JPH07242577A - Optically active cyclopropane derivative - Google Patents

Abstract

(57) [Summary] [Purpose] The above aragusterol having excellent antitumor activity.
To provide an optically active cyclopropane derivative for use in the synthetic chemical production of A and aragusterol B. [Structure] Expression (In the formula, X is a hydroxyl group or a halogen atom.) An optically active cyclopropane derivative.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an intermediate for producing naturally occurring antitumor steroids (aragusterol A and aragusterol B).

[0002]

2. Description of the Related Art Recently, among natural products derived from sponges of the genus Xestospongia from Okinawa, aragusterol A (Japanese Patent Laid-Open No. 5-4998) and aragusterol B (Taiji Yamada et al., Marine Biotechnology Research Conference, Abstracts, 510C, 129
Pp. 1993), cyclopropane-containing steroids having excellent antitumor activity have been found and are expected as new anticancer agents. However, since it is a rare sponge-derived substance, it is difficult to secure stable resources, and therefore it has been desired to establish a production method by a synthetic chemical method.

[0003]

The object of the present invention is to provide the above-mentioned aragusterol A and aragust having excellent antitumor activity.
An object of the present invention is to provide an optically active cyclopropane derivative used for producing erol B by a synthetic chemical method.

[0004]

Means for Solving the Problems The present inventors have earnestly studied an optically active cyclopropane derivative useful for producing the above-mentioned sponge-derived antitumor substance and a production method for efficiently obtaining the same, and as a result, from L-ascorbic acid, The present invention has been completed by finding an efficient synthetic method using a derived unsaturated lactone as a starting material.

The present invention will be outlined below. The present invention has the formula

[0006]

(Wherein X is a hydroxyl group or a halogen atom) is an optically active cyclopropane derivative.

The halogen atom in the present invention means chlorine, bromine and iodine. The compound of the present invention can be synthesized according to the production method shown in Scheme 1 below.
The production method of the compound of the present invention will be outlined below in order.

[0009]

Known optically active unsaturated lactone (1) derived from L-ascorbic acid [Carbohydrate Researc
h, 216, p. 511, 1991] in the presence of a base such as imidazole and the like and a hydroxyl group is protected by reacting with tert-butyldimethylsilyl chloride (2).
And then reacting the compound (2) with lithium dimethylcopper to obtain a methylated compound (3).

Subsequently, the compound (3) is treated with a reducing agent such as lithium aluminum hydride and then further treated with an acid such as acetic acid to obtain a triol (4). Next, the compound (4) is reacted with lead tetraacetate in the presence of a base such as potassium carbonate and then reacted with a Wittig reagent to obtain an α, β-unsaturated ester (5).

Subsequently, the compound (5) is reacted with tert-butyldiphenylsilyl chloride in the presence of a base such as imidazole to give a derivative (6) having a protected hydroxyl group, and further a reducing agent such as diisobutylaluminum hydride is acted on. This gives allyl alcohol (7). Then, the compound (7) is reacted with diiodomethane in the presence of diethyl zinc to induce the compound (8),
After the steps of bromination with carbon tetrabromide and triphenylphosphine, debromination with a reducing agent such as lithium aluminum hydride, and desilylation etherification with tetra n-butylammonium fluoride, etc. An optically active cyclopropane derivative (9) which is a compound of the invention can be obtained.

Further, the compound (9) is reacted with a general halogenating agent (for example, thionyl chloride, carbon tetrabromide-triphenylphosphine, etc.) to give the optically active cyclopropane of the present invention in which X is a halogen atom. The derivative (10) can be obtained.

To confirm the structure, compound (9) was converted to 4-nitrobenzoate (11a) by a conventional method.

