KR101925198B1

KR101925198B1 - METHOD OF SYNTHESIZING β-SUBSTITUTED GAMMA NITRO DI-THIOESTER COMPOUNDS, β-SUBSTITUTED GAMMA NITRO DI-THIOESTERS COMPOUNDS SYNTHESIZED BY THE METHOD, GAMMA AMINO ACID COMPOUND DERIVATED FROM THE β-SUBSTITUTED GAMMA NITRO DI-THIOESTERS COMPOUNDS, AND METHOD OF SYNTHESIZING GAMMA AMINO BUTYRIC ACID FROM THE β-SUBSTITUTED GAMMA NITRO DI-THIOESTER COMPOUNDS OR THE GAMMA AMINO ACID COMPOUND

Info

Publication number: KR101925198B1
Application number: KR1020170000624A
Authority: KR
Inventors: 송충의; 심재훈
Original assignee: 성균관대학교산학협력단
Priority date: 2017-01-03
Filing date: 2017-01-03
Publication date: 2018-12-04
Also published as: KR20180079896A; WO2018128386A1

Abstract

A method of synthesizing a gamma-nitro dithioester compound is disclosed. The gamma-nitro dithio ester compound is prepared by reacting a β, β-disubstituted nitroalkene compound (β-Disubstituted nitroalkene compound) having two carbon-containing substituents at the β-position in the presence of a base- The dithiomalonate compound can be synthesized by a Michael reaction, and the synthesized gamma-nitro dithioester compound has two carbon-containing substituents at the beta position.

Description

TECHNICAL FIELD The present invention relates to a method for synthesizing a beta-substituted gamma-nitro dithioate compound, a beta-substituted gamma-nitro dithioate compound prepared thereby, a novel gamma-amino acid compound derived from the same and a beta-substituted gamma-aminobutyric acid compound OF SYNTHESIZING β-SUBSTITUTED GAMMA NITRO DI-THIOESTER COMPOUNDS, β-SUBSTITUTED GAMMA NITRO DI-THIOESTERS COMPOUNDS SYNTHESIZED BY THE METHOD, GAMMA AMINO ACID COMPOUND DERIVATED FROM THE β-SUBSTITUTED GAMMA NITRO DI-THIOESTER COMPOUNDS, AND METHOD OF SYNTHESIZING GAMMA AMINO BUTYRIC ACID FROM THE β-SUBSTITUTED GAMMA NITRO DI-THIOESTER COMPOUNDS OR THE GAMMA AMINO ACID COMPOUND}

The present invention relates to a method for synthesizing a gamma-nitro dithioester compound by Michael-reacting a malonate compound with a β-disubstituted nitroalkene having two carbon-containing substituents at the β-position, A gamma-nitro dithio ester compound, a chiral gamma-amino acid compound derived therefrom, and a method for producing a chiral gamma-aminobutyric acid compound therefrom.

The creation of new carbon-carbon bonds is the most fundamental goal in organic synthesis. Despite numerous research and development efforts, the synthesis of quaternary carbon centers, in which all substituents are carbon, remains a very difficult challenge due to electronic and steric barrier. One of the syntheses of this quaternary carbon center that has not been possible so far is the linkage between malonate and malonate equivalents with two β-disubstituted nitroalkenes having two carbon-containing substituents in the beta position. The Michael compound of the present reaction is a gamma-nitro dithioester compound having two carbon-containing substituents at the beta position, which can act as a gamma-aminobutyric acid precursor having two carbon-containing substituents at the beta position.

Gamma Aminobutyric acid is an amino acid that acts as a major regulatory neurotransmitter in the central nervous system and is widely used as an agent acting on the neuropsychiatric system. Among them, compounds such as pregabalin, baclofen, gabapentin and the like are known to be a drug of great demand worldwide. Therefore, it has been a great interest among scientists to efficiently synthesize various gamma-aminobutyric acid derivatives, and numerous attempts and studies have been conducted. In the case of beta-substituted gamma-aminobutyric acid including pregabalin, baclofen, gabapentin, etc., efficient synthesis of many derivatives has been developed in particular.

However, due to the electronic and steric barrier, the synthesis of the 4th carbon center is limited to the case where one substituent is electronically activated, and all of the studies so far fail if they are not electronically activated.

One object of the present invention is to provide a process for preparing a β-disubstituted nitroalkene compound having two carbon-containing substituents at the β-position by Michael reaction of a dithiomalonate compound with a β- And a method for synthesizing a chiral gamma-nitro dithio ester compound having two carbon-containing substituent groups.

Another object of the present invention is to provide a chiral gamma nitroredithiothiourea compound synthesized by the above method.

It is another object of the present invention to provide a chiral gamma amino acid compound derived from the above chiral gamma nitroredithiothiourea compound.

It is still another object of the present invention to provide a process for preparing the chiral gamma-nitro dicarboxylic acid compound or the chiral gamma-aminobutyric acid compound from the chiral gamma-amino acid compound.

A process for the synthesis of a gamma-nitro dithioester compound according to an embodiment of the present invention comprises reacting two carbon containing substituents in the beta position in the presence of a catalyst comprising a base in aqueous water or inorganic salt solution The present invention includes a Michael reaction of a β, β-disubstituted nitroalkene compound and a dithiomalonate compound, wherein the synthesized gamma-nitro dithiourea compound Having two carbon containing substituents in the beta position.

In one embodiment, the catalyst may comprise an asymmetric catalyst comprising an acidic moiety capable of activating the nitroalkyne compound and a Bronsted base moiety capable of activating the dithiomalonate compound. For example, the asymmetric catalyst may include at least one compound selected from the group consisting of the following chemical formulas 1-1 to 1-16.

[Formula 1-1]

[Formula 1-2]

[Formula 1-3]

[Formula 1-4]

[Formula 1-5]

[Chemical Formula 1-6]

[Chemical Formula 1-7]

[Chemical Formula 1-8]

[Chemical Formula 1-9]

[Chemical Formula 1-10]

[Formula 1-11]

[Formula 1-12]

[Formula 1-13]

[Chemical Formula 1-14]

[Chemical Formula 1-15]

[Chemical Formula 1-16]

In the above Chemical Formulas 1-1 to 1-16, R is an ethyl group or a vinyl group, R 'is a methoxy group or hydrogen, R ₁ and R ₂ are each an alkyl group, , R ₃ and R ₄ are each a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, Ar is a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, and n may be 0 or 1.

In one embodiment, the catalyst may comprise a tertiary amine compound. For example, the tertiary amine compound may include a compound of the following formula 1-17.

[Formula 1-17]

In Formula 1-17, R ₁ to R ₃ each independently represent an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, a heteroaryl group having 4 to 30 carbon atoms, Gt; is selected from the group consisting of halogen, nitrogen, oxygen or sulfur substituted substituents.

In one embodiment, the catalyst may be used in an amount of 0.1 to 100 mol% based on the nitroalkene compound.

In one embodiment, the nitroalkyne compound having two carbon-containing substituents at the beta position includes a compound having a structure represented by the following formula (2), wherein the dithiomalonate compound has a structure represented by the following formula . &Lt; / RTI >

(2)

(3)

Wherein R ¹ _, R ² , R ³ and R ⁴ each independently represent an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, an aryl group having 4 to 30 carbon atoms, A halogen atom, a halogen atom, a nitrogen atom, an oxygen atom or a sulfur atom, and X is a hydrogen atom or a halogen atom.

In one embodiment, the dithiomalonate may comprise at least one of the following compounds of Formula 3-1 and the compounds of Formula 3-2:

[Formula 3-1]

[Formula 3-2]

In one embodiment, the dithiomalonate compound may be used in an amount of 1 to 5 equivalents based on the nitroalkyne compound.

In one embodiment, the inorganic salt aqueous solution may comprise one or more selected from the group consisting of aqueous sodium chloride solution, aqueous lithium chloride solution, aqueous potassium chloride solution and aqueous cesium chloride solution.

In one embodiment, the gamma nitroredithiothiourethane compound having two carbon-containing substituents at the beta position may comprise a compound having the structure of Formula 4 below.

[Chemical Formula 4]

In Formula 4, R ¹ to R ⁴ each independently represent an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, a heteroaryl group having 4 to 30 carbon atoms, , Nitrogen, oxygen, or sulfur, and X is hydrogen or a halogen atom.

In one embodiment, the Michael reaction can be carried out with stirring at a temperature of -15 ° C to 60 ° C. In this case, the Michael reaction can be carried out in the presence of an organic additive together with the asymmetric catalyst, and the organic additive is selected from the group consisting of toluene, ortho-xylene, meta-xylene, para-xylene, n-hexane, Cyclohexane, cyclohexane, cyclohexane, cyclohexane, and cyclohexane.

In one embodiment, the organic additive may be used in an amount greater than or equal to 0 and less than or equal to 15 equivalents based on the nitroalkyne.

The chiral gamma-nitro dithioester compound according to an embodiment of the present invention includes a compound having a chemical structure represented by the following formula (4).

[Chemical Formula 4]

The chiral gamma amino acid compound according to an embodiment of the present invention may include one compound selected from the group consisting of the compounds represented by the following formulas (5) to (7).

[Chemical Formula 5]

[Chemical Formula 6]

(7)

In formulas (5) to (7), R ₁ to R ₃ independently represent, independently of each other, an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, an aryl group having 4 to 30 carbon atoms A heteroaryl group and substituents substituted by halogen, nitrogen, oxygen or sulfur thereof, and X is hydrogen or a halogen atom.

A method for preparing a chiral gamma-aminobutyric acid compound according to an embodiment of the present invention comprises: preparing a compound of the following formula (5) from a compound of the formula (4); And refluxing the compound of formula (5) in an aqueous hydrochloric acid solution to prepare a compound of formula (8).

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 8]

In formulas (4), (5) and (8), R ₁ to R ₄ are each independently selected from the group consisting of an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, To 30 heteroaryl groups and substituents substituted by halogen, nitrogen, oxygen or sulfur thereof, and X is hydrogen or a halogen atom.

A method for preparing a chiral gamma-aminobutyric acid compound according to an embodiment of the present invention comprises: preparing a compound of the following formula (5) from a compound of the formula (4); Reacting the compound of Formula 5 with a hydroxy group to prepare a compound of Formula 6; Refluxing a compound of formula (6) in an aqueous hydrochloric acid solution to prepare a compound of formula (7); And refluxing the compound of formula (7) in an aqueous hydrochloric acid solution to prepare a compound of formula (8).

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(7)

[Chemical Formula 8]

In the general formulas (4) to (8), R ₁ to R ₄ independently represent, independently of each other, an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, A heteroaryl group and substituents substituted by halogen, nitrogen, oxygen or sulfur thereof, and X is hydrogen or a halogen atom.

According to the present invention, there is provided a process for producing a dithiomalonate compound having two carbon-containing substituent groups in the presence of a base-containing asymmetric catalyst in an aqueous solution of water or an inorganic salt, (Michael reaction) to form a new carbon-carbon bond that was not previously possible without the use of as many chiral auxiliary and expensive peptide catalysts as the number of equivalents, resulting in two carbon-containing substituents at the beta position The gamma-nitro dithio ester compound can be synthesized as racemic or highly enantioselective.

