JPH0473420B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to a method for producing 3-deoxyaphidicolin. 3-deoxyaphidicolin is found in eukaryotic cells.
It is already known as a physiologically active substance that has specific inhibitory activity against DNA polymerase α, and is described, for example, in JP-A-58-220689. BACKGROUND TECHNOLOGY The above-mentioned publication describes a biological method of culturing and extracting microorganisms belonging to Homa bethe as a method for producing 3-deoxyaphidicolin. Problems to be Solved by the Present Invention However, the above-mentioned method using microorganisms is inefficient in production, requires large-scale equipment for production, and requires a long period of time for production. It wasn't. The present invention was developed in view of the above circumstances, and involves synthesizing 3-deoxyaphidicoline by a chemical method using abietic acid, which is the main component of rosin and is inexpensive and easily available, as a raw material. , the purpose is to provide a new method. Means to Solve the Problems The present invention isomerizes abietic acid to reduce the ring, and converts the structural formula into

[Formula] and

A step of obtaining a mixture of dienes represented by the formula; decomposing the mixture of dienes to introduce a carbonyl group at the 7-position, and esterifying the carboxyl group at the 4-position,
General structural formula (R is an alkyl group having 1 or more carbon atoms) A step of obtaining an enone represented by (R is an alkyl group having 1 or more carbon atoms) A step of obtaining a substance represented by By removing the group and introducing a double bond at position 6a, the general structural formula (R is an alkyl group having 1 or more carbon atoms) The process of obtaining an enone represented by (R is an alkyl group having 1 or more carbon atoms) The step of obtaining an enone represented by Acylated, general structural formula (R and R ₁ are alkyl groups having 1 or more carbon atoms) A step of obtaining a substance represented by , general structural formula (R and R ₁ are alkyl groups having 1 or more carbon atoms) A step of obtaining a substance represented by By etherifying a glycol with a dihydric alcohol, the general structural formula (R and _R2 are alkyl groups having 1 or more carbon atoms) A step of obtaining a substance represented by (R and R 2 are alkyl groups having 1 or more carbon atoms), removing the 7-position hydroxyl group of this substance, and reducing the 4-position methoxycarbonyl group to form a hydroxymethylene group; This method is characterized in that the steps of hydrolyzing the 9-position to obtain glycol to obtain 3-deoxyaphidicoline are sequentially performed. Effects According to the present invention, the ring serving as the backbone of abietic acid is reduced, the propyl group at the 8-position of abietic acid is removed, and a new ring is formed between the 8-position and the 9a-position to form a 3-deoxyafine ring. 3-deoxyaphidicoline can be synthesized by forming a skeletal ring of ideicoline, setting a hydroxymethylene group at the 4th position of the skeletal ring, and introducing a hydroxyl group and a hydroxymethylene group at the 9th position. Effects of the Invention According to the present invention, 3-deoxyaphidicolin is synthesized by a purely chemical method using abietic acid, which is contained in large amounts in inexpensive and easily available rosin, as a raw material. It can be manufactured in large quantities in a short period of time without requiring any equipment. And, by the method of the present invention, it is possible to produce exactly the same substances as those produced by known biological methods. EXAMPLE An example of the method of the present invention will be described step by step. The characteristics of the intermediate materials in each of the following steps are as follows: Nuclear magnetic resonance spectra are JNM-
FX100 and R-600 manufactured by Hitachi, Ltd., infrared absorption spectrum is A- manufactured by JASCO Corporation.
102, mass spectrometry using JEOL Ltd. DX-300;
The optical rotation was measured using DIP-140 manufactured by JASCO Corporation, and the melting point was measured using MP-21 manufactured by Yamato Kiki Co., Ltd., respectively. In addition, silica gel chromatography is used as a packing material manufactured by Merck & Co.
Wecogel C-200 was used. In the present invention, abietic acid (1) is used as a raw material.
use. Abietic acid exists as a main component of rosin and is separated by methods such as alcohol leaching and steam distillation. Step 1 In the present invention, first, the ring of abietic acid (1) is reduced, and the 6-membered ring bonded with a propyl group is reduced to a 5-membered ring. Procedure 1: First, dissolve 40g of abietic acid (1) in 140ml of methylene chloride, and add 96% sulfuric acid 320g under ice cooling.
ml and isomerize to reduce the skeletal ring. The reaction solution takes on an orange-red color. After stirring vigorously for 1.5 hours under ice-cooling, the mixture was heated to room temperature and further stirred for 3 hours. After confirming by thin layer chromatography that the raw material abietic acid (1) had completely disappeared, the reaction solution was poured into ice water in step 2 and extracted three times with ether (approximately 3 times). Wash the extract with saturated saline solution (1),
Next, the mixture of diene (2) and (2') was washed three times with saturated sodium bicarbonate solution (approximately 1.5 times), and finally washed again with saturated saline solution, dried over anhydrous sodium sulfate, and concentrated. Obtained as oil. Step 2 Next, the 7-position of the diene (2), (2') is converted into a carbonyl group, and the 4-position carboxyl group is converted into a methyl sterilization. Step 2: Dissolve the mixture of dienes (2) and (2') in a mixed solvent of 400 ml of methylene chloride and 160 ml of methanol, and heat at -78°C with oxygen at 2.5/min and voltage.
