JP2014108942A - Bisoxazolidine ligand and catalyst using the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To establish a manufacturing method of a bisoxazolidine ligand and a catalytic reaction using the same.SOLUTION: There is provided a bisoxazolidine ligand represented by the formula (1) or (2). (1) (2), where Ris any of CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, C(CH3)3, Ph or CH2 Ph, Ris any of CH3, C2H5 or Ph, Ris any of H, CH3, Br or NO2 and Ph represents an aromatic ring.

Description

  The present invention relates to a bisoxazolidine ligand and a catalyst using 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.

  At present, catalytic asymmetric synthesis is achieved by using various metal catalysts. As an asymmetric ligand that realizes a useful catalytic asymmetric reaction, a C2 symmetric optically active bisoxazoline has been widely studied. Among them, the optically active bisoxazoline ligand described in Non-Patent Document 1 below, the optically active bisimidazoline ligand described in Non-Patent Document 2, and the optical activity described in Patent Document 1 Development of a bisimidazolidine ligand has been reported as a tridentate ligand by linking to a pyridine ring.

JP 2011-111426 A

Nishiyama, H .; Sakaguchi, H; Nalamura, T .; Horihata, M .; Kondo, M .; Itoh, K .; Organometallics 1989, 8, 846.

Bhor, S.M. Anilkumar, G .; Tse, M .; K. Klawonn, M .; Dobler, C .; Bitterlich, B .; Grotevendt, A .; Beller, M .; Org. Lett. 2005, 7, 3393.

The bisoxazoline described in Non-Patent Document 1 and the bisimidazoline described in Non-Patent Document 2 are useful for various reactions, but because of their highly planar structure, the coordination field is a simple four-coordinate configuration. It is a coordination hall. These ligands require more than three steps for synthesis. Further, in the ligands described in Non-Patent Document 2 and Patent Document 1, commercially available optically active diamines are few and expensive, and thus lack practicality.

  Therefore, in view of the above problems, the present invention aims to construct a more complex coordination field (a distorted planar four-coordination field) by changing oxazoline to oxazolidine, and is inexpensive and capable of dealing with various reactions. The purpose is to develop a ligand that realizes practical catalytic asymmetric synthesis.

  The inventors of the present invention have been diligently studying the above-mentioned problems, and from a readily available amino acid ester, succeeded in two-step synthesis by deriving from an optically active amino alcohol and then reacting with an aldehyde. The present invention has been completed.

That is, the ligand according to one aspect of the present invention is represented by the following chemical formula (1) or (2).

In the above formula, R ¹ is CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) C ₂ H ₅ , C (CH ₃ ) ₃ , Ph, CH ₂ Ph, R ² is any one of CH ₃ , C ₂ H ₅ , and Ph, and R ³ is any one of H, CH ₃ , Br, and NO ₂ . Here, Ph represents an aromatic ring.

A catalyst according to another aspect of the present invention is represented by the following chemical formula (3) or (4).

In the above formula, R ¹ is any of CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) C ₂ H ₅ , C (CH ₃ ), Ph, CH ₂ Ph. R ² is any one of CH ₃ , C ₂ H ₅ , and Ph, and R ³ is any one of H, CH ₃ , Br, and NO ₂ . Here, Ph represents an aromatic ring.

  Further, the catalyst according to the present invention is not limited, but can be suitably used for Friedel-Crafts type reaction of nitroalkene and indole.

  As described above, according to the present invention, an efficient ligand can be synthesized in two steps. To provide an optimal asymmetric coordination field according to various catalytic reactions and substrates by electronic and steric effects by changing the structure of aminoalcohol derived from various amino acids as an asymmetric source Can do. Moreover, the problem of a planar ligand can be overcome and a more complex coordination field can be constructed.

  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.

The ligand according to this embodiment is represented by the chemical formula (1) or (2). A bimolecular oxazolidine skeleton having an amino acid as a building unit can be constructed by reacting an amino alcohol derived from an amino acid with pyridine having an aldehyde group at the 2nd and 6th positions. Further, the side chain at the 4-position of the oxazolidine ring is changed to CH ₃ , CH (CH ₃ ) ₂ , CH ₂ CH (CH ₃ ) ₂ , CH (CH ₃ ) C ₂ H ₅ , by changing the amino acid as an asymmetric source. Substitution can be made with C (CH ₃ ) ₃ , Ph, CH ₂ Ph and the like. When proline is used, the ligand is represented by the chemical formula (2). As a result, coordination ability and coordination field complexity can be changed by electronic and steric effects. (Here, Ph represents an aromatic ring.)

  The ligand is amorphous at room temperature in air, and can be stored for 1 month or longer in a cool and dark place. It is soluble in many organic solvents (acetone, tetrahydrofuran, methylene chloride, chloroform, toluene, dimethylformamide, dimethyl sulfoxide, acetonitrile, dioxane, etc.), and complex formation and catalytic asymmetric reaction using these as solvents Can be used.

Moreover, the ligand which concerns on this embodiment is compoundable with the following method.

  In addition, the ligand according to this embodiment can be used as a catalyst by coordinating to a metal, and can be particularly preferably used in a Friedel-Crafts type reaction.

Moreover, as a method of coordinating the ligand according to the present embodiment to a metal, a method of reacting the target metal salt in an organic solvent using an equivalent amount of the ligand can be considered. 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 salts include, but are not limited to, when the metal is copper, it is possible to use _{CuOTf, CuCl, CuOAc,} the _{CuCl 2, Cu (OAc) 2} , Cu (OTf) 2 and the like.

  As described above, according to the present invention, it is possible to achieve synthesis of bisoxazolidine ligands that are versatile and versatile, and to provide a ligand with a high degree of freedom and a catalyst using the same.

  Here, the ligand and catalyst which concern on the said embodiment were produced, and the effect was confirmed. This is specifically shown below.

Example 1
As an example according to the above embodiment, bisoxazolidine (6) was synthesized as shown in the following formula. This will be described below.

(Experiment 1)
Synthesis of [(S) -2-amino-3-methyl-1,1-diphenylbutan-1-ol] (5):
The above (5) Org. Chem. 2009, 74, 2541-2546. Synthesized by the method described.

(Experiment 2)
Synthesis of [2,6-bis ((4S) -4-isopropyl-5,5-diphenyloxazolidin-2-yl) pyridine] (6):

  Under an argon atmosphere, 2,6-pyridylaldehyde (67 mg, 0.5 mmol) was dissolved in anhydrous methylene chloride (2 ml), the above (5) (255 mg, 1 mmol) was added, and the mixture was stirred at room temperature for 6 hours. Was confirmed by thin layer chromatography (developing solvent 3: 1 n-hexane / ethyl acetate). Thereafter, the mixture was concentrated under reduced pressure to obtain 94% yield of white amorphous (6).

Device data of (6):
¹ HNMR (400 MHz, CDCl ₃ ) δ 7.89 (t, J = 7.6 Hz, 1H) 7.59 (d, J = 7.6 Hz, 2H), 7.53 (d, J = 7.2 Hz, 4H), 7.39 (d, J = 7.8 Hz, 4H), 7.34-7.28 (m, 6H), 7.21-7.11 (m, 6H), 5.64 (s, 2H), 4.05 (d, J = 3.7 Hz, 2H), 1.99-1.93 (m, 2H), 1.19 (d, J = 6.9 Hz, 6H), 0.34 ( d, J = 6.9 Hz, 6H);
¹³ C NMR (500 MHz, CDCl ₃ ) 155.04, 146.38, 143.76, 138.10, 128.14, 127.77, 127.56, 127.47, 127.23, 126.71, 124. 56, 90.22, 87.99, 73.01, 28.60, 23.26, 16.82;
FT / IR 2956.34, 2924.52, 2854.13, 1456.96, 1377.89, 1003.77, 938.20, 813.81, 755.96, 728.96, 700.03 cm ^-1 ;
[Α] _D ²⁶ = −42.9 (c = 1.05, CHCl ₃ );
FTMS (ESI ⁺ ) calcd for C ₄₉ H ₄₅ N ₅ Na (M ⁺ + Na) 726.3567;

As described above, a ligand represented by the following structural formula (6) was obtained.

(Example 2)
The following structural formula (7) was synthesized in two steps in the same manner as in Example 1 except that R ² was a methyl group.

Device data of (7):
¹ HNMR (400 MHz, CDCl 3) 7.90 (t, J = 7.6 Hz, 1H), 7.61 (d, J = 7.6 Hz, 2H), 7.55-7.53 (m, 4H), 7.43-7.39 (m, 4H), 7.35-7.31 (m, 6H), 7.21-7.09 (m, 6H), 5.70 (s, 2H), 4. 29 (q, J = 6.6 Hz, 2H), 1.14 (d, J = 6.6 Hz, 6H);
¹³ C NMR (500 MHz, CDCl ₃ ) δ 155.33, 145.70, 143.57, 138.22, 128.19, 127.50, 127.33, 127.09, 126.68, 124.46, 90 64, 88.23, 63.73, 53.40, 18.07;
FT / IR 2952.48, 2922.59, 2853.17, 1458.89, 939.16, 700.03 cm ^-1 ;
[Α] _D ²⁶ = −82.1 (c = 1.01, CHCl ₃ );
_{FTMS (ESI +) calcd for C} 49 H 45 N 5 Na (M + + Na) 726.3567; found 726.3567.

(Example 3)
The following structural formula (8) was synthesized in two steps in the same manner as in Example 1 except that R ² was an isobutyl group.

Device data of (8):
¹ HNMR (400 MHz, CDCl ₃ ) δ 7.88 (t, J = 7.6 Hz, 1H), 7.59 (d, J = 7.6H, 2H), 7.52-7.55 (m, 4H) ), 7.41 (t, J = 7.8 Hz, 4H), 7.35-7.10 (m, 12H), 5.67 (s, 2), 4.20 (d, J = 9. 5Hz, 2H), 2.06-2.00 (m, 2H), 1.43-1.36 (m, 2H), 1.12 (d, 6H), 0.91 (d, 6H), 0 .83-0.75 (m, 2H);
¹³ C NMR (500 MHz, CDCl ₃ ) δ 155.40, 146.02, 143.95, 138.04, 128.19, 127.44, 127.37, 127.10, 126.65, 124.60, 91 .03, 87.64, 66.70, 42.46, 26.69, 24.09, 21.69;
FT / IR2922.59, 2853.17, 1451.17, 1377.89, 1992.20, 700.03 cm ⁻¹ ;
[Α] _D ²⁶ = −99.3 (c = 1.17, CHCl ₃ );
FTMS (ESI ⁺ ) calcd for C ₄₉ H ₄₅ N ₅ Na (M ⁺ + Na) 726.3567; found 726.3567.

Example 4
The following structural formula (9) was synthesized in two steps in the same manner as in Example 1 except that R ² was a sec-butyl group.

Device data of (9):
¹ HNMR (400 MHz, CDCl ₃ ) δ 7.89 (t, J = 7.4 Hz, 1H), 7.57 (d, J = 7.4 Hz, 2H), 7.52 (d, J = 7.2 Hz) , 4H), 7.39 (t, J = 7.2 Hz, 4H), 7.34-7.29 (m, 6H), 7.19-7.10 (m, 6H), 5.61 (s) , 2H), 4.08 (s, 2H), 3.77 (brs, 2H), 1.71-1.68 (m, 2H), 1.19 (d, J = 6.8 Hz, 3H), 0.81-0.77 (m, 2H), 0.69-0.64 (m, 2H), 0.47 (t, J = 7.2 Hz, 3H):
¹³ C NMR (500 MHz, CDCl ₃ ) δ 154.96, 146.56, 143.77, 138.08, 128.14, 127.65, 127.49, 127.45, 127.21, 126.59, 124 64, 90.27, 87.89, 73.20, 35.02, 23.63, 19.18, 11.61;
FT / IR 292.356 2854.13, 1459.85, 1376.93, 992.20, 700.03 cm ^-1 ;
[Α] _D ²⁶ = −37.7 (c = 1.16, CHCl ₃ );
FTMS (ESI ⁺ ) calcd for C ₄₉ H ₄₅ N ₅ Na (M ⁺ + Na) 726.3567; found 726.3567

(Example 5)
The following structural formula (2) was synthesized based on the method described above.

