KR20030044364A - Novel phase transfer catalyst and its application for the synthesis of α-amino acid - Google Patents

Abstract

PURPOSE: A new asymmetric phase-transfer catalyst which is obtained from Cinchona alkaloid, and is used in the synthesis of amino acid to synthesize alpha amino acid in simple and productive ways. CONSTITUTION: The compound is expressed by the chemical formula 1, wherein X is a halogen atom such as fluorine, chlorine, bromine and iodine, IO4-, CIO4-, OTf-, or HSO4-. In the formula 1, R1 is hydrogen, low alkyl with the carbon number of 1-4, hydroxy, or -OR4 (provided that R4 is low alkyl group with the carbon numbers of 1-4), R2 is vinyl or ethyl group, R3 is hydrogen, low alkyl with the carbon numbers of 1-10, allyl, benzyl, naphthalene-1-mono-methyl, naphthalene-2-mono-methyl, or anthracene-9-mono-methyl.

Description

Novel phase transfer catalyst and its application for the synthesis of α-amino acid}

The present invention relates to a chiral phase-transfer catalyst and asymmetric phase-transfer catalysis using the catalyst, specifically, an asymmetric phase derived from Cinchona alkaloid. It relates to a transfer catalyst and a method for asymmetric synthesis of alpha amino acids using the same.

Alpha amino acids having optical activity are widely used in biological sciences, and the synthetic method has attracted much attention recently. Among them, a simple and easy mass reaction method is a phase transfer catalysis that uses a quaternary ammonium salt as a phase transfer catalyst.

The use of ammonium salts derived from chiral alkaloids enabled the asymmetric synthesis of alpha amino acids with optical activity, which are tetraalkylammonium halides derived from the chiral alkaloids, cinona alkaloids, by MJ O'Donnell. Asymmetric synthesis of alpha amino acids was first reported using the compound of A as a catalyst. O'Donnell, MJ; Bennett, WD; Wu, S. J. Am. Chem. Soc. 1989 , 111 , 2353.] The B. Lygo Research Group [Lygo, B .; Wainwright, PG Tetrahedron Lett. 1997 , 38 , 8595.] and EJ Corey Research Group [Corey, EJ; Xu, F .; Noe, MC J. Am. Chem. Soc. 1997 , 119 , 12414.] developed a compound of B, a new catalyst derived from synacona alkaloids, and asymmetrically synthesized alpha amino acids through monoalkylation using phase transfer catalysis. However, the compound of A of Odonnell has a low optical yield of about 80% ee and the compound of B such as Lygo and Corey has high economical cost in synthesis, and especially in case of Corey, the reaction condition is -78 ° C. There is a limit to practical industrial applications. Therefore, there is a need for a catalyst capable of asymmetrically synthesizing alpha amino acids with high optical yield (95% -99% ee) under industrially easy reaction conditions.

The present inventors continued to search for a new asymmetric phase transfer catalyst, and as a result, the present invention has been completed by developing an asymmetric phase transfer catalyst having excellent optical yield and an asymmetric phase transfer catalyst reaction using the same. It is therefore an object of the present invention to provide an asymmetric phase transfer catalyst derived from cinnaco or alkaloids. Another object of the present invention to provide an asymmetric synthesis method of alpha amino acid using the asymmetric phase transfer catalyst.

The present invention relates to novel compounds of the general formulas (1) and (2).

In the above formula,

In the formula, X is a halogen atom or an IO ₄ of fluorine, chlorine, bromine and iodine ^{_{-, ClO 4 -, OTf -}} , HSO 4 - , and;

R ¹ is hydrogen, lower alkyl having 1-4 carbons, hydroxy, or —OR ⁴ , provided that R ⁴ is 1-4 lower alkyl groups;

R ² is a vinyl or ethyl group;

R ³ is hydrogen, lower alkyl having 1-10 carbon atoms, allyl, benzyl, naphthalen-1-yl-methyl, naphthalen-2-yl-methyl, or anthracene-9-yl-methyl.

The compounds of the present invention can be chemically synthesized by the method shown by the following schemes. However, this is merely for illustrative purposes and the present invention is not limited thereto.

As shown in Schemes 1 and 2, bis (bromomethyl) naphthalene was added to synconin, synconidine, quinine, and quinidine to carry out di-N-alkylation, followed by di-O (9) in alkaline basic conditions. ) -Allylation was performed to synthesize the phase transfer catalyst in high yield.

In order to measure the efficiency of the phase transfer catalyst synthesized in Schemes 1 and 2, the resulting product was subjected to benzylation reaction based on N- (diphenylmethylene) glycine tert -butyl ester as in Scheme 3 below. Optical yield was measured by HPLC (chiral HPLC).

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples, but the present invention is not limited only to these examples.

Example 1: 1,4-bis (syncondidinium- N -Methyl) naphthalene dibromide (5)

To a 50 mL round bottom flask was placed 1,4-bis (bromomethyl) naphthalene (500 mg, 1.59 mmol) in (-)-cinconidine [(-)-cinchonidine] (1.0 g, 3.34 mmol). It was stirred under reflux for 4 hours in N , N -dimethylformamide: chloroform (5: 6: 2) mixed solvent (7 mL). The reaction mixture was cooled to room temperature, diluted with methanol (10 ml), and added dropwise to ether (100 mL) to precipitate a solid, which was filtered under reduced pressure. The obtained solid was recrystallized from methanol-ether to give the desired product (1.3 g) as a pale pink solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 9.02 (d, J = 4.4 Hz, 2H), 8.56-8.70 (m, 2H), 8.44 (d, J = 8.3 Hz, 2H), 8.20 (s , 2H), 8.13 (d, J = 8.5 Hz, 2H), 7.75-7.92 (m, 8H), 6.92 (s, 2H), 6.79 (s, 2H), 5.83 (d, J = 13.4 Hz, 2H) , 5.65-5.72 (m, 2H), 5.47 (d, J = 12.4 Hz, 2H), 5.06-5.11 (m, 2H), 4.91-5.00 (m, 2H), 4.27-4.39 (m, 2H), 4.19 -4.25 (m, 2H), 3.75-4.00 (m, 4H), 3.42-3.51 (m, 2H), 2.70-2.76 (m, 2H), 2.11-2.23 (m, 2H), 1.82-2.08 (m, 6H), 1.25-1.41 (m, 2H).

Example 2: 1,4-bis [ O (9) -allylconydinium- N -Methyl] niphthalene dibromide (6)

Compound 5 (500 mg, 0.554 mmol) obtained by the method of Example 1 was suspended in dichloromethane (3 mL), followed by 50% aqueous potassium hydroxide solution (0.62 mL, 5.54 mmol) and allyl bromide (0.29 mL, 3.324 mmol). Put and stirred at room temperature for 7 hours. The reaction solution was diluted with water (5 mL), extracted with dichloromethane (2 × 20 mL), and the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-hexane to give the desired product (480 mg) as a pale yellow solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 9.05 (d, J = 4.3 Hz, 2H), 8.39 (d, J = 8.5 Hz, 2H), 8.16-8.21 (m, 6H), 7.63-7.92 (m, 8H), 6.69 (s, 2H), 6.20-6.29 (m, 2H), 5.62-5.81 (m, 4H), 5.30-5.60 (m, 6H), 4.92-5.23 (m, 4H), 4.45 -4.52 (m, 2H), 4.02-4.38 (m, 6H), 3.78-3.99 (m, 4H), 3.74-3.85 (m, 2H), 2.52-2.69 (m, 2H), 2.30-2.48 (m, 2H), 1.85-2.25 (m, 4H), 1.70-1.80 (m, 2H), 1.39-1.51 (m, 2H).

Example 3: 1,4-bis (hydrocinconidinium- N Methyl) naphthalene dibromide (5-1)

To a 50 mL round bottom flask was placed 1,4-bis (bromomethyl) naphthalene (303 mg, 0.964 mmol) in (-)-hydrocinconidine [(-)-hydrocinchonidine] (600 mg, 2.024 mmol). : N , N -dimethylformamide: chloroform (5: 6: 2) was stirred under reflux for 4 hours in a mixed solvent (4 mL). The reaction mixture was cooled to room temperature, diluted with methanol (5 ml), and added dropwise to ether (250 mL) to precipitate a solid, which was filtered under reduced pressure. The solid obtained was recrystallized from methanol-ether to give the desired product (900 mg) as a pale yellow solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 9.02 (d, J = 4.4 Hz, 2H), 8.66-8.72 (m, 2H), 8.44 (d, J = 8.3 Hz, 2H), 8.15-8.23 (m, 4H), 7.76-7.93 (m, 8H), 6.90 (d, J = 3.9 Hz, 2H), 6.78 (s, 2H), 5.79 (d, J = 12.9 Hz, 2H), 5.38 (d, J = 13.2 Hz, 2H), 4.32-4.44 (m, 2H), 4.21-4.30 (m, 2H), 3.57-3.63 (m, 2H), 3.29-3.33 (m, 2H), 2.21-2.50 (m, 4H), 1.97-2.20 (m, 2H), 1.80-1.95 (m, 2H), 1.61-1.79 (m, 4H), 1.26-1.48 (m, 2H), 1.11-1.24 (m, 4H), 0.66 ( t, J = 6.8 Hz, 6H).

