JPS5920672B2 - Method for producing sesquiterpene derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula: [wherein R1 and R2 represent CH3 or COOCH3].

] is used as a starting material, this is oxidized with ozone to cleave the aromatic ring, and treated with a reducing agent to obtain the general formula: [wherein R, and R2 are the same as above.

] was obtained and treated with an aluminum hydride compound to obtain a compound represented by the general formula: [wherein R, and R2 are the same as above.

The present invention relates to a method for producing a sesquiterpene derivative, which is characterized by obtaining a compound represented by the following. The starting materials used in the process of the invention are various diselpene derivatives, especially l
- Can be easily derived from abietic acid. L-Abietic acid (1) is easily and inexpensively available as the main component of pine resin, and its structural formula including its three-dimensional structure has already been determined, and its total synthesis has also been achieved. [W. H. Shulleretal: J. Am. C
hem. SOc. , 83, 2563 (1961), E.
Wenkertetal: J. Am. Chem. SOc
．． , 86, 2O38 (1964), etc. ] The target compound obtained in the present invention, such as [(-)-Pallescensin A]AlR,2CH3,R22CH3, has been isolated from a sponge [G
．． CiminOetalTetrahedrOnLet
ters, 1975, 1425], and the intermediate products, butenolides (9), are expected to have physiological activity.

Since the above-mentioned Pallescensin A), that is, the target compound al of the present invention exhibits a feeding inhibitory effect, it is expected to be used as a feeding inhibitor against pests.

On the other hand, as a method for deriving the compound aω from other raw materials, there are, for example, the following methods.

[T. Matsum10t0eta1. Chemist
See ry Letters, 1978, 105. However, the above method has the disadvantage that the yield is low and that it is obtained as a racemate, which requires optical resolution.

In addition, there is a drawback that only trace amounts can be isolated from natural seaweeds.In contrast, according to the present invention, the 13-hydroxy form (1), which can be easily derived from l-abietic acid (1), is
Using 7) and (8) as starting materials, the target product can be easily obtained directly from them without optical resolution.
First, the 13-hydroxy derivatives (e.g. (7), (8)) which are the starting materials of the present invention are derived from devidroabietic acid (2), which can be easily obtained from l-abietic acid (1') by the following method. can be obtained as a starting material.

[In the case of 4β-methyl-4α monoester (8): see Japanese Patent Publication No. 51-21982] 4,4-dimethyl compound (
In the case of the 13-hydroxy compound (7), which is the starting material of the present invention, first obtain the 7-oxo-13-amino compound (3) from (1), and then use the following method to obtain the 13-hydroxy compound (7), which is the starting material of the present invention.
Dissolve 3-amino-J me[oxo compound (3) in methanol under stirring under ice-cooling (0 to 5°C), and add concentrated sulfuric acid until the internal temperature reaches 5.
After the temperature drops below 0.degree. C., add NaNO, and stir to return to room temperature.

Thereafter, a small amount of urea is added and after further stirring, methanol is distilled off to the i-position on a water bath. Add water to the residue and extract from benzene. The benzene layer was washed with saturated Na2cO3 solution and saturated brine, dehydrated and dried over Na, sO4, and the solvent was distilled off to obtain an oily substance. This was subjected to column chromatography using silica gel, and from the eluate of petroleum ether ether = 19:1, a single oily 7-oxo compound (6) (yield: 22%
) and a single oily substance 13-methoxy J me[oxo form (4)
(yield: 28%). Also, petroleum ether ether =
Crystals of 13-hydroxy-J were obtained from the eluate of 3:1 to 2:1.
Me[oxo compound (5) (yield: 14%) is obtained. This is n
Recrystallize from -hexane-ethyl acetate to obtain pale yellow brism crystals. In addition, the above 13-methoxy J me [oxo form (4)
Demethylation of 13-hydroxy-J me[oxo form (
5) can be obtained. That is, 13-methoxy
J me[oxo form (4) in acetic acid solution, Hl-47% HBr
and stir under reflux under a stream of N. After the reaction is completed, the solvent is distilled off under reduced pressure, water is added to the residue, and the mixture is extracted from ether. ether layer saturated Na2s2O, solution, saturated Na2cO,
The solution was washed successively with a saturated saline solution, dehydrated and dried over Na and sO4, and the solvent was distilled off to obtain an oily substance. This was recrystallized from n-hexane-ethyl acetate to form crystals of 13-hydroxy
[Oxo compound (5) (yield: 49%) is obtained. Obtained 1
3-Hydroxy-J me[oxo compound (5) was converted into ethyl acetate 50
d, add a trace amount of 10% Pd-Cl6O% HCl1O4, and subject to normal pressure catalytic reduction.

After hydrogen absorption, the catalyst is separated, the bottom liquid is concentrated, water is added to the residue, and the mixture is extracted from ether. Saturate the ether layer with Na2c
After washing with O, solution and saturated saline, the mixture is dehydrated and dried over Na2sO4 and the solvent is distilled off to quantitatively obtain the 13-hydroxy form (7) of an oily substance, which is the starting material of the present invention. This is n-
Recrystallization from hexane gives colorless needles. In addition, 13-methoxy J me[o-isomer (4) is H2/Pd-C, 6O%
reduced using HClO4 and then HI-47(!)H
The 13-hydroxy form can also be obtained by demethylation using Br. The 13-hydroxy compounds (7) and (8) thus obtained are used as starting materials to lead to the target compound, for example, by the following reaction. The present invention will be explained below. The 13-hydroxy compound (7) or (8) is oxidized with ozone to open the aromatic ring, and then treated with a reducing agent to obtain the lactone compound (9).

This ozone oxidation reaction is carried out in a solvent such as methylene chloride-methanol, chloroform, methylene chloride, ethyl acetate, etc. The amount of ozone used is preferably in large excess so that the reaction proceeds sufficiently, and the reaction temperature is -80°C. A range of 0°C to 0°C is suitable. As a reducing agent, in addition to NaBH4,
For example, 10% Pd-c catalyst, Zn-CH3COOHlN
a2SO3(CH3)2S etc. can be used, but NaBH4
is optimal. Reaction temperature and reaction time are 0 to 30, respectively.
°C for about 15 minutes to 12 hours. Solvents can be used in ordinary reduction reactions, but C}{2C12-methanol,
It is preferable to use ethanol, water, etc. After treating the obtained lactone compound (9) with an aluminum hydride compound,
Acidification with 10% sulfuric acid yields the target compound.

As the aluminum hydrogen compound, diisobutylaluminum hydride [HAI(1-Bu)2] is most suitable, and the reaction is carried out in a solvent such as anhydrous tetrahydrofuran, toluene, bezene or the like.

Reaction time and reaction temperature were 1 to 4 hours, -70-0, respectively.
°C is appropriate. Next, the present invention will be explained by giving specific examples.

13-hydroxy compound (7) or (8) in methylene chloride-
Dissolved in methanol and cooled with dry ice-acetone.
Inject ozone.

Thereafter, the temperature was returned to room temperature, and NaBH4-50% (v/v) ethanol and water were added and stirred. After the reaction is completed, water is added and extracted from ether. The aqueous layer is acidified with 10% HCI solution and then extracted from chloroform. The ether layer (neutral part) and the chloroform layer (acidic part) are each washed with saturated saline, dehydrated and dried over Na2sO4, and the solvent is distilled off to obtain an oily substance from each.〇These are combined together and subjected to silica gel column chromatography. .

A single oily lactone form (9) is obtained from the eluate of petroleum ether ether = 2:1 to 1:1.Next, under cooling with a cryogen (-25 to -20°C), the lactone form (9) is obtained. A small amount of diisobutylaluminum hydride (20%, 95% liquid in hexane) is added to a solution of anhydrous tetrahydrofuran under a nitrogen stream, and after stirring, a small amount of 10% H2SO4 solution is added and further stirred.

