JPH01186833A - Trans decalin derivative and forskolin derivative derived therefrom - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to transdecalin derivatives, which are important as intermediates for the synthesis of forskolin and its derivatives, a method for producing forskolin derivatives from the derivatives, and forskolin derivatives prepared by the method. be.

[Conventional technology]

Forskolin has a blood pressure lowering effect, muscle contraction effect, and intraocular pressure lowering effect based on its strong adenylate cyclase activation effect.
It is a compound that has various physiologically active actions such as bronchial spasmolytic action, and is attracting attention for development as a medicine. Forskolin is a labthane-based compound composed of ring A, ring B, and ring C, as represented by the following structural formula 1 [wherein Ac represents an acetyl group]. Currently an intermediate for synthesizing forskolin,
In particular, there are no reports on intermediates suitable for constructing the C ring of forskolin, and one method for synthesizing forskolin derivatives is to introduce various exchange groups at the same time as constructing the C ring. Although it is possible, an efficient production method that allows various substituents to be introduced simultaneously with the construction of C11 has not been found. The present inventors conducted various studies regarding the stereospecific synthesis of forskolin and its derivatives, and found that (±)-1
,6,7-dolideoxyphorskolin was successfully synthesized (J, Chs, Soc. Cham, Co1n5un, 24-25 (198
7)). However, the 1-position hydroxyl group is essential for the expression of forskolin activity, and there have been no reports of successful creation of this active form of forskolin, its derivatives, or useful intermediates for synthesizing them. is the current situation. [Problems to be Solved by the Invention] In other words, one object of the present invention is to provide a novel synthetic intermediate suitable for synthesizing forskolin and its derivatives, an efficient method for producing forskolin derivatives from the intermediate, and A forskolin derivative obtained by the method is provided. (Means for Solving the Problems) As a result of various studies on intermediates for synthesizing forskolin and its derivatives, the present inventors synthesized a new compound represented by the following formula [!] [In the formula, R'', Ra, Rml, R1 and -R''
each represents a hydroxyl protecting group, and R8 and Ra and/
Alternatively, R'' and R'' may be the same protecting group.] A compound represented by general formula (1) (hereinafter referred to as the compound of the present invention)
It is also sometimes called. ) was found to be an extremely useful synthetic intermediate that can easily construct the C ring of labtan-based compounds and also allows for the synthesis of forskolin analogs by introducing various substituents at the same time as constructing the C ring. . Furthermore, as a result of repeated research on efficient synthesis methods for forskolin and its derivatives from this compound, we established a method for synthesizing forskolin and its derivatives,
The invention has been completed. That is, the present invention relates to a transdecalin derivative represented by the above formula (1) useful for synthesizing forskolin and its derivatives. The present invention also provides a transdecalin derivative represented by the above-mentioned formula (1) represented by the general formula (n) [wherein R″, R8 and R1 are hydroxyl group protecting groups, and R4 represents an alkyl or aryl group] A method for producing a forskolin derivative (hereinafter sometimes referred to as the compound of the present invention) represented by The present invention relates to a method for producing a forskolin derivative, which is characterized by sequentially adding acetylide to the aldehyde group of a transdecalin derivative represented by the following structural formula (1) to obtain a compound of the following structural formula (A). Reaction step (addition reaction step of acetylide to aldehyde residue) [wherein R1, R8, R", R", R"o, and R
' has the same meaning as above,] ■ A reaction step (oxidation reaction step of the alcohol group) in which the alcohol group of the compound of the following structural formula (a) is oxidized to obtain the compound of the following structural formula (b). (In the formula % R', R", R" % R", R" and R
4 has the same meaning as above; [1] A reaction step of reacting the compound of the following structural formula (b) with lithium dimethyl steel to obtain the compound of the following structural formula (c) (1,4 addition reaction step using lithium dimethyl steel). [In the formula, R1, R3, Rm', Rm, R'' and R4 have the same meanings as above.] ■ The protecting groups represented by R8'' and R'' of the compound of the following structural formula (c) are removed to form the following structural formula. (d) Reaction step for obtaining a compound (the bonds represented by R3' and R'''' have the same meanings as above); ■ Reacting the compound of the following structural formula (d) with an electrophilic reagent, and then subjecting it to a reduction treatment. (The electrophilic reagent and reducing agent have the same meanings as above,
Furthermore, the present invention relates to a forskolin derivative represented by the above general formula (II) produced by the above production method. The present invention will be explained in detail below. 1, l A l and ■ The compound I of the present invention is represented by the above general formula (1), and in formula 1, R'S R"% R" % R' and R
” respectively indicate a hydroxyl group-protecting group. As the hydroxyl group-protecting group represented by R1, benzyl, p
-Methoxybenzyl, 3,4-dimethoxybenzyl%0
Preferred are -nitrobenzyl, p-nitrobenzyl, p-halopencyl, diphenylmethyl, triphenylmethyl, α- or β-naphthylmethyl, α-naphthyldiphenylmethyl, p-methodyl, 3,4-dimethoxybenzyl. Examples of the protecting group for the hydroxyl group represented by R3, R", R", R" include lower alkyloxymethyl groups such as methoxymethyl, ethoxymethyl, t-butoxymethyl, 2,2.2-trichloroethoxymethyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, 0-nitrobenzyl, po-nitrobenzyl, p-halopencyl, diphenylmethyl, triphenylmethyl, α or β-naphthylmethyl, α-naphthyldiphenylmethyl,
p-methoxyphenyldiphenylmethyl ■, aralkyl group, trimethylsilyl, triethylsilyl, t-
Silyl groups such as butyldimethylsilyl, methyldi-t-butylsilyl, ethylidene, isopropylidene, cyclohexylidene, cyclopentylidene, benzylidene, methoxymethylidene, ethoxymethylidene, methoxyethylidene, ethoxyethylidene, dimethoxymethylidene,
Acetal or ketal type protecting groups such as jetoxymethylidene can be used, with acetal or ketal type protecting groups being particularly preferred. More specifically, the protecting group for the secondary hydroxyl group represented by ul and R1 is an isopropylidene group and R3'. As the protecting group for the tertiary hydroxyl group represented by R'', an alkoxymethylidene group such as methoxymethylidene can be used. In formula [1], the hydroxyl protecting groups represented by R″ to Rm can be exemplified by the same groups as R1 to R1 of the compound I of the present invention. Further, R4 represents an alkyl or aryl group, and examples of the alkyl group include methyl, ethyl,
1-5 carbon atoms such as propyl, isopropyl, butyl
Examples of lower alkyl groups and aryl groups include phenyl, tolyl, p-chlorophenyl, p-aminophenyl, naphthyl, etc., and these alkyl groups and aryl groups may be substituted with halogen or hydroxyl group. good. In addition, in order to synthesize forskolin, the compound of the present invention ■
When using, it is preferable to use a compound in which R4 is a hydroxyethyl group protected with a silyl group or the like. Compound I of the present invention of n, h ^ summer is, for example, a conjugated lactone (Tatrahedro
n Latt, 3307 (1985), Abstracts of the 106th Congress of the Pharmaceutical Society of Japan, p. 384 (1986
)). The reaction process from a conjugated lactone is shown by a reaction formula. It is as follows. (O (lower raw white) In the formula c, R″ R″, R″ Ra, R″ have the same meanings as above, Tr represents a trityl group, and Aa represents an acetyl group.) 1st step, lactone moiety 3 reactions This step is a reaction step in which the lactone moiety of the conjugated lactone represented by the above structural formula 2 is ring-opened using a reducing agent, and then a trityl group is introduced into the generated primary hydroxyl group.As a reducing agent that can be used in this reaction step, is preferably a hydride transfer reagent, specifically lithium aluminum hydride, lithium trialkoxyhydridoaluminate (for example, lithium trimethoxyhydridoaluminate, lithium tri-t-butoxyhydridoaluminate, etc.),
Examples include diisobutylaluminum hydride, sodium tetrahydroborate, and sodium cyanotrihydroborate. The ring-opening reaction of the lactone moiety of compound 2 with a reducing agent is 1
A reaction solvent (for example, an alcohol such as ethanol,
ethers such as ethyl ether and tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene, diglyme, dimethylformamide, etc.) at a reaction temperature of 0°C to
This can be carried out by reacting at a solvent reflux temperature for 1 to 10 hours. Next, the primary hydroxyl group generated by ring opening of the lactone moiety is protected with a trityl group. The trityl group may be introduced according to a conventional method, for example, 1 mole of compound 2:
The reaction can be carried out by reacting 1.5 times the mole of trityl chloride (eg, trityl chloride, trityl chloride, etc.) in pyridine at room temperature to 100° C. for 1 to 24 hours. Compound 3 obtained in this way can be synthesized using various chromatography methods such as adsorption chromatography and partition chromatography, countercurrent distribution method, countercurrent extraction method, and precipitation method using the difference in solubility. Isolation and purification can be carried out by appropriately combining methods commonly used as means for separation and purification. 2 Step Mu 3 → Mu 4 This reaction step is a reaction step in which Compound 3 is oxidized using osminium tetroxide to obtain the osminate ester of Compound-3, and this is subjected to reductive treatment to obtain Compound 4. be. Osminium tetroxide to oxidize compound 3 is usually used alone, but co-oxidation with chlorates (e.g., sodium chlorate, potassium chlorate, etc.), periodates (e.g., sodium periodate, etc.) Agents may also be used together. The oxidation reaction of compound 3 using osminium tetroxide is performed using a reaction solvent (e.g., ethanol, pyridine, benzene,
One or more solvents such as dioxane, tetrahydrofuran, carbon tetrachloride, and ethyl acetate) are used at a reaction temperature of 0°C to room temperature using 1 to 1.5 times the mole of osminium tetroxide per 1 mole of compound 3. This can be carried out by reacting for 24 to 96 hours. Furthermore, when using something other than pyridine as a reaction solvent in the above oxidation reaction, it is preferable to add a tertiary amine such as pyridine to the reaction solution in order to promote the oxidation reaction. A suitable amount is 2 to 5 times the mole of osminium oxide. After the oxidation reaction, the generated osminate ester of Compound 3 is subjected to a reductive treatment to obtain Compound 4. The reductive treatment may be carried out according to conventional methods, such as heating in a dilute alcohol solution or water-pyrimidine solution of sodium sulfite or sodium hydrogen sulfite and filtering off the precipitate, or reductive decomposition through hydrogen sulfide. A method of reductive decomposition by heating with formaldehyde in an alkaline aqueous solution can be used as appropriate, and a reductive decomposition method using hydrogen sulfide is particularly suitable. Compound 4 obtained in this manner can be obtained by various chromatography methods such as adsorption chromatography and partition chromatography, countercurrent distribution method, self-current extraction method, and precipitation method using the difference in solubility, as well as compound 3. Isolation and purification can be carried out by appropriately combining methods commonly used as means for isolating and purifying low-molecular-weight compounds. 3° Engineering Mu 4 → Mu 5 This reaction step is a reaction step in which the 1-position hydroxyl group of compound 4 is protected with a protecting group. The protecting group for the 1-position hydroxyl group of compound 4 is a real alkyl group as described above. Introduction of an aralkyl group may be carried out according to a conventional method. For example, for the introduction of a p-methoxybenzyl group, 1 to 5 times the mole of sodium hydride or potassium carbonate is added to 1 mole of compound 4, and 1 to 5 times the mole of sodium hydride or potassium carbonate. of pendyl halide (benzyl chloride, benzyl bromide, etc.) and hexamethylphosphoric triamide in an equimolar or more amount in a reaction solvent (e.g. dimethylformamide, tetrahydrofuran, etc.) at a reaction temperature of 0°C to solvent reflux temperature. So 3-1
