JPS63287780A - Production of 3,7-dioxabicyclo(3.3.0)octane derivative - Google Patents

Abstract

PURPOSE:To produce, in high yield, the compound which is used as an agrochemical or medicine, by using a substituted benzylidene succinic acid ester and a substituted aromatic aldehyde as starting materials to effect twice reduction reactions, epoxidation and cyclization. CONSTITUTION:The reaction of a substituted benzylidenesuccinic acid ester of formula I (R is alkyl; X1 is H, halogen, alkyl, alkoxy; m is 1-5) with a substituted aromatic aldehyde of formula II (X2 is H, halogen, alkyl, alkoxy; m is 1-5) is followed by acid treatment to give a compound of formula III. Then, the lactone ring is reduced to give an ester of formula IV, then reduced to give compounds of formulas Va and Vb. They are separated, the alcohol is protected, if necessary, then epoxidation is effected to convert the compound of formula Va into those of formulas VIa (Z is H, tetrahydropyranyl) VIb and the compound of formula Vb into formulas VIIa and VIIb. These products are ring-closed with an acid or alkali to give the compounds of formulas VIII and IX.

Description

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

[Conventional technology]

3. A compound represented by the formula that is a 7-thioxabicyclo[3,3,0)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.S. 78, 1242, supra. (1956) cannot produce useful compounds in which Y at the 1-position is a hydroxyl group.

The present invention provides a novel method for producing derivatives (some of which are new compounds) in which Y is a hydroxyl group in the formula (N).

[Means for solving problems]

The present inventor has discovered that 1- represented by the following formula (8) or (9)
3,7-thioxabicyclo[3,3
, 0) We have discovered a method for stereoselectively producing octane derivatives based on the following reaction scheme.

1↓ The present invention will be explained below.

(Method for producing the compound represented by formula (3)) (1) 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. reaction with the substituted aromatic aldehyde of formula (2), preferably at -20°C to -80°C with a strong base such as lithium diisopropylamide (L D A ) or lithium diethylamide in an amount of 2 to 3 times the mole. By treating with a mineral acid such as sulfuric acid, phosphoric acid, or hydrochloric acid, 3-
Alkoxycarbonyl-4-substituted phenyl-2-substituted benzylidene butyrolactones can be obtained. Formula (3
) is a cis/trans mixture, but there is no particular need to separate it by chromatography or the like.

3-Flucoxycarbonyl-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 19= or -20 to After reacting with a reducing agent such as diisobutylaluminum hydride (DIBAH), lithium tri-t-butoxyaluminum hydride, or lithium triethoxyaluminum hydride in an amount of 3 to 4 times the mole at -80°C, treatment with a weak acid such as acetic acid (0 ~50
The lactol (lactone ring of formula (3) C-
〇 becomes 10H). Subsequently, the lactol is mixed with triethylsilane (Et3Si I-
1) By reacting an alkylsilane such as trimethylsilane (Me3SiH) or tributylsilane with a Lewis acid such as boron trifluoride ether complex salt (BF3-OR14), and treating with a weak alkali such as sodium bicarbonate. An oxolane ester represented by formula (4) can be obtained. This oxolane ester is 'I]-NMR, c
It can be seen that it is a mixture of is/1rans, but ci
The s/trans mixture can proceed to the next reaction.

(References; G. A. Kraus et al., J.
-Org, Chem-+ 46° method) (Iil) The oxolane ester of formula (4) obtained by the above method is added freshly, preferably from 1 to 2 times the molar amount of sodium aluminum hydride bismethoxyethoxyaluminum hydride (Red-AI) or lithium methoxyaluminum rhamnohydride is reacted with a reducing agent, preferably at -10 to 10°C, for reduction, followed by ethyl acetate. By adding water and treating (stirring), alcohols represented by formulas (5a) and (5b) can be obtained. This alcohol was converted into trans alcohol (5a) by silica gel chromatography.
and cis alcohol (5b).

(References; H, C, Brolnet, at.
J. Org.
In an inert solvent such as anhydrous ether, tetrahydrofuran, or dichloromethane, in the presence of a weak alkali such as sodium bicarbonate or potassium fluoride,
1 to 5 times the mole of m-chloroperbenzoic acid, perbenzoic acid, p
-By the action of an oxidizing agent such as nitroperbenzoic acid, the formula (6a
).

(6b) or a expressed by formula (7a) or (7b)
An epoxy body containing a mixture of nti body and syn body is obtained.

In producing the final target compound represented by formula (8) or formula (9), only the anti form (6a) or (7a) of this epoxy form is required.
It is also possible to produce an epoxy compound after attaching a bulky protecting group to increase the production ratio of ti/syn, and the yield of epoxidation is also high.

That is, in order to produce a large amount of the anti-isomer (6a) or (7a), a tetrahydropyranyl group (
THP) or t-butyldimethylsilicon method) (V) Formula (6a) and formula (6b) obtained by the method described above
An epoxy compound that is a mixture of or a mixture of formulas (7a) and (7b) is ring-closed with an acid or alkali, but an t
Although it is preferable to use only the i-isomer, it is not necessary to use the anti
It is not necessary to use separate bodies and Syn bodies.

Although the ring-closing reaction can occur under both basic and acidic conditions, the following three typical methods will be described here.

(1) Ring-closing method using cesium fluoride/DMF Anti-epoxy (6a) converted into TBDMS in an anhydrous dimethylformamide solution (0.2 molar solution) of cesium fluoride
Alternatively, add (7a) and react overnight, treat according to conventional methods, and purify by silica gel chromatography to obtain the desired 3,7-thioxabicyclo[3,3,0,: 1 octane derivative is obtained.

Anti-epoxy compound (6a) or (
7a) was added, reacted at room temperature, neutralized with sodium bicarbonate, treated according to a conventional method, and purified by silica gel chromatography to obtain the desired formula (8) or formula (9).
) to obtain a 3,7-thioxabicyclo[3,3,0]octane derivative.

The anti epoxy compound (6a) or (7a) was added to an anhydrous tetrahydrofuran solution containing 1 mol of tetra-n-butylammonium fluoride, reacted at room temperature, acidified by adding 0.5N hydrochloric acid, and then subjected to silica gel chromatography. The target 3,7-thioxabicyclo(:3,3.
O'll octane derivatives can be obtained.

The starting material of the present invention is the formula (formula (1), where R is lower alkyl, Xl is a hydrogen atom, a halogen atom, a lower alkyl having 1 to 3 carbon atoms, and an alkoxy or methylenedioxy group, and n is ~5
The substituted benzylidene succinic acid ester is 5 to
It can be produced through the following steps through the bbe condensation reaction.

(References; Organic Reaction 6
Volume 1, page 1 (1,951), etc.) [Effects of the Invention] The method of the present invention produces 3.7
-Shioxabicyclo(3,3,0)octane derivative can now be obtained in good yield.

〔Example〕

The present invention will be further explained below with reference to Examples. In the Examples, "common procedure" 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) The reaction steps of Example 1 are illustrated below.

(To) - Pourounin: (IR, 2S, 58.f3R)
-1-hydroxy-2,6-di(314'-methylenedioxyphenyl) -3,7-thioxabicyclo(3,
Synthesis of 3,0) octane: (il 3'-methoxycarbonyl-4-(314'
-methylenedioxyphenyl)-2-(31′4″-methylenedioxybenzylidene)protylactone (11)
Synthesis: Lithium diisopropylamide (LDA) under nitrogen flow
diisopropy/L/7mi/(4) with n-butyllithium (n-BuLi) (20ml, 15% hexane solution w/w) in anhydrous tetrahydrofuran (70ml)
, 2 ml) at -10°C. While cooling this solution to -78°C, 3.4-methylenedioxybenzylidene succinic acid methyl ester (10) (3,96 g,
A solution of 0.0015 mol) in 15 ml of anhydrous tetrahydrofuran is added dropwise. After stirring for 2.5 hours, piveronal (2,
A solution (15 ml) of anhydrous tetrahydrofuran (25 g, 0.0 j5 mol) was added dropwise at -78°C, and the
Stir for an hour, then treat with 70 ml of cold 6M sulfuric acid, immediately extract twice with ether, and dilute with 5% bicarbonate).
Wash with IJum water and use conventional procedures to obtain a pale yellow oil. Add a small amount of ether to this product to crystallize it, filter it, and wash with cold ether to obtain the desired product 3.2.
g (54%) as white crystals (m, p, 149-b NMR, more cis, trans mixture (22 near 8).

