JPS6048515B2 - Method for producing hydroxy delta lactones - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing hydroxy delta-lactones.

That is, the present invention provides 2-hydroxy-2-anokyl-6
- Heptenal is reduced to give 2-alkyno-6-hepten-1,2-diol, and after protecting the primary hydroxyl group, the double bond is oxidatively cleaved to give the general formula (I) (wherein R" is It represents an alkyl group, and X represents a hydroxyl group protecting group.

) and further oxidize it,
General formula (■) (in the formula, R represents the same meaning as above,
represents a hydroxyl protecting group.

), and then the protecting group is removed after alkylation.
) (in the formula, R" has the same meaning as above, and R° represents an alkyl group.

) is a method for producing hydroxy delta lactones.

Examples of the compound of the general formula (■) which is the subject of the present invention include a methyl group, an ethyl group, an n-propyl group,
Isopropyl group, n-butyl group, isobutyl group, n-amine group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, etc., as R2 methyl group, ethyl group, n-propyl group , isopropyl group, n-butyl group,
Examples include isobutyl group and n-amyl group.

Here, starting from the raw material compound 2-hydroxy-2-alkyl-6-heptenal in the production method of the present invention, the intermediate 2-alkyl-6-hepten-1,2-diol, the lactols of the general formula (I) and the general formula The lactones in (■) include optically active forms or racemic forms, and the final products of general formula (■) are optically active forms or (In the formula, R'' and R゜ are the same as above.) According to the method of the present invention, the optically active starting compound 2-hydroxy-2-alkyl-6
- When using heptenal, via an optically active intermediate,
Gives an optically active final product (■).

The hydroxydelta-lactones of the general formula (■) obtained by the present invention have antibacterial activity, for example (2RN5S
)-2-methyl-5-nonyl-5-(hydroxymethyl)deltavalerolactone [R1 in general formula (■)
is a nonyl group, R2 is a methyl group] is called (-)-malingolide, and Marineblue-Greena
It is a marine natural product contained in Yamajuscula GOmOnt, and MycObacteriu
msmegmatis and StreptOcOccu
It is known to have antibacterial activity against spyOgenes and is a very important compound.

(J.Org.Chem., 444O39 (1979)
) According to the method of the present invention, by using (S)-2-hydroxy-2-nonyl-6-heptenal, (1)-
Malingolide was converted into (+)-malingolide by using (R)-2-hydroxy-2-nonyl-6-heptenal, and racemic malingolide was further converted into new racemic malingolide by using racemic 2-hydroxy-2-nonyl-6-heptenal. It can be produced industrially advantageously. 2-Hydroxy-2- which is the raw material compound of the present invention
Alkyl-6-heptenal can be produced from 6-hepten-2-one-1-al aminal, for example, as shown in the Reference Examples below.

Each process i for producing hydroxy delta-lactone will be described in more detail below.

) Reduction 2-alkyl-166-hepten-1,2-diol is produced by reducing 2-hydroxy-2-alkyl-6-heptenal. In reducing the compound, the reducing agent is, for example, lithium aluminum hydride. , sodium borohydride, diisobutylaluminum hydride, lithium borohydride, and other conventional reducing agents that do not act on double bond IZ bonding and can reduce carbonyl groups may be used.

The solvent used for reduction varies depending on the type of reducing agent, but may be one commonly used for that reducing agent. For example, when reducing with lithium aluminum hydride or lithium borohydride, ether, tetrahydrofuran, etc. are used, when reducing with sodium borohydride, ethanol is used, and when reducing diglyme, etc. with diisobutylaluminum hydride, benzene, toluene, etc. , ether, tetrahydrofuran and the like. Although the reaction temperature is not particularly limited, the reaction can be carried out at a temperature below the boiling point of the solvent used. 2) Protection The primary hydroxyl group of 2-alkyl-6-heptene-1,2-diol is protected, and any protecting group that can be used may be one that can withstand basic conditions and oxidizing conditions, such as trimethylsilyl group, Examples include dimethyl, t-butylsilyl group, benzyl group, methoxyethoxymethyl group, and tetrahydropyranyl group.

The method of introducing the protecting group differs depending on the protecting group, but may be any method commonly used for the introduction 3 of the protecting group. For example, in the case of a trimethylsilyl group or dimethyl t-butylsilyl group, a method of reacting trimethylsilyl chloride or dimethyl t-butylsilyl chloride with an alcohol in the presence of an amine, and in the case of a benzyl group, a method of reacting benzyl chloride with sodium alkoxide. In the case of a methoxyethoxymethyl group, a method of reacting methoxyethoxymethyl chloride with an alcohol in the presence of an amine, and a method of reacting methoxyethoxymethyl chloride with an alcohol in the presence of an amine;
, 3-dihydrobyran and alcohol. (3) Oxidation Lactols are produced by oxidizing 2-alkyl-6-hepten-2-ols, but any oxidizing agent that does not act on hydroxyl groups and oxidatively cleaves double bonds may be used. .

