KR101430116B1 - METHOD FOR PREPARING CHIRAL α-AMINO NITRILE USING CATALYST FOR STRECKER REACTION - Google Patents

Abstract

The present invention relates to a process for preparing a chiral α-aminonitrile characterized by reacting with a cyanide source in the presence of a catalyst of the formula (1) or (2) wherein the ethylene glycol is derivatized. According to the present invention, chiral α-aminonitriles having various structures can be synthesized with extremely high stereoselectivity and α-aminonite (R) -form precursor of the (R) -α-amino acid, which is an unnatural amino acid A combination of an alkali metal cyanide alone or an alkali metal cyanide and an alkali metal sulfinate or sulfinic acid can be used as a source of a cyanide source, a reel can be produced with a high optical purity, an excellent thermal stability and storage property, Therefore, it is a very economical and convenient method which is very useful for industrialization.

Description

[0001] The present invention relates to a process for producing chiral α-aminonitrile,

The present invention relates to a process for preparing a chiral α-aminonitrile using a catalyst for the reaction of a styrene, and more particularly, to a process for producing chiral α-aminonitrile using a catalyst for the reaction of a styrene with an alkali metal cyanide alone or an alkali metal cyanide (S) - or (R) -a-aminonitrile having a stereoselective selectivity through a stereoselective strecher reaction using a cyanide source which is a combination of an alkali metal salt of sulfinic acid or a sulfinic acid.

Alpha-amino acids play a very important role in vivo as a basic material for making proteins. In particular, the development of an efficient and economical synthesis method of non-natural amino acids widely used as a constituent of pharmaceuticals and chiral catalysts is regarded as one of the most important research tasks for modern organic synthetic chemists. The Strecker Synthesis reaction, which is considered to be the most important in the synthesis of these alpha amino acids, is a method for producing alpha-amino acid by hydrolyzing iminonitrile obtained through the reaction of imine and hydrogen cyanide, Is one of the most commonly used methods. However, in known methods, it is generally difficult to use mass-produced products because it requires the use of expensive chiral auxiliary materials of an equivalent amount or more, or the use of only a substance such as trimethylsilyl cyanide or HCN which is very dangerous and difficult to handle as a cyanide source in the case of catalytic reaction .

Therefore, the present inventors have succeeded in synthesizing an asymmetric stacker using a cyanide source such as KCN, which is excellent in thermal stability, storage stability, economical and easy to use by using a catalyst derived from a small amount of chiral ethylene glycol derived from an organic material The present inventors succeeded in obtaining chiral amino nitrile as a synthesis precursor of chiral alpha amino acid with high yield and high optical selectivity.

Further, according to the present invention, it is possible to synthesize chiral α-aminonitriles having various structures from α-amidosulfone, which is a precursor of imine, which is a stable starting material as well as immigrants which are sensitive to hydrolysis, with high yield and very high stereoselectivity .

It is an object of the present invention to provide a chiral α-aminonite which is more efficient, economical and suitable for mass production through a stereoselective strecher reaction between a cyanide ion source which is less toxic and easy to handle and amidosulfone which is a precursor thereof, And to provide a method of manufacturing a reel.

In order to accomplish the above object, the present invention provides a process for preparing a cyanide compound, which comprises reacting a cyanide source with a cyanide source in the presence of a catalyst represented by Chemical Formula 1 or Chemical Formula 2, wherein the cyanide source is selected from the group consisting of (i) alkali metal cyanide; (Ii) an alkali metal salt of an alkali metal cyanide and a sulfinic acid represented by the formula (6); And (iii) one selected from the group consisting of an alkali metal cyanide and a sulfinic acid represented by the general formula (7).

[Chemical Formula 1]

(2)

In the above formulas (1) and (2), R is halogen and n is 1 to 5.

[Chemical Formula 6]

In Formula 6, M is an alkali metal, Ar ₁ is a C _{6 -12} aryl group.

(7)

In the formula 7, Ar ₂ is C _{6 -12} aryl group.

More specifically, the present invention comprises a step of reacting an imine of formula (3) or? -Amidosulfone of formula (4) with a cyanide source in the presence of a catalyst represented by formula (1) or , Wherein the cyanide source is selected from the group consisting of (i) alkali metal cyanide; (Ii) an alkali metal salt of an alkali metal cyanide and a sulfinic acid represented by the formula (6); And (iii) one selected from the group consisting of an alkali metal cyanide and a sulfinic acid represented by the general formula (7).

[Chemical Formula 1]

(2)

In the above formulas (1) and (2), R is halogen and n is 1 to 5.

(3)

[Chemical Formula 4]

[Chemical Formula 5]

Wherein R ³ is selected from the group consisting of a C _{1 -30} alkyl group, a C _{3 -30} cycloalkyl group, a C _{6 -30} aryl group, and a C _{4 -30} heteroaryl group, and the alkyl group, the cycloalkyl group , aryl, and heteroaryl groups unsubstituted or substituted with halogen, nitrogen, oxygen or sulfur, P is an amine protecting group, Ar is a C _{6 -12} aryl group or C _{4 -12} heteroaryl group.

[Chemical Formula 6]

In Formula 6, M is an alkali metal, Ar ₁ is a C _{6 -12} aryl group.

(7)

In the formula 7, Ar ₂ is C _{6 -12} aryl group.

The present invention provides a chiral? -Aminonitrile prepared according to the process of the present invention.

The present invention provides a method for producing a chiral? -Amino acid by hydrolyzing a chiral? -Aminonitrile produced by the method of the present invention with an acid.

The present invention provides chiral < RTI ID = 0.0 > a-amino < / RTI > acids prepared according to the methods of the present invention.

The present invention also provides a catalyst for the reaction of a styrene selected from the following Tables.

In the formulas of the above table, R is halogen.

Hereinafter, the present invention will be described in more detail.

According to the present invention, chiral α-aminonitrile can be produced with high optical yield by reacting with a cyanide source according to the present invention in the presence of a catalyst represented by the following formula (1) or (2).

The term " Strecker reaction "in the present specification is well known for the synthesis of? -Aminonitrile, a precursor useful for amino acid synthesis, and is generally referred to as a compound having an imine group or a precursor of an imine, Refers to a process that takes place under the action of a specific catalyst in an organic solvent. Since the term itself includes the definition of a substance participating in a striker reaction, it is not necessary to specifically define a substance which reacts with a cyanide source in the present invention, that is, a compound having an imine group or a precursor of an imine.

According to one embodiment of the present invention, there is provided a process for producing an imine of formula (3) or an amidosulfone of formula (4) in an organic solvent by adding a catalyst represented by formula (1) Enantiomeric excess of the chiral α-aminonitrile of formula (5) can be prepared by carrying out a streaker reaction such as Scheme 1 or Scheme 2. According to the invention, it is possible to obtain chiral .alpha.-aminonitrile of formula (5) with very high optical selectivity under optimized conditions of the cyanation reaction, in particular over 90% enantiomeric excess.

