JP2007031344A

JP2007031344A - Process for producing optically active β-amino alcohol compound and catalyst

Info

Publication number: JP2007031344A
Application number: JP2005217154A
Authority: JP
Inventors: Osamu Kobayashi; 修小林; Takashi Manabe; 敬眞鍋
Original assignee: Japan Science and Technology Agency
Current assignee: Japan Science and Technology Agency
Priority date: 2005-07-27
Filing date: 2005-07-27
Publication date: 2007-02-08

Abstract

【課題】アミンによるエポキシドの開環反応において、高収率かつ高立体選択的に光学活性β−アミノアルコール化合物を製造する方法及びそのための触媒の提供をする。
【解決手段】キラルビピリジン配位子とスカンジウムトリスドデシルスルフェート［Sc(DS)₃］等とを混合させてなる触媒を用いることにより、エポキシドと１級又は２級アミン化合物との反応において光学活性β−アミノアルコール化合物が高い不斉選択性で得られる。
【選択図】なし
PROBLEM TO BE SOLVED: To provide a method for producing an optically active β-aminoalcohol compound with high yield and high stereoselectivity in an epoxide ring-opening reaction with an amine, and a catalyst therefor.
SOLUTION: By using a catalyst obtained by mixing a chiral bipyridine ligand and scandium trisdodecyl sulfate [Sc (DS) ₃ ] or the like, optical activity is obtained in the reaction of an epoxide with a primary or secondary amine compound. A β-amino alcohol compound is obtained with high asymmetric selectivity.
[Selection figure] None

Description

この発明は、光学活性β−アミノアルコール化合物を製造する方法に関し、より詳細には、水溶液中でエポキシドをアミンにより不斉開環反応させて光学活性β−アミノアルコール化合物を製造する方法及びそのための触媒に関する。 The present invention relates to a method for producing an optically active β-aminoalcohol compound, and more specifically, a method for producing an optically active β-aminoalcohol compound by asymmetric ring-opening reaction of an epoxide with an amine in an aqueous solution, and for the same Relates to the catalyst.

光学活性なβ−アミノアルコール化合物は、天然物や生物活性物質の構成成分などに広く見出されており、それらの合成中間体や不斉合成反応の配位子などとして重要な化合物である。従来、光学活性β−アミノアルコール化合物の合成法としては、α−アミノ酸など入手が容易な光学活性化合物からの誘導化法やラセミ体の光学分割法が用いられてきた。また近年、不斉合成法の進歩に伴いエポキシドの触媒的不斉開環反応が注目されている（非特許文献１〜６）。
一方、化学工業の分野では環境負荷の低減が重要課題となっており、従来実施されてきた有機溶媒中での反応を、環境に優しい水系反応で代替する試みが活発に検討されている。しかしながら、水系溶媒中でエポキシドのアミンによる開環反応を用いたβ−アミノアルコールの合成例はラセミ体の合成では知られているものの（非特許文献７〜９）、触媒的不斉合成の例はない。 Optically active β-aminoalcohol compounds are widely found in components of natural products and biologically active substances, and are important compounds as synthetic intermediates and ligands for asymmetric synthesis reactions. Conventionally, as a method for synthesizing optically active β-aminoalcohol compounds, derivatization methods from readily available optically active compounds such as α-amino acids and racemic optical resolution methods have been used. In recent years, catalytic asymmetric ring-opening reactions of epoxides have attracted attention with the progress of asymmetric synthesis methods (Non-Patent Documents 1 to 6).
On the other hand, in the field of chemical industry, reduction of environmental load is an important issue, and attempts to replace the reaction in an organic solvent, which has been conventionally performed, with an environmentally friendly aqueous reaction are being actively studied. However, examples of synthesis of β-aminoalcohol using ring-opening reaction of epoxide with amine in an aqueous solvent are known for the synthesis of racemates (Non-Patent Documents 7 to 9), but examples of catalytic asymmetric synthesis There is no.

近年、本発明者らは、スカンジウムトリスドデシルスルフェート［Sc(DS)₃］をルイス酸−界面活性剤一体型触媒として用いることにより、水溶液中でのルイス酸触媒反応において反応の加速効果や水に不安定な基質の安定化効果を見出している（非特許文献１０）。また本発明者らはスカンジウムトリフラート［Sc(OTf)₃］とキラルビピリジンから調整される不斉触媒を用いて、ケイ素エノラートとホルムアルデヒドによる不斉ヒドロキシメチル化反応を水系溶媒中で高収率かつ高エナンチオ選択的に実現した（非特許文献１１）。一方、最近シュナイダーらはスカンジウムトリフラート［Sc(OTf)₃］とキラルビピリジンから調整される不斉触媒を用いたエポキシドの不斉開環反応によるエナンチオ選択的なβ−アミノアルコールの合成を報告しているが、ここでは塩化メチレンが溶媒として用いられている（非特許文献１２）。 In recent years, the present inventors have used scandium trisdodecyl sulfate [Sc (DS) ₃ ] as a Lewis acid-surfactant-integrated catalyst, thereby accelerating the reaction in the Lewis acid-catalyzed reaction in an aqueous solution. Has been found to stabilize the substrate which is unstable (Non-Patent Document 10). In addition, the present inventors used an asymmetric catalyst prepared from scandium triflate [Sc (OTf) ₃ ] and chiral bipyridine to carry out an asymmetric hydroxymethylation reaction with silicon enolate and formaldehyde in an aqueous solvent at a high yield and a high yield. This was realized enantioselectively (Non-patent Document 11). On the other hand, Schneider et al. Recently reported the enantioselective synthesis of β-aminoalcohol by asymmetric ring-opening reaction of epoxide using asymmetric catalyst prepared from scandium triflate [Sc (OTf) ₃ ] and chiral bipyridine. However, here, methylene chloride is used as a solvent (Non-patent Document 12).

Tetrahedron; Asymmetry 1998, 9, 1747.Tetrahedron; Asymmetry 1998, 9, 1747. J. Org. Chem. 1999, 64, 4962.J. Org. Chem. 1999, 64, 4962. Tetrahedron 2002, 58, 75.Tetrahedron 2002, 58, 75. Org. Lett. 2005, 7, 1023.Org. Lett. 2005, 7, 1023. Org. Lett. 2004, 6, 2173.Org. Lett. 2004, 6, 2173. Eur. J. Org. Chem. 2001, 4149.Eur. J. Org. Chem. 2001, 4149. Org. Biomol. Chem. 2003, 1, 724.Org. Biomol. Chem. 2003, 1, 724. J. Org. Chem. 2003, 68, 726.J. Org. Chem. 2003, 68, 726. Tetrahedron Lett. 2004, 45, 49.Tetrahedron Lett. 2004, 45, 49. J. Am. Chem. Soc. 2000, 122, 7202.J. Am. Chem. Soc. 2000, 122, 7202. J. Am. Chem. Soc. 2004, 126, 12236.J. Am. Chem. Soc. 2004, 126, 12236. Angew. Chem. Int. Ed. 2004, 43, 5691.Angew. Chem. Int. Ed. 2004, 43, 5691.

本発明は、水溶液中でアミンによるエポキシドの開環反応において、広い基質一般性を有し、高収率かつ高立体選択的に光学活性β−アミノアルコール化合物を製造する方法及びそのための触媒の提供を目的とする。 The present invention provides a method for producing an optically active β-aminoalcohol compound with high substrate yield and high stereoselectivity in a ring opening reaction of an epoxide with an amine in an aqueous solution, and a catalyst therefor With the goal.

本発明者らは、ルイス酸と光学活性なビピリジン化合物とから成る不斉触媒として、一定以上の炭素数の疎水鎖を持つ有機スルホン酸又はスルホン酸モノエステルと金属とから成るルイス酸を用いることにより、水溶液中のエポキシドとアミンとの不斉開環反応が高収率かつ高立体選択的に進行することを見出し、光学活性β−アミノアルコール化合物の新規な製法を完成するに至った。 The present inventors use a Lewis acid comprising an organic sulfonic acid or sulfonic acid monoester having a hydrophobic chain having a certain number of carbon atoms and a metal as an asymmetric catalyst comprising a Lewis acid and an optically active bipyridine compound. As a result, it was found that the asymmetric ring-opening reaction between the epoxide and the amine in the aqueous solution proceeded in a high yield and with high stereoselectivity, and a novel method for producing an optically active β-aminoalcohol compound was completed.

即ち、本発明は、水溶液中又は水と有機溶媒との混合溶媒中で下式(化１)

（式中、Ｒ^１は、炭素数が３以上のアルキル基又はアリール基を表し、Ｒ^２は、水素原子又は炭素数１〜４のアルキル基若しくはアルコキシ基を表し、Ｘは、−ＯＨ、−ＳＨ、又は−ＮＨＲ^３（式中、Ｒ^３は水素原子又はアルキル基を表す。）を表す。）で表される配位子又はその対称体とＭ（ＯＳＯ_２Ｒ^４）_３又はＭ（ＯＳＯ_３Ｒ^４）_３（式中、ＭはＳｃ、Ｙ又はランタノイド元素を表し、Ｒ^４は炭素数が６以上の脂肪族炭化水素基、芳香族炭化水素基又はパーフルオロアルキル基を表す。）で表されるルイス酸とを混合させて得られる触媒の存在下で、下式（式２）

（式中、Ｒ^５及びＲ^６は、それぞれ同じであっても異なってもよく、水素原子、又は置換基を有していてもよい脂肪族炭化水素基、芳香脂族炭化水素基若しくは複素環基を表し、但し、Ｒ^５及びＲ^６の少なくとも一方は水素原子ではない。）で表されるエポキシドと、Ｒ^７Ｒ^８ＮＨ（式中、Ｒ^７及びＲ^８は、それぞれ同じであっても異なってもよく、水素原子、置換基を有していてもよい脂肪族炭化水素基、芳香脂族炭化水素基又は複素環基を表し、但し、Ｒ^７及びＲ^８の少なくとも一方は水素原子ではない。）で表される１級又は２級アミン化合物とを反応させることから成る光学活性β−アミノアルコール化合物の製法である。 That is, the present invention provides the following formula (chemical formula 1) in an aqueous solution or a mixed solvent of water and an organic solvent.

(In the formula, R ¹ represents an alkyl group having 3 or more carbon atoms or an aryl group, R ² represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group, and X represents —OH, — A ligand represented by SH or —NHR ³ (wherein R ³ represents a hydrogen atom or an alkyl group) or a symmetric product thereof and M (OSO ₂ R ⁴ ) ₃ or M (OSO ₃ R ⁴ ) ₃ (wherein M represents Sc, Y or a lanthanoid element, and R ⁴ represents an aliphatic hydrocarbon group having 6 or more carbon atoms, an aromatic hydrocarbon group or a perfluoroalkyl group). In the presence of a catalyst obtained by mixing with the Lewis acid represented, the following formula (Formula 2)

(In the formula, R ⁵ and R ⁶ may be the same or different and each represents a hydrogen atom, an aliphatic hydrocarbon group, an araliphatic hydrocarbon group or a heterocyclic ring which may have a substituent. An epoxide represented by a group, provided that at least one of R ⁵ and R ⁶ is not a hydrogen atom, and R ⁷ R ⁸ NH (wherein R ⁷ and R ⁸ are the same, respectively) They may be different and each represents a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, an araliphatic hydrocarbon group or a heterocyclic group, provided that at least one of R ⁷ and R ⁸ is not a hydrogen atom. No.) is produced by reacting with a primary or secondary amine compound.

本発明で用いる触媒は、下記構造

の配位子とＭ（ＯＳＯ_２Ｒ^４）_３又はＭ（ＯＳＯ_３Ｒ^４）_３で表されるルイス酸とを混合させて得られる。 The catalyst used in the present invention has the following structure:

Of the ligand and _{M (OSO} ² R _{4) 3} or _M by mixing a Lewis acid represented by _(OSO ^₃ R ₄₎ ³ is obtained.

Ｒ^１は、アルキル基又はアリール基を表す。このアルキル基は嵩高いこと、具体的には炭素数が３以上であることを要する。このアリール基はメトキシ基やハロゲン原子等の置換基を有していてもよい。
Ｒ^２は水素原子又は炭素数１〜４のアルキル基若しくはアルコキシ基、好ましくは水素原子を表す。
Ｘは−ＯＨ、−ＳＨ、又は−ＮＨＲ^３を、好ましくは−ＯＨを表す。Ｒ^３は水素原子又はアルキル基、好ましくは水素原子を表し、アルキル基の炭素数は好ましくは１〜３である。 R ¹ represents an alkyl group or an aryl group. This alkyl group needs to be bulky, specifically having 3 or more carbon atoms. This aryl group may have a substituent such as a methoxy group or a halogen atom.
R ² represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group, preferably a hydrogen atom.
X represents —OH, —SH, or —NHR ³ , preferably —OH. R ³ represents a hydrogen atom or an alkyl group, preferably a hydrogen atom, and the alkyl group preferably has 1 to 3 carbon atoms.

一般式Ｍ（ＯＳＯ_２Ｒ^４）_３又はＭ（ＯＳＯ_３Ｒ^４）_３で表されるルイス酸において、金属ＭはＳｃ（３価）、Ｙ（３価）又はランタノイド元素（^５７Ｌａ〜^７１Ｌｕ）（３価）、好ましくはＳｃを表す。
Ｒ^４は、炭素数が６以上、好ましくは６〜２０の、脂肪族炭化水素基、芳香族炭化水素基又はパーフルオロアルキル基を表し、より好ましくは炭素数が６〜２０のアルキル基又はアルキルアリール基を表す。即ち、有機スルホン酸（−ＯＳＯ_２Ｒ_４）としてアルカンスルホン酸基やアルキルアレーンスルホン酸基が好ましく、例えば、ドデカンスルホン酸基、オクチルベンゼンスルホン酸基又はドデシルベンゼンスルホン酸基などが挙げられる。スルホン酸モノエステル（−ＯＳＯ_３Ｒ_４）としては、スルホン酸モノアルキルエステルが好ましく、例えば、スルホン酸ドデシルエステルが挙げられる。Ｒ^４の炭素数が短い場合は、塩化メチレンなどの有機溶媒中では比較的良好な収率と立体選択性で目的とするβ−アミノアルコール化合物を与えるが（後述の比較例４参照）、水溶媒中では収率が大きく低下する（後述の比較例２参照）。 In the Lewis acid represented by the general formula M (OSO ₂ R ⁴ ) ₃ or M (OSO ₃ R ⁴ ) ₃ , the metal M is Sc (trivalent), Y (trivalent), or a lanthanoid element ( ⁵⁷ La to ⁷¹ Lu ) (Trivalent), preferably Sc.
R ⁴ represents an aliphatic hydrocarbon group, an aromatic hydrocarbon group or a perfluoroalkyl group having 6 or more carbon atoms, preferably 6 to 20 carbon atoms, more preferably an alkyl group or alkyl having 6 to 20 carbon atoms. Represents an aryl group. That is, as the organic sulfonic acid (—OSO ₂ R ₄ ), an alkanesulfonic acid group or an alkylarenesulfonic acid group is preferable, and examples thereof include a dodecanesulfonic acid group, an octylbenzenesulfonic acid group, and a dodecylbenzenesulfonic acid group. The sulfonic acid monoester (—OSO ₃ R ₄ ) is preferably a sulfonic acid monoalkyl ester, and examples thereof include sulfonic acid dodecyl ester. When R ⁴ has a short carbon number, the target β-aminoalcohol compound is obtained in an organic solvent such as methylene chloride with a relatively good yield and stereoselectivity (see Comparative Example 4 described later), but water The yield is greatly reduced in the solvent (see Comparative Example 2 described later).

触媒調整時の金属Ｍと配位子とのモル比は１：１〜１：２付近が好ましく、より好ましくは１：１〜１．０：１．２である。
溶媒は、水又は水と有機溶媒との混合溶媒、好ましくは水が用いられる。水と混合する有機溶媒として、好ましくはジメトキシエタン（ＤＭＥ）、テトラヒドロフラン（ＴＨＦ）、アセトニトリル、ジオキサン、炭素数が４以下のアルコールなどが挙げられ、水と混和しない有機溶媒として、好ましくは塩化メチレン、クロロホルム、ベンゼン、エーテルなどが挙げられるが、これらの中からどの溶媒有機溶媒を用いるかは、基質に対する溶解能により適宜選択される。また、水と有機溶媒との混合比（体積）は、一般的には水が１０％以上、より好ましくは５０％以上である。 The molar ratio between the metal M and the ligand during catalyst preparation is preferably in the vicinity of 1: 1 to 1: 2, more preferably 1: 1 to 1.0: 1.2.
As the solvent, water or a mixed solvent of water and an organic solvent, preferably water is used. The organic solvent mixed with water preferably includes dimethoxyethane (DME), tetrahydrofuran (THF), acetonitrile, dioxane, alcohol having 4 or less carbon atoms, and the organic solvent immiscible with water is preferably methylene chloride, Chloroform, benzene, ether and the like can be mentioned. Of these solvents, which organic solvent is used is appropriately selected depending on the solubility in the substrate. Further, the mixing ratio (volume) of water and the organic solvent is generally 10% or more, more preferably 50% or more of water.

触媒の調整温度に制限はないが室温付近が好ましく、調整時間は通常１５分間〜３時間程度である。
この配位子とＭ（ＯＳＯ_２Ｒ^４）_３又はＭ（ＯＳＯ_３Ｒ^４）_３で表されるルイス酸とを溶媒中で混合すると、Ｍ^３＋が配位子に配位し、触媒を形成する。溶媒中の濃度は0.01〜0.1mol/l程度が好ましい。
反応に用いる触媒の量は通常０．３〜５モル％程度であるが、多くの場合１モル％で良好な結果を与える。
反応温度は溶媒が水であることから通常は０℃以上であり、好ましくは室温付近である。反応温度を下げ過ぎると反応速度が低下し、上げすぎると立体選択性が低下する。反応時間は一般的には数時間〜数十時間程度である。 Although there is no restriction | limiting in the adjustment temperature of a catalyst, the room temperature vicinity is preferable and adjustment time is about 15 minutes-about 3 hours normally.
When this ligand and a Lewis acid represented by M (OSO ₂ R ⁴ ) ₃ or M (OSO ₃ R ⁴ ) ₃ are mixed in a solvent, M ³⁺ coordinates to the ligand to form a catalyst. To do. The concentration in the solvent is preferably about 0.01 to 0.1 mol / l.
The amount of catalyst used in the reaction is usually about 0.3 to 5 mol%, but in many cases 1 mol% gives good results.
Since the solvent is water, the reaction temperature is usually 0 ° C. or higher, preferably around room temperature. If the reaction temperature is lowered too much, the reaction rate is lowered, and if it is raised too much, the stereoselectivity is lowered. The reaction time is generally about several hours to several tens of hours.

本発明で用いるエポキシドの構造としては、下式(化２)

で表される一置換及び二置換のエポキシドが用いられる。
Ｒ^５及びＲ^６は、それぞれ同じであっても異なってもよく、水素原子、置換基を有していてもよい脂肪族炭化水素基、芳香脂族炭化水素基又は複素環基、好ましくはアルキル基、アリール基又はアルキルアリール基を表す。但し、Ｒ^５及びＲ^６の少なくとも一方は水素原子ではない。またＲ^５及びＲ^６は、ハロゲン原子、水酸基、ニトロ基、シアノ基、エステル基、エーテル基、チオエーテル基、アミド基等の置換基を有していてもよい。
このエポキシドは好ましくは二置換のシス体のエポキシド、より好ましくはメソ体（即ち、Ｒ^５とＲ^６とが同一である。）のエポキシドである。 The structure of the epoxide used in the present invention is as follows:

And mono- and di-substituted epoxides represented by
R ⁵ and R ⁶ may be the same or different and each is a hydrogen atom, an aliphatic hydrocarbon group, an araliphatic hydrocarbon group or a heterocyclic group which may have a substituent, preferably an alkyl group. Represents a group, an aryl group or an alkylaryl group. However, at least one of R ⁵ and R ⁶ is not a hydrogen atom. R ⁵ and R ⁶ may have a substituent such as a halogen atom, a hydroxyl group, a nitro group, a cyano group, an ester group, an ether group, a thioether group, or an amide group.
This epoxide is preferably a disubstituted cis epoxide, more preferably a meso epoxide (ie, R ⁵ and R ⁶ are the same).

エポキシドへの求核剤となるアミンは、下式
Ｒ^７Ｒ^８ＮＨ
で表される一級又は二級アミンが用いられる。
Ｒ^７及びＲ^８は、それぞれ同じであっても異なってもよく、水素原子、置換基を有していてもよい脂肪族炭化水素基、芳香脂族炭化水素基又は複素環基を表し、但し、Ｒ^７及びＲ^８の少なくとも一方は水素原子ではない。これらのアミンの中でも特に芳香族アミンが好ましい。またＲ^７及びＲ^８は、ハロゲン原子、水酸基、ニトロ基、シアノ基、エステル基、エーテル基、チオエーテル基、アミド基等の置換基を有していてもよい。 Amines that are nucleophiles for epoxides are represented by the formula R ⁷ R ⁸ NH
The primary or secondary amine represented by these is used.
R ⁷ and R ⁸ may be the same or different and each represents a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, an araliphatic hydrocarbon group or a heterocyclic group, provided that , R ⁷ and R ⁸ are not hydrogen atoms. Among these amines, aromatic amines are particularly preferable. R ⁷ and R ⁸ may have a substituent such as a halogen atom, a hydroxyl group, a nitro group, a cyano group, an ester group, an ether group, a thioether group, or an amide group.

