JP2009023927A - Method for producing optically active cyanohydrin - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a commercially advantageous method for producing an optically active cyanohydrin. <P>SOLUTION: The method for producing an optically active cyanohydrin comprises reacting a carbonyl compound represented by general formula (b) (wherein, R<SP>4</SP>and R<SP>5</SP>are different groups and each a hydrogen atom, an alkyl group or the like) and hydrogen cyanide, in the presence of an optically active titanium compound prepared from a reaction product of a titanium tetraalkoxide compound with water, and an optically active ligand represented by general formula (a) (wherein, R<SP>1</SP>, R<SP>2</SP>and R<SP>3</SP>are each independently a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, an aromatic heterocyclic group, an acyl group, an alkoxycarbonyl group or an aryloxycarbonyl group, which may have a substituent, and two or more of R<SP>1</SP>, R<SP>2</SP>and R<SP>3</SP>may form a ring which may have a substituent by binding with each other; A<SP>*</SP>is an asymmetric carbon or a ≥3C-hydrocarbon-containing group having axial asymmetry). <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a method for producing an optically active cyanohydrin by reacting a carbonyl compound using an optically active titanium compound with hydrogen cyanide. Optically active cyanohydrins are useful as synthetic intermediates for medicines and agrochemicals.

  Numerous examples have already been known for producing optically active cyanohydrins from carbonyl compounds using metal complexes prepared from metal salts or metal alkoxides and organometallics and optically active compounds as catalysts. . In particular, the production method using trimethylsilylcyanide as a cyanating agent achieves a high optical yield, for example, from an optically active tridentate ligand Schiff base and a hydrolyzate of titanium tetraalkoxide. A method using a prepared catalyst is known (Patent Document 1). However, when trimethylsilylcyanide is used, a trimethylsilyl ether form of cyanohydrin is produced. In order to obtain cyanohydrin, it is necessary to further hydrolyze this to remove the trimethylsilyl group. Therefore, it is needless to say that synthesizing cyanohydrin directly from hydrogen cyanide is economically advantageous from the viewpoint of atom economy because the synthesis step can be shortened.

  A method for producing an optically active cyanohydrin from a carbonyl compound and hydrogen cyanide is already known. For example, the following cases have been reported.

(1) A method using a Schiff base prepared from optically active dipeptides and salicylaldehydes and a catalyst prepared from titanium tetraalkoxide (Patent Document 2, Non-Patent Document 1),
(2) A method in which a vanadium complex prepared from a tetradentate optically active ligand called a salen type is used as a catalyst (Patent Document 3).

  However, in the method (1), a low temperature condition of −20 ° C. or lower is required in order to obtain the target product with high enantioselectivity. In addition, the catalyst amount must be 10 mol% based on the substrate aldehyde. In the method (2), although these points are improved, the enantioselectivity is not sufficient.

In this way, it can be applied to a wide range of substrates, exhibits high yield, high enantioselectivity, and can obtain the target product in a short time.Hydrogen cyanide can be used as a cyanating agent. There is no known asymmetric cyanation catalyst that is not required.
In addition, development of an asymmetric cyanation catalyst that is easy to prepare, highly active, and can be used in a low amount, and that meets industrially desirable conditions is also desired.
WO 2006/041000 Publication JP-A-5-261295 WO2004 / 055028 J. Am. Chem. Soc., 114, 7969 (1992)

  An object of the present invention is to provide an industrially advantageous method for producing an optically active cyanohydrin.

As a result of intensive studies to solve the above problems, the present inventors have found that a novel optically active titanium compound prepared from a titanium tetraalkoxide compound, water, and a tridentate optically active ligand has a carbonyl compound and hydrogen cyanide. From the above, it was found that it is effective as a catalyst for producing optically active cyanohydrin.
That is, the present invention includes the following inventions.
(1) Reaction product of titanium tetraalkoxide compound and water, and general formula (a):

(Wherein R ¹ , R ² and R ³ are each independently a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, an aromatic heterocyclic group, an acyl group, an alkoxycarbonyl group, or an aryloxycarbonyl group. These may have a substituent, and two or more of R ¹ , R ² and R ³ may be connected to each other to form a ring, and the ring has a substituent. A ^* is an asymmetric carbon or a hydrocarbon-containing group having 3 or more carbon atoms having axial asymmetry.)
In the presence of an optically active titanium compound prepared from an optically active ligand represented by:
General formula (b):

(Wherein R ⁴ and R ⁵ are different groups, each of which is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group, It may have a substituent, and R ⁴ and R ⁵ may be bonded to each other to form a ring.), And hydrogen cyanide is reacted. A method for producing optically active cyanohydrin.

  According to the present invention, an optically active cyanohydrin having a high optical purity can be easily and efficiently produced in a shorter amount of catalyst use and in a shorter time than when produced using a conventional asymmetric catalyst. This optically active cyanohydrin is useful as a synthetic raw material in synthetic intermediates, functional materials, fine chemicals, and the like of physiologically active compounds such as pharmaceuticals and agricultural chemicals.

Hereinafter, the present invention will be described in detail.
[Titanium tetraalkoxide compound]
Although the titanium tetraalkoxide compound used as the raw material of the optically active titanium compound of the present invention is not particularly limited, the general formula (d) is preferably:

The thing represented by is mentioned. In the general formula (d), R ¹¹ is an alkyl group or an aryl group, and these may have a substituent.

As the alkyl group for R ^11, a linear, branched or cyclic alkyl group having 20 or less carbon atoms is preferable. Examples of the linear alkyl group for R ¹¹ include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an n-heptyl group, an n-octyl group, Examples include n-nonyl group and n-decyl group. Examples of the branched alkyl group for R ¹¹ include isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, 2-pentyl group, 3-pentyl group, isopentyl group, neopentyl group, amyl group, and the like. It is done. Examples of the cyclic alkyl group represented by R ¹¹ include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

  The linear, branched, or cyclic alkyl group includes, as a substituent, a halogen atom, an aryl group having 20 or less carbon atoms, an aromatic heterocyclic group having 20 or less carbon atoms, and a non-aromatic complex having 20 or less carbon atoms. It may have a cyclic group, an oxygen-containing group having 20 or less carbon atoms, a nitrogen-containing group having 20 or less carbon atoms, a silicon-containing group having 20 or less carbon atoms, and the like.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the oxygen-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as alkoxy groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and acyloxy groups. Examples of the nitrogen-containing group having 20 or less carbon atoms include amino groups having 20 or less carbon atoms, amide groups, nitro groups, and cyano groups. Examples of the silicon-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as silyl group and silyloxy group.

  Examples of the alkyl group having a halogen atom include a chloromethyl group, a 2-chloroethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a perfluoroethyl group, and a perfluorohexyl group. Examples of the alkyl group having an aryl group include substituted or unsubstituted aralkyl groups such as a benzyl group, a 4-methoxybenzyl group, a 2-phenylethyl group, a cumyl group, and an α-naphthylmethyl group. Examples of the alkyl group having an aromatic heterocyclic group include 2-pyridylmethyl group, 2-furfuryl group, 3-furfuryl group, 2-thienylmethyl group and the like. Examples of the alkyl group having a non-aromatic heterocyclic group include 2-tetrahydrofurfuryl group and 3-tetrahydrofurfuryl group.

Examples of the alkyl group having an oxygen-containing group include a methoxyethyl group and a phenoxyethyl group. Examples of the alkyl group having a nitrogen-containing group include 2- (dimethylamino) ethyl group and 3- (diphenylamino) propyl group. Examples of the alkyl group having a silicon-containing group include a 2- (trimethylsiloxy) ethyl group.
The aryl group of R ^11, preferably an aryl group having 6 to 20 carbon atoms. Specific examples include a phenyl group, a naphthyl group, a biphenyl group, and an anthryl group.

  The aryl group has a halogen atom, an alkyl group having 20 or less carbon atoms, an oxygen-containing group having 20 or less carbon atoms, a nitrogen-containing group having 20 or less carbon atoms, a silicon-containing group having 20 or less carbon atoms, and the like as a substituent. You may do it.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the oxygen-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as alkoxy groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and acyloxy groups. Examples of the nitrogen-containing group having 20 or less carbon atoms include amino group, amide group, nitro group and cyano group having 20 or less carbon atoms. Examples of the silicon-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as silyl group and silyloxy group.

  Examples of the aryl group having a halogen atom include a 4-fluorophenyl group and a pentafluorophenyl group. As the aryl group having an alkyl group, for example, tolyl group, dimethylphenyl group, 2,4,6-trimethylphenyl group, 4-isopropylphenyl group, 2,6-diisopropylphenyl group, 4-tert-butylphenyl group, Examples include 2,6-di-tert-butylphenyl group. Examples of the aryl group having an oxygen-containing group include alkoxy groups such as 4-methoxyphenyl group, 3,5-dimethoxyphenyl group, 3,5-diisopropoxyphenyl group, and 2,4,6-triisopropoxyphenyl group. And aryloxy-substituted aryl groups such as substituted aryl groups and 2,6-diphenoxyphenyl groups. Examples of the aryl group having a nitrogen-containing group include 4- (dimethylamino) phenyl group and 4-nitrophenyl group. Examples of the aryl group having a silicon-containing group include a 3,5-bis (trimethylsilyl) phenyl group and a 3,5-bis (trimethylsiloxy) phenyl group.

Among these, as R ¹¹ , methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n A linear alkyl group having 10 or less carbon atoms, such as a -decyl group, is particularly preferable.

  The titanium tetraalkoxide compound can be prepared according to a known method. For example, it can be purified by distillation after adding a predetermined amount of the corresponding alcohol to titanium tetrachloride in the presence or absence of a base and stirring. In the present invention, a solution prepared from titanium tetrachloride and alcohol can be used as it is for the preparation of an optically active titanium compound without purification.

[Reaction product of titanium tetraalkoxide compound and water]
The reaction product of the titanium tetraalkoxide compound and water in the present invention is 0.1 mol or more and less than 2.0 mol, preferably 0.2 mol or more and less than 1.5 mol, with respect to 1 mol of the titanium tetraalkoxide. More preferably, 0.5 mol or more and less than 1.3 mol of water is reacted. The reaction product of the obtained titanium tetraalkoxide compound and water may be used without being purified as it is, or may be used after further purification.

  When the titanium tetraalkoxide and water are reacted, it is preferable to add water after dissolving the titanium tetraalkoxide in a solvent. The solvent to be used is not particularly limited, but halogenated hydrocarbon solvents such as dichloromethane, chloroform, fluorobenzene and trifluoromethylbenzene, aromatic hydrocarbon solvents such as toluene and xylene, ester solvents such as ethyl acetate, tetrahydrofuran Ether solvents such as dioxane, diethyl ether and dimethoxyethane, nitrile solvents such as acetonitrile, and alcohol solvents such as ethanol and n-butanol are preferred. Among these, a halogen-based solvent, an aromatic hydrocarbon-based solvent, or an alcohol-based solvent is particularly preferable. Furthermore, these can be used alone or as a mixed solvent. The solvent to be used is preferably used after being dried by a known method.

  The total amount of the solvent used when adding water is not particularly limited, but is preferably 0.01 to 500 mL, more preferably about 0.1 to 50 mL with respect to 1 mmol of the titanium tetraalkoxide compound.

  Water can be added diluted in a solvent. Moreover, water can also be added directly by the method of adding water in the form of a mist, the method of using the reaction tank provided with the highly efficient stirrer, etc. Instead of adding water, inorganic salts containing crystal water, molecular sieves with moisture absorption, non-dehydrated silica gel, and the like can be used.

Inorganic salts containing water of crystallization include Na ₂ B ₄ O ₇ · 10H ₂ O, Na ₂ SO ₄ · 10H ₂ O, Na ₃ PO ₄ · 12H ₂ O, MgSO ₄ · 7H ₂ O, CuSO ₄ · 5H Hydrates such as ₂ O, FeSO ₄ · 7H ₂ O, AlNa (SO ₄ ) ₂ · 12H ₂ O, AlK (SO ₄ ) ₂ · 12H ₂ O can be used, but are limited to these examples is not. Among these, Na ₂ B ₄ O ₇ · 10H ₂ O is particularly preferable.

  In the case of using molecular sieves that have absorbed moisture, commercially available products such as molecular sieves 3A and 4A may be used, and both powder and pellets can be used. When a crystal water-containing inorganic salt or molecular sieve is used, these can be easily removed by filtration before reacting with the ligand.

  The temperature at which the titanium tetraalkoxide compound and water are reacted is preferably a temperature at which the solvent does not freeze, and can usually be carried out at about room temperature, for example, 15 to 30 ° C. You may react by heating according to the boiling point of the solvent to be used.

  The step of reacting the titanium tetraalkoxide compound with water is preferably performed in a dry inert gas atmosphere. Examples of the inert gas include nitrogen, argon, helium and the like.

The reaction product of the titanium tetraalkoxide compound and water obtained by the above method can be used as a raw material for a catalyst for producing optically active cyanohydrin without being purified as it is.
In addition, the reaction product of the titanium tetraalkoxide compound thus obtained and water is purified by a known method to obtain the general formula (e):

It can also be isolated as a titanium oxoalkoxide compound represented by In the general formula (e), R ¹¹ represents the same meaning as in the general formula (d). That is, R ¹¹ is the same alkyl group or aryl group as in the general formula (d), and these may have a substituent. x is an integer of 2 or more, y is an integer of 1 or more, and generally y / x is in a range of 0.1 <y / x ≦ 1.5.

R ¹¹ in the general formula (e) is methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl. A linear alkyl group having 10 or less carbon atoms, such as a group or an n-decyl group, is particularly preferable.

  It is known that possible values of x and y in the general formula (e) vary depending on the type of alkoxide and the amount of water used for hydrolysis (reference: DC Bradley et al, Alkoxo and Aryloxo Derivatives of Metals, Academic Press, San Diego, 2001.). It has also been reported that even a mixture in a solution can be stably isolated (reference: for example, J. Am. Chem. Soc., 113, 8190 (1991)).

The titanium oxoalkoxide compound thus obtained can be used as a raw material for a catalyst for producing optically active cyanohydrin as a mixture or as a single composition.
[Optically active ligand]
The optically active ligand in the present invention (hereinafter referred to as optically active ligand) is represented by the general formula (a):

Preferably general formula (c):

It is represented by

The optically active ligand represented by the general formula (c) corresponds to a compound in which R ² and R ³ in the general formula (a) are combined to form a benzene ring, and the general formula (a ) Is included in the concept of the optically active ligand represented by

[Optically active ligand represented by general formula (a)]
In the general formula (a), R ¹ , R ² and R ³ independently represent a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, an aromatic heterocyclic group, an acyl group, an alkoxycarbonyl group, or an aryloxy A carbonyl group, which may have a substituent, and two or more of R ¹ , R ² and R ³ may be linked to each other to form a ring; It may have a group. A ^* is a hydrocarbon-containing group having 3 or more carbon atoms having asymmetric carbon or axial asymmetry.

As the alkyl group in R ¹ , R ² and R ³ , a linear, branched or cyclic alkyl group having 20 or less carbon atoms is preferable, and specifically, a methyl group, an ethyl group, an n-propyl group, isopropyl Group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, cyclopentyl group, cyclohexyl group and the like.

  The linear, branched, or cyclic alkyl group includes, as a substituent, a halogen atom, an aryl group having 20 or less carbon atoms, an aromatic heterocyclic group having 20 or less carbon atoms, and a non-aromatic complex having 20 or less carbon atoms. It may have a cyclic group, an oxygen-containing group having 20 or less carbon atoms, a nitrogen-containing group having 20 or less carbon atoms, a silicon-containing group having 20 or less carbon atoms, and the like.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the oxygen-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as alkoxy groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and acyloxy groups. Examples of the nitrogen-containing group having 20 or less carbon atoms include an amino group having 20 or less carbon atoms, an amide group having 20 or less carbon atoms, a nitro group, and a cyano group. Examples of the silicon-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as silyl group and silyloxy group.

  Examples of the alkyl group having a halogen atom include a chloromethyl group, a 2-chloroethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a perfluoroethyl group, and a perfluorohexyl group. Examples of the alkyl group having an aryl group include substituted or unsubstituted aralkyl groups such as benzyl group, 4-methoxybenzyl group, 2-phenylethyl group, cumyl group, α-naphthylmethyl group, diphenylmethyl group, and trityl group. Etc. Examples of the alkyl group having an aromatic heterocyclic group include 2-pyridylmethyl group, 2-furfuryl group, 3-furfuryl group, 2-thienylmethyl group and the like. Examples of the alkyl group having a non-aromatic heterocyclic group include a 2-tetrahydrofurfuryl group and a 3-tetrahydrofurfuryl group. Examples of the alkyl group having an oxygen-containing group include a methoxymethyl group, an isopropoxymethyl group, a tert-butoxymethyl group, a cyclohexyloxymethyl group, an L-menthyloxymethyl group, a D-menthyloxymethyl group, a phenoxymethyl group, Examples include benzyloxymethyl group, phenoxyethyl group, acetyloxymethyl group, 2,4,6-trimethylbenzoyloxymethyl group and the like. Examples of the alkyl group having a nitrogen-containing group include 2- (dimethylamino) ethyl group and 3- (diphenylamino) propyl. Examples of the alkyl group having a silicon-containing group include a 2- (trimethylsiloxy) ethyl group.

As the alkenyl group in R ¹ , R ² and R ³ , a linear or branched alkenyl group having 2 to 20 carbon atoms is preferable, and specific examples include a vinyl group, an allyl group, and an isopropenyl group. .

The linear or branched alkenyl group may have a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom as a substituent.
Examples of the alkenyl group having a halogen atom include 2-chlorovinyl group, 2,2-dichlorovinyl group, 3-chloroisopropenyl group and the like.

The aryl group in R ¹ , R ² and R ³ is preferably an aryl group having 6 to 20 carbon atoms, and specific examples thereof include a phenyl group, a naphthyl group, a biphenyl group, and an anthryl group.

  The aryl group has a halogen atom, an alkyl group having 20 or less carbon atoms, an oxygen-containing group having 20 or less carbon atoms, a nitrogen-containing group having 20 or less carbon atoms, a silicon-containing group having 20 or less carbon atoms, and the like as a substituent. You may do it.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the oxygen-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as alkoxy groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and acyloxy groups. Examples of the nitrogen-containing group having 20 or less carbon atoms include an amino group having 20 or less carbon atoms, an amide group having 20 or less carbon atoms, a nitro group, and a cyano group. Examples of the silicon-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as silyl group and silyloxy group.

  Examples of the aryl group having a halogen atom include a 4-fluorophenyl group and a pentafluorophenyl group. As the aryl group having an alkyl group, for example, tolyl group, dimethylphenyl group, 2,4,6-trimethylphenyl group, 4-isopropylphenyl group, 2,6-diisopropylphenyl group, 4-tert-butylphenyl group, Examples include 2,6-di-tert-butylphenyl group. Examples of the aryl group having an oxygen-containing group include alkoxy groups such as 4-methoxyphenyl group, 3,5-dimethoxyphenyl group, 3,5-diisopropoxyphenyl group, and 2,4,6-triisopropoxyphenyl group. And aryloxy-substituted aryl groups such as substituted aryl groups and 2,6-diphenoxyphenyl groups. Examples of the aryl group having a nitrogen-containing group include 4- (dimethylamino) phenyl group and 4-nitrophenyl group. Examples of the aryl group having a silicon-containing group include a 3,5-bis (trimethylsilyl) phenyl group and a 3,5-bis (trimethylsiloxy) phenyl group.

As the aromatic heterocyclic group for R ¹ , R ² and R ^3, an aromatic heterocyclic group having 3 to 20 carbon atoms is preferable, and specific examples include imidazolyl group, furyl group, thienyl group, pyridyl group and the like. It is done.

  The aromatic heterocyclic group may have an alkyl group having 20 or less carbon atoms, an oxygen-containing group having 20 or less carbon atoms, a nitrogen-containing group having 20 or less carbon atoms, a silicon-containing group having 20 or less carbon atoms, or the like. Good.

Examples of the oxygen-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as alkoxy groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and acyloxy groups. Examples of the nitrogen-containing group having 20 or less carbon atoms include an amino group having 20 or less carbon atoms, an amide group having 20 or less carbon atoms, a nitro group, and a cyano group. Examples of the silicon-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as silyl group and silyloxy group.
For example, an aromatic heterocyclic group having an alkyl group includes an N-methylimidazolyl group.

As the acyl group in R ¹ , R ² and R ³ , an alkylcarbonyl group and an arylcarbonyl group having 2 to 20 carbon atoms are preferable. Specifically, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a pivaloyl group, and the like And arylcarbonyl groups such as an alkylcarbonyl group, a benzoyl group, a naphthoyl group, and an anthrylcarbonyl group.
The alkylcarbonyl group may have a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom as a substituent on the alkyl group.
Examples of the alkylcarbonyl group having a halogen atom include a trifluoroacetyl group.

  The arylcarbonyl group includes, as a substituent on the aryl group, a halogen atom, an alkyl group having 20 or less carbon atoms, an oxygen-containing group having 20 or less carbon atoms, a nitrogen-containing group having 20 or less carbon atoms, or silicon having 20 or less carbon atoms. You may have a containing group.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the oxygen-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as alkoxy groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and acyloxy groups. Examples of the nitrogen-containing group having 20 or less carbon atoms include an amino group having 20 or less carbon atoms, an amide group having 20 or less carbon atoms, a nitro group, and a cyano group. Examples of the silicon-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as silyl group and silyloxy group.

  Examples of the arylcarbonyl group having a halogen atom include a pentafluorobenzoyl group. Examples of the arylcarbonyl group having an alkyl group include a 3,5-dimethylbenzoyl group and a 2,4,6-trimethylbenzoyl group. Examples of the arylcarbonyl group having an oxygen-containing group include a 2,6-dimethoxybenzoyl group and a 2,6-diisopropoxybenzoyl group. Examples of the arylcarbonyl group having a nitrogen-containing group include 4- (dimethylamino) benzoyl group and 4-cyanobenzoyl group. Examples of the arylcarbonyl group having a silicon-containing group include a 2,6-bis (trimethylsilyl) benzoyl group and a 2,6-bis (trimethylsiloxy) benzoyl group.

The alkoxycarbonyl group in R ¹ , R ² and R ³ is preferably a linear, branched or cyclic alkoxycarbonyl group having 2 to 20 carbon atoms, specifically, a methoxycarbonyl group, an ethoxycarbonyl group, n -Butoxycarbonyl group, n-octyloxycarbonyl group, isopropoxycarbonyl group, tert-butoxycarbonyl group, cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group, cyclooctyloxycarbonyl group, L-menthyloxycarbonyl group, D-menthyloxy group A carbonyl group etc. are mentioned.

  The alkoxycarbonyl group includes a halogen atom, an aryl group having 20 or less carbon atoms, an aromatic heterocyclic group having 20 or less carbon atoms, a non-aromatic heterocyclic group having 20 or less carbon atoms, etc. as a substituent on the alkyl group. You may have.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the alkoxycarbonyl group having a halogen atom include a 2,2,2-trifluoroethoxycarbonyl group. Examples of the alkoxycarbonyl group having an aryl group include substituted or unsubstituted benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 2-phenylethoxycarbonyl group, cumyloxycarbonyl group, α-naphthylmethoxycarbonyl group and the like. And an aralkyloxycarbonyl group. Examples of the alkoxycarbonyl group having an aromatic heterocyclic group include a 2-pyridylmethoxycarbonyl group, a furfuryloxycarbonyl group, a 2-thienylmethoxycarbonyl group, and the like. Examples of the alkoxycarbonyl group having a non-aromatic heterocyclic group include a tetrahydrofurfuryloxycarbonyl group.

The aryloxycarbonyl group in R ¹ , R ² and R ³ is preferably an aryloxycarbonyl group having 7 to 20 carbon atoms, and specific examples include a phenoxycarbonyl group and an α-naphthyloxycarbonyl group.

  The aryloxycarbonyl group includes, as a substituent on the aryl group, a halogen atom, an alkyl group having 20 or less carbon atoms, an oxygen-containing group having 20 or less carbon atoms, a nitrogen-containing group having 20 or less carbon atoms, or a carbon group having 20 or less carbon atoms. It may have a silicon-containing group.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the oxygen-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as alkoxy groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and acyloxy groups. Examples of the nitrogen-containing group having 20 or less carbon atoms include an amino group having 20 or less carbon atoms, an amide group having 20 or less carbon atoms, a nitro group, and a cyano group. Examples of the silicon-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as silyl group and silyloxy group.

  Examples of the aryloxycarbonyl group having a halogen atom include a pentafluorophenoxycarbonyl group. Examples of the aryloxycarbonyl group having an alkyl group include a 2,6-dimethylphenoxycarbonyl group and a 2,4,6-trimethylphenoxycarbonyl group. Examples of the aryloxycarbonyl group having an oxygen-containing group include a 2,6-dimethoxyphenoxycarbonyl group and a 2,6-diisopropoxyphenoxycarbonyl group. Examples of the aryloxycarbonyl group having a nitrogen-containing group include 4- (dimethylamino) phenoxycarbonyl group, 4-cyanophenoxycarbonyl group and the like. Examples of the aryloxycarbonyl group having a silicon-containing group include a 2,6-bis (trimethylsilyl) phenoxycarbonyl group and a 2,6-bis (trimethylsiloxy) phenoxycarbonyl group.

Two or more of R ¹ , R ² and R ³ may be connected to each other to form a ring. The ring is preferably an aliphatic or aromatic hydrocarbon ring, which may be condensed with each other to form a ring.

  In the case of an aliphatic hydrocarbon ring, the ring is preferably a ring having 10 or less members, particularly preferably a 3 to 7 member ring, and most preferably a 5 or 6 member ring. The aliphatic hydrocarbon ring may contain an unsaturated bond.

In the case of an aromatic hydrocarbon ring, a 6-membered ring, that is, a benzene ring is preferable. For example, when R ² and R ³ are connected to each other to form — (CH ₂ ) ₄ — or —CH═CH—CH═CH—, they are each included in a cyclohexene ring (an aliphatic hydrocarbon ring). ) Or a benzene ring (included in an aromatic hydrocarbon ring).

  The ring thus formed has one or more substituents selected from halogen atoms, alkyl groups, aryl groups, alkoxy groups, aryloxy groups, amino groups, nitro groups, cyano groups, silyl groups, and silyloxy groups. You may have.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The alkyl group is preferably a linear, branched or cyclic alkyl group having 20 or less carbon atoms, and these may have a substituent. Specifically, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, cyclopentyl group, cyclohexyl group, adamantyl group, trifluoro A methyl group, a benzyl group, a trityl group, etc. are mentioned. As the aryl group, a substituted or unsubstituted aryl group having 20 or less carbon atoms is preferable. For example, phenyl group, naphthyl group, biphenyl group, anthryl group, 2,6-dimethylphenyl group, 2,4,6-trimethylphenyl Group, 2,6-dimethoxyphenyl group and the like. The alkoxy group is preferably a substituted or unsubstituted alkoxy group having 20 or less carbon atoms, and examples thereof include a methoxy group, an ethoxy group, an isopropoxy group, a tert-butoxy group, and a benzyloxy group. The aryloxy group is preferably a substituted or unsubstituted aryloxy group having 20 or less carbon atoms, and examples thereof include a phenoxy group and a 2,6-dimethylphenoxy group. The amino group is preferably a substituted or unsubstituted amino group having 20 or less carbon atoms, and examples thereof include a dimethylamino group, a diethylamino group, and a diphenylamino group. The silyl group is preferably a silyl group having an alkyl group having 20 or less carbon atoms or an aryl group, and examples thereof include a trimethylsilyl group and a triethylsilyl group. The silyloxy group is preferably a silyloxy group having 20 or less carbon atoms, and examples thereof include a trimethylsiloxy group.
The benzene ring may be condensed to form a condensed polycycle such as a naphthalene ring.

[Hydrocarbon-containing group A ^* ]
In the general formula (a), A ^* is an optically active hydrocarbon-containing group having 3 or more carbon atoms, preferably 3 to 40 carbon atoms, having an asymmetric carbon or axial asymmetry. You may have.

As the hydrocarbon-containing group in A ^*, optically active hydrocarbon-containing groups represented by the following general formulas (A-1) to (A-3) are preferable. In the formula, the portions represented by (N) and (OH) are portions other than A ^* , and mean the corresponding nitrogen atom and hydroxyl group in the general formula (a) to which A ^* is bonded.

[Hydrocarbon-containing group A ^* : general formula (A-1)]
In the general formula (A-1), R ^a , R ^b , R ^c and R ^d are each independently a hydrogen atom, an alkyl group, an aryl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonyl group. Yes, these may have a substituent. Two or more of R ^a , R ^b , R ^c and R ^d may be connected to each other to form a ring, and the ring may have a substituent. In addition, at least one of R ^a , R ^b , R ^c and R ^d is a different group, and both or at least one of the carbon atoms indicated by * is an asymmetric center.

The alkyl group, aryl group, alkoxycarbonyl group and aryloxycarbonyl group in R ^a , R ^b , R ^c and R ^d are the same as the alkyl group, aryl group, alkoxycarbonyl group and aryloxycarbonyl group of R ^{1 to} R ^3. It is the same.

As an aminocarbonyl group in R ^a , R ^b , R ^c and R ^d , an aminocarbonyl group having a hydrogen atom, an alkyl group having 20 or less carbon atoms or an aryl group having 20 or less carbon atoms is preferable, and a carbonyl bonded to a nitrogen atom Two substituents other than the group may be connected to each other to form a ring. Specific examples of the aminocarbonyl group having an alkyl group or an aryl group include isopropylaminocarbonyl group, cyclohexylaminocarbonyl group, tert-butylaminocarbonyl group, tert-amylaminocarbonyl group, dimethylaminocarbonyl group, diethylaminocarbonyl group, Examples include diisopropylaminocarbonyl group, diisobutylaminocarbonyl group, dicyclohexylaminocarbonyl group, tert-butylisopropylaminocarbonyl group, phenylaminocarbonyl group, pyrrolidylcarbonyl group, piperidylcarbonyl group, indolecarbonyl group and the like.

  The aminocarbonyl group may have a halogen atom, an aryl group having 20 or less carbon atoms, an alkyl group having 20 or less carbon atoms, or the like as a substituent on the alkyl group or aryl group.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the aminocarbonyl group having an alkyl group substituted with a halogen atom include a 2-chloroethylaminocarbonyl group and a perfluoroethylaminocarbonyl group.

  Examples of the aminocarbonyl group having an aryl group substituted with a halogen atom include a 4-chlorophenylaminocarbonyl group, a pentafluorophenylaminocarbonyl group, and the like. Examples of the aminocarbonyl group having an alkyl group substituted with an aryl group include substituted or unsubstituted aralkylaminocarbonyl groups such as benzylaminocarbonyl group, 2-phenylethylaminocarbonyl group, α-naphthylmethylaminocarbonyl group, etc. Is mentioned. Examples of the aminocarbonyl group having an aryl group substituted with an alkyl group include a 2,4,6-trimethylphenylaminocarbonyl group.

Also, two or more of R ^a , R ^b , R ^c and R ^d may be connected to each other to form a ring. The ring is preferably an aliphatic hydrocarbon, and the ring may be further condensed to form a ring, preferably a 3- to 7-membered ring, particularly preferably a 5-membered ring or a 6-membered ring. For example, when R ^a and R ^c are connected to each other to form — (CH ₂ ) ₃ —, a 5-membered ring is formed.

The ring thus formed has one or more substituents selected from halogen atoms, alkyl groups, aryl groups, alkoxy groups, aryloxy groups, amino groups, nitro groups, cyano groups, silyl groups, and silyloxy groups. You may have.
Specific examples of the optically active hydrocarbon-containing group represented by the general formula (A-1) include the following formulas (A-1a) to (A-1x) and enantiomers thereof.

[Hydrocarbon-containing group A ^* : general formula (A-2)]
In the general formula (A-2), R ^e and R ^f are a hydrogen atom, an alkyl group, or an aryl group, and these may have a substituent. R ^e and R ^f are different substituents, and * represents an asymmetric carbon. The alkyl group and aryl group in R ^e and R ^f are the same as the alkyl group and aryl group of R ^{a to} R ^d described above.
Specific examples of the optically active hydrocarbon-containing group represented by the general formula (A-2) include the following formulas (A-2a) to (A-2p) and enantiomers thereof.

[Hydrocarbon-containing group A ^* : general formula (A-3)]
In the general formula (A-3), R ^g , R ^h , R ⁱ and R ^j are each independently a hydrogen atom, a halogen atom, an alkyl group, an aryl group, or an alkoxy group, and these have a substituent. And R ⁱ and R ^j on the same benzene ring may be connected to each other or condensed to form a ring, and * ′ represents axial asymmetry.

Examples of the halogen atom in R ^g , R ^h , R ^i, and R ^j include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The alkyl group and aryl group in R ^g , R ^h , R ⁱ and R ^j are the same as the alkyl group and aryl group of R ^{1 to} R ³ . The alkoxy group in R ^g , R ^h , R ⁱ and R ^j is preferably an alkoxy group having 20 or less carbon atoms, such as a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a tert-butoxy group, Can be mentioned.

When R ⁱ and R ^j on the same benzene ring are connected to each other to form a ring, the ring is an aliphatic or aromatic hydrocarbon ring, or a non-aromatic heterocyclic ring containing an oxygen atom. Are preferable, and they may be condensed to form a ring.

In the case of an aliphatic hydrocarbon ring, it is preferably a 5-membered ring or a 6-membered ring. In the case of an aromatic hydrocarbon ring, a 6-membered ring, that is, a benzene ring is preferable. For example, when R ⁱ and R ^j are connected to each other to form —CH═CH—CH═CH—, — (CH ₂ ) ₄ —, or —OCH ₂ O—, a naphthalene ring, a tetrahydronaphthalene ring, A benzodioxolane ring is formed.

  The thus formed naphthalene ring, tetrahydronaphthalene ring, benzodioxolane ring and the like ring may have one or more substituents selected from, for example, a halogen atom, an alkyl group, an aryl group, and an alkoxy group. Good.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The alkyl group is preferably a linear, branched or cyclic alkyl group having 20 or less carbon atoms, and these may have a substituent. Specific examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a tert-butyl group, a cyclopentyl group, and a cyclohexyl group. As the aryl group, a substituted or unsubstituted aryl group having 20 or less carbon atoms is preferable, and specific examples thereof include a phenyl group, a naphthyl group, a biphenyl group, and an anthryl group. As the alkoxy group, a substituted or unsubstituted alkoxy group having 20 or less carbon atoms is preferable, and specific examples include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, and a tert-butoxy group.

The benzene ring may be condensed to form a condensed polycycle such as a naphthalene ring.
Specific examples of the optically active hydrocarbon-containing group represented by the general formula (A-3) include the following formulas (A-3a) to (A-3c) and enantiomers thereof.

[Optically active ligand represented by general formula (c)]
As a preferable embodiment of the optically active ligand represented by the general formula (a), an optically active ligand represented by the general formula (c) can be exemplified.

In the general formula (c), R ^a , R ^b , R ^c and R ^d represent the same meaning as in the general formula (A-1). That is, R ^a , R ^b , R ^c and R ^d are a hydrogen atom, an alkyl group, an aryl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonyl group, and these may have a substituent. Of these, two or more of R ^a , R ^b , R ^c and R ^d may be connected to each other to form a ring, and the ring may have a substituent. In addition, at least one of R ^a , R ^b , R ^c and R ^d is a different group, and both or at least one of the carbon atoms indicated by * is an asymmetric center.
In the general formula (c), R ⁶ is a hydrogen atom, an alkyl group, or an aryl group, and these may have a substituent.

In the general formula (c), R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an aryl group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group. A cyclic group, an alkoxycarbonyl group, an aryloxycarbonyl group, a hydroxyl group, an alkoxy group, an aryloxy group, an amino group, a cyano group, a nitro group, a silyl group, or a siloxy group, and these may have a substituent. Alternatively, they may be connected to each other to form a ring.

The alkyl group in R ⁶ is preferably a linear, branched or cyclic alkyl group having 20 or less carbon atoms, and specifically includes a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a sec-butyl group. , Cyclopropyl group, cyclopentyl group, cyclohexyl group and the like.

  The linear, branched, or cyclic alkyl group includes, as a substituent, a halogen atom, an aryl group having 20 or less carbon atoms, an aromatic heterocyclic group having 20 or less carbon atoms, and a non-aromatic complex having 20 or less carbon atoms. It may have a cyclic group, an oxygen-containing group having 20 or less carbon atoms, a nitrogen-containing group having 20 or less carbon atoms, a silicon-containing group having 20 or less carbon atoms, and the like.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the oxygen-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as alkoxy groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and acyloxy groups. Examples of the nitrogen-containing group having 20 or less carbon atoms include an amino group having 20 or less carbon atoms, an amide group having 20 or less carbon atoms, a nitro group, and a cyano group. Examples of the silicon-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as silyl group and silyloxy group.

  Examples of the alkyl group having a halogen atom include a chloromethyl group, a 2-chloroethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a perfluoroethyl group, and a perfluorohexyl group. Examples of the alkyl group having an aryl group include substituted or unsubstituted aralkyl groups such as benzyl group, 4-methoxybenzyl group, 2-phenylethyl group, cumyl group, α-naphthylmethyl group, and trityl group. . Examples of the alkyl group having an aromatic heterocyclic group include a 2-pyridylmethyl group, a furfuryl group, and a 2-thienylmethyl group. Examples of the alkyl group having a non-aromatic heterocyclic group include a tetrahydrofurfuryl group. Examples of the alkyl group having an oxygen-containing group include a methoxyethyl group and a phenoxyethyl group. Examples of the alkyl group having a nitrogen-containing group include 2- (dimethylamino) ethyl group and 3- (diphenylamino) propyl group. Examples of the alkyl group having a silicon-containing group include a 2- (trimethylsiloxy) ethyl group.

The aryl group for R ⁶ is preferably an aryl group having 6 to 20 carbon atoms, and specific examples include a phenyl group, a naphthyl group, a biphenyl group, and an anthryl group.

  The aryl group has a halogen atom, an alkyl group having 20 or less carbon atoms, an oxygen-containing group having 20 or less carbon atoms, a nitrogen-containing group having 20 or less carbon atoms, a silicon-containing group having 20 or less carbon atoms, and the like as a substituent. You may do it.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the oxygen-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as alkoxy groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and acyloxy groups. Examples of the nitrogen-containing group having 20 or less carbon atoms include an amino group having 20 or less carbon atoms, an amide group having 20 or less carbon atoms, a nitro group, and a cyano group. Examples of the silicon-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as silyl group and silyloxy group.

  Examples of the aryl group having a halogen atom include a 4-fluorophenyl group and a pentafluorophenyl group. As the aryl group having an alkyl group, for example, tolyl group, dimethylphenyl group, 2,4,6-trimethylphenyl group, 4-isopropylphenyl group, 2,6-diisopropylphenyl group, 4-tert-butylphenyl group, Examples include 2,6-di-tert-butylphenyl group. Examples of the aryl group having an oxygen-containing group include alkoxy groups such as 4-methoxyphenyl group, 3,5-dimethoxyphenyl group, 3,5-diisopropoxyphenyl group, and 2,4,6-triisopropoxyphenyl group. And aryloxy-substituted aryl groups such as substituted aryl groups and 2,6-diphenoxyphenyl groups. Examples of the aryl group having a nitrogen-containing group include 4- (dimethylamino) phenyl group and 4-nitrophenyl group. Examples of the aryl group having a silicon-containing group include a 3,5-bis (trimethylsilyl) phenyl group and a 3,5-bis (trimethylsiloxy) phenyl group.

Examples of the halogen atom in R ⁷ , R ⁸ , R ⁹ and R ¹⁰ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. As the alkyl group in R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , a linear, branched or cyclic alkyl group having 20 or less carbon atoms is preferable. Specific examples include a methyl group, an ethyl group, and n-propyl. Group, isopropyl group, sec-butyl group, tert-butyl group, cyclopentyl group, cyclohexyl group, adamantyl group and the like.

  The linear, branched, or cyclic alkyl group includes, as a substituent, a halogen atom, an aryl group having 20 or less carbon atoms, an aromatic heterocyclic group having 20 or less carbon atoms, and a non-aromatic complex having 20 or less carbon atoms. It may have a cyclic group, an oxygen-containing group having 20 or less carbon atoms, a nitrogen-containing group having 20 or less carbon atoms, a silicon-containing group having 20 or less carbon atoms, and the like.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the oxygen-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as alkoxy groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and acyloxy groups. Examples of the nitrogen-containing group having 20 or less carbon atoms include an amino group having 20 or less carbon atoms, an amide group having 20 or less carbon atoms, a nitro group, and a cyano group. Examples of the silicon-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as silyl group and silyloxy group.

  Examples of the alkyl group having a halogen atom include 20 carbon atoms such as a chloromethyl group, a 2-chloroethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a perfluoroethyl group, and a perfluorohexyl group. The following halogenated alkyl groups are exemplified. Examples of the alkyl group having an aryl group include benzyl group, 4-methoxybenzyl group, 2-phenylethyl group, cumyl group, α-naphthylmethyl group, 2-phenylisopropyl group, trityl group, 2-phenylnaphthalene-1 -Substituted or unsubstituted aralkyl groups such as an -yl group. Examples of the alkyl group having an aromatic heterocyclic group include a 2-pyridylmethyl group, a furfuryl group, and a 2-thienylmethyl group. Examples of the alkyl group having a non-aromatic heterocyclic group include a tetrahydrofurfuryl group. Examples of the alkyl group having an oxygen-containing group include a methoxyethyl group and a phenoxyethyl group. Examples of the alkyl group having a nitrogen-containing group include 2- (dimethylamino) ethyl group and 3- (diphenylamino) propyl. Examples of the alkyl group having a silicon-containing group include a 2- (trimethylsiloxy) ethyl group.

As the alkenyl group in R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , a linear or branched alkenyl group having 2 to 20 carbon atoms is preferable. Specific examples include a vinyl group, an allyl group, an isopropenyl group, and the like. Is mentioned.

  The linear or branched alkenyl group has a halogen atom, an oxygen-containing group having 20 or less carbon atoms, a nitrogen-containing group having 20 or less carbon atoms, a silicon-containing group having 20 or less carbon atoms, and the like as a substituent. It may be.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the oxygen-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as alkoxy groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and acyloxy groups. Examples of the nitrogen-containing group having 20 or less carbon atoms include an amino group having 20 or less carbon atoms, an amide group having 20 or less carbon atoms, a nitro group, and a cyano group. Examples of the silicon-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as silyl group and silyloxy group.
For example, examples of the alkenyl group having a halogen atom include a 2-chlorovinyl group, a 2,2-dichlorovinyl group, and a 3-chloroisopropenyl group.

As the aryl group in R ⁷ , R ⁸ , R ⁹ and R ^10, an aryl group having 6 to 20 carbon atoms is preferable. Specifically, a phenyl group, a naphthyl group, a biphenyl group, an anthryl group, 2-phenyl-1 -A naphthyl group etc. are mentioned.

  The aryl group has a halogen atom, an alkyl group having 20 or less carbon atoms, an oxygen-containing group having 20 or less carbon atoms, a nitrogen-containing group having 20 or less carbon atoms, a silicon-containing group having 20 or less carbon atoms, and the like as a substituent. You may do it.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the oxygen-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as alkoxy groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and acyloxy groups. Examples of the nitrogen-containing group having 20 or less carbon atoms include an amino group having 20 or less carbon atoms, an amide group having 20 or less carbon atoms, a nitro group, and a cyano group. Examples of the silicon-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as silyl group and silyloxy group.

  Examples of the aryl group having a halogen atom include a pentafluorophenyl group. As the aryl group having an alkyl group, for example, tolyl group, dimethylphenyl group, 2,4,6-trimethylphenyl group, isopropylphenyl group, diisopropylphenyl group, tert-butylphenyl group, di-tert-butylphenyl group, etc. Is mentioned. Examples of the aryl group having an oxygen-containing group include alkoxy groups such as 4-methoxyphenyl group, 3,5-dimethoxyphenyl group, 3,5-diisopropoxyphenyl group, and 2,4,6-triisopropoxyphenyl group. And aryloxy-substituted aryl groups such as substituted aryl groups and 2,6-diphenoxyphenyl groups. Examples of the aryl group having a nitrogen-containing group include 4- (dimethylamino) phenyl group and 4-nitrophenyl group. Examples of the aryl group having a silicon-containing group include a 3,5-bis (trimethylsilyl) phenyl group and a 3,5-bis (trimethylsiloxy) phenyl group.

As the aromatic heterocyclic group for R ⁷ , R ⁸ , R ⁹ and R ^10, an aromatic heterocyclic group having 3 to 20 carbon atoms is preferable, and specifically, an imidazolyl group, a furyl group, a thienyl group, a pyridyl group. Etc.

  The aromatic heterocyclic group includes an alkyl group having 20 or less carbon atoms, an aryl group having 20 or less carbon atoms, an oxygen-containing group having 20 or less carbon atoms, a nitrogen-containing group having 20 or less carbon atoms, and a silicon-containing group having 20 or less carbon atoms. It may have a group or the like.

Examples of the oxygen-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as alkoxy groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and acyloxy groups. Examples of the nitrogen-containing group having 20 or less carbon atoms include an amino group having 20 or less carbon atoms, an amide group having 20 or less carbon atoms, a nitro group, and a cyano group. Examples of the silicon-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as silyl group and silyloxy group.
For example, an aromatic heterocyclic group having an alkyl group includes an N-methylimidazolyl group.

As the non-aromatic heterocyclic group in R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , a non-aromatic heterocyclic group having 4 to 20 carbon atoms is preferable, and specifically, a pyrrolidinyl group, piperidyl group, tetrahydrofuryl group. And tetrahydropyranyl group.

  The non-aromatic heterocyclic group includes an alkyl group having 20 or less carbon atoms, an aryl group having 20 or less carbon atoms, an oxygen-containing group having 20 or less carbon atoms, a nitrogen-containing group having 20 or less carbon atoms, and silicon having 20 or less carbon atoms. You may have a containing group.

  Examples of the oxygen-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as alkoxy groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and acyloxy groups. Examples of the nitrogen-containing group having 20 or less carbon atoms include an amino group having 20 or less carbon atoms, an amide group having 20 or less carbon atoms, a nitro group, and a cyano group. Examples of the silicon-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as silyl group and silyloxy group.

  For example, examples of the non-aromatic heterocyclic group having an aryl group include aryl-substituted non-aromatic heterocyclic groups having 20 or less carbon atoms such as an N-phenyl-4-piperidyl group.

The alkoxycarbonyl group in R ⁷ , R ⁸ , R ⁹ and R ¹⁰ is preferably a linear, branched or cyclic alkoxycarbonyl group having 2 to 20 carbon atoms. Specific examples include a methoxycarbonyl group, ethoxycarbonyl group, Group, n-butoxycarbonyl group, n-octyloxycarbonyl group, isopropoxycarbonyl group, tert-butoxycarbonyl group, cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group, cyclooctyloxycarbonyl group and the like.

  The alkoxycarbonyl group includes a halogen atom, an aryl group having 20 or less carbon atoms, an aromatic heterocyclic group having 20 or less carbon atoms, a non-aromatic heterocyclic group having 20 or less carbon atoms, etc. as a substituent on the alkyl group. You may have.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the alkoxycarbonyl group having a halogen atom include a 2,2,2-trifluoroethoxycarbonyl group. Examples of the alkoxycarbonyl group having an aryl group include substituted or unsubstituted benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 2-phenylethoxycarbonyl group, cumyloxycarbonyl group, α-naphthylmethoxycarbonyl group and the like. And an aralkyloxycarbonyl group. Examples of the alkoxycarbonyl group having an aromatic heterocyclic group include a 2-pyridylmethoxycarbonyl group, a furfuryloxycarbonyl group, a 2-thienylmethoxycarbonyl group, and the like. Examples of the alkoxycarbonyl group having a non-aromatic heterocyclic group include a tetrahydrofurfuryloxycarbonyl group.

The aryloxycarbonyl group in R ⁷ , R ⁸ , R ⁹ and R ¹⁰ is preferably an aryloxycarbonyl group having 7 to 20 carbon atoms, and specific examples include a phenoxycarbonyl group and an α-naphthyloxycarbonyl group. It is done.

  The aryloxycarbonyl group includes, as a substituent on the aryl group, a halogen atom, an alkyl group having 20 or less carbon atoms, an oxygen-containing group having 20 or less carbon atoms, a nitrogen-containing group having 20 or less carbon atoms, or a carbon group having 20 or less carbon atoms. It may have a silicon-containing group.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the oxygen-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as alkoxy groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and acyloxy groups. Examples of the nitrogen-containing group having 20 or less carbon atoms include an amino group having 20 or less carbon atoms, an amide group having 20 or less carbon atoms, a nitro group, and a cyano group. Examples of the silicon-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as silyl group and silyloxy group.
Examples of the aryloxycarbonyl group having a halogen atom include a pentafluorophenoxycarbonyl group.

  Examples of the aryloxycarbonyl group having an alkyl group include a 2,6-dimethylphenoxycarbonyl group and a 2,4,6-trimethylphenoxycarbonyl group. Examples of the aryloxycarbonyl group having an oxygen-containing group include a 2,6-dimethoxyphenoxycarbonyl group and a 2,6-diisopropoxyphenoxycarbonyl group. Examples of the aryloxycarbonyl group having a nitrogen-containing group include 4- (dimethylamino) phenoxycarbonyl group, 4-cyanophenoxycarbonyl group and the like. Examples of the aryloxycarbonyl group having a silicon-containing group include a 2,6-bis (trimethylsilyl) phenoxycarbonyl group and a 2,6-bis (trimethylsiloxy) phenoxycarbonyl group.

The alkoxy group for R ⁷ , R ⁸ , R ⁹ and R ¹⁰ is preferably a linear, branched or cyclic alkoxy group having 20 or less carbon atoms. Specific examples include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, tert-butoxy group, cyclopentyloxy group, cyclohexyloxy group, menthyloxy group and the like.

  The alkoxy group has a halogen atom, an aryl group having 20 or less carbon atoms, an aromatic heterocyclic group having 20 or less carbon atoms, a non-aromatic heterocyclic group having 20 or less carbon atoms, etc. as a substituent on the alkyl group. You may do it.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the alkoxy group having a halogen atom include a 2,2,2-trifluoroethoxy group. Examples of the alkoxy group having an aryl group include substituted or unsubstituted aralkyloxy groups such as benzyloxy group, 4-methoxybenzyloxy group, 2-phenylethoxy group, cumyloxy group, α-naphthylmethoxy group and the like. . Examples of the alkoxy group having an aromatic heterocyclic group include 2-pyridylmethoxy group, furfuryloxy group, 2-thienylmethoxy group and the like. Examples of the alkoxy group having a non-aromatic heterocyclic group include a tetrahydrofurfuryloxy group.

The aryloxy group in R ⁷ , R ⁸ , R ⁹ and R ¹⁰ is preferably an aryloxy group having 6 to 20 carbon atoms. Specific examples include a phenoxy group and a naphthyloxy group. The aryloxy group includes, as a substituent on the aryl group, a halogen atom, an alkyl group having 20 or less carbon atoms, an oxygen-containing group having 20 or less carbon atoms, a nitrogen-containing group having 20 or less carbon atoms, or silicon having 20 or less carbon atoms. You may have a containing group.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the oxygen-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as alkoxy groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and acyloxy groups. Examples of the nitrogen-containing group having 20 or less carbon atoms include an amino group having 20 or less carbon atoms, an amide group having 20 or less carbon atoms, a nitro group, and a cyano group. Examples of the silicon-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as silyl group and silyloxy group.
Examples of the aryloxy group having a halogen atom include halogenated aryloxy groups such as a pentafluorophenoxy group.

  Examples of the aryloxy group having an alkyl group include alkyl-substituted aryloxy groups such as 2,6-dimethylphenoxy group and 2,4,6-trimethylphenoxy group. Examples of the aryloxy group having an oxygen-containing group include a 2,6-dimethoxyphenoxy group and a 2,6-diisopropoxyphenoxy group.

  Examples of the aryloxy group having a nitrogen-containing group include 4- (dimethylamino) phenoxy group and 4-cyanophenoxy group. Examples of the aryloxy group having a silicon-containing group include a 2,6-bis (trimethylsilyl) phenoxy group and a 2,6-bis (trimethylsiloxy) phenoxy group.

The amino group in R ⁷ , R ⁸ , R ⁹ and R ¹⁰ is preferably a hydrogen atom, a linear, branched or cyclic alkyl group having 20 or less carbon atoms, or an amino group having an aryl group. Two substituents to be bonded may be connected to each other to form a ring.

  Specific examples of the amino group having an alkyl group or aryl group include isopropylamino group, cyclohexylamino group, tert-butylamino group, tert-amylamino group, dimethylamino group, diethylamino group, diisopropylamino group, diisobutylamino group, Examples include dicyclohexylamino group, tert-butylisopropylamino group, pyrrolidyl group, piperidyl group, indole group and the like.

  The amino group may have a halogen atom, an aryl group having 20 or less carbon atoms, an alkyl group having 20 or less carbon atoms, or the like as a substituent on the alkyl group or aryl group.

  Examples of the amino group having an alkyl group substituted with a halogen atom include a 2,2,2-trichloroethylamino group, a perfluoroethylamino group, and the like. Examples of the amino group having an aryl group substituted with a halogen atom include a pentafluorophenylamino group. Examples of the amino group having an alkyl group substituted with an aryl group include substituted or unsubstituted aralkylamino groups such as a benzylamino group, a 2-phenylethylamino group, and an α-naphthylmethylamino group. Examples of the amino group having an aryl group substituted with an alkyl group include a 2,4,6-trimethylphenylamino group.

The silyl group in R ⁷ , R ⁸ , R ⁹ and R ¹⁰ is preferably a silyl group having 20 or less carbon atoms, and specific examples include a trimethylsilyl group and a tert-butyldimethylsilyl group.

As the siloxy group in R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , a siloxy group having 20 or less carbon atoms is preferable, and specifically, a trimethylsiloxy group, a tert-butyldimethylsiloxy group, a tert-butyldiphenylsiloxy group and the like Is mentioned.

Two or more of R ⁷ , R ⁸ , R ⁹ and R ¹⁰ may be linked to each other to form a ring. The ring is preferably an aliphatic or aromatic hydrocarbon ring, which may be condensed with each other to form a ring. In the case of an aliphatic hydrocarbon ring, the ring is preferably a ring having 10 or less members, particularly preferably a 3 to 7 member ring, and most preferably a 5 or 6 member ring. The aliphatic hydrocarbon ring may contain an unsaturated bond. In the case of an aromatic hydrocarbon ring, a 6-membered ring, that is, a benzene ring is preferable.

For example, when R ⁸ and R ⁹ are connected to each other to form — (CH ₂ ) ₄ — or —CH═CH—CH═CH—, they are each included in a cyclohexene ring (an aliphatic hydrocarbon ring). ) Or a benzene ring (included in an aromatic hydrocarbon ring).

  The ring thus formed has one or more groups selected from halogen atoms, alkyl groups, aryl groups, alkoxy groups, aryloxy groups, amino groups, nitro groups, cyano groups, silyl groups, and silyloxy groups. You may do it.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The alkyl group is preferably a linear, branched or cyclic alkyl group having 20 or less carbon atoms, and these may have a substituent. Specifically, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, cyclopentyl group, cyclohexyl group, adamantyl group, trifluoro A methyl group, a benzyl group, a trityl group, etc. are mentioned. As the aryl group, a substituted or unsubstituted aryl group having 20 or less carbon atoms is preferable. For example, phenyl group, naphthyl group, biphenyl group, anthryl group, 2,6-dimethylphenyl group, 2,4,6-trimethylphenyl Group, 2,6-dimethoxyphenyl group and the like.

The alkoxy group is preferably a substituted or unsubstituted alkoxy group having 20 or less carbon atoms, and examples thereof include a methoxy group, an ethoxy group, an isopropoxy group, a tert-butoxy group, and a benzyloxy group. The aryloxy group is preferably a substituted or unsubstituted aryloxy group having 20 or less carbon atoms, and examples thereof include a phenoxy group and a 2,6-dimethylphenoxy group. The amino group is preferably a substituted or unsubstituted amino group having 20 or less carbon atoms, and examples thereof include a dimethylamino group, a diethylamino group, and a diphenylamino group. The silyl group is preferably a silyl group having an alkyl group having 20 or less carbon atoms or an aryl group, and examples thereof include a trimethylsilyl group and a triethylsilyl group. The silyloxy group is preferably a silyloxy group having 20 or less carbon atoms, and examples thereof include a trimethylsiloxy group.
The benzene ring may be condensed to form a condensed polycycle such as a naphthalene ring.

More preferable examples of the optically active ligand represented by the general formula (c) include those in which R ¹⁰ is a substituted or unsubstituted alkyl group or aryl group.

  The optically active ligand represented by the general formula (a) or the general formula (c) can be prepared according to a known method. For example, the optically active ligand represented by the general formula (a) can be synthesized in one step from an optically active amino alcohol and a 1,3-diketone derivative by a dehydration reaction. In addition, the optically active ligand represented by the general formula (c) is obtained in one step by dehydration reaction from an optically active amino alcohol and an o-hydroxybenzaldehyde derivative or from an amino alcohol and an o-hydroxyphenyl ketone derivative. Can be synthesized.

Optically active amino alcohols are obtained, for example, by reducing the carboxyl group of natural or unnatural α-amino acids, and many types are industrially available. Examples of the carbonyl compound having a hydroxyl group as a substituent include salicylaldehyde and derivatives thereof, and many of these can be easily obtained. Examples of the 1,3-diketone derivative include 2-acetyl-3-oxo-butyraldehyde.
[Specific Examples of Optically Active Ligands Represented by General Formula (a) and General Formula (c)]

  Specific examples of the optically active ligands represented by the general formula (a) and the general formula (c) include the following general formulas (a-1) to (a-3) and enantiomers thereof, and the following formula: (C-1) to (c-20) and their enantiomers.

[Method for producing optically active titanium compound]
In the present invention, an optically active titanium compound used as a catalyst for producing an optically active cyanohydrin is prepared from a reaction product of the titanium tetraalkoxide compound and water and an optically active ligand. A specific preparation method is described below.

  An optically active ligand is added to the reaction mixture of the titanium tetraalkoxide compound and water. At that time, the amount of the optically active ligand with respect to 1 mole of titanium is preferably 0.1 to 3.0 moles, more preferably 0.2 to 2.0 moles. Add and stir. In that case, it is preferable to use a solvent. At that time, the same or different solvent as the solvent used in the step of preparing the reaction product of the titanium tetraalkoxide compound and water can be used. The solvent to be used is not particularly limited, but halogenated hydrocarbon solvents such as dichloromethane, chloroform, fluorobenzene and trifluoromethylbenzene, aromatic hydrocarbon solvents such as toluene and xylene, ester solvents such as ethyl acetate, tetrahydrofuran Ether solvents such as dioxane, diethyl ether and dimethoxyethane, nitrile solvents such as acetonitrile, and alcohol solvents such as ethanol and n-butanol are preferred. Among these, a halogen-based solvent or an aromatic hydrocarbon-based solvent is particularly preferable. Furthermore, these can be used alone or as a mixed solvent. The solvent to be used is preferably used after being dried by a known method.

  Although the usage-amount of a solvent is not specifically limited, Usually, it is 1-5000 mL with respect to 1 mmol of titanium atoms, Preferably it is about 10-500 mL. At this time, although reaction temperature is not specifically limited, Usually, it can prepare by stirring at about room temperature, for example, 15-30 degreeC for about 5 minutes-1 hour.

The optically active titanium compound of the present invention is preferably prepared in a dry inert gas atmosphere. Examples of the inert gas include nitrogen, argon, helium and the like.
The optically active titanium compound prepared as described above can be used as it is for the asymmetric cyanation reaction of the carbonyl compound without any special purification operation.

[Method for producing optically active cyanohydrin]
The method for producing optically active cyanohydrin will be described below.

In the method of the present invention, the carbonyl compound used as a starting material is not particularly limited as long as it is a prochiral compound having a carbonyl group in the molecule, and can be appropriately selected according to the target optically active cyanohydrin.
The process according to the invention is in particular a general formula (b)

It is suitable when producing the corresponding optically active cyanohydrin using a carbonyl compound represented by

In the general formula (b), R ⁴ and R ⁵ are groups different from each other, and each represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aromatic heterocyclic group, or a non-aromatic heterocyclic ring. A group, which may have a substituent, and R ⁴ and R ⁵ may be bonded to each other to form a ring.

As the alkyl group in R ⁴ and R ^{5, a} linear, branched or cyclic alkyl group having 20 or less carbon atoms is preferable. Specifically, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, n -Butyl group, isobutyl group, sec-butyl group, tert-butyl group, cyclopentyl group, cyclohexyl group and the like. The linear, branched, or cyclic alkyl group includes, as a substituent, a halogen atom, an aryl group having 20 or less carbon atoms, an aromatic heterocyclic group having 20 or less carbon atoms, and a non-aromatic complex having 20 or less carbon atoms. It may have a cyclic group, an oxygen-containing group having 20 or less carbon atoms, a nitrogen-containing group having 20 or less carbon atoms, a silicon-containing group having 20 or less carbon atoms, and the like.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the oxygen-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as alkoxy groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and acyloxy groups. Examples of the nitrogen-containing group having 20 or less carbon atoms include an amino group having 20 or less carbon atoms, an amide group having 20 or less carbon atoms, a nitro group, and a cyano group. Examples of the silicon-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as silyl group and silyloxy group.

  Examples of the alkyl group having a halogen atom include a chloromethyl group, a 2-chloroethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a perfluoroethyl group, and a perfluorohexyl group. Examples of the alkyl group having an aryl group include substituted or unsubstituted aralkyl groups such as benzyl group, 4-methoxybenzyl group, 2-phenylethyl group, cumyl group, α-naphthylmethyl group, and trityl group. . Examples of the alkyl group having an aromatic heterocyclic group include a 2-pyridylmethyl group, a furfuryl group, and a 2-thienylmethyl group. Examples of the alkyl group having a non-aromatic heterocyclic group include a tetrahydrofurfuryl group. Examples of the alkyl group having an oxygen-containing group include a methoxyethyl group and a phenoxyethyl group. Examples of the alkyl group having a nitrogen-containing group include 2- (dimethylamino) ethyl group and 3- (diphenylamino) propyl. Examples of the alkyl group having a silicon-containing group include a 2- (trimethylsiloxy) ethyl group.

As the alkenyl group in R ⁴ and R ⁵ , a linear, branched or cyclic alkenyl group having 2 to 20 carbon atoms is preferable. Specifically, a vinyl group, an allyl group, an isopropenyl group, a crotyl group, a cyclo A hexenyl group etc. are mentioned.

  The linear, branched or cyclic alkenyl group includes, as a substituent, a halogen atom, an aryl group having 20 or less carbon atoms, an aromatic heterocyclic group having 20 or less carbon atoms, and a non-aromatic complex having 20 or less carbon atoms. It may have a cyclic group, an oxygen-containing group having 20 or less carbon atoms, a nitrogen-containing group having 20 or less carbon atoms, a silicon-containing group having 20 or less carbon atoms, and the like.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the oxygen-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as alkoxy groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and acyloxy groups. Examples of the nitrogen-containing group having 20 or less carbon atoms include an amino group having 20 or less carbon atoms, an amide group having 20 or less carbon atoms, a nitro group, and a cyano group. Examples of the silicon-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as silyl group and silyloxy group.

  Examples of the alkenyl group having a halogen atom include C2-C20 halogenated alkenyl groups such as 2-chlorovinyl group, 2,2-dichlorovinyl group, and 3-chloroisopropenyl group. Examples of the alkenyl group having an aryl group include substituted or unsubstituted aralkenyl groups such as a 2-phenylethenyl group and a 3-phenyl-2-propenyl group. Examples of the alkenyl group having an aromatic heterocyclic group include 2- (2-pyridyl) ethenyl group. Examples of the alkenyl group having a non-aromatic heterocyclic group include a 2- (2-tetrahydrofuryl) ethenyl group. Examples of the alkenyl group having an oxygen-containing group include a 2-methoxyethenyl group and a 2-phenoxyethenyl group. Examples of the alkenyl group having a nitrogen-containing group include 2- (dimethylamino) ethenyl group and 3- (diphenylamino) propenyl group. Examples of the alkenyl group having a silicon-containing group include a 2- (trimethylsiloxy) ethenyl group.

As the alkynyl group in R ⁴ and R ^5, an alkynyl group having 2 to 20 carbon atoms is preferable. Specific examples include ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 1-pentynyl group and the like. Is mentioned.

  The above alkynyl group includes, as a substituent, a halogen atom, an aryl group having 20 or less carbon atoms, an aromatic heterocyclic group having 20 or less carbon atoms, a non-aromatic heterocyclic group having 20 or less carbon atoms, and oxygen having 20 or less carbon atoms. It may have a containing group, a nitrogen-containing group having 20 or less carbon atoms, a silicon-containing group having 20 or less carbon atoms, and the like.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the oxygen-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as alkoxy groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and acyloxy groups. Examples of the nitrogen-containing group having 20 or less carbon atoms include an amino group having 20 or less carbon atoms, an amide group having 20 or less carbon atoms, a nitro group, and a cyano group. Examples of the silicon-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as silyl group and silyloxy group.

  Examples of the alkynyl group having a halogen atom include halogenated alkynyl groups having 2 to 20 carbon atoms such as a 3-chloro-1-propynyl group. Examples of the alkynyl group having an aryl group include substituted or unsubstituted aralkynyl groups such as a 2-phenylethynyl group and a 3-phenyl-2-propynyl group. Examples of the alkynyl group having an aromatic heterocyclic group include a 2- (2-pyridylethynyl) group. Examples of the alkynyl group having a non-aromatic heterocyclic group include a 2-tetrahydrofurylethynyl group. Examples of the alkynyl group having an oxygen-containing group include a 2-methoxyethynyl group and a 2-phenoxyethynyl group. Examples of the alkynyl group having a nitrogen-containing group include 2- (dimethylamino) ethynyl group and 3- (diphenylamino) propynyl. Examples of the alkynyl group having a silicon-containing group include a 2- (trimethylsiloxy) ethynyl group.

The aryl group in R ⁴ and R ⁵ is preferably an aryl group having 6 to 20 carbon atoms, and specific examples include a phenyl group, a naphthyl group, a biphenyl group, and an anthryl group.

  The aryl group has a halogen atom, an alkyl group having 20 or less carbon atoms, an oxygen-containing group having 20 or less carbon atoms, a nitrogen-containing group having 20 or less carbon atoms, a silicon-containing group having 20 or less carbon atoms, and the like as a substituent. You may do it.

  Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the oxygen-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as alkoxy groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and acyloxy groups. Examples of the nitrogen-containing group having 20 or less carbon atoms include an amino group having 20 or less carbon atoms, an amide group having 20 or less carbon atoms, a nitro group, and a cyano group. Examples of the silicon-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as silyl group and silyloxy group.

  Examples of the aryl group having a halogen atom include a 4-fluorophenyl group and a pentafluorophenyl group. Examples of the aryl group having an alkyl group include a tolyl group, 3,5-dimethylphenyl group, 2,4,6-trimethylphenyl group, 4-isopropylphenyl group, 3,5-diisopropylphenyl group, 4-tert- Examples thereof include a butylphenyl group and a 2,6-di-tert-butylphenyl group. Examples of the aryl group having an oxygen-containing group include alkoxy groups such as 4-methoxyphenyl group, 3,5-dimethoxyphenyl group, 3,5-diisopropoxyphenyl group, and 2,4,6-triisopropoxyphenyl group. And aryloxy-substituted aryl groups such as substituted aryl groups and 2,6-diphenoxyphenyl groups. Examples of the aryl group having a nitrogen-containing group include 4- (dimethylamino) phenyl group and 4-nitrophenyl group. Examples of the aryl group having a silicon-containing group include 3,5-bis (trimethylsilyl) phenyl group and 3,5-bis (trimethylsiloxy) phenyl group.

The aromatic heterocyclic group for R ⁴ and R ⁵ is preferably an aromatic heterocyclic group having 3 to 20 carbon atoms, and specific examples include an imidazolyl group, a furyl group, a thienyl group, and a pyridyl group.

  The aromatic heterocyclic group may have an alkyl group having 20 or less carbon atoms, an oxygen-containing group having 20 or less carbon atoms, a nitrogen-containing group having 20 or less carbon atoms, a silicon-containing group having 20 or less carbon atoms, or the like. Good.

  Examples of the oxygen-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as alkoxy groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and acyloxy groups. Examples of the nitrogen-containing group having 20 or less carbon atoms include an amino group having 20 or less carbon atoms, an amide group having 20 or less carbon atoms, a nitro group, and a cyano group. Examples of the silicon-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as silyl group and silyloxy group. Examples of the aromatic heterocyclic group having an alkyl group include an N-methylimidazolyl group and a 4,5-dimethyl-2-furyl group. Examples of the aromatic heterocyclic group having an oxygen-containing group include a 5-butoxycarbonyl-2-furyl group. Examples of the aromatic heterocyclic group having a nitrogen-containing group include a 5-butylaminocarbonyl-2-furyl group.

The non-aromatic heterocyclic group in R ⁴ and R ⁵ is preferably a non-aromatic heterocyclic group having 4 to 20 carbon atoms, and specific examples include a pyrrolidyl group, piperidyl group, tetrahydrofuryl group and the like.

  The non-aromatic heterocyclic group includes an alkyl group having 20 or less carbon atoms, an aryl group having 20 or less carbon atoms, an oxygen-containing group having 20 or less carbon atoms, a nitrogen-containing group having 20 or less carbon atoms, and silicon having 20 or less carbon atoms. It may be substituted with a containing group or the like.

  Examples of the oxygen-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as alkoxy groups, aryloxy groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and acyloxy groups. Examples of the nitrogen-containing group having 20 or less carbon atoms include an amino group having 20 or less carbon atoms, an amide group having 20 or less carbon atoms, a nitro group, and a cyano group. Examples of the silicon-containing group having 20 or less carbon atoms include those having 20 or less carbon atoms such as silyl group and silyloxy group.

Examples of the non-aromatic heterocyclic group having an alkyl group include a 3-methyl-2-tetrahydrofuranyl group. Examples of the non-aromatic heterocyclic group having an aryl group include an N-phenyl-4-piperidyl group. Examples of the non-aromatic heterocyclic group having an oxygen-containing group include a 3-methoxy-2-pyrrolidyl group.
In the method of the present invention, specifically, an aldehyde or a ketone can be used as the carbonyl compound, and it is particularly preferable to use an aldehyde.

  Representative examples of aldehydes include propionaldehyde, butyraldehyde, valeraldehyde, isovaleraldehyde, hexaaldehyde, heptaldehyde, octylaldehyde, nonylaldehyde, decylaldehyde, isobutyraldehyde, 2-methylbutyraldehyde, 2-ethylbutyraldehyde, 2-ethylhexanal, pivalaldehyde, 2,2-dimethylpentanal, cyclopropanecarbaldehyde, cyclohexanecarbaldehyde, phenylacetaldehyde, (4-methoxyphenyl) acetaldehyde, 3-phenylpropionaldehyde, benzyloxyacetaldehyde, crotonaldehyde, 3-methylcrotonaldehyde, methacrolein, trans-2-hexenal, trans-cinnamic aldehyde, benzaldehyde, o-, m- or p-tolylaldehyde, 2,4,6-trimethylbenzaldehyde, 4-biphenylcarbaldehyde, o-, m- or p-fluorobenzaldehyde, o-, m- or p-chlorobenzaldehyde, o-, m- or p- Bromobenzaldehyde, 2,3-, 2,4- or 3,4-dichlorobenzaldehyde, 4- (trifluoromethyl) benzaldehyde, 3- or 4-hydroxybenzaldehyde, 3,4-dihydroxybenzaldehyde, o-, m- or p-anisaldehyde, 3,4-dimethoxybenzaldehyde, 3,4- (methylenedioxy) benzaldehyde, m- or p-phenoxybenzaldehyde, m- or p-benzyloxybenzaldehyde, 2,2-dimethylchroman-6-carbo Aldehyde, 1- or 2-naphthaldehyde, 2- or 3-furancarbaldehyde, 2- or 3-thiophenecarbaldehyde, 1-benzothiophene -3-carbaldehyde, N-methylpyrrole-2-carbaldehyde, 1-methylindole-3-carbaldehyde, 2-, 3- or 4-pyridinecarbaldehyde.

In addition, as representative examples of ketones that can be used as starting materials in the method of the present invention, 2-butanone, 2-pentanone, 2-hexanone, 2-heptanone, 2-octanone, isopropyl methyl ketone, cyclopentyl methyl ketone, cyclohexyl Methyl ketone, phenylacetone, p-methoxyphenylacetone, 4-phenylbutan-2-one, cyclohexylbenzylketone, acetophenone, o-, m- or p-methylacetophenone, 4-acetylbiphenyl, o-, m- or p -Fluoroacetophenone, o-, m- or p-chloroacetophenone, o-, m- or p-bromoacetophenone, 2 ', 3'-, 2', 4'- or 3 ', 4'-dichloroacetophenone, m -Or p-hydroxyacetophenone, 3 ', 4'-dihydroxyacetophenone, o-, m- or p-methoxyacetophenone, 3', 4'-dimethoxyacetophene M- or p-phenoxyacetophenone, 3 ', 4'-diphenoxyacetophenone, m- or p-benzyloxyacetophenone, 3', 4'-dibenzyloxyacetophenone, 2-chloroacetophenone, 2-bromoacetophenone, Propiophenone, 2-methylpropiophenone, 3-chloropropiophenone, butyrophenone, phenylcyclopropylketone, phenylcyclobutylketone, phenylcyclopentylketone, phenylcyclohexylketone, 1- or 2-acenaphthone, chalcone, 1-indanone 1- or 2-tetralone, 4-chromanone, trans-4-phenyl-3-buten-2-one, 2- or 3-acetylfuran, 2- or 3-acetylthiophene, 2-, 3- or 4- Examples include acetylpyridine.
In the present invention, an optically active cyanohydrin is produced by reacting the carbonyl compound with hydrogen cyanide in the presence of the optically active titanium compound.

  The optically active titanium compound used in the present invention is used in an amount of 0.01 to 30 mol%, preferably 0.05 to 10 mol% as a titanium atom with respect to 1 mol of the carbonyl compound. Is also about 0.01 to 30 mol%, preferably about 0.05 to 10 mol%.

  The amount of hydrogen cyanide used in the method of the present invention is preferably 1 to 3 mol, more preferably 1.05 to 2 mol, relative to 1 mol of the carbonyl compound. In this case, hydrogen cyanide in a liquid state or a gas state can be added to the reaction solution as it is, or it can be used for the reaction or dissolved in a different organic solvent and then added to the reaction solution.

  In the method of the present invention, it is preferable to use a solvent. The solvent to be used is not particularly limited, but halogenated hydrocarbon solvents such as dichloromethane, chloroform, fluorobenzene and trifluoromethylbenzene, aromatic hydrocarbon solvents such as toluene and xylene, ester solvents such as ethyl acetate, tetrahydrofuran Ether solvents such as dioxane, diethyl ether and dimethoxyethane, nitrile solvents such as acetonitrile, and alcohol solvents such as ethanol and n-butanol are preferred. Among these, a halogen-based solvent or an aromatic hydrocarbon-based solvent is particularly preferable. Furthermore, these can be used alone or as a mixed solvent. The total amount of the solvent used is preferably 0.1 to 50 mL, more preferably about 0.2 to 25 mL per 1 mmol of the substrate carbonyl compound.

  Although reaction temperature is not specifically limited, It is desirable to carry out around room temperature. Although reaction time is not specifically limited, The range of 5 minutes-24 hours is preferable, and the range of 30 minutes-8 hours is more preferable.

  The cyanohydrin obtained by the method of the present invention can be derivatized by a known method. For example, the obtained cyanohydrin can be converted to the corresponding acetylated form by reacting with acetic anhydride in the presence of pyridines. Moreover, it can convert into a corresponding hydroxy carboxylic acid by hydrolyzing a nitrile group.

  The cyanohydrin obtained in the present invention can be derivatized by such derivatization after isolation and purification, or can be derivatized by adding the operation to a reaction mixture or an unpurified crude product. .

  EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited to these Examples.

  The cyanohydrin obtained in the examples was derived into an acetylated form by a known method without isolation in order to measure the yield and optical yield. In the present specification, cyanohydrin and such derivatives are collectively referred to as cyanohydrins.

Optically active cyanohydrins are identified by ESI mass spectrum (using Shimadzu Corporation LC-20AT) and ¹ H NMR spectrum in deuterated chloroform solvent (using Bruker 400 Bruker) Was compared with previously reported values.

  The conversion rate, asymmetric yield and isolation yield of the asymmetric cyanation reaction were measured using gas chromatography (Agilent 6890N). At this time, CHIRALDEX G-TA (manufactured by Advanced Separation Technologies) was used as the chiral column. The absolute configuration of the optically active cyanohydrins was determined by comparing the optical rotation (using P-1030 manufactured by JASCO) with the reported values.

Dichloromethane for organic synthesis (hereinafter referred to as “dehydrated dichloromethane”) manufactured by KANTO CHEMICAL CO., INC. Was used as the dichloromethane used in the examples. Titanium tetra-n-butoxide was used without purification of the Fluka reagent. Na ₂ B ₄ O ₇ · 10H ₂ O was used without purification of a reagent manufactured by KANTO CHEMICAL CO., INC. The optically active ligand was synthesized according to a previously reported method. For other compounds, commercially available reagents were used as they were without purification.
All reactions were carried out under a nitrogen atmosphere. The equipment used for the reaction was sufficiently dried.

(Production Example 1)
In a sample bottle, 0.0191 g of Na ₂ B ₄ O ₇ · 10H ₂ O (0.0500 mmol, equivalent to 1.00 mol of water per 1 mol of titanium) is weighed, 0.17 g (0.50 mmol) of titanium tetra-n-butoxide, dehydrated 3 mL of dichloromethane was added. The mixture was sealed with a lid, stirred at room temperature for 20 hours, and filtered through a membrane filter having a pore size of 0.2 μm. The filtrate was transferred to a 10 mL volumetric flask, diluted with dehydrated dichloromethane to 10 mL, and a uniform, colorless and transparent solution of a reaction product of a titanium tetraalkoxide compound and water was obtained.

(Production Example 2)
In a sample bottle, weigh out 0.0238 g of Na ₂ B ₄ O ₇ · 10H ₂ O (0.0625 mmol, equivalent to 1.25 mol of water relative to 1 mol of titanium), 0.17 g (0.50 mmol) of titanium tetra-n-butoxide, dehydrated 3 mL of dichloromethane was added. After sealing with a lid, the mixture was stirred at room temperature for 18 hours, and then filtered through a membrane filter having a pore size of 0.2 μm. The filtrate was transferred to a 10 mL volumetric flask, diluted with dehydrated dichloromethane to 10 mL, and a uniform, colorless and transparent solution of a reaction product of a titanium tetraalkoxide compound and water was obtained.

(Production Example 3)
In a sample bottle, weigh out 0.0238 g of Na ₂ B ₄ O ₇ · 10H ₂ O (0.0625 mmol, equivalent to 1.25 mol of water relative to 1 mol of titanium), 0.17 g (0.50 mmol) of titanium tetra-n-butoxide, dehydrated 3 mL of dichloromethane was added. The mixture was sealed with a lid, stirred at room temperature for 20 hours, and filtered through a membrane filter having a pore size of 0.2 μm. The filtrate was transferred to a 10 mL volumetric flask, diluted with dehydrated dichloromethane to 10 mL, and a uniform, colorless and transparent solution of a reaction product of a titanium tetraalkoxide compound and water was obtained.

(Production Example 4)
In a sample bottle, 0.0191 g of Na ₂ B ₄ O ₇ · 10H ₂ O (0.0500 mmol, equivalent to 1.00 mol of water per 1 mol of titanium) is weighed, 0.17 g (0.50 mmol) of titanium tetra-n-butoxide, dehydrated 3 mL of dichloromethane was added. After sealing with a lid, the mixture was stirred at room temperature for 48 hours, and then filtered through a membrane filter having a pore size of 0.2 μm. The filtrate was transferred to a 10 mL volumetric flask, diluted with dehydrated dichloromethane to 10 mL, and a uniform, colorless and transparent solution of a reaction product of a titanium tetraalkoxide compound and water was obtained.

(Production Example 5)
In a 5 mL volumetric flask, 1.0 mL of the solution of the reaction product of the titanium tetraalkoxide compound obtained in Production Example 1 and water was weighed (0.050 mmol as titanium). Subsequently, (S) -2- (N-3,5-di-tert-butylsalicylidene) amino-3-methyl-1-butanol (the above formula (c-8) was used as a solution of the optically active ligand. )) In dichloromethane (0.020 mol / L) was added to 2.5 mL (0.050 mmol), and dehydrated dichloromethane solution was added to dilute to 5 ml. The mixture was stirred at room temperature for 30 minutes to obtain a yellow titanium compound solution.

(Production Example 6)
As a solution of a reaction product of a titanium tetraalkoxide compound and water, the solution obtained in Production Example 2 was used instead, and a solution of an optically active ligand (S) -2- (N-3-tert-butyl-5 -Methoxysalicylidene) amino-3-methyl-1-butanol (formula (c-20)) was used in the same manner as in Production Example 5 except that a dichloromethane solution (0.020 mol / L) was used. A titanium compound solution was obtained.

(Production Example 7)
A yellow titanium compound solution was obtained in the same manner as in Production Example 5, except that the reaction product of the titanium tetraalkoxide compound and water was used instead of the solution obtained in Production Example 3.
(Production Example 8)

  A yellow titanium compound solution was obtained in the same manner as in Production Example 5, except that the reaction product of the titanium tetraalkoxide compound and water was used instead of the solution obtained in Production Example 4.

(Production Example 9)
A yellow titanium compound solution was obtained in the same manner as in Production Example 7 except that the concentration of the optically active ligand in dichloromethane was changed to 0.010 mmol / L. At this time, the amount of the optically active ligand with respect to 1 mole of titanium was 0.5 mole.

(Production Example 10)
A yellow titanium compound solution was obtained in the same manner as in Production Example 7, except that the concentration of the optically active ligand in dichloromethane was changed to 0.0067 mmol / L. At this time, the amount of the optically active ligand relative to 1 mole of titanium was 0.33 mole.

[Example 1]
To 0.90 mL of the catalyst solution prepared in Production Example 5 (0.0090 mmol as Ti, corresponding to 3 mol% with respect to the substrate), 0.60 mL of anhydrous dichloromethane was added for dilution. Furthermore, 34 mg (0.30 mmol) of heptaldehyde and 0.35 mL (0.45 mmol) of a hydrogen cyanide solution in dichloromethane (1.3 M) were sequentially added. After stirring at room temperature for 1 hour and reacting, 0.14 ml (1.5 mmol) of acetic anhydride and 0.12 ml (0.15 mmol) of pyridine were sequentially added, followed by stirring at room temperature for 1 hour. Further, 0.034 ml (0.015 mmol) of dodecane was added as an internal standard substance for gas chromatography analysis. The reaction mixture was washed 3 times with 3 ml of water and then dried over magnesium sulfate. The obtained reaction product was analyzed by gas chromatography. The conversion rate of the raw material is 98%, the yield of the acetylated product of 2-hydroxyoctanenitrile produced is 92%, the asymmetric yield is 85% ee, and the (S) isomer is preferentially obtained. I understood.

[Example 2]
The reaction solution was obtained in the same manner as in Example 1 except that the amount of catalyst solution used was 1.50 ml (0.015 mmol as Ti, equivalent to 5 mol% with respect to the substrate), and it was not diluted with anhydrous dichloromethane. It was. The conversion rate of the raw material was 99%, the asymmetric yield of the acetylated form of 2-hydroxyoctanenitrile produced was 83% ee, and it was found that the (S) form was preferentially obtained.

[Example 3]
A reaction product was obtained in the same manner as in Example 2 except that the amount of added hydrogen cyanide was changed to 0.33 mmol. The conversion rate of the raw material was 98%, the asymmetric yield of the acetylated product of 2-hydroxyoctanenitrile produced was 83% ee, and it was found that the (S) isomer was preferentially obtained.

[Example 4]
A reaction product was obtained in the same manner as in Example 1 except that the catalyst solution prepared in Production Example 6 was used. The conversion rate of the raw material was 97%, the asymmetric yield of the acetylated product of 2-hydroxyoctanenitrile produced was 85% ee, and it was found that the (S) product was obtained preferentially.

[Example 5]
A reaction product was obtained in the same manner as in Example 1 except that cyclohexanecarboxaldehyde was used in place of heptaldehyde and the catalyst solution prepared in Production Example 7 was used. The conversion rate of the raw material was 99%, the yield of the acetylated 2-cyclohexyl-2-hydroxyacetonitrile produced was 99%, and the asymmetric yield was 92% ee. I found out.

[Example 6]
A reaction product was obtained in the same manner as in Example 1 except that pivalaldehyde was used instead of heptaldehyde and that the catalyst solution prepared in Production Example 8 was used. The conversion rate of the raw material was 99%, the yield of acetylated 2-hydroxy-3,3-dimethylbutanenitrile produced was 96%, and the asymmetric yield was 91% ee. It was found that it was obtained.

[Example 7]
A reaction product was obtained in the same manner as in Example 1 except that benzaldehyde was used instead of heptaldehyde and the reaction time was changed to 4 hours. The conversion rate of the raw material was 75%, the yield of the acetylated product of 2-hydroxy-2-phenylacetonitrile produced was 75%, and the asymmetric yield was 80% ee. I found out.

[Example 8]
Using 2-fluorobenzaldehyde instead of heptaldehyde, using the catalyst solution prepared in Production Example 7 and using the same reaction as in Example 1 except that the reaction time was 4 hours. I got a thing. The conversion rate of the raw material was 88%, the yield of the acetylated 2- (2-fluorophenyl) -2-hydroxyacetonitrile produced was 88%, the asymmetric yield was 91% ee, and the (S) isomer was It turns out that it is given priority.

[Example 9]
A reaction product was obtained in the same manner as in Example 1 except that isobutyraldehyde was used in place of heptaldehyde and the catalyst solution prepared in Production Example 9 was used. The conversion rate of the raw material was 99%, the yield of the acetylated 2-hydroxy-3-methylbutanenitrile produced was 93%, and the asymmetric yield was 90% ee. I found out.

[Example 10]
A reaction product was obtained in the same manner as in Example 1 except that isobutyraldehyde was used in place of heptaldehyde and the catalyst solution prepared in Production Example 10 was used. The conversion rate of the raw material was 99%, the yield of the acetylated product of 2-hydroxy-3-methylbutanenitrile produced was 93%, and the asymmetric yield was 89% ee. I found out.

[Example 11]
A reaction product was obtained in the same manner as in Example 1 except that the catalyst solution prepared in Production Example 9 was used. The conversion rate of the raw material is 96%, the yield of the acetylated form of 2-hydroxyoctanenitrile produced is 90%, the asymmetric yield is 85% ee, and the (S) form is preferentially obtained. I understood.

[Example 12]
A reaction product was obtained in the same manner as in Example 1 except that the catalyst solution prepared in Production Example 10 was used. The conversion rate of the raw material is 96%, the yield of the acetylated form of 2-hydroxyoctanenitrile produced is 90%, the asymmetric yield is 85% ee, and the (S) form is preferentially obtained. I understood.

[Example 13]
A reaction product was obtained in the same manner as in Example 5 except that the catalyst solution prepared in Production Example 9 was used. The conversion rate of the raw material was 99%, the yield of the acetylated 2-cyclohexyl-2-hydroxyacetonitrile produced was 99%, and the asymmetric yield was 91% ee. I found out.

[Example 14]
A reaction product was obtained in the same manner as in Example 5 except that the catalyst solution prepared in Production Example 10 was used. The conversion rate of the raw material was 99%, the yield of the acetylated 2-cyclohexyl-2-hydroxyacetonitrile produced was 99%, and the asymmetric yield was 91% ee. I found out.

[Example 15]
A reaction product was obtained in the same manner as in Example 6 except that the catalyst solution prepared in Production Example 9 was used. The conversion rate of the raw material was 99%, the yield of acetylated 2-hydroxy-3,3-dimethylbutanenitrile produced was 96%, and the asymmetric yield was 89% ee. It was found that it was obtained.

[Example 16]
A reaction product was obtained in the same manner as in Example 6 except that the catalyst solution prepared in Production Example 10 was used. The conversion rate of the raw material was 99%, the yield of acetylated 2-hydroxy-3,3-dimethylbutanenitrile produced was 96%, and the asymmetric yield was 89% ee. It was found that it was obtained.

[Example 17]
A reaction product was obtained in the same manner as in Example 7, except that the catalyst solution prepared in Production Example 9 was used. The conversion rate of the raw material was 69%, the yield of acetylated 2-hydroxy-2-phenylacetonitrile produced was 68%, and the asymmetric yield was 80% ee. I found out.

[Example 18]
A reaction product was obtained in the same manner as in Example 7, except that the catalyst solution prepared in Production Example 10 was used. The conversion rate of the raw material is 70%, the yield of the acetylated product of 2-hydroxy-2-phenylacetonitrile produced is 70%, and the asymmetric yield is 80% ee. I found out.

(Comparative Example 1)
The same operation as in Example 1 was performed except that the catalyst solution was not added and the amount of anhydrous dichloromethane added was 1.5 mL. The obtained reaction product was analyzed by gas chromatography. The conversion rate of the raw material was 9%, and the asymmetric yield of the produced 2-acetyloctanenitrile acetylated product was 0% ee.

Claims (5)

Reaction product of titanium tetraalkoxide compound and water, and general formula (a):

(Wherein R ¹ , R ² and R ³ are each independently a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, an aromatic heterocyclic group, an acyl group, an alkoxycarbonyl group, or an aryloxycarbonyl group. These may have a substituent, and two or more of R ¹ , R ² and R ³ may be connected to each other to form a ring, and the ring has a substituent. A ^* is an asymmetric carbon or a hydrocarbon-containing group having 3 or more carbon atoms having axial asymmetry.)
In the presence of an optically active titanium compound prepared from an optically active ligand represented by:
General formula (b):

(Wherein R ⁴ and R ⁵ are different groups, each of which is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group, It may have a substituent, and R ⁴ and R ⁵ may be bonded to each other to form a ring.), And hydrogen cyanide is reacted. A method for producing optically active cyanohydrin. The hydrocarbon-containing group A ^* in the general formula (a) is represented by the general formula (A-1):

(Wherein, R ^a , R ^b , R ^c and R ^d are each independently a hydrogen atom, an alkyl group, an aryl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an aminocarbonyl group, and these are substituents. And two or more of R ^a , R ^b , R ^c and R ^d may be connected to each other to form a ring, and the ring has a substituent. In addition, at least one of R ^a , R ^b , R ^c and R ^d is a different group, and both or at least one of the carbon atoms indicated by * is an asymmetric center. , (N) and (OH) are moieties other than A ^* , meaning the corresponding nitrogen atom and hydroxyl group in general formula (a) to which A ^* is bonded), general formula ( A-2):

(Wherein R ^e and R ^f are a hydrogen atom, an alkyl group, or an aryl group, which may have a substituent. In addition, R ^e and R ^f are different substituents. , * Represents an asymmetric carbon, and the moiety represented by (N) and (OH) represents the same meaning as in general formula (A-1)), or general formula (A -3):

(Wherein R ^g , R ^h , R ⁱ and R ^j are independently a hydrogen atom, a halogen atom, an alkyl group, an aryl group, or an alkoxy group, and these may have a substituent. In addition, R ⁱ and R ^j on the same benzene ring may be connected to each other or condensed to form a ring, and * ′ represents axial asymmetry. And the moiety represented by (OH) represents the same meaning as in the general formula (A-1).)
The method for producing an optically active cyanohydrin according to claim 1, which is a hydrocarbon-containing group represented by any one of: The optically active ligand represented by the general formula (a) is represented by the following general formula (c):

(Wherein R ^a , R ^b , R ^c and R ^d represent the same meaning as in the general formula (A-1). R ⁶ represents a hydrogen atom, an alkyl group or an aryl group, R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an aryl group, an aromatic heterocyclic group, or a non-aromatic heterocyclic ring. Group, alkoxycarbonyl group, aryloxycarbonyl group, hydroxyl group, alkoxy group, aryloxy group, amino group, cyano group, nitro group, silyl group, or siloxy group, and these may have a substituent , Each may be linked together to form a ring.)
The method for producing an optically active cyanohydrin according to claim 1. The titanium tetraalkoxide compound has the general formula (d):

(In the formula, R ¹¹ is an alkyl group or an aryl group, and these may have a substituent.)
The manufacturing method of the optically active cyanohydrin in any one of Claims 1-3 represented by these.   The production method according to claim 1, wherein the carbonyl compound is an aldehyde.