Stereospecific cyanation reaction using copper catalyst

Abstract

To provide a method for synthesizing a cyanide that is a precursor to a β-amino acid derivative having bulky optical activity, intended for peptide synthesis including a β-amino acid having bulky optical activity.SOLUTION: The present invention provides a method for synthesizing a cyanation product having a bulky tertiary alkylated structure and having optical activity, by reacting an α-haloamide having a bulky tertiary alkylated structure and having optical activity with a cyanohydrin in the presence of a copper catalyst.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a copper-catalyzed stereospecific cyanation reaction, and to a cyanated product and a β-amino acid derivative synthesized by the copper-catalyzed stereospecific cyanation reaction. [Background technology]

[0002] Derivatives of β-amino acids, which have a distance between the amino group and the carbonyl group that is one carbon atom longer than that of α-amino acids, are organic compounds used as raw materials for the synthesis of fine chemicals such as pharmaceuticals, and the development of efficient synthetic methods for them is required to promote the development of pharmaceuticals, etc. In particular, the development of efficient synthetic methods for optically active β-amino acid derivatives is required.

[0003] Various transition metals and chiral ligands have been used to synthesize optically inactive β-amino acid derivatives. The most frequently used synthetic methods are catalytic asymmetric hydrogenation, the Mannich reaction, and the conjugate addition of carbon and nitrogen nucleophiles to alkenes. Meanwhile, it has been reported that optically active β-amino acid derivatives can be synthesized by asymmetric reduction of enamide esters or the Mannich reaction, but bulky β-amino acid derivatives have not been synthesized by these reactions (Non-Patent Documents 1 and 2).

[0004] Cyanides are precursors of β-amino acid derivatives, and examples of the synthesis of bulky cyanides that serve as precursors of bulky β-amino acid derivatives include those that use zinc cyanide and a copper catalyst, but these examples do not yield bulky cyanides with optical activity (Non-Patent Document 3). As described above, due to steric hindrance at the reaction site, the synthesis of cyanides, which are precursors of bulky, optically active β-amino acid derivatives, has not been reported to date, and there has been a strong demand for the development of new synthetic methods. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] WDLubell, M.Kitamura and R.Noyori, Tetrahedron: Asymmetry, 1991, 2, 543 [Non-patent document 2] Y.Hashimoto, N.Sasamoto, D.Hotta, H.Somei, N.Umebayashi and M.Sodeoka, Angew. Chem., Int. Ed., 2005, 44, 1525 [Non-patent document 3] N.Miwa, C.Tanaka, S.Ishida,G.Hirata, J.Song, T.Torigoe, Y.Kuninobu, T.Nishikata, J. Am. Chem. Soc., 2020,142, 1692-1697 Summary of the Invention [Problem to be solved by the invention]

[0006] In view of the above circumstances, an objective of the present invention is to provide a method for synthesizing a cyanide compound that serves as a precursor of a bulky, optically active β-amino acid derivative for synthesizing a peptide containing a bulky, optically active β-amino acid. [Means for solving the problem]

[0007] The present inventors have conducted extensive research to solve the above-mentioned problems, and have discovered the stereospecificity of the reaction, in which an active copper cyanide species specifically coordinates to the carbonyl of a bulky, optically active α-halogen amide, thereby controlling the directionality of the reaction and giving a bulky, optically active cyanation product. Based on this discovery, the present invention has been completed.

[0008] That is, the present invention relates to the following. [1] A method for synthesizing a cyanation product having a bulky tertiary alkylated structure and optically active by reacting an α-halogen amide having a bulky tertiary alkylated structure and optically active with a cyanohydrin in the presence of a copper catalyst. [2] A method for synthesizing a β-amino acid derivative by further reducing the cyanated product having a bulky tertiary alkylated structure and optical activity in the synthesis method of [1]. [3] A cyanation product represented by the following formula: [ka] [4] A β-amino acid derivative represented by the following formula: [ka] [Effects of the Invention]

[0009] According to the method for synthesizing a cyanation product of the present invention, a stereospecific cyano reaction proceeds in which the optical purity of the substrate α-halogen amide is maintained almost unchanged, and a bulky, optically active cyanation product can be synthesized. Furthermore, according to the method for synthesizing a β-amino acid derivative of the present invention, a bulky, optically active β-amino acid derivative can be synthesized by reducing the bulky, optically active cyanation product obtained by the method for synthesizing a cyanation product of the present invention, and therefore the bulky, optically active β-amino acid can be used in peptide synthesis. DETAILED DESCRIPTION OF THE INVENTION

[0010] In the method for synthesizing a cyanation product of the present invention, the α-halogen amide having a bulky tertiary alkylated structure and optical activity, which is used as a substrate, is not particularly limited, and examples thereof include 2-bromo-2-ethyl-N-phenylhexanamide, 2-bromo-N-(2,6-diisopropylphenyl)-2-ethylhexanamide, 2-bromo-N-(2,6-diisopropylphenyl)-2-methylheptanamide, 2-bromo-N-(2,6-diisopropylphenyl)-2-methylpentanamide, and 2-chloro-2-(4-chlorophenyl)-3-methyl-N-phenylbutanamide.

[0011] In the method for synthesizing a cyanation product of the present invention, the cyanohydrin to be reacted with the substrate is not particularly limited, but examples thereof include acetone cyanohydrin, mandelonitrile, and 2-hydroxypropanenitrile, and acetonenitrile is preferred. The amount used in the reaction is about 1.2 equivalents per equivalent of the substrate.

[0012] The copper catalyst used in the method for synthesizing the cyanation product of the present invention is not particularly limited, but the yield can be increased by using copper thiophene-2-carboxylate (1), copper bromide dimethyl sulfide complex, etc.

[0013] In the synthesis method of the cyanation product of the present invention, an electrolyte such as tetrabutylammonium hexafluorophosphate can be present in an amount of about 2.0 equivalents per equivalent of substrate, and a base catalyst such as cesium carbonate can be present in an amount of about 1.5 equivalents per equivalent of substrate.

[0014] The synthesis method of the cyanation product of the present invention can be carried out in an organic solvent. The organic solvent is not particularly limited, but examples thereof include acetonitrile. Furthermore, the synthesis method of the present invention can be carried out under mild temperature conditions, such as room temperature, and the reaction time can be appropriately set within a range of several hours to approximately 24 hours.

[0015] According to the method for synthesizing a cyanation product of the present invention, a cyanation product represented by the following formula can be synthesized. [ka] The cyanation product obtained by the method for synthesizing a cyanation product of the present invention can be suitably used as a precursor of a β-amino acid derivative.

[0016] Furthermore, the method for synthesizing a β-amino acid derivative of the present invention further reduces the cyanated product obtained by the method for synthesizing a cyanated product of the present invention, and the reduction conditions are not particularly limited, and conditions typically used for reducing cyanated products can be applied. In the following examples, the cyanated product obtained by the method for synthesizing a cyanated product of the present invention was reduced in methanol with cobalt chloride, sodium borohydride, and di-tert-butyl dicarbonate by stirring in an ice bath for 30 minutes and then at room temperature for 3.5 hours.

[0017] The method for synthesizing a β-amino acid derivative of the present invention can synthesize a β-amino acid derivative represented by the following formula: [ka] The β-amino acid derivatives obtained by the method for synthesizing β-amino acid derivatives of the present invention can be suitably used as raw materials for synthesizing pharmaceuticals and agricultural chemicals. [Example]

[0018] The present invention will be described in more detail below using examples, but the present invention is not limited to these examples in any way. [Example 1]

[0019] 2-Cyano-2-ethyl-N-phenylhexanamide was synthesized according to the following reaction scheme. [ka] In a 5 mL screw cap vial containing a stir bar, 2-bromo-2-ethyl-N-phenylhexanamide (74.5 mg, 0.25 mmol), acetone cyanohydrin (25.3 mg, 0.3 mmol), and copper(I) 2-thiophenecarboxylate (14.5 mg, 7.5 × 10 -2 The mixture was charged with cesium carbonate (CsCO (122.6 mg, 0.38 mmol)), tetrabutylammonium hexafluorophosphate (193.9 mg, 0.5 mmol), and acetonitrile (MeCN (0.25 mL, 1.0 M)). The vial was filled with nitrogen, capped, and stirred at room temperature for 24 hours. After the reaction, the mixture was filtered through silica gel and purified by flash column chromatography (Hex:AcOEt = 20:1) to give compound 3 (2-cyano-2-ethyl-N-phenylhexanamide) in 87% yield (53.4 mg, 0.22 mmol) with 99% elution. IR;3310, 3144,2958, 2931, 2872, 2241, 1660, 1601, 1540, 1500, 1441, 1381, 1312, 1251, 1161,1067, 1032, 917, 864, 808, 759, 691 1H NMR (CDCl3); 8.00 (brs, 1H),7.55 (d. J = 7.8 Hz, 2H), 7.37 (t, J = 7.8 Hz, 2H), 7.19 (t, J = 7.4 Hz, 1H), 2.13-2.01 (m, 2H),1.88-1.74 (m, 2H), 1.61-1.51 (m, 1H), 1.42-1.33 (m, 3H), 1.11 (t, J = 7.4 Hz, 3H), 0.91 (t, J = 7.0 Hz, 3H) 13 C NMR(CDCl3); 136.6, 129.2, 125.5, 121.2, 120.6, 51.8, 37.2, 31.2, 27.8,22.5, 13.8, 9.9 [Example 2]

[0020] 2-cyano-N-(2,6-diisopropylphenyl)-2-ethylhexanamide represented by the following formula was synthesized by the same reaction as in Example 1, except that the copper catalyst was changed to copper bromide dimethyl sulfide complex. [ka] In a 5 mL screw vial containing a stir bar, 2-bromo-N-(2,6-diisopropylphenyl)-2-ethylhexanamide (95.4 mg, 0.25 mmol), acetone cyanohydrin (25.5 mg, 0.3 mmol), and copper bromide dimethyl sulfide complex (CuBr SMe (15.4 mg, 7.5 × 10 -2The reaction mixture was charged with 122.3 mg (0.38 mmol), cesium carbonate (CsCO (122.3 mg, 0.38 mmol)), tetrabutylammonium hexafluorophosphate (193.4 mg, 0.5 mmol), and acetonitrile (MeCN (0.25 mL, 1.0 M)). The vial was filled with nitrogen, capped, and stirred at room temperature for 24 hours. After the reaction, the mixture was filtered through silica gel and purified by flash column chromatography to give 2-cyano-N-(2,6-diisopropylphenyl)-2-ethylhexanamide in 67% yield (55.0 mg) with 95% elution yield. IR;3294, 2960,2868, 2292, 1648, 1590, 1508, 1465, 1380, 1332, 1269, 1269, 1220, 1160, 1102,1057, 794, 733 1 H NMR (CDCl3); 7.63 (s, 1H), 7.33(t, J = 7.8 Hz, 1H), 7.20 (d, J = 7.8 Hz, 2H), 3.07 (sept, J = 6.8 Hz, 2H), 2.17-2.02 (m, 2H),1.92-1.78 (m, 2H), 1.68-1.60 (m, 1H), 1.55-1.34 (m, 3H), 1.23 (d, J = 7.4 Hz, 12H), 1.19 (t, J = 8.0 Hz, 3H), 0.95 (t, J = 8.0 Hz, 3H) 13 C NMR(CDCl3); 167.1, 146.0, 130.2, 128.9, 123.7, 121.6, 51.2, 36.8, 30.8,28.8, 27.9, 23.8, 22.6, 14.0, 10.0 [Example 3]

[0021] By the same reaction as in Example 2, 2-cyano-N-(2,6-diisopropylphenyl)-2-methylheptanamide represented by the following formula was synthesized. [ka] In a 5 mL screw vial containing a stir bar, 2-bromo-N-(2,6-diisopropylphenyl)-2-methylheptanamide (95.6 mg, 0.25 mmol), acetone cyanohydrin (25.4 mg, 0.3 mmol), and copper bromide dimethyl sulfide complex (CuBr SMe (15.7 mg, 7.5 × 10 -2 The reaction mixture was charged with 122.4 mg (0.38 mmol), cesium carbonate (CsCO (122.4 mg, 0.38 mmol)), tetrabutylammonium hexafluorophosphate (193.5 mg, 0.5 mmol), and acetonitrile (MeCN (0.25 mL, 1.0 M)). The vial was filled with nitrogen, capped, and stirred at room temperature for 24 hours. After the reaction, the mixture was filtered through silica gel and purified by flash column chromatography to give 2-cyano-N-(2,6-diisopropylphenyl)-2-methylheptanamide in 73% yield (60.2 mg) with 99% elution yield. IR;3256, 2961,2929, 2865, 1654, 1592, 1507, 1458, 1382, 1332, 1279, 1139, 1103, 1059, 943,800, 734 1 H NMR (CDCl3); 7.61 (s, 1H), 7.33(t, J = 7.4 Hz, 1H), 7.20 (d, J = 8.1 Hz, 2H), 3.03 (sept, J = 6.8 Hz, 2H), 2.14-2.08 (m, 1H),1.79-1.72 (m, 1H), 1.69 (s, 3H), 1.66-1.60 (m, 1H), 1.56-1.46 (m, 1H),1.42-1.29 (m,4H), 1.22 (dd, J = 1.5,5.1 Hz, 12H), 0.92 (t, J = 6.8 Hz,3H) 13C NMR(CDCl3); 167.6, 146.1, 130.1, 129.0, 123.7, 122.4, 44.7, 37.9, 31.4,28.9, 25.5, 24.4, 23.7, 22.5, 13.9 [Example 4]

[0022] By the same reaction as in Example 2, 2-cyano-N-(2,6-diisopropylphenyl)-2-methylpentanamide represented by the following formula was synthesized. [ka] 2-bromo-N-(2,6-diisopropylphenyl)-2-methylpentanamide (89.2 mg, 0.25 mmol), acetone cyanohydrin (25.2 mg, 0.3 mmol), and copper bromide dimethyl sulfide complex (CuBr SMe) (15.5 mg, 7.5 × 10 -2 The reaction mixture was charged with 122.2 mg (0.38 mmol), cesium carbonate (CsCO (122.2 mg, 0.38 mmol)), tetrabutylammonium hexafluorophosphate (193.6 mg, 0.5 mmol), and acetonitrile (MeCN (0.25 mL, 1.0 M)). The vial was filled with nitrogen, capped, and stirred at room temperature for 24 hours. After the reaction, the mixture was filtered through silica gel and purified by flash column chromatography to give 2-cyano-N-(2,6-diisopropylphenyl)-2-methylpentanamide in 83% yield (62.6 mg) with 99% elution yield. IR;3291, 2963,2868, 2243, 1648, 1590, 1508, 1464, 1382, 1331, 1256, 1238, 1199, 1156, 1108,1057, 908, 799, 733 1H NMR (CDCl3); 7.61 (s, 1H), 7.33(t, J = 7.3 Hz, 1H), 7.20 (d, J = 7.9 Hz, 2H), 3.02 (sept, J = 6.9 Hz, 2H), 2.12-2.08 (m, 1H),1.78-1.72 (m, 1H), 1.69 (s, 3H), 1.67-1.61 (m, 1H), 1.58-1.48 (m, 1H), 1.22(dd, J = 3.4, 3.4 Hz, 12H), 1.03 (t, J = 7.1 Hz, 3H) 13 C NMR(CDCl3); 167.6, 146.1, 130.1, 129.0, 123.7, 122.3, 44.6, 39.8, 28.9,24.4, 23.7, 23.6, 19.1, 13.9 [α] 25 D = -1.95050 (c 0.101, CH2Cl2) [Example 5]

[0023] By the same reaction as in Example 2, 2-(4-chlorophenyl)-2-cyano-3-methyl-N-phenylbutanamide represented by the following formula was synthesized. [ka] In a 5 mL screw vial containing a stir bar, 2-chloro-2-(4-chlorophenyl)-3-methyl-N-phenylbutanamide (80.6 mg, 0.25 mmol), acetone cyanohydrin (25.1 mg, 0.3 mmol), and copper bromide dimethyl sulfide complex (CuBr SMe (15.7 mg, 7.5 × 10 -2The reaction mixture was charged with cesium carbonate (CsCO (122.0 mg, 0.38 mmol)), tetrabutylammonium hexafluorophosphate (193.3 mg, 0.5 mmol), and acetonitrile (MeCN (0.25 mL, 1.0 M)). The vial was filled with nitrogen, capped, and stirred at room temperature for 24 hours. After the reaction, the mixture was filtered through silica gel and purified by flash column chromatography to give 2-(4-chlorophenyl)-2-cyano-3-methyl-N-phenylbutanamide in 75% yield (58.6 mg) with 93% ES. IR;3339, 3059,2971, 2930, 2874, 2244, 1686, 1600, 1533, 1487, 1440, 1403, 1310, 1246, 1204,1147, 1095, 1012, 931, 903, 865, 839, 820, 777, 751, 688 1 H NMR (CDCl3); 8.01 (s, 1H), 7.65(d, J = 9.1 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.33 (t, J = 7.7 Hz, 2H), 7.16 (t, J = 7.3 Hz, 1H), 2.94 (sept, J = 6.7 Hz, 1H), 1.28 (d, J = 6.3 Hz, 3H), 0.83 (d, J = 7.0Hz, 3H) 13 C NMR(CDCl3); 167.6, 146.1, 130.1, 129.0, 123.7, 122.4, 44.7, 37.9, 31.4,28.9, 25.5, 24.4, 23.6, 22.5, 13.9 [α] 25 D = +66.61458 (c 0.192, CH2Cl2) [Example 6]

[0024] According to the following reaction scheme, the corresponding β-amino acid derivative was synthesized by reducing 2-cyano-2-ethyl-N-phenylhexanamide obtained in Example 1. [ka] A 5 mL screw cap vial containing a stir bar was charged with 2-cyano-2-ethyl-N-phenylhexanamide (48.9 mg, 0.20 mmol), cobalt(II) chloride (CoCl2 (51.6 mg, 0.40 mmol), sodium borohydride (NaBH4 (30.4 mg, 0.80 mmol)), di-tert-butyl dicarbonate (Boc2O (0.12 mL, 0.40 mmol)), and methanol (MeOH (1.0 mL, 0.2 M)). The mixture was capped and stirred in an ice bath for 30 min, then at room temperature for 3.5 h. The reaction mixture was quenched with 1 M aqueous sodium hydroxide (NaOH) and extracted with ethyl acetate. After filtration through magnesium sulfate (MgSO4), the product was purified by flash column chromatography to give the product in 69% yield (48.0 mg) with a 99% elution yield. 1 H NMR (CDCl3); 8.06 (s, 1H), 7.56(d, J = 7.9 Hz, 2H), 7.30 (t, J = 7.4 Hz, 2H), 7.09 (t, J = 7.4 Hz, 1H), 5.01 (s, 1H), 3.46-3.38(m, 2H), 1.75-1.54 (m, 4H), 1.41 (s, 9H),1.35-1.25 (m, 4H), 0.93 (t, J = 7.7 Hz, 3H), 0.89 (t, J = 6.9 Hz, 3H) [Industrial Applicability]

[0025] The obtained cyanation product, which can synthesize bulky optically active β-amino acid derivatives, will facilitate the synthesis of peptides containing bulky optically active β-amino acid derivatives, and is expected to be applied to the development of new pharmaceuticals, agricultural chemicals, or electronic materials.

Claims

1. A method for synthesizing a cyanation product having a bulky tertiary alkylated structure and optically active by reacting an α-halogen amide having a bulky tertiary alkylated structure and optically active with a cyanohydrin in the presence of a copper catalyst.

2. 2. A method for synthesizing a β-amino acid derivative according to claim 1, wherein the cyanated product has a bulky tertiary alkylated structure and is optically active, and is further reduced.

3. A cyanation product represented by the following formula: 【Chemical 1】

4. A β-amino acid derivative represented by the following formula: 【Chemistry 2】

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