JPS63280085A - Production of 3,7-dioxabicyclo(3,3,0)octane derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a chemical for agriculture and medicine, by reacting a substituted benzylidene succinic acid ester with a substituted aromatic aldehyde and then successively subjecting to acid treatment, reduction, substitution, oxidation and ring-closing. CONSTITUTION:A substituted benzylidene succinic acid ester expressed by formula I (R is lower alkyl; X1 is H, halogen, 1-3C alkyl, etc.; n is 1-5) is reacted with a substituted aromatic aldehyde expressed by formula II (X2 is H, halogen, 1-3C alkyl, etc.; m is 1-5) and the resultant reaction product is subjected to acid treatment to afford 3-alkoxycarbonyl-4-substituted phenyl-2-substituted benzylidenebutylolactone expressed by formula III, whose lactone ring is then reduced to give an oxolane ester expressed by formula IV, whose ester ring is reduced to give diastereomer of alcohol expressed by formula IV, etc., whose benzylidene part is successively oxidized to give a diol compound expressed by formula VI (Z is eliminating group), which is then subjected to ring closure in the presence of a base to provide the aimed compound expressed by formula VII.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing 3,7-thioxabicycloIn3,3.0)octane derivatives. By this method, it is possible to use porphyrin and greminol as agricultural chemicals and medicines.

[Conventional technology]

3.7-dioxabicyclo[3,3,0), a compound represented by the formula that is an octane derivative, in which Y is a hydrogen atom (
Sesamin) manufacturing method is J, C, S 78.1242° (1
956).

[Problem that the invention seeks to solve]

J.C., 87 C. 1242. (1956) cannot produce useful compounds in which Y at the l-position is a hydroxyl group.

The present invention aims to provide a new method for producing derivatives (some of which are new compounds) in which Y is a hydroxyl group in formula (A).

[Means to solve the problem]

The present inventor has discovered that 1 represented by formula (6) or formula (7) below
3,7-thioxabicyclo (3,3
, 0) We have discovered a method for stereoselectively producing octane derivatives based on the following reaction scheme.

The present invention will be explained in detail below.

The substituted benzylidene succinic acid ester represented by formula (1) of the present invention is dissolved in an inert solvent such as anhydrous tetrahydrofuran, ether or 1,2-dimethoxyethane, preferably at a temperature of -20°C to -80°C, 2 to 3 times the mole. By reacting the substituted aromatic aldehyde of formula (2) with a strong base such as lithium diimpropylamide CLDA) or lithium diethylamide, and treating with a mineral acid such as sulfuric acid, phosphoric acid, or hydrochloric acid, the formula ( 3) A 3-alkoxycarbonyl, 4-substituted phenyl-2-substituted benzylidene butyrolactone is obtained.

Although the compound represented by formula (3) is a cis/trans mixture, there is no particular need for separation by chromatography or the like.

The 3-alkoxycarbonyl, 4-substituted phenyl-2-substituted benzylidene butyrolactone represented by formula (3) obtained by the above method is mixed in an inert solvent such as anhydrous tetrahydrofuran, preferably at -20 to -80°C for 3 to 4 hours. twice the molar amount of diinoptylaluminoidide (PIB)
After reacting with a reducing agent such as lithium t-butoxyaluminum hydride or lithium t-butoxyaluminum hydride, it is treated with a weak acid such as acetic acid preferably at 0 to 50°C and then treated with a reducing agent such as dichloromethane. Extraction is performed with an active solvent to obtain lactol (>C=0 of the lactone ring in formula (3) becomes monoOH).

The lactol is then dissolved in an inert solvent such as anhydrous tetrahydrofuran or ether, preferably from -20° to
At -80°C, preferably 2 to 3 times the amount of triethylsilane (
EtaSiH), trimethylsilane (Men
Si H ) or alkyl 7-ranes such as tributylsilane and boron trifluoride ether complex salt (BP, -OR14
The oxolane ester represented by formula (4) can be obtained by treating with a weak alkali such as bicarbonate and a weak alkali such as IJium. Although this oxolane ester is found to be a cis/trans mixture by 'H-NMR, it can proceed to the next reaction as a cis/trans mixture.

(References; G.A. Kraus et. al.,
J. Org-Chem. .

1 Hama, 2417 (1981)) Add 1 to 2 moles of fresh sodium aluminum hydride to a solution of the oxolane ester represented by formula (4) obtained by the method described above in an inert solvent such as anhydrous ether or tetrahydrofuran. Formulas (5a) and (5b) are obtained by reacting a reducing agent such as bismethoxyethoxyaluminum hydride (Red-AI) or lithium methoxyaluminum hydride, preferably at -10 to 10°C, adding ethyl acetate and then water and stirring. It is possible to obtain the alcohol shown in This alcohol was purified by silica gel chromatography.
Separates into alcohol (5a) and cis alcohol (5b).