Add water to the reaction solution and extract from ether. The ether layer was washed with saturated Na2cO3 solution, saturated brine, then Na
After dehydration and drying with 2sO4, the solvent is distilled off to obtain an oil. This is subjected to silica gel column chromatography, and the target furan compound (self) is obtained as a single colorless oil from the n-hexane eluate. Example 1 Compound (8) 1,0009 was dissolved in CH2Cl2 (10ml)
- Dissolve in methanol (10ml) and blow ozone into it for 1 hour while cooling with dry ice-acetone.

After that, return to room temperature and add NaBH4 (800~)-50
Add % (v/v) ethanol and water (10 wL1) and stir at room temperature for 30 minutes. After the reaction is complete, add water and extract from ether. The aqueous layer is acidified with 10% hydrochloric acid solution and then extracted from chloroform. The ether layer (neutral part) and chloroform layer (acidic part) were washed with each saturated saline solution, and N
After dehydration and drying with a2sO4, the solvent was distilled off to obtain an oily substance from each. These are combined together and subjected to column chromatography using silica gel 909. petroleum ether ether=
A single oil (9) (R1
=CH3, R2=COOCH3)269TI9 (yield:
28%).

[Physical properties of (9) (R1=CH3, R22COOCH3)] Example 2 Using compound (7) 1.7779, reaction, washing, drying, and solvent distillation were carried out in the same manner as in Example 1. Obtain oily substances from the acidic part and the acidic part, respectively.

These are combined together and subjected to column chromatography using silica gel 1609.

Crystals (
9) (R,=CH3, R2=CH3)・371W1y(
Yield: 22%). This is further recrystallized from n-hexane to obtain colorless prism crystals. Example Under cooling with cryogen (-25 to -20°C) Compound (9) R1=C
H3, R2=CH382! Diisobutylaluminum hydride [HAII(1-Bu)2] (2096 mL in hexane) was added to a solution of anhydrous tetrahydrofuran (2 ml).
, 95% liquid) was added under nitrogen flow, and after stirring for 3 hours, 2 ml of 10% H2SO4 solution was added, and
Stir for a minute.

Add water to the reaction solution and extract from the ether. The ether layer is washed with saturated sodium carbonate solution and saturated brine, dehydrated and dried over sodium sulfate, and the solvent is distilled off to obtain oily substance 74. This was subjected to column chromatography using silica gel 159, and a single colorless oil Q was obtained from the n-hexane eluate.
I(R,=CH.

,R,=CH. ) 38~ (yield: 50%) is obtained. [
Physical properties of a-cut (R, diCH3, R2diCH,) Elemental analysis: Mass spectrum as C,,H22O M=218 N. M. R(CCl4):ζ0.93S6H(4-Ge
mCH3), 60MHz1.18S3H (10-CH3
) 5.97dJ22HzIH (14-H) 705dJ=2HzIH (13-H) MeOH U. V. :λ 220nm (10gε=3,7096)
MaX Specific rotation: [α]D+ 60.4° (CHCl3, C20.9) Mamas vector, N. M. R. was completely consistent with the natural product.

Claims (1)

[Claims] 1 General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [However, in the formula, R_1 and R_2 are CH_3 or COOC
Represents H_3. ] is used as a starting material, it is oxidized with ozone to cleave the aromatic ring, and treated with a reducing agent to form the general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [However, in the formula, R_1, R_2 is the same as above. ] is obtained and treated with an aluminum hydride compound to obtain the general formula: ▲ Numerical formula, chemical formula, table, etc. ▼ [However, in the formula, R_1 and R_3 are the same as above. ] A method for producing a sesquiterpene derivative, characterized by obtaining a compound represented by the following.