JP2009191000A - Intermediate compound, method for producing the same, and method for producing ansamycin-based antibiotic - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To establish the total synthesis method of cytotrienin A, to provide an intermediate compound for synthesizing an ansamycin-based antibiotic comprising the cytotrienin A, to provide a method for producing the intermediate compound, and to provide a method for producing the ansamycin-based antibiotic. <P>SOLUTION: The cytotrienin A is divided into four segments of a C1-C6 segment, a C7-C16 segment, a cyclopropanecarboxylic acid, and an aromatic segment, and the segments are linked, respectively to synthesize the cytotrienin A. A triene is constructed from a compound represented by formula (g) by a ring-closing metathesis reaction, and the protecting groups are then removed, particularly in the final stage of the synthesis. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an intermediate compound for the synthesis of ansamycin antibiotics such as cytotrienin A, a method for producing the same, and a method for producing an ansamycin antibiotic.

  A large number of compounds called ansamycin antibiotics have been found from bacteria belonging to the genus Streptomyces, and have an aliphatic chain bridge structure between two non-adjacent sites of an aromatic ring as a basic skeleton. Two types of aromatic ring are known, a benzene ring and a naphthalene ring, and the number of rings is known to be a 19-membered ring, a 21-membered ring, a 25-membered ring, or the like.

  Among these, examples of the compound having a 21-membered macrolactam structure include mycotrienol and mycotrienol II. These compounds are isolated from the culture solution of Streptomyces rishiriensis T-23 and are known to exhibit antifungal activity. As structural features, it has four asymmetric points including three consecutive asymmetric centers and a triene unit.

In addition, many analogs in which the C11 position of mycotrienol or mycotrienol II is esterified or an analog having a different aromatic ring site have been reported to date. For example, mycotrienins I and II are compounds isolated from the same culture solution as mycotrienol and the like, and ansatrienins A ₂ , A ₃ and A ₄ were isolated from the culture solution of Streptomyces collinus. Compounds, both exhibit antifungal activity. Trienomycin A-F is a compound isolated from Streptomyces sp. 83-16 and exhibits antitumor activity against leukemia cells. Thiazinotrienomycin A-E is a compound isolated from the Streptomyces genus MJ672-m3 strain and exhibits antitumor activity against cancer cells of esophageal cancer, colon cancer, gastric cancer and breast cancer. Cytotrienin A is a compound isolated from the genus Streptomyces 95-74 and exhibits antitumor activity against various cancer types including leukemia cells. Furthermore, it has been clarified that cytotrienin A induces the activation of protein kinase MST / Krs protein having an important function in inducing apoptosis (see Non-Patent Document 1). This cytotrienin A has a cyclopropanecarboxylic acid site in the side chain at the C11 position in addition to the basic skeleton similar to that of mycotrienol II.

  Thus, a series of compounds having a 21-membered macrolactam structure isolated from Streptomyces bacteria differ only in the side chain structure at the C11 position and the aromatic ring site, and exhibit various biological activities. However, since these compounds have a small supply amount from nature, artificial supply by organic chemical synthesis is desired for the purpose of elucidating the mechanism of action and synthesizing derivatives.

Against this background, synthetic studies on ansamycin antibiotics having a 21-membered macrolactam structure have been conducted. For example, the group of Smith and Panek et al. Reported a total synthesis method of trienomycin A, F, mycotrienol, mycotrienin I, thiazinotrienomycin E (see Non-Patent Documents 2 to 4). . On the other hand, the group of Panek and Kirschning et al. Attempted the total synthesis of cytotrienin A and synthesized the macrocyclic core (see Non-Patent Documents 5 and 6), but the entire chain including the side chain at the C11 position was used. It has not reached synthesis.
Kakeya, H .; Onese, R .; Osada, H .; Cancer Res. 1998, 58, p. 4888 Smith, A.M. B. , III. Barbosa, J .; Wong, W .; Wood, J .; L. J .; Am. Chem. Soc. 1996, 118, p. 8316 Masse, C.I. E. Yang, M .; Solomon, J .; Panek, J .; S. J .; Am. Chem. Soc. 1998, 120, p. 4123 Smith, A.M. B. , III. Wan, Z .; J .; Org. Chem. l; 2000, 65, p. 3738 Evano, G.M. Schaus, J .; V. Panek, J .; S. Org. Lett. 2004, 6, 525 Kashin, D.H. Meyer, A .; Wittenberg, R .; Schoning, K .; U. Kammlage, S .; Kirschning, A .; ; Synthesis; 2007, 304

  Accordingly, the present invention establishes a method for total synthesis of cytotrienin A, and provides an intermediate compound for the synthesis of ansamycin antibiotics containing cytotrienin A, a method for producing the same, and a method for producing an ansamycin antibiotic. The purpose is to provide.

  In order to solve the above problems, the inventors of the present invention tried to perform a reverse synthesis analysis of cytotrienin A. As a result, the inventors divided into four segments: C1-C6 segment, C7-C16 segment, cyclopropanecarboxylic acid, and aromatic segment. It was found that total synthesis is possible by linking them together. In addition, it is difficult to introduce a bulky side chain after forming the macrocyclic core, and it is necessary to avoid changing the unstable triene unit. It was introduced in the middle, and it was found that the triene unit was constructed by ring closing metathesis (RCM) at the final stage of synthesis. Furthermore, of the three consecutive asymmetric centers, two consecutive asymmetric centers are constructed by an asymmetric aldol reaction using an organic catalyst, and the remaining one asymmetric center is an asymmetric α using an organic catalyst. -It was found to be constructed by aminooxylation reaction. Thus, a total synthesis method of cytotrienin A can be established, and an intermediate compound for synthesizing an ansamycin antibiotic containing cytotrienin A, a method for producing the same, and a method for producing an ansamycin antibiotic are provided. It became possible to do. More specifically, the present invention is as follows.

（式（ａ）中、Ｒ^１は置換基を有していてもよいアリール基又はヘテロアリール基を示す。） (1) An intermediate compound for synthesizing an ansamycin antibiotic represented by the following formula (a).

(In formula (a), R ¹ represents an aryl group or a heteroaryl group which may have a substituent.)

（式（ｂ）中、Ｒ^２，Ｒ^４は保護基を示し、Ｒ^３は水素原子又は保護基を示す。） (2) An intermediate compound for synthesizing an ansamycin antibiotic represented by the following formula (b).

(In formula (b), R ² and R ⁴ represent a protecting group, and R ³ represents a hydrogen atom or a protecting group.)

（式（ｃ）中、Ｒ^５，Ｒ^６は保護基を示し、Ｒ^７は水素原子又は保護基を示し、Ｒ^８は水素原子又はトリチル基を示す。） (3) An intermediate compound for synthesizing an ansamycin antibiotic represented by the following formula (c).

(In formula (c), R ⁵ and R ⁶ represent a protecting group, R ⁷ represents a hydrogen atom or a protecting group, and R ⁸ represents a hydrogen atom or a trityl group.)

（式（ｄ）中、Ｒ^９は置換基を有していてもよいアリール基又はヘテロアリール基を示し、Ｒ^１０は水素原子又は水酸基を示す。） (4) An intermediate compound for synthesizing an ansamycin antibiotic represented by the following formula (d).

(In formula (d), R ⁹ represents an aryl group or heteroaryl group which may have a substituent, and R ¹⁰ represents a hydrogen atom or a hydroxyl group.)

（式（ｅ）中、Ｒ^１１は保護基を示し、Ｒ^１２は水素原子又はメチル基を示す。） (5) An intermediate compound for synthesizing an ansamycin antibiotic represented by the following formula (e).

(In formula (e), R ¹¹ represents a protecting group, and R ¹² represents a hydrogen atom or a methyl group.)

(6) An intermediate compound for synthesizing an ansamycin antibiotic represented by the following formula (f).

（式（ｇ）中、Ｒ^１３は保護基を示し、Ｒ^１４は下記式

のいずれかを示し、Ｒ^１６，Ｒ^１７は水素原子又は保護基を示し、Ｒ^１８は水素原子又は−ＯＲ^１９（Ｒ^１９は保護基）を示す。Ｒ^１５は下記式

のいずれかを示す。） (7) An intermediate compound for synthesizing an ansamycin antibiotic represented by the following formula (g).

(In formula (g), R ¹³ represents a protecting group, and R ¹⁴ represents the following formula:

R ¹⁶ and R ¹⁷ represent a hydrogen atom or a protecting group, and R ¹⁸ represents a hydrogen atom or —OR ¹⁹ (R ¹⁹ represents a protecting group). R ¹⁵ is the following formula

Indicates one of the following. )

（式（ａ）中、Ｒ^１は置換基を有していてもよいアリール基又はヘテロアリール基を示す。） (8) A compound represented by the following formula (a) is obtained by allowing an arylaldehyde dialkyl acetal, heteroaryl aldehyde dialkyl acetal, aryl aldehyde, or heteroaryl aldehyde to act on the compound represented by the following formula (h). A method for producing an intermediate compound for the synthesis of ansamycin antibiotics.

(In formula (a), R ¹ represents an aryl group or a heteroaryl group which may have a substituent.)

  (9) Intermediate compound for synthesizing an ansamycin antibiotic according to (8), wherein furfural and propanal are reacted in the presence of proline or a proline derivative to obtain a compound represented by the formula (h) Manufacturing method.

（式（ｇ）中、Ｒ^１３は保護基を示し、Ｒ^１４は下記式

のいずれかを示し、Ｒ^１６，Ｒ^１７は水素原子又は保護基を示し、Ｒ^１８は水素原子又は−ＯＲ^１９（Ｒ^１９は保護基）を示す。Ｒ^１５は下記式

のいずれかを示す。） (10) A method for producing an ansamycin antibiotic, wherein a triene is constructed from a compound represented by the following formula (g) by a ring-closing metathesis reaction, and then the protecting group is deprotected.

(In formula (g), R ¹³ represents a protecting group, and R ¹⁴ represents the following formula:

R ¹⁶ and R ¹⁷ represent a hydrogen atom or a protecting group, and R ¹⁸ represents a hydrogen atom or —OR ¹⁹ (R ¹⁹ represents a protecting group). R ¹⁵ is the following formula

Indicates one of the following. )

  ADVANTAGE OF THE INVENTION According to this invention, the intermediate compound for ansamycin type antibiotics synthesis containing cytotrienin A, its manufacturing method, and the manufacturing method of an ansamycin type antibiotics can be provided.

[Intermediate compound]
The intermediate compound according to the present invention is represented by the above formulas (a) to (g). All of these intermediate compounds were newly discovered in the process of total synthesis of cytotrienin A, but as intermediate compounds for the synthesis of not only cytotriene A but also ansamycin antibiotics. Can be used.

  Examples of the aryl group in the above formulas (a) and (d) include a phenyl group and a naphthyl group. In addition, examples of the heteroaryl group include a furyl group and a thienyl group. Moreover, as a substituent which the aryl group and heteroaryl group may have, a C1-C6 alkyl group, an alkoxy group, etc. are mentioned.

  In addition, as the protective group in the above formulas (b), (c), (e), and (g), commonly used protective groups such as an alkyl group, an acyl group, and a silyl group can be used. Among these, examples of silyl groups include trimethylsilyl (TMS) group, triethylsilyl (TES) group, t-butyldimethylsilyl (TBS) group, triisopropylsilyl (TIPS) group, t-butyldiphenylsilyl (TBDPS) group. Etc.

[Method for producing intermediate compound]
The intermediate compound represented by the above formula (a) is an aryl which may have a substituent on the compound represented by the above formula (h), as shown in reactions 2a and 2b of Examples described later. It can be produced by reacting an aldehyde dialkyl acetal, heteroaryl aldehyde dialkyl acetal, aryl aldehyde, or heteroaryl aldehyde. The compound represented by the formula (h) is an asymmetric cross aldol of furfural and propanal using proline or a proline derivative as an asymmetric catalyst, as shown in reactions 1a and 1b of Examples described later. It can be produced by reaction.

As the proline derivative for producing the intermediate compound represented by the above formula (a), those represented by the following formula (i) can be used.

  In the above formula (i), A represents an alkoxy group, an aryloxy group, an acyloxy group, an alkoxycarbonyloxy group, or a silyloxy group which may have a substituent. Of these, an alkoxycarbonyloxy group is preferable.

  The intermediate compounds represented by the above formulas (b) and (c) can be produced by using the intermediate compound represented by the above formula (a) as in Examples described later. In addition, the intermediate compound represented by the above formula (d) can be produced from compounds known in the literature according to the reactions 29 and 30 in Examples described later. Similarly, the intermediate compounds represented by the above formulas (e) and (f) can be produced from compounds known in the literature according to the reactions 31 to 36 in Examples described later. Moreover, the intermediate compound represented by the said formula (g) can be manufactured like the Example mentioned later using the intermediate compound represented by the said formula (a)-(f).

[Method for producing ansamycin antibiotics]
Ansamycin antibiotics such as cytotrienin A can be produced via the intermediate compounds represented by the above formulas (a) to (g), as shown in Examples described later. In particular, in the final stage of the synthesis, a triene is constructed from the intermediate compound represented by the above formula (g) by a ring-closing metathesis reaction, and then the protecting group is deprotected. Thus, by constructing the triene unit in the final stage, it is possible to prevent the unstable triene unit from changing during the synthesis.

  Examples of the present invention will be described below, but the scope of the present invention is not limited to these examples.

[Total synthesis method of cytotrienin A]
Total synthesis of cytotrienin A was performed according to the following synthesis scheme. The compound numbers shown below are based on this synthetic scheme.

<Reaction 1a: Synthesis of (1R, 2R) -1- (furan-2-yl) -2-methylpropane-1,3-diol (4)>

To a mixture of furfural (1) (0.91 mL, 10.4 mmol) and 4-acyloxyproline (3) (297 mg, 0.04 mmol) under an argon atmosphere at 4 ° C. over 46 hours, propanal (2) (2.25 mL, 31.2 mmol) was added. The reaction was stirred at 4 ° C. for 2 hours, after which methanol (10 mL) and NaBH ₄ (1.2 g, 31.2 mmol) were added. The reaction solution was further stirred at 0 ° C. for 1 hour, and then the reaction was stopped by adding a phosphate buffer adjusted to pH 7.0, and the organic matter was extracted five times with ethyl acetate. Subsequently, the organic substance was extracted 5 times with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After filtering these and concentrating under reduced pressure, the low boilers were removed azeotropically with methanol three times. The self-aldol body (S1) and a small amount of furfuryl alcohol (S2) were removed with Kugelrohr (115 ° C., 0 to 1 Torr). By using ethyl acetate as an effluent solvent, the residue was passed through a silica gel pad (SiO ₂ : 7 g) to give a pale yellow oily diol (4) (1.34 g, 83%, anti: syn = 6.2: 1, 91%). ee) was obtained.

After converting the diol (4) to the corresponding monobenzoyl ester, the enantiomeric excess was calculated using HPLC. The measurement conditions are as follows.
Column: Chiralpac AS-H column (2-propanol: hexane = 1: 100)
Flow rate: 0.5 mL / min Major enantiomer: t _R = 45.7 min Minor enantiomer: t _R = 52.0 min

<Reaction 2a: Synthesis of (4R, 5R) -4- (furan-2-yl) -2- (4-methoxyphenyl) -5-methyl-1,3-dioxane (5)>

  P-Anisaldehyde dimethyl was added to a benzene solution (16 mL) containing the diol (4) synthesized in the above reaction 1a (1.22 g, anti: syn = 6.2: 1, 7.81 mmol) at room temperature under an argon atmosphere. Acetal (1.6 mL, 9.37 mmol) and pyridinium p-toluenesulfonic acid (PPTS, 98 mg, 0.39 mmol) were added. The reaction solution was heated to 80 ° C. and stirred for 1 hour. After cooling the reaction solution to 23 ° C., a saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction. The organic matter was extracted three times with ethyl acetate, washed three times with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was recrystallized from n-hexane containing 33% ethyl acetate to give a white needle-like acetal protector (5) (1.36 g, 64%,> 99%). ee) was obtained.

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, specific rotation and melting point of the acetal protected body (5) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.74 (3H, d, J = 6.7 Hz), 2.37-2.52 (1H, m), 3.61 (1H, t, J = 1.11. 4 Hz), 3.78 (3 H, s), 4.26 (1 H, dd, J = 11.4, 4.7 Hz), 4.49 (1 H, d, J = 10.4 Hz), 5.59 ( 1H, s), 6.36 (1H, dd, J = 3.2, 1.0 Hz), 6.39 (1H, br d, J = 3.2 Hz), 6.87 (2H, br d, J = 8.7 Hz), 7.41 (1H, d, J = 1.0 Hz), 7.45 (2H, br d, J = 8.7 Hz);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 12.4, 32.8, 55.3, 73.2, 78.7, 101.6, 108.5, 110.1, 113.6 (2C), 127 .6 (2C), 130.7, 142.4, 152.5, 160.0;
IR (KBr): ν 2958, 2927, 2845, 1618, 1587, 1520, 1455, 1425, 1392, 1354, 1308, 1254, 1174, 1074, 1036, 822, 748, 652, 606 cm ⁻¹ ;
HRMS (ESI): [M + Na] ⁺ calculated [C ₁₆ H ₁₈ NaO ₄ ] ⁺ : 297.1097, found: 297.1096;
[Α] _D ³³ -7.7 (c = 0.99, MeOH);
Melting point: 104-105 ° C

The enantiomeric excess of the acetal protector (5) was calculated using HPLC. The measurement conditions are as follows.
Column: Chiralpac IC column (2-propanol: hexane = 1: 30)
Flow rate: 1.3 mL / min Major enantiomer: t _R = 8.5 min Minor enantiomer: t _R = 10.0 min

<Reaction 1b: Synthesis of (1R, 2R) -1- (furan-2-yl) -2-methylpropane-1,3-diol (4)>

To a mixture of furfural (1) (1 g, 10.4 mmol) and proline (3 ′) (119.6 mg, 0.1 mmol) in an argon atmosphere at 4 ° C., propanal (2) (3.02 g, 52. 1 mmol) was added. The reaction was stirred at 4 ° C. for 96 hours, after which methanol (10 mL) and NaBH ₄ (787 mg, 20.8 mmol) were added. Furthermore, after stirring the reaction solution at 4 ° C. for 1 hour, the reaction was stopped by adding a phosphate buffer adjusted to pH 7.0, the organic substance was extracted five times with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. It was. After distilling off the low boilers under reduced pressure (10 to 20 mmHg), the self-aldol form (S1) and a small amount of furfuryl alcohol (S2) were removed under reduced pressure (115 to 120 ° C. and 0 to 1 mmHg). The residue was passed through a silica gel pad (SiO ₂ : 7 g) using ethyl acetate as an effluent solvent to give a pale yellow oily diol (4) (1.14 g, 70%, anti: syn = 3.8: 1, 97%). ee) was obtained.

<Reaction 2b: Synthesis of (4R, 5R) -4- (furan-2-yl) -2- (4-methoxyphenyl) -5-methyl-1,3-dioxane (5)>

  P-Anisaldehyde dimethyl was added to a benzene solution (13 mL) containing the diol (4) (1.14 g, anti: syn = 3.8: 1, 7.3 mmol) synthesized in the above reaction 1b at room temperature in an argon atmosphere. Acetal (2.6 g, 14.3 mmol) and pyridinium p-toluenesulfonic acid (PPTS, 150 mg, 0.6 mmol) were added. The reaction solution was heated to 80 ° C. and stirred for 1.5 hours. After cooling the reaction solution to 23 ° C., a saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction. The organic matter was extracted three times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solid obtained by distilling off the low boilers under reduced pressure (10-20 mmHg) was recrystallized from ethyl acetate (2 mL) to give a white needle-like acetal protector (5) (953 mg, 48%,> 99% ee). )

<Reaction 3: Synthesis of (2R, 3R) -3- (furan-2-yl) -3- (4-methoxybenzyloxy) -2-methylpropan-1-ol (6)>

Diisobutylaluminum hydride (DIBAL-H, 268 mL, 0 .2) was added to an ethanol solution (875 mL) containing the protected acetal compound (5) (24 g, 87.5 mmol) synthesized in the above reaction 2a at −78 ° C. in an argon atmosphere. 98M hexane solution, 262 mmol) was added. The reaction solution was heated to −10 ° C. over 128 hours, and a saturated Rochelle salt aqueous solution was added to stop the reaction. The organic matter was extracted three times with ethyl acetate, washed three times with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 10: 1) to give colorless oily alcohol (6) (19.3 g, 80%). Obtained. At the same time, the acetal protector (5) (3.1 g, 13%) was recovered.

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, specific rotation of alcohol (6) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.71 (3H, d, J = 7.0 Hz), 2.25-2.38 (1H, m), 2.87 (1H, br s), 3. 59 (1H, dd, J = 10.7, 7.0 Hz), 3.64-3.72 (1H, m), 3.80 (3H, s), 4.21 (1H, d, J = 11 .5 Hz), 4.22 (1 H, d, J = 9.0 Hz), 4.45 (1 H, d, J = 11.5 Hz), 6.32 (1 H, br d, J = 3.1 Hz), 6.38 (1H, dd, J = 3.1, 1.3 Hz), 6.87 (2H, br d, J = 8.6 Hz), 7.21 (2H, br d, J = 8.6 Hz) , 7.44 (1H, d, J = 1.3 Hz);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 13.4, 39.4, 55.1, 66.7, 70.0, 78.5, 109.0, 109.9, 113.8 (2C), 129 .4 (2C), 129.6, 142.3, 153.0, 159.2;
IR (neat): ν 3448, 2962, 1612, 1514, 1466, 1302, 1250, 1174, 1151, 1035, 1010, 822, 741 cm ⁻¹ ;
HRMS (ESI): [M + Na] ⁺ calculated [C ₁₆ H ₂₀ NaO ₄ ] ⁺ : 299.1254, found: 299.1259;
[Α] _D ²⁹ +91.5 (c = 0.77, MeOH)

<Reaction 4: Synthesis of (2S, 3R) -3- (furan-2-yl) -3- (4-methoxybenzyloxy) -2-methylpropanal (7)>

To a dichloromethane solution (17 mL) containing alcohol (6) (4.7 g, 17 mmol) synthesized in the above reaction 3 was added triethylamine (11.8 mL, 85 mmol), dimethyl sulfoxide (DMSO, 17 mL, 1.0M), and SO ₃ • pyridine complex (7.8 g, 51 mmol). After stirring the reaction solution at 0 ° C. for 45 minutes, the reaction was stopped by adding a phosphate buffer adjusted to pH 7.0. The organic matter was extracted three times with ethyl acetate, washed three times with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtering these and concentrating under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 10: 1) to give a pale yellow oily aldehyde (7) (4.7 g, quantitative yield). Rate).

The results of ¹ H NMR, ¹³ C NMR and IR of aldehyde (7) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.86 (3H, d, J = 7.1 Hz), 2.91-3.02 (1H, m), 3.78 (3H, s), 4.21 (1H, d, J = 11.5 Hz), 4.45 (1H, d, J = 11.5 Hz), 4.48 (1H, d, J = 9.1 Hz), 6.30-6.41 ( 2H, m), 6.84 (2H, br d, J = 8.5 Hz), 7.16 (2H, br d, J = 8.5 Hz), 7.44 (1H, br s), 9.76. (1H, br d, J = 2.3 Hz);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 10.7, 49.9, 55.2, 70.1, 74.5, 109.8, 110.1, 113.8 (2C), 129.5, 129 .6 (2C), 143.0, 151.7, 159.3, 203.3;
IR (neat): ν 2993, 2851, 1729, 1613, 1514, 1457, 1249, 1063, 819, 739 cm ⁻¹

<Reaction 5: (1R, 2R, 3R, Z) -1- (furan-2-yl) -1- (4-methoxybenzyloxy) -2,4-dimethyl-6- (triisopropylsiloxy) hexa-4 -Synthesis of ene-3-ol (9)>

A THF solution (20 mL) containing compound (8) (1.46 g, 4.13 mmol) (the synthesis method will be described later) was added to t-butyllithium (5.2 mL, 8.27 mmol, 1) at −78 ° C. in an argon atmosphere. .59M pentane solution) was added. After the reaction solution was stirred at −78 ° C. for 1 hour, dimethylzinc (4.13 mL, 4.13 mmol, 1.0 M hexane solution) was added. Further, the reaction solution was stirred at 0 ° C. for 20 minutes and then lowered to −78 ° C. again, and a THF solution (20 mL) of the aldehyde (7) (945 mg, 3.45 mmol) synthesized in the above reaction 4 was added to the reaction solution. ) Was added dropwise. The reaction temperature was gradually raised to −35 ° C. over 3 hours, and the reaction was stopped by adding a phosphate buffer adjusted to pH 7.0. After passing the crude product through a celite pad, the organic matter was extracted three times with ethyl acetate, washed three times with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After these were filtered and concentrated under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 50: 1) to give a pale yellow oily alcohol (9) (1.36 g, 79%). Got.

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, specific rotation of alcohol (9) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.83 (3H, d, J = 7.0 Hz), 1.05 (21 H, s), 1.73 (3H, s), 2.14 (1H, dq , J = 3.2, 7.0 Hz), 2.75 (1H, br d, J = 3.1 Hz), 3.80 (3H, s), 4.10-4.20 (2H, m), 4.24 (1H, d, J = 11.4 Hz), 4.37 (1 H, d, J = 7.0 Hz), 4.48 (1H, d, J = 11.4 Hz), 4.74 (1H , Br s), 5.42 (1H, dt, J = 1.0, 5.6 Hz), 6.32 (1H, d, J = 3.1 Hz), 6.37 (1H, dd, J = 1) .8, 3.1 Hz), 6.86 (2H, d, J = 8.5 Hz), 7.22 (2H, d, J = 8.5 Hz), 7.42 (1H, br d, J = 1) .8Hz ;
¹³ C NMR (100 MHz, CDCl ₃ ): δ 10.7, 12.0 (3C), 18.0 (6C), 20.5, 42.2, 55.2, 59.5, 70.7, 71. 2, 76.7, 108.7, 110.0, 113.8 (2C), 127.0, 129.5 (2C), 130.1, 138.4, 142.2, 153.6, 159. 3;
IR (neat): ν2942, 2866, 1614, 1514, 1458, 1386, 1249, 1173, 1056, 1011, 882, 821, 738, 683, 432 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd ^{_{[C 29 H 46 NaO 5 Si}} ] +: 525.3007, Found: 525.3014;
[Α] _D ²⁹ +55.2 (c = 1.54, MeOH)

<Reaction 6: (1R, 2S, 3R, Z) -1- (furan-2-yl) -1- (4-methoxybenzyloxy) -2,4-dimethyl-3,6-bis (triisopropylsiloxy) Synthesis of Hex-4-ene (10)>

To a dichloromethane solution (99 mL) containing the alcohol (9) (5.0 g, 9.95 mmol) synthesized in the above reaction 5, 2,6-lutidine (1.97 mL, 16.9 mmol) was added at 0 ° C. under an argon atmosphere. And triisopropylsilyl trifluoromethanesulfonate (TIPSOTf, 4.0 mL, 14.9 mmol) was added. The reaction solution was stirred at 0 ° C. for 23 hours, and then a saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction. The organic matter was extracted three times with ethyl acetate, washed three times with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 100: 1) to give pale red oily compound (10) (6.43 g, 99%). Got.

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, specific rotation of the compound (10) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.85 (3H, d, J = 6.8 Hz), 1.05 (42H, s), 1.75 (3H, s), 2.10-2.21 (1H, m), 3.80 (3H, s), 4.16 (1H, br ddd, J = 12.8, 4.4, 1.6 Hz), 4.21 (1H, d, J = 11 .2 Hz), 4.25 (1 H, d, J = 7.6 Hz), 4.28-4.36 (2 H, m), 4.80 (1 H, d, J = 4.4 Hz), 5.30. (1H, br t, J = 6.0 Hz), 6.29 (1H, br d, J = 3.2 Hz), 6.35 (1H, br dd, J = 3.2, 1.6 Hz), 6 .83 (2H, d, J = 8.8 Hz), 7.18 (2H, d, J = 8.4 Hz), 7.39 (1H, br d, J = 1.2 Hz);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 11.1, 12.0 (3C), 12.9 (3C), 18.0 (6C), 18.2 (3C), 18.2 (3C), 19 3, 44.4, 55.2, 59.7, 69.9, 70.9, 75.6, 109.2, 109.9, 113.6 (2C), 127.3, 129.2 ( 2C), 130.7, 138.3, 142.0, 153.9, 159.0;
IR (neat): ν2942, 2866, 2360, 1614, 1514, 1463, 1384, 1249, 1173, 1105, 1060, 1011, 919, 883, 821, 737, 682, 599, 421 cm ⁻¹ ;
HRMS (ESI): [M + Na] ⁺ calculated [C ₃₈ H ₆₆ NaO ₅ Si ₂ ] ⁺ : 681.4341, found: 681.4358;
[Α] _D ³³ +31.1 (c = 1.71, MeOH)

<Reaction 7: (2E, 5R, 6S, 7R, 8Z) -5- (4-methoxybenzyloxy) -6,8-dimethyl-7,10-bis (triisopropylsiloxy) deca-2,8-diene- Synthesis of 1,4-diol (11)>

Presence of Rose Bengal (38.7 mg, 0.038 mmol) in an oxygen atmosphere in a propionitrile solution (EtCN, 15.2 mL) containing compound (10) (500 mg, 0.76 mmol) synthesized in Reaction 6 above Then, after irradiation with a fluorescent lamp (22 W) at −78 ° C. for 8 hours, dimethyl sulfide (3.3 mL, 45.6 mmol) was added under an argon atmosphere. After raising the reaction temperature to −20 ° C. for 15 hours, a propionitrile solution of 1,4-diazabicyclo [2.2.2] octane (DABCO, 85.2 mg, 0.76 mmol) (EtCN, 2 mL) was added. The reaction was stirred at −20 ° C. for 2 hours, quenched with saturated aqueous ammonium chloride and filtered through a celite pad. The organic matter was extracted three times with ethyl acetate, washed three times with a saturated aqueous ammonium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. These were filtered and concentrated under reduced pressure, and then the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 10: 1) to obtain a pale yellow oily unstable aldehyde (S3) (493 mg). It was.

