JPS58105983A - Preparation of optical active dihydrochrysanthemolactone - Google Patents

Abstract

PURPOSE:To obtain easily the titled compound useful as an intermediate for optical active chrysanthemum-monocarboxylic acid without requiring an expensive reagent, by using optical active carbone obtainable easily from a natural substance as a starting substance, introducing a novel electrolytic oxidation into the process. CONSTITUTION:Methyl group is introduced into the 1-position of optical active carbone: 5-isopropenyl-2-methyl-2-cyclohexane-1-one, shown by the formulaIoccuring as a natural substance itself, the resultant compound is oxidized with chromic acid in the presence of a mineral acid to give a conjugated enone shown by the formula III, to which hydrogen chloride is added, the prepared compound is reacted with H2O2 in the presence of an aqueous solution of a caustic alkali to give an epoxyketone shown by the formula V. The compound shown by the formula V is subjected to electrolytic oxidation in the presence of a lower alcohol using lithium perchlorate as a supporting electrolyte to give a carboxylic ester shown by the formula VI, to which methyl group is introduced to give a delta-lactone shown by the formula VII, which is treated with a strong base to give the desired compound shown by the formula VIII.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing an optically active dihydrothalisan semolactone represented by the formula @: (wherein * represents an asymmetric carbon). For further evaluation, an optically active carboxyl group (5-
Impropenyl-2-methyl-2-cyclihexene-1
The present invention relates to a method for producing di*Yvs crinan semolactone represented by the formula (to) using the -one>tt starting material according to the route shown below.

(I) (1) (Shu @
(G) (2) (To) (In the formula, R represents a lower alkyl group, *Each symbol has the same meaning as above.) Biresilin contained in natural pyrethrum has insecticidal power and fast-acting properties. Although it has low toxicity to bleeding animals,
Because of these desirable A properties, it has been used as a household insecticide since ancient times.

In recent years, analogs that have the above properties but can be synthesized at low cost have been discovered, and are now used in the same way as natural pyrethrins.O Natural pyrethrin and its analogs are collectively called Virethroy F. It's been revealed. All of these compounds that have been put into practical use are esters consisting of a carboxylic acid and an alcohol, and one of the representative acid components is di-chrylic acid.

Since the m-th acid has two asymmetric groups in its molecule, there are a total of 4 isomers, and the m-th acid contained in natural pyrethrin is the (IR) -) Huns form. , 1iI
It is generally known that (IR)-trans-chrysanthemum acid esters have high biological activity among various synthetic biresurades having a tertiary acid as a tertiary component. Also (1R
)-cis-chrysanthemum acid also has activity, while (1S)
It is also known that monolithic chrysanthemum acid esters are almost inert.

By the way, the primary dilute acid produced industrially in a conventional manner is a mixture of (IR8)-cis, F-lance, and therefore various methods are available to obtain active (IR) monomers from these mixtures. It is being considered.

A typical method for obtaining (1R) from a (IR5)-cis,F-lance mixture is an optical resolution method using an optically active amine as a resolving agent, but this method requires complicated operations. There are various restrictions when drawing a solid line.

On the other hand, various attempts have been made to produce optically active dilute acids using methods other than optical resolution.
Synthesis methods using naturally occurring (+)-5·-carene and (+)-2-pinene as starting materials are known (P@5t
io, Sai, t 11.102 (1980))
oHowever, although such methods do not require complicated optical resolution operations, they require complicated steps to reach the desired product, require expensive reagents, and have problems in terms of synthesis yield. This method has various drawbacks, such as the fact that the method is difficult to implement industrially.

Under these circumstances, the present inventors conducted various studies on the production method of an optically active dilute acid, and found that the optically active carvone represented by the above formula (1) is used as a starting material, and during the reaction process. By incorporating a new electrolytic oxidation reaction into
The present inventors have discovered that dihydrochrysansemolactone represented by the above formula (2) can be produced very advantageously, and have completed the present invention by further conducting various studies.

That is, the present invention introduces a methyl group into the 1-position of the optically active carboxyl group represented by the formula (I) to form an optically active alcohol represented by the formula (1), and then converts the alcohol into an optically active alcohol in the presence of a mineral acid. By chromic acid oxidation to obtain an optically active conjugated enone represented by formula (g), and then by adding hydrogen chloride to the conjugated enone, an optically active hydrogen chloride adduct represented by formula (t) is obtained. , hydroxylated to the hydrogen chloride adduct) 9
After hydrogen peroxide is reacted in the presence of an aqueous solution of aluminum to form an optically active epoxy ketone represented by the formula (g), the compound is subjected to electrolytic oxidation in the presence of a lower alcohol to form the compound represented by the general formula (6). An optically active carboxylic acid ester represented by the following formula is prepared, and a methyl group is introduced into the 5-position of the ester to obtain an optically active δ-laccine represented by the formula (to). This is then treated with a strong base. Expression (2) by processing
The present invention provides a method for producing optically active dihydrocychlisan heptamolactone shown in the following.

The dihydro-v chrysansemolactone obtained according to the present invention can be converted into an optically active dilute acid by, for example, heat treatment at 230°0 with methanol in diethylene glycol according to a known method (S, Dev et al.
Thtrahs<Lran, 30.2927 (197
4), P@1iti0.801-t 11.102 (
1980') ), and the optically active carvone, which is the starting material for the method of the present invention, itself exists as a natural product.
Furthermore, since it can be easily derived from other natural grasses, the method of the present invention can be said to be an extremely advantageous method for producing optically active primary acids.

Next, the method of the present invention will be explained in detail.

First, when introducing a methyl group into the 1-position of the optically active carbon in the first step, the methyl group-introducing agent is methyl halide! Methylmagnesiumpalite and methyllithium prepared from base metal are used.

Further, the solvent used in this step is not particularly limited, but ether, tesilahydride, etc. are usually used, and the reaction temperature is below home temperature, more preferably 0°C in order to suppress side reactions. 〇- or less is desirable.

Next, in the second step, the optically active alcohol represented by formula (2) is oxidized with chromic acid in the presence of a mineral acid to lead to the C-antibiotic conjugated enone represented by formula (2). The amount of the salt is used in excess as in the usual oxidation reaction, and the reaction temperature is kept below room temperature, preferably around 0°'o, in order to avoid side reactions.

Further, at this time, sulfuric acid is usually used as the mineral acid.

In this way, the sixth step of adding hydrogen chloride to the optically active conjugated enone represented by the formula (2) obtained by simultaneously performing the oxidation reaction and allyl transfer is simply adding an excess amount of hydrogen chloride. ◇ Then, the fourth step of epoxidizing the hydrogen chloride adduct is carried out under normal epoxidation conditions, i.e. using caustic soda etc. It is carried out by reaction with hydrogen peroxide in an aqueous caustic solution. At this time, in order to suppress side reactions, the reaction mixture may be cooled to below room temperature, preferably 0 to 5°0, and methanol or the like may be added as a co-solvent in order to carry out the reaction smoothly.

Next, as the fifth step, the formula (7) obtained in this way
The optically active epoxy quine represented by is subjected to an electrolytic oxidation reaction, which is one of the characteristics of the method of the present invention, in the presence of a lower alcohol. The method of synthesizing a ketoester by electrolytic cleavage of a,β-epoxyketone in this step has not been known so far, and is a method discovered for the first time by the present inventors.

In the electrolytic oxidation reaction, lithium perchlorate, lithium boron tetra7tride, and lithium serial oxide can be used as the supporting electrolyte, but lithium perchlorate is less effective in terms of reaction conversion rate and yield. The use is particularly preferred. Further, the concentration of the supporting electrolyte used is in the range of 0.02 to 0.1M, particularly preferably 0.047M.

As the reaction solvent in this step, lower alcohols such as methanol and ethanol are preferably used because they interfere with the solubility of the electrolyte and the reactant and are themselves reactants. In addition, other co-solvents as necessary,
For example, acetate esters of lower alcohols (01-5) such as methyl acetate and ethyl acetate can also be used.

Moreover, the reaction temperature is below room temperature, preferably in the range of 0 to 10°0, in order to suppress side reactions.

The electrolytic reaction can be carried out at a current density in the range of about 5 to 500 mA/am, preferably in the range of about 10 to 50 mA/am.
Carbon, lead oxide, nickel, etc. can be used. When performing an electrolytic reaction, a diaphragm may be used or no diaphragm may be used. The amount of current required for this electrolytic reaction varies depending on the shape of the electrolytic cell, type of electrode, substrate concentration, reaction temperature, etc., but is approximately 4 to 50 p.
By applying electricity of ffiOj, 85 to 90
By introducing a methyl group into the 5-position of the carboxylic acid ester represented by the formula (4) thus obtained, the desired product can be obtained as a nearly pure product with the desired yield. In the sixth step, which leads to an optically active δ-lactone, methylmagxiumide or methyllithium, which is prepared by the reaction of methyl halogenide and magnesium metal, is used as the methyl group-introducing agent. It will be done.

At this time, in order to clarify the difference in reactivity between the charcoal carbonyl group and the ester carbonyl group of the carboxylic acid ester, the reaction temperature is set to 0.090°C or lower, preferably 12.0°C or less.
It is preferable to carry out the process at a temperature of about 0'O.

The optically active δ-lactone thus obtained is reacted with a strong base to form a three-membered ring to obtain the desired optically active dihydrothalisan semolacone.
In the step, the strong bases used include lithium diisopribylamide, lithium amide, sodium amide,
Mention may be made of t@rt-butoxide, t@rt-anolate, etc., but the use of lithium diisopropylacetate is preferred. In addition, the reaction temperature at this time is below room temperature in order to avoid side reactions. It's a method.

The method of the present invention will be explained in more detail below with reference to Examples and Reference Examples, but the present invention is not limited to these Examples.

In addition, in the following Examples and Reference Examples, parts and percentages are based on weight unless otherwise specified.

Example 1 (Production of optically active alcohol represented by formula ([)) [1-M] 5 equipped with a magnetic rotor, a temperature needle and a reflux condenser
(+)-Carvone (2,0,,1
6-! immoj) and ether (10aj). The reaction flask was cooled to -30°O in a dry ice bath.

To this was added a 1.1M ether solution of methyllithium 11 (16
aj, 14.5 mmoj) was added dropwise. The reaction mixture -
Stir for 1 hour while maintaining the temperature at 6,000℃, and then stir at 0 to 1
Stir for hours. The reaction mixture was poured into a 10% aqueous ammonium chloride solution to stop the reaction, and the organic layer was separated and washed with water until neutral. Then, after distilling off the solvent,
The obtained oil was heated to 113-115°O (20aaug)
(58) -5-isoprobenyy' -1
, 2-dimethyl-2-citalohexyn-1-ol to 2
．． 1 g was obtained (yield: 95%).

[α) fi'+66.22° (c = 2-S, 0HO
j, ) Engineering R (n・at): 3520 (lrOH)
, 3066 (νHO=o), 1640 (yo=o), 1
120.1098.1050.975.880.805
am1MMhlR(oDOls)+81.52(s
, 6, G11I3), 1.60-2.20 (, l.

5, OH2, OH), 1・75(s, 6, box 3o=a
), 2.45 (brs, 1.011), 4.75 (br
s, 2, H20=O) p% Elemental analysis value: 079.5jS; H10, 80%
(Teno calculated value as OuHlaO: 079.53 i
H10,91 attack) (11) In the above (1-, *), the (
By using ←)-carvone in place of +)-carvone, (5R)-5-isopropenyl-1,2-dimethyl-2-sitaphexyn-1-ol was obtained in a yield of 95 times. .

bp! 113~115°0 (20wxMg) (
1) fi'-66,2° (o-1-61, aHO13)
Elemental analysis value: 079.43; H10,92% (01
Calculated value as lH180: 3079.5! i H11
91≦)(1-o) (+)-carvone (2 furnaces, 1!1.5 mmoj) and: r--44 (10
aj) was added. The reaction flask was cooled to ooo in a water bath and previously dissolved in ether (10d) with methyl iodide (4,14F).
, 294mmoJ) and metallic magnesium (650mp,
A methylmagnesium iodide reagent prepared from 266 mmoj was added dropwise. The reaction mixture was heated in a water bath for 60 minutes.
After stirring at room temperature for 2 hours, the reaction was stopped by pouring into a 10% aqueous ammonium chloride solution. Subsequently, this was extracted with benzene-ethyl acetate (1st) fi 1m medium, and the organic layer was washed with brine, and then the solvent was distilled off. The remaining oil was filtered onto a silica gel column with hexane-ethyl acetate (5
'! When purified by elution with the mixed solvent of 1) (5 g) -5-isopribenyl-1,2-dimethyl-
2-Jitter to 7pm-1-all 2.08. obtained (yield: 94%). The analytical data of this substance is described in [1-
was identical to that shown by the pure sample prepared in [Mu].

(1-D) (+) used as a starting material in (1-0) above
By using (he)-carvone in place of -carvone, (SR)-5-impropenyl-1,2-dimethyl-2-schiftetrahexen-1-ol was obtained in a yield of 94 times. The analytical data for this material were identical to those shown by the pure sample in (1-!I) above.

Example 2 (Production of an optically active conjugated enone represented by the formula (Shu)) (2-A) 100mj equipped with a stirrer, temperature needle and dropping sound
(53)-5-isopribenyl-1,2-
Dimethyl-2-Schifdenhexen-1-ol (2,6p
-15,4mmo)) and ether (48aj),
The reaction flask was cooled to 0°0 in a water bath. To this, anhydrous aA @ (4-2p, 42.0 mmoj) was added to 5-sulfuric acid (4
2aj) was added dropwise over 1 hour while stirring vigorously. The reaction mixture was further stirred for 1 hour at 0-2°0 and left at room temperature overnight.

Separate the organic layer, wash the organic layer with water until it becomes neutral,
The solvent was distilled off. The remaining oily substance is 74°0 (10 min.)
(SR) -5-isobubenyl-2,6-
2.289 dimethyl-2-cyclohexen-1-one
(Yield: 89%). The sample for analysis is prepared sea bream gas supply fee (column! 8111oonox%5m
-50 (10%), 3m14φ, Medium Yarya pX:H2,
Flow rate: 42 m441n, column temperature: 146°0
).

(1) D"-104,6° (0=2.1, cmot3
)IR (mat): 5055 (lJHO=o),
1662 (νo=o), 1650 (yo=O), 165
5 (νo=o), 8890!111-1 (cox+13
): J 1.75 (br s, 6.0H3), 1.
94 (s, 3, OH3), 2410-2-2-85 (0
H5B, 4), 4.71 (br s, Q, HeO=0)
vpm elemental analysis value + 080.26; H9,67% (0
Calculated value as uH160: a 80.44+H9,8
2%) (2-m) (5-m) used as the starting material in [2-m] above
8) -5-isopropenyl-1,2-dimethyl-2-
Instead of cyclohexen-1-ol (SR) -5-
By using isoptetrabenyl-1,2-dimethyl-2-cyclohexen-1-ol, (5S)-5
-isopropenyl-2,5-dimethyl-2-cyclohexen-1-one was obtained in a yield of 88%.

bp: 74°C (10 octopuses) [α)D”+ 103.5° (6-2,1,0HOj3
) Elemental analysis value: o80.49t1.76
”Calculated value as 160: 080.44iH9-82
%) Example 6 (Production of optically active hydrogen chloride adduct represented by formula (g)) [6-M] In a 30-volume flask equipped with a magnetic rotor and a thermometer, (S
R) -5-impropenyl-2,5-dimethyl-2-
15 cen-1-one to cyclo(58~, 0.35 a+
moj ) and ether (6 m)) and the reaction flask was cooled to 0.000 m in a water bath. Dry hydrochloric acid gas was passed through this through a calcium chloride tube for 4 hours. The reaction was stopped by pouring the reaction mixture into bicarbonate of water for 5 minutes,
Extracted with benzene-ethyl acetate (1+1). After washing the organic layer with brine until it became neutral, the solvent was distilled off.

The remaining oil was purified on a silica gel column by elution with a mixed solvent of hexane-ethyl acetate (7:1) to give (SR)-5-(1-chloro-1-methylethyl)-2,S- Dimethyl-2-cyclohexene-1
-one was obtained from 62 (yield: 87 ha).

bp: 150-132°O (4maHg) (a)
D-10S, So (o=1.0, CHO13) Engineering R (neat): 1665 (0=O), 1658 (
0=O), 1110.1042aa+1 1HNMR (GDOjsu; δL58(s, 6, aa30
oj ), 1.76 (@, 3.0H3), 1.95 (1
, 3,0H3), 1.95-2.85 (Ill, 5, O
H, 2, OH') vpa elemental analysis value: a6B, 98
; H8, 65 regret (011H17 (calculated value as MO 1
045.85iH8-54%) (a-n) (SR
) -5-isopropenyl-2,5-dimethyl-2-cyclyhexyn-1-one was replaced with (58) -5-isopropenyl-2,6-cymethyl-2-cyclylhexyl-1-one. By doing so, (5s) −5−(1
-chloro-1-methylethyl)-2,5-1methyl-2
-Sita-4-hexyn-1-one was obtained in a yield of 87%.

bp: 119-121°O (2.5mmHg) [α
Swamp 1+ 1015° (0=1.!l, 0H043) Elemental analysis value: O65,65i H8,49% (0IIH1
70toshite f) tt calculated value: o65.85; H8,
54%) Example 4 (Production of epoxy ketone represented by formula (b)) [4 people] In a 50wn 1 volume 7 ladle equipped with a magnetic rotor (SR)
-5-(1-ri■ru-1-methylethyl>-21, s-
Dimethyl-2-Schiff-4-hexane-1-one <46WLg
, 0-25 mmoj), 6M caustic soda aqueous solution (0,0
21 ml) and methanol (5 mj,) were added. The reaction mixture was cooled to 5 qO in an ice water bath, and 60% hydrogen peroxide (0,067 mj) was added thereto. The reaction mixture was stirred for 2 hours in a water bath and for 1 hour at a rich temperature.
Extracted with benzene-ethyl acetate (1:1). The organic layer was washed with brine until neutral, and the solvent was distilled off. The remaining oil was purified by elution on a silica gel column with a mixed solvent of dF-ethyl acetate (7M) to give (51) -5-(1-methylethyl-1-methylethyl)-2,5 -Epoxy-2,6-dimethylcycouhexane-1-one was obtained from 44 to 44 (yield window 89).

1111i11109~110・o (HeStnyo')
Re 1ttJ &) Caf + 494° (6-1-7,0
1073)1m()IuJol)! 1700 (Ox
O), 1460.1380.1611.1245.11
00.1061.888, Ji091m1iim(am
13): J 1.42 (s, 6, four 3), 1.47
(s, 6, town), 1-52 (s, black, -), L59 (s
, 6, qXl-20~2.75 (m, 5, town, 0H)
7% 13o trace (0 koro) 073) wealth-111,5 (
q), ζ 19.4 (French !0.6(q), 10.7
(0,61,7(i),i,a,6(t),i9.8(
dJ.

614 (禦), 64. ! (-λ72.4(s), 20B
-4(s) PMllll Elemental analysis: 06L 8 i H7,97 (0uH
Calculated value as 170tO2: 060.97; H7,
91%) (4-ml) Used as the starting material in [4-m] above (5!
I) -5-(1-talru-1-methylethyl)-2,
(SR) -5-(1-cryl-1-methylethyl)- in place of 6-dimethyl-2-cyclohexen-1-one
By using 2,5-dimethyl-2-cytalohene-1-one, (SR)-5-(1-ta mv:10
9-110°a (recrystallized from hexane) (a) Gei' -
49.2° (o=1-8.0HQ13) Elemental analysis value: 061. +a8.07 Regret (01IH17010B
Calculated value as: 060-97+H7-91%) Example 5 (Production of optically active carboxylic acid ester represented by general formula (to)) [5-mu] ... Gas outlet connected to calcium chloride pipe, magnetic u-trochanter,
Temperature 1t$5 and 2 platinum plates (2X1, 5 (II
g) Cylindrical electrolytic reactor with electrodes (inner diameter 2.5 (2)
x height 10.0) was assembled. Add to this (8)-6-(
1-Cool-1-methylethyl)-2,5-ethyl-2,6-dimethylcitalehexan-1-one (750 m
P, 3.46 oj), methanol (14 aj), and ethyl acetate (2 wLt), and lithium perchlorate (somg) as a supporting electrolyte were added to the electrolysis reactor. Keep it! Electrolysis was carried out under a constant current density value of Om4/am2. At this time, the test was carried out under a terminal voltage of 6.0 to 8 OV (electrode potential: 2
．． 10~2-2! Vvg Ag10-I MAg(3
7) After applying a current of o 12 VmOl, the reaction mixture was concentrated, most of the methanol was distilled off, and extracted with benzene-ethyl acetate (1!1). After washing the organic layer with brine, The solvent was distilled off. The remaining oil was purified by elution on a silica gel column with a mixed solvent of hexane-ethyl acetate (6:1) to give (distilled)-6-(
665q (yield: 87%) of methyl sohexanoate in 1-ta11f-1-methylethyl)-6-o was obtained.

D171 ~ 7 black ~ (2,5-1 [,, B'F + 4.28° (51 = 1.1, aHO
4) IR (mat): 1769 (:LX chill 0=O
), 1720 (0=O) (m1NIIR(aooJs)
: 81.59(s, 6, ■(), 2.05-3.1
0 (m, 5, OH2,, OH), 2.21 (*, 3, a
H3oo), is, 67(s, S, OCnis)p
pm”oMMR(aDol,): a 30.0(Tsuru30.7(q)a31.2(q), !6-A(t),
42.0 (gradient, 45.6 (t), 51, 8 (+1)
, 76, black (-), 170-3 (s), 206.6 (m
) vya elemental analysis value s o 54.60 s H7,
75 whispers (calculated value as 0xoHxyOjOs + o54
．． 42 H7,77 Sorry) (51) (5R
) -5-(1-fumar-1-methylethyl)-2, toe""tX,), instead of chihexan-1-one (
68) -6-(1-Rita-1-methylethyl)-2
, Toe 吃4≠Tese? By using hexan-1-one, also known as V, methyl (de)-3-(1-ta-1-methylethyl)-5-oxohexanoate was obtained in a yield of 88%.

bp171~76°o (2,5m111!g) [spasticity] also '-4,24° (o-1,7, writhing t3) elemental analysis value +
054.60iH7,75% (calculated value as 010H17010s: 054.42iH7,77%) Example 6 (Production of optically active δ-thichton represented by formula (to)) (6-A) Equipped with a magnetic rotor into a 20smj flask (&R)-
Methyl 6-(1-xyl-1-methylethyl)-5-oxohexane (100y, 0.45mmoj) and ether (5-) were added. The reaction mixture was cooled to −2060 °C in a dry ice bath and mixed with methyl iodide (160 mg, 1.0 mm) and methyl iodide (22 ~, 0.9 mm) previously prepared in ether (Saj). Iodide reagent was added dropwise. The reaction mixture was stirred at -2090 for 2 hours and then at -10°0 for 1 hour, and then poured into a 10% aqueous ammonium chloride solution to stop the reaction. This was then extracted with a benzene-ethyl acetate (111) mixed solvent, the organic layer was washed with brine, and the solvent was distilled off.

The remaining oil was purified on a silica gel column by elution with a mixed solvent of hexane-ethyl acetate (5:1) to yield (3R) -'6- (1-talo-1-methylethyl)-5-methylhexane. -5-olide is 76■
(Yield: 82%) was obtained.

11m1! 86-87'O (recrystallized from hexane)
[α]p-zs°((1=1.5, As)IR(li
uJol) 1718 (Ester O=O) OmLHja
(onot3): a 1.25~2.65(,,5
, OH2, OH), 1.59 (LS, 0H3), 1.
48 (1, ink, snout), 1.57 (1, 6, 43)% 1
-69 (1, black, aa 3% νp inhibition 1 ~ age (■013): J 27.4 ((L), 29
．． 9(ω,!0.4(ω,50.8(French 31.6(t)
, ! s6.2(t), 41.1(d), 71.5
(1), 81 1(a), 170-7(s) vr;a
Elemental analysis value + 058-80iH8,59% (010H
Calculated value as 17070g: a58.68; a84
7%) (6-11) (house) used as the starting material in [6-m] above
-Bokuichi (1-taloru-1-methylethyl)-5-1 instead of methyl methyl <ss> -! l −(1
-Ta! % (3s) -6-(
1-t4-1-methylethyl)-5-methylhexane-5-olide was obtained in a yield of 83 arcs.

! Il]> : 86-8700 (Heetnyo') Reconnection Ji+ ) (a) j' -15,2° (o=1.5.
0HOj3) Elemental analysis value: 058.81M8.50%
Calculated value 1058.68 as (0IOHI)0109
;) 18.37%) (6-o') 201 equipped with a magnetic rotor into a flask (cheat) -6-
(1-methylethyl)-5-oxohexanoate (300~, 145mmj) and ether (1-methylethyl)-5-oxohexanoate (300~, 145mmj)
0mj) was inserted. The reaction flask was cooled to -78 ml in a dry ice bath. Add to this 1.1M for methyl ethyl
Ether solution (2-Saj, 2-7mimoj) was added dropwise. The reaction mixture was stirred for 2 hours while maintaining the temperature at -60°. The reaction mixture was poured into a 10% aqueous ammonium chloride solution to stop the reaction. The organic layer was separated, washed with water until neutral, and then the solvent was left in place. The obtained crude product was loaded onto a silica gel column with ethyl butyrate AI (11
) When purified by elution with a mixed solvent of
201311111 of -6-(1-chloro-1-methylethyl)-5-methylhexane-5-olide (yield near 6) was obtained. The analytical data for this material were identical to those shown by the pure sample prepared in [6-m] above.

(6-I)) (醇) used as a starting material in (6-0) above
Methyl -5-(1-tal-1-methylethyl)-5-oxohexanoate may be used instead of methyl -5-(1-tal-1-methylethyl)-5-oxohexanoate (5s). (sg)-6-(1-talo-1-methylethyl)-5-methylhenol-5-olide was obtained in a yield of 75 times. The analytical data of this substance is described in (6)
-11) was identical to that shown by the pure sample prepared in Example 1.

