JP2018145120A - Isosamidin analog and samidin analog production method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a simple method of industrial-scale production of an isosamidin analog or samidin analog.SOLUTION: In the production method, a compound represented by the formula (1) in the figure is 1) senecioylated and 2) acetylated. [X is O or the like; Rare each independently a C1-3 alkyl group or the like; Ris H or the like; Rare each a C1-3 alkyl group; m is an integer from 0 to 2; n is 1 or 2; and the symbol * represents an asymmetric center.]SELECTED DRAWING: None

Description

  The present invention relates to an isosamidine analog and a method for producing a samidin analog. In particular, the present invention relates to a method for producing an isosamidine analog.

  Isosamidine (compound name: 3-methyl-2-butenoic acid 9α- (acetoxy) -9,10-dihydro-8,8-dimethyl-2-oxo-2H, 8H-benzo [1,2-b: 3,4 -B '] dipyran-10α-yl) ester) (CAS number 53023-18-0), and Samidine (compound name: 3-methyl-2-butenoic acid (9R, 10R) -10-acetoxy-9,10- Dihydro-8,8-dimethyl-2-oxo-2H, 8H-benzo [1,2-b: 3,4-b ′] dipyran-9-yl) ester) (CAS number 477-33-8) It is a natural product contained in the celery family plant, Buttonbow Fu (long life grass), which grows naturally in Okinawa and Yakushima (Patent Document 1). Isosamidine has been reported to exhibit vasodilatory action, anti-arteriosclerotic action, and diuretic promoting action (Non-Patent Document 1), and foods and supplements containing this are known.

  Until now, as a method for obtaining isosamidine or samidin, a method using alcohol extraction from button pea (long-life grass) is known. For example, isosamidine is prepared by adjusting only about 1.3 g from 3 kg of button fountain dry powder. (Patent Document 1). Further, in the method using alcohol extraction, labor is also required to isolate and purify only the desired isosamidine or the samidin compound from the alcohol extract. Therefore, it is difficult to produce a large amount of isosamidine or samidin itself by the conventional method.

  Therefore, a method for producing an isosamidine analog and a samidin analog, particularly an isosamidine analog by an organic chemical technique is desired.

JP 2011-37829 A

Ohnoki, H .; Deguchi, S .; Adachi, S .; Kato, Y., Smooth muscle relaxant, JP37829A, 2011-2-24.

  The present invention relates to the industrial scale of isosamidine and related compounds (hereinafter referred to as “isosamidine analogs”), and samidine and related compounds (hereinafter referred to as “samidine analogs”), particularly isosamidine analogs. An object of the present invention is to provide a simple production method useful for the production of

  As a result of intensive studies on an isosamidine analog or a production method capable of producing a samidin analog on an industrial scale, the present inventors have conducted several steps using a low molecular weight compound as a starting material. Alternatively, it was found that a Samidine analog can be chemically synthesized. Specifically, the kelactone intermediate compound represented by the formula (1) is first subjected to a seneciolization step by reacting with a seneciolization source compound, and then reacted with the acetylation source compound to perform acetylation. It has been found that by performing the process, the isosamidine analog can be produced at a superior ratio to the samidin analog. In particular, by using a seneci oil halide compound as a seneciolization source compound and reacting with a kelactone intermediate compound, peujaponicinol B in which the 4-position of the pyran ring is seneciolized can be obtained regioselectively. I found. It has also been found that an optically active isosamidine analog or a samidin analog can be obtained.

［式中、
Ｘは、酸素原子または硫黄原子であり；
Ｒ^１は各々独立して、Ｃ１〜３アルキル基またはＣ２〜Ｃ３アシル基であり；
Ｒ^２は、水素原子、Ｃ１〜３アルキル基またはＣ２〜Ｃ３アシル基であり；
Ｒ^３は、Ｃ１〜３アルキル基であり；
ｍは、０〜２の整数であり；
ｎは、１〜２の整数であり；そして、
記号＊は、不斉中心を表す］
で示される化合物を、
i）セネシオイル化供給源化合物と反応させてセネシオイル化を行う工程；および
ii）アセチル化供給源化合物と反応させてアセチル化を行う工程、
を含む、ここで、工程i）および工程ii）の順序はいずれが先であってもよい、
下式（Ｉ）で示されるイソサミジン類縁体化合物（以下、「化合物（Ｉ）」と呼称する）もしくは下式（II）で示されるサミジン類縁体化合物（以下、「化合物（ＩＩ）」と呼称する）のいずれか、またはそれらの混合物を製造する方法

［式中、
Ｘ、Ｒ^１、Ｒ^２、Ｒ^３、ｍ、ｎおよび＊は、前記するとおりである］。
項［２］ 前記工程i）において、スズ触媒および塩基の存在下で反応を行うことを含み、該セネシオイル化供給化合物がセネシオ酸、無水セネシオ酸、およびセネシオイルハライドからなる群から選ばれる、項［１］記載の製造方法。
項［３］ 前記工程ii）において、塩基の存在下で反応を行うことを含み、該アセチル化供給源化合物が酢酸、無水酢酸、およびアセチルハライドからなる群から選ばれる、項［１］または項［２］記載の製造方法。
項［４］ 前記工程i）の反応に続いて、前記工程ii）の反応を行うことを含む、項［１］記載の製造方法。
項［５］ 前記工程i）において、該セネシオイル化供給化合物としてセネシオイルハライドを用いてスズ触媒および塩基の存在下で反応を行うことにより、化合物（６−１）：

によって示される化合物を得る、項［４］記載の製造方法。
項［６］ 製造される式（Ｉ）で示される化合物が、式（ＩＡ−１）および式（ＩＡ−２）：

［式中、
Ｘ、Ｒ^１、Ｒ^２、Ｒ^３、ｍ、ｎおよび＊は、項［１］において前記するとおりである］
からなる群から選ばれる少なくとも１つの３，４位−シス体のエナンチオマー、またはそれらのラセミ混合物である、項［１］〜［５］のいずれか１項に記載の製造方法。
項［７］ 生成物が、式（Ｉ）中、Ｘが酸素原子であり、Ｒ^２が水素原子であり、ｍが０であり、そしてｎが２である、項［６］記載の製造方法。
項［８］ 得られる生成物が、イソサミジンおよびサミジンの比率が５：１である混合物である、項［５］または項［６］記載の製造方法。
項［９］ 式（Ｉ）で示される化合物もしくは式（II）で示される化合物のいずれか、またはそれらの混合物を製造する方法であって、
工程２）式（３）：

［式中、
Ｘ、Ｒ^１、Ｒ^２、およびｍは、項［１］において前記するとおりである］
によって示される化合物を、１，１−ジエトキシ−３−メチル−２−ブテンまたは１，１−ジエトキシ−２−ブテンと反応させて、式（２）：

［式中、
Ｘ、Ｒ^１、Ｒ^２、Ｒ^３、ｎ、およびｍは、前記するとおりである］
によって示される化合物を得る工程；
工程３’）得られた式（２）によって示される化合物を、四酸化オスミウムおよび再酸化剤と反応させて、項［１］に記載の式（１Ａ−１）および式（１Ａ−２）：

［式中、
Ｘ、Ｒ^１、Ｒ^２、Ｒ^３、ｎ、ｍおよび＊は、前記するとおりである］
によって示される化合物を得る工程；および、
工程４）得られた式（１Ａ−１）および式（１Ａ−２）によって示される化合物について、
i）セネシオイル化供給源化合物と反応させてセネシオイル化を行う工程、および、
ii）アセチル化供給源化合物と反応させてアセチル化を行う工程、
を行って、式（Ｉ）で示される化合物もしくは式（II）で示される化合物のいずれか、またはそれらの混合物を得て、ここで、工程i）および工程ii）の順序はいずれが先であってもよい、
式（Ｉ）で示される化合物もしくは式（II）で示される化合物のいずれか、またはそれらの混合物を製造する方法。
項［１０］ 工程１）式（４）：

［式中、
Ｘ、Ｒ^１およびｎは、項［１］において前記するとおりである］
で示される化合物と、式（５）：

［式中、
Ｒ^２は、項［１］において前記するとおりである］
で示される化合物とを反応させて、項［９］に記載の工程１に記載の式（３）：

［式中、
Ｘ、Ｒ^１、Ｒ^２、およびｍは、項［１］において前記するとおりである］
で示される化合物を得る工程を含む、項［９］記載の製造方法。
項［１１］ 項［９］に記載の工程３’に代わって、
工程３’’−１）式（２）によって示される化合物と過酸とを反応させて、式（８）：

［式中、
Ｘ、Ｒ^１、Ｒ^２、Ｒ^３、ｍ、ｎおよび＊は、項［１］において前記するとおりである］
で示されるエポキシド化合物を得る工程；および、
工程３’’−２）得られた式（８）で示されるエポキシド化合物を、無機酸を用いて処理する、
ことを含む、式（１Ｂ−１）および式（１Ｂ−２）：

［式中、
Ｘ、Ｒ^１、Ｒ^２、Ｒ^３、ｍ、ｎおよび＊は、項［１］において前記するとおりである］
で示される化合物からなる群から選ばれる、少なくとも１つの３，４位−トランス体、またはそれらのエナンチオマーのラセミ混合物を得ることを含む、項［９］記載の製造方法。
項［１２］ 製造される式（Ｉ）で示される化合物が、式（ＩＢ−１）および式（ＩＢ−２）：

［式中、
Ｘ、Ｒ^１、Ｒ^２、Ｒ^３、ｍ、ｎおよび＊は、項［１］において前記するとおりである］
からなる群から選ばれる少なくとも１つの３，４位−トランス体のエナンチオマー、またはそれらのラセミ混合物である、項［１１］記載の製造方法。
項［１３］ 項［９］に記載の工程３’に代わって、
工程３’’’）式（２）によって示される化合物を、不斉配位子の存在下、四酸化オスミウムおよび再酸化剤を用いた、シャープレス不斉ジヒドロキシ化を行って、式（１Ａ−１）および（１Ａ−２）：

［式中、
Ｘ、Ｒ^１、Ｒ^２、Ｒ^３、ｍ、ｎおよび＊は、項［１］において前記するとおりである］
で示される化合物からなる群から選ばれる、少なくとも１つの３，４位−シス体の（Ｒ）−もしくは（Ｓ）−エナンチオマーまたはそれらの混合物を得ることを含む、項［９］記載の製造方法。
項［１４］ 製造される式（Ｉ）で示される化合物が、式（ＩＡ−１）および式（ＩＡ−２）：

［式中、
Ｘ、Ｒ^１、Ｒ^２、Ｒ^３、ｍ、ｎおよび＊は、項［１］において前記するとおりである］
からなる群から選ばれる、少なくとも１つの３，４位−シス体の（Ｒ）−もしくは（Ｓ）−エナンチオマーまたはそれらの混合物である、項［１３］記載の製造方法。 That is, the present invention is as follows, but is not limited thereto.
Term [1] Formula (1):

[Where:
X is an oxygen atom or a sulfur atom;
Each R ¹ is independently a C1-3 alkyl group or a C2-C3 acyl group;
R ² is a hydrogen atom, a C1-3 alkyl group or a C2-C3 acyl group;
R ³ is a C1-3 alkyl group;
m is an integer from 0 to 2;
n is an integer from 1 to 2;
Symbol * represents an asymmetric center]
A compound represented by
i) reacting with a seneciolization source compound to effect seneciolization; and
ii) reacting with an acetylated source compound to effect acetylation;
Where the order of step i) and step ii) may be first,
An isosamidin analog compound represented by the following formula (I) (hereinafter referred to as “compound (I)”) or a samidin analog compound represented by the following formula (II) (hereinafter referred to as “compound (II)”) ) Or a method of producing a mixture thereof

[Where:
X, R ¹ , R ² , R ³ , m, n and * are as described above].
Item [2] In the step i), comprising reacting in the presence of a tin catalyst and a base, wherein the seneciolized feed compound is selected from the group consisting of senecioic acid, senecioic anhydride, and senecioyl halide. [1] The production method according to [1].
Item [3] Item [1] or Item [3], wherein in the step ii), the reaction is performed in the presence of a base, and the acetylated source compound is selected from the group consisting of acetic acid, acetic anhydride, and acetyl halide. [2] The production method according to [2].
Item [4] The production method according to Item [1], which comprises carrying out the reaction of Step ii) following the reaction of Step i).
Item [5] In the step i), a compound (6-1) is obtained by performing a reaction in the presence of a tin catalyst and a base using seneci oil halide as the seneciolization feed compound.

The production method according to item [4], wherein a compound represented by the formula (4) is obtained
Item [6] The compound represented by formula (I) to be produced is represented by formula (IA-1) and formula (IA-2):

[Where:
X, R ¹ , R ² , R ³ , m, n and * are as described above in the term [1]]
Item 6. The production method according to any one of Items [1] to [5], which is at least one 3,4-position cis enantiomer selected from the group consisting of: or a racemic mixture thereof.
Item [7] The production method according to Item [6], wherein the product is represented by formula (I), wherein X is an oxygen atom, R ² is a hydrogen atom, m is 0, and n is 2. .
Item [8] The production method according to Item [5] or [6], wherein the product obtained is a mixture having a ratio of isosamidine and samidin of 5: 1.
Item [9] A method for producing either the compound represented by the formula (I) or the compound represented by the formula (II), or a mixture thereof,
Step 2) Formula (3):

[Where:
X, R ¹ , R ² , and m are as described above in the term [1]]
Is reacted with 1,1-diethoxy-3-methyl-2-butene or 1,1-diethoxy-2-butene to give a compound of formula (2):

[Where:
X, R ¹ , R ² , R ³ , n, and m are as described above]
Obtaining a compound represented by:
Step 3 ′) The obtained compound represented by the formula (2) is reacted with osmium tetroxide and a reoxidant to give the formula (1A-1) and the formula (1A-2) described in the item [1]:

[Where:
X, R ¹ , R ² , R ³ , n, m and * are as described above]
Obtaining a compound represented by: and
Step 4) Regarding the compounds represented by the obtained formula (1A-1) and formula (1A-2),
i) reacting with a seneciolization source compound to effect seneciolization, and
ii) reacting with an acetylated source compound to effect acetylation;
To obtain either the compound represented by formula (I) or the compound represented by formula (II), or a mixture thereof, wherein the order of step i) and step ii) May be,
A method for producing either the compound represented by formula (I) or the compound represented by formula (II), or a mixture thereof.
Item [10] Step 1) Formula (4):

[Where:
X, R ¹ and n are as described above in the term [1]]
A compound of formula (5):

[Where:
R ² is as described above in item [1]]
And the compound represented by formula (3) according to the step 1 according to the item [9]:

[Where:
X, R ¹ , R ² , and m are as described above in the term [1]]
The manufacturing method of claim | item [9] including the process of obtaining the compound shown by these.
Item [11] Instead of step 3 ′ according to item [9],
Step 3 ″ -1) A compound represented by the formula (2) is reacted with a peracid to obtain a formula (8):

[Where:
X, R ¹ , R ² , R ³ , m, n and * are as described above in the term [1]]
Obtaining an epoxide compound represented by:
Step 3 ″ -2) The obtained epoxide compound represented by the formula (8) is treated with an inorganic acid.
Including formula (1B-1) and formula (1B-2):

[Where:
X, R ¹ , R ² , R ³ , m, n and * are as described above in the term [1]]
The production method according to item [9], comprising obtaining at least one 3,4-trans-isomer, or a racemic mixture of enantiomers thereof, selected from the group consisting of compounds represented by:
Item [12] The compound represented by the formula (I) to be produced is represented by the formula (IB-1) and the formula (IB-2):

[Where:
X, R ¹ , R ² , R ³ , m, n and * are as described above in the term [1]]
Item 12. The production method according to Item [11], which is at least one 3,4-position trans enantiomer selected from the group consisting of: or a racemic mixture thereof.
Item [13] Instead of step 3 ′ according to item [9],
Step 3 ′ ″) The compound represented by the formula (2) is subjected to sharpless asymmetric dihydroxylation using osmium tetroxide and a reoxidant in the presence of an asymmetric ligand to obtain a compound represented by the formula (1A- 1) and (1A-2):

[Where:
X, R ¹ , R ² , R ³ , m, n and * are as described above in the term [1]]
The production method according to item [9], comprising obtaining at least one 3,4-positioned (R)-or (S) -enantiomer or a mixture thereof selected from the group consisting of compounds represented by: .
Item [14] The compound represented by the formula (I) to be produced is represented by the formula (IA-1) and the formula (IA-2):

[Where:
X, R ¹ , R ² , R ³ , m, n and * are as described above in the term [1]]
The production method according to item [13], which is at least one 3,4-positioned (R)-or (S) -enantiomer selected from the group consisting of: or a mixture thereof.

  The production method of the present invention is useful for production of an isosamidine analog or a samidin analog, particularly an isosamidine analog on an industrial scale. It has also been found that an optically active isosamidine analog or a samidin analog can be obtained by the production method of the present invention.

The production methods of compound (I) and compound (II) of the present invention will be specifically described below. The total synthesis scheme of Compound I and Compound II is shown below in order.
First, the production of compound (3) (step 1) and the subsequent production of compound (2) (step 2) are as shown below.

Next, manufacture (process 3) of a compound (1) is as showing below. Here, the reaction for producing the compound (1) is carried out in the structure of the compound (1), followed by the carbons at the 3- and 4-positions of the pyran ring in the structure of the compound (I) and the compound (II) as the final target product. The desired reaction is selected according to the configuration of the asymmetric center.
(Process 3 ')
First, when producing a racemic mixture of enantiomers in which the hydroxy substituents at the 3- and 4-positions of the pyran ring in the structure of the compound (1) are in cis configuration, the reaction is carried out according to the method of Step 3 ′ shown below, and the compound ( A racemic mixture of 1A-1) and compound (1A-2) is prepared.
(Process 3 ″)
On the other hand, when producing a racemic mixture of enantiomers in which the hydroxy substituents at the 3- and 4-positions of the pyran ring in the structure of the compound (1) are in the trans configuration, the reaction is performed according to the method of Step 3 '' shown below A racemic mixture of compound (1B-1) and compound (1B-2) is prepared.
(Process 3 ''')
Alternatively, in the case of producing enantiomers in which the hydroxy substituents at the 3- and 4-positions of the pyran ring in the structure of compound (1) are in the trans configuration or a mixture thereof (enantiomer-excess mixture), step 3 ′ ″ shown below is used. The compound (1A-1) and each enantiomer of the compound (1A-2) or a mixture thereof (enantiomer-excess mixture) are produced by performing the reaction according to the method.

上記各式中、各記号Ｘ、Ｒ^１、Ｒ^２、Ｒ^３、ｎ、ｍおよび＊は、明細書中に定義するとおりである。 Next, i) a step of reacting the compound (1) produced in each of step 3 ′, step 3 ″, and step 3 ′ ″ with a seneciolization source compound to effect seneciolization, and ii) Producing a mixture of compound I and compound II by reacting with an acetylated source compound to effect acetylation (wherein step i) and step ii) may be in any order) Can do. Here, the steric configuration at the 3,4-position of the pyran ring in the structures of Compound I and Compound II is (−)-cis, (+)-cis, (−, depending on the compound (1) used in the reaction. ) -Trans, or (+)-trans enantiomers, or mixtures (including enantiomeric excess mixtures and racemic mixtures with a 1: 1 enantiomeric ratio).

In the above formulas, the symbols X, R ¹ , R ² , R ³ , n, m and * are as defined in the specification.

  Next, the reaction in each step will be specifically described.

Production of Compound (3) (Step 1)
Reaction of compound (4) and compound (5) described in the literature known as Peckman condensation reaction (see, for example, S.-S. Xie et al. European Journal of Medicinal Chemistry 2013, 64, 540-553.) The compound (3) can be produced by carrying out the reaction in the presence of an acid catalyst according to the method according to. Or a compound (3) can also be obtained as a commercial item.

化合物（４）の好ましい例としては、レゾルシノールが挙げられる。
化合物（５）において、式中、Ｒ^２は水素原子、Ｃ１〜３アルキル基またはＣ２〜Ｃ３アシル基である。Ｒ^２は水素原子またはＣ１〜３アルキル基が好ましく、水素原子がより好ましい。Ｒ^２の具体例としては、水素原子、メチル、エチル、またはアセチルが挙げられる。化合物（５）の具体例としては、２−ヒドロキシブタン二酸（別名：リンゴ酸）、１−メチル−２−ヒドロキシブタン二酸等が挙げられるが、これらに限定されるものではない。 In the compound (4), in the formula, X is an oxygen atom or a sulfur atom, and each R ¹ is independently a C1-3 alkyl group (for example, methyl, ethyl, n-propyl, and i-propyl) or C2- A C3 acyl group (eg, acetyl and ethanoyl) and m is an integer from 0 to 2; In particular, X is preferably an oxygen atom. R ¹ is preferably a C1-3 alkyl group, and specific examples of R ¹ include methyl, ethyl, or acetyl. m is preferably an integer of 0 to 1, more preferably 0. Specific examples of the compound (4) include, but are not limited to, the following compounds.

A preferred example of compound (4) is resorcinol.
In the compound (5), in the formula, R ² is a hydrogen atom, a C1-3 alkyl group, or a C2-C3 acyl group. R ² is preferably a hydrogen atom or a C1-3 alkyl group, more preferably a hydrogen atom. Specific examples of R ² include a hydrogen atom, methyl, ethyl, or acetyl. Specific examples of the compound (5) include 2-hydroxybutanedioic acid (also known as malic acid), 1-methyl-2-hydroxybutanedioic acid, and the like, but are not limited thereto.

In the compounds of the product (3), wherein, X is oxygen atom or sulfur atom; ^{R 1} is each independently a C1~3 alkyl group or a C2~C3 acyl group; ^{R 2} is A hydrogen atom, a C1-3 alkyl group or a C2-C3 acyl group; and m is an integer of 0-2.
X is preferably an oxygen atom. R ¹ is preferably a C1-3 alkyl group, and specific examples of R ¹ include methyl, ethyl, or acetyl. m is preferably an integer of 0 to 1, more preferably 0. R ² is preferably a hydrogen atom or a C1-3 alkyl group, more preferably a hydrogen atom.
In one embodiment, compound (3) has the formula:
X is an oxygen atom or a sulfur atom;
Each R ¹ is independently a C 1-3 alkyl group;
R ² is a hydrogen atom or a C1-3 alkyl group;
m is an integer from 0 to 1,
Compounds.

化合物（３）の好ましい例としては、７−ヒドロキシ−２Ｈ−１−ベンゾピラン−２−オン（別名：ウンベリフェロン）、７−ヒドロキシ−２Ｈ−１−ベンゾチオピラン−２−オンが挙げられる。 Specific examples of compound (3) include, but are not limited to, the following compounds.

Preferable examples of compound (3) include 7-hydroxy-2H-1-benzopyran-2-one (also known as umbelliferone) and 7-hydroxy-2H-1-benzothiopyran-2-one.

In the compound (4) and the compound (5) used in this reaction, the compound (5) is 0.5 to 5.0 molar equivalents, preferably 1.0 to 1 molar equivalent of the compound (4). 2.0 molar equivalents, more preferably 1.0 to 1.5 molar equivalents.
Examples of the acid catalyst used in this reaction include inorganic acids (for example, concentrated hydrochloric acid, concentrated nitric acid, concentrated sulfuric acid), and concentrated sulfuric acid is preferred. The acid catalyst can be used in an excess amount from the catalyst amount relative to the compound (4).
The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, aromatic hydrocarbons (for example, benzene, toluene, xylene, etc.), ethers (for example, diethyl ether, 1,4-dioxane, tetrahydrofuran, etc.) or a mixed solvent of these organic solvents and water. Moreover, you may use the acid used as an acid catalyst as a solvent.
The reaction temperature for this reaction varies depending on the reagent or reaction conditions to be used, but is generally room temperature to heating (eg, heating under reflux), preferably about 80 ° C. to about 140 ° C., typically about 100 ° C.
While the reaction time of this reaction varies depending on the reagent or reaction condition to be used, it is generally within the range of about 1 to about 24 hours, preferably about 1 to about 12 hours, and typically about 6 hours.
This reaction may be performed in the presence of an inert gas, for example, in the presence of nitrogen gas or argon gas.

  As a post-treatment method after the reaction in this reaction, as described in the above-mentioned literature, the reaction mixture after the reaction is quenched by pouring into ice water, and then the precipitated product can be filtered. In particular, according to the present invention, the reaction mixture after the reaction is extracted using an organic solvent (for example, ethers (for example, diethyl ether), halogenated hydrocarbon (for example, dichloromethane)) instead of the filtration treatment described above. Then, by performing post-treatment operations such as drying and concentration of the organic layer, the yield of the target compound (3) is improved. By repeating the extraction operation from the aqueous layer with an organic solvent, the yield of the compound (3) can be improved. Furthermore, the isolated compound (3) can be further purified by chromatography, recrystallization and the like.

Production of compound (2) (step 2)
Compound (3) obtained in Step 1 is converted to 1,1-diethoxy-3-methyl-2-butene or 1,1-diethoxy-2-butene with, for example, literature (for example, Marumoto, S .; Miyazawa, M Bioorg. Med. Chem. 2012, 20, 784-788) can be reacted to produce compound (2).

  Both 1,1-diethoxy-3-methyl-2-butene and 1,1-diethoxy-2-butene can be used, but 1,1-diethoxy-3-methyl-2-butene is used. It is preferable.

Compound as the product in (2), wherein, X is oxygen atom or sulfur atom; ^{R 1} is each independently a C1~3 alkyl group or a C2~C3 acyl group; ^{R 2} is a hydrogen atom, a C1~3 alkyl group or a C2~C3 acyl group; ^{R 3} is C1~3 alkyl group; m is an integer from 0 to 2; and n is 1-2 integer is there.
X is preferably an oxygen atom. R ¹ is preferably a C1-3 alkyl group, and specific examples of R ¹ include methyl, ethyl, or acetyl. m is preferably an integer of 0 to 1, more preferably 0. R ² is preferably a hydrogen atom or a C1-3 alkyl group, more preferably a hydrogen atom. Examples of R ³ include methyl, ethyl or propyl, and methyl is preferable. n is preferably an integer of 2.
In one embodiment, compound (2) has the formula:
X is an oxygen atom or a sulfur atom;
Each R ¹ is independently a C 1-3 alkyl group;
R ² is a hydrogen atom or a C1-3 alkyl group;
Each R ³ is independently a C1-3 alkyl group;
m is an integer from 0 to 1; and
n is an integer of 2.
Compounds.

化合物（２）の好ましい例としては、２，２−ジメチル−１，５−ジオキサフェナントレン−６（２Ｈ）−オン（別名：セセリン）、および２−メチル−１，５−ジオキサフェナントレン−６（２Ｈ）−オンが挙げられる。 Specific examples of the compound (2) include the following compounds, but are not limited thereto.

Preferred examples of the compound (2) include 2,2-dimethyl-1,5-dioxaphenanthrene-6 (2H) -one (also known as seserin) and 2-methyl-1,5-dioxaphenanthrene-6. (2H) -one.

The compound (3), 1,1-diethoxy-3-methyl-2-butene and 1,1-diethoxy-2-butene used in this reaction are 1,1 with respect to 1 molar equivalent of the compound (3). 1-diethoxy-3-methyl-2-butene or 1,1-diethoxy-2-butene is 0.5 to 10.0 molar equivalents, preferably 1.0 to 5.0 molar equivalents, more preferably 1.0. -2.0 molar equivalents.
Examples of the base used in this reaction include inorganic bases (for example, sodium carbonate), organic bases (for example, N, N-dimethylaniline, N, N-diethylaniline, pyridine) and the like. Organic bases are preferred, with N, N-dimethylaniline or N, N-diethylaniline being more preferred. The usage-amount of a base can be used by 1.0 molar equivalent-excess amount (for example, 1.0-5.0 molar equivalent) with respect to 1 molar equivalent of a compound (3).
The solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include ethers (for example, diethyl ether, 1,4-dioxane, tetrahydrofuran and the like), halogenated hydrocarbons (for example, dichloromethane) and the like. It is done. A base (for example, N, N-dimethylaniline, N, N-diethylaniline) may be used as a solvent.
The reaction temperature of this reaction varies depending on the reagent or reaction conditions to be used, but is usually room temperature to heating (eg, heating under reflux), preferably in the range of about 80 ° C. to about 160 ° C., and typically about 140 ° C. ° C.
While the reaction time of this reaction varies depending on the reagent or reaction conditions to be used, it is generally in the range of about 6 to about 72 hours, preferably about 12 to about 48 hours, and typically about 24 hours.
This reaction may be performed in the presence of an inert gas, for example, in the presence of nitrogen gas or argon gas.

  After completion of the reaction, the compound (2) can be obtained by performing post-treatment operations such as filtration of the reaction mixture, extraction with an organic solvent as necessary, and drying and concentration of the organic layer. The isolated compound (2) can be further purified by chromatography, recrystallization and the like.

Production of compound (1) (step 3)
Step 3 ′, step 3 ″, and step 3 ′ ″ will be sequentially described below.
(Process 3 ')
First, (Step 3 ′) will be described.
Compound (2) obtained in step 2 is mixed with osmium tetroxide and a reoxidant, for example, literature (for example, Chemical Society of Japan (2004) "5th edition Experimental Chemistry Course 17 Synthesis of Organic Compounds V-Oxidation Reaction") , Maruzen Co., Ltd.), the compound (1) can be produced.

A commercial item can be used for the osmium tetroxide used for this reaction. The amount of osmium tetroxide is usually a catalytic amount to about 1 molar equivalent with respect to 1 molar equivalent of the compound (2), and a catalytic amount (for example, about 2% molar equivalent) is preferable. Osmium tetroxide may be added to the reaction solution in several batches or dropwise.
The reoxidant used in this reaction is not particularly limited as long as it is a reoxidant usually used in an oxidation reaction using osmium tetroxide as a catalyst. For example, N-methylmorpholine-N -Oxides (NMO). The amount of the reoxidant to be used is generally within the range of about 1.0 to about 2.0 molar equivalent, preferably about 1.0 to about 1.5 molar equivalent, relative to 1 molar equivalent of compound (2). Yes, typically about 1.1 molar equivalents.

上記化合物（１Ａ−１）および（１Ａ−２）において、式中、Ｘは、酸素原子または硫黄原子であり；Ｒ^１は各々独立して、Ｃ１〜３アルキル基またはＣ２〜Ｃ３アシル基であり；Ｒ^２は、水素原子、Ｃ１〜３アルキル基またはＣ２〜Ｃ３アシル基であり；Ｒ^３は、Ｃ１〜３アルキル基であり；ｍは、０〜２の整数であり；ｎは、１〜２の整数であり；そして、記号＊は、不斉中心を表す。
Ｘは、酸素原子が好ましい。Ｒ^１はＣ１〜３アルキル基が好ましく、Ｒ^１の具体例としては、メチル、エチル、またはアセチルが挙げられる。ｍは０〜１の整数が好ましく、０がより好ましい。Ｒ^２は水素原子またはＣ１〜３アルキル基が好ましく、水素原子がより好ましい。Ｒ^３は、メチル、エチルまたはプロピルが挙げられ、メチルが好ましい。ｎは２の整数が好ましい。
化合物（１Ａ−１）および（１Ａ−２）の具体例としては下記の化合物を挙げられるが、これらに限定されるものではない。ここで、下記に示す具体例としては、３，４−位がシス配置のエナンチオマーの一方のみを例示するが、他方のエナンチオマーをも含む、１；１のラセミ混合物を意図すると解釈されるべきである。

化合物（１Ａ−１）および（１Ａ−２）の好ましい例としては、前記ケルラクトンが挙げられる。 The compound (1) produced in Step 3 ′ is a racemic mixture (1: 1) of cis isomers represented by the following formulas (1A-1) and (1A-2).

In the compounds (1A-1) and (1A-2), X is an oxygen atom or a sulfur atom; each R ¹ is independently a C1-3 alkyl group or a C2-C3 acyl group. ; ^{R 2} is a hydrogen atom, a C1~3 alkyl group or a C2~C3 acyl group; ^{R 3,} a in there C1~3 alkyl group; m is an integer from 0 to 2; n is 1 to And the symbol * represents an asymmetric center.
X is preferably an oxygen atom. R ¹ is preferably a C1-3 alkyl group, and specific examples of R ¹ include methyl, ethyl, or acetyl. m is preferably an integer of 0 to 1, more preferably 0. R ² is preferably a hydrogen atom or a C1-3 alkyl group, more preferably a hydrogen atom. Examples of R ³ include methyl, ethyl or propyl, and methyl is preferable. n is preferably an integer of 2.
Specific examples of the compounds (1A-1) and (1A-2) include, but are not limited to, the following compounds. Here, the specific examples shown below illustrate only one of the enantiomers in the cis configuration at the 3,4-position, but should also be construed to mean a 1: 1 racemic mixture that also includes the other enantiomer. is there.

Preferable examples of the compounds (1A-1) and (1A-2) include the aforementioned kellactone.

The solvent is not particularly limited as long as it is inert to the reaction. For example, ethers (for example, diethyl ether), halogenated hydrocarbons (for example, dichloromethane), ketones (for example, acetone), etc., or these A mixed solvent of an organic solvent and water can be mentioned.
The reaction temperature of this reaction varies depending on the reagent or reaction conditions to be used, but is usually under ice cooling to heating, preferably under ice cooling to room temperature.
While the reaction time of this reaction varies depending on the reagent or reaction condition to be used, it is generally about 1 to 48 hr, preferably about 6 to about 24 hr, and typically about 18 hr.
This reaction may be performed under an inert gas, for example, in the presence of nitrogen gas or argon gas.

  After completion of the reaction, the compound (1) can be obtained by performing post-treatment operations such as filtration of the reaction mixture, extraction with an organic solvent as necessary, and drying and concentration of the organic layer. The isolated compound (1) can be further purified by chromatography, recrystallization and the like.

(Process 3 ″)
Next, (Step 3 ″) will be described.
Compound (2) obtained in Step 2 can be obtained from, for example, literature (for example, Bulman Page, PC; Appleby, LF; Day, D .; Chan, Y .; Buckley, BR; Allin, SM; McKenzie, MJ Org. Lett 2009, 11, 1991-1993.) To produce an epoxide compound of the formula (8) by reacting with a peracid according to the reaction described in (Step 3 ″ -1), and then the resulting epoxide compound (8 ) For example according to the reaction described in the literature (Iranpoor, N .; Baltork, IM; Zardaloo, FS Tetrahedron 1991, 47, 9861-9866), compound (1) can be produced.

(Process 3 ″ -1)
Examples of peracids used in this reaction include, but are not limited to, hydrogen peroxide, perchloric acid, sodium permanganate, and m-chloroperbenzoic acid. Sodium permanganate and m-chloroperbenzoic acid are preferred. The amount of peracid used is generally about 1 mol to about 5 mol equivalent, preferably about 1 mol to about 2 mol equivalent, more preferably about 1 mol to 1 mol equivalent of compound (2). Within the range of about 1.2 molar equivalents, typically about 1 molar equivalent.

で示される。ここで、化合物（８）は、下式に示す通り、

３，４−位のシス体のエナンチオマーのラセミ混合物（１：１）である。
化合物（８）の具体例としては下記の化合物を挙げられるが、これらに限定されるものではない。ここで、下記に示す具体例としては、３，４−位がシス配置のエナンチオマーの一方のみを例示するが、他方のエナンチオマーをも含む、１：１のラセミ混合物を意図すると解釈されるべきである。

化合物（８）の好ましい例としては、

（1a,9c-ジヒドロ-2,2-ジメチル-2H,8H-オキシレノ[c]ピラノ[2,3-f][1]ベンゾピラン-8-オン）
が挙げられる。 Compound (8) produced in Step 3 ″ -1 has the following formula:

Indicated by Here, the compound (8) has the following formula:

A racemic mixture (1: 1) of the cis enantiomer in the 3,4-position.
Specific examples of the compound (8) include the following compounds, but are not limited thereto. Here, the specific examples shown below illustrate only one of the enantiomers in the cis configuration at the 3,4-position, but should be construed to mean a 1: 1 racemic mixture that also includes the other enantiomer. is there.

As a preferable example of the compound (8),

(1a, 9c-dihydro-2,2-dimethyl-2H, 8H-oxyleno [c] pyrano [2,3-f] [1] benzopyran-8-one)
Is mentioned.

The solvent is not particularly limited as long as it is inert to the reaction. For example, ethers (for example, diethyl ether), halogenated hydrocarbons (for example, dichloromethane, chloroform) and the like, or these organic solvents and water The mixed solvent is mentioned.
The reaction temperature of this reaction varies depending on the reagent or reaction conditions to be used, but is usually under ice cooling to heating, preferably under ice cooling to room temperature.
While the reaction time of this reaction varies depending on the reagent or reaction condition to be used, it is generally about 1 to 48 hours, preferably about 1 to 12 hours, and typically about 5 to about 6 hours.
This reaction may be performed under an inert gas, for example, in the presence of nitrogen gas or argon gas.

  After completion of the reaction, the reaction mixture is quenched by treatment with an aqueous sodium thiosulfate solution according to a conventional method, and then neutralized with an aqueous alkaline solution. Further, the reaction mixture is filtered, extracted with an organic solvent as necessary, and post-treatment operations such as drying and concentration of the organic layer are performed, whereby compound (8) can be obtained. The isolated compound (8) can be further purified by chromatography, recrystallization and the like.

(Process 3 ″ -2)
Examples of the acid used in this reaction include inorganic acids (for example, dilute hydrochloric acid, dilute nitric acid, dilute sulfuric acid), and dilute sulfuric acid is preferred. The acid is used in an amount of about 1 to about 100 molar equivalents, preferably about 2 to about 20 molar equivalents, typically 1 molar amount of compound (8) obtained in step 3 ″ -1. Is in the range of about 5 to about 8 equivalents.

上記化合物（１Ｂ−１）および（１Ｂ−２）において、式中、Ｘは、酸素原子または硫黄原子であり；Ｒ^１は各々独立して、Ｃ１〜３アルキル基またはＣ２〜Ｃ３アシル基であり；Ｒ^２は、水素原子、Ｃ１〜３アルキル基またはＣ２〜Ｃ３アシル基であり；Ｒ^３は、Ｃ１〜３アルキル基であり；ｍは、０〜２の整数であり；ｎは、１〜２の整数であり；そして、記号＊は、不斉中心を表す。
Ｘは、酸素原子が好ましい。Ｒ^１はＣ１〜３アルキル基が好ましく、Ｒ^１の具体例としては、メチル、エチル、またはアセチルが挙げられる。ｍは０〜１の整数が好ましく、０がより好ましい。Ｒ^２は水素原子またはＣ１〜３アルキル基が好ましく、水素原子がより好ましい。Ｒ^３は、メチル、エチルまたはプロピルが挙げられ、メチルが好ましい。ｎは２の整数が好ましい。
化合物（１Ｂ−１）および（１Ｂ−２）の具体例としては下記の化合物を挙げられるが、これらに限定されるものではない。ここで、下記に示す具体例としては、３，４−位がトランス配置のエナンチオマーの一方のみを例示するが、他方のエナンチオマーをも含む、１；１のラセミ混合物を意図すると解釈されるべきである。

化合物（１Ｂ−１）および（１Ｂ−２）の好ましい例としては、前記ケルラクトンが挙げられる。 Compound (1) produced in Step 3 ″ -2 is a racemic mixture (1: 1) of a trans isomer represented by the following formulas (1B-1) and (1B-2).

In the compounds (1B-1) and (1B-2), X is an oxygen atom or a sulfur atom; R ¹ is each independently a C1-3 alkyl group or a C2-C3 acyl group. ; ^{R 2} is a hydrogen atom, a C1~3 alkyl group or a C2~C3 acyl group; ^{R 3,} a in there C1~3 alkyl group; m is an integer from 0 to 2; n is 1 to And the symbol * represents an asymmetric center.
X is preferably an oxygen atom. R ¹ is preferably a C1-3 alkyl group, and specific examples of R ¹ include methyl, ethyl, or acetyl. m is preferably an integer of 0 to 1, more preferably 0. R ² is preferably a hydrogen atom or a C1-3 alkyl group, more preferably a hydrogen atom. Examples of R ³ include methyl, ethyl or propyl, and methyl is preferable. n is preferably an integer of 2.
Specific examples of the compounds (1B-1) and (1B-2) include, but are not limited to, the following compounds. Here, the specific examples shown below illustrate only one of the enantiomers in the trans configuration at the 3,4-position, but should also be construed as intending a 1: 1 racemic mixture that also includes the other enantiomer. is there.

Preferable examples of the compounds (1B-1) and (1B-2) include the aforementioned kellactone.

The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, organic solvents such as ethers (eg, diethyl ether, 1,4-dioxane, tetrahydrofuran, etc.), halogenated compounds Hydrocarbon (for example, chloroform), ketone (for example, ketone) or the like, or a mixed solvent of these organic solvents and water is included.
The reaction temperature of this reaction varies depending on the reagent used or reaction conditions, but is usually under ice cooling to heating, preferably room temperature.
While the reaction time of this reaction varies depending on the reagent or reaction conditions to be used, it is generally within the range of about 10 minutes to about 6 hours, preferably about 30 minutes to about 3 hours, and typically about 1 hour. .
This reaction may be performed in the presence of an inert gas, for example, in the presence of nitrogen gas or argon gas.

Next, (Step 3 ′ ″) will be described.
Compound (2) obtained in step 2 is combined with osmium tetroxide and a reoxidant in the presence of an asymmetric ligand, for example, literature (eg Sharpless, KB; Amberg, W .; Bennani, YL; Crispino, GA; Hartung, J .; Jeong, K.-S .; Kwong, H.-L .; Morikawa, K .; Wang, Z.-M .; Xu, D .; Zhang, X.-LJ Org. Chem 1992, 57, 2768-2771.), The compound (1) can be produced by the reaction according to the reaction of the sharpless asymmetric hydroxylation described in the above.

As the osmium tetroxide used in this reaction, a commercially available product can be used as in Step 3 ′. The amount of osmium tetroxide is usually a catalytic amount to about 1 molar equivalent with respect to 1 molar equivalent of the compound (2), and a catalytic amount (for example, about 1% to about 5% molar equivalent) is preferable. Osmium tetroxide may be added to the reaction solution in several batches or dropwise.
The reoxidant used in this reaction is not particularly limited as long as it is a reoxidant usually used in an oxidation reaction using osmium tetroxide as a catalyst. For example, methanesulfonamide and N- And methylmorpholine-N-oxide (NMO). The amount of the reoxidant to be used is generally within the range of about 1.0 to about 2.0 molar equivalent, preferably about 1.0 to about 1.5 molar equivalent, relative to 1 molar equivalent of compound (2). Yes, typically about 1.1 molar equivalents.

The asymmetric ligand used in this reaction is a ligand derived from quinidine or quinine, which is known to be usable in a normal sharpened asymmetric hydroxylation reaction. Specific examples include (DHQ) ₂ PHAL (also known as hydroquinine 1,4-phthalazinediyl diether) (CAS number 140924-50-1), (DHQD) ₂ PHAL (also known as hydroquinidine 1,4-phthalazinediyl diether) (CAS number 140853-10) -7), (DHQ) ₂ AQN (alias: hydroquinine anthraquinone-1,4-diyl diether) (CAS number 176097-24-8), and (DHQD) ₂ AQN (aka: hydroquinidine anthraquinone-1,4-diyl) Diether) (CAS number 176298-44-5) and the like, but is not limited thereto. The amount of the asymmetric ligand to be used is usually a catalytic amount to about 1 molar equivalent with respect to 1 molar equivalent of the compound (2), and a catalytic amount (for example, about 1% to about 5% molar equivalent) is preferable. .

に示す本反応を、種々の不斉配位子を用いて、配位子の量、および反応時間、反応温度、さらに溶媒の条件を変えて、生成物のケラクトンのエナンチオ選択性を調べた。光学純度の決定は、シス−ケラクトンの比旋光度の文献（例えば、Panthong, K.; Srisud, Y.; Rukachaisirikul, V.; Hutadilok-Towatana, N.; Voravuthikunchai, S. P.; Tewtrakul, S. Phytochemistry, 2013, 88, 79-84.）記載の値を基準として算出した。
R体, 文献値：[α]_D ＋80.9 (c 1.04, CHCl₃);
S体, 文献値：[α]_D -82.3 (c 0.5, CHCl₃)
結果を、表１に示す。
反応条件検討の結果

上記表１の結果から、不斉配位子として、(DHQ)₂PHAL系の配位子を用いた場合には、生成物のシス−ケラクトンの光学純度は（Ｓ）体が優先して生成し、一方で(DHQ)₂系の配位子を用いた場合には、生成物の光学純度は（Ｒ）体が優先して生成することを見出した。
得られた光学活性な生成物の光学分割は、例えば光学活性なクロマトグラフィーを用いる分割、あるいは光学活性な塩基とのジアステレオマー塩を形成後に分別再結晶による分離によって行うことができる。 Examination of reaction conditions Further, the following reaction formula:

In this reaction, the enantioselectivity of the product kelactone was investigated by using various asymmetric ligands and changing the amount of ligand, reaction time, reaction temperature, and solvent conditions. Determination of optical purity can be accomplished using literature on the specific rotation of cis-kelactone (eg, Panthong, K .; Srisud, Y .; Rukachaisirikul, V .; Hutadilok-Towatana, N .; Voravuthikunchai, SP; Tewtrakul, S. Phytochemistry, (2013, 88, 79-84.)
R form, literature value: [α] _D +80.9 (c 1.04, CHCl ₃ );
S form, literature value: [α] _D -82.3 (c 0.5, CHCl ₃ )
The results are shown in Table 1.
Results of reaction condition study

From the results of Table 1 above, when a (DHQ) ₂ PHAL-based ligand is used as the asymmetric ligand, the optical purity of the product cis-kelactone is preferentially produced by the (S) isomer. On the other hand, when the (DHQ) ₂ type ligand was used, it was found that the (R) isomer was preferentially produced as the optical purity of the product.
Optical resolution of the obtained optically active product can be performed, for example, by resolution using optically active chromatography or by separation by fractional recrystallization after formation of a diastereomeric salt with an optically active base.

上記化合物（１Ａ−１）および（１Ａ−２）において、式中、Ｘは、酸素原子または硫黄原子であり；Ｒ^１は各々独立して、Ｃ１〜３アルキル基またはＣ２〜Ｃ３アシル基であり；Ｒ^２は、水素原子、Ｃ１〜３アルキル基またはＣ２〜Ｃ３アシル基であり；Ｒ^３は、Ｃ１〜３アルキル基であり；ｍは、０〜２の整数であり；ｎは、１〜２の整数であり；そして、記号＊は、不斉中心を表す。
Ｘは、酸素原子が好ましい。Ｒ^１はＣ１〜３アルキル基が好ましく、Ｒ^１の具体例としては、メチル、エチル、またはアセチルが挙げられる。ｍは０〜１の整数が好ましく、０がより好ましい。Ｒ^２は水素原子またはＣ１〜３アルキル基が好ましく、水素原子がより好ましい。Ｒ^３は、メチル、エチルまたはプロピルが挙げられ、メチルが好ましい。ｎは２の整数が好ましい。
化合物（１Ａ−１）および（１Ａ−２）の具体例としては、ラセミ混合物（１：１）ではなく、シス体のいずれかのエナンチオマー、またはいずれかのエナンチオマーが過剰な混合物であることを除いて、前記工程３’において記載の具体例と同じものが挙げられる。 The compound (1) produced in the step 3 ′ ″ is a cis enantiomer represented by the following formulas (1A-1) and (1A-2), or an enantiomerically excess mixture.

In the compounds (1A-1) and (1A-2), X is an oxygen atom or a sulfur atom; each R ¹ is independently a C1-3 alkyl group or a C2-C3 acyl group. ; ^{R 2} is a hydrogen atom, a C1~3 alkyl group or a C2~C3 acyl group; ^{R 3,} a in there C1~3 alkyl group; m is an integer from 0 to 2; n is 1 to And the symbol * represents an asymmetric center.
X is preferably an oxygen atom. R ¹ is preferably a C1-3 alkyl group, and specific examples of R ¹ include methyl, ethyl, or acetyl. m is preferably an integer of 0 to 1, more preferably 0. R ² is preferably a hydrogen atom or a C1-3 alkyl group, more preferably a hydrogen atom. Examples of R ³ include methyl, ethyl or propyl, and methyl is preferable. n is preferably an integer of 2.
Specific examples of the compounds (1A-1) and (1A-2) are not a racemic mixture (1: 1) but any enantiomer of a cis isomer, or any enantiomer is an excess mixture. And the same thing as the specific example as described in the said process 3 'is mentioned.

  The enantiomeric excess of the reaction products (1A-1) and (1A-2) can be determined using, for example, chiral liquid chromatography. Alternatively, if the specific rotation of each enantiomer of the reaction product is known, the specific rotation of the resulting reaction product is measured and compared to the known specific rotation value to The enantiomeric excess of the enantiomer can be determined.

The solvent is not particularly limited as long as it is inert to the reaction. For example, alcohols (for example, t-butyl alcohol), ethers (for example, diethyl ether), ketones (for example, acetone), etc., or these And a mixed solvent of an organic solvent and water (for example, a mixed solvent of t-butyl alcohol / water = 1/1).
The reaction temperature of this reaction varies depending on the reagent or reaction conditions to be used, but is usually in the range of −25 ° C. to room temperature, preferably −10 ° C. to ice-cooling (0 ° C.), typically 0 ° C. is there.
While the reaction time of this reaction varies depending on the reagent or reaction condition to be used, it is generally about 6 hr to about 12 days, typically about 12 hr to about 10 days.
This reaction may be performed under an inert gas, for example, in the presence of nitrogen gas or argon gas.

  After completion of the reaction, the compound (1) can be obtained by performing post-treatment operations such as filtration of the reaction mixture, extraction with an organic solvent as necessary, and drying and concentration of the organic layer. The isolated compound (1) can be further purified by chromatography, recrystallization and the like.

Production of Compound (I) and Compound (II) (Step 4)
Compound (1) obtained in step 3 is reacted with a seneciolization source compound according to the method described in i) literature (eg Swager, TM; Cardellina II, JH Phytochemistry 1985, 24, 805-813). Step of carrying out seneciolization (step 4-i), and ii) reacting with an acetylated source compound according to the method described in the literature (eg Swager, TM; Cardellina II, JH Phytochemistry 1985, 24, 805-813). Then, the step of performing acetylation (step 4-ii) can be carried out to produce compound I and compound II as the final target product. Here, the order of step 4-i) and step 4-ii) may be any first, but step 4-i) is preferably performed first.

(Step 4-ia)
The senecioylating feed compound used in this reaction includes senecioic acid, senecioic anhydride, and senecioyl halide (eg, literature (eg, Bartlett, CJ; Day, DP; Chan, Y .; Allin, SM; McKenzie, MJ Slawin, AMZ; Page, PCBJ Org. Chem. 2012, 77, 772-774)), and is different depending on the reaction compound (1) used and / or the reagent used.
In the reaction in Step 4-i, for example, a compound (1) and a senecioylation supply compound (for example, senecioic acid or senecioic anhydride) are subjected to a coupling reaction appropriately using a dehydration reaction condensing agent in the presence of a base. Thus, compound (6) converted to seneci oil (including compound (6-1) and compound (6-2)) can be produced.
The senecioylation supply compound used in this reaction includes a compound selected from the group consisting of senecioic acid, senecioic anhydride, and senecioyl halide, and senecioic acid and senecioic anhydride are preferred. The amount of the seneciolization feed compound used ranges from about 0.5 molar equivalents to about 1.5 molar equivalents, preferably from about 1 molar equivalents to about 1.2 molar equivalents, relative to 1 molar equivalent of compound (1). Within, typically about 1.1 equivalents.
Examples of the dehydration reaction condensing agent used in the reaction may be any generally known reagent, such as dicyclohexylcarbodiimide (also known as DCC). The amount of the dehydration reaction condensing agent to be used is generally within the range of about 1.0 to about 2.0 molar equivalents, preferably about 1.0 to about 1.5 molar equivalents, relative to 1 molar equivalent of compound (1). Typically about 1.1 molar equivalents.
Examples of the base used in the reaction may be any base that is known to be used in combination with a dehydration reaction condensing agent. Examples thereof include dimethylaminopyridine (also known as DMAP) and pyridine. The amount of the base to be used is generally in the range of catalytic amount to about 2.0 molar equivalent, preferably catalytic amount to about 1.0 molar equivalent, more preferably catalyst relative to 1 molar equivalent of compound (1). Amount (eg, about 1 mol%). Alternatively, when a dehydration reaction condensing agent is not used, the amount of the base used is generally about 1.0 molar equivalent to about 10 molar equivalents, preferably about 2 molar equivalents with respect to 1 molar equivalent of compound (1). Within the range of 0 molar equivalents to about 5.0 molar equivalents, typically about 3.0 molar equivalents.
The solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include dry solvents such as ethers (for example, diethyl ether) and halogenated hydrocarbons (for example, dichloromethane and chloroform).
The reaction temperature of this reaction varies depending on the reagent or reaction conditions to be used, but is usually in the range of from ice cooling to heating, typically room temperature.
While the reaction time of this reaction varies depending on the reagent or reaction conditions to be used, it is generally in the range of about 1 hr to about 48 hr, preferably about 1 hr to about 24 hr, typically about 5 to about 6 It's time.
This reaction may be performed under an inert gas, for example, in the presence of nitrogen gas or argon gas.
After completion of the reaction, the compound (6) can be obtained by performing post-treatment operations such as filtration of the reaction mixture, extraction with an organic solvent as necessary, and drying and concentration of the organic layer. Compound (6) can be further purified by chromatography, recrystallization and the like.

(Another method of step 4-ib)
As another method of the reaction of step 4-i, for example, literature (for example, Iwasaki, F .; Maki, T .; Onomura, O .; Nakashima, W .; Matsumura, YJ Org. Chem. 2000, 65, 996-1002 The compound (1) and the seneciolized feed compound are reacted in the presence of a tin catalyst and a base in accordance with the method described in (1) to give a seneciolized compound (6) (compound (6-1) and compound ( 6-2) can be produced.
Examples of the seneciolization feed compound used in this reaction include compounds selected from the group consisting of senecioic acid, senecioic anhydride, and senecioyl halide, and senecioyl halide is preferred. Specific examples include senecioyl chloride, senecioyl bromide, or senecioyl iodide. The amount of the seneciolization feed compound used is in the range of about 0.5 molar equivalents to about 10 molar equivalents, preferably about 1 molar equivalents to about 8 molar equivalents relative to 1 molar equivalent of compound (1). Typically about 2 to 6 molar equivalents.
Examples of tin catalysts used in the reaction include alkyl tin halides, and specific examples include, but are not limited to, dimethyl tin dichloride. The amount of the tin catalyst used is usually in the range of about 1 mol% to about 30 mol%, preferably about 5 mol% to about 20 mol%, based on 1 mol equivalent of the compound (1). Is about 10 mol%.
Examples of the base used in the reaction may be either an inorganic base or an organic base (for example, pyridine), but an inorganic base is preferable. Specific examples include alkali metal carbonates (for example, sodium carbonate and potassium carbonate). The amount of the base to be used is in the range of about 1 molar equivalent to about 10 equivalents, preferably about 1 molar equivalent to about 5 molar equivalents, typically about 2 molar equivalents relative to 1 molar equivalent of compound (1). Molar equivalent.
The solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include ethers (for example, tetrahydrofuran), halogenated hydrocarbons (for example, dichloromethane), and ethers are preferable. Alternatively, a base can be used as a solvent.
The reaction temperature of this reaction varies depending on the reagent or reaction conditions to be used, but is usually in the range of −25 ° C. to heating, preferably −15 ° C. to room temperature, and typically 0 ° C.
While the reaction time of this reaction varies depending on the reagent or reaction condition to be used, it is generally within the range of about 3 hours to about 10 days, preferably about 12 hours to about 7 days, and typically about 4 days. .
This reaction may be performed under an inert gas, for example, in the presence of nitrogen gas or argon gas.

As a result of examining the reaction product compound (6) by various analytical methods, only compound 6-1 (for example, peujaponicinol B) in which the 4-position of the pyran ring was converted to senesioil was regioselectively produced. On the other hand, it was found that the compound 6-2 (Peujaponicinol A) in which the 3-position of the pyran ring was converted to senesioil was not produced.
After completion of the reaction, the compound (6-1) can be obtained by performing post-treatment operations such as filtration of the reaction mixture, extraction with an organic solvent as necessary, and drying and concentration of the organic layer. Compound (6-1) can be further purified by chromatography, recrystallization and the like.

からなる混合物である。
ここで、式中、Ｘは、酸素原子または硫黄原子であり；Ｒ^１は各々独立して、Ｃ１〜３アルキル基またはＣ２〜Ｃ３アシル基であり；Ｒ^２は、水素原子、Ｃ１〜３アルキル基またはＣ２〜Ｃ３アシル基であり；Ｒ^３は、Ｃ１〜３アルキル基であり；ｍは、０〜２の整数であり；ｎは、１〜２の整数であり；そして、記号＊は、不斉中心を表す。
Ｘは、酸素原子が好ましい。Ｒ^１はＣ１〜３アルキル基が好ましく、Ｒ^１の具体例としては、メチル、エチル、またはアセチルが挙げられる。ｍは０〜１の整数が好ましく、０がより好ましい。Ｒ^２は水素原子またはＣ１〜３アルキル基が好ましく、水素原子がより好ましい。Ｒ^３は、メチル、エチルまたはプロピルが挙げられ、メチルが好ましい。ｎは２の整数が好ましい。 Compound (6) produced in Step 4-i is compound (6-1) or compound (6-2) represented by the following formula (for example, peujaponicinol A) or compound (6-1) And compound (6-2):

Is a mixture of
Here, in the formula, X is oxygen atom or sulfur atom; ^{R 1} is each independently a C1 -3 alkyl group or a C2~C3 acyl group; ^{R 2} is a hydrogen atom, C1 -3 alkyl R ³ is a C1-3 alkyl group; m is an integer of 0-2; n is an integer of 1-2; and the symbol * is Represents an asymmetric center.
X is preferably an oxygen atom. R ¹ is preferably a C1-3 alkyl group, and specific examples of R ¹ include methyl, ethyl, or acetyl. m is preferably an integer of 0 to 1, more preferably 0. R ² is preferably a hydrogen atom or a C1-3 alkyl group, more preferably a hydrogen atom. Examples of R ³ include methyl, ethyl or propyl, and methyl is preferable. n is preferably an integer of 2.

Specific examples of the compound (6-1) include the following compounds, but are not limited thereto. A specific example of the compound (6-2) is that in the case of the compound (6-2), the bond position of the senecioyl substituent is the 4-position of the pyran ring in the case of the compound (6-1). Is the third place. Here, as a specific example shown below, a configuration in which the steric configuration at the 3rd and 4th positions of the pyran ring is a cis isomer is described. It may vary depending on the configuration of the compound (1) produced in 3 ′ ″.

（ペウジャポニシノール Ｂ）
が挙げられる。 As a preferable example of the compound (6-1),

(Peujaponicinol B)
Is mentioned.

  The enantiomeric excess of each of the reaction product compounds (6-1) and (6-2) can be determined using, for example, chiral liquid chromatography. Alternatively, if the specific rotation of each enantiomer of the reaction product is known, the specific rotation of the resulting reaction product is measured and compared to the known specific rotation value to The enantiomeric excess of the enantiomer can be determined.

(Step 4-iia)
The acetylation supply compound used in this reaction is a compound selected from acetic acid, acetic anhydride, and acetyl chloride, and varies depending on the reaction compound (1) used and / or the reagent used.

The reaction in Step 4-ii is performed, for example, by subjecting compound (1) and an acetylated supply compound (for example, acetic acid or acetic anhydride) to a coupling reaction using a dehydration reaction condensing agent as appropriate in the presence of a base. Acetylated compound (9) (including compound (9-1) and compound (9-2)) can be produced.
Examples of the acetylation supply compound used in this reaction include compounds selected from the group consisting of acetic acid, acetic anhydride, and acetyl halide, with acetic acid and acetic anhydride being preferred. The amount of the acetylated feed compound used is in the range of about 0.5 molar equivalent to about 1.5 molar equivalent, preferably about 1 molar equivalent to about 1.2 molar equivalent, relative to 1 molar equivalent of compound (1). Within, typically about 1.1 molar equivalents.
Examples of the dehydration reaction condensing agent used in the reaction may be any generally known reagent, such as dicyclohexylcarbodiimide (also known as DCC). The amount of the dehydration reaction condensing agent to be used is generally within the range of about 1.0 to about 2.0 molar equivalents, preferably about 1.0 to about 1.5 molar equivalents, relative to 1 molar equivalent of compound (1). Typically about 1.1 molar equivalents.
Examples of the base used in the reaction may be any base that is known to be used in combination with a dehydration reaction condensing agent. Examples thereof include dimethylaminopyridine (also known as DMAP) and pyridine. The amount of the base to be used is generally in the range of catalytic amount to about 2.0 molar equivalent, preferably catalytic amount to about 1.0 molar equivalent, more preferably catalyst relative to 1 molar equivalent of compound (1). Amount (for example, 1 mol%). Alternatively, when a dehydration reaction condensing agent is not used, the amount of the base used is generally about 1.0 molar equivalent to about 10 molar equivalents, preferably about 2 molar equivalents with respect to 1 molar equivalent of compound (1). Within the range of 0 molar equivalents to about 5.0 molar equivalents, typically about 3.0 molar equivalents.
The solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include dry solvents such as ethers (for example, diethyl ether) and halogenated hydrocarbons (for example, dichloromethane and chloroform). Alternatively, a base can be used as a solvent.
The reaction temperature of this reaction varies depending on the reagent or reaction conditions to be used, but is usually in the range of from ice cooling to heating, typically room temperature.
While the reaction time of this reaction varies depending on the reagent or reaction conditions to be used, it is generally in the range of about 1 hr to about 48 hr, preferably about 1 hr to about 24 hr, typically about 5 to about 6 It's time.
This reaction may be performed under an inert gas, for example, in the presence of nitrogen gas or argon gas.
After completion of the reaction, the compound (9) can be obtained by performing post-treatment operations such as filtration of the reaction mixture, extraction with an organic solvent as necessary, and drying and concentration of the organic layer. Compound (9) can be further purified by chromatography, recrystallization and the like.

(Another method of step 4-iib)
As another method of the reaction of step 4-ii, for example, literature (for example, Iwasaki, F .; Maki, T .; Onomura, O .; Nakashima, W .; Matsumura, YJ Org. Chem. 2000, 65, 996-1002 In the same manner as in Step 4-ib, the compound (1) is reacted with an acetylated feed compound in the presence of a tin catalyst and a base to give an acetylated compound (9) (compound (9-1) and compound (9-2)) can be produced.
Examples of the acetylation supply compound used in this reaction include compounds selected from acetic acid, acetic anhydride, and acetyl halide, and acetyl halide is preferred. Specific examples include acetyl chloride, acetyl bromide, or acetyl iodide. The amount of the acetylated feed compound used is about 0.5 molar equivalent to about 10 molar equivalent, preferably about 1 molar equivalent to about 6 molar equivalent, more preferably about 1 molar equivalent to 1 molar equivalent of compound (1). It is in the range of molar equivalents to about 2 molar equivalents, typically about 1 to 1.5 molar equivalents.
Examples of tin catalysts used in the reaction include alkyl tin halides, and specific examples include, but are not limited to, dimethyl tin dichloride. The amount of the tin catalyst used is usually in the range of about 1 mol% to about 30 mol%, preferably about 5 mol% to about 20 mol%, based on 1 mol equivalent of the compound (1). Is about 10 mol%.
Examples of the base used in the reaction may be either an inorganic base or an organic base (for example, pyridine), but an inorganic base is preferable. Specific examples include alkali metal carbonates (for example, sodium carbonate and potassium carbonate). The amount of the base to be used is in the range of about 1 molar equivalent to about 10 equivalents, preferably about 1 molar equivalent to about 5 molar equivalents, typically about 2 molar equivalents relative to 1 molar equivalent of compound (1). Molar equivalent.
The solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include ethers (for example, tetrahydrofuran), halogenated hydrocarbons (for example, dichloromethane), and ethers are preferable. Alternatively, a base can be used as a solvent.
The reaction temperature of this reaction varies depending on the reagent or reaction conditions to be used, but is usually in the range of −25 ° C. to heating, preferably −15 ° C. to room temperature, and typically 0 ° C.
While the reaction time of this reaction varies depending on the reagent or reaction condition to be used, it is generally within the range of about 3 hours to about 10 days, preferably about 12 hours to about 7 days, and typically about 4 days. .
This reaction may be performed under an inert gas, for example, in the presence of nitrogen gas or argon gas.
After completion of the reaction, the compound (9) can be obtained by performing post-treatment operations such as filtration of the reaction mixture, extraction with an organic solvent as necessary, and drying and concentration of the organic layer. Compound (9) can be further purified by chromatography, recrystallization and the like.

からなる混合物である。
ここで、式中、Ｘは、酸素原子または硫黄原子であり；Ｒ^１は各々独立して、Ｃ１〜３アルキル基またはＣ２〜Ｃ３アシル基であり；Ｒ^２は、水素原子、Ｃ１〜３アルキル基またはＣ２〜Ｃ３アシル基であり；Ｒ^３は、Ｃ１〜３アルキル基であり；ｍは、０〜２の整数であり；ｎは、１〜２の整数であり；そして、記号＊は、不斉中心を表す。
Ｘは、酸素原子が好ましい。Ｒ^１はＣ１〜３アルキル基が好ましく、Ｒ^１の具体例としては、メチル、エチル、またはアセチルが挙げられる。ｍは０〜１の整数が好ましく、０がより好ましい。Ｒ^２は水素原子またはＣ１〜３アルキル基が好ましく、水素原子がより好ましい。Ｒ^３は、メチル、エチルまたはプロピルが挙げられ、メチルが好ましい。ｎは２の整数が好ましい。 Compound (9) produced in Step 4-ii is compound (9-1) or compound (9-2) represented by the following formula, or compound (9-1) and compound (9-2):

Is a mixture of
Here, in the formula, X is oxygen atom or sulfur atom; ^{R 1} is each independently a C1 -3 alkyl group or a C2~C3 acyl group; ^{R 2} is a hydrogen atom, C1 -3 alkyl R ³ is a C1-3 alkyl group; m is an integer of 0-2; n is an integer of 1-2; and the symbol * is Represents an asymmetric center.
X is preferably an oxygen atom. R ¹ is preferably a C1-3 alkyl group, and specific examples of R ¹ include methyl, ethyl, or acetyl. m is preferably an integer of 0 to 1, more preferably 0. R ² is preferably a hydrogen atom or a C1-3 alkyl group, more preferably a hydrogen atom. Examples of R ³ include methyl, ethyl or propyl, and methyl is preferable. n is preferably an integer of 2.

Specific examples of compound (9-1) include, but are not limited to, the following compounds. In the specific example of the compound (9-2), the bonding position of the acetyl substituent is the 4-position of the pyran ring when the compound (9-1) is bonded, whereas the compound (9-2) is bonded. Is the third place. Here, as a specific example shown below, a configuration in which the steric configuration at the 3rd and 4th positions of the pyran ring is a cis isomer is described. It may vary depending on the configuration of the compound (1) produced in 3 ′ ″.

が挙げられる。 As a preferable example of the compound (9-1),

Is mentioned.

  The enantiomeric excess of each of the reaction product compounds (9-1) and (9-2) can be determined, for example, using chiral liquid chromatography. Alternatively, if the specific rotation of each enantiomer of the reaction product is known, the specific rotation of the resulting reaction product is measured and compared to the known specific rotation value to The enantiomeric excess of the enantiomer can be determined.

の混合物を製造する。
ここで、式中、Ｘは、酸素原子または硫黄原子であり；Ｒ^１は各々独立して、Ｃ１〜３アルキル基またはＣ２〜Ｃ３アシル基であり；Ｒ^２は、水素原子、Ｃ１〜３アルキル基またはＣ２〜Ｃ３アシル基であり；Ｒ^３は、Ｃ１〜３アルキル基であり；ｍは、０〜２の整数であり；ｎは、１〜２の整数であり；そして、記号＊は、不斉中心を表す。
Ｘは、酸素原子が好ましい。Ｒ^１はＣ１〜３アルキル基が好ましく、Ｒ^１の具体例としては、メチル、エチル、またはアセチルが挙げられる。ｍは０〜１の整数が好ましく、０がより好ましい。Ｒ^２は水素原子またはＣ１〜３アルキル基が好ましく、水素原子がより好ましい。Ｒ^３は、メチル、エチルまたはプロピルが挙げられ、メチルが好ましい。ｎは２の整数が好ましい。 The reaction of step 4-i is carried out to produce compound (6), and then the reaction of step 4-ii is carried out, or the reaction of step 4-ii is carried out to produce compound (9), and then step 4- By carrying out the reaction of i, the final target compound I or compound II, or compound I and compound II:

A mixture of
Here, in the formula, X is oxygen atom or sulfur atom; ^{R 1} is each independently a C1 -3 alkyl group or a C2~C3 acyl group; ^{R 2} is a hydrogen atom, C1 -3 alkyl R ³ is a C1-3 alkyl group; m is an integer of 0-2; n is an integer of 1-2; and the symbol * is Represents an asymmetric center.
X is preferably an oxygen atom. R ¹ is preferably a C1-3 alkyl group, and specific examples of R ¹ include methyl, ethyl, or acetyl. m is preferably an integer of 0 to 1, more preferably 0. R ² is preferably a hydrogen atom or a C1-3 alkyl group, more preferably a hydrogen atom. Examples of R ³ include methyl, ethyl or propyl, and methyl is preferable. n is preferably an integer of 2.

Specific examples of Compound I and Compound II include the following compounds, but are not limited thereto. Here, as a specific example shown below, a configuration in which the steric configuration at the 3rd and 4th positions of the pyran ring is a cis isomer is described. It may vary depending on the configuration of the compound (1) produced in 3 ′ ″.

  A preferred example of compound I is isosamidine.

  A preferred example of Compound II is Samidine.

  The ratio of Compound I and Compound II as the final products obtained by performing Steps i and ii is as follows, but is dependent on the reaction conditions and is not limited to these ratios.

  First, when the reaction of step 4 ii is first performed according to the above step 4-iib and then the reaction of step 4 i is performed according to the above step 4-ia, for example, the ratio of compound I to compound II is About 1: 1.

  Secondly, when the reaction of step i is performed according to the above step 4-ia and then the reaction of step 4 ii is performed according to the above step 4-iia, for example, the ratio of compound I to compound II is About 2: 1.

  Third, when the reaction of step 4 i is first performed according to the above step 4-ib and then the reaction of step 4 ii is performed according to the above step 4-iia, for example, the ratio of compound I to compound II is About 5: 1.

の化合物を製造することができる。 (Synthesis of Derivative 1)
A derivative 1 in which the substituents at the 3-position and 4-position of the pyran ring of Compound 1 are both senecioyl groups can also be produced.
Specifically, the compound (1) produced in step 3 is converted into a seneciolized feed compound (eg, senecioic acid, senecioic anhydride) by 1 molar equivalent of compound (1) according to the method described in step 4-ia above. By reacting at about 5 molar equivalents to about 20 molar equivalents (preferably in the range of about 5 molar equivalents to about 10 molar equivalents, typically about 8 molar equivalents). :

Can be produced.

の化合物を製造することができる。
上記各式中、各記号Ｘ、Ｒ^１、Ｒ^２、Ｒ^３、ｎ、ｍおよび＊は、明細書中に定義するとおりである。 (Synthesis of Derivative 2)
A derivative 2 in which the substituents at the 3-position and the 4-position of the pyran ring of Compound 1 are both acetyl groups can also be produced.
Specifically, the compound (1) produced in Step 3 is added to an acetylated supply compound (for example, acetic acid, acetic anhydride) based on 1 molar equivalent of Compound (1) according to the method described in Step 4-iia above. By reacting at about 5 molar equivalents to about 20 molar equivalents (preferably in the range of about 5 molar equivalents to about 10 molar equivalents, typically about 8 molar equivalents):

Can be produced.
In the above formulas, the symbols X, R ¹ , R ² , R ³ , n, m and * are as defined in the specification.

に示す化合物である。 (Synthesis of Derivative 3)
It is a diastereomer by reacting (±) -cis-kelactone represented by the above compound (1) with an optically active ketone compound in the presence of an acid to chirally acetalize the hydroxy group of kelactone. Cis-kelactone derivatives can be prepared.
The acid used in this reaction may be either an inorganic acid or an organic acid, preferably an organic acid, and specific examples thereof include p-toluenesulfonic acid.
Examples of the optically active ketone compound used in this reaction include optically active menthone (for example, (−)-menton, (+)-menton). The product when (-)-menton is used is:

It is a compound shown in.

Examples relating to the present invention will be described below, but the present invention is not limited thereto.
In addition, analysis and separation / purification of the compounds were performed using the following equipment and reagents.
Silica gel for column chromatography: Fuji Silysia Chemical BW-200
TLC plate: Merck TLC Silica gel 60 F ₂₅₄
Melting point measuring device: J-SCIENCE RFS-10
NMR spectrum: JEOL JNM-AL-400; ¹ H NMR (400 MHz), ¹³ C NMR (100 MHz.); Chemical shift value was expressed in δ (ppm), and TMS was used as an internal standard.
Polarimeter: JASCO Polarimeter P-2000
A vanillin-sulfuric acid solution was used for TLC color development.

50 mLのナスフラスコにレゾルシノール（1.0 g, 9.08 mmol）、リンゴ酸（1.34 g, 9.99 mmol, 1.1 eq.）を加え、溶媒として濃硫酸を加えた。室温で30分間撹拌した後、100 ℃で2時間半撹拌した。その後、反応液を室温まで冷却し、反応液に氷を加え、室温で30分撹拌した。ジエチルエーテルで3回抽出し、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥させ、濾過、濃縮を行った。残渣をヘキサン/酢酸エチル混合溶媒で再結晶し、ベージュ色固体としてのウンベリフェロンを633.2 mg (43%)で得た。
mp: 214-215 ℃, Rf=0.50 (CHCl₃:MeOH=19/1); ¹H NMR (400 MHz, CD₃OD): δ 7.84 (1H, d, J=9.2 Hz), 7.44 (d, J=8.4 Hz, 1H), 6.78 (dd, J=8.0, 2.4 Hz, 1H), 6.70 (d, J=2.0 Hz, 1H), 6.17 (d, J=9.6 Hz, 1H). ¹³C NMR (100MHz, CD₃OD)δ＝163.7, 163.1, 157.2, 146.0, 130.7, 114.5, 113.1, 112.4, 103.4 Example 1
Manufacture of umbelliferone

Resorcinol (1.0 g, 9.08 mmol) and malic acid (1.34 g, 9.99 mmol, 1.1 eq.) Were added to a 50 mL eggplant flask, and concentrated sulfuric acid was added as a solvent. The mixture was stirred at room temperature for 30 minutes and then stirred at 100 ° C. for 2.5 hours. Thereafter, the reaction solution was cooled to room temperature, ice was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The mixture was extracted 3 times with diethyl ether, and the organic layer was washed with saturated brine. The extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was recrystallized with a mixed solvent of hexane / ethyl acetate to obtain 633.2 mg (43%) of umbelliferone as a beige solid.
mp: 214-215 ° C, Rf = 0.50 (CHCl ₃ : MeOH = 19/1); ¹ H NMR (400 MHz, CD ₃ OD): δ 7.84 (1H, d, J = 9.2 Hz), 7.44 (d, J = 8.4 Hz, 1H), 6.78 (dd, J = 8.0, 2.4 Hz, 1H), 6.70 (d, J = 2.0 Hz, 1H), 6.17 (d, J = 9.6 Hz, 1H). ¹³ C NMR ( 100MHz, CD ₃ OD) δ = 163.7, 163.1, 157.2, 146.0, 130.7, 114.5, 113.1, 112.4, 103.4

三口フラスコにウンベリフェロン（1.15 g, 7.06 mmol）を加え、窒素置換した。そこに、1,1‐ジエトキシ‐3‐メチル−2−ブテン（2.29 mL, 12.1 mmol, 2.0 eq.）、塩基・溶媒としてＮ,Ｎ‐ジメチルアニリン20 mLを加え、140 ℃で24時間加熱還流を行った。その後、1規定の塩酸で反応を停止した。酢酸エチルで3回抽出し、有機層を1規定の塩酸で5回、飽和食塩水で1回洗浄した。無水硫酸ナトリウムで乾燥させ、濾過、濃縮を行った。残渣をカラムクロマトグラフィー（ヘキサン/酢酸エチル＝9/1）により精製し、黄色固体としてのセセリンを969 mg (61%)で得た。
mp: 117.1-117.6 ℃, Rf=0.46(hexane:EA=3/2) ; ¹H NMR（400 MHz, CDCl₃）δ＝7.60 (d, J=8.0 Hz, 1H ),7.21 (d, J=8.0 Hz, 1H), 6.89 (d, J=10 Hz,1H), 6.72 (d, J=8.0 Hz, 1H),6.23 (d, J=9.6 Hz, 1H), 5.73 (d, J=10.4 Hz, 1H), 1.48 (s, 6H). ¹³C NMR(100MHz, CDCl₃)δ＝161.0, 156.2, 150.0, 143.9, 130.7, 127.7, 114.9, 113.5, 112.5, 112.5, 109.2, 77.5, 28.0 (2C) Example 2
Manufacture of Seselin

Umbelliferone (1.15 g, 7.06 mmol) was added to the three-necked flask, and the atmosphere was replaced with nitrogen. 1,1-diethoxy-3-methyl-2-butene (2.29 mL, 12.1 mmol, 2.0 eq.) And 20 mL of N, N-dimethylaniline as a base / solvent were added thereto, and the mixture was refluxed at 140 ° C. for 24 hours. Went. Thereafter, the reaction was stopped with 1N hydrochloric acid. The mixture was extracted 3 times with ethyl acetate, and the organic layer was washed 5 times with 1N hydrochloric acid and once with saturated brine. The extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (hexane / ethyl acetate = 9/1) to obtain 969 mg (61%) of cerine as a yellow solid.
mp: 117.1-117.6 ° C, Rf = 0.46 (hexane: EA = 3/2); ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.60 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 10 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.23 (d, J = 9.6 Hz, 1H), 5.73 (d, J = 10.4 Hz , 1H), 1.48 (s, 6H). 13 C NMR (100MHz, CDCl 3) δ = 161.0, 156.2, 150.0, 143.9, 130.7, 127.7, 114.9, 113.5, 112.5, 112.5, 109.2, 77.5, 28.0 (2C)

50 mLのナスフラスコにN‐メチルモルホリンオキシド（62.0 mg, 0.530 mmol, 1.1 eq.）を加え、溶媒としてアセトン/水の1:2混合溶媒を5.0 mL加えた。そこに、2％四酸化オスミウム水溶液（0.2 mL, 0.018 mmol, 4 mol%）をゆっくり滴下し、セセリン（100 mg, 0.438 mmol）を加え、室温で24時間撹拌した。TLCで反応の進行を確認した後、アセトンを減圧留去した。残渣に食塩を過剰量加え、クロロホルムで4回抽出し、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥させ、濾過、濃縮を行った。残渣をカラムクロマトグラフィー（ヘキサン/酢酸エチル＝3/2）により精製し、白色固体としての（±）-シス-ケラクトンを113.0 mg (98%)で得た。
mp: 153.0-155.4 ℃, Rf=0.13 (hexane:EA=3/2); ¹H NMR（400 MHz, CDCl₃）δ＝7.67 (d, J=9.6 Hz, 1H),7.33 (d, J=8.4 Hz, 1H),6.79 (d, J=8.8 Hz, 1H), 6.25 (d, J=9.6 Hz, 1H), 5.21 (d, J=4.8 Hz, 1H), 3.87 (d, J=4.8 Hz, 1H), 1.46 (s, 3H), 1.42 (s, 3H). ¹³C NMR(100MHz, CDCl₃) δ=161.1, 156.4, 154.5, 144.3, 128.6, 114.9, 112.2, 112.0, 110.9, 79.0, 71.0, 61.0, 25.0, 21.6. Example 3
(±) -Manufacture of Khellactone

N-methylmorpholine oxide (62.0 mg, 0.530 mmol, 1.1 eq.) Was added to a 50 mL eggplant flask, and 5.0 mL of a 1: 2 mixed solvent of acetone / water was added as a solvent. There, 2% osmium tetroxide aqueous solution (0.2 mL, 0.018 mmol, 4 mol%) was dripped slowly, cerine (100 mg, 0.438 mmol) was added, and it stirred at room temperature for 24 hours. After confirming the progress of the reaction by TLC, acetone was distilled off under reduced pressure. An excessive amount of sodium chloride was added to the residue, followed by extraction four times with chloroform, and the organic layer was washed with saturated brine. The extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (hexane / ethyl acetate = 3/2) to give 11 ± mg (98%) of (±) -cis-kelactone as a white solid.
mp: 153.0-155.4 ° C, Rf = 0.13 (hexane: EA = 3/2); ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.67 (d, J = 9.6 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.25 (d, J = 9.6 Hz, 1H), 5.21 (d, J = 4.8 Hz, 1H), 3.87 (d, J = 4.8 Hz , 1H), 1.46 (s, 3H), 1.42 (s, 3H). 13 C NMR (100MHz, CDCl 3) δ = 161.1, 156.4, 154.5, 144.3, 128.6, 114.9, 112.2, 112.0, 110.9, 79.0, 71.0 , 61.0, 25.0, 21.6.

50 mLのナスフラスコに3-メチルクロトン酸（42 mg, 0.42 mmol, 1.1 eq.）を加え、(±)-シス-ケラクトン（100 mg, 0.38 mmol）、DMAP（46 mg, 0.38 mmol, 1.0 eq.）、溶媒としてジクロロメタンを3.0 mL加えた。室温で10分間撹拌した後、氷上でDCC（87 mg, 0.42 mmol, 1.1 eq.）を加え、室温で5時間撹拌した。TLCで反応終了を確認した後、反応液をセライトで濾過し、濃縮を行った。残渣をカラムクロマトグラフィー（ヘキサン/酢酸エチル＝4/1）により精製し、無色固体であるエステル位置異性体の1/1混合物を88.3 mg (67%)で得た。生成物はポイジャポニシノールＡおよびポイジャポニシノールＢの1:1の混合物であり、この生成比はδ＝1.49 (s, 3H), δ＝1.46 (s, 3H)の積分比から算出した。
mp: 96.5-102.4 ℃; Rf=0.72 (hexane:EA=3/2) ¹H NMR（400 MHz, CDCl₃）δ＝7.60 (d, J=9.6 Hz, 1H),7.33 (d, J=3.2 Hz, 1H),6.79 (d, J=6.4 Hz, 1H),6.45 (d, J=4.8 Hz, 1H), 6.22 (d, J=9.6 Hz, 1H), 5.72 (s, 1H), 4.04 (dd, J=4.6, 2.6 Hz, 1H), 3.05 (d, J=2.8 Hz, 1H), 2.24 (s, 3H), 1.91 (s, 3H), 1.49 (s, 3H), 1.44 (s, 3H). ¹³C NMR(100MHz, CDCl₃) δ=167.4, 160.1, 159.6, 157.0, 154.4, 129.2, 114.9, 114.6, 112.9, 112.3, 107.2, 78.7, 71.6, 62.9, 27.5, 25.5, 21.2, 20.5. Example 4
Production of Peujaponisinol A and Peujaponisinol B

Add 3-methylcrotonic acid (42 mg, 0.42 mmol, 1.1 eq.) To a 50 mL eggplant flask, (±) -cis-kelactone (100 mg, 0.38 mmol), DMAP (46 mg, 0.38 mmol, 1.0 eq.) .), And 3.0 mL of dichloromethane was added as a solvent. After stirring at room temperature for 10 minutes, DCC (87 mg, 0.42 mmol, 1.1 eq.) Was added on ice, and the mixture was stirred at room temperature for 5 hours. After confirming the completion of the reaction by TLC, the reaction solution was filtered through celite and concentrated. The residue was purified by column chromatography (hexane / ethyl acetate = 4/1) to obtain 88.3 mg (67%) of a 1/1 mixture of ester regioisomers as a colorless solid. The product is a 1: 1 mixture of Poijaponicinol A and Poijaponicinol B, and this product ratio was calculated from the integral ratio of δ = 1.49 (s, 3H), δ = 1.46 (s, 3H). .
mp: 96.5-102.4 ° C; Rf = 0.72 (hexane: EA = 3/2) ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.60 (d, J = 9.6 Hz, 1H), 7.33 (d, J = 3.2 Hz, 1H), 6.79 (d, J = 6.4 Hz, 1H), 6.45 (d, J = 4.8 Hz, 1H), 6.22 (d, J = 9.6 Hz, 1H), 5.72 (s, 1H), 4.04 ( dd, J = 4.6, 2.6 Hz, 1H), 3.05 (d, J = 2.8 Hz, 1H), 2.24 (s, 3H), 1.91 (s, 3H), 1.49 (s, 3H), 1.44 (s, 3H ¹³ C NMR (100 MHz, CDCl ₃ ) δ = 167.4, 160.1, 159.6, 157.0, 154.4, 129.2, 114.9, 114.6, 112.9, 112.3, 107.2, 78.7, 71.6, 62.9, 27.5, 25.5, 21.2, 20.5.

50 mLのナスフラスコにクロトン酸エステル位置異性体混合物（589.9 mg, 1.71 mmol）、DMAP（104.6 mg, 0.86 mmol, 0.5 eq.）、塩基兼溶媒としてピリジンを6 mL加えた。氷上で無水酢酸3 mLを滴下し、室温で6時間反応を行った。その後、氷上で１規定の塩酸で反応を停止した。酢酸エチルで3回抽出し、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥させ、濾過、濃縮を行った。残渣をカラムクロマトグラフィー（ヘキサン/酢酸エチル＝9/1）により精製し、白色固体としてのイソサミジンとサミジンの2:1混合物を551 mg (83%)で得た。生成物はイソサミジンとサミジンの2:1混合物であり、この生成比はδ＝7.60 (d, J=9.6 Hz, 1H)とδ＝7.59 (d, J=9.6 Hz, 1H)の積分比から算出した。
mp: 104.2-112.1 ℃; Rf=0.44 (hexane:EA=3/2) ¹H NMR（400 MHz, CDCl₃）δ＝7.59 (d, J=9.6 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 6.57 (d, J=4.8 Hz, 1H), 6.22 (d, J=9.6 Hz, 1H), 5.64 (s, 1H), 5.31 (d, J=4.8 Hz, 1H), 2.23 (s, 3H), 2.09 (s, 3H), 1.90 (s, 3H), 1.46 (s, 3H), 1.42 (s, 3H). ¹³C NMR(100MHz, CDCl₃) δ=170.0, 165.2, 159.9, 158.3, 156.6, 154.0, 143.2, 129.1, 115.0, 114.3, 113.3, 112.6, 107.4, 77.2, 70.6, 59.5, 27.5, 25.3, 23.2, 20.7, 20.4． Example 5
Manufacture of Isosamidin and Samidin

Crotonic ester positional isomer mixture (589.9 mg, 1.71 mmol), DMAP (104.6 mg, 0.86 mmol, 0.5 eq.), And 6 mL of pyridine as a base and solvent were added to a 50 mL eggplant flask. 3 mL of acetic anhydride was added dropwise on ice, and the reaction was performed at room temperature for 6 hours. Thereafter, the reaction was stopped with 1N hydrochloric acid on ice. The mixture was extracted 3 times with ethyl acetate, and the organic layer was washed with saturated brine. The extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (hexane / ethyl acetate = 9/1) to obtain 551 mg (83%) of a 2: 1 mixture of isosamidine and samidin as a white solid. The product is a 2: 1 mixture of isosamidine and samidin, and the product ratio is calculated from the integration ratio of δ = 7.60 (d, J = 9.6 Hz, 1H) and δ = 7.59 (d, J = 9.6 Hz, 1H). did.
mp: 104.2-112.1 ° C; Rf = 0.44 (hexane: EA = 3/2) ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.59 (d, J = 9.6 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 4.8 Hz, 1H), 6.22 (d, J = 9.6 Hz, 1H), 5.64 (s, 1H), 5.31 ( d, J = 4.8 Hz, 1H), 2.23 (s, 3H), 2.09 (s, 3H), 1.90 (s, 3H), 1.46 (s, 3H), 1.42 (s, 3H). ¹³ C NMR (100 MHz , CDCl ₃ ) δ = 170.0, 165.2, 159.9, 158.3, 156.6, 154.0, 143.2, 129.1, 115.0, 114.3, 113.3, 112.6, 107.4, 77.2, 70.6, 59.5, 27.5, 25.3, 23.2, 20.7, 20.4.

50 mLのナスフラスコに(±)-シス-ケラクトン（100 mg, 0.38 mmol）、溶媒としてTHFを加えた。そこにジメチルチンジクロリド、炭酸カリウム、アセチルクロリドを加え、0 ℃で24時間反応を行った。反応の進行を確認した後、反応液を水中に注ぎ、ジクロロメタンで4回抽出を行った。無水硫酸ナトリウムで乾燥させ、濾過、濃縮を行った。残渣をカラムクロマトグラフィー（ヘキサン/酢酸エチル＝3/2）で精製し、白色針状固体としてのモノアセチル化体であるキアンフクマリンＡおよびキアンフクマリンＢの混合物を86 mg (74％)で得た。生成物はイソサミジンとサミジンの混合物であり、この生成比は¹H NMRの特徴的な化学シフト値の積分比から算出した。
mp: 158.4-159.8 ℃; Rf=0.49 (hexane:EA=3/2); ¹H NMR（400 MHz, CDCl₃）δ＝7.64 (d, J=9.6 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 6.30 (d, J=9.6 Hz, 1H), 5.41 (d, J=2.8 Hz, 1H), 5.25 (d, J=2.8 Hz, 1H), 5.31 (d, J=4.8 Hz, 1H), 2.23 (s, 3H), 2.09 (s, 3H), 1.90 (s, 3H), 1.46 (s, 3H), 1.42 (s, 3H). Example 6
Production of Qianhucoumarin A and Kianfucoumarin B

(±) -cis-kelactone (100 mg, 0.38 mmol) and THF as a solvent were added to a 50 mL eggplant flask. Dimethyltin dichloride, potassium carbonate and acetyl chloride were added thereto and reacted at 0 ° C. for 24 hours. After confirming the progress of the reaction, the reaction solution was poured into water and extracted four times with dichloromethane. The extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (hexane / ethyl acetate = 3/2), and a mixture of kianfucoumarin A and chianfucoumarin B, monoacetylated compounds as white needle-like solids, was obtained at 86 mg (74%). Obtained. The product was a mixture of isosamidine and samidine, and the product ratio was calculated from the integral ratio of characteristic chemical shift values of ¹ H NMR.
mp: 158.4-159.8 ° C; Rf = 0.49 (hexane: EA = 3/2); ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.64 (d, J = 9.6 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 6.30 (d, J = 9.6 Hz, 1H), 5.41 (d, J = 2.8 Hz, 1H), 5.25 (d, J = 2.8 Hz , 1H), 5.31 (d, J = 4.8 Hz, 1H), 2.23 (s, 3H), 2.09 (s, 3H), 1.90 (s, 3H), 1.46 (s, 3H), 1.42 (s, 3H) .

30 mLのナスフラスコに、キアンフクマリンＣ（88.6 mg, 0.29 mmol）、セネシオ酸 (32 mg, 0.32 mmol, 1.1 eq.)、DMAP (3.5 mg, 0.029 mmol, 10 mol%)、溶媒としてクロロホルムを5 mL加えた。氷上でDCC（66 mg, 0.32 mmol, 1.1 eq.）を加え、0 ℃で48時間反応を行った。TLCで反応の進行を確認後、反応液をセライトで濾過し、濃縮を行った。残渣をカラムクロマトグラフィー（ヘキサン/酢酸エチル＝4/1）により精製し、無色油状物としてのイソサミジンおよびサミジンの１：２の混合物を42.4 mg (43%)得た。生成物はイソサミジンおよびサミジンの1:2混合物であり、この生成比はδ＝6.62 (d, J=4.8 Hz, 1H)とδ＝6.58 (d, J=4.8 Hz, 1H)の積分比から算出した。
Rf=0.33 (hexane:EA=3/2); ¹H NMR（400 MHz, CDCl₃）δ＝7.61 (d, J=9.6 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 6.81 (d, J=8.8 Hz, 1H), 6.58 (d, J=4.8 Hz, 1H), 6.23 (d, J=9.6 Hz, 1H), 5.69 (s, 1H), 5.36 (d, J=4.8 Hz, 1H), 2.17 (s, 3H), 2.12 (s, 3H), 1.90 (s, 3H), 1.45 (s, 3H), 1.42 (s, 3H). ¹³C NMR(100MHz, CDCl₃) δ=169.8, 165.2, 159.9, 158.9, 156.7, 153.9, 143.3, 129.0, 115.0, 114.3, 113.0, 112.5, 106.8, 77.3, 68.7, 61.2, 31.5, 27.5, 24.4, 22.6, 20.3. Example 7
Preparation of isosamidine and a 1: 2 mixture of samidin

In a 30 mL eggplant flask, kianfucoumarin C (88.6 mg, 0.29 mmol), senecioic acid (32 mg, 0.32 mmol, 1.1 eq.), DMAP (3.5 mg, 0.029 mmol, 10 mol%), and chloroform as a solvent. 5 mL was added. DCC (66 mg, 0.32 mmol, 1.1 eq.) Was added on ice, and the reaction was performed at 0 ° C. for 48 hours. After confirming the progress of the reaction by TLC, the reaction solution was filtered through celite and concentrated. The residue was purified by column chromatography (hexane / ethyl acetate = 4/1) to give 42.4 mg (43%) of a 1: 2 mixture of isosamidine and samidin as a colorless oil. The product is a 1: 2 mixture of isosamidine and samidin, and the product ratio is calculated from the integral ratio of δ = 6.62 (d, J = 4.8 Hz, 1H) and δ = 6.58 (d, J = 4.8 Hz, 1H) did.
Rf = 0.33 (hexane: EA = 3/2); ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.61 (d, J = 9.6 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.58 (d, J = 4.8 Hz, 1H), 6.23 (d, J = 9.6 Hz, 1H), 5.69 (s, 1H), 5.36 (d, J = 4.8 Hz , 1H), 2.17 (s, 3H), 2.12 (s, 3H), 1.90 (s, 3H), 1.45 (s, 3H), 1.42 (s, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ = 169.8, 165.2, 159.9, 158.9, 156.7, 153.9, 143.3, 129.0, 115.0, 114.3, 113.0, 112.5, 106.8, 77.3, 68.7, 61.2, 31.5, 27.5, 24.4, 22.6, 20.3.

30mLのナスフラスコにセネシオ酸(500 mg, 5.0 mmol)、溶媒としてクロロホルムを5mL加えた。ここに、オキサリルクロリド（0.4 mL, 0.55 mmol, 11 mol%）を5分かけてゆっくり滴下した。室温で反応を開始し、発泡が終わってからさらに1時間撹拌を続けた。その後、溶媒のクロロホルムを減圧留去した。残渣はクロロホルムに再度溶解させ、続いてクロロホルムの減圧留去を2回繰り返すことで過剰のオキサリルクロリドを除去し、淡黄色の油状物としてのセネシオ酸塩化物を得た。 Example 8
Manufacture of Peujaponicinol B

Senecioic acid (500 mg, 5.0 mmol) was added to a 30 mL eggplant flask, and 5 mL of chloroform was added as a solvent. Oxalyl chloride (0.4 mL, 0.55 mmol, 11 mol%) was slowly added dropwise over 5 minutes. The reaction was started at room temperature, and stirring was continued for another hour after the foaming was completed. Thereafter, the solvent chloroform was distilled off under reduced pressure. The residue was redissolved in chloroform, and then the excess oxalyl chloride was removed by repeating the distillation of chloroform under reduced pressure twice to obtain a senecio acid chloride as a pale yellow oil.

Next, 4 mL of THF as a solvent was added to a 30 mL eggplant flask. (±) -cis-kelactone (84 mg, 0.32 mmol), potassium carbonate (89 mg, 0.64 mmol, 2.0 eq.) And dimethyltin dichloride (7.04 mg, 0.032 mmol, 10 mol%) were added to the synthesis. Senecio acid chloride (0.57 mL, 5 mmol, 6.0 eq.) Was added dropwise and stirred at 0 ° C. for 60 hours. After confirming the progress of the reaction, the reaction solution was poured into water and extracted four times with dichloromethane. The extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (hexane / ethyl acetate = 3/2), and pejaponicinol B in which the 4-position of the pyran ring, which is a monoacylated product, was converted to seneciol oil as a pale yellow oily substance, 47 mg (42 %). ^{From 1} H, ¹³ C NMR spectrum data, it was confirmed that peujaponicinol A in which the 3rd position of the pyran ring was converted to senesioil was not produced.
Rf = 0.31 (hexane: EA = 3/2); ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.60 (d, J = 9.2 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.45 (d, J = 4.8 Hz, 1H), 6.22 (d, J = 9.2 Hz, 1H), 5.73 (s, 1H), 4.04 (d, J = 4.8 Hz , 1H), 2.24 (s, 3H), 1.91 (s, 3H) 1.46 (s, 3H), 1.44 (s, 3H). 13 C NMR (100MHz, CDCl 3) δ = 167.4, 160.1, 159.7, 157.0, 143.3, 129.2, 114.9, 114.5, 112.9, 112.2, 107.2, 78.7, 71.5, 62.8, 27.6, 25.5, 21.1, 20.5.
The production of peujaponicinol B was confirmed by ¹ H, ¹³ C NMR from the values described in the following documents.
Gonzalez, AG; Barroso, JT; Lopez-Dorta, H .; Luis, JR; Rodriguez-Luis, F. Phytochemistry 1979, 18, 1021-1023. (B) Ikeshiro, Y .; Mase, I .; Tomita, Y Phytochemistry, 1993, 33, 1543-1545

30 mLナスフラスコに、ペウジャポニシノール Ｂ（13.7 mg, 0.04 mmol)、無水酢酸 (0.05 mL, 0.05 mmol, 1.2 eq.)、ピリジン (0.1 mL, 0.12 mmol, 3.0 eq.)を加え、0 ℃で24時間反応を行った。TLCで反応の進行を確認後、1規定 塩酸を加え、酢酸エチルで3回抽出を行い、飽和炭酸水素ナトリウム水溶液で2回洗浄後、無水硫酸ナトリウムで乾燥させ、濾過、濃縮を行った。淡黄色結晶としてのイソアミジンおよびサミジンの５：１の混合物を20.6 mg (99%)得た。生成物はイソサミジンおよびサミジンの5:1混合物であり、この生成比はδ＝5.31 (d, J=4.8 Hz, 1H)とδ＝5.36 (d, J=4.8 Hz, 1H)の積分比から算出した。
mp: 143.0-144.1 ℃; Rf=0.42 (hexane:EA=3/2); ¹H NMR（400 MHz, CDCl₃）δ＝7.59 (d, J=10.0 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 6.80 (d, J=8.8 Hz, 1H), 6.59 (d, J=4.8 Hz, 1H), 6.22 (d, J=9.6 Hz, 1H), 5.64 (m, 1H), 5.31 (d, J=4.8 Hz, 1H), 2.23 (s, 3H), 2.09 (s, 3H), 1.90 (s, 3H), 1.46 (s, 3H), 1.42 (s, 3H). ¹³C NMR(100MHz, CDCl₃) δ=170.0, 165.1, 159.8, 158.3, 156.6, 154.0, 143.1, 129.1, 114.9, 114.3, 113.2, 112.5, 107.4, 77.3, 70.6, 59.5, 27.5, 25.3, 22.2, 20.7, 20.4. Example 9
Preparation of a 5: 1 mixture of isosamidine and samidin

To a 30 mL eggplant flask was added peujaponicinol B (13.7 mg, 0.04 mmol), acetic anhydride (0.05 mL, 0.05 mmol, 1.2 eq.), Pyridine (0.1 mL, 0.12 mmol, 3.0 eq.). The reaction was carried out at 24 ° C. for 24 hours. After confirming the progress of the reaction by TLC, 1N hydrochloric acid was added, extracted three times with ethyl acetate, washed twice with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated. 20.6 mg (99%) of a 5: 1 mixture of isoamidine and samidine as pale yellow crystals was obtained. The product is a 5: 1 mixture of isosamidine and samidin, and the product ratio is calculated from the integral ratio of δ = 5.31 (d, J = 4.8 Hz, 1H) and δ = 5.36 (d, J = 4.8 Hz, 1H) did.
mp: 143.0-144.1 ° C; Rf = 0.42 (hexane: EA = 3/2); ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.59 (d, J = 10.0 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.59 (d, J = 4.8 Hz, 1H), 6.22 (d, J = 9.6 Hz, 1H), 5.64 (m, 1H), 5.31 (d, J = 4.8 Hz, 1H), 2.23 (s, 3H), 2.09 (s, 3H), 1.90 (s, 3H), 1.46 (s, 3H), 1.42 (s, 3H). ¹³ C NMR ( 100MHz, CDCl ₃ ) δ = 170.0, 165.1, 159.8, 158.3, 156.6, 154.0, 143.1, 129.1, 114.9, 114.3, 113.2, 112.5, 107.4, 77.3, 70.6, 59.5, 27.5, 25.3, 22.2, 20.7, 20.4.

50 mLのナスフラスコに(±)-シス-ケラクトン（100 mg, 0.38 mmol）、DMAP（23.1 mg, 0.19 mmol, 0.5 eq.）、塩基兼溶媒としてピリジンを1 mL加えた。氷上で無水酢酸（0.5 mL, 5.28 mmol, 14 eq.）を加え、室温で24時間反応を行った。TLCで反応の進行を確認した後、氷上で1規定の塩酸で反応を停止した。酢酸エチルで3回抽出し、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥させ、濾過、濃縮を行った。残渣をカラムクロマトグラフィー（ヘキサン/酢酸エチル＝3/2）で精製し、黄色固体としてのジアセチル化体であるキアンフクマリンＤを74.1 mg（56%）で得た。
mp:162.0-164.1 ℃ (lit.^27b) 165-166 ℃) ; Rf=0.38 (hexane:EA=3/2); ¹H NMR（400 MHz, CDCl₃）δ＝7.60 (d, 1H, J=9.6 Hz), 7.36 (d, 1H, J=8.8 Hz), 6.81 (d, 1H, J=8.4 Hz), 6.54 (d, 1H, J=4.8 Hz), 6.24 (d, 1H, J=9.6 Hz),5.31 (d, 1H, J=4.8 Hz), 2.14 (s, 3H), 2.10 (s, 3H), 1.45 (s, 3H), 1.41 (s, 3H). ¹³C NMR(100MHz, CDCl₃) δ= 169.9, 159.8, 156.6, 153.9, 143.3, 129.2, 114.4, 113.2, 112.6, 106.8, 77.3, 70.0, 60.9, 24.7, 22.8, 20.6. Example 10
Manufacture of Kianfucoumarin D

To a 50 mL eggplant flask, (±) -cis-kelactone (100 mg, 0.38 mmol), DMAP (23.1 mg, 0.19 mmol, 0.5 eq.), And 1 mL of pyridine as a base and solvent were added. Acetic anhydride (0.5 mL, 5.28 mmol, 14 eq.) Was added on ice, and the reaction was performed at room temperature for 24 hours. After confirming the progress of the reaction by TLC, the reaction was stopped with 1N hydrochloric acid on ice. The mixture was extracted 3 times with ethyl acetate, and the organic layer was washed with saturated brine. The extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (hexane / ethyl acetate = 3/2) to obtain 74.1 mg (56%) of kianfucoumarin D as a diacetylated product as a yellow solid.
mp: 162.0-164.1 ℃ (lit. ^27b) 165-166 ℃); Rf = 0.38 (hexane: EA = 3/2); ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.60 (d, 1H, J = 9.6 Hz), 7.36 (d, 1H, J = 8.8 Hz), 6.81 (d, 1H, J = 8.4 Hz), 6.54 (d, 1H, J = 4.8 Hz), 6.24 (d, 1H, J = 9.6 Hz) ), 5.31 (d, 1H, J = 4.8 Hz), 2.14 (s, 3H), 2.10 (s, 3H), 1.45 (s, 3H), 1.41 (s, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ = 169.9, 159.8, 156.6, 153.9, 143.3, 129.2, 114.4, 113.2, 112.6, 106.8, 77.3, 70.0, 60.9, 24.7, 22.8, 20.6.

30mLナスフラスコに、(±)-シス-ケラクトン（100 mg, 0.38 mmol）、溶媒としてクロロホルムを10 mL加えた。ここにセネシオ酸（30 mg, 3.04 mmol, 8.0 eq.）、DCC（314 mg, 1.52 mmol, 4.0 eq.）、DMAP（4.6 mg, 0.038 mmol, 10 mol%）を加え、50 ℃で42時間反応を行った。TLCで反応の進行を確認した後、反応液をセライトで濾過し、濃縮を行った。残渣をカラムクロマトグラフィー（ヘキサン/酢酸エチル＝9/1）により精製し、淡白色固体としてのジアシル化体である３，４−ジセネシオイル−３，４−ジヒドロセセリンを21.8 mg (13%）で得た。
mp: 122.3-123.8 ℃ (lit.^28b) 127- 129 ℃); Rf=0.46 (hexane:EA=3/2); ¹H NMR（400 MHz, CDCl₃）δ＝7.57 (d, 1H, J=9.6 Hz), 6.79 (d, 1H, J=8.8 Hz), 6.62 (d, 1H, J=5.2 Hz), 6.20 (d, 1H, J=9.6 Hz), 5.36 (d, 1H, J=4.8 Hz), 2.19 (s, 3H), 2.15 (s, 3H), 1.88 (s, 3H), 1.87 (s, 3H), 1.46 (s, 3H), 1.42 (s, 3H). ¹³C NMR(100MHz, CDCl₃) δ= 165.2, 165.0, 158.3, 157.6, 154.0, 143.2, 129.0, 115.3, 114.3, 113.1, 112.5, 107.5, 77.7, 69.3, 59.8, 27.4, 24.8, 22.6, 20.3, 20.2. Example 11
Manufacture of 3,4-disenecioyloxy-3,4-dihydroseselin

(±) -cis-kelactone (100 mg, 0.38 mmol) and 10 mL of chloroform as a solvent were added to a 30 mL eggplant flask. Senecioic acid (30 mg, 3.04 mmol, 8.0 eq.), DCC (314 mg, 1.52 mmol, 4.0 eq.) And DMAP (4.6 mg, 0.038 mmol, 10 mol%) were added here and reacted at 50 ° C for 42 hours Went. After confirming the progress of the reaction by TLC, the reaction solution was filtered through celite and concentrated. The residue was purified by column chromatography (hexane / ethyl acetate = 9/1), and 21.8 mg (13%) of 3,4-disenecioyl-3,4-dihydroserine, which is a diacylated product as a pale white solid. Obtained.
mp: 122.3-123.8 ° C (lit. ^28b) 127- 129 ° C); Rf = 0.46 (hexane: EA = 3/2); ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.57 (d, 1H, J = 9.6 Hz), 6.79 (d, 1H, J = 8.8 Hz), 6.62 (d, 1H, J = 5.2 Hz), 6.20 (d, 1H, J = 9.6 Hz), 5.36 (d, 1H, J = 4.8 Hz) ), 2.19 (s, 3H), 2.15 (s, 3H), 1.88 (s, 3H), 1.87 (s, 3H), 1.46 (s, 3H), 1.42 (s, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ = 165.2, 165.0, 158.3, 157.6, 154.0, 143.2, 129.0, 115.3, 114.3, 113.1, 112.5, 107.5, 77.7, 69.3, 59.8, 27.4, 24.8, 22.6, 20.3, 20.2.

30mLのナスフラスコに、セセリン（100 mg, 0.44 mmol）、溶媒としてクロロホルムを8 mL加えた。ここにmCPBA（75.6 mg, 0.44 mmol, 1.0 eq.）を加え、室温で5時間反応を行った。飽和チオ硫酸ナトリウム水溶液を加えて、反応を停止後、炭酸水素ナトリウム水溶液で洗浄し、飽和食塩水で有機層を洗浄した。その後、無水硫酸ナトリウムで乾燥させ、濾過、濃縮を行った。残渣をカラムクロマトグラフィー (ヘキサン/酢酸エチル＝4/1)で精製し、白色固体としてのエポキシ体である目的化合物を57.6 mg (54％)で得た。
mp: 141.6-143.4 ℃ (lit.¹⁶⁾ 144-146 ℃); Rf=0.46 (hexane:EA=3/2); ¹H NMR（400 MHz, CDCl₃）δ＝7.64 (d, 1H, J=9.2 Hz), 7.33 (d, 1H, J=8.4 Hz), 6.74 (d, 1H, J=8.8 Hz), 6.28 (d, 1H, J=9.6 Hz), 4.62 (d, 1H, J=4.8 Hz), 3.58 (d, 1H, J=4.8 Hz), 1.62 (s, 3H), 1.33 (s, 3H). ¹³C NMR(100MHz, CDCl₃) δ= 160.5, 156.1, 154.3, 143.7, 128.9, 114.9, 113.0, 112.7, 107.8, 74.5, 61.7, 44.3, 25.4, 22.9. Example 12
1a, 9c-Dihydro-2,2-dimethyl-2H, 8H-oxyleno [c] pyrano [2,3-f] [1] benzopyran-8-one (1a, 9c-dihydro-2,2-dimethyl-2H , 8H-Oxireno [c] pyrano [2,3-f] [1] benzopyran-8-one)

Cererine (100 mg, 0.44 mmol) and 8 mL of chloroform as a solvent were added to a 30 mL eggplant flask. MCPBA (75.6 mg, 0.44 mmol, 1.0 eq.) Was added thereto, and the reaction was performed at room temperature for 5 hours. Saturated aqueous sodium thiosulfate solution was added to stop the reaction, and the mixture was washed with aqueous sodium hydrogen carbonate solution, and the organic layer was washed with saturated brine. Then, it dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (hexane / ethyl acetate = 4/1) to obtain 57.6 mg (54%) of the target compound as an epoxy compound as a white solid.
mp: 141.6-143.4 ° C (lit. ¹⁶⁾ 144-146 ° C); Rf = 0.46 (hexane: EA = 3/2); ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.64 (d, 1H, J = 9.2 Hz), 7.33 (d, 1H, J = 8.4 Hz), 6.74 (d, 1H, J = 8.8 Hz), 6.28 (d, 1H, J = 9.6 Hz), 4.62 (d, 1H, J = 4.8 Hz) ), 3.58 (d, 1H, J = 4.8 Hz), 1.62 (s, 3H), 1.33 (s, 3H). 13 C NMR (100MHz, CDCl 3) δ = 160.5, 156.1, 154.3, 143.7, 128.9, 114.9 , 113.0, 112.7, 107.8, 74.5, 61.7, 44.3, 25.4, 22.9.

30 mLナスフラスコに室温で、セセリンエポキシド（20 mg, 0.08 mmol）、溶媒としてアセトンを1 mL加えた。ここに1M 硫酸を0.5 mL加え、室温で1時間撹拌を行った。炭酸水素ナトリウムにより、pH 7まで中性化し、クロロホルムで3回抽出を行い、無水硫酸ナトリウムで乾燥させ、濾過、濃縮を行った。白色固体としての(±)-トランス−ケラクトンを33.8 mg (56 %)で得た。
mp:186.1- 188.8 ℃, Rf=0.08 (hexane:EA=3/2); ¹HNMR（400 MHz, CDCl₃）δ＝7.66 (d, 1H, J=9.6 Hz), 7.32 (d, 1H, J=8.4 Hz), 6.79 (d, 1H, J=8.8 Hz), 6.26 (d, 1H, J=9.2 Hz), 1.54 (s, 3H), 1.31 (s, 3H). ¹³C NMR(100MHz, CDCl₃) δ= 156.1, 154.3, 144.2, 128.6, 114.7, 112.4, 112.2, 79.3, 74.8, 66.7, 25.5, 19.9. Example 13
Production of (±) -trans-kelactone

Cererine epoxide (20 mg, 0.08 mmol) and 1 mL of acetone as a solvent were added to a 30 mL eggplant flask at room temperature. 0.5 mL of 1M sulfuric acid was added thereto, and the mixture was stirred at room temperature for 1 hour. The mixture was neutralized with sodium hydrogencarbonate to pH 7, extracted with chloroform three times, dried over anhydrous sodium sulfate, filtered and concentrated. (±) -Trans-kelactone as a white solid was obtained in 33.8 mg (56%).
mp: 186.1- 188.8 ℃, Rf = 0.08 (hexane: EA = 3/2); ¹ HNMR (400 MHz, CDCl ₃ ) δ = 7.66 (d, 1H, J = 9.6 Hz), 7.32 (d, 1H, J = 8.4 Hz), 6.79 (d, 1H, J = 8.8 Hz), 6.26 (d, 1H, J = 9.2 Hz), 1.54 (s, 3H), 1.31 (s, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ = 156.1, 154.3, 144.2, 128.6, 114.7, 112.4, 112.2, 79.3, 74.8, 66.7, 25.5, 19.9.

30 mLナスフラスコにtBuOH/水＝1/1混合溶液（10 mL）を入れ、AD-mix-α（(DHQ)₂PHAL0.0016モル、炭酸カリウム粉末0.4988モル、フェリシアン化カリウム0.4988モル、ならびにオスミウム酸カリウム二水和物0.0007モルを含む混合物、アルドリッチ社製）（0.6 g）を加え、15分間室温で撹拌した。その後、氷上にフラスコを移し、メタンスルホンアミド（12.3 mg, 0.129 mmol, 0.3 eq.）を加え、反応液がオレンジ色に変化したことを確認した後、セセリンを加え、0 ℃で8日間反応を行った。TLCで反応の進行を確認した後、反応液に亜硫酸ナトリウムを約100 mg加え、室温で4時間撹拌を行った。ジクロロメタンで3回抽出を行い、無水硫酸ナトリウムで乾燥させ、濾過、濃縮を行った。残渣をカラムクロマトグラフィー（ヘキサン/酢酸エチル＝3/2）により精製し、エナンチオ選択的に、白色固体としての(−)−シス−ケラクトンを85.7 mg (80%, 47% ee)で得た。光学純度は文献記載の(−)−シス−ケラクトンの[α]_Dを100% eeの比旋光度として、測定した比旋光度との比により算出した。
mp: 153.0-155.4 ℃, Rf=0.13 (hexane:EA=3/2); [α]_D +36.8 (c=0.05, CHCl₃) (lit. [α]_D+78.5(c=0.05, CHCl₃)); ¹H NMR（400 MHz, CDCl₃）δ＝7.67 (d, J=9.6 Hz, 1H),7.33 (d, J=8.4 Hz, 1H),6.79 (d, J=8.8 Hz, 1H), 6.25 (d, J=9.6 Hz, 1H), 5.21 (d, J=4.8 Hz, 1H), 3.87 (d, J=4.8 Hz, 1H), 1.46 (s, 3H), 1.42 (s, 3H). ¹³C NMR(100MHz, CDCl₃) δ=161.1, 156.4, 154.5, 144.3, 128.6, 114.9, 112.2, 112.0, 110.9, 79.0, 71.0, 61.0, 25.0, 21.6. Example 14
Preparation of enantiomers of cis-kelactone

Add tBuOH / water = 1/1 mixed solution (10 mL) to a 30 mL eggplant flask, AD-mix-α ((DHQ) ₂ PHAL 0.0016 mol, potassium carbonate powder 0.4988 mol, potassium ferricyanide 0.4988 mol, and osmic acid A mixture containing 0.0007 mol of potassium dihydrate (manufactured by Aldrich) (0.6 g) was added, and the mixture was stirred for 15 minutes at room temperature. Then, transfer the flask onto ice, add methanesulfonamide (12.3 mg, 0.129 mmol, 0.3 eq.), Confirm that the reaction solution turned orange, add ceserine, and react at 0 ° C for 8 days. went. After confirming the progress of the reaction by TLC, about 100 mg of sodium sulfite was added to the reaction solution, and the mixture was stirred at room temperature for 4 hours. Extraction was performed 3 times with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (hexane / ethyl acetate = 3/2), and (-)-cis-kelactone as a white solid was obtained enantiomerically as 85.7 mg (80%, 47% ee). The optical purity was calculated from the ratio of the measured specific rotation, with [α] _D of (−)-cis-kelactone described in the literature as the specific rotation of 100% ee.
mp: 153.0-155.4 ° C, Rf = 0.13 (hexane: EA = 3/2); [α] _D +36.8 (c = 0.05, CHCl ₃ ) (lit. [α] _D +78.5 (c = 0.05, CHCl ₃ )); ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.67 (d, J = 9.6 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H) , 6.25 (d, J = 9.6 Hz, 1H), 5.21 (d, J = 4.8 Hz, 1H), 3.87 (d, J = 4.8 Hz, 1H), 1.46 (s, 3H), 1.42 (s, 3H) ¹³ C NMR (100 MHz, CDCl ₃ ) δ = 161.1, 156.4, 154.5, 144.3, 128.6, 114.9, 112.2, 112.0, 110.9, 79.0, 71.0, 61.0, 25.0, 21.6.

50mL 2口ナスフラスコに、(±)−シス−ケラクトン（100 mg, 0.38 mmol）、溶媒としてベンゼンを20 mL加えた。ここにp-TsOH（0.05 mg, 0.08 mol%）、(-) - メントン（0.08 mL, 1.2 eq.）を加え、85 ℃で24時間加熱還流を行った。室温まで冷却後、DBU（0.2 mL）を添加し、濃縮を行った。残渣をカラムクロマトグラフィー（ヘキサン/酢酸エチル＝4/1）により精製し、無色油状物としてのメントンアセタール化体を27.3 mg（18.1％）で得た。
Rf=0.19; ¹H NMR（400 MHz, CDCl₃）δ＝7.62 (d, 1H, J=9.2 Hz), 6.73 (d, 1H, J=8.4 Hz), 6.25 (d, 1H, J=9.6 Hz), 5.57 (d, 1H, J=7.2 Hz), 4.26 (d, 1H, J=6.8 Hz), 3.71 (d, 1H, J=7.2 Hz), 1.94 (m, 2H), 1.25-1.20 (m, 10H), 0.89 (s, 3H), 0.88 (s, 3H), 0.59 (d, 3H, J=6.8 Hz), 0.53 (d, 3H, J=7.2 Hz). ¹³C NMR(100MHz, CDCl₃) δ= 161.1, 156.0, 154.3, 143.6, 128.2, 114.5, 113.4, 112.8, 110.4, 65.5, 48.1, 43.8, 34.4, 31.5, 30.5, 25.3, 24.0 (2C), 23.2, 23.0, 22.6, 22.3, 22.0, 18.0. Example 15
Production of chiral acetalized product of (±) -cis-kelactone

(±) -cis-kelactone (100 mg, 0.38 mmol) and 20 mL of benzene as a solvent were added to a 50 mL 2-necked eggplant flask. P-TsOH (0.05 mg, 0.08 mol%) and (-)-menthone (0.08 mL, 1.2 eq.) Were added thereto, and the mixture was heated to reflux at 85 ° C. for 24 hours. After cooling to room temperature, DBU (0.2 mL) was added and concentrated. The residue was purified by column chromatography (hexane / ethyl acetate = 4/1) to obtain 27.3 mg (18.1%) of menthone acetalized product as a colorless oil.
Rf = 0.19; ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.62 (d, 1H, J = 9.2 Hz), 6.73 (d, 1H, J = 8.4 Hz), 6.25 (d, 1H, J = 9.6 Hz) ), 5.57 (d, 1H, J = 7.2 Hz), 4.26 (d, 1H, J = 6.8 Hz), 3.71 (d, 1H, J = 7.2 Hz), 1.94 (m, 2H), 1.25-1.20 (m , 10H), 0.89 (s, 3H), 0.88 (s, 3H), 0.59 (d, 3H, J = 6.8 Hz), 0.53 (d, 3H, J = 7.2 Hz). ¹³ C NMR (100 MHz, CDCl ₃ ) δ = 161.1, 156.0, 154.3, 143.6, 128.2, 114.5, 113.4, 112.8, 110.4, 65.5, 48.1, 43.8, 34.4, 31.5, 30.5, 25.3, 24.0 (2C), 23.2, 23.0, 22.6, 22.3, 22.0, 18.0.

  By the production method of the present invention, an isosamidine analog that has a vasodilatory action, an anti-arteriosclerotic action, a diuretic promotion action, and the like and is contained in foods and supplements can be easily produced.

Claims (14)

Formula (1):

[Where:
X is an oxygen atom or a sulfur atom;
Each R ¹ is independently a C1-3 alkyl group or a C2-C3 acyl group;
R ² is a hydrogen atom, a C1-3 alkyl group or a C2-C3 acyl group;
R ³ is a C1-3 alkyl group;
m is an integer from 0 to 2;
n is an integer from 1 to 2;
Symbol * represents an asymmetric center]
A compound represented by
i) reacting with a seneciolization source compound to effect seneciolization; and
ii) reacting with an acetylated source compound to effect acetylation;
Where the order of step i) and step ii) may be first,
A method for producing a compound represented by the following formula (I) or a compound represented by the following formula (II), or a mixture thereof:

[Where:
X, R ¹ , R ² , R ³ , m, n and * are as described above].
A method for producing either the compound represented by formula (I) or the compound represented by formula (II), or a mixture thereof.   The step i), comprising reacting in the presence of a tin catalyst and a base, wherein the senecioylation feed compound is selected from the group consisting of senecioic acid, senecioic anhydride, and senecioyl halide. Production method.   The process according to claim 1 or 2, wherein in step ii), the reaction is carried out in the presence of a base, and the acetylated source compound is selected from the group consisting of acetic acid, acetic anhydride, and acetyl halide. Method.   The production method according to claim 1, comprising performing the reaction of the step ii) following the reaction of the step i). In step i), compound (6-1) is obtained by reacting in the presence of a tin catalyst and a base using seneci oil halide as the seneciolization feed compound.

The manufacturing method of Claim 4 which obtains the compound shown by these. The compound represented by formula (I) to be produced is represented by formula (IA-1) and formula (IA-2):

[Where:
X, R ¹ , R ² , R ³ , m, n and * are as described above in claim 1]
The production method according to any one of claims 1 to 5, which is at least one enantiomer of a 3,4-position cis isomer selected from the group consisting of: or a racemic mixture thereof. The production method according to claim 6, wherein the product is represented by formula (I), wherein X is an oxygen atom, R ² is a hydrogen atom, m is 0, and n is 2.   The production method according to claim 5 or 6, wherein the obtained product is a mixture having a ratio of isosamidine and samidin of 5: 1. A process for producing either a compound of formula (I) or a compound of formula (II), or a mixture thereof,
Step 2) Formula (3):

[Where:
X, R ¹ , R ² , and m are as described above in claim 1]
Is reacted with 1,1-diethoxy-3-methyl-2-butene or 1,1-diethoxy-2-butene to give a compound of formula (2):

[Where:
X, R ¹ , R ² , R ³ , n, and m are as described above]
Obtaining a compound represented by:
Step 3 ′) The obtained compound represented by the formula (2) is reacted with osmium tetroxide and a reoxidant to form the formula (1A-1) and the formula (1A-2) according to claim 1:

[Where:
X, R ¹ , R ² , R ³ , n, m and * are as described above]
Obtaining a compound represented by: and
Step 4) Regarding the compounds represented by the obtained formula (1A-1) and formula (1A-2),
i) reacting with a seneciolization source compound to effect seneciolization, and
ii) reacting with an acetylated source compound to effect acetylation;
To obtain either the compound represented by formula (I) or the compound represented by formula (II), or a mixture thereof, wherein the order of step i) and step ii) May be,
A method for producing either the compound represented by formula (I) or the compound represented by formula (II), or a mixture thereof. 1) Formula (4):

[Where:
X, R ¹ and n are as described above in claim 1]
A compound of formula (5):

[Where:
R ² is as described above in claim 1]
Is reacted with a compound of formula (3) according to step 1 of claim 8:

[Where:
X, R ¹ , R ² , and m are as described above in claim 1]
The manufacturing method of Claim 9 including the process of obtaining the compound shown by these. Instead of step 3 ′ according to claim 9,
Step 3 ″ -1) A compound represented by the formula (2) is reacted with a peracid to obtain a formula (8):

[Where:
X, R ¹ , R ² , R ³ , m, n and * are as described above in claim 1]
Obtaining an epoxide compound represented by:
Step 3 ″ -2) The obtained epoxide compound represented by the formula (8) is treated with an inorganic acid.
Including formula (1B-1) and formula (1B-2):

[Where:
X, R ¹ , R ² , R ³ , m, n and * are as described above in claim 1]
The production method according to claim 9, comprising obtaining at least one 3,4-trans-enantiomer selected from the group consisting of the compounds represented by: or a racemic mixture thereof. The compound of formula (I) to be produced is represented by formula (IB-1) and formula (IB-2):

[Where:
X, R ¹ , R ² , R ³ , m, n and * are as described above in claim 1]
The production method according to claim 11, which is at least one 3,4-positioned trans enantiomer selected from the group consisting of, or a racemic mixture thereof. Instead of step 3 ′ according to claim 9,
Step 3 ′ ″) The compound represented by the formula (2) is subjected to sharpless asymmetric dihydroxylation using osmium tetroxide and a reoxidant in the presence of an asymmetric ligand to obtain a compound represented by the formula (1A- 1) and (1A-2):

[Where:
X, R ¹ , R ² , R ³ , m, n and * are as described above in claim 1]
The production method according to claim 9, comprising obtaining at least one 3,4-positioned (R)-or (S) -enantiomer or a mixture thereof selected from the group consisting of compounds represented by: The compound represented by formula (I) to be produced is represented by formula (IA-1) and formula (IA-2):

[Where:
X, R ¹ , R ² , R ³ , m, n and * are as described above in claim 1]
The production method according to claim 13, which is at least one 3,4-positioned (R)-or (S) -enantiomer selected from the group consisting of or a mixture thereof.