JP2015051955A - Optically active asymmetric bisindole compound and method for manufacturing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To establish a methodology for synthesizing an optically active asymmetric bisindole compound.SOLUTION: The provided optically active asymmetric bisindole compound is expressed by the following formula (2): (where Rand Rare mutually independent and express H, halogen, alkyl group, or alkoxy group; a plurality of Rand Rmay, furthermore, be coupled at any position on the benzene ring of an indole or oxyindole skeleton; moreover, Ris an ester group; Ris H, Me, Et, Bn, Boc, MOM, MEM, SEM, or Alloc).

Description

  The present invention relates to an optically active asymmetric bisindole compound and a method for producing the same.

  A biopolymer having an optically active amino acid or sugar as a basic structural unit constructs a highly asymmetric space, and a drug using the biopolymer as a receptor needs to have optical activity. Such a method for synthesizing an optically active substance is called an asymmetric synthesis method. Among the asymmetric synthesis methods, a catalytically capable of synthesizing a theoretically infinite optically active substance from a small amount of an asymmetric source. Asymmetric synthesis methods are extremely useful and important.

  The optically active asymmetric bisindole compound has been achieved by catalytic asymmetric synthesis by using various chiral catalysts. For example, in the presence of a chiral palladium catalyst as a conventional technique, 3'-indolyl-3-oxindole and An example using allene is described in Non-Patent Document 1 below, and an example using pyrrole or indole and isatin in the presence of an indium catalyst is described in Non-Patent Document 2 below.

Trost, B.M. M.M. Xie, J .; Sieber, J .; D. J. et al. Am. Chem. Soc. 2011, 133, 20611. Gutierreaz, E .; G. Wong, C .; J. et al. Sahin, A .; H. Franz, A .; K. Org. Lett. 2011, 13, 5754

  However, in any of the documents described above, there is no example in which an asymmetric 1,4-addition reaction using nitroethylene and 3′-indolyl-3-oxindole is applied to a catalytic asymmetric synthesis method. Development of a new reaction system is desired for the supply of an optically active asymmetric bisindole compound having the above.

  In view of the above problems, the present invention provides an asymmetric 1,4-addition reaction of 3′-indolyl-3-oxindole and nitroethylene by a metal catalyst, and an optically active asymmetric bisindole compound obtained thereby. The purpose is to do.

  The inventors of the present invention have been diligently studying the above problem, and reacting a 3′-indolyl-3-oxindole compound with nitroelene in the presence of a catalyst in which an imidazoline ligand is coordinated to a metal. Thus, it was discovered that an optically active asymmetric bisindole compound can be obtained, and the present invention has been completed.

That is, in the method for producing an optically active asymmetric bisindole compound according to one means of the present invention, a 3′-indolyl-3-oxindole compound and nitroelene are reacted in the presence of a catalyst represented by the following formula (1). .
(Here, X is a bromo group or a nitro group.)

As a result, an optically active asymmetric bisindole compound represented by the following formula (2) can be obtained.
(Wherein R ¹ and R ³ are each independently H, halogen, an alkyl group, or an alkoxy group. R ¹ and R ³ may be any one on the benzene ring of the indole or oxindole skeleton) (A plurality may be bonded to the position, R ² is an ester group, and R ⁴ is H, Me, Et, Bn, Boc, MOM, MEM, SEM, or Alloc.)

  As described above, according to the present invention, it is possible to provide 1,4-addition reaction of 3′-indolyl-3-oxindole and nitroethylene and the optically active asymmetric bisindole compound obtained thereby, and the optically active asymmetric bisindole obtained is obtained. The diversity of indole compounds can be expanded. Also, according to the present invention, a very high yield can be obtained.

  Embodiments of the present invention will be described below with reference to the drawings. However, the present invention can be implemented in many different modes and is not limited to the embodiments shown below.

