JP3037965B2 - 2-Alkoxycarbonyl-2-methyl-1-oxo-1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a compound represented by the general formula [I] (Wherein, R ¹ is a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms, R ² and R ⁴ are each independently a hydrogen atom or a protecting group for the same or different amino group, R ³ And R ⁵ each independently represent a hydrogen atom or the same or a different hydroxyl-protecting group.)
-Methyl-1-oxo-1,2,3,6,7,8-hexahydro-
Benzo [1,2-b; 4,3-b '] dipyrrole derivative and the general formula [IIa] used as an intermediate for the production thereof (Wherein, R ³ and R ⁹ are each independently a hydrogen atom or a protecting group for the same or different hydroxyl group, and R ⁶ is a hydrogen atom or a C 1 -C 1
6, a linear or branched lower alkyl group, R ⁸ represents a hydrogen atom or an amino-protecting group. A 4-alkoxycarbonyl-2,3-dihydro-1H-indole derivative represented by the formula: ) And the general formula [II d] (Wherein, R ¹ is a linear or branched lower alkyl group having 1 to 6 carbon atoms, R ² and R ⁸ are each independently a hydrogen atom or an amino-protecting group, and R ³ and R ⁹ are each independently Represents a hydrogen atom or a protecting group for the same or different hydroxyl group, and R ⁶ represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms.) , 3−
A dihydro-1H-indole derivative, and a compound represented by the general formula (II
I] (Wherein, R ⁸ is a hydrogen atom or an amino-protecting group, R ³ and R
Each ¹⁰ independently represents a hydrogen atom or the same or different hydroxyl-protecting group. 1,2-dioxo-1,2,3,
6,7,8-Hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole derivatives. The above general formulas (III) and (I
2-alkoxycarbonyl-2-methyl-1-oxo- represented by the general formula [I] produced via the compound of formula [I]
1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3-
b '] Dipyrrole derivative has the formula [IV], which is expected to be used as an anticancer drug due to its strong cytotoxicity. A compound represented by the general formula [V], which is derived from duocarmycin A and is expected to be used as an anticancer agent due to strong cytotoxicity Wherein X represents a chlorine or bromine atom. Duocarmycin C ₂ , (pyridinmycin A) or B ₂ ,
And the general formula [VI] derived from duocarmycin A and expected to be used as an anticancer drug due to strong cytotoxicity Wherein X represents a chlorine or bromine atom. Duocarmycin C ₁ , (pyridinmycin B) or B
₁ (Chem. Pharm. Bull., 36 , 3728 (1988)., J. Antibiot., 4
2 , 1299, 1515, 1713 (1989)., Natural Organic Compound Symposium, Fukuoka, 1988, Abstracts p300.) (See Reference Examples below). In addition, the general formulas (III) and (II)
2- represented by the general formula [I] produced via the compound of
Alkoxycarbonyl-2-methyl-1-oxo-1,2,
3,6,7,8-hexahydro-benzo [1,2-b; 4,3-b ']
From the dipyrrole derivative, 2-position epimers of duocarmycins represented by the formulas [IV], [V] and [VI] can also be produced (see Reference Examples below).
The use of these 2-position epimers of duocarmycins as anticancer agents due to cytotoxicity can be expected.

[Conventional technology]

Conventionally, duocarmycins A, C ₁ , C ₂ , B ₁ and B ₂ have been extracted and isolated from a culture of actinomycetes. Further, duocarmycin C ₁ and C ₂ and hydrochloric acid duocarmycin A, also duocarmycin B ₁ and B ₂ can also be obtained by treating the duocarmycin A and in the water-containing acetone of potassium bromide (Chem. Pharm. Bull., 36 , 3728 (198
8)., J. Antibiot., 42 , 1299, (1989). Symposium on Natural Organic Compounds, Fukuoka, 1989, Abstracts p300.). However,
The production efficiency of duocarmycins by actinomycetes is low,
In order to efficiently obtain duocarmycins, including their 2-position epimers, which are highly expected to be used as anticancer agents due to their strong cytotoxicity, development of a chemical synthesis method is strongly desired.

[Problems to be solved by the invention]

An object of the present invention is to provide a raw material for producing duocarmycin A, which is the most important among duocarmycins expected to be used as an anticancer agent, and a 2-position epimer thereof.

[Means for solving the problem]

The present invention relates to a compound represented by the general formula (Wherein, R ¹ is a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms, R ² and R ⁴ are each independently a hydrogen atom or a protecting group for the same or different amino group, R ³ And R ⁵
Each independently represents a hydrogen atom or a hydroxyl-protecting group. 2-alkoxycarbonyl-2-methyl-1- represented by
Oxo-1,2,3,6,7,8-hexahydro-benzo [1,2-b;
4,3-b '] dipyrrole derivative and the general formula [IIa] used as an intermediate for the production thereof (Wherein, R ³ and R ⁹ are each independently a hydrogen atom or a protecting group for the same or different hydroxyl group, and R ⁶ is a hydrogen atom or a C 1 -C 1
6, a linear or branched lower alkyl group, R ⁸ represents a hydrogen atom or an amino-protecting group. A 4-alkoxycarbonyl-2,3-dihydro-1H-indole derivative represented by the formula: ) And the general formula [II d] (Wherein, R ¹ is a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms, R ² and R ⁸ are each independently a hydrogen atom or an amino-protecting group, R ³ and R ⁹ Each independently represents a hydrogen atom or a protecting group for the same or different hydroxyl group, and R ⁶ represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms.) Carbonyl-2,3-dihydro-1H-indole derivative, and general formula (III) (In the formula, R ³ and R ¹⁰ each independently represent a hydrogen atom or a protecting group for the same or different hydroxyl group, R ⁸ represents a hydrogen atom or an amino group protecting group, and R ¹⁰ represents a hydrogen atom or a hydroxyl protecting group.) 1,2-dioxo-1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole derivative represented by the formula: 2-alkoxycarbonyl-2-methyl-1-oxo-1,2,3,6,7,8- represented by the general formula (I)
Hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole derivative is obtained by the following general formula [III]
1,2-dioxo-1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3-b ′] dipyrrole derivative represented by the following general formula [II] 4-alkoxycarbonyl-
It can be produced via a 2,3-dihydro-1H-indole derivative.

(Wherein, R ¹ , R ³ , R ⁶ , R ⁸ , and R ⁹ represent the same meaning as described above,
R ² ′ is an amino-protecting group, R ¹⁰ ′ is a hydroxyl-protecting group, R ¹¹
Represents a linear or branched lower alkyl group having 1 to 6 carbon atoms or a substituted or unsubstituted aryl group. ).

The protecting groups for the hydroxyl group and the amino group used in this production step can be appropriately removed by a method usually used for these protecting groups.

Further, even in the case of an ester having R ¹ and R ⁶ which are the same or different linear or branched lower alkyl groups having 1 to 6 carbon atoms, the ester can be hydrolyzed by a known method to lead to a free carboxylic acid. Needless to say.

[First Step] This step comprises two steps of a 2- (2-nitrophenyl) propane-1,3-diol derivative having a hydroxyl group protected at the 4-position on the benzene ring represented by the general formula [VII] A protecting group for a hydroxyl group is introduced into one of the primary alcohols of the general formula [VI
II] to produce a 2- (2-nitrophenyl) propanol derivative. The protecting group for the hydroxyl group that can be introduced at the 4-position of the benzene ring is stably present from the first step to the later-described 18th step, and is removed without damaging other parts of the compound in the 19th and 20th steps. Are selected. Hydroxyl protecting groups satisfying such requirements include a benzyl group, a p-methoxybenzyl group,
2,4-dimethoxybenzyl group, benzhydryl group, di-
A substituted or unsubstituted allylmethyl group such as a (p-methoxyphenyl) methyl group and a trityl group is exemplified, and a benzyl group is preferably used. 4 on these benzene rings
2- (2-nitrophenyl) propane-1,3-diol derivative having a hydroxyl group protected at the 2-position can be produced according to a known method (J. Am. Chem. Soc., 103 , 5622 (198).
1)., J. Med. Chem., 31 , 590 (1988.).

The hydroxyl-protecting group introduced into the 2- (2-nitrophenyl) propane-1,3-diol derivative represented by the general formula [VII] is stably present from the second step to the sixth step. Those that can be removed in step 7 without damaging other sites of the compound are selected. Hydroxyl protecting groups satisfying such requirements include formyl group, acetyl group, propionyl group, butyryl group, pentanoyl group,
1 carbon atom such as a methylpropionyl group and a pivaloyl group
And substituted or unsubstituted aryloyl groups such as straight-chain or branched lower alkanoyl groups, benzoyl groups, p-methoxybenzoyl groups, p-nitrobenzoyl groups, and 2,4-dimethoxybenzoyl groups. Preferably, an acetyl group is used. These hydroxyl-protecting groups can be introduced into a 2- (2-nitrophenyl) propane-1,3-diol derivative represented by the general formula [VII] according to a known method (“Protective Groups in Organic Synthesis”).
s, "John Wiley & Sons, New York, 1981, pp 50-72).

[Second Step] In this step, a 2- (2-nitrophenyl) propanol derivative represented by the general formula [VIII] is sulfonylated to produce a sulfonic acid ester represented by the general formula [IX]. .

Examples of the sulfonylating agent include methanesulfonyl chloride, methanesulfonyl bromide, ethanesulfonyl chloride, ethanesulfonyl bromide, benzenesulfonyl chloride, sulfonyl halides such as p-toluenesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, Sulfonic anhydrides such as benzenesulfonic anhydride and p-toluenesulfonic anhydride are exemplified, and methanesulfonyl chloride is preferably used. Sulfonylation can be performed according to a known method (“Organic Functional G
roup Preparations, "2nd Ed., Academic Press, New Yor
k, 1983, Vol. 1, pp619-639.).