'H-NMR (CDCl3); δ (ppm) 3.
34 (0,22X 3H.

s L 3.76 (0,78X3H,s), 4.
17 (0,78XIH, dd, mountain=3Hz, J2=2
H2), 4.52 (0,22x I H, dd, J
, =8Hz, J2=2Hz).

5.64 (0,78xlI(,d,J=3Hz),
5.68 (0,22XII-1,d, J=8Hz)
, 5.96 (2H, s).

6.02 (2H,s), 6.70-7.15 (
6I-1,m)+7.60 (0,22X I H,d
, J=2Hz, 7.64(0,78XIH,d,J
= 2Hz).

(11) Methoxycarbonyl-(E)4-(3h4
'-methylenedioxybensyritene) -2-(374
Synthesis of ″-methylenedioquinphenyl)oxolane (12): Lactone body (11) (ci
s/1rans = 22: mixture of 78) 52
g (13 mmol) of anhydrous tetrahydrofuran solution 1
Add 40 ml of IM diisobutylaluminum hydride -hexane [(DIB, A, H) to 00 ml under a nitrogen stream, stir for 1 hour at the same temperature, and quickly add the reaction solution to 14 ml of acetic acid and 50 g of ice. . Add 50 ml of dichloromethane and stir vigorously for 10 minutes, then add another 100 ml of dichloromethane and stir vigorously for another hour. Separate the aqueous layer from the organic layer and add 5% bicarbonate. After washing with IJum water, crude lactol is obtained by a conventional procedure.

This crude lactol contains 4.5 g (38.8 mmol
) of triethylsilane (Et38i H) in anhydrous dichloromethane is added at -78°C under a nitrogen stream.

Further, when 4.0 ml (32.4 mmol) of boron trifluoride ether complex salt (BF30Et2) is added dropwise, the color becomes deep red.The mixture is further stirred at the same temperature for 2 hours, and then 20 ml of 5% bicarbonate (IJ) is added dropwise. Add some water. Gradually raise the temperature to room temperature, separate the organic layer and the aqueous layer, wash the organic layer with 5% sodium bicarbonate water, and obtain an oily substance by conventional procedures. This oily substance was subjected to silica gel chromatography (eluent; n-hexane/ether = 2:1 to 1:
2) to obtain 2.8 g (7.3 mmol) of oxolane (cis/1 rans=36:64 mixture) as an oil with a yield of 56%.

'H-NMR (CDCl3): trans body; δ
3.60 (3H,s).

3.74 (I H, dd, mountain = 6 H2, J2 =
2 Hz).

4.67 (2H, S), 5.10 (IJ (, d, J
=61-1z).

5.86 (4H,s), 6.41 (IH,d,
J=2Hz).

6.60-6.90 (6H, m), cis body;
3.40 (3H.

s), 3.96 (lH, dd, mountain-5H2, J2
= 2 Hz).

4.60 (IH, d, J=1.5I-1z), 4.
96 (ll-1, d.

J-15l-1z), 5.05 (LH, d, J
=5I-1z).

5.88 (4H,s L 6.36 (IH,d,
J=2Hz).

6.60-6.90 (6H, m).

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

(iii) 3-hydroxymethyl-ta 4- (
3n'-methylenedioxybensyritene)-2-(37
4“-methylenedioxyphenyl)oxolane (13a
), Synthesis of (13b): Oxolaneeste fiv produced by the above method (II)
(12) (cis/trans = 36:
An ether solution of 0.56 M aluminum hydride (AlH3) made from lithium aluminum hydride and aluminum chloride was added dropwise to 1.65 g (4.3' mmol) of anhydrous ether (125 ml) 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 material was purified by silica gel chromatography (eluent: n-hexane/ether-1:1), and 052 g = 2
2- (34%) cis alcohol as an oil followed by 0.94 g (62%) of trans 7 alcohol as an oil. These crystallize from ether. trans s form (mp1o9-11°C), cis
body (m, p, 88-89°G).

(13a): 'I-do NMR, (CDCl3)
; δl, 28 (11-1, broad).

3.24-3.65 (3I-(,m), 4.45
(IH, dd.

Mountain-=151-12. J2=2H2), 4.68 (
IH, d, J-15Hz), 5.02 (IH, b
road), 5.93 (2H.

s ), 5.95 (2H, s ) + 6.68-7
．． 00 (6H.

”L 6.35 (IH,brd,s).

(13a): 'I(NMR(CDCl3):δ
1.88 (IH, broad).

3.20-3.45 (IH, m), 3.72 (2
H, d, J=6Hz), 4.56 (2I(,s
), 5.06 (IH, d.

J=41-1z), 5.90 (2I-1,s)
, 5.92 (2H,s).

6.37 (IH, broad), 6.55-6.
90 (6H, m).

II% (KBr); νmax1030. I 240
．． 1480°1500.3400cm.

UV (ether); λmax 217+ 27
5+ 2851306nm.

MSm/z (%); 354 (M+, 69), 186 (4
7).

174-(100), 149(50), 135
(42).

116(13).

(iii) trans -3-tert-butyldimethy/l/silyloxymethyl-2-<3',4'-
methylenedioxyphenyl) = (E)'4. - (3
74“-methylenedioxybenzylidene)oxolane (
Synthesis of 14): tran produced by the above method (iH)
s Alcohol (13a) 100”g (0.28m
mol ) of anhydrous dimethylformamide solution, 48 m
g (0.7 mmol) of imidazole and 51 mg (
0.34 mol) of tert-butyldimethylsilyl chloride was added, and the mixture was allowed to react at room temperature for 20 hours. After that, add ether to the reaction solution, add 0.5N hydrochloric acid, and then add 5% bicarbonate)
Wash with Jum water and obtain an oily substance by conventional operations.

θy) 4.5-trans-4-tert-butyldimethyloxymethyl-2,5-bis(31·4'
Synthesis of -methylenedioxyphenyl)-1,5-dioxaspiro[1,4]hebutane (15a), (15b): 5 ml of TBDMS form of trans alcohol (14) produced by the above method (*ii) of anhydrous dichloromethane to give 150 mg (0.87 mmol) of m
-Rioo benzoic acid (MCPBA) and 450 + 11 g of sodium bicarbonate are added to 10 ml of anhydrous dichloromethane solution and allowed to react for 20 hours at room temperature. Ether is added to the reaction solution, washed with 10% sodium sulfite water, followed by 5% bicarbonate, and subjected to conventional procedures to obtain the precursor material. Oily substances can be analyzed by silica gel chromatography (
Purify with eluent: n-hexane/ether = 2:1),
5y of 1231T1g (0.26mmol, 91%)
n-epoxy body (15a) and anti=epoxy body (1
5a) is obtained.

A portion of the product is further purified by flash chromatography on silica gel to obtain 14% of the 5yn monomer (151), followed by 86% of the anti-5yn monomer (15a).

antI-epoxy form (15a): 'H-NMR (
CDCl5); δ-0,14(3I-1,s), -
0.10(31-1,s), 0.83(9I-1,s
), 2.21 (11-1, m), 3.11 (
20,d.

J=5I-1z), 3.84 (IH, d, J=
10Hz), 4.03-25=(LH,s), 4.19 (LH,d, J=10
I(z)+4.97(LH,d, J=5Hz
), 5.91 (2H,s).

5.93 (2H,s), 6.55-7. OO(
61 (, m).

S Yn -: L box body (lsb): 'H-NM
R(CDCl3); δ-0,01(31-1,s
)+0.03(3H,s), 0.86(9H
, sL 1.76 (LH, m), 3.60 (IH, d
.

J26Hz), 3.65 (LH,d, , J=8
Hz), 3.98(LH,s), 4.02
(2H, s), 5.04 (LH, d.

J=6Hz), 5.86 (2H, s), 5.
90(2)7S).

6.46-6.82 (6H, m).

In order to obtain a large amount of anti-epoxide (15a), trans alcohol (13a) is added as described in step IV.
Tetrahydropyranyl group (THP) or t-buf/l
This can be achieved by protecting with a z-di,methylsilyl group (TBDMS) or by examining the epoxidation conditions. The results are shown in Table I.

Table 1 Anti-epoxy form/5yn due to differences in protecting groups and epoxidation conditions of hydroxymethyl form (13a)
- Change in epoxy body production ratio = 26- 1 HA 50:50
422 HB 4]:59
263 THP A
70:30 514 T
HP B 56:44 6
75 TBDMS A
86:14 91M (d Synthesis of pourounin (Cs F/DMF method): anti-epoxy body (15a) produced by the above method (1v) 36■ (7,4X
10-5 mol) and 30 ml (0.2 mmol) of cesium fluoride were dissolved in 2 ml of anhydrous dimethylformamide and reacted at room temperature for 17 hours. Add water, extract with ether, and obtain an oily substance by conventional procedures. The oily substance was purified by silica gel chromatography (eluent: n-hexane/ether-1=3) to give 23 mg (6,3
x 10-5 mol) of racemic pouronin
Obtained as needle-shaped crystals with a yield of 4%.

It has a melting point of 83-85°C when re-solidified from 95% ethanol.

'H-NMR (CDCl2); δ1.64 (I H,
broad).

2.03 (IH, m), 3.80 (IH, dd,
J1=9Hz.

J2=6H2), 3.88 (LH,d, J=9
Hz).

4.04 (If-1, d, J=9Hz), 4.
50 (ll-1, dd.

JI=9H2, J2=8H2L 4=79 (LH,s
C4,82 (IH, d, J=4I-1z), 5
．． 92 (2H, s).

5.96 (2H,S), 6.60-6.96 (
6I-1, m).

13C-NMR (acetona-d6); δ6
25(+d), 71. ．． 7(t).

76.1(t), 86.5(d), 88.4(
d), 92.7(s), 101.7(11,1
01,9(11,] 07.5(dl, ,108.2
(dl, 108.6(d), 109.1(d)
, 120.4(d), 121.5(d),
132.0 (Sl, 136.7(s), 148
．． 0(S), 148.1(Sl, 148.7(
S).

IR (KBr); νmax 1035, 1250, 1
440°1495, 1635. 34.30cm
.

UV (EtOH); λmax (ε) 287 (7,400
), 237 (7,300) nm.

MSm/z (%); 370 (M, 100), 235
(23).

220 (31), 2 (15 (75), 163 (
49).

161 (50), 151 (58), 150 (5
4).

149 (60), 135 (58), 133 (27)
.

131 (3’9).

Anal, Ca1cd, for C20H180?
・1/2 (H2O): C, 63, 32; I(
,5,05,Found: C,63,07;To1,
5.13゜(V) (a) Synthesis of pourounin (tetra-n-butylammonium fluoride/TI-IF method): 29 Trans-3- obtained by the method shown in step V
tert-butyldimethylsilyloxymethyl-2,5
-His(3',4'-methylenedioxyphenyl)-
1,5-dioxaspiro[1,4]hebutane (syn:
anti=16:84) of 321■(0,66mmo
l) in iomt anhydrous tetrahydrofuran to dissolve I
Tetrahydrofuran solution of M tetra-n-butylammonium fluoride 1.32 ml (1,32 mmol)
and react at room temperature for 4 hours. Ether was added to the reaction solution, washed with 0.5N hydrochloric acid, and an oily substance was obtained by a conventional procedure.

The oily substance was purified by silica gel chromatography (eluent: n
-hexane/ether-1:1 to 1:2),
78 mg (0.48 mol) of racemic boronine are obtained with a yield of 73%.

M (a) Synthesis of pourounin (acid ring closure method) = 4, 5
-trans -3-tetrahydropyranyloxymethyl-2,5-bis(314'-methylenedioxyphenyl)-1,5-dioxaspiro[1,4]hebutane 30
111 g was dissolved in 2.5 ml of methanol containing a small amount of p-toluenesulfonic acid hydrate, and reacted at room temperature for 1 hour. Neutralize by adding an appropriate amount of bicarbonate, remove the solvent under reduced pressure, add anhydrous dichloromethane and remove inorganics with a filter. Add a small amount of p-toluenesulfonic acid and stir at room temperature for 12 hours. Add another appropriate amount of sodium bicarbonate and pass through the filter. Concentrate the r liquid under reduced pressure to obtain an oily substance. The oily substance was purified by silica gel chromatography (eluent: n-hexane/ether-1=1) and purified with 17Q (4,6×10 mol
) is obtained in a yield of 70%.

(Example 2) Impouronin is obtained in the same manner as in Example 1 using the cis alcohol (13b) described in Example 1. Melting point 133-4℃'H-NMR (CDCIa); δ1.60 (I
H, broad), 3.08 (I Hr rr+ )
+ 3.12 (I Hr dcl+ Jl-17H
z + J2-8Hz), 3.65 (LH, d,
J=9Hz), 3.92 (IH, dd, mountain==9
Hz, J2=8Hz), 4.15 (IH.

d, J=9Hz), 4-. 52(LH,s), 5.14
(IH.

d, J=5Hz), 5.93(2H,s), 5
．． 95 (2H.

s), 6.60-6.96 (6H, m).

Claims (2)

[Claims] (1) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (1) (In the formula, R is lower alkyl, and and n is an integer value from 1 to 5 indicating 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 lower alkyl and alkoxy or methylenedioxy groups up to 3, and 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, which is represented by (R, There are chemical formulas, tables, etc. ▼(5b) (In the formula, X_1, In some cases, the alcohol is protected with an appropriate protecting group and then epoxidized to form the formula (
From 5a) we get a mixture of the following formulas (6a) and (6b), and from formula (5b) we get a mixture of formulas (7a) and (7b), and there are ▲mathematical formulas, chemical formulas, tables, etc.▼( 6a) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (6b) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (7a) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (7b) (In the formula, X_1, X_2, m , n means the same as above, Z represents a hydrogen atom, a tetrahydropyranyl group or a t-butyldimethylsilyl group) Then, the formula is characterized by ring closure in the presence of an acid or alkali ▲ Formula, There are chemical formulas, tables, etc. ▼ (8) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (9) (In the formula, X_1, X_2, m, n mean the same as above) 3,7- A method for producing a dioxabicyclo[3,3,0]octane derivative. (2) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (5a) and Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (5b) (In the formula, X_1 is a hydrogen atom, a halogen atom, a carbon number of 1 to
lower alkyl and alkoxy or methylenedioxy groups up to 3, and m and n are integer values from 1 to 5 and indicate the number of the same or different substituents). By protecting with t-butyldimethylsilyl group, the anti-isomer (
6a) or (7a) is obtained in a larger amount, and then the 3,7-dioxabicyclo[3,3,0]octane derivative represented by formula (8) or formula (9) is sterically converted by ring-closing with acid or alkali. Claim No. 1 (1) selectively manufactured
) method.