JPH04316530A - Chain terpenes - Google Patents

Abstract

PURPOSE:To obtain a new chain terpene useful as an intermediate for inexpensively producing and supplying a large amount of sarcophytol A having anti- carcinogenic promoter action and antitumor action. CONSTITUTION:A chain terpene shown by the formula [X is Cl, OC(O)R<1> (R<1> is H, 1-4C alkyl or phenyl which may contain substituent group), SR<2>, S(O)R<2> (R<2> is 1-4C alkyl or phenyl which may contain substituent group), NR<3>R<4> or N(O)R<3>R<4> (R<3> and R<4> are 1-4C alkyl or R<3> and R<4> are bonded to from ring); R is cyano, formyl or C(O)OR<5> (R<5> is 1-4C alkyl); n is 0 or 1 with the proviso that X is Cl or OC(O)R<1> when n=0]. The compound shown by formula, for example, is obtained by reacting geranial with Wittig-Horner reagent in the presence of a base.

Description

[Detailed description of the invention]

0001

TECHNICAL FIELD The present invention relates to novel chain terpenes. Specifically, the compounds of the present invention exhibit anti-carcinogenic promoter activity (Cancer Surveys,
2, 540 (1983); Metabolism, Vol. 25 Special Issue Cancer ■88, 3 (1988)) and an important intermediate for the production of sarcophytol A, which has antitumor effects (Japanese Patent Publication No. 1983-20213) This relates to chain terpenes, which are the main body of terpenes.

0002

BACKGROUND OF THE INVENTION Sarcophytol A represented by the following structural formula is a Semblan-type diterpene alcohol having a total of four double bonds, including one conjugated double bond, in its 14-membered ring.

[Case 2]

[0003] Conventionally, a method for synthesizing sarcophytol A was not known, but the present inventors used the sesquiterpenoid shown below as a starting material and synthesized the formyl compound, compound (F).
We proposed a synthetic route for sarcophytol A using sarcophytol A as a key intermediate (Japanese Patent Application No. 1-181710). This synthetic route is shown below.

0004

[Formula 3] (In the above formula, R6 represents a C1 to C4 lower alkyl group, R7 represents a trimethylsilyl group, 1-ethoxyethyl group, or a hydrogen atom, and Y represents a halogen atom such as a chlorine atom or a bromine atom.)

[0005] When attempting to industrially produce Sarcophytol A using the production route for Sarcophytol 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 the oxidation process of the methyl group could not be avoided.

[0006]

[Problems to be Solved by the Invention] As a result of intensive studies aimed at manufacturing and supplying sarcophytol A in large quantities and at low cost by an industrially more advantageous method, the present inventors have discovered that the chain terpene of the present invention The inventors have discovered that these are useful intermediates 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 the following general formula (I)

[Formula 4] [where X is a chlorine atom, -OC(O)R1(R
1 represents a hydrogen atom, a C1 to C4 alkyl group, or a phenyl group which may have a substituent), -SR2, -S
(O)R2 (R2 represents a C1-C4 alkyl group or a phenyl group which may have a substituent), -NR3R
4, -N(O)R3R4 (R3 and R4 each independently represent a C1-C4 alkyl group or an alkyl group formed together to form a ring), R is a cyano group,
It represents a formyl group or -C(O)OR5 (R5 represents a C1-C4 alkyl group), and n represents 0 or 1. However, when n is 0, X is a chlorine atom or -OC(O)R
Represents 1. The object of the present invention is to provide chain terpenes represented by the following. Hereinafter, the present invention will be explained in detail.

In the above definition, the C1 to C4 alkyl group of R1 includes methyl group, ethyl group, n-propyl group, TSO-propyl group, n-butyl group, tert-butyl group, etc. Examples of the phenyl group which may have a phenyl group include a phenyl group, a p-tolyl group, an o-chlorophenyl group, a p-nitrophenyl group, and the like.

[0008] As the C1 to C4 alkyl group of R2,
Methyl group, ethyl group, n-propyl group, TSO-propyl group, tert-butyl group, phenyl group which may have substituents include phenyl group, p-tolyl group, p-chlorophenyl group, o- Examples include nitrophenyl group, o, p-dinitrophenyl group, and the like.

Specific examples of R3 or R4 include methyl group, ethyl group, n-propyl group, n-butyl group, or cyclopentyl group and cyclohexyl group in which R3 and R4 together form a ring. and R5 is a methyl group, ethyl group, n-propyl group, i-propyl group, t-
Examples include butyl group.

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

[0011]

[Table 1]

0012

[Table 2]

[0013]

[Table 3]

[0014]

[Table 4]

[0015]

[Table 5]

[0016]

[Table 6]

[0017]

[Table 7]

[0018]

[Table 8]

Next, the method for producing the compound of the present invention will be explained. The compound represented by the general formula (I) is, for example, monoterpenoid, geranial (compound (K), n=0
) or sesquiterpenoid, farnesal (compound (K), n=1) according to the following synthetic route.

[0020]

embedded image (wherein R1, R2, R3, R4 and R5 are as defined above)

That is, compound (K) is mixed with 0.1 to 10 equivalents of 2-(dimethylphosphono)-isovaleronitrile,
2-(diethylphosphono)-isovaleronitrile, 2-
W such as ethyl (diethylphosphono)-isovalerate
Ittig-Horner reagents include tetrahydrofuran, ether solvents such as diethyl ether, toluene, n
- Witti as a base at -100 to 100°C in a hydrocarbon solvent such as hexane or an aprotic polar solvent such as dimethylformamide or dimethyl sulfoxide.
Add 1 equivalent or less of metal hydrides such as sodium hydride and potassium hydride to the g-Horner reagent, organometallics such as n-butyl lithium and lithium diisopropylamide, and metal alkoxides such as sodium methoxide and t-butoxypotassium. A method of processing at a temperature of -100 to 100°C with anions generated by

A phosphorane compound such as [Chem.
A compound in which R of the compound (L) is represented by a cyano group or -CO2R5 is obtained by a method of reacting at 00°C for 5 minutes to 24 hours, and these are further treated with a hydrocarbon-based compound such as n-hexane, heptane, benzene, toluene, etc. -10 in solvent
A compound in which R in compound (L) is represented by a formyl group can be produced by a method in which 0.1 to 10 equivalents of a metal hydride such as diisobutylaluminum hydride is applied at 0 to 150°C, followed by hydrolysis.

[0022] R is a cyano group, a formyl group, -CO2R5
Regardless of whether n is 0 or 1, the compound (L) is subjected to a so-called ene-type chlorination reaction (for example, Bull. Chem. Soc. Jpn., 63,
1328 (1990) and its cited references), in a solvent such as methylene chloride, chloroform, to name a few,
In the presence of a base such as sodium carbonate or potassium carbonate, 0.
1 to 1.5 equivalents of sulfuryl chloride at -50 to +50°C
A compound in which X is a chlorine atom in the general formula (I) can be produced by subjecting the compound to conditions such as allowing the compound to react with a chlorine atom.

[0023] From this chloro compound, for example, 0.1 to 10 equivalents of sodium formate, potassium acetate,
Metal salts of organic acids such as sodium benzoate, ammonium salts of organic acids such as tetra-n-butylammonium formate, tetra-n-butylammonium acetate, and tetra-n-butylammonium benzoate, and polar aprotons such as dimethylformamide and dimethyl sulfoxide. At room temperature to 150°C, in a neutral solvent or an ether solvent such as tetrahydrofuran or dimethoxyethane, or in some cases in the coexistence of a crown ether, etc.
The general formula (I
), a compound in which X is OC(O)R1 can be produced. In addition, metal salts of mercaptans such as methanethiol and thiophenol can be dissolved in polar aprotic solvents such as dimethylformamide and dimethyl sulfoxide, ether solvents such as tetrahydrofuran and diethyl ether, or alcoholic solvents such as methanol and ethanol. A compound in which X is represented by SR2 in general formula (I) is reacted with 0.1 to 20 equivalents of secondary amines such as dimethylamine, diethylamine, and morpholine by a method such as allowing the reaction to occur at 150°C for 10 minutes to 20 hours. in an alcoholic solvent such as methanol or ethanol, or a polar aprotic solvent such as dimethylformamide or dimethyl sulfoxide, or in a method in which the amine is used as a solvent without using a solvent, at 0°C to 100°C for 30 minutes to 50 hours. etc., in general formula (I), X is N
Compounds represented by R3R4 can be produced respectively. The compound in which X is represented by SR2 in the general formula (I) is:
Compound (L) (n=1) is mixed with 0.1 to 1.5 equivalents of a sulfenyl chloride such as phenylsulfenyl chloride or o-chlorophenylsulfenyl chloride in a halogenated solvent such as methylene chloride or chloroform. -50~+
Once the compound (M
) in the presence of an amine such as triethylamine or pyridine, in a solvent such as dimethylformamide or toluene, and then heated to 50 to 150°C (T
etrahedron, 40, 3481 (1984
)).

From the thus obtained compound of general formula (I) in which X is represented by SR2 and NR3R4, 0.0.
1 to 1.5 equivalents of an organic peracid such as peracetic acid or m-chloroperbenzoic acid is allowed to act at -50 to 50°C for 10 minutes to 10 hours. Hydrogen peroxide, t-butyl hydroperoxide, etc. in an amount of 0.1 to 5 equivalents are added in alcoholic solvents such as methanol and ethanol, or in these water-containing solvents, in some cases with the coexistence of a metal salt such as tungsten as a catalyst. Organic peroxide, periodate salts such as sodium periodate, potassium periodate, etc. are heated at -20 to 100°C for 10 minutes to 1
In the general formula (I), X is S(O)R2 and N(O)R3R, respectively, by a method such as reacting for 00 hours.
A compound represented by 4 can be produced.

From the compound of the present invention, the above-mentioned patent application No. 1-
The key intermediate (F) in the sarcophytol A synthesis route described in No. 181710 can be produced by the route exemplified below without going through the oxidation step of the terminal methyl group, making sarcophytol A more advantageous industrially. can be manufactured.

[0026]

[C7]

That is, in general formula (I), X is S(
O) From the compound represented by R2, 0.1 to 20 equivalents of a trivalent phosphorus compound such as trimethyl phosphite or triethyl phosphite is added at 0 to 150°C in an appropriate solvent such as methanol or toluene, or without a solvent. , 10 minutes to 10
[2,3] sigmatropic rearrangement and reduction proceed simultaneously (Tetrahed
ron Lett. , 1385 (1973)),
Compound (M) can be produced. Compound (M) can also be obtained from a compound in which X is represented by N(O)R3R4 in general formula (I), and heated to 40 to 100°C for 10 minutes in an appropriate solvent such as toluene or acetone, or without solvent. Allyloxyamine, compound (N) by heating for ~5 hours
After that, for example, in aqueous acetic acid at 0 to 100°C, 3
Methods such as allowing metallic zinc to act for 0 minutes to 50 hours (Ch
emistry Lett. , 2035 (1986)).

Furthermore, in general formula (I), X is OC
(O) A method of transesterification of a compound in which R1, n is 0, in which a catalytic amount to 2 equivalents of a metal alkoxide is reacted at -50 to 50°C in a solvent such as methanol, ethanol, etc., methanol, ethanol, tetrahydrofuran Compound (P) can be produced by a hydrolysis method in which an aqueous solution of 0.5 to 10 equivalents of sodium hydroxide, potassium hydroxide, etc. in a solvent such as The above compound (M) can be produced according to the synthetic route described in Japanese Patent Application No. 2-7614 below.

[0029]

[Chemical formula 8]

That is, compound (P) has a concentration of 0.1 to 50
An equivalent amount of 3,3-dimethoxy-2-methyl-2-butanol is added without a solvent or in a solvent such as toluene, xylene, quinoline, etc., and 0.01 to 5 equivalents of 2,4-dinitrophenol, oxalic acid, o-nitrobenzoic acid are added. In the presence of acids such as acids,
It can be converted to compound (Q) by Claisen rearrangement, etc., which is carried out at 100 to 250° C. for 5 minutes to 10 hours while distilling off the methanol produced.

From compound (Q), for example, methanol,
Compound (R) is produced by a method of reacting 0.1 to 10 equivalents of a reducing agent such as sodium borohydride or sodium cyanoborohydride at -80 to 100°C for 5 minutes to 5 hours in a solvent such as ethanol. This can be mixed with methanol,
0.1 to 10 equivalents of sodium metaperiodate in a solvent such as ethanol or aqueous methanol or alcohol;
-50 to 10 for periodic acids such as potassium metaperiodine
The compound (S
). Compound (S) can also be compound (
P) is directly reacted with 1 to 100 equivalents of an alkyl vinyl ether such as ethyl vinyl ether in the presence of 0.1 to 5 equivalents of a mercury salt such as mercury acetate at 0 to 100°C to obtain a vinyl ether form of compound (P). or as known in the literature (J. Org. Chem., 48, 5406
(1983)) to give 3-alkoxyacrylic acid, and in the presence of a catalytic amount of hydroquinone etc.
It can be produced by a method such as heating to 0 to 250°C.

From compound (S), for example, 0.1 to 5 equivalents of a Wittig reagent such as carbomethoxyethylidene triphenylphosphorane, carboethoxyethylidene triphenylphosphorane, or 2-(diethylphosphono)
- Wittig of propionic acid ethyl ester, 2-(dimethylphosphono)-propionic acid ethyl ester, etc.
The anion prepared from Horner's reagent is dissolved in an ether solvent such as diethyl ether or tetrahydrofuran, an aprotic polar solvent such as dimethylformamide or dimethyl sulfoxide, a halogen solvent such as dichloromethane or chloroform, or an alcohol solvent such as methanol or ethanol. Compound (T) can be produced by a method of reacting at 80 to 100°C for 5 minutes to 10 hours.

[0033] Compound (T) is further mixed with 0.1 to 10
An equivalent amount of a metal hydride complex compound such as lithium aluminum hydride is reacted at -70 to 100°C, or 0.1 to 10 equivalents of a metal hydride complex compound such as lithium aluminum hydride is reacted at -70 to 100°C, or 0.1 to 10 equivalents of a metal hydrogen complex compound such as lithium aluminum hydride is reacted at -70 to 100 °C, or 0.1 to 10 equivalents of a metal hydride complex compound such as lithium aluminum hydride is reacted at -70 to 100 °C. Metal hydride such as dibutylaluminum hydride at -70 to 100°C for 5 minutes to
Compound (M) (R
=CHO).

Now, in the general formula (I), X is OC(
O) From a compound in which R1 and n are 1, the same reaction conditions as for the conversion from a compound in which X is OC(O)R1 and n is 0 to compound (P) in the general formula (I) described above. Compound (O) can be produced by subjecting to.

Compound (M) and compound (O) which can be produced by the above method are disclosed in Japanese Patent Application No. 2-7614 and Japanese Patent Application No.
-170785, the key intermediate described above,
It can be converted to compound (F).

That is, a method for halogenating allyl alcohol from compound (M) without allyl rearrangement, for example, converting an equivalent to 10 equivalents of carbon tetrahalide to an equivalent of 10 to 10 equivalents of carbon tetrahalide.
In the presence of an equivalent amount of triphenylphosphine, in an inert solvent such as acetonitrile, or in the case of chlorination, using carbon tetrachloride as a solvent, at a temperature from room temperature to 100°C.
A method of reacting for 8 hours, or a method of reacting an equivalent to 10 equivalents of methanesulfonyl chloride with a halogenated metal salt, S-collidine in a polar aprotic solvent such as dimethylformamide at a temperature of -40°C to room temperature for 1 to 10 hours, When R is a cyano group or -C(O)OR5, in an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane, or a hydrocarbon solvent such as benzene, toluene, n-hexane, n-heptane, -100 ℃
Compound (F) can be produced by applying a method such as allowing 0.1 to 10 equivalents of a metal hydride such as dibutylaluminum hydride or a metal complex compound such as sodium aluminum hydride to react at ~50°C for 5 minutes to 5 hours. .

Further, from compound (O), ether solvents such as diethyl ether, tetrahydrofuran, dioxane, diisopropyl ether, dibutyl ether, n-
0.1 to 100 equivalents of a halogenating agent such as thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus tribromide, hydrogen chloride, or hydrogen bromide in a hydrocarbon solvent such as pentane, n-hexane, or cyclohexane. -100℃~+100℃ for 5 minutes~
After 100 hours of reaction, R is a cyano group or -C(O)O
In the case of R5, dibutylaluminum hydride or the like is further added at -100 to 50°C in an ether solvent such as diethyl ether, tetrahydrofuran, or dimethoxyethane, or a hydrocarbon solvent such as benzene, toluene, n-hexane, or n-heptane. Compound (F) can be produced by applying a method such as allowing a metal complex compound such as a metal hydride or sodium aluminum hydride to act in an amount of 0.1 to 10 equivalents for 5 minutes to 5 hours.

From compound (F), patent application No. 1-18171
Sarcophytol A can be produced according to the method described in 0.

That is, among the compounds represented by compound (G) in the above route, the compound in which R7 is a trimethylsilyl group is, for example, the compound produced by the above method (F
), in a solvent such as methylene chloride, chloroform, ethyl acetate, or without a solvent, add from 10 equivalents of trimethylsilylnitrile to a small amount of metal cyanide-18-crown-
It can be produced by reacting at -20 to 50°C for 30 minutes to 5 hours in the presence of a catalyst such as a 6-ether complex or tetraalkylammonium cyanide, and this compound is added to a solvent such as tetrahydrofuran or methanol. After dissolution, 0
．． A method in which a 1 to 3N mineral acid aqueous solution such as hydrochloric acid or sulfuric acid is reacted at 0°C to room temperature for 5 minutes to 5 hours, or a catalyst amount to 10 equivalents in a solvent such as tetrahydrofuran or dioxane at -20°C to room temperature. A compound or cyanohydrin compound in which R7 is a hydrogen atom can be produced by a method of reacting with a tetraalkylammonium such as tetrabutylammonium fluoride. A compound in which R7 is a 1-ethoxyethyl group is prepared by adding 1 to 10 equivalents of ethyl vinyl ether to a catalytic amount of a mineral acid such as hydrochloric acid, sulfuric acid, or p-toluenesulfone in a solvent such as ethyl ether or ethyl acetate. It can be produced by a method such as allowing the reaction to occur at -20°C to room temperature for 30 minutes to 5 hours in the presence of a strong organic acid such as an acid or a salt of a strong acid such as a pyridinium salt of para-toluenesulfonic acid.

Among the compounds (G) in the above route, compounds in which R7 is a trimethylsilyl group or a 1-ethoxyethyl group are preferable to ether solvents such as ethyl ether and tetrahydrofuran, and aromatic hydrocarbons such as benzene and toluene. In a solvent or a saturated hydrocarbon solvent such as n-hexane or n-heptane, an equivalent to 10 equivalents of a base such as lithium diisopropylamide, lithium bis(trimethylsilyl)amide, or sodium hydride is added to -70 to 1
By a method of acting at 00℃ for 5 minutes to 10 hours, etc.
In compound (H), R7 is a trimethylsilyl group or 1-
Compounds that are ethoxyethyl groups can be produced,
Furthermore, in solvents such as tetrahydrofuran and methanol,
A method in which an aqueous solution of a mineral acid such as 0.1 to 3N hydrochloric acid or sulfuric acid is allowed to react at 0°C to room temperature for 5 minutes to 5 hours, or a catalytic amount in a solvent such as tetrahydrofuran or dioxane at -20°C to room temperature. A compound in which R7 is a hydrogen atom in compound (H) can be produced by a method of reacting with 10 equivalents of tetraalkylammonium such as tetrabutylammonium fluoride.

From a compound (H) in which R7 is a hydrogen atom, a solution of the compound in an organic solvent such as ethyl ether or ethyl acetate is added to an aqueous sodium hydrogen carbonate solution at 0°C.
~ By reacting for 5 minutes to 5 hours at room temperature, or from a compound in which R6 is a trimethylsilyl group in compound (H), a catalytic amount to 10 equivalents of fluoride is produced in a solvent such as hydrous tetrahydrofuran or dioxane. It can be directly converted to a ketone body, compound (J), by a method such as a method in which alkylammonium fluoride such as tetrabutylammonium is reacted with, and from this, ether solvents such as ethyl ether, tetrahydrofuran, benzene, toluene, etc. aromatic hydrocarbon solvent or n
-In saturated hydrocarbon solvents such as hexane and n-heptane-
Sarcophytol A can be produced by a method of reacting an equivalent to 10 equivalents of a metal hydride such as dibutylaluminum hydride or a metal complex compound such as lithium aluminum hydride for 5 minutes to 5 hours at 70 to 50°C. can.

The above-described synthetic route for sarcophytol A using the compound of the present invention as an intermediate is an industrially excellent route for producing sarcophytol A, and therefore the compound of the present invention can be used for its purpose. It is an extremely important synthetic intermediate. The present invention will be described in more detail with reference to Examples below, but the present invention is not limited by the Examples unless it exceeds the gist thereof.

Synthesis Example 1

[Chemical formula 9]

Under an argon atmosphere, 2-(diethylphosphono)-isovaleronitrile (6.54 g, 30 mmol)
), add 56 ml of a 0.5 M toluene solution of potassium bis(trimethylsilyl)amide to the toluene solution (55 ml) of
was added while stirring on a -70°C bath. After 30 minutes, add geranial (3.80g,
25 mmol) was added thereto, and the temperature was raised to room temperature over about 10 hours. Water was added to the reaction mixture, the organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried (anhydrous MgSO4), filtered, and concentrated. The resulting residue was subjected to silica gel column chromatography (developing solution: n-hexane). : ethyl acetate 100:1) to obtain the desired nitrile compound (4.
87 g, 90%, 2Z:2E=22.4:1) was obtained. The spectral data of the 2Z form is shown below.

IR (film) cm-1; 2980,2
940, 2890, 2220, 1640, 1450, 1
390,1375,1295,1225,1105,1
030. NMR (CDCl3, 250MHz) δppm
; 1.17(d, J=6.8Hz, 6H, CH(CH
3)2), 1.61, 1.69 (each bs, each 3H, -C=CCH3), 1.83 (d, J=1.2
Hz, 3H, -C=CCH3), 2.1-2.2(m
, 4H, -CH2CH2-), 2.53 (hep, J=
6.8Hz, 1H, CH(CH3)2), 5.08(
m, 1H, -C=CHCH2-), 6.28, 6.
82 (each d, J=11.5Hz, each 1H, =CH-
CH=).

Synthesis example 2

[Chemical formula 10]

Nitrile compound (2Z compound, 217 mg, 1 mm
ol) in 4 ml of n-hexane under an argon atmosphere.
At −70° C., 2 ml of a 1M toluene solution of diisobutylaluminum hydride was added dropwise with stirring. After 1 hour at the same temperature, 0.8 ml of water was added, the bath was removed, the mixture was stirred well, and the resulting white solid was filtered off and washed (n-hexane).
The filtrate was vigorously stirred with 5 ml of 10% aqueous oxalic acid solution for 3 hours. Separate the organic layer, wash with water, and dry (anhydrous MgSO4
), filtered and concentrated. All of the above operations were performed under an argon atmosphere. The obtained residue was subjected to silica gel chromatography (developing solution: n-hexane: ethyl acetate 50:1) to obtain the desired product (198 mg, 90%).

IR (film) cm-1; 2980,
2940, 2880, 1670, 1630, 1455,
1375, 1295, 1235, 1135, 1105,
1075. NMR (CDCl3, 250MHz) δpp
m; 1.07(d, J=6.8Hz, 6H, -CH(
CH3)2), 1.62, 1.69 (bs, respectively)
3H, -C=CCH3), 1.89 (d, J=1
．． 0Hz, 3H, -C=CCH3), 2.1-2.3
(m, 4H, -CH2CH2-), 2.91(hep
, J=6.8Hz, 1H, -CH(CH3)2), 5
．． 10(m, 1H, =CH-CH2-), 6.83,
7.14 (each d, J=12.0Hz, each 1H,=
CH-CH=), 10.29(s,1H,-CHO)
．．

Example 1

[Chemical formula 11]

Conjugated dienenitrile (431 mg, 1.9
8 mmol) of methylene chloride (2.1 ml) was added with 873 mg of powdered anhydrous sodium carbonate, stirred vigorously on an ice-water bath, and sulfuryl chloride (0.17 ml, 2
．． A solution of 12 mmol) in methylene chloride (2.1 ml) was gradually added dropwise over a period of 20 minutes. After the dropwise addition was completed, stirring was continued for another 30 minutes at the same temperature. After methylene chloride was distilled off under reduced pressure, n-hexane was added, filtered, and washed with n-hexane. The crude product obtained by concentrating the filtrate was subjected to SiO2 column chromatography (developing solution, n-hexane: ethyl acetate 15
:1) Unreacted starting material (34 mg, 7.9%)
Then add the desired secondary allyl chloride (438 mg,
88%).

IR (film) cm-1; 2970,
2940, 2880, 2210, 1635, 1465,
1450, 1390, 1375, 1290, 1030,
905,875.1H NMR (250MHz, CDC
l3) δppm; 1.14 (d, 6H, J=6.8H
z, -CH(CH3)2), 1.78(d,3H,J
=1.0Hz, CH3C=), 1.82(d,3H,
J=1.1Hz, CH3C=), 1.8-2.3(m
, 4H, -CH2CH2-), 2.50(hep, 1
H, J=6.8Hz, -CH(CH3)2), 4.3
2(t, 1H, J=7.0Hz, -CHCl-), 4
．． 90 (m, 1H, HaHbC=), 5.01 (s,
1H, HaHbC=), 6,26(bd,1H,J=
11.5Hz,=CHaHbC=), 6.78(dd
, 1H, J=11.5, 0.7Hz, =CHa-Hb
C=).

Example 2

[Chemical formula 12]

Allyl chloride (493mg, 1.96m
mol) and tetrabutylammonium acetate (71
0 mg, 2.36 mmol) of dimethylformamide (
3.0 ml) solution was heated to 90° C. for 6 hours under an argon atmosphere. After the reaction was completed, the reaction mixture was poured into ice water and extracted with diethyl ether, and the organic layer was washed with water and dried (MgSO4).
The residue obtained by concentration was purified by SiO2 column chromatography to obtain the desired secondary acetate (480 mg
, 89%) was obtained.

IR (film) cm-1; 2980,
2950, 2880, 2210, 1740, 1635,
1450, 1370, 1295, 1240, 1025,
905.1H-NMR (250MHz, CDCl3) δ
ppm; 1.13 (d, 6H, J=6.8Hz, -C
H(CH3)2), 1.70(s,3H,=CCH3
), 1.7-1.8(m,2H,-C(OAc)CH
2-), 1.80 (d, 3H, J=1.0Hz, =C
CH3), 2.04(s,3H,OAc), 2.0
-2.2(m,2H, -C(OAc)CH2CH2-)
, 2.49(hep, 1H, J=6.8Hz, -CH
(CH3)2), 4.89(m,1H,=CHaHb
), 4.93(bs,1H,=CHaHb), 5.
10 (t, 1H, J=6.7Hz, -CH(OAc))
, 6.23(dd, 1H, J=11.5, 1.2H
z, =CHa-CHb=), 6.78(dd, 1H,
J=11.5, 0.6Hz, =CHa-CHb=).

Reference example 1

[Chemical formula 13]

Acetate (317 mg, 1.15 mmo
To a solution of 1) in ethanol (2.0 ml) was added 0.6 ml of a 2N aqueous sodium hydroxide solution while stirring on an ice-water bath. After 2 hours, it was confirmed that the raw materials had disappeared, and most of the ethanol was distilled off under reduced pressure. Water and ether were added to the residue, the layers were separated, and the organic layer was dried (MgSO4) and concentrated. Si the residue
O2 column chromatography purification (developing solution, n-hexane: Et
OAc6:1) to obtain the desired product (263 mg, 98%).

IR (film) cm-1; 3450,
2980, 2950, 2880, 2210, 1640,
1450, 1390, 1295, 1030, 900. NMR (CDCl3, 250MHz) δppm; 1.
14(d, J=6.9Hz, 6H, -CH(CH3)2
), 1.6-1.75(m,2H,=CCH2CH2
-), 1.71(s,3H,=CCH3), 1.8
2 (d, J=1.0Hz, 3H,=CCH3), 2.
0-2.3(m,2H,=CCH2CH2-), 2.
50(hep, J=6.9Hz, 1H, -CH(CH3
)2), 4.03(t, J=6.3Hz, -CHOH
), 4.84, 4.94 (each bs, each 1H, C
=CH2), 6.27(dd, J=1.0, 11.5
Hz, =CH-CH=), 6.8 (d, J=11.5
Hz, =CH-CH=).

Synthesis Example 3

[Chemical formula 14]

2-(Diethylphosphono)-isovaleronitrile (8.72 g, 40 mmol) in toluene (75
ml) solution of potassium bis(trimethylsilyl)amide with stirring at −70° C. under an argon atmosphere.
75 ml of 5M toluene solution was gradually added, the bath was removed, and the mixture was stirred at room temperature for 30 minutes. Cool again to -70°C,
While stirring, add farnesal (5.88 g, 26.7 m
mol) was added, and the temperature was raised to room temperature. Water was added to the reaction mixture, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. After filtration, the residue obtained by concentration was subjected to silica gel column chromatography (developing solution, n-hexane: ethyl acetate =
100:1) to obtain the desired nitrile (7.2
3g, 96%, 2Z:2E=25.6:1) was obtained. 2
The spectral data of the Z-form is shown below.

IR (film) cm-1; 2980,
2940, 2210, 1640, 1450, 1390,
1290, 1225, 1110, 1030. NMR (CDCl3, 250MHz) δppm; 1.
14 (d, J=6.8Hz, 6H, CH(CH3)2)
, 1.58 (bs, 3H×2, -C=CCH3),
1.65 (bs, 3H, -C=CCH3), 1.81
(d, J=1.2Hz, 3H, -C=CCH3), 1
．． 9-2.2 (m, 8H, -CH2CH2-x2),
2.50(hep, J=6.8Hz, 1H, -CH(C
H3)2), 5.06 (m, 1H, =CHCH2-)
, 6.26, 6.80 (respectively d, J=11.5Hz
, each 1H, =CH-CH=).

Synthesis Example 4

[Chemical formula 15]

[0062] Nitrile compound (856 mg, 3.0 mmol
) was added with 6 ml of a 0.5M toluene solution of diisobutylaluminum hydride while stirring at -70°C under an argon atmosphere, and after 1 hour, 3 ml of water was added, the bath was removed, and the mixture was stirred well. . After the obtained white solid was filtered off, the filtrate obtained by washing was concentrated. This residue was dissolved in n-hexane (10 ml), mixed with 10% oxalic acid aqueous solution (5 ml), and stirred for 3 hours. The organic layer was extracted and separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. After concentration, it was subjected to silica gel column chromatography (developing solution, n-hexane:ethyl acetate = 10:1) to obtain the desired formyl compound (865 mg, 84%).

IR (film) cm-1; 2980,
2940, 2210, 1640, 1450, 1390,
1290, 1225, 1110, 1030. NMR (CDCl3, 250MHz) δppm; 1.
07(d, J=6.8Hz, 6H, -CH(CH3)2
), 1.59, 1.61, 1.67 (bs, respectively)
3H×3, -C=CCH3), 1.89(d, J=1
．． 0Hz, 3H, -C=CCH3), 2.0-2.2
(m, 8H, -CH2CH2- x 2), 2.91 (h
ep, J=6.8Hz, 1H, -CH(CH3)2),
5.10 (m, 1H, -C=CCH3), 6.81
, 7.16 (each d, J=12.0Hz, each 1H,
=CH-CH=), 10.29(s,1H,-CHO
).

Example 3

[Chemical formula 16]

61% calcium hypochlorite (2.58g
, 11 mmol) in a saturated aqueous solution of sodium sulfate (7.5
ml) to the suspension in conjugated dienenitrile (2.ml).
Add a solution of 85 g, 10 mmol) in methylene chloride (66 ml) and add dry ice (15 g, 10 mmol) while stirring vigorously.
) was added little by little. After filtering off the insoluble portion, the organic layer was separated, dried (MgSO4), and concentrated. Si the residue
It was purified by O2 column chromatography (developing solution, n-hexane:ethyl acetate 40:1) to obtain the desired chloride (2.69 g, 84%).

IR (film) cm-1; 2970,
2930, 2880, 2205, 1635, 1450,
1390, 1375, 1365, 1295, 1225,
1160, 1100, 1025, 905, 875. 1H-NMR (250MHz, CDCl3) δppm;
1.14(d, 6H, J=6.8Hz, -CH(CH
3)2), 1.59, 1.78(s, 3H each, =
CCH3), 1.81(d,3H,J=1.0Hz,
=CCH3), 1.8-2.1(m,4H,-CCl
CH2CH2C=), 2.1(m,4H,=CCH2
CH2C=), 2.50 (hep, 1H, J=6.8
Hz, -CH(CH3)2), 4.31(t, 1H,
J=7.2Hz, -CHCl-), 4.87(m, 1
H, HaHbC=), 4.97 (bs, 1H, HaH
bC=), 5.11(bm,1H,=CHCH2-)
, 6.26(bd,1H,J=11.5Hz,=CH
a-CHb=), 6.80 (dd, 1H, J=11.
5, 0.7Hz, =CHa-CHb=).

[0067]
Example 4

[Chemical formula 17]

The same reaction as in Example was carried out to obtain the desired secondary ester with a yield of 92%.

IR (film) cm-1; 2970,
2930, 2880, 2210, 1740, 1635,
1430, 1370, 1240, 1050, 1025,
910.1H-NMR (250MHz, CDCl3) δ
ppm; 1.14 (d, 6H, J=6.8Hz, -C
H(CH3)2), 1.58, 1.69 (s, each 3H, = CCH3), 1.6-1.8 (m, 2H, -
C(OAc)CH2-), 1.80(d,3H,J=
1.0Hz,=CCH3), 1.8-2.0(m,2
H, -C(OAc)CH2CH2-), 2.02(s
,3H,-OAc), 2.1(m,4H,=CCH2
CH2C=), 2.50(hep, 1H, -CH(C
H3)2), 4.86 (m, 1H, = CHaHb),
4.90 (bs, 1H, = CHaHb), 5.0-
5.2(m,2H,=CHCH2- and -CH(OAc)
-), 6.24 (bd, 1H, J=11.5Hz, =
CHa-CHb=), 6.79 (d, 1H, J=11.
5Hz, =CHa-CHb=).

Example 5

[Chemical formula 18]

Sodium hydride (60%, 30 mg, 0
．． 75 mmol) in dimethylformamide (0.7 ml
), thiophenol (98 mg, 0.89 mmol) was added while stirring on an ice-water bath under an argon atmosphere. After stirring for 30 minutes to obtain a homogeneous solution, secondary allyl chloride (240 mg, 0.75 mmol) was added and stirred well. After 20 minutes, ice water and ether were added, the layers were separated, and the organic layer was dried (MgSO4) and concentrated. The residue was subjected to SiO2 column chromatography (developing solution, n-
Purification was performed using hexane:ethyl acetate (25:1) to obtain the desired sulfide (261 mg, 88%).

IR (film) cm-1; 3080,
2970, 2930, 2870, 2205, 1635,
1580, 1435, 1385, 1370, 1290,
1220, 1090, 1070, 1025, 895. 1H-NMR (250MHz, CDCl3) δppm;
1.17(d, 6H, J=6.8Hz, -CH(CH
3)2), 1.60, 1.77(s, 3H each, =
CCH3), 1.7-1.90(m, 2H, -C(S
ph)CH2-), 1.83(d,3H,J=1.1
Hz,=CCH3), 2.06(bt,2H,J=7
．． 6Hz, -C(Sph)CH2CH2-), 2.5
2(hep, 1H, J=6.8Hz, -CH(CH3)
2), 3.58 (dd, 1H, J=8.4, 6.6H
z, -CH(Sph)-), 4.61(bs, 1H,
=CHaHb), 4.73(m, 1H, =CHaHb
), 5.11(bm,1H,=CHCH2-), 6
．． 28 (bd, 1H, J = 11.5Hz, = CHa-C
Hb=),6.81(d,1H,J=11.5Hz,=
CHa-CHb=), 7.2-7.4(m, 5H, -
Sph).

Example 6

[Chemical formula 19]

Sulfide (255 mg, 0.65 mmo
An aqueous solution of sodium metaperiodate (166 mg, 0.78 mmol) was added to a methanol (1.5 ml) solution of 1), and the mixture was stirred at room temperature for 3 days. Methanol was distilled off under reduced pressure, ether and water were added to the residue, the layers were separated, and the organic layer was dried (MgSO4) and concentrated. The crude product was subjected to SiO2 column chromatography (developing solution, n-hexane:ethyl acetate 7:1) to obtain the desired product, a sulfone compound (200 mg, 74%).

IR (film) cm-1; 3070,
2970, 2930, 2880, 2205, 1635,
1585, 1445, 1390, 1305, 1150,
1085, 1025, 910. 1H-NMR (250MHz, CDCl3) δppm;
1.17(d, 6H, J=6.8Hz, -CH(CH
3)2), 1.54, 1.79, 1.83(s,
3H,=CCH3), 1.8-2.1(m, 4H
, -C(Sph)CH2CH2-), 2.15(m,
4H,=CCH2CH2C=), 2.53(hep,
1H, J=6.8Hz, -CH(CH3)2), 3.
50 (dd, 1H, J=11.0, 3.0Hz, -C
HS(O)ph), 4.70, 5.06 (s, each 1H, =CH2), 5.06 (bm, 1H, =CHCH
2-), 6.27 (bd, 1H, J=11.5Hz,
=CHa-CHb=), 6.82(d, 1H, J=1
1.5Hz, =CHa-CHb=), 7.5-7.9
(m,5H,-S(O)ph).

Example 7

[C20]

Chlor compound (182 mg, 0.57 mmol
) was added with 0.5 ml of a 50% dimethylamine aqueous solution in ethanol (1.5 ml) and left at room temperature for 2 days. Excess dimethylamine and ethanol were distilled off under reduced pressure, and ether and 1N aqueous sodium hydroxide solution were added. The organic layer was dried (MgSO4) and the residue obtained by concentration was SiO2.
Purified by chromatography (developing solution, n-hexane: ethyl acetate 1:1) to obtain the target amine (130 mg, 70
%) was obtained.

IR (film) cm-1; 2970,
2950, 2880, 2820, 2780, 2210,
1635, 1465, 1450, 1390, 1365,
1150, 1100, 1045, 1025, 900. 1H-NMR (250MHz, CDCl3) δppm;
1.6(d, 6H, J=6.8Hz, -CH(CH3
)2), 1.58, 1.63(s, each 3H, =C
CH3), 1.6-2.1(m,4H,C(NMe2
)CH2CH2-), 1.80 (d, 3H, J=1.
0Hz,=CCH3), 2.15(m,4H,=CC
H3), 2.17(s,6H,-NMe2), 3.
36 (dd, 1H, J=10.5, 4.0Hz, -C
H(NMe2)), 2.50(hep, 1H, J=6
．． 8Hz, -CH(CH3)2), 4.76(bs,
1H,=CHaHb), 4.84(m,1H,=CH
aHb), 5.05(bm,H,=CHCH2-),
6.25(bd,1H,J=11.5Hz,=CHa
-CHb=), 6.79 (d, 1H, J=11.5Hz
,=CHa−CHb=).

Reference example 2

[C21]

Allyl alcohol compound (470 mg, 2.0
2 mmol) and 3,3-dimethoxy-2-methyl-2-
In a mixture of butanol (1.48 g, 10 mmol),
2,4-dinitrophenol (28 mg, 0.15 mm
ol) and placed on an oil bath at 140°C under an argon atmosphere.
Heated for 5 hours. After cooling, the excess reagent was distilled off under reduced pressure, and the residue was subjected to SiO2 column chromatography (developing solution, n-
Purification was performed using hexane:ethyl acetate (6:1) to obtain the desired α-hydroxyketone (609 mg, 95%).

IR (film) cm-1; 3520,
2990, 2950, 2890, 2220, 1715,
1640, 1470, 1450, 1370, 1165,
1075, 1025, 965. NMR (CDCl3, 250MHz) δppm; 1.
14(d, J=6.8Hz, 6H, -CH(CH3)2
), 1.35(s,6H,-C(CH3)2OH),
1.61 (s, 3H, = CCH3), 1.80 (d,
J=1.2Hz,=CCH3), 2.1(m,4H,
=CCH2CH2C=), 2.26 (bt, J=7.
5Hz, 2H, -CH2CH2-O), 2.50(h
ep, J=6.8Hz, 1H, -CH(CH3)2),
2.63(t, J=7.5Hz, 2H, -CH2C=
O), 5.09 (bm, 1H, =CHCH2-),
6.24 (dd, J=0.8, 11.5Hz, 1H,
=CH-CH=), 6.79(dd, J=0.7,
11.5Hz, 1H, =CH-CH=).

[0082]
Reference example 3

[C22]

α-Hydroxyketone body (93.3 mg,
0.29 mmol) in methanol (4 ml) was added 5.5 mg of sodium borohydride while stirring on an ice-water bath. After stirring at the same temperature for 2 hours, methanol was distilled off under reduced pressure, diethyl ether and water were added, and the organic layer was washed with water, dried, and concentrated. The resulting residue was subjected to SiO2 column chromatography (developing solution, n-hexane: ethyl acetate 3:1
~2:1) to obtain the desired α-diol (8
1.7 mg, 87%) was obtained.

IR (film) cm-1; 3450,
2970, 2930, 2870, 2210, 1635,
1450, 1385, 1290, 1220, 1160,
1075, 1015, 915. NMR (CDCl3, 250MHz) δppm; 1.
12, 1.16 (each s, each 3H, -C(CH3)
2OH), 1.13 (d, J=6.8Hz, 6H, -
CH(CH3)2), 1.3-1.7(m,2H,=
CCH2CH2CHOH), 1.59 (d, J=0.
6Hz, 3H, = CCH3), 1.80 (d, J = 1
．． 1Hz, 3H, =CCH3), 2.0-2.3(m
,6H,=CCH2CH2CHOH, -CCH2CH2
C=), 2.49(hep, J=6.8Hz, 1H,
-CH(CH3)2), 3.30 (bd, J=10.
3Hz, 1H, -CHOH), 5.13(bm, 1H
,=CHCH2-), 6.23(dd, J=0.7,
11.5Hz, 1H, =CH-CH=), 6.79
(dd, J=0.6, 11.5Hz, 1H,=CHa
-CHb=).

Reference example 4

[C23]

α-diol (503mg, 1.58m
mol) in methanol (15 ml) was added sodium metaperiodate (450 mg, 2.1 mmol) and stirred at room temperature for 1 day. Methanol was distilled off under reduced pressure, and the whole was dissolved in diethyl ether and water. The organic layer was washed with water, dried (MgSO4), and concentrated. The resulting residue was subjected to SiO2 column chromatography (developing solution, n-hexane: ethyl acetate 10: 1) to obtain the desired formyl compound (348
mg, 85%) was obtained.

IR (film) cm-1; 2970,
2930, 2720, 2200, 1725, 1630,
1440, 1385, 1020. NMR (CDCl3, 250MHz) δppm; 1.
14(d, J=6.9Hz, 6H, -CH(CH3)2
), 1.60 (d, J=0.6Hz, 3H,=CCH
3), 1.79 (d, J=1.0Hz, 3H,=CC
H3), 2.14(m,4H,=CCH2CH2C=
), 2.30 (bt, J=7.4Hz, 2H, -CH
2CH2CHO), 2.4-2.6(m, 3H, -C
H2CHO, -CH(CH3)2), 6.23(d,
J=10.2Hz, 1H, =CH-CH=), 6.7
9 (dd, J=0.8, 10.2Hz, 1H, =CH-
CH=), 9.72 (t, J=1.8Hz, 1H, -
CHO).

Reference example 5

[C24]

[0089] Formyl compound (130 mg, 0.5 mmol
) in methylene chloride solution (4 ml) was added ethoxycarbonylethylidene triphenylphosphorane (217 mg, 0
．． 6 mmol) was added thereto, and the mixture was stirred at room temperature for 5 hours under an Ar atmosphere. The residue obtained by distilling off methylene chloride under reduced pressure was
2 column chromatography (developing solution, n-hexane:
Ethyl acetate 5:1) to obtain the desired ester form 168m
g (97%) was obtained.

