JP2006028105A - Optically active aminopyridyl-group-containing pyrrolidine derivative and asymmetric synthesis using the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a stable optically active aminopyridyl-group-containing pyrrolidine derivative which is metal-free, is usable as an asymmetric synthesis catalyst usable for a carbon-carbon bond formation reaction and excellent in both enantioselectivity and diastereoselectivity and capable of being obtained simply and inexpensively and to provide an asymmetric synthesis using the same. <P>SOLUTION: The pyrrolidine derivative is represented by formula (I) (wherein -R<SP>1</SP>and -R<SP>2</SP>are each an alkyl group, an aryl group, or an aralkyl group or may be combined with each other to form an alkylene group or an alkenylene group; n is 0 to 2; and the carbon atom marked with * is an optically active carbon atom). The asymmetric synthesis comprises subjecting a nucleophilic reagent and an electrophilic reagent to a carbon-carbon bond formation reaction in the presence of at least the asymmetric synthesis catalyst represented by formula (I). <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to an optically active aminopyridyl group-containing pyrrolidine derivative used as a catalyst when an optically active compound is asymmetrically synthesized with good optical yield, and an asymmetric synthesis method using the same.

  Many chemical products and pharmaceuticals are manufactured using optically active compounds as raw materials.

  When such an optically active compound is synthesized by a carbon-carbon bond forming reaction such as a Michael addition reaction or an aldol condensation reaction, a solid metal-containing asymmetric synthesis catalyst has been used. Metal-containing asymmetric synthesis catalysts are unstable to water and oxygen. Further, when this catalyst is used, complicated and troublesome operations such as removal of solid catalyst and prevention of metal contamination are required in the purification process of the reaction product.

  Recently, therefore, metal-free asymmetric synthesis catalysts have been used. For example, Non-Patent Documents 1 and 2 include the following chemical reaction formulas:

As described above, a method for synthesizing an optically active ketone compound by aldol condensation reaction or Michael addition reaction using L-proline as an asymmetric synthesis catalyst is described.

B. List et al., J. Am. Chem. Soc., 122, 2395 (2000) D. Ender, A. Seki, Synlett, 2002, No.1, 26.

  Non-Patent Document 3 describes a method of synthesizing an optically active ketone compound by a Michael addition reaction using an optically active pyrrolidine ring-containing amine compound as an asymmetric synthesis catalyst.

O. Andrey, A. Alexakis, G. Bernardinelli, Org. Lett., 5, 2559 (2003)

  However, even when a conventional metal-free asymmetric synthesis catalyst is used in a carbon-carbon bond forming reaction such as a Michael addition reaction, there is a problem that the enantioselectivity and / or diastereoselectivity of the reaction product is not so high. It was.

  INDUSTRIAL APPLICABILITY The present invention is a stable optically active aminopyridyl which can be used as an asymmetric synthesis catalyst for a carbon-carbon bond forming reaction which does not contain a metal and is excellent not only in enantioselectivity but also in diastereoselectivity, and can be obtained simply and inexpensively It is an object to provide a group-containing pyrrolidine derivative and an asymmetric synthesis method using the same.

  The optically active aminopyridyl group-containing pyrrolidine derivative of the present invention made to solve the above problems has a structure of the following chemical formula (I).

（Ｉ）

(I)

(In the formula (I), -R ¹ and -R ² are an alkyl group, an aryl group, an aralkyl group, or an alkylene group or an alkenylene group linked to each other; n is 0 to 2; * is an optically active carbon atom; display)
It is shown by.

In the formula (I), -R ¹ and -R ² are the same or different, for example, a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms; an aryl such as a phenyl group Group; an aralkyl group such as a benzyl group may be mentioned. -R ¹ and -R ² are connected to each other, and an alkylene group that may be substituted with an alkyl group or an arylene group, such as a butylene group; an alkyl group or an arylene group that may be substituted, and a main chain An alkenylene group which may contain an arylene group in a part of the above is mentioned.

  The optically active carbon may be S-type or R-type.

The optically active aminopyridyl group-containing pyrrolidine derivative preferably has a pyrrolidine ring bonded to the 2-position of the pyridine ring via a — (CH ₂ ) _n — group. The following chemical formula (II)

（ＩＩ）

(II)

(In formula (II), -R ¹ , -R ² , and * are the same as those described above) are preferable. Among them, the following chemical formula (III) or (IV)

（ＩＩＩ） （ＩＶ）

(III) (IV)

It is still more preferable that it is shown by.

  The asymmetric synthesis catalyst of the present invention contains an optically active aminopyridyl group-containing pyrrolidine derivative represented by the above formula (I).

  The asymmetric synthesis catalyst preferably further contains an organic acid. Examples of the organic acid include organic sulfonic acids such as 2,4-dinitrobenzenesulfonic acid.

  The asymmetric synthesis method of the present invention is to carry out a carbon-carbon bond forming reaction between a nucleophile and an electrophile in the presence of the asymmetric synthesis catalyst.

  The asymmetric synthesis catalyst is used, for example, in an amount of 0.05 to 0.2 molar equivalents relative to 1 molar equivalent of the nucleophilic reagent or electrophilic reagent.

  The carbon-carbon bond forming reaction is preferably a Michael addition reaction.

  Examples of the nucleophile include ketone derivatives and aldehyde derivatives such as cyclohexanone and tetrahydrothiopyranone. As electrophiles, α, β-unsaturated nitro derivatives such as β-nitrostyrene, α, β-unsaturated nitrile derivatives; α, β-unsaturated carboxylic acid derivatives such as cinnamic acid, acid amides thereof Examples include nucleophile receptors exemplified by derivatives and ester derivatives.

  The optically active aminopyridyl group-containing pyrrolidine derivative of the present invention is used as an asymmetric synthesis catalyst when performing a carbon-carbon bond forming reaction such as a Michael addition reaction. This pyrrolidine derivative does not contain harmful metals and does not cause environmental pollution. When a carbon-carbon bond forming reaction is performed using this pyrrolidine derivative, a product with high optical purity can be obtained diastereoselectively and enantioselectively.

  The details of the optically active aminopyridyl group-containing pyrrolidine derivative to which the present invention is applied and an asymmetric synthesis method using the same will be described below.

  The optically active aminopyridyl group-containing pyrrolidine derivative is synthesized as follows.

  According to the method described in D. Alker, KJ Doyle, LM Harwood and A. McCregor, Tetrahedron: Asymmetry, 1, 877 (1990), as shown in the following chemical reaction formula, optically active L in the presence of a tertiary amine -Reacting sulfuryl chloride with prolinol (V) leads to S-type cyclic sulfamate (VI).

（Ｖ） （ＶＩ）

(V) (VI)

Next, as shown in the following chemical reaction formula, this cyclic sulfamate (VI) was reacted with a 2-lithiopyridine derivative obtained by lithiation of a 2-bromopyridine derivative having a —NR ¹ R ² group at the 4-position. Thereafter, it is hydrolyzed under acidic conditions. Then, a desired optically active aminopyridyl group-containing pyrrolidine derivative (IIs) having a (S) -2- (2-pyridylmethyl) pyrrolidine skeleton is obtained.

  Further, when cyclic sulfamate derived from D-prolinol is used instead of L-prolinol, an R-type optically active aminopyridyl group-containing pyrrolidine derivative can be synthesized.

  The obtained optically active aminopyridyl group-containing pyrrolidine derivative is allowed to coexist as an asymmetric synthesis catalyst, and a carbon-carbon bond forming reaction such as a Michael addition reaction is performed.

  As an asymmetric synthesis catalyst (cat.), An S-type optically active aminopyridyl group-containing pyrrolidine derivative (IIs) having a (S) -2- (2-pyridylmethyl) pyrrolidine skeleton is used, which is represented by the following chemical reaction formula An example in which a Michael addition reaction between cyclohexanone, which is a nucleophilic reagent, and β-nitrostyrene, which is an electrophilic reagent, is described.

  When an excess amount of cyclohexanone, 1 molar equivalent of β-nitrostyrene, and 0.05 to 0.2 molar equivalent of optically active aminopyridyl group-containing pyrrolidine derivative (IIs) are mixed and stirred, the main product is syn type. Of (2S, 1′R)-(2-nitro-1-phenyl) ethylcyclohexanone (VII) was obtained with high optical purity, diastereoselectively and enantioselectively.