This can be carried out by reacting for 2 hours. Compound 5 thus obtained, like compounds 3 and 4, can be subjected to various chromatography methods such as adsorption chromatography and partition chromatography, countercurrent distribution method, countercurrent extraction method,
It can be isolated and purified by a method commonly used for isolating and purifying organic low-molecular compounds, such as a precipitation method that utilizes a difference in solubility. 4EhiA 5→Him 6 This reaction step is a reaction step in which Compound 5 is subjected to acid treatment to remove the trityl group, and then acetylated to obtain Compound 6. Removal of the trityl group and introduction of the acetyl group may all be carried out according to conventional methods. That is, trityl groups can be removed by heating in a mixed solution such as tosylic acid-methanol, formic acid-chloroform, hydrochloric acid-chloroform, hydrogenated bromo-acetic acid, etc., and acetyl groups can be introduced by heating in a mixed solution such as acetic anhydride and pyridine. This can be carried out by reacting with a tertiary amine at room temperature. Compound 6 thus obtained, like compounds 3 to 5, can be used as an organic low molecule by various chromatography methods such as adsorption chromatography and partition chromatography, self-current distribution method, countercurrent extraction method, and precipitation method using the difference in solubility. It can be isolated and purified by a method commonly used as a means for isolating and purifying compounds. 5 E Him 6 → ゛ Day A ■ This reaction step consists of: ■ protecting the 8- and 9-position hydroxyl groups with protective groups, ■ removing the acetyl group, and ■ oxidizing the generated primary alcohol residue to achieve the present invention. This is a reaction step to obtain Compound I. Introducing a protecting group into the 8- and 9-position hydroxyl groups of compound 6 can be carried out according to a conventional method. For example, an acetal or ketal type protecting group can be introduced by combining compound 6 with a catalytic amount of an acid (for example, tosylic acid, pyridine- Hydrochloric acid, perchloric acid, etc.) and an excess amount of an acetal or ketalizing reagent (for example, methyl orthoformate, etc.) can be reacted at room temperature for 5 to 60 minutes. Next, the acetyl group may be removed by a conventional method such as transesterification using a basic catalyst such as ammonia in methanol or reduction treatment using lithium aluminum hydride. Finally, the oxidation of primary alcohol residues generated by the removal of acetyl groups is known as Collins oxidation (Tetrahedro
n Lett, 3363 (1968)). Its expedient (in methylene dichloride'', chromium oxide (Vl) -
Using pyridine (J, Org, Chem, 3rd,
4000 (1970)) or Parikh-Doe
ring method (DMSO. Sulfur trioxide-pyridine method (J, A., Chaen, Soc.
, , and. The oxidation method can be appropriately selected from known oxidation methods such as 5505 (1967)). For example, Pari
In the kh-Doering method, in the presence of triethylamine,
This is an oxidation reaction that uses a sulfur dioxide-pyridine complex as an activation reagent for DMSO (dimethyl sulfoxide). DMSO is used as the reaction solvent and oxidizing agent, and the reaction is carried out at room temperature for 1 to 60 minutes to quantitatively determine the first grade. Compound I of the invention can be obtained by oxidizing the alcohol group. Compound I of the present invention obtained in this manner can be prepared by various chromatography methods such as adsorption chromatography and partition chromatography, self-current distribution method, countercurrent extraction method, and precipitation method using the difference in solubility, as in Compounds 2 to 6. Isolation and purification can be carried out by appropriately combining ordinary means for isolating and purifying low-molecular-weight compounds. The compound of the present invention prepared in this manner has an aldehyde group at the 9-position for constructing the C ring and a hydroxyl group at the 1-position which is essential for the expression of activity. It is an extremely useful compound as a synthetic intermediate. Next, 1. Preparation method of the present invention compound (2) from the present invention compound I (
Hereinafter, this method may also be referred to as the method of the present invention. ) and the preparation of forskolin from the compound (1) of the present invention will be described in detail below. Compound (2) of the present invention can be prepared from Compound (1) of the present invention I of Him (2) by sequentially carrying out the following reaction steps. (2) Addition reaction process of acetylide to aldehyde residue The reaction process described above is shown in the following reaction formula. (Nnn (lower hair ≧ei) [In the formula, R', R"%R", R", R" and R4 have the same meanings as above.] As the acetylide used in the addition reaction, - formula X- = -
It can be represented by R' (wherein R4 has the same meaning as above or represents an alkali metal). Specific examples of the acetylide represented by the formula are alkali metal salts such as 1-propyne, 1-butyne, phenylacetylene, naphthylacelene, and 4-silyloxy-1-butyne, particularly preferably lithium salts. The acetylides may be appropriately selected from these acetylides depending on R4 of the compound (1) of the present invention. The reaction between the compound 1 of the present invention and acetylide is carried out using 1 to 10 times the mole of acetylide per mole of the compound of the present invention.
The reaction can be carried out by reacting in a reaction solvent (for example, an ether solvent such as ethyl ether or tetrahydrofuran) at a reaction temperature of -78°C to room temperature for 1 to 5 hours. (2) As the oxidizing agent that can be used in the oxidation reaction of the hyalcohol group of alcohol, any oxidizing agent that can oxidize the secondary hydroxyl group may be used, and manganese dioxide is particularly suitable. The oxidation reaction is carried out by adding an excess amount of oxidizing agent in a reaction solvent (benzene, toluene, acetonitrile, etc.) and reducing the reaction temperature to 0.
1.4 The lithium dimethyl steel ((Cll, ), CuLi) used in the addition reaction was prepared from methyllithium and cupric halide immediately before the reaction. is preferred. 1.4 The addition reaction is carried out using 1 to 6 times the molar amount of lithium dimethyl steel per mole of the compound in a reaction solvent (e.g., ethyl ether, tetrahydrofuran, etc.).
It can be carried out by reacting at 8 to 0°C for 10 to 60 minutes. ■ R11, R31 of the group represented by R” and R”
- For the removal of the protecting group, a removal method commonly used for the protecting group used may be adopted. For example, when an acetal or ketal type protecting group is used as the R", R"-protecting group, acid-catalyzed Decomposition (hydrochloric acid-tetrahydrofuran-
The compound - can be obtained by using a combination of water, etc.) and base-catalyzed hydrolysis (sodium hydroxide-tetrahydrofuran-water, etc.). ■ Electrophilic reagents used in the cyclization reaction include phenylselenenyl halogenides (e.g., phenylselenenyl chloride and phenylselenenyl bromide), metal acetates (e.g., acetic acid), and metal acetates (e.g., acetic acid). mercury, mercury trifluoroacetate, etc.), and phenylselenenyl halide is particularly suitable. In the bicyclization reaction, 1 to 1 mol of the electrophilic reagent to 1 mol of the compound
Reaction solvent (e.g., methylene chloride,
dichloroethane, etc.) at a reaction temperature of -78 to 0°C.
This can be carried out by reacting for 100 hours. As a reducing agent to be added to the reaction solution, by adding a small amount of iodine and reacting for 10 to 60 minutes at room temperature to solvent reflux temperature, various methods such as partition or adsorption chromatography can be performed as in the case of the compound of the present invention. Isolation and purification can be carried out using means commonly used for isolating and purifying organic low-molecular compounds, such as chromatography, self-current distribution, countercurrent extraction, and precipitation using differences in solubility. Furthermore, if it is necessary to isolate and purify the synthetic intermediate during the process of the present invention described above, it may be isolated and purified using ordinary isolation and purification means in the same manner as for the compound (1) of the present invention. IV, lt: ^ Preparation of forskolin from the compound of the present invention from (1) Forskolin can be carried out by suitably applying known reactions. For example, if R4 is used to synthesize forskolin, the reaction steps for the specific synthesis are as shown below. (5 margins 2 (Route address) (In the formula, R″, R3, R″, and Ao have the same meanings as above. R4 represents a t-butyldiphenylsilyloxyethyl group.) -A 8C Compound of the present invention ■→Compound 11] This reaction step involves removing the silyl protecting group portion of R4 of compound (1) of the present invention,
This is a reaction step in which a vinyl group is constructed by the method of Griaco et al. (J, Org. Chew, Earthworks, 1485 (1976)) to obtain Compound 11. Removal of the silyl group may be carried out according to a conventional method, for example, by acid-catalyzed hydrolysis using hydrochloric acid-tetrahydrofuran-water, or by reaction with tetrabutylammonium fluoride in tetrahydrofuran at room temperature. The method of Grieco et al. applied to the construction of vinyl groups is
For example, using 1 to 2 times the mole of orthotritrophenyl selenium cyanide (0-NO, phSecN) and tributylphosphine, respectively, for 1 mole of the present compound (2),
Compound 11 can be obtained by reacting in a reaction solvent (e.g. ethyl ether, tetrahydrofuran, etc.) at a reaction temperature of 0°C to room temperature for 10 to 60 minutes, and then reacting with an excess amount of hydrogen peroxide at 0°C to room temperature. . Compound 11 thus obtained can be purified by conventional isolation and purification methods for organic low-molecular compounds, such as various chromatography methods such as partitioning or adsorption, countercurrent distribution method, countercurrent extraction method, and precipitation method that utilizes the difference in solubility. It can be isolated and purified by applying the method. Step B [Compound 11 → Forskolin] This reaction step is
This is a reaction step in which forskolin is obtained by introducing an acetyl group after removing the protecting groups of R1, R'' and R3. Removal of R1, R3 and R1-protecting groups is a commonly used method for removing the used protecting groups. For example, when R1 is a methoxybenzyl group,
2.3-dichloro-5,6-dicyano-1,4-benzoquinone was used in a molar range of 1 to 3 times per mole of Compound 11, and the solution was prepared in a mixed solvent of methylene chloride and water at 0°C to room temperature.