[Third Step] In this step, the nitro group on the benzene ring of the sulfonic acid ester represented by the general formula [IX] is reduced to an amino group, the ring is closed in the molecule, and a protecting group for the amino group is further introduced. Thus, a 2,3-dihydro-1H-indole derivative represented by the general formula [X] is produced.

The reduction of the nitro group to the amino group is performed according to a known method (“Organic Functional Group Preparation”).
s, "2nd Ed., Academic Press, New York, 1983, Vol.1, pp37
7-433.), Preferably in the presence of a tertiary amine such as triethylamine or diisopropylethylamine by hydrogenation using platinum or palladium supported on carbon powder as a catalyst. The reaction is carried out in a solvent under a hydrogen pressure of 1 to 10 atm. As the solvent, any solvent can be used as long as it does not participate in the reaction. Preferably, ether solvents such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane are used. Hydrogenation proceeds smoothly from 0 ° C to 50 ° C.

The amino group generated by hydrogenation immediately reacts with an intramolecular sulfonyloxy group in the presence of a tertiary amine such as triethylamine or diisopropylethylamine to perform an intramolecular ring closure reaction. The protecting group for the amino group to be introduced into the 1-position amino group of the formed 2,3-dihydro-1H-indole derivative is stably present in the fourth to twelfth steps, and is preferably present in the thirteenth and fourteenth steps. In the above, those which can be removed without damaging other sites of the compound are selected. Examples of the amino-protecting group satisfying such requirements include a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group and a t-butoxycarbonyl group.
6, a linear or branched lower alkoxycarbonyl group, a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a benzhydryloxycarbonyl group,
Di- (p-methoxyphenyl) methoxycarbonyl group,
A substituted or unsubstituted aralkyloxycarbonyl group such as a trityloxycarbonyl group is exemplified, and a t-butoxycarbonyl group is preferably used. These protecting groups can be introduced by a known method.
(“Protective Groups in Organic Synthesis,” John W
iley & Sons, New York, 1981, pp. 226-248).

[Fourth Step] In this step, 2,3-dihydro-1 represented by the general formula [X] is used.
By introducing a nitro group at the 5-position of the H-indole derivative, 5-nitro-2,3-dihydro-1H-
It is for producing indole derivatives.

Introduction of a nitro group is performed according to a known method for nitrating a benzene ring (“Organic Functional Group P.
reparations, "2nd.Ed.Academic Press, 1983, Vol.1 pp49
8-548.), Preferably using acetyl nitrate. The reaction is carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but preferably, a halogenated hydrocarbon solvent such as chloroform, dichloromethane, carbon tetrachloride, nitromethane, nitrobenzene, etc. Is used. The reaction proceeds smoothly at -40 ° C to 20 ° C.

[Fifth Step] The present step comprises the steps of 5-nitro-2,3 represented by the general formula [XI].
A 5-amino-2,3-dihydro-1H-indole derivative represented by the general formula [XII] by reducing the 5-position nitro group of the -dihydro-1H-indole derivative.

The reduction of the nitro group to the amino group is performed according to a known method (“Organic Functional Group Preparation”).
s, "2nd.Ed.Academic Press, New York, 1983, Vol.1 pp377
-433.), Preferably by hydrogenation using platinum, palladium on charcoal powder or the like as a catalyst. The reaction is 1
It is carried out in a solvent under a hydrogen pressure of 1010 atm. As the solvent, any solvent can be used as long as it does not participate in the reaction. Preferably, ether solvents such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane are used. Hydrogenation proceeds smoothly from 0 ° C to 50 ° C.

[Sixth step] The present step comprises the steps of 5-amino-2,3 represented by the general formula [XII].
-Dihydro-1H-indole derivative, S-chloro-S prepared from alkyl methylthioacetate and sulfuryl chloride
-Methyl-S-alkoxycarbonylmethylsulfonium chlorosulfinate is reacted in the presence of a base to form 4- (1-methylthio-1-alkoxycarbonyl) methyl-5-amino-2,3-dihydro-1H-indole 1-methylthio-2-oxo-1,2,3,6,7,8-benzo [1,2-b; 4,3-b '] dipyrrole derivative by inner ring closure in which the derivative is further treated with carboxylic acid and separated And further oxidizing the 1-position to obtain a compound of the present invention represented by the general formula [III
a], a 1,2-dioxo-1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole derivative.

S- from alkyl methylthioacetate and sulfuryl chloride
The preparation of chloro-S-methyl-S-alkoxycarbonylmethylsulfonium chlorosulfinate is carried out according to the method described in the literature (J. Med. Chem., 31 , 590 (198
8). ). Examples of the alkyl methylthioacetate to be used include linear or branched lower alkyl esters of methylthioacetic acid having 1 to 6 carbon atoms, such as methyl methylthioacetate, ethyl methylthioacetate, and isopropyl methylthioacetate. Methyl methylthioacetate is used.

The obtained chlorosulfinate and 5-amino-2,3-
The reaction with the dihydro-1H-indole derivative is performed in the presence of a tertiary amine. As the tertiary amine used, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, 1,8-bisdimethylaminonaphthalene (proton sponge), 1,4-diazabicyclo [2.2.2] octane, 1,8- Diazabicyclo (5.4.
0] undec-7-ene is exemplified, but preferably 1,8
-Bisdimethylaminonaphthalene (proton sponge)
Is used.

4- (1-) formed by the reaction of chlorosulfinate with the 5-amino-2,3-dihydro-1H-indole derivative
Methylthio-1-alkoxycarbonyl) methyl-5-
The amino-2,3-dihydro-1H-indole derivative is treated with a carboxylic acid to close the ring and give 1-methylthio-2-oxo-1,2,3,6,7,8-hexahydro-benzo [1, 2-b; 4,3-b '] dipyrrole derivatives. Examples of the carboxylic acid to be used include linear or branched lower fatty acids having 1 to 6 carbon atoms, such as formic acid, acetic acid, propionic acid, butyric acid, and isobutyric acid. Preferably, acetic acid is used.

Preparation of chlorosulfinate, reaction of chlorosulfinate with 5-amino-2,3-dihydro-1H-indole derivative, and further 1-methylthio-2-oxo-1,2,
3,6,7,8-hexahydro-benzo [1,2-b; 4,3-b ']
The ring closure to the dipyrrole derivative is carried out in the same or different solvent, and any solvent can be used as long as it does not participate in the reaction, preferably diethyl ether, tetrahydrofuran, dioxane, 1,2- Ether solvents such as dimethoxyethane, and halogenated hydrocarbon solvents such as chloroform, dichloromethane, and carbon tetrachloride are used.

The preparation of the chlorosulfinate and the reaction of the chlorosulfinate with the 5-amino-2,3-dihydro-1H-indole derivative proceed smoothly at -100 ° C to -20 ° C. -Methylthio-2-oxo-1,2,3,6,
Ring closure to the 7,8-hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole derivative proceeds smoothly from 0 ° C to 50 ° C.

By oxidizing a 1-methylthio-2-oxo-1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3-b ′] dipyrrole derivative, the compound of the present invention is obtained. A 1,2-dioxo-1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3-b ′] dipyrrole derivative represented by a general formula [IIIa] is obtained. Can be As the oxidizing agent, a combination of copper (II) chloride and copper (II) oxide is preferably used. The oxidation is performed in a solvent, and any solvent can be used as long as it does not take part in the reaction.Preferably, ether solvents such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane are used. , Acetone, methyl ethyl ketone, diethyl ketone, and cyclohexanone. The reaction is-
It proceeds smoothly at 20 ° C to 50 ° C.

[Seventh step] The present step is carried out by reacting 1,2-dioxo-1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3 −
b '] The protecting group of the protected hydroxymethyl group present at the 8-position of the dipyrrole derivative is removed to obtain a compound of the general formula [IIIb]
8-hydroxymethyl-1,2-dioxo-1, represented by
2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3-
b ′] for producing a dipyrrole derivative.

The removal of the protecting group is performed according to a known method depending on the type of the protecting group introduced in the first step (“Protecti
ve Groups in Organic Synthesis, "John Wiley & Son
s, New York, 1981, pp 50-72.).

[Eighth Step] This step comprises the steps of 8-hydroxymethyl-1,2-dioxo-1,2,3,6,7,8-hexahydro-benzo [1,2- b; 4,3-b '] dipyrrole derivative at the 8-position hydroxymethyl group, 1,2 represented by the general formula [IIIa]
Dioxo-1,2,3,6,7,8-hexahydro-benzo [1,2
-B; 4,3-b '] re-introducing a hydroxyl-protecting group different from the protecting group of the dipyrrole derivative, and represented by the general formula (IIIc)
1,2-dioxo-1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole derivative represented by the following formula:

The protecting group to be introduced is selected from those which are stably present in the ninth to twelfth steps and can be removed in the thirteenth and fourteenth steps without damaging other parts of the compound. Hydroxyl protecting groups satisfying such requirements include:
Triethylsilyl group, isopropyldimethylsilyl group,
A silyl group such as a t-butyldimethylsilyl group and a t-butyldiphenylsilyl group can be exemplified, but a t-butyldimethylsilyl group is preferably used. These protecting groups are represented by the general formula [IIIb], 8-hydroxymethyl-1,2-dioxo-1,2,3,6,7,8-hexahydro-benzo [1,2- b; 4,3-b '] dipyrrole derivative (“Protective Groups in Organic Synth
esis, "John-Wiley & Sons, New York, 1981, pp 39-5
0.).

[Ninth Step] This step comprises the steps of: 1,2-dioxo-1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3 −
b '] The dipyrrole derivative is oxidized to an isatoic anhydride derivative, and the isatoic anhydride derivative is subjected to alcoholysis to give a 5-amino-4-compound of the present invention represented by the general formula [IIa]. This is for producing an alkoxycarbonyl-2,3-dihydro-1H-indole derivative.