[Reaction Scheme 1]

[Reaction Scheme 2]

The catalyst used in the present invention is a compound represented by formula (1) or (2) wherein ethylene glycol is derivatized:

[Chemical Formula 1]

(2)

In the above formulas (1) and (2), R is halogen and n is 1 to 5.

In formulas (1) and (2), it is preferred that R is Cl, Br or I and n is 1 to 4.

In formula (1) and (2), it is particularly preferred that R is Br or I and n is 2 or 3.

In formulas (1) and (2), it is most preferred that R is I and n is 2.

In the production process of the present invention, the catalyst represented by the general formula (1) or (2) can be used by selecting an appropriate range of the conventional catalyst based on the imine of the general formula (3) or? -Amidosulfone of the general formula In an amount of preferably 0.01 to 100 mol%, particularly preferably 1 to 30 mol%.

Compounds participating in the inventor's streaker reaction are imines of formula (3) or? -Amidosulfone of formula (4):

(3)

[Chemical Formula 4]

R ³ is selected from the group consisting of a C _{1 -30} alkyl group, a C _{3 -30} cycloalkyl group, a C _{6 -30} aryl group and a C _{4 -30} heteroaryl group, and the alkyl group, cycloalkyl group, aryl, and heteroaryl groups unsubstituted or substituted with halogen, nitrogen, oxygen or sulfur, P is an amine protecting group, Ar is a C _{6 -12} aryl group or C _{4 -12} heteroaryl group.

As used herein, the term " amine protecting group " refers to a functional group capable of protecting the nitrogen atom of an amine during the reaction, and suitable amine protecting groups are known in the art and include, for example, Protecting Groups in Organic Synthesis, John Wiley and Sons, 1991, and Green and Wuts, Protective Groups in Organic Synthesis, Wiley and Sons, Thus, the amine protecting group may be any known amine protecting group. Examples of the amine protecting group include methyloxycarbonyl group, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, t-butyloxycarbonyl group (Boc), 9-fluorenylmethyloxycarbonyl group (FMOC), allyloxycarbonyl (Alloc) A benzyl group (Bn), a p-methoxybenzyl group (PMB), a 3,4-dimethoxybenzyl group (DMPM), a p-methoxyphenyl group (PMP), a tosyl group (Ts) Silyl ethyloxycarbonyl group (Teoc), benzhydryl, triphenylmethyl (Trityl), (4-methoxyphenyl) diphenylmethyl (Mmt), dimethoxytrityl (DMT), diphenylphosphino group and the like have.

In formulas (3) and (4), Ar is preferably phenyl or tolyl.

In the formulas (3) and (4), P is an amine protecting group which may be substituted with a methyloxycarbonyl group, a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a t- butyloxycarbonyl group (Boc), and a 9- And the like.

After the streaker reaction of the present invention, the chiral α-aminonitrile of formula (5) can be obtained:

[Chemical Formula 5]

In the formula (5), R ³ and P are as defined in the formulas (3) and (4).

In the preparation process of the present invention, the cyanide source, which is a nucleophile for the streaker reaction, comprises (i) an alkali metal cyanide; (Ii) an alkali metal salt of an alkali metal cyanide and a sulfinic acid represented by the formula (6); And (iii) one selected from the group consisting of an alkali metal cyanide and a sulfinic acid represented by the general formula (7).

[Chemical Formula 6]

In Formula 6, M is an alkali metal, Ar ₁ is a C _{6 -12} aryl group, preferably phenyl or tolyl.

(7)

In the formula 7, Ar ₂ is C _{6 -12} aryl group, preferably phenyl or tolyl.

As the alkali metal cyanide, potassium cyanide or sodium cyanide is preferably used, and in particular potassium cyanide is preferably used.

Hydrogen cyanide (HCN), acetone cyanohydrin, trimethylsilyl cyanide (TMSCN), alkali metal cyanide, and the like can be given as known cyanide sources for the striker reaction. The preparation method according to the present invention makes it possible to effectively carry out the streaker reaction by using an alkali metal cyanide which is easy to handle in place of hydrogen cyanide, acetone cyanohydrin and trimethylsilyl cyanide which are highly toxic among known cyanide sources. This is because the structure of the catalyst represented by Formula 1 or Formula 2 according to the present invention contributes to the reactivity of the cyanide source participating in the streaker reaction. Specifically, the ether group possessed by the catalyst of the present invention acts as a Lewis base on the alkali metal cations to liberate the counteranion, to improve the solubility of the alkali metal salt, It is based on the fact that the transition state (-OH) can stabilize the transition state by activating the eletrophile through hydrogen bonding.

The cyanide source of the present invention can be selected and used in a suitable range for the imine of the formula (3) or the? -Amidosulfone of the formula (4), but is preferably 1 to 50 equivalents, more preferably 1 to 10 And most preferably 1 to 2 equivalents.

The organic solvent usable in the present invention may be an aprotic solvent and may be selected from the group consisting of methyl t-butyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, dichloroethane, Tetrachloride, benzene, toluene, methylcyclohexane, and mixtures thereof. Particularly, dichloromethane, dichloroethane, benzene, toluene, and mixtures thereof are preferable.

The conditions of the production method of the present invention, that is, the streaker reaction conditions can be appropriately selected according to a known method, but it is preferable in the production method of the present invention to carry out the reaction at a temperature of -70 ° C to 30 ° C . Preferably -20 캜 to 30 캜, and most preferably -20 캜 to 20 캜. Such a temperature range includes a temperature range of 0 ° C to room temperature, and thus can be said to be very useful for industrialization for mass production.

The present invention also provides a process for producing a chiral? -Amino acid by hydrolyzing a chiral? -Aminonitrile produced by the process of the present invention with an acid. The acid hydrolysis reaction for synthesizing a chiral? -amino acid from? -aminonitrile is well known in the art, so that detailed discussion is omitted. The chiral α-amino acid is a very important compound in the pharmaceutical industry in that it provides an important structure for manufacturing various medicines. According to the present invention, it is possible to easily produce a non-natural α-amino acid, Natural α-amino acids also become available as pharmaceuticals through mass production.

According to the present invention, it is possible to synthesize chiral α-aminonitriles having various structures from α-amidosulfone, which is a precursor of imine, which is a stable starting material as well as immigrants, which are sensitive to hydrolysis, have. In addition, since the (R) -type? -Aminonitrile which is a precursor of the (R) -? - amino acid which is an unnatural amino acid can be produced with high optical purity, the industrial usefulness is further increased.

In addition, the production method of the present invention is characterized in that instead of hydrogen cyanide (HCN), acetone cyanohydrin and trimethylsilyl cyanide (TMSCN) which are highly toxic as a cyanide source, they are excellent in thermal stability and storability, Is a very economical and simple method which is very useful for industrialization because it can be used alone or in combination with alkali metal cyanide and sulfinic acid alkali metal salt or sulfinic acid and can effectively perform the streaker reaction at a temperature of 0 캜 to room temperature.

Hereinafter, the present invention will be described in more detail by way of examples in order to facilitate understanding of the present invention. It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit and scope of the invention as defined by the appended claims. It is natural.

Example  1 to 44: Chiral  α- Aminonitrile  Produce

Amine of formula (3) or? -Amidosulfone of formula (4) was dissolved in an organic solvent, and then 10% by mole of the catalyst of the formula (1) or (2) and 1.05 equivalent of the cyanide source were added thereto. . The prepared? -Aminonitrile was analyzed by high performance liquid chromatography (HPLC) and gas chromatography (GC) to determine the enantiomeric excess.

Example Reactant product Cyanide source reaction
Temperature catalyst time yield % ee menstruum One

Potassium cyanide 0 ℃ R in formula (1) is I and n is 2 60 89 95 toluene 2

Potassium cyanide 0 ℃ R in formula (2) is I and n is 2 60 88 95 toluene 3

Potassium cyanide 0 ℃ R in formula (1) is I and n is 2 60 90 98 toluene 4

Potassium cyanide 0 ℃ R in formula (2) is I and n is 2 60 92 97 toluene 5

Potassium cyanide 0 ℃ R in formula (1) is I and n is 2 60 93 93 toluene 6

Potassium cyanide 0 ℃ R in formula (2) is I and n is 2 60 91 93 toluene 7

Potassium cyanide 0 ℃ R in formula (1) is I and n is 2 60 89 93 toluene 8

Potassium cyanide 0 ℃ R in formula (2) is I and n is 2 60 88 93 toluene 9

Potassium cyanide 0 ℃ R in formula (1) is I and n is 2 60 90 98 toluene 10

Potassium cyanide 0 ℃ R in formula (2) is I and n is 2 60 94 98 toluene 11

Potassium cyanide 0 ℃ R in formula (1) is I and n is 2 60 87 92 toluene 12

Potassium cyanide 0 ℃ R in formula (2) is I and n is 2 60 89 92 toluene 13

Potassium cyanide 0 ℃ R in formula (1) is I and n is 2 60 90 92 toluene 14

Potassium cyanide 0 ℃ R in formula (2) is I and n is 2 60 90 91 toluene 15

Potassium cyanide 0 ℃ R in formula (1) is I and n is 2 60 91 80 toluene 16

Potassium cyanide 0 ℃ R in formula (2) is I and n is 2 60 92 80 toluene 17

Potassium cyanide 0 ℃ R in formula (1) is I and n is 2 60 83 89 toluene 18

Potassium cyanide 0 ℃ R in formula (2) is I and n is 2 60 83 89 toluene 19

Potassium cyanide 0 ℃ R in formula (1) is I and n is 2 60 88 86 toluene 20

Potassium cyanide 0 ℃ R in formula (2) is I and n is 2 60 86 85 toluene 21

Potassium cyanide 0 ℃ R in formula (1) is I and n is 2 60 94 96 toluene 22

Potassium cyanide 0 ℃ R in formula (2) is I and n is 2 60 89 97 toluene 23

Potassium cyanide 0 ℃ R in formula (1) is I and n is 2 60 94 93 toluene 24

Potassium cyanide 0 ℃ R in formula (2) is I and n is 2 60 93 93 toluene 25

Potassium cyanide 0 ℃ R in formula (1) is I and n is 2 60 87 90 toluene 26

Potassium cyanide 0 ℃ R in formula (2) is I and n is 2 60 86 90 toluene 27

Potassium cyanide Room temperature R in formula (1) is Br and n is 2 36 87 43 toluene 28

Potassium cyanide Room temperature R in formula (1) is I and n is 2 20 97 70 Dichloroethane 29

Potassium cyanide Room temperature R in formula (1) is I and n is 2 20 99 78 toluene 30

Potassium cyanide 0 ℃ R in formula (1) is I and n is 2 60 24 69 toluene 31

Potassium cyanide 0 ℃ R in formula (2) is I and n is 2 60 86 85 toluene 32

Potassium cyanide 0 ℃ R in formula (2) is I and n is 2 60 86 80 toluene 33

Potassium cyanide 0 ℃ R in formula (2) is I and n is 2 60 93 90 toluene 34

Potassium cyanide 0 ℃ R in formula (1) is I and n is 2 60 88 40 Dichloromethane 35

Potassium cyanide 0 ℃ R in formula (1) is I and n is 2 60 80 50 Dichloroethane 36

Potassium cyanide 0 ℃ R in formula (1) is I and n is 2 60 80 24 Dioxane 37

Potassium cyanide 0 ℃ R in formula (1) is I and n is 2 60 82 10 Tetrahydrofuran 38

Potassium cyanide 0 ℃ R in formula (1) is I and n is 2 60 72 10 Acetonitrile 39

Potassium cyanide / KSO ₂ Ph 0 ℃ R in formula (1) is I and n is 2 60 85 85 toluene 40

Potassium cyanide / HSO ₂ Ph 0 ℃ R in formula (1) is I and n is 2 60 55 89 toluene 41

Potassium cyanide / HSO ₂ Ph 0 ℃ R in formula (1) is I and n is 2 60 63 99 toluene 42

Potassium cyanide 0 ℃ R in formula (1) is Cl and n is 2 60 91 38 toluene 43

Potassium cyanide 0 ℃ R in formula (1) is Br and n is 2 60 91 43 toluene 44

Potassium cyanide 0 ℃ R in formula (1) is Br and n is 1 60 44 9 toluene

Example  One

After 1.0 mmol of? -Amidosulfone (1a) was dissolved in 12 mL of toluene at 0 ° C, 10 mol% of a compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to obtain? -Aminonitrile (2a, 89% yield; 95% ee, (R) Respectively. The enantioselectivity was measured using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 5.45 (d, J = 8.1 Hz, 1H), 5.78 (d, J = 6.9 Hz, 1H), 7.39-7.46 (m, 5H)

¹³ C NMR (75 MHz, CDCl 3)? 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22.

Example  2

After 1.0 mmol of? -Amidosulfone (1a) was dissolved in 12 mL of toluene at 0 ° C, 10 mol% of a compound of the formula (2) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to obtain? -Aminonitrile (2a, 88% yield; 95% ee, (S) Respectively. The enantiomeric selectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.7 mL / min, t (byproduct) = 33 min, t minute).

1H, NMR (300 MHz, CDCl3)? 1.47 (s, 9H), 5.45 (d, J = 8.1 Hz, 1H), 5.78 (d, J = 6.9 Hz, 1H), 7.39-7.46

¹³ C NMR (75 MHz, CDCl 3)? 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22.

Example  3

After 1.0 mmol of? -Amidosulfone (1b) was dissolved in 12 mL of toluene at 0 占 폚, 10 mol% of a compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to give? -Aminonitrile (2b, 90% yield; 98% ee, (R) Respectively. The enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 1.0 mL / min, t (main product) = 33 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 3.81 (s, 3H), 5.34 (d, J = 7.2 Hz, 1H), 5.75 (d, J = 8.1 Hz, 1H), 6.92 -7.07 (m, 3 H), 7.29-7.35 (m, 1 H)

¹³ C NMR (75 MHz, CDCl3) 灌 27.92, 45.68, 55.09, 81.24, 112.16, 114.68, 117.47, 118.67, 130.10, 134.62, 153.97, 159.83

Example  4

After 1.0 mmol of? -Amidosulfone (1b) was dissolved in 12 mL of toluene at 0 ° C, 10 mol% of a compound represented by the formula (2) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-hexane / triethylamine = 1: 5: 0.025) to give? -Aminonitrile (2b, 92% yield; 97% ee, (S) Respectively. The enantiomeric selectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.7 mL / min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 3.81 (s, 3H), 5.34 (d, J = 7.2 Hz, 1H), 5.75 (d, J = 8.1 Hz, 1H), 6.92 -7.07 (m, 3 H), 7.29-7.35 (m, 1 H)

¹³ C NMR (75 MHz, CDCl3) 灌 27.92, 45.68, 55.09, 81.24, 112.16, 114.68, 117.47, 118.67, 130.10, 134.62, 153.97, 159.83

Example  5

After 1.0 mmol of? -Amidosulfone (1c) was dissolved in 12 mL of toluene at 0 ° C, 10 mol% of a compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-hexane / triethylamine = 1: 5: 0.025) to give? -Aminonitrile (2c, 93% yield; 93% ee, (R) Respectively. The enantiomeric selectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 1.0 mL / min, t (main product) = 23 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.48 (s, 9H), 3.82 (s, 3H), 5.02 (s, 1H), 5.70 (s, 1H), 6.93 (d, J = 9.0 Hz, 2H) , 7.39 (d, J = 8.4 Hz, 2H)

¹³ C NMR (75 MHz, CDCl 3)? 22.01, 29.08, 46.69, 82.29, 118.79, 127.66, 130.76, 140.35, 155.03

Example  6

After 1.0 mmol of? -Amidosulfone (1c) was dissolved in 12 mL of toluene at 0 占 폚, 10 mol% of a compound of the formula (2) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to obtain? -Aminonitrile (2c, 91% yield; 93% ee, (S) Respectively. Enantioselectivity was measured using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 1.0 mL / min, t (byproduct) = 23 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.48 (s, 9H), 3.82 (s, 3H), 5.02 (s, 1H), 5.70 (s, 1H), 6.93 (d, J = 9.0 Hz, 2H) , 7.39 (d, J = 8.4 Hz, 2H)

¹³ C NMR (75 MHz, CDCl 3)? 22.01, 29.08, 46.69, 82.29, 118.79, 127.66, 130.76, 140.35, 155.03

Example  7

After 1.0 mmol of? -Amidosulfone (1d) was dissolved in 12 mL of toluene at 0 占 폚, 10 mol% of a compound of the formula (1) wherein R1 and R2 are I and n was 2 was added and potassium cyanide 1.05 equivalent were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to give? -Aminonitrile (2d, 89% yield; 93% ee, (R) Respectively. The enantioselectivity was measured using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 1.0 mL / min, t (main product) = 57 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 2.36 (s, 3H), 5.23 (d, J = 7.2 Hz, 1H), 5.73 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H)

¹³ C NMR (75 MHz, CDCl3) δ 21.09, 28.15, 45.76, 81.36, 117.87, 126.74, 129.84, 130.43, 139.43, 154.11

Example  8

After 1.0 mmol of? -Amidosulfone (1d) was dissolved in 12 mL of toluene at 0 占 폚, 10 mol% of a compound of the formula (2) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / naltre-nuclear / triethylamine = 1: 5: 0.025) to give? -Aminonitrile (2d, 88% yield; 93% ee, (S) Respectively. The enantiomeric selectivity was measured using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 1.0 mL / min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 2.36 (s, 3H), 5.23 (d, J = 7.2 Hz, 1H), 5.73 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H)

¹³ C NMR (75 MHz, CDCl3) δ 21.09, 28.15, 45.76, 81.36, 117.87, 126.74, 129.84, 130.43, 139.43, 154.11

Example  9

After 1.0 mmol of? -Amidosulfone (1e) was dissolved in 12 mL of toluene at 0 占 폚, 10 mol% of a compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to obtain? -Aminonitrile (2e, 90% yield; 98% ee, (R) Respectively. The enantiomeric selectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 1.0 mL / min, t (main product) = 20 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.48 (s, 9H), 2.38 (s, 3H), 5.18 (d, J = 6.9 Hz, 1H), 5.74 (d, J = 7.2 Hz, 1H), 7.19 -7. 31 (m, 4H)

¹³ C NMR (75 MHz, CDCl3) δ 21.29, 28.16, 46.01, 81.43, 117.82, 123.87, 127.46, 129.11, 130.14, 133.26, 139.20, 154.11

Example  10

After dissolving 1.0 mmol of? -Amidosulfone (1e) in 12 mL of toluene at 0 占 폚, 10 mol% of a compound of the formula (2) (wherein R is I and n is 2) as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / naltre-nuclear / triethylamine = 1: 5: 0.025) to give? -Aminonitrile (2e, 94% yield; 98% ee, (S) Respectively. The enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 1.0 mL / min, t (byproduct) = 20 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.48 (s, 9H), 2.38 (s, 3H), 5.18 (d, J = 6.9 Hz, 1H), 5.74 (d, J = 7.2 Hz, 1H), 7.19 -7. 31 (m, 4H)

¹³ C NMR (75 MHz, CDCl3) δ 21.29, 28.16, 46.01, 81.43, 117.82, 123.87, 127.46, 129.11, 130.14, 133.26, 139.20, 154.11

Example  11

After 1.0 mmol of? -Amidosulfone (1f) was dissolved in 12 mL of toluene at 0 占 폚, 10 mol% of a compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to give? -Aminonitrile (2f, 87% yield; 92% ee, (R) Respectively. The enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 1.0 mL / min, t (main product) = 36 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.48 (s, 9H), 5.43 (s, 1H), 5.89 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H)

¹³ C NMR (75 MHz, CDCl 3)? 28.11, 45.53, 81.96, 117.08, 121.74, 126.25, 127.27, 131.44, 131.68, 137.47, 154.14

Example  12

After 1.0 mmol of? -Amidosulfone (1f) was dissolved in 12 mL of toluene at 0 占 폚, 10 mol% of a compound of the formula (2) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to give? -Aminonitrile (2f, 89% yield; 92% ee, (S) Respectively. The enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 1.0 mL / min, t (byproduct) = 36 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.48 (s, 9H), 5.43 (s, 1H), 5.89 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H)

¹³ C NMR (75 MHz, CDCl 3)? 28.11, 45.53, 81.96, 117.08, 121.74, 126.25, 127.27, 131.44, 131.68, 137.47, 154.14

Example  13

After 1.0 mmol of? -Amidosulfone (1 g) was dissolved in 12 mL of toluene at 0 占 폚, 10 mol% of a compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / naltre-nuclear / triethylamine = 1: 5: 0.025) to give? -Aminonitrile (2 g, 90% yield; 92% ee, (R) Respectively. The enantiomeric selectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 1.0 mL / min, t (main product) = 13 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.48 (s, 9H), 5.34 (d, J = 7.8 Hz, 1H), 5.83 (d, J = 8.1 Hz, 1H), 7.37-7.47 (m, 3H) , 7.54-7.63 (m, 6H)

¹³ C NMR (75 MHz, CDCl 3) δ 28.16, 45.74, 81.50, 117.71, 127.03, 127.26, 127.79, 127.84, 128.85, 132.29, 139.78, 142.32, 154.17

Example  14

After 1.0 mmol of? -Amidosulfone (1 g) was dissolved in 12 mL of toluene at 0 占 폚, 10 mol% of a compound of the formula (2) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2 g, 90% yield; 91% ee, (S) Respectively. The enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 1.0 mL / min, t (byproduct) = 13 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.48 (s, 9H), 5.34 (d, J = 7.8 Hz, 1H), 5.83 (d, J = 8.1 Hz, 1H), 7.37-7.47 (m, 3H) , 7.54-7.63 (m, 6H)

¹³ C NMR (75 MHz, CDCl 3) δ 28.16, 45.74, 81.50, 117.71, 127.03, 127.26, 127.79, 127.84, 128.85, 132.29, 139.78, 142.32, 154.17

Example  15

After 1.0 mmol of? -Amidosulfone (1h) was dissolved in 12 mL of toluene at 0 占 폚, 10 mol% of a compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to obtain? -Aminonitrile (2h, 91% yield; 80% ee, (R) Respectively. The enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 1.0 mL / min, t (main product) = 25.7 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) 1.46 (s, 9H), 5.43 (s, 1H), 5.74 (s, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 6.0 Hz , 2H)

¹³ C NMR (75 MHz, CDCl 3) 28.20, 45.48, 82.02, 117.35, 127.76, 128.52, 128.92, 132.40, 154.20

Example  16

After 1.0 mmol of? -Amidosulfone (1h) was dissolved in 12 mL of toluene at 0 ° C, 10 mol% of a compound of the formula (2) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to obtain? -Aminonitrile (2h, 92% yield; 80% ee, (S) Respectively. The enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 1.0 mL / min, t (byproduct) = 25.7 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) 1.46 (s, 9H), 5.43 (s, 1H), 5.74 (s, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 6.0 Hz , 2H)

¹³ C NMR (75 MHz, CDCl 3) 28.20, 45.48, 82.02, 117.35, 127.76, 128.52, 128.92, 132.40, 154.20

Example  17

After 1.0 mmol of? -Amidosulfone (1i) was dissolved in 12 mL of toluene at 0 占 폚, 10 mol% of a compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to obtain? -Aminonitrile (2i, 83% yield; 89% ee, (R) Respectively. The enantiomeric selectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.5 mL / min, t (main product) = 67 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.46 (s, 9H), 5.38 (d, J = 8.1 Hz, 1H), 5.80 (br, 1H), 7.07-7.13 (m, 2H), 7.45-7.49 ( m, 2H)

¹³ C NMR (75 MHz, CDCl 3)? 28.00, 45.19, 81.50, 115.95, 116.25, 117.43, 128.62, 128.73, 161.28, 164.59

Example  18

After 1.0 mmol of? -Amidosulfone (1a) was dissolved in 12 mL of toluene at 0 ° C, 10 mol% of a compound of the formula (2) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to give? -Aminonitrile (2i, 83% yield; 89% ee, (S) Respectively. The enantiomeric selectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.5 mL / min, t (byproduct) = 67 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.46 (s, 9H), 5.38 (d, J = 8.1 Hz, 1H), 5.80 (br, 1H), 7.07-7.13 (m, 2H), 7.45-7.49 ( m, 2H)

¹³ C NMR (75 MHz, CDCl 3)? 28.00, 45.19, 81.50, 115.95, 116.25, 117.43, 128.62, 128.73, 161.28, 164.59

Example  19

After 1.0 mmol of? -Amidosulfone (1j) was dissolved in 12 mL of toluene at 0 ° C, 10 mol% of the compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to obtain? -Aminonitrile (2j, 88% yield; 86% ee, (R) Respectively. The enantiomeric selectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 1.0 mL / min, t (main product) = 69 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.46 (s, 9H), 5.39 (d, J = 8.4 Hz, 1H), 5.78 (d, J = 7.5 Hz, 1H), 7.38 (d, J = 9.0 Hz , 2H), 7.41 (d, J = 9.0 Hz, 2H)

¹³ C NMR (75 MHz, CDCl 3)? 28.12, 45.35, 81.74, 117.34, 128.18, 129.38, 132.03, 135.44, 154.11

Example  20

After 1.0 mmol of? -Amidosulfone (1j) was dissolved in 12 mL of toluene at 0 占 폚, 10 mol% of a compound of the formula (2) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-hexane / triethylamine = 1: 5: 0.025) to give? -Aminonitrile (2j, 86% yield; 85% ee, (S) Respectively. The enantiomeric selectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.7 mL / min, t (byproduct) = 69 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.46 (s, 9H), 5.39 (d, J = 8.4 Hz, 1H), 5.78 (d, J = 7.5 Hz, 1H), 7.38 (d, J = 9.0 Hz , 2H), 7.41 (d, J = 9.0 Hz, 2H)

¹³ C NMR (75 MHz, CDCl 3)? 28.12, 45.35, 81.74, 117.34, 128.18, 129.38, 132.03, 135.44, 154.11

Example  21

After dissolving 1.0 mmol of? -Amidosulfone (1k) in 12 mL of toluene at 0 占 폚, 10 mol% of a compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-hexane / triethylamine = 1: 5: 0.025) to give? -Aminonitrile (2k, 94% yield; 96% ee, (R) Respectively. The enantioselectivity was measured using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 1.0 mL / min, t (byproduct) = 44 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 5.19 (d, J = 7.2 Hz, 1H), 6.43 (d, J = 8.4 Hz, 1H), 7.45-7.62 (m, 3H) , 7.81-7.94 (m, 4H)

¹³ C NMR (75 MHz, CDCl 3) δ 28.18, 44.33, 81.52, 117.99, 122.42, 125.10, 126.082, 126.58, 127.51, 128.65, 129.10, 129.74, 130.69, 133.95, 153.99

Example  22

After 1.0 mmol of? -Amidosulfone (1k) was dissolved in 12 mL of toluene at 0 ° C, 10 mol% of a compound of the formula (2) (wherein R is I and n is 2) was added as a catalyst, and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / naltre-nuclear / triethylamine = 1: 5: 0.025) to give? -Aminonitrile (2k, 89% yield; 97% ee, (S) Respectively. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 1.0 mL / min, t (byproduct) = 54 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 5.19 (d, J = 7.2 Hz, 1H), 6.43 (d, J = 8.4 Hz, 1H), 7.45-7.62 (m, 3H) , 7.81-7.94 (m, 4H)

¹³ C NMR (75 MHz, CDCl 3) δ 28.18, 44.33, 81.52, 117.99, 122.42, 125.10, 126.082, 126.58, 127.51, 128.65, 129.10, 129.74, 130.69, 133.95, 153.99

Example  23

After dissolving 1.0 mmol of? -Amidosulfone (1) in 12 mL of toluene at 0 占 폚, 10 mol% of a compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to obtain α-aminonitrile (2l, 94% yield; 93% ee, (R) Respectively. Enantioselectivity was measured using gas chromatography (RT-BetaDEX-sm chiral chromatography, isothermal temperature: 175 캜, inlet temperature: 235 캜, detection temperature: 235 캜, 0.7 mL / = 17 min, t (main product) = 20 min).