Example 4: 1,4-bis [ O (9) -allylhydrocinconinidinium- N -Methyl] naphthalene dibromide (6-1)

Compound 5-1 (500 mg, 0.554 mmol) obtained by the method of Example 3 was suspended in dichloromethane (3 mL), followed by 50% aqueous potassium hydroxide solution (0.62 mL, 5.54 mmol) and allyl bromide (0.29 mL, 3.324 mmol). ) Was added and stirred at room temperature for 5 hours. The reaction solution was diluted with water (10 mL), extracted with dichloromethane (2 × 20 mL), and the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-hexane to give the desired product (420 mg) as a pale yellow solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 8.98 (d, J = 4.6 Hz, 2H), 8.14-8.23 (m, 6H), 7.75-7.82 (m, 4H), 7.66-7.74 (m, 4H), 7.64 (d, J = 4.4 Hz, 2H), 6.14 (s, 2H), 6.01-6.15 (m, 2H), 5.83 (d, J = 15.8 Hz, 2H), 5.75 (d, J = 10.0 Hz, 2H), 5.39 (d, J = 17.2 Hz, 2H), 5.24 (d, J = 10.5 Hz, 2H), 4.31-4.45 (m, 4H), 4.21-4.30 (m, 2H), 3.90-4.01 (m, 2H), 3.76-3.89 (m, 2H), 3.60-3.71 (m, 2H), 3.45-3.52 (m, 2H), 2.02-2.25 (m, 4H), 1.94-2.00 (m, 2H) , 1.74-1.90 (m, 4H), 1.43-1.51 (m, 2H), 1.19-1.32 (m, 4H), 0.72 (t, J = 7.3 Hz, 6H).

Example 5: 1,5-bis (syncondinium- N -Methyl) naphthalene dibromide (7)

To a 50 mL round bottom flask was placed 1,5-bis (bromomethyl) naphthalene (261 mg, 0.832 mmol) in (-)-cinconidine [(-)-cinchonidine] (500 mg, 1.70 mmol). The mixture was stirred under reflux for 4 hours in a N , N -dimethylformamide: chloroform (5: 6: 2) mixed solvent (2.5 mL). The reaction mixture was cooled to room temperature, diluted in methanol (5 ml), and added dropwise to ether (100 mL) to precipitate a solid, which was filtered under reduced pressure. The solid obtained was recrystallized from methanol-ether to give the desired product (606 mg) as a yellow solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 9.02 (d, J = 4.4 Hz, 2H), 8.75 (d, J = 8.6 Hz, 2H), 8.44 (d, J = 8.3 Hz, 2H), 8.08-8.19 (m, 4H), 7.80-7.95 (m, 8H), 6.97 (d, J = 3.9 Hz, 2H), 6.80 (s, 2H), 5.91 (d, J = 12.9 Hz, 2H), 5.64 -5.75 (m, 2H), 5.47 (d, J = 13.1 Hz, 2H), 5.16 (d, J = 17.3 Hz, 2H), 4.98 (d, J = 10.5 Hz, 2H), 4.38-4.47 (m, 2H), 4.15-4.29 (m, 2H), 3.87-4.00 (m, 2H), 3.16-3.24 (m, 2H), 2.61-2.70 (m, 2H), 1.92-2.25 (m, 8H), 1.63- 1.74 (m, 2 H), 1.26-1.40 (m, 2 H).

Example 6: 1,5-bis [ O (9) -allylconydinium- N -Methyl] naphthalene dibromide (8)

Compound 7 (300 mg, 0.332 mmol) obtained by the method of Example 5 was suspended in dichloromethane (2 mL), followed by 50% aqueous potassium hydroxide solution (0.372 mL, 3.32 mmol) and allyl bromide (0.17 mL, 1.992 mmol). Put and stirred at room temperature for 5 hours. The reaction solution was diluted with water (20 mL), extracted with dichloromethane (2 x 30 mL), and the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-hexane to give the desired product (230 mg) as a yellow solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 9.05 (d, J = 4.4 Hz, 2H), 8.31-8.44 (m, 2H), 8.11-8.23 (m, 4H), 7.70-7.92 (m, 10H), 6.70 (s, 2H), 6.17-6.28 (m, 2H), 5.62-5.88 (m, 4H), 5.32-5.60 (m, 6H), 4.90-5.23 (m, 4H), 4.41-4.52 ( m, 2H), 4.25-4.38 (m, 2H), 4.06-4.20 (m, 4H), 3.75-3.91 (m, 4H), 3.22-3.30 (m, 2H), 2.51-2.61 (m, 2H), 2.27-2.84 (m, 2H), 2.06-2.20 (m, 2H), 1.82-2.02 (m, 2H), 1.61-1.79 (m, 2H), 1.40-1.52 (m, 2H).

Example 7: 1,5-bis (hydrocinconidinium- N Methyl) naphthalene dibromide (7-1)

To a 50 mL round bottom flask was added 1,5-bis (bromomethyl) naphthalene (260 mg, 0.832 mmol) to (-)-hydrocinconidine [(-)-hydrocinchonidine] (500 mg, 1.687 mmol). : N , N -dimethylformamide: chloroform (5: 6: 2) was stirred under reflux for 4 hours in a mixed solvent (4 mL). The reaction mixture was cooled to room temperature, diluted with methanol (5 ml), and added dropwise to ether (100 mL) to precipitate a solid, which was filtered under reduced pressure. The solid obtained was recrystallized from methanol-ether to give the desired product (671 mg) as a pink solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 9.02 (d, J = 4.4 Hz, 2H), 8.73 (d, J = 8.8 Hz, 2H), 8.42 (d, J = 8.5 Hz, 2H), 8.13 (d, J = 7.6 Hz, 4H), 7.75-7.94 (m, 8H), 6.94 (d, J = 4.1 Hz, 2H), 6.79 (s, 2H), 5.88 (d, J = 12.9 Hz, 2H ), 5.34 (d, J = 13.2 Hz, 2H), 4.40-4.45 (m, 2H), 4.19-4.32 (m, 2H), 3.55-3.63 (m, 2H), 3.32-3.40 (m, 2H), 3.01-3.22 (m, 2H), 2.21-2.35 (m, 2H), 2.02-2.19 (m, 2H), 1.83-1.95 (m, 2H), 1.62-1.73 (m, 4H), 1.34-1.45 (m 2H), 1.15-1.25 (m, 4H), 0.68 (t, J = 7.3 Hz, 6H).

Example 8: 1,5-bis [ O (9) -allylhydrocinconinidinium- N -Methyl] naphthalene dibromide (8-1)

Compound 7-1 (300 mg, 0.33 mmol) obtained by the method of Example 7 was suspended in dichloromethane (2 mL), followed by 50% aqueous potassium hydroxide solution (0.37 mL, 3.3 mmol) and allyl bromide (0.17 mL, 1.98 mmol). ) Was added and stirred at room temperature for 5 hours. The reaction solution was diluted with water (10 mL), extracted with dichloromethane (2 × 20 mL), and the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-hexanes to give the desired product (210 mg) as an orange solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 9.05 (d, J = 4.4 Hz, 2H), 8.59 (d, J = 8.3 Hz, 2H), 8.39 (d, J = 8.5 Hz, 2H), 8.11-8.18 (m, 4H), 7.76-7.92 (m, 8H), 6.70 (s, 2H), 6.21-6.30 (m, 2H), 5.83 (d, J = 13.2 Hz, 2H), 5.56 (d, J = 16.1 Hz, 2H), 5.40 (d, J = 10.0 Hz, 2H), 5.34 (d, J = 13.0 Hz, 2H), 4.45-4.51 (m, 2H), 4.12-4.35 (m, 6H), 3.59-3.68 (m, 2H), 3.26-3.42 (m, 4H), 2.31-2.40 (m, 2H), 2.02-2.15 (m, 2H), 1.90-1.99 (m, 2H), 1.63-1.75 (m , 4H), 1.46-1.52 (m, 2H), 1.11-1.22 (m, 4H), 0.67 (t, J = 7.2 Hz, 6H).

