JPS5940819B2 - Method for producing diterpene derivative compounds - Google Patents

Description

[Detailed description of the invention] The present invention General formula: / H3CO\CH3 (1) ゛、H (R1 represents a methoxycarbonyl group.

) is oxidized with ozone to cleave the aromatic ring, then treated with a catalytic reducing agent or zinc, and then treated with diazomethane to form a diselpene phenol derivative (1) of the formula 2., H (where R1 The present invention relates to a method for producing a diselpene derivative compound, which is characterized by obtaining a compound represented by (same as above).

The starting materials of the present invention can be derived from diselpene derivatives having an aromatic C ring, particularly more easily than 1-abietic acid.

1-Abietic acid has the following structural formula, [1st
Abstracts of the 9th Symposium on Flavor, Terpene and Essential Oil Chemistry, 149 pages, S. MurakOshietal. A
gr. BIO. Chem. 39, 1167. (1975
)] To convert 1-abietic acid (A) into these compounds, convert the aromatic C ring of dehydroabietic acid [B], which can be easily obtained from [A], in the (a) or (b) direction* It can be easily and inexpensively obtained as a main component of similar resins, and its structural formula including its three-dimensional structure has already been determined as described above, and its total synthesis has been achieved.

[W. H. Schulleretal: J. Am. Ch
em. SOc. , 83, 2563 (1961), E. W
enkertal: J. Am. Chem. SOc.
, 86, 2038 (1964)] Also, examples of compounds that are considered to be easily convertible from l-abietic acid [A] include skin fungi (e.g., TricOphytO
n. Cinnamolide (CinnamOllde) [C], which exhibits antifungal activity against MicrOspOrum);
DimethylSciadinOnate, which inhibits the growth of silkworm larvae
There is [D].

selective cleavage is required. On the other hand, it has been reported that a bicyclic compound [F] can be obtained by ozone oxidation of levopimaric acid (1ev0pimaricacid) [E], but according to this method, the raw material levopimaric acid [E] is difficult to obtain. Moreover, it has the disadvantage of poor ozone oxidation yield.

[S. W. Pelletier etal,. Chem.
Commun. , 1967, 96] According to the present invention, when the 12-hydroxy starting material is oxidized with ozone and treated with various reducing agents, the desired bicyclic ring is selectively cleaved in the (a) direction. are obtained, and these are
It can be an important synthetic intermediate in the conversion to the above-mentioned physiologically active substances.

The present invention will be explained in detail below.

> First, the diselpene phenol derivative represented by formula (1), which is the starting material of the present invention, can be easily obtained from l-abietic acid [A] according to the known method as follows, for example.

CR. C. Cambie&R. A. Franich,.
AUSt-J-Chem゜, 11, 117 (1971)
Reference] The thus obtained starting material, 12-hydroxy compound (1), is oxidized with ozone to cleave the aromatic ring, and then reduced using various reducing agents to obtain the desired product.

Ozone oxidation is carried out in a solvent, and the solvent used may be chloroform, methylene chloride, ethyl acetate, etc., but it is particularly advantageous to use CH2Cl2-CH3OH (1:1).

The amount of ozone used is preferably in large excess, and the reaction temperature is preferably in the range of -80°C to 0°C. As the reducing agent used, a catalytic reducing agent (10% Pd-C catalyst) or zinc is used.The reaction temperature and reaction time are respectively 0 to 30%.
C, 30 minutes to 12 hours is preferred.

As the solvent, those commonly used for reduction can be used, including CH2Cl2-MeOH. EtOH
-H2O, water, acetic acid, etc. are preferably used.

Next, an example of the present invention will be described as follows.

Examples of the compounds obtained by the method of the present invention are as follows.

The products were named according to the labdane (1aBdane) skeleton. 8-Oxo-(13→17)-pentanollabdan-12,18-dioic acid 12,1
8-dimethyl ester [8-0x0-(13→17)-PentanOrlabdan-12・18-DiOi
cAcidl2・18-DimethylEster]
(5).

EXAMPLES The present invention will be explained below with reference to Examples, but the present invention is not limited to these in any way. Example 1 Synthesis of compound (5) 12-0H form (C2lH3OO3-330) (1)5.
0007 (CH2Cl2:MeOH (1:1) 100m
1) was cooled with dry ice and acetone, ozone was blown into it for 3 hours, the temperature was returned to room temperature, 10% Pd-Cl7 was added, and the mixture was subjected to normal pressure catalytic reduction.

