WO2004067504A1

WO2004067504A1 - 2-substituted vitamin d derivative

Info

Publication number: WO2004067504A1
Application number: PCT/JP2004/001003
Authority: WO
Inventors: Hiroaki Takayama; Atsushi Kittaka; Toshie Fujishima; Nozomi Saito
Original assignee: Chugai Seiyaku Kabushiki Kaisha
Priority date: 2003-01-31
Filing date: 2004-02-02
Publication date: 2004-08-12

Abstract

A novel vitamin D derivative. It is a compound represented by the general formula (1); wherein R1 represents optionally hydroxylated, linear or branched C3-8 alkyl or optionally hydroxylated, linear or branched C3-8 alkenyl; and R2 represents optionally hydroxylated, linear or branched C1-12 alkyl.

Description

Specification

2-substituted vitamin D derivative

Technical field

The present invention relates to novel vitamin D derivatives, and more particularly, to novel 2-substituted-19-norvitamin D derivatives and 2-substituted vitamin D derivatives.

Background art

Active vitamin D ₃ (l, 25-dihydroxy itamin D ₃ ) is known to have many physiological activities, including calcium metabolism regulation, tumor cell growth suppression, differentiation induction, and immunomodulation. I have. However, active vitamin D ₃ is liable to cause hypercalcemia due to long-term and continuous administration, so that it has been difficult to use it as an antitumor agent, an antirheumatic agent or the like. Therefore, the synthesis of a number of vitamin D derivatives has been studied for the purpose of separating these actions.

10, 19 Ekisomechiren Torisa from structure of active bi evening Min D 3 ivy 1 alpha, 25-dihydroxy-19-Bruno Le vitamin _{D 3 (1, 25-di} ydroxy-19-norvitamin D 3) , the cells It is a compound with low calcium action (bone calcification activity) while retaining the ability to induce differentiation. However, 1, 25-dihydroxy-19-Norubi glutamic 0 ₃ of VDR binding activity is lower and approximately 30 active vitamin D _3, has been desired to develop a more VD R binding activity is higher compounds.

According to previous studies by the present inventors, it has been found that the introduction of a di-methyl group into the A-ring portion of active vitamin D ₃ increases the vitamin D receptor (VDR) binding ability by a factor of half. Leno Konno, K. et al. J. Med. Cem. 2000, 43, 4247; Suhara, Y. et al. J. Org. Chem. 2001, 66, 6760; Kittaka, A. et al. Org. Lett. 2000, 2, 2619.). To date, vitamin D derivatives and 19-norvitamin D derivatives containing various substituents at the 2-position have been synthesized (Sicinski RR, Perlman K.L., DeLuca H.F., J. Med. Chem., 1994, 37, 3730-3738 .; Sicinski RR, Prahl JM, Smith CM, DeLuca HF, J. Med. Chem., 1998, 41, 4662-4674 .; Sicin ski RR, Rotkiewicz P., Kolinskx A., Sicinska W., Prahl J.

M., Smith C .., DeLuca H.F., J. Med. Chem., 2002, 45, 336 6-3380; Akihiro Yoshida et al., Abstracts of the 121st Annual Meeting of the Pharmaceutical Society of Japan 3, p. 17, 29 [PB] II-014, 2001; Yukiko Iwasaki et al. Abstracts of the 122nd Annual Meeting 2, p.180, 28 [P] I-183, 2002; Akihiro Yoshida et al., Abstracts of the 122nd Annual Meeting of the Pharmaceutical Society of Japan, p.180, 28 [P] I-184, 2002 Year; Masato Shimizu et al., The 54th Annual Meeting of the Vitamin Society of Japan, Abstracts, Vitamins, 2002, 76, 155-156, 025, 2002; Masato Shimizu et al., 28th Symposium on Advances in Reactions and Synthesis, 2002 ( Tokyo), pp 234-235; Toshie Fujishima et al., The 122nd Annual Meeting of the Pharmaceutical Society of Japan 2, p.381, 28 [P] 1-186 (Chiba; 2002;).

However, there has been no report on the synthesis of a 19-norvitamin D derivative having a functional group of three or more carbon atoms at the 2-position or a vitamin D derivative having a spiro ring at the 2-position, and its physiological activity has not been studied.

Disclosure of the invention

That is, an object of the present invention is to synthesize and provide a novel 2-substituted -19-norubimin D derivative or a 2-substituted vitamin D derivative. Another object of the present invention is to evaluate the biological activity of the synthesized 2-substituted-19-norvitamin D derivative or 2-substituted vitamin D derivative.

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, a 19-norvitamin D derivative having a functional group of tricarbon or more at the 2-position and a vitamin D derivative having a spiro ring at the 2-position Having learned that the intended purpose was achieved, the present invention was completed.

That is, according to the present invention, general formula (1):

Represents a substituted C ₃ also show good straight or branched chain optionally ₈ alkyl group or a hydroxyl group in a straight optionally substituted or branched C ₃ _ ₈ cycloalkenyl group with a hydroxyl group;

R ₂ represents a linear or branched C i-alkyl group which may be substituted with a hydroxyl group)

Is provided.

In the general formula (1), preferably, a linear or may be substituted by a hydroxyl group or branched C ₃ _ ₅ alkyl group or a straight-chain may be substituted with a hydroxyl group or branched C represents ₃ _ ₅ alkenyl group, 'R ₂ is a linear optionally substituted with a hydroxyl group or branched C ₃ _. Represents an alkyl group.

More preferably, 1 ^ is substituted by a hydroxyl group may linear or branched also C ₃ _ ₄ alkyl group linear substituted or with or hydroxyl branched C ₃ _ ₄ alkenyl It represents a group, R ₂ represents a straight chain may be substituted with a hydroxyl group or branched C _5. ₈ alkyl group.

More preferably, represents a linear or branched C ₃ alkyl group optionally substituted with a hydroxyl group or a linear or branched C ₃ alkenyl group optionally substituted with a hydroxyl group, ₂ represents a 4-hydroxy-4-methylpentyl group.

According to another aspect of the invention, the general formula (2):

Equation (2)

(Where:

R ₃ and R _4, together a connexion to form optionally substituted C ₃ _ ₆ spirocyclic § alkyl group;

R 5 represents a linear or branched alkyl group which may be substituted with a hydroxyl group)

Is provided.

Preferably, in the general formula (2), R ₃ and R _4, together a connexion, a C ₃ _ ₅ spirocyclic alkyl groups of the non-replacement form, R ₅ may be substituted by a hydroxyl group It represents a linear or branched C ₅ _ ₈ alkyl group.

According to still another aspect of the present invention, there is provided a pharmaceutical composition comprising the compound represented by the general formula (1) or (2). Such a pharmaceutical composition preferably contains a pharmaceutically acceptable carrier or diluent together with the compound represented by the general formula (1) or (2). BEST MODE FOR CARRYING OUT THE INVENTION

Japanese Patent Application No. 2003-242, which is the application on which the priority claimed by the present application is based.

No. 25 is fully incorporated herein by reference.

Hereinafter, embodiments of the compound represented by the general formula (1) and the method of the present invention will be described in more detail.

In the present invention, "vitamin D derivative" refers to 9,10-seco-5,7,10 9)-

Four Refers to a compound having a restatriene structure. In the present invention, "19-nor-1,2,5-dihydroxyvitamin D derivative" refers to a compound having a 9,10-seco-5,7,10 (19) -cholestatriene structure and a 10 (19) -exomethylene A compound from which a group has been removed is meant.

In the definition of the general formula (1) of the present invention, "good not straight or even be substituted by a hydroxyl group branched c ₃ - ₈ alkyl" refers to carbon unsubstituted or hydroxyl is substitution It means a linear or branched alkyl group of the number 3 to 8. The number of carbon atoms is preferably from 3 to 5, more preferably from 3 to 4. Examples of the unsubstituted linear or branched alkyl group having 3 to 8 carbon atoms include n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, and t. -Butyl group, and linear and branched pentyl groups, hexyl groups, heptyl groups, octyl groups and the like. In addition, the straight-chain or branched-chain alkyl group having 3 to 8 carbon atoms substituted with a hydroxyl group refers to any hydrogen atom of the above-described unsubstituted straight-chain or branched-chain alkyl group having 3 to 8 carbon atoms. Is substituted with a hydroxyl group, for example, a hydroxypropyl group, a hydroxybutyl group, a hydroxypentyl group, a hydroxyhexyl group, a hydroxyheptyl group, a hydroxyoctyl group and the like. In the definition of the general formula (1) of the present invention, "a hydroxyl group but it may also be substituted with a straight-chain or branched C ₃ _ ₈ alkenyl group", the number of carbon atoms which is substituted by unsubstituted or hydroxyl It means 3 to 8 linear or branched alkenyl groups having at least one double bond. The number of carbon atoms is preferably from 3 to 5, more preferably from 3 to 4. Examples of the unsubstituted linear or branched alkenyl group having 3 to 8 carbon atoms include an aryl group, an n-butenyl group, a sec-butenyl group, a pentenyl group, a heptenyl group and an octenyl group. Further, the straight-chain or branched alkenyl group having 3 to 8 carbon atoms substituted with a hydroxyl group is any of the unsubstituted straight-chain or branched alkynyl groups having 3 to 8 carbon atoms described above. The hydrogen atom is substituted with a hydroxyl group, and examples thereof include a hydroxyaryl group, a hydroxybutenyl group, a hydroxypentenyl group, a hydroxyheptenyl group, and a hydroxyoctenyl group. In particular, n-propyl, n-butyl, linear pentyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, aryl, n-butenyl, pentenyl, hydroxyaryl And n-propyl, n-butyl, hydroxypropyl, hydroxybutyl, aryl, n-butenyl and hydroxyaryl groups. And a hydroxybutenyl group.

In the definition of R ₂ , “a straight-chain or branched-chain alkyl group which may be substituted with a hydroxyl group” is a straight-chain or branched-chain alkyl group having 1 to 12 carbon atoms, which is unsubstituted or substituted with a hydroxyl group. Means Preferably it has 3 to 10 carbon atoms, more preferably 5 to 8 carbon atoms, and even more preferably 7 carbon atoms. Examples of the unsubstituted linear or branched alkyl group having 1 to 12 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an s-butyl group, Examples thereof include an i-butyl group, a t-butyl group, a linear and branched pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decanyl group. In addition, the straight-chain or branched-chain alkyl group having 1 to 12 carbon atoms substituted by a hydroxyl group means any hydrogen atom of the above-mentioned unsubstituted straight-chain or branched-chain alkyl group having 1 to 12 carbon atoms. Is substituted with a hydroxyl group, for example, hydroxymethyl group, hydroxyethyl group, hydroxybutyl group, hydroxypropyl group, hydroxypentyl group, hydroxyhexyl group, hydroxyheptyl group, hydroxyoctyl group, hydroxy Nonyl group, hydroxydecanyl group, 4-hydroxy-4-methylpentyl group, 1,4-dihydroxy-4-methylpentyl group, 4-ethyl-4-hydroxyhexyl group, 6-hydroxy-6-methyl-2 -Heptyl group, 7-hydroxy-7-methyl-2-octyl group, 5,6-dihydroxy-6-methyl-2-heptyl group and the like. Preferably, R ₂ is a 4-hydroxy-4-methylpentyl group.

The configuration at the 2-position in the general formula (1) of the present invention may be an R configuration or an S configuration.

Specific compounds among the compounds of the general formula (1) of the present invention include the following. ₍

Formula (2) R ₃ and R ₄ of the "optionally substituted C ₃ - ₆ scan pyromellitic cyclic alkyl group" in the definitions refers to unsubstituted or substituted spirocyclic alkyl group 3-6 carbon atoms Means The number of carbon atoms is preferably from 3 to 5, more preferably from 3 to 4. An unsubstituted spirocyclic alkyl group having 3 to 6 carbon atoms Examples thereof include a spirocyclopropyl group, a spirocyclobutyl group, a spirocyclopentyl group, and a spirocyclohexyl group. Further, the substituted spirocyclic alkyl group having 3 to 6 carbon atoms refers to an unsubstituted spirocyclic alkyl group having 3 to 6 carbon atoms in which at least one hydrogen atom is substituted, Examples of the group include a halogen atom, a hydroxy group, an alkyl group, and a hydroxyalkyl group.

In the definition of R ₅ 'may be substituted by a hydroxyl group may linear or branched ^ ₂ alkyl group "and, of has been C1-12 unsubstituted or substituted with a hydroxyl group linear or branched It means an alkyl group. Preferably it has 3 to 10 carbon atoms, more preferably 5 to 8 carbon atoms, and even more preferably 7 carbon atoms. Examples of the unsubstituted linear or branched alkyl group having 1 to 12 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an s-butyl group, Examples thereof include an i-butyl group, a t-butyl group, a linear and branched pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decanyl group. In addition, the straight-chain or branched-chain alkyl group having 1 to 12 carbon atoms substituted by a hydroxyl group means any hydrogen atom of the above-mentioned unsubstituted straight-chain or branched-chain alkyl group having 1 to 12 carbon atoms. Is substituted with a hydroxyl group, for example, hydroxymethyl group, hydroxyethyl group, hydroxybutyl group, hydroxypropyl group, hydroxypentyl group, hydroxyhexyl group, hydroxyheptyl group, hydroxyoctyl group, hydroxy Nonyl group, hydroxydecanyl group, 4-hydroxy-4-methylpentyl group, 1,4-dihydroxy-4-methylpentyl group, 4-ethyl-4-hydroxyhexyl group, 6-hydroxy-6-methyl- 2-heptyl group, 7-hydroxy-7-methyl-2-octyl group, 5,6-dihydroxy-6-methyl-2-heptyl group and the like. Preferably, R ₅ is a 4-hydroxy-4-methylpentyl group.

In the general formula (2) of the present invention, the 1, 2, and 3 configuration may be R configuration or S configuration, respectively.

Specific compounds among the compounds of the general formula (2) of the present invention include the following. It is.

The compound represented by the general formula (1) or (2) of the present invention can also be used as an active ingredient of a pharmaceutical composition (for example, a calcium metabolism regulator or the like).

The compound of the present invention is preferably formulated into an appropriate dosage form together with a pharmaceutically acceptable carrier, excipient, disintegrant, lubricant, binder, flavor, coloring agent and the like, and used in such a form. Dosage forms include tablets, granules, fine granules, capsules, powders, injections, solutions, suspensions, emulsions, transdermal absorbers, suppositories, and the like.

The administration route of the compound of the present invention is not particularly limited, and may be oral administration or parenteral administration (intravenous administration, intramuscular administration, intraperitoneal administration, transdermal administration, etc.).

The dose of the compound of the present invention can be appropriately selected depending on the target disease, patient condition, body weight, constitution, age, sex, administration route, dosage form, and the like. Range of 0.000 l g-0.lg per day, preferably 0.0 1 βg, the upper limit of the dose is lOO g- 100 per adult per day

The dose can be selected within the range of 0,000 g, preferably within the range of 200 g-1000 g, and can be administered in 1 to 3 times a day.

The compound represented by the general formula (1) of the present invention is a novel compound, and its synthesis method is not limited. For example, it can be synthesized as shown in the following schemes 1 to 3.

The A ring precursor of the compound of the general formula (1) can be synthesized by a method as shown in Scheme 1.

(-)-Quinic acid is used as a starting material in order to obtain final compounds having the desired stereochemical configuration at the 1- and 3-positions, respectively. First, the hydroxyl group at the starting material is esterified, and both hydroxyl groups at the 3- and 5-positions of quinic acid are protected with bulky silyl-type protecting groups (tert-butyldimethylsilyl group, triethylsilyl group, etc.). At this time, since the protecting group cannot be attached to the 4-position due to the steric hindrance of the protected hydroxyl groups at the 3- and 5-positions, the 4-position hydroxyl group is imidazolylthiocarbonylated (or even if it is phenoxythiocarbonylated). Good) Then, a C 4 carbon radical is generated by a tin radical (heating AIBN-aryl tributyltin), and an aryl group is introduced at the 4-position by a radial coupling with the aryl tin. The resulting compound is subjected to a high-end portation to convert the 4-position to a hydroxypropyl group. Or, resulting 1-position of the functional groups in the compounds and diol was reduced with N a BH ₄ (or not good even L i A 1 H _4), then oxidatively cleaved with sodium periodate Alternatively, the aryl group at the 4-position may be hydrogenated to be converted to a propyl group. Scheme 1

The CD ring precursor of the compound of the general formula (1) can be synthesized from a 25-hydroxygrandmanketone compound by a method as shown in Scheme 2. That is, the hydroxyl group at the 25-position of the 25-hydroxygrandmanketone is methoxymethylated (or may be trimethylsilylated), and the 8-position is ethoxylated with ethylethyl phosphonoacetate. The obtained ester was reduced by DI BAL-H, and the obtained aryl alcohol was dehydrated and condensed with 2-mercaptobenzothiazole by Mitsunobu reaction, and then subjected to an oxidation reaction using Mo catalyst-hydrogen peroxide water. As a sulfone, a CD ring precursor is obtained.

The 25-hydroxygrandmanketone compound can be synthesized by ozonolysis of a known vitamin D derivative having a desired CD ring (Sandina, FJ, Mourino, S., Castedo, L., J. Org. Chem., 1986, 51, 1264-1269 .: Kiegiel, J., Wovkulic, PM, Uskokovic, M.R.Tetrahedron Lett., 1991, 32, 6057-6060 .: Fernadez, B., Pe rez , J. A. Grana, J. R., Castefo, L., Mourino, A., J. Org. Chem., 1992, 57, 3173-3178 .: Fujishima, T., Konno, K. , Nakaga wa, K., Kurobe, M., Okano,., Takayama, H., Bioogr. Med. Chem., 2000, 8, 123-134.)

The desired compound of the present invention can be obtained by coupling the synthesized A-ring precursor and CD-ring precursor with a Ju1ia-type coupling by the method shown in Scheme 3. Scheme 3

In general, if the coupling reaction is carried out without protecting the hydroxyl group at position 25, the yield will decrease. Therefore, the hydroxyl group at position 25 of the CD ring precursor is replaced with an acyl group, a substituted silyl group, or a substituted alkyl group. It is preferable to protect with a suitable protecting group such as a triethylsilyl group and a methoxymethyl group. The CD ring precursor is treated with a strong base (such as butyl lithium) and reacted with the A ring precursor. The obtained protected product is subjected to a deprotection operation, and purified by a conventional method such as reverse phase HPLC or thin layer chromatography to obtain the desired compound. Alternatively, the protected product may be subjected to deprotection after purification, and then further purified.

The compound represented by the general formula (2) of the present invention is a novel compound and its synthesis method is not limited at all. For example, it can be synthesized as shown in the following scheme 4 or schemes 5 and 6. it can.

Starting materials include commercially available 1,1-bis (hydroxymethyl) cyclopropane (Aldrich, etc.) ゃ Jetyl 1,1-cycloalkanecarboxylate, for example, getyl 1,1-cyclobutanecarboxylate (4-membered ring, Wako Pure Chemical Industries, Ltd.) Medicine) Ethyl 1,1-cyclopentanecarboxylate (5-membered ring), getyl 1,1-cyclohexanecarboxylate (6-membered ring, Wako Pure Chemical Industries) and the like can be used. One of the hydroxyl groups of 1,1-bis (hydroxymethyl) cycloalkane is protected to form a protected P-methoxybenzyl ether, which is then subjected to TPAP oxidation to form an aldehyde. This aldehyde is reacted with vinylmagnesium bromide to produce an aryl alcohol derivative. After the secondary hydroxyl group is silylated, the protecting group on the primary hydroxyl group is deprotected to give an alcohol. This alcohol is subjected to TPAP oxidation or the like to form an aldehyde, which is then reacted with arenylmagnesium bromide to form a desired eneine form, and its secondary hydroxyl group is silylated to form an A ring part precursor.

A compound having a vitamin D skeleton having a cycloalkane at the 2-position can be obtained by reacting the obtained A-ring part precursor with a CD-ring promoter in a suitable solvent using palladium. . The obtained compound is subjected to a deprotection operation, and is separated and purified by a conventional method such as reverse phase HPLC or thin layer chromatography to obtain a target vitamin D derivative.

Scheme 4

HC T OH 1) NaH PMBO ^ "OH TPAP / NMO PMBO

2) PMBCI 4AMS

A DMF CH2CI2

2,6-lutidine

toluene CH2CI2

DDQ

4AMS

CH2CI2

MgBr

2,6-lutidine

ether CH2CI2

Here, as the compound of the CD ring portion of the vitamin D derivative, a known compound such as (E) -de-A, B-8- (bromomethylene) cholestan-25-ol can be used. Alternatively, starting from a known CD ring compound, the desired A CD ring compound may be obtained. Alternatively, it can be synthesized from a known vitamin D derivative having a side chain corresponding to a desired _CD ring compound. Example

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

In the following examples, the following abbreviations were used.

MeOH: methanol

TsOH: P-toluenesulfonic acid

Et ₃ N: Triethylamine

DMF: dimethylformamide

TBSC1: tert-butyresimetizoresilizolechloride

AcOEt: Ethyl acetate

AIBN: 2,2'-azobisisobutyronitrile

EtOH: Ethanore

Pd-C: Palladium on carbon

MOMC1: Methoxymethyl mouth lid

DIEA: Disopropylethylamine

DIBAL-H: diisobutyl aluminum hydride

PPh3: Triphenyl phosphine

L1HMDS: lithium bis (trimethylsilyl) amide

CSA: camphorsulfonic acid

PMBC1: P-methoxybenzyl chloride

4A MS: Molecular sieve 4A

NMO: N-methylmorpholine N-oxide

TPAP: Tetrapropylammonium Pearl Tenate

TBSOTf: tert-butyldimethylsilyl trifluoromethanesulfonate DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone

TBAF: Tetrabutylammonium fluoride

Reagents and solvents were used as purchased after purchase, unless otherwise noted.

Nuclear magnetic resonance spectra were measured using J EOL AL-400 or J E〇L EC P-600.

EIMS and HREIMS were measured by the £ 1 method using JEOL JMS-SX 1028.

Infrared absorption (IR) was measured with JASCO FT-IR 8000.

Ultraviolet absorption (UV) was measured with Shimadzu UV-1600.

Optical rotations were measured with JASCO DIP-370.

Silica gel column chromatography used Merck silica gel 60 (Merck sili ca gel 60 70-230 mesh). For preparative thin-layer chromatography, Merck silica gel 5744 was used.

Recycling reversed phase HPLC was performed at a flow rate of 9.9 mL / min using a YMC-pac ODS column (20 x 150 mm) and a Waters 510 HP LC pump. Waters 484 t unab le ab b or b ba n c e de t e c t or was used for detection.

(Example 1) Methyl ^{(1R, 3R, 4S, 5} R) - 3, 5 - bis [(tert- butyldimethylsilyl) Okishi] -1,4-hexane Cal poke Sile one Bok to dihydroxycyclobuta (methy 1 ( lR, 3R, 4S, 5R) -3,5-Bis [(tert-butyldimethylsilyl) oxy] -1,4-dihydroxycyclohexanecarboxylate compound 4)

(-) - quinic acid (1.92 g 10 ol) was dissolved in _{MeOH (30 mL), TsOH'H 2} 0 a (57 mg 0.3 mmol) was added, followed by stirring at room temperature for 1 day. Et ₃ N (2 mL) was added to the reaction solution to stop the reaction, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was dissolved in dehydrated DMF (10 mL), Et ₃ N (5.6 mL 40 mmol) and TBSC1 (3.77 g 25 mmol) were added in that order, and the mixture was stirred at room temperature for 1 day. The reaction solution was poured into a saturated aqueous solution of NH ₄ C1 and extracted with AcOEt. Saturate organic layer NH ₄ C1 aqueous solution The mixture was washed with a saturated saline solution and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / AcOEt = 6: 1) to obtain 3.91 g of Compound 4 (yield 90%).

[a] ² _D ² -32.2 (σ 1.00, CHC1 ₃ )

^{_{X HR (400 MHz, CDC1 3}} ) δ 0.07 (s, 3H), 0.08 (s, 3H), 0.12 (s, 3H), 0.13 (s, 3H), 0.87 (s, 9H), 0.89 (s, 9H ), 1.89 (dd, J = 10.0, 13.2 Hz, 1H), 1.98 (ddd, J = 2.3, 4.5, 14.3 Hz, 1H), 2.06 (dd, J = 2.6, 14.3 Hz, 1H), 2.15 (ddd, J = 2.3, 4.5, 13.2 Hz, 1H), 2.33 (br.s, 1H) 3.40 (dd, J = 2.6, 8.2 Hz, 1H), 3.73 (s, 1H), 4.08 (ddd, J = 4.5, 8.2 , 10.0 Hz, 1H), 4.34 (dt, J = 4.5, 2.6 Hz, 1H), 4.48 (br.s, 1H).

^{1 3 C NMR (100 MHz,} CDC1 3) δ -5.2, -4.9, -4.7, -4.4, 17.9, 18,0, 25.6, 25.7, 37.7, 42.4, 52.5, 68.5, 71.3, 75.8, 76.0, 173.9. IR (neat) 3465, 2955, 2932, 2896, 2859, 2359, 2342, 1742, 1472, 1256, 1098, 1055, 1017, 938, 903, 880, 837, 779, 671 cm ^-1 .

(Example 2) Methyl (1R, 3R, 4S, 5R) -3,5-bis [(tert-butyldimethylsilyl) oxy]-1 -hydroxy-4-[(1 -imidazolylcarpotioyl) oxy

] Cyclohexanecarboxylyl (Methyl (lR, 3R, 4S, 5R) -3,5-Bis [(t ert-butyldimethylsilyl) oxy 1-1 -hydroxy- 4-[(1-imidazolylcarbo thioyl) oxy ] cyclohexanecarboxylat e

The diol compound 4 (2.34 g, 5.38 mmol) was dissolved in dehydrated THF (18 mL), thiocarbonyl-1,1'-diimidazole (1.25 g, 7.01 mmol) was added, and the mixture was stirred and stirred at 80 ° C. The mixture was heated under reflux for 11 hours. After returning to room temperature, the solvent was distilled off under reduced pressure, and the mixture was subjected to silylation gel column chromatography (hexane: AcOEt = 2: 1).

) To give 2.595 g of Compound 5 (88% yield).

[] ² _D ² -41.5 (c 1.00, CHC1 ₃ )

^{X H NMR (400 MHz, CDC1} 3) δ -0.11 (s, 3H), 0.01 (s, 3H), 0.07 (s, 3H), 0.09 (s, 3H), 0.77 (s, 9H), 0.90 (s , 9H), 2.00 (dd, J = 9.8, 13.5 Hz, 1H), 2.08 (ddd, J = 3.0, 4.3, 14.7 Hz, 1H), 2.27 (dd, J = 2.2, 14.7 Hz, 1H), 2.32 ( ddd, J = 3.0, 4.7, 13.5 Hz, 1H), 3.80 (s, 3H), 4.43 (br.s, 1H), 4.57 (dt, J = 4.7, 9.8 Hz, 1H), 4.64-4.66 (m, 1H), 5.51 (dd, J = 2.6, 4.7 Hz, 1H), 7.05 (s, 1H), 7.64 (s, 1H), 8.37 (s, 1H).

^{1 3 C NMR (100 MHz,} CDC1 3) δ -5.6, -4.8, -4.6, -4.0, 17.8, 17.9, 25.5, 25.6, 25.7, 37.9, 43.7, 52.8, 65.2, 68.8, 75.5, 86.5, 117.7, 130.8, 137.0, 173.1, 183.6.

IR (neat) 3135, 2955, 2932, 2889, 2859, 1744, 1472, 1389, 1335, 1287, 1250, 1233, 1105, 1061, 999, 947, 903, 862, 837,

487.1754, found 487.1751.

(Example 3) Methyl ^{^{(1R, 3 R, 4 RS}} , 5 R) _ 4 _ Ariru - ^3, ⁵ - bis [(tert- Petit Le butyldimethylsilyl) Okishi] -1-hexane carboxylates one Bok to hydroxycyclopentyl (

Methyl (1R, 3R, 4RS, 5R) -4 -Allyl -3,5-bis [(tert-butyldimethylsilyl) oxy]-1-ydroxycyclohexanecarboxylate>

Compound 5 (1.53 g, 2.82 mmol) was dissolved in dehydrated benzene (4 mL), tributyltin (1.9 mL, 8.46 mmol) was added, and the mixture was heated under reflux. There dehydrated benzene

AIBN (462 mg, 2.81 mmol) dissolved in (10 mL) was added dropwise over 3 hours. After heating under reflux for another 3 hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / AcOEt = 10: 1) to give Compound 6.

775 mg (60 yield) were obtained.

^{X H NMR (400 MHz, CDC1} 3) major isomer: δ 0.06 (s, 3H), 0.08 (s, 3H), 0.10 (s, 3H), 0.88 (s, 9H), 1.7-1.8 (m, 3H) , 1.9- 2.0 (m, 2H), 2.09 (dd, J = 1.8, 9.8 Hz, 1H), 2.59 (dm, J = 9.8 Hz, 1H), 3.77 (s, 3H), 4.2-4.3 (m, 1H ), 4.4-4.5 (m, 1H), 4.79 (s, 1H), 5.0-5.1 (m, 2H), 5.7-5.8 (m, 1H) .minor isomer: 3.76 (s, 3H).

IR (neat) 3484, 2955, 2930, 2859, 1740, 1642, 1464, 1389, 1362, 1256, 1103, 876, 837, 777, 669 cm " ¹ .

EIMS = 361 (M ⁺ ^-t Bu).

HREIMS calcd for Ci ₉ H ₃₇ 0 ₅ Si ₂ (M ⁺ -^ u) 401.2180, found 401.2186.

(Example ^{4) (1R, 3 R,} 4 RS, SR) - 4 - Ariru - ^3, ⁵ - bis [(tert - Buchirujime Chirushiriru) Okishi] -1-hydroxymethyl - cyclohexane - 1 - ol (( 1R,

3R, 4RS, 5R)-4 -Allyl-3, 5 -bis [(tert -butyldimethylsilyl) oxy]-1-hy dr oxymethy 1 -cyclohexan-l-ol compound 7)

Compound 6 (1.52 g, 3.31 mmol) as an ester was dissolved in EtOH (30 mL), NaBH ₄ (375 mg, 9.93 ol) was added at 0 ° C, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into saturated NH ₄ C1 solution and extracted with CH ₂ C1 _2. The organic layer was washed with saturated saline, dried over anhydrous MgSO _4. The solvent was evaporated under reduced pressure, silica gel column chromatography (hexane / AcOEt = 5: 1) to give Compound 7 1. ² 9 g (yield: ⁹ 1) was obtained.

^{1 H MR (600 MHz, CDC1} 3) δ 0.06 (s, 3H), 0.07 (s, 3H), 0.09 (s, 6H), 0.89 (s, 9H), 0.90 (s, 3H), 1.5-1.8 ( m, 4H), 1.9- 2.2 (m, 3H), 2.55 (dm, J = 14.4 Hz, 1H), 3.31 (d, J = 11.1 Hz, 1H), 3.44 (d, J = 11.1 Hz, 1H), 4.1-4.2 (m, 1H), 4.46 (dt, J = 11.4, 4.8 Hz, 1H), 4.58 (br.s, 1H), 5.0-5.1 (m, 2H), 5.7-5.8 (m, 1H).

IR (neat) 3486, 3079, 2932, 2859, 1640, 1470, 1391, 1362, 1226, 1111, 1051, 911, 874, 833, 802, 777, 667 cm " ¹ .

EIMS = 430 (M ⁺ ).

HREIMS calcd for C ₂₂ H ₄₆ 0 ₄ Si ₂ (M ⁺ ) 430.2935, found 430.2939.

(Example 5) (3R, 5R) -4- 4-aryl-3,5-bis [(tert-butyldimethylsilyl) oxy] cyclohexanone ((3R, 5R) -4-4-Allyl-3,5- bis [(tert -butyl dime ty 1 si ly 1) oxy] cyclohexanone ¾ of tT compound 8)

A diol compound 7 (41 mg, 95 mol) was dissolved in a mixture of MeOH (2 mL) and _{H 2 0 (1 m L)} , 0 ° NaI0 4 (31 mg, 0.14 strokes ol) at C a In addition, the mixture was stirred at room temperature for 30 minutes. Saturated saline was added to the reaction solution, and extracted with AcOEt. Yes The machine layer was washed with saturated brine and dried over anhydrous MgSO _4. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / AcOEt = 9: 1) to obtain 34 ma (yield: 90%) of compound 8.

[a] ² _D ⁴ -33.6 (c 1.23, CHC1 ₃ )

_{1H MR (400 MHz, CDC1 3} ) δ 0.05 (s, 12H), 0.86 (s, 9H), 0.88 (s, 9H), 1.7-1.9 (m, 1H), 2.2-2.3 (m, 1H), 2.3 -2.4 (m, 2H), 2.43 (dd, J = 3.6, 14.4 Hz, 1H), 2.49 (ddd, J = 1.5, 5.7, 14.4 Hz, 1H), 2.64 (ddd, J = 1.5, 4.8, 14.4 Hz , 1H) 4.0- 4.1 (m, 1H), 4.2-4.3 (m, 1H), 5.08 (d, J = 10.5 Hz, 1H), 5.09 (br.d, J = 17.7 Hz, 1H), 5.81 (ddt , J = 10.5, 17.7, 6.9 Hz, 1H).

^{13 C NMR (100 MHz, CDC1} 3) δ - 4.7, -4.3, - 4.0, 18.1, 25.9 29.8, 30.9, 48.8, 49.2, 67.9, 69.6, 116.4, 136.9, 212.0.

IR (neat) 2955, 2932, 2896, 2859, 2361, 1725, 1641, 1472, 1389, 1362, 1333, 1256, 1161, 1094, 980, 938, 889, 837, 777 cm ^-1

EIMS = 398 (M ⁺ ).

HREIMS calcd for C ₂ iH ₄₂ 0 ₃ Si ₂ (M ⁺ ) 398.2673, found 398.2675.

Example 6 (3R, 5R) -3,5-Bis [(tert-butyldimethylsilyl) oxy] -4-propylhexanone ((3R, 5R) -3,5-Bis [(tert-butyldime thy lsilvl) oxy]-4-propylcyclohexanone, compound 9)

Compound 8 (527 mg 1.32 ol), which is an aryl form, was dissolved in dehydrated MeOH (15 mL), and Pd-C (50 mg) was added. After being made to flow under H _{2, the} mixture was stirred at room temperature for 15 hours. The reaction solution was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane: AcOEt = 5: 1) to afford to give Compound 9 524 mg (9 ^9% yield).

[a] ² _D ⁴ -29.5 (c 1.08, CHC1 ₃ )

Response R (400 MHz, CDCI3) δ 0.036 (s, 3H), 0.045 (s, 3H), 0.050 (s, 6H), 0.85 (s, 9H), 0.88 (s, 9H), 0.95 (t, J = 7.2 Hz, 3H), 1.33 (m, 1H), 1.40-1.54 (m, 3H), 1.71 (ddt, J = 5.1, 8.0, 2.6 Hz, 1H), 2.31 (dd, J = 8.0, 14.3 Hz, 1H), 2.43 (m, 2H), 2.62 (dd, J = 4.7, 14.3 Hz, 1H), 4.02 (dt, J = 4.7, 8.0 Hz, 1H), 4.31 (dt, J = 2.8, 5.1 Hz, 1H ).

^{13 C NMR (100 MHz, CDC1} 3) δ -4.9, -4.8, -4.7, -4.3, -4.2, 14.5, 18.1, 20.8, 25.8, 25.9, 28.7, 48.5, 48.8, 49.3, 68.2, 70.3, 207.7.

IR (neat) 2957, 2932, 2896, 2859, 1725, 1464, 1362, 1335, 1256, 1171, 1088, 1005, 953, 920, 884, 835, 777, 666 cm ^-1 .EI S = 400 (M ⁺ ).

HREIMS calcd for C ₂₁ H ₄₄ 0 ₃ Si ₂ (M ⁺ ) 400.2829, found 400.2822.

(Example 7) (3R, 5R) -3,5-bis [(tert-butyldimethylsilyl) oxy] -4- (3-hydroxypropyl) cyclohexanone ((3R, 5R) -3,5 -Bis [(tert-butyldimethylsilyl) oxy] -4- (3'-hydroxypropyl) cyclohexanone, compound 10)

Compound 6 (50 mg, 0.11 mmol) was dissolved in dehydrated THF (1 mL), BH ₃ 'THF (0.27 mL, 0.27 mmol) was added at 0 ° C, and the mixture was stirred at room temperature for 2 hours. . The reaction solution was again cooled to 0 ° C and, 3 N NaOH (1 mL) and 30 Ru _{_{H 2 0 2 (2 m L}} ) and the mixture was further stirred for 2 hours at room temperature. The reaction solution was quenched by adding a saturated aqueous solution of Na ₂ SO ₃ and extracted with AcOEt. The organic layer was washed with saturated brine and dried over anhydrous MgSO _4. The solvent was distilled off under reduced pressure to obtain a crude product.

The obtained crude product was dissolved in EtOH (1 mL), NaBH ₄ (13 mg, 34 mmol) was added at 0 ° C, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into a saturated aqueous solution of H ₄ C1 and extracted with Et ₂₀ . The organic layer was washed with saturated NH ₄ C1 solution and saturated brine, and dried over anhydrous MgSO _4. The solvent was distilled off under reduced pressure to obtain a crude product.

The resulting crude product was dissolved in a mixture of MeOH (2 mL) and _{H 2 0 (1 mL),} 0 ° C at NaI0 ₄ a (70 mg, 327 mmol) was added, stirred for 14 hours at room temperature did. Saturated saline was added to the reaction solution, and extracted with AcOEt. The organic layer was washed with saturated brine and dried over anhydrous MgSO _4. The solvent is distilled off under reduced pressure. Purification by filtration (hexane / AcOEt = 2: 1) gave 31 mg of Compound 10 (yield 68).

_{U NMR (400 MHz, CDC1 3} ) δ 0.051 (s, 3H), 0.056 (s, 6H), 0.063 (s, 3H), 0.86 (s, 9H), 0.88 (s, 9H), 1.52-1.75 (m , 5H), 2.33 (dd, J = 7.9, 14.4 Hz, 1H), 2.46 (m, 2H), 2.64 (dd, J = 4.6, 14.4 Hz, 1H), 3.69 (t, J = 6.0 Hz, 2H) , 4.04 (dt, J = 4.6 , 7.9 Hz, 1H), 4.33 (dt, J = 2.9, 5.9 Hz, 1H) 13 C NMR (100 MHz, CDC1 3) δ -4.8, -4.7, -4.3,. - 4.2, 18.1, 18.2, 22.7, 25.8, 25.9, 30.9, 48.7, 48.8, 49.2, 63.1, 68.3, 70.3, 207.5.

IR (neat) 3426, 2955, 2930, 2894, 2859, 1719, 1472, 1362, 1256, 1096, 1061, 835, 775 cm " ¹ .

359.2074, found 359.2078.

Example 8 (3R, 5R) -3,5-bis [(tert-butyldimethylsilyl) oxy] -4- [3 (tert-butyldimethylsilyloxy) propyl] cyclohexanone ((3R, 5R) -3, 5 -Bis [(tert-butyldimethylsilyl) oxy]-4-[3 '-(tert-butyldimethylsilyloxy) propyl] cyclohexanone compound 11)

Compound 10 (204 mg, 0.49 iranol) an alcohol body was dissolved in anhydrous _{_{CH 2 C1 2 (5 mL)}} , at _{0 ° C, Et 3 N (} 0.1 mL, 0.72 mmol) and BSC1 (88 mg, 0.58 mmol) t DMAP (6 mg, 50 mol) was obtained and stirred at room temperature for 2 hours. The reaction solution was poured into a saturated aqueous solution of H ₄ C1 and extracted with AcOEt. The organic layer was washed with saturated NH ₄ C1 solution and saturated brine, and dried over anhydrous MgSO _4. The solvent was removed distillation under reduced pressure, silica gel column chromatography (hexane / AcOEt = 10: 1) to afford the compound 11 ²⁵ 9 mg (quantitatively).

^{_{^{[a] 2 D 7 -29.47 (}}} c 1.38, CHC1 3).

_{1H NMR (400 MHz, CDC1 3} ) δ 0.043 (s, 3H), 0.047 (s, 6H) 0.052 (s, 9H), 0.851 (s, 9H), 0.877 (s, 9H), 0.896 (s, 9H) 1.52-1.70 (m, 5H), 2.32 (dd, J = 7.9, 14.6 Hz, 1H), 2.44 (m, 2H), 2.63 (dd, J = 4.6, 14.6 Hz, 1H), 3.64 (t, J = 5.8 Hz, 2H), 4.03 (dt, J = 4.6, 7.9 Hz, 1H), 4.32 (dt, J = 2.4, 4.8 Hz, 1H).

^{13 C NMR (100 MHz, CDC1} 3) δ - 5.11, -5.08, -4.78, -4.64, -4.26,

-4.20, 18.11, 18.13, 18.52, 23.10, 25.84, 25.93, 26.12,

31.16, 48.82, 48.87, 49.35, 63.52, 68.30, 70.31, 207.7.

IR (neat) 2955, 2930, 2894, 2859, 1725, 1472, 1256, 1098,

909, 835, 775 cm " ¹ .

EIMS = 530 (M ⁺ ).

HREIMS calcd for C ₂₇ H ₅₈ 0 ₄ Si ₃ (M ⁺ ) 530.3643, found 530.3649.

(Example 9) (lR, 6R, 7R) -7-[(R) -6-methoxymethoxy-6-methylheptan-2-ylyl] -1-6-methylebicyclo [4.3.0] nonan-2-one ( (lR, 6R, 7R) -7- [(R) -6-Met hoxyme t hoxy-6-methylhe tan-2-yl] -6-methyl-bicyclo [4.3.0] nonan-2-one compound 12)

25-Hydroxygrandman ketone (946 mg 3.376 ol) was dissolved in CH ₂ C ₁₂ (30 mL) at 0 ° C and MOMC1 (1.087 g 13.504 mmol) t DIEA

(3.0 mL 16.9 mmol) and stirred at room temperature for 1 day. The reaction solution was poured into a saturated aqueous solution of H ₄ C1 and extracted with AcOEt. The organic layer was washed with saturated H ₄ C1 solution and saturated Japanese brine, and dried over anhydrous MgSO _4. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / AcOEt = 4: 1) to obtain 1.10 g (quantitatively) of Compound 12.

[a] _D +4.90 (σ 1.00, CHC1 ₃ )

_{¾ NMR (400 MHz, CDC1 3} ) δ 0.64 (s, 3H), 0.96 (d, J = 5.6 H z, 3H), 1.07 (m, 1H), 1.21 (s, 6H), 1.31-1.62 (m, 10H), 1.71- 1.75 (m, 1H), 1.89-1.92 (m, 2H), 2.00 (m, 1H), 2.12 (br.d, J = 12.8 Hz, 1H), 2.21-2.27 (m, 2H) , 2.45 (dd, J = 7.4, 11.4 Hz, 1H), 3.37 (s, 3H), 4.70 (s, 2H).

^{13 C NMR (100 MHz, CDC1} 3) δ 12.7, 18.9, 19.2, 20.6, 24.2, 2 6.4, 26.5, 27.6, 35.6, 36.4, 39.1, 41.1, 42.3, 50.0, 55.1, 56 .8, 62.0, 76.3, 91.0, 211.7.

EIMS = 324 (M ⁺ ).

HREIMS calcd for C ₂₀ H ₃₆ O ₃ (M ⁺ ) 324.2655, found 324.2659.

(Example 10) Echiru [(lR, 2E, 6R, 7R) -7 - [(R) -6- methoxymethoxy - ₆ one methyl heptane - ₂ _ I le] _ ₆ _ methyl - bicyclo ^[4 .3.0] Nonane-2-ylidene

] Acetate (Ethyl [(lR, 2E, 6R, 7R) -7- [(R) -6-Methoxymethoxy-6-metylheptan-2-yl]-6-methyl-bicyclo [4.3.0] nonan -2 -ylidene] ace tate, compound 13)

NaH (675 mg 20.256 mmol) was dissolved in THF (20 mL), and getyl phosphonoacetate (3.7 mL 23.6 mmol) was added at 0 V, and the mixture was stirred at room temperature for 1 day. Compound 12 (1.10 g 3.38 ol) dissolved in THF (10 mL)

) Was added and the mixture was further stirred for 1 day. The reaction solution was poured into a saturated aqueous solution of H ₄ C1 and extracted with AcOEt. The organic layer was washed with saturated H ₄ C1 solution and saturated brine, and dried over anhydrous M GS0 _4. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / AcOEt = 8: 1) to obtain 1.31 g of Compound 13 (98% yield).

_{U MR (400 MHz, CDC1 3} ) major δ 0.57 (s, 3H), 0.93 (d, J = 6.4 Hz, 3H), 1.04 (m, 1H), 1.21 (s, 6H), 1.276 (t, J = 7.2 Hz, 3H), 1.46-1.31 (m, 7H), 1.48-1.55 (m, 3H), 1.60- 1.75 (m, 4H), 1.87-1.89 (m, 1H), 2.01 (br.d, J = 15.6 Hz, 1H), 2.09 (dt, J = 1.2, 10.0 Hz, 1H), 3.36 (s, 3H), 3.84 (br.d, J = 14.4 Hz, 1H), 4.14 (dq, J = 1.8, 7.2 Hz, 2H), 4.70 (s, 2H), 5.45 (s, 1H) .minor δ 0.88 (d, J = 6.4 Hz, 3H), 1.26 (s, 6H), 1.269 (t, J = 7.2 Hz, 3H ), 5.65 (s, 1H).

^{13 C NMR (100 MHz, CDC1} 3) δ 12.3, 14.5, 18.9, 20.7, 22.3, 24.0, 26.4, 26.5, 27.6, 29.7, 29.8, 36.1, 36.4, 40.2, 42.4, 47.2, 55.1, 56.8, 56.9, 59.5, 76.3, 91.0, 111.9, 163.1, 166.7.

IR (neat) 2944, 2870, 2774, 2124, 2060, 1958, 1717, 1647, 1466, 1381, 1368, 1308, 1271, 1254, 1146, 1096, 1042, 918, 866, 754 cm one ^1.

EIMS = 394 (M ⁺ ).

HREIMS calcd for C ₂₄ H ₄₂ 0 ₄ (M ⁺ ) 394.3083, found 394.3091.

(Example 11) 2-[(lR, 2E, 6R, 7R) -7-[(R) -6-methoxymethoxy-6-methylheptane-2-yl] -6-methylbicyclo [4.3.0] Nonane-2-ylidene] ethanol (2-[(1R, 2E, 6R, 7R)-7-[(R)-6-ethoxymethoxy-6 -methylhept an-2-yl]-6 -methylbicyclo [4.3 .0] nonan-2-ylidene] ethanol, compound 14)

Compound 13 (751 mg, 1.90 mmol) as an ester was dissolved in toluene (14 mL), DIBAL-H (4.6 mL, 4.78 mmol) was added at -78 ° C, and the mixture was stirred for 1 hour. The reaction solution to stop the reaction was added a saturated Na ₂ S0 ₄ aqueous solution and Na _₂ S0 ₄ * 10H ₂ O, sequentially, and filtered through celite. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / AcOEt = 5: 1) to obtain 666 mg of Compound 14 (yield: 99).

, CDC1 ₃ ) major δ 0.55 (s, 3H), 0.93 (d, J = 6.4 Hz, 3H), 1.03 (m, 1H), 1.22 (s, 6H), 1.25-1.30 (m, 3H), 1.32- 1.41 (m, 4H), 1.44-1.56 (m, 5H), 1.65-1.68 (m, 3H), 1.8 4-2.05 (m, 3H), 2.63 (dd, J = 4.2, 12.2 Hz, 1H), 3.37 (s, 3H),

4.21 (d, J = 7.2 Hz, 2H), 4.71 (s, 2H), 5.22 (t, J = 7.0 Hz, 1H) .minor δ 0.88 (d, J = 6.4 Hz, 3H), 5.41 (t, J = 7.0 Hz, 1H ^{13 C MR (100 MHz, CDC1} 3) δ 12.0, 18.9, 20.7, 22.3, 23.6, 2 6.4, 26.5, 27.7, 28.8, 36.2, 36.5, 40.5, 42.3, 45.4, 55.1, 55

7, 56.7, 58.7, 76.4, 90.9, 119.143.5

Example 12 (1R, 2E, 6R, 7R) _7-[(R) -6-methoxymethoxy-6-methylheptane-2-yl] -6-methyl-2- [2- (benzothiazole- 2-sulfonyl) ethylidene] bicyclo [4.3.0] nonane ((1R, 2E, 6R, 7) -7- [(R) -6-Me t hoxyme t hoxy-6-me t hy 1 hep tan-2_yl] -6-metlr ^ -2 [2_ (benzothiazole_2-sulfoiiyl) ethylideiie] bicyclo [4.3 .OJ bandage ane, compound 15)

2 - mercapto Bok benzothiazole Ichiru (451 mg, 2.70 strokes 1) was dissolved in anhydrous CH ₂ C1 ₂ (5 inL), at _{0 ° C, PPh 3 (707} mg, 2.70 thigh ol) and dehydrated CH ₂ C1 ₂ (5 mL) to the compound 14 (633 mg, 1.80 thigh ol) was dissolved with, diisopropyl § zone radical Pokishireto (0.52 mL, 1.80 negation ol) and added sequentially, and stirred for 1 hour. The solvent was reduced pressure evaporated, redissolved in EtOH (10 mL), at _{_{0 ° C (ΝΗ 4) 6}} Μο 7 0 24 · 4Η 2 0 (444 mg, 0.36 negation ol) 30% 0 ₂ aqueous solution (1 mL) and were added in that order, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into a saturated aqueous solution of Na ₂ SO ₃ and extracted with AcOEt. The organic layer was washed with saturated brine and dried over anhydrous MgSO _4. The solvent was evaporated under reduced pressure, silica gel column inlet Mato chromatography (hexane _{/ Et 2 0 = 3: 1} ) to give purified compound 15 849 mg (89% yield) of.

_{NMR (400 MHz, CDC1 3)} major δ 0.26 (s, 3H), 0.86 (d, J = 6.4 Hz, 3H), 1.00 (m, 1H), 1.20 (s, 6H), 1.22-1.53 (m, 14H ), 1.81-1.91 (m, 3H), 2.55 (br.d, J = 12.4 Hz, 1H), 3.36 (s, 3H), 4.21 (dd, J = 6.8, 14.0 Hz, 1H), 4.43 (dd, J = 8.8, 14.0 Hz, 1H), 4.70 (s, 2H), 5.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 8.0 Hz Minor δ 0.78 (d, J = 6.4 Hz, 3H), 1.21 (s, 6H), 3.37 (s, 3H), 4.71 (S, 2H).

¹³ C丽_{R (100 MHz, CDC1 3)} δ 11.7, 18.9, 20.6, 22.2, 23.2, 26.4, 26.5, 27.6, 29.1, 36.0, 36.4, 40.0, 42.3, 45.8, 53.9, 55.1, 56.0, 56.4, 76.3, 90.9, 104.0, 122.0, 125.2, 127.4, 127.7, 136.8, 151.9, 152.6, 165.7.

IR (neat) 2948, 2874, 2363, 1657, 1599, 1567, 1472, 1424, 1381, 1327, 1240, 1148, 1090, 1040, 916, 853, 762, 731, 689, 639 cm " ¹ .

EIMS = 533 (M ⁺ ).

HREIMS calcd for C ₂₉ H ₄₃ 0 ₄ NS ₂ (M ⁺ ) 533.2634, found

533.2637.

(Example 13) (aRS, 1R, 3R, 7E) -2-Alyl-9,10-seco-19-norcholes-u-5,7-gen-1,3,25-triol ((aRS, 1R, 3R , 7E) -2-Allyl-9, 10-seco-19-norcholes ta-5, 7-diene-l, 3,25-trioK Compound 1)

Compound 15 (65 mg, 122 mol) as a sulfone derivative was dissolved in dehydrated THF (1 mL), LiHMDS (120 U 120 imol) was added at -78 ° C, and the mixture was stirred for 1 hour. Compound 8 (34 mg, 85 / mol) was dissolved in dehydrated THF (1 mL), added to the reaction solution, and stirred for 2 hours. The reaction solution was poured into a saturated aqueous solution of NH ₄ C1 and extracted with Et ₂₀ . The organic layer was washed with saturated saline and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / AcOEt = 30: 1) to obtain 10 mg (yield 16%) of a crude product containing the protected compound of the title compound.

The obtained crude product (9 mg, 13 mol) was dissolved in dehydrated MeOH (2 mL) and (+) -CSA (10 mg, (23 mol) was added and 19 h攙拌at room temperature. The AcOEt was added to the reaction solution, washed with saturated NaHCO ₃ aqueous solution and brine, over anhydrous Na ₂ S0 ₄ The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / AcOEt = 3: 2) to obtain 4 mg of a mixture of compound 1a and compound 1b (yield: 72%). Was.

The mixture of the compound 1a and the compound 1b was separated and purified by reversed-phase HPLC (YMC-Pack ODS column, 20 × 150 mm, 9.9 mL / min, CH ₃ CN IH ₂₀ = 85: 15).

(35,111,311,7 £) -2-aryl-9,10-seco-19-norcholesta-5,7-gen-1,3,25-triol (Compound 1b, 2 / 3-aryl) .131, CHC1 ₃ )

CDC1 ₃ ) δ 0.55 (s, 3H, 6.6 Hz, 3H, 21-H ₃ ), 16H, 26-H ₃ and 27-H ₃ ),

.37-1.57 (m, 11H), 1.66-1.70 (m, 2H), 1.88-1.92 (m, 2H), 1.99-2.02 (m, 2H), 2.28 (ddd, J = 7.4, 7.7, 14.6 Hz, 1H, -CH ₂ CH = CH ₂ ), 2.34 (ddd, J = 1.4, 3.4, 14.0 Hz, 1H, 4β-H), 2.40 (br.d, J = 14.0 Hz, 1Η, 4α- Η), 2.53 (ddd, J = 6.7, 7.4, 14.6 Hz, 1H, -CH ₂ CH = CH ₂ ), 2.80 (dd, J = 4.2, 12.9 Hz, 1H, 9β-Η), 3.11 (ddd, J = 1.4, 4.7, 12.8 Hz, 1H, 10β-Η), 3.62 (ddd, J = 4.7, 10.3, 10.3 Hz, 1H, 1β-Η), 4.02 (ddd, J = 3.4, 6.3, 6.9 Hz, 1H, 3α-Η), 5.07 (d, J = 10.2 Hz, 1H, -CH ₂ CH = CH ₂ ), 5.16 (d, J = 17.0 Hz, 1H, -CH ₂ CH = CH ₂ ), 5.87 (d , J = 11.3 Hz, 1H, 7-H), 5.93 (dddd, J = 7.3, 7.3, 10.2, 17.0 Hz, 1H, -CH ₂ CH = CH ₂ ), 6.26 (d, J = 11.3 Hz, 1H, 6-H).

^{13 C NMR (150 MHz, CDC1} 3) δ 12.0, 18.8, 20.8, 22.3, 23.5, 27.7, 29.0, 29.2, 29.4, 33.2, 36.1, 36.4, 37.7, 40.4, 44.0, 44.4, 45.8, 49.2, 56.3, 56.5 , 68.8, 71.0, 71.1, 115.3, 116.5, 123.5, 131.1, 137.6, 143.1.

IR (neat) 3420, 2928, 2868, 1640 cm ^-1 .

EIMS = 444 ( ⁺ ).

HREIMS calcd for C ₂₉ H ₄₈ 0 ₃ (M ⁺ ) 444.3603, found 444.3609. (311,11¾, 311,7 £) -2-are-9,10-se3-19-norire3less--5 , 7-Gen-1,

3,25- triol (Compound 1 a, 2α- Ariru) 0.162, CHC1 ₃₎

z, CDC1 ₃ ) δ 0.53 (s, J = 6.3 Hz, 3H, 21- 1.22 (s, 6H, 26-H ₃

and 27-H3), 1.24-1.32 (m, 6H), 1.36-1.58 (m, 10H), 1.67 (m, 2H), 1.86-1.93 (m, 2H), 1.99-2.01 (m, 2H), 2.13 -2.17 (m, 2H), 2.30 (ddd, J = 6.0, 7.0, 14.2 Hz, 1H, -CH ₂ CH = CH ₂ ), 2.50 (ddd, J = 7.0, 8.4, 14.2 Hz, 1H,-CH ₂ CH = CH ₂ ), 2.61 (dd, J = 4.7, 12.9 Hz, 1H, 4α-Η), 2.80 (dd, J = 4.4, 12.9 Hz, 1H, 9β-), 2.86 (dd, J = 4.1, 13.8 Hz, 1H, 10a-H), 3.70 (ddd, J = 4.7, 9.6, 9.6 Hz, 1H, 3a-H), 4.08 (ddd, J = 4.1, 7.1, 7.1 Hz, 1H, 1β-Η), 5.07 (d, J = 10.2 Hz, 1H, -CH ₂ CH = CH ₂ ), 5.15 (d, J = 17.0 Hz, 1H, -CH ₂ CH = CH ₂ ), 5.81 (d, J = 11.3 Hz, 1H , 7-H), 5.92 (dddd, J = 6.9, 6.9, 10.2, 17.0 Hz, 1H,-CH ₂ CH = CH ₂ ), 6.34 (d, J = 11.3 Hz, 1H, 6-H).

^{13 C NMR (150 MHz, CDC1} 3) δ 12.0, 18.8, 20.8, 22.2, 23.4, 27.6, 28.9, 29.1, 29.3, 32.8, 35.5, 36.1, 36.4, 40.4, 44.4, 45.2, 45.8, 48.9, 56.3, 56.5 , 68.7, 71.0, 71.2, 115.2, 116.5, 124.1, 131.2.

IR (neat) 3353, 2936, 1644 cm " ¹ .

EIMS = 444 ( ⁺ )

_{_{HREIMS calcd. For C 29 H 48}} 0 3 (M +) 444.3603, found 444.3597. (Example 14) 1 «, 11, 31, 78) -2-propyl-9, 10-seco_19-norcholesta-5, 7-gen-1,3,25-triol ((aRS, 1R, 3R, 7E) -2-Propyl-9, 10- seco- 19- norchol est a- 5, 7, -diene-l, 3, 25-trioK compound 2)

Compound 15 (74 mg, 139 mol), which is a sulfone derivative, was dissolved in dehydrated THF (1 mL), and LiHMDS 130 zL (UO mo \) was added at -78 ° C, followed by stirring for 1 hour. Compound 9 (43 mg, 107 11101) was dissolved in dehydrated 111? (1 mL), added to the reaction solution, and stirred for 6 hours. The reaction solution was poured into a saturated aqueous solution of NH ₄ C1 and extracted with Et ₂₀ . The organic layer was washed with saturated saline and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / AcOEt = 40: 1) to obtain 51 mg (yield 66%) of a crude product containing a protected form of the title compound. .

The obtained crude product (46 mg, 64 zmol) was dissolved in dehydrated MeOH (2 mL), 45 mg (194 zmol) of (+)-CSA was added at 0 ° C, and the mixture was stirred at room temperature for 22 hours. The AcOEt was added to the reaction solution, washed with saturated NaHCO ₃ aqueous solution and saturated brine, and dried over anhydrous Na ₂ S0 _4. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / AcOEt = 3: 2) to obtain 22 mg of a mixture of compound 2a and compound 2b (77% yield).

The mixture of compound 2a and compound 2b was separated and purified by reversed-phase HPLC (YMC-Pack ODS column, 20 × 150 mm, 9.9 mL / min, CH ₃ CN / H ₂₀ = 90: 10).

(aR, 1R, 3R, 7E)-2-Propyl-9,10-seco-19-norcoles e-5,7-Gen-1,3,25-triol (Compound 2b, 2 β-propyl form)

.323, CHC1 ₃ )

CDC1 ₃ ) δ 0.55 (s, 3H, 6.6 Hz, 3H, 21-H ₃ ), 3H, -CH ₂ CH ₂ CH

, 1.07

(m, 1H), 1.219 (s, 6H, 26-H ₃ and 27- H ₃ ), 1.24-1.33 (m, 5H), 1.37-1.53 (m, 11H), 1.66-1.67 (m, 3H), 1.88-1.91 (m, 2H), 1.99-2.02 (m, 2H), 2.35 (ddd, J = 1.2, 3.8, 12.9 Hz, 1H, 4β-Η), 2.40 (br.d, J = 13.9 Hz, 1H, 4a-H), 2.80 (dd, J = 4.7, 12.6 Hz, 1H, 9β-Η) , 3.10 (ddd, J = 1.2, 4.4, 12.7 Hz, 1H, 10β-Η), 5.34 (dt, J = 4.4, 9.8 Hz, 1H, 1β-Η), 4.05 (br.s, 1H, 3a-H) ), 5.87 (d, J = 11.3 Hz, 1H, 7-H), 6.26 (d, J = 11.3 Hz, 1H, 6-H).

^{13 C MR (150 MHz, CDC1} 3) δ 12.0, 14.4, 18.8, 20.2, 20.8, 22.3, 23.5, 27.7, 29.0, 29.2, 29.4, 29.6, 36.1, 36.4, 37.8, 40.5, 44.1, 44.4, 45.8, 49.1 , 56.3, 56.5, 68.0, 71.1, 71.2, 115.3, 123.4, 131.3, 143.0.

IR (neat) 3382, 2942, 2872, 1613 cm- ¹ .

EIMS = 446 (M ⁺ ).

_{_{HREIMS calcd for C 29 H 50 O}} 3 (M +) 446.3760, found 446.3757 (aS, IR, 3R, 7E) _2- propyl - 9, 10-seco-19-Norukoresu evening - 5, 7 - Gen -1, 3 , 25-triol (Compound 2a, 2α-propyl form)

0.362, CHC1 ₃ )

, CDC1 ₃ ) δ 0.53 (s, 3H, = 6.6 Hz, 3H, 21-H ₃ ), Hz, 3H, -ΟΗ ₂ ΟΗ ₂ ΟΗ ₃ ),

(s, 6H, 26-H ₃ and 27-H ₃ ), 1.24-1.32 (m, 5H), 1.36-1.40 (m, 4H), 1.45-1.56 (m, 7H), 1.60-1.68 (m, 4H ), 1.89 (m, 1H), 1.99-2.01 (m, 2H), 2.12- 2.17 (m, 2H), 2.60 (dd, J = 4.5, 12.5 Hz, 1H, 4α-Η), 2.80 (dd, J = 4.7, 12.6 Hz, 1H, 9β-Η), 2.84 (dd, J = 4.7, 14.0 Hz, 1H, 10a-H), 3.64 (dt, J = 4.5, 9.2 Hz, 1H, 3a-H), 4.09 (br.s, 1H, 1β-Η), 5.82 (d, J = 11.3 Hz, 1H, 7-H), 6.37 (d, J = 11.3 Hz, 1H, 6-H). ¹³ C R (150 MHz, CDCI3) δ 12.0, 14.4, 18.8, 20.4, 20.8, 22.2, 23.5, 27.6, 28.9, 29.2, 29.3, 29.4, 35.5, 36.1, 36.4, 40.5, 44.4, 45.2, 45.8, 48.9 , 56.3, 56.5, 68.3, 71.1, 71.6, 115.2, 124.0, 131.3, 143.2.

IR (neat) 3384, 2955, 2872, 1613 cm " ¹ .

EIMS = 446 (M ⁺ ).

_{_{HREIMS calcd for C 29 H 50 O}} 3 (M +) 446.3760, found 446.3763

(Example 15) (aRS, 1R, 3R, 7E) _2- (3-hydroxypropyl) -9,10-seco-19-norcholesu-5,7-gen-1,3,25-triol ((aRS , 1R, 3R, 7E) -2- (3-Hydroxypropyl) -9, 10-seco-19-norcholesta-5, 7-diene-1,3,25-trioK Compound 3)

Compound 15 (109 mg, 203 mol) as a sulfone derivative was dissolved in dehydrated THF (1 mL), LiHMDS (200DS, 200 / imol) was added at -78 ° C, and the mixture was stirred for 1 hour. Compound 11 (56 mg, 105 xmol) was dissolved in dehydrated THF (1 mL), added to the reaction solution, and stirred for 6 hours. The reaction solution was poured into a saturated M ₄ C1 solution and extracted with Et ₂ 0. The organic layer was washed with saturated saline and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / AcOEt = 10: 1) to obtain 9.6 mg (yield 11%) of a crude product containing the protected compound of the title compound.

The obtained crude product (9.6 mg, ll mol) was dissolved in dehydrated MeOH (1 mL), (+)-CSA (10 mg, 43 xmol) was added at 0.0 ° C, and the mixture was stirred at room temperature for 23 hours. did. The Ac OEt was added to the reaction solution, saturated NaHCO ₃ and washed with aqueous solution and saturated brine, anhydrous and Na ₂ S (T dry. The solvent was distilled off under reduced pressure, silica gel column chromatography (hexane / AcOEt I MeOH = Purification by 5: 15: 2) yielded 4.6 mg (88% yield) of a mixture of compound 3a and compound 3b.

The mixture of compounds 3 a and Compound 3 b reverse phase HPLC (YMC-Pack ODS column, 20 X 150 mm, 9.9 mL / min, CH 3 CN IH 2 0 = 80: 20) was separated and purified by.

(aR, 1R, 3R, 7E) -2- (3-Hydroxypropyl) -9,10-seco-19-norcholes -5,7-gen-1,3,25-triol (Compound 3b , 2-i3 hydroxypropyl form) t _R = 10.1 rain.

[H] ² . ^{_{1 +6.81 (c 0.162, CHC1 3}} )

_{XH MR (600 MHz, CDC1 3} ) δ 0.55 (s, 3H, I8-H3), 0.94 (d, J = 6.3 Hz, 3H, 21- H 3), 1.07 (m, 1H), 1.22 (s, 6H , 26-H ₃ and 27-

H ₃ ), 1.24-1.33 (m, 5H), 1.37-1.48 (m, 5H), 1.53-1.60 (m, 6H), 1.66-1.68 (m, 2H), 1.79-1.82 (m, 2H), 1.88 -1.92 (m, 2H), 1.99-2.02 (m, 2H), 2.36 (ddd, J = 1.5, 3.6, 13.7 Hz, 1H, 4β-Η), 2.41 (br.d, J = 13.7 Hz, 1H, 4a- H), 2.80 (dd, J = 4.7, 12.9 Hz, 1H, 9β-Η), 3.10 (dd, J =

I.5, 4.8, 12.9 Hz, 1H, 10β-Η), 3.56 (ddd, J = 4.8, 10.2, 10.2 Hz, 1H, 1β-Η), 3.69-3.71 (m, 2H, -CH ₂ CH ₂ CH ₂ OH), 4.05 (m, 1H, 3a-H), 5.87 (d, J = 11.3 Hz, 1H, 7-H), 6.26 (d, J =

II.3 Hz, 1H, 6-H).

^{1 3 C NMR (150 MHz,} CDC1 3) δ 12.0, 18.8, 20.8, 22.3, 23.5,

23.8, 27.7, 29.0, 29.2, 29.4, 29.9, 36.1, 36.4, 37.9, 40.4, 44.1, 44.4, 45.8, 49.0, 56.3, 56.5, 63.0, 68.3, 71.1, 71.2, 115.2, 123.5, 131.0, 143.2.

IR (neat) 3360, 2924, 2855, 1653 cm one ^1.

EIMS = 462 (M ⁺ ).

_{_{HREIMS calcd for C 29 H 50 O}} 4 (+) 462.3709, found 462.3723.

(aS, IR, 3R, 7E) -2- (3-hdroxypropyl) -9,10 seco-19-norcholes-1,5,7-gen-1,3,25-triol (Compound 3a, 2-hydroxypropyl form)

0.185, CHC1 ₃ )

, CDC1 ₃ ) δ 0.53 (s, 3H, 18- = 6.6 Hz, 3H, 21-H ₃ ), 1.07 (s, 6H, 26-H ₃ and 27-H ₃ ),

1.24-1.33 (m, 5H), 1.36-1.42 (m, 4H), 1.44-1.56 (m, 5H), 1.59-1.61 (m, 3H), 1.66-1.70 (m, 2H), 1.77-1.78 (m , 2H), 1.89 (m, 1H), 2.00-2.02 (m, 2H), 2.13-2.18 (m, 2H), 2.60 (dd, J = 4.7, 12.7 Hz, 1H, 4ot-H), 2.80 (dd , J = 4.7, 12.6 Hz, 1H, 9β-Η), 2.86 (dd, J = 4.3, 13.9 Hz, 1H, 10a-H), 3.66 (ddd, J = 4.7, 9.6, 9.6 Hz, 1H, 3- H), 3.70-3.72 (m, 2H,-CH ₂ CH ₂ CH ₂ OH), 4.10 (ddd, J = 4.3, 7.1, 7.1 Hz, 1H, 1β-Η), 5.82 (d, J = 11.1 Hz, 1H, 7-H), 6.38 (d, J = 11.1 Hz, 1H, 6-H).

^{13 C NMR (150 MHz, CDC1} 3) δ 12.4, 18.8, 20.8, 22.2, 23.5, 27.7, 28.9, 29.2, 29.4, 30.2, 35.6, 36.1, 36.4 (2C), 40.5, 44.4, 45.3, 45.8, 48.8, 56.3, 56.5, 63.0, 68.6, 71.1, 71.7, 115.2, 124.1, 131.1, 143.3.

IR (neat) 3362, 2924, 2855, 1635 cm " ¹ .

EIMS = 462 (M ⁺ ).

_{_{HREIMS calcd for C 29 H 50 O}} 4 (M +) 462.3709, found 462.3712.

(Example 16) 3 _ [(4-Methoxybenzyl) oxy] -2,2-ethanepropane-1-ol (3-[(4-Methoxybenzyl) oxy] -2, 2-ethanopropan-l-oK Compound B )

While stirring a suspension of NaH (392 mg, 60% in mineral oil, 9.79 ol) in DMF (10 mL), the diol compound A (1, tribis (hydroxymethyl) cyclopropane) was stirred. A solution of (1.00 g, 9.79 mmol) in DMF (10 mL) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 40 minutes. To the reaction mixture, PMBCl (1.4 mL, 1.05 eq) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 8 hours. After water was added to the reaction mixture at 0 ° C., the whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3) to give Compound B (1.88 g). ) Was obtained as a colorless oil (yield 86%).

_{1H NMR (600 MHz, CDC1 3} ) δ 0.47 (2 H, m), 0.54 (2 H, m), 2.49 (1 H, br.s), 3.42 (2 H, s), 3.54 (2 H, s ), 3.81 (3 H, s), 4.47 (2 H, s), 6.88 (2 H, d, J = 8.8 Hz), 7.25 (2 H, d, J = 8.8 Hz); ¹³ C NMR (150 MHz , CDC1 ₃ ) δ 8.9 (t), 22.5 (s), 55.3 (q), 69.3 (t), 72.8 (t), 76.4 (t), 113.9 (d), 129.3 (d), 130.1 (s), 159.3 (s); MS 222 [M] +, 203 [M- ¾0] +; HRMS calcd. For [Ci ₃ His0 ₃ ] 222.1256, found 222.1251.

Example 17 3-[(4-Methoxybenzyl) oxy] -2,2-ethanopropanal (3-[(4-Methoxybenzyl) oxy] -2,2-ethanopropanal, compound B) Compound B (1.88 g, 8.46 mmol), powdered 4 A MS (188 mg), and NMO (2.97 g, 3 eq) in CH ₂ C ₁₂ (20 mL) with stirring under an argon atmosphere 0

At ° C, it was treated with TPAP (289 mg, 0.82 mmol, 097 eq). Reaction mixture at 0 ° C 1

After stirring for 5 minutes, silica gel column chromatography (ethyl acetate n-hexane)

= 1: 5) to give aldehyde compound C (1.47 g) as a colorless oil (yield 79%). This colorless oil was used as such in the next step.

(Example 18) 5-[(4-Methoxybenzyl) oxy] _4,4-ethanovent-toluene-3-ol (5-[(4-Methoxybenzyl) oxy] -4,41-ethanopent—l_en_3_ol, compound D)

A solution of compound C (1.47 g, 6.67 t) in dry toluene (15 mL) was stirred at _78 ° C under an argon atmosphere at vinyl magnesium bromide (0.97 M in THF,

(7.6 mL, 1.1 eq) was added dropwise. The reaction mixture was stirred for 35 minutes, quenched by the addition of saturated aqueous M ₄ C1 and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the solvent was distilled off. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9) to give Compound D (1.59 g) as a colorless oil (yield 96%).

