JP2007182419A - Proline derivative and optically active anti-selection promoting catalyst - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a catalyst having promoted anti-selectivity and a method for producing an optically active anti-form aldol compound by using the catalyst. <P>SOLUTION: The optically active anti-selection promoting catalyst is composed of a combination of proline and a substance or functional group to increase the lipid solubility of proline. The substance to increase the lipid solubility is a carboxylic acid, tetrazole, a carboxamide or a carboxamide having aryl group, heterocyclic group or alkyl group on nitrogen atom, and the functional group is aryl group, heterocyclic group, alkyl group, acyl group or silyl group which may have a substituent. Exclusively water or a non-polar solvent can be used as the solvent by carrying out the reaction in the presence of the catalyst. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a proline derivative useful as a catalyst for aldol reaction, and further relates to a method for producing an optically active form of a β-hydroxycarbonyl compound which is important as a basic skeleton of pharmaceuticals, agricultural chemicals and the like.

  The aldol reaction is an excellent reaction for producing a β-hydroxycarbonyl compound. β-hydroxycarbonyl compounds are important optically active synthetic intermediates found in the basic skeletons of many useful biologically active compounds, pharmaceuticals, agricultural chemicals and the like.

  As an excellent method for producing an optically active aldol compound, there is an asymmetric catalytic aldol reaction. Non-Patent Documents 1 and 2 listed below disclose a method in which a ketone or ester is once led to silyl enol ether or ketene silyl acetal and an optically active Lewis acid catalyst is allowed to act.

  Non-Patent Document 3 below discloses that a derivative obtained by substituting the carboxylic acid moiety of proline with sulfonamide can obtain a very high asymmetric yield of 98% ee in the aldol reaction of acetone and nitrobenzaldehyde. Non-Patent Document 4 below discloses that Wu et al. Give a very high asymmetric yield when a proline amide having a diphenylaminoethanol moiety is used for a catalyst having a modified amide moiety. .

  In Non-Patent Document 5, an adduct is obtained with a high optical yield in a reaction using a silyl enol ether and an optically active Lewis acid catalyst as an activator as a reaction performed in a mixed system of water and an organic solvent. It is disclosed.

  Non-Patent Document 6 includes 4-thianone, and Non-patent Document 7 includes 2,2-dimethyl-1,3-dioxane-5-one and aldol reactions of various aldehydes with high anti-selectivity and high levels. It is disclosed to proceed enantioselectively.

Non-Patent Document 8 discloses an asymmetric catalytic aldol reaction between aldehyde and aldehyde. This is a technique in which proline is used as a catalyst, and an excessive amount of electrophilic aldehyde is used and a nucleophilic aldehyde is dropped little by little over a long period of time.
Modern Aldol Reactions Vols 1,2; Mahrwald, R. Ed ,; Wiley-VCH: Weinheim, 2004. Comprehensive Asymmetric Catalysis I-III; Jacobsen, EN; Pfaltz, A .; Yamamoto, H. Eds .; Springer: Berlin, 1999. A. Berkessel, B. Koch,. Lex, Adv. Synth. Catal., 346, 1141 (2004) Z. Tang, F. Jiang, X. Cui, L. Gong, A. Mi, Y. Jiang, Y. Wu, Proc. Natl. Acad. Sci. USA, 101, 5755 (2004) Hamada, T .; Manabe, K .; Ishikawa, S .; Nagayama, S .; Shiro, M .; Kobayashi, SJ Am. Chem. Soc. 2003, 125, 2989 AI Nyberg, A. Usano, PM Pihko, Synlett, 2004, 1891 D. Enders, C. Grondal, Angew. Chem. Int. Ed. 2005, 44, 1210 Northup, AB; MacMillan, D. W, CJ Am. Chem. Soc. 2002, 124, 6798

  However, the methods of Non-Patent Documents 1 and 2 have the problem that the carbonyl compound must be once led to silyl enol ether or ketene silyl acetal, making it difficult to obtain an optically active Lewis acid catalyst.

  In addition, in the aldol reaction using a derivative in which the carboxylic acid moiety of proline is substituted with sulfonamide, only one example of the reaction example of Non-Patent Document 3 is disclosed, and it has not reached the stage of practical use.

In the reaction of Non-Patent Document 4, acetone as a reaction substrate is used as a solvent, but in other reactions, solvents that can be used are DMSO (dimethyl sulfoxide), DMF (dimethylformamide), NMP (1 - methyl-2-pyrrolidone), is limited to a polar solvent such as _CH 3 CN (acetonitrile). When these polar organic solvents were used, a liquid separation operation had to be performed after completion of the reaction. Further, since the solvent is mixed in the aqueous phase, there has been a problem in the treatment of the aqueous phase.

  In the reaction of Non-Patent Document 5, it is necessary to once convert the ketone to silyl enol ether, and water is not directly used as a solvent in the aldol reaction. Proline can obtain a high asymmetric yield in an organic solvent, but the reaction proceeds in water, but the asymmetric yield is very low.

  In the reactions of Non-Patent Documents 6 and 7, the ketones used are 4-thianone and 2,2-dimethyl-1,3-dioxan-5-one. High anti-selectivity was realized only with a sulfur atom or a ketone containing two oxygen atoms. When proline is used as a catalyst in the reaction of cyclohexanone, which is a simple cyclic ketone, with nitrobenzaldehyde, the diastereoselectivity is as low as 1.7: 1.0. The selectivity was as low as 1.7: 1.0.

  In addition, regarding the asymmetric catalytic aldol reaction between aldehyde and aldehyde, only one example described in Non-Patent Document 8 has been disclosed, and has not yet reached the stage of practical use.

  The present invention has been made in view of the above problems, and provides a catalyst having enhanced optically active antiselectivity and a method for producing the same, and an optically active anti-aldol compound using the catalyst, and It aims at providing the manufacturing method.

  As a result of intensive studies to solve the above problems, the present inventors have reacted with various organic solvents by using a catalyst that combines proline and a substituent that increases fat solubility or a substituent that moves between phases. It has been found that the reaction proceeds in water without using an organic solvent that dissolves the substrate, and the present invention has been completed.

  (1) A proline derivative which is an enantiomer of a compound represented by the following formula (12) or (14) to (28) or a compound represented by the following formula (11) to (31).

（式中Ｒ^６は、炭素数２から１５の直鎖状又は分岐状のアルキル基、又は置換基を有してもよいアリール基を示す。） (2) A compound represented by the following general formula (9-6) (except when R ⁶ is a phenyl group, a tolyl group, a p-nitrophenyl group, or a 2,4,6-triisopropylphenyl group) Or a proline derivative which is an enantiomer of a compound represented by the following general formula (9-6).

(In the formula, R ⁶ represents a linear or branched alkyl group having 2 to 15 carbon atoms, or an aryl group which may have a substituent.)

  (3) An optically active anti-selectivity enhancing catalyst in an aldol reaction using water, comprising a combination of proline and a substance or functional group that increases the fat solubility of proline.

  (4) The substance that increases the liposolubility of proline is carboxylic acid, tetrazole, carboxamide, carboxamide having an aryl group, heterocycle, alkyl group in nitrogen, carboxamide having a sulfonyl group which may have a substituent, substitution An alkylhydroxyl group which may have a group, an alkylsilyloxy group which may have a substituent, an arylsilyloxy group which may have a substituent, or a silyloxy group which has both an alkyl group and an aryl group (3) The optically active anti-selectivity enhancing catalyst according to (3).

  (5) The optical group according to (3) or (4), wherein the functional group that increases the lipid solubility of the proline is an aryl group, a heterocycle, an alkyl group, an acyl group, or a silyl group that may have a substituent. Active anti-selectivity enhancing catalyst.

  (6) Optically active anti-selectivity enhancement wherein the optically active anti-selectivity enhancing catalyst according to any one of (3) to (5) is a compound represented by the following general formulas (9-1) to (9-8) catalyst.

（式中Ｒ^３は、アルキル基、又はアリール基を示す。なお、それぞれのＲ^３は同一又は異なっていてもよい。Ｒ^４は、アルキル基、アリール基、又はアシル基を示す。Ｒ^５は、水素、アルキル基、又はアリール基を示す。Ｒ^６は、アルキル基、又はアリール基を示す。Ｒ^７は、官能基を有してもよいアルキル基、置換基を有してもよいアリール基、又は置換基を有してもよいヘテロアリール基を示す。）

(In the formula, R ³ represents an alkyl group or an aryl group. Each R ³ may be the same or different. R ⁴ represents an alkyl group, an aryl group, or an acyl group. R ⁵ represents , Hydrogen, an alkyl group, or an aryl group, R ⁶ represents an alkyl group, or an aryl group, and R ⁷ represents an alkyl group that may have a functional group, or an aryl group that may have a substituent. Or a heteroaryl group which may have a substituent.

  (7) The optically active anti-selectivity enhancing catalyst according to any one of (3) to (6) is a compound represented by the following formulas (11) to (34), or represented by the following formulas (11) to (34): An optically active anti-selectivity enhancing catalyst which is an enantiomer of the compound obtained.

  The optically active anti-selectivity-enhancing catalyst of the present invention comprises a combination of proline and a substance or functional group that increases the fat solubility of proline. Therefore, the catalyst can be dissolved in the organic phase that is the reaction substrate and used efficiently for the reaction in the organic layer. Proline is inexpensive and easy to obtain, so the amount of catalyst can be increased.

  (8) A method for producing a proline derivative represented by the following formula (12), wherein a proline derivative is produced by reacting a pyrrolidine derivative having a substituent at the 2-position and 4-position with a silylating agent. how to.

  (9) A method for producing a proline derivative represented by the following formula (12) or (14) to (28), wherein nitrogen of a pyrrolidine derivative having substituents at the 2-position and 4-position or 2-position and 3-position A method for producing a proline derivative by protecting an atom with a benzyloxycarbonyl group or a t-butoxycarbonyl group, reacting with a silylating agent or acylating agent, and then deprotecting with catalytic hydrogenation or acid.

  According to the production method of the present invention, it is a practical synthesis method capable of synthesizing a large amount from inexpensive hydroxyproline in one step or several steps, and has an economic merit.

  (10) An optically active anti-aldol compound obtained by reacting in the presence of the optically active anti-selectivity enhancing catalyst according to any one of (3) to (7).

  The optically active anti-aldol compound of the present invention is a site found in many pharmaceutical components, and has an economical effect in the development of an inexpensive method for synthesizing these compounds.

  (11) A ketone represented by the following general formula (1a) and an aldehyde represented by the following general formula (2a) are reacted in a solvent or reacted without using a solvent. A method for producing an optically active anti-aldol compound represented by the following general formula (3a), which is selected from amino acid derivatives represented by the following general formulas (10-1) to (10-5) and enantiomers thereof: A method for producing an optically active anti-aldol compound obtained by reacting in the presence of a catalyst. (However, in the case where the reaction is carried out without using a solvent, the case where the ketone represented by the general formula (1a) is acetone is excluded.)

（式中、Ｒ^８はアリール基、ヘテロ環、アルキル基、アシル基、又は置換基を有してもよいシリル基を示す。Ｒ^９はカルボキシル基、テトラゾール、カルボキサミド、窒素にアリール基、ヘテロ環、アルキル基などの置換基を有するカルボキサミド、置換基を有してもよいスルホニル基を有するカルボキサミド又は置換基を有してもよいアルキルヒドロキシル基を示す。Ｒ^１０はカルボキサミド、窒素にアリール基、ヘテロ環、アルキル基を有するカルボキサミド、置換基を有してもよいスルホニル基を有するカルボキサミド、置換基を有してもよいアルキルヒドロキシル基、置換基を有してもよいアルキルシリルオキシ基、置換基を有してもよいアリールシリルオキシ基、又はアルキル基とアリール基を合わせ持つシリルオキシ基を示す。）

(In the formula, R ⁸ represents an aryl group, a heterocycle, an alkyl group, an acyl group, or a silyl group which may have a substituent. R ⁹ represents a carboxyl group, tetrazole, carboxamide, an aryl group or a heterocycle on nitrogen. , A carboxamide having a substituent such as an alkyl group, a carboxamide having a sulfonyl group which may have a substituent or an alkylhydroxyl group which may have a substituent, R ¹⁰ represents a carboxamide, an aryl group on nitrogen, hetero A ring, a carboxamide having an alkyl group, a carboxamide having a sulfonyl group which may have a substituent, an alkyl hydroxyl group which may have a substituent, an alkylsilyloxy group which may have a substituent, and a substituent. An arylsilyloxy group which may have, or a silyloxy group having both an alkyl group and an aryl group )

  (12) The method for producing an optically active anti-aldol compound according to (11), wherein, when the reaction is carried out using a solvent, the solvent is water.

  (13) The method for producing an optically active anti-aldol compound according to (11), wherein when the solvent is used for the reaction, the solvent is a nonpolar solvent.

  (14) An aldehyde represented by the following general formula (4a) and an aldehyde represented by the following general formula (5a) are reacted in a solvent, or are reacted without using a solvent. A method for producing an optically active anti-aldol compound represented by the following general formula (6a), which is selected from amino acid derivatives represented by the following general formulas (10-1) to (10-5) and enantiomers thereof: A method for producing an optically active anti-aldol compound obtained by reacting in the presence of a catalyst.

（式中、Ｒ^８はアリール基、ヘテロ環、アルキル基、アシル基、又は置換基を有してもよいシリル基を示す。Ｒ^９はカルボキシル基、テトラゾール、カルボキサミド、窒素にアリール基、ヘテロ環、アルキル基などの置換基を有するカルボキサミド、置換基を有してもよいスルホニル基を有するカルボキサミド又は置換基を有してもよいアルキルヒドロキシル基を示す。Ｒ^１０はカルボキサミド、窒素にアリール基、ヘテロ環、アルキル基を有するカルボキサミド、置換基を有してもよいスルホニル基を有するカルボキサミド、置換基を有してもよいアルキルヒドロキシル基、置換基を有してもよいアルキルシリルオキシ基、置換基を有してもよいアリールシリルオキシ基、又はアルキル基とアリール基を合わせ持つシリルオキシ基を示す。）

(In the formula, R ⁸ represents an aryl group, a heterocycle, an alkyl group, an acyl group, or a silyl group which may have a substituent. R ⁹ represents a carboxyl group, tetrazole, carboxamide, an aryl group or a heterocycle on nitrogen. , A carboxamide having a substituent such as an alkyl group, a carboxamide having a sulfonyl group which may have a substituent or an alkylhydroxyl group which may have a substituent, R ¹⁰ represents a carboxamide, an aryl group on nitrogen, hetero A ring, a carboxamide having an alkyl group, a carboxamide having a sulfonyl group which may have a substituent, an alkyl hydroxyl group which may have a substituent, an alkylsilyloxy group which may have a substituent, and a substituent. An arylsilyloxy group which may have, or a silyloxy group having both an alkyl group and an aryl group )

  (15) The method for producing an optically active anti-aldol compound according to (14), wherein, when the reaction is performed using a solvent, the solvent is water.

  (16) The method for producing an optically active anti-aldol compound according to (14), wherein when the solvent is used for the reaction, the solvent is a nonpolar solvent.

  According to the method for producing an optically active anti-aldol compound of the present invention, since the optically active anti-selectivity enhancing catalyst described in (3) to (7) is used, an aldol reaction between a ketone and an aldehyde, an aldehyde In the aldol reaction of aldehyde with aldehyde, high optically active antiselectivity and diastereoselectivity can be obtained. In addition, since only water can be used as the reaction solvent, an environment-friendly reaction system can be provided. In the case of a nonpolar solvent, since the boiling point is low, it can be concentrated at a lower temperature than when a polar solvent is used, and the reaction can be made more efficient.

  (17) The following general formula (3b) obtained by reacting a ketone represented by the following general formula (1b) with an aldehyde represented by the following general formula (2b) using water as a solvent and proline as a catalyst. The manufacturing method of the optically active anti-aldol compound represented by these.

  (18) The following general formula (6b) formed by reacting an aldehyde represented by the following general formula (4b) with an aldehyde represented by the following general formula (5b) using water as a solvent and proline as a catalyst. The manufacturing method of the optically active anti-aldol compound represented by these.

  According to the method for producing an optically active anti-aldol compound of the present invention, since a proline that is inexpensive and easily available is used as a catalyst, the amount of the catalyst can be increased, and a useful synthetic intermediate is easily produced. be able to. Moreover, since water is used as the solvent, a reaction system that is good for the environment can be provided.

  According to the optically active anti-selectivity enhancing catalyst of the present invention, it is possible to provide an environmentally conscious reaction using only water as a solvent for the aldol reaction. Further, since a low boiling point solvent can be used as the solvent without using a polar solvent, the efficiency of the reaction can be improved.

  Hereinafter, the present invention will be described in more detail.

<Optically active anti-selectivity enhancing catalyst>
The optically active anti-selectivity-enhancing catalyst of the present invention comprises a combination of proline and a substance or functional group that increases the fat solubility of proline. Specifically, compounds represented by the following general formulas (10-1) to (10-5) and enantiomers thereof can be used.

Here, R ⁸ is a substituent for increasing fat solubility, and examples thereof include an aryl group, a heterocyclic ring, an alkyl group, an acyl group, and a silyl group which may have a substituent. R ⁹ and R ¹⁰ may be any substituent having an acidic proton, and R ⁹ has, for example, a carboxyl group, a tetrazole, a carboxamide, or a nitrogen-containing substituent such as an aryl group, a heterocyclic ring, or an alkyl group. Examples thereof include carboxamide, carboxamide having a sulfonyl group which may have a substituent, and alkylhydroxyl group which may have a substituent. R ¹⁰ includes carboxamide, a carboxamide having an aryl group, a heterocycle, and an alkyl group on the nitrogen, a carboxamide having a sulfonyl group that may have a substituent, an alkylhydroxyl group that may have a substituent, a substituted An alkylsilyloxy group which may have a group, an arylsilyloxy group which may have a substituent, or a silyloxy group having both an alkyl group and an aryl group are shown.

Moreover, as a combination of R ⁸ and R ^9, a silyl group (R ⁸ ) and a carboxyl group (R ⁹ ), an acyl group (R ⁸ ) and a carboxyl group (R ⁹ ), which may have a substituent, a substituent A proline derivative having a silyl group (R ⁸ ) and tetrazole (R ⁹ ), which may have benzene, may be preferably used.

More specifically, compounds represented by the following formulas (9-1) to (9-8) can be used. In the formulas (9-1) to (9-3), R ⁹ in the general formula (10-1) or (10-2) is a carboxyl group, and the formula (9-1) increases fat solubility. A silyl group having an alkyl group or an aryl group as a substituent. Formula (9-2) is a compound having an alkyl group, an aryl group, or an acyl group as a substituent for increasing fat solubility and a substituent at the 4-position of proline. As in formula (9-3), the same effect can be obtained even if the substituent for increasing fat solubility is present at the 3-position of proline.

  Formulas (9-4) to (9-6) are functional groups having acidic protons, Formula (5-4) is a tetrazole, Formulas (9-5) and (9-6) are nitrogen substituents. The carboxamide which may have, Formula (9-7) is a hydroxyl group, Formula (9-8) is an alkylsiloxy group. As shown in the formulas (9-5) and (9-6), the amide moiety of carboxamide can be given lipophilicity. In this case, a lipophilic group is introduced into the 3rd and 4th positions of proline. The effect of the present invention can be obtained without this.

In the formula, R ³ represents an alkyl group or an aryl group. The alkyl group is preferably a linear or branched alkyl group having 1 to 20 carbon atoms, and the aryl group has a phenyl group or a linear or branched alkyl group having 1 to 20 carbon atoms. An aryl group is preferred. Also, each R ³ may be the same or different.

R ⁴ represents an alkyl group, an aryl group, or an acyl group. The alkyl group is preferably a linear or branched alkyl group having 1 to 20 carbon atoms, and the aryl group has a phenyl group or a linear or branched alkyl group having 1 to 20 carbon atoms. An aryl group is preferred. In addition, the acyl group preferably has 1 to 20 carbon atoms.

R ⁵ represents hydrogen, an alkyl group, or an aryl group. The alkyl group is preferably a linear or branched alkyl group having 1 to 20 carbon atoms, and the aryl group has a phenyl group or a linear or branched alkyl group having 1 to 20 carbon atoms. An aryl group is preferred.

R ⁶ represents an alkyl group or an aryl group. The alkyl group is preferably a linear or branched alkyl group having 1 to 20 carbon atoms, and the aryl group has a phenyl group or a linear or branched alkyl group having 1 to 20 carbon atoms. An aryl group is preferred.

R ⁷ represents an alkyl group that may have a functional group, an aryl group that may have a substituent, or a heteroaryl group that may have a substituent. As a functional group, an alkoxy group or an acyl group can be mentioned, for example. Examples of the substituent include a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, or an alkyl group substituted with a halogen atom. Examples of the alkyl group substituted with a halogen atom include a trifluoromethyl group. The alkyl group preferably has 1 to 20 carbon atoms, and the aryl group is preferably a phenyl group or an aryl group having an alkyl group having 1 to 20 carbon atoms. Further, R ⁷ is preferably a phenyl group or 3,5-bistrifluorophenyl. Also, each R ⁷ may be the same or different.

  Further, the optically active anti-selectivity enhancing catalyst is represented by the above formulas (11) to (34) from the viewpoint of solubility in water and the steric positional relationship between the amine, which is the reaction site, the acidic proton, and the fat-soluble site. It is preferable that it is a catalyst.

  The optically active anti-selectivity enhancing catalyst of the present invention can be produced, for example, by the method shown below. Addition of a silylating agent and a base to 3-hydroxyproline or 4-hydroxyproline which is a starting material, and silylation of alcohol can be performed to obtain catalysts (11), (12) and (13) in one step. .

  Catalysts (11) to (13) and (20) to (25) can be produced, for example, by the method shown below. The starting material 3-hydroxyproline or 4-hydroxyproline is reacted with a benzyloxycarbonylation reagent, for example, benzyloxycarbonyl chloride, under basic conditions, and the nitrogen atom is converted into a benzyloxycarbonyl group (Z group, Cbz group). Protect. A benzylating agent such as benzyl chloride and a base are added to make the carboxylic acid a benzyl ester. In the presence of an amine salt, a silylating agent such as silyl chloride is added to silylate the hydroxyl group. Catalysts (11) to (13) and (20) to (25) can be obtained by catalytic hydrogenation and deprotection of the obtained compound.

  Further, in the catalysts (14) to (19), a starting material, 4-hydroxyproline, is reacted with a benzyloxycarbonylation reaction reagent such as benzyloxycarbonyl chloride under basic conditions to protect the nitrogen atom with a Z group. A benzylating agent such as benzyl chloride and a base are added to benzylate the carboxylic acid. In the presence of a base, an acylating agent such as acyl chloride is allowed to act to give an ester. Catalysts (14) to (19) are obtained by catalytic hydrogenation and deprotection of the resulting compound.

  In the catalysts (26) to (28), a starting material, 4-hydroxyproline, is reacted with a benzyloxycarbonylation reaction reagent such as benzyloxycarbonyl chloride under basic conditions, and the nitrogen atom is protected with a Z group. For example, chloroformate is allowed to act on carboxylic acid in the presence of a base, and then ammonia is allowed to act to obtain an amide. The amide is reacted with, for example, phosphorous oxychloride in the presence of a base to obtain a nitrile. For example, sodium azide is allowed to act on the nitrile to convert it into tetrazole. Catalysts (26) to (28) can be obtained by subjecting the obtained compound to catalytic hydrogenation and deprotection.

  In the catalyst represented by the general formula (9-6), a benzyloxycarbonylation reaction reagent such as benzyloxycarbonyl chloride is allowed to act on proline in the presence of a base to protect a nitrogen atom with a Z group. Next, p-nitrophenol is allowed to act in the presence of a condensing agent and a base to lead the carboxylic acid to an ester of p-nitrophenol. In this case, for example, DCC (1,3-dicyclohexylcarbodiimide) or the like is used as the condensing agent, and pyridine is used as the base. The corresponding sulfonic acid amide is allowed to act on this active ester in the presence of a base. At this time, for example, sodium hydride is used as the base. The catalyst represented by the general formula (9-6) can be obtained by performing catalytic hydrogenation on the obtained sulfonic acid amide and deprotecting the Z group.

  As the benzyloxycarbonylation reaction reagent used in the production of the optically active anti-selectivity enhancing catalyst of the present invention, benzylcyanoformate, dibenzyl carbonate, etc. can be used in addition to benzyloxycarbonyl chloride. As a catalyst used also for catalytic hydrogenation, a palladium-carbon catalyst, a palladium hydroxide catalyst, etc. can be used.

  Moreover, in the said manufacturing method, although the benzyloxycarbonyl group (Z group) is used for protection of nitrogen, t-butoxycarbonyl group (Boc group) can be used. As a reagent in this case, di-t-butyl dicarbonate or the like can be used. When the Boc group is used, it can be produced not by catalytic hydrogenation but by deprotection with an acid.

<Optically active anti-aldol compound>
[Aldol reaction between ketone and aldehyde]
In the method for producing an optically active anti-aldol compound of the present invention, the ketone represented by the following general formula (1a) and the aldehyde represented by the following general formula (2a) are increased in fat solubility of proline and proline. It is produced by reacting in the presence of a catalyst (10) selected from a proline derivative consisting of a combination with a substance or a functional group and its enantiomer.

The ketone represented by the general formula (1a) is not particularly limited, and a commonly used ketone can be used. R ¹¹ and R ¹² may be an alkyl group, an alkenyl group, an optionally substituted group, Or it is preferable that it is an alkynyl group. R ¹¹ and R ¹² may be combined to form a ring. In addition, the aldehyde represented by the general formula (2a) is not particularly limited, and a commonly used aldehyde can be used, but R ¹³ may be an aryl group, a heterocycle, an alkyl which may have a substituent. It is preferably a group, an alkenyl group or an alkynyl group.

  Moreover, as a catalyst (10) used for reaction, the optically active anti-selectivity enhancement catalyst mentioned above can be used.

The reaction temperature is −20 ° C. to 50 ° C., the reaction time is 1 hour to 48 hours, and water or an organic solvent that is not a polar solvent is used as the solvent. Organic solvents that are not polar solvents include hexane, CH ₂ Cl ₂ (dichloromethane), AcOEt (ethyl acetate), THF (tetrahydrofuran), toluene, benzene, Et ₂ O (diethyl ether), CHCl ₃ (chloroform), dioxane, DME. (Dimethoxyethane), acetonitrile and the like can be used.

  Moreover, the manufacturing method of the optically active anti-aldol compound of this invention can be made to react without a solvent. By reacting in the absence of a solvent, the reaction can be carried out only with the reactants, which are environmentally friendly and excellent reaction conditions.

[Aldol reaction between aldehyde and aldehyde]
The optically active anti-selectivity enhancing catalyst of the present invention is used for an asymmetric catalytic aldol reaction between an aldehyde and an aldehyde of an aldehyde represented by the following general formula (4a) and an aldehyde represented by the following general formula (5a). Can do.