Catalytic reduction is carried out until hydrogen is no longer absorbed, and then passed through the mouth. After concentrating the oral fluid, ether is added to the residue, and the ether layer is extracted with 10% KOH. Alkaline layer is 10%H
Acidify with Cl solution and extract from chloroform. After washing the chloroform layer and ether layer with each saturated saline solution,
After dehydration and drying with Na2sO4, the respective solvents were distilled off.
After distilling off the solvent, the chloroform layer is further methylated by adding a diazomethane-ether solution, and then the ether is distilled off. Ether layer (neutral part) Oil 1.7547 GLC:4A1.5% 0V-17 Simalite (Shi
supported on malle), temperature 200°C TR-2.45,
2.3min There were many others, and I tried purification with silica gel chromatography, but it was not purified, and the chloroform layer (acidic part) :1.0517 (22%) of oil (5) was obtained from the eluate of 1, and 618 η (14%) of crystal (3) was obtained from the ether eluate.

(5): Recrystallized from n-hexane 835η colorless prismatic crystal Mp: 94.5~95℃ Elemental analysis (C, 7H26
(as O5) Theoretical value: C65.78H8.44 Actual value: C65.83H8.37KBr IR: ν Max l74Oll725, 1715? -1 NMR (CDCl3): δ 0.74S3H (10-M
e) 1,18S3H(4-Me) 3.62 }S. 3H (4-COOMe, 3.68 9-CH2COOMe) (3) Recrystallized from ethyl acetate-n-hexane Colorless needle crystals Mp: 187-19 'C elemental analysis (ClOH22O5
) Theoretical value C65.29H7.53 Actual value C65.5lH7.6lKBr IR: ν Max 34OOll75Oll7l6, 1645 礪-1 NMR (CDCl3) δ 1.23S3H (4-Me)
1.33S3H (10-Me) 3.67S3H (COOMe) 4.63-4.83 (4.73) Br. S. HWh/2
-5Hz (9-0H) 5.58SIH (11-H) . EtOH UV: λ 209 nm (ε=12348) Ma
x(4):(5) is levopimaric acid (1ev0pim
aricacid) to pelletizer one (Pelleti)
(mixing point:
94-95°C), there was no decrease in the melting point, and the IR. ．． G
LCl Hatake was in complete agreement.

Example 2 Synthesis of compound (5) 12-0H compound (1) 10007 (CH2Cl2:MeO
H (1:1) in 20ml) was cooled with dry ice-acetone, ozone was blown into it for 2 hours, the temperature was returned to room temperature, and acetic acid 20ml was added.
After adding 10 tons of zinc powder and stirring for 2 hours and 30 minutes, it was filtered.

Concentrate the filtrate, add water to the residue, and extract from ether. The ether layer was extracted with 10% KOH, and the alkali layer was extracted with 1
Acidify with 0% HCl and extract from chloroform. The chloroform layer and the ether layer are each washed with saturated brine, dehydrated and dried over Na2sO4, and then the solvent is distilled off. After the solvent is distilled off, the chloroform layer is methylated by adding a diazomethane-ether solution, and the ether is distilled off. Ether layer (neutral part) Oil 274m9 GLC: 4A1.5% O-17 simalite (Shim
Supported on alite), temperature 22'CtR=0.701
0.8013.8 minutes Chloroform layer (acidic part) Oily substance 702m9 GLC:4A1.5% 0V-17 Simalite (Shi
Supported on malle), temperature 220℃TR=0.85
, 2.05 minutes Reference: Standard TR-2.05 minutes Residue 702~ was subjected to column chromatography using silica gel 507, and from the eluate of petroleum ether ether 2:1 oil (5) 465η (50 %).

(5): Recrystallize from n-hexane to obtain colorless prism crystals 397~.

Even when mixed with the standard product (mixed melting point: 92-93.5°C), there was no drop in the melting point, and the IR. NMR. ．． GLC was in perfect agreement.

Claims (1)

[Claims] 1. General formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(1) The diterpene phenol derivative (1) represented by (R_1 represents a methoxycarbonyl group) is oxidized with ozone to open the aromatic ring, and then a catalytic reducing agent or A diterpene derivative compound characterized in that it is treated with zinc and then treated with diazomethane to obtain a compound represented by the formula: ▲Mathematical formula, chemical formula, table, etc.▼ (in the formula, R_1 is the same as above) Manufacturing method.