JPS5850222B2 - Sesquiterpene derivative compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel sesquiterpene derivative compound represented by the structural formula:

The compound of the present invention can be obtained by the following method.

The starting diterpene phenol derivative has the general formula: (However, in the formula, R represents hydrogen or an isopropyl group.

), and can be easily derived from diterpene derivatives having an aromatic C ring, especially l-abietic acid.

l-Abietic acid has the following structural formula and can be easily and inexpensively obtained as the main component of phase detection resins, and the structural formula including its three-dimensional structure has already been determined as described above. and its total synthesis has also been achieved.

(W, H, 5chuller et al: J
. Am, Chem, Soc ++, 83.2563 (
1961), E. Wenkert et al.
J,Am,Chem,Soc,,86.2038
(1964)] ☆ In addition, compounds that can be derived from l-abietic acid (A) include, for example, skin fungi (such as Tricophy
ton, Microsporum), including cinnamoride [B], which exhibits antifungal activity against drimane types
Quiterpene) (C) to (G) are known.

(C): Confertifolln, [D]: Isodrimenin, [E] Nitrimenin, [F]: Valdiviolide, [G]: Wint erin) book The object compound of the invention is the above-mentioned Confertifolin [
Since it has the same skeleton as C], it is expected to have the same physiological activity as the natural antifungal activity mentioned above.

In order to convert (A) to the Doliman-type sesquiterpene group, it is necessary to cleave the aromatic C ring of dehydroabietic acid, which is easily obtained from (A), in the (a) direction.

On the other hand, some of the compounds of the Drimane-type sesquiterpene group have been completely synthesized, but the synthesis process is long and
At present, the yield is also poor.

(E, Wenkert & D, P, 5trike
, J., Am.

Chem, Soc, 86.2044 (1964), G.
.

Brieger, Tetrahedron Let
ters 11965.4429, Y, Kitahar
a et al., Chem.

Commun,, 1969 342Synthesis
1970°257, Bull, Chem, Soc
, Japan, , 43.1268 (1970),
Tetrahedron Letters1971.1
961, Tetrahedron Letters1
972.4257, etc.] The method of the present invention will be described in detail below.

First, the diterpene-based phenol derivative as the starting material of the present invention can be easily obtained from l-abietic acid [A] according to the following known method, for example.

(A, Tahara and H, Akita,
Chem. Pharm, Bull (Tokyo
) 23.1976 (1975), 23.1984 (
(1): Methyl 14'-hydroxydeh
(2): Methyl 14-hyd
roxydeisopropyl dehydroa
bietate) The starting material thus obtained, 14-
The target compound of the present invention can be obtained by subjecting the hydroxy compound (1) and 2) to ozone oxidation to cleave the aromatic ring and then treating it with various reducing agents.

This reaction is preferably carried out in a solvent, and the solvent to be removed can be chloroform, methylene chloride, ethyl acetate, etc., but in particular CH2Cl2-CH30H (
It is advantageous to use a 1:1) system.

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.

In addition, as a reducing agent used for reduction, catalytic reduction (10% P
dC catalyst), sodium borohydride, sodium sulfite, zinc-acetic acid, dimethyl sulfide, and the like.

The reaction temperature and reaction time were 0°C to 30°C and 30°C, respectively.
Minutes to 12 hours are preferred.

As the solvent, those normally used for reduction can be used, but CH2Cl2-CH30H, EtOH-H2
Advantageously, O, acetone, acetic acid, water and the like are used.

Among the above reducing agents, for example, when using 10% Pd-C1 sodium sulfite, first the hydroxylactone form 3)
However, if the compound is further treated with, for example, sodium borohydride, the lactone compound (4), which is the compound of the present invention, can be obtained.

Moreover, when sodium borohydride is used, the lactone compound (4) of the present invention can be obtained all at once.

Next, a specific example of the above synthesis method will be explained as follows.

That is, the starting material 14-hydroxy compound (1) or (2) was cooled in dry ice acetone in CH2Cl□-CH30H, ozone was blown into it, the temperature was returned to room temperature, and the concentration was reduced to 10%.
Pd-C is added and subjected to atmospheric pressure catalytic reduction.

Catalytic reduction is carried out until hydrogen is no longer absorbed, and then
Filter.

After concentrating solution F, ether was added to the residue, and the ether layer was diluted with
% KOH solution.

The alkaline layer is acidified with 10% HCI solution and extracted from chloroform.

The chloroform layer and the ether layer were each washed with saturated brine, dehydrated and dried over Na2SO4, and the solvent was 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.

The obtained oil is subjected to silica gel column chromatography, and the ether eluate is recrystallized from ether-n-hexane to obtain hydroxylactone compound (3).

In the above method, hydroxylactone compound 3) can also be obtained by performing the same reaction using sodium sulfite instead of 10% Pd-C as the reducing agent.

The obtained hydroxylactone body (3) was reduced to 50% (V/V
) E t Dissolved in OHH20 solution and stirred under water cooling.
Add NaBH4 and stir.

Then add water and extract from ether.

The ether layer was washed with saturated brine, dehydrated and dried over Na25O, and the solvent was distilled off to obtain an oily lactone (4).

Further, the starting material 14-hydroxy compound 1) was cooled with dry ice-acetone, blown with ozone, returned to room temperature, and NaBH4-50% (v/V) EtOH20 was added thereto and stirred.

Then add water and extract from ether.

After washing with ether saturated brine, dehydration and drying over Na2SO4 were carried out, and the solvent was distilled off.

The residue is subjected to silica gel column chromatography, and an oily lactone (4) can be obtained from the petroleum ether-ether eluate.

This can be expressed in a diagram as follows.

The name of the compound aflA4) of the present invention is as follows.

11-Hydroxy-trim-8-en-12,13-dioic acid 13-methyl ester 11→12-lactone (11-Hydroxy-drim-8-en-
12・13-dioic Ac1d 13-Meth
ylEsterll→12-Lactone).

The products were named according to the Doliman-type skeleton.

The present invention will be explained below with reference to Examples. It is not limited to these in any way.

Example 1 In the present invention, 14-OH substance (1) 2.0091 (in 40 m of CH2C12:MeOH (1:1)) was cooled with dry ice-acetone, ozone was blown into it for 3 hours, and the mixture was returned to room temperature and 10% Pd- Add C700■ and subject to normal pressure catalytic reduction.

Catalytic reduction is carried out until hydrogen is no longer absorbed, and then
1 pass.

After concentrating solution F, ether was added to the residue, and the ether layer was diluted with 1
Extract with 0% KOH solution.

The alkaline layer is acidified with 10% HCI solution and extracted from chloroform.

The chloroform layer and the ether layer were each washed with saturated brine, dehydrated and dried over Na2SO4, and the 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 594m9 GLC:4A 1.5% 0V-17, Simalite (
Supported on Shimalite), temperature 220℃ jR = 3.8.4.45 minutes and many others Chloroform layer (acidic part) Oily substance 1.243r GLC: 4A 1.5% 0V-17 Shimalite (
Supported on Shimalite), temperature 220°C tR = 2.95.1.05 minutes, others available Silica gel 8
The product was subjected to column chromatography using 0P, and the ether eluate was recrystallized from ether-n-hexane to obtain colorless Prism 3) 271 (15%).

(3): mp 195-196° Elemental analysis (as C16H2205) Theoretical value: C65,29R7,53 ☆ 14-OHHI31.44 S' (CH2C12:
MeOH (1:1) in 22.8 ml) on dry ice.
While cooling with acetone, ozone was blown in for 2 hours, the temperature was returned to room temperature, and a sodium sulfite aqueous solution (Na25o34?→H2
Add O80m and stir at room temperature for 2 hours, then add 10% MC.
Acidify with I and extract from chloroform.

After washing the chloroform layer with saturated saline, Na 2 SO
4 to remove the solvent.

The residue (952cm) was subjected to column chromatography using silica gel 30P, and the ether eluate was recrystallized from ether-n-hexane to give colorless prism crystals (3), 168m9 (1
6%).

This is the same as that obtained in Example 1, I, R1, N, M,
R, U, and V completely matched.

Example 3 14-OH body 2) 5007V (CH2C12:MeOH
(1:1) in 10TLl) was cooled with dry ice-acetone and ozone was blown into it for 2 hours, and the temperature was returned to room temperature.
After stirring at room temperature for 2 hours, add 10% HCl
acidify and extract from chloroform.

The chloroform layer was washed with saturated brine, dehydrated and dried over Na2SO4, and the solvent was distilled off.

The residue (484Tn9) was subjected to column chromatography using silica gel 301, and ether: petroleum ether - 1:10
The eluate was recrystallized from ether-n-hexane to obtain colorless prism crystals (4) 1271v (25%).

This is the same as that obtained in Example 1 and 1. Ro, N, M,
R,, U, and V completely matched.

Example 4 Hydroxylactone (3) 17911I9 (50% V/
V) EtOH-H2O in 5 ml) at 50% (V/V) E
Dissolved in tOH-H2O solution and stirred with water cooling NaBH42
Add 001FM& and stir for 30 minutes.

Then add water and extract from ether.

The ether layer was washed with saturated brine, dehydrated and dried over Na2SO4, and the solvent was distilled off to obtain 100 g of oil (4).

(4) Two oily substances Elemental analysis (by high-resolution mass spectrometry).

(as C15H2204) 14-OH form (1) 1.087? (CH2Cl2
: MeOH (1:1) in 22 ml) under cooling with acetone, ozone was blown into the mixture for 1 hour, the temperature was returned to room temperature, and NaBH4 (8001Q) -50% (V/V)
Add EtOH-H2O (10ml1) solution and stir for 30 minutes.

Then add water and extract from ether.

The ether layer was washed with saturated brine, dehydrated and dried over Na25O, and the solvent was distilled off.

The residue (787rrI9) was subjected to column chromatography using silica gel 50P, petroleum ether: needle=
The 2:1 eluate yields an oil 4) 446 .mu.m (49%).

This is the same as that obtained in Example 4 and 1. R,,N,M,
R, completely matched.

Example 6 14-OH compound 2) 500■ (in 10 ml of CH2C12:MeOH (1:1)) was cooled with dry ice-acetone, ozone was blown into it for 30 minutes, the temperature was returned to room temperature, and NaBH4 (4001n9)-50
% (v/v) EtOH-H2O (5 rul) solution and stir for 30 minutes.

Then add water and extract from ether.

The ether layer was washed with saturated brine, dehydrated and dried over Na2SO4, and the solvent was distilled off.

The residue (300 μm) was subjected to column chromatography using silica gel 30f, and oily ajlA4) 233TI9 (48%) was obtained from the eluate of petroleum ether:ether=2:1.

This is the same as that obtained in Example 4 and I,R,,N,1M
, R, were completely consistent.

Claims (1)

[Claims] A sesquiterpene derivative compound represented by