Lithocholic acid derivatives with vitamin D activity

Abstract

The purpose of the present invention is to provide a novel lithocholic acid derivative having sufficient vitamin D3 activity. A compound represented in general formula (I), a salt thereof, or a prodrug thereof is provided. (R1 and R2 independently represent a hydrogen atom or an alkyl group with a carbon number of 1-8. n represents an integer 1-3. X represents -C(=O)NH-Z, or -CH(OH)-(Y)m-CH(OH)R3. Z represents a hydrogen atom, an alkyl group with carbon number 1-8, an alkoxyl group with carbon number 1-8, or a hydroxyl group, Y represents -C(R4)(R5)-, -C(=O)-, or -C(=CH2)-, and m represents an integer 0-3. R3, R4 and R5 independently represent a hydrogen atom or an alkyl group with carbon number 1-8. Alkyl groups with carbon number 1-8 represented by Z, R3, R4 and R5 may optionally have a substituent selected from a carboxylic group or a hydroxyl group.)

Description

[Technical field]

[0001] The present invention relates to a lithocholic acid derivative having vitamin D activity. The present invention further relates to a medicine, a vitamin D receptor activator, and a preventive and / or therapeutic agent for vitamin D receptor-related diseases, each comprising the lithocholic acid derivative. [Background technology]

[0002] Vitamin D is activated by 1α,25-dihydroxyvitamin D3, which binds to the vitamin D receptor (VDR) and controls the expression of specific genes. By controlling the expression of these genes, vitamin D plays important physiological roles such as maintaining calcium levels in the blood, bone formation, immune function, and cell differentiation and proliferation control. To date, many VDR ligands have been developed for the purpose of developing therapeutic drugs for osteoporosis, psoriasis, cancer, and other conditions, and some of these have been used clinically as medicines. Many of the existing VDR ligands have a secosteroid skeleton, similar to natural 1α,25-dihydroxyvitamin D3. Although the secosteroid skeleton is useful for developing derivatives with high activity, it generally has low chemical stability and requires complicated synthesis, limiting the diverse medical applications of vitamin D. Therefore, the development of VDR ligands with non-secosteroid skeletons is desired, but there have been few reports of such non-secosteroid VDR ligands.

[0003] Lithocholic acid has been found to be an endogenous ligand of VDR, but its affinity to VDR is very weak, and its physiological significance is unclear. Patent Document 1 describes that lithocholic acid derivative lithocholic acid propionate can activate VDR, and Non-Patent Document 1 describes lithocholic acid acetate and lithocholic acid propionate. Patent Document 2 describes a lithocholic acid derivative with high vitamin D3 activity. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Patent No. 5283043 [Patent Document 2] International Publication No. WO2017 / 131144 [Non-patent literature]

[0005] [Non-Patent Document 1] Masuno et al, Journal of Lipid Research, Volume 54, 2013, pages 2206-2213 DISCLOSURE OF THEINVENTION [Problem to be solved by the invention]

[0006] Although there have been reports of lithocholic acid derivatives having vitamin D3 activity, the existing lithocholic acid derivatives have a weak affinity for the vitamin D3 receptor and have insufficient vitamin D3 activity. The lithocholic acid derivative described in Patent Document 2 has high vitamin D3 activity, but has the drawback of being rapidly eliminated from the blood in the body.

[0007] The present invention aims to provide a novel lithocholic acid derivative having sufficient vitamin D3 activity, and further aims to provide a medicine, a vitamin D receptor activator, and a preventive and / or therapeutic agent for vitamin D receptor-related diseases, each of which contains the lithocholic acid derivative. [Means for solving the problem]

[0008] As a result of intensive research conducted by the inventors to solve the above-mentioned problems, they discovered that, in lithocholic acid derivatives having a hydroxyalkyl group at the 3-position, a derivative in which an amide bond has been introduced into the side chain at the 17-position, and a derivative in which a hydroxyl group has been introduced into the side chain at the 17-position, have excellent vitamin D3 activity, and thus completed the present invention.

[0009] According to the present invention, the following inventions are provided. [1] A compound represented by the following general formula (I), a salt thereof, or a prodrug thereof: [ka] (In the formula, R1 and R2 each independently represent a hydrogen atom or an alkyl group having 1 to 8 carbon atoms. n represents an integer of 1 to 3. X represents -C(=O)NH-Z or -CH(OH)-(Y) m Z represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, or a hydroxyl group; Y represents -C(R4)(R5)-, -C(=O)-, or -C(=CH2)-; m represents an integer of 0 to 3. R3, R4, and R5 each independently represent a hydrogen atom or an alkyl group having 1 to 8 carbon atoms. The alkyl group having 1 to 8 carbon atoms represented by Z, R3, R4, and R5 may have a substituent selected from a carboxyl group or a hydroxyl group. [2] The compound according to [1], its salt, or its prodrug, wherein X is -C(=O)NH-Z (wherein Z is as defined in [1]). [3] The compound, salt or prodrug thereof according to [2], wherein Z is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkoxy group having 1 to 8 carbon atoms. [4] X is -CH(OH)-(Y) m The compound according to [1], its salt, or its prodrug, which represents -CH(OH)R3 (wherein Y, m, and R3 are as defined in [1]). [5] The compound, salt or prodrug thereof according to [4], wherein Y is -CH2-. [6] The compound, salt, or prodrug thereof according to [4] or [5], wherein R3 is a hydrogen atom. [7] The compound, its salt, or its prodrug according to any one of [1] to [6], wherein R1 and R2 are methyl. [8] The compound, its salt, or its prodrug according to any one of [1] to [7], wherein n is 1. [9] Any of the following compounds, their salts, or their prodrugs: [ka]

[10] A pharmaceutical composition comprising the compound according to any one of [1] to [9], a salt thereof, or a prodrug thereof.

[11] A vitamin D receptor activator comprising a compound according to any one of [1] to [9], a salt thereof, or a prodrug thereof.

[12] A preventive and / or therapeutic agent for a vitamin D receptor-associated disease, comprising the compound according to any one of [1] to [9], a salt thereof, or a prodrug thereof.

[0010] The present invention further provides the following inventions.

[13] A method for activating a vitamin D receptor, comprising administering a compound described in any one of [1] to [9], a salt thereof, or a prodrug thereof to a mammal, including a human.

[14] A method for preventing and / or treating a vitamin D receptor-associated disease, comprising administering a compound described in any one of [1] to [9], a salt thereof, or a prodrug thereof to a mammal, including a human.

[15] A compound, a salt thereof, or a prodrug thereof according to any one of [1] to [9] for use in activating a vitamin D receptor.

[16] A compound, a salt thereof, or a prodrug thereof according to any one of [1] to [9] for use in the prevention and / or treatment of a vitamin D receptor-associated disease.

[17] Use of a compound, a salt thereof, or a prodrug thereof according to any one of [1] to [9] for the manufacture of a medicine.

[18] Use of the compound, a salt thereof, or a prodrug thereof according to any one of [1] to [9] for the manufacture of a vitamin D receptor activator.

[19] Use of the compound, a salt thereof, or a prodrug thereof according to any one of [1] to [9] for the manufacture of an agent for the prevention and / or treatment of a vitamin D receptor-associated disease. Effect of the Invention

[0011] The compound of the present invention is a novel lithocholic acid derivative having sufficient vitamin D3 activity. The compound of the present invention is useful as a vitamin D receptor activator, and a pharmaceutical agent for preventing and / or treating vitamin D receptor-related diseases. In addition, since the compound of the present invention does not have a secosteroid skeleton, it generally has higher chemical stability than compounds having a secosteroid skeleton. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 shows the dose-response curve of the differentiation-inducing effect on HL-60 cells. [Diagram 2] FIG. 2 shows the dose-response curve of the differentiation-inducing effect on HL-60 cells. [Diagram 3] FIG. 3 shows the dose-response curve of the differentiation-inducing effect on HL-60 cells. [Figure 4] FIG. 4 shows the dose-response curve of the differentiation-inducing effect on HL-60 cells. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The present invention will now be described in more detail. The compound of the present invention is represented by the following general formula (I). [ka] In the formula, R1 and R2 each independently represent a hydrogen atom or an alkyl group having 1 to 8 carbon atoms. n represents an integer of 1 to 3. X represents -C(=O)NH-Z or -CH(OH)-(Y). m Z represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, or a hydroxyl group; Y represents -C(R4)(R5)-, -C(=O)-, or -C(=CH2)-; m represents an integer of 0 to 3. R3, R4, and R5 each independently represent a hydrogen atom or an alkyl group having 1 to 8 carbon atoms. The alkyl group having 1 to 8 carbon atoms represented by Z, R3, R4, and R5 may have a substituent selected from a carboxyl group or a hydroxyl group.

[0014] Since the compound of the present invention does not have a carboxyl group in the side chain at position 17, it is expected that the problem of rapid excretion in the body will be solved.

[0015] In this specification, the alkyl group having 1 to 8 carbon atoms may be linear, branched, cyclic, or a combination thereof. The alkyl group having 1 to 6 carbon atoms is not particularly limited, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropylmethyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, a cyclobutyl group, a cyclobutylmethyl group, a cyclopentyl group, and a cyclohexyl group. Among these, a methyl group and an ethyl group are preferable, and a methyl group is particularly preferable.

[0016] In the present specification, the alkoxyl group having 1 to 8 carbon atoms may be linear, branched, cyclic, or a combination thereof. The alkoxyl group having 1 to 8 carbon atoms is not particularly limited, and examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a cyclopropylmethyloxy group, an n-butoxy group, a sec-butoxy group, a tert-butoxy group, a cyclobutyloxy group, a cyclobutylmethoxy group, a cyclopentyloxy group, and a cyclohexyloxy group. Among these, a methoxy group and an ethoxy group are preferable, and a methoxy group is particularly preferable.

[0017] In this specification, the alkyl moiety in the carboxyalkyl group having 1 to 8 carbon atoms may be linear, branched, cyclic, or a combination thereof, and is a divalent group in which one hydrogen atom has been removed from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropylmethyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, a cyclobutyl group, a cyclobutylmethyl group, a cyclopentyl group, or a cyclohexyl group.

[0018] In the present invention, when X represents -C(=O)NH-Z (wherein Z is defined as above), the compound of the present invention is represented by the following general formula (II). [ka]

[0019] Z represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, or a hydroxyl group. Preferably, Z is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkoxyl group having 1 to 8 carbon atoms.

[0020] In the present invention, X is -CH(OH)-(Y) m When -CH(OH)R3 (wherein Y, m, and R3 are defined as above) is shown, the compound of the present invention is represented by the following general formula (III): [ka]

[0021] Y represents -C(R4)(R5)-, -C(=O)-, or -C(=CH2)-, preferably -C(R4)(R5)-, and more preferably -CH2-. m represents an integer of 0 to 3, and is preferably 0 or 1. R3 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, and is preferably a hydrogen atom or a methyl group. The alkyl group having 1 to 8 carbon atoms represented by Z, R3, R4, and R5 may or may not have a substituent selected from a carboxyl group or a hydroxyl group. When the alkyl group has a carboxyl group, it is preferably a carboxyalkyl group having 1 to 8 carbon atoms.

[0022] R1 and R2 may be independently the same or different groups, but are preferably the same groups. It is particularly preferred that R1 and R2 are both methyl or ethyl groups. n represents an integer of 1 to 3, preferably 1 or 2, and more preferably 1.

[0023] Specific examples of the compound of the present invention include the following compounds.

[0024] [ka]

[0025] The compound represented by general formula (I) may have one or more asymmetric carbons. Any optically active substance based on the asymmetric carbons, stereoisomers such as diastereoisomers, any mixture of stereoisomers, racemates, etc. are all included in the scope of the present invention.

[0026] The compound represented by the general formula (I) may exist in the form of a salt such as an acid addition salt or a base addition salt, which are also included in the scope of the present invention. Examples of the acid addition salt include mineral acid salts such as hydrochloride, hydrobromide, sulfate, and nitrate, and organic acid salts such as p-toluenesulfonate, methanesulfonate, oxalate, tartrate, and maleate. Examples of the base addition salt include metal salts such as sodium salt, potassium salt, magnesium salt, and calcium salt, and organic amine salts such as ammonium salt, triethylamine salt, and ethanolamine salt. In addition, amino acid salts such as glycine salt are also included in the scope of the present invention.

[0027] The compound represented by the general formula (I) may be made into a prodrug. After being administered to a living body, the prodrug becomes a medicamentously active compound by the action of an enzyme or metabolic hydrolysis. The prodrug may be an acid derivative known to those skilled in the art, and examples thereof include, but are not limited to, an ester produced by reacting the compound represented by the general formula (I) with a suitable alcohol, an amide produced by reacting the compound represented by the general formula (I) with a suitable amine, and a 24-alcohol as a reduced type of a carboxyl group.

[0028] The compound represented by the general formula (I), its salt and its prodrug may exist in the form of an adduct (hydrate or solvate) with water or various solvents, and these adducts are also within the scope of the present invention. Examples of the solvent in the solvate include, but are not limited to, methanol, ethanol, acetonitrile, etc. The adduct (hydrate or solvate) may be a single one or a mixture of multiple types.

[0029] Any crystalline form of the compound represented by formula (I), its salts and its prodrugs are also within the scope of the present invention.

[0030] The methods for producing representative compounds included in the general formula (I) are described in detail and specifically in the Examples of this specification. Those skilled in the art can produce compounds included in the general formula (I) by appropriately selecting raw material compounds, reaction conditions, reagents, etc., and appropriately modifying or altering these methods as necessary, while referring to the specific production methods described in the Examples.

[0031] The synthesis of compound 1 is not particularly limited, but can be carried out according to the method described in Example 1 below.

[0032] In Example 1, compound 18 can be produced by converting the side chain at position 17 of lithocholic acid using lithocholic acid as a starting material in the following steps. Compound 9 is obtained by reacting lithocholic acid with acetyl chloride. Compound 10 is obtained by reacting compound 9 with benzyl-2,2,2-trichloroacetimidate. Compound 11 is obtained by reacting compound 10 with lithium aluminum hydride. Compound 12 is obtained by reacting compound 11 with pyridinium chlorochromate. Compound 13 is obtained by reacting compound 12 with vinyl magnesium bromide. Compound 13 is obtained by reacting compound 13 with vinyl acetate to obtain compound (24R)-14 and compound (24S)-15. Compound (24S)-15 is reacted with an aqueous potassium carbonate solution to obtain compound (24S)-14.

[0033] Compound (24R)-14 or compound (24S)-14 is reacted with borane, followed by reaction with aqueous sodium hydroxide and hydrogen peroxide to give compound (24R)-16 or compound (24S)-16, respectively. Compound (24R)-16 or compound (24S)-16 is reacted with palladium hydroxide and hydrogen to give compound (24R)-17 or compound (24S)-17, respectively. Compound (24R)-17 or compound (24S)-17 is reacted with paratoluenesulfonic acid monohydrate and acetone dimethyl acetal to give compound (24R)-18 or compound (24S)-18, respectively.

[0034] Then, starting from compound 18, the side chain at the 3-position is converted by the following steps to produce compound 1. Compound (24R)-18 or compound (24S)-18 ​​is reacted with tosyl chloride to obtain compound (24R)-19 or compound (24S)-19, respectively. Compound (24R)-19 or compound (24S)-19 is reacted with sodium cyanide to obtain compound (24R)-20 or compound (24S)-20. Compound (24R)-20 or compound (24S)-20 is reacted with diisobutylaluminum hydride to obtain compound (24R)-21 or compound (24S)-21. Compound (24R)-21 or compound (24S)-21 is reacted with potassium carbonate to obtain compound (24R)-22 or compound (24S)-22. Compound (24R)-22 or compound (24S)-22 is reacted with sodium borate to obtain compound (24R)-23 or compound (24S)-23. Compound (24R)-23 or compound (24S)-23 is reacted with tosyl chloride to obtain compound (24R)-24 or compound (24S)-24. Compound (24R)-24 or compound (24S)-24 is reacted with sodium cyanide to obtain compound (24R)-25 or compound (24S)-25. Compound (24R)-25 or compound (24S)-25 is reacted with methyllithium to obtain compound (24R)-26 or compound (24S)-26. Compound (24R)-26 or compound (24S)-26 is reacted with methyllithium to obtain compound (24R)-27 or compound (24S)-27. Compound (24R)-27 or compound (24S)-27 is reacted with paratoluenesulfonic acid monohydrate to obtain compound (24R)-1 or compound (24S)-1.

[0035] The synthesis of compound (24R,25R)-2, compound (24R,25S)-2, compound (24S,25R)-2, and compound (24S,25S)-2 is not particularly limited, and can be carried out in accordance with the method described in Example 2 below.

[0036] For example, compound (24R, 25S)-2 can be synthesized by the following steps. Compound (24R)-14 is reacted with 3-chloroperoxybenzoic acid, and then with 2-methyl-2-butene to obtain compound (24R)-28. Compound (24R)-28 is reacted with magnesium iodide, and then with AIBN and tributyltin hydride to obtain compounds (24R, 25R)-29 and (24R, 25S)-29. Compound (24R, 25S)-29 is reacted with palladium hydride to obtain compound (24R, 25S)-30. Compound (24R, 25S)-30 is reacted with 2,2-dimethoxypropane and p-toluenesulfonic acid-H2O to obtain compound (24R, 25S)-31. Compound (24R, 25S)-31 is reacted with p-toluenesulfonyl chloride to obtain compound (24R, 25S)-32. Compound (24R, 25S)-32 is reacted with sodium cyanide to obtain compound (24R, 25S)-33. Compound (24R, 25S)-33 is reacted with DIBAL to obtain compound (24R, 25S)-34. Compound (24R, 25S)-34 is reacted with potassium carbonate to obtain compound (24R, 25S)-35. Compound (24R, 25S)-35 is reacted with sodium borohydride to obtain compound (24R, 25S)-36. Compound (24R, 25S)-36 is reacted with p-toluenesulfonyl chloride to obtain compound (24R, 25S)-37. Compound (24R, 25S)-37 is reacted with sodium cyanide to obtain compound (24R, 25S)-38. Compound (24R, 25S)-38 is reacted with methyllithium and then with ammonium chloride to obtain compound (24R, 25S)-39. Compound (24R, 25S)-39 is reacted with methyllithium and then with ammonium chloride to obtain compound (24R, 25S)-40. Compound (24R, 25S)-40 is reacted with p-toluenesulfonic acid to obtain compound (24R, 25S)-2.

[0037] The synthesis of compounds 3 to 8 is not particularly limited, and can be carried out in accordance with the method described in Example 3 below. In Example 3, compound 41 (compound 2 described in International Publication WO2017 / 131144) was used as a starting material.

[0038] Compound 41 is reacted with ethyl chloroformate and then with O-methylhydroxylamine hydrochloride to give compound 3. Compound 41 is reacted with acetyl chloride to obtain compound 42. Compound 42 is reacted with methylamine to obtain compound 4. Compound 5 is obtained by reacting compound 42 with ammonia.

[0039] Compound 41 is reacted with O-benzylhydroxylamine hydrochloride, N,N-diisopropylethylamine, 1-hydroxybenzotriazole monohydrate, and N,N'-dicyclohexylcarbodiimide to give compound 43. Compound 43 is reacted with palladium carbon to give compound 6.

[0040] Compound 41 is reacted with glycine methyl hydrochloride, N-methylmorpholine, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride to obtain compound 44. Compound 44 is reacted with an aqueous sodium hydroxide solution to obtain compound 7.

[0041] Compound 41 is reacted with β-alanine methyl ester hydrochloride, N-methylmorpholine, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride to obtain compound 45. Compound 45 is reacted with an aqueous sodium hydroxide solution to obtain compound 8.

[0042] The compound of the present invention can bind to vitamin D receptor (VDR) and activate VDR. The compound of the present invention can be verified by assaying the cell differentiation-inducing activity on human acute promyelocytic leukemia cell HL-60, as described in Test Example 1 below. The assay for cell differentiation induction can be performed according to the method described in "4.3.1. Assay of HL-60 cell differentiation-inducing activity" in Fujii et al. Bioorg. Med. Chem. 22 (2014) 5891-5901.

[0043] As described above, the compound of the present invention represented by formula (I) has an effect of activating VDR. Therefore, a medicine containing the compound of the present invention represented by formula (I), its salt, or its prodrug as an active ingredient is useful as a vitamin D receptor activator or a vitamin D agonist. The compound of the present invention represented by formula (I), its salt, or its prodrug can be used as a prophylactic and / or therapeutic agent for vitamin D receptor-related diseases. Examples of vitamin D receptor-related diseases include, but are not limited to, rickets, osteomalacia, osteoporosis, bone diseases due to kidney disorders, hypoparathyroidism, skin diseases such as psoriasis, cancer (leukemia, breast cancer, prostate cancer, colon cancer, pancreatic cancer, etc.), autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, etc.), infectious diseases (tuberculosis, etc.), non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, etc.

[0044] As the active ingredient of the medicament, vitamin D receptor activator, and preventive and / or therapeutic agent for vitamin D receptor-related diseases of the present invention, a compound represented by general formula (I), a salt thereof, or a prodrug thereof can be used. As the medicament, vitamin D receptor activator, and preventive and / or therapeutic agent for vitamin D receptor-related diseases of the present invention, the above-mentioned active ingredient may be administered as it is, but in general, it is desirable to prepare and administer a pharmaceutical composition containing the above-mentioned active ingredient and one or more formulation additives.

[0045] The administration route of the medicament, vitamin D receptor activator, and preventive and / or therapeutic agent for vitamin D receptor-related diseases of the present invention is not particularly limited. It may be oral or parenteral. Parenteral administration includes, but is not limited to, intravenous, intramuscular, subcutaneous or intradermal injection, rectal administration, transmucosal administration, and the like.

[0046] Examples of pharmaceutical compositions suitable for oral administration include tablets, capsules, powders, fine granules, granules, liquids, and syrups. Examples of pharmaceutical compositions suitable for parenteral administration include injections, drops, suppositories, inhalants, nasal drops, transdermal agents, ointments, creams, and patches.

[0047] Examples of additives for formulations that can be used include excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, dyes, diluents, bases, solubilizers or solubilization aids, isotonicity agents, pH regulators, stabilizers, propellants, and adhesives. Appropriate ones can be selected and used depending on the form of the pharmaceutical composition.

[0048] Examples of formulation additives that can be used in preparing formulations for oral administration include excipients such as glucose, lactose, D-mannitol, starch, or crystalline cellulose; disintegrants or disintegration aids such as carboxymethylcellulose, starch, or carboxymethylcellulose calcium; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or gelatin; lubricants such as magnesium stearate or talc; coating agents such as hydroxypropylmethylcellulose, sucrose, polyethylene glycol, or titanium oxide; and bases such as petrolatum, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, or hard fat.

[0049] Examples of formulation additives that can be used in preparing formulations for injection or infusion include dissolving agents or solubilizing agents that can constitute aqueous or ready-to-use injections, such as distilled water for injection, physiological saline, propylene glycol, and surfactants; isotonicity agents, such as glucose, sodium chloride, D-mannitol, and glycerin; and pH adjusters, such as inorganic acids, organic acids, inorganic bases, and organic bases.

[0050] The medicine, vitamin D receptor activator, and prophylactic and / or therapeutic agent for vitamin D receptor-related diseases of the present invention can be administered to mammals such as humans. The dosage of the medicament, vitamin D receptor activator, and prophylactic and / or therapeutic agent for vitamin D receptor-related diseases of the present invention should be appropriately increased or decreased depending on conditions such as the age, sex, weight, symptoms, and administration route of the patient, but is generally in the range of about 10 μg / kg to 5000 mg / kg, and preferably about 100 μg / kg to 1000 mg / kg, in terms of the amount of active ingredient per day for an adult. The above dosage of the drug may be administered once a day, or may be administered in several divided doses (e.g., about 2 to 4 times).

[0051] In addition, the compound represented by the general formula (I) of the present invention, its salt or its prodrug can also be used as an experimental reagent. The vitamin D receptor can be activated by treating cells, tissues, organs or individual animals having a vitamin D receptor with the compound represented by the general formula (I) of the present invention, its salt or its prodrug. Examples of cells having a vitamin D receptor include, but are not limited to, cells derived from the kidney, intestinal mucosa, bone marrow, bone, mammary gland, skin, and nerves. In addition, recombinant cells obtained by introducing a vitamin D receptor gene into an established animal cell line can also be used. Examples of tissues and organs having a vitamin D receptor include, but are not limited to, the kidney, intestinal mucosa, bone marrow, lymphatic tissue, bone, mammary gland, skin, and nerves. Examples of individual animals include, but are not limited to, mice, rats, hamsters, rabbits, and chickens. The activation of the vitamin D receptor can be confirmed by measuring the induction of expression of VDR target genes (e.g., CYP24, etc.), but is not limited to this.

[0052] The present invention will be specifically described with reference to the following examples, but the present invention is not limited to these examples. EXAMPLES

[0053] The abbreviations have the following meanings: DMF: N,N-dimethylformamide AcOEt: ethyl acetate DMSO: Dimethyl sulfoxide

[0054] <Example 1> [Synthetic scheme]

[0055] [ka]

[0056] [ka]

[0057] [Experimental Procedure] Synthesis of compound 9 Lithocholic acid (15.8981g, 42.22mmol) was added to ultra-dehydrated methanol (790.0ml), and the mixture was replaced with argon and cooled to 0℃. Acetyl chloride (3.3ml, 46.24mmol, 1.1eq) was added and stirred at room temperature for 2 hours. The mixture was then cooled to 0℃, quenched by adding water, and filtered by suction to obtain a precipitate. This was dissolved in ethyl acetate, and the solvent was removed by evaporating and drying the sample to obtain compound 9 (17.6951g, 45.30mmol, quant.) as white crystals.

[0058] Compound 9: 1 H-NMR (400MHz, CDCl3) δ 0.63 (s, 3H), 0.90-1.96 (m, 32H), 2.17-2.37 (m, 2H), 3.61-3.64 (m, 1H) 3.66 (s, 3H). 13 C-NMR (150 MHz, CDCl3) δ 14.80, 71.81, 56.39, 55.62, 51.46, 42.64, 41.98, 40.31, 40.05, 36.34, 35.74, 35.30, 35.24, 34.48, 30.97, 30.90, 30.44, 28.12, 27.09, 26.32, 24.13, 23.30, 20.73, 18.18, 11.96.

[0059] Synthesis of compound 10 Compound 9 (16.1853g, 41.44mmol) and benzyl-2,2,2-trichloroacetimidate (15.5ml, 83.48mmol, 2.0eq) were added to 1,4-dioxane (215.0ml) and cooled to 0°C. Trifluoromethanesulfonic acid (3.3ml, 37.60mmol, 0.9eq) was added and stirred at room temperature for 1 hour. The mixture was cooled to 0°C, quenched with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The mixture was washed with saturated saline, dehydrated with sodium sulfate, and the solvent was removed by evaporating and drying the sample to obtain a crude product. The product was purified by flash silica gel column chromatography (AcOEt : n-hexane = 1 : 20) to obtain compound 10 (13.6371g, 28.37mmol, 68%) as a white solid.

[0060] Compound 10: 1 H-NMR (400MHz, CDCl3) δ 0.63 (s, 3H), 0.90-1.97 (m, 32H), 2.17-2.37 (m, 2H), 3.31-3.38 (m, 1H), 3.66 (s, 3H), 4.55 (s, 2H), 7.24-7.36 (m, 5H). 13 C-NMR (150 MHz, CDCl3) δ 138.89, 128.40, 127.67, 127.44, 78.41, 69.78, 56.31, 55.66, 51.69, 42.60, 41.92, 40.06, 39.99, 35.67, 35.34, 35.22, 34.82, 33.02, 30.94, 30.85, 29.76, 28.21, 27.21, 27.04, 26.30, 24.18, 23.39, 20.69, 18.20, 11.99.

[0061] Synthesis of compound 11 Lithium aluminum hydride (1.6098g, 42.42mmol, 1.2eq.) was added to simply distilled tetrahydrofuran (25.0ml), purged with argon, and cooled to 0°C. Compound 10 (16.9402g, 35.24mmol) dissolved in simply distilled tetrahydrofuran (110.0ml) was added and stirred at room temperature for 1 hour. The mixture was quenched with water, extracted with ethyl acetate, washed with saturated saline, and dehydrated with sodium sulfate. The solvent was removed using an evaporator and sample drying to obtain colorless, transparent oily compound 11 (17.3941g, 38.42mmol, quant.).

[0062] Compound 11: 1 H-NMR (400MHz, CDCl3) δ 0.63 (s, 3H), 0.90-1.97 (m, 34H), 3.31-3.38 (m, 1H), 3.61 (dd, J=11.4, 5.2, 2H), 4.56 (s, 2H), 7.25-7.36 (m, 5H). 13 C-NMR (150 MHz, CDCl3) δ 139.06, 128.31, 127.57, 127.34, 78.55, 69.81, 63.60, 56.41, 56.06, 42.63, 42.06, 40.22, 40.11, 35.77, 35.56, 35.31, 34.85, 33.15, 31.73, 29.36, 28.28, 27.27, 27.13, 26.34, 24.18, 23.36, 20.75, 18.57, 11.99.

[0063] Synthesis of compound 12 Pyridinium chlorochromate (13.4142g, 62.23mmol, 1.6eq), ultra-dehydrated dichloromethane (150.0m), and Celite (approximately 3.0g) were placed in a two-necked eggplant flask, purged with argon, and cooled to 0°C. Compound 11 (17.2717g, 38.15mmol) dissolved in ultra-dehydrated dichloromethane (100.0ml) was added and stirred at room temperature for 8 hours. Celite filtration was performed using silica gel, and the solvent was removed using an evaporator and sample drying to obtain a pale orange oily crude. The product was purified by flash silica gel column chromatography (AcOEt : n-hexane = 1 : 10) to obtain colorless, transparent oily compound 12 (11.4500g, 25.40mmol, 67%).

[0064] Compound 12: 1 H-NMR (400MHz, CDCl3) δ 0.63 (s, 3H), 0.90-1.97 (m, 32H), 2.33-2.45 (m, 2H), 3.31-3.38 (m, 1H), 4.55 (s, 2H), 7.25-7.36 (m, 5H), 9.76 (t, J=2.0, 1H). 13 C-NMR (150 MHz, CDCl3) δ 203.45, 139.10, 128.37, 127.62, 127.40, 78.58, 69.87, 56.43, 55.90, 42.73, 42.08, 40.92, 40.25, 40.12, 35.81, 35.35, 35.34, 34.89, 33.19, 28.27, 27.92, 27.29, 27.19, 26.37, 24.21, 23.39, 20.78, 18.35, 12.05.

[0065] Synthesis of compound 13 Compound 12 (11.4590g, 25.42mmol) dissolved in simply distilled tetrahydrofuran (120.0ml) was placed in a dry two-necked eggplant flask, purged with argon, and cooled to 0°C. Vinyl magnesium bromide (14%, ca.1mol / L, 39.0ml, 39.00mmol, 1.5eq.) was added and stirred at 0°C for 2 hours. The mixture was quenched with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, washed with saturated saline, and dehydrated with sodium sulfate. The solvent was removed using an evaporator and sample drying to obtain a pale yellow oily crude product. The product was purified by flash silica gel chromatography (AcOEt:n-hexane = 1:10, CH2Cl2:n-hexane:MeOH = 100:20:0.5) to give compound 13 (6.1758g, 12.90mmol, 51%) as a colorless, transparent oil.

[0066] Compound 13: 1 H-NMR (400MHz, CDCl3) δ 0.63 (s, 3H), 0.90-1.97 (m, 34H), 3.34-3.40 (m, 1H), 4.02-4.09 (m, 1H), 4.56 (s, 2H), 5.10 (dm, J=10.5, 1H), 5.22 (dt, J=17.6, 1.2, 1H), 5.86 (m, 1H), 7.25-7.34 (m, 5H). 13 C-NMR (150 MHz, CDCl3) δ 141.34, 141.19, 139.05, 128.29, 127.54, 127.31, 114.72, 114.45, 78.53, 73.88, 73.60, 69.79, 56.38, 55.92, 42.60, 42.04, 40.20, 40.08, 35.76, 35.57, 35.54, 35.29, 34.83, 33.44, 33.42, 33.14, 31.34, 31.27, 28.24, 28.21, 27.25, 27.11, 26.32, 24.15, 23.34, 20.73, 18.57, 11.96.

[0067] Synthesis of compounds (24R)-14 and (24S)-15 Compound 13 (4.5616g, 9.5280mmol) was dissolved in dehydrated isopropyl ether (228.0ml), vinyl acetate (0.882ml, 9.5280mmol, 1.0eq.), powdered molecular sieves (4A, 190.98mg), and lipase (CAL_B, 1.5556g) were added, sealed, and stirred at room temperature for 17 hours. After filtration, the solvent was removed using an evaporator and sample drying to obtain a crude product. The product was purified by silica gel chromatography (AcOEt:n-hexane = 1:4) to give compound (24R)-14 (2.2486g, 4.6967mmol, 49%, 99%de or more) as a white solid and compound (24S)-15 (2.4658g, 4.7526mmol, 50%, 98%de) as a yellow oil.

[0068] Compound (24R)-14: 1 H-NMR (400MHz, CDCl3) δ 0.64 (s, 3H), 0.89-1.97 (m, 34H), 3.34-3.40 (m, 1H), 4.02-4.09 (m, 1H), 4.56 (s, 2H), 5.10 (dd, J=10.6, 1.2, 1H), 5.22 (dt, J=17.2, 1.2, 1H), 5.869 (ddd, J=17.2, 10.5, 6.4, 1H), 7.25-7.36 (m, 5H). 13 C-NMR (150 MHz, CDCl3) δ 141.36, 139.07, 128.31, 127.57, 127.33, 114.48, 78.54, 73.63, 69.81, 56.40, 55.94, 42.62, 42.06, 40.22, 40.10, 35.78, 35.56, 35.31, 34.85, 33.46, 33.16, 31.29, 28.26, 27.27, 27.13, 26.34, 24.17, 23.36, 20.75, 18.60, 11.98. Compound (24S)-15:1 H-NMR (400MHz, CDCl3) δ 0.63 (s, 3H), 0.90-1.96 (m, 35H), 2.06 (s, 3H), 3.32-3.43 (m, 1H), 4.56 (s, 2H), 5.16 (dd, d=9.6, 1.2, 1H), 5.16 (m, 1H), 5.23 (d, J=17.6, 1H), 5.759 (ddd, J=17.2, 10.6, 6.6, 1H), 7.25-7.36 (m, 5H). 13 C-NMR (150 MHz, CDCl3) δ 170.42, 139.06, 136.51, 128.33, 127.58, 127.35, 116.77, 78.56, 75.46, 69.84, 56.40, 55.87, 42.63, 42.06, 40.22, 40.10, 35.78, 35.40, 35.32, 34.86, 33.16, 30.99, 30.53, 28.18, 27.27, 27.15, 26.35, 24.17, 23.36, 21.31, 20.75, 18.52, 11.99.

[0069] Synthesis of compound (24S)-14 Compound (24S)-15 (2.4639g, 4.7490mmol) was dissolved in ultra-dehydrated methanol (588.0ml), and potassium carbonate solution (approximately 36%, 50ml) was added dropwise and stirred at room temperature for 5 hours. After quenching with water and removing the solvent with an evaporator, the mixture was extracted with ethyl acetate, washed with saturated saline, dehydrated with sodium sulfate, and the solvent was removed with an evaporator and sample drying to obtain a pale yellow oily crude. Compound (24S)-14 (2.0922g, 4.3700mmol, 92%) was obtained as a colorless, transparent oil by purification with silica gel chromatography (AcOEt : n-hexane = 1 : 4).

[0070] Compound (24S)-14: 1H-NMR (400MHz, CDCl3) δ 0.63 (s, 3H), 0.89-1.97 (m, 34H), 3.34-3.40 (m, 1H), 4.01-4.07 (m, 1H), 4.56 (s, 2H), 5.11 (dt, J=10.4, 1.2, 1H), 5.22 (dt, J=16.8, 1.2, 1H), 5.858 (ddd, J=17.2, 10.4, 6.4, 1H), 7.25-7.36(m, 5H). 13 C-NMR (150 MHz, CDCl3) δ 141.20, 139.06, 128.31, 127.57, 127.34, 114.74, 78.54, 73.89, 69.81, 56.40, 55.93, 42.62, 42.05, 40.21, 40.10, 35.77, 35.58, 35.30, 34.84, 33.43, 33.15, 31.36, 28.23, 27.27, 27.13, 26.34, 24.17, 23.36, 20.74, 18.58, 11.97.

[0071] Synthesis of compound (24R)-16 Compound (24R)-14 (2.0743g, 4.333mmol) was dissolved in simply distilled tetrahydrofuran (39.0ml), purged with argon, and cooled to 0℃. Borane (tetrahydrofuran solution, ca.0.9M, 13.0ml, 11.70mmol, 2.7eq.) was added and stirred at room temperature for 2 hours. After cooling to 0℃ and removing the argon, aqueous sodium hydroxide solution (2M, 10.0ml) and aqueous hydrogen peroxide (30%, 10.0ml) were added and stirred again at room temperature for 30 minutes. Quenched with water, extracted with ethyl acetate, washed with saturated saline, dehydrated with sodium sulfate, and the solvent was removed by evaporating and drying the sample to obtain a white solid crude. The residue was purified by flash silica gel chromatography (AcOEt:hexane = 1:1) to give compound (24R)-16 (1.3576g, 2.733mmol, 63%) as a white solid.

[0072] Compound (24R)-16: 1 HNMR (400MHz, CDCl3) δ 0.63 (s, 3H), 0.88-2.00 (m, 36H), 2.15 (d, J=3.6, 1H), 2.27 (t, J=5.2, 1H), 3.32-3.42 (m, 1H), 3.78-3.96 (m, 3H), 4.56 (s, 2H), 7.25-7.38 (m, 5H). 13 C-NMR (150 MHz, CDCl3) δ 139.06, 128.32, 127.57, 127.35, 78.55, 72.92, 69.82, 62.06, 56.40, 55.94, 42.64, 42.05, 40.22, 40.10, 38.32, 35.78, 35.59, 35.31, 34.85, 34.23, 33.15, 31.44, 28.32, 27.27, 27.14, 26.34, 24.18, 23.36, 20.75, 18.60, 12.00.

[0073] Synthesis of compound (24S)-16 Compound (24S)-14 (2.0445g, 4.270mmol) was dissolved in simply distilled tetrahydrofuran (38.0ml), purged with argon, and cooled to 0℃. Borane (tetrahydrofuran solution, ca.0.9M, 11.5ml, 10.35mmol, 2.4eq.) was added and stirred at room temperature for 3 hours. After cooling to 0℃ and removing the argon, aqueous sodium hydroxide solution (2M, 10.0ml) and aqueous hydrogen peroxide (30%, 10.0ml) were added and stirred at room temperature for 30 minutes again. Quenched with water, extracted with ethyl acetate, washed with saturated saline, dehydrated with sodium sulfate, and the solvent was removed by evaporating and drying the sample to obtain a crude white solid. The residue was purified by flash silica gel chromatography (AcOEt:hexane = 1:2) to give compound (24S)-16 (1.4033g, 2.825mmol, 66%) as a white solid.

[0074] Compound (24S)-16: 1HNMR (400MHz, CDCl3) δ 0.63 (s, 3H), 0.88-2.00 (m, 36H), 2.20 (d, J=3.6, 1H), 2.29 (t, J=4.8, 1H), 3.32-3.42 (m, 1H), 3.77-3.95 (m, 3H), 4.56 (s, 2H), 7.25-7.38 (m, 5H). 13 C-NMR (150 MHz, CDCl3) δ 139.06, 128.32, 127.57, 127.35, 78.55, 73.31, 69.82, 62.07, 56.40, 55.91, 42.63, 42.06, 40.22, 40.11, 37.98, 35.78, 35.73, 35.31, 34.85, 34.29, 33.16, 31.61, 28.27, 27.27, 27.14, 26.35, 24.17, 23.36, 20.75, 18.63, 11.99.

[0075] Synthesis of compound (24R)-17 Compound (24R)-16 (1.3882g, 2.794mmol) was dissolved in simply distilled tetrahydrofuran (27.0ml) and palladium hydroxide (240.0mg) was added. After replacing with hydrogen and stirring at room temperature for 2 hours, the mixture was filtered through Celite, and the solvent was removed using an evaporator and sample drying to obtain compound (24R)-17 (1.1184g, 2.750mmol, 98%) as a white powder.

[0076] Compound (24R)-17: 1 HNMR (400MHz, CDCl3) δ 0.64 (s, 3H), 0.90-2.00 (m, 37H), 2.17 (br, 1H), 2.26 (br, 1H), 3.56-3.67 (m, 1H), 3.79-3.95 (m, 3H). 13C-NMR (150 MHz, CDCl3) δ 72.88, 71.83, 62.03, 56.42, 55.95, 42.62, 42.00, 40.33, 40.09, 38.32, 36.36, 35.76, 35.56, 35.26, 34.50, 34.20, 31.44, 30.46, 28.30, 27.12, 26.36, 24.16, 23.32, 20.75, 18.59, 11.99.

[0077] Synthesis of compound (24S)-17 Compound (24S)-16 (1.4293g, 2.877mmol) was dissolved in simply distilled tetrahydrofuran (27.0ml) and palladium hydroxide (246.7mg) was added. After hydrogen replacement, the mixture was stirred at room temperature for 2.5 hours, and then palladium hydroxide (60.0mg) was added again, hydrogen replacement was performed, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered through Celite, and the solvent was removed using an evaporator and sample drying to obtain compound (24S)-17 (1.1936g, 2.935mmol, quant.) as a white powder.

[0078] Compound (24S)-17: 1 HNMR (400MHz, CDCl3) δ 0.64 (s, 3H), 0.90-2.00 (m, 37H), 2.23 (br, 1H), 2.29 (br, 1H), 3.59-3.69 (m, 1H), 3.79-3.95 (m, 3H). 13 C-NMR (150 MHz, CDCl3) δ 73.29, 71.87, 62.07, 56.46, 55.95, 42.65, 42.03, 40.37, 40.13, 38.00, 36.39, 35.79, 35.74, 35.29, 34.53, 34.30, 31.63, 30.49, 28.28, 27.16, 26.39, 24.18, 23.36, 20.78, 18.66, 12.01.

[0079] Synthesis of compound (24R)-18 Compound (24R)-17 (1.1366g, 2.795mmol) was dissolved in dehydrated N,N-dimethylformamide (26.0ml) and argon purged, then p-toluenesulfonic acid monohydrate (158.0mg, 0.8306mmol, 0.3eq.) and acetone dimethyl acetal (3.6ml, 29.38mmol, 10.5eq.) dissolved in N,N-dimethylformamide (4.0ml) were added and stirred at room temperature for 2.5 hours. The mixture was quenched with a saturated aqueous solution of sodium bicarbonate, extracted with chloroform, washed with saturated saline, dehydrated with sodium sulfate, and then evaporated. The remaining DMF was removed, and the solvent was removed again using an evaporator and sample drying to obtain a white solid crude. The product was purified by silica gel chromatography (AcOEt:hexane = 1:2) to give compound (24R)-18 (1.1260 g, 2.521 mmol, 90% in 2 steps) as a white solid.

[0080] Compound (24R)-18: 1 HNMR (400MHz, CDCl3) δ 0.64 (s, 3H), 0.89-2.00 (m, 42H), 3.58-3.68 (m, 1H), 3.74-3.85 (m, 2H), 3.95 (td, J=12.0, 2.8, 1H). 13 C-NMR (150 MHz, CDCl3) δ 98.10, 71.86, 69.17, 60.05, 56.46, 55.92, 42.62, 42.03, 40.35, 40.10, 36.38, 35.79, 35.45, 35.28, 34.52, 32.87, 31.32, 30.66, 30.49, 30.02, 28.23, 27.15, 26.39, 24.18, 23.34, 20.76, 19.22, 18.57, 11.98.

[0081] Synthesis of compound (24S)-18 Compound (24S)-17 (1.2867g, 3.164mmol) was dissolved in dehydrated N,N-dimethylformamide (24.0ml) and argon purged, then p-toluenesulfonic acid monohydrate (181.6mg, 0.9547mmol, 0.3eq.) and acetone dimethyl acetal (3.9ml, 31.83mmol, 10eq.) dissolved in N,N-dimethylformamide (6.0ml) were added and stirred at room temperature for 2 hours and 40 minutes. The mixture was quenched with a saturated aqueous solution of sodium bicarbonate, extracted with chloroform, washed with saturated saline, dehydrated with sodium sulfate, and then evaporated. The remaining DMF was removed by distillation, and the solvent was removed again by evaporating and drying the sample to obtain a pale yellow solid crude. The product was purified by silica gel chromatography (AcOEt:hexane = 1:2) to give compound (24S)-18 ​​(1.2832 g, 2.873 mmol, 99% in 2 steps) as a white solid.

[0082] Compound (24S)-18: 1 HNMR (400MHz, CDCl3) δ 0.64 (s, 3H), 0.90-2.00 (m, 42H), 3.59-3.68 (m, 1H), 3.74-3.85 (m, 2H), 3.95 (td, J=12.0, 3.2, 1H). 13 C-NMR (150 MHz, CDCl3) δ 98.08, 71.86, 69.64, 60.02, 56.46, 55.91, 42.62, 42.02, 40.35, 40.12, 36.38, 35.79, 35.62, 35.28, 34.52, 32.87, 31.12, 30.85, 30.49, 30.02, 28.22, 27.15, 26.38, 24.17, 23.35, 20.76, 19.24, 18.55, 11.99.

[0083] Synthesis of compound (24R)-19 Compound (24R)-18 (1.2111g, 2.711mmol) was dissolved in dehydrated pyridine (15.0ml) and cooled to 0℃. Tosyl chloride (1.8136g, 9.513mmol, 3.5eq.) dissolved in dehydrated pyridine (3.0ml) was added and stirred at 0℃ for 1 hour. The mixture was further stirred at room temperature for 22 hours, quenched with water, and extracted with ethyl acetate. The mixture was washed with 2M hydrochloric acid and saturated saline, dehydrated with sodium sulfate, and the solvent was removed by evaporating and drying the sample to obtain a pale yellow oily crude. Compound (24R)-19 (1.4875g, 2.475mmol, 91%) was obtained as a white powder by purification with silica gel chromatography (AcOEt : hexane = 1 : 6).

[0084] Compound (24R)-19: 1 HNMR (400MHz, CDCl3) δ 0.62 (s, 3H), 0.87-2.04 (m, 42H), 2.44 (s, 3H), 3.72-3.85 (m, 2H), 3.95 (td, J=12.0, 2.8, 1H), 4.40-4.50 (m, 1H), 7.33 (d, J=8.0, 2H), 7.79 (d, J=8.4, 2H). 13 C-NMR (150 MHz, CDCl3) δ 144.32, 134.62, 129.71, 127.56, 98.09, 83.26, 69.15, 60.05, 56.36, 55.89, 42.58, 42.06, 40.26, 39.98, 35.64, 35.44, 34.95, 34.29, 33.02, 32.88, 31.31, 30.64, 30.02, 28.19, 27.47, 26.79, 26.15, 24.12, 23.08, 21.63, 20.70, 19.22, 18.56, 11.96.

[0085] Synthesis of compound (24S)-19 Compound (24S)-18 ​​(1.3255 g, 2.967 mmol) was dissolved in dehydrated pyridine (15.0 ml) and cooled to 0°C. Tosyl chloride (2.0020 g, 10.50 mmol, 3.5 eq.) dissolved in dehydrated pyridine (3.0 ml) was added and stirred at 0°C for 1 hour. The mixture was further stirred at room temperature for 23 hours, quenched with water, and extracted with ethyl acetate. The mixture was washed with 2M hydrochloric acid and saturated saline, dehydrated with sodium sulfate, and the solvent was removed by evaporating and drying the sample to obtain a pale yellow oily crude. The mixture was purified by silica gel chromatography (AcOEt : hexane = 1 : 6) to obtain compound (24S)-19 (1.4489 g, 2.411 mmol, 81%) as a white powder.

[0086] Compound (24S)-19: 1 HNMR (400MHz, CDCl3) δ 0.62 (s, 3H), 0.87-2.04 (m, 42H), 2.44 (s, 3H), 3.72-3.85 (m, 2H), 3.95 (td, J=12.0, 3.2, 1H), 4.40-4.50 (m, 1H), 7.33 (d, J=8.0, 2H), 7.79 (d, J=8.4, 2H). 13 C-NMR (150 MHz, CDCl3) δ 144.32, 134.61, 129.71, 127.56, 98.08, 83.26, 69.63, 60.01, 56.36, 55.88, 42.58, 42.06, 40.26, 39.99, 35.63, 35.61, 34.95, 34.28, 33.02, 32.88, 31.12, 30.84, 30.01, 28.18, 27.46, 26.78, 26.15, 24.11, 23.08, 21.63, 20.71, 19.23, 18.54, 11.97.

[0087] Synthesis of compound (24R)-20 Compound (24R)-19 (1.5818g, 2.632mmol) was dissolved in dehydrated dimethyl sulfoxide (44.0ml), sodium cyanide (618.8mg, 12.63mmol, 4.8eq.) was added, and the mixture was stirred in an oil bath at 80.5℃ for 6 hours. The mixture was returned to room temperature, quenched with water, extracted with ethyl acetate, washed with water and saturated saline, and dehydrated with sodium sulfate. The solvent was removed using an evaporator and sample drying to obtain a yellow oily crude. Compound (24R)-20 (604.0mg, 1.325mmol, 50%) was obtained as a white solid by purification using flash silica gel chromatography (AcOEt : hexane = 1 : 15).

[0088] Compound (24R)-20: 1 HNMR (400MHz, CDCl3) δ 0.64 (s, 3H), 0.88-2.10 (m, 42H), 3.00 (br, 1H), 3.73-3.85 (m, 2H), 3.950 (td, J=12.0, 3.2, 1H). 13 C-NMR (150 MHz, CDCl3) δ 122.68, 98.09, 69.15, 60.04, 56.51, 55.87, 42.62, 40.30, 40.06, 39.26, 35.64, 35.35, 35.08, 32.77, 32.62, 31.32, 30.64, 30.02, 28.63, 28.17, 27.93, 26.55, 26.31, 24.12, 23.70, 23.14, 20.83, 19.22, 18.58, 11.99.

[0089] Synthesis of compound (24S)-20 Compound (24S)-19 (1.4993g, 2.495mmol) was dissolved in dehydrated dimethyl sulfoxide (40.0ml), sodium cyanide (579.5mg, 11.82mmol, 4.7eq.) was added, and the mixture was stirred in an oil bath at 80.5℃ for 6 hours. The mixture was returned to room temperature, quenched with water, extracted with ethyl acetate, washed with water and saturated saline, and dehydrated with sodium sulfate. The solvent was removed using an evaporator and sample drying to obtain a yellow oily crude. Compound (24S)-20 (550.7mg, 1.208mmol, 48%) was obtained as a white solid by purification using flash silica gel chromatography (AcOEt : hexane = 1 : 15).

[0090] Compound (24S)-20: 1 HNMR (400MHz, CDCl3) δ 0.64 (s, 3H), 0.88-2.10 (m, 42H), 3.00 (br, 1H), 3.73-3.85 (m, 2H), 3.95 (td, J=12.0, 3.2, 1H). 13 C-NMR (150 MHz, CDCl3) δ 122.65, 98.07, 69.59, 59.97, 56.48, 55.82, 42.60, 40.27, 40.05, 39.24, 35.62, 35.47, 35.06, 32.72, 32.60, 31.08, 30.76, 29.99, 28.61, 28.13, 27.91, 26.52, 26.29, 24.10, 23.68, 23.12, 20.81, 19.21, 18.55, 11.98.

[0091] Synthesis of compound (24R)-21 Compound (24R)-20 (611.5mg, 1.342mmol) was dissolved in dehydrated toluene (22.0ml), purged with argon, and cooled to -78℃ (acetone / dry ice). Diisobutylaluminum hydride (toluene solution, 1.5M, 3.8ml, 5.700mmol, 4.2eq.) was added and stirred at -78℃ for 1 hour and 50 minutes. The mixture was quenched with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, washed with water and saturated saline, dehydrated with sodium sulfate, and the solvent was removed using an evaporator and sample drying to obtain a crude product (605.0mg) containing compound (24R)-21.

[0092] Compound (24R)-21: 1 H-NMR (400MHz, CDCl3) δ 0.64 (s, 3H), 0.82-0.95 (m, 7H), 1.02-2.10 (m, 35H), 2.46 (br, 1H), 3.73-3.85 (m, 2H), 3.95 (td, J=12.0, 3.2, 1H), 9.72 (s, 1H). 13 C-NMR (150 MHz, CDCl3) δ 206.54, 98.12, 69.19, 60.06, 56.57, 55.93, 47.07, 42.66, 40.12, 39.98, 39.59, 35.58, 35.40, 34.90, 33.47, 32.82, 31.34, 30.68, 30.03, 28.22, 26.91, 26.07, 24.99, 24.17, 23.85, 20.84, 19.60, 19.24, 18.60, 12.01.

[0093] Synthesis of compound (24S)-21 Compound (24S)-20 (575.7mg, 1.263mmol) was dissolved in dehydrated toluene (20.0ml), purged with argon, and cooled to -78℃ (acetone / dry ice). Diisobutylaluminum hydride (toluene solution, 1.5M, 1.9ml, 2.850mmol, 2.3eq.) was added and stirred at -78℃ for 1 hour and 20 minutes. The mixture was quenched with a saturated aqueous ammonium chloride solution, extracted with chloroform, washed with water and saturated saline, dehydrated with sodium sulfate, and the solvent was removed using an evaporator and sample drying to obtain a crude product (600.1mg) containing compound (24S)-21.

[0094] Compound (24S)-21: 1 H-NMR (400MHz, CDCl3) δ 0.64 (s, 3H), 0.82-0.95 (m, 7H), 1.00-2.10 (m, 35H), 2.45 (br, 1H), 3.73-3.85 (m, 2H), 3.95 (td, J=12.0, 3.2, 1H), 9.72 (s, 1H). 13 C-NMR (150 MHz, CDCl3) δ 206.53, 98.10, 69.64, 60.02, 56.56, 55.90, 47.07, 42.66, 40.14, 39.97, 39.58, 35.57, 35.55, 34.89, 33.47, 32.79, 31.12, 30.82, 30.03, 28.20, 26.90, 26.07, 24.99, 24.16, 23.85, 20.84, 19.60, 19.25, 18.60, 12.01.

[0095] Synthesis of compound (24R)-22 The crude containing compound (24R)-21 (692.6mg, 1.510mmol) was dissolved in a mixture of simply distilled tetrahydrofuran (20.0ml) and dehydrated methanol (20.0ml), potassium carbonate (395.4mg, 2.861mmol, 1.9eq.) was added, and the mixture was stirred at room temperature for 23.5 hours. After quenching with water and distilling off the solvent, the mixture was extracted with chloroform, washed with saturated saline, and dehydrated with sodium sulfate. The solvent was removed using an evaporator and sample drying to obtain a crude white powder. The product was purified by flash silica gel chromatography (CH2Cl2: n-hexane: MeOH = 200:60:1) to obtain compound (24R)-22 (119.5mg, 0.2605mmol, 19% in 2 steps) as a colorless, transparent oil.

[0096] Compound (24R)-22: 1 H-NMR (400MHz, CDCl3) δ 0.64 (s, 3H), 0.88-2.00 (m, 42H), 2.27 (dt, J=12.4, 3.2, 1H), 3.73-3.85 (m, 2H), 3.95 (td, J=12.0, 3.2, 1H), 9.64 (d, J=1.6, 1H). 13 C-NMR (150 MHz, CDCl3) δ 205.14, 98.11, 69.17, 60.07, 56.37, 55.95, 51.33, 42.63, 42.58, 40.32, 40.02, 36.08, 35.75, 35.48, 35.12, 32.92, 31.34, 30.68, 30.03, 28.23, 27.18, 26.30, 24.17, 23.83, 20.78, 19.24, 18.58, 12.00.

[0097] Synthesis of compound (24S)-22 The crude containing compound (24S)-21 (583.1mg, 1.271mmol) was dissolved in simply distilled tetrahydrofuran (15.0ml) and dehydrated methanol (15.0ml), potassium carbonate (338.9mg, 2.452mmol, 1.9eq.) was added, and the mixture was stirred at room temperature for 18 hours. After quenching with water and distilling off the solvent, the mixture was extracted with chloroform, washed with saturated saline, and dehydrated with sodium sulfate. The solvent was removed using an evaporator and sample drying to obtain a white powder crude. The product was purified by flash silica gel chromatography (CH2Cl2: n-hexane: MeOH = 200:60:1) to obtain compound (24S)-22 (166.9mg, 0.3638mmol, 29% in 2 steps) as a colorless, transparent oil.

[0098] Compound (24S)-22: 1 H-NMR (400MHz, CDCl3) δ 0.64 (s, 3H), 0.88-2.00 (m, 42H), 2.28 (dt, J=11.8, 3.2, 1H), 3.73-3.85 (m, 2H), 3.95 (td, J=12.0, 3.2, 1H), 9.64 (d, J=1.6, 1H). 13 C-NMR (150 MHz, CDCl3) δ 205.15, 98.10, 69.65, 60.03, 56.37, 55.94, 51.33, 42.62, 42.57, 40.32, 40.03, 36.08, 35.75, 35.64, 35.12, 32.91, 31.14, 30.86, 30.03, 28.21, 27.17, 26.29, 24.16, 23.82, 20.78, 19.25, 18.56, 12.00.

[0099] Synthesis of compound (24R)-23 Compound (24R)-22 (123.5mg, 0.2692mmol) was dissolved in dehydrated methanol (15.0ml) and cooled to 0℃. Sodium borate (30.8mg, 0.8142mmol, 3.0eq.) was added and stirred at 0℃ for 1 hour. After quenching with water, the solvent was distilled off, extracted with ethyl acetate, washed with saturated saline, and dehydrated with sodium sulfate. Compound (24R)-23 (116.2mg, 0.2522mmol, 94%) was obtained by drying using an evaporator and a sample dryer.

[0100] Compound (24R)-23: 1 H-NMR (400MHz, CDCl3) δ 0.64 (s, 3H), 0.88-1.60 (m, 39H), 1.80-2.00 (m, 4H), 3.48 (d, J=5.2, 2H), 3.73-3.85 (m, 2H), 3.95 (td, J=12.0, 3.2, 1H). 13 C-NMR (150 MHz, CDCl3) δ 98.12, 69.18, 68.84, 60.07, 56.48, 55.98, 42.98, 42.66, 41.32, 40.48, 40.13, 36.71, 35.83, 35.46, 35.32, 32.90, 31.35, 30.69, 30.09, 30.03, 28.24, 27.41, 26.44, 24.20, 24.11, 23.99, 20.80, 19.24, 18.60, 12.01.

[0101] Synthesis of compound (24S)-23 Compound (24S)-22 (212.9mg, 0.4641mmol) was dissolved in dehydrated methanol (18.0ml) and cooled to 0℃. Sodium borate (53.0mg, 1.401mmol, 3.0eq.) was added and stirred at 0℃ for 1 hour. After quenching with water, the solvent was distilled off, extracted with ethyl acetate, washed with saturated saline, and dehydrated with sodium sulfate. Compound (24S)-23 (157.0mg, 0.3408mmol, 73%) was obtained as a white solid by drying using an evaporator and a sample dryer.

[0102] Compound (24S)-23: 1 H-NMR (400MHz, CDCl3) δ 0.64 (s, 3H), 0.90-1.60 (m, 39H), 1.80-2.00 (m, 4H), 3.48 (d, J=4.8, 2H), 3.73-3.85 (m, 2H), 3.95 (td, J=12.0, 3.2, 1H). 13 C-NMR (150 MHz, CDCl3) δ 98.09, 69.64, 68.84, 60.02, 56.47, 55.94, 42.97, 42.64, 41.31, 40.47, 40.14, 36.70, 35.82, 35.59, 35.31, 32.86, 31.13, 30.86, 30.08, 30.02, 28.22, 27.40, 26.43, 24.18, 24.10, 23.98, 20.80, 19.25, 18.58, 12.01.

[0103] Synthesis of compound (24R)-24 Compound (24R)-23 (115.4mg, 0.2505mmol) was dissolved in dehydrated pyridine (7.0ml) and cooled to 0℃. Tosyl chloride (195.2mg, 1.024mmol, 4.1eq.) dissolved in dehydrated pyridine (3.0ml) was added and stirred at 0℃ for 30 minutes, then stirred at room temperature for 17 hours. Quenched with water, extracted with ethyl acetate, washed with water, 2M hydrochloric acid, and saturated saline, and dehydrated with sodium sulfate. The crude was obtained by drying in an evaporator and sample drying. The product was purified by silica gel chromatography (AcOEt : n-hexane = 1 : 4) to obtain compound (24R)-24 (132.0mg, 0.2147mmol, 86%) as a colorless, transparent oil.

[0104] Compound (24R)-24: 1H-NMR (400MHz, CDCl3) δ 0.62 (s, 3H), 0.85-2.00 (m, 43H), 2.45 (s, 3H), 3.72-3.87 (m, 4H), 3.95 (td, J=12.0, 3.2, 1H), 7.35 (d, J=8.4, 2H), 7.79 (d, J=8.8, 2H). 13 C-NMR (150 MHz, CDCl3) δ 144.58, 133.09, 129.78, 127.88, 98.11, 75.51, 69.17, 60.06, 56.41, 55.97, 42.68, 42.62, 40.41, 40.05, 38.08, 36.27, 35.75, 35.44, 35.07, 32.90, 31.34, 30.68, 30.03, 29.57, 28.22, 27.17, 26.31, 24.17, 23.84, 23.75, 21.65, 20.74, 19.23, 18.59, 11.99.

[0105] Synthesis of compound (24S)-24 Compound (24S)-23 (157.0mg, 0.3408mmol) was dissolved in dehydrated pyridine (9.0ml) and cooled to 0℃. Tosyl chloride (261.9mg, 1.374mmol, 4.0eq.) dissolved in dehydrated pyridine (2.0ml) was added and stirred at 0℃ for 30 minutes, then stirred at room temperature for 11 hours and 20 minutes. Quenched with water, extracted with ethyl acetate, washed with water, 2M hydrochloric acid, and saturated saline, and dehydrated with sodium sulfate. The crude was obtained by drying in an evaporator and sample drying. The product was purified by silica gel chromatography (AcOEt : n-hexane = 1 : 4) to obtain colorless, transparent oily compound (24S)-24 (189.5mg, 0.3082mmol, 90%).

[0106] Compound (24S)-24: 1H-NMR (400MHz, CDCl3) δ 0.62 (s, 3H), 0.85-2.00 (m, 43H), 2.45 (s, 3H), 3.72-3.87 (m, 4H), 3.95 (td, J= J=12.0, 3.2, 1H), 7.35 (d, J=7.6, 2H), 7.79 (d, J=8.4, 2H). 13 C-NMR (150 MHz, CDCl3) δ 144.58, 133.10, 129.78, 127.89, 98.10, 75.51, 69.64, 60.03, 56.41, 55.94, 42.69, 42.63, 40.41, 40.07, 38.08, 36.28, 35.75, 35.60, 35.08, 32.88, 31.14, 30.86, 30.04, 29.58, 28.21, 27.18, 26.32, 24.17, 23.85, 23.75, 21.66, 20.76, 19.25, 18.58, 12.00.

[0107] Synthesis of compound (24R)-25 Compound (24R)-24 (148.3mg, 0.2412mmol) was dissolved in dehydrated dimethyl sulfoxide (9.0ml), sodium cyanide (61.2mg, 1.249mmol, 5.2eq.) was added, and the mixture was stirred at 80℃ for 3 hours. After returning to room temperature, the mixture was quenched with water, extracted with chloroform, washed with water and saturated saline, and dehydrated with Na2SO4. The solvent was removed using an evaporator and sample drying to obtain a crude product. The product was purified by flash silica gel chromatography (AcOEt : n-hexane = 1 : 10) to obtain compound (24R)-25 (85.0mg, 0.1810mmol, 75%) as a white solid.

[0108] Compound (24R)-25: 1H-NMR (400MHz, CDCl3) δ 0.64 (s, 3H), 0.89-2.00 (m, 43H), 2.27 (d, J=6.4, 2H), 3.73-3.85 (m, 2H), 3.95 (td, J=12.0, 3.2, 1H). 13 C-NMR (150 MHz, CDCl3) δ 119.08, 98.13, 69.19, 60.08, 56.44, 55.97, 43.05, 42.66, 40.54, 40.07, 36.60, 35.80, 35.65, 35.48, 34.81, 33.08, 32.93, 31.36, 30.70, 30.05, 28.24, 27.20, 27.15, 26.38, 24.70, 24.19, 23.80, 20.81, 19.26, 18.62, 12.03.

[0109] Synthesis of compound (24S)-25 Compound (24S)-24 (200.6mg, 0.3262mmol) was dissolved in dehydrated dimethyl sulfoxide (11.0ml), sodium cyanide (81.1mg, 1.655mmol, 5.0eq.) was added, and the mixture was stirred at 80℃ for 3 hours. After returning to room temperature, the mixture was quenched with water, extracted with chloroform, washed with water and saturated saline, and dehydrated with Na2SO4. The solvent was removed using an evaporator and sample drying to obtain a crude product. The product was purified by flash silica gel chromatography (AcOEt : n-hexane = 1 : 10) to obtain compound (24S)-25 (143.6mg, 0.3057mmol, 94%) as a white solid.

[0110] Compound (24S)-25: 1 H-NMR (400MHz, CDCl3) δ 0.64 (s, 3H), 0.89-2.00 (m, 43H), 2.27 (d, J=6.4, 2H), 3.73-3.85 (m, 2H), 3.95 (td, J=12.0, 3.2, 1H). 13C-NMR (150 MHz, CDCl3) δ 119.07, 98.12, 69.66, 60.05, 56.43, 55.93, 43.04, 42.65, 40.54, 40.08, 36.59, 35.79, 35.63, 34.81, 33.06, 32.90, 31.16, 30.87, 30.05, 28.23, 27.19, 27.15, 26.38, 24.70, 24.18, 23.80, 20.81, 19.27, 18.60, 12.03.

[0111] Synthesis of compound (24R)-26 Compound (24R)-25 (88.8mg, 0.1890mmol) was dissolved in distilled diethyl ether (15.0ml), purged with argon, and cooled to 0℃. Methyllithium (diethyl ether solution, 1.16M, 0.75ml, 0.8700mmol, 4.6eq.) was added and stirred at 0℃ for 2 hours, then saturated aqueous ammonium chloride solution (6.0ml) was added dropwise and stirred for 40 minutes. The mixture was quenched with 28% aqueous ammonia, extracted with dichloromethane, washed with saturated saline, and dehydrated with sodium sulfate. The crude product was obtained by distilling off the solvent using an evaporator and drying the sample. The product was purified by flash silica gel chromatography (CH2Cl2: n-hexane: MeOH = 80:80:1) to give compound (24R)-26 (68.0 mg, 0.1397 mmol, 74%).

[0112] Compound (24R)-26: 1 H-NMR (400MHz, CDCl3) δ 0.63 (s, 3H), 0.89-1.62 (m, 38H), 1.73-2.00 (m, 5H), 2.13 (s, 3H), 2.33 (d, J=6.8, 2H), 3.73-3.85 (m, 2H), 3.95 (td, J=12.0, 3.2, 1H). 13C-NMR (150 MHz, CDCl3) δ 209.35, 98.12, 69.20, 60.08, 56.56, 55.97, 51.59, 43.18, 42.66, 40.51, 40.16, 36.97, 35.81, 35.44, 34.87, 34.81, 33.65, 32.88, 31.35, 30.70, 30.57, 30.05, 28.25, 27.73, 27.26, 26.44, 24.20, 23.93, 20.78, 19.25, 18.61, 12.02.

[0113] Synthesis of compound (24S)-26 Compound (24S)-25 (150.2mg, 0.3197mmol) was dissolved in distilled diethyl ether (20.0ml), purged with argon, and cooled to 0℃. Methyllithium (diethyl ether solution, 1.16M, 1.30ml, 1.508mmol, 4.7eq.) was added and stirred at 0℃ for 1 hour and 40 minutes, then saturated aqueous ammonium chloride solution (14.0ml) was added dropwise and stirred for 50 minutes. The mixture was quenched with 28% aqueous ammonia, extracted with dichloromethane, washed with saturated saline, and dehydrated with sodium sulfate. The solvent was removed using an evaporator and a vacuum pump to obtain a crude product. The product was purified by flash silica gel chromatography (CH2Cl2: n-hexane: MeOH = 80:80:1) to give compound (24S)-26 (13.6 mg, 0.02794 mmol, 8.7%).

[0114] Compound (24S)-26: 1 H-NMR (400MHz, CDCl3) δ 0.63 (s, 3H), 0.89-1.60 (m, 38H), 1.73-1.98 (m, 5H), 2.12 (s, 3H), 2.33 (d, J=7.2, 2H), 3.73-3.85 (m, 2H), 3.95 (td, J=12.0, 3.2, 1H). 13C-NMR (150 MHz, CDCl3) δ 209.38, 98.11, 69.66, 60.04, 56.55, 55.93, 51.59, 43.18, 42.66, 40.51, 40.18, 36.97, 35.80, 35.58, 34.87, 34.82, 33.64, 32.83, 31.14, 30.85, 30.56, 30.04, 28.23, 27.73, 27.26, 26.44, 24.19, 23.93, 20.79, 19.26, 18.60, 12.02.

[0115] Synthesis of compound (24R)-27 Compound (24R)-26 (66.0mg, 0.1356mmol) was dissolved in distilled diethyl ether (9.0ml), purged with argon, and cooled to -72℃. Methyllithium (diethyl ether solution, 1.16M, 0.75ml, 0.8700mmol, 6.4eq.) was added and stirred for 3 hours. The mixture was quenched with saturated aqueous ammonium chloride, returned to room temperature, and the solvent was removed using an evaporator. The mixture was extracted with chloroform, washed with saturated saline, dehydrated with sodium sulfate, and the solvent was removed using an evaporator and sample drying to obtain a crude product. The product was purified by silica gel chromatography (AcOEt : n-hexane = 1 : 5) to obtain compound (24R)-27 (60.4mg, 0.1201mmol, 86%) as a colorless, transparent oil.

[0116] Compound (24R)-27: 1 H-NMR (400MHz, CDCl3) δ 0.63 (s, 3H), 0.88-1.60 (m, 42H) 1.72-2.00 (m, 4H), 1.22 (s, 6H), 3.73-3.85 (m, 2H), 3.95 (td, J=12.0, 3.2, 1H). 13C-NMR (150 MHz, CDCl3) δ 98.14, 71.71, 69.21, 60.09, 56.57, 56.00, 51.26, 43.61, 42.69, 40.51, 40.20, 37.40, 35.94, 35.86, 35.48, 35.02, 34.73, 32.91, 31.37, 30.72, 30.05, 30.04, 30.01, 29.81, 28.28, 27.47, 26.52, 24.23, 24.02, 20.81, 19.26, 18.63, 12.04.

[0117] Synthesis of compound (24S)-27 Compound (24S)-26 (53.3mg, 0.1095mmol) was dissolved in distilled diethyl ether (7.0ml), purged with argon, and cooled to -72℃. Methyllithium (diethyl ether solution, 1.16M, 0.70ml, 0.8120mmol, 7.4eq.) was added and stirred for 2 hours and 40 minutes. After quenching with saturated aqueous ammonium chloride, the mixture was returned to room temperature and the solvent was removed using an evaporator. The crude was obtained by extracting with chloroform, washing with saturated saline, dehydrating with sodium sulfate, and removing the solvent using an evaporator and drying the sample. The crude was obtained by purifying with silica gel chromatography (AcOEt : n-hexane = 1 : 5) to obtain compound (24S)-27 (37.8mg, 007518mmol, 69%) as a colorless, transparent oil.

[0118] Compound (24S)-27: 1 H-NMR (400MHz, CDCl3) δ 0.63 (s, 3H), 0.88-1.60 (m, 42H) 1.72-2.00 (m, 4H), 1.22 (s, 6H), 3.73-3.85 (m, 2H), 3.95 (td, J=12.0, 3.2, 1H). 13C-NMR (150 MHz, CDCl3) δ 98.12, 71.71, 69.67, 60.05, 56.56, 55.96, 51.26, 43.60, 42.68, 40.51, 40.21, 37.47, 35.94, 35.86, 35.62, 35.02, 34.73, 32.88, 31.15, 30.88, 30.05, 30.04, 30.01, 29.80, 28.26, 27.46, 26.52, 24.22, 24.01, 20.82, 19.27, 18.61, 12.04.

[0119] Synthesis of compound (24R)-1 Compound (24R)-27 (61.1mg, 0.1215mmol) was dissolved in dehydrated methanol (6.0ml), to which was added paratoluenesulfonic acid monohydrate (14.0mg, 0.07360mmol, 0.6eq.) dissolved in dehydrated methanol (1.5ml) and argon purged. After stirring at room temperature for 2 hours and 20 minutes, the mixture was quenched with saturated aqueous sodium bicarbonate and the solvent was removed using an evaporator. The mixture was extracted with chloroform, washed with saturated saline, dehydrated with sodium sulfate, and the solvent was removed using an evaporator and sample drying to obtain a white solid crude. Compound (24R)-1 (47.5mg, 0.1026mmol, 84%) was obtained as a white solid by recrystallization from chloroform.

[0120] Compound (24R)-1: 1 H-NMR (400MHz, CDCl3) δ 0.64 (s, 3H), 0.78-2.00 (m, 46H), 1.22 (s, 6H), 2.19 (d, J=4.4, 1H), 2.28 (dd, J=5.8, 4.2 1H), 3.79-3.95 (m, 3H). 13C-NMR (150 MHz, CDCl3) δ 72.95, 71.71, 62.08, 56.56, 56.05, 51.27, 43.60, 42.71, 40.51, 40.21, 38.37, 37.47, 35.94, 35.85, 35.63, 35.01, 34.72, 34.26, 31.53, 30.05, 30.00, 29.81, 28.36, 27.45, 26.50, 24.22, 24.01, 20.82, 18.66, 12.06.

[0121] Synthesis of compound (24S)-1 Compound (24S)-27 (35.8mg, 0.07120mmol) was dissolved in dehydrated methanol (4.5ml), and paratoluenesulfonic acid monohydrate (8.4mg, 0.04460mmol, 0.6eq.) dissolved in dehydrated methanol (1.5ml) was added and argon was substituted. After stirring at room temperature for 1 hour, the mixture was quenched with saturated aqueous sodium bicarbonate and the solvent was removed using an evaporator. The mixture was extracted with chloroform, washed with saturated saline, dehydrated with sodium sulfate, and the solvent was removed using an evaporator and sample drying to obtain a white solid crude. Recrystallization from chloroform gave compound (24S)-1 (27.0mg, 0.05835mmol, 82%) as a white solid.

[0122] Compound (24S)-1: 1 H-NMR (400MHz, CDCl3) δ 0.64 (s, 3H), 0.90-2.00 (m, 46H), 1.22 (s, 6H), 2.22 (d, J=4.0, 1H), 2.23 (dd, J=4.2, 1H), 3.79-3.95 (m, 3H). 13C-NMR (150 MHz, CDCl3) δ 73.31, 71.71, 62.08, 56.56, 56.01, 51.26, 43.59, 42.70, 40.52, 40.21, 38.01, 37.46, 35.94, 35.84, 35.75, 35.01, 34.71, 34.31, 31.66, 30.04, 30.00, 29.81, 28.32, 27.44, 26.50, 24.21, 24.01, 20.82, 18.70, 12.05.

[0123] <Example 2> [Synthetic scheme] [ka]

[0124] [Experimental Procedure] Synthesis of compound (24R)-28 3-Chloroperoxybenzoic acid (70%, 6.1877 g, 25.10 mmol, 4.5 equiv.) in dry CHCl (45.0 ml) was added to a solution of compound (24R)-14 (2.6673 g, 5.5713 mmol) in dry CHCl (25.0 ml). The reaction mixture was stirred at 0° C. for 16 h, then 2-methyl-2-butene (2.4 ml, 22.66 mmol, 4.1 equiv.) was added. The mixture was stirred at room temperature for 1 h, quenched with saturated aqueous sodium bicarbonate, and extracted with CHCl. ​​The organic layer was washed with saturated aqueous sodium sulfite, 2M aqueous sodium hydroxide, and water, then dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (AcOEt : n-hexane = 1:3) to give compound (24R)-28 (2.3589 g, 4.7678 mmol, 24R,25R : 24R,25S = 3 : 2, 86%) as a white solid.

[0125] Compound (24R)-28: 1H-NMR (400MHz, CDCl3)δ 0.64(s, 3H), 0.88-2.00(m, 35H), 2.70-2.76(m, 1H), 2.80-2.84(m, 1H), 2.96-3.04(m, 1H), 3.30-3.40(m, 1.6H), 3.76-3.82(m, 0.4H), 4.56(s, 2H), 7.25-7.38(m, 5H). 13 C-NMR (150 MHz, CDCl3)δ 139.10, 128.36, 127.60, 127.38, 78.58, 71.92, 69.85, 68.70, 56.44, 55.93, 55.89, 55.42, 54.58, 45.20, 43.47, 42.68, 42.09, 40.25, 40.14, 35.81, 35.59, 35.51, 35.35, 34.89, 33.19, 31.28, 31.25, 30.87, 29.80, 28.31, 27.30, 27.17, 26.38, 24.20, 23.39, 20.79, 18.55, 12.03; HRMS calcd for OODNaOOOB(M + Na) + 517.3658, found 517.3643.

[0126] ·Synthesis of compound (24R, 25R)-29および(24R, 25S)-29 A solution of magnesium iodide (1.5973 g, 5.7434 mmol, 1.2 equiv) in dry Et2O (16.0 ml) was added to a cooled solution of compound (24R)-28 (2.3589 g, 4.7678 mmol) in dry toluene (80.0 ml) at -60 °C under Ar. Stir vigorously at -55 to 59 °C for 1 h and then warm to room temperature. AIBN (278.7 mg, 1.6972 mmol, 0.36 equiv) and tributyltin hydride (1.2 ml, 4.4609 mmol, 0.94 equiv) in dry toluene (12.0 ml) were added to the reaction mixture and stirred at 70 °C for 2 h. Tributyltin hydride (0.25 ml, 0.9294 mmol, 0.19 equiv) was added to the reaction mixture and stirred at 70 °C for 0.5 h. After removing the solvent in vacuum, the residue was filtered by chromatography on silica gel containing dry potassium carbonate (10 wt%) to remove the tin compounds. The filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (AcOEt : n-hexane = 1:1) to give compounds (24R, 25R)-29 (33%) and (24R, 25S)-29 (22%).

[0127] Compound (24R, 25R)-29: 1 H-NMR (400MHz, CDCl3)δ 0.64(s, 3H), 0.88-2.00(m, 38H), 2.10(d, J=4.8, 1H), 3.27-3.42(m, 2H), 3.57-3.65(m, 1H), 4.56(s, 2H), 7.25-7.38(m, 5H). 13 C-NMR (150 MHz, CDCl3)δ 139.06, 128.32, 127.57, 127.35, 78.55, 76.52, 71.00, 69.82, 56.40, 56.02, 42.66, 42.06, 40.22, 40.12, 35.78, 35.57, 35.31, 34.85, 33.15, 31.45, 29.73, 28.32, 27.27, 27.14, 26.35, 24.18, 23.36, 20.75, 19.47, 18.47, 12.01; HRMS calcd for OODNaOOOB(M + Na)+ 519.3814, found 519.3797. Compound (24R, 25S)-29: 1H-NMR (400MHz, CDCl3) δ 0,64 (s, 3H), 0.88-2.00 (m, 39H), 3.32-3.42 (m, 1H), 3.55-3.62 (m, 1H), 3.75-3.85 (m, 1H), 4.56 (s, 2H), 7.25-7.38 (m, 5H). 13C-NMR (150 MHz, CDCl3) δ 139.07, 128.32, 127.57, 127.34, 78.55, 75.20, 70.46, 69.81, 56.39, 55.95, 42.65, 42.06, 40.22, 40.10, 35.78, 35.58, 35.31, 34.86, 33.15, 31.96, 28.33, 28.06, 27.27, 27.14, 26.35, 24.18, 23.36, 20.75, 18.53, 16.73, 12.00; HRMS calcd for C33H52NaO3 (M + Na)+ 519.3814, found 519.3796.

[0128] Synthesis of compound (24R, 25S)-30 Palladium hydride (95.3 mg) was added to a solution of (24R, 25S)-29 (490.4 mg, 0.9872 mmol) in distilled THF (8.0 ml). Stirred at room temperature under H2 for 2 h, filtered through Celite, and then removed under reduced pressure. The crude product (465.9 mg) containing compound (24R, 25S)-30 was obtained as a white solid.

[0129] Compound (24R, 25S)-30: 1 H-NMR (400MHz, CDCl3)δ 0.65(s, 3H), 0.90-2.00(m, 40H), 3.55-3.67(m, 2H), 3.75-3.85(m, 1H). 13C-NMR (150 MHz, CDCl3)δ 75.23, 71.89, 70.49, 56.46, 56.00, 42.68, 42.05, 40.38, 40.14, 36.41, 35.81, 35.61, 35.31, 34.55, 32.01, 30.52, 28.35, 28.06, 27.17, 26.41, 24.21, 23.37, 20.79, 18.57, 16.76, 12.04; HRMS calcd for OODNaOOOB(M + Na) + 429.3345, found 429.3334.

[0130] Synthesis of compound (24R, 25S)-31 p-Toluenesulfonic acid-H2O (69.0 mg, 0.3627 mmol, 0.3 eq.) in DMF (5.0 ml) and 2,2-dimethoxypropane (1.15 ml, 9.3855 mmol, 8.2 eq.) was added to a solution of compound (24R, 25S)-30 (462.9 mg, 1.1383 mmol) in DMF (10.0 ml) at room temperature. After stirring the reaction mixture at room temperature for 1 h, the reaction mixture was quenched with saturated aqueous NaHCOOOA solution and the solvent was removed under reduced pressure. The residue was extracted with CHCl3. The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (AcOEt : n-hexane = 1:2) to give compound (24R, 25S)-31 (432.7 mg, 0.9686 mmol, 98% for two steps) as a white solid.

[0131] Compound (24R, 25S)-31: 1 H-NMR (400MHz, CDCl3)δ 0.64(s, 3H), 0.90-2.00(m, 44H), 3.58-3.68(m, 1H), 3.95-4.03(m, 1H), 4.23(quin., J=6.4, 1H). 13C-NMR(150 MHz, CDCl3)δ 107.19, 78.62, 73.82, 71.89, 56.47, 55.94, 42.67, 42.06, 40.39, 40.14, 36.43, 35.92, 35.82, 35.32, 34.56, 32.18, 30.53, 28.66, 28.31, 27.18, 26.41, 26.27, 25.94, 24.22, 23.38, 20.80, 18.60, 15.55, 12.02; + Na) + 469.3658, found 469.3641.

[0132] Synthesis of compound (24R, 25S)-32 p-Toluenesulfonyl chloride (308.7 mg, 1.619 mmol, 3.6 equiv.) in dry pyridine (1.0 ml) was added to a solution of compound (24R, 25S)-31 (202.5 mg, 0.4533 mmol) in dry pyridine (4.0 ml) at 0° C. The mixture was stirred at 0° C. for 1 h and then at room temperature for 17.5 h. The reaction mixture was quenched with water and extracted with AcOEt. The organic phase was washed with 2M hydrochloric acid and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (AcOEt : n-hexane=1:4) to give compound (24R, 25S)-32 (230.4 mg, 0.3834 mmol, 86%) as a colorless oil.

[0133] Compound (24R, 25S)-32: 1 H-NMR (400MHz, CDCl3)δ 0.62(s, 3H), 0.87-2.04(m, 43H), 2.44(s, 3H), 3.95-4.03(m, 1H), 4.23(quin., J=6.4, 1H), 4.40-4.50(m, 1H), 7.326(d, J=8.0, 2H), 7.79(d, J=8.4, 2H). 13C-NMR (150 MHz, CDCl3)δ 144.30, 134.74, 129.71, 127.57, 107.18, 83.25, 78.59, 73.80, 56.38, 55.93, 42.64, 42.11, 40.31, 40.02, 35.88, 35.68, 35.00, 34.32, 33.07, 32.17, 28.63, 28.26, 27.53, 26.82, 26.29, 26.17, 25.92, 24.16, 23.10, 21.63, 20.75, 18.58, 15.53, 11.99; HRMS calcd for OODNaOOOBS(M + Na) + 623.3746, found 623.3741.

[0134] Synthesis of compound (24R, 25S)-33 Sodium cyanide (194.3 mg, 3.9645 mmol, 5.0 equiv.) was added to a solution of compound (24R, 25S)-32 (476.1 mg, 0.7923 mmol) in dry DMSO (10.0 ml) and stirred at 80.5° C. for 5 h. The reaction mixture was cooled to room temperature, then quenched with water and extracted with AcOEt. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (AcOEt : n-hexane=1:15) to give compound (24R, 25S)-33 (139.2 mg, 0.3054 mmol, 39%) as a colorless oil.

[0135] Compound (24R, 25S)-33: 1 H-NMR (400MHz, CDCl3)δ 0.65(s, 3H), 0.90-2.10(m, 43H), 3.00(br. 1H), 3.95-4.03(m, 1H), 4.23(quin., J=6.4, 1H). 13C-NMR(150 MHz, CDCl3)δ 122.72, 107.20, 78.62, 73.80, 56.52, 55.96, 42.67, 40.32, 40.10, 39.30, 35.89, 35.67, 35.11, 32.66, 32.18, 28.65, 28.28, 27.97, 26.57, 26.32, 26.25, 25.93, 24.17, 23.73, 23.18, 20.87, 18.60, 15.52, 12.03; HRMS calcd for OOENNaOOOB(M + Na) + 478.3661, found 478.3654.

[0136] Synthesis of compound (24R, 25S)-34 DIBAL in toluene solution (1.5 mol / L, 0.20 ml, 0.3000 mmol, 2.2 equiv.) was added to a cooled solution of compound (24R, 25S)-33 (62.3 mg, 0.1367 mmol) in dry toluene (7.0 ml) at −68° C. under Ar and stirred at −68° C. for 1.5 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with CHCl3. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to give the crude product containing compound (24R, 25S)-34 (60.4 mg) as a white solid.

[0137] Compound (24R, 25S)-34: 1 H-NMR (400MHz, CDCl3)δ 0.64(s, 3H), 0.82-2.08(m, 43H), 2.43-2.48(m. 1H), 3.95-4.00(m, 1H), 4.23(quin., J=6.4, 1H), 9.71(s, 1H). 13C-NMR (150MHz, CDCl3)δ 206.55, 107.19, 78.64, 73.81, 56.57, 55.97, 47.09, 42.69, 40.15, 39.99, 39.61, 35.91, 35.59, 34.91, 33.49, 32.20, 28.65, 28.31, 26.92, 26.26, 26.07, 25.94, 25.01, 24.20, 23.86, 20.87, 19.61, 18.61, 15.53, 12.03; HRMS calcd for OODNaOOOB(M + Na) + 481.3658, found 481.3639.

[0138] Synthesis of compound (24R, 25S)-35 Potassium carbonate (51.0 mg, 0.3690 mmol, 2.6 equiv.) was added to a solution of crude compound (24R, 25S)-34 (65.3 mg, 0.1412 mmol) in dry methanol (3.0 ml) containing distilled THF (3.0 ml) and stirred at room temperature for 13 h. After quenching with water and removing under reduced pressure, the residue was extracted with CHCl3. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel flash chromatography (CHCl2: n-hexane: MeOH = 200:100:1) to give compound (24R, 25S)-35 (33.0 mg, 0.07194 mmol, 53% for two steps) as a colorless oil.

[0139] Compound (24R, 25S)-35: 1 H-NMR (400MHz, CDCl3)δ 0.65(s, 3H), 0.90-2.00(m, 43H), 2.23-2.33(m, 1H), 3.95-4.03(m, 1H), 4.23(quin., J=6.4, 1H), 9.64(d, J=1.2, 1H). 13C-NMR (150MHz, CDCl3)δ 205.11, 107.19, 78.61, 73.81, 56.37, 55.93, 51.33, 42.65, 42.58, 40.33, 40.03, 36.08, 35.92, 35.76, 35.12, 32.18, 28.65, 28.29, 27.18, 26.31, 26.29, 25.93, 24.19, 23.83, 20.80, 18.59, 15.54, 12.01; HRMS calcd for OODNaOOOB(M + Na) + 481.3658, found 481.3647.

[0140] Synthesis of compound (24R, 25S)-36 Sodium borohydride (8.2 mg, 0.2168 mmol, 3.1 equiv) was added to a solution of compound (24R, 25S)-35 (31.7 mg, 0.06910 mmol) in dry methanol (4.0 ml) at 0° C. and stirred for 1 h. The reaction mixture was quenched with water, the solution was removed in vacuo, and the residue was extracted with AcOEt. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give compound (24R, 25S)-36 (31.6 mg, 0.06858 mmol, 99%).

[0141] Compound (24R, 25S)-36: 1 H-NMR (400MHz, CDCl3)δ 0.65(s, 3H), 0.91-1.65(m, 41H), 1.75-2.00(m, 4H), 3.48(d, J=6.0, 2H), 3.95-4.03(m, 1H), 4.23(quin., J=6.4, 1H). 13C-NMR(150MHz, CDCl3)δ 107.19, 78.65, 73.81, 68.87, 56.48, 55.96, 42.99, 42.68, 41,33, 40.48, 40.15, 36.73, 35.93, 35.84, 35.33, 32.22, 30.10, 28.65, 28.32, 27.41, 26.44, 26.28, 25.94, 24.22, 24.13, 24.00, 20.83, 18.62, 15.54, 12.03; HRMS calcd for OOENaOOOB(M + Na) + 483.3814, found 483.3807.

[0142] Synthesis of compound (24R, 25S)-37 p-Toluenesulfonyl chloride (99.8 mg, 0.5235 mmol, 4.0 equiv.) in dry pyridine (1.0 ml) was added to a cooled solution of compound (24R,25S)-36 (60.0 mg, 0.1302 mmol) in dry pyridine (3.0 ml) at 0 °C. The mixture was stirred at 0 °C for 30 min and then at room temperature for 2.5 h. p-Toluenesulfonyl chloride (47.3 mg, 0.2481 mmol, 1.9 equiv.) was added to the cooled mixture at 0 °C. The mixture was stirred at 0 °C for 30 min and then at room temperature for 16 h. p-Toluenesulfonyl chloride (95.1 mg, 0.4988 mmol, 3.8 equiv.) was added to the cooled mixture at 0 °C. The mixture was stirred at 0 °C for 30 min and then at room temperature for 30 min. Dry pyridine (0.4ml) was added to the mixture solution and then stirred for 2 hours. The reaction mixture was quenched with water and extracted with AcOEt. The organic layer was washed with water, 2M hydrochloric acid solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (AcOEt : n-hexane = 1:4) to give compound (24R, 25S)-37 (73.6mg, 0.1197mmol, 92%) as a colorless oil.

[0143] Compound (24R, 25S)-37: 1H-NMR (400MHz, CDCl3)δ 0.63(s, 3H), 0.85-2.00(m, 44H), 2.45(s, 3H), 3.84(d, J=6.8, 2H), 3.95-4.03(m, 1H), 4.23(quin., J=6.4, 1H), 7.35(d, J=8.0, 2H), 7.79(d, J=8.4, 2H). 13 C-NMR (150 MHz, CDCl3)δ 144.60, 133.11, 129.80, 127.90, 107.20, 78.64, 75.54, 73.81, 56.41, 55.95, 42.70, 42.65, 40.42, 40.07, 38.10, 36.30, 35.92, 35.76, 35.09, 32.21, 29.58, 28.65, 28.29, 27.18, 26.31, 26.28, 25.93, 24.19, 23.85, 23.77, 21.67, 20.77, 18.60, 15.54, 12.01; HRMS calcd for OODNaOOOBS(M + Na) + 637.3903, found 637.3890.

[0144] Synthesis of compound (24R, 25S)-38 Sodium cyanide (33.1 mg, 0.6754 mmol, 4.9 equiv.) was added to a solution of compound (24R, 25S)-37 (84.8 mg, 0.1379 mmol) in dry DMSO (6.0 ml) and stirred at 80° C. for 2 h 10 min. After cooling to room temperature, it was quenched with water and extracted with CHCl3. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (AcOEt : n-hexane=1:8) to give compound (24R, 25S)-38 (52.9 mg, 0.1126 mmol, 82%) as a yellow oil.

[0145] Compound (24R, 25S)-38: 1H-NMR (400MHz, CDCl3)δ 0.65(s, 3H), 0.90-2.00(m, 44H), 2.26(d, J=6.8, 2H), 3.95-4.03(m, 1H), 4.23(quin., J=6.4, 1H). 13 C-NMR(150 MHz, CDCl3)δ 119.07, 107.20, 78.64, 73.81, 56.41, 55.92, 43.04, 42.66, 40.53, 40.07, 36.60, 35.92, 35.79, 35.63, 34.80, 33.07, 32.21, 28.65, 28.29, 27.19, 27.14, 26.36, 26.28, 25.93, 24.70, 24.19, 23.79, 20.81, 18.61, 15.54, 12.03; HRMS calcd for OOENNaOOOB(M + Na) + 492.3818, found 492.3803.

[0146] Synthesis of compound (24R, 25S)-39 Methyllithium in diethyl ether (1.16 mol / L, 0.4 ml, 0.4640 mmol, 3.6 equiv.) was added to a solution of compound (24R, 25S)-38 (60.5 mg, 0.1289 mmol) in distilled diethyl ether (8.0 ml) under Ar at 0° C. After stirring the reaction mixture at 0° C. for 1 h 45 min, saturated ammonium chloride solution (3.5 ml) was added and then stirred for 40 min. The reaction mixture was quenched with 28% aqueous ammonia solution and extracted with CHCl. ​​The organic layer was washed with brine, dried over NaSO, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (CHCl: n-hexane: MeOH = 80:80:1) to give compound (24R, 25S)-39 (35.6 mg, 0.07313 mmol, 57%).

[0147] Compound (24R, 25S)-39: 1H-NMR (400MHz, CDCl3)δ 0.64(s, 3H), 0.90-2.00(m, 44H), 2.12(s, 3H), 2.33(d, J=6.8, 2H), 3.95-4.03(m, 1H), 4.23(quin., J=6.4, 1H). 13 C-NMR(150MHz, CDCl3)δ 209.36, 107.20, 78.65, 73.82, 56.55, 55.97, 51.58, 43.19, 42.68, 40.52, 40.18, 36.98, 35.93, 35.81, 34.88, 34.81, 33.65, 32.22, 30.60, 28.66, 28.32, 27.74, 27.27, 26.44, 26.27, 25.94, 24.21, 23.93, 20.81, 18.61, 15.54, 12.03; HRMS calcd for OOENaOOOB(M + Na) + 509.3971, found 509.3966.

[0148] Synthesis of compound (24R, 25S)-40 Methyllithium in diethyl ether (1.16 mol / L, 0.40 ml, 0.4640 mmol, 6.1 equiv.) was added to a solution of compound (24R, 25S)-39 (37.2 mg, 0.07642 mmol) in distilled diethyl ether (5.0 ml) under Ar at -78 °C. The reaction mixture was stirred for 2.5 h, then quenched with saturated ammonium chloride solution, and the solution was removed under vacuum. After the residue was extracted with CHCl3, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (AcOEt : n-hexane = 1:4) to give compound (24R, 25S)-40 (31.8 mg, 0.06324 mmol, 83%) as a colorless oil.

[0149] Compound (24R, 25S)-40: 1H-NMR (400MHz, CDCl3)δ 0.64(s, 3H), 0.90-1.60(m, 44H),1.22(s, 6H), 1.73-2.00(m, 3H), 3.95-4.03(m, 1H), 4.23(quin., J=6.4, 1H). 13 C-NMR(150MHz, CDCl3)δ 107.19, 78.65, 73.82, 71.70, 56.55, 55.96, 51.27, 43.60, 42.69, 40.51, 40.20, 37.47, 35.94, 35.85, 35.01, 34.72, 32.22, 30.05, 30.00, 29.81, 28.65, 28.33, 27.45, 26.50, 26.27, 25.94, 24.23, 24.01, 20.82, 18.62, 15.54, 12.03; HRMS calcd for OOENaOOOB(M + Na) + 525.4284, found 525.4271.

[0150] Synthesis of compound (24R, 25S)-2 p-Toluenesulfonic acid-H2O (10.2 mg, 0.05362 mmol, 0.8 equiv.) in dry methanol (3.5 ml) was added to a solution of compound (24R, 25S)-40 (31.8 mg, 0.06324 mmol) in dry methanol (1.0 ml). The reaction mixture was stirred at room temperature under Ar for 1 h, then quenched with saturated sodium bicarbonate solution and the solution was removed in vacuo. After extraction of the residue with CHCl3, the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give compound (24R, 25S)-2 (30.0 mg, 0.06483 mmol, quant.) as a white solid.

[0151] Compound (24R, 25S)-2: 1 H-NMR (400MHz, CDCl3)δ 0.64(s, 3H), 0.90-1.97(m, 43H), 1.22(s, 6H), 3.55-3.62(m, 1H), 3.75-3.85(m, 1H). 13C-NMR (150MHz, CDCl3)δ 75.25, 71.70, 70.49, 56.55, 56.03, 51.26, 43.59, 42.70, 40.50, 40.20, 37.46, 35.93, 35.84, 35.61, 35.00, 34.71, 32.04, 30.04, 29.99, 29.80, 28.36, 28.05, 27.44, 26.49, 24.21, 24.00, 20.81, 18.58, 16.74, 12.05; HRMS calcd for OODNaOOOB(M + Na) + 485.3971, found 485.3962.

[0152] Synthesis of compound (24R, 25R)-2 Compound (24R, 25R)-2 was synthesized from compound (24R, 25R)-29 in the same manner as compound (24R, 25S)-2.

[0153] Compound (24R, 25R)-2: 1 H-NMR (400MHz, CDCl3)δ 0.65(s, 3H), 0.90-1.60(m, 36H), 1.22(s, 6H), 1.70-2.00(m, 6H), 2.08(d, J=4.2, 1H), 3.27-3.33(m, 1H), 3.57-3.62(m, 1H). 13 C-NMR (150MHz, CDCl3)δ 76.54, 71.65, 71.02, 56.58, 56.17, 51.29, 43.62, 42.73, 40.55, 40.25, 37.48, 35.96, 35.87, 35.61, 35.02, 34.72, 31.56, 30.00, 29.82, 28.36, 27.45, 26.50, 24.21, 23.98, 20.83, 19.52, 18.53, 12.06; HRMS calcd for OODNaOOOB(M + Na) + 485.3971, found 485.3953.

[0154] Synthesis of compound (24S)-28 3-Chloroperoxybenzoic acid (70%, 6.7813 g, 27.51 mmol, 4.4 equiv.) in dry CHCl (70.0 ml) was added to a solution of compound (24S)-14 (2.9601 g, 6.1828 mmol) in dry CHCl (20.0 ml). The reaction mixture was stirred at 0° C. for 17.5 h, then 2-methyl-2-butene (2.6 ml, 24.53 mmol, 4.0 equiv.) was added. It was stirred at room temperature for 1 h, quenched with saturated aqueous sodium bicarbonate, and extracted with CHCl. ​​The organic layer was washed with saturated aqueous sodium sulfite, 2M aqueous sodium hydroxide, water, dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (AcOEt : n-hexane = 1:3) to give compound (24S)-28 (3.0969 g, 6.2594 mmol, 24S25S : 24S25R = 3 : 2, quantitative) as a white solid.

[0155] Compound (24S)-28: 1 H-NMR (400MHz, CDCl3)δ 0.64(s, 3H), 0.88-2.00(m, 35H), 2.70-2.75(m, 1H), 2.80-2.85(m, 1H), 2.97-3.00(m, 0.6H), 3.02-3.05(m, 0.4H), 3.30-3.40(m, 1.6H), 3.76-3.82(m, 0.4H), 4.56(s, 2H), 7.25-7.38(m, 5H). 13 C-NMR (150 MHz, CDCl3)δ 139.09, 128.35, 127.60, 127.38, 78.58, 72.29, 69.86, 68.86, 56.44, 55.91, 55.32, 54.49, 45.35, 43.31, 42.67, 42.08, 40.25, 40.15, 35.81, 35.76, 35.34, 34.88, 33.19, 31.38, 31.00, 30.01, 28.29, 27.30, 27.17, 26.37, 24.20, 23.39, 20.78, 18.58, 12.02; HRMS calcd for OODNaOOOB(M + Na)+ 517.3658, found 517.3642.

[0156] Synthesis of compound (24S, 25S)-29 and compound (24S, 25R)-29 Magnesium iodide (2.1366 g, 7.6826 mmol, 1.2 equiv.) in dry Et2O (30.0 ml) was added to a cooled solution of compound (24S)-28 (3.1648 g, 6.3966 mmol) in dry toluene (80.0 ml) at Ar-60 °C. After vigorously stirring at -55 to 59 °C for 1.5 h, it was warmed to room temperature. AIBN (318.6 mg, 1.9402 mmol, 0.3 equiv.) and tributyltin hydride (2.0 ml, 7.4349 mmol, 1.2 equiv.) in dry toluene (20.0 ml) were added to the reaction mixture, which was then stirred at 70 °C for 1.5 h. After the solvent was removed in vacuum, the residue was filtered by chromatography on silica gel containing dry potassium carbonate (10 wt%) to remove the tin compounds. The filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (AcOEt : n-hexane=1:1) to give compound (24S,25S)-29 (18%) and compound (24S,25R)-29 (6%).

[0157] Compound (24S, 25S)-29: 1 H-NMR (400MHz, CDCl3)δ 0.64(s, 3H), 0.88-2.00(m, 38H), 2.10(d, J=4.8, 1H), 3.25-3.32(m, 1H), 3.33-3,42(m, 1H), 3.57-3.66(m, 1H), 4.56(s, 2H), 7.25-7.38(m, 5H). 13C-NMR (150 MHz, CDCl3)δ 139.10, 128.36, 127.61, 127.38, 78.59, 76.93, 70.74, 69.86, 56.43, 55.93, 42.68, 42.10, 40.27, 40.15, 35.85, 35.82, 35.35, 34.89, 33.20, 31.73, 29.91, 28.29, 27.31, 27.18, 26.39, 24.22, 23.40, 20.79, 19.64, 18.71, 12.04; HRMS calcd for OODNaOOOB(M + Na) + 519.3814, found 519.3797. Compound (24S, 25R)-29: 1H-NMR (400MHz, CDCl3) δ 0.64 (s, 3H), 0.88-2.00 (m, 39H), 3.32-3.42 (m, 1H), 3.55-3.59 (m, 1H), 3.77-3.83 (m, 1H), 4.56 (s, 2H), 7.25-7.38 (m, 5H). 13C-NMR (150 MHz, CDCl3) δ 139.10, 128.36, 127.61, 127.38, 78.59, 75.59, 70.24, 69.86, 56.43, 55.99, 42.68, 42.09, 40.26, 40.15, 35.92, 35.82, 35.35, 34.89, 33.19, 32.14, 28.56, 28.30, 27.31, 27.18, 26.38, 24.22, 23.40, 20.79, 18.64, 16.40, 12.03; HRMS calcd for C33H52NaO3 (M + Na)+ 519.3814, found 519.3801.

[0158] ·Synthesis of compound (24S, 25R)-2 Compound (24S, 25R)-29 is the same method as compound (24R, 25S)-2, and compound (24S, 25R)-2 is synthesized by the same method.

[0159] Compound (24S, 25R)-2: 1H-NMR (400MHz, CDCl3)δ 0,64(s, 3H), 0.90-1.97(m, 43H), 1.22(s, 6H), 3.55-3.59(m, 1H), 3.80(qd, J=4.4, 2.0, 1H). 13 C-NMR (150MHz, CDCl3)δ 75.60, 71.70, 70.24, 56.56, 56.02, 51.27, 43.59, 42.71, 40.52, 40.22, 37.46, 35.94, 35.89, 35.84, 35.01, 34.71, 32.16, 30.05, 30.00, 29.81, 28.49, 28.32, 27.45, 26.50, 24.22, 24.00, 20.82, 18.68, 16.42, 12.05; HRMS calcd for OODNaOOOB(M + Na) + 485.3971, found 485.3961.

[0160] Synthesis of compound (24S, 25S)-2 Compound (24S, 25S)-2 was synthesized from compound (24S, 25S)-29 in the same manner as compound (24R, 25S)-2.

[0161] Compound (24S, 25S)-2: 1 H-NMR (400MHz, CDCl3)δ 0.64(s, 3H), 0.90-1.63(m, 36H), 1.22(s, 6H), 1.70-2.00(m, 6H), 2.03(d, J=4.8, 1H), 3.25-3.30(m, 1H), 3.58-3.64(m, 1H). 13C-NMR (150MHz, CDCl3)δ 76.91, 71.65, 70.70, 56.57, 56.03, 51.30, 43.62, 42.72, 40.55, 40.24, 37.48, 35.96, 35.86, 35.83, 35.02, 34.72, 31.75, 30.05, 30.00, 29.92, 29.82, 28.29, 27.45, 26.50, 24.21, 23.98, 20.83, 19.62, 18.72, 12.04; HRMS calcd for OODNaOOOB(M + Na) + 485.3971, found 485.3951.

[0162] <Example 3> [Synthetic scheme] [ka]

[0163] [Experimental Procedure] Synthesis of compound 3 Compound 41 (20.4 mg, 0.047 mmol) was dissolved in N,N-dimethylformamide (1.0 mL), triethylamine (11.7 mg, 0.115 mmol, 2.5 eq.) was added, and the mixture was cooled to 0°C. Ethyl chloroformate (6.0 mg, 0.055 mmol, 1.2 eq.) dissolved in N,N-dimethylformamide (0.5 mL) was added, and the mixture was stirred at 0°C for 45 minutes. O-Methylhydroxylamine hydrochloride (4.3 mg, 0.052 mmol, 1.1 eq.) and triethylamine (12.4 mg, 0.122 mmol, 2.6 eq.) dissolved in N,N-dimethylformamide (0.5 mL) were added, and the mixture was stirred at room temperature for 4 hours. N,N-Dimethylformamide was removed by distillation using a vacuum pump, and the mixture was extracted with ethyl acetate, washed with saturated saline, and dehydrated with sodium sulfate. The solvent was removed using an evaporator and sample drying to obtain a white solid crude. The crude was purified by gel permeation chromatography (CHCl3) and recrystallized from chloroform and n-hexane to obtain compound 3 (13.1 mg, 0.0283 mmol, 73%) as a white solid.

[0164] Compound 3: 1 H NMR (400 MHz, CDCl3) δ 7.98 (brs, 1H), 3.76 (s, 3H), 2.17 (brs, 1H), 1.94 (d, J = 10.5, 1H), 1.87-1.73 (m, 4H), 1.59-0.91 (m, H), 1.22 (s, 6H), 0.92 (d, J = 8.2 Hz, 3H), 0.91 (s, 3H), 0.64 (s, 3H); HRMS calcd for C29H51NaO3 (M + Na) + 484.3761, found 484.3762.

[0165] Synthesis of compound 42 Compound 41 (63.8 mg, 0.021 mmol) was dissolved in ultra-dehydrated methanol (5.0 mL), purged with argon, and cooled to 0°C. Acetyl chloride (0.01 mL, 0.140 mmol, 0.9 eq.) and ultra-dehydrated methanol (2.0 mL) were added and stirred at room temperature for 2 hours. The mixture was cooled to 0°C and quenched with water. The precipitated solid was collected by suction filtration to obtain compound 42 (71.7 mg, 0.161 mmol, quant.) as a white solid.

[0166] Compound 42: 1 H NMR (400 MHz, CDCl3) δ 3.66 (s, 3H), 2.39-2.31 (m, 1H), 2.25-2.17 (m, 1H), 1.94 (d, J = 11.4 Hz, 1H), 1.89-1.73 (m, 4H), 1.59-0.90 (m, 25H), 1.22 (s, 6H), 0.91 (d, J = 6.4 Hz, 3H), 0.91 (s, 3H), 0.64 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 174.84, 71.65, 60.39, 56.50, 55.89, 51.50, 51.23, 43.55, 42.70, 40.46, 40.15, 37.43, 35.89, 35.80, 35.34, 34.97, 34.68, 31.01, 30.97, 30.02, 29.97, 28.18, 27.40, 26.45, 24.17, 23.97, 21.07, 20.78, 18.24, 14.17, 12.01; HRMS calcd for C29H50NaO3 (M + Na) + 469.3652, found 484.3.655.

[0167] Synthesis of compound 4 Methylamine (40% methanol solution, 6.0 mL) was added to compound 42 (37.3 mg, 0.084 mmol), sealed and stirred at room temperature for 4 days. The solvent was removed using an evaporator, and methylamine (40% methanol solution, 6.0 mL) was added again, and the mixture was stirred at room temperature for 3 days and at 30°C for 4 days. The solvent was removed using an evaporator and the sample was dried to obtain a white solid crude. The product was purified by flash silica gel chromatography (AcOEt : n-Hexane = 2 : 1 → 1 : 0) and recrystallized from chloroform and n-hexane to obtain compound 4 (6.8 mg, 0.0152 mmol, 18%) as a white solid.

[0168] Compound 4: 1 H NMR (400 MHz, CDCl3) δ 5.38 (brs, 1H), 2.80 (d, J = 5.0 Hz, 3H), 2.23-2.19 (m, 1H), 2.08-2.02 (m, 1H), 1.94 (d, J = 11.4 Hz, 1H), 1.85-1.73 (m, 4H), 1.49-0.90 (m, 25H), 1.22 (s, 6H), 0.91 (d, J = 6.4 Hz, 3H), 0.91 (s, 3H), 0.63 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 174.19, 71.66, 56.51, 55.97, 51.23, 43.55, 42.70, 40.47, 40.17, 37.43, 35.89, 35.80, 35.52, 34.97, 34.68, 33.55, 31.82, 30.03, 29.96, 29.77, 28.24, 27.40, 26.45, 26.30, 24.17, 23.97, 20.78, 18.35, 12.02; HRMS calcd for C29H51NaO2 (M + Na) + 468.3796, found 468.3805.

[0169] Synthesis of compound 5 Ammonia (saturated methanol solution, 4.0 mL) was added to compound 42 (37.4 mg, 0.084 mmol), sealed and stirred at room temperature for 4 days. The solvent was removed using an evaporator, ammonia (saturated methanol solution, 4.0 mL) was added again, sealed and stirred at room temperature for 3 days and at 30°C for 4 days. The solvent was removed using an evaporator and dried to obtain a white solid crude. Compound 5 (18.3 mg, 0.0424 mmol, 51%) was obtained by purifying using gel permeation chromatography (CHCl3).

[0170] Compound 5: 1 H NMR (400 MHz, CDCl3) δ 5.36 (brs, 1H), 5.22 (brs, 1H), 2.32-2.25 (m, 1H), 2.15-2.07 (m, 1H), 1.95 (d, J = 11.4 Hz, 1H), 1.87-1.73 (m, 4H), 1.59-0.91 (m, 25H), 1.22 (s, 6H), 0.93 (d, J = 6.4 Hz, 3H), 0.91 (s, 3H), 0.64 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 175.82, 71.65, 56.50, 55.93, 51.22, 43.54, 42.72, 40.46, 40.17, 37.42, 35.89, 35.80, 35.45, 34.97, 34.67, 32.75, 31.59, 30.03, 29.96, 29.76, 28.25, 27.39, 26.45, 24.17, 23.96, 20.78, 18.33, 12.02; HRMS calcd for C28H49NaO2 (M + Na) + 454.3656, found 454.3649.

[0171] Synthesis of compound 43 Compound 41 (34.7 mg, 0.0802 mmol), O-benzylhydroxylamine hydrochloride (17.5 mg, 0.110 mmol, 1.4 eq.), N,N-diisopropylethylamine (13.6 mg, 0.105 mmol, 1.3 eq.), and 1-hydroxybenzotriazole monohydrate (12.8 mg, 0.0947 mmol, 1.2 eq.) were dissolved in ultra-dehydrated dichloromethane (9.0 mL) and left to stand for 10 minutes, after which N,N'-dicyclohexylcarbodiimide (20.6 mg, 0.0998 mmol, 1.2 eq.) was added and stirred for 23 hours and 30 minutes. The reaction solution was filtered, washed with 5% hydrochloric acid and saturated saline, dehydrated with sodium sulfate, and the solvent was removed by evaporation and sample drying to obtain a white solid crude. The residue was purified by silica gel chromatography (AcOEt:n-hexane = 2:3) and gel permeation chromatography (CHCl3) to give compound 43 (32.6 mg, 0.0606 mmol, 76%) as a white solid.

[0172] Compound 43: 1 H NMR (400 MHz, CDCl3) δ 7.81 (br, 1H), 7.39 (br, 5H), 4.91 (br, 2H), 1.94-1.73 (m, 5H), 1.49-0.93 (m, 27H), 1.22 (s, 6H), 0.91 (s, 3H), 0.89 (d, J = 6.4 Hz, 3H), 0.63(s, 3H); 13 C NMR (150 MHz, CDCl3) δ 171.63, 135.26, 129.22, 128.71, 128.58, 78.01, 71.62, 56.44, 55.84, 51.17, 34.39, 42.66, 40.41, 40.11, 37.37, 35.84, 35.74, 35.37, 34.92, 34.62, 31.38, 30.21, 29.98, 29.90, 29.72, 28.15, 27.34, 26.39, 24.11, 23.91, 20.73, 18.22, 11.98.

[0173] Synthesis of compound 6 Compound 43 (30.8 mg, 0.0572 mmol) was dissolved in ultra-dehydrated methanol (8.0 mL), palladium carbon (6.6 mg) was added, and the mixture was substituted with H2 and stirred at room temperature for 24 hours. After filtration through Celite using benzene, the solvent was removed using an evaporator and sample drying to obtain a crude red solid. The crude was purified by silica gel chromatography (AcOEt : n-hexane = 2 : 1) and gel permeation chromatography (CHCl3), and recrystallized from chloroform and n-hexane to obtain compound 6 (3.6 mg, 0.0080 mmol, 14%) as a white solid.

[0174] Compound 6: 1 H NMR (400 MHz, CDCl3) δ 5.37 (br, 1H), 5.28 (br, 1H), 2.32-2.24 (m, 1H), 2.17-2.07 (m, 1H), 1.96-1.93 (m, 1H), 1.87-1.73 (m, 4H), 1.51-0.96 (m, 25H), 1.22 (s, 6H), 0.93 (d, J = 6.4 Hz, 3H) 0.91 (s, 3H), 0.64 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 175.89, 71.59, 56.40, 55.82, 51.12, 43.44, 42.62, 40.36, 40.07, 37.33, 35.79, 35.70, 35.36, 34.87, 34.58, 32.67, 31.50, 29.93, 29.86, 29.67, 28.17, 27.30, 26.35, 24.08, 23.88, 20.68, 18.24, 11.93.

[0175] Synthesis of compound 44 Compound 41 (20.2 mg, 0.0467 mmol), glycine methyl hydrochloride (7.5 mg, 0.0597 mmol, 1.3 eq.), and N-methylmorpholine (12.5 mg, 0.123 mmol, 2.6 eq.) were dissolved in ultra-dehydrated dichloromethane (8.0 mL) and argon purged. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (11.6 mg, 0.0605 mmol, 1.3 eq.) was added and stirred at room temperature for 24 hours. Dichloromethane was added to dilute, washed with 2M hydrochloric acid and saturated saline, dehydrated with sodium sulfate, and the solvent was removed by evaporation and sample drying to obtain a white solid crude. The residue was purified by silica gel chromatography (CH2Cl2:MeOH = 19:1) to give compound 44 (19.4 mg, 0.0385 mmol, 83%) as a colorless, transparent oil.

[0176] Compound 44: 1 H NMR (400 MHz, CDCl3) δ 5.91 (br, 1H), 4.06 (d, J = 5.0 Hz, 2H), 3.77 (s, 3H), 2.35-2.27 (m, 1H), 2.18-2.10 (m, 1H), 1.96-1.94 (m, 1H), 1.87-1.74 (m, 4H), 1.52-0.96 (m, 25H), 1.23 (s, 6H), 0.93 (d, J = 6.4 Hz, 3H), 0.91 (s, 3H), 0.64 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 173.58, 170.52, 71.55, 56.40, 55.85, 52.29, 51.13, 43.45, 42.61, 41.07, 40.36, 40.07, 37.33, 35.79, 35.70, 35.36, 34.87, 34.58, 33.14, 31.46, 29.93, 29.86, 29.67, 28.13, 27.30, 26.35, 24.07, 23.87, 20.68, 18.23, 11.92.

[0177] Synthesis of compound 7 Compound 44 (17.6 mg, 0.0349 mmol) was dissolved in ethanol (5.0 mL), 15% (w / v) aqueous sodium hydroxide solution (1.0 mL) was added, and the mixture was stirred at room temperature for 3 hours. After the solvent was removed using an evaporator, concentrated hydrochloric acid (1.0 mL) was added. The resulting precipitate was suction filtered, washed with water, and the solvent was removed by drying to obtain a crude white solid. Compound 7 (7.6 mg, 0.0155 mmol, 44%) was obtained as a white solid by recrystallization with methanol and water.

[0178] Compound 7: 1 H NMR (400 MHz, DMSO) δ 8.05 (br, 1H), 3.97 (s, 1H), 3.67 (d, J = 5.5 Hz, 2H), 2.15-2.10 (m, 1H), 2.09-1.97 (m, 1H), 1.92-1.89 (m, 1H), 1.79-1.76 (m, 2H), 1.69-1.63 (m, 2H), 1.51-0.93 (m, 25H), 1.05 (s, 6H), 0.87 (s, 3H), 0.86 (d, J = 6.9 Hz, 3H), 0.60 (s, 3H); 13 C NMR (150 MHz, DMSO) δ 173.07, 69.49, 56.24, 55.75, 51.10, 43.28, 42.43, 37.40, 35.71, 35.55, 35.05, 34.66, 34.51, 31.63, 30.23, 29.61, 27.88, 27.27, 26.34, 24.03, 20.61, 18.47, 12.06.

[0179] Synthesis of compound 45 Compound 41 (19.6 mg, 0.0453 mmol), β-alanine methyl ester hydrochloride (7.5 mg, 0.0537 mmol, 1.2 eq.), and N-methylmorpholine (12.0 mg, 0.119 mmol, 2.6 eq.) were dissolved in ultra-dehydrated dichloromethane (8.0 mL) and argon purged. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (11.0 mg, 0.0574 mmol, 1.3 eq.) was added and stirred at room temperature for 23 hours. Dichloromethane was added to dilute, washed with 2M hydrochloric acid and saturated saline, dehydrated with sodium sulfate, and the solvent was removed by evaporation and sample drying to obtain a colorless, transparent, oily crude. The residue was purified by silica gel chromatography (CH2Cl2:MeOH = 19:1) to give compound 45 (21.9 mg, 0.0423 mmol, 94%) as a colorless, transparent oil.

[0180] Compound 45: 1 H NMR (400 MHz, CDCl3) δ 6.00 (br, 1H), 3.71 (s, 3H), 3.51 (q, J = 5.9 Hz, 2H), 2.54 (t, J= 5.7 Hz, 2H), 2.2.25-2.17 (m, 1H), 2.08-2.00 (m, 1H), 1.953-1.925 (m, 1H), 1.88-1.73 (m, 4H), 1.52-0.96 (m, 25H), 1.22 (s, 6H), 0.90 (s, 3H), 0.90 (d, J = 6.4 Hz, 3H), 0.63 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 173.52, 173.26, 71.61, 56.44, 55.90, 51.76, 51.17, 43.49, 42.64, 40.40, 40.11, 37.37, 35.84, 35.74, 35.41, 34.91, 34.62, 34.57, 33.74, 33.55, 31.63, 29.96, 29.90, 29.71, 28.17, 27.34, 26.39, 24.11, 23.91, 20.72, 18.26, 11.94.

[0181] Synthesis of compound 8 Compound 45 (19.3 mg, 0.0373 mmol) was dissolved in ethanol (5.0 mL), 15% (w / v) aqueous sodium hydroxide solution (1.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the solvent was removed using an evaporator, concentrated hydrochloric acid (1.0 mL) was added. The resulting precipitate was suction filtered, washed with water, and the solvent was removed by drying to obtain a crude white solid. Compound 8 (7.7 mg, 0.0153 mmol, 41%) was obtained as a white solid by recrystallization with ethanol and water.

[0182] Compound 8: 1 H NMR (400 MHz, DMSO) δ 7.82 (brt, J = 5.5 Hz, 1H), 3.96 (br,1H), 3.18 (q, J = 6.9 Hz, 2H), 2.30 (t, J= 6.9 Hz, 2H), 2.08-2.01 (m, 1H), 1.96-1.88 (m, 2H), 1.79-0.90 (m, 29H), 1.05 (s, 6H), 0.87 (s, 3H), 0.85 (d, J = 6.4 Hz, 3H), 0.59 (s, 3H); 13C NMR (150 MHz, DMSO) δ 172.60, 69.36, 56.09, 55.55, 50.95, 43.14, 42.48, 37.25, 35.57, 35.41, 34.96, 34.86, 34.51, 34.36, 34.21, 32.27, 31.58, 30.08, 29.47, 27.75, 27.12, 26.20, 23.89, 20.46, 18.32, 11.90.

[0183] Test Example 1: Cell differentiation induction assay in HL-60 cells (1) The compound (24R)-1 and compound (24S)-1 of Example 1 were examined for their cell differentiation-inducing activity against human acute promyelocytic leukemia cells HL-60. Activated vitamin D3 was used for comparison.

[0184] The assay for cell differentiation induction was performed in the same manner as described in "4.3.1. Assay of HL-60 cell differentiation-inducing activity" in Fujii et al. Bioorg. Med. Chem. 22 (2014) 5891-5901. Specifically, the assay was as follows.

[0185] HL-60 cells were cultured in RPMI-1640 medium supplemented with 5% FBS (fetal bovine serum), penicillin G, and streptomycin at 37°C and 5% CO. Cells were cultured at 8.0 × 10 4 The test compound was diluted to a final concentration of 10 -10 ~10 -51α,25-dihydroxyvitamin D3 was added to the cells at 100 mM. Control cells were treated with the same volume of ethanol alone. 1α,25-dihydroxyvitamin D3 was assayed simultaneously as a positive control. Cells were incubated at 37°C and 5% CO2 for 4 days. The percentage of differentiated cells was measured by measuring the reduction potential of nitroblue tetrazolium (NBT). Cells were incubated for 20 min at 37°C in an equal volume of RPMI-1640 (5% FBS) and phosphate-buffered saline (PBS) containing NBT (0.2%) and 12-O-tetradecanoylphorbol 13-acetate (TPA; 200 ng / mL). The percentage of cells containing blue-black formazan was measured in a minimum of 200 cells. The percentage (%) of differentiated cells calculated from the NBT reducing activity is shown in FIG.

[0186] As can be seen from the results in FIG. 1, compound (24R)-1 and compound (24S)-1 of Example 1 of the present invention have a high differentiation-inducing effect on HL-60 cells, similar to active vitamin D3.

[0187] Test Example 2: Cell differentiation induction assay in HL-60 cells (2) The compound (24R, 25R)-2, compound (24R, 25S)-2, compound (24S, 25R)-2, and compound (24S, 25S)-2 of Example 2 were examined for their cell differentiation induction effect on human acute promyelocytic leukemia cell HL-60. The method was similar to that of Test Example 1. Activated vitamin D3 was used for comparison. The results are shown in Figures 2 and 3.

[0188] As can be seen from the results of Figures 2 and 3, compound (24R,25R)-2, compound (24R,25S)-2, compound (24S,25R)-2, and compound (24S,25S)-2 of Example 2 of the present invention have a high differentiation-inducing effect on HL-60 cells, similar to active vitamin D3.

[0189] Test Example 3: Cell differentiation induction assay in HL-60 cells (3) The cell differentiation induction activity of compound 3, compound 4, and compound 5 in Example 3 against human acute promyelocytic leukemia cell HL-60 was examined. The method was similar to that in Test Example 1. For comparison, active vitamin D3 was used. The results are shown in FIG.

[0190] As can be seen from the results in FIG. 4, compound 3, compound 4, and compound 5 of Example 3 of the present invention have a high differentiation-inducing effect on HL-60 cells, similar to active vitamin D3.

Claims

1. A compound represented by the following general formula (I), or a salt thereof: 【Chemistry 1】 (In the formula, R １ and R ２ each independently represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms; n represents an integer of 1 to 3; X represents -C(=O)NH-Z or -CH(OH)-(Y) ｍ -CH(OH)R ３ Z represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or a hydroxyl group, and Y represents -C(R ４ ) (R ５ )-, -C(=O)-, or -C(=CH ２ )-, and m is an integer of 0 to 3. ３ , R ４ and R ５ Each of Z and R independently represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms. ３ , R ４ and R ５ The alkyl group having 1 to 8 carbon atoms represented by may have a substituent selected from a carboxyl group or a hydroxyl group.

2. The compound according to claim 1, wherein X represents -C(=O)NH-Z (wherein Z has the same definition as in claim 1), or a salt thereof.

3. The compound or salt thereof according to claim 2 , wherein Z is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkoxyl group having 1 to 8 carbon atoms.

4. X is -CH(OH)-(Y) ｍ -CH(OH)R ３ (Wherein, Y, m, and R ３ The compound according to claim 1, wherein the definition of is as defined in claim 1, or a salt thereof.

5. Y is -CH ２ The compound according to claim 4, or a salt thereof, wherein

6. R ３ The compound or salt thereof according to claim 4 or 5, wherein is a hydrogen atom.

7. R １ and R ２ The compound according to any one of claims 1 to 6, or a salt thereof, wherein is methyl.

8. 8. The compound according to claim 1 , or a salt thereof, wherein n is 1.

9. Any of the following compounds or salts thereof: 【Chemistry 2】

10. A medicament comprising a compound according to any one of claims 1 to 9, or a salt thereof.

11. A vitamin D receptor activator comprising the compound according to any one of claims 1 to 9 or a salt thereof.

12. A preventive and / or therapeutic agent for a vitamin D receptor-associated disease, comprising the compound according to any one of claims 1 to 9 or a salt thereof.

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