JPS62209033A - Production of 2-methylene-1, 4-diol compound - Google Patents

Abstract

PURPOSE:To produce the titled compound useful as a raw material for alpha- methylene-gamma-butyrolactone known as an antitumor agent and antibacterial agent, in high yield, by using an easily producible homoallyl alcohol as a starting substance and oxidizing the substance with oxygen in the presence of a strongly basic substance. CONSTITUTION:The objective 2-methylene-1, 4-diol compound of formula II (e.g. 2-methylene-3-hydroxymethyl-6-methyl-5-heptadien-1ol) can be produced by oxidizing a homoallyl alcohol of formula I (R<1>-R<3> are H or 1-15C aliphatic hydrocarbon group; two of R<1>-R<3> may together with bonded C form a 5-10C ring) [e.g. lavandulol (2,6-dimethyl-3-hydroxymethyl-1,6-heptadiene)] with oxygen in the presence of a strongly basic substance such as sec-butyllithium. Preferably, the basic substance is used in combination with a tert-amine such as te tramethylethylenediamine.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention is based on the general formula (where Ht, Bz and R3 each represent a hydrogen atom or a saturated or unsaturated aliphatic hydrocarbon group having 1 to 15 carbon atoms) Two of R1, R2 and R3 together with the carbon atoms to which they are bonded have 5 to 5 carbon atoms.
Form 10 rings. ) 2-methylene-1,
The present invention relates to a method for producing 4-diols.

2-methylene-1,4- produced by the method of the present invention
Diols are useful as raw materials for α-methylene-γ-butyrolactone, which has antitumor and antibacterial effects.

Among α-methylene-γ-butyrolactone, vernolepin, 7a machiia 7 (a
romaticin), x levantbin (eleph
antopin), = rsteunolide (costun)
It is known that elmanthin, elemanthin, etc. have antitumor activity.
It is known that alantolactone, tulipalin A, and the like have antibacterial activity.

[Conventional technology]

2-(1-hydroxymethyleden-1-yl)-5, conventionally known as 2-methylene-1,4-diols
-Methylcyclohexanol m-
It has been reported that it can be produced by oxidizing with chloroperbenzoic acid to give the corresponding epoxy compound, and then isomerizing the epoxy compound with lithium diethylamide.

Chem, Int, Ed, Engl, 24 (198
5), 94-110 [Problems to be Solved by the Invention] Many of the physiologically active α-methylene-γ-butyrolactones have a substituent having a carbon-carbon double bond.
2-methylene-1 produced by using the reaction of these α-methylene-γ-butyrolactones according to the above-mentioned conventional method.
, 4-diols, it is necessary to select homoallyl alcohol having a substituent having a carbon-carbon double bond as the starting material. However, when homoallyl alcohol having a substituent having a carbon-carbon double bond is subjected to an epoxidation reaction, selectivity can be given to the epoxidation reaction at the target carbon-carbon double bond. As a result, it is difficult to produce α-methylene-γ-butyrolactone having this substituent in a good yield. Therefore, one of the objects of the present invention is to eliminate carbon-carbon double bonds. Another object of the present invention is to provide a method that can easily and efficiently produce a raw material that provides α-methylene-γ-butyrolactone having a substituent in a wide range of α- It is an object of the present invention to provide a method by which a raw material that provides methylene-γ-butyrolactone easily and with a high yield can be produced easily and with a high yield.

[Means for solving problems]

According to the invention, the above object is achieved by the general formula (wherein R1,R
2 and R3 are as defined above. ) is oxidized with oxygen in the presence of a strong basic substance.
- This is achieved by providing a method for producing methylene-1,4-diols.

Examples of the saturated or unsaturated aliphatic hydrocarbon group having 1 to 15 carbon atoms represented by R1, R2, and R3 in the above general formula include methyl, ethyl, n-propyl, inglovil, n-butyl, isobutyl, and 5ec-butyl. ,te
Alkyl groups such as rt-butyl, n-amyl, 3,7-dimethyloctyl, n-decyl; vinyl, allyl, frenyl, cheranyl, farnesyl, 10-methyl-10
-Alkenyl groups such as undecenyl; alkynyl groups such as ether and propynyl; and the like. '! 9. A ring having 5 to 10 carbon atoms formed by two of R1, R2 and R3 together with the carbon atom to which they are bonded, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclodecane, cyclodecene, Examples include cyclodecadiene.

Representative examples of the homoallyl alcohol represented by the general formula (■) used as a raw material in the method of the present invention include 3-methyl-3-buten-1-ol, lavandulol (2
, 6-dimethyl-3-hydroxymethyl-1,6-hebutadiene), 3-impropenyl-6-methyl-5-hepten-2-ol, isopulegol (2-isopropenyl-S-methylcyclohexanol), 1- (2-Methyl-3-propenyl)cyclohexanol, 2-isopropenyl-5,9-dimethyl-5,9-cyclodecadienol, 3-hydroxymethyl-2,6,10-trimethyl-1,5,9 -undecatriene, 3-hydroxymethyl-2,13-dimethyl-1,13-tetradecadiene, and the like.

The oxygen used in the oxidation reaction according to the method of the invention may be diluted with nitrogen, argon, helium, water vapor, etc.

Specifically, it is convenient to use air. As the strong basic substance to be present in the reaction system, for example, n-butyllithium, 5ec-butyllithium, tert-butyllithium, potassium tert-butoxide, potassium hydride, sodium hydride, potassium amide, or a mixture thereof can be used. It will be done. The amount of the strong basic substance used is usually about 2 to 10 mol, preferably 2 to 5 mol, per 1 mol of the homoallylic alcohol represented by the general formula (If).

Further, preferable results can be obtained by using a tertiary amine such as tetramethylethylenediamine in combination with the strong basic substance. The reaction temperature varies depending on the strong basic substance employed, but is generally in the range of -100°C to about 100°C, preferably in the range of about -80°C to about 60°C. This reaction is carried out in the presence or absence of a solvent, and examples of solvents include ethers such as tetrahydrofuran and diethyl ether; hydrocarbons such as n-hexane, n-hebutane, and cyclohexane. is used.

Separation of the 2-methylene-1,4-diols represented by the general formula (I) thus obtained from the reaction mixture.
Purification is carried out according to the method used for separating and purifying products obtained by general organic synthesis reactions from reaction mixtures.

Among homoallyl alcohols represented by general formula (n),
Homoallylic alcohol in which moieties and R2 are hydrogen atoms can be easily produced, for example, by the following method (1). However, homoallylic alcohol represented by general formula (I) can be easily produced from homo71J alcohol represented by general formula (■') by method (11) using Grignard reaction.

Static (■') (II) (In the above formula, R3 is as defined above, and X represents a halogen atom.) 2-methylene-1,4-diols represented by the general formula (1) are: For example, it can be easily converted to α-methylene-γ-butyrolactone by oxidizing it with activated manganese dioxide (Angew, Chem, Int.

Ed, Engl., 24 (1985), 94-110 [Example] The present invention will be explained below with reference to Examples, but the present invention is not limited to these Examples. Example 1 Nitrogen atmosphere Lavandulol 0.27 mmol and tetramethylethylenediamine 0.75 mmol below
was added to 1.5 rIL of dry diethyl ether,
Cooled to -78°C. Next, while maintaining the same temperature, 5ee-
0.75 mmol of chilllithium was added dropwise into the solution, and after the addition, the reaction solution was heated to room temperature and stirred for 1 hour. At this point, the reaction solution turned yellow. After the reaction solution was cooled again to -78°C, oxygen was introduced, the temperature was again raised to room temperature, and the mixture was stirred for 20 minutes. The reaction solution became colorless.

After the reaction was completed, an aqueous ammonium chloride solution was added to the reaction mixture, and then ether was added for extraction, and the ether was distilled off from the extract. Ethyl acetate 3d was added to the obtained residue, 25% sodium sulfite aqueous solution 3117 was added, and -
Stirred overnight. Next, it was extracted with ether, and the extract was washed with saturated brine. The solvent was distilled off and the residue was subjected to silica gel chromatography to obtain 2-methylene-3-hydroxymethyl-6-methyl-5-hebutadien-1-ol in a yield of 66%. Identification data for this item is shown below.

IR(neat): 3350.2900.1650.
1440.1380°10B0,1030,900,8
40,720(m)II(-NMR(CDα3+ 9
0 MHz) δ (ppm): 5.16 (wide s
, IH) 4.97 (same as above, IH) 5.02 (m, IH) 4.04 (wide 8.2H) 3.57 (m, IH) 2.40-1.97 (m, 3H) 1 .67
(Wide s, 3H) 1.59 (Same, J:, 3H) L3C-NMR (CDα3.22.5MHz) δ(pp
m): 149.8. 133.0. 122.1.1
13.2.65.5°65.3. 46.5. 29.
3. 17.8 Example 2 Isobregol l, Q mmo in the same manner as in Example 1
11 Tetramethylethylenediamine4. Q mmol
and n-butyllithium4. Using Q mmol,
2-(]-]Hydroxymethylenon-1-yl-5-methylcyclohexanol was reacted in 10% tetrahydrofuran, followed by work-up and purification.
It was obtained in a yield of . Full identification data for this item is shown below.

"H-NMR (CDCb, 90 MHz) δ(p
pm): 5.19 (wide s, 1II) 5.04 (same as above, IH) 4.11 (same as above, 2H) 3.82 (dt, J=4.1Hz and 10.2H
z, I I()0.95 (d, J=6.2Hz,
3H) Example 3 2-Methyl-2-propene-1-
Using 1 mmol of cyclohexanol and 4.0 mmol of n-butyl lithium, 10 rd of tetrahydro7 run was added in the absence of tetramethylethylenediamine.
1-(3-
Hydrodacy-2-methylenepropyl)cyclohexanol was obtained with a yield of 25%.