The oxidation is carried out in the presence of a base using a peroxide such as hydrogen peroxide, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, or monoperphthalic acid. Preferably, m-chloroperbenzoic acid is used. Is used. Examples of the base include alkali metal acidic carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; lithium hydroxide, sodium hydroxide, and potassium hydroxide. Is used, and preferably, sodium hydrogen carbonate is used. The reaction is carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but preferably a halogenated hydrocarbon solvent such as chloroform, dichloromethane, or carbon tetrachloride is used. . The reaction proceeds smoothly at -20 ° C to 50 ° C.

The alcoholysis of the isatonic anhydride derivative obtained by the oxidation is performed using an alcohol in the presence of a base. Examples of the alcohol used include those having 1 to 6 carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol and pentanol.
Is exemplified, but methanol is preferably used. Examples of the base include alkali metal carbonates such as lithium carbonate and potassium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, and 1,8-bisdimethylaminonaphthalene. (Proton sponge), 1,
Tertiary amines such as 4-diazabicyclo [2.2.2] octane and 1,8-diazabicyclo [5.4.0] undec-7-ene are exemplified, but potassium carbonate is preferably used. The reaction proceeds smoothly at -20 ° C to 50 ° C.

[Tenth Step] The present step is a 5-amino-4 represented by the general formula [IIa].
A (1-alkoxycarbonyl) ethyl group is introduced into the 5-position amino group of the -alkoxycarbonyl-2,3-dihydro-1H-indole derivative to give a compound of the present invention represented by the general formula [IIb]. [(1-Alkoxycarbonyl) ethyl] amino-4-alkoxycarbonyl-2,3
-Dihydro-1H-indole derivatives.

Introduction of the (1-alkoxycarbonyl) ethyl group is performed using 2-halopropionic acid ester in the presence of a base. Examples of the 2-halopropionic acid ester used include 2-bromopropionic acid and 2-iodopropionic acid such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and ester.
-A straight-chain or branched lower alkyl ester of halopropionic acid having 1 to 6 carbon atoms is exemplified.
-Methyl bromopropionate is used. Examples of chlorine include alkali metal carbonates such as sodium carbonate, calcium carbonate, and cesium carbonate, and alkali metal carbonates such as magnesium carbonate, calcium carbonate, and barium carbonate. Cesium carbonate is preferably used. The reaction is carried out in a solvent, and any solvent may be used as long as it does not participate in the reaction, but preferably, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphorous triamide is used. An aprotic polar solvent such as amide is used, and more preferably, N, N
-Dimethylformamide is used. Reaction from 30 ℃
Proceeds smoothly at 120 ° C.

[Eleventh Step] The present step is a method for preparing a 5-[(1-alkoxycarbonylethyl)] amino-4-alkoxycarbonyl-2,3-dihydro-1H-indole derivative represented by the general formula [IIb]: A (1-alkoxycarbonylethyl) amino group protected at the 5-position represented by the general formula [IIc], which is a compound of the present invention, by introducing a protecting group into the nitrogen atom of the (1-alkoxycarbonylethyl) amino group To produce a 5- (1-alkoxycarbonylethyl) amino-4-alkoxycarbonyl-2,3-dihydro-1H-indole derivative having the formula:

As the protecting group to be introduced, those which are stably present in the twelfth step and can be removed in the thirteenth and fourteenth steps without damaging other parts of the compound are used. Satisfies such requirements (1-alkoxycarbonylethyl)
As the protecting group for the amino group, formyl group, acetyl group,
A linear or branched lower alkanoyl group having 1 to 6 carbon atoms such as a propionyl group, a 2-methylpropionyl group, a butyryl group, a 3-methylbutyryl group, a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group, a t- A linear or branched lower alkoxycarbonyl group having 1 to 6 carbon atoms such as a butoxycarbonyl group, a trimethylsilyl group, a triethylsilyl group, an isopropyldimethylsilyl group, a t-butyldimethylsilyl group, a t-
A silyl group such as a butyldiphenylsilyl group is exemplified, but a formyl group or a t-butoxycarbonyl group is preferably used, and a formyl group is more preferably used. These protecting groups are introduced into the 5- (1-alkoxycarbonylethyl) amino-4-alkoxycarbonyl-2,3-dihydro-1H-indole derivative represented by the general formula [IIc] by a known method. (“Protec
tive Groups in Organic Synthesis, "John-Wiley & S
ons, New York, 1981. pp 223-257 and p 283.).

[Twelfth Step] The present invention relates to 5- (1-alkoxycarbonylethyl) amino-4 having a (1-alkoxycarbonylethyl) amino group protected at the 5-position represented by the general formula [IIc]:
An alkoxycarbonyl-2,3-dihydro-1H-indole derivative is intramolecularly closed with a base to give a compound of the general formula (I
a) and (Ia ′) of the present invention (2R
^* , 8S ^* )-2-Alkoxycarbonyl-2-methyl-
1-oxo-1,2,3,6,7,8-hexahydro-benzo [1,2
-B; 4,3-b '] dipyrrole derivative and its (2R ^* , 8
S ^* )-to produce the isomer.

As the base used for the intramolecular ring closure reaction, lithium hydride, sodium hydride, alkali metal hydrides such as potassium hydride, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide,
Sodium ethoxide, potassium ethoxide, sodium t-butoxide, potassium t-butoxide, sodium phenoxide, alkali metal alkoxide such as potassium phenoxide, lithium amide, sodium amide, potassium amide, lithium diisopropylamide,
Although an alkali metal amide such as lithium hexamethyldisilazide is exemplified, lithium diisopropylamide is preferably used. The reaction is carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction.
Ether solvents such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane are used. Reaction is -100
It proceeds smoothly from ℃ to -20 ℃.

[Steps 13 and 14] In this step, (2R ^* , 8S ^* )-and (2S ^* , 8S ^* )-2-alkoxycarbonyl-2 represented by the general formulas [Ia] and [Ia '] -Methyl-1-oxo-1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole derivative at the 3-, 6- and 7-position hydroxy The protective group for the methyl group is removed at a stretch, and the compounds of the present invention represented by the general formulas [Ib] and [Ib '] are (2R ^* , 8S ^* )-and (2S ^* ).
^* , 8S ^* )-2-Alkoxycarbonyl-8-hydroxymethyl-2-methyl-1-oxo-1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3- b ′] for producing a dipyrrole derivative.

The removal of the protecting group is performed according to a known method depending on the type of the protecting group used for the 3-, 6-, and 7-position hydroxymethyl groups (“Protective Groups in O
rganic Synthesis, "John-Wiley & Sons, New York, 198
1.pp 223-257 and p 283.), preferably with methanol saturated with hydrogen chloride. Reaction is from 0 ° C to 50 ° C
It progresses smoothly.

The general formula (I) produced according to the synthesis process described above
c] and [I c ′].
^* , 8S ^* )-and (2S ^* , 8S ^* )-8-hydroxymethyl-2-methoxycarbonyl-2-methyl-1-oxo-
1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3-
b '] Dipyrrole derivative can be used as a carcinostatic agent due to its strong cytotoxicity by the following synthesis process, duocarmycin A (IV) and its 2-epimer (I
V ').

(In the formula, R ¹² represents a linear or branched lower alkyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted allyl group.)

[Fifteenth and Sixteenth Steps] In this step, 2R ^* , 8S ^* )-and (2S ^* , 8S ^* ) represented by general formulas [Ic] and [Ic '], which are compounds of the present invention, are used.
-Hydroxymethyl-2-methoxycarbonyl-2-methyl-1-oxo-1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole derivative is represented by the formula (XIII)
5,6,7-trimethoxy-1H-indole-2 represented by
And (2R ^* , 8S ^* )-and (2S ^* , 8S ^* )-8-hydroxymethyl-2-methoxycarbonyl-6 represented by the general formulas [XIV] and [XIV ']. (5,6,7
-Trimethoxy-1H-indole-2-carbonyl)-
This is to produce a 2-methyl-1-oxo-1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole derivative.

The 5,6,7-trimethoxy-1H-indole-2-carboxylic acid represented by the formula (XIII) used in this reaction is 3,4,
It is a compound that can be easily produced from 5-trimethoxybenzaldehyde (see Reference Example below). The reaction is carried out using a condensing agent. As the condensing agent, those usually used for producing a corresponding amide derivative by condensing a primary or secondary amine derivative with a carboxylic acid derivative are used ("" Advanced Organic Chemistry: Reactions, Mechanism
s, and Structure, "MuGraw-Hill Kogakusha, Tokyo, 197
7, pp384-385.), Preferably 1,3-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl)-
A carbodiimide derivative such as 3-ethylcarbodiimide hydrochloride is used. The reaction is carried out in a solvent, and any solvent may be used as long as it does not participate in the reaction, but preferably N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphorous triamide And an aprotic polar solvent such as acetonitrile. The reaction proceeds smoothly at 0 ° C to 50 ° C.

[Steps 19 and 20] In this step, (2R ^* , 8S ^* )-and (2S ^* , 8S ^* )-8-hydroxymethyl-2-methoxy represented by the general formulas [XIV] and (XIV ') Carbonyl-6- (5,6,7-trimethoxy-1H-indole-2-carbonyl) -2-methyl-1-oxo-1,2,3,6,7,8-hexahydro-benzo [1,2- b; 4,3-b ′] dipyrrole derivative sulfonylates the 8-position hydroxymethyl group to obtain a compound represented by the general formula [XV] or [X
V '] (2R ^* , 8S ^* )-and (2S ^* , 8S ^* )-
2-methoxycarbonyl-6- (5,6,7-trimethoxy-1H-indole-2-carbonyl) -2-methyl-1
-Oxo-8-sulfonyloxymethyl-1,2,3,6,7,8
-Hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole derivatives.

