JP6168665B2 - Pyrophosphate ester compound, bisphosphate ester compound and catalyst - Google Patents

Pyrophosphate ester compound, bisphosphate ester compound and catalyst Download PDF

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JP6168665B2
JP6168665B2 JP2014525854A JP2014525854A JP6168665B2 JP 6168665 B2 JP6168665 B2 JP 6168665B2 JP 2014525854 A JP2014525854 A JP 2014525854A JP 2014525854 A JP2014525854 A JP 2014525854A JP 6168665 B2 JP6168665 B2 JP 6168665B2
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石原　一彰
一彰 石原
彰 坂倉
彰 坂倉
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Description

本発明は、新規なピロリン酸エステル化合物、ビスリン酸エステル化合物及び触媒に関する。   The present invention relates to a novel pyrophosphate ester compound, a bisphosphate ester compound and a catalyst.

近年、リン酸エステル化合物をブレンステッド酸触媒として用いる反応が報告されている。例えば、特許文献１では、リン酸エステル化合物である３，３’−ジアリール−１，１’−ビナフチル−２，２’−ジイル ハイドロジェンホスフェートを、マンニッヒ反応やヒドロホスホリル化反応、アザ ディールスアルダー反応などの触媒として利用している。   In recent years, reactions using phosphate ester compounds as Bronsted acid catalysts have been reported. For example, in Patent Document 1, 3,3′-diaryl-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate, which is a phosphate ester compound, is converted into Mannich reaction, hydrophosphorylation reaction, aza diels alder reaction. It is used as a catalyst.

国際公開第２００４／０９６７５３号International Publication No. 2004/096753

しかしながら、これまでに知られているリン酸エステル化合物は、酸性度があまり高くなかったため、例えばアルデヒドやケトンなどのカルボニル化合物を十分活性化することができなかった。そのため、基質一般性が十分とはいえなかった。   However, since the phosphoric acid ester compounds known so far have not been so acidic, carbonyl compounds such as aldehydes and ketones cannot be activated sufficiently. Therefore, it cannot be said that the generality of the substrate is sufficient.

本発明はこのような課題を解決するためになされたものであり、新規なピロリン酸エステル化合物やビスリン酸エステル化合物を提供することを主目的とする。   The present invention has been made to solve such problems, and has as its main object to provide a novel pyrophosphate ester compound and a bisphosphate ester compound.

本発明者らは、３，３’位に置換基を有するＢＩＮＯＬ誘導体（ＢＩＮＯＬは１，１’−ビ−２−ナフトールの略）に対して、水素化ナトリウム及び塩化ジアリルリン酸を反応させた後、アリル保護基を除去することにより、新規なビスリン酸エステル化合物を得た。また、このビスリン酸エステル化合物を塩化オキサリルと反応させることにより、新規なピロリン酸エステル化合物を得た。このようにして得られた新規なピロリン酸エステル化合物やビスリン酸エステル化合物を触媒として分子内エン反応やマンニッヒ反応を行ったところ、従来のリン酸エステル化合物を触媒とした場合に比べて活性が高いことを確認し、本発明を完成するに至った。   The present inventors reacted sodium hydride and diallyl phosphate with a BINOL derivative having a substituent at the 3,3 ′ position (BINOL is an abbreviation for 1,1′-bi-2-naphthol). By removing the allyl protecting group, a novel bisphosphate compound was obtained. Moreover, the novel pyrophosphate ester compound was obtained by making this bisphosphate ester compound react with oxalyl chloride. When the intramolecular ene reaction or Mannich reaction was carried out using the novel pyrophosphate ester compound or bisphosphate ester compound thus obtained as a catalyst, the activity was higher than in the case where a conventional phosphate ester compound was used as the catalyst. This was confirmed and the present invention was completed.

本発明のピロリン酸エステル化合物は、式（１）で表されるものである。但し、式（１）中、Ｒは、アリール基、有機シリル基又はハロゲン原子である。   The pyrophosphate ester compound of the present invention is represented by the formula (1). However, in Formula (1), R is an aryl group, an organic silyl group, or a halogen atom.

本発明のビスリン酸エステル化合物は、式（２）で表されるものである。但し、式（２）中、Ｒは、アリール基、有機シリル基又はハロゲン原子である。   The bisphosphate compound of the present invention is represented by the formula (2). However, in Formula (2), R is an aryl group, an organic silyl group, or a halogen atom.

本発明の新規なピロリン酸エステル化合物やビスリン酸エステル化合物は、分子内に複数のリン酸水酸基を有するため、従来のリン酸エステル化合物に比べて酸性度が高い。そのため、カルボニル化合物やイミン化合物などを活性化する能力が高い。また、配位子としても有用性が期待される。更に、ビナフチル骨格を有するため、キラルなピロリン酸エステル化合物やビスリン酸エステル化合物とすることもできる。   Since the novel pyrophosphate ester compound and bisphosphate ester compound of the present invention have a plurality of phosphate hydroxyl groups in the molecule, the acidity is higher than that of conventional phosphate ester compounds. Therefore, the ability to activate carbonyl compounds and imine compounds is high. In addition, it is expected to be useful as a ligand. Furthermore, since it has a binaphthyl skeleton, it can be a chiral pyrophosphate ester compound or bisphosphate ester compound.

本発明のピロリン酸エステル化合物は、上記式（１）で表されるものであり、Ｒは、アリール基、有機シリル基又はハロゲン原子である。また、本発明のビスリン酸エステル化合物は、上記式（２）で表されるものであり、Ｒは、アリール基、有機シリル基又はハロゲン原子である。   The pyrophosphate ester compound of the present invention is represented by the above formula (1), and R is an aryl group, an organic silyl group or a halogen atom. The bisphosphate compound of the present invention is represented by the above formula (2), and R is an aryl group, an organic silyl group, or a halogen atom.

ここで、アリール基としては、例えば、フェニル基やナフチル基、アントラセニル基などが挙げられる。ナフチル基は、１−ナフチル基でもよいし、２−ナフチル基でもよい。アントラセニル基は、１−アントラセニル基でもよいし、２−アントラセニル基でもよいし、９−アントラセニル基でもよい。また、フェニル基やナフチル基、アントラセニル基は、少なくとも１つの水素原子が置換基で置換されていてもよい。置換基としては、例えば、アリール基、アルキル基、シクロアルキル基、アルコキシ基、ペルフルオロアルキル基、ニトロ基、シアノ基、ハロゲン原子などが挙げられる。その場合、アリール基としては、フェニル基やナフチル基、アントラセニル基などのほか、これらの少なくとも１つの水素原子がアルキル基、アルコキシ基、ペルフルオロアルキル基、ニトロ基、シアノ基、ハロゲン原子などで置換されていてもよい。アルキル基としては、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基などが挙げられる。シクロアルキル基としては、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基などが挙げられる。アルコキシ基としては、メトキシ基、エトキシ基、ｎ−プロポキシ基、イソプロポキシ基、ｎ−ブトキシ基、イソブトキシ基、ｓｅｃ−ブチトキシ基、ｔｅｒｔ−ブトキシ基などが挙げられる。ペルフルオロアルキル基としては、トリフルオロメチル基、ペンタフルオロエチル基などが挙げられる。ハロゲン原子としては、塩素原子、臭素原子、ヨウ素原子などが挙げられる。   Here, examples of the aryl group include a phenyl group, a naphthyl group, and an anthracenyl group. The naphthyl group may be a 1-naphthyl group or a 2-naphthyl group. The anthracenyl group may be a 1-anthracenyl group, a 2-anthracenyl group, or a 9-anthracenyl group. In the phenyl group, naphthyl group, and anthracenyl group, at least one hydrogen atom may be substituted with a substituent. Examples of the substituent include an aryl group, an alkyl group, a cycloalkyl group, an alkoxy group, a perfluoroalkyl group, a nitro group, a cyano group, and a halogen atom. In this case, the aryl group includes a phenyl group, a naphthyl group, an anthracenyl group, and the like, and at least one of these hydrogen atoms is substituted with an alkyl group, an alkoxy group, a perfluoroalkyl group, a nitro group, a cyano group, a halogen atom, or the like. It may be. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Examples of the alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group. Examples of the perfluoroalkyl group include a trifluoromethyl group and a pentafluoroethyl group. Examples of the halogen atom include a chlorine atom, a bromine atom, and an iodine atom.

このようなアリール基としては、特に、２−ナフチル基、３，５−ジフェニルフェニル基又は３，５−ビス（２−ナフチル）フェニル基が好ましい。   As such an aryl group, a 2-naphthyl group, a 3,5-diphenylphenyl group, or a 3,5-bis (2-naphthyl) phenyl group is particularly preferable.

有機シリル基としては、例えば、トリアルキルシリル基、トリアリールシリル基、アルキルジアリールシリル基、アリールジアルキルシリル基、トリス（トリアルキルシリル）シリル基、トリス（トリアリールシリル）シリル基などが挙げられる。トリアルキルシリル基は、３つのアルキル基がすべて同じでもよいし、２つが同じでもよいし、すべて異なっていてもよい。トリアリールシリル基は、３つのアリール基がすべて同じでもよいし、２つが同じでもよいし、すべて異なっていてもよい。アルキルジアリールシリル基は、２つのアリール基が同じでもよいし異なっていてもよい。アリールジアルキルシリル基は、２つのアルキル基が同じでもよいし異なっていてもよい。トリアルキルシリル基としては、例えば、トリメチルシリル基、トリエチルシリル基、トリイソプロピルシリル基、ジエチルイソプロピルシリル基、ジメチルイソプロピルシリル基、ジ−ｔｅｒｔ−ブチルメチルシリル基、イソプロピルジメチルシリル基、ｔｅｒｔ−ブチルジメチルシリル基などが挙げられる。トリアリールシリル基としては、例えばトリフェニルシリル基などが挙げられる。アルキルジアリールシリル基としては、例えば、ジフェニルメチルシリル基、ｔｅｒｔ−ブチルジフェニルシリル基などが挙げられる。アリールジアルキルシリル基としては、例えば、ジメチルフェニルシリル基などが挙げられる。トリス（トリアルキルシリル）シリル基としては、例えば、トリス（トリメチルシリル）シリル基などが挙げられる。トリス（トリアリールシリル）シリル基としては、例えば、トリス（トリフェニルシリル）シリル基などが挙げられる。   Examples of the organic silyl group include a trialkylsilyl group, a triarylsilyl group, an alkyldiarylsilyl group, an aryldialkylsilyl group, a tris (trialkylsilyl) silyl group, and a tris (triarylsilyl) silyl group. In the trialkylsilyl group, all three alkyl groups may be the same, two may be the same, or all may be different. In the triarylsilyl group, all three aryl groups may be the same, two may be the same, or all may be different. In the alkyldiarylsilyl group, two aryl groups may be the same or different. In the aryldialkylsilyl group, two alkyl groups may be the same or different. Examples of the trialkylsilyl group include trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, diethylisopropylsilyl group, dimethylisopropylsilyl group, di-tert-butylmethylsilyl group, isopropyldimethylsilyl group, tert-butyldimethylsilyl group. Group and the like. Examples of the triarylsilyl group include a triphenylsilyl group. Examples of the alkyldiarylsilyl group include a diphenylmethylsilyl group and a tert-butyldiphenylsilyl group. Examples of the aryldialkylsilyl group include a dimethylphenylsilyl group. Examples of the tris (trialkylsilyl) silyl group include a tris (trimethylsilyl) silyl group. Examples of the tris (triarylsilyl) silyl group include a tris (triphenylsilyl) silyl group.

ハロゲン原子としては、塩素原子、臭素原子、ヨウ素原子などが挙げられる。   Examples of the halogen atom include a chlorine atom, a bromine atom, and an iodine atom.

本発明のピロリン酸エステル化合物やビスリン酸エステル化合物の製法は、特に限定されるものではないが、一例を以下に示す。すなわち、ビスリン酸エステル化合物は、例えば、３，３’位に置換基Ｒ（Ｒは前出のとおり）を有するＢＩＮＯＬ誘導体に対して、水素化ナトリウム及び塩化ジアリルリン酸を反応させた後、アリル保護基を除去することにより、得ることができる。また、ピロリン酸エステル化合物は、例えば、上述したビスリン酸エステル化合物を塩化オキサリルと反応させることにより、得ることができる。   Although the manufacturing method of the pyrophosphate ester compound and bisphosphate ester compound of the present invention is not particularly limited, an example is shown below. That is, for example, a bisphosphate compound is prepared by reacting a BINOL derivative having a substituent R (R is as described above) at the 3,3′-position with sodium hydride and diallyl chloride and then protecting allyl. It can be obtained by removing the group. The pyrophosphate ester compound can be obtained, for example, by reacting the bisphosphate ester compound described above with oxalyl chloride.

本発明のピロリン酸エステル化合物やビスリン酸エステル化合物の用途は、特に限定されるものではないが、反応触媒や配位子などが挙げられる。例えば、６−オクテナール誘導体（シトロネラールなど）の分子内エン反応の触媒やマンニッヒ反応の触媒、フリーデル−クラフツ反応の触媒として用いることができる。また、ＢＩＮＯＬ骨格はＣ２対称を持つため、キラルなピロリン酸エステル化合物やキラルなビスリン酸エステル化合物を容易に得ることができる。こうしたキラルな化合物は、不斉合成反応の触媒として用いることが期待される。なお、ビスリン酸エステル化合物は、ピロリン酸エステル化合物の合成中間体としても有用である。   The use of the pyrophosphate ester compound or bisphosphate ester compound of the present invention is not particularly limited, and examples thereof include reaction catalysts and ligands. For example, it can be used as a catalyst for intramolecular ene reaction of 6-octenal derivatives (such as citronellal), a Mannich reaction catalyst, and a Friedel-Crafts reaction catalyst. Further, since the BINOL skeleton has C2 symmetry, a chiral pyrophosphate ester compound or a chiral bisphosphate ester compound can be easily obtained. Such chiral compounds are expected to be used as catalysts for asymmetric synthesis reactions. The bisphosphate compound is also useful as a synthesis intermediate for pyrophosphate compounds.

１．ビスリン酸エステル化合物の合成
ビスリン酸エステル化合物を下記のスキーム１にしたがって合成した。以下の実施例１〜３にその詳細を示す。1. Synthesis of Bisphosphate Compound A bisphosphate compound was synthesized according to Scheme 1 below. The details are shown in Examples 1 to 3 below.

［実施例１］
（Ｒ）−３，３’−ジフェニルＢＩＮＯＬ（４．４ｇ，１０ｍｍｏｌ）のＴＨＦ（５０ｍＬ）溶液に０℃にて６０％水素化ナトリウム鉱油分散物（０．８９ｇ，２２ｍｍｏｌ）を加え、３０分間撹拌した。この溶液に塩化ジアリルリン酸（７．８ｇ，４０ｍｍｏｌ）を加え、室温にて２時間撹拌した。反応混合物に水を加え、ジクロロメタンで抽出した後、有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した。この溶液を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（シリカゲル，ヘキサン−酢酸エチル＝２０：１→５：１）で精製し、ＢＩＮＯＬビスリン酸アリルエステル（６．６ｇ，８７％）を得た。そのスペクトルデータは、以下のとおり。31P NMR (160MHz, CDCl3) δ-6.0 ppm.[Example 1]
60% sodium hydride mineral oil dispersion (0.89 g, 22 mmol) was added to a solution of (R) -3,3′-diphenylBINOL (4.4 g, 10 mmol) in THF (50 mL) at 0 ° C. and stirred for 30 minutes. did. To this solution was added diallyl phosphoric acid chloride (7.8 g, 40 mmol), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The crude product obtained by concentrating this solution was purified by silica gel column chromatography (silica gel, hexane-ethyl acetate = 20: 1 → 5: 1), and BINOL bisphosphate allyl ester (6.6 g, 87%) Got. The spectrum data is as follows. 31 P NMR (160MHz, CDCl 3 ) δ-6.0 ppm.

次に、ＢＩＮＯＬビスリン酸アリルエステル（５．４ｇ，７．１ｍｍｏｌ）およびピロリジン（１．３ｍＬ，１５．７ｍｍｏｌ）のＤＭＦ（７２ｍＬ）溶液に、Ｐｄ（ＰＰｈ3）4（３．３ｇ，２．９ｍｍｏｌ）を加え、０℃にて４時間撹拌した。反応混合物に塩酸を加え、ジクロロメタンで抽出した後、有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した。この溶液を濃縮して得られた粗生成物をＡｍｂｅｒｌｉｔｅ ＩＲ−１２０（Ｈ ｆｏｒｍ）に通した。次いで、ＤＯＷＥＸ（Ｎａ ｆｏｒｍ）に吸着させて洗浄した後、濃塩酸−ＴＨＦ（１：５）で溶出させた。溶媒を減圧濃縮した後、ジクロロメタンに溶解して水で洗浄した。ジクロロメタンを減圧濃縮することにより、目的とするＢＩＮＯＬビスリン酸エステル（化合物Ｂ１，４．２ｇ，９８％）を得た。このビスリン酸エステルの構造は、ＮＭＲスペクトルおよびマススペクトルを測定することにより確定した。そのスペクトルデータは、以下のとおり。1H NMR (400 MHz, THF-d8) δ7.31 (t, J = 7.3 Hz, 2H), 7.36-7.43 (m, 6H), 7.47 (t, J = 6.9 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 6.9 Hz, 4H), 7.82 (d, J = 8.2 Hz, 2H), 8.02 (s, 2H)ppm; 13C NMR (100 MHz, THF-d8) δ125.5 (2C), 125.9 (2C), 126.2 (2C), 126.9 (2C), 127.5 (2C), 128.1 (4C), 128.6 (2C), 130.6 (4C), 131.6 (2C), 132.2 (2C), 133.0 (2C), 136.3 (2C), 139.1 (2C), 146.9 (2C)ppm; 31P NMR (160 MHz, THF-d8) δ-0.2 ppm; HRMS (FAB, negative mode) calcd for C32H23O8P2[M-H]- 597.0868, found 597.0826.Next, to a DMF (72 mL) solution of BINOL bisphosphate allyl ester (5.4 g, 7.1 mmol) and pyrrolidine (1.3 mL, 15.7 mmol), Pd (PPh 3 ) 4 (3.3 g, 2.9 mmol) was added. ) And stirred at 0 ° C. for 4 hours. After adding hydrochloric acid to the reaction mixture and extracting with dichloromethane, the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The crude product obtained by concentrating this solution was passed through Amberlite IR-120 (H form). Next, after adsorbing on DOWEX (Na form) and washing, it was eluted with concentrated hydrochloric acid-THF (1: 5). The solvent was concentrated under reduced pressure, then dissolved in dichloromethane and washed with water. Dichloromethane was concentrated under reduced pressure to obtain the desired BINOL bisphosphate (Compound B1, 4.2 g, 98%). The structure of this bisphosphate was determined by measuring the NMR spectrum and mass spectrum. The spectrum data is as follows. 1 H NMR (400 MHz, THF-d 8 ) δ7.31 (t, J = 7.3 Hz, 2H), 7.36-7.43 (m, 6H), 7.47 (t, J = 6.9 Hz, 2H), 7.54 (d , J = 8.2 Hz, 2H), 7.69 (d, J = 6.9 Hz, 4H), 7.82 (d, J = 8.2 Hz, 2H), 8.02 (s, 2H) ppm; 13 C NMR (100 MHz, THF- d 8 ) δ125.5 (2C), 125.9 (2C), 126.2 (2C), 126.9 (2C), 127.5 (2C), 128.1 (4C), 128.6 (2C), 130.6 (4C), 131.6 (2C), 132.2 (2C), 133.0 (2C), 136.3 (2C), 139.1 (2C), 146.9 (2C) ppm; 31 P NMR (160 MHz, THF-d 8 ) δ-0.2 ppm; HRMS (FAB, negative mode) calcd for C 32 H 23 O 8 P 2 [MH] - 597.0868, found 597.0826.

［実施例２］
実施例１で用いた（Ｒ）−３，３’−ジフェニルＢＩＮＯＬの代わりに、（Ｒ）−３，３’−ビス［４−（２，４，６−トリメチルフェニル）フェニル］ＢＩＮＯＬを用いた以外は、実施例１と同様にしてビスリン酸エステル化合物（化合物Ｂ２）を得た。そのスペクトルデータは、以下のとおり。1H NMR (400 MHz, THF-d8) δ2.05 (s, 12H), 2.28 (s,6H), 6.90 (s, 4H), 7.16 (d, J = 8.2 Hz, 4H), 7.40 (dd, J = 6.9, 7.8 Hz, 2H), 7.47 (dd, J = 6.9, 7.8 Hz, 2H), 7.55 (d, J = 7.8 Hz, 2H), 7.72 (d, J = 8.2 Hz, 4H), 7.99 (d, J = 7.8 Hz, 2H), 8.10 (s, 2H)ppm; 13C NMR (100 MHz, THF-d8) δ20.6 (4C), 20.7 (2C), 125.2 (2C), 125.8 (2C), 126.1 (2C), 126.8 (2C), 128.2 (4C), 128.4(2C), 129.0 (4C), 130.8 (4C), 131.1 (2C), 132.1 (2C), 133.0 (2C), 136.0 (4C), 136.3 (2C), 136.4 (2C), 137.1 (2C), 139.4 (2C), 140.5 (2C), 147.1 (2C)ppm; 31P NMR (160 MHz, THF-d8) δ-1.3 ppm; HRMS (FAB, negative mode) calcd for C50H43O8P2[M-H]- 833.2433, found 833.2427.[Example 2]
Instead of (R) -3,3′-diphenyl BINOL used in Example 1, (R) -3,3′-bis [4- (2,4,6-trimethylphenyl) phenyl] BINOL was used. Except for the above, a bisphosphate compound (Compound B2) was obtained in the same manner as in Example 1. The spectrum data is as follows. 1 H NMR (400 MHz, THF-d 8 ) δ2.05 (s, 12H), 2.28 (s, 6H), 6.90 (s, 4H), 7.16 (d, J = 8.2 Hz, 4H), 7.40 (dd , J = 6.9, 7.8 Hz, 2H), 7.47 (dd, J = 6.9, 7.8 Hz, 2H), 7.55 (d, J = 7.8 Hz, 2H), 7.72 (d, J = 8.2 Hz, 4H), 7.99 (d, J = 7.8 Hz, 2H), 8.10 (s, 2H) ppm; 13 C NMR (100 MHz, THF-d 8 ) δ20.6 (4C), 20.7 (2C), 125.2 (2C), 125.8 ( 2C), 126.1 (2C), 126.8 (2C), 128.2 (4C), 128.4 (2C), 129.0 (4C), 130.8 (4C), 131.1 (2C), 132.1 (2C), 133.0 (2C), 136.0 ( 4C), 136.3 (2C), 136.4 (2C), 137.1 (2C), 139.4 (2C), 140.5 (2C), 147.1 (2C) ppm; 31 P NMR (160 MHz, THF-d 8 ) δ-1.3 ppm ; HRMS (FAB, negative mode) calcd for C 50 H 43 O 8 P 2 [MH] - 833.2433, found 833.2427.

［実施例３］
実施例１で用いた（Ｒ）−３，３’−ジフェニルＢＩＮＯＬの代わりに、（Ｒ）−３，３’−ビス［３，５−ビス（トリフルオロメチル）フェニル］ＢＩＮＯＬを用いた以外は、実施例１と同様にしてビスリン酸エステル化合物（化合物Ｂ３）を得た。そのスペクトルデータは、以下のとおり。1H NMR (400 MHz, THF-d8) δ7.46-7.61 (m, 6H), 8.02 (s,2H), 8.07 (d, J = 7.8 Hz, 2H), 8.23 (s, 2H), 8.30 (s, 4H)ppm; 13C NMR (100 MHz,THF-d8) δ121.2 (2C), 124.1 (d, J = 270.8 Hz, 4C), 125.3 (2C), 126.0 (2C), 126.4 (2C), 127.9 (2C), 128.7 (2C), 131.1 (4C), 131.2 (d, J = 32.4 Hz, 4C), 131.9 (2C), 132.1 (2C), 132.8 (2C), 133.4 (2C), 141.0 (2C), 146.1 (2C)ppm; 31P NMR (160 MHz, THF-d8) δ-0.4 ppm; HRMS (FAB, negative mode)) calcd for C36H19F12O8P2[M-H]- 869.0364, found 869.0379.[Example 3]
Except for using (R) -3,3′-bis [3,5-bis (trifluoromethyl) phenyl] BINOL instead of (R) -3,3′-diphenyl BINOL used in Example 1. In the same manner as in Example 1, a bisphosphate compound (Compound B3) was obtained. The spectrum data is as follows. 1 H NMR (400 MHz, THF-d 8 ) δ7.46-7.61 (m, 6H), 8.02 (s, 2H), 8.07 (d, J = 7.8 Hz, 2H), 8.23 (s, 2H), 8.30 (s, 4H) ppm; 13 C NMR (100 MHz, THF-d 8 ) δ121.2 (2C), 124.1 (d, J = 270.8 Hz, 4C), 125.3 (2C), 126.0 (2C), 126.4 ( 2C), 127.9 (2C), 128.7 (2C), 131.1 (4C), 131.2 (d, J = 32.4 Hz, 4C), 131.9 (2C), 132.1 (2C), 132.8 (2C), 133.4 (2C), 141.0 (2C), 146.1 (2C) ppm; 31 P NMR (160 MHz, THF-d 8 ) δ-0.4 ppm; HRMS (FAB, negative mode)) calcd for C 36 H 19 F 12 O 8 P 2 (MH ] - 869.0364, found 869.0379.

［追加実施例］
更に、下記のビスリン酸エステル化合物Ｂ４〜Ｂ１２も合成した。このうち、化合物Ｂ４〜Ｂ１０は、実施例１で用いた（Ｒ）−３，３’−ジフェニルＢＩＮＯＬの代わりに、化合物Ｂ４〜Ｂ１０に対応するＢＩＮＯＬを用いた以外は、実施例１と同様にして合成した。化合物Ｂ１１，Ｂ１２は、下記式に示す別法にしたがって合成した。[Additional Examples]
Furthermore, the following bisphosphate ester compounds B4 to B12 were also synthesized. Of these, compounds B4 to B10 were the same as Example 1 except that BINOL corresponding to compounds B4 to B10 was used instead of (R) -3,3′-diphenylBINOL used in Example 1. And synthesized. Compounds B11 and B12 were synthesized according to another method shown in the following formula.

化合物Ｂ１１，Ｂ１２の合成手順を以下に説明する。１段階目の反応は、実施例１に準じて行った。但し、ここでは３，３’位の置換基が嵩高いため、リン酸基は１つしか導入されなかった。２段階目以降の反応は以下のようにして行った。１段階目の反応生成物のＴＨＦ溶液に対して、トリエチルアミン（４当量）を加え、０℃まで冷却し、三塩化リン（１．２当量）を加えた後、室温まで昇温し、１０分間撹拌した。この混合溶液を再び０℃まで冷却しアリルアルコール（４当量）を加え、室温まで昇温し、３０分間撹拌した。水を加えて反応を停止し、酢酸エチルで通常の分液操作を行い、有機層を減圧留去して得られた粗生成物に対して、ジクロロメタンを加えた。この溶液にＴＢＨＰ（２当量）のノナン溶液を０℃で加え、室温まで昇温し、３０分間撹拌した。チオ硫酸ナトリウムを加えて反応を停止し、酢酸エチルで通常の分液操作を行った。フラッシュカラムクロマトグラフィ−（ヘキサン：酢酸エチル＝５：１〜３：１）で生成し、目的のビスリン酸エステル化合物Ｂ１１，Ｂ１２を表記の収率で得た。   The synthesis procedure of compounds B11 and B12 will be described below. The first stage reaction was carried out according to Example 1. However, since the substituent at the 3,3′-position is bulky, only one phosphate group was introduced. The reaction after the second stage was performed as follows. To the THF solution of the first stage reaction product, triethylamine (4 equivalents) is added, cooled to 0 ° C., phosphorus trichloride (1.2 equivalents) is added, and then the temperature is raised to room temperature for 10 minutes. Stir. The mixed solution was cooled again to 0 ° C., allyl alcohol (4 equivalents) was added, the temperature was raised to room temperature, and the mixture was stirred for 30 minutes. Water was added to stop the reaction, normal separation operation was performed with ethyl acetate, and dichloromethane was added to the crude product obtained by distilling off the organic layer under reduced pressure. To this solution, a nonane solution of TBHP (2 equivalents) was added at 0 ° C., the temperature was raised to room temperature, and the mixture was stirred for 30 minutes. Sodium thiosulfate was added to stop the reaction, and a normal liquid separation operation was performed with ethyl acetate. The product was produced by flash column chromatography (hexane: ethyl acetate = 5: 1 to 3: 1), and the desired bisphosphate compounds B11 and B12 were obtained in the indicated yield.

化合物Ｂ４〜Ｂ１２のスペクトルデータは、以下のとおり。   The spectrum data of compounds B4 to B12 are as follows.

化合物Ｂ４：1H NMR(400 MHz, THF-d8) δ 7.42-7.51 (m, 8H), 7.62 (d, J = 5.2 Hz, 2H), 7.86-7.94(m, 8H), 8.01 (d, J = 5.2 Hz, 2H), 8.15 (s, 2H), 8.23 (s, 2H) ppm; 13C NMR (100 MHz, THF-d8) δ 126.1 (2C), 126.2 (2C), 126.3 (4C), 126.7 (2C), 127.3 (2C), 127.8 (2C), 128.2 (2C), 128.9 (2C), 129.1 (2C), 129.3 (2C), 129.9 (2C), 132.3 (2C), 132.6 (2C), 133.5 (2C), 133.7 (2C), 134.5 (2C), 136.5 (2C), 137.2 (2C) , 147.6 (2C) ppm; 31P NMR (160 MHz, THF-d8) δ -0.4 ppm.Compound B4: 1 H NMR (400 MHz, THF-d 8 ) δ 7.42-7.51 (m, 8H), 7.62 (d, J = 5.2 Hz, 2H), 7.86-7.94 (m, 8H), 8.01 (d, J = 5.2 Hz, 2H), 8.15 (s, 2H), 8.23 (s, 2H) ppm; 13 C NMR (100 MHz, THF-d 8 ) δ 126.1 (2C), 126.2 (2C), 126.3 (4C) , 126.7 (2C), 127.3 (2C), 127.8 (2C), 128.2 (2C), 128.9 (2C), 129.1 (2C), 129.3 (2C), 129.9 (2C), 132.3 (2C), 132.6 (2C) , 133.5 (2C), 133.7 (2C), 134.5 (2C), 136.5 (2C), 137.2 (2C), 147.6 (2C) ppm; 31 P NMR (160 MHz, THF-d 8 ) δ -0.4 ppm.

化合物Ｂ５：1H NMR (400 MHz, THF-d8) δ 7.32 (t, J = 7.3, 4H), 7.38-7.49 (m, 12H), 7.56 (d, J = 8.2, 2H), 7.81 (d, J = 6.9 Hz, 8H), 7.87 (s, 2H), 8.01-8.03 (m, 6H), 8.23 (s, 2H) ppm; 13C NMR (100 MHz, THF-d8) δ 125.7 (2C), 126.1 (2C), 126.5 (2C), 126.7 (2C), 127.6 (2C), 128.0 (4C), 128.2 (8C), 129.0 (4C), 129.1 (2C), 129.5 (8C), 132.5 (2C), 132.7 (2C), 133.6 (2C), 136.4 (2C), 140.4 (2C), 142.3 (4C), 142.4 (4C), 147.4 (2C) ppm; 31P NMR (160 MHz, THF-d8) δ 0.02 ppm.Compound B5: 1 H NMR (400 MHz, THF-d 8 ) δ 7.32 (t, J = 7.3, 4H), 7.38-7.49 (m, 12H), 7.56 (d, J = 8.2, 2H), 7.81 (d , J = 6.9 Hz, 8H), 7.87 (s, 2H), 8.01-8.03 (m, 6H), 8.23 (s, 2H) ppm; 13 C NMR (100 MHz, THF-d 8 ) δ 125.7 (2C) , 126.1 (2C), 126.5 (2C), 126.7 (2C), 127.6 (2C), 128.0 (4C), 128.2 (8C), 129.0 (4C), 129.1 (2C), 129.5 (8C), 132.5 (2C) , 132.7 (2C), 133.6 (2C), 136.4 (2C), 140.4 (2C), 142.3 (4C), 142.4 (4C), 147.4 (2C) ppm; 31 P NMR (160 MHz, THF-d 8 ) δ 0.02 ppm.

化合物Ｂ６：1H NMR (400 MHz, THF-d8) δ 7.48-7.51 (m, 14H), 7.62 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 7.3 Hz, 4H), 8.00-8.06 (m, 12H), 8.19 (s, 2H), 8.21 (s, 4H), 8.31 (s, 2H), 8.36 (s, 4H) ppm; 13C NMR (100 MHz, THF-d8) δ 126.0 (2C), 126.1 (2C), 126.4 (8C), 126.6 (4C), 126.8 (4C), 127.5 (2C), 128.2 (4C), 128.9 (6C), 129.0 (6C), 129.2 (4C), 132.4 (2C), 132.6 (2C), 133.5 (2C), 133.7 (4C), 134.8 (4C), 136.2 (2C), 139.5 (4C), 140.4 (2C), 142.1 (4C), 147.3 (2C) ppm; 31P NMR (160 MHz, THF-d8) δ 0.2 ppm.Compound B6: 1 H NMR (400 MHz, THF-d 8 ) δ 7.48-7.51 (m, 14H), 7.62 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 7.3 Hz, 4H), 8.00 -8.06 (m, 12H), 8.19 (s, 2H), 8.21 (s, 4H), 8.31 (s, 2H), 8.36 (s, 4H) ppm; 13 C NMR (100 MHz, THF-d 8 ) δ 126.0 (2C), 126.1 (2C), 126.4 (8C), 126.6 (4C), 126.8 (4C), 127.5 (2C), 128.2 (4C), 128.9 (6C), 129.0 (6C), 129.2 (4C), 132.4 (2C), 132.6 (2C), 133.5 (2C), 133.7 (4C), 134.8 (4C), 136.2 (2C), 139.5 (4C), 140.4 (2C), 142.1 (4C), 147.3 (2C) ppm ; 31 P NMR (160 MHz, THF-d 8 ) δ 0.2 ppm.

化合物Ｂ７：1H NMR (400 MHz, THF-d8) δ 2.37 (s, 24H), 6.99 (s, 4H), 7.38-7.48 (m, 12H), 7.57 (d, J = 5.4 Hz, 2H), 7.78 (s, 2H), 7.94 (s, 4H), 8.01 (d, J = 5.2 Hz, 2H), 8.18 (s, 2H) ppm; 13C NMR (100 MHz, THF-d8) δ 21.4 (8C), 125.6 (2C), 126.0 (10C), 126.3 (2C), 126.6 (2C), 127.3 (2C), 128.7 (4C), 128.9 (2C), 129.4 (4C), 132.3 (2C), 132.6 (2C), 133.5 (2C), 136.6 (2C), 138.6 (8C), 140.2 (2C), 142.3 (4C), 142.4 (4C), 147.4 (2C) ppm; 31P NMR (160 MHz, THF-d8) δ -0.5 ppm.Compound B7: 1 H NMR (400 MHz, THF-d 8 ) δ 2.37 (s, 24H), 6.99 (s, 4H), 7.38-7.48 (m, 12H), 7.57 (d, J = 5.4 Hz, 2H) , 7.78 (s, 2H), 7.94 (s, 4H), 8.01 (d, J = 5.2 Hz, 2H), 8.18 (s, 2H) ppm; 13 C NMR (100 MHz, THF-d 8 ) δ 21.4 ( 8C), 125.6 (2C), 126.0 (10C), 126.3 (2C), 126.6 (2C), 127.3 (2C), 128.7 (4C), 128.9 (2C), 129.4 (4C), 132.3 (2C), 132.6 ( 2C), 133.5 (2C), 136.6 (2C), 138.6 (8C), 140.2 (2C), 142.3 (4C), 142.4 (4C), 147.4 (2C) ppm; 31 P NMR (160 MHz, THF-d 8 ) δ -0.5 ppm.

化合物Ｂ８：1H NMR (400 MHz, THF-d8) δ 7.20 (t, J = 5.4 Hz, 8H), 7.40 (t, J = 4.7 Hz, 2H), 7.48 (t, J = 4.3 Hz, 2H), 7.55 (d, J = 5.2 Hz, 2H), 7.82- 7.85 (m, 10H), 7.99 (s, 4H), 8.02 (d, J = 5.2 Hz, 2H), 8.23 (s, 2H) ppm; 13C NMR (100 MHz, THF-d8) δ 116.1 (d, 8C), 125.3 (2C), 126.0 (2C), 126.5 (d, 4C), 127.5 (2C), 128.8 (4C), 128.9 (2C), 129.9 (d, 8C), 132.3 (2C), 132.6 (2C), 133.5 (2C), 136.5 (2C), 138.5 (4C), 140.4 (2C), 141.1 (4C), 147.3 (2C), 162.2 (2C), 164.7 (2C) ppm; 31P NMR (160 MHz, THF-d8) δ 0.3 ppm.Compound B8: 1 H NMR (400 MHz, THF-d 8 ) δ 7.20 (t, J = 5.4 Hz, 8H), 7.40 (t, J = 4.7 Hz, 2H), 7.48 (t, J = 4.3 Hz, 2H ), 7.55 (d, J = 5.2 Hz, 2H), 7.82-7.85 (m, 10H), 7.99 (s, 4H), 8.02 (d, J = 5.2 Hz, 2H), 8.23 (s, 2H) ppm; 13 C NMR (100 MHz, THF-d 8 ) δ 116.1 (d, 8C), 125.3 (2C), 126.0 (2C), 126.5 (d, 4C), 127.5 (2C), 128.8 (4C), 128.9 (2C ), 129.9 (d, 8C), 132.3 (2C), 132.6 (2C), 133.5 (2C), 136.5 (2C), 138.5 (4C), 140.4 (2C), 141.1 (4C), 147.3 (2C), 162.2 (2C), 164.7 (2C) ppm; 31 P NMR (160 MHz, THF-d 8 ) δ 0.3 ppm.

化合物Ｂ９：1H NMR (400 MHz, THF-d8) δ 7.42 (t, J = 5.2 Hz, 2H), 7.52 (t, J = 4.6 Hz, 2H), 7.60 (d, J = 5.2 Hz, 2H), 8.05 (d, J = 5.2 Hz, 2H), 8.06 (s, 4H), 8.12 (s, 2H), 8.20 (s, 4H), 8.32 (s, 2H), 8.46 (s, 8H) ppm; 31P NMR (160 MHz, THF-d8) δ -0.7 ppm.Compound B9: 1 H NMR (400 MHz, THF-d 8 ) δ 7.42 (t, J = 5.2 Hz, 2H), 7.52 (t, J = 4.6 Hz, 2H), 7.60 (d, J = 5.2 Hz, 2H ), 8.05 (d, J = 5.2 Hz, 2H), 8.06 (s, 4H), 8.12 (s, 2H), 8.20 (s, 4H), 8.32 (s, 2H), 8.46 (s, 8H) ppm; 31 P NMR (160 MHz, THF-d 8 ) δ -0.7 ppm.

化合物Ｂ１０：1H NMR (400 MHz, THF-d8) δ 7.31 (t, J = 4.0 Hz, 2H), 7.40-7.45 (m, 6H), 7.49 (t, J = 4.3 Hz, 2H), 7.58 (d, J = 5.2 Hz, 2H), 7.70-7.73 (m, 8H), 7.82 (d, J = 5.2 Hz, 4H), 8.00 (d, J = 5.2 Hz, 2H), 8.10 (s, 2H) ppm; 13C NMR (100 MHz, THF-d8) δ 125.9 (2C), 126.3 (2C), 126.6 (2C), 127.0 (4C), 127.3 (2C), 127.6 (4C), 127.9 (2C), 128.9 (2C), 129.4 (4C), 131.4 (4C), 132.0 (2C), 132.6 (2C), 133.3 (2C), 136.2 (2C), 138.5 (2C), 140.6 (2C), 141.7 (2C), 147.2 (2C) ppm; 31P NMR (160 MHz, THF-d8) δ 0.1 ppm.Compound B10: 1 H NMR (400 MHz, THF-d 8 ) δ 7.31 (t, J = 4.0 Hz, 2H), 7.40-7.45 (m, 6H), 7.49 (t, J = 4.3 Hz, 2H), 7.58 (d, J = 5.2 Hz, 2H), 7.70-7.73 (m, 8H), 7.82 (d, J = 5.2 Hz, 4H), 8.00 (d, J = 5.2 Hz, 2H), 8.10 (s, 2H) ppm; 13 C NMR (100 MHz, THF-d 8 ) δ 125.9 (2C), 126.3 (2C), 126.6 (2C), 127.0 (4C), 127.3 (2C), 127.6 (4C), 127.9 (2C), 128.9 (2C), 129.4 (4C), 131.4 (4C), 132.0 (2C), 132.6 (2C), 133.3 (2C), 136.2 (2C), 138.5 (2C), 140.6 (2C), 141.7 (2C), 147.2 (2C) ppm; 31 P NMR (160 MHz, THF-d 8 ) δ 0.1 ppm.

化合物Ｂ１１：1H NMR (400 MHz, THF-d8) δ 7.34-7.46 (m, 22H), 7.55 (d, J = 5.0 Hz, 2H), 7.59-7.63 (m, 16H), 7.72 (d, J = 4.9 Hz, 4H), 7.96 (d, J = 5.2 Hz, 2H), 8.04 (s, 2H) ppm; 13C NMR (100 MHz, THF-d8) δ 125.7 (2C), 126.2 (2C), 126.6 (2C), 127.3 (2C), 128.6 (12C), 128.9 (2C), 130.2 (6C), 130.5 (4C), 131.7 (2C), 132.5 (2C), 133.4 (4C), 135.3 (6C), 136.6 (2C), 136.6 (4C), 137.2 (12C), 140.7 (2C), 147.3 (2C) ppm; 31P NMR (160 MHz, THF-d8) δ -0.6 ppm.Compound B11: 1 H NMR (400 MHz, THF-d 8 ) δ 7.34-7.46 (m, 22H), 7.55 (d, J = 5.0 Hz, 2H), 7.59-7.63 (m, 16H), 7.72 (d, J = 4.9 Hz, 4H), 7.96 (d, J = 5.2 Hz, 2H), 8.04 (s, 2H) ppm; 13 C NMR (100 MHz, THF-d 8 ) δ 125.7 (2C), 126.2 (2C) , 126.6 (2C), 127.3 (2C), 128.6 (12C), 128.9 (2C), 130.2 (6C), 130.5 (4C), 131.7 (2C), 132.5 (2C), 133.4 (4C), 135.3 (6C) , 136.6 (2C), 136.6 (4C), 137.2 (12C), 140.7 (2C), 147.3 (2C) ppm; 31 P NMR (160 MHz, THF-d 8 ) δ -0.6 ppm.

化合物Ｂ１２：1H NMR (400 MHz, THF-d8) δ 1.65-1.89 (m, 6H), 2.11-2.16 (m, 2H), 2.75-2.96 (m, 8H), 7.26 (s, 2H), 7.31 (t, J = 4.3 Hz, 4H), 7.43 (t, J = 4.3 Hz, 8H), 7.76-7.81 (m, 14H) ppm; 13C NMR (100 MHz, THF-d8) δ 23.8, (2C), 24.1 (2C), 28.1 (2C), 30.4 (2C), 125.2 (2C), 127.9 (4C), 128.1 (8C), 128.8 (4C), 129.4 (8C), 130.8 (2C), 132.7 (2C), 133.9 (2C), 135.1 (2C), 137.1 (2C), 140.9 (2C), 142.0 (4C), 142.5 (4C), 146.2 (2C) ppm; 31P NMR (160 MHz, THF-d8) δ 0.3 ppm.Compound B12: 1 H NMR (400 MHz, THF-d 8 ) δ 1.65-1.89 (m, 6H), 2.11-2.16 (m, 2H), 2.75-2.96 (m, 8H), 7.26 (s, 2H), 7.31 (t, J = 4.3 Hz, 4H), 7.43 (t, J = 4.3 Hz, 8H), 7.76-7.81 (m, 14H) ppm; 13 C NMR (100 MHz, THF-d 8 ) δ 23.8, ( 2C), 24.1 (2C), 28.1 (2C), 30.4 (2C), 125.2 (2C), 127.9 (4C), 128.1 (8C), 128.8 (4C), 129.4 (8C), 130.8 (2C), 132.7 ( 2C), 133.9 (2C), 135.1 (2C), 137.1 (2C), 140.9 (2C), 142.0 (4C), 142.5 (4C), 146.2 (2C) ppm; 31 P NMR (160 MHz, THF-d 8 ) δ 0.3 ppm.

２．ピロリン酸エステル化合物の合成
ピロリン酸エステル化合物を下記のスキーム２にしたがって合成した。以下の実施例４〜６にその詳細を示す。2. Synthesis of Pyrophosphate Compound A pyrophosphate compound was synthesized according to Scheme 2 below. The details are shown in Examples 4 to 6 below.

［実施例４］
ＢＩＮＯＬビスリン酸エステル（化合物Ｂ１，６２ｍｇ，０．１０ｍｍｏｌ）およびＤＭＦ（０．０１０ｍＬ）のジクロロメタン（１．０ｍＬ）溶液に塩化オキサリル（０．０３０ｍＬ，０．３５ｍｍｏｌ）を室温にて加えた後、速やかに４０℃に昇温して３０分間撹拌した。反応混合物を減圧濃縮することにより、目的とするＢＩＮＯＬピロリン酸エステル（化合物Ａ１，５．９ｍｇ，１００％）を得た。このピロリン酸エステルの構造は、ＮＭＲスペクトルおよびマススペクトルを測定することにより確定した。スペクトルデータは以下のとおり。1H NMR (400 MHz, CDCl3) δ7.02-7.20 (m, 8H), 7.30-7.40 (m, 6H), 7.52 (t, J = 7.8 Hz, 2H), 7.94-8.02 (m, 2H), 7.98 (s, 2H)ppm; 13C NMR (100 MHz, CDCl3) δ125.0 (2C), 125.3 (2C), 126.4 (2C), 127.2 (2C), 128.1 (4C), 128.3 (2C), 129.6 (2C), 131.6 (2C), 131.7 (2C), 132.8 (2C), 137.8 (2C), 144.8 (2C), 164.2(2C)ppm; 31P NMR (160 MHz, CDCl3) δ-21.2 ppm; HRMS (FAB, negative mode) calcd for C32H21O7P2[M-H]- 579.0763, found 579.0772.[Example 4]
After adding oxalyl chloride (0.030 mL, 0.35 mmol) to a solution of BINOL bisphosphate (Compound B 1,62 mg, 0.10 mmol) and DMF (0.010 mL) in dichloromethane (1.0 mL) at room temperature, The mixture was heated to 40 ° C. and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the desired BINOL pyrophosphate ester (Compound A1, 5.9 mg, 100%). The structure of this pyrophosphate ester was determined by measuring NMR spectrum and mass spectrum. The spectrum data is as follows. 1 H NMR (400 MHz, CDCl 3 ) δ7.02-7.20 (m, 8H), 7.30-7.40 (m, 6H), 7.52 (t, J = 7.8 Hz, 2H), 7.94-8.02 (m, 2H) , 7.98 (s, 2H) ppm; 13 C NMR (100 MHz, CDCl 3 ) δ125.0 (2C), 125.3 (2C), 126.4 (2C), 127.2 (2C), 128.1 (4C), 128.3 (2C) , 129.6 (2C), 131.6 (2C), 131.7 (2C), 132.8 (2C), 137.8 (2C), 144.8 (2C), 164.2 (2C) ppm; 31 P NMR (160 MHz, CDCl 3 ) δ-21.2 ppm; HRMS (FAB, negative mode ) calcd for C 32 H 21 O 7 P 2 [MH] - 579.0763, found 579.0772.

［実施例５］
実施例４で用いた化合物Ｂ１の代わりに、化合物Ｂ２を用いた以外は、実施例４と同様にしてピロリン酸エステル化合物（化合物Ａ２）を得た。そのスペクトルデータは、以下のとおり。1H NMR (400 MHz, CDCl3) δ 2.02 (s, 12H), 2.32 (s, 6H), 6.93 (s, 4H), 7.10 (d, J = 8.5 Hz, 4H), 7.15 (d, J = 8.7 Hz, 2H), 7.36 (dd, J = 8.2, 8.3 Hz, 2H), 7.50-7.63 (m, 6H), 8.06 (d, J = 8.2 Hz, 2H), 8.15 (s, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 20.8 (4C), 21.1 (2C), 125.2 (4C), 126.6 (2C), 127.3 (2C), 128.1 (4C), 128.3 (2C), 129.2 (4C), 129.5 (4C), 131.4 (2C), 131.7 (2C), 132.8 (2C), 134.4 (2C), 135.9 (6C), 136.5 (2C), 138.8 (2C), 140.1 (2C), 145.1 (2C) ppm; 31P NMR(160 MHz, CDCl3) δ -21.7 ppm; HRMS (FAB, negative mode) calcd for C50H41O7P2[M-H]- 815.2328, found 815.2347.[Example 5]
A pyrophosphate ester compound (Compound A2) was obtained in the same manner as in Example 4 except that Compound B2 was used instead of Compound B1 used in Example 4. The spectrum data is as follows. 1 H NMR (400 MHz, CDCl 3 ) δ 2.02 (s, 12H), 2.32 (s, 6H), 6.93 (s, 4H), 7.10 (d, J = 8.5 Hz, 4H), 7.15 (d, J = 8.7 Hz, 2H), 7.36 (dd, J = 8.2, 8.3 Hz, 2H), 7.50-7.63 (m, 6H), 8.06 (d, J = 8.2 Hz, 2H), 8.15 (s, 2H) ppm; 13 C NMR (100 MHz, CDCl 3 ) δ 20.8 (4C), 21.1 (2C), 125.2 (4C), 126.6 (2C), 127.3 (2C), 128.1 (4C), 128.3 (2C), 129.2 (4C), 129.5 (4C), 131.4 (2C), 131.7 (2C), 132.8 (2C), 134.4 (2C), 135.9 (6C), 136.5 (2C), 138.8 (2C), 140.1 (2C), 145.1 (2C) ppm ; 31 P NMR (160 MHz, CDCl 3) δ -21.7 ppm; HRMS (FAB, negative mode) calcd for C 50 H 41 O 7 P 2 [MH] - 815.2328, found 815.2347.

［実施例６］
実施例４で用いた化合物Ｂ１の代わりに、化合物Ｂ３を用いた以外は、実施例４と同様にしてピロリン酸エステル化合物（化合物Ａ３）を得た。そのスペクトルデータは、以下のとおり。1H NMR (400 MHz, CDCl3) δ 7.08 (d, J = 7.8 Hz, 2H), 7.40 (t, J = 7.8 Hz, 2H), 7.55 (t, J = 7.8 Hz, 2H), 7.77 (s, 2H), 7.92-8.14 (m, 8H) ppm; 13C NMR (100 MHz, CDCl3) δ121.1 (2C), 123.5 (d, J = 270.8 Hz, 4C), 125.4 (2C), 126.9 (2C), 128.3 (2C), 128.6 (2C), 129.8 (4C), 131.39 (d, J = 33.4 Hz, 4C), 131.42 (2C), 131.5 (2C), 132.1 (2C), 133.5 (2C), 140.3 (2C), 144.3 (2C), 165.4 (2C)ppm; 31PNMR (160 MHz, CDCl3) δ-21.1 ppm; HRMS (FAB, negative mode) calcd for C36H17F12O7P2[M-H]- 851.0258, found 851.0251.[Example 6]
A pyrophosphate ester compound (Compound A3) was obtained in the same manner as in Example 4 except that Compound B3 was used instead of Compound B1 used in Example 4. The spectrum data is as follows. 1 H NMR (400 MHz, CDCl 3 ) δ 7.08 (d, J = 7.8 Hz, 2H), 7.40 (t, J = 7.8 Hz, 2H), 7.55 (t, J = 7.8 Hz, 2H), 7.77 (s , 2H), 7.92-8.14 (m, 8H) ppm; 13 C NMR (100 MHz, CDCl 3 ) δ121.1 (2C), 123.5 (d, J = 270.8 Hz, 4C), 125.4 (2C), 126.9 ( 2C), 128.3 (2C), 128.6 (2C), 129.8 (4C), 131.39 (d, J = 33.4 Hz, 4C), 131.42 (2C), 131.5 (2C), 132.1 (2C), 133.5 (2C), 140.3 (2C), 144.3 (2C), 165.4 (2C) ppm; 31 PNMR (160 MHz, CDCl 3 ) δ-21.1 ppm; HRMS (FAB, negative mode) calcd for C 36 H 17 F 12 O 7 P 2 [ MH] - 851.0258, found 851.0251.

［追加実施例］
更に、下記のピロリン酸エステル化合物Ａ４〜Ａ１２も合成した。化合物Ａ４〜Ａ１２は、実施例４で用いた化合物Ｂ１の代わりに化合物Ｂ４〜Ｂ１２を用いた以外は、実施例４と同様にして合成した。[Additional Examples]
Furthermore, the following pyrophosphate ester compounds A4 to A12 were also synthesized. Compounds A4 to A12 were synthesized in the same manner as in Example 4 except that compounds B4 to B12 were used instead of compound B1 used in Example 4.

化合物Ａ４〜Ａ１２のスペクトルデータは、以下のとおり。   The spectrum data of the compounds A4 to A12 are as follows.

化合物Ａ４：1H NMR (400 MHz, THF-d8) δ 7.12 (d, J = 5.4 Hz, 2H), 7.31 (t, J = 4.9 Hz, 2H), 7.39-7.49 (m, 6H),7.71-7.81 (m, 6H), 7.90 (s, 4H), 8.02-8.06 (m, 4H), 8.15 (s, 2H) ppm; 31P NMR (160 MHz, THF-d8) δ -19.5 ppm.Compound A4: 1 H NMR (400 MHz, THF-d 8 ) δ 7.12 (d, J = 5.4 Hz, 2H), 7.31 (t, J = 4.9 Hz, 2H), 7.39-7.49 (m, 6H), 7.71 -7.81 (m, 6H), 7.90 (s, 4H), 8.02-8.06 (m, 4H), 8.15 (s, 2H) ppm; 31 P NMR (160 MHz, THF-d 8 ) δ -19.5 ppm.

化合物Ａ５：1H NMR (400 MHz, THF-d8) δ 7.12 (d, J = 8.3 Hz, 2H), 7.29-7.32 (m, 4H), 7.39-7.48 (m, 12H), 7.79 (d, J = 7.4 Hz, 8H), 7.85 (s, 2H), 7.99 (s, 4H), 8.04 (d, J = 8.2 Hz, 2H), 8.30 (s, 2H) ppm; 13C NMR (100 MHz, THF-d8) δ 125.4 (2C), 125.9 (2C), 126.1 (2C), 126.6 (2C), 127.7 (2C), 127.8 (4C), 128.0 (8C), 128.2 (4C), 128.9 (2C), 129.3 (8C), 132.2 (2C), 132.5 (2C), 134.0 (2C), 135.2 (2C), 140.3 (2C), 142.1 (4C), 142.3 (4C), 146.4 (2C) ppm; 31P NMR (160 MHz, THF-d8) δ -20.1 ppm.Compound A5: 1 H NMR (400 MHz, THF-d 8 ) δ 7.12 (d, J = 8.3 Hz, 2H), 7.29-7.32 (m, 4H), 7.39-7.48 (m, 12H), 7.79 (d, J = 7.4 Hz, 8H), 7.85 (s, 2H), 7.99 (s, 4H), 8.04 (d, J = 8.2 Hz, 2H), 8.30 (s, 2H) ppm; 13 C NMR (100 MHz, THF -d 8 ) δ 125.4 (2C), 125.9 (2C), 126.1 (2C), 126.6 (2C), 127.7 (2C), 127.8 (4C), 128.0 (8C), 128.2 (4C), 128.9 (2C), 129.3 (8C), 132.2 (2C), 132.5 (2C), 134.0 (2C), 135.2 (2C), 140.3 (2C), 142.1 (4C), 142.3 (4C), 146.4 (2C) ppm; 31 P NMR ( 160 MHz, THF-d 8 ) δ -20.1 ppm.

化合物Ａ６：1H NMR (400 MHz, THF-d8) δ 7.16 (d, J = 7.8 Hz, 2H), 7.31 (t, J = 7.3 Hz, 2H), 7.46 (br, 12H), 7.85-8.08 (m, 16H), 8.14 (s, 2H), 8.20 (s, 4H), 8.36 (s, 4H), 8.39 (s, 2H) ppm; 13C NMR (100 MHz, THF-d8) δ 125.9 (2C), 126.2 (2C), 126.5 (4C), 126.6 (4C), 126.7 (8C), 127.8 (2C), 128.2 (4C), 128.6 (4C), 129.0 (12C), 132.4 (2C), 132.6 (2C), 133.6 (4C), 134.1(2C), 134.7 (4C), 135.2 (2C), 139.4 (4C), 140.6 (2C), 142.2 (4C), 146.6 (2C) ppm; 31P NMR (160 MHz, THF-d8) δ -20.1 ppm.Compound A6: 1 H NMR (400 MHz, THF-d 8 ) δ 7.16 (d, J = 7.8 Hz, 2H), 7.31 (t, J = 7.3 Hz, 2H), 7.46 (br, 12H), 7.85-8.08 (m, 16H), 8.14 (s, 2H), 8.20 (s, 4H), 8.36 (s, 4H), 8.39 (s, 2H) ppm; 13 C NMR (100 MHz, THF-d 8 ) δ 125.9 ( 2C), 126.2 (2C), 126.5 (4C), 126.6 (4C), 126.7 (8C), 127.8 (2C), 128.2 (4C), 128.6 (4C), 129.0 (12C), 132.4 (2C), 132.6 ( 2C), 133.6 (4C), 134.1 (2C), 134.7 (4C), 135.2 (2C), 139.4 (4C), 140.6 (2C), 142.2 (4C), 146.6 (2C) ppm; 31 P NMR (160 MHz , THF-d 8 ) δ -20.1 ppm.

化合物Ａ７：1H NMR (400 MHz, THF-d8) δ 2.35 (s, 24H), 6.97 (s, 4H), 7.09 (d, J = 5.2 Hz, 2H), 7.30 (t, J = 4.6 Hz, 2H), 7.40 (s, 8H), 7.46 (t, J = 4.6 Hz, 2H), 7.77 (s, 2H), 7.94 (s, 4H), 8.03 (d, J = 4.9 Hz, 2H), 8.29 (s, 2H) ppm; 13C NMR (100 MHz, THF-d8) δ 21.4 (8C), 126.0 (10C), 126.3 (2C), 126.6 (2C), 127.7 (2C), 128.0 (4C), 128.9 (4C), 129.4 (4C), 132.3 (2C), 132.6 (2C), 134.1 (2C), 135.6 (2C), 138.6 (8C), 140.3 (2C), 142.3 (4C), 142.6 (4C), 146.4 (2C) ppm; 31P NMR (160 MHz, THF-d8) δ -20.3 ppm.Compound A7: 1 H NMR (400 MHz, THF-d 8 ) δ 2.35 (s, 24H), 6.97 (s, 4H), 7.09 (d, J = 5.2 Hz, 2H), 7.30 (t, J = 4.6 Hz , 2H), 7.40 (s, 8H), 7.46 (t, J = 4.6 Hz, 2H), 7.77 (s, 2H), 7.94 (s, 4H), 8.03 (d, J = 4.9 Hz, 2H), 8.29 (s, 2H) ppm; 13 C NMR (100 MHz, THF-d 8 ) δ 21.4 (8C), 126.0 (10C), 126.3 (2C), 126.6 (2C), 127.7 (2C), 128.0 (4C), 128.9 (4C), 129.4 (4C), 132.3 (2C), 132.6 (2C), 134.1 (2C), 135.6 (2C), 138.6 (8C), 140.3 (2C), 142.3 (4C), 142.6 (4C), 146.4 (2C) ppm; 31 P NMR (160 MHz, THF-d 8 ) δ -20.3 ppm.

化合物Ａ８：1H NMR (400 MHz, THF-d8) δ 7.11 (d, J = 5.2 Hz, 2H), 7.14-7.19 (m, 8H), 7.31 (t, J = 5.2 Hz, 2H), 7.48 (t, J = 4.9 Hz, 2H), 7.80-7.83 (m, 8H), 7.90 (s, 2H), 7.95 (s, 4H), 8.03 (d, J = 4.9 Hz, 2H), 8.30 (s, 2H) ppm; 13C NMR (100 MHz, THF-d8) δ 116.1 (d, 8C), 125.3 (2C), 125.9 (2C), 126.7 (2C), 127.9 (2C), 128.1 (6C), 128.8 (2C), 129.0 (4C), 129.9 (d, 8C), 132.3 (2C), 132.6 (2C), 134.1 (2C), 135.1 (2C), 138.4 (d, 4C), 140.5 (2C), 141.4 (4C), 146.3 (2C) ppm; 31P NMR (160 MHz, THF-d8) δ -20.1 ppm.Compound A8: 1 H NMR (400 MHz, THF-d 8 ) δ 7.11 (d, J = 5.2 Hz, 2H), 7.14-7.19 (m, 8H), 7.31 (t, J = 5.2 Hz, 2H), 7.48 (t, J = 4.9 Hz, 2H), 7.80-7.83 (m, 8H), 7.90 (s, 2H), 7.95 (s, 4H), 8.03 (d, J = 4.9 Hz, 2H), 8.30 (s, 2H) ppm; 13 C NMR (100 MHz, THF-d 8 ) δ 116.1 (d, 8C), 125.3 (2C), 125.9 (2C), 126.7 (2C), 127.9 (2C), 128.1 (6C), 128.8 (2C), 129.0 (4C), 129.9 (d, 8C), 132.3 (2C), 132.6 (2C), 134.1 (2C), 135.1 (2C), 138.4 (d, 4C), 140.5 (2C), 141.4 ( 4C), 146.3 (2C) ppm; 31 P NMR (160 MHz, THF-d 8 ) δ -20.1 ppm.

化合物Ａ９：1H NMR (400 MHz, THF-d8) δ 7.13 (d, J = 5.5 Hz, 2H), 7.34 (t, J = 4.9 Hz, 2H), 7.52 (t, J = 4.6 Hz, 2H), 8.06 (s, 6H), 8.09 (d, J = 6.6 Hz, 2H), 8.19 (s, 4H), 8.40 (s, 2H), 8.49 (s, 8H) ppm; 31P NMR (160 MHz, THF-d8) δ -20.0 ppm.Compound A9: 1 H NMR (400 MHz, THF-d 8 ) δ 7.13 (d, J = 5.5 Hz, 2H), 7.34 (t, J = 4.9 Hz, 2H), 7.52 (t, J = 4.6 Hz, 2H ), 8.06 (s, 6H), 8.09 (d, J = 6.6 Hz, 2H), 8.19 (s, 4H), 8.40 (s, 2H), 8.49 (s, 8H) ppm; 31 P NMR (160 MHz, THF-d 8 ) δ -20.0 ppm.

化合物Ａ１０：1H NMR (400 MHz, THF-d8) δ 7.13 (d, J = 5.2 Hz, 2H), 7.29-7.34 (m, 4H), 7.39-7.48 (m, 8H), 7.59-7.72 (m, 10H), 8.03 (d, J = 5.2 Hz, 2H), 8.15 (s, 2H) ppm; 13C NMR (100 MHz, THF-d8) δ 125.8 (2C), 126.7 (2C), 127.1 (4C), 127.5 (4C), 127.7 (2C), 128.8 (2C), 129.0 (2C), 129.4 (4C), 130.8 (4C), 131.4 (2C), 132.0 (2C), 132.6 (2C), 133.9 (2C), 135.3 (2C), 138.4 (2C), 140.2 (2C), 141.6 (2C), 146.2 (2C) ppm; 31P NMR (160 MHz, THF-d8) δ -20.2 ppm.Compound A10: 1 H NMR (400 MHz, THF-d 8 ) δ 7.13 (d, J = 5.2 Hz, 2H), 7.29-7.34 (m, 4H), 7.39-7.48 (m, 8H), 7.59-7.72 ( m, 10H), 8.03 (d, J = 5.2 Hz, 2H), 8.15 (s, 2H) ppm; 13 C NMR (100 MHz, THF-d 8 ) δ 125.8 (2C), 126.7 (2C), 127.1 ( 4C), 127.5 (4C), 127.7 (2C), 128.8 (2C), 129.0 (2C), 129.4 (4C), 130.8 (4C), 131.4 (2C), 132.0 (2C), 132.6 (2C), 133.9 ( 2C), 135.3 (2C), 138.4 (2C), 140.2 (2C), 141.6 (2C), 146.2 (2C) ppm; 31 P NMR (160 MHz, THF-d 8 ) δ -20.2 ppm.

化合物Ａ１１：1H NMR (400 MHz, THF-d8) δ 7.08 (d, J = 5.4 Hz, 2H), 7.21 (t, J = 4.9 Hz, 2H), 7.31-7.38 (m, 20H), 7.54-7.61 (m, 16H), 7.67 (d, J = 4.9 Hz, 4H), 7.97 (d, J = 5.2 Hz, 2H), 8.13 (s, 2H) ppm; 13C NMR (100 MHz, THF-d8) δ 125.7 (2C), 126.1 (2C), 126.8 (2C), 127.7 (2C), 128.6 (12C), 129.0 (2C), 129.9 (4C), 130.2 (6C), 132.2 (2C), 132.6 (2C), 133.3 (2C), 133.8 (2C), 135.2 (6C), 136.8 (4C), 137.1 (12C), 140.6 (2C), 146.1 (2C) ppm; 31P NMR (160 MHz, THF-d8) δ -20.4 ppm.Compound A11: 1 H NMR (400 MHz, THF-d 8 ) δ 7.08 (d, J = 5.4 Hz, 2H), 7.21 (t, J = 4.9 Hz, 2H), 7.31-7.38 (m, 20H), 7.54 -7.61 (m, 16H), 7.67 (d, J = 4.9 Hz, 4H), 7.97 (d, J = 5.2 Hz, 2H), 8.13 (s, 2H) ppm; 13 C NMR (100 MHz, THF-d 8 ) δ 125.7 (2C), 126.1 (2C), 126.8 (2C), 127.7 (2C), 128.6 (12C), 129.0 (2C), 129.9 (4C), 130.2 (6C), 132.2 (2C), 132.6 ( 2C), 133.3 (2C), 133.8 (2C), 135.2 (6C), 136.8 (4C), 137.1 (12C), 140.6 (2C), 146.1 (2C) ppm; 31 P NMR (160 MHz, THF-d 8 ) δ -20.4 ppm.

化合物Ａ１２：1H NMR (400 MHz, THF-d8) δ 2.01-2.07 (m, 4H), 2.46-2.52 (m, 4H), 2.84-2.93 (m, 8H), 7.29-7.35 (m, 6H), 7.42 (t, J = 4.6 Hz, 8H), 7.76-7.81 (m, 14H) ppm; 13C NMR (100 MHz, THF-d8) δ 23.5 (2C), 23.8 (2C), 27.9 (2C), 30.4 (2C), 125.1 (2C), 127.8 (4C), 128.0 (4C), 128.1 (8C), 129.3 (8C), 131.1 (2C), 132.6 (2C), 133.1 (2C), 135.8 (2C), 136.9 (2C), 140.6 (2C), 142.2 (4C), 142.3 (4C), 144.7 (2C) ppm; 31P NMR (160 MHz, THF-d8) δ -20.4 ppm.Compound A12: 1 H NMR (400 MHz, THF-d 8 ) δ 2.01-2.07 (m, 4H), 2.46-2.52 (m, 4H), 2.84-2.93 (m, 8H), 7.29-7.35 (m, 6H ), 7.42 (t, J = 4.6 Hz, 8H), 7.76-7.81 (m, 14H) ppm; 13 C NMR (100 MHz, THF-d 8 ) δ 23.5 (2C), 23.8 (2C), 27.9 (2C ), 30.4 (2C), 125.1 (2C), 127.8 (4C), 128.0 (4C), 128.1 (8C), 129.3 (8C), 131.1 (2C), 132.6 (2C), 133.1 (2C), 135.8 (2C ), 136.9 (2C), 140.6 (2C), 142.2 (4C), 142.3 (4C), 144.7 (2C) ppm; 31 P NMR (160 MHz, THF-d 8 ) δ -20.4 ppm.

３．各種反応例
３−１．分子内エン反応（その１）
シトロネラールの分子内エン反応について、化合物Ａ１〜Ａ３を触媒に用いた場合と、従来公知のリン酸エステル化合物Ｃ（表１の欄外参照）を触媒に用いた場合との活性を比較した。化合物Ａ１を触媒に用いた場合の具体的手順を以下に説明する。3. Various reaction examples 3-1. Intramolecular ene reaction (part 1)
Regarding the intramolecular ene reaction of citronellal, the activity was compared between the case where the compounds A1 to A3 were used as the catalyst and the case where the conventionally known phosphate ester compound C (see the column in Table 1) was used as the catalyst. A specific procedure when Compound A1 is used as a catalyst will be described below.

直前に調製した化合物Ａ１（０．０１ｍｍｏｌ）のジクロロメタン溶液（２ｍＬ）に対して、−７８℃にてシトロネラール（０．０３６ｍＬ，０．２ｍｍｏｌ）を加えて、２４時間撹拌した。反応溶液に対してトリエチルアミン（０．１ｍＬ）を加えて反応を停止した後、減圧下で溶媒を除去した。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（ヘキサン−酢酸エチル＝２０：１）で精製することにより、環化生成物（２５．６ｍｇ，８３％収率）を得た。この環化生成物は既知化合物である。その構造は，ＮＭＲスペクトルを文献記載のデータと比較することにより確認した。   Citronellal (0.036 mL, 0.2 mmol) was added at −78 ° C. to a dichloromethane solution (2 mL) of compound A1 (0.01 mmol) prepared immediately before, and the mixture was stirred for 24 hours. After the reaction was stopped by adding triethylamine (0.1 mL) to the reaction solution, the solvent was removed under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate = 20: 1) to obtain a cyclized product (25.6 mg, 83% yield). This cyclization product is a known compound. The structure was confirmed by comparing the NMR spectrum with the data described in the literature.

同様の分子内エン反応を、化合物Ａ２，Ａ３，Ｃを触媒に用いて行った。それらの結果を表１に示す。なお、表１には反応条件も記載した。表１から、化合物Ａ１〜Ａ３を触媒に用いた場合には、化合物Ｃを触媒に用いた場合に比べて活性がかなり高いことがわかる。   A similar intramolecular ene reaction was carried out using compounds A2, A3 and C as catalysts. The results are shown in Table 1. Table 1 also shows the reaction conditions. From Table 1, it can be seen that when the compounds A1 to A3 are used as the catalyst, the activity is considerably higher than when the compound C is used as the catalyst.

３−２．分子内エン反応（その２）
上記３−１のシトロネラールの代わりに、３，３，７−トリメチル−６−オクテナールを用いた以外は、上記３−１と同様にして分子内エン反応を行った。それらの結果を表２に示す。なお、表２には反応条件も記載した。表２から明らかなように、化合物Ａ１〜Ａ３は優れた触媒活性を示したのに対して、化合物Ｃを触媒に用いた場合には生成物がほとんど得られなかった。また、反応温度を−７８℃としたところ、触媒活性は化合物Ａ２，Ａ３が化合物Ａ１よりも高い触媒活性を示した。このことから、ＢＩＮＯＬの３，３’位に無置換のフェニル基が結合している場合よりも置換基を有するフェニル基が結合している場合の方が高い触媒活性を示すことが示唆された。3-2. Intramolecular ene reaction (part 2)
Intramolecular ene reaction was carried out in the same manner as in 3-1, except that 3,3,7-trimethyl-6-octenal was used in place of the citronellal of 3-1. The results are shown in Table 2. Table 2 also shows the reaction conditions. As is clear from Table 2, compounds A1 to A3 showed excellent catalytic activity, whereas when compound C was used as a catalyst, almost no product was obtained. Further, when the reaction temperature was -78 ° C, the catalytic activities of the compounds A2 and A3 were higher than those of the compound A1. From this, it was suggested that when the phenyl group having a substituent is bonded to the 3,3′-position of BINOL, a higher catalytic activity is exhibited when the phenyl group having a substituent is bonded. .

３−３．マンニッヒ反応
イミンに対するアミドのマンニッヒ反応について、化合物Ａ１，Ｂ１を触媒に用いた場合と、従来公知のリン酸エステル化合物Ｃを触媒に用いた場合との活性を比較した。化合物Ａ１を触媒に用いた場合の具体的手順を以下に説明する。3-3. Mannich Reaction Regarding the Mannich reaction of amides with imines, the activity was compared between the case where compounds A1 and B1 were used as a catalyst and the case where a conventionally known phosphate ester compound C was used as a catalyst. A specific procedure when Compound A1 is used as a catalyst will be described below.

直前に調製した化合物Ａ１（０．０３ｍｍｏｌ）のジクロロメタン溶液（２ｍＬ）にモレキュラーシーブス４Ａ（３２３ｍｇ）を加え、０℃に冷却した。この溶液に、４−クロロベンズアミド（３２ｍｇ，０．２ｍｍｏｌ）およびＮ−（ベンジルオキシカルボニル）ベンズアルジミン（７４ｍｇ，０．３ｍｍｏｌ）を加え、０℃にて３０分間撹拌した。反応溶液に水を加えて反応を停止した後、ジクロロメタンで抽出した。有機層を合わせて飽和食塩水で洗浄し、無水炭酸ナトリウムで乾燥後、減圧濃縮した。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（クロロホルム−酢酸エチル＝５０：１→３０：１）で精製することにより、目的とする付加体（７８．５ｍｇ，＞９９％収率）を得た。この付加体は既知化合物である。その構造は，ＮＭＲスペクトルを文献記載のデータと比較することにより確認した。   Molecular sieves 4A (323 mg) was added to a dichloromethane solution (2 mL) of compound A1 (0.03 mmol) prepared immediately before, and the mixture was cooled to 0 ° C. To this solution, 4-chlorobenzamide (32 mg, 0.2 mmol) and N- (benzyloxycarbonyl) benzaldimine (74 mg, 0.3 mmol) were added, and the mixture was stirred at 0 ° C. for 30 minutes. Water was added to the reaction solution to stop the reaction, followed by extraction with dichloromethane. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium carbonate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform-ethyl acetate = 50: 1 → 30: 1) to obtain the desired adduct (78.5 mg,> 99% yield). . This adduct is a known compound. The structure was confirmed by comparing the NMR spectrum with the data described in the literature.

同様のマンニッヒ反応を、化合物Ｂ１，Ｃを触媒に用いて行った。それらの結果を表３に示す。なお、表３には反応条件も記載した。表３から、化合物Ｃに比べて化合物Ａ１，Ｂ１の触媒活性、特に化合物Ａ１の触媒活性が高かった。このことから、ビスリン酸エステル化合物よりもピロリン酸エステル化合物の方が高い触媒活性を示すことが示唆された。   A similar Mannich reaction was performed using compounds B1 and C as catalysts. The results are shown in Table 3. Table 3 also shows the reaction conditions. From Table 3, compared with the compound C, the catalytic activity of compound A1, B1, especially the catalytic activity of compound A1 was high. This suggests that the pyrophosphate compound exhibits higher catalytic activity than the bisphosphate compound.

３−４．フリーデル−クラフツ反応（その１）
アルジミンとクレゾールとのフリーデル−クラフツ反応について、化合物Ａ１〜Ａ６を触媒に用いた場合と、従来公知のリン酸エステル化合物Ｃを触媒に用いた場合との活性を比較した。化合物Ａ１を触媒に用いた場合（表４のエントリー２）の具体的手順を以下に説明する。3-4. Friedel-Crafts reaction (1)
Regarding the Friedel-Crafts reaction between aldimine and cresol, the activity was compared between when the compounds A1 to A6 were used as the catalyst and when the conventionally known phosphate ester compound C was used as the catalyst. A specific procedure when compound A1 is used as a catalyst (entry 2 in Table 4) will be described below.

直前に調製した化合物Ａ１（０．０１ｍｍｏｌ）の塩化メチレン溶液（１ｍＬ）に対して、Ｎ−ベンジルオキシカルボニル（Ｃｂｚ）アルジミン（２ｍｍｏｌ）を室温で溶解させた後、ｏ−クレゾール（３ｍｍｏｌ）の塩化メチレン溶液を０℃で添加し、３時間撹拌した。反応溶液に対して水（２ｍＬ）を加えて反応を停止した後、酢酸エチルで分液し、減圧下で溶媒を除去した。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（ヘキサン−酢酸エチル＝１０：１→５：１）で精製することにより、パラ位に選択的なフリーデル−クラフツ反応の生成物を収率８５％、光学収率４％ｅｅで得た。この生成物のスペクトルデータは以下のとおり。   N-benzyloxycarbonyl (Cbz) aldimine (2 mmol) was dissolved at room temperature in a methylene chloride solution (1 mL) of compound A1 (0.01 mmol) prepared immediately before, and o-cresol (3 mmol) was salified. Methylene solution was added at 0 ° C. and stirred for 3 hours. Water (2 mL) was added to the reaction solution to stop the reaction, followed by liquid separation with ethyl acetate, and the solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate = 10: 1 → 5: 1) to obtain a product of the Friedel-Crafts reaction selective for the para position in a yield of 85%. And an optical yield of 4% ee. The spectral data of this product is as follows.

1H NMR (400 MHz, THF-d8) δ 2.17 (s, 3H), 5.11 (s, 2H), 5.33 (br, 1H), 5.38 (d, J = 4.0 Hz, 1H), 5.88 (d, J = 4.6 Hz, 1H), 6.64 (d, J = 4.9 Hz, 1H), 6.87 (d, J = 4.9 Hz, 1H), 6.96 (s, 1H), 7.22-7.35 (m, 10H) ppm;13C NMR (100 MHz, THF-d8) δ 15.9 (1C), 58.4 (1C), 67.1 (1C), 114.9 (1C), 124.3 (1C), 125.8 (1C), 127.1 (2C), 127.3 (2C), 128.2 (2C), 128.5 (4C), 129.8 (1C), 133.2 (1C), 136.1 (1C), 141.8 (1C), 153.5 (1C), 155.2 (1C) ppm. 1 H NMR (400 MHz, THF-d 8 ) δ 2.17 (s, 3H), 5.11 (s, 2H), 5.33 (br, 1H), 5.38 (d, J = 4.0 Hz, 1H), 5.88 (d, J = 4.6 Hz, 1H), 6.64 (d, J = 4.9 Hz, 1H), 6.87 (d, J = 4.9 Hz, 1H), 6.96 (s, 1H), 7.22-7.35 (m, 10H) ppm; 13 C NMR (100 MHz, THF-d 8 ) δ 15.9 (1C), 58.4 (1C), 67.1 (1C), 114.9 (1C), 124.3 (1C), 125.8 (1C), 127.1 (2C), 127.3 (2C ), 128.2 (2C), 128.5 (4C), 129.8 (1C), 133.2 (1C), 136.1 (1C), 141.8 (1C), 153.5 (1C), 155.2 (1C) ppm.

同様のフリーデル−クラフツ反応を、化合物Ａ２〜Ａ６，Ｃを触媒に用いて行った。それらの結果を表４に示す。表４から、化合物Ｃに比べて化合物Ａ１〜Ａ６の触媒活性がかなり高く、フェノールの４位で付加した生成物が選択的に得られた。また、化合物Ａ４〜Ａ６（特にＡ５）を用いた場合に良好なエナンチオ選択性が発現することがわかった。更に、触媒に化合物Ａ５を用い、溶媒にクロロホルムを用いた場合（表４のエントリー７）、より高いエナンチオ選択性を示した。なお、溶媒に二塩化エチレン、トルエン、トリフルオロメチルベンゼン、ニトロエタンを用いたところ、いずれもフリーデル−クラフツ反応の生成物が得られたが、クロロホルムを用いた場合の成績が最も良かった。   A similar Friedel-Crafts reaction was performed using compounds A2 to A6 and C as catalysts. The results are shown in Table 4. From Table 4, the catalytic activity of the compounds A1 to A6 was considerably higher than that of the compound C, and the product added at the 4-position of phenol was selectively obtained. Moreover, it turned out that favorable enantioselectivity is expressed when the compounds A4 to A6 (particularly A5) are used. Further, when compound A5 was used as the catalyst and chloroform was used as the solvent (entry 7 in Table 4), higher enantioselectivity was exhibited. When ethylene dichloride, toluene, trifluoromethylbenzene, or nitroethane was used as the solvent, the Friedel-Crafts reaction product was obtained, but the results with chloroform were the best.

３−５．フリーデル−クラフツ反応（その２）
化合物Ａ５を触媒に用いて、各種の保護基を有するアルジミンとクレゾールとのフリーデル−クラフツ反応を行った。メトキシカルボニルを保護基とするアルジミンを用いた場合（表５のエントリー１）の具体的手順を以下に説明する。3-5. Friedel-Crafts reaction (part 2)
Using Compound A5 as a catalyst, Friedel-Crafts reaction between aldimine having various protecting groups and cresol was performed. A specific procedure in the case of using aldimine having methoxycarbonyl as a protecting group (entry 1 in Table 5) will be described below.

直前に調製した化合物Ａ５（０．０１ｍｍｏｌ）のクロロホルム溶液（１ｍＬ）に対して、Ｎ−メトキシカルボニルアルジミン（２ｍｍｏｌ）を室温で溶解させた後、ｏ−クレゾール（３ｍｍｏｌ、アルジミンの１．５当量）のクロロホルム溶液を０℃で添加し、３時間撹拌した。反応溶液に対して水（２ｍＬ）を加えて反応を停止した後、酢酸エチルで分液し、減圧下で溶媒を除去した。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（ヘキサン−酢酸エチル＝１０：１→５：１）で精製することにより、パラ位に選択的なフリーデル−クラフツ反応の生成物を得た。この生成物のスペクトルデータは以下のとおり。   N-methoxycarbonylaldimine (2 mmol) was dissolved at room temperature in a chloroform solution (1 mL) of compound A5 (0.01 mmol) prepared immediately before o-cresol (3 mmol, 1.5 equivalents of aldimine). Was added at 0 ° C. and stirred for 3 hours. Water (2 mL) was added to the reaction solution to stop the reaction, followed by liquid separation with ethyl acetate, and the solvent was removed under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane-ethyl acetate = 10: 1 → 5: 1) to obtain a Friedel-Crafts reaction product selective to the para position. The spectral data of this product is as follows.

1H NMR (400 MHz, THF-d8) δ 2.20 (s, 3H), 3.69 (s, 3H), 5.29 (d, J = 5.7 Hz, 1H), 5.87 (d, J = 4.3 Hz, 1H), 6.69 (d, J = 5.2 Hz, 1H), 6.90 (d, J = 4.9 Hz, 1H), 6.98 (s, 1H), 7.23-7.34 (m, 5H) ppm; 13C NMR (100 MHz, THF-d8) δ 15.9 (1C), 52.4 (1C), 58.3 (1C), 114.9 (1C), 124.3 (1C), 125.7 (1C), 127.1 (1C), 127.3 (2C), 128.5 (2C), 129.8 (1C), 133.2 (1C), 141.9 (1C), 153.6 (1C), 156.5 (1C) ppm. 1 H NMR (400 MHz, THF-d 8 ) δ 2.20 (s, 3H), 3.69 (s, 3H), 5.29 (d, J = 5.7 Hz, 1H), 5.87 (d, J = 4.3 Hz, 1H) , 6.69 (d, J = 5.2 Hz, 1H), 6.90 (d, J = 4.9 Hz, 1H), 6.98 (s, 1H), 7.23-7.34 (m, 5H) ppm; 13 C NMR (100 MHz, THF -d 8 ) δ 15.9 (1C), 52.4 (1C), 58.3 (1C), 114.9 (1C), 124.3 (1C), 125.7 (1C), 127.1 (1C), 127.3 (2C), 128.5 (2C), 129.8 (1C), 133.2 (1C), 141.9 (1C), 153.6 (1C), 156.5 (1C) ppm.

保護基がＢｏｃ（ｔｅｒｔ−ブトキシカルボニル）基やＢｚ（ベンゾイル）基であるアルジミンを用いたフリーデル−クラフツ反応を、上述した手順と同様にして行った。それらの結果を表５のエントリー２，３に示す。なお、表５のエントリー１〜３では、ｏ−クレゾールをアルジミンの１．５当量用い、触媒使用量、濃度、収率はアルジミンを基準として算出した。   Friedel-Crafts reaction using aldimine whose protecting group is Boc (tert-butoxycarbonyl) group or Bz (benzoyl) group was carried out in the same manner as described above. The results are shown in entries 2 and 3 of Table 5. In entries 1 to 3 in Table 5, 1.5 equivalents of o-cresol of aldimine were used, and the amount of catalyst used, concentration and yield were calculated based on aldimine.

一方、表５のエントリー４では、表５のエントリー１の濃度を１０ｍＭに変更した以外は、このエントリー１と同様にして反応を行った。そうしたところ、８１％ｅｅまでエナンチオ選択性が向上し、収率も９７％まで向上した。更に、表５のエントリー５では、表５のエントリー４の触媒使用量を１ｍｏｌ％に変更した以外は、このエントリー４と同様にして反応を行った。そうしたところ、触媒使用量が１ｍｏｌ％であっても、７９％ｅｅという高いエナンチオ選択性を示した。なお、表５のエントリー４，５では、Ｎ−メトキシカルボニルアルジミンをｏ−クレゾールの１．５当量用い、触媒使用量、濃度、収率はｏ−クレゾールを基準として算出した。   On the other hand, in entry 4 in Table 5, the reaction was performed in the same manner as in entry 1 except that the concentration of entry 1 in Table 5 was changed to 10 mM. As a result, the enantioselectivity improved to 81% ee, and the yield also improved to 97%. Furthermore, in entry 5 of Table 5, the reaction was performed in the same manner as in entry 4 except that the amount of catalyst used in entry 4 of Table 5 was changed to 1 mol%. As a result, even if the amount of the catalyst used was 1 mol%, it showed a high enantioselectivity of 79% ee. In entries 4 and 5 in Table 5, 1.5 equivalents of o-cresol was used for N-methoxycarbonylaldimine, and the amount of catalyst used, concentration and yield were calculated based on o-cresol.

３−６．フリーデル−クラフツ反応（その３）
化合物Ａ５を触媒に用いて、各種の保護基を有するアルジミンと各種の置換基を有するクレゾールとのフリーデル−クラフツ反応を行った。ここでは、表５のエントリー４の手順に準じて反応を行った。その結果を表６に示す。表６のエントリー１〜５に示すように、いずれも反応生成物を高エナンチオ選択的に高収率で得ることができた。3-6. Friedel-Crafts reaction (3)
Using Compound A5 as a catalyst, Friedel-Crafts reaction between aldimine having various protective groups and cresol having various substituents was performed. Here, the reaction was performed according to the procedure of entry 4 in Table 5. The results are shown in Table 6. As shown in entries 1 to 5 in Table 6, all of the reaction products could be obtained in high yield with high enantioselectivity.

４．応用例
化合物Ａ５を触媒に用いて、ＰｈＣＨ＝ＮＣｂｚと置換基を持たないフェノールとのフリーデル−クラフツ反応を行ったところ、対応する反応生成物を６２％ｅｅで得ることができた。また、下記式に示す手順にしたがって、この反応生成物を抗真菌剤であるビフォナゾール（Bifonazol)へ誘導することができた。4). Application Example Using a compound A5 as a catalyst, a Friedel-Crafts reaction between PhCH = NCbz and phenol having no substituent was performed, and the corresponding reaction product could be obtained at 62% ee. Moreover, according to the procedure shown in the following formula, this reaction product could be induced to bifonazol, which is an antifungal agent.

本出願は、２０１２年７月１９日に出願された日本国特許出願第２０１２−１６００９２号を優先権主張の基礎としており、引用によりその内容の全てが本明細書に含まれる。   This application is based on Japanese Patent Application No. 2012-160092 filed on Jul. 19, 2012, the contents of which are incorporated herein by reference in their entirety.

本発明は、主に化学産業に利用可能であり、例えば医薬品や農薬、化粧品及びそれらの中間体などを製造する際に利用したり、金属の配位子として利用したりすることができる。   The present invention is mainly applicable to the chemical industry, and can be used, for example, in the production of pharmaceuticals, agricultural chemicals, cosmetics and intermediates thereof, and can be used as a metal ligand.

Claims (9)

式（１）で表される、ピロリン酸エステル化合物。
（Ｒは、アリール基、有機シリル基又はハロゲン原子である）A pyrophosphate ester compound represented by the formula (1).
(R is an aryl group, an organic silyl group or a halogen atom) 前記アリール基は、少なくとも１つの置換基を有していてもよいフェニル基、ナフチル基又はアントラセニル基であり、前記置換基は、アリール基、ペルフルオロアルキル基、アルキル基、アルコキシ基、ニトロ基又はハロゲン原子である、
請求項１に記載のピロリン酸エステル化合物。The aryl group is a phenyl group, a naphthyl group or an anthracenyl group which may have at least one substituent, and the substituent is an aryl group, a perfluoroalkyl group, an alkyl group, an alkoxy group, a nitro group, or a halogen atom. An atom,
The pyrophosphate compound according to claim 1. Ｒは、２−ナフチル基、３，５−ジフェニルフェニル基又は３，５−ビス（２−ナフチル）フェニル基である、
請求項１に記載のピロリン酸エステル化合物。R is a 2-naphthyl group, a 3,5-diphenylphenyl group, or a 3,5-bis (2-naphthyl) phenyl group.
The pyrophosphate compound according to claim 1. 式（２）で表される、ビスリン酸エステル化合物。
（Ｒは、アリール基、有機シリル基又はハロゲン原子である）A bisphosphate compound represented by the formula (2).
(R is an aryl group, an organic silyl group or a halogen atom) 前記アリール基は、少なくとも１つの置換基を有していてもよいフェニル基、ナフチル基又はアントラセニル基であり、前記置換基は、アリール基、ペルフルオロアルキル基、アルキル基、アルコキシ基、ニトロ基又はハロゲン原子である、
請求項４に記載のビスリン酸エステル化合物。The aryl group is a phenyl group, a naphthyl group or an anthracenyl group which may have at least one substituent, and the substituent is an aryl group, a perfluoroalkyl group, an alkyl group, an alkoxy group, a nitro group, or a halogen atom. An atom,
The bisphosphate ester compound according to claim 4. Ｒは、２−ナフチル基、３，５−ジフェニルフェニル基又は３，５−ビス（２−ナフチル）フェニル基である、
請求項４に記載のビスリン酸エステル化合物。R is a 2-naphthyl group, a 3,5-diphenylphenyl group, or a 3,5-bis (2-naphthyl) phenyl group.
The bisphosphate ester compound according to claim 4. 請求項１〜３のいずれか１項に記載のピロリン酸エステル化合物を含む分子内エン反応用触媒。   A catalyst for intramolecular ene reaction comprising the pyrophosphate ester compound according to any one of claims 1 to 3. 請求項１〜３のいずれか１項に記載のピロリン酸エステル化合物を含むマンニッヒ反応用触媒。   The catalyst for Mannich reaction containing the pyrophosphate ester compound of any one of Claims 1-3. 請求項１〜３のいずれか１項に記載のピロリン酸エステル化合物を含むフリーデル−クラフツ反応用触媒。   A Friedel-Crafts reaction catalyst comprising the pyrophosphate ester compound according to any one of claims 1 to 3.
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