The methoxybenzyl group can be removed by reacting for ~30 hours. Further, when an isopropylidene group is used as a protecting group for R3 and R1, it can be removed by acidic hydrolysis using hydrochloric acid or perchloric acid in a mixed solvent of tetrahydrofuran and water. Introduction of an acetyl group to the 7-position hydroxyl group can be carried out by reacting an excess amount of acetic anhydride in pyridine at 0°C to room temperature. The forskolin thus obtained is processed as appropriate by various chromatography methods such as distribution and adsorption, which are the usual means of isolating and purifying forskolin, countercurrent extraction method, countercurrent distribution method, and precipitation method that takes advantage of the difference in solubility. Can be isolated and purified in combination. (Effects of the Invention) As mentioned above, the compound 1 of the present invention allows the construction of the C ring of the basic structure of forskolin and the introduction of various substituents at the same time as the construction of the C ring, making it possible to easily synthesize forskolin analogs. Therefore, it is a novel compound that is extremely useful as an intermediate for synthesizing forskolin and its derivatives. There is no need to separate structural isomers generated during one reaction, and therefore, forskolin derivatives can be efficiently synthesized using extremely simple operating means. Other forskolin derivatives can also be prepared by the method of the present invention. That is, in place of the lithium dimethyl steel used in the reaction step ① of the method of the present invention described above, - Formula Li(R'
), Cu (wherein R5 represents alkyl, aryl, alkenyl, etc.), further various forskolin derivatives can be prepared by using the organocopper reagents represented by the following.Furthermore, various forskolin derivatives can be prepared by the method of the present invention. The compound of the present invention (■) has a 1-position hydroxyl group that is essential for the expression of activity, so it can be expected to have various physiological activities and can also be converted into forskolin. As an intermediate for forskolin synthesis. [Example] Hereinafter, the present invention will be explained in more detail by showing Examples and Application Examples. Note that in this Example and Application Example, a racemate was used as the conjugated lactone, so the intermediate All of the identification data for the compounds of the present invention are racemic identification data. Example 1 Under an argon atmosphere, lithium aluminum hydride (30
0we 7 , 91 mmol) of ethyl ether (20
A solution of conjugated lactone (R1-Rm = isopropylidene) (483@, 1.58 mmol) in ethyl ether (5 ml) was added dropwise to the suspension and the mixture was further heated under reflux for 1 hour.The reaction was stopped by adding Next, after stirring at room temperature for 1 hour, the mixture was filtered using Celite, and the filtrate and washing liquid (ethyl ether, 200 mIa) were combined and dried over anhydrous sodium sulfate.After removing the solvent, the obtained crude product was Column chromatography (silica gel: 20 g, eluent: hexane/ethyl acetate, 2
/1) to obtain the diol as a colorless crystalline powder.
3f3@(yield 89%) was obtained. 4-dimethylaminopyridine (413, 3, 39 a+mol) and trityl chloride (471m, 1, 69IIs+ol) were added to a dichloroethane (20d) solution of the diol (436@, 1, 41ml eol) and heated under reflux for 6 hours. After cooling the reaction solution, saturated ammonium chloride (10-Ω),
It was washed with a saturated aqueous sodium bicarbonate solution (10I111) and a saturated aqueous sodium chloride solution (10aQ2), and dried using anhydrous sodium sulfate. Next, the crude product obtained by removing the solvent was purified by column chromatography (silica gel; 100 g, eluent: hexane/ethyl acetate, 10/1) to obtain compound 3 as a foamy substance of 701 μm (yield: 90 g). %)Obtained. High resolution mass spectrum (HR-MS), vI/e (C
,,H440,-Tr, M"-Tr), calculated value (ca
lcd) 309. 2066, Actual value (obsd) 309.20'70 Osmium tetroxide (445■,
1.75 mmol) was added thereto, and the mixture was reacted at room temperature for 87 hours with stirring. The reaction solution was concentrated to dryness, the residue was washed with petroleum ether (20-), and the chloroform-dioxane mixture (5/1.90a
Q), saturated with hydrogen sulfide under water cooling, and reacted at room temperature for 1 hour with stirring. The resulting black precipitate was filtered off through Celite, and the filtrate and washing solution (ethyl acetate, 10011Q) were combined and concentrated to dryness. The obtained crude product was subjected to column chromatography (silica gel; 50
g, eluent; hexane/ethyl acetate, 4/1) to yield 710 wg of compound 4 as a colorless foam (yield: 8
3%) obtained. HR-MS, m/e (CitH*10s-Tr
e M”-Tr), calcd343.2121.o
bsd 343.2102 Under an argon atmosphere, a mixed solution of compound 4 (646■. 1.1■-ol) of hexamethylphosphoric triamide (1,3aQ) and tetrahydrofuran (6-) was added with sodium hydride (126■ 5.3 mmol) was added thereto, and the mixture was reacted at room temperature for 5 minutes with stirring. Next, p-methoxybenzyl chloride (0.77%)
After stirring for 3 hours, the reaction solution was diluted with ethyl acetate (30 Q), and a saturated aqueous ammonium chloride solution (10+jl) was added to stop the reaction. The organic layer was washed with a saturated aqueous sodium chloride solution (11O 2 - x 2) and dried over anhydrous sodium sulfate. Next, the crude product obtained by removing the solvent was purified by column chromatography (silica gel; 40 g, eluent: hexane/ethyl acetate, 5/1) to obtain compound 5 as a colorless powder.
07m (yield 91%) was obtained. Melting point (mp) 2Q9-210°C (ethyl acetate) HR-M
S, m/a (C*iHs*0t-Tr s
M◆-Tr), calcd463.2696, ob
sd 463, 2698 compound 5 (210m, Q,
p-Toluenesulfone was added to a mixed solution of 3 mmol) of chloroform (6+gjl) and methanol (1211i1), and the mixture was stirred for 1140 minutes. Pyridine (0.2 IIl) was added to the reaction solution to remove the solvent, and the resulting residue was dissolved in pyridine (3-), acetic anhydride (1.5 aQ) was added, and the mixture was reacted at room temperature for 2 hours with stirring. After adding methanol (1.5w+jl) to the reaction solution and stirring for 10 minutes to stop the reaction, it was diluted with ethyl ether (30-), water (10m x 2), 5% sodium hydrogen sulfate (
4MIX5), saturated aqueous sodium hydrogen carbonate solution (5mm
), washed with saturated aqueous sodium chloride solution (5-), and dried over anhydrous sodium sulfate. The crude product 6 obtained by removing the solvent from Example 1 was used in the next reaction. Add p-toluenesulfonic acid (15μ) and dissolve 1
The reaction was allowed to proceed for 5 minutes with stirring. After adding pyridine (0.1 Q) to the reaction solution and stopping the reaction,
Diluted with ethyl ether (30a), washed with saturated saturated aqueous sodium bicarbonate solution (5m) and saturated aqueous sodium chloride solution (5-), dried over anhydrous sodium sulfate, and dissolved. The crude product obtained by removing the solvent was purified by column chromatography (20 g of silica gel, eluent: hexane/ethyl acetate, 6/1) to obtain the orthosteroid form 15 of compound 6.
