JPH0459740A - Chain terpenes - Google Patents

Abstract

NEW MATERIAL:Chain terpenes expressed by formula I (R<1> represents formula II, formula III, formula IV or formula V and R<2> is cyano, formyl or -CO2R<3>; R<3> is 1-4C alkyl; X is halogen). EXAMPLE:A compound expressed by formula VI. USE:Useful as an intermediate for production of sarcophytol A having anticancer promoter action and antiulcer action. PREPARATION:For example, as shown in the reaction formula, a compound expressed by formula VII and e.g. obtained by reacting geranial with 0.1-10 equivalent Wittig-Horrer reagent and base is reacted with an organic peracid in a solvent and the resultant product is reacted with an aluminum alkoxide to afford a compound expressed by formula VIII, which is successively subjected to Claisen rearrangement to provide the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to novel chain terpenes. Specifically, the compounds of the present invention exhibit anti-carcinogenic promoter activity (C
ancer 5urveys, 2.540 (1983
) 1 Metabolism, vo125 Special Issue Cancer “88, 3 (198
The present invention relates to chain terpenes which are important intermediates for the production of sarcotuitol A, which has 8)) and anti-tumor activity (Japanese Patent Publication No. 63-20213).

(Prior art) Sarcotuitol A represented by the following structural formula is
It is a Sembrene-type diterpene alcohol having a total of four double bonds, including one conjugated double bond in the four-membered ring.

Sarcotuitol A Conventionally, the method for synthesizing sarcotuitol A was not known, and the present inventors previously synthesized sarcotuitol A using the sesquiterpenoid shown below as a starting material, the L1 formyl formyl compound, and compound (F) as a key intermediate. proposed a synthetic route (Japanese Patent Application No. 1-181710). This synthetic route is shown below.

(Hereinafter, blank space) (A) (B) (C) (D) Trimethyl (F) (J) Sarcotuitol A (In the above formula, R4 is a lower alkyl group of C1 to C4, R5
represents a trimethylsilyl group, a 1-ethochinoethyl group, or a hydrogen atom, and Y represents a chlorene atom (such as a chlorine atom or a bromine atom). ) When trying to industrially produce sarcotuitol A using the production route for sarcotuitol A described above, both the yield and selectivity are not high, and a highly toxic selenium compound must be used. There was a major problem in that it was impossible to avoid the oxidation process of the group.

(Problems to be Solved by the Invention) As a result of intensive studies aimed at manufacturing and supplying sarcotuitol A in large quantities and at low cost by an industrially more advantageous method, the present inventors found that the chain terpenes of the present invention The inventors have discovered that this is a useful intermediate in the production route that can solve the above problems, and have arrived at the present invention. That is, the gist of the present invention is that in the following general formula (1), R2 is a Noah 7 group, a formyl group, or 10○ R3 (R3
represents a C0-C4 alkyl group), and X represents a halogen atom.

Hereinafter, the present invention will be explained in detail.

In the above definition, R3 is a methyl group, an ethyl group, an n-
Propyl group, isopropyl group, loobyl group, or t
-butyl group is preferred.

Specific examples of preferred compounds represented by general formula (I) are shown below.

CN CHO CO, Et Co, Et CN CHO o2Me Co, Et 0ziPr CN CHO Co, Me CO, Et CO, iPr Q CN (L) (M) 16 CN 17 CHO 18CO, Me 19 Co, Et 20 C0yiPr (above) expression In, Me is a methyl group, Et is an ethyl group, i
Pr represents an isopropyl group. ) Next, the method for producing the compound of the present invention will be explained.

- The compound represented by sterilization (1) can be produced, for example, from a monoterpenoid, geranial (compound (K)), according to the following synthetic route.

(wherein R1 and X are as defined above) That is, cheranial (compound (K)) is
Wittig- with 2-(dimethylphosphono)-isono\L102), 2-(diethylphosphono)-isovaleronitrile, ethyl 2-(diethylphosphono)-isovalerate, etc. Horner reagent in an ether solvent such as tetrahydrofuran or diethyl ether, a hydrocarbon solvent such as toluene or n-beef sanitation, or an aprotic polar solvent such as dimethylformamide or dimethylformochint at -1000C to 1000C. , metal hydrides such as potassium hydride, organometallics such as n-butyllithium, lithium diisopropylamide, sodium methoxide, t~
Anion generated by the action of a metal alkoxide such as butoxypotassium at a temperature of -100 to 100°C Fn3 Halogen solvents such as tyrene and chloroform, ether solvents such as ethyl ether and tetrahydrofuran, or methanol and ethanol. In alcoholic solvent,
Depending on the method of acting at -50 to 100°C for 5 minutes to 24 hours, R2 of compound (L) or cyano group or -〇○
A compound represented by R3 was obtained, and these were further hydrogenated to n-hydrogenation at 100 to 150°C in a hydrocarbon solvent such as beef sanitation, heptano, Hensen, toluene, etc. in an amount of 01 to 10 equivalents/metal such as isobutylaluminum. Acting on hydrides,
Thereafter, R of compound (L) is hydrolyzed.
A compound in which ' is represented by a formyl group can be produced.

