CN116803971A

CN116803971A - Chiral monofluoromalonate-substituted allyl compounds and their asymmetric catalytic synthesis methods and applications

Info

Publication number: CN116803971A
Application number: CN202210263029.3A
Authority: CN
Inventors: 余金生; 廖玲; 张颖
Original assignee: East China Normal University
Current assignee: East China Normal University
Priority date: 2022-03-17
Filing date: 2022-03-17
Publication date: 2023-09-26
Anticipated expiration: 2042-03-17
Also published as: CN116803971B

Abstract

本发明公开了含手性单氟丙二酸二酯取代烯丙基类化合物及其不对称催化合成方法及其应用，该类化合物具有如下式所示的结构，其具有潜在的生物活性和药效活性，为新药的开发提供强大的技术支持，具有很高的实用价值；所述合成方法从1,3‑二烯与亲核试剂氟代丙二酸二酯为原料出发，通过手性金属催化剂催化高效合成所述手性单氟丙二酸二酯取代烯丙基类化合物。本发明方法具有：原料廉价易得；无须加入碱，反应条件温和，操作简便；底物适用范围广，均可取得优秀的对映选择性，良好到优秀的产率等特点。本发明制备所得产物是一类有用的含氟砌块，经过简单化学转化可以合成多种含氟化合物。 The invention discloses chiral monofluoromalonate diester-substituted allyl compounds and their asymmetric catalytic synthesis methods and applications. The compounds have the structure shown in the following formula and have potential biological activity and pharmaceutical properties. It provides strong technical support for the development of new drugs and has high practical value; the synthesis method starts from 1,3-diene and the nucleophile fluoromalonate diester as raw materials, and uses chiral metal The catalyst catalyzes the efficient synthesis of the chiral monofluoromalonate diester-substituted allyl compound. The method of the invention has the following characteristics: the raw materials are cheap and easy to obtain; no alkali needs to be added, the reaction conditions are mild, and the operation is simple; the substrate has a wide applicable range, and excellent enantioselectivity and good to excellent yields can be obtained. The product prepared by the invention is a kind of useful fluorine-containing building block, and a variety of fluorine-containing compounds can be synthesized through simple chemical transformation.

Description

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

Technical Field

The invention belongs to the technical field of organic compounds, and relates to chiral monofluoromalonate substituted allyl compounds, and an asymmetric catalytic method for synthesizing the compounds from fluoromalonate and 1, 3-diene and application thereof.

Background

The fluorine element is located in the VII main group of the second period of the periodic table, is the element with the largest electronegativity, and has smaller atomic radius. Many studies have shown that the introduction of fluorine atoms or monofluoroalkyl groups into organic compounds, while improving the physical and chemical properties of the corresponding compounds, also increases the bioavailability, lipophilicity, binding affinity, metabolic stability, membrane permeability, etc. of biologically active molecules. For example, the structural units of the fluorine-containing natural product nucelocidin, the drug fluticasone propionate Fluticasone propionate for treating allergic rhinitis or bronchial asthma, the first-line drug Sofosbuvir for treating hepatitis C, the new drug Clofarabine for treating acute leukemia and the structural units all containing monofluoroalkyl are provided. Therefore, the selective introduction of fluorine atoms or monofluoroalkyl groups into known drugs or bioactive molecules is an important means for drug engineering and the creation of new drugs. Therefore, development of an efficient synthesis of alpha chiral perfluoroalkyl substituted compound has important significance for development of new drugs.

Some representative monofluoroalkyl substituted compound molecules of formula (1)

In view of the fact that the selective hydrofluoroalkyl reaction of olefins is one of the important methods for synthesizing fluoroalkyl substituted compounds, it has important potential application value in the development of fluorine-containing drugs, and although anti-mahalanobis hydrofluoroalkyl reactions achieved by fluoroalkyl radical addition strategies have been widely studied, compared with the anti-mahalanobis hydrofluoroalkyl reactions, branched-chain type mahalanobis regioselective hydrofluoroalkyl reactions, particularly asymmetrically catalyzed hydrofluoroalkyl reactions, have not been reported yet. Literature studies have shown that there is currently only one report of the racemization of olefin mahalanobis by acid-catalyzed carbonium process (Nature Communication,2020,11,5500), an asymmetric hydrofluoroalkyl of an olefin has not been achieved. Considering the cheap and easily available sources of simple olefin raw materials and the potential medicinal value of chiral monofluoroalkyl compounds, developing the mahalanobis asymmetric hydrofluoroalkyl reaction of olefin to efficiently synthesize the fluorine-containing chiral compounds has important significance and promotion on the research and development of fluorine-containing new drugs.

Disclosure of Invention

The invention aims to provide a synthesis method for synthesizing chiral monofluoro malonate substituted allyl compounds with simple operation and high efficiency; the method has the advantages of good universality of the substrate, mild reaction conditions and easy acquisition of raw materials and catalysts. The invention also aims to provide a series of chiral monofluoro malonate substituted allyl compounds with potential bioactivity and pharmacodynamics and application thereof, and provides technical support for new drug development.

The chiral monofluoromalonic acid diester substituted allyl compounds provided by the invention are shown as a formula (I):

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 group comprises thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine and thiazole; r is R ¹ Aryl substituted by C1-C10 alkyl and phenyl, C1-C10 alkyl or alkoxy, aryl substituted by halogen; the chiral configuration of the allylic position can be either (R) or (S).

Preferably, formula (I) is:

the invention provides a method for synthesizing chiral monofluoromalonate substituted allyl compounds, which comprises the step of carrying out a Markov regioselective asymmetric hydrofluonylation reaction on olefin and fluoromalonate under the action of a chiral metal catalyst in a solvent to generate a target compound formula (I). The method is shown in the following reaction formula (A):

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 group comprises thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine and thiazole; r is R ¹ Is C1-C10 alkyl andphenyl, C1-C10 alkyl or alkoxy substituted aryl, halogen substituted aryl; the chiral configuration of the allylic position can be either (R) or (S).

Specifically, the synthesis method of the invention comprises the following steps: adding a catalyst and a chiral ligand into a reaction vessel, sequentially adding 1, 3-diene, fluoromalonate and solvent, stirring at room temperature for 5 minutes, continuing to react at the corresponding temperature until TLC shows complete disappearance or almost no change of the fluoromalonate, stopping the reaction, rotating the solvent, separating by column chromatography to obtain the product, and measuring the enantioselectivity (ee value) of the product by high performance liquid chromatography HPLC.

In the invention, the catalyst is transition metal nickel acetylacetonate, cyclooctadiene nickel, nickel acetate, palladium acetate and the like; the chiral ligand is selected from chiral Box, py-Box ligand, foxaPL ligand, binap ligand, josiphos ligand, PHOX ligand, quinox P ligand, segphos ligand; preferably, the chiral ligand is a chiral bisoxazoline ligand, a Binap ligand, a Josiphos ligand, a PHOX ligand, a quinox p ligand;

in the invention, the dosage of the chiral catalyst is 0.1-50mol% based on the dosage of malonate; preferably 5mol%, 10mol%;

in the invention, the solvent is selected from one or more of ethyl acetate, dichloromethane, toluene, tetrahydrofuran, chloroform, 1, 2-dichloroethane, diethyl ether, ethanol, methanol, isopropanol and the like; preferably, it is methanol, ethanol, isopropanol.

In the present invention, the solvent is used in an amount of 0.1mL to 50mL per millimole (mmol) of the olefin; preferably 5 and 10mL.

In the invention, the molar ratio of the fluoromalonate to the olefin is 1: (0.1-20); preferably, it is 1:1.5.

in the invention, the temperature of the reaction is-10-100 ℃; preferably 25 ℃,40 ℃,50 ℃,60 ℃.

In the invention, the reaction time is 1-120h.

In the present invention, the olefins are 1, 3-dienes having different aryl or alkyl substitutions, which can be conveniently synthesized according to literature methods [ (a) J.S.Marcum, T.N.Cervarich, R.S.Manan, C.C.Roberts, S.J.Meek, ACS catalyst.2019, 9,5881. (b) A.Bhowmik, R.A.Fernandes, org.Lett.2019,21,9203. The structure is shown as the following formula (a):

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 group comprises thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine and thiazole; preferably, R is phenyl, naphthyl, thiophene, furan, p-methylphenyl, p-fluorophenyl, p-chlorophenyl, p-methoxyphenyl, n-pentyl, cyclohexyl, phenethyl.

In the invention, the fluoromalonate has a structure shown in the following formula (b):

formula (b) R ¹ Each independently selected from C1-C10 alkyl and phenyl, C1-C10 alkyl or alkoxy substituted aryl, halogen substituted arylalkyl; preferably, R ¹ Is C1-C10 alkyl or aryl.

In the synthesis method, the chiral monofluoro malonic acid diester substituted allyl compounds are efficiently synthesized by catalysis of the cheap metal nickel catalyst. The current synthesis method for chiral monofluoromalonic acid diester substituted allyl compounds is mainly realized by substitution reaction of the allyl compounds containing leaving groups under the catalysis of noble metal palladium, and the method generally needs to add equivalent alkali, generates stoichiometric waste and needs to perform pre-functionalization on olefins. The method of the invention comprises the following steps: the raw materials are cheap and easy to obtain; no pre-functionalization is required; no alkali is needed, the reaction condition is mild, and the operation is simple; the substrate has the characteristics of wide application range, excellent enantioselectivity, good to excellent yield and the like. The product prepared by the invention is a useful fluorine-containing building block, and can synthesize various fluorine-containing compounds through simple chemical conversion.

