JP2555830B2 - Method for producing polycyclic compound - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a polycyclic compound.

[0002]

2. Description of the Related Art In recent years, the active ingredients in crude drugs have been separated and identified by the development of instrumental analysis and compound separation means. Further, based on these results, chemical synthesis of the active ingredients of crude drugs has been attempted. . However, many herbal medicines have complicated ring systems and chemical synthesis is extremely difficult.
In many cases, it is a bottleneck for establishing a chemical synthesis method for crude drug ingredients.

For example, as an active ingredient of a crude drug, the following formula

Embedded image Some compounds having a dibenzocyclooctane or dibenzocyclooctene ring represented by are known, but it is difficult to synthesize this ring system by a conventionally known method, and these crude drug components are industrially synthesized by a chemical synthesis method. It was said that it was difficult to manufacture it.

[0004]

DISCLOSURE OF INVENTION Problems to be Solved by the Invention Once the active ingredient of a crude drug has been clarified, side effects are prevented and the dose of the drug is reduced.
It may be preferable to administer only the active ingredient. However, in order to obtain only the active ingredient from a crude drug, there is a problem that a complicated process for removing other components is required and the yield is poor, and further, the production amount of the crude drug raw material itself is limited. However, there were problems in terms of economy and resources. Therefore, there has been a demand for the development of a synthetic method for polycyclic compounds that can be industrially used.

[0005]

[Means for Solving the Problems] The inventors of the present invention have conducted diligent research on a coupling reaction for introducing a polycyclic system.

Embedded image (In the formula, R _{1 to} R ₈ represent a hydrogen atom, a hydroxy group, an alkoxy group or a benzyloxy group which may have a substituent, or two adjacent groups are combined to form an alkylenedioxy group. Represents an alkylene group which may be substituted with an alkoxycarbonyl group, an alkenylene group which may be substituted with an alkoxycarbonyl group or the following formula

[Chemical 6] A compound represented by the formula (I)

[Chemical 7] The present invention was completed by finding that a polycyclic compound represented by the formula (wherein R _{1 to} R ₈ and A have the above-mentioned meanings) can be obtained.

That is, the present invention provides a polycyclic compound represented by the formula (I), which comprises reacting a compound represented by the formula (II) with trifluoroacetic acid in the presence of iron perchlorate. It is a manufacturing method.

To carry out the method of the present invention, 1
2 mol or more of iron perchlorate based on 1 mol of the compound (II),
An organic solvent such as halogenated hydrocarbons such as methylene chloride and chloroform and aromatic hydrocarbons such as toluene and benzene is preferably used in an amount of about 2 to 3 mol, trifluoroacetic acid of 5 mol or more, preferably about 5 to 100 mol. Medium,-
The reaction may be carried out at about 10 to 30 ° C. for about 0.5 to 3 hours, whereby the compound represented by the general formula (I) is prepared.

Embedded image

The compound (II) as the starting material of the present invention also includes, for example, the compound represented by the formula (II ').
The compound (II ′) includes novel compounds, for example, a compound (III) which is easily synthesized according to the following reaction formula, or a known compound or a method for producing a known compound, and a benzaldehyde derivative (IV). It may be prepared by allowing it to act.

[Chemical 9] (In the formula, R _{1 to} R ₈ have the above-mentioned meanings)

An example of iron perchlorate used in the present invention is ferric perchlorate.

In the above reaction, since the optical activity of the starting material (II) is preserved, the optically active compound (I) of the present invention can be obtained by using the optically active compound (II).

The compound (I) of the present invention obtained as described above is easily subjected to partial ring opening, reduction, oxidation, side chain cleavage treatment, chemical modification, etc., if desired, to easily obtain the desired compound. The compound can be obtained.

[0012]

EFFECTS OF THE INVENTION According to the method of the present invention, a polycyclic compound which has been conventionally obtained only from natural products can be easily produced from a compound having two benzene rings in one molecule. It is extremely useful as a method for producing a chemical synthesis intermediate.

EXAMPLES The present invention will be described in more detail with reference to Examples and Reference Examples.

Example 1 (3aRS, SRbiar) -3a, 4-dihydro-6,
7,8,9,10,11-hexamethoxydibenzo [4,
5: 6,7] cycloocta [1,2-c] furan-1 (3
Production of H) -one: (1) Method with iron perchlorate (RS)-(E) -2- (3,4,5-trimethoxybenzylidene) -3- [1- (3,4,5- Trimethoxyphenyl) methyl] butanolide (3.0 g, 6.8 mmol,
Y. Landais, Alebrun, and JP Robin, Tetrahedron
Lett., 27 , 5377, (1986)) trifluoroacetic acid (20
ml) solution to iron perchlorate (9.37g, 20.3mmo)
1) was added, and the mixture was stirred at room temperature for 2.5 hours. Distill off trifluoroacetic acid under reduced pressure, dilute with ethyl acetate (60 ml),
It was washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to yield 3.1 g.
Of colorless oily substance was obtained. Purification by column chromatography (silica gel Merck # 9385, 30 g, ether-benzene 1: 1) gave the title compound as a colorless solid (2.66 g, 89%).

(2) Method using iron perchlorate (RS)-(E) -2- (3,4,5-trimethoxybenzylidene) -3- [1- (3,4,5-trimethoxyphenyl) Methyl] butanolide (100mg, 0.23mm
ol) in methylene chloride (1 ml) was added trifluoroacetic acid (0.1 ml), and iron perchlorate (0.30 g,
0.65 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was dissolved in ethyl acetate (10 ml), and 2N-HCl was added.
The extract was washed with (10 ml) and saturated saline (10 ml), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a brown oil (107 mg). Purification by column chromatography (silica gel, Merck # 9385, 5 g, ethyl acetate-hexane 1: 1) gave the title compound as a pale yellow oil (81 mg, 81%).

Melting point: 153.5-154.5 ° C. (colorless prism crystals, ethyl acetate-hexane) ¹ HNMR (CDCl ₃ ): 2.45 (1H, d, J = 14)
Hz), 3.06 (1H, dd, J = 714Hz), 3.4
4-3.64 (1H, m), 3.59 (3H, s), 3.64
(3H, s), 3.88 (3H, s), 3.89, (3H,
s), 3.90 (3H, s), 3.91 (3H, s), 4.11
(1H, dd, J = 9,10Hz), 4.47 (1H, t, J
= 9 Hz), 6.41 (1H, s), 6.59 (1H, s),
7.53 (1H, d, J = 3Hz). IR (KBr, cm ^-1 ): 2936, 2836, 1758,
1674, 1594, 1488, 1462, 1406, 13
46,1318,1238,1200,106,1016,
928. M S: 442 (M ⁺ , base)

Reference Example 1 Synthesis of 2,3-bis [1- (3,4,5-trimethoxyphenyl) methyl] butanolide: (RS)-(E) -2
-(3,4,5-Trimethoxybenzylidene) -3- [1
Triethylsilane (6 ml, 37.8 m) was added to a toluene solution (6 ml) of-(3,4,5-trimethoxyphenyl) methyl] butanolide (324.3 mg, 0.73 mmol).
mol), Wilkinson's complex (5 mg, 0.0054)
mmol) was added and the mixture was stirred at 110 ° C. for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (2 ml). After adding 2N hydrochloric acid (0.5 ml) and stirring at room temperature for 1 hour, the reaction solution was dissolved in ethyl acetate (20 ml),
It was washed with water and saturated aqueous sodium hydrogen carbonate. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give a brown oily substance (470 m
g) was obtained. Purification by column chromatography (silica gel, Merck # 9385, 15 g, ethyl acetate-hexane 1: 4) gave the title compound as a colorless oil (270 mg, 83%).

NMR (CDCl ₃ ): 2.44-2.71
(4H, m), 2.97 (2H, d, J = 5Hz), 3.80
(6H, s), 3.81 (6H, s), 3.82 (6H, s),
4.08-4.27 (2H, m), 6.21 (1.6H, s),
6.28 (0.4H, s), 6.38 (1.6H, s), 6.5
3 (0.4H, s). M S: 446 (M ⁺ ), 181 (base).

Example 2 3a, 4,13,13a-tetrahydro-6,7,8,9,1
Synthesis of 0,11-hexamethoxydibenzo [4,5: 6,7] cycloocta [1,2-c] furan-1 (3H) -one: 2,3-bis [1- (3,4,5- Trimethoxyphenyl) methyl] butanolide (50mg, 0.112m
mol) was dissolved in dichloromethane (0.5 ml) and trifluoroacetic acid (0.05 ml), and iron perchlorate (1
(50 mg, 0.32 mmol) was added, and the mixture was stirred at room temperature for 19 hours. It was dissolved in ethyl acetate (10 ml) and washed with 2N hydrochloric acid, water and saturated aqueous sodium hydrogen carbonate. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give a colorless oil, which was subjected to thin layer chromatography (silica gel, Merck).
# 5744, acetone-hexane 1: 3),
The title compound was obtained as a colorless solid (28.5 mg, 57%).

NMR (CDCl ₃ ): 2.10-2.72
(5H, m), 3.16 (1H, d, J = 13Hz), 3.6
0 (2.4H, s), 3.62 (2.4H, s), 3.65
(0.6H, s), 3.66 (0.6H, s), 3.67-3.
90 (1H, m), 3.87 (6H, s), 3.90 (3H,
s), 3.91 (3H, s), 4.34-4.48 (1H,
m), 6.38 (0.2H, s), 6.53 (0.8H, s),
6.64 (0.8H, s), 6.74 (0.2H, s). IR (KBr) cm ^-1 : 2936,1778,1596,
1492, 1462, 1454, 1402, 1328, 12
00, 1126, 1104, 990. M S: 444 (M ⁺ , base)

Reference Example 2 (RS)-(E) -3- [1- (5-methoxy-3,4)
-Methylenedioxyphenyl) methyl] -2- (3,4,
Synthesis of 5-trimethoxybenzylidene) butanolide: Sodium hydride (60%, 0.43 g, 10.8 mmol) and methanol (0.016 ml, 0.4 mmol) were added to toluene (20 ml) in an argon stream, and further,
(RS) -3- [1- (5-methoxy-3,4-methylenedioxyphenyl) methyl] butanolide (1.0 g,
4 mmol, GESchneiders and R. Stevenson, J.
Chem. Soc. Perkin I, 999, (1982)) and 3,4,5-trimethoxybenzaldehyde (1.24 g, 6.3 mo)
l) was added. After stirring at room temperature for 24 hours, 2N aqueous hydrochloric acid was added to the reaction solution. After dissolving in ethyl acetate and removing the aqueous layer, the organic layer was washed with saturated brine and dried over magnesium sulfate. The residue obtained by distilling off the solvent was subjected to column chromatography (silica gel, Merck # 938).
The title compound was obtained as a colorless solid (732 mg, 43%) by purification with 5,50 g, ethyl acetate-hexane 1: 2).

Melting point: 132-132.5 ° C. (colorless prismatic crystals, ethyl acetate-hexane) ¹ HNMR (CDCl ₃ ): 2.64 (1H, dd, J = 1)
0,14Hz), 3.02 (1H, dd, J = 5,14H
z), 3.66-3.90 (1H, m), 3.87 (3H,
s), 3.89 (6H, s), 3.91 (3H, s), 4.24
-4.31 (2H, m), 5.94 (2H, s), 6.29
(1H, d, J = 1Hz), 6.34 (1H, d, J = 1H
z), 6.77 (2H, s), 7.52 (1H, d, J = 2H
z). IRνmax (KBr) cm ^-1 : 2940,1748,16
44,1582. M S: 428 (M ⁺ ), 165 (base). Elemental analysis value (as C ₂₃ H ₂₄ O ₈ ): Calculated value; C 64.48, H 5.65. Measured value; C 64. 48, H 5.67.

Example 3 (3aRS, SRbiar) -3a, 4-dihydro-8,
9,10,11-Tetramethoxy-6,7-methylenedioxydibenzo [4,5: 6,7] cycloocta [1,2-
c] Furan-1 (3H) -one and (3aRS, SR
baria) -3a, 4-dihydro-6,9,10,11-tetramethoxy-7,8-methylenedioxydibenzo [4,
5: 6,7] cycloocta [1,2-c] furan-1 (3
Synthesis of H) -one: (RS)-(E) -3- [1- (5
-Methoxy-3,4-methylenedioxyphenyl) methyl] -2- (3,4,5-trimethoxybenzylidene) butanolide (50 mg, 0.117 mmol) in dichloromethane solution (0.5 ml) at room temperature. Iron chlorate hexahydrate (150 mg, 0.324 mmol) and trifluoroacetic acid (0.05 ml) were added, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was washed with 2N aqueous hydrochloric acid, water and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting brown oil (52 mg) was purified by thin layer chromatography (silica gel, Merck # 5744, benzene-ether 1: 1) to give (3aRS, SRb
iaar) -3a, 4-dihydro-8,9,10,11-tetramethoxy-6,7-methylenedioxydibenzo [4,
5: 6,7] cycloocta [1,2-c] furan-1 (3
From the fraction containing H) -one, 23 mg (46
%) As a colorless oil. Furthermore, (3aRS, SRb
iaar) -3a, 4-dihydro-6,9,10,11-tetramethoxy-7,8-methylenedioxydibenzo [4,
5: 6,7] cycloocta [1,2-c] furan-1 (3
From the fraction containing H) -one, 3.7 mg (7
%) As a colorless oil.