(References; H, C-Brownet, aL,, J
, Org. After reacting with trifluoromethanesulfonic acid etc. to replace the hydroxyl group of the alcohol with a leaving group, it is oxidized with preferably a catalytic amount of osnium tetroxide etc. in the presence of a slight excess of N-methylmorpholine N-oxide <NMO). Diol (6) can be obtained.

Subsequently, the diol can be ring-closed with a base to obtain a 3°7-thioxapicyclo(3,3,0:]octane derivative.

The starting material of the present invention is the formula (1) (In the formula (1), R is lower alkyl, and XI is a hydrogen atom, a halogen atom, a lower alkyl and alkoxy group having 1 to 3 carbon atoms, or a methylenedioxy group. , n is 1~
Substituted benzylidene succinic acid esters are 5t
It can be produced by the following steps through an obbe condensation reaction.

(References; Organic Reaction 6
Vol. 1, p. 1 (1951)) etc. [Effects of the Invention] The method of the present invention produces 3 useful agricultural chemicals and pharmaceuticals.
．． A 7-thioxabicyclo[3,3,o]octane derivative can now be obtained in good yield.

〔Example〕

The present invention will be further explained with reference to Examples below. In the examples, "common procedure 1" refers to a series of steps consisting of dilution with water, extraction with an organic solvent, washing until the extract becomes neutral, drying with anhydrous magnesium sulfate, filtration, and solvent removal by vacuum concentration. It is used as an abbreviation for the operation.

(Example 1) fj:) neoho o sea urchin y: (IR”, 2R:,
5S", 6R)-1-hydroxy-2,6-di<3',
Synthesis of 4'-methylenedioxyphenyl)-3,7-thioxabicyclo(3,3,0)octane (13): The reaction steps of Example 1 are illustrated below.

(13) (tlNeopaulownin(i)
Synthesis of 3'-methoxycarbonyl-4'-<3',4'-methylenedioxyphenyl)-2-(3:'4"-methylenedioxybenzylidene)butyrolactone (9): Lithium diisopropylamide under nitrogen stream (LDA)
in anhydrous tetrahydrofuran (70 ml)
JLy Lithium (nBuLi) (20ml, 15%
Hexane bath W w/w ) and diisopropylamine (4
, 2 ml) at -10°C. Add this solution to 7
Under cooling to 8°C, 3.4-methylenedioxybenzylideneconomonolyric acid methyl ester (10) (3,96 g,
A solution of 0.015 mol) in 15 ml of anhydrous tetrahydrofuran is added dropwise. After stirring for 2.5 hours, piperonal (
A solution (15 mt) of anhydrous tetrahydrofuran (2.25 g, 0.015 mol) was added dropwise at -78°C, and the mixture was stirred at the same temperature for 9 hours. It is then treated with 70 mt of cold 6M sulfuric acid, immediately extracted twice with ether, washed with 5% aqueous sodium bicarbonate, and subjected to conventional procedures to give a pale yellow oil.

Add a small amount of ether to this substance to crystallize it, filter it, and wash it with cold ether.
(54%) as white crystals (m, p.

149-155°C). This one is 1H-NM
It is a trans mixture (22 near 8) from R.

'H-NMR (CDC13); δ (ppm) 3.3
4 (0,22X3H,s), 3.76 (0,78x3
H,s)t 4.17(0,78X I H,dd,
J1=3Hz, J2=2Hz).

4.5 2 (0,22X I H, dd, Js
=8Hz, Jz=2Hz).

5.64 (0,78xlH,a, J=3Hz), 5.6
8(0,22X l)(,a, J=8Hz), 5
．． 96 (2H.

s ) t 6.02 (2H, s ), 6.70
~7.15 (6H.

m ), 7.60 (0,22X IH, d, J
= 2Hz).

7.64 (0,78xlH,d, J=2Hz) (1i)
Synthesis of methoxycarbonyl-(E)4-(3:4'-methylenedioxybenzylidene)-2-4374'-methylenedioxyphenyl)oxolane (10): Lactone compound (9) produced by the above method (i) )(cis
/ trans=22:78 mixture) 5.2g
(13 mmol) of anhydrous tetrahydrofuran solution 10
0ml to 49ml of IM water diisobutylaluminum hydride-hexane solution (DIRAH) under nitrogen X stream,
After adding dropwise and stirring for 1 hour at the same temperature, the reaction solution was
Add ml of acetic acid and 50 g of ice. Add 50 ml of dichloromethane and boil for 10 minutes (after washing, add 1 ml of dichloromethane)
Add 00 ml of dichloromethane and stir vigorously for another hour. After separating the aqueous and organic layers and washing with 5% aqueous sodium bicarbonate, crude lactol is obtained by a conventional procedure.