NaBH ₄ (82.5 mg, 2.18 mmol) was added to an ethanol solution (18.3 mL) containing this aldehyde (S3) (493 mg) and cerium chloride heptahydrate at 0 ° C. under an argon atmosphere. The reaction solution was stirred at 0 ° C. for 20 minutes, and then saturated sodium chloride aqueous solution was added to stop the reaction. The organic matter was extracted twice with chloroform and twice with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After these were filtered and concentrated under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 5: 1) to give a pale orange oily diol (11) (417 mg, 81%, two steps). )

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, and specific rotation of diol (11) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.04 (21 H, br s), 1.07 (21 H, br s), 1.18 (3 H, d, J = 6.8 Hz), 1.73 (3 H , S), 2.03-2.20 (1H, m), 2.63 (1H, d, J = 7.2 Hz), 3.25 (1H, t, J = 3.2 Hz), 3.80 (3H, s), 4.04-4.20 (4H, m), 4.33 (1H, dd, J = 12.8, 7.2 Hz), 4.41 (1H, d, J = 1.11. 2 Hz), 4.48 (1 H, d, J = 8.4 Hz), 4.59 (1 H, d, J = 8.4 Hz), 5.36 (1 H, dd, J = 12.0, 6.0 Hz) ), 5.66 (1H, dd, J = 15.6, 7.2 Hz), 5.89 (1H, dt, J = 15.6, 10.4 Hz), 6.86 (2H, d, J = .4Hz), 7.22 (2H, d, J = 8.4Hz) (OH × 1, not detected);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 12.0 (3C), 12.7 (3C), 13.1, 18.0 (7C), 18.2 (3C), 18.3 (3C), 40 6,55.3,59.7,63.0,70.8,72.0,72.6,81.1,113.8 (2C), 128.4,129.4 (2C), 130 .3,130.4,132.7,137.3,159.3;
IR (neat): ν 3419, 2943, 2866, 1614, 1515, 1464, 1384, 1302, 1250, 1173, 1056, 1013, 883, 822, 777, 682, 595 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd _{[C 38 H 70 NaO 6 Si} 2] +: 701.4603, Found: 701.4634;
[Α] _D ³³ -6.5 (c = 0.46, MeOH)

<Reaction 8: (2E, 5R, 6S, 7R, 8Z) -5- (4-methoxybenzyloxy) -6,8-dimethyl-7,10-bistriisopropylsiloxy-1-trityloxy-dec-2,8 -Synthesis of dien-4-ol (12)>

Triethylamine (6.5 mL, 46.4 mmol) and triphenyl chloride were added to a dichloromethane solution (23 mL) containing the diol (11) (7.9 g, 11.6 mmol) synthesized in the above reaction 7 at 23 ° C. under an argon atmosphere. Methyl (TrCl, 6.5 g, 23.2 mmol) was added. After stirring the reaction solution at 23 ° C. for 3 hours, an excess amount of methanol and a phosphate buffer adjusted to pH 7.0 were added to stop the reaction. The organic substance was extracted three times with chloroform, washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 30: 1) to give a pale yellow oily alcohol (12) (9.3 g, 89%). Got.

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, specific rotation of alcohol (12) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ0.99 (21H, s), 1.07 (21H, brs), 1.18 (3H, d, J = 6.8 Hz), 1.72 (3H, s), 2.02-2.13 (1H, m), 2.54 (1H, d, J = 7.8 Hz), 3.29 (1H, dd, J = 4.0, 2.8 Hz), 3.61 (2H, br d, J = 2.4 Hz), 3.76 (3H, s), 4.08-4.16 (2H, m), 4.32 (1H, dd, J = 12. 8, 7.8 Hz), 4.51 (1 H, dd, J = 18.6, 7.8 Hz), 4.53 (1 H, d, J = 7.2 Hz), 4.59 (1 H, d, J = 10.8 Hz), 5.33 (1 H, br t, J = 6.4 Hz), 5.84 (1 H, d, J = 3.2 Hz), 5.86 (1 H, d, J = 4.0 Hz) ) 6.80 (2H, d, J = 8.4Hz), 7.20-7.31 (11H, m), 7.45 (6H, d, J = 7.2Hz);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 12.0 (3C), 12.8 (3C), 13.1, 18.0 (7C), 18.2 (3C), 18.3 (3C), 41 0.0, 55.2, 59.6, 64.2, 70.9, 72.0, 73.0, 81.4, 86.8, 113.8 (2C), 126.9 (3C), 127 7 (7C), 128.1, 128.6 (6C), 129.3 (2C), 130.3, 133.0, 137.6, 144.2 (3C), 159.3;
IR (neat): ν2943, 2866, 1614, 1514, 1458, 1386, 1249, 1173, 1056, 882, 822, 764, 704, 681 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd _{[C 57 H 84 NaO 6 Si} 2] +: 943.5699, Found: 943.5663;
[Α] _D ³⁴ +3.9 (c = 0.92, MeOH)

<Reaction 9: (2E, 5R, 6S, 7R, 8Z) -formic acid 2- (4-methoxybenzyloxy) -3,5-dimethyl-4,7-bistriisopropylsiloxy-1- (3-trityloxypropenyl) -Synthesis of hepta-5-enyl ester (14)>

To a dichloromethane solution (8.0 mL) containing alcohol (12) (3.7 g, 4.02 mmol) and 4-dimethylaminopyridine (DMAP, 147 mg, 1.21 mmol) synthesized in the above reaction 8, was added under an argon atmosphere. N-formylbenzotriazole (13) (1.7 g, 9.25 mmol, purity 80%) was added at 23 ° C. After the reaction solution was stirred at 23 ° C. for 4 hours, a phosphate buffer adjusted to pH 7.0 was added to stop the reaction. The organic substance was extracted three times with chloroform, washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtering these and concentrating under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 30: 1) to give the pale yellow oily aldehyde (14) (3.8 g, quantitative yield). Rate).

  Note that N-formylbenzotriazole (13) is obtained from Katrisky, A. et al. R. Chang, H .; X. Yang, B .; Synthesis; Synthesis with reference to 1995, 503.

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, specific rotation of aldehyde (14) are shown below.
¹ H NMR (600 MHz, CDCl ₃ ): δ0.99 (21H, s), 1.06 (21H, brs), 1.12 (3H, d, J = 7.2 Hz), 1.71 (3H, s), 2.04 (1H, dq, J = 12.1, 5.1 Hz), 3.41 (1H, t, J = 4.8 Hz), 3.60 (2H, br d, J = 4. 2 Hz), 3.75 (3 H, s), 4.18 (1 H, br dd, J = 12.8, 4.1 Hz), 4.37 (1 H, dd, J = 12.8, 7.9 Hz) , 4.59 (2H, s), 4.62 (1H, d, J = 7.2 Hz), 5.35 (1H, br t, J = 6.4 Hz), 5.55 (1H, br t, J = 5.1 Hz), 5.84 (1H, dt, J = 15.5, 8.3 Hz), 5.91 (1H, dd, J = 15.7, 6.4 Hz), 6.7 (2H, d, J = 9.0Hz), 7.21-7.32 (11H, m), 7.43 (6H, d, J = 7.8Hz), 8.11 (1H, s);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 12.0 (3C), 12.8 (3C), 13.6, 18.0 (7C), 18.2 (3C), 18.2 (3C), 40 1, 55.1, 59.8, 63.8, 71.3, 73.3, 73.7, 81.5, 86.9, 113.7 (2C), 126.2, 127.0 ( 3C), 127.8 (6C), 128.5, 128.6 (6C), 129.3 (2C), 130.4, 131.7, 137.4, 144.0 (3C), 159.2. 160.3;
IR (neat): ν2943, 2866, 2724, 1727, 1613, 1587, 1514, 1491, 1463, 1449, 1383, 1248, 1173, 1057, 1013, 883, 822, 763, 745, 704, 682, 633, 595 , 462 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd _{[C 58 H 84 NaO 7 Si} 2] +: 971.5648, Found: 971.5658;
[Α] _D ³³ -5.4 (c = 1.51, MeOH)

<Reaction 10: (2E, 4R, 5S, 6S, 8E) -6- (4-methoxybenzyloxy) -3,5-dimethyl-1,4-bis (triisopropylsiloxy) -10-trityloxy-deca- Synthesis of 2,8-diene (15)>

Degassed 1,4 containing aldehyde (14) synthesized in reaction 9 (940 mg, 0.99 mmol), ammonium formate (125 mg, 1.98 mmol), and tributylphosphine (0.39 mL, 1.58 mmol) - dioxane solution (9.9 mL), under argon, _Pd 2 at _{23 ℃ (dba) 3 · CHCl} 3 (205mg, 0.20mmol) was added. After the reaction solution was stirred at 23 ° C. for 67 hours, a phosphate buffer adjusted to pH 7.0 was added to stop the reaction. The organic matter was extracted three times with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 40: 1) to obtain compound (15) (683 mg, 76%) as a pale yellow oil. It was.

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS and specific rotation of the compound (15) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ0.95-1.10 (45H, m), 1.71 (3H, s), 1.95 (1H, br dd, J = 14.6, 6.2 Hz) ), 2.02-2.15 (1H, m), 2.24 (1H, br dt, J = 15.2, 7.4 Hz), 3.20 (1H, br ddd, J = 10.0, 6.5, 2.3 Hz), 3.49 (2H, br dd, J = 7.8, 5.2 Hz), 3.70 (3H, s), 4.06 (1H, br dd, J = 12) .6, 3.2 Hz), 4.21-4.51 (4H, m), 5.32 (1H, br dd, J = 6.6, 5.2 Hz), 5.61 (1H, dt, J = 10.6, 6.5 Hz), 5.70 (1H, dt, J = 12.6, 6.5 Hz), 6.74 (2H, d, J = 8.6 Hz), 7.17. 7.29 (11H, m), 7.41-7.46 (6H, m);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 11.1, 11.9 (3C), 12.7 (3C), 18.0 (7C), 18.2 (3C), 18.3 (3C), 33 2,40.3,55.2,59.6,64.9,70.8,72.1,78.9,86.7,113.7 (2C), 126.9 (3C), 127 7 (6C), 128.0, 128.4, 128.7 (6C), 129.2, 129.7 (2C), 130.9, 137.1, 144.3 (3C), 159.0 ;
IR (neat): ν2943, 2866, 1613, 1514, 1464, 1383, 1247, 1058, 882, 772, 705, 682, 594, 460 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd _{[C 57 H 84 NaO 5 Si} 2] +: 927.5749, Found: 927.5761;
[Α] _D ³³ +1.9 (c = 1.03, MeOH)

<Reaction 11: (2E, 5S, 6S, 7R, 8Z) -6,8-dimethyl-7,10-bis (triisopropylsiloxy) -1- (trityloxy) dec-2,8-dien-5-ol Synthesis of (16)>

To a solution of dichloromethane (4.1 mL) containing Compound (15) (450 mg, 0.50 mmol) synthesized in the above Reaction 10 and phosphate buffer (0.8 mL) adjusted to pH 7.0, under an argon atmosphere, 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 136 mg, 0.60 mmol) was added at 0 ° C. The reaction solution was stirred at 0 ° C. for 4 hours, quenched with saturated aqueous sodium thiosulfate solution, and filtered through a celite pad. The organic matter was extracted three times with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 50: 1) to obtain a pale yellow oily alcohol (16) (375 mg, 96%). It was.

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, specific rotation of alcohol (16) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.76 (3H, d, J = 6.8 Hz), 0.96-1.10 (42H, m), 1.86 (3H, s), 1.91 (1H, br dd, J = 13.6, 7.2 Hz), 2.00-2.13 (1H, m), 2.30 (1H, br d, J = 14.4 Hz), 3.46 ( 1H, s), 3.55 (2H, d, J = 5.2 Hz), 3.61 (1H, br t, J = 6.8 Hz), 4.11 (1H, br dd, J = 12.4) , 3.6 Hz), 4.28 (1H, dd, J = 12.4, 7.6 Hz), 4.69 (1H, d, J = 4.8 Hz), 5.45 (1H, br t, J = 6.4 Hz), 5.65 (1 H, dt, J = 15.2, 5.2 Hz), 5.72-5.85 (1 H, m), 7.16-7.29 (10 H m), 7.42 (5H, d, J = 7.6Hz);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 12.0 (3C), 12.4 (3C), 13.0, 18.0 (6C), 18.1 (6C), 19.9, 38.0, 44.2, 59.6, 65.0, 73.1, 74.9, 86.7, 126.8 (3C), 127.7 (6C), 128.4, 128.7 (6C), 128 .7, 129.5, 136.8, 144.3 (3C);
IR (neat): ν 3480, 2943, 2866, 1490, 1464, 1383, 1104, 1055, 1013, 882, 763, 745, 705, 682 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calculated values _{[C 49 H 76 NaO 4 Si} 2] +: 807.5174, Found: 807.5197;
[Α] _D ²⁴ -7.3 (c = 0.69, CHCl ₃ )

<Reaction 12: (2E, 5S, 6S, 7R, 8Z) -6,8-dimethyl-7,10-bis (triisopropylsiloxy) -1- (trityloxy) dec-2,8-dien-5-yl Synthesis of 1-azidocyclopropanecarboxylate (18)>

To a benzene solution (20 mL) containing carboxylic acid (17) (2.48 g, 19.5 mmol) and N, N-dimethylformamide (DMF, 0.15 mL, 1.95 mmol) at 0 ° C. under an argon atmosphere. (1.33 mL, 15.6 mmol) was added and stirred at 23 ° C. for 1 hour. On the other hand, to a dichloromethane solution (20 mL) containing alcohol (16) (5.1 g, 6.5 mmol) and triethylamine (5.44 mL, 39 mmol) synthesized in the above reaction 11, 4-dimethylaminopyridine (DMAP, 236 mg, 1.95 mmol) was added. The solution of carboxylic acid (17) was transferred into a solution of alcohol (16) at 0 ° C, and the reaction solution was stirred at 0 ° C for 20 minutes, and then the reaction was stopped by adding a phosphate buffer adjusted to pH 7.0. I let you. The organic matter was extracted three times with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After these were filtered and concentrated under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 80: 1) to obtain a colorless oily azide (18) (5.67 g, 98%). Obtained.

  Carboxylic acid (17) can be obtained from Pirrun, M .; C. McGeehan, G .; M.M. J .; Org. Chem. 1983, 48, p. Synthesized with reference to 5143.

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, specific rotation of azide (18) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ1.00-1.09 (45H, m), 1.23-1.45 (4H, m), 1.84 (3H, s), 2.03-2 .16 (2H, m), 2.31-2.39 (1H, m), 3.50 (2H, br t, J = 4.2 Hz), 4.13 (1H, dd, J = 12.0) , 4.8 Hz), 4.35 (2H, dd, J = 14.4, 7.8 Hz), 4.80 (1 H, br ddd, J = 10.2, 4.2, 2.4 Hz), 5 .42 (1H, br t, J = 6.0 Hz), 5.57 (1H, br dt, J = 14.1, 6.0 Hz), 5.62 (1H, dt, J = 15.6, 4 .8 Hz), 7.23 (3H, t, J = 7.8 Hz), 7.29 (6H, t, J = 7.2 Hz), 7.42 (6H, d, J = 7.2 Hz);
¹³ C NMR (100 MHz, CDCl ₃ ): δ11.2, 12.0 (3C), 12.7 (3C), 16.5, 16.6, 18.0 (6C), 18.1 (3C), 18.2 (3C), 32.4, 41.2, 42.7, 59.4, 64.5, 72.1, 75.7, 86.8, 126.9 (3C), 127.4 127.7 (6C), 128.2, 128.6 (7C), 130.1, 137.2, 144.2 (3C), 170.6;
IR (neat): ν2943, 2866, 2360, 2104, 1732, 1464, 1383, 1317, 1288, 1208, 1155, 1058, 882, 771, 745, 704, 681 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd _{[C 53 H 79 N 3 NaO} 5 Si 2] +: 916.5450, Found: 916.5489;
[Α] _D ¹⁸ +0.8 (c = 1.0, CHCl ₃ )

<Reaction 13: (2E, 5S, 6S, 7R, 8Z) -10-hydroxy-6,8-dimethyl-7- (triisopropylsiloxy) -1- (trityloxy) deca-2,8-diene-5 Synthesis of yl-1-azidocyclopropanecarboxylate (19)>

To a THF solution containing the azide (18) synthesized in the above reaction 12 (5.47 g, 6.12 mmol), 65% HF · pyridine (6.9 mL, 245 mmol) was added at 0 ° C. under an argon atmosphere. The reaction solution was stirred at 23 ° C. for 17 hours, and then saturated sodium bicarbonate aqueous solution was added at 0 ° C. to stop the reaction. The organic matter was extracted three times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtering these and concentrating under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 30: 1) to give colorless oily alcohol (19) (3.77 g, 84%). Obtained.

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, specific rotation of alcohol (19) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ0.99 (21H, d, J = 3.6 Hz), 1.03 (3H, d, J = 6.4 Hz), 1.27-1.37 (4H, m), 1.78 (3H, s), 2.02-2.17 (2H, m), 2.23-2.34 (1H, m), 3.46 (2H, s), 3.99 -4.18 (3H, m), 4.33 (1H, d, J = 8.4 Hz), 4.73-4.82 (1H, m), 5.39 (1H, t, J = 6. 8 Hz), 5.56 (2H, s), 7.10-7.23 (10 H, m), 7.35 (5 H, d, J = 7.6 Hz);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 11.4, 12.6 (3C), 16.6, 16.7, 18.1 (6C), 32.9, 41.6, 42.7, 58. 6, 64.4, 72.4, 76.0, 86.8, 126.9 (4C), 127.0, 127.7 (6C), 128.5 (7C), 130.3, 139.8. , 144.1 (3C), 171.0;
IR (neat): ν 3446, 2944, 2866, 2106, 1729, 1448, 1384, 1318, 1287, 1209, 1158, 1058, 883, 746, 706, 681, 633, 420 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd _{[C 44 H 59 N 3 NaO} 5 Si] +: 760.4116, Found: 760.4085;
[Α] _D ²³ -12.4 (c = 1.08, CHCl ₃ )

<Reaction 14: (2E, 5S, 6S, 7R, 8Z) -11- (2-hydroxy-5-methoxy-3-nitrophenyl) -6,8-dimethyl-11- (phenylsulfonyl) -7- (tri Synthesis of Isopropylsiloxy) -1- (trityloxy) undeca-2,8-dien-5-yl-1-azidocyclopropanecarboxylate (21)>

The benzene solution (7.0 mL) containing alcohol (19) (328 mg, 0.44 mmol), imidazole (181 mg, 2.66 mmol) and iodine synthesized in the above reaction 13 was added at 23 ° C. for 30 minutes under an argon atmosphere. Then, a benzene solution (2.0 mL) containing triphenylphosphine (466 mg, 1.78 mmol) was added dropwise. Then, saturated sodium thiosulfate aqueous solution was added to the reaction liquid, and reaction was stopped. The organic matter was extracted three times with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 20: 1), and pale yellow oil iodide (S4) (378 mg, quantitative yield). )

On the other hand, lithium bis (trimethylsilyl) amide (LHMDS, 4.7 mL, 1.0 M) was added to a THF solution of the aromatic segment (20) (718 mg, 2.22 mmol) (the synthesis method will be described later) under an argon atmosphere at −90 ° C. (THF solution, 4.66 mmol) was added and the reaction was stirred at −90 ° C. for 40 min. The reaction was transferred at −90 ° C. into a THF solution (10 mL) containing iodide (S4) (378 mg, 0.44 mmol) and the temperature was raised to −65 ° C. for 2 hours. After the reaction solution was further stirred at -65 ° C. for 18 hours, the reaction was stopped by adding a cooled phosphate buffer adjusted to pH 7.0. The organic matter was extracted three times with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 20: 1) to give azide (21) (361 mg, 78%) as a yellow amorphous powder. , 2 steps).

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, specific rotation of azide (21) are shown below.
¹ H NMR (400 MHz, CDCl ₃ , as a mixture of diastereomers): δ 0.86-1.07 (24H, m), 1.15-1.33 (4H, m), 1.62 (3H, s) 1.89-2.10 (2H, m), 2.23-2.37 (1 H, m), 2.55 (1 H, br t, J = 13.2 Hz), 3.24 (1 H, br) t, J = 11.2 Hz), 3.42-3.54 (2H, m), 3.59 (3H, s), 4.32 (1H, br d, J = 7.6 Hz), 4.60. -4.82 (3H, m), 5.46-5.65 (2H, m), 7.09-7.59 (22H, m), 10.29 (1H, br s);
¹³ C NMR (100 MHz, CDCl ₃ , as a mixture of diastereomers): δ11.2, 11.3, 12.7, 16.6, 16.4, 18.1, 18.1, 18.2, 18. 2, 25.9, 26.6, 32.6, 32.9, 41.5, 42.7, 55.9, 56.0, 64.5, 64.8, 72.1, 75.1, 76.0, 86.8, 86.9, 106.9, 107.3, 124.2, 124.6, 126.4, 126.9, 127.0, 127.4, 127.8, 128. 6, 128.7, 128.9, 130.5, 130.7, 133.1, 133.8, 133.9, 137.5, 137.7, 141.1, 144.2, 144.2 148.5, 148.6, 152.1, 170.7;
IR (neat): ν 3022, 2944, 2866, 2166, 1729, 1596, 1542, 1466, 1448, 1430, 1383, 1320, 1254, 1215, 1150, 1085, 1056, 883, 760, 706, 687, 602, 555 , 518, 443 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd _{[C 58 H 70 N 4 NaO} 10 SSi] +: 1065.4474, found: 1065.4425;
[Α] _D ²³ +11.2 (c = 2.93, CHCl ₃ )

<Reaction 15: (2E, 5S, 6S, 7R, 8Z) -11- [2- (tert-butoxycarbonyloxy) -5-methoxy-3-nitrophenyl] -6,8-dimethyl-11- (phenylsulfonyl) ) -7- (Triisopropylsiloxy) -1- (trityloxy) undeca-2,8-dien-5-yl-1-azidocyclopropanecarboxylate (22)>

To a dichloromethane solution (63 mL) containing azide (21) (956 mg, 0.92 mmol) synthesized in the above reaction 14 and 4-dimethylaminopyridine (DMAP, 224 mg, 1.83 mmol) at 0 ° C. under an argon atmosphere ( Boc) ₂ O (0.66 mL, 2.75 mmol) was added. After stirring the reaction solution at 23 ° C. for 30 minutes, the reaction was stopped by adding a cooled phosphate buffer adjusted to pH 7.0. The organic matter was extracted three times with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 5: 1) to give azide (22) (1.01 g, 1.01 g, 96%).

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, specific rotation of azide (22) are shown below.
¹ H NMR (400 MHz, CDCl ₃ , as a mixture of diastereomers): δ 0.95-1.11 (24H, m), 1.35 to 1.46 (4H, m), 1.49 (6H, s) , 1.53 (3H, s), 1.69 (3H, s), 1.99-2.23 (2H, m), 2.31-2.47 (1H, m), 2.62 (1H , Br t, J = 14.0 Hz), 3.25-3.38 (1 H, m), 3.57 (2 H, t, J = 4.8 Hz), 3.65 (3 H, s), 4. 40 (1H, brd, J = 7.6 Hz), 4.59 (1H, brd, J = 12.0 Hz), 4.74-4.83 (2H, m), 5.57-5.77 (2H, m), 7.20-7.35 (9H, m), 7.39-7.49 (8H, m), 7.49-7.60 (3H, m), 7.64 (2 , D, J = 7.6Hz);
¹³ C NMR (100 MHz, CDCl ₃ , as a mixture of diastereomers): δ 11.0, 11.3, 12.7, 14.1, 14.2, 16.6, 16.6, 18.1, 18. 1, 18.2, 18.2, 20.7, 21.0, 22.6, 25.2, 26.9, 27.5, 31.5, 32.9, 33.0, 34.5, 34.6, 41.7, 41.8, 42.7, 42.8, 56.0, 56.1, 60.3, 61.7, 62.2, 64.5, 64.7, 72. 2, 75.5, 75.7, 85.2, 85.6, 86.8, 86.9, 110.6, 111.2, 119.6, 120.1, 120.5, 126.9, 126.9, 127.8, 128.6, 128.7, 128.9, 129.1, 129.6, 130.5, 130.8, 131.9 134.0,137.2,137.3,141.2,142.3,144.2,149.6,156.6,170.6,170.6;
IR (neat): ν 2944, 2867, 1771, 1727, 1621, 1584, 1543, 1448, 1315, 1211, 1146, 1058, 1003, 910, 882, 820 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd _{[C 63 H 78 N 4 NaO} 12 SSi] +: 1165.4998, found: 1165.5044;
[Α] _D ²⁹ +15.5 (c = 0.84, CHCl ₃ )

<Reaction 16: (2E, 5S, 6S, 7R, 8Z) -11- [2- (tert-butoxycarbonyloxy) -5-methoxy-3-nitrophenyl] -6,8-dimethyl-11- (phenylsulfonyl) ) -7- (Triisopropylsiloxy) -1- (trityloxy) undeca-2,8-dien-5-yl-1-aminocyclopropanecarboxylate (23)>

To a methanol solution (79 mL) containing the azide (22) (1.08 g, 0.95 mmol) and triethylamine (6.6 mL, 47.3 mmol) synthesized in the above reaction 15 was added 1,3 at 23 ° C. under an argon atmosphere. -Propanedithiol (4.7 mL, 47.3 mmol) was added. The reaction solution was stirred at 23 ° C. for 18 hours and then dried under vacuum to remove the solvent and the like, and a phosphate buffer adjusted to pH 7.0 was added to the crude product. The organic substance was extracted three times with chloroform, washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 2: 1) to give a yellow amorphous powdery amine (23) (918 mg, 87%). )

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, specific rotation of amine (23) are shown below.
¹ H NMR (400 MHz, CDCl ₃ , as a mixture of diastereomers): δ 0.97 (3H, d, J = 6.4 Hz), 1.06 (21 H, d, J = 5.6 Hz), 1.23- 1.32 (3H, m), 1.45 (1H, s), 1.49 (6H, s), 1.70 (3H, s), 1.82-2.18 (6H, m), 2 .25-2.38 (1H, m), 2.61 (1H, br t, J = 13.6 Hz), 3.25-3.38 (1H, m), 3.57 (2H, br t, J = 6.4 Hz), 3.65 (3H, s), 4.33-4.46 (1H, m), 4.53-4.63 (1H, m), 4.64-4.71 ( 1H, m), 4.78 (1H, brd, J = 8.8 Hz), 4.83-4.88 (1H, m), 5.52-5.73 (2H, m), 7.20 7.34 (9H, m), 7.39-7.49 (8H, m), 7.51-7.59 (3H, m), 7.63 (2H, d, J = 7.6Hz);
¹³ C NMR (100 MHz, CDCl ₃ , as a mixture of diastereomers): δ 11.2, 12.7, 18.0, 18.2, 18.2, 20.7, 25.2, 27.5, 32. 8, 34.6, 35.8, 41.6, 55.9, 61.6, 64.5, 74.4, 85.2, 86.8, 111.0, 120.2, 126.9, 127.3, 127.8, 128.6, 128.6, 128.7, 128.9, 129.0, 130.0, 134.0, 137.2, 142.2, 144.1, 144. 2, 149.6, 156.5, 175.8;
IR (neat): ν3884, 3022, 2944, 2867, 1771, 1717, 1585, 1543, 1448, 1312, 1287, 1214, 1146, 1056, 1003, 882, 753, 705, 599, 525 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd _{[C 63 H 80 N 2 NaO} 12 SSi] +: 1139.5093, found: 1139.5050;
[Α] _D ²⁴ +9.2 (c = 1.18, CHCl ₃ )

<Reaction 17: (2E, 5S, 6S, 7R, 8Z) -11- [2- (tert-butoxycarbonyloxy) -5-methoxy-3-nitrophenyl] -6,8-dimethyl-11- (phenylsulfonyl) Synthesis of) -7- (triisopropylsiloxy) -1- (trityloxy) undeca-2,8-dien-5-yl-1- (cyclohex-1-enecarboxamide) cyclopropanecarboxylate (24)>

To a dichloromethane solution (17 mL) containing amine (23) (918 mg, 0.82 mmol) and 4-dimethylaminopyridine (DMAP, 802 mg, 6.57 mmol) synthesized in the above reaction 16, was added 1 at 23 ° C. under an argon atmosphere. -A dichloromethane solution (10 mL) containing cyclohexenecarboxylic acid (311 mg, 2.46 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI.HCl, 630 mg, 3.28 mmol) were added. The reaction solution was stirred at 23 ° C. for 21 hours, and then saturated sodium hydrogen carbonate aqueous solution was added to stop the reaction. The organic substance was extracted three times with chloroform, washed three times with a saturated aqueous sodium bicarbonate solution and twice with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 3: 1) to give amide (24) (780 mg, 78%) as a yellow amorphous powder. )

The results of ¹ H NMR, ¹³ C NMR, IR, MS and specific rotation of amide (24) are shown below.
¹ H NMR (400 MHz, CDCl ₃ , as a mixture of diastereomers): δ 0.94-1.09 (24H, m), 1.23-1.35 (3H, m), 1.42-1.77 ( 16H, m), 1.82-1.93 (1H, m), 1.95-2.09 (4H, m), 2.10-2.40 (6H, m), 2.62 (1H, br t, J = 13.6 Hz), 3.41 (1H, br t, J = 12.0 Hz), 3.50-3.66 (1H, m), 3.70 (3H, s), 4. 32 (1H, br d, J = 10.4 Hz), 4.51 (1 H, br d, J = 5.2 Hz), 4.65-4.85 (2H, m), 5.52-5.79. (2H, m), 6.52 (2H, br s), 6.95 (1H, br s), 7.18-7.34 (7H, m), 7.35-7.6 (12H, m);
¹³ C NMR (100 MHz, CDCl ₃ , as a mixture of diastereomers): δ 10.9, 12.8, 14.1, 17.4, 18.1, 18.2, 18.2, 20.7, 21. 1, 21.5, 21.8, 22.0, 22.6, 24.0, 24.1, 25.3, 26.1, 31.6, 33.2, 33.8, 34.5, 34.7, 56.0, 62.3, 65.0, 75.1, 86.8, 111.0, 120.4, 126.9, 127.6, 127.8, 128.7, 128. 9, 130.0, 133.2, 133.6, 134.1, 137.3, 142.3, 143.9, 144.3, 156.6, 169.3, 172.0;
IR (neat): ν 3398, 2941, 2866, 1734, 1669, 1639, 1541, 1491, 1446, 1311, 1190, 1056, 1009, 924, 883, 754, 705, 601 cm ⁻¹ ;
_{MS (ESI): 1147.65 (C} 65 H 80 N 2 NaO 11 SSi: Boc group is deprotected);
[Α] _D ²³ +4.8 (c = 1.45, CHCl ₃ )

<Reaction 18: (2E, 5S, 6S, 7R, 8Z) -11- (2-hydroxy-5-methoxy-3-nitrophenyl) -6,8-dimethyl-7- (triisopropylsiloxy) -1- ( Synthesis of Trityloxy) Undeca-2,8-dien-5-yl-1- (cyclohex-1-enecarboxamido) cyclopropanecarboxylate (25)>

Pyrrolidine (9.4 mL, 112.6 mmol) was added to a dichloromethane solution (32 mL) containing the amide (24) (780 mg, 0.64 mmol) synthesized in the above reaction 17 at 23 ° C. under an argon atmosphere. The reaction solution was stirred at 23 ° C. for 5 hours, and then saturated ammonium chloride aqueous solution was added to stop the reaction. The organic matter was extracted three times with chloroform, washed three times with a saturated aqueous ammonium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtering these and concentrating under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 2: 1) to give compound (S5) (698 mg, 97%) as a yellow amorphous powder. )

NaBH ₄ (192 mg, 5.06 mmol) was added to an ethanol solution (9.4 mL) containing this compound (S5) (143 mg, 0.13 mmol) at 0 ° C. under an argon atmosphere. After the reaction solution was stirred at 50 ° C. for 21 hours, a saturated aqueous ammonium chloride solution was added to stop the reaction. The organic matter was extracted three times with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtering these and concentrating under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 10: 1) to give compound (25) (125 mg, 57%) as a yellow amorphous powder. , 2 steps).

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS and specific rotation of the compound (25) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.96-1.11 (24H, m), 1.11-1.19 (2H, m), 1.49-1.68 (7H, m), 1 .81 (3H, s), 2.06-2.19 (5H, m), 2.19-2.34 (2H, m), 2.36-2.50 (1H, m), 2.63 -2.82 (2H, m), 3.52 (2H, d, J = 4.0 Hz), 3.75 (3H, s), 4.36 (1H, d, J = 9.2 Hz), 4 .70-4.80 (1H, m), 5.25 (1H, br t, J = 6.4 Hz), 5.50-5.63 (2H, m), 6.10 (1H, s), 6.52 (1H, br s), 7.05 (1H, d, J = 3.2 Hz), 7.18-7.32 (10H, m), 7.35 (1H, d, J = 3. 2Hz), 7.37- .45 (6H, m);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 11.1, 12.6 (3C), 14.2, 17.2 (2C), 18.1 (3C), 18.2 (3C), 21.5, 22.0, 24.1, 25.3, 27.7, 30.6, 32.4, 33.9, 40.9, 55.8, 64.7, 72.1, 74.7, 86. 8, 103.4, 126.1, 126.9 (3C), 127.4 (6C), 127.7, 128.3, 128.6 (6C), 129.6, 133.0, 133.2. , 133.7, 134.0, 137.7, 144.2 (3C), 148.8, 151.8, 169.2, 171.7;
IR (neat): ν 3422, 3338, 2941, 2865, 1727, 1668, 1634, 1539, 1493, 1466, 1430, 1374, 1327, 1255, 1174, 1055, 999, 883, 758, 705 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd _{[C 59 H 76 N 2 NaO} 9 Si] +: 1007.5212, found: 1007.5195;
[Α] _D ²³ -3.9 (c = 1.33, CHCl ₃ )

<Reaction 19: (2E, 5S, 6S, 7R, 8Z) -11- [2- (allyloxycarbonyloxy) -5-methoxy-3-nitrophenyl] -1-hydroxy-6,8-dimethyl-7- Synthesis of (Triisopropylsiloxy) undeca-2,8-dien-5-yl-1- (cyclohex-1-enecarboxamide) cyclopropanecarboxylate (26)>

  To a dichloromethane solution (1.8 mL) containing the compound (25) (36 mg, 0.037 mmol) synthesized in the above reaction 18 and triethylamine (127 μL, 0.91 mmol) at 0 ° C. in an argon atmosphere, allyl chloride formate ( AllocCl, 50.3 μL, 0.48 mmol) was added. The reaction solution was stirred at 23 ° C. for 40 minutes, and then the phosphate buffer adjusted to pH 7.0 was added to stop the reaction. The organic matter was extracted three times with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. These were filtered and concentrated under reduced pressure to obtain a crude product (S6) (41.3 mg) as a pale yellow amorphous powder.

To a methanol solution (3.7 mL) containing this crude product (S6) (41.3 mg), p-toluenesulfonate (TsOH · H ₂ O, 5.6 mg, 0.029 mmol) was added at 23 ° C. under an argon atmosphere. ) Was added. After the reaction solution was stirred at 23 ° C. for 1 hour, a phosphate buffer adjusted to pH 7.0 was added to stop the reaction. The organic substance was extracted three times with chloroform, washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtering these and concentrating under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 1: 4) to obtain a pale yellow amorphous powdery alcohol (26) (28.3 mg). 94%, 2 steps).

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, specific rotation of alcohol (26) are shown below.
_{^{1 H NMR (400MHz, CDCl 3}} ): δ0.94-1.15 (25H, m), 1.42-1.52 (1H, m), 1.52-1.70 (5H, m), 1 .76 (4H, s), 1.99 (2H, br d, J = 11.6 Hz), 2.07-2.29 (6H, m), 2.29-2.44 (1H, m), 2.55-2.73 (2H, m), 3.61 (1H, brs), 3.85 (3H, s), 4.01 (2H, brd, J = 5.2 Hz), 4. 33 (1H, d, J = 8.4 Hz), 4.76 (2H, d, J = 7.6 Hz), 4.84 (1H, br d, J = 11.2 Hz), 5.21 (1H, br t, J = 6.4 Hz), 5.34 (1H, d, J = 10.4 Hz), 5.37-5.47 (2H, m), 5.61 (1H, dt, J = 14. 8 5.6 Hz), 5.93-6.06 (1 H, m), 6.23 (1 H, s), 6.62 (1 H, br s), 7.00 (1 H, br d, J = 2. 8 Hz), 7.46 (1H, br d, J = 3.2 Hz);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 11.3, 12.7 (3C), 17.0 (2C), 17.5, 18.1 (3C), 18.2 (3C), 21.4, 22.0, 24.1, 25.4, 28.2, 30.3, 32.6, 33.7, 41.6, 56.0, 63.3, 70.0, 72.2, 74. 3, 108.1, 119.7, 121.8, 125.6, 126.8, 130.8, 132.9, 133.6, 134.6, 136.2, 138.1, 138.3 142.1, 152.6, 157.0, 169.7, 171.5;
IR (neat): ν 3332, 2942, 2866, 1771, 1726, 1664, 1630, 1540, 1462, 1349, 1288, 1231, 1203, 1083, 1058, 995, 941, 883, 757, 681, 600, 445 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd _{[C 44 H 66 N 2 NaO} 11 Si] +: 849.4328, Found: 849.4337;
[Α] _D ²⁰ +120.8 (c = 0.31, CHCl ₃ )

<Reaction 20: (3E, 6S, 7S, 8R, 9Z) -12- [2- (allyloxycarbonyloxy) -5-methoxy-3-nitrophenyl] -7,9-dimethyl-8- (triisopropylsiloxy) ) Synthesis of Dodeca-1,3,9-trien-6-yl-1- (cyclohexenylmethylamino) cyclopropanecarboxylate (27)>

An excess amount of MnO ₂ was added to a dichloromethane solution (5 mL) containing the alcohol (26) (21 mg, 0.0254 mmol) synthesized in the above Reaction 19 at 23 ° C. under an argon atmosphere. The reaction solution was stirred at 23 ° C. for 40 minutes, and MnO ₂ was filtered through a celite pad. The organic matter was concentrated under reduced pressure to obtain a pale yellow amorphous powdery crude product (S7) (19 mg).

On the other hand, tert-butoxy potassium (10 mg, 0.0889 mmol) was added to a THF solution (1.5 mL) containing methyltriphenylphosphonium iodide (46.2 mg, 0.114 mmol) at 0 ° C. in an argon atmosphere. The reaction solution was stirred at 0 ° C. for 30 minutes, and then transferred to a THF solution (0.5 mL) containing the crude product (S7) (19 mg, 0.023 mmol). The reaction solution was further stirred for 30 minutes, and then saturated ammonium chloride aqueous solution was added to stop the reaction. The organic matter was extracted three times with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtering these and concentrating under reduced pressure, the residue was purified by preparative TLC (SiO ₂ , hexane: ethyl acetate = 3: 1) to give diene (27) (15.4 mg) as a pale yellow amorphous powder. 74%, 2 steps).

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS and specific rotation of diene (27) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.97-1.08 (25H, m), 1.45-1.72 (6H, m), 1.79 (3H, brs), 1.98- 2.46 (10H, m), 2.56-2.74 (2H, m), 3.85 (3H, s), 4.33 (1H, d, J = 8.8 Hz), 4.72 ( 1H, br dt, J = 9.6, 2.4 Hz), 4.76 (2H, d, J = 6.0 Hz), 4.97 (1H, d, J = 10.0 Hz), 5.07 ( 1H, d, J = 16.8 Hz), 5.19 (1H, br t, J = 6.8 Hz), 5.35 (1H, d, J = 10.4 Hz), 5.44 (1H, br dd , J = 16.0, 1.2 Hz), 5.51 (1H, dd, J = 14.4, 6.8 Hz), 5.92-6.07 (2H, m), 6.12 (1H , S), 6.17-6.32 (1H, m), 6.58 (1H, br s), 7.01 (1H, d, J = 2.8 Hz), 7.46 (1H, d, J = 3.2 Hz);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 11.0, 12.7 (3C), 17.2, 17.3, 18.1 (3C), 18.2 (3C), 21.5, 22.1 24.2, 25.4, 28.1, 30.3, 32.5, 33.9, 41.1, 56.0, 69.9, 72.2, 74.9, 108.1, 115. .9, 119.7, 121.8, 125.4, 129.9, 130.8, 133.3, 133.6, 133.7, 136.2, 136.7, 138.3, 138.4 , 142.1, 152.6, 157.0, 169.2, 171.8;
IR (neat): ν 3327, 3089, 2941, 2867, 1771, 1726, 1665, 1631, 1540, 1459, 1349, 1203, 1060, 1004, 945, 883, 758, 682 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd _{[C 44 H 66 N 2 NaO} 10 Si] +: 845.4379, Found: 845.4348;
[Α] _D ²⁰ -1.9 (c = 0.87, CHCl ₃ )

<Reaction 21: (3E, 6S, 7R, 8R, 9Z) -12- [2- (allyloxycarbonyloxy) -5-methoxy-3-nitrophenyl] -8-hydroxy-7,9-dimethyl-dodeca- Synthesis of 1,3,9-trien-6-yl-1- (cyclohex-1-enecarboxamide) cyclopropanecarboxylate (28)>

46% HF (0.8 mL, 44 mmol) was added to an acetonitrile solution (8.0 mL) containing the diene (27) (80 mg, 0.0972 mmol) synthesized in the above reaction 20 at 0 ° C. under an argon atmosphere. The reaction solution was stirred at 23 ° C. for 16 hours, and then saturated sodium bicarbonate aqueous solution was added at 0 ° C. to stop the reaction. The organic matter was extracted three times with ethyl acetate and once with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtering these and concentrating under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 1: 1) to obtain a pale yellow amorphous powdery alcohol (28) (43.8 mg). 68%). At the same time, diene (27) (21 mg, 26%) was recovered.

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, specific rotation of alcohol (28) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.92 (3H, d, J = 7.2 Hz), 1.06-1.20 (2H, m), 1.46-1.76 (9H, m) 1.77-1.85 (1H, m), 2.08-2.22 (4H, m), 2.23-2.44 (5H, m), 2.58-2.74 (2H, m), 3.85 (3H, s), 4.33 (1H, br d, J = 4.8 Hz), 4.77 (2H, dt, J = 6.0, 1.2 Hz), 4.82. (1H, dt, J = 7.6, 4.0 Hz), 4.98 (1H, d, J = 10.4 Hz), 5.08 (1H, d, J = 16.8 Hz), 5.20 ( 1H, br t, J = 14.4 Hz), 5.35 (1 H, dd, J = 10.4, 0.8 Hz), 5.44 (1 H, dt, J = 16.8, 1.2 Hz), 5.5 -5.60 (1H, m), 5.94-6.08 (2H, m), 6.16-6.33 (2H, m), 6.55-6.63 (1H, m), 7 .09 (1H, d, J = 3.2 Hz), 7.45 (1H, d, J = 3.2 Hz);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 10.2, 17.4, 17.5, 20.0, 21.5, 22.0, 24.1, 25.4, 27.7, 30.4, 33.8, 34.4, 40.9, 56.1, 70.0 (2C), 75.8, 108.0, 115.9, 119.8, 122.0, 125.1, 129.4 , 130.8, 133.0, 133.8, 134.3, 136.2, 136.7, 138.1, 138.7, 142.0, 152.6, 156.9, 169.5, 172 .5;
IR (neat): ν 3416, 3089, 2935, 1770, 1725, 1664, 1629, 1538, 1448, 1352, 1283, 1203, 1038, 1005, 946, 861, 823, 769, 738, 704 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd _{[C 36 H 46 N 2 NaO} 10] +: 689.3045, Found: 689.3076;
[Α] _D ²⁰ +5.1 (c = 1.0, MeOH)

<Reaction 22: (3E, 6S, 7R, 8R, 9Z) -12- [2- (allyloxycarbonyloxy) -5-methoxy-3-nitrophenyl] -7,9-dimethyl-8- (triethylsiloxy) Synthesis of Dodeca-1,3,9-trien-6-yl-1- (cyclohexenylmethylamino) cyclopropanecarboxylate (29)>

Diisopropylethylamine (44.5 μL, 0.0255 mmol) and triethylsilyl were added to a dichloromethane solution (1.5 mL) containing the alcohol (28) (17 mg, 0.0255 mmol) synthesized in the above reaction 21 at 23 ° C. under an argon atmosphere. Triflate (TESOTf, 29 μL, 0.128 mmol) was added. The reaction solution was stirred at 23 ° C. for 30 minutes, and then the phosphate buffer adjusted to pH 7.0 was added to stop the reaction. The organic matter was extracted three times with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtering these and concentrating under reduced pressure, the residue was purified by preparative TLC (SiO ₂ , hexane: ethyl acetate = 4: 1) to give diene (29) (19.7 mg) as a pale yellow amorphous powder. 99%).

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, specific rotation of diene (29) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.52 (6H, q, J = 7.6 Hz), 0.91 (9H, t, J = 7.6 Hz), 1.13 (2H, d, J = 2.0Hz), 1.46-1.51 (2H, m), 1.55-1.70 (6H, m), 1.75 (3H, s), 1.98-2.08 (1H, m), 2.08-2.32 (8H, m), 2.32-2.46 (1H, m), 2.61-2.71 (2H, m), 3.85 (3H, s) 4.19 (1H, d, J = 8.0 Hz), 4.70 (1H, ddd, J = 9.2, 4.0, 2.8 Hz), 4.76 (2H, d, J = 6) .0 Hz), 4.96 (1 H, d, J = 10.4 Hz), 5.07 (1 H, d, J = 17.2 Hz), 5.18 (1 H, t, J = 6.4 Hz), 5 .34 (1H, dd J = 10.4, 0.8 Hz), 5.44 (1H, dd, J = 17.2, 1.2 Hz), 5.47-5.57 (1H, m), 5.93-6.06 (2H, m), 6.14 (1H, s), 6.25 (1H, dt, J = 17.2, 10.4 Hz), 6.53-6.62 (1H, m), 7.05 (1H, d, J = 2.8 Hz), 7.46 (1H, d, J = 2.8 Hz);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 4.8 (3C), 5.8, 6.8 (3C), 10.7, 17.2, 18.6, 21.5, 22.1, 24. 2, 25.3, 28.0, 30.3, 32.7, 33.9, 40.8, 56.0, 69.9, 71.7, 75.1, 108.1, 115.8, 119.7, 121.8, 125.1, 129.9, 130.8, 133.3, 133.5, 133.7, 136.2, 136.8, 138.4, 138.5, 142. 1,152.6, 156.9, 169.2, 171.8;
IR (neat): ν3671, 3327, 3088, 2937, 1771, 1732, 1667, 1633, 1584, 1537, 1504, 1494, 1455, 1361, 1294, 1203, 1066, 1006, 946, 853, 823, 742, 611 cm ^-1 ;
HRMS (ESI): [M + Na]] + calcd _{[C 42 H 60 N 2 NaO} 10 Si] +: 803.3909, Found: 803.3909;
[Α] _D ²⁰ +3.4 (c = 1.92, MeOH)

<Reaction 23: (3E, 6S, 7R, 8R, 9Z) -12- {2-hydroxy-5-methoxy-3-[(3R, 4E) -3-methoxy-hepta-4,6-dienoylamino] phenyl} Synthesis of -7,9-dimethyl-8- (triethylsiloxy) dodeca-1,3,9-trien-6-yl-1- (cyclohexenylmethylamino) cyclopropanecarboxylate (31)>

To a THF solution (3.8 mL) containing the diene (29) (21.7 mg, 0.0278 mmol) synthesized in the above reaction 22 was added sulfur (31.2 mg, 0.973 mmol) and NaBH at 23 ° C. under an argon atmosphere. ₄ (21 mg, 0.556 mmol) was added. The reaction solution was stirred at 50 ° C. for 2.5 hours, and then saturated sodium hydrogen carbonate aqueous solution was added to stop the reaction. The organic substance was extracted three times with chloroform, washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. These were filtered and concentrated under reduced pressure to obtain a pale yellow amorphous powdery crude product (S8).

  Diisopropylethylamine (248 μL, 1.39 mmol) was added to a toluene solution (3.8 mL) containing the crude product (S8) at 23 ° C. under an argon atmosphere. This reaction solution was added to a THF solution (10 mL) containing C1-C6 segment (30) (26 mg, 0.167 mmol) (the synthesis method will be described later) at 23 ° C., and bis (2-oxo-3-oxazolidinyl) phosphine. Acid chloride (BOPCl, 21.2 mg, 0.0834 mmol) was added. The reaction solution was stirred at 23 ° C. for 8 hours, and a saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction. The organic substance was extracted three times with chloroform, washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. These were filtered and concentrated under reduced pressure to obtain a pale yellow amorphous powdery crude product (S9).

To a methanol solution (4.0 mL) containing the crude product (S9), potassium carbonate (40 mg) was added at 23 ° C. under an argon atmosphere. The reaction solution was stirred at 23 ° C. for 10 minutes, and then a saturated aqueous ammonium chloride solution was added to stop the reaction. The organic substance was extracted three times with chloroform, washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtering these and concentrating under reduced pressure, the residue was purified by preparative TLC (SiO ₂ , hexane: ethyl acetate = 2: 1) to give compound (31) (17.6 mg) as a pale yellow amorphous powder. 79%, 3 steps).

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS and specific rotation of the compound (31) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.53 (6H, t, J = 8.0 Hz), 0.86-0.98 (9H, m), 1.13 (2H, d, J = 3. 2Hz), 1.51-1.70 (9H, m), 1.75 (3H, s), 1.98 (1H, q, J = 6.8 Hz), 2.06-2.31 (8H, m), 2.37-2.50 (1H, m), 2.57-2.77 (3H, m), 3.37 (3H, s), 3.73 (3H, s), 4.06 -4.14 (1H, m), 4.30 (1H, d, J = 7.2 Hz), 4.74 (1H, q, J = 6.0 Hz), 4.95 (1H, d, J = 10.0 Hz), 5.06 (1 H, d, J = 16.4 Hz), 5.15-5.33 (3H, m), 5.49-5.62 (2 H, m), 6.00 ( 1H, dd, J = 15 2,10.4Hz), 6.18-6.41 (4H, m), 6.57 (3H, s), 8.16 (1H, br s), 8.66 (1H, s);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 4.8 (3C), 6.9 (3C), 10.8, 17.2, 17.3, 18.8, 21.5, 22.1, 24. 2, 25.3, 28.2, 29.7, 31.6, 33.0, 33.9, 41.2, 42.9, 55.7, 56.5, 71.3, 75.5. 78.6, 105.5, 113.2, 115.4, 119.2, 126.4, 126.6, 130.2, 130.8, 133.1, 133.3, 133.5, 133. 7, 134.6, 135.6, 137.1, 137.5, 140.6, 152.9, 169.5, 170.3;
IR (neat): ν 3328, 2932, 2876, 2360, 1726, 1660, 1627, 1488, 1347, 1297, 1236, 1176, 1065, 1006, 841, 742 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd _{[C 46 H 68 N 2 NaO} 8 Si] +: 827.4637, Found: 827.4604;
[Α] _D ²⁰ +7.3 (c = 0.47, MeOH)

<Reaction 24: (3E, 6S, 7R, 8R, 9Z) -12- {2,5-dihydroxy-3-[(3R, 4E) -3-methoxy-hepta-4,6-dienoylamino] phenyl} -7 , 9-Dimethyl-8- (triethylsiloxy) dodeca-1,3,9-trien-6-yl-1- (cyclohexenylmethylamino) cyclopropanecarboxylate (32)>

To a dichloromethane solution (5 mL) containing the compound (31) synthesized in the reaction 23 (10 mg, 0.0124 mmol), an excess amount of MnO ₂ was added at 23 ° C. in an argon atmosphere. After the reaction solution was stirred at 23 ° C. for 5 minutes, MnO ₂ was filtered through a celite pad. The organic matter was concentrated under reduced pressure to obtain a yellow amorphous powdery quinone (S10).

NaBH ₄ (9.4 mg, 0.248 mmol) was added to a methanol solution (1.5 mL) containing this quinone (S10) at 0 ° C. under an argon atmosphere. The reaction solution was stirred at 0 ° C. for 2 seconds, and then saturated ammonium chloride aqueous solution was added to stop the reaction. The organic substance was extracted three times with chloroform, washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. These were filtered and concentrated under reduced pressure to obtain hydroquinone (32) (9.7 mg) as a pale yellow amorphous powder.

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, specific rotation of hydroquinone (32) are shown below.
¹ H NMR (600 MHz, CDCl ₃ ): δ 0.46-0.60 (6H, m), 0.86-0.96 (9H, m), 1.06-1.23 (2H, m), 1 .42-1.50 (1H, m), 1.53-1.79 (12H, m), 1.84-1.92 (1H, m), 2.09-2.28 (6H, m) 2.33-2.39 (1H, m), 2.39-2.48 (1H, m), 2.59-2.75 (3H, m), 3.35 (3H, s), 4 .08 (1H, td, J = 8.4, 3.6 Hz), 4.42 (1H, brs), 4.78-4.86 (1H, m), 4.97 (1H, d, J = 10.2 Hz), 5.08 (1 H, d, J = 16.8 Hz), 5.18 (1 H, d, J = 9.6 Hz), 5.22-5.32 (2 H, m), 5 .47-5.63 (2 H, m), 6.00 (1H, dd, J = 15.0, 10.2 Hz), 6.20-6.47 (6H, m), 6.65 (2H, br dd, J = 9. 0, 3.0 Hz), 8.14 (1H, s), 8.73 (1H, s);
¹³ C NMR (150 MHz, CDCl ₃ ): δ 4.7 (3C), 6.9 (3C), 10.7, 14.1, 17.1, 17.2, 21.4, 22.0, 24. 1, 25.4, 28.2, 29.7, 30.1, 33.7, 34.0, 41.9, 42.8, 56.5, 76.4, 78.6, 106.7, 114.5, 115.6, 119.1, 126.2, 130.0, 130.9, 132.7, 133.0, 133.7, 134.6, 135.0, 135.6, 136. 2, 136.9, 137.7, 140.0, 149.9, 170.2, 170.4, 171.9;
IR (neat): ν 3306, 2930, 1725, 1660, 1627, 1501, 1464, 1374, 1292, 1236, 1178, 1072, 1006, 906, 851, 741, 605, 549 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd _{[C 45 H 66 N 2 NaO} 8 Si] +: 813.4481, Found: 813.4453;
[Α] _D ²¹ +6.0 (c = 0.56, MeOH)

<Reaction 25: (3E, 6S, 7R, 8R, 9Z) -12- {3-[(3R, 4E) -3-methoxy-hepta-4,6-dienoylamino] -2,5-bis (triethylsiloxy) Synthesis of -phenyl} -7,9-dimethyl-8- (triethylsiloxy) dodeca-1,3,9-trien-6-yl-1- (cyclohexenylmethylamino) cyclopropanecarboxylate (34)>

To hydroquinone (32) (9.7 mg) and N, N-dimethylformamide solution (DMF, 0.4 mL), an excess amount of compound (33) was added at 23 ° C. under an argon atmosphere. The reaction solution was stirred at 23 ° C. for 1 hour, and further stirred at 50 ° C. for 8 hours, and water was added to stop the reaction. The organic matter was extracted three times with ethyl acetate, washed four times with water, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 5: 1) to obtain diene (34) (9.7 mg) as a pale yellow amorphous powder. , 77%, 3 steps) from compound (31).

  In addition, compound (33) can be synthesized from (a) Robert, W. et al. J .; Am. Chem. Soc. 1958, 80, p. 3246. (B) Veysoglu, T .; Mitscher, L .; A. Tetrahedron Lett. 1981, 22, p. 1303. (C) Feigenson, G .; B. Eggerson, M .; Danishefsky, S .; J. et al. J .; Org. Chem. 1988, 53, p. Synthesized with reference to 3391.

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, specific rotation of diene (34) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.55 (6H, t, J = 8.0 Hz), 0.69-0.80 (12H, m), 0.87-1.02 (27H, m) 1.15 (2H, br d, J = 1.6 Hz), 1.23-1.35 (2H, m), 1.45-1.70 (9H, m), 1.76 (3H, s) ), 2.00-2.40 (8H, m), 2.46-2.62 (3H, m), 3.30 (3H, s), 4.11-4.24 (2H, m), 4.71 (1H, br dt, J = 10.4, 2.8 Hz), 4.95 (1H, d, J = 10.0 Hz), 5.05 (1H, d, J = 17.2 Hz), 5.14 (1H, d, J = 10.0 Hz), 5.20 (1 H, t, J = 7.2 Hz), 5.25 (1H, d, J = 17.2 Hz), 5.45-5 .5 (1H, m), 5.59 (1H, dd, J = 14.4, 8.0 Hz), 5.98 (1H, dd, J = 15.2, 10.4 Hz), 6.07 (1H, s), 6.17-6.39 (4H, m), 6.56 (1H, br s), 7.80 (1H, br d, J = 2.4 Hz), 7.83 (1H, s) ;
¹³ C NMR (150 MHz, CDCl ₃ ): δ4.9 (3C), 5.0 (3C), 5.4 (3C), 6.6 (3C), 6.7 (3C), 6.9 (3C) ), 10.9, 17.2, 18.3, 21.5, 22.1, 24.2, 25.4, 28.2, 29.7, 31.1, 32.5, 33.9, 40.5, 44.9, 56.6, 71.7, 75.0, 78.6, 110.3, 115.4, 115.6, 118.4, 126.3, 130.1, 130. 3, 131.8, 132.1, 133.2, 133.4, 133.7, 133.8, 135.9, 136.8, 137.2, 137.3, 149.7, 168.0, 169.2, 171.8;
IR (neat): ν 3429, 3318, 2956, 2878, 1726, 1666, 1631, 1523, 1448, 1349, 1290, 1239, 1174, 1068, 1006, 899, 815, 743 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd _{[C 57 H 94 N 2 NaO} 8 Si 3] +: 1041.6210, found: 1041.6228;
[Α] _D ²⁰ +14.1 (c = 1.07, CHCl ₃ )

<Reaction 26: (5R, 6E, 8E, 10E, 13S, 14R, 15R, 16Z) -1-[(cyclohex-1-enecarbonyl) -amino] -cyclopropanecarboxylic acid-5-methoxy-14,16- Dimethyl-3-oxo-15,22,24-tris-triethylsiloxy-2-aza-bicyclo [18.3.1] tetracosa-1 (23), 6,8,10,16,20 (24), 21 -Synthesis of heptaen-13-yl ester (35)>

A Grubbs first generation catalyst (3.9 mg, 0) was added to a degassed dichloromethane solution (7.5 mL) containing diene (34) (12 mg, 0.0118 mmol) synthesized in the above reaction 25 under an argon atmosphere at 23 ° C. .00472 mmol) was added. The reaction solution was stirred at 23 ° C. for 71 hours in the dark, and then passed through silica gel using n-hexane containing 33% ethyl acetate as a solvent, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO ₂ , hexane: ethyl acetate = 3: 1) to obtain triene (35) (4.6 mg, 39%) as a pale yellow amorphous powder. At the same time, diene (34) (2.8 mg, 23%) was recovered.

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS and specific rotation of triene (35) are shown below.
¹ H NMR (600 MHz, CDCl ₃ ): δ 0.55-0.62 (6H, m), 0.73 (12H, t, J = 7.8 Hz), 0.97 (27H, t, J = 7. 8Hz), 1.9-1-1.18 (2H, m), 1.20-1.35 (2H, m), 1.45-1.48 (2H, m), 1.62-1.69 ( 3H, m), 1.70-1.82 (4H, m), 1.91-2.00 (2H, m), 2.08-2.26 (6H, m), 2.27-2. 38 (2H, m), 2.45-2.65 (2H, m), 2.66-2.73 (1H, m), 2.86 (1H, dd, J = 11.4, 3.6 Hz) ), 3.34 (3H, s), 4.01-4.07 (1H, m), 4.20 (1H, brd, J = 9.0 Hz), 4.67-4.73 (1H, m), 5.16-5 .26 (2H, m), 5.30-5.38 (1H, m), 5.56 (1H, dd, J = 14.4, 7.2 Hz), 5.72-5.79 (1H, m), 5.89-6.02 (3H, m), 6.12 (1H, s), 6.26 (1H, d, J = 3.0 Hz), 6.60 (1H, br s), 7.87 (1H, d, J = 3.0 Hz);
¹³ C NMR (150 MHz, CDCl ₃ ): δ 5.0 (3C), 5.0 (3C), 5.5 (3C), 6.7 (6C), 6.9 (3C), 10.5, 17 2, 17.3, 21.5, 22.1, 22.7, 24.2, 25.4, 29.7, 31.9, 32.8, 34.0, 41.3, 46.2 , 56.6, 70.7, 74.5, 79.6, 108.6, 115.2, 128.9, 129.7, 130.3 (2C), 131.6, 132.0, 132. 8 (2C), 133.3 (2C), 133.8 (2C), 136.4, 149.6, 167.8, 169.4, 171.5;
IR (neat): ν 3545, 3419, 3330, 2925, 2871, 1732, 1693, 1633, 1520, 1445, 1378, 1288, 1240, 1172, 1098, 1003, 898, 808, 743, 614 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd _{[C 55 H 90 N 2 NaO} 8 Si 3] +: 1013.5897, found: 1013.5922;
[Α] _D ²⁰ +10.8 (c = 0.24, CHCl ₃ )

<Reaction 27: Synthesis of cytotrienin A>

To a solution of degassed THF (1.0 mL) and water (0.1 mL) containing triene (35) (4.0 mg, 0.004 mmol) synthesized in the above reaction 26, Amberlyst was added at 23 ° C. under an argon atmosphere. 15 ™ (240 mg, 6000 wt%) was added. After stirring the reaction solution in the dark at 23 ° C. for 47 hours, the reaction solution was purified by flash column chromatography (SiO ₂ , methanol: trichloromethane = 1: 20), and the target product was a pale yellow solid cytotrie. Nin A (2.8 mg, 95%) was obtained.

The results of ¹ H NMR, HRMS, specific rotation, and HPLC of cytotrienin A are shown below.
¹ H NMR (600 MHz, CDCl ₃ ): δ 0.76 (3H, d, J = 6.6 Hz), 1.12-1.37 (3H, m), 1.42-1.82 (9H, m) 1.93-2.38 (8H, m), 2.54 (1H, dd, J = 9.6, 13.2 Hz), 2.57-2.64 (1H, m), 2.81 ( 1H, br s), 2.94 (1H, dd, J = 4.2, 13.2 Hz), 2.99-3.06 (1H, m), 3.36 (3H, s), 4.17 -4.24 (1H, m), 4.49 (1H, br s), 4.74-4.80 (1H, m), 5.09 (1H, br d, J = 9.0 Hz), 5 .49 (1H, dd, J = 7.8, 15.6 Hz), 5.62 (1H, ddd, J = 4.8, 10.2, 15.0 Hz), 6.02 (1H, t, J = 12. Hz), 6.05 (1H, t, J = 11.4 Hz), 6.18 (1H, dd, J = 10.8, 15.0 Hz), 6.26 (1H, dd, J = 10.8) , 15.6 Hz), 6.33 (1 H, s), 6.44 (1 H, d, J = 2.4 Hz), 6.58 (1 H, d, J = 2.4 Hz), 6.71 (1 H , Br s), 7.05 (1H, s), 7.76 (1H, s), (OH × 1, not detected);
HRMS (ESI): [M + Na] + calcd _{[C 37 H 48 N 2 NaO} 8] +: 671.3303, Found: 671.3291;
[Α] _D ²⁸ +186.6 (c = 0.029, MeOH);
HPLC conditions; Column: Shiseido CAPCELL PAK C18 UG120, column temperature: 10 ° C., flow rate: 0.8 mL / min, solvent: 62% MeOH / H ₂ O, UV: 254 nm, t _R = 30 min

[Synthesis Method of Compound (8)]
<Reaction 28: Synthesis of (Z) -3-iodo-1-triisopropylsiloxy-2-butene (8)>

To an ethanol solution (286 mL) containing sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al ™ with toluene as a solvent, 78.3 mL, 261 mmol) in an argon atmosphere at 0 ° C., 2-butene An ethanol solution (27 mL) containing -1-ol (36) (12.2 g, 174 mmol) was added. The reaction solution was stirred at 23 ° C. for 4 hours, and ethyl acetate (17 mL) and iodine (66 g, 261 mmol) were added at 0 ° C. in the dark. The reaction was stirred at 23 ° C. for a further 12 hours, quenched with saturated aqueous sodium thiosulfate and 2N HCl was added. The organic matter was extracted three times with ethyl acetate, washed twice with water, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 20: 1) to give a pale yellow oily alcohol (S11) (34.5 g, quantitative yield). Rate).

Imidazole (25 g, 368 mmol) and triisopropylsilyl chloride (TIPSCl, 47.2 mL, 221 mmol) were added to a DMF solution (184 mL) containing this alcohol (S11) (36.4 g, 221 mmol) at 0 ° C. in an argon atmosphere. It was. After stirring the reaction solution at 0 ° C. for 1.5 hours, the reaction was stopped by adding a phosphate buffer adjusted to pH 7.0. The organic matter was extracted twice with ethanol, washed three times with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 30: 1) to give colorless oily compound (8) (60.6 g, 93%, 2 Step).

The results of ¹ H NMR, ¹³ C NMR, IR, and HRMS of compound (8) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.03-1.12 (21H, m), 2.50-2.53 (3H, m), 4.23-4.27 (2H, m), 5 .70-5.76 (1H, m);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 12.0 (3C), 18.0 (6C), 33.4, 68.8, 98.3, 135.6;
IR (neat): ν2943, 2866, 1655, 1464, 1426, 1371, 1246, 1104, 1055, 1009, 882, 768, 684 cm ⁻¹ ;
HRMS (ESI): [M + Na] ⁺ calculated value [C ₁₃ H ₂₇ INaOSi] ⁺ : 377.0768, found: 377.0765

[Synthesis Method of Aromatic Segment (20)]
<Reaction 29: Synthesis of 2-hydroxymethyl-4-methoxy-6-nitro-phenol (38)>

NaBH ₄ (890 mg, 23.6 mmol) was added to a solution of aldehyde (37) (3.1 g, 15.7 mmol) in ethyl acetate (105 mL) and methanol (52 mL) at 0 ° C. under an argon atmosphere. The reaction solution was stirred at 0 ° C. for 2 hours, and then saturated ammonium chloride aqueous solution was added to stop the reaction. The organic matter was extracted three times with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. These were filtered and concentrated under reduced pressure, then purified by silica gel chromatography using ethyl acetate as a solvent, and concentrated under reduced pressure to obtain a yellow solid alcohol (38) (2.6 g, 83%). .

  Aldehyde (37) can be prepared according to Baker, R. et al. Castro, J .; L. J .; Chem. Soc. Perkin Trans. 1; synthesized with reference to 1990, 47.

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, and melting point of the alcohol (38) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.26 (1H, t, J = 6.0 Hz), 3.82 (3H, s), 4.78 (2H, d, J = 5.6 Hz), 7 .34 (1H, d, J = 3.2 Hz), 7.44 (1H, d, J = 3.2 Hz), 10.68 (1H, s);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 56.0, 60.4, 104.8, 125.3 (2C), 133.0, 147.7, 152.3;
IR (neat): ν3410, 1529, 1460, 1427, 1328, 1248, 1194, 1157, 1059, 773, 763, 671 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd _{[C 8 H 9 NNaO 5]} +: 222.0373, Found: 222.0366;
Melting point: 103-106 ° C

<Reaction 30: Synthesis of 2-benzenesulfonylmethyl-4-methoxy-6-nitro-phenol (20)>

  HBr (30 mL, 173.3 mmol) was added to an acetic acid solution (347 mL) containing the alcohol (38) (6.9 g, 34.7 mmol) synthesized in the above reaction 29 at 4 ° C. under an argon atmosphere. The reaction solution was stirred at 23 ° C. for 2.5 hours, and then water was added to stop the reaction. The insoluble organic material was then filtered and washed with water, and the residue was dissolved in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product (S12) (7.36 g) as a yellow solid.

NaSO ₂ Ph (9.2 g, 56.2 mmol) was added to an N, N-dimethylformamide solution (DMF, 281 mL) containing this crude product (S12) (7.36 g, 28.1 mmol) at 23 ° C. under an argon atmosphere. ) Was added. The reaction was stirred at 120 ° C. for 3 hours and cooled to 0 ° C. to form yellow crystals. The precipitate was collected by filtration, washed with water, and then recrystallized from n-hexane containing 33% ethyl acetate to give a yellow needle-like aromatic segment (20) (5.86 g, 53%, 2 steps) Got.

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, and melting point of the aromatic segment (20) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.82 (3H, s), 4.49 (2H, s), 7.32 (1H, d, J = 2.8 Hz), 7.47 (2H, bt , J = 8.0 Hz), 7.53 (1H, d, J = 3.2 Hz), 7.59-7.65 (1H, m), 7.72-7.76 (2H, m), 10 .29 (1H, s);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 55.4, 56.1, 107.7, 120.5, 128.5 (2C), 129.0 (3C), 133.2, 134.0, 138. 3, 148.2, 151.8;
IR (neat): ν 1540, 1474, 1431, 1309, 1238, 1166, 1137, 1085, 1048, 934, 896, 746, 717, 686, 545, 529 cm ⁻¹ ;
HRMS (ESI): [M + Na] ⁺ calculated [C ₁₄ H ₁₃ NNaO ₆ S] ⁺ : 346.0356, found: 346.0361;
Melting point: 137-138 ° C

[Synthesis Method of C1-C6 Segment (30)]
<Reaction 31: Synthesis of (R, E) -ethyl-6- (tert-butyldimethylsiloxy) -4-hydroxy-hex-2-enoate (40)>

To an acetonitrile solution (0.6 mL) containing compound (39) (50.6 mg, 0.25 mmol) and nitrosobenzene (51.1 mg, 0.5 mmol), L-proline (2. 9 mg, 0.025 mmol) was added and the reaction was stirred at −20 ° C. for 24 hours. On the other hand, a THF solution (0 mg) containing triethylphosphonoacetate (40) (112 mg, 0.5 mmol) in a THF solution (0.3 mL) containing NaH (20.9 mg, 0.48 mmol) at 0 ° C. under an argon atmosphere. 2 mL) and the reaction was stirred at 23 ° C. for 45 min. Next, the mixture of compound (S12) was transferred to a solution of triethylphosphonoacetate (40) at 0 ° C., stirred at 0 ° C. for 30 minutes, and then the reaction was stopped by adding a phosphate buffer adjusted to pH 7.0. I let you. After filtration through a celite pad, the organic matter was extracted three times with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. These were filtered and concentrated under reduced pressure, and then the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 10: 1) to obtain a pale red oily compound (S13) (107 mg).

  Compound (39) was prepared according to Taylor, C .; Gille, B .; Bellosta, V .; Cossy, J .; J .; Org. Chem. 2005, 70, p. Synthesized with reference to 2097.

Anhydrous copper sulfate (12 mg, 0.075 mmol) was added to a methanol solution (1.6 mL) containing this compound (S13) (107 mg, 0.28 mmol) at 0 ° C. in an argon atmosphere. After the reaction solution was stirred at 0 ° C. for 46 hours, the reaction was stopped by adding a cooled saturated sodium chloride aqueous solution. After filtration through a celite pad, the organic matter was extracted three times with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtering these and concentrating under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 10: 1) to give pale brown oily compound (41) (32.9 mg, 46%, 98% ee, 3 steps).

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, specific rotation of the compound (41) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.06 (6H, s), 0.89 (9H, br d, J = 0.8 Hz), 1.27 (3H, t, J = 6.8 Hz), 1.67-1.76 (1H, m), 1.80-1.90 (1H, m), 3.67 (1H, br s), 3.76-3.92 (2H, m), 4 .18 (2H, q, J = 7.2 Hz), 4.53 (1H, brs), 6.09 (1H, d, J = 15.6 Hz), 6.92 (1H, dd, J = 15) .6, 5.2 Hz);
¹³ C NMR (100 MHz, CDCl ₃ ): δ-5.7, −5.6, 14.2, 18.0, 25.8 (3C), 37.4, 60.2, 61.8, 70. 8, 120.2, 150.0, 166.6;
IR (neat): ν 3480, 2954, 2930, 2857, 1722, 1658, 1472, 1390, 1368, 1304, 1258, 1174, 1097, 1040, 981, 940, 836, 778, 720, 664 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd ^{_{[C 14 H 28 NaO 4 Si}} ] +: 311.1649, Found: 311.1660;
[Α] _D ²⁵ +5.0 (c = 0.5, CHCl ₃ )

The enantiomeric excess of compound (41) was calculated using HPLC. The measurement conditions are as follows.
Column: Chiralpac IC column (2-propanol: hexane = 1: 30)
Flow rate: 1 mL / min Major enantiomer: t _R = 16.8 min Minor enantiomer: t _R = 20.8 min

<Reaction 32: Synthesis of (R, E) -ethyl-6- (tert-butyldimethylsiloxy) -4-methoxy-hex-2-enoate (42)>

NaH (153 mg, 6.38 mmol) was added to an N, N-dimethylformamide solution (DMF, 16 mL) containing the compound (41) (920 mg, 3.19 mmol) synthesized in the above reaction 31 at 0 ° C. under an argon atmosphere. added. The reaction was stirred at 0 ° C. for 10 minutes and treated with MeI (0.79 mL, 12.8 mmol). The reaction solution was further stirred for 1 hour, and then the phosphate buffer adjusted to pH 7.0 was added to stop the reaction. Insoluble matter was filtered through a celite pad, and the organic matter was extracted three times with ethyl acetate, washed three times with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtering these and concentrating under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 3: 1) to give a pale yellow oily ethyl ester (42) (906 mg, 94%). Obtained.

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, specific rotation of ethyl ester (42) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.02 (6H, br d, J = 1.6 Hz), 0.87 (9H, s), 1.27 (3H, t, J = 7.2 Hz), 1.71 (2H, dt, J = 12.8, 6.0 Hz), 3.28 (3H, s), 3.58-3.79 (2H, m), 3.92 (1H, q, J = 6.4 Hz), 4.18 (2H, q, J = 7.2 Hz), 5.96 (1H, d, J = 15.6 Hz), 6.80 (1H, dd, J = 15.6, 6.4 Hz);
¹³ C NMR (100 MHz, CDCl ₃ ): δ-5.5 (2C), 14.2, 18.2, 25.9 (3C), 38.0, 57.1, 58.7, 60.3, 77.3, 121.7, 148.1, 166.1;
IR (neat): ν2954, 2929, 2857, 1725, 1658, 1471, 1368, 1257, 1165, 1096, 1039, 984, 945, 836, 776, 720, 663 cm ⁻¹ ;
HRMS (ESI): [M + Na] ⁺ calculated [C ₁₅ H ₃₀ NaO ₄ Si] ⁺ : 325.1806, found: 325.1816;
[Α] _D ²⁴ +12.9 (c = 0.87, CHCl ₃ )

<Reaction 33: Synthesis of (R, E) -6- (tert-butyldimethylsiloxy) -4-methoxy-hex-2-en-1-ol (43)>

Diisobutylaluminum hydride (DIBAL-H, 1.6 mL, 0) was added to a dichloromethane solution (2 mL) containing the ethyl ester (42) synthesized in the above reaction 32 (185 mg, 0.61 mmol) under an argon atmosphere at −78 ° C. .94M hexane solution, 1.53 mmol) was added. The reaction temperature was raised to −40 ° C. for 2 hours, and the reaction was stopped by adding a saturated aqueous Rochelle salt solution. The organic matter was extracted three times with ethyl acetate, washed three times with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 3: 1) to obtain a pale yellow oily alcohol (43) (131 mg, 82%). It was.

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, specific rotation of alcohol (43) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.03 (6H, br d, J = 2.4 Hz), 0.88 (9H, s), 1.59-1.71 (1H, m), 1. 71-1.82 (1H, m), 1.87 (1H, br s), 3.25 (3H, s), 3.57-3.61 (1H, m), 3.61-3.81 (2H, m), 4.15 (2H, br d, J = 5.2 Hz), 5.55 (1H, dd, J = 15.6, 7.6 Hz), 5.81 (1H, dt, J = 15.6, 5.2 Hz);
¹³ C NMR (100 MHz, CDCl ₃ ): δ-5.4 (2C), 18.2, 25.9 (3C), 38.6, 56.2, 59.2, 62.8, 78.4 131.6, 131.9;
IR (neat); ν3421, 2953, 2929, 2858, 2361, 1472, 1389, 1255, 1187, 1095, 1007, 973, 837, 776 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd ^{_{[C 13 H 28 NaO 3 Si}} ] +: 283.1700, Found: 283.1694;
[Α] _D ²⁴ +12.8 (c = 0.56, CHCl ₃ )

<Reaction 34: Synthesis of (R, E) -1- (tert-butyldimethylsiloxy) -3-methoxy-hepta-4,6-diene (44)>

An excess amount of MnO ₂ was added to a dichloromethane solution (14 mL) containing the alcohol (43) (262 mg, 1.0 mmol) synthesized in the above reaction 33 at 23 ° C. in an argon atmosphere. After the reaction solution was stirred at 23 ° C. for 2 hours, MnO ₂ was filtered through a celite pad. The organic matter was concentrated under reduced pressure to obtain a pale yellow oily crude product (S14) (317 mg).

On the other hand, tert-butoxypotassium (215 mg, 1.9 mmol) was added to a THF solution (8 mL) containing methyltriphenylphosphonium iodide (814 mg, 2.0 mmol) at 0 ° C. in an argon atmosphere. The reaction solution was stirred at 0 ° C. for 30 minutes, and then transferred to a THF solution (2.1 mL) containing the crude product (S14) (317 mg). The reaction solution was further stirred for 15 minutes, and then saturated ammonium chloride aqueous solution was added to stop the reaction. The organic matter was extracted three times with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtering these and concentrating under reduced pressure, the residue was purified by preparative TLC (SiO ₂ , hexane: ethyl acetate = 5: 1) to give diene (44) (207 mg, 80%, 2 steps) as a pale yellow oil. )

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS and specific rotation of diene (44) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ0.05 (6H, d, J = 2.0 Hz), 0.90 (9H, s), 1.61-1.72 (1H, m), 1.75 -1.85 (1H, m), 3.26 (3H, s), 3.63 (1H, dt, J = 10.4, 6.0 Hz), 3.67-3.81 (2H, m) , 5.09 (1H, br dd, J = 10.0, 1.2 Hz), 5.21 (1 H, br dd, J = 16.4, 1.2 Hz), 5.55 (1 H, dd, J = 15.6, 8.0 Hz), 6.19 (1H, dd, J = 15.6, 10.4 Hz), 6.35 (1H, dt, J = 16.8, 10.4 Hz);
¹³ C NMR (100 MHz, CDCl ₃ ): δ-5.4 (2C), 18.3, 25.9 (3C), 38.7, 56.3, 59.2, 78.6, 117.3 133.0, 134.3, 136.4;
IR (neat): ν2954, 2929, 2857, 2820, 1604, 1471, 1389, 1362, 1254, 1190, 1099, 1004, 953, 934, 903, 837, 776, 664 cm ⁻¹ ;
HRMS (ESI): [M + Na] ⁺ calculated [C ₁₄ H ₂₈ NaO ₂ Si] ⁺ : 279.1751, found: 279.1753;
[Α] _D ²² +8.1 (c = 0.99, MeOH)

<Reaction 35: Synthesis of (R, E) -3-methoxy-hepta-4,6-dien-1-ol (45)>

To an acetonitrile solution (2.6 mL) containing the diene (44) (132 mg, 0.52 mmol) synthesized in the above reaction 34 was added 65% HF · pyridine (0.27 mL, 10.3 mmol) at 0 ° C. in an argon atmosphere. Was added. The reaction solution was stirred at 0 ° C. for 1.5 hours, and then saturated sodium hydrogen carbonate aqueous solution was added to stop the reaction. The organic matter was extracted three times with ethyl acetate, washed three times with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (SiO ₂ , hexane: ethyl acetate = 3: 1) to obtain a pale yellow oily alcohol (45) (51 mg, 70%). It was.

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, specific rotation of alcohol (45) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.71-1.90 (2H, m), 2.41 (1H, br s), 3.28 (3H, s), 3.69-3.81 ( 2H, m), 3.85 (1H, dt, J = 8.0, 4.8 Hz), 5.12 (1H, br dd, J = 10.4, 1.6 Hz), 5.23 (1H, br dd, J = 16.8, 1.2 Hz), 5.57 (1H, dd, J = 15.2, 8.0 Hz), 6.21 (1H, dd, J = 15.2, 10.4 Hz) ), 6.35 (1H, dt, J = 16.8, 10.4 Hz);
¹³ C NMR (150 MHz, CDCl ₃ ): δ 37.8, 56.3, 60.8, 81.8, 118.0, 133.2, 133.4, 136.0;
IR (neat): ν 3417, 3084, 2937, 2885, 2820, 1817, 1650, 1604, 1467, 1343, 1185, 1101, 1055, 1006, 953, 906, 791, 656 cm ⁻¹ ;
HRMS (ESI): [M + Na] ⁺ calculated [C ₈ H ₁₄ NaO ₂ ] ⁺ : 165.0886, found: 165.0889;
[Α] _D ²⁰ +34.8 (c = 0.54, MeOH)

<Reaction 36: Synthesis of (R, E) -3-methoxy-hepta-4,6-dienoic acid (30)>

To a dichloromethane solution (176 μL) containing the alcohol (45) (25 mg, 0.18 mmol) synthesized in the above reaction 35, triethylamine (123 μL, 0.88 mmol), dimethyl sulfoxide (DMSO, 176 μL, 1.0M), and SO ₃ · pyridine complex (82 mg, 0.53 mmol) were added. After the reaction solution was stirred at 0 ° C. for 50 minutes, the reaction was stopped by adding a phosphate buffer adjusted to pH 7.0. The organic matter was extracted three times with ethyl acetate, washed three times with water, and the organic layer was dried over anhydrous sodium sulfate. These were filtered and concentrated under reduced pressure to obtain aldehyde (S15) (25 mg) as a pale yellow oil.

To a solution of this aldehyde (S15) (14 mg, 0.1 mmol) in tert-butyl alcohol (145 μL) and water (48 μL) under an argon atmosphere at 23 ° C., NaH ₂ PO ₄ .2H ₂ O (30 mg,. 2 mmol), 2-methyl-2-butene (41 μL, 0.4 mmol), and NaClO ₂ (33 mg, 0.3 mmol) were added. The reaction solution was stirred at 23 ° C. for 1 hour, and saturated sodium thiosulfate aqueous solution and saturated sodium hydrogen carbonate aqueous solution were added to stop the reaction. The aqueous layer was washed twice with diethyl ether and adjusted to pH 1 with 2N HCl. The organic layer was extracted twice with diethyl ether, washed three times with a saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. These were filtered and concentrated under reduced pressure to obtain a pale yellow oily carboxylic acid (30) (12 mg, 80%, 2 steps).

The results of ¹ H NMR, ¹³ C NMR, IR, HRMS, specific rotation of carboxylic acid (30) are shown below.
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.56 (1H, dd, J = 15.6, 4.4 Hz), 2.65 (1H, dd, J = 15.6, 8.0 Hz), 3. 32 (3H, s), 4.08 (1H, dt, J = 8.4, 4.8 Hz), 5.17 (1H, d, J = 10.0 Hz), 5.28 (1H, d, J = 16.8 Hz), 5.56 (1H, dd, J = 14.8, 8.0 Hz), 6.24-6.41 (2H, m), (COOH × 1, not detected);
¹³ C NMR (100 MHz, CDCl ₃ ): δ 40.8, 56.5, 78.0, 118.6, 131.6, 134.2, 135.8, 176.1;
IR (neat): ν 2935, 2826, 1712, 1605, 1415, 1345, 1303, 1206, 1099, 1047, 1007, 957, 910, 843, 661 cm ⁻¹ ;
HRMS (ESI): [M + Na] + calcd ^{_{[C 8 H 12 NaO 3]}} +: 179.0679, Found: 179.0679;
[Α] _D ²⁹ +7.8 (c = 0.69, CHCl ₃ )

Claims (10)

An intermediate compound for synthesizing an ansamycin antibiotic represented by the following formula (a).

(In formula (a), R ¹ represents an aryl group or a heteroaryl group which may have a substituent.) An intermediate compound for synthesizing an ansamycin antibiotic represented by the following formula (b).

(In formula (b), R ² and R ⁴ represent a protecting group, and R ³ represents a hydrogen atom or a protecting group.) An intermediate compound for synthesizing an ansamycin antibiotic represented by the following formula (c).

(In formula (c), R ⁵ and R ⁶ represent a protecting group, R ⁷ represents a hydrogen atom or a protecting group, and R ⁸ represents a hydrogen atom or a trityl group.) An intermediate compound for synthesizing an ansamycin antibiotic represented by the following formula (d).

(In formula (d), R ⁹ represents an aryl group or heteroaryl group which may have a substituent, and R ¹⁰ represents a hydrogen atom or a hydroxyl group.) An intermediate compound for synthesizing an ansamycin antibiotic represented by the following formula (e).

(In formula (e), R ¹¹ represents a protecting group, and R ¹² represents a hydrogen atom or a methyl group.) An intermediate compound for synthesizing an ansamycin antibiotic represented by the following formula (f).

An intermediate compound for synthesizing an ansamycin antibiotic represented by the following formula (g).

(In formula (g), R ¹³ represents a protecting group, and R ¹⁴ represents the following formula:

R ¹⁶ and R ¹⁷ represent a hydrogen atom or a protecting group, and R ¹⁸ represents a hydrogen atom or —OR ¹⁹ (R ¹⁹ represents a protecting group). R ¹⁵ is the following formula

Indicates one of the following. ) A compound represented by the following formula (h) is represented by the following formula (a) by reacting an arylaldehyde dialkyl acetal, heteroaryl aldehyde dialkyl acetal, aryl aldehyde, or heteroaryl aldehyde which may have a substituent. For producing an intermediate compound for synthesizing an ansamycin antibiotic.

(In formula (a), R ¹ represents an aryl group or a heteroaryl group which may have a substituent.)   The method for producing an intermediate compound for synthesizing an ansamycin antibiotic according to claim 8, wherein the furfural and propanal are reacted in the presence of proline or a proline derivative to obtain the compound represented by the formula (h). A method for producing an ansamycin antibiotic, wherein a triene is constructed from a compound represented by the following formula (g) by a ring-closing metathesis reaction, and then a protecting group is deprotected.

(In formula (g), R ¹³ represents a protecting group, and R ¹⁴ represents the following formula:

R ¹⁶ and R ¹⁷ represent a hydrogen atom or a protecting group, and R ¹⁸ represents a hydrogen atom or —OR ¹⁹ (R ¹⁹ represents a protecting group). R ¹⁵ is the following formula

Indicates one of the following. )