Synthesis method of chiral 3-aryl-2-piperidone compound

Abstract

The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a synthesis method of a chiral 3-aryl-2-piperidone compound. Comprising the following steps: by taking an aryl halogenated compound or a trifluoromethanesulfonate compound and a chlorinated lactam electrophilic compound as raw materials, carrying out reductive coupling reaction at room temperature in a protective atmosphere in a reaction system consisting of a nickel-based catalyst, a chiral biimidazole ligand, a metal-based reducing agent, an additive and a solvent; and the chiral 3-aryl-2-piperidone compound is obtained. According to the invention, based on a reduction coupling strategy of nickel catalysis, an aryl halogenated compound or a trifluoromethanesulfonate compound and a simple and easily available 3-chloro-2-piperidone electrophilic reagent are used as initial raw materials, so that the defects of harsh reaction conditions of noble metals, biological enzymes and the like, complex substrate synthesis, limited range and the like are overcome; a series of chiral 3-aryl-2-piperidone compounds are efficiently, mildly and conveniently synthesized.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis technology, specifically relating to a method for synthesizing chiral 3-aryl-2-piperidinone compounds. Background Technology

[0002] 2-Piperidinones, as six-membered nitrogen-containing saturated heterocycles, provide a rigid framework, while the presence of a chiral center endows compounds with significant steric selectivity and stereochemical properties. This property is crucial for the design of bioactive molecules, as most biological systems are highly sensitive to chirality. In medicinal chemistry, chiral piperidinone compounds are widely used as active molecules or drug prodrugs. Their stereostructure can significantly influence interactions with biological targets such as enzymes and receptors, thereby determining drug efficacy, metabolic pathways, and toxicity. Currently, chiral 3-substituted piperidinone compounds are widely found in various drug molecules and bioactive molecules, but obtaining them remains a challenge, especially chiral 3-aryl-substituted piperidinone structures.

[0003] Currently, there are relatively few reports on chiral 3-substituted piperidinones, with only a few successful cases. In 1998, Koga's group reported the use of chiral tetradentate lithium amino and lithium bromide to obtain chiral 3-substituted-2-piperidinone compounds by enol lithium via enantioselective alkylation of lactams. However, this reaction only yielded alkyl-substituted chiral 2-piperidinone compounds.

[0004] .

[0005] In 2022, Chen Yifeng's research group reported a nickel-catalyzed intramolecular asymmetric alkylacylation reaction of olefins, which can synthesize various chiral 3-substituted piperidinone compounds. However, this reaction is mainly used to obtain chiral 3-substituted benzopiperidinone compounds, and only three 3-alkyl-substituted chiral 2-piperidinone compounds were obtained.

[0006] .

[0007] In summary, current methods for synthesizing chiral-chiral 3-substituted piperidinones involve harsh reaction conditions and poor substrate compatibility and enantioselectivity of the products. Summary of the Invention

[0008] To address the aforementioned problems, this invention provides a method for synthesizing chiral 3-aryl-2-piperidinone compounds. Based on a nickel-catalyzed reductive coupling strategy, it uses aryl halogenated compounds or trifluoromethanesulfonate compounds and readily available 3-chloro-2-piperidinone electrophilic reagents as starting materials. This method overcomes obstacles such as harsh reaction conditions for noble metals and biological enzymes, and the complexity and limited scope of substrate synthesis. It efficiently, mildly, and conveniently synthesizes a series of chiral 3-aryl-2-piperidinone compounds. Chiral 3-arylpiperidine compounds can be rapidly obtained through reduction reactions and can be used in the synthesis of key intermediates for related chiral 3-arylpiperidine drug molecules.

[0009] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0010] The purpose of this invention is to provide a method for synthesizing chiral 3-aryl-2-piperidinone compounds, comprising the following steps: Using aryl halogenated compounds or trifluoromethanesulfonate compounds and electrophilic chlorolactam compounds as raw materials, a reductive coupling reaction is carried out at room temperature under a protective atmosphere in a reaction system consisting of a nickel-based catalyst, a chiral biimidazole ligand, a metal-based reducing agent, additives and solvents to obtain chiral 3-aryl-2-piperidinone compounds.

[0011] Furthermore, the molar ratio of the electrophilic chlorolactam compound to the aryl halogenated compound is 0.1:0.2-0.5, and the molar ratio of the electrophilic chlorolactam compound to the trifluoromethanesulfonate compound is 0.1:0.2-0.5.

[0012] Furthermore, the molar ratio of the chlorolactam compound to the nickel-based catalyst is 0.1:0.01–0.025; the molar ratio of the chlorolactam compound to the ligand is 0.1:0.015–0.03; the molar ratio of the chlorolactam compound to the metal reducing agent is 0.1:0.3–0.5; the molar ratio of the additive to the chlorolactam compound is 0.1:0.1; the additive is tetrabutylammonium iodide; and the metal-based reducing agent is manganese.

[0013] Furthermore, the nickel-based catalyst is nickel bromide in ethylene glycol dimethyl ether.

[0014] Furthermore, the structural formula of the chiral biimidazole ligand is shown below: .

[0015] Furthermore, the reductive coupling reaction takes 12 to 24 hours.

[0016] Furthermore, the electrophilic compounds of chlorolactams are 3-chloro-1-pivaloylpiperidin-2-one, 3-chloro-1-pivaloyl-3,4-dihydropyridine-2(1H)-one, 3-chloro-1-pivaloylazheptan-2-one, or 3-chloro-1-pivaloyl-3,4-dihydroquinoline-2(1H)-one.

[0017] Furthermore, the structural formulas of aryl halogenated compounds are shown below: or ; Wherein, R1 is benzene, biphenyl, benzothiophene, tert-butyl indole-1-carboxylate, thiophene, pyridine containing a substituent, phenyl containing a substituent, or pyrimidine containing a substituent. , , or ; " is the connection point; The substituents of the phenyl group are selected from halogens, C2-C3 alkenyl groups, -R3COOR4, -NHR3COOR4, -R3COR4, cyano, C1-C3 aldehyde groups, C1-C3 trifluoroalkoxy groups, C2-C3 alkynylsilanes, C1-C4 alkyl groups, C1-C4 alkoxy groups, C1-C3 alkylthio groups, or dioxopentane rings, where R3 is a C1-C3 alkyl group and R4 is a C1-C4 alkyl group. The substituents of pyridine are selected from halogens and C1-C4 alkoxy groups; The substituents of pyrimidine are selected from C1-C4 alkoxy groups; Wherein, R2 is indene or a C2-C3 olefin phenyl group, and the olefin in indene or a C2-C3 olefin phenyl group is the linking site.

[0018] Furthermore, the trifluoromethanesulfonate compound is cyclohexyl-1-en-1-yl trifluoromethanesulfonate.

[0019] Furthermore, the aryl halogenated compounds are iodobenzene, p-fluoroiodobenzene, p-chloroiodobenzene, p-iodostyrene, methyl p-iodobenzoate, p-iodobenzonitrile, p-iodobenzaldehyde, 1-iodo-4-trifluoromethoxybenzene, ((4-iodophenyl)ethynyl)trimethylsilane, 4-iodo-1,1'-biphenyl, 1-iodo-4-methylbenzene, 1-(tert-butyl)-4-iodobenzene, 1-iodo-4-methoxybenzene, (4-iodophenyl)(methyl)thion, (4-iodophenyl)carbamate tert-butyl ester, 1-iodo-3-methoxybenzene, 2-iodonaphthalene, 1-(3-iodophenyl)-1-ethyl ketone, 1-iodo-3,4-methylene Dioxane, 1-iodo-2-methylbenzene, 4-iododibenzo[b,d]thiophene, tert-butyl 5-iodo-1H-indole-1-carboxylate, 3-iodothiophene, 2-fluoro-4-iodopyridine, 5-iodo-2-methoxypyridine, 2-chloro-6-iodopyridine, 5-iodo-2-methoxypyrimidine, cyclohexyl-1-en-1-yl trifluoromethanesulfonate, 2-bromo-1H-indene, 3-bromo-1,2-dihydronaphthalene, (2-bromovinyl)benzene, ethyl 4-(8-iodo-5,6-dihydro-11H-benzo[5,6]cycloheptano[1,2-b]pyridin-11-ylidene)piperidine-1-carboxylate, (3 aR 5 R 6 S 6 aR )-5-(( R )-2,2-dimethyl-1,3-dioxolane-4-yl)-2,2-dimethyltetrahydrofuran[2,3-d][1,3]dioxol-6-yl-4-iodobenzoate, ( S )-1-(4-fluorophenyl)-3-((2 S ,3 R )-1-(4-fluorophenyl)-2-(4-iodophenyl)-4-oxazolidine-3-yl)propyl acetate or (1 R ,2 S 5 R )-2-isopropyl-5-methylcyclohexyl-3-iodobenzoate.

[0020] Compared with the prior art, the present invention has the following advantages: This invention provides a synthetic method for chiral 3-aryl-2-piperidinone compounds. Based on a nickel-catalyzed reductive coupling strategy, it uses aryl halogenated compounds or trifluoromethanesulfonate compounds, readily available 3-chloro-2-piperidinone electrophiles as starting materials, and aryl iodide / bromine / trifluoromethanesulfonate reagents and readily available chlorolactam electrophiles as starting materials. This method overcomes obstacles such as harsh reaction conditions due to noble metals and biological enzymes, and the limited scope of complex substrate synthesis. It efficiently, mildly, and conveniently synthesizes a series of 3-chiral piperidine compounds. This is the first time that a modular synthesis of 3-chiral piperidine compounds has been achieved through a reductive coupling strategy. Chiral 3-arylpiperidine compounds can be rapidly obtained through reduction reactions and can be used in the synthesis of key intermediates for related chiral 3-arylpiperidine drug molecules.

[0021] The present invention provides a simple method for the synthesis of chiral 3-aryl-2-piperidinone compounds, which achieves modular synthesis of 3-chiral piperidine compounds under mild reaction conditions. Attached Figure Description

[0022] Figure 1 The 2,2'-(2-phenylpropane-1,3-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane) prepared in Example 1 of this invention 1 H NMR spectrum.

[0023] Figure 2 The 2,2'-(2-phenylpropane-1,3-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane) prepared in Example 1 of this invention 13 C NMR spectrum. Detailed Implementation

[0024] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0025] Current methods for synthesizing chiral 3-substituted piperidinones suffer from harsh reaction conditions, poor substrate compatibility, and poor enantioselectivity. However, chiral 3-aryl-2-piperidinones are widely found in drug and bioactive molecules and are also reducing precursors of chiral 3-arylpiperidine structures, making them highly valuable. Therefore, developing an efficient strategy for synthesizing chiral 3-aryl-2-piperidinones is essential.

[0026] Based on this, the present invention provides a method for synthesizing chiral 3-aryl-2-piperidinone compounds, comprising the following steps: Using aryl halogenated compounds or trifluoromethanesulfonate compounds and electrophilic chlorolactam compounds as raw materials, a reductive coupling reaction is carried out at room temperature under a protective atmosphere in a reaction system consisting of a nickel-based catalyst, a chiral biimidazole ligand, a metal-based reducing agent, additives and solvents to obtain the chiral 3-aryl-2-piperidinone compound aryl.

[0027] As a preferred embodiment of the present invention, the electrophilic compound of the chlorolactam can be 3-chloro-1-pivaloylpiperidin-2-one, 3-chloro-1-pivaloyl-3,4-dihydropyridin-2(1H)-one, 3-chloro-1-pivaloylpyrrolidine-2-one, 3-chloro-1-pivaloylazheptan-2-one, or 3-chloro-1-pivaloyl-3,4-dihydroquinoline-2(1H)-one. The reaction routes and mechanisms for the reductive coupling reaction with aryl halogenated compounds or trifluoromethanesulfonate compounds using the aforementioned electrophilic compounds as starting materials are the same. This invention takes 3-chloro-1-pivaloylpiperidin-2-one as an example to further illustrate the reaction route and mechanism for the reductive coupling reaction. The synthetic route for the chiral 3-aryl-2-piperidinone compound is as follows:

[0028] .

[0029] The reaction mechanism is as follows: .

[0030] Using metallic manganese as a reducing agent, Ni is reduced II Pre-catalyst formation of Ni 0 L n Catalyst. Subsequently, Ni 0 L n The catalyst undergoes an oxidative addition reaction with an aryl iodine compound to generate X-Ni. II L n (Ar) species, X-Ni II / L n (Ar) species are oxidized by alkyl radical IV, resulting in a single-electron transfer to generate X-Ni. III L n (Ar) intermediate. Subsequently, X-Ni III L n The (Ar) intermediate undergoes reductive elimination to yield X-Ni. II L n Species V. Then via alkyl chloride and X-Ni II L n Halogen atom transfer reduction occurs between species V to yield X-NiII L n (Cl) complex VI, and finally Ni is regenerated by reducing with metallic manganese. 0 L n The catalyst, thus ending the catalytic cycle.

[0031] The following specific examples will provide further explanation.

[0032] Example 1 ( R The preparation method of 3-phenyl-1-pentaylpiperidin-2-one (compound 3a) includes the following steps: Under a nitrogen atmosphere in a glove box, ethylene glycol dimethyl ether nickel bromide (0.01 mmol, 10 mol%), ligand (0.015 mmol, 15 mol%), tetrabutylammonium iodide (0.1 mmol, 1.0 equiv.), manganese powder (0.3 mmol, 3.0 equiv.), and solvent THF (tetrahydrofuran: 1 mL, 0.1 M) were added to a 10 mL reaction tube and stirred at room temperature for about 15 min. Then, 3-chloro-1-pentaylpiperidin-2-one (1a, 0.1 mmol) and iodobenzene (2a, 0.2 mmol) were added sequentially to the reaction system. Under a nitrogen atmosphere, the mixture was stirred at room temperature for 12 h. The target chiral piperidine compound 3a was obtained by column chromatography purification. Compound 3a was a white solid with an enantioselectivity of 98:2 and a yield of 82%. The synthetic route is as follows:

[0033] .

[0034] Compound 3a was characterized. 1 H NMR (400MHz, CDCl3) Figure 1 As shown, 13 C NMR (400MHz, CDCl3) graph as shown Figure 2 As shown, by Figure 1 and Figure 2 It can be seen that compound 3a was successfully synthesized.

[0035] ¹H NMR characterization: 1H NMR (400 MHz, CDCl₃) δ 7.42 – 7.34 (m, 2H), 7.33 – 7.25 (m, 3H), 3.76 – 3.62 (m, 3H), 2.33 – 2.23 (m, 1H), 2.15 – 2.05 (m, 2H), 2.04 – 1.94 (m, 1H), 1.31 (s, 9H).

[0036] Carbon NMR characterization: 13C NMR (100 MHz, CDCl3) δ 190.3, 174.4, 139.6, 128.8, 128.6, 127.3, 50.9, 47.7, 44.1, 30.9, 28.0, 22.5. HRES (ESI+): Calculated for [C 16 H 21 NO2, M+Na] + : 282.14645; Found:282.14774.

[0037] Example 2 ( R Preparation of 3-(4-fluorophenyl)-1-pentanoylpiperidin-2-one (compound 3b) The only difference between this embodiment and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with p-fluoroiodobenzene (2b, 0.2 mmol), and the target chiral piperidine compound 3b was obtained by column chromatography purification. Compound 3b is a white solid with an enantioselectivity ratio of 98:2 and a yield of 82%. Its synthetic route is as follows:

[0038] .

[0039] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.23 – 7.16 (m, 2H), 7.08 –7.00 (m, 2H), 3.74 – 3.58 (m, 3H), 2.27 – 2.20 (m, 1H), 2.11 – 1.93 (m, 3H),1.27 (s, 9H). Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.3, 174.3, 163.3, 160.9,135.3 (d, J = 3.33 Hz), 130.2 (d, J = 8.02 Hz), 115.6 (d, J = 21.45 Hz), 50.1, 47.7, 44.1, 30.9, 28.0, 22.6.

[0040] Example 3 ( R Preparation of 3-(4-chlorophenyl)-1-pentanoylpiperidin-2-one (compound 3c) The only difference between this embodiment and Example 1 is that iodobenzene (2a, 0.2 mmol) is replaced with p-chloroiodobenzene (2c, 0.2 mmol). The target chiral piperidine compound 3c was obtained by column chromatography purification. Compound 3c is a white solid with an enantioselectivity of 99:1 and a yield of 85%. Its synthetic route is as follows:

[0041] .

[0042] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.4 Hz, 2H), 7.19 –7.14 (m, 2H), 3.72 – 3.58 (m, 3H), 2.25 – 2.20 (m, 1H), 2.09 – 1.94 (m, 3H), 1.26 (s, 9H).

[0043] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.2, 174.0, 138.0, 133.2, 130.0, 128.9, 50.2, 47.7, 47.7, 44.3, 44.1, 30.7, 28.0, 22.6.

[0044] Example 4 ( R Preparation of 1-pivaloyl-3-(4-vinylphenyl)piperidin-2-one (compound 3d) The only difference between this embodiment and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with p-iodostyrene (2d, 0.2 mmol). The target chiral piperidine compound 3d was obtained by column chromatography purification. Compound 3d was a white solid with an enantioselectivity of 99:1 and a yield of 61%. Its synthetic route is as follows:

[0045] .

[0046] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 7.9 Hz, 2H), 7.19(d, J = 7.8 Hz, 2H), 6.70 (dd, J = 17.6, 10.9 Hz, 1H), 5.72 (d, J= 17.6 Hz, 1H), 5.23 (d, J = 10.9 Hz, 1H), 3.67 (ddd, J = 12.3, 8.5, 5.7 Hz, 3H), 2.21 (d, J = 8.1Hz, 1H), 2.05 (tdd, J = 14.0, 7.3, 3.9 Hz, 3H), 1.27 (s, 9H).

[0047] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.2, 174.3, 139.1, 136.7,136.5, 128.7, 126.6, 113.9, 50.6, 47.7, 44.1, 30.7, 28.0, 22.5.

[0048] Example 5 ( R Preparation of methyl 4-(2-oxo-1-pentanoylpiperidin-3-yl)benzoate (compound 3e) The only difference between this embodiment and Example 1 is that iodobenzene (2a, 0.2 mmol) is replaced with methyl p-iodobenzoate (2e, 0.2 mmol). The target chiral piperidine compound 3e was obtained by column chromatography purification. Compound 3e is a white solid with an enantioselectivity of 99:1 and a yield of 46%. Its synthetic route is as follows:

[0049] .

[0050] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 8.03 – 7.98 (m, 2H), 7.32 –7.28 (m, 2H), 3.89 (s, 3H), 3.77 – 3.58 (m, 3H), 2.23 (dtt, J = 10.7, 4.6, 2.2Hz, 1H), 2.11 – 1.93 (m, 3H), 1.26 (s, 9H).

[0051] Carbon NMR characterization: 13C NMR (100 MHz, CDCl3) δ 190.2 173.6, 166.9, 144.8,130.0, 129.1, 128.7, 52.2, 50.7, 47.7, 44.1, 30.6, 27.9, 22.4.

[0052] Example 6 ( R Preparation of 4-(2-oxo-1-tervapotranylpiperidin-3-yl)benzonitrile (compound 3f) The only difference between this embodiment and Example 1 is that iodobenzene (2a, 0.2 mmol) is replaced with p-iodobenzonitrile (2f, 0.2 mmol). The target chiral piperidine compound 3f was obtained by column chromatography purification. Compound 3f is a white solid with an enantioselectivity of 98:2 and a yield of 35%. Its synthetic route is as follows:

[0053] .

[0054] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.68 – 7.57 (m, 2H), 7.38 –7.29 (m, 2H), 3.78 – 3.66 (m, 2H), 3.59 (dtd, J = 12.5, 4.6, 1.6 Hz, 1H), 2.24(dt, J = 7.8, 5.5 Hz, 1H), 2.12 – 1.96 (m, 3H), 1.25 (s, 9H).

[0055] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.1, 173.0, 144.9, 132.5,129.6, 118.8, 111.2, 50.7, 47.7, 44.0, 30.5, 27.9, 22.5.

[0056] Example 7 ( R Preparation of 4-(2-oxo-1-tervalinepiperidin-3-yl)benzaldehyde (compound 3g) The only difference between this embodiment and Example 1 is that iodobenzene (2a, 0.2 mmol) is replaced with p-iodobenzaldehyde (2 g, 0.2 mmol). The target chiral piperidine compound was obtained by column chromatography purification. The 3 g compound was a white solid with an enantioselectivity of 99:1 and a yield of 42%. The synthetic route is as follows:

[0057] .

[0058] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 7.89 – 7.85 (m,2H), 7.43 – 7.39 (m, 2H), 3.81 – 3.69 (m, 2H), 3.63 (dtd, J = 9.3, 4.8, 2.3 Hz,1H), 2.27 (dddd, J = 14.2, 8.0, 5.1, 2.0 Hz, 1H), 2.12 – 1.98 (m, 3H), 1.28 (s,9H).

[0059] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 192.0, 190.2, 173.4, 146.6,135.6, 130.2, 129.5, 51.0, 47.7, 44.1, 30.7, 28.0, 22.6.

[0060] Example 8 ( R Preparation of 1-pivaloyl-3-(4-(trifluoromethoxy)phenyl)piperidin-2-one (compound 3h) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with 1-iodo-4-trifluoromethoxybenzene (2h, 0.2 mmol). The target chiral piperidine compound 3h was obtained by column chromatography purification. Compound 3h was a white solid with an enantioselectivity of 99:1 and a yield of 70%. The synthetic route is as follows:

[0061] .

[0062] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.28 – 7.23 (m, 2H), 7.21 –7.15 (m, 2H), 3.79 – 3.54 (m, 3H), 2.24 (dtt, J = 10.3, 4.5, 2.1 Hz, 1H), 2.11– 1.90 (m, 3H), 1.28 (s, 9H).

[0063] Carbon NMR characterization:13 C NMR (100 MHz, CDCl3) δ 190.3, 173.9, 148.4 (q, J = 2.01Hz), 138.3, 130.0, 129.8, 121.3, 50.2, 47.9, 47.8, 44.1, 31.0, 28.0, 22.6.

[0064] Example 9 ( R Preparation of 1-pivaloyl-3-(4-((trimethylsilyl)ethynyl)phenyl)piperidin-2-one (compound 3i) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with ((4-iodophenyl)ethynyl)trimethylsilane (2i, 0.2 mmol). The target chiral piperidine compound 3i was obtained by column chromatography purification. Compound 3i was a white solid with an enantioselectivity of 98:2 and a yield of 89%. Its synthetic route is as follows:

[0065] .

[0066] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.47 – 7.38 (m, 2H), 7.20 –7.13 (m, 2H), 3.73 – 3.57 (m, 3H), 2.25 – 2.16 (m, 1H), 2.09 – 1.91 (m, 3H), 1.26 (s, 9H), 0.23 (s, 9H).

[0067] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.3, 173.9, 140.0, 132.3,128.5, 122.2, 105.0, 94.4, 50.7, 47.7, 44.1, 30.6, 28.0, 22.4, 0.1.

[0068] Example 10 ( R Preparation of 3-([1,1'-biphenyl]-4-yl)-1-piperylpiperidin-2-one (compound 3j) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with 4-iodo-1,1'-biphenyl (2j, 0.2 mmol). The target chiral piperidine compound 3j was obtained by column chromatography purification. Compound 3j was a white solid with an enantioselectivity of 98:2 and a yield of 89%. Its synthetic route is as follows:

[0069] .

[0070] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.6 Hz, 4H), 7.43(t, J = 7.5 Hz, 2H), 7.33 (dd, J = 14.9, 7.6 Hz, 3H), 3.80 – 3.62 (m, 3H), 2.30 –2.24 (m, 1H), 2.09 (tq, J = 9.2, 5.1 Hz, 2H), 2.04 – 1.96 (m, 1H), 1.30 (s,9H).

[0071] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.4, 174.5, 141.0, 140.3,138.6, 129.0, 128.9, 127.6, 127.4, 127.3, 50.6, 47.8, 44.1, 30.9, 28.0,22.6..

[0072] Example 11 ( R Preparation of 1-piperyl-3-(p-tolyl)piperidin-2-one (compound 3k) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with 1-iodo-4-methylbenzene (2k, 0.2 mmol). The target chiral piperidine compound 3k was obtained by column chromatography purification. Compound 3k was a white solid with an enantioselectivity of 97:3 and a yield of 37%. The synthetic route is as follows:

[0073] .

[0074] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.14 (q, J= 8.2 Hz, 4H), 3.72 –3.37 (m, 3H), 2.33 (d, J = 3.6 Hz, 3H), 2.27 – 2.17 (m, 1H), 2.12 – 1.88 (m, 3H), 1.28 (s, 9H).

[0075] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.3, 174.7, 136.9, 136.5,129.4, 128.4, 50.6, 47.7, 44.0, 30.8, 28.0, 22.6, 21.2.

[0076] Example 12 ( R Preparation of methyl 4-(2-oxo-1-pentanoylpiperidin-3-yl)benzoate (compound 3l) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with 1-(tert-butyl)-4-iodobenzene (2l, 0.2 mmol). The target chiral piperidine compound 3l was obtained by column chromatography purification. Compound 3l was a white solid with an enantioselectivity of 97:3 and a yield of 35%. Its synthetic route is as follows:

[0077] .

[0078] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.40 – 7.33 (m, 2H), 7.20 –7.13 (m, 2H), 3.73 – 3.58 (m, 3H), 2.22 (dddd, J = 14.1, 7.5, 3.7, 1.7 Hz, 1H), 1.95 (s, 3H), 1.31 (s, 9H), 1.29 (s, 9H).

[0079] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.4, 174.6, 149.9, 136.5, 128.2, 125.7, 50.4, 47.7, 44.0, 34.5, 31.4, 30.9, 28.0, 22.5.

[0080] Example 13 ( RPreparation of 3-(4-methoxyphenyl)-1-pentanoylpiperidin-2-one (compound 3m) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) is replaced with 1-iodo-4-methoxybenzene (2m, 0.2 mmol). The target chiral piperidine compound 3m was obtained by column chromatography purification. Compound 3m is a white solid with an enantioselectivity of 99:1 and a yield of 90%. Its synthetic route is as follows:

[0081] .

[0082] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.18 – 7.13 (m, 2H), 6.91 –6.85 (m, 2H), 3.79 (s, 3H), 3.69 – 3.59 (m, 3H), 2.26 – 2.18 (m, 1H), 2.10 –1.92 (m, 3H), 1.27 (s, 9H).

[0083] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.3, 174.8, 158.8, 131.6,129.6, 114.2, 55.4, 50.1, 47.7, 44.1, 30.8, 28.0, 22.6.

[0084] Example 14 ( R Preparation of methyl 4-(2-oxo-1-pentanoylpiperidin-3-yl)benzoate (compound 3n) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with (4-iodophenyl)(methyl)thione (2n, 0.2 mmol). The target chiral piperidine compound 3n was obtained by column chromatography purification. Compound 3n was a white solid with an enantioselectivity of 97:3 and a yield of 49%. Its synthetic route is as follows:

[0085] .

[0086] Characterization by proton nuclear magnetic resonance (NMR): 1H NMR (400 MHz, CDCl3) δ 7.26 – 7.21 (m, 2H), 7.18 –7.12 (m, 2H), 3.72 – 3.57 (m, 3H), 2.46 (s, 3H), 2.26 – 2.16 (m, 1H), 2.10 –1.89 (m, 3H), 1.27 (s, 9H).

[0087] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.3, 174.4, 141.0, 140.2,138.6, 129.0, 128.8, 127.5, 127.2, 50.6, 47.8, 44.1, 30.9, 28.0, 22.6.

[0088] Example 15 ( R Preparation of methyl 4-(2-oxo-1-pentanoylpiperidin-3-yl)benzoate (compound 3o) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with tert-butyl (4-iodophenyl)carbamate (2o, 0.2 mmol). The target chiral piperidine compound 3o was obtained by column chromatography purification. Compound 3o was a white solid with an enantioselectivity of 98:2 and a yield of 58%. Its synthetic route is as follows:

[0089] .

[0090] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.1 Hz, 2H), 7.16 –7.11 (m, 2H), 3.70 – 3.58 (m, 3H), 2.19 (tt, J = 8.4, 5.7 Hz, 1H), 2.03 (tdd, J =12.9, 5.5, 2.4 Hz, 2H), 1.97 – 1.90 (m, 1H), 1.50 (s, 9H), 1.26 (s, 9H).

[0091] Carbon NMR characterization: 13C NMR (100 MHz, CDCl3) δ 190.3, 174.6, 152.9, 137.5,134.0, 129.0, 118.9, 80.5, 50.2, 47.7, 44.0, 30.7, 28.4, 28.0, 22.4.

[0092] Example 16 ( R Preparation of 3-(3-methoxyphenyl)-1-pentanoylpiperidin-2-one (compound 3p) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with 1-iodo-3-methoxybenzene (2p, 0.2 mmol). The target chiral piperidine compound 3p was obtained by column chromatography purification. Compound 3p was a white solid with an enantioselectivity of 98:2 and a yield of 65%. Its synthetic route is as follows:

[0093] .

[0094] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 15.9 Hz, 1H), 6.85 –6.75 (m, 3H), 3.79 (s, 3H), 3.71 – 3.61 (m, 3H), 2.28 – 2.18 (m, 1H), 2.06(ddt, J = 12.8, 6.6, 2.5 Hz, 2H), 1.98 – 1.90 (m, 1H), 1.28 (s, 9H).

[0095] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.3, 174.2, 159.8, 141.1,129.7, 120.9, 114.6, 112.5, 55.3, 50.9, 47.7, 44.1, 30.8, 28.0, 22.4.

[0096] Example 17 ( R Preparation of 3-(naphth-2-yl)-1-tervalinepiperidin-2-one (compound 3q) The only difference between this embodiment and Example 1 is that iodobenzene (2a, 0.2 mmol) is replaced with 2-iodonaphthalene (2q, 0.2 mmol). The target chiral piperidine compound 3q was obtained by column chromatography purification. Compound 3q is a white solid with an enantioselectivity of 99:1 and a yield of 78%. Its synthetic route is as follows:

[0097] .

[0098] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.86 – 7.78 (m, 3H), 7.71 (d, J =1.9 Hz, 1H), 7.50 – 7.43 (m, 2H), 7.36 (dd, J = 8.5, 1.9 Hz, 1H), 3.88 (dd, J =10.7, 6.3 Hz, 1H), 3.82 – 3.62 (m, 2H), 2.34 – 2.25 (m, 1H), 2.23 – 2.06 (m,2H), 2.06 – 1.95 (m, 1H), 1.31 (s, 9H).

[0099] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.3, 174.4, 137.0, 133.5,132.7, 128.4, 127.8, 127.7, 127.4, 126.6, 126.2, 125.9, 51.0, 47.8, 44.1,30.8, 28.0, 22.6..

[0100] Example 18 ( R Preparation of 3-(3-acetylphenyl)-1-pentanoylpiperidin-2-one (compound 3r) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with 1-(3-iodophenyl)-1-ethylone (2r, 0.2 mmol). The target chiral piperidine compound 3r was obtained by column chromatography purification. Compound 3r was a white solid with an enantioselectivity of 98:2 and a yield of 58%. Its synthetic route is as follows:

[0101] .

[0102] Characterization by proton nuclear magnetic resonance (NMR): 1H NMR (400 MHz, CDCl3) δ 7.92 – 7.79 (m, 2H), 7.45 (dd, J = 4.7, 2.1 Hz, 2H), 3.80 – 3.68 (m, 2H), 3.67 – 3.60 (m, 1H), 2.60 (s, 3H), 2.30 – 2.21 (m, 1H), 2.15 – 2.04 (m, 2H), 2.04 – 1.98 (m, 1H), 1.27 (s, 9H).

[0103] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 198.0, 190.3, 173.9, 140.3,137.6, 133.5, 129.0, 128.4, 127.6, 50.8, 47.8, 44.1, 30.9, 28.0, 26.8, 22.6.

[0104] Example 19 ( R Preparation of methyl 4-(2-oxo-1-pentanoylpiperidin-3-yl)benzoate (compound 3s) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with 1-iodo-3,4-methylenedioxybenzene (2s, 0.2 mmol). The target chiral piperidine compound 3s was obtained by column chromatography purification. Compound 3s was a white solid with an enantioselectivity of 98:2 and a yield of 82%. Its synthetic route is as follows:

[0105] .

[0106] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 6.81 – 6.74 (m, 1H), 6.74 –6.66 (m, 2H), 5.93 (dq, J = 5.1, 1.5 Hz, 2H), 3.70 – 3.50 (m, 3H), 2.25 – 2.17(m, 1H), 2.09 – 1.91 (m, 3H), 1.27 (s, 9H).

[0107] Carbon NMR characterization: 13C NMR (100 MHz, CDCl3) δ 190.3, 174.6, 147.9, 146.9,133.3, 121.9, 109.0, 108.5, 101.2, 50.6, 47.7, 44.1, 30.9, 28.0, 22.6.

[0108] Example 20 ( R Preparation of 1-pivaloyl-3-(o-tolyl)piperidin-2-one (compound 3t) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) is replaced with 1-iodo-2-methylbenzene (2t, 0.2 mmol). The target chiral piperidine compound 3t was obtained by column chromatography purification. Compound 3t is a white solid with an enantioselectivity of 98:2 and a yield of 37%. Its synthetic route is as follows:

[0109] .

[0110] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.24 – 7.12 (m, 4H), 3.97 –3.85 (m, 1H), 3.72 (ddd, J = 12.3, 9.7, 4.1 Hz, 1H), 3.63 (dtd, J = 12.3, 4.7,1.7 Hz, 1H), 2.33 (s, 3H), 2.26 – 1.99 (m, 3H), 2.03 – 1.89 (m, 1H), 1.30 (s,9H).

[0111] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.5, 174.2, 138.2, 136.2,130.9, 128.2, 127.3, 126.4, 47.9, 47.4, 44.1, 30.0, 28.0, 22.8, 20.0.

[0112] Example 21 ( R Preparation of 3-(dibenzo[b,d]thiophen-4-yl)-1-tervaline-piperidin-2-one (compound 3u) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with 4-iododibenzo[b,d]thiophene (2u, 0.2 mmol). The target chiral piperidine compound 3u was obtained by column chromatography purification. Compound 3u was a white solid with an enantioselectivity of 98:2 and a yield of 58%. Its synthetic route is as follows:

[0113] .

[0114] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 8.18 – 8.12 (m, 1H), 8.09 (dd, J = 7.9, 1.1 Hz, 1H), 7.88 – 7.82 (m, 1H), 7.52 – 7.42 (m, 3H), 7.34 (dd, J =7.4, 1.1 Hz, 1H), 4.05 (dd, J = 10.5, 6.8 Hz, 1H), 3.82 (ddd, J = 12.5, 10.0, 4.5Hz, 1H), 3.68 (dtd, J = 12.5, 4.8, 1.3 Hz, 1H), 2.42 – 2.27 (m, 2H), 2.17 –2.00 (m, 2H), 1.32 (s, 9H).

[0115] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.3, 172.8, 139.4, 138.8,136.4, 136.2, 134.3, 127.0, 126.3, 125.1, 124.6, 122.8, 121.9, 120.7, 50.2,47.9, 44.1, 29.1, 28.0, 22.9..

[0116] Example 22 ( R Preparation of tert-butyl 5-(2-oxo-1-tert-pentanoylpiperidin-3-yl)-1H-indole-1-carboxylic acid (compound 3v) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with tert-butyl 5-iodo-1H-indole-1-carboxylate (2v, 0.2 mmol). The target chiral piperidine compound 3v was obtained by column chromatography purification. Compound 3v was a white solid with an enantioselectivity of 99:1 and a yield of 58%. The synthetic route is as follows:

[0117] .

[0118] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.6 Hz, 1H), 7.58(d, J = 3.8 Hz, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.18 (dd, J = 8.6, 1.8 Hz, 1H), 6.53(d, J = 3.7 Hz, 1H), 3.79 (dd, J = 10.4, 6.2 Hz, 1H), 3.68 (pd, J = 12.4, 4.8 Hz, 2H), 2.27 (dq, J = 11.7, 5.6 Hz, 1H), 2.15 – 2.05 (m, 2H), 1.98 (ddt, J = 14.6,9.5, 4.8 Hz, 1H), 1.66 (s, 9H), 1.28 (s, 9H).

[0119] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.3, 174.9, 149.8, 134.4,133.9, 131.0, 126.4, 124.8, 120.9, 115.5, 107.4, 83.8, 50.8, 47.7, 44.1,31.1, 28.3, 28.0, 22.6..

[0120] Example 23 ( R Preparation of 1-pivaloyl-3-(thiophen-3-yl)piperidin-2-one (3w) (compound 3w) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with 3-iodothiophene (2w, 0.2 mmol). The target chiral piperidine compound 3w was obtained by column chromatography purification. Compound 3w was a white solid with an enantioselectivity of 97:3 and a yield of 73%. Its synthetic route is as follows:

[0121] .

[0122] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.33 – 7.27 (m, 1H), 7.14 (dt, J = 3.0, 1.0 Hz, 1H), 7.04 (dd, J = 5.0, 1.3 Hz, 1H), 3.84 (dd, J = 9.3, 6.1 Hz, 1H), 3.61 (dd, J = 6.9, 5.0 Hz, 2H), 2.28 – 2.20 (m, 1H), 2.13 – 2.02 (m, 2H), 1.98 – 1.89 (m, 1H), 1.27 (s, 9H).

[0123] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.3, 173.9, 139.3, 127.8,125.9, 122.2, 47.6, 45.7, 44.1, 29.7, 28.0, 22.1.

[0124] Example 24 ( R Preparation of 3-(2-fluoropyridin-4-yl)-1-tervalinepiperidin-2-one (compound 3x) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with 2-fluoro-4-iodopyridine (2x, 0.2 mmol). The target chiral piperidine compound 3x was obtained by column chromatography purification. Compound 3x was a white solid with an enantioselectivity of 93:7 and a yield of 70%. Its synthetic route is as follows:

[0125] .

[0126] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 8.17 (dd, J= 10.0, 5.2 Hz, 1H),7.07 (ddt, J = 5.2, 3.4, 1.7 Hz, 1H), 6.82 (t, J = 1.7 Hz, 1H), 3.82 – 3.65 (m,2H), 3.65 – 3.56 (m, 1H), 2.29 – 2.18 (m, 1H), 2.13 – 1.92 (m, 3H), 1.27 (s,9H).

[0127] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.1, 172.1, 164.1 (d, J =238.6 Hz), 154.0 (d, J = 7.9 Hz), 147.9 (d, J = 15.3 Hz), 121.7 (d, J = 4.2 Hz), 109.8 (d, J = 37.9 Hz), 49.8, 49.8, 47.6, 44.1, 30.0, 27.9, 22.3. 19 F NMR (376MHz, CDCl3) δ -66.22.

[0128] Example 25 ( R Preparation of 3-(6-methoxypyridin-3-yl)-1-tervalinepiperidin-2-one (compound 3y) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with 5-iodo-2-methoxypyridine (2y, 0.2 mmol). The target chiral piperidine compound 3y was obtained by column chromatography purification. Compound 3y was a white solid with an enantioselectivity of 97:3 and a yield of 64%. The synthetic route is as follows:

[0129] .

[0130] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 2.5 Hz, 1H), 7.48 –7.41 (m, 1H), 6.73 (d, J= 8.6 Hz, 1H), 3.91 (s, 3H), 3.73 – 3.58 (m, 3H), 2.21(q, J = 7.2 Hz, 1H), 2.09 – 1.95 (m, 3H), 1.26 (s, 9H).

[0131] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.2, 174.1, 163.6, 146.6,138.8, 127.8, 111.1, 53.6, 47.7, 47.6, 44.1, 30.6, 28.0, 22.7.

[0132] Example 26 ( R Preparation of 3-(6-chloropyridin-2-yl)-1-tervalinepiperidin-2-one (compound 3z) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with 2-chloro-6-iodopyridine (2z, 0.2 mmol). The target chiral piperidine compound 3z was obtained by column chromatography purification. Compound 3z was a white solid with an enantioselectivity of 98:2 and a yield of 58%. Its synthetic route is as follows:

[0133] .

[0134] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.62 (t, J = 7.8 Hz, 1H), 7.21(dd, J = 9.6, 7.7 Hz, 2H), 3.86 (dd, J = 9.2, 7.1 Hz, 1H), 3.75 – 3.55 (m, 2H), 2.25 (dq, J = 10.4, 4.7 Hz, 2H), 2.12 (dq, J = 14.5, 4.8 Hz, 1H), 1.93 (ddq, J =14.1, 9.2, 4.8 Hz, 1H), 1.26 (s, 9H).

[0135] Carbon NMR characterization: 13C NMR (100 MHz, CDCl3) δ 190.3, 172.6, 160.0, 151.0,139.2, 122.9, 122.4, 52.2, 47.7, 44.2, 28.9, 28.0, 22.1.

[0136] Example 27 ( R Preparation of 3-(2-methoxypyrimidin-5-yl)-1-tervalinepiperidin-2-one (compound 3aa) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with 5-iodo-2-methoxypyrimidine (2aa, 0.2 mmol). The target chiral piperidine compound 3aa was obtained by column chromatography purification. Compound 3aa was a white solid with an enantioselectivity of 97:3 and a yield of 71%. The synthetic route is as follows:

[0137] .

[0138] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 8.40 (s, 2H), 4.00 (s, 3H), 3.78 – 3.57 (m, 3H), 2.29 – 2.20 (m, 1H), 2.12 – 1.98 (m, 3H), 1.27 (s, 9H).

[0139] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 189.9, 173.0, 165.1, 159.2, 125.9, 55.1, 47.7, 45.3, 44.1, 30.1, 27.9, 22.7.

[0140] Example 28 ( R Preparation of 3-(cyclohex-1-en-1-yl)-1-piperylpiperidin-2-one (compound 3ab) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with cyclohexyl-1-en-1-yl trifluoromethanesulfonate (2ab, 0.2 mmol). The target chiral piperidine compound 3ab was obtained by column chromatography purification. Compound 3ab was a white solid with an enantioselectivity of 96:4 and a yield of 30%. Its synthetic route is as follows:

[0141] .

[0142] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 5.57 (tt, J = 3.7, 1.5 Hz, 1H), 3.58 – 3.46 (m, 2H), 3.02 (dd, J = 9.5, 6.5 Hz, 1H), 1.97 (s, 7H), 1.67 – 1.52(m, 5H), 1.27 (s, 9H).

[0143] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.6, 174.5, 135.9, 125.7, 52.6, 47.6, 44.1, 28.0, 27.4, 26.6, 25.4, 22.9, 22.4, 22.3.

[0144] Example 29 ( R Preparation of 3-(1H-inden-2-yl)-1-pentanoylpiperidin-2-one (compound 3ac) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with 2-bromo-1H-indene (2ac, 0.2 mmol). The target chiral piperidine compound 3ac was obtained by column chromatography purification. Compound 3ac was a white solid with an enantioselectivity of 95:5 and a yield of 59%. The synthetic route is as follows:

[0145] .

[0146] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.4 Hz, 1H), 7.32(d, J = 7.5 Hz, 1H), 7.23 (td, J = 7.4, 1.1 Hz, 1H), 7.15 (td, J = 7.4, 1.2 Hz,1H), 6.76 – 6.72 (m, 1H), 3.66 (dd, J = 9.2, 6.0 Hz, 1H), 3.63 – 3.57 (m, 2H), 3.53 (d, J = 3.8 Hz, 1H), 3.46 (dd, J= 22.6, 1.6 Hz, 1H), 2.23 – 2.13 (m, 1H), 2.13 – 2.00 (m, 2H), 1.94 (ddt, J = 15.1, 8.1, 2.8 Hz, 1H), 1.29 (s, 9H).

[0147] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.3, 173.7, 146.3, 144.6,143.4, 129.4, 126.4, 124.6, 123.7, 120.8, 47.5, 46.3, 44.1, 40.4, 28.4, 28.0,22.0.

[0148] Example 30 ( R Preparation of 3-(3,4-dihydronaphth-2-yl)-1-tervapotranylpiperidin-2-one (compound 3ad) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with 3-bromo-1,2-dihydronaphthalene (2ad, 0.2 mmol). The target chiral piperidine compound 3ad was obtained by column chromatography purification. Compound 3ad was a white solid with an enantioselectivity of 94:6 and a yield of 52%. Its synthetic route is as follows:

[0149] .

[0150] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.14 – 7.07 (m, 3H), 7.00 (d, J =6.7 Hz, 1H), 6.37 (s, 1H), 3.63 – 3.53 (m, 2H), 3.32 (dd, J = 9.8, 5.8 Hz, 1H),2.94 – 2.75 (m, 2H), 2.30 (t, J = 8.1 Hz, 2H), 2.06 – 1.91 (m, 4H), 1.30 (s, 9H).

[0151] Carbon NMR characterization: 13C NMR (100 MHz, CDCl3) δ 190.4, 173.9, 138.8, 135.0,134.2, 127.3, 127.0, 126.5, 126.0, 126.0, 52.2, 47.6, 44.1, 28.3, 28.0, 27.4,26.0, 22.3.

[0152] Example 31 ( R , E Preparation of 1-pivaloyl-3-styrylpiperidin-2-one (compound 3ae) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with (2-bromovinyl)benzene (2ae, 0.2 mmol). The target chiral piperidine compound 3ae was obtained by column chromatography purification. Compound 3ae was a white solid with an enantioselectivity of 93:7 and a yield of 75%. The synthetic route is as follows:

[0153] .

[0154] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.37 – 7.27 (m, 5H), 6.71 (d, J =11.5 Hz, 1H), 5.72 (dd, J = 11.5, 9.9 Hz, 1H), 3.69 – 3.57 (m, 2H), 3.50 (dtd, J = 12.4, 5.1, 1.6 Hz, 1H), 1.99 (ddt, J = 17.8, 9.7, 3.8 Hz, 2H), 1.79 (dddd, J =23.8, 12.7, 9.2, 3.8 Hz, 2H), 1.30 (s, 9H).

[0155] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.1, 175.0, 136.8, 132.2,128.9, 128.7, 128.5, 127.4, 47.7, 44.0, 43.5, 29.4, 28.1, 21.9.

[0156] Example 32 ( RPreparation of methyl 4-(2-oxo-1-pentanoylpiperidin-3-yl)benzoate (compound 3ba) The only difference between this example and Example 1 is that 3-chloro-1-pivaloylpiperidin-2-one (1a, 0.1 mmol) was replaced with 3-chloro-1-pivaloyl-3,4-dihydropyridine-2(1H)-one (1b, 0.1 mmol). The target chiral piperidine compound 3ba was obtained by column chromatography purification. Compound 3ba was a white solid with an enantioselectivity of 99:1 and a yield of 53%. Its synthetic route is as follows:

[0157] .

[0158] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, Chloroform-d) δ7.39 – 7.33 (m, 2H), 7.33 – 7.27 (m, 3H), 6.50 (dd, J = 7.9, 1.7 Hz, 1H), 5.37 (ddt, J = 8.6, 5.6, 2.8 Hz, 1H), 3.86 (t, J = 8.6 Hz, 1H), 2.74 – 2.66(m, 2H), 1.25 (s, 9H).

[0159] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 186.8, 171.5, 137.9, 128.8,128.3, 127.8, 127.4, 107.4, 77.5, 77.2, 76.8, 48.7, 44.0, 29.0, 27.8.

[0160] Example 33 ( R Preparation of methyl 4-(2-oxo-1-pivaloylpiperidin-3-yl)benzoate (compound 3ca) The only difference between this example and Example 1 is that 3-chloro-1-pivaloylpiperidin-2-one (1a, 0.1 mmol) was replaced with 3-chloro-1-pivaloylpyrrolidine-2-one (1c, 0.1 mmol). The target chiral piperidine compound 3ca was obtained by column chromatography purification. Compound 3ca was a white solid with an enantioselectivity of 90:10 and a yield of 95%. Its synthetic route is as follows:

[0161] .

[0162] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.38 (dd, J = 8.2, 6.6 Hz, 2H), 7.31 – 7.23 (m, 3H), 3.98 (ddd, J = 11.5, 8.4, 2.9 Hz, 1H), 3.89 – 3.75 (m,2H), 2.51 (dddd, J = 13.0, 8.8, 7.0, 2.9 Hz, 1H), 2.29 – 2.15 (m, 1H), 1.35(s, 9H).

[0163] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 180.5, 173.8, 138.0, 129.0, 128.1, 127.6, 51.2, 46.1, 41.8, 27.0, 26.2.

[0164] Example 34 ( R Preparation of methyl 4-(2-oxo-1-pentanoylpiperidin-3-yl)benzoate (compound 3da) The only difference between this example and Example 1 is that 3-chloro-1-pivaloylpiperidin-2-one (1a, 0.1 mmol) was replaced with 3-chloro-1-pivaloylazetane-2-one (1d, 0.1 mmol). The target chiral piperidine compound 3da was obtained by column chromatography purification. Compound 3da was a white solid with an enantioselectivity of 95:5 and a yield of 74%. Its synthetic route is as follows:

[0165] .

[0166] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.35 (dd, J = 8.1, 6.7 Hz, 2H), 7.30 – 7.24 (m, 1H), 7.24 – 7.19 (m, 2H), 3.99 – 3.88 (m, 2H), 3.50 (dd, J =15.1, 10.5 Hz, 1H), 2.19 – 2.04 (m, 3H), 2.02 – 1.94 (m, 1H), 1.77 – 1.61 (m, 2H), 1.26 (s, 9H).

[0167] Carbon NMR characterization: 13C NMR (100 MHz, CDCl3) δ 191.0, 177.9, 140.8, 128.5,128.5, 127.1, 52.1, 47.0, 44.2, 31.3, 29.1, 29.0, 28.1.

[0168] Example 35 ( R Preparation of 3-phenyl-1-pentayl-3,4-dihydroquinoline-2(1H)-one (compound 3ea) The only difference between this example and Example 1 is that 3-chloro-1-pivaloylpiperidin-2-one (1a, 0.1 mmol) was replaced with 3-chloro-1-pivaloyl-3,4-dihydroquinoline-2(1H)-one (1e, 0.1 mmol). The target chiral piperidine compound 3ea was obtained by column chromatography purification. Compound 3ea was a white solid with an enantioselectivity of 95:5 and a yield of 68%. Its synthetic route is as follows:

[0169] .

[0170] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.36 – 7.30 (m, 2H), 7.29 –7.18 (m, 5H), 7.07 (td, J = 7.5, 1.1 Hz, 1H), 6.73 (dd, J = 8.0, 1.1 Hz, 1H), 3.88 (dd, J = 10.4, 6.0 Hz, 1H), 3.36 – 3.20 (m, 2H), 1.33 (s, 9H).

[0171] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 188.5, 171.0, 137.3, 137.0,128.8, 128.7, 128.3, 127.9, 127.6, 124.9, 124.2, 115.6, 47.1, 44.7, 33.4,27.9.

[0172] Example 36 ( RPreparation of ethyl piperidine-1-carboxylate (compound 3af)-4-(8-(2-oxo-1-pentanoylpiperidin-3-yl)-5,6-dihydro-11H-benzo[5,6]cycloheptane[1,2-b]pyridine-11-ylidene)piperidine-1-carboxylate (compound 3af) The only difference between this example and Example 1 is that iodobenzene (2a, 0.2 mmol) was replaced with ethyl 4-(8-iodo-5,6-dihydro-11H-benzo[5,6]cycloheptano[1,2-b]pyridin-11-ylidene)piperidine-1-carboxylate (2af, 0.2 mmol). The target chiral piperidine compound 3af was obtained by column chromatography purification. Compound 3af was a white solid with an enantioselectivity of 99:1 and a yield of 95%. The synthetic route is as follows:

[0173] .

[0174] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 4.8 Hz, 1H), 7.42(d, J = 7.6 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.07 (dd, J = 7.7, 4.8 Hz, 1H), 7.00(d, J = 5.4 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.80 (s, 2H), 3.63 (pd, J = 12.4,4.0 Hz, 3H), 3.44 – 3.29 (m, 2H), 3.10 (ddt, J = 13.2, 9.7, 4.9 Hz, 2H), 2.82(p, J = 7.1 Hz, 2H), 2.44 – 2.36 (m, 2H), 2.31 – 2.15 (m, 2H), 1.98 (ddp, J =26.2, 16.8, 4.7 Hz, 4H), 1.26 (s, 12H).

[0175] Carbon NMR characterization: 13C NMR (100 MHz, CDCl3) δ 190.5, 174.3, 157.9, 155.6,146.6, 138.8, 138.7, 137.8, 137.4, 136.9, 135.0, 133.9, 129.9, 122.3, 61.4,50.6, 47.8, 45.0, 44.1, 32.2, 31.6, 31.2, 30.9, 30.8, 29.8, 28.0, 22.6,14.8.

[0176] Example 37 (3) aR 5 R 6 S 6 Ar Preparation of 5-((R)-2,2-dimethyl-1,3-dioxopent-4-yl)-2,2-dimethyltetrahydrofuran[2,3-d][1,3]dioxo-6-yl 4-((R)-2-oxo-1-piperylpiperidin-3-yl)benzoate (compound 3ag) The only difference between this embodiment and Example 1 is that iodobenzene (2a, 0.2 mmol) is replaced with 3 aR 5 R 6 S 6 aR 5-((R)-2,2-dimethyl-1,3-dioxolane-4-yl)-2,2-dimethyltetrahydrofuran[2,3-d][1,3]dioxo-6-yl-4-iodobenzoate (2 ag, 0.2 mmol). The target chiral piperidine compound 3 ag was obtained by column chromatography purification. Compound 3 ag was a white solid with an enantioselectivity of 99:1 and a yield of 95%. The synthetic route is as follows:

[0177] .

[0178] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.1 Hz, 2H), 7.32(d, J = 8.0 Hz, 2H), 5.93 (d, J = 3.6 Hz, 1H), 5.49 (d, J = 2.6 Hz, 1H), 4.59 (d, J=3.7 Hz, 1H), 4.37 – 4.29 (m, 2H), 4.13 – 4.06 (m, 2H), 3.79 – 3.60 (m, 3H), 2.28 – 2.19 (m, 1H), 2.12 – 1.97 (m, 3H), 1.55 (s, 3H), 1.41 (s, 3H), 1.31(s, 3H), 1.27 (s, 12H).

[0179] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.2, 173.5, 165.0, 145.5,130.2, 128.9, 128.6, 112.5, 109.6, 105.3, 83.5, 80.1, 76.7, 72.7, 67.4, 50.8,47.7, 44.1, 30.6, 28.0, 27.0, 26.9, 26.3, 25.3, 22.5.

[0180] Example 38 (3) S )-1-(4-fluorophenyl)-3-((3 R 4 S Preparation of 1-(4-fluorophenyl)-2-oxo-4-(4-((R)-2-oxo-1-pentanoylpiperidin-3-yl)phenyl)azacyclobutane-3-yl)propyl acetate (compound 3ah) The only difference between this embodiment and Example 1 is that iodobenzene (2a, 0.2 mmol) is replaced with ( S )-1-(4-fluorophenyl)-3-((2 S ,3 R 1-(4-fluorophenyl)-2-(4-iodophenyl)-4-oxazolidine-3-yl)propyl acetate (2ah, 0.2 mmol). The target chiral piperidine compound 3ah was obtained by column chromatography purification. Compound 3ah was a white solid with an enantioselectivity of 98:2 and a yield of 38%. The synthetic route is as follows:

[0181] .

[0182] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.26 (s, 8H), 7.02 (t, J = 8.6Hz, 2H), 6.97 – 6.88 (m, 2H), 5.69 (td, J= 6.8, 1.9 Hz, 1H), 4.58 (d, J = 2.3Hz, 1H), 3.78 – 3.53 (m, 4H), 3.06 (tt, J = 7.8, 2.6 Hz, 1H), 2.22 (dd, J = 7.9,4.6 Hz, 1H), 2.05 (s, 3H), 2.04 – 1.91 (m, 4H), 1.90 – 1.80 (m, 2H), 1.27 (d, J = 2.4 Hz, 9H).

[0183] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.4, 174.0, 170.3, 167.1,167.0, 162.6 (d, J = 245.8 Hz), 159.1 (d, J = 241.8 Hz), 140.3, 136.4, 135.8 (d, J = 3.3 Hz), 133.9 (d, J = 2.6 Hz), 129.6 (d, J = 1.8 Hz), 128.4 (d, J = 8.4 Hz),126.2, 118.6, 118.5, 116.1, 115.9, 115.8, 115.5, 75.0, 61.1, 60.2, 50.5,47.8, 44.1, 33.8, 31.0, 28.0, 25.1, 22.6, 21.3.