4.5 g (38.8 mmol) of this crude lactol
45 ml of an anhydrous dichloromethane solution of triethylsilane (EhSi'H) is added at -78°C under a nitrogen stream.

Further, when 4.0 ml (32.4 mmol) of boron trifluoride ether complex salt (BFs-0Etz) is added dropwise, the color becomes deep red, and the mixture is further stirred at the same temperature for 2 hours, and then 20 mt of 5% sodium bicarbonate is added. Add water. The temperature was gradually raised to room temperature, the organic layer and the aqueous layer were separated, the organic layer was washed with 5% sodium bicarbonate water, and an oily substance was obtained by conventional procedures. This oily substance was subjected to silica gel chromatography (eluent; n-hexane/ether = 2:l-1:
2) to obtain 2.8 g (7.3 mmol) of oxolane (cis/trans = 36:64 mixture) as an oil with a yield of 56%.

'I-l-1-N (CDCl5): trans body; δ3.60 (3H.

s), 3.74 (I H, dd, mountain = 6 l-
12, δ2 = 2 Hz).

4.67 (2H,s), 5.10 (1)1.
d, J=6I-1z).

5.86 (4H,s), 6.4 1
(LH, d, J=2Hz).

6.60-6.90 (6H,m), cis body; 3
．． 40 (3■7S), 3.96 (IH, dd
, mountain = 5 H2, δ2 = 2) - IZ), 4
．． 60 (IH, d, J=15Hz),
4.9 6 (IH, d, J=t 5Hz), 5.
05 (1i-i, atJ=5Hz)+5.88
(48,s), 6.36 (IH.

d, J = 2Hz), 6.60-6.90 (61
(,m).

Although the cis and trans forms were not isolated, they were described separately for the purpose of describing the spectral data.

song) 3-hydroxymethyl-ta4-<3',4'-methylenedioxybenzylidene)-2-(374"-methylenedioxyphenyl)oxolane (lla), (l
Synthesis of lb): Oxolane ester (1) produced by the above method (11)
0) (cis/trans=35:54
A 0.56 M ether solution of aluminum hydride (AlH3) made from lithium aluminum hydride and aluminum chloride was added dropwise to 1.65 g (4.3 mmol) of anhydrous Azo #125ml under a nitrogen stream. After stirring at the same temperature for 20 minutes, carefully add ethyl acetate and then water. The organic layer is washed with 0.5N hydrochloric acid, and a gummy substance is obtained by a conventional procedure. This gummy substance was purified by silica gel chromatography (eluent: n-hexane/Ezo/
L/: 1:1), 0.52g (3
4%) cis alcohol as an oily substance, followed by 0
．． 94 g (62%) of trans alcohol are obtained as an oil. These crystallize from ether. tra
ns form (lla) (mp 109-110'C), c
is body (llb) (mp 8 8 ~8
9℃).

(lib): 'H-NMR (CDC1,); δ
1.28 (L H, broad).

3.24-3.65 (3H, m), 4.45 (I
H, dd, Jt=15Hz, J2==2Hz),
4.68 (I H, d, J = 15 Hz).

5.02 (LH, broad), 5.93 (2H, s
), 5.95 (2H, s), 6.68-7.00 (6
H, m), 6.35 (IH, brd, s).

(lla): 'H-NMR (CDCl5); δ1
．． 8R (181broad).

3.20-3.45 (IH, m), 3.72 (2H,
d, J=6 Hz), 4.56 (2H2s) +
5.06 (I H-d, J=4Hz), 5.
90 (2H,s)t 5.92 (2H,s)
t6.37 (LH, broad), 6.55~6
．． 90 (6H, m)-IR(KBr); νmax
1030, 1240, 1480゜4500, 3400
cm.

UV (ether); λmax217,275+
285,306nmMS m/z (%) p3
54 (M”, 69), 186 (47) 517
4 (100), 149 (50), 135 (42).

116(13)'.

(iV) tranS-3-rioomethi/l/-2-
(3:4'-methylenedioxyphenyl)-4(El-
Synthesis of (3':4''-methylenedioxybenzylidene)oxolane (12a): 0.5 g (1,4
mmol) in 30 ml of anhydrous pyridine and
．． Add 5 ml (7.0 mmol) of thionyl chloride and react for 15 hours. Pour into ice water, extract with ether, wash the ether layer with dilute hydrochloric acid and 5% sodium bicarbonate water, and obtain an oily substance by conventional procedures. The oily substance was subjected to silica gel chromatography (eluent 20-hexane/ether = 3:
2) and purified with chloride-(117n+g, 0.3 mm
ol) with a yield of 22%.

'H-NMR, (CDC13); δ3.36-3.7
1 (3H, m).

4.59 (2H, d, J=2Hz), 5.18 (L
H,d.

J=2Hz), 5.90 (2H,s)t5.
92 (2H.

S)t 6.35 (LH, br, s), 6.
50-6.96 (6H, m).

M (to) - Synthesis of neobouuronin: This chloride (
12a) (117■, 0.3 mmol) in 10 m
Ice-cooled N-methylmorpholine N- made from N-methylmorpholine and aqueous hydrogen peroxide dissolved in 1 acetone.
60 μm (0.13 mmol) of oxide was added dropwise, and water-acetone-t-butanol (6:
3:1) Add 2 ml of a solution containing a small amount of osnium tetroxide to the mixed solvent. After reacting at room temperature for 2 hours, ethyl acetate was added to the reaction solution and filtered.

After washing the P solution with sodium sulfite water and then with 2N hydrochloric acid, rhodiol is obtained by a conventional procedure. The halodiol is dissolved in methanol and the excess carbonate is treated briefly at room temperature. Then, an oily substance is obtained by extraction with ether and a conventional procedure. The oily substance was subjected to silica gel chromatography (eluent: n-hexane/ether =
1:3) and purified with 75■ (0.2 mmo!, 67%)
The racemic neobouuronin is converted into an amorphous substance (
13).

'H-NM(CDCl2): δ 2.58(IH
, m), 2.90 (IH, broad L 3.40
(IH, d, J=10Hz).

3.58 (IH, d, J = 10Hz), 3.
8 (1-4, 15 (2H, m), 4.37 (LH
, d, J=8Hz).

4.61 (LH, s), 5.90 (2H, s), 5.9
2(21-1,s)e 6.56~7.04 (6H
, m).

Claims (2)

[Claims] (1) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (1) (In the formula, R is lower alkyl, and X_1 is a hydrogen atom, a halogen atom, a lower alkyl having 1 to 3 carbon atoms, and an alkoxy or methylenedioxy group. , where n is an integer value from 1 to 5 and indicates the number of the same or different substituents). , X_2 is a hydrogen atom, a halogen atom, and has 1 or more carbon atoms
It represents up to 3 alkyl and alkoxy or methylenedioxy groups, where m is an integer value from 1 to 5 and represents the number of the same or different substituents. ) By reacting with a substituted aromatic aldehyde represented by the formula and treating with acid, the formula ▲mathematical formula, chemical formula, table, etc. is created▼(3) (wherein, R, X_1, X_2, m, and n are the same as above) 3-alkoxycarbonyl-4-substituted phenyl-2-substituted benzylidene butyrolactone represented by ,R, X_1, and ▲Mathematical formulas, chemical formulas, tables, etc.▼(5b) (In the formula, X_1, The hydroxyl group in the alcohol moiety is replaced with a leaving group, and then the benzylidene moiety is oxidized to produce a diol with the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (6) (wherein, X_1, X_2, m, and n are as above) The same thing, and Z represents a leaving group such as a halogen atom, mesyl group, tosyl group, trifluoromethanesulfonyl group, etc.) is obtained, and the compound is then ring-closed in the presence of a base. , chemical formulas, tables, etc.▼(7) (In the formula, X_1, X_2, m, and n have the same meanings as above.) 3,7-dioxabicyclo[3,3,0]octane Method for producing derivatives. (2) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (5a) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (5b) (In the formula, X_1, X_2, m, and n have the same meanings as above. ) The -OH group of the alcohol represented by is substituted with a leaving group such as a halogen atom, methanesulfonyl group, tosyl group, trifluoromethanesulfonyl group, etc., and then the benzylidene moiety is oxidized to form a diol with the formula ▲ Mathematical formula, chemical formula, table etc.▼(6) (In the formula, X_1, X_2, m, and n are the same as above, and Z represents a leaving group such as a halogen atom, mesyl group, tosyl group, or trifluoromethanesulfonyl group.) By obtaining the diol compound shown and then ring-closing it in the presence of a base, the formula ▲Mathematical formula, chemical formula, table, etc.▼(7) (In the formula, X_1, X_2, m, and n have the same meanings as above. ) A method according to claim (1) for producing a 3,7-dioxabicyclo[3,3,0]octane derivative represented by: