In a 10.0 mL sealed tube, cyclooctadiene nickel (3.5 mg, 0.0125 mmol), chiral ligand (R,R)-QuinoxP* (4.6 mg, 0.01375 mmol), 1,3-diene I-5 (54.2 mg, 0.375 mmol), diethyl fluoro malonate II-1 (44.5 mg, 0.25 mmol), anhydrous ethanol (2.5 mL) were added successively. The reaction was stirred at 25 °C for 24 h. TLC detection showed that the starting material was almost reacted completely, and the reaction was stopped. After spin-drying, column chromatography was performed with eluent (petroleum ether / ethyl acetate = 1 / 20) to give product III-6 as a colorless liquid 74.4 mg in 97% yield. D 20 = -101.9 (c = 0.71, CHCI3); 97% ee. (Chiralcel AD-H column, 98:2 n-hexane: isopropanol). 1 HNMR (400 MHz, CDC13): δ 7.55 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 6.54 (d, J = 15.6 Hz, 1H), 6.23 (dd, J = 16.0, 9.2 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 4.23 (q, J = 7.2 Hz, 2H), 3.49 - 3.34 (m, 1H), 1.33 (t, J = 7.2 Hz, 3H), 1.24 - 1.20 (m, 6H); 13C NMR (100 MHz, CDC13): δ 165.40 (d, J = 25.8 Hz), 165.35 (d, J = 25.4 Hz), 140.08, 131.73, 129.72 (d, J = 2.6 Hz), 129.45 (q, J = 32.1 Hz), 126.48, 125.44 (q, J = 3.5 Hz), 124.07 (q, J = 270.1 Hz), 96.78 (d, J = 204.2 Hz), 62.69, 62.50, 42.55 (d, J = 20.5 Hz), 14.47 (d, J = 3.7 Hz), 13.99, 13.94; 19 F NMR (376 MHz, CDC13): δ -177.95 (s, IF), -62.55 (s, 3F); IR (ATR): 1749, 1616, 1323, 1234, 1163, 1066, 824, 737 cm -1 ; HRMS (ESI): Exact mass calcd for C 18 H 20 F4NaO4[M + Na] + : 399.1190, Found: 399.1181.

[0058] Example 7

[0059] Synthesis of chiral monofluoromalonate substituted allyl compound III-7:

[0060]

[0061] In a 10.0 mL sealed tube, cyclooctadiene nickel (3.5 mg, 0.0125 mmol), chiral ligand (S)-PhPHOX (7.1 mg, 0.01375 mmol), 1,3-diene I-6 (xx mg, 0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg, 0.25 mmol), anhydrous ethanol (2.5 mL) were added successively. The reaction was stirred at 50 °C for 24 h. TLC detection showed that the starting material was almost completely reacted, and the reaction was stopped. After rotary evaporation, column chromatography was performed with eluent (petroleum ether / ethyl acetate = 1 / 20) to give product III-7 as a colorless liquid 67.7 mg in 83% yield. [a] D 20 = -66.2 (c = 0.49, CHCI3); 95% ee. 1H NMR (400 MHz, CDC13): δ 7.42 (t, J = 8.0 Hz, 1H), 7.22-7.17 (m, 1H), 7.09-6.98 (m, 2H), 6.69 (d, J = 16.4 Hz, 1H), 6.19 (dd, J = 16.0, 9.2 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 4.24 (q, J = 7.2 Hz, 2H), 3.47-3.36 (m, 1H), 1.33 (t, J = 6.4 Hz, 3H), 1.26-1.21 (m, 6H); 13 C NMR (100 MHz, CDC13): δ 165.49 (d, J = 25.3 Hz), 165.45 (d, J = 26.0 Hz), 160.07 (d, J = 247.6 Hz), 129.47 (dd, J = 25.3, 3.0 Hz), 128.99 (d, J = 8.4 Hz), 127.23 (d, J = 3.6 Hz), 125.44 (d, J = 3.8 Hz), 124.41 (d, J = 12.3 Hz), 124.06 (d, J = 3.6 Hz), 115.59 (d, J = 21.9 Hz), 96.95 (d, J = 203.5 Hz), 62.67, 62.54, 43.00 (d, J = 20.4 Hz), 14.57 (d, J = 4.0 Hz), 14.00, 13.97; 19 F NMR (376 MHz, CDC13): δ -178.11 (s, IF), -118.54 (s, IF); IR (ATR): 1749, 1487, 1456, 1271, 1230, 1041, 972, 756 cm -1 ; HRMS (ESI): Exact mass calcd for C 17 H 20 F2NaO4[M + Na] + : 349.1222, Found: 349.1213.

[0062] Example 8

[0063] Synthesis of chiral monofluoromalonate substituted allyl compound III-8:

[0064]

[0065] In a 10.0 mL vial, cyclooctadiene nickel (3.5 mg, 0.0125 mmol), chiral ligand (R,R)-QuinoxP* (4.6 mg, 0.01375 mmol), 1,3-diene I-7 (54.1 mg, 0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg, 0.25 mmol), anhydrous isopropanol (1.5 mL) were added successively. The reaction was stirred at 50 °C for 24 h. TLC detection showed that the starting material was almost completely reacted, and the reaction was stopped. After drying, column chromatography was performed, and the eluent was petroleum ether / ethyl acetate (1 / 20) to obtain the product III-8 as a colorless liquid 76.2 mg, yield 86%.[α] D 20 = -121.1 (c = 0.84, CHCl3); 97% ee. 1 H NMR (400 MHz, CDCl3): δ 7.22 (d, J = 7.6 Hz, 2H), 7.09 (d, J = 7.6 Hz, 2H), 6.47 (d, J = 16.0 Hz, 1H), 6.06 (dd, J = 16.0, 9.2 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.21 (q, J = 6.8 Hz, 2H), 3.44-3.30 (m, 1H), 2.32 (s, 3H), 1.33 (t, J = 8.8 Hz, 3H), 1.23-1.19 (m, 6H); 13 C NMR (100 MHz, CDCl3): δ 165.57 (d, J = 25.4 Hz), 165.52 (d, J = 25.7 Hz), 137.43, 133.86, 132.91, 129.15, 126.22, 125.73 (d, J = 2.6 Hz), 97.09 (d, J = 203.8 Hz), 62.55, 62.37, 42.71 (d, J = 20.3 Hz), 21.07, 14.67 (d, J = 4.3 Hz), 14.01, 13.96; 19 F NMR (376 MHz, CDCl3): δ -178.28 (s, 1F); IR (ATR): 1747, 1446, 1232, 1271, 1232, 1039, 970, 804 cm -1 ; HRMS (ESI): Exact mass calcd for C 18 H 23 FNaO4[M+Na] + : 345.1473, Found: 345.1475.

[0066] Example 9

[0067] Synthesis of chiral monofluoro-malonate substituted allyl compound III-9:

[0068]

[0069] In a 10.0 mL sealed tube, cyclooctadiene nickel (1.4 mg, 0.005 mmol), chiral ligand (R,R)-QuinoxP* (1.9 mg, 0.0055 mmol), 1,3-diene I-8 (60.1 mg, 0.375 mmol), diethyl fluoro-malonate II-1 (44.5 mg, 0.25 mmol), anhydrous ethanol (2.5 mL) were added successively. The reaction was stirred at 50 °C for 26 h. TLC detection showed that the starting material was almost completely reacted, and the reaction was stopped. After drying, column chromatography was performed, and the eluent was petroleum ether / ethyl acetate (1 / 20) to obtain the product III-9 as a colorless liquid 80.4 mg, yield 95%. [a] D 20 = -121.1 (c = 0.84, CHCl3); 97% ee. 1 H NMR (400 MHz, CDCl3): δ 7.27 (d, J = 7.2 Hz, 2H), 6.84-6.82 (m, 2H), 6.44 (d, J = 16.0 Hz, 1H), 5.97 (dd, J = 16.0, 9.2 Hz, 1H), 4.32 (q, J = 6.8 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 3.80 (s, 3H), 3.43-3.29 (m, 1H), 1.33 (t, J = 6.8 Hz, 3H), 1.24-1.19 (m, 6H); 13 C NMR (100 MHz, CDCl3): δ 166.15 (d, J = 25.5 Hz), 165.60 (d, J = 26.0 Hz), 159.27, 132.48, 129.47, 127.53, 124.56 (d, J = 2.7 Hz), 113.92, 97.21 (d, J = 203.9 Hz), 62.60, 62.42, 55.25, 42.79 (d, J = 20.3 Hz), 14.78 (d, J = 4.3 Hz), 14.07, 14.02; 19 F NMR (376 MHz, CDCl3): δ -178.47 (s, 1F); IR (ATR): 1747, 1512, 1246, 1174, 1032, 968, 856, 820 cm -1 ; HRMS (ESI): Exact mass calcd for C 18 H 23 FNaO5[M + Na] +:361.1422, Found: 361.1419.