Identification data for this product is shown below.

"H-NMR (CDα3.gQMHz) δ (ppm)
:5.12 (wide s, IH) 4.88 (same as above, IH) 4.06 (same as above, 2H) 2.32 (same as above, 2H) 1.50 (m, IOH) 13C-NMR (CDQ!s, 22.5MHz) δ(p
pm): 144.9.116.2.71.2.87.
3.46.9゜37.9.25.7.22.5 Example 4 3-hydroxymethyl-2,13 was prepared in the same manner as in Example 3.
-dimethyl-1,13-tetradecadiene 0,081
mmol and n-butyllithium A O.
13-Methyl-13-tetradecen-1-ol'! 1
Obtained with a yield of -7Q%. Identification data for this item is shown below.

')(-NMR(CDαa, 90MH2)δ(pPm
): 5.20 (wide 8. IH) 5.00 (same as above, IH) 4.67 (same as above, 2) I) 4.08 (same as above, 2H) 3.60 (m, 2H) 1.72 (wide) s, 3H) 1.25 (m, 16H) 13C-NMR (CDα3.22.5MHz) δ(pp
m) :149.8.146.3.113.4.10'
), 6.66.1゜65.3.46.6.37.9.3
0.4.29.8.29.6゜29.6.29.4.2
7.7.27.4.22.5 Example 5 0.12 mmol of 2-impropenyl-5゜9-dimethyl-5,9-cyclohexanol was prepared in the same manner as in Example 1.
, tetramethylethylene diamy (0.59 mmol
) and 5ec-butyllithium Q, 59 mmol
was reacted in 1.2 Mt of tetrahydrofuran, followed by post-treatment and purification to give 2-(1-hydroxymethyletheno-1-yl)-5,9-dimethyl-5,9-
Cyclodecadienol was obtained with a yield of 54%. Identification data for this item is shown below.

IH-NMR (CDα3.90MHz) δ (ppm)
:5.16 (wide s, IH) 5.01 (same as above, IH) 4430 (m, IH) 4.69 (wide d, J=10.OHz, IH) 4.1
9 (dd, J=9.2Hz and 9,2Hz, I
H) 4.14 (wide s, 2H) 1.66 (same as above, 3H) 1.40 (same as above, 3H) 13C-NMR (CDα3) δ (ppm): 153.
0.137.9.134.7.132.9.126.7
゜112.0.71.4.65.1.55.0.41.
6.39.5゜32.2.25.8.1? , 0.16.
3 Example 6 In Example 5, te was used instead of 5ec-butyllithium.
The reaction was carried out using rt-butyllithium in the absence of tetramethylethylenediamine. 2-(1-hydroxymethyletheno-1-yl)-5,9-dimethyl-5
,9-cyclodecadienol was obtained in a yield of 40.

Reference Example 1 Synthesis of Costeunolide 0.042 mmol of 2-(1-hydroxymethylethen-1-yl)-5,9-dimethyl-5°9-cyclododecadienol obtained in Example 5 was dissolved in ether 2.
．． Activated manganese dioxide in o y 1. f34 mmol
and reacted at room temperature for 12 hours. The reaction suspension was passed through 70 Lysyl, and the P solution was concentrated under reduced pressure to obtain a crude product.

The crude product was purified by silica gel column chromatography to obtain costeunolide'H-NMR with a yield of 80%.
(CDα3.90MHz) δ (ppm): 6.26 (
d, J=3.4Hz, LH)5.52(d, J=3
．． 4Hz, IH) 4, ss (m, IH) 4.72 (d, J=9.8Hz, IH) 4.55 (d
d, J=9.8Hz and g, OHz, 3H)1.
71 (d, J=1.3Hz, 3H) 1.43 (wide a
, 3H) 13C-NMR (CDα3)δ (ppm): 170.
3. 141.3.140.2. 136.9.127
．． 4°127.1. 119.5. 81.9. 50
．． 5. 41.1°39.5. 28.2. 26.2
．． 17.3. 16.1 [Effects of the Invention] According to the present invention, as is clear from the Examples and Reference Examples, α-methylene-γ-butyrolactone having a substituent having a carbon-carbon double bond can be easily and efficiently produced. The 2-methylene-1,4-diols represented by the following general formula (I) can be easily produced with good yield.

Claims (1)

[Claims] General formula ▲ Numerical formulas, chemical formulas, tables, etc. represents a hydrocarbon group, or two of R^1, R^2 and R^3 together with the carbon atoms to which they are bonded form a ring having 5 to 10 carbon atoms.) There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. that are characterized by oxygen oxidation of the homoallylic alcohol shown in the presence of a strong basic substance ▼ (where R^1, R^2 and R^3 are the same as above) As defined above.) A method for producing 2-methylene-1,4-diols represented by: