WO2012153991A2 - Method for preparing chiral α-aminonitrile using a catalyst for a strecker reaction - Google Patents

Abstract

The present invention relates to a method for preparing chiral α-aminonitrile through a strecker reaction by using a cyanide source under a catalyst having Chemical Formula 1 or Chemical Formula 2 of ethylene glycol derivatives. According to the present invention, chiral α-aminonitriles having various structures and high stereoselectivity can be synthesized. In addition, (R)-type α-aminonitrile, which is a precursor of a synthetically obtainable amino acid, (R)-α-amino acid, can be synthesized to have high optical purity. As the cyanide source, an alkali metal cyanide having good thermal stability, good storing properties, low cost and easy-to-use properties can be used solely, or a combination of the alkali metal cyanide and an alkali metal sulfinate or sulfinic acid can be used. The method according to the present invention is very useful in industrial development, very economical, and simple.

Description

Method for producing chiral α-aminonitrile using catalyst for striking reaction

The present invention relates to a method for preparing chiral α-aminonitrile using a catalyst for a striker reaction, and more particularly, alkali metal cyanide alone or alkali metal cyanide in the presence of a catalyst derivatized with ethylene glycol. And a method for producing (S)-or (R) -α-aminonitrile having enantioselectivity through stereoselective stretcher reaction using a cyanide source which is a combination of a sulfonic acid alkali metal salt or sulfinic acid.

Alpha-amino acids play a very important role in vivo as the building blocks of proteins. In particular, the development of efficient and economical synthesis of non-natural amino acids widely used as components of pharmaceuticals and chiral catalysts is considered 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 such alpha amino acids, is a method of producing alpha-amino acids by hydrolyzing iminonitrile obtained through the reaction of imine and hydrogen cyanide. This is one of the most commonly used methods. Known methods, however, are difficult to mass-produce because they typically use more than the equivalent of expensive chiral auxiliaries, or use only very dangerous and intractable materials such as trimethylsilyl cyanide or HCN as a cyanide source in the case of catalysis. There was this.

Therefore, the present inventors have used a catalyst derived from a small amount of chiral ethylene glycol composed of organic material to synthesize asymmetrical stretcher using cyanide source such as KCN, which is excellent in thermal stability, storage stability, economical and easy to use. It has been successful to obtain chiral aminonitrile, a synthetic precursor of chiral alpha amino acids, in high yield and high optical selectivity.

Furthermore, according to the present invention, chiral α-aminonitrile of various structures can be synthesized from α-amido sulfone, which is a precursor of imine, which is a sensitive starting material, as well as a hydrolysis-sensitive starting material, in high yield and very high stereoselectivity. Can be.

It is an object of the present invention to provide a more efficient, economical, high-volume, chiral α-aminokite suitable for mass production through a stereoselective strainer reaction of a low-toxic and easy-to-handle cyanide ion source with imine or its precursor amido sulfone. It is to provide a method for producing a reel.

In order to achieve the above object, the present invention comprises the step of using a cyanide source in the presence of a catalyst represented by the formula (1) or formula (2), and the cyanide source is (i) alkali metal cyanide; (ii) alkali metal cyanide and alkali metal salts of sulfinic acids represented by formula (6); And (iii) one selected from the group consisting of alkali metal cyanide and sulfinic acid represented by the formula (7).

[Formula 1]

[Formula 2]

In Chemical Formulas 1 and 2, R is halogen and n is 1-5.

[Formula 6]

In Chemical Formula 6, M is an alkali metal, and Ar ₁ is a C _6-12 aryl group.

[Formula 7]

In Formula 7, Ar ₂ is a C _6-12 aryl group.

More specifically, the present invention includes the steps of a stretcher reaction of an imine of formula 3 or an α-amido sulfone of formula 4 with a cyanide source in an organic solvent in the presence of a catalyst represented by formula 1 or formula 2 Wherein the cyanide source is (i) an alkali metal cyanide; (ii) alkali metal cyanide and alkali metal salts of sulfinic acids represented by formula (6); And (iii) one selected from the group consisting of alkali metal cyanide and sulfinic acid represented by the general formula (7).

[Formula 1]

[Formula 2]

In Chemical Formulas 1 and 2, R is halogen and n is 1-5.

[Formula 3]

[Formula 4]

[Formula 5]

In Chemical Formulas 3, 4, and 5, R ³ is selected from the group consisting of C _1-30 alkyl group, C _3-30 cycloalkyl group, C _6-30 aryl group, and C _4-30 heteroaryl group, wherein the alkyl group, cycloalkyl group , Aryl group and heteroaryl group are 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.

[Formula 6]

In Chemical Formula 6, M is an alkali metal, and Ar ₁ is a C _6-12 aryl group.

[Formula 7]

In Formula 7, Ar ₂ is a C _6-12 aryl group.

The present invention provides chiral α-aminonitrile prepared according to the method of the present invention.

The present invention provides a method for producing a chiral α-amino acid by hydrolyzing chiral α-aminonitrile prepared according to the method of the present invention with an acid.

The present invention provides chiral α-amino acids prepared according to the process of the invention.

The present invention also provides a catalyst for a striker reaction selected from the following table.

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

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

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

As used herein, the term "stretcher reaction" is well known for the synthesis of α-aminonitrile, a precursor useful in amino acid synthesis, and is generally a compound having an imine group or a precursor of α-amidosulfone and cyanide. It means a process occurring under the action of a specific catalyst under this organic solvent. Since the term itself includes the definition of a substance that participates in a striker reaction, it is not necessary to specifically limit the substance that reacts with the cyanide source, i.e., a compound having an imine group or a precursor of imine.