The chiral monofluoromalonic acid diester substituted allyl compound and the synthesis method thereof have high practical value, and the synthesis method has the remarkable characteristics that: the raw materials are cheap and easy to obtain, the reaction conditions are mild, other additives are not required to be added, and the operation is simple and convenient; the application range of the substrate is wide, and good yield and good to excellent enantioselectivity (up to 98% yield and 99% ee value) can be obtained; the chiral monofluoromalonate substituted allyl compounds have potential important medicinal values.

Moreover, the chiral monofluoromalonate substituted allyl compound can be used for synthesizing various fluorine-containing compounds through simple chemical conversion, and has wide application prospect as shown in the following formula (B).

Detailed Description

The present invention will be described in further detail with reference to the following examples, which illustrate various aspects of the invention, but the scope of protection of the invention is not limited to the following examples. Variations and advantages that would occur to one skilled in the art are included in the invention without departing from the spirit and scope of the inventive concept, and the scope of the invention is defined by the appended claims. The procedures, conditions, reagents, experimental methods, etc. for carrying out the present invention are common knowledge and common knowledge in the art, except for those specifically mentioned below, and the present invention is not particularly limited. The data presented in the examples below include the operation and reaction conditions and products of asymmetric synthesis. Enantioselectivity (ee value) was determined by HPLC.

Example 1

Synthesizing chiral monofluoromalonate substituted allyl compounds III-1:

to a 10.0mL vial was added sequentially cyclooctadiene nickel (3.5 mg,0.0125 mmol), chiral ligand (S, S) -Quinox P (4.6 mg, 0.015 mmol), 1, 3-diene I-1 (48.8 mg,0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg,0.25 mmol), absolute ethanol (2.5 mL), and the reaction mixture was stirred at 50℃for 15 hours. TLC detects that the starting material has substantially reacted and stops the reaction. Spin-drying followed by column chromatography, eluting with petroleum ether/ethyl acetate=1/20, gave product III-1 as a colourless liquid 66.3mg, 97% yield. [ alpha ]] _D ²⁰ ＝-84.7(c＝0.51,CHCl ₃ ) The method comprises the steps of carrying out a first treatment on the surface of the 96% ee. (Chiralcel AD-H column, 98:2 n-hexane: isopropanol) ¹ H NMR(400MHz,CDCl3):δ7.29-7.17(m,5H),6.46(d,J＝16.0Hz,1H),6.07(dd,J＝15.6,9.2Hz,1H),4.27(q,J＝7.2Hz,2H),4.20–4.15(m,2H),3.42–3.29(m,1H),1.28(t,J＝7.2Hz,3H),1.19-1.15(m,6H)； ¹³ C NMR(100MHz,CDCl3):δ165.56(d,J＝25.3Hz),165.55(d,J＝25.7Hz),136.67,133.09,128.51,127.67,126.85(d,J＝2.7Hz),126.36,97.08(d,J＝203.9Hz),62.65,62.48,42.73(d,J＝20.4Hz),14.70(d,J＝4.4Hz),14.06,14.03； ¹⁹ F NMR(376MHz,CDCl3):δ-178.21(s,1F).IR(ATR):1747,1369,1232,1097,968,858,746,694cm-1；HRMS(ESI):Exact mass calcd for C ₁₇ H ₂₁ FNaO ₄ [M+Na] ⁺ :331.1316,Found:331.1309。

Example 2

Synthesizing chiral monofluoromalonate substituted allyl compounds III-2:

to a 10.0mL vial was added sequentially cyclooctadiene nickel (6.9 mg,0.0125 mmol), chiral ligand (R, R) -Quinox P (4.6 mg, 0.015 mmol), 1, 3-diene I-1 (48.8 mg, 0.37mmol), diethyl fluoromalonate II-1 (44.5 mg,0.25 mmol), absolute ethanol (2.5 mL), and the reaction was stirred at 50deg.C for 15 h. The TLC detects that the starting material has substantially reacted,the reaction was stopped. Spin-drying followed by column chromatography, eluting with petroleum ether/ethyl acetate=1/20, gave product III-2 as a colourless liquid 66.3mg, 97% yield. [ alpha ]] _D ²⁰ ＝+84.7(c＝0.51,CHCl ₃ ) The method comprises the steps of carrying out a first treatment on the surface of the -96% ee. (ChiralcelAD-H column, 98:2 n-hexane: isopropanol) ¹ H NMR(400MHz,CDCl3):δ7.29-7.17(m,5H),6.46(d,J＝16.0Hz,1H),6.07(dd,J＝15.6,9.2Hz,1H),4.27(q,J＝7.2Hz,2H),4.20–4.15(m,2H),3.42–3.29(m,1H),1.28(t,J＝7.2Hz,3H),1.19-1.15(m,6H)； ¹³ C NMR(100MHz,CDCl3):δ165.56(d,J＝25.3Hz),165.55(d,J＝25.7Hz),136.67,133.09,128.51,127.67,126.85(d,J＝2.7Hz),126.36,97.08(d,J＝203.9Hz),62.65,62.48,42.73(d,J＝20.4Hz),14.70(d,J＝4.4Hz),14.06,14.03； ¹⁹ F NMR(376MHz,CDCl3):δ-178.21(s,1F).IR(ATR):1747,1369,1232,1097,968,858,746,694cm-1；HRMS(ESI):Exact mass calcd for C ₁₇ H ₂₁ FNaO ₄ [M+Na] ⁺ :331.1316,Found:331.1309。

Example 3

Synthesizing chiral monofluoromalonate substituted allyl compounds III-3:

nickel acetate (2.2 mg,0.0125 mmol), chiral ligand (S) -PyBox (5.1 mg, 0.0135mmol), 1, 3-diene I-2 (55.6 mg,0.375 mmol) and diethyl fluoromalonate II-1 (44.5 mg,0.25 mmol) were added sequentially to a 10.0mL tube, and the reaction mixture was stirred at 50℃for 24 hours. TLC detects that the starting material has substantially reacted and stops the reaction. Spin-drying followed by column chromatography, eluting with petroleum ether/ethyl acetate=1/20, gave product III-3 as a colorless liquid 66.9mg, 82% yield. [ alpha ]] _D ²⁰ ＝-28.4(c＝0.50,CHCl ₃ ) The method comprises the steps of carrying out a first treatment on the surface of the 97% ee. (ChiralcelAD-H column, 98:2 n-hexane: isopropanol) ¹ H NMR(400MHz,CDCl3):δ7.31–7.28(m,2H),7.00–6.96(m,2H)6.47(d,J＝15.6Hz,1H),6.04(dd,J＝16.4,9.2Hz,1H),4.32(q,J＝7.2Hz,2H),4.22(q,J＝7.2Hz,2H),3.44–3.30(m,1H),1.33(t,J＝7.2Hz,3H),1.24-1.20(m,6H)； ¹³ C NMR(100MHz,CDCl3):δ165.54(d,J＝25.5Hz,2C),162.37(d,J＝245.5Hz),132.82(d,J＝3.3Hz),131.87,127.85(d,J＝7.9Hz),126.64(t,J＝2.4Hz),97.03(d,J＝204.1Hz),62.66,62.47,42.65(d,J＝20.3Hz),14.66(d,J＝4.3Hz),14.06,14.02； ¹⁹ F NMR(376MHz,CDCl3):δ-178.21(s,1F),-114.33(s,1F)；IR(ATR):1747,1369,1226,1159,1097,970,858,821cm-1；HRMS(ESI):Exact mass calcd for C17H20F2NaO4[M+Na]+:349.1222,Found:349.1219

Example 4

Synthesizing chiral monofluoromalonate substituted allyl compounds III-4:

nickel acetylacetonate (3.2 mg,0.0125 mmol), chiral ligand (R, R) -Quinox P (4.6 mg, 0.0135mmol), 1, 3-diene I-3 (61.7 mg,0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg,0.25 mmol), anhydrous methanol (2.5 mL) were added sequentially to a 10.0mL tube, and the reaction mixture was stirred at 50℃for 20h. TLC detects that the starting material has substantially reacted and stops the reaction. Column chromatography after spin-drying, eluting with petroleum ether/ethyl acetate=1/20, gave product III-4 as a colourless liquid 74.6mg, 83% yield. [ alpha ]] _D ²⁰ ＝-40.0(c＝0.52,CHCl ₃ ) The method comprises the steps of carrying out a first treatment on the surface of the 95% ee. (Chiralcel AD-H column, 98:2 n-hexane: isopropanol) ¹ H NMR(400MHz,CDCl ₃ ):δ7.26(s,4H),6.45(d,J＝16.0Hz,1H),6.10(dd,J＝16.0,9.2Hz,1H),4.32(q,J＝7.2Hz,2H),4.22(q,J＝7.2Hz,2H),3.45–3.32(m,1H),1.33(t,J＝7.2Hz,3H),1.23-1.20(m,6H)； ¹³ C NMR:(100MHz,CDCl ₃ ):δ165.51(d,J＝25.6Hz),165.49(d,J＝25.3Hz),135.14,133.35,131.87,128.69,127.60(d,J＝1.8Hz),127.56,96.96(d,J＝204.2Hz),62.71,62.51,42.66(d,J＝20.3Hz),14.61(d,J＝4.3Hz),14.07,14.03； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-178.19(s,1F)；IR(ATR):1747,1369,1232,1163,1093,1039,970,810cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₁₇ H ₂₀ ClFNaO ₄ [M+Na] ⁺ :365.0926,Found:365.0920.

Example 5

Synthesizing chiral monofluoromalonate substituted allyl compounds III-5:

palladium acetate (2.8 mg,0.0125 mmol), chiral ligand (S) -BINAP (8.6 mg, 0.0135mmol), 1, 3-diene I-4 (74.3 mg,0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg,0.25 mmol) and absolute ethanol (2.5 mL) were successively added to a 10.0mL tube, and the reaction mixture was stirred at 40℃for 24 hours. TLC detects that the starting material has substantially reacted and stops the reaction. Spin-drying followed by column chromatography, eluting with petroleum ether/ethyl acetate=1/20, gave product III-5 as a colorless liquid 90.7mg, 96% yield. -47.4 (c=0.71, chcl) ₃ ) The method comprises the steps of carrying out a first treatment on the surface of the 93% ee. (ChiralcelAD-H column, 98:2 n-hexane: isopropanol). ¹ H NMR(400MHz,CDCl ₃ ):δ7.55(d,J＝8.0Hz,2H),7.43(d,J＝8.0Hz,2H),6.54(d,J＝15.6Hz,1H),6.23(dd,J＝16.0,9.2Hz,1H),4.33(q,J＝7.2Hz,2H),4.23(q,J＝7.2Hz,2H),3.49–3.34(m,1H),1.33(t,J＝7.2Hz,3H),1.24-1.20(m,6H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ165.40(d,J＝25.8Hz),165.35(d,J＝25.4Hz),140.08,131.73,129.72(d,J＝2.6Hz),129.45(q,J＝32.1Hz),126.48,125.44(q,J＝3.5Hz),124.07(q,J＝270.1Hz),96.78(d,J＝204.2Hz),62.69,62.50,42.55(d,J＝20.5Hz),14.47(d,J＝3.7Hz),13.99,13.94； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-177.95(s,1F),-62.55(s,3F)；IR(ATR):1749,1616,1323,1234,1163,1066,824,737cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₁₈ H ₂₀ F ₄ NaO ₄ [M+Na] ⁺ :399.1190,Found:399.1181.

Example 6

Synthesizing chiral monofluoromalonate substituted allyl compounds III-6:

to a 10.0mL tube seal was added sequentially nickel cyclooctadiene (3.5 mg,0.0125 mmol)) Chiral ligand (R, R) -Quinox P (4.6 mg, 0.0135mmol), 1, 3-diene I-5 (54.2 mg,0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg,0.25 mmol), absolute ethanol (2.5 mL) and the reaction was stirred at 25℃for 24 h. TLC detects that the starting material has substantially reacted and stops the reaction. Spin-drying followed by column chromatography, eluting with petroleum ether/ethyl acetate=1/20, gave product III-6 as a colourless liquid 74.4mg, 97% yield. [ alpha ]] _D ²⁰ ＝-101.9(c＝0.71,CHCl ₃ ) The method comprises the steps of carrying out a first treatment on the surface of the 97% ee. (ChiralcelAD-H column, 98:2 n-hexane: isopropanol). ¹ HNMR(400MHz,CDCl ₃ ):δ7.55(d,J＝8.0Hz,2H),7.43(d,J＝8.0Hz,2H),6.54(d,J＝15.6Hz,1H),6.23(dd,J＝16.0,9.2Hz,1H),4.33(q,J＝7.2Hz,2H),4.23(q,J＝7.2Hz,2H),3.49–3.34(m,1H),1.33(t,J＝7.2Hz,3H),1.24-1.20(m,6H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ165.40(d,J＝25.8Hz),165.35(d,J＝25.4Hz),140.08,131.73,129.72(d,J＝2.6Hz),129.45(q,J＝32.1Hz),126.48,125.44(q,J＝3.5Hz),124.07(q,J＝270.1Hz),96.78(d,J＝204.2Hz),62.69,62.50,42.55(d,J＝20.5Hz),14.47(d,J＝3.7Hz),13.99,13.94； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-177.95(s,1F),-62.55(s,3F)；IR(ATR):1749,1616,1323,1234,1163,1066,824,737cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₁₈ H ₂₀ F ₄ NaO ₄ [M+Na] ⁺ :399.1190,Found:399.1181.

Example 7

Synthesizing chiral monofluoromalonate substituted allyl compounds III-7:

to a 10.0mL tube was added, in order, 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) and absolute ethanol (2.5 mL), and the reaction mixture was stirred at 50℃for 24 hours. TLC detects that the starting material has substantially reacted and stops the reaction. Spin-drying column chromatography, eluting with petroleum ether/ethyl acetate=1/20 to obtain colorless liquid 67.7mg of III-7The rate was 83%. [ alpha ]] _D ²⁰ ＝-66.2(c＝0.49,CHCl ₃ )；95％ee。 ¹ H NMR(400MHz,CDCl ₃ ):δ7.42(t,J＝8.0Hz,1H),7.22-7.17(m,1H),7.09-6.98(m,2H),6.69(d,J＝16.4Hz,1H),6.19(dd,J＝16.0,9.2Hz,1H),4.33(q,J＝7.2Hz,2H),4.24(q,J＝7.2Hz,2H),3.47-3.36(m,1H),1.33(t,J＝6.4Hz,3H),1.26-1.21(m,6H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ165.49(d,J＝25.3Hz),165.45(d,J＝26.0Hz),160.07(d,J＝247.6Hz),129.47(dd,J＝25.3,3.0Hz),128.99(d,J＝8.4Hz),127.23(d,J＝3.6Hz),125.44(d,J＝3.8Hz),124.41(d,J＝12.3Hz),124.06(d,J＝3.6Hz),115.59(d,J＝21.9Hz),96.95(d,J＝203.5Hz),62.67,62.54,43.00(d,J＝20.4Hz),14.57(d,J＝4.0Hz),14.00,13.97； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-178.11(s,1F),-118.54(s,1F)；IR(ATR):1749,1487,1456,1271,1230,1041,972,756cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₁₇ H ₂₀ F ₂ NaO ₄ [M+Na] ⁺ :349.1222,Found:349.1213.

Example 8

Synthesis of chiral monofluoromalonate substituted allyl compounds III-8:

to a 10.0mL vial was added sequentially cyclooctadiene nickel (3.5 mg,0.0125 mmol), chiral ligand (R, R) -Quinox P (4.6 mg, 0.015 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), and the reaction was stirred at 50deg.C for 24 hours. TLC detects that the starting material has substantially reacted and stops the reaction. Spin-drying followed by column chromatography, eluting with petroleum ether/ethyl acetate=1/20, gave product III-8 as a colourless liquid 76.2mg, 86% yield. [ alpha ]] _D ²⁰ ＝-121.1(c＝0.84,CHCl ₃ )；97％ee。 ¹ H NMR(400MHz,CDCl ₃ ):δ7.22(d,J＝7.6Hz,2H),7.09(d,J＝7.6Hz,2H),6.47(d,J＝16.0Hz,1H),6.06(dd,J＝16.0,9.2Hz,1H),4.32(q,J＝7.2Hz,2H),4.21(q,J＝6.8Hz,2H),3.44-3.30(m,1H),2.32(s,3H),1.33(t,J＝8.8Hz,3H),1.23-1.19(m,6H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ165.57(d,J＝25.4Hz),165.52(d,J＝25.7Hz),137.43,133.86,132.91,129.15,126.22,125.73(d,J＝2.6Hz),97.09(d,J＝203.8Hz),62.55,62.37,42.71(d,J＝20.3Hz),21.07,14.67(d,J＝4.3Hz),14.01,13.96； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-178.28(s,1F)；IR(ATR):1747,1446,1232,1271,1232,1039,970,804cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₁₈ H ₂₃ FNaO ₄ [M+Na] ⁺ :345.1473,Found:345.1475.

Example 9

Synthesis of chiral monofluoromalonate substituted allyl compounds III-9:

to a 10.0mL tube was added, in order, cyclooctadiene nickel (1.4 mg,0.005 mmol), chiral ligand (R, R) -Quinox P (1.9 mg,0.0055 mmol), 1, 3-diene I-8 (60.1 mg,0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg,0.25 mmol), absolute ethanol (2.5 mL), and the reaction mixture was stirred at 50℃for 26 hours. TLC detects that the starting material has substantially reacted and stops the reaction. Column chromatography after spin drying, eluting with petroleum ether/ethyl acetate=1/20, gave product III-9 as a colourless liquid 80.4mg, 95% yield. [ alpha ]] _D ²⁰ ＝-121.1(c＝0.84,CHCl ₃ )；97％ee。 ¹ H NMR(400MHz,CDCl ₃ ):δ7.27(d,J＝7.2Hz,2H),6.84-6.82(m,2H),6.44(d,J＝16.0Hz,1H),5.97(dd,J＝16.0,9.2Hz,1H),4.32(q,J＝6.8Hz,2H),4.22(q,J＝7.2Hz,2H),3.80(s,3H),3.43-3.29(m,1H),1.33(t,J＝6.8Hz,3H),1.24-1.19(m,6H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ166.15(d,J＝25.5Hz),165.60(d,J＝26.0Hz),159.27,132.48,129.47,127.53,124.56(d,J＝2.7Hz),113.92,97.21(d,J＝203.9Hz),62.60,62.42,55.25,42.79(d,J＝20.3Hz),14.78(d,J＝4.3Hz),14.07,14.02； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-178.47(s,1F)；IR(ATR):1747,1512,1246,1174,1032,968,856,820cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₁₈ H ₂₃ FNaO ₅ [M+Na] ⁺ :361.1422,Found:361.1419.

Example 10

Synthesis of chiral monofluoromalonate substituted allyl compounds III-10:

to a 10.0mL vial was added sequentially cyclooctadiene nickel (3.5 mg,0.0125 mmol), chiral ligand (R, R) -Quinox P (4.6 mg, 0.015 mmol), 1, 3-diene I-9 (60.1 mg, 0.37mmol), diethyl fluoromalonate II-1 (44.5 mg,0.25 mmol), anhydrous methanol (2.5 mL), and the reaction was stirred at 50deg.C for 16 h. TLC detects that the starting material has substantially reacted and stops the reaction. Column chromatography after spin-drying, eluting with petroleum ether/ethyl acetate=1/20, gave product III-10 as a colourless liquid 67.1mg, 72% yield. [ alpha ]] _D ²⁰ ＝-66.2(c＝0.49,CHCl ₃ )；97％ee。 ¹ H NMR(400MHz,CDCl ₃ ):δ7.23-7.19(m,1H),6.93(d,J＝7.6Hz,1H),6.86(s,1H),6.78(d,J＝7.6Hz,1H),6.48(d,J＝16.0Hz,1H),6.11(dd,J＝15.6,9.2Hz,1H),4.33(q,J＝7.2Hz,2H),4.23(q,J＝7.2Hz,2H),3.81(s,3H),3.46-3.31(m,1H),1.33(t,J＝7.2Hz,3H),1.25-1.20(m,6H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ165.57(d,J＝25.4Hz),165.53(d,J＝25.7Hz),159.78,138.12,133.02,129.48,127.16(d,J＝2.7Hz),119.06,113.36,111.64,97.01(d,J＝204.1Hz),62.65,62.48,55.21,42.43(d,J＝20.3Hz),14.68(d,J＝4.3Hz),14.06,14.02； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-178.24(s,1F)；IR(ATR):1747,1580,1230,1157,1039,775,734,690cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₁₈ H ₂₃ FNaO ₅ [M+Na] ⁺ :361.1422,Found:361.1419.

Example 11

Synthesis of chiral monofluoromalonate substituted allyl compounds III-10:

to a 10.0mL tube was added, in order, cyclooctadiene nickel (3.5 mg,0.0125 mmol), chiral ligand (R, R) -Quinox P (4.6 mg, 0.015 mmol), 1, 3-diene I-10 (60.1 mg,0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg,0.25 mmol), anhydrous isopropyl alcohol (2.5 mL), and the reaction mixture was stirred at 50℃for 16 hours. TLC detects that the starting material has substantially reacted and stops the reaction. Spin-drying followed by column chromatography, eluting with petroleum ether/ethyl acetate=1/20, gave product III-11 as a colorless liquid 68.1mg, 80% yield. [ alpha ]] _D ²⁰ ＝-15.3(c＝0.3,CHCl ₃ )；99％ee。 ¹ H NMR(400MHz,CDCl ₃ ):δ7.23-7.19(m,1H),6.93(d,J＝7.6Hz,1H),6.86(s,1H),6.78(d,J＝7.6Hz,1H),6.48(d,J＝16.0Hz,1H),6.11(dd,J＝15.6,9.2Hz,1H),4.33(q,J＝7.2Hz,2H),4.23(q,J＝7.2Hz,2H),3.81(s,3H),3.46-3.31(m,1H),1.33(t,J＝7.2Hz,3H),1.25-1.20(m,6H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ165.57(d,J＝25.4Hz),165.53(d,J＝25.7Hz),159.78,138.12,133.02,129.48,127.16(d,J＝2.7Hz),119.06,113.36,111.64,97.01(d,J＝204.1Hz),62.65,62.48,55.21,42.43(d,J＝20.3Hz),14.68(d,J＝4.3Hz),14.06,14.02； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-178.24(s,1F)；IR(ATR):1747,1580,1230,1157,1039,775,734,690cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₁₈ H ₂₃ FNaO ₅ [M+Na] ⁺ :361.1422,Found:361.1419.

Example 12

Synthesizing chiral monofluoromalonate substituted allyl compounds III-12:

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) and diethyl fluoromalonate II-1 (44.5 mg,0.25 mmol) were added sequentially to a 10.0mL tube, and the reaction mixture was stirred at 25℃for 24 hours. TLC detects that the starting material has substantially reacted and stops the reaction. Spin-drying column chromatography, eluting with petroleum ether/ethyl acetate=1/20 to obtain product III-12 as colorless liquid 88.7mg, yield96％。[α] _D ²⁰ ＝-55.8(c＝0.50,CHCl ₃ )；97％ee。 ¹ H NMR(400MHz,CDCl ₃ ):δ6.48(s,2H),6.43(d,J＝15.6Hz,1H),6.36(s,1H),6.09(dd,J＝15.6,9.2Hz,1H),4.32(q,J＝6.8Hz,2H),4.22(q,J＝7.2Hz,2H),3.79(s,6H),3.45-3.30(m,1H),1.33(t,J＝6.8Hz,3H),1.25-1.20(m,6H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ165.55(d,J＝25.3Hz),165.51(d,J＝25.8Hz),160.87,138.67,133.13,127.31(d,J＝2.6Hz),104.45,99.99,97.05(d,J＝204.0Hz),62.67,62.51,55.33,42.68(d,J＝20.4Hz),14.68(d,J＝4.3Hz),14.08,14.02； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-178.30(s,1F)；IR(ATR):1747,1591,1265,1205,1153,968,734,702cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₁₉ H ₂₅ FNaO ₆ [M+Na] ⁺ :391.1527,Found:391.1534.

Example 13

Synthesis of chiral monofluoromalonate substituted allyl compounds III-13:

nickel acetate (8.9 mg,0.005 mmol), chiral ligand (R, R) -Quinox P (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 sequentially to a 10.0mL tube, and the reaction mixture was stirred at 50℃for 26 hours. TLC detects that the starting material has substantially reacted and stops the reaction. Spin-drying followed by column chromatography, eluting with petroleum ether/ethyl acetate=1/20, gave product III-13 as a colorless liquid 71.1mg, 81% yield. [ alpha ]] _D ²⁰ ＝-64.0(c＝0.52,CHCl ₃ )；95％ee。 ¹ H NMR(400MHz,CDCl ₃ ):δ6.87(s,1H),6.76-6.70(m,2H),6.40(d,J＝15.6Hz,1H),5.96-5.90(m,3H),4.31(q,J＝6.8Hz,2H),4.21(q,J＝8.0Hz,2H),3.39-3.28(m,1H),1.31(t,J＝6.8Hz,3H),1.23-1.17(m,6H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ165.56(d,J＝25.2Hz),165.52(d,J＝25.7Hz),147.95,147.24,132.62,131.07,124.92(d,J＝2.6Hz),120.98,108.16,105.61,101.03,97.11(d,J＝204.1Hz),62.63,62.45,42.68(d,J＝20.3Hz),14.71(d,J＝4.4Hz),14.07,14.00； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-178.58(s,1F)；IR(ATR):1745,1489,1444,1247,1093,927,858,792cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₁₈ H ₂₁ FNaO ₆ [M+Na] ⁺ :375.1214,Found:375.1216.

Example 14

Synthesis of chiral monofluoromalonate substituted allyl compounds III-14:

to a 10.0mL vial was added sequentially cyclooctadiene nickel (3.5 mg,0.0125 mmol), chiral ligand (R, R) -Quinox P (4.6 mg, 0.015 mmol), 1, 3-diene I-13 (67.6 mg,0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg,0.25 mmol), absolute ethanol (2.5 mL), and the reaction mixture was stirred at 25℃for 17 h. TLC detects that the starting material has substantially reacted and stops the reaction. Spin-drying followed by column chromatography, eluting with petroleum ether/ethyl acetate=1/20, gave product III-14 as a white solid 77.0mg, 87% yield. [ alpha ]] _D ²⁰ ＝-66.7(c＝0.26,CHCl ₃ )；97％ee。 ¹ H NMR(400MHz,CDCl ₃ ):δ7.80-7.76(m,3H),7.69(s,1H),7.55(d,J＝8.4Hz,1H),7.48–7.41(m,2H),6.67(d,J＝16.0Hz,1H),6.26(dd,J＝15.6,6.8Hz,1H),4.34(q,J＝6.8Hz,2H),4.28(q,J＝6.8Hz,2H),3.53–3.38(m,1H),1.34(t,J＝7.2Hz,3H),1.26–1.20(m,6H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ165.56(d,J＝25.4Hz,2C),134.09,133.48,133.17,132.99,128.14,127.90,127.60,127.21(d,J＝2.6Hz),126.23(d,J＝1.4Hz),125.86,123.48,97.09(d,J＝204.1Hz),62.63,62.46,42.85(d,J＝20.4Hz),14.71(d,J＝4.4Hz),14.03,13.99； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-178.20(s,1F).IR(ATR):1747,1367,1265,1230,1095,966,813,734cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₂₁ H ₂₃ FNaO ₄ [M+Na] ⁺ :381.1473,Found:381.1474.

Example 15

Synthesis of chiral monofluoromalonate substituted allyl compounds III-15:

to a 10.0mL tube seal was added sequentially cyclooctadiene nickel (3.5 mg,0.0125 mmol), chiral ligand (S) ⁱ Pr-Pyox (4.6 mg, 0.0135mmol), 1, 3-diene I-14 (67.6 mg,0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg,0.25 mmol), absolute ethanol (2.5 mL) and the reaction mixture was stirred at 50℃for 36 h. TLC detects that the starting material has substantially reacted and stops the reaction. Column chromatography after spin drying, eluting with petroleum ether/ethyl acetate=1/20, gave product III-15 as a colourless liquid 87.7mg, 98% yield. [ alpha ]] _D ²⁰ ＝-26.3(c＝0.71,CHCl ₃ )；93％ee。 ¹ H NMR(400MHz,CDCl ₃ ):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,CDCl ₃ ):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),128.51,128.03,126.02,125.74,125.59,124.04,123.65,97.19(d,J＝204.2Hz),62.70,62.57,43.01(d,J＝20.3Hz),14.72(d,J＝4.3Hz),14.05(s,2C)； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-178.35(s,1F)；IR(ATR):1745,1456,1367,1228,1099,968,858,771cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₂₁ H ₂₃ FNaO ₄ [M+Na] ⁺ :381.1473,Found:381.1479.

Example 16

Synthesis of chiral monofluoromalonate substituted allyl compounds III-16:

cyclooctadiennickel (6.9 mg,0.025 mmol) and chiral ligand were added sequentially to a 10.0mL vial(R, R) -Quinox P (4.6 mg,0.0275 mmol), 1, 3-diene I-15 (45.0 mg,0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg,0.25 mmol), anhydrous tetrahydrofuran (1.5 mL), and the reaction mixture was stirred at 50℃for 22 hours. TLC detects that the starting material has substantially reacted and stops the reaction. Column chromatography after spin-drying, eluting with petroleum ether/ethyl acetate=1/20, gave product III-16 as a colourless liquid 69.4mg, 81% yield. [ alpha ]] _D ²⁰ ＝-73.06(c＝0.99,CHCl ₃ )；94％ee。 ¹ H NMR(400MHz,CDCl ₃ ):δ7.32(s,1H),6.34-6.29(m,2H),6.20(s,1H),6.06(dd,J＝16.0,9.2Hz,1H),4.32(q,J＝7.2Hz,2H),4.24(q,J＝6.8Hz,2H),3.40-3.29(m,1H),1.32(t,J＝6.8Hz,3H),1.26-1.18(m,6H)； ¹³ CNMR(100MHz,CDCl ₃ ):δ165.54(d,J＝25.5Hz),165.49(d,J＝25.6Hz),152.13,141.98,125.43(d,J＝2.8Hz),121.38,111.14,107.87,96.90(d,J＝204.4Hz),62.64,62.49,42.29(d,J＝20.4Hz),14.51(d,J＝4.4Hz),13.99,13.96； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-178.14(s,1F)；IR(ATR):1747,1232,1095,1037,962,929,738.596cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₉ H ₁₂ F[M+H]:299.1217,Found:299.1286.

Example 17

Synthesis of chiral monofluoromalonate substituted allyl compounds III-17:

to a 10.0mL tube was added, in order, cyclooctadiene nickel (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 fluoromalonate II-1 (44.5 mg,0.25 mmol), absolute ethanol (2.5 mL), and the reaction mixture was stirred at 50℃for 24 hours. TLC detects that the starting material has substantially reacted and stops the reaction. Spin-drying followed by column chromatography, eluting with petroleum ether/ethyl acetate=1/20, gave product III-17 as a colorless liquid 77.1mg, 98% yield. [ alpha ]] _D ²⁰ ＝-5.23(c＝0.15,CHCl ₃ )；98％ee。 ¹ H NMR(400MHz,CDCl ₃ ):δ7.14(d,J＝5.2Hz,1H),6.95-6.92(m,2H),6.62(d,J＝15.6Hz,1H),5.95(dd,J＝16.0,9.2Hz,1H),4.32(q,J＝7.2Hz,2H),4.24(q,J＝7.2Hz,2H),3.42–3.27(m,1H),1.32(t,J＝7.2Hz,3H),1.26–1.19(m,6H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ165.53(d,J＝25.3Hz,2C),141.67,127.25,126.38(d,J＝2.6Hz),126.22,125.69,124.38,96.95(d,J＝204.4Hz),62.68,62.53,42.56(d,J＝20.6Hz),14.58(d,J＝4.4Hz),14.05,14.02； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-178.11(s,1F)；IR(ATR):1749,1463,1269,1165,1095,958,856,698cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₁₅ H ₁₉ FNaO ₄ S[M+Na] ⁺ :337.0880,Found:337.0877.

Example 18

Synthesis of chiral monofluoromalonate substituted allyl compounds III-18:

palladium acetate (5.6 mg,0.025 mmol), chiral ligand (R, R) -Quinox P (9.2 mg,0.0275 mmol), conjugated triene I-17 (78.1 mg,0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg,0.25 mmol), absolute ethanol (2.5 mL) were successively added to a 10.0mL tube, and the reaction mixture was stirred at 50℃for 27 hours. TLC detects that the starting material has substantially reacted and stops the reaction. Column chromatography after spin drying, eluting with petroleum ether/ethyl acetate=1/20, gave product III-18 as a colourless liquid 81.9mg, 98% yield. [ alpha ]] _D ²⁰ ＝-57.1(c＝0.50,CHCl ₃ )；91％ee。 ¹ H NMR(400MHz,CDCl ₃ ):δ7.38-7.29(m,4H),7.24-7.20(m,1H),6.71(dd,J＝16.0,10.8Hz,1H),6.50(d,J＝3.9Hz,1H),6.31(dd,J＝15.2,10.9Hz,1H),5.71(dd,J＝15.2,9.2Hz,1H),4.32(q,J＝7.2Hz,2H),4.29-4.23(m,2H),3.38-3.27(m,1H),1.33(t,J＝7.2Hz,3H),1.27(t,J＝7.2Hz,3H),1.17(d,J＝6.8Hz,3H)； ¹³ CNMR(100MHz,CDCl ₃ ):δ165.56(d,J＝25.5Hz),165.53(d,J＝25.7Hz),137.05,133.54,132.54,130.83(d,J＝2.8Hz),128.59,128.27,127.59,126.32,96.99(d,J＝203.9Hz),62.65,62.51,42.45(d,J＝20.5Hz),14.58(d,J＝4.3Hz),14.11,14.03； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-178.43(s,1F)；IR(ATR):1747,1265,1236,1161,989,858,734,692cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₁₉ H ₂₃ FNaO ₄ [M+Na] ⁺ :357.1473,Found:357.1475.

Example 19

Synthesis of chiral monofluoromalonate substituted allyl compounds III-19:

to a 10.0mL vial was added sequentially nickel cyclooctadiene (6.9 mg,0.0125 mmol), chiral ligand (R, R) -Quinox P (4.6 mg, 0.0135mmol), 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), and the reaction was stirred at 50deg.C for 30 h. TLC detects that the starting material has substantially reacted and stops the reaction. Spin-drying followed by column chromatography, eluting with petroleum ether/ethyl acetate=1/20, gave product III-19 as a colorless liquid 78.8mg, 94% yield. [ alpha ]] _D ²⁰ ＝-34.9；97％ee。 ¹ H NMR(400MHz,CDCl ₃ ):δ7.38-7.29(m,4H),7.24-7.20(m,1H),6.71(dd,J＝16.0,10.8Hz,1H),6.50(d,J＝3.9Hz,1H),6.31(dd,J＝15.2,10.9Hz,1H),5.71(dd,J＝15.2,9.2Hz,1H),4.32(q,J＝7.2Hz,2H),4.29-4.23(m,2H),3.38-3.27(m,1H),1.33(t,J＝7.2Hz,3H),1.27(t,J＝7.2Hz,3H),1.17(d,J＝6.8Hz,3H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ165.56(d,J＝25.5Hz),165.53(d,J＝25.7Hz),137.05,133.54,132.54,130.83(d,J＝2.8Hz),128.59,128.27,127.59,126.32,96.99(d,J＝203.9Hz),62.65,62.51,42.45(d,J＝20.5Hz),14.58(d,J＝4.3Hz),14.11,14.03； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-178.43(s,1F)；IR(ATR):1747,1265,1236,1161,989,858,734,692cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₁₉ H ₂₃ FNaO ₄ [M+Na] ⁺ :357.1473,Found:357.1475.

Example 20

Synthesis of chiral monofluoromalonate substituted allyl compounds III-20:

to a 10.0mL vial was added sequentially cyclooctadiene nickel (6.9 mg,0.0125 mmol), chiral ligand (R, R) -Quinox P (4.6 mg, 0.0135mmol), 1, 3-diene I-19 (68.0 mg,0.50 mmol), diethyl fluoromalonate II-1 (44.5 mg,0.25 mmol), absolute ethanol (1.5 mL), and the reaction was stirred at 50℃for 24 hours. TLC detects that the starting material has substantially reacted and stops the reaction. Spin-drying followed by column chromatography, eluting with petroleum ether/ethyl acetate=1/20, gave product III-20 as a colorless liquid 76.6mg in 97% yield. [ alpha ]] _D ²⁰ ＝-25.5(c＝0.49,CHCl ₃ )；90％ee。 ¹ H NMR(400MHz,CDCl ₃ ):δ5.51(dd,J＝14.4,6.8Hz,1H),5.29(dd,J＝15.6,9.2Hz,1H),4.29(q,J＝7.2Hz,2H),4.22(q,J＝7.2Hz,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(100MHz,CDCl ₃ ):δ165.77(d,J＝25.5Hz),165.63(d,J＝26.3Hz),140.27,124.60(d,J＝2.7Hz),97.45(d,J＝202.7Hz),62.48,62.27,42.45(d,J＝20.2Hz),40.56,32.85,32.77,26.06,25.90,25.88,14.79(d,J＝4.2Hz),14.07,14.01； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-179.36(s,1F)；IR(ATR):2924,2380,2349,1747,1448,1230,1031,970cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₁₇ H ₂₇ FNaO ₄ [M+Na] ⁺ :337.1786,Found:337.1778.

Example 21

Synthesis of chiral monofluoromalonate substituted allyl compounds III-21:

to a 10.0mL vial was added sequentially cyclooctadiene nickel (6.9 mg,0.0125 mmol), chiral ligand (R, R) -Quinox P (4.6 mg, 0.015 mmol), 1, 3-diene I-20 (46.6 mg,0.375 mmol), diethyl fluoromalonate II-1 (44.5 mg,0.25 mmol), absolute ethanol (1.5 mL), and the reaction mixture was stirred at 60℃for 26 hours. TLC detection of the starting material substantially reacted, stoppingAnd (3) reacting. Spin-drying followed by column chromatography, eluting with petroleum ether/ethyl acetate=1/20, gave product III-21 as a colorless liquid 72.8mg, 95% yield. [ alpha ]] _D ²⁰ ＝-32.7(c＝0.95,CHCl ₃ )；96％ee。 ¹ HNMR(400MHz,CDCl ₃ ):5.61-5.54(m,1H),5.34(dd,J＝15.2,8.8Hz,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＝6.8Hz,3H),0.87(t,J＝7.2Hz,3H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ165.77(d,J＝25.5Hz),165.67(d,J＝25.9Hz),134.55,126.93(d,J＝2.6Hz),97.4(d,J＝203.2Hz),62.49,62.28,42.35(d,J＝20.2Hz),32.39,31.25,28.87,22.46,14.77(d,J＝4.3Hz),14.05,14.01,14.00； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-179.19(s,1F)；IR(ATR):1751,1267,1240,1168,1041,974,738,704cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₁₆ H ₂₇ FNaO ₄ [M+Na] ⁺ :325.1786,Found:325.1778.

Example 22

Synthesis of chiral monofluoromalonate substituted allyl compounds III-22:

to a 10.0mL tube was added, in order, cyclooctadiene nickel (13.8 mg,0.050 mmol), chiral ligand (R, R) -Quinox P (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), and the reaction was stirred at 60℃for 30 hours. TLC detects that the starting material has substantially reacted and stops the reaction. Column chromatography after spin drying, eluting with petroleum ether/ethyl acetate=1/20, gave product III-22 as a colourless liquid 84.6mg, 95% yield. [ alpha ]] _D ²⁰ ＝-32.7(c＝0.95,CHCl ₃ )；11:1dr。 ¹ H NMR(400MHz,CDCl ₃ ):5.60-5.53(m,1H),5.34(dd,J＝15.2,8.8Hz,1H),5.09-5.06(m,1H),4.29(q,J＝7.2Hz,2H),4.23(q,J＝7.2Hz,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＝6.8Hz,3H),0.83(d,J＝6.4Hz,3H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ165.77(d,J＝25.4Hz),165.68(d,J＝25.9Hz),132.94,131.12,128.23(d,J＝2.7Hz),124.72,97.27(d,J＝203.4Hz),62.25,62.30,42.45(d,J＝1.0Hz),39.75,36.57,32.53,25.68.25.55,19.18,17.59,14.85(d,J＝4.3Hz),14.03,14.01； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-179.07(s,1F)；IR(ATR):1749,1456,1367,1267,1230,1041,972,860cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₂₀ H ₃₃ FNaO ₄ [M+Na] ⁺ :379.2255,Found:379.2249.

Example 23

Synthesis of chiral monofluoromalonate substituted allyl compounds III-23:

to a 10.0mL tube was added, in order, cyclooctadiene nickel (3.5 mg,0.0125 mmol), chiral ligand (R, R) -Quinox P (4.6 mg, 0.015 mmol), 1, 3-diene I-1 (48.8 mg,0.375 mmol), dimethyl fluoromalonate II-2 (37.5 mg,0.25 mmol), absolute ethanol (2.5 mL), and the reaction mixture was stirred at 25℃for 15 hours. TLC detects that the starting material has substantially reacted and stops the reaction. Spin-drying followed by column chromatography, eluting with petroleum ether/ethyl acetate=1/20, gave product III-23 as a colourless liquid 66.3mg, 97% yield. [ alpha ]] _D ²⁰ ＝-84.7(c＝0.51,CHCl ₃ ) The method comprises the steps of carrying out a first treatment on the surface of the 96% ee. (Chiralcel AD-H column, 98:2 n-hexane: isopropanol) ¹ H NMR(400MHz,CDCl3):δ7.33-7.24(m,5H),6.44(d,J＝16.0Hz,1H),6.06(dd,J＝15.6,9.2Hz,1H),4.24(m,1H),3.66(s,6H),0.91(d,J＝7.2Hz,3H)； ¹³ C NMR(100MHz,CDCl3):δ165.56(d,J＝25.3Hz),165.55(d,J＝25.7Hz),136.67,133.09,128.51,127.67,126.85(d,J＝2.7Hz),126.36,97.08(d,J＝203.9Hz),51.91,33.50,11.63； ¹⁹ F NMR(376MHz,CDCl3):δ-178.41(s,1F).IR(ATR):1727,1349,1225,1043,946,824,777,705cm-1；HRMS(ESI):Exact mass calcd for C ₁₇ H ₂₁ FNaO ₄ [M+Na] ⁺ :303.1115,Found:303.1119。

Example 24

Synthesis of chiral alpha-allyl substituted fluoromalonate compound III-24:

to a 10.0mL tube was added, in order, cyclooctadiene nickel (3.5 mg,0.0125 mmol), chiral ligand (R, R) -Quinox P (4.6 mg, 0.015 mmol), 1, 3-diene I-1 (48.8 mg,0.375 mmol), diisopropyl fluoromalonate II-3 (51.6 mg,0.25 mmol), absolute ethanol (2.5 mL), and the reaction mixture was stirred at 60℃for 24 hours. TLC detects that the starting material has substantially reacted and stops the reaction. Spin-drying followed by column chromatography, eluting with petroleum ether/ethyl acetate=1/10, gave product III-24 as a colourless liquid 66.3mg, 97% yield. [ alpha ]] _D ²⁰ ＝-84.7(c＝0.51,CHCl ₃ ) The method comprises the steps of carrying out a first treatment on the surface of the 96% ee. (Chiralcel AD-H column, 98:2 n-hexane: isopropanol). ¹ H NMR(400MHz,CDCl3):δ7.33-7.24(m,5H),6.44(d,J＝16.0Hz,1H),6.06(dd,J＝15.6,9.2Hz,1H),4.24(m,1H),3.66(s,6H),0.91(d,J＝7.2Hz,3H)； ¹³ C NMR(100MHz,CDCl3):δ165.56(d,J＝25.3Hz),165.55(d,J＝25.7Hz),136.67,133.09,128.51,127.67,126.85(d,J＝2.7Hz),126.36,97.08(d,J＝203.9Hz),51.91,33.50,11.63； ¹⁹ F NMR(376MHz,CDCl3):δ-178.41(s,1F).IR(ATR):1727,1349,1225,1043,946,824,777,705cm-1；HRMS(ESI):Exact mass calcd for C ₁₇ H ₂₁ FNaO ₄ [M+Na] ⁺ :303.1115,Found:303.1119。

Example 25

Synthesis of chiral α -allyl substituted fluorocarboxylic acid III-25:

a mixed solvent of phosphate (20 mL, pH=8) and DMSO (6 mL) was sequentially added to a 10.0mL reaction tube, and III-1 (308.5 mg,1.0mmol,1.0 equiv) was Pig Liver Esterase (PLE) (20 mg,200 units), and after stirring the reaction solution at 60℃for 24 hours, TLC detection of the starting material was substantially completed and the reaction was stopped. Aqueous hydrochloric acid was added to bring the pH of the solution to 3, and the aqueous layer was extracted with dichloromethane. MergingThe organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and column chromatographed after spin-drying to give product III-25 as colorless liquid 263.5mg, yield 94%; [ alpha ]] _D ²⁰ ＝-60.9(c＝0.51,CHCl ₃ ) The method comprises the steps of carrying out a first treatment on the surface of the 12:1dr. (Chiralcel AD-H column, 98:2 n-hexane: isopropanol). ¹ H NMR(400MHz,CDCl ₃ ):δ7.33-7.21(m,5H),6.52(d,J＝16.0Hz,1H),6.12(dd,J＝16.0,9.2Hz,1H),4.29(q,J＝7.2Hz,2H),3.42-3.31(m,1H),1.29(t,J＝7.2Hz,3H),1.19(d,J＝6.8Hz,3H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ168.67(d,J＝28.7Hz),165.84(d,J＝26.0Hz),136.62,133.35,128.50,127.70,126.44,97.05(d,J＝203.5Hz),63.03,42.73(d,J＝20.6Hz),14.63(d,J＝3.9Hz),13.94； ¹⁹ FNMR(376MHz,CDCl ₃ ):δ-176.84(s,1F)；IR(ATR):1749,1296,1267,1043,1014,1014,750,694cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₁₅ H ₁₇ FNaO ₄ [M+Na] ⁺ :303.1003,Found:303.0989.

Example 26

Synthesis of chiral alpha-allyl substituted fluorodicarboxylic acid III-26:

methanol (0.2 mL) and methylene chloride (1.2 mL) were added sequentially to a 10.0mL reaction tube, III-1 (61.6 mg,0.2mmol,1.0 equiv), followed by sodium hydroxide (17.6 mg,0.44mmol,2.2 equiv). TLC detection of the starting materials substantially completed, stopping the reaction, then adding water and hydrochloric acid, extracting the aqueous layer with dichloromethane, washing the combined organic phases with brine, drying over anhydrous sodium sulfate and concentrating under reduced pressure, spin-drying followed by column chromatography, eluting with eluent (petroleum ether/ethyl acetate=1/20), to give product III-26 as a colorless liquid 49.9mg, yield 99%; [ alpha ]] _D ²⁰ ＝-3.6(c＝0.52,CHCl ₃ ). ¹ HNMR(400MHz,MeOD-d ₄ ):δ7.35(d,J＝7.6Hz,2H),7.28(t,J＝7.2Hz,2H),7.22-7.18(m,1H),6.56(d,J＝16.0Hz,1H),6.15(dd,J＝15.6,8.8Hz,1H),3.45-3.34(m,1H),1.21(d,J＝6.8Hz,3H)； ¹³ C NMR(100MHz,MeOD-d ₄ ):δ167.81(d,J＝26.3Hz),167.65(d,J＝25.8Hz),136,97,132.73,128.17,127.24,126.88(d,J＝2.5Hz),125.97,97.13(d,J＝199.2Hz),42.13(d,J＝20.4Hz),13.69(d,J＝4.2Hz)； ¹⁹ F NMR(376MHz,MeOD-d ₄ ):δ-178.78(s,1F)；IR(ATR):1732,1448,1159,1132,1014,970,746,694cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₁₃ H ₁₃ FNaO ₄ [M+Na] ⁺ :275.0690,Found:275.0686.

Example 27

Synthesis of chiral alpha-allyl substituted fluoro diol III-27:

methanol (5.0 mL) and tetrahydrofuran (5.0 mL) were sequentially added to a 10.0mL reaction tube, and III-1 (308.5 mg,1.0mmol,1.0 equiv), sodium borohydride (314.5 mg,5.0mmol,5.0 equiv) were added to the tube, TLC detected that the starting materials were substantially reacted, the reaction was stopped, water was then added, the aqueous layer was extracted with methylene chloride, the combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, column chromatography after spin-drying, and a eluent (petroleum ether/ethyl acetate=1/1) to give product III-27 as colorless liquid 186.6mg, yield 83%;97% ee; [ alpha ]] _D ²⁰ ＝-13.6(c＝0.42,CHCl ₃ ) The method comprises the steps of carrying out a first treatment on the surface of the 97% ee. (Chiralcel OJ-H column, 25:75 n-hexane: isopropanol). ¹ H NMR(400MHz,CDCl ₃ ):δ7.37-7.31(m,4H),7.23-7.21(m,1H),6.47(d,J＝16.0Hz,1H),6.19(dd,J＝16.0,8.8Hz,1H),3.96-3.80(m,4H),2.90-2.82(m,1H),1.94(s,br,2H),1.20(d,J＝6.8Hz,3H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ136.92,131.63,129.33(d,J＝5.9Hz),128.57,127.50,126.21,98.64(d,J＝175.5Hz),63.65(d,J＝25.4Hz,2C),40.05(d,J＝20.9Hz),14.33(d,J＝5.2Hz)； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-177.69(s,1F)；IR(ATR):3334,1448,1265,1055,1024,916,748,692cm ^-1 ；HRMS(ESI):Exact mass calcd forC ₁₃ H ₁₇ FNaO ₂ [M+Na] ⁺ :247.1105,Found:247.1107.

Example 28

Synthesis of fluorinated 1, 3-dioxane III-28:

to a chloroform solution of III-27 (22.4 mg,0.1mmol,1.0 equiv), 1- (dimethoxymethyl) -4-methoxybenzene (27.3 mg,0.15mmol,1.5 equivs) and zinc chloride (21.8 mg,0.16mmol,1.6 equivs) were added sequentially, TLC was used to detect that the starting material was substantially reacted, the reaction was stopped, column chromatography after spinning dry was performed, and the eluent (petroleum ether/ethyl acetate=5/1) to give product III-28 as a white solid 19.8mg, yield 56%;97% ee; [ alpha ]] _D ²⁰ ＝-13.6(c＝0.42,CHCl ₃ ) The method comprises the steps of carrying out a first treatment on the surface of the 97% ee. (Chiralcel OX-H column, 10:90 n-hexane: isopropanol). [ alpha ]] _D ²⁰ ＝-13.9(c＝0.49,CHCl ₃ )；97％ee； ¹ H NMR(400MHz,CDCl ₃ ):δ7.44(d,J＝8.8Hz,2H),7.38-7.31(m,4H),7.27-7.23(m,1H),6.88(d,J＝8.8Hz,2H),6.44(d,J＝15.6Hz,1H),6.16(dd,J＝15.6,9.2Hz,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＝6.8Hz,3H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ160.09,136.56,132.19,130.03,128.62,128.27(d,J＝4.3Hz),127.70,127.46,126.25,113.59,100.76,89.66(d,J＝183.7Hz),71.56(d,J＝22.4Hz),71.38(d,J＝22.3Hz),55.27,41.50(d,J＝20.5Hz),13.96(d,J＝4.0Hz)； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-177.35(s,1F).IR(ATR):2924,2852,1517,1247,1035,977,738,696cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₂₁ H ₂₃ FO ₃ [M+H]:343.1631,Found:343.1702.

Example 29

Synthesis of fluorinated 1, 3-dioxane-2-one iii-29:

in a solution of III-27 (22.4 mg,0.1mmol,1.0 equiv) in dichloromethane, cooling at-30deg.C for 10 min, adding sequentiallyTriphosgene (44.5 mg,0.15mmol,1.5 equivs), triethylamine (20.2 mg,0.2mmol,1.6 equivs), TLC detected that the starting material was essentially reacted, stopped the reaction, spin-dried, column chromatographed, eluting with eluent (petroleum ether/ethyl acetate=2/1) to give product III-29 as a white solid 19.8mg, 56% yield; [ alpha ]] _D ²⁰ ＝-13.6(c＝0.42,CHCl ₃ ) The method comprises the steps of carrying out a first treatment on the surface of the 97% ee. (Chiralcel OX-H column, 30:70 n-hexane: isopropanol). [ alpha ]] _D ²⁰ ＝-4.3(c＝0.34,CHCl ₃ )；97％ee； ¹ H NMR(400MHz,CDCl ₃ ):δ7.37-7.26(m,5H),6.49(d,J＝15.6Hz,1H),6.08(dd,J＝15.6,9.2Hz,1H),4.55-4.34(m,4H),2.69-2.60(m,1H),1.24(d,J＝6.8Hz,3H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ147.40,135.82,133.70,128.73,128.24,126.38,125.97(d,J＝4.2Hz),89.32(d,J＝182.0Hz),72.05(d,J＝21.4Hz),71.63(d,J＝24.4Hz),41.01(d,J＝20.9Hz),14.17(d,J＝4.0Hz)； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-175.22(s,1F)；IR(ATR):1753,1456,1184,1087,1020,831,752,692cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₁₄ H ₁₅ FNaO ₃ [M+Na] ⁺ :273.0897,Found:273.0895.

Example 30

Synthesis of fluorinated oxetane III-30:

a solution of III-27 (56.1 mg,0.25mmol,1.0 equiv) in tetrahydrofuran was added in portions at 0deg.C ⁿ After BuLi ((100. Mu.L, 2.5M in hexanes,1.0equiv)) was stirred at 0deg.C for 30 minutes, a solution of p-toluenesulfonyl chloride (47.7 mg,0.25mmol,1.0 eq.) in THF (1.0 mL) was added, the resulting mixture was stirred at 0deg.C for 1 hour, then added ⁿ BuLi (100. Mu.L, 2.5Min hexanes,1.0equiv). After stirring at 60 ℃ for 6 hours, TLC detects that the starting material had substantially reacted, stopping the reaction, cooling the reaction mixture and diluting with diethyl ether and water, extracting the aqueous layer with diethyl ether, drying the combined organic layer with anhydrous sodium sulfate, spin-drying followed by column chromatography, eluting with a eluent (petroleum ether/ethyl acetate=5/1), to give product III-30 as a white solid 34.0mg,yield 66%; (ChiralcelAD-H column, 10:90 n-hexane: isopropanol). [ alpha ]] _D ²⁰ ＝-1.5(c＝0.31,CHCl ₃ )；97％ee； ¹ H NMR(400MHz,CDCl ₃ ):7.38-7.36(m,2H),7.33-7.29(m,2H),7.25-7.22(m,1H),6.53(d,J＝15.6Hz,1H),6.15(dd,J＝15.6,8.4Hz,1H),4.80-4.69(m,2H),4.64-4.57(m,2H),2.94-2.81(m,1H),1.17(d,J＝6.8Hz,3H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ137.46,133.07,129.26,128.46(d,J＝3.8Hz),128.29,126.96,97.48(d,J＝210.1Hz),80.31(d,J＝24.3Hz),80.23(d,J＝24.2Hz),42.95(d,J＝22.3Hz),14.12(d,J＝4.6Hz)； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-158.95(s,1F)；IR(ATR):2924,1494,1450,1249,974,881,748,692cm ^-1 ；HRMS(EI):Exact mass calcd for C ₁₃ H ₁₅ FNaO[M+Na] ⁺ :229.1109,Found:229.1107

Example 31

Synthesis of chiral fluorinated epoxide III-31:

to a dichloromethane solution of III-1 (30.8 mg,0.1mmol,1.0 equiv), m-chloroperoxybenzoic acid (34.5 mg,0.2mmol,2.0 equiv) was added, and TLC was resumed to check that the starting material was substantially reacted, the reaction was stopped, column chromatography was performed after spinning to dryness, and the eluent (petroleum ether/ethyl acetate=10/1) to give product III-31 as a white solid 19.5mg, yield 73%; [ alpha ]] _D ²⁰ ＝-16.7(c＝0.52,CHCl ₃ ) The method comprises the steps of carrying out a first treatment on the surface of the 97% ee. (Chiralcel OX-H column, 10:90 n-hexane: isopropanol). ¹ H NMR analysis for the mixture diastereomers(400MHz,CDCl ₃ ):δ7.35-7.21(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(100MHz,CDCl ₃ ):δ165.51(d,J＝14.6Hz),165.48(d,J＝19.3Hz),165.24,164.98,136.67,136.58,128.47,128.36,128.34,125.61,125.53,95.65(d,J＝204.6Hz),95.47(d,J＝203.1Hz),62.93,62.92,62.85,62.80,61.81(d,J＝3.6Hz),61.17(d,J＝3.2Hz),59.51,57.58,41.94(d,J＝20.6Hz),41.38(d,J＝19.7Hz),13.98(d,J＝2.0Hz),13.73,11.33(d,J＝4.1Hz),10.88(d,J＝3.6Hz)； ¹⁹ F NMR for mixture diastereomers(376MHz,CDCl ₃ ):δ-176.59(s),-178.46(s)；IR(ATR):2384,2349,1751,1369,1155,1043,752,698cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₁₇ H ₂₁ OF ₅ Na[M+Na] ⁺ :347.1265,Found:347.1263.

Example 32

Synthesis of fluorinated hydroxy ester III-32:

in III-1 (61.6 mg,0.2mmol,1.0 equiv) in tetrahydrofuran, cooled at-78deg.C for 10 min, added with lithium aluminum tri-tert-butoxide (45 μL,1.0m in THF,4.5 eq.) and allowed to react at room temperature, TLC detected the starting material was essentially reacted, stopped the reaction, spin-dried, column chromatography, eluent (petroleum ether/ethyl acetate=5/1) to give product III-31 as a yellow liquid 34.5mg, 67% yield; [ alpha ]] _D ²⁰ ＝-31.5(c＝0.60,CHCl ₃ ) The method comprises the steps of carrying out a first treatment on the surface of the 97% ee. (Chiralcel OX-H column, 10:90 n-hexane: isopropanol). ¹ H NMR for the mixture diastereomers(400MHz,CDCl ₃ ):δ7.35-7.23(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＝7.2Hz,1H),1.26(t,J＝7.2Hz,2H),1.20-1.15(m,3H)； ¹³ C NMR for the mixture diastereomers(100MHz,CDCl ₃ ):δ169.88(d,J＝25.8Hz),169.83(d,J＝25.6Hz),136.75,136.62,132.47,132.08,128.58,128.52,128.28(d,J＝5.1Hz),127.67,127.63,127.59,126.30,126.28,99.79(d,J＝190.9Hz),99.68(d,J＝191.1Hz),66.07(d,J＝23.3Hz),65.19(d,J＝23.5Hz),61.89,61.74,41.70,41.48,41.27,15.29(d,J＝4.5Hz),14.48(d,J＝3.4Hz),14.23； ¹⁹ FNMR for the mixture diastereomers(376MHz,CDCl ₃ ):δ-183.59(s),-179.11(s)；IR(ATR):1747,1367,1238,1095,1037,958,856,696cm ^-1 ；HRMS(ESI):Exact mass calcd for C ₁₅ H ₁₉ FNaO ₃ [M+Na] ⁺ :289.1210,Found:289.1219.

Example 33

Synthesis of fluoro compound III-33:

dichloromethane, III-27 (22.4 mg,0.1mmol,1.0 eq.) and carboxylic acid-containing drug molecules (0.12 mmol,2.4 equivs), N, N' -diisopropylcarbodiimide (16.0 mg,0.13mmol,2.6 eq.), 4-dimethylaminopyridine (6.1 mg,0.02mmol,0.4 eq.) were added sequentially to a 10.0mL reaction tube, stirred overnight at room temperature, TLC detected that the starting material had substantially reacted, the reaction stopped, column chromatography after spin drying, eluting with a eluent (petroleum ether/ethyl acetate=5/1) to give product III-33 as a white solidHz,3H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ173.69,173.64,157.73,157.66,136.63,135.16,135.08,133.77,133.71,132.04,129.30,129.24,128.87(d,J＝4.0Hz),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＝180.0Hz),63.54(d,J＝27.4Hz),63.39(d,J＝30.4Hz),55.26,45.34,45.28,40.00(d,J＝20.5Hz),18.05,17.84,14.08(d,J＝5.1Hz)； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-174.68(s,1F)；IR(ATR):1737,1606,1392,1265,1031,925,812,694；HRMS(ESI):Exact mass calcd for C ₄₁ H ₄₁ FNaO ₆ [M+Na] ⁺ :671.2779,Found:671.2783.

2.97-2.92(m,4H),2.85-2.76(m,1H),1.14(d,J＝7.2Hz,3H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ171.24,161.42,145.47,136.66,135.12,132.36,128.91,128.62,128.52,128.46,128.04,127.85,127.58,126.49,126.26,95.66(d,J＝180.1Hz),63.41(d,J＝27.5Hz),62.96(d,J＝28.8Hz),40.14(d,J＝20.9Hz),30.85,23.35,14.11(d,J＝4.4Hz)； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-173.90(s,1F)；IR(ATR):2382,2349,1743,1219,1155,1026,763,692；HRMS(ESI):Exact mass calcd for C ₄₉ H ₄₃ FN ₂ NaO ₆ [M+Na] ⁺ :797.2997,Found:797.3004.

3H),7.01-6.97(m,2H),6.54(d,J＝16.0Hz,1H),6.23(dd,J＝15.6,8.4Hz,1H),4.67-4.52(m,4H),3.90(d,J＝6.4Hz,4H),3.04-2.96(m,1H),2.74(s,6H),2.24-2.18(m,2H),1.34(d,J＝7.2Hz,3H),1.10(d,J＝8.4Hz,12H)； ¹³ C NMR(100MHz,CDCl ₃ ):δ167.77,162.61,162.28,161.24,161.12,161.08,136.55,132.60,132.10,132.07,128.58,127.80,126.31,125.68(d,J＝2.7Hz),120.53,120.44,115.29,115.27,112.59,112.56,102.96,95.50(d,J＝180.7Hz),75.71,64.16(d,J＝28.4Hz),63.69(d,J＝20.9Hz),41.11(d,J＝20.8Hz),28.15,19.03,17.53,14.34(d,J＝4.8Hz)； ¹⁹ F NMR(376MHz,CDCl ₃ ):δ-171.53(s,1F)；IR(ATR):1716,1604,1508,1371,1253,1085,1012,754；HRMS(ESI):Exact mass calcd for C ₄₅ H ₄₅ FN ₄ NaO ₆ S ₂ [M+Na] ⁺ :843.2657,Found:843.2666.

The foregoing embodiments are merely for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the present invention and implement the same according to the present invention, not to limit the scope of the present invention. All equivalent changes or modifications made in accordance with the essence of the present invention are intended to be included in the scope of the present invention.

Claims

1. A chiral monofluoromalonate diester-substituted allyl compound, characterized in that the structure of the compound is as shown in the following formula (I):

in,

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 group includes thiophene, furan, pyridine, pyrrole, pyrazole, pyrimidine, pyrazine, pyridazine, and thiazole;

R ¹ is C1-C10 alkyl and phenyl, C1-C10 alkyl or alkoxy-substituted aryl group, halogen-substituted aryl group;

The chiral configuration of the allyl position may be the (R) configuration or the (S) configuration.

2. The chiral monofluoromalonate-substituted allyl compound as claimed in claim 1, characterized in that its structure is:

3. A method for synthesizing chiral monofluoromalonate-substituted allyl compounds, which is characterized in that, under the conditions of a chiral metal catalyst, olefins and fluoromalonate are reacted in a solvent to obtain The chiral monofluoromalonate substituted allyl compound of the formula (I) structure; the method is shown in the following reaction formula (A),

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

4. The synthesis method according to claim 3, wherein the chiral catalyst is a complex of a transition metal and a chiral ligand, and the transition metal is selected from the group consisting of iron, copper, nickel, palladium, and rhodium. , one or more of cobalt and iridium; the chiral ligand is selected from (R) or (S)-configured Binap ligand, Josiphos ligand, PHOX ligand, QuinoxP ligand, Segphos ligand One or several.

5. The synthesis method according to claim 3, wherein the dosage of the chiral metal catalyst is 0.1-50 mol% based on the dosage of the fluoromalonate; the olefin, fluoropropyl The molar ratio of diacid esters is 1: (0.1-20).

6. The synthesis method according to claim 3, wherein the amount of the chiral metal catalyst is 5 mol% or 10 mol% based on the amount of fluoromalonate compound.

7. The synthetic method as claimed in claim 3, wherein the solvent is water, toluene, methylene chloride, ether, ethyl acetate, THF, acetone, acetonitrile, DMF, n-hexane, ethanol, methyl alcohol, isopropyl One or more of propanol, nitromethane, glycerin, 1,4-dioxane, NMP, DMAc, 1,2-dichloroethane, chloroform, and carbon tetrachloride; the amount of the solvent is The amount used per millimole of fluoromalonate is 0.1 mL to 50 mL.

8. The synthesis method according to claim 3, characterized in that the reaction temperature is -10°C to 100°C, and the reaction time is 1-120 hours.

9. Use of the chiral monofluoromalonate-substituted allyl compound as claimed in claim 1 in constructing or preparing fluorine-containing compounds.