JP2010159211A - Method for producing withanolide compounds - Google Patents

Abstract

（式中、Ｒ_１、Ｒ_２は水素原子、メチル基等、Ｒ_３、Ｒ_４は水素原子または水酸基を意味し；水素原子または水酸基を意味し；Ｒ_５は、水酸基、糖鎖等を意味する）で表される化合物またはその塩の製造方法。
【選択図】なしProvided is a novel method for producing withanolides.
The following formula (2)

(Wherein R ₁ and R ₂ are a hydrogen atom, a methyl group, etc., R ₃ and R ₄ are a hydrogen atom or a hydroxyl group; a hydrogen atom or a hydroxyl group is meant; R ₅ is a hydroxyl group, a sugar chain, etc. Or a salt thereof.
[Selection figure] None

Description

  The present invention relates to a method for producing withanolides.

  Witanolides are ergostanic steroids having a delta-lactone that can be isolated from the plants of the family Solanaceae belonging to Withania, Acnistus (Dunalia), Physalis, Nicandra, Datura and the like.

  Withanolides include various derivatives such as withaferrin A, withanolide D, withanolide E, and sominone, and some withanolides are known to have an anti-tumor action and an insect feeding inhibitory action. The amount of witanolides obtained from nature is very small, and various synthetic methods have been developed.

  Specifically, for example, a method of synthesizing witherferin A and deoxyvitaferin A using a steroidal epoxide as a raw material and a phenylthiolactone body as a synthetic intermediate (Non-patent Document 1), an α-phenylthiolactone body Raw material, alkylation of thiophenyl group, synthesis method of witaferin A and deoxyvitaferin A using allyl sulfoxide-sulfenate transfer reaction (Non-patent Document 2), gamma coupling reaction, allyl sulfoxide-sulfenate using pregnenolone as raw material A method for synthesizing Witanolide D using rearrangement reaction (Non-patent Document 3), a method for synthesizing Witanolide E using steroidal diacetate as a raw material and utilizing heterodiels Alder reaction (Non-Patent Document 4), 20-carboxaldehyde As raw material, A method for synthesizing a side chain of withanolide using a furyl carbinol compound as a synthetic intermediate (Non-patent Document 5) is disclosed.

  However, since all the conventional synthesis methods have many steps and low yields, development of a more efficient method for producing withanolides has been desired.

N. Ikekawa, et al., Chem. Lett., Pp.491-494, 1982. N. Ikekawa, et al., Tetrahedron Lett., Vol. 23, No. 45, pp. 4725-4728, 1982. N. Ikekawa, et al., J. Chem. Soc., Perkin Trans. 1., pp.449-454, 1984. P. Grieco, et al., J. Am. Chem. Soc., 1991, 113, 1057-1059. T. Honda, et al., J. Org. Chem. 1992, 57, 2930-2934.

  An object of the present invention is to develop a novel production method capable of efficiently synthesizing withanolides.

  The inventors of the present invention have made extensive studies to solve the above-mentioned problems. As a result, by applying a ring-closing metathesis reaction to the side chain portion of the steroid skeleton, a lactone ring is efficiently formed on the side chain, and witanolide is formed. It has been found that it can be easily produced.

（式中、Ｒ_１は、水素原子、メチル基またはＣＨ_２ＯＨを意味し；Ｒ_２は、水素原子またはメチル基を意味し；Ｒ_３は、水素原子または水酸基を意味し；Ｒ_４は、水素原子または水酸基を意味し；Ｒ_５は、水素原子、糖鎖または保護基を意味する。）で表される化合物と触媒とを共存させて、閉環メタセシス反応を行う、下記式（２）

（式中、Ｒ_１〜Ｒ_５は式（１）のＲ_１〜Ｒ_５と同意義を示す。）で表される化合物またはその塩の製造方法。
〔２〕前記式（１）で表される化合物またはその塩が、下記式（３）

（式中、Ｒ_２〜Ｒ_５は〔１〕に記載のＲ_２〜Ｒ_５と同意義を示す。）で表される化合物と、下記式（４）

（式中、Ｒ_１は〔１〕に記載のＲ_１と同意義を示し、Ｘはハロゲン原子を意味する。）で表される化合物とを反応させて得られる、〔１〕に記載の製造方法。
〔３〕前記保護基が「−ＴＢＳ」である、〔１〕または〔２〕に記載の製造方法。
〔４〕前記糖鎖が「−^１ｇｌｃ^６−^１ｇｌｃ、」である、〔１〕〜〔３〕のいずれかに記載の製造方法。
〔５〕前記Ｒ_１〜Ｒ_５が以下の（ａ）〜（ｄ）のいずれかの組合せからなる、〔１〕〜〔４〕のいずれかに記載の製造方法；
（ａ）Ｒ_１＝ＣＨ_２ＯＨ、Ｒ_２＝メチル基、Ｒ_３＝水素原子、Ｒ_４＝水酸基、Ｒ_５＝−^１ｇｌｃ^６−^１ｇｌｃ、
（ｂ）Ｒ_１＝メチル基、Ｒ_２＝メチル基、Ｒ_３＝水酸基、Ｒ_４＝水酸基、Ｒ_５＝−^１ｇｌｃ^６−^１ｇｌｃ、
（ｃ）Ｒ_１＝ＣＨ_２ＯＨ、Ｒ_２＝メチル基、Ｒ_３＝水素原子、Ｒ_４＝水酸基、Ｒ_５＝水素原子、および
（ｄ）Ｒ_１＝水素原子、Ｒ_２＝水素原子、Ｒ_３＝水素原子、Ｒ_４＝水素原子、Ｒ_５＝−ＴＢＳ。
〔６〕前記触媒が第一世代グラブズ触媒である、〔１〕〜〔５〕のいずれかに記載の製造方法。
〔７〕下記工程１〜８；

（式中、Ｒ_１〜Ｒ_５は〔１〕に記載のＲ_１〜Ｒ_５と同意義を示す。）を含む、〔１〕〜〔６〕に記載の製造方法。 That is, the present invention includes the following.
[1] The following formula (1)

(In the formula, _{R 1} represents a hydrogen atom, and a methyl group or _{CH 2} OH; _R 2 means a hydrogen atom or a methyl group; _{R 3} means a hydrogen atom or a hydroxyl group; _{R 4} is, A hydrogen atom or a hydroxyl group; R ₅ represents a hydrogen atom, a sugar chain or a protecting group) and a catalyst is used in the presence of a compound represented by the following formula (2):

(Wherein R _{1 to} R ₅ have the same meanings as R _{1 to} R ₅ in formula (1)), or a method for producing a salt thereof.
[2] The compound represented by the formula (1) or a salt thereof is represented by the following formula (3):

_(Wherein, R 2 to R ₅ are _R 2 to R ₅ and the same significance. Of [1]) and the compound represented by the following formula (4)

(Wherein R ₁ has the same meaning as R ₁ described in [1], and X represents a halogen atom), which is obtained by reacting with the compound represented by [1]. Method.
[3] The production method according to [1] or [2], wherein the protecting group is “-TBS”.
[4] The sugar chain ^"- 1 ^glc 6 ^- 1 glc," a method according to any one of [1] to [3].
[5] The production method according to any one of [1] to [4], wherein R _{1 to} R ₅ are composed of any combination of the following (a) to (d):
_{(A) R 1 = CH 2} OH, R 2 = methyl, _{R 3} = hydrogen atom, _{R 4} = ^{_{hydroxyl, R 5 = - 1 glc 6}} - 1 glc,
(B) _{R 1} = methyl, _{R 2} = methyl, _{R 3} = hydroxyl, _{R 4} = ^{_{hydroxyl, R 5 = - 1 glc 6}} - 1 glc,
(C) R ₁ = CH ₂ OH, R ₂ = methyl group, R ₃ = hydrogen atom, R ₄ = hydroxyl group, R ₅ = hydrogen atom, and (d) R ₁ = hydrogen atom, R ₂ = hydrogen atom, R ₃ = hydrogen atom, R ₄ = hydrogen atom, R ₅ = -TBS.
[6] The production method according to any one of [1] to [5], wherein the catalyst is a first generation Grubbs catalyst.
[7] The following steps 1 to 8;

(In the formula, R _{1 to} R ₅ have the same meanings as R _{1 to} R ₅ described in [1].) The production method according to [1] to [6].

  Since the present invention applies the ring-closing metathesis reaction to the compound represented by the formula (1), the compound represented by the formula (2) or a salt thereof can be produced efficiently and in high yield. . Further, the production method of the present invention can proceed under mild conditions and can be easily isolated, and thus is excellent for industrial use.

（式中、Ｒ_１は、水素原子、メチル基またはＣＨ_２ＯＨを意味し；Ｒ_２は、水素原子またはメチル基を意味し；Ｒ_３は、水素原子または水酸基を意味し；Ｒ_４は、水素原子または水酸基を意味し；Ｒ_５は、水素原子、糖鎖または保護基を意味する。）で表される化合物から、下記式（２）

（式中、Ｒ_１〜Ｒ_５は式（１）のＲ_１〜Ｒ_５と同意義を示す。）で表される化合物またはその塩（ウィタノライド類）を合成する新規な製造方法を提供するものである。 [Embodiment of the Invention]
In the present invention, a ring-closing metathesis reaction using a catalyst is represented by the following formula (1):

(In the formula, _{R 1} represents a hydrogen atom, and a methyl group or _{CH 2} OH; _R 2 means a hydrogen atom or a methyl group; _{R 3} means hydrogen atom or a hydroxyl group; _{R 4} is, A hydrogen atom or a hydroxyl group; R ₅ represents a hydrogen atom, a sugar chain or a protecting group.) From the compound represented by the following formula (2)

(Wherein R _{1 to} R ₅ have the same meanings as R _{1 to} R ₅ in formula (1)) and provide a novel production method for synthesizing a compound represented by the compound or a salt thereof (vitanolides) It is.

  In the present specification, the “sugar chain” refers to a group in which various sugars such as glucose are bonded by a glycosidic bond.

If _{R 5} is a sugar of the formula (1) and the compound represented by formula (2), sugar chains, ^"- 1 ^glc 6 ^- 1 glc" are preferred. Incidentally, means glucose as "glc", "- ¹ glc 6 ^- 1 ^glc" and combines with the oxygen atom bonded to the 1-position and 3-position carbon atom in the formula of one glucose, the It means a group in which the 6-position of glucose and the 1-position of other glucose are linked by 1,6.

  Examples of the protecting group in the present specification include those commonly used as a protecting group for a hydroxyl group. Specific examples of such protecting groups include silyl ether-based protection such as t-butyldimethylsilyl (TBS) group, trimethylsilyl (TMS) group, triethylsilyl (TES) group, and t-butyldiphenylsilyl (TBDPS) group. Groups, ether protecting groups such as benzyl (Bn) group, p-methoxybenzyl (PMB) group, acetals such as methoxymethyl (MOM) group, 2-methoxyethoxymethyl (MEM) group, tetrahydropyranyl (THP) group Examples thereof include acyl protecting groups such as a system protecting group, an acetyl group, a pivaloyl group, and a benzoyl group.

When R _{5 of the} compounds represented by the formulas (1) and (2) is a protecting group, the protecting group is preferably a silyl ether protecting group, and among the silyl ether protecting groups, a TBS group is preferred. .

