Asymmetric catalyst systems and uses thereof

Abstract

The invention relates to asymmetric catalyst systems and uses thereof. The asymmetric catalyst system comprises a copper catalyst, a ligand and a solvent, the solvent comprises a solvent of which the molecular structure contains a benzene ring; the ligand comprises at least one compound with the structure shown as the formula IV and the formula V. According to the preparation method, an asymmetric catalyst system with a specific structure and composition is selected, so that the problem of three-dimensional control caused by small energy difference of a cis / trans path in fluorocyclopropanation is solved, and high enantioselectivity and diastereoselectivity of the product are realized. Formula IV and formula V

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, and in particular to asymmetric catalyst systems and their applications. Background Technology

[0002] Fluorocyclopropanes, as a subclass of cyclopropanes, can enhance metabolic stability, membrane permeability, and target binding affinity by introducing fluorine atoms, as well as improve the activity and selectivity of compounds, making them indispensable in pharmaceutical and pesticide research and development.

[0003] However, the strong electron-withdrawing effect of fluorine narrows the energy difference between cis and trans-cyclopropanation pathways, making precise stereochemical control extremely challenging—a long-standing core problem in this field. While contemporary rhodium catalysis systems can achieve high selectivity in donor-acceptor systems, their reliance on expensive noble metals and poor performance in purely acceptor-type diazo compound systems (Tetrahedron Lett. 56, 1805–1807 (2015), Chem. Eur. J. 22, 6239-6242 (2016), ACS Catal. 9, 2594–2598 (2019), Synthesis 10, 1479–1490 (2000)). Copper catalysts, as a resource-rich alternative, currently only achieve high enantioselectivity in acceptor systems, but exhibit low diastereoselectivity. Summary of the Invention

[0004] Therefore, it is necessary to provide asymmetric catalyst systems and their applications.

[0005] One aspect of the present invention provides an asymmetric catalyst system comprising a copper catalyst, a ligand, and a solvent;

[0006] The solvent includes solvents containing a benzene ring in their molecular structure;

[0007] The ligand comprises a compound having at least one of the structures shown in Formula IV and Formula V:

[0008] Formula IV

[0009] Formula V

[0010] R 41 and R 42 Each is independently selected from any one of alkyl groups having 1-20 carbon atoms, aralkyl groups having 7-30 carbon atoms, and aryl groups having 6-20 ring atoms;

[0011] R 43 and R 44Each is independently selected from any one of alkyl groups having 2-20 carbon atoms or aralkyl groups having 7-30 carbon atoms, or R 43 and R 44 It forms saturated or unsaturated rings with 3-8 ring atoms;

[0012] Ring M1 and ring M2 are each independently selected from any one or more of the following: substituted or unsubstituted cycloalkyl groups with 5-7 ring atoms, aryl groups with 6-20 ring atoms, and fused rings containing aryl groups with 10-24 ring atoms.

[0013] R 45 and R 46 Each is independently selected from any one of H, alkyl groups having 2-20 carbon atoms, and aralkyl groups having 7-30 carbon atoms, or the R... 45 and R 46 It forms saturated or unsaturated rings with 3-8 ring atoms.

[0014] A second aspect of this application provides an application of any of the above-mentioned asymmetric catalyst systems in asymmetric catalytic reactions.

[0015] Optionally, the application includes the use of the asymmetric catalyst system in the stereoselective preparation of fluorocyclopropanes.

[0016] A third aspect of this application provides a method for the highly stereoselective preparation of fluorocyclopropane, comprising:

[0017] In the presence of any of the above-mentioned asymmetric catalyst systems, α-fluoroolefins and diazo compounds are subjected to an asymmetric catalytic reaction to prepare fluorocyclopropane compounds; wherein the α-fluoroolefin has the structure shown in Formula I, the diazo compound has the structure shown in Formula II, and the fluorocyclopropane compound has the structure shown in Formula III.

[0018] Formula I

[0019] Formula II

[0020] Formula III

[0021] In the formula, R1 is selected from any one of H, aryl with 6-30 substituted or unsubstituted carbon atoms, heteroaryl with 6-30 substituted or unsubstituted carbon atoms, alkoxy with 1-30 substituted or unsubstituted carbon atoms, ether with 2-30 substituted or unsubstituted carbon atoms, and alkyl with 1-30 substituted or unsubstituted carbon atoms; R2 is selected from any one of hydrogen, aryl with 6-30 substituted or unsubstituted carbon atoms, aralkyl with 7-40 substituted or unsubstituted carbon atoms, and heteroaryl with 5-40 substituted or unsubstituted carbon atoms; and R3 is selected from any one of any one of alkyl with 1-10 substituted or unsubstituted carbon atoms, aryl with 6-50 substituted or unsubstituted carbon atoms, and aralkyl with 7-50 substituted or unsubstituted carbon atoms.

[0022] In the aforementioned asymmetric catalyst system, by selecting ligands with specific structures, copper catalysts, and solvents containing benzene rings in their molecular structures, the synergistic effects can be achieved, improving the enantioselectivity and diastereoselectivity of products in asymmetric catalytic reactions, especially for the synthesis of fluorocyclopropane compounds, where high enantioselectivity and diastereoselectivity are observed. Furthermore, this asymmetric catalyst system uses relatively inexpensive copper catalysts and the aforementioned ligands with specific structures, making them widely available and adaptable to various reaction substrates, thus significantly reducing the preparation cost of stereoselective products. Detailed Implementation

[0023] To facilitate understanding of the present invention, a more complete description will be provided below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a thorough and complete understanding of the disclosure of the present invention.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0025] the term

[0026] Unless otherwise stated or in case of contradiction, the terms or phrases used herein shall have the following meanings:

[0027] In this application, unless otherwise specified, the term "substituted or unsubstituted" means that the defined group may or may not be substituted. When the defined group is substituted, it should be understood that the defined group may be substituted by one or more substituents R, wherein R is selected from, but is not limited to: deuterium, cyano, isocyano, nitro, halogen, C1-20 Alkyl groups (i.e., alkyl groups containing 1-20 carbon atoms), alicyclic groups containing 3-20 ring atoms, aryl groups containing 6-20 ring atoms, heteroaryl groups containing 5-20 ring atoms, -NR'R”, silyl groups, carbonyl groups, alkoxycarbonyl groups, aryloxycarbonyl groups, carbamoyl groups, halocarbamoyl groups, formyl groups, isocyanate groups, thiocyanate groups, isothiocyanate groups, hydroxyl groups, or trifluoromethyl groups, and the above groups may be further substituted by suitable substituents; it is understood that R' and R” in -NR'R” can be independently selected from, but not limited to: H, deuterium atom, cyano, isocyano, nitro, halogen, alkyl groups containing 1-10 carbon atoms, heterocyclic groups containing 3-20 ring atoms, and groups containing 6-20 ring atoms. An aromatic group containing 5-20 ring atoms, or a heteroaryl group containing 5-20 ring atoms. Optionally, R is selected from, but not limited to: deuterium, cyano, isocyano, nitro, or halogen, alkyl containing 1-10 carbon atoms, heterocyclic group containing 3-10 ring atoms, aromatic group containing 6-20 ring atoms, heteroaromatic group containing 5-20 ring atoms, silyl, carbonyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, halocarbamoyl, formyl, isocyanate group, thiocyanate group, isothiocyanate group, hydroxyl, trifluoromethyl, and the above groups may be further substituted with suitable substituents. The above suitable substituents are selected from, but not limited to: aryl, heteroaryl, alkyl, alkyl containing a functional group, and alkyl with an aryl group attached.

[0028] In this application, unless otherwise specified, the term "cyclic compound" refers to a compound containing a cyclic skeleton, such as monocyclic compounds, fused-ring compounds, cross-linked compounds, carbocyclic compounds, heterocyclic compounds, etc. "Ring atom" refers to the constituent atoms of the ring skeleton in a cyclic compound, and "number of ring atoms" or "number of cyclic atoms" indicates the number of ring atoms in the cyclic compound. When the cyclic skeleton is substituted by substituents, the atoms contained in the substituents are not included in the ring atoms. For example, a benzene ring has 6 ring atoms, a naphthalene ring has 10 ring atoms, and a thiophene ring has 5 ring atoms.

[0029] In this application, unless otherwise specified, the term "hydrocarbon" or "hydrocarbon compound" refers to an organic compound composed of carbon and hydrogen atoms. Hydrocarbon compounds can be aliphatic or aromatic compounds. Aliphatic compounds are non-aromatic and do not contain aromatic rings. Aromatic compounds are aromatic and contain aromatic rings.

[0030] In this application, unless otherwise specified, the term "alkyl" refers to a residue formed by the loss of a hydrogen atom from a saturated hydrocarbon, and alkyl can represent a straight-chain, branched, and / or cyclic alkyl group. The number of carbon atoms contained in an alkyl group can be 1 to 50, 1 to 30, 1 to 20, 1 to 10, 1 to 6, or other suitable ranges. Phrases containing the term "alkyl," such as "C1-C9 alkyl," refer to alkyl groups containing 1 to 9 carbon atoms, and each occurrence can independently be C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, or C9 alkyl. Suitable examples include, but are not limited to: methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(C H3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butyl(-CH2CH(CH3)CH2CH3), 1-hexyl(-CH2CH2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 3-hexyl(-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl(-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl(-CH(CH3)CH( CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3 and octyl (-(CH2)7CH3).

[0031] In this application, unless otherwise specified, the term "heterocyclic" can refer to alicyclic, aryl, or heteroaryl.

[0032] In this application, unless otherwise specified, the term "alicyclic group" refers to a cyclic group with aliphatic properties, that is, an alicyclic group is not aromatic and does not contain an aromatic ring. The ring atoms of an alicyclic group may or may not contain heteroatoms. "Cycloalkyl" refers to an alicyclic group whose ring atoms are all carbon atoms. "Alicyclic heterocyclic group" refers to an alicyclic group whose ring atoms contain heteroatoms.

[0033] In this application, unless otherwise specified, the term "aromatic group" refers to an aromatic cyclic group, which may be aryl or heteroaryl.

[0034] In this application, unless otherwise specified, the term "aryl" refers to an aromatic hydrocarbon group derived from an aromatic cyclic hydrocarbon compound by losing a hydrogen atom from the aromatic ring; that is, the aryl group's linking site is located on a ring atom of the aromatic ring. The aryl group can be a monocyclic aryl, a fused-ring aryl, or a polycyclic aryl; for polycyclic compounds, at least one is an aromatic ring system. For example, "C5~C..." 20 "Aryl" refers to an aryl group containing 5 to 20 carbon atoms. Each time it appears, it can independently be C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 ... 10 Aryl, C 14 Aryl, C 18 Aryl or C 20 Aryl group. Suitable examples include, but are not limited to: benzene, biphenyl, naphthalene, anthracene, phenanthrene, dinaphthalene, triphenylene and their derivatives. Understandably, multiple aryl groups can also be indirectly linked by short non-aromatic units (e.g., <10% non-H atoms, such as C, N or O atoms), specifically acenaphthene, fluorene, or 9,9-diarylfluorene, triarylamines, and diaryl ether systems should also be included in the definition of aryl.

[0035] In this application, unless otherwise specified, the term "ether group" refers to a residue of a compound containing an ether bond (COC) that has lost a hydrogen atom bonded to a carbon atom.

[0036] In this application, unless otherwise specified, the term "aralkyl" refers to an aromatic hydrocarbon group derived from an aromatic cyclic hydrocarbon compound by losing a hydrogen atom from the alkyl group; that is, the linkage site of the aromatic hydrocarbon is located on the alkyl group.

[0037] In this application, unless otherwise specified, the term "heteroaryl" refers to an aromatic heterocyclic group, which may be an aryl group in which at least one carbon atom is replaced by a non-carbon atom, or a cyclopentadienyl group in which at least one carbon atom is replaced by a heteroatom. The heteroatoms in the cyclic atoms of a heteroaryl group may, exemplarily, include one or more of N, O, and S.

[0038] In this application, "adjacent groups" means that there are no substituted sites between two substituents.

[0039] In this application, unless otherwise specified, "*" in the chemical structural formula indicates a linking site.