IR (film) cm-1; 2970,
2930, 2880, 2210, 1710, 1640,
1445, 1390, 1365, 1270, 1180,
1120, 1095, 1080, 1025. NMR (CDCl3, 250MHz) δppm: 1.1
4 (d, J=6.8Hz, 6H, -CH(CH3)2)
, 1.26 (t, J=7.2Hz, 3H, -CH2CH
3), 1.60 (d, J=0.7Hz, 3H,=CCH
3), 1.805, 1.809 (each s, each 3H, =
CCH3), 2.0-2.3(m, 8H, -CH2CH
2-), 2.50 (hep, J=6.8Hz, 1H,-
CH(CH3)2), 4.16(q, J=7.2Hz,
2H, -CH2CH3), 5.1(m, 1H, =CHC
H2-), 6.26 (d, J=11.5Hz, 1H,=
CH-CH=), 6.71 (tq, J=7.3, 1.4
Hz, 1H, = CHCH2-), 6.80 (dd, J =
0.7, 11.5Hz, 1H, =CH-CH=).

0
091 Reference example 6

[C25]

Cyanoester (175mg, 0.51
To a toluene (5 ml) solution of 1M diisobutylaluminum hydride (2.1 ml, 2.1 mmol) was gradually added dropwise at -70°C under an argon atmosphere. After stirring at the same temperature for 2 hours, an oxalic acid aqueous solution (1M, 4.2 ml) was added to create an argon atmosphere again, and the mixture was heated to room temperature over about 2 hours while stirring. After confirming the completion of hydrolysis by liquid chromatography, the organic layer was washed with water and a saturated aqueous sodium bicarbonate solution, and the residue obtained by drying, filtration, and concentration was purified with SiO2.
It was prepared by column chromatography (developing solution, n-hexane: ethyl acetate 7:1) to obtain the desired hydroxyformyl compound (123 mg, 79%).

IR (film) cm-1; 3430,
2960, 2920, 2870, 1670, 1630,
1450, 1390, 1295, 1230, 1130,
1070, 1010. NMR (CDCl3, 250MH
z) δppm; 1.04 (d, 6H, J=6.8Hz
, -CH(CH3)2), 1.59(d,3H,J=
0.6Hz, -CH3-C=), 1.63(bs, 3
H, -CH3-C=), 1.86 (d, 3H, J=1
．． 2Hz, -CH3-C=), 1.7-2.2(m,
8H, -CH2CH2-), 2.88(hep, 1H
, J=6.8Hz, -CH(CH3)2), 3.95
(bs, 2H, -CH2OH), 5.09 (m, 1H
, -CH2CH=), 5.38 (bt, 1H, J=6
．． 8Hz, -CH2CH=), 6.80(d, 1H,
J=12.0Hz, =CH-CH=), 7.11(d
, 1H, J=12.0Hz, =CH-CH=), 10
．． 25(s, 1H, -CHO).

Reference example 7

[C26]

Dry lithium chloride (64 mg, 1.5
mmol), 2,6-lutidine (0.23ml, 2.0
mmol), and hydroxyformyl compound (305 mg
, 1.0 mmol) of dimethylformamide (1.0 m
l) The solution was cooled on ice water and methanesulfonyl chloride (160 mg, 1.4
mmol) was added. After about 8 hours, disappearance of the raw material was confirmed, and the entire solution was dissolved in water and ether. The organic layer was washed with water, dried (MgSO4), and concentrated, and the resulting residue was purified by SiO2 column chromatography (developing solution, n-hexane: ethyl acetate 15:1) to obtain the target compound F (281 m
g, 87%) was obtained.

IR (film) cm-1; 2970,
2930, 2880, 1670, 1630, 1445,
1390, 1295, 1265, 1135. NMR (CDCl3, 250MHz) δppm; 1.
04(d, J=7.0Hz, 6H, -CH(CH3)2
), 1.59, 1.70 (each bs, each 3H, -
C=CCH3), 1.87(d, J=1.3Hz, 3
H, -C=CCH3), 1.9-2.2(m, 8H,
-CH2CH2-), 2.89 (hep, J=7.0
Hz, 1H, -CH(CH3)2), 3.98(bs
, 2H, -CH2Cl), 5.09(m, 1H, -C=
CHCH2-), 5.47 (bt, J=6.5Hz,
1H, -C=CHCH2-), 6.82 (d, J=1
2.0Hz, 1H, -C=CH-CH=C(CHO)-
), 7.11 (d, J=12.0Hz, -C=CH-
CH=C(CHO)-), 10.27(s,1H,-
CHO).

Reference example 8

[C27]

The same reaction as in Reference Example 1 was carried out to obtain the desired allyl alcohol compound with a yield of 97%.

IR (film) cm-1; 3380,
2990, 2950, 2895, 2220, 1635,
1450, 1390, 1295, 1060, 1025,
900. NMR (CDCl3, 250MHz) δppm
; 1.14(d, J=6.8Hz, 6H, -CH(C
H3)2), 1.60(s,3H,=CCH3),
1.6-1.7(m, 2H, -CH(OH)CH2-)
, 1.70(s,3H,=CCH3), 1.81(
d, J=1Hz, 3H,=CCH3), 1.9-2.1
(bm, 2H, -CH(OH)CH2CH2-), 2
．． 15 (m, 4H, =CCH2CH2C=), 2.5
0(hep, 1H, J=6.8Hz, -CH(CH3)
2), 4.01 (bm, -CH(OH)-), 4.8
1 (m, 1H, -C=CHaHb), 4.91 (bs
, 1H, -C=CHaHb), 5.11(bm, 1H
, =CH-(CH2)2-), 6.25(bd,J=
11.5Hz, 1H, =CHa-CHb=), 6.8
0 (d, J=11.5Hz, 1H, -CHa-CHb)
．．

Reference example 9

[C28]

[0101] Allyl alcohol compound (117 mg, 0.3
Dissolve thionyl chloride (0.029 mmol) in diethyl ether (1.0 ml) and stir on an ice-water bath.
ml, 0.40 mmol) was added. After 3 hours, the solvent was distilled off under reduced pressure, and the residue was subjected to SiO2 column chromatography (developing solution: n-hexane:ethyl acetate 10:1) to obtain the desired chloride (112 mg, 90%).

IR (film) cm-1; 2980,
2940, 2880, 2215, 1635, 1445,
1390, 1265, 1025. NMR (CDCl3, 250MHz) δppm; 1.
14 (d, J=6.8Hz, 6H, CH(CH3)2)
, 1.59, 1.64 (each bs, each 3H, -C
= CCH3), 1.81 (d, J=1.0Hz, 3H
, -C=CCH3), 1.9-2.2(m,8H, -
CH2CH2−×2), 2.50 (hep, J=6.8
Hz, 1H, -CH(CH3)2), 3.96(bs
, 2H, -CH2OH), 5.08(m, 1H, -C
HCH2-), 5.36 (bt, J=5.5Hz, 1
H, =CHCH2-), 6.25, 6.80 (respectively d, J=11.5Hz, each 1H, =CH-CH=).

Reference example 10

[C29]

[0104] Alcohol (904 mg, 3.0 mmo
Triphenylphosphine (1.02 g, 3.9 mmol) was added to a solution of 1) in carbon tetrachloride (2 ml) and heated under reflux for 1 hour. After most of the carbon tetrachloride was distilled off under reduced pressure, n-hexane was added to the residue, and after filtration and washing, the filtrate was concentrated and the resulting residue was subjected to silica gel column chromatography (developing solution, n-hexane: ethyl acetate = 10 :1) to obtain the desired chloride (890 mg, 93%).

Reference example 11

[C30]

Sulfoxide (70.3 mg, 0.17 m
mol) and trimethylphosphite (43 mg, 0.3
A solution of 5 mmol) in methanol (0.5 ml) was left at room temperature for 3 days under an argon atmosphere. Methanol was distilled off under reduced pressure, and the residue was subjected to SiO2 column chromatography (developing solution, n-hexane: ethyl acetate 6:1) to obtain the desired alcohol (37.1 mg, 72%).

IR (film) cm-1; 3450,
2975, 2930, 2880, 2210, 1635,
1445, 1385, 1220, 1020. NMR (CDCl3, 250MHz) δppm; 1.
17 (d, J=6.7Hz, 6H, CH(CH3)2)
, 1.62, 1.67 (each bs, each 3H, -C
= CCH3), 1.84 (d, J=1.2Hz, 3H
, -C=CCH3), 2.0-2.2(m,8H,-
CH2CH2−×2), 2.53(hep, J=6.7
Hz, 1H, -CH(CH3)2), 3.99(bs
, 2H, -CH2OH), 5.11(m, 1H, -C
HCH2-), 5.39 (bt, J=5.5Hz, 1
H, -CHCH2-), 6.28, 6.83 (each d, J=11.5Hz, each 1H, =CH-CH=).

Reference example 12

[Chemical formula 31]

Nitrile compound (890 mg, 2.78 mmo
1) was dissolved in 30 ml of n-hexane, and 4.2 ml of a 1M toluene solution of diisobutylaluminum hydride was gradually added dropwise at -70°C under an argon atmosphere. After 1 hour, 2 ml of water was added, the bath was removed and the mixture was stirred vigorously. The resulting white solid was filtered and washed with n-hexane, and the resulting filtrate was further stirred with a 10% aqueous oxalic acid solution. After washing, drying, filtering and concentrating the organic layer, it was subjected to silica gel column chromatography (developing solution, n-hexane: ethyl acetate = 20:1) to obtain compound (F) (781 mg, 8
7%).

Reference example 13

[C32]

Compound F (640 mg, 2.0 mmol)
Trimethylsilylnitrile (0.35ml, 2.6m
A very small amount of potassium cyanide/18-crown 6-
Added ether complex. After 2 hours, it was confirmed that the raw material had disappeared, and the excess trimethylsilylnitrile was distilled off to obtain the crude target product (
647 mg, quantitative) was obtained.

IR (film) cm-1; 2960,
2930, 2880, 2320, 1445, 1255,
1080,875,845. NMR (CDCl3, 250MHz) δppm; 1.
11, 1.15 (each d, J = 6.9Hz, each 3H
, -CH(CH3)2), 1.60, 1.71,
1.77 (each s, each 3H, -C=CCH3), 1
．． 9-2.2 (m, 8H, -CH2CH2-), 2.
64(hep, J=6.9Hz, 1H, -CH(CH3
)2), 3.99(s,1H,-CH2Cl), 5
．． 11 (m, 1H, -C=CHCH2-), 5.33
(s, 1H, -CHCN), 5.48 (bt, J=6
．． 5Hz, 1H, -C=CHCH2-), 6.04,
6.25 (each d, J=11.3Hz, each 1H, -
C=CH-CH=C-).

Reference example 14

[Chemical formula 33]

Under an argon atmosphere, a solution of lithium hexamethyldisilazide in tetrahydrofuran (20 ml, 5.
0 mmol, 0.25 M) was stirred on a 55°C oil bath, and the starting material (378 mg, 0.895 mmol) was added to this solution.
A tetrahydrofuran solution (15 ml) of was added dropwise over 50 minutes. After stirring at this temperature for 20 minutes, the reaction solution was poured into a mixture of saturated brine (30 ml) and hexane (20 ml) containing ice (50 g) to stop the reaction. After separating the organic layer, the aqueous layer was diluted with hexane-ether (5:1, 30m
The extract obtained in step 1) was dried (Na2SO4), the solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography to yield the desired product (288 mg, 83%) and the ketone body (42.9 mg, 0.11 mmol). , 16%) was obtained. The physical properties of the target object are as follows.

IR (film) cm-1; 2970,
2920, 1440, 1385, 1253, 1125,
1085,940,845,755. PMR (CDCl3, 250MHz) δppm; 0.
23(s,9H,-SiMe3), 1.09, 1.1
5 (respectively d, J = 6.7Hz, each 3H, -CH (CH
3) 2), 1.50, 1.62 (each bs, each 3
H, -C=CCH3), 1.70 (d, J=1.3H
z, 3H, -C=CCH3), 2.0-2.2(m,
8H, -CH2CH2×2), 2.51(sep, J
=6.7Hz, 1H, -CH(CH3)2), 2.5
5, 2.65 (each d, J = 14.2Hz, each 1H
, -CHaHbCN-), 4.94 (bt, J=6.
1Hz, 1H, -C=CHCH2-), 5.15(b
t, J=5.6Hz, 1H, -C=CHCH2-),
6.17, 6.44 (each d, J=11.8Hz, each 1H, -C=CH-CH=C-).

Reference example 15

[C34]

Under an argon atmosphere, the starting material (288 mg
, 0.74 mmol) in tetrahydrofuran solution (10
ml) and water (0.3 ml) and a solution of tetrabutylammonium fluoride in tetrahydrofuran (16 μl, 0.3 ml).
016 mmol, 1.0 M) was added. After stirring the reaction solution at room temperature for 17 hours, saturated brine (10 ml) was added, and the organic matter was dissolved in hexane-ether (5:1, 30 ml x 2).
) was extracted. After drying the extract (Na2SO4), the solvent was distilled off under reduced pressure to obtain the target macrocyclic ketone (200
mg, 94%) was obtained.

Reference example 16

[C35]

Under an argon atmosphere, a diethyl ether solution of lithium aluminum hydride (2.94 ml, 2.0
mmol, 0.68M), and (S)-2-
(2,6-xylidinomethyl)pyrrolidine (490mg
, 2.4 mmol) was slowly added dropwise at room temperature, and 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 a macrocyclic ketone (69 mg,
A diethyl solution (3 ml) of 0.24 mmol) was added dropwise over 10 minutes. After stirring at -74°C for 1 hour, a saturated aqueous sodium sulfate solution (1 ml) was added, and the mixture was stirred for a while at room temperature. diethyl ether (10 ml) and dilute hydrochloric acid (
After separating the organic layer, the aqueous layer was extracted with diethyl ether (20 ml). Pour the extract into saturated saline (
After washing with 20 ml) and drying over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain optically active sarcophytol A (61 mg, 88%).

The optical purity of the optically active sarcophytol A obtained was determined by HPL using CHIRALCELL OD.
C analysis revealed that it was 93%. [α]24
D: +204.4° (C=0.27, CHCl3)

0
121]

INDUSTRIAL APPLICABILITY The compound of the present invention is extremely useful as a synthetic intermediate for sarcophytol A, which has anti-carcinogenic promoter activity and anti-tumor activity.

Claims (1)

[Claims] Claim 1: The following general formula (I) [Formula 1] [wherein, X is a chlorine atom, -OC(O)R1(R
1 represents a hydrogen atom, a C1 to C4 alkyl group, or a phenyl group which may have a substituent), -SR2, -S
(O)R2 (R2 represents a C1-C4 alkyl group or a phenyl group which may have a substituent), -NR3R
4, -N(O)R3R4 (R3 and R4 each independently represent a C1-C4 alkyl group or an alkyl group formed together to form a ring), R is a cyano group,
It represents a formyl group or -C(O)OR5 (R5 represents a C1-C4 alkyl group), and n represents 0 or 1. However, when n is 0, X is a chlorine atom or -OC(O)R
Represents 1. ] Chained terpenes.