JP2006045109A - Osteoporosis-treating agent using vitamin d3 lactone derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an osteoporosis-treating agent containing a vitamin D3 derivative having a vitamin D3 antagonistic activity or its medicinally acceptable solvated material as an active ingredient. <P>SOLUTION: This osteoporosis-treating agent containing a compound expressed by formula (1) [wherein, R<SP>1</SP>is H, a hydroxy-substitutable 1-6C alkyl or a hydroxy-substitutable 1-6C alkoxy; and R<SP>2a</SP>, R<SP>2b</SP>are each H, a hydroxy-substitutable 1-10C alkyl, a hydroxy-substitutable 6-10C aryl, a hydroxy-substitutable 7-12C aralkyl or ethylene by bonding together, provided that compounds having R<SP>1</SP>of H or methyl and R<SP>2a</SP>and R<SP>2b</SP>of both H are excluded] or its medicinally acceptable solvated material as the active ingredient. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

The present invention relates to an osteoporosis therapeutic agent using a vitamin D ₃ lactone derivative useful as a pharmaceutical product. More specifically, the present invention relates to a therapeutic agent for osteoporosis based on an osteogenesis promoting action, comprising a 1α-hydroxyvitamin D ₃ lactone derivative or a pharmaceutically acceptable solvate thereof as an active ingredient.

Osteoporosis is a decrease in bone mass as a result of bone resorption exceeding bone formation, and most often develops after menopause or with aging. As therapeutic drugs, bisphosphonates, vitamin D ₃ derivatives, estrogens, calcitonin and the like are used. Furthermore, in recent years, parathyroid hormone (PTH) having an unprecedented powerful bone formation promoting action has appeared in the clinical field, and more effective drug treatment has become possible. However, since PTH is an injection, there are problems in terms of convenience, drug compliance, price, and the like. Therefore, if an effect equivalent to that of PTH can be achieved with an inexpensive oral preparation, it can be a useful drug.

However, PTH is 1α is blood calcium and activated vitamin D _3, has received the secretion controlled by 25-dihydroxyvitamin D _3, PTH secretion increases with these concentrations decrease. Therefore, a compound that antagonizes the action of 1α, 25-dihydroxyvitamin D ₃ , that is, a vitamin D ₃ antagonist, can be expected to promote PTH secretion and exert the same action as the above PTH preparation.

The following are known in the prior art relating to the compounds of the present invention. Patent Document 1 discloses a compound having an α-methylene lactone structure as a D-ring side chain of vitamin D ₃ . However, the compounds of the present invention do not contain these compounds, and whether or not the described compounds have a vitamin D ₃ antagonistic action, and further have an osteogenesis treatment action based on a PTH promoting action. There is no description or suggestion about the indication to the drug.

Non-Patent Document 1 and Non-Patent Document 2 show that the compound described in Patent Document 1 has a vitamin D ₃ antagonistic action. However, these compounds are not contained in the compounds of the present invention, and furthermore, there is no description or suggestion about application to a therapeutic agent for osteoporosis having an osteogenesis promoting action based on a PTH promoting action.

Also shown is a compound having α- methylene cycloalkanone structure as D-ring side chain of vitamin D ₃ in the patent document 2. However, the compounds of the present invention do not contain the above-mentioned compounds, and furthermore, there is no description or suggestion about adaptation to a therapeutic agent for osteoporosis having an osteogenesis promoting action based on a PTH promoting action.

Patent Document 3 and Patent Document 4 show compounds having a methyl group as a 2-position substituent of vitamin D ₃ . However, the compound of the application specification is such that the D-ring side chain of vitamin D ₃ is 1α, 25-dihydroxyvitamin D ₃ type (6-hydroxy-6-methylheptan-2-yl), and α disclosed in the present invention. -Different from compounds having a methylene lactone structure. Further, in the specification, there is no description about whether or not the described compound has a vitamin D ₃ antagonistic action, and further, an indication for an osteoporosis therapeutic agent having a bone formation promoting action based on a PTH promoting action. There is no suggestion.

International Publication No. 95/33716 International Publication No. 00/24712 Specification Japanese Patent Laid-Open No. 11-116551 International Publication No. 98/50353 Specification J. et al. Biol. Chem. 274, 16392-16399, 1999 J. et al. Biol. Chem. 274, 32376-32381, 1999

The purpose of the present invention is to
The object is to provide a therapeutic agent for osteoporosis containing a vitamin D ₃ derivative having a vitamin D ₃ antagonistic action or a pharmaceutically acceptable solvate thereof as an active ingredient.

The present invention is an osteoporosis therapeutic agent containing a vitamin D ₃ derivative represented by the following formula (1) or a pharmaceutically acceptable solvate thereof as an active ingredient.

［式中、Ｒ^１は水素原子、水酸基で置換されていてもよいＣ_１−Ｃ_６のアルキル基、または水酸基で置換されていてもよいＣ_１−Ｃ_６のアルコキシ基を表し、Ｒ^２ａおよびＲ^２ｂは同一もしくは異なり、水素原子、水酸基で置換されていてもよいＣ_１−Ｃ_１０のアルキル基、水酸基で置換されていてもよいＣ_６−Ｃ_１０のアリール基、水酸基で置換されていてもよいＣ_７−Ｃ_１２のアラルキル基を表す。または、Ｒ^２ａとＲ^２ｂが一緒になってそれらが結合する炭素原子とともにシクロプロパン環を形成してもよい。ただし、Ｒ^１、Ｒ^２ａ、およびＲ^２ｂが同時に水素原子である化合物、ならびにＲ^１がメチル基であり、Ｒ^２ａ、およびＲ^２ｂが水素原子である化合物を除く。］

[Wherein, R ¹ represents a hydrogen atom, a C ₁ -C ₆ alkyl group optionally substituted with a hydroxyl group, or a C ₁ -C ₆ alkoxy group optionally substituted with a hydroxyl group, R ^2a and R ^2b is the same or different and is substituted with a hydrogen atom, a C ₁ -C ₁₀ alkyl group that may be substituted with a hydroxyl group, a C ₆ -C ₁₀ aryl group that may be substituted with a hydroxyl group, or a hydroxyl group. Or a C ₇ -C ₁₂ aralkyl group. Alternatively, R ^2a and R ^2b may be combined to form a cyclopropane ring with the carbon atom to which they are attached. However, a compound in which R ¹ , R ^2a , and R ^2b are simultaneously a hydrogen atom, and a compound in which R ¹ is a methyl group, and R ^2a , and R ^2b are hydrogen atoms are excluded. ]

  According to the present invention, a therapeutic agent for osteoporosis is provided.

The definitions of terms in the present invention are as follows.
The C ₁ -C ₆ alkyl group represents a linear, branched or cyclic aliphatic hydrocarbon group having 1 to 6 carbon atoms. For example, specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, cyclopropyl, cyclopropylmethyl, and cyclohexyl groups. Can do.

The alkyl group of C ₁ -C _10, represents a straight-chain, branched-chain or cyclic aliphatic hydrocarbon group, having 1 to 10 carbon atoms. Specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, octyl, decyl, cyclopropyl, cyclopropylmethyl, and cyclohexyl. Can be cited as a typical group.

The C ₁ -C ₆ alkoxy group represents a linear, branched, or cyclic aliphatic hydrocarbon oxy group having 1 to 6 carbon atoms. For example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, pentyloxy group, isopentyloxy group, hexyloxy group, cyclopropoxy group, cyclopropylmethoxy group, cyclohexyloxy group, etc. Can be cited as a typical group.

The C ₆ -C ₁₀ aryl group represents an aromatic hydrocarbon group having 6 to 10 carbon atoms. Specifically, it is a phenyl group or a naphthyl group. For example, a phenyl group, 1-naphthyl group, 2-naphthyl group, etc. can be mentioned as specific groups.

The C ₇ -C ₁₂ aralkyl group represents a linear, branched or cyclic aliphatic hydrocarbon group substituted with an aromatic hydrocarbon group having 7 to 12 carbon atoms. Specifically, it means a phenylalkyl group or naphthylalkyl group having 7 to 13 carbon atoms in total. For example, a benzyl group, a phenethyl group, a 3-phenylpropyl group, a naphthylmethyl group, a 2-naphthylethyl group, and the like can be given as specific groups.

In the above formula (1), R ¹ represents a hydrogen atom, a C ₁ -C ₆ alkyl group which may be substituted with a hydroxyl group, or a C ₁ -C ₆ alkoxy group which may be substituted with a hydroxyl group. Among them, hydrogen atom, methyl group, ethyl group, propyl group, butyl group, hydroxymethyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, 4-hydroxybutyl group, 2-hydroxyethoxy group, 3-hydroxypropoxy Or a 4-hydroxybutoxy group, particularly preferably a methyl group, a 3-hydroxypropyl group, or a 3-hydroxypropoxy group.

In the formula (1), R ^2a and R ^2b are the same or different and are a hydrogen atom, a C ₁ -C ₁₀ alkyl group optionally substituted with a hydroxyl group, or a C ₆ -C ₁₀ optionally substituted with a hydroxyl group. An aryl group, and a C ₇ -C ₁₂ aralkyl group optionally substituted by a hydroxyl group. Alternatively, R ^2a and R ^2b may be combined to form a cyclopropane ring with the carbon atom to which they are attached. Especially, the combination of R ^2a and R ^2b is a hydrogen atom and a methyl group, a hydrogen atom and an ethyl group, a hydrogen atom and a propyl group, a hydrogen atom and an isopropyl group, a hydrogen atom and a butyl group, a hydrogen atom and an isobutyl group, a hydrogen atom and Hexyl group, hydrogen atom and octyl group, hydrogen atom and phenyl group, hydrogen atom and phenethyl group, hydrogen atom and 2-hydroxyethyl group, both hydrogen atoms, both methyl groups, or R ^2a and R ^2b together It is preferable to form a cyclopropane ring together with the carbon atom to which they are bonded, and in particular, a hydrogen atom and a methyl group, a hydrogen atom and an ethyl group, a hydrogen atom and a propyl group, a hydrogen atom and a butyl group, a hydrogen atom and an isobutyl group, It is preferable that a hydrogen atom and a hexyl group or both be a methyl group.

In the above formula (1), when an asymmetric carbon is contained in the compound structure, the steric configuration may be any of (S) configuration, (R) configuration, α configuration, and β configuration unless otherwise specified. . The 1st position is the α configuration and the 3rd position is the β configuration, or the 1st position is the α configuration and the 3rd position is preferably the α configuration, and the 1st position is the α configuration and the 3rd position is most preferably the β configuration. In the case of a C ₁ -C ₆ alkyl group optionally substituted with a hydroxyl group at the 2-position or a C ₁ -C ₆ alkoxy group optionally substituted with a hydroxyl group, the configuration at the 2-position has an α configuration. preferable. The α and β configurations used here represent the configuration on the carbon constituting the A ring in the vitamin D ₃ derivative or its synthesis precursor, and the configuration that is up with respect to the paper surface is the α configuration. The down arrangement is called β arrangement.

Preferable specific examples of the vitamin D ₃ derivative represented by the formula (1) of the present invention include compounds shown in the following table. In addition, when the compound in the table has an asymmetric carbon in the chemical structure, the steric configuration may be any of (S) configuration, (R) configuration, α configuration, and β configuration unless otherwise specified. Good.

  Among the compounds shown in these tables, Compound No. 101 (where the configuration at the 1-position is the α configuration and the configuration at the 3-position is the β configuration (hereinafter this is referred to as (1α, 3β)). ), 102 (1α, 3β), 103 (1α, 3β), 104 (1α, 3β), 105 (1α, 3β), 106 (1α, 3β), 107 (1α, 3β), 108 (1α, 3β), 109 (1α, 3β), 110 (1α, 3β), 111 (1α, 3β), 113 (1α, 3β), 114 (1α, 3β), 201 (1α, 2α, 3β), 202 (1α, 2α, 3β), 203 (1α, 2α, 3β), 205 (1α, 2α, 3β), 206 (1α, 2α, 3β), 207 (1α, 2α, 3β), 209 (1α, 2α) 3β), 211 (1α, 2α, 3β), 213 (1α, 2α, 3β), 801 (1α, 2α) 3β), 802 (1α, 2α, 3β), 803 (1α, 2α, 3β), 804 (1α, 2α, 3β), 806 (1α, 2α, 3β), 807 (1α, 2α, 3β), 808 (1α, 2α, 3β), 810 (1α, 2α, 3β), 812 (1α, 2α, 3β), 814 (1α, 2α, 3β), 1101 (1α, 2α, 3β), 1102 (1α, 2α, 3β), 1103 (1α, 2α, 3β), 1104 (1α, 2α, 3β), 1106 (1α, 2α, 3β), 1107 (1α, 2α, 3β), 1108 (1α, 2α, 3β), 1110 ( 1α, 2α, 3β) and 1112 (1α, 2α, 3β) and 1114 (1α, 2α, 3β) can be mentioned as particularly preferred.

Vitamin D ₃ derivatives of the present invention can be converted to a solvate of their pharmaceutically acceptable as needed. Such solvents include water, methanol, ethanol, propyl alcohol, isopropyl alcohol, butanol, t-butanol, acetonitrile, acetone, methyl ethyl ketone, chloroform, ethyl acetate, diethyl ether, t-butyl methyl ether, benzene, toluene, DMF. , And DMSO. Particularly preferred are water, methanol, ethanol, propyl alcohol, isopropyl alcohol, acetonitrile, acetone, methyl ethyl ketone, and ethyl acetate.

Production of vitamin D ₃ derivative represented by the above formula (1) can be performed, for example, as follows. That is, by reacting an aldehyde compound represented by the following formula (2) (Z = (2-1)) with an acrylic acid derivative represented by the following formula (3a), the following formula (4) (Z = ( 2-1)) is converted to a lactone compound, and this is coupled with an ene-in compound represented by the following formula (7) in the presence of a palladium catalyst, followed by deprotecting the protecting group of the hydroxyl group. (Scheme 1).

［上記スキーム中、Ｙは臭素原子またはヨウ素原子を表し、Ｒ^３はトリメチルシリル基、トリエチルシリル基、トリイソプロピルシリル基、ｔ−ブチルジメチルシリル基、ｔ−ブチルジフェニルシリル基、アセチル基、メトキシメチル基、またはテトラヒドロ−４Ｈ−ピラン−２−イル基を表し、Ｒ^６は水素原子、Ｒ^３で定義される基で保護された水酸基で置換されていてもよいＣ_１−Ｃ_６のアルキル基、またはＲ^３で定義される基で保護された水酸基で置換されていてもよいＣ_１−Ｃ_６のアルコキシ基を表し、Ｒ^７はＣ_１−Ｃ_６のアルキル基を表し、Ｒ^２ｄおよびＲ^２eはＲ^３で定義される基で保護された水酸基で置換されていてもよいＣ_１−Ｃ_１０のアルキル基、Ｒ^３で定義される基で保護された水酸基で置換されていてもよいＣ_６−Ｃ_１０のアリール基、またはＲ^３で定義される基で保護された水酸基で置換されていてもよいＣ_７−Ｃ_１２のアラルキル基を表す。または、Ｒ^２ｄとＲ^２eが一緒になってそれらが結合する炭素原子とともにシクロプロパン環を形成してもよい。］

[In the above scheme, Y represents a bromine atom or an iodine atom, R ³ is trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, t- butyl dimethyl silyl group, t- butyl diphenyl silyl group, an acetyl group, a methoxymethyl group Or a tetrahydro-4H-pyran-2-yl group, wherein R ⁶ is a hydrogen atom, a C ₁ -C ₆ alkyl group optionally substituted with a hydroxyl group protected by a group defined by R ³ , or R ₁ represents a C ₁ -C ₆ alkoxy group optionally substituted with a hydroxyl group protected by a group defined by R ³ , R ⁷ represents a C ₁ -C ₆ alkyl group, and R ^2d and R ^2e represent alkyl group R ³ group protected may be substituted by a hydroxyl group C ₁ -C ₁₀ defined by, be substituted with a hydroxyl group protected by a group as defined by R ³ A C ₆ -C ₁₀ aryl group, or a C ₇ -C ₁₂ aralkyl group optionally substituted with a hydroxyl group protected by a group defined by R ³ ; ^{Alternatively} , R ^2d and R ^2e may be combined to form a cyclopropane ring with the carbon atom to which they are attached. ]

  In the aldehyde compound (2) (Z = (2-1)) used here, the steric configuration of the * mark carbon is the (R) isomer, for example, by combining known methods as shown in the following scheme 2. Can be obtained.

［上記スキーム中、Ｙは前記定義に同じ。］

[In the above scheme, Y is as defined above. ]

  Further, these (2) (Z = (2-1)) and those in which the steric configuration of the * -marked carbon is the (S) form are shown in the following scheme 3 using the intermediate diol obtained in scheme 2, for example. Can be obtained by such a method.

［上記スキーム中、Ｙは前記定義に同じ。］

[In the above scheme, Y is as defined above. ]

The acrylic acid derivative (3a) used in Scheme 1 can be obtained as follows.
A compound in which both R ^2d and R ^2e are hydrogen atoms is commercially available.
One of R ^2d and R ^2e is a hydrogen atom and the other is not a hydrogen atom, as described in the literature (for example, Helv. 1984)). A compound in which both R ^2d and R ^2e are not hydrogen atoms can be obtained by a method as shown in the following scheme 4, for example.

［上記スキーム中、Ｒ^７、Ｒ^２ｄ、およびＲ^２ｅは前記定義に同じ。］

[In the above scheme, R ⁷ , R ^2d and R ^2e are the same as defined above. ]

  (2) To the lactone compound represented by (4) (Z = (2-1)) by reacting the compound represented by (Z = (2-1)) with the compound represented by (3a) For example, as shown in Scheme 1, (2) (Z = (2-1)) and the compound represented by (3a) are reacted in the presence of zinc and an aqueous ammonium chloride solution as shown in Scheme 1. The obtained hydroxy ester can be treated with tetra n-butylammonium fluoride (TBAF), or after hydrolysis of the ester, if necessary, with dilute hydrochloric acid.

The enyne compound (7) used in Scheme 1 can be obtained by a method described in the literature. For example, when R ³ is a t-butyldimethylsilyl (TBS) group and R ⁶ is a hydrogen atom, Trost et al., Journal of American Chemical Society (J. Am. Chem. Soc.), 114, 9836-9845 (1992); Tetrahedron Letters, 35, 8119-8122 (1994), etc., when R ³ is a TBS group and R ⁶ is a methyl group, Kanno et al., Journal of Medicinal Chemistry (J. Med. Chem.), 43, 4247-4265 (2000), etc., R ³ is t-butyldimethylsilyl (TBS) group and R ⁶ is ethyl. Group, propyl group, butyl group, t-butyldimethylsilyloxymethyl group, 2-t-butyldimethylsilyl In the case of a ruoxyethyl group, a 3-t-butyldimethylsilyloxypropyl group, and a 4-t-butyldimethylsilyloxybutyl group, Suhara et al., The Journal of Organic Chemistry (J. Org. Chem.), 66, 8760-871 (2001), R ³ is t-butyldimethylsilyl (TBS) group, R ⁶ is 2-t-butyldimethylsilyloxyethoxy group, 3-t-butyldimethylsilyloxypropoxy. The group and 4-t-butyldimethylsilyloxybutoxy group are described in Tachibanataka et al., Organic Letters (Org. Lett.), Vol. 2, pages 2619-2622 (2000).

  (4) The coupling reaction of the compound represented by (Z = (2-1)) and the compound represented by (7) is carried out by the method of Trost et al. (Journal of American Chemical Society ( J. Am. Chem. Soc.), 114, 9836-9845 (1992)).

  The deprotection reaction of the hydroxyl-protecting group of the obtained coupling product is carried out according to a known method (for example, Green et al., Protective Groups in Organic Synthesis Edition, John, Protective Groups in Organic Synthesis, 3rd edition). Wiley & Sons, Inc (1999)).

  More specifically, when the protecting group is an acetyl group or a benzoyl group, ordinary alkali hydrolysis, potassium cyanide, ammonia-methanol, or the like can be used. When the protecting group is a methoxymethyl group or a tetrahydro-4H-pyran-2-yl group, for example, hydrochloric acid, acetic acid, trifluoroacetic acid, pyridinium p-toluenesulfonate (PPTS) or the like may be used under acid conditions. it can. When the protecting group is a tri (alkyl / aryl) silyl group such as trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, It can be carried out according to a known method. For example, TBAF, PPTS (pyridinium p-toluenesulfonate), p-toluenesulfonic acid, hydrogen fluoride, camphorsulfonic acid, hydrochloric acid, sulfuric acid, a reagent composed of a combination of tetrafluoroborate alkali metal salt and sulfuric acid can be used. .

Furthermore, vitamin D ₃ derivative represented by the above formula (1), the compound together with the carbon atom attached they R ^2a and R ^2b together represent a cyclopropyl group, compound (4) (Z = ( 2-1), R ^2d —R ^2e ═CH ₂ —CH ₂ ), and reacting according to the above-mentioned scheme 1. Compound (4) (Z = (2-1), R ^2d -R ^2e = CH ₂ -CH ₂ ) can be obtained, for example, according to Scheme 5 below. That is, by reacting an aldehyde compound represented by the following formula (2) (Z = (2-1)) with an acetylene derivative represented by the following formula (8) and subsequently oxidizing the generated hydroxyl group, the following formula The acetylene compound represented by (9) is obtained. Ethylene is added thereto using a Grubbs complex to obtain a diene compound represented by the following formula (10). Next, after cyclopropanation, the carbonyl group is reduced to obtain a cyclopropane compound represented by the following formula (11). After deprotecting the hydroxyl protecting group (R ⁹ ), the resulting primary hydroxyl group is oxidized to form a lactone ring, whereby (4) (Z = (2-1), R ^2d -R ^2e = _{CH 2} -CH 2) can be obtained.

［上記スキーム中、Ｒ^９はトリメチルシリル基、トリエチルシリル基、トリイソプロピルシリル基、ｔ−ブチルジメチルシリル基、ｔ−ブチルジフェニルシリル基などの水酸基の保護基を表し、Ｙは前記式（２）の定義に同じ。］

[In the above scheme, R ⁹ represents a protective group for a hydroxyl group such as a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, and Y represents the formula (2). Same as definition. ]

In addition, production of a vitamin D ₃ derivative represented by the above formula (1), wherein R ¹ is a hydrogen atom, the configuration at the 1-position is α-configuration, and the configuration at the 3-position is β-configuration is For example, as shown in Scheme 6 below, compound (12) obtained from vitamin D ₂ is derived into compound (17) by combining photoisomerization reaction and 20-position aldehyde conversion reaction, followed by deprotection of the hydroxyl protecting group. It can be done by protecting.

［上記スキーム中、Ｒ^３、Ｒ^２ｄ、およびＲ^２ｅは前記定義に同じ。］

[In the above scheme, R ³ , R ^2d and R ^2e are the same as defined above. ]

The compound represented here by the above formula used (12) and the formula (13), from vitamin _{D 2,} literature (Delon to tetra (Tetrahedron), 20, pp. 4609-4619 (1987)) according Can be obtained by the method.

  The conversion from the compound represented by the above formula (14) to the compound represented by the above formula (15) and the compound represented by the above formula (16) to the compound represented by the above formula (17) This can be achieved by photoisomerization in the same manner as the conversion from the compound represented by the formula (12) to the compound represented by the above formula (13).

  From the compound represented by the formula (14) to the compound represented by the formula (16), from the compound represented by the formula (15) to the compound represented by the formula (17), and the formula (17) The compound represented by formula (1) can be converted to the compound represented by the above formula (1) by carrying out the method described in scheme 1 in the same manner.

In addition, among the lactone compounds (4) shown above, one in which either R ^2d or R ^2e is a hydrogen atom and the other is not a hydrogen atom is obtained by the method shown in the following scheme 7 by the method of the lactone ring oxygen atom. The compound (4syn) and the compound (4anti) in which the relative configuration of the carbon a to be bonded to the carbon b to which the adjacent R ² is bonded are syn (sin) and anti (4anti) can be selectively obtained. That is, (4syn) can be selectively obtained by reacting the aldehyde compound represented by (2) with the acrylate compound represented by (3) in the presence of divalent chromium (Okuda et al., Chemistry Letters, 481-484 (1985)). The obtained (4syn) lactone ring is reduced, and the primary hydroxyl group thus produced is protected to obtain an alcohol compound represented by (5syn). The secondary hydroxyl group of this compound is oxidized to obtain a ketone compound represented by (6), and the ketone group of this compound is reduced to obtain an alcohol compound represented by (5anti). Finally, R ⁸ of this compound is deprotected, and then the resulting primary hydroxyl group is oxidized to form a lactone ring, whereby carbon a to which the lactone ring oxygen atom is bonded and carbon b to which the adjacent R ² is bonded. The compound (4anti) whose relative configuration is anti can be obtained. By performing the reactions of Schemes 1 and 5 using (4syn) and (4anti) obtained stereoselectively, the asymmetric carbon to which the lactone ring oxygen atom is bonded and the adjacent R ² are bonded. The compound (1) having a controlled steric configuration can be stereoselectively obtained.

［上記式（２）、（４ｓｙｎ）、（５ｓｙｎ）、（６）、（５ａｎｔｉ）、および（４ａｎｔｉ）中、Ｚは下記式（２−１）、（２−２）、（２−３）、（２−４）、および（２−５）のいずれかを表す。］

[In the above formulas (2), (4syn), (5syn), (6), (5anti), and (4anti), Z represents the following formulas (2-1), (2-2), (2-3) , (2-4), and (2-5). ]

In said formula (2-1), Y represents a bromine atom or an iodine atom. Of these, a bromine atom is preferable.
In the above formulas (2-2), (2-4), and (2-5), R ³ is a trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group. , An acetyl group, a benzoyl group, a methoxymethyl group, or a tetrahydro-4H-pyran-2-yl group. Of these, a trimethylsilyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, and a methoxymethyl group are preferable.

In the above formula (2-3), R ⁴ and R ⁵ each independently represent a methyl group, an ethyl group, a propyl group, a trichloroethyl group, or R ⁴ and R ⁵ together represent an ethylene group or a propylene group. Of these, a methyl group, R ⁴ and R ⁵ are preferably ethylene groups, or R ⁴ and R ⁵ are preferably propylene groups.
In said formula (2-3), X represents an oxygen atom or a sulfur atom. Of these, an oxygen atom is preferable.

In the above formulas (2-4) and (2-5), R ⁶ is a hydrogen atom, a C ₁ -C ₆ alkyl group optionally substituted with a hydroxyl group protected by a group defined by R ³ , or be substituted with a hydroxyl group protected by a group as defined by R ³ represents an alkoxy group optionally C ₁ -C _6. Among them, hydrogen atom, methyl group, ethyl group, propyl group, butyl group, trimethylsilyloxymethyl group, t-butyldimethylsilyloxymethyl group, 2-trimethylsilyloxyethyl group, 2-t-butyldimethylsilyloxyethyl group, 3 -Trimethylsilyloxypropyl group, 3-t-butyldimethylsilyloxypropyl group, 4-trimethylsilyloxybutyl group, 4-t-butyldimethylsilyloxybutyl group, 2-trimethylsilyloxyethoxy group, 2-t-butyldimethylsilyloxy An ethoxy group, 3-trimethylsilyloxypropoxy group, 3-t-butyldimethylsilyloxypropoxy group, 4-trimethylsilyloxybutoxy group, or 4-t-butyldimethylsilyloxybutoxy group is preferable. Group is preferably a 3-t-butyldimethylsilyloxy-propyl or 3-t-butyldimethylsilyloxy propoxy group.

In the above formulas (3), (4syn), (5syn), (6), (5anti), and (4anti), R ^2c may be substituted with a hydroxyl group protected by a group defined by R ^3. alkyl C ₁ -C _10, aryl group of group protected which do good C ₆ -C ₁₀ be substituted by a hydroxyl group as defined in R ^3, a hydroxyl group protected by a group as defined by R ³ An optionally substituted C ₇ -C ₁₂ aralkyl group is represented. Of these, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a hexyl group, an octyl group, a phenyl group, a phenethyl group, or a 2-hydroxyethyl group is preferable. It is preferably a group, a butyl group, an isobutyl group, or a hexyl group.
In the above formula (3), R ⁷ represents a C ₁ -C ₆ alkyl group. Of these, a methyl group or an ethyl group is preferable.

In the above formulas (5syn), (5anti), and (6), R ⁸ represents an acetyl group, 4-oxopentanoyl group, pivaloyl group, benzoyl group, triisopropylsilyl group, t-butyldimethylsilyl group, or t- Represents a butyldiphenylsilyl group. Of these, a pivaloyl group or a benzoyl group is preferable.

  In the reaction to obtain (4syn) by reacting the aldehyde compound represented by (2) and the acrylic acid derivative represented by (3) in the presence of divalent chromium, the divalent chromium is chromium chloride ( III) and lithium aluminum hydride (LAH) can be mixed or generated, or chromium (II) chloride can be used. Examples of the organic solvent used in the reaction include halogen solvents such as methylene chloride, chloroform and carbon tetrachloride; hydrocarbon solvents such as hexane and toluene; ether solvents such as tetrahydrofuran (THF) and dioxane; N, N-dimethyl Examples thereof include water-soluble solvents such as formamide and acetonitrile; and mixed solvents thereof. These can be selected in consideration of the solubility and reactivity of the compound. Particularly preferred is THF. The reaction temperature is generally in the range of −20 ° C. to the boiling point of the solvent. In particular, the range from 0 ° C. to room temperature is preferable. The reaction time varies depending on the reaction raw material, the reaction solvent, and the reaction temperature, and it is usually desirable to use an analytical means such as thin layer chromatography until the starting material disappears.

  The reaction of reducing the lactone ring of the lactone compound represented by (4syn) and subsequently protecting the generated primary hydroxyl group to obtain the alcohol compound represented by (5syn) can be performed as follows. The reduction reaction can be performed with diisobutylaluminum hydride (DIBAL-H), LAH, sodium borohydride, or the like. In particular, DIBAL-H is preferable. Examples of the organic solvent used in the reaction include halogen solvents such as methylene chloride, chloroform and carbon tetrachloride; hydrocarbon solvents such as hexane and toluene; ether solvents such as tetrahydrofuran (THF) and dioxane; N, N-dimethyl Examples thereof include water-soluble solvents such as formamide and acetonitrile; and mixed solvents thereof. These can be selected in consideration of the solubility and reactivity of the compound. In particular, toluene, THF, and methanol are preferable. The reaction temperature is generally in the range of −78 ° C. to the boiling point of the solvent. In particular, the range from −20 ° C. to room temperature is preferable. The reaction time varies depending on the reaction raw material, the reaction solvent, and the reaction temperature, and it is usually desirable to use an analytical means such as thin layer chromatography until the starting material disappears. The reaction for protecting the primary hydroxyl group varies depending on the protecting group, and is described in the literature (Green et al., Protective Groups in Organic Synthesis Edition, John Wiley & Sons, Inc. (1999)).

The reaction to obtain the ketone compound represented by (6) by oxidizing the secondary hydroxyl group of the alcohol compound represented by (5syn) is tetrapropylammonium pearlate (Pr ₄ NRuO ₄ ) and N-methylmorpholine N— A combination of oxide (NMO), dichlorotris (triphenylphosphine) ruthenium (II) and NMO, pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), or the like can be used. Examples of the organic solvent used in the reaction include halogen solvents such as methylene chloride, chloroform and carbon tetrachloride; hydrocarbon solvents such as hexane and toluene; ether solvents such as tetrahydrofuran (THF) and dioxane; N, N-dimethyl Examples thereof include water-soluble solvents such as formamide, acetonitrile, and acetone; and mixed solvents thereof. These can be selected in consideration of the solubility and reactivity of the compound. Particularly preferred are methylene chloride, acetone, toluene, and THF. The reaction temperature is generally in the range of −78 ° C. to the boiling point of the solvent. In particular, the range from −20 ° C. to room temperature is preferable. The reaction time varies depending on the reaction raw material, the reaction solvent, and the reaction temperature, and it is usually desirable to carry out the reaction until the starting material disappears using an analytical means such as thin layer chromatography.

  The reaction of obtaining the alcohol compound represented by (5anti) by reducing the ketone group of the ketone compound represented by (6) includes lithium aluminum hydride triisopropoxide, lithium aluminum hydride, sodium borohydride, Alternatively, it can be performed using K-selectride or the like. Particularly preferred are lithium aluminum hydride triisopropoxide and lithium aluminum hydride. Examples of the organic solvent used in the reaction include halogen solvents such as methylene chloride, chloroform and carbon tetrachloride; hydrocarbon solvents such as hexane and toluene; ether solvents such as tetrahydrofuran (THF) and dioxane; N, N-dimethyl Examples thereof include water-soluble solvents such as formamide, acetonitrile, and acetone; and mixed solvents thereof. These can be selected in consideration of the solubility and reactivity of the compound. Particularly preferred are THF and methanol. The reaction temperature is generally in the range of −78 ° C. to the boiling point of the solvent. In particular, the range from −20 ° C. to room temperature is preferable. The reaction time varies depending on the reaction raw material, the reaction solvent, and the reaction temperature, and it is usually desirable to use an analytical means such as thin layer chromatography until the starting material disappears.

The reaction for obtaining the lactone compound represented by (4anti) by deprotecting the R ⁸ portion of the alcohol compound represented by (5anti) and then oxidizing the primary hydroxyl group formed to form a lactone ring is as follows. Can be done. The reaction for protecting the primary hydroxyl group differs depending on the protecting group, and is described in the literature (Green et al., Protective Groups in Organic Synthesis Edition), John Wiley & Sons, Inc. (1999)). The oxidation reaction can be performed with manganese dioxide, AgCO ₃ -celite, platinum dioxide or the like. Examples of the organic solvent used in the reaction include halogen solvents such as methylene chloride, chloroform and carbon tetrachloride; hydrocarbon solvents such as hexane, benzene and toluene; ether solvents such as tetrahydrofuran (THF) and dioxane; N, N -Water-soluble solvents such as dimethylformamide and acetonitrile; and mixed solvents thereof, and the like, which can be selected in consideration of the solubility and reactivity of the compound. Particularly preferred are methylene chloride, toluene, THF, and methanol. The reaction temperature is generally in the range of −78 ° C. to the boiling point of the solvent. In particular, the range from −20 ° C. to room temperature is preferable. The reaction time varies depending on the reaction raw material, the reaction solvent, and the reaction temperature, and it is usually desirable to carry out the reaction until the starting material disappears using an analytical means such as thin layer chromatography.

The compound represented by the formula (4syn) or (4anti) thus obtained can be derived into the vitamin D ₃ lactone derivative represented by (1) as follows. That is, when Z = (2-1), it can be induced to vitamin D ₃ lactone derivative (1) by reacting according to Scheme 1. In the case of Z = (2-2) and (2-3), it can be derived into vitamin D ₃ lactone derivative (1) by reacting according to the following scheme 8. That is, when Z = (2-2), the alcohol obtained by deprotecting the hydroxyl protecting group R ³ is oxidized to a ketone group. When Z = (2-3), the ketone group The protecting group R ⁴ X / R ⁵ X is deprotected to obtain the compound (18). This is bromomethyleneated or iodomethyleneated to give compound (4syn) (Z = (2-1)) or compound (4anti) (Z = (2-1)). By reacting this in accordance with scheme 1, it can be derived into vitamin D ₃ lactone derivative (1). Compound (18) is obtained by the method described in the literature (for example, The Journal of Organic Chemistry (J. Org. Chem.), 67, 1580 (2002)) and The vitamin D ₃ lactone derivative (1) can also be derived by performing a Wittig reaction and deprotecting the hydroxyl-protecting group of the resulting triene derivative.

Ｚ＝（２−４）およびＺ＝（２−５）の場合は、スキーム６に従って反応することにより、ビタミンＤ_３ラクトン誘導体（１）に誘導することができる。

In the case of Z = (2-4) and Z = (2-5), it can be derived into vitamin D ₃ lactone derivative (1) by reacting according to Scheme 6.

The vitamin D ₃ lactone derivative obtained as described above can be converted into a pharmaceutically acceptable solvate as described above, if necessary.

Further, the present invention is a therapeutically effective amount of the above formula (1) in the treatment agent for Paget's disease or hypercalcemia containing vitamin D ₃ derivative or a pharmaceutically acceptable solvate thereof represented.

  The therapeutic agent of the present invention can be administered orally, parenterally, such as intravenously, subcutaneously, intramuscularly, transdermally, nasally, intrarectally, or by inhalation.

  Examples of the dosage form for oral administration include tablets, pills, powders, granules, solutions, suspensions, syrups, capsules and the like.

When preparing tablets, excipients such as lactose, starch, calcium carbonate, crystalline cellulose, or silicic acid according to conventional methods; binders such as carboxymethylcellulose, methylcellulose, calcium phosphate, or polyvinylpyrrolidone; sodium alginate, heavy soda Dissolving agents such as sodium lauryl sulfate and monoglyceride stearate; lubricants such as glycerin; absorbents such as kaolin and colloidal silica; and additives such as lubricants such as talc and granular boric acid. .
Pills, powders or granules are also formulated according to conventional methods using additives as described above.

  Liquid preparations such as solutions, suspensions and syrups are also formulated according to conventional methods. Examples of carriers include glycerol esters such as tricaprylin, triacetin, iodized poppy oil fatty acid ester; water; alcohols such as ethanol; oily bases such as liquid paraffin, coconut oil, soybean oil, sesame oil, and corn oil. .

  Capsules are molded by filling powders, granules, liquid preparations, etc. into capsules such as gelatin.

  Intravenous, subcutaneous, and intramuscular dosage forms include injections in the form of sterile aqueous or non-aqueous solutions. As the water-soluble liquid agent, for example, physiological saline is used. Non-aqueous solutions include, for example, vegetable oils such as propylene glycol, polyethylene glycol or olive oil, injectable organic esters such as ethyl oleate, iodized poppy oil fatty acid esters, and the like. These preparations are supplemented with isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, etc. as necessary, and are filtered through a bacteria-retaining filter, mixed with a bactericide, or treated such as irradiation. Can be sterilized by appropriately performing. In addition, a sterile solid preparation can be produced and dissolved in sterile water or a sterile solvent for injection just before use. The compound of the present invention can also be used after forming an inclusion compound with α, β, γ-cyclodextrin, methylated cyclodextrin or the like. Moreover, the injection in the form of lipolysis may be used.

  Examples of dosage forms for transdermal administration include ointments, creams, lotions, and liquids. Ointment bases include, for example, fatty oils such as castor oil, olive oil, sesame oil, safflower oil; lanolin; white, yellow or hydrophilic petrolatum; waxes; higher grades such as oleyl alcohol, isostearyl alcohol, octylide decanol, hexyl decanol Examples of alcohols include glycols such as glycerin, diglycerin, ethylene glycol, propylene glycol, sorbitol, and 1,3-butanediol. Further, ethanol, dimethyl sulfoxide, polyethylene glycol or the like may be used as a solubilizer for the compound of the present invention. If necessary, a preservative such as paraoxybenzoic acid ester, sodium benzoate, salicylic acid, sorbic acid or boric acid; an antioxidant such as butylhydroxyanisole or dibutylhydroxytoluene may be used. In order to promote percutaneous absorption, absorption promoters such as diisopropyl adipate, diethyl sebacate, ethyl caproate, ethyl laurate may be added. For stabilization, the compound of the present invention can also be used by forming an inclusion compound with α, β, γ-cyclodextrin, methylated cyclodextrin or the like.

  An ointment can be manufactured by a normal method. As the cream, an oil-in-water cream is preferable in terms of stabilizing the compound of the present invention. As the base, fatty oils, higher alcohols, glycols and the like are used as described above, and emulsifiers such as diethylene glycol, propylene glycol, sorbitan monofatty acid ester, polysorbate 80, and sodium lauryl sulfate are used. Furthermore, you may add the preservative, antioxidant, etc. which were mentioned above as needed. As in the case of the ointment, the compound of the present invention can be used as an inclusion compound for cyclodextrin and methylated cyclodextrin. The cream can be produced by a usual method.

  Examples of the lotion include suspension type, emulsion type, and solution type lotion. The suspension lotion is obtained by using a suspending agent such as sodium alginate, tragacanth or sodium carboxymethylcellulose, and adding an antioxidant or a preservative as necessary. The emulsification type lotion is obtained by an ordinary method using an emulsifier such as sorbitan monofatty acid ester, polysorbate 80, sodium lauryl sulfate. Examples of the solvent include those obtained by dissolving the compound of the present invention in an alcohol solution such as ethanol and adding an antioxidant, a preservative and the like as necessary.

  In addition to these dosage forms, dosage forms such as pasta agents, cataplasms, aerosols and the like can be mentioned. Such a preparation can be produced by a usual method.

  Formulations for nasal administration are given as liquid or powdered compositions. As the base of the liquid agent, water, saline, phosphate buffer, acetate buffer and the like are used, and a surfactant, an antioxidant, a stabilizer, a preservative, and a viscosity imparting agent may be further included. The base of the powdery agent is preferably a water-absorbing one, for example, water-soluble polyacrylates such as sodium polyacrylate, potassium polyacrylate, ammonium polyacrylate, methylcellulose, hydroxyethylcellulose, hydroxypropyl Cellulose lower alkyl ethers such as cellulose and sodium carboxymethyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, amylose, pullulan and the like can be mentioned. Also, poorly water-soluble crystalline cellulose, α-cellulose, cellulose such as sodium carboxymethylcellulose, hydroxypropyne starch, carboxymethyl starch, crosslinked starch, starch such as amylose, amylopectin, pectin, gelatin, casein, sodium caseinate, etc. Proteins, gums such as gum arabic, tragacanth gum, glucomannan, polyvinyl polypyrrolidone, crosslinked polyacrylic acid and salts thereof, crosslinked polyvinyl alcohol, and the like may be used as a mixture. Furthermore, you may add antioxidant, a coloring agent, a preservative, antiseptic | preservative, etc. to a powdery agent. Such liquid agents and powder agents can be administered using, for example, a spray device.

For rectal administration, ordinary suppositories such as gelatin soft capsules are used.
For inhalation, the vitamin D ₃ derivative of the active ingredient of the present invention is used alone or in combination with an appropriate biocompatible excipient using a spray, nebulizer, atomizer or other administration device. The composition can be administered to the disease site. Alternatively, it can be administered to a diseased site by suspending in an aerosol propellant such as Freon.

The therapeutically effective amount of the active ingredient of the present invention varies depending on the route of administration, patient age, sex, and degree of disease, but is usually about 0.001-10000 μg / day, and the number of administration is usually 1-3 times / day to It is preferably 1-3 times / week, and the preparation is preferably prepared so as to satisfy such conditions.
The therapeutic agent of the present invention can be used in combination with existing drugs.

The usefulness of the vitamin D ₃ derivative represented by the above formula (1) of the present invention as a therapeutic agent for osteoporosis, as specifically shown in Examples below, is 1α, 25-dihydroxyvitamin D _{3 of the} compound of the present invention. The binding ability to the receptor (VDR), differentiation-inducing action using HL-60 cells, and changes in blood PTH concentration in monkeys were shown as indices. That is, it was found that the compound of the present invention binds to VDR with very high affinity and specifically inhibits differentiation of HL-60 cells induced by 1α, 25-dihydroxyvitamin D ₃ . This revealed that the compound of the present invention acts as a vitamin D ₃ antagonist. Furthermore, monkeys to which the compound of the present invention was administered had an increased blood PTH concentration. Therefore, since the administration of the compound of the present invention can be expected to have the same effect as when a PTH preparation is administered, that is, a strong osteogenesis promoting effect, these vitamin D ₃ antagonists are useful as therapeutic agents for osteoporosis.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited by this. In each example, the compound No. Is the compound No. shown in the above table. Indicates. In addition, Compound No. Those with alphabets are those isomers.

[Reference Example 1]
Preparation of ethyl 2-bromomethyl-2-butenoate (compound (3a) (R ^2d / R ^2e = Me / hydrogen atom, R ⁷ = Et))

It was carried out according to the literature (Helv. Chem. Acta, 67, 413-415, 1984).
(1) Ethyl acrylate 1 g (9.99 mmol), acetaldehyde about 0.6 ml, DABCO (1,4-diazabicyclo [2.2.2] octane) 168 mg (1.50 mmol) were mixed and stirred at room temperature for 9 days. . The reaction solution was extracted with diethyl ether, and the organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain allyl alcohol (1.7 g). Yield 100%.
(2) To a suspension of 950 mg (5.3 mmol) of NBS (N-bromosuccinimide) in dichloromethane (4 ml) was added 431 μl (5.9 mmol) of dimethyl sulfide at 0 ° C., and the mixture was stirred at 0 ° C. for 10 minutes. Into this reaction solution, a solution of allyl alcohol 700 mg (4.86 mmol) obtained above in dichloromethane (6 ml) was added dropwise at 0 ° C. and stirred at room temperature for 22 hours. The reaction solution was poured into a mixture of saturated brine and ice, and the dichloromethane layer was separated. The aqueous layer was washed with diethyl ether, combined with the previous dichloromethane layer, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (diethyl ether: dichloromethane = 1: 1) to obtain 730 mg of ethyl 2-bromomethyl-1-butenoate. Yield 73%.
¹ H-NMR (CDCl ₃ ) δ: 1.32 (t, J = 7.1 Hz, 3 H), 1.92 (d, J = 7.3 Hz, 3 H), 4.25 (s, 2 H), 4.27 (q, J = 7.1 Hz, 2 H), 7.07 (q, J = 7.3 Hz, 1 H).

参考例１と同様に、アセトアルデヒドをプロピオンアルデヒドに替えて行った。収率４２％（プロピオンアルデヒドより）。
¹H-NMR (CDCl₃) δ: 1.13 (t, J = 7.6 Hz, 3 H), 1.33 (t, J = 7.1 Hz, 3 H), 2.32 (dt, J = 7.6, 15.2 Hz, 2 H), 4.23 (s, 2 H), 4.26 (q, J = 7.1 Hz, 2 H), 6.96 (t, J = 7.6 Hz, 1 H). [Reference Example 2]
Preparation of ethyl 2-bromomethyl-2-pentenoate (compound (3a) (R ^2d / R ^2e = Et / hydrogen atom, R ⁷ = Et))

As in Reference Example 1, acetaldehyde was replaced with propionaldehyde. Yield 42% (from propionaldehyde).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (t, J = 7.6 Hz, 3 H), 1.33 (t, J = 7.1 Hz, 3 H), 2.32 (dt, J = 7.6, 15.2 Hz, 2 H) , 4.23 (s, 2 H), 4.26 (q, J = 7.1 Hz, 2 H), 6.96 (t, J = 7.6 Hz, 1 H).

参考例１と同様に、アセトアルデヒドをブチルアルデヒドに替えて行った。収率２９％（ブチルアルデヒドより）。
¹H-NMR (CDCl₃) δ: 0.99 (t, J = 7.4 Hz, 3 H), 1.33 (t, J = 7.1 Hz, 3 H), 1.49-1.62 (m, 2 H), 2.28 (q, J =7.4 Hz, 2 H), 4.24 (s, 2 H), 4.26 (q, J = 7.1 Hz, 2 H), 6.97 (t, J = 7.6 Hz, 1 H). [Reference Example 3]
Preparation of ethyl 2-bromomethyl-2-hexenoate (compound (3a) (R ^2d / R ^2e = Pr / hydrogen atom, R ⁷ = Et))

As in Reference Example 1, acetaldehyde was replaced with butyraldehyde. Yield 29% (from butyraldehyde).
¹ H-NMR (CDCl ₃ ) δ: 0.99 (t, J = 7.4 Hz, 3 H), 1.33 (t, J = 7.1 Hz, 3 H), 1.49-1.62 (m, 2 H), 2.28 (q, J = 7.4 Hz, 2 H), 4.24 (s, 2 H), 4.26 (q, J = 7.1 Hz, 2 H), 6.97 (t, J = 7.6 Hz, 1 H).

参考例１と同様に、アセトアルデヒドをイソブチルアルデヒドに替えて行った。収率２７％（１段階目反応）、２９％（２段階目反応）。
¹H-NMR (CDCl₃) δ: 1.10 (d, J = 6.6 Hz, 5 H), 1.33 (t, J = 7.1 Hz, 3 H), 2.72-2.82 (m, 1 H), 4.24 (s, 2 H), 4.26 (q, J = 7.1 Hz, 1 H), 6.76 (d, J = 10.5 Hz, 1 H). [Reference Example 4]
Preparation of ethyl 2-bromomethyl-4-methyl-2-pentenoate (compound (3a) (R ^2d / R ^2e = i-Pr / hydrogen atom, R ⁷ = Et))

As in Reference Example 1, acetaldehyde was replaced with isobutyraldehyde. Yield 27% (first stage reaction), 29% (second stage reaction).
¹ H-NMR (CDCl ₃ ) δ: 1.10 (d, J = 6.6 Hz, 5 H), 1.33 (t, J = 7.1 Hz, 3 H), 2.72-2.82 (m, 1 H), 4.24 (s, 2 H), 4.26 (q, J = 7.1 Hz, 1 H), 6.76 (d, J = 10.5 Hz, 1 H).

参考例１と同様に、アセトアルデヒドをバレルアルデヒドに替えて行った。収率２５％（バレルアルデヒドより）。
¹H-NMR (CDCl₃) δ: 0.94 (t, J = 7.3 Hz, 3 H), 1.32 (t, J = 7.1 Hz, 3 H), 1.34-1.59 (m, 4 H), 2.30 (q, J = 7.3 Hz, 2 H), 4.24 (s, 2 H), 4.25 (q, J = 7.1 Hz, 2 H), 6.97 (t, J = 7.6 Hz, 1 H). [Reference Example 5]
Preparation of ethyl 2-bromomethyl-2-heptenoate (compound (3a) (R ^2d / R ^2e = Bu / hydrogen atom, R ⁷ = Et))

As in Reference Example 1, acetaldehyde was replaced with valeraldehyde. Yield 25% (from valeraldehyde).
¹ H-NMR (CDCl ₃ ) δ: 0.94 (t, J = 7.3 Hz, 3 H), 1.32 (t, J = 7.1 Hz, 3 H), 1.34-1.59 (m, 4 H), 2.30 (q, J = 7.3 Hz, 2 H), 4.24 (s, 2 H), 4.25 (q, J = 7.1 Hz, 2 H), 6.97 (t, J = 7.6 Hz, 1 H).

参考例１と同様に、アセトアルデヒドをイソ吉草酸アルデヒドに替えて行った。収率２２％（１段階目反応）、８３％（２段階目反応）。
¹H-NMR (CDCl₃) δ: 0.97 (d, J = 6.8 Hz, 6 H), 1.33 (t, J = 7.1 Hz, 3 H), 1.78-1.92 (m, 1 H), 2.16-2.22 (m, 2 H), 4.23 (s, 2 H), 4.26 (q, J = 7.1 Hz, 2 H), 7.00 (t, J = 7.8 Hz, 1 H). [Reference Example 6]
Preparation of ethyl 2-bromomethyl-5-methyl-2-hexenoate (compound (3a) (R ^2d / R ^2e = i-Bu / hydrogen atom, R ⁷ = Et))

As in Reference Example 1, acetaldehyde was replaced with isovaleric aldehyde. Yield 22% (first stage reaction), 83% (second stage reaction).
¹ H-NMR (CDCl ₃ ) δ: 0.97 (d, J = 6.8 Hz, 6 H), 1.33 (t, J = 7.1 Hz, 3 H), 1.78-1.92 (m, 1 H), 2.16-2.22 ( m, 2 H), 4.23 (s, 2 H), 4.26 (q, J = 7.1 Hz, 2 H), 7.00 (t, J = 7.8 Hz, 1 H).

参考例１と同様に、アセトアルデヒドをヘプタナールに替えて行った。収率４４％（ヘプタナールより）。
¹H-NMR (CDCl₃) δ: 0.89 (t, J = 7.1 Hz, 3 H), 1.29-1.53 (m, 11 H), 2.26-2.33 (m, 4 H), 4.19-4.28 (m, 4 H), 6.97 (t, J = 7.6 Hz, 1 H). [Reference Example 7]
Preparation of ethyl 2-bromomethyl-2-nonenoate (compound (3a) (R ^2d / R ^2e = Hex / hydrogen atom, R ⁷ = Et))

In the same manner as in Reference Example 1, the acetaldehyde was changed to heptanal. Yield 44% (from heptanal).
¹ H-NMR (CDCl ₃ ) δ: 0.89 (t, J = 7.1 Hz, 3 H), 1.29-1.53 (m, 11 H), 2.26-2.33 (m, 4 H), 4.19-4.28 (m, 4 H), 6.97 (t, J = 7.6 Hz, 1 H).

参考例１と同様に、アセトアルデヒドをノニルアルデヒドに替えて行った。収率６２％（ノニルアルデヒドより）。
¹H-NMR (CDCl₃) δ: 0.88 (t, J = 7.1 Hz, 3 H), 1.24-1.65 (m, 15 H), 2.29 (q, J =7.6 Hz, 2 H), 4.19-4.34 (m, 4 H), 6.97 (t, J = 7.6 Hz, 1 H). [Reference Example 8]
Preparation of ethyl 2-bromomethyl-2-undecenoate (compound (3a) (R ^2d / R ^2e = Octyl / hydrogen atom, R ⁷ = Et))

As in Reference Example 1, acetaldehyde was replaced with nonyl aldehyde. Yield 62% (from nonyl aldehyde).
¹ H-NMR (CDCl ₃ ) δ: 0.88 (t, J = 7.1 Hz, 3 H), 1.24-1.65 (m, 15 H), 2.29 (q, J = 7.6 Hz, 2 H), 4.19-4.34 ( m, 4 H), 6.97 (t, J = 7.6 Hz, 1 H).

