JP2012144471A - Asymmetric phosphonite compound, asymmetric synthesis catalyst, method of manufacturing asymmetric phosphonite compound, and method of manufacturing organic compound having optical activity - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide asymmetric phosphonite compound used for a catalyst ligand or the like of axially asymmetric biaryl synthesis excellent in reactivity, turn over number, and asymmetric yield.SOLUTION: There are disclosed an asymmetric phosphonite compound represented by compound 02 and compound 03, a tautomer or stereoisomer of the compound or a salt thereof. Compound 01 is a reference example for comparison with the compound.

Description

  The present invention relates to an asymmetric phosphonite compound, an asymmetric synthesis catalyst, a method for producing an asymmetric phosphonite compound, and a method for producing an organic compound having optical activity.

The Suzuki-Miyaura cross-coupling reaction (hereinafter referred to as “Suzuki-Miyaura reaction”) is one of the most versatile sp ² carbon-sp ² carbon bond forming reactions. Among the Suzuki-Miyaura reactions, axially asymmetric biaryl synthesis by “catalytic asymmetric” has attracted attention in recent years, and many research results have been reported. The reason is that optically active biaryls having axial asymmetry are extremely important in fields such as synthetic chemistry, medicinal chemistry, material chemistry, supramolecular chemistry, and the like. If axially chiral biaryl can be supplied inexpensively, in large quantities, safely and with high quality by catalytic asymmetric Suzuki-Miyaura reaction, the impact on the above fields will be enormous, and a great contribution to industrial development is expected. .

  Among axial asymmetric biaryl syntheses by the Suzuki-Miyaura reaction, for example, the research results of Lassaletta et al. (Non-Patent Document 1) and Uozumi et al.

  Further, the present inventors have succeeded in synthesizing axially asymmetric biaryls with high reactivity and catalyst rotation number (TON; Turn Over Number) by the Suzuki-Miyaura reaction using a phosphonite compound as a metal catalyst ligand. (Non-Patent Document 3).

Lassaletta et al., J. Am. Chem. Soc. 2008, 130 (47), 15798-15799. Uozumi et al., Angew. Chem., Int. Ed. 2009, 48 (15) 2708-2710. Tetsuro Iwasawa “Catalyst Development for Practical Synthesis of Axially Biaryl” (2009 Ryukoku University Research Center for Innovative Materials and Processes, “Research and Development of Innovative Materials for Effective Use of Energy”, 2010 Issued in March, p177)

  The methods of Non-Patent Documents 1 and 2 have a very high asymmetric yield, but there is a problem of high cost for practical use. That is, first, these methods are difficult to use for substrates (reaction raw materials) with relatively low reactivity, such as aromatic chlorides. Therefore, expensive aromatic bromide or aromatic iodide must be used, which increases the cost. Further, these methods have a low TON (that is, the number of target molecules that can be generated per molecule of the catalyst is small), necessitates a large amount of expensive catalyst, and increases the cost. Not only the methods of Non-Patent Documents 1 and 2, but the conventional asymmetric biaryl synthesis by the Suzuki-Miyaura reaction similarly has a problem of high cost due to low reactivity and low TON.

  On the other hand, the method of Non-Patent Document 3 is highly reactive and easy to use for aromatic chlorides and has a high TON, but the asymmetric yield is not so high.

  Accordingly, an object of the present invention is to provide an asymmetric phosphonite compound that can be used, for example, as a catalyst ligand for axially asymmetric biaryl synthesis excellent in reactivity, TON, and asymmetric yield. Furthermore, the present invention provides an asymmetric synthesis catalyst, a method for producing an asymmetric phosphonite compound, and a method for producing an organic compound having optical activity.

前記化学式（Ｉ）中、
各Ａｒは、置換または無置換のアリール基であり、同一でも異なっていてもよく、
Ａｒのうち少なくとも一つは、下記化学式（II）で表される基であり、

前記化学式（II）中、
ｍ１は、０から３までの置換数であり、
Ｒ^１は、任意の置換基であり、複数の場合は同一でも異なっていてもよく、
Ｐは、水素原子または任意の置換基であり、複数の場合は同一でも異なっていてもよく、
または、Ｒ^１およびＰの少なくとも二つが、前記化学式（II）中のベンゼン環とともに縮合環を形成してもよく、
ただし、前記化学式（Ｉ）の全てのＡｒ中、少なくとも一つのＰは、下記化学式（III）で表される基またはその幾何異性体もしくは立体異性体であり、

前記化学式（III）中、
ｍ２は、０から４までの置換数であり、各ｍ２は同一でも異なっていてもよく、
ｍ３は、０から１までの置換数であり、各ｍ３は同一でも異なっていてもよく、
Ｒ^２は、任意の置換基であり、各Ｒ^２は同一でも異なっていてもよく、
Ｒ^３は、任意の置換基であり、複数の場合は同一でも異なっていてもよく、
または、Ｒ^２およびＲ^３の二つ以上が一体となって、それらが結合しているベンゼン環とともに縮合環を形成してもよい。 In order to achieve the above object, the asymmetric phosphonite compound of the present invention is an asymmetric phosphonite compound represented by the following chemical formula (I), a tautomer or stereoisomer thereof, or a salt thereof.

In the chemical formula (I),
Each Ar is a substituted or unsubstituted aryl group, which may be the same or different;
At least one of Ar is a group represented by the following chemical formula (II),

In the chemical formula (II),
m1 is the number of substitutions from 0 to 3,
R ¹ is an optional substituent, and when plural R ¹ may be the same or different,
P is a hydrogen atom or an arbitrary substituent, and when plural, they may be the same or different,
Alternatively , at least two of R ¹ and P may form a condensed ring together with the benzene ring in the chemical formula (II),
However, in all Ar of the chemical formula (I), at least one P is a group represented by the following chemical formula (III) or a geometric isomer or stereoisomer thereof,

In the chemical formula (III),
m2 is the number of substitutions from 0 to 4, and each m2 may be the same or different,
m3 is the number of substitutions from 0 to 1, and each m3 may be the same or different,
R ² is an optional substituent, and each R ² may be the same or different,
R ³ is an arbitrary substituent, and in the case of plural, R ³ may be the same or different,
Alternatively, two or more of R ² and R ³ may be combined to form a condensed ring together with the benzene ring to which they are bonded.

  The asymmetric synthesis catalyst of the present invention is an asymmetric synthesis catalyst containing the asymmetric phosphonite compound of the present invention, a tautomer or stereoisomer thereof, or a salt thereof, and a metal atom or ion.

前記化学式（Ｉ'）中、
Ａｒ^２は、前記化学式（III）で表される基またはその幾何異性体もしくは立体異性体に代えてハロゲノ基を有する以外は、前記化学式（Ｉ）中のＡｒと同じであり、
前記化学式（III’）中、
ｍ２、ｍ３、Ｒ^２およびＲ^３は、前記化学式（III）と同じである。 The method for producing an asymmetric phosphonite compound of the present invention is represented by the following chemical formula (I ′), a tautomer or stereoisomer thereof, or a salt thereof, and the following chemical formula (III ′). Asymmetric phosphonite represented by the above chemical formula (I) by coupling a compound, a tautomer or stereoisomer thereof, or a salt thereof in the presence of an organic alkali metal and a halide of phosphorus. The method for producing an asymmetric phosphonite compound of the present invention, a tautomer or stereoisomer thereof, or a salt thereof, comprising an asymmetric phosphonite compound synthesis step of synthesizing the compound.

In the chemical formula (I ′),
Ar ² is the same as Ar in the chemical formula (I) except that it has a halogeno group instead of the group represented by the chemical formula (III) or a geometric isomer or stereoisomer thereof,
In the chemical formula (III ′),
m @ 2, m3, ^{R 2} and ^{R 3} are the same as the chemical formula (III).

  The method for producing an organic compound having optical activity (asymmetric synthesis) according to the present invention is characterized by producing the organic compound having optical activity by an asymmetric synthesis reaction using the asymmetric synthesis catalyst of the present invention. And

  ADVANTAGE OF THE INVENTION According to this invention, the asymmetric phosphonite compound which can be used for the catalyst ligand etc. of the axial asymmetric biaryl synthesis | combination excellent in reactivity, TON, and an asymmetric yield can be provided. Furthermore, according to the present invention, an asymmetric synthesis catalyst, a method for producing an asymmetric phosphonite compound, and a method for producing an organic compound having optical activity can be provided.

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

<Asymmetric phosphonite compound>
In the asymmetric phosphonite compound of the present invention,
In the chemical formula (II), R ¹ is preferably a chain hydrocarbon group, an alicyclic hydrocarbon group, or an aryl group. However, the chain hydrocarbon group may be saturated or unsaturated, linear or branched, may or may not have a substituent, and the alicyclic hydrocarbon group is It may be saturated or unsaturated, may or may not have a substituent, and the aryl group may or may not have a substituent.
P is preferably a hydrogen atom, a group represented by the chemical formula (III) or a geometrical isomer or stereoisomer thereof, a chain hydrocarbon group, an alicyclic hydrocarbon group, or an aryl group. However, the chain hydrocarbon group may be saturated or unsaturated, linear or branched, may or may not have a substituent, and the alicyclic hydrocarbon group is It may be saturated or unsaturated, may or may not have a substituent, and the aryl group may or may not have a substituent.
Alternatively , at least two of R ¹ and P may form a condensed ring together with the benzene ring in the chemical formula (II).
However, in all Ar of the chemical formula (I), at least one P is a group represented by the chemical formula (III) or a geometric isomer or stereoisomer thereof.

In the chemical formula (III), R ² is preferably a chain hydrocarbon group, an alicyclic hydrocarbon group, or an aryl group. However, the chain hydrocarbon group may be saturated or unsaturated, linear or branched, may or may not have a substituent, and the alicyclic hydrocarbon group is It may be saturated or unsaturated, may or may not have a substituent, and the aryl group may or may not have a substituent.
R ³ is preferably a chain hydrocarbon group, an alicyclic hydrocarbon group, or an aryl group. However, the chain hydrocarbon group may be saturated or unsaturated, linear or branched, may or may not have a substituent, and the alicyclic hydrocarbon group is It may be saturated or unsaturated, may or may not have a substituent, and the aryl group may or may not have a substituent.
Alternatively, two or more of R ² and R ³ may be combined to form a condensed ring together with the benzene ring to which they are bonded.

The compound of Non-Patent Document 3 (ligand of the asymmetric synthesis catalyst) does not have a substituent corresponding to R ² in the chemical formula (III), whereas the asymmetric phosphonite compound of the present invention is R ² is different. Thereby, the asymmetric phosphonite compound of this invention can implement | achieve a high asymmetric yield, for example, when it uses for an asymmetric synthesis catalyst. Although the mechanism by which a high asymmetric yield can be realized by having R ² is unknown, for example, the interaction between a bulky substituent and a reactant is considered to be one of the factors. In addition, the asymmetric phosphonite compound of the present invention has a structure as a monodentate ligand with respect to, for example, a metal atom or ion, and generates an active species that achieves a high catalyst rotation speed, and as an aromatic ring linking molecule. It is thought that this structure stabilizes this active species. However, these mechanisms are speculations and do not limit the present invention.

  When the asymmetric phosphonite compound of the present invention has isomers such as tautomers or stereoisomers (eg, geometric isomers, conformational isomers and optical isomers), any isomers are present. Can be used for invention. For example, when the optical isomer is used for asymmetric synthesis or the like, it is preferable to selectively use either the R isomer or the S isomer depending on the purpose. Moreover, the salt of the asymmetric phosphonite compound of this invention can be used for this invention similarly. The salt may be an acid addition salt or a base addition salt. Furthermore, the acid forming the acid addition salt may be an inorganic acid or an organic acid, and the base forming the base addition salt may be an inorganic base or an organic base. The inorganic acid is not particularly limited. For example, sulfuric acid, phosphoric acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, hypofluorite, hypochlorous acid, hypobromite, Hypoiodous acid, fluorinated acid, chlorous acid, bromic acid, iodic acid, fluoric acid, chloric acid, bromic acid, iodic acid, perfluoric acid, perchloric acid, perbromic acid, periodic acid, etc. Can be mentioned. Although the organic acid is not particularly limited, for example, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, hydroxycarboxylic acid, propionic acid , Malonic acid, adipic acid, fumaric acid, maleic acid and the like. Examples of the inorganic base include, but are not limited to, ammonium hydroxide, alkali metal hydroxide, alkaline earth metal hydroxide, carbonate, bicarbonate, sulfate, and the like. More specifically, Examples thereof include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, calcium hydroxide, calcium carbonate, potassium sulfate, calcium sulfate and the like. The organic base is not particularly limited, and examples thereof include alcohol amine, trialkylamine, tetraalkylammonium, and tris (hydroxymethyl) aminomethane. Examples of the alcohol amine include ethanolamine. Examples of the trialkylamine include trimethylamine, triethylamine, tripropylamine, tributylamine, and trioctylamine. Examples of the tetraalkylammonium include tetramethylammonium, tetraethylammonium, tetrapropylammonium, tetrabutylammonium, tetraoctylammonium and the like. The method for producing these salts is not particularly limited. For example, the salt can be produced by a method such as appropriately adding the above acid or base to the asymmetric phosphonite compound by a known method.

  In the present invention, examples of the chain hydrocarbon group include an alkyl group, an alkenyl group, and an alkynyl group. An alkenyl group may have a structure in which any carbon-carbon bond of an alkyl group is converted to a double bond by dehydrogenation, and an alkynyl group is a structure in which any carbon-carbon bond of an alkyl group is converted to a triple bond by dehydrogenation. It may be a structure. Carbon number of the said chain hydrocarbon group is 1-32, for example, Preferably it is 1-24, More preferably, it is 1-18, More preferably, it is 1-12, More preferably, it is 1-6, Most preferably, it is 1-2. is there. The same applies to groups derived from chain hydrocarbon groups (for example, haloalkyl groups, hydroxyalkyl groups, aminoalkyl groups, alkanoyl groups, alkoxy groups, alkoxyalkyl groups, alkylamino groups, perfluoroalkyl groups, etc.). However, when the chain hydrocarbon group contains a substituent, the carbon number does not include the carbon number of the substituent. In the present invention, the alkyl group specifically includes, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group and tert-butyl group, pentyl group, Examples include hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl and the like. In groups derived from alkyl groups (for example, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, aminoalkyl groups, alkanoyl groups, alkoxy groups, alkylamino groups, perfluoroalkyl groups, alkenyl groups, alkoxyalkyl groups, etc.) Is the same. In the present invention, the acyl group is not particularly limited. For example, formyl group, acetyl group, propionyl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, cyclohexanoyl group, benzoyl group, ethoxycarbonyl The same applies to groups containing an acyl group in the structure (acyloxy group, alkanoyloxy group, etc.). In the present invention, the carbon number of the acyl group includes carbonyl carbon. For example, an alkanoyl group having 1 carbon atom (acyl group) refers to a formyl group. Furthermore, in the present invention, “halogen” refers to any halogen element, and examples thereof include fluorine, chlorine, bromine and iodine. Similarly, the halogeno group includes, for example, a fluoro group, a chloro (chloro) group, a bromo group, and an iodo group.

  In the present invention, the number of ring members (the number of atoms constituting the ring) of a cyclic group such as an alicyclic hydrocarbon group and an aryl group is, for example, 5-32, preferably 5-24, more preferably 6-18, More preferably, it is 6-12, Most preferably, it is 6-10. In the present invention, the alicyclic hydrocarbon group means a non-aromatic cyclic hydrocarbon group. In the alicyclic hydrocarbon group, for example, at least one of carbon atoms constituting the ring may be replaced by a heteroatom such as oxygen (O), sulfur (S), nitrogen (N), or the like. It does not have to be. In the present invention, the aryl group is not limited to an aromatic hydrocarbon group unless otherwise specified, and includes a heteroaryl group. In the present invention, examples of the alicyclic hydrocarbon group include a cyclopentyl group, a cyclohexyl group, a cyclobutyl group, and a cyclopropyl group. Aryl groups include, for example, phenyl group, naphthyl group, anthryl group, phenanthryl group, pyrenyl group, pyridyl group, quinolyl group, acridyl group, furanyl group, thienyl group, carbazoyl group, fluorenyl group, orthoxyl group, tolyl group, etc. Can be mentioned.

  In the present invention, when an aryl group, a chain hydrocarbon group, an alicyclic hydrocarbon group or the like further has a substituent, the substituent is not particularly limited, and examples thereof include an alkyl group, a hydroxy group, an alkoxy group, and an amino group. Group, alkylamino group, dialkylamino group, carboxy group, alkoxycarbonyl group, acyl group, alkanoyl group, aryl group, chain hydrocarbon group, alicyclic hydrocarbon group and the like. The substituent may be one, plural, or absent unless specifically limited, and in the case of plural, they may be the same or different.

  In the present invention, a chain group such as an alkyl group, an alkoxy group, an alkenyl group, and an alkanoyl group may be linear or branched unless otherwise limited. In the present invention, when an isomer is present in a substituent, a functional group, etc., any isomer may be used unless otherwise limited. For example, when simply referring to “propyl group”, it may be either an n-propyl group or an isopropyl group. When simply referred to as “butyl group”, any of n-butyl group, isobutyl group, sec-butyl group and tert-butyl group may be used. When simply referred to as “naphthyl group”, either a 1-naphthyl group or a 2-naphthyl group may be used.

前記化学式（IV）中、
Ｒ^１１〜Ｒ^２８は、それぞれ、水素原子もしくは任意の置換基であるか、または、同一のベンゼン環に結合しているＲ^ａ（ａは、１１〜２８のいずれか）の少なくとも二つが一体となって、前記ベンゼン環とともに縮合環を形成していてもよく、
Ｐは、前記化学式（III）で表される基またはその幾何異性体もしくは立体異性体である。 The asymmetric phosphonite compound of the present invention is preferably represented by the following chemical formula (IV).

In the chemical formula (IV),
R ^{11 to} R ²⁸ are each a hydrogen atom, an arbitrary substituent, or at least two of R ^a (a is any one of ^{11 to 28)} bonded to the same benzene ring. And may form a condensed ring together with the benzene ring,
P is a group represented by the chemical formula (III) or a geometric isomer or stereoisomer thereof.

In the chemical formula (IV),
R ^{11 to} R ²⁸ are each a hydrogen atom, a chain hydrocarbon group, an alicyclic hydrocarbon group, or an aryl group,
The chain hydrocarbon group may be saturated or unsaturated, linear or branched, may or may not have a substituent,
The alicyclic hydrocarbon group may be saturated or unsaturated, and may or may not have a substituent,
The aryl group may or may not have a substituent,
Alternatively, at least two of R ^a (a is any one of 11 to 28) bonded to the same benzene ring may be combined to form a condensed ring together with the benzene ring.

In the chemical formula (IV), it is more preferable that R ^{11 to} R ¹⁵ are methyl groups, and R ^{16 to} R ²⁸ are hydrogen atoms.

In the asymmetric phosphonite compound of the present invention, the group represented by the chemical formula (III) is a group represented by the following chemical formula (V) or (VI), or a geometric isomer or stereoisomer thereof. It is particularly preferred.

  The application of the asymmetric phosphonite compound of the present invention is not particularly limited and may be used for any application, but is preferably used for the asymmetric synthesis catalyst of the present invention.

<Asymmetric synthesis catalyst>
As described above, the asymmetric synthesis catalyst of the present invention is an asymmetric synthesis catalyst containing the asymmetric phosphonite compound of the present invention, a tautomer or stereoisomer thereof, or a salt thereof, and a metal atom or ion. is there. The structure of the asymmetric synthesis catalyst of the present invention is not particularly limited. For example, the asymmetric phosphonite compound of the present invention, a tautomer or stereoisomer thereof, or a salt thereof is converted into a ligand of the metal atom or ion. It may be a complex. Although the said metal is not specifically limited, For example, palladium, nickel, etc. are mentioned. The metal is preferably a transition metal, and particularly preferably palladium. The present invention is not limited to the present invention, but the same can be said for the general Suzuki-Miyaura reaction. Palladium has the advantage that it has less adverse effects on the environment because of its relatively low toxicity among metals.

  The asymmetric synthesis catalyst of the present invention may be used for any asymmetric synthesis reaction, but is particularly preferably used for the Suzuki-Miyaura reaction or the asymmetric biaryl synthesis, and used for the asymmetric biaryl synthesis by the Suzuki-Miyaura reaction. It is particularly preferred.

  Conventionally, academic research in asymmetric synthesis has been conducted mainly to increase the asymmetric yield as much as possible. However, even if the asymmetric yield is high, as described above, if an expensive synthetic raw material is required, the cost becomes high. A catalyst using a noble metal such as palladium is expensive. Therefore, if TON is low, a large amount of catalyst is required, resulting in high cost. If this high cost problem cannot be solved, even a reaction with a high asymmetric yield is unsuitable for mass production of industrially useful compounds. On the other hand, if an inexpensive synthetic raw material can be used or if the amount of catalyst used is small due to high TON, the reaction will be low in cost. A low-cost reaction is extremely advantageous for industrial use even if the asymmetric yield is somewhat low.

  Since the asymmetric synthesis catalyst of the present invention is excellent in reactivity, even if it is a substrate (reaction raw material) having a relatively low reactivity, such as an aromatic chloride, as shown in the examples described later, for example, The product can be obtained with good yield. In addition, according to the asymmetric catalyst of the present invention, a high TON and a high asymmetric yield can be obtained. For this reason, according to the asymmetric synthesis using the asymmetric synthesis catalyst of the present invention, the target product can be obtained efficiently at a low cost, which is extremely advantageous from an industrial viewpoint. However, the substrate (reaction raw material) of the asymmetric synthesis reaction using the asymmetric synthesis catalyst of the present invention is not particularly limited, and may be aromatic chloride, but may be aromatic bromide, aromatic iodide, or the like. . Further, as described above, the asymmetric synthesis catalyst of the present invention is particularly preferably used for asymmetric biaryl synthesis, but is not limited thereto, and a substrate other than an aromatic compound (for example, a halogenated alkyne) is used. Also good.

  In the present invention, the “asymmetric yield” is synonymous with the enantiomeric excess of the reaction product (may be abbreviated as ee). The asymmetric yield (ee) can be expressed as a value obtained by subtracting the smaller amount of substances from the larger amount of R and S forms in the reaction product and dividing the result by the total amount of substances. . In the present invention, “TON (also referred to as“ Turn Over Number ”or“ catalyst rotation number ”) refers to the number of molecules of the target product that can be generated per molecule of catalyst, and asymmetric synthesis until all of the catalyst is consumed. It can be expressed by a numerical value obtained by dividing the number of molecules of the target product obtained by the reaction by the number of molecules of the catalyst.

前記化学式（Ｉ'）中、
Ａｒ^２は、前記化学式（III）で表される基またはその幾何異性体もしくは立体異性体に代えてハロゲノ基を有する以外は、前記化学式（Ｉ）中のＡｒと同じであり、
前記化学式（III’）中、
ｍ２、ｍ３、Ｒ^２およびＲ^３は、前記化学式（III）と同じである。 <Method for producing asymmetric phosphonite compound>
The method for producing the asymmetric phosphonite compound of the present invention is not particularly limited and may be produced in any way, but is preferably produced by the production method of the present invention. As described above, the method for producing an asymmetric phosphonite compound of the present invention includes a compound represented by the following chemical formula (I ′), a tautomer or stereoisomer thereof, or a salt thereof, and the following chemical formula (III ′). And a tautomer or stereoisomer thereof, or a salt thereof, in the presence of an organic alkali metal and a halide of phosphorus, is represented by the above chemical formula (I). A step of synthesizing an asymmetric phosphonite compound.

In the chemical formula (I ′),
Ar ² is the same as Ar in the chemical formula (I) except that it has a halogeno group instead of the group represented by the chemical formula (III) or a geometric isomer or stereoisomer thereof,
In the chemical formula (III ′),
m @ 2, m3, ^{R 2} and ^{R 3} are the same as the chemical formula (III).

In the asymmetric phosphonite compound synthesis step (coupling reaction of the compounds (I ′) and (III ′)), the organic alkali metal is not particularly limited, but n-BuLi (normal butyl lithium), MeLi (methyl lithium) ), Sec-BuLi (secondary butyl lithium), t-BuLi (tertiary butyl lithium), and the like, and n-BuLi is particularly preferable. The phosphorus halide is not particularly limited, and examples thereof include PCl ₃ (phosphorus trichloride), and PCl ₃ is particularly preferable. The asymmetric phosphonite compound synthesis step may be further performed in the presence of a base. The base is preferably a tertiary amine such as triethylamine (Et ₃ N) or diisopropylethylamine (i-Pr ₂ NEt). The asymmetric phosphonite compound synthesis step is preferably performed in the presence of a solvent. The solvent is preferably an ether such as THF, diethyl ether, dioxane, dimethyl ether, ethyl methyl ether, cyclopentyl methyl ether. The reaction temperature and reaction time are not particularly limited, and may be appropriately set with reference to similar known reactions. For example, the reaction may be started while cooling in a dry ice bath or a liquid nitrogen bath so that the reaction does not run away, and the reaction temperature may be gradually raised to room temperature. In the present invention, “room temperature” is not particularly limited, but is, for example, 5 to 35 ° C. The reaction time is, for example, 1 to 12 hours (hr), preferably 1 to 6 hours (hr), more preferably 1 to 2 hours (hr). There are no particular limitations on the ratio of the reactants and solvents used, and for example, the stoichiometric ratio or other ratios may be used. Moreover, it is preferable that the said asymmetric phosphonite compound synthesis | combination process is performed in inert gas atmosphere, such as nitrogen and argon, from viewpoints, such as side reaction prevention.

The compound (III ′), that is, the 1,1′-binaphthyl derivative having the substituent R ² at the 3-position and the 3′-position may be used as long as a commercially available product is available, or produced by any method. You may do it. Although the manufacturing method is not specifically limited, For example, the following two manufacturing methods are mentioned.

前記化学式（VII）〜（IX）中、ｍ２、ｍ３およびＲ^３は、前記化学式（III’）と同じであり、
前記化学式（IX）中、Ｒ^２は、前記化学式（III’）と同じであり、
前記化学式（VIII）および（IX）中、Ｑは、保護基であり、各Ｑは、同一でも異なっていてもよい。 That is, first, the production of the compound (III ′) is as follows:
The following compound (VIII), its tautomer or stereoisomer, or a salt thereof is protected by protecting the hydroxyl group of the following compound (VII), its tautomer or stereoisomer, or a salt thereof with a protecting group. A hydroxyl group protecting step to be produced;
A substituent introduction step of introducing the substituent R ² into the following compound (VIII) to introduce the following compound (IX);
You may carry out by the manufacturing method including the deprotection process of deprotecting the following compound (IX) and manufacturing the said compound (III ').

In the chemical formulas (VII) to (IX), m2, m3 and R ³ are the same as those in the chemical formula (III ′).
In the chemical formula (IX), R ² is the same as the chemical formula (III ′),
In the chemical formulas (VIII) and (IX), Q is a protecting group, and each Q may be the same or different.

In the chemical formulas (VIII) and (IX), the protecting group Q is not particularly limited, and examples thereof include a methoxymethyl group (MOM), a 2-methoxyethoxymethyl group (MEM), a tetrahydrofuranyl group (THP), and benzyloxymethyl. Group (BOM), methylthiomethyl group (MTM), acetyl group (Ac), pivaloyl group (Piv), 4-methoxybenzyl group (MPM) and the like. Conditions such as reaction temperature, reaction time, reagents used in the hydroxyl group protecting step, the substituent introducing step and the deprotecting step are not particularly limited, and may be appropriately set with reference to similar known reactions and the like. . Although depending on the kind of the protecting group Q, the substituent OQ in the compound (VIII) tends to have ortho-para orientation derived from its electron donating property. Further, as can be seen from the compound (VIII), the ortho and para positions of OQ are blocked so that substituents cannot be introduced except at the R ² introduction target sites (positions 3 and 3 ′). Therefore, in the substituent introduction step, it is extremely easy to selectively introduce the substituent R ² into the R ² introduction target site (3 and 3 ′ positions). The substituent introduction step uses, for example, a reaction in which the R ² introduction target site (positions 3 and 3 ′) of the compound (VIII) is lithiated or halogenated and then converted to the target substituent R ^2. Alternatively, any other reaction may be used.

前記化学式（Ｘ）、（III’’）、（XI’）および（XI）中、ｍ２、ｍ３、Ｒ^２およびＲ^３は、前記化学式（III’）と同じであり、二分子の（Ｘ）の構造は同一でも異なっていてもよく、
前記化学式（XI’）および（XI）中、Ｑ^２は、水素原子または任意の置換基であり、同一でも異なっていてもよく、少なくとも一方は光学活性な基である。 Further, the production of the compound (III ′) can be carried out in place of the production method described above,
A binaphthyl production step of producing a binaphthyl compound (III ″), which is a mixture of the compound represented by the chemical formula (III ′) and its optical isomer, by subjecting the following compound (X) to a bimolecular coupling reaction;
An optically active group introduction step for producing the following compound (XI ′) by introducing an optically active group into at least one of the hydroxyl groups of the compound (III ″);
An optical resolution step of optically resolving the following compound (XI ′) to obtain the following compound (XI) or an optical isomer thereof;
An optically active group for producing a compound represented by the chemical formula (III ′), a tautomer or stereoisomer thereof, or a salt thereof by removing the optically active group from the following compound (XI) You may perform by the manufacturing method which further includes a desorption process.

In the chemical formulas (X), (III ″), (XI ′) and (XI), m2, m3, R ² and R ³ are the same as those in the chemical formula (III ′), and bimolecular (X) The structure may be the same or different,
In the chemical formulas (XI ′) and (XI), Q ² is a hydrogen atom or an arbitrary substituent, which may be the same or different, and at least one is an optically active group.

The reagent, operation, reaction temperature, reaction time, etc. in the binaphthyl production process, the optically active group introduction process, the optical resolution process, and the optically active group elimination process are not particularly limited, and similar known reactions are referred to. May be set as appropriate. For example, the optical resolution step may be appropriately performed using an optical resolution column or the like. In the chemical formulas (XI ′) and (XI), both of Q ² may be optically active groups, but from the viewpoint of synthesis efficiency and cost, it is preferable that only one of Q ² is an optically active group. More preferably, only one of Q ² is an optically active group and the other is a hydrogen atom. That is, in the optically active group introduction step, it is more preferable to introduce one actually optically active group of the hydroxyl group of binaphthyl. The optically active group is not particularly limited. For example, when the optically active group is bonded to a sulfonyl group, a carbonyl group, an azo group, or the like, deprotection can be easily performed by a reduction reaction in the deprotection step. This is preferable because it is possible. In Q ² in the chemical formulas (XI ′) and (XI), the optically active group may be, for example, a group represented by the following chemical formula (XII) or an optical isomer thereof. In Q ² , the optically active group may be, for example, a group in which a sulfonyl group of the following chemical formula (XII) is replaced with a carbonyl group, an azo group, or any other group.

<Asymmetric synthesis (production method of organic compound having optical activity)>
The method for producing an organic compound having optical activity according to the present invention (hereinafter sometimes simply referred to as “asymmetric synthesis” or “asymmetric synthesis of the present invention”) is as described above. The organic compound having the optical activity is produced by an asymmetric synthesis reaction using. The asymmetric synthesis reaction is preferably an asymmetric synthesis coupling reaction. The asymmetric synthesis coupling reaction is preferably a coupling reaction between an organic halide and an organic boron compound. The organic halide may be, for example, an aryl halide, a halogenated alkyne, or the like, and the organic boron compound may be, for example, an aromatic compound or a boron compound derived from an alkyne. Such a reaction may be referred to as a Suzuki-Miyaura cross-coupling reaction (Suzuki-Miyaura reaction) as described above.