* (3aRS, SRbiar) -3a, 4-
Dihydro-8,9,10,11-tetramethoxy-6,7-
Methylenedioxydibenzo [4,5: 6,7] cycloocta [1,2-c] furan-1 (3H) -one: ¹ HNMR (CDCl ₃ ): 2.42 (1H, dd, J = 1.
5,14Hz), 3.00 (1H, dd, J = 7,14H
z), 3.42-3.60 (1H, m), 3.63 (3H,
s), 3.81 (3H, s), 3.89 (3H, s), 3.91
(3H, s), 4.44 (1H, tJ = 9Hz), 4.09
(1H, dd, J = 9,10Hz), 5.96 (1H, dJ =
1.5Hz), 5.98 (1H, d, J = 1.5Hz), 6.5
8 (1H, s), 6.34 (3H, s), 7.51 (1H, d,
J = 2 Hz). IRνmax (CHCl ₃ ) cm ⁻¹ : l2964, 2940,
1754, 1674, 1620, 1590. M S: 426 (M ⁺ , base).

* (3aRS, SRbiar) -3a, 4-
Dihydro-6,9,10,11-tetramethoxy-7,8-
Methylenedioxydibenzo [4,5: 6,7] cycloocta [1,2-c] furan-1 (3H) -one: ¹ HNMR (CDCl ₃ ): 2.45 (1H, dd, J = 1,
14Hz), 3.07 (1H, dd, J = 714Hz),
3.43-3.64 (1H, m), 3.72 (3H, s), 3.
89 (3H, s), 3.91 (3H, s), 3.94 (3H,
s), 4.12 (1H, dd, J = 8, 10Hz), 4.47
(1H, t, J = 9Hz), 5.88 (1H, d, J = 1H
z), 5.98 (1H, d, J = 1 Hz), 6.28 (1H,
s), 6.62 (1H, s), 7.51 (1H, d, J = 2.5)
Hz). IRνmax (CHCl ₃ ) cm ^-1 : 2936,1754,1
674, 1644, 1592. M S: 426 (M ⁺ , base)

Reference Example 3 (RS)-(E) -3- [1- (3,4-dihydroxy-5-methoxyphenyl) methyl] -2- (3,4,5-
Synthesis of trimethoxybenzylidene) butanolide: (R
S)-(E) -3- [1- (5-methoxy-3,4-methylenedioxyphenyl) methyl] -2- (3,4,5-
Trimethoxybenzylidene) butanolide (1.0 g, 2.
34 mmol) in dichloromethane (5 ml) was added to a solution of boron trichloride in dichloromethane (1.0 M, 4.7 ml,
(4.7 mmol) was added at 0 ° C. and the mixture was stirred as it was for 40 minutes. The solvent was distilled off under reduced pressure, and methanol (15 m) was added to the residue.
l) 4N aqueous hydrochloric acid was added, and the mixture was stirred at room temperature for 45 minutes.
The reaction solution was dissolved in ethyl acetate (20 ml) and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give the title compound as a yellow foam (747
mg, 77%).

NMR (CDCl ₃ ): 2.61 (1H, d
d, J = 10,14 Hz), 3.04 (1H, dd, J = 5,
14Hz), 3.83 (3H, s), 3.89 (6H, s),
3.90 (3H, s), 3.83-3.97 (1H, m), 4.
25-4.30 (2H, m), 5.34 (1H, s), 5.3
0 (1H, s), 6.44 (1H, d, J = 2Hz), 6.2
3 (1H, d, J = 2Hz), 6.79 (2H, s), 7.5
2 (1H, d, J = 2Hz).

Example 4 (3aRS, SRbiar) -3a, 4-dihydro-6,
7-Dihydroxy-8,9,10,11-tetramethoxydibenzo [4,5: 6,7] cycloocta [1,2-c]
Synthesis of furan-1 (3H) -one: (RS)-(E)-
3- [1- (3,4-Dihydroxy-5-methoxyphenyl) methyl] -2- (3,4,5-trimethoxybenzylidene) butanolide (828 mg, 2.0 mmol) was added to dichloromethane (25 ml) and trifluoroacetic acid. (25m
l) dissolved in a mixture of iron perchlorate (1.93g, 4.1
7 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen sulfite was added to the reaction solution, and ethyl acetate (50 ml) was further added. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, the obtained brown solid (740 mg) was washed with ether, and the remaining crystals were collected by filtration to give the title compound as pale brown prismatic crystals (573 mg, 70%). Was obtained as.

Melting point: 246-246.5 ° C. (methanol) IRνmax (KBr) cm ⁻¹ : 3548, 3364, 29
40,1740,1670,1620,1590,1492,
1200. M S: 414 (M ⁺ , base) NMR: 2.42 (1 H, dd, J = 1.5, 14 Hz),
3.02 (1H, dd, J = 714Hz), 3.40-3.
60 (1H, m), 3.31 (3H, s), 3.57 (3H,
s), 3.91 (3H, s), 3.93 (3H, s), 4.11
(1H, dd, J = 8,10Hz), 4.46 (1H, t, J
= 9 Hz), 5.38 (1H, s), 5.54 (1H, s),
6.62 (1H, s), 6.51 (1H, s), 7.50 (1
H, d, J = 3.4 Hz).

Reference Example 4 Synthesis of (R)-(E) -2- (3,4,5-trimethoxybenzylidene) -3- [1- (3,4,5-trimethoxyphenyl) methyl] butanolide : In argon flow,
(R) -3- [1- (3,4,5-Trimethoxyphenyl) methyl] butanolide (10.52 g, 0.04mo)
l; K. Lalami, D. Dhai, and E. Brown, Heterocycles,
27 , 1131 (1988)) and 3,4,5-trimethoxybenzaldehyde (11.4 g, 0.058 mol) in toluene (150 ml) were cooled to 0 ° C., and sodium hydride (60%, 4.0 g, 4.0 g, 0.1 mol) and methanol (0.15 ml, 0.0037 mol) were added. After stirring at room temperature for 45 hours, the reaction solution was ice-cooled and 2N hydrochloric acid water (100 ml) was added. After removing the aqueous layer, the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. Residue obtained by distilling off the solvent (20 g)
Column chromatography (Merck silica gel #
9385, 500 g, ethyl acetate-hexane 1: 2)
The title compound was obtained as a pale yellow oil (5.71 g, 33
%).

[Α] ²⁷ _D : −75.64 ° (C = 0.5
5, CHCl ₃ ) ¹ HNMR (CDCl ₃ ): 2.64 (1H, dd, J = 1)
0,14Hz), 3.10 (1H, dd, J = 4,14H
z), 3.81-3.96 (1H, m), 3.81 (3H,
s), 3.83 (6H, s), 3.89 (6H, s), 3.91
(3H, s), 4.29-4.32 (1H, m), 6.82
(2H, s), 6.38 (2H, s), 7.53 (1H, d, J
= 1.5 Hz). IRνmax (CHCl ₃ ) cm ⁻¹ : 2940,2840,1
746, 1648, 1586. M S: 444 (M ⁺ ), 181 (base). HRMS (as C ₂₄ H ₂₈ O ₈ ; M ⁺ ) calculated value; 444.17844 measured value; 444.17894

Example 5 (3aR, Sbiar) -3a, 4-dihydro-6,7,
8,9,10,11-hexamethoxydibenzo [4,5:
6,7] Cycloocta [1,2-c] furan-1 (3H)
Synthesis of --one: (R)-(E) -2- (3,4,5-trimethoxybenzylidene) -3- [1- (3,4,5-trimethoxyphenyl) methyl] butanolide (5.6 g , 0.
Trifluoroacetic acid (5 ml) was added to a methylene chloride solution (50 ml) of 013 mol), and iron perchlorate (1
6.8 g, 0.036 mol) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was water (50 ml), 2N HCl (50 m
After washing with 1) and drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give a brown oil (6.9 g). Column chromatography (silica gel, Merck # 938
5,50 g, ethyl acetate-hexane 1: 1) and the title compound was pale yellow oil (5.18 g, 93%).
Got as.

¹ HNMR (CDCl ₃ ): 2.46 (1H,
dd, J = 1,14 Hz), 3.06 (1H, dd, J = 6.
6,14 Hz), 3.43-3.59 (1 H, m), 3.59
(3H, s), 3.64 (3H, s), 3.88 (3H, s),
3.89 (3H, s), 3.90 (3H, s), 3.91 (3
H, s), 4.10 (1H, dd, J = 8.5,10Hz),
4.47 (1H, t, J = 9Hz), 6.59 (1H, s),
6.41 (1H, s), 7.53 (1H, d, J = 3Hz). IRνmax (CHCl ₃ ) cm ⁻¹ : 2940,2840,1
756, 1674, 1596, 1484, 1460, 139
8, 1346, 1316. M S: 442 (M ⁺ , base) HRMS (as C ₂₄ H ₂₆ O ₈ ; M ⁺ ), calculated value: 442.16279, measured value: 442.16279

Reference Example 5 Synthesis of 1-methyl = hydrogen = (R) -2- [1- (5-methoxy-3,4-methylenedioxyphenyl) methyl] butanedioate: 1-methyl = hydrogen = (RS) -2-
[1- (5-Methoxy-3,4-methylenedioxyphenyl) methyl] butanedioate (racemic, 10 g;
GESchneider and R. Stevenson, J. Chem. Soc. Perki
n 1,999 (1982)) and L-(-)-α-aminocaprolactam (4.33 g) heated acetone (120 ml)
After dissolving in, the mixture was stirred at room temperature for 3 hours. The precipitated crystals were collected by filtration to give 10.72 g of the aminocaprolactam salt of the title compound. Add this salt to saturated sodium bicarbonate water (1
(00 ml) and washed with ether (100 ml x
3) Acidified with 10% aqueous oxalic acid and extracted with dichloromethane (200 ml x 3). The dichloromethane layers were combined, washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 6.69 g of the title compound with 44% ee. This in methanol (7 ml),
The mixture was stirred at room temperature for 1 hour, and insoluble matter was removed by filtration. The filtrate was evaporated under reduced pressure to give the title compound with 100% ee of 2.05.
g was obtained.

Melting point: 97.5-98 ° C. (colorless needle crystals,
Methanol) ¹ HNMR: 2.46 (1H, dd, J = 5,17 Hz),
2.62-2.77 (2H, m), 2.93-3.13 (2
H, m), 3.69 (3H, s), 3.88 (3H, s), 5.
94 (2H, s), 6.31 (1H, s), 6.34 (1H,
s). [α] ²³ _D : +27.4 (C = 0.985, CHCl ₃ ) IRνmax (KBr) cm ⁻¹ : 3148, 2912, 17
26,1678,1638,1510. M S: 296 (M ⁺ ), 165 (base). Elemental analysis value (as C ₁₄ H ₁₆ O ₇ ) Calcd value C; 56.75, H; 5.44 Measured value C 56.69, H; 5.37

Reference Example 6 Synthesis of (R) -3- [1- (5-methoxy-3,4-methylenedioxyphenyl) methyl] butanolide: 1-methyl = hydrogen = (R) -2- [1 -(5-methoxy-3,
4-Methylenedioxyphenyl) methyl] butanedioate (32.0 g, 0.108 mol) was added to ethanol (4
(00 ml) and dissolve in potassium hydroxide (85%, 7.44
g, 0.113 mol) in ethanol (200 ml) was added. Calcium chloride under ice cooling (23.0g, 0.21)
mol), sodium borohydride (16g, 0.42m)
ol) was added and the mixture was stirred at 0 ° C. for 17 hours. Under ice cooling, 6
Aqueous NH Cl solution (500 ml) was added, and the mixture was further added at room temperature to 1.
After stirring for 5 hours, extract with methylene chloride (200 ml x
3) Then, the combined organic layers were washed with saturated saline and dried over anhydrous magnesium sulfate. 2 if the solvent is distilled off under reduced pressure
7.23 g of a colorless solid was obtained. Recrystallize from ethyl acetate-hexane to give the title compound (22.57 g, 83.5%)
Was obtained as colorless prism crystals.

Melting point: 88-89 ° C. [α] ²³ _D : + 7.12 ° (C = 1.0095, CHCl ₃ ) ¹ HNMR (CDCl ₃ ): 2.45 (1H, dd, J = 6,
7Hz), 2.55-2.70 (3H, m), 2.74-2.
88 (1H, m), 3.90 (3H, s), 4.03 (1H,
dd, J = 5.5,9 Hz), 4.34 (1H, dd, J = 6.
7.9 Hz), 5.95 (2H, s), 6.30 (1H, d, J
= 1.5 Hz), 6.34 (1H, d, J = 1.5 Hz). IRνmax (KBr) cm ^-1 : 1782,1632,15
08 M S: 250 (M ⁺ ), 165 (base) Elemental analysis value (as C ₁₃ H ₁₄ O ₅ ): Calculated value C; 62.39, H; 5.64 Measured value C; 62.36, H; 5.76

Reference Example 7 (R)-(E) -3- [1- (5-methoxy-3,4-
Methylenedioxyphenyl) methyl] -2- (3,4,5)
-Trimethoxybenzylidene) butanolide synthesis: (R) -3- [1- (5-methoxy-3,
4-Methylenedioxyphenyl) methyl] butanolide (21.0 g, 0.084 mol) and 3,4,5-trimethoxybenzaldehyde (26.0 g, 0.133 mo)
l) Toluene solution (350 ml) was cooled to 0 ° C. and sodium hydride (60%, 9.1 g, 0.228 mol) was added.
And methanol (0.33 ml, 0.0082 mol)
Was added. After stirring at 0 ° C. for 15 minutes and at room temperature for 18 hours, the reaction solution was ice-cooled and acidified by adding 2N hydrochloric acid water. Ethyl acetate (100 ml) was added, the aqueous layer was separated, and the aqueous layer was extracted with ethyl acetate (50 ml × 2),
Combined with the organic layer obtained earlier. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The residue (52.9 g) obtained by distilling off the solvent was subjected to column chromatography (Merck # 9385, 500).
g, ethyl acetate-hexane 1: 2) to give the title compound as a colorless oil (16.62 g, 46%).

