JPWO2009104605A1 - A novel synthetic intermediate of ascofuranone with various physiological activities and a new shortened total synthesis method using it - Google Patents

Abstract

When synthesizing ascofuranone, compounds represented by the following formulas (III), (IV), (V), and (VII), or optical isomers thereof are used as synthetic intermediates. Wherein R1 and R2 are the same or different and are a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a phenoxyalkyl group having a halogen atom on the carbon atom of the benzene ring, or a carbon atom of the benzene ring. A phenyl group having an alkoxy group having 1 to 7 carbon atoms or an alkoxycarbonyl group having 1 to 7 carbon atoms, X is a halogen atom or an R5SO3 group (R5 is an alkyl group having 1 to 7 carbon atoms or benzene; Represents a phenyl group having an alkyl group having 1 to 7 carbon atoms on a ring carbon atom). By using the above compound, the total synthesis of ascofuranone requiring 12 steps according to the conventional method can be shortened to 7 steps or 8 steps.

Description

  The present invention relates to a novel synthetic intermediate of ascofuranone having various physiological activities and a novel shortened total synthesis method using the same. Specifically, the present invention relates to a short synthesis process characterized by a shortening of the synthesis step of the terpene side chain moiety of ascofuranone and a direct introduction method into an aromatic ring, and a novel synthetic intermediate thereof.

Ascofuranone, a phenolic physiologically active substance, has the structure shown in formula (I) and has not only antiviral and anticancer activity, but also has the effect of lowering blood cholesterol and lowering blood pressure. In addition, since it has extremely low hepatotoxicity, it is expected as a promising adult disease drug (see Patent Document 1, Patent Document 2, etc.).
JP-A-48-91278 JP-A 51-36450

Ascofuranone is also attracting attention as a chemotherapeutic agent for trypanosomiasis (see Patent Document 3, Non-Patent Document 1, etc.). Trypanosomiasis (African sleeping sickness) is caused by Trypanosoma protozoa, and it is said that 200,000 to 300,000 new patients develop each year. African sleeping sickness has significantly hampered the health and economic development of African people, which is one of the infectious diseases that WHO should control.
JP-A-9-165332 Parasitol. Int. 1998, 47, 131-137; 2003, 52, 155-164; 2006, 55, 39-43

When considering the practical use of ascofuranone has the disadvantage that the method (see Patent Document 1) culturing a ascofuranone producing bacteria belonging to Asukokiita genus aerobically purified and isolated operation ascofuranone is complicated For this reason, several methods of total synthesis have been developed. The world's first total synthesis (see Non-Patent Document 2, etc.) and the subsequent method (see Non-Patent Document 3, etc.) are the methods of connecting the parts constituting the ascofuranone molecule sequentially from the end, and the reaction process is long Had drawbacks.
Tetrahedron 1984, 40, 2711-2720; 1985, 41, 3049-3062 J. Org. Chem. 1985, 50, 3997-4005

As an improvement to the total synthesis method, the ascofuranone molecule represented by Formula I was constructed by dividing it into an aromatic ring segment IX on the left side and a terpene side chain segment X on the right side. A method of coupling was reported (see Patent Document 4, Patent Document 5, Non-Patent Document 4, etc.). However, even this method, which was the shortest step at that time, required a total of 12 steps from the commercially available starting material geranyl acetate. The geranyl acetate was not directly used for the synthesis of the terpene side chain segment, but a step for exchanging the acetate portion with another protecting group was necessary, and the same aldehyde group as that of ascofuranone was used as the aromatic ring segment. It was not possible to use an ester-type synthetic intermediate, and it was necessary to convert the left and right segments into an aldehyde group, and then to remove the hydroxyl group on the aromatic ring segment IX after protecting it. There was a problem that the process was not sufficiently shortened due to factors such as the need for a process to protect. Therefore, it has been strongly desired to develop a total synthesis method in a short process that enables efficient synthesis of ascofuranone.
JP-A 61-152665 JP-A 62-36334 Bull. Chem. Soc. Jpn. 1995, 68, 2727-2734

(In the above formula, R ² and R ⁴ are the same or different and are a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a phenoxyalkyl group having a halogen atom on the carbon atom of the benzene ring, or on the carbon atom of the benzene ring. Represents a phenyl group having an alkoxy group having 1 to 7 carbon atoms or an alkoxycarbonyl group having 1 to 7 carbon atoms, R ³ represents a Me ₃ SiCH ₂ CH ₂ OCH ₂ group, and R ⁵ represents tetrahydropyran-2-yl. And X represents halogen.)

  The problem to be solved is to develop a short synthesis process that enables efficient synthesis of ascofuranone.

