JPH0119392B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a general formula useful as a synthetic intermediate for nanaomycins and frenolicins having antibacterial activity. (In the formula, R represents a lower alkyl group, R ¹ represents a hydrogen atom or a lower alkyl group, and R ² represents a hydrogen atom, an alkyl group, or an aralkyl group.)

In this specification, an alkyl group refers to methyl,
In addition to lower alkyl groups such as ethyl, propyl, isopropyl, butyl, and tertiary butyl, aralkyl groups include pentyl, hexyl, octyl, decyl, dodecyl, pentadecyl, octadecyl, etc., and halogen atoms and alkyl groups as substituents. ,
The term halogen atom refers to benzyl, phenylethyl, etc., which may have an alkoxy group, hydroxyl group, nitro group, amino group, etc., and chlorine, bromine, etc.

Conventionally, as a method for synthesizing nanaomycin A, frenolicin, and deoxyfrenolicin, the method by Ichihara et al. [Tetrahedron Letters, Vol. 21, 4469] has been used.
-4472 pages (1980)] and the method of Li et al. [Journal of the American Chemical Society, Vol. 100, pp. 6263-6265 (1978)] are known.

However, these methods only yield racemic forms, not natural optically active forms, and are also insufficient in terms of the number of steps and yield. There is a need for a versatile and highly efficient synthesis method with shorter steps.

In view of this point, the present inventors have conducted extensive research, and as a result, the synthetic intermediates of the general formula ()
The present invention has been completed by developing a method for easily producing the compound in high yield. That is, the present invention provides the general formula (In the formula, each symbol has the same meaning as above.) A compound represented by the general formula Z-X...() (In the formula, Z represents a protecting group and X represents a reactive atom or group.) The general formula produced by reacting the compounds represented by (In the formula, each symbol has the same meaning as above.) By subjecting the compound represented by the formula to a reduction reaction, the general formula (In the formula, each symbol has the same meaning as above.) By subjecting this to a ring-closing reaction, the general formula (In the formula, each symbol has the same meaning as above.) The present invention relates to a method for producing a compound of the general formula (), which is characterized in that the compound is subjected to an oxidation reaction.

The reactions in each step are known per se and proceed according to conventional methods, but preferred methods will be explained below.

As a compound of the general formula (), for example, the following general formula R ³ R ⁴ R ⁵ SiX ... (') (wherein R ³ , R ⁴ , and R ⁵ are the same or different and are lower alkyl group, phenyl group , X represents a reactive atom or group such as a halogen atom).

Examples of the compound of general formula (') include trimethylsilyl chloride, tertiary-butyldimethylsilyl chloride, and triphenylsilyl chloride.

The reaction between the compound of general formula () and the compound of general formula (') is conveniently carried out in the presence of imidazole.

In the reduction reaction of the compound of general formula () obtained by the reaction of the compound of general formula () with the compound of general formula (), the carbonyl group of the acyl side chain in the molecule is usually selectively reduced. A suitable reagent is used as a metal hydride complex compound, such as sodium borohydride.

The ring-closing reaction for converting the thus obtained compound of general formula () into a compound of general formula () usually proceeds by using an alcoholic solution of a metal alkoxide or metal hydroxide.

The oxidation reaction in the final step proceeds in a solvent such as acetonitrile, ether, methylene chloride, etc. using an oxidizing agent such as ceric ammonium nitrate or Flemy salt.

The obtained target product can be isolated and purified by conventional methods such as recrystallization and silica gel chromatography.

The compound of the present invention can be converted into nanaomycin A, frenolicin, and deoxyfrenolicin according to the method of Ichihara et al. or the method of Lee et al.

The compound of general formula () is a new compound,
For example, the general expression (In the formula, each symbol has the same meaning as above.) Compounds represented by and general formula (In the formula, R ⁶ , R ⁷ and R ⁸ are the same or different and represent an alkyl group or a phenyl group, and R ² has the same meaning as above.)

