JP7518533B2 - Novel ynone compounds and their uses - Google Patents

Description

The present invention relates to novel ynone compounds and their uses.

で表されるエノン化合物が、強力な抗炎症作用を有することが知られている（非特許文献１）。 It is obtained from the fermentation broth of the fungus Curvularia verruculosa and has the following formula:

It is known that an enone compound represented by the following formula has a strong anti-inflammatory effect (Non-Patent Document 1).

H. Du et al., Bioorg. Med. Chem. Lett. 19(2009), pp. 6196-6199.

The object of the present invention is to provide a novel ynone compound that is useful for inducing endoplasmic reticulum stress response, etc.

［式中、
Ａ^１は、置換基を有していてもよい芳香環であり、
Ｘ^１は、酸素原子、硫黄原子、又は式：－Ｎ(Ｒ^Ｘ１)－（式中、Ｒ^Ｘ１は、水素原子又はアルキル基である）で表される基であり、
Ｘ^２は、単結合又は二重結合であり、
Ｒ^１及びＲ^２は、同一又は異なって、水素原子、又はアルキル基であり、
Ｒ^３及びＲ^４は、同一又は異なって、水素原子、アルキル基、アシル基、アルコキシアルキル基、又はアルコキシアルコキシアルキル基である、或いは
Ｒ^３Ｏ及びＲ^４Ｏは、隣接する２つの炭素原子と共に環を形成していてもよい。
但し、下記式：

で表される化合物を除く。］
項２．
Ａ^１が、置換基を有していてもよいＣ_６－１０芳香族炭化水素環、又は置換基を有していてもよい５～１０員芳香族複素環である、項１に記載の化合物又はその塩。
項３．
Ａ^１が、下記式で表される環である、項１又は２に記載の化合物又はその塩：

（式中、
Ｒ^５は、－ＯＲ^５ａ又は－ＮＲ^５ｂＲ^５ｃであり、
Ｒ^５ａは、水素原子、アルキル基、アシル基、アルコキシアルキル基、又はアルコキシアルコキシアルキル基であり、
Ｒ^５ｂ及びＲ^５ｃは、それぞれ独立して、水素原子、アルキル基、又はアリール基であり、
ｎは、０～４の整数であり、
ｎが２以上の整数である場合、複数のＲ^５は、互いに同一であっても異なっていてもよい。）
項４．
Ａ^１が、下記式で表される環である、項１～３のいずれか一項に記載の化合物又はその塩：

（式中、
Ｒ^５１及びＲ^５２は、同一又は異なって、水素原子、アルキル基、アルコキシアルキル基、又はアルコキシアルコキシアルキル基であり、
Ｒ^５３は、水素原子、アルキル基、アルコキシアルキル基、又はアルコキシアルコキシアルキル基であり、
Ｒ^５４及びＲ^５５は、同一又は異なって、水素原子、アルキル基、又はアリール基である。）
項５．
Ｘ^１が、酸素原子である、項１～４のいずれか一項に記載の化合物又はその塩。
項６．
Ｘ^２が、二重結合である、項１～５のいずれか一項に記載の化合物又はその塩。
項７．
Ｒ^１がアルキル基であり、Ｒ^２が水素原子である、項１～６のいずれか一項に記載の化合物又はその塩。
項８．
Ｒ^３及びＲ^４が、同一又は異なって、水素原子、アルキル基、又はアルコキシアルキル基である、項１～７のいずれか一項に記載の化合物又はその塩。
項９．
項１に記載の式（１Ａ）で表される化合物又はその塩の製造方法であって、
（１）下記式（１－５）：

（式中、Ａ^１、Ｘ^１、Ｒ^１、Ｒ^２、Ｒ^３、及びＲ^４は前記と同じである）
で表される化合物を、三重結合の保護化剤と反応させる工程、
（２）前記工程（１）で得られる生成物を環化し、必要に応じて二重結合を還元する工程、及び
（３）前記工程（２）で得られる生成物から三重結合の保護基を除去する工程
を含む、方法。
項１０．
下記式（２Ａ）で表される化合物又はその塩：

［式中、
Ｘ^３は、単結合、二重結合、又は三重結合であり、
Ｒ^６は、水素原子、置換基を有していてもよいアルキル基、又は置換基を有していてもよい芳香環基であり、
Ｒ^７及びＲ^８は、同一又は異なって、水素原子、アルキル基、アシル基、アルコキシアルキル基、又はアリール基である、或いは、
Ｒ^７Ｏ及びＲ^８Ｏは、隣接する２つの炭素原子と共に環を形成していてもよく、
Ｒ^９は、水素原子、アルキル基、又はアリール基である。
但し、下記式：

で表される化合物を除く。］
項１１．
Ｒ^６が、置換基としてヒドロキシル基を有していてもよいＣ_１－４アルキル基である、項１０に記載の化合物又はその塩。
項１２．
Ｒ^７Ｏ及びＲ^８Ｏが、隣接する２つの炭素原子と共に、下記式：

（式中、Ｒ^７ａ及びＲ^８ａは、同一又は異なって、水素原子、アルキル基、又はアリール基であり、＊は、カルボニル炭素との結合位置を示す）
で表される環を形成している、項１０又は１１に記載の化合物又はその塩。
項１３．
Ｒ^９が、水素原子である、項１０～１２のいずれか一項に記載の化合物又はその塩。
項１４．
項１０に記載の式（２Ａ）で表される化合物又はその塩の製造方法であって、
塩基の存在下、下記式（２－６）：

（式中、Ｒ^１０及びＲ^１１は、同一又は異なって、アルキル基、アルコキシ基、又はアリール基であり、Ｘ^３、Ｒ^７、Ｒ^８、及びＲ^９は前記と同じである）
で表される化合物を、下記式（９）：

（式中、Ｒ^６は、前記と同じである）
で表される化合物と反応させる工程を含む、方法。
項１５．
下記式（１）で表される化合物又はその塩：

［式中、
Ａ^１は、置換基を有していてもよい芳香環であり、
Ｘ^１は、酸素原子、硫黄原子、又は式：－Ｎ(Ｒ^Ｘ１)－（式中、Ｒ^Ｘ１は、水素原子又はアルキル基である）で表される基であり、
Ｘ^２は、単結合又は二重結合であり、
Ｒ^１及びＲ^２は、同一又は異なって、水素原子、又はアルキル基であり、
Ｒ^３及びＲ^４は、同一又は異なって、水素原子、アルキル基、アシル基、アルコキシアルキル基、又はアルコキシアルコキシアルキル基である、或いは
Ｒ^３Ｏ及びＲ^４Ｏは、隣接する２つの炭素原子と共に環を形成していてもよい。］及び下記式（２）で表される化合物又はその塩：

［式中、
Ｘ^３は、単結合、二重結合、又は三重結合であり、
Ｒ^６は、水素原子、置換基を有していてもよいアルキル基、又は置換基を有していてもよい芳香環基であり、
Ｒ^７及びＲ^８は、同一又は異なって、水素原子、アルキル基、アシル基、アルコキシアルキル基、又はアリール基である、或いは、
Ｒ^７Ｏ及びＲ^８Ｏは、隣接する２つの炭素原子と共に環を形成していてもよく、
Ｒ^９は、水素原子、アルキル基、又はアリール基である。］
から選択される少なくとも一種を含む、医薬組成物。
項１６．
小胞体ストレス応答誘起剤である、項１５に記載の医薬組成物。
項１７．
プロテインジスルフィドイソメラーゼ阻害剤である、項１５又は１６に記載の医薬組成物。
項１８．
癌、骨疾患、及びリウマチから選択される少なくとも一種の予防又は治療剤である、項１５～１７のいずれか一項に記載の医薬組成物。 As a result of intensive research to achieve the above object, the present inventors have found that a compound having an ynone skeleton induces an endoplasmic reticulum stress response. Based on this finding, the present inventors have further researched and completed the present invention.
The present invention includes the following aspects.
Item 1.
A compound represented by the following formula (1A) or a salt thereof:

[Wherein,
A ¹ is an aromatic ring which may have a substituent;
X ¹ is an oxygen atom, a sulfur atom, or a group represented by the formula: -N(R ^X1 )- (wherein R ^X1 is a hydrogen atom or an alkyl group);
^X2 is a single bond or a double bond;
R ¹ and R ² are the same or different and each is a hydrogen atom or an alkyl group;
R ³ and R ⁴ are the same or different and each is a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, or R ³ O and R ⁴ O may form a ring together with the two adjacent carbon atoms.
However, the following formula:

excluding compounds represented by the following formula:
Item 2.
Item 2. The compound or a salt thereof according to Item 1, wherein A ¹ is an optionally substituted C _6-10 aromatic hydrocarbon ring, or an optionally substituted 5- to 10-membered aromatic heterocycle.
Item 3.
Item 3. The compound or salt thereof according to item 1 or 2, wherein A ¹ is a ring represented by the following formula:

(Wherein,
R ⁵ is -OR ^5a or -NR ^5b R ^5c ;
R ^5a is a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group;
R ^5b and R ^5c each independently represent a hydrogen atom, an alkyl group, or an aryl group;
n is an integer from 0 to 4,
When n is an integer of 2 or more, the multiple ^R5s may be the same or different.
Item 4.
The compound or salt thereof according to any one of items 1 to 3, wherein A ¹ is a ring represented by the following formula:

(Wherein,
R ⁵¹ and R ⁵² are the same or different and each is a hydrogen atom, an alkyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group;
R ⁵³ is a hydrogen atom, an alkyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group;
R ⁵⁴ and R ⁵⁵ are the same or different and each is a hydrogen atom, an alkyl group, or an aryl group.
Item 5.
Item 5. The compound or salt thereof according to any one of items 1 to 4, wherein X ¹ is an oxygen atom.
Item 6.
Item 6. The compound or salt thereof according to any one of Items 1 to 5, wherein ^X2 is a double bond.
Item 7.
Item 7. The compound or salt thereof according to any one of Items 1 to 6, wherein R ¹ is an alkyl group and R ² is a hydrogen atom.
Item 8.
Item 8. The compound or salt thereof according to any one of Items 1 to 7, wherein R ³ and R ⁴ are the same or different and each represent a hydrogen atom, an alkyl group, or an alkoxyalkyl group.
Item 9.
A method for producing the compound represented by formula (1A) or a salt thereof according to item 1, comprising the steps of:
(1) The following formula (1-5):

(In the formula, A ¹ , X ¹ , R ¹ , R ² , R ³ , and R ⁴ are the same as above.)
with a triple bond protecting agent;
(2) cyclizing the product obtained in step (1) and optionally reducing the double bond; and (3) removing the protecting group of the triple bond from the product obtained in step (2).
Item 10.
A compound represented by the following formula (2A) or a salt thereof:

[Wherein,
^X3 is a single bond, a double bond, or a triple bond;
^R6 is a hydrogen atom, an alkyl group which may have a substituent, or an aromatic ring group which may have a substituent;
R ⁷ and R ⁸ are the same or different and each is a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an aryl group; or
R ⁷ O and R ⁸ O may form a ring together with the adjacent two carbon atoms;
R ⁹ is a hydrogen atom, an alkyl group, or an aryl group.
However, the following formula:

excluding compounds represented by the following formula:
Item 11.
Item 11. The compound or a salt thereof according to item 10, wherein R ⁶ is a C _1-4 alkyl group optionally having a hydroxyl group as a substituent.
Item 12.
R ⁷ O and R ⁸ O, together with the two adjacent carbon atoms, form the following formula:

(In the formula, R ^7a and R ^8a are the same or different and each is a hydrogen atom, an alkyl group, or an aryl group, and * indicates the bonding position to the carbonyl carbon.)
Item 12. The compound or salt thereof according to item 10 or 11, wherein the compound or salt forms a ring represented by the following formula:
Item 13.
Item 13. The compound or salt thereof according to any one of items 10 to 12, wherein R ⁹ is a hydrogen atom.
Item 14.
Item 10. A method for producing a compound represented by formula (2A) or a salt thereof, comprising the steps of:
In the presence of a base, the following formula (2-6):

(In the formula, R ¹⁰ and R ¹¹ are the same or different and each is an alkyl group, an alkoxy group, or an aryl group, and X ³ , R ⁷ , R ⁸ , and R ⁹ are the same as defined above.)
The compound represented by the following formula (9):

(Wherein, ^R6 is the same as defined above.)
The method includes reacting a compound represented by the formula:
Item 15.
A compound represented by the following formula (1) or a salt thereof:

[Wherein,
A ¹ is an aromatic ring which may have a substituent;
X ¹ is an oxygen atom, a sulfur atom, or a group represented by the formula: -N(R ^X1 )- (wherein R ^X1 is a hydrogen atom or an alkyl group);
^X2 is a single bond or a double bond;
R ¹ and R ² are the same or different and each is a hydrogen atom or an alkyl group;
R ³ and R ⁴ are the same or different and each is a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, or R ³ O and R ⁴ O may form a ring together with the two adjacent carbon atoms.] and a compound represented by the following formula (2) or a salt thereof:

[Wherein,
^X3 is a single bond, a double bond, or a triple bond;
^R6 is a hydrogen atom, an alkyl group which may have a substituent, or an aromatic ring group which may have a substituent;
R ⁷ and R ⁸ are the same or different and each is a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an aryl group; or
R ⁷ O and R ⁸ O may form a ring together with the adjacent two carbon atoms;
R ⁹ is a hydrogen atom, an alkyl group, or an aryl group.
A pharmaceutical composition comprising at least one selected from the group consisting of
Item 16.
Item 16. The pharmaceutical composition according to Item 15, which is an endoplasmic reticulum stress response inducer.
Item 17.
Item 17. The pharmaceutical composition according to Item 15 or 16, which is a protein disulfide isomerase inhibitor.
Item 18.
Item 18. The pharmaceutical composition according to any one of Items 15 to 17, which is an agent for preventing or treating at least one disease selected from cancer, bone diseases, and rheumatism.

The compounds of the present invention can, for example, induce an endoplasmic reticulum stress response, and are useful for preventing or treating diseases involving endoplasmic reticulum stress. In addition, the compounds of the present invention can inhibit the activity of protein disulfide isomerase (PDI), and are useful for preventing or treating diseases involving PDI. Furthermore, the compounds of the present invention are useful for preventing or treating at least one disease selected from cancer, bone disease, and rheumatism. In addition, the compounds of the present invention do not inhibit normal hematopoiesis, and therefore have few side effects.

FIG. 1 shows the expression levels of CHOP related to endoplasmic reticulum stress response in Examples 2, 8, and 9. FIG. 2 shows the inhibition of tumor progression in myeloma model mice by the compound of Example 2. FIG. 3 shows the inhibition of tumor progression in myeloma model mice by the compound of Example 8. FIG. 4 shows the effect of the compound of Example 2 on the cytotoxic activity against hematopoietic stem cells. FIG. 5 shows the effect of the compound of Example 8 on the cytotoxic activity against hematopoietic stem cells. FIG. 6 shows the inhibition of osteoclast formation by the compound of Example 8. FIG. 7 shows the inhibition of osteoclast formation by the compound of Example 2. FIG. 8 shows the inhibition of cancer bone lesion formation by the compound of Example 8. FIG. 9 shows the antirheumatic effect of the compound of Example 2.

<Definition of terms>
As used herein, "C _ab " means that the number of carbon atoms of interest is an integer between a and b.
In this specification, the term "aromatic ring" is a concept that encompasses aromatic hydrocarbon rings and aromatic heterocycles.
The aromatic hydrocarbon ring refers to an aromatic ring whose constituent atoms are composed only of carbon atoms.
The number of constituent atoms of the aromatic hydrocarbon ring is not particularly limited, but may be, for example, 6 to 20.
The aromatic hydrocarbon ring can be monocyclic or fused polycyclic.
An example of the monocyclic aromatic hydrocarbon ring is benzene.
Examples of the condensed polycyclic aromatic hydrocarbon ring include two rings (eg, indene, naphthalene), three rings (eg, fluorene, anthracene, phenanthrene), and four rings (eg, pyrene).
The aromatic heterocycle refers to an aromatic ring containing, as ring-constituting atoms, a carbon atom and a heteroatom selected from an oxygen atom, a sulfur atom, a nitrogen atom, and the like.
The number of constituent atoms of the aromatic heterocycle is not particularly limited, but may be, for example, 5 to 20. In addition, the number of heteroatoms among the constituent atoms of the aromatic heterocycle is not particularly limited, but may be, for example, 1 to 4.
The aromatic heterocycle can be monocyclic or fused polycyclic.
Examples of monocyclic aromatic heterocycles include 5-membered rings (e.g., furan, isoxazole, oxazole, thiophene, isothiazole, thiazole, pyrrole, pyrazole, imidazole, and triazole) and 6-membered rings (e.g., pyridine, pyridazine, pyrimidine, pyrazine, and triazine).
Examples of fused ring aromatic heterocycles include bicyclic (e.g., benzofuran, benzothiophene, indole, indazole, benzimidazole, purine, quinoline, isoquinoline, cinnoline, quinoxaline, phthalazine, 1,8-naphthyridine, and pteridine) and tricyclic (e.g., carbazole, acridine, phenazine, phenanthridine, phenanthroline, phenoxazine, and phenothiazine).
In the present specification, the term "aromatic ring group" refers to a group in which one hydrogen atom has been removed from the aromatic ring. Examples of the aromatic ring group include aryl groups such as a phenyl group and a naphthyl group; and heteroaryl groups such as a furanyl group, a thienyl group, and a pyridyl group.

In this specification, "halogen atom" includes, for example, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In this specification, the term "alkyl group" is a concept that includes linear alkyl groups and branched alkyl groups.
Examples of the straight-chain alkyl group include straight-chain C _1-10 alkyl groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, s-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
Examples of branched alkyl groups include branched C _3-10 alkyl groups such as isopropyl, isobutyl, s-butyl, t-butyl, isopentyl, neopentyl, isohexyl, isoheptyl, isooctyl, and 2-ethylhexyl.

In the present specification, examples of the "cycloalkyl group" include a _C3-10 cycloalkyl group such as cyclopropyl, cyclopentyl, cyclohexyl, etc.

As used herein, the term "aryl group" refers to a monovalent group derived from an aromatic hydrocarbon ring. Examples of the aryl group include C _6-10 aryl groups such as phenyl and naphthyl.

In the present specification, examples of the "aralkyl group" include C _6-10 aryl C _1-4 alkyl groups such as benzyl and phenethyl.

As used herein, the term "alkoxy group" refers to a group represented by the formula: R ^A O- (wherein R ^A is an alkyl group). Examples of the alkoxy group include C _1-4 alkoxy groups such as methoxy, ethoxy, propoxy (n-propoxy, isopropoxy), and butoxy (n-butoxy, isobutoxy, s-butoxy, t-butoxy).

In the present specification, examples of an "alkoxyalkyl group" include a group represented by the formula: ( _C1-4 alkyl)-O-( _C1-4 alkylene)-O-. Examples of the group represented by the formula include _C1-3 alkoxy _C1-3 alkyl groups such as methoxymethyl, methoxyethyl, ethoxymethyl, and ethoxyethyl.

In the present specification, examples of the "alkoxyalkoxy group" include a group represented by the formula: ( _C1-4 alkyl)-O-( _C1-4 alkylene)-. Examples of the group represented by the formula include _C1-3 alkoxy _C1-3 alkyl groups such as methoxymethoxy, methoxyethoxy, ethoxymethoxy, and ethoxyethoxy.

In the present specification, examples of an "alkoxyalkoxyalkyl group" include a group represented by the formula: ( _C1-6 alkyl)-O-( _C1-4 alkylene)-O-( _C1-4 alkylene)-. Examples of the group represented by the formula include _C1-3 alkoxy _C1-3 alkoxy _C1-3 alkyl groups such as methoxymethoxyethyl, methoxyethoxymethyl, ethoxymethoxymethyl, ethoxymethoxyethyl, ethoxyethoxymethyl, and ethoxyethoxyethyl.

In the present specification, examples of the "alkoxyalkoxyalkoxy group" include a group represented by the formula: ( _C1-6 alkyl)-O-( _C1-4 alkylene)-O-( _C1-4 alkylene)-O-. Examples of the group represented by the formula include _C1-3 alkoxy _C1-3 alkoxy _C1-3 alkoxy groups such as methoxymethoxyethoxy, methoxyethoxymethoxy, ethoxymethoxymethoxy, ethoxymethoxyethoxy, ethoxyethoxymethoxy, and ethoxyethoxyethoxy.

In this specification, the term "acyl group" includes a group represented by the formula: -C(=O)-R ^B1 (wherein R ^B1 is a hydrocarbon group) and a group represented by the formula: -C(=O)-O-R ^B2 (wherein R ^B2 is a hydrocarbon group). The hydrocarbon groups represented by R ^B1 and R ^B2 may be chain-like hydrocarbon groups (e.g., alkyl), saturated or unsaturated cyclic hydrocarbon groups (e.g., cycloalkyl, aryl), or combinations thereof (e.g., aralkyl).
Acyl groups include alkylcarbonyl, arylcarbonyl, and aralkylcarbonyl groups.
Examples of the alkylcarbonyl group include (C _1-10 alkyl)carbonyl groups such as acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, and decanoyl.
Examples of arylcarbonyl groups include (C _6-14 aryl)carbonyl groups such as benzoyl or naphthoyl (i.e., α-naphthoyl or β-naphthoyl). Examples of aralkylcarbonyl groups include (C _6-14 aryl C _1-4 alkyl)carbonyl groups such as benzylcarbonyl.

As used herein, an "alkylthio group" refers to a group represented by the formula: R ^C -S- (wherein R ^C is an alkyl group). Examples of the alkylthio group include C _1-4 alkylthio groups such as methylthio, ethylthio, propylthio (n-propylthio, isopropylthio), and butylthio (n-butylthio, isobutylthio, s-butylthio, t-butylthio).

As used herein, a "monoalkylamino group" refers to a group represented by the formula: R ^D1 -NH- (wherein R ^D1 is an alkyl group). Examples of the monoalkylamino group include mono-C _1-4 alkylamino groups such as monomethylamino, monoethylamino, and monopropylamino (mono-n-propylamino, monoisopropylamino).

As used herein, a "dialkylamino group" refers to a group represented by the formula: R ^D2 R ^D3 N- (wherein R ^D1 and R ^D3 are the same or different and each is an alkyl group). Examples of the dialkylamino group include diC _1-4 alkylamino groups such as dimethylamino, ethylmethylamino, diethylamino, and propylmethylamino.

（式中、Ａ^１、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、及びＲ^４は、前記と同じである。） <Compound (1)>
In one embodiment, the compound of the present invention or a salt thereof is a compound represented by formula (1) or a salt thereof (hereinafter referred to as “compound (1)”):

(In the formula, A ¹ , X ¹ , X ² , R ¹ , R ² , R ³ , and R ⁴ are the same as defined above.)

^A1 is preferably a _C6-10 aromatic hydrocarbon ring which may have a substituent, or a 5- to 10-membered aromatic heterocycle which may have a substituent, more preferably a _C6-10 aromatic hydrocarbon ring which may have a substituent, a 5- to 10-membered nitrogen-containing aromatic heterocycle which may have a substituent, a 5- to 10-membered oxygen-containing aromatic heterocycle which may have a substituent, or a 5- to 10-membered sulfur-containing aromatic heterocycle which may have a substituent, still more preferably a _C6-10 aromatic hydrocarbon ring, and particularly preferably a benzene ring which may have a substituent.

Examples of the substituent include a halogen atom, a hydroxyl group, a mercapto group, an amino group, an alkyl group, an alkoxy group, an alkoxyalkoxy group, an alkoxyalkoxyalkoxy group, an acyl group, an alkylthio group, a monoalkylamino group, and a dialkylamino group. The number of the substituents is not particularly limited, but is, for example, an integer of 0 to 4, preferably an integer of 1 to 4, and more preferably an integer of 1 to 3.

（式中、Ｒ^５及びｎは、前記と同じである。）
で表される環が好ましい。－ＯＲ^５ａ又は－ＮＲ^５ｂＲ^５ｃであり、
Ｒ^５が－ＯＲ^５ａである場合、Ｒ^５ａは、好ましくは、水素原子、アルキル基、アルコキシアルキル基、又はアルコキシアルコキシアルキル基であり、さらに好ましくは、水素原子、Ｃ_１－４アルキル基、Ｃ_１－４アルコキシＣ_１－４アルキル基、又はＣ_１－４アルコキシＣ_１－４アルコキシＣ_１－４アルキル基であり、特に好ましくは、水素原子、Ｃ_１－２アルキル基、Ｃ_１－２アルコキシＣ_１－２アルキル基、又はＣ_１－２アルコキシＣ_１－２アルコキシＣ_１－２アルキル基である。
Ｒ^５が－ＮＲ^５ｂＲ^５ｃである場合、Ｒ^５ｂ及びＲ^５ｃは、好ましくは、水素原子、Ｃ_１－４アルキル基、又はＣ_６－１２アリール基である。Ｒ^５ｂ及びＲ^５ｃの組合せとしては、Ｒ^５ｂ及びＲ^５ｃが水素原子である組合せ、Ｒ^５ｂ及びＲ^５ｃの一方が水素原子であり、他方がアルキル基である組合せ、Ｒ^５ｂ及びＲ^５ｃがアルキル基である組合せ、Ｒ^５ｂ及びＲ^５ｃの一方が水素原子であり、他方がアリール基である組合せ、Ｒ^５ｂ及びＲ^５ｃがアリール基である組合せなどが好ましい。
ｎは、好ましくは１～４の整数であり、さらに好ましくは１～３の整数である。
ｎが２以上の整数である場合、複数のＲ^５は、互いに同一であっても異なっていてもよく、例えば、複数のＲ^５は、すべて－ＯＲ^５ａであってもよく、－ＯＲ^５ａ及び－ＮＲ^５ｂＲ^５ｃの組合せであってもよい。 In addition, ^A1 is represented by the following formula:

(In the formula, ^R5 and n are the same as above.)
A ring represented by ^{the following formula} is preferred:
When R ⁵ is -OR ^5a , R ^5a is preferably a hydrogen atom, an alkyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, more preferably a hydrogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy C _1-4 alkyl group, or a C _1-4 alkoxy C _1-4 alkoxy C _1-4 alkyl group, and particularly preferably a hydrogen atom, a C _1-2 alkyl group, a C _1-2 alkoxy C _1-2 alkyl group, or a C _1-2 alkoxy C _1-2 alkoxy C _1-2 alkyl group.
When R ⁵ is -NR ^5b R ^5c , R ^5b and R ^5c are preferably a hydrogen atom, a C _1-4 alkyl group, or a C _6-12 aryl group. Preferred combinations of R ^5b and R ^5c include a combination where R ^5b and R ^5c are hydrogen atoms, a combination where one of R ^5b and R ^5c is a hydrogen atom and the other is an alkyl group, a combination where R ^5b and R ^5c are alkyl groups, a combination where one of R ^5b and R ^5c is a hydrogen atom and the other is an aryl group, and a combination where R ^5b and R ^5c are aryl groups.
n is preferably an integer of 1 to 4, and more preferably an integer of 1 to 3.
When n is an integer of 2 or more, the multiple R ^5s may be the same or different from each other. For example, the multiple R ^5s may all be -OR ^5a , or may be a combination of -OR ^5a and -NR ^5b R ^5c .

（式中、Ｒ^５１、Ｒ^５２、Ｒ^５３、Ｒ^５４、及びＲ^５５は、前記と同じである。）
で表される環が好ましい。
Ｒ^５１及びＲ^５２の好適な組合せとしては、Ｒ^５１が水素原子であり、且つ、Ｒ^５２がアルキル基である組合せ、Ｒ^５１がアルキル基、アルコキシアルキル基、又はアルコキシアルコキシアルキル基であり、且つ、Ｒ^５２がアルキル基である組合せが挙げられる。
Ｒ^５３、Ｒ^５４、及びＲ^５５の好適な組合せとしては、Ｒ^５１が水素原子であり、Ｒ^５４が水素原子であり、且つ、Ｒ^５５がアルキル基である組合せが挙げられる。 Further, A ¹ is represented by the following formula:

(In the formula, R ⁵¹ , R ⁵² , R ⁵³ , R ⁵⁴ , and R ⁵⁵ are the same as defined above.)
A ring represented by the following formula is preferred.
Suitable combinations of R ⁵¹ and R ⁵² include a combination in which R ⁵¹ is a hydrogen atom and R ⁵² is an alkyl group, and a combination in which R ⁵¹ is an alkyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group and R ⁵² is an alkyl group.
A suitable combination of R ⁵³ , R ⁵⁴ and R ⁵⁵ includes a combination in which R ⁵¹ is a hydrogen atom, R ⁵⁴ is a hydrogen atom and R ⁵⁵ is an alkyl group.

X ¹ is preferably an oxygen atom, a sulfur atom, or the formula: —N(R ^X11 )— (wherein R ^X11 is a hydrogen atom or a C _1-4 alkyl group), more preferably an oxygen atom or a sulfur atom, and particularly preferably an oxygen atom.

（式中、＊は、Ａ^１との結合位置を示す）
Ｘ^２が二重結合である場合、化合物（１）は、シス体又はトランス体であることができる。Ｘ^２は、好ましくは、二重結合である。 As described above, ^X2 is a single bond or a double bond.

(wherein * indicates the bonding position with ^A1 )
When ^X2 is a double bond, compound (1) can be in a cis or trans form. ^X2 is preferably a double bond.

^R1 is preferably an alkyl group, more preferably a _C1-4 alkyl group, and particularly preferably a _C1-2 alkyl group.
When R ¹ is an alkyl group, the carbon atom to which R ¹ is bonded is an asymmetric carbon atom. The configuration of this asymmetric carbon atom may be either the R configuration or the S configuration, but is preferably the S configuration.

^R2 is preferably a hydrogen atom or a _C1-4 alkyl group, more preferably a hydrogen atom or a _C1-2 alkyl group, and particularly preferably a hydrogen atom.
When ^R2 is an alkyl group, the carbon atom to which ^R2 is bonded is an asymmetric carbon atom. The configuration of this asymmetric carbon atom may be either the R configuration or the S configuration, but is preferably the R configuration.

R ³ and R ⁴ are each preferably a hydrogen atom, an alkyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, more preferably a hydrogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy C _1-4 alkyl group, or a C _1-4 alkoxy C _1-4 alkoxy C _1-4 alkyl group, and particularly preferably a hydrogen atom, a C _1-2 alkyl group, a C _1-2 alkoxy C _1-2 alkyl group, or a C _1-2 alkoxy C _1-2 alkoxy C _1-2 alkyl group.
Suitable combinations of ^R3 and ^R4 include a combination in which ^R3 and ^R4 are both hydrogen atoms, a combination in which ^R3 and ^R4 are both alkyl groups, and a combination in which ^R3 and ^R4 are both alkoxyalkyl groups.

（式中、Ｒ^３ａ及びＲ^４ａは、同一又は異なって、水素原子、アルキル基、又はアリール基である。）
で表される環であってもよい。
Ｒ^３ａ及びＲ^４ａは、それぞれ、好ましくは、水素原子、Ｃ_１－４アルキル基、又はＣ_６－１０アリール基である。
Ｒ^３ａ及びＲ^４ａの好適な組合せとしては、Ｒ^３ａ及びＲ^４ａが共にアルキル基である組合せ、Ｒ^３ａが水素原子であり、且つ、Ｒ^４ａがアリール基である組合せが挙げられる。 R ³ O and R ⁴ O may form a ring together with the two adjacent carbon atoms, and the ring is represented by the following formula:

(In the formula, R ^3a and R ^4a are the same or different and each represents a hydrogen atom, an alkyl group, or an aryl group.)
The ring may be represented by the following formula:
R ^3a and R ^4a are each preferably a hydrogen atom, a C _1-4 alkyl group, or a C _6-10 aryl group.
Suitable combinations of R ^3a and R ^4a include a combination in which R ^3a and R ^4a are both alkyl groups, and a combination in which R ^3a is a hydrogen atom and R ^4a is an aryl group.

The carbon atoms to which R ³ O and R ⁴ O are bonded are asymmetric carbon atoms. The configurations of the asymmetric carbon atoms to which R ³ O and R ⁴ O are bonded may be either the R configuration or the S configuration, but both are preferably the S configuration.

（式中、Ｒ^１１は、アルキル基であり、Ｒ^３１及びＲ^４１は、同一又は異なって、水素原子、アルキル基、又はアルコキシアルキル基である）
で表される構造部分である。
Ｒ^１１は、好ましくはＣ_１－４アルキル基であり、さらに好ましくはＣ_１－２アルキル基である。
Ｒ^３１及びＲ^４１は、それぞれ、好ましくは、水素原子、Ｃ_１－４アルキル基、又はＣ_１－４アルコキシＣ_１－４アルキル基であり、さらに好ましくは、水素原子、Ｃ_１－２アルキル基、又はＣ_１－２アルコキシＣ_１－２アルキル基である。 The structural moiety containing R ¹ , R ² , R ³ O, and R ⁴ O preferably has the following formula:

(In the formula, R ¹¹ is an alkyl group, and R ³¹ and R ⁴¹ are the same or different and are a hydrogen atom, an alkyl group, or an alkoxyalkyl group.)
It is a structural portion represented by:
R ¹¹ is preferably a C _1-4 alkyl group, more preferably a C _1-2 alkyl group.
R ³¹ and R ⁴¹ are each preferably a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkoxy C _1-4 alkyl group, more preferably a hydrogen atom, a C _1-2 alkyl group, or a C _1-2 alkoxy C _1-2 alkyl group.

Compound (1) has at least two asymmetric carbon atoms (carbon atoms to which R ³ O and R ⁴ O are bonded) and includes both enantiomers and diastereomers. Compound (1) may be a mixture containing two types of enantiomers. The mixture may be a mixture containing an excess of one enantiomer, or may be an equal mixture of two types of enantiomers (racemate).

（式中、Ａ^１、Ｘ^１、Ｘ^２、Ｒ^１、Ｒ^２、Ｒ^３、及びＲ^４は前記と同じである。
但し、下記式：

で表される化合物を除く。） Compound (1) is preferably a compound represented by the following formula (1A) or a salt thereof:

(In the formula, A ¹ , X ¹ , X ² , R ¹ , R ² , R ³ , and R ⁴ are the same as defined above.
However, the following formula:

(Excluding compounds represented by the formula:

なお、上記において、ベンゼン環に結合するメトキシ基が、モノメチルアミノ基などのモノアルキルアミノ基に変更された化合物又はその塩も好ましい。 Compound (1) is preferably a compound selected from the following group or a salt thereof:

In addition, among the above, compounds in which the methoxy group bonded to the benzene ring is changed to a monoalkylamino group such as a monomethylamino group, or salts thereof are also preferred.

When compound (1) is in the form of a salt, the salt is preferably a pharma- ceutical acceptable salt.
The salt can be an inorganic salt or an organic salt.
Examples of such salts include inorganic acid salts (e.g., hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate, and phosphate), organic acid salts (e.g., methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, and maleate), and amino acid salts (e.g., glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate).

［式中、
Ｚ^１は、脱離基であり、
Ｚ^２は、水素原子、アルキル基、又はアシル基である、或いは、式：Ｚ^２ＯＣ(＝Ｏ)－で表される基及びそのオルト位に置換し得るヒドロキシル基は、隣接するＡ^１の構成原子と共に環を形成していてもよく、
Ｚ^３は、シリル基であり、
Ｍは、アルカリ金属であり、
Ｌは、脱離基であり、
Ａ^１、Ｘ^１、Ｘ^２、及びＲ^１～Ｒ^４は、前記と同じである。］ <Method for producing compound (1)>
The compounds can be prepared, for example, according to the following reaction scheme.

[Wherein,
^Z1 is a leaving group;
^Z2 is a hydrogen atom, an alkyl group, or an acyl group; or the group represented by the formula: ^Z2OC (=O)-- and the hydroxyl group which may be substituted at the ortho position thereof may form a ring together with the adjacent constituent atom of ^A1 ;
^Z3 is a silyl group;
M is an alkali metal;
L is a leaving group,
A ¹ , X ¹ , X ² , and R ¹ to R ⁴ are the same as defined above.]

（式中、Ｚ^２１及びＺ^２２は、同一又は異なって、水素原子、アルキル基、又はアリール基であり、Ａ^１及びＺ^１は、前記と同じである。）
Ｚ^２１及びＺ^２２は、それぞれ、好ましくは、水素原子、Ｃ_１－４アルキル基、又はＣ_６－１０アリール基である。
Ｚ^２１及びＺ^２２の好適な組合せとしては、Ｚ^２１及びＺ^２２が共に水素原子である組合せ、Ｚ^２１及びＺ^２２が共にアルキル基である組合せ、Ｚ^２１が水素原子であり、且つ、Ｚ^２２がアリール基である組合せが挙げられる。
式（３）において、Ｍで示されるアルカリ金属としては、例えば、リチウム、ナトリウム、カリウムが挙げられる。
式（３）で表される化合物の使用量は、式（１－１）で表される化合物１モルに対して、通常、１～５モル、好ましくは１．５～３．０モル、さらに好ましくは１．５～２．０モルである。
工程（Ａ）の反応は、塩基の存在下で行うことが好ましい。
当該塩基としては、例えば、トリアルキルアミン（例：トリエチルアミン等のトリＣ_１－４アルキルアミン）、炭酸塩（例：Ｎａ_２ＣＯ_３、Ｋ_２ＣＯ_３等のアルカリ金属炭酸塩）が挙げられる。これらの塩基は単独で又は二種以上組み合わせて使用することができる。これらのうち、トリアルキルアミンが好ましい。
当該塩基の使用量は、式（１－１）で表される化合物１モルに対して、通常、１～５モル、好ましくは１．５～３．０モル、さらに好ましくは１．５～２．０モルである。
工程（Ａ）の反応は、触媒の存在下で行うことが好ましい。
当該触媒としては、例えば、パラジウム触媒［例：テトラキス(トリフェニルホスフィン)パラジウム(0)、トリス(ジベンジリデンアセトン)ジパラジウム(0)、パラジウム炭素、ジクロロ[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)、トランス-ジクロロビス(トリシクロヘキシルホスフィン)パラジウム(II)、ジクロロビス(トリ-o-トリルホスフィン)パラジウム(II)、ジクロロビス(トリフェニルホスフィン)パラジウム(II)、酢酸パラジウム(II)］、ニッケル触媒［例：ジクロロ[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ニッケル(II)、ジクロロビス(トリフェニルホスフィン)ニッケル(II)］、ルテニウム触媒が挙げられる。これらの触媒は単独で又は二種以上組み合わせて使用することができる。これらのうち、パラジウム触媒が好ましい。
触媒の使用量は、式（１－１）で表される化合物１モルに対して、通常、０．１～１．０モル、好ましくは０．１～０．５モル、さらに好ましくは０．１～０．２モルである。 工程（Ａ）の反応は、溶媒の存在下で行うことが好ましい。
溶媒としては、例えば、水、アルコール系溶媒（例：メタノール、エタノール）、エーテル系溶媒（例：ジエチルエーテル等の鎖状エーテル、テトラヒドロフラン、ジオキサン等の環状エーテル）が挙げられる。これらの溶媒は単独で又は二種以上組み合わせて使用することができる。これらのうち、アルコール系溶媒が好ましい。
工程（Ａ）の反応において、反応温度及び反応時間は、反応が進行する限り特に制限されるものではない。反応温度は、例えば、２０～２００℃、好ましくは３０～１５０℃である。反応時間は、例えば、１２～２４時間、好ましくは１２～１４時間である。 <Step (A)>
Step (A) is a step of reacting a compound represented by formula (1-1) with a compound represented by formula (3) to obtain a compound represented by formula (1-2).
In formula (1-1), examples of the leaving group represented by ^Z1 include a halogen atom (e.g., a chlorine atom, a bromine atom, an iodine atom), an alkylsulfonyloxy (e.g., a _C1-4 alkylsulfonyloxy such as mesyloxy), a haloalkylsulfonyloxy (e.g., a perfluoro _C1-4 alkylsulfonyloxy such as trifluoromethylsulfonyloxy), and an arylsulfonyloxy (e.g., a _C6-10 arylsulfonyloxy such as tosyloxy).
^Z2 is preferably a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkylcarbonyl group.
When the group represented by the formula: Z ² OC(═O)— and the hydroxyl group which can be substituted at the ortho position thereof form a ring together with the adjacent constituent atom of A ¹ , the compound represented by formula (1-1) is preferably a compound represented by the following formula (1-1-1):

(In the formula, ^Z21 and ^Z22 are the same or different and each is a hydrogen atom, an alkyl group, or an aryl group, and ^A1 and ^Z1 are the same as defined above.)
Z ²¹ and Z ²² are each preferably a hydrogen atom, a C _1-4 alkyl group, or a C _6-10 aryl group.
Suitable combinations of Z ²¹ and Z ²² include a combination in which Z ²¹ and Z ²² are both hydrogen atoms, a combination in which Z ²¹ and Z ²² are both alkyl groups, and a combination in which Z ²¹ is a hydrogen atom and Z ²² is an aryl group.
In the formula (3), examples of the alkali metal represented by M include lithium, sodium, and potassium.
The amount of the compound represented by formula (3) used is usually 1 to 5 mol, preferably 1.5 to 3.0 mol, and more preferably 1.5 to 2.0 mol, per mol of the compound represented by formula (1-1).
The reaction in step (A) is preferably carried out in the presence of a base.
Examples of the base include trialkylamines (e.g., tri-C _1-4 alkylamines such as triethylamine) and carbonates (e.g., alkali metal carbonates such as Na ₂ CO ₃ and K ₂ CO ₃ ). These bases can be used alone or in combination of two or more. Among these, trialkylamines are preferred.
The amount of the base used is usually 1 to 5 mol, preferably 1.5 to 3.0 mol, and more preferably 1.5 to 2.0 mol, per 1 mol of the compound represented by formula (1-1).
The reaction in step (A) is preferably carried out in the presence of a catalyst.
Examples of the catalyst include palladium catalysts [e.g., tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), palladium on carbon, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II), trans-dichlorobis(tricyclohexylphosphine)palladium(II), dichlorobis(tri-o-tolylphosphine)palladium(II), dichlorobis(triphenylphosphine)palladium(II), palladium acetate(II)], nickel catalysts [e.g., dichloro[1,1'-bis(diphenylphosphino)ferrocene]nickel(II), dichlorobis(triphenylphosphine)nickel(II)], and ruthenium catalysts. These catalysts can be used alone or in combination of two or more. Among these, palladium catalysts are preferred.
The amount of the catalyst used is usually 0.1 to 1.0 mol, preferably 0.1 to 0.5 mol, and more preferably 0.1 to 0.2 mol, per mol of the compound represented by formula (1-1). The reaction in step (A) is preferably carried out in the presence of a solvent.
Examples of the solvent include water, alcohol-based solvents (e.g., methanol, ethanol), and ether-based solvents (e.g., chain ethers such as diethyl ether, and cyclic ethers such as tetrahydrofuran and dioxane). These solvents can be used alone or in combination. Among these, alcohol-based solvents are preferred.
In the reaction of step (A), the reaction temperature and reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, 20 to 200° C., preferably 30 to 150° C. The reaction time is, for example, 12 to 24 hours, preferably 12 to 14 hours.

<Step (B)>
The step (B) is a step of reacting a compound represented by formula (1-2) with a compound represented by formula (4) to obtain a compound represented by formula (1-3).
In formula (4), the silyl group represented by ^Z3 is not particularly limited, and examples thereof include trialkylsilyl (e.g., _triC1-4 alkylsilyl such as trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, etc.) and alkyldiarylsilyl (e.g., _{C1-4 alkyldiC6-10} arylsilyl such as t-butyldiphenylsilyl).
The amount of the compound represented by formula (4) used is usually 1.0 to 1.5 mol, preferably 1.0 to 1.2 mol, and more preferably 1.0 to 1.1 mol, per mol of the compound represented by formula (1-2).
The reaction in step (B) is preferably carried out in the presence of a base.
Examples of the base include alkali metal amides such as lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS), etc. These bases can be used alone or in combination of two or more.
The amount of the base used is usually 1 to 3 moles, preferably 1.5 to 2.5 moles, and more preferably 2.0 to 2.5 moles, per mole of the compound represented by formula (1-2).
The reaction in step (B) is preferably carried out in the presence of a solvent.
Examples of the solvent include ether solvents (e.g., chain ethers such as diethyl ether, and cyclic ethers such as tetrahydrofuran and dioxane). These solvents can be used alone or in combination of two or more kinds.
In the reaction of step (B), the reaction temperature and reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, −10° C. to 10° C., preferably −5° C. to 5° C. The reaction time is, for example, 0.2 to 2.0 hours, preferably 0.5 to 1.0 hour.

<Step (C)>
Step (C) is a step of removing the silyl group ^Z3 from the compound represented by formula (1-3) to obtain a compound represented by formula (1-4).
The silyl group ^Z3 can be removed by a conventional method, for example, by reacting the compound represented by formula (1-3) with a fluorine compound.
Examples of the fluorine compound include an amine complex of hydrogen fluoride, a metal fluoride (e.g., potassium fluoride), ammonium fluoride, and tetrabutylammonium fluoride (TBAF). These fluorine compounds can be used alone or in combination. Among these, TBAF is preferred.
The reaction in step (C) is preferably carried out in the presence of a solvent.
Examples of the solvent include carboxylic acid solvents (e.g., acetic acid) and ether solvents (e.g., chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane). These solvents can be used alone or in combination of two or more. Among these, carboxylic acid solvents are preferred.
In the reaction of step (C), the reaction temperature and reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, −5° C. to 40° C., preferably 0 to 30° C. The reaction time is, for example, 6 to 24 hours, preferably 12 to 15 hours.

<Step (D)>
The step (D) is a step of reacting the compound represented by formula (1-4) with the compound represented by formula (5) to obtain the compound represented by formula (1-5).
In formula (5), examples of the leaving group represented by L include a halogen atom (e.g., a chlorine atom, a bromine atom, an iodine atom), alkylsulfonyloxy (e.g., C _1-4 alkylsulfonyloxy such as mesyloxy), haloalkylsulfonyloxy (e.g., perfluoro C _1-4 alkylsulfonyloxy such as trifluoromethylsulfonyloxy), arylsulfonyloxy (e.g., C _6-10 arylsulfonyloxy such as tosyloxy), and a group represented by the formula: N(R ^L1 )(R ^L2 )- (wherein R ^L1 and R ^L2 are the same or different and are an alkyl group or an alkoxy group).
Of these, a group represented by the formula: N(R ^L1 )(R ^L2 )- is preferred. R ^L1 and R ^L2 are each preferably a C _1-4 alkyl group or a C _1-4 alkoxy group. A suitable combination of R ^L1 and R ^L2 is a combination in which R ^L1 is an alkyl group and R ^L2 is an alkoxy group.
The amount of the compound represented by formula (5) used is usually 1.0 to 1.5 mol, preferably 1.0 to 1.2 mol, and more preferably 1.0 to 1.1 mol, per 1 mol of the compound represented by formula (1-4).
The reaction in step (D) is preferably carried out in the presence of a base.
Examples of the base include alkyl alkali metal salts (e.g., butyl lithium) and alkali metal amides (e.g., LDA, LHMDS, NaHMDS, KHMDS). These bases can be used alone or in combination of two or more. Among these bases, alkyl alkali metal salts are preferred.
The amount of the base used is usually 1.0 to 1.5 mol, preferably 1.0 to 1.2 mol, and more preferably 1.0 to 1.1 mol, per 1 mol of the compound represented by formula (1-3). The reaction in step (D) is preferably carried out in the presence of a solvent.
Examples of the solvent include ether solvents (e.g., chain ethers such as diethyl ether, and cyclic ethers such as tetrahydrofuran and dioxane). These solvents can be used alone or in combination of two or more kinds.
In the reaction of step (D), the reaction temperature and reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, −10° C. to 10° C., preferably −5° C. to 5° C. The reaction time is, for example, 0.2 to 1.0 hour, preferably 0.3 to 0.5 hour.

<Step (E)>
Step (E) is a step of reacting the compound represented by formula (1-5) with a triple bond protecting agent to obtain a compound represented by formula (1-6).
_An example of a triple bond protecting agent is _Co2CO8 .
The amount of the triple bond protecting agent used is usually 2 to 10 moles, preferably 3 to 6 moles, and more preferably 4 to 5 moles, per mole of the compound represented by formula (1-5).
The reaction in step (E) is preferably carried out in the presence of a solvent.
Examples of the solvent include halogen-based solvents (e.g., dichloromethane). These solvents can be used alone or in combination.
In the reaction of step (E), the reaction temperature and reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, −10° C. to 10° C., preferably −5° C. to 5° C. The reaction time is, for example, 6 to 24 hours, preferably 12 to 15 hours.

触媒の使用量は、式（１－６）で表される化合物１モルに対して、通常、０．１～１．０モル、好ましくは０．２～１．０モル、さらに好ましくは０．４～１．０モルである。 工程（Ｆ）の反応は、溶媒の存在下で行うことが好ましい。
溶媒としては、例えば、ハロゲン系溶媒（例：ジクロロメタン）が挙げられる。これらの溶媒は単独で又は二種以上組み合わせて使用することができる。
工程（Ｆ）の反応において、反応温度及び反応時間は、反応が進行する限り特に制限されるものではない。反応温度は、例えば、－１０℃～１０℃、好ましくは－５℃～５℃である。反応時間は、例えば、９６～１４４時間、好ましくは９６～１２０時間である。 <Step (F)>
In step (F), a compound of formula (1-6) is cyclized and, if necessary, hydrogenated to obtain a compound of formula (1-7).
The cyclization can be carried out by a conventional method, for example, the compound represented by formula (1-6) can be cyclized by metathesis reaction in the presence of a catalyst.
Examples of the catalyst include a catalyst represented by the following formula (second generation Pierce-Grubbs catalyst).

The amount of the catalyst used is usually 0.1 to 1.0 mol, preferably 0.2 to 1.0 mol, and more preferably 0.4 to 1.0 mol, per 1 mol of the compound represented by formula (1-6). The reaction in step (F) is preferably carried out in the presence of a solvent.
Examples of the solvent include halogen-based solvents (e.g., dichloromethane). These solvents can be used alone or in combination.
In the reaction of step (F), the reaction temperature and reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, −10° C. to 10° C., preferably −5° C. to 5° C. The reaction time is, for example, 96 to 144 hours, preferably 96 to 120 hours.

<Step (G)>
Step (G) is a step of removing the protective group of the triple bond from the compound represented by formula (1-7) to obtain the compound represented by formula (1).
The deprotection can be carried out by a conventional method. For example, the protecting group of the triple bond can be removed by reacting the compound represented by formula (1-7) with a deprotecting agent [e.g., ammonium hexanitratocerate(IV) (CAN), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), N-methylmorpholine N-oxide, or a combination thereof].
The amount of the deprotecting agent used is usually 4 to 10 mol, preferably 4 to 8 mol, and more preferably 4 to 6 mol, per mol of the compound represented by formula (1-7).
The reaction in step (G) is preferably carried out in the presence of a solvent.
Examples of the solvent include halogen-based solvents (e.g., dichloromethane), ether-based solvents (e.g., chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran and dioxane), and ketone-based solvents (e.g., acetone and methyl ethyl ketone). These solvents can be used alone or in combination of two or more. Among these, ketone-based solvents are preferred.
In the reaction of step (G), the reaction temperature and reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, −10° C. to 10° C., preferably −5° C. to 5° C. The reaction time is, for example, 1 to 8 hours, preferably 1 to 2 hours.

The method for producing compound (1) may include a step of purifying the intermediate product and/or the final product, if necessary. Purification can be carried out by conventional methods, such as filtration or chromatography.
Alternatively, a suitable protecting group may be introduced before the reaction and then removed after the reaction. Protection and deprotection can be carried out by a conventional method.

The method for producing compound (1) may include a step of separating isomers as necessary. Separation of isomers can be carried out by conventional methods.

（式中、Ｘ^３及びＲ^６～Ｒ^９は、前記と同じである。） <Compound (2)>
In another embodiment, the compound or a salt thereof of the present invention is a compound represented by formula (2) or a salt thereof (hereinafter referred to as “compound (2)”):

(In the formula, ^X3 and ^R6 to ^R9 are the same as defined above.)

（式中、＊は、Ｒ^９との結合位置を示す）
Ｘ^３が二重結合であり、且つ、Ｒ^９がアルキル基又はアリール基である場合、化合物（２）は、シス体又はトランス体であることができる。 As described above, ^X3 is a single bond, a double bond, or a triple bond.

(In the formula, * indicates the bonding position with ^R9 .)
When ^X3 is a double bond and ^R9 is an alkyl group or an aryl group, compound (2) can be in a cis or trans form.

（式中、Ｘ^４は、ヒドロキシル基、メルカプト基、又はアミノ基であり、Ｒ^６１及びＲ^６２は、同一又は異なって、水素原子又はアルキル基である）
で表される基である。
Ｘ^４は、好ましくはヒドロキシル基である。
Ｒ^６１は、好ましくはアルキル基であり、さらに好ましくはＣ_１－４アルキル基であり、特に好ましくはＣ_１－２アルキル基である。
なお、Ｒ^６１がアルキル基である場合、Ｒ^６１が結合する炭素原子は、不斉炭素原子である。この不斉炭素原子の立体配置は、Ｒ配置又はＳ配置のいずれであってもよいが、Ｓ配置であるのが好ましい。 ^R6 is preferably a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted heteroaryl group (e.g., a furanyl group, a thienyl group, a pyridyl group), more preferably an optionally substituted alkyl group, even more preferably an optionally substituted _C1-6 alkyl group, and particularly preferably an optionally substituted _C1-4 alkyl group.
Examples of the substituent include a hydroxyl group, a mercapto group, an amino group, an alkoxy group, an alkoxyalkoxy group, and an alkoxyalkoxyalkoxy group. Among these, a hydroxyl group, a mercapto group, or an amino group is preferred.
The number of the substituents is preferably an integer of 1 to 3, and more preferably 1 or 2.
^R6 is preferably represented by the following formula:

(In the formula, ^X4 is a hydroxyl group, a mercapto group, or an amino group, and ^R61 and ^R62 are the same or different and are a hydrogen atom or an alkyl group.)
It is a group represented by the following formula:
^X4 is preferably a hydroxyl group.
R ⁶¹ is preferably an alkyl group, more preferably a C _1-4 alkyl group, and particularly preferably a C _1-2 alkyl group.
When R ⁶¹ is an alkyl group, the carbon atom to which R ⁶¹ is bonded is an asymmetric carbon atom. The configuration of this asymmetric carbon atom may be either the R configuration or the S configuration, but is preferably the S configuration.

R ⁶² is preferably a hydrogen atom or a C _1-4 alkyl group, more preferably a hydrogen atom or a C _1-2 alkyl group, and particularly preferably a hydrogen atom.
When R ⁶² is an alkyl group, the carbon atom to which R ⁶² is bonded is an asymmetric carbon atom. The configuration of this asymmetric carbon atom may be either the R configuration or the S configuration, but is preferably the R configuration.

R ⁷ and R ⁸ are each preferably a hydrogen atom, an alkyl group, an alkoxyalkyl group, or an aryl group, more preferably a hydrogen atom, an alkyl group, or an alkoxyalkyl group, still more preferably a hydrogen atom, a C _1-4 alkyl group, or a C _1-4 alkoxy C _1-4 alkyl group, and particularly preferably a hydrogen atom, a C _1-2 alkyl group, or a C _1-2 alkoxy C _1-2 alkyl group.

（式中、Ｒ^７ａ及びＲ^８ａは、前記と同じであり、＊は、カルボニル炭素との結合位置を示す）
で表される環が好ましい。
Ｒ^７ａ及びＲ^８ａは、それぞれ、好ましくは、水素原子、Ｃ_１－４アルキル基、又はＣ_６－１０アリール基である。
Ｒ^７ａ及びＲ^８ａの好適な組合せとしては、Ｒ^７ａ及びＲ^８ａが共に水素原子である組合せ、Ｒ^７ａ及びＲ^８ａが共にアルキル基である組合せ、Ｒ^７ａが水素原子であり、且つ、Ｒ^８ａがアリール基である組合せが挙げられる。
なお、Ｒ^７Ｏ及びＲ^８Ｏが結合する炭素原子は、不斉炭素原子である。Ｒ^７Ｏ及びＲ^８Ｏが結合する不斉炭素原子の立体配置は、それぞれ、Ｒ配置又はＳ配置のいずれであってもよいが、共にＳ配置であることが好ましい。 It is preferable that R ⁷ O and R ⁸ O form a ring together with the two adjacent carbon atoms, and the ring is represented by the following formula:

(In the formula, R ^7a and R ^8a are the same as defined above, and * indicates the bonding position to the carbonyl carbon.)
A ring represented by the following formula is preferred.
R ^7a and R ^8a are each preferably a hydrogen atom, a C _1-4 alkyl group, or a C _6-10 aryl group.
Suitable combinations of R ^7a and R ^8a include a combination in which R ^7a and R ^8a are both hydrogen atoms, a combination in which R ^7a and R ^8a are both alkyl groups, and a combination in which R ^7a is a hydrogen atom and R ^8a is an aryl group.
The carbon atoms to which R ⁷ O and R ⁸ O are bonded are asymmetric carbon atoms. The configurations of the asymmetric carbon atoms to which R ⁷ O and R ⁸ O are bonded may be either the R configuration or the S configuration, but it is preferable that both are the S configuration.

R ⁹ is preferably a hydrogen atom or an alkyl group, more preferably a hydrogen atom or a C _1-4 alkyl group, particularly preferably a hydrogen atom or a C _1-2 alkyl group, and most preferably a hydrogen atom.

Compound (2) has at least two asymmetric carbon atoms (carbon atoms to which R ⁷ O and R ⁸ O are bonded) and includes both enantiomers and diastereomers. Compound (2) may be a mixture containing two enantiomers. The mixture may be a mixture containing an excess of one enantiomer, or may be an equal mixture of two enantiomers (racemate).

（式中、Ｘ^３、Ｒ^６、Ｒ^７、Ｒ^８、及びＲ^９は、前記と同じである。但し、下記式：

で表される化合物を除く。） In a preferred embodiment, compound (2) is a compound represented by the following formula (2A) or a salt thereof:

(In the formula, X ³ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are the same as defined above. However, when the compound represented by the formula:

(Excluding compounds represented by the formula:

In another preferred embodiment, compound (2) is a compound selected from the following group or a salt thereof:

When compound (2) is in the form of a salt, the salt is preferably a pharma- ceutical acceptable salt.
The salt can be an inorganic salt or an organic salt.
Examples of such salts include inorganic acid salts (e.g., hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate, and phosphate), organic acid salts (e.g., methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, and maleate), and amino acid salts (e.g., glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate).

［式中、
Ｑ^１～Ｑ^３は、同一又は異なって、アルキル基又はアリール基であり、
Ｑ^４は、ハロゲン化物イオンであり、
Ｑ^５は、トリアルキルシリル基又はアルキルジアリールシリル基であり、
Ｒ^１０及びＲ^１１は、同一又は異なって、アルキル基、アルコキシ基、又はアリール基であり、
Ｒ^６～Ｒ^９は、前記と同じである。］ <Method for producing compound (2)>
A compound or a salt thereof in which R ⁷ and R ⁸ of formula (2) are the same or different and each is an alkyl group, an acyl group, an alkoxyalkyl group, or an aryl group (corresponding to a protecting group for a hydroxyl group), or a compound or a salt thereof in which R ⁷ O and R ⁸ O form a ring together with the two adjacent carbon atoms (corresponding to a protecting group for a hydroxyl group), can be produced, for example, according to the following reaction scheme.

[Wherein,
Q ¹ to Q ³ are the same or different and each is an alkyl group or an aryl group;
^Q4 is a halide ion;
^Q5 is a trialkylsilyl group or an alkyldiarylsilyl group;
R ¹⁰ and R ¹¹ are the same or different and each is an alkyl group, an alkoxy group, or an aryl group;
R ⁶ to R ⁹ are the same as defined above.

<Step (a)>
The step (a) is a step of reacting a compound represented by formula (2-1) with a compound represented by formula (6) to obtain a compound represented by formula (2-2).
In formula (6), Q ¹ to Q ³ are each preferably an aryl group, more preferably a C _6-10 aryl group.
^Q4 is preferably a bromide ion or a chloride ion.
Examples of the compound represented by formula (6) include methyltriphenylphosphonium bromide, ethyltriphenylphosphonium bromide, propyltriphenylphosphonium bromide, butyltriphenylphosphonium bromide, pentyltriphenylphosphonium bromide, hexyltriphenylphosphonium bromide, heptyltriphenylphosphonium bromide, benzyltriphenylphosphonium bromide, (1-naphthylmethyl)triphenylphosphonium bromide, and chlorides corresponding thereto. These compounds can be used alone or in combination of two or more.
The amount of the compound represented by formula (6) used is usually 1 to 5 moles, preferably 2 to 4 moles, and more preferably 3 to 4 moles, per mole of the compound represented by formula (2-1).
The reaction in step (a) is preferably carried out in the presence of a base.
Examples of the base include alkyl alkali metals (eg, n-butyllithium) and alkali metal amides (eg, LDA, LHMDS, NaHMDS, KHMDS).
The amount of the base used is usually 1 to 5 moles, preferably 2 to 4 moles, and more preferably 3 to 4 moles, per mole of the compound represented by formula (2-1).
The reaction in step (a) is preferably carried out in the presence of a solvent.
Examples of the solvent include ether solvents (e.g., chain ethers such as diethyl ether, and cyclic ethers such as tetrahydrofuran and dioxane). These solvents can be used alone or in combination.
In the reaction of step (a), the reaction temperature and reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, −100 to 10° C., preferably −80 to 0° C. The reaction time is, for example, 1 to 24 hours, preferably 4 to 12 hours.

<Step (b)>
The step (b) is a step of hydrogenating the compound represented by the formula (2-2) to obtain a compound represented by the formula (2-3).
The amount of hydrogen used is usually 1 to 50 mol, preferably 2 to 40 mol, and more preferably 10 to 20 mol, per mol of the compound represented by formula (2-2).
The reaction in step (b) is preferably carried out in the presence of a catalyst.
The catalyst may be any catalyst commonly used in hydrogenation, such as palladium on carbon or platinum on carbon.
The amount of the catalyst used is usually 0.01 to 1 mol, preferably 0.1 to 0.5 mol, and more preferably 0.2 to 0.3 mol, per mol of the compound represented by formula (2-2). The reaction in step (b) is preferably carried out in the presence of a solvent.
Examples of the solvent include alcohol-based solvents (e.g., methanol, ethanol), and ether-based solvents (e.g., chain ethers such as diethyl ether, and cyclic ethers such as tetrahydrofuran and dioxane). These solvents can be used alone or in combination of two or more. Among these, alcohol-based solvents are preferred.
In the reaction of step (b), the reaction temperature and reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, 0 to 50° C., preferably 5 to 35° C. The reaction time is, for example, 1 to 24 hours, preferably 10 to 12 hours.
It is also possible to omit step (b) and, prior to step (e), hydrogenate a compound of formula (2-5) in which ^X3 is a double bond in the same manner as in step (b) to obtain a compound of formula (2-5) in which ^X3 is a single bond.

<Step (c)>
The step (c) is a step of reacting the compound represented by formula (2-1) with the compound represented by formula (7) to obtain the compound represented by formula (2-4).
In formula (7), examples of the trialkylsilyl group represented by ^Q5 include _{triC1-4 alkylsilyl such as trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, etc. Examples of the alkyldiarylsilyl group represented by Q5 include C1-4} ^alkyldiC6-10 _{arylsilyl such} as t-butyldiphenylsilyl, etc.
The amount of the compound represented by formula (7) used is usually 1 to 5 moles, preferably 2 to 4 moles, and more preferably 3 to 4 moles, per mole of the compound represented by formula (2-1).
The reaction in step (c) is preferably carried out in the presence of a base.
Examples of the base include alkali metal amides (e.g., LDA, lithium 2,2,6,6-tetramethylpiperazine, LHMDS, NaHMDS, and KHMDS). The amount of the base used is usually 0.8 to 1.2 mol, preferably 0.9 to 1.1 mol, and more preferably 1.0 to 1.1 mol, per mol of the compound represented by formula (2-1). The reaction in step (c) is preferably carried out in the presence of a solvent.
Examples of the solvent include ether solvents (e.g., chain ethers such as diethyl ether, and cyclic ethers such as tetrahydrofuran and dioxane). These solvents can be used alone or in combination of two or more kinds.
In the reaction of step (c), the reaction temperature and reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, −100 to 10° C., preferably −80 to 0° C. The reaction time is, for example, 1 to 24 hours, preferably 10 to 12 hours.

<Step (d)>
The step (d) is a step of reacting a compound represented by the formula (2-2), (2-3), or (2-4) with an oxidizing agent to obtain a compound represented by the formula (2-5).
The oxidizing agent may be a nitroxy radical-based oxidizing agent, such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), 2-azaadamantane-N-oxyl (AZADO), or the like.
The amount of the oxidizing agent used is usually 0.1 to 1.0 mol, preferably 0.1 to 0.5 mol, and more preferably 0.2 to 0.3 mol, per mol of the compound represented by formula (2-2), (2-3), or (2-4).
The oxidizing agent may be used in conjunction with a reoxidizing agent.
Examples of the reoxidizing agent include sodium hypochlorite and iodobenzene diacetate. These reoxidizing agents can be used alone or in combination. The amount of the reoxidizing agent used is usually 1 to 3 moles, preferably 1.0 to 2.5 moles, and more preferably 2.0 to 2.5 moles, per mole of the compound represented by formula (2-2), (2-3), or (2-4).
The reaction in step (d) may be carried out in the presence of a base.
The reaction in step (d) is preferably carried out in the presence of a solvent.
Examples of the solvent include water, nitrile-based solvents (e.g., acetonitrile), and halogen-based solvents (e.g., dichloromethane). These solvents can be used alone or in combination.
In the reaction of step (d), the reaction temperature and reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, −20 to 15° C., preferably −10 to 10° C. The reaction time is, for example, 1 to 5 hours, preferably 3 to 4 hours.

<Step (e)>
The step (e) is a step of reacting the compound represented by formula (2-5) with the compound represented by formula (8) to obtain the compound represented by formula (2-6).
In formula (8), R ¹⁰ and R ¹¹ are preferably a C _1-4 alkyl group, a C _1-4 alkoxy group, or a C _6-12 aryl group, preferably a C _1-4 alkyl group or a C _1-4 alkoxy group, and more preferably a C _1-2 alkyl group or a C _1-2 alkoxy group.
A suitable combination of R ¹⁰ and R ¹¹ includes a combination in which R ¹⁰ is an alkyl group and R ¹¹ is an alkoxy group.
The amount of the compound represented by formula (8) used is usually 1 to 2 moles, preferably 1.1 to 1.5 moles, and more preferably 1.2 to 1.4 moles, per mole of the compound represented by formula (2-5).
The reaction in step (e) is preferably carried out in the presence of a condensing agent.
Condensation agents include, for example, N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(dimethylaminopropyl)carbodiimide (EDC), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate (HBTU), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide tetrafluoroborate (TATU), 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide tetrafluoroborate (TBTU), and diphenylphosphoryl azide (DPPA). These condensation agents can be used alone or in combination of two or more.
The amount of the condensing agent used is usually 1 to 3 mol, preferably 1.2 to 2.5 mol, and more preferably 1.2 to 1.5 mol, per mol of the compound represented by formula (2-5).
The reaction in step (e) is preferably carried out in the presence of a base.
Examples of the base include trialkylamines (e.g., triC _1-4 alkylamines such as triethylamine), N-methylmorpholine, and N,N-dimethylaminopyridine. These bases can be used alone or in combination of two or more.
The amount of the base used is usually 1 to 5 mol, preferably 1.1 to 2.0 mol, and more preferably 1.2 to 1.5 mol, per mol of the compound represented by formula (2-5).
The reaction in step (e) is preferably carried out in the presence of a solvent.
Examples of the solvent include halogen-based solvents (e.g., dichloromethane) and ether-based solvents (e.g., chain ethers such as diethyl ether, and cyclic ethers such as tetrahydrofuran and dioxane). These solvents can be used alone or in combination.
In the reaction of step (e), the reaction temperature and reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, −20 to 15° C., preferably −10 to 10° C. The reaction time is, for example, 12 to 24 hours, preferably 12 to 20 hours.

<Step (f)>
The step (f) is a step of reacting the compound represented by formula (2-6) with the compound represented by formula (9) to obtain the compound represented by formula (2).
The amount of the compound represented by formula (9) used is usually 1.0 to 1.5 mol, preferably 1.0 to 1.3 mol, and more preferably 1.0 to 1.1 mol, per mol of the compound represented by formula (2-6).
The reaction in step (f) is preferably carried out in the presence of a base.
Examples of the base include alkyl alkali metal salts (e.g., butyl lithium) and alkali metal amides (e.g., LDA, LHMDS, NaHMDS, KHMDS). These bases can be used alone or in combination of two or more. Among these bases, alkyl alkali metal salts are preferred.
The amount of the base used is usually 1.0 to 1.5 mol, preferably 1.0 to 1.3 mol, and more preferably 1.0 to 1.1 mol, per 1 mol of the compound represented by formula (2-6). The reaction in step (f) is preferably carried out in the presence of a solvent.
Examples of the solvent include ether solvents (e.g., chain ethers such as diethyl ether, and cyclic ethers such as tetrahydrofuran and dioxane). These solvents can be used alone or in combination of two or more kinds.
In the reaction of step (f), the reaction temperature and reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, −10° C. to 10° C., preferably −5° C. to 5° C. The reaction time is, for example, 1 to 5 hours, preferably 2 to 3 hours.

In the formula (2), the compound in which R ⁷ and R ⁸ are hydrogen atoms can be produced by deprotecting the compound in which R ⁷ and R ⁸ are hydroxyl-protecting groups, obtained according to the above reaction scheme, by a conventional method.

The method for producing compound (2) may include a step of purifying the intermediate product and/or the final product, if necessary. Purification can be carried out by conventional methods, such as filtration or chromatography.
Alternatively, a suitable protecting group may be introduced before the reaction and then removed after the reaction. Protection and deprotection can be carried out by a conventional method.

The method for producing compound (2) may include a step of separating isomers as necessary. Separation of isomers can also be carried out by conventional methods.

<Pharmaceutical Composition>
The pharmaceutical composition contains at least one compound (1) or (2) (hereinafter referred to as the "active ingredient").
The lower limit of the content of the active ingredient is, for example, 0.001% by mass, preferably 0.01% by mass, and more preferably 0.05% by mass, based on the total mass of the pharmaceutical composition, in terms of activity. The upper limit of the content of the active ingredient is not particularly limited, and is, for example, 99% by mass, 95% by mass, or 90% by mass, based on the total mass of the pharmaceutical composition. The content of the active ingredient is within an arbitrarily selected range between the lower limit and upper limit, for example, 0.001 to 99% by mass, preferably 0.01 to 95% by mass, and more preferably 0.05 to 90% by mass.

The pharmaceutical composition may further contain an additive, preferably a pharma- ceutically acceptable additive.
The pharmaceutical composition may be in the form of a solid preparation (e.g., granules, powders, tablets, capsules, dry syrup), a semi-solid preparation (e.g., cream, ointment, gel), or a liquid preparation (e.g., injection).
The solid preparation can be produced, for example, by mixing the active ingredient and additives (e.g., excipients, binders, disintegrants, lubricants, colorants) and, if necessary, granulating, sizing, compressing, and/or coating the mixture.
The semi-solid preparation can be produced, for example, by mixing the active ingredient, the semi-solid carrier, and optionally other additives.
The liquid formulation can be produced, for example, by mixing an active ingredient, a liquid carrier [e.g., an aqueous carrier (e.g., purified water), an oily carrier], and other additives as desired (e.g., emulsifiers, dispersing agents, suspending agents, buffers, antioxidants, surfactants, osmotic pressure regulators, chelating agents, antibacterial agents), and sterilizing the mixture as necessary.

The pharmaceutical composition may be administered orally or parenterally (e.g., intravenously, intramuscularly, subcutaneously). The pharmaceutical composition may be administered topically.
The subject to which the pharmaceutical composition is administered may be any of humans, non-human mammals (eg, monkeys, sheep, dogs, mice, rats), and non-mammals.

<Unfolded protein response inducers>
The endoplasmic reticulum stress response inducer contains at least one (active ingredient) selected from compounds (1) and (2). The content of the active ingredient, the type of optional additive, the dosage form, and the administration form of the endoplasmic reticulum stress response inducer may be the same as those described for the pharmaceutical composition.

<Protein disulfide isomerase inhibitors>
The protein disulfide isomerase inhibitor (PDI inhibitor) contains at least one active ingredient selected from compounds (1) and (2). The content of the active ingredient, the type of optional additive, the dosage form, and the administration form of the PDI inhibitor may be the same as those described for the pharmaceutical composition.

<Disease prevention or treatment agent>
The preventive or therapeutic agent for a disease contains at least one type (active ingredient) selected from compounds (1) and (2).
Since the compound of the present invention can induce an endoplasmic reticulum stress response, the disease may be a disease in which endoplasmic reticulum stress is involved.In addition, since the compound of the present invention can inhibit the activity of PDI, the disease may be a disease in which PDI is involved.
Examples of the disease include cancer (e.g., blood cancer such as multiple myeloma), diabetes (e.g., type 1 diabetes, type 2 diabetes), inflammatory diseases (e.g., inflammatory bowel disease, rheumatism), neurodegenerative diseases (e.g., Parkinson's disease, Huntington's disease, Alzheimer's disease), and diseases associated with these diseases (e.g., bone disease associated with multiple myeloma).
The disease is preferably at least one selected from cancer, bone disease, and rheumatism.
In the preventive or therapeutic agent for a disease, the content of the active ingredient, the type of any additive, the dosage form, and the administration mode can be the same as those described for the pharmaceutical composition.

The present invention will be described in more detail below based on examples, but the present invention is not limited to these examples.

In the examples below, the progress of the reaction was monitored by thin layer chromatography, and 1H-NMR was used to identify the compounds.

既知化合物((4R,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)メタノール 4.07 g (23.6 mmo)にアセトニトリル 80 mLと精製水 40 mLに溶解させた後、ヨードベンゼンジアセテート 17.0 g (52.0 mmol)と2,2,6,6-テトラメチルピペリジン1-オキシル フリーラジカル 734 mg (4.70 mmol)を室温で加えた。室温で2時間撹拌した後、精製水を加え、酢酸で反応液を酸性にしてから、酢酸エチルで分液を5回行った。得られた有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去して(4S,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-カルボン酸の粗生成物を得た。
この粗生成物をジクロロメタン 118 mLに溶解させた後、0度に冷却し、N-メチルモルホリン 2.9 mL (26.0 mmol)、N,O-ジメチルヒドロキシアミン塩酸塩 2.50 g (26.0 mmol)と1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド 5.00 g (26.0 mmol)を加えた。0度で1時間撹拌した後、精製水を加え、ジクロロメタンで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。得られた粗生成物を酢酸 192 mLと精製水 48 mLに溶解させた後、60度で12時間撹拌した。溶媒を減圧留去した後、トルエンを加えた共沸操作により酢酸を除去した。
得られた組成生物をジクロロメタン118 mLに溶解した後、0度に冷却した。ここにN,N-ジイソプロピルエチルアミン 611 mL (354 mmol)とクロロメチルメチルエーテル 18.8 mL (236 mmol)、テトラブチルアンモニウムヨージド 26.0 g (71.0 mmol)を0度で加えた。30度で20時間撹拌した後、0度に冷却し、飽和塩化アンモニウム水溶液を加え、ジクロロメタンで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン= 4 : 6 から 2 : 8)にて精製し、(2S,3S)-N-メトキシ-2,3-ビス (メトキシメトキシ)-N-メチルヘキセ-5-エナミドを得た (5.20 g、収率79%)。
¹H-NMR (CDCl₃, 400 MHz) δppm: 5.90 (m, 1H), 5.13 (d, J = 17.6 Hz, 1H), 5.10 (d, J = 9.2 Hz, 1H), 4.69-4.61 (overlapped, 5H), 3.96 (m, 1H), 3.75 (s, 3H), 3.37 (s, 3H), 3.36 (s, 3H), 3.22 (s, 3H), 2.52-2.42 (overlapped, 2H) Example 1 11E-ynone macrolide A
(1-1) (2S,3S)-N-Methoxy-2,3-bis(methoxymethoxy)-N-methylhex-5-enamide was synthesized as follows.

The known compound ((4R,5R)-5-allyl-2,2-dimethyl-1,3-dioxolane-4-yl)methanol 4.07 g (23.6 mmo) was dissolved in 80 mL of acetonitrile and 40 mL of purified water, and then 17.0 g (52.0 mmol) of iodobenzene diacetate and 734 mg (4.70 mmol) of 2,2,6,6-tetramethylpiperidine 1-oxyl free radical were added at room temperature. After stirring at room temperature for 2 hours, purified water was added, the reaction solution was acidified with acetic acid, and then the liquid was separated five times with ethyl acetate. Sodium sulfate was added to the obtained organic layer to remove water. The solvent was distilled off under reduced pressure to obtain the crude product of (4S,5R)-5-allyl-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid.
This crude product was dissolved in 118 mL of dichloromethane, cooled to 0 degrees, and 2.9 mL (26.0 mmol) of N-methylmorpholine, 2.50 g (26.0 mmol) of N,O-dimethylhydroxyamine hydrochloride, and 5.00 g (26.0 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide were added. After stirring at 0 degrees for 1 hour, purified water was added and the mixture was separated three times with dichloromethane. The organic layer obtained was washed with saturated saline, sodium sulfate was added to the organic layer to remove water, and the solvent was distilled off under reduced pressure. The crude product obtained was dissolved in 192 mL of acetic acid and 48 mL of purified water, and then stirred at 60 degrees for 12 hours. After the solvent was distilled off under reduced pressure, acetic acid was removed by azeotropic operation with toluene added.
The obtained crude product was dissolved in 118 mL of dichloromethane and cooled to 0°C. 611 mL (354 mmol) of N,N-diisopropylethylamine, 18.8 mL (236 mmol) of chloromethyl methyl ether, and 26.0 g (71.0 mmol) of tetrabutylammonium iodide were added to the mixture at 0°C. After stirring at 30°C for 20 hours, the mixture was cooled to 0°C, a saturated aqueous solution of ammonium chloride was added, and the mixture was separated three times with dichloromethane. The obtained organic layer was washed with saturated saline, and then sodium sulfate was added to the organic layer to remove water, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate:hexane = 4:6 to 2:8) to obtain (2S,3S)-N-methoxy-2,3-bis (methoxymethoxy)-N-methylhex-5-enamide (5.20 g, yield 79%).
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 5.90 (m, 1H), 5.13 (d, J = 17.6 Hz, 1H), 5.10 (d, J = 9.2 Hz, 1H), 4.69-4.61 (overlapped, 5H), 3.96 (m, 1H), 3.75 (s , 3H), 3.37 (s, 3H), 3.36 (s, 3H), 3.22 (s, 3H), 2.52-2.42 (overlapped, 2H)

既知化合物(S)-5-(トリメチルシリル)ペント-4-イン-2-オール1.26 g (8.08 mmol)をテトラヒドロフラン108 mLに溶解した後、ナトリウムビス（トリメチルシリル）アミド溶液16.2 mL (16.2 mmol)を0度で加えた。0度で15分間撹拌した後、既知化合物7-メトキシ-2,2-ジメチル-5-ビニル-4H-ベンゾ[d][1,3]ジオキシン-4-オン 1.26 g (5.39 mmol)をテトラヒドロフランに溶解させて反応液に加えた。0度で20分間撹拌した後、酢酸 0.97 mL (16.2 mmol)とテトラブチルアンモニウムフルオリド 8.08 mL (8.08 mmol)を加え、室温で12時間撹拌した。0度に冷却後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。
得られた粗生成物をジクロロメタン 53.9 mLに溶解させた後、N,N-ジイソプロピルエチルアミン 9.4 mL (53.9 mmol)と2-メトキシエトキシメチルクロリド 3.07 mL (26.9 mmol)、テトラブチルアンモニウムヨージド 6.0 g (16.2 mmol)を加えた。40度で5時間撹拌した後、0度に冷却し、飽和塩化アンモニウム水溶液を加え、ジクロロメタンで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン= 4 : 6 から 2 : 8)にて精製し、(S)-ペント-4-イン-2-イル4-メトキシ-2-((2-メトキシエトキシ)メトキシ)-6-ビニルベンゾエートを得た (563 mg、収率30%)。
¹H-NMR (CDCl₃, 400 MHz) δppm: 6.41 (dd, J = 17.6, 10.8 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 5.70 (dd, J = 17.2, 1.2 Hz), 5.33-5.23 (overlapped, 4H), 3.83-3.81 (overlapped, 5H), 3.55 (m, 2H), 3.37 (s, 3H), 2.60 (ddd, J = 16.8, 5.6, 2.8 Hz, 1H), 2.54 (ddd, J = 16.8, 5.6, 2.8 Hz, 1H), 2.02 (t, J = 2.8 Hz, 1H), 1.44 (d, J = 6.4 Hz, 3H) (1-2) (S)-Pent-4-yn-2-yl 4-methoxy-2-((2-methoxyethoxy)methoxy)-6-vinylbenzoate was synthesized as follows.

1.26 g (8.08 mmol) of the known compound (S)-5-(trimethylsilyl)pent-4-yn-2-ol was dissolved in 108 mL of tetrahydrofuran, and then 16.2 mL (16.2 mmol) of sodium bis(trimethylsilyl)amide solution was added at 0°C. After stirring for 15 minutes at 0°C, 1.26 g (5.39 mmol) of the known compound 7-methoxy-2,2-dimethyl-5-vinyl-4H-benzo[d][1,3]dioxin-4-one was dissolved in tetrahydrofuran and added to the reaction solution. After stirring for 20 minutes at 0°C, 0.97 mL (16.2 mmol) of acetic acid and 8.08 mL (8.08 mmol) of tetrabutylammonium fluoride were added and stirred at room temperature for 12 hours. After cooling to 0°C, a saturated aqueous solution of ammonium chloride was added, and the mixture was separated three times with ethyl acetate. The obtained organic layer was washed with saturated saline, sodium sulfate was added to the organic layer, water was removed, and the solvent was distilled off under reduced pressure.
The obtained crude product was dissolved in 53.9 mL of dichloromethane, and then 9.4 mL (53.9 mmol) of N,N-diisopropylethylamine, 3.07 mL (26.9 mmol) of 2-methoxyethoxymethyl chloride, and 6.0 g (16.2 mmol) of tetrabutylammonium iodide were added. After stirring at 40 degrees for 5 hours, the mixture was cooled to 0 degrees, and a saturated aqueous solution of ammonium chloride was added. The mixture was separated three times with dichloromethane. The obtained organic layer was washed with saturated saline, and then sodium sulfate was added to the organic layer to remove water, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate:hexane = 4:6 to 2:8) to obtain (S)-pent-4-yn-2-yl 4-methoxy-2-((2-methoxyethoxy)methoxy)-6-vinylbenzoate (563 mg, yield 30%).
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 6.41 (dd, J = 17.6, 10.8 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 5.70 (dd, J = 17.2, 1.2 Hz), 5.33-5.23 (overlapped, 4H), 3.83-3.81 (overlapped, 5H), 3.55 (m, 2H), 3.37 (s, 3H), 2.60 (ddd, J = 16.8, 5.6, 2.8 Hz, 1H), 2.54 (ddd, J = 16.8, 5.6, 2. 8Hz, 1H), 2.02 (t, J = 2.8 Hz, 1H), 1.44 (d, J = 6.4 Hz, 3H)

（1-2）で製造した(S)-ペント-4-イン-2-イル4-メトキシ-2-((2-メトキシエトキシ)メトキシ)-6-ビニルベンゾエート106 mg (0.23 mmol)をテトラヒドロフラン4.7 mLに溶解した後、－78度に冷却し、ノルマルブチルリチウム0.17 mL (0.260 mmol)を滴下した。-78度で15分間撹拌した後、（1-1）で製造した(2S,3S)-N-メトキシ-2,3-ビス (メトキシメトキシ)-N-メチルヘキサ-5-エナミド 71.0 mg (0.260 mmol)をテトラヒドロフラン 1.0 mLに溶解させ、反応液に加えた。-78度で10分間撹拌した後、飽和塩化アンモニウム水溶液を加えて0度に昇温し、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン= 4 : 6 から 1 : 1)にて精製し、(2S,7S,8S)-7,8-ビス(メトキシメトキシ)-6-オシソウンデク-10-エン-4-イン-2-イル 4-メトキシ-2-((2-メトキシエトキシ)メトキシ)-6-ビニルベンゾエートを透明の液体として得た (86 mg、収率55%)。
¹H-NMR (CDCl₃, 400 MHz) δppm: 6.76-6.69 (overlapped, 3H), 5.82 (m, 1H), 5.69 (dd, J = 17.2, 0.8 Hz, 1H), 5.36-5.28 (overlapped, 2H), 5.25 (s, 2H), 5.10 (m, 1H), 4.71-4.65 (overlapped, 4H), 4.21 (d, J = 4.8 Hz, 1H), 4.08 (m, 1H), 3.82-3.79 (overlapped, 5H), 3.55 (m, 2H), 3.37 (s, 6H), 3.33 (s, 3H), 2.81 (m, 2H), 2.43 (m, 2H), 1.47 (d, J = 6.4 Hz, 3H) (1-3) (2S,7S,8S)-7,8-Bis(methoxymethoxy)-6-oxound-10-en-4-yn-2-yl 4-methoxy-2-((2-methoxyethoxy)methoxy)-6-vinylbenzoate was synthesized as follows.

106 mg (0.23 mmol) of (S)-pent-4-yn-2-yl 4-methoxy-2-((2-methoxyethoxy)methoxy)-6-vinylbenzoate prepared in (1-2) was dissolved in 4.7 mL of tetrahydrofuran, cooled to -78°C, and 0.17 mL (0.260 mmol) of normal butyllithium was added dropwise. After stirring at -78°C for 15 minutes, 71.0 mg (0.260 mmol) of (2S,3S)-N-methoxy-2,3-bis (methoxymethoxy)-N-methylhexa-5-enamide prepared in (1-1) was dissolved in 1.0 mL of tetrahydrofuran and added to the reaction solution. After stirring at -78°C for 10 minutes, a saturated aqueous ammonium chloride solution was added, the temperature was raised to 0°C, and separation was performed three times with ethyl acetate. The obtained organic layer was washed with saturated saline, sodium sulfate was added to the organic layer, water was removed, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate:hexane = 4:6 to 1:1) to obtain (2S,7S,8S)-7,8-bis(methoxymethoxy)-6-oxound-10-en-4-yn-2-yl 4-methoxy-2-((2-methoxyethoxy)methoxy)-6-vinylbenzoate as a transparent liquid (86 mg, yield 55%).
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 6.76-6.69 (overlapped, 3H), 5.82 (m, 1H), 5.69 (dd, J = 17.2, 0.8 Hz, 1H), 5.36-5.28 (overlapped, 2H), 5.25 (s, 2H), 0 (m, 1H), 4.71-4.65 (overlapped, 4H), 4.21 (d, J = 4.8 Hz, 1H), 4.08 (m, 1H), 3.82-3.79 (overlapped, 5H), 3.55 (m, 2H), 3.37 (s, 6H), 3.33 (s, 3H), 2.81 (m, 2H), 2.43 (m, 2H), 1.47 (d, J = 6.4 Hz, 3H)

（1-3）で製造した(2S,7S,8S)-7,8-ビス(メトキシメトキシ)-6-オシソウンデク-10-エン-4-イン-2-イル 4-メトキシ-2-((2-メトキシエトキシ)メトキシ)-6-ビニルベンゾエート 283 mg (0.50 mmol)をジクロロメタン10 mLに溶解した後、ジコバルトオクタカルボニル1.80 g (5.00 mmol)を0度で加えた。4度で12時間撹拌した後、反応溶液を減圧留去し、粗生成物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン= 1 : 4から2 : 3)にて精製を行い、環化前駆体[(2S,7S,8S)-7,8-ビス(メトキシメトキシ)-6-オシソウンデク-10-エン-4-イン-2-イル 4-メトキシ-2-((2-メトキシエトキシ)メトキシ)-6-ビニルベンゾエート] ジコバルトヘキサカルボニルを褐色の液体として得た (355 mg、収率82%)。¹H-NMR (CDCl₃, 400 MHz) δppm: 6.78 (dd, J = 17.3, 10.8 Hz, 1H), 6.72 (s, 2H), 5.87 (m, 1H), 5.69 (d J = 17.3 Hz, 1H), 5.32-5.21 (overlapped, 4H), 5.14 (m, 1H), 5.11 (m, 1H), 4.67 (overlapped, 3H), 4.57 (d, J = 6.8 Hz, 1H), 4.21 (d, J = 7.6 Hz, 1H), 4.04 (m, 1H), 3.82-3.79 (overlapped, 5H), 3.54 (m, 2H), 3.37 (s, 3H), 3.30 (s, 6H), 3.05 (dd, J = 16.2, 7.0 Hz, 1H), 3.05 (dd, J = 16.2, 7.0 Hz, 1H), 2.59 (m, 1H), 2.47 (m, 1H), 1.55 (d, J = 6.4 Hz, 3H) (1-4) The cyclization precursor [(2S,7S,8S)-7,8-bis(methoxymethoxy)-6-oxound-10-en-4-yn-2-yl 4-methoxy-2-((2-methoxyethoxy)methoxy)-6-vinylbenzoate] dicobalt hexacarbonyl was synthesized as follows.

283 mg (0.50 mmol) of (2S,7S,8S)-7,8-bis(methoxymethoxy)-6-oxoundec-10-en-4-yn-2-yl 4-methoxy-2-((2-methoxyethoxy)methoxy)-6-vinylbenzoate prepared in (1-3) was dissolved in 10 mL of dichloromethane, and 1.80 g (5.00 mmol) of dicobalt octacarbonyl was added at 0°C. After stirring at 4°C for 12 hours, the reaction solution was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography (ethyl acetate:hexane = 1:4 to 2:3) to obtain the cyclization precursor [(2S,7S,8S)-7,8-bis(methoxymethoxy)-6-oxound-10-en-4-yn-2-yl 4-methoxy-2-((2-methoxyethoxy)methoxy)-6-vinylbenzoate] dicobalt hexacarbonyl as a brown liquid (355 mg, yield 82%). ¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 6.78 (dd, J = 17.3, 10.8 Hz, 1H), 6.72 (s, 2H), 5.87 (m, 1H), 5.69 (d J = 17.3 Hz, 1H), 5.32-5.21 (overlapped, 4H), 5.14 (m, 1H), 5.11 (m, 1H), 4.67 (overlapped, 3H), 4.57 (d, J = 6.8 Hz, 1H), 4.21 (d, J = 7.6 Hz, 1H), 4.04 (m, 1H), 3.82-3.79 (overlapped, 5H), 3.54 (m , 2H), 3.37 (s, 3H), 3.30 (s, 6H), 3.05 (dd, J = 16.2, 7.0 Hz, 1H), 3.05 (dd, J = 16.2, 7.0 Hz, 1H), 2.59 (m, 1H), 2.47 (m, 1H), 1.55 (d, J = 6.4 Hz, 3H )

（1-4）で製造した環化前駆体[(2S,7S,8S)-7,8-ビス(メトキシメトキシ)-6-オシソウンデク-10-エン-4-イン-2-イル 4-メトキシ-2-((2-メトキシエトキシ)メトキシ)-6-ビニルベンゾエート] ジコバルトヘキサカルボニル551 mg (0.640 mmol)をジクロロメタン127mLに溶解した後、第2世代ピアース-グラブス触媒219 mg (0.246 mmol)をジクロロメタン5.0 mLに溶解させ反応液に0度で加えた。4度で7日間撹拌した後、反応溶液の溶媒を減圧留去し、粗生成物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン= 3 : 7から1 : 1)にて精製を行い、11E-環化体ジコバルトヘキサカルボニル (163 mg、収率31%)と11Z-環化体ジコバルトヘキサカルボニル (312 mg、収率58%)で、それぞれ褐色の液体として得た。
11E-環化体ジコバルトヘキサカルボニル, ¹H-NMR (CDCl₃, 400 MHz) δ ppm: 6.64 (d, J = 2.4 Hz, 1H), 6.59 (d, J = 16.0 Hz, 1H), 6.39 (d, J = 2.0 Hz, 1H), 5.91 (m, 1H), 5.37 (sext, J = 5.6 Hz, 1H), 5.26 (m, 2H), 5.01 (d, J = 7.2 Hz, 1H), 4.71-4.66 (overlapped, 2H), 4.33 (d, J = 7.2 Hz, 1H), 4.27 (d, J = 8.4 Hz, 4.11 (m, 1H), 3.83 (m, 2H), 3.79 (s, 3H), 3.62 (dd, J = 16.0, 6.0 Hz, 1H), 3.56 (m, 2H), 3.38 (s, 3H), 3.30 (s, 3H), 3.27 (s, 3H), 3.23 (dd, J = 16.2, 6.0 Hz, 1H)2.77 (m, 1H), 2.54 (m, 1H), 1.56 (d, J = 6.0 Hz, 3H)11Z-環化体ジコバルトヘキサカルボニル, ¹H-NMR (CDCl₃, 400 MHz) δ ppm: 6.75 (br-s, 1H), 6.63 (d, J = 11.6 Hz, 1H), 6.44 (br-s, 1H), 5.79 (m, 1H), 5.19 (q, J = 7.2 Hz, 2H), 4.93 (m, 1H), 4.72 (d, J = 6.8 Hz, 1H), 4.49 (d, J = 7.2 Hz, 1H), 4.39 (d, J = 8.8 Hz, 1H), 3.98-3.93 (overlapped, 2H), 3.83-3.73 (overlapped, 4H), 3.80 (s, 3H), 3.62 (dd, J = 14.8, 10.8 Hz, 1H), 3.53 (m, 2H), 3.37 (s, 3H), 3.31 (s, 3H), 3.11 (s, 3H), 3.05 (m, 1H), 2.37 (m, 1H), 1.66 (d, J = 6.0 Hz, 1H) (1-5) 11E- and 11Z-cyclized dicobalt hexacarbonyls were synthesized as follows.

The cyclization precursor [(2S,7S,8S)-7,8-bis(methoxymethoxy)-6-oxoundec-10-en-4-yn-2-yl 4-methoxy-2-((2-methoxyethoxy)methoxy)-6-vinylbenzoate] dicobalt hexacarbonyl (551 mg, 0.640 mmol) prepared in (1-4) was dissolved in 127 mL of dichloromethane, and then 219 mg (0.246 mmol) of the second generation Pierce-Grubbs catalyst was dissolved in 5.0 mL of dichloromethane and added to the reaction solution at 0°C. After stirring at 4°C for 7 days, the solvent of the reaction solution was distilled off under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate:hexane = 3:7 to 1:1) to obtain 11E-cyclized dicobalt hexacarbonyl (163 mg, yield 31%) and 11Z-cyclized dicobalt hexacarbonyl (312 mg, yield 58%) as brown liquids.
11E-cyclized dicobalt hexacarbonyl, ¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 6.64 (d, J = 2.4 Hz, 1H), 6.59 (d, J = 16.0 Hz, 1H), 6.39 (d, J = 2.0 Hz, 1H), 5.91 (m, 1H) , 5.37 (sext, J = 5.6 Hz, 1H), 5.26 (m, 2H), 5.01 (d, J = 7.2 Hz, 1H), 4.71-4.66 (overlapped, 2H), 4.33 (d, J = 7.2 Hz, 1H), 4.27 (d, J = 8.4 Hz, 4.11 ( m, 1H), 3.83 (m, 2H), 3.79 (s, 3H), 3.62 (dd, J = 16.0, 6.0 Hz, 1H), 3.56 (m, 2H), 3.38 (s, 3H), 3.30 (s, 3H), 3.27 (s, 3H), 3.23 (dd, J = 16.2, 6.0 Hz, 1H)2.77 (m, 1H), 2.54 (m, 1H), 1.56 (d, J = 6.0 Hz, 3H)11Z-cyclized dicobalt hexacarbonyl, ^1H -NMR ( _CDCl3 , 400 MHz) δ ppm: 6.75 (br-s, 1H), 6.63 (d, J = 11.6 Hz, 1H), 6.44 (br-s, 1H), 5.79 (m, 1H), 5.19 (q, J = 7.2 Hz, 2H), 4.93 (m, 1H), 4.72 (d, J = 6.8 Hz, 1H), 4.49 (d, J = 7.2 Hz, 1H), 4.39 (d, J = 8.8 Hz, 1H), 3.98-3.93 (overlapped, 2H), 3.83-3.73 (overlapped, 4H), 3.80 (s, 3H), 3.62 (dd, J = 14.8, 10.8 Hz, 1H), 3.53 (m, 2H), 3.37 (s, 3H), (s, 3H), 3.11 (s, 3H), 3.05 (m, 1H), 2.37 (m, 1H), 1.66 (d, J = 6.0 Hz, 1H)

（1-5）で製造した11E-環化体ジコバルトヘキサカルボニル86.0 mg (0.105 mmol)をアセトン2.0 mLに溶解し、セリウムアンモニウムナイトレート57 mg (0.105 mmol)を0度で加えた。0度で15分間撹拌した後、同量のセリアムアンモニウムナイトレートを加え、0度で15分間攪拌した。同じ作業を3回繰り返し行なった。薄層クロマトグラフィーにて原料の消失を確認後、精製水を1.0 mL加え、ジクロロメタンで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。粗生成物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン= 1 : 1)にて精製し、11E-イノンマクロライドAを透明の液体として得た(41 mg、収率74%)。
¹H-NMR (CDCl₃, 400 MHz) δppm: 6.78 (d, J = 16.0 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 6.15 (m, 1H), 5.32-5.25 (overlapped, 3H), 4.80 (d, J = 7.2Hz, 1H), 4.74-4.65 (overlapped, 3H), 4.47 (d, J = 2.8 Hz, 1H), 4.37 (m, 1H), 3.83-3.80 (overlapped, 2H), 3.81 (s, 3H), 3.56 (m, 2H), 3.40 (s, 3H), 3.35 (s, 6H), 2.88 (dd, J = 17.4, 3.2 Hz, 1H), 2.74-2.61 (overlapped, 2H), 2.29 (m, 1H), 1.45 (d, J = 6.4 Hz, 3H) (1-6) 11E-ynone macrolide A was synthesized as follows.

86.0 mg (0.105 mmol) of the 11E-cyclized dicobalt hexacarbonyl produced in (1-5) was dissolved in 2.0 mL of acetone, and 57 mg (0.105 mmol) of cerium ammonium nitrate was added at 0°C. After stirring at 0°C for 15 minutes, the same amount of cerium ammonium nitrate was added and stirred at 0°C for 15 minutes. The same procedure was repeated three times. After confirming the disappearance of the raw material by thin layer chromatography, 1.0 mL of purified water was added and the mixture was separated three times with dichloromethane. The obtained organic layer was washed with saturated saline, sodium sulfate was added to the organic layer to remove water, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1) to obtain 11E-ynone macrolide A as a transparent liquid (41 mg, yield 74%).
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 6.78 (d, J = 16.0 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 6.15 (m, 1H), 5.32-5.25 (overlapped, 3H) ), 4.80 (d, J = 7.2Hz, 1H), 4.74-4.65 (overlapped, 3H), 4.47 (d, J = 2.8 Hz, 1H), 4.37 (m, 1H), 3.83-3.80 (overlapped, 2H), 3.81 (s, 3H), 3.56 (m, 2H), 3.40 (s, 3H), 3.35 (s, 6H), 2.88 (dd, J = 17.4, 3.2 Hz, 1H), 2.74-2.61 (overlapped, 2H), 2.29 (m, 1H), 1.45 (d, J = 6.4 Hz, 3H)

（1-6）で製造した11E-イノンマクロライドA 4.04 mg (0.00753 mmol)に47%フッ化水素水溶液とアセトニトリルの混合液(1 : 10)を1.9mL (4.14 mmol)加えた。室温で5時間撹拌した後、炭酸水素ナトリウム水溶液を0度で加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。粗生成物をプレパラティブTLCで精製を行い、Compound #13を白色の固体として得た (1.10 mg、収率40%)。
¹H-NMR (CDCl₃, 500 MHz) δppm: 11.5 (s, 1H), 7.27 (d, J = 13.9 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 6.41 (d, J = 2.5 Hz, 1H), 6.07 (ddd, J = 14.7, 9.9, 4.4 Hz, 1H), 5.41 (m, 1H), 4.44 (d, J = 2.9 Hz, 1H), 4.32 (td, J = 8.4, 2.9 Hz, 1H), 2.94 (dd, J = 17.4, 3.5 Hz, 1H), 2.80 (dd, J = 17.4, 5.6 Hz, 1H), 2.56-2.50 (overlapped, 2H), 1.54 (d, J = 6.3 Hz, 1H) Example 2 11E-ynone macrolide A'
11E-ynone macrolide A' was synthesized as follows.

1.9mL (4.14mmol) of a mixture of 47% aqueous hydrogen fluoride and acetonitrile (1:10) was added to 4.04mg (0.00753mmol) of 11E-ynone macrolide A prepared in (1-6). After stirring at room temperature for 5 hours, aqueous sodium bicarbonate was added at 0°C, and the mixture was separated three times with ethyl acetate. The organic layer obtained was washed with saturated saline, sodium sulfate was added to the organic layer, water was removed, and the solvent was distilled off under reduced pressure. The crude product was purified by preparative TLC to obtain Compound #13 as a white solid (1.10mg, 40% yield).
¹ H-NMR (CDCl ₃ , 500 MHz) δppm: 11.5 (s, 1H), 7.27 (d, J = 13.9 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 6.41 (d, J = 2.5 Hz, 1H), 6.07 (ddd, J = 14.7, 9.9, 4.4 Hz, 1H), 5.41 (m, 1H), 4.44 (d, J = 2.9 Hz, 1H), 4.32 (td, J = 8.4, 2.9 Hz, 1H), 2.94 (dd, J = 17.4, 3.5 Hz, 1H), 2.80 (dd, J = 17.4, 5.6 Hz, 1H), 2.56-2.50 (overlapped, 2H), 1.54 (d, J = 6.3 Hz, 1H)

（1-6）で製造した11E-環化体ジコバルトヘキサカルボニル87.0 mg (0.106 mmol)をアセトン2.0 mLに溶解し、セリウムアンモニウムナイトレート57.7 mg (0.106 mmol)を0度で加えた。0度で15分間撹拌した後、同量のセリアムアンモニウムナイトレートを加え、0度で15分間攪拌した。同じ作業を3回繰り返し行なった。薄層クロマトグラフィーにて原料の消失を確認後、精製水を1.0 mL加え、ジクロロメタンで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。粗生成物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン= 1 : 1)にて精製し、11Z-イノンマクロライドBを透明の液体として得た(45 mg、収率81%)。
¹H-NMR (CDCl₃, 400 MHz) δppm: 6.67 (d, J = 2.4 Hz, 1H), 6.55 (d, J = 11.6 Hz, 1H), 6.39 (d, J = 1.6 Hz, 1H), 5.53 (m, 1H), 5.30-5.17 (overlapped, 3H), 4.69-4.64 (overlapped, 3H), 4.60 (d, J = 6.8 Hz, 1H), 4.30 (d, J = 2.4 Hz, 1H), 4.20 (m, 1H), 3.84-3.79 (overlapped, 2H), 3.80 (s, 3H), 3.57 (m, 2H), 3.38 (s, 3H), 3.35 (s, 3H), 3.34 (s, 3H), 2.88-2.80 (overlapped, 2H), 2.61 (dd, J = 17.4, 8.4 Hz, 1H), 2.50 (m, 1H), 1.42 (d, J = 6.4 Hz, 3H) Example 3 11Z-ynone macrolide B
11Z-ynone macrolide B was synthesized as follows.

87.0 mg (0.106 mmol) of the 11E-cyclized dicobalt hexacarbonyl produced in (1-6) was dissolved in 2.0 mL of acetone, and 57.7 mg (0.106 mmol) of cerium ammonium nitrate was added at 0°C. After stirring at 0°C for 15 minutes, the same amount of cerium ammonium nitrate was added and stirred at 0°C for 15 minutes. The same procedure was repeated three times. After confirming the disappearance of the raw material by thin layer chromatography, 1.0 mL of purified water was added and the mixture was separated three times with dichloromethane. The obtained organic layer was washed with saturated saline, sodium sulfate was added to the organic layer to remove water, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1) to obtain 11Z-ynone macrolide B as a transparent liquid (45 mg, yield 81%).
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 6.67 (d, J = 2.4 Hz, 1H), 6.55 (d, J = 11.6 Hz, 1H), 6.39 (d, J = 1.6 Hz, 1H), 5.53 (m, 1H), 5.30-5.17 (overlapped, 3H) ), 4.69-4.64 (overlapped, 3H), 4.60 (d, J = 6.8 Hz, 1H), 4.30 (d, J = 2.4 Hz, 1H), 4.20 (m, 1H), 3.84-3.79 (overlapped, 2H), 3.80 (s, 3H), 3.57 (m, 2H) , 3.38 (s, 3H), 3.35 (s, 3H), 3.34 (s, 3H), 2.88-2.80 (overlapped, 2H), 2.61 (dd, J = 17.4, 8.4 Hz, 1H), 2.50 (m, 1H), 1.42 (d, J = 6.4 Hz, 3H)

実施例３で製造した11Z-イノンマクロライドB 4.8 mg (0.00975 mmol)に47%フッ化水素水溶液とアセトニトリルの混合液(1 : 10)を2.3 mL (4.92 mmol)加えた。室温で1時間撹拌した後、炭酸水素ナトリウム水溶液を0度で加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。粗生成物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン= 2 : 8から1 : 1)にて精製し、11Z-イノンマクロライドCを得た(1.6 mg、収率50%)。
¹H-NMR (CDCl₃, 500 MHz) δppm: 11.70 (s, 1H), 6.73 (d, J = 11.6 Hz, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.27 (d, J = 2.0 Hz, 1H), 5.54 (m, 1H), 5.40 (m, 1H), 4.75-4.71 (overlapped, 2H), 4.52 (d, J = 6.8 Hz, 1H), 4.35 (d, J = 2.8 Hz, 1H), 4.30 (d, J = 6.8 Hz, 1H), 4.16 (dt, J = 10.8, 3.2 Hz, 1H), 3.81 (s, 3H), 3.40 (s, 3H), 3.15 (s, 3H), 3.12 (m, 1H), 2.62-2.45 (over;apped, 3H), 1.53 (d, J = 6.4 Hz, 3H) Example 4 11Z-ynone macrolide C
11Z-ynone macrolide C was synthesized as follows.

2.3 mL (4.92 mmol) of a mixture of 47% aqueous hydrogen fluoride and acetonitrile (1:10) was added to 4.8 mg (0.00975 mmol) of 11Z-ynone macrolide B produced in Example 3. After stirring at room temperature for 1 hour, aqueous sodium bicarbonate was added at 0 degrees, and separation was performed three times with ethyl acetate. The obtained organic layer was washed with saturated saline, sodium sulfate was added to the organic layer, water was removed, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate:hexane = 2:8 to 1:1) to obtain 11Z-ynone macrolide C (1.6 mg, yield 50%).
¹ H-NMR (CDCl ₃ , 500 MHz) δppm: 11.70 (s, 1H), 6.73 (d, J = 11.6 Hz, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.27 (d, J = 2.0 Hz, 1H), 5.54 (m, 1H), 0 (m, 1H), 4.75-4.71 (overlapped, 2H), 4.52 (d, J = 6.8 Hz, 1H), 4.35 (d, J = 2.8 Hz, 1H), 4.30 (d, J = 6.8 Hz, 1H), 4.16 (dt, J = 10.8, 3.2 Hz, 1H), 3.81 (s, 3H), 3.40 (s, 3H), 3.15 (s, 3H), 3.12 (m, 1H), 2.62-2.45 (over;apped, 3H), 1.53 (d, J = 6.4 Hz, 3H)

実施例３で製造した11Z-イノンマクロライドB 4.9 mg (0.00975 mmol)に47%フッ化水素水溶液とアセトニトリルの混合液(1 : 10)を2.4 mL (5.0 mmol)加えた。室温で8時間撹拌した後、炭酸水素ナトリウム水溶液を0度で加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。粗生成物をHPLCにて精製を行い、Compound #26を白色の固体として得た(0.3 mg、収率9.1%)。
¹H-NMR (CDCl₃, 500 MHz) δppm: 11.60 (s, 1H), 6.72 (d, J = 11.5 Hz, 1H), 6.42 (d, J = 2.5 Hz, 1H), 6.25 (d, J = 1.8 Hz, 1H), 5.50 (m, 1H), 5.20 (td, J = 11.2, 5.5 Hz, 1H), 4.40 (m, 1H), 4.10 (m, 1H), 3.82 (s, 3H), 3.64 (m, 1H), 3.08 (dd, J = 17.1, 14.8 Hz, 1H), 2.67 (m, 1H), 2.57 (dd, J = 17.1, 2.8 Hz, 1H), 2.26 (td, J = 11.8, 5.8 Hz, 1H), 1.52 (d, J = 6.4 Hz, 3H) Example 5 11Z-ynone macrolide D
11Z-ynone macrolide D was synthesized as follows.

4.9 mg (0.00975 mmol) of 11Z-ynone macrolide B prepared in Example 3 was mixed with 2.4 mL (5.0 mmol) of a mixture of 47% aqueous hydrogen fluoride and acetonitrile (1:10). After stirring at room temperature for 8 hours, aqueous sodium bicarbonate was added at 0 degrees, and the mixture was separated three times with ethyl acetate. The organic layer obtained was washed with saturated saline, and sodium sulfate was added to the organic layer to remove water, and the solvent was distilled off under reduced pressure. The crude product was purified by HPLC to obtain Compound #26 as a white solid (0.3 mg, yield 9.1%).
¹ H-NMR (CDCl ₃ , 500 MHz) δppm: 11.60 (s, 1H), 6.72 (d, J = 11.5 Hz, 1H), 6.42 (d, J = 2.5 Hz, 1H), 6.25 (d, J = 1.8 Hz, 1H), 5.50 (m, 1H), 0 (td, J = 11.2, 5.5 Hz, 1H), 4.40 (m, 1H), 4.10 (m, 1H), 3.82 (s, 3H), 3.64 (m, 1H), 3.08 (dd, J = 17.1, 14.8 Hz, 1H), 2.67 (m, 1H), (dd, J = 17.1, 2.8 Hz, 1H), 2.26 (td, J = 11.8, 5.8 Hz, 1H), 1.52 (d, J = 6.4 Hz, 3H)

（1-5）で製造した11Z-環化体ジコバルトヘキサカルボニル2.9 mg (0.00353 mmol)をメタノール0.7 mLに溶解した後、ロジウムカーボン16 mg (0.00353 mmol)を加え、－40度に冷却した。その後、内部を水素ガスで置換し、－40度で3日間撹拌した。質量分析にて反応の進行を確認後、フィルターろ過を行い、ロジウムカーボンを除去した。溶媒を減圧留去した後、得られた粗生成物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン= 1 : 1から2 : 1)にて精製し、11飽和-環化体ジコバルトヘキサカルボニルを透明の液体として得た(1.2 mg、収率42%)。
¹H-NMR (CDCl₃, 500 MHz) δppm: 6.54 (d, J = 2.4 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H), 5.28 (m, 1H), 5.20 (s, 2H), 4.73-4.61 (overlapped, 5H), 4.08 (m, 1H), 3.82-3.77 (overlapped, 2H), 3.77 (s, 3H), 3.55 (m, 2H), 3.37 (s, 6H), 3.32-3.26 (overlapped, 2H), 2.62 (m, 2H), 1.75-1.63 (overlapped, 4H), 1.57 (d, J = 6.0 Hz, 3H) Example 6 11-saturated ynone macrolide A
(6-1) 11-Saturated cyclized dicobalt hexacarbonyl was synthesized as follows.

2.9 mg (0.00353 mmol) of the 11Z-cyclized dicobalt hexacarbonyl produced in (1-5) was dissolved in 0.7 mL of methanol, and then 16 mg (0.00353 mmol) of rhodium carbon was added and cooled to -40°C. The inside of the flask was then replaced with hydrogen gas and stirred at -40°C for 3 days. After confirming the progress of the reaction by mass spectrometry, the rhodium carbon was removed by filtration. After the solvent was distilled off under reduced pressure, the obtained crude product was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1 to 2:1) to obtain 11 saturated-cyclized dicobalt hexacarbonyl as a transparent liquid (1.2 mg, 42% yield).
¹ H-NMR (CDCl ₃ , 500 MHz) δppm: 6.54 (d, J = 2.4 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H), 5.28 (m, 1H), 5.20 (s, 2H), 4.73-4.61 (overlapped, 5H), 4.08 (m, 1H), 3.82-3.77 (overlapped, 2H), 3.77 (s, 3H), 3.55 (m, 2H), 3.37 (s, 6H), 3.32-3.26 (overlapped, 2H), 2.62 (m, 2H), 1.75-1.63 (overlapped, 4H), 1.57 (d , J = 6.0 Hz, 3H)

（6-1）で製造した11飽和-環化体ジコバルトヘキサカルボニル1.2 mg (0.00146 mmol)をアセトン0.15 mLに溶解しセリウムアンモニウムナイトレート0.8 mg (0.00146 mmol)を0度で加えた。0度で15分間撹拌した後、同量のセリアムアンモニウムナイトレートを加え、0度で15分間攪拌した。同じ作業を3回繰り返し行なった。薄層クロマトグラフィーにて原料の消失を確認後、精製水を1.0 mL加え、ジクロロメタンで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。粗生成物をシリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン= 2 : 1)にて精製し、11飽和-イノンマクロライドAを透明の液体として得た(0.8 mg、収率99%)。
¹H-NMR (CDCl₃, 500 MHz) δppm: 6.62 (d, J = 2.4 Hz, 1H), 6.41 (d, J = 2.4 Hz, 1H), 5.32 (m, 1H), 5.25 (s, 2H), 4.82 (d, J = 6.8 Hz, 1H), 4.66-4.62 (overlapped, 3H), 4.47 (d, J = 2.4 Hz, 1H), 4.05 (m, 1H), 3.84-3.79 (overlapped, 2H), 3.79 (s, 3H), 3.58-3.55 (overlapped, 2H), 3.40 (s, 3H), 3.39-3.32 (overlapped, 1H), 3.38 (s, 3H), 3.37 (s, 3H), 2.73-2.58 (overlapped, 3H), 1.80-1.78 (overlapped, 4H), 1.48 (d, J = 6.4 Hz, 3H) (6-2) 11-Saturated ynone macrolide A was synthesized as follows.

1.2 mg (0.00146 mmol) of the 11-saturated cyclized dicobalt hexacarbonyl prepared in (6-1) was dissolved in 0.15 mL of acetone and 0.8 mg (0.00146 mmol) of cerium ammonium nitrate was added at 0°C. After stirring at 0°C for 15 minutes, the same amount of cerium ammonium nitrate was added and stirred at 0°C for 15 minutes. The same procedure was repeated three times. After confirming the disappearance of the raw material by thin layer chromatography, 1.0 mL of purified water was added and the mixture was separated three times with dichloromethane. The obtained organic layer was washed with saturated saline, sodium sulfate was added to the organic layer to remove water, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate:hexane = 2:1) to obtain 11-saturated ynone macrolide A as a transparent liquid (0.8 mg, yield 99%).
¹ H-NMR (CDCl ₃ , 500 MHz) δppm: 6.62 (d, J = 2.4 Hz, 1H), 6.41 (d, J = 2.4 Hz, 1H), 5.32 (m, 1H), 5.25 (s, 2H), 4.82 (d, J = 6.8 Hz, 1H), 4.66- 4.62 (overlapped, 3H), 4.47 (d, J = 2.4 Hz, 1H), 4.05 (m, 1H), 3.84-3.79 (overlapped, 2H), 3.79 (s, 3H), 3.58-3.55 (overlapped, 2H), 3.40 (s, 3H), 2 (overlapped, 1H), 3.38 (s, 3H), 3.37 (s, 3H), 2.73-2.58 (overlapped, 3H), 1.80-1.78 (overlapped, 4H), 1.48 (d, J = 6.4 Hz, 3H)

実施例６で製造した11飽和-イノンマクロライドA 0.8 mg (0.00146 mmol)に47%フッ化水素水溶液とアセトニトリルの混合液(1 : 10)を0.4 mL (0.8 mmol) 加えた。室温で8時間撹拌した後、炭酸水素ナトリウム水溶液を0度で加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行い、溶媒を減圧留去した。溶媒を減圧留去した後、HPLCにて精製を行い、11飽和-イノンマクロライドBを白色の固体として得た(0.05 mg、収率9.3%)。
¹H-NMR (CDCl₃, 500 MHz) δppm: 11.95 (s, 1H), 6.37 (d, J = 2.5 Hz, 1H), 6.34 (d, J = 2.5 Hz, 1H), 5.41 (m, 1H), 4.39 (d, J = 2.5 Hz, 1H), 4.05 (m, 1H), 3.82 (s, 3H), 3.45 (td, J = 12.6, 2.5 Hz, 1H), 3.19 (dd, J = 17.5, 4.1 Hz, 1H), 2.75 (dd, J = 17.5, 4.1 Hz, 1H), 2.49 (m, 1H), 2.14-1.97 (overlapped, 4H), 1.55 (d, J = 6.7 Hz, 3H) Example 7 11-saturated ynone macrolide B
The 11-saturated ynone macrolide B was synthesized as follows.

0.8 mg (0.00146 mmol) of 11-saturated ynone macrolide A prepared in Example 6 was mixed with 0.4 mL (0.8 mmol) of a mixture of 47% aqueous hydrogen fluoride and acetonitrile (1:10). After stirring at room temperature for 8 hours, aqueous sodium bicarbonate was added at 0 degrees, and the mixture was separated three times with ethyl acetate. The organic layer obtained was washed with saturated saline, sodium sulfate was added to the organic layer, water was removed, and the solvent was distilled off under reduced pressure. After the solvent was distilled off under reduced pressure, the mixture was purified by HPLC to obtain 11-saturated ynone macrolide B as a white solid (0.05 mg, yield 9.3%).
¹ H-NMR (CDCl ₃ , 500 MHz) δppm: 11.95 (s, 1H), 6.37 (d, J = 2.5 Hz, 1H), 6.34 (d, J = 2.5 Hz, 1H), 5.41 (m, 1H), 4.39 (d, J = 2.5 Hz, 1H), (m, 1H), 3.82 (s, 3H), 3.45 (td, J = 12.6, 2.5 Hz, 1H), 3.19 (dd, J = 17.5, 4.1 Hz, 1H), 2.75 (dd, J = 17.5, 4.1 Hz, 1H), 2.49 (m, 1H), -1.97 (overlapped, 4H), 1.55 (d, J = 6.7 Hz, 3H)

2-デオキシ-D-リボース6.0 g (44.7 mmol)をアセトン90 mL に溶解した後、2,2-ジメトキシプロパン18.8 mLを加え、室温で１５分間撹拌した。その後、p－トシル酸170 mg ( 1.00 mmol)を加え、室温で2時間撹拌した。0度に冷却後、炭酸水素ナトリウム水溶液を加え、ジクロロメタンで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン= 1 : 2から4 : 1)にて精製し、(3aR,7aS)-2,2-ジメチルテトラヒドロ-4H-[1,3]ジオキソロ [4,5-c]ピラン-6-オールを透明の液体として得た(5.9 g、収率76%)。 Example 8 (S)-1-((4S,5R)-5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl)-5-hydroxyhex-2-yn-1-one (8-1) The known compound (3aR,7aS)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-ol was synthesized as follows.

6.0 g (44.7 mmol) of 2-deoxy-D-ribose was dissolved in 90 mL of acetone, and 18.8 mL of 2,2-dimethoxypropane was added and stirred at room temperature for 15 minutes. Then, 170 mg (1.00 mmol) of p-tosylic acid was added and stirred at room temperature for 2 hours. After cooling to 0 degrees, an aqueous solution of sodium bicarbonate was added and the mixture was separated three times with dichloromethane. The organic layer obtained was washed with saturated saline, and sodium sulfate was added to the organic layer to remove water. After distilling off the solvent under reduced pressure, the product was purified by silica gel column chromatography (ethyl acetate:hexane = 1:2 to 4:1) to obtain (3aR,7aS)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-ol as a transparent liquid (5.9 g, 76% yield).

メチルトリフェニルホスホニウムブロミド 370 mg (1.04 mmol)をテトラヒドロフラン 2.5 mLに溶解させ、-78度に冷却した後、ノルマルブチルリチウム 0.74 mL (0.888 mmol)を加えた。-78度で15分間撹拌した後、0度に昇温して30分間撹拌した。再度、-78度に反応液を冷却した後、（8-1）で製造した(3aR,7aS)-2,2-ジメチルテトラヒドロ-4H-[1,3]ジオキソロ [4,5-c]ピラン-6-オール 52 mg (0.296 mmol)をテトラヒドロフラン 0.5 mLに溶解させて反応液に加えた。室温で4時間撹拌した後、0度に冷却し、飽和塩化アンモニウム水溶液を加え、クロロホルムで分液を３回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン＝3:7から1:1)にて精製し、((4R,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)メタノールを透明な液体として得た (44.4 mg、収率87%)。 (8-2) The known compound ((4R,5R)-5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl)methanol was synthesized as follows.

370 mg (1.04 mmol) of methyltriphenylphosphonium bromide was dissolved in 2.5 mL of tetrahydrofuran and cooled to -78°C, and then 0.74 mL (0.888 mmol) of n-butyllithium was added. After stirring at -78°C for 15 minutes, the temperature was raised to 0°C and stirred for 30 minutes. After cooling the reaction solution to -78°C again, 52 mg (0.296 mmol) of (3aR,7aS)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-ol prepared in (8-1) was dissolved in 0.5 mL of tetrahydrofuran and added to the reaction solution. After stirring at room temperature for 4 hours, the mixture was cooled to 0°C, a saturated aqueous solution of ammonium chloride was added, and the mixture was separated three times with chloroform. The obtained organic layer was washed with saturated saline, and sodium sulfate was added to the organic layer to remove water. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 3:7 to 1:1) to give ((4R,5R)-5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl)methanol as a transparent liquid (44.4 mg, yield 87%).

（8-2）で製造した((4R,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)メタノール 2.99 g (17.4 mmo)にアセトニトリル 60 mLと精製水 30 mLに溶解させた後、ヨードベンゼンジアセテート 12.3 g (38.2 mmol)と2,2,6,6-テトラメチルピペリジン1-オキシル フリーラジカル 543 mg (3.47 mmol)を室温で加えた。室温で2時間撹拌した後、精製水を加え、酢酸で反応液を酸性にしてから、酢酸エチルで分液を5回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去して(4S,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-カルボン酸の粗生成物を得た。
この粗生成物をジクロロメタン 90 mLに溶解させた後、0度に冷却し、N-メチルモルホリン 2.3 mL (20.8 mmol)、N,O-ジメチルヒドロキシアミン塩酸塩 1.87 g (19.1 mmol)と1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド 4.00 g (20.8 mmol)を加えた。0度で2時間撹拌した後、精製水を加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン＝3:7から1:1)にて精製し、(4S,5R)-5-アリル-N-メトキシ-N,2,2-トリメチル-1,3-ジオキソラン-4-カルボキサミドを白色な固体として得た (3.37 g、二工程収率85%)。
¹H-NMR (CDCl₃, 400 MHz) δppm: 5.83 (m, 1H), 5.12 (dd, J = 16.8, 2.0 Hz, 1H), 5.10 (d, J = 10.0, 2.0 Hz, 1H), 4.96 (d, J = 6.4 Hz, 1H), 4.56 (q, J = 6.8 Hz, 1H), 3.74 (s, 3H), 3.20 (s, 3H), 2.25 (t, J = 6.8 Hz, 2H), 1.66 (s, 3H), 1.43 (s, 3H) (8-3) (4S,5R)-5-Allyl-N-methoxy-N,2,2-trimethyl-1,3-dioxolane-4-carboxamide was synthesized as follows.

2.99 g (17.4 mmo) of ((4R,5R)-5-allyl-2,2-dimethyl-1,3-dioxolane-4-yl)methanol prepared in (8-2) was dissolved in 60 mL of acetonitrile and 30 mL of purified water, and then 12.3 g (38.2 mmol) of iodobenzene diacetate and 543 mg (3.47 mmol) of 2,2,6,6-tetramethylpiperidine 1-oxyl free radical were added at room temperature. After stirring at room temperature for 2 hours, purified water was added, the reaction solution was acidified with acetic acid, and then separated five times with ethyl acetate. The obtained organic layer was washed with saturated saline, and sodium sulfate was added to the organic layer to remove water. The solvent was distilled off under reduced pressure to obtain a crude product of (4S,5R)-5-allyl-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid.
The crude product was dissolved in 90 mL of dichloromethane, cooled to 0°C, and 2.3 mL (20.8 mmol) of N-methylmorpholine, 1.87 g (19.1 mmol) of N,O-dimethylhydroxyamine hydrochloride, and 4.00 g (20.8 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide were added. After stirring at 0°C for 2 hours, purified water was added and the mixture was separated three times with ethyl acetate. The organic layer obtained was washed with saturated saline, and sodium sulfate was added to the organic layer to remove water. After distilling off the solvent under reduced pressure, the mixture was purified by silica gel column chromatography (ethyl acetate:hexane = 3:7 to 1:1) to obtain (4S,5R)-5-allyl-N-methoxy-N,2,2-trimethyl-1,3-dioxolane-4-carboxamide as a white solid (3.37 g, two-step yield 85%).
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 5.83 (m, 1H), 5.12 (dd, J = 16.8, 2.0 Hz, 1H), 5.10 (d, J = 10.0, 2.0 Hz, 1H), 4.96 (d, J = 6.4 Hz, 1H), 4.56 (q , J = 6.8 Hz, 1H), 3.74 (s, 3H), 3.20 (s, 3H), 2.25 (t, J = 6.8 Hz, 2H), 1.66 (s, 3H), 1.43 (s, 3H)

既知化合物(S)-t-ブチル (ペント-4-イン-2-イロキシ)ジフェニルシラン 4.90g (15.2 mmol)をテトラヒドロフラン 70 mLに溶解させ、-78度に冷却した後、ノルマルブチルリチウム 5.8 mL (15.2 mmol)を加えた。-78度で1時間撹拌した後、（8-3）で製造した(4S,5R)-5-アリル-N-メトキシ-N,2,2-トリメチル-1,3-ジオキソラン-4-カルボキサミド 3.16 g (11.4 mmol)をテトラヒドロフラン 20 mLに溶解させて反応液に-78度で加えた。0度で1時間撹拌した後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン＝1:1)にて精製し、(S)-1-((4S,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)-5-((t-ブチルジフェニルシリル)オキシ)ヘキサ-2-イン-1-オンを薄黄色の液体として得た (6.14 g、収率100%)。
¹H-NMR (CDCl₃, 400 MHz) δppm: 7.72-7.66 (overlapped, 4H), 7.43-7.35 (overlapped, 6H), 5.80 (m, 1H), 5.11 (d, J = 10.8 Hz, 1H), 5.09 (d, J = 9.2 Hz, 1H), 4.95 (d, J = 6.4 Hz, 1H), 4.45 (q, J = 6.8 Hz, 1H), 3.99 (sext, J = 6.0 Hz, 1H), 2.37-2.22 (overlapped, 4H), 1.62 (s, 3H), 1.49 (s, 3H), 1.20 (d, J = 6.4 Hz, 3H), 1.07 (s, 9H) (8-4) (S)-1-((4S,5R)-5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl)-5-((t-butyldiphenylsilyl)oxy)hex-2-yn-1-one was synthesized as follows.

The known compound (S)-t-butyl (pent-4-yn-2-yloxy)diphenylsilane 4.90g (15.2 mmol) was dissolved in 70 mL of tetrahydrofuran and cooled to -78 degrees, and then normal butyllithium 5.8 mL (15.2 mmol) was added. After stirring at -78 degrees for 1 hour, (4S,5R)-5-allyl-N-methoxy-N,2,2-trimethyl-1,3-dioxolane-4-carboxamide 3.16 g (11.4 mmol) prepared in (8-3) was dissolved in 20 mL of tetrahydrofuran and added to the reaction solution at -78 degrees. After stirring at 0 degrees for 1 hour, a saturated aqueous ammonium chloride solution was added and the mixture was separated three times with ethyl acetate. The obtained organic layer was washed with saturated saline, and then sodium sulfate was added to the organic layer to remove water. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1) to give (S)-1-((4S,5R)-5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl)-5-((t-butyldiphenylsilyl)oxy)hex-2-yn-1-one as a pale yellow liquid (6.14 g, 100% yield).
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 7.72-7.66 (overlapped, 4H), 7.43-7.35 (overlapped, 6H), 5.80 (m, 1H), 5.11 (d, J = 10.8 Hz, 1H), 5.09 (d, J = 9.2 Hz, 1H), 4.95 (d, J = 6.4 Hz, 1H), 4.45 (q, J = 6.8 Hz, 1H), 3.99 (sext, J = 6.0 Hz, 1H), 2.37-2.22 (overlapped, 4H), 1.62 (s, 3H), 1.49 (s, 3H), 1.20 (d, J = 6.4Hz, 3H), 1.07 (s, 9H)

（8-4）で製造した(S)-1-((4S,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)-5-((t-ブチルジフェニルシリル)オキシ)ヘキサ-2-イン-1-オン 5.6 mg (0.0114 mmol)をテトラヒドロフラン 0.17 mLに溶解させ、酢酸 7.0 μL (0.114 mmol)とn-テトラブチルアンモニウムフロリド溶液 0.17 mL (0.171 mmol)を室温で加えた。室温で9時間撹拌した後、0度で飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン＝1:1)にて精製し、(S)-1-((4S,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)-5-((t-ブチルジフェニルシリル)オキシ)ヘキサ-2-イン-1-オンを薄黄色の液体として得た (1.3 mg、収率45%)。
¹H-NMR (CDCl₃, 400 MHz) δppm: 5.84 (m, 1H), 5.15 (d, J = 14.8 Hz, 1H), 5.12 (d, J = 8.0 Hz, 1H), 4.52 (d, J = 7.6 Hz), 4.44 (m, 1H), 4.08 (m, 1H), 2.65-2.54 (overlapped, 1H), 2.40 (m, 1H), 2.29 (m, 1H), 1.65 (s, 3H), 1.40 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H) (8-5) (S)-1-((4S,5R)-5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl)-5-hydroxyhex-2-yn-1-one was synthesized as follows.

5.6 mg (0.0114 mmol) of (S)-1-((4S,5R)-5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl)-5-((t-butyldiphenylsilyl)oxy)hex-2-yn-1-one prepared in (8-4) was dissolved in 0.17 mL of tetrahydrofuran, and 7.0 μL (0.114 mmol) of acetic acid and 0.17 mL (0.171 mmol) of n-tetrabutylammonium fluoride solution were added at room temperature. After stirring at room temperature for 9 hours, a saturated aqueous solution of sodium bicarbonate was added at 0 degrees, and the mixture was separated three times with chloroform. The obtained organic layer was washed with saturated saline, and sodium sulfate was added to the organic layer to remove water. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1) to give (S)-1-((4S,5R)-5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl)-5-((t-butyldiphenylsilyl)oxy)hex-2-yn-1-one as a pale yellow liquid (1.3 mg, yield 45%).
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 5.84 (m, 1H), 5.15 (d, J = 14.8 Hz, 1H), 5.12 (d, J = 8.0 Hz, 1H), 4.52 (d, J = 7.6 Hz), 4.44 (m, 1H), 4.08 (m, 1H), 2.65-2.54 (overlapped, 1H), 2.40 (m, 1H), 2.29 (m, 1H), 1.65 (s, 3H), 1.40 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H)

テトラヒドロフラン1.5 mLにジイソプロピルアミン105 μL (0.755 mmol)を加え、0度に冷却した後、ノルマルブチルリチウム281 μL (0.755 mmol)を加えた。0度で15分間撹拌した後、－78度に冷却し15分間撹拌した。調製したリチウムジイソプロピルアミドに対し、トリメチルシリルジアゾメタン187 μL (0.374 mmol)を加え、－78度で30分間撹拌した。ここに、実施例1で得られた(3aR,7aS)-2,2-ジメチルテトラヒドロ-4H-[1,3]ジオキソロ [4,5-c]ピラン-6-オール 50.0 mg (0.287 mmol)をテトラヒドロフラン 0.3 mLに溶解した溶液を加え、－78度で30分間撹拌した。室温まで昇温させ、2時間撹拌した後、0度に冷却し、塩化アンモニウム水溶液を加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン= 1 : 4から2 : 3)にて精製し、((4R,5R)-2,2-ジメチル-5-(プロピ-2-イン-1-イル)-1,3-ジオキソラン-4-イル)メタノールを得た(32.1 mg、収率66%)。 Example 9 (S)-1-((4S,5R)-2,2-dimethyl-5-(prop-2-yn-1-yl)-1,3-dioxolan-4-yl)-5-hydroxyhex-2-yn-1-one (9-1) The known compound ((4R,5R)-2,2-dimethyl-5-(prop-2-yn-1-yl)-1,3-dioxolan-4-yl)methanol was synthesized as follows.

105 μL (0.755 mmol) of diisopropylamine was added to 1.5 mL of tetrahydrofuran, and the mixture was cooled to 0°C, followed by the addition of 281 μL (0.755 mmol) of n-butyllithium. After stirring at 0°C for 15 minutes, the mixture was cooled to -78°C and stirred for 15 minutes. 187 μL (0.374 mmol) of trimethylsilyldiazomethane was added to the prepared lithium diisopropylamide, and the mixture was stirred at -78°C for 30 minutes. A solution of 50.0 mg (0.287 mmol) of (3aR,7aS)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-ol obtained in Example 1 dissolved in 0.3 mL of tetrahydrofuran was added thereto, and the mixture was stirred at -78°C for 30 minutes. The mixture was warmed to room temperature, stirred for 2 hours, and then cooled to 0°C, and an aqueous ammonium chloride solution was added, followed by separation with ethyl acetate three times. The organic layer was washed with saturated saline, and sodium sulfate was added to the organic layer to remove water. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:4 to 2:3) to obtain ((4R,5R)-2,2-dimethyl-5-(prop-2-yn-1-yl)-1,3-dioxolan-4-yl)methanol (32.1 mg, yield 66%).

（9-1）で製造した((4R,5R)-2,2-ジメチル-5-(プロピ-2-イン-1-イル)-1,3-ジオキソラン-4-イル)メタノール 1.43 g (8.43 mmo)にアセトニトリル 30 mLと精製水 15 mLに溶解させた後、ヨードベンゼンジアセテート 5.97 g (18.5 mmol)と2,2,6,6-テトラメチルピペリジン1-オキシル フリーラジカル 263 mg (1.69 mmol)を室温で加えた。室温で2時間撹拌した後、精製水を加え、酢酸で反応液を酸性にしてから、酢酸エチルで分液を5回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去して(4S,5R)-2,2-ジメチル-5-(プロピ-2-イン-1-イル)-1,3-ジオキソラン-4-カルボン酸の粗生成物を得た。
この粗生成物をジクロロメタン 90 mLに溶解させた後、0度に冷却し、N-メチルモルホリン 1.86 mL (18.5 mmol)、N,O-ジメチルヒドロキシアミン塩酸塩 1.64 g (16.9 mmol)と1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド 3.23 g (18.5 mmol)を加えた。0度で20時間撹拌した後、精製水を加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン＝3:7から1:1)にて精製し、(4S,5R)-N-メトキシ-N,2,2-トリメチル-5-(プロピ-2-イン-1-イル)-1,3-ジオキソラン-4-カルボキサミドを透明な液体として得た (1.11 g、二工程収率58%)。¹H-NMR (CDCl₃, 400 MHz) δppm: 4.96 (d, J = 6.4 Hz, 1H), 4.56 (q, J = 6.4 Hz, 1H), 3.72 (s, 3H), 3.19 (s, 3H), 2.42-2.39 (overlapped, 2H), 2.01 (t, J = 2.8 Hz, 1H), 1.61 (s, 3H), 1.41 (s, 3H) (9-2) (4S,5R)-N-Methoxy-N,2,2-trimethyl-5-(prop-2-yn-1-yl)-1,3-dioxolane-4-carboxamide was synthesized as follows.

1.43 g (8.43 mmo) of ((4R,5R)-2,2-dimethyl-5-(prop-2-yn-1-yl)-1,3-dioxolane-4-yl)methanol prepared in (9-1) was dissolved in 30 mL of acetonitrile and 15 mL of purified water, and then 5.97 g (18.5 mmol) of iodobenzene diacetate and 263 mg (1.69 mmol) of 2,2,6,6-tetramethylpiperidine 1-oxyl free radical were added at room temperature. After stirring at room temperature for 2 hours, purified water was added, the reaction solution was acidified with acetic acid, and then separated five times with ethyl acetate. The obtained organic layer was washed with saturated saline, and sodium sulfate was added to the organic layer to remove water. The solvent was distilled off under reduced pressure to obtain a crude product of (4S,5R)-2,2-dimethyl-5-(prop-2-yn-1-yl)-1,3-dioxolane-4-carboxylic acid.
The crude product was dissolved in 90 mL of dichloromethane, cooled to 0°C, and 1.86 mL (18.5 mmol) of N-methylmorpholine, 1.64 g (16.9 mmol) of N,O-dimethylhydroxyamine hydrochloride, and 3.23 g (18.5 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide were added. After stirring at 0°C for 20 hours, purified water was added and the mixture was separated three times with ethyl acetate. The organic layer obtained was washed with saturated saline, and sodium sulfate was added to the organic layer to remove water. The solvent was removed under reduced pressure, and the mixture was purified by silica gel column chromatography (ethyl acetate:hexane = 3:7 to 1:1) to obtain (4S,5R)-N-methoxy-N,2,2-trimethyl-5-(prop-2-yn-1-yl)-1,3-dioxolane-4-carboxamide as a transparent liquid (1.11 g, two-step yield 58%). ¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 4.96 (d, J = 6.4 Hz, 1H), 4.56 (q, J = 6.4 Hz, 1H), 3.72 (s, 3H), 3.19 (s, 3H), 2.42-2.39 (overlapped, 2H), 2.01 (t, J = 2.8 Hz, 1H), 1.61 (s, 3H), 1.41 (s, 3H)

既知化合物(S)-t-ブチル (ペント-4-イン-2-イロキシ)ジフェニルシラン 92.3 mg (0.286 mmol)をテトラヒドロフラン 0.9 mLに溶解させ、-78度に冷却した後、ノルマルブチルリチウム 174 μL (0.286 mmol)を加えた。-78度で1時間撹拌した後、実施例19で製造した(4S,5R)-N-メトキシ-N,2,2-トリメチル-5-(プロピ-2-イン-1-イル)-1,3-ジオキソラン-4-カルボキサミド 50.0 mg (0.220 mmol)をテトラヒドロフラン 0.2 mLに溶解させて反応液に-78度で加えた。0度で10分間撹拌した後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン＝1:1)にて精製し、(S)-1-((4S,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)-5-((t-ブチルジフェニルシリル)オキシ)ヘキサ-2-イン-1-オンを薄黄色の液体として得た (51.3 mg、収率48%)。
¹H-NMR (CDCl₃, 400 MHz) δppm: 7.68-7.65 (overlapped, 4H), 7.46-7.36 (overlapped), 4.57-4.50 (overlapped, 2H), 4.03 (sext, J = 6.0 Hz, 1H), 2.56-2.50 (overlapped, 2H), 2.42 (ddd, J = 17.2, 7.6, 2.4 Hz, 1H), 2.02 (t, J = 2.8 Hz, 1H), 1.59 (s, 3H), 1.39 (s, 3H), 1.24 (d, J = 6.0 Hz, 3H), 1.05 (s, 9H) (9-3) (S)-5-((t-butyldiphenylsilyl)oxy)-1-((4S,5R)-2,2-dimethyl-5-(prop-2-yn-1-yl)-1,3-dioxolan-4-yl)hex-2-yn-1-one was synthesized as follows.

92.3 mg (0.286 mmol) of the known compound (S)-t-butyl (pent-4-yn-2-yloxy)diphenylsilane was dissolved in 0.9 mL of tetrahydrofuran and cooled to -78 degrees, and then 174 μL (0.286 mmol) of normal butyllithium was added. After stirring at -78 degrees for 1 hour, 50.0 mg (0.220 mmol) of (4S,5R)-N-methoxy-N,2,2-trimethyl-5-(prop-2-yn-1-yl)-1,3-dioxolane-4-carboxamide prepared in Example 19 was dissolved in 0.2 mL of tetrahydrofuran and added to the reaction solution at -78 degrees. After stirring for 10 minutes at 0 degrees, a saturated aqueous ammonium chloride solution was added, and separation was performed three times with ethyl acetate. The obtained organic layer was washed with saturated saline, and then sodium sulfate was added to the organic layer to remove water. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1) to give (S)-1-((4S,5R)-5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl)-5-((t-butyldiphenylsilyl)oxy)hex-2-yn-1-one as a pale yellow liquid (51.3 mg, yield 48%).
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 7.68-7.65 (overlapped, 4H), 7.46-7.36 (overlapped), 4.57-4.50 (overlapped, 2H), 4.03 (sext, J = 6.0 Hz, 1H), 2.56-2.50 (overlapped, 2H) , 2.42 (ddd, J = 17.2, 7.6, 2.4 Hz, 1H), 2.02 (t, J = 2.8 Hz, 1H), 1.59 (s, 3H), 1.39 (s, 3H), 1.24 (d, J = 6.0 Hz, 3H), 1.05 (s, 9H)

（9-3）で製造した(S)-1-((4S,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)-5-((t-ブチルジフェニルシリル)オキシ)ヘキサ-2-イン-1-オン 5.0 mg (0.0103 mmol)をテトラヒドロフラン 0.1 mLに溶解させ、酢酸 3.7 μL (0.102 mmol)とn-テトラブチルアンモニウムフロリド溶液 150 μL (0.150 mmol)を室温で加えた。室温で10時間撹拌した後、0度で飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン＝1:1)にて精製し、(S)-1-((4S,5R)-2,2-ジメチル-5-(プロピ-2-イン-1-イル)-1,3-ジオキソラン-4-イル)-5-ヒドロキシヘキセ-2-イン-1-オンを薄黄色の液体として得た (0.64 mg、収率25%)。
¹H-NMR (CDCl₃, 400 MHz) δppm: 4.57 (overlapped, 2H), 4.06 (sext, J = 6.0 Hz, 1H), 2.65-2.53 (overlapped, 3H), 2.47 (ddd, J = 16.4, 6.8, 2.4 Hz, 1H), 2.06 (t, J = 2.8 Hz, 1H), 1.65 (s, 3H), 1.41 (s, 3H), 1.31 (d, J = 6.0 Hz, 3H) (9-4) (S)-1-((4S,5R)-2,2-dimethyl-5-(prop-2-yn-1-yl)-1,3-dioxolan-4-yl)-5-hydroxyhex-2-yn-1-one was synthesized as follows.

5.0 mg (0.0103 mmol) of (S)-1-((4S,5R)-5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl)-5-((t-butyldiphenylsilyl)oxy)hex-2-yn-1-one prepared in (9-3) was dissolved in 0.1 mL of tetrahydrofuran, and 3.7 μL (0.102 mmol) of acetic acid and 150 μL (0.150 mmol) of n-tetrabutylammonium fluoride solution were added at room temperature. After stirring at room temperature for 10 hours, a saturated aqueous solution of sodium bicarbonate was added at 0 degrees, and the mixture was separated three times with chloroform. The obtained organic layer was washed with saturated saline, and then sodium sulfate was added to the organic layer to remove water. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1) to obtain (S)-1-((4S,5R)-2,2-dimethyl-5-(prop-2-yn-1-yl)-1,3-dioxolan-4-yl)-5-hydroxyhex-2-yn-1-one as a pale yellow liquid (0.64 mg, yield 25%).
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 4.57 (overlapped, 2H), 4.06 (sext, J = 6.0 Hz, 1H), 2.65-2.53 (overlapped, 3H), 2.47 (ddd, J = 16.4, 6.8, 2.4 Hz, 1H), 2.06 ( t, J = 2.8 Hz, 1H), 1.65 (s, 3H), 1.41 (s, 3H), 1.31 (d, J = 6.0 Hz, 3H)

1-ペンチン 4.3 μL (0.0436 mmol)をテトラヒドロフラン 0.4 mLに溶解させ、-78度に冷却した後、ノルマルブチルリチウム 16 μL (0.0436 mmol)を加えた。-78度で1時間撹拌した後、（8-3）で製造した(4S,5R)-5-アリル-N-メトキシ-N,2,2-トリメチル-1,3-ジオキソラン-4-カルボキサミド 10.0 mg (0.0436 mmol)をテトラヒドロフラン 0.1 mLに溶解させて反応液に-78度で加えた。0度で3時間撹拌した後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン＝1:1)にて精製し、1-((4S,5R)-5-アリル-2,2-ジメチル-1,3-ジオキソラン-4-イル)ヘキシ-2-イン-1-オンを薄黄色の液体として得た (5.0 mg、収率45%)。
¹H-NMR (CDCl₃, 400 MHz) δppm: 5.82 (m, 1H), 5.20-5.02 (overlapped, 2H), 4.53 (d, J = 7.4 Hz), 4.44 (m, 1H), 2.40-2.30 (overlapped, 3H), 2.28 (m, 1H), 1.70-1.63 (overlapped, 2H), 1.65 (s, 3H), 1.38 (s, 3H), 0.98 (d, J = 6.4 Hz, 3H) Example 10 1-((4S,5R)-5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl)hex-2-yn-1-one
1-((4S,5R)-5-Allyl-2,2-dimethyl-1,3-dioxolan-4-yl)hex-2-yn-1-one was synthesized as follows.

4.3 μL (0.0436 mmol) of 1-pentyne was dissolved in 0.4 mL of tetrahydrofuran and cooled to -78°C, and then 16 μL (0.0436 mmol) of n-butyllithium was added. After stirring at -78°C for 1 hour, 10.0 mg (0.0436 mmol) of (4S,5R)-5-allyl-N-methoxy-N,2,2-trimethyl-1,3-dioxolane-4-carboxamide prepared in (8-3) was dissolved in 0.1 mL of tetrahydrofuran and added to the reaction solution at -78°C. After stirring at 0°C for 3 hours, a saturated aqueous ammonium chloride solution was added and the mixture was separated three times with ethyl acetate. The obtained organic layer was washed with saturated saline, and then sodium sulfate was added to the organic layer to remove water. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1) to give 1-((4S,5R)-5-allyl-2,2-dimethyl-1,3-dioxolan-4-yl)hex-2-yn-1-one as a pale yellow liquid (5.0 mg, yield 45%).
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 5.82 (m, 1H), 5.20-5.02 (overlapped, 2H), 4.53 (d, J = 7.4 Hz), 4.44 (m, 1H), 2.40-2.30 (overlapped, 3H), 2.28 (m, 1H), 1.70-1.63 (overlapped, 2H), 1.65 (s, 3H), 1.38 (s, 3H), 0.98 (d, J = 6.4 Hz, 3H)

（8-3）で製造した(4S,5R)-5-アリル-N-メトキシ-N,2,2-トリメチル-1,3-ジオキソラン-4-カルボキサミド 20 mg (0.0872 mmol)をメタノール 0.4 mLに溶解させた後、パラジウム/カーボン 9.3 mg (0.00872 mmol)を加えた。水素雰囲気下、室温で12時間撹拌した後、セライト濾過でパラジウム/カーボンを除去した。溶媒を留去した後、粗生成物をシリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン＝1:1)にて精製し、(4S,5R)-N-メトキシ-N,2,2-トリメチル-5-プロピル-1,3-ジオキソラン-4-カルボキサミドを薄黄色の液体として得た (19.8 g、収率99%)。
¹H-NMR (CDCl₃, 400 MHz) δppm: 4.92 (d, J = 6.8 Hz, 1H), 4.38 (ddd, J = 9.6, 6.8, 2.8 Hz, 1H), 3.69 (s, 3H), 3.18 (s, 3H), 1.60 (s, 3H), 1.58-1.31 (overlapped, 4H), 1.38 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H) Example 11 (S)-1-((4S,5R)-2,2-dimethyl-5-propyl-1,3-dioxolan-4-yl)-5-hydroxyhex-2-yn-1-one (11-1) (4S,5R)-N-methoxy-N,2,2-trimethyl-5-propyl-1,3-dioxolane-4-carboxamide was synthesized as follows.

20 mg (0.0872 mmol) of (4S,5R)-5-allyl-N-methoxy-N,2,2-trimethyl-1,3-dioxolane-4-carboxamide prepared in (8-3) was dissolved in 0.4 mL of methanol, and 9.3 mg (0.00872 mmol) of palladium/carbon was added. After stirring at room temperature for 12 hours under a hydrogen atmosphere, the palladium/carbon was removed by filtration through Celite. After distilling off the solvent, the crude product was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1) to obtain (4S,5R)-N-methoxy-N,2,2-trimethyl-5-propyl-1,3-dioxolane-4-carboxamide as a pale yellow liquid (19.8 g, yield 99%).
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 4.92 (d, J = 6.8 Hz, 1H), 4.38 (ddd, J = 9.6, 6.8, 2.8 Hz, 1H), 3.69 (s, 3H), 3.18 (s, 3H), 1.60 (s, 3H), 8-1.31 (overlapped, 4H), 1.38 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H)

既知化合物(S)-t-ブチル (ペント-4-イン-2-イロキシ)ジフェニルシラン 27.6 mg (0.0856 mmol)をテトラヒドロフラン 0.8 mLに溶解させ、-78度に冷却した後、ノルマルブチルリチウム 31 μL (0.0856 mmol)を加えた。-78度で1時間撹拌した後、（11-1）で製造した(4S,5R)-N-メトキシ-N,2,2-トリメチル-5-プロピル-1,3-ジオキソラン-4-カルボキサミド 19.8 mg (0.0856 mmol)をテトラヒドロフラン 0.2 mLに溶解させて反応液に-78度で加えた。0度で1時間撹拌した後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン＝1:4から1:1)にて精製し、(S)-5-((t-ブチルジフェニルシリル)オキシ)-1-((4S,5R)-2,2-ジメチル-5-プロピル-1,3-ジオキソラン-4-イル)ヘキシ-2-イン-1-オンを薄黄色の液体として得た (16.9 mg、収率40%)。
¹H-NMR (CDCl₃, 400 MHz) δppm: 7.68-7.64 (overlapped, 4H), 7.47-7.33 (overlapped, 6H), 4.94 (d, J = 6.8 Hz, 1H), 4.57-4.50 (overlapped, 2H), 4.33 (ddd, J = 9.6, 6.8, 2.8 Hz, 1H), 4.03 (sext, J = 6.0 Hz, 1H), 1.62 (s, 3H), 1.58-1.31 (overlapped, 4H), 1.38 (s, 3H), 1.22 (t, J = 6.4 Hz, 3H), 0.89 (t, J = 7.0 Hz, 3H) (11-2) (S)-5-((t-butyldiphenylsilyl)oxy)-1-((4S,5R)-2,2-dimethyl-5-propyl-1,3-dioxolan-4-yl)hex-2-yn-1-one was synthesized as follows.

The known compound (S)-t-butyl (pent-4-yn-2-yloxy)diphenylsilane (27.6 mg (0.0856 mmol)) was dissolved in 0.8 mL of tetrahydrofuran and cooled to -78 degrees, after which 31 μL (0.0856 mmol) of n-butyllithium was added. After stirring at -78 degrees for 1 hour, 19.8 mg (0.0856 mmol) of (4S,5R)-N-methoxy-N,2,2-trimethyl-5-propyl-1,3-dioxolane-4-carboxamide (11-1) was dissolved in 0.2 mL of tetrahydrofuran and added to the reaction solution at -78 degrees. After stirring at 0 degrees for 1 hour, a saturated aqueous ammonium chloride solution was added, and the mixture was separated three times with ethyl acetate. The resulting organic layer was washed with saturated saline, and then sodium sulfate was added to the organic layer to remove water. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:4 to 1:1) to obtain (S)-5-((t-butyldiphenylsilyl)oxy)-1-((4S,5R)-2,2-dimethyl-5-propyl-1,3-dioxolan-4-yl)hex-2-yn-1-one as a pale yellow liquid (16.9 mg, yield 40%).
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 7.68-7.64 (overlapped, 4H), 7.47-7.33 (overlapped, 6H), 4.94 (d, J = 6.8 Hz, 1H), 4.57-4.50 (overlapped, 2H), 4.33 (ddd, J = 9.6, 6.8, 2.8 Hz, 1H), 4.03 (sext, J = 6.0 Hz, 1H), 1.62 (s, 3H), 1.58-1.31 (overlapped, 4H), 1.38 (s, 3H), 1.22 (t, J = 6.4 Hz, 3H), 0.89 (t, J = 7.0 Hz , 3H)

（11-2）で製造した(S)-5-((t-ブチルジフェニルシリル)オキシ)-1-((4S,5R)-2,2-ジメチル-5-プロピル-1,3-ジオキソラン-4-イル)ヘキシ-2-イン-1-オン 6.0 mg (0.0122 mmol)をテトラヒドロフラン 0.18 mLに溶解させ、酢酸 7.0 μL (0.114 mmol)とn-テトラブチルアンモニウムフロリド溶液 0.17 mL (0.171 mmol)を室温で加えた。室温で9時間撹拌した後、0度で飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで分液を3回行った。得られた有機層を飽和食塩水で洗浄した後、有機層に硫酸ナトリウムを加え水の除去を行った。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー (酢酸エチル:ヘキサン＝1:4から1:1)にて精製し、(S)-1-((4S,5R)-2,2-ジメチル-5-プロピル-1,3-ジオキソラン-4-イル)-5-ヒドロキシヘキシ-2-イン-1-オンを薄黄色の液体として得た (1.1 mg、収率35%)。
¹H-NMR (CDCl₃, 400 MHz) δppm: 4.90 (d, J = 6.8 Hz, 1H), 4.30 (m, 1H), 1.62 (s, 3H), 1.59-1.29 (overlapped, 4H), 1.37 (s, 3H), 1.27 (t, J = 6.4 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H) (11-3) (S)-1-((4S,5R)-2,2-dimethyl-5-propyl-1,3-dioxolan-4-yl)-5-hydroxyhex-2-yn-1-one was synthesized as follows.

6.0 mg (0.0122 mmol) of (S)-5-((t-butyldiphenylsilyl)oxy)-1-((4S,5R)-2,2-dimethyl-5-propyl-1,3-dioxolan-4-yl)hex-2-yn-1-one prepared in (11-2) was dissolved in 0.18 mL of tetrahydrofuran, and 7.0 μL (0.114 mmol) of acetic acid and 0.17 mL (0.171 mmol) of n-tetrabutylammonium fluoride solution were added at room temperature. After stirring at room temperature for 9 hours, a saturated aqueous solution of sodium bicarbonate was added at 0 degrees, and the mixture was separated three times with chloroform. The obtained organic layer was washed with saturated saline, and then sodium sulfate was added to the organic layer to remove water. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:4 to 1:1) to obtain (S)-1-((4S,5R)-2,2-dimethyl-5-propyl-1,3-dioxolan-4-yl)-5-hydroxyhex-2-yn-1-one as a pale yellow liquid (1.1 mg, yield 35%).
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 4.90 (d, J = 6.8 Hz, 1H), 4.30 (m, 1H), 1.62 (s, 3H), 1.59-1.29 (overlapped, 4H), 1.37 (s, 3H), 1.27 (t, J = 6.4 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H)

Test Example 1 Endoplasmic Reticulum Stress in Human Multiple Myeloma Cell Line RPMI8226 Human multiple myeloma cell line RPMI8226 was seeded in a 3.5 cm dish at a density of 10,000 cells/well and incubated overnight at 37° C. in a 5% carbon dioxide atmosphere. Separately, the compounds of the examples (Examples 7 and 18) were dissolved in dimethyl sulfoxide and added to each well so that the final compound concentration was 10 μM.
Next, after culturing for 24 hours at 37°C in a 5% carbon dioxide atmosphere, the cells were harvested, a cell extract was prepared using PBS buffer, electrophoresed on SDS-PAGE, and transferred to a PVDF membrane using a semi-dry transfer device.
Antibody Treatment
Primary antibody: Anti-CHOP #2895 Lot: 4 [CST]
Secondary antibody: anti-mouse IgG #7076 Lot: 32 [CST]
+ Anti-biotin #7075 Lot: 32 [CST]
<Detection conditions>
Detection reagent: Ultra
Detection strength: Standard
Exposure time: 4 seconds Gel concentration: 15%
Protein amount: 50 μg/lane The results are shown in Figure 1. As shown in Figure 1, the compounds of Examples 2, 8, and 9 induced the endoplasmic reticulum stress response.

Test Example 2 Anticancer activity (1) Anticancer activity against human multiple myeloma cell line RPMI8226 Human multiple myeloma cell line RPMI8226 was seeded in a 96-well plate at a density of 1 x ¹⁰⁴ cells/well and incubated overnight in a 5% carbon dioxide atmosphere at 37°C. Separately, the compound of the Example was dissolved in dimethyl sulfoxide and added to each well so that the final compound concentration was 0.78125 μM, 1.5625 μM, 3.125 μM, 6.25 μM, 12.5 μM, 25 μM, or 50 μM.
After culturing for 3 days at 37°C in a 5% carbon dioxide atmosphere, the absorbance (420 nm) of the orange pigment (formazan) produced by the viable cells was measured using a cell culture/cytotoxicity measurement reagent (Dojindo Chemical Industries, Cell Counting Kit-8). The _IC50 value was calculated from the relative absorbance when the absorbance without the addition of the compound of the present invention or melphalan was taken as 100.
(2) Anticancer activity against each human cancer cell line Human cancer cell lines HCT116, A549, HeLa or human embryonic kidney-derived cells (HEK293) were seeded on a 96-well plate at a density of 1 x ¹⁰⁴ cells/well and incubated overnight at 37°C under a 5% carbon dioxide atmosphere. Separately, the compounds of the examples were dissolved in dimethyl sulfoxide and added to each well so that the final compound concentrations were 0.78125 μM, 1.5625 μM, 3.125 μM, 6.25 μM, 12.5 μM, 25 μM or 50 μM.
After culturing for 3 days at 37°C in a 5% carbon dioxide atmosphere, the absorbance (420 nm) of the orange pigment (formazan) produced by the viable cells was measured using a cell culture/cytotoxicity measurement reagent (Dojindo Chemical Industries, Cell Counting Kit-8). The _IC50 value was calculated from the relative absorbance when the absorbance without the addition of the compound of the present invention or melphalan was taken as 100.
The results are shown in Table 1.

Test Example 3: Measurement of PDI activity
PDI activity was measured using Abcam's PDI Inhibitor Screening Assay Kit (detection sensitivity > 37 μM). First, 50 μL/well of Insulin solution (320 μM) diluted with Mill-Q H ₂ O or Mill-Q H ₂ O (Blank) was added to each well of a 96-well plate. Next, 10 μL/well of PDI working solution or Mill-Q H ₂ O (Negative control) was added to each well. Furthermore, 10 μL/well of diluted compound (solution with 8 times the final concentration) was added to each well (10 μL/well of Mill-Q H ₂ O for Untreated, Negative control, and Blank). Next, 10 μL/well of DTT was added to each well and the plate was gently tapped to mix. After that, the plate was incubated at room temperature for 30 minutes in the dark, and 10 μL/well of Stop Reagent working solution was added to each well. Furthermore, 10 μL/well of PDI Detection Reagent working solution was added to each well. After incubation at room temperature for 15 minutes, the fluorescence was measured using a plate reader at an excitation wavelength of 500 nm and an emission wavelength of 603 nm.
The IC50 of Bacitracin, a positive control, was 169.7 μM, and those of Example 2 and Example 9 were 24.1 μM and 164.4 μM, respectively.

Test Example 4 Anticancer activity in a mouse model ¹⁰⁶ cells of mouse myeloma cell line 5TGM-1, which constitutively expresses luciferase, were transplanted into the right tibia bone marrow of 6-week-old female ICR mice, and after confirming engraftment one week later, the compound of the example was intraperitoneally administered to the mice every other day at a final concentration of 20 mg/kg. After two weeks of administration, luciferin was intraperitoneally administered and detected by an IVIS imaging system to observe the proliferation of tumor cells in the body.
The results are shown in Figures 2 and 3. As shown in Figures 2 and 3, the compounds of Examples 2 and 8 inhibited tumor progression in myeloma model mice.

Test Example 5: Effect on cytotoxic activity on hematopoietic stem cells Human peripheral blood stem cells were seeded in a 12-well plate at a density of ^2X106 cells/well, and the compound of the Example was dissolved in dimethylsulfoxide and added to each well to a final concentration of 10 μM, followed by culturing for 24 hours. The cells were collected and mixed with human hematopoietic stem cell colony measurement medium MethoCult to a concentration of ^2X105 cells/ml, and then seeded in 1 ml of the mixture in a 35 mm dish and cultured at 37°C for 14 days under a 5% carbon dioxide atmosphere. After culturing, the formation of leukocyte colonies (CFU-GM) and erythroid colonies (BFU-E) was observed under a bright-field microscope, and the numbers were counted.
The results are shown in Figures 4 and 5. As shown in Figures 4 and 5, the compounds of Examples 2 and 8 did not affect normal hematopoiesis.

Test Example 6: Inhibitory activity against bone lesion formation (1) Inhibitory activity against osteoclast formation using mouse osteoclast precursor cell line RAW264.7 cells from the mouse osteoclast precursor cell line were seeded in a 96-well plate at a density of ¹⁰³ cells/well, and a compound was added to a final concentration of 5 μM in the presence of recombinant human M-CSF (10 ng/ml) and recombinant human RANKL (25 ng/ml), and cultured for 4 days at 37° C. under a 5% carbon dioxide atmosphere. After culture, TRAP staining was performed, and the number of TRAP-positive osteoclasts with 3 or more nuclei was counted.
The results are shown in Figure 6. As shown in Figure 6, the compound of Example 8 inhibited osteoclast formation.
(2) Inhibitory activity against osteoclast formation using primary cultured mouse cells Bone marrow cells extracted from the tibia and femur of 6-week-old C57BL6 mice were incubated overnight at 37°C under a 5% carbon dioxide atmosphere, and only floating cells were separated and seeded on a 96-well plate at a density of 4 x ¹⁰⁵ cells/well. The cells were treated with recombinant human M-CSF (10 ng/ml) for 3 days, and then the compound was added to a final concentration of 5 μM in the presence of recombinant human M-CSF (10 ng/ml) and recombinant human RANKL (25 ng/ml) and cultured for 4 days. After culture, TRAP staining was performed, and the number of TRAP-positive osteoclasts with 3 or more nuclei was counted.
The results are shown in Figure 7. As shown in Figure 7, the compound of Example 2 inhibited osteoclast formation.
(3) Inhibitory activity against cancerous bone lesion formation ¹⁰⁶ cells of mouse myeloma cell line 5TGM-1, which constitutively expresses luciferase, were transplanted into the tibia bone marrow of 6-week-old female ICR mice. After confirming the survival of the cells one week later, the compound was intraperitoneally administered to the mice every other day at a final concentration of 20 mg/kg. After two weeks of administration, the tibia was removed and photographed with soft X-ray.
The results are shown in Figure 8. As shown in Figure 8, the compound of Example 8 inhibited the formation of bone lesions.

Test Example 7 Anti-Rheumatic Effect Bovine type II collagen was dissolved in 10 mM acetic acid to prepare a 2 mg/ml solution, which was then mixed with an equal amount of Complete Freund's adjuvant to prepare an emulsion. 100 μl of the prepared emulsion was injected intradermally at the base of the tail of 6-week-old male DBA/1J mice. After 3 weeks, booster immunization was performed in the same manner, and after confirming that arthritis had been induced 2 days later, the compound was intraperitoneally administered to the mice every other day so that the final concentration was 20 mg/kg. To evaluate arthritis, the Clinical Score was measured every other day after booster immunization. Clinical Score was determined using the following criteria, and was measured for each limb, with the total score being the measured value for one individual.
0: Normal 1: Redness, swelling, and deformation observed in one finger 2: Redness, swelling, and deformation observed in two or more fingers 3: Redness, swelling, and deformation observed in the entire foot The results are shown in Figure 9. As shown in Figure 9, the compound of Example 2 had an anti-rheumatic effect.

Claims (11)

A compound represented by the following formula (1A) or a salt thereof:

[Wherein,
^A1 is represented by the following formula:

(Wherein,
R ⁵ is -OR ^5a or -NR ^5b R ^5c ;
R ^5a is a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group;
R ^5b and R ^5c each independently represent a hydrogen atom, an alkyl group, or an aryl group;
n is an integer from 0 to 4,
When n is an integer of 2 or more, the multiple ^R5s may be the same or different.
A ring represented by
^X1 is an oxygen atom;
^X2 is a double bond;
^R1 is _{a C1-4} alkyl group ;
R2 is a hydrogen atom ^;
R ³ and R ⁴ are the same or different and each is a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, or R ³ O and R ⁴ O may form a ring together with the two adjacent carbon atoms. The compound or salt thereof according to claim 1, wherein A ¹ is a ring represented by the following formula:

(Wherein,
R ⁵¹ and R ⁵² are the same or different and each is a hydrogen atom, an alkyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group;
R ⁵³ is a hydrogen atom, an alkyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group;
R ⁵⁴ and R ⁵⁵ are the same or different and each is a hydrogen atom, an alkyl group, or an aryl group. The compound or salt thereof according to claim 1 or 2 , wherein R ³ and R ⁴ are the same or different and each represent a hydrogen atom, an alkyl group, or an alkoxyalkyl group. A method for producing a compound represented by formula (1A) or a salt thereof according to claim 1, comprising the steps of:
(1) The following formula (1-5):

(In the formula, A ¹ , X ¹ , R ¹ , R ² , R ³ , and R ⁴ are the same as above.)
with a triple bond protecting agent;
(2) a step of cyclizing the product obtained in step (1); and (3) a step of removing the protecting group of the triple bond from the product obtained in step (2). A compound represented by the following formula (2A) or a salt thereof:

[Wherein,
^X3 is a single bond, a double bond, or a triple bond;
^R6 is represented by the following formula:

is a group represented by
X4 ^is a hydroxyl group;
R ⁶¹ is a C _1-4 alkyl group;
R ⁶² is a hydrogen atom;
R ⁷ O and R ⁸ O, together with the two adjacent carbon atoms, represent the following formula:

(In the formula, R ^7a and R ^8a are the same or different and each is a hydrogen atom, an alkyl group, or an aryl group, and * indicates the bonding position to the carbonyl carbon.)
It forms a ring represented by
R ⁹ is a hydrogen atom, an alkyl group, or an aryl group.
However, the following formula:

The compounds represented by the formula (I) are excluded. The compound or salt thereof according to claim 5 , wherein R ⁹ is a hydrogen atom. A method for producing a compound represented by formula (2A) or a salt thereof according to claim 5 , comprising the steps of:
In the presence of a base, the following formula (2-6):

(In the formula, R ¹⁰ and R ¹¹ are the same or different and each is an alkyl group, an alkoxy group, or an aryl group, and X ³ , R ⁷ , R ⁸ , and R ⁹ are the same as defined above.)
The compound represented by the following formula (9):

(Wherein, ^R6 is the same as defined above.)
The method includes reacting a compound represented by the formula: A compound represented by the following formula (1) or a salt thereof:

[Wherein,
^A1 is represented by the following formula:

(Wherein,
R ⁵ is -OR ^5a or -NR ^5b R ^5c ;
R ^5a is a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group;
R ^5b and R ^5c each independently represent a hydrogen atom, an alkyl group, or an aryl group;
n is an integer from 0 to 4,
When n is an integer of 2 or more, the multiple ^R5s may be the same or different.
A ring represented by
^X1 is an oxygen atom;
^X2 is a double bond;
^R1 is _{a C1-4} alkyl group ;
R2 is a hydrogen atom ^;
R ³ and R ⁴ are the same or different and each is a hydrogen atom, an alkyl group, an acyl group, an alkoxyalkyl group, or an alkoxyalkoxyalkyl group, or R ³ O and R ⁴ O may form a ring together with the two adjacent carbon atoms.
and a compound represented by the following formula (2) or a salt thereof:

[Wherein,
^X3 is a single bond, a double bond, or a triple bond;
^R6 is represented by the following formula:

is a group represented by
X4 ^is a hydroxyl group;
R ⁶¹ is a C _1-4 alkyl group;
R ⁶² is a hydrogen atom;
R ⁷ O and R ⁸ O, together with the two adjacent carbon atoms, represent the following formula:

(In the formula, R ^7a and R ^8a are the same or different and each is a hydrogen atom, an alkyl group, or an aryl group, and * indicates the bonding position to the carbonyl carbon.)
It forms a ring represented by
R ⁹ is a hydrogen atom, an alkyl group, or an aryl group.
A pharmaceutical composition comprising at least one selected from the group consisting of The pharmaceutical composition according to claim 8 , which is an endoplasmic reticulum stress response inducer. The pharmaceutical composition according to claim 8 or 9 , which is a protein disulfide isomerase inhibitor. The pharmaceutical composition according to any one of claims 8 to 10 , which is an agent for preventing or treating at least one disease selected from cancer, bone diseases, and rheumatism.

Images