[Α] _D ²⁷ : -53.7 ° (c = 1.04,
CHCl ₃ ) ¹ HNMR (CDCl ₃ ): 2.64 (1H, dd, J = 1)
0,14Hz), 3.02 (1H, dd, J = 5,14H
z), 3.71-3.93 (1H, m), 3.86 (3H,
s), 3.89 (6H, s), 3.90 (3H, s), 4.24
-4.36 (2H, m), 5.93 (2H, s), 6.28
(1H, d, J = 1.5Hz), 6.34 (1H, d, J = 1.
5Hz), 6.77 (2H, s), 7.52 (1H, d, J =
2 Hz) IRνmax (CHCl ₃ ) cm ^-1 : 2940, 1744,1
642,1584 M S: 428 (M ⁺ ), 165 (base) HRMS (as C ₂₃ H ₂₄ O ₈ ): Calculated value: 428.14712 Measured value: 428.14972

Example 6 (3aR, Sbiar) -3a, 4-dihydro-8,9,1
0,11-Tetramethoxy-6,7-methylenedioxydibenzo [4,5: 6,7] cycloocta [1,2-c] furan-1 (3H) -one and (3aR, Sbiar)
-3a, 4-dihydro-6,9,10,11-tetramethoxy-7,8-methylenedioxydibenzo [4,5: 6,
7] Cycloocta [1,2-c] furan-1 (3H)-
Preparation of one: (R)-(E) -3- [1- (5-methoxy-3,4-methylenedioxyphenyl) methyl] -2
A solution of (3,4,5-trimethoxybenzylidene) butanolide (6.19 g, 0.014 mol) in dichloromethane (60 ml) was added at room temperature to iron perchlorate hexahydrate (18.
5 g, 0.04 mol), trifluoroacetic acid (6 ml)
Was added and the mixture was stirred at room temperature for 3.5 hours. Saturated aqueous sodium hydrogen carbonate (50 ml) was added to the reaction solution, the insoluble matter was filtered off, and the filtrate was extracted with dichloromethane (100 ml × 3).
The combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting brown oil (5.8 g) was subjected to column chromatography (Merck silica gel # 938).
5,400 g, ethyl acetate-hexane 1:10) and purified (3aR, Sbiar) -3a, 4-dihydro-8,
9,10,11-Tetramethoxy-6,7-methylenedioxydibenzo [4,5: 6,7] cycloocta [1,2-
From the fraction containing c] furan-1 (3H) -one, 2.055 g of a colorless solid was obtained. Recrystallize from ethyl acetate-hexane to give (3aS, Rbiar) -3a, 4-dihydro-8,9,10,11-tetramethoxy-6,7-methylenedioxydibenzo [4,5: 6,7] cycloocta. [1,2-c] Furan-1 (3H) -one was obtained as colorless plate crystals (1.69 g, 27%). Furthermore, (3a
R, Sbiar) -3a, 4-dihydro-6,9,10,1
From the fraction containing 1-tetramethoxy-7,8-methylenedioxydibenzo [4,5: 6,7] cycloocta [1,2-c] furan-1 (3H) -one, 0.22
3 g of a pale yellow solid was obtained. Recrystallized from ethyl acetate-hexane to give (3aR, Sbiar) -3a, 4-dihydro-
6,9,10,11-tetramethoxy-7,8-methylenedioxydibenzo [4,5: 6,7] cycloocta [1,2
-C] Furan-1 (3H) -one is a colorless needle crystal (0.
18 g, 2.9%).

* (3aR, Sbiar) -3a, 4-dihydro-8,9,10,11-tetramethoxy-6,7-methylenedioxydibenzo [4,5: 6,7] cycloocta [1,2- c] Furan-1 (3H) -one: melting point: 221-21.5 ° C. [α] _D ²⁷ : + 340 ° (c = 1.00, CHCl ₃ ) ¹ HNMR (CDCl ₃ ): 2.42 (1H , dd, J = 1,
14Hz), 3.00 (1H, dd, J = 714Hz),
3.60-3.80 (1H, m), 3.63 (3H, s), 3.
81 (3H, s), 3.89 (3H, s), 3.91 (3H,
s), 4.09 (1H, dd, J = 9, 10Hz), 4.44
(1H, t, J = 9Hz), 5.96 (1H, d, J = 1.5)
Hz), 5.98 (1H, d, 1.5Hz), 6.34 (1H,
s) 6.58 (1H, s), 7.51 (1H, s). IRvmax (KBr) cm ^-1 : 2940,1758,16
74,1620,1592 M S: 426 (M ⁺ , base). Elemental analysis value (as C ₂₃ H ₂₂ O ₈ ): Calculated value C; 64.78, H; 5.20. Measured value C; 64.75 , H; 5.13.

* (3aR, Sbiar) -3a, 4-dihydro-6,9,10,11-tetramethoxy-7,8-methylenedioxydibenzo [4,5: 6,7] cycloocta [1,2- c] Furan-1 (3H) -one: melting point: 179.5-180 ° C. [α] _D ²⁷ : + 369 ° (c = 0.96, CHCl ₃ ) ¹ HNMR (CDCl ₃ ): 2.45 (1H , dd, J = 1.
2.15.4Hz), 3.07 (1H, dd, J = 6.5,14)
Hz), 3.40-3.61 (1H, m), 3.72 (3H,
s), 3.89 (3H, s), 3.91 (3H, s), 3.9
4 (3H, s), 4.12 (1H, dd, J = 8,10H
z), 4.46 (1H, t, J = 9Hz), 5.88 (1H,
d, J = 1.5Hz), 5.97 (1H, d, J = 1.5H
z), 6.28 (1H, s), 6.61 (1H, s), 7.51
(1H, d, J = 3Hz) IRνmax (KBr) cm ^-1 : 2944,2908,1746,1666,1642,15
. 90 M S: 426 (as _{C 23 H 22 O 8) (} M +, base) Elemental analysis: Calculated C; 64.78, H; 5.20 Found C; 64.71, H; 5. 27

Reference Example 8 Synthesis of (S) -3- [1- (3,4,5-trimethoxyphenyl) methyl] butanolide: (S) -3- [1-
(5-methoxy-3,4-methylenedioxyphenyl)
Methyl] butanolide (500 mg, 2 mmol) was dissolved in dichloromethane (5 ml), a solution of boron trichloride in dichloromethane (1.0 M, 4 ml, 4 mmol) was added, and the mixture was stirred at 0 ° C for 45 minutes. The solvent was evaporated under reduced pressure, and the residue was methanol (10 ml), 4N hydrochloric acid water (5 ml).
And was stirred at room temperature for 1.5 hours. The reaction solution was dissolved in ethyl acetate (50 ml) and washed with water and saturated saline.
After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give a yellow foamy substance (371 mg). This was dissolved in DMF (5 ml) and potassium carbonate (2.6 g,
18.8 mmol), iodomethane (1.3 ml, 20.8 mmol)
mmol) was added and the mixture was stirred at 50 ° C. for 1 hour. The reaction solution was acidified with 2N hydrochloric acid and extracted with dichloromethane (10 ml × 2). After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the obtained oily substance was purified by column chromatography (silica gel, Merck # 9385, ethyl acetate-hexane 1: 2) to give the title compound as a colorless solid (261 mg, 49%).

Melting point: 101.5-103 ° C. (colorless prismatic crystals, ethyl acetate) [α] _D ²⁵ : −8.50 ° (c = 1.13, CHC
l ₃ ) ¹ HNMR (CDCl ₃ ): 2.31 (1H, dd, J = 7,
17Hz), 2.63 (1H, dd, J = 8,17Hz),
2.71 (2H, d, J = 9Hz), 2.79-2.94 (1
H, m), 3.84 (3H, s), 3.85 (6H, s), 4.
06 (1H, dd, J = 6.9Hz), 4.36 (1H, d
d, J = 7.9 Hz), 6.36 (2H, s) IRνmax (KBr) cm ^-1 : 2992,2972,29
28,1766,1592,1506,1462,1424,
1336, 1246, 1232, 1170, 1118 M S: 266 (M ⁺ ), 181 (base). Elemental analysis value (as C ₁₄ H ₁₈ O ₅ ): Calculated value C; 63.14, H; 6.81. Found C; 63.02, H; 6.87.

Reference Example 9 Synthesis of (S)-(E) -2- (3,4,5-trimethoxybenzylidene) -3- [1- (3,4,5-trimethoxyphenyl) methyl] butanolide : A compound (500 mg, 1.88 mmol) of Reference Example 8 and 3,4,5 in a hexane solution of lithium hexamethyldisilazide (1.0 mol / l, 5.6 ml, 5.6 mmol) at room temperature in an argon stream. -Trimethoxybenzaldehyde (400m
g, 2.04 mmol) in toluene solution (15 ml) was added, and the mixture was stirred for 30 minutes. Then, acetic anhydride (0.20m
Toluene solution (1 ml) of 1, 2.0 mmol) was added and stirred at room temperature for 30 minutes. Further, a toluene solution (1 ml) of diazabicycloundecene (0.37 ml, 2.5 mmol) was added, and the mixture was stirred at 60 ° C for 1 hr. The reaction solution was 2N HCl (50 ml), saturated aqueous sodium hydrogen carbonate (50 ml),
The extract was washed with saturated brine (50 ml) and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a yellow oil (1.
0 g) was obtained. Purification by column chromatography (silica gel, Fuji Devison BW300, 20 g, ethyl acetate-hexane 1: 1) gave the title compound as a pale yellow oil (0.45 g, 54%).

[Α] _D ²⁶ : + 77.0 ° (c = 1.07,
CHCl ₃ ). ¹ HNMR (CDCl ₃ ): 2.65 (1H, dd, J = 1)
0,14Hz), 3.11 (1H, dd, J = 5,14H
z), 3.82 (3H, s), 3.83 (6H, s) 3.89
(6H, s) 3.91 (3H, s), 3.82-3.91 (1
H, m), 4.29-4.31 (2H, m), 6.38 (2H,
s), 6.82 (2H, s), 7.53 (1H, d, J = 2H
z). IRνmax (CHCl ₃ ) cm ^-1 : 2940,1748,1
648, 1588, 1496, 1460, 1416, 133
6,1152,1128, 998. M S: 444 (M ⁺ ), 181 (base) HRMS (as C ₂₄ H ₂₈ O ₈ ; M ⁺ ): Calcd: 444.17833 Found: 444.17793

Example 7 (3aS, Rbiar) -3a, 4-dihydro-6,7,
8,9,10,11-hexamethoxydibenzo [4,5:
6,7] Cycloocta [1,2-c] furan-1 (3H)
Synthesis of --one: (S)-(E) -2- (3,4,5-trimethoxybenzylidene) -3- [1- (3,4,5-trimethoxyphenyl) methyl] butanolide (491 mg,
Trifluoroacetic acid (0.44 ml) was added to a methylene chloride solution (5 ml) of 1.1 mmol), iron perchlorate (1.47 g, 3.2 mol) was further added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was dissolved in ethyl acetate (40 ml), washed with water (50 ml), 2N HCl (50 ml x 2) and saturated brine (50 ml), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a brown oil. (506 mg)
I got Column chromatography (silica gel, Merck # 9385, 25 g, ethyl acetate-hexane 1:
1) and the title compound as a pale yellow oil (441 m
g, 90%).

[Α] _D ²⁶ : -284 ° (C = 0.895,
CHCl ₃ ) ¹ HNMR (CDCl ₃ ): 2.46 (1H, dd, J = 1,
14Hz), 3.07 (1H, dd, J = 714Hz),
3.40-3.60 (1H, m), 3.59 (3H, s), 3.
64 (3H, s), 3.88 (3H, s), 3.89 (3H,
s), 3.90 (3H, s), 3.91 (3H, s), 4.11
(1H, dd, J = 8,10Hz), 4.47 (1H, t, J
= 8 Hz), 6.59 (1H, s), 6.41 (1H, s),
7.53 (1H, d, J = 3Hz). IRνmax (CHCl ₃ ) cm ^-1 : 2940,1754,1
668,1596,1578,1484,1460,139
6,1346,1316,1162,1128,1106,1
016,1002. M S: 442 (M ⁺ , base) HRMS (as C ₂₄ H ₂₆ O ₈ ; M ⁺ ): Calculated value; 442.16279 Measured value; 442.16279

Reference Example 10 Preparation of 1-methyl = hydrogen = (S) -2- [1- (5-methoxy-3,4-methylenedioxyphenyl) methyl] butanedioate: 1-methyl = hydrogen = (RS) -2-
[1- (5-Methoxy-3,4-methylenedioxyphenyl) methyl] butanedioate (racemic, 20 g)
And D-(+)-α-aminocaprolactam (8.65
g) was dissolved in heated acetone (640 ml),
Stir at room temperature for 3 hours. The precipitated crystals were collected by filtration to find that the aminocaprolactam salt of the title compound was 17.5%.
4 g was obtained. This salt was dissolved in saturated aqueous sodium hydrogen carbonate (200 ml) and washed with ether (200 ml × 3), 10%
It was made acidic with oxalic acid water and extracted with dichloromethane (500 ml × 3). The dichloromethane layers were combined, washed with saturated saline and then dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and about 60% ee of 1-methyl = hydrogen = (RS) -2- [1- (5-methoxy-3,4-methylenedioxyphenyl) methyl] butanedioate was obtained. 29 g were obtained. This in methanol (20 ml),
The mixture was stirred at room temperature for 1 hour, and insoluble matter was removed by filtration. The filtrate was evaporated under reduced pressure to give 100% ee of the title compound as 5.04.
g was obtained.

Melting point: 96.5-97.0 ° C. (colorless prismatic crystal) [α] _D ²³ : −26.6 ° (c = 1.18, CHCl ₃ ) ¹ HNMR (CDCl ₃ ): 2. 46 (1H, dd, J = 4.
5,17 Hz), 2.62-2.77 (2H, m), 2.93
-3.13 (2H, m), 3.69 (3H, s), 3.88
(3H, s), 5.94 (2H, s), 6.31 (1H, s),
6.34 (1H, s). No carboxylic acid protons were observed. IR ν max (KBr) cm ⁻¹ : 3136, 2912, 17
24, 1680, 1638, 1512. M S: 296 (M ⁺ ), 165 (base). Elemental analysis (as C ₁₄ H ₁₆ O ₇ ): Calculated value; C 62.39, H 5.64 measured value; C 62.38, H 5.69

Reference Example 11 Synthesis of (S) -3- [1- (5-methoxy-3,4-methylenedioxyphenyl) methyl] butanolide: 1-methyl = hydrogen = (S) -2- [1 -(5-methoxy-3,
4-Methylenedioxyphenyl) methyl] butanedioate (71.8 g, 0.24 mol) was added to ethanol (90
0 ml) and dissolve in potassium hydroxide (85%, 16.7
g, 0.27 mol) in ethanol (450 ml) was added. Calcium chloride under ice cooling (51.6g, 0.46m)
ol), sodium borohydride (36g, 0.95m
ol) was added and the mixture was stirred at 0 ° C. for 19 hours. Under ice cooling, 1
2N HCl water (500 ml) was added, and the mixture was further stirred at room temperature for 3 hours.
After stirring for 0 minutes, extract with methylene chloride (300 ml x
3) The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 68.76 g of a colorless solid. Recrystallize from ethyl acetate-hexane to give the title compound (46.85 g,
75%) as colorless prism crystals.

Melting point: 88.5-89.5 ° C. [α] _D ²³ : −6.82 ° (c = 1.12, CHCl ₃ ) ¹ HNMR (CDCl ₃ ): 2.27 (1H, dd, J = 7,
17 Hz), 2.55-2.89 (4 H, m), 3.90 (3
H, s), 4.03 (1H, dd, J = 6.9 Hz), 4.34
(1H, dd, J = 7.9Hz), 5.95 (2H, s), 6.
30 (1H, d, J = 2Hz), 6.34 (1H, d, J = 2)
Hz). IRνmax (KBr) cm ^-1 : 1784,1768,16
32,1510. M S: 250 (M ⁺ ), 165 (base)

Reference Example 12 (S)-(E) -3- [1- (5-methoxy-3,4-
Methylenedioxyphenyl) methyl] -2- (3,4,5)
-Trimethoxybenzylidene) butanolide synthesis: (S) -3- [1- (5-methoxy-3,
4-Methylenedioxyphenyl) methyl] butanolide (25.0 g, 0.1 mol), 3,4,5-trimethoxybenzaldehyde (31.0 g, 0.16 mol) in toluene solution (400 ml) was cooled to 0 ° C. , Sodium hydride (60%, 10.8 g, 0.27 mol) and methanol (0.4 ml, 0.01 mol) were added. 0 ° C
After stirring for 15 minutes at room temperature for 48 hours at room temperature, the reaction solution was ice-cooled and 6N hydrochloric acid water (100 ml) was added. After removing the aqueous layer, the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The solvent was evaporated and the obtained residue was purified by column chromatography (silica gel Merck # 9385, 500 g, ethyl acetate-hexane 1: 2) to give the title compound as a colorless oil (20.3).
8 g, 48%).

[Α] _D ²⁵ : + 55.1 ° (c = 0.955,
CHCl ₃ ) ¹ HNMR (CDCl ₃ ): 2.64 (1H, dd, J = 1)
0,14Hz), 3.01 (1H, dd, J = 5,14H
z), 3.83-3.90 (1H, m), 3.86 (3H,
s), 3.89 (6H, s), 3.90 (3H, s), 4.22
-4.36 (2H, m), 5.93 (2H, s), 6.28
(1H, d, J = 1.5Hz), 6.33 (1H, d, J = 1.
5Hz), 6.77 (2H, s), 7.51 (1H, d, J =
1.7 Hz). IRνmax (CHCl ₃ ) cm ⁻¹ : 1746, 1644,1
582. M S: 428 (M ⁺ ), 263 (base) HRMS (as C ₂₃ H ₂₄ O ₈ ): calculated value; 428.14707 measured value; 428.146677.

Reference Example 13 (S)-(E) -3- [1- (3,4-dihydroxy-
Synthesis of 5-methoxyphenyl) methyl] -2- (3,4,5-trimethoxybenzylidene) butanolide: (S)-
(E) -3- [1- (5-Methoxy-3,4-methylenedioxyphenyl) methyl] -2- (3,4,5-trimethoxybenzylidene) butanolide (0.84 g, 1.96)
mmol) in dichloromethane (10 ml) and boron trichloride (1.0 M dichloromethane solution, 4 ml, 4 ml).
mmol) was added and the mixture was stirred at 0 ° C. for 30 minutes. The solvent was evaporated under reduced pressure, the residue was dissolved in methanol (20 ml), 2N hydrochloric acid water (6 ml), and the mixture was stirred at 0 ° C. for 2 hr. The reaction solution was extracted with ethyl acetate (50 ml x 1,20 ml x
2) Then, the combined organic layer was washed with water and saturated aqueous sodium hydrogen carbonate. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give the title compound as a pale-yellow oil (0.79 g, 97%).

[Α] _D ²⁷ : + 50.3 ° (c = 0.70,
CHCl ₃ ) ¹ H-NMR (CDCl ₃ ): 2.60 (1H, dd, J = 1)
0,14Hz), 3.04 (1H, dd, J = 4,14H
z), 3.78-3.90 (1H, m), 3.83 (3H,
s), 3.89 (6H, s), 3.90 (3H, s), 4.24
-4.37 (2H, m), 5.31 (1H, s), 5.36
(1H, s), 6.23 (1H, d, J = 2Hz), 6.43
(1H, d, J = 2Hz), 6.79 (2H, s), 7.51
(1H, d, J = 2Hz). IRνmax (CHCl ₃ ) cm ^-1 : 3556,2940,1
746, 1646, 1620, 1582. M S: 416 (M ⁺ ), 263 (base). HRMS (C ₂₂ H ₂₄ O ₈ ): Calculated value; 416.14702 Measured value; 416.14562.

Example 8 (3aS, Rbiar) -3a, 4-dihydro-6,7-
Synthesis of dihydroxy-8,9,10,11-tetramethoxydibenzo [4,5: 6,7] cycloocta [1,2-c] furan-1 (3H) -one: (S)-(E) -3 -[1- (3,4-dihydroxy-
5-Methoxyphenyl) methyl] -2- (3,4,5-trimethoxybenzylidene) butanolide (200 mg, 0.
48 mmol) in dichloromethane (6 ml),
Trifluoroacetic acid (6 ml), iron perchlorate (500 m
g, 1.08 mmol) was added, and the mixture was stirred at room temperature for 1 hour and 15 minutes. After adding saturated aqueous sodium hydrogen sulfite, ethyl acetate (20 ml) was added, and the organic layer was washed with water and saturated aqueous sodium hydrogen carbonate. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a brown oily substance (280 mg), which was subjected to column chromatography (silica gel, Fujidebison B).
W-300, 20 g, ethyl acetate-hexane 1: 1)
The title compound was purified as a colorless solid (133 mg, 67
%).

Melting point: 223-223.5 ° C. (colorless needle crystals, ethyl acetate-hexane) [α] _D ²⁷ : −282.8 ° (c = 0.29, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ): 2.42 (1H, dd, J =
1,14Hz), 3.01 (1H, dd, J = 6,14H
z), 3.31 (3H, s), 3.40-3.60 (1H,
m), 3.57 (3H, s), 3.91 (3H, s), 3.93
(3H, s), 4.11 (1H, dd, J = 9,10Hz),
4.46 (1H, t, J = 9Hz), 5.37 (1H, s),
5.53 (1H, s), 6.51 (1H, s), 6.62 (1
H, s), 7.50 (1H, d, J = 3.7Hz). IRνmax (KBr) cm ^-1 : 3556,3472,32
84,2968,2940,1756,1676,1594,
1492, 1462, 1304, 1348, 1202, 10
76. M S: 414 (M ⁺ , base)

Example 9 (3aS, Rbiar) -3a, 4-dihydro-8,9,1
0,11-Tetramethoxy-6,7-methylenedioxydibenzo [4,5: 6,7] cycloocta [1,2-c] furan-1 (3H) -one and (3aS, Rbiar)-
3a, 4-dihydro-6,9,10,11-tetramethoxy-7,8-methylenedioxydibenzo [4,5: 6,7]
Synthesis of cycloocta [1,2-c] furan-1 (3H) -one: (S)-(E) -3- [1- (5-methoxy-
3,4-Methylenedioxyphenyl) methyl] -2-
A solution of (3,4,5-trimethoxybenzylidene) butanolide (20.0 g, 0.047 mol) in dichloromethane (200 ml) was added at room temperature to iron perchlorate hexahydrate (6
0.0 g, 0.13 mol), trifluoroacetic acid (20.
0 ml) was added and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was washed with 6N aqueous hydrochloric acid, water and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained brown oil (19.24 g) was purified by column chromatography (Merck silica gel # 9385, 1 kg, ethyl acetate-hexane 1:10 to 1: 2), and the product was purified (3
aS, Rbiar) -3a, 4-dihydro-8,9,10,
From the fraction containing 11-tetramethoxy-6,7-methylenedioxydibenzo [4,5: 6,7] cycloocta [1,2-c] furan-1 (3H) -one, 4.2
6 g of colorless solid was obtained. Recrystallize from ethyl acetate-hexane to give (3aS, Rbiar) -3a, 4-dihydro-
8,9,10,11-Tetramethoxy-6,7-methylenedioxydibenzo [4,5: 6,7] cycloocta [1,2
-C] Furan-1 (3H) -one as colorless plate crystals (3.
54 g, 18%). Furthermore, (3aS, Rb
iaar) -3a, 4-dihydro-6,9,10,11-tetramethoxy-7,8-methylenedioxydibenzo [4,
5: 6,7] cycloocta [1,2-c] furan-1 (3
From the fractions containing H) -one 0.75 g of a pale yellow solid was obtained. Recrystallized from ethyl acetate-hexane,
(3aS, Rbiar) -3a, 4-dihydro-6,9,1
0,11-Tetramethoxy-7,8-methylenedioxydibenzo [4,5: 6,7] cycloocta [1,2-c] furan-1 (3H) -one was added to colorless prism-like crystals (0.5
5 g, 2.8%).

* (3aS, Rbiar) -3a, 4-dihydro-8,9,10,11-tetramethoxy-6,7-methylenedioxydibenzo [4,5: 6,7] cycloocta [1,2- c] Furan-1 (3H) -one: melting point: 220.5-221.5 ° C. [α] _D ²⁷ : −329 ° (c = 1.165, CHCl ₃ ) ¹ HNMR (CDCl ₃ ): 2. 43 (1H, d, J = 14
Hz), 2.99 (1H, dd, J = 6,14Hz), 3.4
0-3.60 (1H, m), 3.63 (3H, s), 3.81
(3H, s), 3.89 (3H, s), 3.91 (3H, s),
4.44 (1H, t, J = 9Hz), 4.09 (1H, dd,
J = 9,10Hz), 5.96 (1H, d, J = 1.5H
z), 5.98 (1H, d, J = 1.5Hz), 6.58 (1
H, s), 6.34 (3H, s), 7.51 (1H, d, J = 3
Hz). IRνmax (KBr) cm ^-1 : 2944,1758,16
74, 1620, 1594. M S: 426 (M ⁺ , base). Elemental analysis (as C ₂₃ H ₂₂ O ₈ ): Calculated value C; 64.78, H; 5.20. Found value C; 64.60. , H; 5.01.

* (3aS, Rbiar) -3a, 4-dihydro-6,9,10,11-tetramethoxy-7,8-methylenedioxydibenzo [4,5: 6,7] cycloocta [1,2- c] Furan-1 (3H) -one: melting point: 179.0-180.0 ° C. [α] _D ²⁷ : −359 ° (c = 1.10, CHCl ₃ ) ¹ HNMR (CDCl ₃ ): 2. 45 (1H, d, J = 14
Hz), 3.07 (1H, dd, J = 6,14Hz), 3.4
5-3.62 (1H, m), 3.72 (3H, s), 3.89
(3H, s), 3.91 (3H, s), 3.94 (3H, s),
4.12 (1H, dd, J = 8,10Hz), 4.47 (1
H, t, J = 9Hz), 5.88 (1H, d, J = 1.5H
z), 5.98 (1H, d, J = 1.5Hz), 6.28 (1
H, s), 6.62 (1H, s), 7.51 (1H, d, J = 3)
Hz) IRν max (KBr) cm ^-1 : 2940,2908,17
46,1666,1642,1590 M S: 426 (M ⁺ , base) Elemental analysis (as C ₂₃ H ₂₂ O ₈ ): Calculated value C; 64.78, H; 5.20 Measured value C; 64.49, H; 5.06

Reference Example 14 (S)-(E) -3- [1- (3,4-dihexyloxy-5-methoxyphenyl) methyl] -2- (3,4,5-
Synthesis of (trimethoxybenzylidene) butanolide: (S)
-(E) -3- [1- (3,4-dihydroxy-5-methoxyphenyl) methyl] -2- (3,4,5-trimethoxybenzylidene) butanolide (324 mg, 0.78)
mmol) in DMF (10 ml), potassium carbonate (500 mg, 3.6 mmol) and 1-iodohexane (1.0 ml, 6.79 mmol) were added, and the mixture was added at 60 ° C. for 4.5.
Stir for hours. Pour into ethyl acetate (50 ml), water,
It was washed with 2N hydrochloric acid water, water, and saturated aqueous sodium hydrogen carbonate. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the obtained brown oily substance was purified by chromatography (Shirigagel, Fujidevison BW-300, ethyl acetate-hexane 1: 3) to give the title compound as a colorless oily substance (310 m
g, 68%).

[Α] _D ²⁷ : + 71.1 ° (c = 0.49)
_{5, CHCl 3) NMR (CDCl} 3): 0.84-1.02 (6H, m),
1.23-1.50 (12H, m), 1.60-1.84 (4
H, m), 2.60 (1H, dd, J = 11,14 Hz), 3.
10 (1H, dd, J = 4, 14Hz), 3.78 to 4.00
(1H, m), 3.80 (3H, s), 3.89 (6H, s),
3.91 (3H, s), 3.92 (4H, t, J = 7Hz),
4.24-4.29 (2H, m), 6.83 (2H, s), 6.
36 (2H, s), 7.52 (1H, d, J = 1.7Hz). IRνmax (CHCl ₃ ) cm ^-1 : 2932,2860,1
748, 1646, 1584, 1504, 1454, 142
8, 1336, 1242, 1202, 1128. M S: 584 (M ⁺ ), 237 (base).

Example 10 (3aS, Rbiar) -3a, 4-dihydro-6,7-
Dihexyloxy-8,9,10,11-tetramethoxydibenzo [4,5: 6,7] cycloocta [1,2-c] furan-1 (3H) -one and (3aS, Rbiar)-
3a, 4-dihydro-7,8-dihexyloxy-6,9,1
Synthesis of 0,11-tetramethoxydibenzo [4,5: 6,7] cycloocta [1,2-c] furan-1 (3H) -one: (S)-(E) -3- [1- (3 , 4-Dihexyloxy-5-methoxyphenyl) methyl] -2- (3,
4,5-Trimethoxybenzylidene) butanolide (92
mg, 0.16 mmol) in dichloromethane (5 m
l), iron perchlorate hexahydrate (200 mg, 0.43 m)
mol) and trifluoroacetic acid (0.5 ml) were added, and the mixture was stirred at room temperature for 1.5 hours. 2N hydrochloric acid water, water,
Wash with saturated aqueous sodium hydrogen carbonate, dry over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The resulting brown oil (100
(mg) was purified by thin layer chromatography (silica gel, Merck # 5744, ethyl acetate-hexane 1: 2) to give (3aS, Rbiar) -3a, 4-dihydro-6,
7-Dihexyloxy-8,9,10,11-tetramethoxydibenzo [4,5: 6,7] cycloocta [1,2-
c] Furan-1 (3H) -one as 44 mg (48%) of colorless oil (3aS, Rbiar) -3a, 4
-Dihydro-7,8-dihexyloxy-6,9,10,11
24 mg of tetramethoxydibenzo [4,5: 6,7] cycloocta [1,2-c] furan-1 (3H) -one
Obtained as a colorless oil (26%).

* (3aS, Rbiar) -3a, 4-dihydro-6,7-dihexyloxy-8,9,10,11-tetramethoxydibenzo [4,5: 6,7] cycloocta [1,2-c] Furan-1 (3H) -one: [α] _D ²⁷ : -225.2 ° (c = 0.50, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ): 0.89-0.95 (6H,
m), 1.22-1.56 (12H, m), 1.66-1.9
0 (4H, m), 2.43 (1H, d, J = 14Hz), 3.
05 (1H, dd, J = 714Hz), 3.40-3.60
(1H, m), 3.60 (3H, s), 3.61 (3H, s),
3.89 (3H, s), 3.91 (3H, s), 3.94-4.
03 (4H, m), 4.10 (1H, dd, J = 9,10H
z), 4.46 (1H, t, J = 9Hz), 6.38 (1H,
s), 6.58 (1H, s), 7.52 (1H, d, J = 3H
z) IRνmax (CHCl ₃ ) cm ⁻¹ : 2932,2864,1
752, 1674, 1594. M S: 582 (M ⁺ , base).

* (3aS, Rbiar) -3a, 4-dihydro-7,8-dihexyloxy-6,9,10,11-tetramethoxydibenzo [4,5: 6,7] cycloocta [1,2-c] Furan-1 (3H) -one: [α] _D ²⁷ : −204 ° (c = 0.345, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ): 0.82 (3H, t, J = 7H
z), 0.89 (3H, t, J = 7Hz), 0.99-1.5
2 (14H, m), 1.65 to 1.82 (2H, m), 2.4
4 (1H, dd, J = 1,14Hz), 3.05 (1H, d
d, J = 714 Hz) 3.40-3.63 (1H, m),
3.36 (1H, dt, J = 10, 6Hz), 3.71 (3
H, s), 3.86 (3H, s), 3.89 (6H, s), 3.
93-4.15 (4H, m), 4.46 (1H, t, J = 9H
z), 6.40 (1H, s), 6.56 (1H, s), 7.50
(1H, d, J = 3Hz). IRνmax (CHCl ₃ ) cm ⁻¹ : 2932,2860,1
752, 1674, 1594. M S: 582 (M ⁺ , base).

Reference Example 15 3,5-dimethoxy-4- (4-nitrobenzyloxy)
Synthesis of benzaldehyde: syringaldehyde (10
g, 55 mmol), p-nitrobenzyl bromide (1
3 g, 60 mmol) and potassium carbonate (9.0 g, 6
A solution of 5 mmol) in acetone (40 ml) was heated under reflux for 4 hours. The solvent was evaporated under reduced pressure, water and dichloromethane were added to the residue, and the organic layer was dried over anhydrous magnesium sulfate. Ether was added to the residue obtained by distilling off the solvent,
After stirring at room temperature, the title compound 1 was obtained by filtration.
6.7 g (93%) was obtained as an insoluble colorless solid.

Melting point: 148-149 ° C. (colorless needle crystals,
Ethyl acetate) IR (KBr): 2948, 2844, 1694, 15
_{. 94,1526,1348,1332 NMR (CDCl 3):} 3.92 (6H, s), 5.22
(2H, s), 7.14 (2H, s), 7.68 (2H,
d, J = 9Hz), 8.21 (2H, d, J = 9H)
z), 9.88 (1H, s). M S: 317 (M ⁺ ), 181 (base). Elemental analysis value (as C ₁₆ H ₁₅ NO ₆ ): Calculated value C; 60.56, H; 4 .77, N; 4.41. Found C; 60.36, H; 4.86, N; 4.57.

Reference Example 16 (S)-(E) -2- [3,5-dimethoxy-4- (4
-Nitrobenzyloxy) benzylidene] -3- (3,3
Synthesis of 4,5-trimethoxybenzyl) butanolide: diisopropylamine (13 ml, 93
mmol) in THF (80 ml) at -60 ° C.
Butyl lithium (1.66 mol / l, 56 ml, 93
mmol) was added and the mixture was cooled to -70 ° C or lower. To this was added T of (S) -3- [1- (3,4,5-trimethoxyphenyl) methyl] butanolide (20 g, 75 mmol).
After adding HF solution (200 ml) and stirring for 30 minutes,
Furthermore, T of 3,5-dimethoxy-4- (4-nitrobenzyloxy) benzaldehyde (30 g, 95 mmol) was used.
HF solution (400 ml) was added and stirred for 3 minutes. After adding saturated aqueous ammonium chloride, the temperature was raised to room temperature, ethyl acetate was added, and the aqueous layer was removed. The organic layer is 2N-hydrochloric acid,
The extract was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a yellow oil (5
2.7 g) was obtained. This oil was dissolved in dichloromethane (200 ml) and triethylamine (15 m
1, 108 mmol), dimethylaminopyridine (50
0 mg, 4 mmol), acetic anhydride (10 ml, 106 m
(mol) was added and the mixture was stirred at room temperature for 9 hours. The reaction solution is 2N-
The extract was washed with hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off from the reaction product to obtain a yellow oily product (62.2 g). Dissolve this in 200 ml of toluene and add diazabicycloundecene (20
ml) was added and the mixture was stirred at 80 ° C. for 1 hour. Ethyl acetate was further added, the organic layer was washed with 2N-hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate,
The solvent was distilled off to obtain a brown oily substance (56 g). This was purified by column chromatography to give the title compound (41.16 g, 97%) as a colorless oil.

IR (CHCl ₃ ): 3012, 296
8,2940,1748,1648,1588,152
2 [α] _D ²⁶ : + 49.16 ° (c = 0.895, CHC
l ₃ ) NMR (CDCl ₃ ): 2.66 (1H, dd, J = 1)
0,14Hz), 3.08 (1H, dd, J = 5,14
Hz), 3.60-3.80 (1H, m), 3.81 (3
H, s), 3.82 (6H, s), 3.87 (6H,
s), 4.29-4.32 (2H, m), 5.17 (2
H, s), 6.37 (2H, s), 6.81 (2H,
s), 7.53 (1H, d, J = 1.5Hz), 7.67
(2H, d, J = 9Hz), 8.22 (2H, d, J =
9 Hz). M S: 565 (M ⁺ ), 181 (base).

Example 11 (3aS, Rbiar) -3a, 4-dihydro-6,
Synthesis of 7,8,9,11-pentamethoxy-10- (4-nitrobenzyloxy) dibenzo [4,5: 6,7] cycloocta [1,2-c] furan-1 (3H) -one:
(S)-(E) -2- [3,5-dimethoxy-4- (4
-Nitrobenzyloxy) benzylidene] -3- (3,3
4,5-Trimethoxybenzyl) butanolide (27.0
g, 47.8 mmol) in dichloromethane (500 m
1), trifluoroacetic acid (50 ml) and iron perchlorate (53.0 g, 115 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was dissolved in ethyl acetate, the organic layer was washed with 2N-hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The oil obtained by distilling off the solvent is purified by column chromatography,
Obtained 25.6 g (95%) of the title compound as a pale yellow solid.

Melting point: 170.5-171.5 ° C. (colorless prismatic crystals, ethyl acetate) IR (KBr): 2940, 1754, 1672, 15
96. [α] _D ²⁹ : -256 ° (c = 1.01, CHCl ₃ ) NMR (CDCl ₃ ): 2.47 (1H, dd, J = 1.
5,14Hz), 3.02 (1H, dd, J = 7, 14)
Hz), 3.40-3.64 (1H, m), 3.56 (3
H, s), 3.60 (3H, s), 3.88 (6H,
s), 3.89 (3H, s), 4.11 (1H, dd, J
= 8,10Hz), 4.48 (1H, t, J = 8H
z), 5.20 (2H, s), 6.42 (1H, s),
6.61 (1H, s), 7.52 (1H, d, J = 3.4
Hz), 7.68 (2H, d, J = 9Hz), 8.23
(2H, d, J = 9 Hz). M S: 563 (M ⁺ ), 428 (base). Elemental analysis value (as C ₃₀ H ₂₉ NO ₁₀ ): Calculated value C; 63.94, H; 5.19 , N; 2.49 Found C; 63.73, H; 5.09, N; 2.57

Reference Example 17 (S)-(E) -2- [3,4,5-trimethoxybenzylidene] -3- (3-methoxy-4,5-bis (4-)
Synthesis of nitrobenzyloxy) benzyl) butanolide:
(S)-(E) -3- [1- (3,4-dihydroxy-
5-methoxyphenyl) methyl-2- (3,4,5-trimethoxybenzylidene) butanolide) (2 g, 4.8
mmol), para-nitrobenzyl bromide (3.05)
g, 14.1 mmol) and potassium carbonate (2.03 g,
14.7 mmol) of acetone (70 ml) in 2.5
Heated to reflux for hours. The solvent was distilled off from the reaction product under reduced pressure, water and dichloromethane were added to the residue, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off from the organic layer, ether was added to the obtained residue, and the mixture was stirred at room temperature and then filtered to obtain 2.88 g (87%) of the title compound as an insoluble yellow solid.

Melting point: 171-172 ° C. (colorless needle crystals,
Ethyl acetate) [α] _D ²⁷ : −20.4 ° (c = 0.495, CHCl ₃ ) IR (KBr): 2940, 1748, 1646, 15
_{. 84,1514,1346 NMR (CDCl 3):} 2.74 (1H, dd, J = 9,
14Hz), 3.00 (1H, dd, J = 5, 14H
z), 3.70-3.90 (1H, m), 3.82 (3
H, s), 3.87 (6H, s), 3.90 (3H,
s), 4.20-4.37 (2H, m), 5.07 (2
H, s), 5.11 (2H, s), 6.36 (1H, d,
J = 1.7Hz), 6.42 (1H, d, J = 1.7H)
z), 6.78 (2H, s), 7.52 (1H, d, J =
2Hz), 7.53 (2H, d, J = 9Hz), 7.61
(2H, d, J = 9Hz), 8.18 (2H, d, J =
9 Hz), 8.22 (2H, d, J = 9 Hz). MS: 686 (M ⁺ ), 263 (base). Elemental analysis value (as C ₃₆ H ₃₄ N ₂ O ₁₂ ): Calcd. 97, H; 4.99, N; 4.08. Found C; 62.73, H; 5.01, N; 4.31.

Example 12 (3aS, Rbiar) -3a, 4-dihydro-8,
9,10,11-Tetramethoxy-6,7-bis (4-
Nitrobenzyloxy) dibenzo [4,5: 6,7] cycloocta [1,2-c] furan-1 (3H) -one and (3aS, Rbiar) -3a, 4-dihydro-6.
9,10,11-Tetramethoxy-7,8-bis (4-
Synthesis of nitrobenzyloxy) dibenzo [4,5: 6,7] cycloocta [1,2-c] furan-1 (3H) -one: (S)-(E) -2- [3,4,5- Trimethoxybenzylidene] -3- (3-methoxy-4,5-bis (4-nitrobenzyloxy) benzyl) butanolide (2.50 g, 3.64 mmol) in dichloromethane (6
0 ml), trifluoroacetic acid (6 ml) and iron perchlorate (4 g, 8.65 mmol) were added, and the mixture was stirred at room temperature for 4 hours.
Stir for hours. The reaction mixture was dissolved in ethyl acetate, the organic layer was washed with 2N-hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The oily substance obtained by distilling the solvent from the reaction solution was purified by column chromatography, and (3aS, Rbiar) -3a, 4-dihydro-8,9,10,11-tetramethoxy-6,7-bis ( 4-nitrobenzyloxy) dibenzo [4,5: 6
7] Cycloocta [1,2-c] furan-1 (3H)-
On and (3aS, Rbiar) -3a, 4-dihydro-6,9,10,11-tetramethoxy-7,8-bis (4-nitrobenzyloxy) dibenzo [4,5: 6.
7] Cycloocta [1,2-c] furan-1 (3H)-
The on was obtained as a pale yellow oil (1.45 g, 58%).

IR (CHCl ₃ ): 3000,294
0,2860,1754,1674,1604,134
_{8. NMR (CDCl 3): 2.42-2.50} (1H,
m), 3.02-3.18 (1H, m), 3.40-3.6.
4 (1H, m), 3.57 (1H, s), 3.58 (2
H, s), 3.63 (1H, s), 3.83 (2H,
s), 3.88 (2H, s), 3.90 (2H, s),
3.91 (1H, s), 3.92 (1H, s), 4.07
(1H, dd, J = 8, 10Hz), 4.40-4.58
(1H, m), 4.64 (0.7H, d, J = 12H
z), 5.02 (0.7H, d, J = 12Hz), 5.1
4-5.30 (2.6H, m), 6.46 (0.3H,
s), 6.49 (0.7H, s), 6.54 (0.7H,
s), 6.61 (0.3H, s), 7.06 (1.3H,
d, J = 9 Hz), 7.37 (0.7H, d, J = 2.6)
Hz), 7.56-7.63 (3H, m), 8.02 (1.
3H, d, J = 9Hz), 8.17 (1.3H, d, J =
9 Hz), 8.25 (1.4 H, d, J = 9 Hz). M S: 684 (M ⁺ ), 548 (base).

Reference Example 18 3,4-dimethoxy-5-[(2-methoxyethoxy)
Synthesis of methoxy] benzaldehyde: (1) Gallic acid (200 g, 1.18 mol) was suspended in water (600 ml) and stirred vigorously with an aqueous solution of sodium hydroxide (300 g, 7.5 mmol) (7).
20 ml) and dimethyl sulfate (480 ml, 3.8 mmo)
1) was added dropwise over 6 hours. After further stirring at room temperature for 13 hours, 6N-hydrochloric acid water was added to the reaction solution. The reaction solution was extracted with ethyl acetate (500 ml × 3), and the combined organic layers were washed with water and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent of this organic layer was dissolved in methanol (1 l), concentrated sulfuric acid (20 ml) was added, and the mixture was heated under reflux for 20 hr. After allowing to cool to room temperature, the solvent was evaporated, and sodium carbonate (70 g) and ice were added to the residue. This was extracted with ethyl acetate (500 ml × 1,300 ml × 2), and the combined organic layers were extracted with ice-cooled 4N-sodium hydroxide aqueous solution (100
ml × 4). Immediately after separation, the aqueous layer extracted with sodium hydroxide was acidified by adding ice-cooled 6N-hydrochloric acid water (400 ml). The acidified aqueous layer was extracted with ethyl acetate (300 ml × 2), the combined organic layers were washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. When the solvent was distilled off from this organic layer, a residue containing methyl 3,4-dimethoxy-5-hydroxybenzoate as a main component was obtained as a brown oil (67.7 g, 27%). _{NMR (CDCl 3): 3.90-4.00 (} 9H,
m), 5.92 (1H, s), 7.20-7.50 (2
H, m)

(2) This methyl ester (30.5 g,
0.14 mol) in THF solution (140 ml) with stirring at 0 ° C. sodium hydride (60% in oil, 60%,
7.5 g, 0.19 mol) was added, and after further 5 minutes, methoxyethoxymethyl chloride (20 ml, 0.17 mo)
1) was added, and the mixture was stirred at 0 ° C for 10 minutes. Further, after heating under reflux for 2 hours, sodium hydride (60% in oil,
(3.0 g, 76 mmol) and methoxyethoxymethyl chloride (10 ml, 85 mmol) were added, and the mixture was heated under reflux for 5 hours. After adding saturated ammonium chloride water, ethyl acetate (300 ml) was added and the aqueous layer was removed. The organic layer was washed with 2N-hydrochloric acid water, water and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography to obtain 3- (2-methoxyethoxy) methoxy-4,5-dimethoxybenzoic acid methyl ester 34.33 g (80%) as a colorless oil. .. _{NMR (CDCl 3): 3.40 (} 3H, s), 3.50
-3.70 (2H, m), 3.90-4.00 (11H,
m), 5.40 (2H, s), 7.25-7.60 (2
H, m)

(3) Lithium aluminum hydride (3.
0 g, 80 mmol) was suspended in a THF solution (50 ml) and obtained in (2) while cooling to 0 ° C. in argon.
(2-Methoxyethoxy) methoxy-4,5-dimethoxybenzoic acid methyl ester (34 g, 0.11 mol)
THF solution (50 ml) was added dropwise over 10 minutes. 0
After stirring at C for 4 hours, the reaction was stopped by adding sodium sulfate decahydrate, and the insoluble matter was removed by filtration. When the solvent was distilled off from the filtrate, the benzyl alcohol compound became a colorless oil (3
0.45 g, 99%). The benzyl alcohol derivative (30 g) was dissolved in toluene (300 ml), active manganese dioxide (100 g, 1.1 mol) was added, and the mixture was stirred at room temperature for 22 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated to give 27.9 g (94%) of the title compound.
Was obtained as a colorless oil.

IR (neat): 2984, 1694,
_{1588. NMR (CDCl 3): 3.40} (3H, s), 3.50
-3.68 (2H, m), 3.88-4.00 (8H,
m), 5.40 (2H, s), 7.16-7.30 (2
H, m), 9.92 (1H, s). M S: 270 (M ⁺ ), 59 (base).

Reference Example 19 Synthesis of (S)-(E) -2- (3,4-dimethoxy-5-hydroxybenzylidene) -3- (3,4,5-trimethoxybenzyl) butanolide: under argon stream , Diisopropylamine (6.6 ml, 47 mmol) TH
N-Butyllithium (1.66 mol / l, 28 ml, 47 mmol) was added to the F solution (50 ml) at -60 ° C, and the mixture was cooled to -70 ° C or lower. (S) -3- [1
-(3,4,5-Trimethoxyphenyl) methyl] butanolide (10 g, 37.6 mmol) in THF (6
0 ml) was added and stirred for 30 minutes, and then 3,4-dimethoxy-5-[(2-methoxyethoxy) methoxy] was added.
T of benzaldehyde (11.2 g, 41.5 mmol)
HF solution (20 ml) was added and stirred for 3 minutes. After adding saturated aqueous ammonium chloride, the temperature was raised to room temperature, ethyl acetate was added, and the aqueous layer was removed. The organic layer was washed with 2N-hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a yellow oil (19
g) was obtained. This residue was added to dichloromethane (100 m
1) dissolved in triethylamine (8 ml, 57.8 m
mol), dimethylaminopyridine (200 mg, 1.
6 mmol) and acetic anhydride (5 ml, 53 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was 2N-hydrochloric acid,
The extract was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a yellow oil. This was dissolved in 60 ml of toluene, diazabicycloundecene (10 ml) was added, and the mixture was stirred at 70 ° C for 1 hr. Ethyl acetate was added, the organic layer was washed with 2N-hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a brown oil (18.75).
g) was obtained. This is dichloromethane (190 ml)
Dissolved in dichloromethane and a solution of boron trichloride in dichloromethane (1.0
M, 50 ml, 50 mmol) was added and the mixture was stirred at 0 ° C. for 10 minutes. Saturated aqueous sodium hydrogen carbonate was added, the organic layer was separated, and dried over magnesium sulfate. The solvent was evaporated from this organic layer, and the obtained residue was purified by column chromatography to give the title compound (10.1 g, 62.5%) as a colorless oil.

IR (CHCl ₃ ): 3532,300
8,2940,1746,1648,1590. NMR (CDCl ₃ ): 2.58 (1H, dd, J = 1)
2,15Hz), 3.04 (1H, dd, J = 6,15
Hz), 3.70-3.90 (1H, m), 3.86 (3
H, s), 3.93 (6H, s), 3.94 (3H,
s), 4.00 (3H, s), 4.22-4.40 (2
H, m), 5.93 (1H, br), 6.50 (2H,
s), 6.66 (1H, d, J = 2Hz), 7.03 (1
H, d, J = 2Hz), 7.52 (1H, d, J = 2H)
z). M S: 430 (M ⁺ ), 181 (base).

Reference Example 20 (S)-(E) -2- [3,4-dimethoxy-5- (4
-Nitrobenzyloxy) benzylidene] -3- (3,3
Synthesis of 4,5-trimethoxybenzyl) butanolide:
(S)-(E) -2- (3,4-dimethoxy-5-hydroxybenzylidene) -3- (3,4,5-trimethoxybenzyl) butanolide (7.5 g, 17.4 mmo)
1), p-nitrobenzyl bromide (4.6 g, 21.3)
mmol) and potassium carbonate (3.0 g, 21.7 mmo)
A solution of 1) in acetone (100 ml) was heated to reflux for 3.5 hours. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was washed with 2N-hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by column chromatography to give the title compound (9 g, 91%) as a colorless foamy substance.

[Α] _D ²⁴ : + 45.6 ° (c = 0.64)
5, CHCl ₃ ) IR (CHCl ₃ ): 3012, 2968, 1746,
_{. 1648,1590,1524,1348 NMR (CDCl 3):} 2.58-2.73 (1H,
m), 3.01 (1H, dd, J = 4, 14Hz), 3.
75-3.90 (1H, m), 3.80 (6Hs), 3.
81 (3H, s), 3.90 (3H, s), 3.93 (3
H, s), 4.25-4.40 (2H, m), 5.20 (2
H, s), 6.36 (2H, s), 6.77 (1H, d,
J = 1.7 Hz), 6.86 (1 H, d, J = 1.7 H)
z), 7.48 (1H, d, J = 1.7Hz), 7.59
(2H, d, J = 9Hz), 8.23 (2H, d, J =
9 Hz). M S: 565 (M ⁺ ), 181 (base).

Example 13 (3aS, Rbiar) -3a, 4-dihydro-6,
7,8,10,11-Pentamethoxy-9- (4-nitrobenzyloxy) dibenzo [4,5: 6,7] cycloocta [1,2-c] furan-1 (3H) -one and (3aS, Rbiar) -3a, 4-dihydro-6,
Synthesis of 7,8,9,10-pentamethoxy-11- (4-nitrobenzyloxy) dibenzo [4,5: 6,7] cycloocta [1,2-c] furan-1 (3H) -one:
(S)-(E) -2- [3,4-dimethoxy-5- (4
-Nitrobenzyloxy) benzylidene] -3- (3,3
4,5-Trimethoxybenzyl) butanolide (91m
g, 0.16 mmol) was dissolved in dichloromethane (2 ml), trifluoroacetic acid (0.2 ml) and iron perchlorate (190 g, 0.41 mmol) were added, and at room temperature 1.
Stir for 25 hours. The reaction mixture was dissolved in ethyl acetate, the organic layer was washed with 2N-hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The oil obtained after evaporation of the solvent was purified by preparative TLC (3aS, Rbiar) -3a, 4-dihydro-6.
7,8,10,11-Pentamethoxy-9- (4-nitrobenzyloxy) dibenzo [4,5: 6,7] cycloocta [1,2-c] furan-1 (3H) -one and (3aS, Rbiar) -3a, 4-dihydro-6,
7,8,9,10-Pentamethoxy-11- (4-nitrobenzyloxy) dibenzo [4,5: 6,7] cycloocta [1,2-c] furan-1 (3H) -one 77 mg
(85%) was obtained as a colorless foam.

IR (CHCl ₃ ): 3012, 296
8, 1754, 1676, 1594, 1522, 134
8. NMR (CDCl ₃ ): 2.27 (0.7H, d, J = 1)
4Hz), 2.46 (0.3H, d, J = 14Hz),
3.85 (0.7H, dd, J = 7, 14Hz), 3.0
9 (0.3H, dd, J = 7, 14Hz), 3.40-
3.60 (1H, m), 3.58 (2H, s), 3.60
(1H, s), 3.66 (1H, s), 3.79 (2H,
s), 3.88 (1H, s), 3.89 (1H, s),
3.90 (2H, s), 3.92 (4H, s), 3.95
(1H, s), 4.08 (1H, q, J = 9 Hz),
4.41-4.49 (1H, m), 4.86 (0.7H,
d, J = 13 Hz), 5.09 (0.7H, d, J = 1)
3Hz), 5.24 (0.6H, s), 6.33 (0.7)
H, s), 6.49 (0.3H, s), 6.61 (0.3)
H, s), 6.64 (0.7H, s), 7.13 (1.4)
H, d, J = 9 Hz), 7.48 (0.3 H, d, J = 3)
Hz), 7.52 (0.7H, d, J = 4Hz), 7.6
7 (0.6H, d, J = 9Hz), 8.03 (1.4H,
d, J = 9Hz), 8.29 (0.6H, d, J = 9H)
z). M S: 563 (M ⁺ , base).

Example 14 1,2,3-Trimethoxy-5H-benzo [3,4] cyclohepta [1,2-f] [1,3] benzodioxole-
Synthesis of 6-carboxylic acid methyl ester: (E) -α-
(1,3-benzodioxol-5-ylmethylene)-
3,4,5-Trimethoxybenzenepropionic acid methyl ester (114 mg, 0.295 mmol; P. Magunus
et.al. J. Am. Chem. Soc., 107 , 4984, (1985)) in a dichloromethane solution (5 ml) at room temperature, iron perchlorate hexahydrate (342 mg, 0.74 mmol), trifluoroacetic acid. (0.5 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was dissolved in ethyl acetate (20 ml), washed with 2N hydrochloric acid water, water and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained brown oil (122 mg) was subjected to thin layer chromatography (silica gel, Merck # 5744, ethyl acetate-hexane 1:
Purification in 1) gave the title compound as a colorless oil, 96 mg (85%).

¹ H-NMR (CDCl ₃ ): 2.66 (1
H, dd, J = 2,13 Hz), 3.49 (3H, s), 3.8
1 (3H, s), 3.81 (1H, dd, J = 2,13H
z), 3.88 (3H, s), 3.90 (3H, s), 6.02
(1H, d, J = 1Hz), 6.08 (1H, d, J = 1H
z), 6.65 (1H, s), 6.86 (1H, s), 7.33
(1H, s), 7.49 (1H, s). IRνmax (neat) cm ^-1 : 2940, 2904,1
702, 1626, 1598, 1482, 1408, 113
8, 1104. M S: 384 (M ⁺ ), 43 (base)

Example 15 1,5,15,15a-Tetrahydro-7,8,9-trimethoxy-3H- [1,3] benzodioxolo [5,6-
e] Synthesis of oxazolo [3,4-b] [2] benzazocin-3-one: 4- [1- (3,4-methylenedioxyphenyl) methyl] -3- [1- (3,4,5) -Trimethoxyphenyl) methyl] oxazolidin-2-one (80 mg, 0.20 mmol, K.Tomioka, Y.Kubota,
H. Kawasaki and K. Koga, Tetrahedron Lett., 30 , 2949,
(1989)) was dissolved in dichloromethane (1 ml), trifluoroacetic acid (0.2 ml) and iron perchlorate (210 mg,
0.45 mmol) was added and the mixture was stirred at room temperature for 40 minutes. Saturated aqueous sodium sulfite was added, and ethyl acetate (20 ml)
Melted into. After washing the organic layer with water and saturated aqueous sodium hydrogen carbonate,
After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give a brown oily substance. Purification by thin layer chromatography (silica gel, Merck # 5744, ether) gave the title compound as a colorless solid (71 mg, 89%).

¹ H-NMR (CDCl ₃ ): 2.40-2.
68 (2H, m), 3.35 (1H, d, J = 14Hz),
3.62 (3H, s), 3.76-3.90 (2H, m), 3.
90 (3H, s), 3.91 (3H, s), 4.47-4.6
7 (2H, m), 6.00 (1H, d, J = 1.5Hz), 6.
03 (1H, d, J = 1.5Hz), 6.71 (1H, s),
6.76 (1H, s), 6.98 (1H, s). IRνmax (CHCl ₃ ) cm ⁻¹ : 2980,1760,1
620, 1500, 1350, 1160, 1130M S
: 399 (M ⁺ , base)

Example 16 (3aRS, 13aRS, RSbiar) -3a, 4, 1
3,13a-tetrahydro-9,10,11-trimethoxy
Ci-6,7-methylenedioxydibenzo [4,5: 6,
7] Cycloocta [1,2-c] furan-1 (3H)-
Synthesis of ON: (2RS, 3RS) -3- [1- (3,4-
Methylenedidioxyphenyl) methyl] -2- [1-
(3,4,5-Trimethoxyphenyl) methyl] butanol
De (88.5 mg, 0.22 mmol, R. D. Damon, R.
H. Schlessinger, and J.F. Bount, J. Org. Chem.,Four
1, 3773, (1976)) in dichloromethane (3 ml)
, Trifluoroacetic acid (0.4 ml), iron perchlorate (4
50 mg, 0.98 mmol) was added and the mixture was stirred at room temperature for 3 hours.
Stirred. Saturated sodium sulfite water was added, and ethyl acetate was added.
It was dissolved in (20 ml). Organic layer with water and saturated sodium bicarbonate water
After washing, dry with anhydrous magnesium sulfate and reduce the solvent.
Evaporation under reduced pressure gave a brown oil. Thin layer chromatography
Ruffy (silica gel, Merck # 5744, ethyl acetate
Purified by ru-hexane 1: 2) and the title compound was obtained as a colorless oil.
Obtained as a substance (65 mg, 74%).

¹ H-NMR (CDCl ₃ ): 2.10-2.
45 (4H, m), 2.64 (1H, d, J = 13Hz),
3.12 (1H, d, J = 13Hz), 3.57 (3H,
s), 3.77 (1H, dd, J = 8, 11Hz), 3.89
(3H, s), 3.90 (3H, s), 4.37 (1H, dd,
J = 6.8Hz), 5.98 (1H, d, J = 1.5Hz),
6.00 (1H, d, J = 1.5Hz), 6.62 (1H,
s), 6.63 (1H, s), 6.70 (1H, s). IRvmax (KBr) cm ^-1 : 2944, 2928,17
78, 1596, 1484. M S: 398 (M ⁺ , base)

Reference Example 21 Synthesis of dimethyl = 1,3-bis (3,4,5-trimethoxyphenyl) propane-2,2-dicarboxylate:
Sodium (230 mg, 10 mmol) was dissolved in methanol (15 ml) under ice cooling, and dimethyl malonate (1.0 ml, 8.8 mmol) was added thereto at room temperature. Further 3,4,5-trimethoxybenzyl bromide (2.3 g,
8.8 mol) was added and the mixture was heated under reflux for 1 hr. After allowing to cool to room temperature, the reaction solution was dissolved in ethyl acetate (50 ml), and washed with 2N hydrochloric acid water, water, and saturated sodium bicarbonate water. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give a colorless oily substance (2.6 g). A solution of this crude product in methanol (10 ml) was added to a solution of sodium methoxide in methanol (sodium 200 mg and methanol 15 ml).
Preparation), 3,4,5-trimethoxybenzyl bromide (2.3 g, 8.8 mmol) was further added, and the mixture was heated under reflux for 1 hour. The reaction solution was dissolved in ethyl acetate (50 ml) and washed with 2N hydrochloric acid water, water and saturated aqueous sodium hydrogen carbonate.
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a colorless solid, which was recrystallized from ethyl acetate-hexane,
Colorless prismatic crystals of the title compound (1.92g, 44%)
Got as.

Melting point: 142.5-143.0 ° C. ¹ H-NMR (CDCl ₃ ): 3.20 (4H, s), 3.6
9 (6H, s), 3.81 (12H, s), 3.82 (6H,
s), 6.35 (4H, s). IRνmax (KBr) cm ^-1 : 2952,1730,15
90,1462,1424,1204 Ms: 492 (M ⁺ ), 181 (base).

Example 17 6,7-Dihydro-1,2,3,9,10,11-hexamethoxy-5H-dibenzo [a, c] cycloheptene-6,6
-Synthesis of dicarboxylic acid dimethyl ester: dimethyl =
1,3-bis (3,4,5-trimethoxyphenyl) propane-2,2-dicarboxylate (200 mg, 0.4
1 mmol) was dissolved in dichloromethane (4 ml), trifluoroacetic acid (0.4 ml), iron perchlorate (580 m)
g, 1.25 mmol) was added, and the mixture was stirred at room temperature for 2 hours.
After adding 2N hydrochloric acid water to the reaction solution, ethyl acetate (20
ml) and the aqueous layer was removed. The organic layer was washed with water and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a residue, which was chromatographed (silica gel, Merck # 9385, 10 g, ethyl acetate-hexane 1: 1). ) And the title compound as a colorless solid (1
83 mg, 92%).

Melting point: 161-162 ° C. (colorless prism crystals, ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ): 2.73 (2H, d, J = 14)
Hz), 3.14 (2H, d, J = 14Hz), 3.66 (6
H, s), 3.75 (6H, s), 3.87 (6H, s), 3.
89 (6H, s), 6.59 (2H, s). IRνmax (KBr) cm ^-1 : 2956,1742,15
98,1576 Ms: 490 (M ⁺ , base).

Reference Example 22 Synthesis of (E) -methyl = 3- (3,4,5-trimethoxyphenyl) prop-2-enoate: 3,4,5-trimethoxybenzaldehyde (8.68 g, 0. 044mo
(triphenylphosphoranylidene) acetic acid methyl ester (15.0 g, 0.03) in a solution of 1) in methanol (50 ml).
(044 mol) was added, and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure and the obtained residue was purified by column chromatography (silica gel, Merck # 9385, ethyl acetate-hexane 1: 1) to give the title compound as a colorless solid (11.24 g, quantitative). It was

NMR (CDCl ₃ ): 3.81 (3H,
s), 3,88 (3H, s), 3,89 (6H, s), 6.35
(1H, d, J = 16Hz), 6.75 (2H, s), 7.6
1 (1H, d, J = 16Hz). IRνmax (KBr) cm ^-1 : 3004,2944,28
40,1694,1632,1584,1434,1422,
1338, 1320, 1286, 1248, 1244, 11
54, 1122. M S: 252 (M ⁺ , base)

Reference Example 23 Synthesis of methyl 3- (3,4,5-trimethoxyphenyl) propanoate: (E) -methyl 3- (3,4,5-)
Trimethoxyphenyl) prop-2-enoate (1
0.2 g) was dissolved in ethyl acetate (50 ml) and 10%
Palladium carbon (300 mg) was added, and the mixture was stirred under a hydrogen atmosphere at 1 atm at room temperature for 19 hours. The insoluble material was filtered off, and the filtrate was evaporated under reduced pressure to give the title compound as a colorless oil (11.03 g, quantitative).

NMR (CDCl ₃ ): 2.63 (2H, t,
J = 8Hz), 2.90 (2H, t, J = 8Hz), 3.69
(3H, s), 3.82 (3H, s), 3.85 (6H, s),
6.42 (2H, s). IR (neat) cm ^-1 : 2944,2840,173
8,1590,1508,1462,1422,1242,1
128. M S: 254 (M ⁺ ), 44 (base).

Reference Example 24 3- (3,4,5-trimethoxyphenyl) propane-1
-Synthesis of all (GO-600-3): Methyl = 3-
A tetrahydrofuran (20 ml) solution of (3,4,5-trimethoxyphenyl) propanoate (11.03 g, 0.043 mol) was cooled to 0 ° C. and lithium aluminum hydride (1.6 g, 0.042 mol) in tetrahydrofuran (20 ml) was added. 20 ml) was added dropwise to the suspension. 1 at room temperature
After stirring for 9 hours, sodium sulfate decahydrate was added,
Furthermore, it stirred at room temperature for 1 hour. The insoluble material was removed by filtration, and the filtrate was concentrated to give the title compound as a colorless oily substance (9.
5 g, 96.8%).

NMR (CDCl ₃ ): 1.51 (1H, b
r), 1.85-1.96 (2H, m), 2.66 (2H, t,
J = 7Hz), 3.70 (2H, t, J = 7Hz), 3.82
(3H, s), 3.85 (6H, s), 6.42 (2H, s). M S: 226 (M ⁺ ), 181 (base)

Reference Example 25 Synthesis of 5- (3-bromopropyl) -1,2,3-trimethoxybenzene: 3- (3,4,5-trimethoxyphenyl) propan-1-ol (9.50 g , 0.042mo
To a solution of 1) in tetrahydrofuran (50 ml) was added dropwise phosphorus tribromide (5.0 ml, 0.053 mol) at 0 ° C.
After stirring at room temperature for 12 hours, water under ice cooling was added. It was dissolved in ethyl acetate (200 ml), and the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the obtained oily substance was subjected to column chromatography (silica gel, Merck # 938).
(5, ether) to give the title compound as a colorless oil (10.2 g, 84%).

NMR (CDCl ₃ ): 2.10-2.23
(2H, m), 2.73 (2H, t, J = 8Hz), 3.37
-3.50 (2H, m), 3.85 (3H, s), 3.88
(6H, s), 6.44 (2H, s). IRνmax (neat) cm ^-1 : 2996,2840,2
836, 1590, 1506, 1464, 1454, 142
2,1262,1246,1134,1126,1008. M S: 290,288 (M ⁺ ), 181 (base)

Reference Example 26 Synthesis of triphenyl [3- (3,4,5-trimethoxyphenyl) propyl] phosphonium bromide: 5-
(3-Bromopropyl) -1,2,3-trimethoxybenzene (7.65 g, 26.5 mmol) and triphenylphosphine (6.9 g, 26.5 mmol) in toluene (5
It was dissolved in 0 ml) and heated under reflux for 23 hours. After cooling to room temperature, the supernatant was decanted off and the crude triphenyl [3
-(3,4,5-Trimethoxyphenyl) propyl] phosphonium bromide was obtained as a colorless oily substance (7.46 g, 51
%). This was directly used for the next reaction without purification.

