JPH04316523A - Optically active dodecane derivative - Google Patents

Abstract

PURPOSE:To obtain an optically active dodecane derivative useful for producing (S) type phytol by using citronellal, a readily obtainable optically active starting substance and treating citronellal through new intermediates while maintaining chirality of citronellal. CONSTITUTION:A compound shown by formula I [R1 to R4 are 1-4C alkyl; R5 is group shown by formula II (A is halogen or A and B are bonded to form carbon-carbon bond; B is H or bonded to A; E is H or 1-4C hydroxy lower alkyl); steric configuration in chiral central carbon atom provided with water is independently and alternatively one of S-configuration and R-configuration] such as methyl(R)-(E)-5,9-dimethyl-2,8-decadienoate. A compound shown by formula III (X11 is halogen), one of compounds shown by formula I, is obtained by passing a diene compound shown by formula IV as a starting compound through partially new 13 intermediates including a compound shown by formula V, an important intermediate.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to optically active dodecane derivatives, intermediates thereof, and methods for producing them.

0002

BACKGROUND OF THE INVENTION Natural phytol is an optically active compound, as shown in the structural formula in Example 15 below, and is useful as an intermediate raw material for various pharmaceuticals or agricultural chemicals, particularly for vitamin E. In the prior art, optically active phytol was obtained by extracting it from natural products such as plant leaves, resulting in variations in quality and yield. Furthermore, with conventional chemical synthesis methods, it was difficult to control chirality, and optical resolution was required.

0003

[Problems to be Solved by the Invention] The purpose of the present invention is to use an easily available optically active starting material, citronellal, to obtain a product with a purity of 100% ee through an intermediate compound with a purity of 100% ee while preserving its chirality. The object of the present invention is to provide a means by which phytol of ee can be easily synthesized.

0004

[Means for Solving the Problems] According to the present invention, the above-mentioned object is achieved by

[0005]

[C5]

[In the formula, R1, R2, R3 and R4
each independently represents a lower alkyl group having 1 to 4 carbon atoms (
For example, methyl group, ethyl group, propyl group or butyl group), and R5 is of the general formula (I') -C(A)=C(B)-E

(I') (wherein A is a halogen atom, such as a chlorine atom, a bromine atom or an iodine atom, or together with B is a direct carbon-carbon bond, and B is a hydrogen atom or together with A (E is a hydrogen atom or a hydroxy lower alkyl group having 1 to 4 carbon atoms, such as a hydroxymethyl group or a hydroxyethyl group)
is a group represented by the formula, and the configuration at the chiral central carbon atom marked with * in the formula shall each independently and alternatively take only one of the S-configuration and R-configuration. ] This can be achieved by a compound represented by:

The present invention also provides a method for producing the above-mentioned compound. The manufacturing method consists of the following steps (a) to (t).

(a) General formula (XII)

[0009]

[C6]

[0010] One double bond of the diene compound represented by the formula (wherein R1, R2, R3 and * have the same meanings as above) is regio- and ethynthio-selectively epoxidized to obtain the general formula (IIa).

[0011]

[C7]

A step of obtaining an optically active hydroxyepoxy compound represented by the formula (in which R1, R2, R3 and * have the same meanings as above) (that is, while preserving the steric configuration).

(b) The optically active hydroxyepoxy compound represented by the general formula (IIa) is treated with a sulfonic acid derivative (for example, sulfonic acid chloride) to form the optically active hydroxyepoxy compound represented by the general formula (IIa).
b)

[0014]

[Chemical formula 8]

(wherein, X21 is a group capable of using a hydroxyl group as a leaving group, preferably a para-toluenesulfonyl group or a methanesulfonyl group,
, R3 and * have the same meanings as above) (that is, while preserving the configuration), obtaining an optically active sulfonic acid esterified epoxy compound.

(c) The optically active protected hydroxyepoxy compound represented by general formula (IIb) is treated with a halogenating agent to form general formula (IIc).

[0017]

[Chemical formula 9]

(In the formula, X22 is a halogen atom, for example,
A chlorine atom, a bromine atom or an iodine atom, and R1, R
2, R3 and * have the same meanings as above) A step of obtaining an optically active halogenated epoxy compound (that is, preserving the configuration).

(d) Instead of the two-step method of steps (b) and (c), the following one-step method is used, namely, the general formula (IIa
) is treated with a halogenating agent to obtain a corresponding optically active halogenated epoxy compound represented by general formula (IIc) (i.e., preserving the configuration) Process.

(e) The optically active halogenated epoxy compound represented by general formula (IIc) is treated with a strong base to form general formula (IIIa).

[0021]

[Chemical formula 10]

A step of obtaining an optically active hydroxyalkyne compound represented by the formula (in which R1, R2, R3 and * have the same meanings as above) (that is, while preserving the steric configuration).

(f) An optically active hydroxyalkyne compound represented by general formula (IIIa) is treated with a trialkylsilylating agent to form general formula (IIIb).

[0024]

[Chemical formula 11]

[In the formula, , R2, R3 and * have the same meanings as above] (that is, while preserving the steric configuration) to obtain an optically active protected hydroxyalkyne compound.

(g) The optically active protected hydroxyalkyne compound represented by general formula (IIIb) is treated with an alkylating agent to form general formula (IIIc).

[0027]

[Chemical formula 12]

(wherein, X31, R1, R2, R3
, R4 and * have the same meanings as above) (that is, while preserving the steric configuration) to obtain an optically active alkylated alkyne compound.

(h) The optically active alkylated alkyne compound represented by the general formula (IIIc) is treated with a desilylating agent to form the general formula (IIId).

[0030]

[Chemical formula 13]

(In the formula, R1, R2, R3, R4
and * have the same meaning as above).
That is, a step of obtaining an optically active alkylated hydroxyalkyne compound while preserving the steric configuration.

(i) The optically active alkylated alkyne compound represented by the general formula (IIId) is treated with a reducing agent to form the general formula (IIIe).

[0033]

[Chemical formula 14]

(In the formula, R1, R2, R3, R4
and * have the same meaning as above).
That is, a step of obtaining an optically active alkylated hydroxy-cis- or trans-configured alkene compound (with steric configuration preserved).

(j) An optically active alkylated hydroxyalkene compound represented by general formula (IIIe) is treated with orthoacetic ester to form general formula (IV).

[0036]

[Chemical formula 15]

(wherein R41 is a lower alkyl group having 1 to 4 carbon atoms, for example, the group listed for the group R1 above, and R1, R2, R3, R4 and * have the same meanings as above) A step of obtaining an optically active γ,δ-unsaturated ester compound corresponding to (ie, preserving the configuration) as shown.

(k) The optically active γ,δ-unsaturated ester compound represented by the general formula (IV) is reduced to form the general formula (
V)

[0039]

[Chemical formula 16]

(In the formula, R41, R1, R2, R3
, R4 and * have the same meanings as above) (that is, while preserving the steric configuration) to obtain an optically active saturated ester compound.

(l) The optically active saturated ester compound represented by general formula (V) is treated with lithium aluminum hydride to form general formula (VI).

[0042]

[Chemical formula 17]

(In the formula, R1, R2, R3, R4
and * have the same meaning as above).
That is, a step of obtaining an optically active saturated alcohol compound while preserving the steric configuration.

(m) An optically active saturated alcohol compound represented by general formula (VI) is treated with a halogenating agent to form general formula (VII).

[0045]

[Chemical formula 18]

(In the formula, X71 is a halogen atom, preferably a chlorine atom, a bromine atom or an iodine atom, and R1,
R2, R3, R4 and * have the same meanings as above)
A step of obtaining an optically active saturated halogen compound represented by (that is, preserving the configuration).

(n) An optically active saturated halogen compound represented by general formula (VII) is treated with acetoso n,n-dimethylhydrazone to form general formula (VIII).

0048
]

[Chemical formula 19]

(In the formula, R1, R2, R3, R4
and * have the same meaning as above).
That is, a step of obtaining an optically active ketone compound while preserving the steric configuration.

(o) An optically active ketone compound represented by general formula (VIII) is treated with a halogenating agent to form general formula (Ia).

[0051]

[C20]

(In the formula, X11 is a halogen atom, for example,
A chlorine atom, a bromine atom or an iodine atom, and R1, R
2, R3, R4 and * have the same meanings as above)
A step of obtaining an optically active alkene compound corresponding to (that is, preserving the configuration) represented by

(p) The optically active alkene compound represented by general formula (Ia) is treated with a strong base to form general formula (Ib).

[0054]

[C21]

(In the formula, R1, R2, R3, R4
and * have the same meaning as above).
That is, a step of obtaining an optically active alkyne compound while preserving the steric configuration.

(q) An optically active alkyne compound represented by general formula (Ib) is treated with paraformaldehyde in the presence of a strong base to form general formula (Ic).

[0057]

[C22]

(In the formula, R1, R2, R3, R4
and * have the same meaning as above).
That is, a step of obtaining an optically active hydroxyalkylated alkyne compound while preserving the steric configuration.

(r) An optically active hydroxyalkylated alkyne compound represented by general formula (Ic) is treated with aluminum hydride [for example, sodium bis(2-methoxyethoxy)aluminum hydride] and then with a halogen, for example, iodine. Then, the general formula (Id)

[0060]

[C23]

(In the formula, X12 is a halogen atom, for example,
A chlorine atom, a bromine atom or an iodine atom, and R1, R
2, R3, R4 and * have the same meanings as above)
A step of obtaining an optically active halogenated alkene compound corresponding to (that is, preserving the configuration) represented by

(s) An optically active halogenated alkene compound represented by general formula (Id) is treated with lithium dialkyl cuporate to form general formula (IX).

[0063]

[C24]

(wherein R91 is a lower alkyl group having 1 to 4 carbon atoms, for example, the group listed for the group R1 above, and R1, R2, R3, R4 and * have the same meanings as above) A step of obtaining an optically active phytol compound corresponding to (ie, preserving the configuration) as shown.

(t) Instead of the three-step method of steps (q) to (s), the following one-step method is used: an optically active alkyne compound represented by the general formula (Ib) is mixed with a metallocene chloride (for example, , zirconocene dichloride or titanocene dichloride) and a trialkylaluminum (e.g. trimethylaluminum), followed by treatment with an alkyllithium (e.g. n-butyllithium) and further treatment with a carbonyl compound (e.g. paraformaldehyde). Then, the corresponding (
That is, a step of obtaining an optically active phytol compound while preserving the steric configuration.

[0066] Hereinafter, the above steps (a) to (t) will be explained in order. Step (a) The starting material, the diene compound represented by general formula (XII), is a known compound, and can be prepared from a known optically active citronellal compound by a known method while preserving its steric configuration. . This diene compound (XI
The epoxidation of I) can be carried out, for example, under an inert gas (e.g. argon or nitrogen gas) atmosphere at low temperatures (e.g. -
l(-) or d(-) tartrate and titanium isobutyl oxide 2-dibutylhydro in an aprotic solvent (e.g. methylene chloride) at 30-0°C, especially -15--10°C). Using peroxide, 4a
It can be carried out in the presence of molecular sieves. In this step (a), the starting material/diene compound (
The configuration of one chiral central carbon atom in XII) remains unchanged in the hydroxyepoxy compound (IIa). Furthermore, two chiral centers are newly generated at the epoxy group bonding site. The configuration of these chiral central carbon atoms is determined by the starting material/diene compound (XI
It can be formed independently of the configuration of the chiral central carbon atom present in I). The obtained hydroxyepoxy compound (IIa) is purified as necessary (for example, by silica gel column chromatography treatment)
and used in the next step (b).

Step (b) As the hydroxy group-protecting group-introducing agent, a sulfonic acid esterifying agent such as para-toluenesulfonium chloride can be used. This reaction can be carried out, for example, in an aprotic solvent (e.g. the base methylene) at room temperature (e.g. -10°C to room temperature, especially room temperature) under an inert gas (e.g. argon or nitrogen gas) atmosphere. can be carried out using para-toluenesulfonium chloride in the presence of triethylamine and 4,4-dimethylaminopyridine. In this step (b), the steric configuration of the three chiral central carbon atoms in the hydroxyepoxy compound (IIa) remains unchanged in the protected hydroxyepoxy compound (IIb). The obtained protected hydroxyepoxy compound (IIb) is purified if necessary (e.g., silica gel column chromatography treatment)
and used in the next step (c).

Step (c) As the halogenating agent, for example, lithium chloride can be used. This reaction is carried out under an inert gas (e.g., argon or nitrogen gas) atmosphere at room temperature to high temperature (e.g., room temperature to 100°C, particularly 50 to 80°C).
It can be carried out in an aprotic polar solvent such as dimethylformamide. In this step (c), 3 in the protected hydroxyepoxy compound (IIb)
The configuration of the chiral central carbon atoms remains unchanged in the halogenated epoxy compound (IIc). The obtained halogenated epoxy compound (IIc) is purified if necessary (for example, by silica gel column chromatography treatment) and used in the next step (e).

Step (d) From the hydroxyepoxy compound (IIa) to the above step (
Instead of the two-step process of b) and step (c), the halogenated epoxy compound (IIc) can be obtained by a one-step process. This reaction is carried out, for example, under an inert gas (e.g. argon or nitrogen gas) atmosphere and at high temperatures (e.g. 50-1
It can be carried out using triphenylphosphine in a solvent (e.g. carbon tetrachloride) serving as a chlorinating agent at a temperature of 00°C, particularly 60-80°C. In this step (d), the configuration of the three chiral center carbon atoms in the hydroxyepoxy compound (IIa) is not changed and is preserved as it is in the halogenated epoxy compound (IIc). The obtained halogenated epoxy compound (IIc) is purified if necessary (for example, by silica gel column chromatography treatment) and used in the next step (e).

Step (e) The elimination reaction is performed, for example, in an inert gas (for example, argon or nitrogen gas) atmosphere at a low temperature (for example, from -70 to 0
℃, especially -40 to -20℃), an ethereal solvent (
For example, it can be carried out using n-butyllithium in tetrahydrofuran). In this step (e), 3 in the halogenated epoxy compound (IIc)
One of the chiral centers disappears, but the configuration of the remaining two chiral center carbon atoms remains unchanged in the hydroxyalkyne compound (IIIa). The obtained hydroxyalkyne compound (IIIa) is purified if necessary (eg, silica gel column chromatography treatment) and used in the next step (f).

Step (f) As the hydroxy group-protecting group-introducing agent, for example, t-butyldimethylsilyl chloride can be used. This reaction is carried out, for example, under an inert gas (e.g. argon or nitrogen gas) atmosphere at room temperature (e.g. 0 to 40°C,
It can be carried out using triethylamine in the presence of 4,4-aminodimethylpyridine in an aprotic solvent (for example methyl chloride) at room temperature. In this step (f), a hydroxyalkyne compound (
The configuration of the two chiral central carbon atoms in IIIa) remains unchanged and the protected hydroxyalkyne compound (I
IIb). The obtained protected hydroxyalkyne compound (IIIb) is purified if necessary (eg, silica gel column chromatography treatment) and used in the next step (g).

Step (g) As the alkyl group-introducing agent, for example, methyl iodide can be used. This reaction can be carried out using, for example, an inert gas (
For example, under an atmosphere of argon or nitrogen gas, and at a low temperature (
For example, n-
This can be carried out by converting it into acetylide using butyllithium and further methylating it with methyl iodide. In this step (g), the alkylated alkyne compound (I
IIc). The obtained alkylated alkyne compound (IIIc) is purified if necessary (eg, silica gel column chromatography treatment) and used in the next step (h).

Step (h) The removal of the protecting group is carried out by using an ethereal solvent ( For example, it can be carried out by stirring with a fluorinated salt, in particular tetra n-butylammonium fluoride, in (eg, tetrahydrofuran) or in the presence of a dilute acid aqueous solvent. In this step (h), an alkylated alkyne compound (II
Ic) without changing the configuration of the two chiral central carbon atoms in the alkylated hydroxyalkyne compound (
IIId). The obtained alkylated hydroxyalkyne compound (IIId) is purified if necessary (eg, silica gel column chromatography treatment) and used in the next step (i).

Step (i) As the reducing agent, for example, lithium aluminum hydride can be used. This reduction reaction is carried out in an inert gas (e.g., argon or nitrogen gas) atmosphere at room temperature to high temperature (e.g., room temperature to 100°C, particularly 70 to 80°C).
0° C.) in an ethereal solvent (eg, tetrahydrofuran). In this step (i), an alkylated hydroxyalkyne compound (III
d) without changing the configuration of the two chiral central carbon atoms in the alkylated hydroxyalkene compound (I
IIe). Also, this step (i)
gives a mixture of cis-trans isomers. This mixture is purified (for example, by silica gel column chromatography treatment) and used in the next step (j).

Step (j) The Claisen rearrangement reaction can be carried out using, for example, an inert gas (for example,
Under an atmosphere of argon or nitrogen gas, at room temperature to high temperature (
For example, 120-180°C, especially 150-160°C)
in ethyl orthoacetate or in an aprotic solvent,
It can be carried out in the presence of sevalic acid. In this step (j), one of the two chiral centers in the alkylated hydroxyalkene compound (IIIe) disappears, but the configuration of the remaining chiral center carbon atom remains unchanged and becomes γ, δ-unsaturated ester compound (IV)
It will be saved as is. Additionally, a new chiral center is generated at the β-position of the ester carbonyl group. The configuration of this chiral central carbon atom is determined by the chirality of the hydroxyl group of the precursor. The obtained γ, δ-unsaturated ester compound (
IV) is purified as necessary (for example, by silica gel column chromatography treatment) and used in the next step (k).

Step (k) The reduction reaction can be carried out, for example, in ethanol at room temperature in the presence of a 10% palladium catalyst under a hydrogen stream. In this step (k), the steric configuration of the chiral center carbon atom in the γ,δ-unsaturated ester compound (IV) remains unchanged in the saturated ester compound (V). Obtained saturated ester compound (V)
is purified as necessary (for example, by silica gel column chromatography treatment) and used in the next step (l).

Step (l) The reduction reaction is carried out, for example, in an inert gas (for example, argon or nitrogen gas) atmosphere at a low temperature (for example, from -10 to 0
It can be carried out using lithium aluminum hydride in an ethereal solvent (e.g. tetrahydrofuran) at temperatures between -5 and 0[deg.]C. This process (
In l), the configuration of the chiral central carbon atom in the saturated ester compound (V) remains unchanged in the saturated alcohol compound (VI). The obtained saturated alcohol compound (VI) is purified if necessary (eg, silica gel column chromatography treatment) and used in the next step (m).

Step (m) The halogenation reaction is carried out, for example, in an inert gas (for example, argon or nitrogen gas) atmosphere at a low temperature (for example, from 0 to
An ethereal solvent (
For example, it can be carried out using carbon tetrabromide in diethyl ether) in the presence of triphenylphosphine. In this step (m), a saturated alcohol compound (V
The configuration of the chiral central carbon atom in I) remains unchanged in the saturated halogen compound (VII). The obtained saturated halogen compound (VII) is purified if necessary (eg, silica gel column chromatography treatment) and used in the next step (n).

Step (n) The alkylation reaction is performed, for example, in an inert gas (for example, argon or nitrogen gas) atmosphere at a low temperature (for example, -7
It can be carried out using n-butyllithium in an ethereal solvent (e.g. tetrahydrofuran) at temperatures ranging from 8°C to room temperature, especially from -78°C to 0°C. In this step (n), the configuration of the chiral center carbon atom in the saturated halogen compound (VII) remains unchanged and the ketone compound (V
III). The obtained ketone compound (VIII) is purified if necessary (for example, by silica gel column chromatography treatment) and used in the next step (o).

Step (o) The chloroalkenylation reaction is carried out, for example, under an inert gas (for example, argon or nitrogen gas) atmosphere at a low temperature (for example, -10 to room temperature, particularly -5 to 0°C). , can be carried out using phosphorus pentachloride in a hydrocarbon solvent (e.g. toluene). In this step (o), the steric configuration of the chiral central carbon atom in the ketone compound (VIII) remains unchanged in the alkene compound (Ia). The obtained alkene compound (Ia) is purified if necessary (eg, silica gel column chromatography treatment) and used in the next step (p).

Step (p) The dehalogenation reaction is carried out, for example, in an inert gas (for example, argon or nitrogen gas) atmosphere at a low temperature (for example, -
It can be carried out in the presence of lithium diisopropylamide in an ethereal solvent (e.g. tetrahydrofuran) at a temperature of 50°C to room temperature, in particular -30°C to -20°C. In this step (p), the steric configuration of the chiral central carbon atom in the alkene compound (Ia) remains unchanged in the alkyne compound (Ib). The obtained alkyne compound (Ib) is purified as necessary (for example, by silica gel column chromatography treatment) and carried out in the next step (
Used for q).

Step (q) The hydroxyl methylation reaction is carried out, for example, in an inert gas (for example, argon or nitrogen gas) atmosphere at a low temperature (for example, -78 to room temperature, especially room temperature) using an ethereal solvent. It can be carried out using paraformaldehyde in (eg, tetrahydrofuran) in the presence of a Grignard reagent. In this step (q), the configuration of the chiral central carbon atom in the alkyne compound (Ib) remains unchanged, and the hydroxyalkylated alkyne compound (Ic)
It will be saved as is. The obtained hydroxyalkylated alkyne compound (Ic) is purified if necessary (eg, silica gel column chromatography treatment) and used in the next step (r).

Step (r) The iodination reaction is carried out, for example, in an inert gas (for example, argon or nitrogen gas) atmosphere at a low temperature (for example, -78
It can be carried out using iodine in an ethereal solvent (e.g. diethyl ether) at ~room temperature, especially from 0<0>C to room temperature). In this step (r), the steric configuration of the chiral center carbon atom in the hydroxyalkylated alkyne compound (Ic) remains unchanged in the hydroxyalkylated haloalkene compound (Id). The resulting hydroxyalkylated haloalkene compound (Id
) is purified as necessary (for example, by silica gel column chromatography treatment) and used in the next step (s).

Step (s) The cross-coupling reaction is carried out, for example, in an inert gas (for example, argon or nitrogen gas) atmosphere at a low temperature (for example, -78 to 0°C, particularly 0°C). It can be carried out using dimethyl curate. In this step (r), the configuration of the chiral central carbon atom in the hydroxyalkylated alkene compound (Id) remains unchanged in the phytol compound (IX). The obtained phytol compound (IX) is purified if necessary (for example, by silica gel column chromatography treatment) and used in the next step.

Step (t) The phytol compound (IX) is prepared in the above steps (q) to (
Instead of the three-step method of s), the alkyne compound (Ib) is
For example, it can be carried out by treating with a mixture of zirconocene chloride and trimethylaluminum, and then reacting with n-butyllithium and further with paraformaldehyde. This reaction is carried out under an inert gas (e.g. argon or nitrogen gas) atmosphere at low temperatures (e.g. -10 to 0°C, especially -5 to 0°C) in a hydrocarbon solvent (e.g. n
-hexane).

The phytol compound thus obtained (IX
), optically active tocopherol can be easily produced by, for example, the enantioselective oxidation method described in Japanese Patent Application No. 2-39322. Purity 100% e. e. chiral phytol compound (IX) of
is useful as an intermediate raw material for various pharmaceuticals, agricultural chemicals, etc., especially as an intermediate raw material for vitamin E.

[0087]

[Examples] The present invention will now be explained in detail with reference to Examples, but these are not intended to limit the scope of the present invention. In addition, in the chemical formula shown in the following examples, Ts is a toluenesulfonyl group, and TBS is a t-butyldimethylsilyl group.

Example 1: Methyl (R)-(E)-5,9
-Preparation of dimethyl-2,8-decadienoate

008
9]

[Math 1]

Sodium hydride (60% oil dispersion 1
．． Methyl diisopropyl phosphonoacetate (9.360 g, 40.0
A solution of 4 mmol) in tetrahydrofuran (30 ml) was added dropwise over 10 minutes. After 5 minutes, the mixture was cooled to -40°C and further stirred for 50 minutes. (R)-citronellal (1
) (5.042 g, 32.7 mmol) in tetrahydrofuran (30 ml) was added dropwise over 45 minutes, and the mixture was further stirred at the same temperature for 1 hour. After raising the temperature to room temperature, the mixture was further stirred for 25 minutes. After cooling on ice again and adding saturated aqueous sodium hydrogen carbonate solution, diluting with diethyl ether, washing with saturated aqueous sodium chloride solution and drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was treated with column chromatography (90 g of silica gel), and a colorless oily ester (2
) (6.220 g, 91%) was obtained. The physical and chemical data are as follows.

