JP2016204322A - Optically active peroxide adduct and manufacturing method thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To establish a technique synthesizing widespread peroxide adduct with high optical purity.SOLUTION: Peroxide adduct is shown in a following formula (2), where Ris electroattracting groups such as hydrogen, electron donating substituent such as alkyl or alkoxy, halogens, nitro or ester, Ris a methyl group, an allyl group or a benzyl group, Ris a tert-butyl group or CHC(CH)group, and a quinoline skeleton that a benzene ring and nitrogen of indole are annulated can be included.SELECTED DRAWING: None

Description

  The present invention relates to an optically active peroxide adduct and a method for producing the same.

  The α-amino peroxide compound is an important compound found in natural products. The peroxide addition reaction to imine is an important reaction capable of directly synthesizing the α-amino peroxide skeleton, and in particular, its development into a catalytic asymmetric reaction has attracted attention.

  In recent years, catalytic peroxide asymmetric addition reaction to imine has been achieved by Antilla (Non-Patent Document 1). Non-Patent Document 2 reports a catalytic asymmetric reaction of an alcohol with an imine derived from isatin.

Zheng W. Wojtas L .; Antilla J .; C. , Angew. Chem. Int. Ed. , 2010, 49, 6589. Li T. -Z. Wang X .; -B. Sha F .; Wu X. -Y. Tetrahedron 2013, 69, 7314.

  However, in the above document, the substrate used for the reaction is limited to the aldehyde-derived imine (aldimine), and from the point that quaternary asymmetric carbon can be constructed, the asymmetry of peroxides using ketone-derived imine (ketimine). The addition reaction was not achieved.

  In view of the above problems, an object of the present invention is to provide a peroxide addition reaction using a metal catalyst and synthesis of an optically active peroxide adduct obtained thereby.

  As a result of diligent investigations on the above-mentioned problems, the present inventors reacted an isatin-derived ketimine with an alcohol-derived peroxide in the presence of a catalyst in which a metal is coordinated with a bisimidazolidinepyridine (PyBidine) ligand. As a result, it was discovered that a peroxide adduct can be obtained enantioselectively and the present invention has been completed.

That is, the enantioselective method for producing a peroxide adduct according to one means of the present invention is a ketimine derived from isatin in the presence of a catalyst comprising a ligand represented by the following formula (1) and a metal or a metal salt. And a peroxide derived from alcohol.

  Although not limited, the ligand and the catalyst represented by the above formula (1) are disclosed in, for example, JP 2011-111426 A, “Arai T .; Mishiro A .; Yokoyama N .; Suzuki K .; Sato H., J. Am. Chem. Soc. 2010, 132, 5338. ".

As a result, a peroxide adduct represented by the following formula (2) can be enantioselectively obtained.

Here, R ¹ is an electron donating group such as hydrogen, alkyl or alkoxy, or an electron withdrawing group such as halogen, nitro or ester. R ² is a methyl group, an allyl group, or a benzyl group. R ³ is a tert-butyl group or a C ₆ H ₅ C (CH ₃ ) ₂ group. Further, it may have a quinoline skeleton in which a benzene ring of nitrogen and nitrogen are crossed.

  As described above, according to the present invention, it is possible to provide an asymmetric addition reaction of a peroxide using a metal catalyst and synthesis of an optically active peroxide adduct obtained thereby. Also, according to the present invention, a very high yield can be obtained.

  Hereinafter, embodiments of the present invention will be described in detail. However, the present invention can be implemented in many different modes, and is not limited only to the description of the embodiments and examples shown below.

(Embodiment 1)
The method for producing an optically active peroxide adduct according to the present embodiment is derived from an isatin-derived ketimine and an alcohol in the presence of a catalyst obtained by coordinating a ligand represented by the following chemical formula (1) to a metal salt. The peroxide is reacted.

The metal for coordinating the ligand is not limited to this as long as it can be coordinated, and examples thereof include nickel, copper, cobalt, and iron. 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 _nickel, can be used _{NiCl 2, Ni (OAc) 2} , Ni (OTf) 2, Ni (ClO 4) 2 and the like.

In addition, the catalyst according to the present embodiment can be used for performing an asymmetric addition reaction of peroxide using an isatin-derived ketimine. Specifically, an optically active peroxide adduct is synthesized by reacting an isatin-derived ketimine with an alcohol-derived peroxide in the presence of the catalyst according to the present embodiment, as shown in the reaction represented by the following formula (3). can do.

Here, R ¹ is an electron donating group such as hydrogen, alkyl, or alkoxy, or an electron withdrawing group such as halogen, nitro, or ester. R ² is a methyl group, an allyl group, or a benzyl group. R ³ is a tert-butyl group or a C ₆ H ₅ C (CH ₃ ) ₂ group. Further, it may have a quinoline skeleton in which a benzene ring of nitrogen and nitrogen are crossed.

As a result, according to the method according to the present embodiment, an optically active peroxide adduct represented by the following formula (2) can be obtained.

Here, R ¹ is an electron donating group such as hydrogen, alkyl, or alkoxy, or an electron withdrawing group such as halogen, nitro, or ester. R ² is a methyl group, an allyl group, or a benzyl group. R ³ is a tert-butyl group or a C ₆ H ₅ C (CH ₃ ) ₂ group. Further, it may have a quinoline skeleton in which a benzene ring of nitrogen and nitrogen are crossed.

(Manufacture of catalyst)
The ligand and the catalyst according to the present embodiment are not limited, but are described in JP 2011-111426 A, “Arai T .; Mishiro A .; Yokoyama N .; Suzuki K .; Sato H., J. Am. Chem. Soc. 2010, 132, 5338. ".