  In the organic halide, the organic halide is preferably an aryl halide. The aryl halide is preferably aryl chloride from the viewpoint of cost. As described above, since the asymmetric synthesis catalyst of the present invention has high reactivity, it can be easily used for aryl chlorides (aromatic chlorides). However, the present invention is not limited to this, and any reaction raw material such as aryl bromide (aromatic bromide), aryl iodide (aromatic iodide) may be used.

前記化学式（１０１）および（１０２）中、Ｘ^１は、ハロゲノ基であり、特に限定されないが、例えば、フルオロ基（フッ素）、クロロ基（塩素）、ブロモ基（臭素）またはヨード基（ヨウ素）である。 The aryl halide may be, for example, a compound represented by the following chemical formula (101) or (102).

In the chemical formulas (101) and (102), X ¹ is a halogeno group and is not particularly limited. For example, fluoro group (fluorine), chloro group (chlorine), bromo group (bromine) or iodo group (iodine) It is.

In the asymmetric synthesis of the present invention, the organic boron compound is preferably an aryl boron compound or an organic boronic acid, and more preferably an aryl boronic acid. The organic boronic acid may be, for example, a compound represented by any of the following chemical formulas (201) to (204).

The organic compound having optical activity produced by the asymmetric synthesis of the present invention is, for example, a compound represented by any one of the following chemical formulas (1001) to (1008), a tautomer or stereoisomer thereof, Alternatively, a salt thereof may be used.

  Conditions such as the reaction temperature and reaction time of the asymmetric synthesis of the present invention are not particularly limited, and may be appropriately set with reference to known reactions except that the asymmetric synthesis catalyst of the present invention is used. For example, the reagent, solvent, reaction temperature, reaction time, etc. in the coupling reaction between the organic halide and the organic boron compound may be appropriately set with reference to the known Suzuki-Miyaura reaction. The coupling reaction between the organic halide and the organoboron compound is preferably performed, for example, in the presence of a base. The base is not particularly limited, and examples thereof include alkali metal fluorides such as potassium fluoride, cesium fluoride, calcium fluoride, and sodium fluoride, and potassium phosphate, cesium carbonate, potassium carbonate, sodium hydroxide, and hydroxide. The base etc. which are generally used by Suzuki-Miyaura reaction, such as barium, are mentioned, You may use individually or may use multiple types together. According to the asymmetric synthesis catalyst of the present invention, for example, it is possible to carry out asymmetric synthesis under mild conditions without using a strong alkali or the like. Further, the coupling reaction between the organic halide and the organic boron compound may be performed without a solvent, but is preferably performed in the presence of a solvent. The solvent is not particularly limited, but for example, an ether such as THF, diethyl ether, dioxane, dimethyl ether, ethyl methyl ether, cyclopentyl methyl ether, and the like, Suzuki-, such as toluene, benzene, N, N-dimethylformamide, hexane, etc. The solvent etc. generally used by the Miyaura reaction are mentioned, You may use independently or may use multiple types together. The coupling reaction between the organic halide and the organoboron compound may be performed in the air, but is preferably performed in an inert gas atmosphere such as nitrogen or argon.

  In the asymmetric synthesis of the present invention, the reaction temperature and reaction time may be appropriately set according to the type of substrate and the like, and are not particularly limited. The said reaction temperature is 40-160 degreeC, for example, Preferably it is 60-140 degreeC, More preferably, it is 80-120 degreeC. The reaction time is, for example, 3 to 24 hours (hr), preferably 3 to 12 hours (hr), more preferably 3 to 6 hours (hr). The conventional Suzuki-Miyaura reaction often took several tens of hours or several days, but the asymmetric synthesis catalyst of the present invention is excellent in reactivity. For example, as described in the examples below, the reaction time It is also possible to complete the process in a few hours, for example. However, as described above, the reaction time in the asymmetric synthesis of the present invention is not limited to this.

  Examples of the present invention will be described below. However, the present invention is not limited to the following examples.

<Asymmetric phosphonite compound of this example>
In this example, Suzuki-Miyaura reaction was carried out using an asymmetric phosphonite compound represented by the following chemical formula 01, 02 or 03 and an asymmetric synthesis catalyst containing palladium, and the performance was confirmed. The following compound 01 is an asymmetric phosphonite compound described in Non-Patent Document 3 and was used as a reference example for comparison with the compound of the present invention (Example). The following compounds 02 and 03 are examples of the asymmetric phosphonite compound of the present invention. In the following, the following asymmetric phosphonite compounds 01, 02 and 03 may be simply referred to as “ligand” or “phosphorous ligand”. In this example, an asymmetric catalytic reaction (asymmetric synthesis) using the Suzuki-Miyaura reaction could be performed using only these ligands as an asymmetric source.

  [Outline of Ligand Synthesis 1] to [Outline of Ligand Synthesis 3] below outlines the synthesis (production) of ligands 01, 02 and 03. A yield, a yield, etc. show a typical thing among the synthesis | combination (manufacture) several times.

<[Summary of ligand synthesis 1] Synthesis of (R) -1,1'-binaphthyl-2,2'-diol derivative 01>
(R) -1,1'-bi-2-naphthol ((R) -1,1'-binaphthyl-2,2'-diol, hereinafter abbreviated as "BINOL") is an axially asymmetric skeleton precursor The following ligand synthesis was performed (Scheme 0-1-01 below). That is, first, iodinated compound 04 was lithiated and reacted with 1,2-dibromobenzene as an electrophile to synthesize a total of 21 g or more of brominated hexaarylbenzene compound 05. Next, 01, which is an optically active asymmetric phosphonite compound (phosphorus ligand), was synthesized by lithiation of the hexaarylbenzene derivative 05 and a coupling reaction (one-pot reaction). That is, first, normal-butyl lithium was reacted with 05 in tetrahydrofuran at −78 ° C. to generate active species, and then the active species were reacted with chlorodiphenylphosphine. After completion of the reaction, the solvent was removed and the residue was dried in vacuo. After drying, (R) -1,1′-bi-2-naphthol was added and reacted in tetrahydrofuran in the presence of triethylamine. After completion of the reaction, the solvent was removed and concentrated, and column purification (hexane / benzene = 2/1) was performed after normal work-up operation, followed by recrystallization from propionitrile. As a result of identification by ¹ H NMR, ¹³ C NMR, ³¹ P NMR, ESI-MS, and elemental analysis, 3.3 g of phosphorus ligand (R) -01 having a hexaarylbenzene group which is a large substituent is obtained. I was able to. Note that “concentration of solvent removal” refers to concentration by removing a solvent from a solution or the like by distillation under reduced pressure or the like.

<[Synthesis of Ligand Synthesis 2] Synthesis of (R) -3,3'-dimethyl-1,1'-binaphthyl-2,2'-diol derivative 02>
Subsequently, a ligand 02 having (R) -3,3′-dimethyl-1,1′-binaphthyl-2,2′-diol as an axial asymmetric skeleton precursor was synthesized (the following scheme 0-2- 01). First, (R) -1,1′-bi-2-naphthol (BINOL) was reacted with chloro (methoxy) methane by generating a dianion with sodium hydride in tetrahydrofuran. In addition, the reaction conditions etc. referred the reference literature 2 and 3 of the postscript. After completion of the reaction, the solvent was removed and concentrated, and recrystallization from 2-propanol after usual work-up operation gave 85% (37 g) of (R) -06. As a result of identification by ¹ H NMR and ¹³ C NMR, it was confirmed to be the target substance (R) -2,2′-bis (methoxymethoxy) -1,1′-binaphthyl (R) -06. Subsequently, the 3,3′-position of the obtained (R) -06 body was dimethylated, and (R) -2,2′-bis (methoxymethoxy) -3,3′-dimethyl-1,1′-binaphthyl was obtained. 90% (5.1 g) of (R) -07 was obtained. ^The target substance was confirmed using physical data such as ¹ H NMR and ¹³ C NMR. Dimethylated product (R) -07 was subjected to deprotection treatment with 6N aqueous hydrochloric acid in ethanol, and (R) -3,3'-dimethyl-1,1'-binaphthyl-2,2 ' -Diol (R) -08 was obtained (Scheme 0-2-01).

Next, a novel phosphonite ligand (R) -02 was synthesized according to the following scheme 0-2-02 using the obtained 08. That is, except that (R) -3,3′-dimethyl-1,1′-binaphthyl-2,2′-diol (R) -08 was used in place of BINOL, the above [Summary of Ligand Synthesis 1 ], The bromo compound was lithiated and reacted with an electrophile in one pot. As a purification operation, column purification (hexane / benzene = 2/1) and reprecipitation operation (benzene / methanol) were performed, and recrystallization operation was performed from acetonitrile. As a result, 69% (3) of the target molecule (R) -02 was obtained. .2g) succeeded in obtaining (Scheme 0-2-02).

<[Summary of ligand synthesis 3] Synthesis of (S) -9,10-biphenanthrene-9 ′, 10-diol derivative 03>
Ligands with (S) -9,10-biphenanthrene-9 ', 10-diol ((S) -9,10-biphenanthrene-9', 10-diol) as axial asymmetric skeleton precursors 03 was synthesized. First, di-μ-hydroxo-bis [(N, N, N ', N'-tetramethylethylenediamine) copper (II)] chloride ([CuCl (OH) TMEDA]) was used as the catalyst, and 9-phenanthrol 09 Was dimerized by oxidative coupling (Scheme 0-3-01 below). Reaction conditions were referred to Reference Document 4 described later. As a result, 16 g or more of racemic biphenanthrol (biphenanthrol) 10 was synthesized in a maximum yield of 53%. In order to optically resolve the resulting racemic biphenanthrol (biphenanthrol) 10, 4-dimethylaminopyridine (DMAP) was used as a catalyst in the presence of triethylamine in a methylene chloride solvent, and (1S)-(+)- Reaction with 10-camphorsulfonyl chloride (Scheme 0-3-01 below). The reaction conditions were referred to Reference Document 5 described later. In addition, (1S)-(+)-10-camphorsulfonyl chloride 1.3 eq, DMAP 0.45 eq, Et ₃ N 2.2 eq was added to bifenantrol 10 and reacted for 22 hours, or (1S)-(+) When the equivalents of -10-camphorsulfonyl chloride, DMAP and Et ₃ N were further increased and reacted for 19 hours, the reaction was difficult to proceed. As described below, first add (1S)-(+)-10-camphorsulfonyl chloride 0.7 eq and let it react for 1.5 hours, then add (1S)-(+)-10-camphorsulfonyl chloride 0.4 eq. When the reaction was continued for an additional 1.5 hours (3 hours in total), the desired product was obtained. In the purification operation, silica gel infiltrated with only hexane was packed in a chromatographic tube, a crude product dissolved in toluene was developed, and then hexane was allowed to flow until toluene was completely removed. Subsequently, the target product was separated with a developing solvent of hexane / ethyl acetate = 4/1.

R-(+)-11 and S-(+)-12 were separated by silica column chromatography and then deprotected with lithium aluminum hydride in a tetrahydrofuran solution. After completion of the reaction, the reaction mixture was worked up, column purified with a developing solvent of hexane / chloroform = 1/1, and recrystallized from acetonitrile. As a result, both optically pure enantiomers (R) -13 and (S) -14 were obtained in a yield of 45% and a yield of 49%, respectively. These yields are based on racemic biphenanthrol (biphenanthrol) 10. The yield of the reduction reaction from R-(+)-11 to (R) -13 is 70% (yield 2.7 g), and the reduction reaction of S-(+)-12 to (S) -14 The yield was 93% (yield 3.6 g).

Further, according to the following scheme 0-3-03, the iodinated compound 04 was lithiated and reacted with 1,2-dibromobenzene as an electrophile to synthesize a brominated hexaarylbenzene compound 05. Next, 03, which is an optically active asymmetric phosphonite compound (phosphorus ligand), was synthesized by lithiation of the hexaarylbenzene derivative 05 and a coupling reaction (one-pot reaction). That is, first, normal-butyl lithium was reacted with 05 in tetrahydrofuran at −78 ° C. to generate active species, and then the active species were reacted with chlorodiphenylphosphine. After completion of the reaction, the solvent was removed and the residue was dried in vacuo. After drying, (S) -9,10′-biphenanthrene-9 ′, 10-diol (S) -14 was added and reacted in tetrahydrofuran in the presence of triethylamine. After completion of the reaction, the solvent was removed and concentrated, and column purification was performed after normal workup (hexane / benzene = 2/1), followed by reprecipitation (benzene / methanol). As a result of identification by ¹ H NMR, ¹³ C NMR, ³¹ P NMR, FAB-MS, and elemental analysis, 70% (3.1 g) of a novel phosphorus ligand (S) -03 having a hexaarylbenzene group as a large substituent It was confirmed that it was obtained.

  Hereinafter, the present embodiment will be described in more detail. The yields, yields, and the like described in [Summary 1 of ligand synthesis] to [Summary 3 of ligand synthesis 3] are representative of the synthesis (manufacturing) multiple times as described above. Therefore, it may be different from the yield and yield described below.

<Equipment and reagents>
¹ H and ¹³ C NMR spectra were measured at 400 MHz and 100 MHz using a BRUKER-SPECTROSPIN-400 (trade name) and a 5 mm QNP probe, respectively. Chemical shift values are expressed in parts per million (ppm) using tetramethylsilane as an internal standard. The abbreviation s represents a single line (singlet), d represents a double line (doublet), t represents a triple line (triplet), q represents a quadruple line (quartet), m is Represents a multiple line. ^{The 31} P NMR spectrum was measured at 162 MHz using BRUKER-SPECTROSPIN-400 (trade name). The ³¹ P NMR data is shown as relative to external 85% H ₃ PO ₄ . Elemental analysis was performed using Yanaco MT-5 CHN-Corder (trade name). Unless otherwise specified, “Anal.” Represents an elemental analysis value. Regarding the elemental analysis value, “Calcd. For” represents a calculated value, and “Found” represents an actual measurement value. Mass spectrum using Bruker Daltonics esquire-2000T (product name) in ESI mode, JEOL JMS-SX102A (product name) in EI mode, and JEOL GC-mate II (product name) in FAB mode. It was measured. Column chromatography was performed using Silica Gel 60N (trade name of Kanto Chemical Co., Inc.) with silica gel as the stationary phase. Thin layer chromatographic analysis was performed using Merck silica gel 60 F ₂₅₄ (trade name). The reaction was carried out under an argon atmosphere unless otherwise specified. Reagents were purchased from Kanto Chemical Co., Inc., Wako Pure Chemical Industries, Ltd., Tokyo Chemical Industry Co., Ltd., and Acros Organics. All purchased reagents were used without further purification. Anhydrous THF solvent was purchased from Kanto Chemical Co., Inc.

化合物05(682mg, 1.0mmol)のTHF(13mL)溶液に、-78℃の温度下でn-BuLi(0.71mmol， 1.57Mヘキサン溶液)を５分間かけて滴下し、その混合物を、５分間撹拌した。PCl₃(149mg, 1.1mmol)を、２分間かけてゆっくりと加え、反応温度を室温まで上昇させた。２時間撹拌後、溶媒を、減圧下で完全に留去し、残渣にTHF(10mL)および(R)-(+)-1,1’-ビ-2-ナフトール(343mg、1.2mmol)を加え、続いてEt₃N(212mg, 2.1mmol)を加えた。室温で２時間撹拌後、揮発性物質を、全て、減圧留去（エバポレート）した。得られた混合物を、ベンゼン(100mL)に溶かし、水(50mL)および生理食塩水(50mL)で洗浄し、Na₂SO₄で乾燥させた。シリカゲルカラムクロマトグラフィー(ヘキサン/ベンゼン=2/1)で精製し、(R)-01(608mg、66%)を、[α]²⁵ _D ＋158.5(c1.04, C₆H₆)の白色固体として得た。 <Reference Example 1: Synthesis of phosphonite compound (R) -01>

N-BuLi (0.71 mmol, 1.57M hexane solution) was added dropwise to a solution of compound 05 (682 mg, 1.0 mmol) in THF (13 mL) at a temperature of −78 ° C. over 5 minutes, and the mixture was stirred for 5 minutes. did. PCl ₃ (149 mg, 1.1 mmol) was added slowly over 2 minutes to raise the reaction temperature to room temperature. After stirring for 2 hours, the solvent was completely distilled off under reduced pressure, and THF (10 mL) and (R)-(+)-1,1′-bi-2-naphthol (343 mg, 1.2 mmol) were added to the residue. Then Et ₃ N (212 mg, 2.1 mmol) was added. After stirring at room temperature for 2 hours, all volatile substances were distilled off under reduced pressure (evaporation). The resulting mixture was dissolved in benzene (100 mL), washed with water (50 mL) and saline (50 mL), and dried over Na ₂ SO ₄ . Purify by silica gel column chromatography (hexane / benzene = 2/1), and (R) -01 (608 mg, 66%) was obtained as [α] ²⁵ _D +158.5 (c1.04, C ₆ H ₆ ) white Obtained as a solid.

Instrumental analysis values for (R) -01:
¹ H NMR (400MHz, C ₆ D ₆ ) δ 7.78-7.67 (m, 4H), 7.62-7.48 (m, 5H), 7.32-6.93 (m, 15H), 6.87-6.62 (m, 11H), 6.32 ( ddd, J = 0.9, 7.6, 7.8Hz, 1H), 1.94 (s, 3H), 1.80 (s, 3H), 1.79 (s, 3H), 1.76 (s, 3H), 1.75 (s, 3H). 13 C NMR (100MHz, C ₆ D ₆ ) δ151.4, 150.21, 150.17, 147.2, 146.8, 142.7, 142.02, 142.01, 141.9, 141.8, 141.4, 139.32, 139.27, 139.1, 139.0, 138.3, 137.9, 135.7, 135.6, 135.3, 135.2, 133.9, 133.7, 133.4, 133.33, 133.29, 132.73, 132.69, 132.53, 132.47, 132.43, 132.39, 132.1, 132.0, 131.4, 130.7, 130.0, 129.5, 129.4, 129.2, 129.0, 128.9, 128.8, 128.6, 128.5, 128.3, 127.7, 127.6, 127.0, 126.8, 126.2, 126.0, 125.5, 125.3, 124.5, 124.4, 123.8, 122.3, 21.5, 21.39, 21.36, 21.35, 21.3. ³¹ P NMR (162 MHz, C ₆ D ₆ ) δ178 .8. ESI-MS m / z: 919 ([M + H] ⁺ ). Anal. Calcd. For C ₆₇ H ₅₁ O ₂ P: C, 87.56; H, 5.59. Found: C, 87.37; H, 5.65 .

上記スキーム1-2-02中の化合物05(682mg, 1.0mmol)のTHF(13mL)溶液に、-78℃でn-BuLi(1.3mmol, 1.67Mヘキサン溶液)を３分間かけて滴下し、その混合物を10分間撹拌した。
さらに、PCl₃(177mg, 1.3mmol)を、２分間かけてゆっくりと加え、反応温度を室温まで上昇させた。２時間撹拌後、溶媒を、減圧下で完全に留去し、残渣にTHF(10mL)および(R)-(+)-3,3’-ジメチル-1,1'-ビナフチル-2,2'-ジオール(408mg, 1.3mmol)を加え、続いてEt₃N(212mg, 2.1mmol)を加えた。室温で２時間撹拌後、揮発性物質を、全て、減圧留去（エバポレート）した。得られた混合物を、ベンゼン(110mL)に溶かし、水(100mL)および生理食塩水(50mL)で洗浄し、Na₂SO₄で乾燥させた。シリカゲルカラムクロマトグラフィー(ヘキサン/ベンゼン=2/1)で精製し、(R)-02(656mg, 69%)を、[α]²⁵ _D +378(c1.00, C₆H₆)の白色固体として得た。 <Example 1: Synthesis of asymmetric phosphonite compound (ligand) (R) -02>

N-BuLi (1.3 mmol, 1.67 M hexane solution) was added dropwise to a THF (13 mL) solution of compound 05 (682 mg, 1.0 mmol) in the above scheme 1-2-02 at −78 ° C. over 3 minutes. The mixture was stirred for 10 minutes.
Further, PCl ₃ (177 mg, 1.3 mmol) was added slowly over 2 minutes to raise the reaction temperature to room temperature. After stirring for 2 hours, the solvent was completely distilled off under reduced pressure, and THF (10 mL) and (R)-(+)-3,3′-dimethyl-1,1′-binaphthyl-2,2 ′ were added to the residue. - diol (408 mg, 1.3 mmol) was added followed by Et ₃ N (212mg, 2.1mmol) was added. After stirring at room temperature for 2 hours, all volatile substances were distilled off under reduced pressure (evaporation). The resulting mixture was dissolved in benzene (110 mL), washed with water (100 mL) and saline (50 mL), and dried over Na ₂ SO ₄ . Purify by silica gel column chromatography (hexane / benzene = 2/1) to obtain (R) -02 (656 mg, 69%) as a white solid of [α] ²⁵ _D +378 (c1.00, C ₆ H ₆ ) Got as.

Instrumental analysis values for (R) -02:
¹ H NMR (400MHz, C ₆ D ₆ ) δ7.69-7.46 (m, 7H), 7.35-6.57 (m, 27H), 6.34 (dd, J = 7.4, 7.4Hz, 1H), 2.81 (s, 3H ), 1.90 (s, 3H), 1.79-1.74 (m, 12H), 1.34 (s, 3H). ¹³ C NMR (100 MHz, C ₆ D ₆ ) δ150.71, 150.69, 150.5, 150.4, 147.3, 146.9, 142.9, 141.77, 141.75, 141.44, 141.41, 141.2, 139.6, 139.5, 139.4, 139.2, 139.0, 138.9, 136.0, 135.6, 135.5, 135.4, 135.3, 133.7, 133.4, 133.2, 133.04, 133.00, 132.9, 132.7, 132.6, 132.4, 132.3, 132.1, 132.0, 131.9, 131.5, 131.1, 130.8, 130.1, 129.9, 129.3, 128.9, 128.6, 128.4, 128.1, 128.0, 126.8, 126.45, 126.38, 126.3, 126.2, 125.8, 125.6, 124.0, 21.7, 21.61, 21.58, 21.55, 18.9, 17.9. ³¹ P NMR (162MHz, C ₆ D ₆ ) δ176.4. MS (FAB) m / z: 947.77 ([M + H] ⁺ ). Anal. Calcd. For C ₆₉ H ₅₅ O ₂ P: C, 87.50; H, 5.85. Found: C, 87.46; H, 5.77.

<Example 2: Synthesis of asymmetric phosphonite compound (ligand) (S) -03>
According to the following scheme 1-3-01 to scheme 1-3-04, an asymmetric phosphonite compound (ligand) (S) -03 was synthesized.

開放系にしたビーカー(200mL)内において、９−フェナンスロール 09(1.55g, 8.0mmol)を、CH₂Cl₂(53mL)に溶かした。この溶液に、CuCl(OH)・TMEDA(18.4g, 0.08mmol)を加え、その反応混合物を１０分間撹拌した。その後、新たにCuCl(OH)・TMEDA(18.4g, 0.08mmol)を加え、さらに８０分間撹拌した。さらに、前記反応混合物をエバポレートし、得られた粗生成物をカラムクロマトグラフィー（溶離剤は、ヘキサン/CHCl₃=1/1）で精製し、化合物10のラセミ体を収率53%で得た。 <Scheme 1-3-01: Synthesis of (±) -9,10′-biphenanthrene 9 ′, 10-diol, 10>

In an open beaker (200 mL), 9-phenanthrol 09 (1.55 g, 8.0 mmol) was dissolved in CH ₂ Cl ₂ (53 mL). To this solution was added CuCl (OH) .TMEDA (18.4 g, 0.08 mmol) and the reaction mixture was stirred for 10 minutes. Thereafter, CuCl (OH) · TMEDA (18.4 g, 0.08 mmol) was newly added, and the mixture was further stirred for 80 minutes. Further, the reaction mixture was evaporated, and the resulting crude product was purified by column chromatography (eluent: hexane / CHCl ₃ = 1/1) to obtain a racemate of compound 10 in a yield of 53%. .

Instrumental analysis of compound 10:
¹ H NMR (400MHz, CDCl ₃ ) δ8.82 (d, J = 8.2Hz, 2H), 8.76 (d, J = 8.2Hz, 2H), 8.48 (d, J = 8.2Hz, 2H), 7.83 (t , J = 7.6Hz, 2H), 7.74 (t, J = 7.6Hz, 2H), 7.55 (t, J = 7.6Hz, 2H), 7.36 (t, J = 7.6Hz, 2H), 7.29 (d, J = 8.4Hz, 2H), 5.57 (s, 2H).

(±)-ビフェナントレノール 10(1.47g, 3.8mmol)、(1S)-(+)-10-カンファスルホニルクロライド(665g, 2.66mmol)、およびDMAP(69.6g, 0.57mmol)を、CH₂Cl₂(60mL)に溶解させた。つぎに、新たに蒸留したトリエチルアミン(0.58mL, 4.2mmol)を、０℃で１０分間かけて滴下した。その溶液を、まず０℃で０．５時間、つぎに室温で１時間撹拌した。その後、新たな(1S)-(+)-10-カンファスルホニルクロライド(380mg, 1.52mmol)を加え、さらに１．５時間撹拌した。続いて、水(30mL)を加え、水相をCH₂Cl₂(10mL×3)で抽出し、その有機相を合わせ、生理食塩水(30mL)で洗浄した。このCH₂Cl₂溶液を乾燥させ、エバポレートし、得られた残渣を、CH₂Cl₂/ベンゼン=1/1のカラムクロマトグラフィーで分離し、R-(+)-(11)およびS-(+)-(12)のジアステレオマー混合物を、合計43％の収率で得た。なお、R-(+)-(11)およびS-(+)-(12)のジアステレオマー混合物は、シリカカラムクロマトグラフで分割することができた。 <Scheme 1-3-02: (±) -9,10′-biphenanthrene 9 ′, 10-diol mono [(1S) -camphor-10-sulfonate] R-(+)-11 and S— Synthesis of (+)-12>

(±) -biphenanthrenol 10 (1.47 g, 3.8 mmol), (1S)-(+)-10-camphorsulfonyl chloride (665 g, 2.66 mmol), and DMAP (69.6 g, 0.57 mmol) were added to CH ₂ Cl Dissolved in ₂ (60 mL). Next, freshly distilled triethylamine (0.58 mL, 4.2 mmol) was added dropwise at 0 ° C. over 10 minutes. The solution was first stirred at 0 ° C. for 0.5 hour and then at room temperature for 1 hour. Thereafter, new (1S)-(+)-10-camphorsulfonyl chloride (380 mg, 1.52 mmol) was added, and the mixture was further stirred for 1.5 hours. Subsequently, water (30 mL) was added, the aqueous phase was extracted with CH ₂ Cl ₂ (10 mL × 3), the organic phases were combined and washed with saline (30 mL). The CH ₂ Cl ₂ solution was dried and evaporated and the resulting residue was separated by column chromatography with CH ₂ Cl ₂ / benzene = 1/1 to give R-(+)-(11) and S- ( A mixture of diastereomers of +)-(12) was obtained with a total yield of 43%. The diastereomeric mixture of R-(+)-(11) and S-(+)-(12) could be resolved by silica column chromatography.

R-(+)-(11) spectral data:
¹ H NMR (400MHz, CDCl ₃ ) δ8.82 (m, 3H), 8.73 (d, J = 8Hz, 1H), 8.60 (d, J = 8Hz, 1H), 8.55 (d, J = 8Hz, 1H) , 7.82 (m, 3H), 7.71 (m, 2H), 7.53 (m, 2H), 7.42 (t, J = 8Hz, 1H), 7.36 (t, J = 8Hz, 1H), 7.26 (d, J = 8Hz, 1H), 5.81 (s, 1H), 2.72 (d, J = 14.9Hz, 1H), 2.14 (m, 2H), 1.75 (m, 4H), 1.4 (m, 1H), 1.18 (m, 1H ), 0.36 (s, 3H), 0.15 (s, 3H).

Spectral data of S-(+)-(12):
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.83 (q, J = 8 Hz, 3 H), 8.74 (d, J = 8 Hz, 1 H), 8.63 (d, J = 8 Hz, 1 H), 8.53 (d, J = 8Hz, 1H), 7.82 (m, 3H), 7.7 (t, J = 7.5Hz, 2H), 7.56 (m, 2H), 7.43 (m 3H), 7.31 (d, J = 8.4Hz, 1H), 5.71 (s, 1H), 2.93 (d, J = 14.8Hz, 1H), 2.05 (m, 2H), 1.79 (m, 4H), 1.46 (dddd, J = 4.6Hz, 1H), 1.24 (m, 1H) , 0.35 (s, 3H), 0.09 (s, 3H).

リチウムアルミニウムハイドライド(LAH）(160mg, 4.2mmol)に、モノエステルS-(+)-12(510mg, 0.848mmol)のTHF(4mL)溶液を、０℃で３５分間かけて滴下した。つぎに、この反応生成物を、６０℃で１時間撹拌した。その後、水(0.16mL)、１５％NaOH水(0.16mL)および再度水(0.48mL)を、この順序で加えた。つぎに、メトキシシクロペンタン(5mL)を加え、生じた沈殿を濾取し、メトキシシクロペンタン(5mL)で洗浄した。エーテル相に水(2mL)を加え、さらにその混合物に０℃でHCl(1N＝１mol/L)を加えてpHを６に調整した。続いて、エーテル相を分離し、水相をメトキシシクロペンタン10mL×3で抽出した。有機相を集め、エバポレーション後、粗生成物を、クロマトグラフィー(ヘキサン/CHCl₃=1/1)で精製し、目的物の(S)-14を、収率70％、および光学収率99.96% eeで得た。なお、前記eeは、商品名Daicel Chiralcel AD-Hを用いたHPLC分析(溶離剤はヘキサン-iPrOH 90/10, 測定波長270nm, 流速0.5mL/min, カラム温度298K)により、99.96%と決定した。保持時間（retention times）は、多いほうのアイソマーが51.8min(存在比99.98％)、少ないほうのアイソマーが44.6min（存在比0.02%)であった。また、前記光学収率は、カラム精製直後では前述のとおり99.96% eeであったが、再結晶により100% eeとなった。¹H NMRデータは、(±)-ビフェナンスロールにおける前記測定値のとおりであった。 <Scheme 1-3-03: Synthesis of (S) -9,10′-biphenanthrene-9 ′, 10-diol, (S) -14>

A solution of monoester S-(+)-12 (510 mg, 0.848 mmol) in THF (4 mL) was added dropwise to lithium aluminum hydride (LAH) (160 mg, 4.2 mmol) at 0 ° C. over 35 minutes. The reaction product was then stirred at 60 ° C. for 1 hour. Then water (0.16 mL), 15% aqueous NaOH (0.16 mL) and again water (0.48 mL) were added in this order. Next, methoxycyclopentane (5 mL) was added, and the resulting precipitate was collected by filtration and washed with methoxycyclopentane (5 mL). Water (2 mL) was added to the ether phase, and HCl (1N = 1 mol / L) was added to the mixture at 0 ° C. to adjust the pH to 6. Subsequently, the ether phase was separated, and the aqueous phase was extracted with 10 mL × 3 of methoxycyclopentane. After the organic phase was collected and evaporated, the crude product was purified by chromatography (hexane / CHCl ₃ = 1/1) to give the desired product (S) -14, yield 70%, and optical yield 99.96. Obtained with% ee. The ee was determined to be 99.96% by HPLC analysis using the trade name Daicel Chiralcel AD-H (eluent: hexane-iPrOH 90/10, measurement wavelength 270 nm, flow rate 0.5 mL / min, column temperature 298 K). . Retention times were 51.8 min (existing ratio 99.98%) for the larger isomer and 44.6 min (existing ratio 0.02%) for the lesser isomer. The optical yield was 99.96% ee as described above immediately after column purification, but it was 100% ee by recrystallization. ¹ H NMR data was as described above for (±) -biphenanthrol.

  Similarly, (R) -13 could be produced by reduction (deprotection) of R-(+)-11. However, LAH was added during the reaction because of low reactivity compared to S-(+)-12. In the same manner as in the production of (S) -14, purification was performed by column chromatography and recrystallization to obtain (R) -13. The optical yield was 99.36% ee immediately after column purification, but became 100% ee by recrystallization.

化合物05(409mg, 0.6mmol)のTHF(7.8mL)溶液に、-78℃の温度下でn-BuLi(0.78mmol, 1.65Mヘキサン溶液)を５分間かけて滴下し、その混合物を、５分間撹拌した。(106 mg, 0.78mmol)を、３分間かけてゆっくりと加え、反応温度を室温まで上昇させた。２時間撹拌後、溶媒を、減圧下で完全に留去し、残渣にTHF(10mL)および(S)-9,10'-ビフェナントレン-9',10-ジオール 14(301mg, 0.78mmol)を加え、続いてEt₃N(127mg, 1.3mmol)を加えた。室温で１．５時間撹拌後、揮発性物質を、全て、減圧留去（エバポレート）した。得られた混合物を、ベンゼン(80mL)に溶かし、水(50mL)および生理食塩水(50mL)で洗浄し、Na₂SO₄で乾燥させた。シリカゲルカラムクロマトグラフィー(ヘキサン/ベンゼン=2/1)で精製し、(S)-03 (430mg, 70%)を、[α]²⁵ _D-272(c 1.01, C₆H₆)の白色固体として得た。 <Scheme 1-304: Synthesis of asymmetric phosphonite compound (ligand) (S) -03>

N-BuLi (0.78 mmol, 1.65 M hexane solution) was added dropwise to a solution of compound 05 (409 mg, 0.6 mmol) in THF (7.8 mL) at a temperature of −78 ° C. over 5 minutes, and the mixture was added for 5 minutes. Stir. (106 mg, 0.78 mmol) was added slowly over 3 minutes to raise the reaction temperature to room temperature. After stirring for 2 hours, the solvent was completely distilled off under reduced pressure, and THF (10 mL) and (S) -9,10′-biphenanthrene-9 ′, 10-diol 14 (301 mg, 0.78 mmol) were added to the residue. Addition was followed by Et ₃ N (127 mg, 1.3 mmol). After stirring at room temperature for 1.5 hours, all volatile substances were distilled off under reduced pressure (evaporate). The resulting mixture was dissolved in benzene (80 mL), washed with water (50 mL) and saline (50 mL), and dried over Na ₂ SO ₄ . Purify by silica gel column chromatography (hexane / benzene = 2/1), and (S) -03 (430 mg, 70%) as a white solid of [α] ²⁵ _D -272 (c 1.01, C ₆ H ₆ ) Obtained.

Instrumental analysis values for (S) -03:
¹ H NMR (400MHz, C ₆ D ₆ ) δ9.06 (d, J = 7.9Hz, 1H), 8.54-8.44 (m, 4H), 7.79 (t, J = 7.2, 7.2Hz 1H), 7.72 (d , J = 7.2Hz, 1H), 7.57-6.51 (m, 32H), 5.95 (t, J = 7.5, 7.5Hz, 1H), 1.98 (s, 3H), 1.81 (s, 3H), 1.75 (s, 3H), 1.70 (d, J = 5.6Hz, 6H). 13 C NMR (100MHz, C 6 D 6) δ148.4, 148.36, 147.0, 146.6, 143.0, 142.7, 142.0, 141.9, 141.50, 141.46, 140.5, 140.1, 139.5, 139.4, 139.2, 139.14, 139.1, 139.0, 136.2, 135.58, 135.57, 135.42, 135.37, 134.1, 133.4, 133.33, 133.28, 133.1, 132.9, 132.82, 132.76, 132.7, 132.5, 132.3, 132.1, 132.0, 131.2, 130.1, 129.8, 129.5, 129.3, 129.18, 129.16, 129.15, 129.14, 129.13, 129.0, 128.9, 128.6, 128.5, 128.4, 128.0, 127.8, 127.5, 127.3, 126.6, 126.3, 126.0, 124.2, 124.0, 123.94, 123.90, 123.8, 123.0, 121.5, 121.4, 22.0, 21.6, 21.5. ³¹ P NMR (162MHz, C ₆ D ₆ ) δ184.1. MS (FAB) m / z: 1019 ([M + H] ⁺ ), 927 ([MC ₇ H ₇ ] ⁺ ). Anal.Calcd. For C ₇₅ H ₅₅ O ₂ P: C, 88.38; H, 5.44. Found: C, 88.28; H, 5.46.

References
1. Iwasawa, T .; Kamei, T .; Watanabe, S .; Nishiuchi, M .; Kawamura, Y. Tetrahedron Lett. 2008, 49, 7430-7433.
2． Robert, TW; Shen, L; Michael, J. C ,; Org. Lett., 2004, 6, 2701-2704.
3. Christopher, RG; Hongying, Z .; Charlotte, LS; SonBinh, TNJ Org. Chem. 2007, 72, 9121-9133.
4. Nakajima, M .; Miyoshi, I .; Kanayama, K .; Hashimoto, SJ Org. Chem. 1999, 64, 2264-2271.
5. Aydin, J .; Kumar, KS; Sayah, MJ; Olov, A.; Wallner, OA Szabo, JKJ Org. Chem. 2007, 72, 4689-4697.

<Reference Example 2: Racemic synthesis of target biaryl compound and optical resolution>
A Suzuki-Miyaura reaction was performed using a non-optically active phosphonite compound as a ligand to synthesize racemates of compounds represented by the following chemical formulas 15 to 22, and optically resolved. The following chemical formula 20 is the same as the chemical formula (1001), the following chemical formula 15 is the same as the chemical formula (1002), the following chemical formula 17 is the same as the chemical formula (1003), and the following chemical formula 16 Is the same as the chemical formula (1004), the following chemical formula 18 is the same as the chemical formula (1005), the following chemical formula 21 is the same as the chemical formula (1006), and the following chemical formula 19 is the chemical formula (1006). 1007), and the following chemical formula 22 is the same as the chemical formula (1008).

<Suzuki-Miyaura reaction using 2- (2-chloro-3-methoxyphenyl) -1,3-dioxolane>
Using 2- (2-chloro-3-methoxyphenyl) -1,3-dioxolane as a starting material, a biaryl shown in the following scheme 2-1-01 was synthesized.

  The outline of the operation in the scheme 2-1-01 is shown below. That is, first, potassium fluoride was added to a Schlenk tube and dried under reduced pressure while heating with a heat gun. After boronic acid was added thereto and replaced with argon, the starting material, catalyst, and ligand were added in this order. The atmosphere was replaced with argon again, and a necessary amount of tetrahydrofuran was added while stirring, followed by stirring for 10 minutes. After 5 minutes, the reaction was started by moving to an oil bath preheated to a preset temperature. Although it was a red suspension immediately after the start of the reaction, the qualitative property gradually changed to a yellow suspension. After completion of the reaction, insoluble matters were filtered through Celite (registered trademark) and Florisil (trade name), and a normal work-up operation was performed. After confirming the crude product by TLC and NMR measurement, column purification operation and recrystallization operation were performed. Separation of racemic peaks using an optically active column for high performance liquid chromatograph (device: GL-7410 (trade name of GL Sciences Inc.), column: CHIRALPAK (registered trademark) AD-H, OD-H manufactured by Daicel Chemical Industries, Ltd. , Or OJ-H).

  The compound 15 was obtained by coupling reaction of 2- (2-chloro-3-methoxyphenyl) -1,3-dioxolane and 2-methoxyphenylboronic acid overnight. After completion of the reaction, compound 15 was obtained as a colorless transparent oil by a work-up operation and column purification (toluene / ethyl acetate = 19/1). The oil solidified when rubbed while cooling in an ice cold bath.

  Compound 16 was obtained by coupling reaction of 2- (2-chloro-3-methoxyphenyl) -1,3-dioxolane and 2-formylboronic acid for 5 hours. After completion of the reaction, the reaction mixture was worked up in the same manner as in Compound 15 and purified by column chromatography (hexane / ethyl acetate = 7/1). Since the qualitative property after column purification was a reddish purple oily substance, it was washed with a mixed solvent of methanol / hexane = 0.5 mL / 0.5 mL. Further, pure compound 16 was obtained by recrystallization from 1-propanol.

  Compound 17 was prepared by subjecting 2- (2-chloro-3-methoxyphenyl) -1,3-dioxolane and 1-naphthaleneboronic acid to a coupling reaction, column purification using a single solvent of toluene, and recrystallization. (2-propanol) was obtained as pure compound 17.

  Furthermore, the compound 20 was also synthesized in the same manner as in the scheme 2-1-01 by a coupling reaction using 2-methylphenylboronic acid (ortho-tolylboronic acid).

<Suzuki-Miyaura reaction using 2-chloro-3-methoxybenzonitrile>
Biaryl shown in the following scheme 2-2-01 was synthesized using 2-chloro-3-methoxybenzonitrile as a starting material.

  The synthesis, identification of the product (target molecule), and investigation of the peak separation of the racemate by an optically active column were performed in the same manner as in the above scheme 2-1-01.

Compound 18 was obtained by coupling overnight reaction of 2-chloro-3-methoxybenzonitrile and ortho-tolylboronic acid. After completion of the reaction, normal work-up operation was performed. In addition, this 6′-methoxy-6-methylbinaphthyl-2-carbonitrile 18 has a spot confirmed at the same Rf value on the starting material and TLC, and a coloring solution (cerium-ammonium molybdate, phosphomolybdic acid, p- Anisaldehyde, basic potassium permanganate, iodine / silica gel), but no obvious difference from the target product was observed. Therefore, when the presence or absence of the starting material was confirmed by ¹ H NMR, complete disappearance of the starting material was observed. Therefore, a column purification operation (toluene / ethyl acetate = 19/1) and a recrystallization operation (ethanol) were performed.

  Compound 19 was obtained by reacting 2-chloro-3-methoxybenzonitrile with 2-naphthaleneboronic acid. After the reaction overnight, the target product 19 was obtained by ordinary work-up operation, column purification operation (hexane / toluene = 1/1) and recrystallization (ethanol).

  The compounds 21 and 22 were synthesized in the same manner as in the scheme 2-2-01 by a coupling reaction using 2-methoxyphenylboronic acid and 2-formylphenylboronic acid, respectively.

<Yield etc.>
Table 1 below shows the yield of the compound (biaryl) 15-22 racemate, the optical resolution by high performance liquid chromatography (HPLC) under the above conditions, and the recrystallization solvent. In addition, “◯” in Table 1 below indicates that optical resolution was possible by HPLC under the above conditions. Compounds 21 and 22 were difficult to optically resolve by HPLC under the above conditions. Compound 15 is not recrystallized.

  Hereinafter, the synthesis and optical resolution of each biaryl will be described more specifically. In addition, since the yield shown in the said Table 1 is a typical thing in which the synthesis | combination was performed in multiple times, it may differ from the yield shown below.

KF(174mg, 3mmol)を、20mLシュレンク管中、ヒートガンで加熱しながら減圧乾燥した。そこに、2-(2-クロロ-3-メトキシフェニル)-1,3-ジオキソラン(214mg, 1.0mmol)、2-メトキシフェニルボロン酸(228mg, 1.5mmol)、Pd₂(dba)₃・CHCl₃(2.6mg, 0.0025mmol)、および上記スキーム2-3-01の化学式21で表される配位子(4.6mg, 0.006mmol)を加えた。その系内を、再度減圧してアルゴンで満たすことを３回繰り返し、さらに、2mLのTHFを加えた。この反応混合物を室温で１０分間撹拌し、続いて、THF還流条件（浴温７５℃）下で１２．５時間反応させた。反応後、前記混合物を、10mLの酢酸エチル（EtOAc）で希釈し、セライト（登録商標）およびフロリジル（商品名）を通して濾過した。さらに、シリカゲルカラムクロマトグラフィー(トルエン/EtOAc=19/1)で精製し、目的物のビアリール15(251mg, 88%)を、無色透明のオイルとして得た。 <Scheme 2-3-01: Synthesis of 2- (6,6′-dimethoxybiphenyl-2-yl) -1,3-dioxolane 15>

KF (174 mg, 3 mmol) was dried under reduced pressure in a 20 mL Schlenk tube while heating with a heat gun. There, 2- (2-chloro-3-methoxyphenyl) -1,3-dioxolane (214 mg, 1.0 mmol), 2-methoxyphenylboronic acid (228 mg, 1.5 mmol), Pd ₂ (dba) ₃ and CHCl ₃ (2.6 mg, 0.0025 mmol) and a ligand (4.6 mg, 0.006 mmol) represented by Formula 21 in Scheme 2-3-01 were added. The system was again decompressed and filled with argon three times, and 2 mL of THF was added. The reaction mixture was stirred at room temperature for 10 minutes and subsequently reacted for 12.5 hours under THF reflux conditions (bath temperature 75 ° C.). After the reaction, the mixture was diluted with 10 mL of ethyl acetate (EtOAc) and filtered through Celite® and Florisil (trade name). Further, the product was purified by silica gel column chromatography (toluene / EtOAc = 19/1) to obtain the target biaryl 15 (251 mg, 88%) as a colorless transparent oil.

Instrumental analysis values for Biaryl 15:
¹ H NMR (400MHz, CDCl ₃ ) δ 7.40-7.34 (m, 2H), 7.29 (dd, J = 7.3Hz, 1H), 7.18 (dd, J = 7.4Hz, 1.8Hz, 1H), 7.03-7.96 (m, 3H), 5.44 (s, 1H), 4.12-4.00 (m, 2H), 3.87-3.79 (m, 2H), 3.73 (s, 3H), 3.72 (s, 3H). ¹³ C NMR (100MHz , CDCl ₃ ) δ157.2, 157.0, 137.3, 132.0, 128.7, 128.4, 127.6, 124.6, 120.0, 118.2, 111.4, 110.8, 101.5, 65.3, 65.0, 55.8, 55.6. Anal.Calcd. For C ₁₇ H ₁₈ O ₄ : C, 71.31; H, 6.34. Found: C, 71.60; H, 6.34.

KF(87mg, 1.5mmol)を、20mLシュレンク管中、ヒートガンで加熱しながら減圧乾燥した。そこに、2-(2-クロロ-3-メトキシフェニル)-1,3-ジオキソラン(107mg, 0.5mmol)、2-ホルミルフェニルボロン酸(113mg, 0.75mmol)、Pd₂(dba)₃・CHCl₃(2.6mg, 0.0025mmol)、および前記スキーム2-3-01と同じ配位子23(4.6mg, 0.006mmol)を加えた。その系内を、再度減圧してアルゴンで満たすことを３回繰り返し、さらに、2mLのTHFを加えた。この反応混合物を室温で５分間撹拌し、続いて、THF還流条件（浴温７５℃）下で５時間反応させた。反応後、前記混合物を、15mLの酢酸エチル（EtOAc）で希釈し、セライト（登録商標）およびフロリジル（商品名）を通して濾過した。さらに、シリカゲルカラムクロマトグラフィー(ヘキサン/EtOAc=7/1)で精製し、メタノール/ヘキサン(=0.5mL/0.5mL)で洗浄し、目的物のビアリール16(108mg, 76%)を、白色固体として得た。 <Scheme 2-3-02: Synthesis of 6 ′-(1,3-dioxolan-2-yl) -2′-methoxybiphenyl-2-carbaldehyde 16>

KF (87 mg, 1.5 mmol) was dried under reduced pressure while heating with a heat gun in a 20 mL Schlenk tube. There, 2- (2-chloro-3-methoxyphenyl) -1,3-dioxolane (107 mg, 0.5 mmol), 2-formylphenylboronic acid (113 mg, 0.75 mmol), Pd ₂ (dba) ₃ and CHCl ₃ (2.6 mg, 0.0025 mmol) and the same ligand 23 (4.6 mg, 0.006 mmol) as in Scheme 2-3-01 were added. The system was again decompressed and filled with argon three times, and 2 mL of THF was added. The reaction mixture was stirred at room temperature for 5 minutes and subsequently reacted for 5 hours under THF reflux conditions (bath temperature 75 ° C.). After the reaction, the mixture was diluted with 15 mL of ethyl acetate (EtOAc) and filtered through Celite® and Florisil (trade name). Further, the product was purified by silica gel column chromatography (hexane / EtOAc = 7/1) and washed with methanol / hexane (= 0.5 mL / 0.5 mL) to obtain the target biaryl 16 (108 mg, 76%) as a white solid. Obtained.

Instrumental analysis values for Biaryl 16:
¹ H NMR (400MHz, CDCl ₃ ) δ9.67 (s, 1H), 8.02 (d, J = 7.6Hz, 1H), 7.36 (t, J = 7.3Hz, 1H), 7.50-7.43 (m, 2H) , 7.32 (d, J = 7.8Hz, 2H), 6.99 (d, J = 7.8Hz, 1H), 5.40 (s, 1H), 3.97-3.68 (m, 7H). ¹³ C NMR (100MHz, CDCl ₃ ) δ192.6, 157.1, 139.6, 137.9, 135.0, 133.4, 132.1, 129.7, 128.2, 126.7, 126.5, 119.2, 111.5, 101.9, 65.6. 65.5, 56.0. FAB-MS m / z: 285 (M + H ⁺ ) Anal. Calcd For C ₁₇ H ₁₆ O ₄ : C, 71.82; H, 5.67. Found: C, 72.10; H, 5.56.

KF(174mg, 3mmol)を、20mLシュレンク管中、ヒートガンで加熱しながら減圧乾燥した。そこに、2-(2-クロロ-3-メトキシフェニル)-1,3-ジオキソラン(214mg, 1mmol)、ナフタレン-1-イルボロン酸(258mg, 1.5mmol)、Pd₂(dba)₃・CHCl₃(2.6mg, 0.0025mmol)、および前記スキーム2-3-01と同じ配位子23(4.6mg, 0.006mmol)を加えた。その系内を、再度減圧してアルゴンで満たすことを３回繰り返し、さらに、2mLのTHFを加えた。この反応混合物を室温で１０分間撹拌し、続いて、THF還流条件（浴温７５℃）下で１９．５時間反応させた。反応後、前記混合物を、５mLの酢酸エチル（EtOAc）で希釈し、セライト（登録商標）およびフロリジル（商品名）を通して濾過した。さらに、シリカゲルカラムクロマトグラフィー(トルエンのみ)で精製し、目的物のビアリール17(292mg, 95%)を、白色固体として得た。 <Scheme 2-3-03: Synthesis of 2- (3-methoxy-2- (naphthalen-1-yl) phenyl) -1,3-dioxolane 17>

KF (174 mg, 3 mmol) was dried under reduced pressure in a 20 mL Schlenk tube while heating with a heat gun. There, 2- (2-chloro-3-methoxyphenyl) -1,3-dioxolane (214 mg, 1 mmol), naphthalen-1-ylboronic acid (258 mg, 1.5 mmol), Pd ₂ (dba) ₃ .CHCl ₃ ( 2.6 mg, 0.0025 mmol) and the same ligand 23 (4.6 mg, 0.006 mmol) as in Scheme 2-3-01 was added. The system was again decompressed and filled with argon three times, and 2 mL of THF was added. The reaction mixture was stirred at room temperature for 10 minutes and subsequently reacted for 19.5 hours under THF reflux conditions (bath temperature 75 ° C.). After the reaction, the mixture was diluted with 5 mL of ethyl acetate (EtOAc) and filtered through Celite® and Florisil (trade name). Further, the product was purified by silica gel column chromatography (toluene only) to obtain the target biaryl 17 (292 mg, 95%) as a white solid.

Instrumental analysis values for Biaryl 17:
¹ H NMR (400MHz, CDCl ₃ ) δ 7.88 (dd, J = 3.6, 8.2Hz, 2H), 7.56-7.34 (m, 7H), 7.04 (dd, J = 1.0, 8.2Hz, 1H), 5.21 ( S, 1H), 4.05-3.95 (m , 2H), 3.76-3.67 (m, 2H), 3.62 (S, 1H). 13 C NMR (100MHz, CDCl 3) δ157.5, 138.1, 133.6, 133.4, 132.9 , 129.3, 129.2, 128.4, 128.2, 127.9, 126.3, 126.0, 125.8, 125.3, 118.7, 111.6, 101.1, 65.5, 65.3, 56.0. FAB-MS m / z: 306 (M ⁺ ). Anal. Calcd For C ₂₀ H ₁₈ O ₃ : C, 78.41; H, 5.92. Found: C, 78.32; H, 5.93.

KF(291mg, 5mmol)を、20mLシュレンク管中、ヒートガンで加熱しながら減圧乾燥した。そこに、2-クロロ-3-メトキシベンゾニトリル(335mg, 2mmol)、o-トリルボロン酸(408mg, 3mmol)、Pd₂(dba)₃・CHCl₃(2.6mg, 0.0025mmol)、および前記スキーム2-3-01と同じ配位子23(11.6mg, 0.0015mmol)を加えた。その系内を、再度減圧してアルゴンで満たすことを３回繰り返し、さらに、2mLのTHFを加えた。この反応混合物を室温で１０分間撹拌し、続いて、THF還流条件（浴温７５℃）下で１７時間反応させた。反応後、前記混合物を、１５mLの酢酸エチル（EtOAc）で希釈し、セライト（登録商標）およびフロリジル（商品名）を通して濾過した。さらに、シリカゲルカラムクロマトグラフィー(トルエン/EtOAc=19/1)で精製し、目的物のビアリール18(416mg, 93%)を、白色固体として得た。 <Scheme 2-304: Synthesis of 6-methoxy-6′-methylbiphenyl-2-carbonitrile 18>

KF (291 mg, 5 mmol) was dried under reduced pressure in a 20 mL Schlenk tube while heating with a heat gun. There, 2-chloro-3-methoxybenzonitrile (335 mg, 2 mmol), o-tolylboronic acid (408 mg, 3 mmol), Pd ₂ (dba) ₃ .CHCl ₃ (2.6 mg, 0.0025 mmol), and Scheme 2- The same ligand 23 (11.6 mg, 0.0015 mmol) as 3-01 was added. The system was again decompressed and filled with argon three times, and 2 mL of THF was added. The reaction mixture was stirred at room temperature for 10 minutes and subsequently reacted for 17 hours under THF reflux conditions (bath temperature 75 ° C.). After the reaction, the mixture was diluted with 15 mL of ethyl acetate (EtOAc) and filtered through Celite® and Florisil (trade name). Further, the product was purified by silica gel column chromatography (toluene / EtOAc = 19/1) to obtain the target biaryl 18 (416 mg, 93%) as a white solid.

Instrumental analysis values for Biaryl 18:
¹ H NMR (400MHz, CDCl ₃ ) δ7.43 (dd, J = 8.0Hz, 1H), 7.36-7.27 (m, 4H), 7.18 (dd, J = .8.0, 1.2Hz, 1H), 7.17 (d , J = 7.6Hz, 1H), 3.78 (S, 3H), 2.10 (S, 3H). 13 C NMR (100MHz, CDCl 3) δ157.1, 136.7, 134.6, 134.4, 130.0, 129.8, 129.4, 128.7, 125.8, 124.6, 117.9, 115.2, 114.2. EI-MS m / z: 223 (M ⁺ ).

KF(174mg, 3mmol)を、20mLシュレンク管中、ヒートガンで加熱しながら減圧乾燥した。そこに、2-クロロ-3-メトキシベンゾニトリル(167mg, 1mmol)、ナフタレン-1-イルボロン酸(258mg, 1.5mmol)、Pd₂(dba)₃・CHCl₃(2.6mg, 0.0025mmol)、および前記スキーム2-3-01と同じ配位子23(11.6mg, 0.015mmol)を加えた。その系内を、再度減圧してアルゴンで満たすことを３回繰り返し、さらに、2mLのTHFを加えた。この反応混合物を室温で１０分間撹拌し、続いて、THF還流条件（浴温７５℃）下で１２時間反応させた。反応後、前記混合物を、１５mLのCH₂Cl₂で希釈し、セライト（登録商標）およびフロリジル（商品名）を通して濾過した。さらに、シリカゲルカラムクロマトグラフィー(ヘキサン/トルエン=1/1)で精製し、目的物のビアリール19(189mg, 73%)を、白色固体として得た。 <Scheme 2-305: Synthesis of 3-methoxy-2- (naphthalen-1-yl) benzonitrile 19>

KF (174 mg, 3 mmol) was dried under reduced pressure in a 20 mL Schlenk tube while heating with a heat gun. There, 2-chloro-3-methoxybenzonitrile (167 mg, 1 mmol), naphthalen-1-ylboronic acid (258 mg, 1.5 mmol), Pd ₂ (dba) ₃ .CHCl ₃ (2.6 mg, 0.0025 mmol), and the above The same ligand 23 (11.6 mg, 0.015 mmol) as in Scheme 2-3-01 was added. The system was again decompressed and filled with argon three times, and 2 mL of THF was added. The reaction mixture was stirred at room temperature for 10 minutes and subsequently reacted for 12 hours under THF reflux conditions (bath temperature 75 ° C.). After the reaction, the mixture was diluted with 15 mL of CH ₂ Cl ₂ and filtered through Celite® and Florisil (trade name). Further, the product was purified by silica gel column chromatography (hexane / toluene = 1/1) to obtain the target biaryl 19 (189 mg, 73%) as a white solid.

Instrumental analysis values for Biaryl 19:
¹ H NMR (400MHz, CDCl ₃ ) δ7.93 (dd, J = 9.4Hz, 2H), 7.60-7.33 (m, 7H), 7.26 (dd, J = .1.0, 8.3Hz, 1H), 3.69 (S ¹³ C NMR (100 MHz, CDCl ₃ ) δ157.9, 133.6, 133.3, 132.7, 131.8, 129.8, 129.2, 128.6, 127.9, 126.4, 126.0, 125.5, 125.4, 124.9, 117.93, 117.92, 115.2, 56.0 GC-MS m / z: 259 (M ⁺ ). Anal. Calcd For C ₁₈ H ₁₃ NO: C, 83.37; H, 5.05; N, 5.40. Found: C, 83.45; H, 4.84; N, 5.28.

<Example 3: Suzuki-Miyaura reaction using asymmetric phosphonite compounds (ligands) 02 and 03>
In the asymmetric Suzuki-Miyaura reaction using aromatic compounds as starting materials, the compounds (ligands) 02 and 03, which are examples of the asymmetric phosphonite compounds of the present invention, are used as external asymmetric sources. confirmed. For comparison, the same test was performed on the compound (ligand) 01 which is an asymmetric phosphonite compound described in Non-Patent Document 3. As the substrate (reaction starting material), an aromatic chloride having a 1,3-dioxolane group and a methoxy group at the ortho position of the chlorine atom described later and ortho-tolylboronic acid were employed (Scheme 3-1-01 below) . The reaction conditions and the like were referred to Reference Document 6 described later.

  Table 2 below shows the reaction conditions, yield and asymmetric yield (ee) of the asymmetric Suzuki-Miyaura reaction. In Table 2 below, Reference Example 3-1 and Examples 3-2 to 3-3 used tetrahydrofuran as a solvent and potassium fluoride as a base under the conditions of P / Pd = 3. In the present invention, P / Pd represents the number of phosphorus atoms in the asymmetric phosphonite compound (ligand) in the reaction system divided by the number of palladium atoms present in the reaction system. In Reference Example 3-1, the target product could be obtained in 94% yield and 52% ee by reacting with ligand 01 for 5 hours. In Example 3-2, when the ligand 02, which is the asymmetric phosphonite compound of the present invention, was used in place of the ligand 01 and reacted for 4 hours, the asymmetric yield was improved to 69% ee. In Example 3-3, the results of 94% yield and 72% ee were obtained by using Ligand 03, which is the asymmetric phosphonite compound of the present invention, instead of Ligand 01. Further, when the reaction was carried out under the conditions of S / C = 200 and P / Pd = 1.2 using the ligand 02, it was 79% yield and 65% ee after column purification (Example 3-4). In the present invention, S / C represents a value obtained by dividing the substance amount of the substrate by the substance amount of the catalyst. The “substance substance amount” is equal to the substance amount of the reaction product theoretically generated from the substrate. That is, in the scheme 3-1-01, for example, 1 mol of 2- (2-chloro-3-methoxyphenyl) -1,3-dioxolane and 2-methylphenylboronic acid (ortho-tolylboronic acid) are contained in the reaction system. Is 2 mol, the “substance amount of the substrate” is 1 mol. Further, under the condition of P / Pd = 2, the solvent was changed to toluene and the base was changed to cesium fluoride for comparison (Reference Example 3-5 and Examples 3-6 to 3-7). In Reference Example 3-5, the ligand 01 was used and reacted for 4 hours, and the target product was recorded in 89% yield and 54% ee. The asymmetric yield was improved to 74% ee by setting the ligand to 02 and reacting for 4 hours (Example 3-6). When ligand 03 was used, the yield was 91% and 78% ee (Example 3-7).

KF(174mg, 3mmol)を、20mLシュレンク管中、ヒートガンで加熱しながら減圧乾燥した。そこに、2-(2-クロロ-3- メトキシフェニル)-1,3-ジオキソラン(214mg, 1mmol)、o-トリルボロン酸(204mg, 1.5mmol)、Pd₂(dba)₃・CHCl₃(2.6mg, 0.0025mmol)、および上記化学式01で表される不斉ホスホナイト化合物（配位子）(13.8mg, 0.015mmol)を加えた。その系内を、再度減圧してアルゴンで満たすことを３回繰り返し、さらに、2mLのTHFを加えた。この反応混合物を室温で5分間撹拌し、続いて、THF還流条件（浴温７５℃）下で22時間反応させた。反応後、前記混合物を、15mLの酢酸エチル（EtOAc）で希釈し、セライト（登録商標）およびフロリジル（商品名）を通して濾過した。さらに、シリカゲルカラムクロマトグラフィー(ヘキサン/EtOAc/C₆H₆=8/1/1)で精製し、目的物のビアリール20(253mg, 94%)を、白色固体として得た。なお、ビアリール20については、前記参考文献３に記載されている。不斉収率eeは、Daicel Chiralcel OJ（商品名）を用いたHPLC分析により、52%と決定した。溶離剤はヘキサン-iPrOH 75/25、測定波長は270nm、流速は0.5mL/min、カラム温度は298K、保持時間は、R体が14.3分（存在比24.0％）、S体が18.7分（存在比76.0％）であった。 <Reference Example 3-1: Synthesis of 2- (6-methoxy-6'-methylbiphenyl-2-yl) -1,3-dioxolane 20>

KF (174 mg, 3 mmol) was dried under reduced pressure in a 20 mL Schlenk tube while heating with a heat gun. There, 2- (2-chloro-3-methoxyphenyl) -1,3-dioxolane (214 mg, 1 mmol), o-tolylboronic acid (204 mg, 1.5 mmol), Pd ₂ (dba) ₃ and CHCl ₃ (2.6 mg , 0.0025 mmol), and an asymmetric phosphonite compound (ligand) represented by the above chemical formula 01 (13.8 mg, 0.015 mmol). The system was again decompressed and filled with argon three times, and 2 mL of THF was added. The reaction mixture was stirred at room temperature for 5 minutes and subsequently reacted for 22 hours under THF reflux conditions (bath temperature 75 ° C.). After the reaction, the mixture was diluted with 15 mL of ethyl acetate (EtOAc) and filtered through Celite® and Florisil (trade name). Further, the product was purified by silica gel column chromatography (hexane / EtOAc / C ₆ H ₆ = 8/1/1) to obtain the target biaryl 20 (253 mg, 94%) as a white solid. Biaryl 20 is described in the above-mentioned Reference 3. The asymmetric yield ee was determined to be 52% by HPLC analysis using Daicel Chiralcel OJ (trade name). Eluent: Hexane-iPrOH 75/25, measurement wavelength: 270 nm, flow rate: 0.5 mL / min, column temperature: 298 K, retention time: R-form 14.3 min (existence ratio 24.0%), S-form 18.7 min (exist) 76.0%).

Instrumental analysis values for Biaryl 20:
¹ H NMR (400MHz, CDCl ₃ ) δ7.41-7.37 (m, 1H), 7.32 (d, J = 7.8Hz, 1H), 7.28-7.21 (m, 3H), 7.16 (d, J = 8.2Hz, 1H), 6.95 (d, J = 8.2Hz, 1H), 5.35 (s, 1H), 4.04-3.95 (m, 2H), 3.80-3.72 (m, 2H), 3.67 (s, 3H), 2.08 (s ¹³ C NMR (100 MHz, CDCl ₃ ) δ156.7, 137.6, 137.2, 135.6, 130.68, 130.65, 129.7, 128.9, 127.8, 125.5, 118.8, 111.5, 101.6, 65.69, 65.57, 56.0, 20.3.EI -MS m / z: 270 (M ⁺ ). Anal. Calcd For C ₁₇ H ₁₈ O ₃ : C, 75.53; H, 6.71. Found: C, 75.52; H, 6.75.

KF(174mg, 3mmol)を、20mLシュレンク管中、ヒートガンで加熱しながら減圧乾燥した。そこに、2-(2-クロロ-3-メトキシフェニル)-1,3-ジオキソラン(214mg, 1mmol)、o-トリルボロン酸(204mg, 1.5mmol)、Pd₂(dba)₃・CHCl₃(2.6mg, 0.0025mmol)、および上記化学式02で表される不斉ホスホナイト化合物（配位子）(14.2mg, 0.015mmol)を加えた。その系内を、再度減圧してアルゴンで満たすことを３回繰り返し、さらに、2mLのTHFを加えた。この反応混合物を室温で5分間撹拌し、続いて、THF還流条件（浴温７５℃）下で21時間反応させた。反応後、前記混合物を、15mLの酢酸エチル（EtOAc）で希釈し、セライト（登録商標）およびフロリジル（商品名）を通して濾過した。さらに、シリカゲルカラムクロマトグラフィー(ヘキサン/EtOAc/C₆H₆=8/1/1)で精製し、目的物のビアリール20(243mg, 90%)を、白色固体として得た。不斉収率eeは、Daicel Chiralcel OJ（商品名）を用いたHPLC分析により、69%と決定した。溶離剤はヘキサン-iPrOH 75/25、測定波長は270nm、流速は0.5mL/min、カラム温度は298K、保持時間は、R体が14.2分（存在比15.5％）、S体が18.7分（存在比84.5％）であった。 <Example 3-2: Synthesis of 2- (6-methoxy-6'-methylbiphenyl-2-yl) -1,3-dioxolane 20>

KF (174 mg, 3 mmol) was dried under reduced pressure in a 20 mL Schlenk tube while heating with a heat gun. There, 2- (2-chloro-3-methoxyphenyl) -1,3-dioxolane (214 mg, 1 mmol), o-tolylboronic acid (204 mg, 1.5 mmol), Pd ₂ (dba) ₃ and CHCl ₃ (2.6 mg , 0.0025 mmol), and an asymmetric phosphonite compound (ligand) represented by the above chemical formula 02 (14.2 mg, 0.015 mmol). The system was again decompressed and filled with argon three times, and 2 mL of THF was added. The reaction mixture was stirred at room temperature for 5 minutes and then reacted for 21 hours under THF reflux conditions (bath temperature 75 ° C.). After the reaction, the mixture was diluted with 15 mL of ethyl acetate (EtOAc) and filtered through Celite® and Florisil (trade name). Further, the residue was purified by silica gel column chromatography (hexane / EtOAc / C ₆ H ₆ = 8/1/1) to obtain the target biaryl 20 (243 mg, 90%) as a white solid. The asymmetric yield ee was determined to be 69% by HPLC analysis using Daicel Chiralcel OJ (trade name). Eluent: Hexane-iPrOH 75/25, measurement wavelength 270 nm, flow rate 0.5 mL / min, column temperature 298 K, retention time 14.2 minutes for R-isomer (15.5% abundance), 18.7 minutes for S-isomer (present) 84.5%).

KF(174mg, 3mmol)を、20mLシュレンク管中、ヒートガンで加熱しながら減圧乾燥した。そこに、2-(2-クロロ-3- メトキシフェニル)-1,3-ジオキソラン(214mg, 1mmol)、o-トリルボロン酸(204mg, 1.5mmol)、Pd₂(dba)₃・CHCl₃(2.6mg, 0.0025mmol)、および上記化学式03で表される不斉ホスホナイト化合物（配位子）(15.3mg, 0.015mmol)を加えた。その系内を、再度減圧してアルゴンで満たすことを３回繰り返し、さらに、2mLのTHFを加えた。この反応混合物を室温で5分間撹拌し、続いて、THF還流条件（浴温７５℃）下で22時間反応させた。反応後、前記混合物を、15mLの酢酸エチル（EtOAc）で希釈し、セライト（登録商標）およびフロリジル（商品名）を通して濾過した。さらに、シリカゲルカラムクロマトグラフィー(ヘキサン/EtOAc/C₆H₆=8/1/1)で精製し、目的物のビアリール20(252mg, 94%)を、白色固体として得た。不斉収率eeは、Daicel Chiralcel OJ（商品名）を用いたHPLC分析により、72%と決定した。溶離剤はヘキサン-iPrOH 75/25、測定波長は270nm、流速は0.5mL/min、カラム温度は298K、保持時間は、R体が14.2分（存在比86.0%）、S体が19.2分（存在比14.0%）であった。 <Example 3-3: Synthesis of 2- (6-methoxy-6'-methylbiphenyl-2-yl) -1,3-dioxolane 20>

KF (174 mg, 3 mmol) was dried under reduced pressure in a 20 mL Schlenk tube while heating with a heat gun. There, 2- (2-chloro-3-methoxyphenyl) -1,3-dioxolane (214 mg, 1 mmol), o-tolylboronic acid (204 mg, 1.5 mmol), Pd ₂ (dba) ₃ and CHCl ₃ (2.6 mg , 0.0025 mmol), and an asymmetric phosphonite compound (ligand) represented by the above chemical formula 03 (15.3 mg, 0.015 mmol). The system was again decompressed and filled with argon three times, and 2 mL of THF was added. The reaction mixture was stirred at room temperature for 5 minutes and subsequently reacted for 22 hours under THF reflux conditions (bath temperature 75 ° C.). After the reaction, the mixture was diluted with 15 mL of ethyl acetate (EtOAc) and filtered through Celite® and Florisil (trade name). Further, the product was purified by silica gel column chromatography (hexane / EtOAc / C ₆ H ₆ = 8/1/1) to obtain the target biaryl 20 (252 mg, 94%) as a white solid. The asymmetric yield ee was determined to be 72% by HPLC analysis using Daicel Chiralcel OJ (trade name). Eluent: Hexane-iPrOH 75/25, measurement wavelength: 270 nm, flow rate: 0.5 mL / min, column temperature: 298 K, retention time: R-form 14.2 min (existence ratio 86.0%), S-form 19.2 min (exist) 14.0%).

<Example 3-4: Synthesis of 2- (6-methoxy-6'-methylbiphenyl-2-yl) -1,3-dioxolane 20>
Biaryl 20 was obtained in the same manner as in Example 3-2 except that the amount of asymmetric phosphonite compound (ligand) 02 was reduced to P / Pd = 1.2 and the reaction time was 6 hours. 79%, asymmetric yield 65% (R-form excess).

CsF(456mg, 3mmol)を、20mLシュレンク管中、ヒートガンで加熱しながら減圧乾燥した。そこに、2-(2-クロロ-3-メトキシフェニル)-1,3-ジオキソラン(214mg, 1mmol)、o-トリルボロン酸(204mg, 1.5mmol)、Pd₂(dba)₃・CHCl₃(2.6mg, 0.0025mmol)、および上記化学式01で表される不斉ホスホナイト化合物（配位子）(9.2mg, 0.01mmol)を加えた。その系内を、再度減圧してアルゴンで満たすことを３回繰り返し、さらに、2mLのトルエンを加えた。この反応混合物を室温で5分間撹拌し、続いて、トルエン還流条件（浴温90℃）下で4時間反応させた。反応後、前記混合物を、15mLの酢酸エチル（EtOAc）で希釈し、セライト（登録商標）およびフロリジル（商品名）を通して濾過した。さらに、シリカゲルカラムクロマトグラフィー(ヘキサン/EtOAc/C₆H₆=8/1/1)で精製し、目的物のビアリール20(241mg, 89%)を、白色固体として得た。不斉収率eeは、Daicel Chiralcel OJ（商品名）を用いたHPLC分析により、54%と決定した。溶離剤はヘキサン-iPrOH 75/25、測定波長は270nm、流速は0.5mL/min、カラム温度は298K、保持時間は、R体が14.1分（存在比23.0%）、S体が18.7分（存在比77.0%）であった。 <Reference Example 3-5: Synthesis of 2- (6-methoxy-6'-methylbiphenyl-2-yl) -1,3-dioxolane 20>

CsF (456 mg, 3 mmol) was dried under reduced pressure in a 20 mL Schlenk tube while heating with a heat gun. There, 2- (2-chloro-3-methoxyphenyl) -1,3-dioxolane (214 mg, 1 mmol), o-tolylboronic acid (204 mg, 1.5 mmol), Pd ₂ (dba) ₃ and CHCl ₃ (2.6 mg , 0.0025 mmol), and an asymmetric phosphonite compound (ligand) represented by the above chemical formula 01 (9.2 mg, 0.01 mmol). The system was again decompressed and filled with argon three times, and 2 mL of toluene was further added. The reaction mixture was stirred at room temperature for 5 minutes, and subsequently reacted for 4 hours under toluene reflux conditions (bath temperature 90 ° C.). After the reaction, the mixture was diluted with 15 mL of ethyl acetate (EtOAc) and filtered through Celite® and Florisil (trade name). Further, the product was purified by silica gel column chromatography (hexane / EtOAc / C ₆ H ₆ = 8/1/1) to obtain the target biaryl 20 (241 mg, 89%) as a white solid. The asymmetric yield ee was determined to be 54% by HPLC analysis using Daicel Chiralcel OJ (trade name). Eluent: Hexane-iPrOH 75/25, measurement wavelength: 270 nm, flow rate: 0.5 mL / min, column temperature: 298 K, retention time: R-form 14.1 min (abundance ratio 23.0%), S-form 18.7 min (existence) 77.0%).

CsF(456 mg, 3mmol)を、20mLシュレンク管中、ヒートガンで加熱しながら減圧乾燥した。そこに、2-(2-クロロ-3- メトキシフェニル)-1,3-ジオキソラン(214mg, 1mmol)、o-トリルボロン酸(204mg, 1.5mmol)、Pd₂(dba)₃・CHCl₃(2.6mg, 0.0025mmol)、および上記化学式02で表される不斉ホスホナイト化合物（配位子）(9.5mg, 0.01mmol)を加えた。その系内を、再度減圧してアルゴンで満たすことを３回繰り返し、さらに、2mLのトルエンを加えた。この反応混合物を室温で5分間撹拌し、続いて、トルエン還流条件（浴温90℃）下で4時間反応させた。反応後、前記混合物を、15mLの酢酸エチル（EtOAc）で希釈し、セライト（登録商標）およびフロリジル（商品名）を通して濾過した。さらに、シリカゲルカラムクロマトグラフィー(ヘキサン/EtOAc/C₆H₆=8/1/1)で精製し、目的物のビアリール20(251mg, 93%)を、白色固体として得た。不斉収率eeは、Daicel Chiralcel OJ（商品名）を用いたHPLC分析により、74%と決定した。溶離剤はヘキサン-iPrOH 75/25、測定波長は270nm、流速は0.5mL/min、カラム温度は298K、保持時間は、R体が14.2分（存在比13.1%）、S体が18.7分（存在比86.9%)）であった。 <Example 3-6: Synthesis of 2- (6-methoxy-6'-methylbiphenyl-2-yl) -1,3-dioxolane 20>

CsF (456 mg, 3 mmol) was dried under reduced pressure in a 20 mL Schlenk tube while heating with a heat gun. There, 2- (2-chloro-3-methoxyphenyl) -1,3-dioxolane (214 mg, 1 mmol), o-tolylboronic acid (204 mg, 1.5 mmol), Pd ₂ (dba) ₃ and CHCl ₃ (2.6 mg , 0.0025 mmol), and an asymmetric phosphonite compound (ligand) represented by the chemical formula 02 (9.5 mg, 0.01 mmol). The system was again decompressed and filled with argon three times, and 2 mL of toluene was further added. The reaction mixture was stirred at room temperature for 5 minutes, and subsequently reacted for 4 hours under toluene reflux conditions (bath temperature 90 ° C.). After the reaction, the mixture was diluted with 15 mL of ethyl acetate (EtOAc) and filtered through Celite® and Florisil (trade name). Further, the product was purified by silica gel column chromatography (hexane / EtOAc / C ₆ H ₆ = 8/1/1) to obtain the target biaryl 20 (251 mg, 93%) as a white solid. The asymmetric yield ee was determined to be 74% by HPLC analysis using Daicel Chiralcel OJ (trade name). Eluent: Hexane-iPrOH 75/25, measurement wavelength 270 nm, flow rate 0.5 mL / min, column temperature 298 K, retention time 14.2 minutes for R-isomer (abundance ratio 13.1%), 18.7 minutes for S-isomer (present) The ratio was 86.9%)).

CsF(456mg, 3mmol)を、20mLシュレンク管中、ヒートガンで加熱しながら減圧乾燥した。そこに、2-(2-クロロ-3-メトキシフェニル)-1,3-ジオキソラン(214mg, 1.0mmol)、o-トリルボロン酸(204mg, 1.5mmol)、Pd₂(dba)₃・CHCl₃(2.6mg, 0.0025mmol)、および上記化学式03で表される不斉ホスホナイト化合物（配位子）(10.2mg, 0.01mmol)を加えた。その系内を、再度減圧してアルゴンで満たすことを３回繰り返し、さらに、2mLのトルエンを加えた。この反応混合物を室温で5分間撹拌し、続いて、トルエン還流条件（浴温90℃）下で6時間反応させた。反応後、前記混合物を、15mLの酢酸エチル（EtOAc）で希釈し、セライト（登録商標）およびフロリジル（商品名）を通して濾過した。さらに、シリカゲルカラムクロマトグラフィー(ヘキサン/EtOAc/C₆H₆=8/1/1)で精製し、目的物のビアリール20(246mg, 91%)を、白色固体として得た。不斉収率eeは、Daicel Chiralcel OJ（商品名）を用いたHPLC分析により、78%と決定した。溶離剤はヘキサン-iPrOH 75/25、測定波長は270nm、流速は0.5mL/min、カラム温度は298K、保持時間は、R体が14.0分（存在比89.1%）、S体が19.0分（存在比10.9%)）であった。 <Example 3-7: Synthesis of 2- (6-methoxy-6'-methylbiphenyl-2-yl) -1,3-dioxolane 20>

CsF (456 mg, 3 mmol) was dried under reduced pressure in a 20 mL Schlenk tube while heating with a heat gun. There, 2- (2-chloro-3-methoxyphenyl) -1,3-dioxolane (214 mg, 1.0 mmol), o-tolylboronic acid (204 mg, 1.5 mmol), Pd ₂ (dba) ₃ and CHCl ₃ (2.6 mg, 0.0025 mmol) and an asymmetric phosphonite compound (ligand) represented by the above chemical formula 03 (10.2 mg, 0.01 mmol) were added. The system was again decompressed and filled with argon three times, and 2 mL of toluene was further added. The reaction mixture was stirred at room temperature for 5 minutes and subsequently reacted for 6 hours under toluene reflux conditions (bath temperature 90 ° C.). After the reaction, the mixture was diluted with 15 mL of ethyl acetate (EtOAc) and filtered through Celite® and Florisil (trade name). Further, the product was purified by silica gel column chromatography (hexane / EtOAc / C ₆ H ₆ = 8/1/1) to obtain the target biaryl 20 (246 mg, 91%) as a white solid. The asymmetric yield ee was determined to be 78% by HPLC analysis using Daicel Chiralcel OJ (trade name). Eluent: Hexane-iPrOH 75/25, measurement wavelength: 270 nm, flow rate: 0.5 mL / min, column temperature: 298 K, retention time: R-form 14.0 min (existence ratio 89.1%), S-form 19.0 min (existence) The ratio was 10.9%)).

上記スキームのとおり、Pd₂(dba)₃・CHCl₃および配位子02の使用量をそれぞれ実施例3-6の５分の１（S/C=1000）とすることと、トルエンを6mL用いて90℃で4.5時間還流させること以外は実施例3-6と同様にしてビアリール20を合成した。これを実施例3-8とする。また、Pd₂(dba)₃・CHCl₃の使用量を実施例3-6の５分の１とし、配位子02の使用量を実施例3-6の15％とする（S/C=2000、P/Pd=3）ことと、トルエンを12mL用いて90℃で15.5時間還流させること以外は実施例3-6と同様にしてビアリール20を合成した。その結果、実施例3-8では、光学収率（ee）75％または76％でビアリール20が得られ、実施例3-9では、光学収率（ee）64％でビアリール20が得られた。このように、S/C=1000または2000まで触媒量を減らしても、良好な光学収率で不斉鈴木−宮浦反応を行うことができた。 Examples 3-8 and 3-9: Synthesis of 2- (6-methoxy-6'-methylbiphenyl-2-yl) -1,3-dioxolane 20

As shown in the above scheme, the amount of Pd ₂ (dba) ₃ · CHCl ₃ and ligand 02 used is set to one fifth of that in Example 3-6 (S / C = 1000) and 6 mL of toluene was used. Biaryl 20 was synthesized in the same manner as in Example 3-6 except that the mixture was refluxed at 90 ° C. for 4.5 hours. This is designated as Example 3-8. In addition, the amount of Pd ₂ (dba) ₃ · CHCl ₃ used is one fifth that of Example 3-6, and the amount of ligand 02 used is 15% of Example 3-6 (S / C = Biaryl 20 was synthesized in the same manner as in Example 3-6 except that 2000, P / Pd = 3), and 12 mL of toluene was refluxed at 90 ° C. for 15.5 hours. As a result, biaryl 20 was obtained with optical yield (ee) of 75% or 76% in Example 3-8, and biaryl 20 was obtained with optical yield (ee) of 64% in Example 3-9. . Thus, even when the catalyst amount was reduced to S / C = 1000 or 2000, the asymmetric Suzuki-Miyaura reaction could be carried out with a good optical yield.

<Axis chirality of biaryl>
As reference data, the biaryl 20 (2- (6-methoxy-6′-methylbiphenyl-2-yl) -1,3-dioxolane, the upper part of Scheme 4 below) and the biaryl 17 (2- (3-methoxy The stability of the asymmetric axis of -2- (naphthalen-1-yl) phenyl) -1,3-dioxolane (lower part of the following scheme 4) is shown. First, as shown in the upper part of the following scheme, asymmetric synthesis was performed under the condition of S / C = 400 using the ligand 01 (the compound of Non-Patent Document 3), and the biaryl 20 obtained at 32% ee was obtained. In contrast, the mixture was heated at 75 ° C. for 12 hours, but no change in the asymmetric yield was observed. Furthermore, although it heated for 12 hours at 90 degreeC in toluene solvent, the significant change was not seen. In addition, as shown in the lower part of the following scheme, 52% ee biaryl 17 was heated at 90 ° C. in toluene for 4 hours or in 2-propanol (isopropyl alcohol) at 107 ° C. for 13.5 hours. I couldn't. As described above, these biaryls synthesized (manufactured) in this example have an optically active substance that is extremely stable and easily retains optical activity. Therefore, the optical activity is easily utilized.

References
6. Kamikawa, K .; Watanabe, T .; Uemura, MJ Org. Chem. 1996, 61, 1375-1384.

<Summary>
As described above, in this example, the following asymmetric phosphonite compound (ligand) 01 (compound of Non-patent Document 3), 02 and 03 (asymmetric phosphonite compound of the present invention) were synthesized, and Suzuki- The performance of the Miyaura reaction as a catalyst was confirmed.

The performance of ligands 01, 02 and 03 in THF solvent was compared according to Scheme 5 below. As a result, with ligand 01, the desired biaryl was obtained in 94% yield and 52% ee. On the other hand, 90% yield and 69% ee were obtained for ligand 02, 94% yield and 72% ee were obtained for ligand 03 (Scheme 5 below). Thus, according to the asymmetric phosphonite compound (ligand) 02 and 03 of this example, the improvement in the asymmetric yield was achieved as compared with the asymmetric phosphonite compound (ligand) of Non-Patent Document 3. It was possible.

Moreover, the performance of the ligand was compared even in toluene solvents. As a result, the target biaryl was obtained with the ligand 01 in 89% yield and 54% ee. Ligand 02 gave 93% yield, 74% ee. On the other hand, in the case of Ligand 03, the target product was obtained with a 91% yield and 78% ee (Scheme 6 below). Whichever ligand was used, the asymmetric yield was improved by 2 to 6% ee than in the THF solvent. Further, as in the THF solvent, according to the asymmetric phosphonite compound (ligand) 02 and 03 of this example, the asymmetric phosphonite compound (ligand) of the non-patent document 3 was compared with the asymmetric phosphonite compound (ligand). The rate could be improved.

  Further, in this example, even when aryl chloride (aromatic chloride) having relatively low reactivity among aryl halides was used, high yield and asymmetric yield were obtained in a relatively short time. Furthermore, even if the amount of catalyst used was reduced to S / C = 1000 or 2000, a high yield and an asymmetric yield could be maintained.

  As described above, according to the present invention, it is possible to provide an asymmetric phosphonite compound that can be used as a catalyst ligand for axially asymmetric biaryl synthesis excellent in reactivity, TON, and asymmetric yield. Furthermore, according to the present invention, an asymmetric synthesis catalyst, a method for producing an asymmetric phosphonite compound, and a method for producing an organic compound having optical activity can be provided. According to the present invention, for example, the Suzuki-Miyaura reaction can be realized at low cost, so that it can make a great contribution to various industrial fields such as synthetic chemistry, pharmaceutical chemistry, material chemistry, supramolecular chemistry, and the like. Furthermore, the asymmetric phosphonite compound of the present invention is not limited to the Suzuki-Miyaura reaction, and may be used for any application.

Claims (22)

An asymmetric phosphonite compound represented by the following chemical formula (I), a tautomer or stereoisomer thereof, or a salt thereof.

In the chemical formula (I),
Each Ar is a substituted or unsubstituted aryl group, which may be the same or different;
At least one of Ar is a group represented by the following chemical formula (II),

In the chemical formula (II),
m1 is the number of substitutions from 0 to 3,
R ¹ is an optional substituent, and when plural R ¹ may be the same or different,
P is a hydrogen atom or an arbitrary substituent, and when plural, they may be the same or different,
Alternatively , at least two of R ¹ and P may form a condensed ring together with the benzene ring in the chemical formula (II),
However, in all Ar of the chemical formula (I), at least one P is a group represented by the following chemical formula (III) or a geometric isomer or stereoisomer thereof,

In the chemical formula (III),
m2 is the number of substitutions from 0 to 4, and each m2 may be the same or different,
m3 is the number of substitutions from 0 to 1, and each m3 may be the same or different,
R ² is an optional substituent, and each R ² may be the same or different,
R ³ is an arbitrary substituent, and in the case of plural, R ³ may be the same or different,
Alternatively, two or more of R ² and R ³ may be combined to form a condensed ring together with the benzene ring to which they are bonded. In the chemical formula (II),
R ¹ is a chain hydrocarbon group, an alicyclic hydrocarbon group, or an aryl group,
The chain hydrocarbon group may be saturated or unsaturated, linear or branched, may or may not have a substituent,
The alicyclic hydrocarbon group may be saturated or unsaturated, and may or may not have a substituent,
The aryl group may or may not have a substituent,
P is a hydrogen atom, a group represented by the chemical formula (III) or a geometric isomer or stereoisomer thereof, a chain hydrocarbon group, an alicyclic hydrocarbon group, or an aryl group,
The chain hydrocarbon group may be saturated or unsaturated, linear or branched, may or may not have a substituent,
The alicyclic hydrocarbon group may be saturated or unsaturated, and may or may not have a substituent,
The aryl group may or may not have a substituent,
Alternatively , at least two of R ¹ and P may form a condensed ring together with the benzene ring in the chemical formula (II),
However, in all Ar in the chemical formula (I), at least one P is a group represented by the chemical formula (III) or a geometrical isomer or stereoisomer thereof.
The asymmetric phosphonite compound according to claim 1, a tautomer or stereoisomer thereof, or a salt thereof. In the chemical formula (III),
R ² is a chain hydrocarbon group, an alicyclic hydrocarbon group, or an aryl group,
The chain hydrocarbon group may be saturated or unsaturated, linear or branched, may or may not have a substituent,
The alicyclic hydrocarbon group may be saturated or unsaturated, and may or may not have a substituent,
The aryl group may or may not have a substituent,
R ³ is a chain hydrocarbon group, an alicyclic hydrocarbon group, or an aryl group,
The chain hydrocarbon group may be saturated or unsaturated, linear or branched, may or may not have a substituent,
The alicyclic hydrocarbon group may be saturated or unsaturated, and may or may not have a substituent,
The aryl group may or may not have a substituent,
Alternatively, two or more of R ² and R ³ may be combined to form a condensed ring together with the benzene ring to which they are bonded.
The asymmetric phosphonite compound according to claim 1 or 2, a tautomer or stereoisomer thereof, or a salt thereof. The asymmetric phosphonite compound according to any one of claims 1 to 3, represented by the following chemical formula (IV), a tautomer or stereoisomer thereof, or a salt thereof.

In the chemical formula (IV),
R ^{11 to} R ²⁸ are each a hydrogen atom, an arbitrary substituent, or at least two of R ^a (a is any one of ^{11 to 28)} bonded to the same benzene ring. And may form a condensed ring together with the benzene ring,
P is a group represented by the chemical formula (III) or a geometric isomer or stereoisomer thereof. In the chemical formula (IV),
R ^{11 to} R ²⁸ are each a hydrogen atom, a chain hydrocarbon group, an alicyclic hydrocarbon group, or an aryl group,
The chain hydrocarbon group may be saturated or unsaturated, linear or branched, may or may not have a substituent,
The alicyclic hydrocarbon group may be saturated or unsaturated, and may or may not have a substituent,
The aryl group may or may not have a substituent,
Or, at least two of R ^a (a is any one of 11 to 28) bonded to the same benzene ring may be combined to form a condensed ring together with the benzene ring.
The asymmetric phosphonite compound according to claim 4, a tautomer or stereoisomer thereof, or a salt thereof. In said chemical formula (IV), R < ¹¹ > -R < ¹⁵ > is a methyl group, R < ¹⁶ > -R < ²⁸ > is a hydrogen atom, The asymmetric phosphonite compound of Claim 5, its tautomer or stereoisomer, or these Salt. The group represented by the chemical formula (III) is a group represented by the following chemical formula (V) or (VI), or a geometrical isomer or a stereoisomer thereof. The described asymmetric phosphonite compound, a tautomer or stereoisomer thereof, or a salt thereof.

  An asymmetric synthesis catalyst comprising the asymmetric phosphonite compound according to any one of claims 1 to 7, a tautomer or stereoisomer thereof, or a salt thereof, and a metal atom or ion.   The asymmetric synthesis catalyst according to claim 8, wherein the metal is palladium. A compound represented by the following chemical formula (I ′), a tautomer or stereoisomer thereof, or a salt thereof; a compound represented by the following chemical formula (III ′), a tautomer or stereoisomer thereof; Or an asymmetric phosphonite compound synthesis step of synthesizing an asymmetric phosphonite compound represented by the above chemical formula (I) by coupling a salt thereof with an organic alkali metal in the presence of a phosphorus halide. A process for producing an asymmetric phosphonite compound according to any one of claims 1 to 7, a tautomer or stereoisomer thereof, or a salt thereof.

In the chemical formula (I ′),
Ar ² is the same as Ar in the chemical formula (I) except that it has a halogeno group instead of the group represented by the chemical formula (III) or a geometric isomer or stereoisomer thereof,
In the chemical formula (III ′),
m @ 2, m3, ^{R 2} and ^{R 3} are the same as the chemical formula (III). further,
The following compound (VIII), its tautomer or stereoisomer, or a salt thereof is protected by protecting the hydroxyl group of the following compound (VII), its tautomer or stereoisomer, or a salt thereof with a protecting group. A hydroxyl group protecting step to be produced;
A substituent introduction step of introducing the substituent R ² into the following compound (VIII) to introduce the following compound (IX);
Deprotecting the following compound (IX) to produce the compound (III ′):
The manufacturing method of Claim 10.

In the chemical formulas (VII) to (IX), m2, m3 and R ³ are the same as those in the chemical formula (III ′).
In the chemical formula (IX), R ² is the same as the chemical formula (III ′),
In the chemical formulas (VIII) and (IX), Q is a protecting group, and each Q may be the same or different. further,
A binaphthyl production step of producing a binaphthyl compound (III ″), which is a mixture of the compound represented by the chemical formula (III ′) and its optical isomer, by subjecting the following compound (X) to a bimolecular coupling reaction;
An optically active group introduction step for producing the following compound (XI ′) by introducing an optically active group into at least one of the hydroxyl groups of the compound (III ″);
An optical resolution step of optically resolving the following compound (XI ′) to obtain the following compound (XI) or an optical isomer thereof;
An optically active group for producing a compound represented by the chemical formula (III ′), a tautomer or stereoisomer thereof, or a salt thereof by removing the optically active group from the following compound (XI) A desorption step,
The manufacturing method of Claim 10.

In the chemical formulas (X), (III ″), (XI ′) and (XI), m2, m3, R ² and R ³ are the same as those in the chemical formula (III ′), and bimolecular (X) The structure may be the same or different,
In the chemical formulas (XI ′) and (XI), Q ² is a hydrogen atom or an arbitrary substituent, which may be the same or different, and at least one is an optically active group. In the chemical formulas (XI ′) and (XI),
In Q ^2, wherein the optically active group, the manufacturing method according to claim 12 wherein the group or its optical isomers represented by the following chemical formula (XII).

A method for producing an organic compound having optical activity,
The manufacturing method characterized by manufacturing the organic compound which has the said optical activity by the asymmetric synthesis reaction using the asymmetric synthesis catalyst of Claim 8 or 9.   The method according to claim 14, wherein the asymmetric synthesis reaction is an asymmetric synthesis coupling reaction.   The production method according to claim 15, wherein the asymmetric synthesis coupling reaction is a coupling reaction between an organic halide and an organic boron compound.   The method according to claim 16, wherein the organic halide is an aryl halide. The production method according to claim 17, wherein the aryl halide is a compound represented by the following chemical formula (101) or (102).

In the chemical formulas (101) and (102), X ¹ is a halogeno group.   The method according to any one of claims 15 to 18, wherein the organic boron compound is an aryl boron compound.   The method according to claim 19, wherein the organoboron compound is an organoboronic acid. The method according to claim 20, wherein the organic boronic acid is a compound represented by any one of the following chemical formulas (201) to (204).

The organic compound having optical activity is a compound represented by any one of the following chemical formulas (1001) to (1008), a tautomer or stereoisomer thereof, or a salt thereof. The manufacturing method according to claim 1.