Ozone is blown into the solution at 40V for 6 hours to decompose the 7-position of diene (2) and (2') into a carbonyl group. After confirming the complete disappearance of the raw material dienes (2) and (2') by thin layer chromatography,
Excess ozone was removed by blowing in nitrogen, 15 ml of thioether was added, the temperature was gradually returned to room temperature, the mixture was concentrated and diluted with ether, and the precipitated substance (3) was collected by filtration as white crystals. ) to 9.354
I got g. The yield of substance (3) from abietic acid (1) was 27%. The properties of substance (3) were as follows. PMR (CDCl ₃ 100MHz) δ1.24 (3H, s), δ1.16 (3H, s) IR (KBr) 3100, 2950, 1710 (dimer), 1670, 1625cm ^-1 MS 262 (M ⁺ ), 247 ( M ⁺ −CH ₃ ), 217 (M ⁺ −
CO ₂ H) Operation 3: Next, substance (3) 33.3805g (127.4mmol)
is dissolved in a mixed solvent of 1.3 ml of chloroform and 60 ml of methanol, and 230 mmol of an ale solution of diazomethane is added thereto at room temperature, and the mixture is left overnight to methyl esterify the carboxyl group at the 4-position of substance (3). This was then concentrated to obtain 35.2 g of enone (4) as pale yellow crystals. The yield of enone (4) was 100%. The characteristics of Enon (4) were as follows. PMR (CDCl ₃ 100MHz) δ3.67 (3H, s), δ1.28 (3H, s), δ1.19 (3H,
s) IR (KBr) 2950, 1720, 1690, 1640cm ^-1 MS 276 (M ⁺ ), 261 (M ⁺ −CO ₃ ), 258 (M ⁺ −
H ₂ O), 217 (M ⁺ −CO ₂ CH ₃ ), 199 (M ⁺ −H ₂ O−
CO ₂ CH ₃ ) Melting point 114-116℃ Elemental analysis Calculated value = C73.82, H8.68 Actual value = C73.82, H8.73 UV λ ^EtOH _nax 238.5 μm, εmax 13100 [α] ²¹ _D +29.6 ( C=1.01, CHCl ₃ ) In this step, either the step of decomposing the 7-position or the step of esterifying the 4-position may be performed first. Further, the esterification at the 4-position may be performed with an alkyl group other than methyl. Step 3 Next, add allene to enone (4). Step 4: Dissolve 11.3 g of enone (4) in 800 ml of ethanol, and pour this solution 1 into a Pyrex container 3 in which the air has been replaced with argon 2, as shown in Figure 1.
Put it in. This container 3 is immersed in the dry ice/ethanol mixed refrigerant 5 in the dewar bottle 4,
Cool to −78° C. and add 70 ml (excess) of allene to solution 1. Furthermore, a high-pressure mercury lamp 9, which had been cooled by refluxing ethanol 7 cooled to -30°C with a cooler 6 to -30°C with a pump 8, was inserted into the solution 1, and ultraviolet rays were irradiated for 5 hours.
is subjected to an addition reaction with allene. After concentrating the reaction solution, silica gel chromatography (30x, n
- Purified with hexane: ethyl acetate = 12:1),
9.647 g of crude substance (5) was obtained as a pale yellow oil, and 1.499 g of raw material enone (4) was recovered. Since substance (5) is difficult to purify, the crudely purified product is reduced to substance (6) in the next step,
After this was purified, it was oxidized again with pyridine chlorochromate to obtain a pure substance (5) in the form of a transparent oil, on which the properties of substance (5) were measured. The yield of substance (5) calculated backward from substance (6) was 65%. The properties of substance (5) were as follows. PMR (CDCl ₃ 100MHz) δ4.80 (2H, br), δ3.69 (3H, s), δ1.22 (3H,
s), δ0.89 (3H, s) IR (neat) 2950, 1720, 1680cm ^-1 MS 316 (M ⁺ ), 301 (M ⁺ −CH ₃ ), 257 (M ⁺ −
CO ₂ CH ₃ ) [α] ^22.5 _D −128 (C=0.84, CHCl ₃ ) Step 4 Next, the 6a position of the substance (5) was decomposed, and the obtained 9
A hydroxyl group is introduced at the terminal of the side chain at position 7, the carbonyl group at position 7 is removed, and a double bond is introduced at position 6a. Procedure 5: First, 139 mg of the crude substance (5) was dissolved in 1.8 ml of ethanol, 14 mg of sodium borohydride was added under ice cooling, and the mixture was stirred for 2 hours.
The carbonyl group at position 7 of substance (5) is reduced to a hydroxyl group. Raw materials in thin layer chromatography
After confirming that (5) has completely disappeared, neutralize with 2N hydrochloric acid, distill off the ethanol, and then extract with ethyl acetate. After drying this with anhydrous sodium sulfate, it was separated and purified using silica gel chromatography (ethyl ether: n-hexane = 1:3) to obtain substance (6) as white amorphous.
I got 125 mg. The yield of substance (6) was 89%. The properties of substance (6) were as follows. PMR (CDCl ₃ 100MHz) δ5.02 (1H, dd, J=2.5Hz), δ4.93 (1H, dd,
J=2.5Hz), δ3.64 (3H, s), δ1.28 (3H, s),
δ0.98 (3H, s) IR (KBr) 3450, 2950, 1730, 1670cm ^-1 MS 318 (M ⁺ ), 303 (M ⁺ −CH ₃ ), 300 (M ⁺ −
H ₂ O), 259 (M ⁺ −CO ₂ CH ₃ ) [α] ²⁴ _D −26.9 (C = 1.012, CHCl ₃ ) Operation 6: Next, add 8.246 g (25.93 mmol) of substance (6),
Dissolved in 270 ml of methylene chloride, 8 ml of mesyl chloride
(4 equivalents) and 20 ml (10 equivalents) of pyridine were added,
Stir and react for 2 days at room temperature. The reaction solution was then poured into ice water, extracted with ethyl acetate, washed with 2N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (methylene chloride) to obtain the substance (7). )
9.441 g) of pale yellow amorphous amorphous was obtained.