For example, ozone etc. can be mentioned. The solvent used for oxidation varies depending on the oxidizing agent used, but for example, when using ozone, methanol, methylene chloride, chloroform,
Any solvent commonly used for ozone oxidation such as ethyl acetate or ether may be used. Although the reaction temperature is not particularly limited, the reaction can be carried out at a temperature below the boiling point of the solvent used. 5-hydroxyhexanals, which are thought to be produced by oxidizing 2-alkyl-6-hepten-2-ols, cyclize during treatment at room temperature and become lactols. (4) Oxidation (general formula (I) → general formula (■)) Lactols are oxidized to produce lactones. As an oxidizing agent, for example, Collins reagent (
Any oxidizing agent commonly used for oxidizing lactols, such as chromic acid-pyridine complex), pyridinium chlorochromate, pyridinium dichromate, silver carbonate, or manganese dioxide, may be used.

The solvent used for oxidation varies depending on the oxidizing agent used, but may be any solvent commonly used for the oxidizing agent. For example, when using Collins reagent or pyridinium chlorochromate, use methylene chloride, etc. When using pyridinium cyclomate, use methylene chloride, N,N-dimethylformamide, etc. When using silver carbonate, use benzene, toluene, etc.
Examples include methylene chloride, and when using manganese dioxide, methylene chloride, petroleum ether, and the like. Although the reaction temperature is not particularly limited, the reaction can be carried out at a temperature below the boiling point of the solvent used. (5) Alkylation When alkylating the lactone ring, a conventional alkylation method may be used.

That is, an anion is created at the a-position of the carbonyl group using a strong base and then alkylated using an alkylating agent. Ru. Examples of strong bases that can be used include lithium amide, lithium diisopropylamide, lithium dicyclohexylamide, and sodium amide. As the alkylating agent, commonly used alkylating agents such as alkyl halides, alkyl tosylenites, and dialkyl sulfates may be used. For example, methyl bromide, methyl iodide, ethyl bromide, ethyl iodide, isopropyl chloride, isopropyl bromide, isopropyl iodide, n-butyl chloride, n-bromide.
Butyl, n-4 butyl iodide, isobutyl chloride, isobutyl bromide, isobutyl iodide, methyl tosylate, ethyl tosylate, n-propyl tosylate, isopropyl tosylate, n-butyl tosylate, dimethyl sulfate, diethyl sulfate, etc. can be mentioned. The solvent used for alkylation varies depending on the strong base used, but lithium amide,
In the case of sodium amide, examples include liquid ammonia, and in the case of lithium diisopropylamide and lithium dicyclohexylamide, ether, tetrahydrofuran, etc. can be cited. In addition, aprotic polar solvents such as hexamethylphosphoric triamide, N,N-dimethylformamide, and dimethyl sulfoxide can also be used.
Further, it can be carried out either alone or in a mixed solvent of two or more types. It is best to carry out the reaction at the bottom temperature.
It is advantageous to carry out the reaction at temperatures below 0°C, preferably below -20°C. (6) Deprotection Deprotection is carried out by a method commonly used for deprotecting the protecting group used.

For example, in the case of trimethylsilyl group, dimethylsilyl t-butylsilyl group, acid treatment such as acetic acid or hydrochloric acid, tetrabutylammonium fluoride treatment, etc. are carried out in the case of trimethylsilyl group, dimethylsilyl t-butylsilyl group, catalytic hydrogenation in the case of benzyl group, and catalytic hydrogenation in the case of methoxyethoxymethyl group. In the case of a tetrahydropyranyl group, treatment with an acid such as acetic acid or hydrochloric acid can be mentioned. EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited only to these Examples.

Customer Example 13.53y (S)-2-(anilinomethyl)
The mixture was dissolved in pyrodine and 2.57y methyl hydroxymethoxyacetate-benzene, refluxed for 3 minutes, and the resulting water was removed azeotropically.

The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 100 mt of tetrahydrofuran. , anhydrous magnesium chloride 1.
Add 89f1 and add 1 hour:! It refluxed. The mixture was cooled to 100°C and 1.5 times equivalent of a diethyl ether solution of 4-pentenylmagnesium bumide was added.

A saturated ammonium chloride aqueous solution was added to the reaction mixture, the temperature was raised to room temperature, and the mixture was extracted with diethyl ether. After drying the extract with Glauber's salt, the solvent was distilled off under reduced pressure to obtain 5.1y of hexahydro-2-phenyl-2-(5'-hexenoyl) -IH-
Pyrrolo[1.2-C]imidazole was obtained. Reference Example 2 Hexahydro 2-(5'-
Hexenoyl)-IH-pyrrolo[1.2-C]imidazole 5.1y was dissolved in 150 mι of diethyl ether and cooled to -100°C.

Diethyl ether solution of n-nonylmagnesium bromide 1. Added 1 equivalent of Akira. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the temperature was raised to room temperature. Separate the aqueous layer;
The diethyl ether layer was cooled to 0°C and diluted with 2% aqueous hydrochloric acid solution.
0wLι was added and reacted for 1 hour. The diethyl ether layer was separated and the aqueous layer was extracted with diethyl ether. The mixed diethyl ether layers were washed with saturated brine and then dried with sodium sulfate. The solvent was distilled off under reduced pressure and 3.82 g of (S)-
2-Hydroxy-2-nonyl-6-heptenal was obtained. Example 1 2.52 Da of (S)-2-hydroxy-2-nonyl-6-heptenal obtained by the method listed in Reference Example 2 was added to 100
The mixture was dissolved in mι of ethanol, 380 mg of sodium borohydride was added, and the mixture was reacted at 0°C for 3 times and at 25°C for 3 minutes.

Water was added to the reaction solution, and the mixture was extracted with methylene chloride. After drying the extract with Glauber's salt, the solvent was distilled off under reduced pressure, and the resulting residue was purified with a silica gel column to obtain 1.49y of (S)-2.
-nonyl-6-heptene-1,2-diol was obtained. N
The MR peak is δ (CCl4, ppm) = 0.87 (3H
, boulevard triplet), 1.23 (20H, plod), 1.80-2.20 (river, multiplet), 3
．． 10 (IH, Prode), 3.23 (2H, Prode), 3.57 (IH, Prode), 4.70-5.10
(2H, multiplet), 5.30-6.00 (IH
, multiplet). The optical rotation is [a] -0.
It was 35° (Neat). Example 2 1.47y of (S)-2-nonyl-6-heptene 1,2-diol obtained in Example 1 was dissolved in 6ml of N,N-dimethylformamide, and 10ml of 4-dimethylaminopyridine and toluethylamine were added. 0.75 da and 0.91 y of dimethyl t-butylsilyl chloride were added and reacted at 0°C for 2 hours.
Water was added to the reaction solution, and the mixture was extracted with n-hexane. After drying the extract with Glauber's salt, the solvent was distilled off under pressure, and the resulting residue was purified with a silica gel column to obtain 1.76y of (S)-2-
Nonyl-1-dimethyl t-butylsiloxy 6-hepten-2-ol was obtained. The NMR peak is δ (CCl4
, ppm) = 0.03 (6H, singlet), 0.9
0 (12H, singlet), 1.23 (20H, prod), 1.70-2.10 (3H, multiplet)
, 3.30 (2H, singlet), 4.60-5.1
0 (2H, multiplet), 5.30-6.00 (I
H, multiplet). The optical rotation is [a) r-0
．． It was 25° (Neat).

Example 3 1.52 da of (S)-2-nonyl-1-dimethyl t-butylsiloxy-6-hepten-2-ol obtained in Example 2 was dissolved in 45 ml of methanol, and
It was cooled to ℃ to react with ozone.

After the raw materials disappeared (confirmed by Tlc), 4 ml of dimethyl sulfide was added, the temperature was raised to room temperature, and the mixture was reacted for 1.5 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified using a silica gel column to obtain 1.06 g of (6S)-6-hydroxymethyl-6-nonyltetrahydro-2H-pyran-2-ol. The NMR peak is δ (CCl.

, ppm) = 0.03 (6H, singlet), 0.
90 (12H, singlet), 1.10-2.00 (
22H, Prode), 3.20 to 3.50 (3H, Prode), and 4.83 (IH, Prode). Example 4 1.03 da of (6S)-6-hydroxyA methyl-6-nonyltetrahydro-2H-pyran-2-ol obtained in Example 3 was dissolved in 8 mι of N,N-dimethylformamide, and pyridinium dimethyl 3.66y of chromate was added and reacted at 25°C for 1 minute.

Water was added to the reaction solution, and the mixture was extracted with diethyl ether. After drying the extract with Glauber's salt, the solvent was distilled off under reduced pressure, and the resulting residue was purified with a silica gel column to obtain 885 mg of (S).
-5-nonyl-5-(dimethylt-butylsiloxymethyl)deltavalerolactone was obtained. The NMR peaks are δ (CCl4, ppm) = 0.03 (6H, singlet), 1.23 (16H, broad), 1.60-2
．． 00 (4H, multiplet), 2.00-2.40
(2H, multiplet) and 3.43 (2H, singlet).

The optical rotation was [a] -0.89° (Cl.57, chloroform). Example 5 Diisopropylamine 55
Dissolve mg in 1.5 mι of tetrahydrofuran and heat at 0°C.
Then, 0.5 mmol of n-hexane solution of n-butyllithium was added dropwise.

After three powder reactions at 0.degree. C., 0.08 ml of hexamethylphosphoric triamide was added. The obtained lithium diisopropylamide solution was cooled to -78°C, and Example 4
(S)-5-nonyl-5-(dimethylt) obtained in
-butylsiloxymethyl)deltavalerolactone 109
A solution prepared by dissolving 1 ml of tetrahydrofuran was added dropwise. After reacting at -78℃ for 3 minutes, 0 methyl iodide
．． A solution prepared by dissolving 0.06 mι in 1 ml of tetrahydrofuran was added dropwise. After carrying out three powder reactions at -78°C, a saturated aqueous ammonium chloride solution was added and extracted with diethyl ether. After drying the extract over Glauber's salt, the solvent was distilled off under reduced pressure, and the resulting residue was purified using a silica gel column.
R,5S)-2-methyl-5-nonyl-5-(dimethylt-butylsiloxymethyl)deltavalerolactone and (2S,5S)-2-methyl-5-nonyl-5-(
A mixture of dimethyl t-butylsiloxymethyl)deltavalerolactone was obtained. Example 6 1.5 of 84 m9 of the lactone mixture obtained in Example 5;
ml of tetrahydrofuran, 130 mg of tetrabutylammonium fluoride was added, and the mixture was reacted at 25° C. for 15 minutes.

Water was added to the reaction solution, and the mixture was extracted with diethyl ether. After drying the extract over Glauber's salt, the solvent was distilled off under reduced pressure, and the resulting residue was separated and purified using a silica gel column to obtain 34 mg of (2
R,5S)-2-methyl-5-nonyl-5-(hydroxymethyl)delta valerolactone ((-)-malingolide) and 17 mg of (2S,5S)-2-methyl-5-nonyl-5-(hydroxymethyl)delta Valerolactone was also obtained. NMR of the obtained (-)-malingolide
The peak is δ (CDCl., ppm) = 0.87G old,
Prode Triplet), 1.30 (19H, Prode), 1.50-2.20 (4H, Multiplet), 2
．． 40 (IH, multiplet), 3.47 (IH, tablet, J = 12Hz), and 3.70 (IH, tablet, J = 12Hz). The optical rotation is [a) Z2-
12.3° (Cl.O7, chloroform) Optical purity is 9
It was 5%. (2R,5S)-2-methyl-5-
The NMR peak of nonyl-5-(hydroxymethyl)deltavalerolactone is δ (CDCl3, ppm) = 0.
87 (3H, Prode triplet), 1.27 (19
H, broad gate), 1.50 to 2.20 (4H, multiplet), 2.30 to 2.70 (IH, multiplet), and 3.50 (2H, broad).

The optical rotation was [a] +19.1° (Cl.l3, chloroform). Example 7 120 mg of (±)-5-nonyl-5-(dimethylt-butylsiloxymethyl)deltavalerolactone was dissolved in 2 ml of tetrahydrofuran, 200 mg of tetrabutylammonium fluoride was added, and the mixture was reacted at 25°C for 15 minutes.

Water was added to the reaction solution, and the mixture was extracted with diethyl ether. After drying the extract over Glauber's salt, the solvent was distilled off under reduced pressure, and the resulting residue was separated and purified using a silica gel column to give 70 m9 of (±)-
5-nonyl-5-(hydroxymethyl)deltavalerolactone was obtained. The NMR peak is δ (CCl4, ppm
) =0°87 (3H, Prode triplet), 1.
l~2.0 (20H, multiplet), 2.1~2.
4 (2H, multiplet), 3.36 (2H, singlet), and 3.60 (IH, probe).

Claims (1)

[Claims] 1. Lactones represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▲Mathematical formula, characterized by removing the protecting group of the hydroxyl group,
There are chemical formulas, tables, etc. ▼ (In the formula, R^1 represents the same meaning as above, and R^2 represents an alkyl group) A method for producing hydroxy delta-lactones. 2 2-Hydroxy-2-alkyl-heptenal is reduced to form 2-alkyl-6-hepten-1,2-diol, and after protecting the primary hydroxyl group, oxidative cleavage of the double bond is performed to obtain the general formula ▲Math. , chemical formulas, tables, etc. ▼ (In the formula, R^1 represents an alkyl group and There are lactones represented by ▼ (in the formula, R^1 represents the same meaning as above, and X represents a hydroxyl group-protecting group), and then alkylation is performed, and then the hydroxyl group-protecting group is removed. A method for producing hydroxy delta-lactones represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 represents the same meaning as above, and R^2 represents an alkyl group.) .