5■Compound 6 (2 2 8w. 0, 4 1 6
An ice-cooled solution of ethyl ether (9wiQ) of lithium aluminum hydride (73μ, 1.92-m
ol) was added thereto, and the mixture was reacted for 10 minutes with stirring. The reaction solution was diluted with ethyl ether (50all),
After stopping the reaction by dropping IN-sodium hydroxide (0.15 all), pyridine (0.15 mIQ) was added and the mixture was filtered through Celite. Next, it was washed with ethyl ether (100d), and the filtrate and washing liquid were combined and dried over anhydrous sodium sulfate. Subsequently, the solvent was removed, the resulting residual liquid was dissolved in dimethyl sulfoxide (2.41 dl), and triethylamine (2.41 dl) was dissolved in dimethyl sulfoxide (2.41 dl).
．． 1 m) was added thereto, and while stirring, sulfur trioxide pyrimidine complex salt (490 cm, 3.08 cm o1) was added little by little, and the reaction was allowed to proceed at room temperature for 24 hours with stirring. Ethyl ether (30all) was added to the reaction mixture, the mixture was diluted, washed with a saturated aqueous sodium chloride solution (10dl×2), and dried over anhydrous sodium sulfate. Next, the crude product obtained by removing the solvent was purified by column chromatography (320 g of silica gel, eluent: hexane/ethyl acetate, 5/1) to obtain the compound I of the present invention as an oil.
70μ (yield: 81%) was obtained. Infrared absorption spectrum (IR (neat, cm)
″″i)] 2945, 2860, 1735, 1615,
1515, 1470.1385, 130011250,
1210, 1170, 1120. 1070, 1040 Hydrogen nuclear magnetic resonance spectrum iH NMR (270 MHz =
C D C l a )-ajor isomar
: δ 1. 11 (3H, s)
, 1.20 (3H,s) , 1.2-1.9 (4
H,m), 1,28 (3H,s), 1.38 (3H
,s), 1,39 (3H,s), 1.44 (3H,
s), 2, 46 (IH, d, J=5Hz), 3.3
8 (LH, brs), 3.40 (3Ht 8), 3
．． 80 (3 Hes), 4-16 (I
H = d − J = 1 2 Hz), 4, 43 (
IH, d, J==9Hz), 4.52(IH, d, J=
12Hz), 4.68 (IH. dd, J=5.9Hz), 5.89 (IH, s),
6.88 (2H, d, J=9Hz), 7.27 (2
H, d, J=9Hz), 9.61 (IH, s); s*1
nor isomer: δ3.24 (3H,!
l), 5.69 (IH, s), 9.5°8 (
IH, s) Electron ion mass spectrum MS (E I), m/e 504 (M+)
, 489°472.444,427 HR-M S g m/e (C*sH*oOs
w M÷) calcd504.2724, obs
d 504, 2723-Example 2 (i) 15-t-butyldiphenylsilyloxy-8,
13-Epoxy-9-hydroxy-6β,7β-isopropylidenedioxy ■Product II: R' = methoxybenzyl, R1-Ra = miniisopropylidene' = t-butylditine (30 ollg, o, 975 mmol) in tetrahydrofuran (1, 5m) The solution was cooled to -78°C, and n-butyllithium (0,51 LQ, 0,878
mmol) was added dropwise, stirred for 30 minutes, and further heated to -20°C.
The reaction was carried out under stirring for 20 minutes. Next, the temperature was recooled to -78°C, and a tetrahydrofuran (:3aQ) solution of the trandecalin derivative obtained in Example 1 (98cm, 0.195-ol) was added dropwise, and after stirring for 10 minutes, the mixture was heated to room temperature. The reaction was continued with stirring for an additional 2 hours. The reaction solution was diluted with ethyl ether (3QaQ), pyridine (0,1 SonoQ) was added, and saturated ammonium chloride (
10dl×2), saturated aqueous sodium chloride solution (10al
1) and dried over anhydrous sodium sulfate. Next, the solvent was distilled off, and the resulting residue was subjected to column chromatography (silica gel; 50 g, eluent: hexane/ethyl acetate, 1
0/1.5/1) to obtain 132 compounds of Compound I□. Next, compound A (132■) was dissolved in benzene (3-), and activated manganese dioxide (455■, 5.23m
(2) ol) was added thereto, and the mixture was allowed to react at room temperature for 3 hours with stirring. The reaction solution was filtered through Celite, the filtrate and washing liquid were combined, the solvent was distilled off, and the resulting residue was subjected to column chromatography (silica gel: 20 g, eluent: hexane/ethyl acetate, 10/1).
Purification was performed to obtain 105 quartz of chemical compound. Next, under an argon atmosphere, iodized steel (78μ, 0.1
An ice-cooled suspension of ethyl ether (2,6aQ) of 29-ol) was added to methyllithium (0,57all,
, 232 mmol) was added dropwise, and the mixture was reacted with stirring for 10 minutes. The obtained pale yellow transparent liquid was cooled to -7Q'C, and ethyl ether (105■, 0.1291 ◇L) was added to the compound
411gI) solution was added dropwise and reacted at -78°C for 15 minutes with stirring. The reaction solution was mixed with saturated ammonium chloride 710% ammonia (
10/1.5d) and ethyl ether (20-) with stirring to stop the reaction. Next, the organic layer was separated, and the aqueous layer was further divided into ethyl nitrite (2
This and the organic layer were combined, washed with a saturated aqueous sodium chloride solution (5d), and dried over anhydrous sodium sulfate. Next, the oily substance (compound C) obtained by distilling off the solvent was dissolved in tetrahydrofuran (4,4mj&), 3N-hydrochloric acid (0,11m) was added, and the mixture was reacted with stirring for 1 hour. The reaction solution was diluted with ethyl ether (30■a), washed with a saturated aqueous sodium bicarbonate solution (5d) and a saturated aqueous sodium chloride solution (511Q), and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was diluted with methanol (2
, 211j1), tetrahydrofuran (2,27) and 0.2N-sodium hydroxide (0,661
Ij&) was added, and the reaction was allowed to proceed for 20 minutes with stirring. The reaction mixture was diluted with ethyl ether (30 Q), washed with saturated ammonium chloride (5m) and a saturated aqueous sodium chloride solution (5-), and the organic layer was dried over anhydrous sodium sulfate. Next, the crude product obtained by distilling off the solvent was purified by column chromatography (silica gel; 20 g, eluent: hexane/ethyl acetate, 3/1), and compound 2 was obtained as an oily product at 86 μm (
Yield: 50%). Phenylselenenyl chloride (4
5 ml, 0 ml, 23 m5 ol) were added thereto, and the mixture was reacted at 0° C. for 38 hours with stirring. The reaction solution was diluted with ethyl ether (Sod), washed with a saturated aqueous sodium bicarbonate solution (5aQ) and a saturated aqueous sodium chloride solution (6aQ), and dried over anhydrous sodium sulfate. The solvent was distilled off, and ethanol (15-) and Raney nickel-W2 (1 ml) were added to the resulting residue. The mixture was heated under reflux for 5 minutes. After cooling the reaction solution, it was filtered and washed with ethyl acetate (20+jl), the filtrate and washing solution were combined, and the solvent was distilled off. The obtained crude product was subjected to column chromatography (silica gel; 20
g, eluent; methylene chloride) to obtain the compound of the present invention.
66 ml (yield 67%) of the following were obtained as an oily substance. I R (CHCI,,a-en-') 3300, aooo, 2940, 2860.171
0, 1615, 1585, 1515.1460.142
5. ．． 1380.1365.1300.1250.12
10■ 1HNMR (270MHz, CDCl5) 61.01
(9H, s), 1.08 (3H, s), 1.1~
1.3 (2H, m), L, 18 (3H. s), 1-25 (3H=s), 1.
30 (3H*s), 1.32 (3H,s)
, 1.50 (3H. s), 1.58 (3H, s), 1.4-1.8 (2
H, m), 1.9-2.0 (2H, m), 2.
11 (IH, d, J = 15Hz), 2.45
(IH, d. J = 5Hz), 3.32 (IH, d. J = 15Hz), 3.71 (3H, s),
3.8-3.9 (2H, m), 4.13 (IH
, d, J=11Hz) , 4.26 (IH, d,
J=7Hz), 4.27 (IH, brs), 4
．． 44 (IH, d. J=11Hz), 4.60 (IH, dd. J=5.
7Hz), 6.77 (2H, d, J=9Hz)
, 7.09 ('2 H= d * J = 9H
z), 7-3~7-4 (6H-m), 7.6~
7.7 (4H, m) M S (E I ) *
mis 727 (M◆-tBu). 663 (M+CH, Ph0C too>, 805,589 Application example 1 Synthesis of (±)-forskolin (1)8.
13-Epoxy-9-hydroxy-6β,7β-isopropylidenedioxy-1-α-(4-methoxybenzyl)oxyrhabd-14-en-11-one [Compound 11
: Synthesis of R'=methoxybenzyl, R3-R3=isopropylidene] Tetrabutylammonium fluoride (0,3-10,3m5ol) was added to a solution of the compound of the present invention (66■, 0.084mmol) in tetrahydrofuran (3II111). The mixture was added and reacted at room temperature for 5 hours with stirring. The reaction solution was diluted with ethyl ether (15 ail), washed with saturated ammonium chloride (3aQ) and saturated aqueous sodium chloride solution (3 ail), and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was subjected to column chromatography (315 g of silica gel, eluent: hexane/ethyl acetate, 2/1
) and refine it! ! 44 ml of l-hydroxyethyl compound was obtained as an oil (yield: 96%). Next, the 13-hydroxyethyl compound (44cm, 0.081 ugliness o1) was added to a solution of orthonitrophenyl selenium cyanide (54cm, 0.243wnol) in tetrahydrofuran (2,21LQ). 10,243 liters (1 dol) was added dropwise, and 30
The reaction solution was distilled off after stirring for a minute, and the resulting residue was purified by column chromatography (silica gel; 30 g, eluent: methylene chloride) to obtain 15-balanitrophenylceranyl compound as a yellow-green oil. 53■ (yield 89%) was obtained. Next, 15-paranitrophenylceranyl compound (53■, 0
．． 072 mmol) of methylene chloride (2,8-) was added with 35% hydrogen peroxide (38 ml) and reacted with stirring at 18° C. for 24 hours. The reaction solution was diluted with methylene chloride (16 all), washed with saturated aqueous sodium chloride solution (5 ail), and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting crude product was subjected to column chromatography (silica gel; 20 g, eluent: hexane/ethyl acetate, 5
/1) to give compound 11 as a colorless crystalline powder.
2. (yield 84%). mp 150-151℃ (ethyl acetate-hexane) HR-MS, intestine/e (C*zH**0t-
HsO*M÷-H2O)calcd 510.2982
．． Obsd 510.297'3(2)(±)-Forskolin (1) Synthesis Compound 11 (16w:, 0.
03 mmol) in methylene chloride (1.1 m), water (
80m) and 2,3-dichloro-5,6-dicyatsubabenzoquinone (Log, 0.045++nol),
The reaction was allowed to proceed at room temperature for 48 hours with stirring. The reaction solution was diluted with ethyl ether (IIMI). It was washed with a saturated aqueous sodium bicarbonate solution (3all) and a saturated aqueous sodium chloride solution (3-), and dried over anhydrous sodium sulfate. The residual liquid obtained by distilling off the solvent was diluted with methanol (1,5
), and add potassium carbonate (80cm),
The reaction was allowed to proceed at room temperature for 40 minutes with stirring. The reaction solution was diluted with ethyl ether (15ml), poured into a bowl with saturated ammonium chloride (5all) and a saturated aqueous sodium chloride solution (5-), and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was subjected to column chromatography (silica gel; 15 g, eluent: hexane/ethyl acetate, 5/1
) to obtain (±)-7-diacetyl-6,7-0-isopropylidene forskolin in the form of a colorless crystalline powder (12 μ) (yield: 98%). Next, (±)-7-diacetyl-6,7-0-isopropylideneforskolin (12■, 0,029■ garden o1)
10% perchloric acid/tetrahydrofuran (1/2,3
a) It was dissolved in a mixed solution and reacted at room temperature for 66 hours with stirring. The reaction solution was diluted with ethyl ether (20 J), washed with a saturated aqueous sodium bicarbonate solution (5all) and a saturated aqueous sodium chloride solution (5d), and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was subjected to column chromatography (silica gel; 15 g, eluent: hexane/ethyl ether, 2
/1.1/1) and (±)-7-diacetyl-6
, 9aQg of 7-0-isopropylideneforskolin
(Yield: 75%) At the same time, (±)-7-diacetylforskolin was obtained as a colorless oil (2μ) (yield: 19%). Next, (±)-7-diacetylforskolin (9■, 0
．． Acetic anhydride (0.2m) was added to a pyridine (0.4aQ) solution of 024-sol), and the mixture was reacted with stirring for 9 hours under water cooling. Methanol (0.2d) was added to the reaction mixture and stirred for 5 minutes, then diluted with ethyl ether (20d) and mixed with 5% sodium hydrogen sulfate (5aJIX3), saturated aqueous sodium hydrogen carbonate solution (5aQ), and saturated aqueous sodium chloride solution (3- )
and dried over anhydrous sodium sulfate. The residual liquid obtained by distilling off the solvent was subjected to column chromatography (silica gel: 15 g, eluent: benzene/ethyl acetate, 6/1
) to obtain (±)-forskolin (1) in the form of a colorless crystalline powder of 8 ml (yield: 80%). mp 199-200℃ (ethyl acetate-petroleum ether)

Claims (1)

[Claims] 1) General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, R^1, R^2, R^2', R^3 and R^
3' each represents a hydroxyl protecting group, R^2 and R^3
and/or R^2' and R^3' may be the same protecting group. ] Trans-decalin derivative. 2) General formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] [In the formula, R^1, R^2 and R^3 are hydroxyl protecting groups, and R^4 is an alkyl or aryl group. show. ]Forskolin derivative represented by. 3) General formula [ I ] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [ I ] [In the formula, R^1, R^2, R^2', R^3 and R^
3' each represents a hydroxyl protecting group, R^2 and R^3
and/or R^2' and R^3' may be the same protecting group. ] From the trans-decalin derivative represented by the general formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] [In the formula, R^1, R^2 and R^3 are hydroxyl protecting groups, R ^4 represents an alkyl or aryl group. ] A method for producing a forskolin derivative represented by the above general formula [I], which uses the transdecalin derivative represented by the general formula [I] as a raw material and sequentially subjects it to the following reaction steps. . [1] A reaction step of adding acetylide to the aldehyde group of a transdecalin derivative represented by the following structural formula [I] to obtain a compound of the following structural formula (A) (addition reaction step of acetylide to an aldehyde residue). ▲There are mathematical formulas, chemical formulas, tables, etc.▼〔I〕→▲Mathematical formulas,
There are chemical formulas, tables, etc. ▼ (A) [In the formula, R^1, R^2, R^2', R^3, R^3'
and R^4 have the same meaning as above. [2] A reaction step of oxidizing the alcohol group of the compound of the following structural formula (a) to obtain the compound of the following structural formula (b) (alcohol group oxidation reaction step). ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (A) → ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (B) [In the formula, R^1, R^2, R^2', R^3, R^ 3'
and R^4 have the same meaning as above. ] [3] Reaction step of reacting the compound of the following structural formula (b) with lithium dimethyl copper to obtain the compound of the following structural formula (c) (
1,4 addition reaction step using lithium dimethyl copper). ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (B) → ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (C) [In the formula, R^1, R^2, R^2', R^3, R^ 3′
and R^4 have the same meaning as above. ] [4] R^2' and R^3 of the compound of the following structural formula (c)
A reaction step for removing the protecting group represented by ' to obtain a compound of the following structural formula (d) (reaction step for removing the protecting groups represented by R^2' and R^3'). ▲There are mathematical formulas, chemical formulas, tables, etc.▼(c)→▲There are mathematical formulas, chemical formulas, tables, etc.▼(d) [In the formula, R^1, R^2, R^2', R^3, R^ 3′
and R^4 have the same meaning as above. ] [5] A reaction step in which the compound of the following structural formula (II) is reacted with an electrophilic reagent and then subjected to a reduction treatment to obtain the compound of the following structural formula [II] (cyclization reaction using an electrophilic reagent and a reducing agent) process). ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (d) → ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] [In the formula, R^1, R^2, R^3 and R^4 are the same as above. significance. ]