[α]D 28: -2.91° (c=1.
05, CHCl3). IRνmax (film) cm −1 : 1730 (C
=O), 1655, 1420, 1380, 1270, 1
180, 1040, 980. 1H-NMR (CDCl3) δ: 0.90 (d, 3
H, J=6.4Hz, C(5)CH3), 1.00~
1.20(m,3H,C(5)CH and C(6)H2
), 1.58 (s, 3H, C(9)CH3 ), 1.6
8(d,3H,J=7.0Hz,C(9)CH3),
1.18-2.43(m,4H,C(4)H2 and C
(7)H2), 3.73(s,3H,OCH3),
4.90-5.24 (m, 1H, C(8)H) 5.81
(dt, 1H, J=15.6, 1.3Hz, C(2)H
), 6.96 (dt, 1H, J=15.6, 7.3Hz
, C(3)H). MSm/e: 210 (M+), 19
5,178,167,141,121,109,95,
69 (100%). High resolution MSm/e: Theoretical value C13H12O2 (M+): 210
．． 1620 actual measurement value
:210.1644.

Example 2: Preparation of (R)-(E)-5,9-dimethyl-2,8-decadien-1-ol

009
3]

[Math 2]

Ester (2) (6.050g, 28.
diisobutylaluminum hydride (8 mmol) in tetrahydrofuran (80 ml) was stirred under ice-cooling.
13.0 ml, 73.0 mmol) was added dropwise. After 80 minutes, saturated ammonium hydroxide aqueous solution and 3.0N saturated sodium hydroxide aqueous solution were added dropwise to decompose excess reagent and complex. Celite and dichloromethane were added, and the mixture was further stirred at room temperature for 10 hours. After filtering through Celite, it was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated with column chromatography (128 g of silica gel) and treated with diethyl ether/n-hexane [1:8 (v/
v)] Colorless oily alcohol (3) (4.
696g; 90%) was obtained. The physical and chemical data are as follows.

[α]D 30: +1.02° (c=1.
03, CHCl3). IRνmax (film) cm −1 :3320(O
H), 1455, 1440, 1380, 1085, 10
00,970. 1H-NMR (CDCl3) δ: 0.89 (d, 3
H, J=6.1Hz, C(5)CH3), 0.90-
2.40 (can be replaced with m, 8H, 1H, D2O), 1
．． 60 (br.s.3H, C(9)CH3), 1.6
9(br.s,3H,C(9)CH3),3.95-
4.23 (m, 2H, C(1)H2OH), 4.92
-5.24 (m, 1H, C(8)H), 5.52-5.
80 (m, 2H, C(2)H and C(3)H). MSm/e: 183 (M+ +1), 182 (M+)
,164(M+-H2O),149,138,124
, 109, 95, 69 (100%). High resolution MSm/e: Theoretical value C12H20(M+ -H2O): 16
4.1565. Actual value
:164.1546.

Example 3: (2S,3S,5R)-2,3
- Preparation of epoxy-5,9-dimethyl-8-decen-1-ol

[0097]

[Math 3]

To a suspension of 4A molecular sieve (2.003 g) in dichloromethane (50 ml) was added (L)-(+) tartrate diisobutyl ester (1.28 g) with stirring at -30°C.
ml, 6.09 mmol) and titanium(IV) isoprofoxide (1.81 ml, 6.08 mol) were added in sequence. After 25 minutes, t-butyl hydroperoxide (1.
After dropping a 76M dichloromethane solution (4.10 ml, 7.22 mmol), the mixture was further stirred at the same temperature for 1 hour. A solution of allyl alcohol compound (3) (1.053 g, 5.78 mmol) in dichloromethane (20 ml) was added dropwise over 30 minutes, and the mixture was further stirred at the same temperature for 11 hours. After adding a 3M aqueous potassium carbonate solution (2.0 ml), the mixture was heated to room temperature and stirred for an additional hour. Add celite and 1 more
Stir for hours. After filtering through Celite, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel 8
diethyl ether-n-hexane [1
:4 (v/v)] A colorless oily epoxy alcohol (4) (1.116 g, 97%) was obtained from the eluate. Analysis of the 1H-NMR spectrum of α-trifluoromethyl-α-methoxyphenylacetate induced by this title compound revealed that the chirality of the methyl group derived from the raw material (R)-citronellal (1) was 71% d. e
．． The chirality of the newly formed epoxy moiety is 90% d. e. It was confirmed that The physical and chemical data are as follows.

[α]D 29: -30.67° (c=1
．． 02, CHCl3). IRνmax (film) cm −1 :3430(O
H), 1460, 1450, 1380, 900. 1H-NMR (CDCl3) δ: 0.96 (d
,3H,J=6.3Hz,C(5)H3),0.90
-2.13 (can be replaced with m, 8H, 1H D2O)
,1.61(s,3H,C(9)CH3),1.68
(d,3H,J=1.2Hz,C(9)CH3),2
．． 75-3.12(m, 2H, C(2)H and C(3)
H), 3.63 (ddd, 1H, J = 12.6, 7.1
, 3.9Hz, C(1)H), 3.94(ddd, 1H
, J=12.6, 6.0, 2.5, Hz, C(1)H)
,5.10(tq,1H,J=7.1,1.2Hz,C
(8)H). MSm/e: 198 (M+), 180, 167, 14
9,109,95,82,69 (100%). High resolution MSm/e: Theoretical value C12H22O2 (M+): 198
．． 1620. Actual value
:198.1622.

Example 4: Preparation of (2R,3S,5R)-1-chloro-2,3-epoxy-5,9-dimethyl-8-decene

[0101]

[Math 4]

Method A: Epoxy alcohol (4) (1.
398 g, 7.05 mmol) of carbon tetrachloride (20 ml
) solution was triphenylphosphine (2.774 g, 10
．． 58 mmol) was added thereto, and the mixture was heated under reflux for 4.5 hours. After cooling, the mixture was filtered through Celite, and the solvent was distilled off under reduced pressure. The residue was treated with column chromatography (75 g of silica gel) and diluted with diethyl ether/n-hexane [1:100
(v/v)] A colorless oily chloroepoxide compound (5) (658 mg, 43%) was obtained from the eluate. The physical and chemical data are as follows.

[α]D 29:-13.34° (c=1
．． 04, CHCl3). IRνmax (film) cm −1 :1450,1
380, 1260, 930, 900, 740. 1H-NMR (CDCl3) δ: 0.98 (d, 3
H, J=6.4Hz, C(5)H3), 1.14-2
．． 10(m, 7H), 1.60(s, 3H, C(9)C
H3), 1.68(d, 3H, J=1.2Hz, C(
9) CH3), 2.77-3.02(m, 2H, C(
2) H and C (3) H), 3.35-3.78 (m, 2
H,C(1)H2),5.09(tt,1H,J=7
．． 1,1.2Hz, C(8)H). MSm/e: 216 (M+), 200, 198, 18
3,163,149,109,95,81,69 (10
0%). High resolution MSm/e: Theoretical value C12H21O35Cl (M+): 2
16.1281. Actual value
:216.1254.

[0104]

[Math 5]

Method B: Epoxy alcohol (4) (77
．． 5 mg, 3915 mmol) of dichloromethane (2.
Add triethylamine (0 ml) to the solution under ice cooling and stirring.
0.12 ml, 861 mmol), 4,4-dimethylaminopyridine (5.3 mg, 43 mmol) and p-toluenesulfonyl chloride (95.0 mg, 498 mmol) were added in sequence. After 5 minutes, the temperature was raised to room temperature, and the mixture was further stirred for 3 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in diethyl ether, washed successively with a 5% aqueous HCl solution, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. I left. The residue was treated with column chromatography (6.0 g of silica gel), and a colorless oily chloroepoxide (5) (5.1 mg, 6 %) and colorless oily (2R,3S,5R)-2,3-epoxy-5,9
-dimethyl-1-toluenesulfonyl)oxy-8-decene (6) (115 mg, 83%) was obtained. The physical and chemical data are as follows.

[α]D 31: -29.94° (c=1
．． 13, CHCl3). IRνmax (film) cm −1 :1600,1
450, 1365, 1190, 1100, 965, 81
5,665. 1H-NMR (CDCl3) δ: 0.93 (d, 3
H, J=6.4Hz, C(5)CH3), 1.06-
2.20 (m, 7H), 1.59 (s, 3H, C (9)
CH3), 1.68(s,3H,C(9)CH3)
,2.45(s,3H,CH3Ar),2.66-3
．． 02 (m, 2H, C(2)H and C(3)H), 3.
83-4.32 (m, 2H, C(1)H2), 5.0
7(tt, 1H, J=7.1, 1.2Hz, C(8)H
), 7.35 (d, 3H, J=8.3Hz, aromaticity)
, 7.80 (d, 3H, J=8.3Hz, aromaticity).

Compound (6) of this example was immediately used in the next reaction. That is, lithium chloride (22.0 mg, 519 mmol) was added to a solution of tosyl compound (6) (115 mg, 326 mmol) in dimethylformamide (2.0 ml),
Stirred at 50°C for 15 minutes. After cooling, dilute with diethyl ether, wash with saturated aqueous sodium chloride solution,
After drying with magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel 6
．． 0g) and diethyl ether/n-hexane [
1:20 (v/v)] A colorless oily chloroepoxide (5) (64.2 mg, 91%) was obtained from the eluate. Various spectral data of this compound were consistent with the data of the compound prepared in Example 4A above.

Example 5: Preparation of (3S,5R)-5,9-dimethyl-8-decen-1-yn-3-ol

01
09]

[Math 6]

Epoxy chloride compound (5) (880 mg, 4.06 mmol) was added to a solution of n-butyllithium (1.40M hexane solution; 14.0 ml, 19.6 mmol) in tetrahydrofuran (15 ml) at -25°C with stirring. ) in tetrahydrofuran (15 ml) was added dropwise over 5 minutes. After 10 minutes, a saturated aqueous ammonium chloride solution was added, and the temperature was raised to room temperature. After diluting with diethyl ether, washing with saturated aqueous sodium chloride solution and drying over magnesium sulfate, the solvent was distilled off under reduced pressure. Column chromatography of the residue (60 g of silica gel)
diethyl ether/n-hexane [1:9 (
v/v)] A colorless oily acetylene body (7) (
730 mg, 100%) was obtained. 1H-NMR of α-trifluoromethyl-α-methoxyphenylacetic acid ester
Analysis of the spectrum revealed that the chirality of the methyl group was 74%e. e. And, regarding the chirality of the hydroxyl group, it is 93% e. e. It was confirmed that The physical and chemical data are as follows.

[α]D 30: -13.71° (c=0
．． 70, CHCl3). IRνmax (film) cm −1 :3390(O
H), 3320, 1450, 1380, 1060, 10
20. 1H-NMR (CDCl3) δ: 0.97 (d, 3
H, J=5.9Hz, C(5)CH3), 0.95-
2.20 (can be replaced with m, 8H, 1H, D2O), 1
．． 61 (br.s, 3H, C(9)CH3) 1.69
(d, 3H, J=1.2Hz, C(9)H3), 2.
47 (d, 1H, J=2.0Hz, C(1)H), 4.
23-4.60(m, 1H, C(3)H), 5.10(
tt, 1H, J=7.1, 1.2Hz, C(8)H). MSm/e: 181 (M+ +1), 180 (M+)
,179,165,147,123,119,109,
95,69 (100%). High resolution MSm/e: Theoretical value C12H20O(M+): 180.1
515. Actual value
:180.1505. Elemental analysis theoretical value: C12H20O:C=70.94;H
=11.18 Actual value: C=70.72
;H=11.14.

Example 6: (3S,5R)-3-(t-butyldimethylsilyl)oxy-5,9-dimethyl-8-
Preparation of decen-1-yne-

[0113]

[Math 7]

Alcohol compound (7) (252 mg, 1.4
To a solution of 0 mmol) in dichloromethane (4.0 ml) was added triethylamine (0.39 ml, 2
．． 80 mmol), 4,4-dimethylaminopyridine (
17.0 mg, 0.14 mol) and t-butyldimethylbutyl chloride (253 mg, 1.68 mmol) were added in sequence. After 5 minutes, the temperature was raised to room temperature, and the mixture was further stirred for 21.5 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in diethyl ether, washed with a saturated aqueous sodium chloride solution, and dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was treated with column chromatography (24 g of silica gel) and diluted with diethyl ether-n-hexane [1:6 (v
/v)] Colorless oily silyl ether compound (8) from the eluted part
(397 mg, 96%) was obtained. The physical and chemical data are as follows.

[α]D 31: -46.95° (c=1
．． 04, CHCl3). IRνmax (film) cm −1 :3300,1
460, 1380, 1360, 1250, 1090, 1
000,935,900,830,775. 1H-NMR (CDCl3) δ: 0.11 (d, 3
H, CH3 Si), 0.14(s, 3H, CH3 S
i), 0.90(d, 3H, J=5.9Hz, C(5)
CH3)0.90(s,9H,(CH3)CSi)
, 1.00-2.17 (m, 7H), 1.60 (br.
s. 3H, C(9)CH3), 1.68(br.s,
3H, C(9)H3), 2.37(d, 1H, J=2
．． 2Hz, C(1)H), 4.26-4.53(m, 1
H, C (3) H), 4.90-5.22 (m, 1H, C
(8)H). MSm/e: 295 (M+ +1), 294 (M+)
,279,269,237,193,147,109,
95,75(100%),69. High resolution MSm/e: Theoretical value C18H34OSi (M+): 294
．． 2379. Actual value
:294.2381. Elemental analysis theoretical value: C18H34OSi: C=73.40
;H=11.63 actual value
:C=72.99;H=11.5
0.

Example 7: (4S,6R)-4-(t-butyldimethylsilyl)oxy-6,10-dimethyl-9
-Preparation of undecen-2-yne

[0117]

[Math. 8]

Silyl ether compound (8) (708 mg, 2
．． 40 mmol) of tetrahydrofuran (15 ml)/
To a mixed solution of hexamethylphosphoric triamide (0.8 ml) was added n-butyllithium (1
．． 40M hexane solution; 2.70 ml, 3.78 mmol) was added. After 20 minutes, iodomethane (0.24 ml
, 3.86 mmol) was added dropwise, the temperature was raised to -5°C, and the mixture was further stirred for 10 hours. After adding a saturated aqueous ammonium chloride solution, the mixture was heated to room temperature, diluted with diethyl ether, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. Column chromatography of the residue (40 g of silica gel)
A colorless oily silyl ether (9) (702 mg, 95%) was obtained from the n-hexane eluate. The physical and chemical data are as follows.

[α]D 31: -50.63° (c=1
．． 03, CHCl3). IRνmax (film) cm −1 :1460,1
375, 1360, 1250, 1090, 980, 90
0,835,775. 1H-NMR (CDCl3) δ: 0.10 (s, 3
H, CH3 Si), 0.12 (s, 3H, CH3 S
i), 0.90(d, 3H, J=5.8Hz, C(6)
CH3),0.90(s,9H,(CH3)3C
Si), 0.98-2.17 (m, 7H), 1.60 (
br. s,3H,C(10)CH3),1.67(d
, 3H, J=1.0Hz, C(10)CH3), 1.
81 (d, 3H, J=2.2Hz, C(1)H3),
4.22-4.50 (m, 1H, C(4)H), 4.9
5-5.22 (m, 1H, C(9)H). MSm/e: 308 (M+), 293, 265, 25
1,223,211,183,161,137,97,
75 (100%), 69. High resolution MSm/e: Theoretical value C19H36OSi (M+): 308
．． 2536. Actual value
:308.2504. Elemental analysis theoretical value: C19H36OSi: C=73.95
;H=11.76 actual value
:C=73.86;H=11.6
6.

Example 8: Preparation of (4S,6R)-6,10-dimethyl-9-undecen-2-yn-4-ol

[0121]

[Math. 9]

Silyl ether (9) (685 mg, 2
．． Tetra n-butylammonium chloride (1.0M solution in tetrahydrofuran; 0.70
ml, 0.70 mol) was added. After 50 minutes, the mixture was diluted with diethyl ether, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was treated with column chromatography (24 g of silica gel) to obtain acetylene alcohol compound (10) (432 mg, 100%) as a colorless oil from the diethyl ether/n-hexane [1:4 (v/v)] eluate. Ta. The physical and chemical data are as follows.

[α]D 27: -10.32° (c=1
．． 04, CHCl3). IRνmax (film) cm −1 :3380(O
H), 1450, 1380, 1140, 1050. 1H-NMR (CDCl3) δ: 0.93 (d, 3
H, J=6.4Hz, C(6)CH3), 0.96-
2.22 (can be replaced with m, 8H, 1H, D2O), 1
．． 60 (br.s, 3H, C(10)CH3), 1.
69 (br.s, 3H, C(10)CH3) 1.84
(d, 3H, J=2.2Hz, C(1)H3), 4.
21-4.58 (m, 1H, C(4)H), 4.96-
5.24 (m, 1H, C(9)H). MSm/e: 194 (M+), 179, 161, 11
9,109,95,69,(100%). High resolution MSm/e: Theoretical value C13H22O(M+): 194.1
671. Actual value
:194.1675.

Example 9: (4S,6R)-(Z)-6,
10-dimethyl-2,9-undecadien-4-ol and (4S,6R)-(E)-6,10-dimethyl-2
, 9-Undecadien-4-ol preparation

[0125]

[Math. 10]

Acetylene compound (10) (432 mg, 2.
Lithium aluminum hydride (22 mmol) was added to a solution of lithium aluminum hydride (10 ml) in tetrahydrofuran (10 ml) under stirring under ice cooling.
02 mg, 2.68 mmol) was added. After heating under reflux for 8 hours, the mixture was cooled on ice again, and a saturated aqueous ammonium hydroxide solution was added dropwise to decompose the excess reagent and complex. Celite and dichloromethane were added, and the mixture was further stirred at room temperature for 12 hours. After filtering through Celite, it was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (
25 g of silica gel) and diethyl ether/n-
The hexane [1:20 (v/v)] eluate was obtained as a colorless oil (E)-allyl alcohol compound (12) (322 mg, 7
4%) and (Z)-allylic alcohol (11) (61
mg, 14%) was obtained. The physical and chemical data are as follows.

(E)-Allyl alcohol (12) [α
] D 29: -10.25° (c=1.01, CHCl
3). IRνmax (film) cm −1 :3350(O
H), 1450, 1380, 965. 1H-NMR (CDCl3) δ: 0.92 (d, 3
H, J=6.1Hz, C(6)CH3), 0.90-
2.17 (m, 7H), 1.33 (d, 1H, J=4.
2Hz, exchangeable with D2 O, OH), 1.60 (br
．． s,3H,C(10)CH3), 1.66(br.
s,3H,C(10)CH3),1.70(d,3H
, J=3.2Hz, C(1)H3), 3.96-4.
30(m, 1H, C(4)H), 4.93-5.26(
m, 1H, C(9)H), 5.26-5.92 (m, 2
H, C(2)H and C(3)H). MSm/e: 196 (M+), 178, 163, 14
9,71(100%),69. High resolution MSm/e: Theoretical value C13H24O(M+): 196.1
828. Actual value
:196.1848.

(Z)-Allyl alcohol (11) [α
] D 30: -8.01° (c=0.78, CHCl3
). IRνmax (film) cm −1 :3350(O
H), 1445, 1380, 960. 1H-NMR (CDCl3) δ: 0.90 (d, 3
H, J=5.6Hz, C(6)CH3), 0.90-
2.16 (m, 7H), 1.38 (d, 1H, J=3.
4Hz, replaceable with D2 O, OH), 1.60 (br
．． s,3H,C(10)CH3), 1.67(br.
s,3H,C(10)CH3),1.70(d,3H
, J=3.4Hz, C(1)H3), 3.92-4.
32(m, 1H, C(4)H), 4.94-5.26(
m, 1H, C(9)H), 5.26-5.88 (m, 2
H, C(2)H and C(3)H)

Example 10: Ethyl (3S,7R)-(E
)-3,7,11-trimethyl-4,10-dodecadienoate preparation

[0130]

[Math. 11]

(E)-Allyl alcohol (12) (2
80 mg, 1.43 mol), pivalic acid (10.0 mg,
0.27 mmol), triethyl orthoacetate (4
．． 0 ml, 21.8 mmol) was heated at 160° C. for 2 hours on a Dean-Stark apparatus. After cooling, it was diluted with diethyl ether, washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (12 g of silica gel).
) and diethyl ether/n-hexane [1:1
00 (v/v)] Colorless oily ester (1
3) (335 mg, 93%) was obtained. The physical and chemical data are as follows.

[α]D 29: +14.51° (c=1
．． 11, CHCl3). IRνmax (film) cm −1 : 1735 (C
=O), 1450, 1375, 970. 1H-NMR (CDCl3) δ: 0.84 (d, 3
H, J=6.1Hz, C(7)CH3), 1.03(
d, 3H, J=6.6Hz, C(3)CH3), 0.
60-2.50 (m, 9H), 1.24 (t, 3H, J
=7.1Hz, OCH2 CH3 ), 1.59(br
．． s,3H,C(11)CH3),1.68(d,3
H, J=1.0Hz, C(11)CH3), 2.25
-2.88 (m, 1H, C(3)H), 4.11 (q,
2H, J=7.1Hz, OCH2 CH3 ), 4.9
2-5.30 (m, 1H, C(10)H), 5.05-
5.66 (m, 2H, C(4)H and C(5)H). 13C-NMR (CDCl3) δ: 14.26 (q)
, 17.56 (q), 19.30 (q), 20.49 (
q), 25.58 (q), 25.58 (t), 32.7
3(d), 33.76(d), 36.58(t), 39
．． 83(t), 42.00(t), 59.93(t),
124.94(d), 127.86(d), 130.8
4(s), 135.45(d), 172.39(s). MSm/e: 267 (M+ +1), 266 (M+)
,251,223,178,135,123,109,
95, 82, 69 (100%). High resolution MSm/e: Theoretical value C17H30O2 (M+): 266
．． 2246. Actual value
:266.2229.

Example 11: Ethyl (3R,7R)-3,
Preparation of 7,11-trimethyldodecanoate

0134
]

[Math. 12]

[0135] Ester (13) (346 mg, 1.3
0 mmol) in ethyl alcohol (5.0 ml) was added 10% palladium-carbon (17.2 mg), and the mixture was stirred at room temperature for 2.5 hours under a hydrogen stream. After filtering through Celite, the solvent was distilled off under reduced pressure. The resulting residue was treated with column chromatography (8.0 g of silica gel) and treated with diethyl ether/n-hexane [1:50 (v/v
)] Colorless oily ester (14) (338
mg, 96%) was obtained. The physical and chemical data are as follows.

[α]D 27: +2.34° (c=1.
02,n-octane) [Literature value: [α]D: +2.2
4 (c=4.99, n-octane)]. IRνmax (film) cm −1 : 1735 (C
=O), 1460, 1370, 1245, 1170, 1
030. 1H-NMR (CDCl3) δ: 0.68-1.7
3 (m, 26H), 1.26 (t, 3H, J = 7.1H
z, OCH2 CH3 ), 1.73 -2.43(
m, 3H, C(2)CH2 and C(3)H), 4.1
3 (q, 2H, J=7.1Hz, OCH2 CH3)
. 13C-NMR (CDCl3) δ: 14.26 (q)
, 19.62 (q), 19.73 (q), 22.55 (
q), 22.66 (q), 23.23 (t), 24.7
7(t), 27.96(d), 30.35(d), 32
．． 73(t), 37.07(d), 37.18(t),
37.19 (t), 39.40 (t), 41.83 (t
), 59.82 (t), 172.93 (s). MSm/e: 271 (M+ +1), 270 (M+)
,255,227,185,157,115,97,8
8 (100%), 83, 69. High resolution MSm/e: Theoretical value C17H34O2 (M+): 270
．． 2559. Actual value 270.2552.

Example 12: (3R,7R)-3,7,1
Preparation of 1-trimethyldodecane-1-ol

0138
]

[Math. 13]

[0139] Ester (14) (121 mg, 447
Lithium aluminum hydride (18 mmol) was added to a solution of lithium aluminum hydride (18
．． 0 mg, 474 mmol) was added. After 50 minutes, a saturated aqueous ammonium hydroxide solution was added dropwise to decompose excess reagent and complex. Add celite and dichloromethane,
The mixture was further stirred at room temperature for 10 hours. After filtering through Celite, it was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Column chromatography of the residue (6.0 g of silica gel)
diethyl ether/n-hexane [1:6 (
v/v)] Colorless oily alcohol from the eluted part (15)
(102 mg, 100%) was obtained. The physical and chemical data are as follows.

[α]D 27: +2.93° (c=1.
02, CHCl3 ) [Literature value: [α]D 18:+3
．． 49° (c=0.98, CHCl3)]. IRνmax (film) cm −1 :3330(O
H), 1460, 1380, 1370, 1055. 1H-NMR (CDCl3) δ: 0.45-1.8
0 (m, 30H, 1H, exchangeable with D2 O), 3.6
9(br.t, 2H, J=6.6Hz, C(1)H2
OH). MSm/e:210(M+-H2O),182,1
40, 125, 111, 97, 83, 69, 57 (10
0%). High resolution MSm/e: Theoretical value C15H30(M+ -H2O): 2
10.2348. Actual value 210.2310.

Example 13: Preparation of (3R,7R)-1-brumo-3,7,11-trimethyldodecane

0142
]

[Math. 14]

Alcohol compound (15) (121 mg, 53
0 mmol) in dichloromethane (3.0 ml),
Carbon tetrabromide (231 mg, 697 mmol) and triphenylphosphine (183 mg, 69 mmol) were dissolved under stirring at room temperature.
8 mmol) was added. After 110 minutes, the solvent was distilled off under reduced pressure, and the residue was dissolved in diethyl ether, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated with column chromatography (20 g of silica gel), and the bromo compound (16) (154
mg, 100%) was obtained. The physical and chemical data are as follows.

[α]D 29: -3.85° (c=1.
04, CHCl3 ) [Literature value: [α]D 24:-4
．． 44° (c=5.0, CHCl3)]. IRνmax (film) cm −1 :1460,1
380,1370. 1H-NMR (CDCl3) δ: 0.70-2.1
7 (m, 29H), 3.28-3.60 (m, 2H, C
(1)H2Br). MSm/e: 292 (M*+), 290 (M+),
277,275,249,247,165,163,1
51,149,113,97,71,83,69,57
(100%). High resolution MSm/e: Theoretical value C15H3181Br (M**): 2
92.1588 actual measurement value
:292.1612. Theoretical value C15H3179Br (M+): 29
0.1610 actual measurement value
:290.1649.

Example 14: (6R,10R)-6,10
, 14-trimethylpentadecane-2-one preparation

0
146]

[Math. 15]

Acetone dimethyl hydrazone (53.7 m
g, 536 mmol) of tetrahydrofuran (1.0 m
l) Add n-butyllithium (
A 1.40M hexane solution; 380 ml, 532 mmol) was added. After 30 minutes, bromine body (16) (91.0 m
g, 312 mmol) of tetrahydrofuran (2.0 m
l) The solution was added dropwise, and the mixture was further stirred at the same temperature for 1 hour. The reaction solution was heated to room temperature and further stirred for 130 minutes. Acetic acid (
0.20 ml) and H2O (1.0 ml) were added and stirred for an additional 50 minutes. After diluting with diethyl ether, washing with saturated aqueous sodium hydrogen carbonate solution and saturated sodium chloride solution, and drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was treated with column chromatography (6.0 g of silica gel), and the diethyl ether/n-hexane [1:10 (v/v)] eluate yielded a colorless oily ketone (17) (67. mg, 80%). ) was obtained. The physical and chemical data are as follows.

[α]D 26:+1.03° (c=1.
02, CHCl3). IRνmax (film) cm −1 : 1720 (C
=O), 1460, 1375, 1360. 1H-NMR (CDCl3) δ: 0.70-1.8
4(m, 31H), 2.13(s, 3H, C(1)H3
), 2.41 (br.t, 2H, J=7.3Hz, C
(3)H2). 13C-NMR (CDCl3) δ: 19.51 (q)
, 19.67 (q), 21.32 (t), 22.55 (
q), 22.64 (q), 24.35 (t), 24.7
3(t), 27.89(d), 29.67(q), 32
．． 60(d), 32.71(d), 36.42(t),
37.17(t), 37.22(t), 37.34(t
), 39.31 (t), 43.96 (t), 208.7
0(s). MSm/e: 268 (M+ 1), 250, 210, 1
24,109,95,85,71,58 (100%). High resolution MSm/e: Theoretical value C18H36O(M+): 268.2
766. Actual value
:268.2742.

Example 15: (6) from natural phytol
Preparation of R,10R)-6,10,14-trimethylpentadecane-2-one

[0150]

[Math. 16]

0151 Natural phytol (22) (2.045g
, 6.90 mmol) of methyl alcohol (30 ml)
Ozone was passed through a mixed solution of -dichloromethane (15 ml) at -78°C for 18 minutes while stirring. Next, add 1 nitrogen gas
After driving off excess ozone for 5 minutes, dimethyl sulfide (3.0 ml, 40.8 mmol) was added dropwise. The reaction solution was heated to room temperature and further stirred for 4 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in diethyl ether, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was treated with column chromatography (40 g of silica gel),
Diethyl ether/n-hexane [1:100 (v/v
)] Colorless oily ketone body (17) (1.79
3g, 97%) was obtained. The physical and chemical data are as follows.

[α]D 26: +1.05° (c=1.
02, CHCl3).

Various spectral data of the compound of this example were consistent with that of the compound previously synthesized in Example 14.

Example 16: Preparation of (6R,10R)-2-chloro-6,10,14-trimethylpentadec-1-ene

[0155]

[Math. 17]

To a solution of phosphorus pentachloride (2.205 g, 10.6 mmol) in toluene (20 ml) was added ketone body (17) (2.146 g, 7.99 mmol) in toluene (20 ml) under stirring under ice cooling. 30 ml) solution was added dropwise over 5 minutes. After raising the temperature to room temperature and stirring for an additional 15 minutes, the mixture was heated under reflux for 9 hours. The mixture was cooled on ice again, neutralized by adding a saturated aqueous sodium bicarbonate solution, diluted with diethyl ether, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was treated with column chromatography (80 g of silica gel) and diluted with diethyl ether/n-hexane [1:20 (
v/v)] Colorless oily vinyl chloride (
18) (2.280 g, 99%) was obtained. The physical and chemical data are as follows.

[α]D 31: -0.39° (c=1.
02, CHCl3). IRnmax (film) cm −1 :1670,1
635, 1470, 1465, 1380, 880. 1H-NMR (CDCl3) δ: 0.70-1.7
8 (m, 31H), 1.90-2.44 (m, 2H, C
(3) H2 ), 5.05-5.20(m, 2H, C(
1)H2). MSm/e: 288 (M*+), 286 (M+),
218, 216, 165, 146, 126, 111, 9
5,83,71 57 (100%). High resolution MSm/e: Theoretical value C18H3637Cl (M**): 2
88.2397. Actual value
:288.2421. Theoretical value C18H3635Cl (M+):
286.2427. Actual value
:286.2410.

Example 17: (6R,10R)-6,10
, 14-trimethylpentadeca-1-yne preparation

01
59]

[Math. 18]

Diisopropylamine (4.00ml, 2
9.2 mmol) in tetrahydrofuran (30 ml) was stirred under ice cooling and n-butyllithium (1.40 M
A hexane solution (22.0 ml, 30.8 mmol) was added. After 20 minutes, the mixture was cooled to -25°C, and a solution of vinylchloride compound (18) (2.286 g, 7.97 mmol) in tetrahydrofuran (30 ml) was added dropwise over 5 minutes, and then heated to room temperature for 4 hours. Stirred. The mixture was cooled on ice again, and after adding a saturated aqueous ammonium chloride solution, the temperature was raised to room temperature again. After diluting with diethyl ether, washing with saturated aqueous sodium chloride solution and drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was treated with column chromatography (80 g of silica gel), and a colorless oily acetylene compound (19) (1
．． 586g; 79%) was obtained. The physical and chemical data are as follows.

[α]D 29: -0.66° (c=1.
03, CHCl3). IRνmax (film) cm −1 :3315,2
130, 1470, 1460, 1380, 1375. 1H-NMR (CDCl3) δ: 0.70-1.7
5 (m, 31H), 1.94 (t, 1H, J=2.7H
z, C(1)H), 2.00-2.32(m, 2H, C
(3)H2).

Example 18: (7R,11R)-7.11
．． Preparation of 15-trimethylhexadec-2-yn-1-ol

[0163]

[Math. 19]

Acetylene body (19) (1.349g, 5
．． To a solution of 39 mmol) in tetrahydrofuran (20 ml) was added bromomagnesium ethyl (3
．． After adding a 0M ether solution (3.60 ml, 10.8 mmol), the temperature was raised to room temperature. After 3 hours, paraformaldehyde (911 mg, 30.3 mmol) was added and stirred for an additional 19 hours. After diluting with diethyl ether, washing with saturated aqueous sodium chloride solution and drying over magnesium sulfate, the solvent was distilled off under reduced pressure. Column chromatography of the residue (60 g of silica gel)
diethyl ether/n-hexane [1:6 (
v/v)] The raw material acetylene compound and colorless oily acetylene compound (20) (1103 g, 73%) were obtained from the eluate. The physical and chemical data are as follows.

[α]D 26: -2.14° (c=1.
09, CHCl3). IRνmax (film) cm −1 :3372,2
224, 1462, 1378, 1138, 1013. 1H-NMR (CDCl3) δ: 0.65-1.8
0 (can be replaced with m, 32H, 1H, D2 O), 2.0
0-2.32 (m, 2H, C(4)H2), 4.25
(dt, 2H, J=5.9Hz, 2.2Hz, C(1)
H2). MSm/e: 294 (M+ -CH2OH), 177
,149,135,125,107,97,83,69
, 57 (100%). High resolution MSm/e: Theoretical value C18H33 (M+ -CH2 OH)
:249.2582. Actual value
:249.2569.

Example 19: Preparation of (7R,11R)-3-iodo-7,11,15-trimethylhexadec-2-en-1-ol

[0167]

[Math. 20]

Alcohol compound (20) (201 mg, 71
Sodium-bis(2-methoxyethoxy)aluminum hydride (70% toluene solution;
0.50 ml, 1.73 mmol) was added. After 10 minutes, the temperature was raised to room temperature, and the mixture was further stirred for 13.5 hours. Cooled on ice again, added ethyl acetate (53 ml, 543 mmol), stirred for an additional 15 minutes, cooled to -78°C, added iodine (358 mg, 1.41 mmol), and immediately warmed to room temperature for 1 Stirred for .5 hours. The mixture was cooled on ice again, and a saturated aqueous ammonium hydroxide solution was added dropwise to decompose the excess reagent and complex. After filtering through Celite, it was diluted with diethyl ether, washed with a saturated aqueous sodium bicarbonate solution, a 5% aqueous sodium thiosulfate solution, and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (10 g of silica gel).
) and diethyl ether/n-hexane [1:1
0 (v/v)] Colorless oily iodo compound (21) from the eluate
(238 mg, 81%) was obtained. The physical and chemical data are as follows.

[α]D 27: -2.44° (c=1.
06, CHCl3). IRνmax (film) cm −1 :3324,1
645,1461. 1H-NMR (CDCl3) δ: 0.70-1.7
6 (m, 32H, 1H, exchangeable with D2O), 2.4
8(br.t, 2H, J=7.1Hz, C(4)H2
), 4.20(br.d, 2H, J=5.9Hz, C(
1) H2 ), 5.84 (tt, J=3.9, 1.2H
z, C(2)H). MSm/e: 408 (M+), 281, 198, 13
7,123,109,95,83,69,57 (100
%). High resolution MSm/e: Theoretical value C19H37OI (M+): 408.
1889. Actual value
:408.1863.

Example 20: Preparation of phytol

0171
]

[Math. 21]

A suspension of copper iodide (504 mg, 2.65 mmol) in diethyl ether (5.0 ml) was heated at -38°C.
Methyllithium (1.40 M diethyl ether solution; 3.80 ml, 5.32 mmol) was added under stirring. After 60 minutes, a solution of iodo compound (21) (180 mg, 441 mmol) in diethyl ether (4.5 ml) was added dropwise over 5 minutes, and the mixture was further stirred at the same temperature for 1.5 hours. The reaction solution was ice-cooled and stirred for 1.5 hours, then warmed to room temperature and further stirred for 18 hours. The mixture was cooled on ice again, and after adding a saturated aqueous ammonium chloride solution, the temperature was raised to room temperature. After filtering through Celite, the organic layer was separated, and the aqueous layer was further extracted using diethyl ether. The organic layers were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was treated with column chromatography (10 g of silica gel), and the phytol compound (22) (109 mg,
83%). The physical and chemical data are as follows.

[α]D 24: -1.50° (c=0.
94, CHCl3) [Natural standard: [α]D 29:
-1.35° (c=1.00, CHCl3)]. IRνmax (film) cm −1 :3340,1
460,1375,1000. 1H-NMR (CDCl3) δ: 0.70-1.8
0 (m, 35H, 1H, exchangeable with D2 O), 1.8
5-2.15 (m, C(4)H2), 4.00-4.
30 (m, 2H, C(1)H2), 5.23-5.57
(m, 1H, C(2)H). 13C-NMR (CDCl3) δ: 16.14 (q)
, 19.72 (q), 19.75 (q), 22.63 (
q), 22.73 (q), 24.59 (t), 24.8
2(t), 25.18(t), 27.98(d), 32
．． 71(d), 32.80(d), 36.73(t),
37.32(t), 37.40(t), 37.46(t
), 39.39 (t), 39.19 (t), 59.16
(t), 123.34(d), 139.63(s). MSm/e: 297 (M+ +1), 296 (M+)
, 278, 196, 123, 71 (100%). High resolution MSm/e: Theoretical value C20H40O (M+): 296.3
079. Actual value
:296.3082. Various spectral data of the compound of this example were consistent with that of the natural standard.

Example 21: (6R,10R)-6,10
Preparation of phytol from ,14-trimethylpentadec-1-yne (19) ──────→ (22)

To a suspension of zirconocene dichloride (91.7 mg, 314 μmol) in dichloromethane (1.0 ml) was added trimethylaluminum (1.96 M dichloromethane solution; 1.00 ml, 1.96 mmol) with stirring under ice cooling. After the addition, the temperature was raised to room temperature and further stirred for 3 minutes. After dropping a solution of acetylene compound (19) (97.0 mg, 387 μmol) in dichloromethane (3.0 ml) over 2 minutes,
The mixture was further stirred for 12.5 hours. After distilling off the solvent and excess trimethylaluminum under reduced pressure, the residue was dissolved in n-hexane (1.0 ml x 3) and decanted using a cannula. After concentrating the n-hexane layer to about 1/3, tetrahydrofuran (2.0 ml) was added, and -
Cooled to 30°C. n-Butyllithium (1.40 M hexane solution; 0.44 ml, 616 μmol) was added dropwise,
The mixture was further stirred at the same temperature for 10 minutes, cooled on ice, and further stirred for 35 minutes. Paraformaldehyde (100.3 mg, 3
．． 34 mmol) in tetrahydrofuran (1.0 ml)
The solution was added dropwise and further stirred for 24 hours. After cooling on ice,
A saturated aqueous ammonium chloride solution was added dropwise. After diluting with diethyl ether, washing with water, and drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was treated with column chromatography (silica gel 8.0 g),
Diethyl ether/n-hexane [1:8 (v/v)]
Colorless oily phytol (48.0 mg, 42
%) was obtained. Various spectral data of the title compound of this example were consistent with that of the natural standard.

[0176]

According to the present invention, the chirality of the optically active citronellal as a starting material is preserved and the purity is 100% e.g. e. Various novel optically active compounds, particularly saturated undecyl alcohol compounds represented by the general formula (VI) and the general formula (IX), which are useful intermediates.
) can be obtained. It is also possible to produce (S) type phytol, which does not exist in nature.

Claims (4)

[Claims] Claim 1: General formula (I) [In the formula, R1, R2, R3 and R4 are each independently a lower alkyl group having 1 to 4 carbon atoms, and R5
is the general formula (I') -C(A)=C(B)-E

(I') (wherein A is a halogen atom or a direct carbon-carbon bond together with B, B is a hydrogen atom or a direct carbon-carbon bond together with A, and E is a hydrogen atom or a hydroxy lower alkyl group having 1 to 4 carbon atoms)
is a group represented by the formula, and the configuration at the chiral central carbon atom marked with * in the formula shall each independently and alternatively take only one of the S-configuration and R-configuration. ] A compound represented by Claim 2: General formula (II) [Formula 2] (wherein, R1, R2 and R3 are each independently a lower alkyl group having 1 to 4 carbon atoms, and R6 is a hydroxy group or a protected hydroxy group) or a halogen atom, and the configuration at the chiral central carbon atom marked with * in the formula is each independently and alternatively S-configuration or R-configuration.
A compound represented by the following configurations: [Claim 3] General formula (III) [In the formula, R1, R2 and R3 are each independently a lower alkyl group having 1 to 4 carbon atoms, and R7 is a hydroxy group or a protected hydroxy group and R8 has the general formula (III') -C(P)=C(Q)-T

(III') (wherein P is a hydrogen atom or a direct carbon-carbon bond together with Q, Q is a hydrogen atom or a direct carbon-carbon bond together with P, and T is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms), and the configuration at the chiral central carbon atom marked with * in the formula can alternatively be S-configuration or R-configuration. Compounds represented by [shall take only one of the configurations]. [Claim 4] General formula (IV) [Image Omitted] (wherein, R1, R2, R3 and R9 each independently represent a lower alkyl group having 1 to 4 carbon atoms, and R10
is a lower alkoxycarbonylmethyl group having 1 to 4 carbon atoms, and the configuration at the chiral central carbon atom marked with * in the formula is each independently and alternatively either the S-configuration or the R-configuration. )
A compound represented by