Reference Example 27 Synthesis of 1,4-bis (3,4,5-trimethoxyphenyl) butane: triphenyl [3- (3,4,5-trimethoxyphenyl) propyl] phosphonium = bromide (1 .
0 g, 1.8 mmol) was suspended in THF (15 ml), and butyllithium (in hexane, 1.57 M,
0.9 ml, 1.4 mmol) was added and stirred for 1 hour.
Furthermore, 3,4,5-trimethoxybenzaldehyde (280 mg, 1.4 mmol) was added, and the mixture was stirred at room temperature for 21 hours. The reaction solution was dissolved in ethyl acetate (30 ml) and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the oily substance (1.05 g) obtained by evaporating the solvent under reduced pressure was chromatographed (silica gel, Merck # 9385, 50 g, ethyl acetate-hexane 1:
Purification in 2) yielded 438 mg of colorless oil. Immediately ethyl acetate (7 ml) and methanol (5 ml)
10% palladium-carbon catalyst (30 mg) was added, and the mixture was stirred at room temperature for 41 hours under a hydrogen atmosphere at 1 atm. The insoluble material was removed by filtration, the filtrate was concentrated, and then recrystallized from ethyl acetate to obtain the title compound as colorless prism crystals (253 mg, 45%).

Melting point: 103-105 ° C. ¹ H-NMR (CDCl ₃ ): 1.67-1.74 (4H,
m), 2.52-2.66 (4H, m), 3.82 (6H,
s), 3.84 (12H, s), 6.38 (4H, s). IRνmax (KBr) cm ^-1 : 2936,2828,15
90,1510,1460,1422,1332,1242,
1122 M S: 390 (M ⁺ , base).

Reference Example 28 1- (3,4-dimethoxyphenyl) -4- (3,4,5)
-Synthesis of trimethoxyphenyl) butane: triphenyl [3- (3,4,5-trimethoxyphenyl) propyl]
Phosphonium bromide (1.23 g, 2.2 mmol)
Was suspended in THF (15 ml), and butyllithium (1.57M in hexane, 1.4 ml, 2.2 mm) under ice cooling.
ol) was added and the mixture was stirred for 1 hour. Furthermore, 3,4-dimethoxybenzaldehyde (365 mg, 2.2 mmol)
Was added and the mixture was stirred at room temperature for 21 hours. The reaction solution was dissolved in ethyl acetate (30 ml) and washed with water and saturated saline.
After drying over anhydrous magnesium sulfate, the oily substance (1.31 g) obtained by evaporating the solvent under reduced pressure was purified by chromatography (silica gel # 9385, 30 g, ethyl acetate-hexane 1: 4) to give 403 mg of colorless. An oily substance was obtained. Immediately dissolve in ethyl acetate (10 ml) and
0% Palladium-carbon catalyst (10 mg) was added, and the mixture was stirred at room temperature for 35 hours under a hydrogen atmosphere at 1 atm. The insoluble material was filtered off, the filtrate was concentrated, and the residue was purified by chromatography (silica gel, Merck # 9385, 10 g, ethyl acetate-hexane 1: 4) to obtain the title compound as a colorless solid (198 mg, 25%). It was

¹ H-NMR (CDCl ₃ ): 1.62-1.69 (4H, m), 2.51-2.65 (4
H, m), 3.82 (3H, s), 3.84 (3H, s), 3.
846 (3H, s), 3.853 (3H, s), 3.86 (3
H, s), 6.38 (2H, s), 6.67-6.81 (3H,
m). IRνmax (KBr) cm ^-1 : 2996,2928,28
52, 1588, 1512, 1462, 1454, 1420,
1264,1238,1132. Ms: 360 (M ⁺ ), 181 (base).

Reference Example 29 1- (3,4-methylenedioxyphenyl) -4- (3,
Synthesis of 4,5-trimethoxyphenyl) butan-1-ol: Magnesium (50 mg) in THF (0.
1 ml) and ethylenedibromide (1 drop) was added. When the reaction started, THF (0.9 ml) was added, followed by 10-solution of 5- (3-bromopropyl) -1,2,3-trimethoxybenzene (318 mg, 1.04 mmol) in THF (1 ml). It dripped over minutes. After stirring at room temperature for 4 hours, piperonal (170 mg, 1.1
3 mmol) in THF (1 ml) was added at room temperature to 1
Stir for 6 hours. Saturated aqueous ammonium chloride was added, and then ethyl acetate (30 ml) was added. Water organic layer,
After washing with saturated saline and drying over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure to obtain 0.33 g of an oily substance. Column chromatography (silica gel, Merck #
7734, 50 g, ethyl acetate-hexane 1: 3), and the title compound was a colorless oil (86 mg, 22%).
Got as.

¹ H-NMR (CDCl ₃ ): 1.59-1.
87 (5H, m), 2.56 (2H, t, J = 8Hz), 3.
82 (3H, s), 3.83 (6H, s), 4.61 (1H,
t, J = 7 Hz), 5.95 (2H, s), 6.36 (2H,
s), 6.765 (1H, s), 6.77 (1H, s), 6.8
5 (1H, s). IRνmax (CHCl ₃ ) cm ⁻¹ : 2940,1592,1
^{486,1462,1128 M S: 360 (M +} ), 342 (M + -H 2 O), 18
1 (base).

Reference Example 30 1- (3,4-methylenedioxyphenyl) -4- (3,
Synthesis of 4,5-trimethoxyphenyl) butane: 1-
(3,4-methylenedioxyphenyl) -4- (3,4,
5-trimethoxyphenyl) butan-1-ol (50
0 mg, 1.39 mmol) in ethyl acetate (20 ml)
Palladium chloride (5 mg) was added, and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere at 1 atm. The insoluble material was filtered off, the filtrate was concentrated, and the residue was purified by chromatography (silica gel, Merck # 9385, 50 g, ethyl acetate-hexane 1: 5) to give the title compound as a colorless oil (388 mg, 81%). Obtained.

¹ H-NMR (CDCl ₃ ): 1.57-1.
70 (4H, m), 2.46-2.64 (4H, m), 3.8
2 (3H, s), 3.84 (6H, s), 5.92 (2H,
s), 6.38 (2H, s), 6.61 (1H, dd, J = 2,
8Hz), 6.67 (1H, d, J = 2Hz), 6.72 (1
H, d, J = 8 Hz). IRνmax (neat) cm ^-1 : 2932,2856,1
590,1504,1490,1462,1422,124
0,1128,1036 M S: 344 (M ⁺ , base)

Example 18 5,6,7,8-Tetrahydro-1,2,3,10,11,12
-Synthesis of hexamethoxydibenzo [a, c] cyclooctene: 1,4-bis (3,4,5-trimethoxyphenyl) butane (50 mg, 0.128 mmol) was dissolved in dichloromethane (1.2 ml) to give trifluoro. Acetic acid (0.
12 ml), iron perchlorate (178 mg, 0.39 mmo)
1) was added, and the mixture was stirred at room temperature for 40 minutes. Ethyl acetate (20
ml), washed with 2N hydrochloric acid water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a brown oily substance. Thin layer chromatography (silica gel, Merck # 5744, ethyl acetate-
Purification with hexane 1: 1) gave the title compound as a colorless oil (3 mg, 6%).

¹ H-NMR (CDCl ₃ ): 1.37-1.
50 (2H, m), 1.96-2.17 (4H, m), 2.5
8 (2H, dd, J = 8, 13Hz), 3.62 (6H,
s), 3.88 (6H, s), 3.90 (6H, s), 6.58
(2H, s). IRνmax (CHCl ₃ ) cm ⁻¹ : 2932,2846,1
598, 1460, 1400, 1126, 1104 M S: 388 (M ⁺ , base)

Example 19 Synthesis of 5,6,7,8-tetrahydro-1,2,3,10,11-pentamethoxydibenzo [a, c] cyclooctene: 1- (3,4-dimethoxyphenyl) -4- (3,
4,5-Trimethoxyphenyl) butane (70 mg, 0.
194 mmol) was dissolved in dichloromethane (1 ml), trifluoroacetic acid (0.1 ml) and iron perchlorate (1
80 mg, 0.39 mmol) was added, and the mixture was stirred at room temperature for 40 minutes. It was dissolved in ethyl acetate (20 ml), washed with 2N hydrochloric acid water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a brown oily substance. Thin layer chromatography (silica gel, Merck #
5744, ethyl acetate-hexane 1: 5), and the title compound was obtained as a colorless oil (17 mg, 24%). The starting material was recovered as a colorless oily substance (15 mg, recovery rate 21%).

¹ H-NMR (CDCl ₃ ): 1.44 (2
H, t, J = 10 Hz), 1.90-2.20 (4H, m),
2.52-2.73 (2H, m), 3.54 (3H, s), 3.
86 (3H, s), 3.91 (6H, s), 3.93 (3H,
s), 6.59 (1H, s ) .6.77 (2H, s) IRνmax (CHCl 3) cm -1: 2932,2856,1
598, 1490, 1462, 1402, 1120, 107
8 M S: 342 (M ⁺ , base)

Example 20 Synthesis of 5,6,7,8-tetrahydro-1,2,3-trimethoxy-10,11-methylenedioxydibenzo [a, c] cyclooctene: 1- (3,4- Methylenedioxyphenyl) -4- (3,4,5-trimethoxyphenyl) butane (73 mg, 0.21 mmol) was dissolved in dichloromethane (1 ml), and trifluoroacetic acid (0.1 m) was added.
l) and iron perchlorate (190 mg, 0.41 mmol) were added, and the mixture was stirred at room temperature for 20 minutes. It was dissolved in ethyl acetate (20 ml), washed with 2N hydrochloric acid water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a brown oily substance. Thin layer chromatography (silica gel, Merck # 5744, ethyl acetate-hexane
1: 5) to give the title compound as a colorless oil (9 mg,
12%). The starting material was recovered as a colorless oily substance (13 mg, recovery rate 18%).

¹ H-NMR (CDCl ₃ ): 1.42 (2
H, t, J = 10 Hz), 1.90-2.17 (4H, m),
2.54-2.63 (2H, m), 3.57 (3H, s), 3.
90 (6H, s), 5.96 (1H, d, J = 1.5Hz),
5.98 (1H, d, J = 1.5Hz), 6.57 (1H,
s), 6.71 (1H, s), 6.75 (1H, s). IR (CHCl ₃ ) cm ^-1 : 2932, 1860, 159
6,1480,1454,1406,1146,1122,1
104. M S: 342 (M ⁺ , base)

Example 21 Diethyl = 5,6,7,8-tetrahydro-1,2,3-trimethoxy-10,11-methylenedioxydibenzo [a, c] cyclooctene-6,6-dicarboxylate Synthesis of: diethyl 4- (3,4-methylenedioxyphenyl) -1- (3,4,5-trimethoxyphenyl) butane-2,2-dicarboxylate (102 mg, 0.2
05mmol, ASKende and LSLiebeskind, J.Am.C
hem.Soc., 98 , 267 (1976)) in dichloromethane (3m
1), trifluoroacetic acid (0.3 ml) and iron perchlorate (210 mg, 0.45 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. It was dissolved in ethyl acetate (10 ml), washed with 2N hydrochloric acid water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a brown oily substance. Thin layer chromatography (silica gel, Merck # 5744, ethyl acetate-hexane 1:
3) and the title compound was obtained as a colorless oil (62 mg, 6
1%).

¹ H-NMR (CDCl ₃ ): 1.24 (3
H, t, J = 7Hz), 1.26 (3H, t, J = 7Hz),
2.61-2.75 (3H, m), 2.69 (1H, d, J =
14Hz), 3.25 (1H, d, J = 14Hz), 3.53
(3H, s), 3.83 (3H, s), 3.88 (3H, s),
4.06 (1H, dq, J = 11.7Hz), 4.14 (1
H, dq, J = 11.7Hz), 4.19 (1H, dq, J =
11,7Hz), 4.32 (1H, dq, J = 11,7H
z), 5.94 (1H, d, J = 1.5Hz), 5.97 (1
H, d, J = 1.5 Hz), 6.59 (1 H, s), 6.69
(1H, s), 6.72 (1H, s), 1.52-1.57
(1H, m). IRνmax (KBr) cm ⁻¹ : 2972, 1936, 1730, 1594, 1484, 12
44.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07C 41/18 C07C 41/18 43/205 7419-4H 43/205 D 43/23 7419-4H 43 / 23 C 69/618 9546-4H 69/618 C07D 307/93 C07D 307/93 498/04 108 498/04 108

Claims (1)

(57) [Claims] 1. The following general formula (II): (In the formula, R _{1 to} R ₈ represent a hydrogen atom, a hydroxy group, an alkoxy group or a benzyloxy group which may have a substituent, or two adjacent groups are combined to form an alkylenedioxy group. Represents an alkylene group which may be substituted with an alkoxycarbonyl group, an alkenylene group which may be substituted with an alkoxycarbonyl group, or a compound represented by the following formula: A compound represented by any of
General formula (I) characterized by reacting iron perchlorate in the presence of trifluoroacetic acid (In the formula, R _{1 to} R ₈ and A have the above-mentioned meanings) A method for producing a polycyclic compound.