Carboxy proline compound and preparation method of γ-nitro carbonyl compound using the same

Abstract

The present invention relates to a carboxyproline compound of a novel structure and a method for efficiently producing gamma nitrocarbonyl compounds that are widely present in natural products and pharmaceuticals with biological activity by applying the same as a catalyst. More specifically, the invention relates to a method for producing chiral gamma nitrocarbonyl compounds with improved stereoselectivity by performing an asymmetric Michael addition reaction between an aldehyde compound and a nitroalkene compound using a carboxyproline compound of a carbonate structure having a prolinamide bond as a catalyst.

Description

Technology Field

[0001] The present invention relates to a carboxyproline compound of a novel structure and a method for efficiently producing a gamma nitrocarbonyl compound, which is widely present in natural products and pharmaceuticals and possesses biological activity, by applying the same as a catalyst. Background Technology

[0002] Asymmetric synthesis is a technique that synthesizes compounds with asymmetric chemical structures, starting from symmetric molecular structures found in biology. This technique utilizes specific chemical reactions to control the types of atoms and bonds, thereby precisely controlling the structure of target molecules and enabling the synthesis of compounds with superior chemical and biological activity.

[0003] Furthermore, asymmetric synthesis is a central task of modern synthetic chemistry, and in particular, the synthesis of optically pure drugs has become an essential requirement for the development of new drugs.

[0004] Although metal catalysts are most widely used for carbon-carbon bond formation and asymmetric synthesis, which are fundamental to all organic synthesis, the excess metal waste generated by these catalysts poses problems such as environmental pollution, toxicity, and risks. Furthermore, the process of synthesizing asymmetric metal complexes is cumbersome and costly, making it uneconomical.

[0005] Gamma-nitrocarbonyl compounds serve as important intermediates in asymmetric synthesis. Since they can be further modified into chiral pyrrolidines, gamma butyrolactones, gamma amino acids, or tetrahydropyrans, they are widely used in the synthesis of useful compounds, particularly amino acids, proteins, antibiotics, and biologically active substances, including pharmaceuticals. A suitable catalyst is used to induce a reaction in a symmetric compound, thereby transforming it into an asymmetric compound. The selection of the catalyst plays a crucial role in this process.

[0006] Gamma nitrocarbonyl compounds can be produced through an asymmetric Michael addition reaction between aldehydes and nitroalkenes, which is used as a practical strategy for forming carbon-carbon bonds.

[0007] Meanwhile, organic catalysts generally have the advantages of not requiring long reaction times, being easy to mass-produce, and having high biological compatibility. Due to these advantages, organic catalysts are used in many asymmetric syntheses and are also widely used in the synthesis of gamma-nitrocarbonyls.

[0008] Since List et al. reported on the intermolecular aldol reaction using proline as an organic catalyst in J. Am. Chem. Soc. 2000, 122, 2395-2396, research on the application of proline has been steadily conducted. However, it still has problems such as limited reactivity due to the low solubility of proline in organic solvents and low selectivity, particularly in the case of aromatic aldehydes, due to the presence of potential side reactions.

[0009] Gamma-nitrocarbonyl compounds are very important structures used as cores for various pharmaceuticals, and new methods for manufacturing them are continuously required.

[0010] Accordingly, the inventors synthesized a carboxyproline compound of a carbonate structure having a proline amide bond of a specific structure, and confirmed that when applied as a catalyst for an asymmetric Michael addition reaction between an aldehyde compound and a nitroalkene compound, a chiral gamma nitrocarbonyl compound with improved stereoselectivity is efficiently produced in high yield, thereby completing the present invention. Prior art literature

[0011] J. Am. Chem. Soc. 2000, 122, 2395-2396. The problem to be solved

[0012] The present invention aims to provide a carboxyproline compound of a novel structure.

[0013] In addition, the present invention aims to provide a method for preparing a chiral gamma nitrocarbonyl compound with improved stereoselectivity by applying the carboxyproline compound as a catalyst for an asymmetric Michael addition reaction between an aldehyde compound and a nitroalkene compound. means of solving the problem

[0014] The present invention provides a carboxyproline compound represented by the following chemical formula 1:

[0015] [Chemical Formula 1]

[0016]

[0017] In the above chemical formula 1,

[0018] L 1 is a C2-C10 alkylene or a C3-C10 cycloalkylene, and the L 1 The alkylene and cycloalkylene of may be further substituted with one or more selected from the group consisting of C1-C10 alkyl, halo-C1-C10 alkyl, C6-C20 aryl-C1-C10 alkyl, C6-C20 aryl, and C3-C20 heteroaryl;

[0019] L 2 is C2-C10 alkenylene, C6-C20 arylene, or C3-C20 heteroarylene, and the above L 2 The alkenylene, arylene, and heteroarylene of may be further substituted with one or more selected from the group consisting of halogen, C1-C10 alkyl, halo-C1-C10 alkyl, C6-C20 aryl-C1-C10 alkyl, C6-C20 aryl, and C3-C20 heteroaryl;

[0020] The above heteroarylene and heteroaryl comprise one or more heteroatoms selected from N, O and S;

[0021] * means stereogenic center.

[0022] In addition, the present invention provides a method for preparing a chiral gamma nitrocarbonyl compound represented by Formula 3 by performing an asymmetric 1,4-Michael addition reaction of an aldehyde compound represented by Formula 4 and a nitroalkene compound represented by Formula 5 using a carboxyproline compound represented by Formula 1 as a catalyst:

[0023] [Chemical Formula 3]

[0024]

[0025] [Chemical Formula 4]

[0026]

[0027] [Chemical Formula 5]

[0028]

[0029] In the above chemical formulas 11 to 13,

[0030] R a is a C1-C10 alkyl, C3-C10 cycloalkyl, or C6-C20 aryl C1-C10 alkyl;

[0031] R b is a C6-C20 aryl or a C3-C20 heteroaryl, and the above R b The aryl and heteroaryl groups may be further substituted with one or more selected from the group consisting of C1-C10 alkoxy, C1-C10 alkyl, halo-C1-C10 alkyl, hydroxyl, and halogen;

[0032] * means stereogenic center. Effects of the invention

[0033] A carboxyproline compound of a specific structure according to the present invention can be applied as a catalyst in an asymmetric 1,4-Michael addition reaction to achieve enhanced hydrogen bonding.

[0034] According to the present invention, by using a carboxyproline compound of a carbonate structure having a specific structure structurally controlled to significantly improve reactivity as a catalyst for an asymmetric 1,4-Michael addition reaction between an aldehyde compound and a nitroalkene compound, a chiral gamma nitrocarbonyl compound having a syn stereochemistry can be efficiently produced in high yield with enhanced stereoselectivity.

[0035] In addition, the method for producing gamma nitro compounds according to the present invention efficiently produces gamma nitro carbonyl compounds that are widely present in natural products and pharmaceuticals with biological activity, and thus has very high industrial utility value for the production of various pharmaceutical products. Furthermore, various chiral gamma nitro carbonyl compounds produced through the present invention can be used to synthesize stereochemically or pharmaceutically useful chiral compounds according to conventional processes. Specific details for implementing the invention

[0036] The present invention will be described in detail below. Unless otherwise defined, technical and scientific terms used herein have the meaning commonly understood by those skilled in the art to which this invention pertains. Furthermore, repetitive descriptions of technical configurations and operations identical to those of the prior art will be omitted. Additionally, while preferred methods or samples are described in this specification, similar or equivalents are also included within the scope of the present invention.

[0037] Throughout this specification, unless otherwise required by the context, the terms “comprising” and “comprising” should be understood to imply that the presented steps or components, or groups of steps or components, are included, but any other steps or components, or groups of steps or components are not excluded.

[0038] In this specification, "room temperature" means a temperature of 20±5℃.

[0039] The terms "substituent," "radical," "group," "moiety," and "fragment" in this specification may be used interchangeably.

[0040] The term "C" in this specification A -C B " means that the number of carbon atoms is A or more and B or less.

[0041] The term “alkyl” in this specification means a monovalent straight-chain or broken-chain saturated hydrocarbon radical composed only of carbon and hydrogen atoms. The alkyl may have 1 to 10 carbon atoms, 1 to 7 carbon atoms, 1 to 4 carbon atoms, or 1 to 4 carbon atoms. The alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, ethylhexyl, etc.

[0042] The term "cycloalkyl" in this specification refers to a monovalent saturated or unsaturated carbocyclic radical composed of one or more rings, which is not aromatic. The cycloalkyl may be monocyclic or a fused, spiro, or cross-linked bicyclic ring system. The cycloalkyl may have 3 to 10, preferably 3 to 8, and more preferably 3 to 7 carbon atoms. Specifically, a monocyclic cycloalkyl ring comprises 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms, in the ring. A bicyclic cycloalkyl ring comprises 6 to 10 carbon atoms, preferably 7 to 9 carbon atoms, in the ring. A preferred bicyclic cycloalkyl ring comprises a 4-, 5-, or 6-membered ring fused to a 5- or 6-membered ring. Specific examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0043] The term “aryl” in this specification refers to an organic radical of monovalent aromatic ring derived from an aromatic hydrocarbon by the removal of one hydrogen, comprising a single or fused ring system having, suitably, 4 to 7, preferably 5 or 6 ring atoms in each ring, and including forms in which multiple aryls are connected by single bonds. Specific examples include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, etc.

[0044] The term “heteroaryl” in this specification refers to an aryl group comprising 1 to 4 heteroatoms selected from N, O, and S as aromatic ring backbone atoms, wherein the remaining aromatic ring backbone atoms are carbons, and is a 5 to 6-membered monocyclic heteroaryl, and a polycyclic heteroaryl condensed with one or more benzene rings. Additionally, the heteroaryls in the present invention also include a form in which one or more heteroaryls are connected by single bonds. Specific examples include, but are not limited to, monocyclic heteroaryls such as furyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, isoxazolyl, oxazolyl, and pyridyl; polycyclic heteroaryls such as benzofuranyl, dibenzofuranyl, dibenzothiopheyl, benzothiophenyl, isobenzofuranyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzoxazolyl, quinolyl, isoquinolyl, and carbazolyl.

[0045] The terms “halo” or “halogen” in this specification refer to halogen elements, including, for example, fluoro, chloro, bromo, and iodo.

[0046] In this specification, the term “nitro” means -NO2, and “hydroxy” means -OH.

[0047] The term “alkoxy” in this specification means -O-alkyl radical, where “alkyl” is defined as above. Specific examples include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, t-butoxy.

[0048] The term “arylalkyl” in this specification means an alkyl radical substituted with at least one aryl, wherein “alkyl” is defined as above. Examples of such arylalkyl radicals include, but are not limited to, benzyl.

[0049] The term “haloalkyl” in this specification means an alkyl radical substituted with at least one halogen, wherein “alkyl” is defined as above. Examples of such haloalkyl radicals include, but are not limited to, fluoromethyl, trifluoromethyl, bromomethyl, perfluoroethyl, etc.

[0050] The present invention provides a proline isothiouronum salt compound of a novel structure.

[0051] [Chemical Formula 1]

[0052]

[0053] In the above chemical formula 1,

[0054] L 1 is a C2-C10 alkylene or a C3-C10 cycloalkylene, and the L 1 The alkylene and cycloalkylene of may be further substituted with one or more selected from the group consisting of C1-C10 alkyl, halo-C1-C10 alkyl, C6-C20 aryl-C1-C10 alkyl, C6-C20 aryl, and C3-C20 heteroaryl;

[0055] L 2 is C2-C10 alkenylene, C6-C20 arylene, or C3-C20 heteroarylene, and the above L 2The alkenylene, arylene, and heteroarylene of may be further substituted with one or more selected from the group consisting of halogen, C1-C10 alkyl, halo-C1-C10 alkyl, C6-C20 aryl-C1-C10 alkyl, C6-C20 aryl, and C3-C20 heteroaryl;

[0056] The above heteroarylene and heteroaryl comprise one or more heteroatoms selected from N, O and S;

[0057] * means stereogenic center.

[0058] In one embodiment, L in Formula 1 1 is a C3-C8 cycloalkylene, and the above L 1 The cycloalkylene of may be further substituted with one or more selected from the group consisting of C1-C6 alkyl and halo-C1-C6 alkyl.

[0059] In one embodiment, L in Formula 1 2 is C2-C6 alkenylene or C6-C12 arylene, and the above L 2 The alkenylene and arylene of may be further substituted with one or more selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C6-C12 aryl-C1-C6 alkyl, and C6-C12 aryl.

[0060] In a preferred embodiment, L in Formula 1 1 It can be selected from the following structures.

[0061]

[0062] In a preferred embodiment, L in Formula 1 2 It can be selected from the following structures.

[0063]

[0064] In the above,

[0065] R 1 and R 2Each is independently hydrogen, C1-C4 alkyl, halo-C1-C4 alkyl, C6-C12 aryl-C1-C4 alkyl, or C6-C12 aryl;

[0066] R 3 and R 4 Each is independently a halogen, C1-C4 alkyl, haloC1-C4 alkyl, or C6-C12 aryl;

[0067] a is an integer from 0 to 4, b is an integer from 0 to 6, and c and d are each independently integers from 0 to 3.

[0068] In one embodiment, the carboxyproline compound may be more specifically selected from the following structures, but is not limited thereto.

[0069]

[0070] According to the present invention, the carboxyproline compound can be used as a catalyst to produce a compound having a desired stereochemical structure through a stereoselective reaction.

[0071] In addition, the present invention relates to a method for efficiently producing a gamma nitrocarbonyl compound that is widely present in natural products and pharmaceuticals having biological activity by applying the above-mentioned carboxyproline compound as a catalyst. More specifically, the invention provides a method for producing a chiral gamma nitrocarbonyl compound represented by Chemical Formula 3 by performing an asymmetric 1,4-Michael addition reaction of an aldehyde compound represented by Chemical Formula 4 and a nitroalkene compound represented by Chemical Formula 5 using the above-mentioned carboxyproline compound as a catalyst.

[0072] [Chemical Formula 3]

[0073]

[0074] [Chemical Formula 4]

[0075]

[0076] [Chemical Formula 5]

[0077]

[0078] In the above chemical formulas 3 to 5,

[0079] R a is a C1-C10 alkyl, C3-C10 cycloalkyl, or C6-C20 aryl C1-C10 alkyl;

[0080] R b is a C6-C20 aryl or a C3-C20 heteroaryl, and the above R b The aryl and heteroaryl groups may be further substituted with one or more selected from the group consisting of C1-C10 alkoxy, C1-C10 alkyl, halo-C1-C10 alkyl, hydroxyl, and halogen;

[0081] * means stereogenic center.

[0082] According to the present invention, a chiral gamma nitrocarbonyl compound having a syn stereochemistry can be effectively produced by using a carboxyproline compound of Formula 1 as a catalyst in the asymmetric 1,4-Michael addition reaction of an aldehyde compound and a nitroalkene compound.

[0083] Specifically, the terminal carboxyl group of the above carboxyproline compound acts as a hydrogen bond donor, and the terminal proline forms an enamine, enabling the production of gamma nitrocarbonyl compounds in high yield with enhanced stereoselectivity in asymmetric reactions through electron donating action.

[0084] That is, the proline terminus of the above carboxyproline compound forms an enamine with the carbonyl group of the aldehyde, and enhances the electrophilicity of the carbonyl group through hydrogen bonding between the OH of the terminal carboxyl group and the nitro of the nitroalkene compound, thereby enabling the preparation of a gamma nitroaldehyde compound; and through a Michael addition reaction possessing excellent stereoselectivity between the aldehyde compound bonded to the proline moiety of the above carboxyproline compound and the nitroalkene compound exhibiting enhanced electrophilicity through hydrogen bonding with the OH of the terminal carboxyl group, as shown in Reaction Scheme 1 below which simulates the transition state syn Gamma nitrocarbonyl compounds having stereochemistry can be prepared.

[0085] [Reaction Equation 1]

[0086]

[0087] In one embodiment, R in Formula 4 a It may be a C1-C10 alkyl or a C6-C12 aryl C1-C10 alkyl, specifically methyl, ethyl, propyl, butyl, pentyl, hexyl, or benzyl.

[0088] In one embodiment, R in Formula 5 b is a C6-C12 aryl or a C3-C12 heteroaryl, and the above R b The aryl group of may be further substituted with one or more selected from the group consisting of C1-C10 alkoxy, C1-C10 alkyl, hydroxy, and halogen. Specifically, R b It may be phenyl, naphthyl, chlorophenyl, bromophenyl, dichlorophenyl, dibromophenyl, hydroxyphenyl, methylphenyl, methoxyphenyl, furyl, thienyl, or pyridinyl.

[0089] In one embodiment, the gamma nitro carbonyl compound may be more specifically selected from the following compounds, but is not limited thereto.

[0090]

[0091] In the above, Ph means phenyl and Bn means benzyl.

[0092] In one embodiment, the carboxyproline compound can be used as a catalyst for an asymmetric 1,4-Michael addition reaction in a range of 1 to 50 mol%, preferably 5 to 20 mol%, per 1 mole of the nitroalkene compound of Formula 5, and is more preferable in terms of reactivity, stereoselectivity, and yield within the above range.

[0093] In one embodiment, the aldehyde compound of Formula 4 can be used in a range of 1 to 10 moles, preferably 2 to 5 moles, per 1 mole of the nitroalkene compound of Formula 5, and is more preferable in terms of reactivity and yield within the above range.

[0094] In one embodiment, a base may be further included to prepare a chiral gamma nitro carbonyl compound with improved stereoselectivity, and the stereoselectivity of the chiral gamma nitro carbonyl compound may be further improved due to the addition of the base.

[0095] The above base may be one or more from the group consisting of 4-methylmorpholine (NMM), N-ethylmorpholine (NEM), triethylamine (TEA), 4-dimethylaminopyridine (DMAP), and diisopropylethylamine (DIPEA), and 4-methylmorpholine (NMM) may preferably be used for improved reactivity and stereoselectivity.

[0096] The above base can be used in a range of 1 to 30 mol%, preferably 5 to 20 mol%, per 1 mole of the nitroalkene compound of Formula 5.

[0097] In one embodiment, the reaction may be carried out under an organic solvent, and there is no need to limit the organic solvent as long as it is capable of dissolving the reactant.

[0098] Specifically, the solvent may be one or more selected from dichloromethane (DCM), dichloroethane (DCE), chloroform, dimethoxyethane (DME), tetrahydrofuran (THF), diethyl ether, and toluene, and dichloromethane or chloroform may be used as a solvent in terms of reducing reaction time and improving stereoselectivity.

[0099] In one embodiment, the asymmetric 1,4-Michael addition reaction may be carried out under a nitrogen atmosphere at 1 to 35°C, preferably 15 to 25°C, and the reaction time may vary depending on the type and amount of reactants and solvents. The reaction is completed after confirming the consumption of the starting material and the simultaneous formation of the product through TLC or the like. Once the reaction is completed, the solvent is distilled under reduced pressure, and the target product can be separated and purified through conventional methods such as column chromatography or recrystallization.

[0100] The chiral gamma nitrocarbonyl compound of Formula 3 produced by the manufacturing method according to the present invention can be widely and usefully utilized as a key structure in the field of natural products and pharmaceuticals having physiological activity, and as an important raw material or intermediate in the field of medicinal chemistry.

[0101] The configuration of the present invention will be explained in more detail below through examples, but the following examples are intended to aid in understanding the present invention and the scope of the present invention is not limited thereto.

[0102] [Example 1] Preparation of Carboxyproline Compound (Cat 1)

[0103]

[0104] Preparation of Compound B

[0105] Amine compound A (1.60 mmol) containing a Boc-proline group, known by synthesis method (J. Am. Chem. Soc. 2015, 137, 36, 11582-11585), tetrabromophthalic anhydride (TBPA) (1.76 mmol), and triethylamine (TEA) (1.76 mmol) were dissolved in dry THF and reacted for one day at room temperature with stirring. After the reaction was complete, the solvent of the reaction mixture was removed under reduced pressure, and the resulting residue was purified by flash chromatography (DCM : MeOH = 9 : 1) to obtain compound B (0.95 g, 75%).

[0106] 1 H NMR (400 MHz, CDCl3) δ 7.80 (dt, J = 7.8, 3.7 Hz, 1H), 7.75 - 7.58 (m, 1H), 4.47 (dd, J = 7.2, 5.2 Hz, 1H), 4.34 - 4.10 (m, 1H), 4.06 - 3.89 (m, 1H), 3.73 - 3.43 (m, 2H), 3.44 - 3.09 (m, 2H), 2.47 (tt, J = 13.2, 7.2 Hz, 1H), 2.23 - 1.53 (m, 16H), 1.52 - 1.38 (m, 9H), 1.38 - 0.99 (m, 9H).

[0107] Preparation of carboxyproline compound (cat 1)

[0108] Compound B was added to trifluoroacetic acid (20% TFA in DCM) and reacted for 2 hours, after which the solvent was removed under reduced pressure to obtain a yellow solid carboxyprolphin compound (cat 1) (0.77 g, yield 70%).

[0109] 1H NMR (300MHz, DMSO): δ 9.51 (s, 1H), 8.62 (dd, J = 32.9, 11.4 Hz, 1H), 7.98 (s, 2H), 4.13 (dd, J = 9.9, 4.4 Hz, 1H), 3.74 - 3.50 (m, 1H), 3.22 (dq, J = 12.5, 6.3 Hz, 1H), 3.01 (dd, J = 10.6, 5.4 Hz, 1H), 2.23 (ddd, J = 13.4, 8.4, 6.7 Hz, 1H), 2.16 - 1.98 (m, 1H), 1.98 - 1.54 (m, 4H), 1.54 - 1.01 (m, 4H).

[0110] [Example 2] Asymmetric 1,4-Michael addition reaction using carboxyproline compound (cat 1) I

[0111] To determine the extent of the asymmetric 1,4-Michael addition reaction according to reaction conditions, an experiment was conducted as follows.

[0112]

[0113] In a 10 ml vial, a solvent (0.2 mL), propionaldehyde (1.02 mmol, 3 eq), trans-beta-nitrostyrene (0.34 mmol, 1 eq), a carboxyproline compound (cat 1) (5 mol%), and a base (0 eq or 5 mol%) were added, respectively, and then reacted at room temperature. After the reaction was finished, the solvent was removed under reduced pressure, and the resulting residue was purified by flash chromatography (n-hexane : ethyl acetate = 9 : 1) to obtain the product.

[0114] Table 1 below lists the product yield, diasteromeric ratio (dr), and enantiomeric excess (ee) values ​​according to the type of solvent and reaction time.

[0115] Examples 0.5 M solvent Reaction temperature (°C) Reaction time (hr) transference number(%) syn:anti(dr) ee(%) 2-1 Chloroform 25 16 89 2.5 88 2-2 Toluene 25 24 85 2.1 : 1 87 2-3 DCM 25 16 95 4.5 : 1 92 2-4 THF 25 16 91 2.2 : 1 85 2-5 i-PrOH 25 3 99 1.9 : 1 75 2-6 water 25 48 85 2.4 : 1 64 2-7 DCM : i-PrOH9 : 1 25 3 99 2.0 : 1 86 2-8 DCM : i-PrOH99 : 1 25 16 95 2.7 : 1 77 2-9 DCM 25 16 80 2.0 : 1 83 2-10 DCM -10 48 95 3.9 : 1 79 2-11 DCM -25 96 52 1.9 : 1 83

[0116] [Example 3] Asymmetric 1,4-Michael Addition Reaction II Using Carboxyproline Compound (Cat 1)

[0117]

[0118] An aldehyde compound (1.02 mmol, 3 eq), a trans-beta-nitroalkene compound (0.34 mmol, 1 eq), a carboxyproline compound (cat 1) (5 mol%), and 4-methylmorpholine (NMM) (5 mol%) were dissolved in DCM (5 mL) and stirred at room temperature. After the reaction was finished, the solvent was removed under reduced pressure, and the resulting residue was purified by flash chromatography (n-hexane : ethyl acetate = 9 : 1) to obtain the target compound, a gamma nitrocarbonyl compound.

[0119] Various gamma nitrocarbonyl compounds were obtained using the method described above, as shown in Table 2 below.

[0120] Examples R a R b Reaction time (h) transference number (%) Dr ( syn / anti ) ee (%) 3-1 Me Ph 16 95 4.5:1 92 3-2 Et Ph 24 98 5.9:1 98 3-3 n-Pr Ph 36 72 5.6:1 99 3-4 Bn Ph 24 85 4.0:1 87 3-5 Me 4-ClPh 12 98 3:1 78 3-6 Me 4-BrPh 16 95 1.8:1 83 3-7 Me 2-BrPh 16 93 1.6:1 78 3-8 Me 3-BrPh 16 86 1.9:1 77 3-9 Me 4-ClPh 16 85 2.6:1 88 3-10 Me 4-HOPh 24 75 4.1:1 75 3-11 Me 4-MePh 24 75 1.7:1 95 3-12 Me 4-MeOPh 24 90 1.8:1 68 3-13 Me 2-Furyl 16 98 1.7:1 90 3-14 Et 4-BrPh 16 98 4.1:1 92 3-15 Et 4-MePh 24 95 10.6:1 85

[0121] The structure and identification data of the compound prepared in Example 3 above are listed in Table 3 below.

[0122] Examples structure 1 H NMR, HPLC column 3-1 1 H-NMR ( δ , CDCl3) 1.00 ppm (d, J = 7.2Hz, 3 H), 2.70 (m, 1 H), 3.74 (ddd, J = 9.3, 9.1, 5.4 Hz, 1 H), 4.63 (dd, J = 12.6, 9.3 Hz, 1 H), 4.71 (dd, J = 12.6, 5.4 Hz, 1 H), 7.09 (m, 2 H), 7.26 (m, 3 H), 9.62 (d, J = 1.5 Hz, 1 H) 13 C-NMR ( δ , CDCl3) 12.2, 44.1, 48.5, 78.1, 128.1, 128.2, 129.1, 136.6, 202.3 HPLC Column : chiralpak IC-3, 9 / 1 hexane / i -PrOH, flow rate 0.8 mL / min, tr (syn, minor) = 22.18 min, tr (syn, major) = 25.40 min. 3-2 %; 1 H-NMR ( δ , CDCl3) 0.83 ppm (t, J = 7.5 Hz), 1.50 (m, 2 H), 2.67 (dddd, J = 10.2, 7.5, 4.5, 2.5 Hz, 1 H), 3.79 (ddd, J = 9.8, 9.8, 4.8 Hz, 1 H), 4.66 (dd, J = 12.7, 9.7 Hz, 1 H), 4.71 (dd, J = 12.7, 4.9 Hz, 1 H), 7.19 (m, 2 H), 7.34 (m, 3 H), 9.72 (d, J = 2.6 Hz, 1 H) 13 C-NMR ( δ , CDCl3) 10.7, 20.4, 42.7, 55.0, 78.6, 128.0, 128.1, 129.1, 136.8, 203.3 . ;HPLC Column : chiralpak IC-3, 9 / 1 hexane / i -PrOH, flow rate 0.8 mL / min, tr (major) = 20.75 min, tr (minor) = 39.65 min. 3-3 %; 1 H-NMR ( δ , CDCl3) 0.80 (dd, J = 7.1 , 7.1 Hz, 3H), 1.34 (m, 3H), 1.48 (m, 1H), 2.70 (dd, J = 9.4, 9.4 Hz, 1H), 3.78 (ddd, J = 9.6, 9.6, 5.2 Hz, 1H), 4.67 (dd, J = 12.8, 9.3 Hz, 2H), 4.70 (dd, J = 12.8, 5.2 Hz, 2H), 7.18 (d, J = 7.5 Hz, 2H), 7.21 (dd, J = 7.3, 7.3 Hz, 1H), 7.33 (dd, J = 7.9, 6.8 Hz, 2H), 9.71 (d, J = 2.5 Hz); 13 C-NMR ( δ , CDCl3) 13.9, 19.8, 29.5, 43.2, 53.8, 78.4, 128.0, 128.2, 129.1, 136.8, 203.3 ppm. ;HPLC Column : chiralpak IC, 9 / 1 hexane / i -PrOH, flow rate 0.8 mL / min, tr (major) =18.90 min, tr (minor) = 21.73 min. 3-4 1 H-NMR ( δ , CDCl3) 2.77 (m, 2 H), 3.12 (dddd, J = 11.2, 11.1, 5.5, 2.1 Hz, 1 H), 3.83 (ddd, J = 8.8, 8.8, 5.9 Hz, 1 H), 4.72 (m, 2H), 7.26 (m, 10H), 9.72 (d, J = 2.2 Hz, 1 H) 13 C-NMR ( δ , CDCl3) 33.2, 42.4, 54.3, 77.0, 127.0, 127.4, 127.7, 127.8, 128.3, 128.5, 135.6, 136.1, 202.1 ppm. ;HPLC Column : chiralpak IC-3, 9 / 1 hexane / i -PrOH, flow rate 0.6 / min, tr (major) = 20.52 min, tr (minor) = 23.17 min. 3-5 1 H-NMR ( δ , CDCl3) 1.00 (d, J = 7.3 Hz, 3H), 2.75 (m, 1H), 3.83 (ddd, J = 9.3, 9.3, 5.2 Hz, 1H), 4.65 (dd, J = 12.8, 9.7 Hz, 1H), 4.79 (dd, J = 12.8, 5.2 Hz, 1H), 7.13 (m, 2H), 7.33 (m, 2H), 9.70 (d, J = 1.4 Hz, 1H); 13 C-NMR ( δ , CDCl3) 12.2, 43.4, 48.3, 77.9, 129.3, 129.5, 134.1, 135.2, 201.9 ppm. ;HPLC Column : chiralpak IC-3, 9 / 1 hexane / i -PrOH, flow rate 1.2 mL / min, tr (major) = 24.1 min, tr (minor) = 25.0 min). 3-6 1 H-NMR ( δ , CDCl3) 1.00 (m, 3H), 2.76 (m, 1H), 3.80 (ddd, J = 9.2, 9.2, 5.1 Hz, 1H), 4.65 (dd, J = 12.8, 9.7 Hz, 1H), 4.77 (dd, J = 12.8, 5.2 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 7.48 (m, 2H), 9.70 (d, J = 1.2 Hz, 1H); 13 C-NMR ( δ , CDCl3) 12.2, 43.5, 48.2, 77.8, 122.2, 129.8, 132.3, 135.7, 201.8 ppm. ;HPLC Column : chiralpak IC-3, 9 / 1 hexane / i -PrOH, flo rate 0.8 mL / min, tr (major) = 24.08 min, tr (minor) = 25.73 min). 3-7 1 H-NMR ( δ , CDCl3) 1.05 (d, J = 7.4 Hz, 3H), 2.98 (m, 1H), 4.44 (m, 1H), 4.79 (m, 2H), 7.20 (m, 2H), 7.30 (m, 1H), 7.61 (m, 1H), 9.74 (m, 1H); 13 C-NMR ( δ , CDCl3) 12.3, 36.2., 48.0, 75.4, 128.1, 129.5, 133.9, 134.0, 201.9 ppm. ;HPLC Column : chiralpak IC-3, 9 / 1 hexane / i -PrOH, flow rate 0.8 mL / min, tr (major) = 24.12min, tr (minor) = 25.65 min). 3-8 %; 1 H-NMR ( δ , CDCl3) 1.01 (m, 3H), 2.78 (m, 1H), 3.78 (m 2H), 4.76 (m, 2H), 7.36 (m, 4H), 9.69 (d, J = 1.2 Hz, 1H); 13 C-NMR ( δ , CDCl3) 12.3, 25.3, 43.6, 48.2, 77.8, 123.2, 126.8, 130.7, 131.2, 131.4, 139.1, 201.8 ppm. ;HPLC Column : chiralpak IC-3, 9 / 1 hexane / i -PrOH, flow rate 0.8 mL / min, tr (major) = 23.23 min, tr (minor) = 26.47 min. 3-9 1 H-NMR ( δ , CDCl3) 1.00 (d, J = 7.3 Hz, 3H), 2.98 (m, 1H), 4.31 (m, 1H),4.81 (m, 2H), 7.17 (m, 1H), 7.26 (m, 1H), 7.45 (m, 1H), 9.73 (d, J = 1.4 Hz, 1H); 13 C-NMR ( δ , CDCl3) 12.3, 47.6., 47.7, 76.4, 127.9, 130.4, 133.2, 134.5, 201.5 ppm. ;HPLC Column : chiralpak IC-3, 9 / 1 hexane / i -PrOH, flow rate 0.8 mL / min, tr (major) = 14.75 min, tr (minor) = 18.68 min. 3-10 1 H-NMR ( δ , CDCl3) 1.03 (m, 3H), 2.75 (s, 1H), 3.78 (m, 1H), 4.71 (m, 2H), 4.68 (mz, 2H), 6.81 (m, 2H), 7.05 (m, 2H), 9.73 (d, J = 1.3 Hz, 1H); 13 C-NMR ( δ , CDCl3) 12.1, 43.4, 48.6, 78.3, 116.0, 129.3, 155.4, 202.6 ppm. ;HPLC Column : chiralpak IC-3, 9 / 1 hexane / i -PrOH, flow rate 0.8 mL / min, tr (major) = 18.15 min, tr (minor) = 19.70 min). 3-11 1 H-NMR ( δ , CDCl3) 0.92 (d, J = 7.3 Hz, 3H), 2.25 (s, 3H), 2.69 (m, 1H), 3.71 (m, 1H), 4.68 (mz, 2H), 7.02 (m, 4H), 9.64 (d, J = 1.3 Hz, 1H); 13 C-NMR ( δ , CDCl3) 12.1, 21.1, 43.7, 48.5, 78.2, 127.9, 129.8, 133.4, 137.9, 202.5 ppm. ;HPLC Column : chiralpak IC-3, 9 / 1 hexane / i -PrOH, flow rate 0.8 mL / min, tr (major) = 23.63 min, tr (minor) = 24.45 min. 3-12 1 HNMR ( δ , CDCl3) 1.00 (d, J = 7.2 Hz, 3 H), 2.76 (m, 1 H), 3.78 (s, 3 H), 4.77 (m, 2 H), 6.86 (m, 2 H), 7.09 (m, 2 H), 9.70 (d, J = 1.7 Hz, 1 H); 13 C-NMR ( δ , CDCl3) 12.1, 43.3, 48.6, 55.3, 78.4, 114.4, 128.3, 129.1, 159.3, 202.5 ppm. ;HPLC Column : chiralpak IC-3, 9 / 1 hexane / i -PrOH, flow rate 0.8 mL / min, tr (major) = 33.10 min, tr (minor) = 37.22 min. 3-13 1 H-NMR ( δ , CDCl3) 1.06 (d, J = 7.3 Hz, 3H), 2.83 (m, 1H), 4.06 (ddd, J = 9.0, 9.0, 5.7 Hz, 1H), 4.72 (m, 2H), 6.19 (m, 1H), 6.31 (s, 1H), 7.36 (s, 1H) 9.71 (d, J = 1.3 Hz, 1H); 13 C-NMR ( δ , CDCl3) 11.0, 37.7, 47.1, 75.8, 108.8, 110.4, 142.7, 149.9, 201.6 ppm. ;HPLC Column : chiralpak IC-3, 9 / 1 hexane / i -PrOH, flow rate 0.8 mL / min, tr (major) = 19.27 min, tr (minor) = 24.30 min). 3-14 1 H-NMR ( δ , CDCl3) 0.83 (t, J = 7.5 Hz, 3H), 1.49 (m, 2H), 2.66 (m, 1H), 3.77 (m, 1H), 4.62 (dd, J = 12.8, 10.0 Hz, 1H), 4.70 (dd, J = 12.8, 4.6 Hz, 1H), 7.08 (m, 2H), 7.47 (m, 2H), 9.70 (d, J = 1.9 Hz, 1H); 13 C-NMR ( δ , CDCl3) 10.5, 20.3, 42.1, 54.6, 78.3, 122.1, 129.7, 132.3, 136.0, 202.8 ppm. ;HPLC Column : chiralpak IC-3, 9 / 1 hexane / i -PrOH, flow rate 0.8 mL / min, tr (major) = 19.20 min, tr (minor) = 21.65 min). 3-15 %; 1 H-NMR ( δ , CDCl3) 0.81 (m, 3H), 1.50 (m, 2H), 2.32 (s, 3H), 2.65 (m, 1H), 3.74 (m, 1H), 4.65 (m, 2H), 7.07 (m 4H), 9.70 (d, J = 1.3 Hz, 1H); 13 C-NMR ( δ , CDCl3) 10.7, 20.3, 21.1, 42.4, 55.1, 78.7, 127.9, 129.8, 133.7, 133.9, 203.4 ppm. ;HPLC Column : chiralpak IC-3, 9 / 1 hexane / i -PrOH, flow rate 0.8 mL / min, tr (major) = 24.1 min, tr (minor) = 25.0 min).

[0123] As described above, by applying the carboxyproline compound according to the present invention as a catalyst for an asymmetric 1,4-Michael addition reaction, chiral gamma nitrocarbonyl compounds with improved stereoselectivity can be efficiently produced in high yield.

[0124] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will understand that other specific forms can be easily modified without altering the technical spirit or essential features of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

Claims

Claim 1 Carboxyproline compound represented by the following chemical formula 1: [Chemical Formula 1] In the above chemical formula 1, L 1 is a C2-C10 alkylene or a C3-C10 cycloalkylene, and the L 1 The alkylene and cycloalkylene of may be further substituted with one or more selected from the group consisting of C1-C10 alkyl, halo-C1-C10 alkyl, C6-C20 aryl-C1-C10 alkyl, C6-C20 aryl, and C3-C20 heteroaryl; 2 is C2-C10 alkenylene, C6-C20 arylene, or C3-C20 heteroarylene, and the above L 2 The alkenylene, arylene, and heteroarylene of may be further substituted with one or more selected from the group consisting of halogen, C1-C10 alkyl, halo-C1-C10 alkyl, C6-C20 aryl-C1-C10 alkyl, C6-C20 aryl, and C3-C20 heteroaryl; said heteroarylene and heteroaryl include one or more heteroatoms selected from N, O, and S; and * means a stereogenic center. Claim 2 In Clause 1, the above L 1 is a C3-C8 cycloalkylene, and the above L 1 The cycloalkylene of may be further substituted with one or more selected from the group consisting of C1-C6 alkyl and halo-C1-C6 alkyl; L 2 is C2-C6 alkenylene or C6-C12 arylene, and the above L 2 A carboxyproline compound in which the alkenylene and arylene of the compound may be further substituted with one or more selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C6-C12 aryl-C1-C6 alkyl, and C6-C12 aryl. Claim 3 The carboxyproline compound of claim 1, wherein the carboxyproline compound is represented by the following chemical formula 2. [Chemical Formula 2] In the above chemical formula 2, L 2 Is , or Igo;R 1 and R 2 are each independently hydrogen, C1-C4 alkyl, halo-C1-C4 alkyl, C6-C12 aryl-C1-C4 alkyl, or C6-C12 aryl; R 3 and R 4 Each is independently a halogen, C1-C4 alkyl, haloC1-C4 alkyl, or C6-C12 aryl; a is an integer from 0 to 4, and b is an integer from 0 to 6. Claim 4 In claim 3, the carboxyproline compound is a carboxyproline compound selected from any one of the following structures. Claim 5 A method for preparing a chiral gamma nitrocarbonyl compound represented by Formula 3 by performing an asymmetric 1,4-Michael addition reaction of an aldehyde compound represented by Formula 4 and a nitroalkene compound represented by Formula 5 using a carboxyproline compound according to any one of Claims 1 to 4 as a catalyst: [Formula 3] [Chemical Formula 4] [Chemical Formula 5] In the above chemical formulas 3 to 5, R a is a C1-C10 alkyl, C3-C10 cycloalkyl, or C6-C20 aryl C1-C10 alkyl; R b is a C6-C20 aryl or a C3-C20 heteroaryl, and the above R b The aryl and heteroaryl groups may be further substituted with one or more selected from the group consisting of C1-C10 alkoxy, C1-C10 alkyl, halo-C1-C10 alkyl, hydroxyl, and halogen;* represents a stereogenic center. Claim 6 In Clause 5, the above R a is a C1-C10 alkyl or C6-C12 aryl C1-C10 alkyl; R b is a C6-C12 aryl or a C3-C12 heteroaryl, and the above R b A method for preparing a chiral gamma nitrocarbonyl compound, wherein the aryl group can be further substituted with one or more selected from the group consisting of C1-C10 alkoxy, C1-C10 alkyl, hydroxy, and halogen. Claim 7 A method for preparing a chiral gamma nitrocarbonyl compound according to claim 5, wherein the carboxyproline compound is used in a range of 1 to 50 mol% per 1 mole of the nitroalkene compound of formula 5, and the aldehyde compound of formula 4 is used in a range of 1 to 10 mol per 1 mole of the nitroalkene compound of formula 5. Claim 8 A method for preparing a chiral gamma nitrocarbonyl compound according to claim 5, wherein the asymmetric 1,4-Michael addition reaction is performed at 1 to 35°C. Claim 9 A method for preparing a chiral gamma nitrocarbonyl compound, wherein, in claim 5, the above-mentioned asymmetric 1,4-Michael addition reaction is performed by further including a base. Claim 10 A method for preparing a chiral gamma nitro carbonyl compound according to claim 9, wherein the base is one or more selected from the group consisting of 4-methylmorpholine (NMM), N-ethylmorpholine (NEM), triethylamine (TEA), 4-dimethylaminopyridine (DMAP), and diisopropylethylamine (DIPEA). Claim 11 A method for preparing a chiral gamma nitrocarbonyl compound according to claim 9, wherein the base is used in a range of 1 to 30 mol% per 1 mole of the nitroalkene compound of formula 5.

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