JPS5834459B2 - Method for producing sesquiterpene compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing the sesquiterpene compound Cinnamodial (also known as Ugandensidial).

Cinnamodial, the object compound of the present invention, is a natural substance derived from the African plant Warburgia.
) or Cinnamosma (T
etrahedron 25.2887, (1969)
], its structural formula has also been determined, and its physiological activity is similar to that of the armyworm.
(Chem, Comm, P, 1013 (197
See 6)].

The present inventors took the opportunity of determining the structure of the substance and conducted intensive research on the production of the substance by a synthetic method. As a result, the present inventors discovered that 8-hydroxymethyl carbonate (
We succeeded in total synthesis of cinnamodial using 1) as a starting material, and hereby completed the present invention.

The present invention will be explained in detail below.

First, 8-hydroxymethyl carbonate (Ml), which is the starting material for the method of the present invention, is a new compound synthesized for the first time by the present inventors, for example, indorimenin (isodrimenin) (J, Chem. ,
Soc, P., 4685 (1960)] by the following steps.

In addition, the above-mentioned indolimenin was developed by the inventors of the present invention as l
- Total synthesis has already been achieved as a sesquiterpene derivative derived from abietic acid, and it is easily available [see Japanese Patent Application No. 52-38628 (Japanese Unexamined Patent Publication No. 53-124256)].

In addition, easily available β-ionone (β-1onone)
The inventors of the present application have also succeeded in synthesizing indolimenin in an extremely short process from
110359)).

8-Hydroxymethyl carbonate H thus obtained
Using 1) as a starting material, the target substance, cinnamodial, is synthesized through the following steps.

Among these compounds, all compounds (2) and 0) are new substances that have not been described in any literature and were obtained in this synthesis process.

According to the method of the present invention, the starting material 8-hydroxymethyl carbonate (1) is first induced into the trichloroethoxycarbonyl compound (2), and then the dinone compound (3), the 6-hydroxy compound (4), and the 6-acetoxycarbonyl compound (2). body (5), alcohol body (6), aldehyde body (7), ketal body (8),
Diol body (9) and α-hydroxyaldehyde body 00
) can be successively converted to synthesize the desired cinnamodial 0υ.

This will be explained below according to the steps.

First, 8-...idroxymethyl carbonate (1), which is the starting material of the present invention, is reacted with β.β.β-trichloroethoxycarbonyl chloride to obtain trichloroethoxycarbonyl compound (2) in a good yield.

In this case, pyridine, triethylamine, etc. can be used as the solvent, but particularly excellent results are obtained in the case of pyridine-ether.

In the above reaction, room temperature is sufficient for the reaction temperature, and a suitable reaction time is about 1 to 4 hours.

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

In this reaction, excellent results are obtained when chromic acid is used as the oxidizing agent and acetic acid is used as the solvent.

The reaction temperature is room temperature, and the reaction time is about 12 to 24 minutes.
The time is appropriate.

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

In the above reaction, sodium borohydride, zinc borohydride, etc. are used as the reducing reagent, and ethers such as ether, dioxane, and tetrahydrofuran are used as the solvent. In particular, zinc borohydride is used in anhydrous ether. When used, favorable results are obtained.

Room temperature is sufficient for the reaction temperature, and a suitable reaction time is about 4 to 12 hours.

Next, by reacting the obtained 6-hydroxy form (4) with an acetylating agent in a solvent, 6-acetoxy form 5)
can be obtained in high yield.

As the acetylating agent, acetic anhydride-pyridine, acetyl chloride-pyridine, etc. are used, and particularly excellent results are obtained when acetic anhydride-pyridine is used in the presence of 4-dimethylaminopyridine.

Room temperature is sufficient for the reaction temperature, and a suitable reaction time is about 1 to 12 hours.

Next, the obtained 6-acetoxy compound (5) is treated with zinc powder in a solvent to remove trichlorethoxycarbonylation, and the alcohol compound (6) is quantitatively obtained.

As the solvent, alcohols and organic acids such as acetic acid can be used, and especially when acetic acid is used, favorable results are obtained.

Room temperature is sufficient for the reaction temperature, and a suitable reaction time is about 2 to 5 hours.

When the obtained alcohol (6) is quickly reacted with an oxidizing agent, the aldehyde (7) can be obtained in high yield.

The oxidizing agent in this oxidation reaction is Jones (Jones).
nes) reagent is preferably used, and acetone is particularly effectively used as a solvent.The reaction temperature and reaction time are not particularly limited, but the reaction can be carried out at about -10° to 0°C and in a short time of about 30 minutes, respectively. proceed.

The obtained aldehyde (7) is further treated with a dialcohol and an organic acid to protect it with an acetal, thereby obtaining an alkali-stable ketal (8).

In this case, organic acids such as p-)luenesulfonic acid and camphorsulfonic acid are used, and aromatic hydrocarbons such as benzene and toluene are used as the solvent.
Examples of dialcohol include ethylene glycol, 1,3-
Propanediol and the like can be used, and it is particularly preferable to use p-toluenesulfonic acid and 1,3-propanediol in a benzene solution.

The reaction temperature and reaction time at this time are not particularly limited, but
Each reaction takes place at approximately 80 to 150°C and for a short time of about 1 hour.

By treating the obtained ketal compound (8) with an alkali, geo-#CE9) can be obtained in high yield.

As the alkali at this time, an aqueous solution of sodium hydroxide, potassium hydroxide, etc. is used, and as the solvent, dioxane,
Although tetrahydrofuran or the like is used, it is particularly preferable to use sodium hydroxide in a dioxane solution.

Although the reaction temperature and reaction time are not particularly limited, about 1 to 3 hours at room temperature is suitable.

The obtained diol (9) is reacted with an oxidizing agent under basic or neutral conditions to obtain α-hydroxyaldehyde (0)
get.

In this reaction, oxidizing agents include DMSO reagent (trifluoroacetic acid, trichloroacetic anhydride, dicyclohexylcarbodiimide, triethylamine, etc.), py-H
Cl, CrO3, py-CrO3, etc. can be used in appropriate combinations, but especially in the presence of pyridine, DMSO,
Gives excellent results when using trifluoroacetic acid and dicyclohexylcarbodiimide.

In this reaction, the reaction temperature and reaction time are not particularly limited, but suitable results can be obtained particularly at room temperature for about 2 to 10 hours.

α-Hydroxyaldehyde compound thus obtained (10)
When heated under reflux with an organic acid, the target product, cinnamodial αυ, is obtained.

The target compound 0υ completely matches the physical properties of the natural product cinnamodial.

As the organic acid in this reaction, organic acids such as p-)luenesulfonic acid and camphorsulfonic acid are used, and acetone, alcohols, etc. can be used as a solvent. It is preferable to use sulfonic acid.

Further, the reaction temperature and reaction time are not particularly limited, and the reaction sufficiently proceeds in about 30 minutes under reflux.

The present invention will be specifically explained below using examples.

In addition, compounds (2), (3), (4), (5), (6)
, (7), (8), (9), and (10) are all new compounds.

Example 1 (1) Dissolve 2801119 (1,00 ml!) in 10 ml of ether, add 2 ml of pyridine, and add β・β・β trichloroethoxycarbonyl chloride 2 under cooling.
Drop 68 μl (2,00 mmol).

After dropping, return to room temperature, stir for 1 hour, extract with ether, and add H2O.
, 5% HCI aqueous solution, washed with 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)] m, p,: 121-122°C (ether to plate crystal) Elemental analysis: Calculated value C: 50.07 H: 5.53 C1: 23.
34 Actual loss 1 ■ Direct C: 50.08 H: 5.53 C1:
23.29 (2) 2281r19 (0,500 mmol) in Ac
Dissolve in 5ml of OH, CrO325Q■ (2,50mm
ol) 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)
09 (yield 64%) was obtained.

[Physical properties of (3)] m, p,: 145-146°C (ether to prismatic crystal) Mass spectrometry: M+468.470 (isotope peak) *Example (3) 1409■ (3,00 mmol) Suspended in 60 ml of anhydrous ether, Zn (BH4,)2 ether solution (containing 34 μ of Zn (BH4)2 in 1 ml) (prepared by W, J Gen5ler, F, J
ohnson, A, D, B.

5loan, J, Am, Chem, 5oc1, Jiao 3.6
074 (1960)) and stirred at room temperature for 5 hours.

After the reaction, it was poured into ice water containing 8 ml of AcOH, extracted with ether, washed with a saturated aqueous NaHCO3 solution and saturated brine, dried over anhydrous MgSO4, the solvent was distilled off, and the resulting oil was reconsolidated with ether-hexane. (4) Crystal 4541
Obtain r1f/.

The mother liquor was subjected to silica gel column chromatography, and crystals 3 of (4) were obtained from the eluate of hexane:ethyl acetate (4:1 to 3:1).
Get 28rr19.

(Yield 454In9+3287!-7827V, 55%
) [Physical properties of (4)] m, p,: 131-132°C (prism crystal from ether-hexane) Elemental analysis: Calculated value C: 48.37 H: 5.34 C1: 22.
55 Actual measurement value C: 48.50 H: 5.38 C1: 22.
35 IR (CHCL3): 1800.1760C1rL
'NMR (100MHz, CDC13) 'δ1.
08 s, 3 Hx 2 (4-gernMe)
※※ 1.29S, 3H (10-Me) 4.39 d, T=10Hz, IH (114,56d
, T=10Hz, IH (11 4,71d, J=13Hz.

1H(>CH2-0CO2-) 4.91 d, J=13Hz, I H(')-cm, -oco2-) 4.76 s, 2H(-〇-CH2-cc13)6.
35 d, J = 5 Hz, IH (7-H) Example 4 H2) H2) (4) 325 m9 (0,696 mmol) was dissolved in 2 rul of pyridine, and under ice-cooling, 2 rr Ll of acetic anhydride and 10 μl of 4-dimethylaminopyridine were added. Add, return to room temperature, and stir for 1 hour.

After the reaction, H20 was added and stirred at room temperature for 1 hour to decompose excess acetic anhydride, extracted with ether, washed with H2O, 5% HCI aqueous solution, saturated NaHco3 aqueous solution, and saturated brine, anhydrous M
Dry with gSO4 and evaporate the solvent.

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

[Physical properties of (5)] m, p,: 146-149°C (ether to needle crystals) Elemental analysis: Calculated value C: 49.09 H: 5.30 C1: 20.
70 Actual value C: 49.05 H: 5.28 (5) 352
(0,685 mmol) was dissolved in 15 rul of AcOH, and 2. Add OOP and stir at room temperature for 2.5 hours.

The precipitate formed after the reaction is dissolved by adding H2O, and the unreacted Z
Separate n.

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

This was subjected to silica gel column chromatography, and 195 cm of crystals of (6) were collected from the eluate of hexane:ethyl acetate (1:1).
(yield 84%).

[Physical properties of (6)] m, p,: 157-159° (ether to prismatic crystal) Elemental analysis: Calculated value C: 63.89 H near, 74
※※ Actual value C: 6378 H near, 84IR (C
HCI3'): 3400.1795, rn1 NMR (100 MHz, CDC13) Near 30 (6) 676 m9 (2,00 mmol) in acetone 3
Jones
) 1.0 ml of reagent was added dropwise over 30 minutes, and immediately
Add O and extract with ether, wash with H2O, saturated NaHCO3 aqueous solution, and saturated brine, dry with anhydrous MgSO4,
When the obtained oil is recrystallized from ether, crystals 455 of (7) are obtained.

The mother liquor was subjected to silica gel column chromatography, and 71m9 of crystals of (7) were obtained from the eluate of hexane:ethyl acetate (3:1).

(Yield 455■+71■-526■, 78%) Also, the washing solution with saturated NaHCO3 aqueous solution was acidified with concentrated HCI, extracted with ether, washed with saturated brine, anhydrous Mg5O,
When the solvent is distilled off, the carboxylic acid 02) becomes 139
It can be obtained immediately (yield 20%).

[Physical properties of (7)] m, p,: 195-200°C (decomposition) (from ether to prismatic crystal) Elemental analysis: Calculated value C: 64.27 H near, 19 actual value C:
64.22 H Near, 25IR (CHCL3): 1
800.1740.1705*(7)4761119(
1,42 mmol) was dissolved in 5 or 1 l of benzene, 5 mL of 1,3-propanediol, 4 o 1 n9 of p-toluenesulfonic acid was added, and the mixture was heated under reflux for 1 hour while removing H2O.

The benzene layer is washed with a reaction wave saturated aqueous NaHCO3 solution and saturated brine, dried over anhydrous MgSO4, and the solvent is distilled off.

The obtained oil was re-crystallized from ether to give crystals 36 of 8).
Get 51n9.

Furthermore, the mother liquor was subjected to silica gel column chromatography, and crystals 8 of (8) were extracted from the eluate of hexane-ethyl acetate (3:1).
Get 01r19.

(Yield 365■+80■-445■, 80%) [Physical properties of (8)] m, p,: 235-237℃ (from ether to prismatic crystal) Elemental analysis: Calculated value C: 63.94, H Near, 69 Actual value C: 64.04, H Near, 72 IR (CHCL3): 1790.1730crfL-
INMR (100 MHz, CDCl s) Example (8) Dissolve 395771p (1,00 mmol) in 5 ml of dioxane and add 5 ml of 10% NaOH aqueous solution.
and stir at room temperature for 2 hours.

After the reaction, the mixture is extracted with ether, washed with H2O and saturated brine, dried over anhydrous Mg5O, and the solvent is distilled off.

The obtained oil was subjected to silica gel column chromatography, and the fraction eluted with hexane-ethyl acetate (5:1) gave 282 square crystals of (9) (77% yield).

[Physical properties of (9)] m, p,: 117-118°C (ether to prismatic crystal) Elemental analysis: *(
9) 2861V (0,776mmol) in benzene 10
rnl, dimethyl sulfoxide CDMSO) pyridine 92m9 (dissolved in benzene 1rrLl), CF
3CO2H44r11F? (Dissolved in 1rrLl of benzene) Dicyclohexylcarbodiimide (DCC) 480
Add ■ sequentially.

After stirring at room temperature for 2.5 hours, the resulting precipitate was separated and the lachrymal fluid was soaked with H
2O, washed with saturated saline, dried with anhydrous MgSO4,
The solvent is distilled off.

The obtained oil was subjected to silica gel column chromatography, and 232 cm of crystals of (10) (yield: 82%) were obtained from the fraction eluted with hexane-ethyl acetate (5:1).

((Physical properties of 11) m, p,: 149-151°C (prismatic crystal than ether) Elemental analysis: Calculated value C: 65.55 H: 8.25 Actual value C:
65.59 H:8.33IR(CHCI3): 1
730.1720cIIL-1NMR (100MIF(
z, CDCl3): δ0.97 Each S 1.133Hx2 (4-golo) 1.40 s, 3H (10-Me) * 2.04 s, 3H (OAc) 3.5-4.3 m (- 0CH2CH2CH20)3
．． 94 d, J = IHz, IH (OH) 4.88
br, s IH(-0-CH-0-)5.66 t
1J=5Hz, IH (6-H) 6.24 dd, 5H
z, IHz, IH (7-H)9.81 d, J=IH
z, IH (9-CHO) Example 10 (10) 32m? (0,087 mmol) in 5 ml of acetone, p-)luenesulfonic acid 151n9
Add this and heat under reflux for 30 minutes.

After the reaction, most of the acetone was distilled off at room temperature, extracted with ether, washed with a saturated aqueous NaHCO3 solution and a saturated aqueous NaCl solution, and anhydrous Mg5O.

The solvent was distilled off to obtain 26% of 0υ crystals (yield: 9
7%).

This one is natural cinnamodial (11) and IR,N
The MR spectra matched.

(Physical properties of (1,1)) m, p,: 128-130°C (ether to prismatic crystal) Elemental analysis: Calculated value C: 66.21 H near, 85 actual value C:
66.22 H Near.

87IR (CHCI3): 3350.1735 (shoulder), 1720.1690CrrL', (CCI4)
3375.1740.1725.1695crfL'
NMR (100■ (z, CDC13): δ1.02 each S 1.163H
d, J=5Hz, IH(5-H)2.12s, 3H(
OAc) 4.07 d, J=1.5Hz, IH (QH) 5.8
8t, J = 5Hz, IH (6-H) 6.78
d, J=5Hz, IH(7-H)9.42s,
IH (8-CHO)

Claims (1)

[Scope of Claims] 1 Structural formula: Cinnamodial represented by reacting a compound represented by: with an organic acid
manufacturing method. 2 A structural formula characterized by reacting a compound represented by the structural formula: with an oxidizing agent under basic or neutral conditions to obtain a compound represented by the structural formula: and reacting the compound with an organic acid: Cinnamodia expressed as
Method of manufacturing l. 3 A compound represented by the structural formula: ) is treated with an alkali to obtain a compound represented by the structural formula: This compound is reacted with an oxidizing agent under basic or neutral conditions to obtain a compound represented by the structural formula: Cinnamodia represented by the structural formula:
l) Manufacturing method. 4 A compound represented by the structural formula: is obtained by treating the compound represented by the structural formula: with a dialcohol and an organic acid, a compound represented by the structural formula: is obtained by treating the compound with an alkali, and the compound is A compound represented by the structural formula: is obtained by reacting with an oxidizing agent under basic or neutral conditions, and the compound is reacted with an organic acid.
ial) production method. 5 A compound represented by the structural formula: is treated with an oxidizing agent to obtain a compound represented by the structural formula: and the compound is treated with a dialcohol and an organic acid to obtain a compound represented by the structural formula: A compound represented by the structural formula: is obtained by treating the compound with an alkali, and the compound is reacted with an oxidizing agent under basic or neutral conditions to obtain a compound represented by the structural formula:, and the compound is treated with an organic acid. A method for producing cinnamodial represented by the structural formula: characterized by reacting with. 6 Structural formula: % Formula %) is treated with zinc dust to obtain a compound represented by Structural formula:; the compound is treated with an oxidizing agent to obtain a compound represented by Structural formula:; By treating the compound with a dialcohol and an organic acid, a compound represented by the structural formula: is obtained; by treating the compound with an alkali, a compound represented by the structural formula: is obtained; Cinnamodia, which is characterized by reacting with an oxidizing agent under conditions to obtain a compound represented by the structural formula:
l) Manufacturing method. 7 A compound represented by the structural formula: is treated with an acetylating agent to obtain a compound represented by the structural formula: This compound is treated with zinc dust to obtain a compound represented by the structural formula: and the compound is oxidized. A compound represented by the structural formula: is obtained by treating the compound with a dialcohol and an organic acid, and a compound represented by the structural formula: is obtained by treating the compound with an alkali. A structural formula characterized by obtaining a compound represented by: and reacting the compound with an oxidizing agent under basic or neutral conditions to obtain a compound represented by the structural formula: and reacting the compound with an organic acid. : Cinnamodial (Cinnamodial) represented by
ial) production method. 8 A compound represented by the structural formula: is treated with a reducing agent to obtain a compound represented by the structural formula: This compound is treated with an acetylating agent to obtain a compound represented by the structural formula: By treating the compound with a dialcohol and an organic acid, a compound represented by the structural formula: is obtained, and the compound is treated with an oxidizing agent to obtain a compound having the structural formula: A compound represented by the formula: is obtained, the compound is treated with an alkali to obtain a compound represented by the structural formula:, and the compound is reacted with an oxidizing agent under basic or neutral conditions to produce a compound represented by the structural formula: A method for producing cinnamodial represented by the structural formula: 9 Structural formula: % formula %) is treated with an oxidizing agent to obtain a compound represented by structural formula:, and the compound is treated with a reducing agent to obtain a compound represented by structural formula: Treating the compound with an acetylating agent to obtain a compound represented by the structural formula: Treating the compound with zinc dust to obtain a compound having the structural formula: Treating the compound with an oxidizing agent , the compound represented by the structural formula: is obtained, the compound is treated with a dialcohol and an organic acid to obtain the compound represented by the structural formula:, and the compound is treated with an alkali to obtain the compound represented by the structural formula: A thinner represented by the structural formula: which is obtained by reacting the compound with an oxidizing agent under basic or neutral conditions to obtain a compound represented by the structural formula: and reacting the compound with an organic acid. How to make mojiar. 10 A compound represented by the structural formula: %formula %) is reacted with β・β・β-trichloroethoxycarbonyl chloride to obtain a compound represented by the structural formula: and the compound is treated with an oxidizing agent to obtain the structural formula A compound represented by: is obtained, the compound is treated with a reducing agent to obtain a compound represented by the structural formula: and the compound is treated with an acetylating agent to obtain a compound represented by the structural formula: Treating a compound with zinc dust to obtain a compound represented by the structural formula: Treating the compound with an oxidizing agent to obtain a compound having the structural formula: Treating the compound with a dialcohol and an organic acid By treating the compound with an alkali, a compound represented by the structural formula: is obtained, and by reacting the compound with an oxidizing agent under basic or neutral conditions, : is obtained by reacting the compound with an organic acid.
l) Manufacturing method.