JPS5850221B2 - Method for producing sesquiterpene derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention uses a compound represented by a patent characterized by the structural formula: as a starting material, oxidizes the compound with ozone to cleave the aromatic C ring, and then converts the compound into borohydride. ) Treatment with IJum gives a compound represented by the structural formula: This compound is subjected to alkaline hydrolysis to obtain a compound represented by the structural formula: The compound is Jones oxidized to obtain a compound represented by the structural formula: The present invention relates to a method for producing sesquiterpene derivatives, which is characterized in that a compound is obtained.

The starting materials used in the present invention can be easily derived from various diterpene derivatives, especially l-abietic acid.

l-Abietic acid 1) can be easily and inexpensively obtained as the main component of phase detection resins, and its structural formula including its three-dimensional structure has already been determined, and its total synthesis has also been achieved [ W., HoShuller et al., J.
, Am, Chem, S oc , , 83.2563
(1961); E., Wenkerttal, J.
.

Am, Chem, S oc, , 86.2038 (
1964) etc.].

Fragrolide (CA), which is the target compound obtained by the present invention, has already been isolated as a natural product and does not have any significant physiological activity in itself, but it has been shown to be capable of producing various physiologically active substances as described below. It is useful as an important intermediate in the conversion.

These compounds include, for example, Agandencidia, which has a strong antifeedant action against African army worms.
l) CB), bemaribolide (Bemar
ivolide) CC), cinnamosmolide (C
innamosmolide ) CD ) etc.
I, Kubo, Yue-Wellee,
M., Pettei.

F, Pilkiwicz and K, Naka
Nishi, Chem.

Comm,, 1976.1013 + Tetrahe
droneLetters A 23, pp, 2137
-2141:TetrahedronVol, 25.
pp, 3895-3902: Vol. 25.
pp. 3903-3808, etc.].

[However, in the formula, Ac represents an acetyl group] The present invention will be explained in detail below.

The 6-hydroxylactone body (14) in the present invention is
Although it can be obtained via the 6-acetoxy-14-hydroxy compound (10), the 6-acetoxy-14-hydroxy compound m) is first obtained by the known method [A
, Tahara and H, Akita, C
hem.

Pharm, Bull (Tokyo) 23 1
976 (1975); 23.1984 (1975);
Patent No. 939593 (see Japanese Patent Publication No. 53-24069) and Japanese Patent Publication No. 54-46763, Japanese Patent Publication No. 54-4
6764].

[However, in the formula, R1 and R2 represent CH3 or COOCH3.

]Then, the obtained 7-oxo-14-methoxy compound (2)
, (3) is converted into enol acetate to produce 14-methoxy-
Enol acetate (4) is obtained.

Obtained 14-methoxy-enol acetate (4)
is treated with peracid to obtain 6-acedoxy 7-oxo 14-methoxy form (6) as the main product and 6-hydroxy 7-oxo 14-methoxy form (5) as a by-product.

The 6-acedoxy 7-oxo 14-methoxy compound (6) can also be obtained by acetylating the father 6-hydroxy 7-oxo 14-methoxy compound (5).

This can be concretely shown as follows.

That is, the aforementioned compounds 2) and (3) are reacted by adding isopropenyl acetate and p-toluenesulfonic acid (p-TSOH) to obtain 14-methoxy-enol acetate (4).

The reaction temperature and reaction time are 20-120℃ and 12-120℃, respectively.
72 hours is appropriate.

Obtained 14-methoxy-enol acetate (4)
in a solvent, add peracid to perform peracid treatment.

In this case, the peracid is m-chloroperbenzoic acid (MCPB
A), perbenzoic acid, peracetic acid, perphthalic acid, permaleic acid, etc. can be used, but good results are obtained when m-chloroperbenzoic acid is used.

It is appropriate to use a halogenated hydrocarbon such as chloroform or methylene chloride as the solvent, and the appropriate reaction temperature and reaction time are 0 to 20°C and 12 to 36 hours, respectively.

In this way, 6-hydroxy 7-oxo 14-methoxy (5) and 6-acedoxy 7-oxo 14-methoxy (6) are obtained.

