JP2014144922A - Pyripyropene a structure-simplified derivative showing acat2 inhibitory activity - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel, non-statin compound that is not derived from natural products, effective in prevention and treatment of arteriosclerosis.SOLUTION: This invention provides compounds represented by the formula, pharmaceutically acceptable salts, solvates and hydrates thereof, wherein Rare specific groups.

Description

  The present invention relates to a pyripyropene A structure simplified derivative having an extremely excellent cholesterol acyltransferase isozyme 2 (hereinafter abbreviated as ACAT2) inhibitory activity.

  It is said that the number of Japanese patients with hyperlipidemia and arteriosclerosis who are at high risk of developing directly into death such as myocardial infarction and stroke is as high as 30 million including the reserve army without subjective symptoms. Yes. Even after the revision of the Atherosclerotic Disease Guidelines, deaths through this process remain the leading cause of death. Hyperlipidemia and arteriosclerosis are serious health problems not only in Japan but also in Western countries.

  Currently, as a prophylactic and therapeutic drug for arteriosclerosis, hydroxy-3-methylglutaryl coenzyme A (hydroxy-3-methylglutaryl Co-A) (hereinafter abbreviated as HMG-CoA) reductase is specifically inhibited. Statins are mainly used. Statin drugs are the most widely sold drugs in the world for eight consecutive years since 2001, and are widely used so that two products are included in the top 30 sales in 2008. However, in reality, only 30 to 40% of statin drugs have an onset suppression effect, and it has become clear that half of patients undergoing treatment do not suppress cardiovascular disease or the like ( Non-patent document 1).

  The reason why HMG-CoA reductase inhibitor, which is a preventive and therapeutic drug for arteriosclerosis, does not sufficiently suppress cardiovascular diseases, etc., is due to the complicated mechanism of atherosclerosis and various factors such as heredity, diabetes, and drugs. It is thought that this is because there are many cases of overlapping. Therefore, diagnosis and treatment tailored to the patient's individual pathology are necessary. Therefore, the mechanism of action is different from that of statin drugs, and there is an urgent need to develop a drug having a new mechanism of action that can be expected to suppress the onset of coronary arteries and regress coronary artery lesions. However, at present, the development of drugs that replace statin drugs has hardly progressed.

  Cholesterol acyltransferase (hereinafter abbreviated as “ACAT”) is an enzyme that introduces an acyl group into cholesterol, and is a drug target that is expected to develop statin-resistant arteriosclerosis and tailor-made medicine according to individual pathologies. (Non-patent Document 2). This enzyme has been attracting attention as an important target molecule for arteriosclerosis preventive and therapeutic agents for many years, and many synthetic ACAT inhibitors have been developed. However, since side effects and sufficient effects have not been observed, they are still in clinical use. It is not tied (nonpatent literature 3).

  Under such circumstances, recently, it has become clear that ACAT has two types of isozymes, ACAT1 and ACAT2, which have different functions and localization in vivo (Non-patent Document 4). ACAT1 is widely distributed in many cells and tissues in the living body, and is highly expressed particularly in macrophages and smooth muscle cells, and causes macrophage foaming that causes arteriosclerosis in the arterial wall. On the other hand, ACAT2 is specifically expressed in the small intestine and liver, and is considered to be involved in absorption of dietary cholesterol and secretion of ultra-low density lipoprotein in each tissue. Thus, the difference in function between ACAT1 and ACAT2 in vivo has been clarified, and the importance of clarifying the selectivity in drug discovery targeting ACAT has been recognized.

  Synthetic ACAT inhibitors that have been discontinued in the past have properties of selective inhibition of ACAT1 (eg, Wu-V-23) or inhibition of both ACAT1 and ACAT2 isozymes (eg, abashimibe and pakimimibe). (Non-Patent Document 5).

  At present, only the natural organic compound pyripyropene A (Non-Patent Document 6) and the pyripyropene A derivative group derived from pyripyropene A by a semisynthetic method are reported as ACAT2-selective inhibitors. (Patent Documents 1 to 3) No synthetic low molecular weight compound not derived from natural organic compounds having ACAT2 selective inhibitory activity has been reported to date. Considering the results of the recently announced knockout mice (Non-patent Document 7) and the results of animal experiments with pyripyropene A (Non-patent Document 8), the possibility of drug discovery by chemical synthesis from ACAT2 selective inhibitors Is strongly expected.

  On the other hand, atorvastatin, a statin-based arteriosclerosis preventive and therapeutic drug, is an example of drug discovery research using natural organic compounds as lead compounds, developed as a result of simplifying the structure starting with compactin. Thus, although it is desired to simplify the structure of pyripyropene A, it is very difficult to simplify the structure using pyripyropene A as a starting material because of the complexity of the structure. However, the recently announced total synthesis of pyripyropene A (Non-Patent Document 9) is considered to be applicable to the synthesis of various simplified derivatives using a total synthetic method.

Libby et al., J. Am. Coll. Cardiol. 46, 1225-1228, 2005 Roth, Drug Discovery Today 3, 19-25, 1998 Meuwese et al., Curr. Opin. Lipidol. 17, 426-431, 2006 Chang et al., Acta. Biochim. Biophys. Sin. 38, 151-156, 2006 Farese, Arterioscler. Thromb. Vasc. Biol. 26, 1684-1686, 2006 Tomoda et al., J. Antibiot. 47, 148-153, 1994 Bell et al., Arterioscler. Thromb. Vasc. Biol. 27, 1396-1402, 2007 Ohsh IRo et al., Arterioscler. Thromb. Vasc. Biol. 31, 1108-1115, 2011 Odani et al., Tetrahedron 67, 8195-8203, 2011

WO2009 / 081957 WO2010 / 150739 WO2011 / 122468

  An object of the present invention is to provide a synthetic pharmaceutical agent not derived from a natural organic compound, which is a drug effective for the prevention or treatment of arteriosclerosis having a mechanism of action different from that of a statin pharmaceutical agent.

  Another object of the present invention is to provide a compound that can inhibit ACAT2 and is useful as a drug effective in preventing or treating arteriosclerosis.

  The present inventors have found that a specific pyripyropene A-structure simplified derivative has extremely high inhibitory activity against ACAT2, which is attracting attention as a target for prophylactic and therapeutic agents for dyslipidemia and arteriosclerosis. Completed the invention.

  Here, the present invention is a compound represented by the following general formula (I) and pharmaceutically acceptable salts, solvates and hydrates thereof.

Where
R ¹ represents an aryl group, an alkyl group or a cycloalkyl group, each of which may be substituted,
R ² represents an optionally substituted alkylcarbonyl group, arylcarbonyl group, alkyl group, or aryl group,
R ³ , R ⁴ , and R ⁵ may be the same or different from each other, and each represents hydrogen, a hydroxy group, or an optionally substituted alkylcarbonyloxy group, arylcarbonyloxy group, or alkoxy group. Or R ³ and R ⁴ together may mean a group represented by —O—CR ⁷ R ⁸ —O—, wherein R ⁷ and R ⁸ may be the same or different from each other; Each represents hydrogen, or an optionally substituted aryl or alkyl group, and R ⁶ represents —C (CH ₃ ) ₂ — or —CH ₂ —.

  In the present specification, the “aryl” may be a substituted aryl group having one or more substituents on the aromatic ring. Examples of the aromatic ring include benzene, naphthalene, pyridine, pyrimidine, furan, thiophene, indole and the like. That is, aryl also includes heteroaryl groups. The same applies to aryl contained in a part of a group such as an arylcarbonyl group. Examples of substituents on the aromatic ring include alkyl, alkoxy, halogen (F, Cl, Br or I), nitro, cyano, amino (including mono- and di-alkyl or arylamino) and the like.

  In the present specification, “alkyl” preferably means a linear or branched alkyl group having 1 to 6 carbon atoms, but the number of carbon atoms and the number of branches are not limited. The same applies to the number of carbon atoms of “alkoxy”. The alkyl group and alkoxy group may be substituted. Examples of substituents for alkyl groups and alkoxy groups include halogen (F, Cl, Br or I), nitro, cyano, amino (including mono- and di-alkyl or arylamino), alkoxy and the like.

  “Cycloalkyl” means a saturated carbocyclic group of 3 to 8 ring carbon atoms. Specific examples thereof include cyclopentyl and cyclohexyl. The hydrogen atom on the carbocyclic ring of the cycloalkyl group may be substituted with the same substituents as described for the aryl group.

  Pharmaceutically acceptable salts of the compounds represented by the above general formula (I) include inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or organic acids (eg, acetic acid, propion) Acid, citric acid, tartaric acid, malonic acid, maleic acid, fumaric acid, toluenesulfonic acid, succinic acid) and the like. Examples of the pharmaceutically acceptable solvate include solvates with lower alcohols and higher alcohols. Here, “lower” means 1 to 6 carbon atoms, and “higher” means 7 or more carbon atoms.

  The pyripyropene A structure simplified derivative and the pharmaceutically acceptable salt, solvate or hydrate thereof according to the present invention have a simplified structure as compared to pyripyropene A. Since it has inhibitory activity, it is useful as a prophylactic or therapeutic agent for arteriosclerotic diseases involving ACAT2. Since the compound according to the present invention can be produced by complete chemical synthesis without using pyripyropene A as a raw material, as described below, various low molecular weight ACAT2 inhibitors that cannot be derived from pyripyropene A can be produced. There is a possibility of supply.

Among the compounds represented by the general formula (I) according to the present invention, R ¹ is a 3-pyridyl group, R ² is a p-cyanobenzoyl group, R ³ , R ⁴ and R ⁵ are H, and R ⁶ is —CH. _The compound 8 meaning _2- can be produced by the following scheme (hereinafter referred to as the first scheme).

  Compound 1 which is the starting compound in the first scheme can be prepared according to a conventional method (for example, E. J. Sorensen et al., J. Am. Chem. Soc. 128, 7025-3035, 2006).

  The conversion from Compound 1 to Compound 2 can be performed by the following epoxidation method. That is, the compound 1 was reacted in an aqueous dioxane solvent for 4 hours at an ice temperature in the presence of 5 equivalents of N-bromosuccinimide and 3 equivalents of 1N perchloric acid, and then subjected to normal post-treatment. To obtain bromohydrin. The resulting bromohydrin can be reacted in a dichloromethane solvent at room temperature for 10 minutes in the presence of 1 equivalent of DBU, and then subjected to ordinary post-treatment to give compound 2.

  Conversion from compound 2 to compound 3 (wherein TBS = t-butyldimethylsilyl) can be carried out by the following method. That is, in the presence of 2.5 equivalents of ylide obtained by a conventional method (preferably prepared at a temperature of ice from a tetrahydrofuran solution of potassium tert-butoxide equivalent to the corresponding phosphonium salt) with respect to Compound 2, After reacting in a tetrahydrofuran solvent at room temperature for 1.5 hours, a hydrous acid (preferably hydrous formic acid) is added and reacted for 30 minutes, followed by normal post-treatment to obtain the corresponding aldehyde. A dimethylformamide solvent in the presence of 3 equivalents of t-butyldimethylsilyl chloride (TBSCl), 6 equivalents of a base (preferably imidazole) and a catalytic amount of an organic amine (preferably dimethylaminopyridine) to the aldehyde obtained. After reacting at 50 ° C. for 1 hour, 3 can be obtained by subjecting to normal post-treatment.

  Conversion from compound 3 to compound 6 can be carried out by a method through compound 4 or compound 5.

  Conversion from compound 3 to compound 4 can be carried out by the following method. That is, 1.5 equivalents of an enolate derived from acetate obtained by a conventional method with respect to compound 3 (preferably tetrahydrofuran solution of ethyl acetate and a small excess of LHMDS <lithium hexamethyldisilazide> at −78 ° C. In the presence of tetrahydrofuran) in tetrahydrofuran solvent at -78 ° C. for 5 minutes and subjected to the usual work-up to give the corresponding intermediate. The obtained intermediate was reacted for 1 hour at room temperature in a dimethyl sulfoxide solvent in the presence of 2.5 equivalents of an oxidizing agent (preferably IBX <2-iodoxybenzoic acid>), Compound 4 can be obtained by post-treatment.

  Conversion from compound 4 to compound 6 can be carried out by the following method. That is, for compound 4, in the presence of 1.3 equivalents of magnesium chloride, 2.7 equivalents of base (preferably pyridine) and 1.3 equivalents of acetyl chloride in dichloromethane solvent at −30 ° C. for 5 minutes. After reacting, the corresponding intermediate is obtained by subjecting it to conventional workup. The resulting intermediate was reacted in a toluene solvent in the presence of 1 equivalent of DBU (diazabicycloundecene) for 15 minutes under reflux conditions, and then subjected to normal post-treatment to give a compound. 6 can be obtained.

  Conversion from compound 3 to compound 5 can be carried out by the following method. That is, 2 equivalents of the corresponding organomagnesium reagent obtained by a conventional method (P. Knochel et al. Tetrahedron Lett. 42, 6847-6850, 2001) with respect to Compound 3 in a tetrahydrofuran solvent at room temperature. The reaction is allowed to proceed for 15 minutes and the corresponding intermediate is obtained by subjecting it to normal work-up. The resulting intermediate was reacted in a dichloromethane solvent at 0 ° C. for 30 minutes in the presence of 1.5 equivalents of an oxidizing agent (preferably DMP <desmartin periodinane>), followed by the usual post-treatment. Compound 5 can be obtained by subjecting to treatment.

  Conversion from compound 5 to compound 6 can be carried out by the following method. That is, the compound 5 is reacted in a methanol / toluene mixed solvent at 80 ° C. for 5 hours, and then subjected to a usual post-treatment to obtain a corresponding intermediate. After reacting in the presence of 1 equivalent of DBU in a toluene solvent at 100 ° C. for 12 hours with respect to the obtained intermediate, compound 6 can be obtained by subjecting to normal post-treatment.

  Conversion from compound 6 to compound 7 can be carried out by the following method. That is, the compound 7 was reacted in a tetrahydrofuran solvent at room temperature for 5 hours in the presence of 5 equivalents of a base (preferably LHMDS etc.), and then 2 equivalents of nicotinic acid chloride hydrochloride was added. The compound 7 can be obtained by reacting for a period of time and subjecting to normal post-treatment.

  Conversion from compound 7 to compound 8 can be carried out by the following method. That is, after reacting compound 7 in the presence of 2 equivalents of acetyl chloride in a methanol solvent at room temperature for 2 hours, the corresponding intermediate is obtained by subjecting to normal post-treatment. 1.5 equivalents of p-cyanobenzoic acid, 2 equivalents of a condensing agent (preferably EDCI <1-ethyl-3- (3-dimethylaminopropyl) carbodiimide>), and a catalytic amount of the resulting intermediate After reacting in a dichloromethane solvent in the presence of dimethylaminopyridine for 2.5 hours at room temperature, the corresponding intermediate is obtained by subjecting to normal post-treatment. The resulting intermediate was reacted in a methanol solvent in the presence of 1.2 equivalents of sodium borohydride at 0 ° C. for 15 minutes, and then subjected to ordinary post-treatment to give (10R) of compound 8 You can get a body. In addition, cerium chloride heptahydrate is added to this reaction, and post-treatment is performed in the same manner to obtain the (10S) form of Compound 8.

  The compound that can be produced in the first scheme is not limited to Compound 8. A compound having the same skeleton as that of Compound 8 and containing a different functional group can be synthesized by appropriately using the corresponding reagent.

Among the compounds represented by the general formula (I) according to the present invention, R ¹ is a 3-pyridyl group, R ² is a p-cyanobenzoyl group, R ³ , R ⁴ and R ⁵ are each H, and R ⁶ is —CMe. ^The compound 15 meaning 2- can be produced by the following scheme (hereinafter, second scheme).

  The starting compound 9 of the second scheme can be prepared by introducing a methyl group into the compound 1 according to a conventional method (A. Srikrishna et al., Chem. Commun. 11, 1369-1370, 1996). .

  Conversion from compound 9 to compound 10 can be performed by the same method as the conversion method from compound 1 to compound 2 in the first scheme. Alternatively, the following method can be implemented as an alternative method. That is, the compound 9 was reacted in the presence of 3 equivalents of N-bromoacetamide and 3 equivalents of silver acetate in an acetic acid solvent at room temperature for 4 hours, and then subjected to ordinary post-treatment to give the corresponding intermediate. obtain. Compound 10 can be obtained by reacting the obtained intermediate in the presence of 3 equivalents of potassium carbonate in a methanol solvent at room temperature for 30 minutes and then subjecting it to a conventional post-treatment.

  Conversion from compound 10 to compound 11 can be carried out by the following method. That is, the presence of 3 equivalents of an organosilicon lithium compound (preferably prepared at −23 ° C. from a tetrahydrofuran solution of the equivalent alkylsilane and an equivalent amount of sec-butyllithium) with respect to Compound 10 The reaction is then carried out in a tetrahydrofuran solvent at −60 ° C. for 40 minutes, and then 4 equivalents of potassium t-butoxide are reacted for 1 hour, followed by normal workup to give the corresponding aldehyde. In the presence of 3 equivalents of t-butyldimethylsilyl chloride, 6 equivalents of base (preferably imidazole) and a catalytic amount of an organic amine (preferably dimethylaminopyridine) in a dimethylformamide solvent with respect to the aldehyde obtained. After reacting at 50 ° C. for 1 hour, Compound 11 can be obtained by subjecting the mixture to ordinary post-treatment.

  The conversion from compound 11 to compound 12 can be performed by the same method as the conversion method from compound 3 to compound 5 in the first scheme.

  The conversion from compound 12 to compound 13 can be performed by the same method as the conversion method from compound 5 to compound 6 in the first scheme.

  Conversion from compound 13 to compound 14 can be carried out by the same method as the conversion method from compound 6 to compound 7 in the first scheme.

  Conversion from compound 14 to compound 15 can be carried out by the following method. That is, after reacting compound 14 in the presence of 2 equivalents of acetyl chloride in a methanol solvent at room temperature for 2 hours, the corresponding intermediate is obtained by subjecting to normal post-treatment. With respect to the resulting intermediate, 1.5 equivalents of p-cyanobenzoic acid, 2 equivalents of a condensing agent (preferably EDCI), and a catalytic amount of dimethylaminopyridine in dichloromethane solvent at room temperature. After reacting for .5 hours, the corresponding intermediate is obtained by subjecting it to normal workup. The obtained intermediate was reacted for 15 minutes at 0 ° C. in a methanol solvent in the presence of 1.2 equivalents of sodium borohydride and 1.2 equivalents of cerium chloride heptahydrate. By subjecting to a post-treatment, compound 15 can be obtained.

  The compound that can be produced in the second scheme is not limited to compound 15. A compound having the same skeleton as that of compound 15 and containing a different functional group can be synthesized by appropriately using the corresponding reagent.

Among the compounds represented by formula (I) according to the present invention, R ¹ is a 3-pyridyl group, R ² is an acetyl group, R ³ and R ⁴ are acetoxy groups, R ⁵ is H, and R ⁶ is -CMe. ^The compound 26 meaning ^2- can be produced by the following scheme (hereinafter, third scheme).

  The starting compound 16 in the third scheme can be synthesized by a conventional method (for example, A. Srikrishna et al., Chem. Commun. 11, Vol. 1369-1370, 1996).

  Conversion from compound 16 to compound 17 can be carried out by the following method. That is, the compound 16 was reacted in hexane solvent at -30 ° C. for 40 minutes in the presence of 1.1 equivalents of t-butyl hypochlorite and silica gel with respect to the compound 16, and then subjected to usual post-treatment to give the compound 17 Can be obtained.

  Conversion from compound 17 to compound 18 can be carried out by the following method. That is, the compound 17 was reacted for 2 hours at room temperature in a DMSO / water mixed solvent in the presence of 1.3 equivalents of cuprous oxide and 1.1 equivalents of an organic acid (preferably p-toluenesulfonic acid). Then, the corresponding alcohol is obtained by subjecting to normal post-treatment. The resulting alcohol can be reacted for 3 hours at room temperature in a dichloromethane solvent in the presence of 2 equivalents of m-chloroperbenzoic acid, and then subjected to ordinary post-treatment to obtain the corresponding epoxide. it can. The obtained epoxide was reacted in the presence of 1.5 equivalents of t-butyldimethylsilyl chloride and 3 equivalents of a base (preferably imidazole) in a dichloromethane solvent at room temperature for 30 minutes, Compound 18 can be obtained by post-treatment.

Conversion from compound 18 to compound 19 can be carried out by the following method. That is, 2.2 equivalents of Cp ₂ TiCl ₂ (titanocene dichloride) and 8 equivalents of manganese to compound 18 were stirred in tetrahydrofuran solvent at room temperature for 15 minutes, and compound 18 and 40 equivalents of water were added at room temperature. After reacting for a period of time, compound 19 can be obtained by subjecting to ordinary post-treatment.

  The conversion from compound 19 to compound 20 can be performed by the same method as in the third step in the conversion from compound 17 to compound 18 in the third scheme.

  The conversion from compound 20 to compound 25 via compounds 21, 22, 23 and 24 can be performed by the same method as the conversion from compound 9 to compound 14 via compounds 10, 11, 12 and 13 in the second scheme. it can.

  Conversion from compound 25 to compound 26 can be carried out by the following method. That is, the compound 25 is reacted for 1 hour at room temperature in a methanol solvent in the presence of 20 equivalents of acetyl chloride, and then subjected to ordinary post-treatment to obtain a corresponding intermediate. The obtained intermediate was reacted at room temperature for 15 hours in a dichloromethane solvent in the presence of 8 equivalents of acetic anhydride, 16 equivalents of triethylamine, and a catalytic amount of dimethylaminopyridine, and then subjected to usual work-up. The corresponding intermediate is obtained by applying. The obtained intermediate was reacted in methanol solvent for 30 minutes at 0 ° C. in the presence of 4 equivalents of sodium borohydride and 4 equivalents of cerium chloride heptahydrate, and then subjected to normal workup. Thus, compound 26 can be obtained.

  The compound that can be produced in the third scheme is not limited to the compound 26. A compound having the same skeleton as the compound 26 and containing a different functional group can be synthesized by appropriately using the corresponding reagent.

  The compound according to the present invention has a high inhibitory activity against ACAT2. Therefore, this compound can be used for the prevention and treatment of arteriosclerosis in animals including humans.

  The present invention also provides an ACAT2 inhibitor comprising the above compound or a pharmaceutically acceptable salt, solvate or hydrate thereof as an active ingredient, and the above compound or a pharmaceutically acceptable salt, solvate or hydrate thereof. Also provided is a pharmaceutical composition for inhibiting ACAT2, comprising a product and a pharmaceutically acceptable carrier.

  The pharmaceutical composition according to the present invention can be formulated by methods known to those skilled in the art. For example, the compound according to the present invention or a pharmaceutically acceptable salt, solvate or hydrate thereof is added to a pharmaceutically acceptable carrier such as sterile water, physiological saline, vegetable oil, emulsifier, suspension, interface. Unit doses required for generally accepted pharmaceutical practice by mixing with one or more selected from active agents, stabilizers, flavoring agents, excipients, vehicles, preservatives, binders, etc. It can be formulated by making it into a form.

  For oral administration, the compounds of the invention or pharmaceutically acceptable salts, solvates or hydrates thereof are mixed with pharmaceutically acceptable carriers well known in the art to produce tablets, pills, It can be formulated as a sugar coating, capsule, liquid, gel, syrup, slurry, suspension, powder, and the like.

  As the carrier, those conventionally known in the art can be widely used. For example, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like. Binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc .; dried starch, sodium alginate, agar powder, laminaran powder, carbonic acid Disintegrating agents such as sodium hydrogen, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose; disintegrating inhibitors such as sucrose, stear cocoa butter, hydrogenated oil; quaternary ammonium salts, La Absorption accelerators such as sodium rilsulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; abundant amounts of purified talc, stearate, boric acid powder, polyethylene glycol, etc. An agent or the like can be used. Furthermore, the tablet can be a tablet coated with a normal coating, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multilayer tablet, if necessary.

For parenteral administration, the compound of the present invention or a pharmaceutically acceptable salt, solvate or hydrate thereof is usually used using a pharmaceutically acceptable vehicle well known in the art as a carrier. It can be prescribed according to the formulation practice. Examples of water-soluble vehicles for injection include isotonic solutions containing, for example, physiological saline, glucose and other adjuvants (for example, water-soluble salts such as D-sorbitol, D-mannose, D-mannitol, sodium chloride). And may be used in combination with an appropriate solubilizing agent such as alcohol, specifically ethanol, polyalcohol such as propylene glycol, polyethylene glycol, nonionic surfactant (eg, polysorbate 80 ^™ , HCO-50, etc.). Good. Oily vehicles include sesame oil and soybean oil, and benzyl benzoate and benzyl alcohol may be used in combination as solubilizing agents. Further, a buffer such as phosphate buffer, sodium acetate buffer, soothing agent such as procaine hydrochloride, stabilizer such as benzyl alcohol, phenol and antioxidant may be added. The prepared injection solution is usually filled in a suitable ampoule.

  Suitable administration routes for the pharmaceutical composition according to the present invention include, but are not limited to, oral, rectal, radial mucosa, or enteral administration, or intramuscular, subcutaneous, intramedullary, intrathecal, direct intraventricular, intravenous , Intravitreal, intraperitoneal, intranasal, or intraocular injection. The administration route can be appropriately selected in consideration of the age and medical condition of the patient, other drugs used in combination, and the like.

  The dosage of the pharmaceutical composition according to the present invention can be selected in the range of 0.001 to 10 mg / kg body weight per administration. Alternatively, the dose can be selected in the range of 0.1 to 100 mg per administration, but is not necessarily limited to these values. Administration can be carried out once or several times a day, or once every few days. The dose and administration method can be appropriately selected by the doctor in charge taking into account the patient's weight, age, symptoms, and other drugs used in combination.

  Hereinafter, the present invention will be described in detail with reference to synthesis examples and examples, but the present invention is not limited thereto. In addition, the number of the compound in an Example respond | corresponds to the number in the said 1st-3rd scheme.

(5aS, 6S, 8S, 9aS, 10R) -10-hydroxy-8-isopropyl-5a-methyl-1-oxo-3- (pyridin-3-yl) -1,5a, 6,7,8,9, 9a, 10-Octahydropyrano [4,3-b] chromen-6-yl acetate (10R) -29, (PT001)
1) Synthesis of (1S, 4R, 6S) -4-isopropyl-1-methyl-7-oxabicyclo [4.1.0] heptan-2-one (2)

To (R)-(-)-carvone (4.13 mL, 26.3 mmol) was added PtO ₂ (6.0 mg, 26.3 μmol), and the mixture was vigorously stirred under a hydrogen atmosphere for 14 hours. Thereafter, Celite filtration was performed, and the filtrate was concentrated under reduced pressure.

NBS (23.4 g, 132 mmol) and 1N perchloric acid (78.9 mL, 78.9 mmol) were added to a hydrous dioxane solution (10%, 220 mL) of the crude product of the obtained compound (1), and 0 ° C was added. For 4 hours. The reaction was quenched with saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate, and the reaction was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure.The resulting crude material was dissolved in CH ₂ Cl ₂ (88 mL), DBU (3.90 mL, 26.3 mmol) was added, and the mixture was stirred at room temperature. Stir for 10 minutes. The reaction solution was diluted with EtOAc, and the organic layer was washed with water three times. The obtained organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (silica gel 200 g, hexane: EtOAc = 80: 1) to obtain Compound (2) (2.44 g, 3 steps 55%) as a colorless oily substance.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.43 (d, 1H, J = 4.8 Hz, CH ₂ C H (O)), 2.56 (t, 1H, J = 13.2 Hz, 1/2 COC H ₂ ) , 2.11-2.03 (m, 2H, 1/2 COC H _{2 ,} 1/2 C H ₂ CH (O)), 1.89-1.81 (m, 2H, 1/2 C H ₂ CH (O), (CH ₃ ) ₂ CHC H ), 1.55-1.48 (m, 1H, (CH ₃ ) ₂ C H CH), 1.39 (s, 3H, Me), 0.90 (d, 3H, J = 6.8 Hz, (C H ₃ ) ₂ CHCH), 0.87 (d, 3H, J = 6.8 Hz, (C H ₃ ) ₂ CHCH);
HRMS (EI) [M] ⁺ calculated value: C ₁₀ H ₁₆ O ₂ 168.1150, found: 168.1148.

  2) Synthesis of (3S, 5S) -3-hydroxy-5-isopropyl-2-methylcyclohex-1-encarbaldehyde (27)

Under a nitrogen atmosphere, tBuOK (799 mg, 7.12 mmol) was added to a THF solution (5.0 mL) of MeOCH ₂ PPh ₃ Cl (2.44 g, 7.12 mmol), and the mixture was stirred at 0 ° C for 1 hour, and then compound (2) (479 mg, 2.85 mmol) in THF (5.0 mL) was dropped and stirred at room temperature for 1.5 hours, H ₂ O (0.500 mL) and HCOOH (1.32 mL) were further added, and the mixture was stirred at room temperature for 30 minutes. The reaction was quenched by adding saturated aqueous K ₂ CO ₃ and extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by column chromatography (silica gel 20 g, hexane: EtOAc = 3: 1) to give a colorless oil (27 ) (493 mg, 95%).

[α] ²⁷ _D +960.1 (c 0.1, CHCl ₃ );
IR (KBr) 3020, 2401, 1665, 1423, 1216, 756, 670, 472, 445, 405 cm ^-1 ;
¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.13 (s, 1H, C H O), 4.29-4.24 (m, 1H, C (CH ₃ ) C H (OH) CH ₂ ), 2.39 (d, 1H , J = 16.6 Hz, 1/2 C H ₂ CCHO), 2.22-2.21 (m, 3H, C H ₃ CCH (OH)), 2.18-2.12 (m, 1H, 1/2 C H ₂ CH (OH) , 1.76-1.67 (m, 1H, 1/2 C H ₂ CCHO), 1.58-1.50 (m, 1H, (CH ₃ ) ₂ C H CH), 1.40-1.30 (m, 1H, (CH ₃ ) ₂ CHC H ), 1.25-1.16 (m, 1H, 1/2 C H ₂ CH (OH)), 0.89 (d, 6H, J = 6.8 Hz, (C H ₃ ) ₂ CHCH);
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 192.6, 156.3, 134.5, 72.9, 38.3, 36.5, 32.5, 26.7, 19.9, 19.6, 13.2;
HRMS (EI) [M] ⁺ calculated value: C ₁₁ H ₁₈ O ₂ 182.1307, found: 182.1311.

  3) Synthesis of (3S, 5S) -3- (tert-butyldimethylsilyloxy) -5-isopropyl-2-methylcyclohex-1-encarbaldehyde (3)

To a DMF solution (25 mL) of compound (27) (460 mg, 2.54 mmol) in a nitrogen atmosphere, imidazole (1.03 g, 15.1 mmol), DMAP (N, N-dimethyl-4-aminopyridine) (37.8 mg, 0.252 mmol) and TBSCl (1.14 g, 7.57 mmol) were added, and the mixture was stirred at 50 ° C. for 1 hour. H ₂ O was added to quench the reaction, EtOAc was added and the organic layer was washed with 2N HCl and water. The organic layer was dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by column chromatography (silica gel 20 g, hexane: EtOAc = 40: 1) to give compound (3) as a colorless oil. (679 mg, 76%) was obtained.

[α] ²⁷ _D +53.5 (c 1.0, CHCl ₃ );
IR (KBr) 3054, 2959, 2934, 1710, 1680, 1423, 1265, 839, 732, 707 cm ^-1 ;
¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.15 (s, 1H, C H O), 4.27 (br s, 1H, CH ₂ C H (OTBS)), 2.41-2.35 (m, 1H, 1/2 C H ₂ CCHO), 2.14 (s, 3H, C = C (C H ₃ )), 2.04-1.96 (m, 1H, 1/2 C H ₂ CH (OTBS), 1.78-1.68 (m, 1H, 1 / 2 C H ₂ CCHO), 1.61-1.49 (m, 1H, (CH ₃ ) ₂ C H CH), 1.33-1.24 (m, 1H, (CH ₃ ) ₂ CHC H ), 1.26 (dd, 1H, J = 11.2, 10.0 Hz, 1/2 C H ₂ CH (OTBS)), 0.92 (s, 9H, Si (CH ₃ ) ₂ C (C H ₃ ) ₃ ) 0.90 (dd, 6H, J = 6.6, 1.8 Hz , (C H ₃ ) ₂ CHCH), 0.12 (d, 6H, J = 4.2 Hz, Si (C H ₃ ) ₂ C (CH ₃ ) ₃ );
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 192.5, 157.2, 134.3, 73.7, 38.2, 36.7, 32.5, 26.4, 26.1, 20.0, 19.5, 18.4, 13.7, -3.6, -4.6;
HRMS (FAB, PEG400) [M + Na] ⁺ calculated value: C ₁₇ H ₃₂ NaO ₂ Si 319.2069, found: 319.2064.

  4) Synthesis of ethyl 3-((3S, 5S) -3- (tert-butyldimethylsilyloxy) -5-isopropyl-2-methylcyclohex-1-enyl) -3-oxopropanoate (4a)

Under an argon atmosphere at −78 ° C., LHMDS (1.06M THF solution, 2.96 mL, 3.14 mmol) was added dropwise to a THF solution (10 mL) of ethyl acetate (300 μL, 2.93 mmol), and the mixture was stirred for 30 minutes. 3) A solution of (580 mg, 1.96 mmol) in THF (10 mL) was added dropwise and stirred for 5 minutes. The reaction was quenched with saturated aqueous NH ₄ Cl and extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated.

IBX (1.37 g, 4.90 mmol) was added to a DMSO solution (20 mL) of the obtained residue, and the mixture was stirred at room temperature for 1 hour. The reaction was stopped by adding a saturated aqueous solution of Na ₂ S ₂ O ₃ , and EtOAc was added and washed with water. The combined organic layers were dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by column chromatography (silica gel 12.9 g, hexane: EtOAc = 80: 1) to give the compound ( 4a) (622 mg, 2 steps 83%) was obtained.

[α] ²⁷ _D +134.9 (c 1.0, CHCl ₃ );
IR (KBr) 3054, 2958, 2933, 2859, 1736, 1617, 1417, 1265, 1218, 1079, 1041, 836, 741 cm ^-1 ;
¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.23-4.14 (m, 3H, CH ₂ C H (OTBS), CO ₂ C H ₂ CH ₃ ), 3.57 (s, 2H, J = 3.6 Hz, COC H ₂ CO ₂ Et), 2.21-2.15 (m, 1H, 1/2 C H ₂ CCOCH ₂ CO ₂ Et), 2.02-1.85 (m, 2H, 1/2 C H ₂ CH (OTBS), 1/2 C H ₂ COCH ₂ CO ₂ Et), 1.82 (s, 3H, C = C (C H ₃ )), 1.59-1.48 (m, 1H, (CH) ₂ C H CH), 1.47-1.41 (m, 1H, (CH ₃ ) ₂ CHC H ), 1.27 (t, 3H, J = 7.2 Hz, CO ₂ CH ₂ C H ₃ ), 1.27-1.21 (m, 1H, 1/2 C H ₂ CH (OTBS)), 0.95 -0.85 (m, 15H, Si (CH ₃ ) ₂ C (C H ₃ ) ₃ , (C H ₃ ) ₂ CHCH), 0.10 (s, 3H, Si (C H ₃ ) ₂ C (CH ₃ ) ₃ ) , 0.08 (s, 3H, Si (C H ₃ ) ₂ C (CH ₃ ) ₃ );
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 175.7, 168.0, 139.6, 129.1, 91.3, 73.1, 61.6, 49.1, 39.0, 36.6, 32.4, 31.6, 30.6, 26.2, 19.5, 18.5, 17.2, 16.7, 14.6, -3.7, -4.5;
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₂₁ H ₃₈ NaO ₄ Si 405.2437, found: 405.2434.

  5) 8-((tert-Butyldimethylsilyl) oxy) -6-isopropyl-2,8a-dimethyl-4-oxo-4a, 5,6,7,8,8a-hexahydron-4H-chromene-3-carvone Acid ・ (4aR, 6S, 8S, 8aS) -Ethyl (6a)

In a nitrogen atmosphere, add MgCl ₂ (22.6 mg, 240 μmol) and pyridine e (38 μL, 480 μmol) to CH ₂ Cl ₂ solution (2.0 mL) of 4a (69.9 mg, 180 μmol), and stir at 0 ° C for 10 minutes. Chloride (17 μL, 240 μmol) was added and stirred at room temperature for 5 minutes. The reaction was stopped by adding H ₂ O and extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated.

DBU (22 μL, 150 μmol) was added to a toluene solution (2.0 mL) of the obtained residue under a nitrogen atmosphere, and the mixture was stirred for 15 minutes under reflux conditions. H ₂ O was added to stop the reaction, EtOAc was added and washed with water. The organic layer was dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by column chromatography (silica gel 1.02 g, hexane: EtOAc = 60: 1) to give a yellow oil 6a (64.5 mg , 2 steps 83%) as a 3: 1 mixture of diastereomers at position 8a.

[α] ²⁷ _D +27.1 (c 1.0, CHCl ₃ );
IR (KBr) 3055, 2983, 2958, 2934, 1725, 1681, 1393, 1265, 1112, 835, 733, 706 cm ^-1 ;
¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.23 (q, 2H, J = 4.4 Hz, CO ₂ C H ₂ CH ₃ ), 3.83 (dd, 1H, J = 11.2, 5.2 Hz, C H OTBS), 2.44 (dd, 1H, J = 12.4, 4.0 Hz, CH ₂ C H CO), 2.17 (s, 3H, C = CC H ₃ ), 2.07 (ddd, 1H, J = 17.6, 9.2, 3.2 Hz, 1 / 2 COCHC H ₂ ), 1.74-1.66 (m, 1H, 1/2 C H ₂ CH (OTBS)), 1.52-1.44 (m, 1H, (CH ₃ ) ₂ C H CH), 1.43-1.38 (m, 1H, (CH ₃ ) ₂ CHC H ), 1.28 (t, 3H, J = 7.2 Hz, CO ₂ CH ₂ C H ₃ ), 1.16 (s, 3H, C (C H ₃ ) CH (OTBS)), 1.13 (dd, 1H, J = 12.4, 1.6 Hz, 1/2 C H ₂ CH (OTBS)), 0.91 (dd, 1H, J = 14.0, 1.6 Hz, 1/2 C H ₂ CHCO), 0.90 (s, 9H, Si (CH ₃ ) ₂ C (C H ₃ ) ₃ ), 0.87 (d, 6H, J = 3.6 Hz, (C H ₃ ) ₂ CHCH), 0.09 (s, 3H, 1/2 Si (C H ₃ ) ₂ C (CH ₃ ) ₃ ), 0.07 (s, 3H, 1/2 Si (C H ₃ ) ₂ C (CH ₃ ) ₃ );
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 189.7, 174.9, 165.9, 110.9, 87.2, 76.2, 60.9, 49.9, 40.5, 36.0, 32.2, 25.9, 24.0, 20.8, 20,1, 19.7, 18.3, 14.4, 10.2, -4.4;
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₂₃ H ₄₀ NaO ₅ Si 447.2543, found: 447.2533.

  6) 5-((3S, 5S) -3-((tert-butyldimethylsilyl) oxy) -5-isopropyl-2-methylcyclohex-1-enecarbonyl) -2,2,6-trimethyl-4H- Synthesis of 1,3-dioxin-4-one (5)

5-iodo-2,2,6-trimethyl-4H-1,3-dioxin-4-one (tetra-hedron Lett., 2001, 42, 6847-6850) at -30 ° C under argon atmosphere (914 mg, 3.41 mmol IPrMgCl (2.0 M THF solution, 1.71 mL, 3.41 mmol) was added dropwise to a THF solution (13 mL) and stirred for 5 minutes, and then a THF solution (4.0 mL) of compound (3) (505 mg, 1.71 mmol) Was added dropwise and stirred at −30 ° C. for 15 minutes. NH ₄ Cl saturated aqueous solution was added to quench the reaction, extraction was performed with CH ₂ Cl ₂ , and the combined organic layers were dried over Na ₂ SO ₄ and concentrated.

DMP (1.08 g, 2.56 mmol) was added to a CH ₂ Cl ₂ solution (10 mL) of the obtained residue at 0 ° C. under a nitrogen atmosphere, and the mixture was stirred for 30 minutes. The reaction was stopped by adding a saturated aqueous solution of Na ₂ S ₂ O _{3 and a} saturated aqueous solution of NaHCO ₃ , EtOAc was added, and the organic layer was washed with a saturated aqueous solution of NaHCO ₃ and water. The organic layer was dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by column chromatography (silica gel 50 g, hexane: EtOAc = 20: 1) to give the compound ( 5) (508 mg, 2 steps, 68%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.21 (bs, 1H, CH ₂ C H OSi), 2.27 (s, 3H, C H ₃ COC (CH ₃ ) ₂ ), 2.15-2.08 (m, 1H, 1/2 CHC H ₂ CHOSi), 1.96-1.90 (m, 2H, 1/2 CHC H ₂ COSi, 1/2 CHC H ₂ C = CCH ₃ ), 1.70 (bs, 9H, C H ₃ CCHOSi, C ( O) OC (C H ₃ ) ₂ ), 1.53-1.46 (m, 2H, C H CH (CH ₃ ) ₂ , 1/2 CHC H ₂ C = CCH ₃ ), 1.34-1.28 (m, 1H, CHC H (CH ₃ ) ₂ ), 0.87 (bs, 15H, CHCH (C H ₃ ) ₂ , Si (CH ₃ ) ₂ C (C H ₃ ) ₃ ), 0.06 (s, 6H, Si (C H ₃ ) ₂ C (CH ₃ ) ₃ );
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 196.8, 175.4, 158.8, 138.5, 136.1, 109.8, 106.6, 73.0, 39.1, 36.7, 32.4, 31.3, 31.1, 26.2, 25.8, 25.7, 20.2, 19.9, 19.7, 18.5, 16.5, -3.7, -4.5;
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₂₄ H ₄₀ NaO ₅ Si, 459.2543, found: 459.2526.

  7) 8-((tert-Butyldimethylsilyl) oxy) -6-isopropyl-2,8a-dimethyl-4-oxo-4a, 5,6,7,8,8a-hexahydro-4H-chromene-3-carvone Synthesis of acids ・ (4aR, 6S, 8S, 8aS) -methyl (6b)

  Toluene (0.8 mL) and MeOH (0.2 mL) were added to compound (5) (43.7 mg, 0.100 mmol), stirred at 90 ° C. for 12 hours, and concentrated.

DBU (15.0 μL, 0.100 mmol) was added to a toluene solution (1.0 mL) of the obtained residue, and the mixture was stirred at 100 ° C. for 12 hours. The reaction was diluted with EtOAc and washed with H ₂ O. The organic layer was dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by column chromatography (silica gel 5 g, hexane: EtOAc = 20: 1) to give a compound (6b ) (43.7 mg, 2 steps, 80%) was obtained as a 4: 1 diastereomeric mixture at position 8a.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.87-3.82 (m, 1H, C H OTBS), 3.79 (s, 3H, CO ₂ C H ₃ ), 2.47 (dd, 1H, J = 16.0, 4.0 Hz , CH ₂ C H CO), 2.22 (s, 3H, C = CC H ₃ ), 2.15-2.07 (m, 1H, 1/2 COCHC H ₂ ), 1.77-1.71 (m, 1H, 1/2 C H ₂ CH (OTBS)), 1.57-1.47 (m, 2H, (CH ₃ ) ₂ C H CH, (CH ₃ ) ₂ CHC H )), 1.19 (s, 3H, C (C H ₃ ) CH (OTBS) ), 1.30-1.25 (m, 1H, 1/2 COCHC H ₂ ), 1.00-0.84 (m, 16H, 1/2 C H ₂ CH (OTBS), Si (CH ₃ ) ₂ C (C H ₃ ) ₃ , (C H ₃ ) ₂ CHCH), 0.11 (d, 6H, J = 9.2 Hz, Si (C H ₃ ) ₂ C (CH ₃ ) ₃ );
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 189.4, 175.3, 166.0, 110.3, 87.5, 76.3, 69.0, 52.2, 50.1, 40.6, 36.1, 32.4, 25.4, 23.6, 20.6, 19.7, 19.4, 17.9, 9.8, -4.8, -5.3;
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₂₂ H ₃₈ NaO ₅ Si, 433.2386, found: 433.2403.

  8) (5aS, 6S, 8S, 9aR) -6-((tert-Butyldimethylsilyl) oxy) -8-isopropyl-5a-methyl-3- (pyridin-3-yl) -5a, 6,7,8 Of 1,9,9a-Hexahydropyrano [4,3-b] chromene-1,10-dione (7)

A THF solution (2.5 mL) of the compound (6a) (212 mg, 500 μmol) was added dropwise to LHMDS (1.06 M THF solution, 2.5 mL, 2.50 mmol) at −78 ° C. under an argon atmosphere, and the mixture was stirred at room temperature for 5 hours. A THF solution (2.5 mL) of nicotinoyl chloride hydrochloride (178 mg, 1.00 mmol) was added dropwise at −78 ° C., and the mixture was stirred at room temperature for 4 hours. AcOH was added to stop the reaction, EtOAc was added and washed with 2N HCl. The organic layer was dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by column chromatography (silica gel 51 g, hexane: EtOAc = 5: 1) to give the compound ( 7) (159 mg, 66%) was obtained as a 3: 1 diastereomeric mixture at position 9a.

[α] ²⁷ _D +11.1 (c 1.0, CHCl ₃ );
IR (KBr) 3055, 2982, 2307, 1758, 1429, 1265, 738 cm ^-1 ;
¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.06 (d, 1H, J = 2.4 Hz, Py), 8.75 (dd, 1H, J = 4.8, 1.6 Hz, Py), 8.19 (dt, 1H, J = 8.0, 2.0 Hz, Py), 7.46 (ddd, 1H, J = 8.0, 4.8, 2.0 Hz, Py), 6.43 (s, 1H, PyC = C H ), 3.97 (dd, 1H, J = 11.2, 5.3 Hz , C H (OTBS)), 2.63 (dd, 1H, J = 12.0, 4.0 Hz, CH ₂ C H CO), 2.20 (dd, 1H, J = 14.0, 2.0 Hz, 1/2 C H ₂ CHCO ₎ , 1.81 (dt, 1H, J = 13.2, 2.4 Hz, 1/2 C H ₂ CH (OTBS)), 1.56 (dd, 1H, J = 12.4, 6.8 Hz, (CH ₃ ) ₂ C H CH), 1.48- 1.40 (m, 1H, (CH ₃ ) ₂ CHC H ), 1.30 (s, 3H, C (C H ₃ ) CCH (OTBS)), 1.22-1.21 (m, 1H, 1/2 C H ₂ CHOSi (CH ₃ ) ₂ C (CH ₃ ) ₃ ), 1.11-1.05 (m, 1H, 1/2 C H ₂ CH (OTBS)), 0.96 (s, 9H, Si (CH ₃ ) ₂ C (C H ₃ ) ₃ ), 0.92 (dd, 6H, J = 6.8, 2.4 Hz, (C H ₃ ) ₂ CHCH), 0.19 (s, 3H, 1/2 Si (C H ₃ ) ₂ C (CH ₃ ) ₃ ), 0.15 ( s, 3H, 1/2 Si (C H ₃ ) ₂ C (CH ₃ ) ₃ );
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 188.0, 173.5, 162.7, 157.0, 152.8, 147.8, 134.1, 127.0, 134.1, 127.0, 124.1, 98.3, 89.9, 76.1, 51.6, 40.4, 36.0, 32.3, 30.0, 26.1, 24.3, 20.1, 19.0, 11.1, -4.1, -4.2;
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₂₇ H ₃₇ NNaO ₅ Si 506.2339, found: 506.2345.

9) (5aS, 6S, 8S, 9aR) -6- (Acetoxy) -8-isopropyl-5a-methyl-3- (phenyl) -5a, 6,7,8,9,9a-hexahydropyrano [4 , 3-b] chromene-1,10-dione ((9aR) -28) and
(5aS, 6S, 8S, 9aS) -6- (Acetoxy) -8-isopropyl-5a-methyl-3- (phenyl) -5a, 6,7,8,9,9a-hexahydropyrano [4,3 Synthesis of -b] chromene-1,10-dione ((9aS) -28)

  Under a nitrogen atmosphere, AcCl (65 μL, 912 μmol) in MeOH (4.5 mL) was added dropwise to a solution of compound (7) (221 mg, 463 μmol) in MeOH (4.5 mL), stirred at room temperature for 2 hours, and concentrated. .

To a CH ₂ Cl ₂ solution (4.5 mL) of the obtained residue, DMAP (6.1 mg, 52.1 μmol), Et ₃ N (254 μL, 1.82 mmol) and Ac ₂ O (86 μL, 911 μmol) were added. Stir for 30 minutes at room temperature under atmosphere. The reaction was stopped by adding H ₂ O and extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by preparative TLC (hexane: EtOAc = 1: 20), whereby each compound (yellow solid material) (9aR) -28) (99.0 mg, 2 steps 53%) and compound ((9aS) -28) (24.5 mg, 2 steps 14%) were obtained separately as single diastereomers.

Identification data of compound ((9aR) -28)
[α] ²⁷ _D +10.2 (c 1.0, CHCl ₃ );
IR (KBr) 2930, 1757, 1628, 1536. 1431, 1262, 738 cm ^-1 ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.06 (dd, 1H, J = 2.1, 0.6 Hz, Py), 8.74 (dd, 1H, J = 4.8, 1.5 Hz, Py), 8.18 (ddd, 1H, J = 8.4, 2.4, 1.8 Hz, Py), 7.44 (dd, 1H, J = 8.1, 0.6 Hz, Py), 6.54 (s, 1H, PyC = C H ), 5.26 (dd, 1H, J = 11.7, 5.1 Hz, C H (OAc)), 2.75 (dd, 1H, J = 12.3, 3.6 Hz, CH ₂ C H CO), 2.27 (ddd, 1H, J = 14.4, 5.7, 3.9 Hz, 1/2 C H ₂ CHCO), 2.19 (s, 3H, COCHC (C H ₃ )), 2.06-1.98 (m, 1H, 1/2 C H ₂ CH (OAc)), 1.64-1.53 (m, 1H, (CH ₃ ) ₂ C H CH), 1.39 (s, 3H, CH (OAc) C (C H ₃ )), 1.40-1.29 (m, 1H, (CH ₃ ) ₂ CHC H ), 1.18-1.05 (m, 1H, 1 / 2 C H ₂ CHCO), 0.87-0.81 (m, 1H, 1/2 C H ₂ CH (OAc)), 0.92 (d, 6H, J = 6.3 Hz, (C H ₃ ) ₂ CHCH);
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 187.0, 173.2, 170.5, 162.9, 156.9, 153.0, 147.9, 134.1, 126.9, 124.1, 100.5, 98.5, 87.4, 76.1, 51.6, 40.4, 32.3, 32.0, 24.5, 21.6, 20.2, 20.0, 12.0;
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₂₃ H ₂₅ NNaO ₆ 434.1580, found: 434.1565.

Identification data of compound ((9aS) -28)
[α] ²⁷ _D +63.5 (c 1.0, CHCl ₃ );
IR (KBr) 2930, 1757, 1628, 1536, 1431, 1262, 737 cm ^-1 ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.08-9.06 (m, 1H, Py), 8.75-8.72 (m, 1H, Py), 8.22 (dd, 1H, J = 7.2, 1.5 Hz, Py), 7.65 (dd, 1H, J = 6.9, 5.1 Hz, Py), 6.41 (s, 1H, PyC = C H ), 5.38 (dd, 1H, J = 11.7, 5.1 Hz, C H ( OAc)), 2.94 ( dd, 1H, J = 4.2, 3.0 Hz, CH ₂ C H CO), 2.67 (dd, 1H, J = 13.2, 2.1 Hz, 1/2 C H ₂ CHCO), 2.09 (s, 3H, COCHC (C H ₃ )), 1.91-1.85 (m, 1H, 1/2 CH ₂ C H CO), 1.67 (s, 3H, CH (OAc) C (C H ₃ )), 1.54-1.35 (m, 2H, (CH ₃ ) ₂ C H CH, (CH ₃ ) ₂ CHC H ), 1.35-1.09 (m, 2H, 1/2 C H ₂ CHCO, 1/2 C H ₂ CH (OAc)), 0.90 (d, 6H, J = 5.1 Hz, (C H ₃ ) ₂ CHCH);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ 186.7, 173.6, 170.3, 162.8, 157.0, 152.4, 147.5, 134.6, 129.1, 124.3, 100.2, 98.7, 88.0, 70.0, 51.6, 37.7, 33.0, 32.4, 30.0, 25.7, 21.6, 21.4, 20.7;
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₂₃ H ₂₅ NNaO ₆ 434.1588, found: 434.1565.

  10) (5aS, 6S, 8S, 9aS, 10R) -10-Hydroxy-8-isopropyl-5a-methyl-1-oxo-3- (pyridin-3-yl) -1,5a, 6,7,8, 9,9a, 10-Octahydropyrano [4,3-b] chromen-6-yl acetate ((10R) -29), (PT001)

Under a nitrogen atmosphere, NaBH ₄ (8.1 mg, 29.5 μmol) was added to a MeOH solution (0.2 mL) of the compound ((9aR) -28) (10.1 mg, 24.6 μmol), and the mixture was stirred at 0 ° C. for 15 minutes. Acetone was added to stop the reaction, and EtOAc was added and washed with water. The combined organic layers were dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by preparative TLC (hexane: EtOAc = 1: 20) to give the compound (( 10R) -29) (PT001) (8.0 mg, 80%) was obtained.

[α] ²⁷ _D +17.8 (c 1.0, CHCl ₃ );
IR (KBr) 3055, 2929, 2309, 1708, 1428, 1264, 897, 735 cm ^-1 ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.03 (d, 1H, J = 4.8 Hz, Py), 8.70 (d, 1H, J = 4.5 Hz, Py), 8.15 (d, 1H, J = 5.1 Hz , Py), 7.44 (dd, 1H, J = 4.8, 3.0 Hz, Py), 6.50 (s, 1H, PyC = C H ), 5.02 (dd, 1H, J = 11.7, 4.8 Hz, C H (OAc) ), 4.64 (d, 1H, J = 4.2 Hz, CHC H (OH)), 2.21 (s, 3H, OCHC (C H ₃ )), 2.01-1.95 (m, 1H, 1/2 C H ₂ CH ( OAc)), 1.90-1.81 (m, 2H, 1/2 C H ₂ CHCH (OH), CH ₂ C H CH (OH)), 1.65-1.42 (m, 3H, 1/2 C H ₂ CHCH (OH ), (CH ₃ ) ₂ C H CH, (CH ₃ ) ₂ CHC H ), 1.50 (s, 3H, CC (C H ₃ ) O), 1.37-1.29 (m, 1H, 1/2 C H ₂ CH (OAc)), 0.95 (d, 3H, J = 4.5 Hz, (C H ₃ ) ₂ CHCH), 0.93 (d, 3H, J = 4.5 Hz, (C H ₃ ) ₂ CHCH);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ 170.8, 164.4, 163.4, 157.7, 151.9, 147.2, 133.4, 103.6, 99.9, 83.0, 62.0, 43.7, 41.4, 32.6, 30.1, 27.8, 23.0, 21.7, 20.2, 20.1, 14.5, 13.0;
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₂₃ H ₂₇ NNaO ₆ 436.1736, found: 436.1723.

  (5aS, 6S, 8S, 9aS, 10S) -10-Hydroxy-8-isopropyl-5a-methyl-1-oxo-3- (pyridin-3-yl) -1,5a, 6,7,8,9, 9a, 10-Octahydropyrano [4,3-b] chromen-6-yl acetate ((10S) -29), (PT002)

Under a nitrogen atmosphere, a solution of the compound ((9aR) -28) (10.0 mg, 24.6 μmol) obtained in Example 1 in MeOH (0.2 mL) was added to CeCl ₃ · 7H ₂ O (11.0 mg, 29.5 μmol) and NaBH. ₄ (1.1 mg, 29.5 μmol was added, and the mixture was stirred at 0 ° C. for 15 minutes. Acetone was added to stop the reaction, EtOAc was added, and the mixture was washed with water. The combined organic layers were dried over Na ₂ SO ₄ . Concentration and purification of the resulting crude material with preparative TLC (hexane: EtOAc = 1: 2) gave compound ((10S) -29), (PT002) (7.3 mg, 74 %).

[α] ²⁷ _D +27.1 (c 1.0, CHCl ₃ );
IR (KBr) 2928, 2859, 1715, 1261, 735 cm ^-1 ;
¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.01 (d, 1H, J = 2.0 Hz, Py), 8.69 (dd, 1H, J = 4.8, 1.6 Hz, Py), 8.10 (ddd, 1H, J = 8.0, 2.4, 1.6 Hz, Py), 7.40 (ddd, 1H, J = 8.4, 5.2, 0.8 Hz, Py), 6.49 (s, 1H, PyC = C H ), 5.06 (dd, 1H, J = 12.0, 4.8 Hz, C H (OAc)), 4.45 (d, 1H, J = 10.0 Hz, CHC H (OH)), 2.33-2.27 (m, 1H, 1/2 C H ₂ CHCH (OH), 2.18 (s , 3H, C H ₃ CO), 2.01-1.95 (m, 1H, 1/2 C H ₂ CH (OAc)), 1.86 (ddd, 1H, J = 12.4, 10.0, 3.6 Hz, CH ₂ C H CH ( OH)), 1.59-1.43 (m, 2H, (CH ₃ ) ₂ C H CH, (CH ₃ ) ₂ CHC H ), 1.28 (s, 3H, CC (C H ₃ ) O), 1.37-1.20 (m , 1H, 1/2 C H ₂ CH (OAc)), 1.02-0.87 (m, 1H, 1/2 C H ₂ CHCH (OH)), 0.93 (d, 3H, J = 4.8 Hz, (C H ₃ ) ₂ CHCH), 0.91 (d, 3H, J = 4.8 Hz, (C H ₃ ) ₂ CHCH);
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.6, 164.0, 163.4, 157.6, 151.2, 146.8, 133.7, 121.0, 100.0, 83.9, 64.5, 63.6, 45.0, 40.9, 32.4, 30.0, 28.9, 23.0, 21.7, 20.2, 20.1, 14.5, 12.3;
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₂₃ H ₂₇ NNaO ₆ 436.1736, found: 436.1734.

  (5aS, 6S, 8S, 9aS, 10R) -10-hydroxy-8-isopropyl-5a-methyl-1-oxo-3- (pyridin-3-yl) -1,5a, 6,7,8,9, 9a, 10-Octahydropyrano [4,3-b] chromen-6-yl 4-cyanobenzoate ((10R) -8), (PT005)

AcCl (48 μL, 0.0681 mmol) was added to a solution of the compound (7) obtained in Example 1 (32.9 mg, 0.0681 mmol) in MeOH (800 μL) at 0 ° C. and stirred for 1 hour, and then CH ₂ Cl ₂ Extracted with. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The resulting crude product CH ₂ Cl ₂ (0.800 mL) was added EDCI (23.5 mg, 0.122 mmol), DMAP (1.0 mg, 0.0122 mmol) and p-cyanobenzoic acid (p- CNBzOH) (15.0 mg, 0.102 mmol) was added and stirred at room temperature for 2.5 hours. Water was added to quench the reaction, and the mixture was extracted with CH ₂ Cl _{2. The} organic layer was dried over Na ₂ SO ₄ and concentrated. NaBH ₄ (3.3 mg, 0.0868 mmol) was added to a solution of the obtained crude substance in MeOH (0.800 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour. Acetone was added to stop the reaction, and the mixture was washed with EtOAc. The organic layer was dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by preparative TLC (EtOAc) to give the compound ((10R) -8) (PT005) ( 8.20 mg, 3 steps 24%) was obtained.

[α] ²⁷ _D +55.3 (c 0.1, CHCl ₃ );
IR (KBr) 3442, 3020, 2400, 2360, 1635, 1215, 1105, 784, 753, 669, 603, 468, 445, 421, 406 cm ^-1 ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.11 (s, 1H, Py), 8.76 (s, 1H, Py), 8.52 (s, 1H, Py), 8.21 (d, 2H, J = 8.4 Hz, Ph), 7.80 (d, 3H, J = 8.4 Hz, Ph, Py), 6.54 (s, 1H, PyC = C H ), 5.31 (dd, 1H, J = 11.1, 5.1 Hz, C H OC (O) PhCN), 4.69 (d, 1H, J = 4.2 Hz, C H (OH) CH), 2.12 (d, 1H, J = 5.1 Hz, 1/2 C H ₂ CHCH (OH), 1.95 (m, 1H, 1/2 CHC H ₂ CHOC (O) PhCN), 1.88 (s, 1H, C H CH (OH)), 1.72-1.54 (m, 1H, C H (CH ₃ ) ₂ ), 1.51-1.49 (m, 1H, C H CH (CH ₃ ) ₂ ), 1.31-1.22 (m, 2H, 1/2 CHC H ₂ CHOC (O) PhCN, 1/2 C H ₂ CHCH (OH), 1.25 (s, 9H, ( C H ₃ ) ₂ CHCH, C H ₃ COC = C);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ 164.3, 162.1, 134.0, 132.5, 130.4, 129.4, 118.0, 116.9, 105.7, 83.6, 77.9, 77.3, 61.4, 43.5, 41.3, 32.4, 32.1, 29.8, 29.7, 29.5, 22.8, 20.0, 19.9, 14.2, 13.2;
HRMS (ESI) [M + Na] ⁺ calculated value: C ₂₉ H ₂₈ N ₂ NaO ₆ 523.1845, found: 523.1843.

  (5aS, 6S, 8S, 9aS, 10S) -10-Hydroxy-8-isopropyl-5a-methyl-1-oxo-3- (pyridin-3-yl) -1,5a, 6,7,8,9, 9a, 10-Octahydropyrano [4,3-b] chromen-6-yl 4-cyanobenzoate ((10S) -8), (PT006)

AcCl (0.048 mL, 0.673 mmol) was added to a solution of the compound (7) (65.1 mg, 0.135 mmol) obtained in Example 1 in MeOH (1.3 mL) at 0 ° C. and stirred for 1 hour, then CH ₂ and extracted with Cl _2. The combined organic layers were dried over Na ₂ SO ₄ and concentrated.

EDCI (46.4 mg, 0.242 mmol) and DMAP (1.6 mg, 0.0135 mmol) and p-CNBzOH (29.7 mg, 0.202 mmol) in a CH ₂ Cl ₂ solution (1.3 mL) of the obtained crude material at room temperature under a nitrogen atmosphere And stirred at room temperature for 2.5 hours. Water was added to quench the reaction, and the mixture was extracted with CH ₂ Cl _{2. The} organic layer was dried over Na ₂ SO ₄ and concentrated. To the resulting crude material MeOH (1.3 mL) solution, at _{0 ℃, NaBH 4 (6.62 mg} , 0.175 mmol) and _{CeCl 3 · 7H 2 O (65.2} mg, 0.175 mmol) was added and 1 hour at 0 ℃ Stir. The reaction was stopped by adding acetone, diluted with EtOAc, and then washed with water. The organic layer was dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by preparative TLC (EtOAc) to give a compound ((10R) -8) (PT006) (8.2 mg, 3 steps 12%).

¹ H-NMR (600 MHz, CDCl ₃ ) δ 8.98 (bs, 1H, Py), 8.69 (bs, 1H, Py), 8.20 (d, 2H, J = 8.4 Hz, Ph), 8.14 (dd, 1H, J = 11.1, 8.7 Hz, Py), 7.80 (d, 2H, J = 8.4 Hz, Ph), 7.46 (dd, 1H, J = 8.1, 5.1 Hz, Py), 6.44 (s, 1H, C H = CPy ), 5.35 (dd, 1H, J = 12.0, 5.0 Hz, C H OC (O) PhCN), 4.50 (d, 1H, J = 9.6 Hz, C H (OH) CHCH ₂ ), 2.37 (ddd, 1H, J = 12.5, 3.5, 2.0 Hz, 1/2 C H ₂ CHCH (OH), 2.15 (ddd, 1H, J = 12.0, 10.0, 3.5, 1/2 CHC H ₂ CHOC (O) PhCN), 1.67 (s , 1H, CH ₂ C H CH (OH)), 1.63-1.53 (m, 1H, CHC H (CH ₃ ) ₂ ), 1.46-1.37 (m, 1H, C H CH (CH ₃ ) ₂ ), 1.25- 1.20 (m, 2H, 1/2 CHC H ₂ CHOC (O) PhCN, 1/2 C H ₂ CHCH (OH), 0.96-0.94 (m, 9H, (C H ₃ ) ₂ CHCH, C H ₃ COC = C);
¹³ C-NMR (150 MHz, CDCl ₃ ) δ 164.0, 163.4, 162.8, 156.9, 150.4, 145.7, 134.0, 132.3, 130.2, 127.5, 124.1, 117.8, 116.7, 103.1, 99.8, 83.6, 77.7, 63.1, 44.7, 40.6, 32.2, 29.7, 28.6, 19.8, 19.7, 12.3;
HRMS (ESI) [M + Na] ⁺ calculated value: C ₂₉ H ₂₈ N ₂ NaO ₆ 523.1845, found: 523.1847.

(5aS, 6S, 8S, 9aS, 10R) -10-Hydroxy-8-isopropyl-5a-methyl-1-oxo-3-phenyl-1,5a, 6,7,8,9,9a, 10-octahydro Production of pyrano [4,3-b] chromen-6-yl acetate (10R) -33, (PT003)
1) (5aS, 6S, 8S, 9aR) -6-((tert-Butyldimethylsilyl) oxy) -8-isopropyl-5a-methyl-3- (phenyl) -5a, 6,7,8,9,9a Of 2-Hexahydropyrano [4,3-b] chromene-1,10-dione (31)

LHFDS (1.06M THF solution, 4.7 mL, 4.71 mmol) and THF solution (4.7 μL, 3.76 mmol) of Compound (6a) (400 mg, 940 μmol) and TMEDA (tetramethylethylenediamine) (560 μL, 3.76 mmol) at −78 ° C. under an argon atmosphere. mL) was added dropwise, and the mixture was stirred at room temperature for 5 hours. Then, a THF solution (4.7 mL) of the above compound (30) (178 mg, 1.00 mmol) was added dropwise at -78 ° C, and the mixture was stirred at room temperature for 4 hours. AcOH was added to quench the reaction, EtOAc was added and washed with 2N aqueous HCl. The organic layer was dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by column chromatography (silica gel 51 g, hexane: EtOAc = 5: 1) to give compound (31 ) (159 mg, 49%) was obtained as a 3: 1 diastereomeric mixture at position 9a.

[α] ²⁷ _D +10.2 (c 1.0, CHCl ₃ );
IR (KBr) 3056, 2957, 1755, 1531, 1428, 1264, 739 cm ^-1 ;
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.85 (d, 2H, J = 0.8 Hz, Ph), 7.54-7.46 (m, 3H, Ph), 6.38 (s, 1H, C = C H (Ph) ), 3.97 (dd, 1H, J = 11.2, 5.2 Hz, C H (OTBS)), 2.63 (dd, 1H, J = 12.0, 3.6 Hz, CH ₂ C H CO), 2.20 (dd, 1H, J = 14.4, 2.0 Hz, 1/2 C H ₂ CHCO), 1.83-1.78 (m, 1H, 1/2 C H ₂ CH (OTBS)), 1.56 (dd, 1H, J = 12.4, 6.8 Hz, (CH ₃ ) ₂ C H CH), 1.49-1.40 (m, 1H, (CH ₃ ) ₂ CHC H ), 1.29 (s, 3H, C (C H ₃ ) CH (OTBS)), 1.22-1.21 (m, 1H, 1/2 C H ₂ CHOSi (CH ₃ ) ₂ C (CH ₃ ) ₃ ), 1.11-1.01 (m, 1H, 1/2 C H ₂ CH (OTBS)), 0.96 (s, 9H, Si (CH ₃ ) ₂ C (C H ₃ ) ₃ ), 0.92 (dd, 6H, J = 6.8, 2.4 Hz, (C H ₃ ) ₂ CHCH), 0.20 (s, 3H, 1/2 Si (C H ₃ ) ₂ C (CH ₃ ) ₃ ), 0.15 (s, 3H, 1/2 Si (C H ₃ ) ₂ C (CH ₃ ) ₃ );
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 188.1, 173.9, 165.2, 157.6, 132.8, 129.5, 126.8, 100.0, 97.2, 89.5, 76.2, 51.6, 40.5, 36.0, 32.3, 30.0, 26.1, 24.4, 20.1, 18.5, 11.2, -4.1, -4.5;
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₂₈ H ₃₈ NaO ₅ Si 505.2386, found: 505.2367.

2) (5aS, 6S, 8S, 9aS, 10R) -6,10-Dihydroxy-8-isopropyl-5a-methyl-3-phenyl-6,7,8,9,9a, 10-hexahydropyrano [ 4,3-b] chromen-1 (5aH) -one ((9aS, 10R) -32), and
(5aS, 6S, 8S, 9aS, 10S) -6,10-Dihydroxy-8-isopropyl-5a-methyl-3-phenyl-6,7,8,9,9a, 10-hexahydropyrano [4, Synthesis of 3-b] chromen-1 (5aH) -one ((9aS, 10S) -32)

  Under a nitrogen atmosphere, AcCl (7 μL, 100 μmol) in MeOH (0.3 mL) was added dropwise to a MeOH solution (0.3 mL) of compound (31) (24.0 mg, 49.8 μmol), stirred at room temperature for 2 hours, and concentrated. did.

NaBH ₄ (2.2 mg, 60.0 μmol) was added to a MeOH solution (0.5 mL) of the obtained residue, and the mixture was stirred at 0 ° C. for 15 minutes. Acetone was added to stop the reaction, and EtOAc was added and washed with water. The combined organic layers were dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by preparative TLC (hexane: EtOAc = 1: 2) to give each compound as a white solid material ( (9aS, 10R) -32) (11.4 mg, 62%) and the compound ((9aS, 10S) -32 (2.4 mg, 13%)) were obtained separately.

Identification data of compound ((9aS, 10R) -32)
[α] ²⁷ _D +27.0 (c 1.0, CHCl ₃ );
IR (KBr) 3055, 2984, 2307, 1674, 1563, 1427, 1265, 745 cm ^-1 ;
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.81-7.79 (m, 2H, Ph), 7.48-7.44 (m, 3H, Ph), 6.48 (s, 1H, PhC = C H ), 4.65 (d, 1H, J = 4.0 Hz, CHC H (OH)), 3.80 (dd, 1H, J = 11.6, 4.8 Hz, CH ₂ C H (OH)), 2.00-1.95 (m, 1H, 1/2 C H ₂ CH (OH)), 1.83-1.76 (m, 2H, 1/2 C H ₂ CHCH (OH), CH ₂ C H CH (OH)), 1.62-1.52 (m, 3H, 1/2 C H ₂ CHCH (OH), (CH ₃ ) ₂ C H CH, (CH ₃ ) ₂ CHC H ), 1.44 (s, 3H, CC (C H ₃ ) O), 1.34-1.21 (m, 1H, 1/2 C H ₂ CH (OH)), 0.96 (d, 3H, J = 4.4 Hz, (C H ₃ ) ₂ CHCH), 0.93 (d, 3H, J = 4.4 Hz, (C H ₃ ) ₂ CHCH);
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 164.9, 163.8, 160.4, 131.4, 129.3, 126.0, 103.0, 98.6, 84.9, 76.4, 62.1, 43.4, 41.6, 34.3, 32.6, 30.4, 28.1, 23.0, 20.4, 20.2, 14.5, 12.0;
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₂₂ H ₂₆ NaO ₅ 393.1678, found: 393.1670.

Identification data of compound ((9aS, 10S) -32)
[α] ²⁷ _D +39.7 (c 1.0, CHCl ₃ );
IR (KBr) 3054, 2369, 2342, 1693, 1265, 745 cm ^-1 ;
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.80-7.76 (m, 2H, Ph), 7.47-7.43 (m, 3H, Ph), 6.48 (s, 1H, PhC = C H ), 4.46 (d, 1H, J = 10.0 Hz, CHC H (OH)), 3.85 (dd, 1H, J = 11.6, 4.8 Hz, CH ₂ C H (OH)), 2.31-2.25 (m, 1H, 1/2 C H ₂ CHCH (OH)), 2.00-1.95 (m, 1H, 1/2 C H ₂ CH (OH)), 1.78 (ddd, 1H, J = 14.0, 10.0, 4.0 Hz, CH ₂ C H CH (OH)) , 1.59-1.52 (m, 1H, (C H ₃ ) ₂ C H CH)), 1.42-1.36 (m, 1H, (CH ₃ ) ₂ CHC H )), 1.29-1.19 (m, 1H, 1/2 C H ₂ CH (OH)), 1.23 (s, 3H, CC (C H ₃ ) O), 1.01-0.95 (m, 1H, 1/2 C H ₂ CHCH (OH)), 0.95 (d, 3H, J = 3.6 Hz, (C H ₃ ) ₂ CHCH), 0.92 (d, 3H, J = 3.6 Hz, (C H ₃ ) ₂ CHCH);
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 164.6, 164.0, 163.9, 131.5, 129.3, 126.0, 102.5, 98.6, 86.0, 75.9, 63.8, 44.7, 41.0, 34.2, 32.6, 30.0, 29.3, 23.0, 20.3, 20.2, 11.3;
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₂₂ H ₂₆ NaO ₅ 393.1678, found: 393.1690.

  3) (5aS, 6S, 8S, 9aS, 10R) -10-Hydroxy-8-isopropyl-5a-methyl-1-oxo-3-phenyl-1,5a, 6,7,8,9,9a, 10- Synthesis of Octahydropyrano [4,3-b] chromen-6-yl acetate ((10R) -33), (PT003)

Compound ((9aS, 10R) -32) (4.2 mg, 11.3 μmol) in CH ₂ Cl ₂ (0.1 mL) was added to DMAP (2.0 mg, 11.3 μmol), EDCI (2.3 mg, 13.5 μmol), and AcOH ( 1 μL, 13.5 μmol) was added, and the mixture was stirred at 0 ° C. for 1 hour under a nitrogen atmosphere. The reaction was stopped by adding H ₂ O and extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by preparative TLC (hexane: EtOAc = 1: 1) to give the compound ((10R ) -33), (PT003) (1.9 mg, 36%).

[α] ²⁷ _D +21.8 (c 0.1, CHCl ₃ );
IR (KBr) 2927, 1736, 1689, 1636, 1571, 1424, 1381, 1258, 733 cm ^-1 0
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.81-7.79 (m, 2H, Ph), 7.47-7.43 (m, 3H, Ph), 6.43 (s, 1H, PhC = C H ), 5.02 (dd, 1H, J = 11.7, 4.8 Hz, C H (OAc)), 4.64 (d, 1H, J = 4.5 Hz, CHC H (OH)), 2.21 (s, 3H, OCHC (C H ₃ )), 2.01- 1.95 (m, 1H, 1/2 C H ₂ CH (OAc)), 1.90-1.80 (m, 2H, 1/2 C H ₂ CHCH (OH), CH ₂ C H CH (OH)), 1.65-1.42 (m, 3H, 1/2 C H ₂ CHCH (OH), (CH ₃ ) ₂ C H CH, (CH ₃ ) ₂ CHC H ), 1.48 (s, 3H, CC (C H ₃ ) O), 1.37 -1.29 (m, 1H, 1/2 C H ₂ CH (OAc)), 0.95 (d, 3H, J = 4.5 Hz, (C H ₃ ) ₂ CHCH), 0.93 (d, 3H, J = 4.5 Hz, (C H ₃ ) ₂ CHCH);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ 170.7, 164.5, 163.8, 160.3, 131.4, 129.3, 126.0, 102.8, 82.6, 62.1, 43.7, 41.5, 32.6, 32.5, 30.1, 27.8, 21.7, 20.2, 20.1, 13.0;
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₂₄ H ₂₈ NaO ₆ 435.1784, found: 435.1773.

  (5aS, 6S, 8S, 9aS, 10S) -10-Hydroxy-8-isopropyl-5a-methyl-1-oxo-3-phenyl-1,5a, 6,7,8,9,9a, 10-octahydro Production of pyrano [4,3-b] chromen-6-yl acetate ((10S) -33), (PT004)

To a CH ₂ Cl ₂ solution (0.3 mL) of the compound ((9aS, 10S) -32) (12.1 mg, 32.7 μmol) obtained in Example 5, DMAP (3.7 mg, 3.27 μmol), Et ₃ N (10 μL , 71.9 μmol) and Ac ₂ O (4 μL, 3.59 μmol) were added, and the mixture was stirred at −10 ° C. for 30 minutes in a nitrogen atmosphere. The reaction was stopped by adding H ₂ O and extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by preparative TLC (hexane: EtOAc = 1: 20) to give a compound ((10S ) -33), (PT004) (9.5 mg, 77%).

[α] ²⁷ _D +37.5 (c 1.0, CHCl ₃ );
IR (KBr) 2927, 1736, 1689, 1263, 740 cm ^-1 ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.81-7.77 (m, 2H, Ph), 7.47-7.26 (m, 3H, Ph), 6.42 (s, 1H, PhC = C H ), 5.05 (dd, 1H, J = 11.7, 4.8 Hz, C H (OAc)), 4.45 (d, 1H, J = 10.2 Hz, CHC H (OH)), 2.34-2.23 (m, 1H, 1/2 C H ₂ CHCH ( OH), 2.18 (s, 3H, C H ₃ CO ₂ ), 2.04-1.94 (m, 1H, 1/2 C H ₂ CH (OAc)), 1.86 (ddd, 1H, J = 12.3, 10.2, 3.6 Hz , CH ₂ C H CH (OH)), 1.59-1.43 (m, 2H, (CH ₃ ) ₂ C H CH, (CH ₃ ) ₂ CHC H ), 1.33-1.27 (m, 1H, 1/2 C H ₂ CH (OAc)), 1.28 (s, 3H, CC (C H ₃ ) O), 1.02-0.87 (m, 1H, 1/2 C H ₂ CHCH (OH)), 0.93 (d, 3H, J = 4.8 Hz, (C H ₃ ) ₂ CHCH), 0.91 (d, 3H, J = 4.8 Hz, (C H ₃ ) ₂ CHCH);
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 170.7, 164.2, 163.5, 160.3, 131.4, 129.3, 126.0, 102.8, 83.2, 76.3, 63.3, 44.7, 41.5, 32.6, 32.5, 32.2, 30.1, 27.8, 21.7, 20.2, 20.1, 12.0;
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₂₄ H ₂₈ NaO ₆ 435.1784, found: 435.1775.

  (5aS, 6S, 8S, 9aS, 10R) -10-Hydroxy-8-isopropyl-5a-methyl-1-oxo-3-phenyl-1,5a, 6,7,8,9,9a, 10-octahydro Preparation of pyrano [4,3-b] chromen-6-yl 4-cyanobenzoate (34), (PT007)

Under a nitrogen atmosphere at room temperature, ((9aS, 10S) -32) (17.0 mg, 0.046 mmol) in CH ₂ Cl ₂ (0.5 mL) was added to EDCI (14.2 mg, 0.074 mmol) and DMAP (8.4 mg, 0.069 mmol) and p-CNBzOH (9.0 mg, 0.055 mmol) were added, and the mixture was stirred at room temperature for 2.5 hours. The reaction was stopped by adding MeOH, and the mixture was extracted with CH ₂ Cl _{2. The} organic layer was dried over Na ₂ SO ₄ and concentrated. The resulting crude material was purified by preparative TLC (hexane: EtOAc = 3: 1) to give compound (34), (PT007) (12.8 mg, 56%) as a white solid material.

[α] ²⁷ _D +68.6 (c 1.0, CHCl ₃ );
IR (KBr) 3436, 2958, 2230, 1723, 1637, 1575, 1415, 1269, 1209, 1100, 757, 472 cm ^-1 ;
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.24-8.21 (m, 1H, Ph), 8.16-8.13 (m, 1H, Ph), 7.83-7.80 (m, 2H, Ph), 7.78-7.73 (m , 3H, Ph, C (O) Ph CN), 7.46-7.40 (m, 2H, C (O) Ph CN), 6.39-6.34 (m, 1H, PhC = C H ), 5.37-5.33 (m, 1H , C H OC (O) PhCN), 4.14-4.10 (m, 1H, CHC H (OH)), 2.27-2.23 (m, 1H, 1/2 C H ₂ CHCH (OH), 2.16-2.13 (m, 1H, 1/2 CHC H ₂ CHOC (O) PhCN), 2.05 (s, 1H, C H CH (OH)), 1.71-1.74 (bs, 3H, C H ₃ COC = C), 1.55-1.15 (m , 4H, C H (CH ₃ ) ₂ , C H CH (CH ₃ ) ₂ , C H ₂ CHCH (OH), 0.84 (m, 6H, (C H ₃ ) ₂ CHCH);
¹³ C-NMR (150 MHz, CDCl ₃ ) δ 164.2, 163.5, 160.1, 131.1, 131.0, 129.0, 125.6, 102.1, 98.2, 85.6, 75.5, 65.7, 65.6, 63.4, 44.4, 40.7, 33.9, 32.2, 31.9, 29.7, 29.3, 29.0, 28.5, 25.8, 24.7, 22.7, 20.0, 19.8, 14.1, 10.9;
HRMS (ESI) [M + Na] ⁺ calculated value: C ₃₀ H ₂₉ NNaO ₆ 522.1893, found: 522.1915.

(5aS, 6S, 8S, 9aS, 10R) -10-hydroxy-8-isopropyl-5a, 9,9-trimethyl-1-oxo-3- (pyridin-3-yl) -1,5a, 6,7, Production of 8,9,9a, 10-octahydropyrano [4,3-b] chromen-6-yl acetate (35), (PT008)
1) Synthesis of (1S, 4S, 6S) -4-isopropyl-1,3,3-trimethyl-7-oxabicyclo [4.1.0] heptan-2-one (10)

PtO ₂ (21.7 mg, 0.096 mmol) was added to (R)-(−)-carvone (15.0 ml, 95.5 mmol), and the mixture was stirred at room temperature for 23 hours in a hydrogen atmosphere. The reaction solution was filtered through Celite, and the resulting crude material was used in the next reaction without purification.

Under an argon atmosphere, n-BuLi (53.3 ml, 143 mmol) was added to a THF (280 ml) solution of i-Pr ₂ NH (20.2 ml, 143 mmol), and the mixture was stirred at 0 ° C. for 1 hour. Thereafter, a solution of the above crude material in THF (20 ml) was added and stirred for 3 hours. MeI (20.8 ml, 334 mmol) was added and stirred for 12 hours. The reaction was quenched with NH ₄ Cl, diluted with EtOAc, and the organic layer was washed with water and dried over Na ₂ SO ₄ . After concentration, the resulting crude material was roughly purified by column chromatography (silica gel 460 g, 100: 1 hexane / EtOAc), and fractions containing the product were concentrated to obtain a crude material.

Under an argon atmosphere, n-BuLi (88.7 ml, 239 mmol) was added to a THF (280 ml) solution of iPr ₂ NH (33.7 ml, 239 mmol), and the mixture was stirred at 0 ° C. for 1 hour. Thereafter, a solution of the above crude substance in THF (20 ml) was added, and the mixture was stirred at room temperature for 6 hours. The reaction was quenched with a saturated aqueous NH ₄ Cl solution, diluted with EtOAc, and the organic layer was washed with water and dried over Na ₂ SO ₄ . After concentration, the resulting crude material was roughly purified by column chromatography (silica gel 400 g, 100: 1 hexane / EtOAc), and fractions containing the product were concentrated to obtain a crude material.

NBA (26.3 g, 191 mmol) and AgOAc (31.9 g, 191 mmol) were added to an AcOH solution (318 mL) of the obtained crude substance, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered through celite, saturated aqueous NaHCO ₃ solution was added, and the mixture was extracted with EtOAc. The organic layer is dried over Na ₂ SO ₄ and concentrated. The resulting crude material is roughly purified by column chromatography (silica gel 1120 g, hexane: EtOAc = 20: 1), and the fraction containing the product is concentrated. The crude material was obtained.

To the obtained crude material in MeOH (318 mL) was added K ₂ CO ₃ (39.6 g, 286 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc, and the organic layer was washed with H ₂ O, dried over Na ₂ SO ₄ and concentrated. The resulting crude material was purified by column chromatography (silica gel 1120 g, hexane: EtOAc = 50: 1) to obtain compound (10) (11.7 g, 5 steps 62%) as a yellow oily substance.

[α] ²⁷ _D -102.7 (c 1.0, CHCl ₃ );
IR (KBr) 2855, 2363, 2343, 1075, 857, 773, 466 cm ^-1 ;
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.42 (d, 1H, J = 4.8 Hz, C H (O) C), 2.15 (dd, 1H, J = 15.6, 10.4 Hz, 1/2 C H ₂ CH (O) C), 2.02 (ddd, 1H, J = 15.6, 6.4, 4.8 Hz, 1/2 C H ₂ CH (O) C), 1.96-1.89 (m, 1H, C H (CH ₃ ) ₂ ), 1.58-1.53 (m, 1H, C H CH (CH ₃ ) ₂ ), 1.38 (s, 3H, C H ₃ COCH), 1.16 (s, 3H, C H ₃ CCH ₃ ), 1.12 (s, 3H , CH ₃ CC H ₃ ), 0.93 (d, 3H, J = 6.8 Hz, CH (C H ₃ ) ₂ ), 0.87 (d, 3H, J = 7.2 Hz, CH (C H ₃ ) ₂ );
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 210.5, 63.3, 57.1, 49.9, 47.5, 27.6, 24.8, 24.4, 20.9, 20.8, 18.9, 16.7;
HRMS (EI) [M] ⁺ calculated value: C ₁₂ H ₂₀ O ₂ 196.1463, found: 196.1451.

  2) 5-((3S, 5S) -3-((tert-butyldimethylsilyl) oxy) -5-isopropyl-2,6,6-trimethylcyclohex-1-enecarbonyl) -2,2,6- Synthesis of trimethyl-4H-1,3-dioxin-4-one (12)

Under an argon atmosphere, s-BuLi (1.1M THF solution, 4.46 mL, 4.73 mmol) was added dropwise to a THF solution (10 mL) of TMSCH ₂ OMe (0.738 mL, 4.73 mmol) at -23 ° C. After stirring for 30 minutes, a THF solution (5.8 mL) of compound (10) (310 mg, 1.58 mmol) was added dropwise at −78 ° C., and the mixture was stirred at −60 ° C. for 40 minutes. Thereafter, t-BuOK (708 mg, 6.31 mmol) was added, the temperature was gradually raised to room temperature, and the mixture was stirred at room temperature for 1 hour. NH ₄ Cl saturated aqueous solution was added and the reaction was stopped by stirring for 15 minutes. CH ₂ Cl ₂ was added and the organic layer was washed with 2N HCl solution, dried over Na ₂ SO ₄ and concentrated.

To a DMF solution (16 mL) of the obtained residue, imidazole (430 mg, 6.31 mmol), DMAP (19.3 mg, 0.158 mmol) and TBSCl (713 mg, 4.73 mmol) were added, and the mixture was added at 50 ° C. under a nitrogen atmosphere. Stir for hours. H ₂ O was added to stop the reaction, EtOAc was added and the organic layer was washed with water. The organic layer is dried over Na ₂ SO ₄ and concentrated, and the resulting crude material is roughly purified by column chromatography (silica gel 51 g, hexane: EtOAc = 100: 1), and the fraction containing the product is concentrated. The crude material was obtained.

5-iodo-2,2,6-trimethyl-4H-1,3-dioxin-4-one (tetrahedron Lett., 2001, 42, 6847-6850) (845 mg, 3.16) at -30 ° C under argon atmosphere iPrMgCl (2.0 M THF solution, 2.37 mL, 4.73 mmol) was added dropwise to a THF solution (10 mL) of (mmol) and stirred for 30 minutes, and then the THF solution (5.8 mL) of the crude material obtained above was added dropwise. Stir at room temperature for 15 minutes. NH ₄ Cl saturated aqueous solution was added to quench the reaction, extraction was performed with CH ₂ Cl ₂ , and the combined organic layers were dried over Na ₂ SO ₄ and concentrated.

DMP (1.00 g, 2.37 mmol) was added to a CH ₂ Cl ₂ solution (16 mL) of the residue obtained above at 0 ° C. under a nitrogen atmosphere, and the mixture was stirred for 15 minutes. Na ₂ S ₂ O ₃ saturated aqueous solution and NaHCO ₃ saturated aqueous solution were added to stop the reaction, and CH ₂ Cl ₂ was added to extract the organic layer. The organic layer was dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by column chromatography (silica gel 73 g, hexane: EtOAc = 10: 1) to give compound (12 ) (321 mg, 4 steps, 44%).

[α] ²⁷ _D +27.7 (c 1.0, CHCl ₃ );
IR (KBr) 3474, 2957, 2858, 1744, 1656, 1545, 1468, 1377, 1346, 1253, 1198, 1088, 1050, 867, 836 cm ^-1 ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ 4.18-4.13 (m, 1H, C H OTBS), 2.45 (s, 3H, C H ₃ COC (CH ₃ ) ₂ ), 1.98-1.89 (m, 1H, C H (CH ₃ ) ₂ ), 1.79-1.71 (m, 1H, C H CH (CH ₃ ) ₂ ), 1.70 (s, 3H, C H ₃ COC = O), 1.69 (s, 3H, C H ₃ COC = O), 1.60-1.55 (m, 2H, C H ₂ CHOTBS), 1.55 (s, 3H, C H ₃ CCHOTBS), 1.13 (s, 3H, C H ₃ C (CH ₃ ) C), 0.95 ( s, 3H, C H ₃ CH (CH ₃ ) CH), 0.93 (d, 3H, J = 6.9 Hz, C H ₃ CH (CH ₃ ) CH), 0.89 (s, 9H, (C H ₃ ) ₃ CSi ), 0.84 (d, 3H, J = 6.9 Hz, C H ₃ CH (CH ₃ ) CH), 0.10 (s, 3H, 1/2 (C H ₃ ) ₂ Si), 0.07 (s, 3H, 1 / 2 (C H ₃ ) ₂ Si);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ 197.6, 179.1, 158.2, 143.4, 132.4, 110.3, 105.8, 77.4, 72.6, 47.3, 39.5, 29.7, 26.0, 25.6, 25.3, 25.3, 25.2, 24.8, 24.6, 23.7, 21.8, 18.8, 18.3, 16.5, -3.8, -4.7;
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₂₆ H ₄₄ NaO ₅ Si 487.2856, found: 487.2841.

  3) (4aR, 6S, 8S, 8aS) -Methyl-8-((tert-butyldimethylsilyl) oxy) -6-isopropyl-2,5,5,8a-tetramethyl-4-oxo-4a, 5, Synthesis of 6,7,8,8a-Hexahydro-4H-chromene-3-carboxylic acid (13)

  Toluene (11 mL) and MeOH (2.7 mL) were added to compound (12) (622 mg, 1.34 mmol), stirred at 90 ° C. for 3 hours, and concentrated.

DBU (0.200 mL, 1.34 mmol) was added to a toluene solution (13 mL) of the obtained residue, and the mixture was stirred at 100 ° C. for 4 hours. The reaction was stopped by adding H ₂ O and extracted with CH ₂ Cl ₂ . The organic layer was dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by column chromatography (silica gel 59 g, hexane: EtOAc = 25: 1) to give compound (13 ) (407 mg, 69%).

[α] ²⁷ _D +19.9 (c 0.1, CHCl ₃ );
IR (KBr) 2371, 2345, 1060, 773, 618, 476 cm ^-1 ;
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.82 (dd, 1H, J = 11.6, 4.8 Hz, C H OTBS), 3.78 (s, 3H, C H ₃ OC = O), 2.39 (s, 1H, C H C = O), 2.13 (s, 3H, C H ₃ C = C), 2.02-1.97 (m, 1H, C H (CH ₃ ) ₂ ), 1.52 (ddd, 1H, J = 13.2, 4.8, 3.2 Hz, 1/2 C H ₂ CHOTBS), 1.39-1.29 (m, 1H, 1/2 C H ₂ CHOTBS), 1.31 (s, 3H, C H ₃ CCHOTBS), 1.25 (s, 3H, C H ₃ CCH ₃ ), 1.04-1.00 (m, 1H, C H CH (CH ₃ ) ₂ ), 1.03 (s, 3H, C H ₃ CCH ₃ ), 0.90 (d, 3H, J = 6.8 Hz, C H ₃ CH (CH ₃ ) CH), 0.91 (s, 9H, (C H ₃ ) ₃ CSi), 0.79 (d, 3H, J = 6.8 Hz, C H ₃ CH (CH ₃ ) CH), 0.10 (s, 3H, 1/2 (C H ₃ ) ₂ Si), 0.10 (s, 3H, 1/2 (C H ₃ ) ₂ Si);
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 189.3, 174.0, 166.6, 111.5, 87.9, 77.2, 58.9, 52.0, 51.3, 37.8, 29.4, 28.9, 25.9, 25.2, 24.6, 20.6, 19.0, 18.3, 16.9, 13.5, -4.4, -4.4;
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₂₄ H ₄₂ NaO ₅ Si 461.2699, found: 461.2697.

  4) (5aS, 6S, 8S, 9aR) -6-((tert-Butyldimethylsilyl) oxy) -8-isopropyl-5a, 9,9-trimethyl-3- (pyridin-3-yl) -5a, 6 Of 7,8,9,9a-Hexahydropyrano [4,3-b] chromene-1,10-dione (14)

  To a THF solution (1.0 mL) of LHMDS (1.06M THF solution, 2.12 mL, 0.212 mmol) under argon atmosphere, a THF solution (1.2 mL) of compound (13) (93.0 mg, 0.212 mmol) was added dropwise at -78 ° C. And stirred at room temperature for 4 hours. Then, nicotinoyl chloride hydrochloride (113 mg, 0.637 mmol) was added at −78 ° C., and the mixture was stirred at 0 ° C. for 15 minutes and then at room temperature for 2 hours. After the reaction was stopped by adding AcOH, silica gel (3 g) was added and concentrated, and the residue was purified by column chromatography (silica gel 7.8 g, hexane: EtOAc = 5: 1) to give the compound as a yellow oily substance ( 14) (52.0 mg, 48%) was obtained.

IR (KBr) 2965, 2361, 2343, 1262, 1075, 750, 669, 647, 483, 468, 428 cm ^-1 ;
¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.04 (br s, 1H, Py), 8.75 (br s, 1H, Py), 8.17 (d, 1H, J = 8.0 Hz, Py), 7.47-7.46 ( m, 1H, Py), 6.38 (s, 1H, C H = C), 3.94 (dd, 1H, J = 11.6, 4.8 Hz, C H OTBS), 2.54 (s, 1H, C H C = O), 2.08-1.99 (m, 1H, C H (CH ₃ ) ₂ ), 1.62-1.56 (m, 2H, C H ₂ CHOTBS), 1.30 (s, 3H, C H ₃ CCHOTBS), 1.24 (s, 3H, C H ₃ CCH ₃ ), 1.11 (s, 3H, C H ₃ CCH ₃ ), 1.11-1.06 (m, 1H, C H CH (CH ₃ ) ₂ ), 0.95 (s, 9H, (C H ₃ ) ₃ CSi ), 0.93 (d, 3H, J = 7.2 Hz, C H ₃ CH (CH ₃ ) CH), 0.80 (d, 3H, J = 6.4 Hz, C H ₃ CH (CH ₃ ) CH), 0.18 (s, 3H, 1/2 (C H ₃ ) ₂ Si), 0.15 (s, 3H, 1/2 (C H ₃ ) ₂ Si);
¹³ C-NMR (100 MHz, CDCl ₃ ) δ 187.5, 172.4, 161.9, 157.1, 151.9, 146.9, 134.5, 100.9, 98.1, 90.8, 90.5, 77.4, 76.9, 60.4, 51.1, 38.2, 29.8, 29.4, 28.8, 25.9, 25.2, 24.6, 22.8, 18.9, 18.3, 16.8, 14.2, -4.2, -4.3;
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₂₉ H ₄₁ NNaO ₅ 534.2652, found: 534.2658.

  5) (5aS, 6S, 8S, 9aS, 10R) -10-hydroxy-8-isopropyl-5a, 9,9-trimethyl-1-oxo-3- (pyridin-3-yl) -1,5a, 6, Synthesis of 7,8,9,9a, 10-octahydropyrano [4,3-b] chromen-6-yl acetate (35), (PT008)

  Compound (14) (20.0 mg, 0.0391 mmol) was dissolved in a mixed solvent of MeOH (0.6 mL) and THF (0.2 mL), AcCl (0.028 mL, 0.391 mmol) was added at 0 ° C., and the mixture was stirred for 1 hour. After that, it was concentrated.

To the CH ₂ Cl ₂ solution (0.8 mL) of the residue obtained above at room temperature under a nitrogen atmosphere, Et ₃ N (0.038 mL, 0.274 mmol), catalytic amount of DMAP, and Ac ₂ O (0.013 mL, 0.137 mmol) ) Was added and stirred at room temperature for 1 hour. The reaction was stopped by adding MeOH, and the solution to which water was added was extracted with CH ₂ Cl ₂ , and the combined organic layer was dried over Na ₂ SO ₄ and concentrated.

The obtained residue was dissolved in MeOH (0.6 mL) and THF (0.2 mL) at -78 ° C, CeCl ₃・ 7H ₂ O (18.9 mg, 0.0510 mmol) and NaBH ₄ (1.9 mg, 0.0510 mmol) And stirred at 0 ° C. for 30 minutes. Acetone was added to stop the reaction, and a solution added with water was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by preparative TLC (hexane: EtOAc = 1: 2) to give compound (35) (PT008) as a white solid material. ) (12.6 mg, 3 steps 73%).

[α] ²⁷ _D +58.3 (c 1.0, CHCl ₃ );
IR (KBr) 3433, 2361, 1638, 1241, 1041, 804, 669, 535, 418 cm ^-1 ;
¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.03 (br s, 1H, Py), 8.70 (br s, 1H, Py), 8.13 (d, 1H, J = 8.4 Hz, Py), 7.44 (bs, 1H, Py), 6.47 (s, 1H, C H = C), 5.05 (d, 1H, J = 4.0 Hz, C H (OH) CH), 5.00 (dd, 1H, J = 12.0, 4.8 Hz, C H OAc), 2.82 (bs, 1H, H OCH), 2.18 (s, 3H, C H ₃ C (O) OCH), 2.06-1.99 (m, 1H, C H (CH ₃ ) ₂ ), 1.79 (ddd , 1H, J = 13.2, 4.8, 3.2 Hz, 1/2 C H ₂ CHOAc), 1.67 (s, 3H, C H ₃ CCHOAc), 1.54 (m, 2H, C H CH (OH), C H CH ( CH ₃ ) ₂ ), 1.32 (m, 1H, 1/2 C H ₂ CHOAc), 1.28 (s, 3H, C H ₃ C (CH ₃ ) CH), 1.23 (s, 3H, C H ₃ C (CH ₃ ) CH), 0.96 (d, 3H, J = 6.8 Hz, C H ₃ CHCH ₃ ), 0.85 (d, 3H, J = 6.8 Hz, C H ₃ CHCH ₃ );
¹³ C-NMR (75 MHz, CDCl ₃ ) δ 170.5, 161.7, 126.5, 105.0, 102.2, 84.3, 78.0, 77.4, 60.6, 53.0, 51.5, 39.8, 29.9, 27.8, 26.3, 25.6, 25.4, 21.6, 19.1, 19.1, 15.9, 15.8;
HRMS (ESI) [M + Na] ⁺ calculated value: C ₂₅ H ₃₁ NNaO ₆ 464.2049, found: 464.2048.

  (5aS, 6S, 8S, 9aS, 10R) -10-hydroxy-8-isopropyl-5a, 9,9-trimethyl-1-oxo-3- (pyridin-3-yl) -1,5a, 6,7, Preparation of 8,9,9a, 10-octahydropyrano [4,3-b] chromen-6-yl 4-cyanobenzoate (15), (PT009)

  Compound (14) (40.0 mg, 0.078 mmol) obtained in Example 8 was dissolved in a mixed solvent of MeOH (0.6 mL) and THF (0.2 mL), and AcCl (0.056 mL, 0.782 mmol) was dissolved at 0 ° C. In addition, the mixture was stirred for 1 hour and concentrated.

To a CH ₂ Cl ₂ solution (1.6 mL) of the obtained residue at room temperature under a nitrogen atmosphere, add EDCI (27.0 mg, 0.141 mmol), catalytic amount of DMAP, and p-CNBzOH (17.3 mg, 0.117 mmol). And stirred for 30 minutes at room temperature. H ₂ O was added to stop the reaction, CH ₂ Cl ₂ was added, and the organic layer was washed with 1N HCl and a saturated aqueous solution of NaHCO ₃ . The obtained organic layer was dried over Na ₂ SO ₄ and concentrated.

The obtained residue was dissolved in a mixed solvent of MeOH (1.3 mL) and THF (0.3 mL) at -78 ° C at CeCl ₃・ 7H ₂ O (37.8 mg, 0.106 mmol) and NaBH ₄ (3.8 mg, 0.106 mmol) and stirred at 0 ° C. for 30 minutes. Acetone was added to stop the reaction, and a solution added with water was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by preparative TLC (hexane: EtOAc = 1: 2) to give compound (15) ( PT009) (10.0 mg, 3 steps, 24%) was obtained.

[α] ²⁷ _D +88.3 (c 0.1, CHCl ₃ );
IR (KBr) 3433, 3020, 2360, 2341, 1637, 1216, 772, 669 cm ^-1 ;
¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.99 (br s, 1H, Py), 8.68 (br s, 1H, Py), 8.23 (d, 2H, J = 8.4 Hz, p-CN Bz ), 8.14 (br s, 1H, Py), 7.80 (d, 2H, J = 8.0 Hz, p-CN Bz ), 7.45 (br s, 1H, Py), 6.41 (s, 1H, C H = C), 5.28 ( dd, 1H, J = 12.2, 5.0 Hz, C H Op-CNBz), 5.09 (d, 1H, J = 3.6 Hz, C H ( OH) CH), 2.85 (br s, 1H, H OCH), 2.10- 2.04 (m, 1H, C H (CH ₃ ) ₂ ), 1.92 (ddd, 1H, J = 13.0, 4.8, 3.2 Hz, 1/2 C H ₂ CHOp-CNBz), 1.82 (s, 3H, C H ₃ CCHOp-CNBz), 1.70 (m, 1H, C H CH (CH ₃ ) ₂ ), 1.62 (d, 1H, J = 4.0 Hz, C H CH (OH)), 1.28 (s, 3H, C H ₃ C (CH ₃ ) CH), 1.25 (m, 4H, C H ₃ C (CH ₃ ) CH, C H ₂ CHOp-CNBz), 0.98 (d, 3H, J = 6.8 Hz, C H ₃ CHCH ₃ ), 0.86 (d, 3H, J = 6.4 Hz, C H ₃ CHCH ₃ );
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₃₁ H ₃₂ N ₂ NaO ₆ 551.2158, found: 511.2171.

2-((5aS, 6S, 8S, 9aS, 10R) -6-acetoxy-10-hydroxy-5a, 9,9-trimethyl-1-oxo-3- (pyridin-2-yl) -1,5a, 6 , 7,8,9,9a, 10-Octahydropyrano [4,3-b] chromen-8-yl) propane-1,3-diyl diacetate (26), (PT010)
1) Synthesis of (R) -5- (3-chloroprop-1-en-2-yl) -2,6,6-trimethylcyclohex-2-enone (17)

α, α-Dimethylcarboxylic acid (16) (1.71 g, 9.59 mmol) (Srikrishna, A. et al., Chem. Commun., 1996, 11, 1369-1370.) in hexane (38 mL) solution in silica gel ( 4.8 g) was added, t-BuOCl (1.19 mL, 10.5 mmol) was added dropwise at -30 ° C, and the mixture was stirred at room temperature for 40 min. The reaction was stopped by adding a saturated aqueous solution of Na ₂ S ₂ O _3. After filtration through celite, EtOAc was added, and the organic layer was washed with water. The organic layer was dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by column chromatography (silica gel 36.8 g, hexane: EtOAc = 80: 1) to give a compound (17 ) (1.76 g, 93%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 6.61 (m, 1H, C H = CCH ₃ ), 5.37 (s, 1H, 1/2 C H ₂ = C), 5.08 (s, 1H, 1/2 C H ₂ = C), 4.04 (m, 2H, C H ₂ Cl), 2.72 (t, 1H, J = 7.2 Hz, C H C (CH ₃ ) ₂ ), 2.45 (m, 2H, C H ₂ CH ), 1.78 (m, 3H, C H ₃ C = CH), 1.10 (s, 3H, C H ₃ CCH ₃ ), 1.02 (s, 3H, C H ₃ CCH ₃ );
HRMS (EI) [M] ⁺ calculated value: C ₁₂ H ₁₇ ClO 212.0968, found: 212.0976.

  2) Synthesis of (S) -5- (3-hydroxyprop-1-en-2-yl) -2,6,6-trimethylcyclohex-2-enone (36)

Under a nitrogen atmosphere, a solution of compound (17) (1.53 g, 7.70 mmol) in DMSO / H ₂ O (1: 2, 12 mL) was added Cu ₂ O (1.43 g, 10.0 mmol) and p-TsOH (1.46 g, 8.47 mmol) and then stirred at room temperature for 2 hours. 1% H ₃ PO ₄ solution and EtOAc were added and stirred for 30 minutes to stop the reaction, followed by Celite filtration and extraction with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by column chromatography (silica gel 32.9 g, hexane: EtOAc = 5: 1) to give the compound ( 36) (1.28 g, 92%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 6.62 (m, 1H, C H = CCH ₃ ), 5.27 (s, 1H, 1/2 C H ₂ = C), 5.00 (s, 1H, 1/2 C H ₂ = C), 4.05 (m, 2H, C H ₂ OH), 2.53 (m, 1H, C H C (CH ₃ ) ₂ ), 2.44 (m, 2H, C H ₂ CH), 1.79 (m , 3H, C H ₃ C = CH), 1.11 (s, 3H, C H ₃ CCH ₃ ), 1.04 (s, 3H, C H ₃ CCH ₃ );
HRMS (EI) [M] ⁺ calculated value: C ₁₂ H ₁₈ O ₂ 194.1307, found: 194.1306.

  3) Synthesis of (R) -5-((S) -2- (hydroxymethyl) oxiran-2-yl) -2,6,6-trimethylcyclohex-2-enone (37)

MCPBA (m-chloroperbenzoic acid) (2.95 g, 11.1 mmol) was added to a CH ₂ Cl ₂ solution (111 mL) of compound (36) (2.00 g, 11.1 mmol) at 0 ° C. under a nitrogen atmosphere, The mixture was stirred at room temperature for 2 hours and 40 minutes. The reaction was stopped by adding a saturated aqueous solution of Na ₂ S ₂ O _{3 at} 0 ° C., and a saturated aqueous solution of NaHCO ₃ was added, followed by extraction with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by column chromatography (silica gel 43.0 g, hexane: EtOAc = 3: 1) to give a compound as a yellow oily substance. (37) (2.16 g, 99%) was obtained as a mixture of diastereomers.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 6.60 (m, 1H, C H = CCH ₃ ), 3.60 (m, 2H, C H ₂ OH), 3.12 (d, 1H, J = 4.5 Hz, 1 / 2 C H ₂ OC), 2.70 (m, 1H, 1/2 C H ₂ CH), 2.66 (d, 1H, J = 4.8 Hz, 1/2 C H ₂ OC), 2.50 (m, 1H, 1 / 2 C H ₂ CH), 1.78 (s, 3H, C H ₃ C = CH), 1.75 (t, 1H, J = 5.1 Hz, C H C (CH ₃ ) ₂ ), 1.21 (s, 3H, C H ₃ CCH ₃ ), 1.17 (s, 3H, C H ₃ CCH ₃ );
HRMS (EI) [M] ⁺ calculated value: C ₁₂ H ₁₈ O ₃ 210.1256, found: 210.1253.

  4) (R) -5-((R) -2-(((tert-butyldimethylsilyl) oxy) methyl) oxilan-2-yl) -2,6,6-trimethylcyclohex-2-enone (18 )

Under a nitrogen atmosphere, imidazole (529 mg, 7.77 mmol) and TBSCl (586 mg, 3.89 mmol) are added to a CH ₂ Cl ₂ solution (26 mL) of compound (37) (509 mg, 2.59 mmol), and at room temperature. Stir for 30 minutes. The reaction was quenched with H ₂ O, EtOAc was added and the organic layer was washed with water. The organic layer was dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by column chromatography (silica gel 10.9 g, hexane: EtOAc = 50: 1) to give the compound ( 18) (750 mg, 89%) was obtained as a mixture of diastereomers.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 6.58 (t, 1H, J = 2.4 Hz, C H = CCH ₃ ), 3.60 (m, 2H, C H ₂ OTBS), 2.94 (d, 1H, J = 5.4 Hz, 1/2 C H ₂ OC), 2.61 (m, 1H, 1/2 C H ₂ CH), 2.61 (d, 1H, J = 2.7 Hz, 1/2 C H ₂ OC), 2.44 (m , 1H, 1/2 C H ₂ CH), 1.93 (dd, 1H, J = 5.1, 6.0 Hz, C H C (CH ₃ ) ₂ ), 1.76 (s, 3H, C H ₃ C = CH), 1.21 (s, 3H, C H ₃ CCH ₃ ), 1.19 (s, 3H, C H ₃ CCH ₃ ), 0.86 (m, 9H, (C H ₃ ) ₃ CSi), 0.01 (m, 6H, (C H ₃ ) ₂ Si);
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₁₈ H ₃₂ NaO ₃ Si 347.2018, found: 347.2021.

  5) (S) -5-((S) -1-((tert-butyldimethylsilyl) oxy) -3-hydroxypropan-2-yl) -2,6,6-trimethylcyclohex-2-enone ( 19) Synthesis

After stirring a THF solution (20 mL) of Cp ₂ TiCl ₂ (1.26 g, 5.08 mmol) and Mn (1.02 g, 18.5 mmol) at room temperature under an argon atmosphere for 15 minutes, compound (18) (750 mg, A solution of 2.31 mmol) and H ₂ O (1.66 mL, 92.4 mmol) in THF (3.0 mL) was added dropwise and stirred for 12 hours. The reaction was stopped by adding NaH ₂ PO ₄ solution, filtered through Celite, and extracted with EtOAc. The combined organic layer was dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by column chromatography (silica gel 16.1 g, hexane: EtOAc = 10: 1) to give a compound as a colorless oily substance. (19) (382 mg, 51%) was obtained as a mixture of diastereomers, and unreacted compound (18) (276 mg, 37%) was recovered.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 6.61 (dd, 1H, J = 1.2, 2.4 Hz, C H = CCH ₃ ), 3.71 (m, 2H, C H ₂ OTBS), 3.71 (m, 2H, C H ₂ OH), 2.31 (m, 2H, C H ₂ CH = C), 2.03 (m, 1H, C H CH ₂ OH), 1.82 (m, 1H, C H C (CH ₃ ) ₂ ), 1.75 (s, 3H, C H ₃ C = CH) 1.20 (s, 3H, C H ₃ CCH ₃ ), 1.07 (s, 3H, C H ₃ CCH ₃ ), 0.89 (m, 9H, (C H ₃ ) ₃ CSi), 0.07 (m, 6H, (C H ₃ ) ₂ Si);
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₁₈ H ₃₄ NaO ₃ Si 349.2175, found: 349.2168.

  6) (S) -2,6,6-Trimethyl-5- (2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane-6 Synthesis of (-yl) cyclohex-2-enone (20)

Under a nitrogen atmosphere, imidazole (233 mg, 3.43 mmol) and TBSCl (258 mg, 1.71 mmol) were added to a CH ₂ Cl ₂ solution (11 mL) of compound (19) (373 mg, 1.14 mmol), and at room temperature. For 30 minutes. H ₂ O was added to stop the reaction, EtOAc was added and the organic layer was washed with water. The organic layer was dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by column chromatography (silica gel 8.03 g, hexane: EtOAc = 200: 1) to give the compound ( 20) (498 mg, 99%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 6.59 (dd, 1H, J = 0.9, 1.8 Hz, C H = CCH ₃ ), 3.55 (m, 4H, 2 x C H ₂ OTBS), 2.35 (m, 2H, C H ₂ CH = C), 2.06 (m, 1H, C H (CH ₂ OTBS) ₂ ), 1.85 (m, 1H, C H C (CH ₃ ) ₂ ), 1.72 (s, 3H, C H ₃ C = CH) 1.16 (s, 3H, C H ₃ CCH ₃ ), 1.02 (s, 3H, C H ₃ CCH ₃ ), 0.86 (m, 18H, 2 x (C H ₃ ) ₃ CSi), 0.01 ( m, 12H, 2 x (C H ₃ ) ₂ Si);
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₂₄ H ₄₈ NaO ₃ Si ₂ 463.3040, found: 463.3061.

  7) (1S, 4S, 6S) -1,3,3-Trimethyl-4- (2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-di Silaundecan-6-yl) -7-oxabicyclo [4.1.0] heptan-2-one (21)

To an AcOH solution (11 mL) of compound (20) (498 mg, 1.13 mmol), add NBA (3-nitrobenzyl alcohol) (468 mg, 3.39 mmol) and AgOAc (566 mg, 3.39 mmol) at room temperature. Stir for 2 hours. After celite filtration, the reaction was quenched with saturated aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was roughly purified by column chromatography (silica gel 10.7 g, hexane: EtOAc = 100: 1), and fractions containing the product were obtained. To give a crude material.

K ₂ CO ₃ (309 mg, 2.23 mmol) was added to the resulting crude material in MeOH (2.5 mL), and the mixture was stirred at room temperature for 15 minutes. H ₂ O was added to stop the reaction, EtOAc was added and the organic layer was washed with water. The organic layer was dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by column chromatography (silica gel 9.05 g, hexane: EtOAc = 200: 1) to give compound (21 ) (312 mg, 2 steps 60%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.60 (m, 4H, 2 x C H ₂ OTBS), 3.38 (ddd, 1H, J = 1.2, 1.5, 3.0 Hz, C H (O) C), 2.17 (m, 2H, C H ₂ CHO), 1.89 (m, 1H, C H (CH ₂ OTBS) ₂ ), 1.74 (m, 1H, C H C (CH ₃ ) ₂ ), 1.38 (s, 3H, C H ₃ COCH) 1.17 (s, 3H, C H ₃ CCH ₃ ), 1.11 (s, 3H, C H ₃ CCH ₃ ), 0.88 (m, 18H, 2 x (C H ₃ ) ₃ CSi), 0.04 (m , 12H, 2 x (C H ₃ ) ₂ Si);
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₂₄ H ₄₈ NaO ₄ Si ₂ 479.2989, found: 479.2967.

  8) 5-((3S, 5S) -3-((tert-butyldimethylsilyl) oxy) -2,6,6-trimethyl-5- (2,2,3,3,9,9,10,10 -Octamethyl-4,8-dioxa-3,9-disilaundecan-6-yl) cyclohex-1-enecarbonyl) -2,2,6-trimethyl-4H-1,3-dioxin-4-one 23) Synthesis

Under an argon atmosphere, s-BuLi (1M THF solution, 0.644 mL, 0.657 mmol) was added dropwise to a THF solution (1.2 mL) of TMSCH ₂ OMe (0.102 mL, 0.657 mmol) at -23 ° C. Stir for minutes. Thereafter, a THF solution (1.0 mL) of compound (21) (100 mg, 0.219 mmol) was added dropwise to this solution at −78 ° C., followed by stirring at −60 ° C. for 20 minutes. Thereafter, t-BuOK (98.3 mg, 0.876 mmol) was added, the temperature was gradually raised to room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding a saturated aqueous NH ₄ Cl solution and stirring for 15 minutes, EtOAc was added and washed with 2N HCl solution, and the organic layer was dried over Na ₂ SO ₄ and concentrated.

To the DMF solution (2.2 mL) of the obtained residue was added imidazole (59.9 mg, 0.880 mmol), catalytic amount of DMAP, and TBSCl (99.5 mg, 0.660 mmol), and the mixture was stirred at 50 ° C. for 1 hour under a nitrogen atmosphere. . H ₂ O was added to stop the reaction, EtOAc was added and the organic layer was washed with water. The organic layer is dried over Na ₂ SO ₄ and concentrated, and the resulting crude material is roughly purified by column chromatography (silica gel 2.22 g, hexane: EtOAc = 200: 1), and the fraction containing the product is concentrated. A crude material was obtained.

To a THF solution (0.7 mL) of 5-iodo-2,2,6-trimethyl-4H-1,3-dioxin-4-one (118 mg, 0.441 mmol) at −30 ° C. under argon atmosphere, iPrMgCl (2.0 M (THF solution, 0.221 mL, 0.441 mmol) was added dropwise and the mixture was stirred for 1 hour, and then the above crude substance in THF (0.7 mL) was added dropwise to the solution and stirred at room temperature for 15 minutes. NH ₄ Cl saturated aqueous solution was added to quench the reaction, extraction was performed with EtOAc, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated.

DMP (93.5 mg, 0.221 mmol) was added to a CH ₂ Cl ₂ solution (1.5 mL) of the obtained residue at 0 ° C. under a nitrogen atmosphere, and the mixture was stirred for 15 minutes. The reaction was stopped by adding a saturated aqueous solution of Na ₂ S ₂ O _{3 and a} saturated aqueous solution of NaHCO ₃ , EtOAc was added, and the organic layer was washed with a saturated aqueous solution of NaHCO ₃ . The organic layer was dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by column chromatography (silica gel 1.84 g, hexane: EtOAc = 30: 1) to give the compound ( 23) (25.4 mg, 4 steps 16%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 4.12 (ddd, 1H, J = 2.7, 6.0, 6.6 Hz, C H OTBS), 3.61 (m, 4H, 2 x C H ₂ OTBS), 2.44 (s, 3H, C H ₃ COC (CH ₃ ) ₂ ), 1.92 (m, 2H, C H ₂ CHOTBS), 1.75 (m, 1H, C H C (CH ₃ ) ₂ ), 1.70 (s, 3H, C H ₃ COC = O), 1.69 (s, 3H, C H ₃ COC = O), 1.62 (m, 1H, C H (CH ₂ OTBS) ₂ ), 1.52 (d, 3H, J = 9.2 Hz, C H ₃ CCHOTBS ) 1.15 (s, 3H, C H ₃ C (CH ₃ ) C), 0.97 (s, 3H, C H ₃ C (CH ₃ ) C), 0.89 (m, 27H, 3 x (C H ₃ ) ₃ CSi ), 0.04 (m, 18H, 3 x (C H ₃ ) ₂ Si);
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₃₈ H ₇₂ NaO ₇ Si ₃ 747.4484, found: 747.4481.

  9) (4aR, 6S, 8S, 8aS) -Methyl 8-((tert-butyldimethylsilyl) oxy) -2,5,5,8a-Tetramethyl-6- (2,2,3,3,9, 9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-yl) -4-oxo-4a, 5,6,7,8,8a-hexahydro-4H-chromene-3 -Carboxylate (24)

  A solution of compound (23) (70 mg, 0.097 mmol) in toluene (0.8 mL) and MeOH (0.2 mL) was stirred at 90 ° C. for 3 hours and 15 minutes, and then concentrated.

DBU (0.015 mL, 0.097 mmol) was added to a toluene solution (1.0 mL) of the obtained residue, and the mixture was stirred at 100 ° C. for 4 hours. H ₂ O was added to stop the reaction, EtOAc was added and the organic layer was washed with water. The organic layer was dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by column chromatography (silica gel 1.46 g, hexane: EtOAc = 50: 1) to give the compound ( 24) (29.8 mg, 44%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 3.79 (ddd, 4H, J = 4.5, 4.8, 6.6 Hz, 2 x C H ₂ OTBS), 3.60 (m, 3H, C H ₃ O), 3.45 (dd , 1H, J = 8.4, 9.9 Hz, C H OTBS), 2.43 (s, 1H, C H C = O), 2.14 (s, 3H, C H ₃ C = C), 1.82 (d, 1H, J = 3.0 Hz, 1/2 C H ₂ CHOTBS), 1.69 (m, 1H, C H (CH ₂ OTBS) ₂ ), 1.50 (d, 1H, J = 13.5 Hz, 1/2 C H ₂ CHOTBS), 1.37 ( d, 1H, J = 11.4 Hz, C H C (CH ₃ ) ₂ ), 1.32 (s, 3H, C H ₃ CCHOTBS) 1.06 (s, 3H, C H ₃ CCH ₃ ), 0.92 (s, 3H, C H ₃ CCH ₃ ), 0.88 (m, 27H, 3 x (C H ₃ ) ₃ CSi), 0.04 (m, 18H, 3 x (C H ₃ ) ₂ Si);
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₃₆ H ₇₀ NaO ₇ Si ₃ 721.4327, found: 721.4349.

  10) (5aS, 6S, 8S, 9aR) -6-((tert-butyldimethylsilyl) oxy) -5a, 9,9-trimethyl-8- (2,2,3,3,9,9,10, 10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-yl) -3- (pyridin-2-yl) -5a, 6,7,8,9,9a-hexahydropyrano [ Synthesis of 4,3-b] chromene-1,10-dione (25)

Under argon atmosphere, add a THF solution (0.2 mL) of kago (24) (30.0 mg, 0.0429 mmol) dropwise at -78 ° C to a THF solution (0.2 mL) of LHMDS (1.0 M THF solution, 0.215 mL, 0.215 mmol). After stirring at room temperature for 4 hours, nicotinoyl chloride hydrochloride (22.9 mg, 0.129 mmol) was added thereto at −78 ° C., followed by stirring at 0 ° C. for 15 minutes and further stirring at room temperature for 2 hours. AcOH was added to quench the reaction, EtOAc was added and the organic layer was washed with water. The organic layer was dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by column chromatography (silica gel 0.645 g, hexane: EtOAc = 5: 1) to give compound (25) as a yellow oil. (11.3 mg, 34%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.05 (s, 1H, Py), 8.76 (s, 1H, Py), 8.22 (d, 1H, J = 8.1 Hz, Py), 7.50 (m, 1H, Py), 6.39 (s, 1H, C H = C), 3.79 (ddd, 4H, J = 5.1, 5.7, 8.7 Hz, 2 x C H ₂ OTBS), 3.50 (m, 1H, C H OTBS), 2.60 (s, 1H, C H C = O), 1.84 (m, 1H, 1/2 C H ₂ CHOTBS), 1.71 (m, 1H, C H (CH ₂ OTBS) ₂ ), 1.56 (m, 1H, 1 / 2 C H ₂ CHOTBS), 1.42 (m, 1H, C H C (CH ₃ ) ₂ ), 1.44 (s, 3H, C H ₃ CCHOTBS) 1.15 (s, 3H, C H ₃ CCH ₃ ), 0.97 ( s, 3H, C H ₃ CCH ₃ ), 0.91 (m, 27H, 3 x (C H ₃ ) ₃ CSi), 0.04 (m, 18H, 3 x (C H ₃ ) ₂ Si);
HRMS (ESI, TFANa) [M +] ⁺ calculated value: C ₄₁ H ₆₉ NO ₇ Si ₃ 772.4460, found: 772.4446.

  11) 2-((5aS, 6S, 8S, 9aS, 10R) -6-acetoxy-10-hydroxy-5a, 9,9-trimethyl-1-oxo-3- (pyridin-2-yl) -1,5a , 6,7,8,9,9a, 10-Octahydropyrano [4,3-b] chromen-8-yl) propane-1,3-diyl diacetate (26), (PT010)

  AcCl (0.0207 mL, 0.292 mmol) was added to a MeOH solution (0.5 mL) of the compound (25) (11.3 mg, 0.0146 mmol) at 0 ° C., and the mixture was stirred for 1 hour and concentrated.

At 0 ° C under a nitrogen atmosphere, CH ₃ CN solution (0.5 mL) of the obtained residue was added Et ₃ N (0.033 mL, 0.234 mmol), catalytic amount of DMAP, and Ac ₂ O (0.011 mL, 0.117 mmol). In addition, the mixture was stirred at room temperature for 15 minutes. MeOH and water were added to quench the reaction, and the mixture was extracted with CH ₂ Cl _{2. The} combined organic layers were dried over Na ₂ SO ₄ and concentrated.

CeCl ₃ · 7H ₂ O (21.8 mg, 0.0584 mmol) and NaBH ₄ (2.2 mg, 0.0584 mmol) were added to a MeOH solution (0.5 mL) of the obtained residue at 0 ° C. and stirred for 30 minutes. Acetone was added to stop the reaction, and water was added, followed by extraction with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated, and the resulting crude material was purified by preparative TLC (hexane: EtOAc = 1: 2) to give compound (26), (PT010 ) (4.2 mg, 3 steps 51%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.04 (s, 1H, Py), 8.71 (s, 1H, Py), 8.20 (m, 1H, Py), 7.50 (m, 1H, Py), 6.50 ( d, 1H, J = 4.8 Hz, C H = C), 5.05 (d, 1H, J = 4.0 Hz, C H OH), 4.94 (m, 1H, C H OAc), 4.19 (m, 2H, C H ₂ OAc), 3.97 (m, 2H, C H ₂ OAc), 2.29 (m, 1H, C H (CH ₂ OAc) ₂ ), 2.16 (m, 3H, C H ₃ C = O), 2.12 (m, 2H, C H ₂ CHOAc), 2.08 (m, 1H, C H C (CH ₃ ) ₂ ), 2.08 (m, 6H, 2 x C H ₃ C = O), 1.97 (m, 1H, C H CHOH) , 1.58 (s, 3H, C H ₃ CO) 1.34 (s, 3H, C H ₃ CCH ₃ ), 1.25 (s, 3H, C H ₃ CCH ₃ );
HRMS (ESI, TFANa) [M + Na] ⁺ calculated value: C ₂₉ H ₃₅ NNaO ₁₀ 580.2159, found: 580.2137.

(Test Example 1)
Each compound produced in the examples was investigated for ACAT2 inhibitory activity as follows.

Method for preparing ACAT2 enzyme source:
Uelmen et al. (J. Biol. Chem. 270, 26192-26210, 1995) was partially modified. As an enzyme source of ACAT2, a membrane fraction derived from mouse liver microsomes was used. The mouse liver was homogenized using a potter type homogenizer (manufactured by Tokyo-RIKO) in buffer A [50 mM Tris-HCl solution (pH 7.8), 1 mM ethylenediaminetetraacetic acid and 1 mM phenylmethanesulfonyl fluoride]. The supernatant obtained by centrifuging the supernatant at 12000 xg was ultracentrifuged at 10,000 xg to make the microsomal fraction, and this fraction was adjusted with buffer A so that the protein concentration would be 5 mg / ml. Prepared.

Method for measuring ACAT2 inhibitory activity and method for evaluating specific activity against pyripyropene A:
ACAT2 activity was measured by adding 200 μg of enzyme source, 200 mM bovine serum albumin, [1- ¹⁴ C] oleoyl coenzyme A (final concentrations 170 μM, 0.09 μCi) and each derivative to buffer A to make a total volume of 200 μl. And allowed to react at 37 ° C. for 5 minutes. As a control, 10 μl of methanol was added in place of each derivative.

Next, 1.2 ml chloroform / methanol (1: 2) was added thereto to stop the reaction, and lipids were collected by the Blish & Dyer method (Can. J. Biochem. Physiol. 37, 911-917, 1959). . The chloroform layer was dried and spotted on a thin layer chromatography (silica gel plate, Merck, thickness 0.5 mm) and developed with a solvent of hexane / diethyl ether / acetic acid (70: 30: 1, v / v). Separated. Next, the amount of [ ¹⁴ C] cholesteryl oleate produced was quantified with FLA 7000 (manufactured by Fuji Film Co., Ltd.), and compared with the control, the inhibitory activity of the test compound was calculated by the following formula. The radioactivity of thin-layer chromatography in which nothing was spotted was used as the background.

Inhibition rate = 100-[(radioactivity at the time of addition of test compound)-(background)] / [(radioactivity of control)-(background)]
From the inhibition rate thus determined, the concentration (IC ₅₀ ) that inhibits the enzyme activity by 50% was calculated. The results are summarized in Table 1 below. The meanings of the symbols in the table are as follows:
***: 0.5 μM ≥ inhibitory activity
**: 10 μM ≧ inhibitory activity> 0.5 μM
*: 100 μM ≧ inhibitory activity> 10 μM
Inhibitory activity = concentration that inhibits ACAT2 by 50%

  From the above results, it can be seen that the compounds according to the present invention all exhibit high inhibitory activity against ACAT2, and are expected to be useful as prophylactic treatments for dyslipidemia and arteriosclerosis as highly active ACAT2 inhibitors. Recognize. In addition, since the compound according to the present invention can be produced by complete chemical synthesis without using pyripyropene A as a raw material, there is a possibility that various compounds that can be used as a raw material for pharmaceuticals can be supplied.

  The ACAT2 inhibitory activity test is not limited to the above method, and for example, microsomes prepared from the small intestine or liver of animals such as rats and monkeys may be used as the ACAT2 enzyme source. Microsomes prepared from cultured cells highly expressing ACAT2 can also be used as the ACAT2 enzyme source.

Claims (3)

Compounds represented by the following general formula (I) and pharmaceutically acceptable salts, solvates and hydrates thereof.

Where
R ¹ represents an aryl group, an alkyl group or a cycloalkyl group, each of which may be substituted,
R ² represents an optionally substituted alkylcarbonyl group, arylcarbonyl group, alkyl group, or aryl group,
R ³ , R ⁴ , and R ⁵ may be the same or different from each other, and each represents hydrogen, a hydroxy group, or an optionally substituted alkylcarbonyloxy group, arylcarbonyloxy group, or alkoxy group. Or R ³ and R ⁴ together may mean a group represented by —O—CR ⁷ R ⁸ —O—, wherein R ⁷ and R ⁸ may be the same or different from each other; Each represents hydrogen, or an optionally substituted aryl or alkyl group, and R ⁶ represents —C (CH ₃ ) ₂ — or —CH ₂ —.   An ACAT2 inhibitor comprising the compound according to claim 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof as an active ingredient.   A pharmaceutical composition for inhibiting ACAT2, comprising the compound according to claim 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof and a pharmaceutically acceptable carrier.