As the substituents of the compounds represented by the formulas (1) and (2), any combination of the following (a) to (d) is preferable;
_{(A) R 1 = CH 2} OH, R 2 = methyl, _{R 3} = hydrogen atom, _{R 4} = ^{_{hydroxyl, R 5 = - 1 glc 6}} - 1 glc,
(B) _{R 1} = methyl, _{R 2} = methyl, _{R 3} = hydroxyl, _{R 4} = ^{_{hydroxyl, R 5 = - 1 glc 6}} - 1 glc,
(C) R ₁ = CH ₂ OH, R ₂ = methyl group, R ₃ = hydrogen atom, R ₄ = hydroxyl group, R ₅ = hydrogen atom, and (d) R ₁ = hydrogen atom, R ₂ = hydrogen atom, R ₃ = hydrogen atom, R ₄ = hydrogen atom, R ₅ = -TBS.

  The configuration at the 22-position in the compound represented by the formula (1), the formula (2) and the formula (3) described later is not limited, but the R form is preferable.

（式中、Ｃｙはシクロヘキシル基を意味する。）、第二世代グラブス触媒；

（式中、Ｃｙはシクロヘキシル基を意味する。）またはシュロック触媒などが挙げられる。これらのうちでは、第一世代グラブス触媒が好ましい。 The catalyst used in the ring-closing metathesis reaction is not particularly limited, but for example, a first generation Grubbs catalyst;

(Wherein Cy means a cyclohexyl group), second generation Grubbs catalyst;

(In the formula, Cy means a cyclohexyl group) or a Schrock catalyst. Of these, the first generation Grubbs catalyst is preferred.

  By using the catalyst for the compound represented by the formula (1), it is possible to synthesize the compound represented by the formula (2) at a high yield under mild conditions.

  The “salt” means an alkali metal salt such as a sodium salt or potassium salt of a compound described herein, an alkaline earth metal salt such as a calcium salt or a magnesium salt, an aluminum salt, or a trimethylamine salt or a triethylamine salt. And organic base salts such as N, N-diisopropylethylamine salt.

  In the present specification, the “ring-closing metathesis reaction” refers to a catalytic reaction in which a cyclic olefin is produced from two types of olefins in a molecule through cleavage and generation of double bonds.

The ring-closing metathesis reaction can be performed in a solvent. The solvent is preferably a nonpolar solvent. Of the nonpolar solvents, CH ₂ Cl ₂ , toluene or 1,2-dichloroethane is preferred, and among these, CH ₂ Cl ₂ is more preferred.

  The reaction temperature of the ring-closing metathesis reaction is usually 15 to 40 ° C., more preferably room temperature. The reaction time of the ring-closing metathesis reaction is usually 1 to 24 hours, preferably 4 to 6 hours.

  By applying a ring-closing metathesis reaction to the compound represented by the formula (1), the compound represented by the formula (2) or a salt thereof can be produced efficiently and in high yield. Further, the production method of the present invention can proceed under mild conditions and can be easily isolated, and thus is excellent for industrial use.

（式中、Ｒ_２は、水素原子またはメチル基を意味し；Ｒ_３は、水素原子または水酸基を意味し；Ｒ_４は、水素原子または水酸基を意味し；Ｒ_５は、水素原子、糖鎖または保護基を意味する。）で表される化合物と、下記式（４）

（式中、Ｒ_１は、水素原子、メチル基またはＣＨ_２ＯＨを意味し；Ｘはハロゲン原子を意味する。）で表される化合物とを反応（エステル化）させることによる、下記式（１）

（式中、Ｒ_２〜Ｒ_５は、前記式（３）に記載のＲ_２〜Ｒ_５を示し、Ｒ_１は、前記式（４）に記載のＲ_１と同意義を示す。）で表される化合物またはその塩の製造方法を提供することである。 As another aspect of the present invention, the following formula (3)

(Wherein R ₂ represents a hydrogen atom or a methyl group; R ₃ represents a hydrogen atom or a hydroxyl group; R ₄ represents a hydrogen atom or a hydroxyl group; R ₅ represents a hydrogen atom or a sugar chain) Or a protecting group.) And a compound represented by the following formula (4):

(In the formula, R ₁ represents a hydrogen atom, a methyl group or CH ₂ OH; X represents a halogen atom.) By reacting (esterifying) with a compound represented by the following formula (1 )

Table _(wherein, R 2 to R ₅ represents a _R 2 to R ₅ as defined in the formula (3), _{R 1} is. Of the same meaning as _{R 1} according to the equation (4)) in And a method for producing the salt thereof.

If _{R 5} is a sugar chain of the compound represented by the formula (3), sugar chains, ^"- 1 ^glc 6 ^- 1 ^glc" are preferred.

When R _{5 of the} compound represented by the formula (3) is a protecting group, the protecting group is preferably a silyl ether protecting group, and among the silyl ether protecting groups, a TBS group is preferred.

As the substituents of the compounds represented by the formulas (3) and (4), any combination of the following (a) to (d) is preferable;
_{(A) R 1 = CH 2} OH, R 2 = methyl, _{R 3} = hydrogen atom, _{R 4} = ^{_{hydroxyl, R 5 = - 1 glc 6}} - 1 glc,
(B) _{R 1} = methyl, _{R 2} = methyl, _{R 3} = hydroxyl, _{R 4} = ^{_{hydroxyl, R 5 = - 1 glc 6}} - 1 glc,
(C) R ₁ = CH ₂ OH, R ₂ = methyl group, R ₃ = hydrogen atom, R ₄ = hydroxyl group, R ₅ = hydrogen atom, and (d) R ₁ = hydrogen atom, R ₂ = hydrogen atom, R ₃ = hydrogen atom, R ₄ = hydrogen atom, R ₅ = -TBS.

  Examples of the halogen atom in the compound represented by the formula (4) include F, Cl, Br, and I. Among these, Cl is preferable.

  A base can be used for the esterification reaction in which the compound represented by the formula (4) is reacted with the compound represented by the formula (3). Preferred examples of the base include trialkylamines such as diisopropylethylamine (DIPEA) and triethylamine, and pyridines. Among these, DIPEA is more preferable.

A solvent can be used for the esterification reaction. The solvent is preferably a nonpolar solvent, and among the nonpolar solvents, CH ₂ Cl ₂ , toluene or THF is more preferable.

  The reaction temperature of the esterification reaction is usually 0 to 30 ° C., preferably room temperature. The reaction time for the esterification reaction is usually 1 to 10 hours, and more preferably 2 to 4 hours.

  By utilizing the esterification reaction, the compound represented by the formula (1) that is a precursor of the ring-closing metathesis reaction can be efficiently produced.

Another aspect of the present invention is a method for producing withanolides using trans dehydroandrosterone or a derivative thereof as a raw material.
This manufacturing method can be implemented along the following scheme A, for example.

In the scheme A, R ₁ represents a hydrogen atom, a methyl group or CH ₂ OH, R ₂ represents a hydrogen atom or a methyl group, R ₃ represents a hydrogen atom or a hydroxyl group, and R ₄ represents , Represents a hydrogen atom or a hydroxyl group, and R ₅ represents a hydrogen atom, a sugar chain or a protecting group.

The first step in Scheme A is a step of introducing R ₅ into the hydroxyl group at the 3-position of compound (5).

When introducing a sugar chain as R _5, sugar chains, ^"- 1 ^glc 6 ^- 1 ^glc" are preferred. The introduction of sugar chains can be carried out, for example, by the method described in the 4th edition, Laboratory Science Course Vol. 26, pp 267-354 (written by Yukinari Ito, Tomoya Ogawa, edited by The Chemical Society of Japan (Maruzen) 1992).

When a protective group is introduced as R ₅ , the protective group is not particularly limited as long as it does not affect the subsequent reaction, but trimethylsilyl (TMS) group, triethylsilyl (TES) group, t-butyldimethylsilyl (TBS) Group, silyl ether protecting group such as triisopropylsilyl (TIPS) group or t-butyldiphenylsilyl (TBDPS) group, ether protecting group such as benzyl (Bn) group, p-methoxybenzyl (PMB) group, methoxymethyl Acetal protecting groups such as (MOM) group, 2-methoxyethoxymethyl (MEM) group, tetrahydropyranyl (THP) group, and acyl protecting groups such as acetyl group, pivaloyl group and benzoyl group can be introduced. Of these, silyl ether-based protecting groups are preferred, and among silyl ether-based protecting groups, TBS groups are preferred.

  The introduction of the protecting group in the first step can be performed, for example, by the method described in “Greene and Wuts,“ Protective Groups in Organic Synthesis ”(2nd edition, John Wiley & Sons 1991)”.

Specifically, for example, R ₅ -L (wherein R ₅ represents the same meaning as described above and L represents a leaving group) is added to the compound represented by the formula (5) to add the formula ( The compound represented by 6) can be synthesized. The leaving group is preferably a trifluoromethanesulfonyloxy (OTf) group.

The second step in the scheme A is a step of converting the carbonyl group at the 17-position of the compound (6) into an olefin, and can be obtained, for example, by a Wittig reaction using a corresponding phosphorus ylide. The phosphorus ylide is preferably Ph ₃ P ⁺ CH (R ₃ ) CH ₃ Br ⁻ (wherein R ₃ represents a hydrogen atom or a protected hydroxyl group), and Ph ₃ P ⁺ CH ₂ CH ₃ Br ⁻ is preferably More preferred. In the second step, a base such as t-butoxypotassium (t-BuOK), n-butyllithium (n-BuLi), lithium diisopropylamide (LDA) can be used.

  Examples of the solvent used in the second step include THF and nonpolar solvents such as ether (diethyl ether). Among these, THF can be preferably used.

  The reaction temperature in the second step is usually 0 to 100 ° C. Moreover, reaction time is 12 to 48 hours normally, Preferably it is 22 to 26 hours. The reaction is preferably carried out at reflux.

  The third step in the scheme A is a step of converting the compound (7) into the compound (8), and can be obtained, for example, by using an ene reaction using formaldehyde or paraformaldehyde.

In the third step, dimethylaluminum chloride (Me ₂ AlCl) or diethylaluminum chloride (Et ₂ AlCl) can be used as a reagent.

Examples of the solvent used in the third step include CH ₂ Cl ₂ and nonpolar solvents such as toluene. Among these, CH ₂ Cl ₂ can be preferably used.

  The reaction temperature in the third step is usually -78 to 0 ° C, preferably -78 to -40 ° C. Moreover, reaction time is 10 minutes-2 hours normally, Preferably it is 20 minutes-40 minutes.

  The fourth step in the scheme A is a step of synthesizing the compound (9) by reducing the double bond between the 16th and 17th positions of the compound (8) to a single bond by a hydrogenation reaction using a catalyst. Preferably, hydrogen gas can be used as the hydrogen source. Moreover, a palladium catalyst, a nickel catalyst, a ruthenium catalyst, and a platinum catalyst can be normally used for a catalyst. Among these, a palladium catalyst is preferable, and among the palladium catalysts, palladium carbon (Pd / C) is preferable.

In the fourth step, either a polar solvent or a nonpolar solvent can be used. Of the nonpolar solvents, THF, toluene, or CH ₂ Cl ₂ can be preferably used.

  The reaction temperature in the fourth step is usually 15 to 40 ° C., preferably room temperature. Moreover, reaction time is 2 to 10 hours normally, Preferably it is 4 to 6 hours.

  The fifth step in the scheme is a step of synthesizing compound (10) by adding an oxidizing agent to compound (9). The oxidizing agent is not particularly limited as long as it can be oxidized from alcohol to aldehyde, but pyridinium dichromate (PDC) and pyridinium chlorochromate (PCC) are preferable, and among these, PDC is more preferable. Also, molecular sieves can be added to the reaction.

Examples of the solvent used in the fifth step include non-polar solvents such as CH ₂ Cl ₂ , toluene, and THF, and among these, CH ₂ Cl ₂ can be preferably used.

  The reaction temperature in the fifth step is usually 15 to 40 ° C., preferably room temperature. Moreover, reaction time is 1 to 5 hours normally, Preferably it is 2 to 4 hours.

（式中、Ｒ_２は水素原子またはメチル基を意味し、Ｘは、ハロゲン原子を意味する。）を用いることができる。ハロゲン原子としては、Ｆ、Ｃｌ、ＢｒまたはＩが挙げられ、これらのうちではＣｌが好ましい。 The sixth step in the scheme A is a step of converting the compound (10) into the compound (4), and can be obtained by using, for example, a Grignard reaction. As a Grignard reagent,

(Wherein R ₂ represents a hydrogen atom or a methyl group, and X represents a halogen atom). Examples of the halogen atom include F, Cl, Br or I, and among these, Cl is preferable.

  Examples of the solvent used in the sixth step include nonpolar solvents such as THF, toluene, or ether (diethyl ether). Among nonpolar solvents, THF can be preferably used.

  The reaction temperature in the sixth step is usually -78 to 0 ° C, preferably -78 to -40 ° C. Moreover, reaction time is 10 minutes-1 hour normally, Preferably it is 20 minutes-40 minutes.

（式中、Ｒ_１は前記と同意義を示し、Ｘはハロゲン原子を意味する。）
を塩基の存在下で反応させることにより得ることができる。反応条件等の詳細は化合物（１）の製造方法で示したとおりである。 The seventh step in Scheme A is a step of converting compound (4) to compound (1), for example, an acid halide having the following structure;

(Wherein R ₁ is as defined above, and X is a halogen atom.)
Can be obtained by reacting in the presence of a base. Details of reaction conditions and the like are as shown in the production method of compound (1).

  The eighth step in Scheme A is a step of synthesizing compound (2) from compound (1) and can be obtained by a ring-closing metathesis reaction. Details of reaction conditions and the like are as shown in the production method of compound (2).

When R ₅ of the compound (2) is a hydrogen atom, the hydrogen atom may be a hydrogen atom of the compound (5), and a protective group is introduced as R _{5 in} the first step, and before any subsequent step or It may be a hydrogen atom produced by a deprotection reaction performed later.

When R ₅ of the compound (2) is a protecting group, a protecting group may be introduced as R _{5 in} the first step, or a protecting group may be introduced before or after any of the subsequent steps.

When R ₅ of compound (2) is a sugar chain, a sugar chain may be introduced as R ₅ in the first step, a protecting group is introduced as R _{5 in} the first step, and before any subsequent step Or you may introduce | transduce a sugar chain into the hydroxyl group liberated by the deprotection reaction performed later.

When R ₅ is a protecting group, the deprotection reaction can be performed, for example, by the method described in “Greene and Wuts,“ Protective Groups in Organic Synthesis ”(2nd edition, John Wiley & Sons 1991). . In addition, the bond between the free hydroxyl group and the sugar chain is performed by the method described in, for example, the 4th edition, Laboratory Science Course Vol. 26 pp 267-354 (Yukinari Ito, Tomoya Ogawa, edited by the Chemical Society of Japan (Maruzen) 1992). Can do.

  By using the synthesis method according to the above scheme A, it is possible to produce witanolides in a shorter number of steps and in a higher yield than conventional methods, using easily available and inexpensive starting materials.

  EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not limited to an Example at all.

Data measurement in the examples was performed using the following equipment.
The melting point was measured using a Yanagimoto micro melting point measuring device. All measured values are uncorrected. Moreover, the infrared absorption spectrum (IR) was measured using JASCO FT / IR-660. Hydrogen and carbon nuclear magnetic resonance spectra (H ¹ -NMR, C ¹³ -NMR) were measured using a Varian FX270, Varian Gemini 300, Varian UNITY puls 500 nuclear magnetic resonance apparatus. Chemical shifts are indicated in ppm, and the following abbreviations are used for signal splitting modes. s = singlet, d = doublelet, t = triplet, q = quartet, m = multiplet, br = broad. The coupling constant (J) is indicated in Hz. Shimadzu GCMS-QP500 type, JEOL D-200, LEOL AX505 (70 eV direct inlet system) was used for low resolution Mass spectrum measurement.
Further, as reagents used in the examples, commercially available reagents were used unless otherwise specified.
[Example 1]
Compound (2a) was produced according to Scheme B below.

First step: 3- (t-butyldimethylsilanyloxy) -10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16- Synthesis of tetradecahydrocyclopenta [a] phenanthren-17-one (compound (6a)) Commercially available transdehydroandrosterone (compound (5a)) (1.44 g, 5.00 mmol) (SIGMA-ALDRICH) under argon atmosphere Triethylamine (2.10 mL, 15.0 mmol) and TBSOTf (1.72 mL, 7.50 mmol) were added to a solution of product number D4000) in dichloromethane (25 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour and diluted with dichloromethane. The reaction solution was washed successively with 10% aqueous HCl, saturated aqueous sodium hydrogen carbonate and saturated brine, and the organic layer was dried over magnesium sulfate. It was filtered and then evaporated to remove the solvent. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ ) to obtain compound (6a) (1.90 g, 4.71 mmol, 94%) as a white solid material (mp 151-153 ° C.). The measurement results such as NMR of the obtained compound (6a) are shown below.

¹ H-NMR (270 MHz) (CDCl ₃ ): δ 5.35 (1H, d, J = 5.1 Hz), 3.52-3.45 (1H, m), 2.51-1.06 (19H, m), 1.03 (3H, s), 0.89 (12H, s), 0.06 (6H, s); ¹³ C-NMR (67.5 MHz) (CDCl ₃ ): δ 221.03, 141.76, 120.37, 72.41, 51.79, 50.31, 47.51, 42.76, 37.29, 36.69, 35.81, 32.00, 31.50, 31.44, 30.80, 25.90, 21.86, 20.33, 19.43, 18.21, 13.52, -4.61; IR (KBr): 2928, 2857, 1748, 1668 cm ^-1 ; MS (EI): m / z 345 (M ⁺ -57); HMRS Calcd for C ₂₁ H ₃₃ O ₂ Si: 345.2250 (M ⁺ -57), found: 345.2271; [α] ^25.3 _D = + 6.10 (c = 1.00, CHCl ₃ )

Second step: t-butyl- (17-ethylidene-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro Synthesis of -1H-cyclopenta [a] phenanthrene-3-yloxy) -dimethylsilane (compound (7a)) To a solution of ethyltriphenylphosphonium bromide (20.87 g, 56.2 mmol) in THF (120 mL) under an argon atmosphere, t -BuOK (6.34 g, 56.2 mmol) was added and stirred at room temperature for 1 hour. Compound (6a) (5.82 g, 14.4 mmol) was added to this solution, and the mixture was heated to reflux for 15 hours. Then, the reaction was stopped with a saturated aqueous ammonium chloride solution, and the organic layer extracted with dichloromethane was dried over magnesium sulfate. Was distilled off. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ : hexane = 1: 4), and compound (7a) (5.08 g, 12.2 mmol, 85%) was obtained as a white solid material (mp 127-130 ° C.). Got. The measurement results such as NMR of the obtained compound (7a) are shown below.

¹ H-NMR (270 MHz) (CDCl ₃ ): δ 5.32 (1H, d, J = 5.4 Hz), 5.13 (H, tq, J = 2.2, 7.0 Hz), 3.52-3.41 (1H, m), 3.47- 1.02 (19H, m), 0.99 (3H, s), 0.87 (15H, m), 0.04 (6H, s); ¹³ C-NMR (67.5 MHz) (CDCl ₃ ): δ 150.28, 141.58, 121.02, 113.45, 72.59, 56.57, 50.24, 44.05, 42.83, 37.34, 37.02, 36.64, 32.09, 31.76, 31.44, 25.94, 24.49, 21.22, 19.40, 18.25, 16.61, 13.13, -4.59; IR (KBr): 3032, 2938, 1771, 1668 cm ^-1 ; MS (EI): m / z 357 (M ⁺ -57); HMRS Calcd for C ₂₃ H ₃₇ OSi: 357.2614 (M ⁺ -57), found: 357.2581; [α] ^28.1 _D = -45.19 (c = 1.00, CHCl ₃ )

Third step: 2- [3- (t-butyldimethylsilanyloxy) -13-methyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H -Synthesis of cyclopenta [a] phenanthren-17-yl] -propan-1-ol (compound (8a)) Under argon atmosphere, a solution of compound (7a) (1.24 g, 3.00 mmol) in dichloromethane (30 mL) Paraformaldehyde (1.80 g, 60.0 mmol) and dimethylaluminum chloride (28.8 mL, 30.0 mmol) were added at −78 ° C., and the mixture was stirred at −78 ° C. for 3 hours, and then the reaction was stopped with saturated aqueous sodium hydrogen carbonate. The reaction solution was filtered through celite, extracted with dichloromethane, dried over magnesium sulfate, and the solvent was distilled off after filtration. The residue was purified by silica gel chromatography (CH ₂ Cl ₂ ) to obtain the compound (8a) (0.960 g, 2.15 mmol, 72%) as a white solid material (mp154-157 ° C.). The measurement results such as NMR of the obtained compound (8a) are shown below.

¹ H-NMR (270MHz) (CDCl ₃ ): δ 5.41 (1H, s), 5.32 (1H, d, J = 5.1Hz), 3.62-3.39 (3H, m), 2.39-1.07 (19H, m), 1.03-1.00 (6H, m), 0.87 (9H, s), 0.80 (3H, s), 0.04 (6H, s); ¹³ C-NMR (67.5 MHz) (CDCl ₃ ): δ 157.59, 141.85, 122.99, 120.93, 72.57, 66.54, 57.39, 50.81, 47.01, 42.84, 37.32, 36.83, 35.37, 34.88, 32.07, 31.61, 31.23, 30.58, 25.93, 20.79, 19.35, 18.24, 18.07, 16.20, -4.59; IR (KBr): 3389, 3031, 2939, 1668, 1618 cm ^-1 ; MS (EI): m / z 387 (M ⁺ -57); HMRS Calcd for C ₂₄ H ₃₉ O ₂ Si: 387.2720 (M ⁺ -57), found: 387.2712; [α] ^28.1 _D = -50.67 (c = 1.00, CHCl ₃ )

Fourth step: 2- [3- (t-butyldimethylsilanyloxy) -10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16 , 17-Tetradecahydro-1H-cyclopenta [a] phenanthren-17-yl] propan-1-ol (Compound (9a)) Compound (8a) (1.52 g, 3.41 mmol) in THF (34 mL) ) Was added with 10% Pd / C (256 mg), charged with hydrogen, and stirred at room temperature for 12.5 hours. The reaction solution was filtered through Celite, and then the solvent was distilled off. The residue was purified by silica gel chromatography (CH ₂ Cl ₂ : hexane = 1: 2), and the compound (9a) (1.27 g, 2.82 mmol, 83%) was obtained as a white solid material (mp 159-161 ° C.). Obtained. The measurement results such as NMR of the obtained compound (9a) are shown below.

¹ H-NMR (270 MHz) (CDCl ₃ ): δ 5.30 (1H, d, J = 5.1 Hz), 3.59 (1H, dd, J = 3.5, 10.5 Hz), 3.46 (1H, m), 3.36 (1H, dd, J = 7.0, 10.5Hz), 2.25-1.05 (19H, m), 1.02 (3H, d, J = 4.3Hz), 0.98 (3H, s), 0.867 (9H, s), 0.68 (3H, s ), 0.04 (6H, s); ¹³ C-NMR (67.5 MHz) (CDCl ₃ ): δ 141.59, 121.07, 72.63, 68.03, 56.54, 52.45, 50.20, 42.82, 42.43, 39.66, 38.75, 37.39, 36.58, 32.08 , 31.93, 27.72, 25.93, 24.38, 21.05, 19.42, 18.25, 16.75, 11.92, -4.59; IR (KBr): 3306, 2936, 2882, 2857, 1669 cm ^-1 ; MS (EI): m / z 389 ( M ⁺ -57); HMRS Calcd for C ₂₄ H ₄₁ O ₂ Si: 389.2876 (M ⁺ -57), found: 389.2871; [α] ^24.4 _D = -37.87 (c = 1.00, CHCl ₃ )

Fifth step: 2- [3- (t-butyldimethylsilanyloxy) -10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16 , 17-Tetradecahydro-1H-cyclopenta [a] phenanthrene-17-yl] -propionaldehyde (Compound (10a)) Compound (9a) (500 mg, 1.12 mmol) in dichloromethane (38 mL) under argon atmosphere ) Was added with molecular sieves 4A (206 mg) and pyridinium dichromate (2.11 g, 5.60 mmol) and allowed to stir at room temperature for 3 hours. The reaction solution was filtered through Celite, and then the solvent was distilled off. The residue was purified by silica gel chromatography (ethyl acetate: hexane = 1: 9) to obtain compound (10a) (241 mg, 0.543 mmol, 48%) as a white solid material (mp 127-131 ° C.). The measurement results such as NMR of the obtained compound (10a) are shown below.

¹ H-NMR (270 MHz) (CDCl ₃ ): δ 9.58 (1H, d, J = 3.2Hz), 5.32 (1H, d, J = 5.1Hz), 3.48-3.46 (1H, m), 2.36-1.17 ( 18H, m), 1.12 (3H, d, J = 4.6), 1.00 (3H.s), 0.87 (9H, s), 0.73 (3H, s), 0.06 (6H, s); ¹³ C-NMR (67.5 (MHz) (CDCl ₃ ): δ 204.94, 141.49, 120.91, 72.53, 56.01, 51.92, 51.01, 50.16, 49.45, 42.93, 42.78, 39.47, 37.35, 32.04, 31.87, 31.84, 27.02, 25.90, 24.63, 20.97, 19.39, 18.21, 13.55, 12.19, -4.61; IR (KBr): 2936, 2898, 2856, 2819, 1730, 1670 cm ^-1 ; MS (EI): m / z 387 (M ⁺ -57); HMRS Calcd for C ₂₄ H ₃₉ O ₂ Si: 387.2720 (M ⁺ -57), found: 387.2742; [α] ^24.9 _D = -42.36 (c = 1.00, CHCl ₃ )

Sixth step: 2- [3- (t-butyldimethylsilanyloxy) -10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16 , 17-Tetradecahydro-1H-cyclopenta [a] phenanthren-17-yl] -hex-5-en-3-ol (Compound (4a)) Compound (10a) (500 mg, 1. 12 mmol) in THF (38 mL) was added allylmagnesium chloride (1.63 mL, 1.63 mmol) at −78 ° C. and stirred at −78 ° C. for 30 minutes, and then the reaction was quenched with saturated ammonium chloride. The reaction solution was extracted with dichloromethane, and the organic layer was washed successively with 10% aqueous HCl, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated. This residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9) to give compound (4a) (235 mg, 0.482 mmol, 89%) (diastereomer) as a white solid material (mp 150-154 ° C.). Ratio = 1: 1). The measurement results such as NMR of the obtained compound (4a) are shown below.

Low polarity side:
¹ H-NMR (270MHz) (CDCl ₃ ): δ 5.80-5.77 (1H, m), 5.30 (1H, d, J = 5.1Hz), 5.12-5.06 (2H, m), 3.70 (1H, dd, J = 5.1, 8.6Hz), 3.52-3.45 (1H, m), 2.25-1.02 (21H, m), 0.98 (3H, s), 0.90 (3H, d, J = 5.1Hz), 0.87 (9H, s) , 0.66 (3H, s), 0.04 (6H, s); ¹³ C-NMR (67.5 MHz) (CDCl ₃ ): δ 141.57, 135.74, 121.09, 117.37, 72.62, 72.47, 56.67, 52.62, 50.16, 42.82, 42.28 , 40.13, 40.09, 39.81, 37.37, 36.56, 32.08, 31.96, 31.88, 27.70, 25.94 24.20, 21.09, 19.42, 18.25, 11.74, 11.69, -4.60; IR (KBr): 3607, 3077, 2935, 2898, 2857, 1640 cm ^-1 ; MS (EI): m / z 429 (M ⁺ -57); HMRS Calcd for C ₂₇ H ₄₅ O ₂ Si: 429.3189 (M ⁺ -57), found: 429.3174; [α] ^24.5 _D = -28.11 (c = 1.00, CHCl ₃ )

High polarity side:
¹ H-NMR (270MHz) (CDCl ₃ ): δ 5.85-5.80 (1H, m), 5.32 (1H, d, J = 5.4Hz), 5.17-5.14 (2H, m), 3.71-3.67 (1H, m ), 3.51-3.43 (1H, m), 2.27-1.01 (21H, m), 0.99 (3H, s), 0.93 (3H, d, J = 7.0Hz), 0.88 (9H, s), 0.70 (3H, s), 0.05 (6H, s)

Seventh step: 1- {1- [3- (t-butyldimethylsilanyloxy) -10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14, Synthesis of 15,16,17-tetradecahydro-1H-cyclopenta [a] phenanthren-17-yl] -ethyl} -but-3-enyl ester (compound (1a)) Compound (4a) (low To a dichloromethane solution (7 mL) of (polar compound) (111 mg, 0.229 mmol), diisopropylethylamine (0.20 mL, 1.13 mmol) and acrylic acid chloride (74.4 μL, 0.916 mmol) were added at 0 ° C. The reaction was performed for 2.5 hours. The reaction solution was diluted with dichloromethane, washed successively with 10% aqueous HCl, saturated aqueous sodium hydrogen carbonate, and saturated brine, and the organic layer was dried over magnesium sulfate and filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9) to obtain compound (1a) (109 mg, 0.202 mmol, 88%) as a white solid substance (mp113-117 ° C.). The measurement results such as NMR of the obtained compound (1a) are shown below.

¹ H-NMR (270 MHz) (CDCl ₃ ): δ 6.32 (1H, dd, J = 1.6, 17.0 Hz), 6.09 (1H, dd, J = 10.4, 17.4 Hz), 5.80 (1H, dd, J = 1.8 , 10.1Hz), 5.70-5.68 (1H, m), 5.27 (1H, d, J = 4.9Hz), 5.08-4.99 (3H, m), 3.52-3.45 (1H, m), 2.38-1.04 (20H, m), 1.01 (3H, d, J = 6.8Hz), 0.97 (3H, s), 0.86 (9H, s), 0.65 (3H, s), 0.03 (6H, s); ¹³ C-NMR (67.5MHz ) (CDCl ₃ ): δ 165.81, 141.43, 134.11, 130.17, 128.95, 121.10, 117.44, 75.41, 72.56, 56.59, 52.49, 50.13, 42.26, 39.73, 38.70, 37.35, 36.88, 36.53, 32.05, 31.91, 31.81, 28.03 , 25.91, 24.21, 21.04, 19.40, 18.21, 12.69, 11.62, -4.60; IR (KBr): 2935, 2861, 1721, 1641 cm ^-1 ; MS (EI): m / z 483 (M ⁺ -57); HMRS Calcd for C ₃₀ H ₄₇ O ₃ Si: 483.3295 (M ⁺ -57), found: 483.3267; [α] ^24.7 _D = -34.13 (c = 0.68, CHCl ₃ )

Eighth step: 6- {1- [3- (t-butyldimethylsilanyloxy) -10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14, Synthesis of 15,16,17-tetradecahydro-1H-cyclopenta [a] phenanthren-17-yl] -ethyl} -5,6-dihydropyran-2-one (compound (2a)) Under an argon atmosphere, the compound ( 1a) First generation Grubbs catalyst (133 mg, 0.162 mmol) (Fluka product no. 09958) was added to dichloromethane solution (11 mL) of (109 mg, 0.202 mmol) and stirred at room temperature for 5.5 hours. Was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 6), and the target compound (2a) (61 mg, 0.119 mmol, 59%) (first) was obtained as a white solid substance (mp213-217 ° C.). The total yield of the process to the eighth process was 8.8%). The measurement results such as NMR of the obtained compound (2a) are shown below.

¹ H-NMR (270MHz) (CDCl ₃ ): δ 6.89 (1H, td, J = 2.0, 9.7Hz), 5.98 (1H, dd, J = 2.1, 9.7Hz), 5.28 (1H, d, J = 5.1 Hz), 4.48 (1H, m), 3.48-3.45 (1H, m), 2.61-2.50 (1H, m), 2.25-1.19 (19H, m), 1.05 (3H, d, J = 6.5Hz), 0.98 (3H, s), 0.87 (9H, s), 0.67 (3H, s), 0.04 (6H, s); ¹³ C-NMR (67.5 MHz) (CDCl ₃ ): δ 164.91, 145.84, 141.44, 121.13, 121.01 , 80.04, 72.54, 56.45, 51.14, 48.00, 42.77, 42.13, 39.54, 39.50, 37.28, 36.47, 32.03, 31.90, 31.76, 27.62, 27.35, 25.89, 24.09, 21.01, 19.37, 18.19, 13.18, 11.67, -4.64; IR (KBr): 2936, 2900, 2882, 2857, 1702 cm ^-1 ; MS (EI): m / z 455 (M ⁺ -57); HMRS Calcd for C ₂₈ H ₄₃ O ₃ Si: 455.2982 (M ⁺ - 57), found: 455.2989; [α] ^24.7 _D = -58.51 (c = 0.92, CHCl ₃ )

Claims (6)

Following formula (1)

(In the formula, _{R 1} represents a hydrogen atom, and a methyl group or _{CH 2} OH; _R 2 denotes hydrogen or methyl; _{R 3} denotes a hydrogen atom or a hydroxyl group; _{R 4} is, A hydrogen atom or a hydroxyl group; R ₅ represents a hydrogen atom, a sugar chain or a protecting group) and a catalyst is used in the presence of a compound represented by the following formula (2):

(Wherein R _{1 to} R ₅ have the same meanings as R _{1 to} R ₅ in formula (1)), or a method for producing a salt thereof. The compound represented by the formula (1) or a salt thereof is represented by the following formula (3):

_(Wherein, R 2 to R ₅ in. Of the same meaning as _R 2 to R ₅ as defined in claim 1) a compound represented by the following formula (4)

(Wherein R ₁ has the same meaning as R ₁ described in claim 1, X means a halogen atom), and is obtained by reacting with a compound represented by claim 1. Method.   The production method according to claim 1, wherein the protecting group is “—TBS”. The sugar chain ^"- 1 ^glc 6 ^- 1 ^glc," a method according to any one of claims 1 to 3. The production method according to any one of claims 1 to 4, wherein R _{1 to} R ₅ are composed of any combination of the following (a) to (d):
_{(A) R 1 = CH 2} OH, R 2 = methyl, _{R 3} = hydrogen atom, _{R 4} = ^{_{hydroxyl, R 5 = - 1 glc 6}} - 1 glc,
(B) _{R 1} = methyl, _{R 2} = methyl, _{R 3} = hydroxyl, _{R 4} = ^{_{hydroxyl, R 5 = - 1 glc 6}} - 1 glc,
(C) R ₁ = CH ₂ OH, R ₂ = methyl group, R ₃ = hydrogen atom, R ₄ = hydroxyl group, R ₅ = hydrogen atom, and (d) R ₁ = hydrogen atom, R ₂ = hydrogen atom, R ₃ = hydrogen atom, R ₄ = hydrogen atom, R ₅ = -TBS.   The manufacturing method in any one of Claims 1-5 whose said catalyst is a 1st generation Grubbs catalyst.