The yield of substance (7) was 92%. The properties of substance (7) were as follows. PMR (CDCl ₃ 100MHz) δ4.98 (2H, br), δ4.60 (1H, dd, J=7Hz,
10Hz), δ3.67 (3H, s), δ3.03 (3H, s),
δ1.30 (3H, s), δ0.98 (3H, s) IR (KBr) 2950, 1715, 1680cm ^-1 MS 396 (M ⁺ ), 381 (M ⁺ −CH ₃ ), 336 (M ⁺ −
HCO ₂ CH ₃ ) Step 7: Next, 40 mg (0.10 mmol) of substance (7) was dissolved in 2 ml of anhydrous tetrahydrofuran under an argon atmosphere, and 0.1 ml of diborane in tetrahydrofuran solution (0.83 mmol/ml) was added under ice cooling. 2 at room temperature
By stirring for a period of time, the 6a-position of substance (7) is decomposed and the methylsulfonyl group at the 7-position is removed.
Introduce a double bond at the position. After confirming that the raw material (7) has completely disappeared by thin layer chromatography, add 0.5 ml of 3N sodium hydroxide aqueous solution.
and reflux for 2 hours. reaction solution
After neutralization with 2N hydrochloric acid, tetrahydrofuran was distilled off, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel chromatography (ethyl ether: n-hexane). = 1:2) to obtain 20 mg of substance (8) as a transparent syrup. The yield of substance (8) was 65%. The properties of substance (8) were as follows. PMR (CDCl ₃ 100MHz) δ5.80~5.40 (1H, ABX, dd), δ5.22 (1H,
d), δ5.24~4.92 (2H, ABX) (JAB=2.5Hz,
JAX=16Hz, JBX=7.5Hz), δ3.67 (3H, s),
δ1.22 (3H, s), δ0.93 (3H, s) IR (neat) 2950, 1715, 1680, 1640cm ^-1 MS 302 (M ⁺ ), 261 (M ⁺ −CH=CH ₂ ), 243
(M ⁺ −CO ₂ CH ₃ ) [α] ²³ _D +19.45 (C = 1.106, CHCl ₃ ) Step 8: Next, 3.672 g (12.16 mmol) of the above substance (8)
was dissolved in 110 ml of anhydrous tetrahydrofuran under an argon atmosphere, and cooled.
{(CH ₃ ) ₂ CHCH(CH ₃ )} 56 ml (5 equivalents) of a tetrahydrofuran solution (1.07 mmol/ml) of ₂ BH
The mixture was added and stirred for 4 hours while cooling with ice, and further stirred at room temperature for 12 hours. Next, drop 40 ml of 3N sodium hydroxide solution, and add 40 ml of 30% hydrogen peroxide solution.
ml slowly dropwise so that the temperature does not rise above 40°C to add water to the double bond at the end of the side chain at position 9a of substance (8) to form a hydroxyl group. After that, stirring was continued for about 2 hours, and after confirming that no bubbles were generated from the interface between the aqueous layer and the organic substance even after the stirring was stopped, neutralization was performed with 2N hydrochloric acid, and after distilling off tetrahydrofuran, ethyl acetate was added. extracted with water, washed with saturated saline, dried with anhydrous sodium sulfate,
After concentration, it was purified by silica gel chromatography (ethyl ether: n-hexane = 4:1) to obtain substance (9) as a transparent syrup with a concentration of 3.735
I got g. The yield of substance (9) was 96%. The properties of substance (9) were as follows. PMR (CDCl ₃ 60MHz) δ5.30 (1H, d), δ3.69 (3H, s), δ1.25 (3H,
s), δ0.92 (3H, s) IR (neat) 3450, 2955, 1730, 1675 cm ^-1 MS 320 (M ⁺ ), 305 (M ⁺ −CH ₃ ), 302 (M ⁺ −
H ₂ O), 261 (M ⁺ -CO ₂ CH ₃ ) Step 5 Next, the double bond at position 6a of substance (9) is moved to position 6, and a carbonyl group is introduced at position 7. Step 9: First, 3.3225g (10.4mmol) of substance (9),
Dissolved in 120 ml of methylene chloride under argon atmosphere,
Cool to -78°C, add 3.8 ml (3 equivalents) of 2,6-lutidine and 3.1 ml (1.3 equivalents) of tert-butyridimethylsilyl triflate in this order, stir for 3 hours to react, and Mask the double bond of . After the reaction, silica gel chromatography (ethyl ether: n-
Hexane (1:10) was used to obtain 4.423 g of substance (10) as a transparent syrup. The yield of substance (10) is
It was 98.2%. The properties of substance (10) were as follows. PMR (CDCl ₃ 100MHz) δ5.24 (1H, d), δ3.67 (3H, s), δ3.60 (2H,
br), δ1.22 (3H, s), δ0.90 (9H, br), δ0.88
(3H, s), δ0.06 (6H, s) IR 2950, 1725cm ^-1 Operation 10: Next, add 4.423g (10.2mmol) of substance (10) to
Anhydrous tetrahydrofuran under argon atmosphere
14 ml (3.3 equivalents) of diborane in tetrahydrofuran solution (2.38 mmol/ml) was added under ice-cooling, stirred overnight at room temperature, and added water to the double bond at position 6a to form a hydroxyl group at position 7. Introduce. After confirming by thin layer chromatography that most of the raw material substance (10) has disappeared, add 40 ml of 3N aqueous sodium hydroxide solution and slowly add 30% hydrogen peroxide solution so that the temperature does not rise above 40°C. dripping. Stirring was continued for about 2 hours after the dropwise addition, and after confirming that no bubbles were generated from the interface between the aqueous layer and the organic layer even after the stirring was stopped, 0.5N citric acid aqueous solution was added to neutralize the mixture, and the tetrahydrofuran was distilled. After removing and extracting with chloroform, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating, and purifying with silica gel chromatography (ethyl ether: n-hexane = 1:1),
4.4475 g of substance (11) was obtained as a transparent oil. material
The yield of (11) was 96.5%. The properties of substance (11) were as follows. PMR (CDCl ₃ 100MHz) δ4.30 (1H, br), δ3.67 (5H=3H, s+2H,
br), δ1.20 (3H, s), δ0.92 (3H, s), δ0.88
(9H, s), δ0.09 (6H, s) IR (neat) 3400 (br), 1725 cm ^-1 MS 452 (M ⁺ ), 437 (M ⁺ −CH ₃ ), 434 (M ⁺ −
H ₂ O) Step 11: Next, add 4.4475 g (9.84 mmol) of substance (11) to
Under an argon atmosphere, dissolve 4.23 ml of pyridine chloromate in 190 ml of methylene chloride and cool on ice.
g (2 equivalents) and stirred for 3 and a half hours under ice cooling.
Through this operation, the 7-position hydroxyl group in substance (11) is oxidized to become a carbonyl group. After the reaction was completed, chromium was removed by filtration through Florisil, washed with ether, and the washings were concentrated, followed by silica gel chromatography (ethyl ether:
After purification with n-hexane (1:2), 4.274 g of substance (12) was obtained as a transparent oil. The yield of substance (12) was 96.5%. The properties of substance (12) were as follows. PMR (CDCl ₃ 100MHz) δ3.64 (3H, s), δ1.16 (3H, s), δ0.92 (9H,
s), δ0.81 (3H, s), δ0.08 (6H, s) IR (neat) 2950, 1720 cm ^-1 Step 12: Next, 101.5 mg (0.226 mmol) of substance (12),
Dissolved in 5 ml of anhydrous carbon tetrachloride under an argon atmosphere, added 0.1 ml of 2,6-lutidine, then added 0.07 mg (1.3 equivalents) of trimethylsilyl triflate, stirred at room temperature for 9 hours to react, and then redistributed at position 6a. It forms a superposition and also masks the hydroxyl group formed at the 7-position. Then water was added, extracted with methylene chloride, dried over anhydrous sodium sulfate, and concentrated to give substance (13) as a clear oil.
I got mg. The yield of substance (13) was 100%. The properties of substance (13) were as follows. PMR (CDCl ₃ 100MHz) δ3.66 (3H, s), δ3.7~3.56 (2H, br), δ1.20
(3H, s), δ0.92, δ0.19, δ0.06 Step 14: Next, add 42.5 mg (0.0814 mmol) of substance (13) to
Under an argon atmosphere, 4μ of bromine was dissolved in 1ml of anhydrous methylene chloride, added with 13μ of pyridine (2 equivalents), and diluted 20 times with methylene chloride under ice cooling.
(2.0 equivalents) is added. As a result, bromine is added to the 6a-position of substance (13), and the 7-position is oxidatively decomposed to become a carbonyl group. Immediately after adding bromine, add saturated sodium bicarbonate solution, extract with methylene chloride, dry over anhydrous sodium sulfate, concentrate, and purify with silica gel chromatography (ethyl ether: n-hexane = 1:10) to extract the substance. 36.5 mg of (14) was obtained as a pale yellow oil.
The yield of substance (14) was 94%. The properties of substance (14) were as follows. PMR (CDCl ₃ 100MHz) δ3.67 (3H, s), δ3.72~3.58 (2H, br),
δ1.13 (3H, s), δ0.93 (9H, s), δ0.82 (3H,
s), δ0.05 (6H, m) IR (neat) 2950, 1740, 1725 cm ^-1 Step 13: Next, 13.249 g (27.7 mmol) of substance (14),
Under an argon atmosphere, 4.56 ml (1.1 equivalent) of 1,5-diazobicyclo[5,4,0]undecene-5 dissolved in 700 ml of anhydrous toluene and diluted 20 times with toluene was added dropwise under ice cooling. at room temperature
Stir for 17 hours to dehydroborate and form a double bond at the 6-position. Next, it was neutralized with a saturated aqueous citric acid solution, extracted with chloroform, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel chromatography (ethyl ether: n-hexane = 1:
2) to produce substance (15) as red oil.
Obtained 6.875g. The yield of substance (15) was 55.4%. The properties of substance (15) were as follows. PMR (CDCl ₃ 100MHz) δ6.59 (1H, dd, J=4Hz), δ3.67 (3H, s),
δ1.25 (3H, s), δ0.90 (9H, s), δ0.87 (3H,
s), δ0.09 (6H, s) IR (neat) 2950, 1740-1720 (br), 1650 cm ^-1 Step 15: Next, add 1.115 g (2.49 mmol) of substance (15) to 70 ml of trahydrofuran. 4 ml of 2N hydrochloric acid is added under ice-cooling for hydrolysis, and the end mask of the side chain at position 9 is removed to form a hydroxyl group.
After stirring for 3 hours, neutralize with saturated aqueous sodium bicarbonate solution,
Tetrahydrofuran was distilled off, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel chromatography ((ethyl ether: n-hexane = 7:1).
740mg of substance (16) as a transparent oil
Obtained. The yield of substance (16) was 89%. The properties of substance (16) were as follows. PMR (CDCl ₃ 100MHz) δ6.63 (1H, dd, J=4Hz), δ3.68 (3H, s),
δ3.60~3.53 (2H, br), δ1.31 (3H, s), δ0.86
(3H, s) IR (neat) 3450, 2950, 1740-1720 (br),
1650cm ^-1 MS 334 (M ⁺ ), 316 (M ⁺ −H ₂ O), 274 (M ⁺ −
HCO ₂ CO ₃ ) [α] ²³ _D −122 (C = 1.00, CHCl ₃ ) In this step, the substance that masks the side chain terminal at position 9 and position 7 is limited to the substances shown in the above examples. Instead, other substances can also be used. Furthermore, the halogen used to introduce a double bond at the 6-position is not limited to bromine, and chlorine may also be used. Step 6: Next, the terminal carbon of the side chain at position 9 and the carbon at position 8 in substance 16 are bonded to cyclize, and the 9 after cyclization is
Acylates the hydroxyl group at position. Step 16: First, 740 mg (2.22 mmol) of substance (16),
Dissolved in 50 ml of methylene chloride under argon atmosphere,
Add 955 mg (2 equivalents) of pyridine chlorochromate under ice-cooling and stir for 5 hours to oxidize the hydroxyl group at the end of the side chain at position 9 to form an aldehyde. Next, the reaction solution was passed through Florisil to remove chromium and washed with ether. After concentrating the washing liquid, it was purified by silica gel chromatography (benzene: ethyl acetate = 3:1) to obtain 535.5 mg of substance (17) as a transparent oil. The yield of substance (17) was 73.3%. The properties of substance (17) were as follows. PMR (CDCl ₃ 100MHz) δ9.70 (1H, s), δ6.67 (1H, dd, J=4Hz),
δ3.67 (3H, s), δ1.31 (3H, s), δ0.87 (3H,
s) IR (neat) 2950, 2740, 1720, 1650cm ^-1 MS 332 (M ⁺ ), 314 (M ⁺ −H ₂ O), 273 (M ⁺ −
CO ₂ CH ₃ ) [α] ²³ _D −125.6 (C = 1.12, CHCl ₃ ) Step 17: Next, 535.5 mg (1.61 mmol) of substance (17),
Under an argon atmosphere, an ethanol solution of sodium ethoxide prepared by adding sodium metal to absolute ethanol was dissolved in 45 ml of absolute ethanol, and 154 mg of sodium ethoxide was added under ice cooling.