_{1H NMR (600 MHz, CDC1 3} ) δ 0.37 (1 H, ddd, J = 9.3, 6.0, 4.9 Hz), 0.51 (1 H, dt, J = 9.1, 4.9 Hz), 0.58 (1 H, ddd, J = 9.1, 5.8, 4.7 Hz), 0.72 (1 H, dddd, J = 9.1, 6.0, 4.9, 1.4 Hz), 3.03 (1 H, d, J = 9.6 Hz), 3.41 (1 H, d, J = 6.6 Hz), 3.69 (1 H, br.t, J = 6.0 Hz), 3.76 (1 H, dd , J = 9.6, 1.4 Hz), 3.81 (3 H, s), 4.43 (2 H, s), 5.17 (1 H, dt, J = 10.4, 1.7 Hz), 5.33 (1 H, dt, J = 17.0 , 1.7 Hz), 5.89 (1 H, ddd, J = 17.0, 10.4, 4.9 Hz), 6.88 (2 H, d, J = 8.8 Hz), 7.24 (2 H, d, J = 8.8 Hz); ¹³ C _{NMR (150 MHz, CDC1 3)} δ 7.2 (t), 10.4 ( Ri, 24.4 (s), 55.3 ( q), 72.9 (t), 75.6 (t), 78.2 (d), 113.8 (d), 115.2 ( t), 129.4 (d), 129.8 (s), 138.5 (d), 159.3 (s); FTIR (neat) 3441, 3076, 3005, 2937, 2862, 1736, 1713, 1612, 1512, 1464, 1365, 1302 , 1246, 1174, 1074, 1033, 933, 925, 823 cm— ¹ ; MS 248 [M] ⁺ , 230 [MH ₂₀ ] ⁺ ; HRMS calcd. For [C ₁₅ H ₂₀ O ₃ ] 248.1412, found 248.1409. (Example 19) 3-[(tert-butyldimethylsilyl) oxy] -5-[(4-methoxybenzyl) hydroxy] -4,4-ethanopent-1-ene (3-[(tert -Butyldimethys i lyl) ox y]-5-L (4-methoxybenzyl) oxy] -4, 4-ethanopent-l-ene, Compound E)

A mixture of compound D (1.00 g, 4.03 IMO I) and 2,6-lutidine (0.75 mL, 2 eq) in dry CH ₂ C ₁₂ (10 mL) was stirred at 0 ° Under an argon atmosphere at C, TBS0Tf (1.4 mL, 1.2 eq) was added. The resulting mixture was stirred for 15 minutes, diluted with ethyl acetate and washed with water and then brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent was removed. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 11) to give compound Ea. 40 g) as a colorless oil (yield 96%).

_{1H NMR (600 MHz, CDC1 3} ) δ 0.00 (3 H, s), 0.04 (3 H, s), 0.29 (1 H, m), 0.43 (1 H, m), 0.51 (1 H, dt, J = 9.3, 4.1 Hz), 0.64 (1 H, dt, J = 9.1, 4.4 Hz), 0.88 (9 H, s), 3.14 (1 H, d, J = 10.2 Hz), 3.53 (1 H, d, J = 10.2 Hz), 3.80 (3 H, s), 4.12 (1 H, d, J = 6.9 Hz), 4.37 (1 H, d, J = 11.8 Hz), 4.44 (1 H, d, J = 11.8 Hz), 5.05 (1 H, d, J = 10.7 Hz), 5.12 (1 H, d, J = 17.3 Hz), 5.80 (1 H, ddd, J = 17.0, 10.2, 6.9 Hz), 6.87 (2 H , d, J = 8.5 Hz), 7.24 (2 H, d, J = 8.5 Hz); ¹³ C NMR (150 MHz, CDCI3) δ -4.8 (q), -4.3 (q), 6.92 (t), 6.94 (t), 18.2 (s), 24.9 (s), 25.6 (q), 55.3 (q), 72.3 (t), 73.5 (t), 74.6 (d), 113.7 (d), 114.7 (t), 129.2 (d), 130.8 (s), 139.8 (d), 159.0 (s); FTIR (neat) 3078, 3003, 2955, 2895, 2856, 1614, 1514, 1464, 1361, 1302, 1250, 1174, 1082, 1037, 922, 837, 775 cm- ¹ ; MS 362 [M] ⁺ , 305 [M- * Bu] ⁺ ; HRMS calcd. For [C ₂ iH ₃₄ 0 ₃ Si] 362.2257, found 362.2267.

(Example 20) 3-[(tert-butyldimethylsilyl) oxy] -2,2-ethanopent-4-en-1-ol (3-[(3-[(tert-Butyldimethysilyl) oxy]- 2, 2-ethanopent- 4-en- lo 1, compound F)

Compound E (1.40 g, 3.86 thigh ol) was dissolved in a mixture of CH ₂ C1 ₂ and (19 mL) and water (2 mL). The resulting solution was treated with DDQ (1.31 g, 1.5 eq) at 0 ° C. with stirring. After stirring at room temperature for 25 minutes, the reaction mixture was diluted with ether (150 mL). The organic layer was washed with saturated NaHCO ₃ solution and brine, dried over magnesium sulfate, filtered and evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9) to give compound F (644 mg) as a colorless oil (yield 69%).

_{1H NMR (600 MHz, CDC1 3} ) δ 0.04 (3 H, s), 0.08 (3 Η, s), 0.39 (1 Η, dt, J = 9.1, 4.6 Hz), 0.46 (1 H, dt, J = 9.1, 4.6 Hz), 0.56 (1 H, dt, J = 9.1, 4.6 Hz), 0.69 (1 H, dt, J = 9.1, 4.6 Hz), 0.92 (9 H, s), 2.93 (1 H, dd , J = 8.2, 1.7 Hz), 3.01 (1 H, dd, J = 11.2, 8.2 Hz), 3.64 (1 H, d, J = 5.5 Hz), 4.00 (1 H, d, J = 11.2 Hz), 5.17 (1 H, d, J = 10.5 Hz), 5.27 (1 H, d, J = 17.0 Hz), 5.97 (1 H, ddd, J = 17.0, 10.5, 5.5 Hz); ¹³ C NMR (150 MHz, CDC1 ₃ ) δ-4.6 (q), -3.0 (q), 7.9 (t), 10.8 (t), 18.1 (s), 25.8 (q), 26.5 (s), 67.6 (t), 80.5 (d) , 115.1 (t), 138.7 (d); FTIR (neat) 3422, 3078, 2957, 2932, 2885, 2858, 1471, 1417, 1390, 1361, 1253, 1115, 1033, 924 cm "¹; MS 242 [M ] ⁺ ; HRMS calcd. For [C ₁₃ H ₂₆₀ ₂ Si] 242.1702, found 242.1691.

(Example 21) 3- [61 "tributyldimethylsilyl) oxy] -2,2-butanol-4-enanol (3-[(tert_Butyldimethysilyl) oxy] _2, 2-ethanopent -4-enaK compound G)

While stirring a mixture of compound F (648 mg, 2.67 benzyl), powdered 4 A MS (100 mg) and NMO (795 mg, 2.5 eq) in CH ₂ C ₁₂ (20 mL), ° C under argon atmosphere And TPAP (94 mg, 0.1 eq). The reaction mixture was stirred at 0 ° C for 10 minutes, stirred at room temperature for 40 minutes, and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9) to give the aldehyde compound G (530 mg). ) Was obtained as a colorless oil (yield 83%). This colorless oil was used as such in the next step

_{1H NMR (600 MHz, CDC1 3} ) δ 0.04 (3 H, s), 0.06 (3 H, s), 0.89 (9 H, s), 1.02 (1 H, m), 1.09 (2 H, m), 1.16 (1 H, m), 4.53 (1 H, d, J = 5.5 Hz), 5.13 (1 H, d, J = 10.6 Hz), 5.29 (1 H, d, J = 17.3 Hz), 5.88 (1 H, ddd, J = 17.3, 10.6, 5.5 Hz), 9.17 (1 H, s); ¹³ C NMR (150 MHz, CDCI3) δ -4.9 (q), -2.9 (q), 11.8 (t), 12.1 (t), 18.2 (s), 25.8 (q), 36.9 (s), 70.6 (d), 115.0 (t), 138.8 (d), 201.7 (d); FTIR (neat) 2957, 2932, 2887, 2858 , 2733, 1713, 1471, 1402 , 1361, 1255, 1134, 1080, 1032, 929, 904, 837, 777 cm '1; MS 183 [M-'Bu] +;. HRMS calcd for [C 9 H 15 0 ₂ Si] 183.0841, found 183.0841.

(Example 22) 6-[(tert-butyldimethylsilyl) oxy] -5,5-ethanol-1 7-en-1 1-in-1 4-ole (6_ [(tert-butyl d imethys i lyl) oxy] — 5, 5-e thanooc t-7-en- 1 -yn-4-ο 1, compound H)

While stirring a solution of compound G (1.20 g, 5.01 ol) in dry ether (30 mL) at -78 under an argon atmosphere, propargyl magnesium bromide (2M in ether, 7.6 mL) , 3 eq). The reaction mixture was stirred for 50 minutes, quenched with saturated aqueous NH ₄ C1 and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the solvent was distilled off. The obtained crude mixture was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9) to give Compound H (979 mg) as a colorless oil (yield 70%).

Low polarity isomer: 1H NMR (600 MHz, CDC1 3) δ 0.04 (3 H, s), 0.08 (3 H, s), 0.44 (1 H, quint, J = 5.2 Hz), 0.50 (1 H, quint , J = 5.2 Hz), 0.68 (1 H, quint, J = 5.2 Hz), 0.75 (1 H, quint, J = 5.2 Hz), 0.91 (9 H, s), 2.01 (1 H, t, J = 2.5 Hz), 2.18 (1 H, ddd, J = 16.5, 5.8, 2.5 Hz), 2.27 (1 H, ddd, J = 16.5, 7.7, 2.5 Hz), 3.70 (1 H, br.s), 3.72 ( 1H, d, J = 5.5 Hz), 4.00 (1 H, br.t, J = 6.6 Hz), 5.19 (1 H, d, J = 10.5 Hz), 5.26 (1 H, d, J = 17.3 Hz) ), 5.89 (1 H, ddd, J = 17.3, 10.5, 5.5 Hz); 13 C NMR (150 MHz, CDC1 3) δ -4.9 (q), -4.3 (q), 8.0 (t), 8.2 (t), 18.0 (s ), 23.3 (t), 25.8 (q), 28.0 (s), 69.8 (s), 71.6 (d), 80.9 (d), 81.6 (d), 116.1 (t), 138.0 (d); FTIR (neat ) 3414, 3017, 2934, 2860, 1699, 1651, 1522, 1471, 1419, 1361, 1255, 1116, 1045, 922, 837, 775 cm- ¹ ; MS 223 [M-'Bu] ⁺ , 223 [M- ⁴ Bu-H ₂ 0] ⁺ ; HRMS calcd. For [C ₁₂ H ₁₉ 0 ₂ Si] 223.1154, found 223.1150.

High polarity isomer: ¾ NMR (600 MHz, CDC1 3) δ 0.02 (3 H, s), 0.07 (3 H, s), 0.51 (2 H, m), 0.70 (2 H, m), 0.92 (9 H, s), 2.01 (1 H, t, 7 = 2.5 Hz), 2.45 (1 H, ddd, J = 16.8, 8.3, 2.5 Hz), 2.58 (1 H, ddd, J = 16.8, 5.3, 2.5 Hz ), 3.02 (1 H, d, J = 5.8 Hz), 3.60 (1 H, dt, J = 8.5, 5.3 Hz), 3.72 (1 H, d, / = 5.8 Hz), 5.15 (1 H, d, J = 10.7 Hz), 5.26 ( 1 H, d, J = 17.0 Hz), 5.99 (1 H, ddd, J = 17.3, 10.5, 5.5 Hz); 13 C NMR (150 MHz, CDC1 3) δ -4.8 ( q), -4.5 (q), 7.1 (t), 10.4 (t), 18.1 (s), 25.8 (q), 26.0 (t), 27.9 (s), 70.0 (s), 73.5 (d), 79.5 (d), 82.1 (d), 115.1 (t), 139.4 (d); FTIR (neat) 3460, 3312, 3013, 2955, 2932, 2893, 2858, 2120, 1645, 1471, 1419, 1361, 1253, 1126 , 1032, 924, 839, 777 cm- 1; MS 223 [M- 4 Bu] +, 223 [Μ-'Βιι-Η 2 0] +;. HRMS calcd for [C 12 H 19 0 2 Si] 223.1154, found 223.1150.

(Example 23) 3,5-Bis [(tert-butyldimethylsilyl) oxy] -4,4-ethanooct-1-ene-7-yne (3,5-Bis [(tert-butyldimethysilyl) oxy) ]-4, 4 -ethanooct— l -en- 7 -yne

The mixture in dry CH ₂ C ₁₂ (3 mL) with t 2, 6-retidine (48 L, 2 eq) was stirred at 0 ° C. with stirring at 0 ° C. Under atmosphere, TBSOTf (75 L, 1.2 eq) was added. The resulting mixture was stirred for 10 minutes, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent was removed. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 10) to obtain Compound 1 (89 mg) as a colorless oil (yield: 86).

Low polarity isomer: 1H NMR (600 MHz, CDC1 3) δ -0.01 (3 H, s), 0.03 (3 Η, s), 0.05 (3 Η, s), 0.08 (3 Η, s), 0.44 ( 1Η, m), 0.49 (1Η, m), 0.54 (1Η, m), 0.57 (1Η, m), 0.88 (9 0.8, s), 0.89 (9Η, s), 1.92 (1Η , t, J = 2.5 Hz), 2.48 (1 H, ddd, J = 17.1, 7.2, 2.5 Hz), 2.55 (1 H, ddd, J = 17.1, 4.4, 2.5 Hz), 3.58 (1 H, dd, J = 7.2, 4.4 Hz), 3.91 (1 H, d, J = 7.2 Hz), 5.06 (1 H, d, J = 10.2 Hz), 5.12 (1 H, d, J = 17.1 Hz), 5.92 (1 H, ddd, J = 17.1, 10.2, 7.2 Hz); ¹³ C NMR (150 MHz, CDC1 ₃ ) δ -4.7 (q), -4.5 (q), -4.31 (q), -4.29 (q), 7.1 (t), 7.4 (t), 18.2 (s), 25.86 (q), 25.88 (q ), 27.0 (t), 29.5 (s), 69.4 (s), 73.4 (d), 76.0 (d), 83.4 (d), 114.6 (t), 141.1 (d); FTIR (neat) 3314, 3076, 3011, 2957, 2932, 2887, 2858, 2121, 1643, 1471, 1419, 1388, 1361, 1253, 1072, 1005, 937, 837, 775 cm ^-1 ; MS 394 [M] +; HRMS calcd. For [C ₂₂ ¾ ₂₀ ₂ Si ₂ ] 394.2724, found 394.2721.

Highly polar isomer: 1H NMR (600 MHz, CDCI3) δ -0.01 (3 H, s), 0.04 (3 H, s), 0.06 (3 H, s), 0.09 (3 H, s), 0.41 (2 H, m), 0.54 (1 H, m), 0.61 (1 H, m), 0.89 (9 H, s), 0.90 (9 H, s), 1.90 (1 H, t, J = 2.5 Hz), 2.41 (1 H, ddd, J = 16.8, 7.4, 2.5 Hz), 2.65 (1 H, ddd, J = 16.8, 3.6, 2.5 Hz), 3.78 (1 H, dd, J = 7.4, 3.8 Hz), 4.00 (1 H, d, J = 5.5 Hz), 5.09 (1 H, d, J = 10.4 Hz), 5.17 (1 H, d, J = 17.1 Hz), 5.80 (1 H, ddd, J = 17.1, 10.4 , 5.5 Hz); ¹³ C NMR (150 MHz, CDCI3) δ -4.7 (q), -4.33 (q), -4.30 (q), -4.2 (q), 6.7 (t), 7.4 (t), 18.16 (s), 18.18 (s), 25.90 (q), 25.94 (q), 26.9 (t), 29.3 (s), 69.3 (s), 71.6 (d), 75.9 (d), 83.4 (d), 114.8 (t), 139.4 (d); FTIR (neat) 3314, 3080, 3011, 2955, 2930, 2893, 2858, 2121, 1471, 1388, 1361, 1253, 1093, 1032, 1005, 937, 837, 775 cm "¹; MS 394 [M] ⁺ ; HRMS calcd. For [C ₂₂ 20 ₂ Si ₂ ] 394.2724, found 394.2729.

(Example 24) (5Z, 7E) -2,2-Ethano-9,10-seco-5,7,10 (19) -cholestatriene-1,3,25-triol Uol ((5Z, 7E) -2,2-Ethano-9,10-seco-5,7,10 (19) -cholestatriene-1, 3, 25-triol> Compound J)

Compound I (55 mg, 140 mol), (E) -de-A, B-8- (bromomethylene) cholestan-25-ol (Compound K) (10 mg, 28 mol) and triethylamine (0.5 mL) ) And (Ph ₃ P) ₄ Pd (16 mg, 14 mol) were added to the mixture in toluene (2 mL) at room temperature under an argon atmosphere, followed by stirring at room temperature for 10 minutes. After refluxing under heat for 70 minutes, the reaction mixture was diluted with ether and the whole was filtered through a silica gel pad (Merck silica gel 60), and then the solvent was distilled off. The resulting crude mixture is subjected to silica gel preparative thin-layer chromatography (ethyl acetate: n-hexane).

= 1: 3) to give a crude product (7.8 mg) containing a protected form of the title compound. A solution of the crude product (7.8 mg) in THF (3 mL) was stirred at 0 with stirring. Under a nitrogen atmosphere, TBAF (1.0 M in THF, 90 il, 90 imol) was added. The reaction mixture was stirred at room temperature for 20 hours, brine was added, and the whole was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent was distilled off. The resulting crude mixture was purified by silica gel preparative thin-layer chromatography (ethyl acetate: n-hexane = 1: 2) to give Compound J (5.9 mg, 48% from two steps) as a white solid. Was. The white solid was further separated and purified by reversed-phase recycling HPLC (YMC-Pack ODS column, 20 150 mm, 9.9 mL / min, acetonitrile: water = 85:15), and the biological activity was evaluated. . The obtained purified compound was subjected to reverse phase HPLC for analysis (Licros orb RP-18 column, 4 × 250 thigh, 1.0 mL / min, acetonitrile: water = 75: 25) to give compound J ad Were each obtained as a single homogeneous peak.

_{10a: t R = 10.441 min;} UV (EtOH) max 266 nm, λ 228 nm; 1H NMR (600 MHz, CDC1 3) δ 0.48-0.58 (2 H, m), 0.55 (3 H, s), 0.62 ( 2H, m), 0.94 (3H, d, J = 6.3 Hz), 1.22 (6 H, s), 2.36 (1 H, dd, J = 12.9, 7.7 Hz), 2.66 (1 H, dd, J = 13.2, 3.6 Hz), 2.84 (1 H, dd, J = 12.9, 4.4 Hz), 3.86 (1 H, dt, J = 7.2, 4.4 Hz), 3.93 (1 H, d, J = 4.1 Hz), 5.01 (1 H, s), 5.23 (1 H, s), 6.05 (1 H, d, J = 11.3 Hz), 6.43 (1 H, d, J = 11.0 Hz); 13 C NMR (150 MHz, CDC1 3 ) δ 5.9, 6.0, 12.0, 18.8, 20.8, 22.3, 23.6, 27.6, 29.1, 29.22, 29.25, 29.36, 36.1, 36.4, 40.5, 44.4, 45.5, 45,9, 56.4, 56.5.70.6, 71.1, 76.3, 112.5, 117.1, 124.9, 133.2, 143.1, 146.6; MS 442 [M] +, 424 [MH 2 0] +, 406 [M-2H 2 0] +;. HRMS calcd for [ Ji ₂₉ ¾ ₆ 0 _3] 442.3447 , Found 442.3459.

_{10b: t R = 10.805 min;} UV (EtOH) max 267 nm, 228 nm; 1H NMR (600 MHz, CDC1 3) δ 0.46 (1 H, m), 0.55 (3 H, s), 0.58 (2 H, m), 0.60 (1 H, m), 0.94 (3H, d, J = 6.6 Hz), 1.22 (6 H, s), 2.37 (1 H, dd, J = 13.2, 6.3 Hz), 2.66 (1 H , dd, J = 13.2, 3.0 Hz), 2.84 (1 H, dd, J = 12.6, 4.1 Hz), 3.73 (1 H, m), 4.07 (1 H, d, J = 5.0 Hz), 5.01 (1 H, s), 5.24 (1 H, s), 6.06 (1 H, d, J = 11.3 Hz), 6.41 (1 H, d, J = 11.3 Hz); 13 C NMR (150 MHz, CDC1 3) δ 5.7, 6.2, 12.0, 18.8, 20.8, 22.3, 23.6, 29.1, 29.19, 29.22, 29.37, 36.1, 36.4, 40.5, 44.2, 44.4, 45.9, 56.4, 56.5, 71.1, 71.8, 111.7, 117.1, 124.9, 133.3, 144.4, 147.0; MS 442 [M] +, 424 [MH ₂ 0] ⁺ , 406 [M-2H ₂ 0] ⁺ ; HRMS calcd. For [C ₂₉ H ₄₆ 0 ₃ ] 442.3447, found 442.3448. _{10c: t R = 14.133 min;} UV (EtOH) max 268 nm, 227 nm; 1H NMR (600 MHz, CDC1 3) δ 0.45 (2 H, m), 0.56 (3 H, s), 0.80 (2 H, m), 0.94 (3H, d, J = 6.6 Hz), 1.22 (6 H, s), 2.47 (1 H, d, J = 4.7 Hz), 2.57 (1 H, dd, J = 13.8, 2.8 Hz) , 2.69 (1 H, d, J = 13.7 Hz),

2.86 (1 H, dd, J = 12.7, 4.4 Hz), 3.02 (1 H, d, J = 7.2 Hz), 3.16 (1 H, m), 3.38 (1 H, d, J = 3.6 Hz), 5.03 (1 H, d, J = 1.7 Hz), 5.19 (1 H, d, J = 1.7 Hz), 6.12 (1 H, d, J = 11.3 Hz),

6.54 (1 H, d, J = 11.0 Hz); 13 C NMR (150 MHz, CDC1 3) δ 10.0, 10.6, 11.9, 18.8, 20.8, 22.4, 23.7, 27.63, 27.67, 29.1, 29.25, 29.36, 36.1, 36.4, 40.5, 44.2, 44.4, 46.0, 56.4, 56.5, 71.1, 76.2, 82.7, 114.7, 116.9, 126.6, 130.8, 143.3, 145.9; MS 442 [M] ⁺ , 424 [MH ₂₀ ] ⁺ , 406 [M -2¾0] +, 388 [M-3H ₂ 0] ⁺ ; HRMS calcd. For [C ₂₉ H ₄₆ 0 ₃ ] 442.3447, found 442.3441. LOd: t _R = 16.448 min; UV (EtOH) _max 267 nm, 227 nm ; 1H NMR (600 MHz, CDCI3) δ 0.45 (2 H, m), 0.54 (3 H, s), 0.80 (2 H, m), 0.93 (3H, d, J = 6.3 Hz), 1.22 (6 H , s), 2.42 (1 H, d, J = 4.7 Hz), 2.57 (1 H, dd, J = 14.0, 2.8 Hz), 2.69 (1 H, d, 7 = 13.7 Hz),

2.87 (1 H, dd, J = 14.0, 4.1 Hz), 3.08 (1 H, d, J = 7.2 Hz), 3.18 (1 H, m), 3.38 (1 H, d, J = 4.7 Hz), 5.00 (1 H, d, / = 1.9 Hz), 5.17 (1 H, d, J = 1.9 Hz), 6.07 (1 H, d, J = 11.3 Hz), 6.55 (1 H, J = 11.0 Hz); ¹³ _{C NMR (150 MHz, CDC1 3} ) δ 9.9, 12.1, 14.7, 18.8, 20.8, 22.2, 23.4, 27.7, 29.1, 29.19, 29.38, 36.1, 36.4, 40.6, 44.2, 44.4, 45.9, 55.4, 56.5, 71.1, 76.4, 82.7, 114.2, 114.6, 117.1, 126.7, 130.5, 148.0; MS 442 Oka +, 424 [MH ₂ 0] +, 406 [M- 2H ₂ 0] ⁺ , 388 [M-3H ₂ 0] ⁺ ; HRMS calcd. for [J _{29 6} 0 ₃ ] 442.3447, found 442.3445. (Example 25) 1, 1-bis (hydroxymethyl) cyclobutane (1,1-Bis Oiyd r oxyme t hy 1) cy c 1 obu t ane ^ 匕合 LI)

To a suspension of LiAlH ₄ (3.79 g, 97.5 mmol) in THF (50 mL) was added getyl 1,1-cyclobutanecarboxylate (13.0 g, 64.9 mmol) in THF ( (50 mL) was added dropwise at 0 ° C. After the addition, the reaction mixture was stirred at 0 ° C for 30 minutes. At 0 ° C., water (4 mL) was added to the reaction mixture, followed by 2 N HCl aqueous solution (20 mL). The reaction mixture was diluted with ethyl acetate (100 mL), filtered through celite, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. Removed below. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) to give compound L 1 (7.40 g) as a colorless oil (98% yield).

_{¾ NMR (600 MHz, CDC1 3} ) δ 1.80 (4 H, t, / = 7.4 Hz), 1.94 (2 H, q, / = 7 .4 Hz), 2.30 (2 H, br.s), 3.75 ( ^{4 H, s); 13 C} NMR (150 MHz, CDC1 3) δ 15.4 (t), 25.7 (t), 43.2 (s), 70.0 (t); MS 116 [M] +;. HRMS calcd for [C ₆ H ₁₂ 0 ₂ ] 116.0837, found 116.0840.

(Example 26) 3-[(4-Methoxybenzyl) oxy] -2,2-propanopropane-1-ole (3-[(4-Methoxybenzyl) oxy] -1,2-propanopropan-l -ol> 匕合 M M 1)

While stirring a suspension of NaH (1.38 g, 60% in mineral oil, 34.4 thigh 01) in 1) ¾ ^ (20 mL), the diol compound L 1 (1, tribis (hydroxymethyl ) A solution of cyclobutane) (4.00 g, 34.4 ol) in DMF (40 mL) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 20 minutes. PMBC1 (5.6 mL, 1.2 eq) was added to the reaction mixture at 0 ° C. The reaction mixture was stirred at room temperature for 130 minutes. After water was added to the reaction mixture at 0 ° C., the whole was extracted with ether. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 3) to give compound Ml (1.88 g) as a colorless oil (yield 86).

¾ thigh _{(600 MHz, CDC1 3) δ} 1.75-1.95 (6 H, m), 2.57 (1 H, br.s), 3.53 (2 H, s), 3.67 (2 H, s), 3.81 (3 H , s), 4.46 (2 H , s), 6.88 (2 H, d, / = 8. 8 Hz), 7.25 (2 H, d, / = 8.8 Hz); 13 C NMR (150 MHz, CDC1 3) δ 15.7 (t), 26.3 (i), 42.5 (s), 55.3 (q), 69.8 (t), 73.2 (t), 77.6 (t), 129.2 (d), 130.1 (s), 159.3 (s); MS 236 [ M] +;. HRMS calcd for [C 14 H 20 0 3] 236.1413, found 236.1412.

(Example 27) 3-[(4-Methoxybenzyl) oxy] -2,2-propanopropanal (3-[(4-Methoxybenzyl) oxy] -2,2_propanopropanal, N1 conjugate)

Compound Ml (1.09 g, 4.61 mmol), powdered 4 A MS (250 mg), 丽 0 (1. 24 g, while stirring the mixture of CH ₂ C1 in ₂ (20 mL) with 10.6 negation ol), at 0 ° C under argon Kiri囲gas, TPAPa40 mg, was treated with 0.40 negation ol). The reaction mixture was stirred at room temperature for 20 minutes, and silica gel column chromatography (ethyl acetate n-hexane =

Purification by 1: 9) afforded the aldehyde, compound N 1 (644 mg), as a colorless oil (65% yield). This colorless oil was used as such in the next step.

_{¾ NMR (600 MHz, CDC1 3} ) δ 1.85-2.00 (6 H, m), 2.37-2.40 (2 Η, m), 3.69 (2 Η, s), 3.83 (3 Η, s), 4.48 (2 Η , s), 6.90 (2 Η , d, / = 8.2 Hz), 7.25 (2 H, d, / = 8.5 Hz), 9.67 (1 H, s); 13 C NMR (150 MHz, CDC1 3) δ 15.7 (t), 24.4 (t), 27.2 (t), 52.4 (s), 55.3 (q), 72.1 (t), 73.0 (t), 113.8 (d), 1 29.2 (d), 130.1 (s), 159.3 (s), 203.1 (d); FTIR (neat) 2945, 2856, 2716,

1722, 1612, 1585, 1514, 1462, 1359, 1302, 1248, 1174, 1089, 1033, 817 cm one ^{^{1; MS 234 [M] +}} ;. HRMS calcd for [C 14 H 18 0 3] 234.1256, found 234.1253 .

(Example 28) 5-[(4-methoxybenzyl) oxy] -4,4-propanovent-1-ene-3-ole

Bier magnesium bromide (1.0 M in THF, 2.9 mL, 1.1 eq) at -78 ° C under an argon atmosphere while stirring a solution of compound N1 (622 mg, 2.65 ol) in dry toluene (6 mL) Was dropped. The reaction mixture was stirred for 55 minutes, the reaction was quenched by the addition of saturated NH ₄ C1 aqueous solution, then extracted with acetate Echiru. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the solvent was distilled off. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9) to give compound Ol (592 mg) as a colorless oil (yield 85%). _{¾ NMR (600 MHz, CDC1 3} ) δ 1.55-1.60 (1 H, m), 1.85-1.95 (4 Η, m), 2.10-2 .15 (1 Η, m), 3.32 (1 Η, d, 7 -7.4 Hz), 3.53 (1 H, dd, / = 9.1, 1.1 Hz), 3.60 (1 H, dd, J = 9.1, 1.1 Hz), 3.81 (3 H, s), 4.15 (1 H, br. t, J = 6.3 Hz), 4.43 (2 H, s), 5.18 (1 H, dt, / = 10.7, 1.4 Hz), 5.32 (1 H, dt, J = 17.0, 1.6 Hz), 5.88 ( 1 H, ddd, J = 17.0, 10.4, 6.3 Hz), 6.88 (2 H, d , / = 8.5 Hz), 7.24 (2 H, d, / = 8.5 Hz); 13 C NMR (150 MHz, CDC1 3) δ 15.2 (t), 25.7 (t), 27.3 (t), 44.4 (s) , 55.3 (q), 73.3 (t), 75.9 (0, 79.2 (d), 113.8 (d), 115.6 (t), 129.3 (d), 129.8 (s), 137.3 (d), 159.3 (s); FT IR (neat) 3489, 3072, 2978, 2943, 2858, 2060, 1884, 1720, 1697, 1684, 16 12, 1514, 1464, 1359, 1302, 1248, 1174, 1035, 993, 924, 821 cm " ¹ ^{; MS 262 [M] +;} . HRMS calcd for [C 16 H 22 0 3] 262.1569, found 262.1563.

Example 29 3-[(tert-butyldimethylsilyl) oxy] -5-[(4-methoxybenzyl) oxy] -4,4-propanovent-1-ene (3-[(tert-butyldimethysilylyl) ) oxy]-5 _ [(4-methoxybenzyl) oxy 」-4,4_propa

Compound 〇 1 (582 mg, 2.22 thigh ol) and 2, 6-lutidine with stirring mixture of (0.6 mL, 2 eq) dry the C¾C1 ₂ (6 mL) in an argon atmosphere at 0 ° C, TBS0Tf (0.8 mL, 1.2 eq) was added. The resulting mixture was stirred for 15 minutes, diluted with ethyl acetate and washed with water and then brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent was removed. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 10) to give compound P1 (735 mg) as a colorless oil (yield 88%).

^{1 H NMR (600 MHz, CDC1} 3) δ 0.01 (3 H, s), 0.05 (3 H, s), 0.89 (1 H, m), 1.55-1.60 (1 H, m), 1.70-1.85 (3 H, m), 1.97-2.07 (2 H, m), 3.34 (1 H, d, J = 9.1 Hz), 3.46 (1 H, d, J = 9.1 Hz), 3.81 (3 H, s) , 4.12 (1 H, d, J = 7.1 Hz), 4.40 (1 H, d, J = 11.8 Hz), 4.46 (1 H, d, J = 11.8 Hz), 5.07 (1 H, dq, J = 10.4 , 1.1 Hz), 5.14 (1 H, dq, J = 17.3, 1.1 Hz), 5.78 (1 H, ddd, J = 17.3, 10.4, 7.1 Hz), 6.88 (2 H, d, J = 8.8 Hz ), 7.26 (2 H, d , J = 8.8 Hz); 13 C NMR (150 MHz, CDC1 3) δ -3.9 (q), -2.9 (q), 15.2 (t), 18.2 (s), 24.5 ( t), 24.8 (t), 25.9 (q), 46.4 (s), 55.3 (q), 72.9 (t), 73.9 (t), 76.4 (d), 113.7 (d), 115.6 (t), 129.0 ( d), 131.0 (s), 138.4 (d), 158.9 (s); FTIR (neat) 3080, 2955, 3934, 2887, 2856, 1614, 1514, 1462, 1359, 1302, 1250, 1172, 1078, 1039, 924, 837, 775 cm "1; MS 319 [M- ^ u] *;. HRMS calcd fo r [C 18 H 27 0 3 Si] 319.1730, found 319.1731.

(Example 30) 3-[(tert-butyldimethylsilyl) oxy] -2,2-propanant-4-en-1-ol (3-[(3-[(tert-Butyldimethysilyl) oxy]- 2,2-propanope nt-4-en-l-oU compound Q1)

Compound? 1 (735 mg, 1.95 thigh ol) was dissolve in a mixture of CH ₂ C1 ₂ and (10 mL) and water (1 mL). The resulting solution was treated with DDQ (664 mg, 1.5 eq) at 0 ° C with stirring. After stirring at 0 ° C for 20 minutes, the reaction mixture was diluted with ethyl acetate (80 mL). The organic layer was washed with saturated NaHCO ₃ solution and brine, dried over magnesium sulfate, filtered and evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 11) to give compound Q1 (444 mg) as a colorless oil (yield 89%).

^{X E MR (600 MHz, CDC1} 3) δ 0.05 (3 Η, s), 0.11 (3 Η, s), 0.90 (9 Η, s), 1.43-1.48 (1 Η, m), 1.72-1.77 (1 Η, m), 1.81-1.87 (1 ,, m), 1.89-1.96 (2 Η, m), 2.07-2.13 (1 Η, m), 3.12 (1 Η, dd, J = 8.6, 2.0 Hz), 3.59 (1 Η, ddd, J = 11.0, 8.6, 1.0 Hz), 3.83 (1 H, ddd, J = 11.0, 1.8, 1.2 Hz), 4.25 (1 H, dd, J = 6.4, 1.0 Hz), 5.18 (1 H, dt, J = 10.5, 1.5 Hz), 5.24 (1 H, dt, J = 17.3, 1.6 Hz), 5.85 (1 H, ddd, J = 17.1, 10.6, 6.5 Hz); ¹³ C _{NMR (1 50 MHz, CDC1 3} ) - 5.1, -4.2, 15.1, 18.0, 25.9, 27.5, 45.4, 67.2, 82.4, 116.3, 136.8; FTIR (neat) 3447, 3079, 2955, 2932, 285 9, 1643, 1471, 1253, 1074, 1028, 924, 837, 777 cm "¹; MS 199 [M- ^ u]" * "; HRMS calcd. For [C ₁₀ H ₁₉ O ₂ Si] 199.1154, found. 199.1162.

(Example 31) 3-[(tert-Butyldimethylsilyl) oxy] _2,2_propanopent-4-enal (3 _ [(tert-ButyldimethysiIyl) oxy] -2,2-propanopent-4-enal, compound R 1)

Compound Ql (238 mg, 0.93 tmol) and powdered 4 A MS (50 mg) and awake 0 (273 mg, 2.5 eQ) and the mixture in CH ₂ C ₁₂ (7 mL) with stirring at 0 ° C under argon.

And TPAP (33 ig, 0.1 eq). The reaction mixture was stirred at room temperature for 2 hours 15 minutes.

The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9) to obtain an aldehyde compound R 1 (201 mg) as a colorless oil (yield: 85%). This colorless oil was used as such in the next step.

_{λΗ MR (600 MHz, CDC1 3} ) δ 0.04 (3 Η, s), 0.08 (3 Η, s), 0.89 (9 Η, s), 1.82 (2 Η, m), 1.95 (1 Η, m), 2.03 (1 Η, m), 2.20 (2 Η, m), 4.33 (1 Η, d, J = 6.9 Hz), 5.18 (1 Η, dt, J = 10.3, 1.4 Hz), 5.25 (1 5., dt) , J = 17.3, 1.4 Hz) , 5.80 (1 H, ddd, J = 17. 3, 10.3, 6.9 Hz), 9.72 (1 H, s); 13 C NMR (150 MHz, CDC1 3) -5.0 (q ), -4.1 (q), 14.9 (t), 18.1 (s), 23.2 (t), 24.7 (t), 25.7 (q), 56.5 (s), 76.9 (d), 116.8 (t), 136.7 ( d), 203.7 (d); FTIR (neat) 2955, 2932, 2895, 2858, 2712, 1720, 1471, 1255, 1080, 1026, 989, 929, 837, 777 cm "¹; MS 239 [M-Me] ^{+ HRMS calcd. fo r [Ci} 3 H 23 0 2 Si] 239.1479, found 239.1468.

(Example 32) (4 ^, 6 ^)-6-[(tert-butyldimethylsilylyl) oxy] -5,5-propanoct-7-en- ^1- yn-4-ol ((4AS ¹ ,-6-[(tert-Butyldimethys ylyl) oxy] -5, 5-propanooct-7-en- 1 -yn-4-οΚ compound Sa 1) and 6-[(tert-butyldimethylsilyl) oxy] _5, 5-propanooct-7-en-1-yn-4-ol (iRS, 6 — 6- [(tert-ButyldimethysilyDoxy]-5, 5-propanooct-7-en-l-yn-4-οΚ compound Sbl)

While stirring a solution of compound Rl (201 mg, 0.79 bandol) in dry ether (4 mL) at -78 under an argon atmosphere, propargyl magnesium bromide (2M in ether, 1.2 mL, 3 eq) was added. The reaction mixture was stirred for 20 minutes, quenched by the addition of saturated aqueous NH ₄ C1 and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the solvent was distilled off. The resulting crude mixture was purified by silica gel column chromatography (CH ₂ C1 _2: the n- hexane = 1: 2) to obtain the compound Sal (78 mg, the less polar isomer) and Compound Sb 1 (144 mg, th e more polar isomer) was obtained as a colorless oil (96% yield).

Compound ^{Sal: X H NMR (600 MHz} , CDC1 3) δ.0.04 (3 Η, s), 0.10 (3 Η, s), 0.91 (9 Η, s), 1.76-1.94 (4 Η, m), 2.00 -2.10 (2 Η, m), 2.03 (1 Η, t, J = 2.8 Hz), 2.37 (1 Η, ddd, J = 16.8, 9.6, 2.8 Hz), 2.60 (1 H, dt, J = 16.8, 2.8 Hz), 2.65 (1 H, d, J = 4.7 Hz), 3.79 (1 H, ddd, J = 8.0, 4.4, 3.3 Hz), 4.26 (1 H, dt, J = 6.9, 1.4 Hz), 5.17 (1 H, dt, J = 10.4, 1.4 Hz), 5.24 (1 H, dt, J = 17.3, 1.4 Hz), 5.90 (1 H, dt, J = 17.3, 10.4, 6.9 Hz); ¹³ CN MR (150 MHz, CDCI3) δ -5.0 (q), -3.9 (q), 14.8 (t), 18.1 (s), 23.6 (t), 24.3 (t), 24.4 (t), 25.9 (q ), 49.0 (s), 70.0 (s), 73.2 (d), 79.1 (d), 82.6 (d), 116.3 (t), 137.6 (d); FTIR (neat) 3412, 3312, 2955, 2891, 2858, 2130, 1471, 1421, 1361, 1253, 1074, 1043, 925, 835, 775 cm "¹; MS 237 [M- ^ u]"", 219 [M- ^ u-Hz 0] ⁺ ; HRMS calcd for [C ₁₃ H ₂₁ 0 ₂ Si] 237.1310, found 237.1326.

Compound Sbl: ^ NMR (600 MHz, CDC1 3) δ.0.07 (3 H, s), 0.12 (3 H, s), 0.89 (9 H, s), 1.74-1.90 (5 H, m), 2.04 ( 1 H, t, J = 2.8 Hz), 2.12-2.17 (1 H, m), 2.51 (1 H, ddd, J = 16.5, 8.3, 2.8 Hz), 2.55 (1 H, dddd, J = 16.5, 4.4, 2.8, 0.8 Hz), 3.98 (1 H, d dd, J = 8.3, 4.4, 1.9 Hz), 4.11 (1 H, s), 4.31 (1 H, d, J = 6.6 Hz), 5.24 (1 H, dt, J = 10.7, 1.7 Hz), 5.27 (1 H, dt, J = 17.3, 1.1 Hz), 5.92 (1 H, dt, J = 17.3, 10.7, 6.6 Hz); ¹³ C NMR (1 50 MHz, CDCI3) δ -5.1 (q), -4.0 (q), 14.8 (t), 18.0 (s), 22.8 (t), 24.5 (t), 25.4 (t), 25.8 (q) , 47.4 (s), 69.4 (s), 72.9 (d), 82.5 (d), 82.6 (d), 117.4 (t), 136.0 (d); FTIR (neat) 347 8, 3314, 2955, 2932, 2885 , 2858, 2121, 1471, 1419, 1361, 1255, 1043, 1005, 925, 837, 777 cm "¹; MS 237 [M- ^ u] ⁴ , 219 〖Μ- τα-Η ₂₀ ] ⁺ ; HRMS calcd . for [C ₁₃ H ₂₁ 0 ₂ Si] 237.1310, found 237.1307.

(Example 33) (3? & 5) -3,5-Bis [(tert-butyldimethylsilyl) oxy] _4,4-propanooct-1-en-7-yne ((3 ^, 5 ^)- 3, 5-Bis [(tert-butyldiiet hysilyOoxy] -4, 4-propanooc tl-en-7-yne compound Ta 1) A mixture of compound Sal (95 mg, 0.32 mmol) and 2,6-lutidine (60 fil, 2 eq) in dry CH ₂ C ₁₂ (6 mL) was stirred at 0 ° C. under an argon atmosphere. TBSOTf (110 ill, 1.2 eq) was added. The resulting mixture was stirred for 2 hours, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent was removed. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 10) to give compound Tal (124 mg) as a colorless oil (yield 95%).

^{X H MR (600 MHz, CDC1} 3) δ.0.03 (3 H, s), 0.07 (3 Η, s), 0.08 (3 Η, s), 0.15 (3 Η, S), 0.90 (9 Η, S ), 0.94 (9 Η, s), 1.64-1.87 (4 Η, m), 1.92 (1 Η, t, J = 2.8 Hz), 2.03 (1 Η, dt, J = 11.8,

9.4 Hz), 2.08 (1 H, dt, J = 11.6, 8.5 Hz), 2.30 (1 H, ddd, J = 17.3, 6.3, 2.7 Hz), 2.53 (1 H, ddd, J = 17.3, 4.1, 2.7 Hz), 3

.84 (1 H, dd, J = 6.3, 4.1 Hz), 4.25 (1 H, d, J = 7.2 Hz), 5.1

4 (1 H, ddd, J = 10.4, 1.9, 1.1 Hz), 5.21 (1 H, ddd, J = 17.0, 1.9, 1.1 Hz), 5.94 (1 H, ddd, J = 17.0, 10.4, 6.9 Hz) ; ¹³ C NMR (150 MHz, CDCI3) δ -4.6 (q), -3.7 (q), -3.6 (q), 14.9 (t), 18

.2 (s), 18.3 (s), 23.2 (t), 23.6 (t), 25.9 (q), 26.0 (q), 50.

7 (s), 69.7 (s), 73.2 (d), 76.4 (d), 83.6 (d), 115.8 (t), 138

.4 (d); FTIR (neat) 3314, 2955, 2932, 2889, 2858, 2121, 1471, 1361, 1255, 1061, 924, 837, 775 cm "¹; MS 408 [M] ⁺ , 393 [M- Me] ⁺

, 369 [M-tBur, ' HRMS calcd. For [C 23 H 44 0 2 Si 2] 408.2880, found. 40

8.2872.

(3W, 5A5)-3,5-Bis [(tert-butyldimethylsilyl) oxy] -4,4-propanooct-1-en-7-yne ((3 ^, 5 ^) -3,5- Bis [(tert-butyldimethysilyl) oxy] -4, -propanooc tl-en-7-yne> Compound 1)

Similarly, compound Tbl was synthesized from compound Sbl.

_{¾ MR (600 MHz, CDC1 3} ) δ.0.03 (3 H, s), 0.08 (6 H, s), 0.15 (3 H, s), 0.915 (9 H, s), 0.918 (9 H, s) , 1.68-1.91 (4 H, m), 1.94 (1 H, t, J = 2.8 Hz), 2.00-2.10 (2 H, m), 2.32 (1 H, ddd. J = 17.6, 6,3, 2.8 Hz), 2.44 (1 H, ddd, J = 17.6, 3.9, 2.8 Hz), 2.79 (1 H, dd, J = 6.3, 3.9 Hz), 4.16 (1 H, d , J = 7.7 Hz), 5.06 (1 H, ddd, J = 10.2, 1.9, 0.8 Hz), 5.12 (1 H, ddd, J = 17.3, 1.9, 1.1 Hz), 5.88 (1 H, ddd, J = 17.3, 10.2, 8.0 Hz ); 13 C negation _{R (150 MHz, CDC1 3)} δ -4.9 (q), -4.6 (q), -3.9 (q), -3.8 (q), 15.0 (t) , 18.2 (s), 18.3 (s), 24.0 (t), 24.7 (t), 25.7 (t), 2 5.9 (q), 26.0 (q), 51.0 (s), 69.7 (s), 75.8 (d ), 77.8 (d), 83.7 (d), 115.6 (t), 138.9 (d); FTIR (neat) 3314, 2955, 2932, 2 889, 2858, 2121, 1471, 1361, 1255, 1064, 925 , 835, 775 cm "¹; MS 408 [M] ⁺ , 393 [M-Me] ⁺ , 369 [M- ^ u]""; HRMS calcd. For [C ₂₃ H ₄₄ 0 ₂ Si ₂ ] 408.2880, found 408.2880.

(Example 34) (5Z, 7E)-(1 & 3-2,2-propano-9,10-seco-5,7,10 (19) -cholestatriene-1,3,25-triol ((5Z , m- (lS, ZR) -2, 2-Propano-9, 10-sec 0-5, 7, 10 (19) -cholestatriene-l, 3, 25-trioU compounds Ual) and (5Z, 7E)- (li?, 3S) -2,2-Propano-9,10-seco-5,7,10 (19) -Cholestriene-1,3,25-triol ((5Z, 7E)-( 3-2, 2-Propano-9, 10-seco-5, 7, 10 (19) -cholestatriene-l, 3, 25-trioK Compound Ub 1)

Compound Tal (30 mg, 73 mol), (E) -de-A, B-8- (bromomethylene) cholestin-25-ol (Compound K) (29 mg, 81 niol) and triethylamine (1.5 (Ph ₃ P) ₄ Pd (43 mg, 37 iiol) was added to a mixture of (mL) t in toluene (4.5 mL) at room temperature under an argon atmosphere, followed by stirring at room temperature for 10 minutes. After refluxing for 45 minutes under heating, the reaction mixture was diluted with ether, the whole was filtered through a silica gel pad (Merck silica gel 60), and then the solvent was distilled off. The resulting crude mixture was purified by silica gel preparative thin-layer chromatography (ethyl acetate: n-hexane = 1: 3) to give a crude product (24 mg) containing the protected compound of the title compound.

While stirring a solution of the obtained crude product (24 mg) in THF (3 mL), TBAF (1.0 M in THF, 350 βΐ, 350 mol) was added at 0 ° C. under an argon atmosphere. The reaction mixture was stirred at room temperature for 20 hours, brine was added, and the whole was extracted with ethyl acetate. Organic The layer was dried over magnesium sulfate, filtered, and the solvent was distilled off. The resulting crude mixture was purified by silica gel preparative thin-layer chromatography (ethyl acetate: n-hexane = 2: 3) to give compounds Ual and Ubl (12 mg, 36 from two steps) as a white solid. . The white solid was further separated and purified by reversed-phase recycling HPLC (YMC-Pack ODS column, 20 × 150 mm, 9.9 mL / min, acetonitrile: water = 90: 10), and the biological activity was evaluated.

Compound Ual: Ή NMR (600 MHz, CDC1 3) δ 0.55 (3 H, s), 0.94 (3Η, d, / = 6 .6 Hz), 1.22 (6 H, s), 1.99 (2 H, m) , 2.17 (2 H, m), 2.39 (1 H, dd, / =

14.3, 3.0 Hz), 2.40 (1 H, s), 2.54 (1 H, d, / = 14.0 Hz), 2.84 (1 H, dd, / = 12.9, 4.9 Hz), 2.96 (1 H, d, / = 7.4 Hz), 3.49 (1 H, s), 3.97 (1 H, m), 4.23 (1 H, d, / = 3.6 Hz), 5.06 (1 H, d, / = 2.2 Hz), 5.29 (1 H, d, / = 1.9 Hz ), 6.08 (1 H, d, / = 11.3 Hz), 6.46 (1 H, d, / = 11.3 Hz); 13 C NMR (150 MHz, CDC1 3) δ 11,9 , 14.5, 18.5, 20.8, 22.4, 23.7, 26.7, 27.6, 28.1, 29.1, 29.2, 29.3, 36.1, 36.4, 40.4, 40.6, 44.4, 45.9, 46.1, 56.3, 56.5, 71.1, 75.9, 81.9, 115.8, 116.9 , 125.9, 131.1, 143.0, 144.8; MS 456 [M] ⁺ , 438 [M-H ₂ 0] ⁺ , 420 [M-2H ₂ 0] ⁺ , 410 [M—H ₂ 0 — C ₂ H ₄ ] ^{_{+, 402 [M-3H 2}} 0] +, 392 [M-2H 2 0-C 2 H 4] +;. HRMS calcd for [C 30 H 48 O 3] 456.3604, found 456.3605.

Compound Ubl: ¾ NMR (600 MHz, CDC1 3) δ 0.53 (3 H, s), 0.93 (3H, d, / = 6 .6 Hz), 1.21 (6 H, s), 1.99 (2 H, m) , 2.17 (2 H, m), 2.35 (1 H, d, / = 4.7 Hz), 2.38 (1 H, dd, / = 14.0, 3.6 Hz), 2.53 (1 H, d, J = 14.3 Hz) ), 2.84 (1 H, dd, 13.6, 4.1 Hz), 3.02 (1 H, d, / = 7.4 Hz), 3.49 (1 H, d, 2.8 Hz), 3.94 (1 H, m), 4.21 (1 H, d, / = 4.4 Hz), 5.01 (1 H, d, J = 2.2 Hz), 5.27 (1 H, d, / = 1.9 Hz), 6.02 (1 H, d, / = 11.3 Hz) ), 6.45 (1 H, d , J = 11.0 Hz); 13 C NMR (150 MHz, CDC1 3) δ 12.1, 14.6, 18.8, 20.8, 22.2, 23.4, 26.5, 27.7, 28.0, 29.0, 29.2, 29.4, 36.1, 36.4, 40.5, 40.6,

44.4, 45.9, 46.2, 56.3, 56.5, 71.1, 75.9, 81.8, 115.6, 116.9, 125.9, 130.9, 142.9, 144.7; MS 456 [M] ⁺ , 438 [M-¾0] ⁺ , 420 [M-2H ₂ 0] ⁺ , 410 [M-¾0-C ₂ ] +, 402 [-3H ₂ 0] ⁺ , 392 [M-2¾0-C ₂ H ₄ ] ⁺ ; HRMS calcd. For [C ₃₀ H ₄₈ 0 ₃ ] 456.3604, f sound 456.3590.

(5Z, W-(\ R, 3-2,2-propano-9,10-seco_5,7,10 (19) -choles triene-1,3,25-triol ((5Z, 7E)- (3-2, 2-Propano-9, 10-seco-5, 7, 10 (19) -cholestatriene-l, 3,25-trioK Compound Ucl) and (5Z, 7E)-(1 & 3-2,2 -Propano-9,10-seco—5,7,10 (19) -Cholesteric triene—1,3,25-triol ((5Z, 7E)-(IS, 3-2,2—Propano-9, 10-seco- 5, 7, 10 (19) -cholestatr iene-1, 3, 25-trioK compound Udl)

Similarly, compounds Uc1 and Ud1 were synthesized from compound Tb1.

Compound ^{Ucl: l R NMR (600 MHz} , CDC1 3) δ 0.53 (3 H, s), 0.93 (3H, ά, U = 6.3 Hz), 1.21 (6 H, s), 2.19 (1 H, d, / = 13.5, 7.7 Hz), 2.49 (1 H, dd, / = 13.8, 3.6 Hz), 2.81 (1 H, dd, / = 12.7, 4.4 Hz), 3.49 (1 H, s), 4.00 (1 H, m), 4.20 (1 H, d, / = 3.3 Hz), 5.03 (1 H, d, / = 0.6 Hz), 5.34 (1 H, d, / = 1.4 Hz), 6.01 (1 H, d, / = 11.3 Hz), 6.35 (1 H, d, / = 11.3 H z); 13 C NMR (150 MHz, CDC1 3) δ 11.9, 14.5, 18.8, 20.8, 22.3, 23.6, 23.7, 24.4, 27.6, 29.1, 29.2, 29.4, 36.1, 36.4, 40.46, 40.49, 44.4, 45.9, 49.0, 56.3, 56.5, 71.1, 72.6, 76.3, 113.1, 116.9, 124.4, 133.2, 142.9, 145.4; MS 456 [M] ⁺ , 438 [MH ₂ 0] ⁺ , 420 [M-2H ₂ 0] ⁺ , 410 [M-0- C ₂ H ₄ ] +, 402 [M-3H ₂₀ ] ⁺ , 392 [M- 2H _20- C ₂ H ₄ ^{..] +; HRMS calcd for} [C 30 H 48 0 3] 456.3604, found 456.3602 compound ^{Udl: l H NMR (600 MHz} , CDC1 3) δ 0.53 (3 H, s), 0.93 (3H, d, / = 6.3 Hz), 1.21 (6 H, s), 2.19 (1 H, d, / = 13.5, 7.7 Hz), 2.49 (1 H, dd, J = 13.8, 3.6 Hz), 2.81 (1 H, dd , /-12.7, 4.4 Hz), 3.4 9 (1 H, s), 4.00 (1 H, m), 4.20 (1 H, d, / = 3.3 Hz), 5.03 (1 H, d, /-0.6 Hz), 5.34 (1 H, d, / - 1.4 Hz), 6.01 (1 H, d, / = 11.3 Hz), 6.35 (1 H, d, / = 11.3 Hz); 13 C NMR (150 MHz, CDC1 3) δ 11.9, 14.5, 18.8, 20.8, 22.3, 23.6, 23.9, 27.6, 29.0, 29.2, 29.4, 36.1, 36.4, 40.5, 40.6, 44.4, 45.9, 48.9, 56.3, 56.5, 71.1, 72.0, 113.8, 116.9, 124.4, 133.1, 143.0, 145.1; MS 456 [M] +, 438 [MH ₂ 0] ⁺ , 420 [M-2H ₂ 0] ⁺ , 410 [M-0-C ₂ H ₄ ] ⁺ , 402 [-3H ₂ 0] ⁺ , 392 [M-2H ₂ 0-C ₂ H 4] +;. HRMS calcd for [C 30 H 48 0 3] 456.3604, found 456.3602.

Example 35 1,1, bis (hydroxymethyl) cyclopentane (l, l_Bis (hydroxymethyl) cyclopentane, compound 2)

To a suspension of LiAlH ₄ (2.21 g, 2.5 eq) in THF (40 mL) was added a solution of getyl 1,1-cyclopentanecarboxylate (5.00 g, 23.3 hexane) in THF (40 mL). It was added dropwise at 0 ° C. After the addition, the reaction mixture was stirred at 0 ° C for 2 hours 30 minutes and at room temperature for 2 hours. At 0 ° C., water was added to the reaction mixture, followed by a 2N HCl aqueous solution. The reaction mixture was filtered through celite, and the aqueous layer was extracted with ether. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 3: 1) to give compound 2 (2.55 g) as colorless crystals (yield 84%). Recrystallization with ethyl acetate-n-hexane gave needle-like crystals.

Mp 94.0-94.5. C (recryst from ethyl acetate - / 7-hexane.);. ¾ NMR (600 MHz, CDC1 3) 51. 1-1 5 (4 H, m), 1.59-1.63 (4 H, m), 2.65 (2 H, br.s), 3.59 (2 H, s), 3.59 (2 H, s); l3 C NMR (150 MHz, CDC1 3) δ 25.2, 31.8, 48.4, 70.6; IR (neat) 3304, 2948, 2865, 1456, 1105, 1036 cm- 1; MS m / z 112 (M - H 2 0) +; HRMS calcd for C 7 H 12 0 112.0888, found 112.0895; Anal, calcd for C 7 H 14 0 2: C , 64.58; H, 10.84; found: C, 64.71; H, 10.98.

Example 36 3-[(4-Methoxybenzylyl) oxy] -2,2-butanopropan-1-ol (3-[(4-Methoxybenzyl) oxy] -2,2-butanopropan-l-oK Compound M2 )

While stirring a suspension of NaH (307 mg, 60% in mineral oil, 7.68 bandages 01) in 1) ¾ (10 mL), the diol compound L 2 (1, tribis (hydroxymethyl A solution of (1.00 g, 7.68 mmol) in DMF (10 mL) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 50 minutes. To the reaction mixture, PMBCK (1.12 mL, 1.1 eq) was added at 0. The reaction mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 75 minutes. After water was added to the reaction mixture at 0 ° C, the whole was Extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4) to give compound M2 (1.45 g) as a colorless oil (yield 75%).

_{¾ NMR (400 MHz, CDC1 3} ) δ 1.34-1.41 (2 H, m), 1.46-1.60 (6 Η, m), 2.83 (1 Η, t, / = 5.9 Hz), 3.39 (2 H, s) , 3.51 (2 H, d, / = 5.9 Hz), 3.81 (3 H, s), 4.45 (2 H, s), 6.81 (2 H, d, / = 8.5 Hz), 7.24 (2 H, d, ^{/ = 8.3 Hz); 13 C} NMR (100 MHz, CDC1 3) 625.2, 32.3, 47.8, 55.3, 70.5, 73.2, 78.3, 11 3.8, 129.1, 130.1, 159.1; IR (neat) 3422, 2950, 2865, 1613 , 1512, 1458, 1302, 1245, 1175, 1090, 1036, 820 cm- ¹ ; MS m / z 250 (M) ⁺ ; HRMS calcd for C ₁₅ H ₂₂ 0 ₃ 250.1569, found 250.1568.

(Example 37) 3-[(4-Methoxybenzyl) oxy] -2,2-butanopropanal (3-[(4-Methoxybenzyl) oxy] -2,2-butanopropanaK compound N2)

While stirring a mixture of compound M 2 (400 mg, 1.60 mmol), powdered 4 A MS (36 mg), and NMO (562 rag, 2.9 eq.) In CH ₂ C ₁₂ (4 mL), Treated with TPAP (55 mg, 0.1 eq.) At 0 ° C under an argon atmosphere. The reaction mixture was stirred at 0 ° C. for 45 minutes, and purified by silica gel column chromatography (ethyl acetate n-hexane = 1: 6) to give the aldehyde compound N 2 (275 mg) as a colorless oil. (69% yield). This colorless oil was used as such in the next step.

_{¾ NMR (400 MHz, CDC1 3} ) δ 1.47-1.64 (6 H, m), 1.90-1.97 (2 Η, m), 3.50 (2 Η, s), 3.81 (3 Η, s), 4.44 (2 Η , s), 6.87 (2 Η , d, / = 8.5 Hz), 7.22 (2 H, d, / = 8.5 Hz), 9.59 (1 H, s); 13 C NMR (100 MHz, CDC1 3) δ 25.6 , 30.4, 55.3, 58.6, 73.0, 73.1, 113.7, 129.0, 130.1, 159.1, 204.2; IR (neat) 29 51, 2867, 2359, 2342, 2330, 1727, 1613, 1514, 1248, 1092, 1036, 818 cm — ¹ ; MS m / z 248 () ⁺ ; HRMS calcd for C ₁₅ H ₂₀ O ₃ 248.1413, found 248.1410.

(Example 38) 5-[(4-methoxybenzyl) oxy] -4,4-butanenovent-1-e 3--3-ol (5-[(4-Methoxybenzyl) oxy] _4, 4-butanopent-l-en-3-ol, compound 〇2)

While stirring a solution of compound N2 (3.20 g, 12.8 r ol) in dry toluene (35 mL) at -78 ° C under argon, piermagnesium bromide (1.0 M in THF, 14 mL, 1.1 eq.) ) Was added dropwise. The reaction mixture was stirred for 65 minutes, quenched by the addition of saturated aqueous M ₄ C1 and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the solvent was distilled off. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 12) to give Compound 02 (3.20 g) as a colorless oil (yield 90%).

_{¾ NR (400 MHz, CDC1 3} ) δ 1.20-1. 6 (1 H, m), 1.46-1.66 (6 Η, m), 1.71-1. 77 (1 Η, m), 3.25 (1 Η, d , / = 8.8 Hz), 3.47 (1Η, d, / = 8.8 Hz), 3.60 (1 H, br.d, / = 3.5 Hz), 3.81 (3 H, s), 3.94 (1 H, t, / = 6.3 Hz), 4.41 (2 H, s), 5.17 (1 H, dt, J = 10.5, 1.7 Hz), 5.31 (1 H, dt, J = 17.1, 1.7 Hz), 5.91 (1 H, ddd , / = 16.7, 10.7, 6.0 Hz), 6.88 (2 H, d, / = 8.5 Hz), 7.23 (2 H, d, / = 8.3 Hz); 13 C NMR (100 MHz, CDC1 3) 625.4, 25.5 , 31.7, 33.2, 50.1, 55.3, 73.3, 76.5, 80.0, 113.8, 115.8, 129.2, 130.0, 138.3, 159.2; IR (neat) 3501, 2951, 2869, 1613, 1514, 1456, 1248, 1175, 1084, 1 034, 995, 924, 820 cm— ¹ ; MS m / z 276 (M) +, 258 (M −) +; HRMS calcd for C ₁₇ H ₂₄ 0 ₃ 276.1725, found 276.1726.

(Example 39) 3-[(tert-butyldimethylsilyl) oxy] _5-[(4-methoxybenzyl) oxy] -4,4-butenopent-1-ene (3-[(terί-Butyldimethys i lyl) ox y] -5- [(4-me thoxybenzy 1) oxy] -4, 4-but anopent-l-ene

A mixture of compound 02 (192 mg, 0.70 tmol) and 2,6-lutidine (0.13 mL, 2 eq) in dry CH ₂ C ₁₂ (2 mL) was stirred at 0 ° C under an argon atmosphere. Then, TBS0Tf (0.24 mL, 1.2 eq) was added. The resulting mixture was stirred for 30 minutes, diluted with ethyl acetate and washed with water and then with brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent was removed. The obtained residue is subjected to silica gel column chromatography. Purification by monoethyl acetate (n-hexane = 1: 25) gave compound P 2 (241 mg) as a colorless oil (89% yield).

^{_{1 HNR (400 MHz, CDC1 3}} ) δ -0.01 (3 H, s), 0.03 (3 Η, s), 0.88 (9 Η, s), 1.23-1.67 (8 Η, m), 3.18 (1 Η, d, J = 8.8 Hz), 3.27 (1 Η, d, J = 8.8 Hz), 3.81 (3 H, s), 4.17 (1 H, d, J = 7.6 Hz), 4.35 (1 H, d, J = 11.7 Hz), 4.43 (1 H, d, J = 11.7 Hz), 5.07 (1 H, d, J = 10.3 Hz), 5.12 (1 H, d, J = 17.3 Hz), 5.79 (1 H, ddd , J = 17.6, 10.1, 7.5 Hz), 6.87 (2 H, d, J = 8.5 Hz) r 7.25 (2 H, d, J = 9.5 Hz); 13 C NMR (100 MHz, CDC1 3) δ -4.9 , -3.7, 18.1, 26.0, 26.2, 26.2, 31.1, 31.2, 51.3, 55.3, 72.8, 74.9, 113.6, 115.8, 128.9, 131.0, 139.4, 158.8; IR (neat) 2955, 2857, 1615, 1514, 1462, 1250, 1080, 1040, 835, 775 cm "¹; MS m / z 390 (M) ⁺ , 333 (-^ u) *; HR S calcd for C ₂ 3H ₃₈ 0 ₃ Si 390.2591, found 390.2605.

Example 40 3-[(tert-butyldimethylsilyl) oxy] -2,2-butanopent-4-en-1-ol (3-[(3-[(tert-butyldimethysilyl) oxy] -2 , 2-butanopent- 4-en-l-oU compound Q2)

Compound P 2 (3.70 g, 9.48 mmol ) was dissolve in a mixture of the CH _₂ C1 ₂ (50 mL) and water (5 mL). The resulting solution was treated with DDQ (3.22 g, 1.5 eq) at 0 ° C. with stirring. After stirring at room temperature for 35 minutes, the reaction mixture was diluted with ether (400 mL). The organic layer was washed with saturated NaHCO ₃ solution and brine, dried over magnesium sulfate, filtered and evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 10) to give compound Q2 (2.50 g) as a colorless oil (yield 97%).

^{1 H NMR (400 MHz, CDC1} 3) δ 0.03 (3 Η, s), 0.09 (3 Η, S), 0.90 (9 Η, s), 1.06-1.13 (1 Η, m), 1.30-1.37 (1 Η, m), 1.49-1.66 (5 Η, m), 1.88-1.94 (1 Η, m), 3.25-3.36 (2 Η, m), 3.72 (1 Η, m) d, J = 10.5 Hz), 4.01 (1 H, d, J = 6.8 Hz), 5.19 (1 H, d, J = 10.3 Hz), 5.22 (1 H, d, J = 17.1 Hz), 5.93 (1 H, ddd, J = 17.3, 10.4, 7.0 Hz); 13 CR (100 MHz, CDC1 3) δ -5.0, -3.9, 18.1, 25.0, 25.0, 25.9, 32.0, 33.1, 51.2, 67.6, 83.0, 116.5, 138.2; IR (neat) 3449, 2955, 2859, 1472, 1254, 1057, 837, 775 cm "¹; MS m / z 213 (M-^ u)" ¹ "; HRMS calcd for CuH ₂₁ 0 ₂ Si 213.1311, found 213.1313.

(Example 41) 3-[(tert-Butyldimethylsilyl) oxy] -2,2-butanopentol 4-en-2-yl (3-[(tert-Butyldimethysilyl) oxy] -2,2-butanopent-4- (enaK compound R2)

Compound Q2 (2.17 g, 8.03 mmol) and powdered 4 A MS (1.60 g) and Awakening: 0 (1.84 g, 1.9 eq) while stirring a mixture of CH _₂ C1 ₂ (30 mL) in a, 0 ° C Treated with TPAP (291 mg, 0.1 eq) under an argon atmosphere. The reaction mixture was stirred at 0 ° C for 15 minutes and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9) to give the aldehyde compound R 2 (1.99 g) as a colorless oil (Yield 92%). This colorless oil was used as such in the next step.

^{X H NMR (400 MHz, CDC1} 3) δ 0.01 (3 H, s), 0.06 (3 H, s), 0.87 (9 H, s), 1.44-1.63 (6 H, m), 1.88-1.96 (2 H, m), 4.22 (1 H, d, J = 7.3 Hz), 5.16 (1 H, ddd, J = 10.3, 1.6, 1.0 Hz), 5.20 (1 H, ddd, J = 17.3, 1.6, 1.1 Hz) ), 5.79 (1 H, ddd , J = 17.3, 10.3, 7.3 Hz), 9.66 (1 H, s); 13 C NMR (100 MHz, CDC1 3) δ -5.0, -3.8, 18.2, 25.5, 25.8, 28.7, 30.5, 63.0, 78.2, 117.0, 137.6, 205.0; IR (neat) 2957, 2859, 1725, 1472, 1256, 1080, 839, 777 cm "¹; MS m / z 211 (-τα) ⁺ 'HRMS calcd for CnHi ₉ 0 ₂ Si 211.1154, found 211.1132.

(Example 42) (^, 6-6-[(tert-butyldimethylsilyl) oxy] -5,5-butanoct-7-en-1-yn-4-ol ((4 ^ 56-[( tert- Butyldimethysil yl) oxy] -5, 5-butanooct-7-en- 1 -yn-4-οΚ compound Sa2) t (iRS, 66-[(ter t-butyldimethylsilyl) oxy] -5,5-butane Noct-7-en-1-yn-4-ol ((US, -6-[(tert-Butyldimethys ilyl) oxy] -5, 5-butanooc t-7-en- 1 -yn-4- ol , Compound Sb2)

While stirring a solution of compound R 2 (949 mg, 3.53 dragonol) in dry ether (20 mL) at -78 under argon atmosphere, propargyl magnesium bromide (2M in ether, 5.3 mL, 3 mL) eq) was added. The reaction mixture was stirred for 10 minutes, the reaction was quenched by the addition of saturated NH ₄ C1 solution and then extracted with acetate Echiru. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the solvent was distilled off. The resulting crude mixture was purified by silica gel column chromatography (CH ₂ C1 _2: the n- hexane = 1: 2) in the paper seminal compound Sa2, to obtain Sb 2 a (936 mg) as a colorless oil (yield 86%). I匕合was ^{Sa2: Χ Η NMR (400 MHz} , CDC1 3) δ 0.02 (3 H, s), 0.07 (3 H, s), 0.90 (9 H, s), 1.47-1.66 (8 H, m) , 2.03 (1 H, t, J = 2.7 Hz), 2.31 (1 H, ddd, J = 16.6, 10.0, 2.7 Hz), 2.54 (1 H, dt, J = 16.8, 2.7 Hz), 2.71 (1 H , br.d, J = 3.7 Hz), 3.79 (1 H, dt, J = 9.9, 3.4 Hz), 4.07 (1 H, d, J = 7.5 Hz), 5.17 (1 H, d, J = 10.1 Hz) ), 5.19 (1 H, d , J = 17.4 Hz), 5.85 (1 H, ddd, J = 17. 4, 10.1, 7.5 Hz); 13 C NMR (100 MHz, CDC1 3) δ -4.8, -3.6 , 18.2, 24.0, 26.0, 26.4, 26.7, 30.1, 30.9, 54.1, 69.9, 74.8, 80.1, 1 16.9, 138.6; IR (neat) 2955, 2859, 2116, 1460, 1254, 1074, 83 7, 775 cm "¹; MS m / z 308 (M) ⁺ , 290 (MH ₂ 0) ⁺ , 251 (M-^ u) *; HRMS calcd for C ₁₈ H ₃₂ 0 ₂ Si 308.2172, found 308.2180.

Compound ^{Sb 2: Χ Η NMR (400} MHz, CDC1 3) δ 0.04 (3 H, s), 0.10 (3

H, s), 0.90 (9 H, s), 1.34-1.78 (8 H, m), 2.03 (1 H, t, J = 2.6 Hz), 2.31 (2 H, dd, J = 2.7, 6.6 Hz) , 3.98 (1 H, d, J =

7.3 Hz), 4.02 (1 H, t, J = 6.4 Hz), 4.42 (1 H, s), 5.24 (1 H, d, J = 16.6 Hz), 5.24 (1 H, d, J = 11.0 Hz) , 5.92-6.01

^{(1 H, m); 13} C NMR (100 MHz, CDC1 3) δ-5.1, -3-8, 23,0, 25.9,

26.3, 26.4, 29.6, 32.3, 53.2, 69.2, 74.6, 82.7, 82.8, 117.8, 137.0; IR (neat) 2955, 2859, 2118, 1460, 1254, 1057, 926, 837, 777 cm "¹; MS m / z 308 (M) ⁺ , 290 (MH ₂ 0) ⁺ , 251 (M-+ ;

HRMS calcd for Ci ₈ H ₃₂ 0 ₂ Si 308.2172, found 308.2169. (Example 43) (3,5Λ?)-3,5-Bis [(tert-butyldimethylsilyl) oxy] -4,4-butane U-1-en-7-yne ((3 ^, 5 ^)-3, 5-Bis [(tert-butyldimethysilyl) oxy] -4, 4-butanoic t-1 -en-7-yne匕

A mixture of the compound Sa2 (530 mg, 1.72 tmol) and 2,6-lutidine (0.32 mL, 2 eq) in dry CH ₂ C ₁₂ (10 iL) was stirred at 0 ° C under an argon atmosphere. Then, TBS0Tf (0.59 mL, 1.2 eq) was added. After stirring the resulting mixture for 40 minutes, 2,6-lutidine (0.08 mL, 0.5 eq) and TBSOTf (0.25 mL, 0.5 eq) were added. The resulting mixture was stirred for 10 minutes and diluted with ethyl acetate. And washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent was removed. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 100) to give compound Ta2 (723 mg) as a colorless oil (yield 100%). ^lambda kappa thigh _{R (400 MHz, CDC1 3)} δ 0.00 (3 H, s), 0.05 (3 H, s), 0.09 (3 H, s), 0.17 (3 H, s), 0.89 (9 H, s ), 0.91 (9 H, s), 1.46-1.65 (8 H, m), 1.96 (1 H, t, J = 2.7 Hz), 2.28 (1 H, ddd, J = 17.5, 6.0, 2.6 Hz), 2.65 (1 H, dt, J = 17.5, 3.1 Hz), 3.89 (1 H, dd, J = 5.9, 3.7 Hz), 4.13 (1 H, d, J = 7.3 Hz), 5.13 (1 H, d, J = 9.3 Hz), 5.16 (1 H, d, J = 17.1 Hz), 5.83 (1 H, ddd, J = 17.5, 10.3, 7.2 Hz); ¹³ C NMR (100 MHz, CDCI3) δ -4.7,- 4.5, -3.5, -3.4, 18.3, 18.4, 24.4, 26.0, 26.2, 26.7, 26.8, 29.0, 31.8, 56.0, 70.0, 75.7, 78.1, 84.1, 116.3, 138.9; IR (neat) 3316, 2955, 2932, 2859, 2120, 1638, 1472, 1360, 1254, 1074, 835, 775 cm ^-1 ; MS m / z 422 (M) ⁺ , 365 (M-^ u) *; HRMS calcd. For C ₂₄ H ₄₆ 0 ₂ Si ₂ 422.3036, found 422.3036. (MS, ^ RS) -3, 5-Bis [(tert-butyldimethylsilyl) thio] -4, 4-butanoct-1_en-7-yne ((3 ^, 5 ^)-3, 5-Bis [(tert-butyldimethysilyl) oxy] -4, 4-butanooct-l-en_7-yne, compound Tb 2)

Similarly, compound Tb2 was synthesized from compound Sb2.

_{MR (400 MHz, CDC1 3)} δ 0.00 (3 H, s), 0.04 (3 Η, s), 0.08 (3 Η, S), 0.15 (3 Η, S), 0.89 (9 Η, s), 0.90 (9Η, s), 1.35-1.42 (1Η, m), 1.49-1.64 (6Η, m), 1.69-1.76 (1Η, m), 1.98 (1Η, t, J = 2.7Ηζ), 2.33 (1Η, ddd, J = 17.7, 6.2, 2.7 Hz), 2.63 (1Η, dt, J = 17.6, 3.3 Hz), 3.78 (1 H, dd, J = 6.2, 3.8 Hz), 4.05 (1 H, d, J = 8.3 Hz), 5.07 (1 H, d, J = 11.0 Hz), 5.08 (1 H, d, J = 16.6 Hz), 5.93 (1 H, ddd, J = 16.8, 10.7 _{^{, 8.4 Hz); 13 C NMR}} (100 MHz, CDC1 3) δ -4.7, -4.5, -3.6, -3.5, 18.3, 18.4, 2 5.1, 26.0, 26.2, 26.4, 26.4, 31.6, 32.3, 56.1, 69.9 , 77.5, 79.3, 84.3, 115.7, 139.9; IR (neat) 3314, 2957, 2932, 2959, 212 0, 1638, 1472, 1360, 1254, 1067, 835, 775 cm "¹; MS m / z 422 (M) +, 365 (M one ^ u) *; HRMS calcd for C 24 H 46 0 2 Si 2 422.3036, found 42 2.3025.

(Example 44) (5Z, 7E)-(1 & U) -2,2-Butano-9,10-seco-5,7,10 (19) -Colestriene-1,3,25-triol ( (5Z, m- (lS, 2> R) -2, 2-Buiano-9, 10-seco-5, 7, 10 (19)-cholestatriene-1, 3, 25-trioK Compound Ua2) and (5Z, 7E)-(3 ^)-2,2-Butano-9,10-seco-5,7,10 (19) -Cholestriene-1,3,25-triol ((5Z, 7E)-(3 -2, 2-Butano- 9, 10-seco-5, 7, 10 (19) -cholestatriene-l, 3, 25-trioK compound Ub2)

To a mixture of compound Ta2 (128 mg, 302 mol), compound K (90 mg, 252 / mol) and triethylamine (2 mL) in toluene (8 mL) was added (Ph ₃ P ) After adding ₄ Pd (144 mg, 126 ^ mol), the mixture was stirred at room temperature for 10 minutes. After refluxing for 50 minutes under heating, the reaction mixture was diluted with ether, the whole was filtered through a silica gel pad (Merck silica gel 60), and then the solvent was distilled off. The obtained crude mixture is subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 10). The crude product containing the protected compound of the title compound (03 mg) was obtained.

While stirring a solution of the obtained crude product (03 mg) in THF (6 mL), TBAF (1.0 M in THF, 0.76 mL, 0.76 mmol) was added at 0 ° C. under an argon atmosphere. Additional TBAF (1.0 M in THF, 1.02 mL, 1.02 mmol) was added, the reaction mixture was stirred at room temperature for 23 hours, brine was added, and the whole was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent was distilled off. The resulting crude mixture was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 7) to obtain compounds Ua2 and Ub2 (60 mg, 50% from two steps) as a white solid. . The white solid was further separated and purified by reversed-phase recycling (YMC-Pack ODS column, 20 150 mm, 9.9 mL / min, aceto nitrile: water = 95: 5), and the biological activity was evaluated. Compound Ua2: [α] "= -90.6 (c = 0.28, CHC1 3); UV (EtOH) 268 nm, 228 nm; ¾ NM (400 MHz, CDC1 3) δ 0.55 (3 H, s),

0.94 (3 H, d, J = 6.6 Hz), 1.02-2.02 (27 H, m), 1.21 (6 H, s), 2.44 (1 H, d, J = 4.4 Hz), 2.44 (1 H, dd , J = 14.4, 3.2 Hz), 2.65 (1 H, d, J = 14.4 Hz), 2.84 (1 H, dd, J = 12.1, 3.8 Hz), 3.11 (1 H, d, J = 7.8 Hz), 3.62-3.65 (1 H, m), 3.87 (1 H, d, J = 3.4 Hz), 5.06 (1 H, d, J = 2.2 Hz), 5.23 (1 H, d, J = 2.2 Hz), 6.10 (1 H, d, J = 11.2 Hz), 6.47 (1 H, dd, J = 11.4, 1.1 Hz); 13 C NMR (100 MHz, CDC1 3) 612.0, 18.9, 20.9, 22.4, 23-8, 25.3 , 25.6, 27.7, 29-2, 29.3, 29.4, 32.6, 34.6, 36.1, 36.4, 40.5, 42.3, 44.4, 46.0, 51.6, 56.4, 56.5, 71.1, 76.5, 81.8, 115.4, 116.8, 126.0, 131.1, 142.9 , 145.7; IR (neat) 3368, 2948, 2870, 2361, 2332, 1699, 1509, 1040, 756 cm "¹; MS m / z 470 (M) +, 452 (M-H ₂₀ ) ⁺ ; HRMS calcd for C31H50O3 470.3760, found 470.3745.

Compound ^{Ub2: [a] 7 = +100.7} (c = 0.52, CHCI3); UV (EtOH) 268 nm, λπ, 1η 228 nm; NMR (600 MHz, CDC1 3) δ 0.53 (3 H, s), 0.93 ( 3 H, d, J = 6.6 Hz), 1.02-2.01 (27 H, ra), 1.21 (6 H, s), 2.36 (1 H, d, J = 3.3 Hz), 2.44 (1 H, dd, J = 14.3, 3.6 Hz), 2.64 (1 H, d, J = 14.3), 2.85 (1 H, dd, J = 13.2, 3.3 Hz), 3.17 (1 H, d, J = 7.2 Hz), 3.63 (1 H, br .s), 3.87 (1 H, d, J = 2.0 Hz), 5.01 (1 H, d , J = 1.9 Hz), 5.21 (1 H, d, J = 2.2 Hz), 6.04 (1 H, d, J = 11.3 Hz), 6.47 (1 H, d, J =

11.3 Hz); ¹³ C MR (150 MHz, CDC1 ₃ ) δ 12.1, 18.8, 20.8, 22.2, 23.4, 25.3, 25.6, 27.7, 29.0, 29.2, 29.4, 32.3, 34.5, 36.1, 36.4, 40.5, 42.3, 44.4 , 45.9, 51.6, 56.3, 56.5, 71.1, 76.4, 81.8, 115.3, 117.0, 126.1, 131.0, 142.9, 145.8; IR (neat) 3320, 2940, 2865, 2363, 1642, 1470, 1036, 905 cm "¹; MS m / z 470 (M) ⁺ , 452 (M-H ₂ 0) ⁺ ; HRMS calcd for C ₃₁ H ₅₀ O ₃ 470.3760, found 470.3764.

(5Z, 7E)-(1 37?) -2,2-Butano-9,10-seco-5,7,10 (19) -Cholestriene-1,3,25-triol ((5Z, 7E) — (1 3-2, 2-Butano-9, 10-seco-5, 7, 10 (19) -chol estatriene-1,3, 25-trioK compound Uc2) and (5Z, 7E)-(15, 36 ) -2,2-Butano-9,10-seco-5,7,10 (19) -Cholestriene-1,3,25-triol ((5Z, 7E)-(, SS)-2 , -Butano-9, 10-seco-5, 7, 10 (19) -cholestatriene-l, 3, 25-trioK Compound Ud 2)

Similarly, the compounds Uc2 and Ud2 were synthesized from the compound Tb2.

I匕合was Uc2: [α] "= +2.5 (σ = 0.67, CHC1 3); UV (EtOH)

_{268 nm, λπ, 1η 229 nm} ; X H NMR (400 MHz, CDC1 3) δθ.53 (3 H, s), 0.93 (3 H, d, J = 6.4 Hz), 1.04-2.02 (27 H, m ), 1.21 (6 H, s), 2.27 (1 H, dd, J = 13.7, 6.8 Hz), 2.58 (1 H, dd, J = 13.4, 3.2 Hz), 2.81 (1 H, dd, J = 11.7) , 3.7 Hz), 3.84 (1 H, br .s), 4.06 (1 H, d, J = 2.4 Hz), 5.02 (1 H, s), 5.29 (1 H, s), 6.02 (1 H, d) , J = 11.2 Hz), 6.36 (1 H, d, J = 11.0 Hz); 13 C NMR (100 MHz, CDC1 3) δ 12.1, 18.9, 20.9, 22.3, 23.7, 26.6, 27.0, 27.7, 29.1, 29.3 , 29.4, 31.2, 31.3, 36.1, 36.4, 40.5, 42.0, 44.4, 45.9, 53.6, 56.4, 56.6, 71.1, 73.3, 77.6, 112.9, 116.9, 124.6, 133.1, 142.9, 146.3; IR (neat) 3422, 2946, 2869, 2338, 1651, 1441, 1377, ^{1067, 911, 733 cm "1} ; MS m / z 470 (M) +, 452 (M - H 2 0) +; HR S calcd for C 31 H 50 O 3 470.3760, found 470.3760.

Compound ^{_{Ud2:. [A] 2 D}} 8 = +24.4 (c = 0.89, CHC1 3); UV (EtOH) 268 nm in 229 nm; 1 H NMR (400 MHz, CDC1 3) δθ.53 (3 H, s ), 0.93 (3 H, d, J = 6.6 Hz), 1.03-2.01 (27 H, m), 1.21 (6 H, s),

2.27 (1 H, dd, J = 13.6, 8.2 Hz), 2.56 (1 H, dd, J = 13.6, 3.8 Hz), 2.81 (1 H, dd, J = 11.6, 3.5 Hz), 3.88 (1 H, dd, J

= 7.8, 3.9 Hz), 4.02 (1 H, s), 5.02 (1 H, d, J = 2.0 Hz),

5.28 (1 H, s), 6.02 (1 H, d, J = 11.2 Hz), 6.37 (1 H, d, J = 11.2 Hz); 13 C NMR (100 MHz, CDC1 3) δ 12.1, 18.9, 20.9 , 22.4, 23.6, 26.6, 26.9, 27.7, 29.1, 29.3, 29.4, 30.6, 31.6, 36.1, 36.4, 40.5, 42.2, 44.4, 45.9, 53.5, 56.4, 56.5, 71.1, 72.8, 78.2, 113.6, 116.9, 124.6 , 133.0, 142.9, 146.0; IR (neat) 3422, 2946, 2870, 2359, 1651, 1472, 1377, 1051, 911, 731 cm '' ^x MS m / z 470 (M) ⁺ , 452 (M-H ₂ 0 ) ⁺ ; HRMS calcd for C ₃ iH ₅₀ O ₃ 470.3760, found 470.3768.

(Example 45) 1, tobis (hydroxymethyl) cyclohexane (1,1-Bis 0ι ydroxymethyOcyclo exane, compound L 3)

To a suspension of LiAlH ₄ (416 mg, 2.5 eq) in THF (10 mL) was added a solution of getyl 1,1-cyclohexanecarboxylate (1.00 g, 4.38 mmol) in THF (10 mL). It was added dropwise at 0 ° C. After the addition, the reaction mixture was stirred at 0 t: for 4 hours. At 0 ° C, water was added to the reaction mixture, and then a 2N HCl aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1 to ethyl acetate: methanol = 95: 5) to give a compound. Compound L 3 (549 mg) was obtained as colorless crystals (yield 87%), and recrystallized from ethyl acetate-n-hexane to obtain needle-like crystals.

Mp 98.5 - 99.5 and ° (recryst from ethyl acetate - n - exane.); 1 HR (400 MHz, CDC1 3) δ 1.33-1.36 (4 H, m), 1.42 - 1.46 (6 H, m), 2.42 ( 2 H, s), 3.61 ( 4 H, s); 13 C NMR (100 MHz, CDC1 3) δ 21.4, 26.5, 29.6, 38.3, 70.3; IR (neat) 3378, 2932, 2863, 1468, 1449, 1399 ^{, 1020 cm "1; MS m} / z 144 () +; HRMS calcd for C 8 H 16 0 2 144.1150, found 144.1149; Anal, calcd for C 8 H 16 0 2: C, 66.63; H, 11.18; found: C, 66.57; H, 11.14.

(Example 46) 3-[(4-Methoxybenzyl) oxy]-2,2-pentanopropane-1-year-old (3-[(4_Methoxybenzyl) oxy] -1-2, -pent anopropan-1-ο 1 ^ 匕合 M M 3)

While stirring a suspension of NaH (286 mg, 60% in mineral oil, 7.14 ranol) in DMF (5 mL), the diol compound L 3 (1,1-bis (hydroxymethyl) A solution of cyclohexane) (515 mg, 3.57 t) in DMF (5 mL) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 45 minutes. To the reaction mixture was added PMBC 642 μΐ, 1.3 eq) at 0 ° C. The reaction mixture was stirred at 0 ° C for 2 hours. After water was added to the reaction mixture at 0 ° C., the whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 5) to give compound M 3 (666 mg) as a colorless oil (yield 71%).

^{X H NMR (400 MHz, CDC1} 3) δ 1.27-1.46 (10 Η, m), 3.38 (2 Η, s), 3.55 (2 Η, s), 4.44 (2 Η, s), 6.88 (2 Η, d, J = 8.5 Hz), 7.23 (2 Η, d, J = 8.3 Hz); 13 C NMR (100 MHz, CDC1 3) 521.5, 26.5, 30.2, 38.2, 55.3, 70.0, 73.2, 78.3, 113.8, 129.0 , 130.1, 159.1; IR (neat) 3461, 2930, 2859, 1613, 1512, 1453, 1453, 1248, 1089, 1034, 826 cm "¹; MS m / z 264 (M) ⁺ ; HRMS calcd for C ₁₆ H ₂₄ 0 ₃ 264.1726, found 264.1722.

Example 47 3-[(4-Methoxybenzyl) oxy] -2,2-pentanopropanal (3 _ [(4-Methoxybenzyl) oxy] —2,2-pentanopropanal, N 3)

While stirring a mixture of compound M 3 (635 mg, 2.40 mmol), powdered 4 A MS (250 mg), and NMO (725 mg, 2.5 eq) in CH ₂ C ₁₂ (6 mL), Treated with TPAP (87 mg, 0.1 eq) at 0 ° C under an argon atmosphere. The reaction mixture was stirred at 0 ° C for 35 minutes and purified by silica gel column chromatography (ethyl acetate n-hexane = 1: 6) to give the aldehyde compound N 3 (571 mg) as a colorless oil. Was obtained (yield 91%). This colorless oil was used as such in the next step.

η丽_{R (400 MHz, CDC1 3)} δ 1.24-1.53 (8 H, m), 1.89-1.95 (2 H, m), 3.40 (2 H, s), 3.80 (3 H, s), 4.39 (2 H, s), 6.85-6.89 (2 H, m), 7.18-7.22 (2 H, m), 9.57 (1 H, s) ¹³ C MR (100 MHz, CDCI3) δ 22.2, 25.8, 28.5, 50.6, 55.3, 73.0, 74.2, 113.7, 128.9, 130.0, 159.0, 206.4; IR (neat) 2932, 2857, 1723, 1613, 1512, 1455, 1360, 1248, 1090 cm ^-1 ; MS m / z 262 (M) ⁺ ; HRMS calcd for C ₁₆ H ₂₂ 0 ₃ 262.1569, found 262.1567.

(Example 48) 5-[(4-Methoxybenzyl) oxy] -4,4-pentanopent-1-ene-3-ole-5-[(4-Methoxybenzyl) oxy] -4,4_pentanopent— l—en—3—ol

While stirring a solution of compound N 3 (719 mg, 2.74 ol) in dry toluene (8 mL) at -78 ° C under an argon atmosphere, vinylmagnesium bromide (1.0 M in THF, 3.0 mL, 1.1 eq) ) Was added dropwise. The reaction mixture was stirred for 50 minutes, quenched with a saturated aqueous solution of M ₄ C1 and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the solvent was distilled off. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9) to give compound 〇3 (555 mg) as a colorless oil (yield 70%) ^X H Bandwidth R (400 MHz, CDCI3) δ 1.16-1.71 (10 H, m), 3.37 (1 H, d, J = 90 Hz), 3.48 (1 H, d, J = 9.0 Hz), 3.61 (1 H, d, J = 8.3 Hz), 3.81 (3 H, s), 3.98 (1 H, br.t, J = 7.2 Hz), 4.39 (1 H, d, J = 11.5 Hz), 4.43 (1 H , d, J = 11.5 Hz), 5.17 (1 H, d, J = 10.5 Hz), 5.26 (1 H, d, J = 17.1 Hz), 5.92 (1 H, ddd, J = 17.0, 10.4, 6.5 Hz) ), 6.88 (2 H, d , J = 8.3 Hz), 7.23 (1 H, d, J = 8.5 Hz); 13 C NMR (100 MHz, CDC1 3) δ 21.3, 21.5, 26.2, 30.0, 30.7, 40.2 , 55.2, 73.3, 74.7, 79.3, 113.7, 115.9, 129.1, 129.7, 137.7, 159.1; IR (neat) 3476, 2934, 2863, 1651, 1613, 1512, 1248 cm "¹; MS m / z 290 (M) ⁺ ; HRMS calcd for Ci ₈ H ₂ 60 ₃ 290.1882, found 290.1882.

Example 49 3-[(tert-butyldimethylsilyl) oxy] -5-[(4-methoxybenzyl) oxy] -4,4-pentanovent-1-ene (3-[(tert-Butyldimethysilylyl) ) oxy]-5 [(4-methoxybenzyl) oxy] -4, 4-pentalord ent-1 -ene, compound? 3)

A mixture of compound 03 (1.16 g, 4.01 ol) and 2,6-lutidine (0.93 mL, 2.5 eq) in dry CH ₂ C ₁₂ (10 mL) was stirred at 0 ° C. under an argon atmosphere. And TBS0T f (1.73 mL, 1.5 eq) were added. The resulting mixture was stirred for 30 minutes, diluted with ethyl acetate, and washed with water and then brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent was removed. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 50) to give compound P 3 (1.62 g) as a colorless oil (yield 100%).

¾ NMR (400 MHz, CDC1 ₃ ) δ -0.02 (3 H, s), 0.02 (3 H, s), 0.88 (9 H, s), 1.15-1.58 (10 H, m), 3.34 (1 H, d, J = 9.0 Hz), 3.43 (1 H, d, J = 9.3 Hz), 3.81 (3 H, s), 4.06 (1 H, br.d, J = 7.8 Hz), 4.36 (1 H, d , J = 11.7 Hz), 4.42 (1 H, d, J = 11.7 Hz), 5.06 (1 H, dd, J = 9.6, 1.2 Hz), 5.07 (1 H, dd, J = 17.6, 1.0 Hz), 5.84 (1 H, ddd, J = 17.6, 9.9, 7,1 Hz), 6.86-6.89 (2 H, m), 7.24-7.26 (2 H, m); ¹³ C MR ( 100 MHz,

_{CDC1 3) δ -4.9, -3.7,} 18.3, 21.8, 26.0, 26.4, 28.3, 28.4, 41.8, 55.3, 70.5, 72.8, 77.9, 113.6, 115.6, 128.8, 131.2, 139.0, 158.8; IR (neat) 2934, 2859, 1613, 1514, 1464, 1250, 1078 cm "¹; MS m / z 404 () ⁺ ; HRMS calcd for C ₂₄ H ₄₀ O ₃ Si 404.2747, found 404.2736.

Example 50 3-[(tert-butyldimethylsilyl) oxy] -2,2-pentanovent-4-en-toluol (3-[(3-[(tert-Butyldimethysilyl) oxy]- 2, 2-pentanope nt-4-en-l-oK compound Q3)

Compound P 3 (1.38 g, 3.41 thigh ol) was dissolve in a mixture of a and CH _₂ Cl ₂ a9 mL) and water (2 mL). The resulting solution was treated with DDQ (1.29 g, 1.5 eq) at 0 ° C. with stirring. After stirring at 0 ° C. for 40 minutes, the reaction mixture was diluted with ether and filtered through celite. The organic layer was washed with saturated NaHCO ₃ solution and brine, dried over magnesium sulfate, filtered and evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 50 to 1:20) to obtain compound Q3 (911 mg) as a colorless oil (yield 94%). .

^{X H NMR (400 MHz, CDC1} 3) δ 0.03 (3 Η, s), 0.09 (3 Η, s), 0.90 (9 Η, s), 1.03-1.92 (10 Η, m), 3.46-3.55 (2 M, m), 3.68 (1 Η, d, J = 10.7 Hz), 4.01 (1 Η, d, J = 7.6 Hz), 5.18 (1 H, dd, J = 17.5, 0.7 Hz), 5.21 (1 H , dd, J = 10.5, 1.0 Hz), 5.92 (1 H, ddd, J = 17.4, 10.3, 7.3 Hz); ¹³ C NMR (100 MHz, CDCI3) δ-5.0, -4.0, 18.1, 21.4, 21.5, 25.9, 26.3, 30.4, 30.5, 40.5, 66.0, 83.2, 117.0, 137.4; IR (neat) 3436, 2930, 2859, 1462, 1254, 1047, 837 cm-- ¹ ; MS m / z 227 (M-ιι) ⁺ ; HRMS calcd for C ₁₂ H ₂ 30 ₂ Si 227.1468, found 227.1462.

(Example 5 1) 3-[(tert-butyldimethylsilyl) oxy] -2,2-pentanobe _4-enal (3 — [(tert_Butyldimethysilyl) oxy] _2, 2-pentanopent-4-enal, compound R3)

Compound Q3 (129 mg, 0.45 mmol) and powdered 4 A MS (65 mg) and丽0 (110 mg, 2.0 eq) with stirring CH _₂ C1 ₂ (3 mL) mixture in the, 0 ° C Treated with TPAP (291 mg, 0.1 eq) under an argon atmosphere. The reaction mixture was stirred at 0 ° C for 55 minutes, and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9) to obtain the aldehyde (Compound R, 3 mg) as a colorless oil. (Yield 96%). This colorless oil was used as such in the next step.

¾ negation _{R (400 MHz, CDC1 3)} δ -0.02 (3 H, s), 0.03 (3 H, s), 0.87 (9 H, s), 1.11-1.36 (6 H, m), 1.56 - 1.65 ( 2 H, m), 1.95-1.96 (1 H, m), 2.07-2.11 (1 H, m), 3.97 (1 H, d, J = 7.8 Hz), 5.12 (1 H, ddd, J = 17.2, 1.6, 1.0 Hz), 5.17 (1 H, ddd, J = 10.4, 1.6, 0.8 Hz), 5.74 (1 H, ddd, J = 17.6, 9.9, 7.2 Hz), 9.62 (1 H, s); ¹³ C negation _{R (100 MHz, CDC1 3)} δ -5.0, -3.9, 18.2, 22.5, 22.8, 25.8, 27.5, 28.9, 54.0, 80.1, 117.3, 137.1; IR (neat) 2934, 2857, 1725, 1455, 1254, ^{1065 cm "1; MS m /} z 282 (M) +; HRMS calcd for Ci 6 H 30 O 2 Si 282.2015, found 282.2013.

(Example 52) (ARS, 6 ^)-6-[(tert-butyldimethylsilyl) oxy] -5,5-pentanocto-7-en-troin-4-ol ((4, 6 -[(tert-Butyldimethys i lyl) oxy] -5, 5-pent anooct-7-en- 1-yn-4- 01, compound Sa3) and (4 & -6- [(tert-butyldimethylsilyl) ) Oxy] -5, 5-pentanooct-7-n-1-yn-4-ol ((4 ^, 6 — [(tert—Butyldimethysilyl) oxy]-5, 5-pentanooct-7-en-l) -yn-4-οΚ compound Sb3)

While stirring a solution of compound R 3 (888 mg, 314 mmol) in dry ether (20 mL) at -78 ° C under an argon atmosphere, propargyl magnesium bromide (2 M in ether, 4.7 mL, 3 eq) was added. The reaction mixture was stirred for 25 minutes, quenched with saturated aqueous NH ₄ C1 and then extracted with ethyl acetate. Wash the organic layer with saline The extract was washed, dried over magnesium sulfate, filtered, and the solvent was distilled off. The resulting crude mixture was purified by silica gel column chromatography (CH ₂ C1 _2: the n- hexane = 2: 3) papermaking rectification, the compounds Sa3, Sb3 a (982 mg) as a colorless oil (yield: 97%). Compound ^{Sa3: λ Κ MR (400 MHz} , CDC1 3) δθ.04 (3 H, s), 0.08 (3 H, s), 0.90 (9 H, s), 1.24-1.69 (10 H, m), 2.02 (1 H, t, J = 2.7 Hz), 2.45 (1 H, ddd, J = 16.7, 10.1, 2.4 Hz), 2.62 (1 H, dt, J = 16.8, 2.6 Hz), 3.35 (1 H, d , J = 6.1 Hz), 3.81 (1 H, ddd, J = 10.1, 6-1, 2.6 Hz), 4.30 (1 H, d, J = 7.8 Hz), 5.15 (1 H, dd, J = 17.3, 0.5 Hz), 5.17 (1 H , dd, J = 9.8, 0.7 Hz), 5.93 (1 H, ddd, J = 17.7, 10.0, 7.3 Hz); 13 C NMR (100 MHz, CDC1 3) δ -5.0, -3.7, 18.2, 21.4, 21.5, 23.9, 25.9, 26.0, 29.9, 30.3, 43.1, 69.3, 75.1, 79.4, 83.5, 116.7, 138.5; IR (neat) 3457, 2928, 2118, 1462, 1254, 1067, 837 ^{cm "1; MS m / z} 322 (M) +; HR S calcd for C 19 H 34 0 2 Si 322.2328, found 322.2325.

Compound ^{Sb3: Χ Η NMR (400 MHz} , CDC1 3) δ 0.07 (3 H, s), 0.10 (3 H, s), 0.88 (9 H, s), 1.18-1.31 (4 H, m), 1.35- 1.68 (5 H, m), 1.93-1.98 (1 H, m), 2.03 (1 H, t, J = 2.7 Hz), 2.36 (1 H, ddd, J = 16.6, 8.8, 2.7 Hz), 2.42 ( 1 H, dt, J = 16.6, 2.7 Hz), 3.94 (1 H, ddd, J = 8.7, 3.8, 1.6 Hz), 4.57 (1 H, d, J = 8.0 Hz), 4.64 (1 H, s) , 5.20 (1 H, d, J = 17.3 Hz), 5.26 (1 H, dd, J = 10.4, 1.3 Hz), 5.99 (1 H, ddd, J = 17.8,

^{9.8, 8.0 Hz); 13 C} NMR (100 MHz, CDC1 3) δ - 5.1, -3.6, 18.1, 20.8, 21.1, 22.0, 25.3, 25.8, 26.3, 29.5, 42.6, 69.2, 74.6, 78.0, 83.1, 117.8 , 137.0; IR (neat) 3486 , 2932, 2859, 2118, 1458, 1254, 1053, 837 cm "1; MS m / z 322 (M) +; HRMS calcd for Ci 9 H 3 40 2 Si 322.2328, found 322.2345 .

(Example 53) (37W, 5 «57?)-3,5-Bis [(tert-butyldimethylsilyl) oxy] ] -4, 4-Pentanoct-1-ene _7-in S, 557?)-3,5-Bis [(tert-butyldiraet hysilyl) oxy]-4, 4-pentaacetyl ct -t en_7_yne, compound T a 3)

Compound S a 3 (277 mg, 8.59 mmol) t 2,6- lutidine (0.2 mL, 2.5 eq) with stirring mixture of dry C¾C1 in ₂ (5 mL) and, under an argon atmosphere at 0 ° C, TBSOTf (0.37 mL, 1.5 eq) was added. The resulting mixture was stirred for 45 minutes, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent was removed. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 100) to give compound Ta 3 (351 mg) as a colorless oil (yield 94%).

_{λΕ WAR (400 MHz, CDC1 3} ) δ 0.02 (3 H, s), 0.06 (3 H, s), 0.07 (3 H, s), 0.17 (3 H, s), 0.89 (9 H, s), 0.92 (9 H, s), 1.23-1.70 (10 H, m), 1.95 (1 H, t, J = 2.7 Hz), 2.29 (1 H, ddd, J = 17.6, 6.6, 2.4 Hz), 3.04 ( 1 H, dt, J = 17.6, 2.9 Hz), 3.79 (1 H, dd, J = 6.5, 2.8 Hz), 4.39 (1 H, d, J = 8.3 Hz), 5.07 (1 H, dd, J = 17.1, 1.7 Hz), 5.13 (1 H, dd, J = 10.3, 1.8 Hz), 5.83 (1 H, ddd, J = 17.1, 9.8, 7.8 Hz); ¹³ CR (100 MHz, CDC1 ₃ ) δ -4.8 , -4.5, -3.4,-3.1, 18.3, 18.5, 21.5, 21.9, 23.9, 25.2, 26.0, 26.3, 29.1, 45.2, 69.5, 74.4, 75.5, 85.0, 116.2, 138.8; IR (neat) 2932, 2859, 2120, 1472, 1254, 1067, 938, 835 cm "¹; MS m / z 436 (M) ⁺ ; HRMS calcd for C25H48O2S 2 436.3193, found 436.3191.

(3,3,5-Bis [(tert-butyldimethylsilyl) oxy] -4,4-pentanoct-1-en-7-yne ((3 ^, 5 ^)-3,5-Bis [( tert-butyldimethysilyl) oxy] -4, -pentanooct-l-en-7-yne compound Tb3)

Similarly, compound Tb3 was synthesized from compound Sb3.

_{NMR (400 MHz, CDC1 3)} δθ.00 (3 Η, s), 0.03 (3 Η, s), 0.07 (3 Η, s), 0.12 (3 Η, s), 0.88 (9 Η, s), 0.90 (9 Η, s). 1.37-1.63 (10 H, m), 1.95 (1 H, t, J = 2.7 Hz), 2.35 (1 H, ddd, J = 17.8, 7.1, 2.6 Hz), 2.99 (1 H, dt, J = 17.7 , 3.1 Hz), 3.87 (1 H, dd, J = 7.1, 3.2 Hz), 4.08 (1 H, d, J = 8.8 Hz), 4.96 (1 H, dd, J = 16.6, 2.0 Hz), 4.97 ( 1 H, dd, J = 10.7 , 2.0 Hz), 6.02-6.11 (1 H, m); 13 C negation _{R (100 MHz, CDC1 3)} δ -5.0, -4.4, -3.6, -3.6, 18.3, 18.5 , 21.7, 21.8, 24.6, 26.0, 26.2, 26.3, 31.0, 31.6, 44.7, 69.3, 77.7, 79.7, 85.5, 114.0, 140.7; IR (neat) 2930, 2859, 2120, 1472, 1254, 1082, 939, 837 ^{cm "1; MS m / z} 436 (M) +; HRMS calcd for C 25 H 48 0 2 Si 2 436.3193, found 436.3187.

(Example 54) (5Z, 7E)-(1,3?)-2,2-Pentano-9,10-seco-5,7,10 (19) -Cholesteryl triene-1,3,25- Triol ((5Z, 1E)-(\ S, 3)-2, 2-Pentano-9, 10-sec o-5, 7, 10 (19) -cholestatriene-l, 3, 25-trioU compound Ua 3) And (5Z, 7E)-(3 -2,2-Pentano-9,10-seco-5,7,10 (19) -cholestriene-1,3,25-triol ((5Z, 7E)- (3, 2-Pentano-9, 10-seco-5, 7, 10 (19) -cholestatr iene-1, 3,25-trioK compound Ub3)

To a mixture of compound Ta3 (128 mg, 293 / mol), compound K (71 mg, 199 mol) and triethylamine (2 mL) in toluene (8 mL) was added (Ph ₃ P ) ₄ Pd (199 mg, 100 ^ mol) was added, followed by stirring at room temperature for 10 minutes. After refluxing under heating for 90 minutes, the reaction mixture was diluted with ether, the whole was filtered through a silica gel pad (Merck silica gel 60), and then the solvent was distilled off. The obtained crude mixture was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9) to give a crude product (92 mg, 65%) containing the protected compound of the title compound.

While stirring a solution of the obtained crude product (87 mg) in THF (1.3 mL), TBAF (1.0 M in THF, 0.77 mL, 0.77 benzyl) was added at 0 ° C under an argon atmosphere. . Further, TBAF (1.0 M in THF, 2.19 mL, 2.19 ol) was added, the reaction mixture was stirred at room temperature for 27 hours, brine was added, and the whole was extracted with ethyl acetate. The organic layer is sulfuric acid, The solvent was distilled off. The resulting crude mixture was purified by silica gel column preparative thin-layer chromatography (ethyl acetate: n-hexane = 1: 3) to obtain compounds Ua3 and Ub3 (33 mg, 56 mg) as a white solid. Was. The white solid was further separated and purified by reversed-phase recycling HPLC (YMC-Pack ODS column, 20 × 150 mm, 9.9 mL / min, aceto nitrile: water = 98: 2), and the biological activity was evaluated. Compound ^{_{Ua3: [a] 2 D °}} = -57.5 (σ = 0.52, CHC1 3); NMR (400 MHz, CDC1 3) δ 0.56 (3 H, s), 0.94 (3 H, d, J = 6.3 Hz) , 1.05-2.02 (28 H, m), 2.34 (1 H, d, J = 4.6 Hz), 2.38 (1 H, dd, J =

14.8, 2.6 Hz), 2.75 (1 H, d, J = 14.4 Hz), 2.85 (1 H, dd, J = 12.0, 3.9 Hz), 3.09 (1 H, d, J = 8.1 Hz), 3.79 (1 H, br.d.

J = 6.6 Hz), 4.13 (1 H, d, J = 2.9 Hz), 5.06 (1 H, d, J = 2.2 Hz), 5.23 (1 H, d, J = 2.2 Hz), 6.11 (1 H, d, J = 11.2 Hz), 6.48 (1 H, dd, J = 11.2, 2.7 Hz); ¹³ C NMR (100 MHz,

CDCI3) δ 12.1, 18.9, 20.9, 20.9, 21.5, 22.5, 23.8, 26.1, 27.7, 29.2, 29.3, 29.4, 30.3, 32.3, 36.1, 36.4, 40.5, 40.6,

40.9, 44.4, 46.0, 56.4, 56.5, 71.1, 77.2, 115.7, 116.8, 126.2, 131.2, 142.9, 145.2; IR (neat) 3349, 2942, 2865, 1453, 1377, 1213, 1040, 909, 756 cm " ¹ MS m / z 484 (M) ⁺ , 466 (M-H ₂ 0) ⁺ ; HR S calcd for C ₃₂ H ₅₂ 0 ₃ 484.3916, found 484.3903. Compound Ut> 3: [a] "= +116.5 (c = 1.00, CHCI3); ^Χι Ά NMR (400 MHz, CDCI3) δ 0.53 (3 H, s), 0.93 (3 H, d, J = 6.6 Hz), 1.03-2.01 (28 H, m), 1.21 (6 H, s), 2.34 (1 H, d, J = 4.6 Hz), 2.38 (1 H, dd, J = 14.8, 2.6 Hz), 2.74 (1 H, br.d, J = 14.4 Hz), 2.84 ( 1 H, dd, J = 12.1, 3.1 Hz), 3.22 (1 H, d, J = 8.1 Hz), 3.79 (1 H, br.s, J = 6.3 Hz), 4.12 (1 H, br.d, J = 3.2 Hz), 5.01 (1 H, d, J = 2.2 Hz), 5.20 (1 H, d, J = 2.2 Hz), 6.04 (1 H, d, J = 11.2 Hz), 6.48 (1 H, dd, J = 11.2, 1.7 Hz); ¹³ C

_{NMR (100 MHz, CDC1 3)} δ 12.1, 18.9, 20.9, 20.9, 21.4, 22.3, 23.5, 26.1, 27.7, 29.1, 29.2, 29.4, 30.3, 32.3, 36.1, 36.5, 40.6, 40.6, 40.9, 44.4, 45.9, 56.3, 56.5, 71.1, 75.1, 80.8, 115.6, 116.9, 126.2, 142.8, 145.2; IR (neat) 3364, 2924, 2867, 2326, 1699, 1451, 1038, 899 cm "¹; MS m / z 484 (M) ⁺ , 466 (M-H ₂₀ ) ⁺ ; HRMS calcd for C ₃₂ H ₅₂ 0 ₃ 484.3916, found 484.3905.

(5Z, 7E)-(l?, 37?)-2,2-Pentano-9,10-seco_5,7,10 (19) -Cholestatriene-1,3,25-triol ((5Z, 7E) -(3 -2, 2-Pentano-9, 10-seco-5, 7, 10 (19) -cholestatriene-l, 3, 25-trioK Compound Uc3) and (5Z, 7E)-(1, 3 — 2 , 2-Pentano-9,10-Seco-5,7,10 (19) -Cholestriene-1,3,25-triol ((5Z, 7E)-(IS, 3i) -2, 2-Pentano -9, 10-seco-5, 7, 10 (19) -cholestatriene-l, 3, 25-trioK compound Ud3)

Similarly, compounds Uc3 and Ud3 were synthesized from compound Tb3.

Compound Uc3: [a] ² _D ² = +9.7 (σ = 0.36, CHC1 ₃ ); ¾ MR (400 MHz, CDC1 ₃ ) δ 0.54 (3 H, s), 0.93 (3 H, d, J = 6.3 Hz ), 1.02-2.02 (28 H, m), 1.21 (6 H, s), 2.35 (1 H, dd, J = 13.7, 7.8 Hz), 2.57 (1 H, dd, J = 13.9, 3.7 Hz), 2.83 (1 H, br.d, J = 12.7 Hz), 3.72 (1 H, dt, J = 12.7, 6.1 Hz), 4.05 (1 H, dd, J = 10.4, 6.7 Hz), 4.29 (1 H, d, J = 4.9 Hz), 5.03 (1 H, s), 5.29 (1 H, s), 6.03 (1 H, d, J = 11.2 Hz), 6.38 (1 H, d, J = 11.2 Hz); ^{13 C NMR (100 MHz, CDC1} 3) δ 12.1, 18.9, 20.9, 21.1, 21.2, 22.3, 23.6, 26.2, 26.8, 27.3, 27.7, 29.1, 29.3, 29.4, 36.1, 36.4, 40.2, 40.5, 43.1, 44.4 , 45.9, 56.4, 56.5, 70.5, 71.1, 75.2, 113.3, 116.9, 124.6, 132.8, 143.0, 145.4; IR (neat) 3405, 2944, 2870, 2359, 1611, 1451, 1373, 1047, 857 cm "¹; MS m / z 484 (M) ⁺ , 466 (M-H ₂₀ ) +; HRMS calcd. For C ₃₂ H ₅₂ 0 ₃ 484.3916, found 484.3905.

I匕合was Ud3: [a] "= -6.5 (c = 0.46, CHC1 3); ¾ NMR (600 MHz, CDCI3) δ 0.55 (3 H, s), 0.94 (3 H, d, J = 6.6 Hz ), 1.05-2.01 (28 H, ra), 2.37 (1 H, dd, J = 13.6, 8.7 Hz), 2.53 (1 H, dd, J = 13.1, 4.3 Hz), 2.82 (1 H, dd, J = 12.0, 3.7 Hz), 4.00 (1 H, dt, J = 8.5, 4.4 Hz), 4.34 (1 H, d, J = 4.7 Hz) , 5.04 (1 H, d, J = 1.9 Hz), 5.29 (1 H, d, J = 1.1 Hz), 6.03 (1 H, d, J = 11.3 Hz), 6.39 (1 H, d, J = 11.3) Hz); ¹³ CR (150 MHz, CDC1 ₃ ) δ 12.1, 18.8, 20.8, 21.0, 21.1, 22.3, 23.6, 27.5, 27.6, 29.1, 29.2, 29.4, 36.1, 36.4, 40.2, 40.5, 42.9, 44.4, 45.9 , 56.3, 56.5, 70.9, 71.1, 75.1, 114.0, 116.9, 124.7, 132.8, 143.0, 145.3; IR (neat) 3447, 2938, 2865, 2355, 1539, 1455, 1375, 1215, 1046 cm "¹; MS m / z 484 (M) +, 466 (M-H ₂₀ ) ⁺ ; HRMS calcd for C ₃₂ H ₅₂ 0 ₃ 484.3916, found 484.3918.

(Test example) 実験 Binding experiment to thymus vitamin D receptor (VDR)

The ability of the vitamin D derivative of the present invention to bind to human thymus VDR was tested. Examples of the vitamin D derivatives of the present invention include the compounds 1a, 1b, 2a, 2b, 3a, 3b, Ja synthesized in Examples 13, 14, 15, 24, 34, 44, 54 described above. , Jb, Jc, Jd, Ual, Ubl, Ucl, Udl, Ua2, Ub2, Uc2, Ud2, Ua3, Ub3, Uc3, Ud3.

ゥ ishi thymus VDR is Yamasa Shoyu Co., Ltd.

1 ampoule (about 25 mg) was dissolved in 75 ml of 0.05 M phosphoric acid 0.5 M potassium buffer (pH 7.4). .

The ethanol solution 50111 of the vitamin D derivative or 1-, 25-dihydroxyvitamin D ₃ of the present invention and the receptor solution 5001 are placed in a test tube, and after precipitating at room temperature for 1 hour, [ ³ H] 50/1 of 1,25-dihydroxyvitamin D ₃ solution was added to a final concentration of 0.1 InM, and the mixture was incubated at 4 ° C. Dextran-coated carcoa 1 was added to the reaction solution, mixed, left to stand at 4 for 30 minutes, and centrifuged at 3000 rpm for 10 minutes to bind [ ³ H] to the receptor. ] 1 a, 25 Hydroxyvitamin D ₃ and free [ ³ H] la, 25 dihydroxyvitamin D ₃ were separated. The supernatant (500 1) was mixed with ACS-II (9.5 ml) (Amersham, Eng 1 and), and the radioactivity was measured.

1 a, 25-binding to VDR of dihydroxyvitamin D ₃ and that it has a 100 Kino was accordance connexion calculated relative binding to the following calculation formula to VDR vitamin D derivative of the present invention.

X = (y / x) X 100

X: Relative binding of the vitamin D derivative of the present invention to VDR

y: concentration at which 1 a, 25-dihydroxyvitamin D ₃ inhibits the binding of [ ³ H] 1,25-dihydroxyvitamin D ₃ to VDR by 50%

X: Concentration of Vitamin D derivative, ^[3 H] 1, 25- binding dihydroxy Vita Mi emissions 0 ₃ and VDR 50% inhibition of the present invention

The results are shown in the table below.

(table 1)

Industrial potential

The compound represented by the general formula (1) or (2) of the present invention is a novel compound. It is expected to be useful as a drug such as a calcium metabolism regulator.

Claims

The scope of the claims

General formula (1)

R2

Equation (1)

(Where:

R! Represents C ₃ _ ₈ alkyl group or a straight optionally substituted by hydroxyl or branched c ₃ _ ₈ alkenyl group of a hydroxyl group linear or optionally substituted branched-chain ;

R ₂ represents a linear or branched alkyl group which may be substituted with a hydroxyl group)

A compound represented by the formula:

2. In the general formula (1), 1 ^ is a hydroxyl group which may straight if also be substituted by Ku the Ku branched C ₃ _ ₅ alkyl group or a hydroxyl group which may straight if also be substituted by the branched C ₃ _ ₅ alkenyl group represents, R ₂ represents a hydroxyl group linear or may be substituted with branched C 3. The compound according to claim 1, which represents an alkyl group.

3. - In general formula (1), 1 ^ is, 7K acid which may straight if also be substituted by a group Ku is optionally substituted with branched C ₃ _ ₄ alkyl group or a hydroxyl group linear If Ku represents a branched C ₃ _ ₄ alkenyl group, R ₂ represents a hydroxyl group in the optionally substituted straight-chain or branched C ₅ _ _s alkyl group, the compound of claim 1 wherein .

4. In the general formula (1), represents a linear or branched C ₃ alkyl group which may be substituted with a hydroxyl group or a linear or branched chain which may be substituted with a hydroxyl group. It represents C ₃ alkenyl group, R ₂ represents a 4-hydroxy-4-methylpentyl group, a compound according to claim 1.

5. General formula (2):

Equation (2)

(Where:

R ₃ and R _4, together a connexion to form optionally substituted C ₃ _ ₆ spirocyclic al Kill group;

R ₅ represents a linear or branched C i _i ₂ alkyl group which may be substituted with a hydroxyl group)

A compound represented by the formula:

6. In the general formula (2), ₃ Oyobi 1 _4, together such connexion, unsubstituted C ₃ _ ₅ spirocyclic alkyl groups to form, R ₅ is a straight optionally substituted by hydroxyl chains properly represents branched C ₅ _ ₈ alkyl group, wherein compound of claim 5.

7. A pharmaceutical composition comprising the compound according to claim 1 together with a pharmaceutically acceptable carrier or diluent.