¹ H NMR (300 MHz, CDCl 3)? 1.07-1.23 (m, 5H), 1.45 (s, 9H), 1.67-1.71 (m, 2H), 1.78-1.87 = 8.7 Hz, 1 H), 4.93 (d, J = 9.0 Hz, 1 H)

¹³ C NMR (75 MHz, CDCl3) δ 25.33, 25.39, 25.68, 28.17, 40.75, 47.60, 81.01, 118.18, 154.44

Example  24

After dissolving 1.0 mmol of? -Amidosulfone (1) in 12 mL of toluene at 0 占 폚, 10 mol% of a compound of the formula (2) (wherein R is I and n is 2) as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-hexane / triethylamine = 1: 5: 0.025) to obtain α-aminonitrile (2l, 93% yield; 93% ee, (S) Respectively. Enantioselectivity was measured using gas chromatography (RT-BetaDEX-sm chiral chromatography, isothermal temperature: 175 캜, inlet temperature: 235 캜, detection temperature: 235 캜, 0.7 mL / = 17 min, t (main product) = 20 min).

¹ H NMR (300 MHz, CDCl 3)? 1.07-1.23 (m, 5H), 1.45 (s, 9H), 1.67-1.71 (m, 2H), 1.78-1.87 = 8.7 Hz, 1 H), 4.93 (d, J = 9.0 Hz, 1 H)

¹³ C NMR (75 MHz, CDCl3) δ 25.33, 25.39, 25.68, 28.17, 40.75, 47.60, 81.01, 118.18, 154.44

Example  25

After 1.0 mmol of? -Amidosulfone (1 m) was dissolved in 12 mL of toluene at 0 占 폚, 10 mol% of a compound of the formula (2) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to give? -Aminonitrile (2m, 87% yield; 90% ee, (R) Respectively. The enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.7 mL / min, t (byproduct) = 28 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 5.89 (d, J = 7.5 Hz, 1H), 6.78 (d, J = 6.9 Hz, 1H), 7.38 (t, J = 5.1 Hz , 7.85 (d, J = 7.8 Hz, 1H), 8.56-8.65 (m, 2H)

¹³ C NMR (75 MHz, CDCl 3)? 28.05, 43.79, 81.48, 116.87, 123.76, 129.99, 134.74, 147.78, 150.08, 154.39

Example  26

After 1.0 mmol of? -Amidosulfone (1 m) was dissolved in 12 mL of toluene at 0 占 폚, 10 mol% of a compound of the formula (2) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-hexane / triethylamine = 1: 5: 0.025) to give? -Aminonitrile (2m, 86% yield; 90% ee, (S) Respectively. The enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.7 mL / min, t (byproduct) = 28 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 5.89 (d, J = 7.5 Hz, 1H), 6.78 (d, J = 6.9 Hz, 1H), 7.38 (t, J = 5.1 Hz , 7.85 (d, J = 7.8 Hz, 1H), 8.56-8.65 (m, 2H)

¹³ C NMR (75 MHz, CDCl 3)? 28.05, 43.79, 81.48, 116.87, 123.76, 129.99, 134.74, 147.78, 150.08, 154.39

Example  27

After 1.0 mmol of? -Amidosulfone (1a) was dissolved in 12 mL of toluene at room temperature, 10 mol% of a compound of the formula (1) (wherein R is Br and n is 2) and 1.05 equivalent of potassium cyanide And the mixture was stirred for 36 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to obtain? -Aminonitrile (2a, 87% yield; 43% ee, (R) Respectively. The enantioselectivity was measured using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 5.45 (d, J = 8.1 Hz, 1H), 5.78 (d, J = 6.9 Hz, 1H), 7.39-7.46 (m, 5H)

¹³ C NMR (75 MHz, CDCl 3)? 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example  28

After 1.0 mmol of? -Amidosulfone (1a) was dissolved in 12 mL of dichloroethane at room temperature, 10 mol% of a compound represented by the formula (1) (wherein R is I and n is 2) and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 20 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-hexane / triethylamine = 1: 5: 0.025) to obtain? -Aminonitrile (2a, 97% yield; 70% ee, (R) Respectively. The enantioselectivity was measured using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 5.45 (d, J = 8.1 Hz, 1H), 5.78 (d, J = 6.9 Hz, 1H), 7.39-7.46 (m, 5H)

¹³ C NMR (75 MHz, CDCl 3)? 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example  29

After 1.0 mmol of? -Amidosulfone (1a) was dissolved in 12 mL of toluene at room temperature, 10 mol% of a compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide And the mixture was stirred for 20 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / naltre-nuclear / triethylamine = 1: 5: 0.025) to give? -Aminonitrile (2a, 99% yield; 78% ee, (R) Respectively. The enantioselectivity was measured using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 5.45 (d, J = 8.1 Hz, 1H), 5.78 (d, J = 6.9 Hz, 1H), 7.39-7.46 (m, 5H)

¹³ C NMR (75 MHz, CDCl 3)? 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example  30

1.0 mmol of imine (1a-2) was dissolved in 12 mL of toluene at 0 ° C. Then, 10 mol% of a compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of sodium cyanide And the mixture was stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-Hexane-Natane / triethylamine = 1: 5: 0.025) to yield? -Aminonitrile (2a-2, 24% yield; 69% ee, (R) ≪ / RTI > The enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 5.45 (d, J = 8.1 Hz, 1H), 5.78 (d, J = 6.9 Hz, 1H), 7.39-7.46 (m, 5H)

¹³ C NMR (75 MHz, CDCl 3)? 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example  31

After 1.0 mmol of 1-amidosulfone (1n) was dissolved in 12 mL of toluene at 0 ° C, 10 mol% of a compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-hexane / triethylamine = 1: 5: 0.025) to give? -Aminonitrile (2n, 86% yield; 85% ee, (R) Respectively. Enantioselectivity was measured using gas chromatography (RT-BetaDEX-sm chiral chromatography, isothermal temperature: 175 캜, inlet temperature: 235 캜, detection temperature: 235 캜, 0.7 mL / = 16 min, t (main product) = 17 min).

¹ H NMR (300 MHz, CDCl 3)? 1.07 (s, 9H), 1.47 (s, 9H), 4.44 (d, J = 9.9 Hz,

¹³ C NMR (75 MHz, CDCl 3)? 25.57, 28.16, 34.90, 52.13, 80.89, 118.03, 154.71

Example  32

After 1.0 mmol of? -Amidosulfone (1o) was dissolved in 12 mL of toluene at 0 ° C, 10 mol% of a compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to obtain? -Aminonitrile (2o, 86% yield; 80% ee, (R) Respectively. Enantioselectivity was measured using gas chromatography (RT-BetaDEX-sm chiral chromatography, isothermal temperature: 175 캜, inlet temperature: 235 캜, detection temperature: 235 캜, 0.7 mL / = 17 min, t (main product) = 16 min).

¹ H NMR (300 MHz, CDCl 3)? 1.07 (s, 9H), 1.47 (s, 9H), 4.45 (d, J = 9.9 Hz,

¹³ C NMR (75 MHz, CDCl 3)? 25.57, 28.16, 34.90, 52.13, 80.89, 118.03, 154.71

Example  33

After 1.0 mmol of? -Amidosulfone (1p) was dissolved in 12 ml of toluene at 0 ° C, 10 mol% of a compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of sodium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to give? -Aminonitrile (2p, 93% yield; 90% ee, (R) Respectively. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL AD-H, 99: 1, hexane: isopropyl alcohol, 1.0 mL / min, t (main product) = 56 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 5.37 (d, J = 1.8 Hz, 1H), 5.78 (d, J = 0.6 Hz, 1H), 7.11 (d, J = 5.1 Hz , 7.37 (d, J = 7.8 Hz, IH), 7.45 (s, IH)

¹³ C NMR (75 MHz, CDCl 3)? 28.12, 41.88, 81.46, 117.67, 123.99, 125.76, 127.61, 134.01, 154.06

Example  34

After 1.0 mmol of? -Amidosulfone (1a) was dissolved in 12 ml of dichloromethane at 0 ° C, 10 mol% of the compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-hexane / triethylamine = 1: 5: 0.025) to give? -Aminonitrile (2a, 88% yield; 40% ee, (R) Respectively. The enantioselectivity was measured using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 5.45 (d, J = 8.1 Hz, 1H), 5.78 (d, J = 6.9 Hz, 1H), 7.39-7.46 (m, 5H)

¹³ C NMR (75 MHz, CDCl 3)? 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example  35

After 1.0 mmol of? -Amidosulfone (1a) was dissolved in 12 ml of dichloroethane at 0 ° C, 10 mol% of the compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide Were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to obtain? -Aminonitrile (2a, 80% yield; 50% ee, (R) Respectively. The enantioselectivity was measured using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 5.45 (d, J = 8.1 Hz, 1H), 5.78 (d, J = 6.9 Hz, 1H), 7.39-7.46 (m, 5H)

¹³ C NMR (75 MHz, CDCl 3)? 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example  36

After 1.0 mmol of? -Amidosulfone (1a) was dissolved in 12 mL of dioxane at 0 ° C, 10 mol% of the compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst and potassium cyanide 1.05 Was added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / naltre-nuclear / triethylamine = 1: 5: 0.025) to give? -Aminonitrile (2a, 80% yield; 24% ee, (R) Respectively. The enantioselectivity was measured using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 5.45 (d, J = 8.1 Hz, 1H), 5.78 (d, J = 6.9 Hz, 1H), 7.39-7.46 (m, 5H)

¹³ C NMR (75 MHz, CDCl 3)? 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example  37

After 1.0 mmol of? -Amidosulfone (1a) was dissolved in 12 mL of tetrahydrofuran at 0 占 폚, 10 mol% of a compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst and potassium cyanide 1.05 equivalent were added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to obtain? -Aminonitrile (2a, 82% yield; 10% ee, (R) Respectively. The enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 5.45 (d, J = 8.1 Hz, 1H), 5.78 (d, J = 6.9 Hz, 1H), 7.39-7.46 (m, 5H)

¹³ C NMR (75 MHz, CDCl 3)? 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example  38

After 1.0 mmol of? -Amidosulfone (1a) was dissolved in 12 ml of acetonitrile at 0 ° C, 10 mol% of a compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst and potassium cyanide 1.05 Was added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to obtain? -Aminonitrile (2a, 72% yield; 10% ee, (R) Respectively. The enantioselectivity was measured using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 5.45 (d, J = 8.1 Hz, 1H), 5.78 (d, J = 6.9 Hz, 1H), 7.39-7.46 (m, 5H)

¹³ C NMR (75 MHz, CDCl 3)? 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example  39

After dissolving 1.0 mmol of the aldimine (3a) and 12 mL of toluene at 0 ° C, 10 mol% of the compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst and 1.05 equivalent of potassium cyanide And stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to give? -Aminonitrile (2a, 85% yield; 85% ee, (R) Respectively. The enantioselectivity was measured using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 5.45 (d, J = 8.1 Hz, 1H), 5.78 (d, J = 6.9 Hz, 1H), 7.39-7.46 (m, 5H)

¹³ C NMR (75 MHz, CDCl 3)? 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example  40

After 1.0 mmol of aldimine (3a) and 1.0 mmol of KSO ₂ Ph were dissolved in 12 mL of toluene at 0 ° C, 10 mol% of the compound of formula (1) (wherein R is I and n is 2) 1.05 equivalent of potassium was added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to obtain? -Aminonitrile (2a, 55% yield; 89% ee, (R) Respectively. The enantioselectivity was measured using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 5.45 (d, J = 8.1 Hz, 1H), 5.78 (d, J = 6.9 Hz, 1H), 7.39-7.46 (m, 5H)

¹³ C NMR (75 MHz, CDCl 3)? 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example  41

1.0 mmol of aldimine (3a) and 1.0 mmol of KSO ₂ Ph were dissolved in 12 mL of toluene at 0 ° C. Then, 10 mol% of a compound of the formula (1) (wherein R is I and n is 2) was added as a catalyst, 1.05 equivalent of hydrogen was added all at once and stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / naltre-nuclear / triethylamine = 1: 5: 0.025) to give? -Aminonitrile (2a, 63% yield; 99% ee, (R) Respectively. The enantioselectivity was measured using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 5.45 (d, J = 8.1 Hz, 1H), 5.78 (d, J = 6.9 Hz, 1H), 7.39-7.46 (m, 5H)

¹³ C NMR (75 MHz, CDCl 3)? 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example  42

After 1.0 mmol of? -Amidosulfone (1a) was dissolved in 12 ml of toluene at 0 ° C, 10 mol% of a compound of the formula (1) (wherein R is Cl and n was 2) and 1.05 equivalent of potassium cyanide And the mixture was stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-hexane / triethylamine = 1: 5: 0.025) to obtain? -Aminonitrile (2a, 91% yield; 38% ee, (R) Respectively. The enantioselectivity was measured using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 5.45 (d, J = 8.1 Hz, 1H), 5.78 (d, J = 6.9 Hz, 1H), 7.39-7.46 (m, 5H)

¹³ C NMR (75 MHz, CDCl 3)? 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example  43

After 1.0 mmol of? -Amidosulfone (1a) was dissolved in 12 ml of toluene at 0 ° C, 10 mol% of a compound of the formula (1) (wherein R is Br and n is 2) and 1.05 equivalent of potassium cyanide And the mixture was stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to obtain? -Aminonitrile (2a, 91% yield; 43% ee, (R) Respectively. The enantioselectivity was measured using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 5.45 (d, J = 8.1 Hz, 1H), 5.78 (d, J = 6.9 Hz, 1H), 7.39-7.46 (m, 5H)

¹³ C NMR (75 MHz, CDCl 3)? 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example  44

After 1.0 mmol of? -Amidosulfone (1a) was dissolved in 12 ml of toluene at 0 ° C, 10 mol% of a compound represented by the formula (1) (wherein R is Br and n is 1) and 1.05 equivalent of potassium cyanide And the mixture was stirred for 60 hours. The reaction was quenched using aqueous potassium carbonate solution. Using ethyl acetate, the water layer was extracted three times, dried and concentrated the combined organic layers with Na ₂ SO _4. The residue was purified by flash chromatography (acetone / n-heptane-nuclear fraction / triethylamine = 1: 5: 0.025) to obtain? -Aminonitrile (2a, 44% yield; 9% ee, (R) Respectively. The enantioselectivity was measured using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 min, t minute).

^{1 H NMR (300 MHz, CDCl3} ) δ1.47 (s, 9H), 5.45 (d, J = 8.1 Hz, 1H), 5.78 (d, J = 6.9 Hz, 1H), 7.39-7.46 (m, 5H)

¹³ C NMR (75 MHz, CDCl 3)? 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example  45: Chiral  Production of? -amino acid

The? -Aminonitrile ((R) -2b) prepared in Example 3 was dissolved in 6N hydrochloric acid at 90 占 폚 and stirred for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, extracted three times with diethyl ether, and the aqueous layer was concentrated. Chirality a-amino acid salt ((R) -3b, 75% yield) was obtained. Enantioselectivity was measured using a polarimeter and high performance liquid chromatography ([?] D ²⁰ = -84.5 (c = 0.5, 1N HCl). (ChiroSil RCA-51002546, 250 * 4.6 mm solution of copper sulfate (1 mM): acetonitrile = 98: 2, 0.5 mL / min), tR = 13 minutes (main product), tS = 10 minutes (by-product).

^{1 H NMR (300 MHz, D2O} ): δ3.84 (s, 3H); 5.05 (s, 1 H), 7.05 - 7.12 (m, 3 H); 7.43 (d, J = 7.5 Hz, 1 H)

¹³ C NMR (75 MHz, D2O):? 55.33, 56.47, 113.48, 115.64, 120.38, 130.86, 133.07, 159.40, 170.78

Claims (25)

Reacting with a cyanide source in the presence of a catalyst represented by the following formula (1) or (2)
Wherein the cyanide source is selected from the group consisting of (i) an alkali metal cyanide; (Ii) an alkali metal salt of an alkali metal cyanide and a sulfinic acid represented by the formula (6); And (iii) the alkali metal cyanide and the sulfinic acid represented by the formula (7).
[Chemical Formula 1]

(2)

In the above formulas (1) and (2), R is halogen and n is 1 to 5.
[Chemical Formula 6]

In Formula 6, M is an alkali metal, Ar ₁ is a C _{6 -12} aryl group.
(7)

In the formula 7, Ar ₂ is C _{6 -12} aryl group.
The method according to claim 1,
In the above formula (1) or (2), R is Br or I, and n is 2 or 3. 2. The process for producing a chiral? -Aminonitrile according to claim 1,
Reacting an imine of the formula (3) or? -Amidosulfone of the formula (4) with a cyanide source in an organic solvent in the presence of a catalyst represented by the following formula (1) or (2)
Wherein the cyanide source is selected from the group consisting of (i) an alkali metal cyanide; (Ii) an alkali metal salt of an alkali metal cyanide and a sulfinic acid represented by the formula (6); And (iii) one selected from the group consisting of an alkali metal cyanide and a sulfinic acid represented by the general formula (7).
[Chemical Formula 1]

(2)

In the above formulas (1) and (2), R is halogen and n is 1 to 5.
(3)

[Chemical Formula 4]

[Chemical Formula 5]

Wherein R ³ is selected from the group consisting of a C _{1 -30} alkyl group, a C _{3 -30} cycloalkyl group, a C _{6 -30} aryl group, and a C _{4 -30} heteroaryl group, and the alkyl group, the cycloalkyl group , aryl, and heteroaryl groups unsubstituted or substituted with halogen, nitrogen, oxygen or sulfur, P is an amine protecting group, Ar is a C _{6 -12} aryl group or C _{4 -12} heteroaryl group.
[Chemical Formula 6]

In Formula 6, M is an alkali metal, Ar ₁ is a C _{6 -12} aryl group.
(7)

In the formula 7, Ar ₂ is C _{6 -12} aryl group.
The method of claim 3,
Wherein R is Cl, Br or I, and n is 1 to 4. 2. The method according to claim 1,
The method of claim 3,
In the above formula (1) or (2), R is Br or I, and n is 2 or 3. 2. The process for producing a chiral? -Aminonitrile according to claim 1,
The method of claim 3,
Wherein R is I and n is 2 or 3 in the general formula (1) or (2).
The method of claim 3,
In the formula (1) or (2), R is I and n is 2. 2. The process for producing a chiral? -Aminonitrile according to claim 1,
The method of claim 3,
In the above formulas (3), (4) and (5), P is a group consisting of a methyloxycarbonyl group, a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a t- butyloxycarbonyl group (BOC), and a 9-fluorenylmethyloxycarbonyl group Lt; RTI ID = 0.0 > a-aminonitrile < / RTI >
The method of claim 3,
Wherein the alkali metal cyanide is potassium cyanide or sodium cyanide.
10. The method of claim 9,
Wherein the alkali metal cyanide is potassium cyanide.
The method of claim 3,
Wherein the organic solvent is an aprotic solvent.
The method of claim 3,
Wherein the organic solvent is selected from the group consisting of methyl t-butyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, dichloroethane, carbon tetrachloride, benzene, toluene, methylcyclohexane, Wherein the chiral α-aminonitrile is a compound represented by the following formula:
The method of claim 3,
Wherein the organic solvent is dichloromethane, dichloroethane, benzene, toluene, and mixtures thereof.
The method of claim 3,
Wherein the organic solvent is toluene.
The method of claim 3,
Wherein M is potassium and Ar < ₁ > is phenyl or tolyl.
The method of claim 3,
Wherein Ar ₂ in Formula 7 is phenyl or tolyl.
The method of claim 3,
The catalyst represented by the formula (1) or (2) is used in an amount of 1 to 30 mol% based on the imine of the formula (3) or? -Amidosulfone of the formula (4) .
The method of claim 3,
Wherein the cyanide source is used in an amount of 1 to 50 equivalents based on the imine of formula (3) or? -Amidosulfone of formula (4).
The method of claim 3,
Wherein the cyanide source is used in an amount of 1 to 2 equivalents based on the imine of formula (3) or? -Amidosulfone of formula (4).
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