JP2005304368A - Method for producing optically active 4-(n-protected amino)-1-alken-3-ol and method for producing 3-benzamide-2-hydroxycarboxylic acid or its salt using the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrially suitable method for producing a 3-benzamide-2-hydroxycarboxylic acid or its salt represented by 3-benzamide-2-hydroxy-3-phenylpropionic acid in a high yield and in high optical purity. <P>SOLUTION: The method for producing a 3-benzamide-2-hydroxycarboxylic acid or its salt comprises producing an optically active 4-(N-protected amino)-1-alken-3-ol represented by formula (R is an alkyl group, an alkenyl group or the like; X is a group for protecting a nitrogen functional group; Z is an acyl group) through a process of four stages and further producing the 3-benzamide-2-hydroxycarboxylic acid or its salt from the compound. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for producing 3-benzamide-2-hydroxycarboxylic acid or a salt thereof useful as an intermediate for various pharmaceutical synthesis, and an intermediate for producing the 3-benzamide-2-hydroxycarboxylic acid or a salt thereof. The present invention relates to a method for producing useful optically active 4- (N-protected amino) -1-alkene-3-ol.

  1,2-aminoalcohol is a structural unit found in various biologically active natural products such as sphingosine, statin, taxol side chain phenyliserine, anisomycin, valanol, febrifugine, and chiral aids in asymmetric synthesis. Widely used as an agent. Among these, 3-benzamido-2-hydroxycarboxylic acid, in particular, (2R, 3S) -3-benzamido-2-hydroxy-3-phenylpropionic acid is very useful as a compound corresponding to the side chain of taxol shown below. It is an important compound.

  Conventionally, for example, the following method has been proposed as a method for synthesizing the side chain of taxol or its analog, taxotere.

  1) (2R, 3S) -3-benzamide in which the hydroxyl group at the 2-position is protected by a 1-ethoxyethyl group using (S)-(+)-phenylglycine as a starting material, as shown in the following reaction formula 2- (1-Ethoxyethoxy) -3-phenylpropionic acid is synthesized, and a compound serving as a side chain of taxol is synthesized from the compound (for example, see Non-Patent Document 1).

  2) As shown in the following reaction formula, starting from N- (tert-butoxycarbonyl) -benzylamine, the hydroxyl group at the 2-position was protected with a 1-ethoxyethyl group, (2R, 3S) -3- (Tert-Butoxycarbamoyl) -2- (1-ethoxyethoxy) -3-phenylpropionic acid is synthesized, and a compound serving as a side chain of taxotere is synthesized from the compound (see, for example, Non-Patent Document 2).

  However, the method 1) is dangerous because it uses lithium aluminum hydride or a Grineer reagent, and is an industrially disadvantageous method. In addition, aminoaldehyde after Swern oxidation is easily isomerized, requiring careful handling and reaction at low temperature.

Also, in the method 2), it is necessary to carry out the reaction at an extremely low temperature, and it is difficult to cope with general production facilities. In addition, optical resolution at the final stage is not a good method in terms of synthesis strategy.
“Journal of Organic Chemistry” (J. Org. Chem.), 1991, Vol. 24, 6939-6942 “Journal of Organic Chemistry” (J. Org. Chem.), 1993, Vol. 1, pp. 255-257

  The present invention can be industrially produced safely without using special equipment, and has a high yield and high optical purity, and is represented by 3-benzamido-2-hydroxy represented by 3-benzamido-2-hydroxy-3-phenylpropionic acid. An object of the present invention is to provide a method for producing a hydroxycarboxylic acid or a salt thereof.

  As a result of intensive studies on the above problems, the present inventors have found that the following general formula (4a) or (4b):

(In the formula, R represents an alkyl group, an alkenyl group, an aryl group, an arylalkyl group or an arylthioalkyl group, and X represents an amino-protecting group.)
By synthesizing 4- (N-protected amino) -1-alkene-3-ol of syn- (±) or anti- (±) represented by We obtained the knowledge that it can be divided kinetically. And paying attention to this point, by adopting a method via the optically active substance, 3-benzamide-2-hydroxycarboxylic acid or a salt thereof can be obtained in a safe and suitable method for industrialization, in a high yield and The present inventors have found that it can be produced with high optical purity and have completed the present invention.

That is, the present invention
(Step 1) The following general formula (1):

(In the formula, R represents an alkyl group, an alkenyl group, an aryl group, an arylalkyl group or an arylthioalkyl group.)
Or a salt thereof is reacted with an azidating agent in the presence of a base to give the following general formula (2):

(In the formula, R is as defined above.)
Obtaining a compound represented by:
(Step 2) The nitrogen functional group of the compound represented by the general formula (2) is protected, and the following general formula (3):

(In the formula, R is as defined above, and X represents a protecting group for the nitrogen functional group.)
And then separated into the following general formulas (3a) and (3b):

(In the formula, R and X are as defined above.)
Obtaining a compound represented by:
(Step 3) The compound represented by the general formula (3a) or the compound represented by the general formula (3b) is subjected to a ring-opening reaction by methanolysis, respectively, and the following general formula (4a):

(In the formula, R and X are as defined above.)
Or a compound represented by the following general formula (4b):

(In the formula, R and X are as defined above.)
Obtaining a compound represented by:
(Step 4) The compound represented by the general formula (4a) or the compound represented by the general formula (4b) is reacted with an acylating agent used for transesterification in the presence of lipase, respectively. The following general formulas (5-RR) and (4-SS):

(In the formula, R and X are as defined above, and Z represents an acyl group.)
Or the following general formulas (5-RS) and (4-SR):

(In the formula, R and X are as defined above, and Z represents an acyl group.)
Each kinetically resolved into the compounds represented by:
Is a method for producing optically active 4- (N-protected amino) -1-alkene-3-ol.

In the above manufacturing method,
(Step 5) Further, the compound represented by the above general formula (5-RR) obtained in Step 4 or the compound represented by the above general formula (5-RS) is deacylated, respectively. Formula (4-RR):

(In the formula, R and X are as defined above.)
Or a compound represented by the following general formula (4-RS):

(In the formula, R and X are as defined above.)
Obtaining a compound represented by:
Can produce optically active 4- (N-protected amino) -1-alkene-3-ol.

In the above production method, the compound represented by the general formula (1) or a salt thereof is
(Step 6) The following general formula (6):

(In the formula, R is as defined above.)
A step of reacting a compound represented by the formula or a salt thereof with acrolein in the presence of a base;
Or may be manufactured by
(Step 7) The following general formula (7):

Wherein R is as defined above, and R ¹ is an alkyl group having 1 to 12 carbon atoms, allyl group, methallyl group, crotyl group, cinnamyl group, prenyl group, geranyl group, benzyl group, 4-methoxybenzyl group. , Diphenylmethyl group, triphenylmethyl group, 2-trimethylsilylethyl group, methoxymethyl group, benzyloxymethyl group, 1-ethoxyethyl group, 2-methoxyethoxymethyl group or tetrahydro-2H-pyran-2-yl group .)
Is reacted with acrolein in the presence of a base to give the following general formula (8):

(In the formula, R and R ¹ are as defined above.)
Obtaining a compound represented by:
(Step 8) A step of hydrolyzing, hydrocracking, or deallylating the ester of the compound represented by the general formula (8) with a palladium catalyst;
May be manufactured.

The present invention also provides:
(Step 4) The compound represented by the general formula (4a) or the compound represented by the general formula (4b) is reacted with an acylating agent used for transesterification in the presence of lipase, respectively. The compounds represented by the general formulas (5-RR) and (4-SS) or the compounds represented by the general formulas (5-RS) and (4-SR) are divided kinetically. Process;
Is a method for producing optically active 4- (N-protected amino) -1-alkene-3-ol.

The present invention also provides:
(Step 9) The following general formula (4):

(In the formula, R represents an alkyl group, an alkenyl group, an aryl group, an arylalkyl group or an arylthioalkyl group, X represents an amino-protecting group, and * represents an asymmetric carbon atom.)
Benzoylation of the hydroxyl group of the compound represented by the following general formula (9):

(In the formula, R and X are as defined above, Bz represents a benzoyl group, and * represents an asymmetric carbon atom.)
Obtaining a compound represented by:
(Step 10) The amino group of the compound represented by the general formula (9) is deprotected, and the following general formula (10):

(In the formula, R and Bz are as defined above, and * represents an asymmetric carbon atom.)
A step of obtaining a compound represented by the formula:
(Step 11) The compound represented by the above general formula (10) or a salt thereof is treated with a base, and the following general formula (11):

(In the formula, R and Bz are as defined above, and * represents an asymmetric carbon atom.)
Obtaining a compound represented by:
(Step 12) The hydroxyl group of the compound represented by the general formula (11) is protected, and the following general formula (12):

(In the formula, R and Bz are as defined above, Y represents a hydroxyl-protecting group, and * represents an asymmetric carbon atom.)
Obtaining a compound represented by:
(Step 13) By oxidizing the olefin of the compound represented by the general formula (12), the following general formula (13):

(In the formula, R, Bz and Y are as defined above, and * represents an asymmetric carbon atom.)
A step of obtaining a compound represented by the formula:
(Step 14) The hydroxyl group of the compound represented by the general formula (13) or a salt thereof is deprotected, and the following general formula (14):

(In the formula, R and Bz are as defined above, and * represents an asymmetric carbon atom.)
A step of obtaining a compound represented by the formula:
A process for producing 3-benzamido-2-hydroxycarboxylic acid or a salt thereof.

  Furthermore, the present invention provides the following general formula (4 '):

(In the formula, R ′ represents an alkyl group, an alkenyl group, an aryl group, an arylalkyl group or an arylthioalkyl group, but excludes a phenyl group. X represents an amino-protecting group, and * represents an asymmetric carbon atom. Represents.)
A novel 4- (N-protected amino) -1-alkene-3-ol represented by

  Furthermore, the present invention provides the following general formula (14 '):

(In the formula, R ′ represents an alkyl group, an alkenyl group, an aryl group, an arylalkyl group or an arylthioalkyl group, but excludes a phenyl group. Bz represents a benzoyl group, and * represents an asymmetric carbon atom.)
A novel 3-benzamido-2-hydroxycarboxylic acid, or a salt thereof.

  In the process for producing optically active 4- (N-protected amino) -1-alkene-3-ol of the present invention, as shown in Step 4, the compound of the general formula (4a) of syn- (±) or anti- By reacting the compound of the general formula (4b) of (±) with an acylating agent used for transesterification in the presence of lipase, only the compound having the R configuration at the 3-position carbon atom is selectively selected. Acylate. A compound having a configuration at the 3-position carbon atom in the S form is not acylated, so that both can be easily separated and purified. According to the kinetic resolution using this lipase, the compound of the general formula (5-RR) or (5-RS) in which the hydroxyl group at the 3-position is acylated and the general formula in which the hydroxyl group at the 3-position is not acylated ( 4-SS) or (4-SR) is obtained in a high yield of nearly 50% and high optical purity.

  When the optically active 4- (N-protected amino) -1-alkene-3-ol thus obtained is used, the side chain of taxol or a derivative thereof represented by the general formula (14) is represented by steps 9-14. The compound or a salt thereof, that is, 3-benzamide-2-hydroxycarboxylic acid or a salt thereof can be obtained in a high yield and high optical purity by a safe and suitable method for industrialization.

  Hereinafter, the present invention will be described in detail. First, each symbol in the above general formula will be described below. General formulas (1) to (14), (3a), (3b), (4a), (4b), (4-RR), (4-SS), (4-RS), (4-SR) , (5-RR), R in (5-RS) and “alkyl group” in R ′ in (4 ′) and (14 ′) preferably have 1 to 20 carbon atoms, and may be linear or branched But you can. Specific examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, and an n-pentyl group. Especially, C2-C12 is especially preferable.

  The “alkenyl group” for R and R ′ preferably has 1 to 20 carbon atoms and may be linear or branched. Specifically, vinyl group, 1-propenyl group, 2-propenyl group, 3-butenyl group, 4-pentenyl group, 5-hexenyl group, 6-heptenyl group, 7-octenyl group, 8-nonenyl group, 9- A decenyl group, 10-undecenyl group, 11-dodecenyl group, etc. are mentioned. Especially, C2-C10 is especially preferable.

Examples of the “aryl group” in R and R ′ include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, and the like, and among them, a phenyl group is preferable. In the present invention, the “aryl group” includes those substituted, and examples of the substituent include a C _1-4 alkyl group, an aryl group, a tri C _1-4 alkylsilyl group, an amino group, C _1-4 alkylamino group, arylamino group, C _1-4 alkylcarbamoyl group, arylcarbamoyl group, nitro group, carboxyl group, C _1-4 alkoxycarbonyl group, C _1-4 alkylsulfonyl group, sulfonate group, halogen Group, cyano group, C _1-4 alkoxyl group, hydroxyl group and the like.

The “arylalkyl group” in R and R ′ may be linear or branched as the alkyl moiety, and preferably has 1 to 10 carbon atoms, particularly preferably 1 to 5 carbon atoms. The aryl moiety is the same as the above “aryl group”. Specific examples of such “arylalkyl group” include benzyl group, phenethyl group, 3-phenylpropyl group, 4-phenylbutyl group, 5-phenylpentyl group, 6-phenylhexyl group and the like. In the present invention, the “arylalkyl group” includes those in which the aryl moiety is substituted. Examples of the substituent include a C _1-4 alkyl group, a C _1-4 alkoxy group, a halogen group, a nitro group. Groups and the like.

As the “arylthioalkyl group” in R and R ′, the alkyl part may be linear or branched, and the number of carbon atoms is preferably 1 to 10, particularly 1 to 5. The aryl moiety is the same as the above “aryl group”. Specific examples of such “arylthioalkyl group” include phenylthiomethyl group, phenylthioethyl group, phenylthiopropyl group, phenylthiobutyl group, phenylthiopentyl group and the like. In the present invention, the “arylthioalkyl group” includes those in which the aryl moiety is substituted. Examples of the substituent include C _1-4 alkyl group, nitro group, sulfonate group, halogen group, C group. Examples include _1-4 alkoxyl groups and hydroxyl groups.

  Examples of the “acyl group” of Z in the above general formulas (5-RR) and (5-RS) include linear or branched alkylcarbonyl groups and arylcarbonyl groups having 2 to 12 carbon atoms, and particularly acetyl. Group, propionyl group, benzoyl group and dodecanoyl group are preferred.

  The above general formulas (3), (3a), (3b), (4), (4 ′), (4a), (4b), (4-RR), (4-SS), (4-RS), As the “protecting group for amino group” and “protecting group for nitrogen functional group” of X in (4-SR), (5-RR), (5-RS) and (9), a tert-butoxycarbonyl group (Boc A protecting group that can be removed by an acid such as benzyloxycarbonyl group (Cbz group), 3-nitro-2-pyridinesulfenyl group (Npys group), allyloxycarbonyl group (alloc), 2, Examples include 2,2-trichloroethoxycarbonyl group (Troc), 9-fluorenylmethoxycarbonyl group (Fmoc group), p-methoxybenzyloxycarbonyl group, p-methoxyphenyl group and the like.

As the “hydroxyl-protecting group” for Y in the general formulas (12) and (13), a tetrahydro-2H-pyran-2-yl group, a benzyl group, a 4-methoxyphenyl group, a methoxymethyl group, tri C _{1- 4} Alkylsilyl group, acetyl group, benzoyl group and the like can be mentioned.

The “C1-C12 alkyl group” of R ¹ in the general formula (7) may be linear or branched. Specific examples include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, and an n-dodecyl group. Especially, C1-C4 is preferable.

In the present invention, R is preferably a phenyl group, X is preferably a tert-butoxycarbonyl group (Boc group), Z is preferably an acetyl group, and Y is a tetrahydro-2H-pyran-2-yl group. R ¹ is preferably a methyl group. In the present invention, an unsubstituted phenyl group is excluded from R ′.

  In the compounds of the general formulas (4), (9) to (14), (14 ′), there are at least two asymmetric carbon atoms, but in the present invention, the steric configuration is not particularly limited. It may be an active form, a mixture of these in any ratio, or a racemate.

  In the present invention, optically active 4- (N-protected amino) -1-alkene-3-ol is produced by the following steps 1 to 4.

  Below, each process is demonstrated.

Process 1
In this step, the compound of general formula (1) or a salt thereof is reacted with an azidating agent in the presence of a base to obtain a compound of general formula (2). In this reaction, after the Curtius rearrangement occurs, cyclization occurs in the molecule. That is, the carboxyl group in the compound of the general formula (1) or a salt thereof is azidated and becomes an isocyanate group by Curtius rearrangement. Then, when the adjacent hydroxyl group attacks the carbonyl carbon of the isocyanate group nucleophilically, it cyclizes within the molecule to form an oxazolidinone ring.

  Examples of the azidating agent used in this step include sodium azide, diphenylphosphoryl azide, 4-acetamidobenzenesulfonyl azide, 4-dodecylbenzenesulfonyl azide, trimethylsilyl azide, and the like. Diphenylphosphoryl azide and sodium azide are preferably used. As for the usage-amount of this azidating agent, 1.0-2.0 mol is preferable with respect to 1 mol of compounds of General formula (1).

  Examples of the base used in this step include organic amines such as triethylamine, tributylamine, trimethylamine, diisopropylethylamine, tetramethylethylenediamine, triethylenediamine, dimethylaniline, and 4-methylmorpholine. Triethylamine and diisopropylethylamine are preferably used. Is done. The amount of the base used is preferably 1.0 to 2.0 mol with respect to 1 mol of the compound of the general formula (1).

  Examples of the solvent used in this step include aromatics such as toluene, benzene, mesitylene, and nitrobenzene; hexane, dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, and the like, and toluene, benzene, and xylene are preferably used. The amount of the solvent used is preferably 1.0 to 20.0 ml with respect to 1 g of the compound of the general formula (1).

  The reaction is carried out by adding the compound of the general formula (1) and a base to a solvent and stirring the mixture, and adding an azidating agent thereto. It is preferable that

  After the addition of the azidating agent, the temperature of the reaction system is returned to room temperature, but after the Curtius rearrangement, the reaction system may be heated to 50 to 110 ° C. as necessary in order to advance intramolecular cyclization, The heating time at that time is preferably 0.5 to 2.0 hours.

  After completion of the reaction, the reaction system is cooled to room temperature and subjected to a conventional process such as a liquid separation operation to obtain the compound of the general formula (2). In addition, you may refine | purify conventional methods, such as column chromatography, as needed.

Process 2
In this step, the nitrogen functional group of the compound of general formula (2) is protected to obtain a compound of general formula (3), which is then separated into a compound of general formula (3a) and a compound of (3b).

Examples of the reagent used for protecting the nitrogen functional group used in this step include di-tert-butyl dicarbonate ((Boc) ₂ O), tert-butyl azidoformate (Boc-N ₃ ), 2- tert-Butoxycarbonyloxyimino-2-phenylacetonitrile (Boc-ON), S-tert-butoxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (Boc-SDP), tert-butoxycarbonyl chloride (Boc-Cl) , [P- (tert-butoxycarbonyloxy) phenyl] dimethylsulfonium methanesulfonate (Boc-ODSP) and the like, which can form a protective group that can be removed by an acid; and other, 9-fluorenylmethylchloroform Mate (Fmoc-Cl), N- (9-fluorenylmethoxy) Carbonyloxy) succinimide (Fmoc-ONSu), allyloxycarbonyl chloride (aloc-Cl), benzyloxycarbonyl chloride (Cbz-Cl), p- (benzyloxycarbonyloxy) phenyldimethylsulfonium methanesulfonate (Z-ODSP) ), P-methoxybenzyloxycarbonyl chloride, 3-nitro-2-pyridinesulfenyl chloride (Npys-Cl), 2,2,2-trichloroethoxycarbonyl chloride (Troc-Cl), p-methoxyphenyl chloride and the like. Among them, those capable of forming a protecting group that can be removed by an acid, particularly (Boc) ₂ O, are preferably used. The amount of the reagent used is preferably 1.0 to 1.5 mol with respect to 1 mol of the compound of the general formula (2).

  This reaction is carried out in the presence of a base. Examples of the base used include organic amines such as trimethylamine, triethylamine, triethylenediamine, dimethylaniline, tributylamine, pyridine, and 4-dimethylaminopyridine. The combination of 4-dimethylaminopyridine is preferred. The amount of the base used is preferably 1.0 to 1.5 mol with respect to 1 mol of the compound of the general formula (2).

  Examples of the solvent used in this step include aromatic systems such as benzene, toluene, xylene, mesitylene, and nitrobenzene; ether systems such as dimethyl ether, diethyl ether, tetrahydrofuran, isopropyl ether, and dioxane, but benzene, toluene, tetrahydrofuran, Isopropyl ether is preferably used. The amount of the solvent used is preferably 1 to 20 ml with respect to 1 g of the compound of the general formula (2).

  The reaction is carried out by adding the compound of the general formula (2) and a base to a solvent and stirring the mixture, and adding a reagent used for protecting the nitrogen functional group thereto. The temperature of the reaction system at the time of adding the reagent is 0. It is preferably ˜40 ° C. In addition, after the addition of the reagent, the temperature of the reaction system may be returned to room temperature as necessary and allowed to react for 1 to 5 hours.

  After completion of the reaction, the compound of the general formula (3) is obtained by performing a conventional process such as a liquid separation operation.

  Next, the compound of the general formula (3) thus obtained is separated into a compound of the general formula (3a) and a compound of (3b). The anti- (±) compound of the general formula (3a) and the syn- (±) compound (3b) are diastereomeric and have different physical properties (especially polarity). Is possible.

  As a separation method used in this step, a conventionally known method is adopted, for example, separation by silica gel column chromatography is common. The eluent at this time depends on R of the compound of the general formula (3), but is hexane-ethyl acetate, benzene-ethyl acetate, toluene-ethyl acetate, chloroform-ethyl acetate, methylene chloride-methanol. The ratio is appropriately set depending on the compound. In the above silica gel column chromatography, pressure may be applied as necessary.

Process 3
In this step, the compound of the general formula (3a) is subjected to a ring-opening reaction by methanolysis to obtain the compound of the general formula (4a). A similar reaction is performed on the compound of the general formula (3b) to obtain the compound of the general formula (4b). In this reaction, methanol attacks the carbonyl of the oxazolidinone ring, resulting in ring opening, and the compound of general formula (3a) in anti- (±) form becomes a compound of general formula (4a) in syn- (±) form. The compound of (3b) in the syn- (±) form becomes the compound of the general formula (4b) in the anti- (±) form.

  The methanol used in this step also serves as a solvent, and the amount used is preferably 2 to 20 ml with respect to 1 g of the compound of the general formula (3a) or (3b).

  This reaction is carried out in the presence of a base. Examples of the base used include weak bases such as cesium carbonate, lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, and barium carbonate. From the viewpoint, cesium carbonate and barium carbonate are preferably used. The amount of the base used is preferably 0.05 to 1.0 mol with respect to 1 mol of the general formula (3a) or (3b).

  The reaction is carried out by stirring a mixture of the compound of the general formula (3a) or (3b) and the base in methanol. The reaction temperature is preferably 0 to 40 ° C., and the reaction time is 1 to It is preferably 20 hours.

  After completion of the reaction, the compound of the general formula (4a) or (4b) is obtained by performing a conventional process such as a liquid separation operation. In addition, you may refine | purify conventional methods, such as column chromatography, as needed.

Process 4
In this step, the compound of the general formula (4a) in the syn- (±) form is reacted with an acylating agent used for transesterification in the presence of lipase, and the optically active general formula ( 5-RR) and (4-SS) are obtained. The same reaction is performed on the compound of the general formula (4b) of anti- (±) to obtain optically active compounds of the general formulas (5-RS) and (4-SR). In this reaction, only the R-configuration compound at the 3-position carbon atom is selectively acylated, so that the configuration at the 3-position carbon atom can be kinetically resolved from the S-configuration compound. Thus, optically active 4- (N-protected amino) -1-alkene-3-ol can be obtained.

  Examples of the acylating agent used in this step include those used for transesterification, such as 2-propenyl acetate, vinyl acetate, vinyl propionate, vinyl butyrate, vinyl caproate, vinyl caprylate, vinyl caprate, Examples include vinyl laurate, vinyl myristate, vinyl palmitate, vinyl stearate, vinyl dodecanoate, vinyl benzoate, divinyl adipate, vinyl monochloroacetate, etc., but 2-propenyl acetate, vinyl acetate, vinyl benzoate, propion Vinyl acid vinyl and vinyl dodecanoate are preferably used. The amount of the acylating agent used is preferably 2 to 10 moles per mole of the compound of the general formula (4a) or (4b).

The lipases used in this step include the genus Pseudomonas, the genus Pichia, the genus Rhodotorula, the genus Saccharopolyspora, the genus Streptomyces choc, Aspergillus genus, Bacillus genus, Candida genus, Cladosporium genus, Fusarium genus, Geotrichum genus, Acinetobacter genus Acinetobacter Kluyveromyces genus, Mi The genus Rosporum, the genus Brevibacillus, the genus Mucor, the genus Actinomadura, the genus Coprinus, the genus Agaricus, the rhodococcus (Rhodococcus) Rhizopus genus, those produced by the genus Commomonas, and those derived from porcine pancreas are used, specifically,
Chirazyme (Candida antarctica lipid type-B (CAL-B) manufactured by Roche),
Lipase AK (Pseudomonas fluorescens Amano)
Lipase AYS (Candida rugosa Amano)
Lipase A (made by Aspergillus niger Amano)
Protease PS (manufactured by Aspergillus melleus Amano)
Lipase M (Mucor javanicus Amano)
Lipase G (manufactured by Penicillium camemberti Amano)
PPL (Pig pancreatic lipase Ardrich)
Among them, Chirazyme (CAL-B) is preferably used from the viewpoint of yield and optical purity. The amount of lipase used is preferably 0.2 to 1.0 g based on 1 g of the compound of the general formula (4a) or (4b).

  Examples of the solvent used in this step include aromatics such as benzene, toluene, xylene, mesitylene, and nitrobenzene, and toluene and xylene are preferably used. The amount of the solvent used is preferably 5 to 30 ml with respect to 1 g of the compound of the general formula (4a) or (4b).

  The reaction is carried out by stirring the compound of the general formula (4a) or (4b), lipase and acylating agent in a solvent. The reaction temperature is preferably 20 to 100 ° C., and the reaction time is It is preferably 20 to 50 hours.

  After completion of the reaction, the lipase is removed by filtration, and a conventional process such as a liquid separation operation is performed. Then, it isolate | separates by well-known methods, such as column chromatography, and obtains the compound of general formula (5-RR) and (4-SS), or the compound of general formula (5-RS) and (4-SR), respectively. . By this step, as the optically active 4- (N-protected amino) -1-alkene-3-ol, which is the target compound of the present invention, the compound of the general formula (4-SS) or the general formula (4-SR) The acylated compound of general formula (5-RR) or the compound of general formula (5-RS) is made the target compound of the present invention by the following step 5.

Process 5
In this step, the compound of general formula (5-RR) or the compound of general formula (5-RS) obtained in step 4 is deacylated, respectively, to give a compound of general formula (4-RR) or a general formula A compound of formula (4-RS) is obtained.

  This deacylation is carried out by treating with a base, and examples of the base to be used include lithium carbonate, potassium carbonate, calcium carbonate, sodium carbonate, sodium acetate and the like, but potassium carbonate and sodium carbonate are preferably used. The As for the usage-amount of this acid, 1.0-2.0 mol is preferable with respect to 1 mol of general formula (5-RR) or (5-RS).

  Examples of the solvent used in this step include alcohols such as methanol, ethanol, 2-propanol, and tert-butanol. Methanol and ethanol are preferably used. The amount of the solvent used is preferably 0.5 to 3.0 ml with respect to 1 g of the compound of the general formula (5-RR) or (5-RS).

  The reaction is carried out by stirring the compound of the general formula (5-RR) or (5-RS) and a base in a solvent. The reaction temperature is preferably 0 to 40 ° C., and the reaction time is It is preferably 0.5 to 10 hours.

  After completion of the reaction, the compound of general formula (4-RR) or (4-RS), which is the target compound of the present invention, is obtained by carrying out a conventional process such as a liquid separation operation. In addition, you may refine | purify conventional methods, such as column chromatography, as needed.

  As described above, optically active 4- (N-protected amino) -1-alkene-3-ol can be produced by steps 1 to 4 (and step 5 if necessary). The compound of the general formula (1) or a salt thereof used as a raw material can be produced, for example, by the method of Step 6 or by the methods of Step 7 and Step 8, as shown below.

Step 6
A compound of the general formula (6) or a salt thereof is reacted with acrolein in the presence of a base to obtain a compound of the general formula (1) or a salt thereof by an aldol reaction.

  As for the usage-amount of the acrolein used at this process, 1.0-1.5 mol is preferable with respect to 1 mol of compounds of General formula (6).

  Examples of the base used in this step include lithium compounds such as lithium diisopropylamide (LDA), lithium isopropylcyclohexylamide (LICA), lithium tetramethylpiperidide (LTMP), lithium hexamethyldisilazide (LHMDS), and sodium hexahexadium. Examples thereof include methyl disilazide (NHMDS) and potassium hexamethyldisilazide (KHMDS), and lithium diisopropylamide is preferably used from the viewpoint of cost and operability. The amount of the base used is preferably 1.0 to 1.5 mol with respect to 1 mol of the compound of the general formula (6). This base may be prepared in the reaction system. For example, in the case of lithium diisopropylamide, it can be prepared by dropping n-butyllithium into diisopropylamine at −78 to 0 ° C.

  Examples of the solvent used in this step include ethers such as tetrahydrofuran and diethyl ether; mixed solvents of ethers and hydrocarbons. A mixed solvent of tetrahydrofuran and hexane is preferably used. As for the usage-amount of this solvent, 1.0-3.0 ml is preferable with respect to 1 g of compounds of General formula (6).

  The reaction is carried out by adding the compound of general formula (6) to the base solution and stirring, followed by the addition of acrolein. The temperature of the reaction system at the time of adding the compound of the general formula (6) is preferably −90 to −30 ° C., and then preferably stirred for 1 to 3 hours. Moreover, it is preferable that the temperature of the reaction system at the time of acrolein addition is -90 to -30 degreeC, and it is preferable to stir for 0.1 to 1.0 hour after acrolein addition.

  After completion of the reaction, the reaction mixture is acidified and subjected to conventional treatments such as extraction with an organic solvent and liquid separation operation to obtain the compound of the general formula (1) or a salt thereof. In addition, you may refine | purify conventional methods, such as column chromatography, as needed.

Step 7 and Step 8
In step 7, the compound of general formula (7) is reacted with acrolein in the presence of a base to obtain a compound of general formula (8) by aldol reaction, and then in step 8, the compound of general formula (8) The ester is hydrolyzed, hydrogenolyzed, or deallylated with a palladium catalyst (when R ¹ = allyl group) to obtain a compound of the general formula (1) or a salt thereof.

  The method in step 7 can be performed in the same manner as in step 6. The hydrolysis in step 8 is performed with alkali. Examples of the alkali used in this step include a sodium hydroxide aqueous solution and a potassium hydroxide aqueous solution, and a sodium hydroxide aqueous solution is preferably used. As for the usage-amount of this alkali, 1.0-2.0 mol is preferable with respect to 1 mol of compounds of General formula (8).

  Examples of the solvent used in this step include alcohols such as methanol, ethanol, 2-propanol and tert-butanol; 1,4-dioxane and the like, but methanol, ethanol and 1,4-dioxane are preferably used. The The amount of the solvent used is preferably 0.5 to 3.0 ml with respect to 1 g of the compound of the general formula (8).

  The reaction is carried out by stirring the compound of the general formula (8) and an alkali in a solvent. The reaction temperature is preferably 0 to 50 ° C., and the reaction time is 0.5 to 12 hours. preferable.

  After completion of the reaction, the reaction mixture is acidified and subjected to conventional treatments such as extraction with an organic solvent and liquid separation operation to obtain the compound of the general formula (1) or a salt thereof. In addition, you may refine | purify conventional methods, such as column chromatography, as needed.

  Hydrogenolysis is carried out by hydrogenation under a catalyst such as Pd / C, and the amount of hydrogen used is preferably 1.0 to 20.0 moles per mole of the compound of the general formula (8). Examples of the solvent used in this step include the same solvents as in the case of hydrolysis and ethyl acetate.

  The reaction is carried out by stirring the compound of formula (8) and the catalyst in a solvent and blowing hydrogen into the solvent. The reaction temperature is preferably 0 to 50 ° C., and the reaction time is 0.00. 5-12 hours are preferred.

  After completion of the reaction, the catalyst is filtered off and then subjected to conventional treatments such as extraction with an organic solvent and liquid separation operation to obtain the compound of the general formula (1) or a salt thereof. In addition, you may refine | purify conventional methods, such as column chromatography, as needed.

Moreover, when R < ¹ > is an allyl group in the said General formula (8), the compound or its salt of General formula (1) can also be obtained by the deallylation by a palladium catalyst. This deallylation is performed by using a hydrogen source such as formic acid or its ammonium salt or a nucleophilic reagent such as morpholine in the presence of a palladium catalyst such as palladium acetate or trisdibenzylideneacetone dipalladium. The amount of the nucleophilic reagent such as a hydrogen source or morpholine is preferably 0.01 to 0.20 moles per mole of the compound of the general formula (8). 1.0-1.5 mol is preferable. Examples of the solvent used in this step include tetrahydrofuran and 1,4-dioxane.

  The reaction is carried out by stirring the compound of the general formula (8) and the catalyst in a solvent and adding a nucleophilic reagent such as a hydrogen source or morpholine thereto. The reaction temperature is preferably 0 to 80 ° C. The reaction time is preferably 0.5 to 12 hours.

  After completion of the reaction, the catalyst is filtered off and then subjected to conventional treatments such as extraction with an organic solvent and liquid separation operation to obtain the compound of the general formula (1) or a salt thereof. In addition, you may refine | purify conventional methods, such as column chromatography, as needed.

  The compound of the general formula (1) or a salt thereof obtained by the method of Step 6 or Steps 7 to 8 is a mixture of an anti- (±) isomer and a syn- (±) isomer. When R of the carboxylic acid compound of the formula (6) or a salt thereof is a phenyl group, the selectivity of the anti- (±) isomer is high, and the resulting compound of the general formula (1) or the salt thereof has an anti / syn ratio. About 10/1 mixture. On the other hand, in the method of steps 7-8, when R of the ester compound of the general formula (7) is a phenyl group, the compound of the general formula (1) or a salt thereof obtained has an anti / syn ratio of about 1/1. It becomes a mixture. In addition, the anti- (±) isomer of the general formula (1) is converted into a syn- (±) isomer in the ring-opening reaction of step 3 through steps 1-2, and from this syn- (±) isomer, in step 4, A compound of the general formula (4-SS) useful as an intermediate of (2R, 3S) -3-benzamido-2-hydroxy-3-phenylpropionic acid which is a side chain of taxol (ie, (3S, 4S)- 4- (N-protected amino) -3-hydroxy-4-phenyl-1-butene) is obtained. Therefore, for the purpose of synthesizing (2R, 3S) -3-benzamido-2-hydroxy-3-phenylpropionic acid, which is the side chain of taxol, from the point of short process and high yield, When R is a phenyl group, the compound of the general formula (1) or a salt thereof is preferably produced by the method of Step 6.

  In general, it is a side chain of taxol or a derivative thereof from optically active 4- (N-protected amino) -1-alkene-3-ol produced by the method as described above, through steps 9 to 14 shown below. A compound of the formula (14) or a salt thereof, that is, 3-benzamide-2-hydroxycarboxylic acid or a salt thereof can be produced.

  Each step will be described below.

Step 9
In this step, the hydroxyl group of the compound of the general formula (4) is benzoylated to obtain the compound of the general formula (9).

  As the benzoylating agent used in this step, conventionally known ones are used, and examples thereof include benzoyl chloride and benzoic anhydride, and benzoyl chloride is preferably used. As for the usage-amount of this benzoylating agent, 1.0-2.0 mol is preferable with respect to 1 mol of compounds of General formula (4).

  This reaction is carried out in the presence of a base. Examples of the base to be used include organic amines such as pyridine, triethylamine and diisopropylethylamine, and pyridine and triethylamine are preferred. The amount of the base used is preferably 1.0 to 2.0 mol with respect to 1 mol of the compound of the general formula (4).

  Examples of the solvent used in this step include dichloromethane and the like. When pyridine is used as the above-mentioned base, it may also serve as the solvent. As for the usage-amount of this solvent, 1.0-5.0 ml is preferable with respect to 1 g of compounds of General formula (4).

  The reaction is carried out by adding the compound of formula (4) and a base to a solvent and stirring, and adding a benzoylating agent thereto. The temperature of the reaction system at the time of adding the benzoylating agent is 0 to 30 ° C. Preferably there is. Further, after the addition of the benzoylating agent, the temperature of the reaction system may be returned to room temperature as necessary, and allowed to react for 1 to 12 hours.

  After completion of the reaction, the compound of the general formula (9) is obtained by performing a conventional process such as a liquid separation operation. In addition, you may refine | purify conventional methods, such as column chromatography, as needed.

Step 10
In this step, the amino group of the compound of the general formula (9) is deprotected to obtain the compound of the general formula (10) or a salt thereof.

  The amino group deprotecting agent depends on the type of amino group protecting group, but when the protecting group is a protecting group that can be removed by an acid such as a Boc group, an acid is used. Examples thereof include trifluoroacetic acid, hydrochloric acid, sulfuric acid, hydrogen bromide / acetic acid, tetrafluoroboric acid and the like, and trifluoroacetic acid is preferably used. As for the usage-amount of this deprotecting agent, 1.0-3.0 mol is preferable with respect to 1 mol of compounds of General formula (9).

  Examples of the solvent used in this step include chlorinated solvents such as dichloromethane, chloroform, and carbon tetrachloride, but dichloromethane is preferably used. The amount of the solvent used is preferably 0.5 to 2.0 ml with respect to 1 g of the compound of the general formula (9).

  The reaction is carried out by stirring the compound of the general formula (9) and the deprotecting agent in a solvent. The reaction temperature is preferably 0 to 30 ° C., and the reaction time is 0.5 to 2 hours. It is preferable that

  After completion of the reaction, the excess deprotecting agent is removed, and then a conventional treatment such as a liquid separation operation is performed to obtain the compound of the general formula (10) or a salt thereof. In addition, you may refine | purify conventional methods, such as column chromatography, as needed. In addition, after removing the excess deprotecting agent, it may be used as it is in the next step 11 without performing a conventional treatment.

Step 11
In this step, the compound of the general formula (10) or a salt thereof is treated with a base to obtain the compound of the general formula (11). In this reaction, a benzoyl group bonded to a hydroxyl group is rearranged to an amino group.

  Examples of the base used in the present invention include triethylamine, trimethylamine, pyridine, triethanolamine, tributylamine and the like, and triethylamine is preferably used. The amount of the base used is preferably 1.0 to 2.0 mol with respect to 1 mol of the compound of the general formula (10).

  Examples of the solvent used in this step include ethers such as tetrahydrofuran, diethyl ether, methyl-tert-butyl ether, isopropyl ether and dioxane; hydrocarbons such as benzene and toluene; dichloromethane and the like, but tetrahydrofuran is preferably used. Is done. As for the usage-amount of this solvent, 1.0-3.0 ml is preferable with respect to 1 g of compounds of General formula (10).

  The reaction is carried out by stirring the compound of formula (10) and the base in a solvent. The reaction temperature is preferably 0 to 50 ° C., and the reaction time is 1 to 10 hours. preferable.

  After completion of the reaction, the compound of the general formula (11) is obtained by performing a conventional process such as a liquid separation operation. In addition, you may refine | purify conventional methods, such as column chromatography, as needed.

Step 12
In this step, the hydroxyl group of the compound of the general formula (11) is protected to obtain the compound of the general formula (12).

Examples of the reagent used for protecting the hydroxyl group include 3,4-dihydro-2H-pyran, benzyl chloride, 4-methoxyphenyl chloride, chlorotri-C _1-4 alkylsilane, chloromethyl methyl ether, acetyl chloride, benzoyl chloride, and the like. 3,4-dihydro-2H-pyran is preferably used. The amount of the reagent used is preferably 1.0 to 2.0 mol with respect to 1 mol of the compound of the general formula (11).

  This reaction is preferably performed in the presence of an acid catalyst because the reaction easily proceeds. Examples of such an acid catalyst include pyridinium p-toluenesulfonate, p-toluenesulfonic acid, and 10-camphorsulfonic acid. Etc. are preferably used. The amount of the acid catalyst used is preferably 0.1 to 1.0 mol per 1 mol of the compound of the general formula (11).

  Examples of the solvent used in this step include chlorinated solvents such as dichloromethane, chloroform, and carbon tetrachloride, but dichloromethane is preferably used. The amount of the solvent used is preferably 0.5 to 2.0 ml with respect to 1 g of the compound of the general formula (11).

  The reaction is performed by stirring the compound of the general formula (11) and the reagent used for protecting the hydroxyl group in a solvent in the presence of an acid catalyst, and the reaction temperature is preferably 0 to 30 ° C. The reaction time is preferably 1 to 12 hours.

  After completion of the reaction, the compound of the general formula (12) is obtained by performing a conventional process such as a liquid separation operation. In addition, you may refine | purify conventional methods, such as column chromatography, as needed.

Step 13
In this step, the olefin of the compound of the general formula (12) is oxidized to obtain the compound of the general formula (13) or a salt thereof.

  Examples of the oxidizing agent (catalyst) used for the olefin oxidation include ruthenium dioxide and ruthenium tetroxide. Ruthenium dioxide is preferably used. The amount of the catalyst used is preferably 0.01 to 0.05 g with respect to 1 g of the compound of the general formula (12). Examples of the co-oxidant include sodium periodate and 4-methylmorpholine N-oxide. As for the usage-amount of a co-oxidant, 1.0-6.0 mol is preferable with respect to 1 mol of compounds of General formula (12).

  Further, this oxidation reaction is preferably carried out in the presence of a buffer solution and kept at pH 5.0 to 7.0.

  Examples of the solvent used in this step include chlorine-based carbon tetrachloride, chloroform, dichloromethane and the like; acetonitrile and the like, and a mixed solvent of carbon tetrachloride and acetonitrile is preferably used. The amount of the solvent used is preferably 0.5 to 3.0 ml with respect to 1 g of the compound of the general formula (12).

  The reaction is carried out by adding the compound of the general formula (12) and the cooxidant to a mixture of a solvent and a buffer and stirring, adding a catalyst to this, and stirring, but the reaction temperature is 0 to 30 ° C. The reaction time is preferably 1 to 12 hours.

  After completion of the reaction, the compound of the general formula (13) or a salt thereof is obtained by performing a conventional process such as a liquid separation operation. In addition, you may refine | purify conventional methods, such as column chromatography, as needed.

Step 14
In this step, the hydroxyl group of the compound of general formula (13) or a salt thereof is deprotected to obtain the compound of general formula (14) or a salt thereof.

  The hydroxyl group deprotecting agent depends on the type of the hydroxyl protecting group. When the protecting group is a tetrahydro-2H-pyran-2-yl group, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, 10 -Camphorsulfonic acid, hydrochloric acid, etc. are mentioned, p-toluenesulfonic acid is used suitably. The amount of the deprotecting agent used is preferably 0.05 to 0.3 mol with respect to 1 mol of the compound of the general formula (13).

  Examples of the solvent used in this step include alcohols such as methanol, ethanol, and isopropanol. Methanol and ethanol are preferably used. As for the usage-amount of this solvent, 1.0-3.0 ml is preferable with respect to 1 g of compounds of General formula (13).

  The reaction is carried out by stirring the compound of the general formula (13) and the deprotecting agent in a solvent. The reaction temperature is preferably 0 to 40 ° C., and the reaction time is 1 to 20 hours. It is preferable.

  After completion of the reaction, a conventional process such as a liquid separation operation is performed, and if necessary, a conventional process such as column chromatography is performed to obtain a compound of the general formula (14), that is, the target compound of the present invention. 3-benzamide-2-hydroxycarboxylic acid or a salt thereof is obtained.

  In Steps 9 to 14 above, the configuration at each asymmetric carbon atom is maintained as it is until Step 14. For example, when the compound of the general formula (4) of (3S, 4S) is used in the step 9, the compound of the general formula (14) of (2R, 3S) or a salt thereof is obtained in the step 14.

  Among the compounds of the general formula (14) thus obtained, the compound in which R is a phenyl group is a compound that becomes a side chain of taxol, that is, (2R, 3S) -3-benzamide-2-hydroxy-3. -Phenylpropionic acid.

  In addition, when R is other than a phenyl group, the compound of the general formula (4), the compound of the general formula (14) or a salt thereof, that is, an optically active 4- (N -Protected amino) -1-alkene-3-ol, and 3-benzamido-2-hydroxycarboxylic acid or a salt thereof, which is a compound of the following general formula (14 ') or a salt thereof, are all novel compounds. .

(In the formula, R ′ represents an alkyl group, an alkenyl group, an aryl group, an arylalkyl group or an arylthioalkyl group, but excludes a phenyl group. X represents an amino-protecting group, Bz represents a benzoyl group, * Represents an asymmetric carbon atom.)
Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.

Synthesis of R = phenyl group compounds in general formulas (5-RR) and (4-SS)
(I) Synthesis of compound of general formula (1) (R = phenyl group) (step 6)
This compound was synthesized by the method described in Synlett, 2002, page 1665. A solution of phenylacetic acid (13.6 g, 100 mmol) in tetrahydrofuran (40 ml) was added dropwise to a solution of lithium diisopropylamide (210 ml) in tetrahydrofuran (140 ml) / hexane (135 ml) with stirring at 0 ° C., and the mixture was stirred at 0 ° C. for 45 minutes. Stir, then at room temperature for 2 hours. Next, after distilling off the solvent and diisopropylamine under reduced pressure, the mixture was vacuum dried at 70 ° C. for 2 hours to obtain a pale yellow viscous product. The lithium enolate thus obtained was dispersed in tetrahydrofuran (100 ml), and acrolein (8.02 ml, 120 mmol) was added dropwise thereto at 0 ° C., followed by stirring at room temperature for 48 hours. After completion of the reaction, the solvent was distilled off, ice-cooled 3N hydrochloric acid (120 ml) was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure to give 3-hydroxy-2-phenyl-4-pentenoic acid as a viscous oil (19.5 g, 100 mmol, anti / syn = about 10/1). ). This was subjected to the next step without purification.

¹ H-NMR (CDCl ₃ ) δ: 3.68 (1H, d, J = 8.9 Hz), 4.70 (1H, m), 5.08 (1H, d, J = 10.4 Hz), 5 .22 (1H, d, J = 17.1 Hz), 5.69 (1H, m), 7.26-7.36 (5H, m).

(II) Synthesis of compound of general formula (2) (R = phenyl group) (step 1)
Triethylamine (16.7 ml, 120 mmol) was added to a solution of 3-hydroxy-2-phenyl-4-pentenoic acid (19.5 g, 100 mmol) in toluene (120 ml), stirred, and diphenylphosphoryl azide (21.2 ml) at 0 ° C. , 120 mmol), the reaction system was returned to room temperature and the reaction was continued for 10 hours. Thereafter, the reaction system was heated at 80 ° C. for 40 minutes. After cooling, the reaction mixture was diluted with ethyl acetate (60 ml), and the organic layer was washed successively with water (100 ml), 1N hydrochloric acid (100 ml × 2), saturated aqueous NaHCO ₃ solution (100 ml), and dried over anhydrous MgSO ₄ . And concentrated under reduced pressure. The residue (15.1 g) was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to obtain anti (±) -4-phenyl-5-vinyl-2-oxazolidinone (12. 8 g, containing inseparable by-products). This was subjected to the next step without purification.

¹ H-NMR (CDCl ₃ ) δ: 4.61 (1H, d, J = 7.3 Hz), 4.71 (1H, m), 5.34 (1H, d, J = 16.8 Hz), 5 .35 (1H, d, J = 11.4 Hz), 5.99 (1H, m), 6.05 (1H, br), 7.33-7.42 (5H, m).

(III) Synthesis of compound of general formula (3a) (R = phenyl group) (step 2)
Anti (±) -4-phenyl-5-vinyl-2-oxazolidinone (12.8 g, containing inseparable by-product) and dimethylaminopyridine (855 mg, 7.0 mmol) were dissolved in tetrahydrofuran (50 ml). , Triethylamine (10.7 ml, 77.0 mmol) was added and stirred, and a solution of di-tert-butyl dicarbonate ((Boc) ₂ O, 18.3 ml, 84.0 mmol) in tetrahydrofuran (10 ml) was added dropwise at room temperature. And stirred at room temperature for 1.5 hours. The reaction mixture was diluted with toluene (50 ml), and the organic layer was washed successively with 1N hydrochloric acid (50 ml × 2) and saturated aqueous NaHCO ₃ solution (50 ml), dried over anhydrous MgSO ₄ and concentrated under reduced pressure to give a crude product. As a product, a solid (17.1 g) was obtained. This was purified by medium pressure silica gel column chromatography (Yamazen, SI-40D column, toluene / ethyl acetate = 20/1 to 10/1 to 5/1) to obtain anti (±) -N-tert-butoxycarbonyl. -4-Phenyl-5-vinyl-2-oxazolidinone (15.5 g, 53.7 mmol, 54% yield over 3 steps) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.27 (9H, s), 4.67 (1H, dd, J = 5.7 Hz, 6.5 Hz), 4.84 (1H, d, J = 5. 7 Hz), 5.40 (1 H, d, J = 10.7 Hz), 5.41 (1 H, d, J = 17.1 Hz), 5.96 (1 H, ddd, J = 6.5 Hz, 10.7 Hz) , 17.1 Hz), 6.05 (1H, br), 7.24-7.43 (5H, m).

(IV) Synthesis of compound of general formula (4a) (R = phenyl group) (step 3)
Anti (±) -N-tert-butoxycarbonyl-4-phenyl-5-vinyl-2-oxazolidinone (8.37 g, 28.9 mmol) was added with methanol (25 ml) and stirred, and cesium carbonate (1 .12 mg, 2.89 mmol) was added and allowed to react for 12 hours at room temperature. After distilling off methanol under reduced pressure, the residue was diluted with ethyl acetate (20 ml), and the organic layer was washed successively with 1N hydrochloric acid (20 ml) and saturated aqueous NaHCO ₃ solution (20 ml), dried over anhydrous MgSO ₄ , Concentrated under reduced pressure. The residue (6.63 g) is purified by medium pressure column chromatography (Yamazen SI-40D column, hexane / ethyl acetate = 4 / 1-3 / 1 to 2/1) to obtain syn (±) -4- ( tert-Butoxycarbamoyl) -3-hydroxy-4-phenyl-1-butene was obtained (5.73 g, 21.7 mmol, 75%).

¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H), 4.40 (1H, br), 4.72 (1H, br), 5.21 (1H, d, J = 10.5 Hz), 5.30 (1H, br), 5.31 (1H, d, J = 17.0 Hz), 5.87 (1H, ddd, J = 5.3 Hz, 10.5 Hz, 17.1 Hz), 7.23 -7.39 (5H).

(V) Synthesis of compounds of general formula (5-RR) and (4-SS) (R = phenyl group) (step 4)
syn (±) -4- (tert-butoxycarbamoyl) -3-hydroxy-4-phenyl-1-butene (2.42 g, 9.17 mmol) in toluene (27.5 ml) and 2-propenyl acetate (3.03 ml) , 27.5 mmol) was added, and the mixture was stirred. Candida antilipase type B (CAL-B, trade name Chirazyme, 917 mg) was added, and the reaction was continued at 70 ° C. for 48 hours. CAL-B was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a solid (2.94 g) as a crude product. This was purified by medium pressure column chromatography (Yamazen SI-40B column, hexane / ethyl acetate = 3/1 to 5/2) to give (3R, 4R) -3-acetoxy-4- (tert-butoxycarbamoyl). ) -4-phenyl-1-butene (compound of general formula (5-RR), 1.27 g, 4.15 mmol, 45%,> 99% ee), and (3S, 4S) -4- (tert-butoxy) Carbamoyl) -3-hydroxy-4-phenyl-1-butene (compound of general formula (4-SS), 1.13 g, 4.29 mmol, 47%,> 99% ee) was obtained, respectively.

NMR data of (3R, 4R) -3-acetoxy-4- (tert-butoxycarbamoyl) -4-phenyl-1-butene (compound of general formula (5-RR))
¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H), 2.03 (3H, s), 4.91 (1H, br), 5.20 (1H, br), 5.22 (1H, d, J = 10.6 Hz), 5.26 (1H, d, J = 17.1 Hz), 5.55 (1H, br), 5.77 (1H, ddd, J = 5.9 Hz, 10.6 Hz) , 17.1 Hz), 7.24-7.36 (5H).

NMR data of (3S, 4S) -4- (tert-butoxycarbamoyl) -3-hydroxy-4-phenyl-1-butene (compound of general formula (4-SS))
¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H), 4.40 (1H, br), 4.72 (1H, br), 5.21 (1H, d, J = 10.5 Hz), 5.30 (1H, br), 5.31 (1H, d, J = 17.0 Hz), 5.87 (1H, ddd, J = 5.3 Hz, 10.5 Hz, 17.1 Hz), 7.23 -7.39 (5H).

Synthesis of (2R, 3S) -3-benzamido-2-hydroxy-3-phenylpropionic acid (R = phenyl compound in general formula (14))
(I) Synthesis of compound of general formula (9) (R = phenyl group) (step 9)
To (3S, 4S) -4- (tert-butoxycarbamoyl) -3-hydroxy-4-phenyl-1-butene (341 mg, 1.29 mmol), pyridine (3 ml) was added and stirred, and benzoyl chloride ( 0.20 ml, 1.7 mmol) was added and allowed to react at room temperature for 2 hours. After adding methanol (0.5 ml) and stirring for 20 minutes, the reaction mixture was diluted with toluene (20 ml), and the organic layer was washed successively with 1N hydrochloric acid (20 ml × 2) and saturated aqueous NaHCO ₃ solution (20 ml). The extract was dried over anhydrous MgSO ₄ and concentrated under reduced pressure to give an oil (815 mg) as a crude product. This was purified by silica gel column chromatography (hexane / ethyl acetate = 20/1 to 15/1) to give (3S, 4S) -3-benzoyloxy-4- (tert-butoxycarbamoyl) -4-phenyl- 1-butene was obtained (458 mg, 1.23 mmol, 95%).

¹ H-NMR (CDCl ₃ ) δ: 1.34 (9H), 5.20 (1H, d, J = 8.7 Hz), 5.25 (1H, d, J = 10.4 Hz), 5.33 (1H, d, J = 16.6 Hz), 5.75-5.88 (2H), 7.25-7.36 (5H), 7.44 (2H, m), 7.57 (1H, m ), 8.03 (2H, m).

(II) Synthesis of compound of general formula (11) (R = phenyl group) (steps 10 and 11)
(3S, 4S) -3-Benzoyloxy-4- (tert-butoxycarbamoyl) -4-phenyl-1-butene (458 mg, 1.23 mmol) was dissolved in dichloromethane (3.0 ml) and trifluoroacetic acid ( 1.0 ml) was added and stirred at room temperature for 3 hours. Volatiles were removed under reduced pressure to give (3S, 4S) -3-benzoyloxy-4-amino-4-phenyl-1-butene trifluoroacetate (530 mg). This was dissolved in tetrahydrofuran (3.0 ml), triethylamine (0.86 ml, 6.2 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with toluene (10 ml) and ethyl acetate (10 ml), and the organic layer was washed successively with 1N hydrochloric acid (20 ml) and saturated aqueous NaHCO ₃ solution (20 ml), dried over anhydrous MgSO ₄ and concentrated under reduced pressure. Thus, (3S, 4S) -4-benzamide-3-hydroxy-4-phenyl-1-butene was obtained as a colorless transparent solid (312 mg, 1.17 mmol, 95%). This was subjected to the next step without purification.

¹ H-NMR (CDCl ₃ ) δ: 4.58 (1H, m), 5.23-5.28 (2H), 5.43 (1H, d, J = 17.1 Hz), 5.95 (1H , Ddd, J = 5.0 Hz, 10.6 Hz, 17.1 Hz), 6.95 (1H, d, J = 4.6 Hz), 7.27-7.40 (5H), 7.44 (2H, m), 7.52 (1H, m), 7.80 (2H, m).

(III) Synthesis of compound of general formula (12) (R = phenyl group) (step 12)
(3S, 4S) -4-benzamido-3-hydroxy-4-phenyl-1-butene (275 mg, 1.03 mmol) and pyridinium p-toluenesulfonate (26 mg, 0.10 mmol) in dichloromethane (5.0 ml) After dissolution, 3,4-dihydro-2H-pyran (0.19 ml, 2.1 mmol) was added and stirred at room temperature for 12 hours. The reaction mixture was diluted with toluene (20 ml), and the organic layer was washed with saturated aqueous NaHCO ₃ solution (20 ml), dried over anhydrous MgSO ₄ and concentrated under reduced pressure to give a colorless transparent solid (483 mg) as a crude product. Obtained. This was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1 to 5/1) to give (3S, 4S) -4-benzamide-3- (tetrahydro-2H-pyran-2-yloxy)- 4-Phenyl-1-butene was obtained (340 mg, 0.97 mmol, 94%).

¹ H-NMR (CDCl ₃ ) δ: 1.38-1.82 (6H), 3.25 (1.2 H, m), 3.32-3.58 (0.8 H, m), 3.75 -3.90 (1H, m), 4.12 (0.4H, m), 3.90-4.02 (1H, m), 4.09-4.45 (1H, m), 5.13 (0.6H, m), 5.23-5.30 (2H, m), 5.46 (0.4H, m), 5.74 (0.6H, m), 6.01 (0.4H M), 7.20-7.53 (9H), 7.81-7.87 (2H, m).

(IV) Synthesis of compound of general formula (13) (R = phenyl group) (step 13)
To a mixed solvent of carbon tetrachloride (4.0 ml), acetonitrile (4.0 ml) and phosphate buffer (pH 6.8, 6.0 ml), (3S, 4S) -4-benzamide-3- (tetrahydro-2H -Pyran-2-yloxy) -4-phenyl-1-butene (167 mg, 0.475 mmol) was dissolved and sodium periodate (610 mg, 2.85 mmol) and ruthenium dioxide (5 mg) were added at room temperature. Stir for 5 hours. The reaction mixture was diluted with toluene (15 ml) and ethyl acetate (15 ml), and the organic layer was diluted with 0.5N hydrochloric acid (10 ml), saturated brine (10 ml × 2), saturated aqueous Na ₂ S ₂ O ₃ (10 ml). Washing sequentially, drying with anhydrous MgSO ₄ , and concentration under reduced pressure, solid (2R, 3S) -3-benzamido-3-phenyl-2- (tetrahydro-2H-pyran-2-yloxy) propionic acid was obtained. (127 mg, 0.344 mmol, 72%).

(V) Synthesis of compound of general formula (14) (R = phenyl group) (step 14)
Methanol (4.0 ml) was added to (2R, 3S) -3-benzamido-3-phenyl-2- (tetrahydro-2H-pyran-2-yloxy) propionic acid (127 mg, 0.344 mmol) and stirred. -Toluenesulfonic acid (5 mg) was added and the reaction continued at room temperature for 8 hours. The reaction mixture was diluted with toluene (30 ml) and extracted with 0.5N aqueous sodium hydroxide solution (5 ml × 2). The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate (10 ml × 2). The organic layer was dried over anhydrous MgSO ₄ and concentrated under reduced pressure to obtain a solid as a crude product (104 mg). This was recrystallized from ethyl acetate to obtain colorless and transparent needle-like (2R, 3S) -3-benzamido-2-hydroxy-3-phenylpropionic acid (79 mg, 0.277 mmol).

mp. 173-176 ° C
[Α _D ²⁵ ] -35.0 (c = 0.95 ethanol)
¹ H-NMR (DMSO-d ₆ ) δ: 4.37 (1H, br), 5.46 (1H, dd, J = 4.5 Hz, 8.9 Hz), 5.51 (1H, br), 7 .23 (1H, m), 7.31 (2H, m), 7.40 (2H, m), 7.46-7.56 (3H, m), 7.84 (2H, m), 8. 52 (1H, d, J = 8.9 Hz).

Synthesis of R = benzyl group compounds in general formulas (5-RR), (4-SS), (5-RS) and (4-SR)
(I) Synthesis of compound of general formula (1) (R = benzyl group) (steps 7 and 8)
Diisopropylamine (15.4 ml, 110 mmol) was dissolved in tetrahydrofuran (70 ml), and n-butyllithium hexane solution (1.56 M, 67.3 ml, 105 mmol) was added to this solution at 0 ° C. and stirred for 10 minutes. Thereafter, the mixture was cooled to −78 ° C., a solution of methyl 3-phenylpropionate (16.42 g, 100 mmol) in tetrahydrofuran (30 ml) was added, and the mixture was stirred at −78 ° C. for 1.5 hours. Thereafter, acrolein (8.02 ml, 120 mmol) was added dropwise and reacted for 15 minutes. The reaction mixture was poured into a mixture of 1N hydrochloric acid (300 ml) and toluene (100 ml), and the layers were separated. The organic layer was washed with a saturated aqueous NaHCO ₃ solution (100 ml), dried over anhydrous MgSO ₄ , and concentrated under reduced pressure. A yellow oily methyl 2-benzyl-3-hydroxy-4-pentenoate was obtained as a crude product (22.2 g). This was dissolved in methanol (150 ml), 2N aqueous sodium hydroxide solution (50 ml) was added thereto at room temperature, and the reaction was continued for 20 hours. After methanol was distilled off under reduced pressure, the residue was diluted with water (200 ml) and washed with toluene (50 ml × 2). The aqueous layer was acidified with 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (50 ml × 2). The organic layer was washed with saturated brine (30 ml × 2), dried over anhydrous MgSO ₄ and concentrated under reduced pressure. Thus, 2-benzyl-3-hydroxy-4-pentenoic acid was obtained (17.0 g, 82.6 mmol, 83% yield over two steps).

(II) Synthesis of compound of general formula (2) (R = benzyl group) (step 1)
2-Benzyl-3-hydroxy-4-pentenoic acid (8.65 g, 41.9 mmol) was dissolved in toluene (50 ml), triethylamine (7.60 ml, 54.5 mmol) was added and stirred, and diphenyl was added at 0 ° C. After adding phosphoryl azide (10.8 ml, 50.3 mmol), the reaction system was returned to room temperature and reacted for 10 hours. Thereafter, the reaction system was heated at 80 ° C. for 40 minutes. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 ml), and the organic layer was washed successively with water (100 ml), 1N hydrochloric acid (50 ml × 2), saturated aqueous NaHCO ₃ solution (50 ml), and anhydrous MgSO _4. And concentrated under reduced pressure. The residue (8.99 g) was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to give 4-benzyl-5-vinyl-2-oxazolidinone (6.50 g, 76%, anti- (±): syn- (±) = about 1: 1 mixture).

(III) Synthesis of compounds of general formulas (3a) and (3b) (R = benzyl group) (step 2)
4-Benzyl-5-vinyl-2-oxazolidinone (6.49 g, 31.9 mmol) and dimethylaminopyridine (391 mg, 3.20 mmol) were dissolved in tetrahydrofuran (30 ml), and triethylamine (4.90 ml, 35.1 mmol) was dissolved. The mixture was stirred and di-tert-butyl dicarbonate ((Boc) ₂ O, 8.80 ml, 38.3 mmol) was added dropwise at room temperature, and the reaction was continued at room temperature for 1.5 hours. The reaction mixture was diluted with toluene (30 ml), and the organic layer was washed successively with 1N hydrochloric acid (30 ml × 2) and saturated aqueous NaHCO ₃ solution (30 ml), dried over anhydrous MgSO ₄ and concentrated under reduced pressure to give a crude product. As a product, a solid (9.791 g) was obtained. This was purified by short silica gel column chromatography (toluene / ethyl acetate = 100/1 to 50/1 to 20/1), and then medium pressure column chromatography (Yamazen SI-40D column, toluene / ethyl acetate = 20/1). To 10/1 to 5/1) to obtain a highly polar syn (±) -N-tert-butoxycarbonyl-4-benzyl-5-vinyl-2-oxazolidinone (a compound of the general formula (3b), 3.97 g, 13.1 mmol. 41%), low polarity anti (±) -N-tert-butoxycarbonyl-4-benzyl-5-vinyl-2-oxazolidinone (compound of general formula (3a), 3.88 g , 12.8 mmol. 40%).

NMR data of syn (±) -N-tert-butoxycarbonyl-4-benzyl-5-vinyl-2-oxazolidinone (compound of general formula (3b))
¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 2.93 (1H, dd, J = 7.8 Hz, 14.0 Hz), 2.97 (1H, dd, J = 5. 8 Hz, 14.0 Hz), 4.61 (1 H, ddd, J = 1.2 Hz, 5.8 Hz, 7.0 Hz), 5.02 (1 H, m), 5.37 (1 H, dd, J = 1) .2 Hz, 10.7 Hz), 5.53 (1 H, dd, J = 1.2 Hz, 17.0 Hz), 5.76 (1 H, ddd, J = 5.8 Hz, 10.7 Hz, 17.0 Hz), 7.19-7.31 (5H).

NMR data of anti (±) -N-tert-butoxycarbonyl-4-benzyl-5-vinyl-2-oxazolidinone (compound of general formula (3a))
¹ H-NMR (CDCl ₃ ) δ: 1.59 (9H, s), 2.84 (1H, dd, J = 9.5 Hz, 13.3 Hz), 3.34 (1H, dd, J = 3. 5 Hz, 13.3 Hz), 4.17 (1 H, m), 4.62 (1 H, m), 5.14-5.18 (2 H), 5.61 (1 H, ddd, J = 5.5 Hz, 10.3 Hz, 17.1 Hz), 7.19-7.36 (5H).

(IV) Synthesis of compounds of general formulas (4a) and (4b) (R = benzyl group) (step 3)
anti (±) -N-tert-butoxycarbonyl-4-benzyl-5-vinyl-2-oxazolidinone (3.56 g, 11.7 mmol) was dissolved in methanol (25 ml) and cesium carbonate (384 mg, 1.18 mmol) Was added and allowed to react for 8 hours at room temperature. After distilling off methanol under reduced pressure, the residue was diluted with ethyl acetate (20 ml), and the organic layer was washed successively with 1N hydrochloric acid (20 ml) and saturated aqueous NaHCO ₃ solution (20 ml), dried over anhydrous MgSO ₄ , Concentrated under reduced pressure. The residue (3.55 g) is purified by medium pressure column chromatography (Yamazen SI-40D column, hexane / ethyl acetate = 4/1 to 3/1 to 2/1) to obtain syn (±) -4- ( (tert-Butoxycarbamoyl) -3-hydroxy-5-phenyl-1-pentene was obtained (compound of general formula (4a), 2.66 g, 9.58 mmol, 82%).

¹ H-NMR (CDCl ₃ ) δ: 1.39 (9H, br), 2.23 (1H, br), 2.80-2.97 (2H), 3.80 (1H, br), 4. 11 (1H, br), 4.77 (1H, br), 5.19 (1H, d, J = 10.7 Hz), 5.28 (1H, d, J = 16.0 Hz), 5.89 ( 1H, ddd, J = 4.9 Hz, 10.7 Hz, 16.0 Hz), 7.20-7.32 (5H).

  In a similar manner, syn (±) -N-tert-butoxycarbonyl-4-benzyl-5-vinyl-2-oxazolidinone (3.97 g, 13.1 mmol) was converted from anti (±) -4- (tert-butoxy). Carbamoyl) -3-hydroxy-5-phenyl-1-pentene (compound of general formula (4b), 3.18 g, 11.5 mmol, 87%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.37 (9H), 2.74 (1H, m), 2.85 (1H, dd, J = 5.4 Hz, 14 Hz), 2.95 (1H, br ), 3.98 (1H, br), 4.24 (1H, br), 4.57 (1H, br), 5.29 (1H, d, J = 10.7 Hz), 5.38 (1H, d, J = 17.1 Hz), 5.94 (1H, ddd, J = 5.5 Hz, 10.7 Hz, 17.1 Hz), 7.19-7.31 (5H).

(V-1) Synthesis of compounds of general formulas (5-RR) and (4-SS) (R = benzyl group) (step 4)
syn (±) -4- (tert-butoxycarbamoyl) -3-hydroxy-5-phenyl-1-pentene (1.80 g, 6.49 mmol) was dissolved in toluene (26 ml), and 2-propenyl acetate (2. 14 ml, 19.5 mmol) was added and stirred, and Candida antilipase type B (CAL-B, trade name Chirazyme, 649 mg) was added, and the reaction was continued at room temperature for 48 hours. CAL-B was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue (2.15 g) was purified by medium pressure column chromatography (Yamazen SI-40B column, hexane / ethyl acetate = 5 / 1-3 / 1) to give (3R, 4R) -3-acetoxy-4- (Tert-Butoxycarbamoyl) -5-phenyl-1-pentene (compound of general formula (5-RR), 1.035 g, 3.24 mmol, 49%,> 99% ee), and (3S, 4S) -4 -(Tert-Butoxycarbamoyl) -3-hydroxy-5-phenyl-1-pentene (compound of general formula (4-SS), 0.828 g, 2.98 mmol, 49%,> 99% ee) was obtained, respectively. .

NMR data of (3R, 4R) -3-acetoxy-4- (tert-butoxycarbamoyl) -5-phenyl-1-pentene (compound of general formula (5-RR))
¹ H-NMR (CDCl ₃ ) δ: 1.39 (9H, br), 2.11 (3H, s), 2.40-2.85 (2H), 4.09 (1H, m), 4. 65 (1H, m), 5.20-5.30 (3H), 5.79 (1H, ddd, J = 5.7 Hz, 10 Hz, 17 Hz), 7.16-7.34 (5H).

NMR data of (3S, 4S) -4- (tert-butoxycarbamoyl) -3-hydroxy-5-phenyl-1-pentene (compound of general formula (4-SS))
¹ H-NMR (CDCl ₃ ) δ: 1.39 (9H, br), 2.23 (1H, br), 2.80-2.97 (2H), 3.80 (1H, br), 4. 11 (1H, br), 4.77 (1H, br), 5.19 (1H, d, J = 10.7 Hz), 5.28 (1H, d, J = 16.0 Hz), 5.89 ( 1H, ddd, J = 4.9 Hz, 10.7 Hz, 16.0 Hz), 7.20-7.32 (5H).

HPLC analysis:
Conditions: Chiralcel OD-H column Hexane / 2-propanol = 30/1
Flow rate 0.8ml / min
Detection at 254 nm (3R, 4R) -3-acetoxy-4- (tert-butoxycarbamoyl) -5-phenyl-1-pentene (compound of general formula (5-RR)): t _R = 9.0 min
(3S, 4S) -4- (tert-Butoxycarbamoyl) -3-hydroxy-5-phenyl-1-pentene (compound of general formula (4-SS)): t _R = 10.1 min.

(V-2) Synthesis of compounds of general formula (5-RS) and (4-SR) (R = benzyl group) (step 4)
In the same manner as described above, from anti (±) -4- (tert-butoxycarbamoyl) -3-hydroxy-5-phenyl-1-pentene (3.17 g, 11.4 mmol), (3R, 4S)- 3-acetoxy-4- (tert-butoxycarbamoyl) -5-phenyl-1-pentene (compound of general formula (5-RS), 1.78 g, 5.58 mmol, 49%,> 99% ee), and ( 3S, 4R) -4- (tert-Butoxycarbamoyl) -3-hydroxy-5-phenyl-1-pentene (compound of general formula (4-SR), 1.55 g, 5.59 mmol, 49%,> 99% ee) was obtained respectively.

NMR data of (3R, 4S) -3-acetoxy-4- (tert-butoxycarbamoyl) -5-phenyl-1-pentene (compound of general formula (5-RS))
¹ H-NMR (CDCl ₃ ) δ: 1.35 (9H, br), 2.10 (3H, s), 2.69 (1H, dd, J = 8.8 Hz, 14.0 Hz), 2.88 (1H, dd, J = 5.5 Hz, 14.0 Hz), 4.00-4.50 (2H), 5.28-5.40 (3H), 5.84 (1H, ddd, J = 6. 4Hz, 10Hz, 17Hz), 7.17-7.30 (5H).

NMR data of (3S, 4R) -4- (tert-butoxycarbamoyl) -3-hydroxy-5-phenyl-1-pentene (compound of general formula (4-SR))
¹ H-NMR (CDCl ₃ ) δ: 1.37 (9H), 2.74 (1H, m), 2.85 (1H, dd, J = 5.4 Hz, 14 Hz), 2.95 (1H, br ), 3.98 (1H, br), 4.24 (1H, br), 4.57 (1H, br), 5.29 (1H, d, J = 10.7 Hz), 5.38 (1H, d, J = 17.1 Hz), 5.94 (1H, ddd, J = 5.5 Hz, 10.7 Hz, 17.1 Hz), 7.19-7.31 (5H).

HPLC analysis:
Conditions: Chiralcel OD-H column Hexane / 2-propanol = 30/1
Flow rate 0.8ml / min
Detection at 254 nm (3R, 4S) -3-Acetoxy-4- (tert-butoxycarbamoyl) -5-phenyl-1-pentene (compound of general formula (5-RS)): t _R = 12.8 min
(3S, 4R) -4- (tert-butoxycarbamoyl) -3-hydroxy-5-phenyl-1-pentene (compound of general formula (4-SR)): t _R = 8.9 min.

Synthesis of R = propyl group compounds in general formulas (5-RR), (4-SS), (5-RS) and (4-SR) In Example 3, valeric acid instead of methyl 3-phenylpropionate Using methyl as a starting material, via anti (±) -N-tert-butoxycarbonyl-4-propyl-5-vinyl-2-oxazolidinone (compound of general formula (3a)) in the same manner as in Example 3. (3R, 4R) -3-acetoxy-4- (tert-butoxycarbamoyl) -1-heptene (compound of general formula (5-RR), 48%, 99% ee), and (3S, 4S)- 4- (tert-butoxycarbamoyl) -3-hydroxy-1-heptene (compound of general formula (4-SS), 49%, 97% ee) was obtained. In addition, via syn (±) -N-tert-butoxycarbonyl-4-propyl-5-vinyl-2-oxazolidinone (compound of general formula (3b)), (3R, 4S) -3-acetoxy-4 -(Tert-butoxycarbamoyl) -1-heptene (compound of general formula (5-RS), 47%,> 99% ee), and (3S, 4R) -4- (tert-butoxycarbamoyl) -3-hydroxy -1-heptene (compound of general formula (4-SR), 44%,> 97% ee) was obtained. The NMR data of general formulas (3a) and (3b) are shown below together with the NMR data of these compounds.

NMR data of anti (±) -N-tert-butoxycarbonyl-4-propyl-5-vinyl-2-oxazolidinone (compound of general formula (3a))
¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, t, J = 7.3 Hz), 1.27-1.42 (2H, m), 1.54 (9H, s), 1.73 (1H, m), 1.82 (1H, m), 3.94 (1H, m), 4.56 (1H, m), 5.32 (1H, d, J = 10.5 Hz), 5. 43 (1H, d, J = 17.1 Hz), 5.86 (1 H, ddd, J = 6.1 Hz, 10.5 Hz, 17.1 Hz).

NMR data of syn (±) -N-tert-butoxycarbonyl-4-propyl-5-vinyl-2-oxazolidinone (compound of general formula (3b))
¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, t, J = 7.3 Hz), 1.31-1.38 (2H, m), 1.55 (9H, s), 1.57 (1H, m), 1.72 (1H, m), 4.26 (1H, m), 4.96 (1H, m), 5.45 (1H, d, J = 10.5 Hz), 5. 53 (1H, d, J = 17.1 Hz), 5.88 (1 H, ddd, J = 6.9 Hz, 10.5 Hz, 17.1 Hz).

NMR data of (3R, 4R) -3-acetoxy-4- (tert-butoxycarbamoyl) -1-heptene (compound of general formula (5-RR))
¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, t, J = 6.9 Hz), 1.32-1.46 (4H, m), 1.44 (9H, brs), 2.10 (3H, s), 3.81 (1H, m), 4.49 (1H, brd, J = 9.6 Hz), 5.20-5.29 (3H, m), 5.80 (1H, ddd) , J = 6.3 Hz, 10.7 Hz, 17.1 Hz).

NMR data of (3S, 4S) -4- (tert-butoxycarbamoyl) -3-hydroxy-1-heptene (compound of general formula (4-SS))
¹ H-NMR (CDCl ₃ ) δ: 0.93 (3H, t, J = 6.9 Hz), 1.30-1.50 (4H, m), 1.44 (9H, brs), 2.23 (1H, m), 3.57 (1H, m), 4.09 (1H, m), 4.60 (1H, m), 5.20 (1H, d, J = 10.4 Hz), 5. 29 (1H, d, J = 17.3 Hz), 5.90 (1 H, ddd, J = 6.0 Hz, 10.4 Hz, 17.3 Hz).

NMR data of (3R, 4S) -3-acetoxy-4- (tert-butoxycarbamoyl) -1-heptene (compound of general formula (5-RS))
¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, t, J = 6.9 Hz), 1.22-1.50 (4H, m), 1.44 (9H, brs), 2.08 (3H, s), 3.86 (1H, m), 4.38 (1H, brd, J = 9.3 Hz), 5.25-5.32 (3H, m), 5.78 (1H, ddd , J = 6.4 Hz, 10.6 Hz, 17.1 Hz).

NMR data of (3S, 4R) -4- (tert-butoxycarbamoyl) -3-hydroxy-1-heptene (compound of general formula (4-SR))
¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, t, J = 7.0 Hz), 1.26-1.50 (4H, m), 1.45 (9H, brs), 2.90 (1H, m), 3.74 (1H, m), 4.20 (1H, m), 4.52 (1H, m), 5.23 (1H, d, J = 10.5 Hz), 5. 34 (1H, d, J = 17.2 Hz), 5.85 (1H, ddd, J = 5.5 Hz, 10.5 Hz, 17.2 Hz).

Synthesis of R = 8-nonenyl group compound in general formula (5-RR), (4-SS), (5-RS) and (4-SR) In Example 3, instead of methyl 3-phenylpropionate In the same manner as in Example 3, starting from methyl 10-undecenoate as the starting material, anti (±) -N-tert-butoxycarbonyl-4- (8-nonenyl) -5-vinyl-2-oxazolidinone (general formula ( 3a)) via (3R, 4R) -3-acetoxy-4- (tert-butoxycarbamoyl) -1,12-tridecadiene (compound of general formula (5-RR), 49%,> 99 % Ee), and (3S, 4S) -4- (tert-butoxycarbamoyl) -3-hydroxy-1,12-tridecadiene (compound of general formula (4-SS), 49%,> 9 % Ee) was obtained, respectively. In addition, via syn (±) -N-tert-butoxycarbonyl-4- (8-nonenyl) -5-vinyl-2-oxazolidinone (compound of general formula (3b)), (3R, 4S) -3 Acetoxy-4- (tert-butoxycarbamoyl) -1,12-tridecadiene (compound of general formula (5-RS), 48%, 97% ee), and (3S, 4R) -4- (tert-butoxycarbamoyl) ) -3-hydroxy-1,12-tridecadiene (compound of general formula (4-SR), 49%, 99% ee) was obtained. The NMR data of general formulas (3a) and (3b) are shown below together with the NMR data of these compounds.

NMR data of anti (±) -N-tert-butoxycarbonyl-4- (8-nonenyl) -5-vinyl-2-oxazolidinone (compound of general formula (3a))
¹ H-NMR (CDCl ₃ ) δ: 1.25-1.40 (10H, m), 1.54 (9H, s), 1.74 (1H, m), 1.84 (1H, m), 2.02 to 2.06 (2H, m), 3.92 (1H, m), 4.55 (1H, m), 4.93 (1H, d, J = 10.4 Hz), 4.99 ( 1H, d, J = 17.0 Hz), 5.33 (1H, dd, J = 0.9 Hz, 10.7 Hz), 5.44 (1H, dd, J = 1.0 Hz, 17.0 Hz), 5 .77-5.89 (2H, m).

NMR data of syn (±) -N-tert-butoxycarbonyl-4- (8-nonenyl) -5-vinyl-2-oxazolidinone (compound of general formula (3b))
¹ H-NMR (CDCl ₃ ) δ: 1.24 to 1.38 (10H, m), 1.54 (9H, s), 1.58 (1H, m), 1.75 (1H, m), 2.00-2.05 (2H, m), 4.25 (1H, m), 4.91-5.01 (3H, m), 5.45 (1H, dd, J = 0.9 Hz, 10 .7 Hz), 5.49 (1H, dd, J = 1.0 Hz, 17.1 Hz), 5.76-5.91 (2H, m).

NMR data of (3R, 4R) -3-acetoxy-4- (tert-butoxycarbamoyl) -1,12-dridecadiene (compound of general formula (5-RR))
¹ H-NMR (CDCl ₃ ) δ: 1.25 to 1.55 (12H, m), 1.44 (9H, brs), 2.01 to 2.04 (2H, m), 2.09 (3H , S), 3.78 (1H, m), 4.48 (1H, brd, J = 9.5 Hz), 4.93 (1H, d, J = 10.4 Hz), 4.99 (1H, d) , J = 17.1 Hz), 5.20-5.29 (3H, m), 5.75-5.84 (2H, m).

NMR data of (3S, 4S) -4- (tert-butoxycarbamoyl) -3-hydroxy-1,12-dridecadiene (compound of general formula (4-SS))
¹ H-NMR (CDCl ₃ ) δ: 1.25-1.68 (12H, m), 1.44 (9H, brs), 2.01-2.05 (2H, m), 2.19 (1H , Brs), 3.58 (1H, m), 4.09 (1H, m), 4.60 (1H, m), 4.92 (1H, d, J = 10.2 Hz), 4.98 ( 1H, d, J = 17.1 Hz), 5.20 (1 H, d, J = 10.7 Hz), 5.29 (1 H, d, J = 17.1 Hz), 5.80 (1 H, ddd, J = 6.9 Hz, 10.2 Hz, 17.1 Hz), 5.90 (1 H, ddd, J = 6.1 Hz, 10.7 Hz, 17.1 Hz).

NMR data of (3R, 4S) -3-acetoxy-4- (tert-butoxycarbamoyl) -1,12-dridecadiene (compound of general formula (5-RS))
¹ H-NMR (CDCl ₃ ) δ: 1.27-1.55 (12H, m), 1.45 (9H, brs), 2.01-2.06 (2H, m), 2.08 (3H , S), 3.84 (1H, m), 4.37 (1H, brd, J = 9.8 Hz), 4.93 (1H, d, J = 10.1 Hz), 4.99 (1H, d) , J = 17.4 Hz), 5.26-5.32 (3H, m), 5.74-5.85 (2H, m).

NMR data of (3S, 4R) -4- (tert-butoxycarbamoyl) -3-hydroxy-1,12-dridecadiene (compound of general formula (4-SR))
¹ H-NMR (CDCl ₃ ) δ: 1.26 to 1.56 (12H, m), 1.45 (9H, brs), 2.01 to 2.06 (2H, m), 2.87 (1H , M), 3.72 (1H, m), 4.20 (1H, m), 4.50 (1H, m), 4.93 (1H, d, J = 10.1 Hz), 4.99 ( 1H, d, J = 17.4 Hz), 5.23 (1H, d, J = 10.7 Hz), 5.33 (1H, d, J = 17.1 Hz), 5.76-5.88 (2H) , M).

Synthesis of R = 2-phenylthioethyl group compounds in general formulas (5-RR), (4-SS), (5-RS) and (4-SR) In Example 3, methyl 3-phenylpropionate Instead, methyl (4-phenylthiobutanoate) was used as a starting material, and anti (±) -N-tert-butoxycarbonyl-4- (2-phenylthioethyl) -5-vinyl-2 was prepared in the same manner as in Example 3. -Oxazolidinone (compound of general formula (3a)) to (3R, 4R) -3-acetoxy-4- (tert-butoxycarbamoyl) -6-phenylthio-1-hexene (general formula (5-RR) 44%,> 99% ee), and (3S, 4S) -4- (tert-butoxycarbamoyl) -3-hydroxy-6-phenylthio-1-hexene (one Compounds of formula (4-SS), to give 45%, 96% ee), respectively. Also, via syn (±) -N-tert-butoxycarbonyl-4- (2-phenylthioethyl) -5-vinyl-2-oxazolidinone (compound of general formula (3b)), (3R, 4S) -3-acetoxy-4- (tert-butoxycarbamoyl) -6-phenylthio-1-hexene (compound of general formula (5-RS), 47%, 99% ee), and (3S, 4R) -4- ( tert-Butoxycarbamoyl) -3-hydroxy-6-phenylthio-1-hexene (compound of general formula (4-SR), 46%,> 99% ee) was obtained respectively. The NMR data of general formulas (3a) and (3b) are shown below together with the NMR data of these compounds.

NMR data of anti (±) -N-tert-butoxycarbonyl-4- (2-phenylthioethyl) -5-vinyl-2-oxazolidinone (compound of general formula (3a))
¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.04-2.20 (2H, m), 2.91-2.99 (2H, m), 4.09 (1H , M), 4.59 (1H, m), 5.34 (1H, d, J = 10.7 Hz), 5.45 (1H, d, J = 17.1 Hz), 5.82 (1H, m ), 7.21-7.36 (5H).

NMR data of syn (±) -N-tert-butoxycarbonyl-4- (2-phenylthioethyl) -5-vinyl-2-oxazolidinone (compound of general formula (3b))
¹ H-NMR (CDCl ₃ ) δ: 1.51 (9H, s), 1.95 (1H, m), 2.09 (1H, m), 2.88-2.93 (2H, m), 4.40 (1H, m), 4.97 (1 H, m), 5.43 (1 H, d, J = 10.7 Hz), 5.53 (1 H, d, J = 17.1 Hz), 5. 79 (1H, ddd, J = 6.4 Hz, 10.7 Hz, 17.1 Hz), 7.19-7.36 (5H).

NMR data of (3R, 4R) -3-acetoxy-4- (tert-butoxycarbamoyl) -6-phenylthio-1-hexene (compound of general formula (5-RR))
¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.66 (1H, m), 1.84 (1H, m), 2.06 (3H, s), 2.90- 3.01 (2H, m), 3.96 (1H, m), 4.54 (brd, J = 9.9 Hz), 5.21-5.29 (3H, m), 5.76 (1H, ddd, J = 6.0 Hz, 10.6 Hz, 17.0 Hz), 7.05 (1H, m), 7.15-7.35 (4H, m).

NMR data of (3S, 4S) -4- (tert-butoxycarbamoyl) -3-hydroxy-6-phenylthio-1-hexene (compound of general formula (4-SS))
¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, brs), 1.86 (1H, m), 1.93 (1H, m), 2.23 (1H, m), 2.92- 3.06 (2H, m), 3.73 (1H, m), 4.13 (1H, m), 4.70 (1H, m), 5.20 (1H, d, J = 10.4 Hz) 5.29 (1H, d, J = 17.4 Hz), 5.87 (1 H, ddd, J = 5.8 Hz, 10.4 Hz, 17.4 Hz), 7.16 (1 H, m), 7. 26-7.36 (4H, m).

NMR data of (3R, 4S) -3-acetoxy-4- (tert-butoxycarbamoyl) -6-phenylthio-1-hexene (compound of general formula (5-RS))
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.62 (1H, m), 1.87 (1H, m), 2.06 (3H, s), 2.91 ( 3H, s), 3.01 (1H, m), 4.00 (1H, m), 4.48 (brd, J = 9.8 Hz), 5.25-5.30 (3H, m), 5 .73 (1H, m), 7.19 (1H, m), 7.26-7.36 (4H, m).

NMR data of (3S, 4R) -4- (tert-butoxycarbamoyl) -3-hydroxy-6-phenylthio-1-hexene (compound of general formula (4-SR))
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, brs), 1.67 (1H, m), 1.85 (1H, m), 2.50 (1H, m), 2.92 ( 1H, m), 3.03 (1H, m), 3.84 (1H, m), 4.23 (1H, m), 4.69 (1H, m), 5.22 (1H, d, J = 10.7 Hz), 5.32 (1H, d, J = 17.2 Hz), 5.81 (1H, ddd, J = 5.5 Hz, 10.7 Hz, 17.2 Hz), 7.18 (1H, m), 7.26-7.36 (4H, m).

Synthesis of R = p-methoxybenzyl group compounds in general formulas (5-RR), (4-SS), (5-RS) and (4-SR) In Example 3, instead of methyl 3-phenylpropionate In the same manner as in Example 3, starting from methyl 3- (4-methoxyphenyl) propionate and anti (±) -N-tert-butoxycarbonyl-4- (4-methoxybenzyl) -5-vinyl Via 2-oxazolidinone (compound of general formula (3a)), (3R, 4R) -3-acetoxy-4- (tert-butoxycarbamoyl) -5- (4-methoxyphenyl) -1-pentene ( Compound of general formula (5-RR), 46%, 97% ee), and (3S, 4S) -4- (tert-butoxycarbamoyl) -3-hydroxy-5- (4-me Kishifeniru) -1- compound of pentene (formula (4-SS), to give 43%,> 99% ee), respectively. Also, via syn (±) -N-tert-butoxycarbonyl-4- (4-methoxybenzyl) -5-vinyl-2-oxazolidinone (compound of general formula (3b)), (3R, 4S)- 3-acetoxy-4- (tert-butoxycarbamoyl) -5- (4-methoxyphenyl) -1-pentene (compound of general formula (5-RS), 41%, 94% ee), and (3S, 4R) -4- (tert-butoxycarbamoyl) -3-hydroxy-5- (4-methoxyphenyl) -1-pentene (compound of general formula (4-SR), 49%, 98% ee) was obtained. The NMR data of general formulas (3a) and (3b) are shown below together with the NMR data of these compounds.

NMR data of anti (±) -N-tert-butoxycarbonyl-4- (4-methoxybenzyl) -5-vinyl-2-oxazolidinone (compound of general formula (3a))
¹ H-NMR (CDCl ₃ ) δ: 1.59 (9H, s), 2.79 (1H, dd, J = 9.5 Hz, 13.4 Hz), 3.25 (1H, dd, J = 3. 4 Hz, 13.4 Hz), 3.80 (3 H, s), 4.12 (1 H, m), 4.61 (1 H, m), 5.17 (1 H, d, J = 10.7 Hz), 5 .18 (1H, d, J = 17.1 Hz), 5.63 (1 H, ddd, J = 5.5 Hz, 10.7 Hz, 17.1 Hz), 6.87 (2H, m), 7.11 ( 2H, m).

NMR data of syn (±) -N-tert-butoxycarbonyl-4- (4-methoxybenzyl) -5-vinyl-2-oxazolidinone (compound of general formula (3b))
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 2.85-2.93 (2H, m), 3.78 (3H, s), 4.55 (1H, dm), 5.01 (1H, m), 5.37 (1H, d, J = 10.7 Hz), 5.52 (1H, d, J = 17.0 Hz), 5.76 (1H, ddd, J = 5) .8 Hz, 10.7 Hz, 17.0 Hz), 6.82 (2H, m), 7.11 (2H, m).

NMR data of (3R, 4R) -3-acetoxy-4- (tert-butoxycarbamoyl) -5- (4-methoxyphenyl) -1-pentene (compound of general formula (5-RR))
¹ H-NMR (CDCl ₃ ) δ: 1.40 (9H, brs), 2.11 (3H, s), 2.72 (2H, d, J = 7.0 Hz), 3.78 (3H, s ), 4.01 (1H, m), 4.65 (1H, m), 5.20-5.30 (3H, m), 5.78 (1H, ddd, J = 6.0 Hz, 10.6 Hz) , 17.0 Hz), 7.05 (1 H, m), 7.15-7.35 (4 H, m).

NMR data of (3S, 4S) -4- (tert-butoxycarbamoyl) -3-hydroxy-5- (4-methoxyphenyl) -1-pentene (compound of general formula (4-SS))
¹ H-NMR (CDCl ₃ ) δ: 1.39 (9H, brs), 2.18 (1H, m), 2.76-2.91 (2H, m), 3.74 (1H, ms), 3.79 (3H, s), 4.11 (1H, m), 4.76 (1H, m), 5.18 (1H, d, J = 10.4 Hz), 5.26 (1H, d, J = 17.3 Hz), 5.91 (1H, ddd, J = 5.5 Hz, 10.4 Hz, 17.3 Hz), 6.83 (2H, m), 7.17 (2H, m).

NMR data of (3R, 4S) -3-acetoxy-4- (tert-butoxycarbamoyl) -5- (4-methoxyphenyl) -1-pentene (compound of general formula (5-RS))
¹ H-NMR (CDCl ₃ ) δ: 1.36 (9H, brs), 2.09 (3H, s), 2.63 (1H, m), 2.80 (1H, dd, J = 5.5 Hz) , 14.3 Hz), 3.78 (3H, s), 4.14 (1H, m), 4.41 (1H, m), 5.26-5.34 (3H, m), 5.82 ( 1H, ddd, J = 6.5 Hz, 10.7 Hz, 17.1 Hz), 6.83 (2H, m), 7.09 (2H, m).

NMR data of (3S, 4R) -4- (tert-butoxycarbamoyl) -3-hydroxy-5- (4-methoxyphenyl) -1-pentene (compound of general formula (4-SR))
¹ H-NMR (CDCl ₃ ) δ: 1.38 (9H, brs), 2.68 (1H, m), 2.78 (1H, dd, J = 5.5 Hz, 14.0 Hz), 2.96 (1H, m), 3.79 (3H, s), 3.93 (1H, m), 4.22 (1H, m), 4.54 (1H, m), 5.28 (1H, d, J = 10.5 Hz), 5.37 (1H, d, J = 17.4 Hz), 5.93 (1 H, ddd, J = 5.8 Hz, 10.5 Hz, 17.4 Hz), 6.84 (2H , M), 7.11 (2H, m).

  According to the present invention, optically active 4- (N-protected amino) -1-alkene-3-ol can be produced with high yield and high optical purity by a safe and suitable method for industrialization. Therefore, using this production method, 3-benzamide-2-hydroxycarboxylic acid or a salt thereof, which is a side chain of taxol or a derivative thereof, is similarly a safe and suitable method for industrialization and high in high yield. It can be produced with optical purity.

Claims (21)

(Step 1) The following general formula (1):

(In the formula, R represents an alkyl group, an alkenyl group, an aryl group, an arylalkyl group or an arylthioalkyl group.)
Or a salt thereof is reacted with an azidating agent in the presence of a base to give the following general formula (2):

(In the formula, R is as defined above.)
Obtaining a compound represented by:
(Step 2) The nitrogen functional group of the compound represented by the general formula (2) is protected, and the following general formula (3):

(In the formula, R is as defined above, and X represents a protecting group for the nitrogen functional group.)
And then separated into the following general formulas (3a) and (3b):

(In the formula, R and X are as defined above.)
Obtaining a compound represented by:
(Step 3) The compound represented by the general formula (3a) or the compound represented by the general formula (3b) is subjected to a ring-opening reaction by methanolysis, respectively, and the following general formula (4a):

(In the formula, R and X are as defined above.)
Or a compound represented by the following general formula (4b):

(In the formula, R and X are as defined above.)
Obtaining a compound represented by:
(Step 4) The compound represented by the general formula (4a) or the compound represented by the general formula (4b) is reacted with an acylating agent used for transesterification in the presence of lipase, respectively. The following general formulas (5-RR) and (4-SS):

(In the formula, R and X are as defined above, and Z represents an acyl group.)
Or the following general formulas (5-RS) and (4-SR):

(In the formula, R and X are as defined above, and Z represents an acyl group.)
Each kinetically resolved into the compounds represented by:
A process for producing optically active 4- (N-protected amino) -1-alken-3-ol.   The method for producing optically active 4- (N-protected amino) -1-alkene-3-ol according to claim 1, wherein R in the general formula (1) is a phenyl group.   The method for producing optically active 4- (N-protected amino) -1-alkene-3-ol according to claim 1, wherein the lipase used in step 4 is Candida antilipase type B (CAL-B).   The optically active 4- (N-protected amino) -1 according to claim 1, wherein the acylating agent used in Step 4 is 2-propenyl acetate, vinyl acetate, vinyl benzoate, vinyl propionate or vinyl dodecanoate. -Manufacturing method of alkene-3-ol.   The method for producing optically active 4- (N-protected amino) -1-alkene-3-ol according to claim 1, wherein X in the general formula (3) is a tert-butoxycarbonyl group (Boc group). (Step 5) Further, the compound represented by the above general formula (5-RR) obtained in Step 4 or the compound represented by the above general formula (5-RS) is deacylated, respectively. Formula (4-RR):

(In the formula, R and X are as defined above.)
Or a compound represented by the following general formula (4-RS):

(In the formula, R and X are as defined above.)
Obtaining a compound represented by:
The process for producing optically active 4- (N-protected amino) -1-alkene-3-ol according to claim 1, characterized in that The compound represented by the general formula (1) or a salt thereof is
(Step 6) The following general formula (6):

(In the formula, R is as defined above.)
A step of reacting a compound represented by the formula or a salt thereof with acrolein in the presence of a base;
The process for producing an optically active 4- (N-protected amino) -1-alkene-3-ol according to claim 1, wherein   The method for producing optically active 4- (N-protected amino) -1-alkene-3-ol according to claim 7, wherein R in the general formula (6) is a phenyl group. The compound represented by the general formula (1) or a salt thereof is
(Step 7) The following general formula (7):

Wherein R is as defined above, and R ¹ is an alkyl group having 1 to 12 carbon atoms, allyl group, methallyl group, crotyl group, cinnamyl group, prenyl group, geranyl group, benzyl group, 4-methoxybenzyl group. , Diphenylmethyl group, triphenylmethyl group, 2-trimethylsilylethyl group, methoxymethyl group, benzyloxymethyl group, 1-ethoxyethyl group, 2-methoxyethoxymethyl group or tetrahydro-2H-pyran-2-yl group .)
Is reacted with acrolein in the presence of a base to give the following general formula (8):

(In the formula, R and R ¹ are as defined above.)
Obtaining a compound represented by:
(Step 8) A step of hydrolyzing, hydrocracking, or deallylating the ester of the compound represented by the general formula (8) with a palladium catalyst;
The process for producing an optically active 4- (N-protected amino) -1-alkene-3-ol according to claim 1, wherein (Step 4) The following general formula (4a):

(In the formula, R represents an alkyl group, an alkenyl group, an aryl group, an arylalkyl group or an arylthioalkyl group, and X represents an amino-protecting group.)
Or a compound represented by the following general formula (4b):

(In the formula, R and X are as defined above.)
Are reacted with an acylating agent used for transesterification in the presence of lipase, respectively, to give the following general formulas (5-RR) and (4-SS):

(In the formula, R and X are as defined above, and Z represents an acyl group.)
Or the following general formulas (5-RS) and (4-SR):

(In the formula, R and X are as defined above, and Z represents an acyl group.)
Each kinetically resolved into the compounds represented by:
A process for producing optically active 4- (N-protected amino) -1-alken-3-ol.   The method for producing optically active 4- (N-protected amino) -1-alkene-3-ol according to claim 10, wherein R in the general formula (4a) or (4b) is a phenyl group.   The method for producing optically active 4- (N-protected amino) -1-alkene-3-ol according to claim 10, wherein the lipase used in Step 4 is Candida antilipase type B (CAL-B).   The optically active 4- (N-protected amino) -1 according to claim 10, wherein the acylating agent used in Step 4 is 2-propenyl acetate, vinyl acetate, vinyl benzoate, vinyl propionate or vinyl dodecanoate. -Manufacturing method of alkene-3-ol.   The optically active 4- (N-protected amino) -1-alkene-3-ol according to claim 10, wherein X in the general formula (4a) or (4b) is a tert-butoxycarbonyl group (Boc group). Production method. (Step 9) The following general formula (4):

(In the formula, R represents an alkyl group, an alkenyl group, an aryl group, an arylalkyl group or an arylthioalkyl group, X represents an amino-protecting group, and * represents an asymmetric carbon atom.)
Benzoylation of the hydroxyl group of the compound represented by the following general formula (9):

(In the formula, R and X are as defined above, Bz represents a benzoyl group, and * represents an asymmetric carbon atom.)
Obtaining a compound represented by:
(Step 10) The amino group of the compound represented by the general formula (9) is deprotected, and the following general formula (10):

(In the formula, R and Bz are as defined above, and * represents an asymmetric carbon atom.)
A step of obtaining a compound represented by the formula:
(Step 11) The compound represented by the above general formula (10) or a salt thereof is treated with a base, and the following general formula (11):

(In the formula, R and Bz are as defined above, and * represents an asymmetric carbon atom.)
Obtaining a compound represented by:
(Step 12) The hydroxyl group of the compound represented by the general formula (11) is protected, and the following general formula (12):

(In the formula, R and Bz are as defined above, Y represents a hydroxyl-protecting group, and * represents an asymmetric carbon atom.)
Obtaining a compound represented by:
(Step 13) By oxidizing the olefin of the compound represented by the general formula (12), the following general formula (13):

(In the formula, R, Bz and Y are as defined above, and * represents an asymmetric carbon atom.)
A step of obtaining a compound represented by the formula:
(Step 14) The hydroxyl group of the compound represented by the general formula (13) or a salt thereof is deprotected, and the following general formula (14):

(In the formula, R and Bz are as defined above, and * represents an asymmetric carbon atom.)
A step of obtaining a compound represented by the formula:
A process for producing 3-benzamido-2-hydroxycarboxylic acid or a salt thereof.   The compound represented by the general formula (4) is a (3S, 4S) isomer, and the resulting 3-benzamide-2-hydroxycarboxylic acid of the general formula (14) is a (2R, 3S) isomer. Item 16. A process for producing 3-benzamide-2-hydroxycarboxylic acid or a salt thereof according to Item 15.   The method for producing 3-benzamide-2-hydroxycarboxylic acid or a salt thereof according to claim 15, wherein R in the general formula (4) is a phenyl group.   The method for producing 3-benzamide-2-hydroxycarboxylic acid or a salt thereof according to claim 15, wherein X in the general formula (4) is a tert-butoxycarbonyl group (Boc group). The following general formula (4 ′):

(In the formula, R ′ represents an alkyl group, an alkenyl group, an aryl group, an arylalkyl group or an arylthioalkyl group, but excludes a phenyl group. X represents an amino-protecting group, and * represents an asymmetric carbon atom. Represents.)
4- (N-protected amino) -1-alkene-3-ol represented by   The 4- (N-protected amino) -1-alkene-3-ol according to claim 19, wherein X in the general formula (4 ') is a tert-butoxycarbonyl group (Boc group). The following general formula (14 ′):

(In the formula, R ′ represents an alkyl group, an alkenyl group, an aryl group, an arylalkyl group or an arylthioalkyl group, but excludes a phenyl group. Bz represents a benzoyl group, and * represents an asymmetric carbon atom.)
Or 3-benzamide-2-hydroxycarboxylic acid represented by the formula: