JPH06116270A - Tetrahydropyrroloindole derivative, its production method and its intermediate - Google Patents

Abstract

(57) [Summary] [Object] To provide an intermediate for producing a compound expected to be used as an anticancer agent, a method for producing the same, and a raw material thereof. [Structure] General formula (1) (In the formula, R ¹ is a hydrogen atom or a hydroxyl group protecting group, R ² is a hydrogen atom or an amino group protecting group, X is a halogen atom, a hydroxyl group, an alkylcarbonyloxy group, an arylcarbonyloxy group, an alkylsulfonyloxy group. Or a tetrahydropyrroloindole derivative represented by (denoting an arylsulfonyloxy group), and an optically active form thereof.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a compound represented by the following formula (hereinafter referred to as "KW-218", which is expected to be used as an anticancer agent.
9 ")

[0002]

[Chemical 6]

The present invention relates to a production intermediate, a production method thereof and a raw material thereof.

[0004]

2. Description of the Related Art Conventionally, K
W-2189 is produced semi-synthetically by chemically modifying duocarmycin A, C ₁ , C ₂ , B ₁ and B ₂ extracted and isolated from the culture solution of actinomycetes. However, since the production efficiency of duocarmycins by actinomycetes is low,
It cannot be said that KW-2189 is an efficient production method, and at the same time, a large amount of a culture solution containing an extremely strong cytotoxic compound must be treated. Therefore, development of a new synthetic method is desired from the viewpoint of environmental pollution. ing.

[0005]

The method for producing a tetrahydropyrroloindole derivative according to the present invention is shown below. That is, the general formula (3)

[0006]

[Chemical 7]

(Wherein R ³ is a hydroxyl-protecting group, R ⁴ is an amino-protecting group, X ¹ Indicates a protected hydroxyl group)
The aminoindoline derivative represented by the formula (2) is added to or condensed with methyl 3-methylacetylenecarboxylate, methyl acetoacetate or substituted methyl crotonate.

[0008]

[Chemical 8]

An aminocrotonic acid derivative represented by Here, the protective group for the hydroxyl group of R ³ is a C ₁ -C ₄ lower alkyl group such as a methyl group or an ethyl group, a benzyl group, 4-
Methoxybenzyl group, 2,4-dimethoxybenzyl group,
Arylmethyl groups such as benzhydryl group and trityl group,
Trimethylsilyl group, t-butyldimethylsilyl group, t
Examples include alkyl- and aryl-substituted silyl groups such as -butyldiphenylsilyl group, and benzyl group is preferably used. As the amino-protecting group for R ^4, a linear or branched lower alkoxycarbonyl group having 1 to 6 carbon atoms such as methoxycarbonyl group, ethoxycarbonyl group, isopropoxycarbonyl group, t-butoxycarbonyl group, 2,
2,2-trichloroethoxycarbonyl group, 2,2,2
Examples thereof include haloalkoxycarbonyl groups such as trichloro-1,1-dimethylethoxycarbonyl group, substituted or unsubstituted aralkyloxycarbonyl groups such as benzyloxycarbonyl group and 4-methoxybenzyloxycarbonyl group, and preferably t-butoxycarbonyl group. Groups are used. Also, X ¹ The protected hydroxyl-protecting group is a linear or branched lower alkanoyl group having 1 to 6 carbon atoms such as acetyl group, butyryl group, pivaloyl group, benzoyl group, 4-methoxybenzoyl group, 4-nitrobenzoyl group. A substituted or unsubstituted aryloyl group such as a group, a benzyl group,
Substituted or unsubstituted arylmethyl groups such as 4-methoxybenzyl group, 2,4-dimethoxybenzyl group, benzhydryl group, trityl group and the like are exemplified, and acetyl group is preferably used. Among such as 5-amino-2,3-dihydro -1H- indole compound represented by the general formula ^{(3) (R 3 = CH} 2 C 6 H 5, R 4 = C (O) OC (C
^{_{H 3) 3, X 1 =}} OCOCH 3) can be prepared according to known methods (JP-A-4-117383).

The compound represented by the general formula (3) and methyl 3-methylacetylenecarboxylate, methyl acetoacetate,
Methyl 3-chlorocrotonate, methyl 3-bromocrotonate, methyl 3-methanesulfonyloxycrotonate,
Methyl 3-trifluoromethanesulfonyloxycrotonate and the like are combined with triethylamine, diazabicyclo base,
Organic bases such as pyridine and diethylaniline; base catalysts such as alkali metal salts such as sodium hydrogencarbonate and potassium carbonate; carboxylic acids such as acetic acid and benzoic acid; sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. The aminocrotonic acid derivative represented by the general formula (2) can be produced by reacting in the presence or absence of an acid catalyst such as. The reaction proceeds smoothly at -10 ° to 100 ° C, and any solvent can be used as long as it does not participate in the reaction.

By intramolecular ring closure of the aminocrotonic acid derivative represented by the general formula (2), the general formula (1a)

[0012]

[Chemical 9]

A tetrahydropyrroloindole derivative represented by the formula (wherein R ³ , R ⁴ and X ¹ are the same as above) can be produced. Palladium catalysts such as palladium chloride, palladium acetate, palladium trifluoroacetate, and acetylacetonatopalladium, transition metal complex catalysts such as nickel chloride and nickel acetate, and heavy metal salt catalysts such as lead tetraacetate and copper acetate alone are used for intramolecular ring closure. Alternatively, they are used in combination and triphenylphosphine is used as a ligand,
The reaction is carried out in the presence or absence of phosphines such as trioctylphosphine or organic bases such as triethylamine, N-methylmorpholine and pyridine, and the reaction solvent is acetonitrile, benzonitrile, acetic acid, dimethylformamide, dimethylacetamide, tetrahydrofuran, Dioxane, dimethoxyethane, toluene and the like can be used. The reaction proceeds smoothly at 0 ° to 100 ° C, and can be easily carried out, for example, by heating in N, N-dimethylacetamide in the presence of palladium acetate for several hours.

The compound of the general formula (1a) is introduced into KW-2189 or its analogues through the following production steps.

[0015]

[Chemical 10]

(In the formula, X ² represents a halogen atom, a lower alkylsulfonyloxy group or an arylsulfonyloxy group, and R ³ , R ⁴ and X ¹ are the same as above.) The production process of KW-2189 shown here is racemic. Although shown in the form of a body, KW-2189 as an optically active substance can be obtained by using an optically active substance of the aminoindoline derivative represented by the general formula (3) as a starting material. The optically active form of the aminoindoline derivative represented by the general formula (3) is, for example, Journal of American
According to the method described in Chemical Society, Volume 112, page 5230, 1990, it can be produced by optically resolving as a diastereomer. Further, the diastereoisomer obtained by esterifying the alcohol represented by the general formula (1b) with an optically active carboxylic acid can be separated and used as an intermediate for producing an optically active substance.

(Example 1)

[0018]

[Chemical 11]

3-acetoxymethyl-5-amino-6-
Benzyloxy-1-t-butoxycarbonyl-2,3
-Dihydro-1H-indole 103.1 mg (0.2
5 mmol), methyl acetoacetate 32.4 μl (0.3
mmol), p-toluenesulfonic acid monohydrate 4.8
mg (0.025 mmol) in 8 ml of benzene at 80 ° C
The mixture was heated to reflux for 4 hours. The solvent was distilled off and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 3- (3) of a pale yellow gum.
-Acetoxymethyl-6-benzyloxy-1-t-butoxycarbonyl-2,3-dihydro-1H-indol-5-yl) aminocrotonic acid methyl ester was 10
Obtained was 6.1 mg (83%).

NMR (CDCl ₃ ) δ: 1.56 (9H, s), 1.8
7 (3H, s), 2.08 (3H, s), 3.56 (1H, br, m), 3.68 (3H, s), 3.70-
3.88 (1H, br, m), 4.04-4.22 (3H, m), 4.68 (1H, s), 5.12 (2H,
s), 6.96 (1H, s), 7.28-7.44 (5H, m), 7.72 (1H, br, s), 10.07
(1H, br, s) (Example 2)

[0021]

[Chemical 12]

221 mg (0.433 mmol) of 3- (3-acetoxymethyl-6-benzyloxy-1-t-butoxycarbonyl-2,3-dihydro-1H-indol-5-yl) aminocrotonic acid methyl ester, acetic acid 194.3 mg (0.866 mmol) of palladium was placed in anhydrous N, N-dimethylacetamide under argon stream 7
Heated at 0 ° C. for 4 hours. The reaction solution was poured into ice water, insoluble materials were filtered off, and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with water, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give colorless crystals of 1-acetoxymethyl-5-benzyloxy-3-t-.
51.4 mg (23%) of methyl butoxycarbonyl-7-methyl-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate was obtained.

NMR (CDCl ₃ ) δ: 1.58 (9H, s), 2.0
3 (3H, s), 2.65 (3H, s), 3.85 (3H, s), 3.88-4.36 (5H, m), 5.16
(2H, s), 7.36-7.46 (5H, m), 7.78 (1H, br, s), 8.62 (1H, br) (Example 3)

[0024]

[Chemical 13]

1-acetoxymethyl-5-benzyloxy-3-t-butoxycarbonyl-7-methyl-1,
Methyl 2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate 51.4 mg (0.101
mmol) in 0.5 ml of methanol, 16.8 mg (0.121 mmol) of potassium carbonate was added, and the mixture was stirred at room temperature for 5 minutes.
Stir for hours. The reaction solution was neutralized with 10% citric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by preparative silica gel thin layer chromatography (hexane: ethyl acetate = 1: 2) to give 5
-Benzyloxy-3-t-butoxycarbonyl-1-
42.0 mg (89%) of methyl hydroxymethyl-7-methyl-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate was obtained.

To this, triphenylphosphine 47.2 m
g (0.18 mmol) was added and anhydrous methylene chloride was added.
Dissolve in 5 ml and carbon tetrachloride 34.7 μl (0.36 mm
ol) was added dropwise and reacted overnight under an argon stream. The solvent was distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give colorless crystals of 5-benzyloxy-3-t-butoxycarbonyl-.
39.3 mg (90%) of methyl 1-chloromethyl-7-methyl-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate was obtained.

NMR (CDCl ₃ ) δ: 1.59 (9H, s), 2.6
8 (3H, s), 3.30 (1H, t, J = 10Hz), 3.85 (1H, dd, J = 2Hz, J = 10H
z), 3.93 (3H, s), 3.98 (1H, dd, J = 9Hz, J = 11Hz), 4.18-4.32 (2
H, m), 5.18 (2H, s), 7.38-7.47 (5H, m), 7.78 (1H, br, s), 8.54
(1H, br, s) (Example 4)

[0028]

[Chemical 14]

5-benzyloxy-3-t-butoxycarbonyl-1-chloromethyl-7-methyl-1,2,
Methyl 3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate 39.3 mg (81 μmol)
Was dissolved in 1.1 ml of tetrahydrofuran, and 23.6 mg of 10% palladium carbon was added. 268.5 μl of 25% ammonium formate was added dropwise at 0 ° C., and the mixture was stirred under an argon stream for 1.5 hours. The reaction solution was diluted with ethyl acetate, the catalyst was filtered off, and dried over anhydrous sodium sulfate. When the solvent was distilled off, colorless crystals of 3-t-butoxycarbonyl-1-chloromethyl-5-hydroxy-7-methyl-1,2,
Methyl 3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate was obtained.

3M hydrogen chloride-ethyl acetate solution
After adding 3 ml and stirring for 1 hour, the solvent was distilled off.
-Trimethoxy-1H-indole-2-carboxylic acid 2
0.3 mg (81 μmol) was added to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 4
In the presence of 6.6 mg (243 μmol), anhydrous N, N-
The reaction was carried out overnight in 0.8 ml of dimethylformamide under an argon stream. The reaction solution is diluted with methylene chloride, water,
It was washed successively with 10% sodium hydrogen carbonate and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off and the obtained crystal was purified by silica gel column chromatography (hexane: tetrahydrofuran = 1: 1). The obtained crystal was washed with ether to give 1-chloromethyl-5-hydroxy-7 as colorless crystal. -Methyl-3- (5,6,7-
Trimethoxy-1H-indol-2-ylcarbonyl) -1,2,3,6-tetrahydropyrrolo [3,2-
e] Methyl indole-8-carboxylate is 37.74 m
g (88%, 3 steps).

NMR (CDCl ₃ ) δ: 2.65 (3H, s), 3.2
8 (1H, t, J = 10Hz), 3.83-3.93 (1H, m), 3.90 (3H, s), 3.91 (3H,
s), 3.96 (3H, s), 4.08 (3H, s), 4.45-4.49 (2H, m), 4.68 (1H,
d, J = 10Hz), 6.82 (1H, s), 6.95 (1H, s), 8.31 (1H, s), 9.19 (1
H, br, s), 9.82 (1H, br, s), 9.90 (1H, br, s) (Reference example 1)

[0032]

[Chemical 15]

1-chloromethyl-5-hydroxy-7-
Methyl methyl-3- (5,6,7-trimethoxy-1H-indol-2-ylcarbonyl) -1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate 35.74 mg (67.7 μmol) was dissolved in 11 ml of anhydrous acetonitrile and dissolved in an argon gas stream for 1,8
-Diazabicyclo [5.4.0] -7-undecene 2
0.2 μl (135.4 μmol) was added dropwise and reacted for 3 hours. The reaction solution was neutralized with a 0.5 M potassium dihydrogen phosphate aqueous solution and diluted with chloroform. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The crystals obtained by distilling off the solvent were purified by silica gel column chromatography (chloroform: methanol = 98: 2) to give 6-methyl-2- (5,6,7) as pale yellow crystals.
-Trimethoxy-1H-indol-2-ylcarbonyl) -1,2,8,8a-tetrahydrocyclopropa [c] pyrrolo [3,2-e] indole-4 (5H)-
27.9 mg (84%) of methyl on-7-carboxylate
Was obtained.

NMR (CDCl ₃ ) δ: 1.37 (1H, t, J = 4H
z), 2.37 (1H, dd, J = 3Hz, J = 8Hz), 2.61 (3H, s), 3.65 (1H, br,
m), 3.83 (3H, s), 3.90 (3H, s), 3.94 (3H, s), 4.08 (3H, s), 4.4
4 (2H, br, m), 6.81 (1H, s), 6.95 (1H, d, J = 2Hz), 7.10 (1H, s),
9.30 (1H, s), 10.72 (1H, br, s) (Reference example 2)

[0035]

[Chemical 16]

6-methyl-2- (5,6,7-trimethoxy-1H-indol-2-ylcarbonyl) -1,
Methyl 2,8,8a-tetrahydrocyclopropa [c] pyrrolo [3,2-e] indole-4 (5H) -one-7-carboxylate (26.0 mg, 52.9 μmol) was dissolved in 6 ml of acetonitrile to give a 1M odor. 3 ml of hydrogenated water was added and stirred for 50 minutes. 3 ml of 0.5 M potassium dihydrogen phosphate aqueous solution was added, and the mixture was extracted with chloroform. Water organic layer,
The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The crystals obtained by distilling off the solvent were purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2.5) to give 1-bromomethyl-5-hydroxy-7-methyl-3- (light yellow crystals as crystals. 5,6,7-trimethoxy-
1H-indol-2-ylcarbonyl) -1,2,
Methyl 3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate was 30.19 mg (99.7).
%) Obtained.

NMR (CDCl ₃ ) δ: 2.65 (3H, s), 3.1
5 (1H, t, J = 10Hz), 3.73 (1H, br, m), 3.915 (3H, s), 3.917 (3
H, s), 3.96 (3H, s), 4.06 (3H, s), 4.39-4.55 (2H, m), 4.64 (1
H, d, J = 10Hz), 6.82 (1H, s), 6.92 (1H, s), 8.31 (1H, s), 9.22
(1H, br, s), 9.94 (2H, br, s) (Reference example 3)

[0038]

[Chemical 17]

1-Bromomethyl-5-hydroxy-7-
Methyl methyl-3- (5,6,7-trimethoxy-1H-indol-2-ylcarbonyl) -1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate 26.5 mg (46.3 μmol) and p-nitrophenyl chloroformate 11.2 mg (55.6 μ)
(mol) was suspended in 1.2 ml of anhydrous methylene chloride, 7.7 μl (55.6 μmol) of triethylamine was added dropwise under ice cooling, and the mixture was stirred for 1 hour. N-methylpiperazine (7.7 µl, 69.4 µmol) was added to the reaction solution, and the mixture was further reacted at room temperature overnight.

The reaction solution was diluted with chloroform and mixed with water and 10
% Aqueous sodium hydrogen carbonate solution It was washed successively with water, and dried over anhydrous sodium sulfate. The solvent was distilled off and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 15: 1) to give colorless crystals of 1
-Bromomethyl-7-methyl-5- (4-methylpiperazin-1-ylcarbonyl) oxy-3- (5,6,7
-Trimethoxy-1H-indol-2-ylcarbonyl) -1,2,3,6-tetrahydropyrrolo [3,2-
e] Methyl indole-8-carboxylate is 23.28 m
g (72%) was obtained.

NMR (CDCl ₃ ) δ: 2.37 (3H, s), 2.5
0 (4H, br, s), 2.68 (3H, s), 3.23 (1H, t, J = 10Hz), 3.63 (2H,
m), 3.80 (2H, m), 3.81 (1H, dd, J = 3Hz, J = 8Hz), 3.92 (3H, s),
3.95 (3H, s), 3.97 (3H, s), 4.08 (3H, s), 4.54 (1H, m), 4.63 (1
H, m), 4.75 (1H, d, J = 9Hz), 6.90 (1H, s), 7.00 (1H, d, J = 2Hz),
8.16 (1H, s), 8.85 (1H, s), 9.35 (1H, s) (Reference example 4)

[0042]

[Chemical 18]

1-Bromomethyl-7-methyl-5- (4
-Methylpiperazin-1-ylcarbonyl) oxy-3
-(5,6,7-trimethoxy-1H-indole-2
-Ylcarbonyl) -1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate 20.47 mg (29.3 μmol) in 3M hydrogen chloride
Ethyl acetate was added. The crystals obtained by distilling off the solvent were washed with ether to give dl-KW-2189 as pale yellow crystals.
21.06 mg (98%) was obtained.

NMR (DMSOd ₆ ) δ: 2.70 (3H, s),
2.86 (3H, br, s), 3.15-3.44 (2H, m), 3.46-3.67 (4H, m), 3.78
-3.82 (1H, m), 3.80 (3H, s), 3.83 (3H, s), 3.85 (3H, s), 3.95
(3H, s), 4.15 (1H, br, s), 4.35-4.55 (4H, m), 4.65 (1H, br,
m), 6.96 (1H, s), 7.00 (1H, s), 7.94 (1H, s), 10.73 (1H, br), 1
1.30 (1H, s), 12.13 (1H, s) (Example 5)

[0045]

[Chemical 19]

By the same method as in Example 1, (3S) -3
-Acetoxymethyl-5-amino-6-benzyloxy-1-t-butoxycarbonyl-2,3-dihydro-1
From H-indole to 3-((3S) -3-acetoxymethyl-6-benzyloxy-1-t-butoxycarbonyl-2,3-dihydro-1H-indol-5-yl)
Aminocrotonic acid methyl ester was obtained.

[Α] _D ²⁵ = + 14 ° (c = 0.5, CHCl ₃ ) (Example 6)

[0048]

[Chemical 20]

In the same manner as in Example 2, 3-((3
S) -3-Acetoxymethyl-6-benzyloxy-1
-T-butoxycarbonyl-2,3-dihydro-1H-
From indole-5-yl) aminocrotonic acid methyl ester to (1S) -1-acetoxymethyl-5-benzyloxy-3-t-butoxycarbonyl-8-methoxycarbonyl-7-methyl-1,2,3,6- Tetrahydropyrrolo [3,2-e] indole was obtained.

Melting point 125-127 ° C. Elemental analysis value (%) As C ₂₈ H ₃₂ N ₂ O ₇ [Α] _D ²⁵ = −74 ° (c = 0.5, CHCl ₃ ) (Example 7)

[0051]

[Chemical 21]

By the same method as in Example 3, (1S) -1
(1S) -5 from methyl -acetoxymethyl-5-benzyloxy-3-t-butoxycarbonyl-7-methyl-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate. -Benzyloxy-3-t
-Butoxycarbonyl-1-hydroxymethyl-7-methyl-1,2,3,6-tetrahydropyrrolo [3,2-
e] Methyl indole-8-carboxylate was obtained.

Melting point 212-214 ° C. Elemental analysis value (%) As C ₂₆ H ₃₀ N ₂ O ₆ .1 / 2H ₂ O [Α] _D ²⁵ = −37 ° (c = 0.22, CHCl ₃ ) (Example 8)

[0054]

[Chemical formula 22]

In the same manner as in Example 3, (1S) -5
-Benzyloxy-3-t-butoxycarbonyl-1-
Methyl hydroxymethyl-7-methyl-1,2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate to (1S) -5-benzyloxy-3-t
-Butoxycarbonyl-1-chloromethyl-7-methyl-1,2,3,6-tetrahydropyrrolo [3,2-e]
Methyl indole-8-carboxylate was obtained.

Melting point 209 to 211 ° C. Elemental analysis value (%) As C ₂₆ H ₂₉ ClN ₂ O ₅ [Α] _D ²³ = −70 ° (c = 0.2, CHCl ₃ ) (Reference Example 5)

[0057]

[Chemical formula 23]

By the same method as in Example 4 and Reference Examples 1 to 4, (1S) -5-benzyloxy-3-t-butoxycarbonyl-1-chloromethyl-7-methyl-1,
From methyl 2,3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate to (S) -KW-218
9 was obtained.

NMR (DMSOd ₆ ) δ: 2.70 (3H, s), 2.
85 (3H, s), 3.15-3.70 (7H, m), 3.75-3.85 (1H, m), 3.80 (3
H, s), 3.82 (3H, s), 3.85 (3H, s), 3.95 (3H, s), 4.10 to 4.24 (1
H, m), 4.34 to 4.52 (3H, m), 4.65 (1H, t, J = 10Hz), 6.96 (1H,
s), 7.01 (1H, s), 7.94 (1H, brs), 10.74 (1H, brs), 11.32 (1H,
s), 12.15 (1H, s) [α] _D ²⁵ = -26 ° (c = 0.31, MeOH)

Claims (3)

[Claims] 1. A compound represented by the general formula (1): (In the formula, R ¹ is a hydrogen atom or a hydroxyl-protecting group, R ^{2 is}
Represents a hydrogen atom or an amino group-protecting group, X represents a halogen atom, a hydroxyl group, an alkylcarbonyloxy group, an arylcarbonyloxy group, an alkylsulfonyloxy group or an arylsulfonyloxy group), and a tetrahydropyrroloindole derivative Optically active form. 2. A general formula (2): (Wherein R ³ represents a hydroxyl-protecting group, R ⁴ represents an amino-protecting group, and X ¹ represents a protected hydroxyl group), and aminocrotonic acid derivatives and optically active forms thereof. 3. A compound represented by the general formula (3): (Wherein R ³ represents a hydroxyl-protecting group, R ⁴ represents an amino-protecting group, and X ¹ represents a protected hydroxyl group), an aminoindoline derivative represented by methyl 3-methylacetylenecarboxylate, methyl acetoacetate Alternatively, a substituted methyl crotonate is allowed to act on the compound represented by the general formula (2): (Wherein R ³ , R ⁴ and X ¹ are the same as above), and then the aminocrotonic acid derivative is subjected to ring closure in the presence of a metal catalyst. (In the formula, R ³ , R ⁴ and X ¹ are the same as the above), and a method for producing a tetrahydropyrroloindole derivative.