JP2022037094A - Production method of polyene compound having hydroxy group - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for simply and stereoselectively producing a polyene compound having a hydroxy group.

SOLUTION: A production method of a polyene compound having a hydroxy group includes a step or the like for reducing a triple bond after subjecting a compound represented by formula (1A) to a specific coupling reaction (in the formula, R indicates an alkyl group that may have a substituent or an alkenyl group that may have a substituent, k indicates an integer of 0-10, * means that an oxygen atom is α-configuration, β-configuration, or an optional mixture (including an equimolar mixture) of α-configuration and β-configuration to the paper face).

SELECTED DRAWING: None

COPYRIGHT: (C)2022,JPO&INPIT

Description

The present invention relates to a method for producing a polyene compound having a hydroxyl group. Specifically, the present invention relates to a method for producing a polyene compound having a hydroxyl group such as 18 (R) -hydroxyeicosapentaenoic acid (hereinafter referred to as “18R-HEPE”).

Omega 3 fatty acids such as eicosapentaenoic acid (EPA) have long been known to have anti-inflammatory effects. Its mechanism of action is that ω3 fatty acids are converted into metabolites and exert anti-inflammatory properties.

For example, resolvin E1 (RvE1) and resolvin E2 (RvE2) have been identified as EPA-derived anti-inflammatory metabolites, which are metabolites in which a hydroxyl group is added to the 18-position (ω3 position) of EPA18. It is known that (R) -hydroxyeicosapentaenoic acid (18R-HEPE) is used as a common precursor and is produced by 5-lipoxygenase (5-LOX) activity of neutrophils. In other words, it is said that the metabolic pathway starting from 18R-HEPE is related to anti-inflammatory function.

In this way, by searching for 18R-HEPE, its metabolites, its peripheral compounds and the like, it may be possible to find compounds having pharmacological activity such as more effective anti-inflammatory substances. Therefore, a method capable of easily and stereoselectively producing various derivatives such as 18R-HEPE is desired.
Non-Patent Document 1 describes a method for producing 18R-HEPE.

M. Inoue, J. Org. Chem. 2015, 80, 7713.

An object of the present invention is to provide a simple and stereoselective method for producing a polyene compound having a hydroxyl group (18R-HEPE or the like). Specifically, an enin compound having a hydroxyl group represented by the formulas (6) to (8) described later (which may be protected), which is a key intermediate for synthesizing a polyene compound having a hydroxyl group, can be simply and easily prepared. It is an object of the present invention to provide a method for producing a polyene compound having a hydroxyl group in a stereoselective manner and a method for producing a polyene compound having a hydroxyl group in a simple and stereoselective manner via a key intermediate thereof.

As a result of diligent studies to solve the above problems, the present inventor made a three-dimensional selection by reacting an epoxy alcohol compound represented by the formula (3) described later with a compound represented by the formula (9). It has been found that an enyne compound having a hydroxyl group represented by the formulas (6) to (8) (which may be protected) can be produced.

Specifically, when the 1,2-disubstituted epoxy alcohol compound of the trans compound represented by the formula (3T) is reacted with the compound represented by the formula (9), the trans represented by the formula (6T) is reacted. When the body enyne compound can be produced and the cis-form 1,2-di-substituted epoxy alcohol compound represented by the formula (3C) is reacted with the compound represented by the formula (9), the formula (6C) is obtained. It was found that the cis-form enyne compound represented by can be produced. These enyne compounds represented by the formulas (6T) and (6C) are converted into enyne compounds having hydroxyl groups represented by the formulas (8T) and (8C), respectively.

Using this reaction, it has been found that a polyene compound (18-HEPE or the like) represented by the formula (1A) can be easily and stereoselectively produced from the epoxy alcohol compound represented by the formula (3). It was also found that by using an optically active epoxy alcohol compound as a raw material, an enyne compound having an optically active hydroxyl group (including 18R-HEPE, protectin D1, derivatives thereof, etc.) can be easily and stereoselectively produced. rice field. Further studies based on these findings have led to the completion of the present invention.

（式中、Ｒは置換基を有していてもよいアルキル基、又は置換基を有していてもよいアルケニル基を示し、Ｒ^０は、トリメチルシリル基、置換基を有していてもよいアルキル基、又は置換基を有していてもよいアリール基を示し、＊は、紙面に対し酸素原子がα－配置、β－配置、又はα－配置及びβ－配置の任意の混合物（等量混合物を含む）であることを意味する。）
で表される化合物の製造方法であって、塩基の存在下、式（３Ｔ）：

（式中、ＴＭＳはトリメチルシリル基を示し、Ｒ及び＊は前記に同じ。）
で表される化合物（当該化合物中の水酸基は保護基で保護されていてもよい）、及び式（１９）：

（式中、Ｒ^０は前記に同じ。）
で表される化合物を反応させて、必要に応じ水酸基の保護基を除去することを特徴とする、製造方法。
［２］ 式（６Ｔ）：

（式中、Ｒは置換基を有していてもよいアルキル基、又は置換基を有していてもよいアルケニル基を示し、ＴＭＳはトリメチルシリル基を示し、＊は、紙面に対し酸素原子がα－配置、β－配置、又はα－配置及びβ－配置の任意の混合物（等量混合物を含む）であることを意味する。）
で表される化合物の製造方法であって、塩基の存在下、式（３Ｔ）：

（式中、Ｒ、ＴＭＳ及び＊は前記に同じ。）
で表される化合物、及び式（９）：

（式中、ＴＭＳは前記に同じ。）
で表される化合物を反応させることを特徴とする、製造方法。
［３］ 式（１２）：

（式中、Ｒは置換基を有していてもよいアルキル基、又は置換基を有していてもよいアルケニル基を示し、Ｒ^１はアルキル基を示し、Ｒ^２は水酸基の保護基を示し、ｋは０～１０の整数を示し、＊は、紙面に対し酸素原子がα－配置、β－配置、又はα－配置及びβ－配置の任意の混合物（等量混合物を含む）であることを意味する。）
で表される化合物の製造方法であって、
（１）塩基の存在下、式（３Ｔ）：

（式中、ＴＭＳはトリメチルシリル基を示す。Ｒ及び＊は前記に同じ。）
で表される化合物、及び式（９）：

（式中、ＴＭＳは前記に同じ。）
で表される化合物を反応させて、式（６Ｔ）：

（式中、Ｒ、ＴＭＳ及び＊は前記に同じ。）
で表される化合物を得る工程、
（２）上記工程（１）で得られた式（６Ｔ）で表される化合物の水酸基をＲ^２で保護し、ＴＭＳ基を除去して、式（８Ｔ）：

（式中、Ｒ、Ｒ^２及び＊は前記に同じ。）
で表される化合物を得る工程、並びに
（３）上記工程（２）で得られた式（８Ｔ）で表される化合物、及び式（１１）：

（式中、Ｘ^１はハロゲン原子を示す。Ｒ^１及びｋは前記に同じ。）
で表される化合物をカップリングさせて、式（１２）で表される化合物を得る工程、
を含む製造方法。
［４］ 式（１Ａ）：

（式中、Ｒは置換基を有していてもよいアルキル基、又は置換基を有していてもよいアルケニル基を示し、ｋは０～１０の整数を示し、＊は、紙面に対し酸素原子がα－配置、β－配置、又はα－配置及びβ－配置の任意の混合物（等量混合物を含む）であることを意味する。）
で表される化合物の製造方法であって、
（１）塩基の存在下、式（３Ｔ）：

（式中、ＴＭＳはトリメチルシリル基を示す。Ｒ及び＊は前記に同じ。）
で表される化合物、及び式（９）：

（式中、ＴＭＳは前記に同じ。）
で表される化合物を反応させて、式（６Ｔ）：

（式中、Ｒ、ＴＭＳ及び＊は前記に同じ。）
で表される化合物を得る工程、
（２）上記工程（１）で得られた式（６Ｔ）で表される化合物の水酸基をＲ^２で保護し、ＴＭＳ基を除去して、式（８Ｔ）：

（式中、Ｒ^２は水酸基の保護基を示す。Ｒ及び＊は前記に同じ。）
で表される化合物を得る工程、
（３）上記工程（２）で得られた式（８Ｔ）で表される化合物、及び式（１１）：

（式中、Ｘ^１はハロゲン原子を示す。Ｒ^１及びｋは前記に同じ。）
で表される化合物をカップリングさせて、式（１２）：

（式中、Ｒ、Ｒ^１、Ｒ^２、ｋ及び＊は前記に同じ。）
で表される化合物を得る工程、
（４）上記工程（３）で得られた式（１２）で表される化合物を還元して、式（１３）：

（式中、Ｒ、Ｒ^１、Ｒ^２、ｋ及び＊は前記に同じ。）
で表される化合物を得る工程、並びに
（５）上記工程（４）で得られた式（１３）で表される化合物の水酸基の保護基（Ｒ^２）を除去し、エステル（ＣＯ_２Ｒ^１）を加水分解して、式（１Ａ）で表される化合物を得る工程、
を含む製造方法。
［５］ 式（１Ａ）：

（式中、Ｒは置換基を有していてもよいアルキル基、又は置換基を有していてもよいアルケニル基を示し、ｋは０～１０の整数を示し、＊は、紙面に対し酸素原子がα－配置、β－配置、又はα－配置及びβ－配置の任意の混合物（等量混合物を含む）であることを意味する。）
で表される化合物の製造方法であって、
（１）式（８Ｔ）：

（式中、Ｒ^２は水酸基の保護基を示す。Ｒ及び＊は前記に同じ。）
で表される化合物、及び式（１１）：

（式中、Ｒ^１はアルキル基を示し、Ｘ^１はハロゲン原子を示す。ｋは前記に同じ。）
で表される化合物をカップリングさせて、式（１２）：

（式中、Ｒ、Ｒ^１、Ｒ^２、ｋ及び＊は前記に同じ。）
で表される化合物を得る工程、
（２）上記工程（１）で得られた式（１２）で表される化合物を還元して、式（１３）：

（式中、Ｒ、Ｒ^１、Ｒ^２、ｋ及び＊は前記に同じ。）
で表される化合物を得る工程、並びに
（３）上記工程（２）で得られた式（１３）で表される化合物の水酸基の保護基（Ｒ^２）を除去し、エステル（ＣＯ_２Ｒ^１）を加水分解して、式（１Ａ）で表される化合物を得る工程、
を含む製造方法。
［６］ 式（２０Ｃ）：

（式中、Ｒは置換基を有していてもよいアルキル基、又は置換基を有していてもよいアルケニル基を示し、Ｒ^０はトリメチルシリル基、置換基を有していてもよいアルキル基、又は置換基を有していてもよいアリール基を示し、＊は、紙面に対し酸素原子がα－配置、β－配置、又はα－配置及びβ－配置の任意の混合物（等量混合物を含む）であることを意味する。）
で表される化合物の製造方法であって、塩基の存在下、式（３Ｃ）：

（式中、ＴＭＳはトリメチルシリル基を示し、Ｒ及び＊は前記に同じ。）
で表される化合物（当該化合物中の水酸基は保護基で保護されていてもよい）、及び式（１９）：

（式中、Ｒ^０は前記に同じ。）
で表される化合物を反応させて、必要に応じ水酸基の保護基を除去することを特徴とする、製造方法。
［７］ 式（６Ｃ）：

（式中、Ｒは置換基を有していてもよいアルキル基、又は置換基を有していてもよいアルケニル基を示し、ＴＭＳはトリメチルシリル基を示し、＊は、紙面に対し酸素原子がα－配置、β－配置、又はα－配置及びβ－配置の任意の混合物（等量混合物を含む）であることを意味する。）
で表される化合物の製造方法であって、塩基の存在下、式（３Ｃ）：

（式中、Ｒ、ＴＭＳ及び＊は前記に同じ。）
で表される化合物、及び式（９）：

（式中、ＴＭＳは前記に同じ。）
で表される化合物を反応させることを特徴とする、製造方法。
［８］ 式（１８）：

（式中、Ｒは置換基を有していてもよいアルキル基、又は置換基を有していてもよいアルケニル基を示し、Ｒ^２は水酸基の保護基を示し、Ｒ^４は置換基を有していてもよいアルキル基、又は置換基を有していてもよいアルケニル基を示し、＊は、紙面に対し酸素原子がα－配置、β－配置、又はα－配置及びβ－配置の任意の混合物（等量混合物を含む）であることを意味する。）
で表される化合物の製造方法であって、
（１）塩基の存在下、式（３Ｃ）：

（式中、ＴＭＳはトリメチルシリル基を示す。Ｒ及び＊は前記に同じ。）
で表される化合物、及び式（９）：

（式中、ＴＭＳは前記に同じ。）
で表される化合物を反応させて、式（６Ｃ）：

（式中、Ｒ、ＴＭＳ及び＊は前記に同じ。）
で表される化合物を得る工程、
（２）上記工程（１）で得られた式（６Ｃ）で表される化合物の水酸基をＲ^２で保護し、ＴＭＳ基を除去して、式（８Ｃ）：

（式中、Ｒ、Ｒ^２及び＊は前記に同じ。）
で表される化合物を得る工程、
（３）上記工程（２）で得られた式（８Ｃ）で表される化合物、及び式（１５）：

（式中、Ｒ^３は、水素原子、又は鎖状、分岐状若しくは環状アルキル基を示し、或いは２個のＲ^３が互いに結合して隣接するホウ素原子と共に環を形成していてもよく、当該環は置換基を有していてもよい。）
で表される化合物を反応させて、式（１６）：

（式中、Ｒ、Ｒ^２、Ｒ^３及び＊は前記に同じ。）
で表される化合物を得る工程、並びに
（４）上記工程（３）で得られた式（１６）で表される化合物、及び式（１７）：

（式中、Ｘ^２はハロゲン原子を示す。Ｒ^４及び＊は前記に同じ。）
で表される化合物を反応させて、式（１８）で表される化合物を得る工程、
を含む製造方法。 That is, the present invention provides the following method for producing an enyne compound having a hydroxyl group, a method for producing a polyene compound having a hydroxyl group, and the like.
[1] Equation (20T):

(In the formula, R indicates an alkyl group which may have a substituent or an alkenyl group which may have a substituent, and R ⁰ is a trimethylsilyl group and an alkyl which may have a substituent. Indicates an aryl group which may have a group or a substituent, and * indicates an α-arranged, β-arranged, or any mixture of α-arranged and β-arranged oxygen atoms with respect to the paper surface (equal amount mixture). Including).)
A method for producing a compound represented by the formula (3T): in the presence of a base.

(In the formula, TMS indicates a trimethylsilyl group, and R and * are the same as above.)
The compound represented by (the hydroxyl group in the compound may be protected by a protecting group), and the formula (19) :.

(In the formula, R ⁰ is the same as above.)
A production method comprising reacting a compound represented by (1) to remove a protecting group for a hydroxyl group, if necessary.
[2] Equation (6T):

(In the formula, R indicates an alkyl group which may have a substituent or an alkenyl group which may have a substituent, TMS indicates a trimethylsilyl group, and * indicates an oxygen atom of α with respect to the paper surface. -Meaning that it is an arrangement, β-arrangement, or any mixture of α-arrangement and β-arrangement (including an equal amount mixture).
A method for producing a compound represented by the formula (3T): in the presence of a base.

(In the formula, R, TMS and * are the same as above.)
The compound represented by, and the formula (9) :.

(In the formula, TMS is the same as above.)
A production method comprising reacting a compound represented by.
[3] Equation (12):

(In the formula, R indicates an alkyl group which may have a substituent or an alkenyl group which may have a substituent, R ¹ indicates an alkyl group, and R ² indicates a hydroxyl-protecting group. , K indicates an integer from 0 to 10, and * indicates that the oxygen atom is an α-arranged, β-arranged, or any mixture of α-arranged and β-arranged (including an equal amount mixture) with respect to the paper surface. Means.)
It is a method for producing a compound represented by
(1) In the presence of a base, the formula (3T):

(In the formula, TMS represents a trimethylsilyl group. R and * are the same as above.)
The compound represented by, and the formula (9) :.

(In the formula, TMS is the same as above.)
By reacting the compound represented by, the formula (6T):

(In the formula, R, TMS and * are the same as above.)
The process of obtaining the compound represented by
(2) The hydroxyl group of the compound represented by the formula (6T) obtained in the above step (1) is protected by R ² , the TMS group is removed, and the formula (8T):

(In the formula, R, R ² and * are the same as above.)
The step of obtaining the compound represented by the above step (3), the compound represented by the formula (8T) obtained in the above step (2), and the formula (11) :.

(In the formula, X ¹ represents a halogen atom. R ¹ and k are the same as above.)
The step of coupling the compound represented by the formula (12) to obtain the compound represented by the formula (12).
Manufacturing method including.
[4] Equation (1A):

(In the formula, R indicates an alkyl group which may have a substituent or an alkenyl group which may have a substituent, k indicates an integer of 0 to 10, and * indicates oxygen with respect to the paper surface. It means that the atom is an α-configuration, a β-configuration, or any mixture of α-configuration and β-configuration (including an equal amount mixture).
It is a method for producing a compound represented by
(1) In the presence of a base, the formula (3T):

(In the formula, TMS represents a trimethylsilyl group. R and * are the same as above.)
The compound represented by, and the formula (9) :.

(In the formula, TMS is the same as above.)
By reacting the compound represented by, the formula (6T):

(In the formula, R, TMS and * are the same as above.)
The process of obtaining the compound represented by
(2) The hydroxyl group of the compound represented by the formula (6T) obtained in the above step (1) is protected by R ² , the TMS group is removed, and the formula (8T):

(In the formula, R ² indicates a hydroxyl-protecting group. R and * are the same as above.)
The process of obtaining the compound represented by
(3) The compound represented by the formula (8T) obtained in the above step (2), and the formula (11):

(In the formula, X ¹ represents a halogen atom. R ¹ and k are the same as above.)
By coupling the compound represented by, the formula (12):

(In the formula, R, R ¹ , R ² , k and * are the same as above.)
The process of obtaining the compound represented by
(4) The compound represented by the formula (12) obtained in the above step (3) is reduced to the formula (13) :.

(In the formula, R, R ¹ , R ² , k and * are the same as above.)
The step of obtaining the compound represented by (5) and (5) the protecting group (R ² ) of the hydroxyl group of the compound represented by the formula (13) obtained in the above step (4) are removed, and the ester (CO ₂ R ¹ ) is removed. ) To obtain the compound represented by the formula (1A),
Manufacturing method including.
[5] Equation (1A):

(In the formula, R indicates an alkyl group which may have a substituent or an alkenyl group which may have a substituent, k indicates an integer of 0 to 10, and * indicates oxygen with respect to the paper surface. It means that the atom is an α-configuration, a β-configuration, or any mixture of α-configuration and β-configuration (including an equal amount mixture).
It is a method for producing a compound represented by
Equation (1): (8T):

(In the formula, R ² indicates a hydroxyl-protecting group. R and * are the same as above.)
The compound represented by, and the formula (11) :.

(In the formula, R ¹ represents an alkyl group and X ¹ represents a halogen atom. K is the same as above.)
By coupling the compound represented by, the formula (12):

(In the formula, R, R ¹ , R ² , k and * are the same as above.)
The process of obtaining the compound represented by
(2) The compound represented by the formula (12) obtained in the above step (1) is reduced to the formula (13) :.

(In the formula, R, R ¹ , R ² , k and * are the same as above.)
The step of obtaining the compound represented by (3) and (3) the protecting group (R ² ) of the hydroxyl group of the compound represented by the formula (13) obtained in the above step (2) are removed, and the ester (CO ₂ R ¹ ) is removed. ) To obtain the compound represented by the formula (1A),
Manufacturing method including.
[6] Equation (20C):

(In the formula, R indicates an alkyl group which may have a substituent or an alkenyl group which may have a substituent, and R ⁰ is a trimethylsilyl group and an alkyl group which may have a substituent. , Or an aryl group which may have a substituent, * indicates an α-arranged, β-arranged, or any mixture of α-arranged and β-arranged oxygen atoms with respect to the paper surface (equal amount mixture). Including).)
A method for producing a compound represented by the formula (3C): in the presence of a base.

(In the formula, TMS indicates a trimethylsilyl group, and R and * are the same as above.)
The compound represented by (the hydroxyl group in the compound may be protected by a protecting group), and the formula (19) :.

(In the formula, R ⁰ is the same as above.)
A production method comprising reacting a compound represented by (1) to remove a protecting group for a hydroxyl group, if necessary.
[7] Equation (6C):

(In the formula, R indicates an alkyl group which may have a substituent or an alkenyl group which may have a substituent, TMS indicates a trimethylsilyl group, and * indicates an oxygen atom of α with respect to the paper surface. -Meaning that it is an arrangement, β-arrangement, or any mixture of α-arrangement and β-arrangement (including an equal amount mixture).
A method for producing a compound represented by the formula (3C): in the presence of a base.

(In the formula, R, TMS and * are the same as above.)
The compound represented by, and the formula (9) :.

(In the formula, TMS is the same as above.)
A production method comprising reacting a compound represented by.
[8] Equation (18):

(In the formula, R indicates an alkyl group which may have a substituent or an alkenyl group which may have a substituent, R ² indicates a protective group of a hydroxyl group, and R ⁴ has a substituent. Indicates an alkyl group which may have an alkyl group or an alkenyl group which may have a substituent, and * indicates an α-arranged, β-arranged, or α-arranged or β-arranged or β-arranged oxygen atom with respect to the paper surface. Means that it is a mixture of (including an equal amount mixture).
It is a method for producing a compound represented by
(1) In the presence of a base, the formula (3C):

(In the formula, TMS represents a trimethylsilyl group. R and * are the same as above.)
The compound represented by, and the formula (9) :.

(In the formula, TMS is the same as above.)
By reacting the compound represented by, the formula (6C):

(In the formula, R, TMS and * are the same as above.)
The process of obtaining the compound represented by
(2) The hydroxyl group of the compound represented by the formula (6C) obtained in the above step (1) is protected by R ² , the TMS group is removed, and the formula (8C):

(In the formula, R, R ² and * are the same as above.)
The process of obtaining the compound represented by
(3) The compound represented by the formula (8C) obtained in the above step (2), and the formula (15):

(In the formula, R ³ represents a hydrogen atom or a chain, branched or cyclic alkyl group, or two R ^3s may be bonded to each other to form a ring together with an adjacent boron atom. The ring may have a substituent.)
By reacting the compound represented by the formula (16) :.

(In the formula, R, R ² , R ³ and * are the same as above.)
The step of obtaining the compound represented by the above step (4), the compound represented by the formula (16) obtained in the above step (3), and the formula (17) :.

(In the formula, X ² represents a halogen atom. R ⁴ and * are the same as above.)
The step of reacting the compound represented by the formula (18) to obtain the compound represented by the formula (18).
Manufacturing method including.

In the present invention, a compound represented by the formula (19) (including the compound represented by the formula (9)) is reacted with the 1,2-disubstituted epoxy alcohol compound of the trans compound represented by the formula (3T). Then, the enyne compound of the trans form represented by the formula (20T) (including the compound represented by the formula (6T)) can be selectively produced.

Further, when the cis-form 1,2-disubstituted epoxy alcohol compound represented by the formula (3C) is reacted with the compound represented by the formula (19) (including the compound represented by the formula (9)), the compound is reacted. , The cis-form enyne compound represented by the formula (20C) (including the compound represented by the formula (6C)) can be selectively produced.

Further, by utilizing this reaction, a polyene compound (18R-HEPE or the like) having a hydroxyl group represented by the formulas (1A) and (1B) can be easily and stereoselected from the epoxy alcohol compound represented by the formula (3). Can be manufactured as a target.

Furthermore, by using an optically active epoxy alcohol compound that is easily available as a raw material, an enyne compound (18R-HEPE, protectin D1, etc.) having an optically active hydroxyl group can be easily and stereoselectively produced.

Since the reaction of the present invention is highly versatile and various substituents can be introduced, it is suitable as a tool for searching for peripheral compounds of bioactive substances such as 18R-HEPE.

で表した場合、紙面に対し原子（Ａ）が向こう側に結合していること（α－配置）を意味し、該結合手を

で表した場合、紙面に対し原子（Ａ）が手前に結合していること（β－配置）を意味し、該結合手を

で表した場合、紙面に対し原子（Ａ）がα－配置、β－配置、又はα－配置及びβ－配置の任意の混合物（等量混合物を含む）のいずれをも意味する。 Hereinafter, the present invention will be described in detail.
1. 1. Explanation of symbols
In the present specification, unless otherwise specified in the chemical structural formula, the bond between the carbon atom (C) and the atom (A)

When represented by, it means that the atom (A) is bonded to the other side of the paper surface (α-arrangement), and the bonded hand is bonded to the other side.

When represented by, it means that the atom (A) is bonded to the front of the paper surface (β-arrangement), and the bonded hand is bonded.

When represented by, the atom (A) means any of α-arranged, β-arranged, or any mixture of α-arranged and β-arranged (including an equal amount mixture) with respect to the paper surface.

In the present specification, the geometric isomer of the 1,2-di-substituted CC double bond is referred to as cis (C) or trans (T).

In the present specification, the stereochemistry of the 1,2-di-substituted epoxy is regarded as the geometric isomer of the 1,2-di-substituted CC double bond from which the oxygen atom of the epoxy has been removed, and the cis (C). ) Or transformer (T).

