JP4373933B2 - (1S, 2S)-or (1R, 2R) -cis-1-arylphosphorane-2-carboxylic acid / borane complex and method for producing the same - Google Patents
(1S, 2S)-or (1R, 2R) -cis-1-arylphosphorane-2-carboxylic acid / borane complex and method for producing the same Download PDFInfo
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本発明は、医薬、農薬、香料、その他各種のファインケミカルズの不斉合成のための不斉配位子もしくはその反応誘導用として有用な、（１Ｓ，２Ｓ）−または（１Ｒ，２Ｒ）−シス−１−アリールホスホラン−２−カルボン酸・ボラン錯体とその製造方法に関するものである。 The present invention provides (1S, 2S)-or (1R, 2R) -cis-, which is useful as an asymmetric ligand for asymmetric synthesis of pharmaceuticals, agricultural chemicals, fragrances, and other various fine chemicals or for reaction induction thereof. The present invention relates to a 1-arylphosphorane-2-carboxylic acid / borane complex and a production method thereof.
遷移金属錯体を用いる不斉合成反応では、配位子として光学活性ホスフィンが有効であるとされ、これまでにＢｌＮＡＰに代表される多くの光学活性ジホスフィン類が開発されている（非特許文献１）。一方、含窒素化合物を配位子とした不斉金属触媒を用いる触媒的不斉合成反応の例も多く、中でもプロリンより誘導される光学活性ジアミン−金属錯体は、向山アルドール反応、アルキル化反応、還元反応などにおいて高い選択性を実現している（非特許文献２〜４）。 In an asymmetric synthesis reaction using a transition metal complex, optically active phosphine is considered to be effective as a ligand, and many optically active diphosphines represented by BlNAP have been developed so far (Non-patent Document 1). . On the other hand, there are many examples of catalytic asymmetric synthesis reactions using an asymmetric metal catalyst with a nitrogen-containing compound as a ligand. Among them, optically active diamine-metal complexes derived from proline include Mukaiyama aldol reaction, alkylation reaction, High selectivity is achieved in reduction reactions and the like (Non-Patent Documents 2 to 4).
そして、本発明者らはプロリンに代わる不斉源として、たとえば次式のようにプロリンの窒素原子をリン原子に置き換えたホスホラン−２−カルボン酸を開発し、その合成及び不斉配位子への応用を提案している（特許文献１）。なお、この場合リン原子上に置換基が入ることにより、２位のカルボキシル基との間の立体関係により、シス、トランスの異性体が生じる。 Then, the present inventors have developed phosphorane-2-carboxylic acid in which the nitrogen atom of proline is replaced with a phosphorus atom as an asymmetric source replacing proline, for example, as shown in the following formula. (Patent document 1). In this case, when a substituent is introduced on the phosphorus atom, cis and trans isomers are generated due to the steric relationship with the carboxyl group at the 2-position.
また、本発明者らによるこれらの検討の過程で、光学活性な様々なホスホラン−２−カルボン酸誘導体も開発してきた。その１つは、合成したホスホラン−２−カルボン酸誘導体混合物から再結晶法により主生成物であるラセミ体のトランス体のホスホラン−２−カルボン酸誘導体を取り出し、続いて光学活性アミンを用いた分別結晶法により光学的に純粋なトランス体のホスホラン−２−カルボン酸を得る方法である（非特許文献５）。もう一つは、（−）−スパルテインを不斉配位子として用いる不斉反応によるものである（非特許文献６）。ただ、これらはいずれもトランス体のホスホラン−２−カルボン酸誘導体を得るための手法にとどまっていた。 In the course of these studies by the present inventors, various optically active phospholane-2-carboxylic acid derivatives have also been developed. One is to extract the racemic trans phospholane-2-carboxylic acid derivative as the main product from the synthesized phospholane-2-carboxylic acid derivative mixture by recrystallization, followed by fractionation using an optically active amine. This is a method for obtaining optically pure trans-phosphoran-2-carboxylic acid by a crystal method (Non-patent Document 5). The other is due to an asymmetric reaction using (−)-sparteine as an asymmetric ligand (Non-patent Document 6). However, all of these methods are limited to methods for obtaining a trans phospholane-2-carboxylic acid derivative.
一方、Ｚｈａｎｇらはリン原子上を硫黄で保護したホスホランを用いて合成したＰ−プロリン誘導体を合成し、これを用いた不斉反応を展開しているが、これらもトランス体を使用している（非特許文献７）。 On the other hand, Zhang et al. Synthesized a P-proline derivative synthesized using phosphorane having a phosphorus atom protected with sulfur, and developed an asymmetric reaction using this, but these also use a trans isomer. (Non-patent document 7).
このような状況の中で最近、本発明者はトランス体のホスホラン−２−カルボン酸誘導体合成時に副生成物として得られるシス体のホスホラン−２−カルボン酸誘導体にも不斉誘起効果があることを見出している。 Under these circumstances, the present inventors have recently demonstrated that the cis-phosphorane-2-carboxylic acid derivative obtained as a by-product during the synthesis of the trans-phosphorane-2-carboxylic acid derivative also has an asymmetric induction effect. Is heading.
本発明は、上記のとおりの背景から、本発明者により不斉誘起効果を有することが新たに見出されたシス体のホスホラン−２−カルボン酸誘導体について、その有用物質としての高効率で選択的な製造方法を提供することを課題としている。 The present invention selects a cis-phosphoran-2-carboxylic acid derivative newly discovered to have an asymmetric induction effect by the present inventor from the background as described above with high efficiency as a useful substance. It is an object to provide a simple manufacturing method.
本発明は、上記の課題を解決するものとして、以下の特徴を有している。 The present invention has the following features to solve the above problems.
第１：次式 First:
（式中のＲ1は炭素数６〜１０のアリール基を示す。）
で表わされる１−アリールホスホラン・ボラン錯体にアルキルリチウムを作用させた後、二酸化炭素を反応させて１−アリールホスホラン−２−カルボン酸・ボラン錯体を製造するに際し、反応系への二酸化炭素ガスの導入速度によってシス体とトランス体の生成比を制御し、シス体を優先的に生成させることを特徴とする１−アリールホスホラン−２−カルボン酸・ボラン錯体の製造方法。
(R 1 in the formula represents an aryl group having 6 to 10 carbon atoms .)
In the production of 1-arylphosphorane-2-carboxylic acid / borane complex by reacting alkyllithium with the 1-arylphosphorane / borane complex represented by A method for producing a 1-arylphosphorane-2-carboxylic acid / borane complex, wherein a production ratio of a cis isomer and a trans isomer is controlled by a gas introduction rate to preferentially produce a cis isomer.
第２：上記第１の方法において、１−アリールホスホラン−２−カルボン酸・ボラン錯体の再結晶によりジアステレオマー分離し、ラセミ体のシス−１−アリールホスホラン−２−カルボン酸・ボラン錯体を得ることを特徴とする１−アリールホスホラン−２−カルボン酸・ボラン錯体の製造方法。 Second: In the first method, diastereomeric separation is performed by recrystallization of 1-arylphosphorane-2-carboxylic acid / borane complex, and racemic cis-1-arylphosphorane-2-carboxylic acid / borane is obtained. A method for producing a 1-arylphosphorane-2-carboxylic acid / borane complex, which comprises obtaining a complex.
第３：上記第２の方法において、ラセミ体のシス−１−アリールホスホラン−２−カルボン酸・ボラン錯体を光学活性なアミンとの塩に変換した後に分別結晶して、（１Ｓ，２Ｓ）−シス−１−アリールホスホラン−２−カルボン酸・ボラン錯体と（１Ｒ，２Ｒ）−シス−１−アリールホスホラン−２−カルボン酸・ボラン錯体とを得ることを特徴とする１−アリールホスホラン−２−カルボン酸・ボラン錯体の製造方法。 Third: In the second method, after the racemic cis-1-arylphosphorane-2-carboxylic acid / borane complex is converted to a salt with an optically active amine, fractional crystallization is carried out to obtain (1S, 2S) A 1-arylphosphoric acid characterized by obtaining a cis-1-arylphosphorane-2-carboxylic acid / borane complex and a (1R, 2R) -cis-1-arylphosphorane-2-carboxylic acid / borane complex A method for producing a run-2-carboxylic acid / borane complex.
上記のとおりの本発明によれば、不斉誘起効果を有することが新たに見出されたシス体のホスホラン−２−カルボン酸誘導体について、その有用物質としての高効率で選択的な製造方法が提供される。 According to the present invention as described above, a highly efficient and selective production method as a useful substance for a cis-phosphorane-2-carboxylic acid derivative newly found to have an asymmetric induction effect is provided. Provided.
本発明は上記のとおりの特徴をもつものであるが、以下にその実施の形態について説明する。 The present invention has the features as described above, and an embodiment thereof will be described below.
本発明の１−アリールホスホラン−２−カルボン酸・ボラン錯体の製造方法においては、前記のとおりの式 In the method for producing a 1-arylphosphorane-2-carboxylic acid / borane complex of the present invention, the formula as described above is used.
で表わされる１−アリールホスホラン・ボラン錯体を原料物質として用いる。このものは、前記のとおり、本発明者らによって見出されたホスホラン−カルボン酸とその誘導体として公知（非特許文献５、特許文献１）のものである。 A 1-arylphosphorane / borane complex represented by the formula: As described above, this is known as a phosphorane-carboxylic acid and its derivative found by the present inventors (Non-patent Document 5, Patent Document 1).
この１−アリールホスホラン・ボラン錯体においては、前記符号Ｒ1は、炭素数６〜１０のアリール基であり、フェニル基、トリル基、キシリル基、ナフチル基等々の各種であってよい。 In the 1-arylphosphorane / borane complex, the symbol R 1 is an aryl group having 6 to 10 carbon atoms, and may be various groups such as a phenyl group, a tolyl group, a xylyl group, and a naphthyl group.
そして、本発明の製造法では、次のプロセスを特徴としている。 The manufacturing method of the present invention is characterized by the following processes.
Ａ）前記の１−アリールホスホラン・ボラン錯体にアルキルリチウムを作用させた後、二酸化炭素（ＣＯ2）を反応させて１−アリールホスホラン−２−カルボン酸・ボラン錯体に変換する際に、反応系、すなわち反応液中へのＣＯ2ガスの導入速度によってシス体とトランス体の生成比を制御し、シス体を優先的に生成させる。 A) When alkyl lithium is allowed to act on the 1-arylphosphorane-borane complex and then reacted with carbon dioxide (CO 2 ) to convert it into a 1-arylphosphorane-2-carboxylic acid-borane complex, The production ratio of the cis isomer and the trans isomer is controlled by the introduction rate of the CO 2 gas into the reaction system, that is, the reaction solution, and the cis isomer is preferentially produced.
Ｂ）１−アリールホスホラン−２−カルボン酸・ボラン錯体の再結晶によりジアステレオマー分離し、ラセミ体のシス−１−アリールホスホラン−２−カルボン酸・ボラン錯体を得る。 B) Diastereomer separation by recrystallization of 1-arylphosphorane-2-carboxylic acid / borane complex to obtain racemic cis-1-arylphosphorane-2-carboxylic acid / borane complex.
Ｃ）ラセミ体のシス−１−アリールホスホラン−２−カルボン酸・ボラン錯体を光学活性なアミンとの塩に変換した後に分別結晶して、（１Ｓ，２Ｓ）−シス−１−アリールホスホラン−２−カルボン酸・ボラン錯体と（１Ｒ，２Ｒ）−シス−１−アリールホスホラン−２−カルボン酸・ボラン錯体を得る。 C) The racemic cis-1-arylphosphorane-2-carboxylic acid / borane complex was converted into a salt with an optically active amine and then fractionally crystallized to obtain (1S, 2S) -cis-1-arylphosphorane. A 2-carboxylic acid / borane complex and a (1R, 2R) -cis-1-arylphosphorane-2-carboxylic acid / borane complex are obtained.
プロセスＡ）については、本発明がＣＯ2を用いてトランス体を生成、回収することをすでに公表している（非特許文献５、特許文献１）が、シス体を優先的に生成させるための手段については、これまで本発明者においても予期できないことであった。本発明では、シス体の生成比を増大させることは、反応系に導入するＣＯ2ガスの導入速度を大きくすることによって可能になるとの新しい知見に基づいている。反応液の容量、そして原料としての１−アリールホスホラン・ボラン錯体の種類と存在量にもよるが、たとえば、生成するカルボン酸ボラン錯体の収率が７０％以上において、シス体の生成割合が５０％を超える場合には、トランス体の生成割合が５０％を超える場合に比べて、ＣＯ2の導入速度は４倍以上、さらには５倍以上であることが考慮される。 Regarding process A), the present invention has already announced that CO 2 is used to produce and recover a trans isomer (Non-patent Document 5, Patent Document 1). As for the means, the present inventors have never been able to expect it. In the present invention, it is based on the new finding that increasing the production ratio of the cis isomer is possible by increasing the introduction rate of the CO 2 gas introduced into the reaction system. Depending on the volume of the reaction solution and the type and abundance of the 1-arylphosphorane / borane complex as a raw material, for example, when the yield of the carboxylic acid borane complex to be produced is 70% or more, the production rate of the cis isomer is In the case where it exceeds 50%, it is considered that the introduction rate of CO 2 is 4 times or more, further 5 times or more, compared with the case where the production ratio of the trans isomer exceeds 50%.
反応は、たとえば公知方法と同様に、ｓ−ＢｕＬｉ、ジピペリジノエタン添加のエーテル溶媒中で行うことができる。 The reaction can be carried out in an ether solvent to which s-BuLi and dipiperidinoethane are added, for example, in the same manner as in a known method.
プロセスＢ）Ｃ）については、これまで公知の方法に従って、適宜な条件のもとに実施することが可能である。すなわち、たとえば、シス体が優先的に得られた、１−フェニルホスホラン２−カルボン酸・ボラン錯体からは、クロロホルムからの再結晶によりジアステレオマーの分離ができ、ラセミ体のシス−１−フェニルホスホラン２−カルボン酸・ボラン錯体が得られる。このものは光学活性なアミンとの塩に変換することで分別結晶でき、光学的に純粋な（１Ｓ，２Ｓ）−シス−１−フェニルホスホラン２−カルボン酸・ボラン錯体と（１Ｒ，２Ｒ）−シス−１−フェニルホスホラン２−カルボン酸・ボラン錯体が得られる。 Processes B) and C) can be carried out under suitable conditions in accordance with known methods so far. That is, for example, from a 1-phenylphosphorane 2-carboxylic acid / borane complex from which a cis isomer was preferentially obtained, diastereomers can be separated by recrystallization from chloroform, and the racemic cis-1- A phenylphosphorane 2-carboxylic acid / borane complex is obtained. This can be fractionally crystallized by converting it into a salt with an optically active amine, and optically pure (1S, 2S) -cis-1-phenylphosphorane 2-carboxylic acid / borane complex and (1R, 2R) A cis-1-phenylphosphorane 2-carboxylic acid / borane complex is obtained.
本発明において得られた（１Ｓ，２Ｓ）−または（１Ｒ，２Ｒ）−のシス−１−アリールホスホラン−２−カルボン酸・ボラン錯体は、そのものが触媒的不斉反応の不斉配位子として有用なだけでなく、このものより、たとえば後述の参考例にも示したように、各種の不斉配位子を反応により誘導することにも有用である。 The (1S, 2S)-or (1R, 2R)-cis-1-arylphosphorane-2-carboxylic acid / borane complex obtained in the present invention is itself an asymmetric ligand of catalytic asymmetric reaction In addition to this, it is also useful for inducing various asymmetric ligands by reaction, as shown in the reference examples described later.
そこで以下に実施例によりさらに詳しく説明する。もちろん以下の例によって発明が限定されることはない。 Therefore, the present invention will be described in more detail with reference to the following examples. Of course, the invention is not limited by the following examples.
以下の説明において、特に記載のない化合物は市販品を必要に応じて精製して使用した。 In the following description, commercially available compounds were used after purification as necessary, unless otherwise specified.
反応は全てアルゴン雰囲気下で実施した。
＜参考例１＞
１−フェニルホスホラン・ボラン錯体（１）の合成
次の反応式
All reactions were carried out under an argon atmosphere.
<Reference Example 1>
Synthesis of 1-phenylphosphorane-borane complex (1)
に従って合成を行った。 The synthesis was performed according to
マグネシウム（２４ｇ：０．９９モル）の入ったＴＨＦ（４００ｍｌ）溶液に、氷冷下で１，４−ジブロモブタン（４８ｍｌ：０．４モル）のＴＨＦ（１００ｍｌ）溶液を１時間かけて滴下した。室温で４時間攪拌後、氷冷下にてジクロロフェニルホスフィン（５５ｍｌ：０．４モル）のＴＨＦ（１００ｍｌ）溶液を１．５時間かけて滴下し、その後室温で１５時間攪拌した。 To a THF (400 ml) solution containing magnesium (24 g: 0.99 mol), a solution of 1,4-dibromobutane (48 ml: 0.4 mol) in THF (100 ml) was added dropwise over 1 hour under ice cooling. . After stirring at room temperature for 4 hours, a solution of dichlorophenylphosphine (55 ml: 0.4 mol) in THF (100 ml) was added dropwise over 1.5 hours under ice cooling, and then stirred at room temperature for 15 hours.
別に用意した反応容器に三フッ化ホウ素−ジエチルエーテル錯体（１０１ｍｌ：０．８ｍｏｌ）の２−メトキシエトキシエーテル（ＤＧＭ）（１００ｍｌ）溶液を入れ、氷浴下、アルゴンガスを通しながら水素化ホウ素ナトリウム（１５．１３ｇ：０．４ｍｏｌ）のＤＧＭ（４００ｍｌ）溶液を滴下し、発生するジボランを氷浴下のグリニャール反応溶液へと送り込んだ。水素化ホウ素ナトリウムの滴下後、ジボラン発生装置を８０oCに加熱し、アルゴンガスを通しながらジボランをグリニャール反応溶液へと送り込んだ。 Into a reaction vessel prepared separately, a solution of boron trifluoride-diethyl ether complex (101 ml: 0.8 mol) in 2-methoxyethoxy ether (DGM) (100 ml) was placed, and sodium borohydride was passed through argon gas in an ice bath. (15.13 g: 0.4 mol) of DGM (400 ml) solution was dropped, and the generated diborane was fed into the Grignard reaction solution in an ice bath. After dropwise addition of sodium borohydride, the diborane generator was heated to 80 ° C., and diborane was fed into the Grignard reaction solution while passing argon gas.
ジボラン発生装置を外し、グリニャール反応溶液を室温で１時間撹拌した後、氷浴下にて１Ｎ 塩酸（１５０ｍｌ）を滴下した。その後酢酸エチルで抽出を行い、有機相を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、乾燥剤を濾別した。 The diborane generator was removed and the Grignard reaction solution was stirred at room temperature for 1 hour, and then 1N hydrochloric acid (150 ml) was added dropwise in an ice bath. Thereafter, extraction was performed with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the desiccant was filtered off.
減圧濃縮により得られたオイルをシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１０／１−５／１）にて精製し、さらに減圧蒸留（沸点１４０oＣ／１ｍｍＨｇ）することにより１を（２８．９ｇ、収率４０％）を油状物として得た。
＜実施例１＞
１−フェニルホスホラン２−カルボン酸・ボラン錯体（２）（ジアステレオマー、エナンチオマー混合物）の合成
次の反応式
The oil obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 10 / 1-5 / 1) and further distilled under reduced pressure (boiling point 140 ° C./1 mmHg) to obtain 1 (28.9 g, Yield 40%) was obtained as an oil.
<Example 1>
Synthesis of 1-phenylphosphorane 2-carboxylic acid / borane complex (2) (mixture of diastereomers and enantiomers)
に従って合成を行った。 The synthesis was performed according to
１，２−ジピペリジノエタン（６４．７ｍｌ：３００ｍｍｏｌ）のエーテル（５００ｍｌ）溶液に、−７８℃でｓ−ブチルリチウム（３００ｍｌ：３００ｍｍｏｌ、１．０Ｍ ヘキサン−シクロヘキサン溶液）を滴下し、１時間攪拌した。上記参考例１において合成したボラン錯体：１（３４．７ｍｌ：２００ｍｍｏｌ）のエーテル（１００ｍｌ）溶液を滴下し１．５時間攪拌した後、メカニカルスターターで良く攪拌しながら（１５０〜６００回転／分）炭酸ガスを一定の速度で加え、−７８oCで２時間撹拌後、冷却装置を外し、炭酸ガスを加えながら反応溶液が室温になるまで１時間撹拌した。 To a solution of 1,2-dipiperidinoethane (64.7 ml: 300 mmol) in ether (500 ml), s-butyllithium (300 ml: 300 mmol, 1.0 M hexane-cyclohexane solution) was added dropwise at −78 ° C. Stir for hours. Borane complex synthesized in Reference Example 1: A solution of ether (100 ml) of 1 (34.7 ml: 200 mmol) was added dropwise and stirred for 1.5 hours, and then well stirred with a mechanical starter (150 to 600 rpm) Carbon dioxide was added at a constant rate, and the mixture was stirred at −78 ° C. for 2 hours. The cooling device was removed, and the reaction solution was stirred for 1 hour while adding carbon dioxide until the reaction solution reached room temperature.
反応混合物をグラスフィルターで濾過した後、得られた固体を塩化メチレンに溶かし、撹拌しながら１Ｎ塩酸水溶液を水相のｐＨが３になるまで加えた。その後有機相と水相を分離し、有機相を１Ｎ塩酸水溶液、飽和食塩水、水で順次洗浄した。有機相を無水硫酸ナトリウムで乾燥し、乾燥剤を濾別後、溶媒を減圧濃縮することで２を（３８，２ｇ、収率８６％、ｔｒａｎｓ／ｃｉｓ＝３０／７０）異性体の混合物として得た。以下の表１に反応条件と収率およびジアステレオマー比を示す。 After filtering the reaction mixture through a glass filter, the obtained solid was dissolved in methylene chloride, and 1N aqueous hydrochloric acid solution was added with stirring until the pH of the aqueous phase reached 3. Thereafter, the organic phase and the aqueous phase were separated, and the organic phase was washed successively with 1N hydrochloric acid aqueous solution, saturated brine and water. The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was concentrated under reduced pressure to obtain 2 as a mixture of isomers (38, 2 g, yield 86%, trans / cis = 30/70). It was. Table 1 below shows reaction conditions, yields, and diastereomeric ratios.
そして、得られたジアステレオマー混合物をクロロホルムより再結晶して、純粋なシス−２を得た（収率：約６０％）。 The obtained diastereomeric mixture was recrystallized from chloroform to obtain pure cis-2 (yield: about 60%).
＜実施例２＞
（１）シンコニジンを用いたｃｉｓ体の光学分割
次の反応式
<Example 2>
(1) Optical resolution of cis body using cinchonidine
に従って反応を行った。 The reaction was carried out according to
ｃｉｓ体である（１Ｒ*，２Ｒ*）−２（５００ｍｇ：２．２５ｍｍｏｌ）をクロロホルム（１０ｍｌ）に溶かし、シンコニジン（６６２ｍｇ、２．２５ｍｍｏｌ）を加え、室温で撹拌した。シンコニジンが溶解したのを確認後、エーテル（２０ｍｌ）を加え室温で撹拌し、（１Ｒ*，２Ｒ*）−２のアンモニウム塩を析出させた。濾別して得られた固体を再度クロロホルム（10 ml）に溶かし、エーテル（２０ｍｌ）により析出させる操作を合計で１０回行った。 The cis form (1R * , 2R * )-2 (500 mg: 2.25 mmol) was dissolved in chloroform (10 ml), cinchonidine (662 mg, 2.25 mmol) was added, and the mixture was stirred at room temperature. After confirming that cinchonidine was dissolved, ether (20 ml) was added and stirred at room temperature to precipitate the ammonium salt of (1R * , 2R * )-2. The solid obtained by filtration was dissolved again in chloroform (10 ml) and precipitated with ether (20 ml) for a total of 10 times.
最終的に得られた固体をクロロホルムで抽出し、有機相を1N塩酸水溶液で洗い、無水硫酸ナトリウムで乾燥した。乾燥剤を濾別後、溶媒を濃縮し（１Ｓ，２Ｓ）−２（３０５ ｍｇ、 収率２６％、１００％ｅｅ）を白色の固形物として得た。分離された化合物2の光学純度は、対応するメチルエステルへと誘導した後、キラルカラムによるＨＰＬＣから求めた。
（２）（Ｒ）−（＋）−フェネチルアミンを用いたｃｉｓ体の光学分割
次の反応式
The finally obtained solid was extracted with chloroform, and the organic phase was washed with 1N aqueous hydrochloric acid and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was concentrated to give (1S, 2S) -2 (305 mg, 26% yield, 100% ee) as a white solid. The optical purity of the separated compound 2 was determined by HPLC using a chiral column after derivatization to the corresponding methyl ester.
(2) Optical resolution of cis body using (R)-(+)-phenethylamine The following reaction formula
に従って反応を行った。 The reaction was carried out according to
ｃｉｓ体である（１Ｒ*，２Ｒ*）−２（２．２５ｍｍｏｌ）をメタノール（１０ｍｌ）に溶かし、（Ｒ）−（＋）−フェネチルアミン（２８６μｌ：２．２５ｍｍｏｌ）を加え室温で撹拌し、エーテル（２０ｍｌ）を加えて（１Ｒ*，２Ｒ*）−２のアンモニウム塩を析出させた。濾別して得られた固体を再度メタノール（１０ｍｌ）に溶かし、エーテル（２０ｍｌ）により析出させる操作を合計で４回行った。 (1R * , 2R * )-2 (2.25 mmol) which is cis form is dissolved in methanol (10 ml), (R)-(+)-phenethylamine (286 μl: 2.25 mmol) is added, and the mixture is stirred at room temperature. (20 ml) was added to precipitate the ammonium salt of (1R * , 2R * )-2. The solid obtained by filtration was dissolved again in methanol (10 ml) and precipitated with ether (20 ml) for a total of 4 times.
最終的に得られた固体をクロロホルムで抽出し、有機相を１Ｎ塩酸水溶液で洗い、無水硫酸ナトリウムで乾燥した。乾燥剤を濾別後、溶媒を濃縮し（１Ｒ*，２Ｒ*）−２（４０ｍｇ、収率８％、１００％ｅｅ）を白色の固形物として得た。分離された化合物２の光学純度は、同様に対応するメチルエステルへと誘導した後、キラルカラムによるＨＰＬＣから求めた。
＜参考例２＞
次の反応式
The finally obtained solid was extracted with chloroform, and the organic phase was washed with 1N aqueous hydrochloric acid and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was concentrated to give (1R * , 2R * )-2 (40 mg, 8% yield, 100% ee) as a white solid. The optical purity of the separated compound 2 was similarly derived to the corresponding methyl ester and then determined by HPLC using a chiral column.
<Reference Example 2>
The following reaction formula
に従って、文献公知（非特許文献５、特許文献１）の方法により合成した（１Ｒ，２Ｒ）−１−シス−フェニルホスホラン−２−カルボン酸−ボラン錯体：２（２２２．１ｍｇ，１．０ｍｍｏｌ）及び１，２，３，４−テトラヒドロイソキノリン（１９９．８ｍｇ，１．５ｍｍｏｌ）の塩化メチレン（５ｍＬ）溶液に、氷冷下で１−〔３−（ジメチルアミノ）プロピル〕−３−エチルカルボジイミド・塩酸塩（ＥＤＣ）（２８７．６ｍｇ，１．５ｍｍｏｌ）を少しずつ加え、氷冷下４時間攪拌した。水と塩化メチレンを加えて反応を停止し、有機相と水相を分離した。有機相を飽和食塩水で洗浄した後に、無水硫酸マグネシウムで乾燥した。ろ過後、溶液を減圧濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製することにより、ｃｉｓ体である（１Ｒ，２Ｓ）−１−シス−フェニルホスホラン−２−カルボン酸アミド−ボラン錯体の合成を行った。（１Ｒ，２Ｒ）−１−シス−フェニルホスホラン−２−カルボン酸アミド−ボラン錯体（２５８．４ｍｇ，収率７７％）、（１Ｒ，２Ｓ）−１−シス−フェニルホスホラン−２−カルボン酸アミド−ボラン錯体（８．０ｍｇ，収率２％）
次いで、（１Ｒ，２Ｒ）−１−シス−フェニルホスホラン−２−カルボン酸アミド誘導体−ボラン錯体（１６０．８ｍｇ，０．４８ｍｍｏｌ）のＴＨＦ（５ｍＬ）溶液にボランのＴＨＦ溶液（１．０Ｍ，４．７ｍＬ，４．７ｍｍｏｌ）を滴下し、その後４０℃にて１４時間攪拌した。室温まで放冷した後水と塩化メチレンを加えて反応を停止し、有機相と水相を分離した。有機相を飽和食塩水で洗浄した後に、無水硫酸マグネシウムで乾燥した。ろ過後、溶液を減圧濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製することにより、（１Ｒ，２Ｒ）−１−シス−フェニルホスホラン−２−カルボン酸アミン誘導体−ボラン錯体を得た。
(1R, 2R) -1-cis-phenylphosphorane-2-carboxylic acid-borane complex synthesized by the method known in the literature (Non-Patent Document 5, Patent Document 1): 2 (222.1 mg, 1.0 mmol) ) And 1,2,3,4-tetrahydroisoquinoline (199.8 mg, 1.5 mmol) in methylene chloride (5 mL) under ice-cooling, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide -Hydrochloride (EDC) (287.6 mg, 1.5 mmol) was added little by little, and the mixture was stirred for 4 hours under ice cooling. Water and methylene chloride were added to stop the reaction, and the organic phase and the aqueous phase were separated. The organic phase was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by concentrating the solution under reduced pressure is purified by silica gel column chromatography to obtain (1R, 2S) -1-cis-phenylphosphorane-2-carboxylic acid amide which is a cis form. -A borane complex was synthesized. (1R, 2R) -1-cis-phenylphosphorane-2-carboxylic acid amide-borane complex (258.4 mg, 77% yield), (1R, 2S) -1-cis-phenylphosphorane-2-carboxylic acid Acid amide-borane complex (8.0 mg, 2% yield)
Then, (1R, 2R) -1-cis-phenylphosphorane-2-carboxylic acid amide derivative-borane complex (160.8 mg, 0.48 mmol) in THF (5 mL) was added to a solution of borane in THF (1.0 M, 4.7 mL, 4.7 mmol) was added dropwise, followed by stirring at 40 ° C. for 14 hours. After allowing to cool to room temperature, water and methylene chloride were added to stop the reaction, and the organic phase and the aqueous phase were separated. The organic phase was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by concentrating the solution under reduced pressure is purified by silica gel column chromatography to obtain (1R, 2R) -1-cis-phenylphosphorane-2-carboxylic acid amine derivative-borane complex. Got.
得られたこの（１Ｒ，２Ｒ）−１−シス−フェニルホスホラン−２−カルボン酸アミン誘導体−ボラン錯体（２２１．７ｍｇ，０．６６ｍｍｏｌ）をジエチルアミン（１．２ｍＬ）に溶解し、４５℃にて２時間攪拌した。反応溶液を減圧濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製することにより、（１Ｒ，２Ｒ）−１−シス−フェニルホスホラン−２−カルボン酸アミン誘導体：３を収率４２％（３ステップ）で得た。
＜参考例３＞
次の反応式
The obtained (1R, 2R) -1-cis-phenylphosphorane-2-carboxylic acid amine derivative-borane complex (221.7 mg, 0.66 mmol) was dissolved in diethylamine (1.2 mL) and heated to 45 ° C. And stirred for 2 hours. The crude product obtained by concentrating the reaction solution under reduced pressure is purified by silica gel column chromatography to yield (1R, 2R) -1-cis-phenylphosphorane-2-carboxylic acid amine derivative: 3. Obtained in 42% (3 steps).
<Reference Example 3>
The following reaction formula
に従って、マロン酸ジエチルのパラジウム触媒を用いての不斉アリル化反応を行った。不斉配位子としては、参考例２で得られた化合物：３を３ｍｏｌ％の割合で用いた。その結果、光学活性なアリル化反応生成物を、９３％収率、９４％ｅｅで得た。
Then, an asymmetric allylation reaction of diethyl malonate using a palladium catalyst was carried out. As an asymmetric ligand, the compound obtained in Reference Example 2: 3 was used in a proportion of 3 mol%. As a result, an optically active allylation reaction product was obtained in 93% yield and 94% ee.
Claims (3)
で表わされる１−アリールホスホラン・ボラン錯体に二酸化炭素を反応させて１−アリールホスホラン−２−カルボン酸・ボラン錯体を製造するに際し、反応系への二酸化炭素ガスの導入速度によってシス体とトランス体の生成比を制御し、シス体を優先的に生成させることを特徴とする１−アリールホスホラン−２−カルボン酸・ボラン錯体の製造方法。 Next formula
In the production of a 1-arylphosphorane-2-carboxylic acid-borane complex by reacting carbon dioxide with a 1-arylphosphorane-borane complex represented by the formula: A method for producing a 1-arylphosphorane-2-carboxylic acid / borane complex, wherein the production ratio of a trans isomer is controlled to preferentially produce a cis isomer.
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