  As described above, according to this embodiment, it is possible to provide an optically active peroxide adduct with a wide range of substrates in the peroxide addition reaction.

  Hereinafter, the catalyst of the above embodiment was actually prepared, and the effect was confirmed. This will be described below.

Example 1
In this example, 15.4 mg of the ligand represented by the following formula (1) was used, and 2.6 mg of nickel (II) chloride was coordinated in methylene chloride to form an asymmetric addition reaction of peroxide as a catalyst. Went.

In this example, tert-butyl- (1-methyl-2-oxindolin-3-ylidene) carbamate 52.1 mg represented by the following formula (4-1) and (2-hydroxypropanpropan represented by the following (5-1) 2-yl) benzone (304.4 mg) was carried out in the presence of the above catalyst at 10 ° C. for 4 hours. As a result, 81.7 mg of the peroxide adduct (2-1) shown below was obtained, and the yield was 99% (94% ee).

Device data of (2-1):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.32 (s, 9H), 1.52 (d, J = 2.0 Hz, 6H), 3.19 (s, 3H), 5.78 (br, 1H), 6.80 (d, J = 7.7 Hz, 1H), 7.07 (ddd, J = 0.91, 7.7 Hz, 1H), 7.21-7.37 (m, 6H), 7.72 (d, J = 5.9 Hz, 1H);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 26.31, 26.38, 28.00, 31.70, 80.51, 83.99, 87.37, 108.16, 122.58, 124.30 , 125.41, 127.16, 128.01, 130.63, 143.80, 144.42, 153.02, 170.18;
_{HRMS (ESI +) calcd for C} 23 H 27 O 5 N 2 (M-H) - 411.1940: found 411.1925;
enantiomerically excess was determined by HPLC with a chiralpak AD-H column (hexane: 2-propanol = 98: 2, 0.9 ml / min, 254 nm);
minor enantiomer Rt = 28.7 min, major enantiomer Rt = 48.9 min;
^{_{[α] D 25 = -12.3 (}} c = 1.0, CHCl 3, ee 94%).

(Example 2)
This example was performed under the same conditions as in Example 1 except that the compound described in the following formula (4-2) was used. As a result, 84.4 mg of the following compound (2-2) could be obtained. The yield of (2-2) was 99% (94% ee).

Device data of (2-2):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.33 (s, 9H), 1.52 (d, J = 4.5 Hz, 6H), 2.33 (s, 3H), 3.17 (s, 3H), 5.78 (br, 1H), 6.68 (d, J = 7.9 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 7.26-7.52 ( m, 6H);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 21.20, 26.45, 26.49, 26.59, 28.19, 77.33, 80.61, 84.07, 87.69, 108.02 , 125.60, 127.31, 128.15, 131.02, 132.29, 141.58, 144.65, 153.26, 170.25;
_{HRMS (ESI +) calcd for C} 24 H 29 O 5 N 2 (M-H) - 425.2082: found 425.2097;
enantiomerically excess was determined by HPLC with a chiralpak AD-H column (hexane: 2-propanol = 98: 2,0.9 ml / min, 254 nm);
minor enantiomer Rt = 20.2 min, major enantiomer Rt = 43.5 min;
[α] _D ²⁰ = −10.3 (c = 1.0, CHCl ₃ , 94% ee)

Example 3
This example was performed under the same conditions as in Example 1 except that the compound of the following formula (4-3) was used. As a result, 86.8 mg of the following compound (2-3) could be obtained. The yield of (2-3) was 99% (90% ee).

Device data of (2-3):
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.36 (s, 9H), 1.53 (d, J = 4.1 Hz, 6H), 1.98 (m, 2H), 2.75 (t, 2H), 3.69 (m, 2H), 5.80 (br, 1H), 6.96 (t, J = 7.7 Hz, 1H), 7.09 (d, J = 7.7 Hz, 1H) 7.2-2.52 (m, 6H), 7.62 (d, J = 5.2 Hz, 1H);
_{HRMS (ESI +) calcd for C} 25 H 31 O 5 N 2 (M + H) + 439.2227: found 439.2217;
enantiomerically excess was determined by HPLC with a chiralpak AD-H column (hexane: 2-propanol = 80: 20, 1.0 ml / min, 254 nm);
minor enantiomer Rt = 5.43 min, major enantiomer Rt = 9.47 min;
[α] _D ²⁵ = −2.1 (c = 1.0, CHCl ₃ , 90% ee).

  As described above, the usefulness of the catalyst according to the present invention can be confirmed by this example, and it has been confirmed that an optically active peroxide adduct can be provided over a wide range of substrates.

INDUSTRIAL APPLICATION Since this invention can supply a peroxide adduct with very high optical purity, it is useful for development and production of a pharmaceutical and an agrochemical, and has industrial applicability.

Claims (2)

A method of enantioselectively synthesizing a peroxide adduct represented by the following formula (2) using a catalyst obtained by coordinating a ligand represented by the following formula (1) to a metal or a metal salt.
Here, R ¹ is hydrogen, an electron donating group, or an electron withdrawing group. R ² is a methyl group, an allyl group, or a benzyl group. R ³ is a tert-butyl group or a C ₆ H ₅ C (CH ₃ ) ₂ group. Further, it may have a quinoline skeleton in which a benzene ring and nitrogen of indole are transferred. A peroxide adduct represented by the following formula (2).
Here, R ¹ is hydrogen, an electron donating group, or an electron withdrawing group. R ² is a methyl group, an allyl group, or a benzyl group. R ³ is a tert-butyl group or a C ₆ H ₅ C (CH ₃ ) ₂ group. Further, it may have a quinoline skeleton in which a benzene ring of nitrogen and nitrogen are crossed.