[0070] Example 10

[0071] Synthesis of chiral monofluoromalonate substituted allyl compound III-10:

[0072]

[0073] In a 10.0 mL sealed tube, cyclooctadiene nickel (3.5 mg, 0.0125 mmol), chiral ligand (R,R)-QuinoxP* (4.6 mg, 0.01375 mmol), 1,3-diene I-9 (60.1 mg, 0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg, 0.25 mmol), anhydrous methanol (2.5 mL) were added successively. The reaction was stirred at 50 °C for 16 h. TLC detection showed that the starting material was almost reacted completely, and the reaction was stopped. After rotary evaporation, column chromatography was performed with eluent (petroleum ether / ethyl acetate = 1 / 20) to give product III-10 as a colorless liquid 67.1 mg in 72% yield. D 20 = -66.2 (c = 0.49, CHCl3); 97% ee. 1 H NMR (400 MHz, CDCl3): δ 7.23-7.19 (m, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.86 (s, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.48 (d, J = 16.0 Hz, 1H), 6.11 (dd, J = 15.6, 9.2 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 4.23 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 3.46-3.31 (m, 1H), 1.33 (t, J = 7.2 Hz, 3H), 1.25-1.20 (m, 6H); 13 C NMR (100 MHz, CDCl3): δ 165.57 (d, J = 25.4 Hz), 165.53 (d, J = 25.7 Hz), 159.78, 138.12, 133.02, 129.48, 127.16 (d, J = 2.7 Hz), 119.06, 113.36, 111.64, 97.01 (d, J = 204.1 Hz), 62.65, 62.48, 55.21, 42.43 (d, J = 20.3 Hz), 14.68 (d, J = 4.3 Hz), 14.06, 14.02; 19F NMR (376 MHz, CDC13): δ -178.24 (s, IF); IR (ATR): 1747, 1580, 1230, 1157, 1039, 775, 734, 690 cm -1 ; HRMS (ESI): Exact mass calcd for C 18 H 23 FNaO5[M+Na] + : 361.1422, Found: 361.1419.

[0074] Example 11

[0075] Synthesis of chiral monofluoro malonate substituted allyl compound III-10:

[0076]

[0077] In a 10.0 mL sealed tube, cyclooctadiene nickel (3.5 mg, 0.0125 mmol), chiral ligand (R,R)-QuinoxP* (4.6 mg, 0.01375 mmol), 1,3-diene I-10 (60.1 mg, 0.375 mmol), diethyl fluoro malonate II-1 (44.5 mg, 0.25 mmol), anhydrous isopropanol (2.5 mL) were added successively. The reaction was stirred at 50 °C for 16 h. TLC detection showed that the starting material was almost reacted completely, and the reaction was stopped. After spin-drying, column chromatography was performed with eluent (petroleum ether / ethyl acetate = 1 / 20) to give product III-11 as a colorless liquid 68.1 mg in 80% yield. D 20 = -15.3 (c = 0.3, CHCI3); 99% ee. 1 H NMR (400 MHz, CDC13): δ 7.23-7.19 (m, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.86 (s, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.48 (d, J = 16.0 Hz, 1H), 6.11 (dd, J = 15.6, 9.2 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 4.23 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 3.46-3.31 (m, 1H), 1.33 (t, J = 7.2 Hz, 3H), 1.25-1.20 (m, 6H); 13CNMR (100 MHz, CDC13): δ 165.57 (d, J = 25.4 Hz), 165.53 (d, J = 25.7 Hz), 159.78, 138.12, 133.02, 129.48, 127.16 (d, J = 2.7 Hz), 119.06, 113.36, 111.64, 97.01 (d, J = 204.1 Hz), 62.65, 62.48, 55.21, 42.43 (d, J = 20.3 Hz), 14.68 (d, J = 4.3 Hz), 14.06, 14.02; 19 F NMR (376 MHz, CDC13): δ -178.24 (s, IF); IR (ATR): 1747, 1580, 1230, 1157, 1039, 775, 734, 690 cm -1 ; HRMS (ESI): Exact mass calcd for C 18 H 23 FNaO5[M + Na] + : 361.1422, Found: 361.1419.

[0078] Example 12

[0079] Synthesis of chiral monofluoromalonate substituted allyl compound III-12:

[0080]

[0081] In a 10.0 mL sealed tube, palladium acetate (5.6 mg, 0.025 mmol), chiral ligand (R)-SEGPHOS (14.8 mg, 0.0275 mmol), 1,3-diene I-11 (71.3 mg, 0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg, 0.25 mmol) were added successively. The reaction was stirred at 25 °C for 24 h. TLC detection showed that the starting material was almost completely reacted, and the reaction was stopped. After spin-drying, column chromatography was performed with eluent (petroleum ether / ethyl acetate = 1 / 20) to obtain product III-12 as a colorless liquid 88.7 mg, yield 96%. [a] D 20 = -55.8 (c = 0.50, CHCI3); 97% ee. 1H NMR (400 MHz, CDC13): δ 6.48 (s, 2H), 6.43 (d, J = 15.6 Hz, 1H), 6.36 (s, 1H), 6.09 (dd, J = 15.6, 9.2 Hz, 1H), 4.32 (q, J = 6.8 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 3.79 (s, 6H), 3.45-3.30 (m, 1H), 1.33 (t, J = 6.8 Hz, 3H), 1.25-1.20 (m, 6H); 13 C NMR (100 MHz, CDC13): δ 165.55 (d, J = 25.3 Hz), 165.51 (d, J = 25.8 Hz), 160.87, 138.67, 133.13, 127.31 (d, J = 2.6 Hz), 104.45, 99.99, 97.05 (d, J = 204.0 Hz), 62.67, 62.51, 55.33, 42.68 (d, J = 20.4 Hz), 14.68 (d, J = 4.3 Hz), 14.08, 14.02; 19 F NMR (376 MHz, CDC13): δ -178.30 (s, IF); IR (ATR): 1747, 1591, 1265, 1205, 1153, 968, 734, 702 cm -1 ; HRMS (ESI): Exact mass calcd for C 19 H 25 FNaO6[M + Na] + : 391.1527, Found: 391.1534.

[0082] Example 13

[0083] Synthesis of chiral monofluoromalonate substituted allyl compound III-13:

[0084]

[0085] In a 10.0 mL sealed tube, nickel acetate (8.9 mg, 0.005 mmol), chiral ligand (R,R)-QuinoxP* (14.8 mg, 0.055 mmol), 1,3-diene I-12 (67.1 mg, 0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg, 0.25 mmol), anhydrous methanol (1.5 mL) were added successively. The reaction was stirred at 50 °C for 26 h. TLC detection showed that the starting material was almost completely reacted, and the reaction was stopped. After rotary evaporation, column chromatography was performed with eluent (petroleum ether / ethyl acetate = 1 / 20) to give product III-13 as a colorless liquid 71.1 mg in 81% yield. [a]D 20 = -64.0 (c = 0.52, CHCI3); 95% ee. 1 H NMR (400 MHz, CDCI3): δ 6.87 (s, 1 H), 6.76-6.70 (m, 2H), 6.40 (d, J = 15.6 Hz, 1 H), 5.96-5.90 (m, 3H), 4.31 (q, J = 6.8 Hz, 2H), 4.21 (q, J = 8.0 Hz, 2H), 3.39-3.28 (m, 1 H), 1.31 (t, J = 6.8 Hz, 3H), 1.23-1.17 (m, 6H); 13 C NMR (100 MHz, CDCI3): δ 165.56 (d, J = 25.2 Hz), 165.52 (d, J = 25.7 Hz), 147.95, 147.24, 132.62, 131.07, 124.92 (d, J = 2.6 Hz), 120.98, 108.16, 105.61, 101.03, 97.11 (d, J = 204.1 Hz), 62.63, 62.45, 42.68 (d, J = 20.3 Hz), 14.71 (d, J = 4.4 Hz), 14.07, 14.00; 19 F NMR (376 MHz, CDCI3): δ -178.58 (s, 1 F); IR (ATR): 1745, 1489, 1444, 1247, 1093, 927, 858, 792 cm -1 ; HRMS (ESI): Exact mass calcd for C 18 H 21 FNaO6[M + Na] + : 375.1214, Found: 375.1216.

[0086] Example 14

[0087] Synthesis of chiral monofluoromalonate substituted allyl compound III-14:

[0088]

[0089] In a 10.0 mL vial, cyclooctadiene nickel (3.5 mg, 0.0125 mmol), chiral ligand (R,R)-QuinoxP* (4.6 mg, 0.01375 mmol), 1,3-diene I-13 (67.6 mg, 0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg, 0.25 mmol), anhydrous ethanol (2.5 mL) were added successively. The reaction was stirred at 25 °C for 17 h. TLC detection showed that the starting material was almost completely reacted, and the reaction was stopped. After drying, column chromatography was performed, and the eluent was petroleum ether / ethyl acetate (1 / 20) to obtain the product III-14 as a white solid 77.0 mg, yield 87%.[α] D 20 = -66.7 (c = 0.26, CHCl3); 97% ee. 1 H NMR (400 MHz, CDCl3): δ 7.80-7.76 (m, 3H), 7.69 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.48-7.41 (m, 2H), 6.67 (d, J = 16.0 Hz, 1H), 6.26 (dd, J = 15.6, 6.8 Hz, 1H), 4.34 (q, J = 6.8 Hz, 2H), 4.28 (q, J = 6.8 Hz, 2H), 3.53-3.38 (m, 1H), 1.34 (t, J = 7.2 Hz, 3H), 1.26-1.20 (m, 6H); 13 C NMR (100 MHz, CDCl3): δ 165.56 (d, J = 25.4 Hz, 2C), 134.09, 133.48, 133.17, 132.99, 128.14, 127.90, 127.60, 127.21 (d, J = 2.6 Hz), 126.23 (d, J = 1.4 Hz), 125.86, 123.48, 97.09 (d, J = 204.1 Hz), 62.63, 62.46, 42.85 (d, J = 20.4 Hz), 14.71 (d, J = 4.4 Hz), 14.03, 13.99; 19 F NMR (376 MHz, CDCl3): δ -178.20 (s, 1F). IR (ATR): 1747, 1367, 1265, 1230, 1095, 966, 813, 734 cm -1 ; HRMS (ESI): Exact mass calcd for C 21 H 23 FNaO4[M + Na] + : 381.1473, Found: 381.1474.

[0090] Example 15

[0091] Synthesis of chiral monofluoromalonate substituted allyl compound III-15:

[0092]

[0093] Add cyclooctadiene nickel (3.5 mg, 0.0125 mmol) and chiral ligand (S)- to a 10.0 mL sealing tube. i Pr-Pyox (4.6 mg, 0.01375 mmol), 1,3-diene I-14 (67.6 mg, 0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg, 0.25 mmol), and anhydrous ethanol (2.5 mL) were added. The reaction mixture was stirred at 50 °C for 36 h. TLC analysis showed that the reactants had largely reacted, and the reaction was stopped. After rotary evaporation and column chromatography, using petroleum ether / ethyl acetate = 1 / 20 as eluent, product III-15 was obtained as a colorless liquid, 87.7 mg, with a yield of 98%. [α] D 20 =-26.3 (c=0.71, CHCl3); 93%ee. 1 H NMR (400MHz, CDCl3): δ8.06(d,J=8.0Hz,1H),7.85-7.83(m,1H),7.77(d,J=8.4Hz,1H),7.55-7.41(m,4H),7.28(d,J=16.4Hz,1H),6.16(dd,J=15 .6,9.2Hz,1H),4.35(q,J=10.8Hz,2H),4.27-4.21(m,2H),3.61-3.48(m, 1H), 1.36 (t, J = 7.2Hz, 3H), 1.29 (d, J = 6.8Hz, 3H), 1.23 (t, J = 7.2Hz, 3H); 13 C NMR (100MHz, CDCl3): δ165.69 (d, J = 25.7Hz), 165.62 (d, J = 25.5Hz), 134.46, 133.53, 131.06, 130.54, 130.23 (d, J = 2.6Hz), 128.51, 128.0 3,126.02,125.74,125.59,124.04,123.65,97.19(d,J=204.2Hz),62.70,62.57,43.01(d,J=20.3Hz),14.72(d,J=4.3Hz),14.05(s,2C); 19F NMR (376 MHz, CDC13): δ -178.35 (s, IF); IR (ATR): 1745, 1456, 1367, 1228, 1099, 968, 858, 771 cm -1 ; HRMS (ESI): Exact mass calcd for C 21 H 23 FNaO4[M+Na] + : 381.1473, Found: 381.1479.

[0094] Example 16

[0095] Synthesis of chiral monofluoro malonate substituted allyl compound III-16:

[0096]

[0097] In a 10.0 mL sealed tube, was added nickelocene (6.9 mg, 0.025 mmol), chiral ligand (R,R)-QuinoxP* (4.6 mg, 0.0275 mmol), 1,3-diene I-15 (45.0 mg, 0.375 mmol), diethyl fluoro malonate II-1 (44.5 mg, 0.25 mmol), anhydrous tetrahydrofuran (1.5 mL), and the reaction was stirred at 50 °C for 22 h. TLC detection showed that the starting material was almost completely reacted, and the reaction was stopped. After spin-drying, column chromatography was performed with eluent (petroleum ether / ethyl acetate = 1 / 20) to give product III-16 as a colorless liquid 69.4 mg, yield 81%. [a] D 20 = -73.06 (c = 0.99, CHCI3); 94% ee. 1 H NMR (400 MHz, CDC13): δ 7.32 (s, 1H), 6.34-6.29 (m, 2H), 6.20 (s, 1H), 6.06 (dd, J = 16.0, 9.2 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.24 (q, J = 6.8 Hz, 2H), 3.40-3.29 (m, 1H), 1.32 (t, J = 6.8 Hz, 3H), 1.26-1.18 (m, 6H); 13CNMR (100 MHz, CDC13): δ 165.54 (d, J = 25.5 Hz), 165.49 (d, J = 25.6 Hz), 152.13, 141.98, 125.43 (d, J = 2.8 Hz), 121.38, 111.14, 107.87, 96.90 (d, J = 204.4 Hz), 62.64, 62.49, 42.29 (d, J = 20.4 Hz), 14.51 (d, J = 4.4 Hz), 13.99, 13.96; 19 F NMR (376 MHz, CDC13): δ -178.14 (s, IF); IR (ATR): 1747, 1232, 1095, 1037, 962, 929, 738.596 cm -1 ; HRMS (ESI): Exact mass calcd for C9H 12 F[M+H]: 299.1217, Found: 299.1286.

