JPS5850224B2 - Method for producing sesquiterpene derivative compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula: (wherein R1 represents hydrogen or an isopropyl group, and R2 represents a methyl or methoxycarbonyl group.

) After ozone oxidation of the diterpene phenol derivative represented by the general formula: (However, R
2 represents a methyl or methoxycarbonyl group, and R3 represents hydrogen or a hydroxyl group.

) The present invention relates to a method for producing a sesquiterpene derivative compound, which is characterized by obtaining a Doliman-type compound represented by:

The diterpene phenol derivative as the starting material for the process of the present invention is a diterpene derivative having an aromatic C ring, especially l-
It can be derived more easily than 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,, 4th, 20
38 (1964)] Compounds that can be derived from l-abietic acid [A] include, for example, skin fungi (e.g., Tricophy
ton, Microsporum)
Quiterpene) CC] to CG] are known.

[C]: Confertifolin, CD): Isodorimenin, [E] Nitrimenin, [F]: Valdiviolide, [G]:
Winterin To convert [A,l] to the Drimane-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.

CE, Wenkert & D, P, 5tr
ike, J., Am.

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

Brieger, Tetrahedron Le
tters, 1965.4429, Y, Kitah
ara et al., Chem.

Comrnin,, 1969 3425ynthes
is1970.257, Bull, Chem, So
c, Japan, 43.1268 (1970), T
etrahedron Letters1971119
61, T etrahedron L etters
1972.4257, etc.] According to the method of the present invention, the 14-hydroxy compounds (1), (2), and (3), which are the starting materials, are oxidized with ozone and then treated with various types of reducing agents, thereby reducing the dremanization at once. The skeleton of type sesquiterpenes can be synthesized.

In particular, the 14-hydroxy-4-dimethyl compound (3) described below
Confertifolin [C] and paldiviolide CF] can be synthesized all at once.

Furthermore, winnarin [G] can also be easily synthesized by Jones oxidation of pardiviolide [F+.

In addition, from the 14-hydroxy-4-methyl-4-methoxycarbonyl compounds (1) and (2), compounds 4) and (5) and the maleic anhydride type derivative (7) described below can be obtained in the same manner. Since these compounds have the same skeleton as paldiviolide [F], confertifolin [C], and winchlin [G], respectively, they are expected to have physiological activities similar to the natural antifungal activity mentioned above. It is something.

The method of the present invention will be explained in detail below.

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

[A, Tahara and H, Akita
, Chem, Pharm, Bull (Tokyo
o) 23.1976 (1975), 23.198
4 (1975), the 96th Annual Meeting of the Pharmaceutical Society of Japan, 1976 Lecture Abstracts, Vol.
(2): Methyl 14-hydroxy diisopropyl dehydroabietate (Me
thy 14-hydroxy deisopro
pyldehydroabietate), (3)
: 14-hydroxy dehydroabietane (14-H
hydroxydehydroabietane).

The starting material thus obtained, 14-hydroxy form (1)
, (2) and (3) are oxidized with ozone to cleave the aromatic ring, and then treated with various reducing agents to obtain the target compound.

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 (l
:1) It is advantageous to use the 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-H
Advantageously, 2O, acetone, acetic acid, water and the like are used.

Among the above-mentioned reducing agents, for example, when 10% Pd-C1 sodium sulfite is used, a hydroxylactone is first obtained, but the compound is further converted to, for example, borohydride).
If treated with IJum, the lactone compound of the present invention can be obtained.

Furthermore, when boron hydride (IJ) is used, the lactone 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), was cooled in dry ice-acetone in CH2Cl2-CH30, with ozone bubbled into it, and the temperature was returned to room temperature, followed by 10% Pd-C.
and subjected to normal pressure catalytic reduction.

Catalytic reduction is carried out until no more hydrogen is absorbed.

After that, 1 hour passes.

After concentrating the P solution, ether was added to the residue, and the ether layer was diluted with
%KOf (extract in 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 (4).

Hydroxylactone compound (4) can also be obtained by performing the same reaction in the above method using sodium sulfite instead of 10% Pd-C as the reducing agent.