Furthermore, even if the obtained 6-hydroxy7-oxo14-methoxy form (5) is acetylated using an acetylating agent such as acetic anhydride, the 6-acedoxy7-oxo14-methoxy form (6) can be obtained. Can be done.

At this time, it is preferable to carry out the reaction in a basic solvent such as pyridine, and the reaction temperature and reaction time are 0 to 25°C, respectively.
12 to 36 hours is suitable.

[However, during the ceremony, Ac represents an acetyl group.

] The 6-acetoxy-7-oxo-14-methoxy compound (6) thus obtained is dissolved in a solvent such as anhydrous benzene or carbon tetrachloride, and aluminum chloride is added to carry out the reaction.

The reaction temperature at this time is suitably 0 to 30°C, but room temperature is sufficient, and the reaction time is suitably 0.5 to 4 hours.

The above reaction produces 6-acedoxy7- as the main product.
Oquine-13-isopropyl-14-hydroxy form (7
) produces 6-acedoxy-7-okine-1 as a by-product.
4-hydroxy form (8) 2/ll''-obtained.

The obtained 6-acedoxy-7-oxo-13-isopropyl-14-hydroxy compound (7) is reacted* in a methanol solvent by adding sodium borohydride.

This reaction is preferably carried out under water cooling, and the reaction time is 1
~4 hours is appropriate.

The above reaction yields 6-acedoxy 7,14-dihydroxy compound 9).

This is subjected to the next catalytic reduction reaction without purification.

That is, the obtained 6-acedoxy7,14-dihydroxy compound (9) is subjected to medium pressure catalytic reduction (hydrogen pressure: 2.8 to 2,9 kg/crA) using 10% Pd-C.

Thus, 6-acetoxy-14-hydroxy form (10)
is obtained as the main product, and 14-hydroxy compound (11) is obtained as a by-product.

[However, R1, R2, and R3 are the same as above.

] The obtained 6-acetoxy-14-hydroxy compound (10) was then oxidized with ozone to cleave the aromatic C ring, and then treated with a reducing agent to form a 6-acetoxylactone compound and a small amount of 11-methoxy-6 - Obtain an acetoxylactone body.

This reaction is preferably carried out in a solvent, for example CH2
This is carried out using Cl2-CH30H, chloroform, methylene chloride, ethyl acetate, etc.

It is preferable to use a large excess amount of ozone so that the reaction proceeds sufficiently, and the reaction temperature is suitably in the range of -80°C to 0°C.

In addition, as a reducing agent, for example, a catalytic reducing agent (10% pb
-c catalyst), sodium borohydride, sodium sulfite,
Zinc-acetic acid, dimethyl sulfide, etc. can be used, but sodium borohydride is most suitable.

Reaction temperature and reaction time are 0 to 30°C, 30 minutes to 1
2 hours is appropriate, and solvents commonly used for reduction can be used, but CH2Cl2-CH30H, C2H60
It is preferable to use H-R20, water, acetic acid, etc.

The obtained 6-acetoxylactone body was converted into 2CO3-R2
When alkaline hydrolysis is performed using 0-CH30H1KOH-CH30H or the like, 6-hydroxylactone is obtained.

The reaction temperature is sufficient at room temperature, and the reaction time is a time for sufficient hydrolysis to occur, and a suitable reaction time is 6 to 36 hours.

This will be explained using a specific example as follows.

That is, 4,4-dimethyl-6-acetoxy-13-
Isopropyl-14-hydroxy body (10') C(1
In 0), R1, R2=CH3, R3=isopropyl group] are dissolved in CH2C12-MeOH, and ozone is blown into the solution under dry ice-acetone cooling.

After that, return to room temperature and Na BH4-C2H50H-R2
0 and stir at room temperature.

After the reaction is complete, add water and extract from ether.

The aqueous layer is acidified with 10% hydrochloric acid solution and then extracted from chloroform.

The ether layer (neutral part) and chloroform layer (acidic part) were each washed with saturated brine, dehydrated and dried over Na2SO4, and the solvent was distilled off to obtain an oily substance.

Both were combined and subjected to silica gel chromatography, and from the eluate of petroleum ether: ether = 1:1, a single oily substance (crystallized when left standing) of 4,4-dimethyl-6-acetoxy-
11-methoxylactone (13), then a single oily 4,4-dimethyl 6-acetoxylactone (1
Get 21.

Then, the obtained 4,4-dimethyl-6-acetoxylactone body (12) was added to 1% of 2CO3-R20-CH30H.
Alternatively, add 1% KOH-CH30H solution, leave to stand at room temperature, 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 crystals.

A part of this is recrystallized from ethyl acetate-n-hexane to obtain colorless plate-like 4,4-dimethyl-6-hydroxylactone (2).

When the 6-hydroxylactone thus obtained is oxidized using an oxidizing agent such as Jones reagent or chromic acid-pyridine, the 6-oxolactone, which is the object of the present invention, is almost quantitatively obtained. can get.

Reaction temperature and reaction time are 10-30℃ and 30 minutes, respectively.
2 hours is appropriate.

Next, a specific example will be given and explained.

4,4-dimethyl-6-hydroxylactone (14)
Dissolve in acetone, add Jones reagent and stir at room temperature, then add methanol and stir further.

Thereafter, it is concentrated under reduced pressure, water is added to the residue, and the mixture is extracted from ether.

The ether layer is washed with saturated brine, dehydrated and dried over Na2SO4, and the solvent is distilled off to obtain crystals.

A portion of this is recrystallized from isopropyl ether to obtain colorless plate-like flagrolide [A], which is the object of the present invention.

A concrete example of the above is shown in the figure below.

Next, the present invention will be explained by examples, but the present invention is not limited thereto.

Example 1 The compound (10') 2.063f was dissolved in CH2Cl2 (
20 ml) -MeOH (20 ml), cooled with triice-acetone, and blown with ozone for 1 hour.

After that, return to room temperature and NaBH4 (1,5F) -50
% (v/v) EtOH-H2O (30 mA) was added and stirred at room temperature for 30 minutes.

After the reaction is complete, add water and extract from ether.

The aqueous layer is acidified with 10% HC1aq and then extracted from chloroform.

The ether layer (neutral part) and the chloroform layer (acidic part) were washed with each saturated saline solution, dehydrated and dried over Na2SO4, and the solvent was distilled off to obtain an oily substance from each layer.

Both (2,207 ft) were combined and subjected to column chromatography using 90 tons of silica gel, and a single oily substance (crystallized when left standing) was obtained from the eluate of petroleum ether: ether = 1:1 (13) 217 (11) , 2%) and then a single oil 12) 9411n9 (53,7%) could be separated.

[Physical properties of compound n]

Elemental analysis: (by high-resolution mass spectrometry) Molecular formula: C1
7H2404 Calculated value: 292.167 Actual value: 292.167 ■R:, CCl4□740.1235cIrL-1 (7
aaX OAc) 1765.1685crrL' (a-β-nonvesicular r-lactone) NMR (CDC13) 100 MHz・: No. 0.96 1.1□ Each... 3 H (4-ge warm degree) 1.
26 s, 3H(10-Me) 1.70 d
, IHJ=12Hz (5-H)2.06 s,
3H (6a -0Ac) 1.94-2.32 2.70-3.03 m, IH (7-H,) respectively
4.63-4.72 (4,67) m12H (11-H
2) 5.23-5.51 m (octet line), 1H (6β
-H) NMR (CDCl2) 60MHz: 0.98th 1.1o respectively, 3H (4-gemMo) 1.2
6s 13H(10-Me)1.67d,I
HJ=12Hz(5-H)2.07s, 3H(
6a -0Ac) 1.89-2.36 2.60-3.13 m, IH (7-H2) respectively
4.59-4.73 (4,65) m, 2H (11H
2S, 10-5.60 m (octet), IH (6β-
H) [Physical properties of compound l] Elemental analysis: (by high-resolution mass spectrometry) Molecular formula: C□
8H260° Calculated value: 322.178 Actual value: 322.176) IR; I/CC'1740, 1235cfrL' (6α
-aX OAc) 1766cIIL-1 (a-β-nonvesicular r-lactone)
NMR (CDC13) 60MHz: δ1.00 1, □.

Each, 3H (4-gehoM) 1.30 s
, 3H(10-Me)1.57 d, IHJ=
12Hz (5-H) 2.09 s, 3H (6a
-0Ac)3.59 s, 3H(11-OMe
) 5.19-5.58 m, IH (6β-H) 5.6
6 br, sWh/2=4.8Hz (11-H) Example 2 2CO3-H2O to 1% of the above compound 1.2103r
After adding 24 ml of -MeOH solution and standing at room temperature for 24 hours, water is added and extracted from ether.

The ether layer was washed with saturated brine, dehydrated and dried over Na2SO4, and the solvent was distilled off to obtain crystal 831 (80.2%).

A part of this is recrystallized from AcOEt-n-hexane to obtain colorless plate crystals m.

[Physical properties of compound (14)] mp: 190.5-191.5° [α),: +79° (CHC13, C=1.00) Elemental analysis: (C15H2203) Calculated value: C71,97H8,86 Actual value: C72,03H8,87, KBr IR, ν 3440cIIL-1(6α-0H)a
X 1736.1677crrL-1 ((1-β-nonvesicular r
-Lactone) High resolution mass spectrometry: (C15H2□03) Calculated value: 25
0.157 Actual value: 250.156 NMR (CDCI 3) 100MHz: δ1.13
s, 3H (4β-Me) 1.22 516H (4a-Me, 10-Me) 1
．． 44 d, IHJ=10Hz (5-H) 1.97~
2.36 2.66~2.98 respectively °・IH(7-H・)
4.65-4.74 (4,68) m, 2H (11H2
)4.30 br, sl 1HWh/2=20Hz(
ax, H: Wh/2-16-25 cycles/sec) Example 3 In Example 2, the compound (one at 651■, 2 at 1%)
1% KOH-M instead of CO3-H2O-MeOH solution
Compound 04) was mixed with 3s 2rII9 (68,!5%) in the same manner except that 10ml of eOH was used.
)Obtained.

The physical properties were completely consistent with those obtained in Example 2.

Example 4 The above compound 14) 425rn9 (crystal) was dissolved in acetone 10
ml, add 1 ml of Jones reagent, stir at room temperature for 30 minutes, add 10 ml of MeOH, and add 2 ml of Jones reagent.
Stir for 0 minutes.

Thereafter, it is concentrated under reduced pressure, water is added to the residue, and extracted from ether.

The ether layer was washed with saturated brine, dehydrated and dried over Na2SO4, and the solvent was distilled off to obtain crystals 420cm (99.6%).

A part of this is recrystallized from isopropyl ether to obtain colorless plate crystals [A].

[Physical properties of compound [A]]

mp:: 163-164゜Elemental analysis: (C15H2O03) Calculated value: C72,55H8,12 Actual value 2C72,50H8,15 High resolution mass spectrometry (C15H2O03) Calculated value: 248.141 Actual value: 248.141 [α ]D+145.1° (CHCI3, C=1.OO
), CHCI IR, 31755, 1675cfrL-1 (α-βaX -biosaturated r-lactone) 1720crfL' (6-oxo) (1755,
1723,1675crrL-1) NMR (CDC13) 100MH2: δ1.04 s, 3H(4(IE-Me)1,18
s, 3H(10-Me)1.30 s, 3H
(4β-Me) 2.44 s, IH(5-H) 3.00-3.14 m, 2H(7H2) 4.8
0-4.88 m12H (11-H2) NMR (CD
Cls) 601MHz: δ1.05s, 3
H(4cc-Me) 1.20 s, 3H(10-
Me ) 1.31 513H (4β-Me) 2.45 sl 1H (5-H)

Claims (1)

[Claims] 1 A compound represented by the structural formula: is used as a starting material, which is oxidized with ozone to cleave the aromatic C ring, and then treated with sodium borohydride to form a compound represented by the structural formula: A method for producing a kiterpene derivative is obtained by obtaining a compound represented by the structural formula: By alkaline hydrolysis, and obtaining a compound represented by the structural formula by Jones oxidation.