JP2894652B2 - Method for producing polycyclic olefin - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a polycyclic olefin. The sterically controlled polycyclic olefins obtained by the present invention are useful as terpenoids or steroids having various physiological activities or synthetic intermediates thereof.

[0002]

2. Description of the Related Art In the synthesis of terpenoids and steroids, attempts have been made to control the stereochemistry of two adjacent rings. For example, in the total synthesis of 3β, 20-dihydroxyprost-24-ene,
An intermediate having an AB ring having a β-hydroxy-4-ene structure is treated with tosyl hydrazide in nitromethane to give 3α-.
There is known a method of converting a hydrazine derivative into an intermediate having an AB ring having a 5α-3 ene structure by heating with sodium acetate in acetic acid [EJCorey].
Et al., Journal of American Chemical Society, 1
12, 6429-6431 (1990)]. However, little is known of a method applicable to the stereospecific synthesis of a wide range of compounds having a terpenoid skeleton or a steroid skeleton.

[0003]

Therefore, at present, it is desired to develop a new stereospecific synthesis of polycyclic compounds applicable to the synthesis of terpenoids and steroids.

Accordingly, an object of the present invention is to provide a method for producing polycyclic olefins such as terpenoids, steroids, and synthetic intermediates thereof in which the ring bonding site of a hydroindene skeleton or a hydronaphthalene skeleton is stereospecifically controlled. To provide.

[0005]

According to the present invention, the above object is achieved by the following general formula (I)

[0006]

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( Wherein , R ¹ represents a hydrogen atom, an alkyl group which may have a substituent, an alkoxycarbonyl group or an acyl group, R ⁴ represents a hydrogen atom or an alkyl group, R ²¹ , R ^{22 , R 31, R 32, R} 51, R 52, R 61,
R ⁶² , R ⁷¹ , R ⁷² , R ⁸¹ and R ⁸² each represent a hydrogen atom or an organic group, and R ²¹ , R ²² , R ³¹ and R ³² , or R ⁵¹ , R ⁵² , R ⁶¹ and R ⁶² may each form a ring together with the carbon atom to which they are bonded, and m and n represent an integer of 0 or 1. ) Is reduced in the presence of a palladium catalyst, characterized by the following general formula (III):

[0008]

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Wherein R ¹ , R ⁴ , R ²¹ , R ²² , R ³¹ , R
^{32, R 51, R 52,} R 61, R 62, R 71, R 72, R 81,
R ⁸² , m and n are as defined above. The method for producing a polycyclic olefin represented by the following general formula (II):

[0010]

Embedded image

Wherein R ¹ , R ⁴ , R ²¹ , R ²² , R ³¹ , R
^{32, R 51, R 52,} R 61, R 62, R 71, R 72, R 81,
R ⁸² , m and n are as defined above. ) Is reduced in the presence of a palladium catalyst, characterized by the following general formula (IV):

[0012]

Embedded image

( Wherein R ¹ , R ⁴ , R ²¹ , R ²² , R ³¹ , R
^{32, R 51, R 52,} R 61, R 62, R 71, R 72, R 81,
R ⁸² , m and n are as defined above. This is achieved by providing a method for producing a polycyclic olefin represented by the formula (1).

The alkyl group represented by R ¹ and R ⁴ includes
A linear or branched lower alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group and a pentyl group is preferred. Examples of the substituent which the alkyl group represented by R ¹ may have include a hydroxyl group, a protected hydroxyl group, a halogen atom, a carboxyl group, and an alkoxycarbonyl group. Examples of the alkoxycarbonyl group represented by R ¹ include a methoxycarbonyl group, an ethoxycarbonyl group, a butoxycarbonyl group, and a benzyloxycarbonyl group. Examples of the acyl group represented by R ¹ include an acetyl group, a propanoyl group, and a p-methoxybenzoyl group.

R ²¹ , R ²² , R ³¹ , R ³² , R ⁵¹ , R ⁵² , R
^{61, R 62, R 71,} R 72, hydroxyl group as the organic group R ⁸¹ and R ⁸² represent each a protected hydroxy group, an alkyl group, an alkoxycarbonyl group, an acyl group. R ²¹ , R ²² , R ³¹ and R ³² , or R ⁵¹ ,
R ⁵² , R ⁶¹ and R ⁶² each form a ring together with the carbon atom to which they are bonded, and may constitute the skeleton of a polycyclic olefin such as terpenoids, steroids and their synthetic intermediates. Good.

The polycyclic olefin includes, for example,
3a, 7a-trans-1β-t-butyldimethylsilyloxy-7aβ-methyl-2,3,3a, 6,7,7
Compounds having a hydroindene skeleton such as a-hexahydroindene, 4a, 8a-trans-1β-t-butyldimethylsilyloxy-8aβ-methyl-1,2,3,
Compounds having a hydronaphthalene skeleton such as 4,4a, 7,8,8a-octahydronaphthalene or steroids such as 5α-cholest-3-ene and 17-tert-butyldimethylsilyloxy-5α-androst-3-ene Examples include compounds having a skeleton.

As the palladium catalyst, palladium acetylacetonate, palladium acetate, palladium chloride,
Palladium salts such as palladium nitrate, bis (acetonitrile) palladium chloride, tris (dibenzylideneacetone) palladium / chloroform,
These palladium catalysts are suitably used in combination with phosphines such as tributylphosphine, trihexylphosphine, trioctylphosphine, tricyclohexylphosphine, triphenylphosphine, and tolylphosphine, or phosphites such as trimethylphosphite and triethylphosphite. It is preferable to further use a base such as triethylamine and diisopropylethylamine as needed. In particular, it is preferable to use equimolar amounts of palladium acetylacetonate or palladium acetate and trialkylphosphine such as tributylphosphine, trihexylphosphine, and trioctylphosphine.

The palladium catalyst is preferably used in the range of 0.0001 to 1 equivalent, more preferably 0.01 to 0.2 equivalent, based on polycyclic allyl formate.

The reaction is usually carried out preferably at a temperature in the range of 0 ° C. to 120 ° C., more preferably at a temperature in the range of 0 ° C. to room temperature. The reaction is carried out in the presence or absence of an organic solvent.Examples of the organic solvent include hydrocarbon solvents such as hexane and benzene, ether solvents such as diethyl ether, tetrahydrofuran and dioxane, acetonitrile, dimethylformamide, and dimethyl sulfoxide. , Chloroform and the like can be used, but it is preferable to use tetrahydrofuran.

The polycyclic allyl form as a raw material can be synthesized by formylating the corresponding known compound, allyl alcohol. This formylation can be carried out in the same manner as a general esterification reaction. For example, a corresponding allyl formate can be obtained by reacting formic acid / acetic acid mixed acid anhydride on allyl alcohol in the presence of pyridine [Helv. Chim. Acta, 37, 45 (1954)].

The polycyclic allyl formate obtained by the above method has α-formate (I) depending on its steric structure.
And β-formate (II). In the present invention, when α-formate (I) is used as a raw material, β-hydrogen (III) of a polycyclic olefin is obtained, and when β-formate (II) is used as a raw material, polycyclic olefin is obtained. Α-Hydrogen (IV) of the reactive olefin is obtained. That is, according to the reaction in the present invention, the hydrogen atom is opposite to the formyloxy group with respect to the ring plane,
The substrate is attacked with the transfer of the double bond to obtain a polycyclic olefin.

Isolation and purification of the thus obtained polycyclic olefin from the reaction mixture can be carried out in the same manner as the isolation and purification method used in a usual organic reaction. For example, the reaction mixture is poured into ice water, extracted with an organic solvent such as diethyl ether, washed sequentially with cold diluted hydrochloric acid, aqueous sodium bicarbonate, and brine, dried and concentrated to obtain a crude product, and further, if necessary, recrystallized. -Purify by chromatography or the like to isolate the polycyclic olefin.

[0023]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

Example 1 Palladium acetylacetonate 4 under an argon atmosphere
To a mixture of 5.7 mg and 2 ml of tetrahydrofuran was added 0.037 ml of tributylphosphine at room temperature,
The mixture was stirred for 5 minutes to prepare a catalyst solution. 1β-t-butyldimethylsilyloxy-7aβ-methyl-2,3,5
155 mg of 6,7,7a-hexahydroindene-5β-yl formate was added to 0.5 ml of tetrahydrofuran
And stirred at room temperature while stirring the above catalyst solution 0.4.
ml was added and stirred for 30 minutes. The resulting reaction solution was subjected to florisil filtration using diethyl ether as an eluent, and the eluate was concentrated under reduced pressure. The obtained concentrate was dissolved in methylene chloride, and the by-product heterocyclic diene was removed by treating with a small excess of m-chloroperbenzoic acid at 0 ° C. Thereafter, an aqueous solution of sodium thiosulfate was added to the above methylene chloride solution with stirring to separate the layers. The organic layer was washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography to give 3a, 7a-trans-1β-t-butyldimethylsilyloxy-7aβ-methyl-2,3,3a, 6 having the following physical properties.
10,7 mg of 7,7a-hexahydroindene was obtained (yield: 82%). ¹ H- NMR spectrum (400 MHz, CDCl ₃ )
δ: 0.017 (s, 3H), 0.023 (s, 3H),
0.730 (s, 3H), 0.890 (s, 9H),
1.250-2.150 (m, 9H), 3.651 (d
d, J = 8.98, 7.15 Hz, 1H), 5.500
−5.620 (m, 2H) ¹³ C- NMR (100 MHz, CDCl ₃ ) δ: −4.82, −4.50, 10.59, 18.11,
4.12, 24.31, 25.86, 31.20, 3
3.97, 42.77, 42.85, 80.39, 12
6.64, 128.16

Example 2 In Example 1, 1β-t-butyldimethylsilyloxy-7aβ-methyl-2,3,5,6,7,7a-hexahydroindene-5β-yl formate 155
155 mg of 1β-t-butyldimethylsilyloxy-7aβ-methyl-2,3,5,6,7,7a-hexahydroindene-5α-yl formate instead of mg
And the reaction and separation and purification were carried out in the same manner as in Example 1 except that the reaction time was changed from 0.5 hour to 2.5 hours, to give 3a, 7a-cis-1β-t having the following physical properties.
-Butyldimethylsilyloxy-7aβ-methyl-2,
3,3a, 6,7,7a-Hexahydroindene is converted to 7
5.8 mg was obtained (57% yield). ¹ H- NMR spectrum (400 MHz, CDCl ₃ )
δ: 0.026 (s, 3H), 0.032 (s, 3H),
0.892 (s, 12H), 1.170-1.560
(M, 4H), 1.900-2.180 (m, 5H),
3.773 (dd, J = 7.60, 5.84 Hz, 1
H), 5.540-5.640 (m, 2H ) 13 C -NMR (100MHz, CDCl 3) δ: -4.88, -4.44,18.09,20.44,2
1.93, 25.86, 28.59, 29.65, 3
2.41, 42.99, 43.29, 78.30, 12
4.30, 131.56

Example 3 In Example 1, 1β-t-butyldimethylsilyloxy-7aβ-methyl-2,3,5,6,7,7a-hexahydroindene-5β-yl formate 155
mg instead of 1β-t-butyldimethylsilyloxy-8aβ-methyl-1,2,3,4,6,7,8,8
Using 162 mg of a-octahydronaphthalen-6β-yl formate, the reaction time was 0.5 to 2.0 hours.
The reaction, separation and purification were carried out in the same manner as in Example 1 except that the time was changed to 4a, 8a-trans-1β-t-butyldimethylsilyloxy-8a having the following physical properties.
128.8 mg of β-methyl-1,2,3,4,4a, 7,8,8a-octahydronaphthalene was obtained (yield 92).
%). ¹ H- NMR spectrum (400 MHz, CDCl ₃ )
δ: 0.028 (s, 6H), 0.770 (s, 3H),
0.888 (s, 9H), 1.090-2.100
(M, 11H), 3.238 (dd, J = 7.70,
7.69 Hz, 1H), 5.280-5.330 (m,
1H), 5.520-5.590 (m, 1H ) 13 C -NMR (100MHz, CDCl 3) δ: -4.82, -3.79,9.66,18.09,2
3.20, 24.59, 25.90, 26.59, 3
0.98, 33.43, 38.18, 43.02, 7
8.52, 125.95, 130.26

Example 4 In Example 1, 1β-t-butyldimethylsilyloxy-7aβ-methyl-2,3,5,6,7,7a-hexahydroindene-5β-yl formate 155
mg instead of 1β-t-butyldimethylsilyloxy-8aβ-methyl-1,2,3,4,6,7,8,8
Using 162 mg of a-octahydronaphthalen-6α-yl formate, the reaction time was reduced from 0.5 hour to 1.0 hour.
Reaction and separation and purification were carried out in the same manner as in Example 1 except that the time was changed to 4a, 8a-cis-1β-t-butyldimethylsilyloxy-8aβ-having the following physical properties.
125 mg of methyl-1,2,3,4,4a, 7,8,8a-octahydronaphthalene was obtained (89% yield). ¹ H- NMR spectrum (400 MHz, CDCl ₃ )
δ: 0.036 (s, 3H), 0.039 (s, 3H),
0.891 (s, 9H), 0.940 (s, 3H),
1.080-2.150 (m, 11H), 3.620
(Dd, J = 9.53, 4.03 Hz, 1H), 5.3
50-5.410 (m, 1H), 5.600-5.67
^{0 (m, 1H) 13 C} -NMR (100MHz, CDCl 3) δ: -4.82, -3.74,14.12,18.12,2
0.93,22.57,25.86,28.19,3
1.03, 31.61, 36.59, 41.33, 7
0.51,126.62,131.91

Example 5 0.031 ml of tributylphosphine was added to a mixture of 28.0 mg of palladium acetate and 2 ml of tetrahydrofuran at room temperature under an argon atmosphere, followed by stirring for 5 minutes to prepare a catalyst solution. Cholest-4-en-3β-yl
207 mg of formate in 0.5 m of tetrahydrofuran
and stirring at room temperature while stirring the catalyst solution.
4 ml was added and the mixture was stirred for 2 hours. The resulting reaction solution was subjected to florisil filtration using diethyl ether as an eluent, and the eluate was concentrated under reduced pressure. The concentrated residue was dissolved in methylene chloride, and the by-product diene was removed by treating with a small excess of m-chloroperbenzoic acid at 0 ° C. afterwards,
An aqueous sodium thiosulfate solution was added to the above methylene chloride solution with stirring to separate the layers. Wash the organic layer with aqueous sodium bicarbonate,
Dry over anhydrous sodium sulfate and then concentrate under reduced pressure. By purifying the obtained concentrated residue by silica gel column chromatography, 5α having the following physical properties is obtained.
-Cholest-3-ene (148 mg, yield 80)
%). ¹ H- NMR spectrum (400 MHz, CDCl ₃ )
δ: 0.668 (s, 3H), 0.772 (s, 3H),
0.865 (d, J = 6.60 Hz, 3H), 0.86
9 (d, J = 6.60 Hz, 3H), 0.910 (d,
J = 6.60 Hz, 3H), 0.920-2.080
(M, 29H), 5.250-5.300 (m, 1
H), 5.500-5.560 (m, 1H) ¹³ C- NMR (100 MHz, CDCl ₃ ) δ: 11.87, 12.17, 18.67, 21.08, 2
2.57, 22.82, 23.52, 23.87, 2
4.19, 27.50, 28.02, 28.27, 3
2.10, 34.14, 34.90, 35.61, 3
5.83, 36.20, 39.53, 40.11, 4
2.75, 45.92, 53.43, 56.32, 5
6.55, 125.41, 131.48

Example 6 Cholest-4-en-3α-yl formate 202
The catalyst solution prepared in Example 5 was dissolved in 0.5 ml of tetrahydrofuran and stirred at room temperature.
was added and stirred for 2 hours. The resulting reaction solution was subjected to florisil filtration using diethyl ether as an eluent, and the eluate was concentrated under reduced pressure. The concentrated residue was dissolved in methylene chloride, and the by-product diene was removed by treating with a small excess of m-chloroperbenzoic acid at 0 ° C. Thereafter, an aqueous solution of sodium thiosulfate was added to the above methylene chloride solution with stirring to separate the layers. The organic layer was washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography to obtain 165 mg of 5β-cholest-3-ene having the following physical properties (89% yield). ¹ H- NMR spectrum (400 MHz, CDCl ₃ )
δ: 0.661 (s, 3H), 0.862 (d, J = 6.6)
0 Hz, 3H), 0.865 (d, J = 6.60 Hz,
3H), 0.900 (d, J = 6.60 Hz, 3H),
0.950 (s, 3H), 0.960-2.050
(M, 29H), 5.310-5.360 (m, 1
H), 5.620-5.690 (m, 1H ) 13 C -NMR (100MHz, CDCl 3) δ: 12.00,18.70,21.50,22.42,2
2.56, 22.80, 22.96, 23.82, 2
4.30, 27.50, 27.69, 28.02, 2
8.31, 33.53, 34.03, 35.63, 3
5.80, 36.19, 39.53, 40.33, 4
0.89, 42.68, 43.50, 56.28, 5
6.34, 126.98, 132.39

Example 7 216 mg of 17-t-butyldimethylsilyloxy-4-androstene-3β-ylformate was dissolved in 0.7 ml of tetrahydrofuran and stirred at room temperature while stirring.
0.37 ml of the catalyst solution prepared in Example 5 was added,
Stir for 1.5 hours. The resulting reaction solution was subjected to florisil filtration using diethyl ether as an eluent, and the eluate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain 192.2 mg of 17-t-butyldimethylsilyloxy-5α-androst-3-ene having the following physical properties (yield: 99.
1%). ¹ H- NMR spectrum (400 MHz, CDCl ₃ )
δ: 0.001 (s, 3H), 0.010 (s, 3H),
0.708 (s, 3H), 0.778 (s, 3H),
0.879 (s, 9H), 0.800-2.090
(M, 20H), 3.548 (dd, J = 8.43,
8.43 Hz, 1H), 5.250-5.300 (m,
1H), 5.520-5.580 (m, 1H ) 13 C -NMR (100MHz, CDCl 3) δ: -4.81, -4.50,11.49,11.90,1
8.11, 10.70, 23.52, 23.53, 2
5.87, 27.38, 30.95, 31.71,3
4.16, 35.00, 35.70, 37.25, 4
3.47, 46.03, 50.76, 53.73, 8
1.87, 125.45, 131.40

Example 8 17 mg of 17-t-butyldimethylsilyloxy-4-androstene-3α-ylformate is dissolved in 0.5 ml of tetrahydrofuran, and the catalyst solution prepared in Example 5 while stirring at room temperature. Add 0.13 ml.
Stir for 5 hours. The resulting reaction solution was subjected to florisil filtration using diethyl ether as an eluent, and the eluate was concentrated under reduced pressure. By purifying the concentrated residue by silica gel column chromatography, one having the following physical properties is obtained.
63.4 mg of 7-t-butyldimethylsilyloxy-5β-androst-3-ene was obtained (yield 94.6).
%). ¹ H- NMR spectrum (400 MHz, CDCl ₃ )
δ: −0.007 (s, 3H), 0.000 (s, 3H),
0.698 (s, 3H), 0.874 (s, 9H),
0.955 (s, 3H), 0.750-2.070
(M, 20H), 3.534 (dd, J = 8.42,
8.42), 5.300-5.360 (m, 1H),
^{5.620-5.690 (m, 1H) 13 C} -NMR (100MHz, CDCl 3) δ: -4.82, -4.51,11.31,18.12,2
1.11,22.39,22.97,23.59,2
5.87, 27.10, 27.55, 30.98, 3
3.63, 34.10, 35.71, 37.48, 4
1.20, 43.37, 43.55, 50.48, 8
1.91,127.01,132.34

[0032]

According to the present invention, it is possible to produce a polycyclic olefin such as a terpenoid, a steroid, or a synthetic intermediate thereof in which the ring bonding site of the hydroindene skeleton or the hydronaphthalene skeleton is stereospecifically controlled. it can.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C 1/22 C07C 1/22 13/48 13/48 43/18 43/18 C07F 7/18 C07F 7/18 A C07J 1 / 00 C07J 1/00 // C07B 61/00 300 C07B 61/00 300 (58) Field surveyed (Int.Cl. ⁶ , DB name) C07C 13/465 B01J 27/13 B01J 27/25 B01J 31/04 B01J 31/12 C07C 1/22 C07C 13/48 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound represented by the following general formula (I) ( Wherein , R ¹ represents a hydrogen atom, an alkyl group which may have a substituent, an alkoxycarbonyl group or an acyl group, R ⁴ represents a hydrogen atom or an alkyl group, R ²¹ , R ^{21
22, R 31, R 32,} R 51, R 52, R 61, R 62, R 71,
R ⁷² , R ⁸¹ and R ⁸² each represent a hydrogen atom or an organic group, and R ²¹ , R ²² , R ³¹ and R ³² , or R ⁵¹ , R
⁵² , R ⁶¹ and R ⁶² may form a ring together with the carbon atom to which they are bonded, and m and n represent an integer of 0 or 1. ) Is reduced in the presence of a palladium catalyst, characterized by the following general formula (III): ( Wherein , R ¹ , R ⁴ , R ²¹ , R ²² , R ³¹ , R ³² , R ⁵¹ , R
^{52, R 61, R 62,} R 71, R 72, R 81, R 82, m and n
Is as defined above. )). 2. The following general formula (II): ( Wherein , R ¹ represents a hydrogen atom, an alkyl group which may have a substituent, an alkoxycarbonyl group or an acyl group, R ⁴ represents a hydrogen atom or an alkyl group, R ²¹ , R ^{21
22, R 31, R 32,} R 51, R 52, R 61, R 62, R 71,
R ⁷² , R ⁸¹ and R ⁸² each represent a hydrogen atom or an organic group, and R ²¹ , R ²² , R ³¹ and R ³² , or R ⁵¹ , R
⁵² , R ⁶¹ and R ⁶² may form a ring together with the carbon atom to which they are bonded, and m and n represent an integer of 0 or 1. ) Is reduced in the presence of a palladium catalyst, characterized by the following general formula (IV): ( Wherein , R ¹ , R ⁴ , R ²¹ , R ²² , R ³¹ , R ³² , R ⁵¹ , R
^{52, R 61, R 62,} R 71, R 72, R 81, R 82, m and n
Is as defined above. )).