Example 9: 1,8-bis (syncondinium- N -Methyl) naphthalene dibromide (9)

To a 50 mL round bottom flask was placed 1,8-bis (bromomethyl) naphthalene (523 mg, 1.664 mmol) in (-)-cinconidine [(-)-cinchonidine] (1.0 g, 3.40 mmol). The mixture was stirred under reflux for 4 hours in a N , N -dimethylformamide: chloroform (5: 6: 2) mixed solvent (5 mL). The reaction mixture was cooled to room temperature, diluted with methanol (20 ml), and added dropwise to ether (200 mL) to precipitate a solid, which was filtered under reduced pressure. The solid obtained was recrystallized from methanol-ether to give the desired product (1.03 g) as a pink solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 8.92 (d, J = 4.4 Hz, 2H), 8.37 (d, J = 8.8 Hz, 2H), 7.98-8.24 (m, 6H), 7.75-7.81 (m, 2H), 7.52-7.69 (m, 6H), 6.46 (s, 2H), 6.00 (s, 2H), 5.74-5.85 (m, 2H), 4.86-5.24 (m, 8H), 3.90-4.02 (m, 2H), 3.49-3.62 (m, 4H), 3.23-3.41 (m, 2H), 2.61-2.70 (m, 2H), 1.92-2.30 (m, 6H), 1.73-1.88 (m, 2H) , 1.41-1.59 (m, 2H), 1.27-1.35 (m, 2H).

Example 10: 1,8-bis [ O (9) -allylconydinium- N -Methyl] niphthalene dibromide (10)

Compound 9 (300 mg, 0.333 mmol) obtained by the method of Example 9 was suspended in dichloromethane (2 mL), followed by 50% aqueous potassium hydroxide solution (0.38 mL, 3.33 mmol) and allyl bromide (0.18 mL, 1.998 mmol). The mixture was stirred at room temperature for 10 hours. The reaction solution was diluted with water (5 mL), extracted with dichloromethane (2 × 20 mL), and the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-hexanes to give the desired product (250 mg) as an orange solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 8.98 (d, J = 4.6 Hz, 2H), 7.92-8.23 (m, 6H), 7.51-7.88 (m, 10H), 5.97-6.21 (m, 4H), 5.63-5.87 (m, 2H), 4.85-5.46 (m, 10H), 4.39-4.52 (m, 2H), 4.15-4.21 (m, 2H), 3.60-4.02 (m, 6H), 3.35- 3.52 (m, 4H), 2.64-2.81 (m, 2H), 1.80-2.35 (m, 8H), 1.31-1.50 (m, 2H).

Example 11: 1,8-bis (hydrocinconidinium- N Methyl) naphthalene dibromide (9-1)

To a 50 mL round bottom flask was placed 1,8-bis (bromomethyl) naphthalene (260 mg, 0.827 mmol) in (-)-hydrocinchonidine [(-)-hydrocinchonidine] (500 mg, 1.687 mmol). : N , N -dimethylformamide: chloroform (5: 6: 2) was stirred under reflux for 4 hours in a mixed solvent (4 mL). The reaction mixture was cooled to room temperature, diluted with methanol (5 ml), and added dropwise to ether (100 mL) to precipitate a solid, which was filtered under reduced pressure. The obtained solid was recrystallized from methanol-ether to give the desired product (525 mg) as a pink solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 8.94 (d, J = 4.4 Hz, 2H), 8.33 (d, J = 8.5 Hz, 2H), 7.96-8.21 (m, 6H), 7.70-7.85 (m, 2H), 7.43-7.65 (m, 6H), 6.43 (d, J = 4.2 Hz, 2H), 5.96 (s, 2H), 5.52-5.65 (m, 2H), 5.23-5.31 (m, 2H ), 3.92-4.08 (m, 2H), 3.42-3.60 (m, 4H), 3.23-3.40 (m, 2H), 2.50-2.65 (m, 2H), 1.90-2.27 (m, 6H), 1.69-1.85 (m, 2H), 1.49-1.60 (m, 2H), 1.36-1.45 (m, 2H), 1.21-1.32 (m, 4H), 0.73 (t, J = 7.3 Hz, 6H).

Example 12: 1,8-bis [ O (9) -allylhydrocinconinidinium- N -Methyl] naphthalene dibromide (10-1)

Compound 9-1 (300 mg, 0.33 mmol) obtained by the method of Example 11 was suspended in dichloromethane (2 mL), followed by 50% aqueous potassium hydroxide solution (0.37 mL, 3.3 mmol) and allyl bromide (0.17 mL, 1.98 mmol). ) Was added and stirred at room temperature for 6 hours. The reaction solution was diluted with water (5 mL), extracted with dichloromethane (2 × 20 mL), and the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-hexanes to give the desired product (150 mg) as a brown solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 9.01 (d, J = 4.4 Hz, 2H), 8.16-8.33 (m, 8H), 7.63-8.13 (m, 8H), 6.05-6.15 (m, 4H), 5.65-5.72 (m, 2H), 5.22-5.41 (m, 6H), 4.35-4.41 (m, 4H), 4.25-4.36 (m, 2H), 3.93-4.10 (m, 2H), 3.69- 3.88 (m, 2H), 3.60-3.72 (m, 2H), 3.44-3.53 (m, 2H), 2.08-2.29 (m, 4H), 1.97-2.06 (m, 2H), 1.69-1.95 (m, 4H ), 1.42-1.53 (m, 2H), 1.20-1.35 (m, 4H), 0.72 (t, J = 7.1 Hz, 6H).

Example 13: 2,3-bis (syncondinium- N -Methyl) naphthalene dibromide (11)

To a 50 mL round bottom flask was placed 2,3-bis (bromomethyl) naphthalene (523 mg, 1.664 mmol) in (-)-cinconidine [(-)-cinchonidine] (1.0 g, 3.40 mmol). The mixture was stirred under reflux for 4 hours in a N , N -dimethylformamide: chloroform (5: 6: 2) mixed solvent (5 mL). The reaction mixture was cooled to room temperature, diluted with methanol (15 ml), and added dropwise to ether (300 mL) to precipitate a solid, which was filtered under reduced pressure. The obtained solid was recrystallized from methanol-ether to give the desired product (1.10 g) as a light brown solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 9.00 (d, J = 4.4 Hz, 2H), 8.75 (s, 2H), 8.31-8.50 (m, 2H), 7.92-8.22 (m, 4H) , 7.70-7.85 (m, 8H), 6.65-6.74 (m, 4H), 5.52-5.76 (m, 4H), 4.95-5.32 (m, 6H), 4.48-5.08 (m, 2H), 4.22-4.31 ( m, 2H), 3.98-4.15 (m, 2H), 3.01-3.14 (m, 2H), 2.59-2.76 (m, 2H), 1.95-2.38 (m, 8H), 1.64-1.81 (m, 2H), 1.25-1.39 (m, 2 H).

Example 14: 2,3-bis [ O (9) -allylconydinium- N -Methyl] niphthalene dibromide (12)

Compound 11 (300 mg, 0.333 mmol) obtained by the method of Example 13 was suspended in dichloromethane (2 mL), followed by 50% aqueous potassium hydroxide solution (0.38 mL, 3.33 mmol) and allyl bromide (0.18 mL, 1.998 mmol). Put and stirred at room temperature for 12 hours. The reaction solution was diluted with water (5 mL), extracted with dichloromethane (2 × 20 mL), and the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-hexane to give the desired product (250 mg) as a tan solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 8.90-9.11 (m, 2H), 8.00-8.45 (m, 8H), 7.55-7.98 (m, 8H), 5.85-6.24 (m, 4H), 5.61-5.80 (m, 4H), 4.77-5.56 (m, 10H), 4.39-4.52 (m, 2H), 3.60-4.12 (m, 8H), 3.35-3.52 (m, 4H), 2.65-2.87 (m , 2H), 1.84-2.37 (m, 8H), 1.30-1.55 (m, 2H).

Example 15 2,3-bis (hydrocinconidinium- N Methyl) naphthalene dibromide (11-1)

To a 50 mL round bottom flask was placed 2,3-bis (bromomethyl) naphthalene (260 mg, 0.827 mmol) in (-)-hydrocinchonidine [(-)-hydrocinchonidine] (500 mg, 1.687 mmol). : N , N -dimethylformamide: chloroform (5: 6: 2) was stirred under reflux for 4 hours in a mixed solvent (4 mL). The reaction mixture was cooled to room temperature, diluted with methanol (5 ml), and added dropwise to ether (100 mL) to precipitate a solid, which was filtered under reduced pressure. The solid obtained was recrystallized from methanol-ether to give the desired product (580 mg) as a yellow solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 9.01 (d, J = 4.4 Hz, 2H), 8.65 (s, 2H), 8.21-8.45 (m, 2H), 7.92-8.18 (m, 4H) , 7.62-7.85 (m, 8H), 6.63-6.75 (m, 4H), 5.47-5.59 (m, 2H), 5.15-5.22 (m, 2H), 4.41-4.51 (m, 2H), 4.05-4.20 ( m, 2H), 3.46-3.61 (m, 4H), 3.25-3.34 (m, 2H), 2.02-2.31 (m, 4H), 1.85-2.00 (m, 2H), 1.62-1.80 (m, 4H), 1.25-1.49 (m, 2H), 1.04-1.24 (m, 4H), 0.76 (t, J = 7.3 Hz, 6H).

Example 16: 2,3-bis [ O (9) -allylhydrocinconinidinium- N -Methyl] naphthalene dibromide (12-1)

Compound 11-1 (300 mg, 0.33 mmol) obtained by the method of Example 15 was suspended in dichloromethane (2 mL), followed by 50% aqueous potassium hydroxide solution (0.37 mL, 3.3 mmol) and allyl bromide (0.17 mL, 1.98 mmol). ) Was added and stirred at room temperature for 6 hours. The reaction solution was diluted with water (5 mL), extracted with dichloromethane (2 × 20 mL), and the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-hexanes to give the desired product (120 mg) as a dark brown solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 8.98 (d, J = 4.5 Hz, 2H), 7.63-8.13 (m, 16H), 6.01-6.13 (m, 4H), 5.73-5.86 (m, 2H), 5.22-5.41 (m, 6H), 4.35-4.41 (m, 4H), 4.23-4.34 (m, 2H), 3.90-4.05 (m, 2H), 3.76-3.88 (m, 2H), 3.61- 3.72 (m, 2H), 3.44-3.53 (m, 2H), 2.01-2.29 (m, 4H), 1.95-2.00 (m, 2H), 1.75-1.98 (m, 4H), 1.44-1.55 (m, 2H ), 1.17-1.33 (m, 4H), 0.75 (t, J = 7.2 Hz, 6H).

Example 17: 2,6-bis (syncondidinium- N -Methyl) naphthalene dibromide (13)

To a 50 mL round bottom flask was added 2,6-bis (bromomethyl) naphthalene (523 mg, 1.664 mmol) in (-)-cinconidine [(-)-cinchonidine] (1.0 g, 3.40 mmol). The mixture was stirred under reflux for 4 hours in a N , N -dimethylformamide: chloroform (5: 6: 2) mixed solvent (5 mL). Ether (100 mL) was added to the reaction mixture, and the precipitated solid was filtered under reduced pressure. The solid obtained was recrystallized from methanol-ether to give the desired product (940 mg) as a pale yellow solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 9.00 (d, J = 4.1 Hz, 2H), 8.46 (s, 2H), 8.37-8.36 (m, 2H), 8.16-8.23 (m, 2H) , 8.04-8.15 (m, 2H), 7.98-8.04 (m, 2H), 7.74-7.96 (m, 6H), 6.81 (d, J = 4.4 Hz, 2H), 6.62 (s, 2H), 5.64-5.76 (m, 2H), 5.05-5.42 (m, 6H), 4.96-5.03 (m, 2H), 4.25-4.41 (m, 2H), 3.75-4.14 (m, 4H), 3.33-3.53 (m, 2H) , 2.58-2.74 (m, 2H), 2.05-2.13 (m, 6H), 1.98-2.03 (m, 2H), 1.80-1.94 (m, 2H), 1.25-1.36 (m, 2H).

Example 18: 2,6-bis [ O (9) -allylconydinium- N -Methyl] naphthalene dibromide (14)

Compound 13 (300 mg, 0.333 mmol) obtained by the method of Example 17 was suspended in dichloromethane (2 mL), followed by 50% aqueous potassium hydroxide solution (0.38 mL, 3.33 mmol) and allyl bromide (0.18 mL, 1.998 mmol). The mixture was stirred at room temperature for 20 hours. The reaction solution was diluted with water (5 mL), extracted with dichloromethane (2 × 20 mL), and the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-hexanes to give the desired product (230 mg) as a pale yellow solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 8.95-9.04 (m, 2H), 8.14-8.50 (m, 8H), 7.66-8.10 (m, 8H), 6.42-6.55 (m, 2H), 6.20-6.34 (m, 2H), 5.69-5.78 (m, 2H), 5.25-5.52 (m, 6H), 4.89-5.24 (m, 6H), 4.32-4.49 (m, 2H), 3.92-4.29 (m , 6H), 3.57-3.78 (m, 2H), 3.35-3.78 (m, 2H), 2.61-2.72 (m, 2H), 2.25-2.41 (m, 2H), 1.92-2.20 (m, 6H), 1.75 -1.89 (m, 2 H), 1.44-1.62 (m, 2 H).

Example 19: 2,6-bis (hydrocinconidinium- N Methyl) naphthalene dibromide (13-1)

To a 50 mL round bottom flask, add 2,6-bis (bromomethyl) naphthalene (260 mg, 0.827 mmol) to (-)-hydrocinconidine [(-)-hydrocinchonidine] (500 mg, 1.687 mmol). : N , N -dimethylformamide: chloroform (5: 6: 2) was stirred under reflux for 4 hours in a mixed solvent (4 mL). The reaction mixture was cooled to room temperature, diluted with methanol (5 ml), and added dropwise to ether (100 mL) to precipitate a solid, which was filtered under reduced pressure. The solid obtained was recrystallized from methanol-ether to give the desired product (610 mg) as a yellow solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 9.00 (d, J = 4.1 Hz, 2H), 8.26-8.41 (m, 4H), 8.01-8.20 (m, 4H), 7.62-7.95 (m, 8H), 6.61-6.78 (m, 2H), 6.45 (s, 2H), 5.35 (d, J = 12.5 Hz, 2H), 5.15 (d, J = 11.7 Hz, 2H), 4.27-4.41 (m, 2H ), 3.92-4.05 (m, 2H), 3.45-3.59 (m, 4H), 3.12-3.27 (m, 2H), 2.00-2.25 (m, 4H), 1.91-1.99 (m, 2H), 1.60-1.72 (m, 4H), 1.39-1.48 (m, 2H), 1.11-1.27 (m, 4H), 0.71 (t, J = 7.1 Hz, 6H).

Example 20: 2,6-bis [ O (9) -allylhydrocinconinidinium- N -Methyl] naphthalene dibromide (14-1)

Compound 13-1 (300 mg, 0.33 mmol) obtained by the method of Example 19 was suspended in dichloromethane (2 mL), followed by 50% aqueous potassium hydroxide solution (0.37 mL, 3.3 mmol) and allyl bromide (0.17 mL, 1.98 mmol). ) Was added and stirred at room temperature for 6 hours. The reaction solution was diluted with water (5 mL), extracted with dichloromethane (2 × 20 mL), and the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-hexane to give the desired product (220 mg) as a brown solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 8.98 (d, J = 4.4 Hz, 2H), 8.11-8.43 (m, 8H), 7.72-7.95 (m, 8H), 6.50 (s, 2H) , 6.01-6.33 (m, 4H), 5.80-5.89 (m, 2H), 5.22-5.52 (m, 4H), 4.35-4.41 (m, 2H), 4.10-4.25 (m, 6H), 3.45-3.65 ( m, 2H), 3.24-3.39 (m, 4H), 2.27-2.39 (m, 2H), 2.14-2.24 (m, 2H), 1.92-2.05 (m, 2H), 1.65-1.80 (m, 4H), 1.44-1.61 (m, 2H), 1.15-1.32 (m, 4H), 0.69 (t, J = 7.2 Hz, 6H).

Example 21: 2,7-bis (syncondinium- N -Methyl) naphthalene dibromide (15)

To a 50 mL round bottom flask was placed 2,7-bis (bromomethyl) naphthalene (523 mg, 1.664 mmol) in (-)-cinconidine [(-)-cinchonidine] (1.0 g, 3.40 mmol). The mixture was stirred under reflux for 4 hours in a N , N -dimethylformamide: chloroform (5: 6: 2) mixed solvent (5 mL). Ether (100 mL) was added to the reaction mixture, and the precipitated solid was filtered under reduced pressure. The obtained solid was recrystallized from methanol-ether to give the desired product (1.26 g) as a pale yellow solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 8.99 (d, J = 4.7 Hz, 2H), 8.45 (s, 2H), 8.35 (d, J = 8.0 Hz, 2H), 8.22 (d, J = 8.5 Hz, 2H), 8.12 (d, J = 8.3 Hz, 2H), 7.95-8.10 (m, 2H), 7.76-7.90 (m, 4H), 7.62-7.72 (m, 2H), 6.81 (d, J = 4.4 Hz, 2H), 6.64 (s, 2H), 5.67-5.76 (m, 2H), 5.23-5.43 (m, 6H), 4.97 (d, J = 10.5 Hz, 2H), 4.36-4.50 (m , 2H), 3.91-4.05 (m, 4H), 3.36-3.51 (m, 4H), 2.60-2.71 (m, 2H), 1.92-2.30 (m, 6H), 1.68-1.91 (m, 2H), 1.32 -1.43 (m, 2 H).

Example 22: 2,7-bis [ O (9) -allylconydinium- N -Methyl] naphthalene dibromide (16)

Compound 15 (500 mg, 0.554 mmol) obtained by the method of Example 21 was suspended in dichloromethane (3 mL), followed by 50% aqueous potassium hydroxide solution (0.62 mL, 5.54 mmol) and allyl bromide (0.29 mL, 3.324 mmol). Put and stirred at room temperature for 5 hours. The reaction solution was diluted with water (10 mL), extracted with dichloromethane (2 x 30 mL), and the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-hexane to give the desired product (490 mg) as a white solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 9.03 (d, J = 4.4 Hz, 2H), 8.46 (s, 2H), 8.32 (d, J = 9.0 Hz, 2H), 8.25 (d, J = 8.5 Hz, 2H), 8.15 (d, J = 9.0 Hz, 2H), 7.98 (d, J = 8.8 Hz, 2H), 7.86-7.94 (m, 2H), 7.72 (d, J = 4.4 Hz, 2H ), 6.53 (s, 2H), 6.16-6.24 (m, 2H), 5.67-5.78 (m, 2H), 5.48-5.55 (m, 2H), 5.32-5.45 (m, 4H), 5.05-5.40 (m , 4H), 4.91-5.01 (m, 2H), 4.35-4.50 (m, 2H), 3.98-4.27 (m, 6H), 3.72-3.90 (m, 2H), 3.33-3.51 (m, 4H), 2.52 -2.74 (m, 2H), 2.24-2.40 (m, 2H), 1.96-2.20 (m, 4H), 1.76-1.93 (m, 2H), 1.42-1.53 (m, 2H).

Example 23: 2,7-bis (hydrocinconidinium- N Methyl) naphthalene dibromide (15-1)

To a 50 mL round bottom flask was placed 2,7-bis (bromomethyl) naphthalene (520 mg, 1.653 mmol) in (-)-hydrocinconidine [(-)-hydrocinchonidine] (1 g, 3.373 mmol). : N , N -dimethylformamide: chloroform (5: 6: 2) was refluxed under stirring for 6 hours in a mixed solvent (5 mL). To the reaction mixture was added dropwise to ether (50 mL) to precipitate a solid which was filtered under reduced pressure. The solid obtained was recrystallized from methanol-ether to give the desired product (1.4 g) as a pink solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 9.00 (d, J = 4.4 Hz, 2H), 8.31-8.37 (m, 4H), 8.21 (d, J = 8.6 Hz, 2H), 8.12 (d , J = 8.6 Hz, 2H), 7.93 (d, J = 7.8 Hz, 2H), 7.82-7.88 (m, 4H), 7.71-7.76 (m, 2H), 6.77 (d, J = 4.6 Hz, 2H) , 6.63 (s, 2H), 5.36 (d, J = 12.4 Hz, 2H), 5.15 (d, J = 12.7 Hz, 2H), 4.32-4.43 (m, 2H), 3.96-4.02 (m, 2H), 3.41-3.54 (m, 2H), 3.27-3.39 (m, 4H), 2.05-2.20 (m, 4H), 1.92-2.01 (m, 2H), 1.61-1.73 (m, 4H), 1.36-1.48 (m , 2H), 1.23-1.31 (m, 4H), 0.71 (t, J = 7.3 Hz, 6H).

Example 24: 2,7-bis [ O (9) -allylhydrocinconinidinium- N -Methyl] naphthalene dibromide (16-1)

Compound 15-1 (600 mg, 0.662 mmol) obtained by the method of Example 23 was suspended in dichloromethane (3 mL), followed by 50% aqueous potassium hydroxide solution (0.75 mL, 6.62 mmol) and allyl bromide (0.35 mL, 3.972 mmol). ) Was added and stirred at room temperature for 4 hours. The reaction solution was diluted with water (5 mL), extracted with dichloromethane (2 × 20 mL), and the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-hexane to give the desired product (605 mg) as a pale orange solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 9.03 (d, J = 4.4 Hz, 2H), 8.41 (s, 2H), 8.29 (d, J = 8.5 Hz, 2H), 8.23 (d, J = 8.5 Hz, 2H), 8.15 (d, J = 7.6 Hz, 2H), 7.76-8.00 (m, 4H), 7.62-7.74 (m, 4H), 6.50 (s, 2H), 6.15-6.24 (m, 2H), 5.50 (d, J = 17.3 Hz, 2H), 5.25-5.45 (m, 4H), 5.09 (d, J = 12.2 Hz, 2H), 4.42 (d, J = 12.7 Hz, 2H), 4.02- 4.22 (m, 6H), 3.50-3.61 (m, 2H), 3.24-3.49 (m, 4H), 2.31-2.39 (m, 2H), 2.11-2.25 (m, 2H), 1.92-2.05 (m, 2H ), 1.65-1.81 (m, 4H), 1.44-1.61 (m, 2H), 1.15-1.34 (m, 4H), 0.71 (t, J = 7.3 Hz, 6H).

Example 25: 2,7-bis [ O (9) -benzylhydrocinconinidinium- N -Methyl] naphthalene dibromide (16-1-1)

Compound 15-1 (200 mg, 0.22 mmol) obtained by the method of Example 23 was suspended in dichloromethane (2 mL), followed by 50% aqueous potassium hydroxide solution (0.25 mL, 2.2 mmol) and benzylbromide (0.25 mL, 1.32 mmol ) Was added and stirred at room temperature for 4 hours. The reaction solution was diluted with water (5 mL), extracted with dichloromethane (2 × 20 mL), and the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-hexanes to give the desired product (195 mg) as a pale yellow solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 9.05 (d, J = 4.4 Hz, 2H), 8.25-8.32 (m, 4H), 8.13-8.22 (m, 4H), 7.81-7.90 (m, 4H), 7.72-7.80 (m, 4H), 7.61-7.68 (m, 4H), 7.48-7.53 (m, 4H), 7.35-7.42 (m, 2H), 6.60 (s, 2H), 5.29 (d, J = 12.2 Hz, 2H), 5.05 (d, J = 12.0 Hz, 2H), 4.93 (d, J = 11.2 Hz, 2H), 4.58 (d, J = 11.2 Hz, 2H), 3.92-4.15 (m, 4H), 3.48-3.59 (m, 2H), 3.25-3.42 (m, 4H), 2.32-2.41 (m, 2H), 1.91-2.19 (m, 4H), 1.65-1.80 (m, 4H), 1.44- 1.58 (m, 2H), 1.19-1.30 (m, 4H), 0.70 (t, J = 7.2 Hz, 6H).

Example 26: 2,7-bis (synconium- N -Methyl) naphthalene dibromide (27)

To a 50 mL round bottom flask was placed 2,7-bis (bromomethyl) naphthalene (261 mg, 0.832 mmol) in (+)-cinconine [(+)-cinchonine] (500 mg, 1.698 mmol) and ethanol: N The mixture was stirred under reflux for 4 hours in a mixed solvent of N -dimethylformamide: chloroform (5: 6: 2) (3 mL). The reaction mixture was diluted with methanol (5 mL), added to ether (60 mL), and the precipitated solid was filtered under reduced pressure. The obtained solid was recrystallized from methanol-ether to give the desired product (730 mg) as a pink solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 9.00 (d, J = 4.4 Hz, 2H), 8.50 (s, 2H), 8.39 (d, J = 8.3 Hz, 2H), 8.23 (d, J = 8.5 Hz, 2H), 8.12 (d, J = 7.3 Hz, 2H), 7.83-7.88 (m, 4H), 7.72-7.77 (m, 2H), 6.87 (d, J = 3.7 Hz, 2H), 6.59 (s, 2H), 5.97-6.08 (m, 2H), 5.36 (d, J = 12.5 Hz, 2H), 5.14-5.25 (m, 6H), 4.28-4.36 (m, 2H), 4.01-4.11 (m , 4H), 3.59-3.67 (m, 2H), 3.02-3.06 (m, 2H), 2.61-2.64 (m, 2H), 2.29-2.48 (m, 2H), 1.83-2.07 (m, 6H), 1.06 -1.11 (m, 2 H).

Example 27: 2,7-bis [ O (9) -allylconinium- N -Methyl] naphthalene dibromide (28)

Compound 27 (300 mg, 0.33 mmol) obtained by the method of Example 26 was suspended in dichloromethane (3 mL), followed by 50% aqueous potassium hydroxide solution (0.37 mL, 3.3 mmol) and allyl bromide (0.17 mL, 1.98 mmol). The mixture was stirred at room temperature for 10 hours. The reaction solution was diluted with water (10 mL), extracted with dichloromethane (2 × 20 mL), and the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-hexanes to give the desired product (300 mg) as an orange solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 8.97-9.03 (m, 2H), 7.95-8.49 (m, 10H), 7.72-7.92 (m, 6H), 6.41-6.55 (m, 2H), 6.24-6.31 (m, 2H), 5.95-6.15 (m, 2H), 5.19-5.53 (m, 12H), 4.26-4.45 (m, 2H), 3.94-4.24 (m, 8H), 3.52-3.74 (m , 2H), 2.85-3.15 (m, 2H), 2.54-2.61 (m, 2H), 2.25-2.93 (m, 2H), 1.82-1.99 (m, 2H), 1.67-1.80 (m, 4H), 1.12 -1.21 (m, 2 H).

Example 28: 2,7-bis (hydrocinconinium- N Methyl) naphthalene dibromide (27-1)

To a 50 mL round bottom flask was added 2,7-bis (bromomethyl) naphthalene (260 mg, 0.827 mmol) in (+)-hydrocinconin [(+)-hydrocinchonine] (500 mg, 1.687 mmol). The mixture was stirred under reflux for 4 hours in a N , N -dimethylformamide: chloroform (5: 6: 2) mixed solvent (5 mL). The reaction mixture was diluted with methanol (5 mL) and added dropwise to ether (100 mL) to precipitate a solid which was filtered under reduced pressure. The obtained solid was recrystallized from methanol-ether to give the desired product (630 mg) as a pink solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 9.00 (d, J = 4.4 Hz, 2H), 8.50 (s, 2H), 8.37 (d, J = 8.5 Hz, 2H), 8.22 (d, J = 8.5 Hz, 2H), 8.12 (d, J = 8.3 Hz, 2H), 8.01 (d, J = 8.0 Hz, 2H), 7.81-7.92 (m, 4H), 7.71-7.79 (m, 2H), 6.84 (d, J = 3.9 Hz, 2H), 6.57 (s, 2H), 5.33 (d, J = 12.9 Hz, 2H), 5.12 (d, J = 12.1 Hz, 2H), 3.97-4.09 (m, 6H) , 3.56-3.60 (m, 2H), 2.97-3.00 (m, 2H), 2.25-2.29 (m, 2H), 1.60-1.89 (m, 8H), 1.42-1.58 (m, 4H), 0.96-1.15 ( m, 2H), 0.85 (t, J = 7.3 Hz, 6H).

Example 29: 2,7-bis [ O (9) -allyl hydrocinconinium- N -Methyl] naphthalene dibromide (28-1)

Compound 27-1 (300 mg, 0.33 mmol) obtained by the method of Example 28 was suspended in dichloromethane (2 mL), followed by 50% aqueous potassium hydroxide solution (0.37 mL, 3.3 mmol) and allyl bromide (0.17 mL, 1.98 mmol). ) Was added and stirred at room temperature for 4 hours. The reaction solution was diluted with water (5 mL), extracted with dichloromethane (2 × 20 mL), and the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-hexane to give the desired product (270 mg) as a pale yellow solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 9.03 (d, J = 4.2 Hz, 2H), 8.13-8.46 (m, 8H), 7.73-8.10 (m, 8H), 6.41-6.44 (m, 2H), 6.12-6.24 (m, 2H), 5.27-5.50 (m, 8H), 4.26-4.40 (m, 2H), 3.79-4.15 (m, 8H), 3.57-3.69 (m, 2H), 2.85- 3.05 (m, 2H), 2.26-2.41 (m, 2H), 1.61-1.92 (m, 8H), 1.45-1.58 (m, 4H), 1.17-1.30 (m, 2H), 0.84 (t, J = 7.3 Hz, 6H).

Example 30: 2,7-bis (quinium- N Methyl) naphthalene dibromide (15-2)

To a 50 mL round bottom flask was placed 2,7-bis (bromomethyl) naphthalene (237 mg, 0.755 mmol) in (-)-quinine [(-)-quinine] (500 mg, 1.541 mmol) and ethanol: N , The mixture was stirred under reflux for 4 hours in a mixed solvent of N -dimethylformamide: chloroform (5: 6: 2) (3 mL). The reaction mixture was diluted with methanol (5 mL), added to ether (60 mL), and the precipitated solid was filtered under reduced pressure. The solid obtained was recrystallized from methanol-ether to give the desired product (656 mg) as a pale orange solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 8.82 (d, J = 3.5 Hz, 2H), 8.30 (s, 2H), 8.19 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 9.0 Hz, 2H), 7.90 (d, J = 9.5 Hz, 2H), 7.76 (d, J = 4.6 Hz, 2H), 7.44-7.53 (m, 4H), 6.74 (d, J = 4.1 Hz, 2H ), 6.65 (s, 2H), 5.72-5.83 (m, 2H), 5.62 (d, J = 12.2 Hz, 2H), 5.13 (d, J = 17.4 Hz, 2H), 5.02 (d, J = 10.5 Hz , 2H), 4.92 (d, J = 12.2 Hz, 2H), 4.25-4.35 (m, 2H), 4.00 (s, 6H), 3.91-3.99 (m, 2H), 3.60-3.85 (m, 2H), 3.39-3.50 (m, 4H), 2.60-2.71 (m, 2H), 2.21-2.42 (m, 4H), 1.95-2.10 (m, 2H), 1.70-1.85 (m, 2H), 1.45-1.65 (m , 2H).

Example 31: 2,7-bis [ O (9) -allylquininium- N -Methyl] naphthalene dibromide (16-2)

Compound 15-2 (300 mg, 0.312 mmol) obtained by the method of Example 30 was suspended in dichloromethane (2 mL), followed by 50% aqueous potassium hydroxide solution (0.35 mL, 3.12 mmol) and allyl bromide (0.16 mL, 1.872 mmol). ) Was added and stirred at room temperature for 10 hours. The reaction solution was diluted with water (10 mL), extracted with dichloromethane (2 x 30 mL), and the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-hexanes to give the desired product (255 mg) as a pink solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 8.86 (d, J = 4.1 Hz, 2H), 8.39 (s, 2H), 8.22 (d, J = 8.3 Hz, 2H), 8.07 (d, J = 9.2 Hz, 2H), 7.92 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 4.4 Hz, 2H), 7.53 (d, J = 9.0 Hz, 2H), 7.46 (s, 2H), 6.59 (s, 2H), 6.15-6.22 (m, 2H), 5.71-5.83 (m, 2H), 5.50 (d, J = 17.0 Hz, 2H), 5.31 (d, J = 10.7 Hz, 2H), 4.90 -5.13 (m, 8H), 4.42-4.56 (m, 2H), 3.99 (s, 6H), 3.95-4.14 (m, 8H), 3.65-3.80 (m, 2H), 3.35-3.50 (m, 2H) , 2.68-2.74 (m, 2H), 2.37-2.48 (m, 2H), 2.15-2.35 (m, 2H), 1.97-2.10 (m, 2H), 1.78-1.95 (m, 2H), 1.47-1.72 ( m, 2H).

Example 32: 2,7-bis [hydroquininium- N -Methyl] naphthalene dibromide (15-3)

To a 50 mL round bottom flask was placed 2,7-bis (bromomethyl) naphthalene (236 mg, 0.751 mmol) in (-)-hydroquinine [(-)-hydroquinine] (500 mg, 1.532 mmol) and ethanol: N The mixture was stirred under reflux for 4 hours in a mixed solvent of N -dimethylformamide: chloroform (5: 6: 2) (3 mL). The reaction mixture was diluted with methanol (5 mL) and added dropwise to ether (100 mL) to precipitate a solid which was filtered under reduced pressure. The solid obtained was recrystallized from methanol-ether to give the desired product (670 mg) as a pink solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 8.82 (d, J = 4.4 Hz, 2H), 8.25 (s, 2H), 8.18 (d, J = 8.5 Hz, 2H), 8.00-8.09 (m , 2H), 7.84-7.98 (m, 2H), 7.76 (d, J = 4.1 Hz, 2H), 7.42-7.56 (m, 4H), 6.71 (d, J = 4.1 Hz, 2H), 6.64 (s, 2H), 5.57 (d, J = 12.7 Hz, 2H), 4.86 (d, J = 12.7 Hz, 2H), 4.25-4.38 (m, 2H), 4.01 (s, 6H), 3.80-3.95 (m, 2H ), 3.41-3.52 (m, 4H), 3.19-3.31 (m, 2H), 2.12-2.36 (m, 4H), 1.90-2.05 (m, 2H), 1.72-1.82 (m, 4H), 1.45-1.54 (m, 2H), 1.20-1.35 (m, 4H), 0.73 (t, J = 7.2 Hz, 6H).

Example 33: 2,7-bis [ O (9) -allylhydroquininium- N -Methyl] naphthalene dibromide (16-3)

Compound 15-3 (300 mg, 0.31 mmol) obtained by the method of Example 32 was suspended in dichloromethane (2 mL), followed by 50% aqueous potassium hydroxide solution (0.35 mL, 3.1 mmol) and allyl bromide (0.16 mL, 1.86 mmol). ) Was added and stirred at room temperature for 4 hours. The reaction solution was diluted with water (5 mL), extracted with dichloromethane (2 × 20 mL), and the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-hexane to give the desired product (280 mg) as a pale pink solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 8.86 (d, J = 4.4 Hz, 2H), 8.37 (s, 2H), 8.22 (d, J = 8.3 Hz, 2H), 8.06 (d, J = 9.0 Hz, 2H), 7.89 (d, J = 9.5 Hz, 2H), 7.68 (d, J = 4.4 Hz, 2H), 7.45-7.54 (m, 4H), 6.58 (s, 2H), 6.11-6.24 (m, 2H), 5.72 (d, J = 11.2 Hz, 2H), 5.50 (d, J = 17.3 Hz, 2H), 5.31 (d, J = 10.5 Hz, 2H), 4.85 (d, J = 12.4 Hz , 2H), 4.51 (d, J = 7.6 Hz, 2H), 3.92-4.08 (m, 6H), 4.01 (s, 6H), 3.28-3.51 (m, 8H), 2.41-2.49 (m, 2H), 2.20-2.35 (m, 2H), 1.92-2.03 (m, 2H), 1.72-1.85 (m, 2H), 1.52-1.69 (m, 2H), 1.22-1.31 (m, 4H), 0.72 (t, J = 7.4 Hz, 6H).

Example 34: 2,7-bis [quinidinium- N -Methyl] naphthalene dibromide (27-2)

To a 50 mL round bottom flask was added 2,7-bis (bromomethyl) naphthalene (237 mg, 0.755 mmol) to (+)-quinidine [(+)-quinidine] (500 mg, 1.541 mmol) and ethanol: N The mixture was stirred under reflux for 4 hours in a mixed solvent of N -dimethylformamide: chloroform (5: 6: 2) (3 mL). The reaction mixture was diluted with methanol (5 mL), added to ether (60 mL), and the precipitated solid was filtered under reduced pressure. The solid obtained was recrystallized from methanol-ether to give the desired product (656 mg) as a light brown solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 8.84 (d, J = 4.4 Hz, 2H), 8.46 (s, 2H), 8.22 (d, J = 8.3 Hz, 2H), 8.04 (d, J = 9.0 Hz, 2H), 7.93 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 4.4 Hz, 2H), 7.54 (d, J = 2.4 Hz, 2H), 7.50 (s, 2H), 6.88 (d, J = 3.4 Hz, 2H), 6.59 (s, 2H), 5.99-6.11 (m, 2H), 5.20-5.27 (m, 6H), 4.99 (d, J = 12.7 Hz, 2H), 4.29 -4.35 (m, 2H), 4.08 (s, 6H), 3.92-4.07 (m, 4H), 3.59-3.67 (m, 2H), 2.95-3.05 (m, 2H), 2.60-2.65 (m, 2H) , 2.37-2.45 (m, 2H), 1.91 (s, 2H), 1.79-1.83 (m, 4H), 1.10-1.16 (m, 2H).

Example 35: 2,7-bis [ O (9) -allylquininidinium- N -Methyl] naphthalene dibromide (28-2)

Compound 27-2 (300 mg, 0.312 mmol) obtained by the method of Example 34 was suspended in dichloromethane (2 mL), followed by 50% aqueous potassium hydroxide solution (0.35 mL, 3.12 mmol) and allyl bromide (0.16 mL, 1.872 mmol). ) Was added and stirred at room temperature for 10 hours. The reaction solution was diluted with water (10 mL), extracted with dichloromethane (2 x 30 mL), and the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-hexane to give the desired product (270 mg) as a pink solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 8.85 (d, J = 4.4 Hz, 2H), 8.46 (s, 2H), 8.23 (d, J = 8.3 Hz, 2H), 8.06 (d, J = 9.3 Hz, 2H), 8.04 (d, J = 9.2 Hz, 2H), 7.93 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 4.7 Hz, 2H), 7.51-7.57 (m, 2H ), 6.48 (s, 2H), 6.17-6.26 (m, 2H), 5.96-6.02 (m, 2H), 5.50 (d, J = 17.3 Hz, 2H), 5.34 (d, J = 10.7 Hz, 2H) , 5.18-5.30 (m, 4H), 4.85-5.11 (m, 2H), 4.35-4.49 (m, 2H), 3.82-4.07 (m, 10H), 4.01 (s, 6H), 3.60-3.76 (m, 4H), 2.85-3.10 (m, 2H), 2.61-2.69 (m, 2H), 1.91-2.00 (m, 2H), 1.72-1.88 (m, 4H), 1.22-1.29 (m, 2H).

Example 36: 2,7-bis [hydroquininidinium- N -Methyl] naphthalene dibromide (27-3)

To a 50 mL round bottom flask was placed 2,7-bis (bromomethyl) naphthalene (236 mg, 0.751 mmol) in (+)-hydroquinidine [(+)-hydroquinidine] (500 mg, 1.532 mmol) and ethanol: It was stirred under reflux for 4 hours in a N , N -dimethylformamide: chloroform (5: 6: 2) mixed solvent (3 mL). The reaction mixture was diluted with methanol (5 mL) and added dropwise to ether (100 mL) to precipitate a solid which was filtered under reduced pressure. The solid obtained was recrystallized from methanol-ether to give the desired product (680 mg) as a pink solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 8.84 (d, J = 4.4 Hz, 2H), 8.44 (s, 2H), 8.22 (d, J = 8.3 Hz, 2H), 8.04 (d, J = 9.3 Hz, 2H), 7.92 (d, J = 9.8 Hz, 2H), 7.83 (d, J = 4.4 Hz, 2H), 7.51 (d, J = 9.3 Hz, 2H), 7.47 (s, 2H), 6.83 (d, J = 3.2 Hz, 2H), 6.58 (s, 2H), 5.20 (d, J = 12.2 Hz, 2H), 4.95 (d, J = 12.5 Hz, 2H), 4.07 (s, 2H), 3.99-4.02 (m, 4H), 3.88-3.94 (m, 2H), 3.60-3.66 (m, 2H), 2.90-2.99 (m, 2H), 2.38-2.42 (m, 2H), 1.74-1.88 (m , 8H), 1.53-1.58 (m, 4H), 1.04-1.10 (m, 2H), 0.86 (t, J = 7.2 Hz, 2H).

Example 37: 2,7-bis [ O (9) -allylhydroquininidinium- N -Methyl] naphthalene dibromide (28-3)

Compound 27-3 (300 mg, 0.31 mmol) obtained by the method of Example 36 was suspended in dichloromethane (2 mL), followed by 50% aqueous potassium hydroxide solution (0.35 mL, 3.1 mmol) and allyl bromide (0.16 mL, 1.86 mmol). ) Was added and stirred at room temperature for 4 hours. The reaction solution was diluted with water (5 mL), extracted with dichloromethane (2 × 20 mL), and the dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-hexanes to give the desired product (280 mg) as a dark pink solid.

¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 8.86 (d, J = 4.4 Hz, 2H), 8.44 (s, 2H), 8.23 (d, J = 8.3 Hz, 2H), 8.05 (d, J = 9.3 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 4.4 Hz, 2H), 7.52-7.56 (m, 4H), 6.47 (s, 2H), 6.14-6.23 (m, 2H), 5.50 (d, J = 17.7 Hz, 2H), 5.34 (d, J = 10.5 Hz, 2H), 4.92-5.10 (m, 4H), 4.39-4.42 (m, 2H), 4.07 ( s, 2H), 3.90-4.04 (m, 8H), 3.55-3.73 (m, 2H), 2.90-2.94 (m, 2H), 2.49-2.52 (m, 2H), 1.85-1.93 (m, 2H), 1.62-1.80 (m, 6H), 1.53-1.58 (m, 4H), 1.15-1.34 (m, 2H), 0.87 (t, J = 7.3 Hz, 2H).

Experimental Example: Asymmetric Phase Transfer Catalysis Under Reaction Conditions N- (Diphenylmethylene) glycine tert Alkylation of butyl ester (benzylation)

Toluene / chloroform (volume ratio = 7: 3, 0.75 mL) and 50% aqueous potassium hydroxide solution (0.25) in N- (diphenylmethylene) glycine tert -butyl ester (50 mg, 0.17 mmol) and asymmetric phase transfer catalyst (0.0085 mmol) mL, 13.0 mmol) was added, and the reaction solution was cooled to 0 ° C., and then benzyl bromide (0.1 mL, 0.85 mmol) was added thereto. The reaction mixture was stirred at 0 ° C. until the substrate was gone. The reaction mixture was diluted with ether (20 mL), the organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was separated by column (mobile phase; hexane: ethyl acetate = 50: 1) to obtain a colorless liquid target product, ( S ) -2- (benzhydrylideneamino) -3-phenylpropionic acid tert -butyl ester. The optical purity of the obtained target product was measured by asymmetric high performance liquid chromatography. [Operating conditions of the equipment; ① Column: DAICEL Chiralcel OD, ② Mobile phase: Hexane: 2-propanol = 500: 2.5, ③ Flow rate: 1.0 mL / min, ④ Measurement temperature: 23 ℃, ⑤ Detector: UV absorbance (wavelength: 254 nm), ⑥ stay Time: R isomer 12.2 min, S isomer 22.5 min].

division Asymmetric Phase Transfer Catalysts Used Chemical yield (%) Optical yield (% ee) Config. Example 1 1,4-bis (synconinium- N -methyl) naphthalene dibromide (5) 93 93 S Example 2 1,4-bis [ O (9) -allylconinidinium- N -methyl] niphthalene dibromide (6) 94 91 S Example 3 1,4-bis (hydrocinconidinium- N -methyl) naphthalene dibromide (5-1) 94 94 S Example 4 1,4-bis [ O (9) -allylhydrocinconinidinium- N -methyl] naphthalene dibromide (6-1) 95 91 S Example 5 1,5-bis (synconinium- N -methyl) naphthalene dibromide (7) 93 91 S Example 6 1,5-bis [ O (9) -allylconinidinium- N -methyl] naphthalene dibromide (8) 94 89 S Example 7 1,5-bis (hydrocinconydinium- N -methyl) naphthalene dibromide (7-1) 92 92 S Example 8 1,5-bis [ O (9) -allylhydrocinconinidinium- N -methyl] naphthalene dibromide (8-1) 90 86 S Example 9 1,8-bis (cinconidinium- N -methyl) naphthalene dibromide (9) 88 47 S Example 10 1,8-bis [ O (9) -allylconydinium- N -methyl] niphthalene dibromide (10) 85 27 S Example 11 1,8-bis (hydrocinconidinium- N -methyl) naphthalene dibromide (9-1) 90 55 S Example 12 1,8-bis [ O (9) -allylhydrocinconinidinium- N -methyl] naphthalene dibromide (10-1) 82 44 S Example 13 2,3-bis (synconinium- N -methyl) naphthalene dibromide (11) 87 44 S Example 14 2,3-bis [ O (9) -allylconinidinium- N -methyl] niphthalene dibromide (12) 90 22 S Example 15 2,3-bis (hydrocinconidinium- N -methyl) naphthalene dibromide (11-1) 91 57 S Example 16 2,3-bis [ O (9) -allylhydrocinconinidinium- N -methyl] naphthalene dibromide (12-1) 92 36 S

division Asymmetric Phase Transfer Catalysts Used Chemical yield (%) Optical yield (% ee) Config. Example 17 2,6-bis (synconinium- N -methyl) naphthalene dibromide (13) 90 76 S Example 18 2,6-bis [ O (9) -allylconinidinium- N -methyl] naphthalene dibromide (14) 89 70 S Example 19 2,6-bis (hydrocinconydinium- N -methyl) naphthalene dibromide (13-1) 92 85 S Example 20 2,6-bis [ O (9) -allylhydrocinconinidinium- N -methyl] naphthalene dibromide (14-1) 92 79 S Example 21 2,7-bis (cinconidinium- N -methyl) naphthalene dibromide (15) 93 86 S Example 22 2,7-bis [ O (9) -allylconydinium- N -methyl] naphthalene dibromide (16) 94 92 S Example 23 2,7-bis (hydrocinconidinium- N -methyl) naphthalene dibromide (15-1) 94 93 S Example 24 2,7-bis [ O (9) -allylhydrocinconinidinium- N -methyl] naphthalene dibromide (16-1) 95 97 S Example 25 2,7-bis [ O (9) -benzylhydrocinconidinium- N -methyl] naphthalene dibromide (16-1-1) 94 93 S Example 26 2,7-bis (cinconium- N -methyl) naphthalene dibromide (27) 91 88 R Example 27 2,7-bis [ O (9) -allylconinium- N -methyl] naphthalene dibromide (28) 93 90 R Example 28 2,7-bis (hydrocinconinium- N -methyl) naphthalene dibromide (27-1) 90 88 R Example 29 2,7-bis [ O (9) -allylhydrocinconinium- N -methyl] naphthalene dibromide (28-1) 92 93 R

division Asymmetric Phase Transfer Catalysts Used Chemical yield (%) Optical yield (% ee) Config. Example 30 2,7-bis (quininium- N -methyl) naphthalene dibromide (15-2) 87 57 S Example 31 2,7-bis [ O (9) -allylquininium- N -methyl] naphthalene dibromide (16-2) 90 65 S Example 32 2,7-bis [hydroquininium- N -methyl] naphthalene dibromide (15-3) 90 75 S Example 33 2,7-bis [ O (9) -allylhydroquininium- N -methyl] naphthalene dibromide (16-3) 92 84 S Example 34 2,7-bis [quinidinium- N -methyl] naphthalene dibromide (27-2) 89 71 R Example 35 2,7-bis [ O (9) -allylquinininium- N -methyl] naphthalene dibromide (28-2) 90 72 R Example 36 2,7-bis [hydroquininidinium- N -methyl] naphthalene dibromide (27-3) 88 67 R Example 37 2,7-bis [ O (9) -allylhydroquininidinium- N -methyl] naphthalene dibromide (28-3) 89 73 R Comparative Example 1 N -benzylcinconidinium chloride 91 79 S Comparative Example 2 N -benzyl- O (9) -allylcinconidinium bromide 94 81 S

Comparative Examples 1 and 2: O'Donnell, MJ; Bennett, WD; Wu, S. J. Am. Chem. Soc. 1989 , 111 , 2353.

As described above, the monobenzylammonium catalysts of Comparative Examples 1 and 2 showed an optical yield of 80% ee, whereas the 2,7-bis [ O (9) -allylhydrocinconidinium- N− of Example 24 was shown. Methyl] naphthalene dibromide (16-1) showed a high optical yield of 97% ee. In addition, it is thought that the above catalyst can be applied to the synthesis of industrial alpha amino acids simply because the production method is also simple.

When the asymmetric phase transfer catalyst of the present invention is used for the amino acid synthesis reaction, alpha amino acids can be synthesized with high yield and high yield.

Claims (3)

The compound represented by following formula (1). In the above formula, In the formula, X is a halogen atom or an IO ₄ of fluorine, chlorine, bromine and iodine ^{_{-, ClO 4 -, OTf -}} , HSO 4 - , and; R ¹ is hydrogen, lower alkyl having 1-4 carbons, hydroxy, or —OR ⁴ , provided that R ⁴ is 1-4 lower alkyl groups; R ² is a vinyl or ethyl group; R ³ is hydrogen, lower alkyl having 1-10 carbon atoms, allyl, benzyl, naphthalen-1-yl-methyl, naphthalen-2-yl-methyl, or anthracene-9-yl-methyl. The compound represented by following formula (2). Wherein X, R ¹ , R ² and R ³ are the same as defined in claim 1. Method for synthesizing alpha amino acid using the compound of claim 1 or 2.