According to one embodiment of the invention, the imine of formula (3) or (alpha) -amido sulfone of formula (4) is added in an organic solvent with the catalyst represented by formula (1) or formula (2) and the cyanide source of the invention A chiral α-aminonitrile of Formula 5 of high enantiomeric excess can be prepared by carrying out a stretcher reaction such as Scheme 1 or Scheme 2. According to the invention, chiral α-aminonitriles of the formula (5) can be obtained with very high optical selectivity under optimized conditions of cyanation reactions, especially with enantiomeric excess of more than 90%.

Scheme 1

Scheme 2

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

[Formula 1]

[Formula 2]

In Chemical Formulas 1 and 2, R is halogen and n is 1-5.

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

In formulas (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 preparation method of the present invention, the catalyst represented by the formula (1) or (2) may be used by those skilled in the art based on the imine of the formula (3) or the α- amido sulfone of the formula (4), but in terms of optical purity In an amount of preferably 0.01 to 100 mol%, particularly preferably 1 to 30 mol%.

Compounds participating in the stretcher reaction of the present invention are imines of formula 3 or α-amido sulfones of formula 4:

[Formula 3]

[Formula 4]

In formulas 3, 4 and 5, R ³ is selected from the group consisting of C _1-30 alkyl group, C _3-30 cycloalkyl group, C _6-30 aryl group and C _4-30 heteroaryl group, wherein the alkyl group, cycloalkyl group, The aryl group and heteroaryl group are unsubstituted or substituted with halogen, nitrogen, oxygen or sulfur, P is an amine protecting group, Ar is a C _6-12 aryl group or a 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 the amine during the reaction, and suitable amine protecting groups are known in the art, for example, Green, the entire teachings of which are incorporated by reference. And Protecting Groups in Organic Synthesis, Wuts, John Wiley and Sons, 1991 and Protecting Groups in Organic Synthesis, Green and Wuts, John Wiley and Sons, 2007. Therefore, the amine protecting group can use a well-known amine protecting group without limitation. Examples of the amine protecting group include methyloxycarbonyl group, benzyloxycarbonyl group, p-methoxybenzyloxy carbonyl group, t-butyloxycarbonyl group (Boc), 9-fluorenylmethyloxycarbonyl group (FMOC), allyloxycarbonyl (Alloc), Benzoyl group (Bz), benzyl (Bn) group, p-methoxybenzyl group (PMB), 3,4-dimethoxybenzyl group (DMPM), p-methoxyphenyl group (PMP), tosyl group (Ts), trimethyl Silylethyloxy carbonyl group (Teoc), benzhydryl, triphenylmethyl (Trityl), (4-methoxyphenyl) diphenylmethyl (Mmt), dimethoxytrityl (DMT), diphenylphosphino group and the like. have.

In formulas (3) and (4), it is preferable that Ar is phenyl or tolyl.

In the general formulas (3) and (4), P is an amine protecting group, and a methyloxycarbonyl group, benzyloxycarbonyl group, p-methoxybenzyloxy carbonyl group, t-butyloxycarbonyl group (Boc), and 9-fluorenylmethyloxycarbonyl group (FMOC) It is preferably selected from the group consisting of.

The chiral α-aminonitrile of formula (5) can be obtained after the stretcher reaction of the present invention:

[Formula 5]

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

In the process of the invention, the cyanide source, which is a nucleophile for the striker reaction, comprises: (i) alkali metal cyanide; (ii) alkali metal cyanide and alkali metal salts of sulfinic acids represented by formula (6); And (iii) an alkali metal cyanide and sulfinic acid represented by the formula (7).

[Formula 6]

In Formula 6, M is an alkali metal, Ar ₁ is a C _6-12 aryl group, preferably phenyl or tolyl.

[Formula 7]

In Formula 7, Ar ₂ is a C _6-12 aryl group, preferably phenyl or tolyl.

As an alkali metal cyanide, it is preferable to use potassium cyanide or sodium cyanide, and especially potassium cyanide is used.

Known cyanide sources for the striker reaction include hydrogen cyanide (HCN), acetone cyanohydrin, trimethylsilyl cyanide (TMSCN), alkali metal cyanide and the like. The preparation method according to the present invention makes it possible to effectively carry out the stretcher reaction using an easy-to-handle alkali metal cyanide in place of the highly toxic hydrogen cyanide, acetone cyanohydrin and trimethylsilyl cyanide among known cyanide sources. This is because the structure of the catalyst represented by the formula (1) or (2) according to the present invention contributes to the reactivity of the cyanide source participating in the striker reaction. Specifically, the ether group possessed by the catalyst of the present invention acts as a Lewis base with respect to the alkali metal cation to release a counteranion and to improve the solubility of the alkali metal salt, and also has a hydroxyl present at the terminal. It is based on the fact that the group (-OH) can stabilize the transition state by activating an electrophile through hydrogen bonding.

The cyanide source of the present invention may be selected and used by the person skilled in the art for an imine of formula (3) or α-amido sulfone of formula (4), but preferably 1 to 50 equivalents, more preferably 1 to 10 It can be used in the equivalent amount, most preferably 1 to 2 equivalents.

