WO2019168269A1 - Bifunctional chiral organocatalytic compound having excellent enantioselectivity, preparation method therefor, and method for producing non-natural gamma-amino acid from nitro compound by using same - Google Patents
Bifunctional chiral organocatalytic compound having excellent enantioselectivity, preparation method therefor, and method for producing non-natural gamma-amino acid from nitro compound by using same Download PDFInfo
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- WO2019168269A1 WO2019168269A1 PCT/KR2019/001003 KR2019001003W WO2019168269A1 WO 2019168269 A1 WO2019168269 A1 WO 2019168269A1 KR 2019001003 W KR2019001003 W KR 2019001003W WO 2019168269 A1 WO2019168269 A1 WO 2019168269A1
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- 0 *N[C@@]([C@@](c1ccccc1)NC(N*)=*)c1ccccc1 Chemical compound *N[C@@]([C@@](c1ccccc1)NC(N*)=*)c1ccccc1 0.000 description 2
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J37/00—Processes, in general, for preparing catalysts; Processes, in general, for activation of catalysts
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/01—Compounds containing nitro groups bound to a carbon skeleton having nitro groups bound to acyclic carbon atoms
- C07C205/03—Compounds containing nitro groups bound to a carbon skeleton having nitro groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C205/04—Compounds containing nitro groups bound to a carbon skeleton having nitro groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/22—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from lactams, cyclic ketones or cyclic oximes, e.g. by reactions involving Beckmann rearrangement
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
Definitions
- the present invention relates to a bifunctional organic chiral catalyst compound having excellent stereoselectivity, a method for producing the same, and a method for producing an unnatural gamma-amino acid from a nitro compound using the organic chiral catalyst compound.
- Amino acids are the basic building blocks of proteins and are divided into natural and unnatural amino acids. Natural amino acids are amino acids that can be obtained in a natural state, mainly used as sweeteners, animal feed, etc., while non-natural amino acids are amino acids that cannot be obtained in a natural state and correspond to isomers of natural amino acids, and are mainly used as raw materials for medicine.
- Optically pure amino acids are of great industrial importance because they are widely used as ligands for asymmetric catalysts or as starting materials or intermediates for the synthesis of various pharmaceuticals and physiologically active substances.
- amino acids obtainable through fermentation are limited to L-amino acids among natural amino acids.
- Optically pure D-amino acids and non-natural amino acids are produced through chrial resolution, optical resolution, and chiral resolution, but due to the high manufacturing costs, natural L-amino acids are produced by fermentation. Compared to this, the unit price is 5-10 times higher and is having difficulty in mass production.
- the present invention seeks to provide a bifunctional organic chiral catalyst compound having excellent stereoselectivity and a method for preparing the same.
- the present invention also provides a method for preparing an unnatural gamma amino acid from a nitro compound using the organic chiral catalyst compound according to the present invention.
- the present invention provides an organic chiral catalyst compound represented by the following [Formula 1] to solve the above problems.
- the present invention is to provide a method for preparing an organic chiral catalyst compound represented by the above [Formula 1] comprising the following (A) step.
- the present invention is to provide a method for producing a non-natural gamma amino acid comprising the following (A) step.
- this functional organic chiral catalyst compound having excellent stereoselectivity can be easily synthesized, and using this, it is possible to obtain a high yield of gamma amino acids having high optical selectivity in an economical and simple manner, as well as a small amount.
- a variety of gamma amino acids in the (R) -form that do not exist in nature can be produced in large quantities with high optical purity, and thus can be widely used in various industrial fields including the pharmaceutical industry.
- FIG. 1 illustrates a structure including a substituent for an organic chiral catalyst compound according to an embodiment of the present invention.
- FIG. 2 shows a synthesis scheme of a single alkylated thiourea catalyst according to one embodiment of the invention.
- Figure 3 shows a synthesis scheme of an arylated thiourea catalyst according to an embodiment of the present invention.
- Figure 4 shows the reaction scheme of the Michael addition reaction according to an embodiment of the present invention.
- Figure 5 shows the reaction scheme of the non-natural gamma amino acid production reaction according to an embodiment of the present invention.
- FIG. 6 shows a scheme of Michael addition reaction for conducting a reaction test according to an organic chiral catalyst compound, a catalyst usage amount, and a type of a solvent according to an embodiment of the present invention.
- Figure 7 shows the reaction scheme of Michael addition reaction for performing a reaction test according to the type of ⁇ , ⁇ -unsaturated nitro compound according to an embodiment of the present invention ( a) used 0.4ml on 0.1 mmol scale ).
- Figure 8 shows the reaction scheme of the non-natural gamma amino acid production reaction according to an embodiment of the present invention.
- Figure 9 shows the reaction scheme of the non-natural gamma amino acid production reaction according to an embodiment of the present invention.
- One aspect of the present invention relates to an organic chiral catalyst compound represented by the following [Formula 1].
- X is any one selected from O, S, PR 3 and NR 4 , and R 1 to R 4 are the same as or different from each other, and each independently hydrogen, deuterium, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted group A substituted C3 to C30 cycloalkyl group, a substituted or unsubstituted C2 to C30 heteroaryl group, a substituted or unsubstituted C6 to C30 aryl group, a substituted or unsubstituted C6 to C30 arylamine group, a substituted or unsubstituted C1 to C30 alkoxy group, substituted or unsubstituted C2 to C30 alkoxycarbonyl group, substituted or unsubstituted C2 to C30 alkoxycarbonylamino group, substituted or unsubstituted C7 to C30 aryloxycarbonylamino group, substituted or unsub
- R 1 may be hydrogen, 3-pentyl, Ph 2 CH, or 3,5- (CF 3 ) 2 -PhCH 2
- R 2 is phenyl, 3,5- (CF 3 ) 2 -Ph, p-tolyl, 4-CF 3 -Ph, C 6 F 5 , 4-NO 2 -Ph, 4-CN-Ph, 4-F-Ph, t-butyl, or 3,5- (Me) 2 -Ph.
- Another aspect of the present invention is to provide a method for preparing an organic chiral catalyst compound represented by the above [Formula 1] comprising the following (A) step.
- Another aspect of the invention relates to a method for preparing a non-natural gamma amino acid comprising the following (A) step.
- Michael addition reaction is performed under the use or non-use of water or organic solvent, more preferably Michael addition reaction under the use or non-use of water solvent, Michael addition reaction Nitrostyl is produced as characterized in that.
- the water is not limited as long as it is a solvent generally called water, lotion, hexagonal water, high temperature vacuum water, distilled water, primary distilled water, secondary distilled water, tertiary distilled water, hydrogen water, extract, salt-containing water, drinking water, sea water , Salt water, brackish water, mineral water, mineral water, rock water, spring water, groundwater, deep water, soft water, tap water, hard water, ionized water, electrolytic water, carbonated water, sweet water, spring water or sea water, the organic solvent is not particularly limited.
- the present invention is characterized in that it further comprises the step of synthesizing pyrrolidinone represented by the following [Formula 3-1] or [Formula 3-2] using the product produced by the Michael addition reaction.
- R 1 and R 2 are the same as or different from each other, and each independently, hydrogen, deuterium, a substituted or unsubstituted C1 to C30 ketone group, a substituted or unsubstituted C1 to C30 nitro group, a substituted or unsubstituted C1 to C30 halogen group, substituted or unsubstituted C1 to C30 cyano group, substituted or unsubstituted C1 to C30 ester group, substituted or unsubstituted C1 to C30 alkyl group, substituted or unsubstituted C3 to C30 cycloalkyl group, substituted or Unsubstituted C2 to C30 heteroaryl group, substituted or unsubstituted C6 to C30 aryl group, substituted or unsubstituted C6 to C30 arylamine group, substituted or unsubstituted C1 to C30 alkoxy group, substituted or unsubstituted C2 To
- the present invention is characterized in that it further comprises the step of preparing a non-natural gamma amino acid represented by the following [Formula 4-1] or [Formula 4-2] by treating pyrrolidinone with hydrochloric acid.
- R is hydrogen, deuterium, substituted or unsubstituted C1 to C30 ketone group, substituted or unsubstituted C1 to C30 nitro group, substituted or unsubstituted C1 to C30 halogen group, substituted or unsubstituted C1 to C30 cyano Groups, substituted or unsubstituted C1 to C30 ester groups, substituted or unsubstituted C1 to C30 alkyl groups, substituted or unsubstituted C3 to C30 cycloalkyl groups, substituted or unsubstituted C2 to C30 heteroaryl groups, substituted or unsubstituted C6 to C30 aryl group, substituted or unsubstituted C6 to C30 arylamine group, substituted or unsubstituted C1 to C30 alkoxy group, substituted or unsubstituted C2 to C30 alkoxycarbonyl group, substituted or unsubstituted C2 to
- R 9 is a phenyl group in [Formula 4-1] or [Formula 4-2], it may be represented by the following [Formula 5-1] or [Formula 5-2], and R is hydrogen Or a halogen group.
- the non-natural gamma amino acid prepared when R is hydrogen is used as a sleep inducing agent as a phenibut (phenibut), and R is chlorine (Cl ),
- the non-natural amino acid produced is baclofen, which is used as a muscle relaxant.
- the basic structure for preparing the organic chiral catalyst compound is (R, R) -1,2-diphenylethylenediamine (DPEN) of the following [Formula 2].
- the basic structure has a structure in which a substituent is bonded toward the amine at position 1,2, and has a form capable of having stereoselectivity at position 1,2.
- Organic chiral catalyst compound of Formula 1 is thiophenyl the R 2 derivative of the element is expected to be higher in this case the nature of the electronic pulling group (electron withdrawing group) substituent of a case attached to the basic structure, R 2 derivative the reaction yield . In addition, it is expected to have excellent stereoselectivity upon reaction by substituting R 1 for two amine groups.
- R 1 when R 1 is hydrogen, R 2 is phenyl (Phenyl, ph), it is an organic chiral catalyst compound 1a; When R 1 is hydrogen and R 2 is 3,5- (CF 3 ) 2 -Ph, it is an organic chiral catalyst compound 1b; An organic chiral catalyst compound 1c when R 1 is a 3-pentyl group and R 2 is p-tolyl; When R 1 is a 3-pentyl group and R 2 is 3,5- (CF 3 ) 2 -Ph, it is an organic chiral catalyst compound 1d; An organic chiral catalyst compound 1e when R 1 is a 3-pentyl group and R 2 is 4-CF 3 -Ph; An organic chiral catalyst compound 1f when R 1 is a 3-pentyl group and R 2 is C 6 F 5 ; When R 1 is a 3-pentyl group and R 2 is 4-NO 2 -Ph, it is 1 g of an organic chiral catalyst compound; When R 1 is a 3-p
- 2-pyrrolidinone is formed as the carboxyl group is dropped through the reaction, and 6N HCl is treated to 2-pyrrolidinone thus formed to the following baclofen of [Formula 4-1] or [Formula 4-2] (Wherein R 9 is phenyl substituted with Cl) or phenibule (unsubstituted phenyl in the formula 4) compound to synthesize (FIGS. 4 and 5).
- ⁇ , ⁇ -unsaturated nitro compound was prepared in the presence of malonitril (2.0 equivalents) and 1 m (0.1-0.001 mol%) of the organic chiral catalyst compound prepared in Example 1, with water (0.4 ml) as a solvent.
- the reaction mixture was stirred at room temperature using and mixed with trans- ⁇ -nitrostyrene (1.0 equiv), malononitrile (2.0 equiv).
- the reaction conversion was monitored by TLC and after completion of the reaction, 6N HCl was added and heated to 65 ° C. for 2 hours. After the reaction mixture was cooled to room temperature, dialkyl carbonate (1.5 equiv) was added and the solution was heated with stirring at 100 ° C. for 3 h.
- Example 2 Using the organic chiral catalyst compound prepared in Example 1, the Michael addition reaction of Example 2 was carried out in the presence of water or toluene as a solvent to confirm the reaction time and yield according to the type of organic chiral catalyst compound and the solvent. (Fig. 6 and Table 3, Table 4).
- trifluoromethyl-substituted organic chiral catalyst compounds can be used in water, which means that the interaction of fluorine atoms in water lowers the activation barrier.
- Example 2 Using the 1 m of the organic chiral catalyst compound prepared in Example 1, the Michael addition reaction of Example 2 was carried out in the presence of water as a solvent, the reaction time and yield according to the type of ⁇ , ⁇ -unsaturated nitro compound Check it. Specifically, to water (0.4 ml) was added trans- ⁇ -nitrostyrene (1.0 equiv), malonitrile (2.0 equiv) and 0.1 to 0.001 mol% of an organic chiral catalyst compound and the reaction mixture was allowed to stand at room temperature (rt). )). Reaction conversion was monitored by TLC. After completion, ethyl acetate (0.2 ml) was added to the reaction mixture.
- IR spectra were recorded on a NICOLET 380 FT-IR spectrophotometer. Optical rotation was measured with a Rudolph Automatic polarimeter (Model name: A20766 APV / 6w).
- 1 H NMR spectra were recorded on Varian Mercury 400 (400 MHz) or Varian Mercury 300 (300 MHz) with TMS as internal reference. 13 C NMR was recorded in Varian Mercury 400 (400 MHz) with TMS or CDCl 3 as internal standard.
- Chiral HPLC analysis was performed on a Jasco LC-1500 Series HPLC system equipped with a UV detector. All reactions were carried out in glassware oven dried under an argon atmosphere. Toluene (CaH 2 ), THF (Na, benzopinone) was dried by distillation before use.
- this functional organic chiral catalyst compound having excellent stereoselectivity can be easily synthesized, and using this, it is possible to obtain a high yield of gamma amino acids having high optical selectivity in an economical and simple manner, as well as a small amount.
- a variety of gamma amino acids in the (R) -form which do not exist in nature can be produced in large quantities with high optical purity, and can be widely used in various industrial fields including the pharmaceutical industry.
Abstract
The present invention relates to a bifunctional chiral organocatalytic compound having excellent enantioselectivity, a preparation method therefor, and a method for producing a non-natural gamma amino acid from a nitro compound by using the chiral organocatalytic compound. According to the present invention, the bifunctional chiral organocatalytic compound having excellent enantioselectivity can be easily synthesized, gamma-amino acids with high optical selectivity can be obtained at a high yield by an economical and convenient method using the chiral organocatalytic compound, and various (R)-configuration gamma-amino acids, which are not present in nature, can be produced with high optical purity in large quantities by using a small amount of a catalyst, and therefore, the present invention can be widely utilized in various industrial fields including the pharmaceutical industry.
Description
본 발명은 입체 선택성이 우수한 이 작용성 유기 키랄 촉매 화합물 및 그 제조 방법과, 상기 유기 키랄 촉매 화합물을 이용한 나이트로 화합물로부터의 비천연 감마-아미노산의 제조 방법에 관한 것이다.The present invention relates to a bifunctional organic chiral catalyst compound having excellent stereoselectivity, a method for producing the same, and a method for producing an unnatural gamma-amino acid from a nitro compound using the organic chiral catalyst compound.
아미노산은 단백질의 기본 구성 단위로 천연 아미노산과 비천연 아미노산으로 구분된다. 천연 아미노산은 자연 상태에서 얻을 수 있는 아미노산으로 주로 감미료, 동물 사료 등으로 이용되는 반면, 비천연 아미노산은 자연 상태에서 얻을 수 없는 아미노산으로 천연 아미노산의 이성질체에 해당하며, 주로 의약품의 원료로 이용된다.Amino acids are the basic building blocks of proteins and are divided into natural and unnatural amino acids. Natural amino acids are amino acids that can be obtained in a natural state, mainly used as sweeteners, animal feed, etc., while non-natural amino acids are amino acids that cannot be obtained in a natural state and correspond to isomers of natural amino acids, and are mainly used as raw materials for medicine.
광학적으로 순수한 아미노산은 비대칭 촉매(asymmetric catalyst)의 리간드로 사용되거나, 각종 의약품 및 생리 활성 물질을 합성하는데 필요한 출발 물질 또는 중간체로 광범위하게 사용되므로 산업적으로 매우 중요한 화합물이다.Optically pure amino acids are of great industrial importance because they are widely used as ligands for asymmetric catalysts or as starting materials or intermediates for the synthesis of various pharmaceuticals and physiologically active substances.
종래 알려진 값싸고 경제적으로 아미노산을 얻는 방법은 발효 방법이다. 그러나 발효를 통해 얻을 수 있는 아미노산은 천연 아미노산 중 L-아미노산에 국한되어 있다. 광학적으로 순수한 D-아미노산 및 비천연 아미노산은 효소법 (chrial resolution), 광학 분할법 (optical resolution), 키랄 분리법 (chiral resolution)을 통해 생산되고 있으나, 제조 비용이 많이 들어 발효로 제조되는 천연 L-아미노산에 비해 단가가 5-10배 가까이 높게 형성되고 있으며 대량 생산에 어려움을 겪고 있다.A cheap and economically known method of obtaining amino acids is a fermentation method. However, amino acids obtainable through fermentation are limited to L-amino acids among natural amino acids. Optically pure D-amino acids and non-natural amino acids are produced through chrial resolution, optical resolution, and chiral resolution, but due to the high manufacturing costs, natural L-amino acids are produced by fermentation. Compared to this, the unit price is 5-10 times higher and is having difficulty in mass production.
아울러, 알데하이드기를 갖는 바이나프톨 유도체를 사용하여 이민 결합을 통해 키랄 아미노알코올 및 아미노산의 키랄성을 인식하고 L-아미노산을 D-아미노산으로 변환시키는 방법이 보고된바 있으나, 경제적이고 간편한 방법으로 높은 광학선택성을 갖는 비천연 아미노산을 제조할 수 있는 방법이 필요한 실정이다.In addition, a method of recognizing chiral aminoalcohol and amino acid chirality and converting L-amino acid to D-amino acid through imine bond using a binaphthol derivative having an aldehyde group has been reported, but high optical selectivity in an economical and convenient manner. There is a need for a method that can produce non-natural amino acids having.
이에, 본 발명자들은 상술한 바와 같은 종래 기술의 문제점을 해결하고자 예의 노력한 결과, 특정한 구조를 가지는 유기 키랄 촉매 화합물을 이용하는 경우, 적은 양의 촉매로, 자연에 존재하지 않는 다양한 비천연 감마 아미노산을 높은 광학 순도로 대량으로 제조할 수 있을 확인하고, 본 발명을 완성하기에 이르렀다.Thus, the present inventors have made efforts to solve the problems of the prior art as described above, when using an organic chiral catalyst compound having a specific structure, a high amount of various non-natural gamma amino acids that do not exist in nature with a small amount of catalyst It confirmed that it could manufacture in large quantities by optical purity, and came to complete this invention.
따라서, 본 발명은 입체 선택성이 우수한 이 작용성 유기 키랄 촉매 화합물과 이의 제조 방법을 제공하고자 한다.Accordingly, the present invention seeks to provide a bifunctional organic chiral catalyst compound having excellent stereoselectivity and a method for preparing the same.
또한, 본 발명은 본 발명에 따른 유기 키랄 촉매 화합물을 이용한 나이트로 화합물로부터의 비천연 감마 아미노산의 제조 방법을 제공하고자 한다.The present invention also provides a method for preparing an unnatural gamma amino acid from a nitro compound using the organic chiral catalyst compound according to the present invention.
본 발명은 상기 과제를 해결하기 위하여, 하기 [화학식 1]로 표기되는 유기 키랄 촉매 화합물을 제공한다.The present invention provides an organic chiral catalyst compound represented by the following [Formula 1] to solve the above problems.
[화학식 1][Formula 1]
상기 [화학식 1]의 구조 및 치환 기에 대한 상세한 설명은 후술하기로 한다.Detailed description of the structure and substituents of the above [Formula 1] will be described later.
또한, 본 발명은 하기 (가) 단계를 포함하여 상기 [화학식 1]로 표시되는 유기 키랄 촉매 화합물의 제조방법을 제공하고자 한다.In addition, the present invention is to provide a method for preparing an organic chiral catalyst compound represented by the above [Formula 1] comprising the following (A) step.
(가) 하기 [화학식 2]로 표시되는 (R,R)-1,2-다이페닐에틸렌다이아민 (DPEN)을 싸이오요소 (thiourea)와 반응시키는 단계.(A) reacting (R, R) -1,2-diphenylethylenediamine (DPEN) represented by the following [Formula 2] with a thiourea (thiourea).
[화학식 2][Formula 2]
또한, 본 발명은 하기 (A) 단계를 포함하여 비천연 감마 아미노산의 제조 방법을 제공하고자 한다.In addition, the present invention is to provide a method for producing a non-natural gamma amino acid comprising the following (A) step.
(A) 상기 [화학식 1]로 표시되는 유기 키랄 촉매 화합물 존재 하에서, α,β-불포화 나이트로 화합물을 말론산 또는 말로나이트릴과 마이클 첨가반응 시키는 단계.(A) reacting the α, β-unsaturated nitro compound with malonic acid or malonitrile and Michael in the presence of an organic chiral catalyst compound represented by the above [Formula 1].
본 발명에 따르면 입체 선택성이 우수한 이 작용성 유기 키랄 촉매 화합물을 쉽게 합성할 수 있으며, 이를 이용하여 경제적이고 간편한 방법으로 높은 광학 선택성을 갖는 감마 아미노산을 높은 수율로 수득할 수 있을 뿐만 아니라, 적은 양의 촉매로, 자연에 존재하지 않는 (R)-형태의 다양한 감마 아미노산을 높은 광학 순도로 대량으로 제조할 수 있는바, 의약품 산업을 비롯한 다양한 산업 분야에 있어서 널리 활용될 수 있다.According to the present invention, this functional organic chiral catalyst compound having excellent stereoselectivity can be easily synthesized, and using this, it is possible to obtain a high yield of gamma amino acids having high optical selectivity in an economical and simple manner, as well as a small amount. As a catalyst of, a variety of gamma amino acids in the (R) -form that do not exist in nature can be produced in large quantities with high optical purity, and thus can be widely used in various industrial fields including the pharmaceutical industry.
도 1은 본 발명의 일 실시예에 따른 유기 키랄 촉매 화합물에 대해서 치환기를 포함한 구조로 나타낸 것이다.1 illustrates a structure including a substituent for an organic chiral catalyst compound according to an embodiment of the present invention.
도 2는 본 발명의 일 실시예에 따른 단일 알킬화된 싸이오요소 촉매의 합성 반응식을 나타낸 것이다.2 shows a synthesis scheme of a single alkylated thiourea catalyst according to one embodiment of the invention.
도 3은 본 발명의 일 실시예에 따른 아릴화된 싸이오요소 촉매의 합성 반응식을 나타낸 것이다.Figure 3 shows a synthesis scheme of an arylated thiourea catalyst according to an embodiment of the present invention.
도 4는 본 발명의 일 실시예에 따른 마이클 첨가 반응의 반응식을 나타낸 것이다.Figure 4 shows the reaction scheme of the Michael addition reaction according to an embodiment of the present invention.
도 5는 본 발명의 일 실시예에 따른 비천연 감마 아미노산 제조 반응의 반응식을 나타낸 것이다.Figure 5 shows the reaction scheme of the non-natural gamma amino acid production reaction according to an embodiment of the present invention.
도 6은 본 발명의 일 실시예에 따른 유기 키랄 촉매 화합물, 촉매 사용량 및 용매의 종류에 따른 반응 시험을 수행하기 위한 마이클 첨가 반응의 반응식을 나타낸 것이다.FIG. 6 shows a scheme of Michael addition reaction for conducting a reaction test according to an organic chiral catalyst compound, a catalyst usage amount, and a type of a solvent according to an embodiment of the present invention.
도 7은 본 발명의 일 실시예에 따른 α,β-불포화 나이트로 화합물의 종류에 따른 반응 시험을 수행하기 위한 마이클 첨가 반응의 반응식을 나타낸 것이다 (
a)는 0.1 mmol 규모 상 0.4ml을 사용하였음을 나타냄).Figure 7 shows the reaction scheme of Michael addition reaction for performing a reaction test according to the type of α, β-unsaturated nitro compound according to an embodiment of the present invention ( a) used 0.4ml on 0.1 mmol scale ).
도 8은 본 발명의 일 실시예에 따른 비천연 감마 아미노산 제조 반응의 반응식을 나타낸 것이다.Figure 8 shows the reaction scheme of the non-natural gamma amino acid production reaction according to an embodiment of the present invention.
도 9는 본 발명의 일 실시예에 따른 비천연 감마 아미노산 제조 반응의 반응식을 나타낸 것이다.Figure 9 shows the reaction scheme of the non-natural gamma amino acid production reaction according to an embodiment of the present invention.
다른 식으로 정의되지 않는 한, 본 명세서에서 사용된 모든 기술적 및 과학적 용어들은 본 발명이 속하는 기술 분야에서 숙련된 전문가에 의해서 통상적으로 이해되는 것과 동일한 의미를 가진다. 일반적으로, 본 명세서에서 사용된 명명법은 본 기술 분야에서 잘 알려져 있고 통상적으로 사용되는 것이다.Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein is well known and commonly used in the art.
본 발명의 일 측면은 하기 [화학식 1]로 표시되는 유기 키랄 촉매 화합물에 관한 것이다.One aspect of the present invention relates to an organic chiral catalyst compound represented by the following [Formula 1].
[화학식 1][Formula 1]
상기 [화학식 1]에서,In [Formula 1],
X는 O, S, P-R
3 및 N-R
4 중에서 선택되는 어느 하나이고, R
1 내지 R
4는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 중수소, 치환 또는 비치환된 C1 내지 C30 알킬기, 치환 또는 비치환된 C3 내지 C30 사이클로알킬기, 치환 또는 비치환된 C2 내지 C30 헤테아릴기, 치환 또는 비치환된 C6 내지 C30 아릴기, 치환 또는 비치환된 C6 내지 C30 아릴아민기, 치환 또는 비치환된 C1 내지 C30 알콕시기, 치환 또는 비치환된 C2 내지 C30 알콕시카르보닐기, 치환 또는 비치환된 C2 내지 C30 알콕시카르보닐아미노기, 치환 또는 비치환된 C7 내지 C30 아릴옥시카르보닐아미노기, 치환 또는 비치환된 C2 내지 C30 알케닐기, 치환 또는 비치환된 C2 내지 C30 알키닐기, 치환 또는 비치환된 C3 내지 C40 실릴기, 치환 또는 비치환된 3 내지 C40 실릴옥시기, 치환 또는 비치환된 C1 내지 30 아실기, 치환 또는 비치환된 C1 내지 C20 아실옥시기 및 치환 또는 비치환된 C1 내지 C20 아실아미노기 중에서 선택되는 어느 하나이다.X is any one selected from O, S, PR 3 and NR 4 , and R 1 to R 4 are the same as or different from each other, and each independently hydrogen, deuterium, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted group A substituted C3 to C30 cycloalkyl group, a substituted or unsubstituted C2 to C30 heteroaryl group, a substituted or unsubstituted C6 to C30 aryl group, a substituted or unsubstituted C6 to C30 arylamine group, a substituted or unsubstituted C1 to C30 alkoxy group, substituted or unsubstituted C2 to C30 alkoxycarbonyl group, substituted or unsubstituted C2 to C30 alkoxycarbonylamino group, substituted or unsubstituted C7 to C30 aryloxycarbonylamino group, substituted or unsubstituted C2 to C30 Alkenyl groups, substituted or unsubstituted C2 to C30 alkynyl groups, substituted or unsubstituted C3 to C40 silyl groups, substituted or unsubstituted 3 to C40 silyloxy groups, substituted or unsubstituted C1 to 30 acyl groups, It is one which is selected from ring or unsubstituted C1 to C20 acyloxy group, and a substituted or unsubstituted C1 to C20 acyl group.
본 발명의 바람직한 구현예에 의하면, R
1은 수소, 3-펜틸, Ph
2CH, 또는 3,5-(CF
3)
2-PhCH
2일 수 있으며, R
2는 페닐, 3,5-(CF
3)
2-Ph, p-톨릴, 4-CF
3-Ph, C
6F
5, 4-NO
2-Ph, 4-CN-Ph, 4-F-Ph, t-부틸, 또는 3,5-(Me)
2-Ph일 수 있다.According to a preferred embodiment of the invention, R 1 may be hydrogen, 3-pentyl, Ph 2 CH, or 3,5- (CF 3 ) 2 -PhCH 2 , and R 2 is phenyl, 3,5- (CF 3 ) 2 -Ph, p-tolyl, 4-CF 3 -Ph, C 6 F 5 , 4-NO 2 -Ph, 4-CN-Ph, 4-F-Ph, t-butyl, or 3,5- (Me) 2 -Ph.
본 발명의 다른 일 측면은 하기 (가) 단계를 포함하여 상기 [화학식 1]로 표시되는 유기 키랄 촉매 화합물의 제조방법을 제공하고자 한다.Another aspect of the present invention is to provide a method for preparing an organic chiral catalyst compound represented by the above [Formula 1] comprising the following (A) step.
(가) 하기 [화학식 2]로 표시되는 (R,R)-1,2-다이페닐에틸렌다이아민 (DPEN)을 싸이오요소 (thiourea)와 반응시키는 단계.(A) reacting (R, R) -1,2-diphenylethylenediamine (DPEN) represented by the following [Formula 2] with a thiourea (thiourea).
[화학식 2][Formula 2]
본 발명의 또 다른 일 측면은 하기 (A) 단계를 포함하여 비천연 감마 아미노산을 제조하는 방법에 관한 것이다.Another aspect of the invention relates to a method for preparing a non-natural gamma amino acid comprising the following (A) step.
(A) 상기 [화학식 1]로 표시되는 유기 키랄 촉매 화합물 존재 하에서, α,β-불포화 나이트로 화합물을 말로네이트 또는 말로나이트릴과 마이클 첨가반응시키는 단계.(A) reacting the α, β-unsaturated nitro compound with malonate or malonitrile and Michael in the presence of an organic chiral catalyst compound represented by the above [Formula 1].
본 발명의 바람직한 구현 예에 의하면, 물 또는 유기용매를 사용 또는 비사용 하에서 마이클 첨가반응이 이루어지며, 보다 바람직하게 물 용매를 사용 또는 비사용 하에서 마이클 첨가반응시키는 것을 특징으로 하며, 상기 마이클 첨가반응으로 나이트로스타일렌이 생성되는 것을 특징으로 한다.According to a preferred embodiment of the present invention, Michael addition reaction is performed under the use or non-use of water or organic solvent, more preferably Michael addition reaction under the use or non-use of water solvent, Michael addition reaction Nitrostyl is produced as characterized in that.
상기 물은 일반적으로 물로 칭해지는 용매이면 제한되지 않으며, 화장수, 육각수, 고온 진공수, 증류수, 1차 증류수, 2차 증류수, 3차 증류수, 수소수, 추출물, 염분을 함유하는 물, 음용수, 해수, 소금물, 기수, 약수, 광천수, 암반수, 샘물, 지하수, 심층수, 연수, 수돗물, 경수, 이온수, 전해수, 탄산수, 단물, 샘물 또는 바닷물일 수 있으며, 상기 유기용매 역시 특별히 제한되지 않는다.The water is not limited as long as it is a solvent generally called water, lotion, hexagonal water, high temperature vacuum water, distilled water, primary distilled water, secondary distilled water, tertiary distilled water, hydrogen water, extract, salt-containing water, drinking water, sea water , Salt water, brackish water, mineral water, mineral water, rock water, spring water, groundwater, deep water, soft water, tap water, hard water, ionized water, electrolytic water, carbonated water, sweet water, spring water or sea water, the organic solvent is not particularly limited.
또한, 본 발명에 있어서, 마이클 첨가반응으로 생성된 생성물을 이용하여 하기 [화학식 3-1] 또는 [화학식 3-2]로 표시되는 피롤리딘온을 합성하는 단계를 더 포함하는 것을 특징으로 한다.In addition, the present invention is characterized in that it further comprises the step of synthesizing pyrrolidinone represented by the following [Formula 3-1] or [Formula 3-2] using the product produced by the Michael addition reaction.
[화학식 3-1][Formula 3-1]
[화학식 3-2][Formula 3-2]
상기 [화학식 3-1] 또는 [화학식 3-2]에서,In [Formula 3-1] or [Formula 3-2],
R
1 및 R
2는 서로 동일하거나 상이하고, 각각 독립적으로, 수소, 중수소, 치환 또는 비치환된 C1 내지 C30 케톤기, 치환 또는 비치환된 C1 내지 C30 나이트로기, 치환 또는 비치환된 C1 내지 C30 할로겐기, 치환 또는 비치환된 C1 내지 C30 사이아노기, 치환 또는 비치환된 C1 내지 C30 에스터기, 치환 또는 비치환된 C1 내지 C30 알킬기, 치환 또는 비치환된 C3 내지 C30 사이클로알킬기, 치환 또는 비치환된 C2 내지 C30 헤테아릴기, 치환 또는 비치환된 C6 내지 C30 아릴기, 치환 또는 비치환된 C6 내지 C30 아릴아민기, 치환 또는 비치환된 C1 내지 C30 알콕시기, 치환 또는 비치환된 C2 내지 C30 알콕시카르보닐기, 치환 또는 비치환된 C2 내지 C30 알콕시카르보닐아미노기, 치환 또는 비치환된 C7 내지 C30 아릴옥시카르보닐아미노기, 치환 또는 비치환된 C2 내지 C30 알케닐기, 치환 또는 비치환된 C2 내지 C30 알키닐기, 치환 또는 비치환된 C3 내지 C40 실릴기, 치환 또는 비치환된 3 내지 C40 실릴옥시기, 치환 또는 비치환된 C1 내지 30 아실기, 치환 또는 비치환된 C1 내지 C20 아실옥시기 및 치환 또는 비치환된 C1 내지 C20 아실아미노기 중에서 선택되는 어느 하나이다.R 1 and R 2 are the same as or different from each other, and each independently, hydrogen, deuterium, a substituted or unsubstituted C1 to C30 ketone group, a substituted or unsubstituted C1 to C30 nitro group, a substituted or unsubstituted C1 to C30 halogen group, substituted or unsubstituted C1 to C30 cyano group, substituted or unsubstituted C1 to C30 ester group, substituted or unsubstituted C1 to C30 alkyl group, substituted or unsubstituted C3 to C30 cycloalkyl group, substituted or Unsubstituted C2 to C30 heteroaryl group, substituted or unsubstituted C6 to C30 aryl group, substituted or unsubstituted C6 to C30 arylamine group, substituted or unsubstituted C1 to C30 alkoxy group, substituted or unsubstituted C2 To C30 alkoxycarbonyl group, substituted or unsubstituted C2 to C30 alkoxycarbonylamino group, substituted or unsubstituted C7 to C30 aryloxycarbonylamino group, substituted or unsubstituted C2 to C30 alkenyl group, substituted or Is an unsubstituted C2 to C30 alkynyl group, a substituted or unsubstituted C3 to C40 silyl group, a substituted or unsubstituted 3 to C40 silyloxy group, a substituted or unsubstituted C1 to 30 acyl group, a substituted or unsubstituted C1 To C20 acyloxy group and substituted or unsubstituted C1 to C20 acylamino group.
또한, 본 발명에 있어서, 피롤리딘온에 염산을 처리하여 하기 [화학식 4-1] 또는 [화학식 4-2]로 표시되는 비천연 감마 아미노산을 제조하는 단계를 더 포함하는 것을 특징으로 한다.In addition, the present invention is characterized in that it further comprises the step of preparing a non-natural gamma amino acid represented by the following [Formula 4-1] or [Formula 4-2] by treating pyrrolidinone with hydrochloric acid.
[화학식 4-1][Formula 4-1]
[화학식 4-2][Formula 4-2]
상기 [화학식 4-1] 또는 [화학식 4-2]에서,In [Formula 4-1] or [Formula 4-2],
R은 수소, 중수소, 치환 또는 비치환된 C1 내지 C30 케톤기, 치환 또는 비치환된 C1 내지 C30 나이트로기, 치환 또는 비치환된 C1 내지 C30 할로겐기, 치환 또는 비치환된 C1 내지 C30 사이아노기, 치환 또는 비치환된 C1 내지 C30 에스터기, 치환 또는 비치환된 C1 내지 C30 알킬기, 치환 또는 비치환된 C3 내지 C30 사이클로알킬기, 치환 또는 비치환된 C2 내지 C30 헤테아릴기, 치환 또는 비치환된 C6 내지 C30 아릴기, 치환 또는 비치환된 C6 내지 C30 아릴아민기, 치환 또는 비치환된 C1 내지 C30 알콕시기, 치환 또는 비치환된 C2 내지 C30 알콕시카르보닐기, 치환 또는 비치환된 C2 내지 C30 알콕시카르보닐아미노기, 치환 또는 비치환된 C7 내지 C30 아릴옥시카르보닐아미노기, 치환 또는 비치환된 C2 내지 C30 알케닐기, 치환 또는 비치환된 C2 내지 C30 알키닐기, 치환 또는 비치환된 C3 내지 C40 실릴기, 치환 또는 비치환된 3 내지 C40 실릴옥시기, 치환 또는 비치환된 C1 내지 30 아실기, 치환 또는 비치환된 C1 내지 C20 아실옥시기 및 치환 또는 비치환된 C1 내지 C20 아실아미노기 중에서 선택되는 어느 하나이다.R is hydrogen, deuterium, substituted or unsubstituted C1 to C30 ketone group, substituted or unsubstituted C1 to C30 nitro group, substituted or unsubstituted C1 to C30 halogen group, substituted or unsubstituted C1 to C30 cyano Groups, substituted or unsubstituted C1 to C30 ester groups, substituted or unsubstituted C1 to C30 alkyl groups, substituted or unsubstituted C3 to C30 cycloalkyl groups, substituted or unsubstituted C2 to C30 heteroaryl groups, substituted or unsubstituted C6 to C30 aryl group, substituted or unsubstituted C6 to C30 arylamine group, substituted or unsubstituted C1 to C30 alkoxy group, substituted or unsubstituted C2 to C30 alkoxycarbonyl group, substituted or unsubstituted C2 to C30 alkoxy Carbonylamino group, substituted or unsubstituted C7 to C30 aryloxycarbonylamino group, substituted or unsubstituted C2 to C30 alkenyl group, substituted or unsubstituted C2 to C30 alkynyl group, substituted or unsubstituted C3 to C40 silyl group, substituted or unsubstituted 3 to C40 silyloxy group, substituted or unsubstituted C1 to 30 acyl group, substituted or unsubstituted C1 to C20 acyloxy group and substituted or unsubstituted C1 to C20 acyl It is either selected from amino groups.
본 발명에 있어서, 상기 [화학식 4-1] 또는 [화학식 4-2]에서 R
9이 페닐기인 경우에 하기 [화학식 5-1] 또는 [화학식 5-2]로 표시될 수 있으며, R은 수소 또는 할로겐기이다.In the present invention, when R 9 is a phenyl group in [Formula 4-1] or [Formula 4-2], it may be represented by the following [Formula 5-1] or [Formula 5-2], and R is hydrogen Or a halogen group.
[화학식 5-1][Formula 5-1]
[화학식 5-2][Formula 5-2]
본 발명에 있어서, 상기 [화학식 5-1] 또는 [화학식 5-2]에서, R이 수소인 경우 제조되는 비천연 감마 아미노산은 페니붓 (phenibut)으로 수면 유도제로 사용되며, R이 염소(Cl)인 경우 제조되는 비천연 아미노산은 바클로펜 (baclofen)으로 근육이완제로 사용된다.In the present invention, in [Formula 5-1] or [Formula 5-2], the non-natural gamma amino acid prepared when R is hydrogen is used as a sleep inducing agent as a phenibut (phenibut), and R is chlorine (Cl ), The non-natural amino acid produced is baclofen, which is used as a muscle relaxant.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as being limited by these examples. Thus, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
실시예 1 : 유기 키랄 촉매 화합물의 제조Example 1 Preparation of Organic Chiral Catalyst Compounds
1-1 : 유기 키랄 촉매 화합물의 기본(backbone) 구조1-1: Backbone Structure of Organic Chiral Catalyst Compound
유기 키랄 촉매 화합물을 제조하기 위한 기본 구조는 하기 [화학식 2]의 (R,R)-1,2-다이페닐에틸렌다이아민 (DPEN)이다.The basic structure for preparing the organic chiral catalyst compound is (R, R) -1,2-diphenylethylenediamine (DPEN) of the following [Formula 2].
[화학식 2][Formula 2]
상기 기본 구조는 1,2번 위치의 아민 쪽으로 치환기가 결합되는 구조를 가지고 있으며, 1,2번 위치에 입체선택성을 가질 수 있는 형태를 가지고 있다.The basic structure has a structure in which a substituent is bonded toward the amine at position 1,2, and has a form capable of having stereoselectivity at position 1,2.
1-2: 유기 키랄 촉매 화합물의 제조1-2: Preparation of Organic Chiral Catalyst Compounds
상기 실시예 1-1의 유기 키랄 촉매 화합물의 기본 구조를 싸이오요소 (thiourea)와 반응시켜 하기 [화학식 1]의 유기 키랄 촉매 화합물을 제조한다 (하기 도 1).The basic structure of the organic chiral catalyst compound of Example 1-1 is reacted with thiourea (thiourea) to prepare an organic chiral catalyst compound of the following [Formula 1] (FIG. 1).
[화학식 1][Formula 1]
상기 [화학식 1]의 유기 키랄 촉매 화합물은 싸이오요소의 R
2 유도체가 기본 구조에 부착된 경우로, R
2 유도체의 특성상 전자 당김 그룹 (electron withdrawing group) 치환기의 경우 반응 수율이 높을 것으로 예측된다. 또한, 2번의 아민기에 R
1을 치환하여 반응 시 우수한 입체선택성을 가질 것으로 예측된다.Organic chiral catalyst compound of Formula 1 is thiophenyl the R 2 derivative of the element is expected to be higher in this case the nature of the electronic pulling group (electron withdrawing group) substituent of a case attached to the basic structure, R 2 derivative the reaction yield . In addition, it is expected to have excellent stereoselectivity upon reaction by substituting R 1 for two amine groups.
단일알킬화된 (monoalkylated) 싸이오요소 촉매의 합성Synthesis of Monoalkylated Thiourea Catalysts
톨루엔 (0.1 M) 내 (R,R)-1,2-다이페닐에틸렌다이아민 (1.0 당량)의 현탁액에 3-펜탄온 (1.1 당량), MgSO
4 용액을 첨가하고, 그 혼합물을 48 시간 동안 환류시켰다. 그 다음 셀라이트(celite) 필터로 MgSO
4를 제거하고 진공농축하였다. NaBH
4
(4.0 당량) 및 에탄올을 첨가하고, 그 혼합물을 실온에서 1시간 동안 교반시켰다. 1N NaOH 용액으로 담금질(quenching)하고, 그 혼합물을 에틸 아세테이트로 추출하였다. 조합된 유기 추출물을 염수 (brine)로 세척하고, 건조시키고 (MgSO
4), 진공 농축하였다. 생성물을 실리카-겔 칼럼 (메탄올 / 메틸렌클로라이드 1 : 20)에서 정제하였다. CH
2Cl
2
(0.1 M) 내 단일알킬화된 DPEN (1.0 당량)에 싸이오요소 (1.1 당량)를 첨가하고, 그 혼합물을 실온에서 1시간 동안 교반시켰다. 에틸 아세테이트 / 헥산 (1 : 5)를 포함하는 실리카 겔에서 플래쉬 칼럼 크로마토 그래피로 정제하여, 백색 발포 고체로서, 순수한 아마이드 생성물 (정량적 수율)을 수득하였다 (도 2).To a suspension of (R, R) -1,2-diphenylethylenediamine (1.0 equiv) in toluene (0.1 M) is added a solution of 3-pentanone (1.1 equiv), MgSO 4 , and the mixture is added for 48 hours. It was refluxed. Then MgSO 4 was removed with a celite filter and concentrated in vacuo. NaBH 4 (4.0 equiv) and ethanol were added and the mixture was stirred at rt for 1 h. Quenched with 1N NaOH solution and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The product was purified on silica-gel column (methanol / methylene chloride 1: 20). CH 2 Cl 2 To a monoalkylated DPEN (1.0 equiv) in (0.1 M) was added thiourea (1.1 equiv) and the mixture was stirred at rt for 1 h. Purification by flash column chromatography on silica gel comprising ethyl acetate / hexanes (1: 5) gave pure amide product (quantitative yield) as a white foamed solid (Figure 2).
아릴화된 (arylated) 싸이오요소 촉매의 합성Synthesis of Arylated Thiourea Catalyst
톨루엔 (0.5 M) 내 (R,R)-1,2-다이페닐에틸렌다이아민 (1.0 당량)의 현탁액에 싸이오요소 (1.0 당량)를 0 ℃에서 첨가하고, 그 혼합물을 30초 동안 교반시켰다. 생성물을 진공농축하고, 에틸 (메탄올 / 메틸렌 클로라이드 1 : 20)을 포함하는 실리카 겔에서 플래쉬 칼럼 크로마토그래피로 정제하였다. CH
2Cl
2
(0.1 M) 내의 싸이오요소 치환된 DPEN (1.0 당량)에 알킬 케톤 (1.1 당량)을 첨가하였고, 그 혼합물을 실온에서 1 시간 동안 교반시켰다. NaBH
4
(2.0 당량) 및 에탄올을 0 ℃에서 첨가하고, 그 혼합물을 실온에서 1 시간 동안 교반시켰다. 생성물을 셀라이트 필터로 여과하고, 그 혼합물을 에틸 아세테이트로 추출하였다. 조합된 유기 추출물을 염수(brine)로 세척하고, 건조시키고 (MgSO
4), 진공 농축하였다. 생성물을 실리카-겔 칼럼 (메탄올 / 메틸렌 클로라이드 1 : 20)에서 크로마토그래피로 정제하여, 갈색 발포 고체로서, 순수한 아마이드 생성물 (정량적 수율)을 수득하였다 (하기 도 3).To a suspension of (R, R) -1,2-diphenylethylenediamine (1.0 equiv) in toluene (0.5 M) was added thiourea (1.0 equiv) at 0 ° C. and the mixture was stirred for 30 seconds. . The product was concentrated in vacuo and purified by flash column chromatography on silica gel containing ethyl (methanol / methylene chloride 1:20). CH 2 Cl 2 To a thiourea substituted DPEN (1.0 equiv) in (0.1 M) was added an alkyl ketone (1.1 equiv) and the mixture was stirred at rt for 1 h. NaBH 4 (2.0 equiv) and ethanol were added at 0 ° C. and the mixture was stirred at rt for 1 h. The product was filtered through a celite filter and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The product was purified by chromatography on a silica-gel column (methanol / methylene chloride 1:20) to give pure amide product (quantitative yield) as a brown foamed solid (Figure 3 below).
상기 [화학식 1]에서, R
1이 수소, R
2가 페닐(Phenyl, ph)인 경우 유기 키랄 촉매 화합물 1a이고; R
1이 수소, R
2가 3,5-(CF
3)
2-Ph인 경우 유기 키랄 촉매 화합물 1b이고; R
1이 3-펜틸기, R
2가 p-톨릴인 경우 유기 키랄 촉매 화합물 1c이고; R
1이 3-펜틸기, R
2가 3,5-(CF
3)
2-Ph인 경우 유기 키랄 촉매 화합물 1d이고; R
1이 3-펜틸기, R
2가 4-CF
3-Ph인 경우 유기 키랄 촉매 화합물 1e이고; R
1이 3-펜틸기, R
2가 C
6F
5인 경우 유기 키랄 촉매 화합물 1f이고; R
1이 3-펜틸기, R
2가 4-NO
2-Ph인 경우 유기 키랄 촉매 화합물 1g이고; R
1이 3-펜틸기, R
2가 4-NC-Ph인 경우 유기 키랄 촉매 화합물 1h이고; R
1이 3-펜틸기, R
2가 4-F-Ph인 경우 유기 키랄 촉매 화합물 1i이고; R
1이 Ph
2CH, R
2가 3,5-(CF
3)
2-Ph인 경우 유기 키랄 촉매 화합물 1j이고; R
1이 Ph
2CH, R
2가 t-부틸인 경우 유기 키랄 촉매 화합물 1k이고; R
1이 Ph
2CH, R
2가 4-CF
3-Ph인 경우 유기 키랄 촉매 화합물 1l이고; R
1이 3,5-(CF
3)
2-Ph-CH
2, R
2가 3,5-(CF
3)
2-Ph인 경우 유기 키랄 촉매 화합물 1m이고; R
1이 3,5-(CF
3)
2-Ph-CH
2, R
2가 3,5-(CF
3)
2-Ph인 경우 유기 키랄 촉매 화합물 1n이다 (하기 도 1 및 표 1).In Formula 1, when R 1 is hydrogen, R 2 is phenyl (Phenyl, ph), it is an organic chiral catalyst compound 1a; When R 1 is hydrogen and R 2 is 3,5- (CF 3 ) 2 -Ph, it is an organic chiral catalyst compound 1b; An organic chiral catalyst compound 1c when R 1 is a 3-pentyl group and R 2 is p-tolyl; When R 1 is a 3-pentyl group and R 2 is 3,5- (CF 3 ) 2 -Ph, it is an organic chiral catalyst compound 1d; An organic chiral catalyst compound 1e when R 1 is a 3-pentyl group and R 2 is 4-CF 3 -Ph; An organic chiral catalyst compound 1f when R 1 is a 3-pentyl group and R 2 is C 6 F 5 ; When R 1 is a 3-pentyl group and R 2 is 4-NO 2 -Ph, it is 1 g of an organic chiral catalyst compound; When R 1 is a 3-pentyl group and R 2 is 4-NC-Ph, it is an organic chiral catalyst compound 1h; When R 1 is a 3-pentyl group and R 2 is 4-F-Ph, it is an organic chiral catalyst compound 1i; When R 1 is Ph 2 CH and R 2 is 3,5- (CF 3 ) 2 -Ph, it is an organic chiral catalyst compound 1j; When R 1 is Ph 2 CH and R 2 is t-butyl, it is an organic chiral catalyst compound 1k; When R 1 is Ph 2 CH and R 2 is 4-CF 3 -Ph, it is an organic chiral catalyst compound 1 l ; When the R 1 is 3,5- (CF 3 ) 2 -Ph-CH 2 , and R 2 is 3,5- (CF 3 ) 2 -Ph, the organic chiral catalyst compound is 1 m; When R 1 is 3,5- (CF 3 ) 2 -Ph-CH 2 , and R 2 is 3,5- (CF 3 ) 2 -Ph, it is an organic chiral catalyst compound 1n (FIG. 1 and Table 1).
| 유기 키랄 촉매화합물Organic Chiral Catalyst | 화합물명Compound name |
| 1a1a | 1-[(1R,2R)-2-Amino-1,2-diphenylethyl]-3-phenylthiourea1-[(1R, 2R) -2-Amino-1,2-diphenylethyl] -3-phenylthiourea |
| 1b1b | 1-[(1R,2R)-2-Amino-1,2-diphenylethyl]-3-[3,5-Bis(trifluoromethyl)phenyl]thiourea1-[(1R, 2R) -2-Amino-1,2-diphenylethyl] -3- [3,5-Bis (trifluoromethyl) phenyl] thiourea |
| 1c1c | 1-[(1R,2R)-2-(Pentan-3-ylamino)-1,2-diphenylethyl]-3-(p-tolyl)thiourea1-[(1R, 2R) -2- (Pentan-3-ylamino) -1,2-diphenylethyl] -3- (p-tolyl) thiourea |
| 1d1d | 1-[3,5-Bis(trifluoromethyl)phenyl]-3-[(1R,2R)-2-(pentan-3-ylamino)-1,2-diphenylethyl]thiourea1- [3,5-Bis (trifluoromethyl) phenyl] -3-[(1R, 2R) -2- (pentan-3-ylamino) -1,2-diphenylethyl] thiourea |
| 1e1e | 1-[(1R,2R)-2-(Pentan-3-ylamino)-1,2-diphenylethyl]-3-[4-(trifluoromethyl) phenyl]thiourea1-[(1R, 2R) -2- (Pentan-3-ylamino) -1,2-diphenylethyl] -3- [4- (trifluoromethyl) phenyl] thiourea |
| 1f1f | 1-[(1R,2R)-2-(Pentan-3-ylamino)-1,2-diphenylethyl]-3-(perfluorophenyl)thiourea1-[(1R, 2R) -2- (Pentan-3-ylamino) -1,2-diphenylethyl] -3- (perfluorophenyl) thiourea |
| 1g1 g | 1-(4-Nitrophenyl)-3-[(1R,2R)-2-(pentan-3-ylamino)-1,2-diphenylethyl]thiourea1- (4-Nitrophenyl) -3-[(1R, 2R) -2- (pentan-3-ylamino) -1,2-diphenylethyl] thiourea |
| 1h1h | 1-(4-Cyanophenyl)-3-[(1R,2R)-2-(pentan-3-ylamino)-1,2-diphenylethyl]thiourea1- (4-Cyanophenyl) -3-[(1R, 2R) -2- (pentan-3-ylamino) -1,2-diphenylethyl] thiourea |
| 1i1i | 1-(4-Fluorophenyl)-3-[(1R,2R)-2-(pentan-3-ylamino)-1,2-diphenylethyl]thiourea1- (4-Fluorophenyl) -3-[(1R, 2R) -2- (pentan-3-ylamino) -1,2-diphenylethyl] thiourea |
| 1j1j | 1-((1R,2R)-2-(benzhydrylamino)-1,2-diphenylethyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea1-((1R, 2R) -2- (benzhydrylamino) -1,2-diphenylethyl) -3- (3,5-bis (trifluoromethyl) phenyl) thiourea |
| 1k1k | 1-((1R,2R)-2-(benzhydrylamino)-1,2-diphenylethyl)-3-tert-butylthiourea1-((1R, 2R) -2- (benzhydrylamino) -1,2-diphenylethyl) -3-tert-butylthiourea |
| 1l1l | 1-((1R,2R)-2-(benzhydrylamino)-1,2-diphenylethyl)-3-(4-(trifluoromethyl)phenyl)th-iourea1-((1R, 2R) -2- (benzhydrylamino) -1,2-diphenylethyl) -3- (4- (trifluoromethyl) phenyl) th-iourea |
| 1m1m | 1-((1R,2R)-2-(3,5-bis(trifluoromethyl)benzylamino)-1,2-diphenylethyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea1-((1R, 2R) -2- (3,5-bis (trifluoromethyl) benzylamino) -1,2-diphenylethyl) -3- (3,5-bis (trifluoromethyl) phenyl) thiourea |
| 1n1n | 1-((1R,2R)-2-(3,5-dimethylbenzylamino)-1,2-diphenylethyl)-3-(3,5-dimethylphenyl)th-iourea1-((1R, 2R) -2- (3,5-dimethylbenzylamino) -1,2-diphenylethyl) -3- (3,5-dimethylphenyl) th-iourea |
본 발명에 따른 상기 유기 키랄 촉매 화합물 1a 내지 1n의 NMR 분석 결과는 각각 하기와 같다.The NMR analysis results of the organic chiral catalyst compounds 1a to 1n according to the present invention are as follows.
(1a) 94% yield; [α]
D
20 = +62.0 (c = 0.02, CH
2Cl
2);
1H NMR (300 MHz, CDCl
3) δ7.76 (s, 1 H), 7.54~7.19 (m, 15 H), 5.54 (s, 1 H), 4.42 (d, 1 H, J = 5 Hz), 1.35 (br s, 1 H);
13C NMR (100 MHz, DMSO-d
6) δ182.09, 134.48, 133.93, 129.89, 128.70, 128.10, 127.91, 127.15, 126.94, 126.82, 126.74, 126.23, 125.59, 125.24, 122.98, 63.07,59.09; IR (KBr) 3287.86, 3027.84, 1521.63, 1241.99, 1072.28, 939.20, 698.13 cm
-1; HRMS (FAB
+) for C
21H
22N
3S [M+H]
+ Calcd: 348.4918, Found: 348.1534(1a) 94% yield; [a] D 2 ° = +62.0 (c = 0.02, CH 2 Cl 2 ); 1 H NMR (300 MHz, CDCl 3 ) δ7.76 (s, 1 H), 7.54-7.19 (m, 15 H), 5.54 (s, 1 H), 4.42 (d, 1 H, J = 5 Hz) , 1.35 (br s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 182.09, 134.48, 133.93, 129.89, 128.70, 128.10, 127.91, 127.15, 126.94, 126.82, 126.74, 126.23, 125.59, 125.24, 122.98, 63.07,59.09; IR (KBr) 3287.86, 3027.84, 1521.63, 1241.99, 1072.28, 939.20, 698.13 cm −1 ; HRMS (FAB + ) for C 21 H 22 N 3 S [M + H] + Calcd: 348.4918, Found: 348.1534
(1b) [α]
D
25 +13.5 (c 1.00, CH
3Cl);
1H NMR (300 MHz, DMSO-d
6) δ10.70 (s, 1H), 8.32 (s, 2H), 7.71(s, 1H), 7.22~7.43(m, 13H), 5.57(d, J = 3 Hz, 1H), 4.44 (d, J = 3 Hz, 1H) ppm;
13C NMR (100 MHz, DMSO-d
6) δ180.80, 143.41, 142.67, 130.94, 130.62, 128.81, 128.61 127.75, 127.57, 127.51, 125.25, 122.54, 121.68, 116.40, 63.86, 60.06 ppm; IR (KBr) 3305, 3032, 2963, 1652, 1601, 1557, 1383, 1277, 1262, 803, 700 cm
-1; HRMS (FAB
+) for C
22H
20N
4S [M+H]
+ Calcd: 372.1487, Found: 372.1456(1b) [a] D 25 +13.5 (c 1.00, CH 3 Cl); 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.70 (s, 1H), 8.32 (s, 2H), 7.71 (s, 1H), 7.22 to 7.43 (m, 13H), 5.57 (d, J = 3 Hz, 1H), 4.44 (d, J = 3 Hz, 1H) ppm; 13 C NMR (100 MHz, DMSO-d 6 ) δ 180.80, 143.41, 142.67, 130.94, 130.62, 128.81, 128.61 127.75, 127.57, 127.51, 125.25, 122.54, 121.68, 116.40, 63.86, 60.06 ppm; IR (KBr) 3305, 3032, 2963, 1652, 1601, 1557, 1383, 1277, 1262, 803, 700 cm −1 ; HRMS (FAB + ) for C 22 H 20 N 4 S [M + H] + Calcd: 372.1487, Found: 372.1456
(1c) 86% yield; [α]
D
20 = +0.19 (c = 1.00, CH
2Cl
2);
1H NMR (300 MHz, DMSO-d
6) δ9.76 (s, 1 H), 7.89 (d, J = 7.0 Hz, 1 H), 7.32~7.18 (m, 14 H), 5.44 (s, 1 H), 4.08 (d, J = 5.1 Hz, 1 H), 2.29 (s, 2 H), 2.02 (s, 1 H), 1.39 (s, 1 H), 1.20~1.06 (m, 4 H), 0.68 (t, J = 7.5 Hz, 3 H), 0.41 (t, J = 7.1 Hz, 3 H);
13C NMR (100 MHz, DMSO-d
6) δ181.04, 141.83, 141.55, 136.71, 134.88, 130.03, 128.67, 128.51, 127.49, 127.40, 124.67, 64.28, 63.77, 55.84, 26.71, 24.02, 21.20, 10.94, 8.30; IR (KBr) 3180.2, 2958.4, 1948.8, 1510.1, 1240.1, 821.6, 700.1, 565.1 cm
-1; HRMS (FAB
+) for C
27H
34N
3S [M+H]
+ Calcd: 432.2473, Found: 432.6537, pattern 432.5, 345.3, 266.4, 176.3, 106.01(1c) 86% yield; [a] D 2 ° = +0.19 (c = 1.00, CH 2 Cl 2 ); 1 H NMR (300 MHz, DMSO-d 6 ) δ9.76 (s, 1 H), 7.89 (d, J = 7.0 Hz, 1 H), 7.32-7.18 (m, 14 H), 5.44 (s, 1 H), 4.08 (d, J = 5.1 Hz, 1 H), 2.29 (s, 2 H), 2.02 (s, 1 H), 1.39 (s, 1 H), 1.20-1.06 (m, 4 H), 0.68 (t, J = 7.5 Hz, 3H), 0.41 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 181.04, 141.83, 141.55, 136.71, 134.88, 130.03, 128.67, 128.51, 127.49, 127.40, 124.67, 64.28, 63.77, 55.84, 26.71, 24.02, 21.20, 10.94, 8.30; IR (KBr) 3180.2, 2958.4, 1948.8, 1510.1, 1240.1, 821.6, 700.1, 565.1 cm −1 ; HRMS (FAB + ) for C 27 H 34 N 3 S [M + H] + Calcd: 432.2473, Found: 432.6537, pattern 432.5, 345.3, 266.4, 176.3, 106.01
(1d) 90% yield; [α]
D
20 = +0.31 (c = 0.11, CH
2Cl
2);
1H NMR (300 MHz, DMSO-d
6) δ10.5 (br, 1 H), 8.30 (s, 2 H), 7.74 (s, 1 H), 7.40~7.19 (m, 10 H), 5.57 (br, 1 H), 4.18 (d, J = 4.9 Hz, 1 H), 2.09 (m, 1 H), 1.24~1.20 (m, 4 H), 0.75 (t, J = 7.1 Hz, 3 H), 0.50 (t, J = 6.0 Hz, 3 H);
13C NMR (100 MHz, DMSO-d
6) δ181.10, 142.49, 140.88, 130.96, 130.64, 128.70, 128.59, 128.56, 127.60, 125.22, 122.52, 122.19, 116.70, 64.34, 63.62, 56.48, 26.64, 23.90, 10.98, 8.54; IR (KBr) 3239.9, 2964.2, 1471.5, 1278.6, 1135.9, 885.2, 700.1 cm
-1; HRMS (FAB
+) for C
28H
30F
6N
3S [M+H]
+ Calcd: 554.2065, Found: 554.2065(1d) 90% yield; [a] D 2 ° = +0.31 (c = 0.11, CH 2 Cl 2 ); 1 H NMR (300 MHz, DMSO-d 6 ) δ10.5 (br, 1 H), 8.30 (s, 2 H), 7.74 (s, 1 H), 7.40-7.19 (m, 10 H), 5.57 ( br, 1H), 4.18 (d, J = 4.9 Hz, 1H), 2.09 (m, 1H), 1.24-1.20 (m, 4H), 0.75 (t, J = 7.1 Hz, 3H), 0.50 (t, J = 6.0 Hz, 3H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 181.10, 142.49, 140.88, 130.96, 130.64, 128.70, 128.59, 128.56, 127.60, 125.22, 122.52, 122.19, 116.70, 64.34, 63.62, 56.48, 26.64, 23.90, 10.98, 8.54; IR (KBr) 3239.9, 2964.2, 1471.5, 1278.6, 1135.9, 885.2, 700.1 cm -1 ; HRMS (FAB + ) for C 28 H 30 F 6 N 3 S [M + H] + Calcd: 554.2065, Found: 554.2065
(1e) 88% yield; [α]
D
20 = +45.5 (c = 0.02, CH
2Cl
2);
1H NMR (300 MHz, DMSO-d
6) δ10.2 (br s, 1H), 8.41 (br s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 7.35~7.15 (m, 10H), 5.53 (br s, 1H), 4.13 (d, J = 5.5 Hz, 1H), 2.07 (m, 1H), 1.30~1.15 (m, 4H), 0.73 (t, J = 7.1 Hz, 3H), 0.49 (t, J = 6.9 Hz, 3H);
13C NMR (100 MHz, DMSO-d
6) δ180.91, 143.97, 141.18, 128.64, 128.52, 127.69, 127.48, 126.29, 122.41, 64.43, 63.71, 56.32, 26.68, 23.98, 10.98, 8.53; IR(KBr) 3205.3, 2962.3, 1945.9, 1741.5, 1517.8, 1324.9, 1245.9, 1066.5, 840.9, 700.1, 597.9 cm
-1; HRMS(FAB
+) for C
27H
31F
3N
3S[M+H]
+ Calcd: 486.2191, Found: 486.2190(1e) 88% yield; [a] D 2 ° = +45.5 (c = 0.02, CH 2 Cl 2 ); 1 H NMR (300 MHz, DMSO-d 6 ) δ10.2 (br s, 1H), 8.41 (br s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.5 Hz , 2H), 7.35-7.15 (m, 10H), 5.53 (br s, 1H), 4.13 (d, J = 5.5 Hz, 1H), 2.07 (m, 1H), 1.30-1.15 (m, 4H), 0.73 (t, J = 7.1 Hz, 3H), 0.49 (t, J = 6.9 Hz, 3H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 180.91, 143.97, 141.18, 128.64, 128.52, 127.69, 127.48, 126.29, 122.41, 64.43, 63.71, 56.32, 26.68, 23.98, 10.98, 8.53; IR (KBr) 3205.3, 2962.3, 1945.9, 1741.5, 1517.8, 1324.9, 1245.9, 1066.5, 840.9, 700.1, 597.9 cm −1 ; HRMS (FAB + ) for C 27 H 31 F 3 N 3 S [M + H] + Calcd: 486.2191, Found: 486.2190
(1f) 89% yield; [α]
D
20 = +80.4 (c = 0.02, CH
2Cl
2);
1H NMR (300 MHz, DMSO-d
6) δ9.47 (s, 1 H), 8.61 (s, 1 H), 7.30~7.15 (m, 10 H), 5.48 (br s, 1 H), 4.13 (d, J = 6.1 Hz, 1 H), 2.08 (m, 1 H), 1.54 (br, 1 H), 1.30~1.14 (m, 4 H), 0.74 (t, J = 7.4 Hz, 3 H), 0.55 (t, J = 6.3 Hz, 3 H);
13C NMR (100 MHz, DMSO-d
6) δ183.63, 145.82, 143.43, 141.90, 140.77, 139.01, 138.84, 136.56, 129.39, 128.61, 128.43, 127.68, 127.60, 115.93, 64.77, 64.53, 56.37, 26.72, 24.16, 10.86, 8.58; IR (KBr) 3299.8, 2964.2, 1525.5, 1344.2, 1145.6, 991.3, 912.2, 700.1, 605.6 cm
-1; HRMS (FAB
+) for C
26H
27F
5N
3S [M+H]
+ Calcd: 508.1846, Found: 508.1848(1f) 89% yield; [a] D 2 ° = +80.4 (c = 0.02, CH 2 Cl 2 ); 1 H NMR (300 MHz, DMSO-d 6 ) δ9.47 (s, 1 H), 8.61 (s, 1 H), 7.30-7.15 (m, 10 H), 5.48 (br s, 1 H), 4.13 (d, J = 6.1 Hz, 1 H), 2.08 (m, 1 H), 1.54 (br, 1 H), 1.30-1.14 (m, 4 H), 0.74 (t, J = 7.4 Hz, 3 H) , 0.55 (t, J = 6.3 Hz, 3H); 13 C NMR (100 MHz, DMSO-d 6 ) δ183.63, 145.82, 143.43, 141.90, 140.77, 139.01, 138.84, 136.56, 129.39, 128.61, 128.43, 127.68, 127.60, 115.93, 64.77, 64.53, 56.37, 26.72 24.16, 10.86, 8.58; IR (KBr) 3299.8, 2964.2, 1525.5, 1344.2, 1145.6, 991.3, 912.2, 700.1, 605.6 cm −1 ; HRMS (FAB + ) for C 26 H 27 F 5 N 3 S [M + H] + Calcd: 508.1846, Found: 508.1848
(1g) 89% yield; [α]
D
20 = +37.7 (c = 0.02, CH
2Cl
2);
1H NMR (300 MHz, DMSO-d
6) δ10.5 (s, 1 H), 8.16 (m, 2 H), 7.90 (d, J = 9.1 Hz, 2 H), 7.37~7.15 (m, 10 H), 5.54 (br s, 1 H), 4.16 (d, J = 5.5 Hz, 1 H), 2.07 (m, 1 H), 1.30~1.15 (m, 4 H), 0.75 (t, J = 7.4 Hz, 3 H), 0.50 (t, J = 7.4 Hz, 3 H);
13C NMR (100 MHz, DMSO-d
6) δ180.51, 146.95, 142.46, 141.92, 140.92, 128.68, 128.56, 127.72, 125.16, 120.92, 64.35, 63.80, 56.35, 55.59, 26.70, 23.96, 11.03, 8.61; IR (KBr) 3330.5, 2960.2, 2599.6, 2456.4, 2345.0, 1951.6, 1743.3, 1496.5, 1346.1, 1110.8, 1072.2, 852.4, 700.0, 586.3 cm
-1; HRMS (FAB
+) for C
26H
31N
4O
2S [M+H]
+ Calcd: 463.2168, Found: 463.2165(1 g) 89% yield; [a] D 2 ° = +37.7 (c = 0.02, CH 2 Cl 2 ); 1 H NMR (300 MHz, DMSO-d 6 ) δ10.5 (s, 1 H), 8.16 (m, 2 H), 7.90 (d, J = 9.1 Hz, 2 H), 7.37-7.15 (m, 10 H), 5.54 (br s, 1 H), 4.16 (d, J = 5.5 Hz, 1 H), 2.07 (m, 1 H), 1.30-1.15 (m, 4 H), 0.75 (t, J = 7.4 Hz, 3H), 0.50 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 180.51, 146.95, 142.46, 141.92, 140.92, 128.68, 128.56, 127.72, 125.16, 120.92, 64.35, 63.80, 56.35, 55.59, 26.70, 23.96, 11.03, 8.61; IR (KBr) 3330.5, 2960.2, 2599.6, 2456.4, 2345.0, 1951.6, 1743.3, 1496.5, 1346.1, 1110.8, 1072.2, 852.4, 700.0, 586.3 cm −1 ; HRMS (FAB + ) for C 26 H 31 N 4 O 2 S [M + H] + Calcd: 463.2168, Found: 463.2165
(1h) 69% yield; [α]
D
20 = +55.5 (c = 0.02, CH
2Cl
2);
1H NMR (300 MHz, DMSO-d
6) δ10.3 (br s, 1 H), 8.54 (br s, 1 H), 7.84~7.72 (m, 4 H), 7.35~7.17 (m, 10 H), 5.54 (br s, 1 H), 4.14 (d, J = 5.2 Hz, 1 H), 2.07 (br s, 1 H), 1.56 (br s, 1 H), 1.21 (m, 4H), 0.74 (t, J = 7.4 Hz, 3 H), 0.49 (t, J = 6.9 Hz, 3H);
13C NMR (100 MHz, DMSO-d
6) δ180.62, 144.83, 141.92, 141.05, 133.40, 128.67, 128.33, 127.68, 127.64, 127.51, 121.76, 119.76, 105.41, 64.41, 63.72, 60.43, 56.33, 26.74, 23.98, 21.42, 14.74, 11.02, 8.56; IR (KBr) 3317.0, 2960.2, 2360.4, 2225.5, 1949.7, 1739.5, 1508.1, 1315.2, 1176.4, 1072.2, 837.0, 700.0, 545.8 cm
-1; HRMS (FAB
+) for C
27H
31N
4S [M+H]
+ Calcd: 443.2269, Found: 443.2271(1h) 69% yield; [a] D 2 ° = +55.5 (c = 0.02, CH 2 Cl 2 ); 1 H NMR (300 MHz, DMSO-d 6 ) δ10.3 (br s, 1 H), 8.54 (br s, 1 H), 7.84 to 7.72 (m, 4 H), 7.35 to 7.17 (m, 10 H ), 5.54 (br s, 1 H), 4.14 (d, J = 5.2 Hz, 1 H), 2.07 (br s, 1 H), 1.56 (br s, 1 H), 1.21 (m, 4H), 0.74 (t, J = 7.4 Hz, 3H), 0.49 (t, J = 6.9 Hz, 3H); 13 C NMR (100 MHz, DMSO-d 6 ) δ180.62, 144.83, 141.92, 141.05, 133.40, 128.67, 128.33, 127.68, 127.64, 127.51, 121.76, 119.76, 105.41, 64.41, 63.72, 60.43, 56.33, 26.74, 23.98, 21.42, 14.74, 11.02, 8.56; IR (KBr) 3317.0, 2960.2, 2360.4, 2225.5, 1949.7, 1739.5, 1508.1, 1315.2, 1176.4, 1072.2, 837.0, 700.0, 545.8 cm −1 ; HRMS (FAB + ) for C 27 H 31 N 4 S [M + H] + Calcd: 443.2269, Found: 443.2271
(1i) 84% yield; [α]
D
20 = +17.9 (c = 0.02, CH
2Cl
2);
1H NMR (300 MHz, DMSO-d
6) δ9.83 (s, 1 H), 8.00 (d, J = 6.7 Hz, 1 H), 7.48~7.43 (m, 2 H), 7.31~7.16 (m, 11 H), 5.46 (br s, 1 H), 4.09 (d, J = 5.22 Hz, 1 H), 2.03 (br s , 1 H), 1.44 (br s, 1 H), 1.14 (m, 4 H), 0.70 (t, J = 10.1, 3 H), 0.44 (t, J = 7.0 Hz, 3 H);
13C NMR (100 MHz, DMSO-d
6) δ181.42, 161.03, 158.62, 141.90, 141.44, 135.97, 128.65, 128.51, 127.57, 127.42, 126.49, 116.13, 115.90, 64.39, 63.76, 56.03, 26.72, 24.02, 10.98, 8.39; IR (KBr) 3193.7, 2962.3, 1889.9, 1511.9, 1218.8, 848.6, 701.9, 555.42 cm
-1; HRMS (FAB
+) for C
26H
31FN
3S[M+H]
+ Calcd: 436.6172, Found: 436.2223. patern 436.5, 349.3, 266.4, 176.3, 106.1(1i) 84% yield; [a] D 2 ° = +17.9 (c = 0.02, CH 2 Cl 2 ); 1 H NMR (300 MHz, DMSO-d 6 ) δ9.83 (s, 1 H), 8.00 (d, J = 6.7 Hz, 1 H), 7.48-7.43 (m, 2H), 7.31-7.16 (m , 11 H), 5.46 (br s, 1 H), 4.09 (d, J = 5.22 Hz, 1 H), 2.03 (br s, 1 H), 1.44 (br s, 1 H), 1.14 (m, 4 H), 0.70 (t, J = 10.1, 3H), 0.44 (t, J = 7.0 Hz, 3H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 181.42, 161.03, 158.62, 141.90, 141.44, 135.97, 128.65, 128.51, 127.57, 127.42, 126.49, 116.13, 115.90, 64.39, 63.76, 56.03, 26.72, 24.02, 10.98, 8.39; IR (KBr) 3193.7, 2962.3, 1889.9, 1511.9, 1218.8, 848.6, 701.9, 555.42 cm −1 ; HRMS (FAB + ) for C 26 H 31 FN 3 S [M + H] + Calcd: 436.6172, Found: 436.2223. patern 436.5, 349.3, 266.4, 176.3, 106.1
(1j) 95% yield; [α]
D
20 = +0.39 (c = 0.16, CH
2Cl
2);
1H NMR (400 MHz, DMSO-d
6) δ7.82~7.09 (m, 23 H), 5.72 (s, 1 H), 3.98 (s, 1 H), 3.35 (s, 1 H), 2.47 (br, 1 H);
13C NMR (100 MHz, DMSO-d
6) δ181.06, 156.63, 153.35,143.36, 142.03, 141.31, 138.68, 129.48, 129.34, 126.90, 125.59, 123.65, 122.55, 122.14, 70.83, 65.14, 55.50; IR (KBr) 3239.9, 2964.2, 1471.5, 1278.6, 1135.9, 885.2, 700.1 cm
-1; HRMS (EI
+) for C
28H
30F
6N
3S [M+H]
+ Calcd: 649.1986, Found: 649.1932(1j) 95% yield; [a] D 2 ° = +0.39 (c = 0.16, CH 2 Cl 2 ); 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.82-7.09 (m, 23 H), 5.72 (s, 1 H), 3.98 (s, 1 H), 3.35 (s, 1 H), 2.47 ( br, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 181.06, 156.63, 153.35,143.36, 142.03, 141.31, 138.68, 129.48, 129.34, 126.90, 125.59, 123.65, 122.55, 122.14, 70.83, 65.14, 55.50; IR (KBr) 3239.9, 2964.2, 1471.5, 1278.6, 1135.9, 885.2, 700.1 cm -1 ; HRMS (EI + ) for C 28 H 30 F 6 N 3 S [M + H] + Calcd: 649.1986, Found: 649.1932
(1k) 93% yield; [α]
D
20 = +115 (c 0.17, CH
2Cl
2);
1H NMR (400 MHz, DMSO-d
6) δ7.61~7.03 (m, 20H), 4.13 (q, 3H), 2.92 (s, 9H), 1.76 (br, 2H);
IR(KBr) 3679.6, 2978.4, 1414.3, 1262.8, 1059.4, 886.1, 735.0 cm
-1; HRMS(EI
+) for C
32H
35N
3S [M+H]
+ Calcd: 493.2552, Found: 493.2587(1k) 93% yield; [a] D 2 ° = +115 (c 0.17, CH 2 Cl 2 ); 1 H NMR (400 MHz, DMSO-d 6 ) δ7.61-7.03 (m, 20H), 4.13 (q, 3H), 2.92 (s, 9H), 1.76 (br, 2H); IR (KBr) 3679.6, 2978.4, 1414.3, 1262.8, 1059.4, 886.1, 735.0 cm −1 ; HRMS (EI + ) for C 32 H 35 N 3 S [M + H] + Calcd: 493.2552, Found: 493.2587
(1l) 89% yield; [α]
D
20 = +124 (c 0.10, CH
2Cl
2);
1H NMR (300 MHz, DMSO-d
6) δ9.44 (br, 1H), 7.77~7.10 (m, 26H), 4.90 (s, 1H), 4.82 (s, 2H), 1.92 (s, 1H);
IR(KBr) 3679.5, 3352.2, 2985.3, 1402.4, 1265.9, 1065.7, 726.8 cm
-1; HRMS(FAB
+) for C
35H
30F
3N
3S [M+H]
+ Calcd: 581.2113, Found: 581.2133(1 l) 89% yield; [a] D 2 ° = +124 (c 0.10, CH 2 Cl 2 ); 1 H NMR (300 MHz, DMSO-d 6 ) δ9.44 (br, 1H), 7.77-7.10 (m, 26H), 4.90 (s, 1H), 4.82 (s, 2H), 1.92 (s, 1H) ; IR (KBr) 3679.5, 3352.2, 2985.3, 1402.4, 1265.9, 1065.7, 726.8 cm −1 ; HRMS (FAB + ) for C 35 H 30 F 3 N 3 S [M + H] + Calcd: 581.2113, Found: 581.2133
(1m) 93% yield; [α]
D
20 = +0.45 (c = 0.11, CH
2Cl
2);
1H NMR (500 MHz, DMSO-d
6) δ7.61 (br, 3 H), 7.39~7.29 (m, 16 H), 4.54 (s, 4 H);
13C NMR (100 MHz, DMSO-d
6) δ171.58, 157.99, 142.12,131.46, 134.14, 129.17, 127.28, 125.67, 122.96, 112.29, 89.59, 89.05, 84.78; IR (KBr) 3032.6, 2871.3, 1663.5, 1386.6, 1275.9, 1117.5, 930.2, 700.2 cm
-1; HRMS (FAB
+) for C
32H
23F
12N
3S [M+H]
+ Calcd: 709.1421, Found: 709.1428(1 m) 93% yield; [a] D 2 ° = +0.45 (c = 0.11, CH 2 Cl 2 ); 1 H NMR (500 MHz, DMSO-d 6 ) δ7.61 (br, 3H), 7.39-7.29 (m, 16H), 4.54 (s, 4H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 171.58, 157.99, 142.12,131.46, 134.14, 129.17, 127.28, 125.67, 122.96, 112.29, 89.59, 89.05, 84.78; IR (KBr) 3032.6, 2871.3, 1663.5, 1386.6, 1275.9, 1117.5, 930.2, 700.2 cm -1 ; HRMS (FAB + ) for C 32 H 23 F 12 N 3 S [M + H] + Calcd: 709.1421, Found: 709.1428
(1n) 89% yield; [α]
D
20 = +112 (c 0.13, CH
2Cl
2);
1H NMR (500 MHz, DMSO-d
6) δ7.38 (t, 6H), 7.32 (d, 2H), 7.27 (d, 4H), 7.00 (s, 4H), 4.54 (s, 4H), 2.21 (s, 12H), 1.25 (br, 1H);
13C NMR (100 MHz, DMSO-d
6) δ167.08, 157.71, 156.95, 143.07, 138.05, 131.22, 129.00, 128.93, 127.09, 127.03, 123.43, 118.64, 112.63, 70.28, 68.05, 67.38, 21.63;
IR(KBr) 3155.0, 2960.2, 2360.4, 1951.6, 1735.6, 1469.5, 1294.0, 1241.9, 1006.7, 837.0, 700.0, 572.8 cm
-1; HRMS(FAB
+) for C26H30F2N
3S[M+H]
+ Calcd: 454.2129, Found: 454.2133.(1n) 89% yield; [a] D 2 ° = +112 (c 0.13, CH 2 Cl 2 ); 1 H NMR (500 MHz, DMSO-d 6 ) δ7.38 (t, 6H), 7.32 (d, 2H), 7.27 (d, 4H), 7.00 (s, 4H), 4.54 (s, 4H), 2.21 (s, 12H), 1.25 (br, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 167.08, 157.71, 156.95, 143.07, 138.05, 131.22, 129.00, 128.93, 127.09, 127.03, 123.43, 118.64, 112.63, 70.28, 68.05, 67.38, 21.63; IR (KBr) 3155.0, 2960.2, 2360.4, 1951.6, 1735.6, 1469.5, 1294.0, 1241.9, 1006.7, 837.0, 700.0, 572.8 cm −1 ; HRMS (FAB + ) for C 26 H 30 F 2 N 3 S [M + H] + Calcd: 454.2129, Found: 454.2133.
실시예 2 : 유기 키랄 촉매 화합물을 이용한 비천연 감마 아미노산의 제조Example 2 Preparation of Non-Natural Gamma Amino Acids Using Organic Chiral Catalyst Compounds
상기 실시예 1에서 제조한 유기 키랄 촉매 화합물을 이용하여, α,β-불포화 나이트로 화합물을 디알킬 말로네이트 또는 말로나이트릴 등과의 마이클 첨가 반응을 수행한다. 24시간 이내에 마이클 첨가 반응이 종결되며, 91~99%의 수득률과 91~99%의 입체선택성을 가진 나이트로스타일렌 등의 화합물을 얻을 수 있다. 상기 마이클 첨가반응으로 생성된 생성물을 이용하여 응용화합물을 합성한다. 마이클 첨가 반응 생성물 중 4-Cl로 치환된 나이트로스타일렌에 NiCl
2·6H
2O·NaBH
4를 넣고 반응을 진행시키면 나이트로기가 환원되고, 고리화(cyclization)되면서 에틸에스터기가 하나 있는 하기 [화학식 3-1] 또는 [화학식 3-2]의 2-피롤리딘온이 생성된다.Using the organic chiral catalyst compound prepared in Example 1, Michael addition reaction of the α, β-unsaturated nitro compound with dialkyl malonate or malonitrile is performed. Within 24 hours, the Michael addition reaction is terminated, and a compound such as nitrosylene having a yield of 91 to 99% and a stereoselectivity of 91 to 99% can be obtained. The applied compound is synthesized using the product produced by the Michael addition reaction. When NiCl 2 · 6H 2 O.NaBH 4 is added to nitrostyrene substituted with 4-Cl in the reaction product of Michael, and the reaction proceeds, the nitro group is reduced, and one ethyl ester group is cyclized while being cyclized. 3-1] or 2-pyrrolidinone of [Formula 3-2] is produced.
[화학식 3-1][Formula 3-1]
[화학식 3-2][Formula 3-2]
그 다음 반응을 통해 카르복실기가 떨어지면서 2-피롤리딘온이 만들어지게 되고, 이렇게 만들어진 2-피롤리딘온에 6N HCl을 처리하여 하기 [화학식 4-1] 또는 [화학식 4-2]의 바클로펜 (하기 화학식에서 R
9은 Cl로 치환된 페닐) 또는 페니붓(하기 화학식 4에서 비치환된 페닐) 화합물을 합성한다 (하기 도 4 및 5).Then, 2-pyrrolidinone is formed as the carboxyl group is dropped through the reaction, and 6N HCl is treated to 2-pyrrolidinone thus formed to the following baclofen of [Formula 4-1] or [Formula 4-2] (Wherein R 9 is phenyl substituted with Cl) or phenibule (unsubstituted phenyl in the formula 4) compound to synthesize (FIGS. 4 and 5).
[화학식 4-1][Formula 4-1]
[화학식 4-2][Formula 4-2]
구체적으로, α,β-불포화 나이트로 화합물을 말로나이트릴 (2.0 당량)과 실시예 1에서 제조한 유기 키랄 촉매 화합물 1m (0.1~0.001 mol %)의 존재 하에서, 물 (0.4 ml)을 용매로 사용하고 트랜스-β-니트로스티렌 (1.0 당량), 말로노니트릴 (2.0 당량)과 혼합하여 반응 혼합물을 실온에서 교반하였다. 반응 전환은 TLC로 모니터링하였으며, 반응완료 후, 6N HCl을 첨가하고 2 시간 동안 65 ℃로 가열하였다. 반응 혼합물을 실온으로 냉각시킨 후, 디알킬카보네이트 (1.5 당량)를 첨가하고 용액을 100 ℃에서 3 시간 동안 교반하면서 가열하였다. 이후 균질한 반응 혼합물을 실온으로 냉각시키고, 10 % NaHCO
3 수용액에 부었으며, 에틸아세테이트 (0.2ml)를 반응 혼합물에 첨가하였다. 이 용액을 물 (2 x 1.0 mL)로 2 회 세척하고, 황산마그네슘상에서 건조시키고, 농축시켜 목적하는 생성물을 수득 하였으며, 생성물을 실리카겔컬럼 (헥산 / 메틸렌 클로라이드 2 : 1)상에서 크로마토그래피로 정제 하였다. (표 2의 2a 내지 2m). 아르곤 대기 하에서, MeOH (8.0 ml) 내 상기 수득된 마이클 첨가반응 생성물 (1.0 당량, >99% ee)과 NiCl
2·6H
2O(1.0 당량)의 현탁액에 NaBH
4
(10 당량)를 0 ℃에서 첨가하였다. 반응 혼합물을 실온에서 7.5 시간 동안 교반한 후에, 반응 혼합물을 NH
4Cl로 담금질(quenching)하고, CHCl
3로 희석하였다. 유기층을 분리하고, MgSO
4로 여과하고, 진공농축하였다. 잔류물을 실리카 겔(용제로서, MeOH/CHCl
3 = 1/20)에서 크로마토그래피로 하여, 무색 분말로서 목적 생성물을 수득하였다(표 2의 2n 및 2o). 6N HCl (2.7 ml) 내 생성물 2n 또는 2o (1.0 당량)을 100 ℃에서 환류시켰다. 12시간 후 반응 혼합물을 진공 농축하여, 무색 고체로서, (R)-(-)-바클로펜, 페니붓(표 2의 2p 및 2q, 97 내지 98%)을 수득하였다.Specifically, α, β-unsaturated nitro compound was prepared in the presence of malonitril (2.0 equivalents) and 1 m (0.1-0.001 mol%) of the organic chiral catalyst compound prepared in Example 1, with water (0.4 ml) as a solvent. The reaction mixture was stirred at room temperature using and mixed with trans-β-nitrostyrene (1.0 equiv), malononitrile (2.0 equiv). The reaction conversion was monitored by TLC and after completion of the reaction, 6N HCl was added and heated to 65 ° C. for 2 hours. After the reaction mixture was cooled to room temperature, dialkyl carbonate (1.5 equiv) was added and the solution was heated with stirring at 100 ° C. for 3 h. The homogeneous reaction mixture was then cooled to room temperature, poured into 10% aqueous NaHCO 3 solution, and ethyl acetate (0.2 ml) was added to the reaction mixture. The solution was washed twice with water (2 × 1.0 mL), dried over magnesium sulfate and concentrated to afford the desired product, which was purified by chromatography on silica gel column (hexanes / methylene chloride 2: 1). . (2a to 2m in Table 2). Under argon atmosphere, NaBH 4 was added to a suspension of the Michael addition product obtained above (1.0 equiv,> 99% ee) and NiCl 2 .6H 2 O (1.0 equiv) in MeOH (8.0 ml). (10 equiv) was added at 0 ° C. After stirring the reaction mixture at room temperature for 7.5 hours, the reaction mixture was quenched with NH 4 Cl and diluted with CHCl 3 . The organic layer was separated, filtered over MgSO 4 , and concentrated in vacuo. The residue was chromatographed on silica gel (MeOH / CHCl 3 = 1/20 as solvent) to give the desired product as a colorless powder (2n and 2o in Table 2). Product 2n or 2o (1.0 equiv) in 6N HCl (2.7 ml) was refluxed at 100 ° C. After 12 hours the reaction mixture was concentrated in vacuo to give (R)-(-)-baclofen, phenibule (2p and 2q in Table 2, 97-98%) as a colorless solid.
| 생성물product | 화합물명Compound name |
| 2a2a | (R)-Dimethyl 2-(2-nitro-1-phenylethyl)malonate(R) -Dimethyl 2- (2-nitro-1-phenylethyl) malonate |
| 2b2b | (R)-Diethyl 2-(2-nitro-1-phenylethyl)malonate(R) -Diethyl 2- (2-nitro-1-phenylethyl) malonate |
| 2c2c | (R)-Diisopropyl 2-(2-nitro-1-phenylethyl)malonate(R) -Diisopropyl 2- (2-nitro-1-phenylethyl) malonate |
| 2d2d | (R)-Dipropyl 2-(2-nitro-1-phenylethyl)malonate(R) -Dipropyl 2- (2-nitro-1-phenylethyl) malonate |
| 2e2e | (R)-Benzyl-2-carbobenzyloxy-4-nitro-3-phenylbutyrate(R) -Benzyl-2-carbobenzyloxy-4-nitro-3-phenylbutyrate |
| 2f2f | (R)-dibutyl 2-(2-nitro-1-phenylethyl)malonate(R) -dibutyl 2- (2-nitro-1-phenylethyl) malonate |
| 2g2 g | (R)-Diethyl 2-[1-(4-bromophenyl)-2-nitroethyl]malonate(R) -Diethyl 2- [1- (4-bromophenyl) -2-nitroethyl] malonate |
| 2h2h | (R)-diethyl 2-(1-(4-chlorophenyl)-2-nitroethyl)malonate(R) -diethyl 2- (1- (4-chlorophenyl) -2-nitroethyl) malonate |
| 2i2i | (R)-Diethyl 2-[2-nitro-1-(p-tolyl)ethyl]malonate(R) -Diethyl 2- [2-nitro-1- (p-tolyl) ethyl] malonate |
| 2j2j | (R)-Diethyl 2-[1-(4-hydroxyphenyl)-2-nitroethyl]malonate(R) -Diethyl 2- [1- (4-hydroxyphenyl) -2-nitroethyl] malonate |
| 2k2k | (R)-Diethyl 2-[1-(4-methoxyphenyl)-2-nitroethyl]malonate(R) -Diethyl 2- [1- (4-methoxyphenyl) -2-nitroethyl] malonate |
| 2l2l | (R)-Diethyl 2-[1-(2-methoxyphenyl)-2-nitroethyl]malonate(R) -Diethyl 2- [1- (2-methoxyphenyl) -2-nitroethyl] malonate |
| 2m2m | (R)-Diethyl 2-[1-(furan-2-yl)-2-nitroethyl]malonate(R) -Diethyl 2- [1- (furan-2-yl) -2-nitroethyl] malonate |
| 2n2n | (R)-ethyl 2-oxo-4-phenylpyrrolidine-3-carboxylate(R) -ethyl 2-oxo-4-phenylpyrrolidine-3-carboxylate |
| 2o2o | (R)-Ethyl 4-(4-chlorophenyl)-2-oxopyrrolidine-3-carboxylate(R) -Ethyl 4- (4-chlorophenyl) -2-oxopyrrolidine-3-carboxylate |
| 2p2p | (R)-4-amino-3-phenyl-butanoic acidhydrochloride(R) -4-amino-3-phenyl-butanoic acidhydrochloride |
| 2q2q | (R)-4-Amino-[3-(4-chlorophenyl)]-butanoic acidhydrochloride(R) -4-Amino- [3- (4-chlorophenyl)]-butanoic acidhydrochloride |
| 3a3a | (S)-4-Nitro-1,3-diphenyl-butan-1-one(S) -4-Nitro-1,3-diphenyl-butan-1-one |
| 3b3b | (S)-3-(4-Chlorophenyl)-4-nitro-1-phenylbutan-1-one(S) -3- (4-Chlorophenyl) -4-nitro-1-phenylbutan-1-one |
| 3c3c | (S)-4-nitro-1-phenyl-3-(p-tolyl)butan-1-one(S) -4-nitro-1-phenyl-3- (p-tolyl) butan-1-one |
| 3d3d | (S)-3-(4-Bromophenyl)-4-nitro-1-phenylbutan-1-one(S) -3- (4-Bromophenyl) -4-nitro-1-phenylbutan-1-one |
| 3e3e | (S)-3-(4-Chlorophenyl)-4-nitro-1-phenylbutan-1-one(S) -3- (4-Chlorophenyl) -4-nitro-1-phenylbutan-1-one |
| 3f3f | (S)-3-(4-Methoxyphenyl)-4-nitro-1-phenylbutan-1-one(S) -3- (4-Methoxyphenyl) -4-nitro-1-phenylbutan-1-one |
| 3g3 g | (S)-3-(2-Methoxyphenyl)-4-nitro-1-phenylbutan-1-one(S) -3- (2-Methoxyphenyl) -4-nitro-1-phenylbutan-1-one |
| 3h3h | (S)-3-(Furan-2-yl)-4-nitro-1-phenylbutan-1-one(S) -3- (Furan-2-yl) -4-nitro-1-phenylbutan-1-one |
| 3i3i | (S)-Phenyl 4-nitro-3-phenylbutanoate(S) -Phenyl 4-nitro-3-phenylbutanoate |
| 3j3j | (S)-Phenyl 3-(4-chlorophenyl)-4-nitrobutanoate(S) -Phenyl 3- (4-chlorophenyl) -4-nitrobutanoate |
| 3k3k | (S)-4-Phenylpyrrolidin-2-one(S) -4-Phenylpyrrolidin-2-one |
| 3l3l | (R)-4-Phenylpyrrolidin-2-one(R) -4-Phenylpyrrolidin-2-one |
| 3m3m | (S)-4-(4-Chlorophenyl)pyrrolidin-2-one(S) -4- (4-Chlorophenyl) pyrrolidin-2-one |
| 3n3n | (R)-4-(4-Chlorophenyl)pyrrolidin-2-one(R) -4- (4-Chlorophenyl) pyrrolidin-2-one |
| 3o3o | (S)-4-Amino-3-phenylbutanoicacid(S) -4-Amino-3-phenylbutanoicacid |
| 3p3p | (S)-4-Amino-3-(4-chlorophenyl)butanoic acid(S) -4-Amino-3- (4-chlorophenyl) butanoic acid |
| 3q3q | (S)-2-(2-oxo-4-phenylpyrrolidin-1-yl)acetamide(S) -2- (2-oxo-4-phenylpyrrolidin-1-yl) acetamide |
| 3r3r | (R)-2-(2-oxo-4-phenylpyrrolidin-1-yl)acetamide(R) -2- (2-oxo-4-phenylpyrrolidin-1-yl) acetamide |
| 3s3s | (S)-2-((R)-2-oxo-4-propylpyrrolidin-1-yl)butanamide(S) -2-((R) -2-oxo-4-propylpyrrolidin-1-yl) butanamide |
상기 생성물 2a 내지 2q, 3a 내지 3s의 분석 결과는 각각 하기와 같다.The analysis results of the products 2a to 2q and 3a to 3s are as follows.
(2a) [α]
D
20 = -1.98 (c 1.33, CH
2Cl
2);
1H NMR (300 MHz, CDCl
3) δ7.40~7.15 (m, 5H), 5.15~5.03 (m, 1H), 4.93 (dd, J = 4.5, 12.8 Hz, 1H), 4.88~4.76 (m, 2H), 4.20 (td, J = 4.5, 9.5 Hz, 1H), 3.76 (d, J = 9.5 Hz, 1H), 1.24 (d, J = 6.1 Hz, 3H), 1.07 (d, J = 6.4 Hz, 3H), 1.01 (d, J = 6.4 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl
3) δ167.1, 166.4, 136.3, 128.9, 128.3, 128.2, 77.9, 69.9, 69.5, 55.1, 42.9, 21.5, 21.4, 21.19, 21.17 ppm; IR(KBr) 3030, 2985,1727, 1557 cm
-1; HRMS(ESI) for C
13H
16N
1O
6[M+H]
+ Calcd: 282.09721, Found: 282.09726; HPLC [Chiralcel AD-H, hexane/2-propanol = 95/5, 1.0 mL/min, λ= 254 nm, retention times: (major) 23.3 min, (minor) 38.0 min](2a) [a] D 2 ° = -1.98 (c 1.33, CH 2 Cl 2 ); 1 H NMR (300 MHz, CDCl 3 ) δ 7.40 to 7.15 (m, 5H), 5.15 to 5.03 (m, 1H), 4.93 (dd, J = 4.5, 12.8 Hz, 1H), 4.88 to 4.76 (m, 2H), 4.20 (td, J = 4.5, 9.5 Hz, 1H), 3.76 (d, J = 9.5 Hz, 1H), 1.24 (d, J = 6.1 Hz, 3H), 1.07 (d, J = 6.4 Hz, 3H), 1.01 (d, J = 6.4 Hz, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ) δ 167.1, 166.4, 136.3, 128.9, 128.3, 128.2, 77.9, 69.9, 69.5, 55.1, 42.9, 21.5, 21.4, 21.19, 21.17 ppm; IR (KBr) 3030, 2985, 1727, 1557 cm −1 ; HRMS (ESI) for C 13 H 16 N 1 O 6 [M + H] + Calcd: 282.09721, Found: 282.09726; HPLC [Chiralcel AD-H, hexane / 2-propanol = 95/5, 1.0 mL / min, λ = 254 nm, retention times: (major) 23.3 min, (minor) 38.0 min]
(2b) [α]
D
20 = -4.61 (c 0.23, CH
2Cl
2);
1H NMR (300 MHz, CDCl
3) δ 7.30~7.20 (m, 5H), 4.93 (dd, J = 4.6, 13.1 Hz, 1H), 4.86 (dd, J = 9.2, 13.1 Hz, 1H), 4.24~4.17 (m, 3H), 3.98~3.97 (q, J = 7.2 Hz, 2H), 3.81~3.79 (d, J = 9.5 Hz, 1H), 1.25 (t, J = 7.2 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl
3) δ167.4, 166. 7, 136.2, 128.8, 128.2, 127.9, 77.6, 62.0, 61.8, 54.9, 42.9, 13.9, 13.6 ppm; IR(KBr) 2989, 2938, 1731, 1557 cm
-1; HRMS(ESI) for C
15H
20N
1O
6[M+H]
+ Calcd: 310.12851, Found: 310.12936; HPLC [Chiralcel AD-H, hexane/ethanol = 90/10, 1.0 mL/min, λ= 254 nm, retention times: (major) 11.5 min, (minor) 15.3 min](2b) [a] D 2 ° = -4.61 (c 0.23, CH 2 Cl 2 ); 1 H NMR (300 MHz, CDCl 3 ) δ 7.30-7.20 (m, 5H), 4.93 (dd, J = 4.6, 13.1 Hz, 1H), 4.86 (dd, J = 9.2, 13.1 Hz, 1H), 4.24- 4.17 (m, 3H), 3.98-3.97 (q, J = 7.2 Hz, 2H), 3.81-3.79 (d, J = 9.5 Hz, 1H), 1.25 (t, J = 7.2 Hz, 3H), 1.03 (t , J = 7.2 Hz, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ) δ 167.4, 166. 7, 136.2, 128.8, 128.2, 127.9, 77.6, 62.0, 61.8, 54.9, 42.9, 13.9, 13.6 ppm; IR (KBr) 2989, 2938, 1731, 1557 cm −1 ; HRMS (ESI) for C 15 H 20 N 1 0 6 [M + H] + Calcd: 310.12851, Found: 310.12936; HPLC [Chiralcel AD-H, hexane / ethanol = 90/10, 1.0 mL / min, λ = 254 nm, retention times: (major) 11.5 min, (minor) 15.3 min]
(2c) [α]
D
20 = -1.24 (c 1.00, CH
2Cl
2);
1H NMR (300 MHz, CDCl
3) δ7.32~7.22 (m, 5H), 5.10 (dd, J = 5.0,13.1 Hz, 1H), 4.91~4.979 (m, 3H), 4.21~4.19 (m, 1H), 1.25 (d, J = 2.0 Hz, 6H), 1.07 (dd, J = 2.0,2.0 Hz, 6H) ppm;
13C NMR (100 MHz, CDCl
3) δ167.27, 166.54, 136.47, 129.07, 128.34, 127.9, 78.15, 70.15, 69.75, 55.35, 43.14, 21.80, 21.67, 21.48 ppm; IR(KBr) 3029, 2956, 1737, 1558 cm
-1; HRMS(ESI) for C
17H
24N
1O
6[M+H]
+ Calcd: 338.15981 Found: 338.16336; HPLC [Chiralcel AD-H, hexane/2-propanol = 95/5, 1.0 mL/min, λ= 254 nm, retention times: (major) 14.8 min, (minor) 34.4 min](2c) [a] D 2 ° = -1.24 (c 1.00, CH 2 Cl 2 ); 1 H NMR (300 MHz, CDCl 3 ) δ7.32 to 7.22 (m, 5H), 5.10 (dd, J = 5.0,13.1 Hz, 1H), 4.91 to 4.979 (m, 3H), 4.21 to 4.19 (m, 1H), 1.25 (d, J = 2.0 Hz, 6H), 1.07 (dd, J = 2.0,2.0 Hz, 6H) ppm; 13 C NMR (100 MHz, CDCl 3 ) δ 167.27, 166.54, 136.47, 129.07, 128.34, 127.9, 78.15, 70.15, 69.75, 55.35, 43.14, 21.80, 21.67, 21.48 ppm; IR (KBr) 3029, 2956, 1737, 1558 cm −1 ; HRMS (ESI) for C 17 H 24 N 1 O 6 [M + H] + Calcd: 338.15981 Found: 338.16336; HPLC [Chiralcel AD-H, hexane / 2-propanol = 95/5, 1.0 mL / min, λ = 254 nm, retention times: (major) 14.8 min, (minor) 34.4 min]
(2d) [α]
D
20 = -1.73 (c 0.10, CH
2Cl
2);
1H NMR (300 MHz, CDCl
3) δ7.31~7.22 (m, 5H), 4.92~4.87 (t, J = 5.0,9.5 Hz, 2H), 4.24 (m, 1H), 4.15~4.09 (m, 2H), 3.92~3.83 (dd,s, J =6.6 9.7 Hz, 3H), 1.68~1.61 (m, 2H), 1.49~1.42 (m, 2H), 0.93~0.88 (t, J = 7.4,7.4 Hz, 3H), 0.82~0.77 (t, J = 7.4,7.4 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl
3) δ167.79, 167.17, 136.46, 129.14, 128.52, 128.17, 77.85, 67.86, 67.65, 55.17, 43.16, 21.97, 21.81, 10.48 ppm; IR(KBr) 3029, 2956, 1737, 1558 cm
-1; HRMS(ESI) for C
17H
24N
1O
6[M+H]
+ Calcd: 338.15981 Found: 338.16336; HPLC [Chiralcel AD-H, hexane/2-propanol = 95/5, 1.0 mL/min, λ= 254 nm, retention times: (major) 18.4 min, (minor) 38.9 min](2d) [a] D 2 ° = -1.73 (c 0.10, CH 2 Cl 2 ); 1 H NMR (300 MHz, CDCl 3 ) δ7.31 to 7.22 (m, 5H), 4.92 to 4.87 (t, J = 5.0,9.5 Hz, 2H), 4.24 (m, 1H), 4.15 to 4.09 (m, 2H), 3.92-3.83 (dd, s, J = 6.6 9.7 Hz, 3H), 1.68-1.61 (m, 2H), 1.49-1.42 (m, 2H), 0.93-0.98 (t, J = 7.4, 7.4 Hz , 3H), 0.82-0.77 (t, J = 7.4, 7.4 Hz, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ) δ 167.79, 167.17, 136.46, 129.14, 128.52, 128.17, 77.85, 67.86, 67.65, 55.17, 43.16, 21.97, 21.81, 10.48 ppm; IR (KBr) 3029, 2956, 1737, 1558 cm −1 ; HRMS (ESI) for C 17 H 24 N 1 O 6 [M + H] + Calcd: 338.15981 Found: 338.16336; HPLC [Chiralcel AD-H, hexane / 2-propanol = 95/5, 1.0 mL / min, λ = 254 nm, retention times: (major) 18.4 min, (minor) 38.9 min]
(2e) [α]
D
20 = -3.25 (c 0.10, CH
2Cl
2);
1H NMR (400 MHz, CDCl
3) δ7.33-7.25 (m, 10H), 7.17-7.07 (m, 5H), 5.16 (d, 1H, J = 12.2 Hz), 5.18 (d, 1H, JAB = 12.2 Hz), 4.93 (S, 1H), 4.84-4.82 (m, 2H), 4.28~4.22 (q, 1H), 3.94 (d, 1H, 9.3 Hz); 13C NMR (100 MHz, CDCl3) δ167.39, 166.78, 136.14, 134.85, 129.25, 128.90, 128.15, 77.63, 68.04, 67.86, 55.14, 43.16 ppm; IR(KBr) 3068, 3036, 2963, 1736, 1558, 1498, 1456, 1378, 1326, 1286, 1217, 1156, 1003, 975, 908, 562 cm
-1; HRMS(EI) for C
25H
23N
1O
6[M+H]
+ Calcd: 433.1525 Found: 433.1525; HPLC [Chiralcel AD-H, hexane/2-propanol = 70/30, 1.0 mL/min, λ= 254 nm, retention times: (major) 26.0 min, (minor) 24.1 min](2e) [a] D 2 ° = -3.25 (c 0.10, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ) δ 7.33-7.25 (m, 10H), 7.17-7.07 (m, 5H), 5.16 (d, 1H, J = 12.2 Hz), 5.18 (d, 1H, JAB = 12.2 Hz), 4.93 (S, 1H), 4.84-4.82 (m, 2H), 4.28-4.22 (q, 1H), 3.94 (d, 1H, 9.3 Hz); 13 C NMR (100 MHz, CDCl 3) δ 167.39, 166.78, 136.14, 134.85, 129.25, 128.90, 128.15, 77.63, 68.04, 67.86, 55.14, 43.16 ppm; IR (KBr) 3068, 3036, 2963, 1736, 1558, 1498, 1456, 1378, 1326, 1286, 1217, 1156, 1003, 975, 908, 562 cm −1 ; HRMS (EI) for C 25 H 23 N 1 O 6 [M + H] + Calcd: 433.1525 Found: 433.1525; HPLC [Chiralcel AD-H, hexane / 2-propanol = 70/30, 1.0 mL / min, λ = 254 nm, retention times: (major) 26.0 min, (minor) 24.1 min]
(2f) [α]
D
20 = -2.55 (c 0.10, CH
2Cl
2);
1H NMR (400 MHz, CDCl
3) δ7.31~7.22 (m, 5H), 4.92~4.87 (t, J = 5.0,9.5 Hz, 2H), 4.24 (m, 1H), 4.15~4.09 (m, 2H), 3.92~3.83 (dd,s, J =6.6 9.7 Hz, 3H), 1.68~1.61 (m, 2H), 1.49~1.42 (m, 2H), 0.93~0.88 (t, J = 7.4,7.4 Hz, 3H), 0.82~0.77 (t, J = 7.4,7.4 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl
3) δ167.79, 167.17, 136.46, 129.14, 128.52, 128.17, 77.85, 67.86, 67.65, 55.17, 43.16, 21.97, 21.81, 10.48 ppm; HRMS(EI) for C
17H
24N
1O
6[M+H]
+ Calcd: 338.15981 Found: 338.16336; HPLC [Chiralcel AD-H, hexane/2-propanol = 95/5, 1.0 mL/min, λ= 254 nm, retention times: (major) 18.4 min, (minor) 38.9 min](2f) [a] D 2 ° = -2.55 (c 0.10, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ) δ 7.31-7.72 (m, 5H), 4.92-4.87 (t, J = 5.0,9.5 Hz, 2H), 4.24 (m, 1H), 4.15-4.09 (m, 2H), 3.92-3.83 (dd, s, J = 6.6 9.7 Hz, 3H), 1.68-1.61 (m, 2H), 1.49-1.42 (m, 2H), 0.93-0.98 (t, J = 7.4, 7.4 Hz , 3H), 0.82-0.77 (t, J = 7.4, 7.4 Hz, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ) δ 167.79, 167.17, 136.46, 129.14, 128.52, 128.17, 77.85, 67.86, 67.65, 55.17, 43.16, 21.97, 21.81, 10.48 ppm; HRMS (EI) for C 17 H 24 N 1 O 6 [M + H] + Calcd: 338.15981 Found: 338.16336; HPLC [Chiralcel AD-H, hexane / 2-propanol = 95/5, 1.0 mL / min, λ = 254 nm, retention times: (major) 18.4 min, (minor) 38.9 min]
(2g) 77 % yield; [α]
D
20 = -3.56 (c 2.33, CH
2Cl
2);
1H NMR (300 MHz, CDCl
3) δ7.44~7.42 (d, J = 8.5 Hz, 2H), 7.13~7.11 (d, J = 8.2 Hz, 2H), 4.88~4.81 (m, 2H), 4.22~4.16 (m, 3H), 4.04~3.97 (q, J = 7.1,6.9 Hz, 2H), 3.78~3.75 (d, J = 9.4 Hz, 1H), 1.26~1.21 (t, J = 7.2,7.1 Hz, 3H), 1.08~1.03 (t, J = 7.1,7.1 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl
3) δ167.42, 166.83, 135.52, 132.29, 130.00, 122.62, 77.55, 62.50, 62.26, 54.86, 42.60, 14.17, 13.99 ppm; IR (KBr) 2983, 2950, 1732, 1556, 1490, 1445 cm
-1 HRMS(ESI) for C
15H
19N
1O
6Br[M+H]
+ Calcd: 388.03903 Found: 388.04495; HPLC [Chiralcel AD-H, hexane/ethanol = 95/5, 1.0 mL/min, λ= 254 nm, retention times: (major) 35.9 min, (minor) 44.4 min](2 g) 77% yield; [a] D 2 ° = -3.56 (c 2.33, CH 2 Cl 2 ); 1 H NMR (300 MHz, CDCl 3 ) δ 7.44 to 7.42 (d, J = 8.5 Hz, 2H), 7.13 to 7.11 (d, J = 8.2 Hz, 2H), 4.88 to 4.81 (m, 2H), 4.22 ~ 4.16 (m, 3H), 4.04-3.97 (q, J = 7.1,6.9 Hz, 2H), 3.78-3.75 (d, J = 9.4 Hz, 1H), 1.26-1.21 (t, J = 7.2,7.1 Hz , 3H), 1.08-0.03 (t, J = 7.1,7.1 Hz, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ) δ 167.42, 166.83, 135.52, 132.29, 130.00, 122.62, 77.55, 62.50, 62.26, 54.86, 42.60, 14.17, 13.99 ppm; IR (KBr) 2983, 2950, 1732, 1556, 1490, 1445 cm −1 HRMS (ESI) for C 15 H 19 N 1 O 6 Br [M + H] + Calcd: 388.03903 Found: 388.04495; HPLC [Chiralcel AD-H, hexane / ethanol = 95/5, 1.0 mL / min, λ = 254 nm, retention times: (major) 35.9 min, (minor) 44.4 min]
(2h) [α]
D
20 = -0.24 (c 0.43, CH
2Cl
2);
1H NMR (300 MHz, CDCl
3) δ7.29~7.17 (dd, J = 20.6,8.2 Hz, 4H), 4.88~4.81 (m, 2H), 4.23~4.16 (m, 3H), 4.04~3.97 (q, J = 7.1,7.1 Hz, 2H), 3.78~3.75 (d, J = 9.3 Hz, 1H), 1.26~1.21 (t, J = 7.1,7.2 Hz, 3H), 1.08~1.03 (t, J = 7.2,6.8 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl
3) δ167.44, 166.83, 134.98, 134.46, 129.69, 129.32, 77.63, 62.49, 62.23, 54.92, 42.55, 14.15, 13.97 ppm; IR (KBr) 2984, 1733, 1557, 1478, 1445, 1371 cm
-1 HRMS(ESI) for C
15H
19N
1O
6Cl[M+H]
+ Calcd: 344.08954 Found: 344.09119; HPLC [Chiralcel AD-H, hexane/ethanol = 90/10, 1.0 mL/min, λ= 254 nm, retention times: (major) 17.9 min, (minor) 24.1 min](2h) [a] D 2 ° = -0.24 (c 0.43, CH 2 Cl 2 ); 1 H NMR (300 MHz, CDCl 3 ) δ 7.29 to 7.17 (dd, J = 20.6,8.2 Hz, 4H), 4.88 to 4.81 (m, 2H), 4.23 to 4.16 (m, 3H), 4.04 to 3.97 ( q, J = 7.1,7.1 Hz, 2H), 3.78-3.75 (d, J = 9.3 Hz, 1H), 1.26-1.21 (t, J = 7.1,7.2 Hz, 3H), 1.08-1.03 (t, J = 7.2,6.8 Hz, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ) δ 167.44, 166.83, 134.98, 134.46, 129.69, 129.32, 77.63, 62.49, 62.23, 54.92, 42.55, 14.15, 13.97 ppm; IR (KBr) 2984, 1733, 1557, 1478, 1445, 1371 cm −1 HRMS (ESI) for C 15 H 19 N 1 O 6 Cl [M + H] + Calcd: 344.08954 Found: 344.09119; HPLC [Chiralcel AD-H, hexane / ethanol = 90/10, 1.0 mL / min, λ = 254 nm, retention times: (major) 17.9 min, (minor) 24.1 min]
(2i) 60 % yield; [α]
D
20 = -1.56 (c 1.33, CH
2Cl
2);
1H NMR (300 MHz, CDCl
3) δ7.09 (d, J = 15.2 Hz, 4H), 4.89~4.78 (m, 2H), 4.22~4.14 (m, 3H), 4.01~3.96 (q, J = 7.0,7.1 Hz, 2H), 3.79 (d, J = 9.3 Hz, 1H), 2.27 (s, 3H), 1.25~1.22 (t, J = 7.1,7.0 Hz, 3H), 1.06~1.02 (t, J = 7.1,8.6 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl
3) δ167.74, 167.08, 138.27, 138.23, 133.30, 129.80, 128.05, 78.00, 62.32, 62.06, 55.24, 42.84, 21.28, 14.18, 13.97 ppm; IR(KBr) 3030, 2987, 1732, 1612, 1557 cm
-1; HRMS(ESI) for C
16H
22N
1O
6[M+H]
+ Calcd: 324.14416 Found: 324.14648; HPLC [Chiralcel AD-H, hexane/ethanol = 98/2, 1.0 mL/min, λ= 254 nm, retention times: (major) 36.0 min, (minor) 42.8 min](2i) 60% yield; [a] D 2 ° = -1.56 (c 1.33, CH 2 Cl 2 ); 1 H NMR (300 MHz, CDCl 3 ) δ7.09 (d, J = 15.2 Hz, 4H), 4.89-4.78 (m, 2H), 4.22-4.14 (m, 3H), 4.01-3.96 (q, J = 7.0,7.1 Hz, 2H), 3.79 (d, J = 9.3 Hz, 1H), 2.27 (s, 3H), 1.25-1.22 (t, J = 7.1,7.0 Hz, 3H), 1.06-1.02 (t, J = 7.1,8.6 Hz, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ) δ 167.74, 167.08, 138.27, 138.23, 133.30, 129.80, 128.05, 78.00, 62.32, 62.06, 55.24, 42.84, 21.28, 14.18, 13.97 ppm; IR (KBr) 3030, 2987, 1732, 1612, 1557 cm −1 ; HRMS (ESI) for C 16 H 22 N 1 O 6 [M + H] + Calcd: 324.14416 Found: 324.14648; HPLC [Chiralcel AD-H, hexane / ethanol = 98/2, 1.0 mL / min, λ = 254 nm, retention times: (major) 36.0 min, (minor) 42.8 min]
(2j) 40 % yield; [α]
D
20 = -1.56 (c = 0.50, CH
2Cl
2);
1H NMR (300 MHz, CDCl
3) δ7.09~7.06 (d, J = 8.3 Hz, 2H), 6.72~6.70 (d, J = 8.2 Hz, 2H), 5.63 (br, 1H), 4.91~4.74 (m, 2H), 4.25~4.12 (m, 3H), 4.05~3.98 (q, J = 7.1,6.8 Hz, 2H), 3.79 (d, J = 9.7 Hz, 1H), 1.29~1.24 (t, J = 7.1,6.6 Hz, 3H), 1.09~1.05 (t, J = 7.1,7.2 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl
3) δ167.74, 167.28, 155.88, 129.54, 128.06, 78.17, 62.44, 62.23, 55.29, 42.53, 29.92, 14.20, 14.00 ppm; HRMS(ESI) for C
15H
20N
1O
7[M+H]
+ Calcd: 326.12343 Found: 326.12903; HPLC [Chiralcel AD-H, hexane/ethanol = 90/10, 1.0 mL/min, λ= 254 nm, retention times: (major) 20.4 min, (minor) 50.6 min](2j) 40% yield; [a] D 2 ° = -1.56 (c = 0.50, CH 2 Cl 2 ); 1 H NMR (300 MHz, CDCl 3 ) δ 7.09-7.06 (d, J = 8.3 Hz, 2H), 6.72-6.70 (d, J = 8.2 Hz, 2H), 5.63 (br, 1H), 4.91-4.74 (m, 2H), 4.25-4.12 (m, 3H), 4.05-3.98 (q, J = 7.1,6.8 Hz, 2H), 3.79 (d, J = 9.7 Hz, 1H), 1.29-1.24 (t, J = 7.1,6.6 Hz, 3H), 1.09-1.05 (t, J = 7.1,7.2 Hz, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ) δ 167.74, 167.28, 155.88, 129.54, 128.06, 78.17, 62.44, 62.23, 55.29, 42.53, 29.92, 14.20, 14.00 ppm; HRMS (ESI) for C 15 H 20 N 1 0 7 [M + H] + Calcd: 326.12343 Found: 326.12903; HPLC [Chiralcel AD-H, hexane / ethanol = 90/10, 1.0 mL / min, λ = 254 nm, retention times: (major) 20.4 min, (minor) 50.6 min]
(2k) 47 % yield; [α]
D
20 = -1.37 (c 0.80, CH
2Cl
2);
1H NMR (300 MHz, CDCl
3) δ7.16~7.13 (d, J = 8.5 Hz, 2H), 6.84~6.81 (d, J = 8.8 Hz, 2H), 4.87~4.80 (m, 2H), 4.24~4.16 (m, 3H), 4.04~3.97 (q, J = 7.1,7.1 Hz, 2H), 3.79~3.78 (d, J = 2.7 Hz, 1H), 3.76 (s, 3H), 1.28~1.23 (t, J = 7.1,7.2 Hz, 3H), 1.08~1.03 (t, J = 7.1,7.1 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl
3) δ167.73, 167.08, 159.61, 129.36, 128.17, 114.48, 78.12, 62.34, 62.06, 55.42, 55.30, 42.53, 14.19, 14.01 ppm; IR(KBr) 2988, 2936, 2904, 1730, 1612, 1552 cm
-1 HRMS(ESI) for C
16H
22N
1O
7[M+H]
+ Calcd: 340.13908 Found: 340.13901; HPLC [Chiralcel AD-H, hexane/ethanol = 90/10, 1.0 mL/min, λ= 254 nm, retention times: (major) 23.8 min, (minor) 39.5 min](2k) 47% yield; [a] D 2 ° = -1.37 (c 0.80, CH 2 Cl 2 ); 1 H NMR (300 MHz, CDCl 3 ) δ7.16 ~ 7.13 (d, J = 8.5 Hz, 2H), 6.84 ~ 6.81 (d, J = 8.8 Hz, 2H), 4.87 ~ 4.80 (m, 2H), 4.24 ~ 4.16 (m, 3H), 4.04-3.97 (q, J = 7.1,7.1 Hz, 2H), 3.79-3.78 (d, J = 2.7 Hz, 1H), 3.76 (s, 3H), 1.28-1.23 (t , J = 7.1,7.2 Hz, 3H), 1.08-1.03 (t, J = 7.1,7.1 Hz, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ) δ 167.73, 167.08, 159.61, 129.36, 128.17, 114.48, 78.12, 62.34, 62.06, 55.42, 55.30, 42.53, 14.19, 14.01 ppm; IR (KBr) 2988, 2936, 2904, 1730, 1612, 1552 cm −1 HRMS (ESI) for C 16 H 22 N 1 O 7 [M + H] + Calcd: 340.13908 Found: 340.13901; HPLC [Chiralcel AD-H, hexane / ethanol = 90/10, 1.0 mL / min, λ = 254 nm, retention times: (major) 23.8 min, (minor) 39.5 min]
(2l) 51 % yield; [α]
D
20 = -7.08 (c 1.30, CH
2Cl
2);
1H NMR (300 MHz, CDCl
3) δ7.26~7.21(m, 1H), 7.15~7.12 (m, 1H), 6.87~6.83 (m, 2H), 5.06~4.98 (dd, J = 3.6,1.1 Hz, 1H), 4.89~4.83 (dd, J = 3.6,1.1 Hz, 1H), 4.37~4.34 (m, 1H), 4.24~4.12 (m, 3H), 3.97~3.90 (q, J = 7.2,7.2 Hz, 2H), 3.85 (s, 3H), 1.28~1.23 (t, J = 7.1,6.9 Hz, 3H), 1.01~0.96 (t, J = 7.2,7.1 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl
3) δ168.14, 167.41, 157.62, 131.09, 129.83, 123.87, 120.96, 111.27, 76.40, 62.18, 61.77, 55.62, 52.89, 40.74, 14.20, 13.94 ppm; IR (KBr) 2984, 2939, 2908, 1732, 1613, 1556 cm
-1 HRMS(ESI) for C
16H
22N
1O
6[M] Calcd: 339.13125 Found: 339.12933; HPLC [Chiralcel AD-H, hexane/2-propanol = 95/5, 1.0 mL/min, λ= 254 nm, retention times: (major) 14.9 min, (minor) 20.6 min](2l) 51% yield; [a] D 2 ° = -7.08 (c 1.30, CH 2 Cl 2 ); 1 H NMR (300 MHz, CDCl 3 ) δ 7.26 ~ 7.21 (m, 1H), 7.15 ~ 7.12 (m, 1H), 6.87 ~ 6.83 (m, 2H), 5.06 ~ 4.98 (dd, J = 3.6,1.1 Hz, 1H), 4.89-4.83 (dd, J = 3.6,1.1 Hz, 1H), 4.37-4.34 (m, 1H), 4.24-4.12 (m, 3H), 3.97-3.90 (q, J = 7.2, 7.2 Hz, 2H), 3.85 (s, 3H), 1.28-1.23 (t, J = 7.1,6.9 Hz, 3H), 1.01-0.96 (t, J = 7.2,7.1 Hz, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ) δ 168.14, 167.41, 157.62, 131.09, 129.83, 123.87, 120.96, 111.27, 76.40, 62.18, 61.77, 55.62, 52.89, 40.74, 14.20, 13.94 ppm; IR (KBr) 2984, 2939, 2908, 1732, 1613, 1556 cm −1 HRMS (ESI) for C 16 H 22 N 1 O 6 [M] Calcd: 339.13125 Found: 339.12933; HPLC [Chiralcel AD-H, hexane / 2-propanol = 95/5, 1.0 mL / min, λ = 254 nm, retention times: (major) 14.9 min, (minor) 20.6 min]
(2m) 78 % yield; [α]
D
20 = +5.06 (c 0.33, CH
2Cl
2);
1H NMR (300 MHz, CDCl
3) δ7.34~7.26 (d, J = 23.9 Hz, 1H), 6.29~6.28 (t, J = 2.9,1.6 Hz, 1H), 6.22~6.21 (d, J = 3.0 Hz, 1H), 4.91~4.88 (m, 2H), 4.39~4.37 (m, 1H), 4.25~4.11 (m, 4H), 3.91~3.88 (d, J = 7.9 Hz, 1H), 1.28~1.23 (t, J = 7.1,6.9 Hz, 3H), 1.22~1.17 (t, J = 7.1,6.9 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl
3) δ167.35, 167.04, 149.74, 142.95, 110.74, 108.67, 75.64, 62.38, 53.20, 37.03, 29.92, 14.17, 14.11 ppm; IR (KBr) 2985, 2940, 1734,1559, 1506, 1466, 1448; HRMS(ESI) for C
13H
18N
1O
7[M+H]
+ Calcd: 300.10778 Found: 300.10742; HPLC [Chiralcel AD-H, hexane/2-propanol = 95/5, 0.6 mL/min, λ= 254 nm, retention times: (major) 22.7 min, (minor) 29.2 min](2m) 78% yield; [a] D 2 ° = +5.06 (c 0.33, CH 2 Cl 2 ); 1 H NMR (300 MHz, CDCl 3 ) δ7.34 to 7.26 (d, J = 23.9 Hz, 1H), 6.29 to 6.28 (t, J = 2.9,1.6 Hz, 1H), 6.22 to 6.21 (d, J = 3.0 Hz, 1H), 4.91-4.88 (m, 2H), 4.39-4.37 (m, 1H), 4.25-4.11 (m, 4H), 3.91-3.88 (d, J = 7.9 Hz, 1H), 1.28-1.23 (t, J = 7.1,6.9 Hz, 3H), 1.22-1.17 (t, J = 7.1,6.9 Hz, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ) δ 167.35, 167.04, 149.74, 142.95, 110.74, 108.67, 75.64, 62.38, 53.20, 37.03, 29.92, 14.17, 14.11 ppm; IR (KBr) 2985, 2940, 1734,1559, 1506, 1466, 1448; HRMS (ESI) for C 13 H 18 N 1 0 7 [M + H] + Calcd: 300.10778 Found: 300.10742; HPLC [Chiralcel AD-H, hexane / 2-propanol = 95/5, 0.6 mL / min, λ = 254 nm, retention times: (major) 22.7 min, (minor) 29.2 min]
(2n) [α]
D
20 = -24.29(c 0.03, CH
2Cl
2);
1H NMR (400 MHz, CDCl
3) δ7.99 (s, 1H), 7.27 (d, J = 8.2 Hz, 2H), 7.17~7.14 (d, J = 8.2 Hz, 2H), 4.20~4.13 (q, J = 6.9,6.9 Hz, 1H), 4.06~3.97 (q, J = 6.9 Hz, 1H), 3.77~3.71 (m, 1H), 3.50~3.46 (d, J = 10.1 Hz, 1H), 3.37~3.31 (t, J = 9.4,9.4 Hz, 1H), 1.23~1.18 (t, J = 7.1 Hz, 3H)ppm; HRMS(EI) for C
13H
15NO
3[M+H]
+ Calcd: 233.1052, Found: 233.1051(2n) [a] D 2 ° = -24.29 (c 0.03, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (s, 1H), 7.27 (d, J = 8.2 Hz, 2H), 7.17 to 7.14 (d, J = 8.2 Hz, 2H), 4.20 to 4.13 (q , J = 6.9,6.9 Hz, 1H), 4.06-3.97 (q, J = 6.9 Hz, 1H), 3.77-3.71 (m, 1H), 3.50-3.46 (d, J = 10.1 Hz, 1H), 3.37- 3.31 (t, J = 9.4,9.4 Hz, 1H), 1.23-1.18 (t, J = 7.1 Hz, 3H) ppm; HRMS (EI) for C 13 H 15 NO 3 [M + H] + Calcd: 233.1052, Found: 233.1051
(2o) [α]
D
20 = -24.29(c 0.03, CH
2Cl
2);
1H NMR (300 MHz, CDCl
3) δ7.99 (s, 1H), 7.27 (d, J = 8.2 Hz, 2H), 7.17~7.14 (d, J = 8.2 Hz, 2H), 4.20~4.13 (q, J = 6.9,6.9 Hz, 1H), 4.06~3.97 (q, J = 6.9 Hz, 1H), 3.77~3.71 (m, 1H), 3.50~3.46 (d, J = 10.1 Hz, 1H), 3.37~3.31 (t, J = 9.4,9.4 Hz, 1H), 1.23~1.18 (t, J = 7.1 Hz, 3H)ppm;
13C NMR (100 MHz, CDCl
3) δ173.15, 169.30, 138.47, 133.51, 129.31, 128.67, 62.11, 55.65, 47.92, 44.04, 14.35 ppm; IR (KBr) 3435, 3229, 3017, 2360, 1710, 1493 cm
-1; HRMS(ESI) for C
13H
14ClNO
3[M+H]
+ Calcd: 267.06567, Found: 267.1026(2o) [a] D 2 ° = -24.29 (c 0.03, CH 2 Cl 2 ); 1 H NMR (300 MHz, CDCl 3 ) δ 7.99 (s, 1H), 7.27 (d, J = 8.2 Hz, 2H), 7.17 to 7.14 (d, J = 8.2 Hz, 2H), 4.20 to 4.13 (q , J = 6.9,6.9 Hz, 1H), 4.06-3.97 (q, J = 6.9 Hz, 1H), 3.77-3.71 (m, 1H), 3.50-3.46 (d, J = 10.1 Hz, 1H), 3.37- 3.31 (t, J = 9.4,9.4 Hz, 1H), 1.23-1.18 (t, J = 7.1 Hz, 3H) ppm; 13 C NMR (100 MHz, CDCl 3 ) δ 173.15, 169.30, 138.47, 133.51, 129.31, 128.67, 62.11, 55.65, 47.92, 44.04, 14.35 ppm; IR (KBr) 3435, 3229, 3017, 2360, 1710, 1493 cm −1 ; HRMS (ESI) for C 13 H 14 ClNO 3 [M + H] + Calcd: 267.06567, Found: 267.1026
(2p) [α]
D
20 = +3.12 (c 2.33, MeOH);
1H NMR (400 MHz, D
2O) δ7.27~7.19 (m, 5H), 3.21 (m, 2H), 3.11~3.08 (d, 1H), 2.69 (dd, 1H, J = 16.0, 6.0 Hz), 2.59~2.55 (dd, 1H, J = 16.5, 8.5 Hz) ppm;
13C NMR (100 MHz, DMSO-d
6) δ175.29, 138.61, 129.57, 128.11, 44.10, 39.94, 38.35 ppm; HRMS(EI
+) for C
9H
12ClNO
2[M+HCl]
+ Calcd: 201.0557, Found: 201.0563(2p) [a] D 2 ° = +3.12 (c 2.33, MeOH); 1 H NMR (400 MHz, D 2 O) δ 7.27 to 7.19 (m, 5H), 3.21 (m, 2H), 3.11 to 3.08 (d, 1H), 2.69 (dd, 1H, J = 16.0, 6.0 Hz ), 2.59-2.55 (dd, 1H, J = 16.5, 8.5 Hz) ppm; 13 C NMR (100 MHz, DMSO-d 6 ) δ 175.29, 138.61, 129.57, 128.11, 44.10, 39.94, 38.35 ppm; HRMS (EI + ) for C 9 H 12 ClNO 2 [M + HCl] + Calcd: 201.0557, Found: 201.0563
(2q) [α]
D
20 = -3.79 (c 2.33, H
2O);
1H NMR (300 MHz, DMSO-d
6) δ8.25 (s, 3H), 7.35 (m, 4H), 3.08 (m, 1H), 2.92 (m, 2H), 2.57 (dd, J = 9.5, 16.5 Hz, 1H) ppm;
13C NMR (100 MHz, DMSO-d
6) δ173.17, 141.20, 132.50, 130.69, 129.36, 129.28, 128.59, 127.93, 44.15, 39.1, 38.66 ppm; HRMS(FAB
+) for C
10H
12ClNO
2[M+H]
+ Calcd: 214.0635, Found: 214.0637.(2q) [a] D 2 ° = -3.79 (c 2.33, H 2 O); 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.25 (s, 3H), 7.35 (m, 4H), 3.08 (m, 1H), 2.92 (m, 2H), 2.57 (dd, J = 9.5, 16.5 Hz, 1H) ppm; 13 C NMR (100 MHz, DMSO-d 6 ) δ 173.17, 141.20, 132.50, 130.69, 129.36, 129.28, 128.59, 127.93, 44.15, 39.1, 38.66 ppm; HRMS (FAB + ) for C 10 H 12 ClNO 2 [M + H] + Calcd: 214.0635, Found: 214.0637.
(3a) [α]
D
20 -18.5 (c 1.0, CHCl
3);
1H NMR (500 MHz, CDCl
3) δ7.91~7.92 (m, 2H), 7.59~7.26 (m, 8H), 4.85~4.81 (dd, J = 12.5, 6.7 Hz, 1H), 4.71~4.67 (dd, J = 12.5, 7.8 Hz, 1H), 4.26~4.20 (m, 1H), 3.51~3.46 (dd, J = 17.7, 6.4 Hz, 1H), 3.45~3.40 (dd, J = 17.7, 7.5 Hz, 1H) ppm;
13C NMR (125 MHz, CDCl
3) δ 196.87, 139.15, 136.39, 133.60, 129.09, 128.77, 128.04, 127.90, 127.48, 79.58, 41.54, 39.30 ppm; IR (KBr) 3058, 3029, 2920, 1687, 1544, 1440, 1367, 1268, 1224, 1084, 988, 764, 703, 623, 559 cm
-1; LRMS (ESI
+) for C
16H
15NO
3
[M+Na]
+ Calcd: 292.1, Found: 292.1; HPLC [Chiralcel AD-H, hexane/2-propanol = 90/10, flow rate = 1.0 mL/min, λ= 254 nm, retention times: (major) 12.8 min, (minor) 17.4 min]; R
f
(SiO
2, EtOAc/n-hexane = 1/5) = 0.40(3a) [α] D 20 -18.5 (c 1.0, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 ) δ7.91 to 7.92 (m, 2H), 7.59 to 7.26 (m, 8H), 4.85 to 4.81 (dd, J = 12.5, 6.7 Hz, 1H), 4.71 to 4.67 ( dd, J = 12.5, 7.8 Hz, 1H), 4.26-4.20 (m, 1H), 3.51-3.46 (dd, J = 17.7, 6.4 Hz, 1H), 3.45-3.40 (dd, J = 17.7, 7.5 Hz, 1H) ppm; 13 C NMR (125 MHz, CDCl 3 ) δ 196.87, 139.15, 136.39, 133.60, 129.09, 128.77, 128.04, 127.90, 127.48, 79.58, 41.54, 39.30 ppm; IR (KBr) 3058, 3029, 2920, 1687, 1544, 1440, 1367, 1268, 1224, 1084, 988, 764, 703, 623, 559 cm −1 ; LRMS (ESI + ) for C 16 H 15 NO 3 [M + Na] + Calcd : 292.1, Found: 292.1; HPLC [Chiralcel AD-H, hexane / 2-propanol = 90/10, flow rate = 1.0 mL / min, λ = 254 nm, retention times: (major) 12.8 min, (minor) 17.4 min]; R f (SiO 2 , EtOAc / n-hexane = 1/5) = 0.40
(3b) [α]
D
20 -24.7 (c 1.0, CH
2Cl
2);
1H NMR (500 MHz, CDCl
3) δ 7.92~7.90 (m, 2H), 7.60~7.57 (m, 1H), 7.48~7.45 (m, 2H), 7.32~7.29 (m, 2H), 7.24~7.22 (m, 2H), 4.83~4.80 (dd, J = 12.5, 6.5 Hz, 1H), 4.68~4.64 (dd, J = 12.5, 8.1 Hz, 1H), 4.25~4.19 (m, 1H), 3.48~3.43 (dd, J = 18.2, 6.4 Hz, 1H), 3.43~3.38 (dd, J = 18.2, 7.3 Hz, 1H) ppm;
13C NMR (125 MHz, CDCl
3) δ 196.50, 137.59, 136.23, 133.74, 129.27, 128.90, 128.82, 128.02, 79.36, 41.36, 38.70 ppm; LRMS (ESI
+) for C
16H
14ClNO
3
[M+Na]
+ Calcd: 326.1, Found: 326.1; HPLC [Chiralcel AD-H, hexane/2-propanol = 95/5, flow rate = 1.0 mL/min, λ = 254 nm, retention times: (major) 24.3 min, (minor) 37.5 min]; R
f
(SiO
2, EtOAc/n-hexane = 1/5) = 0.31(3b) [α] D 20 -24.7 (c 1.0, CH 2 Cl 2 ); 1 H NMR (500 MHz, CDCl 3 ) δ 7.92 ~ 7.90 (m, 2H), 7.60 ~ 7.57 (m, 1H), 7.48 ~ 7.45 (m, 2H), 7.32 ~ 7.29 (m, 2H), 7.24 ~ 7.22 (m, 2H), 4.83-4.80 (dd, J = 12.5, 6.5 Hz, 1H), 4.68-4.64 (dd, J = 12.5, 8.1 Hz, 1H), 4.25-4.19 (m, 1H), 3.48-3.43 (dd, J = 18.2, 6.4 Hz, 1H), 3.43-3.38 (dd, J = 18.2, 7.3 Hz, 1H) ppm; 13 C NMR (125 MHz, CDCl 3 ) δ 196.50, 137.59, 136.23, 133.74, 129.27, 128.90, 128.82, 128.02, 79.36, 41.36, 38.70 ppm; LRMS (ESI + ) for C 16 H 14 ClNO 3 [M + Na] + Calcd : 326.1, Found: 326.1; HPLC [Chiralcel AD-H, hexane / 2-propanol = 95/5, flow rate = 1.0 mL / min, λ = 254 nm, retention times: (major) 24.3 min, (minor) 37.5 min]; R f (SiO 2 , EtOAc / n-hexane = 1/5) = 0.31
(3c) [α]
D
20 -19.4 (c 1.0, CHCl
3);
1H NMR (500 MHz, CDCl
3) δ 7.91 (d, J = 7.0 Hz, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 8.0 Hz, 2H), 7.18~7.13 (m, 4H), 4.83~4.79 (dd, J = 12.5, 6.5 Hz, 1H), 4.68~4.64 (dd, J = 12.5, 8.0 Hz, 1H), 4.22~4.16 (m, 1H), 3.48~3.44 (dd, J = 17.5, 6.5 Hz, 1H), 3.43~3.38 (dd, J = 18.0, 7.5 Hz, 1H), 2.31 (s, 3H) ppm;
13C NMR (125 MHz, CDCl
3) δ 196.96, 137.60, 136.42,136.05, 133.56, 129.76, 128.75, 128.05, 127.31, 79.73, 41.59, 38.96, 21.07 ppm; IR (KBr) 3058, 2922, 2862, 1685, 1551, 1516, 1446, 1377, 1270, 1225, 998, 817, 755, 691, 551 cm
-1; LRMS (ESI
+) for C
17H
17NO
3
[M+Na]
+ Calcd: 306.1, Found: 306.2; HPLC [Chiralcel AD-H, hexane/2-propanol = 90/10, flow rate = 1.0 mL/ min, λ = 254 nm, retention times: (major) 11.9 min, (minor) 16.3 min]; R
f
(SiO
2, EtOAc/n-hexane = 1/10) = 0.33(3c) [α] D 20 -19.4 (c 1.0, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 ) δ 7.91 (d, J = 7.0 Hz, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 8.0 Hz, 2H), 7.18-7.13 (m, 4H), 4.83-4.79 (dd, J = 12.5, 6.5 Hz, 1H), 4.68-4.64 (dd, J = 12.5, 8.0 Hz, 1H), 4.22-4.16 (m, 1H), 3.48-3.44 (dd, J = 17.5, 6.5 Hz, 1H), 3.43-3.38 (dd, J = 18.0, 7.5 Hz, 1H), 2.31 (s, 3H) ppm; 13 C NMR (125 MHz, CDCl 3 ) δ 196.96, 137.60, 136.42,136.05, 133.56, 129.76, 128.75, 128.05, 127.31, 79.73, 41.59, 38.96, 21.07 ppm; IR (KBr) 3058, 2922, 2862, 1685, 1551, 1516, 1446, 1377, 1270, 1225, 998, 817, 755, 691, 551 cm -1 ; LRMS (ESI + ) for C 17 H 17 NO 3 [M + Na] + Calcd : 306.1, Found: 306.2; HPLC [Chiralcel AD-H, hexane / 2-propanol = 90/10, flow rate = 1.0 mL / min, λ = 254 nm, retention times: (major) 11.9 min, (minor) 16.3 min]; R f (SiO 2 , EtOAc / n-hexane = 1/10) = 0.33
(3d) [α]
D
20 -25.8 (c 1.0, CHCl
3);
1H NMR (500 MHz, CDCl
3) δ 7.90 (d, J = 7.0 Hz, 2H), 7.58 (t, J = 7.5 Hz, 1H), 7.48~7.45 (m, 4H), 7.18~7.16 (m, 2H), 4.83~4.79 (dd, J = 12.5, 6.5 Hz, 1H), 4.68~4.64 (dd, J = 12.5, 8.5 Hz, 1H), 4.23~4.17 (m, 1H), 3.48~3.43 (dd, J = 17.0, 6.5 Hz, 1H), 3.43~3.38 (dd, J = 17.0, 7.0 Hz, 1H) ppm;
13C NMR (125 MHz, CDCl
3) δ 196.47, 138.14, 136.21, 133.74, 132.22, 129.24, 128.82, 128.02, 121.85, 79.28, 41.30, 38.76 ppm; LRMS (ESI
+) for C
16H
14BrNO
3
[M+Na]
+ Calcd: 370.0, Found: 370.1; HPLC [Chiralcel AD-H, hexane/2-propanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm, retention times: (major) 16.4 min, (minor) 22.4 min]; R
f
(SiO
2, EtOAc/n-hexane = 1/5) = 0.30(3d) [α] D 20 -25.8 (c 1.0, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 ) δ 7.90 (d, J = 7.0 Hz, 2H), 7.58 (t, J = 7.5 Hz, 1H), 7.48-7.45 (m, 4H), 7.18-7.16 (m, 2H), 4.83-4.79 (dd, J = 12.5, 6.5 Hz, 1H), 4.68-4.64 (dd, J = 12.5, 8.5 Hz, 1H), 4.23-4.17 (m, 1H), 3.48-3.43 (dd, J = 17.0, 6.5 Hz, 1H), 3.43-3.38 (dd, J = 17.0, 7.0 Hz, 1H) ppm; 13 C NMR (125 MHz, CDCl 3 ) δ 196.47, 138.14, 136.21, 133.74, 132.22, 129.24, 128.82, 128.02, 121.85, 79.28, 41.30, 38.76 ppm; LRMS (ESI + ) for C 16 H 14 BrNO 3 [M + Na] + Calcd : 370.0, Found: 370.1; HPLC [Chiralcel AD-H, hexane / 2-propanol = 90/10, flow rate = 1.0 mL / min, λ = 254 nm, retention times: (major) 16.4 min, (minor) 22.4 min]; R f (SiO 2 , EtOAc / n-hexane = 1/5) = 0.30
(3e) [α]
D
20 -24.7 (c 1.0, CH
2Cl
2);
1H NMR (500 MHz, CDCl
3) δ 7.92~7.90 (m, 2H), 7.60~7.57 (m, 1H), 7.48~7.45 (m, 2H), 7.32~7.29 (m, 2H), 7.24~7.22 (m, 2H), 4.83~4.80 (dd, J = 12.5, 6.5 Hz, 1H), 4.68~4.64 (dd, J = 12.5, 8.1 Hz, 1H), 4.25~4.19 (m, 1H), 3.48~3.43 (dd, J = 18.2, 6.4 Hz, 1H), 3.43~3.38 (dd, J = 18.2, 7.3 Hz, 1H) ppm;
13C NMR (125 MHz, CDCl
3) δ 196.50, 137.59, 136.23, 133.74, 129.27, 128.90, 128.82, 128.02, 79.36, 41.36, 38.70 ppm; LRMS (ESI
+) for C
16H
14ClNO
3
[M+Na]
+ Calcd: 326.1, Found: 326.1; HPLC [Chiralcel AD-H, hexane/2-propanol = 95/5, flow rate = 1.0 mL/min, λ = 254 nm, retention times: (major) 24.3 min, (minor) 37.5 min]; R
f
(SiO
2, EtOAc/n-hexane = 1/5) = 0.31(3e) [α] D 20 -24.7 (c 1.0, CH 2 Cl 2 ); 1 H NMR (500 MHz, CDCl 3 ) δ 7.92 ~ 7.90 (m, 2H), 7.60 ~ 7.57 (m, 1H), 7.48 ~ 7.45 (m, 2H), 7.32 ~ 7.29 (m, 2H), 7.24 ~ 7.22 (m, 2H), 4.83-4.80 (dd, J = 12.5, 6.5 Hz, 1H), 4.68-4.64 (dd, J = 12.5, 8.1 Hz, 1H), 4.25-4.19 (m, 1H), 3.48-3.43 (dd, J = 18.2, 6.4 Hz, 1H), 3.43-3.38 (dd, J = 18.2, 7.3 Hz, 1H) ppm; 13 C NMR (125 MHz, CDCl 3 ) δ 196.50, 137.59, 136.23, 133.74, 129.27, 128.90, 128.82, 128.02, 79.36, 41.36, 38.70 ppm; LRMS (ESI + ) for C 16 H 14 ClNO 3 [M + Na] + Calcd : 326.1, Found: 326.1; HPLC [Chiralcel AD-H, hexane / 2-propanol = 95/5, flow rate = 1.0 mL / min, λ = 254 nm, retention times: (major) 24.3 min, (minor) 37.5 min]; R f (SiO 2 , EtOAc / n-hexane = 1/5) = 0.31
(3f) [α]
D
20 -20.2 (c 1.0, CHCl
3);
1H NMR (500 MHz, CDCl
3) δ 7.93~7.91 (m, 2H), 7.59~7.44 (m, 3H), 7.20 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7, 2H), 4.82~4.78 (dd, J = 12.3, 6.7 Hz, 1H), 4.67~4.63 (dd, J = 12.3, 7.9 Hz, 1H), 4.21~4.15 (m, 1H), 3.78 (s, 3H), 3.47~3.43 (dd, J = 16.5, 6.5 Hz, 1H), 3.43~3.37 (dd, J = 16.5, 6.6 Hz, 1H) ppm;
13C NMR (125 MHz, CDCl
3) δ 196.99, 159.10, 136.42, 133.56, 130.99, 128.75, 128.52, 128.04, 114.45, 79.85, 55.27, 41.67, 38.65 ppm; LRMS (ESI
+) for C
17H
17NO
4
[M+Na]
+ Calcd: 322.1, Found: 322.2; HPLC [Chiralcel AD-H, hexane/2-propanol = 80/20, flow rate = 1.0 mL/min, λ = 254 nm, retention times: (major) 11.8 min, (minor) 16.0 min]; R
f
(SiO
2, EtOAc/n-hexane = 1/5) = 0.31(3f) [α] D 20 -20.2 (c 1.0, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 ) δ 7.93-7.91 (m, 2H), 7.59-7.44 (m, 3H), 7.20 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7, 2H ), 4.82-4.78 (dd, J = 12.3, 6.7 Hz, 1H), 4.67-4.63 (dd, J = 12.3, 7.9 Hz, 1H), 4.21-4.15 (m, 1H), 3.78 (s, 3H), 3.47-3.43 (dd, J = 16.5, 6.5 Hz, 1H), 3.43-3.37 (dd, J = 16.5, 6.6 Hz, 1H) ppm; 13 C NMR (125 MHz, CDCl 3 ) δ 196.99, 159.10, 136.42, 133.56, 130.99, 128.75, 128.52, 128.04, 114.45, 79.85, 55.27, 41.67, 38.65 ppm; LRMS (ESI + ) for C 17 H 17 NO 4 [M + Na] + Calcd : 322.1, Found: 322.2; HPLC [Chiralcel AD-H, hexane / 2-propanol = 80/20, flow rate = 1.0 mL / min, λ = 254 nm, retention times: (major) 11.8 min, (minor) 16.0 min]; R f (SiO 2 , EtOAc / n-hexane = 1/5) = 0.31
(3g) [α]
D
20 -5.2 (c 1.4, CHCl
3);
1H NMR (500 MHz, CDCl
3) δ 7.94~7.92 (m, 2H), 7.58~7.55 (m, 1H), 7.47~7.44 (m, 2H), 7.26~7.20 (m, 2H), 6.92~6.88 (m, 2H), 4.89~4.82 (m, 2H), 4.45~4.39 (m, 1H), 3.86 (s, 3H), 3.54 (d, J = 7.5 Hz, 2H) ppm;
13C NMR (125 MHz, CDCl
3) δ 197.64, 157.20, 136.63, 133.38, 129.52, 128.99, 128.68, 128.05, 126.70, 120.96, 110.05, 77.90, 55.38, 39.80, 35.95 ppm; IR (KBr) 3063, 2923, 2852, 1684, 1598, 1550, 1494, 1445, 1377, 1246, 1120, 1025, 754, 690 cm
-1; LRMS (ESI
+) for C
17H
17NO
4
[M+Na]
+ Calcd: 322.1, Found: 322.2; HPLC [Chiralcel AD-H, hexane/2-propanol = 85/15, flow rate = 1.0 mL/min, λ = 254 nm, retention times: (major) 9.4 min, (minor) 12.7 min]; R
f (SiO
2, EtOAc/n-hexane = 1/5) = 0.30(3 g) [α] D 20 -5.2 (c 1.4, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 ) δ 7.94 to 7.72 (m, 2H), 7.58 to 7.55 (m, 1H), 7.47 to 7.44 (m, 2H), 7.26 to 7.20 (m, 2H), 6.92 to 6.88 (m, 2H), 4.89-4.82 (m, 2H), 4.45-4.39 (m, 1H), 3.86 (s, 3H), 3.54 (d, J = 7.5 Hz, 2H) ppm; 13 C NMR (125 MHz, CDCl 3 ) δ 197.64, 157.20, 136.63, 133.38, 129.52, 128.99, 128.68, 128.05, 126.70, 120.96, 110.05, 77.90, 55.38, 39.80, 35.95 ppm; IR (KBr) 3063, 2923, 2852, 1684, 1598, 1550, 1494, 1445, 1377, 1246, 1120, 1025, 754, 690 cm −1 ; LRMS (ESI + ) for C 17 H 17 NO 4 [M + Na] + Calcd : 322.1, Found: 322.2; HPLC [Chiralcel AD-H, hexane / 2-propanol = 85/15, flow rate = 1.0 mL / min, λ = 254 nm, retention times: (major) 9.4 min, (minor) 12.7 min]; R f (SiO 2 , EtOAc / n-hexane = 1/5) = 0.30
(3h) [α]
D
20 -12.9 (c 1.0, CHCl
3);
1H NMR (500 MHz, CDCl
3) δ 7.96~7.94 (m, 2H), 7.61~7.58 (m, 1H), 7.49~7.46 (m, 2H), 7.34 (m, 1H), 6.30~6.29 (m, 1H), 6.19 (d, J = 3.3 Hz, 1H), 4.83~4.79 (dd, J = 11.6, 5.4 Hz, 1H), 4.77~4.73 (dd, J = 11.6, 6.0 Hz, 1H), 4.36~4.31 (m, 1H), 3.55~3.50 (dd, J = 17.7, 6.1 Hz, 1H), 3.46~3.41 (dd, J = 17.7, 7.3 Hz, 1H) ppm;
13C NMR (125 MHz, CDCl
3) δ 196.55, 151.95, 142.32, 136.26, 133.69, 128.80, 128.07, 110.53, 107.20, 77.27, 38.99, 33.19 ppm; IR (KBr) 3121, 3062, 2918, 1685, 1596, 1553, 1505, 1448, 1377, 1213, 1183, 1012, 917, 749, 691, 599 cm
-1; LRMS(ESI
+) for C
14H
13NO
4 [M+Na]
+ Calcd: 282.1, Found: 282.1; HPLC [Chiralcel AD-H, hexane/2-propanol = 95/5, flow rate = 1.0 mL/min, λ = 254 nm, retention times: (major) 12.9 min, (minor) 15.6 min]; R
f
(SiO
2, EtOAc/n-hexane = 1/5) = 0.32(3h) [α] D 20 -12.9 (c 1.0, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 ) δ 7.96 ~ 7.94 (m, 2H), 7.61 ~ 7.58 (m, 1H), 7.49 ~ 7.46 (m, 2H), 7.34 (m, 1H), 6.30 ~ 6.29 (m , 1H), 6.19 (d, J = 3.3 Hz, 1H), 4.83-4.79 (dd, J = 11.6, 5.4 Hz, 1H), 4.77-4.73 (dd, J = 11.6, 6.0 Hz, 1H), 4.36- 4.31 (m, 1 H), 3.55-3.50 (dd, J = 17.7, 6.1 Hz, 1H), 3.46-3.41 (dd, J = 17.7, 7.3 Hz, 1H) ppm; 13 C NMR (125 MHz, CDCl 3 ) δ 196.55, 151.95, 142.32, 136.26, 133.69, 128.80, 128.07, 110.53, 107.20, 77.27, 38.99, 33.19 ppm; IR (KBr) 3121, 3062, 2918, 1685, 1596, 1553, 1505, 1448, 1377, 1213, 1183, 1012, 917, 749, 691, 599 cm −1 ; LRMS (ESI + ) for C 14 H 13 NO 4 [M + Na] + Calcd : 282.1, Found: 282.1; HPLC [Chiralcel AD-H, hexane / 2-propanol = 95/5, flow rate = 1.0 mL / min, λ = 254 nm, retention times: (major) 12.9 min, (minor) 15.6 min]; R f (SiO 2 , EtOAc / n-hexane = 1/5) = 0.32
(3i)
1H NMR (500 MHz, CDCl
3) δ 7.38~7.16 (m, 8H), 6.87~6.85 (m, 2H), 4.75~4.71 (dd, J = 11.6, 6.6 Hz, 1H), 4.68~4.64 (dd, J = 11.6, 6.4 Hz, 1H), 4.10~4.04 (m, 1H), 3.04~3.0 (dd, J = 13.7, 4.6 Hz, 1H), 2.99~2.94 (dd, J = 13.7, 5.6 Hz, 1H) ppm;
13C NMR (125 MHz, CDCl
3) δ 169.33, 150.33, 137.96, 129.50, 129.22, 128.29, 127.55, 126.12, 121.39, 79.38, 40.38, 37.87 ppm; LRMS (ESI
+) for C
16H
15NO
4
[M+Na]
+ Calcd: 308.1, Found: 308.1; R
f
(SiO
2, EtOAc/n-hexane = 1/5) = 0.40(3i) 1 H NMR (500 MHz, CDCl 3 ) δ 7.38 ~ 7.16 (m, 8H), 6.87 ~ 6.85 (m, 2H), 4.75 ~ 4.71 (dd, J = 11.6, 6.6 Hz, 1H), 4.68 ~ 4.64 (dd, J = 11.6, 6.4 Hz, 1H), 4.10-4.04 (m, 1H), 3.04-3.0 (dd, J = 13.7, 4.6 Hz, 1H), 2.99-2.94 (dd, J = 13.7, 5.6 Hz, 1H) ppm; 13 C NMR (125 MHz, CDCl 3 ) δ 169.33, 150.33, 137.96, 129.50, 129.22, 128.29, 127.55, 126.12, 121.39, 79.38, 40.38, 37.87 ppm; LRMS (ESI + ) for C 16 H 15 NO 4 [M + Na] + Calcd : 308.1, Found: 308.1; R f (SiO 2 , EtOAc / n-hexane = 1/5) = 0.40
(3j)
1H NMR (500 MHz, CDCl
3) δ 7.35~7.22 (m, 7H), 6.92~6.90 (m, 2H), 4.79~4.75 (dd, J = 12.7, 7.3 Hz, 1H), 4.71~4.67 (dd, J = 12.7, 7.9 Hz, 1H), 4.11~4.06 (m, 1H), 3.08~3.03 (dd, J = 14.7, 5.3 Hz, 1H), 3.01~2.96 (dd, J = 14.7, 6.5 Hz, 1H) ppm;
13C NMR (125 MHz, CDCl
3) δ 169.01, 150.17, 136.37,134.23, 129.53, 129.43, 128.88, 126.20, 121.26, 79.08, 39.70, 37.67 ppm; LRMS (ESI
+) for C
16H
14ClNO
4
[M+Na]
+ Calcd: 342.1, Found: 342.1; R
f
(SiO
2, EtOAc/n-hexane = 1/5) = 0.31(3j) 1 H NMR (500 MHz, CDCl 3 ) δ 7.35-7.22 (m, 7H), 6.92-6.70 (m, 2H), 4.79-4.75 (dd, J = 12.7, 7.3 Hz, 1H), 4.71- 4.67 (dd, J = 12.7, 7.9 Hz, 1H), 4.11-4.06 (m, 1H), 3.08-3.03 (dd, J = 14.7, 5.3 Hz, 1H), 3.01-2.96 (dd, J = 14.7, 6.5 Hz, 1H) ppm; 13 C NMR (125 MHz, CDCl 3 ) δ 169.01, 150.17, 136.37,134.23, 129.53, 129.43, 128.88, 126.20, 121.26, 79.08, 39.70, 37.67 ppm; LRMS (ESI + ) for C 16 H 14 ClNO 4 [M + Na] + Calcd: 342.1, Found: 342.1; R f (SiO 2 , EtOAc / n-hexane = 1/5) = 0.31
(3k) [α]
D
20 +36.0 (c 0.01, CHCl
3)(3k) [α] D 20 +36.0 (c 0.01, CHCl 3 )
(3l) [α]
D
20 -36.4 (c 0.01, CHCl
3);
1H NMR (500 MHz, CDCl
3) δ 7.37~7.33 (m, 2H), 7.29~7.27 (m, 2H), 7.26~7.25 (m, 1H), 5.92 (br s, 1H), 3.81~3.77 (m, 1H), 3.71 (q, J = 8.0 Hz, 1H), 3.45~3.41 (dd, J = 9.4, 2.0 Hz, 1H), 2.77~2.72 (dd, J = 16.8, 8.7 Hz, 1H), 2.54~2.49 (dd, J = 17.0, 8.5 Hz, 1H) ppm;
13C NMR (125 MHz, CDCl
3) δ 177.93, 142.14, 128.88, 127.13, 126.79, 49.60, 40.31, 38.02 ppm; LRMS (ESI
+) for C
10H
11NO[M+H]
+Calcd: 162.10, Found: 162.20(3l) [α] D 20 -36.4 (c 0.01, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 ) δ 7.37 ~ 7.33 (m, 2H), 7.29 ~ 7.27 (m, 2H), 7.26 ~ 7.25 (m, 1H), 5.92 (br s, 1H), 3.81 ~ 3.77 ( m, 1H), 3.71 (q, J = 8.0 Hz, 1H), 3.45-3.41 (dd, J = 9.4, 2.0 Hz, 1H), 2.77-2.72 (dd, J = 16.8, 8.7 Hz, 1H), 2.54 ˜2.49 (dd, J = 17.0, 8.5 Hz, 1H) ppm; 13 C NMR (125 MHz, CDCl 3 ) δ 177.93, 142.14, 128.88, 127.13, 126.79, 49.60, 40.31, 38.02 ppm; LRMS (ESI + ) for C 10 H 11 NO [M + H] + Calcd: 162.10, Found: 162.20
(3m) [α]
D
22 +33.0 (c 1.0, EtOH)(3m) [α] D 22 +33.0 (c 1.0, EtOH)
(3n) [α]
D
30 -39.7 (c 1.00, CHCl
3);
1H NMR (500 MHz, CDCl
3) δ 7.32 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 5.72 (br s, 1H), 3.80~3.77 (m, 1H), 3.69 (q, J = 8.5 Hz, 1H), 3.40~3.36 (dd, J = 8.4, 2.5 Hz, 1H), 2.77~2.71 (dd, J = 17.8, 8.5 Hz, 1H), 2.48~2.43 (dd, J = 16.9, 8.5 Hz, 1H) ppm;
13C NMR (125 MHz, CDCl
3) δ 177.68, 140.59, 132.93, 129.03, 128.15, 49.49, 39.66, 37.90 ppm; HRMS (ESI
+) for C
10H
10ClNO [M+H]
+ Calcd: 196.0445, Found: 196.1160(3n) [α] D 30 -39.7 (c 1.00, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 ) δ 7.32 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 5.72 (br s, 1H), 3.80-3.77 (m, 1H ), 3.69 (q, J = 8.5 Hz, 1H), 3.40-3.36 (dd, J = 8.4, 2.5 Hz, 1H), 2.77-2.71 (dd, J = 17.8, 8.5 Hz, 1H), 2.48-2.43 ( dd, J = 16.9, 8.5 Hz, 1H) ppm; 13 C NMR (125 MHz, CDCl 3 ) δ 177.68, 140.59, 132.93, 129.03, 128.15, 49.49, 39.66, 37.90 ppm; HRMS (ESI + ) for C 10 H 10 ClNO [M + H] + Calcd: 196.0445, Found: 196.1160
(3o) [α]
D
25 +5.8 (c 0.5, H
2O);
1H NMR (500 MHz, D
2O) δ 7.47~7.44 (m, 2H), 7.41~7.36 (m, 3H), 3.47~3.36 (m, 2H), 3.27 (t, J = 11.0 Hz, 1H), 2.89~2.85 (dd, J = 16.0, 5.9 Hz, 1H), 2.81~2.76 (dd, J = 16.0, 8.8 Hz, 1H) ppm;
13C NMR (125 MHz, D
2O) δ 175.62, 138.37, 129.37, 128.30, 127.87, 43.81, 40.0, 38.34 ppm; LRMS (ESI
+) for C
10H
13NO
2
[M+H]
+ Calcd: 180.1, Found: 180.2; R
f
(SiO
2, CH
2Cl
2/MeOH = 10/1) = 0.48(3o) [a] D 25 +5.8 (c 0.5, H 2 O); 1 H NMR (500 MHz, D 2 O) δ 7.47 to 7.44 (m, 2H), 7.41 to 7.36 (m, 3H), 3.47 to 3.36 (m, 2H), 3.27 (t, J = 11.0 Hz, 1H) , 2.89-2.85 (dd, J = 16.0, 5.9 Hz, 1H), 2.81-2.76 (dd, J = 16.0, 8.8 Hz, 1H) ppm; 13 C NMR (125 MHz, D 2 O) δ 175.62, 138.37, 129.37, 128.30, 127.87, 43.81, 40.0, 38.34 ppm; LRMS (ESI + ) for C 10 H 13 NO 2 [M + H] + Calcd : 180.1, Found: 180.2; R f (SiO 2 , CH 2 Cl 2 / MeOH = 10/1) = 0.48
(3p) [α]
D
25 +1.8 (c 0.5, H
2O);
1H NMR (500 MHz, D
2O) δ 7.40~7.37 (m, 2H), 7.29~7.26 (m, 2H), 3.39~3.30 (m, 2H), 3.22~3.16 (m, 1H), 2.81~2.76 (dd, J = 16.1, 5.9 Hz, 1H), 2.70~2.65 (dd, J = 16.1, 8.9 Hz, 1H) ppm;
13C NMR (125 MHz, D
2O) δ 175.46, 137.02, 133.38, 129.41, 129.25, 43.60, 39.47, 38.33 ppm; HRMS (FAB
+) for C
10H
12ClNO
2
[M+H]
+ Calcd: 214.0635, Found: 214.0627; R
f
(SiO
2, CH
2Cl
2/MeOH = 10/1) = 0.46(3p) [a] D 25 +1.8 (c 0.5, H 2 O); 1 H NMR (500 MHz, D 2 O) δ 7.40 to 7.37 (m, 2H), 7.29 to 7.26 (m, 2H), 3.39 to 3.30 (m, 2H), 3.22 to 3.16 (m, 1H), 2.81 to 2.76 (dd, J = 16.1, 5.9 Hz, 1H), 2.70-2.65 (dd, J = 16.1, 8.9 Hz, 1H) ppm; 13 C NMR (125 MHz, D 2 O) δ 175.46, 137.02, 133.38, 129.41, 129.25, 43.60, 39.47, 38.33 ppm; HRMS (FAB + ) for C 10 H 12 ClNO 2 [M + H] + Calcd: 214.0635, Found: 214.0627; R f (SiO 2 , CH 2 Cl 2 / MeOH = 10/1) = 0.46
(3q) [α]
D
20 = -8.4 (c = 3.0, MeOH)(3q) [a] D 2 ° = -8.4 (c = 3.0, MeOH)
(3r) [α]
D
20 = +8.5 (c = 3.0, MeOH);
1H NMR spectrum (CDCl
3), δ, ppm: 2.59 d.d (1H, 3-H, 3JHH = 8.4, 2JHH = 17.0 Hz), 2.81 d.d (1H, 3-H, 3JHH = 8.4, 2JHH = 17.0 Hz), 3.53 m (1H, 5-H), 3.63 m (1H, 4-H), 3.85 m (1H, 5-H), 3.97 d.d (2H, NCH2CO, 3JHH = 16.3, 2JHH = 33.0 Hz); 6.24 br.s and 6.66 br.s (1H each, NH2), 7.22-7.31 m (5H, Ph).
13C NMR spectrum (CDCl
3), δC, ppm: 37.48, 38.54, 46.25, 55.55, 126.89, 127.27, 129.01, 141.97, 170.78, 175.03 pp; HRMS (ESI
+) for C
10H
13NO
2
[M+Na]
+ Calcd: 241.0957, Found: 241.0947;(3r) [a] D 2 ° = +8.5 (c = 3.0, MeOH); 1 H NMR spectrum (CDCl 3 ), δ, ppm: 2.59 dd (1H, 3-H, 3JHH = 8.4, 2JHH = 17.0 Hz), 2.81 dd (1H, 3-H, 3JHH = 8.4, 2JHH = 17.0 Hz) , 3.53 m (1H, 5-H), 3.63 m (1H, 4-H), 3.85 m (1H, 5-H), 3.97 dd (2H, NCH2CO, 3JHH = 16.3, 2JHH = 33.0 Hz); 6.24 br.s and 6.66 br.s (1H each, NH 2), 7.22-7.31 m (5H, Ph). 13 C NMR spectrum (CDCl 3 ), δ C, ppm: 37.48, 38.54, 46.25, 55.55, 126.89, 127.27, 129.01, 141.97, 170.78, 175.03 pp; HRMS (ESI + ) for C 10 H 13 NO 2 [M + Na] + Calcd: 241.0957, Found: 241.0947;
(3s) [α]
D
25 -62.0 (c 1.0, MeOH);
1H NMR (CDCl
3, 500 MHz) 6.51 (s, 1 H) 5.93 (s, 1 H) 4.46 (dd, J = 8.9, 7.9, 1 H) 3.47 (dd, J = 9.8, 7.8 Hz, 1 H) 3.05 (dd, J = 9.8, 7.1 Hz, 1 H) 2.54 (dd, J = 16.7, 8.6, 1 H) 2.39-2.23 (m, 1 H) 2.06 (dd, J = 16.7, 8.1, 1 H) 1.99-1.85 (m, 1 H) 1.70-1.62 (m, 1 H) 1.45-1.37 (m, 2 H) 1.37-1.25 (m, 2 H) 0.94-0.84 (m, 6 H) ppm ;
13C NMR (CDCl3, 100 MHz) 175.4, 172.6, 55.7, 49.4, 37.8, 36.4, 31.9, 21.2, 20.5, 13.9, 10.4 ppm; HRMS calculated for [M+Na]
+ C
11H
20O
2N
2 235.1422, found 235.1418. (3s) [α] D 25 -62.0 (c 1.0, MeOH); 1 H NMR (CDCl 3 , 500 MHz) 6.51 (s, 1 H) 5.93 (s, 1 H) 4.46 (dd, J = 8.9, 7.9, 1 H) 3.47 (dd, J = 9.8, 7.8 Hz, 1 H ) 3.05 (dd, J = 9.8, 7.1 Hz, 1 H) 2.54 (dd, J = 16.7, 8.6, 1 H) 2.39-2.23 (m, 1 H) 2.06 (dd, J = 16.7, 8.1, 1 H) 1.99-1.85 (m, 1H) 1.70-1.62 (m, 1H) 1.45-1.37 (m, 2H) 1.37-1.25 (m, 2H) 0.94-0.84 (m, 6H) ppm; 13 C NMR (CDCl 3, 100 MHz) 175.4, 172.6, 55.7, 49.4, 37.8, 36.4, 31.9, 21.2, 20.5, 13.9, 10.4 ppm; HRMS calculated for [M + Na] + C 11 H 20 O 2 N 2 235.1422, found 235.1418.
실시예 3 : 유기 키랄 촉매 화합물 및 용매의 종류에 따른 반응 시험 결과Example 3 Result of Reaction Test According to Kinds of Organic Chiral Catalyst Compound
실시예 1에서 제조한 유기 키랄 촉매 화합물을 이용하여, 용매로 물 또는 톨루엔의 존재 하에서, 실시예 2의 마이클 첨가 반응을 수행하여, 유기 키랄 촉매 화합물 및 용매의 종류에 따른 반응 시간 및 수율을 확인한다 (도 6 및 표 3, 표 4).Using the organic chiral catalyst compound prepared in Example 1, the Michael addition reaction of Example 2 was carried out in the presence of water or toluene as a solvent to confirm the reaction time and yield according to the type of organic chiral catalyst compound and the solvent. (Fig. 6 and Table 3, Table 4).
| 유기 키랄 촉매화합물Organic Chiral Catalyst | R 1 R 1 | R 2 R 2 | 용매menstruum | 시간(h)Hours (h) | 수율(%) b Yield (%) b | ee(%) e ee (%) e | |
| 1d1d | MeMe | HH | 물 a Water a | 1414 | 9797 | 9999 | |
| 1d1d |
Me | HH | 톨루엔toluene | 9696 | 8989 | 8080 | |
| 1j1j |
Me | HH | 물water | 1010 | 9898 | 9999 | |
| 1k1k | MeMe | HH | 물water | 1919 | 9595 | 9494 | |
| 1j1j |
Et | HH | 물water | 1212 | 9797 | 9999 | |
| 1j1j |
Et | HH | 톨루엔toluene | 9696 | 8181 | 8080 | |
| 1l1l |
Et | HH | 물water | 1212 | 8181 | 9494 | |
| 1l1l |
Et | HH | 톨루엔toluene | 9696 | 8686 | 9393 | |
| 1j1j | BnBn | HH | 물water | 1414 | 9393 | 9898 | |
| 1k1k | BnBn | HH | 물water | 2626 | 9191 | 9898 |
(
a5 당량,
b분리 수율,
cee 값은 AD-H, OD-H 칼럼을 이용한 키랄 상 HPLC로 결정)( a 5 equivalents, b separation yield, c ee values determined by chiral phase HPLC using AD-H, OD-H columns)
| 유기 키랄 촉매화합물Organic Chiral Catalyst | R 1 R 1 | R 2 R 2 | 용매menstruum | 시간(min)Time (min) | 수율(%) b Yield (%) b | ee(%) e ee (%) e | |
| 1m1m | EtEt | HH | -- | 6060 | 9797 | 9191 | |
| 1n1n | EtEt | HH | -- | 6060 | 9595 | 9999 | |
| 1m1m |
Et | HH | 물water | 55 | 9999 | 9999 | |
| 1m1m | EtEt | EtEt | 물water | 3030 | 9595 | 9999 | |
| 1n1n | EtEt | HH | 물water | 6060 | 9696 | 9090 | |
| 1m1m | BnBn | HH | 물water | 1515 | 9494 | 9999 | |
| 1n1n | BnBn | HH | 물water | 6060 | 9292 | 9999 | |
| 1m1m |
Et | BrBr | 물water | 1010 | 9595 | 9999 | |
| 1n1n | EtEt | BrBr | 물water | 9090 | 9696 | 9999 |
(
a5 당량,
b분리 수율,
cee 값은 AD-H, OD-H 칼럼을 이용한 키랄 상 HPLC로 결정)( a 5 equivalents, b separation yield, c ee values determined by chiral phase HPLC using AD-H, OD-H columns)
그 결과, 트리플루오로메틸이 치환된 유기 키랄 촉매 화합물이 물에서 사용될 수 있음을 확인할 수 있고, 이는 물에서의 불소(fluorine) 원자의 상호작용이 활성화 장벽을 낮춘다는 것을 의미한다.As a result, it can be seen that trifluoromethyl-substituted organic chiral catalyst compounds can be used in water, which means that the interaction of fluorine atoms in water lowers the activation barrier.
실시예 4 : α,β-불포화 나이트로 화합물의 종류에 따른 반응 시험 결과Example 4 Results of Reaction Test According to Kind of α, β-unsaturated Nitro Compound
실시예 1에서 제조한 유기 키랄 촉매 화합물 중 1m을 이용하여, 용매로서 물의 존재 하에서, 실시예 2의 마이클 첨가 반응을 수행하여, α,β-불포화 나이트로 화합물의 종류에 따른 반응 시간 및 수율을 확인한다. 구체적으로, 물 (0.4 ml)에 트랜스-β-나이트로스티렌 (1.0 당량), 말로나이트릴 (2.0 당량) 및 0.1 내지 0.001 mol%의 유기 키랄 촉매 화합물 1m을 첨가하고, 반응 혼합물을 실온(rt)에서 교반시켰다. TLC로 반응 전환을 모니터하였다. 완료 후에, 에틸 아세테이트 (0.2 ml)을 반응 혼합물에 첨가하였다. 이 용액을 물 (2X1.0 mL)로 두 번 씻어내고, 황산 마그네슘에서 건조시킨 후, 농축하여, 목적 생성물을 수득하였다. 생성물을 실리카-겔 칼럼(헥산 / 메틸렌클로라이드, 2 : 1)에서 크로마토 그래피로 정제하였다(도 7 및 표 5). Using the 1 m of the organic chiral catalyst compound prepared in Example 1, the Michael addition reaction of Example 2 was carried out in the presence of water as a solvent, the reaction time and yield according to the type of α, β-unsaturated nitro compound Check it. Specifically, to water (0.4 ml) was added trans-β-nitrostyrene (1.0 equiv), malonitrile (2.0 equiv) and 0.1 to 0.001 mol% of an organic chiral catalyst compound and the reaction mixture was allowed to stand at room temperature (rt). )). Reaction conversion was monitored by TLC. After completion, ethyl acetate (0.2 ml) was added to the reaction mixture. This solution was washed twice with water (2X1.0 mL), dried over magnesium sulfate and concentrated to afford the desired product. The product was purified by chromatography on a silica-gel column (hexane / methylene chloride, 2: 1) (Figure 7 and Table 5).
| R 1 R 1 | R 2 R 2 | ArAr | 시간(시)Hour | 수율(%) b ) Yield (%) b ) | ee(%) c) ee (%) c) | ||
| 1One | MeMe | MeMe | PhPh | 2424 | 9898 | 9999 | |
| 22 | EtEt | EtEt | PhPh | 2424 | 9898 | 9999 | |
| 3 d) 3 d) | EtEt | EtEt | PhPh | 0.50.5 | 9898 | 9999 | |
| 4 e) 4 e) |
Et | EtEt | PhPh | 66 | 9898 | 9999 | |
| 55 | i-Pri-Pr | i-Pri-Pr | PhPh | 2424 | 9696 | 9999 | |
| 66 | n-Prn-Pr | n-Prn-Pr | PhPh | 2424 | 9696 | 9999 | |
| 77 | BuBu | BuBu | PhPh | 2424 | 9999 | 9999 | |
| 88 | EtEt | EtEt | 4-Br-Ph4-Br-Ph | 2424 | 9494 | 9999 | |
| 99 | EtEt | EtEt | 4-Cl-Ph4-Cl-Ph | 2424 | 9595 | 9999 | |
| 1010 | EtEt | EtEt | 4-Me-Ph4-Me-Ph | 2424 | 9191 | 9393 | |
| 1111 | EtEt | EtEt | 4-OMe-Ph4-OMe-Ph | 2424 | 9393 | 9191 | |
| 1212 | EtEt | EtEt | 2-OMe-Ph2-OMe-Ph | 2424 | 9191 | 9696 | |
| 1313 | EtEt | EtEt | 4-OH-Ph4-OH-Ph | 2424 | 9595 | 9696 | |
| 1414 | EtEt | EtEt | furylfuryl | 2424 | 9797 | 9999 |
(
b)분리 수율,
c)ee 값은 키랄 HPLC 분석으로 결정,
d)0.1mol% 촉매로 반응,
e)0.01mol% 촉매로 반응)( b) separation yield, c) ee value determined by chiral HPLC analysis, d) reaction with 0.1 mol% catalyst, e) reaction with 0.01 mol% catalyst)
실시예 5 : α,β-불포화 케톤(트랜스 칼콘) 화합물의 종류에 따른 반응 시험 결과Example 5 Reaction Test Results According to Kinds of α, β-unsaturated Ketone (Trans Calcon) Compounds
실시예 1에서 제조한 유기 키랄 촉매 화합물 중 1m을 이용하여, 용매로서 물의 존재 하에서, 나이트로 에틸에스터와 마이클 첨가 반응을 수행하여, α,β 불포화 케톤 화합물의 종류에 따른 반응 시간 및 수율을 확인한다. 구체적으로, 물 (0.4 ml)에 α,β 불포화 케톤 (1.0 당량), 나이크로 에틸에스터 (2.0 당량) 및 0.1 내지 0.009 mol%의 유기 키랄 촉매 화합물 1m을 첨가하고, 반응 혼합물을 실온(rt)에서 교반시켰다. TLC로 반응 전환을 모니터하였다. 완료 후에, 수산화나트륨 (1.0 당량), 에탄올을 넣고 상온에서 12시간을 교반한다. 이 후에 감압 농축하여, 목적 생성물을 수득하였다. 생성물을 실리카-겔 칼럼(헥산 / 에틸렌아세테이트, 10 : 1)에서 크로마토 그래피로 정제하였다(도 8 및 표 6).Using 1 m of the organic chiral catalyst compound prepared in Example 1, the addition reaction with nitro ethyl ester and Michael in the presence of water as a solvent to confirm the reaction time and yield according to the type of α, β unsaturated ketone compound do. Specifically, α, β unsaturated ketone (1.0 equiv), nitro ethylester (2.0 equiv) and 0.1 to 0.009 mol% of an organic chiral catalyst compound were added to water (0.4 ml), and the reaction mixture was cooled to room temperature (rt). Stirred at. Reaction conversion was monitored by TLC. After completion, add sodium hydroxide (1.0 equiv), ethanol and stir 12 hours at room temperature. Thereafter, the mixture was concentrated under reduced pressure to obtain the desired product. The product was purified by chromatography on a silica-gel column (hexane / ethylene acetate, 10: 1) (Figure 8 and Table 6).
| ArAr | 시간(시)Hour | 수율(%) b ) Yield (%) b ) | ee(%) c) ee (%) c) | |
| 1One | C 6H 5 C 6 H 5 | 2424 | 8585 | 9999 |
| 22 | 4-MeC 6H 4 4-MeC 6 H 4 | 2424 | 8282 | 8888 |
| 33 | 4-BrC 6H 4 4-BrC 6 H 4 | 2424 | 8383 | 9292 |
| 44 | 4-ClC 6H 4 4-ClC 6 H 4 | 2424 | 8080 | 9292 |
| 55 | 4-MeOC 6H 4 4-MeOC 6 H 4 | 2424 | 7878 | 9494 |
| 66 | 2-MeOC 6H 4 2-MeOC 6 H 4 | 2424 | 7575 | 8282 |
| 77 | 2-furyl2-furyl | 2424 | 8383 | 9898 |
(
b)분리 수율,
c)ee 값은 키랄 HPLC 분석으로 결정)( b) separation yield, c) ee value determined by chiral HPLC analysis)
일반적인 실험 방법General Experiment Method
IR 스펙트럼은 NICOLET 380 FT-IR 분광광도계에 기록하였다. 광 회전(optical rotaion)은 루돌프 자동 편광계(Rudolph Automatic polarimeter; 모델명: A20766 APV/6w)로 측정하였다.
1H NMR 스펙트럼은 내부 기준으로 TMS를 가지는 Varian Mercury 400 (400 MHz) 또는 Varian Mercury 300 (300 MHz)에 기록하였다.
13C NMR은 내부 기준으로 TMS 또는 CDCl
3를 가지는 Varian Mercury 400 (400 MHz)에 기록하였다. 키랄 HPLC 분석은 UV 검출기가 구비된 Jasco LC-1500 Series HPLC 시스템에서 수행하였다. 모든 반응은 아르곤 대기 하에서 오븐 건조된 유리기구 내에서 수행하였다. 톨루엔(CaH
2), THF(Na, 벤조피논)은 사용 전에 증류로 건조하였다.IR spectra were recorded on a NICOLET 380 FT-IR spectrophotometer. Optical rotation was measured with a Rudolph Automatic polarimeter (Model name: A20766 APV / 6w). 1 H NMR spectra were recorded on Varian Mercury 400 (400 MHz) or Varian Mercury 300 (300 MHz) with TMS as internal reference. 13 C NMR was recorded in Varian Mercury 400 (400 MHz) with TMS or CDCl 3 as internal standard. Chiral HPLC analysis was performed on a Jasco LC-1500 Series HPLC system equipped with a UV detector. All reactions were carried out in glassware oven dried under an argon atmosphere. Toluene (CaH 2 ), THF (Na, benzopinone) was dried by distillation before use.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는바, 당 업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적 기술은 단지 바람직한 실시예일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.The specific parts of the present invention have been described in detail above, and it should be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments, and thus the scope of the present invention is not limited thereto. will be. Thus, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
본 발명에 따르면 입체 선택성이 우수한 이 작용성 유기 키랄 촉매 화합물을 쉽게 합성할 수 있으며, 이를 이용하여 경제적이고 간편한 방법으로 높은 광학 선택성을 갖는 감마 아미노산을 높은 수율로 수득할 수 있을 뿐만 아니라, 적은 양의 촉매로, 자연에 존재하지 않는 (R)-형태의 다양한 감마 아미노산을 높은 광학 순도로 대량으로 제조할 수 있는바, 의약품 산업을 비롯한 다양한 산업 분야에 있어서, 널리 활용될 수 있다.According to the present invention, this functional organic chiral catalyst compound having excellent stereoselectivity can be easily synthesized, and using this, it is possible to obtain a high yield of gamma amino acids having high optical selectivity in an economical and simple manner, as well as a small amount. As a catalyst of, a variety of gamma amino acids in the (R) -form which do not exist in nature can be produced in large quantities with high optical purity, and can be widely used in various industrial fields including the pharmaceutical industry.
Claims (12)
- 하기 [화학식 1]로 표시되는 유기 키랄 촉매 화합물:An organic chiral catalyst compound represented by the following [Formula 1]:[화학식 1][Formula 1]
상기 [화학식 1]에서,In [Formula 1],X는 O, S, P-R 3 및 N-R 4 중에서 선택되는 어느 하나이고, R 1 내지 R 4는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 중수소, 치환 또는 비치환된 C1 내지 C30 알킬기, 치환 또는 비치환된 C3 내지 C30 사이클로알킬기, 치환 또는 비치환된 C2 내지 C30 헤테아릴기, 치환 또는 비치환된 C6 내지 C30 아릴기, 치환 또는 비치환된 C6 내지 C30 아릴아민기, 치환 또는 비치환된 C1 내지 C30 알콕시기, 치환 또는 비치환된 C2 내지 C30 알콕시카르보닐기, 치환 또는 비치환된 C2 내지 C30 알콕시카르보닐아미노기, 치환 또는 비치환된 C7 내지 C30 아릴옥시카르보닐아미노기, 치환 또는 비치환된 C2 내지 C30 알케닐기, 치환 또는 비치환된 C2 내지 C30 알키닐기, 치환 또는 비치환된 C3 내지 C40 실릴기, 치환 또는 비치환된 3 내지 C40 실릴옥시기, 치환 또는 비치환된 C1 내지 30 아실기, 치환 또는 비치환된 C1 내지 C20 아실옥시기 및 치환 또는 비치환된 C1 내지 C20 아실아미노기 중에서 선택되는 어느 하나이다.X is any one selected from O, S, PR 3 and NR 4 , and R 1 to R 4 are the same as or different from each other, and each independently hydrogen, deuterium, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted group A substituted C3 to C30 cycloalkyl group, a substituted or unsubstituted C2 to C30 heteroaryl group, a substituted or unsubstituted C6 to C30 aryl group, a substituted or unsubstituted C6 to C30 arylamine group, a substituted or unsubstituted C1 to C30 alkoxy group, substituted or unsubstituted C2 to C30 alkoxycarbonyl group, substituted or unsubstituted C2 to C30 alkoxycarbonylamino group, substituted or unsubstituted C7 to C30 aryloxycarbonylamino group, substituted or unsubstituted C2 to C30 Alkenyl groups, substituted or unsubstituted C2 to C30 alkynyl groups, substituted or unsubstituted C3 to C40 silyl groups, substituted or unsubstituted 3 to C40 silyloxy groups, substituted or unsubstituted C1 to 30 acyl groups, It is one which is selected from ring or unsubstituted C1 to C20 acyloxy group, and a substituted or unsubstituted C1 to C20 acyl group. - 제1항에 있어서,The method of claim 1,상기 [화학식 1]에서, R 1은 수소, 3-펜틸, Ph 2CH, 또는 3,5-(CF 3) 2-PhCH 2이고, R 2는 페닐, 3,5-(CF 3) 2-Ph, p-톨릴, 4-CF 3-Ph, C 6F 5, 4-NO 2-Ph, 4-CN-Ph, 4-F-Ph, t-부틸, 또는 3,5-(Me) 2-Ph인 것을 특징으로 하는 유기 키랄 촉매 화합물.In [Formula 1], R 1 is hydrogen, 3-pentyl, Ph 2 CH, or 3,5- (CF 3 ) 2 -PhCH 2 , R 2 is phenyl, 3,5- (CF 3 ) 2 − Ph, p-tolyl, 4-CF 3 -Ph, C 6 F 5 , 4-NO 2 -Ph, 4-CN-Ph, 4-F-Ph, t-butyl, or 3,5- (Me) 2 It is -Ph, an organic chiral catalyst compound characterized by the above-mentioned.
- 제1항에 있어서,The method of claim 1,상기 [화학식 1]로 표시되는 유기 키랄 촉매 화합물은 하기 화학식으로 표시되는 화합물 중에서 선택되는 어느 하나인 것을 특징으로 하는 유기 키랄 촉매 화합물:The organic chiral catalyst compound represented by the above [Formula 1] is an organic chiral catalyst compound, characterized in that any one selected from compounds represented by the following formula:
- 하기 [화학식 2]로 표시되는 (R,R)-1,2-다이페닐에틸렌다이아민 (DPEN)을 싸이오요소 (thiourea)와 반응시키는 단계를 포함하는, 하기 [화학식 1]로 표시되는 유기 키랄 촉매 화합물의 제조 방법:Organic represented by the following [Formula 1] comprising the step of reacting (R, R) -1,2-diphenylethylenediamine (DPEN) represented by the following [Formula 2] with a thiourea (thiourea) Process for preparing chiral catalyst compound:[화학식 1][Formula 1]
[화학식 2][Formula 2]
상기 [화학식 1]에서,In [Formula 1],X는 O, S, P-R 3 및 N-R 4 중에서 선택되는 어느 하나이고, R 1 내지 R 4는 서로 동일하거나 상이하고, 각각 독립적으로 수소, 중수소, 치환 또는 비치환된 C1 내지 C30 알킬기, 치환 또는 비치환된 C3 내지 C30 사이클로알킬기, 치환 또는 비치환된 C2 내지 C30 헤테아릴기, 치환 또는 비치환된 C6 내지 C30 아릴기, 치환 또는 비치환된 C6 내지 C30 아릴아민기, 치환 또는 비치환된 C1 내지 C30 알콕시기, 치환 또는 비치환된 C2 내지 C30 알콕시카르보닐기, 치환 또는 비치환된 C2 내지 C30 알콕시카르보닐아미노기, 치환 또는 비치환된 C7 내지 C30 아릴옥시카르보닐아미노기, 치환 또는 비치환된 C2 내지 C30 알케닐기, 치환 또는 비치환된 C2 내지 C30 알키닐기, 치환 또는 비치환된 C3 내지 C40 실릴기, 치환 또는 비치환된 3 내지 C40 실릴옥시기, 치환 또는 비치환된 C1 내지 30 아실기, 치환 또는 비치환된 C1 내지 C20 아실옥시기 및 치환 또는 비치환된 C1 내지 C20 아실아미노기 중에서 선택되는 어느 하나이다.X is any one selected from O, S, PR 3 and NR 4 , and R 1 to R 4 are the same as or different from each other, and each independently hydrogen, deuterium, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted group A substituted C3 to C30 cycloalkyl group, a substituted or unsubstituted C2 to C30 heteroaryl group, a substituted or unsubstituted C6 to C30 aryl group, a substituted or unsubstituted C6 to C30 arylamine group, a substituted or unsubstituted C1 to C30 alkoxy group, substituted or unsubstituted C2 to C30 alkoxycarbonyl group, substituted or unsubstituted C2 to C30 alkoxycarbonylamino group, substituted or unsubstituted C7 to C30 aryloxycarbonylamino group, substituted or unsubstituted C2 to C30 Alkenyl groups, substituted or unsubstituted C2 to C30 alkynyl groups, substituted or unsubstituted C3 to C40 silyl groups, substituted or unsubstituted 3 to C40 silyloxy groups, substituted or unsubstituted C1 to 30 acyl groups, It is one which is selected from ring or unsubstituted C1 to C20 acyloxy group, and a substituted or unsubstituted C1 to C20 acyl group. - 제4항에 있어서, The method of claim 4, wherein상기 [화학식 1]에서, R 1은 수소, 3-펜틸, Ph 2CH, 또는 3,5-(CF 3) 2-PhCH 2이고, R 2는 페닐, 3,5-(CF 3) 2-Ph, p-톨릴, 4-CF 3-Ph, C 6F 5, 4-N0 2-Ph, 4-CN-Ph, 4-F-Ph, t-부틸, 또는 3,5-(Me) 2-Ph인 것을 특징으로 하는 유기 키랄 촉매 화합물의 제조 방법.In [Formula 1], R 1 is hydrogen, 3-pentyl, Ph 2 CH, or 3,5- (CF 3 ) 2 -PhCH 2 , R 2 is phenyl, 3,5- (CF 3 ) 2 − Ph, p-tolyl, 4-CF 3 -Ph, C 6 F 5 , 4-N0 2 -Ph, 4-CN-Ph, 4-F-Ph, t-butyl, or 3,5- (Me) 2 -Ph, the method for producing an organic chiral catalyst compound.
- 제4항에 있어서,The method of claim 4, wherein상기 [화학식 1]로 표시되는 유기 키랄 촉매 화합물은 하기 화학식 중에서 선택되는 어느 하나인 것을 특징으로 하는 유기 키랄 촉매 화합물의 제조 방법:The organic chiral catalyst compound represented by the above [Formula 1] is a method for producing an organic chiral catalyst compound, characterized in that any one selected from the following formula:
- 하기 [반응식 1]에 따라 제1항에 따른 유기 키랄 촉매 화합물 존재 하에서,In the presence of the organic chiral catalyst compound according to claim 1 according to the following [Scheme 1],α,β-불포화 나이트로 화합물을 디알킬 말로네이트 또는 말로나이트릴과 마이클 첨가반응 시키는 단계를 포함하는 비천연 감마-아미노산의 제조 방법:A process for preparing an unnatural gamma-amino acid comprising Michael addition reaction of an α, β-unsaturated nitro compound with dialkyl malonate or malonitrile:[반응식 1]Scheme 1
상기 [반응식 1]에서,In [Scheme 1],A 및 B는 서로 동일하거나 상이하고, 각각 독립적으로, 수소, 중수소, 치환 또는 비치환된 C1 내지 C30 케톤기, 치환 또는 비치환된 C1 내지 C30 나이트로기, 비치환된 C1 내지 C30 사이아노기, 치환 또는 비치환된 C1 내지 C30 에스터기, 치환 또는 비치환된 C1 내지 C30 알킬기, 치환 또는 비치환된 C3 내지 C30 사이클로알킬기, 치환 또는 비치환된 C2 내지 C30 헤테아릴기, 치환 또는 비치환된 C6 내지 C30 아릴기, 치환 또는 비치환된 C6 내지 C30 아릴아민기, 치환 또는 비치환된 C1 내지 C30 알콕시기, 치환 또는 비치환된 C2 내지 C30 알콕시카르보닐기, 치환 또는 비치환된 C2 내지 C30 알콕시카르보닐아미노기, 치환 또는 비치환된 C7 내지 C30 아릴옥시카르보닐아미노기, 치환 또는 비치환된 C2 내지 C30 알케닐기, 치환 또는 비치환된 C2 내지 C30 알키닐기, 치환 또는 비치환된 C3 내지 C40 실릴기, 치환 또는 비치환된 3 내지 C40 실릴옥시기, 치환 또는 비치환된 C1 내지 30 아실기, 치환 또는 비치환된 C1 내지 C20 아실옥시기 및 치환 또는 비치환된 C1 내지 C20 아실아미노기 중에서 선택되는 어느 하나이며,A and B are the same as or different from each other, and each independently, hydrogen, deuterium, a substituted or unsubstituted C1 to C30 ketone group, a substituted or unsubstituted C1 to C30 nitro group, an unsubstituted C1 to C30 cyano group , Substituted or unsubstituted C1 to C30 ester group, substituted or unsubstituted C1 to C30 alkyl group, substituted or unsubstituted C3 to C30 cycloalkyl group, substituted or unsubstituted C2 to C30 heteroaryl group, substituted or unsubstituted C6 to C30 aryl group, substituted or unsubstituted C6 to C30 arylamine group, substituted or unsubstituted C1 to C30 alkoxy group, substituted or unsubstituted C2 to C30 alkoxycarbonyl group, substituted or unsubstituted C2 to C30 alkoxycar Carbonylamino group, substituted or unsubstituted C7 to C30 aryloxycarbonylamino group, substituted or unsubstituted C2 to C30 alkenyl group, substituted or unsubstituted C2 to C30 alkynyl group, substituted or unsubstituted C3 To C40 silyl group, substituted or unsubstituted 3 to C40 silyloxy group, substituted or unsubstituted C1 to 30 acyl group, substituted or unsubstituted C1 to C20 acyloxy group, and substituted or unsubstituted C1 to C20 acylamino group Is any one selected fromR 5 및 R 6는 서로 동일하거나 상이하고, 각각 독립적으로, 수소, 중수소, 치환 또는 비치환된 C1 내지 C30 케톤기, 치환 또는 비치환된 C1 내지 C30 나이트로기, 치환 또는 비치환된 C1 내지 C30 할로겐기, 치환 또는 비치환된 C1 내지 C30 사이아노기, 치환 또는 비치환된 C1 내지 C30 에스터기, 치환 또는 비치환된 C1 내지 C30 알킬기, 치환 또는 비치환된 C3 내지 C30 사이클로알킬기, 치환 또는 비치환된 C2 내지 C30 헤테아릴기, 치환 또는 비치환된 C6 내지 C30 아릴기, 치환 또는 비치환된 C6 내지 C30 아릴아민기, 치환 또는 비치환된 C1 내지 C30 알콕시기, 치환 또는 비치환된 C2 내지 C30 알콕시카르보닐기, 치환 또는 비치환된 C2 내지 C30 알콕시카르보닐아미노기, 치환 또는 비치환된 C7 내지 C30 아릴옥시카르보닐아미노기, 치환 또는 비치환된 C2 내지 C30 알케닐기, 치환 또는 비치환된 C2 내지 C30 알키닐기, 치환 또는 비치환된 C3 내지 C40 실릴기, 치환 또는 비치환된 3 내지 C40 실릴옥시기, 치환 또는 비치환된 C1 내지 30 아실기, 치환 또는 비치환된 C1 내지 C20 아실옥시기 및 치환 또는 비치환된 C1 내지 C20 아실아미노기 중에서 선택되는 어느 하나이다.R 5 and R 6 are the same as or different from each other, and each independently, hydrogen, deuterium, a substituted or unsubstituted C1 to C30 ketone group, a substituted or unsubstituted C1 to C30 nitro group, a substituted or unsubstituted C1 to C30 halogen group, substituted or unsubstituted C1 to C30 cyano group, substituted or unsubstituted C1 to C30 ester group, substituted or unsubstituted C1 to C30 alkyl group, substituted or unsubstituted C3 to C30 cycloalkyl group, substituted or Unsubstituted C2 to C30 heteroaryl group, substituted or unsubstituted C6 to C30 aryl group, substituted or unsubstituted C6 to C30 arylamine group, substituted or unsubstituted C1 to C30 alkoxy group, substituted or unsubstituted C2 To C30 alkoxycarbonyl group, substituted or unsubstituted C2 to C30 alkoxycarbonylamino group, substituted or unsubstituted C7 to C30 aryloxycarbonylamino group, substituted or unsubstituted C2 to C30 alkenyl group, substituted or Is an unsubstituted C2 to C30 alkynyl group, a substituted or unsubstituted C3 to C40 silyl group, a substituted or unsubstituted 3 to C40 silyloxy group, a substituted or unsubstituted C1 to 30 acyl group, a substituted or unsubstituted C1 To C20 acyloxy group and substituted or unsubstituted C1 to C20 acylamino group. - 제7항에 있어서,The method of claim 7, wherein물 또는 유기 용매를 사용 또는 비사용 하에서 마이클 첨가반응시키는 것을 특징으로 하는 비천연 감마-아미노산의 제조 방법.A method for producing a non-natural gamma-amino acid, wherein the Michael addition reaction is carried out with or without water or an organic solvent.
- 제8항에 있어서,The method of claim 8,물 용매를 사용 또는 비사용 하에서 마이클 첨가반응시키는 것을 특징으로 하는 비천연 감마-아미노산의 제조 방법.A method for producing a non-natural gamma-amino acid, wherein the Michael addition reaction is carried out with or without a water solvent.
- 제7항에 있어서,The method of claim 7, wherein마이클 첨가반응으로 나이트로스타일렌이 생성되는 것을 특징으로 하는 비천연 감마 아미노산의 제조 방법.A method for producing a non-natural gamma amino acid, characterized in that nitrostyrene is produced by Michael addition reaction.
- 제7항에 있어서,The method of claim 7, wherein마이클 첨가반응으로 생성된 생성물을 이용하여 하기 [화학식 3-1] 또는 [화학식 3-2]로 표시되는 피롤리딘온을 합성하는 단계를 더 포함하는 것을 특징으로 하는 비천연 감마-아미노산의 제조 방법:Method for producing a non-natural gamma-amino acid further comprising the step of synthesizing pyrrolidinone represented by the following [Formula 3-1] or [Formula 3-2] using the product produced by the Michael addition reaction :[화학식 3-1][Formula 3-1]
[화학식 3-2][Formula 3-2]
상기 [화학식 3-1] 또는 [화학식 3-2]에서,In [Formula 3-1] or [Formula 3-2],R 1 및 R 2는 서로 동일하거나 상이하고, 각각 독립적으로, 수소, 중수소, 치환 또는 비치환된 C1 내지 C30 케톤기, 치환 또는 비치환된 C1 내지 C30 나이트로기, 치환 또는 비치환된 C1 내지 C30 할로겐기, 치환 또는 비치환된 C1 내지 C30 사이아노기, 치환 또는 비치환된 C1 내지 C30 에스터기, 치환 또는 비치환된 C1 내지 C30 알킬기, 치환 또는 비치환된 C3 내지 C30 사이클로알킬기, 치환 또는 비치환된 C2 내지 C30 헤테아릴기, 치환 또는 비치환된 C6 내지 C30 아릴기, 치환 또는 비치환된 C6 내지 C30 아릴아민기, 치환 또는 비치환된 C1 내지 C30 알콕시기, 치환 또는 비치환된 C2 내지 C30 알콕시카르보닐기, 치환 또는 비치환된 C2 내지 C30 알콕시카르보닐아미노기, 치환 또는 비치환된 C7 내지 C30 아릴옥시카르보닐아미노기, 치환 또는 비치환된 C2 내지 C30 알케닐기, 치환 또는 비치환된 C2 내지 C30 알키닐기, 치환 또는 비치환된 C3 내지 C40 실릴기, 치환 또는 비치환된 3 내지 C40 실릴옥시기, 치환 또는 비치환된 C1 내지 30 아실기, 치환 또는 비치환된 C1 내지 C20 아실옥시기 및 치환 또는 비치환된 C1 내지 C20 아실아미노기 중에서 선택되는 어느 하나이다.R 1 and R 2 are the same as or different from each other, and each independently, hydrogen, deuterium, a substituted or unsubstituted C1 to C30 ketone group, a substituted or unsubstituted C1 to C30 nitro group, a substituted or unsubstituted C1 to C30 halogen group, substituted or unsubstituted C1 to C30 cyano group, substituted or unsubstituted C1 to C30 ester group, substituted or unsubstituted C1 to C30 alkyl group, substituted or unsubstituted C3 to C30 cycloalkyl group, substituted or Unsubstituted C2 to C30 heteroaryl group, substituted or unsubstituted C6 to C30 aryl group, substituted or unsubstituted C6 to C30 arylamine group, substituted or unsubstituted C1 to C30 alkoxy group, substituted or unsubstituted C2 To C30 alkoxycarbonyl group, substituted or unsubstituted C2 to C30 alkoxycarbonylamino group, substituted or unsubstituted C7 to C30 aryloxycarbonylamino group, substituted or unsubstituted C2 to C30 alkenyl group, substituted or Is an unsubstituted C2 to C30 alkynyl group, a substituted or unsubstituted C3 to C40 silyl group, a substituted or unsubstituted 3 to C40 silyloxy group, a substituted or unsubstituted C1 to 30 acyl group, a substituted or unsubstituted C1 To C20 acyloxy group and substituted or unsubstituted C1 to C20 acylamino group. - 제10항에 있어서,The method of claim 10,피롤리딘온에 염산을 처리하여 하기 [화학식 4-1] 또는 [화학식 4-2]로 표시되는 비천연 감마-아미노산을 제조하는 단계를 더 포함하는 것을 특징으로 하는 비천연 감마-아미노산의 제조 방법:A method for producing a non-natural gamma-amino acid further comprising the step of treating pyrrolidinone with hydrochloric acid to produce a non-natural gamma-amino acid represented by the following [Formula 4-1] or [Formula 4-2]. :[화학식 4-1][Formula 4-1]
[화학식 4-2][Formula 4-2]
상기 [화학식 4-1] 또는 [화학식 4-2]에서,In [Formula 4-1] or [Formula 4-2],R은 수소, 중수소, 치환 또는 비치환된 C1 내지 C30 케톤기, 치환 또는 비치환된 C1 내지 C30 나이트로기, 치환 또는 비치환된 C1 내지 C30 할로겐기, 치환 또는 비치환된 C1 내지 C30 사이아노기, 치환 또는 비치환된 C1 내지 C30 에스터기, 치환 또는 비치환된 C1 내지 C30 알킬기, 치환 또는 비치환된 C3 내지 C30 사이클로알킬기, 치환 또는 비치환된 C2 내지 C30 헤테아릴기, 치환 또는 비치환된 C6 내지 C30 아릴기, 치환 또는 비치환된 C6 내지 C30 아릴아민기, 치환 또는 비치환된 C1 내지 C30 알콕시기, 치환 또는 비치환된 C2 내지 C30 알콕시카르보닐기, 치환 또는 비치환된 C2 내지 C30 알콕시카르보닐아미노기, 치환 또는 비치환된 C7 내지 C30 아릴옥시카르보닐아미노기, 치환 또는 비치환된 C2 내지 C30 알케닐기, 치환 또는 비치환된 C2 내지 C30 알키닐기, 치환 또는 비치환된 C3 내지 C40 실릴기, 치환 또는 비치환된 3 내지 C40 실릴옥시기, 치환 또는 비치환된 C1 내지 30 아실기, 치환 또는 비치환된 C1 내지 C20 아실옥시기 및 치환 또는 비치환된 C1 내지 C20 아실아미노기 중에서 선택되는 어느 하나이다.R is hydrogen, deuterium, substituted or unsubstituted C1 to C30 ketone group, substituted or unsubstituted C1 to C30 nitro group, substituted or unsubstituted C1 to C30 halogen group, substituted or unsubstituted C1 to C30 cyano Groups, substituted or unsubstituted C1 to C30 ester groups, substituted or unsubstituted C1 to C30 alkyl groups, substituted or unsubstituted C3 to C30 cycloalkyl groups, substituted or unsubstituted C2 to C30 heteroaryl groups, substituted or unsubstituted C6 to C30 aryl group, substituted or unsubstituted C6 to C30 arylamine group, substituted or unsubstituted C1 to C30 alkoxy group, substituted or unsubstituted C2 to C30 alkoxycarbonyl group, substituted or unsubstituted C2 to C30 alkoxy Carbonylamino group, substituted or unsubstituted C7 to C30 aryloxycarbonylamino group, substituted or unsubstituted C2 to C30 alkenyl group, substituted or unsubstituted C2 to C30 alkynyl group, substituted or unsubstituted C3 to C40 silyl group, substituted or unsubstituted 3 to C40 silyloxy group, substituted or unsubstituted C1 to 30 acyl group, substituted or unsubstituted C1 to C20 acyloxy group and substituted or unsubstituted C1 to C20 acyl It is either selected from amino groups.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112608282A (en) * | 2019-12-20 | 2021-04-06 | 山东先达农化股份有限公司 | Compound containing quinazolinedione and N-O structure and preparation method and application thereof |
| CN112608267A (en) * | 2020-12-23 | 2021-04-06 | 南京艾斯特医药科技有限公司 | Synthetic method of 4-phenyl-2-pyrrolidone |
| CN113735668A (en) * | 2021-10-15 | 2021-12-03 | 温州大学 | Chiral delta-amino-beta-keto ester compound and synthesis method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007332129A (en) * | 2005-12-09 | 2007-12-27 | Sumitomo Chemical Co Ltd | Method of manufacturing optically active 4-amino-3-substituted phenylbutanoic acid |
-
2019
- 2019-01-24 WO PCT/KR2019/001003 patent/WO2019168269A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007332129A (en) * | 2005-12-09 | 2007-12-27 | Sumitomo Chemical Co Ltd | Method of manufacturing optically active 4-amino-3-substituted phenylbutanoic acid |
Non-Patent Citations (5)
| Title |
|---|
| HAN, B.: "Discovery of Bifunctional Thiourea/Secondary-Amine Organocatalysts for the Highly Stereoselective Nitro-Mannich Reaction of a-Substituted Nitroacetates", CHEMISTRY-A EUROPEAN JOURNAL, vol. 14, no. 27, 2008, pages 8094 - 8097, XP055634746 * |
| LU , A: "Enantioselective Synthesis of trans-Dihydrobenzofurans via Primary Amine-Thiourea Organocatalyzed Intramolecular Michael Addition", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 77, no. 14, 21 June 2012 (2012-06-21), pages 6208 - 6214, XP055634732, ISSN: 0022-3263, DOI: 10.1021/jo301006e * |
| MENINNO, S.: "Stereoselective amine-thiourea-catalysed sulfa-Michael/nitroaldol cascade approach to 3,4,5-substituted tetrahydrothiophenes bearing a quaternary stereocenter", BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY, vol. 12, 2016, pages 643 - 647, XP055634740, DOI: 10.3762/bjoc.12.63 * |
| ORGANOCATALYTIC ASYMMETRIC MICHAEL ADDITIONS OF KETONES TO ALPHA,BETA-UNSATURATED NITRO COMPOUNDS, vol. 1 - 117, February 2017 (2017-02-01), pages 7 - 19 * |
| ZHANG, J.: "Michael-Michael Addition Reactions Promoted by Secondary Amine-Thiourea: Stereocontrolled Construction of Barbiturate-Fused Tetrahydropyrano Scaffolds and Pyranocoumarins", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 82, no. 24, 2017, pages 13594 - 13601, XP055634737, ISSN: 0022-3263, DOI: 10.1021/acs.joc.7b01902 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112608282A (en) * | 2019-12-20 | 2021-04-06 | 山东先达农化股份有限公司 | Compound containing quinazolinedione and N-O structure and preparation method and application thereof |
| CN112608267A (en) * | 2020-12-23 | 2021-04-06 | 南京艾斯特医药科技有限公司 | Synthetic method of 4-phenyl-2-pyrrolidone |
| CN112608267B (en) * | 2020-12-23 | 2022-10-25 | 赣州中能实业有限公司 | Synthetic method of 4-phenyl-2-pyrrolidone |
| CN113735668A (en) * | 2021-10-15 | 2021-12-03 | 温州大学 | Chiral delta-amino-beta-keto ester compound and synthesis method thereof |
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