WO2017122822A1

WO2017122822A1 - Production intermediate of depsipeptide compound, and method for producing same

Info

Publication number: WO2017122822A1
Application number: PCT/JP2017/001140
Authority: WO
Inventors: 千加史石岡; 憲西條; 加藤　正; 紘一成田
Original assignee: 国立大学法人東北大学
Priority date: 2016-01-13
Filing date: 2017-01-13
Publication date: 2017-07-20
Also published as: JP2019052091A

Abstract

The present invention addresses the problem of providing an industrially advantageous method for producing an optically active amidocarboxylic acid derivative, which is an important intermediate of a depsipeptide compound expected to be an excellent novel molecular target anticancer agent, a production intermediate of the depsipeptide compound, and a method for producing the production intermediate. The present invention provides an optically active amidocarboxylic acid ester derivative represented by formula (I) below (in the formula, R¹, R², *, †, and TrS are the same as described in the specification).

Description

Intermediate for producing depsipeptide compounds and method for producing the same

The present invention relates to a method for producing an optically active amide carboxylic acid derivative useful as an intermediate for producing a depsipeptide compound, which is expected as an excellent novel molecular target anticancer agent, and a novel production intermediate thereof.

The present inventors have a dual inhibitory action of histone deacetylase (histone deacetylase; hereinafter referred to as “HDAC”) and phosphatidyl inositol 3-kinase (hereinafter referred to as “PI3K”). The inventors have found a depsipeptide compound represented by the formulas (1 ′) and (2 ′), which is expected to be used as a new molecular target anticancer agent (Patent Document 1).

Wherein R ¹ ′ represents an amino acid side chain, a lower alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group, and R ³ ′ and R ⁴ ′ are the same or different and represent hydrogen An atom, an amino acid side chain, a lower alkyl group, a lower alkylidene group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aralkyl group is represented.
The broken bond represents a single bond or a double bond. )
Synthetic pathways and detailed synthesis methods of depsipeptide compounds (1) and (2) known so far are described in Patent Documents 1 to 6 and Non-Patent Documents 1 to 14, but a multi-step reaction process is described. Therefore, this method is not suitable for industrial mass production.

International Publication Gazette WO2013047509 A1 International Publication WO2009141657 A1 International Publication WO2009022182 A1 International Publication WO2006129105 A1 International Publication WO2006129105 A1 International Publication WO2015131355 A1

Development of a methodology for obtaining a production intermediate in a shorter reaction step has been desired compared to the conventional method described above. The present invention seeks to solve the problems of such conventional methods, and provides a method for producing a depsipeptide compound intermediate that can be achieved in a shorter reaction step, and a production intermediate and a method for producing the same. The purpose is to provide.

The present inventor has established an efficient method for obtaining an important intermediate of a depsipeptide compound, which is expected as an excellent novel molecular target anticancer agent, as a single optical isomer in a short process. Completed the invention.

The present invention includes the following aspects.

Item 1, the following formula (I)

(Wherein R ¹ represents an amino acid side chain other than hydrogen, methyl and n-butyl, R ² represents an optionally substituted hydrocarbon group having 1 to 10 carbon atoms, and * represents an asymmetric carbon. 3′R or 3 ′S configuration, † represents an asymmetric carbon, D configuration or L configuration, and TrS represents a tritylthio group.)
An optically active amide carboxylic acid ester derivative represented by:

Item 2, the following formula (II)

(In the formula, R ¹ represents an amino acid side chain other than hydrogen, methyl, and n-butyl. * Represents an asymmetric carbon, and is a configuration of 3′R or 3 ′S. † indicates an asymmetric carbon. And represents the configuration of D or L. TrS represents a tritylthio group.)
An optically active amide carboxylic acid derivative represented by

Item 3, the following formula (III)

(In the formula, * represents an asymmetric carbon, and the bond indicated by a wavy line is a mixture of 3′R and 3 ′S configurations. TrS represents a tritylthio group.)
(RS, E) -3-hydroxy-7-tritylthio-4-heptenoic acid represented by the following formula (IV):

(Wherein R ¹ represents an amino acid side chain other than hydrogen and methyl, R ² represents an optionally substituted hydrocarbon group having 1 to 10 carbon atoms, † represents an asymmetric carbon, D Body or L configuration.)
Comprising the step of reacting the optically active amino acid ester derivative represented by formula (I) and the step of separating the two diastereomeric mixtures to be produced.

(Wherein, R ^1, R ² and † are as defined above. * Represents an asymmetric carbon, a configuration of the 3'R, or 3'S body.)
A production method for obtaining an amide carboxylate derivative represented by the formula:

Section 4, R ¹ is hydrogen, amino acid side chain other than methyl and n- butyl, The process according to claim 3.

Item 5, the following formula (I)

(Wherein R ¹ represents an amino acid side chain other than hydrogen, methyl and n-butyl, R ² represents an optionally substituted hydrocarbon group having 1 to 10 carbon atoms, and * represents an asymmetric carbon. 3′R or 3 ′S configuration, † represents an asymmetric carbon, D configuration or L configuration, and TrS represents a tritylthio group.)
And a step of hydrolyzing the optically active amide carboxylic acid ester derivative represented by formula (II):

(Wherein R ¹ , * and † are as defined above)
The manufacturing method of the optically active amide carboxylic acid derivative shown by these.

The present invention also includes the following aspects.

・ The following formula (V)

(E) -5-tritylthio-2-pentenal represented by the following formula (VI) in the presence of a base:

(In the formula, R ⁵ represents an alkyl group having 1 to 10 carbon atoms which may have a substituent.)
Wherein the acetate derivative represented by formula (VII) is reacted.

(In the formula, R ⁵ is as described above. * Represents an asymmetric carbon, and the bond indicated by a wavy line is a mixture of 3′R and 3 ′S configurations.)
(RS, E) -3-Hydroxy-7-tritylthio-4-heptenoic acid ester derivative, which is a mixture of isomers represented by

・ The following formula (VII)

(Wherein R ⁵ represents an alkyl group having 1 to 10 carbon atoms which may have a substituent. * Represents an asymmetric carbon, and the bond shown by a wavy line is a 3′R isomer or a 3 ′S isomer. A mixture of configurations.)
(RS, E) -3-hydroxy-7-tritylthio-4-heptenoate derivative, which is a mixture of isomers represented by the following formula (III):

(In the formula, the combination of * and the wavy line is as described above.)
(RS, E) -3-Hydroxy-7-tritylthio-4-heptenoic acid, which is a mixture of isomers represented by

By using the production method and the production intermediate of the present invention, the number of steps is shorter than that of the conventional method, and the formula (1) is an important common intermediate of depsipeptide compounds represented by formulas (1) and (2). An optically active amide carboxylic acid derivative represented by IV) can be obtained. In addition, according to the present invention, the number of steps from the starting material to the compound represented by the formula (IV) can be reduced from 14 steps of the conventional method to 6 steps, and the total yield of important intermediates and the overall reaction can be reduced. Efficiency can be improved dramatically. As a result, according to the present invention, production costs can be reduced, production management, etc. can be greatly improved, and depsipeptide compounds expected as excellent novel molecular target anticancer agents can be efficiently produced. It becomes possible.

From the optically active amide carboxylic acid derivative (compound of formula (II ′)) that can be produced according to the present invention, the compounds of formula (1) and (2) can be synthesized by following the schemes A and B below. it can. In the compound of the formula (II ′) shown in Scheme B, the hydroxyl group of the compound of the formula (II) is protected with a p-methoxybenzyl (hereinafter referred to as “PMB”) group. The compound of the formula (II ′) is a known compound described in the literature (see Non-Patent Documents 1 to 3 above), but the compound of the formula (II) in which the hydroxyl group is unprotected is a novel compound not described in the literature. is there. First, each step of Scheme A will be described. In step (i), the compounds of formulas (II ′) and (3) are condensed, and then the PMB group is removed and ester hydrolysis is performed to obtain a tetrapeptide derivative (compound of formula (4)). In step (ii), intramolecular esterification and intramolecular disulfide bond formation are performed to achieve synthesis of the depsipeptide compound (1). On the other hand, the synthesis of the depsipeptide compound (2) is carried out in the same manner as in the method of Scheme A as shown in Scheme B. That is, in step (i), the compounds of formulas (II ′) and (5) are condensed to obtain a tetrapeptide derivative (compound of formula (6)). In step (ii), intramolecular esterification, intramolecular disulfide bond formation, and tert-butyldimethylsilyl (hereinafter referred to as “TBS”) group deprotection are sequentially performed to synthesize a compound of formula (2) Has been completed. A feature of the synthesis method of the depsipeptide compounds shown in the above-mentioned schemes A and B (compounds of the formulas (1) and (2)) is that the optically active amide carboxylic acid derivative (II ′) is used as a common intermediate. It is.

Scheme A

(R ¹ represents an amino acid side chain, an alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aralkyl group, preferably an amino acid side chain.
R ³ and R ⁴ are the same or different and each represents a hydrogen atom, an amino acid side chain, a lower alkyl group, a lower alkylidene group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group.
A broken bond represents a single bond or a double bond. )
Scheme B

(Wherein R ¹ , R ³ and the bond of the broken line are as described above)
Non-patent documents 1 to 3 describe the synthesis route and detailed synthesis method of the compound of formula (II ′). With reference to Schemes C, D and E, a method for synthesizing the compound of formula (II ′) will be described. First, as shown in Scheme C, commercially available 1,3-propanediol (compound of formula (7)) was used as a starting material, and after 5 steps, an intermediate sulfone (formula (12) Compound). The other optically active aldehyde (compound of formula (16)), which is the other intermediate, is a known compound and is synthesized according to the method described in the literature (Non-patent Document 4). That is, as shown in Scheme D, a commercially available L-(−)-malic acid (compound of formula (13)) is used as a starting material, which is converted into a compound of formula (16) through three steps. Next, as shown in Scheme E, both intermediates (compounds of formulas (12) and (16)) are linked, and further through five steps, the optically active amide arbonic acid derivative represented by formula (II ′) is converted. It has gained.

Scheme C

Scheme D

However, in the synthetic routes shown in the above schemes C, D, and E, the number of steps required to obtain the compound of formula (II ′), which is an important intermediate, is large (in formulas (7) and (13) as starting materials). 14 steps from the compound), and the total yield was low (about 10%). The present invention has been made in view of the above prior art, and is excellent in terms of the number of steps and yield, a method for producing a depsipeptide compound intermediate, a production intermediate that can be suitably used in the method, and the method An object is to provide a manufacturing method.

Scheme E

(Wherein R ¹ is as described above)
In the present specification, the “hydrocarbon group” means a hydrocarbon group in which the group is linear, branched, cyclic, or a combination thereof. The hydrocarbon group may be a saturated hydrocarbon group or an unsaturated hydrocarbon group.

Examples of “hydrocarbon groups having 1 to 10 carbon atoms” include alkyl groups, alkenyl groups, alkynyl groups, aryl groups, aralkyl groups, and the like.

Examples of the “alkyl group” include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, Examples thereof include alkyl groups such as decyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, and cyclooctyl group.

Examples of the “alkenyl group” include alkenyl groups such as vinyl group, propenyl group, butenyl group, pentenyl group, hexenyl group, heptenyl group, octenyl group, nonenyl group and decenyl group.

Examples of the “alkynyl group” include alkynyl groups such as ethynyl group, propynyl group, butynyl group, pentynyl group, hexynyl group, heptynyl group, octynyl group, nonynyl group, decynyl group and the like.

Examples of the “aryl group” include aryl groups such as a phenyl group, a tolyl group, and a naphthyl group.

"Aralkyl group" represents an arylalkyl group. Examples of the “aralkyl group” include benzyl group, 1-phenylethyl group, naphthalen-1-ylmethyl group, naphthalen-2-ylmethyl group and the like.

Examples of the “alkylidene group” include methylene, ethylidene, propylidene, cyclopropylidene, butylidene, pentylidene, hexylidene and the like.

Preferred examples of the hydrocarbon group include lower hydrocarbon groups such as those having 1 to 6 carbon atoms, particularly 1 to 3 carbon atoms.

Examples of the substituent that the hydrocarbon group may have include halogen groups such as a fluoro group, a chloro group, a bromo group, and an iodo group, a nitro group, a cyano group, a hydroxyl group, a hydroxyl group protected with a protective group, an amino group, and a protective group. And an amino group protected with a group. In the case of having a substituent, the number of substituents is exemplified by about 1 to 3.

Examples of the hydroxyl protecting group include a lower alkyl group, a benzyl group, a p-methoxybenzyl group (PMB group), a tert-butyldimethylsilyl group (TBS group), and the like. In the above, the “lower alkyl group” means a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, isopropyl group, t-butyl group, propyl group. Group, cyclopropyl group, butyl group, isobutyl group, cyclobutyl group, pentyl group, cyclopentyl group, hexyl group, cyclohexyl group and the like. Protecting groups for amino groups include tert-butoxycarbonyl group (Boc group), benzyloxycarbonyl group (Cbz group), 9-fluorenylmethyloxycarbonyl group (Fmoc group), p-toluenesulfonyl group (tosyl group) Etc. are exemplified.

“Amino acid side chain other than hydrogen, methyl and n-butyl” refers to any amino acid side chain moiety present in natural or unnatural amino acids (particularly α-amino acids) other than glycine, alanine and norleucine. Examples of natural amino acid side chain moieties (the name of the amino acid from which it is derived are shown in parentheses) are —CH (CH ₃ ) ₂ [valine], —CH ₂ CH (CH ₃ ) ₂ [leucine], —CH ( CH ₃ ) CH ₂ CH ₃ [isoleucine], — (CH ₂ ) ₄ NH ₂ [lysine], — (CH ₂ ) ₃ NHC (═NH) NH ₂ [arginine], —CH ₂ (5-1H-imidazolyl) [Histidine], —CH ₂ CONH ₂ [asparagine], —CH ₂ CO ₂ H [aspartic acid], —CH ₂ SH [cysteine], —CH ₂ CH ₂ CONH ₂ [glutamine], —CH ₂ CH ₂ CO ₂ H _{_{_{[glutamate], - CH 2 C 6 H}}} 5 [ _{phenylalanine], - CH 2 (4-} OH-C 6 H 4) [ tyrosine], - CH ₂ (3-1H- indolyl) [Toriputofu _{_{Down], - CH 2 CH 2 SCH}} 3 [ methionine], - _CH 2 OH [serine], - CH (OH) CH 3 [ threonine], and the like. Examples of the unnatural amino acid side chain moiety (the amino acid name from which it is derived are shown in parentheses) are —CH ₂ CH ₃ [α-aminobutyric acid], —CH ₂ CH ₂ CH (CH ₃ ) ₂ [ Homoleucine], —CH ₂ C ₆ H ₁₁ [cyclohexylalanine], — (CH ₂ ) ₃ NHCONH ₂ [citrulline], —CH ₂ CH ₂ OH [homoserine], — (CH ₂ ) ₃ NH ₂ [ornithine] and the like can give. Among these, amino acid side chains of nonpolar or low polarity amino acids such as valine, leucine, isoleucine, phenylalanine, methionine, homoleucine, cyclohexylalanine and the like are preferable.

The “unnatural amino acid” refers to an amino acid that does not exist in normal natural proteins.
“Amino acid side chain other than hydrogen and methyl” refers to the amino acid side chain and n-butyl described above as “amino acid side chain other than hydrogen, methyl and n-butyl”.

“TrS” represents the following tritylthio group.

In the formula (I), * represents an asymmetric carbon and is a configuration of 3'R or 3'S. † represents an asymmetric carbon, and is a D configuration or an L configuration. That is, the compound of the formula (I) represents any one of the following compounds.

(Wherein R ¹ and R ² are as described above.)
In formula (II), * represents an asymmetric carbon and is a configuration of 3′R or 3 ′S. † represents an asymmetric carbon, and is a D configuration or an L configuration. That is, the compound of the formula (II) represents any of the following compounds.

(Wherein R ¹ is as described above.)
In the formula (III), * represents an asymmetric carbon, and the bond indicated by the wavy line is a mixture of 3′R and 3 ′S configurations. That is, the isomer mixture represented by the formula (III) is a mixture of a 3′R compound represented by the following formula (IIIa) and a 3 ′S compound represented by the following formula (IIIb).

The isomer mixture of the present invention contains the compound represented by the formula (IIIa) and the compound represented by the formula (IIIb) constituting the isomer mixture in an arbitrary ratio. A racemate containing an equal amount of each isomer may be used.

In the formula (IV), † represents an asymmetric carbon and has a configuration of either D-form or L-form. In the case of D form, the compound of the formula (IV) refers to a compound represented by the following formula (IVa). In the case of the L form, the compound of the formula (IV) refers to a compound represented by the following formula (IVb). Note that the configuration of the asymmetric carbon is maintained through the reaction of the present invention.

(Wherein R ¹ and R ² are as described above.)
In the present specification, the following broken bond indicates a single bond or a double bond.

Specifically, R ³ , R ³ ′, R ⁴ and R ⁴ ′ are monovalent groups (for example, hydrogen atom, amino acid side chain, lower alkyl group, lower alkenyl group, substituted or unsubstituted aryl group or substituted Or an unsubstituted aralkyl group), the bond is a single bond.

When R ³ , R ³ ′, R ⁴ and R ⁴ ′ are divalent groups (for example, alkylidene groups), the bond is a double bond.

<Manufacturing method>
The synthetic route for producing optically active amide carboxylic acid derivatives (compounds of formulas (IIa) and (IIb)) is as shown in Scheme F below. The compound of formula (IIa) has a 3 ′S configuration, the compound of formula (IIb) has a 3′R configuration, and both compounds can be obtained as single optical isomers. A compound of the formula (IIa) having a 3 ′S configuration is usually used as an intermediate for producing a depsipeptide compound (see Non-Patent Documents 1 to 3 and Reference Examples 4 to 7). On the other hand, the compound of the formula (IIb) having a 3′R configuration is useful as an intermediate for the production of romidepsin (a cancer molecular target therapeutic agent), which is a kind of depsipeptide compound (see Non-Patent Document 1). .

Scheme F

(Wherein R ¹ , R ² , R ⁵ , *, † and the wavy line are as described above)
In Scheme F, (E) -5-tritylthio-2-pentenal represented by the formula (V) is a known compound described in the literature (Non-Patent Documents 5 and 6), and is represented by the formula (VII) (R = tert- (S, E)-and (R, E) -3-hydroxy-7-tritylthio-4-heptenoic acid tert-butyl ester (Patent Document 2) and both enantiomers of formula (III) (S, E)-and (R, E) -3-hydroxy-7-tritylthio-4-heptenoic acid (Non-Patent Documents 7 to 12) are also known compounds. On the other hand, the optically active amide carboxylic acid ester derivatives represented by the formulas (Ia) and (Ib), respectively, and the optically active amide carboxylic acid derivatives represented by the formulas (IIa) and (IIb) are novel compounds not described in the literature, It is a compound first discovered by the present inventors.

Hereinafter, each step of the scheme F (steps (i) to (vi)) will be described.

[Steps (i) and (ii)]
(E) -5-tritylthio-2-pentenal represented by formula (V) in step (ii) is a known compound, and is commercially available according to known methods (Non-Patent Documents 5 and 6) (formula (22) Can be synthesized through two steps (see Reference Examples 1 and 2).

[Step (iii)]
In the step (iii), an acetate ester derivative represented by the formula (VI) is added to (E) -5-tritylthio-2-pentenal represented by the formula (V) in the presence of a base to obtain a compound represented by the formula (VII) (RS, E) -3-Hydroxy-7-tritylthio-4-heptenoate derivative, which is a mixture of the isomers shown (see Example 1).

Usable bases include, for example, alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as potassium tert-butoxide and sodium tert-butoxide; lithium diisopropylamide (LDA), lithium isopropylcyclohexyl Examples thereof include alkali metal amides such as amide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, and potassium bistrimethylsilylamide. Two or more of these bases may be used in combination. Alkali metal amides are preferable, and LDA is more preferable.

The base used is 0.1 to 10 equivalents, preferably 0.8 to 1.2 equivalents, based on the acetate derivative.

The reaction is preferably performed in a solvent, and any solvent may be used as long as it does not adversely affect the reaction in this step. For example, hydrocarbon solvents such as pentane, hexane, benzene, toluene and xylene; halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, chloroform, 1,1,1-trichloroethane and monochlorobenzene; diethyl ether, Ether solvents such as tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane and cyclopentylmethyl ether; acetonitrile, propionitrile, nitromethane, nitroethane, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, etc. And polar aprotic solvents. Moreover, you may mix and use 2 or more types among the said solvent. An ether solvent is preferable, and THF is more preferable.

Although the reaction temperature can vary depending on the solvent used, it can usually be carried out from −100 ° C. to the reflux temperature of the reaction solvent. For example, when LDA is used as the base, it is preferably carried out at −80 to −20 ° C.

The reaction time may vary depending on the solvent used and the reaction temperature, but is usually 10 minutes to 24 hours. Preferably, it is 30 minutes to 3 hours.

The acetic acid ester derivative used is used in an amount of 1.0 to 10.0 equivalents relative to (E) -5-tritylthio-2-pentenal (compound represented by the formula (V)). 0-4.0 equivalents are used.

The obtained product (compound of formula (VII)) can be subjected to usual post-treatment. Here, the normal post-treatment includes, for example, quench (reaction stop) and extraction. Furthermore, it can refine | purify by applying conventional methods, such as precipitation, crystallization, gel filtration, and silica gel column chromatography, as needed.

According to the reaction in this step, the product (compound represented by the formula (VII)) is an isomer mixture in which the configuration of hydroxyl groups is mixed (in some embodiments, a racemate (an equivalent mixture of R and S forms)). As obtained.

[Step (iv)]
In step (iv), the (RS, E) -3-hydroxy-7-tritylthio-4-heptenoate derivative, which is a mixture of isomers represented by formula (VII), is hydrolyzed in the presence of a base or an acid. Thus, (RS, E) -3-hydroxy-7-tritylthio-4-heptenoic acid, which is a mixture of isomers represented by the formula (III), is produced (see Example 2).

Examples of the base used in this step include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, and lithium bicarbonate. . Examples of the acid include sulfuric acid, hydrochloric acid, phosphoric acid and acetic acid. Preferred is a base, and more preferred is sodium hydroxide.

The reaction is preferably performed in a solvent, and any solvent may be used as long as it does not adversely affect the reaction in this step. For example, alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butyl alcohol; ether solvents such as THF and 1,4-dioxane; polar aprotic solvents such as acetonitrile, N, N-dimethylformamide and dimethyl sulfoxide Sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid and water. Moreover, you may mix and use 2 or more types among the said solvent. Preferred are methanol, ethanol, THF, acetonitrile, and water, and more preferred are methanol, ethanol, and water.

Although the reaction temperature can vary depending on the solvent used, it can usually be carried out from −100 ° C. to the reflux temperature of the reaction solvent. Preferably, it is 0 to 80 ° C.

The obtained product (compound of formula (III)) can be subjected to usual post-treatment. Furthermore, it can refine | purify by applying conventional methods, such as precipitation, crystallization, gel filtration, and silica gel column chromatography, as needed.

[Step (v)]
Step (v) is represented by formula (IV) in the presence of a condensing agent to (RS, E) -3-hydroxy-7-tritylthio-4-heptenoic acid, which is a racemate represented by formula (III). The optically active amide carboxylic acid ester derivatives represented by the formulas (Ia) and (Ib) are each converted into a single optical compound by reacting the optically active amino acid derivative, and separating and purifying the resulting two diastereomeric mixtures. It is produced as an isomer (see Examples 3 to 5).

Examples of the condensing agent used in this step include 1H-benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexa Phosphonium condensing agents such as fluorophosphate (PyBOP) and chlorotripyrrolidinophosphonium hexafluorophosphate (PyCrop); N, N′-diisopropylcarbodiimide (DIC) and 1-ethyl-3- (3-dimethylamino) Carbodiimide condensing agents such as propyl) carbodiimide (EDC); triazine condensates such as (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholium chloride n-hydrate Agent; N, N′-carbonylimidazole (CDI ) Imidazole condensing agents; O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU) and O- (7-azabenzotriazole -1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU) and the like. Preferred is a phosphonium condensing agent, and more preferred is PyBOP.

In this step, additives can be added to make the reaction proceed more efficiently. Usable additives include triazole compounds such as 1-hydroxybenzotriazole (HOBt) and 1-hydroxyazabenzotriazole (HOAt); triatylamine, pyridine, 4-dimethylaminopyridine, diethylamine and N, N- Examples thereof include amine compounds such as diisopropylethylamine. An amine compound is preferred, and N, N-diisopropylethylamine is therefore preferred.

The reaction is preferably performed in a solvent, and any solvent may be used as long as it does not adversely affect the reaction in this step. For example, alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butyl alcohol; hydrocarbon solvents such as pentane, hexane, benzene, toluene and xylene; dichloromethane, 1,2-dichloroethane, chloroform, 1,1,1 -Halogenated hydrocarbon solvents such as trichloroethane and monochlorobenzene; ether solvents such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane and cyclopentylmethyl ether; acetonitrile, propionitrile, nitromethane, nitroethane, Examples thereof include polar aprotic solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl sulfoxide. Moreover, you may mix and use 2 or more types among the said solvent. A polar aprotic solvent is preferred, and acetonitrile is more preferred.

Although the reaction temperature can vary depending on the solvent used, it can usually be carried out from −100 ° C. to the reflux temperature of the reaction solvent. Preferably, it is 0 to 50 ° C.

Separation and purification of the two diastereomeric mixtures produced (mixtures of compounds (Ia) and (Ib)) should be carried out by applying conventional techniques such as precipitation, crystallization, gel filtration and silica gel column chromatography. Each compound can be obtained as a single optical isomer. A preferred separation / purification method is silica gel column chromatography.

In this step, it is an important point to use a compound represented by the formula (III) in which the hydroxyl group is unprotected. If a compound in which the hydroxyl group is protected by a PMB group is used, the compound is produced. Separation / purification of a mixture of various diastereomers is difficult, and it is difficult to obtain a corresponding optically active amide carboxylic acid ester derivative as a single optical isomer (see Reference Example 8).

In addition, a method using an optical resolving agent is known as a method for preparing an optically active compound. However, when an optical resolution agent is used, it is necessary to operate the optical resolution agent before performing optical resolution and to remove the optical resolution agent after performing optical resolution. On the other hand, there is no need to perform such an operation in this step, and there is a feature in that optical resolution of a compound used in the next step is performed as it is.

[Step (vi)]
In the step (vi), the optically active amide carboxylic acid ester derivatives represented by the formulas (Ia) and (Ib) are hydrolyzed in the presence of a base or an acid to give the corresponding formulas (IIa) and (IIb), respectively. ) Which is an optically active amide carboxylic acid derivative. (See Examples 6 to 11)
Examples of the base used in this step include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, and lithium bicarbonate. . Examples of the acid include sulfuric acid, hydrochloric acid, phosphoric acid and acetic acid. Preferred is a base, and more preferred is lithium hydroxide.

The reaction is preferably performed in a solvent, and any solvent may be used as long as it does not adversely affect the reaction in this step. For example, alcohol solvents such as methanol, ethanol, isopropyl alcohol and t-butyl alcohol; ether solvents such as THF and 1,4-dioxane; polar aprotic solvents such as acetonitrile, N, N-dimethylformamide and dimethyl sulfoxide Sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid and water. Moreover, you may mix and use 2 or more types among the said solvent. Preferred are methanol, ethanol, THF, acetonitrile, and water, and more preferred are methanol, ethanol, and water.

The reaction time may vary depending on the solvent used and the reaction temperature, but is usually 10 minutes to 24 hours. Preferably, it is 30 minutes to 5 hours.

The obtained product (compounds of the formulas (IIa) and (IIb)) can be subjected to usual post-treatment. Furthermore, it can refine | purify by applying conventional methods, such as precipitation, crystallization, gel filtration, and silica gel column chromatography, as needed.

Using the optically active amide carboxylic acid derivative (IIa-1) obtained by the above synthetic route, the transformation shown in the following scheme G is carried out according to the methods described in Patent Document 1 and Non-Patent Documents 1 and 2, and depsipeptide It was confirmed that a similar compound (compound of formula (1′a)) can be synthesized (see Reference Examples 4 to 7). The optically active tripeptide derivative represented by the formula (3a) was prepared according to the method described in Non-Patent Documents 1 and 2 (see Reference Example 3). Note that the production intermediate represented by the formula (IIa-1) does not require a step of deprotecting the protecting group because the hydroxyl group is unprotected. Therefore, by using the production intermediate of the present invention, the desired depsipeptide compound can be produced with a smaller number of steps than in the conventional method (see Scheme A).

Scheme G

(Wherein R ¹ , R ³ and the bond of the broken line are as described above)

Hereinafter, the present invention will be described in more detail with reference to examples and reference examples, but it goes without saying that the present invention is not limited to these examples.

Example 1

Under an argon atmosphere, n-butyllithium (1.6 M hexane solution, 27.9 ml, 45 mmol) was slowly added dropwise to a solution of diisopropylamine (6.0 ml, 42 mmol) in tetrahydrofuran (28 ml) at −78 ° C. at the same temperature. Stir for 30 minutes. Next, ethyl acetate (VI-1) (4.0 ml, 42 mmol) was slowly added dropwise to the reaction solution at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. Further, a solution of (E) -5-tritylthio-2-pentenal (V) (4.45 g, 12 mmol) in tetrahydrofuran (36 ml) was slowly added dropwise to the reaction solution at −78 ° C., followed by stirring at the same temperature for 1 hour. Saturated aqueous ammonium chloride (50 ml) was added to the reaction mixture to quench the reaction and then extracted with ethyl acetate (50 ml × 3). The extract was washed with saturated brine (80 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and (RS, E) -3-hydroxy-7-tritylthio-4-heptenoic acid ethyl ester (racemic mixture) (VII-1) (4.73 g, 88%) was obtained as a pale yellow solid. Obtained. This compound was used for the next reaction without purification (see Example 2).
Mp. 94-96 ° C. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.24 (3H, t, J = 6.3 Hz), 2.04-2.10 (2H, m), 2.18-2.22 (2H, m), 2.42 -2.52 (2H, m), 2.86 (1H, d, J = 4.4 Hz), 4.14 (2H, q, J = 7.2 Hz), 4.40-4.46 (1H, m), 5.38-5.44 (1H, m), 5.53-5.61 (1H, m), 7.19-7.41 ppm (15H, m). ¹³ C NMR (100 MHz, CDCl ₃ ) δ: 14.1, 31.3, 31.4, 41.4, 60.7, 66.6, 68.6, 126.6 (3C), 127.8 (6C), 129.6 (6C), 130.1, 132.0, 144.9 (3C), 172.2 ppm. FT-IR (KBr): 3454, 3056, 2980, 2925, 1733, 1594, 1489, 1444, 1371, 1275, 1182 , 1097, 1033, 971, 852, 743, 700 620 cm ⁻¹ . HRMS (FAB) C ₂₈ H ₃₁ O ₃ S [(M + H) ⁺ ] calculated 447.1994; measured 447.1992.

Example 2

(RS, E) -3-Hydroxy-7-tritylthio-4-heptenoic acid ethyl ester (racemic mixture) (VII-1) (4.73 g, 11 mmol) in ethanol / tetrahydrofuran (1: 1, 60 ml) A 20% aqueous sodium hydroxide solution (7.8 ml) was added to the mixed solution at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was adjusted to pH 2-3 with 1M hydrochloric acid and extracted with ethyl acetate (50 ml × 3). The extract was washed with saturated brine (80 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethyl acetate / hexane (1: 1) to give (RS, E) -3-hydroxy-7-tritylthio-4-heptenoic acid (racemic mixture) (III) (4.40 g, 99%) was obtained as pale yellow needles.
Mp. 131-133 ° C. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 2.05-2.10 (2H, m), 2.19-2.23 (2H, m), 2.49-2.59 (2H, m), 4.45 (1H, dd, J = 11.2, 7.3 Hz), 5.42 (1H, dd, J = 15.6, 6.3 Hz), 5.59 (1H, dt, J = 15.6, 6.8 Hz), 7.19-7.41 ppm (15H, m). ¹³ C NMR (100 MHz, CDCl ₃ ) δ: 31.3, 31.4, 41.2, 66.6, 68.5, 126.6 (3C), 127.8 (6C), 129.6 (6C), 130.7, 131.6, 144.9 (3C), 176.9 ppm. FT-IR (KBr): 3395, 3055, 3030, 2924, 1711, 1594, 1489, 1443, 1279, 1183, 1033, 970, 910, 742, 700 cm ⁻¹ .HRMS (FAB) C ₂₆ H ₂₆ O ₃ SNa [( M + Na) ⁺ ] Calculated 441.1500; Found 441.1513.

Example 3

Under an argon atmosphere, (RS, E) -3-hydroxy-7-tritylthio-4-heptenoic acid (racemic mixture) (III) (4.40 g, 11 mmol) and D-valine methyl ester hydrochloride (IV-1) (2.64 g, 16 mmol) in anhydrous acetonitrile (50 ml) was added 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (8.20 g, 16 mmol) and N, N- Diisopropylethylamine (11 mL, 63 mL) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate 1: 1), and (R) -2-[(S, E) -3-hydroxy-7-tritylthio-4-heptenamide] -3-methylbutanoic acid methyl ester (Ia-1) (1.53 g, 27%), its diastereomer (R) -2-[(R, E) -3-hydroxy-7-tritylthio-4-heptenamide ] 3-methylbutanoic acid methyl ester (Ib-1) (1.48 g, 26%) and a mixture of both compounds (diastereomer mixture) (2.55 g, 46%) were obtained. The diastereomeric mixture was further separated and purified by silica gel column chromatography (hexane / ethyl acetate 1: 1) to give (S, E) -isomer (Ia-1) (1.30 g, 23%) and ( R, E) -isomer (Ib-1) (1.30 g, 23%) was obtained. The total yield (total yield) of the (S, E) -isomer (Ia-1) and (R, E) -isomer (Ib-1) was 2.83 g (50%) and 2.78 g (49%), respectively. )Met.

(R) -2-[(S, E) -3-Hydroxy-7-tritylthio-4-heptenamide] -3-methylbutanoic acid methyl ester (Ia-1): colorless oil. [α] _D ²⁵ = -12.6 (c = 1.0, CHCl ₃ ). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 0.89 (3H, d, J = 6.8 Hz), 0.93 (3H, d, J = 6.8 Hz), 2.04-2.09 (2H, m), 2.12-2.22 (3H, m), 2.34-2.46 (2H, m), 3.43 (1H, br s), 3.73 (3H, s), 4.40-4.44 (1H , m), 4.54 (1H, dd, J = 8.8, 4.9 Hz), 5.42 (1H, dd, J = 15.1, 6.3 Hz), 5.57 (1H, dt, J = 15.1, 6.8 Hz), 6.40 (1H, d, J = 8.3 Hz), 7.18-7.44 ppm (15H, m). ¹³ C NMR (100 MHz, CDCl ₃ ) δ: 17.8, 19.0, 31.0, 31.3, 31.4, 43.0, 52.2, 57.1, 66.6, 69.2, 126.6 (3C), 127.8 (6C), 129.6 (6C), 130.0, 132.2, 144.9 (3C), 171.7, 172.5 ppm. FT-IR (neat): 3320, 3057, 2963, 2928, 1741, 1650, 1538, 1489, 1443, 1313, 1209, 1153, 1034, 974, 744, 700 cm ⁻¹ . HRMS (FAB) C ₃₂ H ₃₈ NO ₄ S [(M + H) ⁺ ] calculated 532.2522; measured 532.2536.
(R) -2-[(R, E) -3-Hydroxy-7-tritylthio-4-heptenamide] -3-methylbutanoic acid methyl ester (Ib-1): colorless oil. [α] _D ²⁵ = −0.6 (c = 1.0, CHCl ₃ ). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 0.88 (3H, d, J = 6.8 Hz), 0.92 (3H, d, J = 6.8 Hz), 2.04-2.22 (5H, m), 2.12-2.22 (3H, m), 2.35 (1H, dd, J = 15.1, 8.8 Hz), 2.45 (1H, dd, J = 15.1, 3.9 Hz), 3.44 (1H, br s), 3.72 (3H, s), 4.39-4.43 (1H, m), 4.55 (1H, dd, J = 8.3, 4.9 Hz), 5.42 (1H, dd, J = 15.1, 6.8 Hz) , 5.56 (1H, dt, J = 15.6, 5.9 Hz), 6.40 (1H, d, J = 8.8 Hz), 7.16-7.41 ppm (15H, m). ¹³ C NMR (100 MHz, CDCl ₃ ) δ: 17.7 , 18.9, 31.2, 31.3, 31.4, 42.6, 52.1, 56.9, 66.6, 69.1, 126.6 (3C), 127.8 (6C), 129.5 (6C), 130.1, 132.2, 144.9 (3C), 171.6, 172.4 ppm. IR (neat): 3326, 3057, 2962, 1741, 1649, 1535, 1490, 1443, 1372, 1313, 1266, 1207, 1033, 974, 744, 700 cm ^-1 . HRMS (FAB) C ₃₂ H ₃₈ NO ₄ S [(M + H) ⁺ ] calculated 532.2522; found 532.2535.

Example 4

(RS, E) -3-Hydroxy-7-tritylthio-4-heptenoic acid (racemic mixture) (III) (100 mg, 0.24 mmol) and D-methionine methyl ester hydrochloride (IV-2) under argon atmosphere (71.5 （mg, 0.36 の mmol) in anhydrous acetonitrile (2.4 ml) solution was added 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (186 mg, 0.36 mmol) and N, N- Diisopropylethylamine (0.24 ml, 1.4 mmol) was added, and the mixture was stirred at the same temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate 1: 1), and (R) -2-[(S, E) -3-hydroxy-7-tritylthio-4-heptenamide]. -4- (Methylthio) butanoic acid methyl ester (Ia-2) (34.2 mg, 25%), (R) -2-[(R, E) -3-hydroxy-7-tritylthio-4-heptenamide] -4 -(Methylthio) butanoic acid methyl ester (Ib-2) (21.8 mg, 16%) and a mixture of both compounds (diastereomeric mixture) (78.0 mg, 58%) were obtained. The diastereomeric mixture was further separated and purified by silica gel column chromatography (hexane / ethyl acetate 1: 1) to give (S, E) -isomer (Ia-2) (33.5 mg, 25%) and ( R, E) -isomer (Ib-2) (44.5 mg, 33%) was obtained. The total yields (total yield) of (S, E) -isomer (Ia-2) and (R, E) -isomer (Ib-2) were 67.7 mg (50%) and 66.3 mg (49%), respectively. )Met.

(R) -2-[(S, E) -3-Hydroxy-7-tritylthio-4-heptenamide] -4- (methylthio) butanoic acid methyl ester (Ia-2): colorless oil. [Α] _D ²⁵ = -21.0 (c = 1.0, CHCl ₃ ). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.95-1.99 (1H, m), 2.06-2.09 (5H, m), 2.12-2.23 (3H, m) , 2.33-2.40 (2H, m), 2.50 (2H, t, J = 7.6 Hz), 3.34 (1H, d, J = 2.9 Hz), 3.75 (3H, s), 4.40-4.45 (1H, m), 4.71 (1H, td, J = 7.6, 5.0 Hz), 5.41 (1H, dd, J = 15.6, 6.3 Hz), 5.57 (1H, dt, J = 15.6, 6.3 Hz), 6.55 (1H, d, J = 7.8 Hz), 7.19-7.41 ppm (15H, m). ¹³ C NMR (100 MHz, CDCl ₃ ) δ: 15.5, 30.0, 31.3, 31.4, 31.5, 43.0, 51.5, 52.6, 66.6, 69.2, 126.6 (3C) , 127.8 (6C), 129.6 (6C), 130.2, 132.1, 144.9 (3C), 171.6, 172.4 ppm. FT-IR (neat): 3309, 3057, 2951, 2918, 1741, 1651, 1534, 1489, 1443, 1367, 1273, 1224, 1178, 1034, 973, 910, 743, 701 cm ^-1 . HRMS (FAB) C ₃₂ H ₃₈ NO ₄ S ₂ [(M + H) ⁺ ] calculated 564.2242; measured 564.2222.
(R) -2-[(R, E) -3-Hydroxy-7-tritylthio-4-heptenamide] -4- (methylthio) butanoic acid methyl ester (Ib-2): colorless oil. [Α] _D ²⁵ = -8.2 (c = 0.85, CHCl ₃ ). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.91-2.00 (1H, m), 2.04-2.10 (5H, m), 2.10-2.26 (3H, m) , 2.35 (1H, dd, J = 15.1, 8.8 Hz), 2.44 (1H, dd, J = 15.4, 3.2 Hz), 2.46−2.53 (2H, m), 3.28 (1H, d, J = 3.4 Hz), 3.75 (3H, s), 4.40−4.44 (1H, m), 4.72 (1H, td, J = 7.3, 4.9 Hz), 5.42 (1H, dd, J = 15.6, 6.3 Hz), 5.57 (1H, dt, J = 15.6, 5.9 Hz), 6.54 (1H, d, J = 7.8 Hz), 7.19-7.44 ppm (15H, m). ¹³ C NMR (100 MHz, CDCl ₃ ) δ: 15.5, 29.9, 31.3, 31.4, 31.5, 42.7, 51.4, 52.6, 66.6, 69.1, 126.6 (3C), 127.8 (6C), 129.6 (6C), 130.0, 132.1, 144.5 (3C), 171.4, 172.3 ppm. FT-IR (neat): 3308, 3057, 2951, 2919, 1742, 1649, 1541, 1489, 1442, 1364, 1274, 1216, 1176, 1034, 971, 744, 701 cm ^-1 . HRMS (FAB) C ₃₂ H ₃₈ NO ₄ S ₂ [(M + H) ⁺ ] Calculated 564.2242 ; Actual value 564.2228.

Example 5

(RS, E) -3-hydroxy-7-tritylthio-4-heptenoic acid (racemic mixture) (III) (100 mg, 0.24 mmol) and D-phenylalanine methyl ester hydrochloride (IV-3) under an argon atmosphere (77.2 mg, 0.36 mmol) in anhydrous acetonitrile (2.4 ml) was added 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (186 mg, 0.36 mmol) and N, N- Diisopropylethylamine (0.24 ml, 1.43 mmol) was added and stirred at the same temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate 1: 1), and (R) -2-[(S, E) -3-hydroxy-7-tritylthio-4-heptenamide] -3-Phenylpropanoic acid methyl ester (Ia-3) (31.4 mg, 23%), (R) -2-[(R, E) -3-hydroxy-7-tritylthio-4-heptenamide] -3-phenyl Propanic acid methyl ester (Ib-3) (31.4 mg, 23%) and a mixture of both compounds (diastereomer mixture) (73.5 mg, 53%) were obtained. The diastereomeric mixture was further separated and purified by silica gel column chromatography (hexane / ethyl acetate 1: 1) to give (S, E) -isomer (Ia-3) (36.0 mg, 26%) and ( R, E) -isomer (Ib-3) (37.4 mg, 27%) was obtained. The total yields (total yield) of (S, E) -isomer (Ia-3) and (R, E) -isomer (Ib-3) were 67.4 mg (49%) and 68.8 mg (50%), respectively. )Met.

(R) -2-[(S, E) -3-Hydroxy-7-tritylthio-4-heptenamide] -3-phenylpropanoic acid methyl ester (Ia-3): colorless oil. [Α] _D ²⁵ = − 35.7 (c = 1.1, CHCl ₃ ). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 2.02-2.08 (2H, m), 2.17-2.21 (2H, m), 2.26-2.37 (2H, m), 3.06 (1H, dd, J = 13.7, 6.3 Hz), 3.16 (1H, dd, J = 13.9, 5.6 Hz), 3.25 (1H, d, J = 3.4 Hz), 3.75 (3H, s), 4.34-4.39 ( 1H, m), 4.86 (1H, dt, J = 7.8, 6.3 Hz), 5.35 (1H, dd, J = 15.6, 6.3 Hz), 5.53 (1H, dt, J = 15.1, 6.8 Hz), 6.26 (1H , d, J = 7.8 Hz), 7.08-7.10 (2H, m), 7.18-7.22 (3H, m), 7.25-7.41 ppm (15H, m). ¹³ C NMR (100 MHz, CDCl ₃ ) δ: 31.3 , 31.4, 37.7, 42.8, 52.4, 53.1, 66.6, 69.2, 126.6 (3C), 127.2, 127.9 (6C), 128.6 (2C), 129.2 (2C), 129.6 (6C), 130.2, 132.1, 135.7, 144.9 ( 3C), 171.4, 172.0 ppm. FT-IR (neat): 3314, 3057, 3029, 2951, 1742, 1649, 1534, 1490, 1443, 1367, 1217, 1081, 1034, 971, 744, 700 cm ^-1 . HRMS (FAB) C ₃₆ H ₃₈ NO ₄ S [(M + H) ⁺ ] calculated 580.2522; found 580.2526.
(R) -2-[(R, E) -3-Hydroxy-7-tritylthio-4-heptenamide] -3-phenylpropanoic acid methyl ester (Ib-3): colorless oil. [Α] _D ²⁵ = − 26.6 (c = 1.1, CHCl ₃ ). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 2.03-2.08 (2H, m), 2.17-2.22 (2H, m), 2.28 (1H, dd, J = 15.1, 8.8 Hz), 2.37 (1H, dd, J = 15.4, 3.2 Hz), 3.06 (1H, dd, J = 14.1, 5.9 Hz), 3.06 (1H, dd, J = 14.1, 5.9 Hz), 3.15 (1H, dd, J = 13.9, 5.6 Hz), 3.15 (1H, d, J = 3.4 Hz), 3.73 (3H, s), 4.34-4.37 (1H, m), 4.88 (1H, dt, J = 7.8, 5.9 Hz ), 5.38 (1H, dd, J = 15.6, 6.3 Hz), 5.53 (1H, dt, J = 14.6, 6.3 Hz), 6.25 (1H, d, J = 7.8 Hz), 7.07-7.10 (2H, m) , 7.18–7.22 ppm (3H, m), 7.24–7.43 ppm (15H, m). ¹³ C NMR (100 MHz, CDCl ₃ ) δ: 31.3, 31.4, 37.8, 42.6, 52.4, 53.0, 66.6, 69.1, 126.6 (3C), 127.2, 127.8 (6C), 128.6 (2C), 129.2 (2C), 129.6 (6C), 130.1, 132.1, 135.7, 144.9 (3C), 171.2, 171.9 ppm. FT-IR (neat): 3309 , 3059, 3029, 2951, 1744, 1651, 1532, 1 . 491, 1443, 1368, 1217 , 1081, 1034, 973, 854, 744, 700 cm -1 HRMS (FAB) C 36 H 38 NO 4 S [(M + H) +] calcd 580.2522; found 580.2543.

Example 6

(R) -2-[(S, E) -3-Hydroxy-7-tritylthio-4-heptenamide] -3-methylbutanoic acid methyl ester (Ia-1) (112 mg, 0.21 mmol) in methanol (4 ml) To the solution was added 1M lithium hydroxide aqueous solution (1 ml) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. A 1M aqueous hydrochloric acid solution was added to the reaction mixture to adjust to pH 2-3, followed by extraction with ethyl acetate (50 ml × 3). The extract was washed with saturated brine (80 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give (R) -2-[(S, E) -3-hydroxy-7-tritylthio- 4-Heptenamide] -3-methylbutanoic acid (IIa-1) (107 mg, 99%) was obtained as a white amorphous. This compound was used in the reaction of Reference Example 4 without purification.
[α] _D ²⁵ = -16.9 (c = 1.0, CHCl ₃ ). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 0.88 (3H, d, J = 6.8 Hz), 0.93 (3H, d, J = 6.8 Hz), 2.01-2.07 (2H, m), 2.12-2.20 (3H, m), 2.38 (2H, d, J = 6.3 Hz), 4.41-4.46 (2H, m), 5.38 (1H, dd, J = 15.2, 6.0 Hz), 5.53 (1H, dt, J = 15.0, 6.3 Hz), 6.85 (1H, d, J = 8.3 Hz), 7.18-7.44 ppm (15H, m). ¹³ C NMR (100 MHz, CDCl ₃ ) δ: 17.7, 19.2, 30.4, 31.3, 31.4, 43.4, 57.5, 66.6, 69.2, 126.6 (3C), 127.9 (6C), 129.5 (6C), 130.0, 132.0, 144.8 (3C), 172.6, 175.1 ppm FT-IR (neat): 3330, 3057, 3018, 2964, 2928, 1716, 1646, 1541, 1489, 1444, 1218, 1034, 972, 744, 700, 617 cm ⁻¹ . HRMS (FAB) C ₃₁ H ₃₆ NO ₄ S [(M + H) ⁺ ] calculated 518.2365; measured 518.2383.

Example 7

(R) -2-[(R, E) -3-Hydroxy-7-tritylthio-4-heptenamide] -3-methylbutanoic acid methyl ester (Ib-1) (207 mg, 0.39 mmol) in methanol (4 ml) To the solution was added 1M lithium hydroxide aqueous solution (1 ml) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. A 1M aqueous hydrochloric acid solution was added to the reaction mixture to adjust to pH 2-3, followed by extraction with ethyl acetate (30 ml × 3). The extract was washed with saturated brine (60 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol 8: 1), and (R) -2-[(R, E) -3-hydroxy-7-tritylthio-4-heptenamide] -3- Methylbutanoic acid (IIb-1) (193 mg, 96%) was obtained as a white amorphous.
[α] _D ²⁵ = −2.4 (c = 1.0, CHCl ₃ ). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 0.89 (3H, d, J = 6.8 Hz), 0.92 (3H, d, J = 6.8 Hz), 2.01−2.07 (2H, m), 2.17−2.20 (3H, m), 2.38−2.45 (2H, m), 4.36−4.41 (1H, m), 4.52 (1H, dd, J = 8.5, 4.6 Hz), 5.39 (1H, dd, J = 15.4, 6.1 Hz), 5.52 (1H, dt, J = 15.6, 6.3 Hz), 6.79 (1H, d, J = 8.8 Hz), 7.17-7.40 ppm (15H, m). ¹³ C NMR (100 MHz, CDCl ₃ / CD ₃ OD 10: 1) δ: 17.6, 19.0, 30.8, 31.3, 31.4, 42.7, 57.1, 66.6, 69.1, 126.6 (3C), 127.8 (6C), 129.5 (6C), 130.2, 132.0, 144.8 (3C), 172.3, 174.5 ppm. FT-IR (neat): 3338, 3057, 3017, 2964, 2930, 1717, 1647, 1541, 1489, 1444, 1217, 1034, 971, 744, 700 cm ^-1 . HRMS (FAB) C ₃₁ H ₃₆ NO ₄ S [(M + H) ⁺ ] calculated 518.2365; measured 518.2357.

Example 8

(R) -2-[(S, E) -3-hydroxy-7-tritylthio-4-heptenamide] -3- (methylthio) butanoic acid methyl ester (Ia-2) (19.8 mg, 35 μmol) in methanol ( 1.2 ml), 1M aqueous lithium hydroxide solution (0.4 ml) was added to the solution at 0 ° C., and the mixture was stirred at room temperature for 2 hours. A 1M aqueous hydrochloric acid solution was added to the reaction mixture to adjust to pH 2-3, followed by extraction with ethyl acetate (10 ml × 3). The extract was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol 8: 1), and (R) -2-[(S, E) -3-hydroxy-7-tritylthio-4-heptenamide] -3- (Methylthio) butanoic acid (IIa-2) (17.6 mg, 91%) was obtained as a white amorphous.
[α] _D ²⁵ = −7.0 (c = 1.6, CHCl ₃ ). ¹ H NMR (400 MHz, CDCl ₃ / CD ₃ OD 10: 1) δ: 1.84−1.94 (1H, m), 2.02−2.12 (6H m), 2.16−2.23 (2H, m), 2.30−2.35 (2H, m), 2.46−2.54 (2H, m), 4.39−4.44 (2H, m), 5.40 (1H, dd, J = 15.4, 6.1 Hz), 5.54 (1H, dt, J = 15.6, 6.3 Hz), 7.18-7.55 ppm (15H, m). ¹³ C NMR (100 MHz, CDCl ₃ / CD ₃ OD 10: 1) δ: 15.1, 29.5 , 30.2, 31.2, 31.4, 43.3, 52.9, 66.5, 68.8, 126.5 (3C), 127.7 (6C), 129.4 (6C), 129.5, 132.4, 144.7 (3C), 172.3, 174.3 ppm. FT-IR (neat) : 3316, 3057, 2923, 2853, 1717, 1644, 1592, 1488, 1443, 1281, 1219, 1184, 1034, 970, 743, 620 cm ⁻¹ .HRMS (FAB) C ₃₁ H ₃₆ NO ₄ S ₂ [( M + H) ⁺ ] Calculated 550.2086; Found 550.2094.

Example 9

(R) -2-[(R, E) -3-hydroxy-7-tritylthio-4-heptenamide] -3- (methylthio) butanoic acid methyl ester (Ib-2) (23.8 mg, 42 μmol) in methanol ( 1.4 ml) was added 1M aqueous lithium hydroxide solution (0.5 ml) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. A 1M aqueous hydrochloric acid solution was added to the reaction mixture to adjust to pH 2-3, followed by extraction with ethyl acetate (10 ml × 3). The extract was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol 8: 1), and (R) -2-[(R, E) -3-hydroxy-7-tritylthio-4-heptenamide] -3- (Methylthio) butanoic acid (IIb-2) (22.3 mg, 96%) was obtained as a white amorphous.
[α] _D ²⁵ = 5.7 (c = 0.91, CHCl ₃ ). ¹ H NMR (400 MHz, CDCl ₃ / CD ₃ OD 10: 1) δ: 1.89-1.98 (1H, m), 2.03-2.14 (6H, m), 2.18-2.22 (2H, m), 2.30-2.42 (2H, m), 2.47-2.54 (2H, m), 4.35-4.40 (1H, m), 4.43-4.46 (1H, m), 5.42 ( 1H, dd, J = 15.4, 6.1 Hz), 5.54 (1H, dt, J = 15.6, 6.3 Hz), 7.06-7.49 ppm (15H, m). ¹³ C NMR (100 MHz, CDCl ₃ / CD ₃ OD 10 : 1) δ: 15.1, 29.5, 30.1, 31.2, 31.4, 42.9, 52.5, 66.5, 68.8, 126.5 (3C), 127.7 (6C), 129.4 (6C), 129.6, 132.4, 144.7 (3C), 172.2, 173.9 FT-IR (neat): 3320, 3057, 2922, 2853, 1716, 1645, 1594, 1489, 1443, 1281, 1218, 1184, 1034, 971, 744, 618 cm ⁻¹ . HRMS (FAB) C ₃₁ H ₃₆ NO ₄ S ₂ [(M + H) ⁺ ] Calculated 550.2086; Found 550.2070.

Example 10

(R) -2-[(S, E) -3-Hydroxy-7-tritylthio-4-heptenamide] -3-phenylpropanoic acid methyl ester (Ia-3) (31.4 mg, 54 μmol) in methanol (1.2 ml) ) 1M aqueous lithium hydroxide solution (0.4 ml) was added to the solution at 0 ° C., and the mixture was stirred at room temperature for 2 hours. A 1M aqueous hydrochloric acid solution was added to the reaction mixture to adjust to pH 2-3, followed by extraction with ethyl acetate (10 ml × 3). The extract was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol 8: 1), and (R) -2-[(S, E) -3-hydroxy-7-tritylthio-4-heptenamide] -3- Phenylpropanoic acid (IIa-3) (30.5 mg, 99%) was obtained as a white amorphous.
[α] _D ²⁵ = −10.0 (c = 1.0, CHCl ₃ ). ¹ H NMR (400 MHz, CDCl ₃ / CD ₃ OD 10: 1) δ: 1.97−2.02 (2H, m), 2.12−2.66 (4H , m), 2.91 (1H, dd, J = 13.7, 8.8 Hz), 3.20 (1H, dd, J = 13.9, 4.1 Hz), 4.32 (1H, dd, J = 11.7, 6.3 Hz), 4.58-4.62 ( 1H, m), 5.28 (1H, dd, J = 15.6, 5.9 Hz), 5.42 (1H, dt, J = 15.6, 6.3 Hz), 7.14-7.41 ppm (20H, m). ¹³ C NMR (100 MHz, _{_{CDCl 3 / CD 3 OD 10:}} 1) δ: 31.2, 31.3, 36.9, 43.2, 54.8, 66.4, 68.6, 126.5 (3C), 126.5, 127.7 (6C), 128.2 (2C), 129.0 (2C), 129.3, 129.4 (6C), 132.3, 137.0, 144.7 (3C), 172.3, 172.4 ppm. FT-IR (neat): 3320, 3059, 3029, 2925, 1741, 1644, 1580, 1490, 1443, 1217, 1081, 1034, 972, 751, 700, 617 cm ⁻¹ . HRMS (FAB) C ₃₅ H ₃₆ NO ₄ SK [(M + K) ⁺ ] calculated 604.1924; measured 604.1911.

Example 11

(R) -2-[(R, E) -3-Hydroxy-7-tritylthio-4-heptenamide] -3-phenylpropanoic acid methyl ester (Ib-3) (31.9 mg, 55 μmol) in methanol (1.2 ml ) 1M aqueous lithium hydroxide solution (0.4 ml) was added to the solution at 0 ° C., and the mixture was stirred at room temperature for 2 hours. A 1M aqueous hydrochloric acid solution was added to the reaction mixture to adjust to pH 2-3, followed by extraction with ethyl acetate (10 ml × 3). The extract was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol 8: 1), and (R) -2-[(R, E) -3-hydroxy-7-tritylthio-4-heptenamide] -3- Phenylpropanoic acid (IIb-3) (27.3 mg, 88%) was obtained as a white amorphous.
[α] _D ²⁵ = −3.05 (c = 0.91, CHCl ₃ ). ¹ H NMR (400 MHz, CDCl ₃ / CD ₃ OD 10: 1) δ: 2.00−2.04 (2H, m), 2.14−2.30 (4H , m), 2.99 (1H, dd, J = 13.7, 7.8 Hz), 3.19 (1H, dd, J = 13.9, 4.1 Hz), 4.22-4.26 (1H, m), 4.58-4.61 (1H, m), 5.30 (1H, dd, J = 15.4, 6.1 Hz), 5.43 (1H, dt, J = 15.1, 6.3 Hz), 7.15-7.39 ppm (20H, m). ¹³ C NMR (100 MHz, CDCl ₃ / CD ₃ OD 10: 1) δ: 31.1, 31.3, 37.1, 42.2, 54.5, 66.4, 68.7, 126.5 (3C), 126.6, 127.7 (6C), 128.2 (2C), 129.1 (2C), 129.4 (6C), 129.5, 132.2, 136.9, 144.7 (3C), 172.2, 172.3 ppm. FT-IR (neat): 3316, 3060, 3029, 2925, 2853, 1715, 1644, 1495, 1444, 1217, 1082, 1034, 972, 744, 700 ^{, 620 cm -1 HRMS (FAB)} C 35 H 36 NO 4 S [(M + H) +] calcd 566.2365;. Found 566.2378.

Example 12

Under an argon atmosphere, (RS, E) -3-hydroxy-7-tritylthio-4-heptenoic acid (racemic mixture) (III) (1.20 g, 2.9 mmol) and D-norleucine methyl ester hydrochloride (IV-4 ) (683 mg, 3.7 mmol) in anhydrous acetonitrile (39 ml), 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (1.94 （g, 3.7 mmol) and N, N -Diisopropylethylamine (2.5 ml, 15 ml) was added and stirred at the same temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate 1: 1), and (R) -2-[(S, E) -3-hydroxy-7-tritylthio-4-heptenamide] Hexanoic acid methyl ester (Ia-4) (400 mg, 26%), (R) -2-[(R, E) -3-hydroxy-7-tritylthio-4-heptenamide] -hexanoic acid methyl ester (Ib -4) (416 mg, 27%) and a mixture of both compounds (diastereomer mixture) (262 mg, 17%). The diastereomeric mixture was further separated and purified by silica gel column chromatography (hexane / ethyl acetate 1: 1) to give (S, E) -isomer (Ia-4) (139 mg, 9%) and ( R, E) -isomer (Ib-4) (123 mg, 8%) was obtained. The total yields (total yields) of (S, E) -isomer (Ia-3) and (R, E) -isomer (Ib-3) were 539 mg (35%) and 539 mg (35%), respectively. )Met.

(R) -2-[(S, E) -3-hydroxy-7-tritylthio-4-heptenamide] -hexanoic acid methyl ester (Ia-4): colorless oil. [Α] _D ²⁵ = −13.1 (c = 0.85, CHCl ₃ ). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 0.89 (1H, t, J = 6.9 Hz), 1.38-1.22 (4H, m), 1.65 (1H, ddd, J = 21.3, 10.7, 6.9 Hz), 1.83 (1H, ddd, J = 14.5, 10.6, 5.5 Hz), 2.07 (2H, dd, J = 14.2, 7.1 Hz), 2.19 (2H, dd, J = 13.5, 6.4 Hz), 2.43-2.31 (2H, m), 3.50 (1H, br s), 3.74 (s, 3H), 4.42 (1H, br s), 4.58 (1H, td, J = 7.7, 5.4 Hz), 5.57 (1H, dt, J = 13.8, 6.6 Hz), 7.21-7.40 ppm (15H, m).
¹³ C NMR (100 MHz, CDCl ₃ ) δ: 13.6, 22.0, 27.2, 31.1, 31.3, 31.6, 42.8, 52.0, 52.1, 66.4, 68.9, 126.5 (3C), 127.7 (6C), 129.5 (6C), 129.7 , 132.3, 144.8 (3C), 171.6, 173.2 ppm. FT-IR (neat): 3058, 2955, 2928, 2861, 1741, 1539, 1488, 1443, 1374, 1281, 1217, 1183, 1082, 972, 850, 679, 661, 617 cm ⁻¹ . HRMS (FAB) C ₃₃ H ₄₀ NO ₄ S [(M + H) ⁺ ] calculated 546.2633; measured 546.2676.
(R) -2-[(R, E) -3-Hydroxy-7-tritylthio-4-heptenamide] -hexanoic acid methyl ester (Ia-4): colorless oil. [Α] _D ²⁵ = −0.8 (c = 0.85, CHCl ₃ ). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 0.88 (3H, t, J = 7.0 Hz), 1.22-1.35 (4H, m), 1.59-1.71 (1H, m), 1.83 (1H, ddd, J = 15.1, 10.6, 5.5 Hz), 2.07 (2H, dd, J = 13.2, 6.2 Hz), 2.20 (2H, t, J = 7.2 Hz), 2.35 (1H, dd, J = 15.3 , 8.6 Hz), 2.44 (1H, dd, J = 15.3, 3.2 Hz, 1H), 3.43 (1H, br s), 3.74 (s, 3H), 4.42 (1H, br s), 4.60 (1H, td, J = 7.7, 5.4 Hz), 5.42 (1H, dd, J = 15.4, 6.3 Hz), 5.55 (1H, dt, J = 15.4, 6.6 Hz), 7.21-7.40 ppm (15H, m). ¹³ C NMR ( 100 MHz, CDCl ₃ ) δ: 13.7, 22.1, 27.2, 31.2, 31.3, 31.9, 42.5, 51.9, 52.2, 66.5, 69.0, 126.6 (3C), 127.8 (6C), 129.6 (6C), 130.0, 132.2, 144.9 (3C), 171.5, 173.1 ppm. FT-IR (neat): 3056, 2954, 2928, 2861, 1742, 1648, 1648, 1595, 1541, 1489, 1443, 1374, 1213, 1154, 1081, 1034, 971, 849, 744, 700, 676, 621 cm ^-1 . HRM _{_{S (FAB) C 33 H 40}} NO 4 S [(M + H) +] calcd 546.2633; found 546.2676.

Example 13

To a solution of (R) -2-[(S, E) -3-hydroxy-7-tritylthio-4-heptenamide] -hexanoic acid methyl ester (Ia-4) (399 mg, 0.73 mmol) in methanol (7 ml) 1 M aqueous lithium hydroxide solution (2.2 ml) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. A 1M aqueous hydrochloric acid solution was added to the reaction mixture to adjust to pH 2-3, followed by extraction with ethyl acetate (20 ml × 3). The extract was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol 8: 1) and (R) -2-[(S, E) -3-hydroxy-7-tritylthio-4-heptenamide] -hexanoic acid. (IIa-4) (349 mg, 89%) was obtained as a white amorphous.
_{^{[α] D 25 = -13.6 (}} c = 1.0, CHCl 3) 1 H NMR (400 MHz, CDCl 3) δ:. 0.89 (3H, t, J = 7.0 Hz), 1.24-1.38 (4H, m), 1.61-1.73 (1H, m), 1.81-1.93 (1H, m), 2.06 (1H, dd, J = 14.0, 7.1 Hz), 2.20 (1h, t, J = 7.1 Hz), 2.38 (2H, t, J = 6.1 Hz), 4.39-4.55 (2H, m), 5.40 (1H, dd, J = 15.4, 6.1 Hz), 5.51-5.61 (1H, m), 6.57 (1H, s), 7.18-7.40 ppm ( ¹³ C NMR (100 MHz, CDCl ₃ ) δ: 13.7, 22.1, 27.4, 31.2, 43.3, 52.4, 60.4, 66.5, 69.0, 126.6 (3C), 127.8 (6C), 129.6 (6C), 129.9, 132.1, 144.9 (3C), 172.5, 175.6 ppm. FT-IR (neat): 2956, 2928, 2861, 2360, 2341, 2087, 1644, 1557, 1540, 1488, 1444, 1219, 1033, 970, 742 , 700, 669, 618 cm ^-1 . HRMS (FAB) C ₃₂ H ₃₇ NO ₄ SNa [(M + Na) ⁺ ] calculated 554.2341; found 554.2336.

Example 14

To a solution of (R) -2-[(R, E) -3-hydroxy-7-tritylthio-4-heptenamide] -hexanoic acid methyl ester (Ib-4) (50.0 mg, 0.092 mol) in methanol (1.8 ml) 1 M aqueous lithium hydroxide solution (0.6 ml) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. A 1M aqueous hydrochloric acid solution was added to the reaction mixture to adjust to pH 2-3, followed by extraction with ethyl acetate (10 ml × 3). The extract was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol 8: 1), and (R) -2-[(R, E) -3-hydroxy-7-tritylthio-4-heptenamide] -hexanoic acid. (IIb-4) (44.6 mg, 92%) was obtained as a white amorphous.
_{^{[α] D 25 = 0.4 (}} c = 1.1, CHCl 3) 1 H NMR (400 MHz, CDCl 3) δ:. 0.86-0.89 (3H, m), 1.23-1.30 (4H, m), 1.65-1.70 ( 1H, m), 1.84-1.87 (1H, m), 2.03-2.08 (3H, m), 2.19 (2H, t, J = 7.3 Hz), 2.35 (1H, dd, J = 15.1, 8.3 Hz), 2.42 (1H, dd, J = 15.1, 3.4 Hz), 4.39-4.42 (1H, m), 4.53 (1H, dd, J = 12.7, 7.3 Hz), 5.41 (1H, dd, J = 15.4, 6.1 Hz), 5.54 (1H, dt, J = 15.6, 6.3 Hz), 6.65 (1H, d, J = 7.8 Hz), 7.18-7.444 ppm (15H, m). ¹³ C NMR (100 MHz, CDCl ₃ ) δ: 13.8, 22.2, 27.4, 31.3, 31.4, 31.6, 42.6, 52.3, 66.6, 69.1, 126.6 (3C), 127.9 (6C), 129.6 (6C), 130.3, 132.0, 144.9 (3C), 172.1, 175.8 ppm. FT-IR (neat):. 3324, 3058 , 2956, 2928, 2861, 1717, 1645, 1541, 1489, 1444, 1217, 1082, 1034, 972, 744, 617 cm -1 HRMS (FAB) C 32 H 37 NO 4 SNa [(M + Na) ⁺ ] calculated 554.2341; found 554.2338.

[Reference example]
Reference example 1

Acrolein (22) (1.3 ml, 20 mmol) and triethylamine (2.8 ml, 20 mmol) were added to a solution of triphenylmethanethiol (5.00 g, 18 mmol) in dichloromethane (36 ml) at room temperature, and the same temperature was maintained for 1 hour. Stir. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain 3- (tritylthio) propanal (23) (6.45 g, 100%) as a white solid. This compound was used in the next reaction without purification (see Reference Example 2).
_{. Mp 107-110 ℃ (CHCl 3 /} hexane) 1 H NMR (400 MHz, CDCl 3) δ:. 2.35-2.38 (2H, m), 2.44-2.48 (2H, m), 7.20-7.40 ppm (15H, . m), 9.56 ppm (1H , s) 13 C NMR (100 MHz, CDCl 3) δ: 24.3, 42.3, 66.9, 126.7 (3C), 127.9 (6C), 129.4 (6C), 144.4 (3C), 200.2 FT-IR (KBr): 3061, 3030, 2966, 2933, 2888, 2838, 2740, 1726, 1490, 1443, 1080, 745, 701 cm ^-1 . FAB-MS: 289 [(M-C ₂ H ₃ O) ⁺ ], 275 [(M−C ₃ H ₅ O) ⁺ ], 243 [(M−C ₃ H ₅ OS) ⁺ ], 89 [(M−C ₁₉ H ₁₅ ) ⁺ ].

Reference example 2

(Triphenylphosphoranylidene) acetaldehyde (5.51 g, 18 mmol) was added to a toluene (36 ml) solution of 3- (tritylthio) propanal (23) (6.45 g, 0.19 mmol), and the mixture was heated to reflux for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / dichloromethane 1: 1) to obtain (E) -5-tritylthio-2-pentenal (V) (3.19 g, 46%) as a pale yellow solid. . Recrystallization from chloroform / hexane (1: 4) gave pale yellow needles.
Mp. 146-148 ° C. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 2.26-2.37 (4H, m), 5.97 (1H, ddt, J = 15.6, 7.8, 1.5 Hz), 6.62 (1H, dt, J = 15.6, 6.3 Hz), 7.20-7.40 (15H, m), 9.42 ppm (1H, d, J = 7.8 Hz). ¹³ C NMR (100 MHz, CDCl ₃ ) δ: 30.0, 31.7, 67.0, 126.8 ( 3C), 127.9 (6C), 129.5 (6C), 133.6, 144.4 (3C), 155.6, 193.6 ppm. FT-IR (KBr): 2924, 2853, 1685, 1487, 1440, 1180, 1111, 1035, 983, 764, 740, 701 cm ⁻¹ . HRMS (FAB) C ₂₄ H ₂₁ O ₃ S [(M−H) ⁺ ] calculated value 357.1312; actual value 357.1304.

Reference example 3

To a mixed solution of 3- (1-naphthyl) -D-alanine (25) (3.00 g, 12 mmol) in tetrahydrofuran / water (1: 1, 40 ml) was added di-tert-butyl dicarbonate (2.86 g, 13). mmol) and sodium hydroxide (1.43 g, 36 mmol) were added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, tetrahydrofuran was distilled off under reduced pressure. The residue was diluted with dichloromethane (200 ml), then 3M aqueous hydrochloric acid solution was added to adjust the aqueous layer to pH 4. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give (R) -2- (tert-butoxycarbonylamino) -3- (naphthalen-1-yl) propanoic acid (26) ( 1.64 g) was obtained. This compound was used in the next reaction without purification.

Glycine was added to a solution of (R) -2- (tert-butoxycarbonylamino) -3- (naphthalen-1-yl) propanoic acid (26) (1.64 g, 13 mmol) in acetonitrile (40 ml) at 0 ° C. Methyl ester hydrochloride (1.64 g, 13 mmol) was added, and 1-hydroxybenzotriazole (HOBt) (2.41 g, 18 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added at the same temperature. Salt (EDC.HCl) (3.42 g, 18 mmol) and N, N-diisopropylethylamine (16.2 ml, 95 mmol) were sequentially added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (200 ml) and washed successively with 3M aqueous hydrochloric acid (50 ml x 2), saturated aqueous sodium bicarbonate (50 ml x 2) and saturated brine (70 ml). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give (R) -2- [2- (tert-butoxycarbonylamino) -3- (naphthalen-1-yl) propanamide] acetic acid methyl ester ( 27) was obtained. This compound was used in the next reaction without purification.

To a solution of the above (R) -2- [2- (tert-butoxycarbonylamino) -3- (naphthalen-1-yl) propanamide] acetic acid methyl ester (27) in dichloromethane (40 ml) at 0 ° C. Acetic acid (10 ml) was added and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain (R) -2- [2-amino-3- (naphthalen-1-yl) propanamide] acetic acid methyl ester trifluoroacetate. This compound was dissolved in acetonitrile (40 ml), then (S) -2- (tert-butoxycarbonylamino) -3- (tritylthio) propanoic acid (6.61 g, 14 mmol), 1-hydroxybenzo Triazole (HOBt) (2.41 g, 18 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC · HCl) (3.42 g, 18 mmol) and N, N-diisopropylethylamine (16.2 mL) , 95 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (200 ml) and washed with 3M aqueous hydrochloric acid (50 ml × 2), saturated aqueous sodium hydrogen carbonate (50 ml × 2) and saturated brine (80 ml). After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off, and 2-{(R) -2-[(S) -2- (tert-butoxycarbonylamino) -3- (tritylthio) propanamide] -3- (Naphthalen-1-yl) propanamide} acetic acid methyl ester (28) was obtained. This compound was used in the next reaction without purification.

2-{(R) -2-[(S) -2- (tert-butoxycarbonylamino) -3- (tritylthio) propanamide] -3- (naphthalen-1-yl) propanamide} acetic acid methyl ester (28 ) In dichloromethane (40 ml) was slowly added dropwise boron trifluoride diethyl ether complex (3.8 ml, 30 mmol) at 0 ° C. and stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution (20 ml) was added to the reaction mixture, and the mixture was extracted with chloroform (30 ml × 3). The extract was washed with saturated brine (50 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / methanol 40: 1) to give 2-{(R) -2-[(S) -2-amino-3- (Tritylthio) propanamide] -3- (naphthalen-1-yl) propanamide} acetic acid methyl ester (3a) (5.36 g, 71%, 5 steps) was obtained as a white amorphous.
[α] _D ²⁵ = 13.8 (c = 1.0, CHCl ₃ ). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.27-1.30 (2H, m), 2.42 (1H, dd, J = 12.9, 8.0 Hz) , 2.55 (1H, dd, J = 12.9, 4.1 Hz), 2.83 (1H, dd, J = 7.8, 4.4 Hz) 3.49 (1H, dd, J = 14.4, 7.6 Hz), 3.55 (1H, dd, J = 14.1, 7.3 Hz), 3.64 (3H, s), 3.70 (1H, dd, J = 18.0, 4.9 Hz), 3.91 (1H, dd, J = 18.0, 5.9 Hz), 4.73 (1H, q, J = 7.5 Hz), 6.40 (1H, t, J = 5.4 Hz), 7.17-7.30 (11H, m), 7.37-7.40 (6H, m), 7.43-7.54 (3H, m), 7.65-7.69 (1H, m) , 7.80-7.81 (1H, m), 8.12 (1H, d, J = 8.3 Hz) ppm. ¹³ C NMR (100 MHz, CDCl ₃ ) δ: 34.6, 36.9, 41.0, 52.2, 53.7, 53.9, 67.0, 123.6 , 125.3, 125.7, 126.4, 126.8 (3C), 127.6, 127.7, 127.9 (6C), 128.8, 129.5 (6C), 132.0, 132.7, 133.8, 144.5 (3C), 169.6, 171.0, 173.4 ppm. FT-IR ( neat): 3316, 3058, 2950, 1750, 1657, 1596, 1511, 1443, 1398, 1372, 1211, 1033, 849, 748, 700 cm ⁻¹ . HRMS (FAB) C ₃₈ H ₃₈ N ₃ O ₄ S [ (M + H) ⁺ ] Calculated value 632.2583; Actual value 632.2601.

Reference example 4

Under an argon atmosphere, (R) -2-[(S, E) -3-hydroxy-7-tritylthio-4-heptenamide] -3-methylbutanoic acid (IIa-1) (107 mg, 0.21 mmol) and 2- { (R) -2-[(S) -2-Amino-3- (tritylthio) propanamide] -3- (naphthalen-1-yl) propanamide} acetic acid methyl ester (3a) (133ａmg, 0.21 mmol) in anhydrous dichloromethane (2 ml) solution to 1-hydroxyazabenzotriazole (HOAt) (37.3 mg, 0.27 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ′, N at −20 ° C. '-Tetramethyluronium hexafluorophosphate (HATU) (104 mg, 0.27 mmol) and N, N-diisopropylethylamine (93 µl, 0.55 mmol) were sequentially added and stirred at the same temperature for 3 hours. To the reaction mixture was added 3% aqueous hydrochloric acid (1 ml), and the mixture was extracted with chloroform (5 ml x 3). The extract was washed with saturated aqueous sodium hydrogen carbonate solution (8 ml) and saturated brine (8 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform / methanol 40: 1) to obtain (7S, 11R, 14S, 17R, E) -7-hydroxy-11-isopropyl-17- (naphthalen-1-ylmethyl). ) -9,12,15,18-tetraoxo-1,1,1-triphenyl-14-tritylthiomethyl-2-thia-10,13,16,19-tetraaza-5-henecocene-21-acid methyl ester (24) (242 mg, 92%) was obtained as a white amorphous.

It was a surprising result that the compound (IIa-1) in which the hydroxyl group is not protected can be used.
[α] _D ²⁵ = −1.6 (c = 1.0, CHCl ₃ ). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 0.85 (3H, d, J = 7.3 Hz), 0.90 (3H, d, J = 6.8 Hz), 2.00−2.22 (7H, m) 2.44 (1H, dd, J = 12.7, 5.4 Hz), 2.58 (1H, dd, J = 12.7, 7.8 Hz), 3.53 (1H, dd, J = 15.1, 9.3 Hz), 3.67 (3H, s), 3.70-3.79 (2H, m), 3.88-3.91 (1H, m), 3.95-4.03 (2H, m), 4.10 (1H, dd, J = 6.8, 4.9 Hz) , 4.85 (1H, td, J = 8.8, 4.7 Hz), 5.11-5.17 (2H, m), 6.69-6.73 (1H, m), 7.05-7.12 (2H, m), 7.15-7.24 (16H, m) , 7.26-7.33 (10H, m), 7.38-7.49 (9H, m), 7.61 (1H, d, J = 7.8 Hz), 7.75 (1H, d, J = 7.8 Hz), 8.13 ppm (1H, d, ^{. J = 8.8 Hz) 13 C} NMR (100 MHz, CDCl 3) δ: 17.5, 19.3, 29.4, 31.1, 31.3, 32.9, 33.7, 41.0, 43.3, 52.1, 52.9, 53.6, 59.6, 66.6, 67.0, 69.2, 123.5, 125.3, 125.6, 126.2, 126.6 (3C), 126.9 (3C), 127.2, 127.8 (6C), 128.0 (6C), 128.55, 128.60, 129.3 (6C), 129.5 (6C), 129.6, 131.9, 132.3, 133.1, 133.7, 144.0 (3C), 144.8 (3C), 169.9, 170.1, 171.4, 172.0, 172.6 ppm. FT-IR (neat): 3375, 3276, 3059, 2960, 1740, 1687, 1631, 152 5, 1443, 1397, 1219, 1083, 1035, 969, 745, 700 cm ⁻¹ . HRMS (FAB) C ₆₉ H ₇₁ N ₄ O ₇ S ₂ [(M + H) ⁺ ] calculated 1131.4764; measured 1131.4757 .

Reference Example 5

(7S, 11R, 14S, 17R, E) -7-hydroxy-11-isopropyl-17- (naphthalen-1-ylmethyl) -9,12,15,18-tetraoxo-1,1,1-triphenyl-14 -Tritylthiomethyl-2-thia-10,13,16,19-tetraaza-5-heneicosene-21-acid methyl ester (24) (121 mg, 0.11 mmol) in tetrahydrofuran / water (4: 1, 2 ml) To the mixed solution was added lithium hydroxide monohydrate (43.3 mg, 0.21 mmol) at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. A 3% aqueous hydrochloric acid solution was added to the reaction mixture to adjust to pH 2-3, followed by extraction with ethyl acetate (10 ml × 3). The extract was washed with saturated brine (10 ml) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give (7S, 11R, 14S, 17R, E) -7-hydroxy-11-isopropyl-17. -(Naphthalen-1-ylmethyl) -9,12,15,18-tetraoxo-1,1,1-triphenyl-14-tritylthiomethyl-2-thia-10,13,16,19-tetraaza-5 Henicosen-21-acid (4a) (115 mg, 93%) was obtained as a white amorphous. This compound was used in the next reaction without purification (see Reference Example 6). [α] _D ²⁵ = −7.4 (c = 1.1, CHCl ₃ ). ¹ H NMR (400 MHz, DMSO-D ₆ ) δ: 0.64 (3H, d, J = 6.8 Hz), 0.66 (3H, d, J = 6.8 Hz), 1.83-1.86 (3H, m), 2.01-2.04 (2H, m), 2.20-2.30 (4H, m), 3.11-3.58 (4H, m), 4.08-4.15 (3H, m), 4.52 (1H, dd, J = 13.7, 7.3 Hz), 5.24-5.35 (2H, m), 7.13-7.25 (31H, m), 7.36-7.42 (2H, m), 7.62 (1H, d, J = 7.8 Hz), 7.78-7.82 (2H, m), 8.05 ppm (1H, d, J = 7.3 Hz); ¹³ C NMR (100 MHz, DMSO-D ₆ ) δ: 17.7, 19.2, 30.29, 30.33, 30.9, 31.1 , 33.2, 42.3, 43.5, 52.2, 55.0, 57.4, 65.9, 66.0, 68.1, 123.5, 125.2, 125.4, 125.9, 126.6 (3C), 126.7 (3C), 126.8, 127.2, 127.3, 127.9 (6C), 128.0 ( 6C), 128.5, 129.01 (6C), 129.04 (6C), 131.5, 133.25, 133.34, 134.2, 144.2 (3C), 144.5 (3C), 169.4, 170.1, 170.4, 171.0, 171.8 ppm. FT-IR (neat) :. 3294, 3058, 3017, 2963, 2928, 1643, 1597, 1538, 1491, 1444, 1397, 1218, 1034, 971, 751, 700, 622 cm -1 HRMS (FAB) C 68 H 68 N 4 O 7 S ₂ K [(M + K) ⁺ ] Calculated 1155.4166; Found 1155.4167.

Reference Example 6

Under an argon atmosphere, (7S, 11R, 14S, 17R, E) -7-hydroxy-11-isopropyl-17- (naphthalen-1-ylmethyl) -9,12,15,18-tetraoxo-1,1,1- Triphenyl-14-tritylthiomethyl-2-thia-10,13,16,19-tetraaza-5-heneicosene-21-acid (4a) (115 mg, 0.10 mmol) in anhydrous dichloromethane / tetrahydrofuran (5: 1, 2.4 ml) was added 2-methyl-6-nitrobenzoic anhydride (MNBA) (47.9 mg, 0.14 mmol) and 4-dimethylaminopyridine (DMAP) (39.2 mg, 0.32 mmol) at room temperature. Stir for 1 hour. Saturated aqueous sodium hydrogen carbonate solution (1 ml) was added to the reaction mixture, and the mixture was extracted with chloroform (5 ml × 3). The extract was washed with saturated brine (8 ml) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate 1: 4), and (6R, 9S, 12R, 16S) -12-isopropyl-6- (naphthalen-1-ylmethyl) -16- [ (E) -4-tritylthio-1-buten-1-yl] -9- (tritylthio) methyl-1-oxa-4,7,10,13-tetraazacyclohexadecane-2,5,8,11,14 -Pentaone (25) (65.6 mg, 58%) was obtained as a white amorphous. [α] _D ²⁵ = 11.4 (c = 1.0, CHCl ₃ ). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 0.84 (3H, d, J = 6.8 Hz), 0.91 (3H, d, J = 6.8 Hz ), 1.90−2.04 (3H, m), 2.16−2.20 (2H, m), 2.25−2.43 (3H, m), 2.87 (1H, t, J = 11.0 Hz), 3.26−3.32 (2H, m), 3.47−3.52 (1H, m), 3.87−3.92 (1H, m), 3.99 (1H, dd, J = 16.8, 5.6 Hz), 4.07−4.12 (1H, m), 4.46−4.51 (1H, m), 5.30 (1H, dd, J = 15.4, 6.6 Hz), 5.39-5.44 (1H, m), 5.52 (1H, dt, J = 15.1, 7.3 Hz), 6.21 (1H, d, J = 6.3 Hz), 6.99 (1H, t, J = 7.6 Hz), 7.12-7.21 (17H, m), 7.23-7.30 (9H, m), 7.33-7.43 (10H, m), 7.58 (1H, d, J = 8.3 Hz), 7.75-7.78 (1H, m), 8.08 (1H, d, J = 7.8 Hz) ppm; ¹³ C NMR (100 MHz, CDCl ₃ ) δ: 18.2, 19.5, 29.7, 30.9, 31.1, 31.3, 33.6, 41.8, 42.0, 54.4, 56.3, 58.5, 66.6, 66.9, 72.2, 123.7, 125.3, 125.7, 126.3, 126.6 (3C), 126.8 (3C), 127.38, 127.43, 127.85 (6C), 127.93 (6C), 128.61, 128.64, 129.4 (6C), 129.5 (6C), 131.8, 132.4, 133.6, 133.8, 144.3 (3C), 144.8 (3C), 168.8, 169.4, 170.5, 170.8, 173.0 ppm. FT-IR (neat): 3306, 3056 , 3015, 2961, 2930, 1741, 1659, 1530, 1444, 1319, 1274, 1216, 1034, 972, 753, 700 cm ⁻¹ .HRMS (FAB) C ₆₈ H ₆₆ N ₄ O ₆ S ₂ [(M + H) ⁺ ] Calculated value 1099.4502; Actual value 1099.4497.

Reference Example 7

(6R, 9S, 12R, 16S) -12-isopropyl-6- (naphthalen-1-ylmethyl) in a mixed solution of iodine (154 mg, 0.6 mmol) in dichloromethane / methanol (9: 1, 86 ml) at room temperature -16-[(E) -4-tritylthio-1-buten-1-yl] -9- (tritylthio) methyl-1-oxa-4,7,10,13-tetraazacyclohexadecane-2,5,8 , 11,14-Pentaone (25) (66.6 mg, 60 μmol) in dichloromethane / methanol (9: 1, 15 ml) was slowly added dropwise at room temperature and stirred at the same temperature for 10 minutes. A 0.2 M aqueous solution of sodium ascorbate / 0.2 M aqueous citric acid solution (pH 4.0 buffer, 30 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 ml × 3). The extract was washed with saturated brine (100 ml × 2), dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform / methanol 20: 1) to obtain a depsipeptide compound (1′a-1) (35.3 mg, 95%) as a white amorphous. [α] _D ²⁵ = 58.0 (c = 0.70, CHCl ₃ ). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.00 (3H, d, J = 6.8 Hz), 1.02 (3H, d, J = 5.9 Hz) ), 2.06−2.15 (1H, m), 2.50−2.56 (2H, m), 2.86−2.76 (1H, m), 2.94−3.12 (4H, m), 3.42 (1H, dd, J = 15.9, 11.5 Hz ), 3.70 (1H, dd, J = 14.4, 10.5 Hz), 3.86-4.01 (3H, m), 4.06 (1H, dd, J = 14.4, 3.7 Hz), 4.50-4.56 (1H, m), 4.59 ( 1H, dd, J = 17.6, 6.8 Hz), 5.72-5.75 (2H, m), 5.79-5.87 (1H, m), 6.17 (1H, d, J = 4.4 Hz), 7.03 (1H, d, J = 5.4 Hz), 7.22 (1H, d, J = 7.3 Hz), 7.27 (1H, d, J = 6.3 Hz), 7.37 (1H, t, J = 7.6 Hz), 7.45-7.49 (2H, m), 7.55 (1H, d, J = 7.3 Hz), 7.73 (1H, d, J = 8.3 Hz), 7.83-7.87 (1H, m), 7.95-7.97 (1H, m). 13 C NMR (100 MHz, CDCl 3 ) δ: 19.38, 19.40, 29.2, 30.8, 31.1, 33.6, 37.5, 38.0, 43.2, 54.6, 56.9, 61.7, 69.4, 123.3, 125.4, 125.6, 126.1, 127.3, 127.4, 129.0, 129.7, 130.7, 131.9, 134.0 , 134.9, 168.2, 169.6 (2C ), 170.2, 172.1 ppm FT-IR (neat):. 3333, 3010, 2965, 2933, 1743, 1654, 1521, 1437, 1396, 1263, 1186, 979, 757, 667 cm ^{_{. 1 HRMS (FAB) C 30}} H 37 N 4 O 6 S 2 [(M + H) +] calcd 613.2155; found 613.2176.

Reference Example 8

Under an argon atmosphere, (RS, E) -3-[(p-methoxybenzyl) oxy] -7-tritylthio-4-heptenoic acid (racemic mixture) (III ') (10.8 mg, 20 μmol) and D-valine 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (15.6 mg) was added to a solution of methyl ester hydrochloride (IV-1) (5.0 mg, 30 μmol) in anhydrous acetonitrile (2 ml). , 30 μmol) and N, N-diisopropylethylamine (20.4 μl, 0.12 mol) were added at room temperature and stirred at the same temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate 3: 1), and (R) -2-[(RS, E) -3-[(p-methoxybenzyl) oxy] -7- Tritylthio-4-heptenamide] -3-methylbutanoic acid methyl ester (mixture of diastereomers) (I′-1) (11.5 mg, 88%) was obtained. Unlike the case of Example 3, this diastereomeric mixture could not be separated by silica gel column chromatography.

The compound of the formula (II) according to the present invention is useful as an intermediate for producing a depsipeptide compound which is expected as an excellent novel molecular target anticancer agent.

The depsipeptide compounds of the formulas (1) and (2) obtained using the compound of the formula (II) according to the present invention have a completely new mechanism of action of HDAC / PI3K double inhibition. As disclosed in International Publication (Patent Document 1), it is also effective against intractable cancers that are ineffective against cancer drugs. In addition, since the depsipeptide compound is a molecular target drug that acts specifically on cancer, it has little effect on cells and tissues other than cancer cells, and it is heavy even when used at high doses for living organisms. It is also disclosed in the above publication that the possibility of serious side effects is low.

And, for the use of the depsipeptide compounds as cancer chemotherapeutic agents for animals including humans, and for the production of pharmaceutical compositions and chemical products using these compounds, by referring to the above publication, It will be apparent to those skilled in the art.

Claims

Formula (I)

(Wherein R 1 represents an amino acid side chain other than hydrogen, methyl and n-butyl, R 2 represents an optionally substituted hydrocarbon group having 1 to 10 carbon atoms, and * represents an asymmetric carbon. 3′R or 3 ′S configuration, † represents an asymmetric carbon, D configuration or L configuration, and TrS represents a tritylthio group.)
An optically active amide carboxylic acid ester derivative represented by:
The following formula (II)

(In the formula, R 1 represents an amino acid side chain other than hydrogen, methyl, and n-butyl. * Represents an asymmetric carbon, and is a configuration of 3′R or 3 ′S. † indicates an asymmetric carbon. And represents the configuration of D or L. TrS represents a tritylthio group.)
An optically active amide carboxylic acid derivative represented by
Formula (III) below

(In the formula, * represents an asymmetric carbon, and the bond indicated by a wavy line is a mixture of 3′R and 3 ′S configurations. TrS represents a tritylthio group.)
(RS, E) -3-hydroxy-7-tritylthio-4-heptenoic acid represented by the following formula (IV):

(Wherein R 1 represents an amino acid side chain other than hydrogen and methyl, R 2 represents an optionally substituted hydrocarbon group having 1 to 10 carbon atoms, † represents an asymmetric carbon, D Body or L configuration.)
Comprising the step of reacting the optically active amino acid ester derivative represented by formula (I) and the step of separating the two diastereomeric mixtures to be produced.

(Wherein, R 1, R 2 and † are as defined above. * Represents an asymmetric carbon, a configuration of the 3'R, or 3'S body.)
A production method for obtaining an amide carboxylate derivative represented by the formula:
The production method according to claim 3, wherein R 1 is an amino acid side chain other than hydrogen, methyl and n-butyl.
Formula (I)

(Wherein R 1 represents an amino acid side chain other than hydrogen and methyl, R 2 represents an optionally substituted hydrocarbon group having 1 to 10 carbon atoms, * represents an asymmetric carbon, 3 (It is the configuration of 'R form or 3' S form. † represents an asymmetric carbon, is the configuration of D form or L form. TrS represents a tritylthio group.)
And a step of hydrolyzing the optically active amide carboxylic acid ester derivative represented by formula (II):

(Wherein R 1 , * and † are as defined above)
The manufacturing method of the optically active amide carboxylic acid derivative shown by these.
The production method according to claim 5, wherein R 1 is an amino acid side chain other than hydrogen, methyl and n-butyl.