参考例１と同様に、アセトアルデヒドをベンズアルデヒドに替えて行った。収率８４％（１段階目反応）、８２％（２段階目反応）。
¹H-NMR (CDCl₃) δ: 1.39 (t, J = 7.1 Hz, 1 H), 4.34 (q, J = 7.1 Hz, 2 H), 4.41 (s, 2 H), 7.38-7.50 (m, 3 H), 7.55-7.60 (m, 2 H), 7.83 (s, 1 H). [Reference Example 9]
Preparation of ethyl 2-bromomethyl-3-phenyl-2-propenoate (compound (3a) (R ^2d / R ^2e = Ph / hydrogen atom, R ⁷ = Et))

As in Reference Example 1, acetaldehyde was replaced with benzaldehyde. Yield 84% (first stage reaction), 82% (second stage reaction).
¹ H-NMR (CDCl ₃ ) δ: 1.39 (t, J = 7.1 Hz, 1 H), 4.34 (q, J = 7.1 Hz, 2 H), 4.41 (s, 2 H), 7.38-7.50 (m, 3 H), 7.55-7.60 (m, 2 H), 7.83 (s, 1 H).

参考例１と同様に、アセトアルデヒドを３−フェニルプロピオンアルデヒドに替えて行った。収率４６％（３−フェニルプロピオンアルデヒドより）。
¹H-NMR (CDCl₃) δ: 1.31 (t, J = 7.1 Hz, 3 H), 2.62 (t, J = 7.6 Hz, 2 H), 2.83 (t, J = 7.6 Hz, 2 H), 4.15 (s, 2 H), 4.25 (q, J = 7.1 Hz, 2 H), 7.00 (t, J = 7.6 Hz, 1 H), 7.19-7.30 (m, 5 H). [Reference Example 10]
Preparation of ethyl 2-bromomethyl-5-phenyl-2-pentenoate (compound (3a) (R ^2d / R ^2e = Phenethyl / hydrogen atom, R ⁷ = Et))

In the same manner as in Reference Example 1, acetaldehyde was replaced with 3-phenylpropionaldehyde. Yield 46% (from 3-phenylpropionaldehyde).
¹ H-NMR (CDCl ₃ ) δ: 1.31 (t, J = 7.1 Hz, 3 H), 2.62 (t, J = 7.6 Hz, 2 H), 2.83 (t, J = 7.6 Hz, 2 H), 4.15 (s, 2 H), 4.25 (q, J = 7.1 Hz, 2 H), 7.00 (t, J = 7.6 Hz, 1 H), 7.19-7.30 (m, 5 H).

（１）文献に従って（Ｈｅｌｖ．Ｃｈｅｍ．Ａｃｔａ ７７巻、１４８０−１４８４頁（１９９４年）、アリルアルコールを得た。収率５０％。
（２）上記で得られたアリルアルコール２００ｍｇ（１．４ｍｍｏｌ）をジエチルエーテル（４．６ｍｌ）に溶解し、０℃でＰＢｒ_３ ０．０８ｍｌ（０．８３ｍｍｏｌ）を加え、室温で1時間撹拌した。０℃で反応液に水を加え、水層をジエチルエーテルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下で溶媒を留去し、得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２０：１）で精製すると、（化合物（３）（Ｒ^２ａ＝Ｒ^２ｂ＝Ｒ^７＝Ｍｅ））が２４０ｍｇ得られた。収率８３％。無色油状物質。
¹H-NMR (CDCl₃) δ: 1.99 (s, 3 H), 2.16 (s, 3 H), 3.79 (s, 3 H), 4.31(s, 2 H).
¹³C-NMR (CDCl₃) δ: 23.0, 24.0, 29.4, 51.7, 124.6, 153.8, 166.9.
LRMS m/z 205 (M⁺), 191, 175
HRMS calcd for C₇H₁₁O₂ ⁷⁹Br 205.9942, found 205.9951 [Reference Example 11]
Preparation of methyl 2-bromomethyl-3-methyl-2-butenoate (compound (3a) (R ^2d = R ^2e = R ⁷ = Me))

(1) According to the literature (Helv. Chem. Acta 77, 1480-1484 (1994)), allyl alcohol was obtained, yield 50%.
(2) 200 mg (1.4 mmol) of allyl alcohol obtained above was dissolved in diethyl ether (4.6 ml), 0.08 ml (0.83 mmol) of PBr ₃ was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. . Water was added to the reaction solution at 0 ° C., and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to give (compound (3) (R ^2a = R ^2b = R ⁷ = Me). ) Was obtained 240 mg. Yield 83%. Colorless oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.99 (s, 3 H), 2.16 (s, 3 H), 3.79 (s, 3 H), 4.31 (s, 2 H).
¹³ C-NMR (CDCl ₃ ) δ: 23.0, 24.0, 29.4, 51.7, 124.6, 153.8, 166.9.
LRMS m / z 205 (M ⁺ ), 191, 175
HRMS calcd for C ₇ H ₁₁ O ₂ ⁷⁹ Br 205.9942, found 205.9951

参考例１と同様に、アセトアルデヒドを３−（ｔ−ブチルジメチルシリルオキシ）プロピオンアルデヒドに替えて行った。収率２０％（３−（ｔ−ブチルジメチルシリルオキシ）プロピオンアルデヒドより）。なお、３−（ｔ−ブチルジメチルシリルオキシ）プロピオンアルデヒドはプロパンジオールをモノ（ｔ−ブチルジメチルシリルオキシ）化し、得られたモノアルコールを酸化することにより得た。
¹H-NMR (CDCl₃) δ: 1.05 (s, 9 H), 1.32 (t, J = 7.1 Hz, 3 H), 2.50-2.57 (m, 2 H), 3.80 (t, J = 6.4 Hz, 2 H), 4.19 (s, 2 H), 4.26 (q, J = 7.1 Hz, 2 H), 7.05(t, J = 7.6 Hz, 1 H), 7.35-7.47 (m, 6 H), 7.63-7.67(m, 4 H). [Reference Example 12]
Preparation of ethyl 2-bromomethyl-5- (t-butyldimethylsilyloxy) -2-pentenoate (compound (3a) (R ^2d / R ^2e = TBSOEt / hydrogen atom, R ⁷ = Et))

In the same manner as in Reference Example 1, acetaldehyde was replaced with 3- (t-butyldimethylsilyloxy) propionaldehyde. Yield 20% (from 3- (t-butyldimethylsilyloxy) propionaldehyde). Note that 3- (t-butyldimethylsilyloxy) propionaldehyde was obtained by mono (t-butyldimethylsilyloxy) propanediol and oxidizing the resulting monoalcohol.
¹ H-NMR (CDCl ₃ ) δ: 1.05 (s, 9 H), 1.32 (t, J = 7.1 Hz, 3 H), 2.50-2.57 (m, 2 H), 3.80 (t, J = 6.4 Hz, 2 H), 4.19 (s, 2 H), 4.26 (q, J = 7.1 Hz, 2 H), 7.05 (t, J = 7.6 Hz, 1 H), 7.35-7.47 (m, 6 H), 7.63- 7.67 (m, 4 H).

[Reference Example 13]
1α, 3β-bis- (t-butyldimethylsilyloxy) -20 (R) -formylmethyl-9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene (compound (15) )Manufacturing of

(1) Compound (13) (PG = TBS, configuration at the 20-position = (S) configuration) obtained by the method described in the literature (Tetrahedron, 20, 4609-4619, 1987) 1.15 g (2. 0 mmol) was dissolved in a mixed solvent of THF (10 ml) and MeOH (10 ml) and ice-cooled. To this solution, 38 mg (2.0 mmol) of sodium borohydride was added and stirred as it was for 1.5 hours. After adding a saturated aqueous ammonium chloride solution to the reaction solution, the reaction solution was concentrated to about half volume. The concentrated solution was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 to 15: 1) to give compound (A ) 200 mg was obtained. Yield 17%.
(2) 200 mg (0.348 mmol) of the compound (A) obtained above was dissolved in 1.5 ml of pyridine, 133 mg (0.696 mmol) of tosyl chloride was added thereto, and the mixture was stirred at room temperature for 7.5 hours. After adding 1M hydrochloric acid to the reaction solution, the reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried and concentrated to obtain a crude tosyl form (257 mg). This was dissolved in 3 ml of anhydrous N, N-dimethylformamide, 45 mg (0.696 mmol) of potassium cyanide and 9 mg (0.035 mmol) of 18-crown-6 were added thereto, and the mixture was stirred at 100 ° C. for 3.5 hours. After adding water to the reaction solution, the reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 40: 1) to obtain 121 mg of compound (B). Yield 60%.
(3) 121 mg (0.207 mmol) of the compound (B) obtained above was dissolved in 3 ml of anhydrous methylene chloride and cooled to -75 ° C. To this, 0.41 ml (1.01 M, 0.41 mmol) of DIBAL-H in toluene was added, and the mixture was stirred as it was for 3 hours. Furthermore, 0.41 ml (1.01 M, 0.41 mmol) of a toluene solution of DIBAL-H was added, and the mixture was stirred for 3 hours while gradually raising the temperature as it was (−75 ° C. to −10 ° C.). Water and 6M hydrochloric acid were added to the reaction solution, and the reaction solution was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 40: 1) to obtain 70 mg of compound (15). Yield 58%.

[Example 1]
20 (R)-(Tetrahydro-3-methylene-2-furanone-4-methyl-5-yl) methyl-9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene-1α , 3β-diol (Compound No. 101a, Compound No. 101b, Compound No. 101c, Compound No. 101d)

(1) Compound (3a) (R ^2d / R ^2e = Me / hydrogen) obtained in Reference Example 1 was added to 113 mg (0.192 mmol) of Compound (15) obtained in Reference Example 13 in anhydrous THF (3 ml). Atom, R ⁷ = Et 80 mg (0.386 mmol), zinc 26 mg (0.397 mmol), and saturated aqueous ammonium chloride (1.7 ml) were added, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by preparative TLC (hexane: ethyl acetate = 4: 1) to obtain three components of compound (C). In order of decreasing polarity, compound (C) (third polarity) 66 mg (yield 48%), compound (C) (second polarity) 22 mg (yield 16%), compound (C) (highest polarity) 39 mg (28% yield). These are isomers derived from the configuration of an asymmetric carbon to which a hydroxyl group is bonded and an asymmetric carbon to which the adjacent methyl group is bonded. Compound (C) (third polarity) is a mixture of two isomers, and compound (C) (second polarity) and compound (C) (highest polarity) are each a single isomer.
Compound (C) (third polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.04-0.07 (m, 12 H), 0.55 (s, 3 H), 0.87 (s, 9 H), 0.88 (s, 9 H), 0.94 (d, J = 6.3 Hz, 2.4 H), 0.95 (d, J = 6.3 Hz, 0.6 H), 1.10 (d, J = 7.0 Hz, 2.4 H), 1.12 (d, J = 6.8 Hz, 0.6 H), 1.15-2.05 ( m, 20 H), 2.21 (dd, J = 12.9, 7.7 Hz, 1 H), 2.42-2.47 (m, 1 H), 2.68-2.86 (m, 2 H), 3.62-3.70 (m, 0.2 H) , 3.73-3.80 (m, 0.8 H), 4.15-4.30 (m, 3 H), 4.36 (dd, J = 6.3, 3.4 Hz, 1 H), 4.86 (d, J = 2.4 Hz, 1 H), 5.16 (d, J = 1.7 Hz, 1 H), 5.58 (s, 0.8 H), 5.61 (s, 0.2 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.23 (d, J = 10.0 Hz, 1 H), 6.26 (d, J = 1.2 Hz, 1 H).
MS m / z 715 (M ⁺ ), 697 ((MH ₂ O) ⁺ ), 583, 451, 249
Compound (C) (second polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.06 (s, 9 H), 0.07 (s, 3 H), 0.53 (s, 3 H), 0.87 (s, 9 H), 0.88 (s, 9 H), 1.01 (d, J = 6.3 Hz, 3 H), 1.16 (d, J = 7.1 Hz, 3 H), 1.00-2.05 (m, 20 H), 2.18-2.25 (m, 1 H), 2.42-2.47 ( m, 1 H), 2.70-2.85 (m, 2 H), 3.66-3.74 (m, 1 H), 4.15-4.30 (m, 3 H), 4.37 (dd, J = 6.6, 3.9 Hz, 1 H) , 4.86 (d, J = 2.4 Hz, 1 H), 5.18 (d, J = 1.5 Hz, 1 H), 5.66 (s, 1 H), 6.01 (d, J = 11.7 Hz, 1 H), 6.20- 6.30 (m, 2 H).
MS m / z 715 (M ⁺ ), 697 ((MH ₂ O) ⁺ ), 583, 451, 249
Compound (C) (highest polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.06 (s, 9 H), 0.07 (s, 3 H), 0.56 (s, 3 H), 0.87 (s, 9 H), 0.88 (s, 9 H), 1.03 (d, J = 5.6 Hz, 3 H), 1.16 (d, J = 6.8 Hz, 3 H), 1.15-2.05 (m, 20 H), 2.21 (dd, J = 13.2, 7.3 Hz, 1 H) , 2.41-2.48 (m, 1 H), 2.75-2.95 (m, 2 H), 3.78-3.83 (m, 1 H), 4.15-4.30 (m, 3 H), 4.35-4.40 (m, 1 H) , 4.86 (d, J = 3.9 Hz, 1 H), 5.17-5.20 (m, 1 H), 5.63 (s, 1 H), 6.02 (d, J = 11.5 Hz, 1 H), 6.23 (d, J = 11.0 Hz, 1 H), 6.32 (s, 1 H).
MS m / z 715 (M ⁺ ), 697 ((MH ₂ O) ⁺ ), 583, 451, 249

(2-a) In a THF solution (1.5 ml) of 66 mg (92 μmol) of the compound (C) obtained above (third polarity) in THF (1.5 ml) at 0 ° C., 92 μl of TBAF in THF (1.0 M, 92 μmol) And stirred at 0 ° C. for 1.5 hours. Further, 92 µl (1.0 M, 92 µmol) of a THF solution of TBAF was added, and the mixture was stirred at 0 ° C for 0.5 hour. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in a mixed solution of toluene and acetonitrile (1: 1, 2 ml), and 35 mg (0.373 mmol) of LiBF ₄ and 3.7 ml (0.1 M, 0.373 mmol) of sulfuric acid in acetonitrile were added at 0 ° C. Stir at 0 ° C. for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by HPLC (reverse phase, A = 95% H ₂ O / CH ₃ CN; B = 95% CH ₃ OH / H ₂ O; B = 80%). No. 101a (low polarity) 3.0 mg (yield 7%, purity 99%) Obtained 8.2 mg (yield 20%, purity 99%) of 101b (high polarity). These are isomers derived from the configuration of the asymmetric carbon to which the methyl group on the lactone ring is bonded.
No. 101a (low polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 1.01 (d, J = 6.3 Hz, 3 H), 1.23 (d, J = 6.8 Hz, 3 H), 1.20-2.15 (m, 18 H), 2.31 (dd, J = 13.4, 6.6 Hz, 1 H), 2.54-2.70 (m, 2 H), 2.83 (dd, J = 12.2, 4.1 Hz, 1 H), 4.02-4.12 (m, 1 H), 4.18-4.28 (m, 1 H), 4.38-4.48 (m, 1 H), 5.01 (s, 1 H), 5.34 (s, 1 H), 5.53 (d, J = 2.9 Hz, 1 H), 6.02 (d, J = 11.2 Hz, 1 H), 6.22 (d, J = 3.2 Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H).
MS m / z 458 ((M + 23) ⁺ ), 441 ((M + 1) ⁺ ), 423 ((M + 1-H ₂ O) ⁺ ), 405
No. 101b (high polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 1.00 (d, J = 6.3 Hz, 3 H), 1.13 (d, J = 7.1 Hz, 3 H), 1.00-2.10 (m, 18 H), 2.31 (dd, J = 13.7, 6.6 Hz, 1 H), 2.53-2.63 (m, 1 H), 2.82 (dd, J = 11.7, 3.2 Hz, 1 H), 3.10-3.20 (m, 1 H), 4.18-4.28 (m, 1 H), 4.38-4.48 (m, 1 H), 4.62-4.72 (m, 1 H), 5.00 (s, 1 H), 5.33 (d, J = 1.5 Hz , 1 H), 5.53 (d, J = 2.4 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.22 (d, J = 2.9 Hz, 1 H), 6.37 (d, J = (11.2 Hz, 1 H).
MS m / z 458 ((M + 23) ⁺ ), 441 ((M + 1) ⁺ ), 423 ((M + 1-H ₂ O) ⁺ ), 405

(2-b) Compound (C) obtained above (second polarity) 22 mg (31 μmol) in anhydrous THF solution (1.0 ml), TBAF in THF solution at 0 ° C. 31 μl (1.0 M, 31 μmol) And stirred at 0 ° C. for 2 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in a mixed solution of toluene and acetonitrile (1: 1, 2 ml), and 12 mg (0.128 mmol) of LiBF ₄ and 1.3 ml (0.1 M, 0.128 mmol) of acetonitrile in sulfuric acid were added at 0 ° C. Stir at 0 ° C. for 25 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate and concentrated. The residue was purified by HPLC (reverse phase, A = 95% H ₂ O / CH ₃ CN; B = 95% CH ₃ OH / H ₂ O; B = 80%). Obtained 2.1 mg of 101c (yield 16%, purity 96%).
No. 101c:
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 1.06 (d, J = 6.1 Hz, 3 H), 1.25 (d, J = 6.8 Hz, 3 H), 1.20-2.15 (m, 18 H), 2.32 (dd, J = 13.7, 6.8 Hz, 1 H), 2.55-2.70 (m, 2 H), 2.78-2.87 (m, 1 H), 4.08 (dt, J = 6.6, 5.4 Hz, 1 H), 4.18-4.28 (m, 1 H), 4.40-4.47 (m, 1 H), 4.99-5.01 (m, 1 H), 5.32-5.34 (m, 1 H), 5.54 (d, J = 2.9 Hz 1 H), 6.02 (d, J = 11.2 Hz, 1 H), 6.23 (d, J = 3.2 Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H).
MS m / z 458 ((M + 23) ⁺ ), 441 ((M + 1) ⁺ ), 423 ((M + 1-H ₂ O) ⁺ ), 405

(2-c) In a THF solution (1.5 ml) of 39 mg (55 μmol) of the compound (C) (most highly polar) obtained above, 55 μl (1.0 M, 55 μmol) of a TBAF solution in TBAF at 0 ° C. The mixture was further stirred at 0 ° C. for 2 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in a mixed solution of toluene and acetonitrile (1: 1, 2 ml), 20 mg (0.213 mmol) of LiBF ₄ and 2.1 ml (0.1 M, 0.213 mmol) of acetonitrile in sulfuric acid were added at 0 ° C., Stir at 0 ° C. for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate and concentrated. The residue was purified by HPLC (reverse phase, A = 95% H ₂ O / CH ₃ CN; B = 95% CH ₃ OH / H ₂ O; B = 80%). Obtained 7.2 mg of 101d (yield 30%, purity 99%).
No. 101d:
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 1.05 (d, J = 6.3 Hz, 3 H), 1.13 (d, J = 7.1 Hz, 3 H), 1.20-2.10 (m, 18 H), 2.32 (dd, J = 13.7, 6.6 Hz, 1 H), 2.59 (d, J = 13.4, 3.7 Hz, 1 H), 2.83 (dd, J = 12.4, 4.4 Hz, 1 H), 3.05 -3.15 (m, 1 H), 4.10-4.20 (m, 1 H), 4.40-4.48 (m, 1 H), 4.55-4.63 (m, 1 H), 4.99-5.01 (m, 1 H), 5.33 -5.35 (m, 1 H), 5.54 (d, J = 2.2 Hz, 1 H), 6.02 (d, J = 11.2 Hz, 1 H), 6.19 (d, J = 2.4 Hz, 1 H), 6.38 ( d, J = 11.2 Hz, 1 H).
MS m / z 458 ((M + 23) ⁺ ), 441 ((M + 1) ⁺ ), 423 ((M + 1-H ₂ O) ⁺ ), 405

[Example 2]
20 (R)-(Tetrahydro-3-methylene-2-furanone-4-ethyl-5-yl) methyl-9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene-1α , 3β-diol (Compound No. 102a, Compound No. 102b, Compound No. 102c, Compound No. 102d)

(1) Compound (3a) (R ^2d / R ^2e = Et / hydrogen) obtained in Reference Example 2 was added to 202 mg (0.344 mmol) of Compound (15) obtained in Reference Example 13 in anhydrous THF solution (3 ml). Atom, R ⁷ = Et 114 mg (0.516 mmol) in anhydrous THF (1.5 ml), zinc 34 mg (0.516 mmol), and saturated aqueous ammonium chloride (3 ml) were added, and the mixture was stirred at room temperature for 3.5 hours. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC (hexane: ethyl acetate = 5: 1) to obtain three components of compound (D). In order of decreasing polarity, compound (D) (third polarity) 101 mg (yield 40%), compound (D) (second polarity) 50 mg (yield 20%), compound (D) (highest polarity) 34 mg (14% yield). These are isomers derived from the configuration of an asymmetric carbon to which a hydroxyl group is bonded and an asymmetric carbon to which the adjacent ethyl group is bonded. Compound (D) (third polarity) is a mixture of two isomers, and compound (D) (second polarity) and compound (D) (highest polarity) are each a single isomer.
Compound (D) (third polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.05 (s, 6 H), 0.06 (s, 6 H), 0.55 (s, 3 H), 0.87 (s, 9 H), 0.88 (s, 9 H), 0.90-0.96 (m, 3 H), 1.23-2.05 (m, 23 H), 2.17-2.25 (m, 2 H), 2.43-2.47 (m, 2 H), 2.80-2.84 (m, 1 H), 3.76 (br, 1 H), 4.08-4.24 (m, 3 H), 4.34-4.36 (m, 1 H), 4.86 (d, J = 2.1 Hz, 1 H), 5.17 (d, J = 1.8 Hz, 1 H), 5.47 & 5.52 (s, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.23- 6.29 (m, 2 H).
MS m / z 729.5 ((M + 1) ⁺ )
Compound (D) (second polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.06 (s, 12 H), 0.53 (s, 3 H), 0.87 (s, 9 H), 0.88 (s, 9 H), 1.00 (d, J = 6.3 Hz , 3 H), 1.23-2.04 (m, 24 H), 2.18-2.25 (m, 1 H), 2.43-2.48 (m, 2 H), 2.79-2.83 (m, 1 H), 3.79 (br, 1 H), 4.08-4.26 (m, 3 H), 4.38 (br, 1 H), 4.86 (d, J = 2.1 Hz, 1 H), 5.18 (s, 1 H), 5.65 (s, 1 H), 6.01 (d, J = 10.9 Hz, 1 H), 6.23 (d, J = 11.2 Hz, 1 H), 6.29 (s, 1 H).
MS m / z 729.5 ((M + 1) ⁺ )
Compound (D) (highest polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.06 (s, 12 H), 0.55 (s, 3 H), 0.87 (s, 9 H), 0.88 (s, 9 H), 1.02 (d, J = 6.1 Hz , 3 H), 1.14-2.05 (m, 24 H), 2.18-2.25 (m, 1 H), 2.41-2.58 (m, 2 H), 2.80-2.84 (m, 1 H), 3.75-3.76 (m , 1 H), 4.08-4.26 (m, 3 H), 4.36-4.38 (m, 1 H), 4.87 (d, J = 2.1 Hz, 1 H), 5.19 (s, 1 H), 5.59 (s, 1 H), 6.02 (d, J = 11.2 Hz, 1 H), 6.23 (d, J = 11.1 Hz, 1 H), 6.34 (s, 1 H).
MS m / z 729.5 ((M + 1) ⁺ )

(2-a) To an anhydrous THF solution (2 ml) of 101 mg (139 μmol) of the compound (D) (third polarity) obtained above, 1.0 ml (4.0 M, 4.0 mmol) of an aqueous lithium hydroxide solution was added. The mixture was further stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in a mixed solution of toluene and acetonitrile (1: 1, 2 ml), and 39 mg (0.42 mmol) of LiBF ₄ was added and ice-cooled. To this solution was added 0.25 ml (1.0 M, 0.25 mmol) of an acetonitrile solution of sulfuric acid, and the mixture was stirred at 0 ° C. for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by Sepppack silica brass cartridge (Waters, hexane: ethyl acetate = 1: 1 → hexane: ethyl acetate: methanol = 3: 6: 1) and HPLC (reverse phase, A = 95% H ₂ O / CH ₃ CN; B = 95% CH ₃ OH / H ₂ O; B = 85%), no. 102a (low polarity) 6.5 mg (yield 10%, purity 97%) and no. 102b (high polarity) 15.3 mg (yield 24%, purity 97%) was obtained. These are isomers derived from the configuration of the asymmetric carbon to which the ethyl group on the lactone ring is bonded.
No. 102a (low polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.98 (t, J = 7.4 Hz, 3 H), 1.03 (d, J = 6.6 Hz, 3 H), 1.26-1.73 (m, 5 H), 1.83-2.05 (m, 13 H), 2.31 (dd, J = 13.4, 6.3 Hz, 1 H), 2.51-2.62 (m, 2 H), 2.80-2.85 (m, 1 H), 4.22 -4.32 (m, 2 H), 4.41-4.46 (m, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.58 (d, J = 2.3 Hz, 1 H), 6.01 ( d, J = 11.1 Hz, 1 H), 6.27 (d, J = 2.8 Hz, 1 H), 6.37 (d, J = 11.4 Hz, 1 H).
MS m / z 455.3 ((M + 1) ⁺ )
No. 102b (high polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.98 (t, J = 7.4 Hz, 3 H), 1.01 (d, J = 6.4 Hz, 3 H), 0.72-2.05 (m, 18 H), 2.31 (dd, J = 13.4, 6.3 Hz, 1 H), 2.57-2.62 (m, 1 H), 2.80-2.92 (m, 2 H), 4.22-4.25 (m, 1 H), 4.41 -4.45 (m, 1 H), 4.64-6.70 (m, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.52 (d, J = 2.3 Hz, 1 H), 6.01 ( d, J = 11.2 Hz, 1 H), 6.22 (d, J = 2.5 Hz, 1 H), 6.37 (d, J = 11.2 Hz, 1 H).
MS m / z 455.3 ((M + 1) ⁺ )

(2-b) 50 mg (69 μmol) of the compound (D) (second polarity) obtained above in an anhydrous THF solution (2.0 ml) was added 0.5 ml (4.0 M, 2.0 mmol) of an aqueous lithium hydroxide solution. ) And stirred at room temperature for 45 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in a mixed solution of toluene and acetonitrile (1: 1, 2 ml), and 19 mg (0.21 mmol) of LiBF ₄ was added and ice-cooled. To this solution was added 0.123 ml (1.0 M, 0.123 mmol) of an acetonitrile solution of sulfuric acid, and the mixture was stirred at 0 ° C. for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by Sepppack silica brass cartridge (Waters, hexane: ethyl acetate = 1: 1 → hexane: ethyl acetate: methanol = 3: 6: 1) and HPLC (reverse phase, A = 95% H ₂ O / CH ₃ CN; B = 95% CH ₃ OH / H ₂ O; B = 85%), no. Obtained 8.9 mg of 102c (yield 29%, purity 99.5%).
No. 102c:
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.98 (t, J = 7.4 Hz, 3 H), 1.06 (d, J = 5.9 Hz, 3 H), 1.14-1.74 (m, 13 H), 1.84-2.07 (m, 5 H), 2.32 (dd, J = 13.4, 6.3 Hz, 1 H), 2.55-2.62 (m, 2 H), 2.80-2.85 (m, 1 H), 4.23 -4.30 (m, 2 H), 4.43 (br, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.59 (d, J = 2.1 Hz, 1 H), 6.01 (d, J = 11.1 Hz, 1 H), 6.28 (d, J = 2.5 Hz, 1 H), 6.37 (d, J = 11.2 Hz, 1 H).
MS m / z 455.4 ((M + 1) ⁺ )

(2-c) 0.34 ml (4.0 M, 1.36 mmol) of an aqueous lithium hydroxide solution was added to 34 mg (47 μmol) of the compound (D) (highest polarity) obtained above in an anhydrous THF solution (2.0 ml). In addition, the mixture was stirred at room temperature for 60 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in a mixed solution of toluene and acetonitrile (1: 1, 2 ml), LiBF ₄ 13 mg (0.14 mmol) was added, and the mixture was ice-cooled. To this solution was added 0.084 ml (1.0 M, 0.084 mmol) of an acetonitrile solution of sulfuric acid, and the mixture was stirred at 0 ° C. for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by Sepppack silica brass cartridge (Waters, hexane: ethyl acetate = 1: 1 → hexane: ethyl acetate: methanol = 3: 6: 1) and HPLC (reverse phase, A = 95% H ₂ O / CH ₃ CN; B = 95% CH ₃ OH / H ₂ O; B = 85%), no. Obtained 9.2 mg of 102d (43% yield, purity 99.7%).
No. 102d:
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.96 (t, J = 7.4 Hz, 3 H), 1.06 (d, J = 6.4 Hz, 3 H), 1.23-1.79 (m, 13 H), 1.87-2.08 (m, 5 H), 2.32 (dd, J = 13.4, 6.4 Hz, 1 H), 2.57-2.62 (m, 1 H), 2.80-2.85 (m, 2 H), 4.24 (br, 1 H), 4.44 (br, 1 H), 4.55-4.62 (m, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.52 (d, J = 1.8 Hz, 1 H), 6.02 (d, J = 11.4 Hz, 1 H), 6.21 (d, J = 1.8 Hz, 1 H), 6.37 (d, J = 11.4 Hz, 1 H).
MS m / z 455.4 ((M + 1) ⁺ )

[Example 3]
20 (R)-(Tetrahydro-3-methylene-2-furanone-4-propyl-5-yl) methyl-9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene-1α , 3β-diol (Compound No. 103a, Compound No. 103b, Compound No. 103c, Compound No. 103d)

(1) Compound (3a) (R ^2d / R ^2e ) obtained in Reference Example 2 was obtained in the same manner as Example 2 (1) using 205 mg (0.349 mmol) of Compound (15) obtained in Reference Example 13. = Et / hydrogen atom, R ⁷ = Et) was replaced with the compound (3a) obtained in Reference Example 3 (R ^2d / R ^2e = Pr / hydrogen atom, R ⁷ = Et), and the compound (E) was obtained. Three components were obtained. In order of decreasing polarity, compound (E) (third polarity) 98 mg (38% yield), compound (E) (second polarity) 43 mg (17% yield), compound (E) (highest polarity) 38 mg (15% yield). These are isomers derived from the configuration of an asymmetric carbon to which a hydroxyl group is bonded and an asymmetric carbon to which the adjacent propyl group is bonded. Compound (E) (third polarity) is a mixture of two isomers, and compound (E) (second polarity) and compound (E) (highest polarity) are each a single isomer.
Compound (E) (third polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.059 (s, 6 H), 0.062 (s, 6 H), 0.55 (s, 3 H), 0.876 (s, 9 H), 0.882 (s, 9 H), 0.92-2.03 (m, 28 H), 2.18-2.25 (m, 2 H), 2.41-2.66 (m, 2 H), 2.79-2.84 (m, 1 H), 3.75 (br, 1 H), 4.18- 4.26 (m, 3 H), 4.36-4.37 (m, 1 H), 4.87 (d, J = 2.0 Hz, 1 H), 5.19 (s, 1 H), 5.54 & 5.59 (s, 1 H), 6.02 (d, J = 11.2 Hz, 1 H), 6.23 (d, J = 11.4 Hz, 1 H), 6.28-6.32 (m, 1 H).
MS m / z 743.5 ((M + 1) ⁺ )
Compound (E) (second polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.06 (s, 6 H), 0.07 (s, 6 H), 0.53 (s, 3 H), 0.87 (s, 9 H), 0.88 (s, 9 H), 1.00 (d, J = 6.8 Hz, 3 H), 1.03-1.96 (m, 26 H), 2.22-2.25 (m, 1 H), 2.41-2.45 (m, 1 H), 2.60-2.61 (m, 1 H), 2.71-2.83 (m, 1 H), 3.78 (br, 1 H), 4.18-4.26 (m, 3 H), 4.38 (br, 1 H), 4.86 (d, J = 2.5 Hz, 1 H ), 5.18 (s, 1 H), 5.65 (d, J = 1.1 Hz, 1 H), 6.01 (d, J = 11.4 Hz, 1 H), 6.23 (d, J = 10.7 Hz, 1 H), 6.28 (d, J = 1.3 Hz, 1 H).
MS m / z 743.5 ((M + 1) ⁺ )
Compound (E) (highest polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.059 (s, 6 H), 0.062 (s, 6 H), 0.55 (s, 3 H), 0.876 (s, 9 H), 0.882 (s, 9 H), 1.02 (d, J = 6.1 Hz, 3 H), 1.15-2.03 (m, 25 H), 2.18-2.25 (m, 1 H), 2.41-2.45 (m, 2 H), 2.64-2.69 (m, 1 H), 2.79-2.84 (m, 1 H), 3.75 (br, 1 H), 4.16-4.26 (m, 3 H), 4.36-4.40 (m, 1 H), 4.87 (d, J = 2.0 Hz, 1 H), 5.19 (s, 1 H), 5.59 (s, 1 H), 6.02 (d, J = 11.2 Hz, 1 H), 6.23 (d, J = 11.4 Hz, 1 H), 6.31 (d, J = 1.2 Hz, 1 H).
MS m / z 743.5 ((M + 1) ⁺ )

(2-a) The same reaction as in Example 2 (2-a) was performed using 98 mg (132 μmol) of the compound (E) (third polarity) obtained above. 103a (low polarity) 16.4 mg (yield 27%, purity 98%) and no. 15.7 mg (yield 25%, purity 99%) of 103b (high polarity) was obtained. These are isomers derived from the configuration of the asymmetric carbon to which the propyl group on the lactone ring is bonded.
No. 103a (low polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.96 (t, J = 7.1 Hz, 3 H), 1.02 (d, J = 6.6 Hz, 3 H), 1.21-2.05 (m, 20 H), 2.31 (dd, J = 13.4, 6.6 Hz, 1 H), 2.58-2.62 (m, 2 H), 2.80-2.85 (m, 1 H), 4.23-4.30 (m, 2 H), 4.40 -4.46 (m, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.57 (d, J = 2.3 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1 H) , 6.26 (d, J = 2.8 Hz, 1 H), 6.37 (d, J = 11.1 Hz, 1 H).
MS m / z 469.3 ((M + 1) ⁺ )
No. 103b (high polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.96 (t, J = 6.9 Hz, 3 H), 1.00 (d, J = 6.6 Hz, 3 H), 1.05-2.05 (m, 20 H), 2.31 (dd, J = 13.4, 6.6 Hz, 1 H), 2.57-2.62 (m, 1 H), 2.80-2.85 (m, 1 H), 2.97-3.00 (m, 1 H), 4.23 -4.24 (m, 1 H), 4.40-4.45 (m, 1 H), 4.63-6.69 (m, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.51 (d, J = 2.3 Hz, 1 H), 6.01 (d, J = 11.4 Hz, 1 H), 6.21 (d, J = 2.6 Hz, 1 H), 6.37 (d, J = 11.2 Hz, 1 H).
MS m / z 469.2 ((M + 1) ⁺ )

(2-b) The same reaction as in Example 2 (2-b) was carried out using 43 mg (58 μmol) of the compound (E) (second polarity) obtained above. 11.0 mg of 103c (yield 41%, purity 99.5%) was obtained.
No. 103c:
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.96 (t, J = 7.1 Hz, 3 H), 1.06 (d, J = 5.9 Hz, 3 H), 1.16-1.74 (m, 14 H), 1.84-2.08 (m, 6 H), 2.32 (dd, J = 13.2, 6.4 Hz, 1 H), 2.58-2.63 (m, 2 H), 2.80-2.85 (m, 1 H), 4.24 -4.28 (m, 2 H), 4.40-4.47 (m, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.58 (d, J = 2.1 Hz, 1 H), 6.01 ( d, J = 11.2 Hz, 1 H), 6.26 (d, J = 2.5 Hz, 1 H), 6.38 (d, J = 10.9 Hz, 1 H).
MS m / z 469.3 ((M + 1) ⁺ )

(2-c) The same reaction as in Example 2 (2-c) was carried out using 38 mg (51 μmol) of the compound (E) (highest polarity) obtained above. 103d 8.5 mg (35% yield, 99% purity) was obtained.
No. 103d:
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.95 (t, J = 6.6 Hz, 3 H), 1.06 (d, J = 6.4 Hz, 3 H), 1.29-1.76 (m, 14 H), 1.87-2.05 (m, 6 H), 2.32 (dd, J = 13.5, 6.4 Hz, 1 H), 2.60 (dd, J = 13.4, 3.5 Hz, 1 H), 2.80-2.92 (m, 2 H), 4.22-4.24 (m, 1 H), 4.41-4.45 (m, 1 H), 4.54-4.61 (m, 1 H), 5.00 (s, 1 H), 5.33 (t, J = 1.6 Hz , 1 H), 5.50 (d, J = 1.8 Hz, 1 H), 6.02 (d, J = 11.1 Hz, 1 H), 6.20 (d, J = 2.0 Hz, 1 H), 6.38 (d, J = (11.2 Hz, 1 H).
MS m / z 469.3 ((M + 1) ⁺ )

[Example 4]
20 (R)-(Tetrahydro-3-methylene-2-furanone-4-isopropyl-5-yl) methyl-9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene-1α , 3β-diol (Compound No. 104a, Compound No. 104b)

(1) Compound (3a) (R ^2d / R ^2e ) obtained in Reference Example 2 was obtained in the same manner as Example 2 (1) using 205 mg (0.349 mmol) of Compound (15) obtained in Reference Example 13. = Et / hydrogen atom, R ⁷ = Et) is replaced with the compound (3a) obtained in Reference Example 4 (R ^2d / R ^2e = i-Pr / hydrogen atom, R ⁷ = Et), and the compound (F) (Low polarity) 46 mg (yield 50%) and compound (F) (high polarity) 22 mg (yield 38%) were obtained. These are isomers derived from the configuration of an asymmetric carbon to which a hydroxyl group is bonded and / or an asymmetric carbon to which the adjacent isopropyl group is bonded.
Compound (F) (low polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.05 (s, 6 H), 0.06 (s, 6 H), 0.54 (s, 3 H), 0.80 (d, J = 6.0 Hz, 3 H), 0.86 (s , 9 H), 0.87 (s, 9 H), 0.95 (d, J = 6.3 Hz, 3 H), 1.04 (d, J = 6.0 Hz, 3 H), 1.05-2.10 (m, 21 H), 2.17 -2.25 (m, 1 H), 2.40-2.50 (m, 1 H), 2.75-2.85 (m, 1 H), 3.00-3.10 (m, 1 H), 3.90-4.00 (m, 1 H), 4.07 -4.15 (m, 3 H), 4.36 (dd, J = 6.1, 3.2 Hz, 1 H), 4.85 (d, J = 2.2 Hz, 1 H), 5.14-5.17 (m, 1 H), 5.50 (d , J = 1.5 Hz, 1 H), 6.00 (d, J = 11.0 Hz, 1 H), 6.10-6.18 (m, 2 H).
MS m / z 743 (M ⁺ ), 625 ((MH ₂ O) ⁺ ), 611
Compound (F) (high polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.06 (s, 9 H), 0.07 (s, 3 H), 0.52 (s, 3 H), 0.81 (d, J = 6.3 Hz, 3 H), 0.87 (s , 9 H), 0.88 (s, 9 H), 0.98 (d, J = 6.6 Hz, 3 H), 1.05 (d, J = 6.3 Hz, 3 H), 1.10-2.20 (m, 21 H), 2.21 (dd, J = 13.2, 7.1 Hz, 1 H), 2.40-2.50 (m, 1 H), 2.75-2.85 (m, 1 H), 3.25-3.35 (m, 1 H), 3.97-4.03 (m, 1 H), 4.15-4.30 (m, 3 H), 4.35-4.40 (m, 1 H), 4.86 (d, J = 2.4 Hz, 1 H), 5.18 (d, J = 1.7 Hz, 1 H), 5.65 (d, J = 1.5 Hz, 1 H), 6.00 (d, J = 11.7 Hz, 1 H), 6.23 (d, J = 11.2 Hz, 1 H), 6.28 (d, J = 1.5 Hz, 1 H ).
MS m / z 743 (M ⁺ ), 625 ((MH ₂ O) ⁺ ), 611

(2-a) The same reaction as in Example 2 (2-b) was performed using 44 mg (59 μmol) of the compound (F) (low polarity) obtained above. 104 mg of 15 mg (yield 54%, purity 99%) was obtained.
No. 104a:
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.94 (d, J = 6.6 Hz, 3 H), 0.95 (d, J = 7.1 Hz, 3 H), 1.04 (d, J = 6.6 Hz, 3 H), 1.10-2.10 (m, 19 H), 2.31 (dd, J = 13.4, 6.6 Hz, 1 H), 2.44-2.52 (m, 1 H), 2.60 (dd, J = 13.2, 3.2 Hz, 1 H), 2.82 (dd, J = 11.7, 3.7 Hz, 1 H), 4.20-4.28 (m, 1 H), 4.40-4.48 (m, 2 H), 5.00 (s, 1 H), 5.32-5.34 (m, 1 H), 5.60 (d, J = 2.0 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.34 (d, J = 2.2 Hz, 1 H), 6.38 (d, J = 11.5 Hz, 1 H).
MS m / z 486 ((M + H ₂ O) ⁺ ), 469 ((M + 1) ⁺ ), 451 ((M + 1-H ₂ O) ⁺ ), 433

(2-b) The same reaction as in Example 2 (2-b) was carried out using 35 mg (47 μmol) of the compound (F) (high polarity) obtained above. 8.7 mg of 104b (yield 39%, purity 99%) was obtained.
No. 104b:
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.93 (d, J = 6.8 Hz, 3 H), 0.95 (d, J = 6.8 Hz, 3 H), 1.06 (d, J = 5.9 Hz, 3 H), 1.10-2.10 (m, 19 H), 2.32 (dd, J = 13.4, 6.6 Hz, 1 H), 2.47-2.55 (m, 1 H), 2.60 (dd, J = 13.7, 3.4 Hz, 1 H), 2.82 (dd, J = 12.4, 4.1 Hz, 1 H), 4.18-4.28 (m, 1 H), 4.35-4.41 (m, 1 H), 4.41-4.48 (m, 1 H ), 4.98-5.00 (m, 1 H), 5.32-5.34 (m, 1 H), 5.61 (d, J = 1.5 Hz, 1 H), 6.01 (d, J = 11.5 Hz, 1 H), 6.33 ( d, J = 2.0 Hz, 1 H), 6.37 (d, J = 11.2 Hz, 1 H).
MS m / z 486 ((M + H ₂ O) ⁺ ), 469 ((M + 1) ⁺ ), 451 ((M + 1-H ₂ O) ⁺ ), 433

[Example 5]
20 (R)-(Tetrahydro-3-methylene-2-furanone-4-butyl-5-yl) methyl-9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene-1α , 3β-diol (Compound No. 105a, Compound No. 105b, Compound No. 105c, Compound No. 105d)

(1) Compound (3a) (R ^2d / R ^2e ) obtained in Reference Example 2 was obtained in the same manner as Example 2 (1) using 201 mg (0.342 mmol) of Compound (15) obtained in Reference Example 13. = Et / hydrogen atom, R ⁷ = Et) was replaced with the compound (3a) obtained in Reference Example 5 (R ^2d / R ^2e = Bu / hydrogen atom, R ⁷ = Et), and compound (G) was obtained. Three components were obtained. In order of decreasing polarity, compound (G) (third polarity) 108 mg (yield 42%), compound (G) (second polarity) 41 mg (yield 16%), compound (G) (highest polarity) 40 mg (15% yield). These are isomers derived from the configuration of an asymmetric carbon to which a hydroxyl group is bonded and an asymmetric carbon to which the adjacent butyl group is bonded. Compound (G) (third polarity) is a mixture of two isomers, and compound (G) (second polarity) and compound (G) (highest polarity) are each a single isomer.
Compound (G) (third polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.05 (s, 6 H), 0.06 (s, 6 H), 0.55 (s, 3 H), 0.87 (s, 9 H), 0.88 (s, 9 H), 0.85-2.04 (m, 31 H), 2.22-2.34 (m, 1 H), 2.43-2.47 (m, 2 H), 2.80-2.84 (m, 1 H), 3.76 (br, 1 H), 4.11- 4.27 (m, 3 H), 4.29-4.34 (m, 1 H), 4.86 (d, J = 2.3 Hz, 1 H), 5.16 (s, 1 H), 5.53 & 5.58 (s, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.23 (d, J = 10.4 Hz, 1 H), 6.25-6.27 (m, 1 H).
MS m / z 757.5 ((M + 1) ⁺ )
Compound (G) (second polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.06 (s, 6 H), 0.07 (s, 6 H), 0.53 (s, 3 H), 0.87 (s, 9 H), 0.88 (s, 9 H), 0.85-1.96 (m, 31 H), 2.17-2.25 (m, 1 H), 2.43-2.46 (m, 1 H), 2.57-2.61 (m, 1 H), 2.72-2.83 (m, 1 H), 3.78 (br, 1 H), 4.11-4.26 (m, 3 H), 4.35-4.37 (m, 1 H), 4.86 (d, J = 2.3 Hz, 1 H), 5.18 (s, 1 H), 5.65 (d, J = 1.5 Hz, 1 H), 6.00 (d, J = 11.2 Hz, 1 H), 6.23 (d, J = 11.1 Hz, 1 H), 6.28 (d, J = 1.3 Hz, 1 H) .
MS m / z 757.5 ((M + 1) ⁺ )
Compound (G) (highest polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.06 (s, 12 H), 0.55 (s, 3 H), 0.876 (s, 9 H), 0.879 (s, 9 H), 0.82-2.02 (m, 31 H ), 2.18-2.25 (m, 1 H), 2.38-2.45 (m, 1 H), 2.63 (br, 1 H), 2.80-2.84 (m, 1 H), 3.75 (br, 1 H), 4.18- 4.26 (m, 3 H), 4.35-4.37 (m, 1 H), 4.87 (d, J = 2.5 Hz, 1 H), 5.18 (s, 1 H), 5.59 (s, 1 H), 6.02 (d , J = 11.1 Hz, 1 H), 6.23 (d, J = 11.4 Hz, 1 H), 6.32 (d, J = 1.2 Hz, 1 H).
MS m / z 757.5 ((M + 1) ⁺ )

(2-a) The same reaction as in Example 2 (2-a) was performed using 108 mg (143 μmol) of the compound (G) obtained above (third polarity). 105a (low polarity) 12.9 mg (19% yield, 98% purity) 14.5 mg (yield 21%, purity 99%) of 105b (high polarity) was obtained. These are isomers derived from the configuration of the asymmetric carbon to which the butyl group on the lactone ring is bonded.
No. 105a (low polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.93 (t, J = 6.6 Hz, 3 H), 1.03 (d, J = 6.4 Hz, 3 H), 1.21-2.05 (m, 22 H), 2.31 (dd, J = 13.4, 6.3 Hz, 1 H), 2.57-2.62 (m, 2 H), 2.81-2.85 (m, 1 H), 4.25-4.28 (m, 2 H), 4.44 (br, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.58 (d, J = 2.3 Hz, 1 H), 6.02 (d, J = 11.1 Hz, 1 H), 6.26 (d, J = 2.6 Hz, 1 H), 6.37 (d, J = 11.2 Hz, 1 H).
MS m / z 483.2 ((M + 1) ⁺ )
No. 105b (high polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.93 (t, J = 6.9 Hz, 3 H), 1.01 (d, J = 6.4 Hz, 3 H), 1.06-2.05 (m, 22 H), 2.31 (dd, J = 13.4, 6.3 Hz, 1 H), 2.60 (dd, J = 13.2, 3.6 Hz, 1 H), 2.80-2.85 (m, 1 H), 2.92-2.97 (m, 1 H), 4.23 (br, 1 H), 4.42-4.43 (m, 1 H), 4.63-6.69 (m, 1 H), 5.00 (s, 1 H), 5.33 (d, J = 1.5 Hz, 1 H), 5.51 (d, J = 2.3 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.21 (d, J = 2.6 Hz, 1 H), 6.37 (d, J = 11.2 Hz , 1 H).
MS m / z 483.5 ((M + 1) ⁺ )

(2-b) The same reaction as in Example 2 (2-b) was carried out using 41 mg (54 μmol) of the compound (G) (second polarity) obtained above. 105c 10.3 mg (yield 39%, purity 98%) was obtained.
No. 105c:
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.92 (t, J = 6.6 Hz, 3 H), 1.06 (d, J = 5.8 Hz, 3 H), 1.13-1.74 (m, 17 H), 1.84-2.08 (m, 5 H), 2.32 (dd, J = 13.5, 6.4 Hz, 1 H), 2.57-2.62 (m, 2 H), 2.80-2.85 (m, 1 H), 4.22 -4.28 (m, 2 H), 4.40-4.47 (m, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.57 (d, J = 2.1 Hz, 1 H), 6.01 ( d, J = 11.2 Hz, 1 H), 6.26 (d, J = 2.5 Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H).
MS m / z 483.2 ((M + 1) ⁺ )

(2-c) The same reaction as in Example 2 (2-c) was carried out using 40 mg (53 μmol) of the compound (G) (highest polarity) obtained above. 105d 13.1 mg (51% yield, 99% purity) was obtained.
No. 105d:
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.92 (t, J = 6.9 Hz, 3 H), 1.06 (d, J = 6.4 Hz, 3 H), 1.19-1.77 (m, 17 H), 1.87-2.05 (m, 5 H), 2.32 (dd, J = 13.5, 6.6 Hz, 1 H), 2.57-2.62 (m, 1 H), 2.80-2.91 (m, 2 H), 4.22 (br, 1 H), 4.42-4.45 (m, 1 H), 4.54-4.61 (m, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.50 (d, J = 1.8 Hz, 1 H), 6.02 (d, J = 11.4 Hz, 1 H), 6.20 (d, J = 2.0 Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H).
MS m / z 483.5 ((M + 1) ⁺ )

[Example 6]
20 (R)-(Tetrahydro-3-methylene-2-furanone-4-isobutyl-5-yl) methyl-9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene-1α , 3β-diol (Compound No. 106a, Compound No. 106b, Compound No. 106c, Compound No. 106d)

(1) Compound (3a) (R ^2d / R ^2e ) obtained in Reference Example 2 was obtained in the same manner as Example 2 (1) using 180 mg (0.307 mmol) of Compound (15) obtained in Reference Example 13. = Et / hydrogen atom, R ⁷ = Et) was carried out in place of the compound (3a) obtained in Reference Example 6 (R ^2d / R ^2e = i-Bu / hydrogen atom, R ⁷ = Et), and the compound (H 3 components were obtained. In order of decreasing polarity, compound (H) (third polarity) 117 mg (yield 52%), compound (H) (second polarity) 50 mg (yield 22%), compound (H) (highest polarity) 79 mg (35% yield). These are isomers derived from the configuration of an asymmetric carbon to which a hydroxyl group is bonded and an asymmetric carbon to which the adjacent isobutyl group is bonded. Compound (H) (third polarity) is a mixture of two isomers, and Compound (H) (second polarity) and Compound (H) (highest polarity) are each a single isomer.
Compound (H) (third polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.05 (s, 6 H), 0.06 (s, 6 H), 0.54 (s, 1.5 H), 0.55 (s, 1.5 H), 0.80-0.98 (m, 9 H ), 0.88 (s, 9 H), 0.89 (s, 9 H), 1.25-2.25 (m, 24 H), 2.42-2.50 (m, 1 H), 2.77-2.85 (m, 1 H), 3.65- 3.77 (m, 1 H), 4.15-4.27 (m, 3 H), 4.36 (dd, J = 6.1, 3.2 Hz, 1 H), 4.86 (d, J = 2.4 Hz, 1 H), 5.15 (d, J = 1.7 Hz, 1 H), 5.54 (s, 0.5 H), 5.58 (d, J = 1.2 Hz, 0.5 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.20-6.27 (m, 1.5 H), 6.28 (d, J = 1.2 Hz, 0.5 H).
MS m / z 758 ((M + 1) ⁺ ), 739 ((MH ₂ O) ⁺ ), 625, 607
Compound (H) (second polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.05 (s, 6 H), 0.06 (s, 6 H), 0.53 (s, 3 H), 0.85-0.90 (m, 6 H), 0.87 (s, 9 H ), 0.88 (s, 9 H), 1.00 (d, J = 6.6 Hz, 3 H), 1.10-2.05 (m, 23 H), 2.21 (dd, J = 12.7, 7.1 Hz, 1 H), 2.42- 2.47 (m, 1 H), 2.64-2.74 (m, 1 H), 2.78-2.85 (m, 1 H), 3.68-3.78 (m, 1 H), 4.15-4.30 (m, 3 H), 4.37 ( dd, J = 6.8, 3.9 Hz, 1 H), 4.86 (d, J = 2.4 Hz, 1 H), 5.18 (d, J = 1.7 Hz, 1 H), 5.65 (d, J = 1.5 Hz, 1 H ), 6.01 (d, J = 11.0 Hz, 1 H), 6.23 (d, J = 11.2 Hz, 1 H), 6.28 (d, J = 1.5 Hz, 1 H).
MS m / z 757 (M ⁺ ), 739 ((MH ₂ O) ⁺ ), 625, 607
Compound (H) (highest polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.05 (s, 6 H), 0.06 (s, 6 H), 0.55 (s, 3 H), 0.84 (d, J = 6.3 Hz, 3 H), 0.88 (s , 18 H), 0.90 (d, J = 6.6 Hz, 3 H), 1.02 (d, J = 6.6 Hz, 3 H), 1.20-2.05 (m, 22 H), 2.21 (dd, J = 13.2, 7.1 Hz, 1 H), 2.35 (d, J = 3.4 Hz, 1 H), 2.44 (dd, J = 13.2, 3.9 Hz, 1 H), 2.75-2.85 (m, 2 H), 3.70-3.80 (m, 1 H), 4.15-4.30 (m, 3 H), 4.37 (dd, J = 6.6, 3.7 Hz, 1 H), 4.87 (d, J = 2.4 Hz, 1 H), 5.17-5.20 (m, 1 H ), 5.60 (s, 1 H), 6.02 (d, J = 11.5 Hz, 1 H), 6.24 (d, J = 11.2 Hz, 1 H), 6.31-6.33 (m, 1 H).
MS m / z 757 (M ⁺ ), 739 ((MH ₂ O) ⁺ ), 625, 607

(2-a) The same reaction as in Example 2 (2-a) was carried out using 112 mg (0.154 mmol) of the compound (H) (third polarity) obtained above. No. 106a (low polarity) 10 mg (yield 14%, purity 99%) 16 mg (yield 22%, purity 99%) of 106b (high polarity) was obtained. These are isomers derived from the configuration of the asymmetric carbon to which the lactone ring oxygen atom is bonded or the asymmetric carbon to which the isobutyl group on the lactone ring is bonded.
No. 106a (low polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.95 (d, J = 6.6 Hz, 3 H), 0.96 (d, J = 6.6 Hz, 3 H), 1.02 (d, J = 6.3 Hz, 3 H), 1.20-2.10 (m, 21 H), 2.31 (dd, J = 13.4, 6.3 Hz, 1 H), 2.53-2.68 (m, 2 H), 2.82 (dd, J = 12.2, 3.9 Hz, 1 H), 4.20-4.28 (m, 2 H), 4.40-4.48 (m, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.57 (d, J = 2.2 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.24 (d, J = 2.7 Hz, 1 H), 6.37 (d, J = 11.2 Hz, 1 H).
MS m / z 500 ((M + H ₂ O) ⁺ ), 483 ((M + 1) ⁺ ), 465 ((M + 1-H ₂ O) ⁺ ), 447
No. 106b (high polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.95 (d, J = 6.6 Hz, 3 H), 0.96 (d, J = 6.6 Hz, 3 H), 1.00 (d, J = 6.3 Hz, 3 H), 1.03-1.13 (m, 1 H), 1.20-2.10 (m, 20 H), 2.31 (dd, J = 13.4, 6.3 Hz, 1 H), 2.63 (dd, J = 13.4, 3.4 Hz, 1 H), 2.82 (dd, J = 12.0, 3.9 Hz, 1 H), 3.05-3.15 (m, 1 H), 4.18-4.28 (m, 1 H), 4.40-4.48 (m, 1 H ), 4.67 (ddd, J = 11.7, 7.1, 1.5 Hz, 1 H), 5.00 (s, 1 H), 5.32-5.34 (m, 1 H), 5.49 (d, J = 2.4 Hz, 1 H), 6.01 (d, J = 11.5 Hz, 1 H), 6.20 (d, J = 2.7 Hz, 1 H), 6.37 (d, J = 11.2 Hz, 1 H).
MS m / z 500 ((M + H ₂ O) ⁺ ), 483 ((M + 1) ⁺ ), 465 ((M + 1-H ₂ O) ⁺ ), 447

(2-b) The same reaction as in Example 2 (2-b) was carried out using 46 mg (61 μmol) of the compound (H) obtained above (second polarity). Obtained 12 mg of 106c (41% yield, 99% purity).
No. 106c:
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.96 (d, J = 6.6 HZ, 3 H), 0.97 (d, J = 6.6 Hz, 3 H), 1.06 (d, J = 6.1 Hz, 3 H), 1.15-2.10 (m, 21 H), 2.32 (dd, J = 13.4, 6.3 Hz, 1 H), 20.66 (dd, J = 13.4, 3.4 Hz, 1 H), 2.63-2.78 (m, 1 H), 2.82 (dd, J = 12.4, 4.1 Hz, 1 H), 4.17-4.27 (m, 2 H), 4.40-4.47 (m, 1 H), 5.00 (s, 1 H), 5.32-5.34 (m, 1 H), 5.58 (d, J = 2.0 Hz 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.24 (d, J = 2.4 Hz, 1 H), 6.38 ( d, J = 11.2 Hz, 1 H).
MS m / z 500 ((M + H ₂ O) ⁺ ), 483 ((M + 1) ⁺ ), 465 ((M + 1-H ₂ O) ⁺ ), 447

(2-c) The same reaction as in Example 2 (2-c) was carried out using 75 mg (99 μmol) of the compound (H) (highest polarity) obtained above. 17 mg of 106d (yield 36%, purity 99%) was obtained.
No. 106d:
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.94 (d, J = 6.6 Hz, 3 H), 0.95 (d, J = 6.6 Hz, 3 H), 1.06 (d, J = 6.3 Hz, 3 H), 1.20-2.10 (m, 21 H), 2.32 (dd, J = 13.4, 6.6 Hz, 1 H), 2.60 (d, J = 13.7, 3.7 Hz, 1 H), 2.82 (dd , J = 13.4, 4.4 Hz, 1 H), 2.98-3.07 (m, 1 H), 4.18-4.28 (m, 1 H), 4.40-4.48 (m, 1 H), 4.59 (ddd, J = 8.8, 6.3, 4.4 Hz, 1 H), 4.99-5.01 (m, 1 H), 5.32-5.34 (m, 1 H), 5.48 (d, J = 1.7 Hz, 1 H), 6.02 (d, J = 11.2 Hz , 1 H), 6.19 (d, J = 2.2 Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H).
MS m / z 500 ((M + H ₂ O) ⁺ ), 483 ((M + 1) ⁺ ), 465 ((M + 1-H ₂ O) ⁺ ), 447

[Example 7]
20 (R)-(Tetrahydro-3-methylene-2-furanone-4-hexyl-5-yl) methyl-9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene-1α , 3β-diol (Compound No. 107a, Compound No. 107, Compound No. 107c, Compound No. 107d)

(1) Compound (3a) (R ^2d / R ^2e ) obtained in Reference Example 2 was obtained in the same manner as Example 2 (1) using 202 mg (0.344 mmol) of Compound (15) obtained in Reference Example 13. = Et / hydrogen atom, R ⁷ = Et) was carried out in place of the compound (3a) obtained in Reference Example 7 (R ^2d / R ^2e = Hex / hydrogen atom, R ⁷ = Et), and the compound (I) was Four components were obtained. In order of decreasing polarity, compound (I) (fourth polarity) 41 mg (yield 15%), compound (I) (third polarity) 37 mg (yield 14%), compound (I) (second polarity) ) 46 mg (17% yield), Compound (I) (highest polarity) 36 mg (13% yield). These are isomers derived from the configuration of an asymmetric carbon to which a hydroxyl group is bonded and an asymmetric carbon to which the adjacent hexyl group is bonded.
Compound (I) (fourth polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.05 (s, 6 H), 0.06 (s, 6 H), 0.55 (s, 3 H), 0.87 (s, 9 H), 0.88 (s, 9 H), 0.84-2.04 (m, 32 H), 2.19-2.24 (m, 2 H), 2.44-2.47 (m, 1 H), 2.54-2.57 (m, 1 H), 2.80-2.83 (m, 1 H), 3.78 (br, 1 H), 4.19-4.24 (m, 3 H), 4.36 (br, 1 H), 4.86 (s, 1 H), 5.17 (s, 1 H), 5.52 (s, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.24 (d, J = 11.7 Hz, 1 H), 6.27 (s, 1 H).
MS m / z 785.5 ((M + 1) ⁺ )
Compound (I) (third polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.05 (s, 6 H), 0.06 (s, 6 H), 0.55 (s, 3 H), 0.87 (s, 9 H), 0.88 (s, 9 H), 0.82-2.04 (m, 32 H), 2.19-2.24 (m, 2 H), 2.44-2.53 (m, 2 H), 2.80-2.83 (m, 1 H), 3.75 (br, 1 H), 4.19- 4.23 (m, 3 H), 4.37 (br, 1 H), 4.86 (s, 1 H), 5.16 (s, 1 H), 5.57 (s, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.24 (d, J = 11.2 Hz, 1 H), 6.25 (s, 1 H).
MS m / z 785.8 ((M + 1) ⁺ )
Compound (I) (second polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.06 (s, 12 H), 0.53 (s, 3 H), 0.876 (s, 9 H), 0.879 (s, 9 H) 1.00 (d, J = 6.1 Hz, 3 H), 0.85-2.01 (m, 29 H), 2.21 (dd, J = 13.2, 7.1 Hz, 1 H), 2.43-2.45 (m, 1 H), 2.57-2.58 (m, 1 H), 2.80 -2.83 (m, 1 H), 3.77 (br, 1 H), 4.19-4.22 (m, 3 H), 4.38 (br, 1 H), 4.86 (s, 1 H), 5.18 (s, 1 H) , 5.65 (s, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.23 (d, J = 11.5 Hz, 1 H), 6.28 (s, 1 H).
MS m / z 785.8 ((M + 1) ⁺ )
Compound (I) (highest polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.06 (s, 6 H), 0.07 (s, 6 H), 0.55 (s, 3 H), 0.87 (s, 9 H), 0.88 (s, 9 H), 1.02 (d, J = 6.3 Hz, 3 H), 0.84-2.08 (m, 28 H), 2.19-2.24 (m, 1 H), 2.43-2.46 (m, 2 H), 2.63-2.66 (m, 1 H), 2.80-2.84 (m, 1 H), 3.75 (br, 1 H), 4.18-4.25 (m, 3 H), 4.38 (br, 1 H), 4.87 (d, J = 2.4 Hz, 1 H ), 5.18 (s, 1 H), 5.59 (s, 1 H), 6.02 (d, J = 11.5 Hz, 1 H), 6.24 (d, J = 11.2 Hz, 1 H), 6.32 (s, 1 H ).
MS m / z 785.8 ((M + 1) ⁺ )

(2-a) Using 41 mg (53 μmol) of the compound (I) (fourth polarity) obtained above, the same reaction as in Example 2 (2-b) was carried out. 6.7 mg of 107a (yield 26%, purity 99%) was obtained.
No. 107a:
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.90 (t, J = 6.6 Hz, 3 H), 1.01 (d, J = 6.6 Hz, 3 H), 1.24-2.05 (m, 26 H), 2.31 (dd, J = 13.4, 6.3 Hz, 1 H), 2.59-2.62 (m, 1 H), 2.82-2.85 (m, 1 H), 2.96-2.97 (m, 1 H), 4.24 (br, 1 H), 4.43 (br, a H), 4.64-4.68 (m, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.50 (d, J = 2.4 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.21 (d, J = 2.4 Hz, 1 H), 6.37 (d, J = 11.2 Hz, 1 H).
MS m / z 511.3 ((M + 1) ⁺ )

(2-b) The same reaction as in Example 2 (2-b) was carried out using 37 mg (47 μmol) of the compound (I) (third polarity) obtained above. 107 mg (yield 26%, purity 97%) of 107b was obtained.
No. 107b:
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.90 (t, J = 6.6 Hz, 3 H), 1.03 (d, J = 6.6 Hz, 3 H), 1.22-2.05 (m, 26 H), 2.31 (dd, J = 13.4, 6.3 Hz, 1 H), 2.55-2.62 (m, 2 H), 2.82-2.85 (m, 1 H), 4.26-4.28 (m, 2 H), 4.44 (br, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.57 (d, J = 2.2 Hz, 1 H), 6.02 (d, J = 11.2 Hz, 1 H), 6.26 (d, J = 2.7 Hz, 1 H), 6.37 (d, J = 11.2 Hz, 1 H).
MS m / z 511.3 ((M + 1) ⁺ )

(2-c) The same reaction as in Example 2 (2-c) was carried out using 46 mg (59 μmol) of the compound (I) (second polarity) obtained above. 4.8 mg of 107c (yield 16%, purity 98%) was obtained.
No. 107c:
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.89 (t, J = 6.6 Hz, 3 H), 1.06 (d, J = 5.9 Hz, 3 H), 1.23-1.70 (m, 20 H), 1.88-2.05 (m, 6 H), 2.32 (dd, J = 13.7, 6.6 Hz, 1 H), 2.59-2.61 (m, 2 H), 2.82-2.85 (m, 1 H), 4.24 -4.27 (m, 2 H), 4.44 (br, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.58 (d, J = 2.2 Hz, 1 H), 6.02 (d, J = 11.5 Hz, 1 H), 6.26 (d, J = 2.4 Hz, 1 H), 6.38 (d, J = 11.5 Hz, 1 H).
MS m / z 511.3 ((M + 1) ⁺ )

(2-d) The same reaction as in Example 2 (2-c) was performed using 36 mg (45 μmol) of the compound (I) (highest polarity) obtained above. 107d 6.4 mg (yield 28%, purity 98%) was obtained.
No. 107d:
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.89 (t, J = 6.6 Hz, 3 H), 1.06 (d, J = 6.6 Hz, 3 H), 1.26-1.74 (m, 20 H), 1.89-2.05 (m, 6 H), 2.32 (dd, J = 13.4, 6.6 Hz, 1 H), 2.59-2.62 (m, 1 H), 2.82-2.88 (m, 2 H), 4.23 (br, 1 H), 4.44 (br, 1 H), 4.55-4.60 (m, 1 H), 5.00 (s, 1 H), 5.33 (t, J = 1.6 Hz, 1 H), 5.50 (d, J = 1.5 Hz, 1 H), 6.02 (d, J = 11.5 Hz, 1 H), 6.19 (d, J = 2.0 Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H).
MS m / z 511.2 ((M + 1) ⁺ )

[Example 8]
20 (R)-(Tetrahydro-3-methylene-2-furanone-4-octyl-5-yl) methyl-9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene-1α , 3β-diol (Compound No. 108a, Compound No. 108b, Compound No. 108c, Compound No. 108d)

(1) Compound (3a) (R ^2d / R ^2e ) obtained in Reference Example 2 was obtained in the same manner as Example 2 (1) using 201 mg (0.342 mmol) of Compound (15) obtained in Reference Example 13. = Et / hydrogen atom, R ⁷ = Et) was carried out in place of the compound (3a) (R ^2d / R ^2e = Octyl / hydrogen atom, R ⁷ = Et) obtained in Reference Example 8, and compound (J) was obtained. Three components were obtained. In order of decreasing polarity, compound (J) (third polarity) 56 mg (yield 20%), compound (J) (second polarity) 37 mg (yield 13%), compound (J) (highest polarity) 29 mg (yield 10%). These are isomers derived from the configuration of an asymmetric carbon to which a hydroxyl group is bonded and an asymmetric carbon to which the adjacent octyl group is bonded. Compound (J) (third polarity) is a mixture of two isomers, and compound (J) (second polarity) and compound (J) (highest polarity) are each a single isomer.
Compound (J) (third polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.05 (s, 3 H), 0.06 (s, 9 H), 0.55 (s, 3 H), 0.87 (s, 9 H), 0.88 (s, 9 H), 0.83-2.04 (m, 38 H), 218-2.24 (m, 1 H), 2.43-2.45 (m, 2 H), 2.80-2.83 (m, 1 H), 3.75 (br, 1 H), 4.11- 4.24 (m, 3 H), 4.37 (br, 1 H), 4.86 (d, J = 2.3 Hz, 1 H), 5.16 (s, 1 H), 5.52 & 5.57 (s, 1 H), 6.01 (d , J = 11.2 Hz, 1 H), 6.24 (d, J = 11.2 Hz, 1 H), 6.27-6.28 (m, 1 H).
MS m / z 813.8 ((M + 1) ⁺ )
Compound (J) (second polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.06 (s, 12 H), 0.53 (s, 3 H), 0.87 (s, 9 H), 0.88 (s, 9 H), 0.85-1.98 (m, 38 H ), 2.22-2.24 (m, 1 H), 2.43-2.45 (m, 1 H), 2.57-2.64 (m, 1 H), 2.80-2.83 (m, 1 H), 3.77 (br, 1 H), 4.11-4.24 (m, 3 H), 4.38 (br, 1 H), 4.86 (d, J = 2.3 Hz, 1 H), 5.18 (s, 1 H), 5.65 (s, 1 H), 6.01 (d , J = 11.0 Hz, 1 H), 6.23 (d, J = 11.1 Hz, 1 H), 6.28 (d, J = 1.3 Hz, 1 H).
MS m / z 813.8 ((M + 1) ⁺ )
Compound (J) (highest polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.06 (s, 12 H), 0.55 (s, 3 H), 0.876 (s, 9 H), 0.879 (s, 9 H), 0.72-1.99 (m, 38 H ), 2.20-2.24 (m, 1 H), 2.37-2.63 (m, 2 H), 2.81-2.84 (m, 1 H), 3.74 (br, 1 H), 4.17-4.27 (m, 3 H), 4.35-4.37 (m, 1 H), 4.87 (d, J = 2.5 Hz, 1 H), 5.18 (s, 1 H), 5.59 (s, 1 H), 6.02 (d, J = 11.0 Hz, 1 H ), 6.23 (d, J = 11.5 Hz, 1 H), 6.31 (d, J = 1.2 Hz, 1 H).
MS m / z 813.8 ((M + 1) ⁺ )

(2-a) The same reaction as in Example 2 (2-a) was carried out using 56 mg (68 μmol) of the compound (J) (third polarity) obtained above. 108a (low polarity) 2.4 mg (yield 7%, purity 95%) 108 mg (high polarity) 108 mg (yield 8%, purity 96%) was obtained. These are isomers derived from the configuration of the asymmetric carbon to which the octyl group on the lactone ring is bonded.
No. 108a (low polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.93 (t, J = 6.8 Hz, 3 H), 1.02 (d, J = 6.6 Hz, 3 H), 1.25-2.04 (m, 30 H), 2.31 (dd, J = 13.4, 6.6 Hz, 1 H), 2.60 (m, 1 H), 2.82 (m, 1 H), 4.25 (m, 2 H), 4.43 (br, 1 H) , 4.63-6.69 (m, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.57 (d, J = 2.4 Hz, 1 H), 6.01 (d, J = 11.5 Hz, 1 H), 6.26 (d, J = 2.7 Hz, 1 H), 6.37 (d, J = 11.2 Hz, 1 H).
MS m / z 539.3 ((M + 1) ⁺ )
No. 108b (high polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.93 (t, J = 6.6 Hz, 3 H), 1.01 (d, J = 6.3 Hz, 3 H), 1.10-2.05 (m, 30 H), 2.31 (dd, J = 13.7, 6.6 Hz, 1 H), 2.59-2.62 (m, 1 H), 2.82-2.85 (m, 1 H), 2.95 (m, 1 H), 4.24 (br , 1 H), 4.43 (br, 1 H), 4.63-4.68 (m, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.50 (d, J = 2.4 Hz, 1 H ), 6.01 (d, J = 11.7 Hz, 1 H), 6.21 (d, J = 2.4 Hz, 1 H), 6.37 (d, J = 11.5 Hz, 1 H).
MS m / z 539.3 ((M + 1) ⁺ )

(2-b) The same reaction as in Example 2 (2-b) was carried out using 37 mg (45 μmol) of the compound (J) (second polarity) obtained above. 108 mg of 2.4c (yield 10%, purity 98%) was obtained.
No. 108c:
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.88 (t, J = 6.6 Hz, 3 H), 1.06 (d, J = 6.1 Hz, 3 H), 1.26-1.70 (m, 25 H), 1.92-2.02 (m, 5 H), 2.32 (dd, J = 13.7, 6.6 Hz, 1 H), 2.59-2.61 (m, 2 H), 2.82-2.85 (m, 1 H), 4.24 -4.25 (m, 2 H), 4.44 (br, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.58 (d, J = 2.0 Hz, 1 H), 6.01 (d, J = 11.0 Hz, 1 H), 6.26 (d, J = 2.4 Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H).
MS m / z 539.3 ((M + 1) ⁺ )

(2-c) The same reaction as in Example 2 (2-c) was performed using 29 mg (36 μmol) of the compound (J) (highest polarity) obtained above. Obtained 108 mg of 108d (yield 11%, purity 99%).
No. 108d:
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.88 (t, J = 6.7 Hz, 3 H), 1.06 (d, J = 6.3 Hz, 3 H), 1.26-1.70 (m, 25 H), 1.94-2.05 (m, 5 H), 2.32 (dd, J = 13.4, 6.6 Hz, 1 H), 2.58-2.62 (m, 1 H), 2.82-2.88 (m, 2 H), 4.23 (br, 1 H), 4.44 (br, 1 H), 4.54-4.61 (m, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.50 (d, J = 1.7 Hz, 1 H), 6.02 (d, J = 11.2 Hz, 1 H), 6.20 (d, J = 2.0 Hz, 1 H), 6.38 (d, J = 11.5 Hz, 1 H).
MS m / z 539.4 ((M + 1) ⁺ )

[Example 9]
20 (R)-(Tetrahydro-3-methylene-2-furanone-4-phenethyl-5-yl) methyl-9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene-1α , 3β-diol (Compound No. 110a, Compound No. 110b, Compound No. 110c, Compound No. 110d)

(1) Compound (3a) (R ^2d / R ^2e ) obtained in Reference Example 2 was obtained in the same manner as Example 2 (1) using 202 mg (0.344 mmol) of Compound (15) obtained in Reference Example 13. = Et / hydrogen atom, R ⁷ = Et) was replaced with the compound (3a) obtained in Reference Example 10 (R ^2d / R ^2e = phenethyl / hydrogen atom, R ⁷ = Et), and compound (K) was obtained. Three components were obtained. In order of decreasing polarity, compound (K) (third polarity) 99 mg (yield 36%), compound (K) (second polarity) 44 mg (yield 16%), compound (K) (highest polarity) 43 mg (yield 16%). These are isomers derived from the configuration of an asymmetric carbon to which a hydroxyl group is bonded and an asymmetric carbon to which the adjacent phenethyl group is bonded. Compound (K) (third polarity) is a mixture of two isomers, and compound (K) (second polarity) and compound (K) (highest polarity) are each a single isomer.
Compound (K) (third polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.06 (s, 12 H), 0.54 (s, 3 H), 0.87 (s, 9 H), 0.88 (s, 9 H), 0.90-0.94 (m, 3 H ), 1.24-2.07 (m, 21 H), 2.18-2.24 (m, 1 H), 2.43-2.84 (m, 5 H), 3.78 (br, 1 H), 4.09-4.26 (m, 3 H), 4.34-4.36 (m, 1 H), 4.86 (d, J = 2.4 Hz, 1 H), 5.17 (d, J = 1.8 Hz, 1 H), 5.58 & 5.62 (s, 1 H), 6.01 (d, J = 11.5 Hz, 1 H), 6.23 (d, J = 11.2 Hz, 1 H), 6.22-6.25 (m, 1 H), 7.14-7.29 (m, 5 H).
Compound (K) (second polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.06 (s, 12 H), 0.52 (s, 3 H), 0.876 (s, 9 H), 0.882 (s, 9 H), 0.91 (d, J = 6.3 Hz , 3 H), 1.22-2.08 (m, 21 H), 2.22-2.24 (m, 1 H), 2.43-2.80 (m, 5 H), 3.81 (br, 1 H), 4.09-4.26 (m, 3 H), 4.38 (br, 1 H), 4.86 (d, J = 2.4 Hz, 1 H), 5.18 (s, 1 H), 5.68 (s, 1 H), 6.00 (d, J = 11.2 Hz, 1 H), 6.23 (d, J = 11.2 Hz, 1 H), 6.33 (s, 1 H), 7.15-7.29 (m, 5 H).
Compound (K) (highest polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.07 (s, 6 H), 0.088 (s, 3 H), 0.094 (s, 3 H), 0.46 (s, 3 H), 0.88 (s, 9 H), 0.90-0.93 (m, 12 H), 1.24-2.08 (m, 21 H), 2.23-2.25 (m, 1 H), 2.40-2.83 (m, 5 H), 3.74 (br, 1 H), 4.09- 4.26 (m, 3 H), 4.39 (br, 1 H), 4.89 (d, J = 2.1 Hz, 1 H), 5.22 (s, 1 H), 5.65 (s, 1 H), 6.02 (d, J = 11.2 Hz, 1 H), 6.24 (d, J = 11.2 Hz, 1 H), 6.39 (s, 1 H), 7.12-7.29 (m, 5 H).

(2-a) The same reaction as in Example 2 (2-a) was performed using 99 mg (123 μmol) of the compound (K) (third polarity) obtained above. 110a (low polarity) 3.7 mg (6% yield, 99% purity) and No. 110 mg (high polarity) 110 mg (yield 12%, purity 99%) was obtained. These are isomers derived from the configuration of the asymmetric carbon to which the phenethyl group on the lactone ring is bonded.
No. 110a (low polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 1.02 (d, J = 6.6 Hz, 3 H), 1.22-2.05 (m, 18 H), 2.32 (dd, J = 13.4, 6.3 Hz, 1 H), 2.59-2.62 (m, 2 H), 2.70 (t, J = 8.1 Hz, 2 H), 2.82-2.85 (m, 1 H), 4.22-4.25 (m, 1 H), 4.34 -4.35 (m, 1 H), 4.41-4.43 (m, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.62 (d, J = 2.2 Hz, 1 H), 6.01 ( d, J = 11.2 Hz, 1 H), 6.30 (d, J = 2.7 Hz, 1 H), 6.37 (d, J = 11.0 Hz, 1 H), 7.17-7.33 (m, 5 H).
MS m / z 531.3 ((M + 1) ⁺ )
No. 110b (high polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 1.00 (d, J = 6.6 Hz, 3 H), 1.11-1.33 (m, 4 H), 1.46-2.03 (m, 14 H) , 2.31 (dd, J = 13.7, 6.3 Hz, 1 H), 2.58-2.76 (m, 3 H), 2.81-2.84 (m, 1 H), 3.00-3.01 (m, 1 H), 4.23 (br, 1 H), 4.43 (br, 1 H), 4.65-4.70 (m, 1 H), 4.99 (s, 1 H), 5.33 (s, 1 H), 5.57 (d, J = 2.2 Hz, 1 H) , 6.01 (d, J = 11.2 Hz, 1 H), 6.26 (d, J = 2.2 Hz, 1 H), 6.36 (d, J = 11.2 Hz, 1 H), 7.18 (d, J = 7.8 Hz, 2 H), 7.21-7.33 (m, 3 H).
MS m / z 531.3 ((M + 1) ⁺ )

(2-b) Using 44 mg (54 μmol) of the compound (K) (second polarity) obtained above, the same reaction as in Example 2 (2-b) was carried out. Obtained 4.4 mg of 110c (15% yield, 99% purity).
No. 110c:
¹ H-NMR (CDCl ₃ ) δ: 0.54 (s, 3 H), 1.06 (d, J = 5.9 Hz, 3 H), 1.09-2.06 (m, 18 H), 2.32 (dd, J = 13.4, 6.3 Hz, 1 H), 2.59-2.72 (m, 4 H), 2.82-2.85 (m, 1 H), 4.23 (br, 1 H), 4.30-4.32 (m, 1 H), 4.44 (br, 1 H ), 5.00 (s, 1 H), 5.33 (t, J = 1.7 Hz, 1 H), 5.64 (d, J = 2.0 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.31 (d, J = 2.4 Hz, 1 H), 6.38 (d, J = 11.5 Hz, 1 H), 7.17-7.33 (m, 5 H).
MS m / z 531.2 ((M + 1) ⁺ )

(2-c) The same reaction as in Example 2 (2-c) was performed using 43 mg (54 μmol) of the compound (K) (highest polarity) obtained above. 110d 5.8 mg (yield 20%, purity 99%) was obtained.
No. 110d:
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 1.05 (d, J = 6.6 Hz, 3 H), 1.07-2.05 (m, 18 H), 2.32 (dd, J = 13.4, 6.6 Hz, 1 H), 2.55-2.62 (m, 2 H), 2.70-2.85 (m, 2 H), 2.92-2.94 (m, 1 H), 4.23 (br, 1 H), 4.43 (br, 1 H ), 4.57-4.62 (m, 1 H), 5.01 (s, 1 H), 5.33 (s, 1 H), 5.52 (d, J = 1.8 Hz, 1 H), 6.02 (d, J = 11.5 Hz, 1 H), 6.26 (d, J = 2.0 Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H), 7.16-7.33 (m, 5 H).
MS m / z 531.3 ((M + 1) ⁺ )

[Example 10]
20 (R)-(Tetrahydro-3-methylene-2-furanone-4- (2-hydroxyethyl) -5-yl) methyl-9,10-secopregna-5 (Z), 7 (E), 10 (19 ) -Triene-1α, 3β-diol (Compound No. 114a, Compound No. 114b, Compound No. 114c)

(1) Compound (3a) (R ^2d / R ^2e ) obtained in Reference Example 2 was obtained in the same manner as Example 2 (1) using 202 mg (0.344 mmol) of Compound (15) obtained in Reference Example 13. = Et / hydrogen atom, R ⁷ = Et) was replaced with the compound (3a) obtained in Reference Example 12 (R ^2d / R ^2e = TBSOEt / hydrogen atom, R ⁷ = Et), and the compound (L) was obtained. Three components were obtained. In order of decreasing polarity, compound (L) (third polarity) 41 mg (yield 12%), compound (L) (second polarity) 40 mg (yield 12%), compound (L) (highest polarity) 23 mg (7% yield). These are isomers derived from the configuration of an asymmetric carbon to which a hydroxyl group is bonded and an asymmetric carbon to which the adjacent 2- (t-butyldimethylsilyloxy) ethyl group is bonded. Compound (L) (third polarity) is a mixture of two isomers, and compound (L) (second polarity) and compound (L) (highest polarity) are each a single isomer.
Compound (L) (third polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.055 (s, 6 H), 0.063 (s, 6 H), 0.55 & 0.56 (s, 3 H), 0.87 (s, 9 H), 0.88 (s, 9 H ), 1.05 & 1.06 (s, 9 H), 0.91-2.04 (m, 23 H), 2.19-2.24 (m, 1 H), 2.40-2.54 (m, 2 H), 2.81-2.84 (m, 1 H ), 3.60-3.82 (m, 3 H), 4.16-4.29 (m, 5 H), 4.37 (br, 1 H), 4.86 (s, 1 H), 5.17 (s, 1 H), 5.46 & 5.55 ( s, 1 H), 6.02 (d, J = 10.7 Hz, 1 H), 6.22-6.26 (m, 2 H), 7.37-7.42 (m, 6 H), 7.64-7.66 (m, 4 H).
MS m / z 983.5 ((M + 1) ⁺ )
Compound (L) (second polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.06 (s, 12 H), 0.54 (s, 3 H), 0.86 (s, 9 H), 0.88 (s, 9 H), 1.03 (s, 9 H), 0.81-2.04 (m, 23 H), 2.19-2.24 (m, 1 H), 2.43-2.46 (m, 1 H), 2.81-2.84 (m, 1 H), 3.00-3.03 (m, 1 H), 3.51-3.57 (m, 1 H), 3.65-3.67 (m, 1 H), 3.81 (m, 1 H), 4.15-4.23 (m, 5 H), 4.38 (br, 1 H), 4.88 (d, J = 2.4 Hz, 1 H), 5.20 (s, 1 H), 5.52 (s, 1 H), 6.02 (d, J = 11.2 Hz, 1 H), 6.23 (d, J = 11.0 Hz, 1 H) , 6.27 (s, 1 H), 7.33-7.43 (m, 6 H), 7.60-7.65 (m, 4 H).
MS m / z 983.5 ((M + 1) ⁺ )
Compound (L) (highest polarity):
¹ H-NMR (CDCl ₃ ) δ: 0.06 (s, 12 H), 0.52 (s, 3 H), 0.88 (s, 18 H), 1.04 (s, 9 H), 0.76-2.04 (m, 23 H ), 2.19-2.28 (m, 1 H), 2.43-2.45 (m, 1 H), 2.80-2.83 (m, 2 H), 3.61-3.81 (m, 3 H), 4.11-4.21 (m, 5 H ), 4.37 (br, 1 H), 4.87 (s, 1 H), 5.18 (s, 1 H), 5.66 (s, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.23 (d , J = 12.0 Hz, 1 H), 6.26 (s, 1 H), 7.35-7.42 (m, 6 H), 7.60-7.65 (m, 4 H).
MS m / z 983.5 ((M + 1) ⁺ )

(2-a) Compound (L) obtained above (third polarity) 41 mg (0.041 mmol) in anhydrous THF solution (2.0 ml) was added 0.31 ml (4.0M, 0.2 mmol) and stirred at room temperature for 60 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. . The residue was dissolved in a mixed solution of toluene and acetonitrile (1: 1 ml), and 16 mg (0.17 mmol) of LiBF ₄ was added to this solution, followed by ice cooling. To this solution was added 0.06 ml (2.0 M, 0.12 mmol) of an acetonitrile solution of sulfuric acid, and the mixture was stirred as it was for 4 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in methanol (2 ml), 0.62 ml (4.0 M, 2.48 mmol) of a hydrochloric acid-dioxane solution was added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was prepared by preparative TLC (chloroform: methanol = 5: 1) and HPLC (reverse phase, A = 95% H ₂ O / CH ₃ CN; B = 60% CH ₃ CN / MeOH; B = 60% (0.5 % H ₂ O)). As a result, 1.6 mg of 114a (yield: 8%, purity: 98%) was obtained. These are a mixture of two isomers derived from the asymmetric carbon to which the lactone ring oxygen atom is bonded or the asymmetric carbon to which the 2-hydroxyethyl group on the lactone ring is bonded.
No. 114a:
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 6 H), 1.01 (d, J = 6.3 Hz, 3 H), 1.02 (d, J = 6.4 Hz, 3 H), 0.83-2.05 (m, 32 H), 2.29-2.34 (m, 4 H), 2.58-2.61 (m, 2 H), 2.82 (m, 3 H), 3.25 (m, 1 H), 3.66-3.78 (m, 4 H), 4.24-4.43 (m, 7 H), 4.73 (m, 1 H), 5.00 (s, 2 H), 5.33 (s, 2 H), 5.57 (d, J = 2.2 Hz, 1 H), 5.63 (d , J = 2.4 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 2 H), 6.26 (d, J = 2.4 Hz, 1 H), 6.29 (d, J = 2.9 Hz, 1 H), 6.37 (d, J = 11.2 Hz, 2 H).
MS m / z 471.2 ((M + 1) ⁺ )

(2-b) The same reaction as in Example 10 (2-a) was performed using 39 mg (0.040 mmol) of the compound (L) (second polarity) obtained above. 114 mg (yield 11%, purity 100%) of 114b was obtained.
No. 114b:
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 1.06 (d, J = 6.1 Hz, 3 H), 0.83-2.05 (m, 16 H), 2.29-2.33 (m, 2 H) , 2.58-2.61 (m, 1 H), 2.80-2.85 (m, 2 H), 3.64-3.77 (m, 2 H), 4.23-4.34 (m, 3 H), 4.44 (br, 1 H), 5.00 (s, 1 H), 5.33 (t, J = 1.7 Hz, 1 H), 5.64 (d, J = 2.1 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.30 (d, J = 2.7 Hz, 1 H), 6.38 (d, J = 11.0 Hz, 1 H).
MS m / z 471.3 ((M + 1) ⁺ )

(2-c) The same reaction as in Example 10 (2-a) was performed using 23 mg (0.023 mmol) of the compound (L) (highest polarity) obtained above. 114c 1.5 mg (14% yield, 100% purity) was obtained.
No. 114c:
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 1.06 (d, J = 6.6 Hz, 3 H), 0.83-2.05 (m, 16 H), 2.17-2.34 (m, 2 H) , 2.59-2.62 (m, 1 H), 2.80-2.84 (m, 1 H), 3.18 (m, 1 H), 3.65-3.80 (m, 2 H), 4.23-4.30 (m, 2 H), 4.44 (br, 1 H), 4.61 (m, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.58 (d, J = 1.7 Hz, 1 H), 6.02 (d, J = 11.2 Hz, 1 H), 6.25 (d, J = 2.0 Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H).
MS m / z 471.3 ((M + 1) ⁺ )

[Example 11]
2α-Methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -methyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z), 7 (E ), 10 (19) -triene-1α, 3β-diol (Compound No. 201a) and 2α-methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -methyl-5 ( Production of S) -yl) methyl-9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene-1α, 3β-diol (Compound No. 201b)

(1) 97 mg (2.6 mmol) of LiAlH ₄ was added at 0 ° C. to a suspension of 811 mg (5.1 mmol) of chromium (III) chloride in THF (26 ml), and the mixture was stirred at room temperature for 30 minutes. In this solution, a solution of 494 mg (2.6 mmol) of Compound (3) (R ^2c = Me, R ⁷ = Me) obtained by using methyl acrylate instead of ethyl acrylate in the same manner as in Reference Example 1 in THF (8 ml) And THF (8 ml) solution of 385 mg (1.3 mmol) of compound (2) (Z = (2-1), Y = Br) obtained by a method known in the literature (for example, International Publication WO95 / 33716) The mixture was stirred at the same temperature for 1 hour. Water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by preparative TLC (chloroform) to obtain compound (4syn) (Z = (2-1), Y = Br, R ^2c = Me, 4R / 5R. ) And compound (4syn) (Z = (2-1), Y = Br, R ^2c = Me, 4S / 5S) were obtained as a mixture (quantity ratio 1: 1). Yield 95%. These were separated by HPLC (normal phase, hexane: ethyl acetate = 3: 1).
Compound (4syn) (Z = (2-1), Y = Br, R ^2c = Me, 4R / 5R):
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 1.01 (d, J = 6.6 Hz, 3 H), 1.10 (ddd, J = 13.3, 10.8, 1.9 Hz, 1 H), 1.13 ( d, J = 7.1 Hz, 3 H), 1.20-1.35 (m, 3 H), 1.40-1.71 (m, 6 H), 1.75 (m, 1 H), 1.86 (m, 1 H), 1.97 (ddd , J = 12.4, 6.7, 1.1 Hz, 1 H), 2.03 (br d, J = 12.4 Hz, 1 H), 5.76 (m, 1 H), 3.17 (ddq, J = 2.5, 7.7, 7.1 Hz, 1 H), 4.68 (ddd, J = 11.8, 7.7, 1.9 Hz, 1 H), 5.53 (d, J = 2.8 Hz, 1 H), 5.65 (s, 1 H), 6.22 (d, J = 2.8 Hz, 1 H).
LRMS m / z 380 (M ⁺ ), 301, 227, 147, 105
HRMS calcd for C ₂₀ H ₂₉ O ₂ ⁷⁹ Br 380.1350, found 380.1353
Compound (4syn) (Z = (2-1), Y = Br, R ^2c = Me, 4S / 5S):
¹ H-NMR (CDCl ₃ ) δ: 0.58 (s, 3 H), 1.06 (d, J = 6.9 Hz, 3 H), 1.14 (d, J = 7.0 Hz, 3 H), 1.22-1.51 (m, 5 H), 1.52-1.72 (m, 6 H), 1.96 (m, 1 H), 1.98-2.05 (m, 2 H), 2.88 (m, 1 H), 3.11 (dddq, J = 2.0, 2.0, 6.8, 7.0 Hz, 1 H), 4.60 (ddd, J = 8.3, 6.8, 5.2 Hz, 1 H), 5.84 (d, J = 2.1 Hz, 1 H), 5.65 (s, 1 H), 6.19 (d , J = 2.1 Hz, 1 H).
LRMS m / z 380 (M ⁺ ), 301, 227, 147, 105
HRMS calcd for C ₂₀ H ₂₉ O ₂ ⁷⁹ Br 380.1351, found 380.1347

(2-a) 37 mg (96 μmol) of the compound (4syn) obtained above (Z = (2-1), Y = Br, R ^2c = Me, 4R / 5R) and methods known in the literature (for example, Fujishima et al., Bioorg.Med.Chem., 8, 123, 2000) 46 mg (0.12 mmol) in a toluene solution (7) (R ³ = TBS, R ⁶ = Me, 3α / 4α / 5β) (0.12 mmol) 3 ml) were added triethylamine (1.5 ml) and tetrakis (triphenylphosphine) palladium (0) 33 mg (29 μmol), and the mixture was stirred at 110 ° C. for 1.5 hours. The reaction solution was filtered through a silica gel pad (eluted with hexane: ethyl acetate = 5: 1) to obtain a crude product (45 mg). This crude product was dissolved in 3 ml of methanol, 47 mg (0.2 mmol) of camphorsulfonic acid was added at 0 ° C., and the mixture was stirred at room temperature for 45 minutes. To the solution was added saturated sodium hydrogen carbonate solution at 0 ° C., and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2). 24 mg of 201a was obtained. Yield 57%.
Compound No. 201a:
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 1.02 (d, J = 6.4 Hz, 3 H), 1.08 (m, 1 H), 1.13 (d, J = 7.3 Hz, 3 H ), 1.15-1.35 (m, 3 H), 1.40-2.10 (m, 14 H), 2.31 (dd, J = 13.4, 6.6 Hz, 1 H), 2.59 (dd, J = 13.4, 3.3 Hz, 1 H ), 2.83 (dd, J = 12.1, 3.8 Hz, 1 H), 3.16 (dq, J = 7.8, 7.3 Hz, 1 H), 4.23 (m, 1 H), 4.43 (m, 1 H), 4.67 ( ddd, J = 11.8, 7.8, 2.0 Hz, 1 H), 4.99 (s, 1 H), 5.33 (s, 1 H), 5.52 (d, J = 2.7 Hz, 1 H), 6.01 (d, J = 11.3 Hz, 1 H), 6.21 (d, J = 2.7 Hz, 1 H), 6.36 (d, J = 11.3 Hz, 1 H).
LRMS m / z 440 (M ⁺ ), 422, 404, 378, 289, 209, 105
HRMS calcd for C ₂₈ H ₄₀ O ₄ 440.2927, found 440.2935

(2-b) 35 mg (92 μmol) of the compound (4syn) (Z = (2-1), Y = Br, R ^2c = Me, 4S / 5S) obtained above and the compound (7) (R ³ = TBS) , R ⁶ = Me, 3α / 4α / 5β) 44 mg (0.12 mmol), the same reaction as in Example 11 (2-a) was carried out. 20 mg of 201b was obtained. Yield 48%.
Compound No. 201b:
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 1.05 (d, J = 6.6 Hz, 3 H), 1.13 (d, J = 7.1 Hz, 3 H), 1.20-1.75 (m, 13 H), 1.87-1.95 (m, 2 H), 1.96-2.08 (m, 3 H), 2.31 (dd, J = 13.4, 6.6 Hz, 1 H), 2.59 (dd, J = 13.4, 3.4 Hz, 1 H), 2.82 (dd, J = 12.5, 4.4 Hz, 1 H), 3.11 (dddq, J = 2.2, 2.2, 6.8, 7.1 Hz, 1 H), 4.22 (m, 1 H), 4.43 (m, 1 H), 4.59 (ddd, J = 8.2, 6.8, 5.3 Hz, 1 H), 4.99 (dd, J = 1.5, 1.5 Hz, 1 H), 5.32 (dd, J = 1.5, 1.5 Hz, 1 H) , 5.53 (d, J = 2.2 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.18 (d, J = 2.2 Hz, 1 H), 6.37 (d, J = 11.2 Hz, 1 H).
LRMS m / z 440 (M ⁺ ), 422, 404, 251, 105
HRMS calcd for C ₂₈ H ₄₀ O ₄ 440.2987, found 440.2932

[Example 12]
2α-Methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -methyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z), 7 (E ), 10 (19) -triene-1α, 3β-diol (Compound No. 201c)

(1) A toluene solution of 15.1 mg (0.04 mmol) of the compound (4syn) (Z = (2-1), Y = Br, R ^2c = Me, 4R / 5R) obtained in Example 11 (1) To this, 0.15 ml (1.04 M, 0.16 mmol) of a DIBAL-H toluene solution was added at 0 ° C., followed by stirring at room temperature for 2 hours. The reaction solution was diluted with diethyl ether, 10% aqueous sodium potassium tartrate solution was added, and the mixture was stirred at room temperature for 1 hr. The aqueous layer was extracted with ethyl acetate, and then the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 14 mg of compound (M) (4R / 5R). Yield 93%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 0.96 (d, J = 6.6 Hz, 3 H), 1.03 (m, 1 H), 1.07 (d, J = 7.0 Hz, 3 H ), 1.20-1.38 (m, 3 H), 1.40-1.73 (m, 7 H), 1.85-2.06 (m, 3 H), 2.30 (dq, J = 3.9, 7.0 Hz, 1 H), 2.53 (br s, 2 H), 2.88 (m, 1 H), 3.71 (ddd, J = 10.6, 3.9, 1.8 Hz, 1 H), 4.06 (br d, J = 12.9, 1 H), 4.13 (br d, J = 12.9 Hz, 1 H), 4.93 (s, 1 H), 5.17 (br s, 1 H), 5.64 (s, 1 H).
LRMS m / z 384 (M ⁺ ), 254, 227, 175, 147, 106, 86
HRMS calcd for C ₂₀ H ₃₃ O ₂ ⁷⁹ Br 384.1664, found 384.1667

(2) To a solution of 261 mg (0.68 mmol) of the compound (M) (4R / 5R) obtained above in methylene chloride (3.4 ml), 0.22 ml (2.7 mmol) of pyridine and 0.11 ml of pivaloyl chloride (0 .89 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give compound (5syn) (Z = (2-1), Y = Br, 272 mg of R ^2c = Me, R ⁸ = Piv, 4R / 5R) was obtained. Yield 86%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.58 (s, 3 H), 0.95 (d, J = 6.6 Hz, 3 H), 1.02 (m, 1 H), 1.09 (d, J = 6.9 Hz, 3 H ), 1.14-1.73 (m, 11 H), 1.22 (s, 9 H), 1.85-2.06 (m, 3 H), 2.15 (dq, J = 5.3, 6.9 Hz, 1 H), 2.86 (m, 1 H), 3.71 (m, 1 H), 4.54 (s, 2 H), 4.97 (s, 1 H), 5.12 (s, 1 H), 5.63 (s, 1 H).
LRMS m / z 468 (M ⁺ ), 389, 299, 269, 227, 170, 147
HRMS calcd for C ₂₅ H ₄₁ O ₃ ⁷⁹ Br 468.2239, found 468.2234

(3) Compound (5syn) obtained above (Z = (2-1), Y = Br, R ^2c = Me, R ⁸ = Piv, 4R / 5R) 273 mg (0.58 mmol) of methylene chloride (2 .9 ml) solution was added tetrapropylammonium pearlate (Pr ₄ NRuO ₄ ) 20 mg (0.058 mmol) and N-methylmorpholine N-oxide (NMO) 102 mg (0.88 mmol), and the mixture was stirred at room temperature for 4 hours. After the reaction solution was filtered, the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1) to obtain compound (6) (Z = (2-1), Y = Br, R ^2c = Me, R ⁸ = 252 mg of Piv, 4R) was obtained. Yield 93%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.85 (d, J = 6.6 Hz, 3 H), 1.17 (d, J = 7.1 Hz, 3 H), 1.18 (s, 9 H ), 1.19-1.30 (m, 3 H), 1.35-1.70 (m, 5 H), 1.79 (m, 1 H), 1.88-2.05 (m, 3 H), 2.22 (dd, J = 16.7, 9.9 Hz , 1 H), 2.45 (dd, J = 16.7, 2.4 Hz, 1 H), 2.82 (m, 1 H), 3.18 (q, J = 7.1 Hz, 1 H), 4.46 (d, J = 14.7 Hz, 1 H), 4.50 (d, J = 14.7 Hz, 1 H), 4.99 (s, 1 H), 5.16 (s, 1 H), 5.59 (s, 1 H).
LRMS m / z 466 (M ⁺ ), 387, 364, 279, 237, 175, 137
HRMS calcd for C ₂₅ H ₃₉ ⁷⁹ BrO ₃ 466.2082, found 466.2086

(4) In a THF (1 ml) solution of the compound (6) obtained above (Z = (2-1), Y = Br, R ^2c = Me, R ⁸ = Piv, 4R) 51 mg (0.11 mmol) 0.33 ml (1.0 M, 0.33 mmol) of a THF solution of LiAlH (Ot-Bu) ₃ was added at 0 ° C., and the mixture was stirred at the same temperature for 9 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in toluene (1 ml). To this solution, 0.41 ml (1.0 M, 0.41 mmol) of a DIBAL-H toluene solution was added at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. A 10% aqueous sodium potassium tartrate solution was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour, and then the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in methylene chloride (2 ml). To the solution, 150 mg (1.7 mmol) of MnO ₂ was added and stirred at room temperature for 29 hours. After the reaction solution was filtered, the residue obtained by concentrating the filtrate was purified by preparative TLC (hexane: ethyl acetate = 10: 1) to give compound (4anti) (Z = (2-1), Y = Br, R ^2c = Me, 4R / 5S) was obtained. Yield 29%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.58 (s, 3 H), 1.07 (d, J = 6.1 Hz, 3 H), 1.25 (d, J = 6.8 Hz, 3 H), 1.20-1.75 (m, 11 H), 1.90-2.10 (m, 3 H), 2.64 (m, 1 H), 2.88 (m, 1 H), 4.07 (dt, J = 6.3, 5.6 Hz, 1 H), 5.53 (d, J = 3.1 Hz, 1 H), 5.65 (s, 1 H), 6.22 (d, J = 3.1 Hz, 1 H).
LRMS m / z 380 (M ⁺ ), 301, 227, 147
HRMS calcd for C ₂₀ H ₂₉ O ₂ ⁷⁹ Br 380.1351, found 380.1354

(5) Compound (4anti) obtained above (Z = (2-1), Y = Br, R ^2c = Me, 4R / 5S) 14 mg (37 μmol) and Compound (7) (R ³ = TBS, R ⁶ = Me, 3α / 4α / 5β) using 17 mg (48 μmol), the same reaction as in Example 11 (2-a) was carried out. 7.8 mg of 201c was obtained. Yield 48%.
Compound No. 201c:
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 1.06 (d, J = 5.9 Hz, 3 H), 1.28 (d, J = 6.8 Hz, 3 H), 1.25-1.80 (m, 13 H), 1.85-2.10 (m, 5 H), 2.32 (dd, J = 13.6, 6.4 Hz, 1 H), 2.55-2.70 (m, 2 H), 2.83 (m, 1 H), 4.07 (dt , J = 5.9, 6.4 Hz, 1 H), 4.23 (m, 1 H), 4.43 (m, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.53 (d, J = 2.9 Hz, 1 H), 6.01 (d, J = 11.1 Hz, 1 H), 6.22 (d, J = 2.9 Hz, 1 H), 6.37 (d, J = 11.1 Hz, 1 H).
LRMS m / z 440 (M ⁺ ), 422, 404, 251, 105
HRMS calcd for C ₂₈ H ₄₀ O ₄ 440.2927, found 440.2929

[Example 13]
2α-Methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -methyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z), 7 (E ), 10 (19) -triene-1α, 3β-diol (Compound No. 201d)

(1) Using Example 12 (1) with 18 mg of the compound (4syn) (Z = (2-1), Y = Br, R ^2c = Me, 4S / 5S) obtained in Example 11 (1) The same reaction was carried out to obtain 17 mg of compound (M) (4S / 5S). Yield 95%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 1.00 (d, J = 6.6 Hz, 3 H), 1.02 (d, J = 7.1 Hz, 3 H), 1.15-1.72 (m, 11 H), 1.86-2.06 (m, 3 H), 2.01 (dq, J = 2.1, 7.1 Hz, 1 H), 2.70-3.05 (m, 3 H), 3.56 (ddd, J = 7.4, 6.0, 2.4 Hz, 1 H), 4.04 (dd, J = 12.9, 0.49 Hz, 1 H), 4.13 (dd, J = 12.9, 0.73 Hz, 1 H), 4.96 (s, 1 H), 6.26 (br d, J = 0.98 Hz, 1 H), 5.63 (br s, 1 H).
LRMS m / z 384 (M ⁺ ), 298, 254, 227, 175, 147
HRMS calcd for C ₂₀ H ₃₃ O ₂ ⁷⁹ Br 384.1664, found 384.1664

(2) The same reaction as in Example 12 (2) was carried out using 220 mg (0.57 mmol) of the compound (M) (4S / 5S) obtained above, and the compound (5syn) (Z = (2-1) ), Y = Br, R ^2c = Me, R ⁸ = Piv, 4S / 5S). Yield 84%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 1.05 (d, J = 6.6 Hz, 3 H), 1.04 (d, J = 6.9 Hz, 3 H), 1.15-1.80 (m, 12 H), 1.23 (s, 9 H), 1.90-2.10 (m, 3 H), 2.26 (dq, J = 2.8, 6.9 Hz, 1 H), 2.87 (m, 1 H), 3.79 (m, 1 H), 4.52 (d, J = 13.7 Hz, 1 H), 4.59 (d, J = 13.7 Hz, 1 H), 5.02 (s, 1 H), 5.17 (d, J = 1.2 Hz, 1 H), 5.63 (s, 1 H).
LRMS m / z 468 (M ⁺ ), 389, 299, 269, 227, 170, 147
HRMS calcd for C ₂₅ H ₄₁ O ₃ ⁷⁹ Br 468.2239, found 468.2240

(3) Example using 210 mg (0.45 mmol) of the compound (5syn) obtained above (Z = (2-1), Y = Br, R ^2c = Me, R ⁸ = Piv, 4S / 5S) performs the same reaction as 12 (3), the compound (6) was obtained ^{(Z = (2-1), Y} = Br, R 2c = Me, R 8 = Piv, 4S) and 196 mg. Yield 94%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 0.92 (d, J = 6.4 Hz, 3 H), 1.20 (d, J = 7.1 Hz, 3 H), 1.22 (s, 9 H ), 1.29 (m, 1 H), 1.35-1.75 (m, 7 H), 1.83 (m, 1 H), 1.93-2.10 (m, 3 H), 2.26 (dd, J = 16.4, 9.9 Hz, 1 H), 2.52 (d, J = 16.4, 2.8 Hz, 1 H), 2.88 (m, 1 H), 3.18 (q, J = 7.1 Hz, 1 H), 4.53 (s, 2 H), 5.06 (s , 1 H), 5.21 (s, 1 H), 5.64 (s, 1 H).
LRMS m / z 466 (M ⁺ , ⁷⁹ Br), 387, 366, 279, 237, 175
HRMS calcd for C ₂₅ H ₃₉ ⁷⁹ BrO ₃ 466.2083, found 466.2083

(4) In a THF (1 ml) solution of the compound (6) obtained above (Z = (2-1), Y = Br, R ^2c = Me, R ⁸ = Piv, 4S) 36 mg (0.076 mmol) At −78 ° C., 0.24 ml (1.0 M, 0.24 mmol) of a LiAlH (Ot-Bu) ₃ solution in THF was added, and the temperature was raised to 0 ° C. over 1.5 hours. The reaction solution was further stirred at 0 ° C., and a saturated aqueous ammonium chloride solution was added. The aqueous layer was extracted with ethyl acetate, and then the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel flash column chromatography (hexane: ethyl acetate = 10: 1) to give compound (5anti) (Z = (2-1), Y = Br). , R ^2c = Me, R ⁸ = Piv, 4S / 5R) was obtained. Yield 74%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 0.96 (d, J = 6.6 Hz, 3 H), 1.03 (d, J = 7.1 Hz, 3 H), 1.16 (m, 1 H ), 1.22 (s, 9 H), 1.20-1.80 (m, 10 H), 1.91 (m, 1 H), 1.98 (ddd, J = 12.4, 6.8, 1.5 Hz, 1 H), 2.03 (m, 1 H), 2.16 (m, 1 H), 2.21 (br s, 1 H), 2.87 (m, 1 H), 3.59 (m, 1 H), 4.50 (d, J = 13.9 Hz, 1 H), 4.58 (d, J = 13.9 Hz, 1 H), 5.04 (s, 1 H), 5.11 (d, J = 1.2 Hz, 1 H), 5.63 (s, 1 H).
LRMS m / z 468 (M ⁺ ), 390, 229, 178, 68, 57
HRMS calcd for C ₂₅ H ₄₁ ⁷⁹ BrO ₃ 468.2239, found 468.2243

(5) Compound (5anti) obtained above (Z = (2-1), Y = Br, R ^2c = Me, R ⁸ = Piv, 4S / 5R) 27 mg (0.057 mmol) of toluene (1 ml) DIBAL-H in toluene (0.22 ml, 1.04 M, 0.23 mmol) was added at 0 ° C., and the mixture was stirred at the same temperature for 2 hours. The reaction solution was diluted with diethyl ether, 10% aqueous sodium potassium tartrate solution was added, and the mixture was stirred at room temperature for 1 hr. The aqueous layer was extracted with ethyl acetate, and then the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in methylene chloride (1 ml). To the solution, 74 mg (0.85 mmol) of MnO ₂ was added and stirred at room temperature for 24 hours. After the reaction solution was filtered, the residue obtained by concentrating the filtrate was purified by preparative TLC (hexane: ethyl acetate = 10: 1) to give compound (4anti) (Z = (2-1), Y = Br, R ^2c = Me, 4S / 5R) was obtained. Yield 52%.
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 1.02 (d, J = 6.6 Hz, 3 H), 1.23 (d, J = 6.6 Hz, 3 H), 1.20-1.95 (m, 12 H), 1.98 (ddd, J = 12.2, 5.4, 1.7 Hz, 1 H), 2.03 (br d, J = 13.2 Hz, 1 H), 2.61 (m, 1 H), 2.89 (m, 1 H) , 4.07 (ddd, J = 10.7, 7.3, 2.2 Hz, 1 H), 5.53 (d, J = 3.1 Hz, 1 H), 5.65 (d, J = 1.7 Hz, 1 H), 6.22 (d, J = 3.1 Hz, 1 H).
LRMS m / z 380 (M ⁺ ), 301, 227, 147
HRMS calcd for C ₂₀ H ₂₉ ⁷⁹ BrO ₂ 380.1351, found 380.1345

(6) Compound (4anti) obtained above (Z = (2-1), Y = Br, R ^2c = Me, 4S / 5R) 19 mg (49 μmol) and compound (7) (R ³ = TBS, R ⁶ = Me, 3α / 4α / 5β) Using 27 mg (74 μmol), the same reaction as in Example 11 (2-a) was carried out. 11 mg of 201d was obtained. Yield 52%.
Compound No. 201d:
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 1.01 (d, J = 6.4 Hz, 3 H), 1.22 (d, J = 6.8 Hz, 3 H), 1.20-1.38 (m, 4 H), 1.40-2.10 (m, 14 H), 2.31 (dd, J = 13.4, 6.4 Hz, 1 H), 2.55-2.65 (m, 2 H), 2.82 (dd, J = 12.2, 3.9 Hz, 1 H), 4.07 (ddd, J = 10.5, 7.3, 2.0 Hz, 1 H), 4.22 (m, 1 H), 4.42 (dd, J = 7.6, 4.4 Hz, 1 H), 4.99 (s, 1 H ), 5.32 (dd, J = 1.7, 1.4 Hz, 1 H), 5.52 (d, J = 2.9 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.21 (d, J = 2.9 Hz, 1 H), 6.36 (d, J = 11.2 Hz, 1 H).
LRMS m / z 440 (M ⁺ ), 422, 404, 251, 105
HRMS calcd for C ₂₈ H ₄₄ O ₄ 440.2927, found 440.2920

[Example 14]
2α-Methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -ethyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z), 7 (E ), 10 (19) -triene-1α, 3β-diol (Compound No. 202a) and 2α-methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -ethyl-5 ( Production of S) -yl) methyl-9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene-1α, 3β-diol (Compound No. 202b)

(1) Example 11 using 660 mg (2.3 mmol) of compound (2) (Z = (2-1), Y = Br) obtained by a method known in the literature (for example, International Publication WO95 / 33716). (1) and carrying out the same reaction, the compound (4syn) (Z = (2-1 ), Y = Br, R 2c = Et, 4R / 5R) of 439 mg (50% yield), compound (4Syn) ( 366 mg (42% yield) of Z = (2-1), Y = Br, R ^2c = Et, 4S / 5S) was obtained. However, the compound (3) obtained by using methyl acrylate instead of ethyl acrylate in the same manner as in Reference Example 2 instead of compound (3) (R ^2c = Me, R ⁷ = Me) in Example 11 (1) ) (R ^2c = Et, R ⁷ = Me).
Compound (4syn) (Z = (2-1), Y = Br, R ^2c = Et, 4R / 5R):
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 0.98 (t, J = 7.4 Hz, 3 H), 1.01 (d, J = 6.6 Hz, 3 H), 1.13 (ddd, J = 14.2, 10.7, 2.0, Hz, 1 H), 1.24-1.34 (m, 3 H), 1.40-1.79 (m, 9 H), 1.84 (m, 1 H), 1.95 (ddd, J = 4.0, 5.6, 11.9 Hz, 1 H), 2.02 (m, 1 H), 2.86-2.92 (m, 2 H), 4.67 (ddd, J = 11.7, 7.0, 1.8 Hz, 1 H), 5.52 (d, J = 2.4 Hz , 1 H), 5.65 (s, 1 H), 6.22 (d, J = 2.4 Hz, 1 H).
LRMS m / z 394 (M ⁺ ) 315, 227, 202, 175, 147
HRMS calcd for C ₂₁ H ₃₁ O ₂ ⁷⁹ Br 394.1507, found 394.1507
Compound (4syn) (Z = (2-1), Y = Br, R ^2c = Et, 4S / 5S):
¹ H-NMR (CDCl ₃ ) δ: 0.58 (s, 3 H), 0.96 (t, J = 7.3 Hz, 3 H), 1.06 (d, J = 6.6 Hz, 3 H), 1.26-1.48 (m, 6 H), 1.53-1.76 (m, 7 H), 1.92-2.05 (m, 3 H), 2.81 (m, 1 H), 2.88 (m, 1 H), 4.59 (ddd, J = 8.7, 6.2, 4.9 Hz, 1 H), 5.52 (d, J = 2.0 Hz, 1 H), 5.65 (s, 1 H), 6.21 (d, J = 2.0 Hz, 1 H).
LRMS m / z 394 (M ⁺ ) 315, 227, 202, 175, 147
HRMS calcd for C ₂₁ H ₃₁ O ₂ ⁷⁹ Br 394.1507, found 394.1507

(2-a) Compound (4syn) obtained above (Z = (2-1), Y = Br, R ^2c = Et, 4R / 5R) 24 mg (61 μmol) and methods known in the literature (for example, Fujishima et al., Bioorg.Med.Chem., 8, 123, 2000) Compound (7) (R ³ = TBS, R ⁶ = Me, 3α / 4α / 5β) 35 mg (91 μmol) in toluene solution (3 ml) Were added triethylamine (1.8 ml) and tetrakis (triphenylphosphine) palladium (0) 21 mg (18 μmol), and the mixture was stirred at 110 ° C. for 1.5 hours. The crude product obtained by concentrating the reaction solution was dissolved in 1.5 ml of acetonitrile, and then a concentrated hydrofluoric acid-acetonitrile mixed solution (mixing ratio 1: 9, 1.5 ml) was added, and the mixture was stirred at room temperature for 3 hours. Stir. Saturated sodium hydrogen carbonate solution was added to the solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by preparative thin layer chromatography (hexane: ethyl acetate = 1: 1). 18 mg of 202a was obtained. Yield 63%.
Compound No. 202a:
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.97 (t, J = 7.6 Hz, 3 H), 1.00 (d, J = 6.3 Hz, 3 H), 1.07 (d, J = 6.8 Hz, 3 H), 1.12 (ddd, J = 14.2, 10.6, 1.8 Hz, 1 H), 1.23-1.34 (m, 3 H), 1.44-1.85 (m, 12 H), 1.88-2.04 (m, 3 H), 2.22 (dd, J = 13.6, 7.7 Hz, 1 H), 2.66 (dd, J = 13.6, 4.1 Hz, 1 H), 2.80-2.91 (m, 2 H), 3.85 (ddd, J = 7.7, 7.6, 4.1 Hz, 1 H), 4.31 (m, 1 H), 4.66 (ddd, J = 11.7, 7.0, 1.8 Hz, 1 H), 5.00 (d, J = 1.7 Hz, 1 H), 5.28 (s, 1 H), 5.51 (d, J = 2.5 Hz, 1 H), 6.00 (d, J = 11.2 Hz, 1 H), 6.21 (d, J = 2.5 Hz, 1 H), 6.37 (d, J = 11.2 Hz, 1 H).
LRMS m / z 468 (M ⁺ ) 450, 432, 265, 223, 211, 171, 148
HRMS calcd for C ₂₉ H ₄₂ O ₄ 468.3240, found 468.3241

(2-b) Compound (4syn) obtained above (Z = (2-1), Y = Br, R ^2c = Et, 4S / 5S) 24 mg (61 μmol) and Compound (7) (R ³ = TBS , R ⁶ = Me, 3α / 4α / 5β) 35 mg (91 μmol), the same reaction as in Example 14 (2-a) was carried out. 32 mg of 202b was obtained. Yield 57%.
Compound No. 202b:
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.95 (t, J = 7.3 Hz, 3 H), 1.05 (d, J = 6.3 Hz, 3 H), 1.07 (d, J = 6.8 Hz, 3 H), 1.21-1.77 (m, 15 H), 1.88-1.96 (m, 2 H), 1.99-2.01 (m, 2 H), 2.23 (dd, J = 13.4, 7.7 Hz, 1 H ), 2.66 (dd, J = 13.4, 4.1 Hz, 1 H), 2.77-2.84 (m, 2 H), 3.84 (ddd, J = 7.7, 7.4, 4.1 Hz, 1 H), 4.30 (m, 1 H ), 4.57 (m, 1 H), 5.00 (d, J = 1.7 Hz, 1 H), 5.27 (s, 1 H), 5.51 (d, J = 1.8 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.20 (d, J = 1.8 Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H).
LRMS m / z 468 (M ⁺ ) 450, 432, 265, 223, 211, 171, 148
HRMS calcd for C ₃₀ H ₄₄ O ₄ 468.3240, found 468.3239

[Example 15]
2α-Methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -ethyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z), 7 (E ), 10 (19) -triene-1α, 3β-diol (Compound No. 202c)

(1) Example 14 using the compound (4syn) (Z = (2-1), Y = Br, R ^2c = Et, 4R / 5R) 55 mg (0.139 mmol) obtained in Example 14 (1) Reaction similar to 12 (1) was performed, and 49 mg of compounds (N) (4R / 5R) were obtained. Yield 88%. Colorless solid.
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 0.86 (t, J = 7.4 Hz, 3 H), 0.95 (d, J = 6.6 Hz, 3 H), 1.03 (br dd, J = 11.6, 11.6 Hz, 1 H), 1.22-1.35 (m, 3 H), 1.40-1.69 (m, 9 H), 1.88-2.05 (m, 4 H), 2.34 (br s, 2 H), 2.88 (m, 1 H), 3.71 (br dd, J = 4.0, 9.9 Hz, 1 H), 4.03 (d, J = 13.3 Hz, 1 H), 4.08 (d, J = 13.3 Hz, 1 H), 4.91 (s, 1 H), 5.20 (s, 1 H), 5.65 (s, 1 H).
LRMS m / z 398 (M ⁺ ) 382, 353, 298, 281, 255, 175
HRMS calcd for C ₂₁ H ₃₁ O ₂ ⁷⁹ Br 398.1820, found 398.1825.

(2) The same reaction as in Example 12 (2) was carried out using 267 mg (0.668 mmol) of the compound (N) (4R / 5R) obtained above, and the compound (5syn) (Z = (2-1) ), Y = Br, R ^2c = Et, R ⁸ = Piv, 4R / 5R). Yield 93%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.88 (t, J = 7.3 Hz, 3 H), 1.02 (d, J = 6.3 Hz, 3 H), 1.18-1.37 (m, 4 H), 1.23 (s, 9 H), 1.39-1.71 (m, 10 H), 1.91-2.03 (m, 4 H), 2.88 (m, 1 H), 3.70 (m, 1 H), 4.49 ( d, J = 13.9 Hz, 1 H), 4.55 (d, J = 13.9 Hz, 1 H), 5.00 (s, 1 H), 5.23 (s, 1 H), 5.65 (s, 1 H).
LRMS m / z 482 (M ⁺ ) 382, 301, 283, 175
HRMS calcd for C ₂₁ H ₃₁ O ₂ ⁷⁹ Br 482.2396, found 482.2399

(3) Example using 220 mg (0.454 mmol) of the compound (5syn) obtained above (Z = (2-1), Y = Br, R ^2c = Et, R ⁸ = Piv, 4R / 5R) performs the same reaction as 12 (3), the compound (6) was obtained ^{(Z = (2-1), Y} = Br, R 2c = Et, R 8 = Piv, 4R) and 189 mg. Yield 86%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 0.86 (t, J = 7.3 Hz, 3 H), 0.88 (d, J = 6.3 Hz, 3 H), 1.18-1.33 (m, 3 H), 1.22 (s, 9 H), 1.42-1.68 (m, 6 H), 1.77-1.88 (m, 2 H), 1.96-2.02 (m, 3 H), 2.25 (dd, J = 16.8, 9.9 Hz, 1 H), 2.46 (dd, J = 16.8, 2.9 Hz, 1 H), 2.88 (m, 1 H), 3.01 (t, J = 7.3 Hz, 1 H), 4.48 (dd, J = 13.9 Hz, 1 H), 4.52 (dd, J = 13.9 Hz, 1 H) 5.06 (s, 1 H), 5.21 (s, 1 H), 5.64 (s, 1 H).
LRMS m / z 480 (M ⁺ ) 401, 300, 175
HRMS calcd for C ₂₆ H ₄₁ O ₃ ⁷⁹ Br 480.2239, found 480.2241

(4) A toluene solution (0.73 ml) of 70 mg (0.145 mmol) of the compound (6) obtained above (Z = (2-1), Y = Br, R ^2c = Et, R ⁸ = Piv, 4R) ) Was added 0.98 ml (1.04 M, 1.0 mmol) of a DIBAL-H toluene solution at 0 ° C. and stirred at the same temperature for 4 hours. Methanol and 10% aqueous sodium potassium tartrate solution were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. This solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel flash column chromatography (hexane: ethyl acetate = 6: 1) to obtain 29 mg of compound (N) (4R / 5S). Yield 50%. Colorless solid.
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.85 (t, J = 7.3 Hz, 3 H), 1.00 (d, J = 6.6 Hz, 3 H), 1.17 (ddd, J = 14.3, 8.5, 6.1 Hz, 1 H), 1.25-1.34 (m, 3 H), 1.39-1.71 (m, 9 H), 1.87-2.02 (m, 3 H), 2.10 (ddd, J = 9.4, 4.8 , 4.8 Hz, 1 H), 2.87 (m, 1 H), 3.04 (br s, 2 H), 3.71 (br dd, J = 10.9, 6.2 Hz, 1 H), 3.97 (d, J = 12.6 Hz, 1 H), 4.08 (d, J = 12.6 Hz, 1 H), 4.96 (s, 1 H), 5.21 (s, 1 H), 5.64 (s, 1 H).
LRMS m / z 398 (M ⁺ ) 380, 300, 256, 175
HRMS calcd for C ₂₁ H ₃₅ O ₂ ⁷⁹ Br 398.1820, found 398.1835

(5) 83 mg (0.208 mmol) of the compound (N) (4R / 5S) obtained above was dissolved in methylene chloride (2 ml). To the solution, 432 mg (5.0 mmol) of MnO ₂ was added and stirred at room temperature for 2.5 days. After the reaction solution was filtered, the residue obtained by concentrating the filtrate was purified by silica gel flash column chromatography (hexane: ethyl acetate = 19: 1) to give compound (4anti) (Z = (2-1). ), Y = Br, R ^2c = Et, 4R / 5S). Yield 94%. Colorless solid.
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.97 (t, J = 7.4 Hz, 3 H), 1.06 (d, J = 6.1 Hz, 3 H), 1.18-1.71 (m, 13 H), 1.88-2.03 (m, 3 H), 2.55 (m, 1 H), 2.87 (m, 1 H), 4.26 (ddd, J = 6.5, 6.5, 4.3 Hz, 1 H), 5.58 (d , J = 2.3 Hz, 1 H), 5.64 (br s, 1 H), 6.27 (d, J = 2.3 Hz, 1 H).
LRMS m / z 394 (M ⁺ ) 315, 227, 202, 175, 147
HRMS calcd for C ₂₁ H ₃₁ O ₂ ⁷⁹ Br 394.1507, found 394.1508

(6) Compound (4anti) obtained above (Z = (2-1), Y = Br, R ^2c = Et, 4R / 5S) 16 mg (40 μmol) and compound (7) (R ³ = TBS, R ⁶ = Me, 3α / 4α / 5β) The same reaction as in Example 14 (2-a) was performed using 23 mg (61 μmol). 23 mg of 202c was obtained. Yield 51%.
Compound No. 202c:
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.97 (t, J = 7.4 Hz, 3 H), 1.05-1.08 (m, 6 H), 1.15-1.73 (m, 15 H) , 1.86-1.96 (m, 2 H), 1.98-2.03 (m, 2 H), 2.23 (dd, J = 13.5, 8.1 Hz, 1 H), 2.56 (m, 1 H), 2.67 (dd, J = 13.5, 4.0 Hz, 1 H), 2.82 (m, 1 H), 3.84 (m, 1 H), 4.26 (m, 1 H), 4.31 (m, 1 H), 5.00 (d, J = 2.0 Hz, 1 H), 5.27 (br s, 1 H), 5.58 (d, J = 2.3 Hz, 1 H), 6.00 (d, J = 11.2 Hz, 1 H), 6.27 (d, J = 2.3 Hz, 1 H ), 6.38 (d, J = 11.2 Hz, 1 H).
LRMS m / z 468 (M ⁺ ) 450, 432, 265, 223, 211, 171, 148
HRMS calcd for C ₃₀ H ₄₄ O ₄ 468.3240, found 468.3241

[Example 16]
2α-Methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -ethyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z), 7 (E ), 10 (19) -triene-1α, 3β-diol (Compound No. 202d)

(1) Using the compound (4syn) (Z = (2-1), Y = Br, R ^2c = Et / hydrogen atom, 4S / 5S) 27 mg (0.068 mmol) obtained in Example 14 (1) In the same manner as in Example 12 (1), 27 mg of compound (N) (4S / 5S) was obtained. Yield 99%. Colorless solid.
¹ H-NMR (CDCl ₃ ) δ: 0.58 (s, 3 H), 0.85 (t, J = 7.4 Hz, 3 H), 1.02 (d, J = 6.3 Hz, 3 H), 1.17-1.37 (m, 5 H), 1.42-1.71 (m, 8 H), 1.92-2.03 (m, 3 H), 2.09 (ddd, J = 10.6, 3.3, 3.3 Hz, 1 H), 2.56 (br s, 2 H), 2.88 (m, 1 H), 3.74 (ddd, J = 6.5, 6.5, 2.5 Hz, 1 H), 4.04 (d, J = 12.9 Hz, 1 H), 4.11 (d, J = 12.9 Hz, 1 H) , 4.96 (s, 1 H), 5.20 (s, 1 H), 5.65 (s, 1 H).
LRMS m / z 398 (M ⁺ ) 382, 353, 298, 281, 255, 175
HRMS calcd for C ₂₁ H ₃₁ O ₂ ⁷⁹ Br 398.1820, found 398.1794

(2) The same reaction as in Example 12 (2) was carried out using 189 mg (0.473 mmol) of the compound (N) (4S / 5S) obtained above, and the compound (5syn) (Z = (2-1) ), Y = Br, R ^2c = Et, R ⁸ = Piv, 4S / 5S). Yield 92%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 0.88 (t, J = 7.3 Hz, 3 H), 0.95 (d, J = 6.3 Hz, 3 H), 1.08 (ddd, J = 2.1, 11.1, 13.5 Hz, 1 H), 1.20-1.36 (m, 3 H), 1.24 (s, 9 H), 1.40-1.75 (m, 10 H), 1.89-2.05 (m, 4 H), 2.88 (m, 1 H), 3.66 (m, 1 H), 4.49 (s, 2 H), 4.94 (s, 1 H), 5.17 (d, J = 1.2 Hz, 1 H), 5.65 (s, 1 H ).
LRMS m / z 482 (M ⁺ ) 382, 301, 283, 175
HRMS calcd for C ₂₁ H ₃₁ O ₂ ⁷⁹ Br 482.2396, found 482.2402

(3) Example using 210 mg (0.434 mmol) of the compound (5syn) obtained above (Z = (2-1), Y = Br, R ^2c = Et, R ⁸ = Piv, 4S / 5S) performs the same reaction as 12 (3), the compound ^{(6) (Z = (2-1} ), Y = Br, R 2c = Et, R 8 = Piv, 4S) was obtained 170 mg. Yield 81%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.86 (t, J = 7.5 Hz, 3 H), 0.91 (d, J = 6.3 Hz, 3 H), 1.21 (s, 9 H ), 1.24-1.34 (m, 3 H), 1.39-1.68 (m, 6 H), 1.77-1.88 (m, 2 H), 1.94-2.02 (m, 3 H), 2.22 (dd, J = 16.8, 9.8 Hz, 1 H), 2.50 (dd, J = 16.8, 2.5 Hz, 1 H), 2.86 (m, 1 H), 2.97 (t, J = 7.3 Hz, 1 H), 4.49 (s, 2 H) , 4.52 (dd, J = 13.9 Hz, 1 H) 5.06 (s, 1 H), 5.20 (s, 1 H), 5.62 (s, 1 H).
LRMS m / z 480 (M ⁺ ) 401, 300, 175
HRMS calcd for C ₂₆ H ₄₁ O ₃ ⁷⁹ Br 480.2239, found 480.2238

(4) Example 13 (70) (0.145 mmol) using the compound (6) obtained above (Z = (2-1), Y = Br, R ^2c = Et, R ⁸ = Piv, 4S) 4) and carrying out the same reaction, the compound ^{(5anti) (Z = (2-1} ), Y = Br, to give ^{R 2c = Et, R 8 =} Piv, 4S / 5R) of 53 mg. Yield 75%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.58 (s, 3 H), 0.86 (t, J = 7.3 Hz, 3 H), 0.96 (d, J = 6.6 Hz, 3 H), 1.14 (m, 1 H ), 1.22 (s, 9 H), 1.25-1.39 (m, 4 H), 1.41-1.58 (m, 5 H), 1.60-1.77 (m, 3 H), 1.85-2.05 (m, 4 H), 2.17 (m, 1 H), 2.87 (m, 1 H), 3.63 (m. 1 H), 4.45 (d, J = 13.9 Hz, 1 H), 4.56 (d, J = 13.9 Hz, 1 H), 5.03 (s, 1 H), 5.20 (s, 1 H), 5.64 (s, 1 H).
LRMS m / z 482 (M ⁺ ) 382, 301, 283, 175
HRMS calcd for C ₂₁ H ₃₁ O ₂ ⁷⁹ Br 482.2396, found 482.2393

(5) Examples using 40 mg (0.083 mmol) of the compound (5anti) obtained above (Z = (2-1), Y = Br, R ^2c = Et, R ⁸ = Piv, 4S / 5R) performs the same reaction and 13 (5), compound (4Anti) to give ^{(Z = (2-1), Y} = Br, R 2c = Et, 4S / 5R) of 77 mg. Yield 94%. Colorless solid.
¹ H-NMR (CDCl ₃ ) δ: 0.58 (s, 3 H), 0.98 (t, J = 7.3 Hz, 3 H), 1.03 (d, J = 6.6 Hz, 3 H), 1.21-1.90 (m, 14 H), 1.95-2.04 (m, 2 H), 2.50 (m, 1 H), 2.88 (m, 1 H), 4.28 (ddd, J = 11.0, 4.9, 2.2 Hz, 1 H), 5.58 (d , J = 2.6 Hz, 1 H), 5.64 (br s, 1 H), 6.27 (d, J = 2.6 Hz, 1 H).
LRMS m / z 394 (M ⁺ ) 315, 227, 202, 175, 147
HRMS calcd for C ₂₁ H ₃₁ O ₂ ⁷⁹ Br 394.1507, found 394.1510

(6) Compound (4anti) (Z = (2-1), Y = Br, R ^2c = Et, 4S / 5R) 14 mg (25 μmol) obtained above and compound (7) (R ³ = TBS, R ⁶ = Me, 3α / 4α / 5β) Using 15 mg (38 μmol), the same reaction as in Example 14 (2-a) was carried out. 8 mg of 202d was obtained. Yield 67%.
Compound No. 202d:
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.98 (t, J = 7.4 Hz, 3 H), 1.02 (d, J = 6.6 Hz, 3 H), 1.08 (d, J = 6.8 Hz, 3 H), 1.22-1.76 (m, 17 H), 2.23 (dd, J = 13.5, 7.9 Hz, 1 H), 2.51 (m, 1 H), 2.67 (dd, J = 13.5, 4.0 Hz , 1 H), 2.82 (m, 1 H), 3.85 (m, 1 H), 4.27-4.31 (m, 2 H), 5.00 (d, J = 1.5 Hz, 1 H), 5.28 (s, 1 H ), 5.58 (d, J = 2.4 Hz, 1 H), 6.00 (d, J = 11.2 Hz, 1 H), 6.27 (d, J = 2.4 Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H).
LRMS m / z 468 (M ⁺ ) 450, 432, 265, 223, 211, 171, 148
HRMS calcd for C ₃₀ H ₄₄ O ₄ 468.3240, found 468.3244

[Example 17]
2α-Methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -butyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z), 7 (E ), 10 (19) -triene-1α, 3β-diol (Compound No. 205a) and 2α-methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -butyl-5 ( Production of S) -yl) methyl-9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene-1α, 3β-diol (Compound No. 205b)

(1) Example 11 using 30 mg (0.101 mmol) of the compound (2) (Z = (2-1), Y = Br) obtained by a method known in the literature (for example, International Publication WO95 / 33716). (1) and carrying out the same reaction, the compound (4syn) (Z = (2-1 ), Y = Br, R 2c = Bu, 4R / 5R) of 21 mg (50% yield), compound (4Syn) ( 18 mg (yield 42%) of Z = (2-1), Y = Br, R ^2c = Bu, 4S / 5S) was obtained. However, the compound (3) obtained by using methyl acrylate instead of ethyl acrylate in the same manner as in Reference Example 5 instead of compound (3) (R ^2c = Me, R ⁷ = Me) in Example 11 (1) ) (R ^2c = Bu, R ⁷ = Me).
Compound (4syn) (Z = (2-1), Y = Br, R ^2c = Bu, 4R / 5R):
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 0.93 (t, J = 7.1 Hz, 3 H), 1.01 (d, J = 6.3 Hz, 3 H), 1.12 (ddd, J = 14.2, 10.5, 2.0 Hz, 1 H), 1.24-1.70 (m, 15 H), 1.75 (m, 1 H), 1.87 (m, 1 H), 1.97 (ddd, J = 12.5, 6.6, 1.6 Hz, 1 H), 2.03 (br d, J = 12.5 Hz, 1 H), 2.88 (m, 1 H), 2.98 (m, 1 H), 4.66 (ddd, J = 11.8, 7.2, 1.9 Hz, 1 H) , 5.51 (d, J = 2.3 Hz, 1 H), 5.65 (dd, J = 1.7, 1.7 Hz, 1 H), 6.21 (d, J = 2.3 Hz, 1 H).
LRMS m / z 422 (M ⁺ ), 343, 281, 227
HRMS calcd for C ₂₃ H ₃₅ O ₂ ⁷⁹ Br 422.1820, found 422.1826
Compound (4syn) (Z = (2-1), Y = Br, R ^2c = Bu, 4S / 5S):
¹ H-NMR (CDCl ₃ ) δ: 0.58 (s, 3 H), 0.92 (t, J = 7.2 Hz, 3 H), 1.06 (d, J = 6.6 Hz, 3 H), 1.20-1.75 (m, 17 H), 1.92-2.05 (m, 3 H), 2.87 (m, 1 H), 2.90 (m, 1 H), 4.58 (ddd, J = 8.8, 6.3, 4.7 Hz, 1 H), 5.51 (d , J = 2.0 Hz, 1 H), 5.65 (dd, J = 1.7, 1.4 Hz, 1 H), 6.20 (d, J = 2.0 Hz, 1 H).
EI-LRMS m / z 422 (M ⁺ ), 343, 281, 227
EI-HRMS calcd for C ₂₃ H ₃₅ O ₂ ⁷⁹ Br 422.1820, found 422.1820

(2-a) Compound (4syn) obtained above (Z = (2-1), Y = Br, R ^2c = Bu, 4R / 5R) 51 mg (121 μmol) and compound (7) (R ³ = TBS , R ⁶ = Me, 3α / 4α / 5β) using 70 mg (182 μmol), the same reaction as in Example 14 (2-a) was carried out. 39 mg of 205a was obtained. Yield 66%.
Compound No. 205a:
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.93 (t, J = 7.0 Hz, 3 H), 1.00 (d, J = 6.6 Hz, 3 H), 1.08 (d, J = 6.8 Hz, 3 H), 1.11 (ddd, J = 14.2, 11.0, 1.5 Hz, 1 H), 1.20-2.05 (m, 22 H), 2.23 (dd, J = 13.4, 7.8 Hz, 1 H), 2.67 (dd, J = 13.4, 4.0 Hz, 1 H), 2.83 (m, 1 H), 2.96 (m, 1 H), 3.85 (m, 1 H), 4.31 (s, 1 H), 4.66 (ddd, J = 11.5, 7.1, 1.5 Hz, 1 H), 5.00 (d, J = 1.7 Hz, 1 H), 5.28 (s, 1 H), 5.51 (d, J = 2.4 Hz, 1 H), 6.01 (d , J = 11.2 Hz, 1 H), 6.21 (d, J = 2.4 Hz, 1 H), 6.37 (d, J = 11.2 Hz, 1 H).
LRMS m / z 496 (M ⁺ ), 478, 460, 434, 265
HRMS calcd for C ₃₂ H ₄₈ O ₄ 496.3553, found 496.3534

(2-b) Compound (4syn) obtained above (Z = (2-1), Y = Br, R ^2c = Bu, 4S / 5S) 49 mg (115 μmol) and compound (7) (R ³ = TBS , R ⁶ = Me, 3α / 4α / 5β) 66 mg (172 μmol), the same reaction as in Example 14 (2-a) was carried out. 32 mg of 205b was obtained. Yield 57%.
Compound No. 205b:
¹ H-NMR (CDCl ₃ ) δ: 0.53 (s, 3 H), 0.92 (t, J = 7.0 Hz, 3 H), 1.05 (d, J = 6.6 Hz, 3 H), 1.08 (d, J = 6.8 Hz, 3 H), 1.20-1.78 (m, 19 H), 1.88-2.07 (m, 4 H), 2.23 (dd, J = 13.5, 7.9 Hz, 1 H), 2.67 (dd, J = 13.5, 3.9 Hz, 1 H), 2.82 (m, 1 H), 2.89 (m, 1 H), 3.84 (m, 1 H), 4.30 (m, 1 H), 4.57 (ddd, J = 11.5, 8.6, 6.1 Hz, 1 H), 5.00 (d, J = 1.5 Hz, 1 H), 5.28 (s, 1 H), 5.50 (d, J = 1.6 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.19 (d, J = 1.6 Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H).
LRMS m / z 496 (M ⁺ ), 478, 460, 434, 265
HRMS calcd for C ₃₂ H ₄₈ O ₄ 496.3553, found 496.3557

[Example 18]
2α-Methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -butyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z), 7 (E ), 10 (19) -triene-1α, 3β-diol (Compound No. 205c)

(1) Example using 15 mg (0.036 mmol) of the compound (4syn) (Z = (2-1), Y = Br, R ^2c = Bu, 4R / 5R) obtained in Example 17 (1) Reaction similar to 12 (1) was performed, and 15 mg of compounds (O) (4R / 5R) were obtained. Yield 98%. Colorless solid.
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.88 (t, J = 7.1 Hz, 3 H), 0.95 (d, J = 6.6 Hz, 3 H), 1.03 (m, 1 H ), 1.10-1.72 (m, 16 H), 1.85-2.05 (m, 3 H), 2.11 (ddd, J = 8.8, 4.2, 4.6 Hz, 1 H), 2.32 (br s, 2 H), 2.87 ( m, 1 H), 3.69 (ddd, J = 6.4, 4.2, 3.2 Hz, 1 H), 4.02 (d, J = 13.2 Hz, 1 H), 4.08 (d, J = 13.2 Hz, 1 H), 4.92 (s, 1 H), 5.18 (s, 1 H), 5.64 (s, 1 H).
LRMS m / z 426 (M ⁺ ), 409, 329, 298, 256, 227, 175
HRMS calcd for C ₂₃ H ₃₉ O ₂ ⁷⁹ Br 426.2134, found 426.2111

(2) The same reaction as in Example 12 (2) was carried out using 455 mg (1.06 mmol) of the compound (O) (4R / 5R) obtained above, and the compound (5syn) (Z = (2-1) ), Y = Br, R ^2c = Bu, R ⁸ = Piv, 4R / 5R). Yield 84%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.88 (t, J = 7.1 Hz, 3 H), 0.95 (d, J = 6.6 Hz, 3 H), 1.06 (ddd, J = 14.0, 10.8, 1.6 Hz, 1 H), 1.13-1.73 (m, 17 H), 1.24 (s, 9 H), 1.85-2.06 (m, 4 H), 2.87 (m, 1 H), 3.65 (m , 1 H), 4.49 (s, 2 H), 4.94 (s, 1 H), 5.16 (d, J = 1.2 Hz, 1 H), 5.66 (s, 1 H).
LRMS m / z 510 (M ⁺ ), 492, 212, 175, 110
HRMS calcd for C ₂₈ H ₄₇ O ₃ ⁷⁹ Br 510.2709, found 510.2709

(3) Example using 455 mg (0.89 mmol) of compound (5syn) obtained above (Z = (2-1), Y = Br, R ^2c = Bu, R ⁸ = Piv, 4R / 5R) performs the same reaction as 12 (3), the compound (6) was obtained ^{(Z = (2-1), Y} = Br, R 2c = Bu, R 8 = Piv, 4R) and 391 mg. Yield 86%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.60 (s, 3 H), 0.88 (t, J = 6.4 Hz, 3 H), 0.89 (d, J = 6.8 Hz, 3 H), 1.23 (s, 9 H ), 1.15-1.72 (m, 13 H), 1.75-1.88 (m, 2 H), 1.92-2.05 (m, 3 H), 2.26 (dd, J = 16.9, 10.0 Hz, 1 H), 2.54 (dd , J = 16.9, 2.7 Hz, 1 H), 2.88 (m, 1 H), 3.09 (t, J = 7.2 Hz, 1 H), 4.48 (d, J = 13.9 Hz, 1 H), 5.52 (d, J = 13.9 Hz, 1 H), 5.05 (s. 1 H), 5.20 (s, 1 H), 5.64 (s, 1 H).
LRMS m / z 508 (M ⁺ ), 423, 407, 351, 279, 237, 175
HRMS calcd for C ₂₈ H ₄₅ O ₃ ⁷⁹ Br 508.2552, found 508.2556

(4) Compound (6) obtained above (Z = (2-1), Y = Br, R ^2c = Bu, R ⁸ = Piv, 4R) 380 mg (0.745 mmol) of THF (1.5 ml) To the solution, 7.5 ml (1.0 M, 7.5 mmol) of a LiAlH (Ot-Bu) ₃ solution in THF was added at 0 ° C., and the mixture was stirred at the same temperature for 19 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution at 0 ° C., and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in toluene (2.5 ml). To the solution, 2.9 ml (1.04 M, 3.0 mmol) of DIBAL-H in toluene was added at 0 ° C. and stirred at the same temperature for 1.5 hours. After adding 10% aqueous sodium potassium tartrate solution to the reaction solution, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel flash column chromatography (hexane: ethyl acetate = 10: 1) to obtain 207 mg of compound (O) (4R / 5S). Yield 65%. Amorphous solid.
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.89 (t, J = 7.2 Hz, 3 H), 1.01 (d, J = 6.6 Hz 3 H), 1.10-1.75 (m, 17 H), 1.85-2.05 (m, 3 H), 2.20 (dt, J = 10.0, 4.8 Hz, 1 H), 2.81 (br s, 2 H), 2.88 (m, 1 H), 3.70 (dt, J = 10.0, 6.2 Hz, 1 H), 3.98 (d, J = 12.5 Hz, 1 H), 4.10 (d, J = 12.5 Hz, 1 H), 4.96 (d, J = 1.7 Hz, 1 H), 5.21 (s, 1 H), 5.64 (s, 1 H).
LRMS m / z 426 (M ⁺ ), 408, 329, 298, 256, 227, 175
HRMS calcd for C ₂₃ H ₃₉ O ₂ ⁷⁹ Br 426.2134, found 426.2117

(5) The same reaction as in Example 15 (5) was carried out using 283 mg (0.556 mmol) of the compound (O) (4R / 5S) obtained above to give the compound (4anti) (Z = (2-1 ), Y = Br, R ^2c = Bu, 4R / 5S). Yield 98%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.58 (s, 3 H), 0.92 (d, J = 6.8 Hz, 3 H), 1.07 (d, J = 6.1 Hz, 3 H), 1.18-1.74 (m, 17 H), 1.88-2.08 (m, 3 H), 2.60 (m, 1 H), 2.88 (m, 1 H), 4.25 (dt, J = 4.2, 6.2 Hz, 1 H), 5.58 (d, J = 2.3 Hz, 1 H), 5.65 (s, 1 H), 6.26 (d, J = 2.3 Hz, 1 H).
LRMS m / z 422 (M ⁺ ), 343, 281, 227
HRMS calcd for C ₂₃ H ₃₅ O ₂ ⁷⁹ Br 422.1820, found 422.1820

(6) 38 mg (90 μmol) of the compound (4anti) (Z = (2-1), Y = Br, R ^2c = Bu, 4R / 5S) obtained above and the compound (7) (R ³ = TBS, R ⁶ = Me, 3α / 4α / 5β) 52 mg (135 μmol) was used to carry out the same reaction as in Example 14 (2-a). 23 mg of 205c was obtained. Yield 51%.
Compound No. 205c:
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.92 (t, J = 6.7 Hz, 3 H), 1.06 (d, J = 6.8 Hz, 3 H), 1.07 (d, J = 7.1 Hz, 3 H), 1.20 (m, 1 H), 1.25-1.75 (m, 18 H), 1.85-2.06 (m, 4 H), 2.23 (dd, J = 13.4, 7.8 Hz, 1 H), 2.60 (m, 1 H), 2.67 (dd, J = 13.4, 4.0 Hz, 1 H), 2.82 (m, 1 H), 3.61 (m, 1 H), 4.25 (dt, J = 3.5, 6.2 Hz, 1 H), 4.31 (m, 1 H), 5.00 (d, J = 1.7 Hz, 1 H), 5.27 (s, 1 H), 5.58 (d, J = 2.3 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.25 (d, J = 2.3 Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H).
LRMS m / z 496 (M ⁺ ), 478, 460, 434, 265
HRMS calcd for C ₃₂ H ₄₈ O ₄ 496.3553, found 496.3545

[Example 19]
2α-Methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -butyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z), 7 (E ), 10 (19) -triene-1α, 3β-diol (Compound No. 205d)

(1) Using the compound (4syn) obtained in Example 17 (1) (Z = (2-1), Y = Br, R ^2c = Bu / hydrogen atom, 4S / 5S) 20 mg (0.048 mmol) In the same manner as in Example 12 (1), 19 mg of compound (O) (4S / 5S) was obtained. Yield 93%. Colorless solid.
¹ H-NMR (CDCl ₃ ) δ: 0.58 (s, 3 H), 0.89 (t, J = 7.1 Hz, 3 H), 1.01 (d, J = 6.3 Hz, 3 H), 0.95-1.75 (m, 17 H), 1.90-2.05 (m, 3 H), 2.18 (ddd, J = 8.8, 5.4, 2.7 Hz, 1 H), 2.55 (br s, 2 H), 2.88 (m, 1 H), 3.73 ( dt, J = 2.7, 6.6 Hz, 1 H), 4.03 (d, J = 12.9 Hz, 1 H), 4.11 (d, J = 12.9 Hz, 1 H), 4.96 (d, J = 1.1 Hz, 1 H ), 5.18 (d, J = 1.1 Hz, 1 H), 5.65 (s, 1 H).
EI-LRMS m / z 426 (M ⁺ ), 409, 329, 298, 256, 227, 175
HRMS calcd for C ₂₃ H ₃₉ O ₂ ⁷⁹ Br 426.2134, found 426.2151

(2) The same reaction as in Example 12 (2) was carried out using 355 mg (0.831 mmol) of the compound (O) (4S / 5S) obtained above, and the compound (5syn) (Z = (2-1) ), Y = Br, R ^2c = Bu, R ⁸ = Piv, 4S / 5S). Yield 81%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.89 (t, J = 7.1 Hz, 3 H), 1.02 (d, J = 6.4 Hz, 3 H), 1.10-1.73 (m, 17 H), 1.23 (s, 9 H), 1.78 (br d, J = 4.4 Hz, 1 H), 1.90-2.04 (m, 3 H), 2.07 (ddd, J = 10.6, 3.9, 3.9 Hz, 1 H), 2.88 (m, 1 H), 3.70 (m, 1 H), 4.48 (d, J = 13.9 Hz, 1 H), 4.56 (d, J = 13.9 Hz, 1 H), 5.00 (s, 1 H), 5.21 (d, J = 0.98 Hz, 1 H), 5.64 (s, 1 H).
LRMS m / z 510 (M ⁺ ), 492, 212, 175, 110
HRMS calcd for C ₂₈ H ₄₇ O ₃ ⁷⁹ Br 510.2709, found 510.2737

(3) Example using 346 mg (0.676 mmol) of the compound (5syn) obtained above (Z = (2-1), Y = Br, R ^2c = Bu, R ⁸ = Piv, 4S / 5S) performs the same reaction as 12 (3), the compound (6) was obtained ^{(Z = (2-1), Y} = Br, R 2c = Bu, R 8 = Piv, 4S) and 294 mg. Yield 85%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 0.88 (t, J = 7.2 Hz, 3 H), 0.92 (d, J = 6.4 Hz, 3 H), 1.22 (s, 9 H ), 1.15-1.72 (m, 13 H), 1.75-1.88 (m, 2 H), 1.94-2.05 (m, 3 H), 2.23 (dd, J = 16.8, 10.0 Hz, 1 H), 2.52 (dd , J = 16.8, 2.9 Hz, 1 H), 2.88 (m, 1 H), 3.06 (t, J = 7.3 Hz, 1 H), 4.50 (s, 2 H), 5.07 (s, 1 H), 5.20 (s, 1 H), 5.64 (s, 1 H).
LRMS m / z 508 (M ⁺ ), 423, 407, 351, 279, 237, 175
HRMS calcd for C ₂₈ H ₄₅ O ₃ ⁷⁹ Br 508.2552, found 508.2534

(4) Example 13 (0.556 mmol) using the compound (6) obtained above (Z = (2-1), Y = Br, R ^2c = Bu, R ⁸ = Piv, 4S) 4) and carrying out the same reaction, the compound ^{(5anti) (Z = (2-1} ), Y = Br, to give ^{R 2c = Bu, R 8 =} Piv, 4S / 5R) of 53 mg. Yield 75%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 0.88 (t, J = 6.8 Hz, 3 H), 0.96 (d, J = 6.4 Hz, 3 H), 1.10-1.80 (m, 17 H), 1.23 (s, 9 H), 1.85-2.10 (m, 4 H), 2.19 (d, J = 3.4 Hz, 1 H), 2.87 (m, 1 H), 3.62 (m, 1 H) , 4.45 (d, J = 13.9 Hz, 1 H), 4.57 (d, J = 13.9 Hz, 1 H), 5.03 (s, 1 H), 5.18 (s, 1 H), 5.64 (s, 1 H) .
LRMS m / z 510 (M ⁺ ), 477, 409, 311, 212, 175, 110
HRMS calcd for C ₂₈ H ₄₇ O ₃ ⁷⁹ Br 510.2709, found 510.2708

(5) Example using 260 mg (0.506 mmol) of the compound (5anti) obtained above (Z = (2-1), Y = Br, R ^2c = Bu, R ⁸ = Piv, 4S / 5R) performs the same reaction and 13 (5), compound (4Anti) to give ^{(Z = (2-1), Y} = Br, R 2c = Bu, 4S / 5R) of 197 mg. Yield 98%. Colorless amorphous solid.
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 0.93 (t, J = 6.8 Hz, 3 H), 1.03 (d, J = 6.3 Hz, 3 H), 1.20-1.92 (m, 18 H), 1.98 (dd, J = 12.5, 7.2 Hz, 1 H), 2.03 (br d, J = 12.5 Hz, 1 H), 2.55 (m, 1 H), 2.88 (m, 1 H), 4.27 (ddd, J = 11.0, 4.9, 2.0 Hz, 1 H), 5.58 (d, J = 2.4 Hz, 1 H), 5.65 (s, 1 H), 6.26 (d, J = 2.4 Hz, 1 H).
LRMS m / z 422 (M ⁺ ), 343, 281, 227
HRMS calcd for C ₂₃ H ₃₅ O ₂ ⁷⁹ Br 422.1820, found 422.1819

(6) 35 mg (82 μmol) of the compound (4anti) (Z = (2-1), Y = Br, R ^2c = Bu, 4S / 5R) obtained above and the compound (7) (R ³ = TBS, R ⁶ = Me, 3α / 4α / 5β) Using 47 mg (123 μmol), the same reaction as in Example 14 (2-a) was carried out. 20 mg of 205d was obtained. Yield 50%.
Compound No. 205d:
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.93 (t, J = 7.0 Hz, 3 H), 1.03 (d, J = 6.6 Hz, 3 H), 1.20-2.08 (m, 24 H), 2.31 (dd, J = 13.6, 6.4 Hz, 1 H), 2.55 (m, 1 H), 2.60 (dd, J = 13.6, 3.1 Hz, 1 H), 2.83 (m, 1 H), 4.23 (m, 1 H), 4.27 (ddd, J = 11.1, 4.9, 2.1 Hz, 1 H), 4.43 (m, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.57 (d, J = 2.6 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.26 (d, J = 2.6 Hz, 1 H), 6.37 (d, J = 11.2 Hz, 1 H) .
LRMS m / z 482 (M ⁺ ), 464, 446, 251, 153
HRMS calcd for C ₃₁ H ₄₆ O ₄ 482.3396, found 482.3398

[Example 20]
2α-Methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -isobutyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z), 7 (E ), 10 (19) -triene-1α, 3β-diol (compound No. 206a) and 2α-methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -isobutyl-5 ( Production of S) -yl) methyl-9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene-1α, 3β-diol (Compound No. 206b)

(1) Example 11 using 30 mg (0.101 mmol) of the compound (2) (Z = (2-1), Y = Br) obtained by a method known in the literature (for example, International Publication WO95 / 33716). The same reaction as in (1) was performed, 23.5 mg (yield 55%) of compound (4syn) (Z = (2-1), Y = Br, R ^2c = i-Bu, 4R / 5R), and 16.9 mg (yield 39%) of compound (4syn) (Z = (2-1), Y = Br, R ^2c = i-Bu, 4S / 5S) was obtained. However, the compound (3) obtained by using methyl acrylate instead of ethyl acrylate in the same manner as in Reference Example 6 instead of compound (3) (R ^2c = Me, R ⁷ = Me) in Example 11 (1) ) (R ^2c = i-Bu, R ⁷ = Me).
Compound (4syn) (Z = (2-1), Y = Br, R ^2c = i-Bu, 4R / 5R):
[α] _D ²⁴ +146.2 (c 1.55, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.95 (d, J = 2.5 Hz, 3 H), 0.96 (d, J = 2.4 Hz, 3 H), 1.01 (d, J = 6.3 Hz, 3 H), 1.09 (ddd, J = 14.3, 10.7, 2.0 Hz, 1 H), 1.20-1.92 (m, 14 H), 1.95-2.05 (m, 2 H), 2.88 (m, 1 H ), 3.09 (m, 1 H), 4.66 (ddd, J = 11.8, 7.1, 1.8 Hz, 1 H), 5.48 (d, J = 2.6 Hz, 1 H), 5.65 (br s, 1 H), 6.21 (d, J = 2.6 Hz, 1 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.9, 18.5, 22.0, 22.5 (2 C), 22.7, 24.9, 27.6, 31.0, 32.6, 36.3, 36.7, 40.0, 41.2, 45.6, 55.9, 56.3, 78.2, 97.7, 120.6, 139.6, 144.8, 170.6.
LRMS m / z 422 (M ⁺ ), 343, 257, 227
HRMS calcd for C ₂₃ H ₃₅ O ₂ ⁷⁹ Br 422.1820, found 422.1820
Compound (4syn) (Z = (2-1), Y = Br, R ^2c = i-Bu, 4S / 5S):
[α] _D ²⁴ +35.6 (c 0.76, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.58 (s, 3 H), 0.95 (d, J = 6.6 Hz, 6 H), 1.06 (d, J = 6.6 Hz, 3 H), 1.22-1.75 (m, 14 H), 1.89-2.06 (m, 3 H), 2.88 (m, 1 H), 3.02 (m, 1 H), 4.59 (m, 1 H), 5.48 (d, J = 2.1 Hz, 1 H) , 5.65 (s, 1 H), 6.19 (d, J = 2.1 Hz, 1 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.7, 19.8, 22.0 (2 C), 22.5, 23.0, 24.4, 27.7, 30.9, 34.5, 36.0, 36.1, 39.7, 41.5, 45.6, 55.7, 56.0, 80.4, 97.5, 120.6, 139.7, 144.9, 170.6.
LRMS m / z 422 (M ⁺ ), 343, 257, 227
HRMS calcd for C ₂₃ H ₃₅ O ₂ ⁷⁹ Br 422.1821, found 422.1819

(2-a) 21 mg (50 μmol) of the compound (4syn) (Z = (2-1), Y = Br, R ^2c = i-Bu, 4R / 5R) obtained above and the compound (7) (R ³ = TBS, R ⁶ = Me, 3α / 4α / 5β) 29 mg (75 μmol) was used to carry out the same reaction as in Example 14 (2-a), and compound No. 13.3 mg of 206a was obtained. Yield 53%.
Compound No. 206a:
[α] _D ²³ +112.6 (c 1.02, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.95 (d, J = 6.6 Hz, 3 H), 0.96 (d, J = 6.6 Hz, 3 H), 1.00 (d, J = 6.6 Hz, 3 H), 1.07 (d, J = 6.8 Hz, 3 H), 1.08 (m, 1 H), 1.18-2.05 (m, 19 H), 2.23 (dd, J = 13.5, 7.8 Hz, 1 H), 2.67 (d, J = 13.5, 4.0 Hz, 1 H), 2.82 (m, 1 H), 3.09 (m, 1 H), 3.85 (m, 1 H), 4.31 (m, 1 H), 4.66 (ddd, J = 11.6, 7.2, 1.6 Hz, 1 H), 5.00 (d, J = 2.0 Hz, 1 H), 5.28 (s, 1 H), 5.48 (d, J = 2.6 Hz, 1 H) , 6.00 (d, J = 11.4 Hz, 1 H), 6.20 (d, J = 2.6 Hz, 1 H), 6.37 (d, J = 11.4 Hz, 1 H).
¹³ C-NMR (CDCl ₃ ) δ: 12.1, 12.5, 18.5, 22.2, 22.5, 22.7, 23.5, 24.9, 27.6, 29.0, 32.6, 36.2, 36.7, 40.5, 41.2, 43.4, 44.1, 46.0, 56.3, 57.0, 71.7, 75.3, 78.3, 113.2, 117.1, 120.6, 124.6, 133.2, 139.6, 142.7, 146.5, 170.6.
LRMS m / z 496 (M ⁺ ), 478, 460, 434, 265
HRMS calcd for C ₃₂ H ₄₈ O ₄ 496.3552, found 496.3570

(2-b) 21 mg (49 μmol) of the compound (4syn) (Z = (2-1), Y = Br, R ^2c = i-Bu, 4S / 5S) obtained above and the compound (7) (R ³ = TBS, R ⁶ = Me, 3α / 4α / 5β) Using 28 mg (74 μmol), the same reaction as in Example 14 (2-a) was carried out. 12 mg of 206b was obtained. Yield 49%.
Compound No. 206b:
[α] _D ²⁴ +11.9 (c 0.92, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.94 (d, J = 6.4 Hz, 3 H), 0.95 (d, J = 6.6 Hz, 3 H), 1.05 (d, J = 6.6 Hz, 3 H), 1.08 (d, J = 6.8 Hz, 3 H), 1.20-1.7 (m, 16 H), 1.88-2.08 (m, 4 H), 2.23 (dd, J = 13.6, 7.8 Hz , 1 H), 2.67 (dd, J = 13.6, 3.9 Hz, 1 H), 2.83 (m, 1 H), 3,02 (m, 1 H), 3.84 (m, 1 H), 4.30 (br s , 1 H), 4.58 (ddd, J = 8.7, 6.4, 4.6 Hz, 1 H), 5.00 (d, J = 2.0 Hz, 1 H), 5.28 (d, J = 2.0 Hz, 1 H), 5.48 ( d, J = 2.1 Hz, 1 H), 6.01 (d, J = 11.4 Hz, 1 H), 6.19 (d, J = 2.1 Hz, 1 H), 6.38 (d, J = 11.4 Hz, 1 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.9, 12.5, 19.8, 22.0, 22.2, 23.1, 23.5, 24.4, 27.9, 29.0, 34.5, 35.9, 36.1, 40.4, 41.4, 43.5, 44.2, 46.0, 56.1, 56.9, 71.7, 75.4, 80.6, 113.2, 117.1, 120.6, 124.7, 133.2, 139.8, 142.8, 146.5, 170.7.
LRMS m / z 496 (M ⁺ ), 478, 460, 434, 265
HRMS calcd for C ₃₂ H ₄₈ O ₄ 496.3553, found 496.3553

[Example 21]
2α-Methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -isobutyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z), 7 (E ), 10 (19) -triene-1α, 3β-diol (Compound No. 206c)

(1) Using the compound (4syn) (Z = (2-1), Y = Br, R ^2c = i-Bu, 4R / 5R) 10 mg (0.024 mmol) obtained in Example 20 (1) Reaction similar to Example 12 (1) was performed, and 10 mg of compounds (P) (4R / 5R) were obtained. Yield 96%. Colorless oil.
[α] _D ¹⁸ +99.7 (c 0.86, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 0.83 (d, J = 6.4 Hz, 3 H), 0.90 (d, J = 6.4 Hz, 3 H), 0.96 (d, J = 6.6 Hz, 3 H), 1.01 (m, 1 H), 1.20-1.35 (m, 4 H), 1.40-1.75 (m, 9 H), 1.85-2.05 (m, 3 H), 2.24 (dt, J = 10.6, 3.9 Hz, 1 H), 2.36 (br s, 2 H), 2.88 (m, 1 H), 3.68 (ddd, J = 10.6, 4.2, 1.8 Hz, 1 H), 4.04 (dd, J = 13.2, 0.7 Hz, 1 H), 4.09 (dd, J = 13.2, 0.7 Hz, 1 H), 4.92 (s, 1 H), 5.18 (d, J = 1.2 Hz, 1 H), 5.64 (s, 1 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.8, 18.7, 21.4, 21.9, 22.4, 23.9, 25.3, 27.7, 30.9, 32.8, 37.2, 39.8, 40.5, 45.5, 48.6, 55.9, 56.3, 65.6, 71.5, 97.4, 114.1, 144.9, 149.1.
LRMS m / z 426 (M ⁺ ), 408, 365, 351, 329, 298, 256, 227, 175, 147
HRMS calcd for C ₂₃ H ₃₉ O ₂ ⁷⁹ Br 426.2134, found 426.2146

(2) The same reaction as in Example 12 (2) was carried out using 219 mg (0.513 mmol) of the compound (P) (4R / 5R) obtained above to give the compound (5syn) (Z = (2-1 ^), Y = ^Br, to give ^{R 2c = i-Bu, R} 8 = Piv, 4R / 5R) of 222 mg. Yield 84%. Colorless oil.
[α] _D ²⁴ +84.6 (c 1.16, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.85 (d, J = 6.6 Hz, 3 H), 0.90 (d, J = 6.6 Hz, 3 H), 0.95 (d, J = 6.6 Hz, 3 H), 1.03 (ddd, J = 13.7, 11.0, 1.7 Hz, 1 H), 1.24 (s, 9 H), 1.20-1.75 (m, 14 H), 1.87-2.05 (m, 3 H ), 2.16 (ddd, J = 11.1, 4.6, 4.6 Hz, 1 H), 2.87 (m, 1 H), 3.64 (ddd, J = 10.0, 4.5, 4.5 Hz, 1 H), 4.51 (s, 2 H ), 4.95 (s, 1 H), 5.16 (s, 1 H), 5.64 (s, 1 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.9, 18.7, 21.5, 22.0, 22.5, 24.0, 25.3, 27.2 (3 C), 27.8, 31.0, 32.9, 37.7, 38.8, 39.9, 40.9, 45.6, 48.1, 55.9, 56.3, 66.1, 70.9, 97.4, 112.6, 144.9, 145.0, 178.2.
LRMS m / z 510 (M ⁺ ), 492, 408, 212, 156
HRMS calcd for C ₂₈ H ₄₇ O ₃ ⁷⁹ Br 510.2709, found 510.2695

(3) Using the compound (5syn) obtained above (Z = (2-1), Y = Br, R ^2c = i-Bu, R ⁸ = Piv, 4R / 5R) 202 mg (0.394 mmol) performs the same reaction as in example 12 (3), the compound (6) was obtained ^{(Z = (2-1), Y} = Br, R 2c = i-Bu, R 8 = Piv, 4R) and 168 mg. Yield 84%. Colorless oil.
[α] _D ²⁶ +6.44 (c 0.82, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.87 (d, J = 6.7 Hz, 3 H), 0.88 (d, J = 6.4 Hz, 3 H), 0.89 (d, J = 6.8 Hz, 3 H), 1.23 (s, 9 H), 1.20-1.75 (m, 11 H), 1.84 (m, 1 H), 1.95-2.05 (m, 3 H), 2.27 (dd, J = 16.9 , 10.0 Hz, 1 H), 2.47 (dd, J = 16.9, 2.5 Hz, 1 H), 2.87 (m, 1 H), 3.23 (t, J = 7.3 Hz, 1 H), 4.47 (d, J = 13.9 Hz, 1 H), 4.55 (d, J = 13.9 Hz, 1 H), 5.05 (s, 1 H), 5.20 (s, 1 H), 5.64 (s, 1 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.9, 19.7, 22.0, 22.4, 22.5, 22.6, 25.9, 27.2 (3 C), 27.7, 31.0, 32.1, 38.8, 39.1, 39.7, 45.5, 48.5, 54.3, 55.4, 55.8, 65.6, 97.5, 115.2, 141.6, 144.7, 177.7, 208.7.
LRMS m / z 508 (M ⁺ ), 429, 406, 350, 297, 227
HRMS calcd for C ₂₈ H ₄₅ O ₃ ⁷⁹ Br 508.2552, found 508.2542

(4) Example using 153 mg (0.30 mmol) of the compound (6) obtained above (Z = (2-1), Y = Br, R ^2c = i-Bu, R ⁸ = Piv, 4R) performs the same reaction as 12 (4), compound (4Anti) to give ^{(Z = (2-1), Y} = Br, R 2c = i-Bu, 4R / 5S) and 84 mg. Yield 69%. Colorless oil.
[α] _D ²⁵ +77.6 (c 0.82, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.58 (s, 3 H), 0.96 (d, J = 6.6 Hz, 3 H), 0.97 (d, J = 6.6 Hz, 3 H), 1.07 (d, J = 6.4 Hz, 3 H), 1.15-1.75 (m, 14 H), 1.88-2.05 (m, 3 H), 2.66 (m, 1 H), 2.88 (m, 1 H), 4.20 (ddd, J = 6.8 , 5.6, 3.9 Hz, 1 H), 5.57 (d, J = 2.3 Hz, 1 H), 5.65 (s, 1 H), 6.24 (d, J = 2.3 Hz, 1 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.8, 19.6, 22.0, 22.3, 22.5, 22.7, 25.2, 27.9, 31.0, 34.3, 39.7, 42.3, 43.1, 43.9, 45.5, 55.7 (2 C), 82.8, 97.5, 121.9, 139.5, 144.7, 170.2.
LRMS m / z 422 (M ⁺ ), 343, 257, 227
HRMS calcd for C ₂₃ H ₃₅ O ₂ ⁷⁹ Br 422.1820, found 422.1820

(5) Compound (4anti) (Z = (2-1), Y = Br, R ^2c = i-Bu, 4R / 5S) 21 mg (49 μmol) obtained above and compound (7) (R ³ = TBS) , R ⁶ = Me, 3α / 4α / 5β) 28 mg (74 μmol), the same reaction as in Example 14 (2-a) was carried out. 13.1 mg of 206c was obtained. Yield 54%.
Compound No. 206c:
[α] _D ²⁴ +55.8 (c 1.01, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.95 (d, J = 6.3 Hz, 3 H), 0.96 (d, J = 6.6 Hz, 3 H), 1.06 (d, J = 6.1 Hz, 3 H), 1.08 (d, J = 6.8 Hz, 3 H), 1.15-1.75 (m, 16 H), 1.85-2.05 (m, 4 H), 2.23 (dd, J = 13.4, 7.8 Hz , 1 H), 2.63-2.71 (m, 2 H), 2.82 (m, 1 H), 3.84 (ddd, J = 7.6, 7.6, 4.2 Hz, 1 H), 4.20 (m, 1 H), 4.30 ( br s, 1 H), 5.00 (d, J = 2.0 Hz, 1 H), 5.27 (dd, J = 1.7, 1.0 Hz, 1 H), 5.57 (d, J = 2.3 Hz, 1 H), 6.01 ( d, J = 11.2 Hz, 1 H), 6.24 (d, J = 2.3 Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.9, 12.5, 19.6, 22.2, 22.3, 22.7, 23.4, 25.1, 27.9, 29.0, 34.3, 40.3, 42.3, 43.0, 43.4, 43.9, 44.2, 45.9, 56.2, 56.5, 71.7, 75.4, 83.0, 113.2, 117.1, 122.1, 124.7, 133.2, 139.7, 142.7, 146.5, 170.5.
LRMS m / z 496 (M ⁺ ), 478, 460, 434, 265
HRMS calcd for C ₃₂ H ₄₈ O ₄ 496.3553, found 496.3539

[Example 22]
2α-Methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -isobutyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z), 7 (E ), 10 (19) -triene-1α, 3β-diol (Compound No. 206d)

(1) Compound (4syn) obtained in Example 20 (1) (Z = (2-1), Y = Br, R ^2c = i-Bu / hydrogen atom, 4S / 5S) 11 mg (0.026 mmol) Was used for the same reaction as in Example 12 (1) to obtain 11 mg of Compound (P) (4S / 5S). Yield 95%. Amorphous solid.
[α] _D ²⁴ +83.7 (c 0.83, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.58 (s, 3 H), 0.83 (d, J = 6.4 Hz, 3 H), 0.91 (d, J = 6.6 Hz, 3 H), 1.01 (d, J = 6.3 Hz, 3 H), 1.10-1.73 (m, 14 H), 1.90-2.05 (m, 3 H), 2.32 (br d, J = 11.7 Hz, 1 H), 2.87 (m, 1 H), 3.03 (br s, 2 H), 3.74 (m, 1 H), 4.02 (d, J = 12.8 Hz, 1 H), 4.11 (d, J = 12.8 Hz, 1 H), 4.96 (s, 1 H), 5.17 (s, 1 H), 5.65 (s, 1 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.8, 19.4, 21.4, 22.0, 22.5, 24.2, 25.3, 27.8, 31.0, 34.2, 34.5, 39.8, 40.4, 45.5, 46.2, 55.8, 56.5, 65.0, 73.2, 97.5, 114.8, 144.9, 149.8.
LRMS m / z 409 ((M-OH) ⁺ ), 408, 351, 329, 298, 256, 227, 175, 147
HRMS calcd for C ₂₃ H ₃₈ O ⁷⁹ Br (M-OH) ⁺ 409.2106, found 409.2107

(2) The same reaction as in Example 12 (2) was carried out using 147 mg (0.343 mmol) of the compound (P) (4S / 5S) obtained above to obtain the compound (5syn) (Z = (2-1 ^), Y = ^Br, to give ^{R 2c = i-Bu, R} 8 = Piv, 4S / 5S) and 173 mg. Yield 99%. Colorless oil.
[α] _D ²³ +67.0 (c 1.17, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.84 (d, J = 6.4 Hz, 3 H), 0.91 (d, J = 6.3 Hz, 3 H), 1.01 (d, J = 6.4 Hz, 3 H), 1.15-1.70 (m, 14 H), 1.23 (s, 9 H), 1.80 (br s, 1 H), 1.90-2.05 (m, 3 H), 2,21 (br d , J = 11.7 Hz, 1 H), 2.87 (m, 1 H), 3.71 (m, 1 H), 4.49 (d, J = 14.2 Hz, 1 H), 4.58 (d, J = 14.2 Hz, 1 H ), 5.01 (s, 1 H), 5.21 (s, 1 H), 5.65 (s, 1 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.7, 19.5, 21.6, 22.0, 22.5, 24.2, 25.2, 27.2 (3 C), 27.8, 31.0, 34.5, 34.6, 38.8, 39.8, 40.3, 45.1, 45.5, 55.8, 56.4, 66.2, 71.9, 97.5, 112.9, 145.0, 145.2, 178.2.
LRMS m / z 510 (M ⁺ ), 492, 408, 391, 212, 110
HRMS calcd for C ₂₈ H ₄₇ O ₃ ⁷⁹ Br 510.2708, found 510.2713

(3) Using 140 mg (0.273 mmol) of the compound (5syn) obtained above (Z = (2-1), Y = Br, R ^2c = i-Bu, R ⁸ = Piv, 4S / 5S) performs the same reaction as in example 12 (3), the compound (6) was obtained ^{(Z = (2-1), Y} = Br, R 2c = i-Bu, R 8 = Piv, 4S) and 117 mg.
Yield 84%. Colorless oil.
[α] _D ²⁶ +128.7 (c 0.78, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 0.87 (d, J = 6.8 Hz, 3 H), 0.89 (d, J = 6.8 Hz, 3 H), 0.92 (d, J = 6.6 Hz, 3 H), 1.22 (s, 9 H), 1.20-1.75 (m, 11 H), 1.84 (m, 1 H), 1.95-2.05 (m, 3 H), 2.24 (dd, J = 16.8 , 9.8 Hz, 1 H), 2.53 (dd, J = 16.8, 2.7 Hz, 1 H), 2.88 (m, 1 H), 3.20 (t, J = 7.1 Hz, 1 H), 4.48 (d, J = 15.0 Hz, 1 H), 4.52 (d, J = 15.0 Hz, 1 H), 5.07, (s, 1 H), 5.20 (s, 1 H), 5.64 (s, 1 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.9, 20.1, 22.0, 22.4, 22.5, 22.7, 25.8, 27.2 (5 C), 27.6, 31.0, 32.6, 38.9, 39.8, 45.6, 48.1, 55.5, 55.9, 65.6, 97.5, 115.3, 141.7, 144.7, 177.7, 209.4.
LRMS m / z 508 (M ⁺ ), 429, 406, 350, 297, 227
HRMS calcd for C ₂₈ H ₄₅ O ₃ ⁷⁹ Br 508.2552, found 508.2556

(4) Example using 103 mg (0.20 mmol) of the compound (6) obtained above (Z = (2-1), Y = Br, R ^2c = i-Bu, R ⁸ = Piv, 4S) performs the same reaction and 13 (4), compound ^{(5anti) (Z = (2-1} ), Y = Br, R 2c = i-Bu, R 8 = Piv, 4S / 5R) to give 103 mg. Yield 100%. Colorless oil.
[α] _D ²⁵ +81.7 (c 0.82, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 0.85 (d, J = 6.6 Hz, 3 H), 0.89 (d, J = 6.6 Hz, 3 H), 0.93 (d, J = 6.6 Hz, 3 H), 1.10-1.80 (m, 14 H), 1.23 (s, 9 H), 1.92 (m, 1 H), 1.98 (ddd, J = 12.9, 6.6, 1.5 Hz, 1 H), 2.03 (ddd, J = 12.9, 2.7, 2.7 Hz, 1 H), 2.15 (ddd, J = 11.5, 7.6, 4.2 Hz, 1 H), 2.24 (br d, J = 3.4 Hz, 1 H), 2.87 ( m, 1 H), 3.59 (m, 1 H), 4.45 (d, J = 14.2 Hz, 1 H), 2.47 (d, J = 14.2 Hz, 1 H), 5.04 (s, 1 H), 5.18 ( s, 1 H), 5.64 (s, 1 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.9, 18.8, 21.5, 22.1, 22.6, 24.0, 25.6, 27.2 (3 C), 27.8, 31.0, 32.8, 38.7, 38.8, 39.9, 41.5, 45.6, 50.6, 56.0, 56.5, 64.9, 70.2, 97.4, 114.6, 144.0, 144.9, 178.3.
LRMS m / z 510 (M ⁺ ), 492, 408, 212, 156
HRMS calcd for C ₂₈ H ₄₇ O ₃ ⁷⁹ Br 510.2708, found 510.2701

(5) Using 103 mg (0.201 mmol) of the compound (5anti) obtained above (Z = (2-1), Y = Br, R ^2c = i-Bu, R ⁸ = Piv, 4S / 5R) performs the same reaction as in example 13 (5), compound (4Anti) to give ^{(Z = (2-1), Y} = Br, R 2c = i-Bu, 4S / 5R) of 77 mg.
Yield 90%.
[α] _D ²⁵ +119.2 (c 0.73, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 0.95 (d, J = 6.6 Hz, 3 H), 0.96 (d, J = 6.6 Hz, 3 H), 1.02 (d, J = 6.6 Hz, 3 H), 1.20-1.95 (m, 15 H), 1.97 (ddd, J = 12.3, 6.8, 1.7 Hz, 1 H), 2.02 (ddd, J = 12.3, 2.9, 2.4 Hz, 1 H) , 2.62 (m, 1 H), 2.89 (m, 1 H), 4.24 (ddd, J = 11.1, 4.6, 2.2 Hz, 1 H), 5.56 (d, J = 2.6 Hz, 1 H), 5.65 (s , 1 H), 6.24 (d, J = 2.6 Hz, 1 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.9, 18.5, 22.0, 22.2, 22.5, 22.9, 25.3, 27.6, 31.0, 32.9, 39.9, 43.0, 43.1, 43.5, 45.6, 55.8, 56.1, 81.2, 97.5, 121.7, 139.8, 144.6, 170.2.
LRMS m / z 422 (M ⁺ ), 343, 257, 227
HRMS calcd for C ₂₃ H ₃₅ O ₂ ⁷⁹ Br 422.1821, found 422.1820

(6) 23 mg (53 μmol) of the compound (4anti) (Z = (2-1), Y = Br, R ^2c = i-Bu, 4S / 5R) obtained above and the compound (7) (R ³ = TBS) , R ⁶ = Me, 3α / 4α / 5β) 31 mg (80 μmol), the same reaction as in Example 14 (2-a) was carried out. 13.1 mg of 206d was obtained. Yield 49%.
Compound No. 206d:
[α] _D ²⁴ +85.3 (c 0.60, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.95 (d, J = 6.6 Hz, 3 H), 0.96 (d, J = 6.3 Hz, 3 H), 1.02 (d, J = 6.6 Hz, 3 H), 1.05 (d, J = 6.8 Hz, 3 H), 1.18-1.35 (m, 4 H), 1.40-208 (m, 16 H), 2.23 (dd, J = 13.6, 7.9 Hz , 1 H), 2.62 (m, 1 H), 2.67 (dd, J = 13.6, 3.8 Hz, 1 H), 2.83 (m, 1 H), 3.85 (m, 1 H), 4.24 (ddd, J = 10.9, 4.8, 2.0 Hz, 1 H), 4.31 (m, 1 H), 5.00 (d, J = 1.7 Hz, 1 H), 5.28 (s, 1 H), 5.56 (d, J = 2.2 Hz, 1 H), 6.50 (d, J = 11.4 Hz, 1 H), 6.24 (d, J = 11.2 Hz, 1 H), 6.38 (d, J = 11.4 Hz, 1 H).
¹³ C-NMR (CDCl ₃ ) δ: 12.1, 12.5, 18.5, 22.1, 22.2, 22.9, 23.5, 25.2, 27.5, 29.0, 33.0, 40.5, 43.0, 43.1, 43.4, 43.5, 44.2, 46.0, 56.3, 56.9, 71.7, 75.4, 81.4, 113.2, 117.1, 121.8, 124.6, 133.2, 140.0, 142.7, 146.5, 170.5.
LRMS m / z 496 (M ⁺ ), 478, 460, 434, 265
HRMS calcd for C ₃₂ H ₄₈ O ₄ 496.3552, found 496.3554

[Example 23]
2α- (3-hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-5 (R) -yl) methyl-9,10-secopregna-5 (Z), 7 (E), Production of 10 (19) -triene-1α, 3β-diol (Compound No. 801a)

Compound (4) (Z = (2-1), Y = Br, R ^2d = R ^2e = H, 5R) 14 mg (38 μmol) obtained by a method known in the literature (for example, International Publication WO95 / 33716) Compound (7) (R ³ = TBS, R ⁶ =-(CH ₂ ) ₃ OTBS, 3α / 4α / 5β) was used in the same manner as in Example 14 (2-a) using 31 mg (57 μmol) to give compound No. 10 mg of 801a was obtained. Yield 56%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 1.02 (d, J = 6.3 Hz, 3 H), 1.26-1.82 (m, 19 H), 1.96-2.04 (m, 3 H) , 2.25 (dd, J = 13.1, 8.3 Hz, 1 H), 2.52 (m, 1 H), 2.67 (dd, J = 13.1, 4.0 Hz, 1 H), 2.84 (m, 1 H), 3.03 (m , 1 H), 3.71 (t, J = 5.3 Hz, 2 H), 3.90 (ddd, J = 8.3, 8.3, 4.5 Hz, 1 H), 4.38 (d, J = 2.0 Hz, 1 H), 4.64 ( m, 1 H), 4.99 (s, 1 H), 5.28 (s, 1 H), 5.62 (s, 1 H), 6.00 (d, J = 11.2 Hz, 1 H), 6.23 (s, 1 H) , 6.39 (d, J = 11.2 Hz, 1 H).
LRMS m / z 484 (M ⁺ ), 466, 448, 438, 389, 338, 309, 253
HRMS calcd for C ₃₀ H ₄₄ O ₅ 484.3189, found 484.3174

[Example 24]
2α- (3-hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-5 (S) -yl) methyl-9,10-secopregna-5 (Z), 7 (E), Production of 10 (19) -triene-1α, 3β-diol (Compound No. 801b)

Compound (4) (Z = (2-1), Y = Br, R ^2d = R ^2e = H, 5S) 12 mg (33 μmol) obtained by a method known in the literature (for example, International Publication WO95 / 33716) Compound (7) (R ³ = TBS, R ⁶ =-(CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 27 mg (49 μmol) was used, and the same reaction as in Example 14 (2-a) was carried out to give compound No. 7.0 mg of 801b was obtained. Yield 45%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 1.03 (d, J = 6.3 Hz, 3 H), 1.22-1.73 (m, 19 H), 1.88-2.04 (m, 3 H) , 2.25 (dd, J = 13.0, 8.8 Hz, 1 H), 2.54 (dddd, J = 16.8, 6.3, 3.1, 3.1 Hz, 1 H), 2.66 (dd, J = 13.0, 4.4 Hz, 1 H), 2.83 (m, 1 H), 3.05 (dddd, J = 16.8, 7.4, 2.3, 2.3 Hz, 1 H), 3.70 (t, J = 5.0 Hz, 2 H), 3.89 (ddd, J = 8.3, 8.3, 4.3 Hz, 1 H), 4.38 (d, J = 2.4 Hz, 1 H), 4.59 (ddt, J = 6.4, 6.3, 5.0 Hz, 1 H), 4.99 (d, J = 2.0 Hz, 1 H), 5.28 (m, 1 H), 5.62 (dd, J = 3.1, 2.3 Hz, 1 H), 5.99 (d, J = 11.4 Hz, 1 H), 6.22 (dd, J = 3.1, 2.3 Hz, 1 H) , 6.40 (d, J = 11.4 Hz, 1 H).
LRMS m / z 484 (M ⁺ ), 466, 448, 438, 389, 338, 309, 253
HRMS calcd for C ₃₀ H ₄₄ O ₅ 484.3189, found 484.3176

[Example 25]
2α- (3-hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -methyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 802a)

19 mg (44 μmol) of the compound (4syn) (Z = (2-1), Y = Br, R ^2c = Me, 4R / 5R) obtained in Example 11 (1) and the compound (7) (R ³ = TBS) , R ⁶ = — (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 41 mg (76 μmol), the same reaction as in Example 14 (2-a) was carried out. 16.6 mg of 802a was obtained. Yield 66%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 1.00 (d, J = 6.6 Hz, 3 H), 1.09 (m, 1 H), 1.13 (d, J = 7.1 Hz, 3 H ), 1.20-1.85 (m, 16 H), 1.90-2.10 (m, 3 H), 2.24 (dd, J = 13.3, 8.8 Hz, 1 H), 2.35 (br s, 2 H), 2.65 (dd, J = 13.3, 4.2 Hz, 1 H), 2.82 (m, 1 H), 3.16 (m, 1 H), 3.60-3.75 (m, 2 H), 2.89 (ddd, J = 8.8, 8.3, 4.2 Hz, 1 H), 4.37 (d, J = 2.7 Hz, 1 H), 4.68 (ddd, J = 11.7, 7.6, 1.8 Hz, 1 H), 4.98 (d, J = 1.9 Hz, 1 H), 5.27 (d , J = 1.5 Hz, 1 H), 5.53 (d, J = 2.6 Hz, 1 H), 5.99 (d, J = 11.2 Hz, 1 H), 6.21 (d, J = 2.6 Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H).
LRMS m / z 498 (M ⁺ ), 480, 462
HRMS calcd for C ₃₁ H ₄₆ O ₅ 498.3345, found 498.3337

[Example 26]
2α- (3-hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -methyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 802b)

Compound (4syn) obtained in Example 11 (1) (Z = (2-1), Y = Br, R ^2c = Me, 4S / 5S) 18 mg (46 μmol) and compound (7) (R ³ = TBS) , R ⁶ = — (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 38 mg (70 μmol) was used to carry out the same reaction as in Example 14 (2-a), and compound No. 14.1 mg of 802b was obtained. Yield 61%.
¹ H-NMR (CDCl ₃ ) δ: 0.54 (s, 3 H), 1.04 (d, J = 6.4 Hz, 3 H), 1.13 (d, J = 7.1 Hz, 3 H), 1.20-2.20 (m, 22 H), 2.24 (dd, J = 13.1, 8.9 Hz, 1 H), 2.65 (dd, J = 13.1, 2.9 Hz, 1 H), 2.82 (m, 1 H), 3.10 (m, 1 H), 3.60-3.75 (m, 2 H), 3.88 (m, 1 H), 4.37 (br d, J = 2.4 Hz, 1 H), 4.58 (m, 1 H), 4.98 (s, 1 H), 5.26 ( s, 1 H), 5.53 (d, J = 1.8 Hz, 1 H), 5.99 (d, J = 11.2 Hz, 1 H), 6.18 (d, J = 1.8 Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H).
LRMS m / z 498 (M ⁺ ), 480, 462, 452
HRMS calcd for C ₃₁ H ₄₆ O ₅ 498.3345, found 498.3350

[Example 27]
2α- (3-hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -methyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 802c)

Compound (4anti) (Z = (2-1), Y = Br, R ^2c = Me, 4R / 5S) 21 mg (56 μmol) obtained in Example 12 (4) and compound (7) (R ³ = TBS) , R ⁶ = — (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 45 mg (83 μmol) was used to carry out the same reaction as in Example 14 (2-a). 15.1 mg of 802c was obtained. Yield 54%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 1.05 (d, J = 5.9 Hz, 3 H), 1.24 (d, J = 6.8 Hz, 3 H), 1.20-1.75 (m, 15 H), 1.85-2.05 (m, 5 H), 2.24 (dd, J = 13.3, 8.9 Hz, 1 H), 2.31 (br s, 2 H), 2.58-2.70 (m, 2 H), 2.82 ( m, 1 H), 3.60-3.75 (m, 2 H), 3.87 (m, 1 H), 4.07 (dt, J = 5.9, 6.4 Hz, 1 H), 4.36 (br d, J = 2.7 Hz, 1 H), 4.98 (d, J = 1.7 Hz, 1 H), 5.26 (d, J = 1.7 Hz, 1 H), 5.52 (d, J = 2.8 Hz, 1 H), 5.99 (d, J = 11.5 Hz , 1 H), 6.21 (d, J = 2.8 Hz, 1 H), 6.38 (d, J = 11.5 Hz, 1 H).
LRMS m / z 498 (M ⁺ ), 480, 462
HRMS calcd for C ₃₁ H ₄₆ O ₅ 498.3345, found 498.3344

[Example 28]
2α- (3-hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -methyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 802d)

Compound (4anti) (Z = (2-1), Y = Br, R ^2c = Me, 4S / 5R) 10 mg (26 μmol) obtained in Example 13 (5) and compound (7) (R ³ = TBS) , R ⁶ = — (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 21 mg (39 μmol), the same reaction as in Example 14 (2-a) was carried out. 2.3 mg of 802d was obtained. Yield 26%.
¹ H-NMR (10% CD ₃ OD in CDCl ₃ ) δ: 0.47 (s, 3 H), 0.93 (d, J = 6.4 Hz, 3 H), 1.15 (d, J = 6.8 Hz, 3 H), 1.12-1.80 (m, 20 H), 1.85-2.00 (m, 2 H), 2.15 (dd, J = 13.2, 9.3 Hz, 1 H), 2.50-2.60 (m, 2 H), 2.75 (m, 1 H), 3.50-3.60 (m, 2 H), 3.73 (ddd, J = 8.4, 8.4, 4.2 Hz, 1 H), 4.02 (m, 1 H), 4.22 (d, J = 2.4 Hz, 1 H) , 4.88 (d, J = 2.0 Hz, 1 H), 5.17 (d, J = 2.0 Hz, 1 H), 5.48 (d, J = 2.9 Hz, 1 H), 5.95 (d, J = 11.2 Hz, 1 H), 6.13 (d, J = 2.9 Hz, 1 H), 6.29 (d, J = 11.2 Hz, 1 H).
LRMS m / z 498 (M ⁺ ), 481, 480, 462, 391
HRMS calcd for C ₃₁ H ₄₆ O ₅ 498.3346 found 498.3346

[Example 29]
2α- (3-hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -ethyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 803a)

Compound (4syn) obtained in Example 14 (1) (Z = (2-1), Y = Br, R ^2c = Et, 4R / 5R) 10 mg (25 μmol) and compound (7) (R ³ = TBS) , R ⁶ = — (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 21 mg (38 μmol), the same reaction as in Example 14 (2-a) was carried out. 7 mg of 803a was obtained. Yield 54%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.98 (t, J = 7.3 Hz, 3 H), 1.00 (d, J = 6.3 Hz, 3 H), 1.12 (ddd, J = 14.2, 10.5, 2.0 Hz, 1 H), 1.22-1.89 (m, 21 H), 1.97 (dd, J = 12.5, 7.4 Hz, 1 H), 2.02 (br d, J = 12.4 Hz, 1 H), 2.25 (dd, J = 13.4, 8.8 Hz, 1 H), 2.66 (dd, J = 13.4, 4.4 Hz, 1 H), 2.83 (m, 1 H), 2.88 (m, 1 H), 3.69 (m, 2 H), 3.90 (ddd, J = 8.4, 8.4, 4.4 Hz, 1 H), 4.38 (d, J = 3.3 Hz, 1 H), 4.66 (ddd, J = 11.7, 4.0, 1.8 Hz, 1 H) , 4.98 (d, J = 1.6 Hz, 1 H), 5.27 (d, J = 1.6 Hz, 1 H), 5.52 (d, J = 2.2 Hz, 1 H), 5.99 (d, J = 11.9 Hz, 1 H), 6.21 (d, J = 12.4 Hz, 1 H), 6.38 (d, J = 11.9 Hz, 1 H).
LRMS m / z 512 (M ⁺ ) 494, 476, 417, 309, 211, 133
HRMS calcd for C ₃₂ H ₄₈ O ₅ 512.3502, found 512.3522

[Example 30]
2α- (3-hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -ethyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 803b)

Compound (4syn) obtained in Example 14 (1) (Z = (2-1), Y = Br, R ^2c = Et, 4S / 5S) 21 mg (53 μmol) and compound (7) (R ³ = TBS) , R ⁶ = — (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 43 mg (80 μmol), the same reaction as in Example 14 (2-a) was carried out. 17 mg of 803b was obtained. Yield 62%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.95 (t, J = 7.3 Hz, 3 H), 1.04 (d, J = 6.3 Hz, 3 H), 1.25-2.04 (m, 22 H), 2.22-2.27 (m, 3 H), 2.65 (dd, J = 13.4, 4.3 Hz, 1 H), 2.77-2.84 (m, 2 H), 3.68 (m, 2 H), 3.88 (ddd , J = 8.0, 8.0, 4.2 Hz, 1 H), 4.37 (d, J = 2.2 Hz, 1 H), 4.57 (dt, J = 8.2, 5.7 Hz, 1 H), 4.98 (d, J = 1.4 Hz , 1 H), 5.26 (d, J = 1.4 Hz, 1 H), 5.51 (d, J = 1.6 Hz, 1 H), 6.00 (d, J = 11.1 Hz, 1 H), 6.20 (d, J = 1.6 Hz. 1 H), 6.39 (d, J = 11.1 Hz, 1 H).
LRMS m / z 512 (M ⁺ ) 494, 476, 417, 309, 211, 133
HRMS calcd for C ₃₂ H ₄₈ O ₅ 512.3502, found 512.3506

[Example 31]
2α- (3-hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -ethyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 803c)

Compound (4anti) (Z = (2-1), Y = Br, R ^2c = Et, 4R / 5S) 21 mg (53 μmol) obtained in Example 15 (5) and compound (7) (R ³ = TBS) , R ⁶ = — (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 43 mg (80 μmol), the same reaction as in Example 14 (2-a) was carried out. 17 mg of 803c was obtained. Yield 62%.
¹ H-NMR (CDCl ₃ ) δ: 0.54 (s, 3 H), 0.97 (t, J = 7.3 Hz, 3 H), 1.05 (d, J = 5.9 Hz, 3 H), 1.17-1.76 (m, 21 H), 1.85-2.27 (m, 7 H), 3.64-3.71 (m, 2 H), 3.88 (ddd, J = 8.3, 8.3, 4.4 Hz, 1 H), 4.26 (m, 1 H), 4.37 (d, J = 2.9 Hz, 1 H), 4.98 (d, J = 1.7 Hz, 1 H), 5.26 (d, J = 1.7 Hz, 1 H), 5.58 (d, J = 2.4 Hz, 1 H) , 5.97 (d, J = 11.2 Hz, 1 H), 6.27 (d, J = 2.4 Hz, 1 H), 6.38 (d, J = 11.2 Hz. 1 H).
LRMS m / z 512 (M ⁺ ) 494, 476, 417, 309, 211, 133
HRMS calcd for C ₃₂ H ₄₈ O ₅ 512.3502, found 512.3501

[Example 32]
2α- (3-hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -ethyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 803d)

Compound (4anti) (Z = (2-1), Y = Br, R ^2c = Et, 4S / 5R) 29 mg (73 μmol) obtained in Example 16 (5) and compound (7) (R ³ = TBS) , R ⁶ =-(CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 60 mg (110 μmol) was used to carry out a reaction similar to Example 14 (2-a), and compound No. 20 mg of 803d was obtained. Yield 53%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.97 (t, J = 7.4 Hz, 3 H), 1.02 (d, J = 6.6 Hz, 3 H), 1.22-2.03 (m, 22 H), 2.21-2.51 (m, 4 H), 2.65 (dd, J = 13.5, 4.3 Hz, 1 H), 2.82 (m, 1 H), 3.64-3.72 (m, 2 H), 3.88 (ddd , J = 8.0, 8.0, 4.5 Hz, 1 H), 4.28 (br dd, J = 10.5, 3.8 Hz, 1 H), 4.36 (J = 2.2 Hz, 1 H), 4.97 (s, 1 H), 5.26 (s, 1 H), 5.57 (d, J = 2.3 Hz, 1 H), 5.99 (d, J = 11.4 Hz, 1 H), 6.26 (d, J = 2.3 Hz, 1 H), 6.34 (d, J = 11.4 Hz, 1 H).
HRMS calcd for C ₃₂ H ₄₈ O ₅ 512.3502, found 512.3506

[Example 33]
2α- (3-Hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -butyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 806a)

Compound (4syn) (Z = (2-1), Y = Br, R ^2c = Bu, 4R / 5R) 60 mg (142 μmol) and compound (7) (R ³ = TBS) obtained in Example 17 (1) , R ⁶ =-(CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 115 mg (213 μmol), the same reaction as in Example 14 (2-a) was carried out. 40 mg of 806a was obtained. Yield 52%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.93 (t, J = 7.0 Hz, 3 H), 1.00 (d, J = 6.6 Hz, 3 H), 1.11 (ddd, J = 14.0, 10.7, 1.6 Hz, 1 H), 1.20-2.05 (m, 24 H), 2.11 (br s, 1 H), 2.24 (dd, J = 13.3, 8.7 Hz, 1 H), 2.49 (br s, 2 H), 2.65 (dd, J = 13.3, 4.2 Hz, 1 H), 2.83 (m, 1 H), 2.96 (m, 1 H), 3.63-3.73 (m, 2 H), 3.89 (m, 1 H), 4.37 (br d, J = 1.9 Hz, 1 H), 4.65 (ddd, J = 11.5, 7.1, 1.5 Hz, 1 H), 4.97 (d, J = 2.0 Hz, 1 H), 5.27 (d , J = 1.5 Hz, 1 H), 5.51 (d, J = 2.3 Hz, 1 H), 6.00 (d, J = 11.1 Hz, 1 H), 6.20 (d, J = 2.3 Hz, 1 H), 6.37 (d, J = 11.1 Hz, 1 H).
LRMS m / z 540 (M ⁺ ), 522, 504
HRMS calcd for C ₃₄ H ₅₂ O ₅ 540.3815, found 540.3818

[Example 34]
2α- (3-hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -butyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 806b)

Compound (4syn) (Z = (2-1), Y = Br, R ^2c = Bu, 4S / 5S) 42 mg (95 μmol) and compound (7) (R ³ = TBS) obtained in Example 17 (1) , R ⁶ = — (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 80 mg (148 μmol), the same reaction as in Example 14 (2-a) was carried out. 27 mg of 806b was obtained. Yield 52%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.92 (t, J = 7.1 Hz, 3 H), 1.05 (d, J = 6.6 Hz, 3 H), 1.15-1.80 (m, 21 H), 1.83-2.08 (m, 5 H), 2.25 (dd, J = 13.3, 8.8 Hz, 1 H), 2.48 (br s, 2 H), 2.65 (dd, J = 13.3, 4.2 Hz, 1 H), 2.83 (m, 1 H), 2.89 (m, 1 H), 3.63-3.75 (m, 2 H), 3.88 (ddd, J = 8.1, 8.1, 4.3 Hz, 1 H), 4.37 (br d , J = 2.7 Hz, 1 H), 4.57 (ddd, J = 8.3, 6.0, 5.2 Hz, 1 H), 4.98 (d, J = 2.0 Hz, 1 H), 5.27 (d, J = 1.5 Hz, 1 H), 5.50 (d, J = 1.8 Hz, 1 H), 6.00 (d, J = 11.2 Hz, 1 H), 6.19 (d, J = 1.8 Hz, 1 H), 6.39 (d, J = 11.2 Hz , 1 H).
LRMS m / z 540 (M ⁺ ), 522, 504
HRMS calcd for C ₃₄ H ₅₂ O ₅ 540.3815, found 540.3812

[Example 35]
2α- (3-Hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -butyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 806c)

Compound (4anti) (Z = (2-1), Y = Br, R ^2c = Bu, 4R / 5S) 40 mg (95 μmol) obtained in Example 18 (5) and compound (7) (R ³ = TBS) , R ⁶ =-(CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 77 mg (142 μmol) was used to carry out a reaction similar to Example 14 (2-a), and compound No. 28 mg of 806c was obtained. Yield 54%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.92 (t, J = 7.0 Hz, 3 H), 1.06 (d, J = 6.0 Hz, 3 H), 1.13-1.80 (m, 22 H), 1.83-2.08 (m, 4 H), 2.25 (dd, J = 13.4, 8.4 Hz, 1 H), 2.43 (br s, 2 H), 2.60 (m, 1 H), 2.65 (dd, J = 13.4, 4.3 Hz, 1 H), 2.83 (m, 1 H), 3.63-3.75 (m, 2 H), 3.99 (ddd, J = 8.4, 8.4, 4.3 Hz, 1 H), 4.25 (ddd, J = 6.2, 6.2, 4.4 Hz, 1 H), 4.37 (br d, J = 2.9 Hz, 1 H), 4.98 (d, J = 2.0 Hz, 1 H), 5.27 (d, J = 1.7 Hz, 1 H), 5.59 (d, J = 2.2 Hz, 1 H), 6.00 (d, J = 11.2 Hz, 1 H), 6.26 (d, J = 2.2 Hz, 1 H), 6.39 (d, J = 11.2 Hz , 1 H).
LRMS m / z 540 (M ⁺ ), 522, 504
HRMS calcd for C ₃₄ H ₅₂ O ₅ 540.3815, found 540.3815

[Example 36]
2α- (3-hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -butyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 806d)

30 mg (105 μmol) of the compound (4anti) (Z = (2-1), Y = Br, R ^2c = Bu, 4S / 5R) obtained in Example 19 (5) and the compound (7) (R ³ = TBS) , R ⁶ = — (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 57 mg (105 μmol) was used to carry out the same reaction as in Example 14 (2-a). 16 mg of 806d was obtained. Yield 40%.
¹ H-NMR (CDCl ₃ ) δ: 0.54 (s, 3 H), 0.92 (t, J = 6.8 Hz, 3 H), 1.01 (d, J = 6.3 Hz, 3 H), 1.20-1.85 (m, 23 H), 1.90-2.50 (m, 5 H), 2.24 (dd, J = 13.2, 8.4 Hz, 1 H), 2.54 (m, 1 H), 2.65 (dd, J = 13.2, 4.2 Hz, 1 H ), 2.82 (m, 1 H), 3.63-3.73 (m, 2 H), 3.88 (ddd, J = 8.4, 8.4, 4.2 Hz, 1 H), 4.26 (ddd, J = 10.8, 4.8, 1.8 Hz, 1 H), 4.36 (br d, J = 2.7 Hz, 1 H), 4.97 (d, J = 1.7 Hz, 1 H), 5.26 (d, J = 1.5 Hz, 1 H), 5.57 (d, J = 2.4 Hz, 1 H), 5.99 (d, J = 11.2 Hz, 1 H), 6.24 (d, J = 2.4 Hz, 1 H), 6.37 (d, J = 11.2 Hz, 1 H).
LRMS m / z 540 (M ⁺ ), 522, 504
HRMS calcd for C ₃₄ H ₅₂ O ₅ 540.38515, found 540.3815

[Example 37]
2α- (3-hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -isobutyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 807a)

19 mg (45 μmol) of the compound (4syn) (Z = (2-1), Y = Br, R ^2c = i-Bu, 4R / 5R) obtained in Example 20 (1) and the compound (7) (R ³ = TBS, R ⁶ =-(CH ₂ ) ₃ OTBS, 3α / 4α / 5β) Using 37 mg (68 μmol), the same reaction as in Example 14 (2-a) was carried out. 12 mg of 807a was obtained. Yield 49%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.95 (d, J = 6.4 Hz, 3 H), 0.96 (d, J = 6.3 Hz, 3 H), 0.99 (d, J = 6.6 Hz, 3 H), 1.08 (ddd, J = 13.9, 10.9, 1.6 Hz, 1 H), 1.20-2.10 (m, 24 H), 2.25 (dd, J = 13.3, 8.8 Hz, 1 H), 2.66 (dd, J = 13.3, 4.2 Hz, 1 H), 2.83 (m, 1 H), 3.09 (m, 1 H), 3.65-3.75 (m, 2 H), 3.90 (ddd, J = 8.1, 8.1, 4.2 Hz, 1 H), 4.38 (br d, J = 2.7 Hz, 1 H), 4.66 (ddd, J = 11.5, 7.0, 1.4 Hz, 1 H), 4.98 (d, J = 2.0 Hz, 1 H) , 5.27 (d, J = 1.5 Hz, 1 H), 5.48 (d, J = 2.6 Hz, 1 H), 5.99 (d, J = 11.2 Hz, 1 H), 6.20 (d, J = 2.6 Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H).
LRMS m / z 540 (M ⁺ ), 522, 504
HRMS calcd for C ₃₄ H ₅₂ O ₅ 540.3815, found 540.3818

[Example 38]
2α- (3-Hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -isobutyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 807b)

20 mg (47 μmol) of the compound (4syn) (Z = (2-1), Y = Br, R ^2c = i-Bu, 4S / 5S) obtained in Example 20 (1) and the compound (7) (R ³ = TBS, R ⁶ =-(CH ₂ ) ₃ OTBS, 3α / 4α / 5β) using 38 mg (70 μmol), the same reaction as in Example 14 (2-a) was carried out. 15 mg of 807b was obtained. Yield 59%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.94 (d, J = 6.6 Hz, 3 H), 0.95 (d, J = 6.2 Hz, 3 H), 1.05 (d, J = 6.4 Hz, 3 H), 1.20-2.08 (m, 23 H), 2.10-2.40 (m, 2 H), 2.25 (dd, J = 13.1, 8.2 Hz, 1 H), 2.65 (dd, J = 13.1, 4.4 Hz, 1 H), 2.82 (m, 1 H), 3.02 (m, 1 H), 3.62-3.75 (m, 2 H), 3.88 (ddd, J = 8.1, 8.1, 4.3 Hz, 1 H), 4.37 (br d, J = 2.9 Hz, 1 H), 4.58 (ddd, J = 8.1, 6.3, 4.5 Hz, 1 H), 4.99 (d, J = 1.7 Hz, 1 H), 5.27 (d, J = 1.7 Hz, 1 H), 5.48 (d, J = 2.1 Hz, 1 H), 6.00 (d, J = 11.2 Hz, 1 H), 6.19 (d, J = 2.1 Hz, 1 H), 6.39 (d, J = 11.2 Hz, 1 H).
LRMS m / z 540 (M ⁺ ), 522, 504
HRMS calcd for C ₃₄ H ₅₂ O ₅ 540.3814, found 540.3813

[Example 39]
2α- (3-Hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -isobutyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 807c)

21 mg (50 μmol) of the compound (4anti) (Z = (2-1), Y = Br, R ^2c = i-Bu, 4R / 5S) obtained in Example 21 (4) and the compound (7) (R ³ = TBS, R ⁶ =-(CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 40 mg (74 μmol) was used to carry out the same reaction as in Example 14 (2-a). 15 mg of 807c was obtained. Yield 57%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.95 (d, J = 6.7 Hz, 3 H), 0.96 (d, J = 6.6 Hz, 3 H), 1.06 (d, J = 6.1 Hz, 3 H), 1.15-2.10 (m, 23 H), 2.18-2.40 (m, 2 H), 2.25 (dd, J = 12.9, 8.5 Hz, 1 H), 2.60-2.72 (m, 2 H ), 2.82 (m, 1 H), 3.62-3.75 (m, 2 H), 3.88 (ddd, J = 8.1, 8.1, 4.3 Hz, 1 H), 4.20 (m, 1 H), 4.37 (br d, J = 2.7 Hz, 1 H), 4.98 (d, J = 1.8 Hz, 1 H), 5.27 (d, J = 1.8 Hz, 1 H), 5.57 (d, J = 2.2 Hz, 1 H), 6.00 ( d, J = 11.2 Hz, 1 H), 6.24 (d, J = 2.2 Hz, 1 H), 6.39 (d, J = 11.2 Hz, 1 H).
LRMS m / z 540 (M ⁺ ), 522, 504
HRMS calcd for C ₃₄ H ₅₂ O ₅ 540.3815, found 540.3816

[Example 40]
2α- (3-hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -isobutyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 807d)

Compound (4anti) (Z = (2-1), Y = Br, R ^2c = i-Bu, 4S / 5R) 18 mg (42 μmol) obtained in Example 22 (5) and compound (7) (R ³ = TBS, R ⁶ =-(CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 34 mg (63 μmol) was used to carry out the same reaction as in Example 14 (2-a). 10 mg of 807d was obtained. Yield 44%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.95 (d, J = 6.6 Hz, 3 H), 0.96 (d, J = 6.4 Hz, 3 H), 1.01 (d, J = 6.6 Hz, 3 H), 1.15-2.20 (m, 25 H), 2.25 (dd, J = 13.1, 9.2 Hz, 1 H), 2.62 (m, 1 H), 2.66 (dd, J = 13.1, 4.1 Hz , 1 H), 2.83 (m, 1 H), 3.65-3.75 (m, 2 H), 3.90 (ddd, J = 7.9, 7.9, 4.4 Hz, 1 H), 4.24 (ddd, J = 10.8, 4.5, 1.9 Hz, 1 H), 4.37 (br d, J = 2.4 Hz, 1 H), 4.98 (d, J = 1.7 Hz, 1 H), 5.27 (d, 1.7 Hz, 1 H), 5.56 (d, J = 2.4 Hz, 1 H), 5.99 (d, J = 11.2 Hz, 1 H), 6.24 (d, J = 2.4 Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H).
LRMS m / z 540 (M ⁺ ), 522, 504
HRMS calcd for C ₃₄ H ₅₂ O ₅ 540.3815, found 540.3814

[Example 41]
2α- (3-hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-5 (R) -yl) methyl-9,10-secopregna-5 (Z), 7 (E), Production of 10 (19) -triene-1α, 3β-diol (Compound No. 1101a)

Compound (4) (Z = (2-1), Y = Br, R ^2d = R ^2e = H, 5R) 16 mg (44 μmol) obtained by a method known in the literature (for example, International Publication WO95 / 33716) and Compound (7) (R ³ = TBS, R ⁶ = -O (CH ₂ ) ₃ OTBS, 3α / 4α obtained by a method known in the literature (eg, Org. Lett., 2, 2619-2622, 2000) / 5β) Using 36 mg (65 μmol), the same reaction as in Example 14 (2-a) was carried out. 10 mg of 1101a was obtained. Yield 46%.
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 1.01 (d, J = 6.3 Hz, 3 H), 1.26-2.03 (m, 16 H), 2.23 (dd, J = 9.0, 13.2 Hz, 1 H), 2.35 (br s, 1 H), 2.54 (m, 2 H), 2.61 (d, J = 3.9 Hz, 1 H), 2.68 (dd, J = 13.2, 4.2 Hz, 1 H) , 2.81-2.84 (m, 1 H), 3.03-3.09 (br dd, J = 7.6, 17.3 Hz, 1 H), 3.37 (dd, J = 3.1, 7.2 Hz, 1 H), 3.76-3.90 (m, 4 H), 4.06 (m, 1 H), 4.44 (br s, 1 H), 4.63-4.64 (m, 1 H), 5.01 (br s, 1 H), 5.39 (br s, 1 H), 5.61 (br s, 1 H), 6.01 (d, J = 11.0 Hz, 1 H), 6.22 (br s, 1 H), 6.41 (d, J = 11.0 Hz, 1 H).
LRMS m / z 500 (M ⁺ ) 482, 464, 406, 390, 352
HRMS calcd for C ₃₀ H ₄₄ O ₆ 500.3138, found 500.3134

[Example 42]
2α- (3-hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-5 (S) -yl) methyl-9,10-secopregna-5 (Z), 7 (E), Production of 10 (19) -triene-1α, 3β-diol (Compound No. 1101b)

Compound (4) (Z = (2-1), Y = Br, R ^2d = R ^2e = H, 5S) 11 mg (29 μmol) obtained by a method known in the literature (for example, International Publication WO95 / 33716) compound ^{(7) (R 3 = TBS} , R 6 = -O (CH 2) 3 OTBS, 3α / 4α / 5β) carrying out the same reaction as in example 14 (2-a) with 25mg (45μmol), Compound No. 11 mg of 1101b was obtained. Yield 73%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 1.02 (d, J = 6.4 Hz, 3 H), 1.21-2.01 (m, 16 H), 2.17 (t, J = 5.0 Hz, 1 H), 2.24 (dd, J = 9.3, 13.0 Hz, 1 H), 2.47 (d, J = 3.4 Hz, 1 H), 2.54 (d, J = 4.4 Hz, 1 H), 2.56 (m, 1 H), 2.69 (dd, J = 4.6, 13.0 Hz, 1 H), 2.81-2.84 (m, 1 H), 3.05 (dddd, J = 2.3, 2.6, 7.4, 16.9 Hz, 1 H), 3.38 (dd , J = 3.5, 7.5 Hz, 1 H), 3.75-3.90 (m, 4 H), 4.06 (m, 1 H), 4.45 (dd, J = 3.5, 3.5 Hz, 1 H), 4.59 (dddd, J = 7.4, 7.0, 7.0, 7.0 Hz, 1 H), 5.09 (br s, 1 H), 5.39 (br s, 1 H), 5.62 (dd, J = 2.3, 2.3 Hz, 1 H), 6.01 (d , J = 11.4 Hz, 1 H), 6.22 (dd, J = 2.6, 2.7 Hz, 1 H), 6.42 (d, J = 11.4 Hz, 1 H).
LRMS m / z 500 (M ⁺ ) 482, 464, 406, 390, 352
HRMS calcd for C ₃₀ H ₄₄ O ₆ 500.3138, found 500.3033

[Example 43]
2α- (3-hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -methyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 1102a)

Compound (4syn) obtained in Example 11 (1) (Z = (2-1), Y = Br, R ^2c = Me, 4R / 5R) 18 mg (46 μmol) and compound (7) (R ³ = TBS) , R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 39 mg (70 μmol) was used to carry out the same reaction as in Example 14 (2-a). 12.1 mg of 1102a was obtained. Yield 51%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.99 (d, J = 6.6 Hz, 3 H), 1.06 (m, 1 H), 1.13 (d, J = 7.1 Hz, 3 H ), 1.15-1.90 (m, 13 H), 1.93-2.05 (m, 2 H), 2.23 (dd, J = 13.4, 9.2 Hz, 1 H), 2.40-2.75 (m, 3 H), 2.67 (dd , J = 13.4, 4.6 Hz, 1 H), 2.82 (m, 1 H), 3.15 (m, 1 H), 3.37 (dd, J = 7.3, 3.0 Hz, 1 H), 3.54-3.90 (m, 4 H), 4.06 (ddd, J = 9.2, 7.3, 4.6 Hz, 1 H), 4.43 (d, J = 3.0 Hz, 1 H), 4.67 (ddd, J = 11.7, 7.7, 1.7 Hz, 1 H), 5.07 (d, J = 1.7 Hz, 1 H), 5.38 (br s, 1 H), 5.52 (d, J = 2.6 Hz, 1 H), 6.00 (d, J = 11.1 Hz, 1 H), 6.20 ( d, J = 2.6 Hz, 1 H), 6.40 (d, J = 11.1 Hz, 1 H).
LRMS m / z 514 (M ⁺ ), 496, 478, 420, 249
HRMS calcd for C ₃₁ H ₄₆ O ₆ 514.3295, found 514.3304

[Example 44]
2α- (3-Hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -methyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 1102b)

19 mg (49 μmol) of the compound (4syn) (Z = (2-1), Y = Br, R ^2c = Me, 4S / 5S) obtained in Example 11 (1) and the compound (7) (R ³ = TBS) , R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 41 mg (73 μmol) was used to carry out a reaction similar to Example 14 (2-a), and compound No. 10.3 mg of 1102b was obtained. Yield 41%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 1.04 (d, J = 6.6 Hz, 3 H), 1.12 (d, J = 7.1 Hz, 3 H), 1.20-1.75 (m, 11 H), 1.80-2.05 (m, 5 H), 2.23 (dd, J = 13.4, 9.0 Hz, 1 H), 2.57 (br s, 3 H), 2.67 (dd, J = 13.4, 4.6 Hz, 1 H), 2.82 (m, 1 H), 3.10 (m, 1 H), 3.37 (dd, J = 7.3, 3.0 Hz, 1 H), 3.75-3.93 (m, 4 H), 4.05 (ddd, J = 9.0, 7.3, 4.6 Hz, 1 H), 4.43 (br d, J = 3.0 Hz, 1 H), 4.58 (dt, J = 5.9, 7.2 Hz, 1 H), 5.08 (d, J = 1.5 Hz, 1 H), 6.28 (d, J = 1.5 Hz, 1 H), 5.53 (d, J = 2.1 Hz, 1 H), 6.00 (d, J = 11.2 Hz, 1 H), 6.18 (d, J = 2.2 Hz , 1 H), 6.41 (d, J = 11.2 Hz, 1 H).
LRMS m / z 514 (M ⁺ ), 496, 478, 420, 249
HRMS calcd for C ₃₁ H ₄₆ O ₆ 514.3294, found 514.3298

[Example 45]
2α- (3-hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -methyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 1102c)

Compound (4anti) (Z = (2-1), Y = Br, R ^2c = Me, 4R / 5S) 17 mg (44 μmol) obtained in Example 12 (4) and compound (7) (R ³ = TBS) , R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 37 mg (66 μmol) was used to carry out the same reaction as in Example 14 (2-a), and compound No. 12.1 mg of 1102c was obtained. Yield 54%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 1.05 (d, J = 6.1 Hz, 3 H), 1.24 (d, J = 6.8 Hz, 3 H), 1.15-1.75 (m, 12 H), 1.80-2.05 (m, 5 H), 2.23 (dd, J = 13.7, 9.2 Hz, 1 H), 2.40-2.75 (m, 3 H), 2.67 (dd, J = 13.7, 4.7 Hz, 1 H), 2.82 (m, 1 H), 3.37 (dd, J = 7.4, 3.3 Hz, 1 H), 3.75-3.93 (m, 4 H), 4.00-4.10 (m, 2 H), 4.44 (d , J = 3.3 Hz, 1 H), 5.08 (d, J = 1.5 Hz, 1 H), 5.38 (d, J = 1.5 Hz, 1 H), 5.53 (d, J = 2.9 Hz, 1 H), 6.00 (d, J = 11.2 Hz, 1 H), 6.22 (d, J = 2.9 Hz, 1 H), 6.41 (d, J = 11.2 Hz, 1 H).
LRMS m / z 514 (M ⁺ ), 476, 478, 420, 402
HRMS calcd for C ₃₁ H ₄₆ O ₆ 514.3294, found 514.3286

[Example 46]
2α- (3-Hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -methyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 1102d)

Compound (4anti) (Z = (2-1), Y = Br, R ^2c = Me, 4S / 5R) 11 mg (26 μmol) obtained in Example 13 (5) and compound (7) (R ³ = TBS) , R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 24 mg (42 μmol), the same reaction as in Example 14 (2-a) was carried out. 7.6 mg of 1102d was obtained. Yield 52%.
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 1.00 (d, J = 6.6 Hz, 3 H), 1.22 (d, J = 6.8 Hz, 3 H), 1.20-1.90 (m, 14 H), 1.93-2.05 (m, 2 H), 2.23 (dd, J = 13.4, 9.3 Hz, 1 H), 2.35-2.70 (m, 4 H), 2.68 (dd, J = 13.4, 4.5 Hz, 1 H), 2.82 (m, 1 H), 3.37 (dd, J = 7.5, 3.2 Hz, 1 H), 3.73-3.93 (m, 4 H), 4.00-4.13 (m, 2 H), 4.44 (d , J = 3.2 Hz, 1 H), 5.68 (d, J = 1.7 Hz, 1 H), 5.38 (d, J = 1.7 Hz, 1 H), 5.51 (d, J = 3.1 Hz, 1 H), 6.01 (d, J = 11.1 Hz, 1 H), 6.21 (d, J = 3.1 Hz, 1 H), 6.40 (d, J = 11.1 Hz, 1 H).
LRMS m / z 514 (M ⁺ ), 497, 496, 478, 420, 402, 249
HRMS calcd for C ₃₁ H ₄₆ O ₆ 514.3294, found 514.3297

[Example 47]
2α- (3-hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -ethyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 1103a)

Compound (4syn) obtained in Example 14 (1) (Z = (2-1), Y = Br, R ^2c = Et, 4R / 5R) 13 mg (33 μmol) and compound (7) (R ³ = TBS) , R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 27 mg (49 μmol) was used to carry out the same reaction as in Example 14 (2-a). 10 mg of 1103a was obtained. Yield 58%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.97 (t, J = 7.4 Hz, 3 H), 1.00 (d, J = 6.3 Hz, 3 H), 1.12 (ddd, J = 14.1, 10.7, 1.7 Hz, 1 H), 1.22-1.89 (m, 15 H), 1.97 (dd, J = 12.1, 7.1 Hz, 1 H), 2.02 (br d, J = 12.4 Hz, 1 H), 2.23 (dd, J = 13.6, 8.8 Hz, 1 H), 2.51 (br, 3 H), 2.68 (dd, J = 13.6, 4.5 Hz, 1 H), 2.82 (m, 1 H), 2.87 (m, 1 H), 3.37 (dd, J = 7.4, 3.3 Hz, 1 H), 3.77 (m, 1 H), 3.80-3.85 (m, 2 H), 4.06 (m, 1 H), 4.44 (d, J = 3.0 Hz, 1 H), 4.66 (ddd, J = 11.5, 7.0, 1.5 Hz, 1 H), 5.08 (d, J = 1.7 Hz, 1 H), 5.39 (s, 1 H), 5.51 (d, J = 2.4 Hz, 1 H), 6.01 (d, J = 11.3 Hz, 1 H), 6.21 (d, J = 2.4 Hz, 1 H), 6.40 (d, J = 11.3 Hz, 1 H).
LRMS m / z 528 (M ⁺ ) 510, 492, 466, 434, 419, 265, 249
HRMS calcd for C ₃₂ H ₄₈ O ₆ 528.3451, found 528.3451

[Example 48]
2α- (3-Hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -ethyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 1103b)

Compound (4syn) obtained in Example 14 (1) (Z = (2-1), Y = Br, R ^2c = Et, 4S / 5S) 27 mg (68 μmol) and compound (7) (R ³ = TBS) , R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 57 mg (102 μmol), the same reaction as in Example 14 (2-a) was carried out. 22 mg of 1103b was obtained. Yield 61%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.94 (t, J = 7.3 Hz, 3 H), 1.04 (d, J = 6.6 Hz, 3 H), 1.24-2.01 (m, 18 H), 2.23 (dd, J = 13.2, 9.0 Hz, 1 H), 2.64-2.83 (m, 6 H), 3.37 (dd, J = 7.4, 3.3 Hz, 1 H), 3.76 (m, 1 H ), 3.80-3.83 (m, 2 H), 3.87 (m, 1 H), 4.04 (m, 1 H), 4.44 (d, J = 2.9 Hz, 1 H), 4.57 (m, 1 H), 5.08 (d, J = 1.3 Hz, 1 H), 5.38 (d, J = 1.3 Hz, 1 H), 5.51 (d, J = 1.8 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1 H) , 6.20 (d, J = 1.8 Hz, 1 H), 6.40 (d, J = 11.2 Hz, 1 H).
LRMS m / z 528 (M ⁺ ) 510, 492, 466, 434, 419, 265, 249
HRMS calcd for C ₃₂ H ₄₈ O ₆ 528.3451, found 528.3453

[Example 49]
2α- (3-hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -ethyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 1103c)

Compound (4anti) (Z = (2-1), Y = Br, R ^2c = Et, 4R / 5S) 21 mg (53 μmol) obtained in Example 15 (5) and compound (7) (R ³ = TBS) , R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 44 mg (80 μmol) was used to carry out the same reaction as in Example 14 (2-a). 19 mg of 1103c was obtained. Yield 68%.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.55 (s, 3 H), 0.97 (t, J = 7.4 Hz, 3 H), 1.05 (d, J = 6.1 Hz, 3 H), 1.14-1.71 (m, 13 H), 1.84-1.92 (m, 3 H), 1.98-2.00 (m, 2 H), 2.23 (dd, J = 13.1, 9.2 Hz, 1 H), 2.53-2.83 (m, 6 H ), 3.37 (dd, J = 7.6, 3.2 Hz, 1 H), 3.74-3.90 (m, 4 H), 4.05 (m, 1 H), 4.26 (m, 1 H), 4.44 (d, J = 2.9 Hz, 1 H), 5.08 (d, J = 2.0 Hz, 1 H), 5.38 (br s, 1 H), 5.59 (d, J = 2.3 Hz, 1 H), 6.00 (d, J = 11.2 Hz, 1 H), 6.27 (d, J = 2.3 Hz, 1 H), 6.40 (d, J = 11.2 Hz, 1 H).
LRMS m / z 528 (M ⁺ ) 510, 492, 466, 434, 419, 265, 249
HRMS calcd for C ₃₂ H ₄₈ O ₆ 528.3451, found 528.3451

[Example 50]
2α- (3-Hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -ethyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 1103d)

Compound (4anti) obtained in Example 16 (5) (Z = (2-1), Y = Br, R ^2c = Et, 4S / 5R) 32 mg (81 μmol) and compound (7) (R ³ = TBS) , R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 68 mg (121 μmol) was used to carry out the same reaction as in Example 14 (2-a), and compound No. 26 mg of 1103d was obtained. Yield 61%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.97 (t, J = 7.4 Hz, 3 H), 1.05 (d, J = 6.1 Hz, 3 H), 1.14-1.71 (m, 13 H), 1.84-1.92 (m, 3 H), 1.98-2.00 (m, 2 H), 2.23 (dd, J = 13.1, 9.2 Hz, 1 H), 2.53-2.83 (m, 6 H), 3.37 (dd, J = 7.6, 3.2 Hz, 1 H), 3.74-3.90 (m, 4 H), 4.05 (m, 1 H), 4.26 (m, 1 H), 4.44 (d, J = 2.9 Hz, 1 H), 5.08 (d, J = 2.0 Hz, 1 H), 5.38 (br s, 1 H), 5.59 (d, J = 2.3 Hz, 1 H), 6.00 (d, J = 11.2 Hz, 1 H) , 6.27 (d, J = 2.3 Hz, 1 H), 6.40 (d, J = 11.2 Hz, 1 H).
LRMS m / z 528 (M ⁺ ) 510, 492, 466, 434, 419, 265, 249
HRMS calcd for C ₃₂ H ₄₈ O ₆ 528.3451, found 528.3451

[Example 51]
2α- (3-Hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -butyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 1106a)

Compound (4syn) obtained in Example 17 (1) (Z = (2-1), Y = Br, R ^2c = Bu, 4R / 5R) 60 mg (142 μmol) and compound (7) (R ³ = TBS) , R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 118 mg (213 μmol) was used to carry out the same reaction as in Example 14 (2-a), and compound No. 45 mg of 1106a was obtained. Yield 57%.
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.93 (t, J = 7.0 Hz, 3 H), 1.00 (d, J = 6.4 Hz, 3 H), 1.11 (ddd, J = 13.7, 11.0, 1.2 Hz, 1 H), 1.20-2.08 (m, 21 H), 2.23 (dd, J = 13.4, 9,0 Hz, 1 H), 2.67 (dd, J = 13.4, 4.4 Hz, 1 H), 2.72-2,90 (m, 4 H), 2.96 (m, 1 H), 3.37 (dd, J = 7.3, 3.2 Hz, 1 H), 3.70-3.95 (m, 4 H), 4.05 ( m, 1 H), 4.45 (br s, 1 H), 4.65 (ddd, J = 10.4, 7.2, 1.1 Hz, 1 H), 5.08 (s, 1 H), 5.38 (s, 1 H), 5.51 ( d, J = 2.3 Hz, 1 H), 6.10 (d, J = 11.2 Hz, 1 H), 6.21 (d, J = 2.3 Hz, 1 H), 6.40 (d, J = 11.2 Hz, 1 H ).
LRMS m / z 556 (M ⁺ ), 538, 520, 462, 444
HRMS calcd for C ₃₄ H ₅₂ O ₆ 556.3764, found 556.3762

[Example 52]
2α- (3-Hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -butyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 1106b)

Compound (4syn) obtained in Example 17 (1) (Z = (2-1), Y = Br, R ^2c = Bu, 4S / 5S) 42 mg (100 μmol) and compound (7) (R ³ = TBS) , R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 84 mg (150 μmol), the same reaction as in Example 14 (2-a) was carried out. 31 mg of 1106b was obtained. Yield 56%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.92 (t, J = 7.0 Hz, 3 H), 1.05 (d, J = 6.6 Hz, 3 H), 1.18-2.08 (m, 22 H), 1.24 (dd, J = 13.4, 8.8 Hz, 1 H), 2.68 (dd, J = 13.4, 4.7 Hz, 1 H), 2.70 (br s, 3 H), 2.83 (m, 1 H) , 2.89 (m, 1 H), 3.37 (dd, J = 7.7, 3.1 Hz, 1 H), 3.74-3.93 (m, 4 H), 4.05 (ddd, J = 8.8, 7.7, 4.7 Hz, 1 H) , 4.44 (br d, J = 3.1 Hz, 1 H), 4.57 (ddd, J = 8.3, 6.0, 5.3 Hz, 1 H), 5.09 (d, J = 2.0 Hz, 1 H), 5.38 (d, J = 1.2 Hz, 1 H), 5.50 (d, J = 1.8 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.19 (d, J = 1.8 Hz, 1 H), 6.41 (d , J = 11.2 Hz, 1 H).
LRMS m / z 556 (M ⁺ ), 538, 520, 462, 444
HRMS calcd for C ₃₄ H ₅₂ O ₆ 556.3764, found 556.3760

[Example 53]
2α- (3-hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -butyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 1106c)

Compound (4anti) (Z = (2-1), Y = Br, R ^2c = Bu, 4R / 5S) 39 mg (92 μmol) obtained in Example 18 (5) and compound (7) (R ³ = TBS) , R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 77 mg (138 μmol) was used to carry out the same reaction as in Example 14 (2-a). 26 mg of 1106c was obtained. Yield 51%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.92 (t, J = 6.5 Hz, 3 H), 1.05 (d, J = 5.4 Hz, 3 H), 1.15-2.05 (m, 22 H), 2.24 (dd, J = 13.2, 9.3 Hz, 1 H), 2.40-2.78 (m, 4 H), 2.68 (dd, J = 13.2, 4.2 Hz, 1 H), 2.82 (m, 1 H ), 3.38 (dd, J = 7.5, 2.8 Hz, 1 H), 3.73-3.93 (m, 4 H), 4.05 (m, 1 H), 4.24 (m, 1 H), 4.44 (br s, 1 H ), 5.51 (s, 1 H), 5.38 (s, 1 H), 5.58 (br d, J = 1.6 Hz, 1 H), 6.01 (d, J = 11.1 Hz, 1 H), 6.26 (br d, J = 1.6 Hz, 1 H), 6.41 (d, J = 11.1 Hz, 1 H).
LRMS m / z 556 (M ⁺ ), 538, 520, 462, 444
HRMS calcd for C ₃₄ H ₅₂ O ₆ 556.3764, found 556.3768

[Example 54]
2α- (3-Hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -butyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 1106d)

Compound (4anti) (Z = (2-1), Y = Br, R ^2c = Bu, 4S / 5R) 39 mg (92 μmol) obtained in Example 19 (5) and compound (7) (R ³ = TBS) , R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 77 mg (138 μmol) was used to carry out the same reaction as in Example 14 (2-a). 23 mg of 1106d was obtained. Yield 44%.
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.92 (t, J = 7.0 Hz, 3 H), 1.02 (d, J = 6.3 Hz, 3 H), 1.20-1.90 (m, 20 H), 1.92-2.08 (m, 2 H), 2.23 (dd, J = 13.4, 9.0 Hz, 1 H), 2.50-2.78 (m, 4 H), 2.68 (dd, J = 13.4, 4.6 Hz, 1 H), 2.83 (m, 1 H), 3.37 (dd, J = 7.5, 3.2 Hz, 1 H), 3.73-3.95 (m, 4 H), 4.06 (ddd, J = 9.0, 7.5, 4.6 Hz, 1 H), 4.27 (ddd, J = 10.8, 4.8, 2.0 Hz, 1 H), 4.45 (br d, J = 2.4 Hz, 1 H), 5.08 (d, J = 1.7 Hz, 1 H), 5.39 ( s, 1 H), 5.57 (d, J = 2.2 Hz, 1 H), 6.01 (d, J = 11.1 Hz, 1 H), 6.25 (d, J = 2.9 Hz, 1 H), 6.40 (d, J = 11.1 Hz, 1 H).
LRMS m / z 556 (M ⁺ ), 538, 520, 462, 444
HRMS calcd for C ₃₄ H ₅₂ O ₆ 556.3764, found 556.3757

[Example 55]
2α- (3-hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -isobutyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 1107a)

Compound (4syn) obtained in Example 20 (1) (Z = (2-1), Y = Br, R ^2c = i-Bu, 4R / 5R) 18 mg (43 μmol) and compound (7) (R ³ = TBS, R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 34 mg (64 μmol) was used to carry out the same reaction as in Example 14 (2-a). 11 mg of 1107a was obtained. Yield 47%.
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.95 (d, J = 6.6 Hz, 3 H), 0.96 (d, J = 6.6 Hz, 3 H), 1.00 (d, J = 6.6 Hz, 3 H), 1.08 (ddd, J = 14.2, 10.7, 1.8 Hz, 1 H), 1.18-1.92 (m, 16 H), 1.93-2.08 (m, 2 H), 2.23 (dd, J = 13.4, 8.9 Hz, 1 H), 2.40-2.75 (m, 3 H), 2.68 (dd, J = 13.4, 4.5 Hz, 1 H), 2.83 (m, 1 H), 3.08 (m, 1 H), 3.37 (dd, J = 7.4, 3.3 Hz, 1 H), 3.73-3.93 (m, 4 H), 4.06 (ddd, J = 8.1, 7.4, 4.4 Hz, 1 H), 4.45 (br d, J = 2.7 Hz, 1 H), 4.66 (ddd, J = 11.5, 7.1, 1.5 Hz, 1 H), 5.08 (d, J = 1.7 Hz, 1 H), 5.39 (br s, 1 H), 5.48 (d, J = 2.6 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.20 (d, J = 2.6 Hz, 1 H), 6.40 (d, J = 11.2 Hz, 1 H).
LRMS m / z 556 (M ⁺ ), 538, 520, 462, 408
HRMS calcd for C ₃₄ H ₅₂ O ₆ 556.3764, found 556.3768

[Example 56]
2α- (3-hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -isobutyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 1107b)

Compound (4syn) obtained in Example 20 (1) (Z = (2-1), Y = Br, R ^2c = i-Bu, 4S / 5S) 22 mg (51 μmol) and compound (7) (R ³ = TBS, R ⁶ = -O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 43 mg (77 μmol) was used to carry out the same reaction as in Example 14 (2-a). 16 mg of 1107b was obtained. Yield 56%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.94 (d, J = 6.4 Hz, 3 H), 0.95 (d, J = 6.4 Hz, 3 H), 1.05 (d, J = 6.4 Hz, 3 H), 1.19-2.05 (m, 19 H), 2.23 (dd, J = 13.3, 9.3 Hz, 1 H), 2.67 (dd, J = 13.3, 4.4 Hz, 1 H), 2.73 (br s, 3 H), 2.83 (m, 1 H), 3.02 (m, 1 H), 3.37 (dd, J = 7.9, 3.1 Hz, 1 H), 3.73-3.93 (m, 4 H), 4.05 (ddd , J = 7.9, 7.9, 4.5 Hz, 1 H), 4.45 (br d, J = 2.4 Hz, 1 H), 4.58 (ddd, J = 8.5, 6.5, 4.1 Hz, 1 H), 5.09 (d, J = 1.5 Hz, 1 H), 5.38 (br s, 1 H), 5.48 (d, J = 1.9 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.19 (d, J = 1.9 Hz, 1 H), 6.41 (d, J = 11.2 Hz, 1 H).
LRMS m / z 556 (M ⁺ ), 538, 520, 462, 444, 408, 393, 249
HRMS calcd for C ₃₄ H ₅₂ O ₆ 556.3764, found 556.3762

[Example 57]
2α- (3-hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -isobutyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 1107c)

19 mg (44 μmol) of the compound (4anti) (Z = (2-1), Y = Br, R ^2c = i-Bu, 4R / 5S) obtained in Example 21 (4) and the compound (7) (R ³ = TBS, R ⁶ = -O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) Using 37 mg (67 μmol), the same reaction as in Example 14 (2-a) was carried out. 11 mg of 1107c was obtained. Yield 43%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.95 (d, J = 6.4 Hz, 3 H), 0.96 (d, J = 6.6 Hz, 3 H), 1.05 (d, J = 5.9 Hz, 3 H), 1.10-1.75 (m, 14 H), 1.82-1.93 (m, 3 H), 1.95-2.05 (m, 2 H), 2.24 (dd, J = 13.1, 9.4 Hz, 1 H ), 2.30-2.70 (m, 4 H), 2.68 (dd, J = 13.1, 4.2 Hz, 1 H), 2.83 (m, 1 H), 3.38 (dd, J = 7.6, 3.2 Hz, 1 H), 3.73-3.93 (m, 4 H), 4.05 (ddd, J = 8.7, 7.6, 4.5 Hz, 1 H), 4.20 (m, 1 H), 4.44 (br d, J = 3.2 Hz, 1 H), 5.09 (d, J = 1.5 Hz, 1 H), 5.38 (d, J = 1.5 Hz, 1 H), 5.57 (d, J = 2.1 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1 H) , 6.13 (d, J = 2.1 Hz, 1 H), 6.41 (d, J = 11.2 Hz, 1 H).
LRMSm / z 556 (M ⁺ ), 538, 520, 462, 444, 408, 393, 249
HRMS calcd for C ₃₄ H ₅₂ O ₆ 556.3764, found 556.3770

[Example 58]
2α- (3-hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -isobutyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 1107d)

Compound (4anti) (Z = (2-1), Y = Br, R ^2c = i-Bu, 4S / 5R) 10 mg (22 μmol) and compound (7) (R ³ ) obtained in Example 22 (5) = TBS, R ⁶ = -O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 19 mg (34 μmol) was used to carry out the same reaction as in Example 14 (2-a). 6 mg of 1107d was obtained. Yield 50%.
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.95 (d, J = 6.6 Hz, 3 H), 0.96 (d, J = 6.6 Hz, 3 H), 1.01 (d, J = 6.6 Hz, 3 H), 1.20-1.90 (m, 17 H), 1.93-2.06 (m, 2 H), 2.23 (dd, J = 13.6, 8.7 Hz, 1 H), 2.30-2.73 (m, 3 H ), 2.62 (m, 1 H), 2.68 (dd, J = 13.6, 4.4 Hz, 1 H), 2.83 (m, 1 H), 3.37 (dd, J = 7.5, 3.2 Hz, 1 H), 3.75- 3.92 (m, 4 H), 4.06 (ddd, J = 8.6, 7.5, 3.2 Hz, 1 H), 4.24 (ddd, J = 11.0, 4.8, 2.1 Hz, 1 H), 4.44 (d, J = 3.2 Hz , 1 H), 5.08 (d, J = 2.0 Hz, 1 H), 5.39 (s, 1 H), 5.56 (d, J = 2.6 Hz, 1 H), 6.01 (d, J = 11.4 Hz, 1 H ), 6.24 (d, J = 2.6 Hz, 1 H), 6.41 (d, J = 11.4 Hz, 1 H).
LRMS m / z 556 (M ⁺ ), 538, 520, 462, 444, 408, 393, 249
HRMS calcd for C ₃₄ H ₅₂ O ₆ 556.3764, found 556.3765

[Example 59]
20 (R)-(Tetrahydro-3-methylene-2-furanone-4 (R) -phenyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z), 7 (E), 10 ( 19) -Triene-1α, 3β-diol (Compound No. 109a) and 20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -phenyl-5 (S) -yl) methyl-9 , 10-secopregna-5 (Z), 7 (E), 10 (19) -triene-1α, 3β-diol (Compound No. 109b)

(1) Example 11 using 30 mg (0.101 mmol) of the compound (2) (Z = (2-1), Y = Br) obtained by a method known in the literature (for example, International Publication WO95 / 33716). The same reaction as in (1) was performed, and 513 mg (yield 49%) of compound (4syn) (Z = (2-1), Y = Br, R ^2c = Ph, 4R / 5R) and compound (4syn) ( 486 mg (yield 47%) of Z = (2-1), Y = Br, R ^2c = Ph, 4S / 5S) was obtained. However, the compound (3) obtained by using methyl acrylate instead of ethyl acrylate in the same manner as in Reference Example 9 instead of compound (3) (R ^2c = Me, R ⁷ = Me) in Example 11 (1) ) (R ^2c = Ph, R ⁷ = Me).
Compound (4syn) (Z = (2-1), Y = Br, R ^2c = Ph, 4R / 5R):
[α] _D ²³ +266.7 (c 1.08, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.54 (s, 3 H), 0.61 (ddd, J = 2.0, 10.7, 14.6 Hz, 1 H), 0.93 (d, J = 6.6 Hz, 3 H), 1.09 ( dddd, J = 9.6, 9.6, 9.6, 9.6 Hz, 1 H), 1.14-1.26 (m, 2 H), 1.34 (ddd, J = 2.3, 12.0, 14.4 Hz, 1 H), 1.37-1.45 (m, 2 H), 1.53 (m, 1 H), 1.59-1.65 (m, 3 H), 1.70 (m, 1 H), 1.87 (ddd, J = 1.6, 6.8, 12.3 Hz, 1 H), 1.95 (br d, J = 12.4 Hz, 1 H), 2.85 (m, 1 H), 4.36 (ddd, J = 8.0, 2.6, 2.6 Hz, 1 H), 4.86 (ddd, J = 2.2, 8.0, 11.8 Hz, 1 H), 5.615 (s, 1 H), 5.617 (d, J = 2.6 Hz, 1 H), 6.46 (d, J = 2.6 Hz, 1 H), 7.11-7.13 (m, 2 H), 7.30 (tt , J = 1.7, 7.3 Hz, 1 H), 7.35 (br t, J = 7.3 Hz, 2 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.8, 18.3, 21.9, 22.4, 27.4, 30.9, 32.6, 39.0, 39.8, 45.5, 49.6, 55.8, 56.0, 88.8, 97.6, 124.3, 127.7, 128.7 (2 C), 129.0 (2 C), 137.6, 139.0, 144.8, 170.4.
LRMS m / z 442 (M ⁺ ), 363, 201, 175, 147
HRMS calcd for C ₂₅ H ₃₁ O ₂ ⁷⁹ Br 442.1507, found 442.1506
Compound (4syn) (Z = (2-1), Y = Br, R ^2c = Ph, 4S / 5S):
[α] _D ²⁴ -24.8 (c 0.69, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.38 (s, 3 H), 0.52 (m, 1 H), 0.97 (d, J = 6.0 Hz, 3 H), 1.16-1.28 (m, 5 H), 1.36 -1.42 (m, 2 H), 1.48-1.55 (m, 2 H), 1.59-1.64 (m, 2 H), 1.88 (ddd, J = 1.5, 6.6, 12.5 Hz, 1 H), 1.91 (br d , J = 14.0 Hz, 1 H), 2.83 (m, 1 H), 4.26 (ddd, J = 2.2, 2.2, 7.2 Hz, 1 H), 4.82 (ddd, J = 7.2, 7.2, 7.2 Hz, 1 H ), 5.58 (dd, J = 1.6, 1.6 Hz, 1 H), 5.61 (d, J = 2.1 Hz, 1 H), 6.41 (d, J = 2.1 Hz, 1 H), 7.12-7.13 (m, 2 H), 7.29 (tt, J = 1.7, 7.3 Hz, 1 H), 7.33 (br t, J = 7.3 Hz, 2 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.7, 19.1, 21.8, 22.4, 26.6, 30.9, 33.1, 37.5, 39.7, 45.4, 49.6, 55.6, 55.8, 80.3, 97.5, 124.2, 127.7, 128.7 (2 C), 129.0 (2 C), 138.4, 139.8, 144.9, 170.5.
LRMS m / z 442 (M ⁺ ), 363, 201, 175, 147
HRMS calcd for C ₂₅ H ₃₁ O ₂ ⁷⁹ Br 442.1507, found 442.1499

(2-a) 15 mg (34 μmol) of the compound (4syn) (Z = (2-1), Y = Br, R ^2c = Ph, 4R / 5R) obtained above and the compound (7) (R ³ = TBS) , R ⁶ = hydrogen atom, 3α / 5β) 19 mg (51 μmmol) was used to carry out the same reaction as in Example 14 (2-a). 8 mg of 109a was obtained. Yield 47%.
Compound No. 109a:
[α] _D ²⁸ +191.6 (c 0.58, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.52 (s, 3 H), 0.61 (ddd, J = 2.0, 10.6, 14.6 Hz, 1 H), 0.92 (d, J = 6.6 Hz, 3 Hz), 1.09- 1.15 (m, 2 H), 1.18-1.43 (m, 5 H), 1.47-1.70 (m, 6 H), 1.86-2.05 (m, 4 H), 2.30 (dd, J = 6.6, 13.4 Hz, 1 H), 2.59 (dd, J = 3.4, 12.9 Hz, 1 H), 2.79 (dd, J = 3.9, 12.0 Hz, 1 H), 4.22 (m, 1 H), 4.36 (ddd, J = 2.7, 2.7 , 7.9 Hz, 1 H), 4.42 (ddd, J = 4.3, 4.3, 8.5 Hz, 1 H), 4.90 (ddd, J = 1.9, 7.9, 11.8 Hz, 1 H), 5.00 (br s, 1 H) , 5.32 (br s, 1 H), 5.61 (d, J = 2.7 Hz, 1 H), 5.98 (d, J = 12.3 Hz, 1 H), 6.35 (d, J = 12.3 Hz, 1 H), 6.46 (d, J = 2.7 Hz, 1 H), 7.11-7.13 (m, 2 H), 7.29-7.37 (m, 3 H).
¹³ C-NMR (CDCl ₃ ) δ: 12.0, 18.3, 22.1, 23.5, 27.4, 29.0, 32.7, 39.1, 40.4, 42.8, 45.2, 45.9, 49.7, 56.3, 56.8, 66.8, 70.7, 78.9, 111.7, 117.1, 124.3, 124.8, 127.7, 128.7 (2 C), 129.1 (2 C), 133.0, 137.6, 139.0, 142.8, 147.6, 170.5.
LRMS m / z 502 (M ⁺ ), 484, 466, 451, 278, 251, 209
HRMS calcd for C ₃₃ H ₄₂ O ₄ 502.3083, found 502.3078

(2-b) Compound (4syn) obtained above (Z = (2-1), Y = Br, R ^2c = Ph, 4S / 5S) 27 mg (61 μmol) and compound (7) (R ³ = TBS , R ⁶ = hydrogen atom, 3α / 5β) 34 mg (92 μmol) was used to carry out the same reaction as in Example 14 (2-a). 18 mg of 109b was obtained. Yield 59%.
Compound No. 109b:
[α] _D ²⁶ -35.5 (c 1.00, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.37 (s, 3 H), 0.52 (m, 1 H), 0.96 (d, J = 5.6 Hz, 3 H), 1.15-1.35 (m, 7 H), 1.41 (dd, J = 7.0, 11.4 Hz, 1 H), 1.47-1.66 (m, 6 H), 1.85-2.04 (m, 4 H), 2.30 (dd, J = 7.0, 13.3 Hz, 1 H), 2.59 (dd, J = 3.3, 13.3 Hz, 1 H), 2.78 (dd, J = 3.8, 12.6 Hz, 1 H), 4.22 (m, 1 H), 4.26 (ddd, J = 2.2, 2.2, 7.2 Hz, 1 H), 4.23 (m, 1 H), 4.82 (ddd, J = 7.2, 7.2, 14.7 Hz, 1 H), 4.98 (s, 1 H), 5.32 (s, 1 H), 5.60 (d, J = 2.2 Hz, 1 H), 5.94 (d, J = 11.2 Hz, 1 H), 6.35 (d, J = 11.2 Hz, 1 H), 6.40 (d, J = 2.2 Hz, 1 H), 7.11-7.13 (m, 2 H), 7.29-7.36 (m, 3 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.9, 19.2, 22.1, 23.5, 26.8, 29.0, 33.3, 37.6, 40.4, 42.9, 45.3, 45.8, 49.7, 56.1, 56.6, 66.8, 70.9, 80.5, 111.9, 117.0, 124.0, 124.9, 127.6, 128.7 (2 C), 128.9 (2 C), 132.8, 138.3, 139.8, 142.8, 147.4, 170.432.
LRMS m / z 502 (M ⁺ ), 484, 466, 451, 278, 251, 209
HRMS calcd for C ₃₃ H ₄₂ O ₄ 502.3083, found 502.3081

[Example 60]
20 (R)-(Tetrahydro-3-methylene-2-furanone-4 (R) -phenyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z), 7 (E), 10 ( 19) Preparation of -triene-1α, 3β-diol (Compound No. 109c)

(1) Example using 400 mg (0.90 mmol) of compound (4syn) (Z = (2-1), Y = Br, R ^2c = Ph, 4R / 5R) obtained in Example 59 (1) Reaction similar to 12 (1) was performed, and 373 mg of compound (Q) (4R / 5R) was obtained. Yield 92%. Colorless solid.
[α] _D ²² +45.2 (c 1.08, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.58 (s, 3 H), 1.02 (d, J = 6.4 Hz, 3 H), 1.20-1.36 (m, 5 H), 1.41-1.75 (m, 8 H) , 1.86 (m, 1 H), 1.96 (ddd, J = 1.7, 6.8, 12.2 Hz, 1 H), 2.03 (m, 1 H), 2.88 (m, 1 H), 3.23 (d, J = 8.3 Hz , 1 H), 3.98 (s, 2 H), 4.23 (br dd, J = 8.3, 8.5 Hz, 1 H), 5.16 (s, 1 H), 5.24 (s, 1 H), 5.63 (s, 1 H), 7.23-7.35 (m, 5 H).
¹³ C-NMR (CDCl ₃ ) δ: 12.0, 18.7, 22.1, 22.6, 27.8, 31.1, 32.9, 40.0, 41.7, 45.7, 56.0, 56.42, 56.43, 65.8, 69.8, 97.4, 111.5, 127.1, 128.6 (2 C ), 128.9 (2 C), 139.6, 145.0, 149.3.
LRMS m / z 446 (M ⁺ ), 428, 349, 331, 254
HRMS calcd for C ₂₅ H ₃₁ O ₂ ⁷⁹ Br 446.1820, found 446.1820

(2) The same reaction as in Example 12 (2) was carried out using 460 mg (1.0 mmol) of the compound (Q) (4R / 5R) obtained above, and the compound (5syn) (Z = (2-1) ), Y = Br, R ^2c = Ph, R ⁸ = Piv, 4R / 5R). Yield 94%. Colorless oil.
[α] _D ¹⁹ +37.1 (c 1.54, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.58 (s, 3 H), 1.02 (d, J = 6.3 Hz, 3 H), 1.19 (s, 9 H), 1.23-1.38 (m, 5 H), 1.41 -1.58 (m, 4 H), 1.60-1.75 (m, 3 H), 1.86 (m, 1 H), 1.96 (br dd, J = 6.6, 12.2 Hz, 1 H), 2.03 (m, 1 H) , 2.88 (m, 1 H), 3.20 (d, J = 8.1 Hz, 1 H), 4.21 (br dd, J = 8.7, 8.7 Hz, 1 H), 4.39 (s, 2 H), 5.22 (s, 1 H), 5.25 (s, 1 H), 5.63 (s, 1 H), 7.24-7.35 (m, 5 H).
¹³ C-NMR (CDCl ₃ ) δ: 12.1, 18.7, 22.2, 22.7, 27.3 (3 C), 27.8, 31.1, 32.9, 38.9, 40.0, 41.7, 45.7, 56.0, 56.2, 56.4, 66.7, 69.6, 97.4, 111.5, 127.2, 128.6 (2 C), 128.8 (2 C), 138.9, 144.5, 144.8, 177.7.
LRMS m / z 429 ((M-OPiv) ⁺ ), 411, 332, 255
HRMS calcd for C ₂₅ H ₃₄ O ⁷⁹ Br 429.1793, found 429.1797

(3) Compound (5syn) obtained above (Z = (2-1), Y = Br, R ^2c = Ph, R ⁸ = Piv, 4R / 5R) 700 mg (1.3 mmol) of methylene chloride (6 6.4 mg), 324 mg (0.92 mmol) of tetrapropylammonium parthenate (Pr ₄ NRuO ₄ ) and 771 mg (6.6 mmol) of N-methylmorpholine N-oxide (NMO) were added and stirred at room temperature for 1 hour. After the reaction solution was filtered, the filtrate was concentrated. The obtained crude product was dissolved in THF (10 ml). To this solution, 82 mg (2.2 mmol) of LiAlH ₄ was added at 0 ° C., and the mixture was stirred at room temperature for 3.5 hours. Water was added to the reaction solution at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain 126 mg of compound (Q) (4R / 5S). Yield 19%. Colorless oil.
[α] _D ²⁵ +44.1 (c 2.31, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.45 (s, 3 H), 0.99 (d, J = 6.6 Hz, 3 H), 1.13-1.38 (m, 5 H), 1.40-1.73 (m, 8 H) , 1.87-1.96 (m, 2 H), 2.25 (m, 1 H), 2.85 (m, 1 H), 3.33 (d, J = 8.0 Hz, 1 H), 3.98 (d, J = 13.4 Hz, 1 H), 4.04 (d, J = 13.4 Hz, 1 H), 4.23 (ddd, J = 4.2, 7.7, 8.0 Hz, 1 H), 5.32 (br s, 1 H), 5.33 (br s, 1 H) , 5.60 (br s, 1 H), 7.20-7.32 (m, 5 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.7, 20.2, 22.1, 22.6, 27.5, 31.0, 35.2, 39.8, 41.8, 45.5, 55.7, 56.4, 57.3, 65.3, 72.4, 97.3, 113.3, 126.9, 128.3 (2 C ), 128.5 (2 C), 140.5, 145.0, 148.8.
LRMS m / z 446 (M ⁺ ), 428, 349, 331, 254
HRMS calcd for C ₂₅ H ₃₅ O ₂ ⁷⁹ Br 446.1820, found 446.1828

(4) 136 mg (0.304 mmol) of the compound (Q) (4R / 5S) obtained above was dissolved in methylene chloride (3 ml). To the solution, 2.4 g (27.6 mmol) of MnO ₂ was added and stirred at room temperature for 32 hours. After filtering this reaction liquid, the residue obtained by concentrating the filtrate was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1) to give compound (4anti) (Z = (2-1) , Y = Br, R ^2c = Ph, 4R / 5S). Yield 77%. Colorless oil.
[α] _D ²⁵ +59.51 (c 0.69, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.48 (s, 3 H), 0.86 (d, J = 6.6 Hz, 3 H), 1.17-1.32 (m, 3 H), 1.34-1.52 (m, 4 H) , 1.57-1.72 (m, 3 H), 1.80 (ddd, J = 3.5, 5.6, 14.3 Hz, 1 H), 1.87-2.00 (m, 3 H), 2.86 (m, 1 H), 3.72 (ddd, J = 3.2, 3, 6.8 Hz, 1 H), 4.46 (ddd, J = 6.5, 6.5, 6.8 Hz, 1 H), 5.34 (d, J = 3.2 Hz, 1 H), 5.63 (s, 1 H) , 6.32 (d, J = 3.3 Hz, 1 H), 7.19-7.21 (m, 2 H), 7.30 (m, 1 H), 7.35-7.38 (m, 2 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.9, 18.5, 22.1, 22.5, 27.6, 31.0, 33.0, 39.9, 41.3, 45.6, 53.5, 55.9, 56.0, 82.8, 97.6, 123.3, 127.8, 128.3 (2 C), 129.1 (2 C), 138.4, 140.2, 144.7, 169.6.
LRMS m / z 442 (M ⁺ ), 363, 227, 201, 175, 147
HRMS calcd for C ₂₅ H ₃₁ O ₂ ⁷⁹ Br 442.1507, found 442.1499

(5) Compound (4anti) obtained above (Z = (2-1), Y = Br, R ^2c = Ph, 4R / 5S) 16 mg (36 μmol) and compound (7) (R ³ = TBS, R ⁶ = hydrogen atom, 3α / 5β) 20 mg (54 μmol) was used to carry out the same reaction as in Example 14 (2-a). 10 mg of 109c was obtained. Yield 55%.
Compound No. 109c:
[α] _D ²⁶ +7.22 (c 0.69, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.46 (s, 3 H), 0.85 (d, J = 6.6 Hz, 3 H), 1.13-1.40 (m, 3 H), 1.46-1.55 (m, 6 H) , 1.63-1.72 (m, 3 H), 1.81 (ddd, J = 3.4, 5.6, 14.2 Hz, 1 H), 1.87-2.05 (m, 5 H), 2.31 (dd, J = 6.3, 13.5 Hz, 1 H), 2.59 (dd, J = 3.5, 13.5 Hz, 1 H), 2.80 (m, 1 H), 3.72 (ddd, J = 3.4, 3.4, 7.0 Hz, 1 H), 4.22 (m, 1 H) , 4.45 (m, 1 H), 4.50 (ddd, J = 6.7, 6.7, 6.9 Hz, 1 H), 4.99 (s, 1 H), 5.32 (br s, 1 H), 5.35 (d, J = 3.1 Hz, 1 H), 6.00 (d, J = 11.1 Hz, 1 H), 6.33 (d, J = 3.1 Hz, 1 H), 6.36 (d, J = 11.1 Hz, 1 H), 7.19-7.21 (m , 2 H), 7.29-7.32 (m, 1 H), 7.35-7.39 (m, 2 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.9, 19.3, 22.3, 23.5, 27.9, 29.1, 34.1, 40.3, 41.7, 42.9, 45.3, 45.9, 53.5, 56.2, 56.5, 66.9, 70.8, 84.3, 111.7, 117.1, 123.4, 124.9, 127.7, 128.3 (2 C), 129.1 (2 C), 133.0, 139.1, 140.5, 142.7, 147.6, 169.7.
LRMS m / z 502 (M ⁺ ), 484, 466, 451, 278, 251, 209
HRMS calcd for C ₃₃ H ₄₂ O ₄ 502.3083, found 502.3077

[Example 61]
20 (R)-(Tetrahydro-3-methylene-2-furanone-4 (S) -phenyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z), 7 (E), 10 ( 19) Production of -triene-1α, 3β-diol (Compound No. 109d)

(1) Example using 330 mg (0.74 mmol) of the compound (4syn) (Z = (2-1), Y = Br, R ^2c = Ph, 4S / 5S) obtained in Example 59 (1) Reaction similar to 12 (1) was performed, and 304 mg of compounds (Q) (4S / 5S) were obtained. Yield 91%. Colorless solid.
[α] _D ²⁴ +105.11 (c 1.08, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 1.05 (d, J = 6.6 Hz, 3 H), 1.17 (ddd, J = 6.8, 8.9, 14.1 Hz, 1 H), 1.24- 1.32 (m, 2 H), 1.38 (ddd, J = 5.2, 12.0, 12.0 Hz, 1 H), 1.43-1.61 (m, 4 H), 1.65-1.83 (m, 6 H), 1.93 (dd, J = 6.8, 12.5 Hz, 1 H), 2.00 (br d, J = 12.7 Hz, 1 H), 2.87 (m, 1 H), 3.35 (d, J = 6.0 Hz, 1 H), 4.00 (d, J = 14.5 Hz, 1 H), 4.07 (d, J = 14.5 Hz, 1 H), 4.23 (ddd, J = 6.0, 6.1, 6.1 Hz, 1 H), 5.16 (s, 1 H), 5.27 (s, 1 H), 5.63 (s, 1 H), 7.26 (m, 1 H), 7.30-7.35 (m, 4 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.8, 19.7, 22.0, 22.5, 27.4, 31.0, 34.8, 39.8, 41.5, 45.5, 54.7, 55.8, 56.5, 65.7, 72.0, 97.4, 113.0, 127.1, 128.5 (2 C ), 129.5 (2 C), 138.9, 145.0, 149.5.
LRMS m / z 428 ((MH ₂ O) ⁺ ) 331, 254, 227
HRMS calcd for C ₂₅ H ₃₃ O ⁷⁹ Br 428.1715, found 428.1718

(2) The same reaction as in Example 12 (2) was performed using 379 mg (0.85 mmol) of the compound (Q) (4S / 5S) obtained above, and the compound (5syn) (Z = (2-1) ), Y = Br, R ^2c = Ph, R ⁸ = Piv, 4S / 5S). Yield 93%. Colorless crystalline material.
[α] _D ¹⁹ +108.55 (c 0.31, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 1.05 (d, J = 6.6 Hz, 3 H), 1.20 (s, 9 H), 1.24-1.34 (m, 4 H), 1.44 -1.63 (m, 5 H), 1.65-1.73 (m, 3 H), 1.79 (m, 1 H), 1.94 (ddd, J = 1.2, 6.8, 12.5 Hz, 1 H), 2.00 (m, 1 H ), 2.87 (m, 1 H), 3.47 (d, J = 5.9 Hz, 1 H), 4.22 (m, 1 H), 4.40 (d, J = 13.3 Hz, 1 H), 4.46 (d, J = 13.3 Hz, 1 H), 5.25 (s, 1 H), 5.28 (s, 1 H), 5.63 (s, 1 H), 7.25-7.33 (m, 5 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.9, 19.8, 22.1, 22.7, 27.3, 27.6, 31.1, 35.0, 38.9, 39.9, 41.6, 45.6, 54.2, 55.8, 56.5, 66.7, 71.7, 97.4, 114.1, 127.1, 128.4 (2 C), 129.4 (2 C), 138.0, 144.78, 144.84, 177.8.
LRMS m / z 429 ((M-OPiv) ⁺ ) 350, 232, 175
HRMS calcd for C ₂₅ H ₃₄ O ⁷⁹ Br 429.1793, found 429.1792

(3) 405 mg (0.76 mmol) of LiAlH using the compound (5syn) obtained above (Z = (2-1), Y = Br, R ^2c = Ph, R ⁸ = Piv, 4S / 5S) ₄ was changed to LiAl (Ot-Bu) ₃ and the same reaction as in Example 60 (3) was performed to obtain 252 mg of compound (Q) (4S / 5R). Yield 62%. Colorless oil.
[α] _D ²⁷ +85.40 (c 1.00, CDCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.99 (d, J = 6.3 Hz, 3 H), 1.10 (m, 1 H), 1.20 (s, 9 H), 1.16-1.33 (m, 3 H), 1.38-1.49 (m, 3 H), 1.51-1.66 (m, 3 H), 1.72-1.85 (m, 2 H), 1.90 (br dd, J = 7.0, 11.8 Hz, 1 H), 1.97 (br d, J = 12.9 Hz, 1 H), 2.36 (br s, 1 H), 2.85 (m, 1 H), 3.26 (d, J = 9.7 Hz, 1 H), 4.27 (br dd, J = 9.7, 9.8 Hz, 1 H), 4.36 (d, J = 13.9 Hz, 1 H), 4.53 (d, J = 13.9 Hz, 1 H), 5.25 (s, 1 H), 5.34 (s , 1 H), 5.62 (s, 1 H), 7.16-7.18 (m, 2 H), 7.21-7.31 (m, 3 H).
¹³ C-NMR (CDCl ₃ ) δ: 12.0, 18.6, 22.1, 22.6, 27.2 (3 C), 27.7, 31.1, 32.8, 38.8, 39.9, 41.1, 45.6, 56.0, 56.2, 58.4, 66.0, 68.9, 97.4, 113.7, 126.9, 128.1 (2 C), 128.6 (2 C), 139.8, 144.6, 145.0, 178.2.
LRMS m / z 512 ((MH ₂ O) ⁺ ) 427, 411, 332, 255
HRMS calcd for C ₃₀ H ₄₁ O ₂ ⁷⁹ Br 512.2290, found 512.2291

(4) Using the compound (Q) (4S / 5R) 229 mg (0.431 mmol) obtained above, the same reaction as in Example 60 (4) was carried out, and the compound (4anti) (Z = (2-1) ), Y = Br, R ^2c = Ph, 4S / 5R). Yield 84%. Colorless oil.
[α] _D ²⁵ +59.5 (c 0.69, CHCl ₃ )
IR (neat) 1765, 1456, 1234, 1140 cm ^-1
1 H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.90 (d, J = 6.6 Hz, 3 H), 1.18-1.29 (m, 2 H), 1.32-1.40 (m, 2 H) , 1.43-1.67 (m, 4 H), 1.78-1.87 (m, 3 H), 1.92-1.99 (m, 2 H), 2.86 (m, 1 H), 3.71 (m, 1 H), 4.46 (br dd, J = 8.3, 8.3 Hz, 1 H), 5.37 (d, J = 3.1 Hz, 1 H), 5.65 (s, 1 H), 6.34 (d, J = 3.1 Hz, 1 H), 7.19-7.21 (m, 2 H), 7.31-7.40 (m, 3 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.9, 18.5, 22.1, 22.5, 27.6, 31.0, 33.0, 39.9, 41.3, 45.6, 53.5, 55.9, 56.0, 82.8, 97.6, 123.3, 127.8, 128.3 (2 C), 129.1 (2 C), 138.4, 140.2, 144.7, 169.6.
LRMS m / z 442 (M ⁺ ), 363, 227, 201, 175, 147
HRMS calcd for C ₂₅ H ₃₁ O ₂ ⁷⁹ Br 442.1507, found 442.1499

(5) Compound (4anti) obtained above (Z = (2-1), Y = Br, R ^2c = Ph, 4S / 5R) 25 mg (56 μmol) and compound (7) (R ³ = TBS, R ⁶ = hydrogen atom, 3α / 5β) 31 mg (84 μmol) was used to carry out the same reaction as in Example 14 (2-a). 14 mg of 109d was obtained. Yield 49%.
Compound No. 109d:
[α] _D ²⁵ +14.60 (c 1.00, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.90 (d, J = 6.3 Hz, 3 H), 1.21-1.31 (m, 3 H), 1.36 (m, 1 H), 1.46 -1.56 (m, 5 H), 1.64-1.69 (m, 2 H), 1.79-2.03 (m, 7 H), 2.31 (dd, J = 6.2, 12.8 Hz, 1 H), 2.60 (br d, J = 12.8 Hz, 1 H), 2.82 (m, 1 H), 3.71 (m, 1 H), 4.24 (m, 1 H), 4.44-4.49 (m, 2 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.37 (d, J = 2.7 Hz, 1 H), 6.00 (d, J = 11.2 Hz, 1 H), 6.34-6.38 (m, 2 H), 7.19-7.21 (m, 2 H), 7.32-7.40 (m, 3 H).
¹³ C-NMR (CDCl ₃ ) δ: 12.1, 18.5, 22.3, 23.5, 27.6, 29.1, 33.0, 40.5, 41.3, 42.9, 45.3, 46.0, 53.5, 56.3, 56.8, 66.9, 70.8, 82.9, 111.8, 117.2, 123.3, 124.8, 127.8, 128.3 (2 C), 129.1 (2 C), 133.0, 138.5, 140.3, 142.6, 147.5, 169.7.
LRMS m / z 502 (M ⁺ ), 484, 466, 451, 278, 251, 209
HRMS calcd for C ₃₃ H ₄₂ O ₄ 502.3083, found 502.3081

[Example 62]
2α-Methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -phenyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z), 7 (E ), 10 (19) -Triene-1α, 3β-diol (Compound No. 209a)

Compound (4syn) obtained in Example 59 (1) (Z = (2-1), Y = Br, R ^2c = Ph, 4R / 5R) 16 mg (36 μmol) and compound (7) (R ³ = TBS) , R ⁶ = Me, 3α / 4α / 5β) 21 mg (55 μmol), the same reaction as in Example 14 (2-a) was carried out. 10 mg of 209a was obtained. Yield 54%.
¹ H-NMR (CDCl ₃ ) δ: 0.51 (s, 3 H), 0.61 (ddd, J = 14.5, 10.7, 2.0 Hz, 1 H), 0.91 (d, J = 6.6 Hz, 3 H), 1.07 ( d, J = 6.8 Hz, 3 H), 1.21 (ddd, J = 12.9, 12.9, 4.0 Hz, 1 H), 1.31-1.45 (m, 4 H), 1.48-1.72 (m, 9 H), 1.86- 1.96 (m, 3 H), 2.22 (dd, J = 13.5, 7.7Hz, 1 H), 2.66 (dd, J = 13.5, 4.2 Hz, 1 H), 2.79 (dd, J = 11.9, 3.8 Hz, 1 H), 3.84 (ddd, J = 12.0, 7.7, 4.2 Hz, 1 H), 4.30 (dd, J = 4.0, 4.0 Hz, 1 H), 4.35 (ddd, J = 7.9, 7.8, 2.7 Hz, 1 H ), 4.86 (ddd, J = 11.7, 7.9, 1.9 Hz, 2 H), 4.99 (d, J = 2.0 Hz, 1 H), 5.27 (s, 1 H), 5.61 (d, J = 2.6 Hz, 1 H), 5.97 (d, J = 11.2 Hz, 1 H), 6.36 (d, J = 11.2 Hz, 1 H), 6.45 (d, J = 2.6 Hz, 1 H), 7.11-7.13 (m, 2 H ), 7.29-7.37 (m, 3 H).
LRMS m / z 516 (M ⁺ ), 498, 480, 454, 265, 223
HRMS calcd for C ₃₄ H ₄₄ O ₄ 516.3240, found 516.3243

[Example 63]
2α-Methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -phenyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z), 7 (E ), 10 (19) -Triene-1α, 3β-diol (Compound No. 209b)

Compound (4syn) obtained in Example 59 (1) (Z = (2-1), Y = Br, R ^2c = Ph, 4S / 5S) 26 mg (59 μmol) and compound (7) (R ³ = TBS) , R ⁶ = Me, 3α / 4α / 5β) 34 mg (89 μmol), the same reaction as in Example 14 (2-a) was carried out. 13 mg of 209b was obtained. Yield 43%.
¹ H-NMR (CDCl ₃ ) δ: 0.35 (s, 3 H), 0.51 (m, 1 H), 0.96 (d, J = 5.4 Hz, 3 H), 1.09 (d, J = 6.8 Hz, 3 H ), 1.17-1.32 (m, 7 H), 1.37-1.68 (m, 7 H), 1.86-1.92 (m, 3 H), 2.22 (dd, J = 13.7, 8.3 Hz, 1 H), 2.65 (dd , J = 13.7, 3.9 Hz, 1 H), 2.78 (dd, J = 12.5, 3.9 Hz, 1 H), 3.82 (m, 1 H), 4.26 (ddd, J = 7.2, 2.3, 2.1 Hz, 1 H ), 4.29 (br s, 1 H), 4.82 (ddd, J = 7.2, 6.8, 6.8 Hz, 1 H), 4.98 (d, J = 2.0 Hz, 1 H), 5.26 (s, 1 H), 5.60 (d, J = 2.2 Hz, 1 H), 5.93 (d, J = 11.1 Hz, 1 H), 6.36 (d, J = 11.1 Hz, 1 H), 6.40 (d, J = 2.2 Hz, 1 H) , 7.11-7.13 (m, 2 H), 7.30-7.36 (m, 3 H).
LRMS m / z 516 (M ⁺ ), 498, 480, 454, 265, 223
HRMS calcd for C ₃₄ H ₄₄ O ₄ 516.3240, found 516.3243

[Example 64]
2α-Methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -phenyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z), 7 (E ), 10 (19) -triene-1α, 3β-diol (Compound No. 209c)

Compound (4anti) (Z = (2-1), Y = Br, R ^2c = Ph, 4R / 5S) 17 mg (38 μmol) obtained in Example 60 (4) and compound (7) (R ³ = TBS) , R ⁶ = Me, 3α / 4α / 5β) 22 mg (57 μmol), the same reaction as in Example 14 (2-a) was carried out. 9 mg of 209c was obtained. Yield 45%.
¹ H-NMR (CDCl ₃ ) δ: 0.45 (s, 3 H), 0.84 (d, J = 6.3 Hz, 3 H), 1.08 (d, J = 6.8 Hz, 3 H), 1.12-1.32 (m, 4 H), 1.34-1.71 (m, 11 H), 1.80 (ddd, J = 14.2, 6.5, 3.3 Hz, 1 H), 1.83-1.94 (m, 3 H), 1.98 (br d, J = 10.4 Hz , 1 H), 2.23 (dd, J = 13.4, 8.0 Hz, 1 H), 2.60 (dd, J = 13.6, 4.1 Hz, 1 H), 2.80 (m, 1 H), 3.72 (ddd, J = 7.0 , 3.2, 3.2 Hz, 1 H), 3.84 (ddd, J = 8.0, 7.6, 4.1 Hz, 1 H), 4.30 (br s, 1 H), 4.50 (ddd, J = 7.0, 6.8, 6.8 Hz, 1 H), 5.00 (d, J = 2.0 Hz, 1 H), 5.27 (s, 1 H), 5.35 (d, J = 3.1 Hz, 1 H), 5.99 (d, J = 11.4 Hz, 1 H), 6.32 (d, J = 3.1 Hz, 1 H), 6.37 (d, J = 11.4 Hz, 1 H), 7.18-7.21 (m, 2 H), 7.30 (m, 1 H), 7.34-7.39 (m, 2 H).
LRMS m / z 516 (M ⁺ ), 498, 480, 454, 265, 223
HRMS calcd for C ₃₄ H ₄₄ O ₄ 516.3240, found 516.3245

[Example 65]
2α-Methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -phenyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z), 7 (E ), 10 (19) -Triene-1α, 3β-diol (Compound No. 209d)

Compound (4anti) (Z = (2-1), Y = Br, R ^2c = Ph, 4S / 5R) 27 mg (61 μmol) obtained in Example 61 (4) and compound (7) (R ³ = TBS) , R ⁶ = Me, 3α / 4α / 5β) 28 mg (73 μmol), the same reaction as in Example 14 (2-a) was carried out. 14 mg of 209d was obtained. Yield 45%.
¹ H-NMR (10% CD ₃ OD in CDCl ₃ ) δ: 0.54 (s, 3 H), 0.90 (d, J = 6.3 Hz, 3 H), 1.08 (d, J = 6.8 Hz, 3 H), 1.21-1.30 (m, 3 H), 1.33-1.41 (m, 2 H), 1.44-1.56 (m, 4 H), 1.60-1.70 (m, 2 H), 1.75-1.82 (m, 2 H), 1.84-1.99 (m, 4 H), 2.22 (dd, J = 13.4, 8.3 Hz, 1 H), 2.67 (dd, J = 13.4, 3.9 Hz, 1 H), 2.81 (m, 1 H), 3.71 ( ddd, J = 7.9, 3.2, 3.2 Hz, 1 H), 3.85 (m, 1 H), 4.31 (dd, J = 4.0, 4.0 Hz, 1 H), 4.47 (ddd, J = 10.3, 7.9, 2.0 Hz , 1 H), 5.00 (d, J = 2.0 Hz, 1 H), 5.28 (s, 1 H), 5.37 (d, J = 3.1 Hz, 1 H), 6.00 (d, J = 11.2 Hz, 1 H ), 6.34 (d, J = 3.1 Hz, 1 H), 6.37 (d, J = 11.2 Hz, 1 H), 7.19-7.21 (m, 2 H), 7.32 (m, 1 H), 7.36-7.40 ( m, 2 H).
LRMS m / z 516 (M ⁺ ), 498, 480, 454, 265, 223
HRMS calcd for C ₃₄ H ₄₄ O ₄ 516.3240, found 516.3242

[Example 66]
2α- (3-Hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -phenyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 810a)

Compound (4syn) obtained in Example 59 (1) (Z = (2-1), Y = Br, R ^2c = Ph, 4R / 5R) 17 mg (38 μmol) and compound (7) (R ³ = TBS) , R ⁶ = — (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 31 mg (57 μmol) was used to carry out a reaction similar to Example 14 (2-a), and compound No. 10 mg of 810a was obtained. Yield 47%.
¹ H-NMR (CDCl ₃ ) δ: 0.50 (s, 3 H), 0.61 (ddd, J = 14.4, 10.7, 2.0 Hz, 1 H), 0.91 (d, J = 6.6 Hz, 3 H), 1.06- 1.14 (m, 2 H), 1.17-1.40 (m, 4 H), 1.45 (m, 1 H), 1.57-1.76 (m, 12 H), 1.88 (dd, J = 11.1, 8.2 Hz, 1 H) , 1.95 (br d, J = 12.7 Hz, 1 H), 2.24 (dd, J = 13.2, 8.4 Hz, 1 H), 2.65 (dd, J = 13.2, 4.3 Hz, 1 H), 2.79 (br dd, J = 12.1, 3.1 Hz, 1 H), 3.70 (t, J = 5.7 Hz, 2 H), 3.90 (ddd, J = 8.4, 8.2, 4.3 Hz, 1 H), 4.34-4.38 (m, 2 H) , 4.86 (ddd, J = 11.8, 7.9, 2.0 Hz, 1 H), 4.97 (d, J = 1.5 Hz, 1 H), 5.27 (d, J = 1.5 Hz, 1 H), 5.61 (d, J = 2.6 Hz, 1 H), 5.96 (d, J = 11.5 Hz, 1 H), 6.37 (d, J = 11.5 Hz, 1 H), 6.45 (d, J = 2.6 Hz, 1 H), 7.11-7.13 ( m, 2 H), 7.28-7.37 (m, 3 H).
LRMS m / z 560 (M ⁺ ), 542, 524, 509, 349, 262
HRMS calcd for C ₃₆ H ₄₈ O ₅ 560.3502, found 560.3510

[Example 67]
2α- (3-Hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -phenyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 810b)

Compound (4syn) obtained in Example 59 (1) (Z = (2-1), Y = Br, R ^2c = Ph, 4S / 5S) 31 mg (70 μmol) and compound (7) (R ³ = TBS) , R ⁶ = — (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 57 mg (105 μmol) was used to carry out the same reaction as in Example 14 (2-a). 22 mg of 810b was obtained. Yield 54%.
¹ H-NMR (CDCl ₃ ) δ: 0.35 (s, 3 H), 0.51 (m, 1 H), 0.95 (d, J = 5.4 Hz, 3 H), 1.14-1.37 (m, 7 H), 1.39 -1.52 (m, 3 H), 1.60-1.78 (m, 9 H), 1.86-1.92 (m, 1 H), 2.24 (dd, J = 13.2, 8.7 Hz, 1 H), 2.66 (dd, J = 13.2, 4.3 Hz, 1 H), 2.78 (m, 1 H), 3.70 (t, J = 4.9 Hz, 2 H), 3.87 (ddd, J = 8.7, 7.5, 4.3 Hz, 1 H), 4.25 (ddd , J = 7.3, 2.1, 2.1 Hz, 1 H), 4.82 (ddd, J = 7.5, 6.8, 6.8 Hz, 1 H), 4.97 (d, J = 1.7 Hz, 1 H), 5.27 (d, J = 1.7 Hz, 1 H), 5.60 (d, J = 2.1 Hz, 1 H), 5.92 (d, J = 11.4 Hz, 1 H), 6.37 (d, J = 11.4 Hz, 1 H), 6.40 (d, J = 2.1 Hz, 1 H), 7.11-7.13 (m, 2 H), 7.28-7.37 (m, 3 H).
LRMS m / z 560 (M ⁺ ), 542, 524, 509, 349, 262
HRMS calcd for C ₃₆ H ₄₈ O ₅ 560.3502, found 560.3502

[Example 68]
2α- (3-hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -phenyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 810c)

19 mg (43 μmol) of the compound (4anti) (Z = (2-1), Y = Br, R ^2c = Ph, 4R / 5S) obtained in Example 60 (4) and the compound (7) (R ³ = TBS) , R ⁶ =-(CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 35 mg (65 μmol) was used to carry out a reaction similar to Example 14 (2-a), and compound No. 10 mg of 810c was obtained. Yield 42%.
¹ H-NMR (CDCl ₃ ) δ: 0.45 (s, 3 H), 0.84 (d, J = 6.3 Hz, 3 H), 1.13-1.39 (m, 4 H), 1.46-1.48 (m, 4 H) , 1.64-2.04 (m, 14 H), 2.24 (dd, J = 13.3, 8.5 Hz, 1 H), 2.65 (dd, J = 13.3, 4.2 Hz, 1 H), 2.80 (br d, J = 12.2 Hz , 1 H), 3.68-3.73 (m, 3 H), 3.88 (ddd, J = 8.5, 8.1, 4.2 Hz, 1 H), 4.37 (s, 1 H), 4.50 (ddd, J = 6.8, 6.8, 6.8 Hz, 1 H), 4.98 (s, 1 H), 5.27 (s, 1 H), 5.34 (d, J = 3.2 Hz, 1 H), 5.98 (d, J = 11.3 Hz, 1 H), 6.32 (d, J = 3.2 Hz, 1 H), 6.38 (d, J = 11.3 Hz, 1 H), 7.18-7.20 (m, 2 H), 7.28-7.38 (m, 3 H).
LRMS m / z 560 (M ⁺ ), 542, 524, 509, 349, 262
HRMS calcd for C ₃₆ H ₄₈ O ₅ 560.3502, found 560.3495

[Example 69]
2α- (3-Hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -phenyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 810d)

Compound (4anti) (Z = (2-1), Y = Br, R ^2c = Ph, 4S / 5R) 21 mg (47 μmol) obtained in Example 61 (4) and compound (7) (R ³ = TBS) , R ⁶ =-(CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 38 mg (70 μmol) was used to carry out the same reaction as in Example 14 (2-a), and compound No. 12 mg of 810d was obtained. Yield 45%.
¹ H-NMR (10% CD ₃ OD in CDCl ₃ ) δ: 0.54 (s, 3 H), 0.89 (d, J = 6.6 Hz, 3 H), 1.20-1.29 (m, 4 H), 1.36 (m , 1 H), 1.43-1.53 (m, 3 H), 1.63-1.98 (m, 14 H), 2.24 (dd, J = 13.4, 8.9 Hz, 1 H), 2.66 (dd, J = 13.4, 4.2 Hz , 1 H), 2.81 (br d, J = 13.7 Hz, 1 H), 3.68-3.73 (m, 3 H), 3.90 (ddd, J = 8.3, 8.3, 4.4 Hz, 1 H), 4.37 (d, J = 2.9 Hz, 1 H), 4.46 (m, 1 H), 4.98 (d, J = 1.7 Hz, 1 H), 5.27 (d, J = 1.7 Hz, 1 H), 5.37 (d, J = 3.2 Hz, 1 H), 6.00 (d, J = 11.2 Hz, 1 H), 6.34 (d, J = 3.2 Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H), 7.19-7.21 (m , 2 H), 7.32 (m, 1 H), 7.36-7.40 (m, 2 H).
LRMS m / z 560 (M ⁺ ), 542, 524, 509, 349, 262
HRMS calcd for C ₃₆ H ₄₈ O ₅ 560.3502, found 560.3502

[Example 70]
2α- (3-hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -phenyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 1110a)

Compound (4syn) obtained in Example 59 (1) (Z = (2-1), Y = Br, R ^2c = Ph, 4R / 5R) 18 mg (41 μmol) and compound (7) (R ³ = TBS) , R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 34 mg (61 μmol) was used to carry out a reaction similar to Example 14 (2-a), and compound No. 12 mg of 1110a was obtained. Yield 51%.
¹ H-NMR (CDCl ₃ ) δ: 0.51 (s, 3 H), 0.61 (ddd, J = 14.4, 10.6, 1.8 Hz, 1 H), 0.91 (d, J = 6.3 Hz, 3 H), 1.06- 1.14 (m, 2 H), 1.21 (ddd, J = 12.8, 12.8, 3.7 Hz, 1 H), 1.31-1.39 (m, 2 H), 1.42-1.71 (m, 6 H), 1.86-1.90 (m , 3 H), 1.95 (br d, J = 12.7 Hz, 1 H), 2.19 (br s, 1 H), 2.22 (dd, J = 13.2, 9.0 Hz, 1 H), 2.39 (br s, 1 H ), 2.52 (br s, 1 H), 2.67 (dd, J = 13.3, 4.4 Hz, 1 H), 2.79 (br d, J = 12.2 Hz, 1 H), 3.38 (dd, J = 7.3, 3.2 Hz , 1 H), 3.74-3.90 (m, 4 H), 4.06 (m, 1 H), 4.35 (ddd, J = 7.8, 2.4, 2.4 Hz, 1 H), 4.43 (br s, 1 H), 4.86 (ddd, J = 11.6, 7.9, 1.8 Hz, 1 H), 5.07 (d, J = 1.5 Hz, 1 H), 5.38 (s, 1 H), 5.61 (d, J = 2.6 Hz, 1 H), 5.97 (d, J = 11.2 Hz, 1 H), 6.39 (d, J = 11.2 Hz, 1 H), 6.45 (d, J = 2.6 Hz, 1 H), 7.11-7.13 (m, 2 H), 7.29 -7.37 (m, 3 H).
LRMS m / z 576 (M ⁺ ), 558, 540, 482, 428, 351, 309, 267
HRMS calcd for C ₃₆ H ₄₈ O ₆ 576.3451, found 576.3447

[Example 71]
2α- (3-Hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -phenyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 1110b)

Compound (4syn) obtained in Example 59 (1) (Z = (2-1), Y = Br, R ^2c = Ph, 4S / 5S) 40 mg (90 μmol) and compound (7) (R ³ = TBS) , R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 75 mg (135 μmol), the same reaction as in Example 14 (2-a) was carried out. 24 mg of 1110b was obtained. Yield 46%.
¹ H-NMR (CDCl ₃ ) δ: 0.35 (s, 3 H), 0.43 (m, 1 H), 0.95 (d, J = 5.1 Hz, 3 H), 1.15-1.31 (m, 6 H), 1.40 -1.52 (m, 3 H), 1.59-1.63 (m, 2 H), 1.87-1.91 (m, 4 H), 2.20-2.25 (m, 2 H), 2.47 (br s, 1 H), 2.53 ( br s, 1 H), 2.66 (dd, J = 13.5, 4.5 Hz, 1 H), 2.77 (br d, J = 11.5 Hz, 1 H), 3.36 (m, 1 H), 3.75-3.92 (m, 4 H), 4.04 (m, 1 H), 4.25 (m, 1 H), 4.44 (s, 1 H), 4.82 (m, 1 H), 5.07 (s, 1 H), 5.38 (s, 1 H ), 5.60 (s, 1 H), 5.93 (d, J = 10.7 Hz, 1 H), 6.37-6.40 (m, 2 H), 7.11-7.12 (m, 2 H), 7.30-7.35 (m, 3 H).
LRMS m / z 576 (M ⁺ ), 558, 540, 482, 428, 351, 309, 267
HRMS calcd for C ₃₆ H ₄₈ O ₆ 576.3451, found 576.3453

[Example 72]
2α- (3-hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -phenyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No 1110c)

Compound (4anti) obtained in Example 60 (4) (Z = (2-1), Y = Br, R ^2c = Ph, 4R / 5S) 21 mg (47 μmol) and compound (7) (R ³ = TBS) , R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 40 mg (72 μmol), the same reaction as in Example 14 (2-a) was carried out. 10 mg of 1110c was obtained. Yield 37%.
¹ H-NMR (CDCl ₃ ) δ: 0.45 (s, 3 H), 0.83 (d, J = 6.6 Hz, 3 H), 1.13-1.38 (m, 3 H), 1.46-1.54 (m, 4 H) , 1.64-1.71 (m, 3 H), 1.77-2.00 (m, 6 H), 2.23 (dd, J = 13.4, 8.6 Hz, 1 H), 2.53 (m, 3 H), 2.67 (dd, J = 13.4, 4.5 Hz, 1 H), 2.80 (br d, J = 12.9 Hz, 1 H), 3.37 (dd, J = 7.3, 3.2 Hz, 1 H), 3.72 (m, 1 H), 3.74-3.91 ( m, 3 H), 4.05 (ddd, J = 8.6, 7.5, 4.5 Hz, 1 H), 4.44 (s, 1 H), 4.56 (ddd, J = 7.5, 6.8, 6.8 Hz, 1 H), 5.08 ( d, J = 2.7 Hz, 1 H), 5.34 (d, J = 3.1 Hz, 1 H), 5.38 (br s, 1 H), 5.99 (d, J = 11.1 Hz, 1 H), 6.32 (d, J = 3.1 Hz, 1 H), 6.40 (d, J = 11.1 Hz, 1 H), 7.18-7.20 (m, 2 H), 7.30 (m, 1 H), 7.34-7.38 (m, 2 H).
LRMS m / z 576 (M ⁺ ), 558, 540, 482, 428, 351, 309, 267
HRMS calcd for C ₃₆ H ₄₈ O ₆ 576.3451, found 576.3452

[Example 73]
2α- (3-Hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -phenyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No 1110d)

17 mg (38 μmol) of the compound (4anti) (Z = (2-1), Y = Br, R ^2c = Ph, 4S / 5R) obtained in Example 61 (4) and the compound (7) (R ³ = TBS) , R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 32 mg (57 μmol), the same reaction as in Example 14 (2-a) was carried out. 9 mg of 1110d was obtained. Yield 41%.
¹ H-NMR (CDCl ₃ ) δ: 0.54 (s, 3 H), 0.89 (d, J = 6.6 Hz, 3 H), 1.18-1.30 (m, 4 H), 1.36 (m, 1 H), 1.45 -1.56 (m, 3 H), 1.60-1.68 (m, 2 H), 1.75-1.82 (m, 2 H), 1.84-1.89 (m, 2 H), 1.92-1.99 (m, 2 H), 2.15 (br s, 1 H), 2.23 (dd, J = 13.7, 8.6 Hz, 1 H), 2.40 (br s, 1 H), 2.50 (br s, 1 H), 2.68 (dd, J = 13.7, 4.3 Hz, 1 H), 2.81 (br d, J = 12.5 Hz, 1 H), 3.38 (dd, J = 7.2, 3.3 Hz, 1 H), 3.71 (ddd, J = 7.7, 3.2, 3.2 Hz, 1 H ), 3.75-3.91 (m, 4 H), 4.06 (ddd, J = 8.6, 8.1, 4.3 Hz, 1 H), 4.44-4.84 (m, 2 H), 5.08 (d, J = 2.0 Hz, 1 H ), 5.37 (d, J = 3.2 Hz, 1 H), 5.39 (br s, 1 H), 6.00 (d, J = 11.5 Hz, 1 H), 6.35 (d, J = 3.2 Hz, 1 H), 6.40 (d, J = 11.5 Hz, 1 H), 7.19-7.21 (m, 2 H), 7.32 (m, 1 H), 7.36-7.40 (m, 2 H).
LRMS m / z 576 (M ⁺ ), 558, 540, 482, 428, 351, 309, 267
HRMS calcd for C ₃₆ H ₄₈ O ₆ 576.3451, found 576.3466

[Example 74]
20 (R)-(Tetrahydro-3-methylene-2-furanone-4,4-dimethyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z), 7 (E), 10 (19 ) -Triene-1α, 3β-diol (Compound No. 111a) and 20 (R)-(tetrahydro-3-methylene-2-furanone-4,4-dimethyl-5 (S) -yl) methyl-9,10 -Production of Secopregna-5 (Z), 7 (E), 10 (19) -triene-1α, 3β-diol compound (No. 111b)

(1) 94 mg (2.3 mmol) of LiAlH ₄ was added to a suspension of 739 mg (4.7 mmol) of chromium (III) chloride in THF (23 ml) at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. To this solution, a solution of compound (3a) (R ^2d = R ^2e = R ⁷ = Me) obtained in Reference Example 11 in 486 mg (2.34 mmol) in THF (8 ml) and a method known in the literature (for example, International Publication WO95 / No. 3716)) (3) (Z = (2-1), Y = Br) in 350 mg (1.17 mmol) in THF (8 ml) was added, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain compound (4) (Z = (2-1), Y = Br, 390 mg of a mixture of R ^2d = R ^2e = Me, 5R) and compound (4) (Z = (2-1), Y = Br, R ^2d = R ^2e = Me, 5S) (yield 80%, isomer contrast 2 : 1) was obtained. These were obtained as a single product by performing the transformations shown in (2), (3-a) and (3-b) below.

(2) Compound (4) obtained above (Z = (2-1), Y = Br, R ^2d = R ^2e = Me, 5R) and Compound (4) (Z = (2-1), Y = Br, R ^2d = R ^2e = Me, 5S) in toluene solution (3.3 ml) of 390 mg (1.0 mmol) at 0 ° C. in toluene solution of DIBAL-H 5 ml (1.04 M, 5.0 mmol) Then, the mixture was stirred at room temperature for 14 hours. Methanol and 10% aqueous potassium potassium tartrate were added to the reaction solution at 0 ° C., and the mixture was stirred at room temperature for 5 minutes, and then the aqueous layer was extracted with ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in 2.8 ml (0.3 mol) of pyridine, 0.16 ml (1.3 mmol) of pivaloyl chloride was added thereto at 0 ° C., and at room temperature. Stir for 1 hour. Water was added to the reaction solution at 0 ° C., and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in 2.8 ml of methylene chloride. At 0 ° C., 0.5 ml (2.1 mmol) of TBSOTf and 0.5 ml of 2,6-lutidine (4. 2 mmol) was added and stirred at room temperature for 5 hours. Water was added to the reaction solution at 0 ° C., and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in a toluene solution (3.0 ml), and 5 ml (1.04 M, 5.0 mmol) of DIBAL-H in toluene was added at 0 ° C. And stirred at room temperature for 14 hours. Methanol and 10% aqueous potassium potassium tartrate were added to the reaction solution at 0 ° C., and the mixture was stirred at room temperature for 5 minutes, and then the aqueous layer was extracted with ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 231 mg of Compound (R) (5R) (54% yield) and the compound ( R) (5S) 69 mg (18% yield) was obtained.
Compound (R) (5R):
¹ H-NMR (CDCl ₃ ) δ: 0.09 (s, 3 H), 0.12 (s, 3 H), 0.56 (s, 3 H), 0.89 (d, J = 6.7 Hz, 3 H), 0.93 (s , 9 H), 1.07 (s, 3 H), 1.10 (s, 3 H), 1.15-1.32 (m, 3 H), 1.37-1.70 (m, 8 H), 1.88-2.02 (m, 3 H) , 2.84-2.88 (m, 2 H), 3.55 (d, J = 9.3 Hz, 1 H), 3.97 (dd, J = 8.1, 13.4 Hz, 1 H), 4.25 (dd, J = 2.2, 13.4 Hz, 1 H), 4.94 (d, J = 1.1 Hz, 1 H), 5.16 (d, J = 1.1 Hz, 1 H) 5.64 (s, 1 H).
LRMS m / z 495 ((M-OH) ⁺ ), 455, 416, 364
HRMS calcd for C ₂₇ H ₄₈ O ⁷⁹ BrSi 495.2658, found 495.2643
Compound (R) (5S):
¹ H-NMR (CDCl ₃ ) δ: 0.13 (s, 6 H), 0.54 (s, 3 H), 0.92 (s, 9 H), 1.00 (d, J = 11.2 Hz, 3 H), 1.05 (m , 1 H), 1.11 (s, 3 H), 1.11 (s, 3 H), 1.14-1.33 (m, 5 H), 1.38-1.68 (m, 4 H), 1.87-2.04 (m, 4 H) , 2.86 (m, 1 H), 3.08 (dd, J = 3.9, 8.7 Hz, 1 H), 3.60 (dd, J = 3.9, 7.3 Hz, 1 H), 3.97 (dd, J = 8.4, 13.0 Hz, 1 H), 4.26 (dd, J = 3.2, 13.0 Hz, 1 H), 5.00 (d, J = 1.1 Hz, 1 H), 5.22 (d, J = 1.1 Hz, 1 H), 5.64 (s, 1 H).
LRMS m / z 495 ((M-OH) ⁺ ), 455, 416, 364
HRMS calcd for C ₂₇ H ₄₈ O ⁷⁹ BrSi 495.2658, found 495.2683

(3-a) 200 mg (0.39 mmol) of the compound (R) (5R) obtained above was dissolved in acetonitrile, hydrofluoric acid / acetonitrile (1: 9, 2 ml) was added, and the mixture was stirred at room temperature for 1 hour. did. Saturated sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in methylene chloride (3.9 ml), 729 mg (8.4 mmol) of MnO ₂ was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was filtered, and the residue obtained by concentrating the filtrate was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give compound (4) (Z = (2-1). Y = Br, R ^2d = R ^2e = Me, 5R) was obtained. Yield 91%. Colorless solid.
[α] _D ²⁴ +141.2 (c 0.38, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 1.00 (d, J = 6.3 Hz, 3 H), 1.05 (s, 3 H), 1.11 (dd, J = 11.2, 13.4 Hz, 1 H), 1.21 (s, 3 H), 1.25-1.36 (m, 3 H), 1.44-1.66 (m, 7 H), 1.89 (m, 1 H), 1.96-2.04 (m, 2 H), 2.89 (dd, J = 6.8, 15.6 Hz, 1 H), 4.14 (d, J = 10.5 Hz, 1 H), 5.47 (s, 1 H), 5.65 (s, 1 H), 6.15 (s, 1 H ).
¹³ C-NMR (CDCl ₃ ) δ: 11.9, 18.6, 22.1, 22.5, 22.8, 25.1, 27.6, 31.0, 32.9, 35.9, 39.9, 41.9, 45.6, 55.9, 56.2, 84.2, 97.6, 119.1, 144.7, 146.1, 170.3.
LRMS m / z 394 (M ⁺ ), 315, 256, 227
HRMS calcd for C ₂₁ H ₃₁ O ₂ ⁷⁹ Br 394.1507, found 394.1508

(3-b) Using the compound (R) (5S) 87 mg (0.17 mmol) obtained above, the same reaction as in Example 74 (3-a) was carried out to give compound (4) (Z = (2- 1), Y = Br, 55 mg of R ^2d = R ^2e = Me, 5S) was obtained. Yield 82%. Colorless solid.
[α] _D ²⁴ +31.4 (c 0.85, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.58 (s, 3 H), 1.05 (s, 3 H), 1.08 (d, J = 6.6 Hz, 3 H), 1.21 (s, 3 H), 1.25-1.70 (m, 11 H), 1.95-2.04 (m, 3 H), 2.88 (dd, J = 3.9, 15.9 Hz, 1 H), 4.10 (dd, J = 2.9, 9.0 Hz, 1 H), 5.46 (s , 1 H), 5.65 (s, 1 H), 6.14 (s, 1 H).
¹³ C-NMR (CDCl ₃ ) δ: 11.8, 19.7, 22.1, 22.5, 23.0, 24.3, 27.8, 31.0, 35.3, 35.5, 39.8, 42.6, 45.6, 55.7, 55.9, 86.1, 97.5, 118.9, 144.8, 146.1, 170.5.
LRMS m / z 394 (M ⁺ ), 315, 256, 227
HRMS calcd for C ₂₁ H ₃₁ O ₂ ⁷⁹ Br 394.1507, found 394.1508

(4-a) Compound (4) obtained above (Z = (2-1), Y = Br, R ^2d = R ^2e = Me, 5R) 30 mg (76 μmol) and compound (7) (R ³ = TBS, R ⁶ = hydrogen atom, 3α / 5β) 42 mg (0.114 μmmol) was used to carry out the same reaction as in Example 14 (2-a). 27 mg of 111a was obtained. Yield 78%.
Compound No. 111a:
[α] _D ²⁴ +56.160 (c 1.15, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.99 (d, J = 6.6 Hz, 3 H), 1.05 (s, 3 H), 1.11 (dd, J = 1.47, 10.5 Hz, 1 H), 1.21 (s, 3 H), 1.26 (m, 3 H), 1.45-1.76 (m, 9 H), 1.83-2.04 (m, 5 H), 2.31 (dd, J = 6.5, 13.3 Hz , 1 H), 2.60 (dd, J = 3.4, 13.4 Hz, 1 H), 2.83 (dd, J = 3.9, 12.0 Hz, 1 H), 4.14 (dd, J = 1.6, 11.6 Hz, 1 H), 4.24 (s, 1 H), 4.43 (s, 1 H), 5.00 (s, 1 H), 5.33 (s, 1 H), 5.47 (s, 1 H), 6.12 (d, J = 11.4 Hz, 1 H), 6.15 (s, 1 H), 6.37 (d, J = 11.4 Hz, 1 H).
¹³ C-NMR (CDCl ₃ ) δ: 12.1, 18.6, 22.3, 22.8, 23.6, 25.1, 27.6, 29.1, 32.9, 35.9, 40.5, 42.0, 42.9, 45.3, 46.0, 56.4, 57.0, 66.8, 70.8, 84.3, 111.7, 117.2, 119.1, 124.7, 133.1, 142.6, 146.2, 147.5, 170.4.
LRMS m / z 454 (M ⁺ ), 418, 403
HRMS calcd for C ₂₉ H ₄₂ O ₄ 454.3083, found 454.3083

(4-b) Compound (4) obtained above (Z = (2-1), Y = Br, R ^2d = R ^2e = Me, 5S) 31 mg (78 μmol) and compound (7) (R ³ = Using TBS, R ⁶ = hydrogen atom, 3α / 5β) 43 mg (0.117 μmmol), the same reaction as in Example 14 (2-a) was carried out. 22 mg of 111b was obtained. Yield 62%.
[α] _D ²⁴ -21.8 (c 0.85, CHCl ₃ )
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 1.05 (s, 3 H), 1.07 (d, J = 6.6 Hz, 3 H), 1.21 (s, 3 H), 1.25-1.72 (m, 13 H), 1.88-2.06 (m, 5 H), 2.32 (dd, J = 6.3, 13.4 Hz, 1 H), 2.60 (dd, J = 3.5, 13.3 Hz, 1 H), 2.83 (dd , J = 3.8, 11.8 Hz, 1 H), 4.10 (dd, J = 3.4, 9.0 Hz, 1 H), 4.23 (s, 1 H), 4.43 (s, 1 H), 5.00 (dd, J = 1.5 , 1.6 Hz, 1 H), 5.33 (dd, J = 1.6, 1.7 Hz, 1 H), 5.45 (s, 1 H), 6.02 (d, J = 11.2 Hz, 1 H), 6.13 (s, 1 H ), 6.38 (d, J = 11.2 Hz, 1 H).
¹³ C-NMR (CDCl ₃ ) δ: 12.0, 19.7, 22.3, 23.0, 23.6, 24.4, 27.9, 29.1, 35.4, 35.6, 40.4, 42.6, 42.9, 45.3, 46.0, 56.2, 56.7, 66.8, 70.8, 86.3, 111.6, 117.1, 118.8, 124.8, 133.0, 142.8, 146.2, 147.6, 170.5.
LRMS m / z 454 (M ⁺ ), 418, 403
HRMS calcd for C ₂₉ H ₄₂ O ₄ 454.3083, found 454.3083

[Example 75]
2α-Methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4,4-dimethyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z), 7 (E) , 10 (19) -Triene-1α, 3β-diol (Compound No. 211a)

Compound (4) obtained in Example 74 (3-a) (Z = (2-1), Y = Br, R ^2d = R ^2e = Me, 5R) 26 mg (66 μmol) and compound (7) (R ³ = TBS, R ⁶ = Me, 3α / 4α / 5β) 40 mg (105 μmol) was used to carry out the same reaction as in Example 14 (2-a). 18 mg of 211a was obtained. Yield 58%.
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 1.00 (d, J = 6.7 Hz, 3 H), 1.06 (s, 3 H), 1.08 (d, J = 6.7 Hz, 3 H ), 1.12 (m, 1 H), 1.21 (s, 3 H), 1.26-1.34 (m, 3 H), 1.46-1.72 (m, 10 H), 1.90-2.04 (m, 3 H), 2.23 ( dd, J = 7.9, 13.3 Hz, 1 H), 2.67 (dd, J = 4.0, 13.5 Hz, 1 H), 2.83 (dd, J = 3.8, 11.9 Hz, 1 H), 3.85 (ddd, J = 4.2 , 7.5, 7.5 Hz, 1 H), 4.15 (dd, J = 1.3, 11.6 Hz, 1 H), 4.31 (br, 1 H), 5.01 (d, J = 2.0 Hz, 1 H), 5.28 (s, 1 H), 5.47 (s, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.15 (s, 1 H), 6.38 (s, J = 11.2 Hz, 1 H).
LRMS m / z 468 (M ⁺ ), 451, 434, 419, 404
HRMS calcd for C ₃₀ H ₄₄ O ₄ 468.3240, found 468.3264

[Example 76]
2α-Methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4,4-dimethyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z), 7 (E) , 10 (19) -Triene-1α, 3β-diol (Compound No. 211b)

Compound (4) obtained in Example 74 (3-b) (Z = (2-1), Y = Br, R ^2d = R ^2e = Me, 5S) 25 mg (63 μmol) and compound (7) (R ³ = TBS, R ⁶ = Me, 3α / 4α / 5β) 41 mg (107 μmol) was used to carry out the same reaction as in Example 14 (2-a). 14 mg of 211b was obtained. Yield 47%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 1.04 (s, 3 H), 1.06 (d, J = 6.7 Hz, 3 H), 1.07 (d, J = 6.7 Hz, 3 H ), 1.21 (s, 3 H), 1.25-1.70 (m, 13 H), 1.88-2.04 (m, 4 H), 2.23 (dd, J = 8.1, 13.7 Hz, 1 H), 2.66 (dd, J = 4.0, 13.8 Hz, 1 H), 2.82 (dd, J = 3.7, 12.2 Hz, 1 H), 3.84 (ddd, J = 4.2, 7.6, 7.6 Hz, 1 H), 4.10 (dd, J = 3.4, 8.8 Hz, 1 H), 4.31 (d, J = 3.2 Hz, 1 H), 5.00 (d, J = 1.7 Hz, 1 H), 5.27 (dd, J = 1.0, 2.0 Hz, 1 H), 5.45 ( s, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.13 (s, 1 H), 6.38 (d, J = 11.2 Hz, 1 H).
LRMS m / z 468 (M ⁺ ), 451, 434, 419
HRMS calcd for C ₃₀ H ₄₄ O ₄ 468.3240, found 468.3248

[Example 77]
2α- (3-hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4,4-dimethyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z) , 7 (E), 10 (19) -triene-1α, 3β-diol (Compound No. 812a)

Compound (4) (Z = (2-1), Y = Br, R ^2d = R ^2e = Me, 5R) 39 mg (76 μmol) obtained in Example 74 (3-a) and compound (7) (R ³ = TBS, R ⁶ = — (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) Using 68 mg (126 μmol), the same reaction as in Example 14 (2-a) was carried out. 18 mg of 812a was obtained. Yield 46%.
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.99 (d, J = 6.3 Hz, 3 H), 1.06 (s, 3 H), 1.11 (m, 1 H), 1.21 (s , 3 H), 1.26-1.35 (m, 5 H), 1.48-1.86 (m, 11 H), 1.97-2.05 (m, 3 H), 2.25 (dd, J = 8.7, 13.1 Hz, 2 H), 2.28 (br, 1 H), 2.66 (dd, J = 4.2, 13.4 Hz, 1 H), 2.83 (m, 1 H), 3.69-3.70 (m, 2 H), 3.90 (ddd, J = 4.3, 8.2 , 8.2 Hz, 1 H), 4.15 (dd, J = 1.1, 11.4 Hz, 1 H), 4.38 (d, J = 2.9 Hz, 1 H), 4.99 (d, J = 1.7 Hz, 1 H), 5.28 (d, J = 1.7 Hz, 1 H), 5.47 (s, 1 H), 6.00 (d, J = 11.2 Hz, 1 H), 6.15 (s, 1 H), 6.39 (d, J = 11.2 Hz, 1 H).
LRMS m / z 512 (M ⁺ ), 495, 478, 461
HRMS calcd for C ₃₂ H ₄₈ O ₅ 512.3502, found 512.3502

[Example 78]
2α- (3-Hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4,4-dimethyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z) , 7 (E), 10 (19) -triene-1α, 3β-diol (Compound No. 812b)

Compound (4) (Z = (2-1), Y = Br, R ^2d = R ^2e = Me, 5S) 18 mg (46 μmol) obtained in Example 74 (3-b) and compound (7) (R ³ = TBS, R ⁶ = — (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) Using 37 mg (68 μmol), the same reaction as in Example 14 (2-a) was carried out. 9 mg of 812b was obtained. Yield 39%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 1.05 (s, 3 H), 1.07 (d, J = 6.6 Hz, 3 H), 1.21 (s, 3 H), 1.24-1.54 (m, 10 H), 1.58-1.77 (m, 7 H), 1.92-2.02 (m, 5 H), 2.25 (dd, J = 13.5, 8.9 Hz, 1 H), 2.66 (dd, J = 4.3, 13.5 Hz, 1 H), 2.83 (m, 1 H), 3.70 (m, 2 H), 3.89 (ddd, J = 4.4, 8.3, 8.3 Hz, 1 H), 4.11 (dd, J = 3.2, 9.0 Hz , 1 H), 4.38 (d, J = 2.9 Hz, 1 H), 5.00 (d, J = 1.6 Hz, 1 H), 5.28 (d, J = 1.6 Hz, 1 H), 5.46 (s, 1 H ), 6.00 (d, J = 11.4 Hz, 1 H), 6.14 (s, 1 H), 6.40 (d, J = 11.4 Hz, 1 H).
LRMS m / z 512 (M ⁺ ), 495, 478, 461
HRMS calcd for C ₃₂ H ₄₈ O ₅ 512.3502, found 512.3490

[Example 79]
2α- (3-hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4,4-dimethyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z) , 7 (E), 10 (19) -triene-1α, 3β-diol (Compound No. 1112a)

Compound (4) obtained in Example 74 (3-a) (Z = (2-1), Y = Br, R ^2d = R ^2e = Me, 5R) 30 mg (76 μmol) and compound (7) (R ³ = TBS, R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 71 mg (128 μmol) was used to carry out the same reaction as in Example 14 (2-a). 23 mg of 1112a was obtained. Yield 57%.
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.99 (d, J = 6.6 Hz, 3 H), 1.05 (s, 3 H), 1.11 (m, 1 H), 1.21 (s , 3 H), 1.23-1.35 (m, 4 H), 1.47-1.56 (m, 3 H), 1.66-1.88 (m, 6 H), 1.96-2.05 (m, 2 H), 2.24 (dd, J = 8.8, 1.34 Hz, 1 H), 2.68 (dd, J = 4.4, 13.7 Hz, 1 H), 2.73 (br, 3 H), 2.83 (m, 1 H), 3.37 (dd, J = 3.2, 7.6 Hz, 1 H), 3.74-3.91 (m, 4 H), 4.06 (ddd, J = 4.4, 8.2, 8.2 Hz, 1 H), 4.15 (dd, J = 1.2, 11.5 Hz, 1 H), 4.45 ( d, J = 2.9 Hz, 1 H), 5.09 (d, J = 1.7 Hz, 1 H), 5.39 (s, 1 H), 5.47 (s, 1 H), 6.12 (d, J = 11.2 Hz, 1 H), 6.15 (s, 1 H), 6.41 (d, J = 11.2 Hz, 1 H).
LRMS m / z 528 (M ⁺ ), 511, 494, 477, 435
HRMS calcd for C ₃₂ H ₄₈ O ₆ 528.3451, found 528.3449

[Example 80]
2α- (3-hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4,4-dimethyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z) , 7 (E), 10 (19) -triene-1α, 3β-diol (Compound No. 1112b)

Compound (4) (Z = (2-1), Y = Br, R ^2d = R ^2e = Me, 5S) 14 mg (35 μmol) obtained in Example 74 (3-b) and compound (7) (R ³ = TBS, R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 35 mg (63 μmol) was used to carry out the same reaction as in Example 14 (2-a). 13 mg of 1112b was obtained. Yield 69%.
¹ H-NMR (CDCl ₃ ) δ: 0.70 (s, 3 H), 1.05 (s, 3 H), 1.06 (d, J = 6.6 Hz, 3 H), 1.21 (s, 3 H), 1.23-1.72 (m, 11 H), 1.84-2.04 (m, 5 H), 2.24 (dd, J = 9.2, 13.5 Hz, 1 H), 2.53 (br, 3 H), 2.68 (dd, J = 4.6, 13.7 Hz , 1 H), 2.82 (m, 1 H), 3.38 (dd, J = 3.3, 7.4 Hz, 1 H), 3.83 (m, 4 H), 4.05 (m, 1 H), 4.10 (dd, J = 3.3, 8.9 Hz, 1 H), 4.45 (d, J = 2.9 Hz, 1 H), 5.10 (d, J = 1.5 Hz, 1 H), 5.39 (d, J = 1.5 Hz, 1 H), 5.46 ( s, 1 H), 6.02 (d, J = 11.2 Hz, 1 H), 6.13 (s, 1 H), 6.42 (d, J = 11.2 Hz, 1 H).
LRMS m / z 528 (M ⁺ ), 511, 494, 477, 435
HRMS calcd for C ₃₂ H ₄₈ O ₆ 528.3451, found 528.3451

[Example 81]
2α-Methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -propyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z), 7 (E ), 10 (19) -triene-1α, 3β-diol (Compound No. 203a) and 2α-methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -propyl-5 ( Production of S) -yl) methyl-9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene-1α, 3β-diol (Compound No. 203b)

(1) Example 11 using 660 mg (2.3 mmol) of compound (2) (Z = (2-1), Y = Br) obtained by a method known in the literature (for example, International Publication WO95 / 33716). (1) and carrying out the same reaction, the compound (4syn) (Z = (2-1 ), Y = Br, R 2c = Pr, 4R / 5R) of 436 mg (48% yield), compound (4Syn) ( 335 mg (yield 37%) of Z = (2-1), Y = Br, R ^2c = Pr, 4S / 5S) was obtained. However, the compound (3) obtained by using methyl acrylate instead of ethyl acrylate in the same manner as in Reference Example 2 instead of compound (3) (R ^2c = Me, R ⁷ = Me) in Example 11 (1) ) (R ^2c = Pr, R ⁷ = Me).
Compound (4syn) (Z = (2-1), Y = Br, R ^2c = Pr, 4R / 5R):
¹ H-NMR (CDCl ₃ ) δ: 0.58 (s, 3 H), 0.96 (t, J = 7.0 Hz, 3 H), 1.01 (d, J = 6.6 Hz, 3 H), 1.11 (ddd, J = 14.2, 10.7, 2.0 Hz, 1 H), 1.20-1.80 (m, 14 H), 1.86 (m, 1 H), 1.97 (ddd, J = 12.0, 6.8, 1.2 Hz, 1 H), 2.02 (br d , J = 12.7 Hz, 1 H), 2.89 (m, 1 H), 2.99 (m, 1 H), 4.66 (ddd, J = 11.7, 7.0, 1.8 Hz, 1 H), 5.50 (d, J = 2.2 Hz, 1 H), 5.65 (s, 1 H), 6.21 (d, J = 2.7 Hz, 1 H).
LRMS m / z 408 (M ⁺ ), 329, 281, 227
HRMS calcd for C ₂₂ H ₃₃ O ₂ ⁷⁹ Br 408.1664, found 408.1660
Compound (4syn) (Z = (2-1), Y = Br, R ^2c = Pr, 4S / 5S):
¹ H-NMR (CDCl ₃ ) δ: 0.58 (s, 3 H), 0.95 (t, J = 7.0 Hz, 3 H), 1.06 (d, J = 6.6 Hz, 3 H), 1.22-1.76 (m, 15 H), 1.90-2.05 (m, 3 H), 2.87 (m, 1 H), 2.92 (m, 1 H), 4.58 (ddd, J = 8.9, 6.4, 4.4 Hz, 1 H), 5.50 (d , J = 1.7 Hz, 1 H), 5.65 (s, 1 H), 6.20 (d, J = 2.2 Hz, 1 H).
LRMS m / z 408 (M ⁺ ), 329, 281, 227
HRMS calcd for C ₂₂ H ₃₃ O ₂ ⁷⁹ Br 408.1664, found 408.1665

(2-a) Compound (4syn) obtained above (Z = (2-1), Y = Br, R ^2c = Pr, 4R / 5R) 26 mg (65 μmol) and compound (7) (R ³ = TBS , R ⁶ = Me, 3α / 4α / 5β) 37 mg (97 μmol), the same reaction as in Example 14 (2-a) was carried out. 15 mg of 203a was obtained. Yield 48%.
Compound No. 203a:
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.96 (t, J = 7.0 Hz, 3 H), 1.00 (d, J = 6.6 Hz, 3 H), 1.08 (d, J = 6.8 Hz, 3 H), 1.10 (ddd, J = 14.3, 10.9, 1.9 Hz, 1 H), 1.20-2.08 (m, 20 H), 2.23 (dd, J = 13.5, 7.9 Hz, 1 H), 2.67 (dd, J = 13.5, 4.2 Hz, 1 H), 2.83 (m, 1 H), 2.98 (m, 1 H), 3.85 (m, 1 H), 4.31 (m, 1 H), 4.65 (ddd, J = 11.7, 7.0, 1.6 Hz, 1 H), 5.00 (d, J = 1.7 Hz, 1 H), 5.28 (s, 1 H), 5.50 (d, J = 2.3 Hz, 1 H), 6.00 (d , J = 11.2 Hz, 1 H), 6.21 (d, J = 2.3 Hz, 1 H), 6.37 (d, J = 11.2 Hz, 1 H).
LRMS m / z 482 (M ⁺ ), 464, 446, 420, 265, 223
HRMS calcd for C ₃₁ H ₄₆ O ₄ 482.3396, found 482.3396

(2-b) Compound (4syn) obtained above (Z = (2-1), Y = Br, R ^2c = Pr, 4S / 5S) 27 mg (67 μmol) and compound (7) (R ³ = TBS , R ⁶ = Me, 3α / 4α / 5β) 38 mg (100 μmol), the same reaction as in Example 14 (2-a) was carried out. 19 mg of 203b was obtained. Yield 59%.
Compound No. 203b:
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.95 (t, J = 6.8 Hz, 3 H), 1.05 (d, J = 6.6 Hz, 3 H), 1.08 (d, J = 6.8 Hz, 3 H), 1.20-1.78 (m, 17 H), 1.88-2.07 (m, 4 H), 2.23 (dd, J = 13.4, 7.9 Hz, 1 H), 2.67 (dd, J = 13.4, 3.8 Hz, 1 H), 2.83 (m, 1 H), 2.91 (m, 1 H), 3.84 (m, 1 H), 4.31 (m, 1 H), 4.57 (ddd, J = 8.5, 5.9, 5.1 Hz, 1 H), 5.01 (s, 1 H), 4.28 (s, 1 H), 5.50 (br s, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.19 (d, J = 1.7 Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H).
LRMS m / z 482 (M ⁺ ), 464, 446, 420, 265, 223
HRMS calcd for C ₃₁ H ₄₆ O ₄ 482.3397, found 482.3405

[Example 82]
2α-Methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -propyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z), 7 (E ), 10 (19) -triene-1α, 3β-diol (Compound No. 203c)

(1) Example using 20 mg (0.049 mmol) of the compound (4syn) (Z = (2-1), Y = Br, R ^2c = Pr, 4R / 5R) obtained in Example 81 (1) Reaction similar to 12 (1) was performed and 20 mg of compounds (S) (4R / 5R) were obtained. Yield 99%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 0.89 (t, J = 7.2 Hz, 3 H), 0.97 (d, J = 6.4 Hz, 3 H), 1.03 (ddd, J = 13.5, 11.2, 1.4 Hz, 1 H), 1.10-1.75 (m, 14 H), 1.85-2.07 (m, 3 H), 2.14 (ddd, J = 10.4, 4.6 Hz, 1 H), 2.28 (br s , 2 H), 2.87 (m, 1 H), 3.70 (ddd, J = 10.4, 4.3, 1.2 Hz, 1 H), 4.03 (d, J = 13.3 Hz, 1 H), 4.08 (d, J = 13.3 Hz, 1 H), 4.92 (s, 1 H), 5.18 (s, 1 H), 5.64 (s, 1 H).
LRMS m / z 412 (M ⁺ ), 394, 351, 315, 254, 227, 175, 81
HRMS calcd for C ₂₂ H ₃₇ O ₂ ⁷⁹ Br 412.1977, found 412.1975

(2) The same reaction as in Example 12 (2) was performed using 160 mg (0.387 mmol) of the compound (S) (4R / 5R) obtained above, and the compound (5syn) (Z = (2-1) ), Y = Br, R ^2c = Pr, R ⁸ = Piv, 4R / 5R). Yield 98%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 0.90 (t, J = 7.2 Hz, 3 H), 0.95 (d, J = 6.6 Hz, 3 H), 1.06 (ddd, J = 13.6, 11.1, 1.2 Hz, 1 H), 1.10-1.73 (m, 15 H), 1.23 (s, 9 H), 1.88-2.10 (m, 4 H), 2.87 (m, 1 H), 3.65 (m , 1 H), 4.49 (s, 2 H), 4.94 (s, 1 H), 5.15 (s, 1 H), 5.64 (s, 1 H).
LRMS m / z 496 (M ⁺ ), 463, 379, 363, 227, 198, 96
HRMS calcd for C ₂₇ H ₄₅ O ₃ ⁷⁹ Br 496.2552, found 496.2549

(3) Example using 121 mg (1.03 mmol) of the compound (5syn) obtained above (Z = (2-1), Y = Br, R ^2c = Pr, R ⁸ = Piv, 4R / 5R) performs the same reaction as 12 (3), the compound (6) was obtained ^{(Z = (2-1), Y} = Br, R 2c = Pr, R 8 = Piv, 4R) and 302 mg. Yield 88%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.60 (s, 3 H), 0.89 (d, J = 6.4 Hz, 3 H), 0.90 (t, J = 7.3 Hz, 3 H), 1.18-1.35 (m, 5 H), 1.23 (s, 9 H), 1.40-1.72 (m, 6 H), 1.74-1.90 (m, 2 H), 1.95-2.05 (m, 3 H), 2.26 (dd, J = 16.8, 10.1 Hz, 1 H), 2.46 (dd, J = 16.8, 2.8 Hz, 1 H), 2.88 (m, 1 H), 3.11 (t, J = 7.3 Hz, 1 H), 4.48 (d, J = 13.8 Hz, 1 H), 4.53 (d, J = 13.8 Hz, 1 H), 5.05 (s, 1 H), 5.20 (s, 1 H), 5.64 (s, 1 H).
LRMS m / z 494 (M ⁺ ), 415, 392, 350, 279, 237, 175
HRMS calcd for C ₂₇ H ₄₃ O ₃ ⁷⁹ Br 494.2396, found 494.2407

(4) Example 18 (0.587 mmol) using the compound (6) obtained above (Z = (2-1), Y = Br, R ^2c = Pr, R ⁸ = Piv, 4R) Reaction similar to 4) was performed, and 169 mg of compound (S) (4R / 5S) was obtained. Yield 70%. amorphous.
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.90 (t, J = 7.2 Hz, 3 H), 1.01 (d, J = 6.6 Hz, 3 H), 1.12-1.73 (m, 15 H), 1.85-2.05 (m, 3 H), 2.22 (dt, J = 4.6, 5.0 Hz, 1 H), 2.83 (br s, 2 H), 2.88 (m, 1 H), 3.70 (dt, J = 4.6, 6.4 Hz, 1 H), 3.98 (d, J = 12.5 Hz, 1 H), 4.09 (d, J = 12.5 Hz, 1 H), 4.96 (d, J = 1.7 Hz, 1 H), 5.21 (s, 1 H), 5.64 (s, 1 H).
LRMS m / z 412 (M ⁺ ), 394, 351, 315, 254, 227, 175, 81
HRMS calcd for C ₂₂ H ₃₇ O ₂ ⁷⁹ Br 412.1977, found 412.1958

(5) 163 mg (0.395 mmol) of the compound (S) (4R / 5S) obtained above was dissolved in methylene chloride (2 ml). The same reaction as in Example 15 (5) was performed using 432 mg (5.0 mmol) of MnO _{2 in} the solution, and compound (4anti) (Z = (2-1), Y = Br, R ^2c = Pr, 4R). / 5S) was obtained 162 mg. Yield 100%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.58 (s, 3 H), 0.96 (t, J = 7.2 Hz, 3 H), 1.07 (J = 6.1 Hz, 3 H), 1.18-1.73 (m, 15 H ), 1.88-2.05 (m, 3 H), 2,61 (m, 1 H), 2.88 (m, 1 H), 4.25 (dt, J = 4.2, 6.2 Hz, 1 H), 5.58 (d, J = 2.6 Hz, 1 H), 5.65 (s, 1 H), 6.26 (d, J = 2.6 Hz, 1 H).
LRMS m / z 408 (M ⁺ ), 329, 281, 227
HRMS calcd for C ₂₂ H ₃₃ O ₂ ⁷⁹ Br 408.1664, found 408.1670

(6) Compound (4anti) obtained above (Z = (2-1), Y = Br, R ^2c = Pr, 4R / 5S) 32 mg (77 μmol) and compound (7) (R ³ = TBS, R ⁶ = Me, 3α / 4α / 5β) 44 mg (116 μmol) was used to carry out the same reaction as in Example 14 (2-a). 23 mg of 203c was obtained. Yield 51%.
Compound No. 203c:
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.96 (t, J = 7.2 Hz, 3 H), 1.06 (d, J = 7.1 Hz, 3 H), 1.08 (d, J = 7.1 Hz, 3 H), 1.13-1.75 (m, 17 H), 1.83-2.07 (m, 4 H), 2.23 (dd, J = 13.6, 7.8 Hz, 1 H), 2.61 (m, 1 H), 2.67 (d, J = 13.6, 3.9 Hz, 1 H), 2.83 (m, 1 H), 3.84 (m, 1 H), 4.24 (m, 1 H), 4.33 (m, 1 H), 5.00 (s , 1 H), 5.27 (s, 1 H), 5.58 (d, J = 2.0 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.25 (d, J = 2.0 Hz, 1 H ), 6.38 (d, J = 11.2 Hz, 1 H).
LRMS m / z 482 (M ⁺ ), 464, 446, 420, 265, 223
HRMS calcd for C ₃₁ H ₄₆ O ₄ 482.3396, found 482.3402

[Example 83]
2α-Methyl-20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -propyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z), 7 (E ), 10 (19) -triene-1α, 3β-diol (Compound No. 203d)

(1) Using the compound (4syn) obtained in Example 81 (1) (Z = (2-1), Y = Br, R ^2c = Pr / hydrogen atom, 4S / 5S) 24 mg (0.057 mmol) In the same manner as in Example 12 (1), 22 mg of Compound (S) (4S / 5S) was obtained. Yield 94%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.58 (s, 3 H), 0.90 (t, J = 7.2 Hz, 3 H), 1.02 (d, J = 6.4 Hz, 3 H), 1.10-1.75 (m, 15 H), 1.90-2.08 (m, 3 H), 2.21 (br d, J = 9.8 Hz, 1 H), 2.50 (br s, 2 H), 2.87 (m, 1 H), 3.74 (dt, J = 9.8, 6.5 Hz, 1 H), 4.04 (d, J = 12.9 Hz, 1 H), 4.11 (d, J = 12.9 Hz, 1 H), 4.96 (s, 1 H), 5.18 (s, 1 H ), 5.65 (s, 1 H).
LRMS m / z 412 (M ⁺ ), 394, 351, 315, 254, 227, 175, 81
HRMS calcd for C ₂₂ H ₃₇ O ₂ ⁷⁹ Br 412.1977, found 412.1975

(2) The same reaction as in Example 12 (2) was carried out using 108 mg (0.262 mmol) of the compound (S) (4S / 5S) obtained above to give the compound (5syn) (Z = (2-1 ), Y = Br, R ^2c = Pr, R ⁸ = Piv, 4S / 5S). Yield 89%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.90 (t, J = 7.2 Hz, 3 H), 1.02 (d, J = 6.2 Hz, 3 H), 1.13-1.73 (m, 15 H), 1.23 (s, 9 H), 1.77 (d, J = 4.4 Hz, 1 H), 1.90-2.23 (m, 3 H), 2.10 (m, 1 H), 2.88 (m, 1 H) , 3.80 (ddd, J = 10.4, 6.5, 4.0 Hz, 1 H), 3.56 (d, J = 13.9 Hz, 1 H), 4.56 (d, J = 13.9 Hz, 1 H), 5.00 (s, 1 H ), 5.21 (d, J = 1.2 Hz, 1 H), 5.64 (s, 1 H).
LRMS m / z 496 (M ⁺ ), 463, 379, 363, 227, 198, 96
HRMS calcd for C ₂₇ H ₄₅ O ₃ ⁷⁹ Br 496.2552, found 496.2542

(3) Example using 245 mg (0.493 mmol) of the compound (5syn) obtained above (Z = (2-1), Y = Br, R ^2c = Pr, R ⁸ = Piv, 4S / 5S) performs the same reaction as 12 (3), the compound (6) was obtained ^{(Z = (2-1), Y} = Br, R 2c = Pr, R 8 = Piv, 4S) and 213 mg. Yield 87%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 0.90 (t, J = 7.2 Hz, 3 H), 0.92 (d, J = 6.6 Hz, 3 H), 1.20-1.35 (m, 5 H), 1.22 (s, 9 H), 1.40-1.72 (m, 6 H), 1.74-1.88 (m, 2 H), 1.94-2.06 (m, 3 H), 2.23 (dd, J = 16.9, 9.8 Hz, 1 H), 2.52 (dd, J = 16.9, 2.9 Hz, 1 H), 2.88 (m, 1 H), 2.09 (t, J = 7.3 Hz, 1 H), 4.50 (s, 2 H) , 5.07 (s, 1 H), 5.20 (s, 1 H), 5.64 (s, 1 H).
LRMS m / z 415, 392, 350, 279, 237, 175
HRMS calcd for C ₂₇ H ₄₃ O ₃ ⁷⁹ Br 494.2396, found 494.2486

(4) Example 18 (0.425 mmol) using the compound (6) obtained above (Z = (2-1), Y = Br, R ^2c = Pr, R ⁸ = Piv, 4S) Reaction similar to 4) was performed, and 95 mg of compounds (S) (4S / 5R) were obtained. Yield 54%. Colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 0.89 (t, J = 7.3 Hz, 3 H), 0.97 (d, J = 6.6 Hz, 3 H), 1.09 (ddd, J = 13.9, 10.9, 1.9 Hz, 1 H), 1.15-1.73 (m, 14 H), 1.85-2.08 (m, 3 H), 2.11 (dt, J = 10.1, 5.8 Hz, 1 H), 2.51 (br s , 2 H), 2.87 (m, 1 H), 3.64 (ddd, J = 10.1, 6.2, 1.6 Hz, 1 H), 3.99 (d, J = 12.5 Hz, 1 H), 4.10 (d, J = 12.5 Hz, 1 H), 4.94 (d, J = 1.7 Hz, 1 H), 5.21 (d, J = 1.0 Hz, 1 H), 5.64 (s, 1 H).
LRMS m / z 412 (M ⁺ ), 394, 351, 315, 254, 227, 175, 81
HRMS calcd for C ₂₂ H ₃₇ O ₂ ⁷⁹ Br 412.1977, found 412.1982

(5) The same reaction as in Example 15 (5) was carried out using 94 mg (0.227 mmol) of the compound (S) (4S / 5R) obtained above to give the compound (4anti) (Z = (2-1 ), Y = Br, R ^2c = Pr, 4S / 5R) was obtained in 92 mg. Yield 99%. Colorless solid.
¹ H-NMR (CDCl ₃ ) δ: 0.58 (s, 3 H), 0.96 (t, J = 7.2 Hz, 3 H), 1.03 (d, J = 6.6 Hz, 3 H), 1.20-1.93 (m, 16 H), 1.97 (ddd, J = 12.6, 6.8, 1.7 Hz, 1 H), 2.02 (br d, J = 12.6 Hz, 1 H), 2.56 (m, 1 H), 2.88 (m, 1 H) , 4.27 (ddd, J = 11.2, 4.9, 2.1 Hz, 1 H), 5.57 (d, J = 2.7 Hz, 1 H), 5.65 (s, 1 H), 6.26 (d, J = 2.7 Hz, 1 H ).
LRMS m / z 408 (M ⁺ ), 329, 281, 227
HRMS calcd for C ₂₂ H ₃₃ O ₂ ⁷⁹ Br 408.1663, found 408.1660

(6) 18 mg (44 μmol) of compound (4anti) (Z = (2-1), Y = Br, R ^2c = Pr, 4S / 5R) obtained above and compound (7) (R ³ = TBS, R ⁶ = Me, 3α / 4α / 5β) 25 mg (65 μmol) was used to carry out the same reaction as in Example 14 (2-a). 11 mg of 203d was obtained. Yield 54%.
Compound No. 203d:
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.96 (t, J = 7.2 Hz, 3 H), 1.02 (d, J = 6.6 Hz, 3 H), 1.08 (d, J = 6.8 Hz, 3 H), 1.20-2.08 (m, 21 H), 2.23 (dd, J = 13.4, 7.9 Hz, 1 H), 2.57 (m, 1 H), 2.67 (dd, J = 13.4, 3.9 Hz , 1 H), 2.83 (m, 1 H), 3.85 (m, 1 H), 4.23-4.38 (m, 2 H), 5.00 (s, 1 H), 5.28 (s, 1 H), 5.57 (d , J = 2.4 Hz, 1 H), 6.00 (d, J = 11.1 Hz, 1 H), 6.25 (d, J = 2.4 Hz, 1 H), 6.38 (d, J = 11.1 Hz, 1 H).
LRMS m / z 482 (M ⁺ ), 464, 446, 420, 265, 223
HRMS calcd for C ₃₁ H ₄₆ O ₄ 482.3396, found 482.3394

[Example 84]
2α- (3-Hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -propyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 804a)

Compound (4syn) obtained in Example 81 (1) (Z = (2-1), Y = Br, R ^2c = Pr, 4R / 5R) 25 mg (60 μmol) and compound (7) (R ³ = TBS) , R ⁶ =-(CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 49 mg (90 μmol) was used to carry out a reaction similar to Example 14 (2-a), and compound No. 14 mg of 804a was obtained. Yield 43%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.96 (t, J = 7.0 Hz, 3 H), 1.00 (d, J = 6.4 Hz, 3 H), 1.11 (ddd, J = 14.1, 10.8, 1.5 Hz, 1 H), 1.20-2.08 (m, 23 H), 2.15-2.30 (m, 3 H), 2.67 (dd, J = 13.4, 4.2 Hz, 1 H), 2.83 (m, 1 H), 2.98 (m, 1 H), 3.63-3.75 (m, 2 H), 3.89 (ddd, J = 8.0, 8.0, 4.4 Hz, 1 H), 4.37 (br d, J = 2.4 Hz, 1 H), 4.65 (ddd, J = 11.6, 7.2, 1.5 Hz, 1 H), 4.98 (d, J = 1.8 Hz, 1 H), 5.27 (d, J = 1.8 Hz, 1 H), 5.50 (d, J = 2.3 Hz, 1 H), 5.99 (d, J = 11.1 Hz, 1 H), 6.20 (d, J = 2.3 Hz, 1 H), 6.38 (d, J = 11.1 Hz, 1 H).
LRMS m / z 526 (M ⁺ ), 508, 490, 309, 267, 255
HRMS calcd for C ₃₃ H ₅₀ O ₅ 526.3658, found 526.3659

[Example 85]
2α- (3-hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -propyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 804b)

Compound (4syn) obtained in Example 81 (1) (Z = (2-1), Y = Br, R ^2c = Pr, 4S / 5S) 28 mg (68 μmol) and compound (7) (R ³ = TBS) , R ⁶ = — (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 56 mg (103 μmol), the same reaction as in Example 14 (2-a) was carried out. 19 mg of 804b was obtained. Yield 51%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.95 (t, J = 7.0 Hz, 3 H), 1.05 (d.J = 6.4 Hz, 3 H), 1.20-2.06 (m, 24 H), 2.25 (dd, J = 13.3, 8.7 Hz, 1 H), 2.35 (br s, 2 H), 2.66 (dd, J = 13.3, 4.3 Hz, 1 H), 2.83 (m, 1 H) , 2.92 (m, 1 H), 3.63-3.73 (m, 2 H), 3.88 (ddd, J = 8.1, 8.1, 4.4 Hz, 1 H), 4.37 (br d, J = 2.4 Hz, 1 H), 4.57 (ddd, J = 8.5, 6.3, 4.7 Hz, 1 H), 4.99 (d, J = 1.7 Hz, 1 H), 5.27 (d, J = 1.7 Hz, 1 H), 5.49 (d, J = 2.0 Hz, 1 H), 6.00 (d, J = 11.2 Hz, 1 H), 6.19 (d, J = 2.0 Hz, 1 H), 6.39 (d, J = 11.2 Hz, 1 H).
LRMS m / z 526 (M ⁺ ), 508, 490, 309, 267, 255
HRMS calcd for C ₃₃ H ₅₀ O ₅ 526.3658, found 526.3660

[Example 86]
2α- (3-Hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -propyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 804c)

Compound (4anti) (Z = (2-1), Y = Br, R ^2c = Pr, 4R / 5S) 34 mg (82 μmol) obtained in Example 82 (5) and Compound (7) (R ³ = TBS) , R ⁶ =-(CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 67 mg (123 μmol) was used to carry out a reaction similar to Example 14 (2-a), and compound No. 21 mg of 804c was obtained. Yield 48%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.96 (t, J = 7.2 Hz, 3 H), 1.05 (d, J = 5.9 Hz, 3 H), 1.13-1.78 (m, 20 H), 1.85-2.07 (m, 4 H), 2.25 (dd, J = 13.3, 8.8 Hz, 1 H), 2.45 (br s, 2 H), 2.61 (m, 1 H), 2.65 (dd, J = 13.3, 4.2 Hz, 1 H), 2.83 (m, 1 H), 3.63-3.75 (m, 2 H), 3.88 (ddd, J = 8.0, 8.0, 4.6 Hz, 1 H), 3.55 (m, 1 H), 4.37 (br d, J = 2.2 Hz, 1 H), 4.98 (d, J = 1.7 Hz, 1 H), 5.27 (d, J = 1.7 Hz, 1 H), 5.58 (d, J = 2.3 Hz, 1 H), 6.00 (d, J = 11.2 Hz, 1 H), 6.25 (d, J = 2.3 Hz, 1 H), 6.38 (d, J = 11.2 Hz, 1 H).
LRMS m / z 526 (M ⁺ ), 508, 490, 309, 267, 255
HRMS calcd for C ₃₃ H ₅₀ O ₅ 526.3658, found 526.3647

[Example 87]
2α- (3-Hydroxypropyl) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -propyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 804d)

Compound (4anti) (Z = (2-1), Y = Br, R ^2c = Pr, 4S / 5R) 17 mg (42 μmol) obtained in Example 83 (5) and compound (7) (R ³ = TBS) , R ⁶ =-(CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 34 mg (63 μmol) was used to carry out the same reaction as in Example 14 (2-a), and compound No. 12 mg of 804d was obtained. Yield 56%.
¹ H-NMR (10% CD ₃ OD in CDCl ₃ ) δ: 0.55 (s, 3 H), 0.96 (t, J = 7.2 Hz, 3 H), 1.02 (d, J = 6.3 Hz, 3 H), 1.20-1.90 (m, 22 H), 1.93-2.07 (m, 2 H), 2.10 (br s, 2 H), 2.25 (dd, J = 13.4, 8.7 Hz, 1 H), 2.56 (m, 1 H ), 2.66 (dd, J = 13.4, 4.2 Hz, 1 H), 2.83 (m, 1 H), 3.63-3.75 (m, 2 H), 3.90 (ddd, J = 8.2, 8.2, 4.3 Hz, 1 H ), 4.27 (ddd, J = 11.0, 4.9, 2.0 Hz, 1 H), 4.37 (br d, J = 2.7 Hz, 1 H), 4.98 (d, J = 2.0 Hz, 1 H), 5.27 (d, J = 1.5 Hz, 1 H), 5.57 (d, J = 2.6 Hz, 1 H), 5.99 (d, J = 11.2 Hz, 1 H), 6.25 (d, J = 2.6 Hz, 1 H), 6.38 ( d, J = 11.2 Hz, 1 H).
LRMS m / z 526 (M ⁺ ), 508, 490, 309, 267, 255
HRMS calcd for for C ₃₃ H ₅₀ O ₅ 526.3658, found 526.3666

[Example 88]
2α- (3-Hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -propyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 1104a)

Compound (4syn) obtained in Example 81 (1) (Z = (2-1), Y = Br, R ^2c = Pr, 4R / 5R) 26 mg (64 μmol) and compound (7) (R ³ = TBS) , R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 53 mg (95 μmol) was used to carry out a reaction similar to Example 14 (2-a), and compound No. 17 mg of 1104a was obtained. Yield 50%.
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.96 (t, J = 7.0 Hz, 3 H), 1.00 (d, J = 6.6 Hz, 3 H), 1.11 (ddd, J = 13.8, 11.1, 1.3 Hz, 1 H), 1.20-2.08 (m, 19 H), 2.23 (dd, J = 13.4, 8.9 Hz, 1 H), 2.63 (br s, 3 H), 1.48 (dd, J = 13.4, 4.4 Hz, 1 H), 2.83 (m, 1 H), 2.98 (m, 1 H), 3.37 (dd, J = 7.4, 2.9 Hz, 1 H), 3.73-3.93 (m, 4 H) , 4.06 (ddd, J = 7.4, 7.4, 4.6 Hz, 1 H), 4.45 (br d, J = 2.2 Hz, 1 H), 4.65 (ddd, J = 11.4, 7.1, 1.2 Hz, 1 H), 5.08 (s, 1 H), 5.39 (s, 1 H), 5.50 (d, J = 2.1 Hz, 1 H), 6.01 (d, J = 11.1 Hz, 1 H), 6.21 (d, J = 2.2 Hz, 1 H), 6.49 (d, J = 11.1 Hz, 1 H).
LRMS m / z 542 (M ⁺ ), 524, 506, 480, 448, 432, 394
HRMS calcd for C ₃₃ H ₅₀ O ₆ 542.3604, found 542.3624

[Example 89]
2α- (3-hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -propyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 1104b)

Compound (4syn) obtained in Example 81 (1) (Z = (2-1), Y = Br, R ^2c = Pr, 4S / 5S) 21 mg (51 μmol) and compound (7) (R ³ = TBS) , R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 43 mg (77 μmol) was used to carry out the same reaction as in Example 14 (2-a), and compound No. 15 mg of 1104b was obtained. Yield 54%.
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.95 (t, J = 7.0 Hz, 3 H), 1.05 (d, J = 6.4 Hz, 3 H), 1.20-2.08 (m, 20 H), 2.23 (dd, J = 13.2, 9.3 Hz, 1 H), 2.50-2.80 (m, 4 H), 2.83 (m, 1 H), 2.91 (m, 1 H), 3.37 (dd, J = 7.3, 3.1 Hz, 1 H), 3.73-3.93 (m, 4 H), 4.05 (ddd, J = 8.6, 7.6, 4.9 Hz, 1 H), 4.44 (br d, J = 3.1 Hz, 1 H) , 4.57 (ddd, J = 8.3, 6.1, 5.1 Hz, 1 H), 5.09 (d, J = 1.7 Hz, 1 H), 5.39 (br s, 1 H), 5.49 (d, J = 2.1 Hz, 1 H), 6.02 (d, J = 11.2 Hz, 1 H), 6.19 (d, J = 2.1 Hz, 1 H), 6.41 (d, J = 11.2 Hz, 1 H).
LRMS m / z 542 (M ⁺ ), 524, 506, 480, 448, 432, 394
HRMS calcd for C ₃₃ H ₅₀ O ₆ 542.3607, found 542.3609

[Example 90]
2α- (3-Hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (R) -propyl-5 (S) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 1104c)

Compound (4anti) (Z = (2-1), Y = Br, R ^2c = Pr, 4R / 5S) 34 mg (83 μmol) obtained in Example 82 (5) and Compound (7) (R ³ = TBS) , R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 69 mg (125 μmol), the same reaction as in Example 14 (2-a) was carried out. 26 mg of 1104c was obtained. Yield 57%.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.96 (t, J = 7.2 Hz, 3 H), 1.05 (d, J = 5.9 Hz, 3 H), 1.15-1.73 (m, 15 H), 1.83-2.05 (m, 5 H), 2.24 (dd, J = 13.4, 8.8 Hz, 1 H), 2.62 (m, 1 H), 2.67 (dd, J = 13.4, 4.4 Hz, 1 H ), 2.79 (br s, 3 H), 2.82 (m, 1 H), 3.37 (dd, J = 7.5, 3.2 Hz, 1 H), 3.73-2.93 (m, 4 H), 4.05 (ddd, J = 8.8, 7.5, 4.4 Hz, 1 H), 4.24 (m, 1 H), 4.44 (br d, J = 2.7 Hz, 1 H), 5.08 (d, J = 1.7 Hz, 1 H), 5.38 (br s , 1 H), 5.59 (d, J = 2.3 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.25 (d, J = 2.3 Hz, 1 H), 6.41 (d, J = (11.2 Hz, 1 H).
LRMS m / z 542 (M ⁺ ), 524, 506, 480, 448, 432, 394
HRMS calcd for C ₃₃ H ₅₀ O ₆ 542.3607, found 542.3596

[Example 91]
2α- (3-hydroxypropoxy) -20 (R)-(tetrahydro-3-methylene-2-furanone-4 (S) -propyl-5 (R) -yl) methyl-9,10-secopregna-5 (Z ), 7 (E), 10 (19) -Triene-1α, 3β-diol (Compound No. 1104d)

Compound (4anti) (Z = (2-1), Y = Br, R ^2c = Pr, 4S / 5R) 18 mg (44 μmol) obtained in Example 83 (5) and compound (7) (R ³ = TBS) , R ⁶ = —O (CH ₂ ) ₃ OTBS, 3α / 4α / 5β) 37 mg (66 μmol) was used to carry out the same reaction as in Example 14 (2-a), and compound No. 13 mg of 1104d was obtained. Yield 53%.
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.96 (t, J = 7.2 Hz, 3 H), 1.02 (d, J = 6.4 Hz, 3 H), 1.20-1.90 (m, 18 H), 1.95-2.08 (m, 2 H), 2.23 (dd, J = 13.4, 8.5 Hz, 1 H), 2.57 (m, 1 H), 2.61 (br s, 3 H), 2.68 (dd, J = 13.4, 4.6 Hz, 1 H), 2.83 (m, 1 H), 3.37 (dd, J = 7.7, 3.2 Hz, 1 H), 3.73-3.93 (m, 4 H), 4.06 (ddd, J = 8.5, 7.7, 4.6 Hz, 1 H), 4.27 (ddd, J = 10.8, 4.8, 1.8 Hz, 1 H), 4.45 (br d, J = 3.2 Hz, 1 H), 5.08 (d, J = 1.7 Hz , 1 H), 5.39 (br s, 1 H), 5.57 (d, J = 2.6 Hz, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.25 (d, J = 2.6 Hz, 1 H), 6.41 (d, J = 11.2 Hz, 1 H).
LRMS m / z 542 (M ⁺ ), 524, 506, 480, 448, 432, 394
HRMS calcd for C ₃₃ H ₅₀ O ₆ 542.3607, found 542.3606

[Example 92]
20 (R)-(Tetrahydro-3-methylene-2-furanone-4-cyclopropanespiro-5-yl) methyl-9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene Of -1α, 3β-diol (Compound No. 113a and No. 113b)

(1) To a solution of propargyl alcohol TBS protector 692 mg (4.1 mmol) in THF (3.8 mL) at −78 ° C., n-BuLi 2.7 mL (1.5 M hexane solution, 4.1 mmol) And stirred at the same temperature for 1 hour. Compound (2) (Z = (2-1), Y = Br) (607 mg, 2.0 mmol) of THF (607 mg, 2.0 mmol) obtained by a method known in the literature (for example, International Publication WO95 / 33716) is added to the solution. (3.0 mL) The solution was added dropwise at −78 ° C., followed by stirring at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution was added and the temperature was raised to 0 ° C., and then the aqueous layer was extracted with ether. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in methylene chloride (6.8 mL). To the solution were added 214 mg (0.61 mmol) of TPAP and 357 mg (3.04 mmol) of NMO at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with ether and then filtered through a silica gel short column (eluted with ether). When the residue obtained by concentrating the filtrate was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1), compound (9) (Z = (2-1), Y = Br, R ⁹ = 733 mg of TBS) was obtained. Yield 77%, colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.13 (s, 6 H), 0.61 (s, 3 H), 0.91 (s, 9 H), 0.99 (d, J = 6.3 Hz, 3 H), 1.25-1.38 (m, 3 H), 1.40-1.72 (m, 5 H), 1.89 (m, 1 H), 1.95-2.03 (m, 2 H), 2.10 (m, 1 H), 2.29 (dd, J = 15.4 , 10.1 Hz, 1 H), 2.64 (dd, J = 15.4, 3.4 Hz, 1 H), 2.88 (m, 1 H), 4.46 (s, 2 H), 5.65 (m, 1 H).
LRMS m / z 466 (M ⁺ ), 409, 255, 175, 147
HRMS calcd for C ₂₄ H ₃₉ O ₂ ⁷⁹ BrSi 466.1902, found 466.1889

(2) Compound (9) obtained above (Z = (2-1), Y = Br, R ⁹ = TBS) 98 mg (0.21 mmol) in methylene chloride (2.1 mL) solution to 0 Bleacht-Grubbs ruthenium complex 15 mg (0.021 mmol) (prepared according to Wakamatsu, H .; Blechert, S. Angew. Chem. Int. Ed. 2002, 41, 2403) was added at 0 ° C., and ethylene (1 atm, undissolved) Purification) The mixture was stirred at 0 ° C. for 1.5 hours under an atmosphere. The residue obtained by concentrating the reaction solution was purified by silica gel flash column chromatography (hexane: ethyl acetate = 50: 1) to obtain compound (10) (Z = (2-1), Y = Br, R ^9). = TBS) was obtained 96 mg. Yield 92%, colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 0.061 (s, 6 H), 0.60 (s, 3 H), 0.90 (s, 9 H), 0.94 (d, J = 6.6 Hz, 3 H), 1.23-1.39 (m, 3 H), 1.41-1.73 (m, 5 H), 1.80-2.13 (m, 4 H), 2.44 (dd, J = 16.1, 10.0 Hz, 1 H), 2.70 (dd, J = 16.1, 2.9 Hz, 1 H), 2.88 (m, 1 H), 4.26 (dd, J = 1.4, 1.4 Hz, 2 H), 5.11 (d, J = 1.4 Hz, 1 H), 5.33 (d, J = 1.4 Hz, 1 H), 5.65 (s, 1 H), 5.68 (s, 1 H), 5.76 (s, 1 H).
LRMS m / z 494 (M ⁺ ), 479, 437, 415, 345, 253, 211, 183
HRMS calcd for C ₂₆ H ₄₃ O ₂ ⁷⁹ BrSi 494.2216, found 494.2208

(3) DMSO (1 mL) was added to trimethylsulfonium iodide (49 mg, 0.22 mmol) and sodium hydride (60% oil dispersion, 11 mg, 0.26 mmol) at room temperature, and the mixture was stirred at the same temperature for 20 minutes. did. Compound (10) obtained above at 10 ° C. (Z = (2-1), Y = Br, R ⁹ = TBS) 104 mg (0.20 mmol) in THF (0.3 mL) -DMSO (2 mL) solution was added and stirred at room temperature for 30 minutes. After the reaction solution was diluted with ether, a saturated aqueous ammonium chloride solution was added at 0 ° C. The aqueous layer was extracted with ether, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel flash column chromatography (hexane: ethyl acetate = 100: 1) to obtain 86 mg of compound (T). Yield 85%, helpless oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.066 (s, 6 H), 0.58 (s, 3 H), 0.85-0.93 (m, 2 H), 0.87 (d, J = 6.4 Hz, 3 H), 0.91 (s, 9 H), 1.20-1.33 (m, 5 H), 1.38-1.70 (m, 5 H), 1.82 (m, 1 H), 1.90-2.05 (m, 3 H), 2.35 (dd, J = 16.5, 10.0 Hz, 1 H), 2.51 (dd, J = 16.5, 3.1 Hz, 1 H), 2.86 (m, 1 H), 4.13 (dd, J = 1.6, 1.6 Hz, 2 H), 5.13 ( d, J = 1.6 Hz, 1 H), 5.41 (d, J = 1.6 Hz, 1 H), 5.63 (br s, 1 H).
LRMS m / z 508 (M ⁺ ), 451, 377, 297, 227
HRMS calcd for C ₂₇ H ₄₅ O ₂ ⁷⁹ BrSi 508.2372, found 508.2366

(4) To a solution of compound (T) 86 mg (0.17 mmol) obtained above in toluene (1.7 mL) at −78 ° C., 0.25 ml of DIBAL-H (1.0 M toluene solution, 0.25) mmol) and stirred at the same temperature for 1 hour. After adding a few drops of methanol at −78 ° C., a saturated aqueous Rochelle salt solution was added and stirred at room temperature for 30 minutes. The aqueous layer was extracted with ether, and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel flash column chromatography (hexane: ethyl acetate = 30: 1) to obtain compound (11) (Z = (2-1), Y = Br). , R ⁹ = TBS) (less polar) is 48 mg (55% yield) and Compound (11) (Z = (2-1), Y = Br, R ⁹ = TBS) (more polar) is 39 mg (yield) 45%) each obtained as a helpless oil.
(Less polar)
¹ H-NMR (CDCl ₃ ) δ: 0.11 (s, 6 H), 0.43-0.53 (m, 2 H), 0.57 (s, 3 H), 0.64-0.78 (m, 2 H), 0.91 (d, J = 6.6 Hz, 3 H), 0.92 (s, 9 H), 1.04 (ddd, J = 13.8, 10.9, 1.7 Hz, 1 H), 1.18-1.72 (m, 11 H), 1.91 (m, 1 H ), 1.96 (ddd, J = 12.5, 7.1, 1.5 Hz, 1 H), 2.01 (ddd, J = 12.5, 2.3, 2.3 Hz, 1 H), 2.80-2.92 (m, 2 H), 4.11 (d, J = 12.5 Hz, 1 H), 4.21 (d, J = 12.5 Hz, 1 H), 4.99 (d, J = 1.7 Hz, 1 H), 5.18 (s, 1 H), 5.63 (s, 1 H) .
LRMS m / z 492 [(MH ₂ O) ⁺ ], 453, 435, 361, 281, 241, 227, 147
HRMS calcd for C ₂₇ H ₄₅ O ⁷⁹ BrSi 492.2423 (MH ₂ O), found 492.2423
(More polar)
¹ H-NMR (CDCl ₃ ) δ: 0.11 (s, 6 H), 0.41 (ddd, J = 9.3, 5.4, 4.1 Hz, 1 H), 0.56 (m, 1 H), 0.57 (s, 3 H) , 0.69 (ddd, J = 9.3, 5.4, 4.1 Hz, 1 H), 0.78 (ddd, J = 9.3, 5.4, 4.1 Hz, 1 H), 0.93 (s, 9 H), 0.97 (d, J = 6.6 Hz, 3 H), 1.18-2.05 (m, 15 H), 2.82-2.93 (m, 2 H), 4.13 (d, J = 12.3 Hz, 1 H), 4.23 (d, J = 12.3 Hz, 1 H ), 5.01 (d, J = 1.9 Hz, 1 H), 5.19 (s, 1 H), 5.63 (s, 1 H).
LRMS m / z 510 (M ⁺ ), 492, 453, 435, 361, 281, 241, 227, 147
HRMS calcd for C ₂₇ H ₄₇ O ₂ ⁷⁹ BrSi 510.2528, found 510.2528

(5-a) Compound (11) obtained above (Z = (2-1), Y = Br, R ⁹ = TBS) (less polar) 146 mg (0.29 mmol) of THF (2.9 To the solution was added TBAF 0.57 mL (1.0 M THF solution, 0.57 mmol) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added at 0 ° C., and the aqueous layer was extracted with ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in methylene chloride (2.9 mL). MnO ₂ 746 mg (8.6 mmol) was added to the solution, and the mixture was stirred at room temperature for 62 hours. The reaction solution was filtered through a silica gel short column (eluted with ether), and the residue obtained by concentrating the filtrate was purified by silica gel flash column chromatography (hexane: ethyl acetate = 30: 1) to give compound (4 _{^{) (Z = (2-1),}} Y = Br, R 2d -R 2e = CH 2 -CH 2) (less polar) was obtained 90 mg. Yield 80%, colorless solid.
¹ H-NMR (CDCl ₃ ) δ: 0.59 (s, 3 H), 0.87 (m, 1 H), 0.91-1.06 (m, 3 H), 0.98 (d, J = 6.6 Hz, 3 H), 1.15 (ddd, J = 10.1, 6.4, 4.8 Hz, 1 H), 1.20-1.38 (m, 3 H), 1.40-1.73 (m, 6 H), 1.74-1.92 (m, 2 H), 1.97 (ddd, J = 12.3, 6.8, 1.6 Hz, 1 H), 2.01 (ddd, J = 12.8, 2.7, 2.7 Hz, 1 H), 2.88 (m, 1 H), 4.50 (dd, J = 11.7, 2.0 Hz, 1 H), 5.02 (s, 1 H), 5.65 (br s, 1 H), 5.94 (s, 1 H).
LRMS m / z 392 (M ⁺ ), 377, 313, 255, 227,147
HRMS calcd for C ₂₁ H ₂₉ O ₂ ⁷⁹ BrSi 392.1351, found 392.1341

(5-b) Example 92 using the compound (11) obtained above (Z = (2-1), Y = Br, R ⁹ = TBS) (more polar) 81 mg (0.16 mmol) (5-a) and carrying out the same reaction, the compound ^{(4) (Z = (2-1} ), Y = Br, R 2d -R 2e = CH 2 -CH 2) a (more polar) was obtained 50 mg. Yield 80%, colorless solid.
¹ H-NMR (CDCl ₃ ) δ: 0.56 (s, 3 H), 0.85 (ddd, J = 9.8, 7.2, 4.9 Hz, 1 H), 0.95 (ddd, J = 10.0, 7.2, 4.9 Hz, 1 H ), 1.01 (ddd, J = 9.8, 6.5, 4.9 Hz, 1 H), 1.06 (d, J = 6.6 Hz, 3 H), 1.21 (ddd, J = 10.0, 6.5, 4.9 Hz, 1 H), 1.25 -1.73 (m, 11 H), 1.88-2.05 (m, 3 H), 2.88 (m, 1 H), 4.49 (dd, J = 8.7, 4.0 Hz, 1 H), 5.02 (s, 1 H), 5.64 (s, 1 H), 5.93 (s, 1 H).
LRMS m / z 392 (M ⁺ ), 377, 313, 255, 227,147
HRMS calcd for C ₂₁ H ₂₉ O ₂ ⁷⁹ BrSi 392.1351, found 392.1368

(6-a) The compound obtained in the above _{^{(4) (Z = (2-1}} ), Y = Br, R 2d -R 2e = CH 2 -CH 2) (less polar) 28mg (71μmol) and the compound ( 7) (R ³ = TBS, R ⁶ = H) Using 39 mg (0.11 mmol), the same reaction as in Example 14 (2-a) was carried out. 25 mg of 113a was obtained. Yield 76%, colorless amorphous solid.
¹ H-NMR (CDCl ₃ ) δ: 0.57 (s, 3 H), 0.82-1.05 (m, 4 H), 0.97 (d, J = 6.6 Hz, 3 H), 1.15 (ddd, J = 10.1, 6.4 , 4.9 Hz, 1 H), 1.20-2.08 (m, 17 H), 2.31 (dd, J = 13.4, 6.6 Hz, 1 H), 2.60 (dd, J = 13.4, 3.2 Hz, 1 H), 2.82 ( m, 1 H), 4.23 (br s, 1 H), 4.42 (br s, 1 H), 4.51 (dd, J = 11.6, 1.8 Hz, 1 H), 5.00 (s, 1 H), 5.02 (s , 1 H), 5.33 (s, 1 H), 5.94 (s, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.46 (d, J = 11.2 Hz, 1 H).
LRMS m / z 452 (M ⁺ ), 434, 416, 311, 285, 134, 105
HRMS calcd for C ₂₉ H ₄₀ O ₄ 452.2927, found 452.2930

(6-b) The compound obtained in the above _{^{(4) (Z = (2-1}} ), Y = Br, R 2d -R 2e = CH 2 -CH 2) (more polar) 25mg (64μmol) and the compound ( 7) (R ³ = TBS, R ⁶ = H) Using 35 mg (0.10 mmol), the same reaction as in Example 14 (2-a) was carried out. 18 mg of 113b was obtained. Yield 62%, colorless amorphous solid.
¹ H-NMR (CDCl ₃ ) δ: 0.55 (s, 3 H), 0.83 (ddd, J = 9.9, 7.1, 5.1 Hz, 1 H), 0.95 (ddd, J = 9.9, 7.1, 4.7 Hz, 1 H ), 1.01 (ddd, J = 9.9, 6.5, 4.7 Hz, 1 H), 1.05 (d, J = 6.6 Hz, 3 H), 1.16-1.75 (m, 14 H), 1.85-2.08 (m, 5 H ), 2.31 (dd, J = 13.5, 6.5 Hz, 1 H), 2.59 (dd, J = 13.5, 3.4 Hz, 1 H), 2.82 (m, 1 H), 4.90 (m, 1 H), 4.43 ( m, 1 H), 4.49 (dd, J = 8.8, 3.9 Hz, 1 H), 4.99 (s, 1 H), 5.01 (s, 1 H), 5.33 (s, 1 H), 5.93 (s, 1 H), 6.01 (d, J = 11.2 Hz, 1 H), 6.37 (d, J = 11.2 Hz, 1 H).
LRMS m / z 452 (M ⁺ ), 434, 416, 311, 285, 134, 105
HRMS calcd for C ₂₉ H ₄₀ O ₄ 452.2926, found 452.2925

[Example 93]
Affinity of binding to 1α, 25-dihydroxyvitamin D ₃ receptor (VDR) in chicken small intestinal mucosa cells Ishizuka et al., Steroids, 37, 33-43, 1982. That, of 15000dpm to 12 × 75 mm polypropylene tubes [26,27- methyl - ³ H] l [alpha], 25-dihydroxyvitamin _D 3 a 40μl ethanol solution of the compound used in 10μl ethanol solution and the invention of (180 Ci / mmol) was added To this, 1 ml of phosphate buffer solution (pH 7.4) dissolved in 0.2 mg of 1α, 25-dihydroxyvitamin D ₃ receptor protein in chicken small intestinal mucosa and 1 mg of gelatin was added and reacted at 25 ° C. for 1 hour. . 1 ml of 40% polyethylene glycol 6000 solution was added to the tube, and after vigorous stirring, centrifuged at 4 ° C. and 2260 × g for 60 minutes. The tube of the precipitation part was cut off with a cutter knife, put into a liquid scintillator vial, 10 ml of dioxane scintillator was added, and the radioactivity was measured with a liquid scintillation counter. Than the measured value to the receptor [26,27- methyl - ³ H] l [alpha], 25-bond the sought compound concentration which inhibits 50% of the dihydroxyvitamin _{D 3,} the concentration l [alpha], 25-50% inhibition of dihydroxyvitamin _{D 3} The relative intensity ratio when the concentration is 1 is shown. The results are shown in the following table.

1α, 25-Dihydroxyvitamin D in chicken small intestinal mucosa cells ₃ Binding affinity of compounds of the present invention for receptors

From this result, it was revealed that the compound used as the active ingredient of the present invention binds to VDR with very high affinity. Therefore, considering the antagonistic action of these compounds as described below, it can be expected high vitamin D ₃ antagonism to them. Therefore, it was shown that the therapeutic agent of the present invention is effective as an osteoporosis therapeutic agent based on the PTH production promoting action.

[Example 94]
Vitamin D ₃ antagonistic action using 1α, 25-dihydroxyvitamin D ₃ as an index of HL-60 cell differentiation inducing action (1) HL-60 cells are cell banks (Japanese Cancer Research Resource Bank, cell number: What was purchased from JCRB0085) was used. Cells were used as cryopreserved stocks to prevent changes in cell properties due to subculture, and those that had been thawed and started subculture before the start of the experiment were used. The experiment was conducted for about 1 month to 6 months. Passage was performed by centrifuging and recovering cells in suspension culture and diluting them in a fresh culture solution to a concentration of about 1/100 (1-2 × 10 ⁴ cells / ml). RPMI-1640 medium containing 10% fetal bovine serum was used as a culture solution.

(2) Cells subcultured in (1) were collected by centrifugation, dispersed in a culture solution at 2 × 10 ⁴ cells / ml, and seeded in a 24-well culture dish at 1 ml / well. To this system was added 1α, 25-dihydroxyvitamin D ₃ at 1 × 10 ⁻⁵ M and the compound of the present invention in ethanol solution at 1 × 10 ⁻⁸ M ⁻¹ to 10 ⁻⁴ M at 1 μl per well. (Final concentration: 1 × 10 ⁻⁸ M for 1α, 25-dihydroxyvitamin D _{3 and} 1 × 10 ⁻¹¹ M to 1 × 10 ⁻⁷ M for the compound of the present invention). For control, 1 μl of ethanol was added per well. After culturing at 37 ° C. under 5% CO ₂ for 4 days, the cells were collected by centrifugation.

(3) Induction of nitro blue tetrazolium (hereinafter referred to as NBT) reducing activity was used as an index of the differentiation-inducing action of HL-60 cells. NBT reduction activity was measured according to the following procedure. That is, after the cells collected by centrifugation were suspended in a fresh culture solution, NBT 0.1%, 12-O-tetradecanoylphorbol-13-acetate 100 ng / ml was added, and the mixture was added at 37 ° C. for 25 After incubating for minutes, cytospin specimens were prepared. After air-drying, Köln human funnel staining was performed, and the ratio of NBT reduction activity positive cells was determined under an optical microscope. From 1 × 10 ⁻⁸ M of 1α, 25-dihydroxyvitamin D ₃ alone to a positive cell ratio, 1 × 10 ⁻⁸ M of 1α, 25-dihydroxyvitamin D ₃ and 1 × 10 ⁻¹¹ M to 1 × 10 The percentage ratio of the positive cell ratio by simultaneous treatment of the compound used in the present invention at ⁻⁷ M is plotted against the treatment concentration of the compound used in the present invention, and the treatment concentration of the compound of the present invention at which the percent ratio is 50% is expressed as IC _50. Calculated as value (nM). The results are shown in the following table.

From this result, it was found that the compound which is an active ingredient of the present invention suppresses the cell differentiation inducing action caused by 1α, 25-dihydroxyvitamin D ₃ . That is, these compounds were shown to act as antagonists to 1α, 25-dihydroxyvitamin D ₃ . Therefore, the therapeutic agent of the present invention is effective as an osteoporosis therapeutic agent based on the PTH production promoting action.

[Example 95]
PTH production-promoting action compound No. 1 of the present compound in monkeys 211b was administered to male cynomolgus monkeys (intravenous, 100 μg / kg, single dose), blood was collected over time after administration, and serum was separated according to a standard method. The intact PTH concentration in the serum was quantified by the RIA method. As a result, it was confirmed that the PTH concentration increased after compound administration.

From this result, it was shown that the therapeutic agent of the present invention promotes PTH production based on the antagonistic action against 1α, 25-dihydroxyvitamin D ₃ . Therefore, the therapeutic agent of the present invention is effective as an osteoporosis therapeutic agent based on the PTH production promoting action.

  The present invention is utilized for pharmaceutical manufacture.

Claims (12)

A therapeutic agent for osteoporosis comprising a compound represented by the following formula (1) or a pharmaceutically acceptable solvate thereof as an active ingredient.

[Wherein, R ¹ represents a hydrogen atom, a C ₁ -C ₆ alkyl group optionally substituted with a hydroxyl group, or a C ₁ -C ₆ alkoxy group optionally substituted with a hydroxyl group, R ^2a and R ^2b is the same or different and is substituted with a hydrogen atom, a C ₁ -C ₁₀ alkyl group that may be substituted with a hydroxyl group, a C ₆ -C ₁₀ aryl group that may be substituted with a hydroxyl group, or a hydroxyl group. Or a C ₇ -C ₁₂ aralkyl group. Alternatively, R ^2a and R ^2b may be combined to form a cyclopropane ring with the carbon atom to which they are attached. However, a compound in which R ¹ , R ^2a , and R ^2b are simultaneously a hydrogen atom, and a compound in which R ¹ is a methyl group and R ^2a , and R ^2b are hydrogen atoms are excluded. ]   The osteoporosis therapeutic agent according to claim 1, wherein the configuration at the 1st position of the formula (1) is an α configuration and the configuration at the 3rd position is a β configuration.   The osteoporosis therapeutic agent according to claim 1 or 2, wherein the configuration at the 2-position of the formula (1) is an α configuration. The osteoporosis therapeutic agent according to claim 1 or 2, wherein R ^{1 in the} formula (1) is a hydrogen atom. R ^{1 in the} above formula (1) is methyl group, ethyl group, propyl group, butyl group, hydroxymethyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, 4-hydroxybutyl group, 2-hydroxyethoxy group, 3 The osteoporosis therapeutic agent according to any one of claims 1 to 3, which is a -hydroxypropoxy group or a 4-hydroxybutoxy group. The therapeutic agent for osteoporosis according to any one of claims 1 to 3, wherein R ^{1 in the} formula (1) is a methyl group, a 3-hydroxypropyl group, or a 3-hydroxypropoxy group. The combination of R ^2a and R ^{2b in} the above formula (1) is a hydrogen atom and a methyl group, a hydrogen atom and an ethyl group, a hydrogen atom and a propyl group, a hydrogen atom and an isopropyl group, a hydrogen atom and a butyl group, a hydrogen atom and an isobutyl group, A hydrogen atom and a hexyl group, a hydrogen atom and an octyl group, a hydrogen atom and a phenyl group, a hydrogen atom and a phenethyl group, a hydrogen atom and a 2-hydroxyethyl group, both a hydrogen atom, or both a methyl group, or R ^2a The therapeutic agent for osteoporosis according to any one of claims 1 to 6, wherein R ^2b and R ^2b together form a cyclopropane ring together with a carbon atom to which they are bonded. The combination of R ^2a and R ^{2b in} the above formula (1) is a hydrogen atom and a methyl group, a hydrogen atom and an ethyl group, a hydrogen atom and a propyl group, a hydrogen atom and a butyl group, a hydrogen atom and an isobutyl group, a hydrogen atom and a hexyl group, Or the osteoporosis therapeutic agent in any one of Claims 1-6 whose both are methyl groups. The combination of R ^2a and R ^{2b in} the above formula (1) is a hydrogen atom and a methyl group, a hydrogen atom and an ethyl group, a hydrogen atom and a propyl group, a hydrogen atom and a butyl group, a hydrogen atom and an isobutyl group, a hydrogen atom and a hexyl group, Or the osteoporosis therapeutic agent of Claim 4 whose both are methyl groups. In the above formula (1), R ¹ is a methyl group, a combination of R ^2a and R ^2b is a hydrogen atom and a methyl group, R ¹ is a methyl group, a combination of R ^2a and R ^2b is a hydrogen atom and an ethyl group, and R ¹ is methyl The combination of R ^2a and R ^2b is a hydrogen atom and a propyl group, R ¹ is a methyl group, the combination of R ^2a and R ^2b is a hydrogen atom and a butyl group, R ¹ is a methyl group and the combination of R ^2a and R ^2b is A hydrogen atom and an isobutyl group, R ¹ is a methyl group and a combination of R ^2a and R ^2b is a hydrogen atom and a hexyl group, or R ¹ is a methyl group and R ^2a and R ^2b are both methyl groups. The therapeutic agent for osteoporosis according to claim 3. In the above formula (1), R ¹ is a 3-hydroxypropyl group, R ^2a and R ^2b are both hydrogen atoms, R ¹ is a 3-hydroxypropyl group, and a combination of R ^2a and R ^2b is a hydrogen atom and a methyl group, R ¹ is a 3-hydroxypropyl group, a combination of R ^2a and R ^2b is a hydrogen atom and an ethyl group, R ¹ is a 3-hydroxypropyl group, a combination of R ^2a and R ^2b is a hydrogen atom and a propyl group, and R ¹ is 3- In the hydroxypropyl group, the combination of R ^2a and R ^2b is a hydrogen atom and a butyl group, R ¹ is a 3-hydroxypropyl group, the combination of R ^2a and R ^2b is a hydrogen atom and an isobutyl group, and R ¹ is a 3-hydroxypropyl group combining a hydrogen atom and hexyl groups R ^2a and ^{R 2b} or ^{R 1} is 3-hydroxypropyl group ^{R 2a} and ^{R 2b,} is a methyl group both, any of claims 1 to 3 Osteoporosis treatment agent according to. In the above formula (1), R ¹ is a 3-hydroxypropoxy group, R ^2a and R ^2b are both hydrogen atoms, R ¹ is a 3-hydroxypropoxy group, and the combination of R ^2a and R ^2b is a hydrogen atom and a methyl group, R ¹ is a 3-hydroxypropoxy group, a combination of R ^2a and R ^2b is a hydrogen atom and an ethyl group, R ¹ is a 3-hydroxypropoxy group, a combination of R ^2a and R ^2b is a hydrogen atom and a propyl group, and R ¹ is 3- R ^2a and R ^2b are a hydrogen atom and a butyl group, R ¹ is a 3-hydroxypropoxy group, R ^2a and R ^2b are a hydrogen atom and an isobutyl group, and R ¹ is a 3-hydroxypropoxy group. R ^2a and combinations ^{R 2b} is a hydrogen atom and a hexyl group or ^{R 1} is 3-hydroxypropoxy group ^{R 2a} and ^{R 2b,} is a methyl group both from claim 1 Osteoporosis therapeutic agent according to any one of Motomeko 3.