Also, according to the present invention, gamma-amino dicarboxylic acid having two carbon-containing substituents at the beta position, which is likely to have a medicinal activity, can be produced at a low cost and high efficiency by using the gamma-nitro dithioester compound.

Hereinafter, embodiments of the present invention will be described in detail. It is to be understood that the invention is not limited to the disclosed embodiments, but, on the contrary, is intended to cover various modifications and similarities. It is to be understood, however, that the invention is not intended to be limited to the particular forms disclosed, but on the contrary, is intended to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention.

The terms first, second, etc. may be used to describe various components, but the components should not be limited by the terms. The terms are used only for the purpose of distinguishing one component from another. For example, without departing from the scope of the present invention, the first component may be referred to as a second component, and similarly, the second component may also be referred to as a first component.

The terminology used in this application is used only to describe a specific embodiment and is not intended to limit the invention. The singular expressions include plural expressions unless the context clearly dictates otherwise. In the present application, the term " comprises " or " having " is intended to designate the presence of stated features, elements, etc., and not one or more other features, It does not mean that there is none.

Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Terms such as those defined in commonly used dictionaries are to be interpreted as having a meaning consistent with the contextual meaning of the related art and are to be interpreted as either ideal or overly formal in the sense of the present application Do not.

A method for synthesizing a gamma-nitro dithioester compound according to an embodiment of the present invention is a method for producing a gamma-nitro dithioester compound in the presence of an asymmetric catalyst or a tertiary amine compound catalyst containing a base in a water or inorganic salt aqueous solution, Michael reaction of a β, β-disubstituted nitroalkene compound and a dithiomalonate compound having two carbon-containing substituents, The gamma-nitro dithioester compound may have two carbon-containing substituents at the beta position.

The asymmetric catalyst may comprise an acidic moiety capable of activating the nitroalkyne compound and a Bronsted base moiety capable of activating the dithiomalonate compound. The Bronsted base moiety may comprise, for example, a tertiary amine. The gamma-nitro dithioester compound synthesized through the Michael reaction in the presence of the asymmetric catalyst may be a chiral compound.

In one embodiment, the asymmetric catalyst may include at least one of the compounds having the structures of Formulas 1-1 through 1-16. For example, in the case of the catalyst compound of the following formula (1-1), since the quinuclidine functional group, which is a base moiety, and the squaroid functional group, which is an acidic moiety, are included, the nitroalkyne compound and the dithiomolonate compound can be simultaneously activated have.

[Formula 1-1]

[Formula 1-2]

[Formula 1-3]

[Formula 1-4]

[Formula 1-5]

[Chemical Formula 1-6]

[Chemical Formula 1-7]

[Chemical Formula 1-8]

In the above Formulas 1-1 to 1-8, R may be an ethyl group or a vinyl group, R 'may be a methoxy group or hydrogen, Ar may be substituted or substituted Or an aryl group having 6 to 20 carbon atoms, and n may be 0 or 1.

[Chemical Formula 1-9]

[Chemical Formula 1-10]

[Formula 1-11]

[Formula 1-12]

[Formula 1-13]

[Chemical Formula 1-14]

[Chemical Formula 1-15]

[Chemical Formula 1-16]

In the above formulas 1-9 to 1-16, R ₁ and R ₂ may each be an alkyl group, and R ₃ and R ₄ may each be a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, An unsubstituted aryl group having 6 to 20 carbon atoms, and n may be 0 or 1.

Meanwhile, the gamma-nitro dithioester compound synthesized through the Michael reaction in the presence of the tertiary amine compound catalyst may be a racemic compound. For example, the tertiary amine compound catalyst may include a trialkylamine having a structure represented by the following Formula 1-17.

[Formula 1-17]

In the formula (1-17), R ₁ to R ₃ are each independently selected from the group consisting of an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, a heteroaryl group having 4 to 30 carbon atoms, And may be unsubstituted or substituted with halogen, nitrogen, oxygen or sulfur.

In one embodiment, in the compounds of Formulas 1-1 to 1-8, R may be an ethyl group or a vinyl group (-CH = CH ₂ ).

In one embodiment, Ar may be benzene, naphthalene, anthracene, pyrene, and the like, and each of these may be substituted with an alkyl group which is unsubstituted or substituted with a halogen atom or a halogen atom . For example, Ar may be 3,5-bis (trifluoromethyl) benzene.

In one embodiment, the catalyst compound of Formula 1-1 may include compounds of Formula 1-1a to Formula 1-1d.

[Formula 1-1a]

[Formula 1-1b]

[Formula 1-1c]

[Chemical Formula (1-1d)

In one embodiment, the catalyst compound of Formula 1-9 may include a compound of Formula 1-9a.

[Chemical Formula 1-9a]

In one embodiment, the catalyst compound of Formula 1-17 may include compounds of Formula 1-17a to Formula 1-17d.

[Formula 1-17a]

[Chemical Formula 1-17b]

[Chemical Formula 1-17c]

[Chemical Formula 1-17d]

The β, β-disubstituted nitroalkenes having two carbon-containing substituents at the β-position may include a compound having a structure represented by the following formula (2).

(2)

In Formula 2, R < ¹ ^> And R ² are each independently selected from the group consisting of an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, a heteroaryl group having 4 to 30 carbon atoms, Or may be substituted with halogen, nitrogen, oxygen or sulfur.

The dithiomalonate compound may include a compound having a structure represented by the following formula (3).

(3)

In Formula 3, R ³ and R ⁴ are each independently selected from the group consisting of an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, a heteroaryl group having 4 to 30 carbon atoms, And these may be unsubstituted or substituted with halogen, nitrogen, oxygen or sulfur. And X may be hydrogen or a halogen element.

[Formula 3-1]

[Formula 3-2]

The Michael reaction between the β, β-disubstituted nitroalkene compound having two carbon-containing substituents at the β-position and the dithiomalonate compound can be carried out by adding water or an aqueous solution of an inorganic salt Lt; / RTI >

When the Michael reaction is carried out in an organic solvent such as dichloromethane, tetrahydrofuran or toluene, the steric hindrance of the β, β-disubstituted nitroalkene compound And a gamma-nitro-dithiourea compound (β, β-Disubstituted γ-nitro compound having two carbon-containing substituents at the β-position, which is a desired Michael addition reaction compound because no new carbon- dithioester compound may not be synthesized. However, as in the present invention, when the Michael reaction takes place in the water or inorganic salt aqueous solution, the hydrophobic hydration effect causes gamma-nitrodithiocarbons having two carbon-containing substituents at the beta position (Β, β-disubstituted γ-nitro dithioester compound) can be synthesized at a high rate.

In one embodiment, the inorganic salt aqueous solution may comprise at least one selected from aqueous sodium chloride solution, lithium chloride aqueous solution, potassium chloride aqueous solution, cesium chloride aqueous solution and the like.

The β-disubstituted γ-nitro dithioester compound having two carbon-containing substituents at the β-position may have a structure represented by the following formula (4).

[Chemical Formula 4]

In Formula 4, R ¹ to R ⁴ are each independently selected from the group consisting of an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, a heteroaryl group having 4 to 30 carbon atoms, And these may be unsubstituted or substituted with halogen, nitrogen, oxygen or sulfur. And X may be hydrogen or a halogen element.

In one embodiment of the present invention, the Michael reaction between the β, β-disubstituted nitroalkene compound having two carbon-containing substituents at the β-position and the dithiomalonate compound Michael reaction) can be carried out according to Scheme 1 below.

[Reaction Scheme 1]

In the Michael reaction of Scheme 1, in one embodiment, the dithiomalonate compound may be used in an amount of about 1 to about 5 equivalents based on the nitroalkyne compound. For example, the guanidithiomalonate compound can be used in an amount of about 1 to 3 equivalents based on the nitroalkyne compound having two carbon-containing substituents at the beta position.

In the Michael reaction of Scheme 1, in one embodiment, the asymmetric catalyst may be used in an amount of about 0.1 to 100 mol% based on the nitroalkene compound. For example, the asymmetric catalyst may be used in an amount of about 5 to 50 mol% based on the nitroalkyne compound.

In one embodiment, the Michael reaction of Scheme 1 may be carried out with stirring at a temperature of about -15 ° C to 60 ° C, taking into account the reaction yield and optical selectivity. For example, the reaction of Scheme 1 may be carried out with stirring at a temperature of about 0 캜 to 30 캜.

Meanwhile, the Michael reaction in Scheme 1 can be performed by the presence of an organic additive together with the asymmetric catalyst. In one embodiment, the organic additive may include one or more selected from toluene, ortho-xylene, meta-xylene, para-xylene, n-hexane, cyclohexane, methylcyclohexane, and the like. In the case where the Michael reaction of Scheme 1 occurs in the presence of the organic additive, the optical selectivity can be improved as well as the stirring can be performed more efficiently. In one embodiment, the organic additive may be used in an amount of about 15 equivalents or less based on the nitroalkyne. For example, the organic additive may be used in an amount of about 3 to 10 equivalents based on the nitroalkyne.

When a β, β-disubstituted γ-nitro dithioester compound having two carbon-containing substituents at the β-position is used, various chiral gamma amino acid compounds can be synthesized through a simple process. For example, when a β, β-disubstituted γ-nitro dithioester compound having two carbon-containing substituents at the β-position is used, the chiral compounds of the following formulas (5) to (8) are synthesized .

[Chemical Formula 5]

[Chemical Formula 6]

(7)

[Chemical Formula 8]

In formulas (5) to (8), R ₁ to R ₃ each independently represent an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, a heteroaryl group having 4 to 30 carbon atoms , And these may be unsubstituted or substituted with halogen, nitrogen, oxygen or sulfur. And X may be hydrogen or a halogen element.

In one embodiment, the chiral lactam thioester compound of Formula 5 is prepared by reacting a chiral gamma nitroredithiothiourea compound having two carbon-containing substituents at the beta position of Formula 4 in an aqueous hydrochloric acid solution according to Reaction Scheme 2-1, The compound is catalytically reacted with zinc particles or a gamma nitroredithiothiourethane compound having two carbon-containing substituents at the beta position of the formula (4) in ethanol according to the following reaction formula 2-2 is reacted with zinc particles and chlorotrimethylsilane (TMSCI). &Lt; / RTI >

[Reaction Scheme 2-1]

[Reaction Scheme 2-2]

In one embodiment, the chiral lactamcarboxylic acid compound of Formula 6 may be prepared by reacting a chiral lactam thioester compound of Formula 5 with a hydroxy group in a mixed solvent of acetone and water in which potassium hydroxide is dissolved according to the following Reaction Scheme 3 .

[Reaction Scheme 3]

In one embodiment, the chiral lactam compound of formula (7) can be prepared by refluxing the chiral lactam carboxylic acid compound of formula (6) in a toluene solvent according to the following reaction formula (4).

[Reaction Scheme 4]

In one embodiment, the chiral gamma aminobutyric acid hydrochloride of Formula 8 may be prepared by refluxing the chiral lactam thioester compound of Formula 5 in an aqueous hydrochloric acid solution according to the following Reaction Scheme 5-1, 7 with a chiral lactam compound in an aqueous hydrochloric acid solution.

[Reaction Scheme 5-1]

[Reaction Scheme 5-2]

According to the present invention, a Michael reaction is performed between a?,? -Dubstituted nitroalkene compound and a dithiomalonate compound to obtain a chiral beta 2-substituted nitro dithioester compound Can be synthesized. By using this, a chiral gamma aminobutyric acid compound can be produced at a low cost and a high efficiency.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the present invention as defined by the appended claims. And it is natural that such variations and modifications are included in the appended claims.

Examples 1-35: Preparation of chiral or racemic gamma-nitro dithioate compounds having two carbon-containing substituents in the beta position

According to Examples 1 to 35, in the presence of an asymmetric catalyst or a tertiary amine compound catalyst comprising a bridged base, a nitroalkyne compound having two carbon-containing substituents at the beta position of the formula (2) Asymmetric Michael reaction of the thiomalonate compound resulted in a high yield and high enantiomeric selectivity of the gamma-nitro dithioester compound having two carbon-containing substituents at the beta position of the formula (4) To Table 5. The synthesized gamma-nitro dithio ester compound was analyzed by high-performance liquid chromatography (HPLC) to determine the enantiomeric excess.

[Example 1]

0.5 mmol of nitroalkyne having two carbon-containing substituents at the beta position of Formula 2a, 1.5 mmol of dithiomalonate of Formula 3-2, 0.075 mmol of the organic catalyst of Formula 1-1a, 4.0 g of brine (saturated sodium chloride aqueous solution) 4.0 mL were mixed with 3.5 mmol of ortho-xylene and reacted with stirring at 20 DEG C for 96 hours. Then, the reaction mixture was extracted with an ethyl acetate solvent, the solvent was removed under reduced pressure, the product was separated using silica chromatography, and the enantiomeric excess was measured using liquid chromatography.

^{1 H NMR (500 MHz, CDCl} 3, Me 4 Si): δ 7.30 ?? 7.11 (m, 15H), 5.56 (d, J = 13.2 Hz, 1H, diastereotopic proton A, C H 2 NO 2), 5.17 (d, J = 13.2 Hz, 1H, diastereotopic proton B, C H 2 NO 2) , 4.05 (s, 1 H), 4.16 3.92 (m, 4 H), 1.80 (s, 3 H).

^{13 C NMR (125 MHz, CDCl} 3): δ 190.96 (d, J = 79.0 Hz), 139.18, 136.17 (d, J = 5.9 Hz), 128.97, 128.84 (d, J = 6.5 Hz), 128.75, 127.89, 127.68 (d, J = 3.0 Hz), 126.23, 80.77, 76.06, 45.88, 34.53 (d, J = 2.7 Hz), 22.29.

Enantioselectivity was measured using high performance liquid chromatography. (AD-H, 90:10, hexane: isopropyl alcohol, 254 nm, 1.0 mL / min, t (by-product) = 19.6 min, t (main product) = 22.1 min

[Example 2]

0.5 mmol of nitroalkyne having two carbon-containing substituents at the beta position of formula (2a), 1.5 mmol of dithiomalonate of formula (3-1), 0.075 mmol of the organic catalyst of formula (1-1b), 4.0 g of brine (saturated sodium chloride aqueous solution) mL were mixed with 3.5 mmol ortho-xylene and reacted at 0 DEG C with stirring for 96 hours. Then, the reaction mixture was extracted with ethyl acetate solvent, the solvent was removed under reduced pressure, and the product was separated using silica chromatography, and the enantiomeric excess was measured using liquid chromatography.

^{1 H NMR (500 MHz, CDCl} 3, Me 4 Si): δ 7.36 ?? 7.31 (m, 4H), 7.29? 7.25 (m, 1H), 5.62 (d, J = 13.3 Hz, 1H, diastereotopic proton A, C H 2 NO 2), 5.20 (d, J = 13.3 Hz, 1H, diastereotopic proton B, C H 2 NO 2) , 4.03 (s, 1 H), 2.93? 2.69 (m, 4H, diastereotopic SC H 2 CH 3 groups), 1.84 (s, 3H), 1.18 (t, J = 7.4 Hz, 3H, diastereotopic SCH 2 C H 3 group), 1.14 (t, J = 7.4 Hz _{, 3H, diastereotopic SCH 2 C H} 3 group); ^{13 C NMR (125 MHz, CDCl} 3): δ 191.73 (d, J = 84.9 Hz), 139.48, 128.73, 127.86, 126.36, 80.71, 76.67, 45.79, 24.67 (d, J = 13.1 Hz), 22.36, 14.16 ( d, J = 12.4 Hz).

Enantioselectivity was measured using high performance liquid chromatography. (AD-H, 90:10, hexane: isopropyl alcohol, 254 nm, 1.0 mL / min, t (by-product) = 7.7 min, t (main product) = 9.3 min

[Example 3]

0.5 mmol of nitroalkyne having two carbon-containing substituents at the beta position of Formula 2c, 1.5 mmol of dithiomalonate of Formula 3-1, 0.075 mmol of the organic catalyst of Formula 1-1b, 4.0 g of brine (saturated sodium chloride aqueous solution) 4.0 mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. Then, the reaction mixture was extracted with ethyl acetate solvent, the solvent was removed under reduced pressure, and the product was separated using silica chromatography, and the enantiomeric excess was measured using liquid chromatography.

^{1 H NMR (500 MHz, CDCl} 3, Me 4 Si): δ 7.36 ?? 7.29 (m, 4H), 7.26? 7.23 (m, 1H), 5.57 (d, J = 14.0 Hz, 1H, diastereotopic proton A, C H 2 NO 2), 5.54 (d, J = 14.0 Hz, 1H, diastereotopic proton B, C H 2 NO 2) , 4.19 (s, 1 H), 2.96? 2.82 (m, 2H, diastereotopic CC H 2 CH 3 groups), 2.75 (dq, J = 14.8, 7.4 Hz, 1H, diastereotopic proton A, SC H 2 CH 3), 2.65 (dq, J = 14.7, 7.4 Hz, 1H, diastereotopic proton B, SC H 2 CH 3), 2.40 (dq, J = 15.1, 7.6 Hz, 1H, diastereotopic proton C, SC H 2 CH 3), 2.26 (dq, J = 14.5, 7.2 Hz, 1H, diastereotopic proton D, SC H ₂ CH ₃ ), 1.23 (t, J = 7.4 Hz, 3H), 1.06 (t, J = 7.4 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H); ^{13 C NMR (125 MHz, CDCl} 3): δ 192.21 (d, J = 3.5 Hz), 139.11, 128.66, 127.72, 127.11, 77.55, 76.02, 49.28, 29.51, 24.76 (d, J = 26.9 Hz), 14.22 ( d, J = 2.2Hz), 9.55.

Enantioselectivity was measured using high performance liquid chromatography. (OZ-H, 95: 5, hexane: isopropyl alcohol, 254 nm, 1.0 mL / min, t (by-product) = 6.4 min, t

[Example 4]

0.5 mmol of nitroalkyne having two carbon-containing substituents at the beta position of Formula 2d, 1.5 mmol of dithiomalonate of Formula 3-1, 0.075 mmol of the organic catalyst of Formula 1-1b, 4.0 g of brine (saturated sodium chloride aqueous solution) 4.0 mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. Then, the reaction mixture was extracted with ethyl acetate solvent, the solvent was removed under reduced pressure, and the product was separated using silica chromatography, and the enantiomeric excess was measured using liquid chromatography.

¹ H NMR (500 MHz, CDCl ₃ , Me ₄ Si):? 7.83 ?? 7.75 (m, 4H), 7.46 (m, 3H), 5.74 (d, J = 13.2 Hz, 1H, diastereotopic proton A, C H 2 NO 2), 5.29 (d, J = 13.2 Hz, 1H, diastereotopic proton B , C H ₂ NO ₂ ), 4.14 (s, 1 H), 2.90? 2.63 (m, 4H, diastereotopic SC H 2 CH 3 groups), 1.95 (s, 3H), 1.12 (t, J = 7.4 Hz, 3H, diastereotopic SCH 2 C H 3 group), 1.05 (t, J = 7.4 Hz _{, 3H, diastereotopic SCH 2 C H} 3 group); ^{13 C NMR (125 MHz, CDCl} 3): δ 191.71 (d, J = 94.3 Hz), 136.89, 133.16, 132.55, 128.47, 128.40, 127.48, 126.55, 126.44, 125.94, 123.89, 80.83, 76.50, 45.96, 24.67 ( d, J = 12.5Hz), 22.43,14.08 (d, J = 13.9Hz).

Enantioselectivity was measured using high performance liquid chromatography. (OZ-H, 98: 2, hexane: isopropyl alcohol, 254 nm, 0.75 mL / min, t (by-product) = 20.3 min, t

[Example 5]

0.5 mmol of nitroalkyne having two carbon-containing substituents at the beta position of Formula 2e, 1.5 mmol of dithiomalonate of Formula 3-1, 0.075 mmol of the organic catalyst of Formula 1-1b, 4.0 g of brine (saturated sodium chloride aqueous solution) 4.0 mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. Then, the reaction mixture was extracted with ethyl acetate solvent, the solvent was removed under reduced pressure, and the product was separated using silica chromatography, and the enantiomeric excess was measured using liquid chromatography.

^{1 H NMR (500 MHz, CDCl} 3, Me 4 Si): δ 7.28 ?? 7.25 (m, 2H), 7.15 (dd, J = 7.8, 1.4 Hz, 1H), 6.92 6.88 (m, 2H), 5.66 (d, J = 11.2 Hz, 1H, diastereotopic proton A, C H 2 NO 2), 4.94 (s, 1H), 4.75 (d, J = 11.2 Hz, 1H, diastereotopic proton B _{, C H 2 NO 2),} 3.97 (s, 3H), 2.93 (q, J = 7.4 Hz, 2H), 2.70 (dq, J = 14.7, 7.4 Hz, 1H, diastereotopic proton A, SC H 2 CH 3) , 2.54 (dq, J = 14.8 , 7.4 Hz, 1H, diastereotopic proton B, SC H 2 CH 3), 1.93 (s, 3H), 1.27 (t, J = 7.4 Hz, 3H, diastereotopic SCH 2 C H 3 group ), 0.91 (t, J = 7.4 Hz, 3H, diastereotopic SCH 2 C H 3 group); ^{13 C NMR (125 MHz, CDCl} 3): δ 192.31 (d, J = 103.3 Hz), 157.68, 129.71, 129.47, 126.19, 121.16, 111.44, 81.71, 69.42, 55.44, 45.94, 24.38 (d, J = 50.4 Hz ), 20.71, 14.29 (d, J = 3.5 Hz).

Enantioselectivity was measured using high performance liquid chromatography. (OD-H, 90:10, hexane: isopropyl alcohol, 254 nm, 1.0 mL / min, t (by-product) = 7.0 minutes, t

[Example 6]

0.5 mmol of nitroalkyne having two carbon-containing substituents at the beta position of Formula 2f, 1.5 mmol of dithiomalonate of Formula 3-1, 0.075 mmol of the organic catalyst of Formula 1-1b, 4.0 g of brine (saturated sodium chloride aqueous solution) 4.0 mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. Then, the reaction mixture was extracted with ethyl acetate solvent, the solvent was removed under reduced pressure, and the product was separated using silica chromatography, and the enantiomeric excess was measured using liquid chromatography.

^{1 H NMR (500 MHz, CDCl} 3, Me 4 Si): δ 7.27 - 7.24 (m, 1H), 6.91 (dd, J = 7.9, 1.3 Hz, 1H), 6.87 (t, J = 2.2 Hz, 1H) , 6.81 (dd, J = 8.0,2.2 Hz, 1H), 5.60 (d, J = 13.3 Hz, 1H, diastereotopic proton A, C H ₂ NO ₂ ), 5.19 (d, J = 13.3 Hz, 1H, diastereotopic proton B, C H ₂ NO ₂ ), 4.02 (s, 1H), 3.80 (s, 3H), 2.95? J = 7.4 Hz, 3H, diastereotopic SCH ₂ C H ₃ group), 1.15 (t, J = 7.4 Hz), 2.70 (m, 4H, diastereotopic SC H ₂ CH ₃ groups) _{, 3H, diastereotopic SCH 2 C H} 3 group); ^{13 C NMR (125 MHz, CDCl} 3): δ 191.78 (d, J = 90.9 Hz), 159.89, 141.24, 129.78, 118.75, 113.23, 112.64, 80.77, 76.67, 55.40, 45.84, 24.76 (d, J = 13.6 Hz ), 22.53, 14.23 (d, J = 12.7 Hz).

Enantioselectivity was measured using high performance liquid chromatography. (By-product) = 8.5 minutes, t (main product) = 11.6 minutes (OD-H, 90:10, hexane: isopropyl alcohol, 254 nm, 1.0 mL /

[Example 7]

0.5 mmol of nitroalkyne having two carbon-containing substituents in the beta position of formula (2g), 1.5 mmol of dithiomalonate of formula (3-1), 0.075 mmol of the organic catalyst of formula (1-1b), 0.02 mmol of brine (saturated sodium chloride aqueous solution) mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. Then, the reaction mixture was extracted with ethyl acetate solvent, the solvent was removed under reduced pressure, and the product was separated using silica chromatography, and the enantiomeric excess was measured using liquid chromatography.

^{1 H NMR (500 MHz, CDCl} 3, Me 4 Si): δ 7.25 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.9 Hz, 2H), 5.56 (d, J = 12.9 Hz, 1H , diastereotopic proton A, C H ₂ NO ₂ ), 5.15 (d, J = 12.9 Hz, 1H, diastereotopic proton B, C H ₂ NO ₂ ), 4.02 (s, 1H), 3.79 ? 2.72 (m, 4H, diastereotopic SC H 2 CH 3 groups), 1.80 (s, 3H), 1.18 (dt, J = 14.9, 7.4 Hz, 6H, diastereotopic SCH 2 C H 3 groups); ^{13 C NMR (125 MHz, CDCl} 3): δ 191.89 (d, J = 90.3 Hz), 159.06, 131.39, 127.71, 114.04, 81.09, 76.90, 55.37, 45.42, 24.73 (d, J = 10.2 Hz), 22.61, 14.24 (d, J = 11.1 Hz).

Enantioselectivity was measured using high performance liquid chromatography. (By-product) = 9.3 minutes, t (main product) = 12.5 minutes (OD-H, 90:10, hexane: isopropyl alcohol, 254 nm, 1.0 mL /

[Example 8]

0.5 mmol of nitroalkyne having two carbon-containing substituents at the beta position of formula (2h), 1.5 mmol of dithiomalonate of formula (3-1), 0.075 mmol of the organic catalyst of formula (1-1b), 4.0 g of brine (saturated sodium chloride aqueous solution) mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. Then, the reaction mixture was extracted with ethyl acetate solvent, the solvent was removed under reduced pressure, and the product was separated using silica chromatography, and the enantiomeric excess was measured using liquid chromatography.

¹ H NMR (500 MHz, CDCl ₃ , Me ₄ Si):? 6.88 ?? 6.83 (m, 2H), 6.80 (d, J = 8.4 Hz, 1H), 5.59 (d, J = 13.0 Hz, 1H, diastereotopic proton A, C H 2 NO 2), 5.12 (d, J = 13.0 Hz, 1H, diastereotopic proton B, C H ₂ NO ₂ ), 4.74 (dt, J = 9.2, 3.1 Hz, 1H), 4.03 (s, 1H), 3.81 2.74 (m, 4H, diastereotopic SC H 2 CH 3 groups), 1.98 ?? 1.82 (m, 6H), 1.81 (s, 3H), 1.67? 1.58 (m, 2H), 1.20 (t, J = 7.4 Hz, 3H, diastereotopic SCH 2 C H 3 group), 1.16 (t, J = 7.4 Hz, 3H, diastereotopic SCH 2 C H 3 group); ^{13 C NMR (125 MHz, CDCl} 3): δ 191.79 (d, J = 93.7 Hz), 149.61, 147.27, 131.58, 118.87, 114.01, 111.57, 81.00, 80.72, 76.82, 55.89, 45.45, 32.84 (d, J = 11.7 Hz), 24.60 (d, J = 14.0 Hz), 24.13 (d, J = 1.9 Hz), 22.68, 14.11 (d, J = 18.7 Hz).

Enantioselectivity was measured using high performance liquid chromatography. (AD-H, 95: 5, hexane: isopropyl alcohol, 254 nm, 1.0 mL / min, t (by-product) = 12.8 min, t

[Example 9]

0.5 mmol of nitroalkyne having two carbon-containing substituents at the beta position of Formula 2i, 1.5 mmol of dithiomalonate of Formula 3-1, 0.075 mmol of the organic catalyst of Formula 1-1b, 4.0 g of brine (saturated sodium chloride aqueous solution) 4.0 mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. Then, the reaction mixture was extracted with ethyl acetate solvent, the solvent was removed under reduced pressure, and the product was separated using silica chromatography, and the enantiomeric excess was measured using liquid chromatography.

^{1 H NMR (500 MHz, CDCl} 3, Me 4 Si): δ 7.22 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 7.8 Hz, 1H ), 5.60 (d, J = 13.3 Hz, 1H, diastereotopic proton A, C H ₂ NO ₂ ), 5.19 (d, J = 13.3 Hz, 1H, diastereotopic proton B, C H ₂ NO ₂ ) 1H), 2.95? 2.69 (m, 4H, diastereotopic SC H 2 CH 3 groups), 2.34 (s, 3H), 1.82 (s, 3H), 1.19 (t, J = 7.4 Hz, 3H, diastereotopic SCH 2 C H 3 group), 1.15 (t, J = 7.4 Hz, 3H, diastereotopic SCH 2 C H 3 group); ^{13 C NMR (125 MHz, CDCl} 3): δ 191.83 (d, J = 89.1 Hz), 139.46, 138.31, 128.66, 127.09, 123.44, 80.81, 76.80, 45.78, 24.74 (d, J = 11.3 Hz), 22.46, 21.84, 14.27 (d, J = 4.8 Hz).

Enantioselectivity was measured using high performance liquid chromatography. (By-product) = 6.1 minutes, t (main product) = 8.3 minutes (OD-H, 90:10, hexane: isopropyl alcohol, 254 nm, 1.0 mL /

[Example 10]

0.5 mmol of nitroalkyne having two carbon-containing substituent groups in the beta position of the formula (2j), 1.5 mmol of dithiomalonate of the formula (3-1), 0.075 mmol of the organic catalyst of the formula (1-1b), 4.0 g of brine (saturated sodium chloride aqueous solution) mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. Then, the reaction mixture was extracted with ethyl acetate solvent, the solvent was removed under reduced pressure, and the product was separated using silica chromatography, and the enantiomeric excess was measured using liquid chromatography.

^{1 H NMR (500 MHz, CDCl} 3, Me 4 Si): δ 7.21 (dd, J = 8.6, 2.0 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 5.58 (d, J = 13.1 Hz , 1H, diastereotopic proton A, C H ₂ NO ₂ ), 5.16 (d, J = 13.1 Hz, 1H, diastereotopic proton B, C H ₂ NO ₂ ), 4.03 (s, 2.71 (m, 4H, diastereotopic SC H 2 CH 3 groups), 2.31 (s, 3H), 1.81 (s, 3H), 1.19 (t, J = 7.4 Hz, 3H, diastereotopic SCH 2 C H 3 group), 1.16 (t, J = 7.4 Hz, 3H, diastereotopic SCH 2 C H 3 group); ^{13 C NMR (125 MHz, CDCl} 3): δ 191.86 (d, J = 83.6 Hz), 137.63, 136.46, 129.46, 126.30, 80.98, 76.76, 45.60, 24.73 (d, J = 10.8 Hz), 22.46, 21.09, 14.22 (d, J = 11.5 Hz).

Enantioselectivity was measured using high performance liquid chromatography. (AD-H, 90:10, hexane: isopropyl alcohol, 254 nm, 1.0 mL / min, t (byproduct) = 7.6 min, t (main product) = 9.5 min

[Example 11]

0.5 mmol of a nitroalkene having two carbon-containing substituent groups in the beta position of the formula (2k), 1.5 mmol of dithiomalonate of the formula (3-1), 0.075 mmol of the organic catalyst of the formula (1-1b), 4.0 ml of a brine (saturated sodium chloride aqueous solution) mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. Then, the reaction mixture was extracted with ethyl acetate solvent, the solvent was removed under reduced pressure, and the product was separated using silica chromatography, and the enantiomeric excess was measured using liquid chromatography.

^{1 H NMR (500 MHz, CDCl} 3, Me 4 Si): δ 7.59 (s, 1H), 7.56 (t, J = 7.2 Hz, 2H), 7.48 (t, J = 7.8 Hz, 1H), 5.65 (d , J = 13.4 Hz, 1H, diastereotopic proton A, C H 2 NO 2), 5.29 (d, J = 13.4 Hz, 1H, diastereotopic proton B, C H 2 NO 2), 3.99 (s, 1H), 2.95? ? 2.71 (m, 4H, diastereotopic SC H 2 CH 3 groups), 1.86 (s, 3H), 1.18 (t, J = 7.4 Hz, 3H, diastereotopic SCH 2 C H 3 group), 1.13 (t, J = 7.4 Hz _{, 3H, diastereotopic SCH 2 C H} 3 group); ^{13 C NMR (125 MHz, CDCl} 3): δ 191.50 (d, J = 97.2 Hz), 140.69, 130.95 (q, 2 J CF = 32.3 Hz), 129.90, 129.27, δ 124.74 (q, 3 J CF = 3.6 ^{Hz), 123.98 (q, 1} J CF = 272.5 Hz), 123.34 (q, 3 J CF = 3.8 Hz), 80.37, 76.12, 45.68, 24.72 (d, J = 11.4 Hz), 22.15, 14.01 (d, J = 21.4 Hz); ¹⁹ F NMR (470 MHz, CDCl ₃ ): 隆 -62.61 (s, 3F).

Enantioselectivity was measured using high performance liquid chromatography. (By-product) = 6.9 minutes, t (main product) = 8.8 minutes (OD-H, 90:10, hexane: isopropyl alcohol, 254 nm, 1.0 mL /

[Example 12]

0.5 mmol of nitroalkyne having two carbon-containing substituents at the beta position of Formula 2, 1.5 mmol of dithiomalonate of Formula 3-1, 0.075 mmol of the organic catalyst of Formula 1-1b, 4.0 g of brine (saturated sodium chloride aqueous solution) 4.0 mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. Then, the reaction mixture was extracted with ethyl acetate solvent, the solvent was removed under reduced pressure, and the product was separated using silica chromatography, and the enantiomeric excess was measured using liquid chromatography.

^{1 H NMR (500 MHz, CDCl} 3, Me 4 Si): δ 7.60 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.3 Hz, 2H), 5.63 (d, J = 13.5 Hz, 1H , diastereotopic proton A, C H ₂ NO ₂ ), 5.24 (d, J = 13.5 Hz, 1H, diastereotopic proton B, C H ₂ NO ₂ ), 3.99 (s, 2.70 (m, 4H, diastereotopic SC H 2 CH 3 groups), 1.86 (s, 3H), 1.19 (t, J = 7.4 Hz, 3H, diastereotopic SCH 2 C H 3 group), 1.14 (t, J = 7.4 Hz _{, 3H, diastereotopic SCH 2 C H} 3 group); ^{13 C NMR (125 MHz, CDCl} 3): δ 191.51 (d, 2 J CF = 87.9 Hz), 143.70 (d, 5 J CF = 1.0 Hz), 130.16 (q, 3 J CF = 32.8 Hz), 127.03, ^{_{125.73 (q, 4 J CF =}} 3.7 Hz), 123.98 (q, 1 J CF = 272.0 Hz), 80.46, 76.19, 45.77, 24.82 (d, J = 17.1 Hz), 22.39, 14.16 (d, J = 11.1 Hz ); ¹⁹ F NMR (470 MHz, CDCl ₃ ):? -62.75 (s, 3F).

Enantioselectivity was measured using high performance liquid chromatography. (AD-H, 90:10, hexane: isopropyl alcohol, 254 nm, 1.0 mL / min, t (byproduct) = 7.4 min, t (main product) = 10.3 min

[Example 13]

0.5 mmol of nitroalkyne having two carbon-containing substituents at the beta position of the formula (2m), 1.5 mmol of dithiomalonate of the formula (3-1), 0.075 mmol of the organic catalyst of the formula (1-1b), 4.0 g of brine (saturated sodium chloride aqueous solution) mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. Then, the reaction mixture was extracted with ethyl acetate solvent, the solvent was removed under reduced pressure, and the product was separated using silica chromatography, and the enantiomeric excess was measured using liquid chromatography.

^{1 H NMR (500 MHz, CDCl} 3, Me 4 Si): δ 7.31 (s, 1H), 7.29 ?? 7.26 (m, 2 H), 7.24? 7.21 (m, 1H), 5.57 (d, J = 13.5 Hz, 1H, diastereotopic proton A, C H 2 NO 2), 5.23 (d, J = 13.4 Hz, 1H, diastereotopic proton B, C H 2 NO 2) , &Lt; / RTI > 3.96 (s, 1H), 2.97 2.70 (m, 4H, diastereotopic SC H 2 CH 3 groups), 1.81 (s, 3H), 1.21 (t, J = 7.4 Hz, 3H, diastereotopic SCH 2 C H 3 group), 1.17 (t, J = 7.4 Hz _{, 3H, diastereotopic SCH 2 C H} 3 group); ^{13 C NMR (125 MHz, CDCl} 3): δ 191.58 (d, J = 96.4 Hz), 141.77, 134.90, 129.99, 128.19, 126.92, 124.67, 80.43, 76.40, 45.66, 24.85 (d, J = 10.6 Hz), 22.35, 14.26.

Enantioselectivity was measured using high performance liquid chromatography. (By-product) = 7.6 minutes, t (main product) = 9.6 minutes (OD-H, 90:10, hexane: isopropyl alcohol, 254 nm, 1.0 mL /

[Example 14]

0.5 mmol of a nitroalkene having two carbon-containing substituent groups in the beta position of the formula (2n), 1.5 mmol of dithiomalonate of the formula (3-1), 0.075 mmol of the organic catalyst of the formula (1-1b), 4.0 g of a brine (saturated sodium chloride aqueous solution) mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. The reaction mixture was then extracted with ethyl acetate solvent, the solvent was removed under reduced pressure and the product was isolated using silica chromatography, and the enantiomeric excess was then determined by liquid chromatography.

^{1 H NMR (500 MHz, CDCl} 3, Me 4 Si): δ 7.33 ?? 7.26 (m, 4H), 5.57 (d, J = 13.3 Hz, 1H, diastereotopic proton A, C H 2 NO 2), 5.18 (d, J = 13.3 Hz, 1H, diastereotopic proton B, C H 2 NO 2) , 3.98 (s, 1 H), 2.95? 2.73 (m, 4H, diastereotopic SC H 2 CH 3 groups), 1.81 (s, 3H), 1.20 (t, J = 7.4 Hz, 3H, diastereotopic SCH 2 C H 3 group), 1.17 (t, J = 7.4 Hz _{, 3H, diastereotopic SCH 2 C H} 3 group); ^{13 C NMR (125 MHz, CDCl} 3): δ 191.64 (d, J = 90.5 Hz), 138.12, 134.02, 128.94, 127.99, 80.68, 76.43, 45.50, 24.83 (d, J = 12.1 Hz), 22.47, 14.21 ( d, J = 10.6 Hz).

Enantioselectivity was measured using high performance liquid chromatography. (AD-H, 90:10, hexane: isopropyl alcohol, 254 nm, 1.0 mL / min, t (by-product) = 9.3 min, t (main product) = 13.6 min

[Example 15]

0.5 mmol of nitroalkyne having two carbon-containing substituents at the beta position of Formula 2 o, 1.5 mmol of dithiomalonate of Formula 3-1, 0.075 mmol of the organic catalyst of Formula 1-1b, 4.0 g of brine (saturated sodium chloride aqueous solution) 4.0 mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. The reaction mixture was then extracted with ethyl acetate solvent, the solvent was removed under reduced pressure and the product was isolated using silica chromatography, and the enantiomeric excess was then determined by liquid chromatography.

^{1 H NMR (500 MHz, CDCl} 3, Me 4 Si): δ 7.46 (s, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 10.5 Hz, 1H), 7.22 (t , J = 7.9 Hz, 1H) , 5.58 (d, J = 13.5 Hz, 1H, diastereotopic proton A, C H 2 NO 2), 5.23 (d, J = 13.5 Hz, 1H, diastereotopic proton B, C H 2 NO ₂ ), 3.95 (s, 1 H), 2.97? 2.70 (m, 4H, diastereotopic SC H 2 CH 3 groups), 1.80 (s, 3H), 1.21 (t, J = 7.4 Hz, 3H, diastereotopic SCH 2 C H 3 group), 1.18 (t, J = 7.4 Hz _{, 3H, diastereotopic SCH 2 C H} 3 group); ^{13 C NMR (125 MHz, CDCl} 3): δ 191.60 (d, J = 97.2 Hz), 141.98, 131.14, 130.26, 129.74, 125.13, 123.11, 80.38, 76.41, 45.61, 24.87 (d, J = 9.5 Hz), 22.35, 14.28.

Enantioselectivity was measured using high performance liquid chromatography. (AD-H, 98: 2, hexane: isopropyl alcohol, 254 nm, 1.0 mL / min, t (byproduct) = 17.8 min, t

[Example 16]

0.5 mmol of nitroalkyne having two carbon-containing substituents at the beta position of Formula 2p, 1.5 mmol of dithiomalonate of Formula 3-2, 0.075 mmol of the organic catalyst of Formula 1-1b, 4.0 ml of brine (saturated sodium chloride aqueous solution) 4.0 mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. The reaction mixture was then extracted with ethyl acetate solvent, the solvent was removed under reduced pressure and the product was isolated using silica chromatography, and the enantiomeric excess was then determined by liquid chromatography.

^{1 H NMR (500 MHz, CDCl} 3, Me 4 Si): δ 7.46 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 5.56 (d, J = 13.3 Hz, 1H , diastereotopic proton A, C H ₂ NO ₂ ), 5.18 (d, J = 13.3 Hz, 1H, diastereotopic proton B, C H ₂ NO ₂ ), 3.97 (s, 2.72 (m, 4H, diastereotopic SC H 2 CH 3 groups), 1.80 (s, 3H), 1.20 (t, J = 7.4 Hz, 3H, diastereotopic SCH 2 C H 3 group), 1.17 (t, J = 7.4 Hz _{, 3H, diastereotopic SCH 2 C H} 3 group); ^{13 C NMR (125 MHz, CDCl} 3): δ 191.62 (d, J = 90.6 Hz), 138.67, 131.91, 128.30, 122.20, 80.62, 76.34, 45.56, 24.83 (d, J = 12.1 Hz), 22.41, 14.21 ( d, J = 10.4 Hz).

Enantioselectivity was measured using high performance liquid chromatography. (AD-H, 90:10, hexane: isopropyl alcohol, 254 nm, 1.0 mL / min, t (byproduct) = 9.8 min, t (main product) = 13.9 min

[Example 17]

0.5 mmol of nitroalkyne having two carbon-containing substituents at the beta position of Formula 2q, 1.5 mmol of dithiomalonate of Formula 3-1, 0.075 mmol of the organic catalyst of Formula 1-1b, 4.0 g of brine (saturated sodium chloride aqueous solution) 4.0 mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. The reaction mixture was then extracted with ethyl acetate solvent, the solvent was removed under reduced pressure and the product was isolated using silica chromatography, and the enantiomeric excess was then determined by liquid chromatography.

^{1 H NMR (500 MHz, CDCl} 3, Me 4 Si): δ 7.37 (d, J = 1.1 Hz, 1H), 6.31 (dd, J = 3.3, 1.8 Hz, 1H), 6.21 (d, J = 3.3 Hz , 5.27 (d, J = 11.9 Hz, 1H, diastereotopic proton A, C H ₂ NO ₂ ), 5.09 (d, J = 11.9 Hz, 1H, diastereotopic proton B, C H ₂ NO ₂ ), 4.25 s, 1 H), 2.98? 2.79 (m, 4H, diastereotopic SC H 2 CH 3 groups), 1.67 (s, 3H), 1.22 (dt, J = 14.7, 7.4 Hz, 6H, diastereotopic SCH 2 C H 3 group); ^{13 C NMR (125 MHz, CDCl} 3): δ 191.26 (d, J = 37.8 Hz), 153.04, 142.46, 110.67, 108.16, 80.08, 73.13, 43.33, 24.62 (d, J = 4.2 Hz), 19.80, 14.22 ( d, J = 4.3 Hz).

Enantioselectivity was measured using high performance liquid chromatography. (By -product) = 26.4 min, t (main product) = 27.5 min. ( Chiralcel (R, R) Whelk-O 1, 99: 1, hexane: isopropyl alcohol, 254 nm, 0.5 mL /

[Example 18]

0.5 mmol of nitroalkyne having two carbon-containing substituents at the beta position of the compound of formula (2r), 1.5 mmol of dithiomalonate of formula (III-1), 0.075 mmol of the organic catalyst of formula (1-1b), 4.0 g of brine (saturated sodium chloride aqueous solution) mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. The reaction mixture was then extracted with ethyl acetate solvent, the solvent was removed under reduced pressure and the product was isolated using silica chromatography, and the enantiomeric excess was then determined by liquid chromatography.

^{1 H NMR (500 MHz, CDCl} 3, Me 4 Si): δ 7.24 (dd, J = 4.3, 1.9 Hz, 1H), 6.94 (d, J = 4.4 Hz, 2H), 5.47 (d, J = 12.7 Hz , 1H, diastereotopic proton A, C H ₂ NO ₂ ), 5.23 (d, J = 12.7 Hz, 1H, diastereotopic proton B, C H ₂ NO ₂ ), 4.17 (s, 2.74 (m, 4H, diastereotopic SC H 2 CH 3 groups), 1.84 (s, 3H), 1.23 (t, J = 7.4 Hz, 3H, diastereotopic SCH 2 C H 3 group), 1.18 (t, J = 7.4 Hz _{, 3H, diastereotopic SCH 2 C H} 3 group); ^{13 C NMR (125 MHz, CDCl} 3): δ 191.64 (d, J = 88.7 Hz), 144.13, 127.13, 125.96, 125.11, 81.41, 76.52, 44.50, 24.76 (d, J = 15.8 Hz), 24.14, 14.20 ( d, J = 9.4 Hz).

Enantioselectivity was measured using high performance liquid chromatography. (By-product) = 6.4 minutes, t (main product) = 8.3 minutes (OD-H, 90:10, hexane: isopropyl alcohol, 254 nm, 1.0 mL /

[Example 19]

0.5 mmol of nitroalkyne having two carbon-containing substituents in the beta position of Formula 2s, 1.5 mmol of dithiomalonate of Formula 3-1, 0.075 mmol of the organic catalyst of Formula 1-1b, 4.0 g of brine (saturated sodium chloride aqueous solution) 4.0 mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. The reaction mixture was then extracted with ethyl acetate solvent, the solvent was removed under reduced pressure and the product was isolated using silica chromatography, and the enantiomeric excess was then determined by liquid chromatography.

^{1 H NMR (500 MHz, CDCl} 3, Me 4 Si): δ 7.28 (dd, J = 5.4, 2.7 Hz, 1H), 7.15 (dd, J = 2.9, 1.5 Hz, 1H), 7.03 (dd, J = 5.1, 1.4 Hz, 1H), 5.46 (d, J = 12.5 Hz, 1H, diastereotopic proton A, C H 2 NO 2), 5.16 (d, J = 12.5 Hz, 1H, diastereotopic proton B, C H 2 NO 2 ), 4.08 (s, 1 H), 2.95? 2.72 (m, 4H, diastereotopic SC H 2 CH 3 groups), 1.79 (s, 3H), 1.20 (t, J = 7.4 Hz, 3H, diastereotopic SCH 2 C H 3 group), 1.17 (t, J = 7.4 Hz _{, 3H, diastereotopic SCH 2 C H} 3 group); ^{13 C NMR (125 MHz, CDCl} 3): δ 191.65 (d, J = 90.5 Hz), 140.92, 126.14 (s, J = 13.2 Hz), 126.03, 122.61, 81.28, 75.86, 44.00, 24.57 (d, J = 13.1 Hz), 22.98, 14.11 (d, J = 10.0 Hz).

Enantioselectivity was measured using high performance liquid chromatography. (AD-H, 95: 5, hexane: isopropyl alcohol, 254 nm, 0.75 mL / min, t (by-product) = 13.7 min, t (main product) = 15.0 min

[Example 20]

0.5 mmol of nitroalkyne having two carbon-containing substituents at the beta position of Formula 2t, 1.5 mmol of dithiomalonate of Formula 3-1, 0.075 mmol of the organic catalyst of Formula 1-1b, 4.0 g of brine (saturated sodium chloride aqueous solution) 4.0 mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. The reaction mixture was then extracted with ethyl acetate solvent, the solvent was removed under reduced pressure and the product was isolated using silica chromatography, and the enantiomeric excess was then determined by liquid chromatography.

^{1 H NMR (500 MHz, CDCl} 3, Me 4 Si): δ 7.28 (t, J = 7.6 Hz, 2H), 7.20 (d, J = 7.2 Hz, 1H), 7.17 (d, J = 7.6 Hz, 2H ), 4.97 (d, J = 11.5 Hz, 1H, diastereotopic proton A, C H ₂ NO ₂ ), 4.88 (d, J = 11.5 Hz, 1H, diastereotopic proton B, C H ₂ NO ₂ ) 1H), 3.03? 2.89 (m, 4H, diastereotopic SC H 2 CH 3 groups), 2.74 (dt, J = 12.9, 7.9 Hz, 1H, diastereotopic proton A, PhCH 2 C H 2), 2.62 (dt, J = 12.7, 7.9 Hz, _{1H, diastereotopic proton A, PhCH 2} C H 2), 1.89 (t, J = 10.0 Hz, 2H, PhC H 2 CH 2), 1.32 (s, 3H), 1.29 (t, J = 7.4 Hz, 6H, diastereotopic SCH ₂ C H ₃ groups); ^{13 C NMR (125 MHz, CDCl} 3): δ 191.85 (d, J = 6.0 Hz), 141.03, 128.70, 128.49, 126.37, 81.68, 72.22, 41.84, 39.13, 30.17, 24.84 (d, J = 16.8 Hz), 21.56, 14.33 (d, J = 10.2 Hz).

Enantioselectivity was measured using high performance liquid chromatography. (AD-H, 95: 5, hexane: isopropyl alcohol, 254 nm, 1.0 mL / min, t (by-product) = 12.9 min, t

[Example 21]

0.5 mmol of a nitroalkane having two carbon-containing substituents at the beta position of the formula (2u), 1.5 mmol of dithiomalonate of the formula (3-1), 0.075 mmol of the organic catalyst of the formula (1-1b), 4.0 g of brine (saturated sodium chloride aqueous solution) mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. The reaction mixture was then extracted with ethyl acetate solvent, the solvent was removed under reduced pressure and the product was isolated using silica chromatography, and the enantiomeric excess was then determined by liquid chromatography.

^{1 H NMR (500 MHz, CDCl} 3, Me 4 Si): δ 7.31 ?? 7.23 (m, 10H), 4.89 (d, J = 11.6 Hz, 1H, diastereotopic proton A, C H 2 NO 2), 4.77 (d, J = 11.6 Hz, 1H, diastereotopic proton B, C H 2 NO 2) , 4.22 ?? 4.09 (m, 5H), 1.68? 1.64 (m, 1 H), 1.58? 1.49 (m, 2H), 1.22 (s, 3H), 0.90 (d, J = 6.5 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H).

^{13 C NMR (125 MHz, CDCl} 3, Me 4 Si): δ 191.38 (d, J = 23.4 Hz), 136.37 (d, J = 6.2 Hz), 128.94, 128.86 (d, J = 2.4 Hz), 127.73 ( d, J = 1.9 Hz), 82.26,71.97,44.53,42.62,34.55 (d, J = 23.6 Hz), 25.20 (d, J = 31.6 Hz), 23.96,21.53.

Enantioselectivity was measured using high performance liquid chromatography. (Main product) = 8.9 min, t (by-product) = 9.9 min (OD-H, 98: 2, hexane: isopropyl alcohol, 254 nm, 0.75 mL /

[Example 22]

0.5 mmol of nitroalkyne having two carbon-containing substituents at the beta position of the formula (2v), 1.5 mmol of the dithiomalonate of the formula (3-1), 0.075 mmol of the organic catalyst of the formula (1-1b), 4.0 g of brine (saturated sodium chloride aqueous solution) mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. The reaction mixture was then extracted with ethyl acetate solvent, the solvent was removed under reduced pressure and the product was isolated using silica chromatography, and the enantiomeric excess was then determined by liquid chromatography.

^{1 H NMR (500 MHz, CDCl} 3, Me 4 Si): δ 7.28 (t, J = 7.6 Hz, 2H), 7.20 (d, J = 7.2 Hz, 1H), 7.17 (d, J = 7.6 Hz, 2H ), 4.97 (d, J = 11.5 Hz, 1H, diastereotopic proton A, C H ₂ NO ₂ ), 4.88 (d, J = 11.5 Hz, 1H, diastereotopic proton B, C H ₂ NO ₂ ) 1H), 3.03? 2.89 (m, 4H, diastereotopic SC H 2 CH 3 groups), 2.74 (dt, J = 12.9, 7.9 Hz, 1H, diastereotopic proton A, PhCH 2 C H 2), 2.62 (dt, J = 12.7, 7.9 Hz, _{1H, diastereotopic proton A, PhCH 2} C H 2), 1.89 (t, J = 10.0 Hz, 2H, PhC H 2 CH 2), 1.32 (s, 3H), 1.29 (t, J = 7.4 Hz, 6H, diastereotopic SCH ₂ C H ₃ groups).

^{13 C NMR (125 MHz, CDCl} 3, Me 4 Si): δ 191.16 (d, J = 45.9 Hz), 136.32 (d, J = 10.8 Hz), 128.97 (d, J = 9.1 Hz), 128.82 (d, J = 13.4 Hz), 127.71 ( d, J = 7.8 Hz), 79.38, 70.43, 45.64 (d, J = 22.0 Hz), 34.63 (d, J = 30.0 Hz), 28.54, 27.16, 27.04 (d, J = 5.7 Hz), 26.18, 21.69.

Enantioselectivity was measured using high performance liquid chromatography. (AD-H, 95: 5, hexane: isopropyl alcohol, 254 nm, 1.0 mL / min, t (main product) = 7.1 min, t (by-product) = 8.7 min

[Example 23]

0.5 mmol of nitroalkyne having two carbon-containing substituents in the beta position of the formula (2u), 1.5 mmol of dithiomalonate of the formula (3-2), 0.075 mmol of the organic catalyst of the formula (1-1b), 0.02 mmol of brine (saturated sodium chloride aqueous solution) mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. The reaction mixture was then extracted with ethyl acetate solvent, the solvent was removed under reduced pressure and the product was isolated using silica chromatography, and the enantiomeric excess was then determined by liquid chromatography.

^{13 C NMR (125 MHz, CDCl} 3, Me 4 Si): δ 191.24 (d, J = 23.4 Hz), 136.23 (d, J = 6.2 Hz), 128.80, 128.72 (d, J = 2.4 Hz), 127.59 ( d, J = 1.9 Hz), 82.12, 71.83, 44.39, 42.48, 34.41 (d, J = 23.6 Hz), 25.07 (d, J = 31.6 Hz), 23.83, 21.40.

Enantioselectivity was measured using high performance liquid chromatography. (By-product) = 12.6 min, t (main product) = 14.2 min (OZ-H, 99: 1, hexane: isopropyl alcohol, 254 nm, 0.75 mL /

[Example 24]

0.5 mmol of nitroalkyne having two carbon-containing substituents at the beta position of the formula (2v), 1.5 mmol of dithiomalonate represented by the formula (3-2), 0.075 mmol of the organic catalyst of the formula (1-1b), 0.02 mmol of brine (saturated sodium chloride aqueous solution) mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. The reaction mixture was then extracted with ethyl acetate solvent, the solvent was removed under reduced pressure and the product was isolated using silica chromatography, and the enantiomeric excess was then determined by liquid chromatography.

Enantioselectivity was measured using high performance liquid chromatography. (AD-H, 90:10, hexane: isopropyl alcohol, 254 nm, 1.0 mL / min, t (main product) = 10.6 min, t

[Example 25]

0.5 mmol of nitroalkyne having two carbon-containing substituents at the beta position of Formula 2a, 1.5 mmol of dithiomalonate of Formula 3-2, 0.075 mmol of the organic catalyst of Formula 1-1a, 4.0 g of brine (saturated sodium chloride aqueous solution) 4.0 mL were mixed together with 3.5 mmol of n-hexane and reacted at 20 ° C for 24 hours with stirring. The reaction mixture was then extracted with ethyl acetate solvent, the solvent was removed under reduced pressure and the product was isolated using silica chromatography, and the enantiomeric excess was then determined by liquid chromatography.

Enantioselectivity was measured using high performance liquid chromatography. (By-product) = 12.6 min, t (main product) = 14.2 min (Chiralcel OZ-H, 99: 1, hexane: isopropyl alcohol, 254 nm, 0.75 mL /

[Example 26]

0.5 mmol of nitroalkyne having two carbon-containing substituents at the beta position of Formula 2a, 1.5 mmol of dithiomalonate of Formula 3-2, 0.075 mmol of the organic catalyst of Formula 1-1a, 4.0 g of brine (saturated sodium chloride aqueous solution) 4.0 mL were mixed with 3.5 mmol of cyclohexane and reacted at 20 DEG C for 24 hours with stirring. The reaction mixture was then extracted with ethyl acetate solvent, the solvent was removed under reduced pressure and the product was isolated using silica chromatography, and the enantiomeric excess was then determined by liquid chromatography.

[Example 27]

0.5 mmol of nitroalkyne having two carbon-containing substituents at the beta position of Formula 2a, 1.5 mmol of dithiomalonate of Formula 3-2, 0.075 mmol of the organic catalyst of Formula 1-1a, 4.0 g of brine (saturated sodium chloride aqueous solution) 4.0 mL were mixed together with 3.5 mmol of methylcyclohexane and reacted with stirring at 20 DEG C for 24 hours. The reaction mixture was then extracted with ethyl acetate solvent, the solvent was removed under reduced pressure and the product was isolated using silica chromatography, and the enantiomeric excess was then determined by liquid chromatography.

[Example 28]

0.5 mmol of nitroalkyne having two carbon-containing substituents at the beta position of Formula 2a, 1.5 mmol of dithiomalonate of Formula 3-2, 0.075 mmol of the organic catalyst of Formula 1-1a, 4.0 g of brine (saturated sodium chloride aqueous solution) 4.0 mL was mixed with toluene (3.5 mmol) and reacted at 20 ° C for 24 hours with stirring. The reaction mixture was then extracted with ethyl acetate solvent, the solvent was removed under reduced pressure and the product was isolated using silica chromatography, and the enantiomeric excess was then determined by liquid chromatography.

[Example 29]

0.5 mmol of nitroalkyne having two carbon-containing substituents at the beta position of Formula 2a, 1.5 mmol of dithiomalonate of Formula 3-2, 0.075 mmol of the organic catalyst of Formula 1-1a, 4.0 g of brine (saturated sodium chloride aqueous solution) 4.0 mL were mixed with 3.5 mmol of metaxylene and reacted with stirring at 20 ° C for 24 hours. The reaction mixture was then extracted with ethyl acetate solvent, the solvent was removed under reduced pressure and the product was isolated using silica chromatography, and the enantiomeric excess was then determined by liquid chromatography.

[Example 30]

0.5 mmol of nitroalkyne having two carbon-containing substituents in the beta position of Formula 2a, 1.5 mmol of dithiomalonate of Formula 3-1, 0.075 mmol of the organic catalyst of Formula 1-1d, 4.0 g of brine (saturated sodium chloride aqueous solution) 4.0 mL were mixed together with 3.5 mmol of ortho-xylene and reacted with stirring at 0 ° C for 96 hours. The reaction mixture was then extracted with ethyl acetate solvent, the solvent was removed under reduced pressure and the product was isolated using silica chromatography, and the enantiomeric excess was then determined by liquid chromatography.

Enantioselectivity was measured using high performance liquid chromatography. (AD-H, 90:10, hexane: isopropyl alcohol, 254 nm, 1.0 mL / min, t (main product) = 7.7 min, t (by-product) = 9.3 min

[Example 31]

1.5 mmol of dithiomalonate of Formula 3-1, 0.075 mmol of an organic catalyst of Formula 1-9a, 0.02 mmol of a brine (aqueous solution of saturated sodium chloride) solution, 0.5 mmol of a nitroalkyne having two substituents other than hydrogen at the beta position of Formula 2x, 4.0 mL was mixed with 3.5 mmol ortho-xylene, and the mixture was reacted at 0 DEG C with stirring for 96 hours. The reaction mixture was then extracted with ethyl acetate solvent, the solvent was removed under reduced pressure and the product was isolated using silica chromatography and then the enantiomeric excess was determined using liquid chromatography.

^{1 H NMR (500 MHz, CDCl} 3, Me 4 Si): δ 7.47 (d, J = 7.5 Hz, 2H), 7.42 ?? J = 15.2, 1.7 Hz, 1H), 5.91 (d, J = 15.2 Hz, 1H), 4.42 (s, 1H), 3.01 (dq, J = J = 14.8, 7.4 Hz, 1H), 2.92 (dq, J = 14.8, 7.4 Hz, 1H), 2.50 (dq, J = J = 7.4 Hz, 3H), 0.99 (t, J = 7.4 Hz, 3H); ^{13 C NMR (125 MHz, CDCl} 3): δ 189.78 (d, J = 59.3 Hz), 131.14 (s), 129.07 (s), 128.95 (s), 127.27 (d, J = 1.9 Hz), 73.08 (d , J = 1.2 Hz), 71.34 (d, J = 1.4 Hz), 57.07 (q, J = 25.5 Hz), 29.71 (s), 24.91 (d, J = 16.6 Hz), 13.91 (d, J = 18.9 Hz ); ^{19 F NMR (470 MHz, CDCl} 3): δ -61.29 (s, 3F).

Enantioselectivity was measured using high performance liquid chromatography. (AD-H, 98: 2, hexane: isopropyl alcohol, 254 nm, 1.0 mL / min, t (byproduct) = 14.8 min, t

[Example 32]

0.5 mmol of a nitroalkene having two substituents other than hydrogen in the beta position of Formula 2a, 1.5 mmol of dithiomalonate of Formula 3-1 and 0.075 mmol of triethylamine of Formula 1-17a were dissolved in a brine solution (saturated aqueous sodium chloride solution ), And reacted with stirring at room temperature for 96 hours. The reaction mixture was then extracted with an ethyl acetate solvent, then the solvent was removed under reduced pressure and the product was isolated using silica chromatography.

[Example 33]

0.5 mmol of nitroalkyne having two substituents other than hydrogen at the beta position of Formula 2a, 1.5 mmol of dithiomalonate of Formula 3-1, 0.075 mmol of normal tributylamine of Formula 1-17b were dissolved in a solution of brine (saturated sodium chloride Aqueous solution) and reacted with stirring at room temperature for 48 hours. The reaction mixture was then extracted with an ethyl acetate solvent, then the solvent was removed under reduced pressure and the product was isolated using silica chromatography.

[Example 34]

0.5 mmol of nitroalkyne having two substituents other than hydrogen in the beta position of Formula 2a, 1.5 mmol of dithiomalonate of Formula 3-1 and 0.075 mmol of normal trihexylamine of Formula 1-17c were dissolved in a solution of brine (saturated sodium chloride Aqueous solution) and reacted with stirring at room temperature for 48 hours. The reaction mixture was then extracted with an ethyl acetate solvent, then the solvent was removed under reduced pressure and the product was isolated using silica chromatography.

[Example 35]

0.5 mmol of nitroalkyne having two substituents other than hydrogen in the beta position of formula (2a), 1.5 mmol of dithiomalonate of formula (III-1) and 0.075 mmol of 2-hydroxytriethylamine of formula (1-17d) Saturated aqueous sodium chloride solution) and reacted with stirring at room temperature for 48 hours. The reaction mixture was then extracted with an ethyl acetate solvent, then the solvent was removed under reduced pressure and the product was isolated using silica chromatography.

Example Reactant 2 Reactant 3 product Reaction temperature catalyst time yield % ee Organic / inorganic salt water solution One

20 ℃ Formula 1-1c 96 65 83 Ortho-xylene / brine 2

0 ℃ Formula 1-1d 96 94 92 Ortho-xylene / brine 3

0 ℃ Formula 1-1d 96 42 42 Ortho-xylene / brine 4

0 ℃ Formula 1-1d 96 99 93 Ortho-xylene / brine 5

0 ℃ Formula 1-1d 96 22 92 Ortho-xylene / brine 6

0 ℃ Formula 1-1d 96 88 92 Ortho-xylene / brine 7

0 ℃ Formula 1-1d 96 97 90 Ortho-xylene / brine 8

0 ℃ Formula 1-1d 96 93 92 Ortho-xylene / brine

Example Reactant 2 Reactant 3 product Reaction temperature catalyst time yield % ee Organic / inorganic salt water solution 9

0 ℃ Formula 1-1d 96 90 95 Ortho-xylene / brine 10

0 ℃ 6 96 92 94 Ortho-xylene / brine 11

0 ℃ Formula 1-1d 96 93 88 Ortho-xylene / brine 12

0 ℃ Formula 1-1d 96 91 92 Ortho-xylene / brine 13

0 ℃ Formula 1-1d 96 92 92 Ortho-xylene / brine 14

0 ℃ Formula 1-1d 96 96 92 Ortho-xylene / brine 15

0 ℃ Formula 1-1d 96 86 96 Ortho-xylene / brine

Example Reactant 2 Reactant 3 product Reaction temperature catalyst time yield % ee Organic / inorganic salt water solution 16

0 ℃ Formula 1-1d 96 99 94 Ortho-xylene / brine 17

0 ℃ Formula 1-1d 96 99 95 Ortho-xylene / brine 18

0 ℃ Formula 1-1d 96 34 92 Ortho-xylene / brine 19

0 ℃ Formula 1-1d 96 74 95 Ortho-xylene / brine 20

0 ℃ Formula 1-1d 96 90 95 Ortho-xylene / brine 21

0 ℃ Formula 1-1d 96 88 61 Ortho-xylene / brine 22

0 ℃ Formula 1-1d 96 90 43 Ortho-xylene / brine 23

-15 ℃ Formula 1-1d 120 70 32 Ortho-xylene / brine

Example Reactant 2 Reactant 3 product Reaction temperature catalyst time yield % ee Organic / inorganic salt water solution 24

0 ℃ Formula 1-1d 120 36 5 Ortho-xylene / brine 25

rt Formula 1-1c 24 80 40 Normal hexane / brine 26

rt Formula 1-1c 24 80 38 Cyclohexane / brine 27

rt Formula 1-1c 24 79 15 Methyl cyclohexane / brine 28

rt Formula 1-1c 24 84 28 Tolloine / Brine 29

rt Formula 1-1c 24 85 21 Metaxylene / Brine 30

0 ℃ Formula 1-1b 96 92 94 Ortho-xylene / brine

Example Reactant 2 Reactant 3 product Reaction temperature catalyst time yield % ee Organic / inorganic salt water solution 30

0 ℃ Formula 1-1b 96 92 94 Ortho-xylene / brine 31

0 ℃ 1-9a 96 16 91 Ortho-xylene / brine 32

rt Formula 1-17a 96 99 0 Brine 33

rt Formula 1-17b 48 95 0 Brine 34

rt Formula 1-17c 48 95 0 Brine 35

rt Formula 1-17d 48 95 0 Brine

Example 36: Preparation of a chiral gamma-lactam compound having two carbon-containing substituents in the beta position

(S) -GammaNitrodithioester compound (4b) having two carbon-containing substituents in the beta position prepared in Example 2 1.26 mmol of water was dissolved in 88.4 mmol of trimethylsilane and 7.0 ml of ethanol, and zinc 4.1 g of powder was added slowly at 0 < 0 > C and stirred for 20 minutes. After completion of the reaction, the reaction mixture was quenched with a saturated solution of sodium hydrogencarbonate and extracted with a dichloromethane solution, the solvent was removed under reduced pressure, and the product was separated by silica chromatography. 96 mg of this compound was dissolved in 1.0 ml of water and 1.0 ml of acetone, and the mixture was stirred at 50 캜 for 90 minutes with potassium hydroxide (61 mg). The mixture was concentrated under reduced pressure, acidified with 6N hydrochloric acid solution, extracted with dichloromethane, and concentrated under reduced pressure. This was dissolved in toluene and refluxed for 12 hours. The solvent was then removed under reduced pressure and the chiral gamma lactam product having two carbon-containing substituents at the beta position was separated using silica chromatography.

^{1 H NMR (500 MHz, CDCl} 3, Me 4 Si): δ 7.84 (s, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.23 ?? 7.19 (m, 3H), 3.64 (d, J = 9.6 Hz, 1H), 3.48 (d, J = 9.4 Hz, 1H), 2.77 (d, J = 16.3 Hz, 1H), 2.44 (d, J = 16.3 Hz, < / RTI > 1H), 1.47 (s, 3H).

¹³ C NMR (125 MHz, CDCl ₃ , Me ₄ Si):? 177.83, 146.89, 128.52, 126.37, 125.17, 54.76, 44.46, 43.13, 29.62.

HRMS (m / z, ESI): Calcd for [C ₁₁ H ₁₃ NO + Na] ⁺ : 198.0889; found, 198.0887.

Example 37: Preparation of chiral gamma aminobutyric acid having two carbon containing substituents in the beta position

1.74 mmol of the (S) -gamma- nated dithiothiourethane compound (4b) having two carbon-containing substituents at the beta position prepared in Example 2 was dissolved in 5.8 ml of a 6N hydrochloric acid solution and 10.0 ml of methanol, 1.1 g of powder was slowly added at 0 캜 and stirred for 20 minutes. After completion of the reaction, the reaction solution was quenched with a saturated solution of sodium hydrogencarbonate, passed through a Celite filter, and the filtrate was extracted with a dichloromethane solution. The solvent was removed under reduced pressure and the product was isolated using silica chromatography. 334 mg of this compound was refluxed in a 6N hydrochloric acid solution for 24 hours and then the solvent was removed under reduced pressure to obtain a gamma amino acid hydrochloride salt having two carbon-containing substituents at the beta position.

^{1 H NMR (500 MHz, D} 2 O): δ 7.40 ?? 7.33 (m, 4H), 7.28? 7.25 (m, 1H), 3.39 (d, J = 13.2 Hz, 1H), 3.24 (d, J = 13.2 Hz, 1H), 2.82 (d, J = 15.1 Hz, 1H), 2.71 (d, J = 15.1 Hz, < / RTI > 1H), 1.50 (s, 3H).

¹³ C NMR (125 MHz, D ₂ O): δ 174.69, 140.87, 129.15, 127.74, 126.29, 49.11, 44.09, 39.10, 21.62.

According to the above embodiments, a chiral beta 2-substituted nitro dithiothiazole compound is synthesized in a short time at a high yield, and a chiral beta 2-substituted gamma-aminobutyric acid compound Can be produced through a simple process.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the present invention as defined by the following claims. It can be understood that it is possible.

Claims

delete

In a method for synthesizing a gamma-nitro dithioester compound,
(Β, β-disubstituted nitroalkene compound) having a structure represented by the following formula (2) and a dithiomalonate compound having a structure represented by the following formula (3) in the presence of a catalyst containing a base in an aqueous solution of water or an inorganic salt dithiomalonate compound to a Michael reaction,
The gamma-nitro dithioester compound has a structure represented by the following formula (4)
Wherein the catalyst comprises at least one compound selected from the group consisting of compounds represented by the following Chemical Formulas 1-1 to 1-16:
[Formula 1-1]

[Formula 1-2]

[Formula 1-3]

[Formula 1-4]

[Formula 1-5]

[Chemical Formula 1-6]

[Chemical Formula 1-7]

[Chemical Formula 1-8]

[Chemical Formula 1-9]

[Chemical Formula 1-10]

[Formula 1-11]

[Formula 1-12]

[Formula 1-13]

[Chemical Formula 1-14]

[Chemical Formula 1-15]

[Chemical Formula 1-16]

(2)

(3)

[Chemical Formula 4]

In the above Chemical Formulas 1-1 to 1-16, R is an ethyl group or a vinyl group, R 'is a methoxy group or hydrogen, R ₁ and R ₂ are each an alkyl group, , R ₃ and R ₄ are each an aryl group having 6 to 20 carbon atoms, Ar is a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, n is 0 or 1,
Wherein R ¹ _, R ² , R ³ and R ⁴ are each independently selected from the group consisting of an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, 30 heteroaryl groups and substituents substituted by halogen, nitrogen, oxygen or sulfur thereof, and X is hydrogen or a halogen atom.

delete

In a method for synthesizing a gamma-nitro dithioester compound,
(Β, β-disubstituted nitroalkene compound) having a structure represented by the following formula (2) in the presence of a catalyst containing a tertiary amine compound in an aqueous solution of water or an inorganic salt and a dithioimonate Michael reaction of the dithiomalonate compound,
The gamma-nitro dithioester compound has a structure represented by the following formula (4)
Wherein the tertiary amine compound comprises a compound represented by the following Formula 1-17: < EMI ID =
[Formula 1-17]

(2)

(3)

[Chemical Formula 4]

In Formula 1-17, R ₁ to R ₃ each independently represent an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, a heteroaryl group having 4 to 30 carbon atoms, Gt; is selected from the group consisting of halogen, nitrogen, oxygen or sulfur substituted substituents,
Wherein R ¹ _, R ² , R ³ and R ⁴ are each independently selected from the group consisting of an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, 30 heteroaryl groups and substituents substituted by halogen, nitrogen, oxygen or sulfur thereof, and X is hydrogen or a halogen atom.

The method according to claim 3 or 5,
Wherein the catalyst is used in an amount of 0.1 to 100 mol% based on the nitroalkene compound.

delete

The method according to claim 3 or 5,
Wherein the dithiomalonate comprises at least one of the following chemical formula 3-1 and chemical formula 3-2: < EMI ID =
[Formula 3-1]

[Formula 3-2]

The method according to claim 3 or 5,
Wherein the dithiomalonate compound is used in an amount of 1 to 5 equivalents based on the nitroalkyne compound.

The method according to claim 3 or 5,
Wherein the inorganic salt aqueous solution comprises at least one selected from the group consisting of aqueous sodium chloride solution, aqueous lithium chloride solution, aqueous potassium chloride solution and aqueous cesium chloride solution.

delete

The method according to claim 3 or 5,
Wherein the Michael reaction is carried out with stirring at a temperature of from -15 DEG C to 60 DEG C inclusive.

13. The method of claim 12,
The Michael reaction is carried out in the presence of an organic additive with the catalyst,
Wherein the organic additive comprises at least one selected from the group consisting of toluene, ortho-xylene, meta-xylene, para-xylene, n-hexane, cyclohexane and methylcyclohexane. Synthesis method of nitrodithioesters.

14. The method of claim 13,
Wherein said organic additive is used in an amount of from greater than 0 to greater than 15 equivalents based on said nitroalkyne.

A chiral gamma-nitro dithioester compound comprising a compound having the chemical structure of the following formula (4):
[Chemical Formula 4]

A chiral gamma amino acid compound comprising a compound of formula
[Chemical Formula 5]

In Formula 5, R ₁ to R ₃ independently represent, independently of each other, an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, a heteroaryl group having 4 to 30 carbon atoms And substituents substituted by halogen, nitrogen, oxygen or sulfur thereof, and X is hydrogen or a halogen atom.

Reacting a compound of the formula (4) below to produce a compound of the formula (5); And
And refluxing the compound of formula (5) in an aqueous hydrochloric acid solution to prepare a compound of formula (8): < EMI ID =
[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 8]

In Formula 4, Formula 5 and Formula 8, each of R ¹ to R ⁴ , R ₁ and R ₂ independently represents an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, A heteroaryl group having 4 to 30 carbon atoms, and substituents substituted with halogen, nitrogen, oxygen or sulfur thereof, and X is a hydrogen atom or a halogen atom.

Reacting a compound of the formula (4) below to produce a compound of the formula (5);
Reacting the compound of Formula 5 with a hydroxy group in a solvent to prepare a compound of Formula 6;
Refluxing a compound of formula (6) in an aqueous hydrochloric acid solution to prepare a compound of formula (7); And
And refluxing the compound of formula (7) in an aqueous hydrochloric acid solution to prepare a compound of formula (8): < EMI ID =
[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(7)

[Chemical Formula 8]

In Formula 4 to Formula 8, each of R ¹ to R ⁴ , R ₁ , R _2, and R ₃ is independently selected from the group consisting of an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 30 carbon atoms, An aryl group having 4 to 30 carbon atoms, a heteroaryl group having 4 to 30 carbon atoms, and substituents substituted by halogen, nitrogen, oxygen or sulfur thereof, and X is a hydrogen atom or a halogen atom.

delete