  When the optically active aminopyridyl group-containing pyrrolidine derivative performs the Michael addition reaction, the reaction mechanism for expressing such excellent diastereoselectivity and enantioselectivity is as shown in the following chemical reaction formula. Conceivable.

  First, as a result of the proton at the α-position of the carbonyl group of cyclohexanone being extracted to the pyridine ring of the optically active aminopyridyl group-containing pyrrolidine derivative (IIs), the enamine intermediate (VIII) is rapidly formed. The pyridinium ring formed thereby sterically shields one side of the double bond of the enamine intermediate (VIII). Next, β-nitrostyrene approaches from its non-shielding surface side, and after transition state (IX), Michael addition reaction proceeds. As a result, (2S, 1′R) type product (VII) is diastereoselective. And enantioselectively with high optical purity. On the other hand, the optically active aminopyridyl group-containing pyrrolidine derivative (IIs) is liberated and acts again as a catalyst for the Michael addition reaction.

  Next, a synthesis example of an optically active aminopyridyl group-containing pyrrolidine derivative and an example in which a Michael addition reaction is performed using the pyrrolidine derivative will be described.

(Synthesis Example 1)
2-Bromo-4-dimethylamino-pyridine 1 in which 7 ml of a 1.59M hexane solution of n-butyllithium (n-butyllithium: 11 mmol) was dissolved in 12 ml of dry tetrahydrofuran (THF) at −78 ° C. To .05 ml (11 mmol) and stirred for 1 hour. Subsequently, 1.37 g (8.4 mmol) of S-type cyclic sulfamate (VI) dissolved in 10 ml of THF was added dropwise at −78 ° C., and the mixture was returned to room temperature and stirred overnight. The solvent was distilled off under reduced pressure to obtain a beige foam. To this, 16 ml of 2N hydrochloric acid and 16 ml of ethanol were added and stirred overnight. The reaction mixture was basified with 50% sodium hydroxide solution and extracted with dichloromethane. The extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (chloroform / isopropylamine = 19/1) to give a pale yellow oil represented by the following chemical formula ( S) -2- [4- (dimethylamino) pyridin-2-ylmethyl] pyrrolidine (IIIs) was obtained with a yield of 80%. It was subjected to thin layer chromatographic analysis, light intensity measurement, infrared spectroscopic analysis (FT-IR), and nuclear magnetic resonance analysis (NMR). The analysis results are shown below. Spectroscopic data support this structure.

（ＩＩＩｓ）

(IIIs)

R _f 0.19 (CHCl ₃ / i-PrNH ₂ = 9: 1).
[α] _D ²² −7.9 (c 0.76, CHCl ₃ ).
FTIR (neat) ν 3327, 1602, 1542, 1507, 1374, 995, 805, 750 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.43 (1H, ddt, J = 12.0, 9.3, 7.6 Hz), 1.67-1.93 (3H, m), 2.47 (1H, br), 2.74 (1H, dd, J = 13.2, 8.0 Hz), 2.81-2.86 (1H, m), 2.85 (1H, dd, J = 13.2, 5.6 Hz), 2.98 (6H, s), 2.95-3.06 (1H, m), 3.46 (1H, quintet, J = 6.6 Hz), 6.35 (1H, dd, J = 6.1, 2.7 Hz), 6.40 (1H, d, J = 2.7 Hz), 8.15 (1H, d, J = 6.1 Hz).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 24.82, 31.18, 39.02 (× 2), 44.80, 46.11, 58.92, 104.53, 105.93, 149.19, 154.71, 159.98.

(Synthesis Example 2)
A light yellow oily (S)-represented by the following chemical formula was prepared in the same manner as in Synthesis Example 1 except that 2-bromo-4-pyrrolidinopyridine was used instead of 2-bromo-4-dimethylaminopyridine. 2- [4- (Pyrrolidino) pyridin-2-ylmethyl] pyrrolidine (IVs) was obtained with a yield of 50%.

（ＩＶｓ）

(IVs)

The analytical results of this compound are shown below. Spectroscopic data support this structure.
R _f 0.50 (CHCl ₃ / i-PrNH ₂ = 9: 1).
[α] _D ²⁴ −12.5 (c 0.56, CHCl ₃ ).
FTIR (neat) ν 3330, 1602, 1541, 1502, 1485, 1457, 1389 cm ^-1 .
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.43 (1H, ddt, J = 12.0, 9.5, 7.6 Hz), 1.67-1.92 (3H, m), 2.00 (4H, m), 2.37 (1H, br), 2.72 (1H, dd, J = 13.2, 8.0 Hz), 2.80-2.84 (1H, m), 2.83 (1H, dd, J = 13.2, 5.6 Hz), 3.03 (1H, ddd, J = 10.0, 7.6, 5.1 Hz), 3.29 (4H, m), 3.45 (1H, quintet, J = 6.4 Hz), 6.23 (1H, dd, J = 5.9, 2.4 Hz), 6.28 (1H, d, J = 2.4 Hz), 8.12 ( (1H, d, J = 5.9 Hz).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 24.87, 25.26 (× 2), 31.22, 44.80, 46.15, 46.87 (× 2), 58.97, 104.89, 106.21, 149.11, 152.16, 159.86.

  Next, with respect to the Michael addition reaction between cyclohexane and β-nitrostyrene, examples using an optically active aminopyridyl group-containing pyrrolidine derivative to which the present invention is applied as an asymmetric synthesis catalyst, and optically active aminos to which the present invention is not applied. A comparative example using a pyridyl group-containing pyrrolidine derivative as a catalyst will be described.

Example 1
Cyclohexanone 0.5 ml, β-nitrostyrene 38 mg (0.25 mmol; 1 molar equivalent), and optically active aminopyridyl group-containing pyrrolidine derivative (IIIs) 4 mg (0.025 ml; obtained in Synthesis Example 1 as an asymmetric synthesis catalyst) 0.1 molar equivalent) was added to 2 ml of chloroform. This was stirred at room temperature for 24 hours while confirming whether the reaction was completed by thin layer chromatography. Then, the reaction solution was quenched with 2 ml of 1N hydrochloric acid at 0 ° C., and extracted twice with 3 ml of dichloromethane. The organic layers were combined, dried over sodium sulfate and filtered. The solvent was distilled off from the furnace liquid under reduced pressure and subjected to thin layer chromatography (hexane / ethyl acetate = 4/1) to isolate a white solid which was a mixture of the main product represented by the formula (VII) and its isomers. Obtained in 78% yield.

When the diastereo ratio (dr) of the syn isomer and the anti isomer of the isomer mixture was measured by ¹ H-NMR, it was 95: 5. The optical purity (ee) of the syn isomer was measured by analytical chiral HPLC (Chiralpak AD column 0.46 × 25 cm; hexane / 2-propanol = 90/10; 0.5 cm ³ / min) and Rt [(2R, 1 ′S)] 13.5 minutes; Rt [(2S, 1′R)] calculated from the peak area ratio of 15.4 minutes was 88ee (%). The results are summarized in Table 1.

(Examples 2 to 5)
A Michael addition reaction was carried out in the same manner as in Example 1 except that the asymmetric synthesis catalyst, reaction time, and reaction temperature were changed to the conditions shown in Table 1. For the obtained product, the isolation yield, the diastere ratio (dr) between the syn and anti isomers, and the optical purity (ee) of the syn isomer were determined in the same manner as in Example 1. The results are summarized in Table 1.

[Comparative Examples 1-3]
Comparative Examples 1 to 3 are represented by the following chemical formulas (X) to (XII), respectively.

（Ｘ） （ＸＩ） （ＸＩＩ）

(X) (XI) (XII)

Was used, and the Michael addition reaction was carried out in the same manner as in Example 1 except that the reaction time and the reaction temperature were set as shown in Table 1. About the obtained product, the isolation yield, the diastereo ratio (dr) between the syn isomer and the anti isomer, and the optical purity (ee) of the syn isomer were determined in the same manner as in Example 1. The results are summarized in Table 1.

  As is clear from Table 1, as in the Michael addition reactions of Examples 1 to 5, an optically active aminopyridyl group-containing pyrrolidine derivative having a dimethylamino group or a pyrrolidino group at the 4-position of the pyridine ring is used as an asymmetric synthesis catalyst. The product had an isolation yield of 78 to 99%, a diastereoselectivity between the syn and anti isomers of 95: 5 to 98: 2, and an optical purity of the syn isomer of 88. It was as high as -99ee (%). In particular, in Example 5, when an organic acid was allowed to coexist at 0 ° C., the diastereoselectivity between the syn and anti isomers was 98: 2 with an isolation yield of 95%, and the optical purity of the syn isomer was 99ee (%) is particularly excellent.

  On the other hand, when an optically active aminopyridyl group-containing pyrrolidine derivative having no dimethylamino group or pyrrolidino group in the pyridine ring as in Comparative Examples 1 to 3 was used as a catalyst, the product was isolated in yield, diastereo ratio, All of the optical purity was not so high.

  Next, for the Michael addition reaction between various ketone derivatives or aldehyde derivatives and various α, β-unsaturated nitro compounds, an optically active aminopyridyl group-containing pyrrolidine derivative to which the present invention is applied was used as an asymmetric synthesis catalyst. Examples will be described.

(Examples 6 to 19)
In 2 ml of chloroform, 0.25 mmol of various α, β-unsaturated nitro compounds, 10 mol% of an optically active aminopyridyl group-containing pyrrolidine derivative described in Table 2, and 5 mol% of 2,4-dinitrobenzenesulfonic acid A Michael addition reaction was carried out in the same manner as in Example 1 except that 20 vol% of various ketone derivatives or aldehyde derivatives were added and reacted at 0 ° C. for the time shown in Table 2. For the obtained product, the isolation yield, the diastere ratio (dr) between the syn and anti isomers, and the optical purity (ee) of the syn isomer were determined in the same manner as in Example 1. The results are summarized in Table 2.

  The absolute structure of the main product was estimated in the same manner as the method described in Non-Patent Document 2.

  As is apparent from Table 2, in the Michael addition reaction using cyclohexanone as a nucleophile and various β-nitrostyrene type derivatives as electrophiles as in Examples 6 to 15, the isolation yield is almost quantitative. The diastereomer ratio between the syn and anti isomers was 99: 1 at the maximum and the optical purity was 98ee (%) at the maximum, indicating not only excellent enantioselectivity but also diastereoselectivity. In addition, in the Michael addition reaction using tetrahydrothiopyran-4-one as a nucleophile and β-nitrostyrene as an electrophile as in Examples 16 to 17, not only excellent enantioselectivity but also diastereoselection Showed sex. Further, as in Examples 18 to 19, the Michael addition reaction using isovaleraldehyde as a nucleophile and β-nitrostyrene as an electrophile showed excellent diastereoselectivity.

The optically active aminopyridyl group-containing pyrrolidine derivative of the present invention is used as an asymmetric synthesis catalyst when performing a carbon-carbon bond forming reaction such as a Michael addition reaction. According to the asymmetric synthesis method in which a carbon-carbon bond forming reaction is performed using this, an optically active compound useful as a raw material for chemical products and pharmaceuticals can be diastereoselectively and enantioselectively obtained in a high isolation yield. Can be synthesized with high optical purity. Furthermore, the optically active aminopyridyl group-containing pyrrolidine derivative itself can be used as a raw material for chemical products and pharmaceuticals.

Claims (5)

The following chemical formula (I)

(I)

(In the formula (I), -R ¹ and -R ² are an alkyl group, an aryl group, an aralkyl group, or an alkylene group or an alkenylene group linked to each other; n is 0 to 2; * is an optically active carbon atom; display)
An optically active aminopyridyl group-containing pyrrolidine derivative characterized by the following: An asymmetric synthesis catalyst comprising at least the optically active aminopyridyl group-containing pyrrolidine derivative according to claim 1. The asymmetric synthesis catalyst according to claim 2, comprising an organic acid. A method for asymmetric synthesis, comprising causing a carbon-carbon bond forming reaction between a nucleophilic reagent and an electrophilic reagent in the presence of the asymmetric synthesis catalyst according to claim 2. The asymmetric synthesis method according to claim 4, wherein the carbon-carbon bond forming reaction is a Michael addition reaction.