(1.4 equivalents) and stirred for 1 hour. As a result, the end of the side chain at position 9a is added to position 8 of the ring, and the aldehyde becomes a hydroxyl group. Next, it was neutralized with 2N hydrochloric acid, ethanol was distilled off, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel chromatography (benzene: ethyl acetate = 1:1). ) to obtain 534 mg of a mixture of substance (18) and substance (18') as white amorphous. The yield of the mixture was 100%. The properties of substance (18) are as follows. PMR (CDCl ₃ 100MHz) δ6.70 (1H, dd, J=7Hz), δ4.23~4.08
(1H, br), δ3.63 (3H, s), δ1.33 (3H, s),
δ0.90 (3H, s) IR (neat) 3450, 2950, 1720, 1650cm ^-1 MS 332 (M ⁺ ), 314 (M ⁺ −H ₂ O) The properties of substance (18′) are as follows It is. PMR (CDCl ₃ 100MHz) δ6.72 (1H, dd, J=4Hz), δ4.00~3.78
(1H, br), δ3.68 (3H, s), δ1.33 (3H, s),
δ0.90 (3H, s) IR (neat) 3450, 2950, 1720, 1650cm ^-1 MS 332 (M ⁺ ), 314 (M ⁺ −H ₂ O) Operation 18: Next, substance (18) and (18' ) 241.5mg mixture with
(0.727 mmol) was dissolved in 8 ml of pyridine under an argon atmosphere, 0.16 ml of glacial acetic acid was added under ice cooling, a small amount of dimethylaminopyridine was added, and the mixture was stirred overnight at room temperature to acetylate the hydroxyl group at the 9-position. Ice water was added to this, pyridine was distilled off, then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel chromatography (ethyl ether: n-hexane = 1:
1) to obtain 213 mg of a mixture of substance (19) and substance (19') as white amorphous. The yield of the mixture was 78%. The properties of the mixture of substances (19) and (19') are as follows. PMR (CDCl ₃ 100MHz) δ6.71 (1H, dd,), δ5.08~4.90 (br, 1H),
δ3.67 (3H, s), δ1.09~1.08 (1H, s), δ1.33
(3H, s), δ0.81 (3H, s) IR (neat) 2950, 1740-1720 (br), 1660 cm ^-1 MS 374 (M ⁺ ), 314 (M ⁺ -HCO ₂ CH ₃ ) Note that this step In this case, instead of bonding an acetyl group to the hydroxyl group at the 9-position, an acyl group having another alkyl group may be introduced. Step 7: Next, in substances (19) and (19'), the double bond at the 6-position is hydrogenated, and the carbonyl group at the 7-position is hydrogenated to form a hydroxyl group. Operation 19: First, a mixture of substance (19) and substance (19′)
213 mg (0.57 mmol) is dissolved in 15 ml of ethyl acetate under an argon atmosphere, 10 mg of platinum dioxide is added, the air is replaced with hydrogen using an aspirator, and the mixture is stirred overnight at room temperature. As a result, the double bond at position 6 is hydrogenated and the double bond disappears. Next, it was confirmed by thin layer chromatography that the raw materials (19) and (19') were consumed,
After removing platinum with a pleated filter paper, it was concentrated and subjected to silica gel chromatography (ethyl ether:
Separate and purify with n-hexane = 1:2) to obtain substance (20)
91 mg and 107 mg of substance (20') were obtained, respectively, as white amorphous. Substance (20) and Substance (20')
The yields were 43% and 50%, respectively. The properties of substance (20) were as follows. PMR (CDCl ₃ 100MHz) δ4.95-4.75 (1H, br), δ3.67 (3H, s),
δ2.09 (3H, s), δ1.24 (3H, s), δ1.09 (3H,
s) IR (neat) 2950, 1740-1720 (br) cm ^-1 MS 376 (M ⁺ ) The properties of substance (20') were as follows. PMR (CDCl ₃ 100MHz) δ4.90-4.70 (1H, m), δ3.67 (3H, s),
δ2.08 (3H, s), δ1.24 (3H, s), δ1.09 (3H,
s) IR (neat) 2950, 1740, 1720 cm ^-1 MS 376 (M ⁺ ), 316 (M ⁺ -HCO ₂ CH ₃ ) Step 20: Next, 55 mg (0.146 mmol) of substance (20),
Dissolve in anhydrous tetrahydrofuran under an argon atmosphere, add 16 mg (5 equivalents) of lithium borohydride, and stir at room temperature for 2 hours to reduce the carbonyl group at the 7-position to a hydroxyl group. After neutralizing with 0.5N hydrochloric acid, tetrahydrofuran was distilled off, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel chromatography (ethyl ether: n-hexane =
2:1) to obtain 51 mg of substance (21) as white amorphous. The yield of substance (21) is 92
It was %. The properties of substance (21) were as follows. PMR (CDCl ₃ 100MHz) δ5.16~5.00 (1H, br), δ5.39 (1H, dd, J=
7Hz, 10Hz), δ3.65 (3H, s), δ2.06 (3H,
s), δ1.28 (3H, s), δ0.96 (3H, s) IR (neat) 3520, 2950, 1730cm ^-1 MS 334 (M ⁺ −CO ₃ CO + 1) [α] ¹⁹ _D +11.4 ( C=1.02, CHCl ₃ ) In this step, the step of hydrogenating the double bond at the 6-position and the step of hydrogenating the carbonyl group at the 7-position to form a hydroxyl group can be carried out first. good. Step 8 Next, the 9-position of substance (21) is hydrolyzed to form a hydroxyl group, and a hydroxymethylene group is further introduced into the 9-position to form glycol, and then the glycol is reacted with a dihydric alcohol to form an ether. . Step 21: First, substance (21) 51 mg (0.135 mmol)
was dissolved in 2 ml of methylene chloride under an argon atmosphere, and 0.055 ml of 2.6-lutidine was dissolved under cooling to -78°C.
(3 equivalents), then 0.045 ml (1.4 equivalents) of tert-butyldimethylsilyl triflate was added, and the mixture was then returned to room temperature and reacted with stirring for 1 hour to mask the 7-position hydroxyl group. After the reaction was completed, water was added and extracted with methylene chloride.
The residue was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl ether:n-hexane=1:2) to obtain 64 mg of substance (22) as a transparent syrup. The yield of substance (22) was 96.4%. The properties of substance (22) were as follows. PMR (CDCl ₃ 100MHz) δ5.30 (1H, dd, J=7Hz, 10Hz), δ3.65
(3H, s), δ2.03 (3H, s), δ1.19 (3H, s),
δ0.90 (9H, m), δ0.05 (6H, m) IR (neat) 2950, 1730cm ^-1 MS 448 (M ⁺ −COCH ₃ ) [α] ¹⁹ _D +4.26 (C = 1.28, CHCl ₃ ) Operation 22: Next, 64 mg (0.13 mmol) of substance (22) is dissolved in 4 ml of methanol, 38 mg of sodium methoxide is added, and the mixture is stirred at room temperature for 1 hour to hydrolyze the acetoxy groups to form hydroxyl groups. After the reaction was completed, it was neutralized with a 0.5N aqueous citric acid solution, methanol was distilled off, extracted with chloroform, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel chromatography (ethyl ether: n -hexane=1:2) to obtain 45.5 mg of substance (23) as a transparent oil. The yield of substance (23) was 77.7%. The properties of substance (22) were as follows. PMR (CDCl ₃ 100MHz) δ5.30 (1H, dd, J=7Hz, 10Hz), δ5.00
(1H, br), δ1.19 (3H, s), δ0.96 (3H, s) IR (neat) 3500 (br), 2950, 1730 cm ^-1 MS 435 (M ⁺ -CH ₃ ), 432 (M ⁺ _−H2O ), 391
(M ⁺ −CO ₂ CH ₃ ) [α] ¹⁹ _D +1.99 (C = 0.91, CHCl ₃ ) Step 23: Next, under an argon atmosphere, add the previously distilled anhydrous methylene chloride to 0.26 ml of the previously distilled Add 0.01 ml of oxalyl chloride, cool to -50°C, add 0.017 ml of dimethyl sulfoxide, and stir for 5 minutes. To this was added 37 mg of the above substance (23) dissolved in 0.3 ml of methylene chloride. The temperature was raised to -30°C and stirred for 20 minutes, then 0.07 ml of triethylamine was added, and the temperature was further gradually raised to room temperature. As a result, the hydroxyl group at position 9 is dehydrogenated to become a carbonyl group. Further water was added, extracted with methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (benzene: ethyl acetate = 10:1) to obtain substance (24). 30 mg was obtained as a yellow oil. The yield of substance (24) is
It was 80%. The properties of substance (24) were as follows. PMR (CDCl ₃ 100MHz) δ4.39 (1H, dd, J=8Hz), δ3.66 (3H, s),
δ2.90 (1H, ddd, J=2.5Hz, 7.5Hz), δ1.20
(3H, s), δ1.02 (3H, s), δ0.84 (9H, s),
δ0.01 (6H, s) IR (neat) 2950, 1720cm ^-1 MS 448 (M ⁺ ), 432 (M ⁺ −CH ₃ ), 389 (M ⁺ −
CO ₂ CH ₃ ) [α] ¹⁷ _D −25.21 (C = 1.45, CHCl ₃ ) Step 24: Next, first, 501 mg (3 equivalents) of triphenylphosphonium methyl bromide was dissolved in 5 ml of anhydrous tetrahydrofuran under an argon atmosphere.
1.05 ml (3 equivalents) of 0.747 ml/mmol n-butyllithium was added dropwise at -78°C, stirred for 20 minutes,
Adjust the ylide by gradually raising the temperature to room temperature. Next, the ylide is added dropwise to 209.5 mg (0.468 mmol) of the substance (24) previously dissolved in 5 ml of anhydrous tetrahydrofuran under an argon atmosphere while heating under reflux. Continue heating and refluxing for 22 hours to convert the carbonyl group at the 9-position to a vinylidene group. After that, some tetrahydrofuran was distilled off, water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and separated and purified by silica gel chromatography (benzene: ethyl acetate = 10:1) to obtain the substance. (twenty five)
Obtained 136.5 mg as clear oil, raw material (24)
41.5mg was recovered. The yield of substance (25) is 65%
It was hot. The properties of substance (25) were as follows. PMR (CDCl ₃ 100MHz) δ4.54 (1H, dd, J=2.1Hz), δ4.45 (1H, dd,
J=2.1Hz), δ4.24(1H, dd, J=7Hz, 10
Hz), δ3.65 (3H, s), δ1.26 (3H, s), δ0.95
(3H, s), δ0.84 (9H, s) IR (neat) 2950, 1730, 1650cm ^-1 MS 446 (M ⁺ ), 441 (M ⁺ −CH ₃ ), 387 (M ⁺ −
CO ₂ CH ₃ ) Step 25: Next, 45 mg (0.101 mmol) of substance (25)
is dissolved in 1.125 ml of tertiary butyl alcohol, and 0.34 ml of water and 0.0375 ml of pyridine are added. Next, 0.3 ml of tert-butyl alcohol solution of osmium tetroxide (1 g/100 ml)
(0.12 equivalent) and N-methylmorpholine N
Add 41 ml (3 equivalents) of oxide and heat at 50℃ for 5.5
Oxidize by heating for a period of time. As a result, the vinylidene group at position 9 is oxidized to produce a hydroxyl group and a hydroxymethylene group, resulting in glycol. next,
A saturated aqueous sodium bicarbonate solution was added, stirred at room temperature for 20 minutes, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl ether: n-hexane = 2:1) to obtain the substance ( 26) was obtained as a transparent oil (40 mg).
The yield of substance (26) was 82.5%. The properties of substance (26) were as follows. PMR (CDCl ₃ 100MHz) δ4.31 (1H, dd, J=7Hz, 10.5Hz), δ3.67
(3H, s), δ3.76-3.60 (2H, br), δ1.26 (3H,
s), δ0.95 (3H, s), δ0.91 (3H, s), δ0.05
(6H, s) IR (neat) 3400 (br), 2950, 1725 cm ^-1 MS 480 (M ⁺ ), 463 (M ⁺ -OH) [α] ²⁴ _D -12.1 (C = 1.00, CHCl ₃ ) Operation 26 : Next, substance (26) 75 mg (0.1563 mmol)
was dissolved in 3 ml of acetone under an argon atmosphere, and 0.1 ml of 2,2-dimethoxypropane was added under ice cooling.
(25 equivalents), add a small amount of para-toluenesulfonic acid, and stir for 1 hour to react.
Masks glycol at position 9. Next, add one drop of triethylamine, distill off the acetone,
Extraction with ethyl acetate and silica gel chromatography (ethyl ether: n-hexane = 1:
6) to obtain 77.5 mg of substance (27) as white amorphous. The yield of substance (27) is 95.4
It was %. The properties of substance (27) were as follows. PMR (CDCl ₃ 100MHz) δ4.28 (1H, dd, J=7Hz, 10.5Hz), δ3.80
(2H, AB, J = 9Hz, δr = 11Hz), δ3.67 (3H,
s), δ1.38 (3H, s), δ1.35 (3H, s), δ1.19
(3H.s), δ0.95 (3H.s), δ0.90 (9H.s), δ0.06
(6H.s) IR (neat) 2950, 1725cm ^-1 MS 520 (M ⁺ ) [α] ²³ _D −18.4 (C = 1.03, CHCl ₃ ) Operation 27: Next, 13 mg (0.025 mmol) of substance (27)
is dissolved in 1 ml of tetrahydrofuran, and at room temperature, 0.1 ml (4 equivalents) of tetra n-butylammonium fluoride (1 molar solution) is added and stirred for 4 days to hydrolyze the 7-position to form a hydroxyl group. Next, some of the tetrahydrofuran was distilled off, extracted with ethyl acetate, and subjected to silica gel chromatography (ethyl ether: n-hexane-2:
Purify in step 1) to obtain substance (28) as white crystals.
Obtained 10.5 mg. The yield of substance (28) was 100%. The properties of substance (28) were as follows. PMR (CDCl ₃ 100MHz) δ4.29 (1H.dd.J=7Hz, 10.5Hz) δ3.87 (2H.
AB.J=9Hz, δr=24Hz), δ3.67 (3H.s), δ1.38
(3H.s), δ1.36 (3H.s), δ0.96 (3H.s), δ1.18
(3H.s) IR (neat) 3400 (br), 2950, 1720 cm ^-1 MS 406 (M ⁺ ) In this step, masking the glycol at position 9 is limited to the 2,2-dimethoxypropane mentioned above. Other acetals can be used. Step 9 Next, the hydroxyl group at the 7-position of substance 28 is removed, and the 9-position is hydrolyzed to give glycol to obtain the target substance, 3-deoxyaphidicoline. Step 28: First, 25.4 mg (10 equivalents) of sodium hydride (50% dispersion) is washed three times with anhydrous ether under an argon atmosphere, the ether is distilled off, and 0.5 ml of anhydrous tetrahydrofuran is added. Next, 21.5 mg of the substance (28) was added to this solution.
(0.0529 mmol) in tetrahydrofuran, a small amount of imidazole, and then heated under reflux for 2 hours. Then carbon disulfide 32μ (10
After further heating for 2 hours, 66μ (20 equivalents) of methyl iodide was added and the mixture was heated for another 1 hour to react. This results in
The 7th position becomes a methylxanthate group. After cooling to room temperature, it was neutralized by adding ammonium chloride, extracted with ethyl acetate, and subjected to silica gel chromatography (ethyl ether: n-hexane =
1:4) to obtain 25 mg of substance (29) as a pale yellow oil. The yield of substance (29) was 95%. The properties of substance (29) were as follows. PMR (CDCl ₃ 100MHz) δ6.14 (1H.dd.J=7Hz, 10.5Hz), δ3.76 (2H.
s), δ3.67 (3H.s), δ2.58 (3H.s), δ1.41 (3H.s
),
δ1.36 (3H.s), δ1.21 (3H.s), δ1.00 (3H.s) IR (neat) 2950, 1725cm ^-1 MS 481 (M ⁺ −CH ₃ ) Step 29: Next, Substance (29) 25mg (0.0504mmol)
was dissolved in 1 ml of anhydrous toluene under an argon atmosphere, and 8 mg (1 ml) of αα'-azoisobutyronitrile was added.
equivalent amount) and heat to 70°C. Next, 40 μm (3 equivalents) of tri-n-butyl silver hydride is added and heated to 110° C. to decompose the 7-position of substance (29). Next, when the reaction solution changed from yellow to transparent, it was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated on a silica gel thin plate (benzene: ethyl ether =
20:1) to obtain 6 mg of substance (30) as a transparent oil. The yield of substance (30) was 30%. The properties of substance (30) were as follows. PMR (CDCl ₃ 100MHz) δ3.65 (3H.s), δ3.65 (AB.J=8.5Hz, δr=23.5
Hz), δ1.41 (3H.s), δ1.35 (3H.s), δ1.19 (3H.s).
s), δ0.97 (3H.s) IR (neat) 2950, 1720cm ^-1 MS 375 (M ⁺ -CH ₃ ) Operation 30: Next, 3 mg of lithium aluminum hydride
(4 equivalents) was suspended in 0.5 ml of anhydrous tetrahydrofuran under an argon atmosphere, and a solution of 8 mg (0.0205 mmol) of substance (30) dissolved in 1.5 ml of anhydrous tetrahydrofuran was added thereto, and the mixture was heated under reflux for 20 minutes. The methoxycarbonyl group of is reduced to a hydroxymethylene group. After cooling to room temperature, excess lithium aluminum hydride was decomposed with a saturated aqueous sodium sulfate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel chromatography (ethyl ether: n-hexane = 1: 1) to obtain 6.5 mg of substance (31) as white crystals.
The yield of substance (31) was 88%. The properties of substance (31) were as follows. PMR (CDCl ₃ 100MHz) δ3.65 (2H.AB.J=8.5Hz, δr=23.5Hz), δ3.22
(2H.AB.J=10.5Hz, δr=34.7Hz), δ1.41 (3H.
s), δ1.36 (3H.s), δ0.98 (3H.s), δ0.78 (3H.s
) IR (neat) 3500, 2950cm ^-1 MS 362 (M ⁺ ), 347 (M ⁺ -CH ₃ ) Operation 31: Next, 6.5 mg (0.018 mmol) of substance (31)
Dissolve in 1 ml of methanol, add 3 drops of 2N hydrochloric acid under ice cooling, and stir for 4 hours. This results in
The 9-position substituent undergoes hydrolysis of the ether bond to form a glycol. Next, it was neutralized by adding sodium bicarbonate, filtered through a cotton plug, concentrated to dryness, and purified by silica gel chromatography (methylene chloride: methanol = 10:1) to obtain 3-deoxyaphidicolin (32). 5.5 as clear oil
I got mg. 3-deoxyafideicorin (32)
The yield was 100%. The properties of the obtained 3-deoxyaphidicolin (32) were as follows. PMR (CDCl ₃ 100MHz) δ3.42 (2H.AB.J=2.6Hz), δ3.225 (2H.AB.J=
10.9Hz, δr=35.4Hz), δ3.5~δ3.3 (3H) δ0.993
(3H.s), δ0.782 (3H.s) IR (neat) 3300 (br), 2950cm ^-1 MS 305 (M ⁺ −OH), 291 (M ⁺ −CH ₂ OH), 273
(M ⁺ −CH ₂ OH−H ₂ O), 255 (M ⁺ −CH ₂ OH−
H ₂ O−H ₂ O) [α] ²³ _D +33.5 (C = 0.275, C ₂ H ₅ OH) The specific rotation of the natural product is [α] ²⁰ _D +22.6 (C = 0.98, C _{2H5OH )} . In this step, the means for removing the 7-position hydroxyl group is not limited to the method using carbon disulfide as shown in the examples, but may be performed using other substances. Further, either the operation of removing the hydroxyl group at the 7-position or the operation of hydrolyzing the methyl carboxyl group at the 4-position to form a hydroxymethylene group may be performed first.

[Brief explanation of the drawing]

FIG. 1 is a central longitudinal sectional view of the ultraviolet irradiation device used in operation 4. 1...Reaction solution, 3...Pyrex container, 5...
...Refrigerant, 9...High pressure mercury lamp.

Claims (1)

[Claims] 1. A step of isomerizing abietic acid to obtain a mixture of dienes represented by the structural formulas [Formula] and [Formula], and decomposing this mixture of dienes to introduce a carbonyl group at the 7-position. step and a step of esterifying the carboxyl group at the 4-position, the general structural formula (R is an alkyl group having 1 or more carbon atoms) A step of obtaining an enone represented by (R is an alkyl group having 1 or more carbon atoms) A step of decomposing the 6a-position of the substance, and the obtained 9
The general structural formula (R is an alkyl group having 1 or more carbon atoms) A step of obtaining a substance represented by the following, a step of moving the double bond at position 6a to position 6,
A step of introducing a carbonyl group at the 7-position is carried out, and the general structural formula is (R is an alkyl group having 1 or more carbon atoms) A step of obtaining a substance represented by Acylated, general structural formula (R and R ₁ are alkyl groups having 1 or more carbon atoms) A step of obtaining a substance represented by (R and R 1 are alkyl groups having one or more carbon atoms) A step of hydrogenating the double bond at the 6-position in the ring,
The carbonyl group at position 7 is hydrogenated to form a hydroxyl group, and the general structural formula is (R and R ₁ are alkyl groups having 1 or more carbon atoms) A step of obtaining a substance represented by By etherifying a glycol with a dihydric alcohol, the general structural formula (R and R ₂ are alkyl groups having 1 or more carbon atoms) A step of obtaining a substance represented by (R and R 2 are alkyl groups having 1 or more carbon atoms) A step of removing the hydroxyl group at the 7-position of this substance,
The method is characterized in that the steps of reducing the methoxycarbonyl group at position to form a hydroxymethylene group and hydrolyzing the 9-position to form glycol to obtain 3-deoxyaphidicoline are carried out in sequence. , a method for producing 3-deoxyaphidicoline.