(Embodiment 1)
In the method for producing an optically active asymmetric bisindole compound according to this embodiment, 3′-indolyl-3-oxindole and nitroethylene are reacted in the presence of a catalyst represented by the following formula (1).
(Here, X is a bromo group or a nitro group.)

  Since the ligand in the catalyst used in the present embodiment has an imidazoline skeleton and a phenyl skeleton bridged with nitrogen in its structure, the reaction field is wide.

Moreover, as long as it can coordinate, the metal which coordinates a ligand is not necessarily limited to this, For example, copper, nickel, cobalt, ruthenium, rhodium, or iron can be illustrated. Moreover, as a method of coordinating a ligand to a metal, a well-known method can be adopted, and although not limited, it can be coordinated by mixing a metal salt and a ligand. The metal salt is not limited, but when the metal is nickel, Ni (OAc) ₂ , NiI ₂ , Ni (OTf) ₂ , Ni (ClO ₄ ) ₂ or the like can be used.

The catalyst according to this embodiment can be used to perform an asymmetric 1,4-addition reaction using 3′-indolyl-3-oxindole. Specifically, in the presence of the catalyst according to this embodiment, an optically active asymmetric bisindole compound is synthesized by reacting 3′-indolyl-3-oxindole and nitroethylene as shown by the following formula. can do.

  The above reaction is preferably performed in a nonpolar solvent, particularly ortho-xylene.

In the above reaction, an alkene having 3′-indolyl-3-oxindole used as a reaction substrate is represented by the following formula (3). Here, R ¹ and R ³ are not limited, and for example, H, halogen, an alkyl group, and an alkoxy group can be used. In addition, R ¹ and R ³ may be bonded at any position as long as they are on the benzene ring of the indole or oxindole skeleton. R ² is an ester group, and R ⁴ can be H, Me, Et, Bn, Boc, MOM, MEM, SEM, or Alloc. In the above reaction, the amount of nitroethylene used is preferably in the range of 1.0 mol or more and 5.0 mol or less, more preferably 3 mol when 3′-indolyl-3-oxindole is 1 mol. It is in the range of 1.2 mol or more and 2.2 mol or less.
(Wherein R ¹ and R ³ are each independently H, halogen, an alkyl group, or an alkoxy group. R ¹ and R ³ may be any one on the benzene ring of the indole or oxindole skeleton) (A plurality may be bonded to the position, R ² is an ester group, and R ⁴ is H, Me, Et, Bn, Boc, MOM, MEM, SEM, or Alloc.)

As a result, according to the method according to the present embodiment, an optically active asymmetric bisindole compound represented by the following formula (2) can be obtained.
(Wherein R ¹ and R ³ are each independently H, halogen, an alkyl group, or an alkoxy group. R ¹ and R ³ may be any one on the benzene ring of the indole or oxindole skeleton) (A plurality may be bonded to the position, R ² is an ester group, and R ⁴ is H, Me, Et, Bn, Boc, MOM, MEM, SEM, or Alloc.)

(Synthesis of ligand)
In addition, the ligand and the catalyst according to this embodiment are not limited as long as they can be synthesized, but can be synthesized by the technique described in, for example, Japanese Patent Application Laid-Open No. 2008-044928.

  Then, 0.0128 g of the obtained ligand was used when X was a bromo group, and nickel (II) acetate was coordinated thereto to carry out an asymmetric 1,4 addition reaction as a catalyst.

Example 1
In this example, tert-butyl 3- (1-methyl-1H-indol-3-yl) -2-oxindolin-1-carboxylate 0.0544 mg at −20 ° C. in the presence of the above catalyst (5 mol%). 1,1,1,3,3,3-Hexafluoro-2-propanol 32 μl was dissolved in 1.5 ml of orthoxylene, and 73 mg of a nitroethylene 30 w / w% toluene solution was dissolved in 0.5 ml of orthoxylene. The solution was slowly added dropwise over 5 hours and then stirred for 20 hours. As a result, 0.063 g of the compound (2-1) shown below could be obtained. The yield of (2-1) was 95% (90% ee).

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.00 (d, J = 8.3 Hz, 1H), 7.44-7.40 (m, 1H), 7.32-7.18 (m, 5H), 7.04-7.01 (m, 1H), 6.86 (s, 1H), 4.43-4.37 (m, 1H), 4.27-4.21 (m, 1H), 3. 72 (s, 3H), 3.36-3.30 (m, 1H), 3.05-2.99 (m, 1H), 1.62 (s, 9H);
¹³ C NMR (100 MHz, CDCl ₃ ) δ 175.3, 149.1, 139.4, 137.6, 129.3 (2C), 127.8, 125.3, 125.0, 124.2, 122. 2, 1204, 119.8, 115.6, 111.8, 109.7, 84.7, 71.3, 50.8, 33.6, 32.9, 28.0;
_{HRMS calcd for C 24 H 25 N} 3 O 5 Na (M + Na) +: 458.1686, found: m / z 458.1680;
Enantiomeric excess was determined by HPLC with a Chiralpack IC-3 column (80:20 hexane: 2-propanol, 1.0 mL / min, 254nm); major enantiomer t r = 13.9, minor enantiomer t r = 17.2 min;
[Α] _D ²¹ = −140.1 (c = 1.0, CHCl ₃ , 90% ee);
IR (neat) 2980, 1764, 1727, 1552, 1287, 1249, 1146, 738 cm ⁻¹ .

(Example 2)
In this example, tert-butyl 5-methyl-3- (1-methyl-1H-indol-3-yl) -2-oxindolin-1-carboxylate was present at −20 ° C. in the presence of the above catalyst (5 mol%). 0.0589 mg, 1,1,1,3,3,3-Hexafluoro-2-propanol 32 μl was dissolved in 1.5 ml of orthoxylene, and 73 mg of nitroethylene 30 w / w% toluene solution was dissolved in 0.5 ml of orthoxylene. The dissolved solution was slowly dropped over 5 hours and then stirred for 20 hours. As a result, 0.066 g of the compound (2-2) shown below could be obtained. The yield of (2-2) was 94% (93% ee).

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.92 (d, J = 9.2 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 8.3 Hz) , 1H), 7.21-7.18 (m, 1H), 7.03-7.00 (m, 1H), 6.94-6.90 (m, 2H), 6.82 (d, J = 2.6 Hz, 1H) 4.42-4.36 (m, 1H), 4.25-4.20 (m, 1H), 3.76 (s, 3H), 3.71 (s, 3H) 3.56-3.30 (m, 1H), 3.02-2.96 (m, 1H), 1.61 (s, 9H);
¹³ C NMR (125 MHz, CDCl ₃ ) δ 175.4, 157.2, 149.2, 137.6, 132.7, 130.8, 127.7, 125.3, 122.1, 120.3, 119 8, 116.5, 113.9, 111.9, 110.4, 109.6, 84.6, 71.3, 55.6, 51.1, 33.6, 32.8, 28.0 ;
HRMS calcd for for C ₂₅ H ₂₇ N ₃ O ₆ Na (M + Na) ⁺ : 488.1792, found: m / z 488.1789;
Enantiomeric excess was determined by HPLC with a Chiralpack IA column (70:30 hexane: 2-propanol, 1.0mL / min, 254nm); major enantiomer t r = 5.9min, minor enantiomer t r = 13.6min;
[Α] _D ²¹ = −120.5 (c = 1.0, CHCl ₃ , 93% ee);
IR (neat) 2931, 1759, 1728, 1551, 1486, 1278, 1249, 1149, 741 cm ⁻¹ .