The aldehyde represented by the general formula (4a) is not particularly limited, and a commonly used aldehyde can be used, but R ¹⁴ is an alkyl group, alkenyl group, or alkynyl group which may have a substituent. It is preferable that In addition, as the aldehyde represented by the general formula (5a) and the catalyst (10), the aldehyde and catalyst described above can be used.

The reaction temperature is -20 ° C to 50 ° C, the reaction time is 1 hour to 48 hours, and water or an organic solvent that is not a polar solvent is used as the solvent. Organic solvents that are not polar solvents include hexane, CH ₂ Cl ₂ (dichloromethane), AcOEt (ethyl acetate), THF (tetrahydrofuran), toluene, benzene, Et ₂ O (diethyl ether), CHCl ₃ (chloroform), dioxane, DME. (Dimethoxyethane), acetonitrile and the like can be used. Moreover, it can also react without a solvent.

[Aldol reaction using proline as catalyst and water as solvent]
Further, using proline as a catalyst and water as a reaction solvent, an aldol reaction between a ketone represented by the following general formula (1b) and an aldehyde represented by the following general formula (2b), and the following general formula ( An optically active anti-aldol compound can be produced by an aldol reaction between the aldehyde represented by 4b) and the aldehyde represented by the following general formula (5b).

  It does not specifically limit as a ketone represented by general formula (1b) used for aldol reaction of a ketone and an aldehyde, The ketone similar to the ketone represented by general formula (1a) can be used. Examples of the ketone represented by the formula (1b) include cyclopentanone, cyclohexanone, and 2,2-dimethyl-1,3-dioxane-5-one.

  Moreover, as the aldehyde represented by the general formula (2b), an aldehyde having an electron attractive group can be used. Examples of the electron withdrawing group include a carboxyl group, a cyano group, an alkoxycarbonyl group, a nitrile group, bromine, chlorine, iodine, and fluorine. Examples of the aldehyde include o-chlorobenzaldehyde, p-fluorobenzaldehyde, p-nitrobenzaldehyde, p-trifluoromethylbenzaldehyde and the like.

  Moreover, it does not specifically limit as an aldehyde represented by General formula (4b) used for the aldol reaction of an aldehyde and an aldehyde, The aldehyde similar to the aldehyde represented by General formula (4a) can be used. Examples of the aldehyde represented by the formula (4b) include propionaldehyde and 3-phenylpropanal.

  Moreover, as the aldehyde represented by the general formula (5b), an aldehyde having an electron attractive group can be used. For example, an aldehyde similar to the above general formula (2b) can be used.

  The proline used for the reaction is preferably used in an amount of 1 mol% to 100 mol%, more preferably 10 mol% to 40 mol%. By performing the reaction within the above range, the catalyst amount and the reaction time are balanced, and the reaction can be carried out efficiently.

  The reaction can be performed at a reaction temperature of −20 ° C. to 50 ° C. for a reaction time of 1 hour to 48 hours.

  Hereinafter, the present invention will be described in more detail with reference to examples.

Example 1: Synthesis of catalyst <Synthesis of (2S, 4R) -4-triisopropylsilyloxy-pyrrolidine-2-carboxylic acid (12)>
To a solution (10 mL) of (2S, 4R) -N-benzyloxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid benzyl ester (3.55 g, 10.0 mmol) in dichloromethane (CH ₂ Cl ₂ ) was added 2,6- Lutidine (1.90 mL, 13.0 mmol) and TIPSOTf (2.96 mL, 13.0 mmol) were added at 0 ° C. The reaction solution was stirred at room temperature for 30 minutes, and then a phosphate buffer solution (pH 7.0) was added and cooled. The organic layer was extracted three times with ethyl acetate (AcOEt), and the extract was dried over sodium sulfate (Na ₂ SO ₄ ), concentrated and purified by column chromatography (ethyl acetate: hexane = 1: 5) (2S , 4R) -N-benzyloxycarbonyl-4-triisopropylsilyloxy-pyrrolidine-2-carboxylic acid benzyl ester (4.8 g, 9.54 mmol, 95%) was obtained.

  (2S, 4R) -N-benzyloxycarbonyl-4-triisopropylsilyloxy-pyrrolidine-2-carboxylic acid benzyl ester (4.8 g, 9.54 mmol) in methanol solution (10 mL) at room temperature at Pd / C ( Palladium carbon) (480 mg, 10 wt%) was added, and the mixture was stirred at room temperature for 20 hours. The inorganic substance was filtered and concentrated to obtain a white powder of (2S, 4R) -4-triisopropylsilyloxy-pyrrolidine-2-carboxylic acid (12) in a yield of 96% (2.8 g).

  (2S, 4R) -N-benzyloxycarbonyl-4-triisopropylsilyloxy-pyrrolidine-2-carboxylic acid benzyl ester was identified by the following NMR, IR and HRMS results.

¹ H NMR (CDCl ₃ ): δ 1.01 (21H, d, J = 4.5Hz), 2.00-2.12 (1H, m), 2.17-2.31 (1H, m), 3.42-3.59 (1H, m), 3.62- 3.76 (1H, m), 4.45-4.60 (2H, m), 4.91-5.26 (4H, m), 7.17-7.37 (10H, m);
¹³ C NMR (CDCl ₃ ): δ 12.4, 18.3, 39.5, 40.4, 55.3, 55.7, 58.5, 58.7, 67.1, 67.3, 67.5, 70.3, 71.0, 128.2, 128.3, 128.4, 128.55, 128.61, 128.65, 128.75, 128.8 , 128.9, 129.0, 135.9, 136.1, 136.9, 137.1, 154.8, 155.5, 172.8, 173.0;
IR (neat): ν 2943, 2866, 1749, 1712, 1458, 1415, 1117, 1022, 883, 696cm ^-1 ;
HRMS (FAB): [M + H] calcd for [C ₂₉ H ₄₂ NO ₅ Si]: 512.2832, found: 512.2809;
[α] _D ²² -35.1 (c = 1.00, CHCl ₃ ).

  (2S, 4R) -4-triisopropylsilyloxy-pyrrolidine-2-carboxylic acid (12) was identified by the following NMR, IR and HRMS results.

¹ H NMR (CDCl ₃ ): δ 0.97-1.05 (21H, m), 2.13 (1H, ddd, J = 12.9, 7.8, 5.4Hz), 2.27 (1H, ddd, J = 12.9, 7.8, 4.1Hz), 3.20 (1H, br-d, J = 9.0Hz), 3.46 (1H, br-s), 4.15 (1H, t, J = 7.8Hz), 4.51 (1H, quintet, J = 4.1Hz);
¹³ C NMR (CDCl ₃ ): δ 11.9, 17.8, 39.2, 52.5, 59.8, 71.0, 173.7;
IR (KBr): ν 3438, 2942, 1624, 1464, 1400, 1389, 1101, 999, 883, 68cm ^-1 ;
HRMS (FAB): [M + H] calcd for [C ₁₄ H ₂₉ NO ₃ Si]: 288.1995, found: 288.2010;
[α] _D ²² -15.9 (c = 1.01, CHCl ₃ ).

<Synthesis of catalyst (16)>
(2S, 4R) -Benzyl-N-benzyloxycarbonyl-4-hydroxypyrrolidine-2-carboxylate (2.34 g, 4.5 mmol) was dissolved in pyridine (9.0 mL) and n-decane at 0 ° C. A catalytic amount of acid chloride (1.37 mL, 6.75 mmol)) and 4-dimethylaminopyridine were added and stirred for 10 minutes, and then stirred at room temperature for 18 hours. The reaction was quenched with saturated aqueous sodium bicarbonate and the aqueous phase was extracted 3 times with ethyl acetate. The organic layer was washed 3 times with a saturated aqueous sodium hydrogen carbonate solution and then washed 3 times with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure and concentrated. Purification by column chromatography (ethyl acetate: hexane = 1: 12) gave 2.06 g (88%) of the desired product. The obtained (2S, 4R) -benzyl-N-benzyloxycarbonyl-4-lauroyloxypyrrolidine-2-carboxylate (2.06 g, 3.93 mmol) was dissolved in ethyl acetate (15.7 mL) and water was added. Palladium oxide (200 mg, 10 wt%) was added, and the mixture was stirred at room temperature in the presence of hydrogen for 15 hours. The mixture was filtered through celite, and the solvent was distilled off under reduced pressure and concentrated to obtain 1.12 g (100%) of the catalyst (16).

  Catalysts (14), (15), (17), (18), and (19) were synthesized in the same manner and identified by the following NMR, IR, and HRMS results.

[NMR, IR, HRMS of catalyst (14)]
¹ H NMR (CDCl ₃ ): δ 0.83 (3H, t, J = 7.0Hz), 1.16-1.31 (4H, m), 1.55 (2H, quint, J = 7.0Hz), 2.18-2.26 (1H, m) , 2.26 (2H, t, J = 7.5Hz), 2.41 (1H, dd, J = 7.4, 13.9Hz), 3.32 (1H, d, J = 13.1Hz), 3.59 (1H, dd, J = 4.5, 13.1 Hz), 4.10 (1H, bt, J = 7.4Hz), 5.29 (1H, bs);
¹³ C NMR (CDCl ₃ ): δ 13.8, 22.2, 24.2, 31.1, 33.9, 35.4, 50.4, 60.0, 72.7, 172.4, 173.2;
IR (KBr): ν2960, 1730, 1624, 1577, 1441, 1419, 1250, 1173, 1038, 640cm ^-1 ;
HRMS (FAB): [M + H] calcd for [C ₁₁ H ₂₀ O ₄ N]: 230.1392, found: 230.1389;
[α] _D ²² -25.1 (c = 0.11, MeOH).

[NMR, IR, HRMS of catalyst (15)]
¹ H NMR (CDCl ₃ ): δ 0.80-0.88 (3H, m), 1.25 (8H, bs), 1.56 (2H, bs), 2.20-2.31 (3H, m), 2.36-2.45 (1H, m), 3.28-3.41 (1H, m), 3.54-3.67 (1H, m), 4.12 (1H, bs), 5.27 (1H, bs);
¹³ C NMR (CDCl ₃ ): δ 14.0, 22.5, 24.6, 28.8, 29.0, 31.5, 33.9, 35.4, 50.2, 59.9, 72.5, 172.7, 173.2;
IR (KBr): ν 2960, 2929, 1736, 1624, 1577, 1441, 1419, 1383, 1227, 1167cm ^-1 ;
HRMS (FAB): [M + H] calcd for [C ₁₃ H ₂₄ O ₄ N]: 258.1705, found: 258.1711;
[α] _D ²² -37.0 (c = 0.09, MeOH).

[NMR, IR, HRMS of catalyst (16)]
¹ H NMR (CD ₃ OD): δ 0.93 (3H, t, J = 6.8Hz), 1.28-1.42 (12H, m), 1.64 (2H, quint, J = 7.0Hz), 2.31 (1H, ddd, J = 4.9, 10.2, 14.5Hz), 2.40 (1H, dt, Jd = 12.6Hz, Jt = 7.5Hz), 2.41 (1H, dt, Jd = 12.6Hz, Jt = 7.5Hz), 2.54 (1H, dd, J = 7.8, 14.5Hz), 3.42 (1H, d, J = 13.0Hz), 3.64 (1H, dd, J = 4.4, 13.0Hz), 4.19 (1H, dd, J = 7.8, 10.2Hz), 5.43 (1H , bt, J = 4.4Hz);
¹³ C NMR (CD ₃ OD): δ 15.3, 24.6, 26.7, 31.0, 31.3, 31.4, 33.9, 35.7, 37.5, 52.8, 62.4, 75.5, 173.8, 175.2;
IR (KBr): ν 2852, 1736, 1620, 1579, 1441, 1417, 1383, 1213, 1165, 640cm ^-1 ;
HRMS (FAB): [M + H] calcd for [C ₁₅ H ₂₈ O ₄ N]: 286.2018, found: 286.2036;
[α] _D ²² -29.4 (c = 0.13, MeOH).

[NMR, IR, HRMS of catalyst (17)]
¹ H NMR (CD ₃ OD): δ 0.93 (3H, t, J = 6.8Hz), 1.24-1.46 (16H, m), 1.66 (2H, J = 6.9Hz), 2.31 (1H, ddd, J = 4.6 , 10.2, 14.4Hz), 2.37 (1H, dt, J _d = 15.5Hz, J _t = 7.3Hz), 2.41 (1H, dt, J _d = 15.5Hz, J _t = 7.3Hz), 2.54 (1H, dd , J = 7.7, 14.4Hz), 3.41 (1H, d, J = 13.1Hz), 3.63 (1H, dd, J = 4.2, 13.1Hz), 4.18 (1H, t, J = 7.7Hz), 5.42 (1H , bs);
¹³ C NMR (CD ₃ OD): δ 15.4, 24.7, 26.8, 31.0, 31.2, 31.4, 31.5, 31.6, 31.7, 34.1, 35.8, 37.6, 53.0, 62.6, 75.7, 174.0, 175.3;
IR (KBr): ν 2920, 2850, 1736, 1616, 1585, 1456, 1417, 1205, 1165, 636cm ^-1 ;
HRMS (FAB): [M + H] calcd for [C ₁₇ H ₃₂ O ₄ N]: 314.2331, found: 314.2307;
[α] _D ²² -17.8 (c = 0.09, MeOH).

[NMR, IR, HRMS of catalyst (18)]
¹ H NMR (CD ₃ OD): δ 0.89-0.99 (3H, m), 1.25-1.46 (20H, m), 1.58-1.70 (2H, m), 2.25-2.34 (1H, m), 2.37 (1H, dt, J _d = 15.6Hz, J _t = 7.4Hz), 2.41 (1H, dt, J _d = 5.6Hz, J _t = 7.4Hz), 2.53 (1H, ddd, J = 1.6, 6.6, 14.4Hz), 3.42 (1H, d, J = 13.1Hz), 3.64 (1H, dd, J = 4.2, 13.1Hz), 4.18 (1H, dt, Jd = 3.1Hz, Jt = 8.4Hz), 5.40-5.45 (1H, m );
¹³ C NMR (CD ₃ OD): δ 15.4, 24.7, 26.8, 31.2, 31.3, 31.4, 31.5, 31.6, 31.72, 31.75, 31.8, 34.1, 35.8, 37.6, 53.0, 62.6, 75.7, 174.0, 175.3;
IR (KBr): ν 2918, 2850, 1736, 1614, 1587, 1456, 1415, 1220, 1165, 636cm ^-1 ;
HRMS (FAB): [M + H] calcd for [C ₁₉ H ₃₆ O ₄ N]: 342.2644, found: 342.2619;
[α] _D ²² -20.8 (c = 0.07, MeOH).

[NMR, IR, HRMS of catalyst (19)]
¹ H NMR (CDCl ₃ ): δ 0.89-0.97 (3H, m), 1.25-1.37 (24H, m), 1.66 (2H, bt, J = 6.5Hz), 2.31 (1H, dddd, 1.8, 4.4, 10.3 , 14.5), 2.34-2.44 (1H, m), 2.53 (1H, ddd, J = 1.2, 7.7, 14.5Hz), 3.40 (1H, d, J = 13.1Hz), 3.63 (1H, dd, J = 4.2 , 13.1Hz), 4.17 (1H, t, J = 8.4Hz), 5.43 (1H, bs);
¹³ C NMR (CD ₃ OD): δ 15.4, 24.7, 26.8, 31.2, 31.4, 31.5, 31.6, 31.72, 31.75, 31.8, 34.1, 35.9, 37.7, 53.0, 62.6, 75.7, 174.0, 175.3;
IR (KBr): ν 2918, 2850, 1736, 1618, 1585, 1441, 1415, 1228, 1167, 721cm ^-1 ;
HRMS (FAB): [M + H] calcd for [C ₂₁ H ₄₀ O ₄ N]: 370.2957, found: 370.2943;
[α] _D ²² -25.9 (c = 0.05, MeOH).

<Synthesis of (2S, 4R) -4- (tert-butyldiphenylsilyloxy) -pyrrolidine-2-carboxylic acid (13)>
To a DMF solution (18 mL) of (2S, 4R) -N-benzyloxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid benzyl ester (3.0 g, 8.4 mmol), 2,6-imidazole (1.14 g, 16.8 mmol) and tert-butyldiphenylsilyloxychloride (TBDPSCl) (3.3 mL, 12.6 mmol) were added at 0 ° C. The reaction solution was stirred at room temperature for 2 hours, and then a phosphate buffer solution (pH 7.0) was added and cooled. The organic layer was extracted three times with ethyl acetate (AcOEt), and the extract was dried over sodium sulfate (Na ₂ SO ₄ ), concentrated and purified by column chromatography (ethyl acetate: hexane = 1: 5) (2S , 4R) -N-benzyloxycarbonyl-4- (tert-butyldiphenylsilyloxy) -pyrrolidine-2-carboxylic acid benzyl ester (5.3 g, 8.4 mmol) was obtained.

  (2S, 4R) -N-benzyloxycarbonyl-4- (tert-butyldiphenylsilyloxy) -pyrrolidine-2-carboxylic acid benzyl ester (5.3 g, 8.4 mmol) in methanol solution (10 mL) at room temperature, Pd / C (530 mg, 10 wt%) was added and stirred at room temperature for 20 hours. The inorganic substance was filtered and concentrated to obtain a white powder of (2S, 4R) -4- (tert-butyldiphenylsilyloxy) -pyrrolidine-2-carboxylic acid (13) in a yield of 3.1 g.

Catalyst (20) ((2R, 4R) -4- (tert-butyldiphenylsilyloxy) -pyrrolidine-2-carboxylic acid) was synthesized by the same method as for catalyst (13), and the following physical properties, NMR, IR, It identified by the result of HRMS.
Colorless solid; mp: 145-146 ° C; ¹ H NMR (400MHz, CDCl ₃ ): 1.00 (9H, s), 2.17-2.29 (1H, m), 2.36 (1H, bd, J = 13.0Hz), 3.21 ( 1H, d, J = 11.6Hz), 3.24 (1H, dd, J = 2.7, 11.6Hz), 4.20 (1H, bd, J = 5.3Hz), 4.39 (1H, bs), 7.32-7.43 (6H, m ), 7.61 (4H, d, J = 5.0 Hz); ¹³ C NMR (100 MHz, CDCl ₃ ): 18.9, 26.6, 38.0, 53.0, 59.2, 71.7, 127.8, 127.9, 130.0, 132.6, 133.0, 135.6, 135.7, 173.2; IR (neat): 3437, 2931, 1589, 1427, 1392, 1319, 1113, 1092, 702, 507cm ^-1 ; HRMS (FAB): [M + H] ⁺ calcd for C ₂₁ H ₂₈ NO ₃ Si 370.1838 , found 370.1858; [α] _D ²² +9.2 (c 1.0, CHCl ₃ ).

  Further, (2R, 4R) -4-hydroxypyrrolidine-1,2-dicarboxylic acid dibenzyl ester, which is an intermediate of catalyst (20), and (2R, 4R) -4- (tert-butyldiphenylsilyloxy) -Pyrrolidine-1,2-dicarboxylic acid dibenzyl ester was identified by the following NMR, IR and HRMS results.

[NMR, IR, HRMS of (2R, 4R) -4-hydroxypyrrolidine-1,2-dicarboxylic acid dibenzyl ester]
A mixture of two conformers; Colorless liquid; ¹ H NMR (400MHz, CDCl ₃ ): δ 2.06 (1H, t, J = 12.5Hz), 2.17-2.32 (1H, m), 3.16 and 3.20 (1H, d x2, J = 7.9Hz, 8.4Hz), 3.51-3.69 (2H, m), 4.25-4.33 (1H, m), 4.37 and 4.43 (1H, d x2, J = 9.0Hz, 8.7Hz), 4.94-5.25 (4H , m), 7.15-7.34 (10H, m); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 37.8, 38.6, 55.5, 55.9, 57.8, 58.2, 67.2, 67.3, 67.4, 70.0, 70.9, 127.78, 127.82, 127.97, 128.0, 128.1, 128.2, 128.31, 128.37, 128.42, 128.5, 135.0, 135.2, 136.2, 136.3, 154.2, 154.9, 174.0, 174.1; IR (neat): 3442, 1749, 1705, 1456, 1417, 1352, 1194 , 1088, 966, 698 cm ^-1 ; HRMS (FAB): [M + H] ⁺ calcd for C ₂₀ H ₂₂ NO ₅ 356.1498, found 356.1470; [α] _D ²² +15.9 (c 0.57, CHCl ₃ ).

[NMR, IR, HRMS of (2R, 4R) -4- (tert-butyldiphenylsilyloxy) -pyrrolidine-1,2-dicarboxylic acid dibenzyl ester]
A mixture of two conformers; Colorless liquid; ¹ H NMR (400MHz, CDCl ₃ ): δ 0.941 and 0.946 (9H, s), 2.02-2.22 (2H, m), 3.39 and 3.42 (1H, dd x2, J = 11.3 , 5.1Hz, 11.3, 3.2Hz), 3.46-3.52 (1H, m), 4.20-4.28 (1H, m), 4.32 and 4.41 (1H, dd x2, J = 8.7, 4.1Hz, 8.7, 3.7Hz), 4.87-5.15 (4H, m), 7.13-7.38 (16H, m), 7.53 (4H, d, J = 7.1Hz); ¹³ C NMR (100MHz, CDCl ₃ ): 19.0, 26.7, 38.3, 39.2, 54.4, 54.8, 57.8, 58.0, 66.8, 66.9, 67.0, 67.1, 70.7, 71.6, 127.69, 127.75, 127.81, 127.87, 128.00, 128.04, 128.1, 128.2, 128.35, 128.40, 128.48, 128.50, 129.8, 135.66, 135.68, 154.4, 154.8, 171.3, 171.6; IR (neat): 2952, 2933, 1757, 1712, 1427, 1356, 1163, 1089, 1022, 700cm ^-1 ; HRMS (FAB): [M + H] ⁺ calcd for C ₃₆ H ₄₀ NO ₅ Si 594.2676, found 594.2650; [α] _D ²² +25.8 (c 0.76, CHCl ₃ ).

Catalyst (21) ((2S, 3S) -3- (tert-butyldiphenylsilyloxy) -pyrrolidine-2-carboxylic acid) was synthesized by the same method as for catalyst (13), and the following physical properties, NMR, IR, It identified by the result of HRMS.
Colorless solid; mp: 164-165 ° C; ¹ H NMR (400MHz, CDCl ₃ : CD ₃ OD = 10: 1): 1.01 (9H, s), 1.56-1.71 (2H, m), 3.27-3.47 (2H, m), 3.95 (1H, s), 4.79 (1H, s), 7.26-7.42 (6H, m), 7.55 (2H, bd, J = 7.6Hz) 7.60 (2H, bd, J = 7.4Hz); ¹³ C NMR (150MHz, CDCl ₃ : CD ₃ OD = 10: 1): 19.0, 26.7, 32.4, 44.0, 69.9, 76.2, 127.82, 127.87, 130.01, 130.03, 132.5, 133.2, 135.6, 135.7, 169.5; IR (neat ): 3477, 2958, 2856, 1635, 1568, 1427, 1367, 1110, 704, 609cm ^-1 ; HRMS (FAB): [M + H] ⁺ calcd for C ₂₁ H ₂₈ NO ₃ Si 370.1838, found 370.1809; [ α] _D ²³ +13.5 (c 1.0, MeOH).

  Further, (2S, 3S) -3-hydroxypyrrolidine-1,2-dicarboxylic acid dibenzyl ester which is an intermediate of catalyst (21), and (2S, 3S) -3- (tert-butyldiphenylsilyloxy) -Pyrrolidine-1,2-dicarboxylic acid dibenzyl ester was identified by the following NMR, IR and HRMS results.

[NMR, IR, HRMS of (2S, 3S) -3-hydroxypyrrolidine-1,2-dicarboxylic acid dibenzyl ester]
A mixture of two conformers; Colorless liquid; ¹ H NMR (400MHz, CDCl ₃ ): dδ 1.84-1.96 (1H, m), 2.00-2.13 (2H, m), 3.55-3.76 (2H, m), 4.31 and 4.40 (1H, s), 4.43 (1H, bs), 4.95-5.23 (4H, m), 7.15-7.39 (10H, m); ¹³ C NMR (150 MHz, CDCl ₃ ): δ 32.0, 32.6, 44.4, 44.8, 67.0, 67.1, 67.18, 67.20, 67.9, 68.3, 74.1, 75.2, 127.7, 127.87, 127.93, 128.0, 128.1, 128.2, 128.4, 128.5, 128.6, 135.2, 135.3, 136.4, 136.5, 154.4, 155.1, 170.2, 170.4; IR (neat): 3435, 1747, 1712, 1456, 1417, 1352, 1167, 1095, 914, 698cm ^-1 ; HRMS (FAB): [M + H] ⁺ calcd for C ₂₀ H ₂₂ NO ₅ 356.1498, found 356.1506 ; [α] _D ²¹ -26.7 (c 1.04, CHCl ₃ ).

[NMR, IR, HRMS of (2S, 3S) -3- (tert-butyldiphenylsilyloxy) -pyrrolidine-1,2-dicarboxylic acid dibenzyl ester]
A mixture of two conformers; Colorless liquid; ¹ H NMR (400MHz, CDCl ₃ ): δ 0.95-1.09 (9H, m), 1.71-1.87 (2H, m), 3.61-3.79 (2H, m), 4.31-4.50 (2H, m), 4.81-5.23 (4H, m), 7.13-7.43 (16H, m), 7.53-7.63 (4H, m); ¹³ C NMR (150MHz, CDCl ₃ ): 19.1, 26.77, 26.81, 32.5 , 33.3, 44.8, 45.1, 66.8, 66.9, 67.0, 67.1, 68.0, 68.4, 75.5, 76.5, 127.6, 127.78, 127.80, 127.81, 127.85, 127.96, 128.00, 128.03, 128.1, 128.2, 128.4, 128.48, 128.50, 129.9 , 130.0, 132.7, 132.9, 133.1, 133.3, 135.3, 135.4, 135.66, 135.69, 136.6, 136.7, 154.5, 155.1, 170.3, 170.4; IR (neat): 2956, 2858, 1747, 1714, 1417, 1348, 1165, 1059, 822, 700cm ^-1 ; HRMS (FAB): [M + H] ⁺ calcd for C ₃₆ H ₄₀ NO ₅ Si 594.2676, found 594.2715; [α] _D ²² -6.4 (c 1.0, CHCl ₃ ).

<Synthesis of (2R, 4R) -4- (tert-butyldiphenylsilyloxy) -2- (1H-tetrazol-5-yl) -pyrrolidine (28)>
(Synthesis of (2R, 4R) -1-benzyloxycarbonyl-4- (tert-butyldiphenylsilyloxy) -pyrrolidine-2-carboxamide)
(2R, 4R) -1-benzyloxycarbonyl-4- (tert-butyldiphenylsilyloxy) -pyrrolidine-2-carboxylic acid (6.87 g, 13.6 mmol) was dissolved in THF (27.2 ml), − After adding methyl chloroformate (1.04 ml, 13.2 mmol) and triethylamine (1.9 ml, 13.6 mmol) at 10 ° C. and stirring for 10 minutes, liquid ammonia was added and the mixture was stirred at −10 ° C. for 1 hour. The reaction is stopped with phosphate buffer solution and the aqueous phase is extracted three times with ethyl acetate. The organic layer was washed once with 1N-hydrochloric acid and then washed once with 1N-sodium bicarbonate solution. Thereafter, the extract was washed once with a saturated saline solution, and the organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was distilled off under reduced pressure and concentrated. 4.87 g of (2R, 4R) -1-benzyloxycarbonyl-4- (tert-butyldiphenylsilyloxy) -pyrrolidine-2-carboxamide was purified by column chromatography (ethyl acetate: hexane = 1: 3). (71%) obtained. (2R, 4R) -1-benzyloxycarbonyl-4- (tert-butyldiphenylsilyloxy) -pyrrolidine-2-carboxamide was identified by the following NMR and IR results.

A mixture of comformers; ¹ H NMR (CDCl ₃ ): δ 1.00 (9H, s), 2.06-2.20 (1H, m), 2.21-2.35 (1H, m), 3.24-3.42 (1H, m), 3.45- 3.62 (1H, m), 4.32-4.55 (2H, m), 5.05-5.40 (3H, m), 7.26-7.44 (11H, m), 7.54-7.62 (4H, m);
IR (KBr): ν 2932, 2857, 1696, 1682, 1427, 1359, 1113, 1022, 702, 509 cm ^-1 ;

(Synthesis of (2R, 4R) -1-benzyloxycarbonyl-4- (tert-butyldiphenylsilyloxy) -2-cyanopyrrolidine)
(2R, 4R) -1-benzyloxycarbonyl-4- (tert-butyldiphenylsilyloxy) -pyrrolidine-2-carboxamide (3.7 g, 7.36 mmol) was dissolved in pyridine (4.1 ml) and −10 A solution of phosphonyl chloride (0.82 ml, 8.83 mmol) in dichloromethane (3.3 ml) was added dropwise at 10 ° C. over 10 minutes. After stirring for 3 hours, the reaction was quenched with phosphate buffer solution and the aqueous phase was extracted three times with ethyl acetate. The organic layer was washed 3 times with a saturated aqueous copper sulfate solution and then washed 3 times with a saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure and concentrated. 2.2 g (2R, 4R) -1-benzyloxycarbonyl-4- (tert-butyldiphenylsilyloxy) -2-cyanopyrrolidine was purified by column chromatography (ethyl acetate: hexane = 1: 6). 62%). (2R, 4R) -1-benzyloxycarbonyl-4- (tert-butyldiphenylsilyloxy) -2-cyanopyrrolidine was identified by the following NMR and IR results.

A mixture of comformers; ¹ H NMR (CDCl ₃ ): δ 1.00 (9H, s), 2.09-2.20 (1H, m), 2.23-2.36 (1H, m), 3.32 and 3.39 (1H, ddx2, J = 4.2 , 11.2Hz), 3.44 and 3.57 (1H, dx2, J = 10.8Hz), 4.44 (1H, bs), 4.62 and 4.70 (1H, tx2, J = 7.3Hz), 5.09-5.28 (2H, m), 7.26 -7.47 (11H, m), 7.57 (4H, dd, J = 7.3, 14.5Hz);
IR (KBr): ν 2932, 2858, 1714, 1410, 1357, 1171, 1114, 1021, 702, 508 cm ^-1 ;

((2R, 4R) -1-benzyloxycarbonyl-4- (tert-butyldiphenylsilyloxy) -2- (1H-tetrazol-5-yl) -pyrrolidine)
(2R, 4R) -1-Benzyloxycarbonyl-4- (tert-butyldiphenylsilyloxy) -2-cyanopyrrolidine (1.94 g, 4.0 mmol) was dissolved in DMF (2.4 ml) and sodium azide. A solution of (273 mg, 4.2 mmol) in ammonium chloride (236 mg, 4.4 mmol) was added and stirred at 92 ° C. for 12 hours. Thereafter, the reaction was stopped with a phosphate buffer solution, and 1N hydrochloric acid was added until the pH reached 2. The aqueous phase was extracted three times with chloroform, and the organic layer was washed once with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure and concentrated. By purification by column chromatography (ethyl acetate: hexane = 1: 3), (2R, 4R) -1-benzyloxycarbonyl-4- (tert-butyldiphenylsilyloxy) -2- (1H-tetrazole-5- Yl) -pyrrolidine 1.70 g (81%) was obtained. (2R, 4R) -1-benzyloxycarbonyl-4- (tert-butyldiphenylsilyloxy) -2- (1H-tetrazol-5-yl) -pyrrolidine was identified by the following NMR and IR results.

A mixture of comformers; ¹ H NMR (CDCl ₃ ): δ 1.03 (9H, s), 2.43-2.55 (1H, m), 2.79 (1H, ddd, J = 4.5, 8.1, 12.5Hz), 3.25 (1H, dd, J = 3.7, 11.5Hz), 3.60 (1H, d, J = 11.5Hz), 4.56 (1H, bs), 5.10 and 5.21 (1H, dx2, J = 12.3Hz), 5.30 (1H, t, J = 7.7Hz), 7.25-7.47 (11H, m), 7.59 (4H, dd, J = 7.6, 12.6Hz);
IR (KBr): ν 2927, 2852, 2360, 1705, 1418, 1357, 1112, 1022, 701, 511 cm ^-1 ;

((2R, 4R) -4- (tert-butyldiphenylsilyloxy) -2- (1H-tetrazol-5-yl) -pyrrolidine)
(2R, 4R) -1-benzyloxycarbonyl-4- (tert-butyldiphenylsilyloxy) -2- (1H-tetrazol-5-yl) -pyrrolidine (54.8 mg, 0.1 mmol) was added to acetic acid (0. 9 ml) and water (0.1 ml), 10% palladium carbon (5.5 mg, 10 wt%) was added, and the mixture was stirred at room temperature in the presence of hydrogen for 8 hours. The mixture was filtered through Celite, and the solvent was distilled off under reduced pressure and concentrated. The obtained residue was purified by thin layer chromatography to obtain 17.1 mg (2R, 4R) -4- (tert-butyldiphenylsilyloxy) -2- (1H-tetrazol-5-yl) -pyrrolidine ( 43%). (2R, 4R) -4- (tert-butyldiphenylsilyloxy) -2- (1H-tetrazol-5-yl) -pyrrolidine was identified by the following NMR and IR results.

¹ H NMR (CDCl ₃ ): δ 0.96 (9H, s), 2.24-2.52 (2H, m), 3.47 (2H, J = 12,0Hz), 4.68 (1H, bs), 5.29 (1H, t, J = 8.7Hz), 7.26-7.43 (6H, m), 7.57 (4H, d, J = 6.9Hz);
¹³ C NMR (CDCl ₃ ): δ 18.9, 26.7, 39.3, 53.1, 53.6, 71.9, 127.98, 127.99, 130.2, 132.6, 132.7, 135.6, 135.64, 156.6;
IR (KBr): ν 2932, 2858, 1710, 1427, 1357, 1112, 1008, 822, 703, 507 cm ^-1 ;
HRMS (FAB): [M + Na] calcd for [C ₂₁ H ₂₇ N ₅ NaOSi]: 416.1877, found: 416.1881;
[α] _D ²² -8.2 (c = 1.00, MeOH).

<Synthesis of (2R) -octane-1-sulfonic acid (pyrrolidine-2-carbonyl) amide (33)>
(Synthesis of (2R)-(octane-1-sulfonylaminocarbonyl) -pyrrolidine-1-carboxylic acid benzyl ester)
Octane-1-sulfonic acid amide (650.7 mg, 3.37 mmol) is dissolved in dimethylformamide (17 ml), sodium hydride (403 mg, 60 wt%) and pyrrolidine-1,2-dicarboxylic acid-benzyl ester 2- (4-Nitro-phenyl) ester was added and stirred at room temperature for 5 hours. After stopping the reaction by adding water, citric acid was added until the pH reached 3. The aqueous phase was extracted three times with ethyl acetate, and the organic layer was washed once with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure and concentrated. By purifying by column chromatography (ethyl acetate: hexane = 1: 3), 909 mg (64%) of 2R- (octane-1-sulfonylaminocarbonyl) -pyrrolidine-1-carboxylic acid benzyl ester was obtained. 2R- (octane-1-sulfonylaminocarbonyl) -pyrrolidine-1-carboxylic acid benzyl ester was identified by the following NMR, IR and HRMS results.

¹ H NMR (CDCl ₃ ): δ 0.86 (3H, t, J = 7.0Hz), 1.15-1.42 (11H, m), 1.58-2.03 (5H, m), 2.36 (1H, bs), 3.03-3.60 ( 4H, m), 4.31 (1H, bs), 5.14 (2H, q, J = 12.0), 7.25-7.40 (5H, m);
¹³ C NMR (CDCl ₃ ): δ 14.1, 22.6, 23.3, 24.4, 25.3, 28.2, 29.0, 29.1, 31.7, 34.7, 47.1, 53.2, 61.7, 67.9, 128.0, 128.2, 128.6, 136.0, 156.8;
IR (KBr): ν 2925, 1685, 1584, 1456, 1422, 1358, 1124, 1088, 767, 697 cm ^-1 ;
HRMS (FAB): [M + Na] calcd for [C ₂₁ H ₃₂ N ₂ NaO ₅ S]: 447.1924, found: 447.1917;
[α] _D ²² -132.4 (c = 0.95, CHCl ₃ ).

(Synthesis of (2R) -octane-1-sulfonic acid (pyrrolidine-2-carbonyl) amide)
The obtained (2R)-(octane-1-sulfonylaminocarbonyl) -pyrrolidine-1-carboxylic acid benzyl ester (829 mg, 1.95 mmol) was dissolved in methanol (3.9 ml), and 10% palladium carbon (83 mg, 83 mg, 10 wt%) and stirred at room temperature in the presence of hydrogen for 20 hours. The reaction mixture was filtered through Celite, and the solvent was distilled off under reduced pressure. (2R) -octane-1-sulfonic acid (pyrrolidine-2-carbonyl) amide was identified by the following NMR, IR and HRMS results.

¹ H NMR (CDCl ₃ ): δ 0.86 (3H, t, J = 7.0Hz), 1.15-1.32 (8H, m), 1.36 (2H, t, J = 6.4Hz), 1.68-1.82 (2H, m) , 1.88-2.12 (3H, m), 2.35 (1H, dt, J = 4.5, 8.1Hz), 3.03 (2H, J = 3.2, 5.4Hz), 3.32 (1H, t, J = 7.0, 14.1Hz), 3.51-3.68 (1H, m), 4.19 (1H, t, J = 7.9Hz);
¹³ C NMR (CDCl ₃ ): δ 14.1, 22.6, 23.7, 24.6, 28.5, 29.1, 29.2, 30.2, 31.8, 46.8, 52.9, 62.6, 173.9;
IR (KBr): ν 3122, 2923, 2853, 1616, 1597, 1564, 1389, 1277, 1125, 854 cm ^-1 ;
HRMS (FAB): [M + Na] calcd for [C ₁₃ H ₂₆ N ₂ NaO ₃ S]: 313.1556, found: 313.1545;
[α] _D ²² -32.2 (c = 1.00, MeOH).

<Synthesis of (2R) -dodecane-1-sulfonic acid (pyrrolidine-2-carbonyl) amide (34)>
(2R)-(Dodecane-1-sulfonylaminocarbonyl) -pyrrolidine-1-carboxylic acid benzyl ester is the same method as (2R)-(octane-1-sulfonylaminocarbonyl) -pyrrolidine-1-carboxylic acid benzyl ester Was synthesized. 2R- (dodecane-1-sulfonylaminocarbonyl) -pyrrolidine-1-carboxylic acid benzyl ester was identified by the following NMR, IR and HRMS results.

¹ H NMR (CDCl ₃ ): δ 0.86 (3H, t, J = 6.8Hz), 1.18-1.42 (19H, m), 1.48-2.00 (5H, m), 2.43 (1H, bs), 3.00-3.62 ( 4H, m), 4.34 (1H, bs), 5.08-5.22 (2H, m), 7.27-7.42 (5H, m);
¹³ C NMR (CDCl ₃ ): δ 14.1, 22.7, 23.0, 24.5, 27.0, 28.0, 29.0, 29.3, 29.33, 29.5, 29.6, 31.9, 47.3, 53.2, 60.9, 68.2, 128.2, 128.5, 128.7, 135.8, 157.1 ;
IR (KBr): ν 2923, 2852, 2360, 1699, 1457, 1422, 1357, 1338, 1125, 697 cm ^-1 ;
HRMS (FAB): [M + Na] calcd for [C ₂₅ H ₄₀ N ₂ NaO ₅ S]: 503.2550, found: 503.2542;
[α] _D ²² -83.4 (c = 0.95, CHCl ₃ ).

  (2R) -dodecane-1-sulfonic acid (pyrrolidine-2-carbonyl) amide was synthesized by the same method as (2R) -octane-1-sulfonic acid (pyrrolidine-2-carbonyl) amide. (2R) -dodecane-1-sulfonic acid (pyrrolidine-2-carbonyl) amide was identified by the following NMR, IR and HRMS results.

¹ H NMR (CDCl ₃ ): δ 0.86 (3H, t, J = 6.8Hz), 1.18-1.32 (16H, m), 1.32-1.37 (2H, m), 1.68-1.84 (2H, m), 1.88- 2.12 (3H, m), 2.28-2.43 (1H, m), 2.94-3.15 (2H, m), 3.26-3.40 (1H, m), 3.48-3.63 (1H, m), 4.16 (1H, t, J = 7.2Hz);
¹³ C NMR (CDCl ₃ ): δ 14.1, 22.7, 23.7, 24.5, 28.5, 29.3, 29.31, 29.4, 29.55, 29.6, 30.1, 31.9, 46.5, 52.8, 62.6, 174.0;
IR (KBr): ν 3124, 2917, 2850, 1597, 1562, 1471, 1387, 1279, 1126, 534 cm ^-1 ;
HRMS (FAB): [M + Na] calcd for [C ₁₇ H ₃₄ N ₂ NaO ₃ S]: 369.2182, found: 369.2174;
[α] _D ²² -61.6 (c = 1.00, CHCl ₃ ).

Example 2: Synthesis of optically active anti-aldol compound <Synthesis of 2- (hydroxyphenylmethyl) cyclohexane-1-one (Table 1: entry 7)>
Suspension of benzaldehyde (40.6 μL, 0.4 mmol) and cyclohexanone (207 μL, 2.0 mmol) in catalyst (15) (14.8 mg, 0.04 mmol) in water (0.13 mL) at room temperature Added to. The reaction was stirred at room temperature for 18 hours, after which a phosphate buffer (pH 7.0) was added and cooled. The organic layer was extracted three times with ethyl acetate, and the extract was dried over anhydrous sodium sulfate (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification by silica gel column chromatography (ethyl acetate: hexane = 1: 10 to 1: 3) gave a liquid of 2- (hydroxyphenylmethyl) -cyclohexanone (63.7 mg, 78%).
Anti-form: Syn-form = 13: 1 (by ¹ H NMR spectroscopy of the crude mixture),> 99% ee (by HPLC on a chiralcel OD-H column, λ = 213 nm, iPrOH / hexane = 1/100, 1.0 mlmin ^-1 ; t _R = 19.4min (major), 25.9min (minor)).

  (2S, 1'R) -2- (hydroxyphenylmethyl) cyclohexane-1-one (Table 2: entry1)

[α] _D ¹⁴ +27.7 (c = 0.85, CHCl ₃ ),> 99% ee.
Lit. [α] _D ²⁴ -24.2 (c = 1.03, CHCl ₃ ). (93% ee, (2R, 1'S) -2- (Hydroxyphenylmethyl) -cyclohexanone).
Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column (100: 1 hexane: 2-propanol), 1.0mL / min; major enantiomer tr = 19.4min, minor enantiomer tr = 25.9min.

  (2S, 1'R) -2- (hydroxynaphthalen-2-ylmethyl) cyclohexane-1-one (Table 2: entry 5) was identified by the following NMR, IR, HRMS and HPLC results.

¹ H NMR (CDCl ₃ ): δ 1.23-1.40 (1H, m), 1.42-1.61 (2H, m), 1.62-1.79 (2H, m), 2.07 (1H, ddd, J = 13.2, 6.6, 3.2Hz ), 2.36 (1H, td, J = 13.2, 5.8Hz), 2.49 (1H, br-d, J = 13.8Hz), 2.64-2.74 (1H, m), 4.02 (1H, br-s), 4.95 ( 1H, d, J = 8.6Hz), 7.41-7.50 (3H, m), 7.73 (1H, s), 7.77-7.86 (3H, m);
¹³ C NMR (CDCl ₃ ): δ 24.6, 27.7, 30.8, 42.6, 57.3, 74.8, 124.6, 125.9, 126.1, 126.2, 127.6, 127.9, 128.2, 133.0, 133.1, 138.2, 215.5;
IR (KBr): ν 3354, 3055, 2933, 2854, 1695, 1444, 1309, 1122, 1057, 833cm ^-1 ;
HRMS (FAB): calcd for [C ₁₇ H ₁₈ O ₂ ]: 254.1307, found: 254.1311;
[α] _D ²² +7.4 (c = 1.07, CHCl ₃ ), (mixture of diastereomers, anti: syn = 19: 1, 97% ee for anti-isomer.)
Enantiomeric excess was determined by HPLC with a Chiralpak AS-H column (50: 1 hexane: 2-propanol), 1.0mL / min; major enantiomer tr = 17.6min, minor enantiomer tr = 20.5min.

  (2S, 1'R) -2- (hydroxypyridin-4-ylmethyl) cyclohexane-1-one (Table 2: entry 7) was identified by the following NMR, IR, HRMS and HPLC results.

¹ H NMR (CDCl ₃ ): δ 1.38 (1H, qd, J = 12.8, 3.8Hz), 1.47-1.73 (3H, m), 1.77-1.86 (1H, m), 2.04-2.14 (1H, m), 2.34 (1H, td, J = 13.3, 6.2Hz), 2.42-2.50 (1H, m), 2.56 (1H, ddd, J = 13.5, 8.2, 3.5Hz), 3.97 (1H, br-s), 4.75 ( 1H, d, J = 8.2Hz), 7.23 (2H, d, J = 5.7Hz), 8.56 (2H, d, J = 5.7Hz);
¹³ C NMR (CDCl ₃ ): δ 24.6, 27.7, 30.7, 42.6, 56.8, 73.5, 122.0, 149.7, 149.8, 214.7;
IR (KBr): ν 3140, 2860, 2738, 1711, 1606, 1415, 1300, 1128, 1047, 835cm ^-1 ;
HRMS (FAB): [M + H] calcd for [C ₁₂ H ₁₆ NO ₂ ]: 206.1181, found: 206.1177;
[α] _D ²¹ +15.8 (c = 1.02, CHCl ₃ ) (mixture of diastereomers, anti: syn = 12: 1, 95% ee for anti-isomer.)
Enantiomeric excess was determined by HPLC with a Chiralpak AD-H column (10: 1 hexane: 2-propanol), 1.0mL / min; major enantiomer tr = 22.5min, minor enantiomer tr = 20.7min.

  Test Example 1: Asymmetric catalytic aldol reaction using water as a reaction solvent

  Asymmetric aldol reaction between cyclohexanone and benzaldehyde was carried out using catalysts (11) to (16), (18) and (19). The results are shown in Table 1. When proline was used as a catalyst, the reaction did not proceed at all. When the catalysts (11) to (16), (18) and (19) are used, the reaction using water proceeds, the yield is 60% or more, high anti-selectivity, and extremely high asymmetric yield. The aldol product was obtained at a high rate. As the catalyst, in any of (11) to (16), (18) and (19), although the yield was slightly different, the reaction proceeded in substantially the same manner, and a very high asymmetric yield was obtained. The amount of water did not affect the reaction.

  Using the catalyst (13), water was used as a solvent, and various ketones and aldehydes were reacted at room temperature. The results are shown in Table 2. It was confirmed that the product was obtained anti-selectively and the asymmetric yield was very high.

  Test Example 2: Examination of various organic solvents

  As a synthesis example, a synthesis method in the case of using ethyl acetate (AcOEt) as a solvent is shown (entry 9). (2S, 4R) -4- (tert-butyldiphenylsilyloxy) -pyrrolidine-2-carboxylic acid (13) (18.5 mg, 0.05 mmol) was added to ethyl acetate (AcOEt) (0.4 mL) and water (45 μl). , 2.5 mmol). To this solution were added cyclohexanone (259 μl, 2.5 mmol) and benzaldehyde (50.8 μl, 0.5 mmol), and the mixture was stirred at room temperature for 18 hours. Thereafter, a phosphate buffer (pH = 7.0) was added to stop the reaction, and the organic matter was extracted three times with ethyl acetate and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was filtered and the solvent was distilled off under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate / hexane = 1 / 10-1 / 3) to give 2- (hydroxyphenylmethyl) cyclohexane-1 -On (49.9 mg, 0.244 mmol) was obtained as a diastereomeric mixture (anti: syn = 9.5: 1) in 49% yield.

  Other solvents were synthesized in the same manner as in the above synthesis method except that the solvent was changed from ethyl acetate to the solvent shown in Table 3. In addition, in a system that does not use dimethyl sulfoxide (DMSO) and an organic solvent, a system in which water was not added was also synthesized (entries 3, 11). The results are shown in Table 3.

  In entries 3 and 11 where water was not added, the selectivity of anti: cin was low, but adducts were obtained with high selectivity by adding water. Moreover, aldol body was able to be obtained with the high asymmetric yield with the yield of 40% or more using which solvent.

  Test Example 3: Aldol-catalyzed aldol reaction between aldehyde and aldehyde using water as a reaction solvent (catalyst study)

  As a synthesis example, a synthesis method using the catalyst (16) is shown (Table 4: entry 9). To a mixture of (2S, 4R) -4-decanoyloxypyrrolidine-2-carboxylic acid (16) (11 mg, 0.04 mmol), water (130 μL) and o-chlorobenzaldehyde (45 μL, 0.4 mmol) was added at 0 ° C. Below, propanal (144 μL, 2.0 mmol) was added. After stirring at room temperature for 24 hours, methanol (2 mL) and sodium borohydride (151 mg, 4 mmol) were added to the reaction solution, and the mixture was stirred at 0 ° C. for 1 hour. The reaction was stopped with a phosphate buffer at pH 7.0, and extracted three times with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate and filtered, and then the solvent was distilled off under reduced pressure. The residue was purified by thin layer chromatography (diethyl ether: benzene = 2: 1) to give (1R, 2R) -1- (o-chlorophenyl) -2-methylpropane-1,3-diol (47 0.8 mg, 0.24 mmol) was obtained as a mixture of diastereomers (anti: syn = 20: 1) with a yield of 60%.

  Other catalysts were synthesized in the same manner as described above except that the catalyst was changed to the catalyst shown in Table 4. In addition, entries 14, 15, 16, and 20 reacted for 70 hours. The results are shown in Table 4.

ｂ：単離した収率。
ｃ：^１Ｈ−ＮＭＲにより決定した。
ｄ：アンチ体の光学収率を示す。ベンゾイルエステルに変換した後、キラルなカラムを用いたＨＰＬＣ分析により決定した。

b: Isolated yield.
c: Determined by ¹ H-NMR.
d: Indicates the optical yield of the anti-isomer. After conversion to the benzoyl ester, it was determined by HPLC analysis using a chiral column.

  In the proline derivative (36) having proline, hydroxyproline (35), and tetrazole, the reaction did not proceed. On the other hand, the catalysts (11) to (13), which were siloxyproline, had activity. . Further, the catalysts (14) to (19) having a long-chain fatty acid moiety in the side chain also had activity.

  Catalysts (16) and (30) were used, water was used as a solvent, and aldol reactions of various aldehydes with aldehydes were performed at 0 ° C. As the catalyst, 10 mol% of the aldehyde used as an electrophile was added. In addition, about entries 14 and 15, it reacted at room temperature. The results are shown in Tables 5 and 6. It was confirmed that the product was obtained anti-selectively and the asymmetric yield was very high.

As a synthesis example, the synthesis method of the following compounds is shown.
(Method for synthesizing (2R, 3R) -1- (o-chlorophenyl) -2-methylpropane-1,3-diol (Table 5: entry1))
To a mixture of (2S, 4R) -4-decanoyloxypyrrolidine-2-carboxylic acid (16) (11.4 mg, 0.04 mmol), water (130 μL) and o-chlorobenzaldehyde (45 μL, 0.4 mmol), Propanal (144 μL, 2.0 mmol) was added at 0 ° C. After stirring at room temperature for 70 hours, methanol (2 mL) and sodium borohydride (151 mg, 4 mmol) were added to the reaction solution, followed by stirring at 0 ° C. for 1 hour. The reaction was stopped with a phosphate buffer at pH 7.0, and extracted three times with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate and filtered, and then the solvent was distilled off under reduced pressure. The residue was purified by thin layer chromatography (ethyl acetate: hexane = 1: 1) to give (2R, 3R) -1- (o-chlorophenyl) -2-methylpropane-1,3-diol (73 .6 mg, 0.37 mmol) was obtained as a diastereomeric mixture (anti: syn = 18: 1) in 92% yield.

(Method for synthesizing (1R, 2R) -1-phenyl-2-methylpropane-1,3-diol (Table 5: entry 6))
To a mixture of (2S, 4R) -4-decanoyloxypyrrolidine-2-carboxylic acid (16) (11 mg, 0.04 mmol), water (130 μL) and benzaldehyde (41 μL, 0.4 mmol) at 0 ° C. Panal (144 μL, 2.0 mmol) was added. After stirring at room temperature for 72 hours, methanol (2 mL) and sodium borohydride (151 mg, 4 mmol) were added to the reaction mixture, and the mixture was stirred at 0 ° C. for 1 hour. The reaction was stopped with a phosphate buffer at pH 7.0, and extracted three times with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate and filtered, and then the solvent was distilled off under reduced pressure. The residue was purified by thin-layer chromatography (diethyl ether: benzene = 2: 1) to give (1R, 2R) -1-phenyl-2-methylpropane-1,3-diol ( 59 mg, 0.35 mmol) was obtained in 88% yield.
Anti-form: Syn-form => 20: 1 (by ¹ H NMR spectroscopy of the crude mixture),> 99% ee (by HPLC on a Chiralpak AD-H column, λ = 254 nm, iPrOH / hexane = 1/80, 1.5 mlmin ^-1 ; t _R = 63.8min (major), 74.3min (minor)).

(Method for synthesizing (1R, 2R) -1- (4-pyridyl) -2-methylpropane-1,3-diol (Table 6: entry 20))
4-pyridinecarbaldehyde (69 μL, 0.70 mmol), (2S) -2- (di- [3,5-bis (trifluoromethyl) phenyl] hydroxymethyl) pyrrolidine (30) (37 mg, 0.07 mmol) and Propanal (252 μL, 3.50 mmol) was added to a mixture of water (0.23 mL) at 0 ° C. After stirring at 0 ° C. for 72 hours, methanol (1 mL) and sodium borohydride (132 mg, 3.50 mmol) were added to the reaction solution, and the mixture was stirred at 0 ° C. for 1 hour. The reaction was stopped with pH 7.0 phosphate buffer and extracted three times with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and filtered, and then the solvent was distilled off under reduced pressure. The residue was purified using thin layer chromatography (methanol: chloroform = 1: 10) to give (1R, 2R) -1- (4-pyridyl) -2-methylpropane-1,3-diol (84 mg, 0.50 mmol) was obtained as a diastereomeric mixture (anti: syn = 6.9: 1) in 72% yield (anti / 93% ee).

ｂ：単離した収率。
ｃ：^１Ｈ−ＮＭＲにより決定した。
ｄ：アンチ体の光学収率を示す。ＨＰＬＣにより分析した。
ｅ：触媒（１６）を２０ｍｏｌ％用いた。

b: Isolated yield.
c: Determined by ¹ H-NMR.
d: Indicates the optical yield of the anti-isomer. Analyzed by HPLC.
e: 20 mol% of the catalyst (16) was used.

ｂ：単離した収率。
ｃ：^１Ｈ−ＮＭＲにより決定した。
ｄ：アンチ体の光学収率を示す。ＨＰＬＣにより分析した。
ｅ：触媒（１６）を２０ｍｏｌ％用いた。
ｆ：室温で反応を行った。

b: Isolated yield.
c: Determined by ¹ H-NMR.
d: Indicates the optical yield of the anti-isomer. Analyzed by HPLC.
e: 20 mol% of the catalyst (16) was used.
f: Reaction was performed at room temperature.

Test Example 4: Asymmetric Catalytic Aldol Reaction Using Water as Reaction Solvent and Catalyst as Proline Aldol reaction was carried out using various ketones and aldehydes at room temperature using proline as the catalyst and water as the solvent. The reaction was performed at room temperature using 2 mmol acceptor aldehyde, 0.4 mmol donor carbonyl compound, 0.12 mmol (30 mol% with respect to acceptor aldehyde) proline, and 5 equivalents of water as a solvent. The results are shown in Table 7.

  As a synthesis example, a method for synthesizing (1R, 2R) -1- (o-chlorophenyl) -2-methylpropane-1,3-diol (Table 7: entry 1) is shown. To a mixture of o-chlorobenzaldehyde (45 μL, 0.4 mmol), L-proline (14 mg, 0.12 mmol) and water (0.13 mL), propanal (144 μL, 2.0 mmol) was added at room temperature. After stirring at room temperature for 72 hours, methanol (1 mL) and sodium borohydride (76 mg, 2.0 mmol) were added to the reaction solution, and the mixture was stirred at 0 ° C. for 1 hour. The reaction was stopped with pH 7.0 phosphate buffer and extracted three times with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and filtered, and then the solvent was distilled off under reduced pressure. The residue was purified by thin layer chromatography (ethyl acetate: hexane = 1: 1) to give (1R, 2R) -1- (o-chlorophenyl) -2-methylpropane-1,3-diol (56 mg 0.28 mmol) was obtained as a diastereomeric mixture (anti / syn = 4.3 / 1, 90% ee (anti)) with a yield of 70%.

ｂ：単離した収率。
ｃ：^１Ｈ−ＮＭＲにより決定した。
ｄ：アンチ体の光学収率について、ＨＰＬＣ分析により決定した。
ｅ：水溶性のアルデヒドで、３．８当量の水を用いた。
ｆ：３当量の水を用いた。
ｇ：水無しで反応を行った。

b: Isolated yield.
c: Determined by ¹ H-NMR.
d: The optical yield of the anti isomer was determined by HPLC analysis.
e: Water-soluble aldehyde, using 3.8 equivalents of water.
f: 3 equivalents of water were used.
g: Reaction was carried out without water.

  As shown in Table 7, it was confirmed that the reaction proceeds in water using proline as a catalyst. It was also confirmed that the product was obtained in an anti-selective manner and the asymmetric yield was very high.

  The compounds synthesized in Test Examples 3 and 4 were identified by the results of NMR, IR, HRMS, and HPLC. As an example, the identification results of the following compounds are shown.

[NMR, IR, HRMS, HPLC of (2R, 3R) -1- (o-chlorophenyl) -2-methylpropane-1,3-diol (Table 4, Table 5: entry 1, Table 7: entry 1)]
¹ H NMR (400MHz, CDCl ₃ ): δ 0.81 (3H, t, J = 7.2Hz), 2.02-2.05 (1H, m), 2.80 (1H, br s), 3.30 (1H, br s), 3.61- 3.70 (2H, m), 5.05 (1H, d, J = 6.8Hz), 7.14 (1H, t, J = 7.6Hz), 7.22-7.27 (2H, m), 7.50 (1H, d, J = 7.6Hz) );
¹³ C NMR (100 MHz, CDCl ₃ ): δ 13.7, 40.7, 67.1, 76.1, 127.2, 128.1, 128.7, 129.4, 132.5, 140.9;
IR (neat): ν 3357, 2966, 2932, 1572, 1471, 1438, 1034, 754, 703 cm ^-1 ;
HRMS (FAB): [M + Na] calcd for [C ₁₀ H ₁₃ ClO ₂ Na]: 223.0504, found: 223.0496;
Enantiomeric excess was determined by HPLC with a Chiralpak AS-H column (100: 1 hexane: 2-propanol, λ = 254nm), 1.2mL / min; major enantiomer tr = 15.2min, minor enantiomer tr = 17.2min, after conversion to the mono benzoyl ester.

[NMR, IR, HRMS, HPLC of (2R, 3R) -1- (p-chlorophenyl) -2-methylpropane-1,3-diol (Table 5: entry3)]
¹ H NMR (400MHz, CDCl ₃ ): δ 0.62 (3H, d, J = 7.2Hz), 1.88-1.95 (1H, m), 2.79 (1H, br s), 3.29 (1H, br s), 3.58- 3.70 (2H, m), 4.45 (1H, d, J = 8.4 Hz), 7.12-7.21 (2H, m), 7.25-7.26 (2H, m);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 13.7, 41.7, 67.8, 76.7, 128.1, 128.6, 133.5, 141.9;
IR (neat): ν 3342, 2927, 2359, 1490, 1456, 1089, 1013, 830 cm ^-1 ;
HRMS (FAB): [M + Na] calced for [C ₁₀ H ₁₃ ClO ₂ Na]: 223.0496, found: 223.0487;
Enantiometric excess was determined by HPLC with a Chiralcel OD-H column (100: 1 hexane: 2-propanol, λ = 254nm), 1.0mL / min; major enantiomer tr = 9.6min, minor enantiomer tr = 13.0min, after conversion to the di benzoyl ester.

[NMR, IR, HRMS, HPLC of (2R, 3R) -1- (p-fluorophenyl) -2-methylpropane-1,3-diol (Table 5: entry5)]
¹ H NMR (400MHz, CDCl ₃ ): δ 0.65 (3H, d, J = 4.0Hz), 1.94-2.01 (1H, m), 3.00 (1H, br s), 3.37 (1H, br s), 3.63- 3.75 (2H, m), 4.49 (1H, d, J = 8.0Hz), 6.98-7.03 (2H, m), 7.25-7.30 (2H, m);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 13.7, 41.7, 67.9, 76.7, 115.3, 128.3, 139.1, 162.3;
IR (neat): ν 3341, 2925, 1604, 1510, 1224, 1025, 834 cm ^-1 ;
HRMS (FAB): [M + Na] calced for [C ₁₀ H ₁₃ FO ₂ Na]: 207.0792, found: 207.0787;
Enantiometric excess was determined by HPLC with a Chiralpak AS-H column (100: 1 hexane: 2-propanol, λ = 254nm), 1.0mL / min; major enantiomer tr = 20.2min, minor enantiomer tr = 26.9min, after conversion to the mono benzoyl ester.

[HPLC of (2R, 3R) -1-phenyl-2-methylpropane-1,3-diol (Table 5: entry 6, Table 7: entry 3)]
Enantiometric excess was determined by HPLC with a Chiralpak AD-H column (80: 1 hexane: 2-propanol, λ = 254nm), 1.5mL / min; major enantiomer tr = 63.8min, minor enantiomer tr = 74.3min.

[NMR, IR, HRMS, HPLC of (2R, 3R) -1- (naphthalen-2-yl) -2-methylpropane-1,3-diol (Table 5: entry8)]
¹ H NMR (400MHz, CDCl ₃ ): δ 0.72 (3H, d, J = 7.2Hz), 2.22-2.10 (1H, m), 3.01 (1H, br d, J = 2.4Hz), 3.46 (1H, br s), 3.66-3.84 (2H, m), 4.71 (1H, d, J = 8.4Hz), 7.43-7.51 (3H, m), 7.76 (1H, s), 7.78-7.86 (3H, m);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 13.9, 41.4, 68.0, 80.9, 124.5, 125.8, 126.0, 126.2, 127.7, 128.0, 128.3, 133.1, 133.2, 140.7;
IR (KBr): ν 3308, 2964, 2925, 2878, 1389, 1357, 1030, 867, 821, 750cm ^-1 ;
HRMS (FAB): [M + Na] calcd for [C ₁₄ H ₁₆ O ₂ Na]: 239.1043, found: 239.1043;
Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column, (50: 1 hexane: 2-propanol), λ = 254nm, 1.0mL / min; major enantiomer tr = 9.0min, minor enantiomer tr = 10.3min after, conversion to the di benzoyl ester.

[NMR, IR, HRMS, HPLC of (2R, 3R) -1- (naphthalen-1-yl) -2-methylpropane-1,3-diol (Table 5: entry 9)]
¹ H NMR (400MHz, CDCl ₃ ): δ 0.79 (3H, d, J = 4.5Hz), 2.30-2.41 (1H, m), 3.04 (1H, br s), 3.15 (1H, br s), 3.67- 3.84 (2H, m), 5.31 (1H, d, J = 7.6Hz), 7.43-7.53 (3H, m), 7.59 (1H, d, J = 7.2Hz), 7.78 (1H, d, J = 8.0Hz ), 7.83-7.89 (1H, m), 8.15-8.22 (1H, m);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 14.4, 40.8, 67.6, 78.0, 123.6, 124.6, 125.3, 125.6, 126.0, 128.3, 128.9, 130.8, 134.0, 139.0;
IR (KBr): ν 3347, 2927, 2360, 1509, 1457, 1167, 1086, 1025, 799, 778cm ^-1 ;
HRMS (FAB): [M + H] calcd for [C ₁₄ H ₁₆ NaO ₂ ]: 239.1043, found: 203.1029;
Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column (100: 1 hexane: 2-propanol), 1.0mL / min; major enantiomer tr = 15.5min, minor enantiomer tr = 18.6min, after conversion to the di benzoyl ester .

[NMR, IR, HRMS, HPLC of (2R, 3R) -1- (p-tolyl) -2-methylpropane-1,3-diol (Table 5: entry 10)]
¹ H NMR (400MHz, CDCl ₃ ): δ 0.68 (3H, d, J = 6.8Hz), 2.01-2.07 (1H, m), 2.33 (3H, s), 2.60 (1H, br s), 2.77 (1H , br s), 3.68-3.80 (2H, m), 4.50 (1H, d, J = 8.4Hz), 7.15 (2H, d, J = 8.0Hz), 7.21 (2H, d, J = 8.0Hz);
¹³ C NMR (150 MHz, CDCl ₃ ): δ 11.0, 13.9, 21.2, 29.7, 41.7, 68.2, 80.9, 126.6, 129.2, 137.7, 140.4;
IR (neat): ν 3358, 2924, 2386, 1558, 1541, 1508, 1457, 1027, 812, 560cm ^-1 ;
HRMS (FAB): [M + Na] calcd for [C ₁₁ H ₁₆ NaO ₂ ]: 203.1043, found: 203.1046;
Enantiomeric excess was determined by HPLC with a Chiralcel OJ-H column (30: 1 hexane: 2-propanol), 1.0mL / min; major enantiomer tr = 19.2min, minor enantiomer tr = 28.3min, after conversion to the di benzoyl ester .

[NMR, IR, HRMS, HPLC of (2R, 3R) -1- (o-methoxyphenyl) -2-methylpropane-1,3-diol (Table 6: entry 11)]
¹ H NMR (400MHz, CDCl ₃ ): δ 0.72 (1H, d, J = 6.8Hz), 2.15-2.27 (1H, m), 3.65-3.76 (2H, m), 3.84 (3H, s), 4.80 ( 1H, d, J = 8.4Hz), 6.9 (1H, d, J = 8.0Hz), 6.96 (1H, t, J = 7.6Hz), 7.22-7.31 (2H, m);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 13.8, 40.4, 55.3, 67.9, 76.2, 110.6, 120.8, 128.1, 128.6, 130,9, 156.6;
IR (KBr): ν 3367, 2931, 2360, 1602, 1491, 1458, 1287, 1241, 1028, 934, 75, 418cm ^-1 ;
HRMS (FAB): [M + Na] calcd for [C ₁₁ H ₁₆ O ₃ ]: 219.0992, found: 219.1015;
Enantiomeric excess was determined by HPLC with a Chiralpak AS-H column (10: 1 hexane: 2-propanol), 1.0mL / min; major enantiomer tr = 6.8min, minor enantiomer tr = 7.2min, after conversion to the di benzoyl ester .

[NMR, IR, HRMS, HPLC of (2R, 3R) -1- (p-methoxyphenyl) -2-methylpropane-1,3-diol (Table 6: entry12)]
¹ H NMR (400MHz, CDCl ₃ ): δ 0.66 (3H, d, J = 7.2Hz), 1.98-2.09 (1H, m), 2.66 (1H, br s), 2.87 (1H, br s), 3.61- 3.77 (2H, m), 3.79 (3H, s), 4.48 (1H, d, J = 8.6Hz), 6.87 (2H, br d, J = 8.7Hz), 7.25-7.27 (2H, m);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 13.8, 41.7, 55.3, 68.1, 80.6, 113.8, 127.9, 135.7, 159.2;
IR (neat): ν 3336, 2959, 1613, 1513, 1247, 1033, 833 cm ^-1 ;
HRMS (FAB): [M + Na] calced for [C ₁₁ H ₁₆ O ₃ Na]: 219.0992, found: 219.0992;
Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column (100: 1 hexane: 2-propanol), 1.2mL / min; minor enantiomer tr = 145.1min, major enantiomer tr = 149.4min

[HPLC of (2R, 3R) -1-cyclohexyl-2-methylpropane-1,3-diol (Table 6: entry 13)]
Enantiomeric excess was determined by HPLC with a Chiralcel OJ-H column (100: 1 hexane: 2-propanol), 0.5mL / min; major enantiomer tr = 11.8min, minor enantiomer tr = 13.6min.

[HPLC of (2R, 3R) -2-methylpentane-1,3-diol (Table 6: entry 14)]
Enantiomeric excess was determined by HPLC with a Chiralpak IA column (100: 1 hexane: 2-propanol λ = 254nm), 1.0mL / min; major enantiomer (syn) tr = 24.6min, minor enantiomer (syn) tr = 29.9min, major enantiomer (anti) tr = 31.5min, minor enantiomer (anti) tr = 34.4min, after conversion to the mono benzoyl ester.

[HPLC of (2R, 3R) -1- (furan-2-yl) -2-methylpropane-1,3-diol (Table 7: entry4)]
Enantiomeric excess was determined by HPLC with a Chiralpak AD-H column (100: 1 hexane: 2-propanol), 1.0mL / min; major enantiomer tr = 43.8min, minor enantiomer tr = 48.7min, after conversion to the di benzoyl ester .

[NMR, IR, HRMS, HPLC of (2R, 3R) -1- (o-chlorophenyl) -2-isopropylpropane-1,3-diol (Table 6: entry 16)]
¹ H NMR (400MHz, CDCl ₃ ): δ 1.01 (3H, dd, J = 1.2, 6.8Hz), 1.13 (3H, dd, J = 1.2, 6.8Hz), 1.97-2.08 (1H, m), 2.41- 2.47 (1H, m), 3.20-3.27 (1H, m), 3.66-3.82 (2H, m), 5.45 (1H, t, J = 4.9Hz), 7.17-7.27 (1H, m), 7.28-7.36 ( 2H, m), 7.61-7.66 (1H, m);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 20.0, 21.1, 25.8, 49.6, 61.2, 62.7, 73.4, 126.9, 128.0, 128.4, 129.5, 131.8, 141.4;
IR (neat): ν 3324, 2960, 1469, 1439, 1194, 1048, 1036, 998, 757, 705cm ^-1 ;
HRMS (FAB): [M + Na] calcd for [C ₁₂ H ₁₇ ClNaO ₂ ]: 251.0809, found: 251.0815;
Enantiomeric excess was determined by HPLC with a Chiralpak IA column (150: 1 hexane: 2-propanol), 1.0mL / min; major enantiomer tr = 21.9min, minor enantiomer tr = 25.2min.

[NMR, IR, HRMS, HPLC of (3R) -1- (o-chlorophenyl) -2,2-dimethylpropane-1,3-diol (Table 6: entry 17)]
¹³ C NMR (100 MHz, CDCl ₃ ): δ 18.8, 22.4, 29.7, 40.3, 72.4, 126.6, 128.6, 129.3, 129.5, 133.4, 139.2;
IR (neat): ν 3335, 2919, 2852, 2360, 1653, 1472, 1438, 1031, 751, 710cm-1;
HRMS (FAB): [M + Na] calcd for [C ₁₁ H ₁₅ ClNaO ₂ ]: 237.0653, found: 237.0635;
Enantiomeric excess was determined by HPLC with a Chiralpak AS-H column (30: 1 hexane: 2-propanol), 1.0mL / min; major enantiomer tr = 11.7min, minor enantiomer tr = 12.9min.

[NMR, IR, HRMS, HPLC of (2R, 3R) -1- (o-chlorophenyl) -2-benzylpropane-1,3-diol (Table 6: entry 18)]
¹ H NMR (400MHz, CDCl ₃ ): δ 2.15-2.23 (1H, m), 2.82-2.96 (2H, m), 3.53 (1H, ddd, J = 5.2, 5.2, 10.8Hz), 3.70 (1H, ddd , J = 2.4, 4.0, 10.8Hz), 5.21 (1H, t, J = 4.8Hz), 7.15-7.38 (8H, m), 7.65 (1H, dd, J = 1.2, 7.6Hz);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 34.9, 45.8, 62.4, 74.5, 126.2, 127.0, 127.8, 128.4, 128.6, 128.8, 129.0, 129.2, 129.5, 131.9, 140.0, 140.9;
IR (neat): ν 3336, 2924, 1440, 1192, 1127, 1073, 1031, 911, 753, 701cm ^-1 ;
HRMS (FAB): [M + Na] calcd for [C ₁₆ H ₁₇ ClNaO ₂ ]: 299.0809, found: 299.0810;
Enantiomeric excess was determined by HPLC with a Chiralcel OJ-H column (30: 1 hexane: 2-propanol), 1.0mL / min; major enantiomer tr = 17.6min, minor enantiomer tr = 22.5min.

[NMR, IR, HRMS, HPLC of (2R, 3R) -1- (pyrrolidin-4-yl) -2-methylpropane-1,3-diol (Table 6: entry 19, 20)]
¹ H NMR (400MHz, CDCl ₃ ): δ 0.83 (3H, t, J = 6.8Hz), 1.97-2.03 (1H, m), 3.01 (1H, br s), 3.65-3.80 (2H, m), 4.14 (1H, br s), 4.61 (1H, d, J = 6.8Hz), 7.28-7.29 (2H, m), 8.52-8.54 (2H, m);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 12.8, 40.1, 65.9, 77.6, 121.0, 148.2, 152.2;
IR (neat): ν 3363, 2963, 2924, 1605, 1559, 1456, 1416, 1261, 1033, 801cm ^-1 ;
HRMS (FAB): [M + H] calced for [C ₉ H ₁₄ NO ₂ ]: 168.1019, found: 168.1012;
Enantiometric excess was determined by HPLC with a Chiralpak AS-H column (20: 1 hexane: 2-propanol, λ = 254nm), 1.0mL / min; major enantiomer tr = 30.8min, minor enantiomer tr = 45.8min.

Claims (18)

A proline derivative which is an enantiomer of a compound represented by the following formula (12) or (14) to (28) or a compound represented by the following formula (11) to (31).

A compound represented by the following general formula (9-6) (except that R ⁶ is a phenyl group, a tolyl group, a p-nitrophenyl group, or a 2,4,6-triisopropylphenyl group); Or the proline derivative which is an enantiomer of the compound represented by the following general formula (9-6).

(In the formula, R ⁶ represents a linear or branched alkyl group having 2 to 15 carbon atoms, or an aryl group which may have a substituent.)   A catalyst for enhancing optically active anti-selectivity in an aldol reaction using water, comprising a combination of proline and a substance or functional group that increases the fat solubility of proline.   Substances that increase the fat solubility of proline include carboxylic acid, tetrazole, carboxamide, carboxamide having an aryl group, a heterocycle, an alkyl group on the nitrogen, a carboxamide having a sulfonyl group which may have a substituent, and a substituent. 4. An alkylhydroxyl group which may be substituted, an alkylsilyloxy group which may have a substituent, an arylsilyloxy group which may have a substituent, or a silyloxy group having both an alkyl group and an aryl group. The optically active anti-selectivity enhancing catalyst as described.   The optically active anti-selectivity enhancement according to claim 3 or 4, wherein the functional group that increases the liposolubility of proline is an aryl group, a heterocycle, an alkyl group, an acyl group, or a silyl group which may have a substituent. catalyst. An optically active anti-selectivity enhancing catalyst, wherein the optically active anti-selectivity enhancing catalyst according to any one of claims 3 to 5 is a compound represented by the following general formulas (9-1) to (9-8).

(In the formula, R ³ represents an alkyl group or an aryl group. Each R ³ may be the same or different. R ⁴ represents an alkyl group, an aryl group, or an acyl group. R ⁵ represents , Hydrogen, an alkyl group, or an aryl group, R ⁶ represents an alkyl group, or an aryl group, and R ⁷ represents an alkyl group that may have a functional group, or an aryl group that may have a substituent. Or a heteroaryl group which may have a substituent. The optically active anti-selectivity enhancing catalyst according to any one of claims 3 to 6 is a compound represented by the following formulas (11) to (34), or an enantiomer of a compound represented by the following formulas (11) to (34) An optically active anti-selectivity enhancing catalyst.

A method for producing a proline derivative represented by the following formula (12):
A method for producing a proline derivative obtained by reacting a pyrrolidine derivative having a substituent at the 2-position and the 4-position with a silylating agent.

A method for producing a proline derivative represented by the following formula (12) or (14) (28),
Protecting the nitrogen atom of the pyrrolidine derivative having a substituent at the 2-position and 4-position or 2-position and 3-position with a benzyloxycarbonyl group or a t-butoxycarbonyl group;
After reacting with a silylating agent or acylating agent,
A method for producing a proline derivative by catalytic hydrogenation or deprotection with an acid.

  An optically active anti-aldol compound obtained by reacting in the presence of the optically active anti-selectivity enhancing catalyst according to any one of claims 3 to 7. A ketone represented by the following general formula (1a) and an aldehyde represented by the following general formula (2a) are reacted in a solvent or reacted without using a solvent. A method for producing an optically active anti-aldol compound represented by (3a),
The manufacturing method of the optically active anti-aldol compound formed by making it react in the presence of the catalyst selected from the amino acid derivative represented by the following general formula (10-1) to (10-5), and its enantiomer. (However, in the case where the reaction is carried out without using a solvent, the case where the ketone represented by the general formula (1a) is acetone is excluded.)

(In the formula, R ⁸ represents an aryl group, a heterocycle, an alkyl group, an acyl group, or a silyl group which may have a substituent. R ⁹ represents a carboxyl group, tetrazole, carboxamide, an aryl group or a heterocycle on nitrogen. , A carboxamide having a substituent such as an alkyl group, a carboxamide having a sulfonyl group which may have a substituent or an alkylhydroxyl group which may have a substituent, R ¹⁰ represents a carboxamide, an aryl group on nitrogen, hetero A ring, a carboxamide having an alkyl group, a carboxamide having a sulfonyl group which may have a substituent, an alkyl hydroxyl group which may have a substituent, an alkylsilyloxy group which may have a substituent, and a substituent. An arylsilyloxy group which may have, or a silyloxy group having both an alkyl group and an aryl group ) A method for producing an optically active anti-aldol compound according to claim 11,
A method for producing an optically active anti-aldol compound, wherein the solvent is water when the reaction is carried out using a solvent. A method for producing an optically active anti-aldol compound according to claim 11,
When making it react using a solvent, the manufacturing method of the optically active anti-aldol compound whose said solvent is a nonpolar solvent. An aldehyde represented by the following general formula (4a) and an aldehyde represented by the following general formula (5a) are reacted in a solvent or reacted without using a solvent, and the following general formula A method for producing an optically active anti-aldol compound represented by (6a),
The manufacturing method of the optically active anti-aldol compound formed by making it react in the presence of the catalyst selected from the amino acid derivative represented by the following general formula (10-1) to (10-5), and its enantiomer.

(In the formula, R ⁸ represents an aryl group, a heterocycle, an alkyl group, an acyl group, or a silyl group which may have a substituent. R ⁹ represents a carboxyl group, tetrazole, carboxamide, an aryl group or a heterocycle on nitrogen. , A carboxamide having a substituent such as an alkyl group, a carboxamide having a sulfonyl group which may have a substituent or an alkylhydroxyl group which may have a substituent, R ¹⁰ represents a carboxamide, an aryl group on nitrogen, hetero A ring, a carboxamide having an alkyl group, a carboxamide having a sulfonyl group which may have a substituent, an alkyl hydroxyl group which may have a substituent, an alkylsilyloxy group which may have a substituent, and a substituent. An arylsilyloxy group which may have, or a silyloxy group having both an alkyl group and an aryl group ) A method for producing the optically active anti-aldol compound according to claim 14,
A method for producing an optically active anti-aldol compound, wherein the solvent is water when the reaction is carried out using a solvent. A method for producing the optically active anti-aldol compound according to claim 14,
When making it react using a solvent, the manufacturing method of the optically active anti-aldol compound whose said solvent is a nonpolar solvent. It is represented by the following general formula (3b) obtained by reacting a ketone represented by the following general formula (1b) with an aldehyde represented by the following general formula (2b) using water as a solvent and proline as a catalyst. A method for producing an optically active anti-aldol compound.

The aldehyde represented by the following general formula (4b) and the aldehyde represented by the following general formula (5b) are reacted by using water as a solvent and proline as a catalyst. A method for producing an optically active anti-aldol compound.