Implementation 4M17 (Manufacture of optically active dihydric talisane heptamoraxine) [7-mu] In 2011j volume 7 class equipped with a magnetic rotator (!+R)
-6-(1-Riga-1-methylethyl)-5-methylhexane-5-olide (66-4ap, 0.18mm
oj ) and tetrahydro7ran (5 mJ) were added. The reaction flask was cooled to -78°0 in a dry ice bath and preliminarily charged with butyl lithium (1,6M solution in hequinane, 0.281
t4゜0.45m+noj) and diisopumaviramine (46,5q, 0-460-46a) were added.The reaction mixture was removed from the dry ice bath, heated to 11mf, and brought to room temperature. The reaction mixture was poured into ice water to stop the reaction, extracted with a mixed solvent of benzene-ethyl acetate (1:1), and the organic layer was washed with brine and the solvent was distilled off. Te(1B,D
)-dihydro ν chrysansemolatacin (29 m weight (yield:
97%) obtained. The analytical data for this substance are identical to those shown by separately prepared pure samples! there were.

lfP: 82~8! 'O (Recrystallized from Hegyu San) (
'l) D 77-80 (tsxx 1.8, rma1
3) (7-B) (house) used as a starting material in [7-m] above
-3-(1-Cryl-1-methylethyl)-6-methylhexane-5-olide instead of -(1-cool-1-methylethyl)-5-methylhexane-5-
By using dihydride, (11%)-dihydride was obtained in a yield of 96%. Analytical data for this material were identical to those shown by separately prepared pure samples.

mp+82~8B~ (recrystallized from hexane) [pe,"
+ 77.6' (o=1.8, 13 times) Reference Example 1 (Production of optically active trans-methyl kojate) (1-a) In a 10 m heavy customer test tube, (1S1)-dihydrotalinane 7 Lactone (100 mm, 0-4 mmoJ), caustic soda (109~, 2.7 mmo)) and diethylene glycol (21117) were added, immersed in a 230-235° oil bath, and heated for 7 hours. The reaction mixture was poured into ice water to stop the reaction, and a 5-hydrochloric acid water bath was added to make it acidic. This was then extracted with benzene-ethyl acetate (111), the organic layer was washed with brine and the solvent was distilled off. The remaining oil was dissolved in ether (1 mJ), and a separately prepared ether solution of diazomethane was added thereto at 0°0 for esterification. Next, the solvent was distilled off, and the residue was purified by eluting with hexane-ethyl acetate (71) on a silica gel column, and (1R)-trans-chrysanthemum acid was collected.

)p:101~10S oO(19swHg)(1
):”+20.69°(a=-L1, ait073
) High-speed wave attack! Togutufui (HFLO) is Wat
ers AXA/GPa2441[FLOsystem
Kara! ! /A-porwil, elution solvent: hexane-ethyl acetate (80:1), 1.511 value n1
The test was carried out at room temperature. The content of (IR)-trans-methyl kojate (retention time + 17.2 min) is 79.2%.
There was.

(1-b) (13) used as a starting material in (1-4) above
．． (MR)-dihydrochrysansemolacin (1
By using R%)-dihydro lisansemolatatone, (18)-) lance-methyl kojate was obtained with a yield of 7.
I got it in 2 hits. Samples for analysis were collected using the same preparative high-performance liquid chromatograph as described above.

bp101~106°o (t9mmHg) (g):”
-20,82'(0=1.0,(IH(M3)il
Example 2 (Production of optically active methyl-3-(2- and droxy-2-methylprevyl)-2,2-nidimethyl-1-Schiftapancarboxylate) (2-4) Equipped with a magnetic rotor into a 20 mj flask (IL 31
1) -Talisun-ni Mockton (145mp, 0.96
mmoj) and methanol (2 mj) were added. Add caustic potash (110q, 1-96 mmoj) to this and water (04ta
j) was added, and the reaction mixture was heated at room temperature for 24 hours.
Stir for hours. The reaction mixture was kept acidic by pouring into 5% aqueous hydrochloric acid and extracted with benzene-ethyl acetate (121).

The extract was washed with brine, and the solvent was distilled off.

Adding an ether solution of diazomethane to the remaining oil to methyl esterify it and distilling off the solvent (IR%'6B)
-ru(2-hydroxy-2-methylpropyl)-2,
2-di1methyl-δ (clopanecarboxylic methyl is 16
7■ (yield: 97%) was obtained.

bp + 84~86°O (35 porcelain) (ff Ura 3-2
1.5° (o-=1.8, CMq13) x R (M&t
) j 5380(OH), 1720(ENGX?# O=
O) amlHMMR(ODOj3)! δ1.15
~2.02 (m, Olm, OH), 1.19 (s,
6, -), 1.21 (s, 6, -), 5.60 (1,3
,0GII3) ppm (2-b) (IR
%3S)-dihydrotetrathalisane heptamolactone (1
By using 8, MR)-dihydrochrysande heptamorataton, (IL deception)
-Methyl sitaripropanecarboxylate was obtained in a yield of 973G.

13p + as~86'O (3BwIHg) (a);
+21.0° (o=2.1, cmat5) Reference Example S (Production of optically active - cis-thin methyl acid) (3-&) In a 20mj volume 7 Tesco equipped with a magnetic rotor and a temperature needle (1B% 3B) -3-(2-Hydroxy-2-methylviel)-2,2-dimethyl-1-cyclophenyl 111 methyl pancarboxylate (42 towns, 0.21 m!lIO and hequinamethyl triad phosphate (HMPA) , l rnl
) was added. To this, oxycyclized phosphorus (49y, 0.3
2 Dragon oj) was added. The reaction mixture was kept at 50 aO on an oil bath and stirred for 1 hour. Furthermore, pyridine (5
0~, Q, 63 mmoj) and stirred at 50'O for 1 hour, followed by 60 minutes at 75°A and 45 minutes at 100°A.
Stir for a minute. The reaction was quenched by pouring the mixture into a 5% aqueous solution of 9 um bicarbonate, and the mixture was poured into benzene-ethyl acetate (1
: Extracted with 1). The organic layer was washed with brine, the solvent was evaporated, and the remaining oil was purified by eluting with hequinane-ethyl acetate (71) on silica gel caffe (11% Ss) -24-dimethyl-8-( 1-
A 2:1 mixture of methyl bier)-1-Schiff gastric propanecarboxylate and methyl (IR)-cis dilute acid! 6
4■ (yield: 95%) was obtained. This mixture was dissolved in methanol (imj) and rhodium trichloride 2BgO (
2q) was heated at 100'O for 12 hours to obtain 25.4 wkp (yield: 65≦) of (1R)-cis-dilute methyl acid.

bp: 102 ~ 10$ '0 (19) (a)F
+59-51' (o = 1-2, aHat3)
In addition, as a result of analyzing the product by the above-mentioned high-performance liquid spectroscopy, the content of the corresponding F-lance isomer was 1% or less.

(5-1)) Used as the starting material in [G1] above (11%
76B> -76-(2-Hydroxy-2-methylpropyl)-2,2-dimethyl-1-Sifterpancarboxylate (ISS9) -5-(2- and DoW
2-methylpvvir) -2,2-dimethyl-1
By using methyl -cyclopancarboxylate, (1B)-cis-dilute methyl acid was obtained in a yield of 65%.

, bp + 102-104°O (19mg) (ri:
1-59.1° (o=1・8) Patent applicant Shigeru Torii Procedural amendment (voluntary) Commissioner of the Japan Patent Office Shima 1) Haruki Tono 1 Indication of case 1982 Patent Application No. 202955 2 Title of invention Relationship with the case of the person making the amendment to the method for producing optically active dihydrochrysansemolactone 3 Subject of the amendment to the patent applicant 5 (1) Contents of the amendment in column 6 of “Detailed Description of the Invention” of the specification (1) Description r on page 66, line 9 266 m mol
Correct J to r 26.7 mmolJ.

(2) “Chrysansemolactone” on page 50, line 14
is corrected to "dihydrochrysansemolactone".

(3) Correct "methanol" in line 6 of page 55 to "isopropyl alcohol."

(4) On page 56, line 4, “2H20J is r5H20J.
and correct it.

that's all

Claims (1)

[Claims] 1 Optically active formula (b); -(1-
1-methylethyl)-5-methylhexane-5
- A method for producing an optically active dihydrolysane semolactone represented by the formula 61Nc (where * is the same as above), which comprises treating the olide with a strong base. 2. The method according to claim 1, in which Shiizubu biramide is used as the strong base. 6 Optically active general formula (■: j (wherein R represents a lower alkyl group and * represents an asymmetric carbon) 6-(1-methylethyl-15-oxohexanecarbon) By introducing a methyl group into the 5-position of the acid ester, 6-(1-cryl-1-methylethyl)-5, which is represented by the optically active formula Qa: C! -Methylhexane-5-OWD, which is then treated with a strong base. manufacturing method. 4. Claim 6, in which the methyl group is introduced using methylmagnesium parite or methyllithium.
The method described in section. 5. The method according to claim 6 or 4, in which a strong base is an abrasive compound. 6 Optically active formula (V): 5-(1-
(cryl-1-methylethyl)-2,5-epoxy-2,
5-dimethylcyclohexan-1-one is subjected to electrolytic oxidation in the presence of a lower alcohol represented by the general formula: (wherein R represents a lower alkyl group) to obtain optically active general formula (6); (where the wings and books are the same as above) 6-(1
-Chloro-1-methylethyl)-5-oxohexanecarboxylic acid ester, and then introducing a methyl group into the 5-position of the ester, an optically active formula@Nia (where * is the same as above) An optically active formula characterized by leading to A-(1-Rita-1-methylethyl)-5-methylhexane-5-olide represented by and then treating this with a strong base @: (in the formula , * is the same as above). 7. The method according to claim 6, in which lithium perchlorate is used as a supporting electrolyte during electrolytic oxidation. 8. Claim 6, in which the methyl group is introduced using methylmagnesium parite or methyllithium.
or the method described in paragraph 7. 9. The method according to claim 6, 7 or 8, in which diisopropylamide is used as the strong base. 10 Optically active formula (T): 5-(1-
p-1-methylethyl)-2Sa-dimethyl-2-
Cyclihexen-1-one is reacted with hydrogen peroxide in the presence of an aqueous caustic solution to obtain an optically active 5-(1-ri) represented by the formula: A (where * is the same as above). p-1-methylethyl)-2,S-epoxy-2,6-dimethylcyclohexane-1-one, and then the compound has the general formula: R-OH (wherein R represents a lower alkyl group) ) is subjected to electrolytic oxidation in the presence of a lower alcohol represented by the formula (2) to produce an optically active 3-(1
-chloro-1-methylethyl)-5-oxohexanecarboxylic acid ester, and then introducing a methyl group into the 5-position of the ester, the optically active formula (4); Optically active formula @: 11. The method according to claim 10, using caustic soda as the caustic alkali. 12. Lithium perchlorate as a supporting electrolyte during electrolytic oxidation. Claim 10 or 11X using
Method described in JI. 13. The method described in claim 10, 11 or 12, wherein the introduction of the methyl group is carried out using methylmagnesium octaphyte or methyllithium. 14 Shiitsubu as a strong base! Claims 10, 11, 12 or 1 for use with viramide
The method described in Section 6. 15 Optically active formula @: 5-impropenyl-2,6-dimethyl-2-cyclohexene-1 represented by (in the formula, * represents an asymmetric carbon)
-By adding hydrogen chloride to one, the optically active formula (g); Qt. After leading to 6-(1-chloro-1-methylethyl)-2,5-dimethyl-2-taxyhexen-1-one represented by (in the formula, * is the same as above), the hydrogen chloride adduct by reacting hydrogen peroxide in the presence of a caustic alkaline water bath solution,
Optically active 2M: 6-(1-cthulu-1-methylethyl)-2,5-epoxy-2, dimethylcyclohexane-1-one represented by Qt (wherein * is the same as above), and then The compound is subjected to electrolysis in the presence of a lower alcohol represented by the general formula: (wherein R represents a lower alkyl group) to obtain an optically active general formula (to): and * are the same as above) - (1
-1-methylethyl)-5-oxohexanecarboxylic acid ester, and then by introducing a methyl group into the 5 groups of the ester, an optically active formula @: l (where * is the same as above) is obtained. ) The optically active formula [1: (in the formula , * is the same as above). 16. The method according to claim 15, in which 1. caustic soda is used as the caustic alkali. 17. 18. The method according to claim 15 or 16, in which lithium chlorate is used. 18. The method according to claim 15, 16, or 16, in which the methyl group is introduced using methylmagnesium parite or methyllithium. 17. The method according to claim 17. 19. Claims 15, 16, 17 or 1 using diisopropyl acid as the strong base.
The method described in Section 8. 20 Optically active formula (■): (In the formula, * represents an asymmetric carbon) 5-isobenyl-1,2-dimethyl-2-citaryhexene-1
-ol in the presence of a mineral acid to give an optically active formula (IO: 5-isobenyl-2,6-cymethyl-2-cyclyhexane-1- 5-(1-taflu-1-methyl)-2tS represented by the optically active formula (T): l (where * is the same as above) by adding hydrogen chloride to the conjugated enone. -dimethyl-2-Schiff-enhexen-1-one, the hydrogen chloride adduct is reacted with hydrogen peroxide in the presence of an aqueous caustic solution to give optically active formula (V): l (in the formula, * is the same as above) 5-(1-methylethyl)-2,3-epoxy-2,5-
Dimethylcyclohexane-1-ontoxy, and then the compound is subjected to electrolytic oxidation in the presence of a lower alcohol represented by the general formula; Formula c%l): 3-(1
-1-methylethyl)-5-oxohexanecarboxylic acid ester, and then introducing a methyl group to 54 of the ester, the optically active formula (2); (where * is the same as above) 111I
A method for producing dihydro ν crinan semolactone represented by the optically active formula @: (wherein * is the same as above) ◇ 21 Claim 20 using sulfuric acid as the mineral acid
The method described in section. 22. The method according to claim 1120 or 21, in which caustic soda is used as the caustic alkali. 26. The FD method described in claim 20, 21, or 22, in which lithium perchlorate is used as a supporting electrolyte during electrolytic oxidation. 24. The method according to claim 20, 21, 22 or 26, wherein the methyl group is introduced using methylmagnesium halide or methyllithium. 25. The method according to claim 20, 21, 4, 26, or 24, in which aviramide is used as the strong base. 26 Optically active formula (1): (In the formula, * represents an asymmetric carbon)
Formula (1) becomes optically active by introducing a methyl group into the 1-position of 5-isobenyl-2-methyl-2-cyclohexen-1-one)! (In the formula, * is the same as above) 5-isof vs. benylated 1,2-dimethyl-2-Schiff is introduced into the middle cen-1-ol in the stomach, and then the alcohol is dissolved in the presence of a mineral acid. Mua! Oxidized and optically active formula (6)
: (wherein the formula is the same as above) 5-isoprepe ink is converted into 2,5-dimethyl-2-cyclohexen-1-one, and then the conjugated enone dihydrogen chloride is added to obtain an optically active formula. @: 5-(1-tri-4-1-methylethyl)-2,3-dimethyl-2-cyccyhexen-1-one represented by l (in the formula is the same as above) is obtained, and then the hydrogen chloride addition to things,
By reacting hydrogen peroxide in the presence of an aqueous caustic alkali solution, optically active 5-
(1-Rita-1-methylethyl)-2,5-2-2,6-dimethylsikta-hexan-1-one, the compound was converted to the general formula: %Formula% (wherein R is lower It is subjected to electrolytic oxidation in the presence of a lower alcohol represented by (representing an alkyl group) to produce an optically active compound of -(1
-Taruru (1-methylethyl)-5-oxohequinanecarboxylic acid ester, and then by introducing a methyl group into the 5-position of the ester, an optically active The optically active formula 61 is characterized by treating it with a strong base after leading to &-(1-qualu-1-methylethyl)-5-methylhexane-5-olide represented by (same): A method for producing dihydricrysansemofuctone (in which * is the same as above). 27 Carvone represented by formula (I) and formula (6
) is the introduction of a methyl group into the ester shown by methyl! 27. The method according to claim 26, which is carried out using gnesium pallide or methyllithium. 28 Claim 26 using sulfuric acid as the mineral acid
or the method according to paragraph 27. 29. The method according to claim 26, 27 or 281j, in which caustic soda is used as the caustic alkali. 30 Claim 26, in which lithium perchlorate is used as a supporting electrolyte during electrolytic oxidation! I. Section 27,
1128 or 29. 31 Claims 26, 273J, 28, 2 using diisoprivyl amidora as a strong base
The method according to item 9 or 30.