JPH0551335A - Cyclic terpene - Google Patents

Abstract

PURPOSE:To provide a new cyclic terpene useful as an intermediate capable of producing an optically active sarcophytol A having anticarcinogenic promoter action and antitumor action in large quantity at a low cost without using highly toxic selenium compound. CONSTITUTION:The compound of formula I [R<1> is H, 1-alkoxyalkyl, SO2R<4> or SiR<5>R<6>R<7>; R<4> to R<7> are 1-4C alkyl or phenyl; R<4> may be phenyl substituted with 1-4C alkyl; R<2> and R<3> are CN or OR<8>; R<2> and R<3> may together form O (when R<1> is SO2R<4>, R<2> and R<3> may together express O); R<8> is H, 1-alkyoxyalkyl or trimethylsilyl], e.g. the compound of formula II. The compound of formula I wherein R<2> and R<3> are CN or OR<8> (R<8> is not H) can be produced by reacting compound of formula III with a base such as lithium diisopropyl amide in a solvent (e.g. tetrahydrofuran) at -70 to +100 deg.C. Sarcophytol A of formula IV can be produced from the above compound on an industrial scale at a low cost.

Description

Detailed Description of the Invention

[0001]

This invention relates to novel cyclic terpenes. Specifically, the compounds of the present invention have anti-carcinogenic promoter action (Cancer Surveys, 2 , 540).
(1983); Metabolism, vol 25 extra edition Cancer '8
8, 3 (1988). ) And antitumor action (Japanese Patent Publication No. 63-
No. 20213), or cyclic terpenes which are important intermediates for the preparation of sarcophitol A or its stereoisomers with expected similar effects.

[0002]

2. Description of the Related Art Sarcophytol A represented by the following structural formula is a sembrane type diterpene alcohol having a total of four double bonds including one conjugated double bond in its 14-membered ring.

[0003]

[Chemical 2]

Heretofore, the synthesis method of sarcophytol A was reported only by the present inventors (Japanese Patent Application No. 3-48633; Tetrahedon).
Letters, 31 , 3317 (1990)). By the manufacturing route of this Zarcophytol A,
When trying to industrially produce Zarcophytol A,
There is a big problem that the yield and the selectivity are not high and the oxidization process of the terminal methyl group which requires the use of a highly toxic selenium compound cannot be avoided.

[0005]

DISCLOSURE OF THE INVENTION As a result of intensive investigations by the present inventors for the purpose of producing and supplying a large amount of an optically active sarcophytol A by an industrially more advantageous method and at a low cost, the ring of the present invention was obtained. The present inventors have found that terpenes are useful intermediates in a novel production route that can solve the above problems, and arrived at the present invention. That is, the gist of the present invention is the following general formula (I)

[0006]

[Chemical 3]

[In the above general formula (I), R¹Is hydrogen
Child, 1-alkoxyalkyl group, -SO ₂R^Four(R^FourIs
An alkyl group having 1 to 4 carbon atoms or an alkyl group having 1 to 4 carbon atoms
Represents a phenyl group which may be substituted with a ru group. )Also
Is -SiR^FiveR⁶R⁷(R^Five, R ⁶And R⁷Is that
Independently, an alkyl group having 1 to 4 carbon atoms or a phenyl group
Represents ), R²And R³Each independently
-CN or -OR⁸(R ⁸Is a hydrogen atom, 1-alkoxy
Represents a silyl group or a trimethylsilyl group. ) Table
But R²And R³Together represent the oxygen atom
Good. In addition, R¹Is -SO₂R^FourTo represent R²
And R³Together represent an oxygen atom. ]]
It exists in cyclic terpenes.

The present invention will be described in detail below. In the above definition, the ¹ -alkoxyalkyl group represented by R ¹ is methoxymethyl group, 1-ethoxyethyl group, 1-n
-Propoxyethyl group and the like, and the group -SO ₂ R ⁴
The _{-SO 2 CH 3, -SO 2 C} 2 H 5, -SO 2
Ph (Ph represents a phenyl group.), - SO ₂ pTol
(PTol represents a paratolyl group) and the like,
Examples of the group —SiR ⁵ R ⁶ R ⁴ include t-butyldimethylsilyl group, dimethylphenylsilyl group, t-butyldiphenylsilyl group and the like.

In the above definition, the 1-alkoxyalkyl group represented by R ^{8 of the} group —OR ⁸ represented by R ² or R ³ includes 1-ethoxyethyl group, 1-n-propoxyethyl group and the like. Specific examples of preferred compounds represented by the above general formula (I) are shown below. (1) R ² and R ³ are CN or OR ⁸ (R ⁸ is 1-
It represents an alkoxyalkyl group or a trimethylsilyl group. ) Is represented.

[0010]

[Chemical 4]

[0011]

[Table 1]

(2) R ² and R ³ are CN or OR ⁸
When R ⁸ represents a hydrogen atom.

[0013]

[Chemical 5]

[0014]

[Table 2]

(3) When R ² and R ³ together represent an oxygen atom.

[0016]

[Chemical 6]

[0017]

[Table 3]

(Me represents a methyl group and Bu represents a butyl group) Next, a method for producing the compound of the present invention will be described. The compound represented by the general formula (I) is, for example, the following general formula (A)

[0019]

[Chemical 7]

(In the above general formula (A), R¹And R⁸Is
As defined above. However, R ⁸Represents a hydrogen atom
I don't. A chain-like precursor represented by
It ) Can be manufactured from. That is, in the above general formula (A)
From the compounds represented, for example, ethyl ether, tet
Ethereal solvents such as lahydrofuran, benzene, and toluene
Aromatic hydrocarbon solvents such as benzene, n-hexane, n-
In a saturated hydrocarbon solvent such as heptane, 1 to 10 equivalents of
Thallium diisopropylamide, lithium bis (trimethyl
Base, such as rusilyl) amide, sodium hydride,
A method of operating at 70 to 100 ° C for 5 minutes to 10 hours, etc.
In the general formula (I)²And R ³Is CN
Or OR⁸(R⁸Does not represent a hydrogen atom. ) Represents
Compound can be produced, tetrahydrofuran, methanol
0.1-3 normal hydrochloric acid, sulfuric acid, and other mineral acid water in a solvent such as
The method of allowing the solution to act at 0 ° C to room temperature for 5 minutes to 5 hours, or
Or in a solvent such as tetrahydrofuran or dioxane, -2
At 0 ° C to room temperature, 1 to 10 equivalents of tetrabutylan fluoride
Acting on tetraalkylammoniums such as monium
R in the above general formula (I)²and
R³A compound can be prepared wherein CN represents CN or OH. Next
And organic compounds such as ethyl ether and ethyl acetate of the above compounds.
Solvent solution is sodium hydrogen carbonate solution or hydroxylated
Let the aqueous solution of sodium act at 0 ° C to room temperature for 5 minutes to 5 hours.
Or in the above general formula (I)
R²And R³Is CN or OR⁸(R⁸Is a hydrogen atom
Not represented. ) From the compound represented by
1 to 10 equivalents of fluorine in a solvent such as lofuran or dioxane
Alkylammonium fluoride such as tetrabutylammonium fluoride
Directly using a method such as reacting the above-mentioned compounds with nickel
In the general formula (I), R²And R³Together
Compounds representing oxygen atoms can be prepared.

Starting from a compound in which R ¹ represents a hydrogen atom and R ² and R ³ together represent an oxygen atom in the above general formula (I), for example, a halogen-based solvent such as dichloromethane or chloroform, or diethyl ether, In an ether solvent such as tetrahydrofuran, 0.1 to 10 equivalents of triethylamine, pyridine and the like in the presence of a base of 0.1
~ 1.5 equivalents of a halogenated substituted sulfonyl such as methanesulfonyl chloride, paratoluenesulfonyl chloride, etc.
By a method such as acting on the above compound at 100 ° C.,
In the above general formula (I), R ¹ is —SO ₂ R ⁴ ,
A compound in which R ² and R ³ together represent an oxygen atom can be prepared.

The compound represented by the above general formula (A) is disclosed in, for example, the literature (J. Org. Chem., 52 , 3860).
The compound (B) described in (1987)) can be used as a starting material according to the following synthetic route.

[0023]

[Chemical 8]

(In the above formula, Ac represents an acetyl group, X
Represents a halogen atom, R¹And R ⁸Is the above general formula
As defined in (I). However, R⁸Is hydrogen
Does not represent a child. ) That is, methano is added to the above compound (B).
1 to 2 equivalents of metal alcohol in a solvent such as ethanol or ethanol.
Of transesterification with oxidant at -50 to 50 ° C
Method, methanol, ethanol, tetrahydrofuran, etc.
0.5 to 10 equivalents of sodium hydroxide in a solvent of
An aqueous solution of potassium or the like or powdered potassium carbonate or the like -5
The method of hydrolysis that works at 0-50 ° C, diethyl ether
Ether, tetrahydrofuran, n-hexane, toluene
0.5 to 10 equivalents of hydrogen at -70 to 50 ° C in a solvent such as
Metal-hydrogen complex compound such as lithium aluminum fluoride or water
Works with metal hydrides such as diisobutylaluminum
The compound (C) is prepared by a method such as a reduction reaction
Can be manufactured.

The above compound (C) is mixed with a halogen-based solvent such as methylene chloride or chloroform, a hydrocarbon-based solvent such as hexane or heptane, or a solvent such as ethyl ether or ethyl acetate in a weight ratio of 5 to 20 times as much as powdered dioxide. Oxidizing agents such as manganese and barium manganate at -50 to 50 ° C for 1 to
The compound (D) can be produced by a method of allowing it to act for 50 hours.

The following formula

[0027]

[Chemical 9]

To a known 2-bromo-2-butenal acetal represented by the following formula, in an ether solvent such as diethyl ether or tetrahydrofuran at -100 to 50 ° C,
The above compound (E) can be produced by adding 0.1 to 1.2 equivalents of an organic metal such as n-butyllithium or i-butyllithium. The compound (F) can be produced by hydrolyzing the compound produced by the above method produced by reacting the compound (D) at -100 to 50 ° C.

Compound (F) produced by the above production method
A halogen-based solvent such as methylene chloride or chloroform,
Hydrochloric acid as a catalyst in an ether solvent such as diethyl ether or tetrahydrofuran, or a solvent such as ethyl acetate,
0.5 in the presence of a mineral acid such as sulfuric acid, an organic sulfonic acid such as paratoluenesulfonic acid, camphorsulfonic acid, or a strong acid salt such as a pyridinium salt of paratoluenesulfonic acid.
10 to 10 equivalents of vinyl ethers such as ethyl vinyl ether and dihydropyran are allowed to act at -20 to 100 ° C, or 0.5 to 10 equivalents of chloromethyl methyl ether and chloromethyl-2-methoxy at -20 to 100 ° C. 1-haloalkyl ethers such as ethyl ether,
0.5-10 in a solvent such as tetrahydrofuran, diethyl ether, dimethylformamide or without solvent
A method in which equivalent amounts of metal hydrides such as sodium hydride and potassium hydride, amines such as triethylamine, pyridine and diisopropylamine are allowed to act together as a base, or 0.1 to 10 equivalents of trimethylchlorosilane and dimethyl-t- Chlorosilanes such as butylchlorosilane are halogenated solvents such as methylene chloride and chloroform, hydrocarbon solvents such as hexane and benzene, ether solvents such as diethyl ether and tetrahydrofuran, or aprotic substances such as ethyl acetate, dimethylformamide and dimethyl sulfoxide. In a polar solvent, 0.1 to 10 equivalents of triethylamine, a nitrogen-containing compound such as dimethylaminopyridine and imidazole, or a metal hydride such as sodium hydride and potassium hydride as a base-2
The said compound (G) can be manufactured by the method of making it work for 5 minutes-24 hours at 0-100 degreeC.

Compound (G) produced by the above method was added to a solvent such as tetrahydrofuran, methanol or ethanol,
The compound (H) can be produced by a method of reacting 0.1 to 3 equivalents of an aqueous mineral acid solution such as hydrochloric acid or sulfuric acid at 0 ° C. to room temperature for 5 minutes to 24 hours. R ^{1 of the} above compound (H) is 1
- when it is alkoxyalkyl group certain of 1-alkoxyalkyl group is hydrolyzed, to give the compound a R ¹ = hydrogen atom.

Metal cyanide-18-crown-6 with 1 to 10 equivalents of trimethylsilylnitrile as a catalyst in the compound (H) produced by the above method in a solvent such as methylene chloride, chloroform, ethyl acetate or without solvent. -In the presence of an ether complex, at -20 to 50 ° C for 30 minutes to 5
R in the general formula (A) may be changed depending on the method of acting for a time.
A compound represented by ⁸ = trimethylsilyl group can be produced. After dissolving this compound in a solvent such as tetrahydrofuran or methanol, a method of reacting 0.1 to 3 equivalents of an aqueous solution of a mineral acid such as hydrochloric acid or sulfuric acid at 0 ° C. to room temperature for 5 minutes to 5 hours, or a method such as tetrahydrofuran or dioxane is used. -20 in solvent
The compound (A) (cyanohydrin form) represented by R ⁸ = hydrogen atom can be produced by a method of reacting 1 to 10 equivalents of a tetraalkylammonium such as tetrabutylammonium fluoride at a temperature of room temperature to room temperature. R ⁸ = 1-
The compound represented by the above general formula (A) represented by an alkoxyalkyl group is hydrochloric acid, sulfuric acid or the like using 1 to 10 equivalents of ethyl vinyl ether or the like in a solvent such as ethyl ether or ethyl acetate as a catalyst to the cyanohydrin compound. In the presence of a mineral acid, an organic strong acid such as p-toluenesulfonic acid, or a salt of a strong acid such as a pyridinium salt of p-toluenesulfonic acid at -20 ° C to room temperature for 30 minutes to 5 hours.

The production of the compound represented by the above general formula (I) of the present invention from the compound represented by the above general formula (A) is as described above. The above general formula (I) of the present invention
From the compound represented by, for example, sarcophytol A can be produced by the following synthetic route, which does not have the problems of the above-mentioned existing production methods.

[0033]

[Chemical 10]

(In the above formula, R¹As already defined
It ) That is, for example, represented by the above general formula (I)
Of the compounds, R²And R ³Together with oxygen atom
From the compound represented by
Lithium copper in diethyl ether at -100 ℃ ~ room temperature,
Those acting in an ether solvent such as tetrahydrofuran
The above compound (J) can be produced by a method such as
Ether solvents such as ruthel and tetrahydrofuran,
Aromatic hydrocarbon solvents such as benzene and toluene, or n-
-7 in a saturated hydrocarbon solvent such as hexane or n-heptane
Metal water such as dibutylaluminum hydride at 0 to 50 ° C
Metal complex compounds such as halides and lithium aluminum hydride
1 to 10 equivalents for 5 minutes to 5 hours
It is possible to produce sarcophytol A.

As described above, the synthetic route of sarcophytol A using the compound of the present invention as an intermediate is an industrially excellent route for producing sarcophytol A, and therefore the compound of the present invention has its object. Is a very important synthetic intermediate.

[0036]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to the following examples unless it exceeds the gist. Synthesis example 1

[0037]

[Chemical 11]

The alcohol compound represented by the above formula (1) [J. Org. Chem. 51, No. 22, 4316-
Item 4319 (1986)] (4.55 g)
_It was dissolved in ₃ CN (50 ml) and triphenylphosphine (5.5 g) was added. CBr ₄ (7g) under cooling at 0 ° C
Was added in 3 portions and added every 5 minutes. After confirming the completion of the reaction, the mixture was concentrated, hexane was added, the mixture was stirred well, filtered through Celite, and the residue obtained after concentration was subjected to silica gel column chromatography (developing solvent, hexane: ethyl ether =
98: 2), and the desired compound (7 g) represented by the above formula (2) was synthesized.

¹ H-NMR (90 MHz) δ = 1.58 (s, 3H) 1.70 (s, 3H) 1.74 (s, 3H) 2.05 (brs, 11H) 3.96 (s, 2H) 4.58 (d, J = 7.03 Hz, 2H) 5.09 (m, 1H) 5.33 (m, 1H) 5.56 (m, 1H) Synthesis example 2

[0040]

[Chemical formula 12]

Acetate (7) represented by the above formula (2)
g) was dissolved in methanol (100 ml), K ₂ CO ₃ (6.7 g) was added under cooling at 0 ° C., and the mixture was sufficiently stirred. One hour later,
After confirming the completion of the reaction and washing with water and saturated saline, the ether layer was separated, dried over anhydrous magnesium sulfate, and concentrated to obtain a residue, which was subjected to silica gel column chromatography (developing solvent, hexane: ethyl ether = The compound (7.37 g) represented by the above formula (3) was synthesized.

¹ H-NMR (90 MHz) δ = 1.60 (s, 3H) 1.67 (s, 3H) 1.74 (s, 3H) 2.05 (brs, 8H) 3.97 (s, 2H) 4.15 (d, J = 6.81 Hz, 2H) 5.10 (m, 1H) 5.40 (m, 1H) 5.56 (m, 1H) Synthesis example 3

[0043]

[Chemical 13]

The hydroxybromine derivative (7.37 g) represented by the above formula (3) was dissolved in a mixed solution of benzene (1 ml) and methylene chloride (1 ml), and manganese dioxide (14
g) was added little by little, and the mixture was stirred at room temperature for 20 hours. After confirming the completion of the reaction, the residue obtained by filtering through Celite and concentrating was purified by silica gel column chromatography (developing solvent, hexane: ethyl ether = 98: 2), and the desired formula (4) was used. The represented compound (1.86 g, total yield 38%) was synthesized.

¹ H-NMR (90 MHz) δ = 1.60 (s, 3 H) 1.74 (s, 3 H) 2.05 (brs, 11 H) 3.95 (s, 2 H) 5.08 (brs, 1H) 5.56 (brs, 1H) 5.80 (brs, 1H) 9.97 (d, J = 7.91 Hz, 1H) Synthesis example 4

[0046]

[Chemical 14]

The crotonaldehyde (10 ml) represented by the above formula (5) was dissolved in methylene chloride (45 ml),
After adding hydroquinone (50 ml), a solution of bromine (6.2 ml) dissolved in methylene chloride (45 ml) was slowly added dropwise over 6 hours under cooling at 0 ° C. Potassium acetate (17.8 g) was added to this under cooling at 0 ° C., and the mixture was allowed to stand at room temperature overnight. Ether was added to this, washed with water and saturated saline, the ether layer was separated, dried over anhydrous magnesium sulfate, and concentrated to synthesize the desired compound (17 g) represented by the above formula (6). ..

¹ H-NMR (90 MHz) δ = 2.15 (d, J = 6.48 Hz, 3 H) 7.20 (d, J = 6.48 Hz, 1 H) 9.21 (s, J H) Synthesis Example 5

[0049]

[Chemical 15]

Formyl body (17) represented by the above formula (6)
g) is dissolved in ethanol (100 ml), and (C ₂ H ₅
O) ₃ CH (24 ml) and paratoluenesulfonic acid were added in small amounts, and the mixture was stirred at room temperature. After 15 hours, the mixture was diluted with ether, washed with water, aqueous NaHCO ₃ , and saturated saline in this order, and then the ether layer was separated and dried over anhydrous magnesium sulfate. After concentrating this, vacuum distillation (49-53 ° C / 3m
The target compound (15.31 g, total yield 57%) represented by the above formula (7) was synthesized with mHg).

¹ H-NMR (90 MHz) δ = 1.31 (t, J = 7.03 Hz, 6 H) 1.50 (dd, J = 0.88 Hz, J = 6.59 Hz, 3 H) 3.55 ( ABXm, 4H) 4.78 (brs, 1H) 6.30 (dq, J = 0.88 Hz, J = 6.59 Hz, 1H) Synthesis example 6

[0052]

[Chemical 16]

Under an argon atmosphere, hexane (15 ml) was added to the acetal (1.26 g) represented by the above formula (7), and normal butyl lithium (1.8) was added under cooling at -78 ° C.
5 ml, 1.1 eq) was added slowly. Then -40 ℃
The temperature was raised to 1 hour, and after 1 hour, it was confirmed by gas chromatography that the acetal had disappeared, then the mixture was cooled to -78 ° C, and the formyl body (843 m) represented by the above formula (4) was obtained.
What melt | dissolved g) in tetrahydrofuran (2 ml) was dripped slowly. 30 minutes later-78 ° C under cooling aqueous NH ₄
After quenching with Cl, it was extracted with ether. This was washed with saturated brine, the ether layer was separated, dried over anhydrous magnesium sulfate, and concentrated to give a residue, which was purified by silica gel column chromatography (developing solvent, hexane: ethyl ether = 98: 2). A target compound (973.2 mg) represented by the above formula (9) was synthesized.

¹ H-NMR (90 MHz) δ = 1.10 to 1.40 (m, 6H) 1.58 (s, 6H) 1.68 (s, 3H) 1.77 (d, J = 6. 30 Hz, 3H) 2.05 to 2.20 (brm, 8H) 3.20 to 3.80 (m, 4H) 3.97 (s, 2H) 4.90 (brs, 1H) 5.00 to 5. 60 (m, 4H) 5.68 (q, J = 6.30Hz, 1H) Synthesis example 7

[0055]

[Chemical 17]

Alcohol represented by the above formula (10) (9
73.2 mg) was dissolved in methylene chloride (1.2 ml), and diisopropylethylamine (1.53 ml, 4 equivalents) and CH ₃ OCH ₂ Cl were added at 0 ° C. under an argon atmosphere.
(0.34 ml, 2 eq) was added to room temperature and after 1 hour diluted with ether. Aqueous 1N hydrochloric acid, aqueous NaHCO ₃ ,
After washing with saturated brine in that order, the ether layer was separated, dried over anhydrous magnesium sulfate, and concentrated to synthesize the desired compound (746 mg) represented by the above formula (11).

¹ H-NMR (90 MHz) δ = 1.00 to 1.30 (m, 6H) 1.57 (s, 6H) 1.72 (s, 3H) 1.80 (d, J = 7. 80 Hz, 3H) 2.05 (brs, 8H) 3.35 (s, 3H) 3.25 to 3.60 (m, 4H) 4.00 (s, 2H) 4.57 (s, 2H) 4. 80 (s, 1H) 5.00 to 5.20 (m, 3H) 5.30 to 5.60 (m, 1H) 5.92 (q, J = 7.80Hz, 1H) Synthesis example 8

[0058]

[Chemical 18]

The acetal represented by the above formula (11) (7
46 mg) was dissolved in methanol (12 ml) and water (3 ml), and copper sulfate (100 mg) was added at room temperature and the mixture was stirred. After 1 hour, dilute with ether, water, aqueous NaHCO 3.
₃ , washed with saturated saline in this order, the ether layer was separated, dried over anhydrous magnesium sulfate, and concentrated to give a residue, which was subjected to silica gel column chromatography (developing solvent, hexane:
The target compound (691.2 m) represented by the above formula (12) was purified by ethyl ether = 9: 1 to 1: 1).
g, total yield 59%) was synthesized.

¹ H-NMR (90 MHz) δ = 1.55 (s, 6 H) 1.72 (s, 3 H) 2.15 (d, J = 7.03 Hz, 3 H) 2.10 to 2.15 ( brm, 8H) 3.33 (s, 3H) 4.00 (s, 2H) 4.48, 4.45 (dd, 2H) 4.98 to 5.20 (brm, 1H) 5.44 (brs, 3H) 6.67 (q, J = 7.03 Hz, 1H) 9.35 (s, 1H) Synthesis example 9

[0061]

[Chemical 19]

The formyl body (6) represented by the above formula (12)
91.2 mg), trimethylsilyl nitrile (0.22 ml) and potassium cyanide 18 crown 6 under cooling at 0 ° C.
Two hours after adding a small amount of ether, the reaction was completed, and the temperature was 0 ° C.
Tetrahydrofuran (10 ml) and aqueous 1N hydrochloric acid (2 ml) were added under cooling. After 20 minutes, the mixture was diluted with ether, washed with water, the ether layer was separated, dried over anhydrous magnesium sulfate, and concentrated. This was dissolved in benzene (10 ml) and cooled at 0 ° C with ethyl vinyl ether (0.25 ml).
Was added, and a small amount of paratoluenesulfonic acid was added. After stirring for 50 minutes, the mixture was diluted with ether under cooling at 0 ° C., water, aqueous N 2
aHCO ₃ and saturated brine were washed in this order, the ether layer was separated, dried over anhydrous magnesium sulfate, and concentrated to obtain a residue, which was subjected to silica gel column chromatography (developing solvent, hexane: ethyl ether = 9: 1 to 1). 1) and the desired compound represented by the above formula (13) (466 mg, total yield 54%) was synthesized.

¹ H-NMR (90 MHz) δ = 1.25 (m, 6 H) 1.59 (brs, 6 H) 1.72 (s, 3 H) 2.05 (brm, 11 H) 3.35 (s, 3H) 3.35 to 3.99 (m, 2H) 4.00 (s, 2H) 4.50 (brs, 2H) 4.80 to 5.20 (brm, 2H) 5.40 to 5.70 ( brm, 1H) 6.48 (q, 1H) IR (film) cm ⁻¹ : 2968, 2926, 172
8, 1689, 1661, 1444, 1380, 126
7, 1147, 1094, 1031, 933, 879 Example 1

[0064]

[Chemical 20]

Under an argon atmosphere, a mixture of hexamethyldihirazane [NH (TMS) ₂ ] (0.087 ml) and tetrahydrofuran (2 ml) was cooled to 0 ° C. and normal butyllithium (0.23 ml, 9.5 equivalents) was added. ) Was gradually added. After stirring for 30 minutes under cooling at 0 ° C., a solution of allyl chloride (21.1 mg) in tetrahydrofuran (2 ml) was slowly added dropwise over 2 hours while heating and refluxing at 60 ° C. This was quenched with NH ₄ Cl, extracted with ether, washed with saturated brine, the ether was separated, dried over anhydrous magnesium sulfate, and concentrated to give a residue, which was then subjected to silica gel column chromatography (developing solvent, hexane: ethyl). The product was purified with ether = 9: 1 to 1: 1) to obtain the desired compound represented by the above formula (14) (10.7 mg, total yield 62%).

(The compound of the above formula (14) is one of the compounds represented by the above general formula (A).) ¹ H-NMR (90 MHz) δ = 1.25 (m, 6H) 1.47 (S, 3H) 1.56 (brs, 6H) 1.95 (d, J = 7Hz, 3H) 2.00 (brs, 8H) 2.16 (brs, 2H) 3.36 (d, J = 3Hz) , 3H) 3.40 to 3.80 (q, 2H) 4.52, 4.63 (dd, 2H) 4.80 to 5.40 (brm, 3H) 5.70 (m, 2H) 6.12 (Q, 1H) Example 2

[0067]

[Chemical 21]

The cyclized cyanohydrin ether compound (201 mg) represented by the above formula (14) was dissolved in tetrahydrofuran (2 ml) and 80% acetic acid, and the mixture was stirred at room temperature. Two
After 7 hours it was diluted with ether and washed vigorously with 2% aqueous NaOH. After the cyanohydrin returned to the ketone, it was washed with water and saturated brine, the ether layer was separated, dried over anhydrous magnesium sulfate, and concentrated. The residue obtained was purified by silica gel column chromatography (developing solvent, hexane: ethyl ether). = 9: 1 to 1: 1) to obtain the desired compound represented by the above formula (15) (45.6 mg, total yield 25%).

(The compounds of the above formulas (14) and (15) are one of the compounds represented by the above general formula (A).) ¹ H-NMR (500 MHz) δ = 1.50 (s, 3H) 1.66 (s, 3H) 1.67 (s, 3H) 2.00 to 2.15 (brs, 8H and d, J = 7.14 Hz, 3H) 3.20 (ABq, J = 14. 62 Hz, 2H) 3.35 (s, 3H) 4.50 (d, J = 6.59 Hz, 1H) 4.60 (d, J = 6.53 Hz, 1H) 4.80 (brm, 2H) 5. 55 (ABq, 2H) 6.75 (q, J = 7.36Hz, 1H) IR (film) cm ^-1 : 3380, 2920, 1658, 1440, 1383, 1290, 1261, 1214, 1149, 1094, 1042. 920 Reference example 1

[0070]

[Chemical formula 22]

Copper iodide (45 mg) purified by a conventional method
Ethyl ether (1 ml) was added under argon atmosphere,
Methyllithium (0.45 ml, 1.0
5 eq.) Was added. After the temperature was raised to 0 ° C., the mixture was stirred for 30 minutes, cooled again to −78 ° C., and methoxymethyl ether (45.6 mg) represented by the above formula (15) was dissolved in ethyl ether (0.2 ml). The thing was dripped slowly.
After 1 hour, it was quenched with aqueous NH ₄ Cl, extracted with ether and washed with saturated brine. The ether layer was separated, dried over anhydrous magnesium sulfate, and concentrated to obtain a residue, which was then subjected to silica gel column chromatography (developing solvent, hexane:
Purification with ethyl ether = 19: 1), and the desired compound represented by the above formula (J) (7.3 mg, total yield 2)
1.4%) was obtained.

(The compound of the above formula (15) is one of the compounds represented by the above general formula (I).) ¹ H-NMR (300 MHz) δ = 1.08 (d, J = 6) .87 Hz, 6 H) 1.46 (s, 3 H) 1.72 (s, 3 H) 1.77 (s, 3 H) 2.10 (brs, 8 H) 2.67 (sept, 1 H) 3.15 (s , 2H) 4.94 (t, J = 6.87 Hz, 1H) 5.00 (t, J = 6.31 Hz, 1H) 5.88 (d, J = 11.88 Hz, 1H) 6.21 (d , J = 11.88 Hz, 1H) Reference Example 2

[0073]

[Chemical formula 23]

Under an argon atmosphere, 2.5 ml of a solution of the ketone body (137 mg, 0.48 mmol) represented by the above formula (J) in dry toluene was stirred on a refrigerant bath at -70 ° C. while stirring for diisobutylaluminum hydride. 0.6 ml of 1M toluene solution was added dropwise. After 1 hour, the disappearance of the raw materials was confirmed, 0.25 ml of water was added, the bath was removed, and the mixture was stirred well. After drying over anhydrous magnesium sulfate, stirring and filtering,
The residue obtained by concentration is subjected to silica gel column chromatography (developing solvent, n-hexane: ethyl acetate = 12: 1).
Purified at the desired sarcophytol A (125m
g, 88%).

[0075]

INDUSTRIAL APPLICABILITY The compound of the present invention is extremely useful as a synthetic intermediate of sarcophytol A having an anticarcinogenic promoter action and an antitumor action.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location C07C 309/66 9160-4H 309/73 9160-4H C07F 7/18 A 8018-4H

Claims (1)

[Claims] 1. The following general formula (I):[In the above general formula (I), R¹Is a hydrogen atom, 1-alco
Xyalkyl group, -SO ₂R^Four(R^FourHas 1 to 4 carbon atoms
Substituted with an alkyl group or an alkyl group having 1 to 4 carbon atoms
Represents a phenyl group which may be present. ) Or -SiR^FiveR
⁶R⁷(R^Five, R ⁶, And R⁷Each independently charcoal
It represents an alkyl group having a prime number of 1 to 4 or a phenyl group. )
Represent, R²And R³Are each independently -CN or
-OR⁸(R⁸Is a hydrogen atom, 1-alkoxyalkyl group
Alternatively, it represents a trimethylsilyl group. ), But R²Oh
And R³May together represent an oxygen atom. Na
Oh, R ¹Is -SO₂R^FourTo represent R²And R³
Together represent an oxygen atom. ] Cyclic tell represented by
Pens.