JP4089181B2 - Determination method of absolute configuration of optically active substance - Google Patents

Description

【０００８】
（Ａｒは置換基を有していてもよい芳香族炭素環基または芳香族複素環基もしくはアラルキル基を表し、ｎは３〜５の整数を表す。）
で示される光学活性trans −２−アリールシクロアルカン−１−オール類と、
一般式[II]
【化１７】

【０００９】
（式中、１位のカルボキシル基またはその誘導基と２位のメチル基の立体配置はcis であり、Ｘは水酸基、アルコキシ基またはハロゲン原子を表し、Ｒ^１ およびＲ^２ は、同一または異なって、置換基を有していてもよいアルキル基を表す。Ｒ^１ およびＲ^２ は、互いに結合して、炭素−炭素二重結合を有していてもよい単環または縮合環を形成する炭化水素基であってもよい。）
で示される絶対配置既知の光学活性カルボン酸またはその誘導体とをエステル化反応により縮合し、一般式[III]
【化１８】

【００１０】
（式中、Ｒ^１ 、Ｒ^２ 、Ａｒおよびｎは上記式のものと同じ意味を表す。）
で示される縮合体を得、該化合物[III] の^１Ｈ ＮＭＲ分析により環状骨格上２位のメチル基のケミカルシフトを測定することにより光学活性trans −２−アリールシクロアルカン−１−オール類の絶対立体配置を決めることを特徴とする光学活性シクロアルカノール類の絶対立体配置決定法である。
【００１１】
本発明による第２の発明は、一般式[VI]
【化１９】

【００１２】
（Ｒ^３ は置換基を有していてもよいアルキル基を表し、Ａｒは置換基を有していてもよい芳香族炭素環基または芳香族複素環基もしくはアラルキル基を表す。）で示される光学活性２級アルコール類と
一般式[II]
【化２０】

【００１３】
（式中、１位のカルボキシル基またはその誘導基と２位のメチル基の立体配置はcis であり、Ｘは水酸基、アルコキシ基またはハロゲン原子を表し、Ｒ^１ およびＲ^２ は、同一または異なって、置換基を有していてもよいアルキル基を表す。Ｒ^１ およびＲ^２ は、互いに結合して、炭素−炭素二重結合を有していてもよい単環または縮合環を形成する炭化水素基であってもよい。）
で示される絶対配置既知の光学活性カルボン酸またはその誘導体とをエステル化反応により縮合し、一般式[VII]
【化２１】

【００１４】
（式中、Ｒ^１ 、Ｒ^２ 、Ｒ^３ およびＡｒは上記式のものと同じ意味を表す。）で示される縮合体を得、該化合物[VII] の^１Ｈ ＮＭＲ分析により環状骨格上２位のメチル基のケミカルシフトを測定することにより光学活性２級アルコール類の絶対立体配置を決めることを特徴とする光学活性２級アルコール類の絶対立体配置決定法である。
【００１５】
本発明による第３の発明は、一般式[VIII]
【化２２】

【００１６】
（Ａｒは置換基を有していてもよい芳香族炭素環基または芳香族複素環基もしくはアラルキル基を表し、Ｒ^４ は置換基を有していてもよいアルキル基またはカルボキシル基を表す。）
で示されるアリール基を有する光学活性２級アミン類と、
一般式[II]
【化２３】

【００１７】
（式中、１位のカルボキシル基またはその誘導基と２位のメチル基の立体配置はcis であり、Ｘは水酸基、アルコキシ基またはハロゲン原子を表し、Ｒ^１ およびＲ^２ は、同一または異なって、置換基を有していてもよいアルキル基を表す。Ｒ^１ およびＲ^２ は、互いに結合して、炭素−炭素二重結合を有していてもよい単環または縮合環を形成する炭化水素基であってもよい。）
で示される絶対配置既知の光学活性カルボン酸またはその誘導体とをアミド化反応により縮合し、一般式[IX]
【化２４】

【００１８】
（式中、Ｒ^１ 、Ｒ^２ 、Ｒ^４ およびＡｒは上記式のものと同じ意味を表す。）
で示される縮合体を得、該化合物[IX] の^１Ｈ ＮＭＲ分析により環状骨格上２位のメチル基のケミカルシフトを測定することにより光学活性２級アミン類の絶対立体配置を決めることを特徴とする光学活性２級アミン類の絶対立体配置決定法である。
【００１９】
【発明の実施の形態】
第１発明において構造を決定すべきラセミ体はtrans −２−アリールシクロアルカン−１−オール類[Ｉ]である。同アルコール類[Ｉ]において、ｎは３〜５の整数を表し、好ましくは４である。一般式[Ｉ]中のＡｒのうち、置換基を有していてもよい芳香族炭素環または芳香族複素環の例としては、フェニル基、ナフチル基、ピリジル基などが挙げられ、Ａｒのうちアラルキル基としてはベンジル基、フェネチル基などが挙げられる。フェニル基の置換基の例としては、例えばＣ_１ 〜Ｃ_３ のような低級アルキル基、Ｃ_１ 〜Ｃ_３ のような低級アルコキシル基、ハロゲン原子が挙げられ、メチル基、メトキシ基または塩素が好ましい。置換基は好ましくはベンゼン環のパラ位に位置する。一般式[Ｉ]中のＡｒとしては、フェニル基、トリル基、メトキシフェニル基、クロロフェニル基、ナフチル基またはピリジル基が好ましく、ｐ−トリル基、ｐ−メトキシフェニル基、ｐ−クロロフェニル基、１−ナフチル基、２−ナフチル基または２−ピリジル基がより好ましい。
【００２０】
第２発明において構造を決定すべきラセミ体はアリール基またはアラルキル基を有する２級アルコール類[VI]である。同アルコール類[VI]中のＡｒのうち、置換基を有していてもよい芳香族炭素環または芳香族複素環の例としては、フェニル基、ナフチル基、ピリジル基などが挙げられ、Ａｒのうちアラルキル基としてはベンジル基、フェネチル基などが挙げられる。フェニル基の置換基の例としては、例えばＣ_１ 〜Ｃ_３ のような低級アルキル基、Ｃ_１ 〜Ｃ_３ のような低級アルコキシル基、ハロゲン原子が挙げられ、メチル基、メトキシ基または塩素が好ましい。置換基は好ましくはベンゼン環のパラ位に位置する。一般式[VI]中のＡｒとしては、フェニル基、トリル基、メトキシフェニル基、クロロフェニル基、ナフチル基、ピリジル基、ベンジル基またはフェネチル基が好ましく、ｐ−トリル基、ｐ−メトキシフェニル基、ｐ−クロロフェニル基、２−ナフチル基またはベンジル基がより好ましい。置換基を有していてもよいアルキル基（Ｒ^３ ）は例えばＣ_１ 〜Ｃ_３ の低級アルキル基が好ましく、特に好ましくはメチル基とエチル基である。
【００２１】
第３発明において構造を決定すべきラセミ体は２級アミン類[VIII]である。同アミン類[VIII]において、Ｒ^４ が置換基を有していてもよいアルキル基である場合、その例としては例えばＣ_１ 〜Ｃ_３ のような低級アルキル基が挙げられ、特に好ましくはメチル基とエチル基である。Ｒ^４ がカルボキシル基である場合、２級アミン類[VIII]はα−アミノ酸である。一般式[VIII]中のＡｒのうち、置換基を有していてもよい芳香族炭素環または芳香族複素環の例としては、フェニル基、ナフチル基、ピリジル基などが挙げられ、Ａｒのうちアラルキル基としてはベンジル基、フェネチル基などが挙げられる。フェニル基の置換基の例としては、例えばＣ_１ 〜Ｃ_３ のような低級アルキル基、Ｃ_１ 〜Ｃ_３ のような低級アルコキシル基、ハロゲン原子が挙げられ、メチル基、メトキシ基または臭素が好ましい。置換基は好ましくはベンゼン環のパラ位に位置する。一般式[VIII]中のＡｒとしては、フェニル基、トリル基、メトキシフェニル基、ブロモフェニル基、ナフチル基またはピリジル基が好ましく、ｐ−トリル基、ｐ−メトキシフェニル基、ｐ−ブロモフェニル基または２−ナフチル基がより好ましい。
【００２２】
第１、第２および第３発明において、ジアステレオマーを形成するために用いる光学活性体としては、上記一般式[II]で示される絶対配置既知の光学活性カルボン酸またはその誘導体であり、好ましくは一般式[IV]
【化２５】

【００２３】
（式中、Ｘは水酸基、アルコキシ基またはハロゲン原子を表す。１３位のメチル基と１７位のカルボキシル基またはその誘導基の立体配置はcis であり、１３位および１７位以外の環形成炭素原子は置換基を有していてもよく隣接炭素間に二重結合を有していてもよい。）
で示されるステロイド骨格を有する絶対配置既知の光学活性カルボン酸またはその誘導体であり、さらに好ましくは一般式[Ｖ]
【化２６】

【００２４】
（式中、Ｘは水酸基、アルコキシ基またはハロゲン原子を表す。）
で示される３β−アセトキシ−Δ５−エチオコレン酸(3β-acetoxy-Δ5-etiocholenic acid)またはその誘導体である。
【００２５】
一般式[Ｉ]で示されるtrans −２−アリールシクロアルカン−１−オール類、一般式[VI]で示されるアリール基またはアラルキル基を有する２級アルコール類、または一般式[VIII]で示される２級アミン類と、一般式[II]で示される光学活性カルボン酸とを縮合させる方法は特に制限されず、例えばtrans −２−アリールシクロアルカン−１−オール類[Ｉ]、アリール基またはアラルキル基を有する２級アルコール類[VI]、または２級アミン類[VIII]とカルボン酸の酸塩化物とを塩基性条件下で、またはカルボジイミド類等の脱水縮合剤の存在下で、エステル化反応またはアミド化反応させることにより縮合する方法等がある。
【００２６】
【実施例】
以下の実施例により本発明を具体的に説明するが、本発明はこれらの実施例に限定されるものではない。
【００２７】
実施例１
ラセミ体のtrans −２−フェニルシクロヘキサン−１−オール（０．２０ｇ，０．９４ｍｍｏｌ）をピリジン（１３ｍＬ）中に溶解し、この溶液に３β−アセトキシ−Δ５−エチオコレン酸クロライド（０．５７ｇ，１．５８ｍｍｏｌ）を加え、全体を室温で２１時間撹拌した。反応液に３Ｍ塩酸水溶液（３５ｍＬ）を氷水で冷却しながら加え、析出した結晶を濾取した。これをカラムクロマトグラフィー（溶離液：酢酸エチル／ヘキサン＝１／４）により精製し、縮合体[（１Ｓ，２Ｒ）−trans −２−フェニルシクロヘキシル−Δ５−３β−アセトキシエチオコレン酸エステルと、（１Ｒ，２Ｓ）−trans −２−フェニルシクロヘキシル−Δ５−３β−アセトキシエチオコレン酸エステルの混合物を０．２７ｇ（５５．７％）得た。
【００２８】
絶対配置は、得られた縮合体のステロイド環上１３位にあるβ−メチル基のδ値を測定することにより決定した。０．０４の場合は（１Ｓ，２Ｒ）−体、０．４５の場合は（１Ｒ，２Ｓ）−体である。
【００２９】
（１Ｓ，２Ｒ）−trans −２−フェニルシクロヘキシル−Δ５−３β−アセトキシエチオコレン酸エステル：
白色結晶；
^１Ｈ ＮＭＲ：０．０４（ｓ，３Ｈ），０．８２−２．３２（ｍ，２８Ｈ），０．９５（ｓ，３Ｈ），２．０３（ｓ，３Ｈ），２．６８（ｍ，１Ｈ），４．５８（ｍ，１Ｈ），５．０５（ｄｔ，１Ｈ，Ｊ＝４．２，１０．８Ｈｚ），５．３２（ｍ，１Ｈ），７．１４−７．２４（ｍ，５Ｈ）
【００３０】
（１Ｒ，２Ｓ）−trans −２−フェニルシクロヘキシル−Δ５−３β−アセトキシエチオコレン酸エステル：
白色結晶；
^１Ｈ ＮＭＲ：０．４５（ｓ，３Ｈ），０．８２−２．３２（ｍ，２８Ｈ），０．９９（ｓ，３Ｈ），２．０３（ｓ，３Ｈ），２．６８（ｍ，１Ｈ），４．５８（ｍ，１Ｈ），５．０５（ｍ，１Ｈ），４．９３（ｄｔ，１Ｈ，Ｊ＝４．８，１０．８Ｈｚ），５．３５（ｍ，１Ｈ），７．１４−７．２４（ｍ，５Ｈ）
【００３１】
実施例２〜７
trans −２−アリールシクロアルカン−１−オール類[Ｉ]として、表１に示すものを用い、その他の点は実施例１と同様の操作を行い、各化合物の絶対配置を決定した。
【００３２】
【表１】

【００３３】
実施例８
ラセミ体の１−フェニルエタノール（０．１２ｇ，１．００ｍｍｏｌ）を塩化メチレン（１６ｍＬ）に溶解し、この溶液に３β−アセトキシ−Δ５−エチオコレン酸クロライド（０．４０ｇ，１．１１ｍｍｏｌ）およびトリエチルアミン（０．４０ｍＬ）を加え、全体を室温で２５時間撹拌した。反応液を水洗した後、塩化メチレンを留去して得られた残査をカラムクロマトグラフィー（溶離液：酢酸エチル／ヘキサン＝１／４）により精製し、縮合体（フェニルエチル−Δ５−３β−アセトキシエチオコレン酸エステルを０．２９ｇ（６３．５％）得た。
【００３４】
絶対配置は、得られた縮合体のステロイド環上１３位にあるβ−メチル基のδ値を測定することにより決定した。０．５１の場合は（Ｓ）−体、０．７１の場合は（Ｒ）−体である。
【００３５】
実施例９〜１４
一般式[VI]で示されるアリール基またはアラルキル基を有する２級アルコール類として、表２に示すものを用い、その他の点は実施例８と同様の操作を行い、各化合物の絶対配置を決定した。
【００３６】
【表２】

【００３７】
実施例１５
絶対配置未知の１−フェニルエチルアミン（０．１２ｇ，０．９８ｍｍｏｌ）を塩化メチレン（１５ｍＬ）に溶解し、この溶液に３β−アセトキシ−Δ５−エチオコレン酸クロライド（０．４０ｇ，１．１１ｍｍｏｌ) およびトリエチルアミン（０．６０ｍＬ）を加え、全体を室温で２０時間撹拌した。反応液を水洗した後、塩化メチレンを留去して得られた残査をカラムクロマトグラフィー（溶離液：酢酸エチル／ヘキサン＝１／３）により精製し、縮合体アミド（Ｎ−フェニルエチル−３β−アセトキシ−Δ５−エチオコレニルカルボキサミド）を０．３２ｇ（７０．６％）得た。
【００３８】
絶対配置は、得られた縮合体のステロイド環上１３位にあるβ−メチル基のδ値を測定することにより決定した。０．６１の場合は（Ｓ）−体、０．７３の場合は（Ｒ）−体である。
【００３９】
実施例１６〜２０
一般式[VIII]で示される２級アミン類として、表３に示すものを用い、その他の点は実施例１５と同様の操作を行い、各化合物の絶対配置を決定した。
【００４０】
【表３】

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to optically active pharmaceuticals and agricultural chemicals, and optically active secondary alcohols having optically active trans-2-arylcycloalkane-1-ols, aryl groups or aralkyl groups useful as optically active synthetic intermediates thereof. And a method for determining the absolute configuration of optically active secondary amines.
[0002]
[Prior art]
In general, the absolute structure of optically active alcohols is determined by a technique using ¹ H NMR measurement such as X-ray crystal structure analysis or improved Mosher method.
[0003]
[Problems to be solved by the invention]
However, in order to determine the absolute structure in the X-ray crystal structure analysis, the target compound is required to be a crystalline substance and further to be a single crystal. Therefore, it is difficult to determine the absolute structure of a compound having no crystallinity by this method. On the other hand, in order to determine the absolute structure by a method using ¹ H NMR such as the modified Mosher method, after preparing (R 1) -isomer and (S) -isomer-derived diastereomeric MTPA ester, ^Since it is necessary to take ¹ H NMR spectrum data, it is difficult to apply this method when there is no room in the sample.
[0004]
It is an object of the present invention to provide a novel absolute configuration determination method for an optically active substance that can solve the above-described problems.
[0005]
[Means for Solving the Problems]
The present invention relates to the absolute configuration of optically active trans-2-arylcycloalkane-1-ols, optically active secondary alcohols having an aryl group or aralkyl group, and optically active secondary amines of these specific derivatives. ^It relates to a method of determining by measuring ¹ H NMR.
[0006]
The principle is that trans-2-arylcycloalkane-1-ols represented by the general formula [I], secondary alcohols having an aryl group or an aralkyl group represented by the general formula [VI], or the general formula [VIII] In the diastereomer represented by the general formula [III], [VII] or [IX], which is a condensate of the secondary amine represented by the general formula [II] and the optically active carboxylic acid represented by the general formula [II] It is considered that the internal CH / π interaction is expressed only in a diastereomer derived from one enantiomer. When this intramolecular CH / π interaction appears, a significant high magnetic field shift of the methyl group at the 2-position on the cyclic skeleton occurs, and observation of this ¹ H NMR spectrum makes it possible to determine the absolute configuration.
[0007]
A first invention according to the present invention is represented by the general formula [I]
Embedded image

[0008]
(Ar represents an optionally substituted aromatic carbocyclic group, aromatic heterocyclic group or aralkyl group, and n represents an integer of 3 to 5.)
An optically active trans-2-arylcycloalkane-1-ol represented by the formula:
Formula [II]
Embedded image

[0009]
(In the formula, the configuration of the carboxyl group at the 1-position or the derivative group thereof and the methyl group at the 2-position is cis, X represents a hydroxyl group, an alkoxy group or a halogen atom, and R ¹ and R ² are the same or different. Represents an alkyl group which may have a substituent, and R ¹ and R ² are bonded to each other to form a hydrocarbon which may have a carbon-carbon double bond to form a single ring or a condensed ring. It may be a group.)
Is condensed with an optically active carboxylic acid of known absolute configuration or a derivative thereof by an esterification reaction, to form a compound represented by the general formula [III]
Embedded image

[0010]
(In the formula, R ¹ , R ² , Ar and n represent the same meaning as in the above formula.)
Of the optically active trans-2-arylcycloalkane-1-ols by measuring the chemical shift of the methyl group at the 2-position on the cyclic skeleton by ¹ H NMR analysis of the compound [III]. An absolute configuration determination method for optically active cycloalkanols characterized by determining an absolute configuration.
[0011]
A second invention according to the present invention is represented by the general formula [VI]
Embedded image

[0012]
(R ³ represents an alkyl group which may have a substituent, and Ar represents an aromatic carbocyclic group, an aromatic heterocyclic group or an aralkyl group which may have a substituent). Optically active secondary alcohols and general formula [II]
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[0013]
(In the formula, the configuration of the carboxyl group at the 1-position or the derivative group thereof and the methyl group at the 2-position is cis, X represents a hydroxyl group, an alkoxy group or a halogen atom, and R ¹ and R ² are the same or different. Represents an alkyl group which may have a substituent, and R ¹ and R ² are bonded to each other to form a hydrocarbon which may have a carbon-carbon double bond to form a single ring or a condensed ring. It may be a group.)
Is condensed with an optically active carboxylic acid having a known absolute configuration or a derivative thereof by an esterification reaction, to form a compound represented by the general formula [VII]
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[0014]
^(Wherein, R ^1, R 2, ^{R 3} and Ar represents. The same meaning as in the formula) to give the condensate represented by the compound [VII] ¹ H NMR cyclic skeleton on the 2-position analysis of the And determining the absolute configuration of the optically active secondary alcohol by measuring the chemical shift of the methyl group.
[0015]
A third invention according to the present invention is represented by the general formula [VIII]
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[0016]
(Ar represents an aromatic carbocyclic group which may have a substituent, an aromatic heterocyclic group or an aralkyl group, and R ⁴ represents an alkyl group or a carboxyl group which may have a substituent.)
An optically active secondary amine having an aryl group represented by:
Formula [II]
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[0017]
(In the formula, the configuration of the carboxyl group at the 1-position or the derivative group thereof and the methyl group at the 2-position is cis, X represents a hydroxyl group, an alkoxy group or a halogen atom, and R ¹ and R ² are the same or different. Represents an alkyl group which may have a substituent, and R ¹ and R ² are bonded to each other to form a hydrocarbon which may have a carbon-carbon double bond to form a single ring or a condensed ring. It may be a group.)
Is condensed with an optically active carboxylic acid having a known absolute configuration or a derivative thereof by an amidation reaction, and represented by the general formula [IX]
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[0018]
(In the formula, R ¹ , R ² , R ⁴ and Ar have the same meaning as in the above formula.)
And the absolute configuration of the optically active secondary amine is determined by measuring the chemical shift of the methyl group at the 2-position on the cyclic skeleton by ¹ H NMR analysis of the compound [IX]. This is a method for determining the absolute configuration of optically active secondary amines.
[0019]
DETAILED DESCRIPTION OF THE INVENTION
In the first invention, the racemate whose structure is to be determined is trans-2-arylcycloalkane-1-ol [I]. In the same alcohol [I], n represents an integer of 3 to 5, preferably 4. Examples of the aromatic carbocyclic ring or aromatic heterocyclic ring that may have a substituent among Ar in the general formula [I] include a phenyl group, a naphthyl group, a pyridyl group, and the like. Examples of the aralkyl group include a benzyl group and a phenethyl group. Examples of the substituent of the phenyl group, for example lower alkyl groups such as C ₁ -C _3, a lower alkoxyl group such as C ₁ -C _3, include halogen atom, a methyl group, a methoxy group or chlorine is preferred . The substituent is preferably located in the para position of the benzene ring. Ar in the general formula [I] is preferably a phenyl group, a tolyl group, a methoxyphenyl group, a chlorophenyl group, a naphthyl group or a pyridyl group, a p-tolyl group, a p-methoxyphenyl group, a p-chlorophenyl group, 1- A naphthyl group, 2-naphthyl group or 2-pyridyl group is more preferred.
[0020]
The racemate whose structure should be determined in the second invention is a secondary alcohol [VI] having an aryl group or an aralkyl group. Examples of the aromatic carbocyclic ring or aromatic heterocyclic ring which may have a substituent among Ar in the alcohol [VI] include a phenyl group, a naphthyl group, a pyridyl group, and the like. Among them, examples of the aralkyl group include a benzyl group and a phenethyl group. Examples of the substituent of the phenyl group, for example lower alkyl groups such as C ₁ -C _3, a lower alkoxyl group such as C ₁ -C _3, include halogen atom, a methyl group, a methoxy group or chlorine is preferred . The substituent is preferably located in the para position of the benzene ring. Ar in the general formula [VI] is preferably phenyl, tolyl, methoxyphenyl, chlorophenyl, naphthyl, pyridyl, benzyl or phenethyl, p-tolyl, p-methoxyphenyl, p -A chlorophenyl group, a 2-naphthyl group or a benzyl group is more preferred. The alkyl group (R ³ ) which may have a substituent is, for example, preferably a C _{1 to} C ₃ lower alkyl group, and particularly preferably a methyl group and an ethyl group.
[0021]
The racemate whose structure is to be determined in the third invention is a secondary amine [VIII]. In the same amines [VIII], when R ⁴ is an alkyl group which may have a substituent, examples thereof include lower alkyl groups such as C _{1 to} C ₃ , particularly preferably methyl. Group and ethyl group. When R ⁴ is a carboxyl group, the secondary amine [VIII] is an α-amino acid. Examples of the aromatic carbocyclic ring or aromatic heterocyclic ring that may have a substituent among Ar in the general formula [VIII] include a phenyl group, a naphthyl group, a pyridyl group, and the like. Examples of the aralkyl group include a benzyl group and a phenethyl group. Examples of the substituent of the phenyl group, for example lower alkyl groups such as C ₁ -C _3, a lower alkoxyl group such as C ₁ -C _3, include halogen atom, a methyl group, a methoxy group or bromine being preferred . The substituent is preferably located in the para position of the benzene ring. Ar in the general formula [VIII] is preferably a phenyl group, a tolyl group, a methoxyphenyl group, a bromophenyl group, a naphthyl group or a pyridyl group, and a p-tolyl group, a p-methoxyphenyl group, a p-bromophenyl group or A 2-naphthyl group is more preferred.
[0022]
In the first, second and third inventions, the optically active form used to form a diastereomer is an optically active carboxylic acid having a known absolute configuration represented by the above general formula [II] or a derivative thereof, preferably Is the general formula [IV]
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[0023]
(In the formula, X represents a hydroxyl group, an alkoxy group or a halogen atom. The steric configuration of the methyl group at position 13 and the carboxyl group at position 17 or a derivative group thereof is cis, and ring-forming carbon atoms other than positions 13 and 17 are used. May have a substituent and may have a double bond between adjacent carbons.)
An optically active carboxylic acid having a steroid skeleton represented by the above known absolute configuration or a derivative thereof, and more preferably a general formula [V]
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[0024]
(In the formula, X represents a hydroxyl group, an alkoxy group or a halogen atom.)
3β-acetoxy-Δ5-etiocholenic acid or a derivative thereof.
[0025]
Trans-2-arylcycloalkane-1-ols represented by general formula [I], secondary alcohols having an aryl group or aralkyl group represented by general formula [VI], or represented by general formula [VIII] The method for condensing the secondary amines and the optically active carboxylic acid represented by the general formula [II] is not particularly limited, and examples thereof include trans-2-arylcycloalkane-1-ols [I], aryl groups or aralkyls. Esterification reaction of a secondary alcohol [VI] having a group or a secondary amine [VIII] and an acid chloride of a carboxylic acid under basic conditions or in the presence of a dehydration condensing agent such as a carbodiimide Alternatively, there is a method of condensing by amidation reaction.
[0026]
【Example】
The present invention will be specifically described by the following examples, but the present invention is not limited to these examples.
[0027]
Example 1
Racemic trans-2-phenylcyclohexane-1-ol (0.20 g, 0.94 mmol) was dissolved in pyridine (13 mL) and 3β-acetoxy-Δ5-ethiocholenoic acid chloride (0.57 g, 1 .58 mmol) was added and the whole was stirred at room temperature for 21 hours. A 3M aqueous hydrochloric acid solution (35 mL) was added to the reaction solution while cooling with ice water, and the precipitated crystals were collected by filtration. This was purified by column chromatography (eluent: ethyl acetate / hexane = 1/4), and the condensate [(1S, 2R) -trans-2-phenylcyclohexyl-Δ5-3β-acetoxyethiocholenate and ( 0.27 g (55.7%) of a mixture of 1R, 2S) -trans-2-phenylcyclohexyl-Δ5-3β-acetoxyethiocholenate was obtained.
[0028]
The absolute configuration was determined by measuring the δ value of the β-methyl group at position 13 on the steroid ring of the resulting condensate. The case of 0.04 is a (1S, 2R) -body, and the case of 0.45 is a (1R, 2S) -body.
[0029]
(1S, 2R) -trans-2-phenylcyclohexyl-Δ5-3β-acetoxyethiocholenate:
White crystals;
¹ H NMR: 0.04 (s, 3H), 0.82-2.32 (m, 28H), 0.95 (s, 3H), 2.03 (s, 3H), 2.68 (m, 1H), 4.58 (m, 1H), 5.05 (dt, 1H, J = 4.2, 10.8 Hz), 5.32 (m, 1H), 7.14-7.24 (m, 5H)
[0030]
(1R, 2S) -trans-2-phenylcyclohexyl-Δ5-3β-acetoxyethiocholate:
White crystals;
¹ H NMR: 0.45 (s, 3H), 0.82-2.32 (m, 28H), 0.99 (s, 3H), 2.03 (s, 3H), 2.68 (m, 1H), 4.58 (m, 1H), 5.05 (m, 1H), 4.93 (dt, 1H, J = 4.8, 10.8 Hz), 5.35 (m, 1H), 7 .14-7.24 (m, 5H)
[0031]
Examples 2-7
As trans-2-arylcycloalkane-1-ols [I], those shown in Table 1 were used, and the other configurations were performed in the same manner as in Example 1, and the absolute configuration of each compound was determined.
[0032]
[Table 1]

[0033]
Example 8
Racemic 1-phenylethanol (0.12 g, 1.00 mmol) was dissolved in methylene chloride (16 mL), and 3β-acetoxy-Δ5-ethiocholenoic acid chloride (0.40 g, 1.11 mmol) and triethylamine ( 0.40 mL) was added and the whole was stirred at room temperature for 25 hours. After the reaction solution was washed with water, the residue obtained by distilling off methylene chloride was purified by column chromatography (eluent: ethyl acetate / hexane = 1/4) to give a condensate (phenylethyl-Δ5-3β- 0.29 g (63.5%) of acetoxy etiocholenate was obtained.
[0034]
The absolute configuration was determined by measuring the δ value of the β-methyl group at position 13 on the steroid ring of the resulting condensate. The case of 0.51 is the (S) -form, and the case of 0.71 is the (R) -form.
[0035]
Examples 9-14
As the secondary alcohols having an aryl group or an aralkyl group represented by the general formula [VI], those shown in Table 2 were used, and the other configurations were the same as in Example 8, and the absolute configuration of each compound was determined. did.
[0036]
[Table 2]

[0037]
Example 15
1-Phenylethylamine of unknown absolute configuration (0.12 g, 0.98 mmol) was dissolved in methylene chloride (15 mL), and 3β-acetoxy-Δ5-ethiocholenoic acid chloride (0.40 g, 1.11 mmol) and triethylamine were dissolved in this solution. (0.60 mL) was added and the whole was stirred at room temperature for 20 hours. The reaction mixture was washed with water, and the residue obtained by distilling off methylene chloride was purified by column chromatography (eluent: ethyl acetate / hexane = 1/3) to give a condensate amide (N-phenylethyl-3β 0.32 g (70.6%) of -acetoxy-Δ5-ethiocholenyl carboxamide).
[0038]
The absolute configuration was determined by measuring the δ value of the β-methyl group at position 13 on the steroid ring of the resulting condensate. The case of 0.61 is the (S) -form, and the case of 0.73 is the (R) -form.
[0039]
Examples 16-20
As the secondary amines represented by the general formula [VIII], those shown in Table 3 were used, and the other configurations were performed in the same manner as in Example 15, and the absolute configuration of each compound was determined.
[0040]
[Table 3]

Claims (9)

Formula [I]

(Ar represents an optionally substituted aromatic carbocyclic group, aromatic heterocyclic group or aralkyl group, and n represents an integer of 3 to 5.)
An optically active trans-2-arylcycloalkane-1-ol represented by the formula:
Formula [II]

(In the formula, the configuration of the carboxyl group at the 1-position or the derivative group thereof and the methyl group at the 2-position is cis, X represents a hydroxyl group, an alkoxy group or a halogen atom, and R ¹ and R ² are the same or different. Represents an alkyl group which may have a substituent, and R ¹ and R ² are bonded to each other to form a hydrocarbon which may have a carbon-carbon double bond to form a single ring or a condensed ring. It may be a group.)
Is condensed with an optically active carboxylic acid of known absolute configuration or a derivative thereof by an esterification reaction, to form a compound represented by the general formula [III]

(In the formula, R ¹ , R ² , Ar and n represent the same meaning as in the above formula.)
Of the optically active trans-2-arylcycloalkane-1-ols by measuring the chemical shift of the methyl group at the 2-position on the cyclic skeleton by ¹ H NMR analysis of the compound [III]. An absolute configuration determination method for optically active cycloalkanols, characterized by determining an absolute configuration. An optically active carboxylic acid having a known absolute configuration represented by the general formula [II] or a derivative thereof is represented by the general formula [IV]

(In the formula, X represents a hydroxyl group, an alkoxy group or a halogen atom. The steric configuration of the methyl group at position 13 and the carboxyl group at position 17 or a derivative group thereof is cis, and ring-forming carbon atoms other than positions 13 and 17 are used. May have a substituent and may have a double bond between adjacent carbons.)
The method for determining an absolute configuration of an optically active cycloalkanol according to claim 1, which is a compound having a steroid skeleton represented by formula (1). An optically active carboxylic acid having a known absolute configuration represented by the general formula [II] or a derivative thereof is represented by the general formula [V].

(In the formula, X represents a hydroxyl group, an alkoxy group or a halogen atom.)
The method for determining the absolute configuration of optically active cycloalkanols according to claim 1, which is 3β-acetoxy-Δ5-ethiocholenoic acid or a derivative thereof represented by the formula: Formula [VI]

(R ³ represents an alkyl group which may have a substituent, and Ar represents an aromatic carbocyclic group, an aromatic heterocyclic group or an aralkyl group which may have a substituent). Optically active secondary alcohols and general formula [II]

(In the formula, the configuration of the carboxyl group at the 1-position or the derivative group thereof and the methyl group at the 2-position is cis, X represents a hydroxyl group, an alkoxy group or a halogen atom, and R ¹ and R ² are the same or different. Represents an alkyl group which may have a substituent, and R ¹ and R ² are bonded to each other to form a hydrocarbon which may have a carbon-carbon double bond to form a single ring or a condensed ring. It may be a group.)
Is condensed with an optically active carboxylic acid having a known absolute configuration or a derivative thereof by an esterification reaction, to form a compound represented by the general formula [VII]

(In the formula, R ¹ , R ² , R ³ and Ar have the same meaning as in the above formula.)
And the absolute configuration of the optically active secondary alcohol is determined by measuring the chemical shift of the methyl group at the 2-position on the cyclic skeleton by ¹ H NMR analysis of the compound [VII]. A method for determining the absolute configuration of optically active secondary alcohols. An optically active carboxylic acid having a known absolute configuration represented by the general formula [II] or a derivative thereof is represented by the general formula [IV]

(In the formula, X represents a hydroxyl group, an alkoxy group or a halogen atom. The steric configuration of the methyl group at position 13 and the carboxyl group at position 17 or a derivative group thereof is cis, and ring-forming carbon atoms other than positions 13 and 17 are used. May have a substituent and may have a double bond between adjacent carbons.)
The method for determining an absolute configuration of an optically active secondary alcohol according to claim 4, wherein the compound has a steroid skeleton represented by the formula: An optically active carboxylic acid having a known absolute configuration represented by the general formula [II] or a derivative thereof is represented by the general formula [V].

(In the formula, X represents a hydroxyl group, an alkoxy group or a halogen atom.)
The method for determining an absolute configuration of an optically active secondary alcohol according to claim 4, which is 3β-acetoxy-Δ5-ethiocholenic acid or a derivative thereof represented by the formula: Formula [VIII]

(Ar represents an aromatic carbocyclic group which may have a substituent, an aromatic heterocyclic group or an aralkyl group, and R ⁴ represents an alkyl group or a carboxyl group which may have a substituent.)
An optically active secondary amine having an aryl group represented by:
Formula [II]

(In the formula, the configuration of the carboxyl group at the 1-position or the derivative group thereof and the methyl group at the 2-position is cis, X represents a hydroxyl group, an alkoxy group or a halogen atom, and R ¹ and R ² are the same or different. Represents an alkyl group which may have a substituent, and R ¹ and R ² are bonded to each other to form a hydrocarbon which may have a carbon-carbon double bond to form a single ring or a condensed ring. It may be a group.)
Is condensed with an optically active carboxylic acid having a known absolute configuration or a derivative thereof by an amidation reaction, and represented by the general formula [IX]

(In the formula, R ¹ , R ² , R ⁴ and Ar have the same meaning as in the above formula.)
And the absolute configuration of the optically active secondary amine is determined by measuring the chemical shift of the methyl group at the 2-position on the cyclic skeleton by ¹ H NMR analysis of the compound [IX]. A method for determining the absolute configuration of optically active secondary amines. An optically active carboxylic acid having a known absolute configuration represented by the general formula [II] or a derivative thereof is represented by the general formula [IV]

(In the formula, X represents a hydroxyl group, an alkoxy group or a halogen atom. The steric configuration of the methyl group at position 13 and the carboxyl group at position 17 or a derivative group thereof is cis, and ring-forming carbon atoms other than positions 13 and 17 are used. May have a substituent and may have a double bond between adjacent carbons.)
The method for determining an absolute configuration of an optically active secondary amine according to claim 7, wherein the compound has a steroid skeleton represented by the formula: An optically active carboxylic acid having a known absolute configuration represented by the general formula [II] or a derivative thereof is represented by the general formula [V].

(In the formula, X represents a hydroxyl group, an alkoxy group or a halogen atom.)
The method for determining the absolute configuration of optically active secondary amines according to claim 7, which is 3β-acetoxy-Δ5-ethiocholenic acid or a derivative thereof represented by the formula: