JP2008001625A - Method for synthesizing pyrrolidine derivatives - Google Patents

Abstract

［式中、Ｌ、Ｚ^２およびＲ^２２は、明細書中に定義したとおりである］の化合物を原料として、式Ｉ：

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５およびＺは、明細書中に定義されたとおりである］の化合物を製造する方法が提供される。
【選択図】なしAn object of the present invention is to provide an efficient method for synthesizing a pyrrolidine dicarboxylic acid compound that can be applied to the synthesis of kainic acid and the like and has a short process and high conversion efficiency in each process.
According to the invention, for example, the formula BI:

Starting from a compound of the formula: wherein L, Z ² and R ²² are as defined in the specification,

Provided is a method for preparing a compound of the formula: wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Z are as defined in the specification.
[Selection figure] None

Description

  The present invention relates to a method for producing a pyrrolidine derivative such as kainic acid, which is a natural product having physiological activity, and a synthetic intermediate useful for the production thereof.

Naturally derived compounds such as kainic acid and domoic acid are dicarboxylic acid compounds having a pyrrolidine ring as a main skeleton, and have physiological activity as glutamate agonists.
Kainic acid is a compound discovered from the red alga Macri (kanin grass) that has long been used as an insecticide, and is still used as an anthelmintic (Non-Patent Document 1). In addition, it is also widely used as an agonist having a high affinity for glutamate receptors as a standard reagent for the study of neuroscience, particularly neuronal cell death.

Several methods for producing kainic acid are already known (Non-patent Documents 1 and 2). For example, a method using optical resolution (Non-patent Document 1) is known. 10 mg is commercially available for about 20,000 yen. Therefore, supply by an efficient synthesis method is desired.

Thirteenth revised Japanese Pharmacopoeia Manual, Yodogawa Shoten, 1998, page C-925 Organic Letters 2005, Vol. 7, No. 5, 815-817

  An object of the present invention is to provide an efficient method for synthesizing a pyrrolidine dicarboxylic acid compound that is applicable to the synthesis of kainic acid and the like and has a short process and high conversion efficiency in each process.

  As a result of intensive research to achieve the above-mentioned problems, the present inventor has found that the target pyrrolidine dicarboxylic acid compound can be efficiently synthesized from an optically active unsaturated lactone serving as a key intermediate. Was completed.

  According to one aspect of the invention, Formula I:

Wherein R ¹ and R ³ are independently selected from a hydrogen atom and C _1-6 alkyl, wherein the alkyl is one or more selected from a halogen atom, hydroxy, C _1-6 alkoxy and aryl R ² , R ⁴ and R ⁵ are independently selected from a hydrogen atom, C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, wherein The alkyl, alkenyl and alkynyl may be substituted by one or more substituents selected from a halogen atom, hydroxy, carboxy, C _1-6 alkoxycarbonyl and aryl; and Z is a hydrogen atom or secondary Amino protecting group]
A method for producing the compound of
Formula AI or A-XI:

Wherein, R ²¹ is an ester forming group; R ²² is as defined for R ² (where a functional group that may be included in R ² may be protected by a protecting group); Z ¹ is A protecting group for secondary amino group; X is a leaving group]
In the presence of a base in the formula A-II:

[Wherein R ²¹ , R ²² and Z ¹ are as defined above]
And a process for the conversion of the compound of formula A-II to the compound of formula I.

  According to another aspect of the invention, Formula I:

Wherein R ¹ and R ³ are independently selected from a hydrogen atom and C _1-6 alkyl, wherein the alkyl is one or more selected from a halogen atom, hydroxy, C _1-6 alkoxy and aryl R ² , R ⁴ and R ⁵ are independently selected from a hydrogen atom, C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, wherein The alkyl, alkenyl and alkynyl may be substituted by one or more substituents selected from a halogen atom, hydroxy, carboxy, C _1-6 alkoxycarbonyl and aryl; and Z is a hydrogen atom or secondary Amino protecting group]
A method for producing the compound of
a-1) Formula AI or A-XI:

[Wherein R ²¹ , R ²² , Z ¹ and X are as already defined herein.]
In the presence of a base of formula A-II:

[Wherein R ²¹ , R ²² and Z ¹ are as already defined herein.]
Converting to a compound of:
a-2) A compound of formula A-II in the presence of a base, of formula A-III:

[Wherein R ²¹ , R ²² and Z ¹ are as previously defined herein; R ²³ is an ester-forming group]
Converting to a compound of:
a-3) A compound of formula A-III is represented by formula A-IV:

[Wherein R ²¹ , R ²² , R ²³ and Z ¹ are as already defined herein.]
Oxidizing to a compound of:
a-4) A compound of formula A-IV is represented by formula AV

[Wherein R ²¹ , R ²² , R ²³ and Z ¹ are as defined previously herein; R ²⁴ and R ²⁵ are as defined for R ⁴ and R ⁵ respectively, provided that The functional group that may be contained in R ²⁴ and R ²⁵ may be protected by a protecting group)]
Converting to a compound of:
Wherein the compound of formula AV further comprises a deprotecting step if the compound comprises a protecting group and / or a step of converting the ester to a carboxyl group. The production method may include a step of desorbing a protecting group at any stage; a step of converting the protecting group; and / or a step of converting a functional group.

  In one embodiment of this aspect of the invention, in step a-1, formula A-Ia or A-XIa:

[Wherein R ²¹ , R ²² , Z ¹ and X are as already defined herein.]
And the final product as formula Ia:

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Z are as already defined herein]
A production method for obtaining the compound is provided. That is, the manufacturing method is
a-1a) Formula A-Ia or A-XIa:

[Wherein R ²¹ , R ²² , Z ¹ and X are as already defined herein.]
In the presence of a base of formula A-IIa:

[Wherein R ²¹ , R ²² and Z ¹ are as already defined herein.]
Converting to a compound of:
a-2a) A compound of formula A-IIa, in the presence of a base, of formula A-IIIa:

Wherein R ²¹ , R ²² and Z ¹ are as previously defined herein; R ²³ is C _1-6 alkyl or C _7-14 aralkyl.
Converting to a compound of:
a-3a) A compound of formula A-IIIa is represented by formula A-IVa:

[Wherein R ²¹ , R ²² , R ²³ and Z ¹ are as already defined herein.]
Oxidizing to a compound of:
a-4a) a compound of formula A-IVa of formula A-Va

[Wherein R ²¹ , R ²² , R ²³ and Z ¹ are as defined previously herein; R ²⁴ and R ²⁵ are as defined for R ⁴ and R ⁵ respectively, provided that The functional group that may be contained in R ²⁴ and R ²⁵ may be protected by a protecting group)]
Converting to a compound of:
And may further comprise a deprotecting step if the compound of formula AV contains a protecting group and / or a step of converting the ester to a carboxyl group. The production method may include a step of introducing a protecting group at any stage; a step of removing the protecting group; a step of converting the protecting group; and / or a step of converting a functional group.

  According to another aspect of the invention, a compound of formula AI or A-XI:

[Wherein R ²¹ , R ²² , Z ¹ and X are as already defined herein.]
A process for producing a compound of
b-1) Formula BI:

[Wherein R ²² is as defined herein; Z ² is a hydroxy protecting group; L is a leaving group]
By alkylating and introducing a substituent on the nitrogen atom:

[Wherein R ²² and Z ² are as previously defined herein; R ³¹ is an ester-forming group; Z ³ is a C _1-6 alkyl or a protecting group for a nitrogen atom]
Converting to a compound of:
b-2) By reducing the compound of formula B-II, the compound of formula B-III:

[Wherein R ²² , R ³¹ , Z ² and Z ³ are as already defined herein.]
Converting to a compound of:
b-3) A compound of formula B-III is represented by formula B-IV:

[Wherein R ²¹ , R ²² , R ³¹ , Z ² and Z ³ are as defined herein; Z ⁴ represents C _1-6 alkylsulfonyl (wherein the alkylsulfonyl is one or more halogens) Optionally substituted with an atom), arylsulfonyl (which may be substituted with one or more substituents selected from nitro, cyano, halogen atoms and C _1-6 haloalkyl). Or a protective group for a secondary amino group as defined in claim ¹ as Z ¹ ]
Converting to a compound of:
b-4) A compound of formula B-IV is represented by formula BV:

[Wherein R ²¹ , R ²² , Z ³ and Z ⁴ are as already defined herein.]
And b-5) converting the compound of formula B-V to the compound of formula AI or A-XI;
And the method of production may further comprise the step of converting Z ⁴ into a group defined as Z ¹ in an optional step.

  In one embodiment of this aspect of the invention, in step b-1, formula B-Ia:

[Wherein R ²² , Z ² and L are as defined herein.]
And the final product is of formula A-Ia or A-XIa:

[Wherein R ²¹ , R ²² , Z ¹ and X are as already defined herein.]
A production method for obtaining the compound is provided. That is, the manufacturing method is
b-1a) Formula B-Ia:

[Wherein R ²² is as defined herein; Z ² is a hydroxy protecting group; L is a leaving group]
By alkylating the compound of and introducing a substituent on the nitrogen atom, the compound of formula B-IIa:

[Wherein R ²² and Z ² are as previously defined herein; R ³¹ is C _1-6 alkyl or C _7-14 aralkyl; Z ³ is C _1-6 alkyl or Nitrogen atom protecting group]
Converting to a compound of:
b-2a) By reducing the compound of formula B-IIa, the compound of formula B-IIIa:

[Wherein R ²² , R ³¹ , Z ² and Z ³ are as already defined herein.]
Converting to a compound of:
b-3a) A compound of formula B-IIIa is represented by formula B-IVa:

[Wherein R ²¹ , R ²² , R ³¹ , Z ² and Z ³ are as defined herein; Z ⁴ represents C _1-6 alkylsulfonyl (wherein the alkylsulfonyl is one or more halogens) Optionally substituted with an atom), arylsulfonyl (wherein the arylsulfonyl is optionally substituted with one or more substituents selected from nitro, cyano, halogen atoms and C _1-6 haloalkyl). Or is a protecting group for a secondary amino group already defined herein as Z ¹ ]
Converting to a compound of:
b-4a) A compound of formula B-IVa is represented by formula B-Va:

[Wherein R ²¹ , R ²² , Z ³ and Z ⁴ are as already defined herein.]
B-5a) converting a compound of formula B-Va to a compound of formula A-Ia or A-XIa;
And may further include the step of converting Z ⁴ to a group defined as Z ¹ in an optional step. The production method may include a step of introducing a protecting group at any stage; a step of removing the protecting group; a step of converting the protecting group; and / or a step of converting a functional group.

  In yet another aspect of the invention, Formula A-Ia:

[Wherein R ²¹ , R ²² and Z ¹ are as already defined herein.]
A process for producing a compound of
c-1) Formula CI:

[Wherein R ³² is C _1-6 alkyl, aryl or C _7-14 aralkyl; R ³⁵ is a hydrogen atom, C _1-6 alkyl, aryl and C _7-14 aralkyl; R ³³ and R ³⁴ is independently selected from a hydrogen atom and C _1-6 alkyl, aryl, and C _7-14 aralkyl.
By reacting a compound of formula C-II with an aldehyde: R ²² CHO, wherein R ²² is as previously defined herein, and introducing a protecting group.

[Wherein R ²² , R ³² , R ³³ , R ³⁴ and R ³⁵ are as previously defined herein; Z ⁵ is a hydroxy protecting group]
Converting to a compound of:
c-2) By reducing the compound of formula C-II, the compound of formula C-III:

[Wherein R ²² , R ³² , R ³³ , R ³⁴ , R ³⁵ and Z ⁵ are as previously defined herein]
Converting to a compound of:
c-3) A compound of formula C-III is reacted with a glycine derivative or a salt thereof and further introduced with a protecting group to give a compound of formula C-IV:

[Wherein R ²¹ , R ²² , R ³⁵ , Z ¹ and Z ⁵ are as defined herein.]
Converting to a compound of:
c-4) The compound of formula C-IV is converted to formula CV by deprotection and esterification:

Wherein R ²¹ , R ²² , R ³⁵ and Z ¹ are as previously defined herein; R ³⁶ is a hydrogen atom, C _1-6 alkyl, aryl or C _7-14 aralkyl. ]
C-4) converting the compound of formula CV to a compound of formula A-Ia in the presence of a catalyst;
Is provided.

  According to yet another aspect of the invention, the compound of formula A-Ia:

[Wherein R ²¹ , R ²² and Z ¹ are as already defined herein.]
A process for producing a compound of
d-1) The compound of formula C-IV as defined in claim 6 is oxidized to give a compound of formula DI:

[Wherein R ²¹ , R ²² , Z ¹ and Z ⁵ are as already defined herein.]
Converting to a compound of:
d-2) A compound of formula DI is represented by formula D-II:

[Wherein R ²¹ , R ²² , Z ¹ and Z ⁵ are as defined above; R ³⁷ is an ester-forming group]
Converting to a compound of:
d-3) converting the compound of formula D-II to a compound of formula A-Ia;
Is provided.

  In one embodiment of this aspect, the compound of formula D-II has the formula D-II-cis:

[Wherein R ²¹ , R ²² , R ³⁷ , Z ¹ and Z ⁵ are as defined above]
It may be. Also, in one embodiment of this aspect, step d-3 comprises reacting a compound of formula D-II with deprotection of the hydroxy group and a thiol: R ³⁸ —SH, wherein R ³⁸ is a C _1-20 alkyl , Aryl or C _7-20 aralkyl) to give a compound of formula D-III:

[Wherein R ²¹ , R ²² , R ³⁸ and Z ¹ are as defined above]
Converting to a compound of formula A; and converting a compound of formula D-III to a compound of formula A-Ia;
May be included.

  According to yet another aspect of the present invention, Formula A-I or A-XII:

Wherein R ²¹ , R ²² and Z ¹ are as previously defined herein; X ¹¹ is amino, hydroxy, or a group defined as X herein.
Or a salt thereof. In one embodiment of this aspect of the invention, the compound of formula A-I is of formula A-Ia:

[Wherein R ²¹ , R ²² and Z ¹ are as already defined herein.]
It is a compound of this. Further, in one embodiment of this aspect, the compound of formula A-XII has the formula A-XIa:

[Wherein R ²¹ , R ²² , Z ¹ and X are as already defined herein.]
It is a compound of this.

  According to yet another aspect of the invention, Formula A-II:

[Wherein R ²¹ , R ²² and Z ¹ are as already defined herein.]
Are also provided. In one aspect of this aspect of the invention, the compound has the formula A-IIa:

[Wherein R ²¹ , R ²² and Z ¹ are as already defined herein.]
It is a compound of this.
Yet another aspect of the present invention is a compound of formula C-VI:

[Wherein R ²¹ , R ²² and Z are as previously defined herein; R ⁶ is —CH═CHR ³⁵ , —CH═CHCO ₂ R ³⁷ or formyl; R ⁷ is A hydrogen atom, Z ⁵ or —COCH═CHR ³⁶ ; Z ⁵ , R ³⁵ , R ³⁶ and R ³⁷ are as previously defined herein]
Are also provided.

X defined in the above formula is a leaving group usually used in organic synthesis, for example, a halogen atom, —NR ⁸ R ⁹ , —N ⁺ R ⁵¹ R ⁵² R ⁵³ , —OR ¹⁰ or —S. (O) _n R ¹¹ ; wherein R ⁸ and R ⁹ are independently C _1-6 alkyl (wherein the alkyl may be substituted by one or more substituents selected from halogen atoms). ), Aryl (the aryl may be substituted by one or more substituents selected from nitro, cyano, halogen atoms and C _1-6 haloalkyl), C _7-14 aralkyl, C _1-6 alkylcarbonyl (The alkylcarbonyl may be substituted with one or more substituents selected from halogen atoms), arylcarbonyl (the arylcarbonyl is nitro B, optionally substituted by one or more substituents selected from cyano, halogen atoms and C _1-6 haloalkyl), C _7-14 aralkylcarbonyl, —COOR ¹¹ , arylsulfonyl (wherein the arylsulfonyl is nitro Optionally substituted by one or more substituents selected from cyano, halogen atoms and C _1-6 haloalkyl, including, for example, benzenesulfonyl, toluenesulfonyl, etc.) and C _1-10 alkylsulfonyl (the alkyl Is optionally substituted by one or more substituents selected from halogen atoms, including methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, etc .; R ¹⁰ is C _1-6 alkyl, aryl , C _7-14 aralkyl, C _1-6 al Kill carbonyl, arylcarbonyl, C _7-14 aralkylcarbonyl, C _1-6 alkylsulfonyl, arylsulfonyl or C _7-14 aralkylsulfonyl; R ¹¹ is C _1-20 alkyl (wherein the alkyl is selected from a halogen atom) Optionally substituted by one or more substituents), aryl (the aryl may be substituted by one or more substituents selected from nitro, cyano, halogen atoms and C _1-6 haloalkyl) ) Or C _7-14 aralkyl; R ⁵¹ , R ⁵² and R ⁵² are independently selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl and C _7-14 aralkyl. .

Specific examples of preferred groups as X include chlorine atom, bromine atom, iodine atom, —NR ⁸ R ⁹ , —S (O) _n R ¹¹ , —NMe ₄ ⁺ , —NBn ₄ ⁺ , —OSO ₂ Me, — OSO ₂ Ph, —OSO ₂ Tol, —OSO ₂ CF ₃ , more preferably chlorine atom, bromine atom, iodine atom, —N (OCOMe) (OCOMe), —N (OCOEt) (OCOEt), -N (OCOt-Bu) (OCOt -Bu), - N (OCOBn) (OCOBn), - N (SO 2 Me) (SO 2 Me), - N (SO 2 CF 3) (SO 2 CF 3), _{-N (SO 2 p-Tol)} (SO 2 p-Tol), - N (OCOBn) (OCOBn), - N (OCOt-Bu) (OCOMe), - N (OCOt-Bu) (OCOtEt), - N ( COt-Bu) (OCOt-Bu ), - N (OCOt-Bu) (OCOBn), - N (OCOt-Bu) (SO 2 Me), - N (OCOt-Bu) (SO 2 CF 3), - N (OCOt-Bu) (SO ₂ Tol), SO ₂ Me, SO ₂ Et, SO ₂ C ₈ H ₁₇ , SO ₂ C ₁₂ H ₂₅ , SO ₂ Ph, SOMe, SOEt, SOC ₈ H ₁₇ , SOC ₁₂ H ₂₅ , —NMe ₄ ⁺ , —OSO ₂ Me, —OSO ₂ Ph, —OSO ₂ Tol, —OSOCF ₃ .

  In the synthesis method provided by the present invention, each step has a high yield and the experimental operation is simple. Therefore, it can be applied as a method for synthesizing pyrrolidine dicarboxylic acid compounds such as kainic acid, and the compound can be supplied stably and economically. The novel synthesis method of the present invention can also be used for the search synthesis of kainic acid analogs having physiological activity.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described more specifically.
As used herein, “C _1-6 alkyl” means a linear, branched, cyclic or partially cyclic alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl. I-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl , 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl, and 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, and the like, for example, C _1-4 alkyl And C _1-3 alkyl are also included.

In the present specification, “C _1-10 alkyl” means a linear, branched, cyclic or partially cyclic alkyl group having 1 to 10 carbon atoms, for example, as C _1-6 alkyl. In addition to the exemplified alkyl groups, linear or branched alkyl groups represented by C ₇ H ₁₅ , C ₈ H ₁₇ , C ₉ H ₁₉ , and C ₁₀ H ₂₁ are included.

In the present specification, “C _1-20 alkyl” means a linear, branched, cyclic or partially cyclic alkyl group having 1 to 20 carbon atoms, for example, as C _1-6 alkyl. In addition to the exemplified alkyl groups, C ₇ H ₁₅ , C ₈ H ₁₇ , C ₉ H ₁₉ , C ₁₀ H ₂₁ , C ₁₁ H ₂₃ , C ₁₂ H ₂₅ , C ₁₃ H ₂₇ , C ₁₄ H ₂₉ , C ₁₅ H _A linear or branched alkyl group represented by ₃₁ , C ₁₆ H ₃₃ , C ₁₇ H ₃₅ , C ₁₈ H ₃₇ , C ₁₉ H ₃₉ , C ₂₀ H ₄₁ is included.

As used herein, “C _2-10 alkenyl” means a linear, branched, cyclic or partially cyclic alkenyl group having 2 to 10 carbon atoms, such as vinyl, 1-propenyl, 2 Linear or branched represented by C ₇ H ₁₃ , C ₈ H ₁₅ , C ₉ H ₁₇ , C ₁₀ H ₁₉ as well as propenyl (allyl), 1-methylvinyl, cyclopentenyl, and cyclohexenyl A chain alkenyl group is included.

In the present specification, “C _2-10 alkynyl” means a linear, branched, cyclic or partially cyclic alkenyl group having 2 to 10 carbon atoms, such as ethynyl, 1-propynyl, 2 - propynyl (propargyl), 2-cyclopropyl other _ethynyl, represented by _{C 7 H 11, C 8 H} 13, C 9 H 15, C 10 H 17, a linear or branched alkynyl group included.

In the present specification, “C _1-6 alkoxy” means an alkyloxy group having an alkyl group having 1 to 6 carbon atoms which has already been defined as an alkyl moiety. For example, methoxy, ethoxy, n-propoxy, i-propoxy N-butoxy, s-butoxy, i-butoxy, t-butoxy, n-pentoxy, 3-methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpen Toxic, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-ethylbutoxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethyloxy, etc. are included, for example, C _1-4 alkoxy and C _{1 -3} alkoxy and the like are also included. In the present specification, “C _1-4 alkoxy” includes, for example, C _1-3 alkoxy and the like.

As used herein, “C _1-6 alkoxycarbonyl” means an alkoxycarbonyl group having a C _1-6 alkyl group already defined as an alkoxy moiety, and includes, for example, C _1-3 alkoxycarbonyl.

“Aryl” in the present specification includes, for example, an aromatic carbocyclic group having 6 to 18 carbon atoms (eg, phenyl, naphthyl, anthracenyl, etc.).
In the present specification, “C _7-14 aralkyl” means an arylalkyl group having 7 to 14 carbon atoms including an aryl group, such as benzyl, 1-phenethyl, 2-phenethyl, 1-naphthylmethyl, 2- Naphthylmethyl and the like are included.

In the present specification, the “protecting group for secondary amino group” is not particularly limited, and means a protecting group usually used by those skilled in organic synthetic chemistry. Specific examples thereof include C _1-10 alkoxycarbonyl (eg, t-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, i-propyloxycarbonyl, etc.), C _3-10 alkynyloxycarbonyl (eg, allyloxycarbonyl, etc.), C _7-14 aralkyloxycarbonyl (eg benzyloxycarbonyl etc.), C _1-10 alkylcarbonyl (eg acetyl and propionyl etc.), phenylcarbonyl (eg benzoyl etc.), C _7-14 aralkyl (eg benzyl etc.) ), Arylsulfonyl (eg, benzenesulfonyl, toluenesulfonyl), C _1-10 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl) and the like. In addition, alkyl, aryl, etc. contained in the protecting group mentioned as a specific example are arbitrary substituents (for example, a halogen atom, C _1-6 alkyl, nitro, C _{1- 1)} within a range not affecting the function as the protecting group. ₁₀ alkoxy, etc.) may have, such embodiments are also a matter to be included in the course of the present invention is capable of understanding of course by those skilled in the art.

In the present specification, the “ester-forming group” is not particularly limited. For example, a group that functions as a protecting group for a carboxy group in each reaction (for example, an _optionally substituted C _1-10 alkyl or an _optionally substituted group). C _7-14 aralkyl, optionally substituted aryl, etc.). Preferably, it is selected from C _1-10 alkyl and C _7-14 aralkyl.

In the present specification, the “hydroxy protecting group” is not particularly limited, and means a protecting group commonly used by those skilled in organic synthetic chemistry. Specific examples thereof include C _1-10 alkylcarbonyl (eg, acetyl and propionyl), C _7-10 allylcarbonyl (eg, benzoyl), triC _1-10 alkylsilyl (eg, trimethylsilyl, triethylsilyl, triisopropyl). Silyl, t-butyldimethylsilyl, t-butyldiphenylsilyl etc.), C _3-10 alkenyl (eg allyl etc.), C _7-14 aralkyl (eg benzyl etc.), C _1-10 alkoxy C _1-10 alkyl (Eg, methoxymethyl, tetrahydropyranyl ether, etc.), C _1-10 alkoxy C _1-10 alkoxy C _1-10 alkyl (eg, methoxyethoxymethyl, etc.), C _1-10 alkoxy C _1-10 alkylthio (eg, methylthio Methyl _{Etc.), C 7-14} aralkyloxy _{C 7-14} aralkyl (e.g., _{benzyloxymethyl), C 1-10} alkyl (e.g., methyl, ethyl, etc. t- butyl), and the like. In addition, alkyl, aryl, etc. contained in the protecting group mentioned as a specific example are arbitrary substituents (for example, a halogen atom, C _1-6 alkyl, nitro, C _{1- 1)} within a range not affecting the function as the protecting group. well such aspects have a ₁₀ alkoxy, etc.) may be included in the naturally present invention is a matter that can be understood of course by those skilled in the art.

In the present specification, the “nitrogen atom protecting group” is not particularly limited, and means a protecting group usually used by those skilled in organic synthetic chemistry. Specific examples thereof include C _1-10 alkoxycarbonyl (eg, t-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, i-propyloxycarbonyl, etc.), C _3-10 alkynyloxycarbonyl (eg, allyloxycarbonyl, etc.), C _7-14 aralkyloxycarbonyl (eg benzyloxycarbonyl etc.), C _1-10 alkylcarbonyl (eg acetyl and propionyl etc.), phenylcarbonyl (eg benzoyl etc.), C _7-14 aralkyl (eg benzyl etc.) ), Arylsulfonyl (eg, benzenesulfonyl, toluenesulfonyl), C _1-10 alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl) and the like. In addition, alkyl, aryl, etc. contained in the protecting group mentioned as a specific example are arbitrary substituents (for example, a halogen atom, C _1-6 alkyl, nitro, C _{1- 1)} within a range not affecting the function as the protecting group. It can be understood by those skilled in the art that it may have ₁₀ alkoxy and the like.

In the present invention, when carboxy contained in a compound is protected by a protecting group, it can be protected by a method well known to those skilled in the art. For example, the carboxyl may be an ester (eg, C _1-10 alkyl ester, C _7-14 aralkyl ester, aryl ester, C _1-10 alkoxy C _1-10 alkyl, etc.) and an amide (eg, C _1-10 alkyl amide). , Di-C _1-10 alkylamide, etc.).

  In the above structural formula, when the three-dimensional structure is not particularly shown, the present invention relating to the compound represented by the structural formula in the present specification includes various tautomers, geometric isomers, optical isomers and the like. Stereoisomers and mixtures thereof are included.

  The salt of the compound of the present invention is not particularly limited as long as it can be usually used in organic chemistry. Examples of the salt formed by the compound of the present invention with a base include salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; salts with organic bases such as methylamine, ethylamine and ethanolamine. The salt may be an acid addition salt. Specific examples of the salt include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and other mineral acids; and formic acid, Acid addition with organic acid acids such as acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid Salt.

Furthermore, the compound of the present invention includes hydrates, various solvates and crystal polymorphs.
The production method according to the present invention can be carried out, for example, according to the following scheme.

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ²¹ , R ²² , R ²² , R ²³ , R ²⁴ , R ²⁵ , Z and Z ¹ have already been defined herein. That ’s right]
The cyclization reaction in step a-1b is carried out by using an appropriate base (for example, lithium hexamethyldisilazide (hereinafter also referred to as LHMDS), lithium diisopropylamide (hereinafter also referred to as LDA), sodium hexamethyldisilazide (hereinafter referred to as NHMDS), potassium hexamethyldisilazide (hereinafter also referred to as KHMDS), potassium t-butoxide, sodium hydride, potassium hydride, calcium hydride, sodium amide, sodium ethoxide, sodium methoxide, etc.) Suitable solvents such as aprotic solvents (eg polar compounds (eg DMF, DMSO, HMPA); nitrile compounds (eg acetonitrile, propionitrile); ether compounds (THF, dioxane, diethyl ether, dibutyl ether) , Dimethoxyethane; ketone compounds (acetone, methyl ethyl ketone, methyl isobutyl ketone); aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.); aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.); halogenated aromatics It can be carried out in an aromatic hydrocarbon (for example, monochlorobenzene, dichlorobenzene, etc.), an aliphatic hydrocarbon (hexane, heptane, octane; and a mixed solvent thereof, etc.) Although this process is not particularly limited, The reaction can be carried out at a reaction temperature of −100 to 100 ° C., preferably −80 to 30 ° C., and for example, an instantaneous time to 3 days, preferably an instantaneous time to 1 hour. In addition to IIb), the diastereomers may be obtained as by-products, Conventional purification methods in the compound obtained in Step obtained compound or a subsequent step (e.g., silica gel column chromatography, silica gel thin layer chromatography, distillation, etc.) in some cases can be separated by.

In step a-2b, the lactone ring-opening reaction is carried out by using a suitable base (eg, amines such as triethylamine, tributylamine, diisopropylethylamine, pyridines such as pyridine, collidine, lutidine, and dimethylaminopyridine (hereinafter also referred to as DMAP); It is carried out by reacting with R ²³ OH in the presence of organic bases such as DBU and DBN; carbonates such as potassium carbonate and cesium carbonate). An excess amount of R ²³ OH may be used, and for example, it may be used as a solvent. Although this process is not specifically limited, For example, it can carry out by the reaction temperature of -30-100 degreeC, Preferably it is 0-50 degreeC, and the reaction time of the instant -7 days, Preferably it is 1 to 24 hours.

The oxidation reaction in steps a-3b is carried out by using a suitable oxidizing agent (for example, a catalytic amount of tetrapropylammonium pearlate (hereinafter also referred to as TPAP) and N-methylmorpholine oxide (hereinafter also referred to as NMO), potassium permanganate. Manganese oxidants such as chromium oxide (VI), pyridinium chlorochromate (PCC), pyrididium dichromate (PDC), etc .; DMSO and (COCl) ₂ (Swern oxidation), DMSO and trifluoroacetic anhydride DMSO oxidizing agents such as (Swern oxidation), DMSO and NCS (Corey-Kim oxidation); 1,1,1-tris (acetoxy) 1,1-dehydro-1,2-benziodoxyl-3- (1H) -one (Dess-Martin periodinane) and other organic periodate oxidants ) In a suitable solvent (for example, dichloromethane, chloroform, dichloroethane, benzene, toluene, xylene, monochlorobenzene, diethyl ether, dibutyl ether, dimethoxyethane, pentane, hexane, octane; and mixed solvents thereof) Can be done. Although this process is not specifically limited, For example, it may be carried out at a reaction temperature of -80 to 100 ° C, preferably -20 to 40 ° C, and a reaction time of, for example, instantaneous to 7 days, preferably 0.1 to 3 hours. it can.

Step a-4b is a step of converting a carbonyl group into an olefin, and can be performed by a method commonly used by those skilled in the art of organic chemistry using, for example, Wittig reagent or Horner-Emmons reagent. For example, when kainic acid or an analog thereof is synthesized by the production method of the present invention (R ²² , R ²⁴ , and R ²⁵ are all hydrogen atoms), this step involves the presence of Zn, TiCl ₄ and, if necessary, a catalytic amount of PbCl _2. Under reaction with diiodomethane or dibromomethane; reaction with cyclo-dibromodi-μmethylene [μ- (tetrahydrofuran)] trizinc (Nysted reagent); [μ-chloro-μ-methylene [bis (cyclopentadienyl) titanium] ] Dimethylaluminum] (Tube reagent) can be used. Examples of the solvent used in the reaction include THF, dioxane, diethyl ether, dibutyl ether, dimethoxyethane, methylene chloride, dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, monochlorobenzene, and mixed solvents thereof. It is. This step is not particularly limited, but is performed at a reaction time of, for example, -80 to 100 ° C, preferably 0 to 30 ° C, and a reaction time of, for example, instantaneous to 7 days, preferably 0.1 to 3 hours. be able to.

Substituent transformations such as attachment / detachment of protecting groups and transformation of ester groups to carboxy groups performed in step a-5b are carried out by methods commonly used by those skilled in the art. Z ¹ and Z used in Scheme 1 include C _1-10 alkoxycarbonyl (eg, t-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, i-propyloxycarbonyl, etc.), C _7-14 aralkyloxycarbonyl, and the like. (Eg benzyloxycarbonyl etc.), C _1-10 alkylcarbonyl (eg acetyl and propionyl etc.), phenylcarbonyl (eg benzoyl etc.), C _7-14 aralkyl (eg benzyl etc.), arylsulfonyl (eg eg Benzenesulfonyl, toluenesulfonyl) and the like.

  The production method according to another aspect of the present invention can be performed, for example, according to the following scheme.

[Wherein R ²¹ , R ²² , R ³¹ , Z ¹ , Z ² , Z ³ , Z ⁴ and L are as defined herein.]
Β-lactam (B-Ib) used as a raw material in step b-1b can be purchased as a reagent (from Kaneka Chemical or Takasago flavor). In this step, alkylation and introduction of a protecting group to the ring nitrogen atom are performed. The alkylation is carried out using the formula: X ¹ —CH ₂ CO ₂ R ³¹ (wherein X ¹ is, for example, BrZn—, ClZn—, IZn—, etc.) as an alkylating reagent, and suitable aprotic properties. Solvent (eg, ether compound (THF, dioxane, diethyl ether, dibutyl ether, dimethoxyethane; polar compound (eg, DMF, DMSO, HMPA)); aromatic hydrocarbon (eg, benzene, toluene, xylene, etc.); aromatic carbonization In hydrogen (eg, benzene, toluene, xylene, etc.); halogenated aromatic hydrocarbons (eg, monochlorobenzene, dichlorobenzene, etc.), aliphatic hydrocarbons (hexane, heptane, octane; and mixed solvents thereof) The leaving group L is, for example, C _1-6 alkoxy. Carbonyl (for example, acetoxy etc.), halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom), arylsulfonyl (for example, benzenesulfonyl, toluenesulfonyl), C _1-10 alkylsulfonyl (for example, methanesulfonyl), C _1-10 haloalkylsulfonyl (for example, trifluoromethanesulfonyl), etc. The alkylation is not particularly limited, but is, for example, a reaction temperature of −80 to 100 ° C., preferably 0 to 70 ° C., and for example, instantaneous to 7 The reaction can be carried out for a day, preferably with a reaction time of 1 to 24 hours The introduction of the protective group is carried out before or after the alkylation, but preferably after the alkylation. Examples of the group include C _7-14 aralkyloxycarbonyl (for example, Benzyloxycarbonyl etc.), C _1-10 alkoxycarbonyl (eg t-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, i-propyloxycarbonyl etc.), C _1-10 alkylcarbonyl (eg acetyl and propionyl etc.), phenyl Examples include carbonyl (for example, benzoyl), C _7-14 aralkyl (for example, benzyl), arylsulfonyl (for example, benzenesulfonyl, toluenesulfonyl), etc. The introduction of a protecting group can be performed with a base (for example, LHMDS, LDA, , NHMDS, KHMDS, potassium t-butoxide, sodium hydride, potassium hydride, butyllithium, sodium amide and other alkali metal compounds; triethylamine, tributylamine, diisopropyl Amines such as ethylamine; pyridine, collidine, pyridine such as lutidine and DMAP, DBU, organic bases such as DBN; and the presence of such a mixed ^solvent), Z 3 -X ² (wherein, ^{X 2} is a halogen This can be done by reacting with an atom (for example, a leaving group such as a chlorine atom). The reaction is not particularly limited but may be performed, for example, at a reaction temperature of −80 to 100 ° C., preferably −20 to 40 ° C., and for example, instantaneous to 7 days, preferably 0.1 to 3 hours. it can.

The reduction reaction in the step b-2b is carried out using a suitable reducing agent (for example, NaBH ₄ , LiBH ₄ , NaBH ₃ CN, NaBH (OAc) ₃ , BH ₃ -THF, BH ₃ -SMe ₂ etc.). (Eg, C _1-6 alkyl alcohol (eg, methanol, ethanol, i-propanol, ethylene glycol, etc.), water, and a mixed solvent thereof). This step is not particularly limited, but for example, at a reaction temperature of -20 to 100 ° C, preferably -20 to 40 ° C, and a reaction time of, for example, instantaneous to 7 days, preferably 0.5 to 24 hours. It can be carried out.

The amination reaction in Step b-3b can be performed using, for example, a glycine derivative represented by the formula: Z ⁴ —NH—CH ₂ CO ₂ R ²¹ . The hydroxy of compound B-IIIb is substituted with a suitable leaving group (eg, halogeno (eg, chloro, bromo, iodo, etc.), optionally substituted C _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, trifluoromethanesulfonyl). An appropriate base (eg, sodium hydride, potassium hydride, sodium carbonate, carbonic acid) after conversion to arylsulfonyloxy (eg, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.) which may be substituted, such as oxy The amination reaction can be carried out in the presence of cesium, etc., but under the conditions of Mitsunobu reaction (for example, in the presence of diethyl azodicarboxylate (hereinafter also referred to as DEAD) and triphenylphosphine). It can also be performed by the Mitsunobu reaction. In the case, Z ⁴ is C _1-6 alkylsulfonyl (wherein the alkylsulfonyl may be substituted with one or more halogen atoms) or arylsulfonyl (wherein the arylsulfonyl is nitro, cyano, halogen atom and C _1-6). The reaction is preferably substituted with one or more substituents selected from haloalkyl, and the reaction is not particularly limited, but may be any suitable solvent (eg, aromatic hydrocarbon (eg, aromatic carbon Hydrogen (eg, benzene, toluene, xylene, etc.); halogenated aromatic hydrocarbon (eg, monochlorobenzene, dichlorobenzene, etc.), aliphatic hydrocarbon (hexane, heptane, octane, etc.); halogenated hydrocarbon (dichloromethane, chloroform, etc.) , Gillorethane, Tetrachloroethane); Ether compounds ( HF, dioxane, diethyl ether, dibutyl ether, dimethoxyethane; ester compounds (ethyl acetate, butyl acetate); and mixed solvents thereof), for example, a reaction temperature of -20 to 150 ° C, preferably 0 to 90 ° C, And, for example, it can be carried out with a reaction time of instantaneous to 7 days, preferably 0.5 to 12 hours.

The lactonization reaction of step b-4b can be performed by removing Z ² of compound B-IVb or by removing both Z ² and R ³¹ . Removal of the protecting group and ester hydrolysis in the reaction can be carried out by conventional methods for those skilled in the art. For example, when Z ² is tri-C _1-6 alkylsilyl (eg, t-butyldimethylsilyl (hereinafter also referred to as TBS) and R ³¹ is t-butyl, an acid catalyst (eg, trifluoroacetic acid, methane) Lactonization can proceed in the presence of sulfonic acid, sulfuric acid, hydrochloric acid, and the like.

Formation of the double bond in step b-5b can be carried out by methods known to those skilled in the art. For example, after removing Z ³ , the amino group is alkylated (eg, C _1-10 alkyl). It can also be achieved by removing from a quaternary ammonium salt. Z ³ can be removed by a conventional method (for example, when Z ³ is benzyloxycarbonyl, it is removed by hydrogenation in the presence of a palladium catalyst). Alkylation of the amino group is not particularly limited, but an alkyl halide (eg, C ₁ such as methyl iodide) in the presence of a suitable base (eg, cesium carbonate, sodium carbonate, sodium hydride, DBU, DBN, etc.). _-6 alkyl iodides). The alkylation is not particularly limited, but may be an appropriate solvent (eg, aromatic hydrocarbon (eg, benzene, toluene, xylene, etc.); polar compound (eg, DMF, DMSO); nitrile compound (eg, acetonitrile, Ether compound (THF, dioxane, diethyl ether, dibutyl ether, dimethoxyethane; ester compound (ethyl acetate, butyl acetate); aromatic hydrocarbon (for example, benzene, toluene, xylene, etc.); halogenated aromatic carbonization In hydrogen (for example, monochlorobenzene, dichlorobenzene, etc.), aliphatic hydrocarbon (hexane, heptane, octane, etc.); and a mixed solvent thereof, for example, −30 to 150 ° C., preferably −10 to 100 ° C. Reaction temperature, and for example, instantaneous to 7 days, preferred Alternatively, the reaction can be performed for a reaction time of 3 to 24 hours.

In step b-5b, the group of Z ⁴ may be converted to a suitable protecting group (Z ¹ ) if necessary. The substituent conversion is carried out by a method commonly used by those skilled in the art. For example, Z ⁴ is C _1-6 alkylsulfonyl (the alkylsulfonyl may be substituted with one or more halogen atoms) or arylsulfonyl. When the arylsulfonyl is optionally substituted with one or more substituents selected from nitro, cyano, halogen atoms and C _1-6 haloalkyl, the group can be, for example, a suitable base (eg, It can be removed by reacting with potassium carbonate, potassium carbonate, sodium carbonate, etc.) or aryl mercaptan (eg, thiophenol). The reaction may be performed before or after the above-described double bond formation, but is preferably performed before the double bond formation reaction.

  The production method according to still another aspect of the present invention can be performed, for example, according to the following scheme.

[Wherein R ²¹ , R ²² , R ³² , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , Z ¹ and Z ⁵ are as already defined herein.]
Compound C-Ib used as a starting material in step c-1b can be prepared by acylating the corresponding oxazolin-2-one by known synthetic techniques or by combinations thereof. R ³² may be, for example, C _7-14 aralkyl (eg, benzyl, etc.), R ³³ and R ³⁴ may be, for example, C _1-6 alkyl (eg, methyl, etc.), and the corresponding oxazolin-2-one is, for example, It can be prepared by alkylating the ester of 1-phenylalanine with methylmagnesium bromide and then cyclizing (Tetrahedron 1999, 55, 3337). Subsequent acylation is carried out by using the oxazolin-2-one and a suitable acylating agent (a compound represented by the formula: R ³⁵ CH ₂ CH═CHCO-X ² (where X ² is a chlorine atom, a bromine atom, etc. Represents a leaving group or an activated ester of an activated ester) or a corresponding acid anhydride), for example, an amine such as triethylamine and diisopropylethylamine, a pyridine such as pyridine and DMAP, DBU, DBN In the presence of organic bases such as LHMDS, LDA, NHMDS, KHMDS, potassium t-butoxide, sodium hydride, potassium hydride, butyllithium, methyllithium, sodium amide, etc.) Organic solvents (eg, THF, dioxane, diethyl ether, dibutyl Ether, dimethoxyethane, DMF, DMSO, is carried out by reacting with acetonitrile, and a mixed solvent thereof and the like) therein.

Step c-1b comprises compound C-Ib and an aldehyde represented by the formula: R ²² CHO with an appropriate reagent (eg, TiCl ₄ , Bu ₂ BOTf, Sn (OTf) ₂ etc.) and an appropriate solvent (eg, aromatic Aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.); halogenated aromatic hydrocarbons (eg, monochlorobenzene, dichlorobenzene, etc.), aliphatic hydrocarbons (hexane, heptane, octane, etc.); halogenated hydrocarbons (dichloromethane) In an ether compound (THF, dioxane, diethyl ether, dibutyl ether, dimethoxyethane; and a mixed solvent thereof), for example, −100 to 20 ° C., preferably −180 to 0 ° C. Reaction temperature, and for example instantaneous to 3 days, preferably The reaction time can be 0.1 to 12 hours.

  The reduction reaction in step c-2b is carried out by using a suitable reducing agent (for example, diisobutylaluminum hydride (hereinafter also referred to as DIBAL), sodium bis (2-methoxyethoxy) aluminum hydride, etc.) Solvents (eg, aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.); halogenated aromatic hydrocarbons (eg, monochlorobenzene, dichlorobenzene, etc.), aliphatic hydrocarbons (hexane, heptane, octane, etc.); halogens Hydrocarbons (dichloromethane, chloroform, zircoroethane, tetrachloroethane); ether compounds (THF, dioxane, diethyl ether, dibutyl ether, dimethoxyethane; and mixed solvents thereof), for example, −100 to 0 ° C., preferably − 80 ~ 30 ° C. reaction temperature, and for example, a moment to 3 days, preferably at a reaction time of the reaction time of 0.1 to 6 hours.

Step c-3b is a reductive amination of compound C-IIIb using a glycine ester represented by the formula: NH ₂ —CH ₂ CO ₂ R ²¹ or a salt thereof (for example, hydrochloride, etc.). In this step, a protecting group is introduced into the secondary amine. The reductive amination reaction can be performed using an appropriate reducing agent (for example, NaBH ₃ CN, NaBH ₄ , LiBH ₄ , NaBH (OAc) _3, etc.). The reaction is not particularly limited, but can be performed, for example, at a reaction temperature of 0 to 150 ° C., preferably 40 to 90 ° C., and a reaction time of, for example, instantaneous to 3 days, preferably 2 to 12 hours. .

Step c-4b is a step of acylating hydroxy generated after removal of Z ⁴ which is a protecting group. The acylation is carried out by a suitable acylating agent (compound represented by the formula: R ³⁶ CH═CHCO—X ³ (where X ³ represents a leaving group such as chloro or an activated group of an activated ester). Or a corresponding acid anhydride, etc., and a suitable base (eg, amines such as triethylamine, tributylamine, diisopropylethylamine; pyridines such as pyridine, collidine, lutidine and DMAP; organic bases such as DBU and DBN) In the presence of sodium hydride, potassium hydride, alkali metal compounds such as butyl lithium and methyl lithium). The reaction is not particularly limited, but is performed, for example, at a reaction time of −100 to 50 ° C., preferably −80 to 30 ° C., and a reaction time of, for example, instantaneous to 3 days, preferably 1 to 24 hours. Can do.

  The ring-closing metathesis reaction in step c-5b is carried out using a suitable aprotic solvent (for example, a halogenated hydrocarbon (eg, pyrrole ethane, dichloromethane, chloroform, trichloroethane, tetrachloroethane) using a Grubbs catalyst or a Hoveyda-Grubbs catalyst; Aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.); halogenated aromatic hydrocarbons (eg, monochlorobenzene, dichlorobenzene, etc.), aliphatic hydrocarbons (hexane, heptane, octane, etc.); ether compounds (THF, dioxane, etc.) , Diethyl ether, dibutyl ether, diisopropyl ether, dimethoxyethane, and mixed solvents thereof, etc.) The catalyst used in this step is represented by the following formula:

A Hoveyda-Grubbs second generation catalyst shown as Catalyst I is preferably used. The reaction is not particularly limited, but is performed, for example, at a reaction temperature of 0 to 150 ° C., preferably 30 to 90 ° C., and a reaction time of, for example, instantaneous to 10 days, preferably 0.5 to 5 days. Can do.

  The production method according to still another aspect of the present invention can be performed, for example, according to the following scheme.

[Wherein R ²¹ , R ²² , R ³⁵ , R ³⁷ , R ³⁸ , Z ¹ and Z ⁵ are as already defined herein]
The oxidation reaction in step d-1b is carried out using a suitable oxidizing agent (ozone, osmium tetroxide, osmium tetroxide, sodium periodate, etc.) starting from compound C-IVb of scheme 3 as a starting material. It is carried out in a solvent. The oxidation reaction is performed by a method commonly used by those skilled in the art of organic chemistry. For example, in the case of oxidation by ozone, an appropriate solvent (for example, a mixed solvent of methanol and dichloromethane) is used, for example. The reaction can be carried out at a reaction temperature of −100 to 0 ° C., preferably −80 to −30 ° C. and a reaction time of, for example, instantaneous to 2 days, preferably instantaneous to 2 hours.

In step d-2b, compound D-Ib is converted to a suitable reagent (eg, formula: (R ⁴¹ O) ₂ PO—CH ₂ CO ₂ R ^{37 and the} like: wherein R ⁴¹ is aryl (such as phenyl) and C _{1- 6} ) represents an appropriate base (for example, alkali metal compounds such as sodium hydride, potassium hydride, butyl lithium, methyl lithium; carbonates such as potassium carbonate and cesium carbonate; DBU, DBN In the presence of an organic base such as a compound D-IIb. The reaction is carried out in a manner conventional for those skilled in the art of organic chemistry.

The lactone formation reaction in the step d-3b is performed by addition reaction of thiol represented by the formula: R ³⁸ —SH and removal of the protecting group Z ⁵ . The addition reaction is carried out in the presence of a suitable base (for example, organic bases such as DBU and DBN; amines such as triethylamine, tributylamine and diisopropylethylamine; pyridines such as pyridine, collidine, lutidine and DMAP). Solvent (eg, polar compound (eg, DMF, DMSO); nitrile compound (eg, acetonitrile, propionitrile); ether compound (THF, dioxane, diethyl ether, dibutyl ether, dimethoxyethane); ketone compound (acetone, methyl ethyl ketone, methyl Isobutyl ketone); aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.); aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.); halogenated aromatic hydrocarbons (eg, monochloroben) Aliphatic hydrocarbons (hexane, heptane, octane, etc.); and mixed solvents thereof; or are carried out without using a solvent, for example, −80 to 200 ° C., preferably 50 to 100 ° C. And a reaction time of, for example, an instantaneous time to 2 days, preferably a reaction time of 0.1 to 2 hours.

Removal of the protecting group can be carried out by a method commonly used by those skilled in the art. For example, when Z ⁵ is a tri-C _1-6 alkylsilyl group (eg, t-butyldimethylsilyl), the protecting group is, for example, a fluorine compound (eg, HF aqueous solution, HF pyridine complex, tetrabutylammonium fluoride, etc.) ), Acidic compounds (sulfuric acid, hydrochloric acid, nitric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, etc.) and the like. The removal of the protecting group may be performed before or after the addition reaction, but is preferably performed before the addition reaction.

In step d-4b, the group —SR ³⁷ is converted into a sulfinyl group (—SOR ³⁷ ) or a sulfonyl group (—SO ₂ R ³⁷ ) by an oxidation reaction, and then removed to obtain the desired α, β unsaturated lactone. (A-Ib) is formed. The oxidizing agent used in the oxidation reaction is not particularly limited as long as it is an oxidizing agent usually used for forming a sulfinyl group or a sulfonyl group. For example, ozone, peracid (for example, hydrogen peroxide solution, metachlorobenzoic acid) And periodic acid (periodic acid, sodium periodate, potassium periodate, etc.) can be used. The oxidation reaction can be performed by a method commonly used by those skilled in the art.

  Subsequent elimination reactions include, for example, suitable bases (eg, amines such as triethylamine, tributylamine, diisopropylethylamine; pyridines such as pyridine, collidine, lutidine and DMAP; organic bases such as DBU and DBN; sodium hydride; A suitable solvent (for example, in the presence or absence of alkali metal compounds such as potassium hydride, butyl lithium and methyl lithium; carbonates such as potassium carbonate and cesium carbonate; organic bases such as DBU and DBN) , Aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.); aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.); halogenated aromatic hydrocarbons (eg, monochlorobenzene, dichlorobenzene, etc.); aliphatic Hydrocarbon (Hexane, Heptane, Oct Ester compounds (ethyl acetate, butyl acetate, etc.); polar compounds (eg, DMF, DMSO); nitrile compounds (eg, acetonitrile, propionitrile); ether compounds (THF, dioxane, diethyl ether, dibutyl ether, Dimethoxyethane; performed without using a ketone compound (acetone, methyl ethyl ketone, methyl isobutyl ketone); alcohol compound (methanol, ethanol, i-propanol, butanol; and a mixed solvent thereof) or a solvent, for example, 0 to 200 ° C. The reaction can be carried out at a reaction temperature of preferably 50 to 150 ° C. and a reaction time of, for example, instantaneous to 2 days, preferably 0.2 to 6 hours.

  The production method according to still another aspect of the present invention can be performed, for example, according to the following scheme.

[Wherein R ²¹ , R ²² , R ³⁷ , Z ¹ and Z ⁵ are as defined herein.]
In step d-5b, appropriate reagents for obtaining the cis-isomer of compound D-Ib as product (e.g., the _{^{formula: (R 42 O) 2 PO}} -CH 2 CO 2 R 37 such as: ^{wherein, R 42} is Represents aryl (eg, phenyl, 3-methylphenyl, 3-ethylphenyl, 3-isopropylphenyl, etc.) or haloalkyl (eg, —CH ₂ CF ₃ ), etc., if necessary, with a suitable base (eg, hydrogen Alkali metal compounds such as sodium hydride, potassium hydride, potassium t-butoxide, butyl lithium, methyl lithium, LDA, LHMDS, and KHMDS; carbonates such as potassium carbonate and cesium carbonate; organic bases such as DBU, DBN, and Triton B The compound D-IIb-cis is obtained by reaction in the presence of an organic chemistry technique. It is carried out in the conventional techniques to those skilled in the art.

The lactone formation in step d-6b is performed by removing the protecting group Z ⁵ and, if necessary, subsequent appropriate treatment. The removal of the protecting group can be performed by a method commonly used by those skilled in the art. For example, when Z ⁵ is a tri-C _1-6 alkylsilyl group (eg, t-butyldimethylsilyl), the protecting group is, for example, a fluorine compound (eg, HF aqueous solution, HF pyridine complex, tetrabutylammonium fluoride, etc.) ), Acidic compounds (sulfuric acid, hydrochloric acid, nitric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, etc.) and the like. Subsequent lactone formation is carried out in a manner conventional for those skilled in the art of organic chemistry, for example, catalytic amounts of Lewis acids (eg, tetraisopropoxy titanium, etc.), catalytic amounts of acids (eg, sulfuric acid, Hydrochloric acid, methanesulfonic acid, camphorsulfonic acid, toluenesulfonic acid, etc.), catalytic amount of base (eg, amines such as triethylamine and diisopropylethylamine, pyridines such as pyridine and DMAP, and organic bases such as DBU and DBN) Can also be performed, but lactone formation can also be formed by heating without a catalyst.

  The production method according to still another aspect of the present invention can be performed, for example, according to the following scheme.

[Wherein R ⁸ , R ⁹ , R ²¹ , R ²² , Z ¹ and Z ³ are as defined herein.]
Step e-1b is a substituent conversion reaction of amino groups, be introduced two new substituents after may be introducing new substituents while retaining the Z ^3, or removed Z ³ Good. Or, if ^{Z 1} and ^{Z 3} are the same when replacing the ^{Z 1,} it may be replaced by ^{Z 1} and ^{Z 3} at a time. This reaction can be carried out by ordinary organic synthetic chemistry techniques.

  The cyclization reaction in step e-2b is carried out using a suitable base (for example, lithium hexamethyldisilazide (hereinafter also referred to as LHMDS), lithium diisopropylamide (hereinafter also referred to as LDA), sodium hexamethyldisilazide (hereinafter referred to as NHMDS), potassium hexamethyldisilazide (hereinafter also referred to as KHMDS), potassium t-butoxide, sodium hydride, potassium hydride, calcium hydride, sodium amide, sodium ethoxide, sodium methoxide, etc.) Suitable solvents such as aprotic solvents (eg polar compounds (eg DMF, DMSO, HMPA); nitrile compounds (eg acetonitrile, propionitrile); ether compounds (THF, dioxane, diethyl ether, dibutyl ether) , Dimethoxyethane; ketone compounds (acetone, methyl ethyl ketone, methyl isobutyl ketone); aromatic hydrocarbons (eg benzene, toluene, xylene, etc.); halogenated aromatic hydrocarbons (eg monochlorobenzene, dichlorobenzene, etc.), fats The reaction can be performed in a group hydrocarbon (hexane, heptane, octane, and mixed solvents thereof, etc.) Although this process is not particularly limited, for example, a reaction of −100 to 100 ° C., preferably −80 to 30 ° C. The reaction can be carried out at a temperature and, for example, instantaneous to 3 days, preferably instantaneous to 1 hour, in which the diastereomer is obtained as a by-product in addition to the desired product (A-IIb). In the compound obtained in this step or the compound obtained in the subsequent steps. Normal purification methods (e.g., silica gel column chromatography, silica gel thin layer chromatography, distillation, etc.) in some cases can be separated by.

Hereinafter, preferred examples of the present invention will be described in more detail, but the present invention is not limited to these examples.
Analytical methods and reagent nuclear magnetic resonance spectra unless otherwise stated JOEL-LA400 [ ¹ H-NMR (400 MHz), ¹³ C-NMR (100 MHz)] or JOEL-ECX500 [ ¹ H-NMR (500 MHz), ¹³ C- NMR (125 MHz)]. The chemical shift of ¹ H-NMR was shown in parts per million (δ: ppm) using tetramethylsilane as an internal standard, and the coupling constant was shown as hertz (Hz). Abbreviations indicating spin multiplicity are as follows: s = singlet, d = doublet, q = quartet, m = multiplet, rb = broad. The chemical shift of ¹³ C-NMR showed the total ppm of 77.0 ppm as the center line of the deuterated chloroform triplet, or ppm with tetramethylsilane as the internal standard. Coupling constants are shown as hertz (Hz). spin. Infrared (IR) spectrum was measured with JASCO FT / IR-410 Fourier Transform Infrared Spectrophotometer and showed wave number (cm ⁻¹ ). High resolution mass spectrometry was measured at 70 eV by direct probe insertion at 70-330 ° C. using a JOEL JMS-GCmate MS-DIP20 quadrupole. Fast atom bombardment (FAB) mass spectrometry was performed using polyethylene glycol as the matrix. Optical rotations were measured using a sodium D line with JASCO DIP-1000 Digital Polarimeter. Melting points (mp) were measured using Yanaco Micro Melting Point Apparatus or Mettler-Toledo FP62 Melting Point Apparatus without correction. Analytical thin layer chromatography, silica gel 60 _{F 254} thick 0.25mm was performed using the analytical plate Merck that are pre-coated. Separated by preparative TLC was performed Merck silica gel 60 _{PF 254} thick 0.5mm in plates 6.7x20cm coated. The compound was eluted from the adsorbent with a 10% methanol / dichloromethane solution or ethyl acetate. Separation by flash column chromatography was performed using Kanto Chemical Silica Gel 60N (spherical, neutral) 40-100 μm or 60N (spherical, neutral) 100-210 μm. Commercially available reagents and solvents were used as they were, but dichloromethane, dimethyl sulfoxide, benzene, toluene, acetonitrile, tetrahydrofuran, N, N-dimethylformamide and 1,2-dichloromethane were molecular sieve 4A, and methanol was molecular sieve 3A. Each was used dry. All reactions affected by oxygen or moisture were performed under an argon atmosphere.

Example 1
(Step 1-1)

LHMDS (THF solution, 1.0 M, 43.6 mL, 43.6 mmol) was added at −60 ° C. to a solution of compound 1-1 (9.11 g, 29.1 mmol) in DMF (270 mL). The mixture was stirred at −60 ° C. for 20 minutes and acetic acid (2.66 mL, 46.5 mmol) was added. After concentrating the mixture under reduced pressure, the residue was diluted with ethyl acetate and filtered through celite. After concentration of the filtrate under reduced pressure, the residue was purified by silica gel column chromatography (30-40% ethyl acetate / hexane solution) to give a mixture of compounds 1-2a and 1-2b as a colorless oil (8. 63 g, 95%; 1-2a: 1-2b = 91: 9) from ¹ H-NMR measurement of Compound 1-4 described later.

IR (film, cm ⁻¹ ) 2979, 1748, 1702, 1479, 1436, 1394, 1368, 1253, 1203, 1178, 1146, 1098, 1062, 999, 896, 859, 775; ¹ H-NMR (C ₆ D ₆ , rotamer mixture) 4.03 (s, 0.4H), 3.77 (s, 0.6H), 3.49-3.42 (m, 1H), 3.29 (s, 1. 8H), 3.27 (s, 1.2H), 3.24-3.07 (m, 1H), 2.91 (d, J = 11.0 Hz, 1H), 2.28 (dd, J = 14.7, 6.4 Hz, 1H), 2.05-1.95 (m, 1H), 1.75-1.64 (m, 1H), 1,45 (s, 3.6H), 1. 42 (s, 5.4H), 1.39-1.35 (m, 1H), 0.74-0.71 (m, ^{H); 13 C-NMR (} CDCl 3, rotamers mixture) 171.9,171.4,171.0,154.6,153.9,81.0,76.2,65.2,64. 9, 52.4, 52.1, 48.5, 48.1, 42.7, 41.8, 39.8, 38.7, 33.5, 28.2, 20.0, 19.7; HRMS (FAB) calcd _{(C 15 H 23 NO 6)} 313.1525, Found 313.1524.
(Step 1-2)

  To a solution of compound 1-2 (6.97 g, 22.2 mmol) in methanol (139 mL) was added triethylamine (0.16 mL, 1.2 mmol). The mixture was stirred at room temperature for 12 hours and acetic acid (0.07 mL) was added. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (40-60% ethyl acetate / hexane solution) to give compound 1-3 as a colorless oil (4.92 g, 64%). In addition, unreacted compound 1-2 was recovered (2.3 g, 33%).

IR (film, cm ⁻¹ ) 3461, 2975, 1743, 1701, 1399, 1368, 1257, 1207, 1173, 1144, 1062, 1006, 913, 888, 858, 773; ¹ H-NMR ₍ CDCl ₃ , rotational isomerism) Body mixture) 4.20 (s, 0.4H), 4.09 (s, 0.6H), 3.74 (s, 4.2H), 3.73 (s, 1.8H), 3.71 -3.53 (m, 3H), 2.89-3.02 (m, 2H), 2.72 (dt, J = 6.5, 16.5 Hz, 1H), 2.46-2.32 ( m, 2H), 1.46 (s, 3.6H), 1.40 (s, 5.4H), 1.20-1.02 (m, 3H); ¹³ C-NMR (CDCl ₃ , rotational isomerism) Body mixture) 173.4, 173.4, 172.3, 172.1, 154. 154.0, 80.3, 80.3, 65.9, 65.8, 65.2, 64.9, 52.4, 52.2, 52.2, 52.1, 47.9, 47 0.0, 46.5, 46.4, 40.6, 39.4, 33.4, 33.3, 28.4, 28.2, 22.7, 22.5; HRMS (FAB) calculated value ( _{C 16 H 25 NO 7) 346.1866} ([M + H] +), Found 346.1853.
(Step 1-3)

  To a solution of compound 1-3 (4.92 g, 58.3 mmol) in dichloromethane (50 mL) was added N-methylmorpholine-N-oxide (2.50 g, 2.13 mmol), molecular sieve 4A (4.7 g), tetrapropyl. Ammonium pearlate (0.13 g, 0.37 mmol) was added at 0 ° C. The mixture was stirred at 0 ° C. for 2 hours. After filtration, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate / hexane solution) to give compound 1-4 as a colorless oil (4.59 g, 94%).

IR (film, cm ⁻¹ ) 2977, 2955, 1742, 1705, 1479, 1437, 1400, 1367, 1256, 1206, 1172, 1135, 1005, 893, 861, 771; ¹ H-NMR (CDCl ₃ , rotational isomerism) Body mixture) 4.23 (d, J = 3.6 Hz, 0.4 H), 4.16 (d, J = 6.4 Hz, 0.6 H), 3.82 (s, 1.2 H), 3. 76 (s, 1.8H), 3.72-3.64 (m, 2H), 3.69 (s, 3H), 3.54-3.46 (m, 1H), 3.00-2. 94 (m, 0.4H), 2.88-2.81 (m, 0.6H), 2.67-2.45 (m, 2H), 2.20 (s, 3H), 1.46 ( s, 2.4H), 1.40 (s, 5.4H); ¹³ C-NMR (CDCl ₃ , rotational isomerism) Body mixture) 206.9, 206.4, 172.5, 172.2, 172.0, 171.8, 154.1, 153.5, 80.5, 64.0, 63.8, 52.5 52.2, 51.9, 51.8, 51.5, 50.4, 47.0, 46.4, 42.0, 40.8, 33.2, 32.7, 30.4, 28 , 38.1; HRMS (FAB) calculated (C ₁₆ H ₂₅ NO ₇ ) 343.1631; found 343.1618.
(Step 1-4)

To a suspension of zinc (3.62 g, 55.4 mmol) and lead (II) chloride (67 mg, 0.23 mmol) in THF (62 mL) was added diiodomethane (1.17 mL, 14.5 mmol). After stirring for 30 minutes, additional zinc (II) chloride (67 mg, 0.23 mmol) was added. After stirring for 30 minutes, TiCl ₄ (19.8% dichloromethane solution, 3.99 mL, 2.97 mmol) was added to the mixture at 0 ° C. The reactor was warmed up to room temperature, and stirred for further 1 h the _mixture, to give a CH ₂ I ₂ -Zn-TiCl ₄ reagent.

CH ₂ I ₂ -Zn-TiCl ₄ reagent Some (44 mL) was added to a solution of THF (5 mL) of Compound 1-4, and the resulting mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into 5% hydrochloric acid and the resulting mixture was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous NaHCO ₃ solution, saturated aqueous Na ₂ S ₂ O ₃ solution and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20-25% ethyl acetate / hexane solution) to give compound 1-5 as a colorless oil (596 mg, 60%).

IR (film, cm ⁻¹ ) 2976, 2953, 1742, 1702, 1648, 1479, 1438, 1399, 1366, 1327, 1257, 1206, 1173, 1132, 1008, 896, 771, 574; ¹ H-NMR ₍ CDCl ₃ , rotamer mixture) 4.92 (s, 1H), 4.69 (s, 1H), 4.16 (d, J = 2.8 Hz, 0.5H), 4.07 (d, J = 2.8 Hz, 0.5 H), 3.77 (s, 1.5 H), 3.77 (s, 1.5 H), 3.75-3.61 (m, 1 H), 3.70 (s, 1.5H), 3.70 (s, 1.5H), 3.50-3.40 (m, 1H), 3.03-2.98 (m, 1H), 2.85-2.82 ( m, 1H), 2.38-2.24 (m, 2H), 1.69 (s, 3H), 1 ^{47 (s, 4.5H), 1.41} (s, 4.5H); 13 C-NMR (CDCl 3, rotamers mixture) 172.6,172.5,172.4,172.3,154 .3, 153.7, 141.40, 141.23, 113.43, 113.16, 80.24, 80.21, 64.0, 63.6, 52.4, 52.2, 51.8 51.6, 47.8, 47.6, 46.0, 45.2, 41.8, 40.9, 32.9, 22.3, 22.2, 28.4, 28.2, 22 .3, 22.2; HRMS (FAB) calculated value (C ₁₇ H ₂₇ NO ₆ ) 341.1838, measured value 341.1824.
(Step 1-5)

  To a solution of compound 1-5 (800 mg, 2.34 mmol) in methanol (8 mL) was added aqueous potassium hydroxide (3%, 27 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 hours. After removing methanol under reduced pressure, the aqueous solution was washed twice with diethyl ether, acidified with 5% hydrochloric acid, and extracted five times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue (N-Boc-kainic acid). The residue was dissolved in dichloromethane (16 mL), trifluoro (2.0 mL) was added at room temperature, and the resulting mixture was stirred for 3 hours. After removal of the solvent under reduced pressure, the residue was purified on a column containing Dowex-50 WX2 hydrogen type (200-400 mesh) (eluted with 3% aqueous ammonia), and the collected fraction was concentrated under reduced pressure, A yellow solid was obtained (516 mg). This was recrystallized from ethanol to obtain (−)-kainic acid (Compound 1-6) as colorless crystals (433 mg, 87% in two steps).

[Α] _D ²³ −14.3 ° (c 0.445, H ₂ O); IR (film, cm ⁻¹ ) 3368, 1650, 1621, 1585, 1407, 1336, 1119, 900; ¹ H-NMR ₍ D ₂ O) 4.85 (s, 1H), 4.57 (s, 1H), 3.90 (d, J = 3.6 Hz, 1H), 3.43 (dd, J = 11.9, 7. 3 Hz, 1 H), 3.24 (dd, J = 11.9, 11.0 Hz, 1 H), 2.92-2.79 (m, 2 H), 2.26 (dd, J = 16.5, 5 .5 Hz, 1 H), 2.17 (dd, J = 16.5, 8.2 Hz, 1 H), 1.57 (s, 3 H); ¹³ C-NMR (D ₂ O) 179.2, 176.0 , 142.6, 116.2, 68.4, 49.1, 48.5, 43.5, 36.2, 24.9; HRMS ( AB) Calculated _{(C 10 H 16 NO 4)} 214.1079 ([M + H] +), Found 214.1080; m. p. 239-243 ° C
Example 2
(Step 2-1)

  Chlorotrimethylsilane (0.39 mL, 3.1 mmol) was added to a suspension of zinc (11.0 g, 0.168 mmol) in THF (75 mL) at room temperature. After stirring for 30 minutes, a solution of t-butyl bromoacetate (6.4 mL, 43.3 mmol) in THF (75 mL) was added dropwise to the mixture at 20-45 ° C., and the resulting mixture was heated to 45 ° C. for 2 hours. did. By cooling and filtering, a THF solution of t-butoxycarbonylmethyl zinc bromide was obtained.

  The THF solution of the t-butoxycarbonylmethyl zinc bromide was added to a solution of compound 2-1 (2.00 g, 6.96 mmol) in THF (44 mL) at 0 ° C. The resulting mixture was stirred at 0 ° C. for 3 hours and then at room temperature for 12 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted three times with chloroform. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-40% ethyl acetate / hexane solution) to give compound 2-2 as a colorless oil (2.22 g, 93%).

[Α] _D ²⁵ + 22.8 ° (c0.770 CHCl ₃ ); IR (film, cm ⁻¹ ) 3195, 2777, 2928, 2856, 2706, 1730, 1472, 1461, 1365, 1314, 1250, 1170, 1144 1106, 1083, 1062, 1032, 1006, 952, 903, 837, 810, 778, 710; ¹ H-NMR ₍ CDCl ₃ ) 6.06 (br s, 1H), 4.22-4.16 (m 1H), 3.93 (dt, J = 2.8, 10.0 Hz, 1H), 2.78 (dd, J = 2.4, 4.4 Hz, 1H), 2.66 (dd, J = 3.6, 16.4 Hz, 1 H), 2.48 (dd, J = 10.2, 16.4 Hz, 1 H), 1.46 (s, 9 H), 1.21 (d, J = 6.4 Hz) 3H), 0.88 (S, 9H), 0.08 (s, 6H); ¹³ C-NMR (CDCl ₃ ) 170.5, 167.9, 81.4, 65.3, 64.0, 46.8, 40.8 , 28.1,25.7,22.5,17.9, -4.3, -5.1; elemental analysis calculated _{(C 17 H 33 NO 4)} C, 59.44; H, 9.68 N, 4.08, found C, 59.45; H, 9.42; N, 4.09; p. (Hexane) 108-110 ° C
(Process 2-2)

LHMDS (1M THF solution, 7.1 mL, 7.1 mmol) was added dropwise at −78 ° C. to a solution of compound 2-2 (2.22 g, 6.46 mmol) in THF (44 mL). After stirring for 20 minutes, benzyl chloroformate (1.01 mL, 7.07 mmol) was added to the solution at −78 ° C. The resulting mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous NaHCO ₃ solution and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate / hexane solution) to give compound 2-3 (2.82 g, 91%) as a colorless oil.

^{_{[Α] D 26 -64.2 ° (}} c 1.390, CHCl 3); IR ( ^film, cm -1) ^{3171,3105,2955,2925,2893,2855,1779,1741,1587,1471,1449,} 1376, 1323, 1281, 1259, 1224, 1187, 1139, 1108, 1090, 1062, 1022, 1006, 965, 936, 904, 841, 810, 782, 758, 718, 688, 668; ¹ H-NMR ₍ CDCl ₃ ) 7.41-7.32 (m, 5H), 5.27 (d, J = 12.4 Hz, 1H), 5.23 (d, J = 12.4 Hz, 1H), 4.42-4 .39 (m, 1H), 4.32-4.26 (m, 1H), 3.08 (t, J = 2.8 Hz, 1H), 2.91 (dd, J = 3.6, 5.6 Hz, 1H), 2.70 (dd, J = 8.4, 15.6 Hz, 1H), 1.42 (s, 9H), 1.21 (d, J = 6.4 Hz, 3H), 0.79 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H); ¹³ C-NMR (CDCl ₃ ) 169.0, 165.2, 148.8, 135.1 , 128.5, 128.3, 128.2, 81.4, 67.7, 64.7, 62.6, 49.4, 37.9, 27.9, 25.5, 22.1, 17 .7, -4.3, -5.4; HRMS ( FAB) calcd _{(C 25 H 40 NO 6 Si} ) 478.2625 ([M + H] +), Found 478.2643.
(Step 2-3)

To a solution of compound 2-3 (8.32 g, 17.4 mmol) in EtOH (125 mL) was added NaBH ₄ (3.29 g, 87.0 mmol) at 0 ° C. After stirring at room temperature for 6 hours, the reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted four times with chloroform. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-35% ethyl acetate / hexane solution) to give compound 2-4 as a colorless oil (6.72 g, 80%).

[Α] _D ²² + 0.3 ° (c 0.285, CHCl ₃ ); IR (film, cm ⁻¹ ) 3383, 2931, 1722, 1530, 1455, 1368, 1254, 1156, 1072, 838, 777, 740 698; ¹ H-NMR ₍ CDCl ₃ ) 7.39-7.29 (m, 5H), 5.95 (d, J = 8.0 Hz, 1H), 5.10 (s, 2H), 4. 19-4.08 (m, 2H), 3.90-3.79 (m, 2H), 3.03 (br s, 1H), 2.65 (dd, J = 5.6, 15.6 Hz, 1H), 2.56 (dd, J = 6.8, 15.6 Hz, 1H), 1.79 (br s, 1H), 1.45 (s, 9H), 1.25 (d, J = 6 .4 Hz, 3 H), 0.90 (s, 9 H), 0.09 (s, 6 H); ¹³ C-NMR (C DCl ₃ ) 170.8, 156.2, 136.4, 128.4, 127.9, 81.1, 68.9, 66.6, 60.4, 49.0, 47.3, 39.1 , 28.0,25.7,20.3,17.8, -4.4, -5.1; HRMS (FAB) calcd _{(C 25 H 44 NO 6 Si} ) 482.2938 ([M + H] + ); Actual value 482.2956.
(Step 2-4) Compound 2-5 used as a starting material in Step 2-5 described later was prepared by the following method with reference to the preparation method described in Tetrahedron 2001, vol. 57, page 7909. (Reference Example 1).

To a suspension of glycine methyl ester hydrochloride (10.4 g, 82.8 mmol) and (5.0 mL) in dichloroethane (120 mL) was added triethylamine (23.5 mL, 169 mmol) and 2-nitrobenzenesulfonyl chloride (20.5 g). 92.5 mmol) was added at 0 ° C. The reaction mixture was gradually warmed to room temperature. After stirring for 12 hours, the mixture was concentrated under reduced pressure. Water was added and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with water, 5% hydrochloric acid, saturated aqueous NaHCO ₃ solution, and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and toluene to obtain the target compound 2-5 as a colorless solid (20.9 g, 92%).

IR (film, cm ⁻¹ ) 3340, 3100, 2956, 1747, 1594, 1540, 1439, 1417, 1361, 1303, 1219, 1166, 1125, 1059, 1010, 854, 784, 741, 701, 655; ¹ H _{-NMR (CDCl 3) 8.11-8.09 (m} , 1H), 7.96-7.94 (m, 1H), 7.76-7.74 (m, 2H), 6.04 (br s, 1H), 4.03 (d, J = 5.6 Hz, 2H), 3.61 (s, 3H); ¹³ C-NMR (CDCl ₃ ) 169.0, 133.9, 133.7, 132 .9,130.6,125.7,52.6,44.8; analysis calculated _{(C 9 H 10 N 2 O} 6 S) C, 39.42; H, 3.68; N, 10. 21, Measured value C, 39.41; H 3.74; N, 10.17; m. p. (Ethyl acetate-toluene) 109-110 ° C.
(Step 2-5)

  To a mixture of compound 2-4 (7.27 g, 15.1 mmol) and compound 2-5 (5.90 g, 21.5 mmol) in toluene (180 mL) was added triphenylphosphine (5.66 g, 21.6 mmol) and Diethyl azodicarboxylate (40% toluene solution, 9.79 mL, 21.6 mmol) was added at 70 ° C. and the resulting mixture was stirred for 30 minutes. After allowing to cool, the reaction mixture was concentrated under reduced pressure. The residue was concentrated by silica gel column chromatography (30-35% ethyl acetate / hexane solution) to give compound 2-6 as a colorless oil (10.1 g, 90%).

[Α] _D ²³ + 5.0 ° (c 0.930, CHCl ₃ ); IR (film, cm ⁻¹ ) 3384, 2954, 2931, 2857, 1725, 1547, 1456, 1439, 1370, 1255, 1165, 1065 , 1003, 964, 927, 838, 777, 737, 698; ¹ H-NMR ₍ CDCl ₃ ) 8.01 (d, J = 6.4 Hz, 1H), 7.69-7.61 (m, 2H) 7.56 (d, J = 9.2 Hz, 1H), 7.36-7.29 (m, 5H), 5.87 (brs, 1H), 5.11 (d, J = 12.8 Hz) 1H), 5.09 (d, J = 12.8 Hz, 1H), 4.37 (d, J = 19.2 Hz, 1H), 4.18-4.13 (m, 2H), 4.05 -4.02 (m, 1H), 3.72 (dd, J = 8.4 14.8 Hz, 1H), 3.57 (s, 3H), 3.48 (dd, J = 5.6, 14.8 Hz, 1H), 2.67-2.54 (m, 2H), 2 .07 (br s, 1H), 1.43 (s, 9H), 1.13 (d, J = 6.4 Hz, 3H), 0.85 (s, 9H), 0.07 (s, 3H) , 0.06 (s, 3H); ¹³ C-NMR (CDCl ₃ ) 170.5, 168.9, 156.0, 148.0, 136.6, 133.6, 132.5, 131.6, 130.8, 128.4, 128.0, 127.9, 124.0, 81.1, 69.1, 66.6, 52.1, 48.2, 47.6, 46.4, 45. 2,39.4,28.0,25.8,20.3,17.9, -4.3, -5.0; HRMS ( FAB) calcd _{(C 30 H} 44 _N 3 O _{1 SiS) 682.2466 ([M-} t-Bu + H] +), Found 682.2470.
(Step 2-6)

  To a solution of compound 2-6 (7.09 g, 19.0 mmol) in dichloromethane (25 mL) was added trifluoroacetic acid (25 mL) at 0 ° C. The reaction mixture was gradually warmed to room temperature. After stirring for 3 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give compound 2-7 as a colorless oil (5.13 g, 97%).

[Α] _D ²⁵ + 8.0 ° (c 1.14, CHCl ₃ ); IR (film, cm ⁻¹ ) 3330, 3092, 3068, 3033, 2985, 2954, 1747, 1588, 1546, 1455, 1439, 1354 1243, 1167, 1126, 1103, 1060, 1026, 914, 853, 778, 735, 699, 651; ¹ H-NMR ₍ CDCl ₃ ) 799 (d, J = 8.4 Hz, 1H), 7. 73-7.66 (m, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.38-7.30 (m, 5H), 5.20-5.12 (m, 1H) ), 5.08 (s, 2H), 4.27-4.16 (m, 3H), 4.00 (br s, 1H), 3.64-3.57 (m, 2H), 3.60. (S, 3H), 2.82 (dd, J = 5 .4, 16.6 Hz, 1 H), 2.65 (dd, J = 4.6, 16.6 Hz, 1 H), 2.14 (br s, 1 H), 1.45 (d, J = 5.2 Hz) 3H); ¹³ C-NMR (CDCl ₃ ) 170.4, 168.7, 155.5, 147.9, 136.0, 134.0, 132.1, 131.7, 130.9, 128. 5, 128.2, 128.0, 124.2, 76.0, 66.9, 52.3, 49.0, 48.1, 47.6, 43.6, 35.3, 20.2; HRMS (FAB) calcd _{(C 24 H 28 N 3 O} 10 S) 550.1495 ([M + H] +), Found 550.1486.
(Step 2-7)

  To a solution of compound 2-7 (5.13 g, 9.33 mmol) in DMF (80 mL) was added benzenethiol (1.25 mL, 12.2 mmol) and potassium carbonate (1.94 g, 14.0 mmol) at 0 ° C. . The resulting mixture was stirred at room temperature for 5 hours. After cooling to 0 ° C., di-t-butyl dicarbonate (6.11 g, 28.0 mmol) and 4-DMAP (57 mg, 47 mmol) were added to the reaction mixture. After stirring for 4 hours, the reaction mixture was poured into saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (90-100% ethyl acetate / hexane solution) to give compound 2-8 as a colorless oil (3.36 g, 78%).

[Α] _D ²⁴ + 17.8 ° (c 1.050, CHCl ₃ ); IR (film, cm ⁻¹ ) 3329, 2979, 1745, 1703, 1530, 1457, 1436, 1391, 1367, 1248, 1152, 1068 1025, 969, 913, 884, 777, 743, 699; ¹ H-NMR ₍ CDCl ₃ , rotamer mixture) 7.38-7.29 (m, 5H), 5.45 (br s, 1H) , 5.08 (s, 2H), 4.19-3.87 (m, 4H), 3.73 (s, 3H), 3.53-3.27 (m, 2H), 2.91-2 .79 (m, 1H), 2.67-2.63 (m, 1H), 1.94 (br s, 1H), 1.46-1.45 (m, 3H), 1.40 (s, ^{9H); 13 C-NMR (} CDCl 3, rotamers mixture ) 170.7, 170.4, 155.6, 155.5, 155.3, 136.1, 136.0, 128.4, 128.1, 128.0, 81.6, 81.2, 76 .4, 75.9, 66.7, 52.2, 52.1, 50.5, 49.8, 49.4, 48.7, 47.8, 47.6, 45.3, 35.9 35.7, 28.2, 28.0, 20.2, 19.9; HRMS (FAB) calculated (C ₂₃ H ₃₃ N ₂ O ₈ ) 465.2237 ([M + H] ⁺ ), found 465 2243.
(Step 2-8)

  In a 10 mL round bottom flask, Argon atmosphere was charged with compound 2-8 (21.9 mg, 0.0471 mol), catalytic amount of palladium on 5% activated carbon (about 3 mg) and ethyl acetate (0.5 mL). The flask was purged with hydrogen gas (balloon) and the suspension was stirred at room temperature for 12 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was diluted with DMF (0.2 mL) and iodomethane (0.029 mL, 0.47 mmol) and cesium carbonate (61.4 mg, 0.188 mmol) were added at 0 ° C. The reaction mixture was stirred at room temperature for 12 hours and diluted with ethyl acetate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (50% ethyl acetate / hexane solution) to give compound 1-1 as a colorless oil (9.5 mg, 64%). .

[Α] _D ²² + 59.9 ° (c 1.82, CHCl ₃ ); IR (film, cm ⁻¹ ) 2979, 1703, 1459, 1435, 1391, 1368, 1321, 1249, 1215, 1169, 1120, 1107 1045, 1003, 978, 886, 828, 778; ¹ H-NMR (CDCl ₃ , rotamer mixture) 6.86-6.80 (m, 1H), 6.06 (t, J = 9.2 Hz) 1H), 4.52-4.45 (m, 1H), 4.00 (d, J = 17.2 Hz, 0.5H), 3.97 (d, J = 17.2 Hz, 0.5H) 3.93 (d, J = 18.2 Hz, 0.5H), 3.88 (d, J = 18.2 Hz, 0.5H), 3.75 (s, 3H), 3.50-3. 43 (m, 1H), 3.31-3.26 (m, 1H), 2 .27-2.26 (m, 0.5H), 2.62-2.52 (m, 0.5H), 1.49 (s, 4.5H), 1.45 (d, J = 7. ^{2Hz, 3H), 1.43 (s} , 4.5H); 13 C-NMR (CDCl 3, rotamers mixture) 170.0,163.0,162.6,155.2,146.5,145 .6, 121.1, 120.7, 81.1, 80.9, 76.0, 75.4, 51.9, 50.4, 49.6, 49.5, 39.4, 39.2 28.0, 27.8, 19.4, 19.4; elemental analysis calculated (C ₁₅ H ₂₃ NO ₆ ) C, 57.50; H, 7.40; N, 4.47, measured C 57.47; H, 7.30; N, 4.38; p. (Ethyl acetate-hexane) 93-95 degreeC.

Example 3
(Step 3-1)

In a solution of compound 3-1 (prepared by the method described in Reference Example 6 below; 22.0 g, 107 mmol), lithium chloride (5.45 g, 129 mmol) and triethylamine (16.3 g, 161 mmol) in THF (500 mL). Crotonic anhydride (19.8 g, 129 mmol) was added at -78 ° C. The mixture was warmed to room temperature, stirred for 12 hours, and concentrated under reduced pressure. The residue was partitioned between 1% hydrochloric acid and ethyl acetate, the aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaHCO ₃ and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate / hexane solution) to obtain Compound 3-2 as a colorless oil (solidified upon standing) (27.5 g, 94%).

[Α] _D ²¹ -42.9 ° (c 2.31, CHCl ₃ ); IR (film, cm ⁻¹ ) 2979, 1775, 1684, 1637, 1497, 1443, 1392, 1356, 1278, 1236, 1209, 1183, 1160, 1120, 1092, 1039, 968, 921, 820, 765, 719, 701; ¹ H-NMR ₍ CDCl ₃ ) 7.30-7.22 (m, 6H), 7.19-7.10 (M, 1H), 4.56 (dd, J = 3.6, 10 Hz, 1H), 3.22 (dd, J = 3.6, 14.4 Hz, 1H), 2.89 (dd, J = 9.2, 14.4 Hz, 1 H), 1.96 (dd, J = 1.6, 6.4 Hz, 3 H), 1.37 (s, 3 H), 1.33 (s, 3 H); ¹³ C -NMR _(CDCl 3) 165.2,1 52.6, 146.5, 137.0, 129.0, 128.6, 126.7, 122.1, 82.1, 63.6, 35.2, 28.5, 22.3, 18. 4; analysis calculated _{(C 16 H 19 NO 3)} C, 70.31; H, 7.01; N, 5.12; Found C, 70.48; H, 7.22; N, 5. 14; m. p. (Ethyl acetate-hexane) 93-95 degreeC.
(Step 3-2)

TiCl ₄ (20.8% dichloromethane solution, 116 mL, 0.168 mmol) was added dropwise at −78 ° C. to a solution of compound 3-2 (43.6 g, 195 mmol) in dichloromethane (1090 mL). After stirring for 5 minutes, N, N-diisopropylethylamine (69.5 mL, 399 mmol) was added dropwise to the obtained yellow solution at −78 ° C. The solution of dark purple titanium enolate was stirred at -78 ° C for 2 hours. Acetaldehyde (62.7 mL, 1.12 mol) was added dropwise to the solution at −78 ° C. The resulting mixture was stirred at -78 ° C for 1 hour and then warmed to room temperature. After stirring for an additional hour, the reaction mixture was poured into saturated aqueous ammonium chloride and extracted three times with dichloromethane. The combined organic layers were washed with saturated aqueous NaHCO ₃ and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20-25% ethyl acetate / hexane solution) to give compound 3-3 as a colorless oil (48.5 g, 97%).

[Α] _D ²² -90.6 ° (c 1.85, CHCl ₃ ); IR (film, cm ⁻¹ ) 3526, 2979, 1775, 1692, 1636, 1497, 1455, 1359, 1278, 1233, 1208, 1182, 1161, 1101, 1003, 966, 967, 827, 767, 734, 701; ¹ H-NMR (CDCl ₃ ) 7.32-7.21 (m, 5H), 5.93-5.84 (m 1H), 5.38 (d, J = 18.4 Hz, 1H), 5.36 (d, J = 10.0 Hz, 1H), 4.56-4.50 (m, 2H), 4.17 -4.14 (m, 1H), 3.08 (dd, J = 3.6, 14.4 Hz, 1H), 2.94 (brs, 1H), 2.87 (dd, J = 9.2) , 14.4 Hz, 1 H), 1.38 (s, 6 H), _{^{.19 (d, J = 6.4Hz,}} 3H); 13 C-NMR (CDCl 3) 174.2,152.2,136.6,131.4,129.0,128.7,126.8, 121.4, 82.2, 68.0, 63.5, 53.5, 35.1, 28.4, 22.2, 19.7; HRMS (FAB) calculated value (C ₁₈ H ₂₄ NO ₄ ) 318.1705 ([M + H] ⁺ ), found 318.1700.
(Step 3-3)

To a solution of compound 3-3 (48.5 g, 155 mmol) and imidazole (16.9 g, 248 mmol) in DMF (490 mL) was added t-butyldimethylsilyl chloride (hereinafter also referred to as TBS-Cl, 30.3 g, 201 mmol). added. The mixture was stirred at 60 ° C. for 4 hours. After allowing to cool, a saturated aqueous NaHCO ₃ solution was added to the reaction mixture, and the mixture was extracted 3 times with hexane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-10% ethyl acetate / hexane solution) to give compound 3-4 as a colorless oil (61.3 g, 92%).

^{_{[Α] D 19 -36.9 ° (}} c 3.72, CHCl 3); IR ( ^film, cm -1) ^{2956,2930,2857,1780,1697,1640,1472,1378,1356,1277,1254, _{1182,1159,1111,996,944,836,776,733,700; 1 H-NMR (CDCl}} 3) 7.44-7.33 (m, 5H), 6.09-6.00 (m, 1H ), 5.34 (d, J = 14.8 Hz, 1H), 5.34 (d, J = 12.0 Hz, 1H), 4.68 (dd, J = 6.4, 9.2 Hz, 1H) 4.61 (dd, J = 2.8, 9.2 Hz, 1H), 4.29-4.23 (m, 1H), 3.22 (dd, J = 3.6, 14.4z, 1H) ), 3.00 (dd, J = 10.0, 14.4z, 1H) 1.49 (s, 3H), 1.48 (s, 3H), 1.32 (d, J = 6.4 Hz, 3H), 0.99 (s, 9H), 0.17 (s, 3H) ), 0.15 (s, 3H); ¹³ C-NMR (CDCl ₃ ) 172.7, 152.2, 136.9, 134.0, 129.1, 128.6, 126.7, 119.1 81.8, 70.2, 63.7, 55.3, 35.1, 28.5, 25.8, 22.2, 21.7, 18.0, -4.5, -4.7 ; HRMS (FAB) calcd _{(C 24 H 37 NO 4 Si} ) 431.2492, Found 431.2491.
(Step 3-4)

To a solution of compound 3-4 (61.3 g, 142 mmol) in dichloromethane (1220 mL) was added DIBAL-H (0.99 mol / L, toluene solution, 358 mL, 355 mmol) at -78 ° C. After stirring for 20 minutes, saturated aqueous ammonium chloride NH ₄ Cl (150 mL) and water (100 mL) were added dropwise to the reaction mixture at −78 ° C., then the temperature was raised to 0 ° C. and stirred for 20 minutes. After filtration, the filtrate was extracted with dichloromethane three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate / hexane solution) to obtain Compound 3-5 as a colorless oil (50.4 g, 84%).

[Α] _D ²³ 11.2 ° (c 1.67, CHCl ₃ ); IR (film, cm ⁻¹ ) 3403, 2955, 2929, 2856, 1732, 1497, 1453, 1421, 1375, 1306, 1252, 1160, 1127, 1051, 1001, 972, 951, 919, 836, 775, 730, 700; ¹ H-NMR (CDCl ₃ ) 7.34-7.19 (m, 5H), 5.69 (dt, J = 10.0, 16.8 Hz, 1H), 5.35 (dd, J = 5.6, 10.0 Hz, 1H), 5.29-5.22 (m, 2H), 4.23-4. 18 (m, 1H), 4.09-4.05 (m, 2H), 3.39 (dd, J = 3.6, 14.8 Hz, 1H), 2.80 (dd, J = 10.0) , 14.4 Hz, 1 H), 2.77-2.72. (M, 1H), 1.29 (s, 3H), 1.17 (d, J = 6.4 Hz, 3H), 1.07 (s, 3H), 0.88 (s, 9H), 0. 11 (s, 3H), 0.09 (s, 3H); ¹³ C-NMR (CDCl ₃ ) 157.0, 137.2, 134.1, 128.7, 126.7, 119.4, 81. 5, 78.4, 69.2, 64.0, 54.2, 35.5, 27.8, 25.7, 22.3, 20.2, 17.9, -4.5, -5. 1; HRMS (FAB) calcd _{(C 24 H 40 NO 4 Si} ) 434.2727 ([M + H] +); Found 434.2707.
(Step 3-5)

  Glycine methyl ester hydrochloride (9.55 g, 76.1 mmol), compound 3-5 (22.0 g, 50.7 mmol) and sodium cyanoborohydride (4.54 g, 66.0 mmol) in methanol (500 mL). The mixture was stirred in a 1 L autoclave at 80 ° C. for 5 hours. After allowing to cool to room temperature, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, compound 3-6 (fraction eluted with 20% ethyl acetate / hexane solution, 8.82 g, 94%) and colorless oil as a colorless oil (followed by standing. Compound 3-7 (fraction eluted with 60% ethyl acetate / hexane solution, 14.4 g, 85%) was obtained as solidified.

Compound 3-6: [α] _D ²⁴ + 5.9 ° (c 1.03, CHCl ₃ ); IR (film, cm ⁻¹ ) 2955, 2930, 2892, 2857, 1746, 1472, 1438, 1375, 1254, 1220, 1200, 1133, 1066, 1005, 917, 837, 774; ¹ H-NMR (CDCl ₃ ) 5.77-5.67 (m, 1H), 5.19-5.08 (m, 2H), 3.92-3.86 (m, 1H), 3.72-3.71 (m, 3H), 3.46-3.34 (m, 2H), 2.72-2.66 (m, 1H) ), 2.64-2.58 (m, 1H), 2.23-2.17 (m, 1H), 1.67 (brs, 1H), 1.10-1.06 (m, 3H) , 0.88-0.88 (m, 9H), 0.04 (s, 3H), 0.03 ( _{^{, 3H); 13 C-NMR}} (CDCl 3) 172.9,137.3,117.9,69.5,52.0,51.7,50.9,50.3,25.8,21. 2,18.0, -4.3, -5.0; HRMS ( FAB) calcd _{(C 15 H 32 NO 3 Si} ) 302.2152 ([M + H] +), Found 302.2164.
(Step 3-6)

  To a solution of compound 3-6 (23.6 g, 78.3 mmol) and triethylamine (27.3 mL, 196 mmol) in acetonitrile (350 mL) was added di-t-butyl dicarbonate (25.6 g, 117 mmol) and DMAP (0. 19 g, 1.6 mmol) was added at 0 ° C. The reaction mixture was gradually warmed to room temperature and stirred for 12 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted four times with hexane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-10% ethyl acetate / hexane solution) to give compound 3-8 as a colorless oil (61.3 g, 92%).

[Α] _D ²³ + 18.4 ° (c 1.35, CHCl ₃ ); IR (film, cm ⁻¹ ) 2955, 2930, 2888, 2857, 1758, 1703, 1463, 1434, 1401, 1366, 1251, 1201 1161, 1132, 1097, 1060, 1004, 959, 917, 886, 837, 775; ¹ H-NMR ₍ CDCl ₃ , rotamer mixture) 5.82-5.69 (m, 1H), 5.15 -5.00 (m, 2H), 4.04 (d, J = 17.1 Hz, 0.5H), 3.91-3.74 (m, 2.5H), 3.72 (s, 3H) 3.50 (dd, J = 10.0, 13.6 Hz, 0.5H), 3.44 (dd, J = 4.8, 14 Hz, 0.5H), 3.28 (dd, J = 10 .0, 14.0 Hz, 0.5 H) 3.20 (dd, J = 4.8, 14.4 Hz, 0.5H), 2.37-2.28 (m, 0.5H), 2.25-2.21 (m, 0.5H) 1.46 (s, 4.5H), 1.41 (s, 4.5H), 1.09 (d, J = 6.4 Hz, 1.5H), 1.08 (d, J = 6. 4 Hz, 1.5 H), 0.88 (s, 4.5 H), 0.87 (s, 4.5 H), 0.05 (s, 6 H); ¹³ C-NMR (CDCl ₃ , rotamer mixture) ) 170.6, 170.5, 155.9, 155.3, 136.6, 136.2, 118.2, 118.1, 80.1, 80.0, 69.2, 69.1, 51 .9, 51.8, 51.5, 51.1, 50.8, 50.5, 50.1, 48.8, 28.4, 28.2, 25.8, 21.7, 21.5 , 18.0, -4 0, -4.1, -4.9, -4.9; HRMS (FAB) calcd _{(C 20 H 39 NO 5 Si} ) 401.2597, Found 401.2585.
(Step 3-7)

To a solution of compound 3-8 (23.4 g, 58.3 mmol) in acetonitrile (187 mL) was added aqueous HF (35%, 15 mL, 260 mmol) at 0 ° C. After stirring at room temperature for 12 hours, the reaction mixture was poured into saturated aqueous NaHCO ₃ and extracted four times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20-35% ethyl acetate / hexane solution) to give compound 3-9 as a colorless oil (15.6 g, 98%).

[Α] _D ²⁰ + 22.6 ° (c 0.380, CHCl ₃ ); IR (film, cm ⁻¹ ) 3460, 2977, 1755, 1683, 1465, 1436, 1406, 1368, 1251, 1212, 1169, 1002 , 897, 778, 703; ¹ H-NMR ₍ CDCl ₃ , rotational isomer mixture) 5.85-5.68 (m, 1H), 5.23-5.06 (m, 2H), 3.98- 3.82 (m, 3H), 3.75 (s, 3H), 3.74-3.71 (m, 0.8H), 3.55 (dd, J = 7.3, 15.6 Hz, 0 .2H), 3.15 (dd, J = 7.3, 14.7 Hz, 0.2H), 2.80 (dd, J = 5.5, 14.6 Hz, 0.8H), 2.30− 2.20 (m, 0.2H), 2.20-2.05 (m, 0.8H), 1 86 (br.s, 0.2H), 1.50 (brs, 0.8H), 1.44 (s, 9H), 1.18 (d, J = 6.4 Hz, 0.6H), 1 .14 (d, J = 6.4 Hz, 2.4H); ¹³ C-NMR (CDCl ₃ , isomer of main product) 170.3, 156.6, 135.0, 118.3, 81.1 , 64.6,52.0,50.4,50.1,49.5,28.1,20.2; HRMS (FAB) calcd _{(C 14 H 26 NO 5)} 288.1811 ([M + H] ⁺ ), Found 288.1824.
(Step 3-8)

Acrylic acid chloride in a solution of compound 3-9 (16.0 g, 58.5 mmol), N, N-diisopropylethylamine (51.5 mL, 293 mmol), and DMAP (0.36 g, 2.9 mmol) in dichloromethane (320 mL). (14.3 mL, 176 mmol) was added at -78 ° C. The reaction mixture was gradually warmed to room temperature and stirred at room temperature for 12 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted four times with dichloromethane. The combined organic layers were washed with saturated aqueous NaHCO ₃ solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15-20% ethyl acetate / hexane solution) to give compound 3-10 as a colorless oil (18.8 g, 94%).

[Α] _D ²² + 21.3 ° (c 0.980, CHCl ₃ ); IR (film, cm ⁻¹ ) 2979, 1755, 1722, 1704, 1638, 1620, 1461, 1406, 1367, 1296, 1271, 1248 , 1199, 1164, 1092, 1051, 999, 923, 885, 811, 776, 664, 570; ¹ H-NMR ₍ CDCl ₃ , mixture of rotational isomers) 6.39 (d, J = 17.6, 0. 5H), 6.38 (d, J = 17.2, 0.5H), 6.12 (dd, J = 2.8, 10.0 Hz, 0.5H), 6.08 (dd, J = 2) .8, 10.0 Hz, 0.5H), 5.84-5.80 (m, 1H), 5.78-5.67 (m, 1H), 5.21-5.11 (m, 2H) , 5.08-5.03 (m, 1H), 3 94 (d, J = 17.6 Hz, 0.5 H), 3.90 (d, J = 17.6 Hz, 0.5 H), 3.85 (d, J = 17.6 Hz, 0.5 H), 3 .78 (d, J = 17.6 Hz, 0.5H), 3.72 (s, 3H), 3.42-3.36 (m, 1H), 3.33-3.22 (m, 1H) 2.58-2.46 (m, 1H), 1.46 (s, 4.5H), 1.40 (s, 4.5H), 1.24 (d, J = 6.4 Hz, 3. ¹³ C-NMR (CDCl ₃ , rotamer mixture) 170.5, 170.4, 165.6, 165.5, 155.7, 155.2, 135.0, 134.9, 130. 7, 130.5, 128.7, 128.7, 119.5, 119.3, 80.5, 70.6, 70.4, 52.0, 51.9, 50.4, 50 0,49.8,49.4,49.1,48.3,28.3,28.2,18.0; HRMS (FAB) calcd _{(C 17 H 28 NO 6)} ([M + H] +) 342.1917, measured value 342.1921.
(Step 3-9)

  To a solution of compound 3-10 (5.00 g, 14.6 mmol) in 1,2-dichloroethane (290 mL) was added Hoveyda-Grubbs (2nd generation) catalyst (73 mg, 0.12 mmol) and the solution was heated to reflux for 3 days. did. After allowing to cool, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50-60% ethyl acetate / hexane solution) to obtain Compound 1-1 as a pale yellow oil (solidified upon standing) (4.55 g, 99%). .

[Α] _D ²² + 59.9 ° (c 1.82, CHCl ₃ ); IR (film, cm ⁻¹ ) 2979, 1703, 1459, 1435, 1391, 1368, 1321, 1249, 1215, 1169, 1120, 1107 1045, 1003, 978, 886, 828, 778; ¹ H-NMR ₍ CDCl ₃ , rotamer mixture) 6.86-6.80 (m, 1H), 6.06 (t, J = 9.2 Hz) 1H), 4.52-4.45 (m, 1H), 4.00 (d, J = 17.2 Hz, 0.5H), 3.97 (d, J = 17.2 Hz, 0.5H) 3.93 (d, J = 18.2 Hz, 0.5H), 3.88 (d, J = 18.2 Hz, 0.5H), 3.75 (s, 3H), 3.50-3. 43 (m, 1H), 3.31-3.26 (m, 1H), .27-2.26 (m, 0.5H), 2.62-2.52 (m, 0.5H), 1.49 (s, 4.5H), 1.45 (d, J = 7. ^{2Hz, 3H), 1.43 (s} , 4.5H); 13 C-NMR (CDCl 3, rotamers mixture) 170.0,163.0,162.6,155.2,146.5,145 .6, 121.1, 120.7, 81.1, 80.9, 76.0, 75.4, 51.9, 50.4, 49.6, 49.5, 39.4, 39.2 , 28.0,27.8,19.4,19.4; elemental analysis calculated _{(C 15 H 23 NO 6)} C, 57.50; H, 7.40; N, 4.47, Found C 57.47; H, 7.30; N, 4.38; m. p. (Ethyl acetate-hexane) 93-95 degreeC.

Example 4
(Step 4-1)

A solution of compound 4-1 (1.02 g, 5.76 mmol), lithium chloride (0.29 g, 6.8 mmol) and triethylamine (1.20 mL, 8.61 mmol) in THF (25 mL) was added crotonic anhydride (1. 02 mL, 6.88 mmol) was added at -15 ° C. The mixture was warmed to room temperature and stirred for 12 hours, and then the reaction mixture was concentrated under reduced pressure. The residue was partitioned between 2% hydrochloric acid and ethyl acetate and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaHCO ₃ and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20-30% ethyl acetate / hexane solution) and recrystallized to obtain compound 4-2 as a colorless solid (1.37 g, 97%).

[Α] _D ²⁴ + 75.1 ° (c 0.855, CHCl ₃ ), IR (film, cm ⁻¹ ) 3028, 2975, 2917, 1778, 1685, 1637, 1497, 1443, 1389, 1354, 1293, 1212 1125, 1095, 1056, 1033, 1009, 970, 930, 831, 805, 762, 733, 702; ¹ H-NMR ₍ CDCl ₃ ) 7.35-7.17 (m, 7H), 4.72- 4.70 (m, 1H), 4.22-4.14 (m, 2H), 3.31 (dd, J = 3.2, 13.4 Hz, 1H), 2.80 (dd, J = 9) .6, 13.4 Hz, 1 H), 1.98 (d, J = 5.2 Hz, 3 H); ¹³ C-NMR (CDCl ₃ ) 164.8, 153.3, 146.8, 135.3, 129 .4, 1 28.8, 127.2, 121.8, 66.0, 55.2, 37.7, 18.5; elemental analysis calculated (C ₁₄ H ₁₅ NO ₃ ) C, 68.56; H, 6. 16; N, 5.71, found C, 68.61; H, 6.21; N, 5.63; p. (AcOEt-hexane) 84-86 ° C.
(Step 4-2)

TiCl ₄ (20.8% dichloromethane solution, 3.43 mL, 5.26 mmol) was added dropwise at −78 ° C. to a solution of compound 4-2 (1.23 g, 5.01 mmol) in dichloromethane (60 mL). After stirring between 5 groups, N, N-diisopropylethylamine (2.18 mL, 12.5 mmol) was added to the obtained yellow solution at -78 ° C. The dark purple solution of titanium enolate was stirred at -78 ° C for 2 hours, and then acetaldehyde (2.0 mL, 35.6 mol) was added dropwise at -78 ° C. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous NaHCO ₃ and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate / hexane solution) to give compound 4-3 as a colorless oil (1.36 g, 94%).

[Α] _D ²³ -7.5 ° (c 3.59, CHCl ₃ ); IR (film, cm ⁻¹ ) 3506, 2978, 1779, 1694, 1635, 1455, 1389, 1289, 1211, 1111, 1052, 997, 930, 818, 763, 703, 594; ¹ H-NMR ₍ CDCl ₃ ) 7.35-7.23 (m, 3H), 7.19 (d, J = 7.2 Hz, 2H), 6. 06-5.97 (m, 1H), 5.41 (d, J = 16.4 Hz, 1H), 5.41 (d, J = 11.6 Hz, 1H), 4.75-4.69 (m 1H), 4.51 (dd, J = 3.6, 9.2 Hz, 1H), 4.23-4.12 (m, 3H), 3.23 (dd, J = 3.6, 13. 6 Hz, 1 H), 3.08 (d, J = 2.8 Hz, 1 H), 2.76 (dd, _{^{= 9.2,13.6Hz, 1H), 1.21 (}} d, J = 5.6Hz, 3H); 13 C-NMR (CDCl 3) 173.9,152.9,134.8,131.1 129.3, 128.8, 127.3, 121.4, 67.9, 65.9, 54.9, 53.3, 37.4, 19.8; calculated HRMS (FAB) (C _{16 H 20 NO 4) 290.1392 ([} M + H] +), Found 290.1389.
(Step 4-3)

To a solution of compound 4-3 (1.83 g, 6.32 mmol) and imidazole (0.65 g, 28.0 mmol) in DMF (20 mL) was added triethylsilyl chloride (1.24 g, 8.23 mmol) to 0 at 0 ° C. Added at ° C. After stirring at room temperature for 4 hours, the reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted three times with hexane. The combined organic layers were washed with saturated aqueous NaHCO ₃ and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-10% ethyl acetate / hexane solution) to give compound 4-4 as a colorless oil (2.50 g, 98%).

[Α] _D ²³ + 36.5 ° (c 1.06, CHCl ₃ ); IR (film, cm ⁻¹ ) 2956, 2913, 2876, 1784, 1697, 1637, 1455, 1381, 1352, 1289, 1209, 1121 , 1052, 1009, 924, 888, 826, 738, 703, 593; ¹ H-NMR ₍ CDCl ₃ ) 7.34-7.26 (m, 3H), 7.20 (d, J = 7.3 Hz, 2H), 6.11-6.01 (m, 1H), 5.27 (d, J = 10.0 Hz, 1H), 5.25 (d, J = 17.2 Hz, 1H), 4.68- 4.62 (m, 1H), 4.55 (dd, J = 5.6, 9.2 Hz, 1H), 4.23-4.12 (m, 3H), 3.27 (dd, J = 2) .8, 12.8 Hz, 1H), 2.76 (dd, J = 9 6, 13.4 Hz, 1 H), 1.21 (d, J = 5.6 Hz, 3 H), 0.94 (t, J = 8.0 Hz, 9 H), 0.58 (q, J = 8.0 Hz) , 6H); ¹³ C-NMR (CDCl ₃ ) 172.4, 153.0, 135.3, 133.5, 129.4, 128.8, 127.2, 119.2, 69.8, 65. 8,55.5,55.0,37.5,21.6,6.7,4.8; HRMS (FAB) calcd ^{_{(C 22 H 34 NO 4 Si}} ) ([M + H] +) 404.2257 , Measured value 404.2268.
(Step 4-4)

LiBH ₄ (2 mol / L diethyl ether solution, 6.19 mL, 12.4 mmol) was added to a solution of compound 4-4 (2.50 g, 6.20 mmol) and methanol (0.502 mL, 12.4 mmol) in diethyl ether (63 mL). ) Was added at 0 ° C. After stirring for 2 hours, the resulting mixture was warmed to room temperature and further stirred for 1 hour. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous solution and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-15% ethyl acetate / hexane solution) to give compound 4-5 as a colorless oil (980 mg, 84%).

[Α] _D ²³ + 3.2 ° (c 1.08, CHCl ₃ ); IR (film, cm ⁻¹ ) 3406, 3075, 2956, 2912, 2877, 1640, 1459, 1416, 1375, 1239, 1133, 1068 1039, 1007, 916, 826, 744, 670; ¹ H-NMR ₍ CDCl ₃ ) 5.74-5.65 (m, 1H), 5.18-5.10 (m, 2H), 4.08 -4.03 (m, 1H), 3.85-3.79 (m, 1H), 3.65-3.60 (m, 1H), 2.68 (t, J = 5.6 Hz, 1H) 2.44-2.38 (m, 1H), 1.16 (d, J = 6.4 Hz, 3H), 0.97 (t, J = 7.8 Hz, 9H), 0.61 (q, J = 7.8 Hz, 6H); ¹³ C-NMR (CDCl ₃ ) 135.6 118.0, 70.4, 63.6, 52.4, 19.9, 6.8, 4.9. ; HRMS (FAB) calcd _{(C 12 H 26 O 2 Si} ) 230.1702, Found 230.1708.
(Step 4-5)

  A solution of compound 4-5 (169 mg, 0.733 mmol) and compound 2-5 (262 mg, 0.955 mmol) in toluene (5 mL) was heated to 70 ° C., triphenylphosphine (250 mg) and diethyl azodicarboxylate. (40% toluene solution, 0.43 mL, 0.95 mmol) was added and the mixture was stirred at 70 ° C. for 20 minutes. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate / hexane solution) to obtain Compound 4-7 as a colorless oil (308 mg, 87%).

[Α] _D ²⁰ −11.9 ° (c 1.34, CHCl ₃ ); IR (film, cm ⁻¹ ) 2955, 2877, 1754, 1547, 1458, 1439, 1417, 1372, 1216, 1165, 1127, 1061, 1004, 962, 928, 852, 781, 741, 585; ¹ H-NMR (CDCl ₃ ) 8.07-8.05 (m, 1H), 7.71-7.66 (m, 2H), 7.61-7.59 (m, 1H), 5.63-5.54 (m, 1H), 5.08-5.04 (m, 2H), 4.33 (d, J = 19.2 Hz 1H), 4.10 (d, J = 19.2 Hz, 1H), 3.91-3.86 (m, 1H), 3.62 (s, 3H), 3.55-3.52 (m) 2H), 2.36-2.29 (m, 1H), 1.08 (t, J = 6 .4 Hz, 3H), 0.94 (t, J = 8.4 Hz, 9H), 0.58 (q, J = 8.4 Hz, 6H); ¹³ C-NMR (CDCl ₃ ) 169.3, 147. 9, 135.5, 133.4, 133.4, 131.5, 130.9, 124.0, 119.0, 69.0, 52.1, 50.7, 49.8, 48.5, 21.1, 6.8, 5.0; HRMS (FAB) calculated (C ₂₁ H ₃₅ N ₂ O ₇ SiS) 487.1934 ([M + H] ⁺ ), found 487.1927.
(Step 4-6)

To a solution of compound 4-7 (655 mg, 1.35 mmol) in DMF (10 mL) was added benzenethiol (0.18 mL, 1.8 mmol) and potassium carbonate (0.28 g, 2.0 mmol) at 0 ° C. After stirring at room temperature for 2 hours, saturated aqueous NaHCO ₃ was added to the reaction mixture and extracted four times with ethyl acetate. The combined organic layers were washed with saturated aqueous NaHCO ₃ and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-20% ethyl acetate / hexane solution) to give compound 4-8 as a colorless oil (410 mg, quantitative).

[Α] _D ²² + 24.2 ° (c 0.570, CHCl ₃ ); IR (film, cm ⁻¹ ) 3460, 2977, 1755, 1684, 1465, 1436, 1368, 1252, 1209, 1168, 1003, 915 , 776, 744, 667; ¹ H-NMR ₍ CDCl ₃ ) 5.77-5.68 (m, 1H), 5.18-5.10 (m, 2H), 3.93-3.87 (m 1H), 3.72 (s, 3H), 3.44 (d, J = 17.6 Hz, 1H), 3.38 (d, J = 17.2 Hz, 1H), 2.72 (dd, J = 11.2, 4.6 Hz, 1H), 2.62 (dd, J = 9.2, 11.2 Hz, 1H), 2.25-2.19 (m, 1H), 1.68 (br s). 1H), 1.10 (t, J = 5.2 Hz, 3H), 0.95 (t, J = 8.0 Hz, 9H), 0.58 (q, J = 8.0 Hz, 6H); ¹³ C-NMR (CDCl ₃ ) 172.9, 137.4, 117.9, 69.6, 52.0 , 51.7,50.9,50.0,21.1,6.9,5.0; HRMS (FAB) calcd _{(C 15 H 32 NO 3 Si} ) 302.2152 ([M + H] +), Found 302.2157.
(Step 4-7)

To a solution of compound 4-8 (385 mg, 1.28 mmol) in acetonitrile (5 mL) was added di-t-butyl dicarbonate (418 mg, 1.92 mmol) and a catalytic amount of DMAP at 0 ° C. After stirring for 2 hours, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 4 times with ethyl acetate. The combined organic layers were washed with saturated aqueous NaHCO ₃ and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate / hexane solution) to obtain Compound 4-9 as a colorless oil (442 mg, 92%).

[Α] _D ²¹ + 20.3 ° (c 0.805, CHCl ₃ ); IR (film, cm ⁻¹ ) 2956, 2877, 1759, 1703, 1461, 1417, 1366, 1245, 1201, 1160, 1097, 1060 , 1005, 961, 916, 885, 744, 667; ¹ H-NMR (CDCl ₃ , rotamer mixture) 5.82-5.69 (m, 1H), 5.12-5.00 (m, 2H) ), 4.02 (d, J = 17.6 Hz, 0.5H), 3.90-3.68 (m, 2.5H), 3.72 (s, 3H), 3.49-3.40 (M, 1H), 3.32 (dd, J = 10.0, 13.6 Hz, 0.5H), 3.25 (dd, J = 4.6, 14.6 Hz, 0.5H), 2. 33-2.22 (m, 1H), 1.46 (s, 4.5H), 1.41 (s, 4.5H), 1.10 (d, J = 6.4 Hz, 1.5H), 1.09 (d, J = 5.6 Hz, 1.5H), 0.95 (t , J = 8.4 Hz, 4.5H), 0.95 (t, J = 7.8 Hz, 4.5H), 0.61-0.55 (m, 6H); ¹³ C-NMR (CDCl ₃ , Rotational isomer mixture) 170.7, 170.6, 155.9, 155.3, 136.6, 136.3, 118.2, 118.0, 80.1, 80.0, 69.1, 69 0.0, 51.9, 51.8, 51.6, 51.0, 50.5, 50.4, 50.0, 49.0, 28.3, 28.2, 21.6, 21.5 , 6.9,5.1; HRMS (FAB) calcd _{(C 20 H 40 NO 5 Si} ) 402.2676 ([M + H] +), Found 402.2687.
(Step 4-8)

To a solution of compound 4-9 (451 mg, 1.12 mmol) in acetonitrile (5 mL) was added aqueous HF (35%, 0.2 mL, 4 mmol) at 0 ° C. After stirring at room temperature for 20 minutes, the reaction mixture was poured into saturated aqueous NaHCO ₃ and extracted four times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate / hexane solution) to give compound 4-10 as a colorless oil (308 mg, quantitative).

[Α] _D ²⁰ + 22.6 ° (c 0.380, CHCl ₃ ); IR (film, cm ⁻¹ ) 3460, 2977, 1755, 1683, 1465, 1436, 1406, 1368, 1251, 1212, 1169, 1002 , 897, 778, 703; ¹ H-NMR ₍ CDCl ₃ , rotational isomer mixture) 5.85-5.68 (m, 1H), 5.23-5.06 (m, 2H), 3.98- 3.82 (m, 3H), 3.75 (s, 3H), 3.74-3.71 (m, 0.8H), 3.55 (dd, J = 7.3, 15.6 Hz, 0 .2H), 3.15 (dd, J = 7.3, 14.7 Hz, 0.2H), 2.80 (dd, J = 5.5, 14.6 Hz, 0.8H), 2.30− 2.20 (m, 0.2H), 2.20-2.05 (m, 0.8H), 1 86 (br.s, 0.2H), 1.50 (br.s, 0.8H), 1.44 (s, 9H), 1.18 (d, J = 6.4 Hz, 0.6H), 1.14 (d, J = 6.4 Hz, 2.4H); ¹³ C-NMR (CDCl ₃ , isomer of main product) 170.3, 156.6, 135.0, 118.3, 81. 2,64.6,52.0,50.4,50.1,49.5,28.1,20.2; HRMS (FAB) calcd _{(C 14 H 26 NO 5)} 288.1811 ([M + H ] ⁺ ), Measured value 288.1824.

Example 5
(Step 5-1)

  A solution of compound 4-9 (2.57 g, 6.40 mmol) in dichloromethane (38 mL) and methanol (13 mL) was bubbled with ozone gas at −78 ° C. After stirring for 30 minutes, the reaction mixture was stirred for 15 minutes while bubbling argon gas to remove excess ozone gas. Dimethyl sulfide (4.9 mL, 64 mmol) was added to the reaction mixture, and then the reaction mixture was warmed to room temperature. After stirring for 1 hour, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-20% ethyl acetate / hexane solution) to obtain Compound 5-1 as a colorless oil (2.33 g, 90%).

[Α] _D ²² −12.7 ° (c 1.31, CHCl ₃ ); IR (film, cm ⁻¹ ) 2955, 2932, 2888, 2858, 1755, 1705, 1463, 1432, 1395, 1367, 1017, 956, 881, 837, 810, 777, 667; ¹ H-NMR ₍ CDCl ₃ , rotamer mixture) 9.84-9.79 (m, 1H), 4.13-3.82 (m, 3H) 3.72 (s, 3H), 3.43-3.26 (m, 2H), 2.75-2.72 (m, 0.6H), 2.66-2.63 (m, 0. 2). 4H), 1.47 (s, 3.6H), 1.40 (s, 5.4H), 1.33 (d, J = 6.4 Hz, 1.8H), 1.29 (d, J = 5.6 Hz, 1.2 H), 0.87 (s, 3.6 H), 0.85 (s, 5.6 H), ^{.05 (s, 6H); 13} C-NMR (CDCl 3, rotamers mixture) 204.1,203.9,170.6,170.5,155.2,155.3,81.0,80 .5, 68.9, 58.9, 58.6, 52.0, 51.9, 50.5, 49.4, 46.7, 46.4, 28.3, 28.1, 25.6 , 22.5,22.5,17.9, -4.2, -4.2, -5.1 , -4.9; HRMS (FAB) calcd _{(C 19 H 38 NO 6 Si} ) 404. 2468 ([M + H] ⁺ ), found 404.2478.
(Step 5-2)

  To a suspension of sodium hydride (60% dispersion in mineral oil, 0.254 g, 6.35 mmol) in THF (50 mL) was added triethyl phosphonoacetate (1.68 g, 7.49 mmol) at 0 ° C. . After stirring for 10 minutes, a solution of compound 5-1 (2.33 g, 5.77 mmol) in THF (10 mL) was added. The reaction mixture was stirred at 0 ° C. for 30 minutes and then partitioned between saturated aqueous ammonium chloride and ethyl acetate. The separated aqueous layer was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-20% ethyl acetate / hexane solution) to give compound 5-2 as a colorless oil (2.40 g, 88%).

[Α] _D ²¹ + 54.8 ° (c 0.745, CHCl ₃ ); IR (film, cm ⁻¹ ) 2956, 2931, 2897, 2858, 1757, 1715, 1655, 1464, 1426, 1404, 1367, 1252 1203, 1164, 1092, 1053, 991, 959, 885, 838, 810, 775, 723, 667; ¹ H-NMR (CDCl ₃ , rotamer mixture) 6.91 (dd, J = 10.0, 15.6 Hz, 1H), 5.83 (dd, J = 7.6, 15.6 Hz, 1H), 4.18 (q, J = 7.4 Hz, 2H), 4.02-3.79 (m 3H), 3.72 (s, 3H), 3.70-3.65 (m, 0.6H), 3.52 (dd, J = 5.0, 15.2 Hz, 0.4H), 3 .29 (dd, J = 10.0 , 14.6 Hz, 0.4 H), 3.18 (dd, J = 3.6, 14.6 Hz, 0.6 H), 2.58-2.49 (m, 0.4 H), 2.43- 2.38 (m, 0.6H), 1.45 (s, 5.4H), 1.37 (s, 3.6H), 1.29 (t, J = 7.4 Hz, 3H), 1. 09 (d, J = 6.4 Hz, 3H), 0.88 (s, 5.4H), 0.88 (s, 3.6H), 0.05 (s, 6H); ¹³ C-NMR (CDCl ₃ , rotamer mixture) 170.4, 170.3, 166.1, 166.0, 155.6, 155.2, 147.0, 146.9, 124.5, 124.4, 80.6 80.4, 69.1, 69.0, 60.2, 52.0, 51.9, 50.8, 50.6, 50.2, 50.0, 48.8, 28.2, 28 .2, 2 5.8,25.8,22.0,21.9,18.0,14.2, -4.0, -4.9; HRMS ( FAB) calcd _{(C 23 H 43 NO 7 Si} ) 473 2809, measured value 4733.2793.
(Step 5-3)

To a solution of compound 5-2 (2.40 g, 5.07 mmol) in acetonitrile (19.2 mL) was added 35% aqueous HF (1.7 mL, 30 mmol) at 0 ° C. After stirring at room temperature for 12 hours, the reaction mixture was poured into saturated aqueous NaHCO ₃ and extracted four times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20-30% ethyl acetate / hexane solution) to give compound 5-3 as a colorless oil (1.48 g, 81%).

[Α] _D ²³ + 40.5 ° (c 1.40, CHCl ₃ ); IR (film, cm ⁻¹ ) 3472, 2978, 1754, 1703, 1466, 1436, 1406, 1368, 1250, 1209, 1166, 1037 , 991, 895, 859, 776, 725; ¹ H-NMR ₍ CDCl ₃ , rotamer mixture) 6.95 (dd, J = 9.7, 15.6 Hz, 0.8H), 6.94-6 .88 (m, 0.2H), 5.88 (d, J = 15.6 Hz, 0.2H), 5.87 (d, J = 15.6 Hz, 0.8H), 4.19 (q, J = 6.4 Hz, 2H), 4.03-3.95 (m, 2.2H), 3.93 (d, J = 17.4 Hz, 0.8H), 3.81 (d, J = 17 .4Hz, 0.8H), 3.75 (s, 2.4H), 3.73 ( 0.6H), 3.52 (dd, J = 7.3, 14.6 Hz, 0.2H), 3.33 (dd, J = 7.3, 14.7 Hz, 0.2H), 2. 81 (dd, J = 4.6, 14.6 Hz, 0.8H), 2.49-2.43 (m, 0.2H), 2.36-2.30 (m, 0.8H), 2 0.00 (br s, 0.2 H), 1.77 (br s, 0.8 H), 1.43 (s, 9 H), 1.29 (t, J = 6.4 Hz, 3 H), 1.18 (D, J = 6.4 Hz, 0.6H), 1.14 (d, J = 6.4 Hz, 2.4H); ¹³ C-NMR (CDCl ₃ , isomer of main product) 170.3, 165.9, 156.6, 145.1, 124.8, 81.6, 64.5, 60.4, 52.1, 50.3, 49.8, 48.2, 28.1, 20. 5, 14.2; H MS (FAB) calcd _{(C 17 H 30 NO 7)} 360.2022 ([M + H] +), Found 360.2011.
(Step 5-4)

  Compound 5-3 (1.30 g, 3.62 mmol), 1-dodecanethiol (1.04 mL, 4.34 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (0.054 mL, 0.064 mmol) was stirred at 80 ° C. for 1 hour. After cooling, the reaction mixture was purified by silica gel column chromatography (30-40% ethyl acetate / hexane solution) to give compounds 5-4a and 5-4b as colorless oils (1.55 g, 83%).

Compound 5-4a:
[Α] _D ²¹ + 70.8 ° (c 0.965, CHCl ₃ ); IR (film, cm ⁻¹ ) 2926, 2854, 1746, 1705, 1458, 1436, 1394, 1367, 1249, 1208, 1170, 1092 1022, 968, 884, 775, 721; ¹ H-NMR ₍ CDCl ₃ , rotamer mixture) 4.47-4.40 (m, 1H), 4.19 (d, J = 17.4, 0) .5H), 4.08 (d, J = 17.4, 0.5H), 4.03-3.97 (m, 1H), 3.75 (s, 3H), 3.70-3.63 (M, 1H), 3.35 (brs, 1H), 3.17-3.11 (m, 1H), 2.91-2.86 (m, 1H), 2.82-2.74 ( m, 1H), 2.63-2.56 (m, 1H), 2.52-2.47 ( m, 1H), 2.40-2.34 (m, 0.5H), 2.6-2.19 (m, 0.5H), 1.65-1.53 (m, 2H), 1. 49 (s, 4.5H), 1.43 (s, 4.5H), 1.41-1.36 (m, 3H), 1.26 (s, 18H), 0.88 (t, J = 5.5 Hz, 3H); ¹³ C-NMR (CDCl ₃ , rotamer mixture) 170.6, 170.4, 168.8, 168.6, 155.7, 155.4, 81.3, 80. 9, 76.4, 76.0, 52.2, 52.1, 51.6, 50.5, 48.6, 47.7, 43.7, 43.2, 39.1, 38.4, 37.4, 37.0, 31.9, 31.0, 29.6, 29.5, 29.5, 29.3, 29.2, 29.2, 29.0, 28.3, 28. 1, 2, 2.6, 22 .7,20.8,20.7,14.1; HRMS (FAB) calcd _{(C 27 H 49 NO 6 S} ) 515.3281, Found 515.3286.

Compound 5-4b:
[Α] _D ²² -14.9 ° (c 1.700, CHCl ₃ ); IR (film, cm ⁻¹ ) 2926, 2854, 1754, 1704, 1459, 1436, 1390, 1367, 1249, 1210, 1171, 1093, 1056, 1005, 967, 884, 775, 721, 567; ¹ H-NMR (CDCl ₃ , rotamer mixture) 4.22-4.18 (m, 1H), 4.06 (d, J = 18.3, 0.7H), 4.07 (d, J = 17.4, 0.3H), 3.96 (d, J = 17.4, 0.3H), 3.82 (d, J = 18.3, 0.7H), 3.76 (s, 3H), 3.64 (dd, J = 7.8, 14.3 Hz, 0.7H), 3.43-3.40 (m, 0.6H), 3.32 (dd, J = 6.0, 14.3 Hz, 0.7H) 3.12-3.08 (m, 0.7H), 2.99-2.96 (m, 0.3H), 2.93 (dd, J = 6.0, 16.5 Hz, 0.7H ), 2.90-2.85 (m, 0.3H), 2.67 (dd, J = 3.7, 16.5 Hz, 1H), 2.50 (t, J = 6.4, 2H) 1.89-1.82 (m, 0.3H), 1.76-1.71 (m, 0.7H), 1.60-1.54 (m, 2H), 1.49 (s, 2.7H), 1.43 (s, 6.3H), 1.36-1.32 (m, 3H), 1.26 (s, 18H), 0.88 (t, J = 6.4 Hz, 3H); ¹³ C-NMR (CDCl ₃ , rotamer mixture) 170.7, 170.4, 170.2, 170.1, 155.9, 155.5, 81.5, 81.0, 76. 3, 76.1, 52.2 52.1, 49.3, 49.1, 48.2, 45.6, 45.2, 38.2, 35.1, 34.9, 31.9, 31.2, 31.0, 29 .6, 29.5, 29.5, 29.3, 29.2, 29.1, 28.9, 28.3, 28.1, 20.6, 20.0, 14.1. ; HRMS (FAB) calcd _{(C 27 H 49 NO 6 S} ) 515.3281, Found 515.3262.
(Step 5-5)

  While stirring a solution of a mixture of compounds 5-4a and 5-4b (1.47 g, 2.85 mmol) in toluene (60 mL), ozone gas was bubbled at -78 ° C. After stirring for 30 minutes, the reaction mixture was bubbled with argon gas for 20 minutes to remove excess ozone gas, and then heated to reflux for 3 hours. After cooling, the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (50-60% ethyl acetate / hexane solution), and compound 1-1 was pale yellow oil (which then solidified upon standing). ) (0.880 g, 98%).

[Α] _D ²² + 59.9 ° (c 1.82, CHCl ₃ ); IR (film, cm ⁻¹ ) 2979, 1703, 1459, 1435, 1391, 1368, 1321, 1249, 1215, 1169, 1120, 1107 1045, 1003, 978, 886, 828, 778; ¹ H-NMR ₍ CDCl ₃ , rotamer mixture) 6.86-6.80 (m, 1H), 6.06 (t, J = 9.2 Hz) 1H), 4.52-4.45 (m, 1H), 4.00 (d, J = 17.2 Hz, 0.5H), 3.97 (d, J = 17.2 Hz, 0.5H) 3.93 (d, J = 18.2 Hz, 0.5H), 3.88 (d, J = 18.2 Hz, 0.5H), 3.75 (s, 3H), 3.50-3. 43 (m, 1H), 3.31-3.26 (m, 1H), .27-2.26 (m, 0.5H), 2.62-2.52 (m, 0.5H), 1.49 (s, 4.5H), 1.45 (d, J = 7. ^{2Hz, 3H), 1.43 (s} , 4.5H); 13 C-NMR (CDCl 3, rotamers mixture) 170.0,163.0,162.6,155.2,146.5,145 .6, 121.1, 120.7, 81.1, 80.9, 76.0, 75.4, 51.9, 50.4, 49.6, 49.5, 39.4, 39.2 , 28.0,27.8,19.4,19.4; elemental analysis calculated _{(C 15 H 23 NO 6)} C, 57.50; H, 7.40; N, 4.47, Found C 57.47; H, 7.30; N, 4.38; m. p. (AcOEt-hexane) 93-95 ° C.

Example 6
(Step 6-1)

To a suspension of sodium hydride (60% dispersion in mineral oil, 105 mg, 2.62 mmol) in THF (20 mL) was added ethyl diphenylphosphonoacetate (909 mg, 2.84 mmol) at 0 ° C. After stirring for 10 minutes, a solution of compound 5-1 (881 mg, 2.18 mmol) in THF (5 mL) was added at −78 ° C. ((a) Ando, KJ Org. Chem, 1994, Vol. 62). 1934; (b) Ando, KJ Org. Chem, 1999, 64, 8408). The reaction mixture was allowed to warm to room temperature and stirred for an additional hour, and the reaction mixture was partitioned between saturated aqueous ammonium chloride and ethyl acetate. The separated aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with saturated aqueous NaHCO ₃ solution (twice) and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The Z / E ratio of the crude product was confirmed to be 83:17 from ¹ H-NMR. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane solution) to obtain Compound 6-1 as a colorless oil (823 mg, 80%).

[Α] _D ²¹ −9.8 ° (c 0.455, CHCl ₃ ); IR (film, cm ⁻¹ ) 2955, 2931, 2857, 1757, 1716, 1647, 1462, 1417, 1366, 1298, 1251, 1182, 1085, 1050, 1005, 960, 885, 837, 776, 668; ¹ H-NMR (CDCl ₃ , mixture of rotamers) 6.33 (t, J = 11.0 Hz, 0.4H), 6 .25 (t, J = 11.0 Hz, 0.6H), 5.94-5.90 (m, 1H), 4.19-4.11 (m, 2H), 3.96-3.73 ( m, 3.6H), 3.71 (s, 3H), 3.53 (dd, J = 9.2, 13.8 Hz, 0.4H), 3.36 (dd, J = 5.5, 13 .8Hz, 0.4H), 3.12 (dd, J = 3.6, 13.7 Hz, 0.6 H), 1.58 (s, 1 H), 1.45 (s, 5.4 H), 1.39 (s, 3.6 H), 1.29 (t, J = 6. 9 Hz, 1.8 H), 1.27 (t, J = 6.9 Hz, 1.2 H), 1.09 (d, J = 6.4 Hz, 1.8 H), 1.08 (d, J = 6 .4 Hz, 1.2 H), 0.89 (s, 5.4 H), 0.89 (s, 3.6 H), 0.08 (s, 1.8 H), 0.07 (s, 1.2 H) ), 0.05 (s, 3H); ¹³ C-NMR (CDCl ₃ , mixture of rotamers) 170.8, 170.7, 166.3, 166.1, 155.6, 155.2, 148 .1, 147.6, 122.9, 122.3, 80.3, 79.9, 69.2, 68.7, 59.9, 59.8, 51.9, 51.8, 49.9 49.6, 4 9.1, 47.8, 44.3, 43.7, 28.3, 28.2, 25.9, 25.8, 22.2, 22.1, 18.0, 14.3, 14. 2, -4.0, -4.2, -4.9, -4.9; HRMS (FAB) calcd _{(C 23 H 43 NO 7 Si} ) 473.2809, Found 473.2792.
(Step 6-2)

To a solution of compound 6-1 (207 mg, 0.437 mmol) in acetonitrile (2 mL) was added 35% aqueous HF (0.2 mL, 3 mmol) at room temperature. After stirring at room temperature for 4 hours, the reaction mixture was poured into saturated aqueous NaHCO ₃ and extracted four times with chloroform. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product alcohol.

  A solution of toluene (3 mL) containing the alcohol and tetraisopropoxytitanium (2 drops) was heated to 80 ° C. for 5 minutes. After cooling, the reaction mixture was purified by silica gel column chromatography (50% ethyl acetate / hexane solution) to obtain Compound 1-1 (117 mg, 85%).

[Α] _D ²² + 59.9 ° (c 1.82, CHCl ₃ ); IR (film, cm ⁻¹ ) 2979, 1703, 1459, 1435, 1391, 1368, 1321, 1249, 1215, 1169, 1120, 1107 1045, 1003, 978, 886, 828, 778; ¹ H-NMR ₍ CDCl ₃ , rotamer mixture) 6.86-6.80 (m, 1H), 6.06 (t, J = 9.2 Hz) 1H), 4.52-4.45 (m, 1H), 4.00 (d, J = 17.2 Hz, 0.5H), 3.97 (d, J = 17.2 Hz, 0.5H) 3.93 (d, J = 18.2 Hz, 0.5H), 3.88 (d, J = 18.2 Hz, 0.5H), 3.75 (s, 3H), 3.50-3. 43 (m, 1H), 3.31-3.26 (m, 1H), .27-2.26 (m, 0.5H), 2.62-2.52 (m, 0.5H), 1.49 (s, 4.5H), 1.45 (d, J = 7. ^{2Hz, 3H), 1.43 (s} , 4.5H); 13 C-NMR (CDCl 3, rotamers mixture) 170.0,163.0,162.6,155.2,146.5,145 .6, 121.1, 120.7, 81.1, 80.9, 76.0, 75.4, 51.9, 50.4, 49.6, 49.5, 39.4, 39.2 , 28.0,27.8,19.4,19.4; elemental analysis calculated _{(C 15 H 23 NO 6)} C, 57.50; H, 7.40; N, 4.47, Found C 57.47; H, 7.30; N, 4.38; m. p. (Ethyl acetate-hexane) 93-95 degreeC.

Example 7
(Step 7-1)

  Glycine ethyl ester hydrochloride (3.10 g, 22.2 mmol), compound 3-5 (6.42 g, 14.8 mmol) and sodium cyanoborohydride (2.07 g, 29.6 mmol) in ethanol (130 mL). The mixture was heated to reflux for 4 hours. After allowing to cool to room temperature, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, compound 7-1 (fraction eluted with a 20% ethyl acetate / hexane solution, 3.35 g, 72%) and a colorless oil (colored after standing as a colorless oil). As a solidified compound 3-7 (fraction eluted with 60% ethyl acetate / hexane solution, 2.88 g, 95%) was obtained.

[Α] _D ²⁰ + 12.2 ° (c 1.20, CHCl ₃ ); IR (film, cm ⁻¹ ) 2956, 2929, 2897, 2857, 1742, 1638, 1472, 1420, 1375, 1254, 1192, 1133 , 1065, 1029, 1005, 971, 917, 837, 809, 775, 662; ¹ H-NMR (CDCl ₃ ) 5.77-5.67 (m, 1H), 5.18-5.09 (m, 2H), 4.21-4.14 (m, 2H), 3.92-3.86 (m, 1H), 3.44-3.32 (m, 2H), 2.71-2.66 ( m, 1H), 2.64-2.59 (m, 1H), 2.23-2.15 (m, 1H), 1.67 (brs, 1H), 1.29-1.26 (m) 3H), 1.09-1.06 (m, 3H), 0.88- _{^{.87 (m, 9H), 0.04-0.03}} (m, 6H); 13 C-NMR (CDCl 3) 172.4,137.3,117.9,69.5,60.6,52 .1,51.1,50.3,25.8,21.2,18.0,14.2, -4.3, -5.0; HRMS ( FAB) calcd _{(C 16 H} 34 NO ₃ Si) 316.2308 ([M + H] ⁺ ), found 316.2302.
(Step 7-2)

  Using Compound 7-1 (3.53 g, 11.2 mmol), Compound 7-2 was obtained as a colorless oil by substantially the same procedure as in Example 3, Step 3-6 (3.92 g). 84%).

[Α] _D ²¹ + 17.8 ° (c 0.590, CHCl ₃ ); IR (film, cm ⁻¹ ) 2777, 2957, 2930, 2896, 2858, 1755, 1704, 1463, 1403, 1366, 1298, 1251 1194, 1160, 1096, 1059, 1031, 1005, 959, 917, 892, 837, 809, 775, 662; ¹ H-NMR ₍ CDCl ₃ , mixture of rotamers) 5.82-5.69 (m 1H), 5.15-4.99 (m, 2H), 4.17 (q, J = 6.8 Hz, 2H), 4.01 (d, J = 17.2 Hz, 0.5H), 3 .90-3.81 (m, 2H), 3.75 (d, J = 17.6 Hz, 0.5H), 3.51-3.40 (m, 1H), 3.27 (dd, J = 9.4, 14.2 Hz, .5H), 3.20 (dd, J = 4.6, 14.6 Hz, 0.5H), 2.33-3.31 (m, 0.5H), 2.24-2.22 (m, 0.5H), 1.46 (s, 4.5H), 1.41 (s, 4.5H), 1.29-1.24 (m, 3H), 1.08 (d, J = 6. 8 Hz, 1.5 H), 1.07 (d, J = 6.4 Hz, 1.5 H), 0.88 (s, 4.5 H), 0.87 (s, 4.5 H), 0.05 ( s, 6H); ¹³ C-NMR (CDCl ₃ , mixture of rotamers) 170.2, 170.0, 155.9, 155.4, 136.6, 136.2, 118.2, 118.1 80.1, 79.9, 69.2, 69.1, 60.9, 60.9, 51.5, 51.1, 50.9, 50.7, 50.2, 49.1, 28 .4, 28.2, 5.8, 25.8, 21.7, 21.6, 18.0, 14.3, 14.2, -4.0, -4.0, -4.9, -4.9; HRMS ( FAB) calculated value (C ₂₁ H ₄₂ NO ₅ Si) 416.2833 ([M + H] ⁺ ), found 416.2847.
(Step 7-3)

  Substantially similar to Example 3, Steps 3-7, except that Compound 7-2 (1.21 g, 2.91 mmol) was used instead of HF aqueous solution instead of HF • pyridine (15 drops). To give compound 7-3 as a colorless oil (856 mg, 98%).

[Α] _D ²⁰ + 24.4 ° (c 2.38, CHCl ₃ ); IR (film, cm ⁻¹ ) 3460, 2977, 2932, 1752, 1683, 1465, 1437, 1406, 1368, 1301, 1252, 1191 1170, 1031, 1003, 970, 919, 898, 864, 776, 703, 667; ¹ H-NMR (CDCl ₃ , mixture of rotamers) 5.85-5.70 (m, 1H), 21-5.07 (m, 2H), 4.23-4.17 (m, 2H), 3.95-3.79 (m, 3.8H), 3.51 (dd, J = 7.4) , 14.6 Hz, 0.2 H), 3.19 (dd, J = 7.7, 14.6 Hz, 0.2 H), 2.81 (dd, J = 4.6, 14.6 Hz, 0.8 H) ) 2.32-2.26 (m, 0.2H), 2.19-2.12 (m, 0.8H), 1.49 (s, 1H), 1.43 (s, 9H), 1.29 (t, J = 7.4 Hz, 2.4H), 1.27-1.25 (m, 0.6H), 1.17 (d, J = 5.2 Hz, 0.6H), 1.13 (d, J = 6.4 Hz, 2.4H); ¹³ C-NMR (CDCl ₃ , mixture of rotamers) 169.9, 169.7, 156.5, 155.6, 135.2, 135.0, 118.9, 118.1, 80.9, 80 .6, 66.2, 64.5, 61.0, 60.9, 50.5, 50.3, 50.2, 49.9, 49.5, 49.4, 28.2, 28.0 , 20.9,20.1,14.1,14.0; HRMS (FAB) calcd _{(C 15 H 28 NO 5)} 302.1967 ([M + H] +), Found 302 1962.
(Step 7-4)

  Using compound 7-3 (763 mg, 2.53 mmol), compound 7-4 was obtained as a colorless oil by substantially the same procedure as in Example 3, steps 3-8 (734 mg, 82%). .

[Α] _D ²³ + 20.3 ° (c 0.510, CHCl ₃ ); IR (film, cm ⁻¹ ) 2979, 1751, 1722, 1703, 1636, 1458, 1406, 1367, 1295, 1270, 1248, 1196 , 1164, 1092, 1031, 985, 923, 895, 862, 810, 772; ¹ H-NMR (CDCl ₃ , mixture of rotamers) 6.39 (d, J = 17.6, 0.5H), 6.39 (d, J = 16.8, 0.5H), 6.13 (dd, J = 3.6, 10.0 Hz, 0.5H), 6.08 (dd, J = 3.6, 10.0 Hz, 0.5 H), 5.85-5.70 (m, 2 H), 5.21-5.05 (m, 3 H), 4.19 (q, J = 7.3 Hz, 1 H), 4.17 (q, J = 7.3 Hz, 1H), 3.93 (D, J = 18.4 Hz, 0.5H), 3.89 (d, J = 18.4 Hz, 0.5H), 3.85 (d, J = 18.4 Hz, 0.5H), 3. 75 (d, J = 18.4 Hz, 0.5H), 3.43-3.36 (m, 1H), 3.32-3.21 (m, 1H), 2.58-2.46 (m 1H), 1.46 (s, 4.5H), 1.41 (s, 4.5H), 1.29-1.23 (m, 6H); ¹³ C-NMR (CDCl ₃ , rotamer) 170.1, 169.9, 165.6, 165.5, 155.7, 155.2, 134.9, 134.9, 130.8, 130.6, 128.7, 128.7 119.5, 119.3, 80.4, 80.3, 70.6, 70.4, 61.0, 50.5, 50.0, 49.8, 49.6, 49.1, 48.3, 28.3, 28.2, 18.0, 14.2, 14.1; HRMS (FAB) calculated value (C ₁₈ H ₃₀ NO ₆ ) 356.2703 ([M + H] ⁺ ), actual value 356.2081.
(Step 7-5)

  Hoveyda-Grubbs' second generation catalyst (26 mg, 0.041 mmol) was added to a solution of compound 7-4 (734 mg, 2.07 mmol) in dichloromethane (41 mL) and heated to 85 ° C. in a 200 mL autoclave for 2 days. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (20-35% ethyl acetate / hexane solution) to obtain Compound 7-5 as a pale yellow oil (548 mg, 81%). ).

[Α] _D ²³ + 62.0 ° (c 1.06, CHCl ₃ ); IR (film, cm ⁻¹ ) 2979, 2937, 1744, 1704, 1460, 1426, 1392, 1367, 1319, 1301, 1249, 1194 , 1169, 1120, 1107, 1031, 978, 896, 862, 828, 778; ¹ H-NMR ₍ CDCl ₃ , mixture of rotamers) 6.88-6.80 (m, 1H), 6.06 ( t, J = 8.9 Hz, 1H), 4.54-4.44 (m, 1H), 4.23-4.18 (m, 2H), 4.00 (d, J = 18.3 Hz, 0 .5H), 3.96-3.91 (m, 1H), 3.85 (d, J = 18.3 Hz, 0.5H), 3.51-3.43 (m, 1H), 3.32. -2.66 (m, 1H), 2.71-2.6 (M, 0.5H), 2.61-2.55 (m, 0.5H), 1.49 (s, 4.5H), 1.46-1.43 (m, 7.5H), 1 .31-1.26 (m, 3H); ¹³ C-NMR (CDCl ₃ , mixture of rotamers) 169.7, 163.3, 162.9, 155.5, 155.4, 146.6, 145.7, 121.5, 121.2, 81.5, 81.2, 76.2, 75.7, 61.4, 51.1, 50.2, 50.0, 50.0, 39. 7, 39.7, 28.3, 28.1, 19.7, 19.7; HRMS (FAB) calculated value (C ₁₆ H ₂₆ NO ₆ ) 328.1760 ([M + H] ⁺ ), measured value 328. 1754.
(Step 7-6)

Using compound 7-5 (548 mg, 1.67 mmol), a mixture of compounds 7-6a and 7-6b was obtained as a colorless oil by substantially the same procedure as in Example 1, step 1-1. (485 mg, 89%). It was determined as 7-6a: 7-6b = 94: 6 from ¹ H-NMR measurement of Compound 7-8 described later.

IR (film, cm ⁻¹ ) 2979, 2937, 1746, 1703, 1478, 1456, 1392, 1368, 1251, 1194, 1146, 1097, 1063, 1025, 998, 913, 865, 775; ¹ H-NMR (CDCl ₃ , a mixture of isomers) 4.59-4.51 (m, 0.2H), 4.31-4.06 (m, 3.8H), 3.89-3.84 (m, 0.2H) ), 3.76-3.79 (m, 0.8H), 3.46 (brd, J = 11.0 Hz, 0.5H), 3.35-3.23 (m, 0.5H), 3.08 (brs, 0.2H), 2.87-2.76 (m, 1.6H), 2.59-2.26 (m, 2H), 2.29 (dd, J = 12. 4, 15.2 Hz, 0.2 H), 1.47-1.37 (m, 12 H), 1. ^{3-1.26 (m, 3H); 13} C-NMR (CDCl 3, mixture of isomers) 171.5,171.4,171.10,154.6,154.0,80.9,80. 8, 76.2, 65.2, 64.9, 48.5, 48.1, 42.7, 41.8, 39.9, 38.7, 33.6, 30.3, 28.2, 20.0, 19.7; HRMS (FAB) calculated (C ₁₆ H ₂₅ NO ₆ ) 327.1682, found 327.1679.
(Step 7-7)

  Using compound 7-6 (66.3 mg, 0.203 mmol), compound 7-7 was obtained as a colorless oil by substantially the same procedure as in Example 1, step 1-2 (44.1 mg). 61%).

IR ₍ film, cm ⁻¹ ) 3460, 2976, 1741, 1701, 1398, 1257, 1200, 1173, 1144, 1059, 1030, 976, 914, 864, 771, 735; ¹ H-NMR ₍ CDCl ₃ , rotational isomerism) Body mixture) 4.25-4.15 (m, 2.4H), 4.07 (s, 0.6H), 3.74 (s, 1.8H), 3.73 (s, 1.2H) ), 3.71-3.52 (m, 3H), 3.02-2.88 (m, 2H), 2.73 (dt, J = 7.2, 16.4 Hz, 1H), 2.56 (Br s, 0.4H), 2.46-2.34 (m, 1.6H), 1.46 (s, 3.6H), 1.41 (s, 5.4H), 1.31- 1.26 (m, 3H), 1.20-1.02 (m, 3H); ¹³ C-NMR (CDCl ₃ , Mixtures of rotamers) 173.5, 173.4, 171.8, 171.5, 154.3, 154.0, 80.2, 80.2, 65.8, 65.7, 65.3 65.1, 52.2, 52.1, 48.0, 47.0, 46.4, 40.6, 39.4, 33.6, 33.5, 28.3, 28.2, 22 .6, 22.4, 14.2, 14.1; HRMS (FAB) calculated (C ₁₇ H ₃₀ NO ₇ ) 360.022 ([M + H] ⁺ ), found 360.0236.
(Step 7-8)

  Using compound 7-7 (44.1 mg, 0.123 mmol), compound 7-8 was obtained as a colorless oil by substantially the same procedure as in Example 1, step 1-3 (39.3 mg). 90%).

IR (film, cm ⁻¹ ) 2979, 1741, 1705, 1400, 1369, 1255, 1200, 1171, 1136, 1097, 1030, 912, 864, 771; ¹ H-NMR (CDCl ₃ , mixture of rotamers) 4.24-4.16 (m, 2.4H), 4.13 (d, J = 6.4 Hz, 0.6H), 3.72-3.64 (m, 2H), 3.69 (s) 3H), 3.54-3.46 (m, 1H), 2.98-2.92 (m, 0.4H), 2.87-2.80 (m, 0.6H), 2.65. (Dd, J = 8.4, 17.2 Hz, 0.6H), 2.56-2.46 (m, 1.4H), 2.20 (s, 3H), 1.46 (s, 2.H). 4H), 1.40 (s, 5.4H ), 1.32-1.28 (m, 3H); 13 C-NMR (CDC _3, mixture of rotamers) 207.0,206.5,172.1,171.8,171.7,154.1,153.5,80.5,80.4,64.1,63. 9, 61.4, 61.2, 51.9, 51.8, 51.7, 51.4, 50.4, 47.2, 47.1, 46.5, 42.1, 40.8, 33.3, 32.8, 30.5, 30.4, 28.3, 28.2, 14.2, 14.1; HRMS (FAB) calculated (C ₁₇ H ₂₈ NO ₇ ) 358.1866 ( [M + H] ⁺ ), found 348.1851.

Example 8
(Step 8-1)

  Example 4, Step 4-5 using compound 4-5 (prepared by the method described in Reference Example 2 below, 677 mg, 2.94 mmol) and compound 8-1 (1.21 g, 3.83 mmol) In substantially the same manner as above, Compound 8-2 was obtained as a colorless oil (1.24 g, 80%).

[Α] _D ²³ -13.4 ° (c 1.96, CHCl ₃ ); IR (film, cm ⁻¹ ) 2957, 2912, 2877, 1743, 1547, 1457, 1418, 1371, 1294, 1231, 1161, 1127, 1061, 1005, 964, 939, 852, 773, 741, 653, 854; ¹ H-NMR (CDCl ₃ ) 8.06-8.03 (m, 1H), 7.70-7.64 (m 2H), 7.59-7.57 (m, 1H), 5.66-5.57 (m, 1H), 5.09-5.05 (m, 2H), 4.19 (d, J = 19.2 Hz, 1H), 4.00 (d, J = 19.2 Hz, 1H), 3.93-3.88 (m, 1H), 3.59-3.47 (m, 2H), 2 .36-2.30 (m, 1H), 1.34 (s, 9H), 1 .94 (d, J = 6.4 Hz, 3H), 0.95 (t, J = 7.8 Hz, 9H), 0.58 (q, J = 7.8 Hz, 6H); ¹³ C-NMR (CDCl ₃ ) 167.7, 147.9, 135.5, 133.7, 133.2, 131.5, 130.9, 123.9, 119.0, 82.1, 68.9, 51.0, 50.0,49.5,27.8,21.2,6.9,5.1; HRMS (FAB) calcd _{(C 24 H 41 N 2 O} 7 SiS) 529.2404 ([M + H] +) Measured value 529.2425.
(Step 8-2)

Benzenethiol (0.30 mL, 2.9 mmol) and potassium carbonate (467 mg, 3.37 mmol) were added at 0 ° C. to a solution of compound 8-2 (1.19 g, 2.25 mmol) in DMF (20 mL) at room temperature. Stir for 2 hours. A saturated aqueous NaHCO ₃ solution was added to the reaction mixture, and the mixture was extracted 4 times with ethyl acetate. The combined organic layers were washed with saturated aqueous NaHCO ₃ (twice) and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product amine.

To a solution of the obtained amine and triethylamine (0.63 mL, 4.5 mmol) in acetonitrile (15 mL), di-t-butyl dicarbonate (740 mg, 3.4 mmol) and a catalytic amount of DMAP were added at 0 ° C. for 1 hour. Stir. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted three times with diethyl ether. The combined organic layers were washed with saturated aqueous NaHCO ₃ and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product carbamate.

Camphorsulfonic acid (30 mg, 0.13 mmol) was added to a solution of the obtained carbamate in methanol (50 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Saturated aqueous NaHCO ₃ solution was added to the reaction mixture and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-20% ethyl acetate / hexane solution) to obtain Compound 8-3 as a colorless oil (573 mg, 74%, 3 steps).

[Α] _D ²² + 20.8 ° (c 2.06, CHCl ₃ ); IR (film, cm ⁻¹ ) 3462, 3074, 2978, 2932, 1747, 1682, 1478, 1464, 1436, 1404, 1368, 1327 1251, 1227, 1154, 1037, 1002, 972, 941, 918, 894, 862, 844, 781, 752, 701; ¹ H-NMR (CDCl ₃ , mixture of rotamers) 5.85-5.72 (M, 1H), 5.22-5.06 (m, 2H), 3.94-3.87 (m, 1.8H), 3.79 (d, J = 17.2 Hz, 1H), 3 .72 (d, J = 17.2 Hz, 1 H), 3.52 (dd, J = 8.6, 14.2 Hz, 0.2 H), 3.12 (dd, J = 7.4, 14.6 Hz) 0.2H), 3.7 6 (dd, J = 4.4, 14.8 Hz, 0.8H), 2.25 (br.s, 0.2H), 2.11 (br.s, 0.8H), 1.48 (s , 9H), 1.45 (s, 9H), 1.17 (d, J = 6.4 Hz, 0.6H), 1.13 (d, J = 6.4 Hz, 2.4H); ¹³ C- NMR (CDCl ₃ , main product isomer) 168.8, 156.8, 135.1, 118.2, 81.6, 80.9, 64.5, 51.0, 50.5, 49. 6, 28.2, 28.0, 20.2; HRMS (FAB) calculated (C ₁₇ H ₃₁ NO ₅ ) 329.2202 ([M + H] ⁺ ), found 329.2208.
(Step 8-3)

  Compound 8-5 was obtained as a colorless oil (613 mg, quantitatively) by substantially the same procedure as Example 3, Step 3-8, using Compound 8-4 (525 mg, 1.59 mmol). ).

[Α] _D ²⁴ + 19.5 ° (c 2.04, CHCl ₃ ); IR (film, cm ⁻¹ ) 3077, 2979, 2934, 1746, 1725, 1704, 1638, 1459, 1405, 1367, 1295, 1271 1247, 1226, 1197, 1154, 1092, 1050, 985, 921, 894, 845, 810, 781; ¹ H-NMR (CDCl ₃ , mixture of rotamers) 6.41-6.36 (m, 1H ), 6.14-6.07 (m, 1H), 5.84-5.80 (m, 1H), 5.78-5.68 (m, 1H), 5.20-5.01 (m) 3H), 3.83 (d, J = 17.6 Hz, 0.5H), 3.76 (d, J = 17.6 Hz, 0.5H), 3.73 (d, J = 18.4 Hz, 0.5H), 3.64 (d, J = 18.4Hz, 0.5H), 3.41-3.34 (m, 1H), 3.30-3.18 (m, 1H), 2.58-2.45 (m, 1H), 1 .46 (s, 9H), 1.48 (s, 4.5H), 1.42 (s, 4.5H), 1.23 (d, J = 6.4 Hz, 3.0H); ¹³ C- NMR (CDCl ₃ , mixture of rotamers) 169.0, 165.6, 165.5, 155.6, 155.4, 135.0, 135.0, 130.6, 130.4, 128.8 128.7, 119.4, 119.2, 81.5, 81.4, 80.2, 80.0, 70.6, 70.4, 51.1, 50.2, 50.0, 49 .6,49.0,48.2,28.3,28.2,28.0,18.0,17.9; HRMS (FAB) calcd _{(C 20} H 34 _NO 6) 3844.2386 ([M + H] ⁺ ), found 3844.2389.
(Step 8-4)

  Using compound 8-5 (450 mg, 1.17 mmol) in substantially the same manner as Example 7, step 7-5, compound 8-6 was a colorless oil (which then solidified upon standing). ) (370 mg, 89%).

[Α] _D ²² + 72.8 ° (c 1.26, CHCl ₃ ); IR (film, cm ⁻¹ ) 2979, 2935, 1740, 1704, 1458, 1426, 1392, 1367, 1326, 1249, 1155, 1120 1106, 1045, 978, 944, 896, 829, 776; ¹ H-NMR (CDCl ₃ , mixture of rotamers) 6.88-6.79 (m, 1H), 6.08-6.03 ( m, 1H), 4.51-4.43 (m, 1H), 3.93-3.72 (m, 2H), 3.49-4.40 (m, 1H), 3.26 (dd, J = 6.4, 13.6 Hz, 1H), 2.69-2.64 (m, 0.6H), 2.61-2.54 (m, 0.4H), 1.49-1.45. ^{(m, 21H); 13 C} -NMR (CDCl 3, rotameric 168.7, 163.3, 155.7, 146.7, 145.9, 121.4, 121.1, 82.0, 82.0, 81.3, 81.0, 76.3 75.8, 51.8, 50.9, 50.2, 49.9, 39.7, 28.3, 28.2, 28.1, 19.7, 19.7; elemental analysis calculated value ( _{C 18 H 29 NO 6) C} , 60.83; H, 8.22; N, 3.94, Found C, 60.75; H, 8.07; N, 3.86; m. p. (Hexane) 107-109 ° C.
(Step 8-5)

Using a compound 8-6 (50.8 mg, 0.162 mmol), a mixture of compounds 8-7a and 8-7b as a colorless oil in substantially the same manner as in Example 1, Step 1-1. Obtained (48.7 mg, 96%). It was determined as 7-6a: 7-6b = 94: 6 from ¹ H-NMR measurement of Compound 8-8 described later.

IR (film, cm ⁻¹ ) 2979, 2935, 1742, 1703, 1479, 1457, 1393, 1368, 1293, 1253, 1158, 1097, 1062, 998, 950, 913, 842, 774, 738; ¹ H-NMR (C ₆ D ₆ , mixture of rotamers) 4.43-4.19 (m, 2H), 4.0-3.95 (m, 1H), 3.74-3.69 (m, 1H) 3.45 (d, J = 11.2 Hz, 0.5H), 3.34-3.26 (m, 0.5H), 3.08-3.05 (m, 0.2H), 2. 86-2.35 (m, 3.8H), 1.50-1.36 (m, 21H); ¹³ C-NMR (CDCl ₃ , mixture of rotamers) 171.8, 171.5, 170. 5, 154.2, 82.8, 82.2, 80.7, 80 6, 76.3, 65.8, 62.7, 48.6, 48.0, 42.8, 42.6, 41.8, 40.0, 38.8, 33.9, 33.8, 30.3, 28.2, 28.1, 28.0, 19.8, 19.6; HRMS (FAB) calculated (C ₁₈ H ₃₀ NO ₆ ) 356.2073, found 356.2078.
(Step 8-6)

  Triethylamine (1 drop) was added to a solution of compound 8-7 (48.7 mg, 0.155 mmol) in methanol (4.8 mL), and the mixture was stirred at room temperature for 12 hours. Acetic acid (1 drop) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel (50% ethyl acetate / hexane solution) to give an alcohol (41.5 mg).

  To a solution of the obtained alcohol (41.5 mg) in dichloromethane (1 mL) was added 4-methylmorpholine N-oxide (36 mg, 0.30 mmol) and tetrapropylammonium pearlatenate (5.5 mg, 0.016 mmol) at 0 ° C. And stirred at the same temperature for 1 hour. The reaction mixture was purified directly by preparative TLC on silica gel (50% ethyl acetate / hexane solution) to give compound 8-8 as a colorless oil (37.8 mg, 63%, 2 steps).

IR (film, cm ⁻¹ ) 2979, 1739, 1705, 1479, 1456, 1437, 1400, 1368, 1324, 1255, 1166, 1135, 1035, 966, 911, 865, 843, 771; ¹ H-NMR (CDCl ₃ , mixture of rotamers); 4.08 (d, J = 4.0 Hz, 0.4 H), 4.01 (d, J = 5.6 Hz, 0.6 H), 3.75-3.60 (M, 2H), 3.69 (s, 3H), 3.51-3.42 (m, 1H), 2.95-2.89 (m, 0.4H), 2.83-2.77 (M, 0.6H), 2.65 (dd, J = 8.2, 16.6 Hz, 0.6H), 2.55-2.45 (m, 1.4H), 2.20 (s, 3H), 1.49 (s, 9H), 1.46 (s, 2.4H), 1.43 (s, 5 ^{4H); 13 C-NMR (} CDCl 3, mixture of rotamers) 206.9,206.6,172.1,171.9,171.1,170.9,154.1,153.8,81 .7, 81.6, 80.4, 80.2, 64.9, 64.6, 51.9, 51.5, 50.4, 47.0, 46.5, 42.3, 40.9 33.5, 33.1, 30.5, 30.4, 28.4, 28.3, 28.0, 28.0; HRMS (FAB) calculated (C ₁₉ H ₃₁ NO ₇ ) 385.2100 Actual value 385.2095.

Example 9
(Step 9-1)

  While stirring, a solution of compound 7-2 (1.21 g, 2.91 mmol) in dichloromethane (30 mL) and methanol (10 mL) was bubbled with ozone gas at −78 ° C. and stirred for 10 minutes. While stirring the reaction mixture, argon gas was bubbled for 15 minutes to remove excess ozone gas. Dimethyl sulfide (2.1 mL, 29 mmol) was added to the reaction mixture and allowed to warm to room temperature. After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography using a short column of silica gel to obtain a crude product aldehyde.

  To a suspension of sodium hydride (60% dispersion in mineral oil, 88.3 mg, 2.2 mmol) in THF (10 mL) was added triethyl phosphonoacetate (571 mg, 2.55 mmol) at 0 ° C. and stirred for 30 minutes. did. A solution of the resulting aldehyde in THF (3 mL) was added to the reaction mixture and stirred at 0 ° C. for 3 hours. The reaction mixture was partitioned between saturated aqueous ammonium chloride and dichloromethane, and the separated aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (10-20% ethyl acetate / hexane solution) to obtain Compound 9-1 as a colorless oil (830 mg, 58%, 2 steps).

[Α] _D ²² + 44.0 ° (c 1.73, CHCl ₃ ); IR (film, cm ⁻¹ ) 2978, 2957, 2931, 2899, 2858, 1754, 1708, 1655, 1464, 1425, 1393, 1367 , 1252, 1198, 1164, 1092, 1053, 1035, 990, 959, 896, 838, 810, 776, 667; ¹ H-NMR (CDCl ₃ , mixture of rotamers) 6.96-6.89 (m 1H), 5.84 (dd, J = 8.2, 15.6 Hz, 1H), 4.21-4.16 (m, 4H), 4.00-3.64 (m, 3.6H) 3.53 (dd, J = 4.2, 14.2 Hz, 0.4 H), 3.27 (dd, J = 9.7, 14.2 Hz, 0.4 H), 3.19 (dd, J = 3.7, 14.7 Hz, 0.6H), 2.56-2.51 (m, 0.4H), 2.44-2.38 (m, 0.6H), 1.45 (s, 5.4H), 1.41 ( s, 3.6H), 1.31-1.24 (m, 6H), 1.10 (d, J = 6.4 Hz, 3H), 0.89 (s, 5.4H), 0.88 ( s, 3.6H), 0.05 (s, 6H); ¹³ C-NMR (CDCl ₃ , mixture of rotamers) 169.9, 169.8, 166.1, 166.0, 155.5, 155.3, 147.0, 146.9, 124.4, 124.3, 80.5, 80.3, 69.0, 68.9, 61.0, 61.1, 60.2, 50. 8, 50.8, 49.9, 49.9, 49.0, 28.2, 28.2, 25.8, 25.8, 22.0, 21.9, 18.0, 18.0, 14.2, 14. 1, -4.1, -4.9, -5.0; HRMS (FAB) calcd _{(C 24 H 45 NO 7 Si} ) 487.2965, Found 487.2969.
(Step 9-2)

An aqueous HF solution (35%, 0.6 mL, 11 mmol) was added to a solution of compound 9-1 (780 mg, 1.6 mmol) in acetonitrile (5 mL) at 0 ° C., and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into saturated aqueous NaHCO ₃ and extracted four times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20-25% ethyl acetate / hexane solution) to give compound 9-2 as a colorless oil (395 mg, 66%).

[Α] _D ²¹ + 43.1 ° (c 1.48, CHCl ₃ ); IR (film, cm ⁻¹ ) 3461, 2979, 1750, 1716, 1466, 1406, 1368, 1251, 1195, 1167, 1033, 990 , 900, 862, 775; ¹ H-NMR ₍ CDCl ₃ , mixture of rotamers) 6.95 (dd, J = 10.0, 15.6 Hz, 0.8H), 6.91-6.88 ( m, 0.2H), 5.87 (d, J = 16.5 Hz, 1H), 4.19 (q, J = 7.3 Hz, 4H), 4.03-3.91 (m, 3.0H) ), 3.77 (d, J = 17.4 Hz, 0.8H), 3.52 (dd, J = 7.4, 14.7 Hz, 0.2H), 3.31 (dd, J = 7. 4, 14.6 Hz, 0.2 H), 2.78 (dd, J = 5.1, 15. Hz, 0.8H), 2.49-1.43 (m, 0.2H), 2.36-2.30 (m, 0.8H), 2.02 (brs, 0.2H), 1 .75 (br s, 0.8 H), 1.49 (s, 9 H), 1.29 (t, J = 6.4 Hz, 6.0 H), 1.18 (d, J = 6.4 Hz, 0 .6H), 1.14 (d, J = 6.4 Hz, 2.4H); ¹³ C-NMR (CDCl ₃ , isomer of main product) 169.7, 165.9, 156.6, 145. 1, 124.8, 81.5, 64.5, 61.3, 60.4, 50.5, 49.9, 48.2, 28.1, 20.4, 14.2; HRMS (FAB) Calculated value (C ₁₈ H ₃₂ NO ₇ ) 374.2179 ([M + H] ⁺ ), measured value 374.2176.
(Step 9-3)

  A mixture of compound 9-2 (375 mg, 1.00 mmol), 1-dodecanethiol (0.72 mL, 3.00 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (6 drops). Stir at 80 ° C. for 1 hour. After cooling, the reaction mixture was purified by silica gel column chromatography (30-40% ethyl acetate / hexane solution) to give compounds 9-3a and 9-3b (393 mg, 69%).

Compound 9-3a
[Α] _D ²² + 67.9 ° (c 0.730, CHCl ₃ ); IR (film, cm ⁻¹ ) 2926, 2854, 1746, 1705, 1459, 1436, 1393, 1367, 1249, 1196, 1170, 1092 1029, 968, 944, 894, 867, 775, 722; ¹ H-NMR (CDCl ₃ , mixture of rotamers) 4.50-4.39 (m, 1H), 4.23-4.15 ( m, 2.5H), 4.06 (d, J = 17.6 Hz, 0.5H), 3.98 (d, J = 17.2 Hz, 0.5H), 3.97 (d, J = 17 .6 Hz, 0.5H), 3.69-3.62 (m, 1H), 3.37-3.35 (m, 1H), 3.18-3.11 (m, 1H), 2.92 -2.85 (m, 1H), 2.82-2.73 (m, 1H ) 2.63-2.47 (m, 2H), 2.41-2.36 (m, 0.5H), 2.26-2.22 (m, 0.5H), 1.62-1 .55 (m, 2H), 1.49 (s, 4.5H), 1.43 (s, 4.5H), 1.38-1.26 (m, 24H), 0.88 (t, J = 6.4 Hz, 3.0 H); ¹³ C-NMR (CDCl ₃ , mixture of rotamers) 170.1, 169.9, 168.9, 168.6, 155.8, 155.5, 81. 3, 80.9, 76.5, 76.0, 61.3, 61.2, 51.8, 50.8, 48.7, 47.7, 43.8, 43.2, 39.1, 38.4, 37.4, 37.0, 31.1, 29.6, 29.6, 29.5, 29.3, 29.2, 29.0, 28.4, 28.2, 22. 7, 20.8, 20. 7, 14.3, 14.2, 14.1; HRMS (FAB) calculated (C ₂₈ H ₅₂ NO ₆ S) 530.3515 ([M + H] ⁺ ), found 530.3516.

Compound 9-3b
[Α] _D ²² −12.9 ° (c 0.780, CHCl ₃ ); IR (film, cm ⁻¹ ) 2926, 2854, 1752, 1704, 1463, 1391, 1367, 1249, 1204, 1171, 1096, 1056, 1030, 970, 893, 868, 773; ¹ H-NMR (CDCl ₃ , mixture of rotamers) 4.22-4.21 (m, 3H), 4.04 (d, J = 18.3) 1.0H), 3.94 (d, J = 17.4, 0.3H), 3.80 (d, J = 17.4, 0.7H), 3.64 (dd, J = 7. 8, 14.6 Hz, 0.7 H), 3.43-3.39 (m, 0.6 H), 3.33 (dd, J = 5.5, 14.6 Hz, 0.7 H), 3.12 -3.08 (m, 0.7H), 2.99-2.85 (m, 1.3H), 2. 67 (dd, J = 3.3, 16.1 Hz, 1H), 2.50 (t, J = 6.4, 2H), 1.90-1.82 (m, 0.3H), 1.76 -1.74 (m, 0.7H), 1.59-1.51 (m, 2H), 1.49 (s, 2.7H), 1.43 (s, 6.3H), 1.35 −1.26 (m, 24H), 0.88 (t, J = 6.0 Hz, 3H); ¹³ C-NMR (CDCl ₃ , mixture of rotamers) 170.8, 170.4, 169.8 169.6, 156.0, 155.6, 81.5, 81.0, 76.4, 76.2, 61.3, 61.2, 49.5, 49.4, 48.3, 45 .6, 45.3, 38.2, 35.2, 35.0, 31.9, 31.2, 31.1, 29.6, 29.6, 29.5, 29.3, 29.2 29.2, 29. 1, 29.0, 28.4, 28.3, 28.1, 22.7, 20.7, 20.1, 14.3, 14.1; HRMS (FAB) calculated value (C ₂₈ H ₅₁ NO ₆ S) 539.3437, found 539.3428.
(Step 9-4)

  A solution of compounds 9-3a and 9-3b (49.2 mg, 0.093 mmol) in toluene (1 mL) was bubbled with ozone gas at −78 ° C., stirred for 5 minutes, and then purged with argon to remove excess ozone gas. The mixture was stirred for 20 minutes while bubbling gas. The reaction mixture was heated to reflux for 2 hours, cooled and concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel (50% ethyl acetate / hexane solution) to give compound 7-5 as a pale yellow oil (27.2 mg, 89%).

[Α] _D ²³ + 62.0 ° (c 1.06, CHCl ₃ ); IR (film, cm ⁻¹ ) 2979, 2937, 1744, 1704, 1460, 1426, 1392, 1367, 1319, 1301, 1249, 1194 , 1169, 1120, 1107, 1031, 978, 896, 862, 828, 778; ¹ H-NMR (CDCl ₃ , mixture of rotamers) 6.88-6.80 (m, 1H), 6.06 ( t, J = 8.9 Hz, 1H), 4.54-4.44 (m, 1H), 4.23-4.18 (m, 2H), 4.00 (d, J = 18.3 Hz, 0 .5H), 3.96-3.91 (m, 1H), 3.85 (d, J = 18.3 Hz, 0.5H), 3.51-3.43 (m, 1H), 3.32. -2.66 (m, 1H), 2.71-2.64 (M, 0.5H), 2.61-2.55 (m, 0.5H), 1.49 (s, 4.5H), 1.46-1.43 (m, 7.5H), 1 .31-1.26 (m, 3H); ¹³ C-NMR (CDCl ₃ , mixture of rotamers) 169.7, 163.3, 162.9, 155.5, 155.4, 146.6, 145.7, 121.5, 121.2, 81.5, 81.2, 76.2, 75.7, 61.4, 51.1, 50.2, 50.0, 50.0, 39. 7, 39.7, 28.3, 28.1, 19.7, 19.7; HRMS (FAB) calculated value (C ₁₆ H ₂₆ NO ₆ ) 328.1760 ([M + H] ⁺ ), measured value 328. 1754.

Example 10
(Step 10-1)

  Using compound 2-4 (640 mg, 1.33 mmol) and compound 10-1 (prepared by the method described in Reference Example 3 below, 767 mg, 2.66 mmol), substantially the same as Example 2, Steps 2-5 In a similar manner, compound 10-2 was obtained as a colorless oil (995 mg, 96%).

[Α] _D ²³ + 8.0 ° (c 1.23, CHCl ₃ ); IR (film, cm ⁻¹ ) 3384, 2955, 2931, 2857, 1726, 1547, 1456, 1370, 1255, 1213, 1165, 1127 , 1065, 936, 915, 838, 777, 740, 698, 585; ¹ H-NMR (CDCl ₃ ) 8.02-8.00 (m, 1H), 7.69-7.60 (m, 2H) 7.57-7.54 (m, 1H), 7.37-7.29 (m, 5H), 5.88 (brs, 1H), 5.12 (d, J = 12.0 Hz, 1H ), 5.08 (d, J = 12.0 Hz, 1H), 4.35 (d, J = 19.2 Hz, 1H), 4.20-3.93 (m, 5H), 3.72 (dd) , J = 7.4, 14.4 Hz, 1H), 3.48 (dd J = 5.6, 14.4 Hz, 1H), 2.67-2.55 (m, 2H), 2.07 (br s, 1H), 1.43 (s, 9H), 1.16-1 .13 (m, 6H), 0.85 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); ¹³ C-NMR (CDCl ₃ ) 170.5, 168.4 156.0, 148.0, 136.6, 133.6, 132.6, 131.6, 130.8, 128.4, 127.9, 127.9, 124.0, 81.0, 69 .1, 66.5, 61.3, 48.2, 47.7, 46.5, 45.3, 39.4, 28.0, 25.8, 20.3, 17.9, 13.9 , -4.3, -5.0; HRMS (FAB ) calcd _{(C 35 H 54 N 3 O} 11 SiS) 752.3249 ([+ H] +), Found 752 3237.
(Step 10-2)

  Using compound 10-2 (486 mg, 0.646 mmol), compound 10-3 was obtained as a colorless oil by substantially the same procedure as in Example 2, step 2-6 (357 mg, 98%). .

[Α] _D ²³ + 7.1 ° (c 1.90, CHCl ₃ ); IR (film, cm ⁻¹ ) 3328, 3092, 2984, 1741, 1545, 1455, 1373, 1245, 1167, 1126, 1102, 1026 913, 853, 777, 736, 699, 651, 586; ¹ H-NMR (CDCl ₃ ) 7.96 (d, J = 8.4 Hz, 1H), 7.73-7.64 (m, 2H) 7.59 (d, J = 9.2 Hz, 1H), 7.37-7.31 (m, 5H), 5.40 (d, J = 7.2 Hz, 1H), 5.07 (s, 2H), 4.25-4.14 (m, 3H), 4.05-4.00 (m, 3H), 3.64-3.52 (m, 2H), 2.81 (dd, J = 6.4, 16.4 Hz, 1H), 2.63 (dd, J = 4.8, 16.4) Hz, 1H), 2.14 (brs, 1H), 1.43 (d, J = 6.4 Hz, 3H), 1.15 (t, J = 6.4 Hz, 3H); ¹³ C-NMR ( CDCl ₃ ) 170.3, 168.2, 155.5, 148.0, 136.0, 134.0, 132.3, 131.7, 130.9, 128.5, 128.2, 128.1 , 124.2, 76.0, 66.9, 61.7, 49.0, 48.3, 47.6, 43.7, 35.3, 20.2, 13.9; HRMS (FAB) calculation value _{(C 25 H 30 N 3 O} 10 S) 564.1651 ([M + H] +), Found 564.1663.
(Step 10-3)

  Using compound 10-3 (163 mg, 0.289 mmol), compound 10-4 was obtained as a colorless oil by substantially the same procedure as in Example 2, step 2-7 (118 mg, 85%). .

[Α] _D ²² + 11.3 ° (c 0.850, CHCl ₃ ); IR (film, cm ⁻¹ ) 3329, 2979, 2937, 1742, 1704, 1531, 1457, 1368, 1248, 1200, 1153, 1068 ¹ H-NMR ₍ CDCl ₃ , mixture of rotamers) 7.38-7.30 (m, 5H), 5.54 (br s, 1H), 1027, 971, 913, 894, 863, 739, 699; ), 5.08 (s, 2H), 4.19 (q, J = 7.0 Hz, 2H), 4.15-3.96 (m, 2H), 3.84 (br s, 2H), 3 .54-3.27 (m, 2H), 2.91-2.79 (m, 1H), 2.67-2.62 (m, 1H), 1.94 (br s, 1H), 1. 46-1.44 (m, 3H), 1.39 (s, 9H), ^{.27 (t, J = 7.0Hz,} 3H); 13 C-NMR (CDCl 3, mixture of rotamers) 170.5,170.0,155.8,155.6,136.2,128. 5, 128.2, 128.1, 81.7, 81.2, 76.5, 75.9, 66.8, 61.4, 50.9, 50.2, 49.6, 49.0, 48.0, 47.8, 45.6, 36.0, 35.8, 28.3, 28.1, 20.4, 20.1, 14.2, 14.1; calculated HRMS (FAB) _{(C 24 H 35 N 2 O} 8) 479.2393 ([M + H] +), Found 465.2396.
(Step 10-4)

  Using Compound 10-4 (208 mg, 0.435 mol), Compound 7-5 was obtained as a pale yellow oil by substantially the same procedure as in Example 2, Step 2-8 (99.6 mg, 70%).

[Α] _D ²³ + 62.0 ° (c 1.06, CHCl ₃ ); IR (film, cm ⁻¹ ) 2979, 2937, 1744, 1704, 1460, 1426, 1392, 1367, 1319, 1301, 1249, 1194 , 1169, 1120, 1107, 1031, 978, 896, 862, 828, 778; ¹ H-NMR (CDCl ₃ , mixture of rotamers) 6.88-6.80 (m, 1H), 6.06 ( t, J = 8.9 Hz, 1H), 4.54-4.44 (m, 1H), 4.23-4.18 (m, 2H), 4.00 (d, J = 18.3 Hz, 0 .5H), 3.96-3.91 (m, 1H), 3.85 (d, J = 18.3 Hz, 0.5H), 3.51-3.43 (m, 1H), 3.32. -2.66 (m, 1H), 2.71-2.64 (M, 0.5H), 2.61-2.55 (m, 0.5H), 1.49 (s, 4.5H), 1.46-1.43 (m, 7.5H), 1 .31-1.26 (m, 3H); ¹³ C-NMR (CDCl ₃ , mixture of rotamers) 169.7, 163.3, 162.9, 155.5, 155.4, 146.6, 145.7, 121.5, 121.2, 81.5, 81.2, 76.2, 75.7, 61.4, 51.1, 50.2, 50.0, 50.0, 39. 7, 39.7, 28.3, 28.1, 19.7, 19.7; HRMS (FAB) calculated value (C ₁₆ H ₂₆ NO ₆ ) 328.1760 ([M + H] ⁺ ), measured value 328. 1754.

Example 11
(Step 11-1)

  To a solution of compound 2-8 (87.4 mg, 0.188 mmol) in DMF (1 mL) were added di-t-butyl dicarbonate and DMAP at room temperature, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted three times with diethyl ether. The combined organic layers were washed with saturated aqueous ammonium chloride and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50-60% ethyl acetate / hexane solution) to give compound 11-1 as a colorless liquid (88.7 mg, 83%).

[Α] _D ²⁴ + 22.7 ° (c 1.31, CHCl ₃ ); IR (film, cm ⁻¹ ) 2979, 1749, 1701, 1458, 1394, 1369, 1338, 1294, 1244, 1217, 1149, 968 , 887, 850, 771, 700, 586; ¹ H-NMR (CDCl ₃ , rotamer mixture) 7.41-7.33 (m, 5H), 5.28-5.23 (m, 1H), 5.16-5.10 (m, 1H), 4.61-4.51 (m, 1H), 4.20-4.07 (m, 1H), 4.03 (d, J = 7.4 Hz) 0.4H), 3.77-3.58 (m, 2.0H), 3.71 (s, 3H), 3.52 (dd, J = 6.4, 14.6 Hz, 0.6H) 3.22 (dd, J = 5.5, 14.6 Hz, 0.6H), 2.97 (d d, J = 7.8, 14.3 Hz, 0.4 H), 2.92-2.85 (m, 1.4 H), 2.75 (dd, J = 5.1, 17.0 Hz, 0. 6H), 2.67-2.59 (m, 0.4H), 2.44-2.36 (m, 0.6H), 1.45 (s, 3.6H), 1.43-1. 41 (m, 8.4H), 1.39 (s, 5.4H), 1.36 (s, 3.6H); 13 C-NMR (CDCl 3, rotamers mixture) 170.4,170. 2, 155.7, 155.6, 153.8, 152.6, 152.2, 134.8, 134.7, 129.2, 128.9, 128.8, 128.7, 128.6, 84.5, 84.4, 81.4, 80.9, 76.9, 76.6, 69.2, 69.0, 53.0, 52.4, 52.0, 52.0, 49. 6. 9.6, 47.9, 41.5, 41.1, 35.5, 35.4, 28.3, 28.1, 27.8, 27.7, 19.9, 19.4; HRMS ( FAB) calcd _{(C 28 H 41 N 2 O} 10) 565.2761 ([M + H] +); Found 565.2774.
(Step 11-2)

  To a solution of compound 11-1 (18.6 mg, 0.0329 mmol) in DMF (0.5 mL) was added LHMDS (THF solution, 1.0 M, 82 μL, 0.082 mmol) at −60 ° C. After stirring for minutes, acetic acid (1 drop) was added. After concentration of the reaction mixture under reduced pressure, the residue was diluted with ethyl acetate, filtered through celite, and concentrated. The residue was purified by preparative TLC on silica gel to give a mixture of compounds 1-2a and 1-2b (9.5 mg, 92%).

IR (film, cm ⁻¹ ) 2979, 1748, 1702, 1479, 1436, 1394, 1368, 1253, 1203, 1178, 1146, 1098, 1062, 999, 896, 859, 775; ¹ H-NMR (C ₆ D ₆ , rotamer mixture) 4.03 (s, 0.4H), 3.77 (s, 0.6H), 3.49-3.42 (m, 1H), 3.29 (s, 1. 8H), 3.27 (s, 1.2H), 3.24-3.07 (m, 1H), 2.91 (d, J = 11.0 Hz, 1H), 2.28 (dd, J = 14.7, 6.4 Hz, 1H), 2.05-1.95 (m, 1H), 1.75-1.64 (m, 1H), 1,45 (s, 3.6H), 1. 42 (s, 5.4H), 1.39-1.35 (m, 1H), 0.74-0.71 (m, ^{H); 13 C-NMR (} CDCl 3, rotamers mixture) 171.9,171.4,171.0,154.6,153.9,81.0,76.2,65.2,64. 9, 52.4, 52.1, 48.5, 48.1, 42.7, 41.8, 39.8, 38.7, 33.5, 28.2, 20.0, 19.7; HRMS (FAB) calcd _{(C 15 H 23 NO 6)} 313.1525, Found 313.1524.

Reference example 2

  Using glycine t-butyl ester hydrochloride (5.00 g, 29.8 mmol), compound 8-1 was obtained as a colorless solid by substantially the same procedure as in Example 2, step 2-4 (8 .91 g, 94%).

IR (film, cm ⁻¹ ) 3342, 3099, 2981, 2936, 1739, 1594, 1542, 1442, 1417, 1395, 1362, 1303, 1250, 1161, 1125, 1059, 1003, 942, 916, 854, 837, 784, 741, 709, 656, 587; ¹ H-NMR (CDCl ₃ ) 8.01-8.08 (m, 1H), 7.94-7.93 (m, 1H), 7.76-7. 74 (m, 2H), 6.05 (br s, 1H), 3.90 (d, J = 4.8 Hz, 2H), 1.32 (s, 9H); ¹³ C-NMR (CDCl ₃ ) 167 .4,133.6,132.8,130.5,125.6,82.9,45.5,27.7; analysis calculated _{(C 12 H 16 N 2 O} 6 S) C, 45. 56; H 5.10; N, 8.86, Found C, 45.79; H, 5.15; N, 8.87; m. p. (Hexane) 98-100 ° C.

Reference example 3

  Using glycine ethyl ester hydrochloride (1.39 g, 9.96 mmol), compound 10-1 was obtained as a colorless solid by substantially the same procedure as in Example 2, step 2-4 (2.30 g). 88%).

IR (film, cm ⁻¹ ) 3342, 3101, 2986, 1744, 1541, 1443, 1418, 1371, 1353, 1301, 1214, 1168, 1125, 1024, 854, 785, 741, 702, 656, 588; ¹ H _{-NMR (CDCl 3) 8.11-8.09 (m} , 1H), 7.95-7.93 (m, 1H), 7.77-7.73 (m, 2H), 6.06 (br s, 1H), 4.06 (q, J = 6.4 Hz, 2H), 4.01 (d, J = 5.6 Hz, 2H), 1.16 (t, J = 6.4 Hz, 3H); ¹³ C-NMR (CDCl ₃ ) 168.5, 133.9, 133.7, 132.9, 130.6, 125.7, 61.9, 44.9, 13.9; elemental analysis calculated value (C _{10 H 12 N 2 O 6 S} ) C, 4 .66; H, 4.20; N, 9.72, Found C, 41.78; H, 4.19; N, 9.72; m. p. (AcOEt-hexane) 88-100 degreeC.

Reference example 4
Compound 12-1 used as a starting material in Reference Example 5 described later was prepared by the following method with reference to the preparation method described in Tetrahedron 1999, Vol. 55, Item 3337.

  To a solution of L-phenylalanine (40.0 g, 380 mmol) in methanol (193 mL) was added thionyl chloride (19.5 mL, 267 mmol) at −10 ° C., and then heated to reflux for 2 hours. After concentration under reduced pressure, the crude product was purified by recrystallization from a mixture of methanol and diethyl ether to give compound 12-1 as a colorless solid (51.9 g, 99%).

IR (film, cm ⁻¹ ) 3190, 2930, 2856, 1761, 1372, 1253, 1054, 964, 829, 777; ¹ H-NMR (D ₂ O) 7.30-7.24 (m, 3H), 7.15-7.13 (m, 2H), 4.63 (br s, 3H), 4.29-4.26 (m, 1H), 3.69 (s, 3H), 2.18 (dd , J = 14.4, 5.8 Hz, 1H), 3.08 (dd, J = 14.4, 7.4 Hz, 1H); elemental analysis calculated (C ₁₀ H ₁₄ ClNO ₂ ) C, 55.69 H, 6.54; N, 6.49, found C, 55.52; H, 6.44; N, 6.36.

Reference Example 5
Compound 12-2 used as a starting material in Reference Example 6 described later was prepared by the following method with reference to the preparation method described in Tetrahedron 1999, 55, 3337.

  To a solution of methylmagnesium bromide (3.0 mol / L, diethyl ether solution, 165 mL, 495 mmol) in diethyl ether (500 mL) was added little by little at 0 ° C. over 30 minutes, and then heated to reflux for 6 hours. After cooling, a saturated aqueous ammonium chloride solution and water were added dropwise with vigorous stirring of the reaction mixture, and the resulting suspension was filtered through celite. After separation of the organic layer, the aqueous layer was made alkaline with aqueous ammonia and extracted three times with diethyl ether. The combined organic layers were dried over potassium carbonate, filtered and concentrated under reduced pressure to give (3S) -3-amino-2-methyl-4-phenylbutan-2-ol as a pale yellow oil (12 .3g).

  Trichloroacetyl chloride (8.4 mL, 75 mmol) was added to a solution of the crude product (3S) -3-amino-2-methyl-4-phenylbutan-2-ol (12.3 g) in pyridine (123 mL). Was added at 0 ° C., then the temperature was gradually raised to room temperature and stirred for 12 hours. The reaction with addition of brine was quenched and extracted four times with chloroform. The combined organic layers were washed with 5% hydrochloric acid and water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20-30% ethyl acetate / hexane solution) to give compound 12-2 (69.3 g, solidified by standing) in two steps. 75%).

[Α] _D ²² -29.4 ° (c 0.770, CHCl ₃ ); IR (film, cm ⁻¹ ) 3414, 2979, 1699, 1520, 1200, 1456, 1374, 1281, 1248, 1200, 1146, 1083, 1034, 951, 879, 821, 757, 724, 699, 678; ¹ H-NMR ₍ CDCl ₃ ) 7.29-7.19 (m, 5H), 6.78 (br s, 1H), 4 .12-4.06 (m, 1H), 3.20 (dd, J = 14, 3.6 Hz, 1H), 2.75 (dd, J = 14.0, 11.2 Hz, 1H), 1. 84 (s, 1 H), 1.41 (s, 3 H), 1.32 (s, 3 H); ¹³ C-NMR (CDCl ₃ ) 161.7, 137.4, 129.1, 128.6, 126 .7, 92.7, 72.9, 0.2,35.5,27.8,27.3; Analysis Calculated _{(C 13 H 16 Cl 3 NO} 2) C, 48.10; H, 4.97; N, 4.31, Found C, 47.86; H, 4.92; N, 4.21; p. (Diethyl ether-hexane) 92-93 ° C.

Reference Example 6
Compound 3-1 used as a starting material in Step 3-1 of Example 3 was prepared by the following method with reference to the preparation method described in Tetrahedron 1999, 55, 3337.

  To a solution of compound 12-2 (13.0 g, 40.0 mmol) in ethanol (390 mL) was added potassium carbonate (2.76 g, 20.0 mmol), and the mixture was heated to reflux for 1 hour. After concentration under reduced pressure, the residue was partitioned between brine and dichloromethane. The aqueous layer was separated and extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15-20% ethyl acetate / hexane solution) to give compound 3-1 as a colorless oil (which solidified after standing) (7.36 g, 90%). .

[Α] _D ²¹ -103.0 ° (c 0.895, CHCl ₃ ); IR (film, cm ⁻¹ ) 3279, 2979, 2933, 1747, 1604, 1696, 1455, 1387, 1375, 1302, 1242, 1219, 1190, 1144, 1086, 997, 940, 913, 884, 771, 744, 702; ¹ H-NMR ₍ CDCl ₃ ) 7.34-7.17 (m, 5H), 5.66 (br s, 1H), 3.72-3.69 (m, 1H), 2.83-2.68 (m, 2H), 1.42 (s, 6H); ¹³ C-NMR (CDCl ₃ ) 158.0, 136.8,128.7,128.7,126.8,83.0,62.8,36.8,27.3,21.7; analysis calculated _{(C 12 H 15 NO 2)} C, 70.22; H 7.37; N, 6.82, Found C, 70.17; H, 6.80; N, 7.34; m. p. (Diethyl ether-hexane) 66-67 degreeC.

Claims (13)

Formula I:

Wherein R ¹ and R ³ are independently selected from a hydrogen atom and C _1-6 alkyl, wherein the alkyl is one or more selected from a halogen atom, hydroxy, C _1-6 alkoxy and aryl R ² , R ⁴ and R ⁵ are independently selected from a hydrogen atom, C _1-10 alkyl, C _2-10 alkenyl and C _2-10 alkynyl, wherein The alkyl, alkenyl and alkynyl may be substituted by one or more substituents selected from a halogen atom, hydroxy, carboxy, C _1-6 alkoxycarbonyl and aryl; and Z is a hydrogen atom or secondary Amino protecting group]
A method for producing the compound of
Formula AI or A-XI:

Wherein, R ²¹ is an ester forming group; R ²² is as defined for R ² (where a functional group that may be included in R ² may be protected by a protecting group); Z ¹ is A protecting group for secondary amino group; X is a leaving group]
In the presence of a base of formula A-II:

[Wherein R ²¹ , R ²² and Z ¹ are as defined above]
And the method of manufacturing comprising the steps of: converting the compound of formula A-II to a compound of formula I; A process for the preparation of a compound of formula I according to claim 1, comprising
a-1) Formula AI or A-XI:

[Wherein R ²¹ , R ²² , Z ¹ and X are as defined in claim 1]
In the presence of a base of formula A-II:

[Wherein R ²¹ , R ²² and Z ¹ are as defined above]
Converting to a compound of:
a-2) A compound of formula A-II in the presence of a base, of formula A-III:

[Wherein R ²¹ , R ²² and Z ¹ are as defined above; R ²³ is an ester-forming group]
Converting to a compound of:
a-3) A compound of formula A-III is represented by formula A-IV:

[Wherein R ²¹ , R ²² , R ²³ and Z ¹ are as defined above]
Oxidizing to a compound of:
a-4) A compound of formula A-IV is represented by formula AV

^Wherein, R ^21, R ^{22, R 23} and ^{Z 1,} are as previously ^{defined; R 24} and ^{R 25} are the same as definitions of ^{R 4} and ^{R 5,} respectively ^{(wherein, R 24} and R ²⁵ may be protected by a protecting group)]
Converting to a compound of:
The method according to claim 1, further comprising a step of deprotecting when the compound of the formula AV includes a protecting group and / or a step of converting the ester to a carboxyl group. In step a-1, formula A-Ia or A-XIa:

[Wherein R ²¹ , R ²² , Z ¹ and X are as defined in claim 1]
And the final product as formula Ia:

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Z are as defined in claim 1]
The manufacturing method of Claim 2 which obtains the compound of. Formula AI or A-XI:

[Wherein R ²¹ , R ²² , Z ¹ and X are as defined in claim 1]
A process for producing a compound of
b-1) Formula BI:

[Wherein R ²² is as defined above; Z ² is a hydroxy protecting group; L is a leaving group]
By alkylating and introducing a substituent on the nitrogen atom:

[Wherein R ²² and Z ² are as defined above; R ³¹ is an ester-forming group; Z ³ is a C _1-6 alkyl or a protecting group for a nitrogen atom]
Converting to a compound of:
b-2) By reducing the compound of formula B-II, the compound of formula B-III:

[Wherein R ²² , R ³¹ , Z ² and Z ³ are as defined above]
Converting to a compound of:
b-3) A compound of formula B-III is represented by formula B-IV:

[Wherein R ²¹ , R ²² , R ³¹ , Z ² and Z ³ are as defined above; Z ⁴ is C _1-6 alkylsulfonyl (wherein the alkylsulfonyl is substituted with one or more halogen atoms) Or arylsulfonyl (wherein the arylsulfonyl is optionally substituted by one or more substituents selected from nitro, cyano, halogen atoms and C _1-6 haloalkyl), or Z ¹ is a protecting group for a secondary amino group as defined in claim 1]
Converting to a compound of:
b-4) A compound of formula B-IV is represented by formula BV:

[Wherein R ²¹ , R ²² , Z ³ and Z ⁴ are as defined above]
B-5) converting the compound of formula BV to a compound of formula AI or A-XI;
The method according to claim 1, further comprising the step of converting Z ⁴ into a group defined as Z ¹ in an optional step. In step b-1, formula B-Ia:

[Wherein R ²² , Z ² and L are as defined in claim 4]
And the final product is of formula A-Ia or A-XIa:

[Wherein R ²¹ , R ²² , Z ¹ and X are as defined in claim 4]
The production method according to claim 4, wherein the compound is obtained. X is a halogen atom, —NR ⁸ R ⁹ , —N ⁺ R ⁵¹ R ⁵² R ⁵³ , —OR ¹⁰ or —S (O) _n R ¹¹ ; R ⁸ and R ⁹ are independently C _{1- 6} alkyl (wherein the alkyl may be substituted by one or more substituents selected from halogen atoms), aryl (wherein the aryl is selected from nitro, cyano, halogen atoms and C _1-6 haloalkyl) Optionally substituted by the above substituents), C _7-14 aralkyl, C _1-6 alkylcarbonyl (the alkylcarbonyl may be substituted by one or more substituents selected from halogen atoms) , arylcarbonyl (where the aryl carbonyl, nitro, cyano, by one or more substituents selected from halogen atoms and C _1-6 haloalkyl Conversion may _{be), C 7 - 14} aralkyl carbonyl-substituted, -COOR ^11, arylsulfonyl (the arylsulfonyl, nitro, cyano, by one or more substituents selected from halogen atoms and _{C 1-6} haloalkyl And C _1-10 alkylsulfonyl (wherein the alkyl is optionally substituted by one or more substituents selected from halogen atoms); R ¹⁰ is C _1-6 alkyl , Aryl, C _7-14 aralkyl, C _1-6 alkylcarbonyl, arylcarbonyl, C _7-14 aralkylcarbonyl, C _1-6 alkylsulfonyl, arylsulfonyl or C _7-14 aralkylsulfonyl; R ¹¹ is C ¹¹ _1-20 alkyl (the alkyl is selected from halogen atoms May be substituted by one or more substituents), aryl (said aryl is nitro, cyano, optionally substituted by one or more substituents selected from halogen atoms and C _1-6 haloalkyl) Or C _7-14 aralkyl; R ⁵¹ , R ⁵² and R ⁵² are independently selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl and C _7-14 aralkyl. The method of any one of claims 1-5. Formula A-Ia:

[Wherein R ²¹ , R ²² and Z ¹ are as defined in claim 1]
A process for producing a compound of
c-1) Formula CI:

[Wherein R ³² is C _1-6 alkyl, aryl or C _7-14 aralkyl; R ³⁵ is a hydrogen atom, C _1-6 alkyl, aryl and C _7-14 aralkyl; R ³³ and R ³⁴ is independently selected from a hydrogen atom and C _1-6 alkyl, aryl, and C _7-14 aralkyl.
Is reacted with an aldehyde: R ²² CHO (wherein R ²² is as defined above) and further introducing a protecting group to give a compound of formula C-II:

[Wherein R ²² , R ³² , R ³³ , R ³⁴ and R ³⁵ are as defined above; Z ⁵ is a hydroxy protecting group]
Converting to a compound of:
c-2) By reducing the compound of formula C-II, the compound of formula C-III:

[Wherein R ²² , R ³² , R ³³ , R ³⁴ , R ³⁵ and Z ⁵ are as defined above]
Converting to a compound of:
c-3) A compound of formula C-III is reacted with a glycine derivative or a salt thereof and further introduced with a protecting group to give a compound of formula C-IV:

[Wherein R ²¹ , R ²² , R ³⁵ , Z ¹ and Z ⁵ are as defined above]
Converting to a compound of:
c-4) The compound of formula C-IV is converted to formula CV by deprotection and esterification:

[Wherein R ²¹ , R ²² , R ³⁵ and Z ¹ are as defined above; R ³⁶ is a hydrogen atom, C _1-6 alkyl, aryl, or C _7-14 aralkyl]
C-4) converting the compound of formula CV to a compound of formula A-Ia in the presence of a catalyst;
The said manufacturing method containing. Formula A-Ia:

[Wherein R ²¹ , R ²² and Z ¹ are as defined in claim 1]
A process for producing a compound of
d-1) oxidation of a compound of formula C-IV according to claim 7 to formula DI:

[Wherein R ²¹ , R ²² , Z ¹ and Z ⁵ are as defined in claim 7.]
Converting to a compound of:
d-2) A compound of formula DI is represented by formula D-II:

[Wherein R ²¹ , R ²² , Z ¹ and Z ⁵ are as defined above; R ³⁷ is an ester-forming group]
Converting to a compound of:
d-3) converting the compound of formula D-II to a compound of formula A-Ia;
The said manufacturing method containing. The compound of formula D-II is of formula D-II-cis:

[Wherein R ²¹ , R ²² , R ³⁷ , Z ¹ and Z ⁵ are as defined in claim 8.]
The manufacturing method of Claim 8 which is a compound of these. Step d-3 removes the compound of formula D-II, deprotection of the hydroxy group, and the thiol: R ³⁸ —SH, where R ³⁸ is C _1-20 alkyl, aryl or C _7-20 aralkyl. ) To give a compound of formula D-III:

[Wherein R ²¹ , R ²² and Z ¹ are as defined in claim 8, and R ³⁸ is as defined above.]
Converting to a compound of formula A; and converting a compound of formula D-III to a compound of formula A-Ia;
The manufacturing method of Claim 8 containing these. Formula AI or A-XII:

[Wherein R ²¹ , R ²² and Z ¹ are as defined in claim 1; X ¹¹ is amino, hydroxy, or a group defined as X in claim 1 or 6]
Or a salt thereof. Formula A-II:

[Wherein R ²¹ , R ²² and Z ¹ are as defined in claim 1]
Or a salt thereof. Formula C-VI:

Wherein R ²¹ , R ²² and Z are as defined in claim 1; R ⁶ is —CH═CHR ³⁵ , —CH═CHCO ₂ R ³⁷ or formyl; R ⁷ is a hydrogen atom , Z ⁵ or —COCH═CHR ³⁶ ; Z ⁵ , R ³⁵ , R ³⁶ and R ³⁷ are as defined in claim 7 or 8]
Or a salt thereof.