JP7201186B2 - Method for producing polyene compound having hydroxyl group - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing a polyene compound having hydroxyl groups. Specifically, it 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").

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

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

Thus, by searching for 18R-HEPE, its metabolites, peripheral compounds, etc., it may be possible to discover compounds having pharmacological activities such as more effective anti-inflammatory substances. Therefore, there is a demand for a method that can easily and stereoselectively produce 18R-HEPE and various other derivatives thereof.
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 (18R-HEPE, etc.) having a hydroxyl group. Specifically, an enyne compound having a hydroxyl group (which may be protected) represented by formulas (6) to (8) described later, which is a key intermediate for synthesizing a polyene compound having a hydroxyl group, can be easily and An object of the present invention is to provide a stereoselective production method and a simple and stereoselective method for producing a polyene compound having a hydroxyl group via its key intermediate.

As a result of intensive studies to solve the above problems, the present inventors have found that stereoselective It was found that enyne compounds having hydroxyl groups (which may be protected) represented by formulas (6) to (8) can be produced in a simple manner.

Specifically, when a trans 1,2-disubstituted epoxy alcohol compound represented by the formula (3T) is reacted with a compound represented by the formula (9), a trans compound represented by the formula (6T) is obtained. and that the cis-form 1,2-disubstituted epoxy alcohol compound represented by formula (3C) is reacted with the compound represented by formula (9) to obtain formula (6C) It was found that a cis enyne compound represented by can be produced. These enyne compounds represented by formulas (6T) and (6C) are converted to hydroxyl-containing enyne compounds represented by formulas (8T) and (8C), respectively.

Using this reaction, it was found that a polyene compound (18-HEPE, etc.) represented by formula (1A) can be produced simply and stereoselectively from an epoxy alcohol compound represented by formula (3). We also found that by using an optically active epoxy alcohol compound as a raw material, enyne compounds having an optically active hydroxyl group (including 18R-HEPE, protectin D1, derivatives thereof, etc.) can be produced simply and stereoselectively. rice field. Further studies based on these findings 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] Formula (20T):

(In the formula, R represents an optionally substituted alkyl group or an optionally substituted alkenyl group, R ⁰ represents a trimethylsilyl group, an optionally substituted alkyl or an aryl group which may have a substituent, * indicates that the oxygen atom is α-configured, β-configured, or any mixture of α-configured and β-configured (equal mixture including ).
A method for producing a compound represented by the formula (3T) in the presence of a base:

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

(In the formula, R ⁰ is the same as above.)
A production method comprising reacting a compound represented by and optionally removing a hydroxyl-protecting group.
[2] Formula (6T):

(Wherein, R represents an optionally substituted alkyl group or an optionally substituted alkenyl group, TMS represents a trimethylsilyl group, * indicates that the oxygen atom is α - configuration, β-configuration, or any mixture of α-configuration and β-configuration (including mixtures of equal amounts).
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.)
and a compound represented by formula (9):

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

(In the formula, R represents an optionally substituted alkyl group or an optionally substituted alkenyl group, R ¹ represents an alkyl group, and R ² represents a hydroxyl-protecting group. , k represents an integer of 0 to 10, * indicates that oxygen atoms are α-configuration, β-configuration, or any mixture of α-configuration and β-configuration (including equivalent mixtures) with respect to the paper surface means.)
A method for producing a compound represented by
(1) in the presence of a base, formula (3T):

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

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

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

(In the formula, R, ^R2 and * are the same as above.)
and (3) the compound represented by formula (8T) obtained in step (2) above, and formula (11):

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

(Wherein, R represents an optionally substituted alkyl group or an optionally substituted alkenyl group, k represents an integer of 0 to 10, * represents an oxygen means that the atom is in the α-configuration, β-configuration, or any mixture of α- and β-configurations, including mixtures of equal amounts.)
A method for producing a compound represented by
(1) in the presence of a base, formula (3T):

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

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

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

(In the formula, ^R2 represents a hydroxyl-protecting group. R and * are the same as above.)
A step of obtaining a compound represented by
(3) the compound represented by formula (8T) obtained in step (2) above, and 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):

(Wherein, R, R ¹ , R ² , k and * are the same as above.)
A step of obtaining a compound represented by
(4) reducing the compound represented by formula (12) obtained in step (3) above to give formula (13):

(Wherein, R, R ¹ , R ² , k and * are the same as above.)
and (5) removing the hydroxyl-protecting group (R ² ) of the compound represented by formula (13) obtained in step (4) above to obtain an ester (CO ₂ R ¹ ) to obtain a compound represented by formula (1A),
Manufacturing method including.
[5] Formula (1A):

(Wherein, R represents an optionally substituted alkyl group or an optionally substituted alkenyl group, k represents an integer of 0 to 10, * represents an oxygen means that the atom is in the α-configuration, β-configuration, or any mixture of α- and β-configurations, including mixtures of equal amounts.)
A method for producing a compound represented by
(1) Formula (8T):

(In the formula, ^R2 represents a hydroxyl-protecting group. R and * are the same as above.)
and a compound represented by formula (11):

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

(Wherein, R, R ¹ , R ² , k and * are the same as above.)
A step of obtaining a compound represented by
(2) reducing the compound represented by formula (12) obtained in step (1) above to give formula (13):

(Wherein, R, R ¹ , R ² , k and * are the same as above.)
and (3) removing the hydroxyl-protecting group (R ² ) of the compound represented by formula (13) obtained in step (2) above to obtain an ester (CO ₂ R ¹ ) to obtain a compound represented by formula (1A),
Manufacturing method including.
[6] Formula (20C):

(In the formula, R represents an optionally substituted alkyl group or an optionally substituted alkenyl group, R ⁰ represents a trimethylsilyl group, an optionally substituted alkyl group , or an aryl group that may have a substituent, * indicates that the oxygen atom is α-configuration, β-configuration, or any mixture of α-configuration and β-configuration (equal mixture (includes).)
A method for producing a compound represented by the formula (3C) in the presence of a base:

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

(In the formula, R ⁰ is the same as above.)
A production method comprising reacting a compound represented by and optionally removing a hydroxyl-protecting group.
[7] Formula (6C):

(Wherein, R represents an optionally substituted alkyl group or an optionally substituted alkenyl group, TMS represents a trimethylsilyl group, * indicates that the oxygen atom is α - configuration, β-configuration, or any mixture of α-configuration and β-configuration (including mixtures of equal amounts).
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.)
and a compound represented by formula (9):

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

(Wherein, R represents an optionally substituted alkyl group or an optionally substituted alkenyl group, R ² represents a hydroxyl-protecting group, R ⁴ has a substituent An alkyl group that may be substituted, or an alkenyl group that may have a substituent, * indicates that the oxygen atom is α-configured, β-configured, or α-configured and β-configured with respect to the paper surface. means a mixture (including mixtures of equal amounts) of
A method for producing a compound represented by
(1) in the presence of a base, formula (3C):

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

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

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

(In the formula, R, ^R2 and * are the same as above.)
A step of obtaining a compound represented by
(3) the compound represented by formula (8C) obtained in step (2) above, and formula (15):

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

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

( ^In the formula, X2 represents a halogen atom. ^R4 and * are the same as above.)
A step of reacting a compound represented by to obtain a compound represented by formula (18),
Manufacturing method including.

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

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

In addition, by utilizing this reaction, polyene compounds (18R-HEPE, etc.) having hydroxyl groups represented by formulas (1A) and (1B) can be conveniently and stereoselectively selected from epoxy alcohol compounds represented by formula (3). can be produced effectively.

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

Since the reaction of the present invention is highly versatile and can introduce various substituents, it is suitable as a tool for searching for peripheral compounds of physiologically active 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。 The present invention will be described in detail below.
1. Explanation of symbols
In this specification, in the chemical structural formulas, unless otherwise specified, the bond between the carbon atom (C) and the atom (A)

means that the atom (A) is bonded to the other side of the paper (α-configuration), and the bond is

means that the atom (A) is bonded to the front of the paper (β-configuration), and the bond is

represents any of the α-configuration, β-configuration, or any mixture of α-configuration and β-configuration (including equivalent mixtures) of the atom (A) with respect to the plane of the paper.

Geometric isomers of 1,2-disubstituted C—C double bonds are designated herein as cis (C) or trans (T).

As used herein, the stereochemistry of 1,2-disubstituted epoxies is considered to be the geometric isomers of the 1,2-disubstituted C—C double bond with the oxygen atom of the epoxy removed, cis (C ) or trans (T).

In this specification, in the epoxy alcohol compound represented by Formula (3), when the epoxy oxygen atom and two carbon atoms are represented by a solid line, the epoxy oxygen atom is bound to the other side of the paper surface. (in the α-configuration) and/or in front of the plane of the paper (in the β-configuration).

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

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

2. Synthesis of polyene compounds with hydroxyl groups
2.1 Synthesis of Polyene Compound Represented by Formula (1A) The polyene compound (including 18R-HEPE) represented by Formula (1A) can be produced according to Reaction Scheme 1.

(In the formula, TMS represents a trimethylsilyl group, R represents an optionally substituted alkyl group or an optionally substituted alkenyl group, R ¹ represents an alkyl group, R ² represents a hydroxyl-protecting group, X ¹ represents a halogen atom, and k represents an integer of 0 to 10. * indicates that the oxygen atom is α-configured, β-configured, or α-configured and β- means any mixture of configurations (including mixtures of equal amounts).)

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

The “alkyl group” in the “alkyl group optionally having substituent(s)” represented by R includes, for example, a chain or branched C1-C10 alkyl group. Specifically, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group, n -heptyl group, n-octyl group, n-nonyl group, n-decyl group and the like. It is preferably a C1-C6 alkyl group, more preferably a C1-C4 alkyl group, 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 (e.g., a C1-C3 alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, etc.), Hydroxy group which may be protected, oxo group (=O), 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 optionally having substituent(s)" include ethyl group, 3-carboxylpropyl group, 3-(methoxycarbonyl)propyl group, 3-(ethoxycarbonyl)propyl group and the like. .

Examples of the "alkenyl group" in the "alkenyl group optionally having substituent(s)" represented by R include chain or branched C2-C12 alkenyl groups. The alkenyl group has one or more (especially 1 to 3) CC double bonds. The geometric isomer of the CC double bond may be either trans or cis, or E or Z. Specifically, for example, vinyl group, 1-propenyl group, allyl group, 1-butenyl group, 2-butenyl group (crotyl group), 3-butenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-hexenyl group, 2-hexenyl group, 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 (e.g., a C1-C3 alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, etc.), An optionally protected hydroxyl group, oxo group (=O), epoxy group, amide group (for example, a group represented by the formula: -CON(R ^A ) ₂ (wherein R ^A is a hydrogen atom or a hydroxyl group represents an alkyl group which may be possessed, 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.

Examples of the "alkenyl group optionally having substituent(s)" include (Z)-2-pentenyl group, (2Z,5Z)-octa-2,5-dienyl group and the like.

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

The compound represented by formula (3T) is described in Tetrahedron Letters 50 (2009) 6079-6082, Org. Biomol. "It can be produced according to or according to the description. In addition, the compound represented by 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 solvents include ether solvents such as diethyl ether (Et ₂ O), diisopropyl ether (iPr ₂ O), tetrahydrofuran (THF), dioxane, cyclopentylmethyl ether, 4-methyltetrahydropyran; - Hydrocarbon solvents such as pentane, and the like. Among these, one or more solvents can be used. THF is preferred.

The base may have sufficient basicity to extract the hydrogen atom (proton) bonded to the sp carbon of the alkyne of the compound represented by the formula (9). , 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 to be used is generally 2-4 mol, preferably 2-3 mol, per 1 mol of the compound represented by formula (9).

This reaction may further use additives to facilitate the reaction. Examples of additives include hexamethylphosphoric triamide (HMPA) and N,N'-dimethylpropylene urea. When an additive is used, the amount used is generally 0 to 5 mol, preferably 0 to 2 mol, per 1 mol of the compound represented by formula (9).

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

The reaction can be carried out usually at -50°C to 50°C (preferably -20°C to 20°C) for 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 epoxy stereochemistry (trans isomer: T) of the compound represented by the formula (3T), which is the starting material, is reflected in the trans isomer of the compound represented by the formula (6T). are doing. This reaction is considered to proceed by the following reaction mechanism. The designations for the α-configuration and β-configuration of the compounds in the formulas below are relative configurations.

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

In this reaction, the hydroxyl group of the compound represented by formula (3T) is protected with an appropriate protecting group (e.g., tert-butyldimethylsilyl (TBS) group, etc.), and then treated with formula (9) in the presence of a base. ) followed by removal of the protecting group can also produce a compound of formula (6T). Protection of hydroxyl groups can be carried out by known methods. However, from the viewpoint of reactivity and shortening of the number of steps, it is preferable to carry out the reaction without protecting the hydroxyl group.

Alternatively, the hydroxyl group of the compound represented by formula (3T) is protected with an appropriate protecting group (e.g., tert-butyldimethylsilyl (TBS) group, etc.), and then in the presence of a base, represented by formula (9). A compound represented by the formula (7T) can also be produced by reacting with a compound represented by the formula (7T).

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

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. and acetal protecting groups such as α-ethoxyethyl group and tetrahydropyranyl (THP) group.

A known method can be used for the reaction of protecting a hydroxyl group with a protecting group. For example, Org. Biomol. Chem., 2017, 15, 8614-8626, J. Org.

For example, in the case of a silyl-based protecting group, a 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 etc.). . In the case of acetal protecting groups, 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):
A compound of formula (8T) can be produced by removing the trimethylsilyl (TMS) group from the compound of formula (7T).

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

The reaction can be carried out, for example, by reacting the compound represented by 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-Stephens coupling reaction, etc.), the compound represented by the formula (12) is produced. can do.

The “alkyl group” represented by R ¹ includes, for example, a chain or branched C1-C6 alkyl group. Specifically, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group, etc. is mentioned. A C1-C3 alkyl group is preferred, and a methyl group or an ethyl group is more preferred.

The halogen atom represented by X ¹ includes, for example, a chlorine atom, a bromine atom and an iodine atom, preferably a bromine atom.

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 formula (11) as a starting 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, or It can be manufactured according to

This reaction can be generally 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. Among these, one or more solvents can be used. DMF is preferred.

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

Copper compounds include monovalent copper (I) compounds, and specific examples include copper chloride (CuCl), copper bromide (CuBr), copper iodide (CuI), and copper cyanide (CuCN). etc. The amount of the copper compound to be used is generally 1-3 mol, preferably 1-1.5 mol, per 1 mol of the compound represented by formula (11).

Examples of bases include organic bases and inorganic bases. Examples of organic bases include triethylamine and diisopropylethylamine. Examples of inorganic bases include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate, sodium hydrogen carbonate and potassium carbonate; carbonates of alkaline earth metals; and phosphates of alkali metals such as disodium hydrogen phosphate and dipotassium hydrogen phosphate. The amount of the base to be used is generally 1-3 mol, preferably 1-2 mol, per 1 mol of the compound represented by formula (11).

Examples of the activating agent include alkali metal halides such as sodium iodide and potassium iodide, preferably sodium iodide. The amount of the activating agent to be used is generally 1-3 mol, preferably 1-2 mol, per 1 mol of the compound represented by 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):
A compound represented by formula (13) can be produced by subjecting the compound represented by formula (12) to a reduction reaction (cis-hydrogenation reaction to the C—C triple bond).

The reduction reaction is not particularly limited as long as it can reduce a C—C triple bond to form a cis C—C double bond, and known methods can be used. For example, Org. Biomol. Chem., 2017, 15, 8614-8626, J. Org.

For the reduction reaction, for example, Ni(OAc) _{2.4H 2 O} /sodium borohydride (NaBH ₄ )/ethylenediamine can be used as a reducing agent. Examples of solvents that can be used include alcohols (methanol, ethanol, isopropyl alcohol, etc.). The reaction can be carried out usually 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. Examples of solvents that can be used include hydrocarbon solvents (n-hexane, etc.), alcohols (methanol, ethanol, isopropyl alcohol, etc.), and the like. The reaction can be carried out usually 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, together with the compound represented by the formula (13), the compound represented by the formula (13a) in which the triple bond at the C14-C15 position of the starting compound represented by the formula (12) remained without being reduced. A mixture containing In that case, by further subjecting the mixture to a reduction reaction (Zn(Cu/Ag), Zn(Cu), etc.), the triple bond at the C14-C15 position is cis-reduced and represented by formula (13). can be obtained.