本発明に於いては、上記触媒と基質であるエポキシド及びアミンを水溶媒中で混合することで、アミンによるエポキシドの不斉開環反応が進行し、下式(化３)で表される光学活性なβ−アミノアルコール化合物が高収率かつ高立体選択的に生成する。

（式中、Ｒ^５〜Ｒ^８は上記と同様を表す。）

以下、実施例にて本発明を例証するが本発明を限定することを意図するものではない。 In the present invention, by mixing the catalyst and the substrate epoxide and amine in an aqueous solvent, an asymmetric ring-opening reaction of the epoxide by the amine proceeds, and the optical system represented by the following formula (Formula 3) An active β-amino alcohol compound is produced with high yield and high stereoselectivity.

(Wherein R ^{5 to} R ⁸ represent the same as above)

The following examples illustrate the invention but are not intended to limit the invention.

本実施例で用いたエポキシド（表１）は、既報（Tetrahedron, 1997, 53, 13727）に従って、対応するシスアルケンをメタクロロ過安息香酸で酸化して合成した。エポキシドの開環反応の溶媒としてイオン交換水を使用し、アルゴン雰囲気下で実施した。¹H NMR 及び ¹³C NMR はJEOL JNM-LA400 (400 MHz)を、赤外吸収スペクトルは JASCO FT/IR-610 を、旋光度は JASCO P-1010 を、質量分析には Bruker Daltonics BioTOF II を用いて測定した。光学純度はキラルカラムを用いたHPLC（Shimadzu VP-series）により決定した。 The epoxide used in this example (Table 1) was synthesized by oxidizing the corresponding cisalkene with metachloroperbenzoic acid, according to a previous report (Tetrahedron, 1997, 53, 13727). Ion exchange water was used as a solvent for the epoxide ring-opening reaction, and the reaction was carried out under an argon atmosphere. ^{For 1} H NMR and ¹³ C NMR, use JEOL JNM-LA400 (400 MHz), infrared absorption spectrum using JASCO FT / IR-610, optical rotation using JASCO P-1010, and mass spectrometry using Bruker Daltonics BioTOF II. Measured. The optical purity was determined by HPLC (Shimadzu VP-series) using a chiral column.

まず、キラルビピリジン配位子（化４（４））を、既報（Ishikawa, S.; Hamada, T.; Manabe, K.; Kobayashi, S. Synlett, 2005, in press.）に従って合成した。合成経路を下式(化４)に示す。

First, a chiral bipyridine ligand (Chemical Formula 4 (4)) was synthesized according to a report (Ishikawa, S .; Hamada, T .; Manabe, K .; Kobayashi, S. Synlett, 2005, in press.). The synthesis route is shown in the following formula (Formula 4).

2,6-ジブロムピリジン(１)をエーテル中でn-ブチルリチウムで処理した後、ピバロニトリルによりアシル化して化合物(２)を得た。化合物(２)のカルボニル基をRuCl[(S,S)-Tsdpen](p-cymene)により立体選択的に還元して(S)-体のアルコール(３)を ee > 99.5 % で得た。アルコール(３)をパラジウム触媒によるホモカップリング反応を行うことにより、C2対称の2,2'-ビピリジン体(４)(S,S)（以下「キラルビピリジン配位子」という。）を得た。 2,6-Dibromopyridine (1) was treated with n-butyllithium in ether and then acylated with pivalonitrile to give compound (2). The carbonyl group of the compound (2) was stereoselectively reduced with RuCl [(S, S) -Tsdpen] (p-cymene) to obtain the (S) -form alcohol (3) at ee> 99.5%. The alcohol (3) was subjected to a palladium-catalyzed homocoupling reaction to obtain a C2 symmetrical 2,2′-bipyridine (4) (S, S) (hereinafter referred to as “chiral bipyridine ligand”). .

上記で得たキラルビピリジン配位子（0.012 mmol）、スカンジウムトリスドデシルスルフェート［Sc(DS)₃・3H₂O］（和光純薬工業（株）製)（0.01 mmol）、水（1.0 ml）の混合物を室温で１時間攪拌した。これにアニリン（1.0 mmol）とスチルベンオキシド（1.0 mmol）を加えて更に２２時間激しく攪拌した。飽和炭酸水素ナトリウム水溶液を加えた後、酢酸エチルで３回抽出した。有機層を無水硫酸ナトリウムで乾燥し、乾燥剤を濾別した後、溶媒を減圧留去した。残渣を調整用薄層クロマトグラフィー（展開溶媒：酢酸エチル／ヘキサン）で精製し、(1S,2S)-1,2-ジフェニル-2-(フェニルアミノ)エタノールを白色結晶として得た（収率８９％）。結果を表１に示す。 Chiral bipyridine ligand (0.012 mmol) obtained above, scandium trisdodecyl sulfate [Sc (DS) ₃ · 3H ₂ O] (manufactured by Wako Pure Chemical Industries, Ltd.) (0.01 mmol), water (1.0 ml) The mixture was stirred at room temperature for 1 hour. To this was added aniline (1.0 mmol) and stilbene oxide (1.0 mmol), and the mixture was further stirred vigorously for 22 hours. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography (developing solvent: ethyl acetate / hexane) to give (1S, 2S) -1,2-diphenyl-2- (phenylamino) ethanol as white crystals (yield 89 %). The results are shown in Table 1.

実施例２〜９
更に、表１に示すアミンとエポキシドを用いて実施例１と同様に反応を行った。結果を表１に示す。いずれも良好な化学収率及び不斉収率で対応するβ−アミノアルコールが得られたことがわかる。

Examples 2-9
Furthermore, the reaction was carried out in the same manner as in Example 1 using the amine and epoxide shown in Table 1. The results are shown in Table 1. It can be seen that the corresponding β-amino alcohol was obtained with good chemical yield and asymmetric yield.

比較例１
キラルビピリジン配位子を加えずに実施例１と同様の反応を行った結果、対応するβ−アミノアルコールを得た（収率１４％）。
比較例２
Sc(DS)_３に代えてSc(OTf)_３を用い、実施例１と同様の反応を行った結果、対応するβ−アミノアルコールを得た（収率１４％、８５％ｅｅ）。
比較例３
Sc(DS)_３に代えてSc(OTf)_３を用い、反応溶媒を水に代えてＴＨＦ／水（９／１）の混合溶媒を用いて実施例１と同様の反応を行った結果、対応するβ−アミノアルコールを得た（収率<５％、７１％ｅｅ）。
比較例４
Sc(DS)_３に代えてSc(OTf)_３を用い、反応溶媒を水に代えて塩化メチレンを用いて実施例１と同様の反応を行った結果、対応するβ−アミノアルコールを得た（収率８５％、７４％ｅｅ）。 Comparative Example 1
As a result of conducting the same reaction as in Example 1 without adding the chiral bipyridine ligand, the corresponding β-amino alcohol was obtained (yield 14%).
Comparative Example 2
As a result of carrying out the same reaction as in Example 1 using Sc (OTf) ₃ instead of Sc (DS) ₃ , the corresponding β-amino alcohol was obtained (yield 14%, 85% ee).
Comparative Example 3
As a result of conducting the same reaction as Example 1 using Sc (OTf) ₃ instead of Sc (DS) ₃ and using a mixed solvent of THF / water (9/1) instead of water as a reaction solvent. Β-amino alcohol was obtained (yield <5%, 71% ee).
Comparative Example 4
As a result of carrying out the same reaction as in Example 1 using Sc (OTf) ₃ instead of Sc (DS) ₃ and using methylene chloride instead of water as the reaction solvent, the corresponding β-amino alcohol was obtained ( Yield 85%, 74% ee).

以上の結果によれば、Sc(DS)₃−ビピリジン（4）を用いて水溶媒中で反応を行った場合、目的とするβ−アミノアルコールが高収率かつ高立体選択的に得られた（実施例１）。この結果は、同じ反応を有機溶媒中でSc(OTf)₃を用いて行った場合（比較例４）よりも、収率、立体選択性とも優れていた。また、Sc(OTf)₃を用いて水溶液中、或いは水とＴＨＦとの混合溶媒（１：９）中で同じ反応を実施した場合、収率がさらに大きく低下した（比較例２、３）。
本触媒系におけるビピリジン配位子は、不斉誘起剤としての役割ばかりでなく収率の向上にも大きく寄与している。ビピリジン配位子を加えないで実施例１と同様の反応を行うと、収率が１４％と大きく低下した（比較例１）。 According to the above results, when the reaction was carried out in an aqueous solvent using Sc (DS) ₃ -bipyridine (4), the intended β-aminoalcohol was obtained with high yield and high stereoselectivity. (Example 1). This result was superior in yield and stereoselectivity compared to the case where the same reaction was carried out using Sc (OTf) ₃ in an organic solvent (Comparative Example 4). Further, when the same reaction was carried out in an aqueous solution or a mixed solvent of water and THF (1: 9) using Sc (OTf) ₃ , the yield was further greatly reduced (Comparative Examples 2 and 3).
The bipyridine ligand in this catalyst system greatly contributes not only to the role as an asymmetric inducer but also to the improvement of yield. When the same reaction as in Example 1 was performed without adding the bipyridine ligand, the yield was greatly reduced to 14% (Comparative Example 1).

実施例１〜９の生成物（アミノアルコール）の物性を以下に示す。
実施例１：
(1S,2S)-1,2-Diphenyl-2-(phenylamino)-ethanol. melting point: 100-102℃ The ee was determined by HPLC using a Daicel Chiralpak AD column (19/1 hexane/i-PrOH; flow rate 1 mL/min; τ_major = 25.5 min; τ_minor = 29.8 min); ee = 91%. [α]²⁴ _D = -45.2° (c = 0.520, CH₂Cl₂). IR (cm^-1): 3404, 3060, 1490, 1453, 1337, 1201, 1105, 1060. ¹H NMR (400 MHz, CDCl₃): δ= 2.75 (br s, 1H), 4.46 (d, J = 6.0 Hz, 1H), 4.54 (br s, 1H), 4.74 (d, J = 6.0 Hz, 1H), 6.48-6.50 (m, 2H), 6.59-6.6 (m, 1H), 7.0-7.04 (m, 2H), 7.12-7.23 (m, 10H). ¹³C NMR (100 MHz, CDCl₃): δ= 64.7, 78.0, 114.1, 117.8, 126.7, 127.2, 127.4, 127.8, 128.1, 128.4, 129.0, 140.1, 140.5, 147.2. HRMS (ESI): [M+H]⁺ calcd. 290.1545, found 290.1537. The physical properties of the products (amino alcohols) of Examples 1 to 9 are shown below.
Example 1:
(1S, 2S) -1,2-Diphenyl-2- (phenylamino) -ethanol. Melting point: 100-102 ° C The ee was determined by HPLC using a Daicel Chiralpak AD column (19/1 hexane / i-PrOH; flow rate 1 mL / min; τ _major = 25.5 min; τ _minor = 29.8 min); ee = 91%. [α] ²⁴ _D = -45.2 ° (c = 0.520, CH ₂ Cl ₂ ). IR (cm ^-1 ) : 3404, 3060, 1490, 1453, 1337, 1201, 1105, 1060. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 2.75 (br s, 1H), 4.46 (d, J = 6.0 Hz, 1H), 4.54 (br s, 1H), 4.74 (d, J = 6.0 Hz, 1H), 6.48-6.50 (m, 2H), 6.59-6.6 (m, 1H), 7.0-7.04 (m, 2H), 7.12-7.23 (m, 10H). ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 64.7, 78.0, 114.1, 117.8, 126.7, 127.2, 127.4, 127.8, 128.1, 128.4, 129.0, 140.1, 140.5, 147.2.HRMS (ESI ): [M + H] ⁺ calcd. 290.1545, found 290.1537.

実施例２：
(1S,2S)-2-(N-Methyl-N-phenylamino)-1,2-diphenylethanol. The title compound was isolated as a white solid; melting point: 57-59℃. The ee was determined by HPLC using a Daicel Chiralpak AS-H column (19/1 hexane/i-PrOH; flow rate 0.8 mL/min; τ_minor = 18.2 min; τ_major = 24.3 min); ee = 96%. [α]²³ _D = +171.7°(c = 0.530, CH₂Cl₂). IR (cm^-1): 3415, 3060, 3030, 2887, 1597, 1499, 1452, 1320, 1190, 754, 698. ¹H NMR (400 MHz, CDCl₃): δ = 2.68 (s, 3H), 3.96 (br s, 1H), 4.87 (d, J =10.1 Hz, 1H), 5.28 (d, J = 9.6 Hz, 1H), 6.88-6.92 (m, 1H), 6.96-7.01 (m, 4H), 7.11-7.29 (m, 8H), 7.38 (d, J =7.7 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃): ( = 32.7, 71.5, 73.7, 117.8, 120.3, 127.6, 127.7, 127.9, 128.2, 128.8, 129.1, 134.6, 140.6, 151.3. HRMS (ESI): [M+H]⁺ calcd. 304.1701, found 304.1691. Example 2:
(1S, 2S) -2- (N-Methyl-N-phenylamino) -1,2-diphenylethanol.The title compound was isolated as a white solid; melting point: 57-59 ° C. The ee was determined by HPLC using a Daicel Chiralpak AS-H column (19/1 hexane / i-PrOH; flow rate 0.8 mL / min; τ _minor = 18.2 min; τ _major = 24.3 min); ee = 96%. [Α] ²³ _D = + 171.7 ° (c = 0.530, CH ₂ Cl ₂ ) .IR (cm ^-1 ): 3415, 3060, 3030, 2887, 1597, 1499, 1452, 1320, 1190, 754, 698. ¹ H NMR (400 MHz, CDCl ₃ ) : δ = 2.68 (s, 3H), 3.96 (br s, 1H), 4.87 (d, J = 10.1 Hz, 1H), 5.28 (d, J = 9.6 Hz, 1H), 6.88-6.92 (m, 1H) , 6.96-7.01 (m, 4H), 7.11-7.29 (m, 8H), 7.38 (d, J = 7.7 Hz, 2H) 13 C NMR (100 MHz, CDCl 3):. (= 32.7, 71.5, 73.7, 117.8, 120.3, 127.6, 127.7, 127.9, 128.2, 128.8, 129.1, 134.6, 140.6, 151.3. HRMS (ESI): [M + H] ⁺ calcd. 304.1701, found 304.1691.

実施例３：
(1S,2S)-2-(2-Methoxyphenylamino)-1,2-diphenylethanol. The title compound was isolated as a white solid; melting point: 93-95℃. The ee was determined by HPLC using a Daicel Chiralpak AS-H column (19/1 hexane/i-PrOH; flow rate 0.8 mL/min; τ_major = 26.9 min; τ_minor = 33.2 min); ee = 93%. [α]²⁴ _D = -48.0° (c = 0.540, CH₂Cl₂). IR (cm^-1): 3398, 3061, 3028, 2934, 2857, 1608, 1509, 1455, 1225, 1027, 738, 701. ¹H NMR (400 MHz, CDCl₃): δ= 2.75 (br s, 1H), 3.80 (s, 3H), 4.46 (d, J = 6.4 Hz, 1H), 4.78 (d, J = 6.4 Hz, 1H), 6.36 (dd, J = 7.8 Hz, J = 1.4 Hz, 1H), 6.58-6.65 (m, 2H), 6.71 (dd, J = 7.8 Hz, J = 1.8 Hz, 1H), 7.11-7.21 (m,10H). ¹³C NMR (100 MHz, CDCl₃): δ = 55.5, 64.9, 78.2, 109.6, 111.7, 117.1, 121.0, 126.7, 127.3, 127.7, 128.0, 128.3, 137.1, 140.2, 140.7, 147.4. HRMS (ESI): [M+H]⁺ calcd. 320.1651, found 320.1638. Example 3:
(1S, 2S) -2- (2-Methoxyphenylamino) -1,2-diphenylethanol. The title compound was isolated as a white solid; melting point: 93-95 ° C. The ee was determined by HPLC using a Daicel Chiralpak AS- H column (19/1 hexane / i-PrOH; flow rate 0.8 mL / min; τ _major = 26.9 min; τ _minor = 33.2 min); ee = 93%. [Α] ²⁴ _D = -48.0 ° (c = 0.540 , CH ₂ Cl ₂ ). IR (cm ^-1 ): 3398, 3061, 3028, 2934, 2857, 1608, 1509, 1455, 1225, 1027, 738, 701. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 2.75 (br s, 1H), 3.80 (s, 3H), 4.46 (d, J = 6.4 Hz, 1H), 4.78 (d, J = 6.4 Hz, 1H), 6.36 (dd, J = 7.8 Hz, J = 1.4 Hz, 1H), 6.58-6.65 (m, 2H), 6.71 (dd, J = 7.8 Hz, J = 1.8 Hz, 1H), 7.11-7.21 (m, 10H). ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 55.5, 64.9, 78.2, 109.6, 111.7, 117.1, 121.0, 126.7, 127.3, 127.7, 128.0, 128.3, 137.1, 140.2, 140.7, 147.4. HRMS (ESI): [M + H] ⁺ calcd. 320.1651, found 320.1638.

実施例４：
(1S,2S)-2-(Naphtalen-1-ylamino)-1,2-diphenylethanol. The title compound was isolated as a white solid; melting point: 52-55℃. The ee was determined by HPLC using a Daicel Chiralpak OD column (19/1 hexane/i-PrOH; flow rate 1 mL/min; τ_minor = 24.9 min; τ_major = 50.3 min); ee = 91%. [α]²² _D = -144.9°(c = 0.390, CH₂Cl₂). IR (cm^-1): 3401, 3058, 3028, 2923, 1630, 1520, 1051, 831, 745, 700. ¹H NMR (400 MHz, CDCl₃): δ = 2.72 (br s, 1H), 4.65 (d, J = 5.5 Hz, 1H ), 4.91 (d, J = 6.0 Hz, 1H), 5.51 (br s, 1H), 6.26 (d, J = 6.9 Hz, 1H), 7.05-7.28 (m, 12H), 7.39-7.47 (m, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃): δ= 64.4, 78.2, 106.6, 117.6, 120.0, 123.9, 124.8, 125.6, 126.4, 126.5, 127.2, 127.5, 127.9, 128.3, 128.5, 128.6, 134.2, 139.9, 140.7, 142.1. HRMS (ESI): [M+H]⁺ calcd. 340.1701, found 340.1698. Example 4:
(1S, 2S) -2- (Naphtalen-1-ylamino) -1,2-diphenylethanol.The title compound was isolated as a white solid; melting point: 52-55 ° C. The ee was determined by HPLC using a Daicel Chiralpak OD column (19/1 hexane / i-PrOH; flow rate 1 mL / min; τ _minor = 24.9 min; τ _major = 50.3 min); ee = 91%. [Α] ²² _D = -144.9 ° (c = 0.390 , CH ₂ Cl ₂ ). IR (cm ^-1 ): 3401, 3058, 3028, 2923, 1630, 1520, 1051, 831, 745, 700. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 2.72 (br s, 1H), 4.65 (d, J = 5.5 Hz, 1H), 4.91 (d, J = 6.0 Hz, 1H), 5.51 (br s, 1H), 6.26 (d, J = 6.9 Hz, 1H), 7.05 -7.28 (m, 12H), 7.39-7.47 (m, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 64.4, 78.2, 106.6, 117.6, 120.0, 123.9, 124.8, 125.6, 126.4, 126.5, 127.2, 127.5, 127.9, 128.3, 128.5, 128.6, 134.2, 139.9, 140.7, 142.1.HRMS (ESI): [ M + H] ⁺ calcd. 340.1701, found 340.1698.

実施例５：
(1S,2S)-2-(4-Bromo-naphtalen-1-ylamino)-1,2-diphenylethanol. The title compound was isolated as a white solid; melting point: 63-65℃. The ee was determined by HPLC using a Daicel Chiralpak OD column (9/1 hexane/i-PrOH; flow rate 1 mL/min; τ_minor = 18 .0 min; τ_major = 24.7 min); ee = 86%. [α]²² _D = -87.8°(c = 0.435, CH₂Cl₂). IR (cm^-1): 3423, 3063, 3009, 2923, 1590, 1523, 1475,1380, 1052, 752, 700. ¹H NMR (400 MHz, CDCl₃): δ= 2.53 (br s, 1H), 4.64 (d, J = 5.5 Hz, 1H), 4.98 (d, J = 5.0 Hz, 1H), 5.61 (br s, 1H), 6.1 (d, J = 8.2 Hz, 1H), 7.19-7.34 (m, 11H), 7.49-7.57 (m, 2H), 7.97 (d, J = 8.2 Hz, 1H), 8.15 (dd, J = 8.7 Hz, J = 1.4 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃): δ= 64.3, 78.2, 107.2, 110.3, 120.4, 125.2, 125.5, 126.4, 127.0, 127.1, 127.7, 127.8, 128.1, 128.4, 128.6, 130.1, 132.1, 139.5, 140.5, 142.1. HRMS (ESI): [M+H]⁺ calcd. 418.0807, found 418.0793. Example 5:
(1S, 2S) -2- (4-Bromo-naphtalen-1-ylamino) -1,2-diphenylethanol. The title compound was isolated as a white solid; melting point: 63-65 ° C. The ee was determined by HPLC using a Daicel Chiralpak OD column (9/1 hexane / i-PrOH; flow rate 1 mL / min; τ _minor = 18.0 min; τ _major = 24.7 min); ee = 86%. [α] ²² _D =- 87.8 ° (c = 0.435, CH ₂ Cl ₂ ) .IR (cm ^-1 ): 3423, 3063, 3009, 2923, 1590, 1523, 1475,1380, 1052, 752, 700. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 2.53 (br s, 1H), 4.64 (d, J = 5.5 Hz, 1H), 4.98 (d, J = 5.0 Hz, 1H), 5.61 (br s, 1H), 6.1 (d, J = 8.2 Hz, 1H), 7.19-7.34 (m, 11H), 7.49-7.57 (m, 2H), 7.97 (d, J = 8.2 Hz, 1H), 8.15 (dd, J = 8.7 Hz, J = 1.4 Hz ¹³ C NMR (100 MHz, CDCl ₃ ): δ = 64.3, 78.2, 107.2, 110.3, 120.4, 125.2, 125.5, 126.4, 127.0, 127.1, 127.7, 127.8, 128.1, 128.4, 128.6, 130.1, 132.1 , 139.5, 140.5, 142.1. HRMS (ESI): [M + H] ⁺ calcd. 418.0807, found 418.0793.

実施例６：
(1S,2S)-2-(Phenylamino)-1,2-di(p-tolyl)-ethanol. The title compoundwas isolated as a white solid; melting point: 41-43 °C. The ee was determined by HPLC using a Daicel Chiralpak OD column (19/1 hexane/i-PrOH;flow rate 1 mL/min; tminor = 26.2 min; tmajor = 31.8 min); ee = 90%. [α]22D= -47.3° (c = 0.54, CH2Cl2). IR (cm-1): 3400, 3019, 2920, 1602, 1503, 1318, 1265, 1050, 820, 749, 691. 1H NMR (400 MHz, CDCl3): d = 2.24 (s, 3H), 2.27 (s, 3H), 2.75 (dr s, 1H), 4.43 (d, J = 6.0 Hz, 1H), 4.72 (d, J = 6.0 Hz, 1H), 6.48 (d, J = 8.2 Hz, 2H), 6.60 (t, J = 7.3 Hz, 1H), 6.99-7.12 (m, 10H). 13C NMR (100 MHz, CDCl3): d =20.9, 21.0, 64.2, 77.7, 114.0, 117.6, 126.4, 127.1, 128.8, 128.9, 129.1, 136.8, 137.2, 137.3, 137.6, 147.3. HRMS (ESI): [M+H]+ calcd. 318.1878, found 418.1900. Example 6:
(1S, 2S) -2- (Phenylamino) -1,2-di (p-tolyl) -ethanol.The title compoundwas isolated as a white solid; melting point: 41-43 ° C. The ee was determined by HPLC using a Daicel Chiralpak OD column (19/1 hexane / i-PrOH; flow rate 1 mL / min; tminor = 26.2 min; tmajor = 31.8 min); ee = 90%. [α] 22D = -47.3 ° (c = 0.54 , CH2Cl2) .IR (cm-1): 3400, 3019, 2920, 1602, 1503, 1318, 1265, 1050, 820, 749, 691.1H NMR (400 MHz, CDCl3): d = 2.24 (s, 3H) , 2.27 (s, 3H), 2.75 (dr s, 1H), 4.43 (d, J = 6.0 Hz, 1H), 4.72 (d, J = 6.0 Hz, 1H), 6.48 (d, J = 8.2 Hz, 2H ), 6.60 (t, J = 7.3 Hz, 1H), 6.99-7.12 (m, 10H) .13C NMR (100 MHz, CDCl3): d = 20.9, 21.0, 64.2, 77.7, 114.0, 117.6, 126.4, 127.1, 128.8, 128.9, 129.1, 136.8, 137.2, 137.3, 137.6, 147.3. HRMS (ESI): [M + H] + calcd. 318.1878, found 418.1900.

実施例７：
(1S,2S)-1,2-(Di-naphthalen-2-yl)-2-phenylamino-ethanol. The title compound was isolated as a white solid; melting point: 146-148℃. The ee was determined by HPLC using a Daicel Chiralpak OD column (9/1 hexane/i-PrOH; flow rate 1 mL/min; τ_minor = 38.2 min; τ_major = 53.7 min); ee = 91%. [α]²² _D = -133.8°(c = 0.410, CH₂Cl₂). IR (cm^-1): 3399, 3052, 2923, 1601, 1503, 1317, 1265,1051, 819, 749. ¹H NMR (400 MHz, CDCl₃): δ= 2.90 (br s, 1H), 4.76 (d, J = 6.0 Hz, 1H), 5.04 (d, J = 5.5 Hz, 1H), 6.52 (d, J = 8.7 Hz, 2H), 6.57-6.61 (m, 1H), 6.98-7.02 (m, 2H), 7.28-7.32 (m, 2H), 7.37-7.43 (m, 4H), 7.66-7.76 (m, 8H). ¹³C NMR (100 MHz, CDCl₃): δ= 64.6, 76.7, 114.1, 117.9, 124.4, 125.3, 125.6, 125.8, 126.0, 126.1, 126.2, 127.9, 128.0, 128.4, 129.0, 132.9, 133.0, 133.1, 133.3, 137.8, 138.0, 147.2. HRMS (ESI): [M+H]⁺ calcd. 390.1858, found 390.1849. Example 7:
(1S, 2S) -1,2- (Di-naphthalen-2-yl) -2-phenylamino-ethanol.The title compound was isolated as a white solid; melting point: 146-148 ° C. The ee was determined by HPLC using a Daicel Chiralpak OD column (9/1 hexane / i-PrOH; flow rate 1 mL / min; τ _minor = 38.2 min; τ _major = 53.7 min); ee = 91%. [α] ²² _D = -133.8 ° (c = 0.410, CH ₂ Cl ₂ ) .IR (cm ^-1 ): 3399, 3052, 2923, 1601, 1503, 1317, 1265,1051, 819, 749. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 2.90 (br s, 1H), 4.76 (d, J = 6.0 Hz, 1H), 5.04 (d, J = 5.5 Hz, 1H), 6.52 (d, J = 8.7 Hz, 2H), 6.57-6.61 (m , 1H), 6.98-7.02 (m, 2H), 7.28-7.32 (m, 2H), 7.37-7.43 (m, 4H), 7.66-7.76 (m, 8H). ¹³ C NMR (100 MHz, CDCl ₃ ) : δ = 64.6, 76.7, 114.1, 117.9, 124.4, 125.3, 125.6, 125.8, 126.0, 126.1, 126.2, 127.9, 128.0, 128.4, 129.0, 132.9, 133.0, 133.1, 133.3, 137.8, 138.0, 147.2.HRMS (ESI ): [M + H] ⁺ calcd. 390.1858, found 390.1849.

