JP2009165440A - METHOD FOR PRODUCING (S)-3-ACYLOXY-1-ALKENE OR (R)-3-HYDROXY-1-ALKENE, AND METHOD FOR PRODUCING OPTICALLY ACTIVE alpha-LIPOIC ACID - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing (S)-3-acyloxy-1-alkenes or (R)-3-hydroxy-1-alkenes in high chemical yield and high optical purity and a method for producing an optically active α-lipoic acid. <P>SOLUTION: The method for producing an (S)-(-)-α-lipoic acid contains a step to react a 3-hydroxy-1-alkene with an acylation agent comprising a carboxylic acid ester in the presence of a lipase or an esterase, and divide the product to an (S)-3-acyloxy-1-alkene or an (R)-3-hydroxy-1-alkene by transesterification. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to (S) -3-acyloxy-1-alkenes useful as intermediates for the production of (R)-(+)-α-lipoic acid or (S)-(−)-α-lipoic acid or ( The present invention relates to a method for producing R) -3-hydroxy-1-alkene and a method for producing (R)-(+)-α-lipoic acid or (S)-(−)-α-lipoic acid.

  α-Lipoic acid (also known as thioctic acid or 6,8-dithiooctanoic acid) has a pharmacological action, for example, properties such as anti-inflammatory, anti-nociceptive (analgesic), and cytoprotective properties. It is known to have In particular, (R)-(+)-α-lipoic acid, which is an optically active substance, is a natural substance and is present in a small proportion in the cells of animals and plants, and is excellent in anti-inflammatory action and important for energy metabolism in the body. It is supposed to have a role. For example, it is known that pyruvate generated by glycolysis of glucose acts as a coenzyme when decarboxylated to acetyl CoA. Moreover, it has an antioxidant ability and is said to be involved as an inhibitor or a scavenger against various oxidative stresses. On the other hand, (S)-(−)-α-lipoic acid is said to be excellent in antinociceptive action. Therefore, it is important to obtain (R)-(+)-α-lipoic acid and (S)-(−)-α-lipoic acid having good optical purity from the viewpoint of exerting an appropriate pharmacological action. .

  In JP-A-9-212466 (Patent Document 1), from 8-chloro-6-hydroxy-octanoic acid, which is a racemate, to (+)-8-chloro-6-hydroxy-octanoic acid, which is an optically active substance. Or (-)-8-chloro-6-hydroxy-octanoic acid can be obtained. Starting from (+)-8-chloro-6-hydroxy-octanoic acid thus obtained, (R)-(+)-α-lipoic acid or (S)-(−)-α-lipoic acid An acid can be obtained, and (R)-(+)-α-lipoic acid or (S)-(−) — starting from (−)-8-chloro-6-hydroxy-octanoic acid It is said that α-lipoic acid can be obtained. However, there is a case where a product with good optical purity is not always obtained with a good yield, and an improvement has been desired.

  In Non-Patent Document 1, racemic 3-hydroxy-5-phenyl-1-pentene is reacted with an acylating agent in the presence of CAL (Candida antarctica lipase, Novozym 435), which is a lipase derived from a microorganism. A process for transesterification and resolution into (S) -3-acyloxy-5-phenyl-1-pentene and (R) -3-hydroxy-5-phenyl-1-pentene is described. However, in some cases, different substrates cannot be divided in the same manner, and (R)-(+)-α-lipoic acid which is an optically active substance after obtaining an intermediate by such a method. Alternatively, there is no description about a method for obtaining (S)-(−)-α-lipoic acid.

  On the other hand, in Non-Patent Document 2, 3-acetoxy-8- (tetrahydropyran-2-yloxy) -octene is hydrolyzed using BLAP (Bovine Liver Acetone Powder), and (R) -3-acetoxy- The process of splitting into 8- (tetrahydropyran-2-yloxy) -octene and (S) -3-hydroxy-8- (tetrahydropyran-2-yloxy) -octene is described. Further, a method for obtaining (R)-(+)-α-lipoic acid from (S) -3-hydroxy-8- (tetrahydropyran-2-yloxy) -octene obtained by resolution is described. However, there is a case where a product with good optical purity is not always obtained with a good yield, and an improvement has been desired.

JP-A-9-212466 Toshiyuki Itoh et al., Lipase-Catalyzed Enantioselective Acylation in the Ionic Liquid Solvent System: Reaction of Enzyme Anchored to the Solvent, Chemistry Letters 2001, Vol. 30, No. 3, p.262-263 D. Basavaiah et al., Bovine Liver Acetone Powder (BLAP) Catalyzed Synthesis of Chiral C-8 Allyl Alcohols: An Application of Substrate Specificity Approach, Tetrahedron 1994, Vol.50, No.14, p.4137-4148

  (S) -3-Acyloxy-1-alkene or (R) -3-hydroxy-1-alkene having a high chemical yield and high optical purity. An object of the present invention is to provide a manufacturing method. In addition, (R)-(+)-α-lipoic acid starting from (S) -3-acyloxy-1-alkene or (R) -3-hydroxy-1-alkene obtained by such a method Or it aims at providing the suitable manufacturing method of (S)-(-)-alpha-lipoic acid.

［式中、ｎは０〜３の整数であり、Ｘは保護されたヒドロキシ基、保護されたチオール基又はハロゲン原子である。］
で示される化合物をリパーゼ又はエステラーゼの存在下でカルボン酸エステルからなるアシル化剤と反応させてトランスエステル化し、下記一般式（Ｓ）−（２ａ）：

又は下記一般式（Ｒ）−（２ｂ）：

［式中、ｎ及びＸは前記と同義であり、Ｙはアシル基である。］
で示される化合物に分割する工程を有することを特徴とする（Ｓ）−３−アシロキシ−１−アルケン又は（Ｒ）−３−ヒドロキシ−１−アルケンの製造方法を提供することによって解決される。 The above problem is solved by the following general formula (1):

[Wherein, n is an integer of 0 to 3, and X is a protected hydroxy group, a protected thiol group, or a halogen atom. ]
Is reacted with an acylating agent comprising a carboxylic acid ester in the presence of lipase or esterase to transesterify, and the following general formula (S)-(2a):

Or the following general formula (R)-(2b):

[Wherein, n and X are as defined above, and Y is an acyl group. ]
It is solved by providing a method for producing (S) -3-acyloxy-1-alkene or (R) -3-hydroxy-1-alkene, which comprises a step of dividing the compound represented by formula (I).

  At this time, it is preferable that the lipase or esterase is derived from a microorganism, and it is preferable to use a lipase derived from the genus Candida. It is also preferred that the acylating agent is a carboxylic acid vinyl ester.

［式中、ｎ及びＸは前記と同義であり、Ｙはアシル基である。］
で示される（Ｓ）−３−アシロキシ−１−アルケン又は下記一般式（Ｒ）−（２ｂ）：

［式中、ｎ及びＸは前記と同義である。］
で示される（Ｒ）−３−ヒドロキシ−１−アルケンを出発化合物として用いることを特徴とする下記式（Ｒ）−（３）：

で示される（Ｒ）−（＋）−α−リポ酸の製造方法を提供することが本発明の好適な実施態様である。 At this time, the following general formula (S)-(2a):

[Wherein, n and X are as defined above, and Y is an acyl group. ]
(S) -3-Acyloxy-1-alkene represented by the following general formula (R)-(2b):

[Wherein, n and X are as defined above. ]
(R) -3-Hydroxy-1-alkene represented by the following formula (R)-(3):

It is a preferred embodiment of the present invention to provide a method for producing (R)-(+)-α-lipoic acid represented by the formula:

［式中、ｎ及びＸは前記と同義であり、Ｙはアシル基である。］
で示される（Ｓ）−３−アシロキシ−１−アルケン又は下記一般式（Ｒ）−（２ｂ）：

［式中、ｎ及びＸは前記と同義である。］
で示される（Ｒ）−３−ヒドロキシ−１−アルケンを出発化合物として用いることを特徴とする下記式（Ｓ）−（３）：

で示される（Ｓ）−（−）−α−リポ酸の製造方法を提供することも本発明の好適な実施態様である。 Furthermore, at this time, the following general formula (S)-(2a):

[Wherein, n and X are as defined above, and Y is an acyl group. ]
(S) -3-Acyloxy-1-alkene represented by the following general formula (R)-(2b):

[Wherein, n and X are as defined above. ]
(R) -3-Hydroxy-1-alkene represented by the following formula (S)-(3):

It is also a preferred embodiment of the present invention to provide a method for producing (S)-(−)-α-lipoic acid represented by the formula:

  According to the production method of the present invention, (S) -3-acyloxy-1-alkene or (R) -3-hydroxy-1-alkene having high optical purity is increased from racemic 3-hydroxy-1-alkene. It can be obtained in chemical yield. The (S) -3-acyloxy-1-alkene or (R) -3-hydroxy-1-alkene thus obtained is either (R)-(+)-α-lipoic acid or (S)-(−) —. It can be suitably used as an intermediate used in the method for producing α-lipoic acid.

  In the production method of the present invention, a racemic 3-hydroxy-1-alkene represented by the following general formula (1) is reacted with an acylating agent comprising a carboxylic acid ester in the presence of lipase or esterase to transesterify. (S) -3-Acyloxy-1-alkene represented by the following general formula (S)-(2a) or (R) -3-hydroxy-1-alkene represented by the following general formula (R)-(2b) It has the process of dividing | segmenting into, It is characterized by the above-mentioned.

［式中、ｎは０〜３の整数であり、Ｘは保護されたヒドロキシ基、保護されたチオール基又はハロゲン原子である。］
で示される化合物をリパーゼ又はエステラーゼの存在下でカルボン酸エステルからなるアシル化剤と反応させてトランスエステル化し、下記一般式（Ｓ）−（２ａ）：

又は下記一般式（Ｒ）−（２ｂ）：

［式中、ｎ及びＸは前記と同義であり、Ｙはアシル基である。］

[Wherein, n is an integer of 0 to 3, and X is a protected hydroxy group, a protected thiol group, or a halogen atom. ]
Is reacted with an acylating agent comprising a carboxylic acid ester in the presence of lipase or esterase to transesterify, and the following general formula (S)-(2a):

Or the following general formula (R)-(2b):

[Wherein, n and X are as defined above, and Y is an acyl group. ]

  In the above general formulas (1), (S)-(2a) and (R)-(2b), X is a protected hydroxy group, a protected thiol group or a halogen atom, and Y is an acyl group. In the production method of the present invention, examples of the protected hydroxy group include an acyloxy group, an alkoxycarbonyloxy group, an alkylsilyloxy group, an alkoxymethoxy group, an arylmethoxy group, and a tetrahydropyranyloxy group. Examples of the protected thiol group include an arylmethylthio group.

  Examples of the acyloxy group include linear or branched alkyl carbonyloxy groups having 2 to 20 carbon atoms and aryl carbonyloxy groups. For example, acetyloxy group, propionyloxy group, butyryloxy group, isobutyryloxy group. Benzoyloxy group, dodecanoyloxy group, and the like. Among them, an acyloxy group suitable for X is an acetyloxy group. A suitable acyl group for Y is an acetyl group.

  Examples of the alkoxycarbonyloxy group include linear, branched or cyclic alkoxycarbonyloxy groups having 2 to 20 carbon atoms, such as a methoxycarbonyloxy group, an ethoxycarbonyloxy group, an n-propoxycarbonyloxy group, and an isocarbonyl group. Propoxycarbonyloxy group, n-butoxycarbonyloxy group, isobutoxycarbonyloxy group, sec-butoxycarbonyloxy group, tert-butoxycarbonyloxy group, pentyloxycarbonyloxy group, hexyloxycarbonyloxy group, heptyloxycarbonyloxy group, Examples include an octyloxycarbonyloxy group.

  Examples of the alkylsilyloxy group include trimethylsilyloxy group, triethylsilyloxy group, triisopropylsilyloxy group, tert-butyldimethylsilyloxy group, tert-butyldiphenylsilyloxy group, and the like.

  The alkoxymethoxy group is not particularly limited as long as it has a structure in which a methoxy group is further bonded to any carbon atom of the alkoxy group, and examples thereof include a methoxymethoxy group and an ethoxymethoxy group. Among these, a suitable alkoxymethoxy group for X is a methoxymethoxy group.

  The arylmethoxy group is not particularly limited as long as it has a structure in which an aryl group is bonded to a methoxy group, and examples thereof include a benzyloxy group. Among them, a suitable arylmethoxy group for X is a benzyloxy group.

  As said arylmethylthio group, a C7-C20 arylmethylthio group is mentioned, For example, a benzylthio group etc. are mentioned. Among them, a suitable arylmethylthio group for X is a benzylthio group.

  As said halogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom etc. are mentioned, for example, Among these, the halogen atom suitable for X is a bromine atom.

  In the present invention, (S) -3-acyloxy-1-alkene or (R) -3-hydroxy-1-alkene is produced by the following step 1.

  That is, 3-hydroxy-1-alkene represented by the following general formula (1) is reacted with an acylating agent composed of a carboxylic acid ester in the presence of lipase or esterase to transesterify, and the following general formula (S)-( (S) -3-Acyloxy-1-alkene represented by 2a) and (R) -3-hydroxy-1-alkene represented by the general formula (R)-(2b) are obtained.

  In the production method of the present invention as in Step 1, an acylating agent composed of a carboxylic acid ester is used. Among them, the acylating agent used in the present invention is a carboxylic acid from the viewpoint of efficient acylation reaction. A vinyl ester is preferred. Examples of carboxylic acid vinyl esters include 1-propenyl acetate, 2-propenyl acetate, isopropenyl acetate, vinyl acetate, vinyl propionate, vinyl butyrate, vinyl crotonate, vinyl caproate, vinyl caprylate, vinyl caprate, laurin Examples thereof include vinyl acid vinyl, vinyl myristate, vinyl palmitate, vinyl stearate, vinyl benzoate, divinyl adipate, and monochlorovinyl acetate. In particular, when vinyl butyrate or vinyl laurate is used, the acylation reaction may proceed too quickly, and when vinyl benzoate or the like is used, the acylation reaction may proceed too slowly. More preferably, 1-propenyl acetate, 2-propenyl acetate, isopropenyl acetate, vinyl acetate, vinyl propionate, and vinyl crotonic acid are used.

  The amount of the acylating agent used is preferably 0.5 mol or more per 1 mol of the compound represented by the general formula (1). When the amount of the acylating agent used is less than 0.5 mol, the acylation reaction may be insufficient, and more preferably 0.8 mol or more. On the other hand, the amount of the acylating agent used is usually 100 mol or less.

  The lipase or esterase used in Step 1 is not particularly limited, but is preferably derived from a microorganism, such as Pseudomonas genus, Pichia genus, Rhodotorula genus, Saccharopolyspora. (Saccharopolyspora), Streptomyces, Actinomucor, Aspergillus, Bacillus, Candida, Candida, and Cladosporum , Geotrichum genus, Acinetobacter genus, Gibe Gibberella genus, Kluyveromyces genus, Microsporum genus, Brevibacillus genus, Mucor genus, Actinomadura genus, Coprius Examples include those derived from the genus Agaricus, the genus Rhodococcus, the genus Rhizomucor, the genus Rhizopus, and the genus Commomonas. In the production method of the present invention, specifically, CAL-B (Candida antilipase type-B, “Chirozyme” manufactured by Roche), lipase AK (Pseudomonas fluorescens, manufactured by Amano), lipase AYS (Candida AmanS ), Lipase A (Aspergillus niger, manufactured by Amano), protease PS (Aspergillus melleus, manufactured by Amano), lipase M (manufactured by Mucor javanicus, manufactured by Amano), lipase G (manufactured by Penicillium amber, etc.) In view of the high chemical yield of the compound used and the good optical purity, Candida (Can ida) derived from the genus is lipase CAL-B "Chirazyme" is more preferably used.

  As for the usage-amount of the said lipase or esterase, 1-1000g is preferable with respect to 1 mol of 3-hydroxy-1-alkene shown by General formula (1). When the amount of lipase or esterase used is less than 1 g, the esterification reaction may not proceed smoothly, and more preferably 2 g or more. On the other hand, when the amount of lipase or esterase used exceeds 1000 g, the reaction rate becomes too fast and it becomes difficult to control the reaction, which may lead to a decrease in optical yield, more preferably 100 g or less. Here, the amount of lipase or esterase used is expressed by the weight including a carrier on which lipase or esterase is supported.

  In the above step 1, as a reaction solvent when the 3-hydroxy-1-alkene represented by the general formula (1) is stirred and reacted with an acylating agent in the presence of lipase or esterase, benzene, toluene, xylene, Aromatic solvents such as mesitylene, nitrobenzene, cumene, etc .; ether solvents such as dimethyl ether, diethyl ether, tetrahydrofuran, isopropyl ether, dioxane and the like can be mentioned, and toluene, xylene and dioxane are preferably used. The amount of the reaction solvent used is preferably 0.01 to 10 liters with respect to 1 mol of 3-hydroxy-1-alkene represented by the general formula (1). Further, it can be reacted neat with an acylating agent without using a solvent.

  As reaction temperature at the time of making it react, it is preferred that it is 0-100 ° C. When reaction temperature is less than 0 degreeC, there exists a possibility that reaction may not fully advance, More preferably, it is 10 degreeC or more. On the other hand, when reaction temperature exceeds 100 degreeC, while there exists a possibility that an enzyme may be deactivated, there exists a possibility that the selectivity of reaction may fall remarkably, More preferably, it is 60 degrees C or less.

  Moreover, as reaction time at the time of making it react, it is preferable that it is 1 hour-10 days. When reaction time is less than 1 hour, there exists a possibility that reaction may not fully advance, More preferably, it is 20 hours or more. On the other hand, when the reaction time exceeds 10 days, the optical yield may be lowered, and more preferably 8 days or less.

In step 1 above, only the hydroxyl group of the compound having the (S) configuration at the 3-position carbon atom is selectively acylated, so the compound at the 3-position carbon atom is the (R) configuration. Leaves the hydroxyl group unreacted, and (S) -3-acyloxy-1-alkene and (R) -3-hydroxy-1-alkene can be obtained. Moreover, after completion | finish of reaction, it is preferable to remove lipase or esterase by filtration and to perform processes, such as liquid separation operation. Then, it isolate | separates and refine | purifies by a well-known method, It shows by (S) -3-acyloxy-1-alkene or general formula (R)-(2b) shown by general formula (S)-(2a) ( R) -3-Hydroxy-1-alkene can be isolated. The isolation method is not particularly limited and may be an isolation method by extraction, distillation, column chromatography, or the like, but from the viewpoint of being easily isolated with good yield, isolation by extraction or distillation. The method is preferred, and the isolation method by extraction is more preferred. When isolated by extraction, the organic solvent phase containing (S) -3-acyloxy-1-alkene and the aqueous phase containing (R) -3-hydroxy-1-alkene can be separated and isolated. it can. As can be seen from Example 3 to be described later, in the case of n = 3 and X = OCH ₂ OCH ₃ in the above-described step 1, it is represented by the general formula (S)-(2a) by the extraction operation (S)- By separating into an organic solvent phase containing 3-acyloxy-1-alkene and an aqueous phase containing (R) -3-hydroxy-1-alkene represented by the general formula (R)-(2b), It is preferable because it can be separated.

  The method for obtaining the 3-hydroxy-1-alkene represented by the general formula (1) as the starting material in Step 1 is not particularly limited, and acrolein, 2-phenyl-1,3-dioxane, 1,3-propanediol Alternatively, it can be synthesized from 1,6-hexanediol or the like. Among them, as a method for obtaining 3-hydroxy-1-pentene represented by the general formula (1) when n = 0, acrolein, 2-phenyl-1,3-phenyl can be obtained from a viewpoint that it can be easily obtained with high yield. It is preferably synthesized from dioxane or 1,3-propanediol. As a method for obtaining 3-hydroxy-1-octene represented by the general formula (1) when n = 3, 1,6-hexanediol is used. It is preferable to synthesize.

  Here, a method for obtaining 3-hydroxy-1-pentene represented by the general formula (1) when n = 0 using acrolein as a starting compound will be described with reference to the following chemical reaction formula (II).

  As shown in the chemical reaction formula (II), 3-hydroxy-1-pentene represented by the general formula (1) can be obtained from acrolein in two steps. As shown in the chemical reaction formula (II), after acrolein is reacted to obtain an aldehyde compound into which a benzylthio group or the like is introduced, a Grignard reaction is performed to convert 3-hydroxy-1-pentene into which the benzylthio group or the like has been introduced. Obtainable.

  Further, a method for obtaining a compound represented by the general formula (1) when n = 0 using 2-phenyl-1,3-dioxane as a starting compound will be described with reference to the following chemical reaction formula (III).

  As shown in the above chemical reaction formula (III), 3-benzyloxy-1-propanol was obtained by adding diisobutylaluminum hydride to a toluene solution of 2-phenyl-1,3-dioxane and reacting them. After oxidizing the unprotected hydroxyl group with an oxidizing agent such as TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical) to form an aldehyde compound, a Grignard reaction is performed to effect benzyloxy 3-hydroxy-1-pentene into which a group or the like is introduced can be obtained. Further, 1,3-propanediol may be used as a starting compound instead of 2-phenyl-1,3-dioxane. In this case, one of the hydroxyl groups of 1,3-propanediol can be protected with benzyl chloride or the like, and then 3-hydroxy-1-pentene can be obtained in the same manner as described above.

  Further, a method for obtaining 3-hydroxy-1-octene represented by the general formula (1) when n = 3 using 1,6-hexanediol as a starting chemical is referred to the following chemical reaction formula (IV). explain.

  As shown in the above chemical reaction formula (IV), one of the hydroxyl groups of 1,6-hexanediol is protected with dimethoxymethane or the like, and then the unprotected hydroxyl group is oxidized with TEMPO or the like. Then, 3-hydroxy-1-octene into which a methoxymethoxy group or the like has been introduced can be obtained by performing a Grignard reaction.

  In the present invention, (S) -3-acyloxy-1-alkene represented by the following general formula (S)-(2a) or the following general formula (R)-(2b) obtained as described above. By using (R) -3-hydroxy-1-alkene as a starting compound, (R)-(+)-α-lipoic acid represented by the following formula (R)-(3) or the following formula (S)- (S)-(−)-α-lipoic acid represented by (3) can be obtained.

［式中、ｎは０〜３の整数であり、Ｘは保護されたヒドロキシ基、保護されたチオール基又はハロゲン原子であり、Ｙはアシル基である。］

[Wherein, n is an integer of 0 to 3, X is a protected hydroxy group, a protected thiol group or a halogen atom, and Y is an acyl group. ]

［式中、ｎ及びＸは前記と同義である。］

[Wherein, n and X are as defined above. ]

  Here, in the (S) -3-acyloxy-1-alkene represented by the general formula (S)-(2a), the compound represented by the general formula (S)-(4) when n = 0 is started. A method for obtaining (R)-(+)-α-lipoic acid as a substance will be described with reference to the following chemical reaction formula (V).

［式中、Ｘ及びＹは前記と同義であり、Ｚはアルコキシカルボニル基、カルボキシル基又はシアノ基である。］

[Wherein, X and Y are as defined above, and Z is an alkoxycarbonyl group, a carboxyl group, or a cyano group. ]

By reacting the compound represented by the general formula (S)-(4) with, for example, hydrogen (H ₂ ) and carbon monoxide (CO) together with a catalyst to hydroformylate the double bond as in Step 2 above. A compound represented by the general formula (R)-(5) can be obtained. Although it does not specifically limit as a catalyst used by this process 2, For example, rhodium dicarbonyl acetylacetonate (Rh (acac) (CO) ₂ ), rhodium acetylacetonate (Rh (acac) ₂ ), Rh (H ) (CO) (PPh ₃ ) ₃ , Rh (COD) (acac), rhodium catalyst such as Rh ₆ (CO) ₁₆ , cobalt catalyst such as Co ₂ (CO) ₈ , Ru ₃ (CO) ₁₂ A ruthenium catalyst such as is preferably used. The amount of the catalyst used is preferably 0.0001 to 0.01 mol with respect to 1 mol of the compound represented by the general formula (S)-(4). Here, it is preferable to supply hydrogen and carbon monoxide as a mixed gas, particularly as a synthesis gas. In this case, it is preferable to cause the total pressure of the mixed gas to be 2 kg / cm ² or more for the reaction. When the total pressure of the mixed gas is less than 2 kg / cm ² , the reaction rate may decrease, and more preferably 5 kg / cm ² or more. On the other hand, the total pressure of the mixed gas is usually 100 kg / cm ² or less. The molar ratio of hydrogen to carbon monoxide (H ₂ / CO) in the mixed gas is not particularly limited, but is preferably 1/10 to 10/1, and preferably 1/5 to 5/1. More preferably, it is more preferably 1/2 to 2/1.

  The solvent used in the step 2 is not particularly limited, and examples thereof include aromatic solvents such as benzene, toluene, xylene, mesitylene, nitrobenzene and cumene; ether solvents such as dimethyl ether, diethyl ether, tetrahydrofuran, isopropyl ether and dioxane. , Toluene, xylene, cumene and the like are preferably used. The usage-amount of the solvent in the said process 2 has preferable 0.01-10 liter with respect to 1 mol of compounds shown by general formula (S)-(4). Although it does not specifically limit as reaction temperature in the said process 2, It is preferable that it is 0-100 degreeC. When reaction temperature is less than 0 degreeC, there exists a possibility that reaction may not fully advance, More preferably, it is 30 degreeC or more. On the other hand, when reaction temperature exceeds 100 degreeC, there exists a possibility that a by-product may increase, and it is 80 degrees C or less more suitably.

  Moreover, it does not specifically limit as reaction time in the said process 2, However, It is preferable that it is 1 to 20 hours. When reaction time is less than 1 hour, there exists a possibility that reaction may not fully advance, More preferably, it is 4 hours or more. On the other hand, when reaction time exceeds 20 hours, there exists a possibility that a by-product may increase, and it is 15 hours or less more suitably. After completion of the reaction, a compound represented by the general formula (R)-(5) can be obtained by performing a treatment such as a liquid separation operation. You may refine | purify using column chromatography etc. as needed.

In step 3, the compound represented by the general formula (R)-(5) is subjected to a Wittig reaction, and then the resulting olefin is subjected to a hydrogenation reaction (hydrogenation). )-(6) can be obtained. Here, the Wittig reaction in the present invention includes a Wittig reaction using phosphorus ylide and the like, a Wittig-Horner reaction using alkylphosphonic acid diester and the like. The phosphorus ylide to be used, for _{example, Ph 3 P = CHCOOEt, Ph} 3 P = COOH, Ph 3 P = CN , and the like, The alkyl phosphonic acid diester, for _{example, (EtO) 2 P (O} ) CH ₂ COOEt, (CF ₃ CH ₂ O) ₂ P (O) CH ₂ CO ₂ Et, and the like. The Wittig-Horner reaction using an alkylphosphonic acid diester or the like is preferably used from the viewpoint that olefin synthesis and hydrogenation can be performed in a high yield without purification.

  The solvent used in Step 3 is not particularly limited, and examples thereof include aromatic solvents such as benzene, toluene, xylene, mesitylene, nitrobenzene, and cumene; ether solvents such as dimethyl ether, diethyl ether, tetrahydrofuran, isopropyl ether, and dioxane. , Toluene, xylene, tetrahydrofuran, dioxane and the like are preferably used. Although it does not specifically limit as a compounding quantity of the phosphorus ylide used in Wittig-Horner reaction in the said process 3, and the alkylphosphonic acid diester, It is 1-5 mol with respect to 1 mol of compounds shown by General formula (R)-(5). Preferably there is. The hydrogenation reaction (hydrogenation) performed on the obtained olefin after the Wittig-Horner reaction is preferably performed using a hydrogenation catalyst. Examples of the hydrogenation catalyst include a palladium catalyst and a platinum catalyst. From the viewpoint of good reaction efficiency, these palladium catalyst and platinum catalyst are preferably used by supporting about 1 to 20% by weight of palladium or platinum on a catalyst carrier such as activated carbon. Hereinafter, a palladium catalyst and a platinum catalyst supported on activated carbon or the like may be abbreviated as Pd / C and Pt / C, respectively. The blending amount of the hydrogenation catalyst used in the hydrogenation in step 3 is not particularly limited, but is preferably 0.01% by weight or more. If the blending amount is less than 0.01% by weight, the reaction rate of the hydrogenation reaction may decrease, and more preferably 0.02% by weight or more. On the other hand, the blending amount of the hydrogenation catalyst is usually 20% by weight or less.

  After completion of the reaction in the above step 3, a compound represented by the general formula (R)-(6) can be obtained by performing a treatment such as a liquid separation operation. You may refine | purify using column chromatography etc. as needed.

  In the general formula (R)-(6) thus obtained, Z is preferably a carboxyalkyl group, a carboxyl group, or a cyano group. In the case of a cyano group, Z is more preferably a carboxyalkyl group or a carboxyl group from the viewpoint that hydrolysis to a carboxylic acid is not easy. Examples of the carboxyalkyl group include a carboxyalkyl group having a linear or branched alkyl group having 1 to 10 carbon atoms. Examples of the linear or branched alkyl group having 1 to 10 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, and pentyl group. Among them, a suitable carboxyalkyl group for Z is a carboxyethyl group.

Subsequently, by using the compound represented by the general formula (R)-(6) obtained as described above, JP-A-9-212466 (Patent Document 1) and D. Basavaiah et al., Bovine Liver Acetone Powder (BLAP) Catalyzed Synthesis of Chiral C-8 Allyl Alcohols: An Application of Substrate Specificity Approach, Tetrahedron 1994, Vol.50, No.14, p.4137-4148 As in Step 4 above, (R)-(+)-α-lipoic acid represented by the formula (R)-(3) can be obtained. Further, as can be seen from the examples described later, the hydroxyl group of the compound represented by the general formula (R)-(6) is substituted with a mesyloxy group, and then Na ₂ S · 9H ₂ O, sulfur, etc. are used. (R)-(+)-α-lipoic acid can also be obtained. Furthermore, in the production method of the present invention, instead of the compound represented by the general formula (S)-(2a), the compound represented by the general formula (R)-(2b) is used as a starting material (R)-(+ ) -Α-lipoic acid can also be obtained. At this time, the S _N 2 type reaction may optionally be performed as an intermediate reaction to reverse the configuration, whereby the compound represented by the general formula (S)-(2a) is converted into (R)-(+ ) -Α-lipoic acid can be obtained, and (S)-(−)-α-lipoic acid can also be obtained from the compound represented by the general formula (R)-(2b). That is, only the necessary optical isomer can be produced from both the compound represented by the general formula (S)-(2a) and the compound represented by the general formula (R)-(2b).

  Next, in (S) -3-acyloxy-1-alkene represented by the general formula (S)-(2a), the compound represented by the general formula (S)-(7) when n = 3 is used as a starting material. A method for obtaining (R)-(+)-α-lipoic acid will be described with reference to the following chemical reaction formula (VI).

［式中、Ｘ及びＹは前記と同義である。］

[Wherein, X and Y are as defined above. ]

  As in step 5 above, the compound represented by the general formula (S)-(8) can be obtained from the compound represented by the general formula (S)-(7) by hydroboration using dicyclohexylborane. Hydroboration is usually performed with a boron compound in a solvent, but the solvent used is not particularly limited, and is preferably a sufficiently dehydrated aprotic solvent such as tetrahydrofuran, dioxane, etc. Is mentioned. Examples of the boron compound to be used include monoborane, diborane, propylborane, texylborane, catecholborane, pinacolborane, dicyclohexylborane, dicyamilborane, diisopinocanphenylborane, 9-borabicyclo [3.3.1] nonane ( 9-BBN). Among them, dicyclohexylborane is preferably used from the viewpoint of easy separation of reaction by-products and good reaction regioselectivity. Although it does not specifically limit as the usage-amount of a boron compound, It is preferable that it is 1-5 mol with respect to 1 mol of compounds shown by General formula (S)-(7). Moreover, it is preferable to perform the reaction temperature of hydroboration at -20-40 degreeC.

The compound represented by the general formula (S)-(8) obtained in the above step 5 is converted into the general formula (A) by an acetalization reaction using paraaldehyde or acetaldehyde diethyl acetal under an acid catalyst as in the above step 6. S)-(9) is obtained, and subsequently, JP-A-9-212466 (Patent Document 1) and D. Basavaiah et al., Bovine Liver Acetone Powder (BLAP) Catalyzed Synthesis of Chiral C-8 Allyl Alcohols: An Application of Substrate Specificity Approach, Tetrahedron 1994, Vol. 50, No. 14, p.4137-4148 (Non-Patent Document 2) etc. (R)-(+)-α-lipoic acid represented by 3) can be obtained. Further, as can be seen from the examples described later, the hydroxyl group of the compound represented by the general formula (R)-(6) is substituted with a mesyloxy group, and then Na ₂ S · 9H ₂ O, sulfur, etc. are used. (R)-(+)-α-lipoic acid can also be obtained. Furthermore, in the production method of the present invention, instead of the compound represented by the general formula (S)-(2a), the compound represented by the general formula (R)-(2b) is used as a starting material (R)-(+ ) -Α-lipoic acid can also be obtained. At this time, the S _N 2 type reaction may optionally be performed as an intermediate reaction to reverse the configuration, whereby the compound represented by the general formula (S)-(2a) is converted into (R)-(+ ) -Α-lipoic acid can be obtained, and (S)-(−)-α-lipoic acid can also be obtained from the compound represented by the general formula (R)-(2b). That is, only the necessary optical isomer can be produced from both the compound represented by the general formula (S)-(2a) and the compound represented by the general formula (R)-(2b).

  (R)-(+)-α-lipoic acid and (S)-(−)-α-lipoic acid, which are optically active substances obtained by the production method of the present invention, are used in the fields of pharmaceuticals, cosmetics, foods and the like. It is useful because it can be suitably used and can exhibit an appropriate pharmacological action.

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

Example 1
Synthesis 1
[Synthesis of 3-benzyloxy-1-propanol]
Slowly add diisobutylaluminum hydride ( ⁱ Bu ₂ AlH (DIBAL-H), 141.4 ml, 140 mmol) to a toluene solution (50 ml) of 2-phenyl-1,3-dioxane (20.9 g, 127 mmol) cooled in ice water. added. The reaction mixture was stirred at room temperature for 22 hours and then carefully poured into a mixture of 6M hydrochloric acid (100 ml) and ice. The separated organic phase was washed with 6M hydrochloric acid (30 ml) followed by saturated aqueous sodium bicarbonate (50 ml). The aqueous phase was extracted with ethyl acetate (50 ml x 2). The extracts were combined and washed with 6M hydrochloric acid (20 ml) and saturated aqueous sodium hydrogen carbonate (30 ml). The previous toluene extract and ethyl acetate extract were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 3-benzyloxy-1-propanol (20.75 g, 98.3 mmol). The chemical reaction formula is shown below.

The NMR data of 3-benzyloxy-1-propanol was as follows.
¹ H NMR (500 MHz) δ: 1.84-1.90 (m, 2H), 2.27 (bs, 1H), 3.67 (t, J = 5.8 Hz, 2H), 3.76-3.83 (m, 2H), 4.52 (s, 2H), 7.25-7.40 (m, 5H)

Synthesis 2
[Synthesis of 3-Benzyloxy-1-propanal]
Commercially available sodium hypochlorite aqueous solution (105 g, 13.64 g, 183.3 mmol) with 13% chlorine concentration was diluted with water (30 ml), and sodium bicarbonate (5 g, 59.5 mmol) was added to adjust the pH to about 9.5. Adjusted. 3-Benzyloxy-1-propanol (27.7 g, 166.6 mmol), TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical) (261 mg, 1.67 mmol) and potassium bromide (1.987 g, 16.7 mmol) was dripped over 50 minutes while maintaining the reaction temperature at 3-8 ° C while stirring vigorously in a two-phase system of water (50 ml) and toluene (166 ml). . After completion of dropping, the mixture was further stirred for 5 minutes. The pale orange organic solvent phase was separated and washed with water (100 ml x 2). Subsequently, the mixture was washed twice with a solution of potassium iodide (1 g) in 3M hydrochloric acid (30 ml) to remove TEMPO. Wash with water (50 ml x 2), saturated aqueous Na ₂ S ₂ O ₃ (50 ml x 2), brine (50 ml x 2), then dry over anhydrous MgSO ₄ , concentrate and aldehyde (23.8 g) Got. The chemical reaction formula is shown below.

Synthesis 3
[Synthesis of 5-Benzyloxy-3-hydroxy-1-pentene]
1,2-Dibromoethane (0.25 ml, 2.898 mmol) was added at once at room temperature in THF (20 ml) mixed with Mg (4.579 g, 188.4 mmol). The reaction started with an exotherm, and after a few minutes, the reaction solution turned light gray. Subsequently, a solution of vinyl bromide (12.26 ml, 173.9 mmol) dissolved in THF (40 ml) was added dropwise over about 1 hour. During the vinyl bromide addition, THF (40 ml) was added in two portions. After completion of the dropwise addition, stirring was continued for about 1 hour. The reaction mixture was diluted with toluene (50 ml) followed by cooling in an ice bath. 3-Benzyloxy-1-propanal (23.8 g, 144.9 mmol) was dissolved in toluene (20 ml) and added dropwise over 25 minutes. After stirring for 10 minutes, the reaction was quenched by careful addition of saturated aqueous ammonium chloride (200 ml) at ice bath temperature. The organic phase was separated, washed with 1M hydrochloric acid (100ml) and saturated aqueous sodium bicarbonate (100ml x 2), dried over anhydrous MgSO ₄ and concentrated to give a pale yellow oily 5-benzyloxy-3 -Hydroxy-1-pentene was obtained. This was purified by distillation (92-95 ° C./0.5 mmHg) to give oily 5-benzyloxy-3-hydroxy-1-pentene (22.79 g). The chemical reaction formula is shown below.

The NMR data of 5-benzyloxy-3-hydroxy-1-pentene were as follows.
¹ H NMR (500 MHz) δ: 1.80-1.92 (m, 2H), 2.80 (d, J = 4.3 Hz), 3.62-3.75 (m, 2H), 4.32-4.39 (m, 1H), 4.52 (s, 2H), 5.10 (d, J = 11 Hz, 1H), 5.27 (d, J = 17.1 Hz, 1H), 5.84-5.93 (m, 1H, 1H), 7.27-7.36 (m, 5H);
¹³ C NMR (125 MHz) δ: 36.3, 68.2, 71.7, 73.2, 114.3, 127.6, 127.7, 128.4, 137.9, 140.5

Synthesis 4
[Synthesis of (3S) -3-acetoxy-5-benzyloxy-1-pentene and (3R) -5-benzyloxy-3-hydroxy-1-pentene]
In toluene (20 ml), 5-benzyloxy-3-hydroxy-1-pentene (3.845 g, 20 mmol) obtained by Synthesis 1-3, isopropenyl acetate (2.20 ml, 20 mmol) and CAL-B ( Candida antarctica lipase type-B, “Chirazyme” manufactured by Roche, 100 mg) was mixed and reacted at 23 ° C. for 70 hours. The reaction mixture was filtered through Celite 545 and the remaining material was washed with 5 ml of toluene. The filtrate was concentrated, dissolved in dichloromethane (20 ml), succinic anhydride (1.2 g, 12 mmol) and triethylamine (1.32 g, 1.81 ml) were added, and the mixture was treated at room temperature for 12 hours. The reaction mixture was washed with 3M HCl (10 ml × 2), and the separated organic solvent phase was washed several times with 5% Na ₂ CO ₃ aqueous solution to extract carboxylic acid. The organic solvent phase was washed twice with brine, dried over anhydrous MgSO ₄ and then concentrated to a yellow oily (3S) -3-acetoxy-5-benzyloxy-1-pentene (2.70 g) Got. The obtained (3S) -3-acetoxy-5-benzyloxy-1-pentene was hydrolyzed with MeOH (10 ml) / water (3 ml) / NaOH (800 mg, 20 mmol), and (3S) -5- Benzyloxy-3-hydroxy-1-pentene (2.168 g, 11.28 mmol) was obtained. The basic aqueous phase was washed with toluene, and then (3R) -5-benzyloxy-3-hydroxy-1-pentene (1.26 g) was added thereto by hydrolysis with NaOH (800 mg, 20 mmol) for 12 hours. 33%). As a result of analysis by HPLC analysis (Chiralcel OD, hexane / 2-propanol = 30/1, 220 nm, 0.7 ml / min), (3S) -5-benzyloxy-3-hydroxy-1-pentene was 68.6% ee, ( 3R) -5-Benzyloxy-3-hydroxy-1-pentene was> 99% ee.

  The enantiomer (3S) -5-benzyloxy-3-hydroxy-1-pentene (2.168 g, 11.28 mmol) was resubmitted. (3S) -5-Benzyloxy-3-hydroxy-1-pentene (67.4% ee, 1.94 g, 10.1 mmol), isopropenyl acetate (0.675 ml, 614 mg, 6.13 mmol) and CAL-B (51 mg) Was reacted in toluene (10 ml) at 30 ° C. for 3 days to give (3S) -3-acetoxy-5-benzyloxy-1-pentene (1.02 g, 4.34 mmol, yield 43%). HPLC analysis (Chiralcel OD, hexane / 2-propanol = 30/1, 220 nm, 0.7 ml / min) revealed 97.8% ee. The chemical reaction formula is shown below.

The NMR data and specific rotation of (3S) -3-acetoxy-5-benzyloxy-1-pentene were as follows.
¹ H NMR (500 MHz) δ: 1.88-2.0 (m, 2H), 2.02 (s, 3H), 3.50 (t, J = 5 Hz, 2H), 4.47 (d, J = 11.5 Hz, 1H), 4.50 (d, J = 11.5 Hz, 1H), 5.17 (d, J = 11.5 Hz, 1H), 5.25 (d, J = 17 Hz, 1H), 5.40-5.45 (m, 1H), 5.75-5.84 (m, 1H), 7.25-7.38 (m, 5H);
¹³ C NMR (125 MHz) δ: 21.0, 34.3, 66.0, 72.9, 72.9, 116.6, 127.5, 127.6, 128.1, 128.3, 136.2, 138.1, 138.2, 170.0;
Specific rotation [α] _D ²⁰ -25.5 (C 1.11, CHCl ₃ , 97.8% ee)

The NMR data and specific rotation of (3R) -5-benzyloxy-3-hydroxy-1-pentene were as follows.
¹ H NMR (500 MHz) δ: 1.80-1.92 (m, 2H), 2.80 (d, J = 4.3 Hz), 3.62-3.75 (m, 2H), 4.32-4.39 (m, 1H), 4.52 (s, 2H), 5.10 (d, J = 11 Hz, 1H), 5.27 (d, J = 17.1 Hz, 1H), 5.84-5.93 (m, 1H, 1H), 7.27-7.36 (m, 5H);
¹³ C NMR (125 MHz) δ: 36.3, 68.2, 71.7, 73.2, 114.3, 127.6, 127.7, 128.4, 137.9, 140.5;
Specific rotation [α] _D ²² -12.2 (C1.24, CHCl ₃ ,> 99% ee)

Synthesis 5
[Synthesis of (3R) -3-acetoxy-5-benzyloxy-1-pentene]
While cooling a solution of (3R) -5-benzyloxy-3-hydroxy-1-pentene (8.6 g, 4.7 mmol) in pyridine (7.08 g, 7.24 ml, 89.5 mmol) in an ice bath, acetic anhydride (6.85 g, 6.34 ml, 67.1 mmol) was added dropwise. After 1 hour, the ice bath was removed and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into water and extracted with toluene. The organic solvent phase was subsequently washed with water, 1M HCl and saturated NaHCO ₃ solution and then dried over anhydrous MgSO ₄ . Concentration under reduced pressure gave (3R) -3-acetoxy-5-benzyloxy-1-pentene (10.2 g, 43.6 mmol, 97.4%). The chemical reaction formula is shown below.

Synthesis 6
[Synthesis of (4S) -acetoxy-6-benzyloxy-1-hexanal]
(3R) -3-acetoxy-5-benzyloxy-1-pentene (4.69 g, 20 mmol), Rh (acac) (CO) ₂ (Aldrich, 3.1 mg, 0.012 mmol) in toluene (20 ml) And a solution in which BIPHEPHOS (19 mg, 0.024 mmol) was dissolved was placed in a 100 ml autoclave and purged twice with synthesis gas (CO / H ₂ , about 10 Kg). The reaction was carried out at 60 ° C for 8 hours at a synthesis gas pressure of 15 Kg / cm ² . The reaction mixture was concentrated under reduced pressure to give a light brown oil, which was purified by silica gel column chromatography (hexane / ethyl acetate = 6 / 1-4 / 1) to give (4S) -acetoxy-6-benzyloxy 1-hexanal (4.7 g, yield 88.9%) was obtained. The chemical reaction formula is shown below.

Synthesis 7
[Synthesis of (6S) -6-acetoxy-8-benzyloxy-2-octenoic acid ethyl ester]
60% sodium hydride (960 mg, 24 mmol) was added, washed with dry hexane (15 ml x 2), and then dry THF (20 ml) was added. Subsequently, a dry THF (20 ml) solution of (EtO) ₂ P (O) CH ₂ CO ₂ Et (5.76 g, 25.7 mmol) was added dropwise under ice cooling. When hydrogen evolution stopped, a toluene (40 ml) solution of (4S) -acetoxy-6-benzyloxy-1-hexanal (4.52 g, 17.1 mmol) was added dropwise while cooling in an ice bath. After stirring for 20 minutes, the reaction mixture was poured into a mixture of toluene (30 ml) and water (100 ml). The separated organic phase was washed with brine, dried over anhydrous MgSO ₄ and then concentrated under reduced pressure. The colorless oil obtained was purified by silica gel column chromatography (hexane / ethyl acetate = 15/1, 10/1) to give (6S) -6-acetoxy-8-benzyloxy-2-octenoic acid ethyl ester. (5.36 g, 93.7% yield) was obtained. The chemical reaction formula is shown below.

The NMR data and specific rotation of (6S) -6-acetoxy-8-benzyloxy-2-octenoic acid ethyl ester were as follows.
¹ H NMR (500 MHz) δ: 1.28 (t, J = 7.0 Hz, 3H), 1.70-1.77 (m, 2H), 1.84-1.90 (m, 2H), 2.0 (s, 3H), 2.20-2.27 ( m, 2H), 3.45-3.54 (m, 2H), 4.18 (q, J = 7.0 Hz, 2H), 4.47 (s, 2H), 5.04-5.10 (m 1H), 5.81 (d, J = 16 Hz, 1H), 6.92 (dt, J = 16.0 and 7.0 Hz, 1H), 7.26-7.37 (m, 5H);
¹³ C NMR (125 MHz) δ: 14.3, 21.1, 28.1, 32.7, 34.3, 60.2, 66.5, 71.2, 73.1, 121.7, 127.6, 127.7, 128.4, 138,2, 147.9, 166.5, 170.6;
Specific rotation [α] _D ^21.4 +31.3 (c = 1.43, Toluene,> 99% ee)

Synthesis 8
[Synthesis of (6S) -6-acetoxy-8-hydroxy-octanoic acid ethyl ester]
(6S) -6-acetoxy-8-benzyloxy-2-octenoic acid ethyl ester (5.36 g, 16 mmol) and 10% Pd / C (400 mg) in ethanol (20 ml) under 1 atm hydrogen atmosphere The reaction was allowed to proceed at room temperature for 40 hours. The reaction mixture was filtered through Celite 545, and the filtrate was concentrated under reduced pressure to obtain (6S) -6-acetoxy-8-hydroxy-octanoic acid ethyl ester (3.81 g, yield 96.7%). The chemical reaction formula is shown below.

The NMR data and specific rotation of (6S) -6-acetoxy-8-hydroxy-octanoic acid ethyl ester were as follows.
¹ H NMR (500 MHz, CDCl ₃ ) δ: 1.25 (t, J = 7.5 Hz, 3H), 1.30-1.85 (m, 9H), 2.09 (s, 3H), 2.30 (t, J = 7.5 Hz, 2H ), 3.50-3.58 (m, 1H), 3.60-3.67 (m, 1H), 4.12 (q, J = 7.5 Hz, 2H), 5.00-5.10 (m, 1H);
¹³ C NMR (125 MHz) δ: 14.2, 21.0, 24.6, 24.9, 34.0, 34.1, 37.4, 58.4, 60.2, 71.2, 171.8, 173.5;
Specific rotation [α] _D ²¹ +28.99 (c = 1.17, Toluene,> 99% ee)

Synthesis 9
[Synthesis of (6S) -6,8-Dihydroxy-octanoic acid ethyl ester]
(6S) -6-acetoxy-8-hydroxy-octanoic acid ethyl ester (739 mg) dissolved in ethanol (2 ml) after hydrogen generation was completed by adding a catalytic amount of metallic sodium to ethanol (3 ml) at room temperature , 3 mmol). The reaction mixture was allowed to stir at room temperature for 1 hour and then poured into a mixture of toluene (30 ml) and water (30 ml). The organic phase was separated, washed with brine, dried over anhydrous MgSO ₄ and then concentrated under reduced pressure to give (6S) -6,8-dihydroxy-octanoic acid ethyl ester (584 mg, 95.4% yield) as colorless Obtained as an oil. The chemical reaction formula is shown below.

The NMR data and specific rotation of (6S) -6,8-dihydroxy-octanoic acid ethyl ester were as follows.
¹ H NMR (500 MHz CDCl ₃ ) δ: 1.26 (t, J = 7.0 Hz, 3H), 1,30-1.78 (m, 8H), 2.30 (bs, 1H), 2.32 (t, J = 7.0 Hz, 2H), 2.46 (bs, 1H), 3.80-3.90 (m, 3H), 4.13 (q, J = 7.0 Hz, 2H);
¹³ C NMR (125 MHz) δ: 14.2, 24.7, 25.0, 34.1, 37.3, 38.2, 60.3, 61.8, 71.8, 173.8;
Specific rotation [α] _D ^22.2 +0.42 (c = 1.02, Toluene,> 99% ee)

Synthesis 10
[Synthesis of (6S) -6,8-Dimesyloxy-octanoic acid ethyl ester]
(6S) -6,8-Dihydroxy-octanoic acid ethyl ester (361 mg, 1.77 mmol) was dissolved in dichloromethane (10 ml) and cooled on ice. Subsequently, triethylamine (1.07 g, 1.48 ml, 10.6 mmol) and methanesulfonyl chloride (0.55 ml, 7.07 mmol) were sequentially added. After stirring in an ice bath for 30 minutes and at room temperature for 3 hours, 1M HCl (20 ml) was added to stop the reaction. The reaction mixture was extracted with dichloromethane (20 ml), and the extract was washed with saturated aqueous NaHCO ₃ (10 ml × 2) and dried over anhydrous MgSO ₄ . (6S) -6,8-Dimesyloxy-octanoic acid ethyl ester (590 mg) was purified by silica gel column chromatography (toluene / ethyl acetate = 5/1 to 3/1). ) The chemical reaction formula is shown below.

The NMR data and specific rotation of (6S) -6,8-dimesyloxy-octanoic acid ethyl ester were as follows.
¹ H NMR (500 MHz CDCl ₃ ) δ: 1.25 (t, J = 7.5 Hz, 3H), 1.40-1.50 (m, 2H), 1.62-1.82 (m, 4H), 2.04-2.19 (m, 2H), 2.33 (t, J = 7.0 Hz, 2H), 3.06 (s, 6H), 4.12 (q, J = 7.5 Hz, 2H), 4.32-4.40 (m, 2H), 4.85-4.95 (m, 1H);
Specific rotation [α] _D ²⁶ +19.4 (c = 1.08, CHCl ₃ ,> 99% ee)

Synthesis 11
[Synthesis of (R)-(+)-α-lipoic acid ethyl ester and (R)-(+)-α-lipoic acid]
In DMF (20 ml), Na ₂ S · 9H ₂ O (608 mg, 2.53 mmol) and sulfur (81 mg, 2.53 mmol) were mixed and reacted at 80 ° C. by blocking light for 1.5 hours. To this reaction mixture, a solution of (6S) -6,8-dimesyloxy-octanoic acid ethyl ester (759 mg, 2.11 mmol) in DMF (5 ml) was added dropwise over 25 minutes using a dropping funnel while blocking light. Then, stirring was continued for 3.5 hours. After the reaction mixture was cooled to room temperature, toluene (30 ml) and water (30 ml) were added. The separated organic phase was washed with brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The resulting yellow oil was purified by silica gel column chromatography (hexane / ethyl acetate = 15/1) to give (R)-(+)-α-lipoic acid ethyl ester (340 mg, yield 68.8% ) In addition, the obtained ester can be hydrolyzed to stably obtain (R)-(+)-α-lipoic acid. The chemical reaction formula is shown below.

The NMR data and specific rotation of (R)-(+)-α-lipoic acid ethyl ester were as follows.
¹ H NMR (500 MHz CDCl ₃ ) δ: 1.26 (t, J = 7.5 Hz, 3H), 1.40-1.75 (m, 6H), 1.87-1.95 (m, 1H), 2.31 (t, J = 7.0 Hz, 2H), 2.43-2.50 (m, 1H), 3.09-3.23 (m, 2H), 3.55-3.62 (m, 1H), 4.12 (q, J = 7.5 Hz, 2H);
¹³ C NMR (125 MHz) δ: 14.2, 24.6, 28.6, 34.0, 34.5, 38.3, 40.1, 56.2, 60.1, 173.3;
Specific rotation [α] _D ²¹ +60.8 (c = 1.57, CHCl ₃ ,> 99% ee)
Specific rotation [α] _D ¹⁹ +71.9 (c = 2.13, Benzene)

(Example 2)
Synthesis 12
[Synthesis of (6R) -6,8-Dimesyloxy-octanoic acid ethyl ester]
Using (3S) -3-acetoxy-5-benzyloxy-1-pentene obtained by Synthesis 4, (6R) -6,8-dihydroxy-octanoic acid ethyl ester was obtained by the same method as Synthesis 6-9. . Dissolve this (6R) -6,8-dihydroxy-octanoic acid ethyl ester (603 mg, 2.95 mmol) in dichloromethane (10 ml) and add to triethylamine (1.79 g, 2.47 ml, 17.7 mmol) while cooling in an ice bath. Subsequently, methanesulfonyl chloride (0.91 ml, 11.8 mmol) was added. After stirring in an ice bath for 30 minutes and at room temperature for 2 hours, toluene (30 ml) and water (30 ml) were added, and the organic phase was separated. The extract was washed successively with 1M HCl (10 ml × 2), saturated aqueous NaHCO ₃ (10 ml × 2) and brine, and dried over anhydrous MgSO ₄ . The oily substance obtained by concentration under reduced pressure was purified by silica gel column chromatography (toluene / ethyl acetate = 3/1) to give (6R) -6,8-dimethyloxy-octanoic acid ethyl ester (957 mg). . The optical yield of the obtained (6R) -6,8-dimesyloxy-octanoic acid ethyl ester is 97.8% ee, similar to the starting compound (3S) -3-acetoxy-5-benzyloxy-1-pentene. . The chemical reaction formula is shown below.

The specific rotation of (6R) -6,8-dimesyloxy-octanoic acid ethyl ester was as follows.
Specific rotation [α] _D ^23.0 -20.8 (c = 1.04, CHCl ₃ )

Synthesis 13
[Synthesis of (6S) -6,8-diacetoxy-octanoic acid ethyl ester, (R)-(+)-α-lipoic acid ethyl ester and (R)-(+)-α-lipoic acid]
(6R) -6,8-Dimesyloxy-octanoic acid ethyl ester (224 mg, 0.62 mmol), Cs ₂ CO ₃ (1.23 g, 3.72 mmol) and NaOAc (610 mg, 7.44 mmol) in dry DMF (5 ml) The reaction was carried out at 65 ° C. for 9 hours and further at 80 ° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into toluene (30 ml) and water (30 ml). The organic phase was separated, washed with brine, dried over anhydrous MgSO ₄ , and the oily substance obtained by concentration under reduced pressure was purified by silica gel column chromatography (toluene / ethyl acetate = 10/1 to 5/1). (6S) -6,8-diacetoxy-octanoic acid ethyl ester was obtained. Using the obtained (6S) -6,8-diacetoxy-octanoic acid ethyl ester, (R)-(+)-α-lipoic acid ethyl ester was obtained in the same manner as in Synthesis 9-11. In addition, the obtained ester can be hydrolyzed to stably obtain (R)-(+)-α-lipoic acid. The optical yields of the obtained (6S) -6,8-diacetoxy-octanoic acid ethyl ester, (R)-(+)-α-lipoic acid ethyl ester and (R)-(+)-α-lipoic acid are As with the starting compound (6R) -6,8-dimesyloxy-octanoic acid ethyl ester, it becomes 97.8% ee. The chemical reaction formula is shown below.

The specific rotation of (6S) -6,8-diacetoxy-octanoic acid ethyl ester was as follows.
Specific rotation [α] _D ^24.2 +14.9 (c = 1.03, CHCl ₃ )

(Example 3)
Synthesis 14
[Synthesis of 6- (methoxymethoxy) -1-hexanol]
Mix 1,6-hexanediol (46.2 g, 0.391 mol), dimethoxymethane (69.6 g, 0.55 mol) and Amberlyst-15 (0.5 g, registered trademark) in dichloromethane (100 ml) at 50 ° C. for 40 hours. The reaction was carried out by heating. After cooling to room temperature, the reaction mixture was filtered through Celite 545 and the filtrate was concentrated under reduced pressure. The colorless remaining oily substance was distilled (Vigreux column) to obtain 6- (methoxymethoxy) -1-hexanol (30.1 g, yield 47.5%). The chemical reaction formula is shown below.

The NMR data of 6- (methoxymethoxy) -1-hexanol was as follows.
¹ H NMR (500 MHz) δ: 1.28 (bs, 1H), 1.38-1.45 (m, 4H), 1.55-1.65 (m, 4H), 3.36 (s, 3H), 3.52 (t, J = 6.8 Hz, 2H), 3.62-3.68 (m, 2H), 4.62 (s, 2H)

Synthesis 15
[Synthesis of 6- (methoxymethoxy) -1-hexanal]
6- (Methoxymethoxy) -1-hexanol (29.5 g, 182 mmol), TEMPO (142 mg, 0.91 mmol), KBr (1.08 g, 9.1 mmol) in dichloromethane / water two-phase system (mixed solvent) (dichloromethane / water = 100 ml / 50 ml) and stirred vigorously while cooling in an ice bath. While maintaining the temperature of the reaction solution at 5-10 ° C., a solution adjusted to pH 9.5 by adding NaHCO ₃ (15.3 g, 182 mmol) to 104 g of 13% NaOCl aqueous solution is added dropwise over 15-20 minutes. did. The reaction mixture was stirred for an additional 5 minutes. After separating the pale orange organic phase, the aqueous phase was extracted with dichloromethane (30 ml x 2). The organic phases were combined and washed with 3M HCl (30 ml) containing potassium iodide (500 mg). Subsequently, the mixture was washed with a saturated aqueous NaHCO ₃ solution (30 ml), a 10% aqueous sodium thiosulfate solution (30 ml), and saturated brine (50 ml). The organic phase was dried over anhydrous MgSO ₄ and then concentrated under reduced pressure to give a pale yellow oil. Distillation (63-65 ° C./0.5 mmHg) gave 6- (methoxymethoxy) -1-hexanal (25.7 g, yield 88%). The chemical reaction formula is shown below.

The NMR data of 6- (methoxymethoxy) -1-hexanal were as follows.
¹ H NMR (500 MHz) δ: 1.39-1.47 (m, 2H), 1.59-1.71 (m, 4H), 2.45 (t, J = 7.6 Hz, 2H), 3.36 (s, 3H), 3.52 (t, J = 6.4 Hz, 2H), 4.61 (s, 2H), 9.77 (bs, 1H);
¹³ C NMR (125 MHz) δ: 21.8, 25.8, 29.5, 43.8, 55.1, 67.5, 96.4, 202.5

Synthesis 16
[Synthesis of 3-hydroxy-8- (methoxymethoxy) -1-octene]
Magnesium (4.26 g, 175.2 mmol) was dispersed in THF (20 ml), and 1,2-dibromoethane (0.17 ml, 376 mg, 2.0 mmol) was added at room temperature. The color of the reaction solution changed from pale yellow to gray with an exotherm. A THF solution (40 ml) of vinyl bromide (11.4 ml, 17.3 g, 162 mmol) was added dropwise over 1 hour using a dropping funnel. Meanwhile, THF (20 ml × 2) was added to the reaction solution 15 minutes and 30 minutes after the dropping. After completion of the dropwise addition, the reaction mixture was further stirred at room temperature for 1 hour, diluted with toluene (50 ml) and cooled in an ice bath. To this was added dropwise a solution of 6- (methoxymethoxy) -1-hexanal (21.5 g, 134.8 mmol) in THF (30 ml) over 30 minutes. After completion of dropping, the mixture was stirred for 10 minutes. The reaction was stopped by adding saturated aqueous ammonium chloride (100 ml). After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure using an evaporator so that the liquid volume became half, and extracted with ethyl acetate (50 ml × 2). The extract was washed with 1M HCl, saturated aqueous NaHCO ₃ solution and saturated brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. Distillation (98-102 ° C./0.5 mmHg) gave 3-hydroxy-8- (methoxymethoxy) -1-octene (23.0 g, yield 90.6%). The chemical reaction formula is shown below.

The NMR data of 3-hydroxy-8- (methoxymethoxy) -1-octene were as follows.
¹ H NMR (500 MHz) δ: 1.35-1.65 (m, 9H), 3.36 (s, 3H), 3.52 (t, J = 6.4 Hz, 2H), 4.06-4.15 (m, 1H), 4.61 (s, 2H), 5.10 (d, J = 11.6 Hz, 1H), 5.22 (d, J = 18.7 Hz, 1H), 5.83-5.90 (m, 1H);
¹³ C NMR (125 MHz) δ: 25.1, 26.1, 29.6, 36.9, 55.0, 67.7, 73.1, 96.3, 114.5, 141.2

Synthesis 17
[Synthesis of (3S) -3-acetoxy-8- (methoxymethoxy) -1-octene and (3R) -3-hydroxy-8- (methoxymethoxy) -1-octene]
3-hydroxy-8- (methoxymethoxy) -1-octene obtained by synthesis 14-16 (9.413 g, 50.0 mmol), isopropenyl acetate (5.51 ml, 5.01 g, 50.0 mmol) in toluene (50 ml) ) And CAL-B (Candida Antarctica lipase type-B, “Chirazyme” manufactured by Roche, 250 mg) were mixed and reacted by gently stirring at room temperature (25 ° C.) for 24 hours. The reaction mixture was filtered through Celite 545 and concentrated under reduced pressure to give a colorless oil (11.05 g).

The above oily substance (11.05 g) was dissolved in dichloromethane (50 ml), succinic anhydride (3.0 g, 30 mmol) and then triethylamine (4.18 ml, 3.04 g, 30 mmol) were added, and the mixture was stirred at room temperature for 12 hours. . The reaction mixture was washed with 3M HCl (20 ml), and the carboxylic acid was extracted several times with 5% Na ₂ CO ₃ aqueous solution. The remaining organic phase was washed with brine, dried over anhydrous MgSO ₄ , and then concentrated under reduced pressure to obtain a crude product of (3S) -3-acetoxy-8- (methoxymethoxy) -1-octene. . This was subjected to short path distillation to obtain (3S) -3-acetoxy-8- (methoxymethoxy) -1-octene (5.65 g, yield 49.2%) as a colorless oily substance.

The 5% Na ₂ CO ₃ extract was washed with toluene (30 ml) to remove neutral substances. NaOH (4.0 g, 100 mmol) was added to this aqueous solution and stirred at room temperature for 6 hours. The reaction mixture was extracted with dichloromethane (30 ml x 2) and the combined extracts were washed with brine (50 ml), dried over anhydrous MgSO ₄ and then concentrated in vacuo. The residual oil thus obtained was subjected to short-path distillation to obtain (3R) -3-hydroxy-8- (methoxymethoxy) -1-octene (4.74 g, yield 50.4%). The chemical reaction formula is shown below.

The NMR data and specific rotation of (3S) -3-acetoxy-8- (methoxymethoxy) -1-octene were as follows.
¹ H NMR (500 MHz) δ: 1.30-1.42 (m, 4H), 1.55-1.70 (m, 4H), 2.06 (s, 3H), 3.36 (s, 3H), 3.51 (t, J = 6.4 Hz, 2H), 4.61 (s, 2H), 5.15-5.26 (m, 3H), 5.74-5.81 (m, 1H);
¹³ C NMR (125 MHz) δ: 21.0, 24.7, 25.8, 29.4, 34.0, 54.9, 67.4, 74.5, 96.2, 116.4, 136.4, 170.0;
Specific rotation [α] _D ^25.2 -7.63 (C 1.20, CHCl ₃ , 96.8% ee)
(3S) -3-Acetoxy-8- (methoxymethoxy) -1-octene was hydrolyzed with NaOH to (3R) -3-hydroxy-8- (methoxymethoxy) -1-octene, and then 3,5 -After reacting with dinitrobenzoyl chloride to give 3,5-dinitroester, it was analyzed with an optically active column. (Chiralcel OD, hexane / EtOH = 9/1, 254 nm, flow rate 1.4 ml / min, 96.8% ee)
Specific rotation [α] _D ^22.5 +10.3 (C 1.05, CHCl ₃ )

The NMR data and specific rotation of (3R) -3-hydroxy-8- (methoxymethoxy) -1-octene were as follows.
¹ H NMR (500 MHz) δ: 1.35-1.65 (m, 9H), 3.36 (s, 3H), 3.52 (t, J = 6.4 Hz, 2H), 4.06-4.15 (m, 1H), 4.61 (s, 2H), 5.10 (d, J = 11.6 Hz, 1H), 5.22 (d, J = 18.7 Hz, 1H), 5.83-5.90 (m, 1H);
¹³ C NMR (125 MHz) δ: 25.1, 26.1,29.6, 36.9, 55.0, 67.7, 73.1, 96.3, 114.5, 141.2;
Specific rotation [α] _D ^27.2 -5.61 (C 1.10, CHCl ₃ , 95.6% ee)
(3R) -3-Hydroxy-8- (methoxymethoxy) -1-octene was reacted with 3,5-dinitrobenzoyl chloride to give 3,5-dinitro ester, and then analyzed with an optically active column. (Chiralcel OD, hexane / EtOH = 9/1, 254 nm, flow rate 1.4 ml / min, 95.6% ee)
Specific rotation [α] _D ^21.5 -9.78 (C 1.02, CHCl ₃ )

Synthesis 18
[Synthesis of (3S) -8- (methoxymethoxy) -1,3-octanediol]
BH ₃ / THF (15 ml, 15 mmol) was cooled in an ice bath (5 ° C. or lower), and a THF (10 ml) solution of cyclohexene (3.04 ml, 2.47 g, 30 mmol) was added dropwise over 30 minutes. After stirring for another 30 minutes at this temperature, a solution of (3S) -3-acetoxy-8- (methoxymethoxy) -1-octene (2.3 g, 9.98 mmol) in THF (10 ml) was added dropwise over 20 minutes. . After stirring at room temperature for 16 hours, 3M NaOH (30 ml) was carefully added while cooling in an ice bath, and then 34.5% H ₂ O ₂ (30 ml) was slowly added dropwise. After stirring in an ice bath for 1 hour and at room temperature for 10 hours, the reaction mixture was concentrated by an evaporator until the liquid volume of the reaction mixture was reduced to about half. Extract with ethyl acetate (30 ml x 3), wash the extract with saturated sodium thiosulfate (30 ml x 2) and saturated brine (30 ml), dry over anhydrous MgSO ₄ , and concentrate under reduced pressure. (3S) -8- (methoxymethoxy) -1,3-octanediol was obtained. This was subjected to short-step distillation to obtain (3S) -8- (methoxymethoxy) -1,3-octanediol (1.75 g, yield 85%). The chemical reaction formula is shown below.

The NMR data and specific rotation of (3S) -8- (methoxymethoxy) -1,3-octanediol were as follows. Here, the optical yield of (3S) -8- (methoxymethoxy) -1,3-octanediol is (3S) -1,3-dibenzoyloxy-8- (methoxymethoxy) obtained by esterification. -Determined by measuring the optical yield of octane.
¹ H NMR (500 MHz) δ: 1.35-1.75 (m, 10H), 2.26-2.40 (m, 2H), 3.36 (s, 3H), 3.53 (t, J = 6.4 Hz, 2H), 3.80-3.95 ( m, 3H), 4.61 (s, 2H);
¹³ C NMR (125 MHz) δ: 25.3, 26.1, 29.6, 37.6, 38.3, 55.0, 61.3, 67.7, 71.6, 96.3;
Specific rotation of (3S) -8- (methoxymethoxy) -1,3-octanediol [α] _D ^21.5 -1.92 (C1.01, CHCl ₃ , 96.5% ee)
Specific rotation of (3S) -1,3-dibenzoyloxy-8- (methoxymethoxy) -octane [α] _D ^23.2 +34.9 (C1.05, CHCl ₃ , 96.5% ee) (Chiralcel OJ-H, hexane / EtOH = 9/1, 254 nm, flow rate 0.8 ml / min)

Synthesis 19
[Synthesis of (4S) -2-methyl-4- (5-hydroxypentyl) -1,3-dioxane]
(3S) -8- (methoxymethoxy) -1,3-octanediol (1.57 g, 7.61 mmol) and Amberlyst-15 (100 mg, registered trademark) were heated to reflux in methanol (30 ml) for 63 hours. After cooling to room temperature, the mixture was filtered through Celite 545, and the filtrate was concentrated to obtain (3S) -8-hydroxy-1,3-octanediol (1.3 g). Subsequently, paraaldehyde (5.03 g, 38.1 mmol), catalytic amounts of CSA (camphorsulfonic acid) and dichloromethane (20 ml) were added, and the mixture was stirred at room temperature for 22 hours for acetalization. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was stirred with THF and 1M HCl at room temperature for 6 hours, and neutralized with a saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate (30 ml), dried over anhydrous MgSO ₄ and then concentrated under reduced pressure. The obtained oily substance was purified by column chromatography to obtain (4S) -2-methyl-4- (5-hydroxypentyl) -1,3-dioxane (768 mg, 53.6%). The optical yield of the obtained (4S) -2-methyl-4- (5-hydroxypentyl) -1,3-dioxane is (3S) -8- (methoxymethoxy) -1,3- It becomes 96.5% ee like octanediol. The chemical reaction formula is shown below.

The NMR data and specific rotation of (4S) -2-methyl-4- (5-hydroxypentyl) -1,3-dioxane were as follows.
¹ H NMR (500 MHz) δ: 1.20-1.70 (m, 10H), 1.32 (d, J = 5.2 Hz, 1H), 3.57-3.80 (m, 4H), 4.07-4.13 (m, 2H), 4.68 ( t, J = 5.2 Hz, 1H);
¹³ C NMR (125 MHz) δ: 21.1, 24.7, 25.7, 31.1, 32.5, 35.9, 62.4, 66.5, 76.5, 98.9;
Specific rotation [α] _D ^23.1 -9.03 (C 1.22, CHCl ₃ )

Synthesis 20
[Synthesis of (6S)-(2-Methyl-1,3-dioxanyl) -6-hexanoic acid]
(4S) -2-methyl-4- (5-hydroxypentyl) -1,3-dioxane (768 mg, 4.08 mmol), TEMPO (31.3 mg, 0.2 mmol), phosphate buffer (pH) in acetonitrile (10 ml) 6.86, 8 ml) and NaClO ₂ aqueous solution (1.38 g: containing 79% by weight, 12.3 mmol) were stirred at room temperature, and then sodium hypochlorite aqueous solution (NaOCl, 0.1 ml: containing 13% by weight) at a time. The mixture was added and stirred for 1.5 hours. The pH was adjusted to about 8-9 by adding water (20 ml) and 2M aqueous NaOH. Saturated aqueous Na ₂ SO ₃ (5 ml) was added to the mixture at ice bath temperature and stirred for 0.5 h. Toluene (20 ml) was added and the organic phase was separated and discarded. CHCl ₃ (30 ml) was added to the aqueous phase followed by 1M HCl to pH 3-4. The organic phase was washed with saturated brine, dried over anhydrous MgSO ₄ , and concentrated under reduced pressure to give a colorless oil (709 mg, yield 86%). The optical yield of the obtained (6S)-(2-methyl-1,3-dioxanyl) -6-hexanoic acid is (4S) -2-methyl-4- (5-hydroxypentyl)- It becomes 96.5% ee like 1,3-dioxane. The chemical reaction formula is shown below.

The NMR data and specific rotation of (6S)-(2-methyl-1,3-dioxanyl) -6-hexanoic acid were as follows.
¹ H NMR (500 MHz) δ: 1.31 (d, J = 5.15 Hz, 3H), 1.37-1.70 (m, 8H), 2.37 (t, J = 7.4 Hz, 2H), 3.56-3.63 (m, 1H) , 3.70-3.76 (m, 1H), 4.06-4.12 (m, 1H), 4.67 (q, J = 5.15 Hz, 1H);
¹³ C NMR (125 MHz) δ: 21.1, 24.4, 24.5, 31.0, 33.8, 35.5, 66.4, 76.3, 98.9, 179.5;
Specific rotation [α] _D ^22.9 -9.79 (C 1.02, CHCl ₃ )

Synthesis 21
[Synthesis of (6S) -6,8-dihydroxy-octanoic acid methyl ester]
The carboxylic acid (709 mg, 3.51 mmol) obtained by Synthesis 20 and Amberlyst-15 (213 mg, registered trademark) were added to methanol (40 ml), and the mixture was heated to reflux for 3 days. The reaction mixture was cooled to room temperature, filtered through Celite 545, and the filtrate was concentrated under reduced pressure to obtain a pale yellow oily ester. Purification by silica gel column chromatography (toluene / ethyl acetate = 1/1 to 100% ethyl acetate) gave (6S) -6,8-dihydroxy-octanoic acid methyl ester (588 mg, yield 88%). . The optical yield of the obtained (6S) -6,8-dihydroxy-octanoic acid methyl ester was the same as that of the starting compound (6S)-(2-methyl-1,3-dioxanyl) -6-hexanoic acid. 96.5% ee. The chemical reaction formula is shown below.

The NMR data and specific rotation of (6S) -6,8-dihydroxy-octanoic acid methyl ester were as follows.
¹ H NMR (500 MHz) δ: 1.34-1.75 (m, 8H), 2.33 (t, J = 7.35 Hz, 2H), 2.82 (bs, 1H), 2.92 (bs, 1H), 3.67 (s, 3H) , 3.80-3.93 (m, 3H);
¹³ C NMR (125 MHz) δ: 24.7, 25.0, 33.9, 37.1, 38.3, 51.5, 61.0, 70.9, 174.4;
Specific rotation [α] _D ^22.6 -3.70 (C 1.13, CHCl ₃ )

Synthesis 22
[Synthesis of (6S) -6,8-Dimesyloxy-octanoic acid methyl ester, (R)-(+)-α-lipoic acid methyl ester and (R)-(+)-α-lipoic acid]
(6S) -6,8-Dimesyloxy-octanoic acid methyl ester was obtained in the same manner as in Synthesis 10 using (6S) -6,8-dihydroxy-octanoic acid methyl ester obtained in Synthesis 21. Subsequently, (R)-(+)-α-lipoic acid methyl ester can be obtained by the same method as in Synthesis 11 using this (6S) -6,8-dimethyloxy-octanoic acid methyl ester. In addition, the obtained ester can be hydrolyzed to stably obtain (R)-(+)-α-lipoic acid. The optical yields of the obtained (6S) -6,8-dimesyloxy-octanoic acid methyl ester, (R)-(+)-α-lipoic acid methyl ester and (R)-(+)-α-lipoic acid are Like the starting compound (6S) -6,8-dihydroxy-octanoic acid methyl ester, it becomes 96.5% ee. The chemical reaction formula is shown below.

The NMR data and specific rotation of (6S) -6,8-dimesyloxy-octanoic acid methyl ester were as follows.
¹ H NMR (500 MHz) δ: 1.41-1.50 (m, 2H), 1.62-1.84 (m, 4H), 2.12-2.19 (m, 2H), 2.34 (t, J = 7.30 Hz, 2H), 3.06 ( s, 6H), 3.68 (s, 3H), 4.32-4.40 (m, 2H), 4.87-4.94 (m, 1H);
¹³ C NMR (125 MHz) δ: 24.0, 24.3, 33.4, 33.8, 34.4, 37.2, 38.5, 51.4, 65.6, 78.5, 173.5;
Specific rotation [α] _D ^22.1 +20.6 (C 1.11, CHCl ₃ )

Claims (6)

The following general formula (1):

[Wherein, n is an integer of 0 to 3, and X is a protected hydroxy group, a protected thiol group, or a halogen atom. ]
The compound represented by the following general formula (S)-(2a) is reacted with an acylating agent comprising a carboxylic acid ester in the presence of lipase or esterase and then transesterified:

Or the following general formula (R)-(2b):

[Wherein, n and X are as defined above, and Y is an acyl group. ]
And (S) -3-acyloxy-1-alkene or (R) -3-hydroxy-1-alkene.   The method for producing (S) -3-acyloxy-1-alkene or (R) -3-hydroxy-1-alkene according to claim 1, wherein the lipase or esterase is derived from a microorganism.   The method for producing (S) -3-acyloxy-1-alkene or (R) -3-hydroxy-1-alkene according to claim 2, wherein a lipase derived from the genus Candida is used.   The method for producing (S) -3-acyloxy-1-alkene or (R) -3-hydroxy-1-alkene according to any one of claims 1 to 3, wherein the acylating agent is a carboxylic acid vinyl ester. The following general formula (S)-(2a) obtained by the method according to claim 1:

[Wherein, n and X are as defined above, and Y is an acyl group. ]
(S) -3-Acyloxy-1-alkene represented by the following general formula (R)-(2b):

[Wherein, n and X are as defined above. ]
(R) -3-Hydroxy-1-alkene represented by the following formula (R)-(3):

The manufacturing method of (R)-(+)-(alpha) -lipoic acid shown by these. The following general formula (S)-(2a) obtained by the method according to claim 1:

[Wherein, n and X are as defined above, and Y is an acyl group. ]
(S) -3-Acyloxy-1-alkene represented by the following general formula (R)-(2b):

[Wherein, n and X are as defined above. ]
(R) -3-Hydroxy-1-alkene represented by the following formula (S)-(3):

The manufacturing method of (S)-(-)-(alpha) -lipoic acid shown by these.