[Identification of Optically Active Cyclopropane Derivative of the Present Invention and Naturally Derived Compound] Chemical decomposition of 4-nitrobenzoate (11a) derived from the compound (9) of the present invention and naturally derived aragusterol B (Scheme 2) ), The cyclopropane derivative 4-nitrobenzoate (11b) showed the same optical rotation, and further, the cyclopropane-containing steroid (16) (synthesized using the compound (10) of the present invention (16) ( Since the optical rotation and various spectral data of aragusterol B of natural origin agree with those of naturally occurring aragusterol B, the compound of the present invention is the same substance as the naturally occurring compound, including its absolute configuration. Became clear.

[0016]

[0017]

INDUSTRIAL APPLICABILITY The present invention provides an optically active cyclopropane derivative which binds to carbon 20 of aragusterol A and aragusterol B, which are promising naturally occurring antitumor substances, and an efficient synthetic method thereof. It enabled the production of antitumor substances by total synthesis. In order to more specifically show the effect of the present invention, aragustero using the compound of the present invention
The outline of the method for producing l B is shown below (Scheme 3).

[0018]

Reference [Chem. Ber. , Volume 100,
Pp. 464 (1967)], the steroid compound (13) described above is reacted with triethylsilyl chloride in the presence of a base such as imidazole to obtain a steroid derivative (14) having a protected hydroxyl group. After reacting this with a lithium salt prepared from the compound (10) of the present invention, tetra-n-butylammonium fluoride was allowed to act to form a triol (15), and then ar by Oppenauer oxidation.
agusterol B (16) was obtained.

[0020]

EXAMPLES The present invention will be described in more detail with reference to Examples and Reference Examples.

Example 1 1) Synthesis of compound (2) Compound (1) (3.36 g, 29.5 mmol)
To a solution of N, N-dimethylformamide (30 ml) was added imidazole (6.03 g, 88.5 mmol) and t.
ert-Butyldimethylsilyl chloride (6.67 g,
(44.3 mmol) was added, and the mixture was stirred at room temperature for 40 minutes.
The reaction mixture was diluted with ether, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: diethyl ether = 1: 1) to give 6.1 g (yield 92%) of the title compound as colorless needles.
Obtained.

Mp: 35 to 36 ° C. [α] _D ²⁷ : + 132.0 ° (c 1.29, CHC
l ₃ ) ¹ H-NMR (300 MHz, CDCl ₃ ) δppm:
0.06 (6H, s), 0.87 (9H, s), 3.9
3 (1H, dd, J = 4.4 and 10.8H
z), 3.97 (1H, dd, J = 5.4 and 1
0.8Hz), 5.05 (1H, m), 6.16 (1
H, dd, J = 2.0 and 5.7 Hz), 7.5
0 (1H, dd, J = 1.5 and 5.7 Hz) EIMS m / z: 229 (M ⁺⁺ 1) Anal. Calcd for C ₁₁ H ₂ O ₃ Si:
C, 57.86; H, 8.84 Found: C, 5
7.83; H, 9.02

2) Synthesis of compound (3) 1.15 M methyllithium was added to a suspension of purified copper iodide (12.0 g, 0.063 mol) in anhydrous diethyl ether (200 ml) at −10 ° C. under an argon stream. Of diethyl ether solution (110 ml) was added dropwise, and the mixture was stirred for 15 minutes. Next, this solution was cooled to −78 ° C., a solution of compound (2) (8.0 g, 0.035 mol) in anhydrous diethyl ether (32 ml) was added dropwise, and the mixture was stirred for 3 hours.
Saturated aqueous ammonium chloride was added little by little to this reaction solution,
The mixture was diluted with diethyl ether, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (n-hexane: diethyl ether = 4: 1) to give 7.76 g (yield 90%) of the title compound as a colorless oil.
Obtained.

[Α] _D ³⁰ : -18.1 ° (c 1.4
9, CHCl ₃ ) ¹ H-NMR (300 MHz, CDCl ₃ ) δppm:
0.07 (6H, s), 0.88 (9H, s), 1.1
7 (3H, d, J = 6.9Hz), 2.14 (1H, d
d, J = 6.7 and 17.3 Hz), 2.52
(1H, m), 2.77 (1H, dd, J = 8.8 a
nd 17.3 Hz), 3.72 (1H, dd, J =
3.3 and 11.3 Hz), 3.84 (1H, d
d, J = 3.2 and 11.3 Hz), 4.09
(1H, m) EIMS m / z: 245 (M ⁺⁺ 1) Anal. Calcd for C ₁₂ H ₂₄ O ₃ Si:
C, 58.98; H, 9.91 Found: C, 5
8.93; H, 10.02

3) Synthesis Step of Compound (4) 1: Compound (3) (15.0 g, 66.8 mmo
1) in anhydrous tetrahydrofuran (150 ml) solution,
Lithium aluminum hydride (2.6 g, 66.8 mol) was added little by little under an argon stream at 0 ° C., and the mixture was stirred for 5 minutes. The reaction mixture was diluted with diethyl ether, saturated brine (50 ml) was added, and the mixture was vigorously stirred at room temperature. The organic layer was decanted, the residue was extracted with tetrahydrofuran, the organic layer was combined with the previous organic layer, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained product was used in the next reaction without further purification.

Step 2: Add 80 to the crude product obtained in Step 1 above.
% Acetic acid (120 ml) was added, and the mixture was stirred at room temperature for 3.5 hours. After concentrating the reaction solution under reduced pressure, silica gel column chromatography (ethyl acetate: methanol = 10:
Purified in 1), 8.0 g of the title compound in the form of a colorless syrup.
(Yield 89%) was obtained.

[Α] _D ²⁹ : + 11.0 ° (c 1.1
_{6, CH 3 OH) IR (} neat): 3359,2933cm -1 1 H-NMR (300MHz, CD 3 OD) δppm:
0.94 (3H, d, J = 6.5Hz), 1.39 (1
H, m), 1.77 (2H, m), 3.50 (2H,
m), 3.58 (3H, m) EIMS m / z: 103 (M ⁺ -CH ₂ OH) Anal. _{Calcd for C 6 H 14 O 3} : C, 5
3.69; H, 10.52 Found: C, 53.4.
9; H, 10.70

4) Synthesis Step of Compound (5) 1: Compound (4) (8.0 g, 59.6 mmol)
A mixture of benzene and benzene (120 ml) with potassium carbonate (2
4.7 g, 178.8 mmol) was added, and lead tetraacetate (39.7 g, 89.4 mmol) was added in 3 portions with stirring, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was filtered through Celite and the filtrate was immediately used in the next reaction.

Step 2: Methyltriphenylphosphoranylidene acetate (40.0%) was added to the filtrate obtained in the above Step 1.
g, 119 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (n-hexane: diethyl ether = 1: 3) to give 6.4 g (yield 67%) of the title compound as a colorless oil. Obtained.

[Α] _D ²³ : -40.8 ° (c 0.9
2, CHCl ₃ ) IR (neat): 3419, 2956, 1724, 1
^{656cm -1 1 H-NMR (400MHz} , CDCl 3) δppm:
1.08 (3H, d, J = 6.8Hz), 1.65 (2
H, dd, J = 6.6 and 13.6 Hz), 2.
52 (1H, m), 3.64 (1H, dd, J = 6.5)
and 6.6 Hz), 3.67 (1H, dd, J =
6.5 and 6.6 Hz, 3.73 (3H,
s), 5.82 (1H, dd, J = 1.2 and 1
5.7 Hz), 6.88 (1H, dd, 8.1 and
15.7 Hz) EIMS m / z: 158 (M ⁺ ) Anal. _{Calcd for C 8 H 14 O 3} : C, 6
0.72; H, 8.92 Found: C, 60.5
5; H, 9.10

5) Synthesis of compound (6) N of compound (5) (489 mg, 3.09 mmol),
To a solution of N-dimethylformamide (3 ml) was added imidazole (505 mg, 7.42 mmol) and tert.
-Butyldiphenylsilyl chloride (1020 mg,
3.71 mmol) was added and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with ether, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The obtained residue was purified by silica gel column chromatography (n-hexane: diethyl ether = 9: 1) to give 1.15 g of the title compound as a colorless oil (yield 9
4%) was obtained.

[Α] _D ²⁹ : -16.4 ° (c 1.1
2, CHCl ₃ ) IR (neat): 3071, 1728, 1657 cm
^{-1 1 H-NMR (400MHz,} CDCl 3) δppm:
1.03 (3H, d, J = 6.8Hz), 1.04 (9
H, s), 1.60 (2H, m), 2.59 (1H,
m), 3.66 (2H, m), 3.73 (3H, s),
5.78 (1H, dd, J = 1.1 and 15.7
Hz), 6.87 (1H, dd, J = 7.8 and
15.7 Hz), 7.40 (6 H, m), 7.65 (4
H, m) EIMS m / z : 339 (M + -C 4 H 9) Anal. Calcd for C ₂₄ H ₃₂ O ₃ Si:
C, 72.69; H, 8.14 Found: C, 7
2.67; H, 8.29

6) Synthesis of Compound (7) A solution of compound (6) (1.15 g, 2.90 mmol) in anhydrous dichloromethane (10 ml) was stirred at -78 ° C while stirring for diisobutylaluminum hydride (0.93M).
n-Hexane solution (6.9 ml, 6.38 mmol) was added dropwise. After stirring at -78 ° C for 30 minutes, the mixture was diluted with diethyl ether, saturated brine (10 ml) was added, and the mixture was vigorously stirred at room temperature. The organic layer was decanted, the residue was extracted with ether, the organic layer was combined with the previous organic layer, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: diethyl ether = 2: 1) to obtain 1.04 g (yield 97%) of the title compound as a colorless oil.

[Α] _D ²⁷ : -7.8 ° (c 0.82
CHCl ₃ ) IR (neat): 3338, 2930, 1428 cm
^{-1 1 H-NMR (400MHz,} CDCl 3) δppm:
0.97 (3H, d, J = 6.8Hz), 1.04 (9
H, s), 1.55 (2H, m), 2.37 (1H,
m), 3.66 (2H, t, J = 10.5Hz), 4.
03 (2H, d, J = 4.6Hz), 5.53 (2H,
m), 7.43 (6H, m), 7.66 (4H, m) EIMS m / z: 311 (M ⁺ -C ₄ H ₉ ) Anal. Calcd for C ₂₃ H ₃₂ O ₂ Si:
C, 74.96; H, 8.76 Found: C, 7
5.02; H, 8.84

7) Synthesis of Compound (8) A solution of compound (7) (0.93 g, 2.53 mmol) in anhydrous dichloromethane (9.0 ml) was added at −20 ° C. under an argon stream to diethyl zinc (1.0 M n-). Hexane solution
(6.3 ml, 6.31 mmol) was added dropwise, and the mixture was stirred for 5 minutes. Then diiodomethane (3.38 g, 12.6
mmol) was added dropwise, and the mixture was stirred at -20 ° C for 10 minutes, 0 ° C for 1 hour, and further stirred at room temperature for 2 hours. The reaction solution was diluted with diethyl ether, saturated aqueous ammonium chloride was added, and the mixture was vigorously stirred at room temperature. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to give 614 mg of the title compound as a colorless oil (yield 57%), and 389 mg of the diastereomer of the title compound (yield). Rate 3
6%) was obtained. (1) Compound (8): Rf value: 0.41 (n-hexane: ethyl acetate = 3:
1, silica gel F ₂₅₄ ; manufactured by Merck) [α] _D ²⁶ : -8.0 ° (c 1.46, CHCl ₃ ) IR (neat): 3348, 3071, 998 cm.
^{-1 1 H-NMR (400MHz,} CDCl 3) δppm:
0.31 (2H, m), 0.38 (1H, m), 0.8
7 (1H, m), 0.91 (3H, d, J = 6.3H
z), 0.99 (1H, m), 1.05 (9H, s),
1.52 (1H, heptet, J = 6.7Hz),
1.66 (1H, heptet, J = 6.7 Hz),
3.33 (2H, m), 3.75 (1H, dd, J =
6.7 and 10.3 Hz), 7.40 (6H,
m), 7.68 (4H, m) EIMS m / z: 382 (M ⁺ ) Anal. Calcd for C ₂₄ H ₃₄ O ₂ Si:
C, 75.35; H, 8.96 Found: C, 7
5.48; H, 9.11.

(2) Diastereomer of compound (8): Rf value: 0.32 (n-hexane: ethyl acetate = 3:
1, silica gel F ₂₅₄ ; manufactured by Merck Ltd.) [α] _D ²⁶ : + 12.8 ° (c 0.89, CHCl ₃ ) IR (neat): 3335, 3071, 998 cm
^{-1 1 H-NMR (400MHz,} CDCl 3) δppm:
0.37 (3H, m), 0.83 (1H, m), 0.9
4 (3H, d, J = 5.9Hz), 1.00 (1H,
m), 1.04 (9H, s), 1.54 (1H, hep
tet, J = 6.7 Hz), 1.68 (1H, hept
et, J = 6.7 Hz), 3.41 (1H, m), 3.
72 (1H, dd, J = 6.7 and 10.2H
z), 3.73 (1H, dd, J = 6.7 and 1)
0.2 Hz), 7.39 (6 H, m), 7.66 (4
H, m) EIMS m / z : 325 (M + -C 4 H 9) Anal. Calcd for C ₂₄ H ₃₄ O ₂ Si:
C, 75.35; H, 8.96 Found: C, 7
5.25; H, 9.24

8) Synthesis Step of Compound (9) 1: Compound (8) (607 mg, 1.59 mmo
1) In anhydrous dichloromethane (5.0 ml) solution, triphenylphosphine (500 mg, 1.91 mmol)
And carbon tetrabromide (630 mg, 1.91 mmol) were added, and the mixture was stirred under an argon stream at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in diethyl ether, and then filtered through silica gel. The solvent was distilled off under reduced pressure to obtain the corresponding bromide. This product was used for the next reaction without purification.

Step 2: The bromide obtained in Step 1 above in diethyl ether-tetrahydrofuran (2: 1) (5.0
Lithium aluminum hydride (90 mg, 2.38 mmo) with stirring at 0 ° C. under an argon stream.
l) was added little by little. The reaction temperature was raised to room temperature and the mixture was stirred for 1 hr, diluted with diethyl ether, saturated brine (2.0 ml) was added little by little, and the mixture was vigorously stirred.
The organic layer was decanted, the residue was extracted with diethyl ether, the organic layer was combined with the previous organic layer, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained crude product was used for the next reaction without purification.

Step 3: A solution of the crude product obtained in Step 2 above in tetrahydrofuran (5.0 ml) was added with tetra n
-Butylammonium fluoride (1.0 M tetrahydrofuran solution 2.4 ml, 2.38 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with diethyl ether, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-pentane: diethyl ether = 1: 1) to obtain 180 mg (yield 88%) of the title compound as a colorless oil.

[Α] _D ²⁹ : -36.6 ° (c 1.2
8, CHCl ₃ ) IR (neat): 3388,3061,994 cm
^{-1 1 H-NMR (300MHz,} CDCl 3) δppm:
0.16 (3H, m), 0.46 (1H, m), 0.8
5 (1H, m), 0.93 (3H, d, J = 6.3H
z), 1.00 (3H, d, J = 5.8Hz), 1.6
3 (1H, heptet, J = 6.9 Hz), 1.65
(1H, heptet, J = 6.9 Hz), 3.72
(1H, t, J = 6.9 Hz) EIMS m / z: 109 (M ⁺ -H ₂ O) Anal. Calcd for C ₂₄ H ₃₄ O ₂ Si:
C, 74.93; H, 12.59 Found: C, 7
4.34; H, 12.85

9) Synthesis of Compound (10, X = Br) A solution of the compound (9) (0.80 g, 6.2 mmol) in anhydrous dichloromethane (20 ml) was added with triphenylphosphine (1.96 g, 7.5 mmol) and four. Carbon bromide (2.48 g, 7.5 mmol) was added, and the mixture was stirred under an argon stream at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in n-pentane, and then filtered through silica gel. The solvent was evaporated under reduced pressure, and the obtained oil was distilled under reduced pressure (3 mmHg, 50 ° C.) to give 1.18 g (yield 100%) of the title compound as a colorless oil.

[Α] _D ²³ : -26.4 ° (c 0.8
_{7, CHCl 3) IR (CHCl} 3): 2875cm -1 1 H-NMR (400MHz, CDCl 3) δppm:
0.13 (2H, d, J = 4.7Hz), 0.20 (1
H, d, J = 8.6 Hz), 0.57 (1 H, m),
0.95 (3H, s), 1.02 (3H, d, J = 6.
0Hz), 1.90 (2H, m), 3.51 (2H, m)
t, J = 7.5 Hz) HREIMS: M ⁺ m / z obsd 190.035
5 C ₈ H ₁₅ Br required 190.035
7

10) Synthesis of Compound (11a) Anhydrous pyridine (0.3 ml) and 4-nitrobenzoyl chloride (5) were added to a solution of compound (9) (17.8 mg, 0.139 mmol) in anhydrous dichloromethane (0.3 ml).
1.6 mg, 0.278 mmol) and 4-dimethylaminopyridine (1.0 mg) were added at room temperature, and the mixture was stirred for 5 hours. The reaction solution was diluted with diethyl ether and washed with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (n-hexane: diethyl ether = 20: 1) to obtain 33.8 mg (yield 88%) of the colorless amorphous title compound.

[Α] _D ²⁶ : -24.3 ° (c 0.2
9, CHCl ₃ ) ¹ H-NMR (400 MHz, CDCl ₃ ) δppm:
0.18 (1H, m), 0.24 (2H, m), 0.5
0 (1H, m), 0.94 (1H, m), 1.02 (3
H, d, J = 6.9 Hz), 1.04 (3H, d, J =
6.0 Hz), 1.85 (2H, br q, J = 6.9
Hz), 4.47 (1H, td, J = 7.1 and
11.6 Hz), 4.48 (1H, td, J = 6.9)
and 11.6 Hz), 8.20 (2H, d, J = 8.
9Hz), 8.28 (2H, d, J = 8.9Hz)

Reference Example 1 Synthesis of cyclopropane derivative by chemical decomposition of Aragusterol B 1) Synthesis step of compound (12) 1: aragusterol B (92 mg, 0.21 mmo
1) in methanol (25 ml), concentrated hydrochloric acid (0.1
5 ml) was added and the mixture was refluxed for 30 minutes. After adding diethyl ether to the reaction solution, the organic layer was washed with saturated aqueous sodium hydrogen carbonate and then with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was used for the next reaction without purification.

Step 2: The crude product (10
1 mg) was dissolved in 80% acetic acid (1 ml), and 2
Stir for 5 minutes. The reaction solution was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (n-hexane: dichloromethane: acetone = 25: 25: 1) to obtain 72 mg of the title compound. This product was recrystallized from n-hexane to give colorless plate crystals.

Mp: 110 ° C. [α] _D ²⁶ : −29.1 ° (c 0.06, CHCl ₃ ) ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm:
0.10 (1H, m), 0.17 (2H, m), 0.4
8 (1H, m), 0.77 (3H, s), 0.92 (3
H, d, J = 6.7 Hz), 0.99 (3H, d, J =
5.9 Hz), 1.02 (3H, s), 1.70 (3
H, br s), 3.61 (1H, dd, J = 4.8)
and 10.6 Hz), 5.55 (1H, t, J =
7.0Hz) EIMS m / z: 426 (M +), 408 (M + -H 2
O) HREIMS: M ⁺ m / z obsd 462.349.
1, C ₂₉ H ₄₆ O ₂ required 426.349
8

2) Compound (11b) [from aragusterol B
The next cyclopropane derivative, 4-nitrobenzoate]
Synthetic compound (12) (44.2 mg, 0.10 mmol) mixed with dichloromethane and methanol (1: 1, 8 ml)
And was cooled to -78 ° C, and then ozone was passed until the reaction liquid became blue. After the reaction, excess ozone was removed through oxygen, and sodium borohydride (18 m
g, 0.48 mmol) was added, and the mixture was further stirred until it returned to room temperature. After adding diethyl ether (30 ml) to the reaction solution, the organic layer was washed with water and then with saturated saline, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, chloroform (1.2 ml) was added to the obtained residue and redissolved, and then triethylamine (0.4 ml),
4-Nitrobenzoyl chloride (120 mg, 0.65
mmol) and 4-dimethylaminopyridine (6 m
g) was added and the mixture was stirred at room temperature for 20 hours. Furthermore, 4-nitrobenzoyl chloride (170 mg) was added, and the
Stir for 8 hours. After adding diethyl ether to the reaction solution, the organic layer was washed with water, saturated aqueous copper sulfate, water, saturated aqueous sodium hydrogen carbonate, water,
Then, it was washed successively with saturated saline and dried over anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure, the obtained residue was subjected to silica gel column chromatography (n-pentane: diethyl ether = 25: 1), and the normal phase H
PLC (silica gel, n-hexane: ethyl acetate = 2
5: 1, UV 254 nm) to obtain 4.0 mg of the title compound as a colorless oil.

[Α] _D ²⁶ : -20.3 ° (c 0.0
7, CHCl ₃ ) ¹ H-NMR (400 MHz, CDCl ₃ ) δppm:
0.18 (1H, m), 0.24 (2H, m), 0.5
0 (1H, m), 0.94 (1H, m), 1.02 (3
H, d, J = 6.9 Hz), 1.04 (3H, d, J =
6.0 Hz), 1.85 (2H, br q, J = 6.9
Hz), 4.47 (1H, td, J = 7.1 and
11.6 Hz), 4.48 (1H, td, J = 6.9)
and 11.6 Hz), 8.20 (2H, d, J = 8.
9Hz), 8.28 (2H, d, J = 8.9Hz)

Reference Example 2 aragusterol B using the compound of the present invention: Compound (1
Synthesis of 6) 1) Synthesis of compound (14) After dissolving compound (13) (100 mg, 0.3 mmol) in anhydrous N, N-dimethylformamide (1 ml), imidazole (100 mg, 1.5 mmol) and triethylsilyl chloride were dissolved. (0.12 ml, 0.7 mmol) was added at 0 ° C. and the mixture was stirred for 20 minutes. 5 minutes at room temperature for 10 minutes
The mixture was stirred at 0 ° C for 15 minutes. The reaction mixture was diluted with diethyl ether, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel chromatography (n-hexane: diethyl ether = 9: 1) to give 143 m of the title compound as a colorless oil.
g (yield 85%) was obtained.

[Α] _D ²⁴ : + 33.1 ° (c 1.6
_{9, CHCl 3) IR (CHCl} 3): 2900,1700cm -1 1 H-NMR (400MHz, CDCl 3) δppm:
0.60 (6H, m), 0.70 (3H, s), 0.8
0 (3H, s), 0.94 (9H, t, J = 7.9H
z), 0.95 (9H, t, J = 7.9Hz), 2.2
2 (3H, s), 2.64 (1H, t, J = 9.0H
z), 3.54 (1H, m), 3.63 (1H, dd,
J = 4.6 and 10.9Hz) EIMS m / z: 533 (M + -C 2 H 5) Anal. Calcd for C ₃₃ H ₆₂ O ₃ Si ₂ :
C, 70.40; H, 11.10 Found: C, 7
0.23; H, 11.27

2) Synthetic Step of Compound (15) 1: In anhydrous diethyl ether (0.60 ml), under argon flow at −78 ° C., tert-butyllithium (1.55M n-pentane solution 0.60 ml, 0. 9
(3 mmol) was added dropwise, and the mixture was stirred for 5 minutes. Then, the compound (10, X = Br) obtained in Example 1-9) was added to this solution.
(65 μl, 0.37 mmol) was added dropwise, and then 4 at 0 ° C.
Stir for hours. Then, the above reaction example 2-1)
Compound (14) obtained in (74 mg, 0.13 mmol)
Anhydrous diethyl ether (0.6 ml) solution was added dropwise.
Stir for 30 minutes. To this reaction solution, saturated aqueous ammonium chloride was added little by little, diluted with diethyl ether, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain a crude product. .

Step 2: To the crude product obtained in Step 1 above, tetrahydrofuran (1.0 ml) and tetra
n-Butyl ammonium fluoride (1.0 M tetrahydrofuran solution, 1.0 ml) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate = 1: 3),
Then, reverse-phase silica gel column chromatography (water:
Purification with methanol = 1: 7) gave 30 mg (yield 53%) of the title compound as colorless crystals.

[0054] _{mp: 106~109 ℃ [α] D} 27: -7.4 ° _{(c 0.38, CHCl 3) IR} (CHCl 3): 3400,2925cm -1 1 H-NMR (400MHz, CDCl 3) δppm:
0.09 (1H, m), 0.17 (2H, m), 0.5
0 (1H, m), 0.82 (3H, s), 0.83 (3
H, s), 0.92 (3H, d, J = 6.7 Hz),
1.03 (3H, d, J = 5.9Hz), 1.15 (3
H, s), 3.35 (1H, dd, J = 4.5 and
11.1 Hz), 3.58 (1 H, m) HREIMS: (M ⁺ -2H ₂ O) m / z obsd
410.3523 C ₂₉ H ₅₀ O ₃ required 410.3549

3) Compound (16): combination of aragusterol B
Compounds for forming anhydrous toluene (5ml) (15) (1.5m
g, 3.4 μmol) in cyclohexanone (2 ml) and aluminum tri-tert-butoxide (10 m)
g, 0.04 mmol) was added, and the mixture was stirred at 105 ° C. for 2 hours. The reaction solvent was evaporated under reduced pressure, the obtained residue was diluted with ethyl acetate, washed with saturated Rochelle salt water, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to obtain 1.0 mg of the title compound as colorless crystals (yield 66%).
Obtained.

Mp: 194-195 ° C. [α] _D ²⁴ : + 4.7 ° (c 0.22, CHCl ₃ ) IR (CHCl ₃ ): 3400, 2950, 1718c
^{m -1 1 H-NMR (400MHz} , CDCl 3) δppm:
0.86 (3H, s), 0.93 (3H, d, J = 6.
7Hz), 1.02 (3H, s), 1.03 (3H,
d, J = 6.1 Hz), 1.18 (3H, s), 3.3
7 (1H, dd, J = 6.4 and 11.1Hz) HREIMS: (M + -2H 2 O) m / z obsd
408.3365 C ₂₉ H ₄₈ O ₃ required 408.3392 Physical data of the compound (16) includes a sign of optical rotation.
In agreement with the physical data of aragusterol B.

Claims (1)

[Claims] 1. A formula (In the formula, X is a hydroxyl group or a halogen atom.) An optically active cyclopropane derivative.