実施例８：
(3S,4S)-1,6-Diphenyl-4-phenylamino-hexan-3-ol. The title compound was isolated as a colorless oil. The ee was determined by HPLC using a Daicel Chiralpak OD column (9/1 hexane/i-PrOH; flow rate 0.8 mL/min; τ_major = 32.3 min; τ_minor = 37.4 min); ee = 60%. [α]²² _D = -1.7°(c = 0.525, CH₂Cl₂). IR (cm^-1): 3047, 3050, 3024, 2926, 2857, 1600, 1497, 1454, 1318, 1060, 748, 698. ¹H NMR (400 MHz, CDCl₃): δ= 1.74-1.86 (m, 3H), 1.90-1.99 (m, 1H), 2.25 (br s, 1H), 2.56-2.73 (m, 3H), 2.77-2.84 (m, 1H), 3.31-3.34 (m, 1H), 3.61-3.65(m, 1H), 5.57-6.60 (m, 2H), 6.70 (td, J = 7.3 Hz, J = 0.9 Hz, 1H), 6.71-7.29 (m, 12H). ¹³C NMR (100 MHz, CDCl₃): δ= 32.2, 32.4, 34.3, 35.8, 57.7, 72.8, 117.6, 125.9, 126.0, 128.4, 128.5, 129.4, 141.6, 141.9, 148.3. HRMS (ESI): [M+H]⁺ calcd. 346.2171, found 346.2182. Example 8:
(3S, 4S) -1,6-Diphenyl-4-phenylamino-hexan-3-ol.The title compound was isolated as a colorless oil.The ee was determined by HPLC using a Daicel Chiralpak OD column (9/1 hexane / i-PrOH; flow rate 0.8 mL / min; τ _major = 32.3 min; τ _minor = 37.4 min); ee = 60%. [α] ²² _D = -1.7 ° (c = 0.525, CH ₂ Cl ₂ ). IR ^{(cm -1): 3047, 3050} , 3024, 2926, 2857, 1600, 1497, 1454, 1318, 1060, 748, 698. 1 H NMR (400 MHz, CDCl 3): δ = 1.74-1.86 (m, 3H ), 1.90-1.99 (m, 1H), 2.25 (br s, 1H), 2.56-2.73 (m, 3H), 2.77-2.84 (m, 1H), 3.31-3.34 (m, 1H), 3.61-3.65 ( m, 1H), 5.57-6.60 (m, 2H), 6.70 (td, J = 7.3 Hz, J = 0.9 Hz, 1H), 6.71-7.29 (m, 12H). ¹³ C NMR (100 MHz, CDCl ₃ ) : δ = 32.2, 32.4, 34.3, 35.8, 57.7, 72.8, 117.6, 125.9, 126.0, 128.4, 128.5, 129.4, 141.6, 141.9, 148.3. HRMS (ESI): [M + H] ⁺ calcd. 346.2171, found 346.2182 .

実施例９：
(5S,6S)- 6-Phenylamino-decan-5-ol. The title compound was isolated as a colorless oil. The ee was determined by HPLC using a Daicel Chiralpak AD-H column (19/1 hexane/i-PrOH; flow rate 0.8 mL/min; τ_minor = 11.7 min; τ_major = 12.8 min); ee = 71%. [α]²² _D = -2.9°(c = 0.515, CH₂Cl₂). IR (cm^-1): 3405, 2950, 2951, 2858, 1601, 1457, 747, 692. ¹H NMR (400 MHz, CDCl₃): δ= 0.84-0.92 (m, 6H), 1.25-1.65 (m, 12H), 3.23-3.28 (m, 1H), 3.56-3.60 (m, 1H), 6.62-6.70 (m, 3H), 7.13-7.24 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): δ= 14.0, 14.1, 22.8, 28.2, 28.4, 32.2, 33.8, 73.5, 113.5, 117.4, 129.3, 148.6. HRMS (ESI): [M+H]⁺ calcd. 250.2171, found 250.2169.
Example 9:
(5S, 6S)-6-Phenylamino-decan-5-ol.The title compound was isolated as a colorless oil.The ee was determined by HPLC using a Daicel Chiralpak AD-H column (19/1 hexane / i-PrOH; flow rate 0.8 mL / min; τ _minor = 11.7 min; τ _major = 12.8 min); ee = 71%. [α] ²² _D = -2.9 ° (c = 0.515, CH ₂ Cl ₂ ). IR (cm ^-1 ): 3405, 2950, 2951, 2858, 1601, 1457, 747, 692.1 ¹ H NMR (400 MHz, CDCl ₃ ): δ = 0.84-0.92 (m, 6H), 1.25-1.65 (m, 12H), 3.23 -3.28 (m, 1H), 3.56-3.60 (m, 1H), 6.62-6.70 (m, 3H), 7.13-7.24 (m, 2H) 13 C NMR (100 MHz, CDCl 3):. δ = 14.0, 14.1, 22.8, 28.2, 28.4, 32.2, 33.8, 73.5, 113.5, 117.4, 129.3, 148.6. HRMS (ESI): [M + H] ⁺ calcd. 250.2171, found 250.2169.

Claims

In an aqueous solution or a mixed solvent of water and an organic solvent,

(In the formula, R ⁵ and R ⁶ may be the same or different and each represents a hydrogen atom, an aliphatic hydrocarbon group, an araliphatic hydrocarbon group or a heterocyclic ring which may have a substituent. An epoxide represented by a group, provided that at least one of R ⁵ and R ⁶ is not a hydrogen atom, and R ⁷ R ⁸ NH (wherein R ⁷ and R ⁸ are the same, respectively) They may be different and each represents a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, an araliphatic hydrocarbon group or a heterocyclic group, provided that at least one of R ⁷ and R ⁸ is not a hydrogen atom. No.). A process for producing an optically active β-aminoalcohol compound comprising reacting with a primary or secondary amine compound.

The process according to claim 1, wherein M is scandium.

The process according to claim 1 or 2, wherein R ⁴ is an alkyl group or alkylaryl group having 6 to 20 carbon atoms.

The method according to any one of claims 1 to 3, wherein the epoxide is a meso form (that is, R ⁵ and R ⁶ are the same).

The said amine compound is an aromatic amine, The manufacturing method as described in any one of Claims 1-4.

An optically active β-amino alcohol compound represented by the following formula (Chemical Formula 3) produced by the production method according to claim 1.

(Wherein R ^{5 to} R ⁸ represent the same as above)

The following formula

(In the formula, R ¹ represents an alkyl group having 3 or more carbon atoms or an aryl group, R ² represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group, and X represents —OH, — A ligand represented by SH or —NHR ³ (wherein R ³ represents a hydrogen atom or an alkyl group) or a symmetric product thereof and M (OSO ₂ R ⁴ ) ₃ or M (OSO ₃ R ⁴ ) ₃ (wherein M represents Sc, Y or a lanthanoid element, and R ⁴ represents an aliphatic hydrocarbon group having 6 or more carbon atoms, an aromatic hydrocarbon group or a perfluoroalkyl group). A catalyst obtained by mixing with the represented Lewis acid.

The catalyst according to claim 7, wherein M is scandium.

The catalyst according to claim 7 or 8, wherein R ⁴ is an alkyl group having 6 to 20 carbon atoms or an alkylaryl group.