[0184] Example 39 (1) R ,2 S 5 R Preparation of 2-isopropyl-5-methylcyclohexyl 3-((R)-2-oxo-1-tervaline-piperidin-3-yl)benzoate (compound 3ai) The only difference between this embodiment and Example 1 is that iodobenzene (2a, 0.2 mmol) is replaced with (1 R ,2 S 5 R2-Isopropyl-5-methylcyclohexyl-3-iodobenzoate (2aI, 0.2 mmol). The target chiral piperidine compound 3ah was obtained by column chromatography purification. Compound 3ah was a white solid with an enantioselectivity of 98:2 and a yield of 78%. The synthetic route is as follows:

[0185] .

[0186] Characterization by proton nuclear magnetic resonance (NMR): 1 H NMR (400 MHz, CDCl3) δ 7.99 – 7.90 (m, 2H), 7.44 –7.38 (m, 2H), 4.93 (tt, J = 10.9, 4.1 Hz, 1H), 3.80 – 3.57 (m, 3H), 2.30 – 2.20(m, 1H), 2.16 – 1.78 (m, 6H), 1.75 – 1.69 (m, 2H), 1.59 – 1.49 (m, 2H), 1.27(s, 9H), 1.15 – 1.05 (m, 2H), 0.91 (t, J = 7.0 Hz, 6H), 0.78 (dd, J = 6.9, 1.8Hz, 3H).

[0187] Carbon NMR characterization: 13 C NMR (100 MHz, CDCl3) δ 190.3, 174.0, 166.0, 140.0,133.1, 131.3, 129.7, 128.7, 128.6, 75.0, 50.7, 47.7, 47.3, 44.1, 41.1, 34.4,31.6, 30.8, 28.0, 26.5, 23.7, 22.5, 22.2, 20.9, 16.6.

[0188] It should be noted that when numerical ranges are involved in this invention, it should be understood that both endpoints of each numerical range and any value between the two endpoints can be selected. Since the steps and methods used are the same as in the embodiments, preferred embodiments are described here to avoid redundancy. Although preferred embodiments of the invention have been described, those skilled in the art, once they understand the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments as well as all changes and modifications falling within the scope of this invention.

[0189] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. A method for synthesizing a chiral 3-aryl-2-piperidinone compound, characterized in that, The method comprises the following steps: The reduction coupling reaction is carried out at room temperature in a reaction system formed by an aryl halide compound or a triflate compound, a lactam electrophile compound, a nickel-based catalyst, a chiral bis-imidazole ligand, a metal-based reducing agent, an additive and a solvent under a protective atmosphere to obtain a chiral 3-aryl-2-piperidone compound.

2. The method for synthesizing chiral 3-aryl-2-piperidone compounds according to claim 1, wherein the method for synthesizing 1,3-diboron compounds is characterized by, The molar ratio of the lactam electrophile compound to the aryl halide compound is 0.1:0.2-0.5, and the molar ratio of the lactam electrophile compound to the triflate compound is 0.1:0.2-0.

5.

3. The method of synthesis of chiral 3-aryl-2 piperidinone compounds as claimed in claim 1 wherein, The molar ratio of the lactam compound to the nickel-based catalyst is 0.1:0.01-0.025, the molar ratio of the lactam compound to the ligand is 0.1:0.015-0.03, the molar ratio of the lactam compound to the metal reducing agent is 0.1:0.3-0.5, and the molar ratio of the additive to the lactam compound is 0.1:0.1, the additive is tetrabutylammonium iodide, and the metal-based reducing agent is manganese.

4. The method of synthesis of chiral 3-aryl-2 piperidinone compounds as claimed in claim 1 wherein, The nickel-based catalyst is ethylene glycol dimethyl ether nickel bromide.

5. The method of synthesis of chiral 3-aryl-2 piperidinone compounds as claimed in claim 1 wherein, The structure of the chiral bis-imidazole ligand is shown in the following formula: 。 6. The method of synthesis of chiral 3-aryl-2 piperidinone compounds as claimed in claim 1 wherein, The time of the reduction coupling reaction is 12-24 hours.

7. The method of synthesis of chiral 3-aryl-2 piperidinone compounds as claimed in claim 1 wherein, The lactam electrophile compound is 3-chloro-1-tert-pentanoyl piperidin-2-one, 3-chloro-1-tert-pentanoyl-3,4-dihydropyridin-2(1H)-one, 3-chloro-1-tert-pentanoylazepan-2-one or 3-chloro-1-tert-pentanoyl-3,4-dihydroquinolin-2(1H)-one.

8. The method of synthesis of chiral 3-aryl-2 piperidinone compounds as claimed in claim 1 wherein, The structure of the aryl halide compound is shown in the following formula: or ; wherein R1is benzene, biphenyl, benzothiophene, indole-1-carboxylic acid tert-butyl ester, thiophene, substituted pyridine, substituted phenyl, substituted pyrimidine, , , or ; is a linking site; The substituent of the phenyl group is selected from halogen, C2-C3 alkenyl, -R3COOR4, -NHR3COOR4, -R3COR4, cyano, C1-C3 aldehyde, C1-C3 trifluoroalkoxy, C2-C3 alkynylsilane, C1-C4 alkyl, C1-C4 alkoxy, C1-C3 alkylthio or dioxolane, R3 is C1-C3 alkyl, and R4 is C1-C4 alkyl; The substituent of the pyridine is selected from halogen and C1-C4 alkoxy; The substituent of the pyrimidine is selected from C1-C4 alkoxy; R2 is indene or C2-C3 alkenyl phenyl, and the alkenyl in the indene or C2-C3 alkenyl phenyl is a connection site.

9. The method of synthesis of chiral 3-aryl-2 piperidinone compounds as claimed in claim 1, wherein, The triflate compound is cyclohex-1-en-1-yl trifluoromethanesulfonate.

10. The method of synthesis of chiral 3-aryl-2 piperidinone compounds as claimed in claim 8 wherein, The aryl halogenated compounds are iodobenzene, p-fluoroiodobenzene, p-chloroiodobenzene, p-iodostyrene, methyl p-iodobenzoate, p-iodobenzonitrile, p-iodobenzaldehyde, 1-iodo-4-trifluoromethoxybenzene, ((4-iodophenyl)ethynyl)trimethylsilane, 4-iodo-1,1'-biphenyl, 1-iodo-4-methylbenzene, 1-(tert-butyl)-4-iodobenzene, 1-iodo-4-methoxybenzene, (4-iodophenyl)(methyl)thion, (4-iodophenyl)carbamate tert-butyl ester, 1-iodo-3-methoxybenzene, 2-iodonaphthalene, 1-(3-iodophenyl)-1-ethyl ketone, and 1-iodo-3,4-methylenedioxybenzene. 1-Iodo-2-methylbenzene, 4-Iododibenzo[b,d]thiophene, 5-Iodo-1H-indole-1-carboxylic acid tert-butyl ester, 3-Iodothiophene, 2-Fluoro-4-iodopyridine, 5-Iodo-2-methoxypyridine, 2-Chloro-6-iodopyridine, 5-Iodo-2-methoxypyrimidine, cyclohexyl-1-en-1-yl trifluoromethanesulfonate, 2-Bromo-1H-indene, 3-Bromo-1,2-dihydronaphthalene, (2-bromovinyl)benzene, 4-(8-Iodo-5,6-dihydro-11H-benzo[5,6]cycloheptano[1,2-b]pyridin-11-ylidene)piperidine-1-carboxylic acid ethyl ester, (3 aR 5 R 6 S 6 aR )-5-(( R )-2,2-dimethyl-1,3-dioxolane-4-yl)-2,2-dimethyltetrahydrofuran[2,3-d][1,3]dioxol-6-yl-4-iodobenzoate, ( S )-1-(4-fluorophenyl)-3-((2 S ,3 R )-1-(4-fluorophenyl)-2-(4-iodophenyl)-4-oxazolidine-3-yl)propyl acetate or (1 R ,2 S 5 R )-2-isopropyl-5-methylcyclohexyl-3-iodobenzoate.

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