KR20020082301A - The new manganese-chiral compounds and thereof use - Google Patents

Abstract

PURPOSE: Provided are a novel manganese-chiral compound and its use as a catalyst in the enantioselective epoxidation of olefin to produce a compound having high stereoselectivity. CONSTITUTION: The novel manganese-chiral compound is represented by formula(1), wherein R1 is phenyl or 6 member ring when two R1 groups are combined together; R2 and R3 are C1-C10 alkyl; R4 is C1-C10 alkyl or phenyl; and X is halogen. An asymmetric epoxide compound is produced by asymmetrical oxidation of olefin compound using the compound of formula(1) as a catalyst, wherein R5 is phenyl or substituted phenyl; R6 is hydrogen, C1 to C3 alkyl or -COOR7, or can form ring compounds together with R5 and R6; R7 is C1 to C10 alkyl or phenyl; Y is hydrogen, -CN or -COOR7; and an oxidizing agent is LiOCl.

Description

Novel manganese-chiral compounds and methods of use thereof {THE NEW MANGANESE-CHIRAL COMPOUNDS AND THEREOF USE}

The present invention relates to novel manganese-chiral compounds and methods for their preparation. More specifically, the novel manganese-chiral compound is represented by the following formula (1), can be used as a catalyst for the stereoselective epoxidation (enantioselective epoxidation) of the olefin represented by the following formula (2).

[Formula 1]

[Wherein, R ₁ is a phenyl group, or two are connected to each other to represent a 6-ring ring,

R <_2> , R <_3> represents a C1-C10 alkyl group,

R ₄ represents a C ₁ to C ₁₀ alkyl group or a phenyl group,

X represents halogen]

[Wherein R ₅ is a phenyl or substituted phenyl group,

R ₆ represents hydrogen, C ₁ -C ₁₀ alkyl or -COOR ₇ (R ₇ is C ₁ -C ₁₀ alkyl or phenyl),

In addition, R ₅ and R ₆ together with phenyl form a ring

Has the same structure as

Y represents hydrogen, -CN, or -COOR ₇ ]

Enantioselective epoxidation, or asymmetric oxidation, has been studied by many organic chemists in recent 20 years. In the 1980s, Groves and Meyers first performed stereoselective epoxidation reactions using chiral metalloporphyrins as catalysts, followed by the development of iron or manganese porphyrins with many optical activities, resulting in unfunctionalized olefins. It was used as a catalyst for the asymmetric epoxidation of styrene, However, the optical purity (ee%) of the epoxy compound having the desired stereoselectivity has been reported to be 50% or less, and furthermore, such porphyrin catalysts are difficult to synthesize and have poor yields.

To date, the best results of asymmetric catalysis and the possibility of industrialization are K.B. Sharpless asymmetric oxidation, high steric reaction by reacting t-butyl hydroperoxide and allyl alcohol in the presence of titanium (IV) alkoxide and optically active tartaric ester. It has been reported to indicate selectivity. However, this method is of limited use only for certain olefins having allyl functionality.

In view of these shortcomings, Jacobsen developed a catalyst called manganese salen complex and showed good stereoselectivity results (80-99% ee). Here, the notation "ee" is an abbreviation of optical purity (enantiomeric excess). Furthermore, the patent filed in 1992 (Publication No. WO 93/03838) mentions a method for the synthesis of intermediates useful for various types of catalysts and pharmaceuticals.

On the other hand, Katsuki's research, which reports good results using manganese salen coordination compounds as a catalyst, shows that the chirality of epoxides can be determined by introducing chiral amines like Jacobsen. In addition, by adding an aryl group to the chiral group, a very good optical purity (83-99% ee) can be obtained. However, the synthesis of Katsuki catalyst has been pointed out by the use of quite expensive reagents and difficult reaction conditions.

In order to improve this problem, the present inventors have envisioned a new manganese salen coordination compound that can improve the stereoselectivity of the asymmetric oxidation reaction while using the properties of the conventional manganese salen coordination compound catalyst.

This new manganese salen compound (Ⅰ) introduces an alkoxy group, an electron-donating alkoxy group, and two alkyl groups or aromatics, each of which can have a steric effect, at the para-position of phenol, thereby providing a selective selectivity during the enantioselective epoxidation reaction. To increase. Based on these results, the present invention was completed by preparing stereoselective epoxy compounds by reacting with various olefins.

The present invention provides novel manganese-chiral compounds and methods of using the same. More specifically, there is provided a novel compound represented by the formula (1) and a method for obtaining a corresponding epoxy compound by asymmetric oxidation of the olefin compound represented by the formula (2) by using the compound as a catalyst.

[Formula 1]

[Wherein, R ₁ is a phenyl group, or two are connected to each other to represent a 6-ring ring,

R <_2> , R <_3> represents a C1-C10 alkyl group,

R ₄ represents a C ₁ to C ₁₀ alkyl group or a phenyl group,

X represents halogen]

[Formula 2]

[Wherein R ₅ is a phenyl or substituted phenyl group,

R ₆ represents hydrogen, C ₁ -C ₁₀ alkyl or -COOR ₇ (R ₇ is C ₁ -C ₁₀ alkyl or phenyl),

And R ₅ and R ₆ form a ring together with phenyl

Has the same structure as

Y represents hydrogen, -CN, or -COOR ₇ ]

The preparation method of the compound represented by Formula 1 according to the present invention is as follows.