As the organic solvent usable in the present invention, an aprotic solvent may be used, and methyl t-butyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, dichloroethane, carbon Preference is given to tetrachloride, benzene, toluene, methylcyclohexane and mixtures thereof, in particular dichloromethane, dichloroethane, benzene, toluene and mixtures thereof.

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

The present invention also provides a process for preparing chiral α-amino acids by hydrolyzing chiral α-amino nitriles prepared according to the process of the present invention with acids. Acid hydrolysis reactions for synthesizing chiral α-amino acids from α-aminonitrile are known in the art and thus detailed discussions are omitted. Chiral α-amino acids are very important compounds in the pharmaceutical industry in that they provide an important structure for the preparation of various pharmaceutical products. According to the present invention, non-natural α-amino acids can be easily prepared according to the present invention. Natural α-amino acids can also be used as pharmaceuticals through mass production.

According to the present invention, chiral α-aminonitrile of various structures can be synthesized with very high stereoselectivity in a short time from not only imine which is sensitive to hydrolysis but also α-amido sulfone, which is a precursor of imine which is a stable starting material. have. Further, since the (R) -form α-aminonitrile of the (R) -form, which is a precursor of the non-natural amino acid (R) -α-amino acid, can be produced with high optical purity, it can be said that the industrial utility is greater.

In addition, the preparation method of the present invention is an alkali metal cyanide that is excellent in thermal stability, storage property, and low cost and easy to use instead of toxic hydrogen cyanide (HCN), acetone cyanohydrin and trimethylsilyl cyanide (TMSCN) as a cyanide source. Using a single or a combination of alkali metal cyanide and sulfinic acid alkali metal salt or sulfinic acid and effectively carrying out the stretcher reaction at a temperature from 0 ° C to room temperature is a very economical and convenient method very useful for industrialization.

Hereinafter, the present invention will be described in more detail with reference to Examples. The following examples are only intended to illustrate the invention, it will be apparent to those skilled in the art that various changes and modifications can be made within the scope and spirit of the invention, and such variations and modifications also belong to the appended claims. It is natural.

Examples 1-44 Preparation of Chiral α-aminonitrile

The imine of formula 3 or α-amido sulfone of formula 4 was dissolved in an organic solvent, and then the result of the stretcher reaction by adding 10 mol% of the catalyst of formula 1 or formula 2 and 1.05 equivalents of cyanide source is shown in Table 1 below. Indicated. The prepared α-aminonitrile was analyzed by high performance liquid chromatography (HPLC) and gas chromatography (GC) to determine enantiomeric excess.

시안화 칼륨 0℃ 화학식 1의 R은 I이며 n은 2임 60 89 95 톨루엔 2

시안화 칼륨 0℃ 화학식 2의 R은 I이며 n은 2임 60 88 95 톨루엔 3

시안화 칼륨 0℃ 화학식 1의 R은 I이며 n은 2임 60 90 98 톨루엔 4

시안화 칼륨 0℃ 화학식 2의 R은 I이며 n은 2임 60 92 97 톨루엔 5

시안화 칼륨 0℃ 화학식 1의 R은 I이며 n은 2임 60 93 93 톨루엔 6

시안화 칼륨 0℃ 화학식 2의 R은 I이며 n은 2임 60 91 93 톨루엔 7

시안화 칼륨 0℃ 화학식 1의 R은 I이며 n은 2임 60 89 93 톨루엔 8

시안화 칼륨 0℃ 화학식 2의 R은 I이며 n은 2임 60 88 93 톨루엔 9

시안화 칼륨 0℃ 화학식 1의 R은 I이며 n은 2임 60 90 98 톨루엔 10

시안화 칼륨 0℃ 화학식 2의 R은 I이며 n은 2임 60 94 98 톨루엔 11

시안화 칼륨 0℃ 화학식 1의 R은 I이며 n은 2임 60 87 92 톨루엔 12

시안화 칼륨 0℃ 화학식 2의 R은 I이며 n은 2임 60 89 92 톨루엔 13

시안화 칼륨 0℃ 화학식 1의 R은 I이며 n은 2임 60 90 92 톨루엔 14

시안화 칼륨 0℃ 화학식 2의 R은 I이며 n은 2임 60 90 91 톨루엔 15

시안화 칼륨 0℃ 화학식 1의 R은 I이며 n은 2임 60 91 80 톨루엔 16

시안화 칼륨 0℃ 화학식 2의 R은 I이며 n은 2임 60 92 80 톨루엔 17

시안화 칼륨 0℃ 화학식 1의 R은 I이며 n은 2임 60 83 89 톨루엔 18

시안화 칼륨 0℃ 화학식 2의 R은 I이며 n은 2임 60 83 89 톨루엔 19

시안화 칼륨 0℃ 화학식 1의 R은 I이며 n은 2임 60 88 86 톨루엔 20

시안화 칼륨 0℃ 화학식 2의 R은 I이며 n은 2임 60 86 85 톨루엔 21

시안화 칼륨 0℃ 화학식 1의 R은 I이며 n은 2임 60 94 96 톨루엔 22

시안화 칼륨 0℃ 화학식 2의 R은 I이며 n은 2임 60 89 97 톨루엔 23

시안화 칼륨 0℃ 화학식 1의 R은 I이며 n은 2임 60 94 93 톨루엔 24

시안화 칼륨 0℃ 화학식 2의 R은 I이며 n은 2임 60 93 93 톨루엔 25

시안화 칼륨 0℃ 화학식 1의 R은 I이며 n은 2임 60 87 90 톨루엔 26

시안화 칼륨 0℃ 화학식 2의 R은 I이며 n은 2임 60 86 90 톨루엔 27

시안화 칼륨 실온 화학식 1의 R은 Br 이며 n은 2임 36 87 43 톨루엔 28

시안화 칼륨 실온 화학식 1의 R은 I이며 n은 2임 20 97 70 디클로로에탄 29

시안화칼륨 실온 화학식 1의 R은 I이며 n은 2임 20 99 78 톨루엔 30

시안화 칼륨 0℃ 화학식 1의 R은 I이며 n은 2임 60 24 69 톨루엔 31

시안화 칼륨 0℃ 화학식 2의 R은 I이며 n은 2임 60 86 85 톨루엔 32

시안화 칼륨 0℃ 화학식 2의 R은 I이며 n은 2임 60 86 80 톨루엔 33

시안화 칼륨 0℃ 화학식 2의 R은 I이며 n은 2임 60 93 90 톨루엔 34

시안화 칼륨 0℃ 화학식 1의 R은 I이며 n은 2임 60 88 40 디클로로메탄 35

시안화 칼륨 0℃ 화학식 1의 R은 I이며 n은 2임 60 80 50 디클로로에탄 36

시안화 칼륨 0℃ 화학식 1의 R은 I이며 n은 2임 60 80 24 다이옥세인 37

시안화 칼륨 0℃ 화학식 1의 R은 I이며 n은 2임 60 82 10 테트라하이드로퓨란 38

시안화 칼륨 0℃ 화학식 1의 R은 I이며 n은 2임 60 72 10 아세토나이트릴 39

시안화 칼륨/KSO₂Ph 0℃ 화학식 1의 R은 I이며 n은 2임 60 85 85 톨루엔 40

시안화 칼륨/HSO₂Ph 0℃ 화학식 1의 R은 I이며 n은 2임 60 55 89 톨루엔 41

시안화 칼륨/HSO₂Ph 0℃ 화학식 1의 R은 I이며 n은 2임 60 63 99 톨루엔 42

시안화 칼륨 0℃ 화학식 1의 R은 Cl이며 n은 2임 60 91 38 톨루엔 43

시안화 칼륨 0℃ 화학식 1의 R은 Br이며 n은 2임 60 91 43 톨루엔 44

시안화 칼륨 0℃ 화학식 1의 R은 Br이며 n은 1개임 60 44 9 톨루엔 Table 1 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 one 60 44 9 toluene

Example 1

1.0 mmol of α-amido sulfone (1a) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of a compound of formula 1 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2a, 89% yield; 95% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 minutes, t (by-product) = 39 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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) δ 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22.

Example 2

1.0 mmol of α-amido sulfone (1a) was dissolved in 12 mL of toluene at 0 ° C., followed by the addition of 10 mol% of a compound of formula 2 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2a, 88% yield; 95% ee, (S) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.7 mL / min, t (by-product) = 33 min, t (main product) = 39 minute).

1 H NMR (300 MHz, CDCl 3) δ 1.47 (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) δ 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22.

Example 3

1.0 mmol of α-amido sulfone (1b) was dissolved in 12 mL of toluene at 0 ° C., followed by the addition of 10 mol% of a compound of formula 1 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2b, 90% yield; 98% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 1.0 mL / min, t (main product) = 33 minutes, t (by-product) = 37 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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, 3H), 7.29-7.35 (m, 1H)

¹³ C NMR (75 MHz, CDCl 3) δ 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

1.0 mmol of α-amido sulfone (1b) was dissolved in 12 mL of toluene at 0 ° C., followed by the addition of 10 mol% of a compound of formula 2 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2b, 92% yield; 97% ee, (S) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.7 mL / min, t (by-product) = 33 min, t (main product) = 37 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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, 3H), 7.29-7.35 (m, 1H)

¹³ C NMR (75 MHz, CDCl 3) δ 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

1.0 mmol of α-amido sulfone (1c) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of a compound of formula 1 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2c, 93% yield; 93% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 1.0 mL / min, t (main product) = 23 minutes, t (by-product) = 20 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.48 (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) δ 22.01, 29.08, 46.69, 82.29, 118.79, 127.66, 130.76, 140.35, 155.03

Example 6

1.0 mmol of α-amido sulfone (1c) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of a compound of formula 2 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2c, 91% yield; 93% ee, (S) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 1.0 mL / min, t (by-product) = 23 min, t (main product) = 20 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.48 (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) δ 22.01, 29.08, 46.69, 82.29, 118.79, 127.66, 130.76, 140.35, 155.03

Example 7

1.0 mmol of α-amido sulfone (1d) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of a compound of formula 1 (wherein R 1 and R 2 are I and n is 2) and potassium cyanide 1.05 equiv was added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to afford α-aminonitrile (2d, 89% yield; 93% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 1.0 mL / min, t (main product) = 57 minutes, t (by-product) = 64 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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, CDCl 3) δ 21.09, 28.15, 45.76, 81.36, 117.87, 126.74, 129.84, 130.43, 139.43, 154.11

Example 8

1.0 mmol of α-amido sulfone (1d) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of a compound of formula 2 (wherein R is I and n is 2) and potassium cyanide was 1.05 equivalents Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to afford α-aminonitrile (2d, 88% yield; 93% ee, (S) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 1.0 mL / min, t (product) = 57 minutes, t (main product) = 64 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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, CDCl 3) δ 21.09, 28.15, 45.76, 81.36, 117.87, 126.74, 129.84, 130.43, 139.43, 154.11

Example 9

1.0 mmol of α-amido sulfone (1e) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of a compound of formula 1 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2e, 90% yield; 98% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 1.0 mL / min, t (main product) = 20 minutes, t (by-product) = 24) minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.48 (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, CDCl 3) 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

1.0 mmol of α-amido sulfone (1e) was dissolved in 12 mL of toluene at 0 ° C., followed by the addition of 10 mol% of a compound of formula 2 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2e, 94% yield; 98% ee, (S) -form) It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 1.0 mL / min, t (product) = 20 minutes, t (main product) = 24 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.48 (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, CDCl 3) 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

1.0 mmol of α-amido sulfone (1f) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of a compound of formula 1 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to afford α-aminonitrile (2f, 87% yield; 92% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 1.0 mL / min, t (main product) = 36 minutes, t (by-product) = 45 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.48 (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) δ 28.11, 45.53, 81.96, 117.08, 121.74, 126.25, 127.27, 131.44, 131.68, 137.47, 154.14

Example 12

1.0 mmol of α-amido sulfone (1f) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of a compound of formula 2 (wherein R is I and n is 2) and potassium cyanide was 1.05 equivalents Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2f, 89% yield; 92% ee, (S) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 1.0 mL / min, t (by-product) = 36 minutes, t (main product) = 45 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.48 (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) δ 28.11, 45.53, 81.96, 117.08, 121.74, 126.25, 127.27, 131.44, 131.68, 137.47, 154.14

Example 13

1.0 mmol of α-amido sulfone (1 g) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of a compound of formula 1 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2 g, 90% yield; 92% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 1.0 mL / min, t (main product) = 13 minutes, t (by-product) = 11 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.48 (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

1.0 mmol of α-amido sulfone (1 g) was dissolved in 12 mL of toluene at 0 ° C., followed by the addition of 10 mol% of a compound of formula 2 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2 g, 90% yield; 91% ee, (S) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 1.0 mL / min, t (by-product) = 13 minutes, t (main product) = 11 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.48 (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

1.0 mmol of α-amido sulfone (1h) was dissolved in 12 mL of toluene at 0 ° C., followed by the addition of 10 mol% of a compound of formula 1 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2h, 91% yield; 80% ee, (R) -form) It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 1.0 mL / min, t (main product) = 25.7 minutes, t (by-product) = 24.3) 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, CDCl3) 28.20, 45.48, 82.02, 117.35, 127.76, 128.52, 128.92, 132.40, 154.20

Example 16

1.0 mmol of α-amido sulfone (1h) was dissolved in 12 mL of toluene at 0 ° C., followed by the addition of 10 mol% of a compound of formula 2 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2h, 92% yield; 80% ee, (S) -form) It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 1.0 mL / min, t (by-product) = 25.7 min, t (main product) = 24.3) 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, CDCl3) 28.20, 45.48, 82.02, 117.35, 127.76, 128.52, 128.92, 132.40, 154.20

Example 17

1.0 mmol of α-amido sulfone (1i) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of a compound of formula 1 (wherein R is I and n is 2) and potassium cyanide was 1.05 equivalents Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to afford α-aminonitrile (2i, 83% yield; 89% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.5 mL / min, t (main product) = 67 minutes, t (by-product) = 73 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.46 (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) δ 28.00, 45.19, 81.50, 115.95, 116.25, 117.43, 128.62, 128.73, 161.28, 164.59

Example 18

1.0 mmol of α-amido sulfone (1a) was dissolved in 12 mL of toluene at 0 ° C., followed by the addition of 10 mol% of a compound of formula 2 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2i, 83% yield; 89% ee, (S) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.5 mL / min, t (product) = 67 minutes, t (main product) = 73 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.46 (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) δ 28.00, 45.19, 81.50, 115.95, 116.25, 117.43, 128.62, 128.73, 161.28, 164.59

Example 19

1.0 mmol of α-amido sulfone (1j) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of a compound of formula 1 (wherein R is I and n is 2) and potassium cyanide was 1.05 equivalents Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2j, 88% yield; 86% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 1.0 mL / min, t (main product) = 69 minutes, t (by-product) = 81 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.46 (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) δ 28.12, 45.35, 81.74, 117.34, 128.18, 129.38, 132.03, 135.44, 154.11

Example 20

1.0 mmol of α-amido sulfone (1j) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of a compound of formula 2 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2j, 86% yield; 85% ee, (S) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.7 mL / min, t (product) = 69 minutes, t (main product) = 81 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.46 (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) δ 28.12, 45.35, 81.74, 117.34, 128.18, 129.38, 132.03, 135.44, 154.11

Example 21

1.0 mmol of α-amido sulfone (1k) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of a compound of formula 1 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2k, 94% yield; 96% ee, (R) -form) It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 1.0 mL / min, t (by-product) = 44 min, t (main product) = 54 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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

1.0 mmol of α-amido sulfone (1k) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of a compound of formula 2 (wherein R is I and n is 2) as potassium catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2k, 89% yield; 97% ee, (S) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexane: isopropyl alcohol, 1.0 mL / min, t (product) = 54 minutes, t (main product) = 44 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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

1.0 mmol of α-amido sulfone (1 l) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of a compound of formula 1 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2l, 94% yield; 93% ee, (R) -form) It was. Enantioselectivity was determined using gas chromatography (RT-BetaDEX-sm chiral chromatography, isothermal temperature: 175 ° C, input temperature: 235 ° C, detection temperature: 235 ° C, 0.7 mL / min, t (by-product) = 17 minutes, t (main product) = 20 minutes).

¹ H NMR (300 MHz, CDCl 3) δ1.07-1.23 (m, 5H), 1.45 (s, 9H), 1.67-1.71 (m, 2H), 1.78-1.87 (m, 4H), 4.43 (d, J = 8.7 Hz, 1H), 4.93 (d, J = 9.0 Hz, 1H)

¹³ C NMR (75 MHz, CDCl 3) δ 25.33, 25.39, 25.68, 28.17, 40.75, 47.60, 81.01, 118.18, 154.44

Example 24

1.0 mmol of α-amido sulfone (1 l) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of a compound of formula 2 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nuxane / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2l, 93% yield; 93% ee, (S) -form) It was. Enantioselectivity was determined using gas chromatography (RT-BetaDEX-sm chiral chromatography, isothermal temperature: 175 ° C, input temperature: 235 ° C, detection temperature: 235 ° C, 0.7 mL / min, t (by-product) = 17 minutes, t (main product) = 20 minutes).

¹ H NMR (300 MHz, CDCl 3) δ1.07-1.23 (m, 5H), 1.45 (s, 9H), 1.67-1.71 (m, 2H), 1.78-1.87 (m, 4H), 4.43 (d, J = 8.7 Hz, 1H), 4.93 (d, J = 9.0 Hz, 1H)

¹³ C NMR (75 MHz, CDCl 3) δ 25.33, 25.39, 25.68, 28.17, 40.75, 47.60, 81.01, 118.18, 154.44

Example 25

1.0 mmol of α-amido sulfone (1 m) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of a compound of formula 2 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2m, 87% yield; 90% ee, (R) -form) It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.7 mL / min, t (by-product) = 28 min, t (main product) = 22 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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 , 1H), 7.85 (d, J = 7.8 Hz, 1H), 8.56-8.65 (m, 2H)

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

Example 26

1.0 mmol of α-amido sulfone (1 m) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of a compound of formula 2 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2m, 86% yield; 90% ee, (S) -form) It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.7 mL / min, t (by-product) = 28 min, t (main product) = 22 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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 , 1H), 7.85 (d, J = 7.8 Hz, 1H), 8.56-8.65 (m, 2H)

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

Example 27

1.0 mmol of α-amido sulfone (1a) was dissolved in 12 mL of toluene at room temperature, followed by addition of 10 mol% of a compound of formula 1 (wherein R is Br and n is 2) and 1.05 equivalents of potassium cyanide It was added all at once and stirred for 36 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2a, 87% yield; 43% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 minutes, t (by-product) = 39 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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) δ 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example 28

1.0 mmol of α-amido sulfone (1a) was dissolved in 12 mL of dichloroethane at room temperature, followed by addition of 10 mol% of a compound of formula 1 (wherein R is I and n is 2) and potassium cyanide was 1.05 equivalents Were added all at once and stirred for 20 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to afford α-aminonitrile (2a, 97% yield; 70% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 minutes, t (by-product) = 39 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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) δ 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example 29

1.0 mmol of α-amido sulfone (1a) was dissolved in 12 mL of toluene at room temperature, followed by addition of 10 mol% of a compound of formula 1 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide It was added all at once and stirred for 20 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to afford α-aminonitrile (2a, 99% yield; 78% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 minutes, t (by-product) = 39 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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) δ 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, followed by the addition of 10 mol% of a compound of formula 1 (wherein R is I and n is 2) and sodium cyanide 1.05 equivalents Added and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2a-2, 24% yield; 69% ee, (R) -form) Obtained. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 minutes, t (by-product) = 39 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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) δ 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example 31

1.0 mmol of α-amido sulfone (1n) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of the compound of formula 1 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2n, 86% yield; 85% ee, (R) -form). It was. Enantioselectivity was determined using gas chromatography (RT-BetaDEX-sm chiral chromatography, isothermal temperature: 175 ° C, input temperature: 235 ° C, detection temperature: 235 ° C, 0.7 mL / min, t (by-product) = 16 minutes, t (main product) = 17 minutes).

¹ H NMR (300 MHz, CDCl 3) δ1.07 (s, 9H), 1.47 (s, 9H), 4.44 (d, J = 9.9 Hz, 1H), 5.15 (s, 1H)

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

Example 32

1.0 mmol of α-amido sulfone (1o) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of the compound of formula 1 (wherein R is I and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2o, 86% yield; 80% ee, (R) -form) It was. Enantioselectivity was determined using gas chromatography (RT-BetaDEX-sm chiral chromatography, isothermal temperature: 175 ° C, input temperature: 235 ° C, detection temperature: 235 ° C, 0.7 mL / min, t (by-product) = 17 minutes, t (main product) = 16 minutes).

¹ H NMR (300 MHz, CDCl 3) δ1.07 (s, 9H), 1.47 (s, 9H), 4.45 (d, J = 9.9 Hz, 1H), 5.15 (s, 1H)

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

Example 33

1.0 mmol of α-amido sulfone (1p) was dissolved in 12 mL of toluene at 0 ° C., followed by the addition of 10 mol% of a compound of formula 1 (wherein R is I and n is 2) as a catalyst and sodium cyanide 1.05 equivalents Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2p, 93% yield; 90% ee, (R) -form) It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL AD-H, 99: 1, hexanes: isopropyl alcohol, 1.0 mL / min, t (main product) = 56 minutes, t (by-product) = 67 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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 , 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.45 (s, 1H)

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

Example 34

1.0 mmol of α-amido sulfone (1a) was dissolved in 12 mL of dichloromethane at 0 ° C., followed by addition of 10 mol% of a compound of formula 1 (wherein R is I and n is 2) and potassium cyanide was 1.05 equivalents Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to afford α-aminonitrile (2a, 88% yield; 40% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 minutes, t (by-product) = 39 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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) δ 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example 35

1.0 mmol of α-amido sulfone (1a) was dissolved in 12 mL of dichloroethane at 0 ° C., followed by addition of 10 mol% of a compound of formula 1 (wherein R is I and n is 2), and potassium cyanide was 1.05 equivalents. Were added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to afford α-aminonitrile (2a, 80% yield; 50% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 minutes, t (by-product) = 39 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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) δ 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example 36

1.0 mmol of α-amido sulfone (1a) was dissolved in 12 mL of dioxane at 0 ° C., followed by the addition of 10 mol% of a compound of formula 1 (wherein R is I and n is 2) as a catalyst and potassium cyanide 1.05 Equivalent weight was added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2a, 80% yield; 24% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 minutes, t (by-product) = 39 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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) δ 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example 37

1.0 mmol of α-amido sulfone (1a) was dissolved in 12 mL of tetrahydrofuran at 0 ° C., followed by addition of 10 mol% of a compound of formula 1 (wherein R is I and n is 2) as a catalyst and potassium cyanide 1.05 equiv was added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to afford α-aminonitrile (2a, 82% yield; 10% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 minutes, t (by-product) = 39 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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) δ 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example 38

1.0 mmol of α-amido sulfone (1a) was dissolved in 12 mL of acetonitrile at 0 ° C., followed by addition of 10 mol% of a compound of Formula 1 (wherein R is I and n is 2) as a catalyst and potassium cyanide 1.05 Equivalent weight was added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to afford α-aminonitrile (2a, 72% yield; 10% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 minutes, t (by-product) = 39 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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) δ 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example 39

After dissolving in 1.0 mmol of aldimine (3a) and 12 mL of toluene at 0 ° C, 10 mol% of the compound of formula 1 (wherein R is I and n is 2) was added and 1.05 equivalents of potassium cyanide were added all at once. And stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2a, 85% yield; 85% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 minutes, t (by-product) = 39 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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) δ 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example 40

1.0 mmol of aldimine (3a) and 1.0 mmol of KSO ₂ Ph were dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of a compound of Formula 1 (wherein R is I and n is 2) as a catalyst and cyanide. 1.05 equiv of potassium was added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2a, 55% yield; 89% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 minutes, t (by-product) = 39 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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) δ 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., followed by addition of 10 mol% of a compound of Formula 1 (wherein R is I and n is 2) as a catalyst and cyanide. 1.05 equiv of hydrogen was added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to afford α-aminonitrile (2a, 63% yield; 99% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 minutes, t (by-product) = 39 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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) δ 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example 42

1.0 mmol of α-amido sulfone (1a) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of a compound of formula 1 (wherein R is Cl and n is 2) as a catalyst and 1.05 equivalents of potassium cyanide It was added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2a, 91% yield; 38% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 minutes, t (by-product) = 39 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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) δ 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example 43

1.0 mmol of α-amido sulfone (1a) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of a compound of formula 1 (wherein R is Br and n is 2) and potassium cyanide was 1.05 equivalents. It was added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to give α-aminonitrile (2a, 91% yield; 43% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 minutes, t (by-product) = 39 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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) δ 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example 44

1.0 mmol of α-amido sulfone (1a) was dissolved in 12 mL of toluene at 0 ° C., followed by addition of 10 mol% of a compound of formula 1 (wherein R is Br and n is 1) and potassium cyanide was 1.05 equivalents. It was added all at once and stirred for 60 hours. This reaction was quenched using aqueous potassium carbonate solution. The water layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (acetone / normal-nucleine / triethylamine = 1: 5: 0.025) to afford α-aminonitrile (2a, 44% yield; 9% ee, (R) -form). It was. Enantioselectivity was determined using high performance liquid chromatography (CHIRALCEL OD-H, 99: 1, hexanes: isopropyl alcohol, 0.7 mL / min, t (main product) = 33 minutes, t (by-product) = 39 minute).

¹ H NMR (300 MHz, CDCl 3) δ 1.47 (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) δ 28.13, 45.96, 81.37, 117.74, 126.79, 129.16, 133.40, 154.22

Example 45 Preparation of Chiral α-Amino Acids

Α-aminonitrile ((R) -2b) prepared in Example 3 was dissolved in 6N hydrochloric acid at 90 ° C. and stirred for 3 hours. After the reaction was completed, the temperature was lowered to room temperature, extracted three times with diethyl ether, and the water layer was concentrated. Chiral α-amino acid salt ((R) -3b, 75% yield) was obtained. Enantioselectivity was measured using a polarimeter and high performance liquid chromatography ([α] D ²⁰ = -84.5 (c = 0.5, 1N HCl). (ChiroSil RCA-51002546, 250 * 4.6 mm (5 μm), aqueous 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, D 2 O): δ 3.84 (s, 3H); 5.05 (s, 1 H), 7.05-7.12 (m, 3 H); 7.43 (d, J = 7.5 Hz, 1H)

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

Claims (25)

A method comprising the steps of using a cyanide source in the presence of a catalyst represented by the formula (1) or formula (2) Wherein said cyanide source is (i) an alkali metal cyanide; (ii) alkali metal cyanide and alkali metal salts of sulfinic acids represented by formula (6); And (iii) an alkali metal cyanide and a sulfonic acid represented by the formula (7). [Formula 1]

[Formula 2]

In Chemical Formulas 1 and 2, R is halogen and n is 1-5. [Formula 6]

In Chemical Formula 6, M is an alkali metal, and Ar ₁ is a C _6-12 aryl group. [Formula 7]

In Formula 7, Ar ₂ is a C _6-12 aryl group. The method of claim 1, In Chemical Formula 1 or Chemical Formula 2, R is Br or I, and n is 2 or 3, wherein the chiral α-aminonitrile is produced. In the presence of a catalyst represented by the following formula (1) or (2), comprising a step of the striker reacting the imine of formula (3) or α- amido sulfone of formula (4) with a cyanide source in an organic solvent Wherein said cyanide source is (i) an alkali metal cyanide; (ii) alkali metal cyanide and alkali metal salts of sulfinic acids represented by formula (6); And (iii) an alkali metal cyanide and one selected from the group consisting of sulfinic acid represented by the formula (7). [Formula 1]

[Formula 2]

In Chemical Formulas 1 and 2, R is halogen and n is 1-5. [Formula 3]

[Formula 4]

[Formula 5]

In Chemical Formulas 3, 4, and 5, R ³ is selected from the group consisting of C _1-30 alkyl group, C _3-30 cycloalkyl group, C _6-30 aryl group, and C _4-30 heteroaryl group, wherein the alkyl group, cycloalkyl group , Aryl group and heteroaryl group are 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. [Formula 6]

In Chemical Formula 6, M is an alkali metal, and Ar ₁ is a C _6-12 aryl group. [Formula 7]

In Formula 7, Ar ₂ is a C _6-12 aryl group. The method of claim 3, In Chemical Formula 1 or Chemical Formula 2, R is Cl, Br or I, and n is 1 to 4, wherein the chiral α-aminonitrile is produced. The method of claim 3, In Chemical Formula 1 or Chemical Formula 2, R is Br or I, and n is 2 or 3, wherein the chiral α-aminonitrile is produced. The method of claim 3, In Chemical Formula 1 or Chemical Formula 2, R is I and n is 2 or 3, wherein the chiral α-aminonitrile is produced. The method of claim 3, In Chemical Formula 1 or Chemical Formula 2, R is I and n is 2, wherein the chiral α-aminonitrile is produced. The method of claim 3, In Chemical Formulas 3, 4, and 5, P is a methyloxycarbonyl group, benzyloxycarbonyl group, p-methoxybenzyloxy carbonyl group, t-butyloxycarbonyl group (BOC), and 9-fluorenylmethyloxycarbonyl group (FMOC) A method for producing chiral α-aminonitrile, characterized in that it is selected from the group. The method of claim 3, The alkali metal cyanide is potassium cyanide or sodium cyanide. The method for producing chiral α-aminonitrile. The method of claim 9, The alkali metal cyanide is potassium cyanide, the method for producing chiral α-aminonitrile. The method of claim 3, A method for producing chiral α-aminonitrile, wherein the organic solvent is an aprotic solvent. The method of claim 3, The organic solvent is methyl t-butyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, dichloroethane, carbon tetrachloride, benzene, toluene, methylcyclohexane and mixtures thereof A process for producing chiral α-aminonitrile, characterized in that. The method of claim 3, The organic solvent is dichloromethane, dichloroethane, benzene, toluene and a mixture thereof. The method for producing chiral α-aminonitrile. The method of claim 3, A process for producing chiral α-aminonitrile, wherein the organic solvent is toluene. The method of claim 3, In Chemical Formula 6, M is potassium, and Ar ₁ is phenyl or tolyl, wherein the chiral α-aminonitrile is produced. The method of claim 3, In Formula 7, Ar ₂ is a method for producing chiral α-aminonitrile, characterized in that phenyl or tolyl. The method of claim 3, The catalyst represented by the formula (1) or (2) is a method for producing a chiral α-aminonitrile, characterized in that it is used in an amount of 1 to 30 mol% based on the imine of formula (3) or α-amido sulfone of formula (4) . The method of claim 3, Wherein said cyanide source is used in an amount of 1 to 50 equivalents based on the imine of formula (3) or the α-amido sulfone of formula (4). The method of claim 3, Wherein said cyanide source is used in an amount of 1 to 2 equivalents based on the imine of formula (3) or the α-amido sulfone of formula (4). A chiral α-aminonitrile prepared according to any one of claims 1 to 19. A method for producing a chiral α-amino acid by hydrolyzing a chiral α-aminonitrile of claim 20 with an acid. A chiral α-amino acid prepared according to the method of claim 21. Catalyst for a striker reaction selected from the following table.

In the formula of the above table, R is halogen. The method of claim 23, wherein In the above formula, R is a catalyst for a striker reaction, characterized in that Br or I. The method of claim 23, wherein In the above formula, R is I for a catalyst for a striker reaction, characterized in that.