JP2005179333A - Catechin derivative having substituent on forth site of flavan skeleton and its manufacturing method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a catechin derivative having a various substituent on the forth site of a flavan skeleton and its manufacturing method. <P>SOLUTION: This catechin derivative (1a) is obtained by reacting a catechin derivative (4) with a nucleophilic reagent (5) in the presence of an organometallic compound (2) and a silver compound (3). In the formulae, R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>, R<SP>4</SP>, R<SP>5</SP>, R<SP>6</SP>, R<SP>7</SP>, R<SP>8</SP>, R<SP>9</SP>, and R<SP>10</SP>represent each independently the same or differently a hydrogen atom, a hydrocarbon group, or the like, A<SP>1</SP>is a substituent containing a hetero atom, or the like, A<SP>2</SP>is a hydrogen atom, a hydrocarbon group, or the like, L<SP>1</SP>and L<SP>2</SP>are an anionic ligand, M is zirconium or hafnium, Z<SP>1</SP>and Z<SP>2</SP>are each a leaving group, Y is a hydrogen atom or a halogen atom, and X is a perchlorate ion or a trifluoromethanesulfonate ion. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a catechin derivative having a substituent at the 4-position of a flavan skeleton and a method for producing the same.

  Catechin is a naturally derived component, and its derivatives can be lead compounds for pharmaceutical development. Catechin derivatives having substituents having nitrogen or oxygen atoms, such as furan, amine, amide, indole, aniline, etc. are highly likely to exhibit important physiological actions and are expected to be used as leads for new drug development. While catechin derivatives have such industrial utility value, it is difficult to obtain them from nature, and therefore development of a general synthetic method is desired.

There have been several reports on the synthesis of oligomers having catechin as a structural unit. There is also a report example regarding a method for synthesizing a catechin derivative in which a hydrocarbon group is introduced at the 4-position of a flavan skeleton in the presence of a Lewis acid (Non-Patent Document 1: Tetrahedron Letters 43 (2002) 7753-7775). On the other hand, with respect to the synthesis methods of catechins containing heterocycles and heteroatoms, there are no reports on general synthesis methods, particularly methods for synthesizing catechin derivatives having these substituents at the 4-position of the flavan skeleton. . In general, this is considered to be caused by the fact that a reaction agent containing a heteroatom such as nitrogen or oxygen inactivates a Lewis acid, and the intended reaction often does not proceed. Therefore, such compounds open the way to the creation of catechin derivatives having unprecedented special functions, and can be expected to have ripple effects in related fields such as material chemistry and polymer chemistry. Its synthesis was difficult.
Tetrahedron Letters 43 (2002) 7753−7756

  An object of the present invention is to provide a catechin derivative having various substituents at the 4-position of a flavan skeleton and a method for producing the same.

[式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸、Ｒ⁹及びＲ¹⁰は、それぞれ、互いに独立し、同一または異なって、水素原子；置換基を有していてもよいＣ₁〜Ｃ₁₀炭化水素基；置換基を有していてもよいＣ₁〜Ｃ₁₀アルコキシ基；置換基を有していてもよいＣ₆〜Ｃ₁₀アリールオキシ基；置換基を有していてもよいシリル基；置換基を有していてもよいシリルオキシ基；又は水酸基である。
Ａ¹は、窒素及び／又は燐を含む置換基である。] In the first aspect of the present invention, a catechin derivative represented by the following formula (1a) is provided.

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently the same or different and are each a hydrogen atom; which may have a group C ₁ -C ₁₀ hydrocarbon radical; an optionally substituted C ₁ -C ₁₀ alkoxy groups; which may have a substituent C ₆ -C ₁₀ aryloxy A silyl group optionally having a substituent; a silyloxy group optionally having a substituent; or a hydroxyl group.
A ¹ is a substituent containing nitrogen and / or phosphorus. ]

[式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸、Ｒ⁹及びＲ¹⁰は、それぞれ、互いに独立し、同一または異なって、水素原子；置換基を有していてもよいＣ₁〜Ｃ₁₀炭化水素基；置換基を有していてもよいＣ₁〜Ｃ₁₀アルコキシ基；置換基を有していてもよいＣ₆〜Ｃ₁₀アリールオキシ基；置換基を有していてもよいシリル基；置換基を有していてもよいシリルオキシ基；又は水酸基である。Ａ¹は、置換基を有していてもよいＣ₁〜Ｃ₁₀炭化水素基；又は窒素、酸素、硫黄及び燐からなる群より選ばれる１種以上のヘテロ原子を含む置換基である。] 下記式（２）で示される有機金属化合物、

[式中、Ｌ¹及びＬ²は、それぞれ、互いに独立し、同一または異なって、アニオン性配位子であり、Ｍは、ジルコニウム又はハフニウムであり、Ｚ¹及びＺ²は脱離基である。] 及び、下記式（３）で示される銀化合物の存在下で、

[式中、Ｘは、過塩素酸イオン（ＣｌＯ₄ ^-）又はトリフルオロメタンスルホン酸エステルイオン（ＯＳＯ₂ＣＦ₃ ^-）である。] 下記式（４）で示されるカテキン誘導体と、

[式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸、Ｒ⁹及びＲ¹⁰は、上記意味を有する。Ａ²は、水素原子；置換基を有していてもよいＣ₁〜Ｃ₁₀炭化水素基；置換基を有していてもよいＣ₁〜Ｃ₁₀アルコキシ基；置換基を有していてもよいＣ₆〜Ｃ₁₀アリールオキシ基；置換基を有していてもよいＣ₆〜Ｃ₁₀アシル基；又は水酸基である。] 下記式（５）で示される求核試薬

[式中、Ａ¹は、上記意味を有する。Ｙは、水素原子又はハロゲン原子である。] とを反応させることを特徴とする、カテキン誘導体の製造方法が提供される。 Moreover, in the 2nd aspect of this invention, the manufacturing method of the catechin derivative containing the catechin derivative concerning the 1st aspect of this invention is provided. Specifically, a method for producing a catechin derivative represented by the following formula (1a),

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently the same or different and are each a hydrogen atom; which may have a group C ₁ -C ₁₀ hydrocarbon radical; an optionally substituted C ₁ -C ₁₀ alkoxy groups; which may have a substituent C ₆ -C ₁₀ aryloxy A silyl group optionally having a substituent; a silyloxy group optionally having a substituent; or a hydroxyl group. A ¹ is a C ₁ -C ₁₀ hydrocarbon group which may have a substituent; or a substituent containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur and phosphorus. ] An organometallic compound represented by the following formula (2):

[Wherein, L ¹ and L ² are each independently the same or different and are anionic ligands, M is zirconium or hafnium, and Z ¹ and Z ² are leaving groups. . And in the presence of a silver compound represented by the following formula (3):

[Wherein, X is a perchlorate ion (ClO ₄ ⁻ ) or a trifluoromethanesulfonate ester ion (OSO ₂ CF ₃ ⁻ ). ] A catechin derivative represented by the following formula (4):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ have the above-mentioned meanings. A ² represents a hydrogen atom; an optionally substituted C _{1 to} C ₁₀ hydrocarbon group; an optionally substituted C _{1 to} C ₁₀ alkoxy group; and an optionally substituted group. A good C ₆ -C ₁₀ aryloxy group; an optionally substituted C ₆ -C ₁₀ acyl group; or a hydroxyl group. ] Nucleophilic reagent represented by the following formula (5)

[Wherein A ¹ has the above-mentioned meaning. Y is a hydrogen atom or a halogen atom. A method for producing a catechin derivative is provided.

  In the second aspect of the present invention, the anionic ligand is preferably an optionally substituted cyclopentadienyl group. Further, M is preferably zirconium.

In the second embodiment of the present invention, A ¹ is preferably a substituent containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

  In the second embodiment of the present invention, 0.1 to 1.0 mol of the organometallic compound represented by the formula (2) is added to 1 mol of the catechin derivative represented by the formula (4). It is preferable to use 0.2 mol to 1.0 mol of the silver compound represented by (3).

[式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸、Ｒ⁹及びＲ¹⁰は、それぞれ、互いに独立し、同一または異なって、水素原子；置換基を有していてもよいＣ₁〜Ｃ₁₀炭化水素基；置換基を有していてもよいＣ₁〜Ｃ₁₀アルコキシ基；置換基を有していてもよいＣ₆〜Ｃ₁₀アリールオキシ基；置換基を有していてもよいシリル基；置換基を有していてもよいシリルオキシ基；又は水酸基である。
Ｂ¹及びＢ²は、それぞれ、互いに独立し、同一または異なって、水素原子；置換基を有していてもよいＣ₁〜Ｃ₁₀炭化水素基；置換基を有していてもよいＣ₁〜Ｃ₁₀アルコキシ基；置換基を有していてもよいＣ₆〜Ｃ₁₀アリールオキシ基；置換基を有していてもよいアミノ基；置換基を有していてもよいシリル基；置換基を有していてもよいシリルオキシ基；又は水酸基である。
Ｂ³は、水素原子；置換基を有していてもよいＣ₁〜Ｃ₁₀炭化水素基；又は置換基を有していてもよいシリル基である。] 下記式（２）で示される有機金属化合物、

[式中、Ｌ¹及びＬ²は、それぞれ、互いに独立し、同一または異なって、アニオン性配位子であり、Ｍは、ジルコニウム又はハフニウムであり、Ｚ¹及びＺ²は脱離基である。] 及び、下記式（３）で示される銀化合物の存在下で、

[式中、Ｘは、過塩素酸イオン（ＣｌＯ₄ ^-）又はトリフルオロメタンスルホン酸エステルイオン（ＯＳＯ₂ＣＦ₃ ^-）である。] 下記式（４）で示されるカテキン誘導体と、

[式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸、Ｒ⁹及びＲ¹⁰は、上記意味を有する。Ａ²は、水素原子；置換基を有していてもよいＣ₁〜Ｃ₁₀炭化水素基；置換基を有していてもよいＣ₁〜Ｃ₁₀アルコキシ基；置換基を有していてもよいＣ₆〜Ｃ₁₀アリールオキシ基；置換基を有していてもよいアシル基；又は水酸基である。] 下記式（６）で示される求核試薬、

[式中、Ｂ¹、Ｂ²及びＢ³は、上記意味を有する。Ｂ⁴は、水素原子；置換基を有していてもよいＣ₁〜Ｃ₁₀炭化水素基；又は置換基を有していてもよいシリル基である。] とを反応させることを特徴とするカテキン誘導体の製造方法が提供される。 A third aspect of the present invention is a method for producing a catechin derivative represented by the following formula (1b),

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently the same or different and represent a hydrogen atom; which may have a group C ₁ -C ₁₀ hydrocarbon radical; an optionally substituted C ₁ -C ₁₀ alkoxy groups; which may have a substituent C ₆ -C ₁₀ aryloxy A silyl group optionally having a substituent; a silyloxy group optionally having a substituent; or a hydroxyl group.
B ¹ and B ² are each independently the same or different and are each a hydrogen atom; an optionally substituted C _{1 to} C ₁₀ hydrocarbon group; an optionally substituted C _1. -C ₁₀ alkoxy group; which may have a substituent C ₆ -C ₁₀ aryloxy group; optionally substituted amino group; an optionally substituted silyl group; substituents A silyloxy group optionally having a hydroxyl group; or a hydroxyl group.
B ³ is a hydrogen atom; a C _{1 to} C ₁₀ hydrocarbon group which may have a substituent; or a silyl group which may have a substituent. ] An organometallic compound represented by the following formula (2):

[Wherein, L ¹ and L ² are each independently the same or different and are anionic ligands, M is zirconium or hafnium, and Z ¹ and Z ² are leaving groups. . And in the presence of a silver compound represented by the following formula (3):

[Wherein, X is a perchlorate ion (ClO ₄ ⁻ ) or a trifluoromethanesulfonate ester ion (OSO ₂ CF ₃ ⁻ ). ] A catechin derivative represented by the following formula (4):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ have the above-mentioned meanings. A ² represents a hydrogen atom; an optionally substituted C _{1 to} C ₁₀ hydrocarbon group; an optionally substituted C _{1 to} C ₁₀ alkoxy group; and an optionally substituted group. A good C ₆ -C ₁₀ aryloxy group; an acyl group which may have a substituent; or a hydroxyl group. A nucleophile represented by the following formula (6):

[Wherein B ¹ , B ² and B ³ have the above-mentioned meanings. B ⁴ is a hydrogen atom; a C _{1 to} C ₁₀ hydrocarbon group which may have a substituent; or a silyl group which may have a substituent. A method for producing a catechin derivative is provided.

  In the third aspect of the present invention, the anionic ligand is preferably an optionally substituted cyclopentadienyl group. Further, M is preferably zirconium.

  In the third aspect of the present invention, the organometallic compound represented by the formula (2) is added in an amount of 0.1 mol to 1.0 mol based on 1 mol of the catechin derivative represented by the formula (4). It is preferable to use 0.2 mol to 1.0 mol of the silver compound represented by (3).

  According to the present invention, catechin derivatives having various substituents at the 4-position of a flavan skeleton that can be expected to be used in various fields such as material chemistry and polymer chemistry can be obtained.

In the first aspect of the present invention, a catechin derivative represented by the following formula (1a) is provided.

In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently the same or different and are each a hydrogen atom; which may have a group C ₁ -C ₁₀ hydrocarbon radical; an optionally substituted C ₁ -C ₁₀ alkoxy groups; which may have a substituent C ₆ -C ₁₀ aryloxy A silyl group optionally having a substituent; a silyloxy group optionally having a substituent; or a hydroxyl group.

In the present specification, the hydrocarbon group of the “C ₁ -C ₁₀ hydrocarbon group” may be saturated or unsaturated acyclic, or may be saturated or unsaturated cyclic. If C ₁ -C ₁₀ hydrocarbon group is acyclic, it may be linear, may be branched. The “C ₁ -C ₁₀ hydrocarbon group” includes a C ₁ -C ₁₀ alkyl group, a C ₂ -C ₁₀ alkenyl group, a C ₂ -C ₁₀ alkynyl group, a C ₄ -C ₁₀ alkyl dienyl group, a C _6- C ₈ aryl group, C ₆ -C ₁₀ alkylaryl group, C ₆ -C ₁₀ arylalkyl group, C ₄ -C ₁₀ cycloalkyl group, C ₄ -C ₁₀ cycloalkenyl group, (C ₃ ~C ₆ cycloalkyl) C ₁ -C ₄ alkyl groups and the like are included.

In the present specification, "C ₁ -C ₁₀ alkyl group" is preferably C ₁ -C ₆ alkyl group, more preferably a C ₁ -C ₄ alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.

In the present specification, "C ₂ -C ₁₀ alkenyl group" is preferably C ₂ -C ₆ alkenyl group, more preferably a C ₂ -C ₄ alkenyl group. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, propenyl, isopropenyl, 2-methyl-1-propenyl, 2-methylallyl, 2-butenyl and the like.

In the present specification, "C ₂ -C ₁₀ alkynyl group" is preferably C ₂ -C ₆ alkynyl group, more preferably a C ₂ -C ₄ alkynyl group. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and the like.

In the present specification, the “C ₄ -C ₁₀ alkyldienyl group” is preferably a C ₄ -C ₆ alkyldienyl group. Examples of alkyldienyl groups include, but are not limited to, 1,3-butadienyl and the like.

In the present specification, examples of the “C ₆ -C ₁₀ aryl group” include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, indenyl and the like.

In the present specification, examples of the “C ₆ -C ₁₀ alkylaryl group” include, but are not limited to, o-tolyl, m-tolyl, p-tolyl, 2,3-xylyl, 2,4-xylyl. 2,5-xylyl, o-cumenyl, m-cumenyl, p-cumenyl, mesityl and the like.

In the present specification, examples of the “C ₆ -C ₁₀ arylalkyl group” include, but are not limited to, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl and the like.

In the present specification, the “C ₄ -C ₁₀ cycloalkyl group” is preferably a C ₄ -C ₆ cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

In the present specification, the “C ₄ -C ₁₀ cycloalkenyl group” is preferably a C ₄ -C ₆ cycloalkenyl group. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.

In the present specification, the “C ₁ -C ₁₀ alkoxy group” is preferably a C ₁ -C ₆ alkoxy group, and more preferably a C ₁ -C ₄ alkoxy group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy and the like.

In the present specification, examples of the “C ₆ -C ₁₀ aryloxy group” include, but are not limited to, phenyloxy, naphthyloxy and the like.

In the first embodiment of the present invention, “C ₁ -C ₁₀ hydrocarbon group” represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , “C ₁ -C ₁₀ alkoxy group”, “C ₆ -C ₁₀ aryloxy group”, “silyl group”, “silyloxy group” may have a substituent introduced therein. Examples of the substituent include a C _{1 to} C ₁₀ hydrocarbon group (for example, methyl, ethyl, propyl, butyl, phenyl, naphthyl, indenyl, tolyl, xylyl, benzyl, etc.), C _{1 to} C ₁₀ alkoxy group (for example, , Methoxy, ethoxy, propoxy, butoxy, etc.), C ₆ -C ₁₂ aryloxy groups (eg, phenyloxy, naphthyloxy, biphenyloxy, etc.), amino groups, hydroxyl groups, halogen atoms (eg, fluorine, chlorine, bromine, iodine) ) Or a silyl group. In this case, one or more substituents may be introduced at substitutable positions, and preferably 1 to 4 substituents may be introduced. When the number of substituents is 2 or more, each substituent may be the same or different.

  In this specification, examples of “optionally substituted silyl group” include, but are not limited to, methylsilyl, ethylsilyl, dimethylsilyl, diethylsilyl, trimethylsilyl, triethylsilyl, trii-propylsilyl. , Tri t-butylsilyl, dimethyl t-butylsilyl, trimethoxysilyl, triethoxysilyl, diphenylmethylsilyl, diphenylethylsilyl, diphenyl i-propylsilyl, diphenyl t-butylsilyl, triphenylsilyl, triphenoxysilyl, dimethylmethoxysilyl, Examples include dimethylphenoxysilyl and methylmethoxyphenylsilyl.

  In the present specification, examples of “optionally substituted silyloxy group” include, but are not limited to, trimethylsiloxy, triethylsiloxy, trii-propylsiloxy, tri-t-butylsiloxy, t- Examples include butyldimethylsiloxy, t-butyldiphenylsiloxy, triphenylsiloxy and the like.

In the first embodiment of the present invention, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently the same or different, hydrogen atom, which may have a substituent C ₁ -C ₁₀ hydrocarbon group which may have a substituent C ₁ -C ₁₀ alkoxy group, which may C ₆ ~ substituted A C ₁₀ aryloxy group, an optionally substituted silyl group, or an optionally substituted silyloxy group is preferred, and R ¹ , R ³ , R ⁶ , R ⁹ and R ¹⁰ are preferred. but a hydrogen atom, a C ₁ -C ₁₀ hydrocarbon group, C ₁ -C ₁₀ alkoxy groups, C ₆ -C ₁₀ aryloxy group, or may have a substituent group silyloxy group, R ^2, R ⁴ and R ⁵ is a hydrogen atom, which may have a substituent C ₁ -C ₁₀ hydrocarbon group which may have a substituent silyl group, or Have a substituent is also optionally silyloxy group, R ⁷ and R ⁸ may have a substituent group C ₁ -C ₁₀ alkoxy groups, optionally C ₆ -C be substituted ₁₀ is more preferably an aryloxy group or a silyloxy group which may have a substituent, and R ¹ , R ³ , R ⁶ , R ⁹ and R ¹⁰ are a hydrogen atom, methyl or ethyl, and R ² R ⁴ and R ⁵ are a hydrogen atom, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, phenyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl. , R ⁷ and R ⁸ are methoxy, ethoxy, propoxy, butoxy, benzyloxy, phenyloxy, naphthyloxy, tert- butyl dimethylsiloxy, or tert- butyl diphenyl siloxane More preferably.

In the first embodiment of the present invention, A ¹ is a substituent containing nitrogen and / or phosphorus.

  In the first embodiment of the present invention, the nitrogen-containing substituent may be azide, nitrile, carbamoyl, amino, dimethylamino, methylamino, methylphenylamino, phenylamino, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl. , Indolyl, adenyl, or thymidyl.

  In the present invention, examples of the substituent containing phosphorus include phosphonyl, phosphoryl, and phosphinyl.

In the first aspect of the present invention, A ¹ is preferably a nitrogen-containing substituent, and more preferably azide, amino, dimethylamino, indolyl, adenyl, or thymidyl.

Moreover, in the 2nd aspect of this invention, the method of manufacturing the catechin derivative containing the catechin derivative concerning the 1st aspect of this invention is provided. Specifically, in the presence of an organometallic compound represented by the following formula (2) and a silver compound represented by the following formula (3), a catechin derivative represented by the following formula (4) and the following formula (5) And a nucleophilic reagent represented by the following formula (1a):

In the second aspect of the present invention, when the substituent A ¹ in the above formula (5) is introduced into the 4-position of the flavan skeleton of the catechin derivative represented by the above formula (4), the above formula (2) shows. The reaction is carried out in the presence of an organometallic compound and a silver compound represented by the above formula (3). The combination of the organometallic compound and the silver compound is considered to function as a promoter for the substituent introduction reaction. As a result, the product (1a) can be obtained regioselectively and immediately.

In the second embodiment of the present invention, in the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are the same as those in the first embodiment of the present invention. It is the same as explained.

In the second embodiment of the present invention, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently the same or different, hydrogen atom, which may have a substituent C ₁ -C ₁₀ hydrocarbon group which may have a substituent C ₁ -C ₁₀ alkoxy group, which may C ₆ ~ substituted A C ₁₀ aryloxy group, an optionally substituted silyl group, or an optionally substituted silyloxy group is preferred, and R ¹ , R ³ , R ⁶ , R ⁹ and R ¹⁰ are preferred. Is a hydrogen atom, a C ₁ -C ₁₀ hydrocarbon group, a C ₁ -C ₁₀ alkoxy group, a C ₆ -C ₁₀ aryloxy group, an optionally substituted silyloxy group, and R ² , R ⁴ and R ⁵ is a hydrogen atom, which may have a substituent C ₁ -C ₁₀ hydrocarbon group which may have a substituent silyl group, or a substituted The have is also good silyloxy group, R ⁷ and R ⁸ may have a substituent group C ₁ -C ₁₀ alkoxy group which may have a substituent C ₆ -C ₁₀ aryl More preferably, it is an oxy group or an optionally substituted silyloxy group, R ¹ , R ³ , R ⁶ , R ⁹ and R ¹⁰ are a hydrogen atom, methyl or ethyl, R ² , R ⁴ and R ⁵ are a hydrogen atom, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, phenyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl; R ⁷ and R ⁸ are methoxy, ethoxy, propoxy, butoxy, benzyloxy, phenyloxy, naphthyloxy, tert- butyl dimethylsiloxy, or tert- butyldiphenylsiloxy There it is more preferable.

In the second aspect of the present invention, in the above formula, A ¹ is an optionally substituted C ₁ -C ₁₀ hydrocarbon group; or one selected from the group consisting of nitrogen, oxygen, sulfur and phosphorus It is a substituent containing the above hetero atom.

In the second aspect of the present invention, the nitrogen-containing substituent includes an azide group, a nitrile group, an optionally substituted carbamoyl group, an optionally substituted amino group, and a substituent. An indolyl group which may have a substituent, a pyrrolyl group which may have a substituent, a pyrazolyl group which may have a substituent, an imidazolyl group which may have a substituent, and a substituent. May have a pyridinyl group which may have a substituent, a pyrazinyl group which may have a substituent, a pyrimidinyl group which may have a substituent, a pyridazinyl group which may have a substituent, and a substituent. Examples thereof include a good adenyl group and a thymidyl group which may have a substituent.
In the present specification, as the substituent containing oxygen, an optionally substituted C ₁ -C ₁₀ alkoxy group; an optionally substituted C ₆ -C ₁₀ aryloxy group; a substituent A C ₁ -C ₁₀ acyl group optionally having a substituent; a C ₁ -C ₁₀ acyloxy group optionally having a substituent; or a heterocyclic ring containing an optionally substituted oxygen (furan, Oxazole, isoxazole, pyran, etc.).

In the present specification, examples of the “C ₁ -C ₁₀ acyl group” include C ₁ -C ₁₀ alkylcarbonyl, C ₆ -C ₁₀ arylcarbonyl, mono-C ₁ -C ₄ alkylphenylcarbonyl, di-C ₁ -C ₃ alkylphenylcarbonyl, phenyl-C ₁ -C ₄ alkylcarbonyl and the like can be mentioned, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, benzoyl, methylbenzoyl, dimethylbenzoyl, methylethylbenzoyl, diethylbenzoyl, benzylcarbonyl It is preferable that

In the present specification, “C ₁ -C ₁₀ acyloxy group” means C ₁ -C ₁₀ alkylcarbonyloxy, C ₆ -C ₁₀ arylcarbonyloxy, mono-C ₁ -C ₄ alkylphenylcarbonyloxy, di-C _1. -C ₃ alkylphenyl alkylcarbonyloxy, there may be mentioned phenyl -C ₁ -C ₄ alkylcarbonyloxy such as acetoxy, propionyloxy, butyryloxy, iso-butyryloxy, valeryloxy, isovaleryloxy, benzoyloxy, methyl benzoyloxy Dimethylbenzoyloxy, methylethylbenzoyloxy, diethylbenzoyloxy and benzylcarbonyloxy are preferred.

In the present specification, as a substituent containing sulfur, an optionally substituted alkylthio group (—SQ ¹ , wherein Q ¹ is a C _{1 to} C ₁₀ alkyl optionally having a substituent. An arylthio group which may have a substituent (-SQ ² , wherein Q ² represents a C _{6 to} C ₁₀ aryl group which may have a substituent); An optionally substituted alkylsulfonyl group (—SO ₂ Q ³ , wherein Q ³ represents an optionally substituted C ₁ -C ₁₀ alkyl group); An arylsulfonyl group (—SO ₂ Q ⁴ , wherein Q ⁴ represents an optionally substituted C ₆ -C ₁₀ aryl group) can be exemplified.

In a second aspect of the present invention, "C ₁ -C ₁₀ hydrocarbon group" represented by A ^1; exemplified as the "substituent containing nitrogen" represented as an example of A ¹ "amino group", "indolyl Group "," pyrrolyl group "," carbamoyl group "," pyrazolyl group "," imidazolyl group "," pyridyl group "," pyrazinyl group "," pyrimidinyl group "," pyridazinyl group "," adenyl group "," thymidyl " A “C ₁ -C ₁₀ alkoxy group”, “C ₆ -C ₁₀ aryloxy group”, “C ₁ -C ₁₀ acyl” exemplified as “oxygen-containing substituent” shown as an example of A ¹ group "," C ₆ -C ₁₀ acyloxy group "," heterocyclic "includes oxygen;" alkylthio group exemplified as the substituent "including" sulfur is shown as an example of a ¹ "," arylthio group ", `` Alkylsulfonyl group '', `` ary The sulfonyl group ", the substituent may be introduced. Examples of the substituent include a C _{1 to} C ₁₀ hydrocarbon group (for example, methyl, ethyl, propyl, butyl, phenyl, naphthyl, indenyl, tolyl, xylyl, benzyl, etc.), C _{1 to} C ₁₀ alkoxy group (for example, , Methoxy, ethoxy, propoxy, butoxy, etc.), C ₆ -C ₁₂ aryloxy groups (eg, phenyloxy, naphthyloxy, biphenyloxy, etc.), C ₁ -C ₁₀ alkoxycarbonyl groups (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl), C ₆ -C ₂₀ aryloxycarbonyl group (e.g., phenoxycarbonyl, naphthoxycarbonyl, phenyl phenoxycarbonyl), an amino group, a hydroxyl group, a halogen atom (e.g., fluorine, chlorine, bromine, iodine) Have a substituent Good formamide alkyl group, or a silyl group can be exemplified. In this case, one or more substituents may be introduced at substitutable positions, and preferably 1 to 4 substituents may be introduced. When the number of substituents is 2 or more, each substituent may be the same or different.
Examples of the “formamidoalkyl group optionally having substituent (s)” include, for example, the following formula: R—CONH—CH ₂ CH ₂ —
[Wherein, R represents a hydrocarbon group which may have a substituent. ]
The substituent represented by these can be mentioned. Here, the “hydrocarbon group” represented by R may have a substituent introduced, for example, a C _{1 to} C ₁₀ alkoxy group (for example, methoxy, ethoxy, propoxy, butoxy, etc.), C _{6 to} C _12. Aryloxy groups (eg, phenyloxy, naphthyloxy, biphenyloxy, etc.), C ₁ -C ₁₀ alkylthio groups (eg, methylthio, ethylthio, propylthio, butylthio, etc.), C ₆ -C ₁₂ arylthio groups (eg, phenylthio, naphthylthio) , Biphenylthio, etc.), amino group, hydroxyl group, halogen atom (for example, fluorine, chlorine, bromine, iodine), or silyl group. In this case, one or more substituents may be introduced at substitutable positions, and preferably 1 to 4 substituents may be introduced. When the number of substituents is 2 or more, each substituent may be the same or different.
Specific examples of the “formamidoalkyl group optionally having substituent (s)” include a phenylvinylformamidoethyl group, a 2-p-hydroxyphenylvinylformamidoethyl group, and a methylvinylformamidoethyl group. .

In the second embodiment of the present invention, A ¹ is azide, arylthio, dialkylarylthio, trialkoxyphenyl, tri (arylalkyloxy) phenyl, alkoxycarbonylalkyl, dialkyl (alkoxycarbonyl) alkyl, indolyl, alkylindolyl, alkyl Preferred is pyrrolyl or pyrrolyl, azide, phenylthio, 2,6-dimethylphenylthio, 2,4-dimethylphenylthio, 2,4,6-trimethoxyphenyl, 2,4,6-tribenzyloxyphenyl More preferably, ethoxycarbonylmethyl, dimethyl (isopropoxycarbonyl) methyl, indolyl, 1-methylindolyl, 1-methylpyrrolyl or pyrrolyl.

[式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷、Ｒ⁸、Ｒ⁹及びＲ¹⁰は、上記意味を有する。］ In the second aspect of the present invention, a catechin derivative represented by the following formula (4) is used.

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ have the above-mentioned meanings. ]

In the above formula, A ² represents a hydrogen atom; an optionally substituted C ₁ -C ₁₀ hydrocarbon group; an optionally substituted C ₁ -C ₁₀ alkoxy group; An optionally substituted C ₆ -C ₁₀ aryloxy group; an optionally substituted C ₆ -C ₁₀ acyl group; or a hydroxyl group.

In the present specification, "C ₁ -C ₁₀ hydrocarbon group" represented by A ^2, "C ₁ -C ₁₀ alkoxy group", "C ₆ -C ₁₀ aryloxy group", "C ₁ -C ₁₀ acyl group May be substituted with a substituent. Examples of the substituent include a C _{1 to} C ₁₀ hydrocarbon group (for example, methyl, ethyl, propyl, butyl, phenyl, naphthyl, indenyl, tolyl, xylyl, benzyl, etc.), C _{1 to} C ₁₀ alkoxy group (for example, , Methoxy, ethoxy, propoxy, butoxy, etc.), C ₆ -C ₁₂ aryloxy groups (eg, phenyloxy, naphthyloxy, biphenyloxy, etc.), amino groups, hydroxyl groups, halogen atoms (eg, fluorine, chlorine, bromine, iodine) ) Or a silyl group. In this case, one or more substituents may be introduced at substitutable positions, and preferably 1 to 4 substituents may be introduced. When the number of substituents is 2 or more, each substituent may be the same or different.

In the second aspect of the present invention, A ² is preferably a hydrogen atom, acetyl, or methyl, and more preferably acetyl.

[式中、Ａ¹は、上記意味を有する。 In the second embodiment of the present invention, a nucleophile represented by the following formula (5) is used.

[Wherein A ¹ has the above-mentioned meaning.

In said formula (5), Y shows a hydrogen atom or a halogen atom. In this case, examples of the halogen atom include F, Cl, Br, and I.
In the present invention, Y is preferably a hydrogen atom.

  In the second embodiment of the present invention, the amount of the nucleophile represented by the above formula (5) is 0.1 mol to 10 mol, preferably 1 mol to 5 mol, relative to 1 mol of the catechin derivative (4). More preferably, it is 2 mol-4 mol.

In the second embodiment of the present invention, an organometallic compound represented by the following formula (2) is used.

In the above formula (2), L ¹ and L ² are independent of each other and are the same or different and are anionic ligands.
The anionic ligand is preferably a delocalized cyclic η ⁵ -coordinated ligand, and more preferably an optionally substituted cyclopentadienyl group.

  In the present specification, examples of the “optionally substituted cyclopentadienyl group” include methylcyclopentadienyl, ethylcyclopentadienyl, isopropylcyclopentadienyl, n-butylcyclopentadienyl, t- Examples thereof include butylcyclopentadienyl, dimethylcyclopentadienyl, diethylcyclopentadienyl, diisopropylcyclopentadienyl, di-t-butylcyclopentadienyl, tetramethylcyclopentadienyl and the like.

In the present invention, L ¹ and L ² are preferably an optionally substituted cyclopentadienyl group or an optionally substituted indenyl group, and more preferably a cyclopentadienyl group.

  In the above formula (2), M is titanium, zirconium or hafnium, preferably zirconium or hafnium.

In the above formula (2), Z ¹ and Z ² are independent of each other and are the same or different and represent a leaving group.
The leaving group is preferably a halogen atom such as F, Cl, Br, or I, or a C _{1 to} C ₁₀ hydrocarbon group, a C _{1 to} C ₁₀ alkyl group, a C _{2 to} C ₁₀ alkenyl group, C ₂ -C ₁₀ alkynyl group, C ₃ -C ₁₀ allyl group, C ₄ -C ₁₀ alkadienyl group, C ₄ -C ₁₀ polyenyl group, C ₆ -C ₁₀ aryl group, C ₆ -C ₁₂ alkylaryl group, C ₆ -C ₁₂ arylalkyl group, C ₄ -C ₁₀ cycloalkyl group, or, may be mentioned C ₄ -C ₁₀ cycloalkenyl group.
In the present invention, Z ¹ and Z ² are preferably halogen atoms, and more preferably chlorine atoms.

  In the second aspect of the present invention, the amount of the organometallic compound represented by the formula (2) is 0.001 mol to 1 mol, preferably 0.01 mol, relative to 1 mol of the catechin derivative (4). It is -1 mol, More preferably, it is 0.1 mol-0.3 mol.

In the second embodiment of the present invention, a silver compound represented by the following formula (3) is used.

In the above formula, X is a perchlorate ion (ClO ₄ ⁻ ) or a trifluoromethanesulfonate ester ion (OSO ₂ CF ₃ ⁻ ), and preferably a perchlorate ion (ClO ₄ ⁻ ).

  In the second aspect of the present invention, the amount of the silver compound represented by the formula (3) is 0.002 mol to 2 mol, preferably 0.02 mol to 1 mol of the catechin derivative (4). It is 2 mol, More preferably, it is 0.2 mol-0.6 mol.

  In the second embodiment of the present invention, typically, a catechin represented by the above formula (4) is added to a solution of a mixture of the organometallic compound represented by the above formula (2) and the silver compound represented by the above formula (3). The catechin derivative represented by the above formula (1a) is obtained by adding the derivative and the nucleophilic reagent represented by the above formula (5) and stirring.

  In the second embodiment of the present invention, the reaction is preferably performed in a temperature range of −100 ° C. to 100 ° C., particularly preferably in a temperature range of −100 ° C. to 0 ° C., more preferably in a range of −80 ° C. to −20 ° C. Performed in the temperature range. The pressure is preferably normal pressure.

  In the second aspect of the present invention, the solvent is preferably a solvent capable of dissolving the organometallic compound represented by the above formula (2) and the silver compound represented by the above formula (3). As the solvent, an aliphatic or aromatic organic solvent is used. Ether solvents such as tetrahydrofuran or diethyl ether; halogenated hydrocarbons such as methylene chloride; halogenated aromatic hydrocarbons such as o-dichlorobenzene; aromatic hydrocarbons such as benzene and toluene are used.

In the third aspect of the present invention, in the presence of an organometallic compound represented by the following formula (2) and a silver compound represented by the following formula (3), a catechin derivative represented by the following formula (4), There is provided a method for producing a catechin derivative represented by the following formula (1b), which comprises reacting with a nucleophile represented by the formula (6).

  In the third aspect of the present invention, as in the second aspect of the present invention, the nucleophile represented by the above formula (6) is substituted at the 4-position of the flavan skeleton of the catechin derivative represented by the above formula (4). In this case, by performing the reaction in the presence of the combination of the organometallic compound represented by the above formula (2) and the silver compound represented by the above formula (3), this combination functions as an accelerator for the substituent introduction reaction. The product (1b) can be obtained regioselectively and immediately.

Also in the third aspect of the present invention, in the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are the first aspect of the present invention. This is the same as described in the above.

In the third embodiment of the present invention, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently the same or different, hydrogen atom, which may have a substituent C ₁ -C ₁₀ hydrocarbon group which may have a substituent C ₁ -C ₁₀ alkoxy group, which may C ₆ ~ substituted A C ₁₀ aryloxy group, an optionally substituted silyl group, or an optionally substituted silyloxy group is preferred, and R ¹ , R ³ , R ⁶ , R ⁹ and R ¹⁰ are preferred. but a hydrogen atom, a C ₁ -C ₁₀ hydrocarbon group, C ₁ -C ₁₀ alkoxy groups, C ₆ -C ₁₀ aryloxy group, or may have a substituent group silyloxy group, R ^2, R ⁴ and R ⁵ is a hydrogen atom, which may have a substituent C ₁ -C ₁₀ hydrocarbon group which may have a substituent silyl group, or Have a substituent is also optionally silyloxy group, R ⁷ and R ⁸ may have a substituent group C ₁ -C ₁₀ alkoxy groups, optionally C ₆ -C be substituted ₁₀ is more preferably an aryloxy group, or an optionally substituted silyloxy group, and R ¹ , R ³ , R ⁶ , R ⁹ and R ¹⁰ are each a hydrogen atom, methyl or ethyl; ² , R ⁴ and R ⁵ are a hydrogen atom, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, phenyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl There, methoxy R ⁷ and R ^8, ethoxy, propoxy, butoxy, benzyloxy, phenyloxy, naphthyloxy, tert- butyl dimethylsiloxy, or tert- butyl diphenylsiloxy More preferably sheet.

In the third aspect of the present invention, as in the second aspect of the present invention, the organometallic compound represented by the above formula (2), the silver compound represented by the above formula (3), and the catechin represented by the above formula (4). Derivatives are used.
These compounds are the same as those described in the second embodiment of the present invention.

  In the third aspect of the present invention, the amount of the organometallic compound represented by the formula (2) is 0.001 mol to 1 mol, preferably 0.01 mol, relative to 1 mol of the catechin derivative (4). It is -1 mol, More preferably, it is 0.1 mol-0.3 mol.

  In the third aspect of the present invention, the amount of the silver compound represented by the formula (3) is 0.002 mol to 2 mol, preferably 0.02 mol to 1 mol of the catechin derivative (4). It is 2 mol, More preferably, it is 0.2 mol-0.6 mol.

In the third embodiment of the present invention, a nucleophile represented by the following formula (6) is used.

In the above formula (6), B ¹ and B ² are each independently the same or different and are each a hydrogen atom; an optionally substituted C ₁ -C ₁₀ hydrocarbon group; and C ₁ optionally -C ₁₀ alkoxy groups; which may have a substituent C ₆ -C ₁₀ aryloxy group; optionally substituted amino group; substituted A silyl group which may have a substituent; a silyloxy group which may have a substituent; or a hydroxyl group.

In the above formula (6), B ³ and B ⁴ are each independently the same or different and are each a hydrogen atom; an optionally substituted C ₁ -C ₁₀ hydrocarbon group; or a substituent. It is a silyl group which may have.

In the present specification, “C ₁ -C ₁₀ hydrocarbon group”, “C ₁ -C ₁₀ alkoxy group”, “C ₆ -C ₁₀ aryloxy group”, “amino group” represented by B ¹ and B ² , Substituents may be introduced into the “silyl group” and “silyloxy group”. Examples of the substituent include a C _{1 to} C ₁₀ hydrocarbon group (for example, methyl, ethyl, propyl, butyl, phenyl, naphthyl, indenyl, tolyl, xylyl, benzyl, etc.), C _{1 to} C ₁₀ alkoxy group (for example, , Methoxy, ethoxy, propoxy, butoxy, etc.), C ₆ -C ₁₂ aryloxy groups (eg, phenyloxy, naphthyloxy, biphenyloxy, etc.), amino groups, hydroxyl groups, halogen atoms (eg, fluorine, chlorine, bromine, iodine) ) Or a silyl group. In this case, one or more substituents may be introduced at substitutable positions, and preferably 1 to 4 substituents may be introduced. When the number of substituents is 2 or more, each substituent may be the same or different.

In the present specification, a substituent may be introduced into the “C ₁ -C ₁₀ hydrocarbon group” and “silyl group” represented by B ³ and B ⁴ . Examples of the substituent include a C _{1 to} C ₁₀ hydrocarbon group (for example, methyl, ethyl, propyl, butyl, phenyl, naphthyl, indenyl, tolyl, xylyl, benzyl, etc.), C _{1 to} C ₁₀ alkoxy group (for example, , Methoxy, ethoxy, propoxy, butoxy, etc.), C ₆ -C ₁₂ aryloxy groups (eg, phenyloxy, naphthyloxy, biphenyloxy, etc.), amino groups, hydroxyl groups, halogen atoms (eg, fluorine, chlorine, bromine, iodine) ) Or a silyl group. In this case, one or more substituents may be introduced at substitutable positions, and preferably 1 to 4 substituents may be introduced. When the number of substituents is 2 or more, each substituent may be the same or different.

In the third aspect of the present invention, B ¹ and B ² have a hydrogen atom, a C ₁ -C ₁₀ hydrocarbon group, a C ₁ -C ₁₀ alkoxy group, a C ₆ -C ₁₀ aryloxy group, or a substituent. It is preferably a silyloxy group which may be a hydrogen atom, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, trimethylsiloxy, tert-butyldimethylsiloxy or the like. It is more preferable.

In the above formula (6), B ³ and B ⁴ are preferably a hydrogen atom, a C ₁ -C ₁₀ alkyl group, or a silyl group which may have a substituent, and the like, a hydrogen atom, methyl, ethyl More preferred are trimethylsilyl, triethylsilyl, trii-propylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, and the like.

  In the third aspect of the present invention, the amount of the nucleophile represented by the above formula (6) is 0.1 mol to 10 mol, preferably 1 mol to 5 mol, relative to 1 mol of the catechin derivative (4). Mol, more preferably 2 mol to 4 mol.

  In the third aspect of the present invention, typically, a catechin represented by the above formula (4) is added to a solution of a mixture of the organometallic compound represented by the above formula (2) and the silver compound represented by the above formula (3). The catechin derivative represented by the above formula (1b) is obtained by adding the derivative and the nucleophilic reagent represented by the above formula (6) and stirring.

  In the third embodiment of the present invention, the reaction is preferably performed in a temperature range of −100 ° C. to 100 ° C., particularly preferably in a temperature range of −100 ° C. to 0 ° C., more preferably in a range of −80 ° C. to −20 ° C. Performed in the temperature range. The pressure is preferably normal pressure.

  In the third aspect of the present invention, the solvent is preferably a solvent capable of dissolving the organometallic compound represented by the above formula (2) and the silver compound represented by the above formula (3). As the solvent, an aliphatic or aromatic organic solvent is used. Ether solvents such as tetrahydrofuran or diethyl ether; halogenated hydrocarbons such as methylene chloride; halogenated aromatic hydrocarbons such as o-dichlorobenzene; aromatic hydrocarbons such as benzene and toluene are used.

  Hereinafter, the present invention will be described based on examples. However, the present invention is not limited to the following examples.

All experiments were performed under a dry argon atmosphere. Dichloromethane was distilled from P ₂ O ₅ and CaH ₂ and stored on a 4A molecular sieve. For thin layer chromatography (TLC) analysis, Merck precoated plates (silica gel 60 F ₂₅₄ , Art 5715, 0.25 mm) were used. For silica gel preparative TLC (PTLC), Merck silica gel 60 PF ₂₅₄ (Art 7747) was used. The melting point (mp) was measured using a Yanako MP-S3 device and not corrected.
^{For 1} H and ¹³ C NMR spectra, JEOL Lambda 300 spectrometer or Bruker DRX500 was used. The infrared (IR) spectrum was a Perkin Elmer 1600 FTIR spectrometer.
High resolution mass spectrometry (HRMS) was performed using a JEOL JMS AX505HA spectrometer.
The optical rotation was measured using the DIP-1000 polarimeter for the optical rotation ([α] _D ).

［上記式中、Ｂｎはベンジル基を意味する。以下の化学式においても同様である。］

[In the above formula, Bn means a benzyl group. The same applies to the following chemical formulas. ]

［上記式中、Ａｃはアセチル基を意味する。以下の化学式においても同様である。］
反応混合物は、10 分間 -78℃にて攪拌し、飽和炭酸水素ナトリウム溶液を加えて反応を停止させた。混合物は、セライトパッドを通して濾過し、EtOAc (x3)で抽出した。結合した有機抽出物を塩水で洗い、乾燥させ(Na₂SO₄)、真空下で濃縮させた。残渣をプレパラティブTLC (ヘキサン/EtOAc = 3/1) で精製し、標題生成物を非晶質固体として得た(42 mg, 80%)。 (Stoichiometric conditions)
In the presence of molecular sieve 4A (63 mg), a mixture of Cp ₂ ZrCl ₂ (22 mg, 0.075 mmol) and AgClO ₄ (31 mg, 0.15 mmol) was placed in CH ₂ Cl ₂ (0.5 mL) for 5 minutes at room temperature. The promoter was prepared in situ by agitation.
To this suspension, CH _{2 of} a mixture of a catechin derivative represented by the following formula (50 mg, 0.063 mmol) and a nucleophile 1-ethoxy-1-dimethylt-butylsiloxyethylene (38 mg, 0.19 mmol) Cl ₂ (0.75 mL) solution was added at −78 ° C.

[In the above formula, Ac means an acetyl group. The same applies to the following chemical formulas. ]
The reaction mixture was stirred for 10 minutes at -78 ° C and quenched with saturated sodium bicarbonate solution. The mixture was filtered through a celite pad and extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated under vacuum. The residue was purified by preparative TLC (hexane / EtOAc = 3/1) to give the title product as an amorphous solid (42 mg, 80%).

（触媒的条件）
有機金属化合物と銀化合物を触媒量用いた他は、実施例１とほぼ同様の操作を行った。
すなわち、モレキュラーシーブ4A (125 mg)存在下、Cp₂ZrCl₂ (3.7 mg, 0.013 mmol) とAgClO₄ (5.2 mg, 0.025 mmol) の混合物をCH₂Cl₂ (1.0 mL)の中で5分間室温にて攪拌することにより、プロモーターは、その場で調製した。
この懸濁液に、下記式で示されるカテキン誘導体 (100 mg, 0.125 mmol) と１−エトキシ−１−ジメチルｔ−ブチルシロキシエチレン(76 mg, 0.38 mmol) の混合物のCH₂Cl₂ (1.5 mL) 溶液を-78 ℃にて加えた。

反応混合物は、15 分間 -78℃にて攪拌し、飽和炭酸水素ナトリウム溶液を加えて反応を停止させた。混合物は、セライトパッドを通して濾過し、EtOAc (x3)で抽出した。結合した有機抽出物を塩水で洗い、乾燥させ(Na₂SO₄)、真空下で濃縮させた。残渣をプレパラティブTLC (ヘキサン/EtOAc = 3/1) で精製し、標題生成物を非晶質固体として得た(88 mg, 85%)。

(Catalytic conditions)
The same operation as in Example 1 was performed except that a catalytic amount of an organometallic compound and a silver compound was used.
That is, in the presence of molecular sieve 4A (125 mg), a mixture of Cp ₂ ZrCl ₂ (3.7 mg, 0.013 mmol) and AgClO ₄ (5.2 mg, 0.025 mmol) in CH ₂ Cl ₂ (1.0 mL) at room temperature for 5 minutes. The promoter was prepared in situ by stirring at
To this suspension, CH ₂ Cl ₂ (1.5 mL) of a mixture of a catechin derivative represented by the following formula (100 mg, 0.125 mmol) and 1-ethoxy-1-dimethylt-butylsiloxyethylene (76 mg, 0.38 mmol) was added. ) The solution was added at -78 ° C.

The reaction mixture was stirred for 15 minutes at -78 ° C and quenched with saturated sodium bicarbonate solution. The mixture was filtered through a celite pad and extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated under vacuum. The residue was purified by preparative TLC (hexane / EtOAc = 3/1) to give the title product as an amorphous solid (88 mg, 85%).

Ethyl ester (ratio of two diastereomeric mixtures α / β = 16/84):
IR (neat) 3064, 3031, 2903 (br), 1732, 1616, 1592, 1514, 1498, 1455, 1439, 1376, 1264, 1216, 1152, 1028, 811, 736, 696 cm ^-1 ;
¹ H NMR (500 MHz, CDCl ₃ , obvious signals of minor isomers marked with asterisks) δ1.06 * (t, 3H, J = 7.1 Hz), 1.07 (t, 3H, J = 7.1 Hz) , 2.24 * (dd, 1H, J = 15.8, 8.5 Hz), 2.61 * (dd, 1H, J = 15.8, 3.2 Hz), 2.64-2.71 (m, 2H), 3.44-3.48 * (m, 1H), 3.71 (dd, 1H, J = 9.9, 5.9 Hz), 3.77 (dq, 1H, J = 10.8, 7.1 Hz), 3.85 (d, 1H, J = 11.4 Hz), 3.88 (dq, 1H, J = 10.8, 7.1 Hz), 3.96 * (dd, 1H, J = 6.5, 5.9 Hz), 3.99 * (d, 1H, J = 11.5 Hz), 4.174.21 (m, 1H), 4.29 (d, 1H, J = 11.4 Hz), 4.77 (d, 1H, J = 9.9 Hz), 4.84 * (d, 2H, J = 6.6 Hz), 4.95 (d, 1H, J = 11.8 Hz), 4.97 (d, 1H, J = 11.8 Hz) ), 5.01 (d, 1H, J = 12.1 Hz), 5.08 (s, 2H), 5.09 (d, 1H, J = 12.1 Hz), 5.10 * (s, 2H), 5.17 * (s, 2H), 5.20 (s, 2H), 6.16 (d, 1H, J = 2.3 Hz), 6.26 * (d, 1H, J = 2.4 Hz), 6.27 (d, 1H, J = 2.3 Hz), 6.27 * (d, 1H, J = 2.4 Hz), 6.816.84 (m, 2H), 6.84 * (d, 1H, J = 2.0 Hz), 6.86 * (d, 1H, J = 1.8 Hz), 6.926.99 (m, 3H), 7.107.15 (m, 3H), 7.277.47 (m, 20H);
¹³ C NMR (125 MHz, CDCl ₃ ) δ14.0, 30.7, 36.6, 60.0, 69.8, 70.0, 70.9, 71.3, 72.2, 75.9, 77.2, 93.8, 94.1, 105.5, 113.9, 114.7, 121.2, 126.7, 127.2, 127.3, 127.5, 127.70, 127.74, 127.8, 128.0, 128.2, 128.42, 128.44, 128.46, 128.6, 132.0, 136.7, 137.2, 137.3, 137.7, 148.8, 155.0, 157.5, 159.2, 172.4;
Calculated elemental analysis C ₅₄ H ₅₀ O ₈ : C, 78.43; H, 6.09.Measured value C, 78.21, H 6.30.

Stereochemical assignments and isomer ratios were determined by NMR. The α- and β-isomers are generally inseparable, but the spectrum has sufficient resolution to allow selective evaluation of both, and both stereoisomers are characteristic as shown below NOE is shown.

Table 1 shows the schemes, reaction conditions, yields, and the like of Example 1 and Example 2.

実施例１と同様の操作を行った。ただし、求核試薬として、１−イソプロポキシ−１−ジメチルｔ−ブチルシロキシ−２−メチル−１−プロペンを用いた。

The same operation as in Example 1 was performed. However, 1-isopropoxy-1-dimethyl t-butylsiloxy-2-methyl-1-propene was used as a nucleophile.

IR (neat) 3064, 3031, 2979, 2934 (br), 1715, 1615, 1590, 1514, 1498, 1454, 1374, 1261, 1218, 1144, 1106, 1028, 910, 817, 734, 696 cm ^-1 ;
¹ H NMR (500 MHz, CDCl ₃ ) δ1.09 (s, 3H), 1.11 (d, 3H, J = 6.2 Hz), 1.15 (s, 3H), 1.15 (d, 3H, J = 5.1 Hz), 3.92 (s, 1H), 4.03 (d, 1H, J = 11.2 Hz), 4.15 (d, 1H, J = 8.1 Hz), 4.36 (d, 1H, J = 8.1 Hz), 4.50 (d, 1H, J = 11.2 Hz), 4.914.97 (m, 1H), 4.96 (d, 1H, J = 11.9 Hz), 4.98 (d, 1H, J = 11.9 Hz), 5.04 (s, 2H), 5.12 (s, 2H ), 5.18 (s, 2H), 6.31 (d, 1H, J = 1.1 Hz), 6.36 (d, 1H, J = 1.1 Hz), 6.93 (d, 1H, J = 8.2 Hz), 7.01 (d, 1H , J = 8.2 Hz), 7.137.16 (m, 3H), 7.197.24 (m, 3H), 7.277.48 (m, 20H);
¹³ C NMR (125 MHz, CDCl ₃ ) δ21.7, 25.6, 25.7, 44.3, 47.9, 68.0, 70.0, 70.1, 71.0, 71.1, 71.2, 84.2, 84.5, 95.4, 96.3, 108.1, 113.3, 115.0, 119.7, 126.9, 127.2, 127.3, 127.59, 127.64, 127.70, 127.72, 128.0, 128.2, 128.41, 128.44, 128.6, 133.8, 136.7, 137.0, 137.2, 137.3, 138.3, 148.5, 148.9, 158.6, 158.9, 159.9, 177.0;
Elemental analysis calculated C ₅₇ H ₅₆ O ₈ : C, 78.78; H, 6.49. Found C, 78.86, H 6.68.

実施例１と同様の操作を行った。ただし、求核試薬として、ベンゼンチオールを用いた。２つのジアステレオマー混合物の比は、α/β = 5/95であった。

The same operation as in Example 1 was performed. However, benzenethiol was used as a nucleophile. The ratio of the two diastereomeric mixtures was α / β = 5/95.

IR (neat) 3063, 3031, 2925, 2868, 1615, 1591, 1513, 1498, 1454, 1438, 1377, 1310, 1263, 1217, 1182, 1151, 1118, 1027, 812, 741, 696 cm ^-1 ;
¹ H NMR (500 MHz, CDCl ₃ , obvious signals of minor isomers marked with asterisks) δ3.60 (d, 1H, J = 11.7 Hz), 3.67 (d, 1H, J = 11.7 Hz), 3.80 (dd, 1H, J = 9.5, 3.9 Hz), 3.90 * (d, 1H, J = 11.5 Hz), 4.02 * (dd, 1H, J = 10.0, 7.4 Hz), 4.33 * (d, 1H, J = 11.5 Hz), 4.54 * (d, 1H, J = 3.9 Hz), 4.82 (d, 1H, J = 3.9 Hz), 4.97 (s, 2H), 5.03 (d, 1H, J = 11.9 Hz), 5.04 (d, 1H, J = 11.2 Hz), 5.09 (d, 1H, J = 11.2 Hz), 5.11 (d, 1H, J = 11.9 Hz), 5.21 (s, 2H), 5.35 (d, 1H, J = 9.5 Hz), 6.14 (d, 1H, J = 2.0 Hz), 6.23 * (d, 1H, J = 2.2 Hz), 6.26 (d, 1H, J = 2.0 Hz), 6.30 * (d, 1H, J = 2.2 Hz), 6.48 (d, 2H, J = 8.3 Hz), 6.937.52 (m, 31H);
¹³ C NMR (125 MHz, CDCl ₃ ) δ45.7, 70.0, 70.6, 70.9, 71.3, 71.4, 77.7, 93.7, 93.9, 102.6, 114.2, 114.7, 121.3, 126.9, 127.2, 127.3, 127.5, 127.7, 127.8, 128.0, 128.2, 128.26, 128.32, 128.40, 128.45, 128.6, 131.9, 133.6, 136.4, 136.6, 136.8, 137.2, 137.3, 137.4, 148.77, 148.81, 155.1, 157.5, 160.2;
Elemental analysis Calculated C ₅₆ H ₄₈ O ₆ S: C, 79.22; H, 5.70; S, 3.78. Found C, 78.95, H 5.85; S, 3.89.

実施例１と同様の操作を行った。ただし、求核試薬として、アジドトリメチルシランを用いた。

The same operation as in Example 1 was performed. However, azidotrimethylsilane was used as the nucleophile.

IR (neat) 3031, 2872, 2099, 1618, 1593, 1513, 1498, 1454, 1377, 1315, 1263, 1216, 1190, 1152, 1123, 1090, 1028, 911, 814, 736, 696 cm ^-1 ;
¹ H NMR (500 MHz, CDCl ₃ ) δ3.73 * (dd, 1H, J = 8.5, 6.2 Hz), 3.68 (dd, 1H, J = 10.1, 3.9 Hz), 3.95 * (d, 1H, J = 11.0 Hz), 4.08 (d, 1H, J = 11.9 Hz), 4.21 (d, 1H, J = 11.9 Hz), 4.34 * (d, 1H, J = 11.0 Hz), 4.76 * (d, 1H, J = 8.5 Hz), 4.77 * (d, 1H, J = 6.2 Hz), 4.97 (s, 2H), 5.00 (d, 1H, J = 10.1 Hz), 5.03 (d, 1H, J = 11.8 Hz), 5.05 ( d, 1H, J = 3.9 Hz), 5.06 (d, 1H, J = 12.2 Hz), 5.10 (d, 1H, J = 11.8 Hz), 5.12 (d, 1H, J = 12.2 Hz), 5.22 (s, 2H), 6.14 (d, 1H, J = 2.2 Hz), 6.26 (d, 1H, J = 2.2 Hz), 6.926.94 (m, 2H), 6.957.03 (m, 3H), 7.157.19 (m , 3H), 7.277.44 (m, 20H);
¹³ C NMR (125 MHz, CDCl ₃ ) δ54.0, 70.2, 70.5, 71.1, 71.4, 72.1, 75.9, 76.7, 93.8, 94.4, 101.0, 114.2, 115.0, 121.1, 127.3, 127.4, 127.53, 127.57, 127.78, 127.84, 128.0, 128.1, 128.2, 128.3, 128.49, 128.51, 128.65, 131.3, 136.4, 136.5, 137.16, 137.20, 137.28, 148.9, 149.1, 155.8, 158.4, 161.2;
Analysis Calculated _{C 50 H 43 N 3 O 6} :. C, 76.81; H, 5.54; N, 5.37 measured values C, 77.35, H 6.12; N , 5.34.

実施例１と同様の操作を行った。ただし、求核試薬として、１，３，５−トリメトキシベンゼンを用いた。２つのジアステレオマー混合物の比は、α/β = 84/16であった。

The same operation as in Example 1 was performed. However, 1,3,5-trimethoxybenzene was used as a nucleophile. The ratio of the two diastereomeric mixtures was α / β = 84/16.

IR (neat) 3030, 2935, 1606, 1591, 1512, 1496, 1454, 1377, 1263, 1215, 1149, 1119 cm ^-1 ;
¹ H NMR (500 MHz; CDCl ₃ , obvious signals of minor isomers marked with asterisks) δ * 3.28 (s, 3H), 3.39 (s, 6H), 3.51 (d, 1H, J = 10.8 Hz ), * 3.56 (s, 3H), 3.66 (d, 1H, J = 10.8 Hz), 3.79 (s, 3H), 3.98 (dd, 1H, J = 8.2, 9.7 Hz), * 4.07 (d, 1H, J = 11.8 Hz), * 4.34 (d, 1H, J = 11.8 Hz), 4.55 (d, 1H, J = 11.4 Hz), 4.59 (d, 1H, J = 9.7 Hz), 4.76 (d, 1H, J = 11.4 Hz), 4.77 (d, 1H, J = 8.2 Hz), 4.95 (s, 2H), 5.09 (d, 1H, J = 12.5 Hz), 5.15 (d, 1H, J = 12.5 Hz), 5.19 ( s, 2H), 5.885.95 (brs, 1H), 6.006.07 (brs, 1H), * 6.11 (d, 1H, J = 2.1 Hz), 6.12 (d, 1H, J = 2.4 Hz), * 6.17 (d, 1H, J = 2.1 Hz), 6.23 (d, 1H, J = 2.4 Hz), 6.596.63 (m, 2H), 6.737.46 (m, 26H);
¹³ C NMR (125 MHz, CDCl ₃ ) δ36.3, 55.2, 56.0, 69.9, 70.0, 71.1, 71.4, 73.8, 81.3, 81.5, 91.2, 92.1, 94.4, 94.5, 109.5, 114.2, 114.5, 115.1, 120.9, 127.1, 127.3, 127.37, 127.39, 127.5, 127.7, 127.8, 127.9, 128.0, 128.2, 128.37, 128.40, 128.43, 133.0, 136.9, 137.1, 137.26, 137.32, 138.0, 148.7, 148.8, 157.1, 157.65, 157.74, 158.6, 159.3;
Elemental analysis calculated C ₅₉ H ₅₄ O ₉ : C, 78.12; H, 6.00. Found: C, 78.39; H, 6.27.

Table 2 shows the schemes, reaction conditions, yields, and the like of Examples 3 to 6.

モレキュラーシーブス 4A (微粉末状, 125 mg)、Cp₂ZrCl₂ (3.7 mg, 0.013 mmol)およびAgClO₄ (5.2 mg, 0.025 mmol)をジクロロメタン (1.0 mL)に懸濁させ、室温下で5分撹拌した後、−78℃に冷却し、カテキン誘導体 (100 mg, 0.125 mmol) およびインドール (44 mg, 0.375 mmol) のジクロロメタン溶液 (1.5 mL) を滴下した。反応液を0 ℃に昇温し、1時間撹拌した後、さらに室温まで昇温し、25時間撹拌した。氷冷下、飽和炭酸水素ナトリウム水溶液を加え、反応を停止した後、セライトろ過し、不溶物を除いた（酢酸エチルで洗浄）。ろ液を酢酸エチルで3回抽出し、有機層を合わせた後、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去して得た残渣をPTLC (ヘキサン/酢酸エチル = 3/1) にて精製し、α-異性体(77.8 mg, 73%)、β-異性体 (18.8 mg, 18%) を得た。

Molecular sieves 4A (fine powder, 125 mg), Cp ₂ ZrCl ₂ (3.7 mg, 0.013 mmol) and AgClO ₄ (5.2 mg, 0.025 mmol) were suspended in dichloromethane (1.0 mL) and stirred at room temperature for 5 minutes. After cooling to −78 ° C., a dichloromethane solution (1.5 mL) of a catechin derivative (100 mg, 0.125 mmol) and indole (44 mg, 0.375 mmol) was added dropwise. The reaction solution was warmed to 0 ° C. and stirred for 1 hour, and then further warmed to room temperature and stirred for 25 hours. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was filtered through Celite to remove insolubles (washed with ethyl acetate). The filtrate was extracted three times with ethyl acetate, and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by PTLC (hexane / ethyl acetate = 3/1), α-isomer (77.8 mg, 73%), β-isomer (18.8 mg, 18%) Got.

α-isomer
1H NMR (400 MHz, CDCl ₃ ) δ 3.68 (d, 1H, J = 11.0 Hz), 3.85 (d, 1H, J = 11.0 Hz), 4.01 (dd, 1H, J = 8.0, 6.3 Hz), 4.48 ( d, 1H, J = 6.3 Hz), 4.56 (d, 1H, J = 12.2 Hz), 4.76 (d, 1H, J = 12.2 Hz), 4.87 (d, 1H, J = 12.4 Hz), 4.88 (d, 1H, J = 8.0 Hz), 4.95 (d, 1H, J = 12.4), 5.02 (d-like, 2H, J = 2.2 Hz), 5.15 (s, 2H), 6.17 (d, 1H, J = 2.2 Hz ), 6.38 (d, 1H, J = 2.2 Hz), 6.47 (d, 1H, J = 2.2 Hz), 6.67 (d, 2H, J = 7.3 Hz) 6.75-7.45 (m, 30H), 7.51 (brs, 1H);
¹³ C NMR (100 MHz, CDCl ₃ ) δ 37.4, 69.7, 70.1, 70.7, 71.2, 73.6, 80.0, 81.7, 94.6, 94.7, 106.9, 110.9, 113.3, 114.9, 118.0, 119.0, 119.3, 120.0, 121.4, 122.7 , 126.7, 127.3, 127.4, 127.5, 127.6, 127.7, 127.8, 127.9, 128.0, 128.1, 128.2, 128.37, 128.43, 128.6, 132.3, 136.2, 136.8, 136.9, 137.2, 137.4, 137.8, 148.2, 148.6, 156.2, 158.6 , 158.9; IR (film) 3433, 3062, 3032, 2900, 2360, 2341, 1614, 1589, 1512, 1454, 1429, 1377, 1263, 1147, 910, 737, 696 cm ^-1 ;
Elemental analysis Calculated value C ₅₈ H ₄₉ NO ₆ : C, 81.38; H, 5.77; N, 1.64.Measured value C, 81.42 H, 5.88. N 1.45.

β-isomer
¹ H NMR (400 MHz, CDCl ₃ ) δ3.83 (dd, 1H, J = 9.8, 5.4 Hz), 3.99 (d, 1H, J = 12.0 Hz), 4.23 (d, 1H, J = 12.0 Hz), 4.68 (d, 1H, J = 12.0 Hz), 4.76 (d, 1H, J = 12.0 Hz), 4.84 (d, 1H, J = 12.0 Hz), 4.93 (s, 2H), 4.87-4.98 (m, 3H ), 5.07 (s, 2H), 6.13 (d, 1H, J = 2.2 Hz), 6.21 (d, 1H, J = 2.2 Hz), 6.63 (d, 1H, J = 2.2 Hz), 6.68-7.40 (m , 31H), 7.55 (d, 1H, J = 8.1 Hz), 7.91 (s, 1H);
¹³ C NMR (100 MHz, CDCl ₃ ) δ31.8, 69.6, 70.1, 70.8, 71.3, 72.3, 76.5, 78.0, 93.90, 93.91, 106.7, 111.0, 114.0, 114.8, 117.1, 119.2, 120.0, 121.2, 121.7, 123.95, 126.6, 127.28, 127.31, 127.35, 127.60, 127.66, 127.72, 127.9, 128.0, 128.1, 128.2, 128.38, 128.41, 128.57, 128.64, 132.5, 136.2, 136.7, 136.8, 137.2, 137.3, 137.6, 148.7, 148.8, 155.0, 157.4, 159.2;
Elemental analysis Calculated value C ₅₈ H ₄₉ NO ₆ : C, 81.38; H, 5.77; N, 1.64.Measured value C, 81.28 H, 6.06.N 1.34.

Molecular sieves 4A (fine powder, 125 mg), Cp ₂ ZrCl ₂ (3.7 mg, 0.013 mmol) and AgClO ₄ (5.2 mg, 0.025 mmol) were suspended in dichloromethane (1.0 mL) and stirred at room temperature for 5 minutes. After cooling to −78 ° C., a dichloromethane solution (1.5 mL) of catechin derivative (100 mg, 0.125 mmol) and 1-methylindole (49 mg, 0.38 mmol) was added dropwise. The reaction mixture was warmed to 25 ° C. and stirred for 29 hours. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was filtered through Celite to remove insolubles (washed with ethyl acetate). The filtrate was extracted three times with ethyl acetate, and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by PTLC (hexane / benzene / ethyl acetate = 5/5/1) to give the title compound [104 mg, 96%, diastereomeric mixture (α / β = 42 / 58)].

Diastereomeric mixture (α / β = 42/58)]:
¹ H NMR (400 MHz, CDCl ₃ , peak derived from α-isomer marked with *) δ3.51 (s, 3H), 3.69 (d, 1H, J = 11.0 Hz), 3.72 * (s, 3H), 3.84 (d, 1H, 11.0 Hz), 3.89 * (dd, 1H, J = 10.0, 5.4 Hz), 4.01 (dd, 1H, J = 8.0, 6.6 Hz), 4.10 * (d, 1H, J = 12.0 Hz), 4.31 * (d, 1H, J = 12.0 Hz), 4.46 (d, 1H, J = 6.6 Hz), 4.54 (d, 1H, J = 12.0 Hz), 4.74-5.04 (m, 13H) , 5.06 (d, 1H, J = 9.8 Hz), 5.14 (s, 2H), 5.17 (s, 2H), 6.18 (d, 1H, J = 2.2 Hz), 6.21 (d, 1H, J = 2.2 Hz) , 6.28 * (d, 1H, J = 2.2 Hz), 6.37 * (d, 1H, J = 2.2 Hz), 6.38 (s, 1H), 6.65 (s, 1H), 6.69-7.46 (m, 57H), 7.62 * (d, 1H, J = 8.1 Hz)
¹³ C NMR (100 MHz, CDCl ₃ ) δ31.6, 32.2, 32.7, 37.3, 69.6, 69.7, 70.03, 70.05, 70.7, 70.8, 71.26, 71.28, 72.2, 73.6, 76.5, 77.9, 80.1, 82.1, 93.8, 93.9, 94.6, 94.7, 106.8, 107.1, 108.9, 109.1, 113.2, 114.0, 114.7, 114.8, 115.3, 116.5, 118.4, 118.7, 119.4, 119.97, 120.0, 120.9, 121.18, w1 121.19, 126.6, 126.9, 127.21, 121.25 , 127.28, 127.30, 127.31, 120.33, 127.4, 127.58, 127.63, 127.68, 127.71, 127.87, 127.89, 127.93, 127.96, 127.80, 128.03, 128.15, 128.18, 128.3, 128.38, 128.4, 128.5, 129.0, 132.3, 132.6, 136.7 , 136.8, 16.76, 136.81, 136.87, 136.91, 137.1, 137.2, 137.3, 137.6, 137.9, 148.4, 148.58, 148.64, 148.8, 154.9, 156.2, 157.3, 158.5, 158.9, 159.2;
Elemental analysis Calculated value C ₅₉ H ₅₁ NO ₆ : C, 81.45; H, 5.91; N, 1.61.Measured value C, 81.48 H, 5.98. N 1.38.

Molecular sieves 4A (fine powder, 125 mg), Cp ₂ ZrCl ₂ (3.7 mg, 0.013 mmol) and AgClO ₄ (5.2 mg, 0.025 mmol) were suspended in dichloromethane (1.0 mL) and stirred at room temperature for 5 minutes. Thereafter, the reaction solution was cooled to −78 ° C., and a dichloromethane solution (1.5 mL) of a catechin derivative (100 mg, 0.125 mmol) and pyrrole (12.6 mg, 0.188 mmol) was added dropwise. The reaction was warmed to 25 ° C. and stirred for 48 hours. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was filtered through Celite to remove insolubles (washed with ethyl acetate). The filtrate was extracted three times with ethyl acetate, and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by PTLC (hexane / ethyl acetate = 3/1) to obtain the title compound (70.9 mg, 70%, α / β = 45/55).

Diastereomeric mixture (α / β = 45/55):
¹ H NMR (400 MHz, CDCl ₃ , peak derived from α-isomer is marked with *) δ3.64 * (d, 1H, J = 10.8 Hz), 3.79 (dd, 1H, J = 9.8, 4.9 Hz), 3.80 * (dd, 1H, J = 8.5, 7.9 Hz), 3.90 * (d, 1H, J = 10.7), 3.98 (d, 1H, J = 4.0), 4.19 (d, 1H, J = 12.0 ), 4.22 (d, 1H, J = 7.3 Hz), 4.60 (d, 1H, J = 4.9 Hz), 4.70 * (d, 1H, J = 8.5 Hz), 4.76 * (d, 1H, J = 11.7 Hz) ), 4.84 (d, 1H, J = 9.8 Hz), 4.81-5.22 (m, 15H), 5.78 (brs, 1H), 5.87 * (brs, 1H), 6.08 * (dd, 1H, J = 5.8, 2.9 Hz), 6.13 (dd, 1H, J = 5.9, 2.7 Hz), 6.22 (d, 1H, J = 2.2 Hz), 6.26 (m, 2H), 6.30 * (d, 1H, J = 2.4 Hz), 6.40 (m, 1H), 6.69 (m, 1H), 6.92-7.50 (m, 28H), 7.68 * (s, 1H), 8.48 (s, 1H);
¹³ C NMR (100 MHz, CDCl ₃ ) δ33.7, 39.5, 70.0, 70.1, 70.2, 70.9, 71.0, 71.2, 71.3, 72.4, 73.8, 76.6, 78.6, 80.5, 83.8, 94.0, 94.3, 94.80, 94.85, 104.2, 104.5, 105.6, 107.7, 108.2, 108.6, 113.5, 114.1, 114.8, 115.0, 115.2, 116.8, 120.4, 121.1, 127.1, 127.2, 127.26, 127.35, 127.37, 127.5, 127.6, 127.68, 127.71, 127.75, 127.8, 128.0, 128.15, 128.17, 128.2, 128.3, 128.40, 128.43, 128.56, 128.58, 131.1, 131.6, 132.2, 134.0, 136.6, 136.7, 136.9, 137.1, 137.17, 137.23, 137.6, 137.7, 148.6, 148.76, 148.82, 148.9, 155.2, 156.6, 157.6, 158.4, 159.2, 159.5; IR (KBr) 3440, 3062, 3032, 2871, 1616, 1591, 1152, 1504, 1512, 1454, 1429, 1377, 1263, 1215, 1149, 1051, 1028, 910, 735, 696 cm ^-1 ;
Elemental analysis Calculated value C ₅₄ H ₄₇ NO ₆ : C, 80.47; H, 5.88; N, 1.74.Observed value C, 80.20; H, 5.83; N, 1.51.

Claims (10)

A catechin derivative represented by the following formula (1a).

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently the same or different and are each a hydrogen atom; which may have a group C ₁ -C ₁₀ hydrocarbon radical; an optionally substituted C ₁ -C ₁₀ alkoxy groups; which may have a substituent C ₆ -C ₁₀ aryloxy A silyl group optionally having a substituent; a silyloxy group optionally having a substituent; or a hydroxyl group.
A ¹ is a substituent containing nitrogen and / or phosphorus. ] A method for producing a catechin derivative represented by the following formula (1a),

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently the same or different and are each a hydrogen atom; which may have a group C ₁ -C ₁₀ hydrocarbon radical; an optionally substituted C ₁ -C ₁₀ alkoxy groups; which may have a substituent C ₆ -C ₁₀ aryloxy A silyl group optionally having a substituent; a silyloxy group optionally having a substituent; or a hydroxyl group.
A ¹ is a C ₁ -C ₁₀ hydrocarbon group which may have a substituent; or a substituent containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur and phosphorus. ]
An organometallic compound represented by the following formula (2):

[Wherein, L ¹ and L ² are each independently the same or different and are anionic ligands, M is zirconium or hafnium, and Z ¹ and Z ² are leaving groups. . ]
And in the presence of a silver compound represented by the following formula (3),

[Wherein, X is a perchlorate ion (ClO ₄ ⁻ ) or a trifluoromethanesulfonate ester ion (OSO ₂ CF ₃ ⁻ ). ]
A catechin derivative represented by the following formula (4):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ have the above-mentioned meanings.
A ² represents a hydrogen atom; an optionally substituted C _{1 to} C ₁₀ hydrocarbon group; an optionally substituted C _{1 to} C ₁₀ alkoxy group; and an optionally substituted group. A good C ₆ -C ₁₀ aryloxy group; an optionally substituted C ₆ -C ₁₀ acyl group; or a hydroxyl group. ]
Nucleophile represented by the following formula (5)

[Wherein A ¹ has the above-mentioned meaning. Y is a hydrogen atom or a halogen atom. ]
And a method for producing a catechin derivative.   The method for producing a catechin derivative according to claim 2, wherein the anionic ligand is an optionally substituted cyclopentadienyl group.   The method for producing a catechin derivative according to claim 2 or 3, wherein M is zirconium. A ¹ is a substituent containing nitrogen, oxygen and one or more heteroatoms selected from the group consisting of sulfur, method for producing a catechin derivative according to any one of claims 2-4.   0.1 mol to 1.0 mol of the organometallic compound represented by the formula (2) and 0 mg of the silver compound represented by the formula (3) with respect to 1 mol of the catechin derivative represented by the formula (4). The method for producing a catechin derivative according to any one of claims 2 to 5, wherein .2 mol to 1.0 mol is used. A method for producing a catechin derivative represented by the following formula (1b),

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently the same or different and are each a hydrogen atom; which may have a group C ₁ -C ₁₀ hydrocarbon radical; an optionally substituted C ₁ -C ₁₀ alkoxy groups; which may have a substituent C ₆ -C ₁₀ aryloxy A silyl group optionally having a substituent; a silyloxy group optionally having a substituent; or a hydroxyl group.
B ¹ and B ² are each independently the same or different and are each a hydrogen atom; an optionally substituted C _{1 to} C ₁₀ hydrocarbon group; an optionally substituted C _1. -C ₁₀ alkoxy group; which may have a substituent C ₆ -C ₁₀ aryloxy group; optionally substituted amino group; an optionally substituted silyl group; substituents A silyloxy group optionally having a hydroxyl group; or a hydroxyl group.
B ³ is a hydrogen atom; a C _{1 to} C ₁₀ hydrocarbon group which may have a substituent; or a silyl group which may have a substituent. ]
An organometallic compound represented by the following formula (2):

[Wherein, L ¹ and L ² are each independently the same or different and are anionic ligands, M is zirconium or hafnium, and Z ¹ and Z ² are leaving groups. . ]
And in the presence of a silver compound represented by the following formula (3),

[Wherein, X is a perchlorate ion (ClO ₄ ⁻ ) or a trifluoromethanesulfonate ester ion (OSO ₂ CF ₃ ⁻ ). ]
A catechin derivative represented by the following formula (4):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ have the above-mentioned meanings.
A ² represents a hydrogen atom; an optionally substituted C _{1 to} C ₁₀ hydrocarbon group; an optionally substituted C _{1 to} C ₁₀ alkoxy group; and an optionally substituted group. A good C ₆ -C ₁₀ aryloxy group; an acyl group which may have a substituent; or a hydroxyl group. ]
A nucleophile represented by the following formula (6):

[Wherein B ¹ , B ² and B ³ have the above-mentioned meanings. B ⁴ is a hydrogen atom; a C _{1 to} C ₁₀ hydrocarbon group which may have a substituent; or a silyl group which may have a substituent. ]
And a method for producing a catechin derivative.   The method for producing a catechin derivative according to claim 7, wherein the anionic ligand is an optionally substituted cyclopentadienyl group.   The method for producing a catechin derivative according to claim 7 or 8, wherein M is zirconium. 0.1 mol to 1.0 mol of the organometallic compound represented by the formula (2) and 0 mg of the silver compound represented by the formula (3) with respect to 1 mol of the catechin derivative represented by the formula (4). The method for producing a catechin derivative according to any one of claims 7 to 9, wherein .2 mol to 1.0 mol are used.