The obtained hydroxylactone body (4) was reduced to 50% (V/V
) Dissolved in EtOH-H20 solution and stirred with water cooling, NaB
Add H4 and stir.

Then add water and extract from ether.

The ether layer is washed with saturated brine, dehydrated and dried over Na2SO4, and the solvent is distilled off to obtain an oily lactone compound 5).

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 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 from the petroleum ether-ether eluate, an oily lactate 7goku 5) can be obtained.

This can be expressed in a diagram as follows.

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

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

■-Dihydroxyterim-8-ene 12-13-dioic acid 13 Methyl ester 1 1→ 12-lactone (11-Dihydroxy-dri
m -8en -12-13-dioicacid
13-Methyl Ester 11-sl
2-Lactone X4), 11-Hydrox
y -drim -8-en -12・13-dioi
c Ac1d 13-Methyl Ester 1
1-12-Lactone) (5), Valdiviolide (6), Confertifolin (Confertifolin) (
7).

Among these, (4) and (5) are new compounds.

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 14 0HCL (1) 2.009r (CH2C12
: MeOH (1:1 in 40 m) was cooled with dry ice-acetone, and ozone was blown into it for 3 hours, and the mixture was returned to room temperature, 10% Pd-C7001v was added, and the mixture was subjected to normal pressure catalytic reduction.

Catalytic reduction is carried out until no more hydrogen is 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 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.

Ether layer (neutral part) Oily substance 594■ GLC: 4A1.5%0V-17 Shimarite (Shim
supported on alite ), temperature 220°C tR = 3.8.4
．． 45 minutes and many others Chloroform layer (acidic part) Oily substance 1.243S' GLC:4A1.5%0v-17 Shimarite (Shim
alite), temperature 220°C tR=2.95.
1.05 minutes, others were subjected to column chromatography using 80 g of silica gel, and the ether eluate was recrystallized from ether-n-hexane to give colorless prism crystals (4) 2
Obtain 71 mg (15%).

(4): MP195-196 ゜ elemental analysis (as C16H2205) Theoretical value: C65, 29H7, 53 Actual measured values: C65, 37H7,41, KBR IR, ν 34301767.1705AX CRIL □ I NMR (CDC13, 100MHz): δ 1 .2
2 1.26 (() eachs, 3H4 1,261,30 Me, 10-Me 3.69 3 (): each s, 3H, COOMe 370 2 5.24 (each ε'・°・wife 屓 Loss 11- 0H 5,26DO) 6.12 (each br, s, IH11-H 6,16 Uv:, 2EtOH aX 208nm (e-21991) Example 2 14-OH(2) body 500112 & (CH2Cl2:M
eOH (1:1) in 101 nl) 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, H2O4
After stirring at room temperature for 2 hours, 10%
Acidify with 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 305', and the eluate of ether dipetroleum ether-1:1 was recrystallized from ether-n-hexane to give colorless prism crystals (4) 127■ (25 %).

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

Example 3 14-OH form (1) 1.44? (CH2C12:MeO
H (1:1) in 22.8 m7) was cooled with dry ice-acetone, ozone was blown into it for 2 hours, the temperature was returned to room temperature, and sodium sulfite aqueous solution (Na2SO34f?→H2
After adding O80rn0 and stirring at room temperature for 2 hours, 10% H
Acidify with CI 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 (952■) was subjected to column chromatography using silica gel 30f, and the ether eluate was recrystallized from ether-n hexane to give colorless prism crystals (4) 168% (16%
).

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

Example 4 I, R, Hydroxylactone (4) 179 (50% (VA')
) in 5 mJ of EtOH-H2O) to 50% (V/V) Et
Dissolved in OH-H20 solution and stirred with water cooling NaBH420
Add 0■ 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 ml of oil (5).

(5): Oily substance Elemental analysis (by high-resolution mass spectrometry).

As Cl5H2□04) Theoretical value: 278.1517 Actual value: 278.1514 *14
-OH form (1) 1.087 fl (CH2C12:
MeOH (1:1 in 22 mJ) was cooled with dry ice and acetone, ozone was blown in for 1 hour, the temperature was returned to room temperature, and N
aBH4 (8009) - 50% (V/V) EtOHH2
0 (10ml) 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 (787μ) was subjected to column chromatography using 50g of silica gel, and petroleum ether:ether-2:1
From the eluted portion, 446 cm (49%) of oil (5) was obtained.

This is the same as that obtained in Example 4, I, RIN, M,
R,, U, and V were completely consistent.

Example 6 14-OH body (2) 5007V (CH2C12:Me
Of ((1:1) in 10 ml) was cooled with dry ice-acetone, bubbled with ozone for 30 minutes, returned to room temperature, and cooled with N.
aBH4(400ral) -50%(V-V)Et
Add OH-H2O (5m7) 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 (3001n?) is subjected to column chromatography using silica gel 30P, and an oily substance 5) 233rn9 (48%) is obtained from the petroleum ether:ether-2:1 eluate.

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

Example 7 14-OH compound 3) 1.1021 was dissolved in 11 ml of methylene chloride
．． Dissolve in 11 mJ of methanol, and blow ozone into it for 70 minutes while cooling with dry ice acetone.

After that, the temperature was returned to room temperature and sodium sulfite aqueous solution (Na2
After stirring 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 to obtain 1.17Or of oil.

This was subjected to column chromatography using silica gel 100f, and the eluate of petroleum ether: ether = 1:1 was recrystallized from petroleum ether-ether to obtain 174 m9 of colorless prism crystals (6) (yield 18%). .

A part was further recrystallized from benzene and mp177-178
Obtain colorless prismatic crystals at °C.

(6):mp: 177-178℃ IR (CHCI3): 176s, 1678Crf1
'[Butenolide] (KB
r): 3360cI11' (11-OH) NMR
(1-0H)N 1 CDC13): δ0.94 s
6H(4-dimethyl)1.27s 3H(1
0-Me) 5.02 br, s IHWh/2=14Hz
(11-OH') 6.14 br, s IH(11-H) (6)
is a natural valdiviolide
) and mp (standard melting point 177 NMR) matched.

Example 8 178℃), IR.

Hydroxylactone (6) 1501n9 (50% (V/
V) EtOH-H205wLl) at 50% (V/V)
Dissolve in EtOHI20 solution and add NaBH,2 under stirring with water cooling.
Add 00m9 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 oil (7) 84WI9.

(7):mp: 153~153.5゜IR (CC
I4): 1769.1680crrL-1 [butenolide]
☆(7) is natural confertifoline (Confer
Tifol in and mp (Mixed melting point: 152-15
3°), IRlNMR, and GLC were all consistent.

Example (9) ) (3) 953■ is dissolved in 10 ml of methylene chloride and 10 ml of methanol, and ozone is blown into the solution for 50 minutes while cooling with dry ice-acetone.

After that, NaBH4800m&-50%(
V/V) Add EtOHI20 (10ml) solution
Stir for 0 minutes.

After the reaction is completed, water is added and extracted from ether.

The ether layer was washed with saturated brine, dehydrated and dried over Na2SO4, and the ether was distilled off to obtain oil 9741n9.

This was recrystallized from n-hexane and colorless prism crystals (7
) 339■ (yield 46%) was obtained.

(7):mp: 153~153.5゜IR (CC
I4): 1769.1680cIrL-1 [butenolide] NMR (100MHz, CDC13): 4.66-4.76 m, 2H(9-CH20
-> (7) is natural confertifoline (Confertif)
olin) and mp (Mixed melting point: 152-153°
), IR.

NMR and GLC were completely consistent.

Claims (1)

[Scope of Claims] (However, R1 represents hydrogen or an isopropyl group, and R2 represents a methyl or methoxycarbonyl group.) After ozone oxidation of the diterpene phenol derivative represented by the formula, a reducing agent treatment is performed to obtain the general formula: ( However, R
2 represents a methyl or methoxycarbonyl group, and R3 represents hydrogen or a hydroxyl group. ) A method for producing a sesquiterpene derivative compound, which is characterized by obtaining a Doliman-type compound represented by