Device data of (2):
¹ HNMR (400 MHz, CDCl ₃ ) δ 7.94-7.88 (m, 3H), 7.59 (d, J = 7.2 Hz, 4H), 7.49 (d, J = 7.2 Hz, 4H) ), 7.35-7.17 (m, 12H), 5.59 (s, 2H), 4.59 (brs, 2H), 2.58-2.47 (m, 4H), 1.87- 1.80 (m, 2H), 1.64-1.48 (m, 4H), 1.34-1.26 (m, 2H);
¹³ C NMR (400 MHz, CDCl ₃ ) δ 156.44, 145.50, 144.01, 136.68, 128.19, 127.97, 127.23, 126.45, 126.17, 121.07, 91 .75, 88.11, 72.48, 48.84, 29.92, 25.99;
FT / IR 2925.48, 2854.13, 1462.74, 14446.35, 1377.89, 1006.66, 701.00 cm ^-1 ;
[Α] _D ²⁶ = −177.6 (c = 1.14, CHCl ₃ );
FTMS (ESI ⁺ ) calcd for C ₄₉ H ₄₅ N ₅ Na (M ⁺ + Na) 726.3567; found 726.3567.

(Example 6)
Next, the ligand obtained in this example was coordinated to a divalent copper salt to prepare a catalyst. And the effect as this catalyst was confirmed. Specifically, the copper complex using the above (6) obtained in Example 1 was adjusted and applied to catalytic asymmetric Friedel-Crafts type reaction.

(Preparation of copper complex using bisoxazolidine (6))
Under an argon atmosphere, Cu (OTf) ₂ (3.6 mg, 0.01 mmol) and bisoxazolidine (6) (0.011 mmol) were dissolved in 1 ml of anhydrous methylene chloride and stirred at room temperature for 1 hour or more. A copper complex was prepared.

(Confirmation of catalytic asymmetric Friedel-Crafts type reaction using (6) -Cu (OTf) ₂ complex)

  The copper complex was dissolved in 1 ml of anhydrous methylene chloride, trans-β-nitrostyrene (60 mg, 0.4 mmol) and indole (23 mg, 0.2 mmol) were added, and the mixture was stirred at room temperature. After 22 hours, 91% yield was obtained by silica gel chromatography (developing solvent 9: 1 n-hexane / ethyl acetate to 2: 1), and the optical purity of the obtained product was 75% ee. (Analysis conditions: DAICEL CHIRALCEL OD-H, flow rate = 0.7 ml / min, hexane: 2-propanol = 70: 30)

  From the above, the effect of this catalyst can be confirmed by this example, and it has been confirmed that a bisoxazolidine ligand linked to a novel pyridine ring having high versatility and a catalyst using the same can be obtained.

  The catalyst provided by the present invention can perform asymmetric reaction and has industrial applicability because it has sufficient stability to withstand industrialization.

Claims (3)

The ligand shown by either following formula (1) or (2).
(Wherein, ^{R 1} is _{CH 3, CH (CH 3)} 2, CH 2 CH (CH 3) 2, CH (CH 3) C 2 H 5, C (CH 3) 3, Ph, CH 2 Ph, either R ² is any one of CH ₃ , C ₂ H ₅ , and Ph, and R ³ is any one of H, CH ₃ , Br, and NO ₂ , where Ph represents an aromatic ring .) The catalyst shown by either following formula (3) or (4).
(Wherein, ^{R 1} is _{CH 3, CH (CH 3)} 2, CH 2 CH (CH 3) 2, CH (CH 3) C 2 H 5, C (CH 3) 3, Ph, CH 2 Ph, either R ² is any one of CH ₃ , C ₂ H ₅ , and Ph, and R ³ is any one of H, CH ₃ , Br, and NO ₂ , where Ph represents an aromatic ring .)   The catalyst according to claim 2, which is used in a Friedel-Crafts type reaction of nitroalkene and indole.