JPS5850223B2 - 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.

■-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 above. and its total synthesis has also been achieved.

C.W., H., Chuller et al: J.
Am, Chem, S oc,, 4th, 2563 (
1961), E. Wenkert et al;
J, Am, Chem, Soc, 4th edition, 2038
(1964)] *Compounds that can be derived from ■-abietic acid [IA] include, for example, skin fungi (e.g., Tricophyton, Mic
Drimane types sesquiterpenes, including cinnamoride CB), which exhibits antifungal activity against
e) CC) to CG) are known.

[゛C]: Confertifoliin, [D]: Isodrimenin, [E] Nitrimenin, [F]: Paldiviolide, [G] :Winterin ) The target compound of the present invention is the above pardiviolide [F)
It has the same skeleton as winchrin [G], and can be easily led to a compound with the same skeleton as winchrin [G] by Jones oxidation as described below.

Since these compounds have the same skeleton as the above-mentioned compounds having natural antifungal activity, they are expected to have similar physiological activities.

[To convert from 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.

C.E., Wenkert & D., P., Strik.
e, J, Am.

Chem, Soc, 86.2044 (1964),
G.

Brieger, Tetrahedron Lette
rs, 1965.4429, Y, Kitahar
a et al., Chem.

Co mmun,, 1969 3425ynthe
sis1970.257, Bull, Chem,
Soc, Japan, 43.1268 (19
70), Tetrahedron Letters 1
971.1961. Tetrahedron Let
ters 1972.4257, 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.

CA, Tahara and H, Akita
, Chem. Pharm, Bull (Tokyo
) 23.1976 (1975), 23.1984
(1975), the 96th Annual Meeting of the Pharmaceutical Society of Japan, 1976 Lecture Abstracts Volume ■, etc.] (1): Methyl 14-hydroxy dehydroabietate
ydroabi etate'.

(2) Dimethyl 14-hydroxy diisopropyl dehydroabietate (Methyl 14-hydro
xydei 5opropyl dehydroabi
etate).

The starting material thus obtained, 14-hydroxy form (1)
Alternatively, (2) can be oxidized with ozone to cleave the aromatic ring, and then treated with various reducing agents to obtain the target compound of the present invention.

This reaction is preferably carried out in a solvent, and the solvent used for this removal can be chloroform, methylene chloride, ethyl acetate, etc., but in particular CH2Cl2CH3on
It is advantageous to use the (1: i ) 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
d-C catalyst), sodium sulfite, etc. are most suitable.

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-CH30H1EtOH-H2
Advantageously, O, acetone, acetic acid, water and the like are used.

That is, if the starting material is oxidized with ozone and then treated with various reducing agents, the skeleton of the Doliman-type sesquiterpene can be completely destroyed 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 CH2Cl2-CH30H, ozone was blown into it, the temperature was returned to room temperature, and 10%
Pd-C is added and subjected to atmospheric pressure catalytic reduction.

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

After concentrating the p-liquid, 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-O-hexane to obtain the hydroxylactone compound (3) of the present invention.

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

This is illustrated in the figure below.

The name of the compound (3) of the present invention is as follows.

11-dihydroxy-trim-8-ene-12,13-
Diic acid 13-methyl ester 11→12-lactone (11-Dihydroxy-drim-8en-
12・13-dioic Acid 13-Methyl
Ester 111→12-Lactone) Furthermore,
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 this in any way.

The present invention *Example 14-OHHI32.009f (CH2C12:MeO
H (1:1) in 407FL) was cooled with dry ice-acetone, ozone was blown into it for 3 hours, and the temperature was returned to room temperature for 10 minutes.
700 mg of %Pd-C is added and subjected to atmospheric pressure catalytic reduction.

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

After concentrating the liquid, add ether to the residue and dilute the ether layer with 1
Extract with 0% KOH solution.

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

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

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) Oily substance 594■ GLC:4A 1.5%0V-17 simalite (Sh
Supported on imalite), temperature 220°C tR = 3.8
．． 4.45 minutes Many others Chloroform layer (acidic part) Oily substance 1.2431 GLC:4A 1.5%0V-17 simalite (Sh
supported on imalite), temperature 220'C* tR=2.95.1.05 min, and other silica gel s
The resulting product was subjected to column chromatography using Oy, and the ether eluate was recrystallized from ether-n-hexane to obtain colorless prism crystals (3), 271 .mu.m (15%).

(3): mp 195-196° Elemental analysis (as C16H2205) Theoretical value: C65,29n 7.53 Actual value: C65,37H7,41, KBr IR, v 343011767.1705Crr
L-1aX NMR (CDC13, 100MHz): δ 1.2
2 1.26 each, 3H4-Me.

(() 1.26 1.30 10-Me 3.693 (: each s, 3 H, COOMe 3.70 2 (5°24 each 5'・°・IHII-OH5,26(D
, 0) 6.12 (Each br, s, IH11-H 6,16 tOH UV: λ 208 nm (ε-21991) aX Example 2 14-OH form (1) 1.44F (CH2C1□:MeO
H (1:1) in 22.8 mJ) with dry ice
While cooling with acetone, ozone was blown in for 2 hours, the temperature was returned to room temperature, and sodium sulfite aqueous solution (Na28034?→H2O
After stirring at room temperature for 2 hours, 10%
Acidify with HCl 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 (9521rI9) was subjected to column chromatography using silica gel 301, and the ether eluate was purified with ether-n-
Colorless prism crystal (3) recrystallized from hexane 16.8
rru? (16%).

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

Example 3 I, R,, 14-OH body (2) 500mlli' (CH2Cl
2:MeOH (1:1 in 1017LAi) was cooled with dry ice-acetone, ozone was blown into it for 2 hours, the temperature was returned to room temperature, and a sodium sulfite aqueous solution (Na2So32P
, in 40 ml of H2O) and stirred at room temperature for 2 hours.
Acidify with 10% HCI 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 (484) was subjected to column chromatography using silica gel 301, and the eluate of ether dipetroleum ether-1:1 was recrystallized from ether-n-hexane to give colorless prism crystals (4), 127 mp (25%). get.

This is the same as that obtained in Example 1, I, R,, N, M,
R,, U, V, are all (matched).

Claims (1)

[Claims] A sesquiterpene derivative compound represented by