In the present specification, in the epoxy alcohol compound represented by the formula (3), when the oxygen atom of the epoxy and the two carbon atoms are represented by a solid line, the oxygen atom of the epoxy is bonded to the other side of the paper surface. (Α-arrangement) and / or bonded to the front of the paper (β-arrangement).

In the present specification, in the epoxy alcohol compound represented by the formula (3), when both the hydroxyl group and the oxygen atom of the epoxy are bonded to the other side of the paper surface (α-arrangement), or the hydroxyl group and the epoxy. When both oxygen atoms are bonded to the front of the paper (β-arranged), it is expressed as syn, and one of the oxygen atoms of the hydroxyl group and the epoxy is in the α-arranged and the other is β-arranged. When it is an arrangement, it is expressed as anti.

As used herein, the term "enyne compound" means a compound having a CC double bond and a CC triple bond in the molecule, and the term "polyene compound" means a CC two bond in the molecule. It means a compound having two or more double bonds.

2. 2. Synthesis of polyene compounds having hydroxyl groups
2.1 Synthesis of polyene compound represented by the formula (1A) The polyene compound (including 18R-HEPE) represented by the formula (1A) can be produced according to the reaction formula 1.

(In the formula, TMS indicates a trimethylsilyl group, R indicates an alkyl group which may have a substituent, or an alkenyl group which may have a substituent, R ¹ indicates an alkyl group, and R ² Indicates a protecting group for a hydroxyl group, X ¹ indicates a halogen atom, k indicates an integer of 0 to 10. * indicates an α-arranged, β-arranged, or α-arranged and β-arranged oxygen atom with respect to the paper surface. It means that it is an arbitrary mixture (including an equal amount mixture) of the arrangement.)

(3T) + (9) → (6T):
By reacting the compound represented by the formula (3T) with the compound represented by the formula (9) in the presence of a base, the compound represented by the formula (6T) can be produced.

Examples of the "alkyl group" in the "alkyl group which may have a substituent" represented by R include chain-shaped or branched C1-C10 alkyl groups. Specifically, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an n-hexyl group, n. -Heptyl group, n-octyl group, n-nonyl group, n-decyl group and the like can be mentioned. It is preferably a C1-C6 alkyl group, more preferably a C1-C4 alkyl group, and particularly preferably a methyl group, an ethyl group or an n-propyl group.

The "alkyl group" may have a substituent, and examples of the substituent include a carboxyl group, an ester group (for example, a C1 to C3 alkoxycarbonyl group such as a methoxycarbonyl group and an ethoxycarbonyl group), and the like. Examples thereof include a hydroxyl group which may be protected, an oxo group (= O), an epoxy group and the like. The "alkyl group" may have at least one (preferably 1 to 3) groups selected from the group consisting of these substituents.

Specific examples of the "alkyl group which may have a substituent" include an ethyl group, a 3-carboxypropyl group, a 3- (methoxycarbonyl) propyl group, a 3- (ethoxycarbonyl) propyl group and the like. ..

Examples of the "alkenyl group" in the "alkenyl group which may have a substituent" represented by R include chain-shaped or branched C2-C12 alkenyl groups. The alkenyl group has one or more (particularly 1 to 3) CC double bonds. The CC double bond geometric isomer may be trans or cis, or E or Z. Specifically, for example, a vinyl group, a 1-propenyl group, an allyl group, a 1-butenyl group, a 2-butenyl group (crotyl group), a 3-butenyl group, a 1-pentenyl group, a 2-pentenyl group, a 3-pentenyl group. Examples thereof include a group, a 4-pentenyl group, a 1-hexenyl group, a 2-hexenyl group, an octa-2,5-dienyl group and the like.

The "alkenyl group" may have a substituent, and examples of the substituent include a carboxyl group, an ester group (for example, a C1 to C3 alkoxycarbonyl group such as a methoxycarbonyl group and an ethoxycarbonyl group), and the like. A hydroxyl group which may be protected, an oxo group (= O), an epoxy group, an amide group (for example, a group represented by the formula: -CON ( ^RA ) ₂ (in the formula, ^RA is a hydrogen atom or a hydroxyl group). It indicates an alkyl group which may have, and ^RA may be the same or different.)) And the like. The "alkenyl group" may have at least one (preferably 1 to 3) groups selected from the group consisting of these substituents.

Specific examples of the "alkenyl group which may have a substituent" include (Z) -2-pentenyl group, (2Z, 5Z) -octa-2,5-dienyl group and the like.

The stereochemistry of the carbon atom marked with * is preferably an equal amount mixture (racemic compound as a compound) of α-configuration, β-configuration, α-configuration and β-configuration, and is preferably β-configuration. More preferred.

The compound represented by the formula (3T) is described in Tetrahedron Letters 50 (2009) 6079-6082, Org. Biomol. Chem., 2017, 15, 8614-8626, etc., or described later in "3. Synthesis of raw material compound". It can be manufactured according to or in accordance with the description of. Further, the compound represented by the formula (9) is a known compound or a compound easily available to those skilled in the art.

This reaction can usually be carried out in a solvent. Examples of the solvent include ether solvents such as diethyl ether (Et ₂ O), diisopropyl ether (iPr ₂ O), tetrahydrofuran (THF), dioxane, cyclopentyl methyl ether, 4-methyltetrahydropyran, etc .; n-hexane, n. -A hydrocarbon solvent such as pentane can be mentioned. From this, one kind or two or more kinds of solvents can be used. THF is preferred.

The base may be basic enough to extract the hydrogen atom (proton) bonded to the sp carbon of the compound represented by the formula (9), for example, alkyllithium (methyllithium, ethyllithium). , Isopropyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, etc.), alkali metal hydrides (sodium hydride, lithium hydride, etc.), lithium dialkylamides (lithium diisopropylamide, etc.) and the like. Preferred is n-butyllithium. The amount of the base used is usually 2 to 4 mol, preferably 2 to 3 mol, based on 1 mol of the compound represented by the formula (9).

In this reaction, an additive may be further used to promote the reaction. Examples of the additive include hexamethylphosphoric acid triamide (HMPA), N, N'-dimethylpropylene urea and the like. When an additive is used, the amount used is usually 0 to 5 mol, preferably 0 to 2 mol, relative to 1 mol of the compound represented by the formula (9).

The amount of the compound represented by the formula (3T) to be used is usually 1 to 2 mol, preferably 1 to 1.5 mol, based on 1 mol of the compound represented by the formula (9).

The reaction can usually be carried out at −50 ° C. to 50 ° C. (preferably −20 ° C. to 20 ° C.) in about 30 minutes to 5 hours.

（式中、Ｒ、ＴＭＳ及び＊は前記に同じ。） This reaction is characterized in that the stereochemistry (trans form: T) of the epoxy of the compound represented by the formula (3T), which is the raw material, is reflected in the trans form of the compound represented by the formula (6T). is doing. This reaction is considered to proceed by the following reaction mechanism. The notation of α-configuration and β-configuration of compounds in the following formula is relative configuration.

(In the formula, R, TMS and * are the same as above.)

In this reaction, the hydroxyl group of the compound represented by the formula (3T) is protected with an appropriate protecting group (for example, a tert-butyldimethylsilyl (TBS) group, etc.), and then the formula (9) is present in the presence of a base. ), And then the protecting group is removed to produce the compound represented by the formula (6T). The protection of the hydroxyl group can be carried out by a known method. However, from the viewpoint of reactivity and shortening of the number of steps, it is preferable to react without protecting the hydroxyl group.

Alternatively, after protecting the hydroxyl group of the compound represented by the formula (3T) with an appropriate protecting group (for example, a tert-butyldimethylsilyl (TBS) group, etc.), it is represented by the formula (9) in the presence of a base. The compound represented by the formula (7T) can also be produced by reacting with the compound.

(6T) → (7T):
By protecting the hydroxyl group of the compound represented by the formula (6T) with a protecting group, the compound represented by the formula (7T) can be produced.

Examples of the “hydroxyl protecting group” represented by R ² include tert-butyldimethylsilyl (TBS), triethylsilyl (TES) group, triisopropylsilyl (TIPS) group, tert-butyldiphenylsilyl (TBDPS) group and the like. Cyril-based protecting group; α-ethoxyethyl group, tetrahydropyranyl (THP) group and other acetal-based protecting groups can be mentioned.

A known method can be used for the reaction of protecting the hydroxyl group with a protecting group. For example, it can be carried out according to or according to the description of Org. Biomol. Chem., 2017, 15, 8614-8626, J. Org. Chem., 2015, 80, 7713-7726.

For example, in the case of a silyl-based protecting group, the hydroxyl group can be protected by reacting a silicon compound having a leaving group such as a corresponding silyl halide (particularly silyl chloride) in the presence of a base (imidazole or the like). .. In the case of an acetal-based protecting group, the hydroxyl group can be protected by reacting the corresponding vinyl ether compound (ethyl vinyl ether, dihydropyran (DHP), etc.) in the presence of an acid catalyst (p-toluenesulfonic acid, etc.). can.

(7T) → (8T):
By removing the trimethylsilyl (TMS) group from the compound represented by the formula (7T), the compound represented by the formula (8T) can be produced.

A known method can be used for the reaction for removing the TMS group. For example, it can be carried out according to or according to the description of J. Org. Chem., 2011, 76, 5433-5437, J. Org. Chem., 2015, 80, 7713-7726.

The reaction can be carried out, for example, by reacting the compound represented by the formula (7T) with a base (alkali metal carbonate such as potassium carbonate) in a solvent (alcohol such as methanol) at 0 to 50 ° C. can.

(11) + (8T) → (12):
By subjecting the compound represented by the formula (11) and the compound represented by the formula (8T) to a coupling reaction (Castro-Steffence coupling reaction, etc.), the compound represented by the formula (12) is produced. can do.

Examples of the "alkyl group" represented by R ¹ include chain or branched C1 to C6 alkyl groups. Specifically, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an n-hexyl group, etc. Can be mentioned. It is preferably a C1-C3 alkyl group, and more preferably a methyl group or an ethyl group.

Examples of the halogen atom represented by X ¹ include a chlorine atom, a bromine atom and an iodine atom, and a bromine atom is preferable.

k is preferably an integer of 1 to 5, more preferably an integer of 1 to 3, and particularly preferably 1.

The compound represented by the formula (11) of the raw material is a known compound or a compound easily available to those skilled in the art, for example, according to the method described in Chem. Commun., 2017, 53, 1813-1816, etc. It can be manufactured according to the above.

This reaction can usually be carried out in a solvent in the presence of a copper compound, a base and an activator.

Examples of the solvent include amide solvents such as dimethylformamide (DMF), dimethylacetamide (DMA) and N-methylpyrrolidone (NMP); ether solvents such as tetrahydrofuran (THF) and dioxane. From this, one kind or two or more kinds of solvents can be used. DMF is preferred.

The amount of the compound represented by the formula (8T) to be used is usually 0.5 to 2 mol, preferably 0.8 to 1.5 mol, based on 1 mol of the compound represented by the formula (11).

Examples of the copper compound include monovalent copper (I) compounds, and specific examples thereof include copper chloride (CuCl), copper bromide (CuBr), copper iodide (CuI), and copper cyanide (CuCN). And so on. The amount of the copper compound used is usually 1 to 3 mol, preferably 1 to 1.5 mol, based on 1 mol of the compound represented by the formula (11).

Examples of the base include organic bases and inorganic bases. Examples of the organic base include triethylamine, diisopropylethylamine and the like. Examples of the inorganic base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate, sodium hydrogencarbonate and potassium carbonate; calcium carbonate, cesium carbonate and the like. Alkali earth metal carbonates; examples include alkali metal phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate. The amount of the base used is usually 1 to 3 mol, preferably 1 to 2 mol, relative to 1 mol of the compound represented by the formula (11).

Examples of the activator include alkali metals halides such as sodium iodide and potassium iodide, and sodium iodide is preferable. The amount of the activator used is usually 1 to 3 mol, preferably 1 to 2 mol, based on 1 mol of the compound represented by the formula (11).

The reaction can usually be carried out at −20 ° C. to 50 ° C. (preferably 0 ° C. to 40 ° C.) for about 30 minutes to 12 hours.

(12) → (13):
By subjecting the compound represented by the formula (12) to a reduction reaction (cis hydrogenation reaction to a CC triple bond), the compound represented by the formula (13) can be produced.

The reduction reaction is not particularly limited as long as it can reduce the CC triple bond to form a cis-C CC double bond, and a known method can be used. For example, it can be carried out according to or according to the description of Org. Biomol. Chem., 2017, 15, 8614-8626, J. Org. Chem., 2015, 80, 7713-7726.

In the reduction reaction, for example, Ni (OAc) _{2.4H 2 O} / sodium borohydride (NaBH ₄ ) / ethylenediamine can be used as the reducing agent. As the solvent, for example, alcohol (methanol, ethanol, isopropyl alcohol, etc.) or the like can be used. The reaction can be carried out at 0 ° C. to 30 ° C. for about 1 minute to 2 hours.

The reduction reaction can also be carried out using a Lindlar catalyst under a hydrogen atmosphere. As the solvent, for example, a hydrocarbon solvent (n-hexane or the like), an alcohol (methanol, ethanol, isopropyl alcohol or the like) or the like can be used. The reaction can usually be carried out at −20 ° C. to 30 ° C. for about 1 minute to 2 hours.

（式中、Ｒ、Ｒ^１、Ｒ^２、ｋ及び＊は前記に同じ。） In the reduction reaction, the compound represented by the formula (13a) and the compound represented by the formula (13a) in which the triple bond at the C14-C15 position of the raw material represented by the formula (12) remains unreduced. Mixtures containing may be obtained. In that case, the triple bond at the C14-C15 position is represented by the formula (13) in which the triple bond at the C14-C15 position is cis-reduced by further subjecting the mixture to a reduction reaction (Zn (Cu / Ag), Zn (Cu), etc.). Compound can be obtained.

(In the formula, R, R ¹ , R ² , k and * are the same as above.)

(13) → (14):
By deprotecting the protecting group (R ² ) of the hydroxyl group of the compound represented by the formula (13), the compound represented by the formula (14) can be produced. A known method can be used for the deprotection reaction.

For example, when the protecting group is a silyl-based protecting group, it can be deprotected by reacting with a compound containing a fluoride ion, an organic acid, a salt thereof, or the like. Examples of the compound containing fluoride ions include tetrabutylammonium fluoride (TBAF), potassium fluoride (KF), tris (dimethylamino) sulfonium difluorotrimethylsilicate (TASF), triethylamine trifluoride hydroxide, and pyridine fluoride. Examples thereof include hydrofluoric acid salt. Examples of the organic acid or a salt thereof include p-toluenesulfonic acid (p-TsOH), pyridinium p-toluenesulfonate (PPTS), acetic acid and the like. Examples of the solvent include ether solvents such as tetrahydrofuran (THF), dioxane, cyclopentyl methyl ether, 4-methyltetrahydropyran and the like, and one or more of these mixed solvents can be used.

When the protecting group is an acetal-based protecting group, it can be deprotected by reacting with an acid. Examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid, organic acids such as p-toluenesulfonic acid (p-TsOH), pyridinium p-toluenesulfonate (PPTS) and acetic acid. Examples of the solvent include water; alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran (THF), dioxane, cyclopentyl methyl ether and 4-methyltetrahydropyran, and one or two of these. The above mixed solvent can be used.

(14) → (1A):
By hydrolyzing the ester of the compound represented by the formula (14), the compound represented by the formula (1A) can be produced. A known method can be used for the hydrolysis reaction.

For example, it can be hydrolyzed in a solvent in the presence of an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide. Examples of the solvent include water; alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran (THF), dioxane, cyclopentyl methyl ether and 4-methyltetrahydropyran, and one or two of these. The above mixed solvent can be used.

The compound represented by the formula (1A) can be synthesized through the steps represented by the reaction formula 1. The stereochemistry of the carbon atom represented by * of the compound represented by the formula (1A) (R-form, S-form or a mixture of both) is the carbon represented by * of the compound represented by the formula (3T) which is a raw material. Derived from the stereochemistry of atoms. That is, the stereochemistry of the compound represented by the formula (3T) is maintained up to the compound represented by the formula (1A). As described in the section of "3. Synthesis of raw material compound" described later, the stereochemistry of the carbon atom represented by * of the compound represented by the formula (3T) can be arbitrarily prepared and thus various. By using the compound represented by the formula (3T) having stereochemistry as a raw material, the stereochemistry of the compound represented by the formula (1) can be arbitrarily controlled.

（式中、ＴＭＳ、Ｒ及びｋは前記に同じ。） For example, the compound represented by the formula ((R) -1A) can be produced from the compound represented by the formula ((R) -3T).

(In the formula, TMS, R and k are the same as above.)

（式中、ＴＭＳ、Ｒ及びｋは前記に同じ。） Further, the compound represented by the formula ((S) -1A) can be produced from the compound represented by the formula ((S) -3T).

(In the formula, TMS, R and k are the same as above.)

（式中、Ｒ^１０はアルキル基を示す。） Since the compound represented by the formula (1A) includes 18R-HEPE having pharmacological activity and its peripheral compounds, it is useful as a pharmaceutical or a precursor thereof. The compound represented by the formula (1A) can be further chemically converted by using a known method in order to exhibit desired physical properties (pharmacological effect and the like). For example, the carboxyl group can be converted into a salt, a carboxylic acid ester, a carboxylic acid amide, or the like, or the hydroxyl group can be converted into a carboxylic acid ester, a phosphoric acid ester, or the like. Examples of the phosphoric acid ester include those in which a group consisting of a phospholipid shown below is bonded to an oxygen atom of a hydroxyl group.

(In the formula, R ¹⁰ represents an alkyl group.)

Examples of the "alkyl group" represented by R ¹⁰ include chain or branched C1 to C30 alkyl groups. More preferably, it is a C1-C20 alkyl group.

Further, the compound represented by the formula (1A) can also be converted into a prodrug or the like by using these chemical conversion methods. A prodrug means a drug that is chemically modified to exert (activate) a pharmacological effect by being converted into a compound having pharmacological activity after reaching the body or target site of a mammal (particularly human). do.

（式中、Ｒ^０は、トリメチルシリル（ＴＭＳ）基、置換基を有していてもよいアルキル基、又は置換基を有していてもよいアリール基を示し、ＴＭＳ、Ｒ及び＊は前記に同じ。） In a reaction for producing a compound represented by the formula (6T) from the compound represented by the formula (3T) and the compound represented by the formula (9) represented by the reaction formula 1, the compound represented by the formula (9) is produced. Even if the TMS group of the compound is a more versatile group, the reaction proceeds in the same manner. That is, the reaction is expressed by the following equation. The compound represented by the formula (19) is a known compound or a compound easily available to those skilled in the art.

(In the formula, R ⁰ indicates a trimethylsilyl (TMS) group, an alkyl group which may have a substituent, or an aryl group which may have a substituent, and TMS, R and * are the same as described above. .)

Examples of the "alkyl group" in the "alkyl group which may have a substituent" represented by ^R0 include chain-shaped or branched C1-C10 alkyl groups. Specifically, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an n-hexyl group, n. -Heptyl group, n-octyl group, n-nonyl group, n-decyl group and the like can be mentioned.

The "alkyl group" may have a substituent, and the substituent is not particularly limited as long as it does not adversely affect the reaction, and is, for example, an alkoxy group (C1 to C6 alkoxy group, etc.). , Aryl group (phenyl group, toluyl group, xsilyl group, etc.) and the like. The "alkyl group" may have at least one (preferably 1 to 3) groups selected from the group consisting of these substituents.

Examples of the "aryl group" in the "aryl group which may have a substituent" represented by R ⁰ include an aryl group in which a single ring or two or more rings are fused. Specific examples thereof include a phenyl group and a naphthyl group.

The "aryl group" may have a substituent, and the substituent is not particularly limited as long as it does not adversely affect the reaction, and is, for example, an alkyl group (C1 to C6 alkyl group, etc.). , Alkoxy groups (C1 to C6 alkoxy groups, etc.) and the like. The "aryl group" may have at least one (preferably 1 to 3) groups selected from the group consisting of these substituents.

In this reaction, the hydroxyl group of the compound represented by the formula (3T) is protected with an appropriate protecting group (for example, a tert-butyldimethylsilyl (TBS) group, etc.), and then the formula (19) is present in the presence of a base. ) Is reacted with the compound represented by the formula (20T) to remove the protecting group, whereby the compound represented by the formula (20T) can also be produced. The protection of the hydroxyl group can be carried out by a known method. However, from the viewpoint of reactivity and shortening of the number of steps, it is preferable to react without protecting the hydroxyl group.

2.2 Synthesis of polyene compound represented by formula (1B) The polyene compound represented by formula (1B) is a compound having a characteristic (Z, E, E) -trienediol skeleton and is known as a pharmacology. Includes active substances such as protectin D1, maresin 1, resolvin E1, and peripheral compounds thereof.

（式中、Ｒ^３は、水素原子、又は鎖状、分岐状若しくは環状アルキル基を示し、或いは２個のＲ^３が互いに結合して隣接するホウ素原子と共に環を形成していてもよく、当該環は置換基を有していてもよい。Ｒ^４は、置換基を有していてもよいアルキル基、又は置換基を有していてもよいアルケニル基を示し、Ｘ^２は、ハロゲン原子を示す。ＴＭＳ、Ｒ、Ｒ^２及び＊は前記に同じ。） The polyene compound represented by the formula (1B) can be produced according to the reaction formula 2.

(In the formula, R ³ represents a hydrogen atom or a chain, branched or cyclic alkyl group, or two R ^3s may be bonded to each other to form a ring together with an adjacent boron atom. The ring may have a substituent. R ⁴ represents an alkyl group which may have a substituent or an alkenyl group which may have a substituent, and X ² represents a halogen atom. Shown. TMS, R, R ² and * are the same as above.)

(3C) → (6C):
By reacting the compound represented by the formula (3C) with the compound represented by the formula (9) in the presence of a base, the compound represented by the formula (6C) can be produced.

The compounds represented by the formula (3C) are Y. Kobayashi, Tetrahedron Lett. 2009, 50, 6079, Y. Kobayashi, Tetrahedron Lett. 2011, 52, 3001, Y. Kobayashi, Tetrahedron Lett. 2014, 55, 2738, etc. , Or according to or in accordance with the description of "3. Synthesis of raw material compound" described later. Further, as described above, the compound represented by the formula (9) is a known compound or a compound easily available to those skilled in the art.

This reaction can be carried out in the same manner as the reaction for producing the compound represented by the formula (6T) from the compound represented by the formula (3T) in the reaction formula 1.

（式中、Ｒ及びＴＭＳは前記に同じ。） This reaction is characterized in that the stereochemistry (cis form: C) of the epoxy of the compound represented by the formula (3C), which is the raw material, is reflected in the cis form of the compound represented by the formula (6C). is doing. This reaction is considered to proceed by the following reaction mechanism. The notation of α-configuration and β-configuration of compounds in the following formula is relative configuration.

(In the formula, R and TMS are the same as above.)

In this reaction, the hydroxyl group of the compound represented by the formula (3C) is protected with an appropriate protecting group (for example, a tert-butyldimethylsilyl (TBS) group, etc.), and then the formula (9) is present in the presence of a base. ), And then the protecting group is removed to produce the compound represented by the formula (6C). The protection of the hydroxyl group can be carried out by a known method. However, from the viewpoint of reactivity and shortening of the number of steps, it is preferable to react without protecting the hydroxyl group.

Alternatively, after protecting the hydroxyl group of the compound represented by the formula (3C) with an appropriate protecting group (for example, a tert-butyldimethylsilyl (TBS) group, etc.), it is represented by the formula (9) in the presence of a base. The compound represented by the formula (7C) can also be produced by reacting with the compound.

(6C) → (7C):
By protecting the hydroxyl group of the compound represented by the formula (6C) with a protecting group, the compound represented by the formula (7C) can be produced.

This reaction can be carried out in the same manner as the reaction for producing the compound represented by the formula (7T) from the compound represented by the formula (6T) in the reaction formula 1.

(7C) → (8C):
By removing the trimethylsilyl group (TMS group) from the compound represented by the formula (7C), the compound represented by the formula (8C) can be produced.

This reaction can be carried out in the same manner as the reaction for producing the compound represented by the formula (8T) from the compound represented by the formula (7T) in the reaction formula 1.

(8C) + (15) → (16):
The compound represented by the formula (16) can be produced by hydroborating the compound represented by the formula (8C) with the compound represented by the formula (15).

This reaction can be carried out according to or according to, for example, Tetrahedron Letters, 50 (2009) 6079-6082, Tetrahedron Letters, 52 (2011) 3001-3004, Tetrahedron Letters, 55 (2014) 2738-2741 and the like. ..

Examples of the "chain, branched or cyclic alkyl group" represented by R ³ include C1 to C12 alkyl groups. Specifically, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, and a sheamil group (Me ₂ CHCHMe). -), N-hexyl group, texyl group (Me ₂ CHCMe _2- ), cyclohexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, isopinocampyl group and the like. .. Preferred examples thereof include a sheamil group (Me ₂ CHCHMe-), a texyl group (Me ₂ CHCMe _2- ), a cyclohexyl group and the like. It is preferred that one of the two ^R3s is a branched or cyclic alkyl group and the other is a hydrogen atom, or the two ^R3s are branched or cyclic alkyl groups.

When "two R ^3s are bonded to each other to form a ring together with an adjacent boron atom, and the ring may have a substituent" represented by R ³ , the group: -B (R ³ ) ₂ Examples include the following groups.

Since this reaction is a reaction in which HB is added to the CC triple bond with anti-Markovnikov, it is preferable that R ³ is a bulky group. Specific examples of the compound represented by the formula (15) include disiamylborane (Sia ₂ BH), texylborane (ThexBH ₂ ), dicyclohexylborane (Cy ₂ BH), and borabicyclo [3,3,1] nonane (9-BBN). ), Catecholborane (CatBH), Pinacolborane (PinBH), Disiamylborane (Ipc ₂ BH) and the like.

This reaction can usually be carried out by reacting 1 mol of the compound represented by the formula (8C) with 1 to 2 mol of the compound represented by the formula (15) in a solvent such as tetrahydrofuran (THF). The reaction temperature is usually −10 to 30 ° C., and the reaction time is usually about 0.5 to 5 hours.

The compound represented by the formula (16) can be directly applied to the Suzuki coupling, which is the next step, but the group: −B (R3) ² is a boronic acid ester derived from catecholborane, _{pinacoleborane} , or the like. If it is a group, the boronic acid ester can be hydrolyzed to convert it to group: −B (OH) ₂ , and then attached to the Suzuki coupling.

(16) + (17) → (18):
By subjecting the compound represented by the formula (16) and the compound represented by the formula (17) to a coupling (Suzuki coupling or the like) reaction in the presence of a catalyst, the compound represented by the formula (18) can be obtained. obtain.

The "alkyl group which may have a substituent" and the "alkenyl group which may have a substituent" represented by R ⁴ may have the "substituted group" represented by R described above. It is the same as the definition of "alkyl group" and "alkenyl group which may have a substituent". R and R ⁴ may be the same or different.

Examples of the halogen atom represented by X ² include a chlorine atom, a bromine atom and an iodine atom, and a bromine atom is preferable.

This reaction can be carried out according to or according to, for example, Tetrahedron Letters, 50 (2009) 6079-6082, Tetrahedron Letters, 52 (2011) 3001-3004, Tetrahedron Letters, 55 (2014) 2738-2741 and the like. ..

This reaction can usually be carried out in a solvent, in the presence of a catalyst and a base.

Examples of the solvent include water; aromatic hydrocarbon solvents (benzene, toluene, xylene, etc.), aliphatic hydrocarbon solvents (pentane, n-hexane, cyclohexane, etc.), ether solvents (diethyl ether, diisopropyl ether, etc.). Hydrocarbon, etc.) and the like. As the solvent, one kind or a mixture of two or more kinds can be used. An ether solvent (particularly, tetrahydrofuran) is preferable.

The amount of the compound represented by the formula (17) to be used is usually 0.5 to 2 mol, preferably 0.8 to 1.5 mol, based on 1 mol of the compound represented by the formula (16). ..

Examples of the catalyst include a palladium catalyst. Examples of the palladium catalyst include a zero-valent or divalent palladium catalyst, for example, Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ , Pd ₂ (dba) ₃ , Pd [P (t-Bu) ₃ ] ₂ , Pd (OAc) ₂ , etc. The amount of the palladium catalyst used is usually about 1 to 30 mol% with respect to the compound represented by the formula (16).

In this reaction, a ligand may be added if necessary. The ligand is preferably a phosphine ligand, for example, triphenylphosphine (PPh ₃ ), tri (o-toluyl) phosphine (P (o-tol) ₃ ), 1,2-bis (diphenylphosphino). ) Etan (dppe), 1,3-bis (diphenylphosphino) propane (dppp), 1,1'-bis (diphenylphosphino) ferrocene (dppf), 2,2'-bis (diphenylphosphino) -1 , 1'-BINAP, bis [2- (diphenylphosphino) phenyl] ether and the like. When a ligand is used, the amount used is usually about 1 to 30 mol% with respect to the compound represented by the formula (16).

Examples of the base include inorganic bases such as alkali metal hydroxides such as lithium hydroxide and sodium hydroxide. In this reaction, the inorganic base can usually be used as an aqueous solution thereof (for example, a 0.5-4 equivalent (N) aqueous solution). The amount of the base used is usually 2 to 20 mol, preferably 4 to 15 mol, relative to the compound represented by the formula (16).

The reaction can be carried out at about 0 to 50 ° C. and about 0.5 to 10 hours.

(18) → (1B):
By deprotecting the protecting group (R ² ) of the hydroxyl group of the compound represented by the formula (18), the compound represented by the formula (1B) can be produced.

This reaction can be carried out in the same manner as the reaction for producing the compound represented by the formula (14) from the compound represented by the formula (13) in the reaction formula 1. Alternatively, this reaction should be carried out according to or in accordance with the description of, for example, Tetrahedron Letters, 50 (2009) 6079-6082, Tetrahedron Letters, 52 (2011) 3001-3004, Tetrahedron Letters, 55 (2014) 2738-2741. Can be done.

In the method for producing a compound represented by the above formula (1B), when the group represented by R or ^R4 has a substituent such as a carboxyl group or a hydroxyl group, the present invention can be used in any step as necessary. The substituent can be protected with a protecting group or the protected substituent can be deprotected by a known method as long as the reaction is not adversely affected.

（式中、Ｒ^０、ＴＭＳ、Ｒ及び＊は前記に同じ。） In a reaction for producing a compound represented by the formula (6C) from the compound represented by the formula (3C) and the compound represented by the formula (9) represented by the reaction formula 2, the compound represented by the formula (9) is produced. Even if the TMS group of the compound is a more versatile group, the reaction proceeds in the same manner. That is, the reaction is expressed by the following equation. The compound represented by the formula (19) is a known compound or a compound easily available to those skilled in the art.

(In the formula, R ⁰ , TMS, R and * are the same as above.)

In this reaction, the hydroxyl group of the compound represented by the formula (3C) is protected with an appropriate protecting group (for example, a tert-butyldimethylsilyl (TBS) group, etc.), and then the formula (19) is present in the presence of a base. ) Is reacted with the compound represented by the formula (20C) to remove the protecting group, whereby the compound represented by the formula (20C) can also be produced.

3. 3. Synthesis of Raw Material Compounds The compounds represented by the formulas (2) and (3), which are the raw material compounds used in the above reaction formulas 1 and 2, can be produced, for example, as follows.

（式中、ＴＭＳ及びＲは前記に同じ。） The compounds represented by the formulas (2T) and (3T), which are transforms of the compounds represented by the formulas (2) and (3), can be produced, for example, as in the reaction formula 3.

(In the formula, TMS and R are the same as above.)

(Rac-2T) → (anti (R) -3T) + ((S) -2T):
By subjecting the compound represented by the formula (rac-2T) to the Sharpless asymmetric epoxidation reaction, the compound represented by the formula (anti (R) -3T) and the compound represented by the formula ((S) -2T) are represented. Can be obtained. In other words, in this reaction, the compound represented by the racemic formula (rac-2T) is kinetic resolution divided into the compound represented by the formula (anti (R) -3T) and the formula (((). S) -The compound represented by -2T) is obtained. This reaction can usually be carried out by reacting the oxidizing agent in a solvent in the presence of a metal catalyst having an asymmetric ligand.

This reaction can be carried out according to or according to, for example, Tetrahedron Letters 50 (2009) 6079-6082, Org. Biomol. Chem., 2017, 15, 8614-8626. The raw material compound represented by the formula (rac-2T) can be produced according to or according to the description in these documents.

Examples of the solvent include halogenated hydrocarbons (methylene chloride, chloroform, etc.) and the like. Methylene chloride is preferred.

Examples of the asymmetric ligand include D- (-)-tartaric acid diester. Specific examples thereof include D- (-)-dimethyl tartrate (DMT), D- (-)-diethyl tartrate (DET), and D- (-)-diisopropyl tartrate (DIPT). The amount of the D- (-)-tartaric acid diester used is usually 1 to 2 mol, preferably 1 to 1.5 mol, based on 1 mol of the compound represented by the formula (rac-2T).

Examples of the metal used as the metal catalyst include titanium (IV). Titanium tetraethoxydo (Ti (OEt) ₄ ), titanium tetra n-propoxide (Ti (OnPr) ₄ ), titanium tetraisopropoxide as precursors that form a complex with an asymmetric ligand in the reaction system. Examples thereof include titanium tetra C1 to C6 alkoxides such as (Ti (OiPr) ₄ ) and titanium tetra tert-butoxide (Ti (OtBu) ₄ ). The amount of the metal catalyst used is usually 1 for 1 mol of the compound represented by the formula (rac-2T) in terms of metal (titanium (IV)) (that is, the amount of titanium tetra C1 to C6 alkoxide used). It is ~ 2 mol, preferably 1 ~ 1.5 mol.

Examples of the oxidizing agent include peroxides such as tert-butyl peroxide (TBHP) and cumene hydroperoxide. The amount of the oxidizing agent used is usually 1 to 2 mol, preferably 1 to 1.5 mol, based on 1 mol of the compound represented by the formula (rac-2T).

This reaction is preferably carried out under anhydrous conditions, for example, in the presence of a dehydrating agent such as Molecular Sieves (MS3A, MS4A). This reaction usually proceeds at −30 to 0 ° C. for 1 to 20 hours.

The compound represented by the formula (anti (R) -3T) and the compound represented by the formula ((S) -2T) obtained by this reaction each have an enantio excess rate (ee) of 95% or more (further 97). % Or more, especially 99% or more).

When the enantiomer L- (+)-tartaric acid diester is used instead of the D- (-)-tartaric acid diester as the asymmetric ligand, the formula (anti (anti) obtained by the reaction formula 3 is used. Instead of the compound represented by R) -3T) and the compound represented by the formula ((S) -2T), the compound represented by the formula (anti (S) -3T) and the compound represented by the formula ((R)), respectively. -The compound represented by -2T) can be obtained.

((S) -2T) → ((S) -3T):
By subjecting the compound represented by the formula ((S) -2T) to an oxidation reaction (epoxidation reaction of an olefin), the compound represented by the formula ((S) -3T) can be obtained. This reaction can usually be carried out by reacting an oxidizing agent in a solvent.

Examples of the solvent include water; alcohol solvents such as methanol, ethanol and isopropyl alcohol; ketone solvents such as acetone, methyl ethyl ketone and diethyl ketone; halogen solvents such as dichloromethane, 1,2-dichloroethane and chloroloform. Be done.

Examples of the oxidizing agent include hydrogen peroxide, m-chloroperbenzoic acid (mCPBA), perbenzoic acid, magnesium monoperoxyphthalate (MMPP), peracetic acid, tert-butyl hydroperoxide (TBHP) and the like. The amount of the oxidizing agent used is usually 1 to 2 mol, preferably 1 to 1.2 mol, based on 1 mol of the compound represented by the formula ((S) -2T).

The reaction usually proceeds at −20 to 30 ° C. for 0.5 to 4 hours.

((S) -3T) → ((R) -3T):
The compound represented by the formula ((S) -3T) is subjected to a Mitsunobu reaction to react with a carboxylic acid compound to form an ester compound, which is then subjected to a hydrolysis reaction to form a carbon solid to which a hydroxyl group is bonded. A compound represented by the inverted formula ((R) -3T) can be obtained.

The Mitsunobu reaction is a reaction well known to those skilled in the art and is usually the presence of dialkyl azodicarboxylate (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.), triphenylphosphine in a solvent. Below, it can be carried out by reacting with a carboxylic acid compound (for example, acetic acid, 4-nitrobenzoic acid, etc.).

The ester compound obtained by the Mitsunobu reaction is hydrolyzed by a known method (for example, an alkali metal hydroxide such as LiOH or NaOH) to obtain a compound represented by the formula ((R) -3T).

（式中、Ｒ及びＴＭＳは前記に同じ。） The compounds represented by the formulas (2T) and (3T), which are trans-forms of the compounds represented by the formulas (2) and (3), and the cis-forms thereof, the formulas (2C) and (3C). The represented compound can be produced, for example, as in Reaction Scheme 4.

(In the formula, R and TMS are the same as above.)

(4) → ((R) -5):
By subjecting the compound represented by the formula (4) to an asymmetric reduction reaction, the compound represented by the formula ((R) -5) can be produced.

This reaction was performed, for example, by J. Org. Chem., 2011, 76, 5433-5437, Org. Biomol. Chem., 2017, 15, 8614-8626, Tetrahedron Letters 55 (2014) 2738-2741, J. Am. It can be carried out in accordance with or in accordance with the description of Chem. Soc. 1997, 119, 8738-8739, etc.

Specifically, this reaction can usually be carried out in a solvent in the presence of a metal catalyst having an asymmetric ligand.

Examples of the solvent include alcohols (particularly, isopropyl alcohol and the like).

・[(R,R)-N-(2-アミノ-1,2-ジフェニルエチル)-p-トルエンスルホンアミド]クロロ(p-シメン)ルテニウム(II)（RuCl[(R,R)-Tsdpen](p-cymene)）、

・[(R,R)-N-(2-アミノ-1,2-ジフェニルエチル)-p-トルエンスルホンアミド]クロロ(メシチレン)ルテニウム(II)（RuCl[(R,R)-Tsdpen](mesitylene)）、

・[(R,R)-N-(2-アミノ-1,2-ジフェニルエチル)ペンタフルオロベンゼンスルホンアミド]クロロ(p-シメン)ルテニウム(II)（RuCl[(R,R)-Fsdpen](p-cymene)）、

等が挙げられる。 Examples of the metal catalyst having an asymmetric ligand include a ketone selective asymmetric hydrogenated ruthenium catalyst, for example.
-Chloro [(R, R) -N- [2- [2- (4-methylbenzyloxy) ethyl] amino-1,2-diphenylethyl] -p-toluenesulfonamide] ruthenium (II),

-[(R, R) -N- (2-amino-1,2-diphenylethyl) -p-toluene sulfonamide] chloro (p-cymene) ruthenium (II) (RuCl [(R, R) -Tsdpen] (p-cymene)),

-[(R, R) -N- (2-amino-1,2-diphenylethyl) -p-toluenesulfonamide] chloro (mesitylene) ruthenium (II) (RuCl [(R, R) -Tsdpen] (mesitylene) )),

-[(R, R) -N- (2-amino-1,2-diphenylethyl) pentafluorobenzene sulfonamide] chloro (p-cymene) ruthenium (II) (RuCl [(R, R) -Fsdpen] ( p-cymene)),

And so on.

The amount of the metal catalyst having an asymmetric ligand used is usually 0.1 to 20 mol%, preferably 0.5 to 10 mol%, based on the compound represented by the formula (4).

（式中、ＴＭＳ及びＲは前記に同じ。） Instead of these metal catalysts having an asymmetric ligand, the metal catalyst having an asymmetric ligand of the enantiomer is used.
-Chloro [(S, S) -N- [2- [2- (4-methylbenzyloxy) ethyl] amino-1,2-diphenylethyl] -p-toluenesulfonamide] ruthenium (II),
-[(S, S) -N- (2-amino-1,2-diphenylethyl) -p-toluenesulfonamide] chloro (p-cymene) ruthenium (II) (RuCl [(S, S) -Tsdpen] (p-cymene)), · [(S, S) -N- (2-amino-1,2-diphenylethyl) -p-toluenesulfonamide] Chloro (mesitylene) ruthenium (II) (RuCl [(S,,) S)-Tsdpen] (mesitylene)), · [(S, S) -N- (2-amino-1,2-diphenylethyl) pentafluorobenzenesulfonamide] Chloro (p-cymene) ruthenium (II) (RuCl) When [(S, S) -Fsdpen] (p-cymene)), etc. are used, the mirror image thereof is used instead of the compound represented by the formula ((R) -5) obtained by the reaction formula 4. The compound represented by the formula ((S) -5) is obtained.

(In the formula, TMS and R are the same as above.)

In the subsequent steps in the reaction formula 4, the compound represented by the formula ((R) -5) is used, and the compound of the (S) form, that is, the formulas ((R) -2T), ((R)). It synthesizes compounds represented by -3T), ((R) -2C) and (syn (R) -3C), and is represented by the above enantiomer formula ((S) -5). By using the compounds, the corresponding compounds of the (S) form, that is, ((S) -2T), ((S) -3T), ((S) -2C) and (syn (S) -3C). ) Can be synthesized.

((R) -5) → ((R) -2T):
By subjecting the compound represented by the formula ((R) -5)) to a reduction reaction (trans hydrogenation reaction to a CC triple bond), the compound represented by the formula ((R) -2T) can be obtained. Can be manufactured. This reaction can be carried out according to or according to, for example, Tetrahedron Letters 50 (2009) 6079-6082, Org. Biomol. Chem., 2017, 15, 8614-8626. Specifically, it can be carried out by reducing the triple bond of the compound represented by the formula ((R) -5)) in a solvent with a reducing agent.

Examples of the solvent include ether solvents such as tetrahydrofuran (THF), dioxane, cyclopentyl methyl ether, 4-methyltetrahydropyran and the like.

Examples of the reducing agent include lithium aluminum hydride (LAlH ₄ ), bis (2-methoxyethoxy) aluminum sodium hydride (Red-Al) and the like. The amount of the reducing agent used is usually 1 to 4 mol, preferably 1 to 2 mol, based on 1 mol of the compound represented by the formula ((R) -5)).

The reaction can usually be carried out at 0-30 ° C. for 1-20 hours. Thereby, the compound represented by the formula ((R) -2T) of the trans form can be produced.

((R) -2T) → ((R) -3T):
By subjecting the compound represented by the formula ((R) -2T) to an oxidation reaction (epoxidation reaction of an olefin), the compound represented by the formula ((R) -3T) can be obtained.

This reaction can be carried out in the same manner as the reaction for producing a compound represented by the formula ((S) -3T) from the compound represented by the formula ((S) -2T) of the reaction formula 3. In this reaction, the compound represented by the formula ((R) -3T) is usually obtained as a mixture of syn and anti.

((R) -5) → ((R) -2C):
By subjecting the compound represented by the formula ((R) -5) to a reduction reaction (cis hydrogenation reaction to a CC triple bond), the compound represented by the formula ((R) -2C) is produced. can do.

This reaction can be carried out according to or according to the description of, for example, Org. Biomol. Chem., 2017, 15, 8614-8626, J. Org. Chem., 2015, 80, 7713-7726. Specifically, it can be carried out by reducing the triple bond of the compound represented by the formula ((R) -5) in a solvent under a hydrogen atmosphere with a reducing agent.

As the reducing agent, for example, Zn (Cu / Ag), Zn (Cu), Lindlar reagent and the like can be used. In that case, for example, water, an alcohol solvent (methanol, ethanol, etc.) or the like can be used as the solvent. The reaction usually proceeds at 0 to 50 ° C. for about 1 minute to 2 hours.

((R) -2C) → (syn (R) -3C):
By subjecting the compound represented by the formula ((R) -2C) to an oxidation reaction (epoxidation reaction of an olefin), a compound represented by the formula (syn (R) -3C) can be obtained.

This reaction can be carried out in the same manner as the reaction for producing a compound represented by the formula ((R) -3T) from the compound represented by the formula ((R) -2T) of the reaction formula 3.

The compounds represented by the formulas (2) and (3) and their enantiomers produced as described above are the raw materials for the reaction shown in the above-mentioned "2. Synthesis of polyene compound having a hydroxyl group". Used as.

Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited thereto.

Example 1
(R) -1-((2R, 3R) -3- (trimethylsilyl) oxylan-2-yl) propan-1-ol [(R) -3T] and (S, E) -1- (trimethylsilyl) pent- Synthesis of 1-en-3-ol [(S) -2T]

D- (-)-DIPT (0.27 mL, 1.29 mmol) was added to an ice-cold solution containing Ti (O-iPr) ₄ (0.30 mL, 1.01 mmol) in CH ₂ Cl ₂ (4 mL). The solution was stirred at 0 ° C. for 30 minutes and cooled to -15 ° C. A solution containing compound rac-2T (159 mg, 1.00 mmol) in CH ₂ Cl ₂ (1 mL) was added to the cooled solution. After stirring at -15 ° C for 30 minutes, the solution was cooled to -40 ° C and t-BuOOH (4.34 M, 0.35 mL, 1.65 mmol in CH ₂ Cl ₂ ) was added dropwise. The reaction was continued at -20 ° C for 8 hours, and Me ₂ S (0.40 mL, 5.4 mmol) was added to stop the reaction. After stirring at -20 ° C for 10 minutes, 10% aqueous tartaric acid solution (0.1 mL), NaF (296 mg, 7.17 mmol) and Celite (150 mg) were added. The mixture was vigorously stirred at room temperature and filtered through a pad of Celite using CH ₂ Cl ₂ . The filtrate was mixed with 1N aqueous NaOH solution (10 mL, 10 mmol). The mixture was stirred at room temperature for 30 minutes and extracted 3 times with CH ₂ Cl ₂ . The combined extracts were washed with saline, dried over DDL ₄ and concentrated. The residue was purified by silica gel chromatography (hexane / EtOAc) to give epoxy alcohol (R) -3T (70 mg, 40%) and allyl alcohol (S) -2T (65 mg, 41%). The enantiomeric excess (ee) of epoxy alcohol and allyl alcohol was 98% and 99%, respectively, by ¹ H NMR spectroscopy of the induced MTPA ester.
Epoxy alcohol (R) -3T:
Liquid; Rf = 0.40 (hexane / EtOAc 5: 1); ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.07 (s, 9 H), 1.01 (t, J = 7.5 Hz, 3 H), 1.45-1.62 ( m, 2 H), 1.86 (br s, 1 H), 2.37 (d, J = 3.8 Hz, 1 H), 2.89 (t, J = 3.6 Hz, 1 H), 3.77-3.86 (m, 1 H) Allyl alcohol (S) -2T:
Liquid; Rf = 0.47; ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.07 (s, 9 H), 0.92 (t, J = 7.5 Hz, 3 H), 1.49-1.64 (m, 3 H), 3.96- 4.07 (m, 1 H), 5.84 (dd, J = 18.7, 1.2 Hz, 1 H), 6.03 (dd, J = 18.7, 5.3 Hz, 1 H).
The ¹ H NMR spectra of compounds (R) -3T and (S) -2T were consistent with those reported (Org. Biomol. Chem., 2017, 15, 8614-2626).

Example 2
Synthesis of (R, E) -7- (trimethylsilyl) hept-4-ene-6-in-3-ol [(R) -6T]

N-BuLi (1.55 M, 8.75 mL, 13.6 mmol in hexanes) was added dropwise to an ice-cold solution containing trimethylsilylacetylene (2.20 mL, 15.9 mmol) in THF (2 mL). After stirring at 0 ° C. for 30 minutes, a solution containing compound (R) -3T (398 mg, 2.28 mmol) in HMPA (4.8 mL) and THF (2 mL) was added. The solution was stirred at room temperature for 4 hours and diluted with saturated aqueous NH ₄ Cl solution. The mixture was extracted twice with EtOAc. The combined extracts were dried over DDL ₄ and concentrated. Chromatography of the residue on silica gel (hexane / EtOAc) gave compound (R) -6T (302 mg, 73%).

Liquid; Rf = 0.53 (toluene / EtOAc 9: 1); ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.19 (s, 9 H), 0.94 (t, J = 7.5 Hz, 3 H), 1.49-1.62 ( m, 3 H), 4.09 (q, J = 6.0 Hz, 1 H), 5.73 (dd, J = 15.9 Hz, 1.5 Hz, 1 H), 6.20 (dd, J = 15.9, 6.0 Hz, 1 H); ¹³ C-APT NMR (75 MHz, CDCl ₃ ) δ -0.1 (+), 9.6 (+), 29.7 (-), 73.3 (+), 94.9 (-), 103.2 (-), 109.8 (+), 146.7 (+).

Example 3
Synthesis of (R, E) -tert-butyldimethyl ((7- (trimethylsilyl) hept-4-ene-6-in-3-yl) oxy) silane [(R) -7T]

Tert-Butyldimethylsilyl chloride (TBSCl) (233 mg, 1.55 mmol) in an ice-cold solution containing compound (R) -6T (231 mg, 1.27 mmol) and imidazole (213 mg, 3.13 mmol) in CH ₂ Cl ₂ (2 mL). ) Was added. The solution was stirred at room temperature for 1 hour and diluted with saturated NaHCO ₃ aqueous solution. The resulting mixture was extracted 3 times with CH ₂ Cl ₂ . The combined extracts were washed with brine, dried over DDL ₄ , concentrated to give a residue, which was purified by silica gel chromatography (hexane / EtOAc) to compound (R) -7T (329 mg, 88%). ) Was obtained.

Liquid; Rf = 0.74 (hexane / EtOAc 9: 1); ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.03 (s, 3H), 0.04 (s, 3 H), 0.19 (s, 9 H), 0.87 ( t, J = 7.5 Hz, 3 H), 0.90 (s, 9 H), 1.45-1.56 (m, 2 H), 4.07-4.15 (m, 1 H), 5.69 (dd, J = 15.9 Hz, 1.8 Hz) , 1 H), 6.18 (dd, J = 15.9, 4.8 Hz, 1 H); ¹³ C-APT NMR (75 MHz, CDCl ₃ ) δ -4.8 (+), -4.5 (+), -0.1 (+) , 9.3 (+), 18.3 (-), 25.9 (+), 30.7 (-), 73.4 (+), 94.2 (-), 103.8 (-), 108.8 (+), 147.4 (+).

Example 4
Synthesis of (R, E) -tert-butyl (hept-4-ene-6-in-3-yloxy) dimethylsilane [(R) -8T]

K ₂ CO ₃ (229 mg, 1.66 mmol) was added to a solution containing compound (R) -7T (313 mg, 1.06 mmol) in MeOH (2 mL). The mixture was stirred at room temperature for 1.5 hours and diluted with saturated aqueous NH ₄ Cl solution. The resulting mixture was extracted twice with EtOAc. The combined extracts were washed with brine, dried over DDL ₄ , concentrated to give a residue, which was purified by silica gel chromatography (hexane / EtOAc) and TBS ether (R) -8T (206 mg, 87). %) Was obtained.

Liquid; Rf = 0.38 (hexane); ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.03 (s, 3H), 0.05 (s, 3 H), 0.87 (t, J = 7.5 Hz, 3 H), 0.90 ( s, 9 H)
, 1.46-1.58 (m, 2 H), 2.86 (d, J = 2.1 Hz, 1 H), 4.07-4.18 (m, 1 H), 5.65 (dm, J = 15.9 Hz, 1 H), 6.23 (dd) , J = 15.9, 5.1 Hz, 1 H); ¹³ C-APT NMR (75 MHz, CDCl ₃ ) δ -4.8 (+), -4.5 (+), 9.3 (+), 18.3 (-), 25.9 (+) ), 30.6 (-), 73.4 (+), 77.3 (-), 82.2 (-), 107.7 (-), 148.2 (+).

Example 5
Synthesis of Methyl (R, E) -18-((tert-butyldimethylsilyl) oxy) Icosa-16-ene-5,8,11,14-tetrinoate [(R) -12)]

Enin compound (R) -8T (122 mg, 0.544 mmol) in a mixture containing CuI (196 mg, 1.03 mmol), Cs ₂ CO ₃ (252 mg, 0.773 mmol), and NaI (154 mg, 1.03 mmol) in DMF (1 mL). ), And a DMF (0.5 mL) solution containing bromide 11 (151 mg, 0.511 mmol) were added. After stirring at room temperature for 7 hours, the mixture was diluted with saturated aqueous NH ₄ Cl solution. The resulting mixture was extracted twice with EtOAc. The combined extracts were dried over DDL ₄ and concentrated. The residue was purified by silica gel chromatography (hexane / EtOAc 9: 1) to give compound (R) -12 (141 mg, 63%).

Liquid; Rf = 0.33 (hexane / EtOAc 9: 1); ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.02 (s, 6 H), 0.04 (s, 6 H), 0.86 (t, J = 7.5 Hz, 3 H), 0.89 (s, 9 H), 1.43-1.57 (m, 2 H), 1.81 (quint., J = 7.2 Hz, 2 H), 2.24 (t, J = 7.0 Hz, 2 H), 2.43 (t, J = 7.5 Hz, 1 H), 3.10-3.19 (m, 4 H), 3.26-3.32 (m, 2 H), 3.68 (s, 3 H), 4.04-4.13 (m, 1 H), 5.62 (d, J = 15.9 Hz, 1 H), 6.09 (dd, J = 15.9, 5.1 Hz, 1 H).

Example 6
Synthesis of Methyl (R, 5Z, 8Z, 11Z, 14Z, 16E) -18-((tert-butyldimethylsilyl) Oxy) Icosa-5,8,11,14,16-Pentaenoate [(R) -13]

NaBH ₄ (20 mg, 0.53 mmol) was added to an ice-cold suspension containing Ni (OAc) _{2.4H 2 O} (105 mg, 0.423 mmol) in EtOH (0.5 mL). The flask was purged with hydrogen and ethylenediamine (0.050 mL, 0.74 mmol) was added. After stirring at room temperature for 10 minutes, a solution of EtOH (0.5 mL) containing compound (R) -12 (149 mg, 0.340 mmol) was added. The mixture is stirred at room temperature for 90 minutes, filtered through a pad of cerite with EtOAc, the filtrate is concentrated under reduced pressure to give an oil, which is purified by silica gel chromatography (hexane / EtOAc) to the compound (R). A mixture of) -13 and (R) -13a (94 mg, 62%) was obtained.

Liquid; Rf = 0.55 (hexane / EtOAc 9: 1). The abundance ratio of compounds (R) -13 and (R) -13a was 4: 1 from the calculation of the peak height of the ¹³ C NMR signal.

Cu (OAc) ₂ (200 mg, 1.1 mmol) was added to the slurry containing Zn (2.0 g, 31 mmol) in H ₂ O (6 mL), and the mixture was stirred at room temperature for 15 minutes. AgNO ₃ (202 mg, 1.19 mmol) was added to this mixture, stirred at room temperature for an additional 30 minutes and filtered using a Hirsch funnel. The remaining solid was continuously washed with H ₂ O (5 mL x 2), MeOH (5 mL x 2), acetone (5 mL x 2), and Et ₂ O (5 mL x 2), and the washed solid was washed with MeOH. A solution containing a mixture of compounds (R) -13 and (R) -13a (4: 1, 64 mg, 0.143 mmol) in (2 mL) and H ₂ O (1 mL) was added under nitrogen. The mixture was stirred at 40-45 ° C. for 12 hours and filtered through a pad of Celite with EtOAc. The filtrate was extracted twice with EtOAc. The combined extracts were washed with brine, dried over DDL ₄ and concentrated to give a residual oil, which was purified by silica gel chromatography (hexane / EtOAc) to compound (R) -13 (57 mg). , 89%).

Liquid; Rf = 0.55 (hexane / EtOAc 9: 1); ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.03 (s, 6 H), 0.05 (s, 6 H), 0.87 (t, J = 7.2 Hz, 3 H), 0.90 (s, 9 H), 1.51 (quint., J = 7.0 Hz, 2 H), 1.70 (quint., J = 7.0 Hz, 2 H), 2.03-2.18 (m, 2 H), 2.32 (t, J = 7.5 Hz, 2 H), 2.71-2.88 (m, 4 H), 2.95 (t, J = 5.9 Hz, 2 H), 3.66 (s, 3 H), 4.10 (q, J = 6.0 Hz, 1 H), 5.28-5.48 (m, 7 H), 5.65 (dd, J = 15.0, 6.0 Hz, 1 H), 5.99 (t, J = 11.0 Hz, 1 H), 6.45 (dd, J) = 15.0, 11.0 Hz, 1 H); ¹³ C-APT NMR (75 MHz, CDCl ₃ ) δ -4.7 (-), -4.3 (-), 9.7 (+), 18.3 (-), 24.8 (-), 25.7 (-), 26.0 (+), 26.1 (-), 26.6 (-), 31.2 (-), 33.5 (-), 51.5 (+), 74.4 (+), 124.2 (+), 128.0 (+), 128.1 (+), 128.3 (+), 128.4 (+), 128.5 (+), 128.9 (+), 129.0 (+), 129.1 (+), 137.3 (+), 174.1 (-).

Example 7
Synthesis of Methyl (R, 5Z, 8Z, 11Z, 14Z, 16E) -18-Hydroxyikosa-5,8,11,14,16-Pentanoate [(R) -14)]

Bu ₄ NF (TBAF) (1.0 M in THF, 0.40 mL, 0.40 mmol) was added to an ice-cold solution containing compound (R) -13 (56 mg, 0.125 mmol) in THF (0.3 mL). The solution was stirred at room temperature for 5 hours and diluted with saturated aqueous NH ₄ Cl solution. The resulting mixture was extracted 3 times with EtOAc. The combined extracts were dried on DDL ₄ and concentrated to give a residual oil, which was purified by silica gel chromatography (hexane / EtOAc) to give compound (R) -14 (28 mg, 67%). rice field.

Liquid; Rf = 0.26 (hexane / EtOAc 5: 1); ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.93 (t, J = 7.2 Hz, 3 H), 1.46-1.82 (m, 4 H), 2.02- 2.22 (m, 2 H), 2.32 (t, J = 7.5 Hz, 2 H), 2.74-2.90 (m, 4 H), 2.97 (t, J = 5.6 Hz, 2 H), 3.67 (s, 3 H) ), 4.06-4.16 (m, 1 H), 5.30-5.47 (m, 7 H), 5.70 (dd, J = 15.0, 6.9 Hz, 1 H), 6.01 (t, J = 11.0 Hz, 1 H), 6.53 (dd, J = 15.0, 11.0 Hz, 1 H); ¹³ C-APT NMR (75 MHz, CDCl ₃ ) δ 9.8, 24.8, 25.71, 25.74, 26.2, 26.6, 30.2, 33.5, 51.6, 74.2, 125.6, 127.7, 128.0, 128.1, 128.4, 128.6, 128.9, 129.1, 130.2, 136.4, 174.2.

Example 8
18R-HEPE synthesis

Aqueous LiOH solution (2.0N, 0.15mL, 0.30 mmol) was added to a solution containing compound (R) -14 (10 mg, 0.030 mmol) in THF (0.2 mL) and MeOH (0.2 mL). The mixture was stirred at room temperature for 1 hour, diluted with buffer (pH 5.0) and the resulting mixture was extracted 3 times with EtOAc. The combined extracts were washed with saline and DDL ₄ and concentrated. The residue was purified by silica gel chromatography (hexane / EtOAc) to give 18R-HEPE (5.4 mg, 56%).

Liquid; Rf = 0.33 (CH ₂ Cl ₂ / THF 9: 1); ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.93 (t, J = 7.6 Hz, 3 H), 1.52-1.64 (m, 2 H) , 1.71 (quint., J = 7.4 Hz, 2 H), 2.13 (q, J = 7.0 Hz, 2 H), 2.36 (t, J = 7.2 Hz, 2 H), 2.82 (t, J = 5.8 Hz, 2 H), 2.85 (t, J = 5.5 Hz, 2 H), 2.98 (t, J = 6.4 Hz, 2 H), 4.14 (q, J = 6.6 Hz, 1 H), 5.32-5.46 (m, 7) H), 5.69 (dd, J = 15.2, 6.6 Hz, 1 H), 6.00 (t, J = 11.0 Hz, 1 H), 6.54 (dd, J = 15.2, 11.0 Hz, 1 H); ¹³ C-APT NMR (75 MHz, CDCl ₃ ) δ 9.8, 24.5, 25.7, 25.8, 26.2, 26.5, 30.2, 33.2, 74.2, 125.7, 127.7, 128.0, 128.1, 128.3, 128.6, 128.9, 129.1, 130.4, 135.9, 178.0.
The ¹ H NMR and ¹³ C NMR spectra were consistent with those reported (J. Biol. Chem., 2012, 287, 10525-10534.).

Example 9
Synthesis of (Z) -1- (trimethylsilyl) octo-1-en-3-ol [16C]

NaBH ₄ (456 mg, 12.1 mmol) was added to an ice-cold suspension containing Ni (OAc) _{2.4H 2 O} (2.99 g, 12.0 mmol) in MeOH (14 mL). The flask was replaced with hydrogen and ethylenediamine (1.36 mL, 20.1 mmol) was added to the mixture. After 10 minutes, a solution containing alcohol 15 (1.99 g, 10.0 mmol) was added to MeOH (6 mL). The mixture was stirred at room temperature overnight and filtered through a silica gel pad to give olefin 16C (1.64 g, 82%).

Liquid; R _f 0.62 (toluene / EtOAc 9: 1); ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.14 (s, 9 H), 0.89 (t, J = 6.6 Hz, 3 H), 1.22-1.66 ( m, 9 H), 4.16-4.28 (m, 1 H), 5.66 (d, J = 14.1, 1 H), 6.23 (dd, J = 14.1, 9.0 Hz, 1 H).

Example 10
Synthesis of 1- [3- (trimethylsilyl) oxylan-2-yl] hexane-1-ol [17C]

M-CPBA (70% purity, 7.02 g, 28.5 mmol) in an ice-cold mixture containing compound 16C (4.72 g, 23.6 mmol) and NaHCO ₃ (4.74 g, 56.4 mmol) in CH ₂ Cl ₂ (50 mL). Was added. The mixture was stirred at room temperature for 4 hours, then Me ₂ S (3.45 mL, 46.6 mmol) was added and quenched. The mixture was filtered through a cerite pad. The residue was diluted with saturated NaHCO ₃ aqueous solution and extracted twice with EtOAc. The combined organic layer was dried with DDL ₄ and then concentrated to obtain a residue. The residue was purified by silica gel chromatography (solvent: hexane / EtOAc) to give epoxy alcohol 17C (3.08 g, 60%).

Liquid; R _f = 0.47 (hexane / EtOAc 5: 1); ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.14 (s, 9 H), 0.90 (t, J = 6.9 Hz, 3 H), 1.18-1.70 (m, 8 H), 2.03 (d, J = 3.3, 1 H), 2.35 (d, J = 5.4, 1 H), 3.12 (dd, J = 7.8, 5.4 Hz, 1 H), 3.30-3.40 ( m, 1 H).

Example 11
Synthesis of compound [20C]

(1) Synthesis of compounds 18C and 19C
N-BuLi (1.55 M in hexane, 0.80 mL, 1.24 mmol) was added dropwise to an ice-cold solution containing trimethylsilylacetylene (0.20 mL, 1.45 mmol) in THF (0.5 mL). After stirring at 0 ° C. for 30 minutes, a solution containing 17C (68 mg, 0.31 mmol) of epoxy alcohol was added to HMPA (0.50 mL, 2.87 mmol) and THF (0.4 mL). The solution was stirred at 0 ° C. for 1.5 hours and diluted with saturated aqueous NH ₄ Cl solution. The mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over DDL ₄ , and then concentrated. The residue was purified by silica gel chromatography (solvent: hexane / EtOAc) to give a mixture of compound 18C (34 mg, 48%) and compound 19C (25 mg, 25%).

Liquid; R _f 0.55 (hexane / EtOAc 5: 1); ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.19 (s, 9 H), 0.89 (t, J = 6.9 Hz, 3 H), 1.24-1.70 ( m, 8 H), 1.87 (d, J = 3.6 Hz, 1 H), 4.60-4.74 (m, 1 H), 5.55 (dd, J = 10.8 Hz, 0.9 Hz, 1 H), 5.93 (dd, J) = 10.8 Hz, 8.4 Hz, 1 H).

(2) Synthesis of enyne compound 20C
K ₂ CO ₃ (67 mg, 0.48 mmol) was added to the solution containing the above mixture in MeOH (1 mL). The mixture was stirred at room temperature for 1 hour and then diluted with saturated aqueous NH ₄ Cl solution. The resulting mixture was extracted twice with EtOAc. The combined extracts were dried on DDL ₄ and then concentrated to give a residue. The residue was purified by silica gel chromatography (solvent: hexane / EtOAc) to give enyne compound 20C (29 mg, 61% from 17C).

Liquid; R _f = 0.30 (hexane / EtOAc 5: 1); ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.88 (t, J = 6.6 Hz, 3 H), 1.20-1.78 (m, 8 H), 1.92 (br s, 1 H), 3.13 (dd, J = 2.4 Hz, 0.9 Hz, 1 H), 4.58-4.76 (m, 1 H), 5.52 (ddd, J = 10.8 Hz, 2.4 Hz, 0.9 Hz, 1 H), 5.98 (ddd, J = 10.8 Hz, 8.4 Hz, 0.9 Hz, 1 H); ¹³ C-APT NMR (75 MHz, CDCl ₃ ) δ 14.1 (+), 22.6 (-), 24.8 (-), 31.8 (-), 36.5 (-), 70.1 (+), 79.6 (-), 82.8 (-), 108.9 (+), 147.6 (+).

Examples 12-18
According to the procedure described in Example 2 and Example 11 (1) above, an enyne compound was synthesized by reacting various epoxy compounds with an alkyne in the presence of a base (n-BuLi). The reaction formula and product data are shown below.

Example 12
Synthesis of compound [22C]

Compound 22C:
Liquid; R _f = 0.66 (hexane); ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.05 (s, 3 H), 0.08 (s, 3 H), 0.19 (s, 9 H), 0.80-1.00 (m) , 12 H), 1.20-1.62 (m, 8 H), 4.54-4.72 (m, 1 H), 5.44 (dd, J = 11.1 Hz, 0.9 Hz, 1 H), 5.87 (dd, J = 11.1 Hz, 8.7 Hz, 1 H); ¹³ C-APT NMR (75 MHz, CDCl ₃ ) δ -4.8 (+), -4.3 (+), -0.03 (+), 14.2 (+), 18.3 (-), 22.7 ( -), 24.9 (-), 26.0 (+), 31.7 (-), 37.5 (-), 70.8 (+), 99.4 (-), 101.6 (-), 108.3 (+), 148.3 (+); HRMS ( FAB ⁺ ) calcd for C ₁₉ H ₃₇ OSi ₂ [(MH) ⁺ ] 337.2383, found 337.2380.

Example 13
Synthesis of compound [24C]

Compound 24C:
Liquid; R _f = 0.57 (hexane); ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.04 (s, 3 H), 0.08 (s, 3 H), 0.88 (s, 9 H), 0.91 (t, J) = 7.2 Hz, 6 H), 1.22-1.62 (m, 14 H), 2.33 (td, J = 6.6 Hz, 2.1 Hz, 2 H), 4.56-4.68 (m, 1 H), 5.41 (dm, J = 10.8 Hz, 1 H), 5.74 (dd, J = 10.8 Hz, 8.7 Hz, 1 H); ¹³ C-APT NMR (75 MHz, CDCl ₃ ) δ-4.8 (+), -4.3 (+), 14.1 ( +), 14.2 (+), 18.3 (-), 19.5 (-), 22.3 (-), 22.7 (-), 25.0 (-), 26.0 (+), 28.6 (-), 31.2 (-), 31.8 ( -), 37.7 (-), 70.9 (+), 77.0 (-), 95.4 (-), 108.6 (+), 145.6 (+); HRMS (FAB ⁺ ) calcd for C ₂₁ H ₃₉ OSi [(MH) ⁺ ] 335.2770, found 335.2769.

Example 14
Synthesis of compound [26T]

Compound 26T:
Liquid; R _f = 0.45 (hexane / EtOAc 5: 1); ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.18 (s, 9 H), 0.97 (t, J = 7.5 Hz, 3 H), 1.67 (d) , J = 4.5 Hz, 1 H), 2.06 (quint., J = 7.5 Hz, 2 H), 2.31 (t, J = 6.3 Hz, 2 H), 4.14-4.26 (m, 1 H), 5.26-5.39 (m, 1 H), 5.53-5.66 (m, 1 H), 5.76 (dd, J = 15.9 Hz, 1.5 Hz, 1 H), 6.22 (dd, J = 15.9 Hz, 5.7 Hz, 1 H); ¹³ C-APT NMR (75 MHz, CDCl ₃ ) δ-0.05 (+), 14.2 (+), 20.8 (-), 34.8 (-), 71.5 (+), 95.3 (-), 103.2 (-), 109.9 ( +), 123.1 (+), 135.9 (+), 146.1 (+); HRMS (FAB ⁺ ) calcd for C ₁₃ H ₂₂ OSiNa [(M + Na) ⁺ ] 245.1338, found 245.1340.

Example 15
Synthesis of compound [28T]

Compound 28T:
Liquid; R _f = 0.67 (toluene / EtOAc 9: 1); ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.19 (s, 9 H), 0.97 (t, J = 7.4 Hz, 3 H), 1.65 (d) , J = 4.5 Hz, 1 H), 2.06 (quint., J = 7.4 Hz, 2 H), 2.34 (t, J = 6.6 Hz, 2 H), 2.80 (t, J = 7.2 Hz, 2 H), 4.14-4.28 (m, 1 H), 5.23-5.46 (m, 3 H), 5.52-5.64 (m, 1 H), 5.76 (dd, J = 15.9 Hz, 1.5 Hz, 1 H), 6.22 (dd, 1 H) J = 15.9 Hz, 5.4 Hz, 1 H); ¹³ C-APT NMR (75 MHz, CDCl ₃ ) δ -0.05 (+), 14.3 (+), 20.6 (-), 25.8 (-), 34.9 (-) , 71.4 (+), 95.3 (-), 103.1 (-), 110.0 (+), 124.1 (+), 126.6 (+), 132.3 (+), 132.4 (+), 146.0 (+); HRMS (FAB ⁺ ) ) calcd for C ₁₆ H ₂₆ OSiNa [(M + Na) ⁺ ] 285.1651, found 285.1655.

Example 16
Synthesis of compound [30T]

Compound 30T:
Liquid; R _f = 0.62 (toluene / EtOAc 9: 1); ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.07 (s, 6 H), 0.18 (s, 9 H), 0.90 (s, 9 H), 1.52-1.78 (m, 4 H), 3.03 (d, J = 4.5 Hz, 1 H), 3.65 (t, J = 5.7 Hz, 2 H), 4.14-4.26 (m, 1 H), 5.77 (dd, dd, J = 16.0 Hz, 1.5 Hz, 1 H), 6.21 (dd, J = 16.0 Hz, 5.4 Hz, 1 H); ¹³ C-APT NMR (75 MHz, CDCl ₃ ) δ -5.4 (+), -0.02 ( +), 18.4 (-), 26.0 (+), 28.6 (-), 34.4 (-), 63.4 (-), 71.5 (+), 94.8 (-), 103.5 (-), 109.4 (+), 147.2 ( +); HRMS (FAB ⁺ ) calcd for C ₁₇ H ₃₄ O ₂ Si ₂ Na [(M + Na) ⁺ ] 349.1995, found 349.1998.

Example 17
Synthesis of compound [32T]

Compound 32T:
Liquid; R _f = 0.61 (toluene / EtOAc 9: 1); ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.88 (t, J = 6.9 Hz, 3 H), 0.90 (t, J = 6.9 Hz, 3 H) ), 1.22-1.60 (m, 15 H), 2.29 (dt, J = 1.8, 7.2 Hz, 2 H), 4.06-4.18 (m, 1 H), 5.67 (dm, J = 15.9 Hz, 1 H), 6.04 (dd, J = 15.9, 6.3 Hz, 1 H); ¹³ C-APT NMR (75 MHz, CDCl ₃ ) δ14.0 (+), 14.1 (+), 19.4 (-), 22.3 (-), 22.6 (-), 25.0 (-), 28.5 (-), 31.1 (-), 31.8 (-), 37.0 (-), 72.6 (+), 78.4 (-), 91.3 (-), 110.5 (+), 144.3 (+).

Example 18
Synthesis of compound [34T]

Compound 34T:
Liquid; R _f = 0.39 (toluene / EtOAc 9: 1); ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.90 (t, J = 6.9 Hz, 3 H), 1.21-1.64 (m, 9 H), 4.21 (q, J = 6.2 Hz, 1 H), 5.93 (dd, J = 16.0, 1.2 Hz, 1 H), 6.24 (dd, J = 16.0 Hz, 6.2 Hz, 1 H), 7.28-7.36 (m, 3) H), 7.39-7.46 (m, 2 H); ¹³ C-APT NMR (75 MHz, CDCl ₃ ) δ 14.1 (+), 22.7 (+), 25.0 (-), 31.8 (-), 37.1 (-) , 72.5 (+), 87.5 (-), 90.1 (-), 109.9 (+), 123.3 (-), 128.2 (+), 128.4 (+), 131.5 (+), 145.9 (+).

INDUSTRIAL APPLICABILITY The present invention can easily and stereoselectively produce a polyene compound having a hydroxyl group (18R-HEPE, etc.). Specifically, a simple and three-dimensional selection of an enin compound having a hydroxyl group represented by the formulas (6) to (8) (which may be protected), which is a key intermediate for synthesizing a polyene compound having a hydroxyl group. It is possible to easily and stereoselectively produce a polyene compound having a hydroxyl group via the key intermediate thereof.

Claims (1)

Equation (1A):

(In the formula, R indicates an alkyl group which may have a substituent or an alkenyl group which may have a substituent, k indicates an integer of 0 to 10, and * indicates oxygen with respect to the paper surface. It means that the atom is an α-configuration, a β-configuration, or any mixture of α-configuration and β-configuration (including an equal amount mixture).
It is a method for producing a compound represented by
Equation (1): (8T):

(In the formula, R ² indicates a hydroxyl-protecting group. R and * are the same as above.)
The compound represented by, and the formula (11) :.

(In the formula, R ¹ represents an alkyl group and X ¹ represents a halogen atom. K is the same as above.)
By coupling the compound represented by, the formula (12):

(In the formula, R, R ¹ , R ² , k and * are the same as above.)
The process of obtaining the compound represented by
(2) The compound represented by the formula (12) obtained in the above step (1) is reduced to the formula (13) :.

(In the formula, R, R ¹ , R ² , k and * are the same as above.)
The step of obtaining the compound represented by (3) and (3) the protecting group (R ² ) of the hydroxyl group of the compound represented by the formula (13) obtained in the above step (2) are removed, and the ester (CO ₂ R ¹ ) is removed. ) To obtain the compound represented by the formula (1A),
Manufacturing method including.