[0040] Unless otherwise specified, in the chemical structural formulas or chemical equations of this application: "Et" represents ethyl, "Me" represents methyl, "MS" represents molecular sieve, "Bn" represents benzyl, "Ph" represents phenyl, "iPr" represents isopropyl, "p-Xylene" represents p-xylene, "o-Xylene" represents o-xylene, and "m-Xylene" represents m-xylene.

[0041] In this application, "optionally," "optionally," and "optional" mean that something is optional, that is, it means that it is selected from either "with" or "without." If there are multiple "optional" entries in a technical solution, unless otherwise specified and there are no contradictions or mutual constraints, each "optional" entry shall be independent.

[0042] In this application, the technical features described in an open-ended manner include both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.

[0043] Because the strong electron-withdrawing effect of fluorine reduces the energy difference between cis and trans cyclopropanation pathways, precise stereochemical control is extremely difficult. Based on this, this application provides at least one asymmetric catalyst system and its application.

[0044] According to a typical embodiment of this application, an asymmetric catalyst system is provided, comprising a copper catalyst, a ligand, and a solvent; the solvent comprises a solvent containing a benzene ring in its molecular structure; the ligand comprises a compound having at least one structure shown in Formula IV and Formula V:

[0045] Formula IV

[0046] Formula V

[0047] In the formula, R 41 and R 42 Each is independently selected from any one of alkyl groups having 1-20 carbon atoms, aralkyl groups having 7-30 carbon atoms, and aryl groups having 6-20 ring atoms;

[0048] R 43 and R 44 Each is independently selected from any one of alkyl groups having 2-20 carbon atoms or aralkyl groups having 7-30 carbon atoms, or R 43 and R 44 It forms saturated or unsaturated rings with 3-8 ring atoms;

[0049] Ring M1 and ring M2 are each independently selected from any one or more of the following: substituted or unsubstituted cycloalkyl groups with 5-7 ring atoms, aryl groups with 6-20 ring atoms, and fused rings containing aryl groups with 10-24 ring atoms.

[0050] R 45 and R 46 Each is independently selected from any one of H, alkyl groups having 2-20 carbon atoms, and aralkyl groups having 7-30 carbon atoms, or R. 45 and R 46 It forms saturated or unsaturated rings with 3-7 ring atoms.

[0051] In the aforementioned asymmetric catalyst system, by selecting ligands with specific structures, copper catalysts, and solvents containing benzene rings in their molecular structures, the synergistic effects can be achieved, improving the enantioselectivity and diastereoselectivity of products in asymmetric catalytic reactions, especially for the synthesis of fluorocyclopropane compounds, where high enantioselectivity and diastereoselectivity are observed. Furthermore, this asymmetric catalyst system uses relatively inexpensive copper catalysts and the aforementioned ligands with specific structures, making them widely available and adaptable to various reaction substrates, thus significantly reducing the preparation cost of stereoselective products.

[0052] In some embodiments, R 41 and R 42 With the same structure, they have better catalytic effects and help improve enantioselectivity and diastereoselectivity.

[0053] In some embodiments, R 41 and R 42 Each is independently selected from any one of alkyl groups having 1-10 carbon atoms and aralkyl groups having 7-15 carbon atoms. Optionally, R 41 and R 42 Each is independently isobutyl or isopropyl.

[0054] In some embodiments, R 43 and R 44 The structures are the same, or R 43 and R 44 It forms a saturated ring with 3-6 ring atoms.

[0055] In some embodiments, R 43 and R 44 Each is independently selected from any one of alkyl groups having 2-10 carbon atoms or aralkyl groups having 7-15 carbon atoms, or R 43 and R 44 Forming a saturated ring with 3-6 ring atoms. Optionally, R 43 and R 44 It is benzyl, or R 43and R 44 It forms a saturated ring with 3-6 ring atoms.

[0056] In some embodiments, ring M1 and ring M2 have the same structure, which helps to improve enantioselectivity and diastereoselectivity.

[0057] In some embodiments, ring M1 and ring M2 are each independently selected from any one or more of the following: substituted or unsubstituted cycloalkyl groups having 5-6 ring atoms, aryl groups having 6-15 ring atoms, and fused rings containing aryl groups having 10-18 ring atoms. Optionally, ring M1 and ring M2 are... .

[0058] In some embodiments, R 45 and R 46 The structures are the same, or R 45 and R 46 It forms a saturated ring with 3-6 ring atoms.

[0059] In some embodiments, R 45 and R 46 Each is independently selected from any one of the following: H carbon atoms, 2-10 alkyl groups, and 7-15 aralkyl groups, or R. 45 and R 46 Forming a saturated ring with 3-6 ring atoms. Optionally, R 45 and R 46 Each is independently selected from H, Any one or more of them, or R 45 and R 46 It forms a ring with 3-6 ring atoms.

[0060] In some embodiments, the ligand is any one or more compounds having the following structures, wherein Bn is benzyl and iPr is isopropyl:

[0061] , , , , , , , , .

[0062] In some embodiments, the copper catalyst is selected from any one or more of monovalent and divalent copper, such as copper trifluoromethanesulfonate, copper acetate, cuprous trifluoromethanesulfonate, a complex of cuprous trifluoromethanesulfonate and benzene, cuprous iodide, copper tetrafluoroborate tetraacetonitrile, and copper hexafluorophosphonate tetraacetonitrile. This allows it to work better with the aforementioned ligands, and the resulting asymmetric catalyst system significantly enhances the enantioselectivity and diastereoselectivity of the product.

[0063] In some embodiments, the molar ratio of copper catalyst to ligand is 1:1 to 1:2, which helps to enhance the catalytic effect of both the copper catalyst and the ligand. Optionally, the molar ratio of copper catalyst to ligand is 1:1 to 1:1.5. Non-limitingly, the molar ratio of copper catalyst to ligand can be 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc.

[0064] In some embodiments, the solvent is selected from any one or more of p-xylene, o-xylene, ethylbenzene, trifluorotoluene, and m-xylene, which is beneficial to improving the enantioselectivity and diastereoselectivity of the product.

[0065] In some embodiments, the asymmetric catalyst system further includes a molecular sieve, optionally selected from any one or more of 4Å, 3Å, and 5Å molecular sieves; optionally, the molar ratio of molecular sieve to copper catalyst is 300 mg / 0.3 mmol to 500 mg / 0.3 mmol. For example, a molecular sieve to copper catalyst molar ratio of 300 mg / 0.3 mmol means that 300 mg of molecular sieve is added for every 0.3 mmol of copper catalyst, and a molecular sieve to copper catalyst molar ratio of 500 mg / 0.3 mmol means that 500 mg of molecular sieve is added for every 0.3 mmol of copper catalyst. Non-limitingly, the molar ratio of molecular sieve to copper catalyst can be 300 mg / 0.3 mmol, 350 mg / 0.3 mmol, 400 mg / 0.3 mmol, 450 mg / 0.3 mmol, 500 mg / 0.3 mmol, etc.

[0066] According to another typical embodiment of this application, the application of any of the above-described asymmetric catalyst systems in asymmetric catalytic reactions is provided. Using the above-described asymmetric catalyst system can significantly improve the enantioselectivity and diastereoselectivity of the products. Furthermore, since the above-described asymmetric catalyst system uses relatively inexpensive copper catalysts and the ligands with specific structures described above, its sources are relatively wide, and it has good adaptability to reaction substrates, significantly reducing the preparation cost of stereoselective products.

[0067] In some embodiments, the application includes the use of asymmetric catalyst systems in the stereoselective preparation of fluorocyclopropanes.

[0068] According to another typical embodiment of this application, a method for preparing fluorocyclopropanes with high stereoselectivity is provided, comprising: subjecting an α-fluoroolefin and a diazo compound to an asymmetric catalytic reaction in the presence of any of the above-mentioned asymmetric catalyst systems to obtain a fluorocyclopropane compound; wherein the α-fluoroolefin has the structure shown in Formula I, the diazo compound has the structure shown in Formula II, and the fluorocyclopropane compound has the structure shown in Formula III.

[0069] Formula I

[0070] Formula II

[0071] Formula III

[0072] In the formula, R1 is selected from any one of H, aryl with 6-30 substituted or unsubstituted carbon atoms, heteroaryl with 6-30 substituted or unsubstituted carbon atoms, alkoxy with 1-30 substituted or unsubstituted carbon atoms, ether with 2-30 substituted or unsubstituted carbon atoms, and alkyl with 1-30 substituted or unsubstituted carbon atoms; R2 is selected from any one of hydrogen, aryl with 6-30 substituted or unsubstituted carbon atoms, aralkyl with 7-40 substituted or unsubstituted carbon atoms, and heteroaryl with 5-40 substituted or unsubstituted carbon atoms; and R3 is selected from any one of any one of alkyl with 1-10 substituted or unsubstituted carbon atoms, aryl with 6-50 substituted or unsubstituted carbon atoms, and aralkyl with 7-50 substituted or unsubstituted carbon atoms.

[0073] The above preparation method overcomes the stereocontrol challenge caused by the small energy difference in the cis / trans pathways during fluorocyclopropaneation by selecting asymmetric catalyst systems with specific structures and compositions, achieving high enantioselectivity and diastereoselectivity in both donor-acceptor and acceptor-only diazo systems. The aforementioned asymmetric catalyst system uses relatively inexpensive copper catalysts and the aforementioned ligands with specific structures, making them widely available and adaptable to various reaction substrates, thus significantly reducing the preparation cost of the aforementioned fluorocyclopropane compounds.

[0074] In some embodiments, R1 is selected from aryl groups with 6-18 substituted or unsubstituted carbon atoms, heteroaryl groups with 6-28 substituted or unsubstituted ring atoms, alkoxy groups with 1-15 substituted or unsubstituted carbon atoms, ether groups with 2-15 substituted or unsubstituted carbon atoms, and alkyl groups with 1-15 substituted or unsubstituted carbon atoms. For example, the aryl group with 6-18 carbon atoms can have 6, 10, 12, 14, 16, 18, etc., specifically phenyl, naphthyl, biphenyl, anthracene, phenanthrene, etc. Optionally, R1 is any one of phenyl, halophenyl, methoxyphenyl, trifluoromethylphenyl, alkyl groups with 10-12 carbon atoms, phenethyl, and methylphenyl.

[0075] In some embodiments, R2 is selected from hydrogen, aryl groups having 6-18 carbon atoms, aralkyl groups having 7-20 carbon atoms, and heteroaryl groups having 5-20 ring atoms; optionally, R2 is selected from hydrogen, phenyl, halophenyl, methoxyphenyl, and trifluoromethylphenyl.

[0076] In some embodiments, R3 is selected from any one of substituted or unsubstituted alkyl groups having 1-6 carbon atoms, substituted or unsubstituted aryl groups having 6-20 carbon atoms, and substituted or unsubstituted aralkyl groups having 7-20 carbon atoms. Optionally, R3 is selected from any one of methyl, ethyl, benzyl, haloethyl, dimethylphenyl, and isopropyl.

[0077] In some embodiments, R1 is phenyl; R2 is selected from hydrogen and phenyl; R3 is selected from methyl and ethyl; R 41 and R 42 It is isopropyl; ring M1 and ring M2 are That is, in the case of a structure with the following formula: Or for In the presence of ligands and an asymmetric catalyst system with copper catalyst, the structural formula is as follows: α-Fluoroolefins and structures with the following structural formulas or Diazo compounds undergo asymmetric catalytic reactions, and the products exhibit high enantioselectivity and diastereoselectivity.

[0078] In some embodiments, R2 is selected from hydrogen, and the ligand is selected from one or more compounds with the following structures: , , and .

[0079] In some embodiments, R2 is selected from phenyl, and the ligand is selected from compounds having a benzene ring in formula IV or V. Optionally, the ligand is selected from any one or more of the following structures: , , , and .

[0080] In some embodiments, the molar ratio of the diazo compound to the α-fluoroolefin is (1:1) to (10:1), which is beneficial to improving the yield of the target product. Non-limitingly, the molar ratio of the diazo compound to the α-fluoroolefin can be 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, etc.

[0081] In some embodiments, the molar ratio of copper catalyst to α-fluoroolefin is (1:40) to (1:5). Non-limitingly, the molar ratio of copper catalyst to α-fluoroolefin can be 1:5, 1:10, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, etc.

[0082] In some embodiments, the molar ratio of the ligand to the α-fluoroolefin is (1:40) to (1:5). Non-limitingly, the molar ratio of the ligand to the α-fluoroolefin is 1:5, 1:10, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, etc.

[0083] In some embodiments, the reaction temperature of the asymmetric catalytic reaction is 25°C-50°C. Non-limitingly, the reaction temperature of the asymmetric catalytic reaction can be 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, etc.

[0084] In some embodiments, the reaction time of the asymmetric catalytic reaction is 1 h to 24 h. Non-limitingly, the reaction time of the asymmetric catalytic reaction is 1 h, 5 h, 10 h, 15 h, 20 h, 24 h, etc.

[0085] In some embodiments, the asymmetric catalytic reaction is carried out in an inert gas atmosphere, and the gas providing the inert gas atmosphere includes, but is not limited to, nitrogen, argon, helium, neon, etc.

[0086] In some embodiments, the preparation method includes: mixing an asymmetric catalyst system, an α-fluoroolefin, and a first solvent, and adding a solution containing a diazo compound dropwise at the reaction temperature of the asymmetric catalytic reaction; optionally, the difference between the dropwise addition time and the reaction time of the asymmetric catalytic reaction is less than or equal to 60 min; optionally, the solvent of the solution containing the diazo compound is selected from any one or more of p-xylene, o-xylene, ethylbenzene, trifluorotoluene, and m-xylene.

[0087] The present application will be specifically described below through specific embodiments. The following embodiments are only some embodiments of the present application and are not intended to limit the present application.

[0088] Example 1

[0089] Synthesis of Compound 3 with high stereoselectivity

[0090]

[0091] Add copper trifluoromethanesulfonate [Cu(OTf)2] (10.9 mg, 0.03 mmol), ligand L1 (14.4 mg, 0.045 mmol), 4 Å molecular sieve (4 Å MS, 500 mg), and p-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 h under a nitrogen (N2) atmosphere. Then add a p-xylene solution (1 mL) of α-fluoroolefin 1 (36.6 mg, 0.3 mmol).

[0092] Subsequently, at 40°C, a 2 mL solution of diazo 2 (102.6 mg, 0.9 mmol) in p-xylene was slowly added via a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0093] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The reaction was determined by ¹H NMR (using CDCl₃ as the solvent). 1 The yield and diastereomeric proportion (dr) were determined by ¹H NMR, with 1,1,2,2-tetrachloroethane as an internal standard; the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0094] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio = 100:1 to 20:1) to obtain target product 3 (51.9 mg, yield 83%). Following the experimental procedures described above, the diastereomer ratio (dr) was 22:1 and the enantiomeric excess (ee) was 98%.

[0095] 1H NMR (600 MHz, Chloroform-d) δ 7.43 – 7.37 (m, 2H), 7.36 – 7.29 (m,3H), 4.30 – 4.17 (m, 2H), 2.30 (ddd, J = 20.3, 7.8, 7.1 Hz, 1H), 2.20 (ddd, J= 9.4, 7.8, 2.9 Hz, 1H), 1.63 (ddd, J = 10.6, 9.4, 7.1 Hz, 1H), 1.30 (t, J =7.1 Hz, 3H).

[0096] 13 C NMR (151 MHz, Chloroform-d) δ 167.90 (d, J = 2.2 Hz), 137.55 (d, J= 21.5 Hz), 128.63, 128.32 (d, J = 1.7 Hz), 124.61 (d, J = 6.5 Hz), 80.90 (d,J = 227.9 Hz), 61.24, 29.10 (d, J = 11.5 Hz), 19.01 (d, J = 12.4 Hz), 14.27.

[0097] 19 F NMR (565 MHz, Chloroform-d) δ -188.00 (dd, J = 20.4, 10.3 Hz).

[0098] HRMS (ESI): Calculated for (C 12 H 14 FO2) [M+H] + : 209.0966, found209.0975.

[0099] = -344.0° (c = 0.1, CHCl3).

[0100] HPLC analysis: Daicel Chiralpak OB-H Column (n-hexane / i-PrOH = 98 / 2,1 mL / min), 40 ℃, 219 nm, t R1 = 6.11 min (major), t R2 = 6.48 min (minor), 98%ee.

[0101] Example 2

[0102] Synthesis of Compound 5 with high stereoselectivity

[0103]

[0104] Add copper trifluoromethanesulfonate [Cu(OTf)2] (10.9 mg, 0.03 mmol), ligand L1 (14.4 mg, 0.045 mmol), 4 Å molecular sieve (4 Å MS, 500 mg), and p-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 h under a nitrogen (N2) atmosphere. Then add a 1 mL solution of α-fluoroolefin 1 (36.6 mg, 0.3 mmol) in p-xylene.

[0105] Subsequently, at 40°C, a 2 mL solution of diazo 4 (158.4 mg, 0.9 mmol) in p-xylene was slowly added via a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0106] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The diastereomeric proportion (dr) of the product was determined by ¹H NMR (in solvent CDCl₃), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0107] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio = 100:1 to 20:1) to obtain target product 5 (60.4 mg, 74%). Following the experimental procedures described above, the diastereomer ratio (dr) was 17:1 and the enantiomeric excess (ee) was 99%.

[0108] 1 H NMR (600 MHz, CDCl3) δ 7.43 – 7.29 (m, 10H), 5.24 (dd, J = 43.9,12.3 Hz, 2H), 2.36 (dt, J = 20.2, 7.4 Hz, 1H), 2.27 (ddd, J = 9.4, 7.8, 2.8Hz, 1H), 1.67 (ddd, J = 10.7, 9.3, 7.1 Hz, 1H).

[0109] 13C NMR (151 MHz, CDCl3) δ 167.71 (d, J = 2.2 Hz), 137.26 (d, J = 21.3Hz), 135.66, 128.55, 128.50, 128.30 (d, J = 1.6 Hz), 128.22, 128.19, 124.55(d, J = 6.5 Hz), 80.97 (d, J = 228.4 Hz), 66.96, 28.93 (d, J = 11.7 Hz), 19.12 (d, J = 12.5 Hz).

[0110] 19 F NMR (565 MHz, CDCl3) δ -187.30 (dd, J = 20.5, 10.8 Hz).

[0111] HRMS (ESI) m / z: Calculated for (C 17 H 16 FO2) [M+H] + : 271.1134, found271.1144.

[0112] = -336.8° (c = 0.05, CHCl3).

[0113] HPLC analysis: Daicel Chiralpak IB Column (n-hexane / i-PrOH = 98 / 2, 1mL / min), 40 ℃, 210 nm, t R1 = 9.05 min (major), t R2 = 9.54 min (minor), 99% ee.

[0114] Example 3

[0115] Synthesis of Compound 7 with high stereoselectivity

[0116]

[0117] Add copper trifluoromethanesulfonate [Cu(OTf)2] (10.9 mg, 0.03 mmol), ligand L1 (14.4 mg, 0.045 mmol), 4 Å molecular sieve (4 Å MS, 500 mg), and p-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 hour under a nitrogen (N2) atmosphere. Then add a 0.3 mmol solution of α-fluoroolefin 1 in p-xylene (1 mL).

[0118] Subsequently, at 40°C, a 2 mL solution of diazo 6 (194.4 mg, 0.9 mmol) in p-xylene was slowly added via a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0119] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The diastereomeric proportion (dr) of the product was determined by ¹H NMR (in solvent CDCl₃), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0120] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio = 100:1 to 20:1) to obtain target product 7 (52.1 mg, 56%). Following the experimental procedures described above, the diastereomer ratio (dr) was 11:1 and the enantiomeric excess (ee) was 99%.

[0121] 1 H NMR (600 MHz, CDCl3) δ 7.44 – 7.40 (m, 2H), 7.39 – 7.37 (m, 1H), 7.37 – 7.33 (m, 2H), 4.84 (dd, J = 50.7, 12.0 Hz, 2H), 2.44 – 2.31 (m, 2H),1.82 – 1.74 (m, 1H).

[0122] 13C NMR (151 MHz, CDCl3) δ 166.48 (d, J = 2.3 Hz), 136.75 (d, J = 21.2Hz), 128.72, 128.66 (d, J = 1.0 Hz), 124.83 (d, J = 6.4 Hz), 94.73, 81.29 (d,J = 229.9 Hz), 74.45, 28.41 (d, J = 11.5 Hz), 19.37 (d, J = 12.3 Hz).

[0123] 19 F NMR (565 MHz, CDCl3) δ -185.66 (dd, J = 20.2, 10.8 Hz).

[0124] HRMS (ESI) m / z: Calculated for (C 12 H 11 C l3 FO2) [M+H] + : 310.9809, found310.9810.

[0125] = -233.6° (c = 0.05, CHCl3).

[0126] HPLC analysis: Daicel Chiralpak OB-H Column (pure n-hexane, 1 mL / min), 40 ℃, 218 nm, t R1 = 13.17 min (major), t R2 = 14.62 min (minor), 99% ee.

[0127] Example 4

[0128] Synthesis of Compound 9 with high stereoselectivity

[0129]

[0130] Add copper trifluoromethanesulfonate [Cu(OTf)2] (10.9 mg, 0.03 mmol), ligand L1 (14.4 mg, 0.045 mmol), 4 Å molecular sieve (4 Å MS, 500 mg), and p-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 h under a nitrogen (N2) atmosphere. Then add a 1 mL solution of α-fluoroolefin 1 (36.6 mg, 0.3 mmol) in p-xylene.

[0131] Subsequently, at 40°C, a 2 mL solution of diazonium acetate 8 (171.1 mg, 0.75 mmol) in p-xylene was slowly added using a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0132] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The diastereomeric proportion (dr) of the product was determined by ¹H NMR (in solvent CDCl₃), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0133] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio = 100:1 to 20:1) to obtain the target product 9 (68.3 mg, 80%). Following the experimental procedures described above, the diastereomer ratio (dr) was 24:1 and the enantiomeric excess (ee) was 98%.

[0134] 1 H NMR (600 MHz, CDCl3) δ 7.46 – 7.37 (m, 5H), 7.09 – 7.03 (m, 3H), 2.54 – 2.38 (m, 2H), 2.20 (s, 6H), 1.79 (ddd, J = 11.0, 9.1, 7.0 Hz, 1H).

[0135] 13C NMR (151 MHz, CDCl3) δ 165.62 (d, J = 2.5 Hz), 148.30, 137.13 (d,J = 21.3 Hz), 130.14, 128.74, 128.60 (d, J = 1.4 Hz), 128.55, 125.91, 124.86(d, J = 6.3 Hz), 81.24 (d, J = 228.5 Hz), 28.71 (d, J = 11.9 Hz), 18.97 (d, J= 12.5 Hz), 16.32.

[0136] 19 F NMR (565 MHz, CDCl3) δ -185.06 (dd, J = 20.0, 10.0 Hz).

[0137] HRMS (ESI) m / z: Calculated for (C 18 H 18 FO2) [M+H] + : 285.1291, found285.1295.

[0138] = -313.6° (c = 0.05, CHCl3).

[0139] HPLC analysis: Daicel Chiralpak IB Column (n-hexane / i-PrOH = 98 / 2, 1mL / min), 40 ℃, 210 nm, t R1 = 7.94 min (minor), t R2 = 8.40 min (major)), 98%ee.

[0140] Example 5

[0141] Synthesis of Compound 11 with high stereoselectivity

[0142]

[0143] Add copper trifluoromethanesulfonate [Cu(OTf)2] (10.9 mg, 0.03 mmol), ligand L1 (14.4 mg, 0.045 mmol), 4 Å molecular sieve (4 Å MS, 500 mg), and p-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 h under a nitrogen (N2) atmosphere. Then add a 1 mL solution of α-fluoroolefin 10 (46.8 mg, 0.3 mmol) in p-xylene.