5-methoxysalicylic acid was used as a starting material. Methyl ester was prepared by reacting potassium carbonate and dimethyl sulfide (Me ₂ S) in acetone solvent at room temperature, and then Grignard reagent made of magnesium and bromobenzene was prepared. To synthesize the diol, the amount of Grignard reagent used is 1 to 100 equivalents, preferably 5 to 50 equivalents, more preferably 2 to 5 equivalents, based on the ester. The resulting diols used sodium hydride (NaI) for the methoxymethoxychloride (hereinafter referred to as MOMCl) reaction to selectively protect only the phenol position, and the remaining 2 ° alcohols were sodium hydride, iomethane (iomethane) Was reacted in a solvent to produce a methoxy compound. This methoxy compound can introduce an aldehyde at the ortho position by reacting dimethylformamide under sodium hydride. Dilute hydrochloric acid and methanol are added to the aldehyde from which the protecting group is removed. The aldehyde thus synthesized was dissolved chiral amine (1R, 2R)-(+)-1,2-diphenylethylenediamine in anhydrous ethanol and refluxed for 2 hours to synthesize chiral ligand and reflux with manganese (II) acetate. Afterwards, lithium chloride (LiCl) was added to synthesize a brown fresh catalyst at least 85% over a total of eight steps.

The present invention will be described in more detail below.

The present inventors conducted asymmetric epoxidation reaction using a newly developed compound of formula 1 as a catalyst to obtain a chiral epoxide compound of compound (III).

The reaction scheme 2 is described in detail as follows. As a starting material, an olefin of compound (II), a manganese-salen catalyst, and additive 4-phenylpyridine-N-oxide (4-PPNO) were added thereto, dissolved in distilled water in the presence of a solvent, and then the pH was adjusted to 2-5. Reaction with time produces chiral epoxide (III).

In the present invention, compound (I) as a catalyst is used in an amount of 1 to 100 mol% equivalent, preferably 1 to 50 mol% equivalent, more preferably 1 to 10 mol% equivalent to compound (II) as a reactant. The additive is not particularly limited, but generally 10 to 50 mol% equivalent is used. LiOCl, an oxidant, has much better results than other oxidants, and generally uses 1 to 5 mol% equivalents. In addition, the reaction temperature was carried out at -78 ℃ to 50 ℃, was carried out in the presence or absence of a solvent. In this case, dichloromethane is most preferred when the reaction is carried out in the presence of a solvent.

The results of the asymmetric epoxidation of the olefins according to the present invention show a considerably high stereoselectivity, with 100% yield and 99% ee for cis-β-methylstyrene. This result is better than any previously reported result. In particular, when LiOCl is used as an oxidant, the reaction rate is much faster and the yield is more than doubled compared to NaOCl, which is a known economical oxidant. In the case of NaOCl, the pH was adjusted with a phosphate buffer solution. However, in the case of LiOCl, the pH was adjusted by only dissolving in water.

EXAMPLE

Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited only to a following example.

In the following examples, the following are common.

Nuclear magnetic resonance spectroscopy (NMR spectrometer) to identify the synthesized compounds are Hitachi R1100 60 MHz CW-NMR, Brucker DPX300 300 MHz FT-NMR, Jeol JMR-LA300 300 MHz FT-NMR, Jasco FT / IR-4300, Varian 3300 GC was used.

The chemical shift in NMR is expressed in δ-units based on the internal standard TMS (Tetramethyl silane) and "chemical shift (integrated intensity, integrated intensity, multiplicity, coupling constant: coupling). constant (Hz)) ".

GC used nitrogen as a supelco β-Dex 325 column and carrier gas, the pressure was fixed at 7 psi during injection, the temperature program was maintained at 90 ° C for 5 minutes, and the temperature was raised to 120 ° C at a rate of 1 ° C / min and then 120 It was continued for 10 minutes at ℃.

Reagents used were Aldrich, Sigma, Lancaster, Acros, and Merk. Tetrahydrofuran (tetrahydrofuran) and methylene chloride, which are reaction solvents, were used by distilling the trielectric chemical product with sodium or calcium hydride (CaH ₂ ) under nitrogen atmosphere. TLC (Thin Layer Chromatography) was used Merk Kiesegel 60F ~ 254, and after TLC, UV-lamp, PMA, vanilin coloring reagent was used, flash column chromatography (230) to 400 mesh Silica gel was used.

Example 1 Synthesis of Methyl 2-hydroxy-5-methoxybenzoate

Under a nitrogen atmosphere, 5-methoxysalicylic acid (1 g, 5.95 mmol) was dissolved in anhydrous acetone (10 mL) in a 50 mL two-neck flask, followed by adding potassium carbonate (830 mg, 6.54 mmol). Stirred at room temperature for about 1 hour. Thereafter, dimethyl sulfate (680 µl, 6.54 mmol) was added thereto and reacted for 1 hour. After completion of the reaction by adding water, methylene chloride was added to extract the product. The water was removed with anhydrous magnesium sulfate, and the methylene chloride solution obtained by filtration was concentrated under reduced pressure to give a yellow liquid of methyl ester compound 1 (1.07 g, yield = 100%).

Rf value: 0.58 (EA: Hex = 1: 3)

¹ H-NMR (CDCl _3, 200 MHz): δ 10.38 (s, 1H), 7.28 (d, 1H), 7.06 (dd, 1H), 6.91 (d, 1H), 3.93 (s, 3H), 3.78 (s, 3H)

EA: calcd. for C ₉ H ₁₀ O ₄ (182.18) C = 59.34, H = 5.53; found C = 61.03, H = 5.61

Example 2 Synthesis of 2- [hydroxy (diphenyl) methyl] -4-methoxyphenol

Magnesium (648 mg, 26.68 mmol) was added to a 50 mL two-neck round flask under nitrogen atmosphere, and dried using a torch. Then, tetrahydrofuran (10 mL) and bromobenzene (2.81 mL, 26.68 mmol) were added thereto. Reaction was performed for a period of time to form phenylmagnesium bromide (phenylmagnesium bromide).

Compound 1 (1.07 g, 5.9 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) in a 50 mL two-neck round flask under a nitrogen atmosphere, and the phenylmagnesium bromide solution prepared above was slowly added thereto, and stirred at room temperature for 1 hour. After completion of the reaction by adding 1 N hydrochloric acid, extraction was performed with methylene chloride, water was removed with anhydrous magnesium sulfate, and the methylene chloride solution obtained by filtration was concentrated under reduced pressure, and recrystallized with ethyl acetate and hexane to obtain a white solid diol compound 2 ( 1.8 g, yield # 100%) were obtained.

Rf value: 0.41 (EA: Hex = 1: 3)

¹ H-NMR (CDCl _3, 400 MHz): δ 7.57 (s, 1H), 7.33 (m, 6H), 7.23 (m, 4H),

6.83 (d, J = 8.8 Hz, 1H), 6.77 (dd, J _A = 8.7 Hz,

J _B = 2.9 Hz, 1H), 6.12 (d, J = 2.9 Hz, 1H), 3.76 (s, 1H),

3.61 (s, 3 H)

IR (KBr): 3304, 3061, 1490, 1446, 1008, 754 cm ^-1

mp: 154-159 ° C.

Example 3 Synthesis of 3- [hydroxy (diphenyl) methyl] -4- (methoxymethoxy) anisole

Diol compound 2 (1 g, 3.27 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) in a 50 mL two-neck round flask under nitrogen atmosphere, and sodium hydride (270 mg, 9.8 mmol) was added thereto, followed by stirring for about 1 hour. . Then MOM-Cl (810 μl, 9.8 mmol) was added and reacted for 1 hour. After completion of the reaction by adding water, the product was extracted with methylene chloride, water was removed with anhydrous magnesium sulfate, and the methylene chloride solution obtained by filtration was concentrated under reduced pressure, and recrystallized with ethyl acetate and hexane to give Compound 3 (1.15 g, Yield # 100%) was obtained.

Rf value: 0.48 (EA: Hex = 1: 3)

¹ H-NMR (CDCl _3, 400 MHz): δ 7.20 (m, 10H), 7.0 (d, J = 9.0 Hz, 1H),

6.68 (dd, J _A = 8.8 Hz, J _B = 3.2 Hz, 1H),

6.07 (d, J = 2.9 Hz, 1H), 4.72 (s, 2H),

3.53 (s, 3H), 3.03 (s, 3H)

Example 4 Synthesis of 3- [methoxy (diphenyl) methyl] -4- (methoxymethoxy) anisole

Compound 3 (1.17 g, 3.34 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) in a 50 mL two-neck round flask under nitrogen atmosphere, and sodium hydride (270 mg, 10 mmol) was added thereto, followed by stirring for about 1 hour. Thereafter, iodine methane (620 µl, 10 mmol) was added thereto and reacted for 1 hour. After completion of the reaction by adding water, the product was extracted with methylene chloride, water was removed with anhydrous magnesium sulfate, and the methylene chloride solution obtained by filtration was concentrated under reduced pressure to give a yellow liquid compound 4 (1.22 g, yield: 100%). Got it.

Rf value: 0.55 (EA: Hex = 1: 3)

¹ H-NMR (CDCl _3, 400 MHz): δ 7.43 (m, 10H), 7.41 (d, J = 3.2 Hz, 1H), 7.21 (m,

6H), 6.95 (d, J = 9.0 Hz, 1H), 6.72 (dd, J _A = 8.8 Hz,

J _B = 3.2 Hz, 1H, 4.58 (s, 2H), 3.77 (s, 3H), 3.05 (s,

3H), 2.98 (s, 3H)

Example 5 Synthesis of 5-methoxy-3- [methoxy (diphenyl) methyl] -2- (methoxymethoxy) benzaldehyde

Compound 4 (1.22 g, 3.3 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) in a 50 mL two-neck round flask under nitrogen atmosphere, and then the temperature was lowered to -78 ° C to give t -butyllithium (7.76 mL, 13.2 mmol) was added and stirred for about 1 hour. Thereafter, dimethylformamide (1.02 mL, 13.2 mmol) was added thereto, followed by reaction for 30 minutes, and the temperature was increased to room temperature for 1 hour. After completion of the reaction by adding water, the product was extracted with methylene chloride, water was removed with anhydrous magnesium sulfate, and the methylene chloride solution obtained by filtration was concentrated under reduced pressure. Compound 5 (1.1 g, yield = 85%) was obtained by flash column chromatography with ethyl acetate: hexane = 1: 5.

Rf value: 0.53 (EA: Hex = 1: 3)

¹ H-NMR (CDCl _3, 400 MHz): δ 10.07 (s, 1H), 7.62 (d, J = 3.2 Hz, 1H), 7.50 (m,

4H), 7.32 (m, 5H), 7.23 (m, 2H), 4.20 (s, 2H),

3.83 (s, 3H), 3.27 (s, 3H), 3.03 (s, 3H)

EA: calcd. for C ₂₄ H ₂₄ O ₅ (392.16) C = 73.44, H = 6.17; found C = 73.19, H = 6.17

mp: 123-124 ℃

Example 6 2-hydroxy-5-methoxy-3- [methoxy (diphenyl) methyl] benzaldehyde and 2-hydroxy-3- [hydroxy (diphenyl) methyl] -5-methoxybenzaldehyde Synthesis of

Compound 5 (1 g, 2.5 mmol) was added to a 50 mL two-necked round flask and dissolved in methanol (5 mL). Then, 2-3 drops of concentrated hydrochloric acid was added and heated to reflux for 30 minutes. After completion of the reaction by adding water, the product was extracted with methylene chloride, water was removed with anhydrous magnesium sulfate, and the methylene chloride solution obtained by filtration was concentrated under reduced pressure. Flash column chromatography (ethyl acetate: hexane = 1: 5) using silica gel gave Compound 6 (260 mg, Yield = 30%) and Compound 7 (480 mg, Yield = 58%).

<Compound 6 >

Rf value: 0.5 (EA: Hex = 1: 3)

¹ H-NMR (CDCl _3, 400 MHz): δ 10.55 (s, 1H), 10.01 (s, 1H), 7.51 (d, J = 3.2 Hz,

1H), 7.45 (m, 4H), 7.32 (m, 6H), 7.0 (d, J = 3.2 Hz,

1H), 3.8 (s, 3H), 3.08 (s, 3H)

¹³ C-NMR (CDCl _3, 400 MHz): δ 193.91, 153.97, 152.17, 140.74, 134.21,

128.88, 127.69, 127.48, 124.37, 121.77,

112.14, 59.68, 44.76, 15.14

EA: calcd. for C ₂₂ H ₂₀ O ₄ (348.14) C = 75.83, H = 5.79; found C = 75.79, H = 5.89

mp: 117-128 ℃

<Compound 7 >

Rf value: 0.4 (EA: Hex = 1: 3)

¹ H-NMR (CDCl _3, 400 MHz): δ 11.5 (s, 1H), 9.87 (s, 1H), 7.29 (m, 10H),

6.96 (d, J = 3.2 Hz, 1H), 6.48 (d, J = 3.2 Hz, 1H),

5.25 (s, 1H), 3.69 (s, 3H)

¹³ C-NMR (CDCl _3, 400 MHz): δ 196.38, 153.84, 151.99, 145.23, 136.70,

127.97, 127.56, 127.48, 126.16, 120.27,

113.64, 81.60, 55.65

EA: calcd. for C ₂₁ H ₁₈ O ₄ (334.37) C = 75.43, H = 5.43; found C = 75.23, H = 5.43

mp: 139-141 ℃

Example 7 Synthesis of Compound 8

In a 50 mL two-necked round flask, Compound 6 (150 mg, 0.43 mmol) and ( 1R , 2R )-(+)-1,2-diphenylethylenediamine (46 mg, 0.22 mmol) were dried with anhydrous ethanol (5 mL). After dissolving in, it was heated to reflux for 2 hours. After cooling to room temperature, the resulting yellow solid compound was filtered to obtain compound 8 (160 mg, yield # 99%).

Rf value: 0.42 (EA: Hex = 1: 3)

¹ H-NMR (CDCl _3, 400 MHz): δ 12.79 (s, 2H), 8.15 (s, 2H), 7.44 (m, 12H),

7.22 (m, 12H), 7.09 (m, 6H), 6.96 (m, 4H), 6.55 (s,

2H), 4.50 (s, 2H), 3.73 (s, 6H), 3.01 (s, 6H)

¹³ C-NMR (CDCl _3, 400 MHz): δ 165.79, 153.00, 151.46, 142.63, 142.15,

138.94, 131.65, 128.58, 128.37, 128.17,

127.96, 127.48, 127.39, 126.71,126.64, 119.55,

118.64, 114.97, 85.66, 80.55, 55.85, 52.10

EA: calcd. for C ₅₈ H ₅₂ O ₆ N ₂ (873.06) C = 79.79, H = 6.00, N = 3.21;

found C = 79.57, H = 6.04, N = 3.16

mp: 127-139 ℃

Example 8 Synthesis of Compound 9

In a 50 mL two-neck round flask, compound 7 (300 mg, 0.9 mmol) and (1R, 2R)-(+)-1,2-diphenylethylenediamine (95 mg, 0.45 mmol) were dried with anhydrous ethanol (5 mL). After dissolving in, it was heated to reflux for 2 hours. After cooling to room temperature, the resulting yellow solid compound was filtered to give compound 9 (308 mg, yield = 97%).

Rf value: 0.32 (EA: Hex = 1: 3)

¹ H-NMR (CDCl _3, 400 MHz): δ 13.84 (s, 2H), 8.26 (s, 2H), 7.28 (m, 20H),

7.15 (m, 6H), 7.03 (m, 4H), 6.57 (d, J = 3.2 Hz, 2H),

6.22 (d, J = 2.9 Hz, 2H), 5.88 (s, 2H), 4.61 (s, 2H),

3.61 (s, 6H)

¹³ C-NMR (CDCl _3, 400 MHz): δ 166.19, 153.48, 151.18, 146.23, 145.89,

138.32, 135.27, 129.43, 127.87, 127.84,

127.80, 137.73, 127.17, 127.14, 118.08,

113.59, 81.97, 79.76, 55.59

IR (KBr): 3494, 3059, 3028, 2935, 1630, 1598, 1459, 1031 cm ^-1

EA: calcd. for C ₅₆ H ₄₈ O ₆ N ₂ (845.01) C = 79.60, H = 5.73, N = 3.32;

found C = 79.85, H = 5.75, N = 3.32

mp: 192-200 ℃

Example 9 Synthesis of Compound 10 (Catalyst)

Compound 8 (45 mg, 0.063 mmol) was dissolved in anhydrous ethanol (5 mL) in a 50 mL two-necked round flask, and manganese (II) acetate (22 mg, 0.125 mmol) was added thereto and heated to reflux for 2 hours. Then lithium chloride (5 mg, 0.125 mmol) was added thereto and then heated to reflux for 1 hour. After cooling to room temperature, water was added to the resulting brown solid compound, which was filtered to give compound 10 (39 mg, yield = 80%).

IR (KBr): 3057, 2931, 1611, 1542, 1449, 1415, 1060cm ^-1

EA: calcd. for C ₅₈ H ₅₀ O ₆ N ₂ MnCl (961.44) C = 72.46, H = 5.24, N = 2.91;

found C = 71.72, H = 5.69, N = 2.67

mp: 195-200 ℃

Example 10 Synthesis of Compound 11 (Catalyst)

Compound 9 (200 mg, 0.28 mmol) was dissolved in anhydrous ethanol (10 mL) in a 50 mL two-necked round flask, and manganese (II) acetate (98 mg, 0.57 mmol) was added thereto and heated to reflux for 2 hours. Then lithium chloride (24 mg, 0.57 mmol) was added thereto and then heated to reflux for 1 hour. After cooling to room temperature, water was added and the resulting brown solid compound was filtered to give compound 11 (200 mg, yield = 94%).

IR (KBr): 3437, 3058, 3030, 2932, 1609, 1547, 1449, 1039, 1018 cm ^-1

EA: calcd. for C ₅₆ H ₄₆ O ₆ N ₂ MnCl (933.38) C = 72.06, H = 4.97, N = 3.00;

found C = 70.68, H = 5.24, N = 2.86

mp: 220-230 ℃

Example 11 Synthesis of 2- (1'-ethyl-1'-hydroxypropyl) -4-methoxyphenol

Magnesium (640 mg, 26.5 mmol) was added to a 50 mL two-neck round flask under nitrogen atmosphere, and dried using a torch. Then, tetrahydrofuran (10 mL) and bromoethane (2 mL, 26.5 mmol) were added thereto. The reaction was carried out for a period of time to give an ethyl magnesium bromide (EtMgBr) solution.

Compound 1 (1.06 g, 5.88 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) in a 50 mL two-neck round flask under nitrogen atmosphere, and the ethylmagnesium bromide solution prepared above was slowly added thereto at room temperature for 1 hour. Stirred. After completion of the reaction by adding 1 N HCl, the product was extracted with methylene chloride, water was removed with anhydrous magnesium sulfate, and the filtered methylene chloride solution was concentrated under reduced pressure to obtain a compound diol 12 (1.24 g, yield: 100%). Got.

Rf value: 0.47 (EA: Hex = 1: 3)

¹ H-NMR (CDCl _3, 400 MHz): δ 9.09 (s, 1H), 6.77 (d, J = 8.8 Hz, 1H),

6.71 (dd, J _A = 8.8 Hz, J _B = 2.9 Hz, 1H),

6.48 (d, J = 2.9 Hz, 1H), 3.74 (s, 3H),

2.50 (s, 1 H), 1.94 (m, 2 H), 1.83 (m, 2 H),

0.88 (t, J = 7.56 Hz, 6H)

EA: calcd. for C ₁₂ O ₁₈ O ₃ (210.27) C = 68.55, H = 8.63; found C = 68.66, H = 8.78

mp: 90-92 ℃

Example 12 Synthesis of 3- (1'-ethyl-1'-hydroxypropyl) -4- (methoxymethoxy) anisole

Using Compound 2 (500 mg, 2.38 mmol), sodium hydride (23 mg, 8.32 mmol) and MOM-Cl (686 μl, 8.32 mmol) in the same manner as in Example 3, compound 3 (560 mg, yield = 93%).

Rf value: 0.5 (EA: Hex = 1: 3)

¹ H-NMR (CDCl _3, 400 MHz): δ 7.06 (d, J = 9.0 Hz, 1H), 6.92 (d, J = 3.0, 1H),

6.71 (dd, J _A = 9.1 Hz, J _B = 3.0 Hz, 1H), 5.17 (s, 2H),

3.77 (s, 3H), 3.51 (s, 1H), 3.49 (s, 3H), 2.04 (m,

2H), 1.81 (m, 2H), 0.79 (t, J = 7.6 Hz, 6H)

EA: calcd. for C ₁₄ H ₂₂ O ₄ (254.33) C = 66.12, H = 8.72; found C = 62.04, H = 8.52

Example 13 Synthesis of 3- (1'-ethyl-1'-methoxypropyl) -4- (methoxymethoxy) anisole

Using Compound 13 (450 mg, 1.77 mmol), potassium hydride (210 mg, 5.32 mmol) and iodine methane (330 μl, 5.32 mmol) in the same manner as in Example 4, compound 14 (475 mg, yield = 95 %) Was obtained.

Rf value: 0.67 (EA: Hex = 1: 3)

¹ H-NMR (CDCl _3, 400 MHz): δ7.17 (d, J = 3.2 Hz, 1H), 7.02 (d, J = 9.0 Hz, 1H),

6.70 (dd, J _A = 8.9 Hz, J _B = 3.2 Hz, 1H), 5.11 (s, 2H),

3.78 (s, 3H), 3.47 (s, 3H), 3.19 (s, 3H), 2.1 (m,

2H), 1.92 (m, 2H), 0.62 (t, J = 7.3 Hz, 6H)

EA: calcd. for C ₁₅ H ₂₄ O ₄ (268.35) C = 67.14, H = 9.01; found C = 67.17, H = 9.03

Example 14 Synthesis of 3- (1'-ethyl-1'-methoxypropyl) -5-methoxy-2- (methoxymethoxy) benzaldehyde

Using Compound 14 (420 mg, 1.57 mmol), t -butyllithium (7 mL, 6.28 mmol) and dimethylformamide (486 μl, 6.28 mmol) in the same manner as in Example 5, compound 15 (335 mg, Yield = 72%).

Rf value: 0.53 (EA: Hex = 1: 3)

¹ H-NMR (CDCl _3, 400 MHz): δ 10.25 (s, 1 H), 7.37 (d, J = 3.4 Hz, 1 H), 7.25 (d,

J = 3.2 Hz, 1H, 4.95 (s, 2H), 3.83 (s, 3H), 3.60 (s,

3H), 3.12 (s, 3H), 2.04 (m, 4H), 0.67 (t, J = 7.3 Hz,

6H)

¹³ C-NMR (CDCl _3, 400 MHz): δ 191.33, 155.54, 153.11, 138.86, 131.23,

124.15, 108.64, 102.02, 81.23, 57.49, 55.57,

48.81, 26.17, 7.79

EA: calcd. for C ₁₆ H ₂₄ O ₅ (296.36) C = 64.84, H = 8.16; found C = 64.63, H = 8.29

Example 15 Synthesis of 3- (1'-ethyl-1'-methoxypropyl) -2-hydroxy-5-methoxybenzaldehyde

Using Compound 15 (170 mg, 0.57 mmol) in the same manner as in Example 6, Compound 16 (138 mg, yield = 96%) was obtained.

Rf value: 0.62 (EA: Hex = 1: 3)

¹ H-NMR (CDCl _3, 400 MHz): δ 10.59 (s, 1H), 10.13 (s, 1H), 7.25 (d, J = 3.16 Hz,

1H), 7.02 (d, J = 3.16 Hz, 1H), 3.81 (s, 3H), 3.24

(s, 3H), 2.08 (m, 2H), 1.93 (m, 2H), 0.68 (t,

J = 7.56 Hz, 6H)

¹³ C-NMR (CDCl _3, 400 MHz): δ 193.83, 154.26, 152.13, 131.99, 124.97,

121.46, 111.07, 83.37, 55.76, 48.68, 26.07,

7.66

Mass (EI) m / z : 252.14, 222.11, 191,07, 163.00, 135.00

HRMS: calcd. for 252.1362 (C ₅ H ₂₀ O ₄ ); found 252.1368

Example 16 Synthesis of Compound 17

Same as Example 7 using compound 16 (110 mg, 0.44 mmol), ( 1R , 2R )-(+)-1,2-diphenylethylenediamine (46 mg, 0.22 mmol), anhydrous ethanol (5 mL) Experimented by the method, compound 17 (135 mg, yield = 91%) was obtained.

Rf value: 0.58 (EA: Hex = 1: 3)

¹ H-NMR (CDCl _3, 400 MHz): δ 13.18 (s, 2H), 8.28 (s, 2H), 7.20 (m, 10H),

7.17 (d, J = 2.9 Hz, 2H), 6.51 (d, J = 3.2 Hz, 2H),

4.65 (s, 2H), 3.68 (s, 6H), 3.14 (s, 6H), 2.22 (m,

4H), 1.9 (m, 4H), 0.57 (t, J = 7.3 Hz, 3H), 0.50 (t,

J = 7.3 Hz, 3H)

¹³ C-NMR (CDCl _3, 400 MHz): δ 166.38, 152.48, 151.21, 139.21, 132.10,

128.33, 128.02, 127.58, 120.62, 117.70, 113.22,

81.28, 80.56, 55.63, 48.29, 25.43, 7.81, 7.74

IR (KBr): 3470, 2964, 2931, 2877, 2828, 1630, 1625, 1596, 1453, 1077 cm ^-1

EA: calcd. for C ₄₂ H ₅₂ O ₆ N ₂ (680.88) C = 74.09, H = 7.70, N = 4.11;

found C = 74.20, H = 7.83, N = 4.03

mp: 94-130 ℃

Example 17 Synthesis of Compound 18 (Catalyst)

Using the compound 17 (200 mg, 0.3 mmol), manganese (II) acetate (104 mg, 0.6 mmol), lithium chloride (64 mg, 1.5 mmol) in the same manner as in Examples 9 and 10 to give a brown solid compound Compound 18 (217 mg, yield = 98%) was obtained.

IR (KBr): 2963, 2932, 1605, 1544, 1413, 1355, 1078 cm ^-1

EA: calcd. for C ₄₂ H ₅₀ O ₆ N ₂ MnCl (769.26) C = 65.58, H = 6.55, N = 3.64;

found C = 64.59, H = 7.14, N = 3.21

mp: 210-212 ℃

Example 18 Synthesis of Styrene Oxide Using Catalyst 10 (NaOCl Oxidizer)

Anhydrous methylene chloride (1 mL) was added to a 20 mL vial, and the temperature was lowered to 0 ° C., followed by styrene (20 μl, 0.17 mmol) and 4-phenylpyridine- N -oxide (6 mg, 0.034 mmol). Put it. After dissolving by adding 10 (5 mg, 0.00698 mmol) as a catalyst, NaOCl (0.35 mmol) [0.05 M Na ₂ HPO ₄ buffer solution (260 μL) and 12% NaOCl (217 μL) were mixed and concentrated hydrochloric acid was used. To adjust pH = 11.3] and the reaction was carried out at 0 ° C. for 4 hours, and the organic layer was taken, and filtered through celite using hexane. A portion of the solution was taken to measure GC, from which yield and ee values were obtained.

Yield = 11%

% e.e = 29%

GC retention time (min): 8.94 (styrene), 23.22 (( R ) -styrene oxide),

23.77 (( S ) -styrene oxide)

GC condition Supelco chiral cyclo β-Dex 325 column, N₂carrier gas,

10 psi, 90 ° C (5 min), 1 ° C / min, 120 ° C (10), injection

temp = 150 ℃, detection temp = 170 ℃

Example 19 Synthesis of Styrene Oxide Using Catalyst 10 ( m CPBA Oxidizer)

Anhydrous methylene chloride (1 mL) was added under nitrogen atmosphere, and after 78 ° C., styrene (10 μl, 0.087 mmol) and 4-methylmorphine- N -oxide (51 mg, 0.436 mmol) were added thereto. Compound 10 (3 mg, 0.0035 mmol), a catalyst, was added and dissolved, followed by adding m-chloroperoxybenzoic acid (hereinafter referred to as m CPBA) (30 mg, 0.174 mmol) for 2 hours at -78 ° C. After completion of the reaction by adding thioanisole (10 μl, 0.087 mmol) (−30 ° C. at 30 ° C.), the reaction mixture was heated to room temperature for 30 minutes, and then an organic layer was added thereto. Light filtration. A portion of the solution was taken to measure GC, from which yield and ee values were obtained.

Yield = 6%

% e.e = 36%

Example 20 Synthesis of Styrene Oxide Using Catalyst 11 (NaOCl Oxidizer)

Experiment was carried out in the same manner as in Example 18, using Catalyst 11 (5 mg, 0.00698 mmol) and NaOCl (0.35 mmol).

Yield = 54%

% e.e = 22%

Example 21 Synthesis of Styrene Oxide Using Catalyst 11 (mCPBA Oxidation Agent)

Experiment was carried out in the same manner as in Example 19, using Catalyst 11 (3 mg, 0.0035 mmol) and m CPBA (30 mg, 0.174 mmol).

Yield = 94%

% e.e = 28%

Example 22 Synthesis of Styrene Oxide Using Catalyst 18 (NaOCl Oxidizer)

Using the compound 18 (3 mg, 0.0035 mmol) and NaOCl (0.35 mmol) as a catalyst in the same manner as in Example 18.

Yield = 47%

% e.e = 72%

Example 22 Synthesis of Styrene Oxide Using Catalyst 18 ( m CPBA Oxidizer)

Using the compound 18 (3 mg, 0.0035 mmol) and m CPBA (30 mg, 0.174 mmol) as a catalyst in the same manner as in Example 19.

Yield = 89%

% e.e = 82%

Example 23 Synthesis of Styrene Oxide Using Catalyst 18 (LiOCl Oxidizer)

Anhydrous methylene chloride (1 mL) was added to a 20 mL sample bottle, and the temperature was lowered to 0 ° C., followed by styrene (10 μl, 0.087 mmol) and 4-phenylpyridine- N -oxide (3 mg, 0.0174 mmol). After dissolving compound 18 (3 mg, 0.0035 mmol) as a manganese (III) catalyst, LiOCl (0.174 mmol) [70% LiOCl (15 mg) was dissolved in distilled water, and then pH = 11.3 was dissolved using concentrated hydrochloric acid. After the reaction was carried out at 0 ° C. for 2 hours, the organic layer was taken, hexane was added thereto, and the mixture was filtered through Celite. A portion of the solution was taken to measure GC, and yields and ee values were determined therefrom.

Yield = 99%

% e.e = 87%

Example 24 Synthesis of cis -β-methylstyrene Oxide Using Catalyst 18 (LiOCl Oxidizer)

The experiment was carried out in the same manner using cis- β-methylstyrene (6 μl, 0.087 mmol) and LiOCl (0.174 mmol).

Yield = 100%

% e.e = 99% (cis / trans = 20)

GC retention time (min): 14.22 ( cis -β-methylstyrene),

27.16 ((R, S)-cis-β-methylstyrene oxide),

28.48 ((S, R) - cis- β-methylstyrene oxide),

26.74 ( trans -β-methylstyrene oxides)

GC condition Supelco chiral cyclo β-Dex 325 column, N₂carrier gas,

10 psi, 90 ° C (5 min), 1 ° C / min, 120 ° C (10), injection

temp = 150 ℃, detection temp = 170 ℃

Example 25 Epoxidation of Indene Using Catalyst 18 (LiOCl Oxidizer)

Indene (65 μl, 0.5 mmol), 4-phenylpyridine- N -oxide (17 mg, 0.1 mmol), compound 9 (15 mg, 0.02 mmol), LiOCl (58 mg, 1 mmol) The reaction was carried out for 4 hours.

Rf value: 0.48 (EA: Hex = 1: 4)

Yield = 95%

% e.e = 96%

HPLC retention time (min): 13.7 ( R , S ), 15.6 ( S , R )

HPLC condition: ( R, R ) -Whelk-O1 5㎛,

4.6 × 250 mm with CN guard 10% CHCl ₃ in hexane,

1.0 mL / min, 20 ° C., 254 nm

¹ H-NMR (CDCl _3, 300 MHz): δ 7.50 (d, J = 6.9 Hz, 1H), 7.30-7.10 (m, 3H),

4.26 (d, J = 2.7 Hz, 1H), 4.13 (t, J = 2.7 Hz, 1H),

3.21 (d, J = 18.0 Hz, 1H),

2.97 (dd, J _A = 3.0 Hz, J _B = 17.7 Hz, 1H)

According to the present invention, an epoxy compound having high stereoselectivity can be synthesized by using the compound of Formula 1 as a catalyst for the stereoselective epoxidation reaction. Chiral epoxy compounds made in accordance with the present invention can be used as intermediates useful in the synthesis of pharmaceuticals. For example, the high stereoselectivity of indene oxide, which can be used in antiviral therapies, is considered to be much more advanced than previously reported results. Epoxychromene derivatives, a key intermediate of hypertension therapeutics, also have excellent stereoselectivity. Indicates. In addition, when the compound of Formula 1 according to the present invention is used as a catalyst, good stereoselectivity (% ee) can be obtained by using an economical oxidizing agent lithium hypochlorite.

Claims (3)

A compound represented by Formula 1; [Formula 1] [Wherein, R ₁ is a phenyl group, or two are connected to each other to represent a 6-ring ring, R <_2> , R <_3> represents a C1-C10 alkyl group, R ₄ represents a C ₁ to C ₁₀ alkyl group or a phenyl group, X represents halogen] A method for preparing an asymmetric epoxide compound, characterized by obtaining an asymmetric epoxide compound by asymmetric oxidation of the olefin compound of formula 2 using the compound of formula 1 as a catalyst; [Formula 1] [Wherein, R ₁ is a phenyl group, or two are connected to each other to represent a 6-ring ring, R <_2> , R <_3> represents a C1-C10 alkyl group, R ₄ represents a C ₁ to C ₁₀ alkyl group or a phenyl group, X represents halogen] [Formula 2] [Wherein R ₅ is a phenyl or substituted phenyl group, R ₆ represents hydrogen, C ₁ -C ₃ alkyl or —COOR ₇ (R ₇ is C ₁ -C ₁₀ alkyl or phenyl), In addition, R ₅ and R ₆ together with phenyl form a ring Has the same structure as Y represents hydrogen, -CN, or -COOR ₇ ] The process according to claim 2, wherein the reaction is carried out using LiOCl as the oxidizing agent.