JPS5842876B2 - Method for producing sesquiterpene compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a sesquiterpene compound represented by the structural formula: which comprises treating the compound represented by the structural formula with an alkali and then with an acid.

The compound obtained according to the present invention is an important intermediate in the synthesis of the natural substance cinnamoamolide.

That is, cinnamosmolide can be easily obtained by acetylating the compound obtained by the present invention (L, Canonica et al.
, ,☆☆T etrahedron 25, see A)].

3895 (1969) (Reference) Cinnamosmolide is isolated as a natural substance as an extract component from the African plant Cinnamosma, and its structural formula has also been determined.

Extracts of these plants exhibit antifungal activity against skin fungi, such as Tricophyton and Microsporum, and cinnamosmolide is one of their active ingredients ( (See document A).

The present inventors took the opportunity of determining the structure of the above-mentioned natural substance to conduct intensive research on the production of the substance by a synthetic method. As a result, using 8-hydroxymethyl carbonate (1) derived from indomenine as a starting material, the present inventors obtained Cinnamos. The present invention was completed in the process of total synthesis of molide.

First, the above 8-hydroxymethyl carbonate (1)
is a novel compound synthesized for the first time by the present inventors, for example, isotrimenin (J.

Chem Soc, P, 4685 (1960)] by the following process.

In addition, the above-mentioned isotrimenine is l-
As a sesquiterpene derivative derived from abietic acid, total synthesis has already been achieved and it is easily available [see JP-A-53-124256].

The inventors of the present application have also achieved the ability to synthesize isotrimenine from easily available β-ionone (β-1onqne) in an extremely short process.
(See specification No. 359).

The 8-hydroxymethyl carbonate can be converted to carboxylic acid (7), the starting material of the present invention, through the following steps.

That is, 8-hydroxymethyl carbonate (1)
is first reacted with β·β·β-trichloroethoxycarbonyl chloride to obtain trichloroethoxycarbonyl compound 2) in a good yield.

The obtained trichloroethoxycarbonyl compound (2) is reacted with an oxidizing agent to obtain an enone compound (3).

The obtained enone form 3) can be reacted with a reducing reagent in an organic solvent to lead to the 6-hydroxy form 4).

By reacting the obtained 6-hydroxy compound 4) with an acetylating agent in a solvent, 6-acetoxy compound 5) can be obtained in high yield.

The obtained 6-acetoxy compound is treated with zinc in a solvent to remove trichlorethoxycarbonylation, thereby quantitatively obtaining alcohol compound (6).

When the obtained alcohol example 6) is sufficiently reacted with an oxidizing agent, carboxylic acid 1 can be obtained almost quantitatively.

Using the thus obtained carboxylic acid 7) as a starting material, it is treated with an alkali and then with an acid to obtain the desired 6β-hydroxylactone 8).

As the alkali in this case, sodium hydroxide, potassium hydroxide, etc. can be used, and as the solvent, a mixed solvent of ethers such as dioxane, tetrahydrofuran, and water can be used. Good results are obtained with sodium.

Although the reaction temperature and reaction time are not particularly limited, the reaction proceeds sufficiently at room temperature and about 1 to 3 hours, respectively.

After the reaction is carried out under the above-mentioned alkaline conditions, an acid treatment is carried out, and when diluted hydrochloric acid is used under water cooling, the reaction sufficiently proceeds in about 10 to 30 minutes.

The present invention will be specifically explained below using reference examples and examples.

In addition, compounds *2), (3), (4), (5), (6),
(7) are all new compounds.

Reference example 1 (1) 280m? (1,00 mmol) was dissolved in lOmJ of ether, 2d of pyridine was added, and β and β were added under water cooling.
・β-Trichloroethoxycarbonyl chloride 268
Add pi (2,00 mmol) dropwise.

After dropping, return to room temperature and stir for 1 hour, then extrude with ether and add H2O.
, washed with 5% HC1 aqueous solution and saturated saline, anhydrous MgS
After drying with O4, the solvent was distilled off, and the residue was subjected to silica gel column chromatography to obtain 439 square crystals of (2) (96% yield) from the hexane-ethyl acetate (3:1) eluate.

[Physical properties of (2)] mp: 121-122°C (ether to plate crystal) Elemental analysis: Calculated values C: 50.07, H: 5.53, C1: 23.
34 Actual measurement values C: 50.08, H: 5.53, C1: 23.
29 IR (CuCl2): 1790.1760crrL'
NMR (100MHz, CDCl5): .

, 9°8.3HX. ) (S! Please °) δ0.83s, 3H 4,40d, J=10Hz, zH (11-Hz) 4.5
3 d, J = 10 Hz, 2 H (11-Hz
) 4.64 d, J= 12Hz, 2H(n-CH2-0CO2-') 4.86 d, J= 12Hz.

(2) 228 m9 (0,500 mmol) in AcOH
Cry32507V (2,50m
mol) and stirred at room temperature for 24 hours.

After the reaction, H20 was added and extracted with ether, H2O, saturated Na
The mixture was washed with an aqueous HCO3 solution and saturated brine, dried over anhydrous MgSO4, and the solvent was distilled off to obtain 192 cm of oil.

This was subjected to silica gel column chromatography, and from the hexane-ethyl acetate (5:1 to 3:1) eluate, (3)
0■ (yield 64%) was obtained.

[Physical properties of (3)] mp: 145-146°C (ether to prismatic crystal) Mass spectrometry: M+4.68.470 (isotope peak) *(
3) Suspend 1409m9 (3,00; imol) in 60 mA of anhydrous ether and prepare a Zn(BH4)2-r--chill solution (containing 349 Zn(BH4)2 in one solution).
(The preparation method is W.

J., Gen5ler, F., Johnson, A.
, D, B, S1oan1J, Am, Ch
Em Soc, 82.6074 (1960)) and stirred at room temperature for 5 hours.

After the reaction, it was poured into ice water containing AcOH8- and extracted with ether, washed with saturated NaHCO3 aqueous solution and saturated brine, dried over anhydrous Mg5O, the solvent was distilled off, and the obtained oil was re-extracted with ether-)xane. The crystal of (4) 454m9
get.

The mother liquor was subjected to silica gel column chromatography, and from the eluate of hexane:ethyl acetate (4:1 to 3:1), crystals of (4) 3281rI? get.

(Yield 454rn9+328TN?-782mp, 55
%] [Physical properties of (4)] m, p,: 131-132°C (prism crystal from ether-hexane) Elemental analysis: Calculated values C: 48.37, H: 5.34, C1: 22.
55 Actual measurements C: 48.50, H: 5.38, C1: 22.
35 IR (CHCIg): 1800. 1760ctrt
-1NMR (100MHz, CDCa)
: *(4) 32 s (0,696mm
ol) to pyridi72rrtl.

Dissolve in 2 m7 of acetic anhydride under water cooling! , 1.0 μl of 4-dimethylaminopyridine was added, and the mixture was returned to room temperature and stirred for 1 hour.

After the reaction, add H20 and stir at room temperature for 1 hour to decompose excess acid anhydride, extract with ether, wash with H2O, 5% HCI aqueous solution, saturated NaHCO3 aqueous solution, saturated brine, anhydrous M
Dry with gSO4 and evaporate the solvent.

The obtained oil is recrystallized from ether to obtain crystals 352rn9 (yield 98%) of (5).

[Physical properties of (5)] m, p,: 146-149°C (ether to needle crystals) (
5) 352m9 (0,685mmol) of AcOH
1577171! and add 2.0 Or of Zn powder,
Stir for 2.5 hours at room temperature.

The precipitate formed after the reaction is dissolved by adding H2O, and the unreacted Z
The end of n is sent door to door.

The r liquid was extracted with ether, washed with H2O, saturated NaHCO3 aqueous solution, and saturated brine, dried over anhydrous MgSO4, and the solvent was distilled off to obtain 247 ml of oil.

This was subjected to silica gel column chromatography, and the eluate of hexane:ethyl acetate (1:1) was extracted with 195 cm of crystals of
Yield: 84%).

[Physical properties of (6)] m, p,: 157-159° (ether to prismatic crystal) Elemental analysis: Calculated value C263.89, ) (Near, 74☆ (6) 1.95rI19 (0, 576 mmol) was dissolved in acetone 20-20°C and heated under water cooling.
) Add 1.0 ml of reagent, return to room temperature, and stir for 1 hour.

After the reaction, 1 ml of Impropatol is added, most of the acetone is distilled off at room temperature, H2O is added and extracted with ether, washed with saturated brine, dried with MgSO4, and the solvent is distilled off.

The obtained oil was re-crystallized from ether to crystallize 20 of 7).
0■ (yield 99%) is obtained.

[Physical properties of (7)] m, p,: 98-100°C (from ether to prismatic crystal) Mass spectrometry: M+352 m/e (M+-AcOH) 292 IR (CuCl2): 180011730cIn-1*
(7) 0.5N-N of 289■ (0,820mmol)
Dissolve aOH in dioxane-H2O (1:1) solution 20a and stir at room temperature for 2.5 hours.

After the reaction, 10% HCI was added under water cooling, stirred for 10 mm, extracted with ether, washed with saturated NaHCO3 aqueous solution and saturated brine, dried over anhydrous MgSO4', and the solvent was distilled off to give crystals 2.
Get 69■.

This crystal was subjected to silica gel thin layer chromatography (hexane:
Developed with ethyl acetate = 2:3) 108 square crystals of (8) (yield 49%) were obtained.

[Physical properties of (8)] m, p,: 189-191°C (from ether to plate crystal) Elemental analysis: Calculated value C: 67.64, H: 8.33 Actual value C: 67.32, H :8.38

Claims (1)

[Scope of Claims] 1. A method for producing a sesquiterpene compound represented by the structural formula: which comprises treating the compound represented by the structural formula with an alkali and then with an acid.