Regardless of whether R' is a cyano group, formyl group, -〇〇, or R3, compound (L) can be converted to a halogen solvent such as methylene chloride or chloroform, an ester solvent such as ethyl acetate or methyl acetate, or diethyl ether, tetrahydrofuran, etc. 01 to 10 equivalents of an organic peracid such as peracetic acid or metachloroperbenzoic acid in an ether solvent of -50 to 100
A method in which N-halocarphonamides such as N-bromosuccinimide, N-chlorosuccinimide, N-bromoacetamide, etc. in an amount of 01 to 10 are reacted with aqueous tetrahydrofuran, /oxane, etc. as a solvent at -20-10°C.
After reacting at 0°C for 5 minutes to 5 hours, the epoxy compound is prepared by reacting with a base such as sodium carbonate or potassium carbonate, or by reacting with hydrogen peroxide in an organic nitrile solvent such as acetonitrile or hendinitrile. By doing so, compound (M) can be produced.

Compound (N) is prepared, for example, from the epoxy compound produced by the above method, compound (M), in a hydrocarbon solvent such as toluene, xylene, ligroin, etc. at 0 to 150'C and 0.1 to 1.
0 equivalent of aluminum triisopropoxide, or in a solvent such as diethyl ether or tetrahydrofuran, -10
It can be produced by a method in which 0.1 to 10 equivalents of metal amides such as lithium diethylamide and lithium diisopropylamide are reacted at 0 to 100'C.

Compound (N) is prepared by adding 001 to 50 equivalents of 3.3-/methoquino-2-methyl-2-halobutano without a solvent or in a solvent such as toluene, xylene, quinoline, etc. to 001 to 5 equivalents of 2.4- In the presence of acids such as /nitrophenol, /ylic acid, and nitrobenzoic acid, the above reaction is carried out at 50 to 250°C for 5 minutes to 10 hours while distilling off the methanol produced. -In R' (1), R' and so on, from now on, for example, 0.1 to 5
0 equivalent of a salt such as lithium chloride, lithium carbonate, potassium carbonate, or a combination thereof in dimethylformamide,
The above-mentioned -killing (+) odor can be produced by a method of reacting in a solvent such as choline, or a method of reacting with an organic base such as pyridine, DBU, DBN, etc. This compound can also be produced directly by using 3,3-dimethoxy-2-methyl-1-butene in place of 3,3-cymethoxy/2-methyl-2-halobutane in the C1aisen rearrangement reaction of compound (N). Ru. In general formula (1), R
It can be converted into a compound represented by the general formula (I) by reducing a metal hydride such as 1-methylaluminum or a metal complex such as sodium aluminum hydride in an amount of 0.1 to IO equivalent. In addition, the compound represented by this formula (I) can be prepared from the compound represented by R1 or -Co, R' in a solvent such as methanol or ethanol, and 01 to 10 equivalents of sodium borohydride.
Add a reducing agent such as sodium cyanoborohydride to 180 to 1
It can be produced by a method of reacting at 00°C for 5 minutes to 5 hours, and further, in an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane, or a hydrocarbon solvent such as benzene, toluene, n-hexasan, etc. 1
A compound in which the hydrogenated dib is represented by a formyl group at 00 to 50°C has the general formula CI) of CO! It can also be produced directly from the compound represented by R3 by a similar reduction reaction.

The compound represented by the general formula (I) can also be produced from a sesquiterpenoid, farol (compound (0)), for example, according to the following synthetic route.

Metal hydrides such as sodium hydride and potassium hydride, organometallics such as n-butyllithium and lithium diisopropylamide, and metal alcohols such as sodium methoxide/F and t-butocinopotassium, in an amount of 1 equivalent or less relative to the reagent. Cow/
The anion generated by the action of
2-(dimethylphosphono)-isono\leronitrile, 2-(diethylphosphono)-isonolsilonitrile, 2-(dimethylphosphono)-isonolsilonitrile, 2 Wittig -Hor such as ethyl -(diethylphosphono)-isovalerate
ner reagent in an ether solvent such as tetrahydrofuran or diethyl ether, a hydrocarbon solvent such as toluene or n-beef sanitation, or an aprotic polar solvent such as dimethylformamide or dimethyl sulfoxide at -100°C to 100°C.
At 00°C, as a base, Wittig-Horner tyrene, halokene solvent such as chloroform, ether solvent such as diethyl ether, tetrahydrofuran, or alcohol solvent 6X such as methanol, ethanol, etc.
R8 of compound (P) is a cyano group or -Co, etc. by a method of acting at -50 to 100 °C for 5 minutes to 24 hours, etc.
A compound represented by R3 is obtained, and these are further mixed with a metal such as diisobutylaluminum hydride in an amount of 0.1 to 10 equivalents at 100 to 150°C in a hydrocarbon solvent such as n-hexane, 2-heptane, benzene, or toluene. A compound in which R2 of compound (P) is represented by a formyl group can be produced by a method of reacting with a hydride and then hydrolyzing it.

Whether R2, ano group, formyl group, -〇〇, or R3, from compound (P), halogen solvents such as methylene chloride and chloroform, ester solvents such as ethyl acetate and methyl acetate, or /ethyl ethyl, tetrahydrofuran, etc. 0.1 to 10 equivalents of an organic peracid such as peracetic acid or metachloroperbenzoic acid in an ether solvent of -50 to loO
A method in which 0.1 to 10 equivalents of N-halocarphonamides such as N-bromosuccinimide, N-chlorosuccinimide, N-bromoacetamide, etc.
After reacting at 100'C for 5 minutes to 5 hours, there is a method of reacting with a base such as sodium carbonate or potassium carbonate, or a method of reacting with hydrogen peroxide in an organic nitrile solvent such as acetonitrile or hendinitrile. The compound expressed as 7-epoxy can be produced.

From the epoxy/body produced by the above method, in a hydrocarbon solvent such as toluene, kiln, Ligroy 7, etc.
A method of reacting aluminum alcokit with 01 to 10 equivalents of aluminum triisopropokit at 50°C, or 01 to 10 equivalents of lithium/ethylamide at 100 to 100°C in a solvent such as ethyl ether or tetrahydrofuran. The compound can be produced by a method of reacting with a metal amide such as lithium isofuropyramide.

From the compound of the present invention, the above-mentioned Japanese Patent Application No. 1-181710
The key intermediate (F) in the synthetic route to sarcotuitol described above can be produced without going through the oxidation step of the terminal methyl group, for example, by the route exemplified below, making sarcotuitol A more industrially advantageous! 8! I can send it to you.

Synthesis route for Sarcotuitol A (Example) Sarcotuitol A (wherein R' and X are as defined above).
01 to 1 in an ether fJ medium such as diethyl ether, tetrahydrofuran, nooxane, noisofropinoether, nbutyl ether, or a hydrocarbon solvent such as n-penotane, n-hexane, or chlorohexane.
Thionyl chloride, thionyl bromide, phosphorus trichloride,
When halokeno-forming agents such as phosphorus tribromide, hydrogen chloride, and hydrogen bromide are reacted at -100°C to -100°C for 5 minutes to 100 hours, R2 is an ano group or -C○, R3. Furthermore, ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane! medium, hensen, rruene, n-
-10 in a hydrocarbon solvent such as hexane or n-heptane
The compound (F ) can be manufactured.

Sarcotuitol A can be produced from compound (F) according to the method described in Japanese Patent Application No. 1,81710.

That is, among the compounds shown as compound (G) in the above route, the compound in which R8 is a trimethylsilyl group can be obtained by, for example, methylene chloride, chloroform, ethyl acetate, etc. from compound (F) produced by the above method. from -10 equivalents of trimethylsilylnitrile in a solvent or without solvent in the presence of a catalytic amount of metal cyanide-18-crown-6-ether complex at -20°C to 50'C for 30
It can be produced by reacting for minutes to 5 hours, and after dissolving this compound in a solvent such as tetrahydrofuran or methanol,
A method of reacting with an aqueous solution of a mineral acid such as 01-3N hydrochloric acid or sulfuric acid at 0°C to room temperature for 5 minutes to 5 hours, or in a solvent such as tetrahydrofuran or dioxane at 20'C to room temperature from a catalyst amount of 10 A compound or cyanohydrin compound in which R5 is a hydrogen atom can be produced by a method in which an equivalent amount of tetraalkylammonium such as tetrabutylammonium fluoride is reacted. R5 is a compound represented by a 1-ethoxyethyl group, from the cyanohydrin compound,
In a solvent such as ethyl ether or ethyl acetate, add a catalytic amount of N to 10 equivalents of ethyl vinyl ether to a mineral acid such as hydrochloric acid or sulfuric acid, a strong organic acid such as para-toluenesulfonic acid, or a pyridinium salt of para-toluenesulfonic acid. It can be produced by a method of reacting in the presence of a salt of a strong acid at -20'C to room temperature for 30 minutes to 5 hours.

Among the compounds (G) in the above route, from the compound represented by R5 or trimethylsilyl group or 1-ethquinethyl group, ether solvents such as ethyl ether and tetrahydrofuran, aromatic hydrocarbon solvents such as Hensen and toluene, or n- A base such as lithium diisopropylamide, lithium bis(trimethylsilyl)amide, or sodium hydride in an amount of 1 to 10 equivalents in a saturated hydrocarbon solvent such as Hegyusan or n-hebutane at -70'C to 100°C, The compound (
Among H), it is possible to produce a compound in which R5 is a trimethylsilyl group or l-ethoxyethyl group, and further add an aqueous solution of a mineral acid such as 01 to 3N hydrochloric acid or sulfuric acid to O' in a solvent such as tetrahydrofuran or methanol. A method of reacting at C to room temperature for 5 minutes to 5 hours, or a method of reacting with a catalytic amount to 10 equivalents of tetraalkylammonium such as tetrabutylammonium fluoride at -20'C to room temperature in a solvent such as tetrahydrofuran or dioxane. Among compounds (H), compounds in which R5 is a hydrogen atom can be produced by a method such as that of

From a compound (H) in which R5 is a hydrogen atom, a solution of an organic solvent such as ethyl ether or ethyl acetate is treated with an aqueous solution of sodium hydrogen carbonate for 5 hours at room temperature. ,or,
From a compound in which R5 is a trimethylsilyl group in compound (H), a method such as a method in which a catalytic amount to 10 equivalents of alkylammonium fluoride such as tetrabutylammonium fluoride is reacted with a catalytic amount to 10 equivalents in a solvent such as hydrous tetrahydrofuran or dioxane. It can be directly converted into a ketone body, compound (J), and from this, ethyl ether, tetrahydrofuran, etc., Hensen,
Aromatic hydrocarbon solvents such as toluene or n-hexane,
-70'C~5 in a saturated hydrocarbon solvent such as n-hebutane
Sarcotuitol A can be produced by a method in which equivalent to 10 equivalents of a metal hydride such as hydride/butylaluminum or a metal complex compound such as lithium aluminum hydride are reacted for 5 minutes to 5 hours at 0°C.

The synthetic route to sarcotuitol using the compound of the present invention as an intermediate described above is an industrially excellent route for the production of sarcotuitol A, and therefore the compound of the present invention is extremely important for that purpose. It is a synthetic intermediate.

(Hereinafter, blank space) (Example) The present invention will be explained in more detail by giving examples below.
The present invention is not limited by the following examples unless it exceeds the gist thereof.

Synthesis Example 1 Potassium bis(trimethyl7lyl) was added to a toluene solution (55+ρ) of 2-(ethylphosphono)isovaleronitrile (6,549,30 mmol) under an N alkone atmosphere.
Amide Q, 5M toluene 1 night 56JIr2 70
'C Added to the bath without stirring. After 30 minutes, keep stirring and cook at the same temperature.
5 mmol) was added thereto, and the temperature was raised to room temperature over about 10 hours. Water was added to the reaction mixture, the layers were separated, and the organic layer was washed with saturated aqueous hydrogen carbonate solution and saturated brine, dried (anhydrous Mg5O), filtered, and concentrated. The resulting residue was purified by silica gel column chromatography. The target 2-(1-methylethyl)-5,9-7methyl 2,4.8-decatrienenitrile (4, 879,90%, 2Z:2E=22
．． 4:l) was obtained.

The spectral data of the 27 bodies are shown below.

JR(film)cz-';2980.2940,28
902220.1640, 1450.1390.1.3
751295.1225.1105.103ONMR(
C103ON, 250MHz) δppm: 1.17 (d
, J=6.8Hz, 6H,CH(CH,)-), 1.6
1169 (each bs, each 3H, -C=CCH3),
183 (d, J= 1.2Hz, 3H, -C=, CC1
-(3), 21-2.2(m, 4H, -CH,CH,-
), 2.53 (hepJ-6,8Hz, IH, CH (C
H3)t), 5.08 (m, LH, -C=CCH3 J -11,5Hz, each IH, -CH-C
H-) Synthesis Example 2 2-(1-methylethyl)-5,9-dimethyl 24.8
-Decatrienenitrile (2Z form, 217uyl mm
ol) to n-beef san 4ff (solution was hydrogenated at -70'C in an alcon atmosphere/isobutylaluminum 1)
Two volumes of M toluene solution were added dropwise without stirring. After 1 hour at the same temperature, the water was 0.8fff! was added, the bath was removed and the mixture was thoroughly stirred, and the resulting white solid was filtered off and washed (n-hexane), and the filtrate was vigorously stirred with 5JIQ of a 10% aqueous nouric acid solution for 3 hours. The organic layer was separated, washed with water, dried (anhydrous Mg5O,), filtered, and concentrated. All of the above operations were performed under an argon atmosphere. The obtained residue was subjected to 7 silica gel chromatography (developing solution n-hexane: ethyl acetate 5
0:1) to obtain the desired 2-(1-methylethyl)
-5,9 dimethyl 2,4,8-decatrienal (19
8ff9.90%) was obtained.

I R(fi1+n)cr';2980.2940,2
8801670.1630,1455,1375,12
95°1235.1135,1105.1075NMR
1075N! 3,250MHz) δppm; 1.07 (
d, J=6.8Hz, 6H, -CH(CH3)-), 1
．． 623H, -C,=CCH,), ] 3H, -C=CCH3), 2 CH, CH2-), 2.91 (hepCH(CI-
(3), ), 5.10 (m), 6.83.7.14 (each lH, -cH-CH-) CH○) 1, , 69 (each bs, each 89 (d, J=1 .o) (z ]-2,3(m, 4H J =6.8Hz, IH IH,=CH-CH.

d, J = I 2. OL (z lo, 29 (s, IH) Synthesis Example 3 Add m-chloroperbenzoic acid (purity 80%, 2. 09.9.3 mmo
The mixture was gradually added. After stirring in an ice water bath for 1 hour, the bath was removed and stirring was continued for an additional 3 hours. After adding a saturated aqueous sodium bicarbonate solution and stirring vigorously for 30 minutes, the organic layer was separated, washed with water, dried, and concentrated. The resulting residue was subjected to chromatography on a gel column 7 (developing solution: hexane-ethyl acetate 101). , the desired epoxy body (2,08
9.97%) was obtained.

TR(film)ci-':2970,2940.28
802210.1640,1460,1380,112
01025°NMR (CDCff3.250MHz) δppm; 1.
17 (d, J=6.8Hz, 6H, CH(CH3)t)
, 1.27°132 (each 8. each 3H, ○C (CH
3)t), 16 1.8(m, 2H,=CCHtCH
3), 1.86 (s.

3 H, = CCH3), 2 2-2, 3 (m,
2H, = CCH2CHz), 2.54(hep
, J=6.8Hz, LH, CH(CH3)=), 2.7
2 (t, J=6.2Hz, LH, -CH〇-), 6.3
1 (dd, J=0.9.11.5Hz, IH=CH-C
H=), 6.83 (d, J=11.5Hz, IH engineering CH
-CH=).

Synthesis Example 4 Aluminum triisopropoxide (1,601j, 7.84 mmol) was added to a dry toluene solution 1 (16x) of the epoxy compound (1,83ij, 7.85 mmol),
Heated on an oil bath at 110°C under N2 atmosphere for 8 hours. After cooling, the mixture was diluted with n-hexane and thoroughly mixed with 2N hydrochloric acid. The organic layer was washed with water and a saturated aqueous sodium bicarbonate solution, dried, and concentrated. The resulting residue was subjected to 5 inch 2 column chromatography (developing solution: n-hexane, EtOAc = 6°1).
The target product, allyl alcohol (1,809,
98%).

IR(film)ex-';3450,2980,29
50°2880.2210,1640,1450,13
901295.1030.90O NMR (CD CQ3.2 v○MHz) δppm: 1
．． 14(d, J=6.9Hz, 6H, -CH(CH3)
-), 1.61.75 (m, 2H, = CCHtCH2)
, 1.71 (s3H,=CCHs), 1.82 (d, J
=1.0Hz, 3H=CCH-), 2.0-2.3(m
, 2H, -CCH,CH.

), 2.50 (hep, J = 6.9Hz, I
H,-C! 1(CH3)t), 4.03(t, J=6.
3Hz, CHOH), 484.4.94 (each bs
, each IH, C=CH,)6.27(dd, J=
1.0.11.5Hz, =CH-CH=), 6.8(
d, J=11.5Hz, =, CH-CH=) Example 1 7') Le'fl: + -/l/body (320ffl+,
1.37 mmo+), 3.3-nmethquine-2-methylbutene (895 mg6, 87 mmol) and 2,4-n nitrophenol (6 m9.0,04
mmol) was heated and stirred at 110° C. for 8 hours under an argon atmosphere while distilling off the generated methanol.

After cooling, the excess reagent is distilled off and the remaining ? i 'e S i
Purification by column chromatography (developing solution: hexane: ethyl acetate 7:1) yielded the desired conjugated ketone (262o, 64%).

IR(film)am-';2980,2940,28
90°2215.1680,1635,1450,13
85°1365.1085,1025.93ONMR(
CDCQ3, 250MHz) δppIIl; 1.14 (
d, d=6.8Hz, 6H, -CH(Cdan, ), ),
1, 60 (s, 3H, -CCH3), 1.80 (d,
3H, J=1.0Hz, -CCH-), 1.84(s,
3H, -CCH3), 214(m, 4H,=, CCH2
CH, C-), 2.25 (btJ=7.5Hz, 2H,
-CH2CH,C-0), 2.50 (hel), J=6
．． 8Hz, CH(CH3)2), 2.75(t, J
=7.5Hz, 2H, -CH2C-0), 5.08(b
m, IH, -CH-(CH2)2-), 5.75
．． 5.95 (each bs, each I H, -C=CHaH
b), 6.24 (bd, J= 11.5Hz, IH,
-CHa-CHb=), 679 (d, J= 11.5H
2, IH, -CHa-CHb-) Example 2 Cθ allyl alcohol (316 mg, 1.36 mmo
l), 2-chloro-3,3-cymethoxy/-2-methylbutane (550m9.4.1 mmol) and 2.4-/
A mixture of nitrophenol (12z9.0.065 mmol) was heated and stirred on an oil bath at 130° C. for 3 hours while distilling off the methanol produced under an argon atmosphere. After cooling, excess reagent was distilled off under reduced pressure, and the residue was subjected to Sin column chromatography (developing solution n-hex+f) ethyl acetate 71
) to obtain the target α-chloroketonoform (31
9zy, 70%) was obtained.

IR(film)cm-';2990.2950,2
8902220.1.720, 1640.1455.1
3851370, ], 290,1120.1075NM
R1075N! 3.2vOMHz) δppm: 1.14
(d, J=6.8Hz, 6H, -CH (mount C) 2), 1
．． 61 (s, 3H, = CCH3), 1.65 (s, 6H
, -C(CH3)2C,], ,80(s,3H,=C
CH3), 2.14(m,4H,-CC!(,CH7C
=), 2.25(bt, J =7.7Hz, 2H,
-CH,CH,C-〇), 2.50(hep, J-
6.8Hz, -CH(CH3)2, 2.83(t,
J = 77Hz, 2H, -CH, C-○), 5.11
(bm, IH,=CH(CH,), ~), 6.25(
bd, J-11,5Hz, IH, -CHa-CHb-)
, 6.79 (d, J=1 ], , 5Hz.

lH,=CHa-CHb-) Example 3 Conjugated nitrile <208m9. m-chloroperbenzoic acid (purity 80%; 165 o,
077 mmol equivalent) was added. After 2 hours, a saturated aqueous sodium bicarbonate solution C2Rρ) was added and stirred well.

The organic layer was separated, washed with water, dried (~1 g S○4), and concentrated. The resulting residue was subjected to Sin column chromatography (developing solution: n-hexane and 7 liters of ethyl acetate) to obtain the desired epoquino compound (165 mg, 7.5%).

IR (film) cm-'; 2980, 2940, 28
902220.1640,1455. l380.122
01120.1025,900,875 NMR (CD Cρ-, 250MHz) δppm: 1.
13(d, J = 6.8Hz, 6H, -C)I'(
CH3)=), 1.23°127 (each S, each 3
H, ○C (CH3), ), 1.51.7 (m, 2H,
-0CHCH,), 1.60(d, J -0,6Hz,
-CCH3), 1.80 (d, J=lHz, =CCH3
), 2.0 2.2 (m, 2H, -0CHCH2CH
2-), 2.14 (m, 4H, -CCH, CH, C-)
, 250 (hep, I H, J = 6.8 Hz, -
CH(CH3), )2.67(t, J=6.3Hz, 1
．． H, -CH○-), 51(bm,]H,=CH(CH
2), ), 6.24 (bd, J-11, 5t (z, l
H, -CHa-CHb=), 6.79<d, J=
l 1.5Hz, IH, = CHa-CHb-) Example 4 α-chloroketone body (319m9.0.95mmol)
was dried/dissolved in methylformamide (51), and lithium carbonate (210+9) and lithium chloride (120R
y) was added, and the mixture was heated and stirred at 110'C for 6 hours under an Alfon atmosphere. After cooling, water and ethyl ether were added, and the organic layer was separated, washed with water, dried (MgSOa), and concentrated.
-Hexane-ethyl acetate 71) to obtain the desired conjugated ketone body (268+yy94%).

Example 5 Conjugated ketone body (4, l 7 m9. l, 4 m
mol) in methanol mo, and add sodium borohydride (40 m 9. mol) to this while stirring on an ice-water bath.
1,1 mmol) was gradually added. After about 30 minutes,
Disappearance of the raw material was confirmed by TLC, and methanol was distilled off under reduced pressure. Add 7 ethyl ether and water to the residue, separate the organic layer, wash with cold IN hydrochloric acid, water, and saturated hydrogen carbonate (1) Wash sequentially with rum aqueous solution, dry (MgSO, ), filtrate, and condense the resulting residue. 5in2 column chromatography (Developing solution n
The desired alcohol compound (403+y, 96%) was obtained by subjecting it to ethyl acetate (61).

l R (film) cm-'; 3380.2990,
29 502895.2220, 1635.1450.
13901295.1060,1025.90ONMR
(CDCI! 3,250MHz) δppm; 1.14 (
d, J=6.8Hz, 6H, -CH(CH3)J, 1.
60(s,3H,-CCH,l), 1.6],,
7 (m, 2H, CH(OH)CH2-), 1.70 (s
,3F(,-CCH3).

1.81 (d, J = IHz, 3H, -CCH3
), 1.92, 1(bm, 2H, -CH(CH)C
H, CH2-), 215(m, 4H, -CCHtCHt
C-), 250 (hepI H,J =6.8H2,C
H(CH3)2), 4.01 (bm.

CH(OH)-), 4.81(m, IH, -C=CHa
Hb), 4.91(bs, IH, -C=CHaHb
), 5. I 1 (bm, IH, =CH (CHz)t
), 6.25 (bd, J=11.5Hz, IH, -
CHa-CHb=), 6.80 (dJ=11.5Hz,
IH, =CHa-CHb) For the same allyl alcohol compound, the conjugated ketone compound was not isolated in the reaction of Example 1, that is, after the reaction was completed, the residue obtained by distilling off the excess reagent was meth/
It was also possible to obtain a product with a yield of 71% (total) by dissolving the product in a solution of 100 ml and reacting with sodium borohydride while stirring on an ice-water bath and carrying out the same operations as in this example.

Example 6 Aluminum triisopropoxide (ri 9.0.62 mmol) was added to a toluene (2ffj) solution of Epo cow/body (186, 0.62 mmol) and heated to 110'C under N2 atmosphere for 10 hours. . After cooling, the mixture was diluted with n-beef sanitation and thoroughly stirred with 2N hydrochloric acid. The organic layer was separated, washed sequentially with water and a saturated aqueous sodium bicarbonate solution, dried (MgSO,), and concentrated. The resulting residue was subjected to Sin column chromatography (developing solution: n-hexane/ethyl acetate-6.1). The desired allyl alcohol compound (
128119,69%) was obtained.

Example 7 Nitrile body (218 parts 9.0, 72 mmol) was added to n
- 0.9 M hydrogen non-isobutylaluminum n-hexane solution (24RQ) dissolved in hexane (511) and stirred on a low a (78°C) bath under an argon atmosphere.
was instilled through a syringe. After the dropwise addition was completed, the refrigerant bath was removed and the mixture was stirred at room temperature for 3 hours. Cool again in a refrigerant bath,
After adding a 10% aqueous acetic acid solution (4%), the bath was changed to an ice-water bath and stirring was continued for an additional 6 hours. Branch the organic layer, wash with water (twice), wash with saturated aqueous sodium bicarbonate solution,
The residue obtained by drying (MgSO,) and concentration was subjected to Sio column chromatography (developing solution: beef sanitation, ethyl acetate, 6.1 g) to obtain the desired formyl compound (152 ug, 6.1 g).
9%).

IR (film) cm”; 3450, 2970, 294
0°2880.1665,1625,1450,139
01295.1230,1180,1130,1100
1065.1020,995,895°NMR (CDC
I23, 250MHz) δppm; 1.02 (d, J-
7.0Hz, 6H, CH(CHa)-), 1.5-1.
65 (m, 2H, C(OH)CHz), 1.59 (
dJ-0.8Hz, 3H,-CCHs), 1.67
(s, 3H.

=CCH3), 1.85(d, J=1.3Hz, 3H=
CCH3), 1.99 (bq, J=7.5Hz, 2H,
C(OH)CHtCHt-), 2.17(m, 4H,=
CCHtCH2C-), 2.86 (hep, J=7.0
Hz, IH-CH(CHs)z), 3.98(bt,
J = 5.7Hz, L HCH(CH)-), 4.7
8, 4.88 (each m, each IH, C=CH2), 5
．． I 1 (bm,' I H, -CHCH2CH,
-), 6.79 (bd, J= 12.OH7:IH
,=CHa-CHb=), l ○9(d, J=12
．． 0Hz, IH=CHa-CHb=), 10.23(s
, LH, -CH○) Reference Example I Allyl alcohol (117 fi, 0, 39 m
Dissolve thionyl chloride (0,029 mQ, mol) in ethyl ether (1,0 m
0.4 Qmmol) was added. After 3 hours, the solvent was distilled off under reduced pressure, and the residue was subjected to 5iOy column chromatography (development: 11tn, beef sanitation: ethyl acetate IO: 1) to obtain the desired chloride (112u, 90%).

IR (film) cm-': 2980, 2940, 28
802215.1635, 1445, 1390.126
5NMR (CDCI23, 250MH2) δppm; 1
．． 14(d, J = 6.8Hz, 6H,CH(Ct
(3), ), 1. ．． 59164 (each bs, each 3
H, -C=CC So, ), 181 (d, J=1.OHz,
3H, -c = cc 3), 19 2.2 (m, 8H, C
HICH2X2), 2. DO(hep, J = 6.8
Hz, l H, -CH(CH3), ), 3.96(
bs, 2H, -CH,OH), 5.08 (m, IH, -
CHCH, -), 5.36 (bt, J=55Hz, LH
, -CHCH2-), 6.25.6.80 (respectively d,
J = 115 Hz, respectively IH, -CH-CH-).

Reference example 2 Nitrile compound (14-ri-4-2-(1-methylethyl)
-5,9,13-trimethyl 2,4,8.12 tetraenitrile, 890xy, 2.78 mmol
) was dissolved in 30 iC of n-hegyosan, and 4.2 ffC of a 1M toluene solution of hydrogenated/isobutylaluminum was gradually added dropwise at -70°C under an Alcon'fJ atmosphere. After 1 hour, 2 IC of water was added, the bath was removed, the mixture was stirred vigorously, and the resulting white solid was filtered, washed with n-hexane, mixed, and the resulting filtrate was further mixed with a 10% aqueous solution of oxalic acid. Share: This was stirred. After washing, drying, filtering and concentrating the organic layer, the desired formyl compound (7
81*y87%) was obtained.

IR(film)cm-':2970.2930,2
8801670.1630,144.5.1390.1
2951265.1135 NMR (CDCI23, 200MH2) δppm; 1.
04(d, J = 7.0Hz, 6H, -CH(CH3
)=), 1. ．． 59170 (each BS, each 3H1
-C=CCH3), 187(d, J=1.3Hz, 3H
, C=CCH, 3), 19 2.2(m, 8H, -CH
, CH=-), 2.89 (hepJ=7.0Hz, LH
, -CH(CH3)=), 3.98(bs2H, -CH
, CQ), 5.09 (m, I H, -C=CCH3),
5.47 (bt, J=6.5Hz, lH, -CH-CH
CH, -), 6.82 (bd, J = 12.OH
z, l HC=CH-CH=C(CHO)-), 7.
11(d, J-12, OHz, -C=CH-CH=C(
CHO)-) 10.27 (s, IH, -CHO) Reference Example 3 Formyl compound (+4-chloro-2-(+-methylethyl)
-5,9,13-Trimethyl 2.4,8.12 Tetratecatetraenal, 640u, 2, Omm.

l) to trimethylnorylnitrile (0.35mQ, 2
．． 6 mmol), stirred on an ice-water bath under a nitrogen atmosphere, and added a very small amount of potassium anhydride/18-crown 6-ether complex. After 2 hours, it was confirmed that the raw material had disappeared, and the excess trimethylrinrylnitrile was distilled off to obtain crude 1
5-ri4ro 3-(1-methylethyl)-6,10,1
4-trimethyl-2-(trimethylnoroquine) 3,5,
9.13-Pentade force tetraenonitrile (647xq
, quantitative) were obtained.

I R(film)c*-';2960.2930.2
8802320.1445.1255.1080.87
5NMR (CD CQ3.250 MHz) δppm
:1.11115 (each d, J=6.9Hz, each 3
H, -CH(CH3L), 1.60, 1.71.1.7
7 (each S each 3) 1. -C=CCH3), 1.9-
2.2<m, 8HCH,CH2-), 2.64 (h
ep, J = 6.9 Hz, ]1-1-CH(CH
3) 2), 3.99 (s, l H, -CH, C of 5
, l l(m, IH, -C=CHCH,), 5.33(
sIH, -CHCN), 5.48 (bt, J=6.5H
z, IH-C=CHCH,-), 6.04.6.25(
Each dJ=11.3Hz, each lH, -C=CH-C
H-(,-) Reference Example 4 Lithium hexamethylsinrashide dissolved in tetrahydrofuran OC20tttQ, 5.00 in an alkone atmosphere.
15-chloro-3-(1-methylethyl)6.10.14-1-methyl-2-trimethylenroxy3, A solution of 5,9.13-pentadecatetraenenitrile (G) (378 m 9.0.895 mmol) in tetrahydrofuran (15 x 12) was added dropwise over 50 minutes.

After stirring at this temperature for 20 minutes, the reaction solution was poured into ice (50 g
) in saturated saline solution (30*12)-to beef san (2O
XQ> mixture was added to stop the reaction. After separating the organic layer, the aqueous layer was extracted with hexane-ether (5:1.30iQ). After drying the extract (Na2So4) and removing the solvent under reduced pressure, the resulting residue was purified using Norikakel column chromatography to obtain 2-(l-methylethyl)-5,9,13
-) Trimethyl-1-trimethylfluoroquino2.4,8.1
2-7 clotetratecatetraene-l-carbonitrino-H) (288, v!?, 83%) and 2-(l-methylethyl)-5,9,13 trimethyl 2,4,8.12
-n clotetradecatetraen-l-one (J) (42
，! 3+9.0.11 mmol.

16%) was obtained.

The physical properties of compound (H) are as follows.

IR(film)cr':2970,2920,144
01385.1253.1125,1085,9408
45.755゜PMR (CDCI23, 2.50MHz) δppm: 0
．． 23(s, 9H, -3iMe3), 1.09, 1.1
5 (d each, J = 6.7 Hz, 3H each, -CH (CH
3), ), 1.50.1.62 (each bs, each 3H
, -C=CCH3) 1.70 (d, J=1.3Hz, 3
H, -C=CCH,) 2.0 2.2 (m, 8H, -C
H2CH, -X2), 251 (sep, J=6.7Hz
, IH, -CH(CH3)2) 2.55, 2.65 (each d, J = 14.2Hz, each I H, -CH, H, C
N-), 4.94 (bt, J=6.1Hz, IH, -C
=CHCH-), 5.15 (bt, J-5,6Hz, I
H, -C=CHCH, -), 6.17.644 (each d
, J = 11.8Hz, respectively lH, -C=CH-
CH=C-) Reference Example 5 1.0M) was added. After stirring the reaction solution at room temperature for 17 hours, saturated brine (I Qu) was added, and the organic matter was extracted with hexane-ether (5:1, 3011ρ×2).

After drying the extract (Naz SO4), the solvent is distilled off under reduced pressure to obtain the target 2-(1-methylethyl) 5.9
．． 13-trimethyl 2,4,8.12-7 clotetratecatetraen-1-one (200 mi, 94%) was obtained.

Reference Example 6 Under argon atmosphere, 2-(1-)limethylethyl)-5
,9,13-trimethyl-1-trimethylsiloxy2,
4,8.12-Cyclotetradecatetraene-1-carbonitrile (288 mg, 0.74 mmol) in tetrahydrofuran solution (10R12), water (03RQ) and tetrabutylammonium fluoride in tetrahydrofuran solution (16μ12, 0.016 mmol (1 ) Lithium aluminum hydride (80,0
z9. 2.11 mmol) to 7 ethyl ether (5 m
Add (IR,2S)-(-) to this suspension and stir.
-N-methylephedrine (38012, 12 mmol
) dissolved in diethyl t&(5IIIQ) was added dropwise at room temperature over 5 minutes. After refluxing the reaction mixture for 1 hour with stirring,
N-ethylaniline (0,53ff12.423mm
ol) was added dropwise over 5 minutes, and the mixture was further stirred for 1 hour before being refluxed. The reaction mixture was cooled to -72°C and the ketone body (136 uy, 0475 mmol)
A solution of 7 ethyl ether (3 mc) was slowly added dropwise thereto, and the mixture was stirred at -72°C for 6 hours. IN hydrochloric acid <9mQ')
After separating the organic layer, the organic layer was diluted with 3N hydrochloric acid (5zf!X
2) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to Rikakel column chromatography to obtain optically active sarcotuitol A (
81m9.60%) and unreacted compound of formula (n) (
51xy, 37%) was obtained.

The optical purity of the optically active sulfuitol A obtained was determined by high performance liquid chromatography (HPLC) analysis using an optical isomer separation column, CHIRALCELL-OD (Tycel Chemical Co., Ltd.) (hereinafter referred to as CHIRALCELL).
This is abbreviated as HPI-C analysis using OD. ), it was 87%.

(2) 1ffl of 7 ethyl ether solution of lithium aluminum hydride (2,94tnQ,
2Ommo1. 0.68~1) and add (S
)-2(2,6-ki/ritsumethyl)pyrrolifune (49
0I92, 4 mmol) was slowly added dropwise at room temperature,
After the addition was completed, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to -74°C, and the ketone body (691
HO, '24 mmol) in 7 ethyl solution (3 m□) was added dropwise over 10 minutes. After stirring at -74°C for 1 hour,
A saturated aqueous solution of sodium sulfate (1 mc) was added, and the mixture was stirred for a while at room temperature. /ethyl ether (10M) and dilute hydrochloric acid (20ml) were added, and after separating the organic layer, the aqueous layer was extracted with diethyl ether (20ml).The extract was washed with saturated brine (20mQ), and anhydrous sulfuric acid was added. After drying on a column, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography to obtain optically active Sarcotuitol A (61.88%).

The optical purity of the optically active sarcotuitol A obtained is CH
HPLC analysis using IRALCELL OD showed 93%.

[α Army: +204. ．． 4° (C=0.27.CHCf!
3) (Effect of the invention) Compound a of the present invention is an =i intermediate of sarcotuitol A having anti-carcinogenic promoter action and anti-tumor action.
Extremely useful.

Claims (1)

[Claims] (1) General formula below (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼,
Represents ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, and R^2 is a cyano group, formyl group, or -CO_2R^3 ( R^3 is C_1~C
_4 represents an alkyl group), and X represents a halogen atom].