[0098] Example 17

[0099] Synthesis of chiral monofluoro-malonate substituted allyl compound III-17:

[0100]

[0101] In a 10.0 mL sealed tube, nickel cyclooctadiene (6.9 mg, 0.025 mmol), chiral ligand (S)-Ph-BOX (4.6 mg, 0.0275 mmol), 1,3-diene I-16 (51.1 mg, 0.375 mmol), diethyl fluoro-malonate II-1 (44.5 mg, 0.25 mmol), anhydrous ethanol (2.5 mL) were added successively. The reaction was stirred at 50 °C for 24 h. TLC detection showed that the starting material was almost completely reacted, and the reaction was stopped. After spin-drying, column chromatography was performed with eluent (petroleum ether / ethyl acetate = 1 / 20) to obtain product III-17 as a colorless liquid 77.1 mg, yield 98%. [a] D 20 = -5.23 (c = 0.15, CHCI3); 98% ee. 1H NMR (400 MHz, CDC13): δ 7.14 (d, J = 5.2 Hz, 1H), 6.95-6.92 (m, 2H), 6.62 (d, J = 15.6 Hz, 1H), 5.95 (dd, J = 16.0, 9.2 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.24 (q, J = 7.2 Hz, 2H), 3.42-3.27 (m, 1H), 1.32 (t, J = 7.2 Hz, 3H), 1.26-1.19 (m, 6H); 13 C NMR (100 MHz, CDC13): δ 165.53 (d, J = 25.3 Hz, 2C), 141.67, 127.25, 126.38 (d, J = 2.6 Hz), 126.22, 125.69, 124.38, 96.95 (d, J = 204.4 Hz), 62.68, 62.53, 42.56 (d, J = 20.6 Hz), 14.58 (d, J = 4.4 Hz), 14.05, 14.02; 19 F NMR (376 MHz, CDC13): δ -178.11 (s, IF); IR (ATR): 1749, 1463, 1269, 1165, 1095, 958, 856, 698 cm -1 ; HRMS (ESI): Exact mass calcd for C 15 H 19 FNaO4S [M + Na] + : 337.0880, Found: 337.0877.

[0102] Example 18

[0103] Synthesis of chiral monofluoro malonate substituted allyl compound III-18:

[0104]

[0105] In a 10.0 mL sealed tube, palladium acetate (5.6 mg, 0.025 mmol), chiral ligand (R,R)-QuinoxP* (9.2 mg, 0.0275 mmol), conjugated triene I-17 (78.1 mg, 0.375 mmol), diethyl fluoro malonate II-1 (44.5 mg, 0.25 mmol), anhydrous ethanol (2.5 mL) were added successively. The reaction was stirred at 50 °C for 27 h. TLC detection showed that the starting material was almost completely reacted, and the reaction was stopped. After rotary evaporation, column chromatography was performed with eluent (petroleum ether / ethyl acetate = 1 / 20) to obtain product III-18 as a colorless liquid 81.9 mg, yield 98%. [a] D 20= -57.1 (c = 0.50, CHCI3); 91% ee. 1 H NMR (400 MHz, CDCI3): δ 7.38-7.29 (m, 4H), 7.24-7.20 (m, 1H), 6.71 (dd, J = 16.0, 10.8 Hz, 1H), 6.50 (d, J = 3.9 Hz, 1H), 6.31 (dd, J = 15.2, 10.9 Hz, 1H), 5.71 (dd, J = 15.2, 9.2 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.29-4.23 (m, 2H), 3.38-3.27 (m, 1H), 1.33 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H), 1.17 (d, J = 6.8 Hz, 3H); 13 CNMR (100 MHz, CDCI3): δ 165.56 (d, J = 25.5 Hz), 165.53 (d, J = 25.7 Hz), 137.05, 133.54, 132.54, 130.83 (d, J = 2.8 Hz), 128.59, 128.27, 127.59, 126.32, 96.99 (d, J = 203.9 Hz), 62.65, 62.51, 42.45 (d, J = 20.5 Hz), 14.58 (d, J = 4.3 Hz), 14.11, 14.03; 19 FNMR (376 MHz, CDCI3): δ -178.43 (s, 1F); IR (ATR): 1747, 1265, 1236, 1161, 989, 858, 734, 692 cm -1 ; HRMS (ESI): Exact mass calcd for C 19 H 23 FNaO4[M + Na] + : 357.1473, Found: 357.1475.

[0106] Example 19

[0107] Synthesis of chiral monofluoromalonate substituted allylic compounds III-19:

[0108]

[0109] In a 10.0 mL vial, cyclooctadiene nickel (6.9 mg, 0.0125 mmol), chiral ligand (R,R)-QuinoxP* (4.6 mg, 0.01375 mmol), 1,3-diene I-18 (79.0 mg, 0.50 mmol), diethyl fluoromalonate II-1 (44.5 mg, 0.25 mmol), anhydrous methanol (2.5 mL) were added successively. The reaction was stirred at 50 °C for 30 h. TLC detection showed that the starting material was almost reacted completely, and the reaction was stopped. After rotary evaporation, column chromatography was performed, and the eluent was petroleum ether / ethyl acetate (1 / 20) to give the product III-19 as a colorless liquid 78.8 mg, yield 94%.[α] D 20 = -34.9; 97% ee. 1 H NMR (400 MHz, CDCl3): δ 7.38-7.29 (m, 4H), 7.24-7.20 (m, 1H), 6.71 (dd, J = 16.0, 10.8 Hz, 1H), 6.50 (d, J = 3.9 Hz, 1H), 6.31 (dd, J = 15.2, 10.9 Hz, 1H), 5.71 (dd, J = 15.2, 9.2 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.29-4.23 (m, 2H), 3.38-3.27 (m, 1H), 1.33 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H), 1.17 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 165.56 (d, J = 25.5 Hz), 165.53 (d, J = 25.7 Hz), 137.05, 133.54, 132.54, 130.83 (d, J = 2.8 Hz), 128.59, 128.27, 127.59, 126.32, 96.99 (d, J = 203.9 Hz), 62.65, 62.51, 42.45 (d, J = 20.5 Hz), 14.58 (d, J = 4.3 Hz), 14.11, 14.03; 19 F NMR (376 MHz, CDCl3): δ -178.43 (s, 1F); IR (ATR): 1747, 1265, 1236, 1161, 989, 858, 734, 692 cm -1 ; HRMS (ESI): Exact mass calcd for C 19 H 23 FNaO4[M+Na] + : 357.1473, Found: 357.1475.

[0110] Example 20

[0111] Synthesis of chiral monofluoro-malonate substituted allyl compound III-20:

[0112]

[0113] In a 10.0 mL sealed tube, cyclooctadiene nickel (6.9 mg, 0.0125 mmol), chiral ligand (R,R)-QuinoxP* (4.6 mg, 0.01375 mmol), 1,3-diene I-19 (68.0 mg, 0.50 mmol), diethyl fluoro-malonate II-1 (44.5 mg, 0.25 mmol), anhydrous ethanol (1.5 mL) were added successively. The reaction was stirred at 50 °C for 24 h. TLC detection showed that the starting material was almost reacted completely, and the reaction was stopped. After rotary evaporation, column chromatography was performed with eluent (petroleum ether / ethyl acetate = 1 / 20) to give product III-20 as a colorless liquid 76.6 mg in 97% yield. D 20 = -25.5 (c = 0.49, CHCl3); 90% ee. 1 H NMR (400 MHz, CDCl3): δ 5.51 (dd, J = 14.4, 6.8 Hz, 1H), 5.29 (dd, J = 15.6, 9.2 Hz, 1H), 4.29 (q, J = 7.2 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 3.20-3.05 (m, 1H), 1.90-1.87 (m, 1H), 1.70-1.61 (m, 5H), 1.33-1.25 (m, 9H), 1.10-1.02 (m, 5H); 13 C NMR (100 MHz, CDCl3): δ 165.77 (d, J = 25.5 Hz), 165.63 (d, J = 26.3 Hz), 140.27, 124.60 (d, J = 2.7 Hz), 97.45 (d, J = 202.7 Hz), 62.48, 62.27, 42.45 (d, J = 20.2 Hz), 40.56, 32.85, 32.77, 26.06, 25.90, 25.88, 14.79 (d, J = 4.2 Hz), 14.07, 14.01; 19 F NMR (376 MHz, CDCl3): δ -179.36 (s, 1F); IR (ATR): 2924, 2380, 2349, 1747, 1448, 1230, 1031, 970 cm -1 ; HRMS (ESI): Exact mass calcd for C 17 H 27FNaO4[M+Na] + : 337.1786, Found: 337.1778.

[0114] Example 21

[0115] Synthesis of chiral monofluoro malonate substituted allyl compound III-21:

[0116]

[0117] In a 10.0 mL sealed tube, cyclooctadiene nickel (6.9 mg, 0.0125 mmol), chiral ligand (R,R)-QuinoxP* (4.6 mg, 0.01375 mmol), 1,3-diene I-20 (46.6 mg, 0.375 mmol), diethyl fluoro malonate II-1 (44.5 mg, 0.25 mmol), anhydrous ethanol (1.5 mL) were added successively. The reaction was stirred at 60 °C for 26 h. TLC detection showed that the starting material was almost completely reacted, and the reaction was stopped. After rotary evaporation, column chromatography was performed, and the eluent was petroleum ether / ethyl acetate = 1 / 20. The product III-21 was obtained as a colorless liquid 72.8 mg, yield 95%.[α] D 20 = -32.7 (c = 0.95, CHCl3); 96% ee. 1 HNMR (400 MHz, CDCl3): 5.61-5.54 (m, 1H), 5.34 (dd, J = 15.2, 8.8 Hz, 1H), 4.32-4.21 (m, 4H), 3.24-3.09 (m, 1H), 1.98-1.93 (m, 2H), 1.33-1.24 (m, 12H), 1.08 (d, J = 6.8 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 165.77 (d, J = 25.5 Hz), 165.67 (d, J = 25.9 Hz), 134.55, 126.93 (d, J = 2.6 Hz), 97.4 (d, J = 203.2 Hz), 62.49, 62.28, 42.35 (d, J = 20.2 Hz), 32.39, 31.25, 28.87, 22.46, 14.77 (d, J = 4.3 Hz), 14.05, 14.01, 14.00; 19 F NMR (376 MHz, CDCl3): δ -179.19 (s, 1F); IR (ATR): 1751, 1267, 1240, 1168, 1041, 974, 738, 704 cm -1HRMS (ESI): Exact mass calcd for C 16 H 27 FNaO4[M+Na] + : 325.1786, Found: 325.1778.

[0118] Example 22

[0119] Synthesis of chiral monofluoromalonate substituted allyl compound III-22:

[0120]

[0121] In a 10.0 mL sealed tube, cyclooctadiene nickel (13.8 mg, 0.050 mmol), chiral ligand (R,R)-QuinoxP* (18.8 mg, 0.055 mmol), 1,3-diene I-21 (66.9 mg, 0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg, 0.25 mmol) were added successively. The reaction mixture was stirred at 60 °C for 30 h. TLC detection showed that the starting material was almost consumed, and the reaction was stopped. After being dried, column chromatography was performed with eluent (petroleum ether / ethyl acetate = 1 / 20) to give product III-22 as a colorless liquid 84.6 mg in 95% yield. D 20 = -32.7 (c = 0.95, CHCl3); 11:1 dr. 1 H NMR (400 MHz, CDCl3): 5.60-5.53 (m, 1H), 5.34 (dd, J = 15.2, 8.8 Hz, 1H), 5.09-5.06 (m, 1H), 4.29 (q, J = 7.2 Hz, 2H), 4.23 (q, J = 7.2 Hz, 2H), 3.24-3.13 (m, 1H), 2.02-1.90 (m, 3H), 1.85-1.78 (m, 1H), 1.67 (s, 3H), 1.59 (s, 3H), 1.46-1.42 (m, 1H), 1.33-1.26 (m, 8H), 1.8 (d, J = 6.8 Hz, 3H), 0.83 (d, J = 6.4 Hz, 3H); 13CNMR (100 MHz, CDC13): δ 165.77 (d, J = 25.4 Hz), 165.68 (d, J = 25.9 Hz), 132.94, 131.12, 128.23 (d, J = 2.7 Hz), 124.72, 97.27 (d, J = 203.4 Hz), 62.25, 62.30, 42.45 (d, J = 1.0 Hz), 39.75, 36.57, 32.53, 25.68. 25.55, 19.18, 17.59, 14.85 (d, J = 4.3 Hz), 14.03, 14.01; 19 FNMR (376 MHz, CDC13): δ -179.07 (s, IF); IR (ATR): 1749, 1456, 1367, 1267, 1230, 1041, 972, 860 cm -1 ; HRMS (ESI): Exact mass calcd for C 20 H 33 FNaO4[M+Na] + : 379.2255, Found: 379.2249.

[0122] Example 23

[0123] Synthesis of chiral monofluoromalonate substituted allyl compound III-23:

[0124]

[0125] In a 10.0 mL sealed tube, cyclooctadiene nickel (3.5 mg, 0.0125 mmol), chiral ligand (R,R)-QuinoxP* (4.6 mg, 0.01375 mmol), 1,3-diene I-1 (48.8 mg, 0.375 mmol), dimethyl fluoromalonate II-2 (37.5 mg, 0.25 mmol), anhydrous ethanol (2.5 mL) were added successively. The reaction was stirred at 25 °C for 15 h. TLC detection showed that the starting material was almost completely reacted, and the reaction was stopped. After rotary evaporation, column chromatography was performed with eluent (petroleum ether / ethyl acetate = 1 / 20) to give product III-23 as a colorless liquid 66.3 mg in 97% yield. D 20 = -84.7 (c = 0.51, CHCI3); 96% ee. (Chiralcel AD-H column, 98:2 n-hexane: isopropanol) 1H NMR (400 MHz, CDC13): δ 7.33-7.24 (m, 5H), 6.44 (d, J = 16.0 Hz, 1H), 6.06 (dd, J = 15.6, 9.2 Hz, 1H), 4.24 (m, 1H), 3.66 (s, 6H), 0.91 (d, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDC13): δ 165.56 (d, J = 25.3 Hz), 165.55 (d, J = 25.7 Hz), 136.67, 133.09, 128.51, 127.67, 126.85 (d, J = 2.7 Hz), 126.36, 97.08 (d, J = 203.9 Hz), 51.91, 33.50, 11.63; 19 F NMR (376 MHz, CDC13): δ -178.41 (s, IF). IR (ATR): 1727, 1349, 1225, 1043, 946, 824, 777, 705 cm-1; HRMS (ESI): Exact mass calcd for C 17 H 21 FNaO4[M+Na] + : 303.1115, Found: 303.1119.

[0126] Example 24

[0127] Synthesis of chiral a-allyl substituted fluoromalonate compound III-24:

[0128]

[0129] In a 10.0 mL sealed tube, cyclooctadiene nickel (3.5 mg, 0.0125 mmol), chiral ligand (R,R)-QuinoxP* (4.6 mg, 0.01375 mmol), 1,3-diene I-1 (48.8 mg, 0.375 mmol), fluoromalonate diisopropyl ester II-3 (51.6 mg, 0.25 mmol), anhydrous ethanol (2.5 mL) were added successively. The reaction was stirred at 60 °C for 24 h. TLC detection showed that the starting material was almost reacted completely, and the reaction was stopped. After spin-drying, column chromatography was performed with eluent (petroleum ether / ethyl acetate = 1 / 10) to give product III-24 as a colorless liquid 66.3 mg in 97% yield. D 20 = -84.7 (c = 0.51, CHCI3); 96% ee. (Chiralcel AD-H column, 98:2 n-hexane: isopropanol). 1H NMR (400 MHz, CDC13): δ 7.33-7.24 (m, 5H), 6.44 (d, J = 16.0 Hz, 1H), 6.06 (dd, J = 15.6, 9.2 Hz, 1H), 4.24 (m, 1H), 3.66 (s, 6H), 0.91 (d, J = 7.2 Hz, 3H); 13 CNMR (100 MHz, CDC13): δ 165.56 (d, J = 25.3 Hz), 165.55 (d, J = 25.7 Hz), 136.67, 133.09, 128.51, 127.67, 126.85 (d, J = 2.7 Hz), 126.36, 97.08 (d, J = 203.9 Hz), 51.91, 33.50, 11.63; 19 F NMR (376 MHz, CDC13): δ -178.41 (s, IF). IR (ATR): 1727, 1349, 1225, 1043, 946, 824, 777, 705 cm-1; HRMS (ESI): Exact mass calcd for C 17 H 21 FNaO4[M+Na] + : 303.1115, Found: 303.1119.

[0130] Example 25

[0131] Synthesis of chiral a-allyl substituted fluorocarboxylic acid III-25:

[0132]

[0133] In a 10.0 mL reaction tube, a mixture of phospholipid (20 mL, pH = 8) and DMSO (6 mL) was added, followed by III-1 (308.5 mg, 1.0 mmol, 1.0 equiv), porcine liver esterase (PLE) (20 mg, 200 units), and the reaction solution was stirred at 60 °C for 24 h. TLC detection showed that the raw material was basically reacted, and the reaction was stopped. Hydrochloric acid aqueous solution was added to make the pH of the solution 3, and the water layer was extracted with dichloromethane. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and column chromatography was performed after rotary evaporation. The eluent was petroleum ether / ethyl acetate = 1 / 20, and the product III-25 was obtained as a colorless liquid 263.5 mg, yield 94%; [a] D 20 = -60.9 (c = 0.51, CHCl3); 12: 1 dr. (Chiralcel AD-H column, 98:2 n-hexane: isopropanol). 1H NMR (400 MHz, CDC13): δ 7.33-7.21 (m, 5H), 6.52 (d, J = 16.0 Hz, 1H), 6.12 (dd, J = 16.0, 9.2 Hz, 1H), 4.29 (q, J = 7.2 Hz, 2H), 3.42-3.31 (m, 1H), 1.29 (t, J = 7.2 Hz, 3H), 1.19 (d, J = 6.8 Hz, 3H); 13 CNMR (100 MHz, CDC13): δ 168.67 (d, J = 28.7 Hz), 165.84 (d, J = 26.0 Hz), 136.62, 133.35, 128.50, 127.70, 126.44, 97.05 (d, J = 203.5 Hz), 63.03, 42.73 (d, J = 20.6 Hz), 14.63 (d, J = 3.9 Hz), 13.94; 19 FNMR (376 MHz, CDC13): δ -176.84 (s, IF); IR (ATR): 1749, 1296, 1267, 1043, 1014, 1014, 750, 694 cm -1 ; HRMS (ESI): Exact mass calcd for C 15 H 17 FNaO4[M + Na] + : 303.1003, Found: 303.0989.

[0134] Example 26

[0135] Synthesis of chiral a-allyl substituted fluorodiacid III-26:

[0136]

[0137] In a 10.0 mL reaction tube, methanol (0.2 mL) and dichloromethane (1.2 mL) were added successively, followed by III-1 (61.6 mg, 0.2 mmol, 1.0 equiv), then sodium hydroxide (17.6 mg, 0.44 mmol, 2.2 equiv). TLC detection showed that the starting material had been substantially reacted, the reaction was stopped, then water and hydrochloric acid were added, the aqueous layer was extracted with dichloromethane, the combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, column chromatography after rotary evaporation, eluent (petroleum ether / ethyl acetate = 1 / 20) to give the product III-26 as a colorless liquid 49.9 mg, yield 99%; [a] D 20 = -3.6 (c = 0.52, CHCI3). 1HNMR (400 MHz, MeOD-d4): δ 7.35 (d, J = 7.6 Hz, 2H), 7.28 (t, J = 7.2 Hz, 2H), 7.22-7.18 (m, 1H), 6.56 (d, J = 16.0 Hz, 1H), 6.15 (dd, J = 15.6, 8.8 Hz, 1H), 3.45-3.34 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H); 13 CNMR (100 MHz, MeOD-d4): δ 167.81 (d, J = 26.3 Hz), 167.65 (d, J = 25.8 Hz), 136,97, 132.73, 128.17, 127.24, 126.88 (d, J = 2.5 Hz), 125.97, 97.13 (d, J = 199.2 Hz), 42.13 (d, J = 20.4 Hz), 13.69 (d, J = 4.2 Hz); 19 F NMR (376 MHz, MeOD-d4): δ -178.78 (s, IF); IR (ATR): 1732, 1448, 1159, 1132, 1014, 970, 746, 694 cm -1 ; HRMS (ESI): Exact mass calcd for C 13 H 13 FNaO4[M+Na] + : 275.0690, Found: 275.0686.

[0138] Example 27

[0139] Synthesis of chiral a-allyl substituted fluorine diol III-27:

[0140]

[0141] In a 10.0 mL reaction tube, methanol (5.0 mL) and tetrahydrofuran (5.0 mL) were added successively, III-1 (308.5 mg, 1.0 mmol, 1.0 equiv), sodium borohydride (314.5 mg, 5.0 mmol, 5.0 equiv), TLC detection of the raw material was basically reacted, stop the reaction, then add water, the water layer was extracted with dichloromethane, the combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, rotary evaporation and column chromatography, eluent (petroleum ether / ethyl acetate = 1 / 1), product III-27 was obtained as a colorless liquid 186.6 mg, yield 83%; 97% ee; [a] D 20= -13.6 (c = 0.42, CHCI3); 97% ee. (Chiralcel OJ-H column, 25:75 n-hexane: isopropanol). 1 H NMR (400 MHz, CDCI3): δ 7.37-7.31 (m, 4H), 7.23-7.21 (m, 1H), 6.47 (d, J = 16.0 Hz, 1H), 6.19 (dd, J = 16.0, 8.8 Hz, 1H), 3.96-3.80 (m, 4H), 2.90-2.82 (m, 1H), 1.94 (s, br, 2H), 1.20 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCI3): δ 136.92, 131.63, 129.33 (d, J = 5.9 Hz), 128.57, 127.50, 126.21, 98.64 (d, J = 175.5 Hz), 63.65 (d, J = 25.4 Hz, 2C), 40.05 (d, J = 20.9 Hz), 14.33 (d, J = 5.2 Hz); 19 F NMR (376 MHz, CDCI3): δ -177.69 (s, 1F); IR (ATR): 3334, 1448, 1265, 1055, 1024, 916, 748, 692 cm -1 ; HRMS (ESI): Exact mass calcd for C 13 H 17 FNaO2[M + Na] + : 247.1105, Found: 247.1107.

[0142] Example 28

[0143] Synthesis of fluorinated 1,3-dioxane III-28:

[0144]

[0145] To a solution of III-27 (22.4 mg, 0.1 mmol, 1.0 equiv) in chloroform, 1-(dimethoxymethyl)-4-methoxybenzene (27.3 mg, 0.15 mmol, 1.5 equivs), zinc chloride (21.8 mg, 0.16 mmol, 1.6 equivs) were added successively. TLC showed that the starting material was almost reacted completely, the reaction was stopped, and the product III-28 was obtained as a white solid 19.8 mg after column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) in 56% yield; 97% ee; [a] D 20= -13.6 (c = 0.42, CHCI3); 97% ee. (Chiralcel OX-H column, 10:90 n-hexane: isopropanol). [α] D 20 = -13.9 (c = 0.49, CHCI3); 97% ee. 1 HNMR (400 MHz, CDCI3): δ 7.44 (d, J = 8.8 Hz, 2H), 7.38-7.31 (m, 4H), 7.27-7.23 (m, 1H), 6.88 (d, J = 8.8 Hz, 2H), 6.44 (d, J = 15.6 Hz, 1H), 6.16 (dd, J = 15.6, 9.2 Hz, 1H), 5.40 (s, 1H), 4.35-4.22 (m, 2H), 4.01-3.82 (m, 2H), 3.79 (s, 3H), 2.50-2.40 (m, 1H), 1.19 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCI3): δ 160.09, 136.56, 132.19, 130.03, 128.62, 128.27 (d, J = 4.3 Hz), 127.70, 127.46, 126.25, 113.59, 100.76, 89.66 (d, J = 183.7 Hz), 71.56 (d, J = 22.4 Hz), 71.38 (d, J = 22.3 Hz), 55.27, 41.50 (d, J = 20.5 Hz), 13.96 (d, J = 4.0 Hz); 19 F NMR (376 MHz, CDCI3): δ -177.35 (s, 1F). IR (ATR): 2924, 2852, 1517, 1247, 1035, 977, 738, 696 cm -1 ; HRMS (ESI): Exact mass calcd for C 21 H 23 FO3 [M+H]: 343.1631, Found: 343.1702.

[0146] Example 29

[0147] Synthesis of fluorinated 1,3-dioxan-2-one III-29:

[0148]

[0149] In a solution of III-27 (22.4 mg, 0.1 mmol, 1.0 equiv) in dichloromethane, cooled at -30 °C for 10 min, added triphosgene (44.5 mg, 0.15 mmol, 1.5 equivs), triethylamine (20.2 mg, 0.2 mmol, 1.6 equivs) successively, TLC detected that the starting material was almost reacted, stopped the reaction, column chromatography after spin dry, eluent (petroleum ether / ethyl acetate = 2 / 1), the product III-29 was obtained as a white solid 19.8 mg, yield 56%; [a] D 20 = -13.6 (c = 0.42, CHCI3); 97% ee. (Chiralcel OX-H column, 30:70 n-hexane: isopropanol).[a] D 20 = -4.3 (c = 0.34, CHCI3); 97% ee. 1 H NMR (400 MHz, CDCI3): δ 7.37-7.26 (m, 5H), 6.49 (d, J = 15.6 Hz, 1H), 6.08 (dd, J = 15.6, 9.2 Hz, 1H), 4.55-4.34 (m, 4H), 2.69-2.60 (m, 1H), 1.24 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCI3): δ 147.40, 135.82, 133.70, 128.73, 128.24, 126.38, 125.97 (d, J = 4.2 Hz), 89.32 (d, J = 182.0 Hz), 72.05 (d, J = 21.4 Hz), 71.63 (d, J = 24.4 Hz), 41.01 (d, J = 20.9 Hz), 14.17 (d, J = 4.0 Hz); 19 F NMR (376 MHz, CDCI3): δ -175.22 (s, IF); IR (ATR): 1753, 1456, 1184, 1087, 1020, 831, 752, 692 cm -1 ; HRMS (ESI): Exact mass calcd for C 14 H 15 FNaO3[M + Na] + : 273.0897, Found: 273.0895.

[0150] Example 30

[0151] Synthesis of fluorinated oxetane III-30:

[0152] Synthesis of fluorinated oxetane III-30:

[0153] A solution of III-27 (56.1 mg, 0.25 mmol, 1.0 equiv) in THF was added dropwise to a solution of BuLi (2.5 M in hexanes, 1.0 equiv.) at 0 °C. After stirring for 30 min at 0 °C, a solution of p-toluenesulfonyl chloride (47.7 mg, 0.25 mmol, 1.0 equiv) in THF (1.0 mL) was added. The resulting mixture was stirred for 1 h at 0 °C, then III-28 (55.0 mg, 0.25 mmol, 1.0 equiv) was added. The reaction mixture was stirred at 60 °C for 6 h, then cooled and diluted with diethyl ether and water. The aqueous layer was extracted with diethyl ether, and the combined organic layers were dried over anhydrous sodium sulfate. After being concentrated in vacuo, the product III-29 was obtained as a white solid 34.0 mg, 66% yield; (Chiralcel AD-H column, 10:90 n-hexane:isopropanol). [a] n BuLi ((100 μL, 2.5 M in hexanes, 1.0 equiv.) was stirred at 0 °C for 30 min, then a solution of p-toluenesulfonyl chloride (47.7 mg, 0.25 mmol, 1.0 equiv) in THF (1.0 mL) was added. The resulting mixture was stirred for 1 h at 0 °C, then III-28 (55.0 mg, 0.25 mmol, 1.0 equiv) was added. The reaction mixture was stirred at 60 °C for 6 h, then cooled and diluted with diethyl ether and water. The aqueous layer was extracted with diethyl ether, and the combined organic layers were dried over anhydrous sodium sulfate. After being concentrated in vacuo, the product III-29 was obtained as a white solid 34.0 mg, 66% yield; (Chiralcel AD-H column, 10:90 n-hexane:isopropanol). [a] n BuLi (100 μL, 2.5 M in hexanes, 1.0 equiv) was stirred at 0 °C for 30 min, then a solution of p-toluenesulfonyl chloride (47.7 mg, 0.25 mmol, 1.0 equiv) in THF (1.0 mL) was added. The resulting mixture was stirred for 1 h at 0 °C, then III-28 (55.0 mg, 0.25 mmol, 1.0 equiv) was added. The reaction mixture was stirred at 60 °C for 6 h, then cooled and diluted with diethyl ether and water. The aqueous layer was extracted with diethyl ether, and the combined organic layers were dried over anhydrous sodium sulfate. After being concentrated in vacuo, the product III-29 was obtained as a white solid 34.0 mg, 66% yield; (Chiralcel AD-H column, 10:90 n-hexane:isopropanol). [a] D 20 = -1.5 (c = 0.31, CHCl3); 97% ee; 1 H NMR (400 MHz, CDCl3): 7.38-7.36 (m, 2H), 7.33-7.29 (m, 2H), 7.25-7.22 (m, 1H), 6.53 (d, J = 15.6 Hz, 1H), 6.15 (dd, J = 15.6, 8.4 Hz, 1H), 4.80-4.69 (m, 2H), 4.64-4.57 (m, 2H), 2.94-2.81 (m, 1H), 1.17 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 137.46, 133.07, 129.26, 128.46 (d, J = 3.8 Hz), 128.29, 126.96, 97.48 (d, J = 210.1 Hz), 80.31 (d, J = 24.3 Hz), 80.23 (d, J = 24.2 Hz), 42.95 (d, J = 22.3 Hz), 14.12 (d, J = 4.6 Hz); 19 F NMR (376 MHz, CDCl3): δ -158.95 (s, 1F); IR (ATR): 2924, 1494, 1450, 1249, 974, 881, 748, 692 cm -1 ; HRMS (EI): Exact mass calcd for C 13 H 15 FNaO [M + Na] +: 229.1109, Found: 229.1107

[0154] Example 31

[0155] Synthesis of chiral fluorinated epoxide III-31:

[0156]

[0157] To a solution of III-1 (30.8 mg, 0.1 mmol, 1.0 equiv) in dichloromethane was added m-chloroperoxybenzoic acid (34.5 mg, 0.2 mmol, 2.0 equivs). TLC indicated that the starting material was almost consumed. The reaction was stopped and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give product III-31 as a white solid 19.5 mg, yield 73%; [a] D 20 = -16.7 (c = 0.52, CHCI3); 97% ee. (Chiralcel OX-H column, 10:90 n-hexane: isopropanol). 1 H NMR analysis for the mixture diastereomers (400 MHz, CDCI3): δ 7.35-7.21 (m, 5H), 4.37-4.19 (m, 4H), 3.79-3.66 (m, 1H), 3.11-3.00 (m, 1H), 2.66-2.50 (m, 1H), 1.35-1.25 (m, 6H), 1.18-1.14 (m, 3H); 13 C NMR for mixture diastereomers (100 MHz, CDCI3): δ 165.51 (d, J = 14.6 Hz), 165.48 (d, J = 19.3 Hz), 165.24, 164.98, 136.67, 136.58, 128.47, 128.36, 128.34, 125.61, 125.53, 95.65 (d, J = 204.6 Hz), 95.47 (d, J = 203.1 Hz), 62.93, 62.92, 62.85, 62.80, 61.81 (d, J = 3.6 Hz), 61.17 (d, J = 3.2 Hz), 59.51, 57.58, 41.94 (d, J = 20.6 Hz), 41.38 (d, J = 19.7 Hz), 13.98 (d, J = 2.0 Hz), 13.73, 11.33 (d, J = 4.1 Hz), 10.88 (d, J = 3.6 Hz); 19F NMR for mixture diastereomers (376 MHz, CDC13): δ -176.59 (s), -178.46 (s); IR (ATR): 2384, 2349, 1751, 1369, 1155, 1043, 752, 698 cm -1 ; HRMS (ESI): Exact mass calcd for C 17 H 21 OF5Na [M + Na] + : 347.1265, Found: 347.1263.

[0158] Example 32

[0159] Synthesis of fluorinated hydroxy ester III-32:

[0160]

[0161] To a solution of III-1 (61.6 mg, 0.2 mmol, 1.0 equiv) in tetrahydrofuran, cooled at -78 °C for 10 min, was added tri-tert-butoxy lithium aluminum hydride (45 μL, 1.0 M in THF, 4.5 equiv), and the reaction was allowed to warm to room temperature. TLC indicated that the starting material was almost completely consumed. The reaction was stopped, and the solvent was removed by evaporation. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give product III-31 as a yellow liquid 34.5 mg, 67% yield; [a] D 20 = -31.5 (c = 0.60, CHCI3); 97% ee. (Chiralcel OX-H column, 10:90 n-hexane: isopropanol). 1 H NMR for the mixture diastereomers (400 MHz, CDC13): δ 7.35-7.23 (m, 5H), 6.49-6.41 (m, 1H), 6.19-6.09 (m, 1H), 4.35-4.23 (m, 2H), 3.99-3.87 (m, 2H), 2.95-2.82 (m, 1H), 2.14 (br, 1H), 1.34 (t, J = 7.2 Hz, 1H), 1.26 (t, J = 7.2 Hz, 2H), 1.20-1.15 (m, 3H); 13C NMR for the mixture diastereomers (100 MHz, CDC13): δ 169.88 (d, J = 25.8 Hz), 169.83 (d, J = 25.6 Hz), 136.75, 136.62, 132.47, 132.08, 128.58, 128.52, 128.28 (d, J = 5.1 Hz), 127.67, 127.63, 127.59, 126.30, 126.28, 99.79 (d, J = 190.9 Hz), 99.68 (d, J = 191.1 Hz), 66.07 (d, J = 23.3 Hz), 65.19 (d, J = 23.5 Hz), 61.89, 61.74, 41.70, 41.48, 41.27, 15.29 (d, J = 4.5 Hz), 14.48 (d, J = 3.4 Hz), 14.23; 19 FNMR for the mixturediastereomers (376 MHz, CDC13): δ -183.59 (s), -179.11 (s); IR (ATR): 1747, 1367, 1238, 1095, 1037, 958, 856, 696 cm -1 ; HRMS (ESI): Exact mass calcd for C 15 H 19 FNaO3[M+Na] + : 289.1210, Found: 289.1219.

[0162] Example 33

[0163] Synthesis of fluoro compound III-33:

[0164]

[0165] In 10.0 mL reaction tube, dichloromethane, III-27 (22.4 mg, 0.1 mmol, 1.0 equiv), carboxylic acid drug molecule (0.12 mmol, 2.4 equivs), N,N'-diisopropylcarbodiimide (16.0 mg, 0.13 mmol, 2.6 equiv), 4-dimethylaminopyridine (6.1 mg, 0.02 mmol, 0.4 equiv) were added successively, stirred at room temperature overnight, TLC detection of raw materials has been basically reacted, stop the reaction, spin dry column chromatography, eluent (petroleum ether / ethyl acetate = 5 / 1), product III-33 as a white solid Hz, 3H); 13C NMR (100 MHz, CDC13): δ 173.69, 173.64, 157.73, 157.66, 136.63, 135.16, 135.08, 133.77, 133.71, 132.04, 129.30, 129.24, 128.87 (d, J = 4.0 Hz), 128.43, 127.47, 127.25, 127.16, 126.17, 126.13, 126.06, 126.04, 125.96, 119.13, 119.02, 105.58, 95.79 (d, J = 180.0 Hz), 63.54 (d, J = 27.4 Hz), 63.39 (d, J = 30.4 Hz), 55.26, 45.34, 45.28, 40.00 (d, J = 20.5 Hz), 18.05, 17.84, 14.08 (d, J = 5.1 Hz); 19 F NMR (376 MHz, CDC13): δ -174.68 (s, IF); IR (ATR): 1737, 1606, 1392, 1265, 1031, 925, 812, 694; HRMS (ESI): Exact mass calcd for C 41 H 41 FNaO6[M+Na] + : 671.2779, Found: 671.2783. 2.97-2.92 (m, 4H), 2.85-2.76 (m, 1H), 1.14 (d, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDC13): δ 171.24, 161.42, 145.47, 136.66, 135.12, 132.36, 128.91, 128.62, 128.52, 128.46, 128.04, 127.85, 127.58, 126.49, 126.26, 95.66 (d, J = 180.1 Hz), 63.41 (d, J = 27.5 Hz), 62.96 (d, J = 28.8 Hz), 40.14 (d, J = 20.9 Hz), 30.85, 23.35, 14.11 (d, J = 4.4 Hz); 19 F NMR (376 MHz, CDC13): δ -173.90 (s, IF); IR (ATR): 2382, 2349, 1743, 1219, 1155, 1026, 763, 692; HRMS (ESI): Exact mass calcd for C 49 H 43 FN2NaO6[M+Na]+ : 797.2997, Found: 797.3004. 3H), 7.01-6.97 (m, 2H), 6.54 (d, J = 16.0 Hz, 1H), 6.23 (dd, J = 15.6, 8.4 Hz, 1H), 4.67-4.52 (m, 4H), 3.90 (d, J = 6.4 Hz, 4H), 3.04-2.96 (m, 1H), 2.74 (s, 6H), 2.24-2.18 (m, 2H), 1.34 (d, J = 7.2 Hz, 3H), 1.10 (d, J = 8.4 Hz, 12H); 13 C NMR (100 MHz, CDC13): δ 167.77, 162.61, 162.28, 161.24, 161.12, 161.08, 136.55, 132.60, 132.10, 132.07, 128.58, 127.80, 126.31, 125.68 (d, J = 2.7 Hz), 120.53, 120.44, 115.29, 115.27, 112.59, 112.56, 102.96, 95.50 (d, J = 180.7 Hz), 75.71, 64.16 (d, J = 28.4 Hz), 63.69 (d, J = 20.9 Hz), 41.11 (d, J = 20.8 Hz), 28.15, 19.03, 17.53, 14.34 (d, J = 4.8 Hz); 19 F NMR (376 MHz, CDC13): δ -171.53 (s, IF); IR (ATR): 1716, 1604, 1508, 1371, 1253, 1085, 1012, 754; HRMS (ESI): Exact mass calcd for C 45 H 45 FN4NaO6S2[M + Na] + : 843.2657, Found: 843.2666.

[0166] The above examples are only for illustrating the technical concepts and features of the present application, and the purpose is to enable those skilled in the art to understand the content of the present application and implement it, and cannot limit the protection scope of the present application. Any equivalent changes or modifications made according to the essence of the present application are covered within the protection scope of the present application.

Claims

1. A method for synthesizing a chiral monofluoromalonate substituted allyl compound, characterized by, The chiral metal catalyst is used in the reaction of olefin and fluorinated malonate in solvent to obtain the chiral monofluorinated malonate substituted allyl compound of formula (I), and the reaction 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 C1-C10 alkyl and phenyl, C1-C10 alkyl or alkoxy substituted aryl, halogen substituted aryl; 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, the transition metal is selected from nickel, the chiral ligand is selected from one or more of (R) or (S)-configuration Binap ligand, PhPHOX ligand, QuinoxP ligand and Segphos ligand, and the reaction temperature is -10-60℃.

2. The method of synthesis of claim 1, wherein, The amount of the chiral metal catalyst is 0.1-50 mol% based on the amount of the fluorinated malonate, and the molar ratio of the olefin to the fluorinated malonate is 1:(0.1-20).

3. The method of synthesis of claim 1, wherein, The amount of the chiral metal catalyst is 5 mol% or 10 mol% based on the amount of the fluorinated malonate.

4. The method of synthesis of claim 1, wherein, The solvent is one or more of water, toluene, dichloromethane, diethyl ether, ethyl acetate, THF, acetone, acetonitrile, DMF, n-hexane, ethanol, methanol, isopropanol, nitromethane, glycerol, 1,4-dioxane, NMP, DMAc, 1,2-dichloroethane, chloroform and carbon tetrachloride, and the amount of the solvent is 0.1-50 mL per mmol of the fluorinated malonate.

5. The method of synthesis of claim 1, wherein, The reaction time is 1-120 hours.

6. The method of synthesis of claim 1, wherein, The chiral monofluorinated malonate substituted allyl compound is characterized in that the structure is

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