[0144] Subsequently, at 40°C, a 2 mL solution of diazo 2 (102.6 mg, 0.9 mmol) in p-xylene was slowly added via a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0145] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The diastereomeric proportion (dr) of the product was determined by ¹H NMR (in solvent CDCl₃), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0146] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio = 100:1 to 20:1) to obtain target product 11 (58 mg, 80%). Following the experimental procedures described above, the diastereomer ratio (dr) was 19:1 and the enantiomeric excess (ee) was 98%.

[0147] 1H NMR (600 MHz, CDCl3) δ 7.35 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.2Hz, 2H), 4.29 – 4.15 (m, 2H), 2.29 (ddd, J = 20.3, 7.8, 7.1 Hz, 1H), 2.15(ddd, J = 9.5, 7.8, 2.8 Hz, 1H), 1.59 (ddd, J = 10.6, 9.5, 7.1 Hz, 1H), 1.29(t, J = 7.1 Hz, 3H)

[0148] 13C NMR (151 MHz, CDCl3) δ 167.57 (d, J = 2.3 Hz), 136.09 (d, J =21.9 Hz), 134.28 (d, J = 1.9 Hz), 128.82, 126.07 (d, J = 6.5 Hz), 80.40 (d, J= 228.3 Hz), 61.35, 29.08 (d, J = 11.9 Hz), 18.96 (d, J = 12.4 Hz), 14.25.

[0149] 19F NMR (565 MHz, CDCl3) δ -187.94 (dd, J = 20.5, 10.6 Hz)

[0150] HRMS (ESI) m / z: Calculated for (C 12 H 13 ClFO2) [M+H + : 243.0588, found243.0586.

[0151] = -404.8° (c = 0.1, CHCl3).

[0152] HPLC analysis: Daicel Chiralpak IC Column (n-hexane / i-PrOH = 98 / 2, 1mL / min), 40 ℃, 227 nm, tR1 = 10.94 min (minor), tR2 = 11.89 min (major), 98%ee.

[0153] Example 6

[0154] Synthesis of Compound 13 with high stereoselectivity

[0155]

[0156] Add copper trifluoromethanesulfonate [Cu(OTf)2] (10.9 mg, 0.03 mmol), ligand L1 (14.4 mg, 0.045 mmol), 4 Å molecular sieve (4 Å MS, 500 mg), and p-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 h under a nitrogen (N2) atmosphere. Then add a 1 mL solution of α-fluoroolefin 12 (45.6 mg, 0.3 mmol) in p-xylene.

[0157] Subsequently, at 40°C, a 2 mL solution of diazo 2 (102.6 mg, 0.9 mmol) in p-xylene was slowly added via a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0158] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The diastereomeric proportion (dr) of the product was determined by ¹H NMR (in solvent CDCl₃), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0159] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio = 100:1 to 20:1) to obtain target product 13 (57.9 mg, 81%). Following the experimental procedures described above, its diastereomer ratio (dr) was 19:1 and its enantiomeric excess (ee) was 96%.

[0160] 1 H NMR (600 MHz, CDCl3) δ 7.29 (d, J = 7.9 Hz, 2H), 6.90 (d, J = 8.3Hz, 2H), 4.28 – 4.18 (m, 2H), 3.81 (s, 3H), 2.23 (dt, J = 19.8, 7.3 Hz, 1H), 2.13 (ddd, J = 9.3, 7.6, 2.6 Hz, 1H), 1.57 (ddd, J = 10.3, 9.4, 7.0 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H).

[0161] 13C NMR (151 MHz, CDCl3) δ168.06 (d, J = 1.9 Hz), 159.78 (d, J = 1.8Hz), 129.23 (d, J = 21.8 Hz), 127.02 (d, J = 5.1 Hz), 113.91, 81.02 (d, J =227.3 Hz), 61.07, 55.27, 28.23 (d, J = 12.1 Hz), 18.30 (d, J = 13.0 Hz), 14.19.

[0162] 19 F NMR (565 MHz, CDCl3) δ -181.87 (dd, J = 19.8, 10.5 Hz).

[0163] HRMS (ESI) m / z: Calculated for (C 13 H 16 FO3) [M+H] + : 239.1083, found239.1098.

[0164] = -423.6° (c = 0.1, CHCl3).

[0165] HPLC analysis: Daicel Chiralpak AD-H Column (n-hexane / i-PrOH = 98 / 2,1 mL / min), 40 ℃, 231 nm, t R1 = 11.54 min (minor), t R2 = 13.06 min (major), 96%ee.

[0166] Example 7

[0167] Synthesis of Compound 15 with high stereoselectivity

[0168]

[0169] Add copper trifluoromethanesulfonate [Cu(OTf)2] (10.9 mg, 0.03 mmol), ligand L1 (14.4 mg, 0.045 mmol), 4 Å molecular sieve (4 Å MS, 500 mg), and p-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 h under a nitrogen (N2) atmosphere. Then add a 1 mL solution of α-fluoroolefin 14 (46.8 mg, 0.3 mmol) in p-xylene.

[0170] Subsequently, at 40°C, a 2 mL solution of diazo 2 (102.6 mg, 0.9 mmol) in p-xylene was slowly added via a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0171] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The diastereomeric proportion (dr) of the product was determined by ¹H NMR (in solvent CDCl₃), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0172] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio = 100:1 to 20:1) to give the target product 15 (56 mg, 77%). Following the experimental procedures described above, the diastereomer ratio (dr) was 22:1 and the enantiomeric excess (ee) was 98%.

[0173] 1 H NMR (600 MHz, CDCl3) δ 7.34 – 7.28 (m, 3H), 7.15 (d, J = 5.9 Hz,1H), 4.29 – 4.17 (m, 2H), 2.31 (dt, J = 20.3, 7.5 Hz, 1H), 2.18 (ddd, J =9.5, 7.9, 2.8 Hz, 1H), 1.62 (ddd, J = 10.6, 9.5, 7.3 Hz, 1H), 1.30 (t, J =7.2 Hz, 3H).

[0174] 13C NMR (151 MHz, CDCl3) δ 167.41 (d, J = 2.4 Hz), 139.61 (d, J = 21.8Hz), 134.67, 129.91, 128.35 (d, J = 21.8 Hz), 124.70 (d, J = 7.2 Hz), 122.41 (d, J = 6.8 Hz), 80.12 (d, J = 229.0 Hz), 61.35, 29.27 (d, J = 11.5 Hz), 19.08 (d, J = 12.1 Hz), 14.19.

[0175] 19 F NMR (565 MHz, CDCl3) δ -189.36 (dd, J = 20.3, 10.5 Hz).

[0176] HRMS (ESI) m / z: Calculated for (C 12 H 13 ClFO2) [M+H + : 243.0588, found243.0591.

[0177] = -368.8° (c = 0.05, CHCl3).

[0178] HPLC analysis: Daicel Chiralpak IC Column (n-hexane / i-PrOH = 98 / 2, 1mL / min), 40 ℃, 210 nm, t R1 = 9.69 min (minor), t R2 = 11.25 min (major), 98%ee.

[0179] Example 8

[0180] Synthesis of Compound 17 with high stereoselectivity

[0181]

[0182] Add copper trifluoromethanesulfonate [Cu(OTf)2] (10.9 mg, 0.03 mmol), ligand L1 (14.4 mg, 0.045 mmol), 4 Å molecular sieve (4 Å MS, 500 mg), and p-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 h under a nitrogen (N2) atmosphere. Then add a 1 mL solution of α-fluoroolefin 16 (46.8 mg, 0.3 mmol) in p-xylene.

[0183] Subsequently, at 40°C, a 2 mL solution of diazo 2 (102.6 mg, 0.9 mmol) in p-xylene was slowly added via a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0184] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The diastereomeric proportion (dr) of the product was determined by ¹H NMR (in solvent CDCl₃), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0185] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio = 100:1 to 20:1) to obtain the target product 17 (49 mg, 67%). Following the experimental procedures described above, the diastereomer ratio (dr) was 1:1 and the enantiomeric excess (ee) was 96%.

[0186] 1 H NMR (600 MHz, CDCl3) δ 7.51 (dt, J = 7.6, 1.9 Hz, 1H), 7.45 (d, J =7.9 Hz, 1H), 7.35 (tt, J = 7.9, 1.8 Hz, 1H), 7.29 (tt, J = 7.5, 1.2 Hz, 1H), 4.33 – 4.22 (m, 2H), 2.26 (dt, J = 18.8, 7.3 Hz, 1H), 2.17 (ddd, J = 9.5,7.7, 2.7 Hz, 1H), 1.58 (ddd, J = 10.3, 9.5, 7.1 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H).

[0187] 13C NMR (151 MHz, CDCl3) δ 168.17, 136.31, 133.34 (d, J = 19.5 Hz), 131.14 (dd, J = 4.3, 2.7 Hz), 130.22 (d, J = 2.2 Hz), 126.79 (d, J = 1.7Hz), 80.13 (d, J = 228.8 Hz), 61.16, 26.38 (d, J = 12.2 Hz), 17.20 (d, J =13.5 Hz), 14.28.

[0188] 19 F NMR (565 MHz, CDCl3) δ -177.14 (dd, J = 18.7, 10.3 Hz).

[0189] HRMS (ESI) m / z: Calculated for (C 12 H 13 ClFO2) [M+H + : 243.0588, found243.0591.

[0190] = -100.8° (c = 0.05, CHCl3).

[0191] HPLC analysis: Daicel Chiralpak IB Column (n-hexane / i-PrOH = 98 / 2, 1mL / min), 40 ℃, 220 nm, t R1 = 8.28 min (minor), t R2 = 9.81 min (major), 96% ee.

[0192] Example 9

[0193] Synthesis of Compound 20 with high stereoselectivity

[0194]

[0195] Add copper trifluoromethanesulfonate [Cu(OTf)2] (10.9 mg, 0.03 mmol), ligand L1 (14.4 mg, 0.045 mmol), 4 Å molecular sieve (4 Å MS, 500 mg), and p-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 h under a nitrogen (N2) atmosphere. Then add a 1 mL solution of α-fluoroolefin 18 (57 mg, 0.3 mmol) in p-xylene.

[0196] Subsequently, at 40°C, a 2 mL solution of diazo 19 (115.2 mg, 0.9 mmol) in p-xylene was slowly added via a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0197] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The diastereomeric proportion (dr) of the product was determined by ¹H NMR (in solvent CDCl₃), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0198] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio = 100:1 to 20:1) to obtain the target product 20 (54.7 mg, 63%). Following the experimental procedures described above, the diastereomer ratio (dr) was 34:1 and the enantiomeric excess (ee) was 99%.

[0199] 1 H NMR (600 MHz, CDCl3) δ 7.64 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.3Hz, 2H), 5.11 (hept, J = 6.3 Hz, 1H), 2.37 (dt, J = 20.4, 7.6 Hz, 1H), 2.21(ddd, J = 9.5, 7.9, 2.9 Hz, 1H), 1.64 (ddd, J = 10.5, 9.6, 7.2 Hz, 1H), 1.28(dd, J = 6.3, 2.5 Hz, 6H).

[0200] 13C NMR (151 MHz, CDCl3) δ 166.71 (d, J = 2.5 Hz), 141.93 (d, J = 21.7Hz), 130.28 (q, J = 32.6 Hz), 125.62 (q, J = 3.8 Hz), 124.28 (d, J = 7.5 Hz), 123.91 (q, J = 272.1 Hz), 80.08 (d, J = 228.7 Hz), 69.04, 30.08 (d, J = 11.4Hz), 21.85 (d, J = 11.9 Hz), 19.50 (d, J = 12.0 Hz).

[0201] 19 F NMR (565 MHz, CDCl3) δ -62.67, -192.01 (dd, J = 20.0, 9.7 Hz).

[0202] HRMS (ESI) m / z: Calculated for (C 14 H 15 F4O2) [M+H + : 291.1008, found291.1005.

[0203] = -199.2° (c = 0.05, CHCl3).

[0204] HPLC analysis: Daicel Chiralpak IG Column (n-hexane / i-PrOH = 98 / 2, 1mL / min), 40 ℃, 223 nm, t R1 = 6.60 min (minor), t R2 = 7.66 min (major), 99% ee.

[0205] Example 10

[0206] Synthesis of Compound 23 with High Stereoselectivity

[0207]

[0208] Add copper trifluoromethanesulfonate [Cu(OTf)2] (10.9 mg, 0.03 mmol), ligand L1 (14.4 mg, 0.045 mmol), 4 Å molecular sieve (4 Å MS, 500 mg), and p-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 h under a nitrogen (N2) atmosphere. Then add a 1 mL solution of α-fluoroolefin 21 (55.8 mg, 0.3 mmol) in p-xylene.

[0209] Subsequently, at 40°C, a 2 mL solution of diazo 22 (570 mg, 3 mmol) in p-xylene was slowly added using a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0210] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The diastereomeric proportion (dr) of the product was determined by ¹H NMR (in solvent CDCl₃), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0211] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio = 100:1 to 20:1) to obtain the target product 23 (49.2 mg, 49%). Following the experimental procedures described above, its diastereomer ratio (dr) was >20:1 and its enantiomeric excess (ee) was 96%.

[0212] 1 H NMR (600 MHz, CDCl3) δ 7.40 – 7.28 (m, 5H), 5.18 (dd, J = 33.4,12.4 Hz, 2H), 1.91 (dt, J = 20.1, 6.9 Hz, 1H), 1.86 – 1.71 (m, 3H), 1.56 (p,J = 7.6 Hz, 2H), 1.40 – 1.24 (m, 12H), 1.10 (ddd, J = 11.1, 9.2, 6.7 Hz, 1H), 0.90 (t, J = 7.0 Hz, 3H).

[0213] 13C NMR (151 MHz, CDCl3) δ 168.75 (d, J = 2.6 Hz), 135.96, 128.56,128.20, 128.17, 81.98 (d, J = 230.1 Hz), 66.71, 35.35 (d, J = 21.8 Hz),31.91, 29.60, 29.54 (d, J = 5.3 Hz), 29.28 (d, J = 16.8 Hz), 25.36, 25.29,25.25 – 25.21 (m), 22.70, 17.59 (d, J = 12.3 Hz), 14.14.

[0214] 19 F NMR (565 MHz, CDCl3) δ -189.85 – -190.05 (m).

[0215] HRMS (ESI) m / z: Calculated for (C 21 H 32 FO2) [M+H] + : 335.2386, found335.2381.

[0216] = -50.8° (c = 0.05, CHCl3).

[0217] HPLC analysis: Daicel Chiralpak OJ-H Column (n-hexane / i-PrOH = 98 / 2,1 mL / min), 40 ℃, 210 nm, t R1 = 8.19 min (minor), t R2 = 10.13 min (major), 96%ee.

[0218] Example 11

[0219] Synthesis of Compound 25 with high stereoselectivity

[0220]

[0221] Add copper trifluoromethanesulfonate [Cu(OTf)2] (10.9 mg, 0.03 mmol), ligand L1 (14.4 mg, 0.045 mmol), 4 Å molecular sieve (4 Å MS, 500 mg), and p-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 h under a nitrogen (N2) atmosphere. Then add a 1 mL solution of α-fluoroolefin 24 (45 mg, 0.3 mmol) in p-xylene.

[0222] Subsequently, at 40°C, a 2 mL solution of diazo 2 (342 mg, 3 mmol) in p-xylene was slowly added using a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0223] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The diastereomeric proportion (dr) of the product was determined by ¹H NMR (in solvent CDCl₃), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0224] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio = 100:1 to 20:1) to give the target product 25 (32.1 mg, 41%). Following the experimental procedures described above, the diastereomer ratio (dr) was 23:1 and the enantiomeric excess (ee) was 97%.

[0225] 1 H NMR (600 MHz, CDCl3) δ 7.32 – 7.27 (m, 2H), 7.24 – 7.19 (m, 3H), 4.19 (qd, J = 7.2, 4.9 Hz, 2H), 2.95 – 2.86 (m, 2H), 2.15 – 2.03 (m, 2H), 1.86 (dt, J = 20.1, 7.0 Hz, 1H), 1.70 (ddd, J = 9.2, 7.2, 3.1 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H), 1.00 (ddd, J = 10.9, 9.3, 6.9 Hz, 1H).

[0226] 13C NMR (151 MHz, CDCl3) δ 168.62 (d, J = 2.5 Hz), 140.83, 128.45,128.42, 126.10, 81.17 (d, J = 230.5 Hz), 60.88, 37.46 (d, J = 21.4 Hz), 31.43 (d, J = 1.3 Hz), 25.20 (d, J = 10.5 Hz), 17.34 (d, J = 12.0 Hz), 14.22.

[0227] 19 F NMR (565 MHz, CDCl3). δ -191.82 (qdd, J = 21.1, 10.9, 3.0 Hz).

[0228] HRMS (ESI) m / z: Calculated for (C 14 H 18 FO2) [M+H] + : 237.1291 found237.1274.

[0229] = -99.0° (c = 0.10, CHCl3).

[0230] HPLC analysis: Daicel Chiralpak IF Column (n-hexane / i-PrOH = 99 / 1, 1mL / min), 40 ℃, 220 nm, t R1 = 8.97 min (minor), t R2 = 9.52 min (major), 97% ee.

[0231] Example 12

[0232] Synthesis of Compound 27 with high stereoselectivity

[0233]

[0234] Add cuprous trifluoromethanesulfonate (CuOTf, 2.14 mg, 0.01 mmol), ligand L2 (5.76 mg, 0.015 mmol), and o-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 hour under a nitrogen (N2) atmosphere. Then add a 1 mL solution of o-xylene containing α-fluoroolefin 1 (24.4 mg, 0.2 mmol).

[0235] Subsequently, at 40°C, a solution (2 mL) of o-xylene (105.6 mg, 0.6 mmol) of diazo-26 was slowly added via a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0236] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The diastereomeric proportion (dr) of the reaction was determined by ¹H NMR (in solvent CDCl₃), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0237] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio = 100:1 to 20:1) to give the target product 27 (46.0 mg, 86%). Following the experimental procedures described above, the diastereomer ratio (dr) was 22:1 and the enantiomeric excess (ee) was 93%.

[0238] 1 H NMR (600 MHz, CDCl3) δ 7.21 – 7.16 (m, 3H), 7.14 (s, 5H), 7.06 –6.97 (m, 2H), 3.75 (s, 3H), 2.80 (dd, J = 21.9, 7.8 Hz, 1H), 2.13 (dd, J =11.7, 7.8 Hz, 1H).

[0239] 13C NMR (151 MHz, CDCl3) δ 168.68 (d, J = 3.7 Hz), 134.11 (d, J = 22.2Hz), 134.00, 130.95 (d, J = 1.7 Hz), 127.97 (d, J = 1.5 Hz), 127.78, 127.75,127.47, 125.60 (d, J = 7.4 Hz), 83.71 (d, J = 225.7 Hz), 52.86, 42.60 (d, J =13.6 Hz), 21.38 (d, J = 10.8 Hz).

[0240] 19 F NMR (565 MHz, CDCl3) δ -176.58 (dd, J = 21.8, 11.6 Hz).

[0241] HRMS (ESI) m / z: Calculated for (C 17 H 16 FO2) [M+H] + : 271.1134, found271.1138.

[0242] = +115.2° (c = 0.1, CHCl3).

[0243] = +140.0° (c = 0.1, CH2Cl2).

[0244] HPLC analysis: Daicel Chiralpak AD-H Column (n-hexane / i-PrOH = 99 / 1,1 mL / min), 40 ℃, 210 nm, t R1 = 8.25 min (minor), t R2 = 10.49 min (major), 93%ee.

[0245] Example 13

[0246] Synthesis of Compound 45 with high stereoselectivity

[0247]

[0248] Add cuprous trifluoromethanesulfonate (CuOTf, 2.14 mg, 0.01 mmol), ligand L2 (5.76 mg, 0.015 mmol), and o-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 hour under a nitrogen (N2) atmosphere. Then add a 1 mL solution of o-xylene containing α-fluoroolefin 1 (24.4 mg, 0.2 mmol).

[0249] Subsequently, at 40°C, a solution (2 mL) of o-xylene containing diazo 44 (152.4 mg, 0.6 mmol) was slowly added via a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0250] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The diastereomeric proportion (dr) of the reaction was determined by ¹H NMR (in solvent CDCl₃), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0251] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio = 100:1 to 20:1) to give the target product 45 (59.0 mg, 85%). Following the experimental procedures described above, the diastereomer ratio (dr) was 36:1 and the enantiomeric excess (ee) was 96%.

[0252] 1 H NMR (600 MHz, CDCl3) δ 7.26 – 7.23 (m, 2H), 7.22 – 7.18 (m, 3H), 7.01 – 6.96 (m, 4H), 3.74 (s, 3H), 2.79 (dd, J = 21.7, 7.8 Hz, 1H), 2.08 (dd,J = 11.6, 7.9 Hz, 1H).

[0253] 13C NMR (151 MHz, CDCl3) δ 168.20 (d, J = 3.6 Hz), 133.68 (d, J = 22.2Hz), 133.21, 132.63 (d, J = 2.1 Hz), 131.03, 128.29 (d, J = 1.6 Hz), 128.00,125.65 (d, J = 7.0 Hz), 121.77, 83.63 (d, J = 226.6 Hz), 53.00, 41.96 (d, J =14.1 Hz), 21.27 (d, J = 10.9 Hz).

[0254] 19 F NMR (565 MHz, CDCl3) δ -176.30 (dd, J = 21.7, 11.6 Hz).

[0255] HRMS (ESI) m / z: Calculated for (C 17 H 15 BrFO2) [M+H] + : 349.0239, found349.0245.

[0256] = +134.4° (c = 0.05, CHCl3).

[0257] HPLC analysis: Daicel Chiralpak IC Column (n-hexane / i-PrOH = 98 / 2, 1mL / min), 40 ℃, 223 nm, t R1 = 9.53 min (minor), t R2 = 10.04 min (major), 96%ee.

[0258] Example 14

[0259] Synthesis of Compound 29 with High Stereoselectivity

[0260]

[0261] Add cuprous trifluoromethanesulfonate (CuOTf, 2.14 mg, 0.01 mmol), ligand L2 (5.76 mg, 0.015 mmol), and o-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 hour under a nitrogen (N2) atmosphere. Then add a 1 mL solution of o-xylene containing α-fluoroolefin 1 (24.4 mg, 0.2 mmol).

[0262] Subsequently, at 40°C, a solution (2 mL) of o-xylene (146.4 mg, 0.6 mmol) of diazo 28 was slowly added via a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0263] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The diastereomeric proportion (dr) of the reaction was determined by ¹H NMR (in solvent CDCl₃), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0264] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio = 100:1 to 20:1) to give the target product 29 (64.0 mg, 95%). Following the experimental procedures described above, the diastereomer ratio (dr) was 53:1 and the enantiomeric excess (ee) was 97%.

[0265] 1 H NMR (600 MHz, CDCl3) δ 7.38 (d, J = 8.2 Hz, 2H), 7.25 – 7.17 (m,5H), 7.02 – 6.98 (m, 2H), 3.75 (s, 3H), 2.85 (dd, J = 21.6, 8.0 Hz, 1H), 2.15(dd, J = 11.6, 7.9 Hz, 1H).

[0266] 13C NMR (151 MHz, CDCl3) δ 167.94 (d, J = 3.3 Hz), 138.19, 133.49 (d,J = 21.9 Hz), 131.37 (d, J = 2.2 Hz), 129.64 (q, J = 32.5 Hz), 128.44 (d, J =1.6 Hz), 128.04, 125.61 (d, J = 7.1 Hz), 124.77 (q, J = 3.6 Hz), 83.63 (d, J= 227.5 Hz), 53.07, 42.20 (d, J = 14.1 Hz), 21.22 (d, J = 10.9 Hz).

[0267] 19 F NMR (565 MHz, CDCl3) δ -62.66, -176.06 (dd, J = 21.6, 11.5 Hz).

[0268] HRMS (ESI) m / z: Calculated for (C 18 H 15 F4O2) [M+H + : 339.1008, found339.0984.

[0269] = +79.2° (c = 0.10, CHCl3).

[0270] HPLC analysis: Daicel Chiralpak IC Column (n-hexane / i-PrOH = 99 / 1, 1mL / min), 40 ℃, 210 nm, t R1 = 8.73 min (minor), t R2 = 9.30 min (major), 97% ee.

[0271] Example 15

[0272] Synthesis of Compound 32 with high stereoselectivity

[0273]

[0274] Add cuprous trifluoromethanesulfonate (CuOTf, 2.14 mg, 0.01 mmol), ligand L2 (5.76 mg, 0.015 mmol), and o-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 hour under a nitrogen (N2) atmosphere. Then add a 1 mL solution of o-xylene containing α-fluoroolefin 1 (24.4 mg, 0.2 mmol).

[0275] Subsequently, at 40 °C, a solution (2 mL) of diazonium 31 (123.6 mg, 0.6 mmol) in o-xylene was slowly added via a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0276] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The diastereomeric proportion (dr) of the reaction was determined by ¹H NMR (in solvent CDCl₃), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0277] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate, volume ratio = 19:1) to obtain the target product 32 (42.2 mg, 70%). Following the experimental procedures described above, the diastereomer ratio (dr) was 20:1 and the enantiomeric excess (ee) was 96%.

[0278] 1 H NMR (600 MHz, CDCl3) δ 7.21 – 7.16 (m, 3H), 7.04 – 6.98 (m, 4H), 6.68 – 6.62 (m, 2H), 3.74 (s, 3H), 3.71 (s, 3H), 2.74 (dd, J = 22.0, 7.7 Hz, 1H), 2.05 (dd, J = 11.8, 7.7 Hz, 1H).

[0279] 13C NMR (151 MHz, CDCl3) δ 169.07 (d, J = 3.9 Hz), 158.79, 134.26 (d, J = 21.9 Hz), 132.06 (d, J = 2.0 Hz), 127.94 (d, J = 1.5 Hz), 127.80, 126.07,125.66 (d, J = 7.2 Hz), 113.26, 83.81 (d, J = 224.9 Hz), 55.09, 52.88, 41.96 (d, J = 13.9 Hz), 21.61 (d, J = 10.8 Hz).

[0280] 19 F NMR (565 MHz, CDCl3) δ -176.87 (dd, J = 21.8, 11.7 Hz).

[0281] HRMS (ESI) m / z: Calculated for (C 18 H 17 FO3) [M+H] + : 301.1240, found 301.1243.

[0282] = +108.0° (c = 0.05, CHCl3).

[0283] HPLC analysis: Daicel Chiralpak AD-H Column (n-hexane / i-PrOH = 97 / 3,1 mL / min), 40 ℃, 224 nm, t R1 = 9.51 min (major), t R2 = 9.85 min (minor), 96%ee.

[0284] Example 16

[0285] Synthesis of Compound 34 with High Stereoselectivity

[0286]

[0287] Add cuprous trifluoromethanesulfonate (CuOTf, 2.14 mg, 0.01 mmol), ligand L2 (5.76 mg, 0.015 mmol), and o-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 hour under a nitrogen (N2) atmosphere. Then add a 1 mL solution of o-xylene containing α-fluoroolefin 1 (24.4 mg, 0.2 mmol).

[0288] Subsequently, at 40 °C, a solution (2 mL) of diazo 33 (152.4 mg, 0.6 mmol) in o-xylene was slowly added via a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0289] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The diastereomeric proportion (dr) of the reaction was determined by ¹H NMR (in solvent CDCl₃), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0290] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio = 100:1 to 20:1) to obtain the target product 34 (66.3 mg, 95%). Following the experimental procedures described above, the diastereomer ratio (dr) was 30:1 and the enantiomeric excess (ee) was 92%.

[0291] 1 H NMR (600 MHz, CDCl3) δ 7.29 – 7.27 (m, 1H), 7.27 – 7.25 (m, 1H), 7.23 – 7.18 (m, 3H), 7.04 – 7.00 (m, 3H), 6.96 (t, J = 7.8 Hz, 1H), 3.75 (s,3H), 2.80 (dd, J = 21.7, 7.9 Hz, 1H), 2.11 (dd, J = 11.6, 7.9 Hz, 1H).

[0292] 13C NMR (151 MHz, CDCl3) δ 168.09 (d, J = 3.3 Hz), 136.41, 133.76 (d, J = 2.2 Hz), 133.57 (d, J = 22.2 Hz), 130.65, 129.93 (d, J = 1.1 Hz), 129.26,128.35 (d, J = 1.1 Hz), 127.97, 125.67 (d, J = 7.0 Hz), 121.64, 83.67 (d, J =227.1 Hz), 53.03, 42.01 (d, J = 14.0 Hz), 21.24 (d, J = 10.8 Hz).

[0293] 19 F NMR (565 MHz, CDCl3) δ -176.21 (dd, J = 21.6, 11.6 Hz).

[0294] HRMS (ESI) m / z: Calculated for (C 17 H 15 BrFO2) [M+H] + : 349.0239, found349.0235.

[0295] = +164.8° (c = 0.05, CHCl3).

[0296] HPLC analysis: Daicel Chiralpak OD-H Column (n-hexane / i-PrOH = 98 / 2,1 mL / min), 40 ℃, 220 nm, t R1 = 9.23 min (minor), t R2 = 9.63 min (major), 92%ee.

[0297] Example 17

[0298] Synthesis of Compound 36 with High Stereoselectivity

[0299]

[0300] Add cuprous trifluoromethanesulfonate (CuOTf, 2.14 mg, 0.01 mmol), ligand L2 (5.76 mg, 0.015 mmol), and o-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 hour under a nitrogen (N2) atmosphere. Then add a 1 mL solution of o-xylene containing α-fluoroolefin 1 (24.4 mg, 0.2 mmol).

[0301] Subsequently, at 40 °C, a solution (2 mL) of o-xylene (116.4 mg, 0.6 mmol) of diazo 35 was slowly added via a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0302] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The diastereomeric proportion (dr) of the reaction was determined by ¹H NMR (in solvent CDCl₃), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0303] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio = 100:1 to 20:1) to give the target product 36 (54.7 mg, 95%). Following the experimental procedures described above, the diastereomer ratio (dr) was 25:1 and the enantiomeric excess (ee) was 94%.

[0304] 1 H NMR (600 MHz, CDCl3) δ 7.15 – 7.04 (m, 4H), 6.97 – 6.95 (m, 2H), 6.93 (td, J = 7.5, 1.8 Hz, 1H), 6.84 (td, J = 7.6, 1.2 Hz, 1H), 6.74 (ddd, J = 10.2, 8.2, 1.2 Hz, 1H), 3.67 (s, 3H), 2.83 (dd, J = 21.9, 8.0 Hz, 1H), 2.09 (dd, J = 11.9, 8.0 Hz, 1H).

[0305] 13C NMR (151 MHz, CDCl3) δ 168.26 (d, J = 2.1 Hz), 162.24 (d, J =250.1 Hz), 134.06 (d, J = 22.3 Hz), 132.35 (t, J = 2.9 Hz), 129.77 (d, J =8.3 Hz), 128.18, 127.70, 125.46 (d, J = 7.5 Hz), 123.51 (d, J = 3.7 Hz), 121.93 (d, J = 13.9 Hz), 115.44 (d, J = 21.8 Hz), 84.19 (d, J = 229.5 Hz),53.02, 37.83 (d, J = 14.2 Hz), 22.38 (d, J = 9.9 Hz).

[0306] 19 F NMR (565 MHz, CDCl3) δ -111.92 – -111.98 (m), -179.94 (dd, J =21.9, 11.8 Hz).

[0307] HRMS (ESI) m / z: Calculated for (C 17 H 15 F2O2) [M+H + : 289.1040, found289.1043

[0308] = +69.6° (c = 0.05, CHCl3).

[0309] HPLC analysis: Daicel Chiralpak IC Column (n-hexane / i-PrOH = 98 / 2, 1mL / min), 40 ℃, 210 nm, t R1 = 9.69 min (minor), t R2 = 10.61 min (major), 94%ee.

[0310] Example 18

[0311] Synthesis of Compound 38 with High Stereoselectivity

[0312]

[0313] Add cuprous trifluoromethanesulfonate (CuOTf, 2.14 mg, 0.01 mmol), ligand L2 (5.76 mg, 0.015 mmol), and o-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 hour under a nitrogen (N2) atmosphere. Then add a 1 mL solution of o-xylene containing α-fluoroolefin 1 (24.4 mg, 0.2 mmol).

[0314] Subsequently, at 40 °C, a solution (2 mL) of o-xylene containing diazo 37 (151.2 mg, 0.6 mmol) was slowly added using a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0315] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The diastereomeric proportion (dr) of the reaction was determined by ¹H NMR (in solvent CDCl₃), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0316] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio = 100:1 to 20:1) to give the target product 38 (62.1 mg, 90%). Following the experimental procedures described above, the diastereomer ratio (dr) was 27:1 and the enantiomeric excess (ee) was 92%.

[0317] 1 H NMR (600 MHz, CDCl3) δ 7.34 – 7.26 (m, 3H), 7.25 – 7.21 (m, 2H), 7.18 – 7.08 (m, 8H), 7.02 – 6.96 (m, 2H), 5.19 (dd, J = 41.4, 12.8 Hz, 2H), 2.80 (dd, J = 21.9, 7.8 Hz, 1H), 2.12 (dd, J = 11.7, 7.8 Hz, 1H).

[0318] 13C NMR (151 MHz, CDCl3) δ 168.09 (d, J = 3.5 Hz), 135.85, 134.11 (d, J = 22.1 Hz), 133.93, 131.01 (d, J = 1.6 Hz), 128.39, 128.01 (d, J = 1.6 Hz),127.91, 127.80, 127.78, 127.52, 127.41, 125.64 (d, J = 7.1 Hz), 83.82 (d, J =225.6 Hz), 67.24, 42.77 (d, J = 13.7 Hz), 21.36 (d, J = 10.8 Hz).

[0319] 19 F NMR (565 MHz, CDCl3) δ -176.14 (dd, J = 21.9, 11.8 Hz).

[0320] HRMS (ESI) m / z: Calculated for (C 23 H 20 FO2) [M+H] + : 347.1447, found347.1447.

[0321] = +35.6° (c = 0.10, CHCl3).

[0322] HPLC analysis: Daicel Chiralpak AS-H Column (n-hexane / i-PrOH = 99 / 1,1 mL / min), 40 ℃, 220 nm, t R1 = 7.09 min (minor), t R2 = 7.63 min (major), 92%ee.

[0323] Example 19

[0324] Synthesis of Compound 40 with high stereoselectivity

[0325]

[0326] Add cuprous trifluoromethanesulfonate (CuOTf, 2.14 mg, 0.01 mmol), ligand L2 (5.76 mg, 0.015 mmol), and o-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 hour under a nitrogen (N2) atmosphere. Then add a 1 mL solution of o-xylene containing α-fluoroolefin 39 (40.0 mg, 0.2 mmol).

[0327] Subsequently, at 40°C, a solution (2 mL) of o-xylene (105.6 mg, 0.6 mmol) of diazo-26 was slowly added via a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0328] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The diastereomeric proportion (dr) of the reaction was determined by ¹H NMR (in solvent CDCl₃), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0329] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio = 100:1 to 20:1) to give the target product 40 (48.8 mg, 70%). Following the experimental procedures described above, the diastereomer ratio (dr) was 21:1 and the enantiomeric excess (ee) was 92%.

[0330] 1 H NMR (600 MHz, CDCl3) δ 7.29 (d, J = 8.6 Hz, 2H), 7.19 – 7.13 (m,3H), 7.13 – 7.08 (m, 2H), 6.83 (d, J = 8.6 Hz, 2H), 3.74 (s, 3H), 2.79 (dd, J= 21.9, 7.9 Hz, 1H), 2.05 (dd, J= 11.6, 7.9 Hz, 1H).

[0331] 13C NMR (151 MHz, CDCl3) δ 168.43 (d, J = 3.6 Hz), 133.61, 133.44 (d,J = 22.6 Hz), 130.96, 130.93 (d, J = 1.7 Hz), 128.05, 127.77, 127.19 (d, J =7.2 Hz), 122.16 (d, J = 1.8 Hz), 83.29 (d, J = 226.1 Hz), 53.00, 42.72 (d, J= 13.6 Hz), 21.68 (d, J = 10.9 Hz).

[0332] 19 F NMR (565 MHz, CDCl3) δ -177.40 (dd, J = 21.7, 11.6 Hz).

[0333] HRMS (ESI) m / z: Calculated for (C 17 H 15 BrFO2) [M+H] + : 349.0239, found349.0244.

[0334] = +69.6° (c = 0.05, CHCl3).

[0335] HPLC analysis: Daicel Chiralpak OJ-H Column (n-hexane / i-PrOH = 99 / 1,1 mL / min), 40 ℃, 236 nm, t R1 = 3.03 min (major), t R2 = 4.71 min (minor), 92%ee.

[0336] Example 20

[0337] Synthesis of Compound 41 with high stereoselectivity

[0338]

[0339] Add cuprous trifluoromethanesulfonate (CuOTf, 2.14 mg, 0.01 mmol), ligand L2 (5.76 mg, 0.015 mmol), and o-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 hour under a nitrogen (N2) atmosphere. Then add a solution of α-fluoroolefin 12 (30.4 mg, 0.2 mmol) in o-xylene (1 mL).

[0340] Subsequently, at 40°C, a solution (2 mL) of diazo-26 (105.6 mg, 0.6 mmol) in o-xylene was slowly added via a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0341] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The diastereomeric proportion (dr) of the reaction was determined by ¹H NMR (in solvent CDCl₃), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0342] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio = 100:1 to 20:1) to give the target product 41 (53.6 mg, 89%). Following the experimental procedures described above, the diastereomer ratio (dr) was 33:1 and the enantiomeric excess (ee) was 96%.

[0343] 1 H NMR (600 MHz, CDCl3) δ 7.13 (s, 5H), 6.95 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.2 Hz, 2H), 3.74 (s, 3H), 3.73 (s, 3H), 2.73 (dd, J = 22.0, 7.7 Hz, 1H), 2.05 (dd, J = 11.5, 7.7 Hz, 1H).

[0344] 13C NMR (151 MHz, CDCl3) δ 168.90 (d, J = 3.2 Hz), 159.39, 134.31,130.96 (d, J = 2.0 Hz), 127.81, 127.41, 127.33 (d, J = 6.6 Hz), 126.11 (d, J= 22.5 Hz), 113.28, 83.91 (d, J = 224.7 Hz), 54.01 (d, J = 343.8 Hz), 42.26 (d, J = 14.2 Hz), 21.16 (d, J = 10.8 Hz).

[0345] 19 F NMR (565 MHz, CDCl3) δ -173.30 (dd, J = 22.0, 11.7 Hz).

[0346] HRMS (ESI) m / z: Calculated for (C 18 H 18 FO3) [M+H] + : 301.1240, found301.1247.

[0347] = +76.4° (c = 0.10, CHCl3).

[0348] HPLC analysis: Daicel Chiralpak OD-H Column (n-hexane / i-PrOH = 98 / 2,1 mL / min), 40 ℃, 237 nm, t R1 = 14.79 min (minor), t R2 = 15.77 min (major), 96%ee.

[0349] Example 21

[0350] Synthesis of Compound 42 with high stereoselectivity

[0351]

[0352] Add cuprous trifluoromethanesulfonate (CuOTf, 4.2 mg, 0.02 mmol), ligand L3 (12.5 mg, 0.03 mmol), and o-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 hour under a nitrogen (N2) atmosphere. Then add a 1 mL solution of o-xylene containing α-fluoroolefin 18 (38.0 mg, 0.2 mmol).

[0353] Subsequently, at 40 °C, a solution (2 mL) of o-xylene (176.0 mg, 1.0 mmol, 5.0 equiv) of diazo 26 was slowly added via a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0354] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The diastereomeric proportion (dr) of the reaction was determined by ¹H NMR (in solvent CDCl₃), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0355] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio = 100:1 to 20:1) to give the target product 42 (56.2 mg, 83%). Following the experimental procedures described above, the diastereomer ratio (dr) was 27:1 and the enantiomeric excess (ee) was 96%.

[0356] 1 H NMR (600 MHz, CDCl3) δ 7.42 (d, J = 8.2 Hz, 2H), 7.18 – 7.13 (m,3H), 7.12 – 7.09 (m, 2H), 7.04 (d, J = 8.2 Hz, 2H), 3.75 (s, 3H), 2.86 (dd, J = 21.7, 7.9 Hz, 1H), 2.12 (dd, J = 11.7, 7.9 Hz, 1H).

[0357] 13C NMR (151 MHz, CDCl3) δ 168.24 (d, J = 3.8 Hz), 138.49 (d, J = 22.2Hz), 133.31, 130.93 (d, J = 2.0 Hz), 129.96 (q, J = 32.6 Hz), 128.12, 127.92,125.66 (d, J = 7.8 Hz), 124.70 (q, J = 4.4, 4.0 Hz), 83.01 (d, J = 226.5 Hz),53.07, 43.18 (d, J = 13.1 Hz), 22.17 (d, J = 10.8 Hz).

[0358] 19 F NMR (565 MHz, CDCl3) δ -62.67, -179.03 (dd, J = 21.8, 11.7 Hz).

[0359] HRMS (ESI) m / z: Calculated for (C 18 H 15 F4O2) [M+H + : 339.1008, found339.0999.

[0360] = +83.2° (c = 0.05, CHCl3).

[0361] HPLC analysis: Daicel Chiralpak OJ Column (n-hexane / i-PrOH = 98 / 2, 1mL / min), 40 ℃, 210 nm, t R1 = 1.61 min (major), t R2 = 2.16 min (minor), 96% ee.

[0362] Example 22

[0363] Synthesis of Compound 42 with high stereoselectivity

[0364]

[0365] Add cuprous trifluoromethanesulfonate (CuOTf, 4.2 mg, 0.02 mmol), ligand L3 (12.5 mg, 0.03 mmol), and o-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 hour under a nitrogen (N2) atmosphere. Then add a 1 mL solution of o-xylene containing α-fluoroolefin 41 (40.0 mg, 0.2 mmol).

[0366] Subsequently, at 40°C, a solution (2 mL) of o-xylene (176 mg, 1.0 mmol) of diazo 26 was slowly added via a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0367] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The diastereomeric proportion (dr) of the reaction was determined by ¹H NMR (in solvent CDCl₃), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0368] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio = 100:1 to 20:1) to give the target product 42 (55.8 mg, 80%). Following the experimental procedures described above, the diastereomer ratio (dr) was 17:1 and the enantiomeric excess (ee) was 87%.

[0369] Status and appearance: colorless oil.

[0370] 1 H NMR (600 MHz, CDCl3) δ 7.31 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.23(t, J = 1.9 Hz, 1H), 7.20 – 7.14 (m, 3H), 7.14 – 7.10 (m, 2H), 6.99 (td, J =7.9, 0.9 Hz, 1H), 6.75 (ddt, J = 7.9, 1.7, 0.8 Hz, 1H), 3.74 (s, 3H), 2.80 (dd, J = 21.8, 7.9 Hz, 1H), 2.07 (dd, J = 11.6, 7.9 Hz, 1H).

[0371] 13C NMR (151 MHz, CDCl3) δ 168.35 (d, J = 3.5 Hz), 136.61 (d, J = 22.2Hz), 133.47, 131.01, 130.94 (d, J = 1.9 Hz), 129.19, 128.79 (d, J = 8.2 Hz), 128.02, 127.81, 123.97 (d, J = 7.1 Hz), 122.07, 82.94 (d, J = 227.1 Hz), 53.02, 42.88 (d, J = 13.2 Hz), 21.77 (d, J = 10.8 Hz).

[0372] 19 F NMR (565 MHz, CDCl3) δ -177.84 (dd, J = 21.9, 11.7 Hz).

[0373] HRMS (ESI) m / z: Calculated for (C 17 H 15 BrFO2) [M+H] + : 349.0239, found349.0219.

[0374] = +72.8° (c = 0.05, CHCl3).

[0375] HPLC analysis: Daicel Chiralpak OD-H Column (n-hexane / i-PrOH = 99 / 1,1 mL / min), 40 ℃, 220 nm, t R1 = 9.24 min (major), t R2 = 9.90 min (minor), 87%ee.

[0376] Example 23

[0377] Synthesis of Compound 44 with High Stereoselectivity

[0378]

[0379] Add cuprous trifluoromethanesulfonate (CuOTf, 4.2 mg, 0.02 mmol), ligand L3 (12.5 mg, 0.03 mmol), and o-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 hour under a nitrogen (N2) atmosphere. Then add a 1 mL solution of o-xylene containing α-fluoroolefin 43 (27.2 mg, 0.2 mmol).

[0380] Subsequently, at 40°C, a solution (2 mL) of o-xylene (176 mg, 1.0 mmol) of diazo 26 was slowly added via a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0381] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The diastereomeric proportion (dr) of the reaction was determined by ¹H NMR (in solvent CDCl₃), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC).

[0382] The crude product was purified by silica gel column chromatography (petroleum ether to ethyl acetate volume ratio = 100:1 to 20:1) to give the target product 44 (41.6 mg, 73%). Following the experimental procedures described above, the diastereomer ratio (dr) was 7:1 and the enantiomeric excess (ee) was 95%.

[0383] 1 H NMR (600 MHz, CDCl3) δ 7.15 – 7.05 (m, 8H), 6.99 (t, J = 7.4 Hz,1H), 4.32 – 4.24 (m, 2H), 2.49 (d, J = 3.2 Hz, 3H), 2.03 (dd, J = 10.5, 7.5Hz, 1H), 1.73 (dd, J = 21.6, 7.5 Hz, 1H).

[0384] 13C NMR (151 MHz, CDCl3) δ 138.92, 137.69 (d, J = 0.9 Hz), 132.16 (d,J = 19.1 Hz), 130.71 (d, J = 2.5 Hz), 129.08 (d, J = 2.7 Hz), 128.53 (d, J =4.8 Hz), 128.10 (d, J = 1.4 Hz), 128.03, 126.67, 125.23, 86.44 (d, J = 222.0Hz), 66.80 (d, J = 9.3 Hz), 38.25 (d, J = 12.6 Hz), 20.04 (d, J = 3.1 Hz),19.60 (d, J = 11.4 Hz).

[0385] 19 F NMR (565 MHz, CDCl3) δ -167.83 (dd, J = 23.4, 10.1 Hz).

[0386] Example 24

[0387] Synthesis of Compound 47 with high stereoselectivity

[0388]

[0389] Add copper trifluoromethanesulfonate [Cu(OTf)2] (10.9 mg, 0.03 mmol), ligand L4 (15.1 mg, 0.045 mmol), 4 Å molecular sieve (4 Å MS, 500 mg), and p-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 h under a nitrogen (N2) atmosphere. Then add a 1 mL solution of α-fluoroolefin 46 (36.6 mg, 0.3 mmol) in p-xylene.

[0390] Subsequently, at 40°C, a 2 mL solution of diazo 2 (102.6 mg, 0.9 mmol) in p-xylene was slowly added via a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0391] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1 The reaction was determined by ¹H NMR (using CDCl₃ as the solvent). 1The yield and diastereomer ratio (dr) were determined by ¹H NMR, with 1,1,2,2-tetrachloroethane as an internal standard. The enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC). The diastereomer ratio (dr) was 2.4:1, and the enantiomeric excess (ee) was 87%.

[0392] 1 H NMR (600 MHz, CDCl3) δ 7.38 (dt, J = 7.6, 1.9 Hz, 1H), 7.31 (tt, J= 7.4, 1.6 Hz, 1H), 7.26 (d, J = 6.9 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 4.35– 4.22 (m, 2H), 2.53 (d, J = 2.1 Hz, 3H), 2.21 (dt, J = 19.0, 7.1 Hz, 1H), 2.13 (ddd, J = 9.4, 7.5, 2.9 Hz, 1H), 1.57 (ddd, J = 10.6, 9.4, 6.8 Hz, 1H),1.33 (t, J = 7.1 Hz, 3H).

[0393] 13 C NMR (151 MHz, CDCl3) δ 168.37 (d, J = 1.7 Hz), 139.49, 133.79 (d,J = 19.1 Hz), 130.74 (d, J = 2.3 Hz), 129.80 (d, J = 2.8 Hz), 128.86 (d, J =3.4 Hz), 125.69 (d, J = 1.6 Hz), 81.00 (d, J = 227.6 Hz), 61.10, 26.45 (d, J= 12.6 Hz), 18.93, 16.54 (d, J = 13.7 Hz), 14.29.

[0394] 19 F NMR (565 MHz, CDCl3) δ -175.67 (dd, J = 19.4, 10.8 Hz).

[0395] HRMS (ESI) m / z: Calculated for (C 13 H 16 FO2) [M+H] +: 223.1134, found223.1139.

[0396] Example 25

[0397] The only difference from Example 24 is that the ligand is replaced with L5 (13.2 mg, 0.045 mmol), the structural formula of which is:

[0398] Its diastereomer ratio (dr) is 3.1:1, and its enantiomeric excess (ee) is 97%.

[0399] Example 26

[0400] The only difference from Example 24 is that the ligand is replaced with L6 (13.8 mg, 0.045 mmol), the structural formula of which is:

[0401]

[0402] Its diastereomer ratio (dr) is 3.2:1, and its enantiomeric excess (ee) is 92%.

[0403] Example 27

[0404] Synthesis of compound 42 with high stereoselectivity:

[0405]

[0406] Add cuprous trifluoromethanesulfonate (CuOTf, 4.2 mg, 0.02 mmol), ligand L7 (22.1 mg, 0.03 mmol), and o-xylene (1 mL) to a thoroughly dried 5 mL flask. Connect the flask to a reflux condenser and stir the reaction at 25 °C for 1 h under a nitrogen (N2) atmosphere. Then add a 1 mL solution of o-xylene containing α-fluoroolefin 18 (38.0 mg, 0.2 mmol).

[0407] Subsequently, at 40 °C, a solution (2 mL) of o-xylene (176.0 mg, 1.0 mmol, 5.0 equiv) of diazo 26 was slowly added via a syringe controlled by a syringe pump over a period of 12 hours. After the reaction was complete, the reaction system was concentrated under vacuum.

[0408] Using nuclear magnetic resonance hydrogen spectroscopy (NMR) 1The diastereomer ratio (dr) of the reaction was determined by ¹H NMR (using CDCl₃ as solvent), and the enantiomeric excess (ee) was determined by high performance liquid chromatography (HPLC). The diastereomer ratio (dr) was 19:1, and the enantiomeric excess (ee) was 92%.

[0409] Example 28

[0410] The difference from Example 27 is that the ligand is replaced with L8 (12.0 mg, 0.03 mmol), the structural formula of which is:

[0411] Its diastereomer ratio (dr) is 7:1, and its enantiomeric excess (ee) is 33%.

[0412] Example 29

[0413] The difference from Example 1 is that the amount of α-fluoroolefin 1 added was 6 mmol, which is 20 times the amount of α-fluoroolefin 1 added in Example 1. The amounts of other materials added in the reaction were also adjusted accordingly to 20 times that of Example 1. After the reaction, 1.06 g of the target product was obtained, with a yield of 85%, a diastereomer ratio (dr) of 23:1, and an enantiomeric excess (ee) of 99% ee. The yield and stereoselectivity were not decreased compared with the milligram level.

[0414] As can be seen from the above examples and comparative examples, the structure of the ligand has a significant impact on the product yield, diastereomers and enantiomers of asymmetric catalytic reactions. Choosing an oxazoline ligand that satisfies the structures shown in Formula IV and Formula V can improve the product yield while exhibiting good stereoselectivity.

[0415] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0416] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. An asymmetric catalyst system, characterized in that, Including copper catalysts, ligands, and solvents; The solvent includes solvents containing a benzene ring in their molecular structure; The ligand comprises a compound having at least one of the structures shown in Formula IV and Formula V: Formula IV Formula V R 41 and R 42 Each is independently selected from any one of alkyl groups having 1-20 carbon atoms, aralkyl groups having 7-30 carbon atoms, and aryl groups having 6-20 ring atoms; R 43 and R 44 Each is independently selected from any one of alkyl groups having 2-20 carbon atoms or aralkyl groups having 7-30 carbon atoms, or R 43 and R 44 It forms saturated or unsaturated rings with 3-8 ring atoms; Ring M1 and ring M2 are each independently selected from any one or more of the following: substituted or unsubstituted cycloalkyl groups with 5-7 ring atoms, aryl groups with 6-20 ring atoms, and fused rings containing aryl groups with 10-24 ring atoms. R 45 and R 46 Each is independently selected from any one of H, alkyl groups having 2-20 carbon atoms, and aralkyl groups having 7-30 carbon atoms, or the R... 45 and R 46 It forms saturated or unsaturated rings with 3-8 ring atoms.

2. The asymmetric catalyst system according to claim 1, characterized in that, It meets at least one of the following characteristics: The R 41 and the R 42 Each is independently selected from any one of alkyl groups having 1-10 carbon atoms and aralkyl groups having 7-15 carbon atoms; The R 43 and R 44 Each is independently selected from any one of alkyl groups having 2-10 carbon atoms and aralkyl groups having 7-15 carbon atoms, or the R... 43 and R 44 Forming saturated rings with 3-6 ring atoms; The ring M1 and the ring M2 are each independently selected from any one or more of the following: substituted or unsubstituted cycloalkyl groups with 5-6 ring atoms, aryl groups with 6-15 ring atoms, and fused rings containing aryl groups with 10-18 ring atoms. The R 45 and R 46 Each is independently selected from any one of the following: alkyl groups having H carbon atoms, 2-10 carbon atoms, and aralkyl groups having 7-15 carbon atoms, or the R... 45 and R 46 Forming saturated rings with 3-6 ring atoms; The R 41 and the R 42 Same structure; The R 43 and the R 44 The structures are the same, or the R is the same. 43 and the R 44 Forming saturated rings with 3-6 ring atoms; The ring M1 and the ring M2 have the same structure; The R 45 and the R 46 The structures are the same, or the R is the same. 45 and the R 46 It forms a saturated ring with 3-6 ring atoms.

3. The asymmetric catalyst system according to claim 1, characterized in that, It meets at least one of the following characteristics: The R 41 and the R 42 Each is independently isobutyl or isopropyl; The R 43 and R 44 It is benzyl, or the R 43 and R 44 Forming saturated rings with 3-6 ring atoms; The ring M1 and the ring M2 are ; The R 45 and R 46 Each is independently selected from H, Any one or more of them, or the R mentioned above 45 and R 46 Forming rings with 3-6 ring atoms; The ligand is any one or more compounds having the following structures, wherein Bn is benzyl and iPr is isopropyl: 、 、 、 、 、 、 、 、 。 4. The asymmetric catalyst system according to any one of claims 1 to 3, characterized in that, It meets at least one of the following characteristics: The copper catalyst is selected from any one or more of copper trifluoromethanesulfonate, copper acetate, cuprous trifluoromethanesulfonate, a complex of cuprous trifluoromethanesulfonate and benzene, cuprous iodide, copper tetrafluoroborate tetraacetonitrile, and copper hexafluorophosphonate tetraacetonitrile. The molar ratio of the copper catalyst to the ligand is 1:1 to 1:2; The solvent is selected from any one or more of p-xylene, o-xylene, ethylbenzene, trifluorotoluene, and m-xylene; The asymmetric catalyst system further includes a molecular sieve, optionally selected from one or more of 4Å molecular sieves, 3Å molecular sieves, and 5Å molecular sieves; optionally, the ratio of the molecular sieve to the copper catalyst is 300 mg / 0.3 mmol to 500 mg / 0.3 mmol.

5. The application of the asymmetric catalyst system according to any one of claims 1 to 4 in asymmetric catalytic reactions; Optionally, the application includes the use of the asymmetric catalyst system in the stereoselective preparation of fluorocyclopropanes.

6. A method for preparing fluorocyclopropane with high stereoselectivity, characterized in that, include: In the presence of the asymmetric catalyst system according to any one of claims 1 to 4, an α-fluoroolefin and a diazo compound are subjected to an asymmetric catalytic reaction to obtain a fluorocyclopropane compound; wherein the α-fluoroolefin has the structure shown in Formula I, the diazo compound has the structure shown in Formula II, and the fluorocyclopropane compound has the structure shown in Formula III. Equation I Formula II Formula III In the formula, R1 is selected from any one of H, aryl with 6-30 substituted or unsubstituted carbon atoms, heteroaryl with 6-30 substituted or unsubstituted carbon atoms, alkoxy with 1-30 substituted or unsubstituted carbon atoms, ether with 2-30 substituted or unsubstituted carbon atoms, and alkyl with 1-30 substituted or unsubstituted carbon atoms; R2 is selected from any one of hydrogen, aryl with 6-30 substituted or unsubstituted carbon atoms, aralkyl with 7-40 substituted or unsubstituted carbon atoms, and heteroaryl with 5-40 substituted or unsubstituted carbon atoms; and R3 is selected from any one of any one of alkyl with 1-10 substituted or unsubstituted carbon atoms, aryl with 6-50 substituted or unsubstituted carbon atoms, and aralkyl with 7-50 substituted or unsubstituted carbon atoms.

7. The method for preparing fluorocyclopropane with high stereoselectivity according to claim 6, characterized in that, It meets any one or more of the following characteristics: R1 is selected from any one of the following: aryl group with 6-18 substituted or unsubstituted carbon atoms, heteroaryl group with 6-28 substituted or unsubstituted ring atoms, alkoxy group with 1-15 substituted or unsubstituted carbon atoms, ether group with 2-15 substituted or unsubstituted carbon atoms, and alkyl group with 1-15 substituted or unsubstituted carbon atoms; R2 is selected from any one of hydrogen, aryl groups with 6-18 carbon atoms, aralkyl groups with 7-20 carbon atoms, and heteroaryl groups with 5-20 ring atoms; R3 is selected from any one of the following: alkyl groups with 1-6 carbon atoms (substituted or unsubstituted), aryl groups with 6-20 carbon atoms (substituted or unsubstituted), and aralkyl groups with 7-20 carbon atoms (substituted or unsubstituted).

8. The method for preparing fluorocyclopropane with high stereoselectivity according to claim 6, characterized in that, It meets any one or more of the following characteristics: R1 is any one of phenyl, halophenyl, methoxyphenyl, trifluoromethylphenyl, alkyl, phenethyl, and methylphenyl with 10-12 carbon atoms; R2 is selected from any one of hydrogen, phenyl, halophenyl, methoxyphenyl, and trifluoromethylphenyl; R3 is selected from any one of methyl, ethyl, benzyl, haloethyl, dimethylphenyl, and isopropyl.

9. The method for preparing fluorocyclopropane with high stereoselectivity according to any one of claims 6 to 8, characterized in that, R2 is selected from hydrogen, and the ligand is selected from any one or more compounds having the following structures: , , and ;or, R2 is selected from substituted or unsubstituted phenyl groups, and the ligand is selected from any one or more compounds with the following structures: , , , and .

10. The method for preparing fluorocyclopropane with high stereoselectivity according to any one of claims 6 to 8, characterized in that, It meets any one or more of the following characteristics: The molar ratio of the diazo compound to the α-fluoroolefin is (1:1) to (10:1). The molar ratio of the copper catalyst to the α-fluoroolefin is (1:40) to (1:5). The molar ratio of the ligand to the α-fluoroolefin is (1:40) to (1:5). The reaction temperature of the asymmetric catalytic reaction is 25℃-50℃; The reaction time for the asymmetric catalytic reaction is 1 h to 24 h. The asymmetric catalytic reaction is carried out in an inert gas atmosphere; The preparation method includes: mixing the asymmetric catalyst system and the α-fluoroolefin, and adding a solution containing the diazo compound dropwise at the reaction temperature of the asymmetric catalytic reaction; optionally, the difference between the dropwise addition time and the reaction time of the asymmetric catalytic reaction is less than or equal to 60 min.

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