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

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

For example, when the protective group is a silyl-based protective group, it can be deprotected by reacting it with a compound containing fluoride ions, an organic acid, or a salt thereof. Examples of compounds containing fluoride ions include tetrabutylammonium fluoride (TBAF), potassium fluoride (KF), tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), triethylamine trihydrofluoride, and pyridine fluoride. Hydrochloride and the like can be mentioned. Examples of organic acids or salts 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, cyclopentylmethyl ether, and 4-methyltetrahydropyran, and a mixed solvent of one or more of these can be used.

When the protecting group is an acetal protecting group, it can be deprotected by reacting with an acid. Examples of acids include inorganic acids such as hydrochloric acid and sulfuric acid, and 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, cyclopentylmethyl ether, and 4-methyltetrahydropyran; A mixed solvent of the above can be used.

(14)→(1A):
The compound represented by formula (1A) can be produced by hydrolyzing the ester of the compound represented by formula (14). 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, cyclopentylmethyl ether, and 4-methyltetrahydropyran; A mixed solvent of the above can be used.

A compound represented by Formula (1A) can be synthesized through the steps represented by Reaction Formula 1. The stereochemistry (R-form, S-form or mixture of both) of the carbon atom * in the compound represented by the formula (1A) is the carbon atom * in the compound represented by the starting formula (3T). It comes from the stereochemistry of the atom. That is, the stereochemistry of the compound represented by formula (3T) is maintained to the compound represented by formula (1A). As described later in the section “3. Synthesis of starting compound”, the stereochemistry of the carbon atom indicated by * in the compound represented by the formula (3T) can be arbitrarily prepared. By using the compound represented by the formula (3T) having stereochemistry as a starting 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, a compound represented by formula ((R)-1A) can be produced from a compound represented by 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, a 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。） The compound represented by formula (1A) includes pharmacologically active 18R-HEPE and peripheral compounds thereof, and is therefore useful as a drug or a precursor thereof. The compound represented by formula (1A) can be further chemically converted using a known method in order to exhibit desired physical properties (pharmacological effects, etc.). For example, a carboxyl group can be converted into a salt, a carboxylic acid ester, a carboxylic acid amide, or the like, or a hydroxyl group can be converted into a carboxylic acid ester, a phosphoric acid ester, or the like. Examples of the phosphate ester include those in which a phospholipid group shown below is bonded to the oxygen atom of a hydroxyl group.

( ^In the formula, R10 represents an alkyl group.)

The “alkyl group” represented by R ¹⁰ includes, for example, a chain or branched C1-C30 alkyl group. More preferably, it is a C1-C20 alkyl group.

In addition, the compound represented by formula (1A) can also be converted to a prodrug or the like using these chemical conversion techniques. A prodrug is a chemically modified drug that is converted into a compound with pharmacological activity after reaching the body or target site of mammals (especially humans) and is chemically modified to exhibit (activate) a pharmacological effect. 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 the reaction for producing the compound represented by Formula (6T) from the compound represented by Formula (3T) and the compound represented by Formula (9) represented by Reaction Scheme 1, Even if the TMS group of the compound is replaced by a more versatile group, the reaction proceeds in the same manner. That is, the reaction is represented by the following formula. The compound represented by Formula (19) is a known compound or a compound easily available to those skilled in the art.

(In the formula, R ⁰ represents a trimethylsilyl (TMS) group, an optionally substituted alkyl group, or an optionally substituted aryl group, and TMS, R and * are the same as above. .)

The “alkyl group” in the “alkyl group optionally having substituent(s)” represented by R ⁰ includes, for example, a chain or branched C1-C10 alkyl group. Specifically, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group, n -heptyl group, n-octyl group, n-nonyl group, n-decyl group and the like.

The "alkyl group" may have a substituent, and the substituent is not particularly limited as long as it is a group that does not adversely affect the reaction. For example, an alkoxy group (C1-C6 alkoxy group, etc.) , aryl groups (phenyl group, toluyl group, xylyl 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 “optionally substituted aryl group” represented by R ⁰ include a monocyclic aryl group or an aryl group in which two or more rings are condensed. Specific examples 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 is a group that does not adversely affect the reaction. For example, an alkyl group (C1-C6 alkyl group, etc.) , alkoxy groups (C1-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 formula (3T) is protected with an appropriate protecting group (e.g., tert-butyldimethylsilyl (TBS) group, etc.), and then treated with formula (19) in the presence of a base. ) to remove the protecting group to produce a compound represented by the formula (20T). Protection of hydroxyl groups can be carried out by known methods. However, from the viewpoint of reactivity and shortening of the number of steps, it is preferable to carry out the reaction 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. Active substances such as protectin D1, maresin 1, resolvin E1, and peripheral compounds thereof are included.

（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 Formula (1B) can be produced according to Reaction Formula 2.

(In the formula, R ³ represents a hydrogen atom, a chain, branched or cyclic alkyl group, or two R ³ may be bonded to each other to form a ring together with the adjacent boron atom, The ring may have a substituent, R ⁴ represents an optionally substituted alkyl group or an optionally substituted alkenyl group, and X ² represents a halogen atom. TMS, R, ^R2 and * are the same as above.)

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

Y. Kobayashi, Tetrahedron Lett. 2009, 50, 6079, Y. Kobayashi, Tetrahedron Lett. 2011, 52, 3001, Y. Kobayashi, Tetrahedron Lett. or according to or according to the description in "3. Synthesis of starting compound" described later. Moreover, as described above, the compound represented by 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 Formula (6T) from the compound represented by Formula (3T) in Reaction Scheme 1.

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

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

In this reaction, the hydroxyl group of the compound represented by formula (3C) is protected with an appropriate protecting group (e.g., tert-butyldimethylsilyl (TBS) group, etc.), and then treated with formula (9) in the presence of a base. ) followed by removal of the protecting group can also produce a compound of formula (6C). Protection of hydroxyl groups can be carried out by known methods. However, from the viewpoint of reactivity and shortening of the number of steps, it is preferable to carry out the reaction without protecting the hydroxyl group.

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

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

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

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

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

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

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

The “linear, branched or cyclic alkyl group” for R ³ includes C1-C12 alkyl groups. Specifically, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, siamyl group (Me ₂ CHCHMe -), n _- hexyl group, thexyl group ( _Me2CHCMe2- ), cyclohexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, isopinocampheyl group, etc. . Preferred are siamyl group ( _Me2CHCHMe- ), _thexyl group ( _Me2CHCMe2- ), cyclohexyl group and the like. Preferably ^, one of the two R3's is a branched or cyclic alkyl group and the other is a hydrogen atom, or two R3's ^are a branched or cyclic alkyl group.

When "two R ³ are bonded to each other to form a ring together with the 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 an anti-Markovnikov addition reaction of HB to a C—C triple bond, R ³ is preferably a bulky group. Specific examples of the compound represented by formula (15) include disiamylborane (Sia ₂ BH), thexylborane (ThexBH ₂ ), dicyclohexylborane (Cy ₂ BH), borabicyclo[3,3,1]nonane (9-BBN ), catecholborane (CatBH), pinacolborane (PinBH), diisopinocampheylborane (Ipc ₂ BH) and the like.

This reaction can usually be carried out by reacting 1 to 2 mol of the compound of formula (15) with 1 mol of the compound of formula (8C) 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 subjected to Suzuki coupling in the next step, but the group —B(R ³ ) ₂ is a boronate ester derived from catecholborane, pinacolborane, or the like. If it is a group, the boronic ester can be hydrolyzed to convert it to the group —B(OH) ₂ before Suzuki coupling.

(16)+(17)→(18):
A compound represented by the formula (18) is obtained by subjecting the compound represented by the formula (16) and the compound represented by the formula (17) to a coupling reaction (such as Suzuki coupling) in the presence of a catalyst. obtain.

The “alkyl group optionally having substituents” and the “alkenyl group optionally having substituents” represented by R ⁴ are the “optionally substituted The definition of "alkyl group" and "alkenyl group optionally having substituent(s)" is the same. R and ^R4 may be the same or different.

^The halogen atom represented by X2 includes a chlorine atom, a bromine atom and an iodine atom, preferably a bromine atom.

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

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

Examples of solvents include water; aromatic hydrocarbon solvents (benzene, toluene, xylene, etc.), aliphatic hydrocarbon solvents (pentane, n-hexane, cyclohexane, etc.), ether solvents (diethyl ether, diisopropyl ether, tetrahydrofuran, etc.). One solvent or a mixture of two or more solvents can be used. Ether solvents (especially tetrahydrofuran) are preferred.

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

Catalysts include palladium catalysts. Palladium catalysts include zero- and _divalent palladium catalysts such as Pd(PPh3) ₄ , _PdCl2 ( _{PPh3)2 ,} Pd2(dba) ₃ , Pd[P(t _- Bu) ₃ ] ₂ , Pd(OAc) ₂ and the like. The amount of the palladium catalyst used is usually about 1 to 30 mol % relative to the compound represented by formula (16).

In this reaction, a ligand may be added as necessary. Preferred ligands are phosphine ligands such as triphenylphosphine (PPh ₃ ), tri(o-toluyl)phosphine (P(o-tol) ₃ ), 1,2-bis(diphenylphosphino ) ethane (dppe), 1,3-bis(diphenylphosphino)propane (dppp), 1,1'-bis(diphenylphosphino)ferrocene (dppf), 2,2'-bis(diphenylphosphino)-1 , 1′-binaphthyl (BINAP), bis[2-(diphenylphosphino)phenyl]ether and the like. When a ligand is used, the amount used is usually about 1 to 30 mol % relative to the compound represented by 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 (eg, 0.5 to 4 normal (N) aqueous solution). The amount of the base to be used is generally 2-20 mol, preferably 4-15 mol, relative to the compound represented by formula (16).

The reaction can be carried out usually at a temperature of about 0 to 50° C. for about 0.5 to 10 hours.

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

This reaction can be carried out in the same manner as the reaction for producing the compound represented by Formula (14) from the compound represented by Formula (13) in Reaction Scheme 1. Alternatively, this reaction can be carried out according to or according to the description in Tetrahedron Letters, 50 (2009) 6079-6082, Tetrahedron Letters, 52 (2011) 3001-3004, Tetrahedron Letters, 55 (2014) 2738-2741, etc. 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, if necessary, in any step, 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 the reaction for producing the compound represented by Formula (6C) from the compound represented by Formula (3C) and the compound represented by Formula (9) represented by Reaction Scheme 2, Even if the TMS group of the compound is replaced by a more versatile group, the reaction proceeds in the same manner. That is, the reaction is represented by the following formula. The compound represented by 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 formula (3C) is protected with an appropriate protecting group (e.g., tert-butyldimethylsilyl (TBS) group, etc.), and then treated with formula (19) in the presence of a base. ) to remove the protecting group to produce a compound represented by formula (20C).

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

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

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

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

Solvents include, for example, halogenated hydrocarbons (methylene chloride, chloroform, etc.). Methylene chloride is preferred.

Chiral ligands include D-(-)-tartaric acid diesters. Specific examples include D-(-)-dimethyl tartrate (DMT), D-(-)-diethyl tartrate (DET), and D-(-)-diisopropyl tartrate (DIPT). The amount of D-(-)-tartaric acid diester to be used is generally 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of the compound represented by the formula (rac-2T).

Metals used as metal catalysts include titanium (IV). Titanium tetraethoxide (Ti(OEt) ₄ ), titanium tetra-n-propoxide (Ti(OnPr) ₄ ), and titanium tetraisopropoxide are examples of precursors that form complexes with chiral ligands in the reaction system. and titanium tetra C1-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 in terms of metal (titanium (IV)) (that is, the amount of titanium tetra C1-C6 alkoxide used) per 1 mol of the compound represented by the formula (rac-2T). to 2 mol, preferably 1 to 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 to be used is generally 1-2 mol, preferably 1-1.5 mol, per 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 enantiomeric excess (ee) of 95% or more (further 97 % or more, especially 99% or more).

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

((S)-2T) → ((S)-3T):
A compound represented by the formula ((S)-3T) can be obtained by subjecting the compound represented by the formula ((S)-2T) to an oxidation reaction (olefin epoxidation reaction). 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 chloroform. be done.

Examples of oxidizing agents 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 to be used is generally 1-2 mol, preferably 1-1.2 mol, per 1 mol of the compound represented by the formula ((S)-2T).

The reaction usually proceeds at -20 to 30°C in 0.5 to 4 hours.

((S)-3T) → ((R)-3T):
A compound represented by the formula ((S)-3T) is subjected to a Mitsunobu reaction to react a carboxylic acid compound to form an ester compound, which is then subjected to a hydrolysis reaction to convert the carbon steric to which the hydroxyl group is bonded. Compounds of 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 performed in the presence of a dialkyl azodicarboxylate (e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.), triphenylphosphine in a solvent. It can be carried out by reacting a carboxylic acid compound (eg, acetic acid, 4-nitrobenzoic acid, etc.).

A compound represented by the formula ((R)-3T) is obtained by hydrolyzing the ester compound obtained by the Mitsunobu reaction by a known method (eg, alkali metal hydroxides such as LiOH and NaOH).

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

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

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

Chem., 2011, 76, 5433-5437, Org. Biomol. Chem., 2017, 15, 8614-8626, Tetrahedron Letters 55 (2014) 2738-2741, J. Am. Chem. Soc. 1997, 119, 8738-8739, etc., or according to the description.

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

Examples of solvents include alcohols (especially isopropyl alcohol, etc.).

・[(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 metal catalysts having chiral ligands include ketone-selective asymmetric ruthenium hydrogenation catalysts, such as
chloro[(R,R)-N-[2-[2-(4-methylbenzyloxy)ethyl]amino-1,2-diphenylethyl]-p-toluenesulfonamido]ruthenium (II),

・[(R,R)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide]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)pentafluorobenzenesulfonamide]chloro(p-cymene)ruthenium(II) (RuCl[(R,R)-Fsdpen]( p-cymene)),

etc.

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

（式中、ＴＭＳ及びＲは前記に同じ。） Instead of these metal catalysts having an asymmetric ligand, a metal catalyst having an enantiomer of the asymmetric ligand,
chloro[(S,S)-N-[2-[2-(4-methylbenzyloxy)ethyl]amino-1,2-diphenylethyl]-p-toluenesulfonamido]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 [(S,S)-Fsdpen](p-cymene)), etc., instead of the compound represented by the formula ((R)-5) obtained in Reaction Scheme 4, the enantiomer thereof A compound represented by the formula ((S)-5) can be obtained.

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

In the subsequent steps in Reaction Scheme 4, the compound represented by the formula ((R)-5) is used to convert the (S)-form compound, that is, the formula ((R)-2T), ((R) -3T), ((R)-2C) and (syn(R)-3C), but the enantiomers of the above formula ((S)-5) By using the compounds, the corresponding (S)-form compounds, namely ((S)-2T), ((S)-3T), ((S)-2C) and (syn(S)-3C ) can be synthesized.

((R)-5) → ((R)-2T):
A compound represented by the formula ((R)-2T) is obtained by subjecting the compound represented by the formula ((R)-5)) to a reduction reaction (trans-hydrogenation reaction to the C—C triple bond). can be manufactured. This reaction can be carried out, for example, according to or according to descriptions such as 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)) with a reducing agent in a solvent.

Examples of solvents include ether solvents such as tetrahydrofuran (THF), dioxane, cyclopentylmethyl ether, and 4-methyltetrahydropyran.

Examples of reducing agents include lithium aluminum hydride (LAlH ₄ ), sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al), and the like. The amount of the reducing agent to be used is generally 1-4 mol, preferably 1-2 mol, per 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. As a result, the compound represented by the trans-form formula ((R)-2T) can be produced.

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

This reaction can be carried out in the same manner as the reaction for producing the compound represented by the formula ((S)-3T) from the compound represented by the formula ((S)-2T) in Reaction Scheme 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):
A compound represented by the formula ((R)-2C) is produced by subjecting the compound represented by the formula ((R)-5) to a reduction reaction (cis-hydrogenation reaction to the C—C triple bond). can do.

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

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

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

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

The compounds represented by the formulas (2) and (3) and their enantiomers produced as described above are used as raw materials for the reactions shown in the above section "2. Synthesis of polyene compounds having hydroxyl groups". used as

EXAMPLES The present invention will be specifically described below by way of examples, but the present invention is not limited to these.

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

To an ice-cold solution of Ti(O-iPr) ₄ (0.30 mL, 1.01 mmol) in CH2Cl2 _{( 4} mL) was added D-(-)-DIPT (0.27 mL, 1.29 mmol). The solution was stirred at 0°C for 30 minutes and cooled to -15°C. A solution of 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 min, the solution was cooled to −40° C. and t-BuOOH (4.34 M in CH ₂ Cl ₂ , 0.35 mL, 1.65 mmol) was added dropwise. The reaction was continued at −20° C. for 8 hours and quenched by the addition of Me ₂ S (0.40 mL, 5.4 mmol). After stirring for 10 min at −20° C., 10% aqueous tartaric acid (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 with CH2Cl2. The filtrate was mixed with 1N aqueous NaOH (10 mL, 10 mmol). _The mixture was stirred at room temperature for 30 minutes and extracted with CH2Cl2 _three times. The combined extracts _were washed with brine, dried over MgSO4 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 derivatized 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-en-6-yn-3-ol [(R)-6T]

To an ice-cold solution of trimethylsilylacetylene (2.20 mL, 15.9 mmol) in THF (2 mL) was added n-BuLi (1.55 M in hexanes, 8.75 mL, 13.6 mmol) dropwise. After stirring for 30 min at 0° C., HMPA (4.8 mL) and a solution of compound (R)-3T (398 mg, 2.28 mmol) in THF (2 mL) were added. The solution was stirred at room temperature for ₄ hours and diluted with saturated aqueous NH4Cl. The mixture was extracted twice with EtOAc. The combined extracts _were dried over MgSO4 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-en-6-yn-3-yl)oxy)silane [(R)-7T]

To an ice-cold solution of compound (R)-6T (231 mg, 1.27 mmol) and imidazole (213 mg, 3.13 mmol) in CH2Cl2 _{( 2} mL) was added tert-butyldimethylsilyl chloride (TBSCl) (233 mg, 1.55 mmol). ) was added. The solution was stirred at room temperature for 1 hour and diluted with saturated aqueous NaHCO ₃ solution. _The resulting mixture was extracted with CH2Cl2 _three times. The combined extracts were washed with brine, dried over MgSO ₄ and concentrated to give a residue, which was purified by silica gel chromatography (hexane/EtOAc) to give compound (R)-7T (329 mg, 88% ).

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-en-6-yn-3-yloxy)dimethylsilane [(R)-8T]

To a solution of compound (R) _-7T (313 mg, 1.06 mmol) in MeOH (2 mL) was added _K2CO3 (229 mg, 1.66 mmol). The mixture was stirred at room temperature for 1.5 hours and diluted with saturated aqueous _NH4Cl . The resulting mixture was extracted twice with EtOAc. The combined extracts were washed with brine, dried over MgSO ₄ and concentrated to give a residue, which was purified by silica gel chromatography (hexane/EtOAc) to give 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, 9H)
, 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)]

To a mixture of CuI (196 mg, 1.03 mmol), _{Cs2CO3 (} 252 mg, 0.773 mmol), and NaI (154 mg, 1.03 mmol) in DMF (1 mL) was added the enyne compound (R)-8T (122 mg, 0.544 mmol). ) in DMF (0.5 mL) and bromide 11 (151 mg, 0.511 mmol) in DMF (0.5 mL) were added. After stirring at room temperature for 7 hours, the mixture was diluted with saturated aqueous NH ₄ Cl. The resulting mixture was extracted twice with EtOAc. The combined extracts _were dried over MgSO4 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]

NaBH4 ₍ 20 mg, 0.53 mmol) was added to an ice-cold suspension of Ni(OAc) _{2-4H2O (} 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 for 10 minutes at room temperature, EtOH (0.5 mL) solution containing compound (R)-12 (149 mg, 0.340 mmol) was added. The mixture was stirred at room temperature for 90 minutes, filtered through a pad of celite with EtOAc, and the filtrate was concentrated in vacuo to give an oil, which was purified by silica gel chromatography (hexane/EtOAc) to give 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 ^13C NMR signal.

Cu(OAc) ₂ (200 mg, 1.1 mmol) was added to a slurry of Zn (2.0 g, 31 mmol) in _H2O (6 mL) and the mixture was stirred at room temperature for 15 min. AgNO ₃ (202 mg, 1.19 mmol) was added to the mixture, stirred at room temperature for an additional 30 minutes and filtered using a Hirsch funnel. The remaining solid was washed successively with _H2O (5 mL x 2), MeOH (5 mL x 2), acetone (5 mL x 2), and _Et2O (5 mL x 2), and the washed solid was washed with MeOH. (2 mL) and _H2O (1 mL) was added under nitrogen to a mixture of compounds (R)-13 and (R)-13a (4:1, 64 mg, 0.143 mmol). 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 MgSO ₄ and concentrated to give a residual oil, which was purified by silica gel chromatography (hexane/EtOAc) to give 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 = 7.5Hz, 2H), 2.71-2.88 (m, 4H), 2.95 (t, J = 5.9Hz, 2H), 3.66 (s, 3H), 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-hydroxyicosa-5,8,11,14,16-pentanoate [(R)-14)]

To an ice-cold solution of compound (R)-13 (56 mg, 0.125 mmol) in THF (0.3 mL) was added _Bu4NF (TBAF) (1.0 M in THF, 0.40 mL, 0.40 mmol). The solution was stirred at room temperature for ₅ hours and diluted with saturated aqueous NH4Cl. The resulting mixture was extracted with EtOAc three times. The combined extracts were dried over MgSO 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, _CDCl3 ) 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
Synthesis of 18R-HEPE

To a solution of compound (R)-14 (10 mg, 0.030 mmol) in THF (0.2 mL) and MeOH (0.2 mL) was added aqueous LiOH (2.0 N, 0.15 mL, 0.30 mmol). The mixture was stirred at room temperature for 1 hour, diluted with buffer (pH 5.0) and the resulting mixture was extracted with EtOAc three times. The combined extracts _were washed with brine, MgSO4 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, _CDCl3 ) 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, 129.9, 129.9, 130.1, 13
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)oct-1-en-3-ol[16C]

NaBH4 ₍ 456 mg, 12.1 mmol) was added to an ice-cooled suspension of Ni(OAc) _{2.4H2O (} 2.99 g, 12.0 mmol) in MeOH (14 mL). The flask was purged with hydrogen and ethylenediamine (1.36 mL, 20.1 mmol) was added to the mixture. After 10 minutes, a solution of alcohol 15 (1.99 g, 10.0 mmol) in MeOH (6 mL) was added. The mixture was stirred overnight at room temperature 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)oxiran-2-yl]hexan-1-ol[17C]

m-CPBA (70% purity, 7.02 g, 28.5 mmol) was added to 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 and then quenched by the addition of _Me2S (3.45 mL, 46.6 mmol). The mixture was filtered through a celite pad. The residue was diluted with saturated aqueous NaHCO ₃ and extracted twice with EtOAc. The combined organic layers _were dried over MgSO4 and then concentrated to give 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, 1H).

Example 11
Synthesis of compound [20C]

(1) Synthesis of compounds 18C and 19C
To an ice-cold solution of trimethylsilylacetylene (0.20 mL, 1.45 mmol) in THF (0.5 mL) was added dropwise n-BuLi (1.55 M in hexane, 0.80 mL, 1.24 mmol). After stirring for 30 min at 0° C., a solution of epoxy alcohol 17C (68 mg, 0.31 mmol) in HMPA (0.50 mL, 2.87 mmol) and THF (0.4 mL) was added. The solution was stirred at 0° C. for 1.5 hours and diluted with saturated aqueous NH ₄ Cl. The mixture was extracted twice with EtOAc. The combined organic layers _were washed with brine, dried over MgSO4, and 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 = 10.8Hz, 8.4Hz, 1H).

(2) Synthesis of enyne compound 20C
_{K2CO3 (} 67 mg, 0.48 mmol) was added to a solution of 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. The resulting mixture was extracted twice with EtOAc. The combined extracts _were dried over MgSO4 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); 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, enyne compounds were synthesized by reacting various epoxy compounds with alkynes in the presence of a base (n-BuLi). Reaction formulas 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 (+); 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 _C21H39OSi [(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); 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, 1H), 5.23-5.46 (m, 3H), 5.52-5.64 (m, 1H), 5.76 (dd, J = 15.9Hz, 1.5Hz, 1H), 6.22 (dd, 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 (+); ) calcd for _C16H26OSiNa [(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, 4H), 3.03 (d, J = 4.5Hz, 1H), 3.65 (t, J = 5.7Hz, 2H), 4.14-4.26 (m, 1H), 5.77 (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 _{C17H34O2Si2Na} [(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 According to the present invention, a polyene compound (18R-HEPE, etc.) having a hydroxyl group can be produced simply and stereoselectively. Specifically, enyne compounds having hydroxyl groups (which may be protected) represented by formulas (6) to (8), which are key intermediates for synthesizing polyene compounds having hydroxyl groups, are conveniently and stereoselectively selected. Through the key intermediate, a polyene compound having a hydroxyl group can be produced simply and stereoselectively.

Claims (1)

Formula (1A):

(Wherein, R represents an optionally substituted alkyl group or an optionally substituted alkenyl group, k represents an integer of 0 to 10, * represents an oxygen means that the atom is in the α-configuration, β-configuration, or any mixture of α- and β-configurations, including mixtures of equal amounts.)
A method for producing a compound represented by
(1) Formula (8T):

(In the formula, ^R2 represents a hydroxyl-protecting group. R and * are the same as above.)
and a compound represented by formula (11):

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

(Wherein, R, R ¹ , R ² , k and * are the same as above.)
A step of obtaining a compound represented by
(2) reducing the compound represented by formula (12) obtained in step (1) above to give formula (13):

(Wherein, R, R ¹ , R ² , k and * are the same as above.)
and (3) removing the hydroxyl-protecting group (R ² ) of the compound represented by formula (13) obtained in step (2) above to obtain an ester (CO ₂ R ¹ ) to obtain a compound represented by formula (1A),
Manufacturing method including.