(Example 3)
In this example, tert-butyl 6-chloro-3- (1-methyl-1H-indol-3-yl) -2-oxindolinine-1-carboxylate is present at −20 ° C. in the presence of the above catalyst (5 mol%). 0.0595 mg, 1,1,1,3,3,3-Hexafluoro-2-propanol 32 μl was dissolved in 1.5 ml of orthoxylene, nitroethylene 30 w / w%, toluene solution 73 mg was dissolved in 0.5 ml of orthoxylene The solution dissolved in was slowly dropped over 5 hours and then stirred for 20 hours. As a result, 0.0592 g of the compound (2-3) shown below could be obtained. The yield of (2-3) was 84% (88% ee).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 (t, J = 1.1 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 8.2 Hz) , 1H), 7.24-7.19 (m, 3H), 7.07-7.03 (m, 1H), 6.84 (s, 1H), 4.43-4.35 (m, 1H) ), 4.28-4.22 (m, 1H), 3.72 (s, 3H), 3.35-3.27 (m, 1H), 3.04-2.96 (m, 1H), 1.62 (s, 9H);
¹³ C NMR (100 MHz, CDCl ₃ ) δ 174.8, 148.9, 140.3, 137.7, 135.0, 127.8, 127.7, 125.2, 125.0 (2C), 122. 3, 120.2, 120.0, 116.3, 111.3, 109.8, 85.4, 71.2, 50.6, 33.5, 32.9, 28.0;
HRMS calcd for for C ₂₄ H ₂₄ N ₃ O ₅ ClNa (M + Na) ⁺ : 492.1297, found: m / z 492.1292;
Enantiomeric excess was determined by HPLC with a Chiralpack IA column (85:15 hexane: 2-propanol, 1.0mL / min, 254nm); major enantiomer t r = 6.4min, minor enantiomer t r = 14.0min;
[Α] _D ²¹ = −73.4 (c = 1.0, CHCl ₃ , 88% ee);
IR (neat) 2979, 1766, 1730, 1552, 1284, 1244, 1144, 740 cm ⁻¹ .

(Example 3)
In this example, tert-butyl 3- (1,7-dimethyl-1H-indol-3-yl) -5-methyl-2-oxindoleline-1 was present at −20 ° C. in the presence of the above catalyst (5 mol%). -Carboxylate 0.0586 mg, 1,1,1,3,3,3-Hexafluoro-2-propanol 32 μl was dissolved in 1.5 ml ortho-xylene, and 73 ml of nitroethylene 30 w / w% toluene solution was dissolved in 0.5 ml. The solution dissolved in orthoxylene was slowly added dropwise over 5 hours, and then stirred for 20 hours. As a result, 0.0674 g of the compound (2-4) shown below could be obtained. The yield of (2-4) was 91% (95% ee).

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.86 (d, J = 8.6 Hz, 1H), 7.19 (dd, J = 8.3, 1.2 Hz 1H), 7.03-7.02 (m , 2H), 6.89-6.82 (m, 3H), 4.42-4.36 (m, 1H), 4.24-4.19 (m, 1H), 4.00 (s, 3H) ), 3.31-3.25 (m, 1H), 3.00-2.93 (m, 1H), 2.71 (s, 3H), 2.31 (s, 3H), 1.61 ( s, 9H);
¹³ C NMR (125 MHz, CDCl ₃ ) δ 175.5, 149.2, 136.9, 136.2, 134.8, 129.7, 129.42, 129.36, 126.4, 124.8, 124 5, 121.6, 120.0, 118.2, 115.3, 111.6, 84.6, 71.3, 50.6, 37.0, 33.6, 28.0, 21.1 , 19.8;
HRMS calcd for for C ₂₆ H ₂₉ N ₃ O ₅ Na (M + Na) ⁺ : 486.1999, found: m / z 486.1996;
Enantiomeric excess was determined by HPLC with a Chiralpack IC-3 column (80:20 hexane: 2-propanol, 1.0mL / min, 254nm); major enantiomer t r = 16.3min, minor enantiomer t r = 20.9min;
[Α] _D ²¹ = −89.3 (c = 1.0, CHCl ₃ , 95% ee);
IR (neat) 2924, 1780, 1560, 1304, 1247, 1147, 742 cm ⁻¹ .

(Example 3)
In this example, tert-butyl 3- (1H-indol-3-yl) -2-oxindolinine-1-carboxylate 0.0523 mg, 1,1, at −20 ° C. in the presence of the above catalyst (5 mol%) A solution prepared by dissolving 32 μl of 1,3,3,3-Hexafluoro-2-propanol in 1.5 ml of orthoxylene and dissolving 73 mg of nitroethylene 30 w / w% toluene solution in 0.5 ml of orthoxylene for 5 hours Over the course of 20 hours. As a result, 0.0536 g of the following compound (2-5) could be obtained. The yield of (2-5) was 88% (89% ee).

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.30 (br, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.43-7.40 (m, 1H), 7.33- 7.31 (m, 2H), 7.27-7.26 (m, 1H), 7.22-7.21 (m, 1H), 7.17-7.14 (m, 1H), 7. 04-7.00 (m, 2H), 4.44-4.38 (m, 1H), 4.27-4.21 (m, 1H), 3.36-3.30 (m, 1H), 3.06-3.00 (m, 1H), 1.63 (s, 9H);
¹³ C NMR (125 MHz, CDCl ₃ ) δ 175.4, 149.1, 139.4, 136.9, 129.4, 129.3, 125.0, 124.8, 124.2, 123.2, 122 6, 120.3 (2C), 115.6, 113.6, 111.6, 85.0, 71.4, 50.9, 33.7, 28.0;
_{HRMS calcd for for C 23 H 23} N 3 O 5 Na (M + Na) +: 444.1530, found: m / z 444.1526;
Enantiomeric excess was determined by HPLC with a Chiralpack AD-H column (90:10 hexane: 2-propanol, 1.0mL / min, 254 nm); major enantiomer t r = 22.4 min, minor enantiomer t r = 26. 1 min;
[Α] _D ²¹ = −96.6 (c = 0.5, CHCl ₃ , 89% ee);
IR (neat) 3351, 2980, 1779, 1731, 1247, 1144, 735 cm ⁻¹ .

  As described above, according to this example, it was confirmed that a useful catalyst capable of performing a 1,4-addition reaction of 3'-indolyl-oxindole could be realized.

INDUSTRIAL APPLICATION Since this invention can supply the optically active asymmetric bisindole compound which has a continuous stereocenter with very high optical purity, it is useful for development and production of a pharmaceutical and an agrochemical, and has industrial applicability.

Claims (2)

Using a catalyst in which a ligand represented by the following formula (1) is coordinated to a metal, an optically active asymmetric bisindole compound represented by the following formula (2) is converted into a 3′- represented by the following formula (3). A method of synthesis using indolyl-3-oxindole and a styrene compound.
(Here, X is a bromo group or a nitro group.)
(Wherein R ¹ and R ³ are each independently H, halogen, an alkyl group or an alkoxy group, and R ¹ and R ³ are any positions on the benzene ring of the indole or oxindole skeleton) And R ² is an ester group, and R ⁴ is H, Me, Et, Bn, Boc, MOM, MEM, SEM, or Alloc.)
(Wherein R ¹ and R ³ are each independently H, halogen, an alkyl group, or an alkoxy group. R ¹ and R ³ may be any one on the benzene ring of the indole or oxindole skeleton) (A plurality may be bonded to the position, R ² is an ester group, and R ⁴ is H, Me, Et, Bn, Boc, MOM, MEM, SEM, or Alloc.) An optically active asymmetric bisindole compound represented by the following formula (2).
(Wherein R ¹ and R ³ are each independently H, halogen, an alkyl group, or an alkoxy group. R ¹ and R ³ may be any one on the benzene ring of the indole or oxindole skeleton) (A plurality may be bonded to the position, R ² is an ester group, and R ⁴ is H, Me, Et, Bn, Boc, MOM, MEM, SEM, or Alloc.)