The present inventors have searched for a total synthesis method of ascofuranone that is more efficient than the conventional total synthesis method, but as a synthesis intermediate, a novel compound diol of formula III, diester of formula IV, formula V The dihydrofuran derivative of formula VII and the furanone derivative of formula VII were found, and a short-step ascofuranone total synthesis method represented by the following reaction formula was established to complete the present invention. Any of these novel compounds can obtain optical isomers by using the already reported method for asymmetric synthesis of ascofuranone (see Non-Patent Document 5, etc.).
Bull. Chem. Soc. Jpn. 1999, 72, 279-284

(Wherein R ¹ , R ² , and X represent the meanings described below.)
The present invention is directed to general formula (XX),

(Wherein Y represents an R ¹ COO group, a halogen atom, or an R ⁵ SO ₃ group (R ⁵ represents an alkyl group having 1 to 7 carbon atoms or an alkyl group having 1 to 7 carbon atoms on a carbon atom of a benzene ring) Represents a phenyl group having
W is the following group

Represents a group selected from
R ¹ and R ² are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a phenoxyalkyl group having a halogen atom on the carbon atom of the benzene ring, or a carbon atom having 1 to 1 carbon atoms on the carbon atom of the benzene ring. 7 represents a phenyl group having an alkoxy group having 7 or an alkoxycarbonyl group having 1 to 7 carbon atoms. However, when Y represents a halogen atom or an R ⁵ SO ₃ group (R ⁵ has the above-mentioned meaning), W represents

Represents a group of )
And optical isomers thereof, and pharmaceutically acceptable salts thereof.

  For example, the present invention provides compounds represented by the following formulas (III), (IV), (V), and (VII), and optical isomers thereof, and pharmaceutically acceptable salts thereof.

(In Formula (III),
R ¹ represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a phenoxyalkyl group having a halogen atom on the carbon atom of the benzene ring, an alkoxy group having 1 to 7 carbon atoms or a carbon number carbon on the carbon atom of the benzene ring. Represents a phenyl group having an alkoxycarbonyl group of the number 1-7)

(In Formula (IV) and Formula (V),
R ¹ and R ² are a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a phenoxyalkyl group having a halogen atom on the carbon atom of the benzene ring, an alkoxy group having 1 to 7 carbon atoms on the carbon atom of the benzene ring, or Represents a phenyl group having an alkoxycarbonyl group having 1 to 7 carbon atoms)

(In the formula (VII),
X represents a halogen atom or an R ⁵ SO ₃ group (R ⁵ represents an alkyl group having 1 to 7 carbon atoms or a phenyl group having an alkyl group having 1 to 7 carbon atoms on the carbon atom of the benzene ring).
Furthermore, the present invention provides a novel total synthesis method of ascofuranone using the compounds represented by formulas (III), (IV), (V), and (VII) as synthesis intermediates,
Formula II

Wherein R ¹ is a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a phenoxyalkyl group having a halogen atom on the carbon atom of the benzene ring, or an alkoxy group having 1 to 7 carbon atoms on the carbon atom of the benzene ring. Or a phenyl group having an alkoxycarbonyl group having 1 to 7 carbon atoms) is reacted with 2-methyl-3-butyn-2-ol to give a compound represented by the general formula (III)

(Wherein R ¹ represents the same meaning as described above), and this compound is represented by the general formula R ² CO (Hal) (wherein R ² is a hydrogen atom, carbon number 1- 7 alkyl groups, phenoxyalkyl groups having a halogen atom on carbon atoms of the benzene ring, or phenyl groups having an alkoxy group having 1 to 7 carbon atoms or an alkoxycarbonyl group having 1 to 7 carbon atoms on carbon atoms of the benzene ring. And (Hal) represents a halogen atom.) By reacting with an acyl halide represented by the general formula (IV)

(Wherein R ¹ and R ² represent the same meaning as described above), and the compound is represented by the general formula (V) by a ring-closing reaction.

(Wherein R ¹ and R ² represent the same meaning as described above), and this compound is converted to a general formula (VI) by a deacylation reaction.

And the terminal OH group of this compound is substituted with a halogen atom to thereby convert the compound represented by the general formula (VII)

(In the formula, X represents a halogen atom.)
Is converted to a compound represented by the general formula (VIII)

Is reacted with a compound represented by the following formula (I):

The production method of ascofuranone is characterized by producing ascofuranone represented by the following formula.

  The production method of the present invention uses compounds represented by the formulas (III), (IV), (V), and (VII) as novel synthetic intermediates, and therefore, compared with the conventional total synthesis method of ascofuranone, There is an advantage that the number of manufacturing steps can be greatly reduced.

  The term “an alkyl group having 1 to 7 carbon atoms” used in the claims and the specification of the present application means a linear or branched alkyl group having 1 to 7 carbon atoms. Examples of the alkyl group include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, n-hexyl, 2,2,2- Examples include trimethylethyl, 2,2,2-trimethyl-1-methylethyl, n-heptyl and the like.

  In the terms used in the claims and the specification of the present application, the “C 1-7 alkoxy group” means “C 1-7 alkyl-O—”. The “alkyl having 1-7 carbons” in the “alkoxy group having 1-7 carbons” has the meaning described for the “alkyl group having 1-7 carbons”.

  In the terms used in the claims and the specification of the present application, the “alkoxycarbonyl group having 1 to 7 carbon atoms” means “alkyl-O—CO— having 1 to 7 carbon atoms”. The “alkyl having 1-7 carbons” in the “alkoxycarbonyl group having 1-7 carbons” has the meaning described for the “alkyl group having 1-7 carbons”.

  The term “halogen” as used in the claims and specification of this application means fluorine, chlorine, bromine, and iodine.

  The term “phenoxyalkyl group” as used in the claims and specification of this application means “phenyl-O-alkyl”. “Alkyl” in the “phenoxyalkyl group” means “an alkyl group having 1 to 3 carbon atoms”. Here, the “C 1-3 alkyl group” means a linear or branched alkyl group having 1-3 carbon atoms. Such alkyl groups include methyl, ethyl, n-propyl, i-propyl.

  The term “ascofuranone” as used in the claims and specification of the present application means ascofuranone and a derivative of ascofuranone in which the substituent on the benzene ring of ascofuranone is different from ascofuranone. Examples of such derivatives include an ascofuranone derivative in which the aldehyde group on the benzene ring of ascofuranone is replaced by an acetyl group, and an ascofuranone derivative in which the aldehyde group on the benzene ring of ascofuranone is replaced by a carboxyl group. it can.

  The term “pharmaceutically acceptable salt” as used in the claims and specification of this application means any salt that can be used in the manufacture of a medicament, such as an alkali metal (eg, sodium, Organic bases that impart physiologically acceptable cations such as salts with potassium or lithium), alkaline earth metals (eg calcium or magnesium); ammonium salts; salts with methylamine, dimethylamine, trimethylamine, piperidine and morpholine And salts thereof. In addition, for compounds that are sufficiently basic, suitable pharmaceutically acceptable salts include acid addition salts with hydrogen chloride, nitric acid, sulfuric acid, phosphoric acid, and acetic acid, tartaric acid, malic acid, citric acid, maleic acid. Acid addition salts with acids, organic acids such as methanesulfonic acid and p-toluenesulfonic acid are included. These salts can be obtained by methods well known or conventional in the art.

  As a synthetic intermediate, the diol derivative of the formula (III), the diester derivative of the formula (IV), the dihydrofuran derivative of the formula (V), the furanone derivative of the formula (VII), and the final product Asco As for furanone, it is possible to obtain optical isomers of any of the already reported asymmetric synthesis methods of ascofuranone (see Non-Patent Document 5, etc.). The outline will be described below.

  The secondary hydroxyl group of the racemic diol prepared in three steps from the aldehyde represented by the formula (II) was oxidized to obtain an alquinone represented by the formula (XIII). This was subjected to an asymmetric reduction reaction to give (S) -form diol stereoselectively. Only the secondary hydroxyl group was acylated to obtain a compound represented by the formula (S) -XI. This was subjected to a ring closure reaction under a silver catalyst to lead to a dihydrofuran derivative represented by the formula (XIV). This is an important intermediate during the synthesis of racemic isomers of ascofuranone represented by the formula (I) previously reported (Non-patent Document 4), and optically active substances can be synthesized using the same method. . In the above reaction formula, “3 steps” means three steps, “oxidation” means oxidation, “enantioselective reduction” means enantioselective reduction, and “known” means a known method described in Non-Patent Document 4.

  According to the present invention, in the short-step ascofuranone total synthesis method represented by the above reaction formula using the compounds represented by the formulas (III), (IV), (V), and (VII) as synthesis intermediates, The compound of II) can be prepared in two steps from geranylol, which is a commercially available starting material, with reference to known methods (see Non-Patent Document 2, etc.). Conventionally, it has been impossible to obtain a compound of formula (III) by directly reacting a compound of formula (II) with a propargyl alcohol derivative anion, so that the hydroxyl protecting group in the compound of formula (II) is an ester type. Then, it is reacted with a propargyl alcohol derivative anion and then esterified to obtain a compound of formula (XI), and this ether type protecting group is removed in a later step, so the total synthesis step becomes longer. This has contributed (see Patent Document 4, Patent Document 5, Non-Patent Document 4, etc.).

However, the present inventors have protected the hydroxyl group in the compound of the formula (II) by suppressing the equivalent of the propargyl alcohol derivative to the compound of the formula (II) to 1 or less and lowering the reaction temperature and the reaction termination temperature. Since the compound of the formula (III) could be synthesized by reacting with the propargyl alcohol derivative anion while the group remained in the ester form, the hydroxyl protecting group in the compound of the formula (II) was changed from the ester form to the ether form. The process of changing could be omitted. Furthermore, in order to prepare a compound of formula (X) which is a conventional synthetic intermediate (wherein X represents a halogen atom), an ester-type protecting group and an ether-type protecting group in the compound of formula (XI) Had to be removed in a separate step. However, since the compound of the formula (V) obtained from the compound of the formula (III) of the present invention via the compound of the formula (IV) is a diester type compound, both ester type protecting groups are removed in one step. Since it could be removed and converted into the alcohol type compound of the formula (VI), the total synthesis process could be shortened. In addition, in the conventional synthesis, since the bond between the aromatic ring segment (IX) and the terpene side chain segment (X) is formed through an intermediate of phenyl lithium type under anhydrous conditions, each ester type functional group Must be converted into aldehyde type and ketone type, which contributes to lengthening the total synthesis process. However, the present inventors have adopted a precursor of the same aldehyde form as ascofuranone as aromatic ring segments (VIII), also a precursor of the same ketone type as ascofuranone as terpene side chain segment (VII), previously developed Since the binding was performed by the method using the calcium chloride / potassium hydroxide composite reactant (see Non-Patent Document 6, etc.), the functional group conversion step could be omitted. As described above, several reports on the total synthesis of ascofuranone have been reported so far, but 12 steps were required at the shortest (see Patent Document 4, Patent Document 5, Non-Patent Document 4, etc.). In the present invention, by finding a new synthetic intermediate, when a commercially available geranyl acetate was used as a starting material, total synthesis was successfully performed in 7 steps.
J. Org. Chem. 1996, 61, 6768-6769

Below, each process in the manufacturing method of this invention is demonstrated.
1. Preparation of Compound of Formula (III) n-Butyllithium at −20 ° C. with stirring in a THF solution of 2-methyl-3-butyn-2-ol (HC≡C—C (CH ₃ ) ₂ OH) (1 equivalent) (2 equivalents) was added, and this was cooled to −50 ° C., and then a THF solution of the aldehyde (1.1 equivalents) represented by the formula (II) was added dropwise thereto and stirring was continued at the same temperature.
2. Preparation of Compound of Formula (IV) Pyridine (3.6 equivalents), 4-dimethylaminopyridine (0.2 equivalents) and general formula R ^{2 in} a chloroform solution of diol (1 equivalent) represented by formula (III) at 0 ° C. An acyl halide (2.2 equivalents) represented by CO (Hal) (wherein R ² and (Hal) represent the above-mentioned meanings) was added, followed by stirring at the same temperature.
3. Production of Formula (V) Compound To a toluene solution of a diester compound (1 equivalent) represented by formula (IV), a catalytic amount of silver tetrafluoroborate was added at room temperature, and the mixture was heated and stirred under light shielding.
4). Preparation of Compound of Formula (VI) Prepared by adding sodium methoxide (0.3 eq as a 1M methanol solution) to a methanol solution of the dihydrofuran derivative (1 eq) represented by formula (V) at room temperature and continuing stirring. .
5). Preparation of Compound of Formula (VII) Carbon tetrabromide (2.5 equivalents) and trioctylphosphine (n- (C ₈ H) were added to a diethyl ether solution of a primary alcohol (1 equivalent) represented by formula (VI) at 0 ° C. _{17) 3} P) (2.5 eq.) was added, was prepared by continuous stirring at the same temperature.
6). Preparation of Compound of Formula (I) (Ascofuranone) To a methanol solution of the compound of formula (VII) (1.2 equivalents), a benzaldehyde derivative (3-chloro-4,6-dihydroxy-) of formula (VIII) was added. 2-Methylbenzaldehyde) (1 equivalent) and calcium chloride dihydrate (0.7 equivalent) were added and cooled to 0 ° C., and then potassium hydroxide (2.1 equivalent as a 1M methanol solution) was added thereto. The solution was added dropwise and stirred at the same temperature.

  In the above, acetyl ascofuranone can be obtained instead of ascofuranone by using 3-chloro-4,6-dihydroxy-2-methylacetophenone instead of the benzaldehyde derivative represented by the formula (VIII). Thus, the corresponding ascofuranone derivative can be obtained by using various phenol derivatives instead of the phenol derivative represented by the formula (VIII). All methods for producing such ascofuranone derivatives are also included in the scope of the present invention.

Hereinafter, the present invention will be described in detail based on examples, but this does not limit the present invention in any way.
Example 1
Acetic acid (2E, 6E) -8,11-dihydroxy-3,7,11-trimethyl-2,6-dodecadiene-9-inyl (2) ((2E, 6E) -8,11-Dihydroxy-3,7, 11-trimethyl-2,6-dodecadien-9-ynyl acetate (2))

2-methyl-3-butyn-2-ol (185 mg, 2.20 mmol) in THF (14 ml) under a stream of Ar at −20 ° C., n-butyllithium (1.58 M hexane solution, 2.7 ml, 4. 3 mmol) was added and stirred for 2 hours. After cooling the reaction solution to −50 ° C., the known (2E, 6E) -8-acetoxy-2,6-dimethyl-2,6-octadienal (Tetrahedron 1974, 30, 715) prepared from commercially available geranyl acetate. ) (505 mg, 2.40 mmol) in THF (18 ml) was added dropwise. After stirring at the same temperature for 9 hours, a saturated aqueous NH ₄ Cl solution (5 ml) was added to stop the reaction. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over Na ₂ SO ₄ . After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to obtain diol 2 (479 mg, 68%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ5.54 (1H, t, J = 7.0 Hz, AcOCH ₂ CH = C), 5.33 (1H, t, J = 7.1 Hz, CH = C (CH ₃ ) CH (OH)}, 4.76 {1H, d, J = 5.1 Hz, CH = C (CH ₃ ) CH (OH)}, 4.59 (2H, d, J = 7.0 Hz, AcOCH ₂ CH = C), 2.20-2.16 (2H, m, CH ₂ ), 2.12-2.09 (2H, m, CH ₂ ), 2.06 (3H, s, CH ₃ C = O), 1.97 (1H, d, J = 5.1 Hz, CH = C (CH ₃ ) CH (OH)}, 1.74 (3H, s, CH ₃ ), 1.71 (3H, s, CH ₃ ), 1.61 {1H, s, C (OH) (CH ₃ ) ₂ }, 1.53 {6H, s , C (OH) (CH ₃ ) ₂ }. IR (neat) 3382, 2978, 2922, 1734, 1711, 1663, 1443, 1362, 1236, 1167, 1024, 951, 864, 712, 610, 554 cm ^-1 .
Example 2
Acetic acid (2E, 6E) -11-hydroxy-3,7,11-trimethyl-8-pivaloxy-2,6-dodecadiene-9-inyl (3) ((2E, 6E) -11-Hydroxy-3,7, 11-trimethyl-8-pivaloxy-2,6-dodecadien-9-ynyl acetate (3))

A solution of diol 2 (1.058 g, 3.594 mmol) in CHCl ₃ (2.8 ml) under a stream of Ar at 0 ° C. with pyridine (1.06 ml, 13.1 mmol), DMAP (88 mg, 0.72 mmol), pivaloyl chloride. (0.97 ml, 7.9 mmol) was added and stirred at the same temperature for 8 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over Na ₂ SO ₄ . After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 7/2) to obtain pivalic acid ester 3 (1.322 g, 97%).
^{1 H-NMR (400 MHz,} CDCl 3) δ5.77 (1H, s, CHOPiv), 5.62 {1H, t, J = 7.0 Hz, CH = C (CH 3) CHOPiv}, 5.35 (1H, t, J _{= 7.3 Hz, AcOCH 2 CH =} C), 4.59 (2H, d, J = 7.3 Hz, AcOCH 2 CH = C), 2.22-2.16 (2H, m, CH 2), 2.12-2.08 (2H, m, CH ₂ ), 2.06 (3H, s, CH- ₃ C = O), 1.71 (3H, s, CH ₃ ), 1.69 (3H, s, CH ₃ ), 1.62 (1H, br, C (OH) (CH ₃ ) ₂ }, 1.51 {6H, s, C (OH) (CH ₃ ) ₂ }. 1.19 {9H, s, C (CH ₃ ) ₃ }. IR (neat) 3460, 2978, 2922, 2866, 1732, 1666 , 1481, 1456, 1366, 1265, 1234, 1144, 1028, 955, 932, 864, 785, 708, 608, 561 cm ^-1 .
Example 3
Pivalic acid 5-[(1E, 5E) -7-acetoxy-1,5-dimethyl-1,5-heptadienyl] -2,2-dimethyl-3-oxolen-3-yl (4) (5-[(1E , 5E) -7-acetoxy-1,5-dimethyl-1,5-heptadienyl] -2,2-dimethyl-3-oxolen-3-yl pivalate (4))

AgBF ₄ (38 mg, 0.20 mmol) was added to a toluene (25 ml) solution of pivalic acid ester 3 (937 mg, 2.48 mmol) under a stream of Ar at room temperature, and the mixture was stirred at 80 ° C. for 4 hours while being protected from light. The reaction solution was returned to room temperature, water was added, and the mixture was extracted with CHCl ₃ . The combined organic layers were washed with saturated brine and dried over Na ₂ SO ₄ . After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane / butyl acetate = 20/1) to obtain dihydrofuran 4 (589 mg, 63%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ5.58 (1H, d, J = 1.5 Hz, CH = CHOPiv), 5.47 (1H, t, J = 6.8 Hz, CH ₂ CH ₂ CH = C), 5.34 (1H, dt, J = 1.1 , 7.0 Hz, AcOCH 2 CH = C), 5.14 (1H, d, J = 0.8 Hz, CH = CHOPiv), 4.58 (2H, d, J = 7.0 Hz, AcOCH 2 CH = C), 2.20-2.15 (2H, m, CH ₂ ), 2.10-2.05 (2H, m, CH ₂ ), 2.06 (3H, s, CH- ₃ C = O), 1.70 (3H, s, CH ₃ ) , 1.60 (3H, s, CH ₃ ), 1.37 {3H, s, C (CH ₃ ) ₂ }, 1.33 {3H, s, C (CH ₃ ) ₂ }, 1.28 {9H, s, C (CH ₃ ) _{. 3} IR (neat) 2978} , 2943, 2860, 1763, 1736, 1655, 1481, 1460, 1366, 1331, 1275, 1234, 1146, 1105, 1028, 955, 876, 837, 760, 604, 586 cm - ¹ .
Example 4
4,5-dihydro-5-[(1E, 5E) -7-hydroxy-1,5-dimethyl-1,5-heptadienyl] -2,2-dimethyl-3 (2H) -furanone (5) (4, 5-Dihydro-5-[(1E, 5E) -7-hydroxy-1,5-dimethyl-1,5-heptadieyl]-2,2-dimethyl-3 (2H) -furanone (5))

To a solution of dihydrofuran 4 (810 mg, 2.14 mmol) in methanol (63 ml) was added NaOMe (1M methanol solution, 0.63 ml, 0.63 mmol) at room temperature, and the mixture was stirred for 3 hours. Water was added to the reaction solution and extracted with ether. The combined organic layers were washed with saturated brine and dried over Na ₂ SO ₄ . After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to obtain furanone 5 (498 mg, 92%).
^{1 H-NMR (500 MHz,} CDCl 3) δ5.56 (1H, t, J = 7.0 Hz, HOCH 2 CH = C), 5.42 (1H, t, J = 6.9 Hz, CH = C), 4.57 (1H , dd, J = 6.4, 10.1 Hz, CHCH 2 C = O), 4.16 (2H, d, J = 6.2 Hz, HOCH 2 CH = C), 2.52 (1H, dd, J = 6.4, 18.2 Hz, CHCH 2 C = O), 2.52 (1H , dd, J = 6.4, 18.2 Hz, CHCH 2 C = O), 2.45 (1H, dd, J = 10.1, 18.2 Hz, CHCH 2 C = O), 2.27-2.14 (2H , m, CH ₂ CH ₂ ), 2.11-2.08 (2H, m, CH ₂ CH ₂ ), 1.67 (3H, s, CH ₃ ), 1.66 (3H, s, CH ₃ ), 1.59 (1H, br, OH ), 1.31 (3H, s, CH ₃ ), 1.24 (3H, s, CH ₃ ). Physical properties and spectral data agreed with literature values (Non-patent Document 5).
Example 5
5-[(1E, 5E) -7-bromo-1,5-dimethyl-1,5-heptadienyl] -4,5-dihydro-2,2-dimethyl-3 (2H) -furanone (6) (5- [(1E, 5E) -7-Bromo-1,5-dimethyl-1,5-heptadienyl] -4,5-dihydro-2,2-dimethyl-3 (2H) -furanone (6))

CBr ₄ (1.482 g, 4.469 mmol), ( ⁿ C ₈ H ₁₇ ) ₃ P (1.642 g, 4) was added to an ether (10 ml) solution of furanone 5 (448 mg, 1.78 mmol) at 0 ° C. in an Ar stream. .430 mmol) was added and stirred at the same temperature for 4 hours. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 20/1) to obtain bromide 6 (538 mg, 96%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ5.54 (2H, m, 2 x CH = C), 4.57 {1H, dd, J = 6.4, 10.2 Hz, C (O) CH ₂ CH}, 4.02 ( 2H, d, J = 8.4 Hz , BrCH 2 CH = C), 2.53 {1H, dd, J = 6.4, 18.2 Hz, C (O) CH 2 CH}, 2.45 {1H, dd, J = 10.2, 18.2 Hz , C (O) CH ₂ CH}, 2.24-2.17 (2H, m, CH ₂ ), 2.15-2.09 (2H, m, CH ₂ ), 1.74 (3H, s, CH ₃ ), 1.67 (3H, s, CH ₃ ), 1.31 {3H, s, C (CH ₃ ) ₂ }, 124 {3H, s, C (CH ₃ ) ₂ }. IR (neat) 2965, 2901, 2860, 1757, 1659, 1460, 1377, 1356, 1342, 1310, 1202, 1170, 1111, 1001, 856, 675 cm ^-1 .
Example 6
3-chloro-4,6-dihydroxy-2-methyl-5-[(2E, 6E) -3-methyl-7- (3,3-dimethyl-4-oxo-2-oxacyclopentyl) -2,6- Octadienyl] benzaldehyde (ascofuranone) (3-Chloro-4,6-dihydroxy-2-methyl-5-[(2E, 6E) -3-methyl-7- (3,3-dimethyl-4-oxo-2- oxacyclopentyl) -2,6-octadienyl] benzaldehyde (ascofuranone))

Bromide 6 (136mg, 0.431mmol) known aldehyde represented by methanol (0.5 ml) the formula solution from 5-methyl resorcinol was prepared in two steps (VIII) of (J. Org. Chem. 1985, 50, 3997-4005) (67 mg, 0.36 mmol) and CaCl ₂ .2H ₂ O (37 mg, 0.25 mmol) were added and cooled to 0 ° C. To this was added KOH (1M methanol solution, 0.76 ml, 0.76 mmol) and stirred at the same temperature for 8 hours. Saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over Na ₂ SO ₄ , the solvent was distilled off, and the residue was recrystallized from PTLC (first time: hexane / THF = 5/1, second time: hexane / ethyl acetate = 5/1) and recrystallization. Purification with (hexane / ethyl acetate) gave dl-ascofuranone (52 mg, 34%). The physical properties and spectrum data coincided with the literature values (see Non-Patent Documents 2, 3, Patent Documents 4, 5, Non-Patent Document 4, etc.). Mp 88-90 ° C.
¹ H-NMR (500 MHz, CDCl ₃ ) δ 12.70 (1H, s, Ar-OH), 10.14 (1H, s, Ar-CHO), 6.43 (1H, s, Ar-OH), 5.51 (1H, t , J = 6.9 Hz, CH = C), 5.21 (1H, d, J = 7.1 Hz, ArCH ₂ CH = C), 4.52 {1H, dd, J = 6.3, 10.1 Hz, C (O) CH ₂ CH} , 3.39 (2H, d, J = 7.1 Hz, ArCH _-2 CH = C), 2.61 (3H, s, Ar-CH ₃ ), 2.42 (1H, dd, J = 6.3, 18.2 Hz, C (O) CH ₂ CH}, 2.35 {1H, dd, J = 10.1, 18.2 Hz, C (O) CH ₂ CH}, 2.18-2.14 (2H, m, CH ₂ ), 2.06-2.02 (2H, m, CH ₂ ), 1.79 (3H, s, CH ₃ ), 1.63 (3H, s, CH ₃ ), 1.28 {3H, s, C (CH ₃ ) ₂ }, 1.22 {3H, s, C (CH ₃ ) ₂ }. IR ( (KBr) 3327, 2985, 2922, 2874, 1740, 1634, 1582, 1460, 1418, 1371, 1325, 1304, 1283, 1248, 1203, 1171, 1111, 1059, 1011, 907, 824, 712, 631, 592, 523 cm ^-1 .
The aldehyde represented by the formula (II) that is the starting material can be produced, for example, by any of the following methods.
Production method 1 of aldehyde represented by formula (II) :
A carboxylic acid ester of geraniol represented by formula 1 or a derivative thereof can be oxidized using selenium dioxide (SeO ₂ ) and manganese dioxide (MnO ₂ ) to obtain an aldehyde compound represented by formula (II).

(Wherein R ¹ represents the same meaning as described above.)
In Non-patent Document 7 below, geranyl acetate is oxidized using selenium dioxide (SeO ₂ ) and manganese dioxide (MnO ₂ ) to obtain an aldehyde compound represented by the formula (II) in a yield of 46%. It is described.
K. Mori, M. Ohki, and M. Matsui, Tetrahedron, 30, 715 (1974)

Production method 2 of aldehyde represented by formula (II) :
Ozone (O ₃ ) decomposition of the carboxylic acid ester of geraniol represented by formula 1 or a derivative thereof can give the corresponding aldehyde represented by formula 2. Further, when 2- (triphenylphosphoranylidene) propionaldehyde is added to the toluene solution of the obtained aldehyde of formula 2 and reacted, an aldehyde compound represented by formula (II) can be obtained.

(Wherein R ¹ represents the same meaning as described above.)
Production method 2 has one production step compared to production method 1, but has the advantage that the aldehyde compound of formula (II) can be obtained without using toxic selenium dioxide (SeO ₂ ). A production example based on production method 2 will be described below.
Production Example 1
Production of (E) -3-methyl-6-oxo-2-hexenyl acetate

The mixture was stirred for 5 hours while blowing O ₃ at −80 ° C. into a mixed solvent of commercially available geranyl acetate (294 mg, 1.5 mmol) in pyridine (0.39 ml) and dichloromethane (12 ml). After completion of the reaction, argon was blown into the solution at the same temperature to remove excess O ₃ , triphenylphosphine (1180 mg, 4.5 mmol) was added at the same temperature, and the mixture was stirred for 3 hours while gradually returning to room temperature. 1 M HCl was added, extracted 3 times with CHCl ₃ , and the combined organic layers were washed with saturated brine and dried over Na ₂ SO ₄ . After evaporation of the solvent, the residue was purified by silica gel chromatography (Hexane: EtOAc = 6: 1) to give the corresponding aldehyde (130 mg, 51% yield). ¹ NMR (400 MHz, CDCl ₃ ) δ 9.78 (s, 1H), 5.36 (t, J = 7.0 Hz, 1 H), 4.58 (d, J = 7.0), 2.59 (t, J = 7.5 Hz, 2H) , 2.38 (t, 7J = 7.5 Hz, 2H), 2.06 (s, 3H), 1.73 (s, 3H).
Production Example 2
Production of (E, E) -3,7-Dimethyl-8-oxo-2,6-octadienyl acetate

2- (Triphenylphosphranylidene) propionaidehyde (130 mg, 0.4 mmol) was added to a solution of (E) -3-methyl-6-oxo-2-hexenyl acetate (36 mg, 0.2 mmol) in toluene (5 ml) at 100 ° C. Stir for 36 hours. After the solvent was distilled off, Et ₂ O was added and filtered. Preparative The crude product obtained by concentrating the filtrate minutes TLC (n-Hexane: EtOAc = 4: 1) purified by the known aldehydes (Tetrahedron, 30, 715 (1974)) was obtained (38 mg, yield 91%). _{^{1 NMR (400 MHz, CDCl 3}} ) δ 9.40 (s, 1H), 6.45 (t, J = 7.0, 1H), 5.39 (t, J = 7.0, 1H), 4.60 (d, J = 7.0, 2H), 2.20-2.50 (m, 4H), 2.06 (s, 3H), 1.76 (s, 3H), 1.75 (s, 3H).

  Since the production method of the present invention uses the compounds represented by the formulas (III), (IV), (V), and (VII) as novel synthetic intermediates, the conventional total synthesis method of ascofuranone and its derivatives Compared to the above, the number of manufacturing processes can be greatly reduced. Therefore, it is extremely useful in terms of time and economy as an industrial process for ascofuranone and its derivatives.

Claims (9)

Formula (XX),

(Wherein Y represents an R ¹ COO group, a halogen atom, or an R ⁵ SO ₃ group (R ⁵ represents an alkyl group having 1 to 7 carbon atoms or an alkyl group having 1 to 7 carbon atoms on a carbon atom of a benzene ring) Represents a phenyl group having
W is the following group

Represents a group selected from
R ¹ and R ² are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a phenoxyalkyl group having a halogen atom on the carbon atom of the benzene ring, or a carbon atom having 1 to 1 carbon atoms on the carbon atom of the benzene ring. 7 represents a phenyl group having an alkoxy group having 7 or an alkoxycarbonyl group having 1 to 7 carbon atoms. However, when Y represents a halogen atom or an R ⁵ SO ₃ group (R ⁵ has the above-mentioned meaning), W represents

Represents a group of )
And optical isomers thereof, and pharmaceutically acceptable salts thereof. Following formula

(Wherein R ¹ represents the same meaning as described above.)
The compound of Claim 1 which is a compound represented by these, its optical isomer, and those pharmaceutically acceptable salts. Following formula

(Wherein R ¹ and R ² represent the same meaning as described above.)
The compound of Claim 1 which is a compound represented by these, its optical isomer, and those pharmaceutically acceptable salts. Following formula

(Wherein R ¹ and R ² represent the same meaning as described above.)
The compound of Claim 1 which is a compound represented by these, its optical isomer, and those pharmaceutically acceptable salts. Following formula

(In the formula, X represents a halogen atom.)
The compound of Claim 1 which is a compound represented by these, its optical isomer, and those pharmaceutically acceptable salts. Formula (II)

Wherein R ¹ is a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a phenoxyalkyl group having a halogen atom on the carbon atom of the benzene ring, or an alkoxy group having 1 to 7 carbon atoms on the carbon atom of the benzene ring. Or a phenyl group having an alkoxycarbonyl group having 1 to 7 carbon atoms) is reacted with 2-methyl-3-butyn-2-ol to give a compound represented by the general formula (III)

(Wherein R ¹ represents the same meaning as described above), and this compound is represented by the general formula R ² CO (Hal) (wherein R ² is a hydrogen atom, carbon number 1- 7 alkyl groups, phenoxyalkyl groups having a halogen atom on carbon atoms of the benzene ring, or phenyl groups having an alkoxy group having 1 to 7 carbon atoms or an alkoxycarbonyl group having 1 to 7 carbon atoms on carbon atoms of the benzene ring. And (Hal) represents a halogen atom.) By reacting with an acyl halide represented by the general formula (IV)

(Wherein R ¹ and R ² represent the same meaning as described above), and the compound is represented by the general formula (V) by a ring-closing reaction.

(Wherein R ¹ and R ² represent the same meaning as described above), and this compound is converted to a general formula (VI) by a deacylation reaction.

And the terminal OH group of this compound is substituted with a halogen atom to thereby convert the compound represented by the general formula (VII)

(In the formula, X represents a halogen atom.)
Is converted to a compound represented by the general formula (VIII)

Is reacted with a compound represented by the following formula (I):

A method for producing ascofuranone, which comprises producing ascofuranone represented by:   The production method according to claim 6, wherein a known asymmetric synthesis method is used. Formula 1

(Wherein R ¹ represents the same meaning as described above.)
The carboxylic acid ester of geraniol represented by the formula (1) or a derivative thereof is oxidized using selenium dioxide (SeO ₂ ) and manganese dioxide (MnO ₂ ) to obtain an aldehyde compound represented by the formula (II). Method. Formula 1

(Wherein R ¹ represents the same meaning as described above.)
By ozonolysis of a carboxylic acid ester of geraniol or its derivative

(Wherein R ¹ represents the same meaning as described above.)
And then the resulting aldehyde of formula 2 is

(In the formula, Ph represents a phenyl group.)
The method of Claim 6 or 7 which obtains the aldehyde compound shown by Formula (II) by adding 2- (triphenyl phospharanylidene) propionaldehyde shown by these, and making it react.