Examples of the sulfonylating agent include methanesulfonyl chloride, methanesulfonyl bromide, ethanesulfonyl chloride, ethanesulfonyl bromide, benzenesulfonyl chloride, sulfonyl halides such as p-toluenesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, Examples thereof include sulfonic anhydrides such as benzenesulfonic anhydride and p-toluenesulfonic anhydride, and methanesulfonyl chloride is preferably used. Sulfonylation can be performed according to a known method. (“Organic Function
al Group Preparations, "2nd.Ed., Academic Press, New
York, 1983, Vol. 1, pp 619-639.).

[Steps 19 and 20] This step is represented by the general formulas [XV] and [XV '] (2R
^* , 8S ^* )-and (2S ^* , 8S ^* )-2-methoxycarbonyl-6- (5,6,7-trimethoxy-1H-indole-2
-Carbonyl) -2-methyl-1-oxo-8-sulfonyloxymethyl-1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole derivative The protecting group at the 4-position hydroxyl group is removed, and (2R ^* , 8S ^* )-and (2S ^* , 8S ^* )-4-hydroxy-2-methoxycarbonyl- represented by the general formulas [XVI] and [XVI ']. 6- (5,6,7-trimethoxy-1H-indole-2-carbonyl-2-methyl-
1-oxo-8-sulfonyloxymethyl-1,2,3,6,7,
This is for producing an 8-hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole derivative.

The removal of the protecting group is performed according to a known method depending on the kind of the protecting group used (“Protective Groups”).
in Organic Synthesis, "John-Wiley & Sons, New Yor
k, 1981, pp 14-39.).

[Steps 21 and 22] In this step, (2R ^* , 8S ^* )-and (2S ^* , 8S ^* )-4-hydroxy- represented by the general formulas [XVI] and [XVI '] are used.
2-methoxycarbonyl-6- (5,6,7-trimethoxy-1H-indole-2-carbonyl) -2-methyl-1
-Oxo-8-sulfonyloxymethyl-1,2,3,6,7,8
-Hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole derivative treated with a base to close the ring inside the molecule, and racemic duocarmycin represented by formulas (IV) and (IV') A and its 2-position epimer (2-epiduocarmycin A)
Is to manufacture.

Examples of the base used for the reaction include alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, lithium carbonate, and sodium carbonate. , Alkali metal carbonates such as potassium carbonate, triethylamine, diisopropylethylamine,
Pyridine, 4-dimethylaminopyridine, 1,8-bisdimethylaminonaphthalene (proton sponge), 1,4-
Tertiary amines such as diazabicyclo [2.2.2] octane and 1,8-diazabicyclo [5.4.0] undec-7-ene are exemplified, preferably an alkali metal hydride, more preferably sodium hydride Is used. The reaction is performed in a solvent, and any solvent can be used as long as it does not participate in the reaction.
Diethyl ether, tetrahydrofuran, dioxane,
An ether solvent such as 1,2-dimethoxyethane is used. The reaction proceeds smoothly at -20 ° C to 50 ° C.

Hereinafter, the present invention will be described in detail with reference to Examples and Reference Examples, but the present invention is not limited thereto.
The following abbreviations are used in Examples and Reference Examples.

Bn: benzyl group Ac: acetyl group Ms: methanesulfonyl group TBDMS: t-butyldimethylsilyl group Boc: t-butoxycarbonyl group 2- (4-benzyloxy-2-nitrophenyl) propane-1,3-diol (1.82 g, 6.0 mmol) synthesized by the method described in the literature (J. Med. Chem., 31 , 590 (1988)). And triethylamine (0.84 ml, 6.0 mmol) were dissolved in dichloromethane (20 ml), and acetic anhydride (0.85 ml, 9.0 mmol) was added under water cooling.
Was added dropwise and stirred for 2.5 hours. The reaction solution was washed sequentially with water, 1% aqueous sodium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by column chromatography (silica gel: dichloromethane-ethyl acetate = 20: 1) to give 3-acetoxy-2- (4-benzyloxy-2-nitrophenyl).
Propanol was obtained as an oil (1.54 g, 74%).

_{NMR (CDCl 3): δ:} 7.19-7.45 (8H, m, C 6 H 5, C 3 -H, C 5 -
H, and _{C 6 -H), 5.09 (2H} , s, PhCH 2 O), 4.49 (1H, dd, J =
11.1,6.8Hz, HCHOAc), 4.32 (1H, dd, J = 11.1,6.2Hz, HCHO
Ac), 3.90 (1H, dd, J = 11.3, 5.8Hz, HCHOH), 3.87 (1H, d
d, J = 11.3,5.5Hz, HCHOH) , 3.65 (1H, m, CHCH 2 OH), 2.04
(3H, s, COCH ₃ ). 3-acetoxy-2- (4-benzyloxy-2-nitrophenyl) propanol (1.53 g, 4.4 mmol) and triethylamine (0.68 ml, 4.9 mmol) were added to dichloromethane (15%).
methanesulfonyl chloride (0.38 ml,
4.9 mmol) was added dropwise and stirred for 30 minutes. The reaction solution was washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue is subjected to column chromatography (silica gel: dichloromethane-ethyl acetate =
50: 1) to give 3-acetoxy-2- (4-benzyloxy-2-nitrophenyl) propylmethanesulfonate as an oil (1.86 g, 100%).

_{NMR (CDCl 3): δ:} 7.19-7.49 (8H, m, C 6 H 5, C 3 -H, C 5 -
H, and _{C 6 -H), 5.11 (2H} , s, PhCH 2 O), 4.53 (1H, dd, J =
11.5,5.9Hz, HCHOMs), 4.50 (1H, dd, J = 11.4,5.7Hz, HCHO
Ms), 4.45 (1H, dd, J = 11.2,6.9Hz, HCHOAc), 4.36 (1H, d
d, J = 11.3,6.0Hz, HCHOAc), 3.94 (1H, m, CHCH ₂ OMs), 2.9
5 (3H, s, SO ₂ CH ₃ ), 2.04 (3H, s, COCH ₃ ). 4-acetoxy-2- (4-benzyloxy-2-nitrophenyl) propyl methanesulfonate (1.85 g, 4.
4 mmol) and triethylamine (0.61 ml, 4.4 mmol) were dissolved in tetrahydrofuran (20 ml), and platinum oxide (139 mg, 0.
In the presence of 61 mmol), hydrogenation was performed at room temperature under a hydrogen pressure of 3 atm for 20 minutes. The catalyst was removed by filtration, and the filtrate was diluted with dichloromethane. After washing with water and saturated saline in this order, the extract was dried over anhydrous magnesium sulfate and the solvent was distilled off. Crude 3-acetoxymethyl-6-benzyloxy-2,3- obtained as residue
Dihydro-1H-indole was dissolved in dichloromethane (5 ml) and anhydrous t-butyl carbonate (1.05 g, 4.8 mmol) was added. After stirring at room temperature for 12 hours, the solvent was distilled off. The obtained residue was purified by column chromatography (silica gel: benzene-ethyl acetate = 20: 1) to give 3-acetoxymethyl-6-benzyloxy-1-t-butoxycarbonyl-2,3-dihydro-1H-indole. Oily substance (1.6
5g, 95%).

NMR (CDCl ₃ : δ: 7.66 (1H, brs, C ₇ -H), 7.28-7.45 (5
_{H, m, C 6 H 5} ), 7.06 (1H, dd, J = 8.2,0.5Hz, C 4 -H), 6.57
(1H, dd, J = 8.2,2.4Hz , C 5 -H), 5.06 (2H, s, PhCH 2 O),
_{3.51-4.27 (5H, m, C 2} -H 2 _{and,, CHCH 2 OAc), 2.08} (3H,
s, COCH ₃ ), 1.56 (9H, COOC (CH ₃ ) ₃ ). 3-acetoxymethyl-6-benzyloxy-1-t
-Butoxycarbonyl-2,3-dihydro-1H-indole (1.65 g, 4.2 mmol) was dissolved in nitromethane (80 ml), acetic anhydride (2.35 ml, 25 mmol) and fuming nitric acid (0.26 ml, 6.
2 mmol) was added dropwise at −20 ° C.
Thereafter, the mixture was stirred for 3 hours. Dilute the reaction with benzene and add 1
The mixture was sequentially washed with a 10% aqueous sodium hydrogen carbonate solution and saturated saline. The residue obtained by drying over anhydrous magnesium sulfate and evaporating the solvent was purified by column chromatography (silica gel: benzene-ethyl acetate = 20: 1) to give 3-acetoxymethyl-6-benzyloxy-1-t-butoxy. Carbonyl-5-nitro-2,3-dihydro-1H-indole was obtained as pale yellow crystals (1.41 g, 77%).

_{NMR (CDCl 3): δ:} 7.88 (1H, d, J = 1.0Hz, C 4 -H), 7.81
_{(1H, brs, C 7 -H} ), 7.30-7.56 (5H, m, C 6 H 5), 5.25 (2
_{H, s, PhCH 2 O)} , 3.58-4.26 (5H, m, C 2 -H 2, and, CHCH ₂ OA
c), 2.10 (3H, s, COCH ₃ ), 1.58 (COOC (CH ₃ ) ₃ ). 3-acetoxymethyl-6-benzyloxy-1-t
-Butoxycarbonyl-5-nitro-2,3-dihydro-1
H-indole (443 mg, 1.0 mmol) was dissolved in tetrahydrofuran (5 ml), and hydrogenated in the presence of platinum oxide (22.7 mg, 0.10 mmol) under a hydrogen pressure of 3 atm at room temperature for 15 minutes. After removing the catalyst by filtration, the solvent was distilled off. The obtained residue was purified by column chromatography (silica gel: benzene-ethyl acetate = 5: 1) to give 3-acetoxymethyl-5-amino-6-benzyloxy-1-t-butoxycarbonyl-.
2,3-Dihydro-1H-indole was converted to an oily substance (390 mg, 95%).
%).

_{NMR (CDCl 3): δ:} 7.64 (1H, brs, C 7 -H), 7.31-7.47
_{(M, 6H, C 4 -H} and C 6 H 5), 5.09 (2H, brs, -OCH 2 Ph), 3.
_{50-4.60 (m, 5H, C 2} -2H and -CHCH 2 O -), 2.09 (s, 3H,
_{-COCH 3), 1.56 (s,} 9H, (CH 3) 3 CCO-). Methyl methylthioacetate (137 mg, 1.1 mmol) was dissolved in dichloromethane (9 ml), and sulfuryl chloride (84.0 μ, 1.
1 mmol) was added dropwise at −78 ° C. and stirred at the same temperature for 20 minutes.
A dichloromethane solution of S-chloro-S-methyl-S-methoxycarbonylmethylsulfonium chlorosulfinate was prepared. To this solution was added 3-acetoxymethyl-5-amino-6-benzinioxy-1-t- at -78 ° C.
A solution of butoxycarbonyl-2,3-dihydro-1H-indole (390 mg, 1.0 mmol) and 1,8-bisdimethylaminonaphthalene (224 mg, 1.1 mmol) in dichloromethane (6 ml) was added to 20
It was added dropwise over a period of minutes. After stirring at −78 ° C. for 3.5 hours, triethylamine (146 μm, 1.1 mmol) was added dropwise. afterwards,
After stirring at −78 ° C. for 2 hours, the mixture was stirred at room temperature for 21 hours. Acetic acid (3 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour.
The extract was washed successively with saturated saline and dried over anhydrous magnesium sulfate. Crude 8-acetoxy-4- obtained by evaporating the solvent
Benzyloxy-6-t-butoxycarbonyl-1-methylthio-2-oxo-1,2,3,6,7,8-hexahydro-
Benzo [1,2-b; 4,3-b '] dipyrrole was converted to acetone (20
dissolved in water and cooled under water with copper (II) chloride (128 mg, 1.0 mmol)
And copper (II) oxide (113 mg, 1.4 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. The reaction was diluted with dichloromethane and washed with saturated aqueous ammonium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by column chromatography (silica gel: dichloromethane: ethyl acetate = 10: 1) to give 8-acetoxymethyl-4-benzyloxy-6-t-. Butoxycarbonyl-1,2-dioxo-1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,
3-b '] dipyrrole was obtained as purple crystals (340 mg, 77%). This was recrystallized from ethanol to obtain an analytical sample.

mp. 178-179 ° C IR (KBr): 3550, 3200, 1740, 1700 cm ^-1 . NMR (CDCl ₃ ): δ: 8.00 (1H, brs, NH), 7.63 (1H, brs, C ₅₎
−H), 7.40 (5H, m, C ₆ H ₅ ), 5.14 (2H, s, PhCH ₂ O), 3.82
−4.42 (5H, m, C ₇ −H ₂ and CHCH ₂ OAc), 2.03 (3H, s, COC
_{H 3), 1.56 (9H,} s, COOC (CH 3) 3). . MS: m / e: 466 (M +), 350,306,249,205,91 Elemental _{analysis: C 25 H 26 O 7 N} 2 Calculated: C, 64.37%; H, 5.62%; N, 6.01%. Analytical values: C, 64.37%; H, 5.51%; N, 5.96%. 8-acetoxymethyl-4-benzyloxy-6-t
-Butoxycarbonyl-1,2-dioxo-1,2,3,6,7,8-
Hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole (163 mg, 0.35 mmol) was dissolved in methanol (7 ml), and potassium carbonate (96.7 mg, 0.70 mmol) was added under cooling with water, and room temperature was maintained for 2.5 hours. And stirred. Acetic acid (50μ) was added, the mixture was stirred for 15 minutes, and diluted with dichloromethane. After washing with saturated saline, the extract was dried over anhydrous sodium sulfate. The solvent was distilled off to give crude 4-benzyloxy-6-t-butoxycarbonyl-8.
-Hydroxymethyl-1,2-dioxo-1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole as purple crystals (129 mg, 87%) Obtained. This was used immediately for the next silylation.

_{NMR (DMSO-d 6):} δ: 11.11 (s, 1H, -NH -), 7.82 (br
_{s, 1H, C 7 -H)} , 7.30-7.60 (m, 6H, C 4 -H and -C 6 H 5),
5.18 (s, 2H, -OCH ₂ Ph), 4.84 (t, 1H, J = 5.7Hz, -O
H), 3.95 (d, 2H , J = 6.5Hz), 3.38-3.74 (m, 3H, C 2 -2H
_{and C 3 -H), 1.50 (} s, 9H, (CH 3) 3 CCO-). MS: m / e: 420 (M ⁺ ), 368, 324, 249, 147, 91. Crude 4-benzyloxy-6-t-butoxycarbonyl-8-hydroxymethyl-1,2-dioxo-1,2,3,
6,7,8-Hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole (149 mg, 0.35 mmol) was dissolved in N, N-dimethylformamide (1.5 ml) and t-butyldimethylchlorosilane was dissolved. (106mg, 0.70mmol) and imidazole (47.7mg, 0.70m
mol), and the mixture was stirred at room temperature for 8 hours. The reaction solution was diluted with benzene and washed sequentially with a saturated aqueous ammonium chloride solution and a saturated saline solution. After drying over anhydrous magnesium sulfate,
The solvent was distilled off. The obtained residue was purified by column chromatography (silica gel: benzene-ethyl acetate = 8: 1) to give 4-benzyloxy-6-t-butoxycarbonyl-8- (t-butyldimethylsilyloxy) methyl-.
1,2-Dioxo-1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3-b ′] dipyrrole was converted to red-purple crystals (169 mg,
90%). This was recrystallized from ethanol to obtain an analytical sample.

. mp.197~198 ℃ IR (KBr): 3200,1740,1715cm -1 NMR (CDCl 3): δ: 7.98 (1H, s, -NH -), 7.61 (1H, s, C 5
−H), 7.40 (5H, brs, −C ₆ H ₅ ), 5.13 (2H, s, −OCH ₂ P
h), 3.85-4.15 (5H, m , C 7 -2H, C 8 -H and-CH 2 O -), 1.
55 (9H, s, (CH 3) 3 CCO -), 0.82 (9H, s, (CH 3) 3 Si
−), 0.04 (3H, s, SiCH ₃ ), −0.06 (3H, s, SiCH ₃ ). MS: m / e: 538 (M ⁺ ), 482, 425, 381, 304, 260, 91. Elemental analysis: C ₂₉ H ₃₈ O ₆ N ₂ Si Calculated: C, 64.66%; H, 7.11%; N, 5.20%. Analytical values: C, 64.61%, H, 7.17%, N, 5.19%. 4-benzyloxy-6-t-butoxycarbonyl-
8- (t-butyldimethylsilyloxy) methyl-1,2
-Dioxo-1,2,3,6,7,8, -hexahydro-benzo [1,
2-b; 4,3-b '] dipyrrole (53.9 mg, 0.10 mmol) was dissolved in dichloromethane (1 ml), and m-chloroperbenzoic acid (31.1 mg, 0.18 mmol) was added at -15 ° C. 1
6.8 mg, 0.20 mmol) were added in sequence, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was diluted with dichloromethane, washed successively with a 1% aqueous sodium hydrogen sulfite solution, a 1% aqueous sodium hydrogen carbonate solution and saturated saline, and then dried over anhydrous sodium sulfate. The crude isatoic anhydride derivative obtained by evaporating the solvent was dissolved in methanol (1 ml), and potassium carbonate (16.
6 mg, 0.12 mmol) and stirred for 1 hour. Acetic acid (70μ)
Was added, and the mixture was diluted with saturated saline and extracted with benzene. After the benzene solution is dried over anhydrous sodium sulfate, the solvent is distilled off, and the residue is purified by column chromatography (silica gel: benzene-ethyl acetate = 50: 1 → 30: 1) to give 5-amino-6-benzyl Oxy-1-t-butoxycarbonyl-3- (t-butyldimethylsilyloxy) methyl-4-methoxycarbonyl-2,3-dihydro-1H-indole was obtained as pale yellow crystals (50.9 mg, 94%). This was recrystallized from methanol to obtain an analytical sample.

mp.120.5~121 ℃ IR (KBr):. 3550,3545,1700cm -1 NMR (CDCl 3): δ: 7.80 (1H, s, C 7 -H), 7.27-7.54 (5
H ,, m, C ₆ H ₅ ), 5.70 (2H, brd, NH ₂ ), 5.16 (2H, s, PhCH)
_{2 O), 3.90 (3H,} s, CO 2 CH 3), 3.15-4.25 (5H, m, C 2 -H 2 _{and, CHCH 2 OTBDMS), 1.54 (} 9H, s, COOC (CH 3) 3), 0.90
(9H, s, SiC (CH ₃ ) ₃ ), 0.15 (3H, s, SiCH ₃ ), 0.01 (3H,
s, SiCH ₃ ). MS: m / e: 542 (M ⁺ ), 486, 231. Elemental analysis: C ₂₉ H ₄₂ O ₆ N ₂ Calculated: C, 64.18%; H, 7.80%; N, 5.16%. Analytical values: C, 64.08%; H, 7.85%; N, 5.04%. 5-amino-6-benzyloxy-1-t-butoxycarbonyl-3- (t-butyldimethylsilyloxy)
Methyl-4-methoxycarbonyl-2,3-dihydro-1H
-Indole (32.5 mg, 60 μmol), methyl 2-bromopropionate (100 μ, 0.90 mmol), cesium carbonate (39 m
g, 0.12 mmol) was added to N, N-dimethylformamide (1.2 ml) and heated at 70 ° C. for 48 hours. After cooling, the reaction solution was diluted with water and extracted with benzene. The benzene layer was washed sequentially with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by preparative thin-layer chromatography (silica gel: benzene-ethyl acetate = 20: 1), and a mixture of diastereomers, 6-benzyloxy-1-tert-butoxycarbonyl-3- ( t-butyldimethylsilyloxy) methyl-4-methoxycarbonyl-5- (1-methoxycarbonylethyl) amino-2,3
-Dihydro-1H-indole was converted to pale yellow caramel (21.4m
g, 57%). This solidified on standing.

_{NMR (CDCl 3): δ:} 7.86 (1H, brs, C 7 -H), 7.30-7.48
_{(5H, m, -C 6 H} 5), 5.09 (2H, brs, -OCH 2 Ph), 4.29-4.41
(1H, q × 2, -NCH <, each diastereoisomer), 3.30-4.1
_{2 (5H, m, C 2} -2H, CHCH 2 -O-, each diastereoisomer),
3.92,3.94 (3H, s, Ar-CO ₂ Me, each diastereoisomer),
3.58,3.55 (3H, s, -CO ₂ Me, each diastereoisomer), 1.5
4 (9H, s, (CH ₃ ) ₃ CCO), 1.28,1.36 (3H, d × 2, J = 7.0,7.
2Hz, each diastereoisomer), 0.84,0.86 (9H, s × 2, (CH
₃ ) ₃ Si, each diastereoisomer), -0.08 to -0.40 (6H,
_{m, Si (CH 3) 2} ). MS: m / e: 628 (M ⁺ ), 572,527,481,349,289,245. Formic acid (58μ, 0.15mmol) and acetic anhydride (132μ, 0.14m
mol) in a mixed anhydride of 6-benzyloxy-1-t-butoxycarbonyl-3- (t-butyldimethylsilyloxy) methyl-4-methoxycarbonyl-5- (1-methoxycarbonylethyl). Amino-2,3-dihydro-1H-indole (43.9 mg, 70 μmmol)
Was added and stirred at room temperature for 9 hours. The reaction solution was diluted with benzene, washed with a 10% aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by preparative thin-layer chromatography (silica gel: benzene: methanol = 20: 1), and a mixture of diastereomers, 6-benzyloxy-1-t-butoxycarbonyl, was obtained. -3- (t-Butyldimethylsilyloxy) methyl-
5- [N-Formyl-N- (1-methoxycarbonylethyl) amino] -2,3-dihydro-1H-indole was obtained as a colorless caramel (42.7 mg, 93%).

NMR (CDCl ₃ ): δ: 7.96-8.10 (1H, m, CHO, two rotemers
for each diastereoisomer, 7.66 (1H, brs, C 7 -H), 7.
_{36 (5H, brs, C 6} H 5), 5.12 (2H, brs, -OCH 2 Ph), 4.96-5.
16 (1H, m, -NH-, two rotemers for each diastereoiso
mer), 3.36-4.26 (5H, m , C 2 -2H and -CHCH 2 O -), 3.8
4-4.01 (3H, m, ArCO ₂ Me, two rotemers for each diaste
reoisomer), 3.53,3.72 (3H, brs, CO ₂ CH ₃ , two rotemers
for each diastereoisomer), 1.42-1.66 (9H, brd, (CH
₃ ) ₃ C-, two rotemers for each diastereoisomer), 1.
06-1.49 (3H, m, CH ₃ , two rotemers for each diastereo
isomer), 0.69-0.96 (9H, m , Sic (CH 3) 3), - 0.20~
0.12 (6H, m, Si ( CH 3) 2). MS: m / e: 656 (M ⁺ ), 599, 543, 499, 367, 323, 245, 91. 6-benzyloxy-1-tert-butoxycarbonyl-
3- (t-butyldimethylsilyloxy) methyl-5-
[N-formyl-N- (1-methoxycarbonylethyl) amino] -2,3-dihydro-1H-indole (38.5 m
g, 59 μmmol) in tetrahydrofuran (2 ml),
At −78 ° C., a solution of lithium diisopropylamide in tetrahydrofuran (0.88 M solution, 100 μ, 88 μmmol) was added dropwise, and the mixture was stirred for 5.5 hours. After adding acetic acid (2 drops), the mixture was diluted with benzene and washed with a saturated aqueous ammonium chloride solution.
After drying over anhydrous sodium sulfate and evaporating the solvent, the residue obtained is purified by preparative thin-layer chromatography (silica gel: hexene: ether = 2: 1) to obtain more polar methyl (2R ^* , 8S ^* ). -4-benzyloxy-6-t-butoxycarbonyl-8- (t-butyldimethylsilyloxy) methyl-3-formyl-2-methyl-1-oxo-
1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3-
b '] dipyrrole-2-carboxylate (10.3 mg, 28
%) And its less polar (2S ^* , 8S ^* )-isomer (1
0.4 mg, 28%) as pale yellow caramel.

(2R ^*, 8S ^*) - Body _{NMR (CDCl 3): δ:} 9.46 (1H, s, CHO), 8.18 (1H, brs, C 5
−H), 7.36−7.46 (5H, m, C ₆ H ₅ ), 5.22 (2H, AB type q,
J = 16.4Hz, PhCH ₂ O), 4.20 (1H, brd, J = 11.3Hz, HCHOTBDM
S), 4.00 (1H, brd, J = 10.1Hz, HCHOTBDMS), 3.87 (1H, d
_{d, J = 12.3,6.0Hz, C 8} -H), 3.67-3.76 (2H, m, C 7 -
_{H 2), 3.71 (3H,} s, COOCH 3), 1.80 (3H, s, CH 3 CCO), 1.57
(9H, s, COOC (CH ₃ ) ₃ ), 0.79 (9H, s, SiC (CH ₃ ) ₃ ),
_{0.00 (3H, s, SiCH 3} ), - 0.15 (3H, s, SiCH 3). . MS: m / e: 624 (M +), 568,511,483,379,273,91 (2S *, 8S *) - Body _{NMR (CDCl 3): δ:} 9.47 (1H, s, CHO), 8.18 (1H, brs, C 5
−H), 7.36−7.46 (5H, m, C ₆ H ₅ ), 5.23 (2H, AB type q,
PhCH ₂ O), 4.19 (1H, brd, J = 10.9Hz, HCHOTBDMS), 3.99
(1H, brd, J = 10.3Hz, HCHOTMDMS), 3.86 (1H, dd, J = 9.0,
_{5.7Hz, C 8 -H), 3.66-3.77} (2H, m, C 7 -H 2), 3.72 (3H,
s, COOCH ₃ ), 1.81 (3H, s, CH ₃ CCO), 1.57 (9H, s, COOC (CH
_{3) 3), 0.79 (9H} , s, Sic (CH 3) 3), 0.01 (3H, s, SiC
_{H 3), - 0.13 (3H} , s, SiCH 3). MS: m / e: 624 (M ⁺ ), 568,524,483,379,273,91. Methyl (2R ^* , 8S ^* )-4-benzyloxy-6-t
-Butoxycarbonyl-8- (t-butyldimethylsilyloxy) methyl-3-formyl-2-methyl-1-oxo-1,2,3,6,7,8-hexahydro-benzo [1,2-b; Four,
3-b '] dipyrrole-2-carboxylate (10.3 mg,
17 μmol), methanol (2 ml) saturated with hydrogen chloride was added, and the mixture was allowed to stand at room temperature for 11 hours. The solvent was distilled off to give crude methyl (2R ^* , 8S ^* )-4-benzyloxy-8-hydroxymethyl-2-methyl-1-oxo-1,2,3,6,7,8-.
Hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole-2-carboxylate hydrochloride was converted into pale yellow crystals (6.9 mg, 10
0%).

_{NMR (DMSO-d 6):} δ: 7.80 (3H, brs, N 3 -H, N 6 -2H), 7.
_{20-7.60 (6H, m, C 5} -H, -C 6 H 5), 3.40-3.95 (5H, m, C 7
−2H, CHCH ₂ O), 3.65 (3H, s, CO ₂ CH ₃ ), 1.45 (3H, s, C
H ₃ ). Methyl (2S ^* , 8S ^* )-4-benzyloxy-6-t
-Butoxycarbonyl-8- (t-butyldimethylsilyloxy) methyl-3-formyl-2-methyl-1-oxo-1,2,3,6,7,8-hexahydro-benzo [1,2-b; Four,
3-b '] dipyrrole-2-carboxylate (10.4 mg,
17 μmol) in the same manner as in Example 8, and crude methyl (2S ^* , 8S ^* )-4-benzyloxy-8-hydroxymethyl-2-methyl-1-oxo-1,2,3,6,7 , 8−
Hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole-2-carboxylate hydrochloride was converted into pale yellow crystals (7.0 mg, 10 mg).
0%).

_{NMR (DMSO-d 6):} δ: 7.79 (3H, brs, N 3 -H, N 6 -2H), 7.
_{20-7.60 (6H, m, C 5} -H, -C 6 H 5), 3.40-3.95 (5H, m, C 7
−2H and −CHCH ₂ O −), 3.62 (3H, s, CO ₂ Me), 1.47 (3H,
s, Me). 3,4,5-trimethoxybenzaldehyde (981 mg, 5 mmo
l) and a methanol solution (10 ml) of methyl azidoacetate (2.30 g, 20 mmol) were added dropwise to an ice-cooled methanol solution of sodium methoxide (1.0 M solution, 5.0 ml, 5.0 mmol) and stirred at room temperature overnight. . Ice water was added, and the precipitated crystals were collected by filtration. After washing with water and drying, methyl 1-azido-2- (3,4,5
-Trimethoxyphenyl) ethene-1-carboxylate was obtained as pale yellow crystals (502 mg, 34%). This was used immediately in the next reaction.

NMR (CDCl ₃ ): δ: 7.10 (2H, s, Ar-H), 6.85 (1H, s,-
CH = C), 3.29−3.93 (12H, m, OCH ₃ × 3 and CO ₂ Me). mp 100.5-101.5 ° C. Elemental _{analysis: C 13 H 15 N 3 O} 5 Calculated: C, 53.24%; H, 5.16%; N, 14.33%. Analytical values: C, 53.58%; H, 5.10%; N, 13.25%. MS: m / e: 293 (M ⁺ ), 256, 206, 160. Methyl 1-azido-2- (3,4,5-trimethoxyphenyl) ethene-2-carboxylate (293 mg, 1 mmol
l) was dissolved in xylene (5 ml), added dropwise to xylene (5 ml) boiling at 150 ° C., and refluxed for 1 hour. The residue obtained by evaporating the solvent was purified by column chromatography (silica gel: benzene: ethyl acetate = 15: 1), and methyl
5,6,7-Trimethoxy-1H-indole-2-carboxylate was obtained as colorless crystals (250 mg, 94%). This was recrystallized from methanol to obtain an analytical sample.

_{mp.106~107 ℃ NMR (CDCl 3):} δ: 8.87 (1H, brs, NH), 7.18 (1H, d, J =
_{2.3Hz, C 3 -H), 6.82} (1H, s, C 4 -H), 4.07 (3H, s, CO
_{H 3), 3.929 (3H,} s, OCH 3), 3.926 (3H, s, OCH 3), 3.90 (3
H, s, COOCH ₃ ). MS; m / e: 265 (M ⁺ ), 218,160. Elemental analysis: as C ₁₃ H ₁₅ NO ₅ Calculated: C, 58.86%; H, 5.70%; N, 5.28%. Analytical values: C, 58.95%; H, 5.59%; N, 5.19%. Methyl 5,6,7-trimethoxy-1H-indole-2
-Carboxylate (50.2 mg, 0.2 mmol) was added to a mixture of a 40% aqueous potassium hydroxide solution (0.5 ml) and methanol (0.5 ml), and the mixture was stirred at 50 ° C for 30 minutes. Neutralized with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration. After washing with water and drying, 5,6,7-trimethoxy-1H-indole-2-carboxylic acid was obtained as colorless crystals (45.5 mg, 96%).

_{mp.215.5~216 ℃ NMR (DMSO-d 6} ); δ: 7.00 (1H, d, J = 1.5Hz, C 3 -H),
_{6.91 (1H, s, C 4} -H), 3.89 (3H, s, OMe), 3.79 (3H, s, OM
e), 3.77 (3H, s , OMe), 3.25 (2H, brs, NH and CO 2 H). . MS; m / e: 251 (M +), 218,160 Elemental analysis: Calculated _{C 12 H 13 O 5 N:} C, 57.37%; H, 5.22%; N, 5.58%. Analytical values: C, 57.21%; H, 5.10%; N, 5.43%. Methyl (2R ^* , 8S ^* )-4-benzyloxy-8-hydroxymethyl-2-methyl-1-oxo-1,2,3,6,7,
8-hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole-2-carboxylate hydrochloride (6.9 mg, 16 μmol)
Was dissolved in N, N-dimethylformamide (0.18 ml), and 5,
6,7-trimethoxy-1H-indole-2-carboxylic acid (4.2 mg, 17 μmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (9.6 mg, 50 μmo
l) and sodium hydrogen carbonate (7.0 mg, 83 μmol) were added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by preparative thin-layer chromatography (silica gel: chloroform: acetone = 4: 1),
Methyl (2R ^* , 8S ^* )-4-benzyloxy-8-hydroxymethyl-6- (5,6,7-trimethoxy-1H-indole-2-carbonyl) -1,2,3,5,6,7 -Hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole-2-carboxylate was obtained as yellow caramethyl (5.8 mg, 57%).

NMR (CDCl ₃ ) δ: 9.35 (1H, brs, ＣC ^′ ₁ ▼ -H), 8.45
_{(1H, s, C 5 -H} ), 7.36-7.51 (5H, m, Ph-H), 6.95 (1
_{^{H, s, ▲ C '3}} ▼ -H), 6.85 (1H, s, C 4 -H), 5.25 (1H,
_{s, C 3 -H), 5.20} (2H, s, OCH 2 Ph), 4.61 (1H, t, J = 9.27H
z, HCHOH), 4.48 (1H, brd.d, J = 10.3Hz, HCHOH), 4.07 (3
H, s, OMe), 3.942 (3H, s, OCH 3), 3.937 (3H, s, OMe), 3.9
1 (3H, s, OCH ₃ ), 3.78 (3H, s, CO ₂ CH ₃ ), 3.86-4.38 (2H,
m, C ₇ −H ₂ ), 3.73−3.86 (1H, m, C ₈ −H), 2.52 (1H, brt,
OH), 1.67 (3H, s , CH 3). MS; m / e: 615 (M ⁺ ), 525,494,382,291,234,201,91. Methyl (2S ^* , 8S ^* )-4-benzyloxy-8-hydroxymethyl-2-methyl-1-oxo-1,2,3,6,7,
8-Hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole-2-carboxylate hydrochloride (7.0 mg, 17 μmol)
Was treated in the same manner as in Reference Example 9 to give methyl (2S ^* , 8
S ^* )-4-Benzyloxy-8-hydroxy-6-
(5,6,7-trimethoxy-1H-indole-2-carbonyl) -1,2,3,6,7,8-hexahydro-benzo [1,2-b;
4,3-b '] dipyrrole-2-carboxylate was obtained as a yellow caramel (6.2 mg, 62%).

NMR (CDCl ₃ ): δ: 9.40 (1H, brs, ＣC ^′ ₁ ▼ -H), 8.4
^{5 (1H, s, ▲ C} '4 ▼ -H), 7.35-7.54 (5H, m, C 6 H 5),
6.95 (1H, d, J = 2.3Hz, ▲ C '3 ▼ -H), 6.85 (1H, s, C 5
-H), 5.28 (1H, s , C 3 -H), 5.21 (2H, s, PhCH 2 O), 4.6
1 (1H, t, J = 9.8Hz, HCHOH), 4.46 (1H, dd, J = 10.4,4.0H
z, HCHOH), (1H, m, C 8 -H), 4.08 (3H, s, OCH 3), 3.88
−4.02 (2H, m, C ₇ −H ₂ ), 3.94 (3H, s, OCH ₃ ), 3.91 (3H,
_{s, OCH 3), 3.78-3.86 (} 1H, m, C 8 -H), 3.77 (3H, s, COOC
_{H 3), 2.73 (1H,} brt, OH), 1.69 (3H, s, CH 3 CCO). Methyl (2R ^* , 8S ^* )-4-benzyloxy-8-hydroxymethyl-6- (5,6,7-trimethoxy-1H-indole-2-carbonyl) -2-methyl-1-oxo-1,2 , 3,6,7,8-Hexahydro-benzo [1,2-b; 4,3-
b '] dipyrrole-2-carboxylate (3.4 mg, 5,6
μmol) was dissolved in dichloromethane (0.6 ml), and methanesulfonyl chloride (0.7 μ, 8.4 μmol) and triethylamine (1.6 μm, 11.2 μmol) were added dropwise under cooling with water, followed by stirring for 30 minutes. The extract was washed with a 1% aqueous sodium hydrogen carbonate solution and saturated saline in this order, dried over anhydrous sodium sulfate, and then the solvent was distilled off.
The obtained residue was purified by preparative thin-layer chromatography (silica gel: dichloromethane: ethyl acetate = 7: 2),
Methyl (2R ^* , 8S ^* )-4-benzyloxy-8-methanesulfonyloxymethyl-6- (5,6,7-trimethoxy-1H-indole-2-carbonyl) -2-methyl-
1-oxo-1,2,3,6,7,8-hexahydro-benzo [1,2
-B; 4,3-b '] dipyrrole-2-carboxylate was obtained as a yellow caramel (3.8 mg, 99%).

NMR (CDCl ₃ ): δ: 9.34 (1H, brs, ＣC ^′ ₁ ▼ -H), 8.4
_{3 (1H, s, C 5} -H), 7.36-7.52 (5H, m, C 6 H 5), 6.95 (1H,
^{d, J = 2.3Hz, ▲ C} '3 ▼ -H), 6.87 (1H, s, ▲ C' 4 ▼
-H), 5.25 (1H, brs , C 3 -H), 5.21 (2H, s, PhCH 2 O),
4.74 (1H, dd, J = 10.0,3.4Hz, HCHOMs), 4.56-4.68 (2H,
_{m, C 7 -H 2),} 4.46 (1H, dd, J = 10.0,8.0Hz, HCHOMs), 4.12
−4.21 (1H, m, C ₈ −H), 4.08 (3H, s, OCH ₃ ), 3.94 (3H,
s, OCH ₃ ), 3.92 (3H, s, OCH ₃ ), 3.78 (3H, s, COOCH ₃ ), 2.9
_{7 (3H, s, SO 2} CH 3), 1.67 (3H, s, CH 3 CCO). MS: m / e: 693 (M ⁺ ), 597, 506, 364, 303, 234, 91. Methyl (2S ^* , 8S ^* )-4-benzyloxy-8-hydroxymethyl-6- (5,6,7-trimethoxy-1H-indole-2-carbonyl) -2-methyl-1-oxo-1,2 , 3,6,7,8-Hexahydro-benzo [1,2-b; 4,3-
b ′] dipyrrole-2-carboxylate (6.2 mg, 10 μl
mol) was treated in the same manner as in Reference Example 11, and methyl (2S ^* ,
8S ^* )-4-Benzyloxy-8-methanesulfonyloxymethyl-6- (5,6,7-trimethoxy-1H-indole-2-carbonyl) -1,2,3,6,7,8-hexahydro- Benzo [1,2-b; 4,3-b '] dipyrrole-2-carboxylate was obtained as a yellow caramel (6.9 mg, 99%).

NMR (CDCl ₃ ): δ: 9.35 (1H, brs, ＣC ^′ ₁ ▼ -H), 8.4
_{2 (1H, s, C 5} -H), 7.35-7.53 (5H, m, C 6 H 5), 6.95 (1H,
^{d, J = 2.3Hz, ▲ C} '3 ▼ -H), 6.87 (1H, s, ▲ C' 4 -
H), 5.21 (2H, s, PhCH ₂ O), 4.80 (1H, dd, J = 9.9,3.4Hz,
HCHOMs), 4.57-4.67 (2H, m , C 7 -H 2), 4.39 (1H, dd, J =
9.8,8.6Hz, HCHOMs), 4.12-4.19 (1H , m, C 8 -H), 4.07
(3H, s, OCH ₃ ), 3.94 (3H, s, OCH ₃ ), 3.91 (3H, s, OCH ₃ ),
3.77 (3H, s, COOCH ₃ ), 3.03 (3H, s, SO ₂ CH ₃ ), 1.68 (3H,
_{s, CH 3 CCO), 1.65} (1H, brs, C 3 -H). MS: m / e: 693 (M ⁺ ), 597,538,506,364,303,234,91. Methyl (2R ^* , 8S ^* )-4-benzyloxy-8-methanesulfonyloxymethyl-6- (5,6,7-trimethoxy-1H-indole-2-carbonyl) -2-methyl-1-oxo-1 , 2,3,6,7,8-Hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole-2-carboxylate (3.8 mg, 5.4 μmol) in tetrahydrofuran (0.5 ml)
And hydrogenated under 1 atmosphere of hydrogen pressure in the presence of 10% palladium on carbon (2 mg). After removing the catalyst by filtration, the solvent was distilled off, and the residue obtained was purified by preparative thin-layer chromatography (silica gel: chloroform: acetone = 2: 1) to give methyl (2R ^* , 8S ^* )-4-hydroxy. -8-methanesulfonyloxymethyl-6- (5,6,7-trimethoxy-1H-indole-2-carbonyl) -2-methyl-1-oxo-1,2,3,6,7,8-hexahydro- Benzo [1,2-b; 4,3-
b '] Dipyrrole-2-carboxylate was obtained as yellow crystals (2.8 mg, 85%).

NMR (CDCl ₃ ): δ: 9.50 (1H, brs, ＣC ^′ ₁ ▼ -H), 9.3
_{0 (1H, brs, C 3} -H), 8.46 (1H, s, C 5 -H), 6.99 (1H, d,
_{^{J = 2.3Hz, ▲ C '3}} ▼ -H), 6.85 (1H, s, ▲ C' 4 ▼ -
H), 4.74 (1H, dd, J = 10.0,3.4Hz, HCHOMs), 4.56-4.67
_{(2H, m, C 7 -H} 2), 4.46 (1H, dd, J = 10.0,8.0Hz, HCHOM
s), 4.10-4.19 (1H, m , C 8 -H), 4.13 (3H, s, OCH 3), 3.
95 (3H, s, OCH ₃ ), 3.91 (3H, s, OCH ₃ ), 3.77 (3H, s, COOCH
_{3), 2.97 (3H, s} , SO 2 CH 3), 1.68 (3H, s, CH 3 CCO). Methyl (2S ^* , 8S ^* )-4-benzyloxy-8-methanesulfonyloxymethyl-6- (6,7,8-trimethoxy-1H-indole-2-carbonyl) -2-methyl-1-oxo-1 , 2,3,6,7,8-Hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole-2-carboxylate (6.9 mg, 9.9 μmol) was treated in the same manner as in Reference Example 13. Methyl (2S ^* , 8S ^* )-4-hydroxy-8-methanesulfonyloxymethyl-6- (5,6,7-trimethoxy-1H-indole-2-carbonyl) -2-methyl-
1-oxo-1,2,3,6,7,8-hexahydro-benzo [1,2
-B; 4,3-b '] dipyrrole-2-carboxylate was obtained as yellow crystals (5.0 mg, 83%).

NMR (CDCl ₃ ): δ: 9.52 (1H, brs, ＣC ^′ ₁ ▼ -H), 8.5
_{2 (1H, brs, C 5} -H), 6.99 (1H, d, J = 2.3Hz, ▲ C '3 ▼
-H), 6.85 (1H, s , ▲ C '4 ▼ -H), 4.79 (1H, dd, J =
10.0,3.5Hz, HCHOMs), 4.56-4.65 (2H , m, C 7 -H 2), 4.39
(1H, m, HCHOMs), 4.14 (3H, s, OCH ₃ ), 3.96 (3H, s, OC
_{H 3), 3.91 (3H,} s, OCH 3), 3.74 (3H, s, COOCH 3), 3.03 (3
_{H, s, SO 2 CH 3} ), 1.69 (3H, s, CH 3 CCO). MS: m / e: 603 (M ⁺ ), 507,448,368,313,213. Methyl (2R ^* , 8S ^* )-4-hydroxy-8-methanesulfonyloxymethyl-6- (5,6,7-trimethoxy-1H-indole-2-carbonyl) -2-methyl-1
-Oxo-1,2,3,6,7,8-hexahydro-benzo [1,2-
b; 4,3-b '] dipyrrole-2-carboxylate (2.8
mg, 4.6 μmol) in tetrahydrofuran (1.5 ml) and sodium hydride (50% oil dispersion)
(0.8 mg, 20 μmol) and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was diluted with ethyl acetate, and washed sequentially with a 0.5 M aqueous solution of potassium dihydrogen phosphate and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was distilled off. The obtained residue is subjected to column chromatography (alumina: chloroform: acetone =
5: 1) to give dl-duocarmycin A as pale yellow crystals (1.4 mg, 60%).

NMR (CDCl ₃ ): δ: 9.23 (1H, brs, 1′-NH), 7.17 (1H,
_{s, C 7 -H), 6.94} (1H, d, J = 2.3Hz, ▲ C '3 ▼ -H), 6.
78 (1H, s, ▲ C '4 ▼ -H), 6.01 (1H, s, 1-NH), 4.37
−4.48 (2H, m, C ₅ −H ₂ ), 4.08 (3H, s, OCH ₃ ), 3.94 (3H,
s, OCH ₃ ), 3.89 (3H, s, OCH ₃ ), 3.75 (3H, s, CO ₂ CH ₃ ), 3.0
3−3.09 (1H, m, C _4a −H), 2.25 (1H, dd, J = 4.0,7.6Hz, C
_{4 -H), 1.25-1.32 (1H,} m, C 4 -H), 1.67 (3H, s, 2-CH
₃ ). This NMR spectrum completely coincided with that of the standard (+)-duocarmycin A (Symposium on Natural Organic Compounds, Fukuoka, 1988, Abstract p300).

MS: m / e: 507 (M ⁺ ), 448,274,234. Methyl (2S ^* , 8S ^* )-4-hydroxy-8-methanesulfonyloxymethyl-6- (5,6,7-trimethoxy-1H-indole-2-carbonyl) -2-methyl-1
-Oxo-1,2,3,6,7,8-hexahydro-benzo [1,2-
b; 4,3-b '] dipyrrole-2-carboxylate (6.0
mg, 9.9 μmol) in the same manner as in Reference Example 15, and dl-
2-Epiduocarmycin A was converted to pale yellow crystals (2.4 mg, 56 mg
%).

NMR (CDCl ₃ ): δ: 9.21 (1H, brs, 1′-NH), 7.16 (1H,
_{s, C 7 -H), 6.94} (1H, d, J = 2.3Hz, ▲ C '3 ▼ -H), 6.
78 (1H, s, ▲ C '4 ▼ -H), 6.01 (1H, s, 1-NH), 4.38
−4.47 (2H, m, C ₅ −H ₂ ), 4.08 (3H, s, OCH ₃ ), 3.94 (3H,
s, OCH ₃ ), 3.89 (3H, s, OCH ₃ ), 3.78 (3H, s, CO ₂ CH ₃ ), 3.0
6−3.11 (1H, m, C _4a −H), 2.23 (1H, dd, J = 3.9,7.6Hz, C
_{4 -H), 1.27 (1H,} m, C 4 -H), 1.65 (3H, s, 2-CH 3). MS: m / e: 507 (M ⁺ ), 448,274,234.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 487 / 04,209 / 12 CA (STN) REGISTRY (STN)

Claims (5)

(57) [Claims] (1) General formula (Wherein, R ¹ is a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms, R ² and R ⁴ are each independently a hydrogen atom or a protecting group for the same or different amino group, R ³ And R ⁵
Each independently represents a hydrogen atom or the same or different hydroxyl-protecting group. ) 2-alkoxycarbonyl-2-methyl-1-oxo-1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole derivative. 2. The compound according to claim 1, wherein
2-alkoxycarbonyl-2-methyl wherein the position is (R ^* )-configuration and the 8-position is (S ^* )-configuration, or the 2-position is (S ^* )-configuration and the 8-position is (S ^* )-configuration. -1-oxo-1,2,3,6,7,8-hexahydro-benzo [1,2-b; 4,3
-B '] a dipyrrole derivative. 3. The general formula (Wherein, R ³ and R ⁹ are each independently a hydrogen atom or a protecting group for the same or different hydroxyl group, and R ⁶ is a hydrogen atom or a C 1 -C 1
6, a linear or branched lower alkyl group, R ⁸ represents a hydrogen atom or an amino-protecting group. A 4-alkoxycarbonyl-2,3-dihydro-1H-indole derivative represented by the formula: 4. General formula (Wherein, R ¹ is a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms, R ² and R ⁸ are each independently a hydrogen atom or an amino-protecting group, R ³ and R ⁹ Each independently represents a hydrogen atom or a protecting group for the same or different hydroxyl group, and R ⁶ represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms.) Carbonyl-2,3-dihydro-1H-indole derivatives. 5. The general formula (Wherein, R ⁸ is a hydrogen atom or an amino-protecting group, R ³ and R
Each ¹⁰ independently represents a hydrogen atom or the same or different hydroxyl-protecting group. 1,2-dioxo-1,2,3,
6,7,8-Hexahydro-benzo [1,2-b; 4,3-b '] dipyrrole derivative.