Further, the compound of the general formula () is synthesized from 1,5-dihydroxynaphthalene, and the compound of the general formula () is synthesized by the general formula CH ₂ =CHCH ₂ SiR ⁶ R ⁷ R ⁸ ... () (in the formula , each symbol has the same meaning as above.) It can be produced by subjecting an ate complex of the compound represented by the following to a carboxylic acid production reaction, and then, if necessary, esterifying it.

The present invention will be specifically explained below using Examples and Reference Examples.

Example 1 (i) 4-(3-acetyl-4-hydroxy-5-
Methoxy-1-oxo-1,2-dihydro-2
tert-butyldimethylsilyl chloride in methyl (naphthyl)-2-butenoate under nitrogen atmosphere
378 mg of imidazole, 408 mg of imidazole, and 2 ml of dimethylformamide were added, and after stirring at room temperature overnight, water was added and extracted with ether.

The ether layer was washed with water and dried in a conventional manner, and then subjected to silica gel column chromatography (eluent: methylene chloride) to obtain 322 mg of the corresponding 1-tert-butyldimethylsilyloxy compound. Colorless needles. Melting point 107-109℃. Yield 73%.

¹ H-NMR [in deuterated chloroform, δ
(ppm)]: 0.16 (s, 6H), 1.10 (s, 9H), 2.58
(s, 3H), 3.68 (s, 3H), 3.72 (d, 2H, J
= 6Hz), 4.02 (s, 3H), 5.68 (d, 1H, J =
16Hz), 6.80 (d, 1H, J=8Hz), 6.93 (d,
t, 1H, J = 6, 16Hz), 7.32 (t, 1H, J =
8Hz), 7.62 (d, 1H, J=8Hz), 9.45 (s,
1H) Infrared spectrum (liquid film method, cm ^-1 ): 3360 (br,
s), 1725 (vs), 1690 (vs) Mass spectrum (m/e): 444 (molecular ion peak) (ii) Hydrogen was added to a methanol solution of 127 mg (0.27 mmol) of this 1-tertiary butyldimethylsilyloxy compound. 3.8 mg of sodium boronate was added, and the mixture was stirred at room temperature for 1 hour. After adding a saturated ammonium chloride solution, extraction was performed with ether, and the ether layer was treated in a conventional manner.

After distilling off the ether under reduced pressure, the residue was subjected to silica gel column chromatography (developing solution: methylene chloride) to obtain 4-[1-tert-butyldimethylsilyloxy-4-hydroxy-3-(1-hydroxyethyl). -5-methoxy-2-naphthyl]-
120 mg of methyl 2-butenoate was obtained. Yield 94
%.

¹ H-NMR [in deuterated chloroform, δ
(ppm)]: 0.12 (s, 3H), 0.15 (s, 3H), 1.08
(s, 9H), 1.62 (d, 3H, J=7Hz), 3.68
(s, 3H), 3.75 (d, 2H, J=6Hz), 4.06
(s, 3H), 4.97 (m, 1H), 5.70 (d, 1H, J
= 16Hz), 6.82 (d, 1H, J = 8Hz), 7.08 (d,
t, 1H, J = 6, 16Hz), 7.27 (t, 1H, J =
8Hz), 7.65 (d, 1H, J=8Hz), 9.75 (s,
1H) (iii) Dissolve 60 mg of the compound thus obtained in methanol and add 0.1 ml of sodium methoxide solution (as a 26% sodium hydroxide solution in methanol) under stirring at room temperature. After stirring for 1 hour, saturated ammonium chloride solution was added, and the mixture was extracted with ether. After the ether layer was treated in a conventional manner and subjected to silica gel column chromatography, 5-tert-butyldimethylsilyloxy-10-hydroxy-9-
Methoxy-1-methyl-3,4-dihydro-
57 mg of methyl 1H-naphtho[2,3-C]pyran-3-yl acetate was obtained as a mixture of two diastereomers. Yield 94%.

¹ H-NMR [in deuterated chloroform, δ
(ppm)]: ~0.1 (s, 6H), 1.1 (s, 9H), 1.60
(d, 3H, J=7Hz), 2.2-3.2 (m), 3.70 (s,
3H), 3.73 (s, 3H), 4.00 (s, 3H), 3.5~4.4
(m, 1H), 5.2 (m, 1H), 6.70 (d, 1H, J=
8Hz), 7.20 (d, 1H, J=8Hz), 7.60 (d,
1H, J=8Hz), 9.25 (s, 1H), 9.32 (s,
1H) (iv) 57 mg of the mixture thus obtained
A solution of 170 mg of ceric ammonium nitrate dissolved in 1 ml of water was added to 2 ml of an acetonitrile solution of (0.12 mmol), and after stirring at room temperature for 5 minutes, water was added and extracted with ether. After treating the ether layer in a conventional manner, two diastereomers were separated using preparative liquid chromatography (developing solution: methylene chloride) to obtain 18 mg of O-methyl nanaomycin A methyl ester as yellow crystals. Yield 46%. Melting point 142-143°C (recrystallized from methanol).

¹ H-NMR [in deuterated chloroform, δ
(ppm)]: 1.54 (d, 3H, J = 7Hz), 2.12~
2.28 (ddd, 2H, J=2, 11, 19Hz), 2.60~
2.92 (d, 2H, J=6Hz; dd, 1H, J=3,
19Hz), 3.73 (s, 3H), 4.00 (s, 3H), 4.16~
4.46 (m, 1H), 4.85~5.10 (m, 1H), 7.20~
7.36 (m, 1H), 7.50-7.80 (m, 2H) Infrared spectrum (liquid film method, cm ^-1 ): 1735 (vs),
1655 (vs), 1585 (vs) Mass spectrum (20eV, relative intensity): 330
(M ⁺ , 80), 257 (100), 256 (85), 241 (43) Example 2 (i) 4-(3-butyryl-4-hydroxy-5-
Methoxy-1-oxo-1,2-dihydro-2
756 mg of tertiary-butyldimethylsilyl chloride, 816 mg of imidazole and 6 ml of dimethylformamide were added to methyl -naphthyl)-2-butenoate, and the mixture was stirred at room temperature under a nitrogen stream for 3 hours.

After adding water and extracting with ether, the resulting ether layer was treated in a conventional manner and then subjected to silica gel column chromatography (developing solution: methylene chloride).
784 mg of the corresponding 1-tert-butyldimethylsilyloxy compound was obtained. Yield 83%.

¹ H-NMR [in deuterated chloroform, δ
(ppm)]: 0.13 (s, 6H), 0.96 (t, 3H, J=
7Hz), 1.68 (sex, 2H, J=7Hz), 2.98 (t,
2H, J=7Hz), 3.65 (m, 5H), 5.65 (d,
1H, J=16Hz), 6.74 (d, 1H, J=8Hz),
6.92 (d, t, 1H, J=7, 16Hz), 7.26 (t,
1H, J = 8Hz), 7.56 (d, 1H, J = 8Hz,
9.28 (s, 1H) (ii) Dissolve 216 mg of this 1-tert-butyldimethylsilyloxy compound in 10 ml of methanol, add 380 mg of sodium borohydride in large excess at room temperature, and after stirring for 1 hour, dissolve in saturated ammonium chloride solution. was added and extracted with ether.

After treating the ether layer in the usual manner, the residue was subjected to silica gel column chromatography (developing solution: methylene chloride).
132 mg of methyl 4-[1-tert-butyldimethylsilyloxy-4-hydroxy-3-(1-hydroxybutyl)-5-methoxy-2-naphthyl]-2-butenoate was obtained.

¹ H-NMR [in deuterated chloroform, δ
(ppm)]: 0.08 (6H), 1.06 (s, 9H), 0.80~
2.30 (m, 7H), 3.65 (s, 3H), 4.04 (s, 3H),
3.60-4.00 (1H), 4.72 (m, 1H), 5.71 (d,
1H, J=16Hz), 6.80 (d, 1H, J=8Hz),
7.10 (d, t, 1H, J = 7, 16Hz), 7.28 (t,
1H, J=8Hz), 7.65 (d, 1H, J=8Hz),
9.78 (s, 1H) (iii) Add 28% sodium methoxide to 10 ml of methanol solution containing 132 mg of the compound thus obtained.
Add the methanol solution at 0°C under nitrogen flow. 1
After stirring for an hour, the mixture was further stirred at 20°C for 2 hours. The mixture was made acidic by adding a saturated aqueous ammonium chloride solution, and then extracted with ether. After treating the ether layer in a conventional manner, when it was subjected to preparative liquid chromatography (developing solution: methylene chloride), 1-
Propyl-5-tertiary butylsilyloxy-10
-Hydroxy-9-methoxy-3,4-dihydro-1H-naphtho[2,3-c]pyran-3-
20 mg of methyl yl acetate was obtained as a diastereomer mixture (product ratio of natural type and non-natural type = 2:5). Yield 15%.

¹ H-NMR [in deuterated chloroform, δ
(ppm)]: 0.16 (s, 6H), 0.18 (s, 6H), 1.10
(s, 9H), 0.80~2.10 (m, 7H), 2.10~3.20
(m, 4H), 3.73 (s, 3H), 4.06 (s, 3H),
3.70-4.50 (1H), 5.24 (1H), 6.75 (d, 1H, J
= 8Hz), 7.24 (t, 1H, J = 8Hz), 7.64 (d,
1H, J=8Hz), 9.28 (s, 1H), 9.34 (s,
1H) Mass spectrum (m/e): 474 (molecular ion peak).

The diastereomer thus obtained can also be produced by the following reaction.

4-(1-tertiary butyldimethylsilyloxy-3-butyryl-4-hydroxy-5-methoxy-1,2-dihydro-2-naphthyl)-2
-61 mg (0.129 mmol) of methyl butenoate (compound produced by (i) above) in 5 ml of dioxane
38 mg ((1.0 mmol)) of sodium borohydride was added under a nitrogen atmosphere, and the mixture was stirred overnight.
Add saturated ammonium chloride aqueous solution and extract with ether. After treating the ether layer in a conventional manner, the residual oil was subjected to silica gel column chromatography (eluent: methylene chloride) to yield 1-propyl-5-tert-butyldimethylsilyloxy-10.
-Hydroxy-9-methoxy-3,4-dihydro-1H-naphtho[2,3-c]pyran-3-
51 mg of methyl yl acetate was obtained as a diaznoreomer mixture (product ratio of natural type and non-natural type = 2:5). Yield 85%.

(iv) 20 mg of this diastereomer mixture
(0.042 mmol) in 1 ml of acetonitrile solution,
43 mg of ceric ammonium nitrate in water at room temperature
A solution dissolved in 0.2 ml was added, and after stirring for 5 minutes, water was added and extracted with ether.

The ether layer was treated in a conventional manner to obtain 13 mg of O-methyldeoxyfrenolicin methyl ester as a diastereomer mixture (product ratio of natural type and non-natural type = 2:5). Yield 89
%.

¹ H-NMR [in deuterated chloroform, δ
(ppm)]: 0.80-3.00 (m.11H), 3.76 (s, 3H),
4.02 (s, 3H), 3.60~4.10 (1H), 4.88 (m,
1H), 7.32 (m, 1H), 7.56-7.90 (m, 2H).

Mass spectrum (m/e, relative intensity): 358
(molecular ion peak, 63%), 3.15 (54%), 285
(75%), 256 (63%), 255 (100%), 241 (50%).

Reference Example 1-1 Preparation agent for compound of general formula () (i) 1,5-dimethoxy-4-hydroxynaphthalene 4.08 g [20 mmol, Rapoport et al., J.Org.
It was synthesized from 1,5-dihydroxynaphthalene according to the method described in Chem., 44 , 2153-2158 (1979). ] with 30 ml of pyridine and 20 ml of acetic anhydride.
After stirring overnight at room temperature, 400 ml of water was added to separate the precipitated crystals, washed with water, and dried. When this was recrystallized from a mixed solvent of benzene-hexane, 4.62 g of pure 4-acetoxy-1,5-dimethoxynaphthalene was obtained as colorless plate-like crystals. Melting point 119-121℃, yield 92%.

¹ H-NMR [in deuterated chloroform, δ
(ppm)]: 2.31 (s, 3H), 3.85 (s, 3H), 3.90
(s, 3H), 6.64-7.00 (m, 3H), 7.30 (t,
1H), 7.81(d, 1H).

Elemental analysis values: C 68.02%, H 5.80% Calculated values as C ₁₄ H ₁₄ O ₄ : C 68.28%, H 5.73% (ii) 4-acetoxy- thus obtained
1,5-dimethoxynaphthalene 4.404g
(17.9 mmol) was heated and melted at about 120°C, and boron trifluoride ether complex salt (19.7 mmol) was added.
A reddish-brown solid was obtained with vigorous evolution of ether. After heating for 5 minutes, the mixture was extracted with 200 ml of water and 100 ml of methylene chloride, and the aqueous layer was further extracted with methylene chloride (3 times x 30 ml). The organic layers were combined, washed with water and then saturated brine, and dried over anhydrous sodium sulfate. After evaporating methylene chloride, the product was purified by silica gel column chromatography (developing solution: methylene chloride) to obtain pure 3-acetyl-4-hydroxy-1,5-dimethoxynaphthalene. Yield 3.842g (87%),
Yellow crystals, melting point 133-135°C (benzene-hexane).

¹ H-NMR [in deuterated chloroform, δ
(ppm)]: 2.71 (s, 3H), 4.04 (s, 3H), 6.80
~6.96 (m, 3H), 7.44 (t, 1H, J=8Hz),
7.72 (d, 1H, J=8Hz), 13.28 (s, 1H).

Infrared spectrum (potassium bromide method, cm ^-1 ):
3335 (s, OH), 1600 (vs).

Elemental analysis values: C 67.98%, H 5.83% Calculated values as C ₁₄ H ₁₄ O ₄ : C 68.28%, H 5.73% (iii) 3-acetyl-4-hydroxy-1,5-dimethoxynaphthalene 492 mg (2.0 mmol ) was dissolved in 35 ml of acetonitrile, and a solution of 2.70 g of ceric ammonium nitrate dissolved in 15 ml of water was added while stirring at room temperature. After 5 minutes, water and methylene chloride were added, shaken, and the methylene chloride layer was separated, and the aqueous layer was further extracted twice with methylene chloride. The methylene chloride solutions were combined, washed with water, and then dried over anhydrous magnesium sulfate. Evaporation of the solvent yields 3-acetyl-5-methoxy-
423 mg of crude crystals of 1,4-naphthoquinone were obtained. Yield 92%. The crude crystals were recrystallized from an ether-hexane mixed solvent to obtain 353 mg of pure product. Yellow needles, melting point 101-105°C (decomposition).

¹ H-NMR [in deuterated chloroform, δ
(ppm)]: 2.59 (s, 3H), 4.01 (s, 3H), 6.93
(s, 1H), 7.36 (dd, J=3,8Hz), 7.55~
7.80 (m, 2H).

Infrared spectrum (potassium bromide method, cm ^-1 ):
1685 (vs), 1655 (vs).

Elemental analysis values: C 67.99%, H 4.47% Calculated values as C ₁₃ H ₁₀ O ₄ : C 67.82%, H 4.38% (iv) 3-acetyl-5-methoxy-1,4-naphthoquinone 492 mg (2.0 mmol) ) methylene chloride 40
Boron tribromide 501 mg (2.0 mmol) dissolved in ml
was added dropwise at -78°C, and the temperature was gradually returned to room temperature. After adding water, the mixture was extracted with ether, the ether layer was treated in a conventional manner, and the solvent was distilled off under reduced pressure to obtain 379 mg of crude crystals of the corresponding hydroquinone compound.
This was dissolved in ether again, an excess amount of silver oxide (1.27 g) was added, and the mixture was stirred overnight. After separating the solids, washing with ether, combining the ether layers, and drying under reduced pressure yields 7-acetyljuglone.
304 mg was obtained as orange needles. Melting point 98℃
(decomposition), yield 78%.

¹ H-NMR [in deuterated chloroform, δ
(ppm)]: 2.60 (s, 3H), 7.02 (s, 1H), 7.20
~7.70 (m, 3H), 11.71 (s, 1H).

Infrared spectrum (potassium bromide tablets, cm ^-1 ):
3400 (br, s), 1695 (vs), 1660 (vs).

Elemental analysis values: C 66.57%, H 3.92% Calculated values as C ₁₂ H ₈ O ₄ : C 66.67%, H 3.73% Reference example 1-2 Preparation example of compound of general formula () (i) 1,5- 5.84 g (28.6 mmol) of dimethoxy-4-hydroxynaphthalene was dissolved in 40 ml of pyridine, and 9.05 g (59 mmol) of butyric anhydride was added thereto, followed by stirring at room temperature overnight. Add 500ml of water,
The precipitated crystals were separated, washed with water, dried, and recrystallized from an ether-hexane mixed solvent to obtain 6.45 g of 4-butyryloxy-1,5-dimethoxynaphthalene as colorless plate-like crystals. Melting point 96-97℃. Yield 82%.

¹ H-NMR [in deuterated chloroform, δ
(ppm)]: 1.08 (t, 3H, J = 88Hz), 1.84 (m,
2H), 2.62 (t, 2H, J=8Hz), 3.90 (s,
3H), 3.99 (s, 3H), 6.70-7.05 (m, 3H),
7.40 (t, 1H, J = 8Hz), 7.92 (d, 2H, J =
8Hz) Infrared spectrum (potassium bromide tablet, cm ^-1 ):
745 (vs) Elemental analysis: C 70.30%, H 6.81% Calculated values as C ₁₆ H ₁₈ O ₄ : C 70.06%, H 6.61% (ii) 4-Butyryloxy-1,5- thus obtained Dimethoxynaphthalene 1.32g
(4.81 mmol) was heated and melted at 120°C, and 0.65 ml of boron trifluoride ether complex salt was added thereto. At this time, ether was violently released and a reddish-brown solid was obtained. After 5 minutes, water was added and extracted with methylene chloride. After washing the organic layer, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, purification by silica gel column chromatography (developing solution: methylene chloride) yielded 3-butyryl-4-hydroxy-1,5-dimethoxynaphthalene 1.09
g was obtained as yellow platelets. Melting point 104~105
°C (benzene-hexane), yield 83%.

¹ H-NMR [in deuterated chloroform, δ
(ppm)]: 1.03 (t, 3H, J=7Hz), 1.82 (sex,
2H, J = 7Hz), 3.02 (t, 2H, J = 7Hz),
3.96 (s, 3H), 4.04 (s, 3H), 6.90~7.04 (m,
2H), 7.52 (t, 1H, J=8Hz), 7.83 (d,
1H, J=8Hz), 13.72 (s, 1H) Infrared spectrum (potassium bromide tablet, cm ^-1 ):
2700 (s), 1615 (vs) (iii) Dissolve 817 mg (2.98 mmol) of 3-butyryl-4-hydroxy-1,5-dimethoxynaphthalene in 50 ml of acetonitrile, and add 4.05 g of ceric ammonium nitrate to 5 ml of water. was added at room temperature and stirred for 5 minutes. After adding water and extracting with ether, the ether layer was treated in a conventional manner and dried over anhydrous magnesium sulfate.

The ether was distilled off, and 747 mg of the obtained crude crystals were recrystallized from a mixed solvent of ether and hexane to obtain 668 mg of 3-butyryl-5-methoxy-1,4-naphthoquinone as yellow needles.
Melting point 100-102℃, yield 87%.

¹ H-NMR [in deuterated chloroform, δ
(ppm)]: 0.98 (t, 3H, J=7Hz), 1.73 (sex,
2H, J = 7Hz), 2.90 (t, 2H, J = 7Hz),
4.04 (s, 3H), 6.92 (s, 1H), 7.30~7.50 (m,
1H), 7.60-7.80 (m, 2H), Infrared spectrum (potassium bromide tablet, cm ^-1 ):
1690 (vs), 1665 (vs), 1655 (vs) Elemental analysis values: C 69.97%, H 5.73% Calculated values as C ₁₅ H ₁₄ O ₄ : C 69.76%, H 5.46% Reference example 2-1 General formula Preparation example of compound () Under a nitrogen atmosphere, 12 ml of a 2.1 M tertiary-butyllithium solution in pentane was added to 60 ml of tetrahydrofuran cooled to -78°C, followed by N, N,
N′,N′-tetramethylethylenediamine 3.75ml
added. To this, triphenylallylsilane
10 ml of a tetrahydrofuran solution containing 6.00 g was added, and then the temperature was gradually raised to -30°C. After the resulting dark yellow solution was cooled again to −78° C., a 15% hexane solution of triethylaluminum was added until the yellow color of the solution disappeared. The temperature of the reaction solution is -78℃
While keeping the temperature at 0°C, continue blowing in dry carbon dioxide and slowly raise the temperature to 0°C. The reaction solution is then poured into ice-saturated ammonium chloride solution. A 5% hydrochloric acid solution was added until the white solid was completely dissolved to make the solution acidic, and then extracted with ether. The ether layers were combined, washed with a saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. Analysis of the residue by ¹ H-NMR revealed that it was a mixture of 2-triphenylsilyl-3-butenoic acid, 4-triphenylsilyl-3-butenoic acid and triphenylallylsilane in a ratio of 65:25:10. Recrystallization from methylene chloride gives 2-triphenylsilyl-3-butenoic acid 1.98
g was obtained. When the mother liquor was subjected to silica gel column chromatography, an additional 1.80 g was obtained. Yield 4.33g
(63%).

This was methylated with diazomethane in ether,
When the product is recrystallized from benzene-hexane,
3.24 g of pure methyl 2-triphenylsilyl-3-butenoate was obtained. Melting point 96-97℃, yield 45%
(for triphenylsilane).

¹ H-NMR [δ (ppm) in deuterated chloroform]:
3.33 (s, 3H), 3.80 (d, 1H, J=10Hz), 4.80
~5.10 (m, 2H), 6.08 (dt, 1H, J=10, 18Hz),
7.2-7.7 (m, 15H).

Infrared spectrum (potassium bromide method, cm ^-1 ):
1715 (vs).

Reference Example 2-2 Preparation Example of Compound of General Formula () Under a nitrogen stream, into 5 ml of tetrahydrofuran cooled to -78°C, 0.72 ml of a 2.1 M tertiary-butyllithium pentane solution and N,N,N',N 0.23 ml of '-tetramethylethylenediamine was added, followed by 176 mg of allyldimethylphenylsilane.
The temperature of the reaction solution was gradually raised to -30°C over 1 hour, then cooled again to -78°C, and a 15% hexane solution of triethylaluminum was added until the yellow color of the reaction solution disappeared. Subsequently, dry carbon dioxide was blown into the reaction solution, and the temperature was gradually raised to 0°C. The reaction mixture was poured into ice-saturated aluminum chloride solution, quickly extracted with ether, dried over anhydrous magnesium sulfate, and then methylated by adding an ether solution containing diazomethane. When applied to a silica gel column using benzene as a developing solution, pure 2
-Methyl dimethylphenylsilyl-3-butenoate
142 mg was obtained as a colorless oil. Yield 61%.

¹ H-NMR [δ (ppm) in deuterated chloroform]:
0.38 (s, 6H), 3.10 (d, 1H, J=10Hz), 3.48
(s, 1H), 4.64-5.00 (m, 2H), 5.95 (d, t,
1H, J=10, 17Hz), 7.24-7.50 (m, 5H).

Infrared spectrum (liquid film method, cm ^-1 ): 1720 (vs),
1630 (vs).

Reference Example 3 Production example of deoxyfrenolicin methyl ester (i) 25 mg of diastereomer mixture of O-methyldeoxyfrenolicin methyl ester
(0.070 mmol) in 10 ml of methylene chloride,
To this was added 58 mg of aluminum chloride at room temperature. After 40 minutes, water and ether were added to separate the organic layer, and the aqueous layer was further extracted with ether.

The ether solutions were combined and treated in a conventional manner to obtain 18 mg of frenolicin methyl ester as a diastereomer mixture (product ratio of natural type and non-natural type = 2:5). Yield 74%.

¹ H-NMR [in deuterated chloroform, δ
(ppm)]: 0.90 (t, 3H, J=8Hz), 1.0 to 3.0
(m, 8H), 3.72 (s, 3H), 3.80 (m, 1H),
4.80 (m, 1H), 7.20 (m, 1H), 7.55 (m, 2H),
11.85 and 11.96 (s, 1H, respectively, intensity ratio 5:2).

(ii) Dissolve 18 mg of this diastereomer mixture in 1 ml of methylene chloride, cool to 0°C, and add 0.5 mg of concentrated sulfuric acid.
ml and stirred for 30 minutes. The methylene chloride layer became colorless, and the sulfuric acid layer became blackish brown.

An aqueous sodium hydrogen carbonate solution was added to this to neutralize it, followed by extraction with ether. When the oily substance obtained by treating the ether layer in a conventional manner was purified using preparatape liquid chromatography, 15 mg of natural deoxyfrenolicin methyl ester (yield 83
%) were obtained as yellow needles. Melting point 139~
140℃ (recrystallized from a benzene-hexane mixture).

¹ H-NMR [in deuterated chloroform, δ
(ppm)]: 1.00 (t, 3H, J = 7Hz), 1.1 to 2.1
(m, 4H), 2.32 (ddd, 1H, J=2, 10, 18
Hz), 2.67 (d, 2H), 2.83 (dd, 1H, J=2,
18Hz), 3.73 (s, 3H), 4.24 (m, 1H), 4.80
(m, 1H), 7.24 (m, 1H), 7.60 (m, 2H),
11.96 (s, 1H).

Infrared spectrum (potassium bromide method, cm ^-1 ):
3400 (vs), 1730 (vs), 1655 (sh), 1635 (vs),
1610(s).

Claims (1)

[Claims] 1. General formula [In the formula, R is a lower alkyl group, R ¹ is a hydrogen atom or a lower alkyl group, R ² is a hydrogen atom, an alkyl group, or an aralkyl group, and Z is R ³ R ⁴ R ⁵ Si— (here, R ³ , R ⁴ and R ⁵ are the same or different and represent a lower alkyl group or a phenyl group). ] General formula characterized by subjecting the compound represented by to an oxidation reaction (In the formula, each symbol has the same meaning as above.) A method for producing a naphthopyranyl acetic acid derivative represented by: 2 General formula (In the formula, R represents a lower alkyl group, R ¹ represents a hydrogen atom or a lower alkyl group, and R ² represents a hydrogen atom, an alkyl group, or an aralkyl group.) , Z is R ³ R ⁴ R ⁵ Si—(where R ³ , R ⁴ ,
R ⁵ is the same or different and represents a lower alkyl group or a phenyl group. ), and X represents a halogen atom. ] The general formula produced by reacting the compound represented by (In the formula, each symbol has the same meaning as above.) By subjecting the compound represented by the formula to a reduction reaction, the general formula (In the formula, each symbol has the same meaning as above.) By subjecting this to a ring-closing reaction, the general formula (In the formula, each symbol has the same meaning as above.) A compound represented by the general formula (In the formula, each symbol has the same meaning as above.) A method for producing a naphthopyranyl acetic acid derivative represented by: