Method for producing cyclopentane compound, method for producing lactone compound, method for producing diol compound, and compound

Abstract

Provided is a method for producing a cyclopentane compound, the method allowing easy synthesis of a cyclopentane compound in a diastereoselective manner and, as necessary, in an enantioselective manner, the compound having multiple asymmetric centers in a molecule. This production method is for producing a cyclopentane compound represented by formula (III), the method including cyclization of a specific α,β-unsaturated aldehyde compound or a cis-trans isomer thereof and a specific α,β-unsaturated ketone compound or a cis-trans isomer thereof, in the presence of a catalyst composed of a pyrrolidine compound.

Description

[Technical field]

[0001] The present invention relates to a method for producing a cyclopentane compound, a method for producing a lactone compound, and a method for producing a diol compound, and to a cyclopentane compound and a lactone compound. This application claims priority based on Japanese Patent Application No. 2019-187643, filed on October 11, 2019, the contents of which are incorporated herein by reference. [Background technology]

[0002] Prostaglandins (hereinafter, also referred to as "PG") are one of the eicosanoids biosynthesized from arachidonic acid, and are known to have physiological activities such as blood pressure lowering, uterine contraction, intraocular pressure lowering, and platelet aggregation. Although PGs are physiologically important, their abundance in nature is extremely low, and therefore many research groups have been working to develop efficient synthetic methods for them.

[0003] One of the efficient methods for synthesizing PGs is the synthesis via Corey lactone. By using Corey lactone as an intermediate in the synthesis of PGs, it is possible to synthesize a wide variety of PGs, including PG derivatives. Even today, Corey lactone is one of the important pharmaceutical raw materials.

[0004] However, Corey lactone, a synthetic intermediate of PGs, has multiple asymmetric centers in the molecule, and therefore requires high diastereoselectivity and high enantioselectivity for synthesis, and therefore the production of Corey lactone generally requires many steps (e.g., Non-Patent Document 1). [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Corey et al., "The Logic of Chemical Synthesis", Wiley, New York, 1995, pp. 255, 258, 259, 278, 279, etc. Summary of the Invention [Problem to be solved by the invention]

[0006] Under the above circumstances, there is a need for the development of a diastereoselective and enantioselective synthesis method for cyclopentane compounds having multiple asymmetric centers in the molecule, including Corey lactone.

[0007] An object of the present invention is to provide a method for simply synthesizing a cyclopentane compound having multiple asymmetric centers in the molecule in a diastereoselective and, if necessary, enantioselective manner. [Means for solving the problem]

[0008] [1] Formula (I)

[0009] [ka]

[0010] (In formula (I), R 1A represents an aromatic hydrocarbon ring group which may have a substituent, an aromatic heterocyclic group which may have a substituent, a substituted silyl group, -C(=O)-OR X , -C(=O)-R X , -C(=O)-N(-R X1 )-R X2 or a hydrogen atom; R 1B is a hydrogen atom, halogen, or C 1-6 represents an alkyl group; R X is C 1-6 represents an alkyl group or an aromatic hydrocarbon ring group which may have a substituent; R X1 and R X2are the same or different R X (Indicates or a cis-trans isomer thereof, and

[0011] [ka]

[0012] (In formula (II), R 2A is -C(=O)-OR X , -C(=O)-SR X , -C(=O)-R X , -C(=O)-N(-R X1 )-R X2 , a cyano group, or a nitro group; R 2B is a hydrogen atom, -C(=O)-OR X , -C(=O)-SR X , -C(=O)-R X , -C(=O)-N(-R X1 )-R X2 , a cyano group, or a nitro group; R 2C represents a hydrogen atom or a halogen; R 2D and R 2E are the same or different and each represents a hydrogen atom, C 1-6 represents an alkyl group, an aromatic hydrocarbon ring group which may have a substituent, or an aromatic heterocyclic group which may have a substituent; R 2C and R 2E are taken together and optionally substituted C 2-4 An alkylene group or a methylene group (-CH2-) which may be substituted is replaced with -O-, -S-, or -N(C 1-6 C replaced with alkyl group)- 2-4 may represent an alkylene group; R X is C 1-6 represents an alkyl group or an aromatic hydrocarbon ring group which may have a substituent; R X1 and R X2 are the same or different R X (Indicates or a cis-trans isomer thereof in the presence of a catalyst comprising a cyclic amine compound or a chain amine compound,

[0013] [ka]

[0014] (In formula (III), R 1A represents an aromatic hydrocarbon ring group which may have a substituent, an aromatic heterocyclic group which may have a substituent, a substituted silyl group, -C(=O)-OR X , -C(=O)-R X , -C(=O)-N(-R X1 )-R X2 or a hydrogen atom; R 1B is a hydrogen atom, halogen, or C 1-6 represents an alkyl group; R 2A is -C(=O)-OR X , -C(=O)-SR X , -C(=O)-R X , -C(=O)-N(-R X1 )-R X2 , a cyano group, or a nitro group; R 2B is a hydrogen atom, -C(=O)-OR X , -C(=O)-SR X , -C(=O)-R X , -C(=O)-N(-R X1 )-R X2 , a cyano group, or a nitro group; R 2C represents a hydrogen atom or a halogen; R 2D and R 2E are the same or different and each represents a hydrogen atom, C 1-6represents an alkyl group, an aromatic hydrocarbon ring group which may have a substituent, or an aromatic heterocyclic group which may have a substituent; R 2C and R 2E are taken together and optionally substituted C 2-4 An alkylene group or a methylene group (-CH2-) which may be substituted is replaced with -O-, -S-, or -N(C 1-6 C replaced with alkyl group)- 2-4 may represent an alkylene group; R X is C 1-6 represents an alkyl group or an aromatic hydrocarbon ring group which may have a substituent; R X1 and R X2 are the same or different R X indicates; The indication of stereochemistry in formula (III) indicates the relative configuration. A method for producing a cyclopentane compound represented by the formula: [2] The method for producing a cyclopentane compound according to [1], wherein the cyclization is carried out in the presence of an acid. [3] The method for producing a cyclopentane compound according to [1] or [2], wherein the cyclic amine compound or the chain amine compound is a pyrrolidine compound having an asymmetric center at the carbon at the α-position to the nitrogen atom of the pyrrolidine ring. [4] The pyrrolidine compound is represented by the formula (IV)

[0015] [ka]

[0016] (In formula (IV), R 4A is a carboxyl group, a tetrazolyl group, or -C(R 4C )(R 4D )-OR 4E Indicate the group; R 4C and R 4Dare the same or different and each represents an aromatic hydrocarbon ring group which may have a substituent, an aromatic heterocyclic group which may have a substituent, or a C 1-6 represents an alkyl group; R 4E is a hydrogen atom, a substituted silyl group, or an optionally substituted C 1-6 represents an alkyl group; R 4B represents a protecting group for a hydroxyl group; n is 0 or 1; The indication of stereochemistry in formula (IV) indicates the absolute configuration. or a compound represented by formula (V)

[0017] [ka]

[0018] (In formula (V), R 4A is a carboxyl group, a tetrazolyl group, or -C(R 4C )(R 4D )-OR 4E Indicate the group; R 4C and R 4D are the same or different and each represents an aromatic hydrocarbon ring group which may have a substituent, an aromatic heterocyclic group which may have a substituent, or a C 1-6 represents an alkyl group; R 4E is a hydrogen atom, a substituted silyl group, or an optionally substituted C 1-6 represents an alkyl group; R 4B represents a protecting group for a hydroxyl group; n is 0 or 1; The indication of stereochemistry in formula (V) indicates the absolute configuration. The method for producing a cyclopentane compound according to [3], wherein the cyclopentane compound is a compound represented by the formula: [5] The method for producing a cyclopentane compound according to [4], wherein the pyrrolidine compound is (R)-2-(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine, (S)-2-(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine, (R)-2-(diphenyl((methyldiphenylsilyl)oxy)methyl)pyrrolidine, or (S)-2-(diphenyl((methyldiphenylsilyl)oxy)methyl)pyrrolidine. [6]R 1A is a substituted silyl group, R 1B is a hydrogen atom,

[0019] [ka]

[0020] and an α,β-unsaturated aldehyde compound represented by R 2A -C(=O)-OR X and R 2B , R 2C , R 2D and R 2E is a hydrogen atom, and R X C 1-6 The alkyl group represented by formula (II)

[0021] [ka]

[0022] in the presence of a catalyst comprising a cyclic amine compound or a chain amine compound,

[0023] [ka]

[0024] (In formula (III-a), R 3A represents a substituted silyl group; R 3B is -C(=O)-ORY indicates; R Y is C 1-6 represents an alkyl group; The indication of stereochemistry in formula (III-a) indicates the relative configuration. A method for producing a cyclopentane compound represented by the following formula: [7] A method for producing a cyclopentane compound represented by formula (III-b), comprising reducing a cyclopentane compound represented by formula (III-a) produced by the method for producing a cyclopentane compound according to the method described in [6] and then lactonizing the cyclopentane compound represented by formula (III-b).

[0025] [ka]

[0026] (In formula (III-b), R 3A represents a substituted silyl group; The indication of stereochemistry in formula (III-b) indicates the relative configuration. A method for producing a lactone compound represented by the formula: [8] A method for producing a lactone compound represented by formula (III-c), comprising oxidizing a lactone compound represented by formula (III-b) produced by the method for producing a lactone compound according to [7] using the Tamao-Fleming reaction.

[0027] [ka]

[0028] (The indication of stereochemistry in formula (III-c) indicates the relative configuration.) A method for producing a diol compound represented by the formula: [9] Formula (III-a)

[0029] [ka]

[0030] (In formula (III-a), R 3A represents a substituted silyl group; R 3B is -C(=O)-OR Y indicates; R Y is C 1-6 represents an alkyl group; The indication of stereochemistry in formula (III-a) indicates the relative configuration. A cyclopentane compound represented by the formula:

[10] Formula (III-b)

[0031] [ka]

[0032] (In formula (III-b), R 3A represents a substituted silyl group; The indication of stereochemistry in formula (III-b) indicates the relative configuration. A lactone compound represented by the formula: Effect of the Invention

[0033] According to the process for producing a cyclopentane compound of the present invention, a cyclopentane compound having a plurality of asymmetric centers in the molecule can be simply synthesized diastereoselectively and, if necessary, enantioselectively. In particular, the cyclopentane compound and lactone compound of the present invention, which can be produced by the method for producing a cyclopentane compound of the present invention, are useful as intermediates for the synthesis of Corey lactone. Furthermore, by using these cyclopentane compounds of the present invention as intermediates for the synthesis of Corey lactone, it is possible to produce Corey lactone in one pot, i.e., in one reaction vessel without the need for so-called isolation and purification procedures.

[0034] In this specification, Corey lactone includes the compound of the following formula, which is generally known as Corey lactone or Corey lactone diol ((1R)-2β-(hydroxymethyl)-3α,5α-dihydroxycyclopentane-1α-acetic acid 1,5-lactone or (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-2-one), as well as compounds in which some or all of the hydroxyl groups in the following formula are protected with the same or different protecting groups, and optical isomers and racemic compounds thereof.

[0035] [ka] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] Hereinafter, the embodiments of the present invention will be described in detail, however, the present invention is not limited to the following embodiments and can be practiced with various modifications within the scope of the gist of the present invention.

[0037] As used herein, the following terms have the following meanings: "C 1-6 The term "alkyl group" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms. Examples include methyl, ethyl, propan-1-yl, propan-2-yl, butan-1-yl, butan-2-yl, 2-methylpropan-2-yl, pentan-1-yl, pentan-2-yl, pentan-3-yl, 2-methylbutan-2-yl, 2-methylbutan-3-yl, and hexan-1-yl. "C 2-6The term "alkenyl group" refers to a linear or branched alkenyl group having 2 to 6 carbon atoms or an alkyl group which may have one or more carbon-carbon unsaturated bonds. Examples include vinyl, allyl, propen-1-yl, but-3-en-1-yl, but-2-en-1-yl, but-1-en-1-yl, pent-4-en-1-yl, propen-2-yl, 1-methylprop-2-en-1-yl, 2-methylprop-2-en-1-yl, and 3-methylbut-3-en-1-yl. "C 3-8 The term "cycloalkyl group" refers to a cycloalkyl group having 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. "Halogen" means fluoro, chloro, bromo, and iodo.

[0038] <Method of producing cyclopentane compound> The production method for a cyclopentane compound of the present invention (hereinafter also simply referred to as "the production method of the present invention") is a production method for a cyclopentane compound represented by formula (III), which comprises cyclization of an α,β-unsaturated aldehyde compound represented by formula (I) or its cis-trans isomer with an α,β-unsaturated ketone compound represented by formula (II) or its cis-trans isomer in the presence of a catalyst consisting of a cyclic amine compound or a chain amine compound (hereinafter also referred to as "amine catalyst"). In the following, "an α,β-unsaturated aldehyde compound represented by formula (I)" is also referred to as "compound (I)", "an α,β-unsaturated ketone compound represented by formula (II)" is also referred to as "compound (II)", and "a cyclopentane compound represented by formula (III)" is also referred to as "compound (III)".

[0039] [ka]

[0040] The symbols in the formula are as defined above.

[0041] In this specification, the stereochemistry of compound (III), which is a cyclopentane compound produced by the production method of the present invention, is represented as in the above chemical formula, but the representation of the stereochemistry in formula (III) indicates the relative configuration. For example, if the amine catalyst used in the cyclization in the production method of the present invention is an optically inactive compound, compound (III) can be obtained as a racemate having the relative configuration shown in formula (III) as a single diastereomer (single isomer). On the other hand, if the amine catalyst used in the cyclization in the production method of the present invention is an optically active compound, compound (III) can be obtained selectively as one of the two enantiomers having the relative configuration shown in formula (III).

[0042] In this specification, when stereochemistry is shown in a chemical formula, it is understood that it indicates the relative configuration unless otherwise specified.

[0043] The cyclization in the production method of the present invention may be carried out in the presence of an acid in order to allow the reaction to proceed more smoothly. The acid used for carrying out cyclization in the presence of an acid in the production method of the present invention is not particularly limited, and examples thereof include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, etc.; organic carboxylic acids such as acetic acid, propionic acid, formic acid, oxalic acid, trifluoroacetic acid, benzoic acid, adamantanecarboxylic acid, etc.; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, etc.; and phenols such as phenol, cresol, hydroxyanisole, chlorophenol, tribromophenol, nitrophenol, cyanophenol, picric acid, etc. Among these, organic carboxylic acids and phenols are preferred. As organic carboxylic acids, benzoic acid and adamantane-1-carboxylic acid are preferred. As phenols, phenols having a nitro group are more preferred, and p-nitrophenol is even more preferred.

[0044] When an acid is used in the cyclization in the production method of the present invention, the amount of the acid used may be a catalytic amount, but in order to proceed with the reaction more smoothly, the amount of the acid used is preferably 10 to 200 mol%, more preferably 30 to 180 mol%, further preferably 50 to 150 mol%, and particularly preferably 80 to 120 mol%, relative to 100 mol% of compound (I). The cyclization in the production method of the present invention is preferably carried out using an acid.

[0045] The reaction temperature in the cyclization in the production method of the present invention may be selected depending on the properties of the substituents of compound (I) and compound (II) and the chemical structure and characteristics of the amine catalyst, and is generally −30 to 120° C., preferably 0 to 50° C. The reaction time for the cyclization in the production method of the present invention may be selected depending on the properties of the substituents of compound (I) and compound (II) and the chemical structure and characteristics of the amine catalyst, and is generally 1 minute to 120 hours, preferably 10 minutes to 10 hours.

[0046] The reaction solvent used for the cyclization in the production method of the present invention is not particularly limited as long as it does not inhibit the reaction, and examples of the reaction solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; ethers such as diethyl ether, tetrahydrofuran, 2-methylhydrofuran, dioxane, etc.; aprotic polar solvents such as acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, etc.; and halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, etc. In particular, when the cyclization in the production method of the present invention is carried out in the presence of an acid, among these, alcohols, ethers, and halogenated hydrocarbons are preferred, alcohols are more preferred, and isopropanol is even more preferred.

[0047] The cyclic amine compound or chain amine compound used as a catalyst in the cyclization in the production method of the present invention can be a compound that reacts with compound (I) in the reaction system to form an iminium salt and enhances the activity of compound (I) as a Michael acceptor, i.e., a secondary cyclic amine compound or a primary or secondary chain amine compound. The cyclic amine compound used as a catalyst in the cyclization in the production method of the present invention means an amine compound which has a non-aromatic optionally substituted 5- to 7-membered ring, at least one ring-constituting atom of which is a nitrogen atom, and which nitrogen atom is a secondary amine nitrogen atom. The chain amine compound used as a catalyst in the cyclization in the production method of the present invention is an optionally substituted C 1-6 Alkyl groups, optionally substituted C 2-6 Alkenyl groups and optionally substituted C 3-8 It means a primary or secondary amine compound substituted with at least one group selected from the group consisting of cycloalkyl groups.

[0048] In particular, as the cyclic amine compound or chain amine compound used as a catalyst in the cyclization in the production method of the present invention, a cyclic amine compound or chain amine compound known as a catalyst for enantioselective Michael addition reaction can be preferably used. If an optically active amine catalyst is used as the amine catalyst used in the cyclization in the production method of the present invention, the Michael addition reaction proceeds enantioselectively, followed by cyclization, but even if a racemic amine catalyst is used, the cyclization in the production method of the present invention proceeds diastereoselectively, so that compound (III) can be produced as a single diastereomer. From the viewpoint of obtaining compound (III) as an optically active substance, specifically, from the viewpoint of using compound (III) as, for example, a synthetic intermediate for optically active Corey lactone, the amine catalyst used in the cyclization in the production method of the present invention is preferably an optically active amine catalyst. In addition, the amine catalyst used in the cyclization in the production method of the present invention is preferably a cyclic amine compound, more preferably a pyrrolidine compound described below. Among pyrrolidine compounds, optically active pyrrolidine compounds are preferred, more preferably a pyrrolidine compound having an asymmetric center at the carbon at the α-position of the nitrogen atom of the pyrrolidine ring, and from the viewpoint of availability, a pyrrolidine compound derived from (L)-proline or (D)-proline and having an optically active carbon at the α-position of the nitrogen atom of the pyrrolidine ring is even more preferred.

[0049] Examples of the amine catalyst other than the pyrrolidine compound described below that is used in the cyclization in the production method of the present invention include the following compounds. In the following chemical formula, only one enantiomer is exemplified, but the other enantiomer or a racemic mixture thereof may be used as the amine catalyst used in the cyclization in the production method of the present invention.

[0050] [ka]

[0051] In the above formula, Me is methyl, Ph is phenyl, TMS is trimethylsilyl, Naph is naphthalene-2-yl, R Z is C 1-6 It means an alkyl group.

[0052] Among the amine catalysts used in the cyclization in the production method of the present invention, examples of cyclic amine compounds include pyrrolidine compounds. Examples of pyrrolidine compounds include the following compounds described in Japanese Patent No. 6003885, a compound represented by formula (IV) (hereinafter also referred to as "compound (IV)"), or a compound represented by formula (V) (hereinafter also referred to as "compound (V)"). In the following chemical formula, only one enantiomer is exemplified, but the other enantiomer or a racemic mixture thereof may be used as the amine catalyst used in the cyclization in the production method of the present invention.

[0053] [ka]

[0054] In the above formula, i-Pr means isopropyl, Tf means trifluoromethanesulfonyl, Ph means phenyl, Me means methyl, n-Bu means n-butyl, Et means ethyl, and TFA means trifluoroacetic acid.

[0055] [ka] (In formula (IV) and formula (V), R 4A is carboxyl, tetrazolyl, or -C(R 4C )(R 4D )-OR 4E Indicate the group; R 4C and R 4D are the same or different and each represents an aromatic hydrocarbon ring group which may have a substituent, an aromatic heterocyclic group which may have a substituent, or a C 1-6 represents an alkyl group; R 4E is a hydrogen atom, a substituted silyl group, or an optionally substituted C 1-6 represents an alkyl group; R 4B represents a protecting group for a hydroxyl group; n is 0 or 1; The indications of stereochemistry in formula (IV) and formula (V) indicate the absolute configuration.

[0056] R 4A As for -C(R 4C )(R 4D )-OR 4E The group is preferred.

[0057] R 4C and R 4D As the aromatic hydrocarbon ring group in 1A The aromatic hydrocarbon ring group may be the same as that in the above. R 4C and R 4D The substituents permitted for the aromatic hydrocarbon ring group are R 1A The substituents are the same as those permitted for the aromatic hydrocarbon ring group.

[0058] R 4C and R 4D The aromatic hydrocarbon ring group which may have a substituent is preferably phenyl which may have a substituent or naphthyl which may have a substituent, more preferably phenyl which may have a substituent, and further preferably phenyl or tolyl (including o-tolyl, m-tolyl and p-tolyl; the same applies below).

[0059] R 4C and R 4D As the aromatic heterocyclic group in the formula (I), R 1A The aromatic heterocyclic groups are the same as those in the above. R 4C and R 4D The aromatic heterocyclic group R 1A The substituents are the same as those permitted for the aromatic heterocyclic group of the formula (I).

[0060] R 4C and R 4D The optionally substituted aromatic heterocyclic group is preferably pyridyl, imidazolyl or thiazolyl.

[0061] R 4C and R 4D C 1-6 Acceptable substituents for the alkyl group include -O-(C 1-6 alkyl group), -N(C 1-6 Alkyl group)-(C 1-6 alkyl group), -C(=O)-O-(C 1-6 alkyl group), -C(=O)-(C 1-6 alkyl group), -C(=O)-N(C 1-6 Alkyl group)-(C 1-6alkyl group), carboxyl, cyano, nitro, halogen, and oxo. In one embodiment, -O-(C 1-6 alkyl group), -C(=O)-O-(C 1-6 alkyl group), -C(=O)-(C 1-6 Examples of the alkyl group include alkyl groups, carboxyl, cyano, halogen, and oxo. Another embodiment includes methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, methylcarbonyl, carboxyl, cyano, fluoro, chloro, and bromo.

[0062] R 4C and R 4D C, which may have the following substituent: 1-6 The alkyl group is preferably unsubstituted, and is more preferably methyl, ethyl, propan-1-yl, propan-2-yl, butan-1-yl, butan-2-yl, or 2-methylpropan-2-yl.

[0063] R 4C and R 4D As the aryl group, an aromatic hydrocarbon ring group which may have a substituent is preferable, phenyl which may have a substituent and naphthyl which may have a substituent are more preferable, phenyl which may have a substituent is even more preferable, and phenyl and tolyl are particularly preferable.

[0064] R 4E The substituted silyl group in R 1A The substituted silyl groups are the same as those in the above. R 4E The substituted silyl group of C 1-6 Alkyl group, -O-(C 1-6

[0043] A silyl group having three substituents independently selected from the group consisting of methyl, ethyl, propan-1-yl, propan-2-yl, 2-methylpropan-2-yl, methoxy, ethoxy, propan-1-yloxy, propan-2-yloxy, and phenyl is preferred, a silyl group having three substituents independently selected from the group consisting of methyl, ethyl, propan-1-yl, propan-2-yl, 2-methylpropan-2-yl, methoxy, ethoxy, propan-1-yloxy, propan-2-yloxy, and phenyl is more preferred, trimethylsilyl, triethylsilyl, triisopropylsilyl, trimethoxysilyl, methyldiphenylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl are further preferred, and trimethylsilyl and methyldiphenylsilyl are particularly preferred.

[0065] R 4E C 1-6 Examples of the substituents permitted for the alkyl group include an aromatic hydrocarbon ring group which may have a substituent, an aromatic heterocyclic group which may have a substituent, -O-(C 1-6 alkyl group), -N(C 1-6 Alkyl group)-(C 1-6 alkyl group), -C(=O)-O-(C 1-6 alkyl group), -C(=O)-(C 1-6 alkyl group), -C(=O)-N(C 1-6 Alkyl group)-(C 1-6 Examples of the alkyl group include an optionally substituted aromatic hydrocarbon ring group, and an optionally substituted aromatic heterocyclic group. Examples of the alkyl group include an optionally substituted aromatic hydrocarbon ring group.

[0066] R 4E C 1-6 Examples of the aromatic hydrocarbon ring group as a substituent permitted for the alkyl group include R 1A The aromatic hydrocarbon ring group may be the same as that in the above. R 4E C 1-6 The substituents permissible for the aromatic hydrocarbon ring group as the substituent for the alkyl group include those described below as R 1AThe substituents are the same as those permitted for the aromatic hydrocarbon ring group.

[0067] R 4E C 1-6 As the aromatic hydrocarbon ring group which may have a substituent as a substituent acceptable for an alkyl group, a phenyl group which may have a substituent and a naphthyl group which may have a substituent are preferable, a phenyl group which may have a substituent and a naphthyl group which may have a substituent are more preferable, and a phenyl group which may have a substituent is even more preferable.

[0068] R 4E C 1-6 Examples of the aromatic heterocyclic group as a substituent for the alkyl group include the R 1A The aromatic heterocyclic groups are the same as those in the above. R 4E C 1-6 The aromatic heterocyclic group as a substituent acceptable for the alkyl group may be substituted with any of the R 1A The substituents are the same as those permitted for the aromatic heterocyclic group.

[0069] R 4E C, which may have the following substituent: 1-6 The alkyl group is an unsubstituted C 1-6 R is preferably an alkyl group or a methyl or ethyl group substituted with an aromatic hydrocarbon ring group which may have a substituent. 4E C, which may have the following substituent: 1-6 C where the alkyl group has no substituent 1-6 When it is an alkyl group, methyl, ethyl, propan-1-yl, propan-2-yl, butan-1-yl, butan-2-yl, and 2-methylpropan-2-yl are more preferred. 4E C, which may have the following substituent: 1-6When the alkyl group is methyl or ethyl substituted with an aromatic hydrocarbon ring group which may have a substituent, optionally substituted benzyl, optionally substituted phenethyl, optionally substituted naphthylmethyl, and optionally substituted naphthylethyl are more preferable, optionally substituted benzyl and optionally substituted naphthylmethyl are even more preferable, and benzyl and naphthylmethyl are particularly preferable.

[0070] R 4E Examples of the silyl group include a substituted silyl group and an optionally substituted C 1-6 An alkyl group is preferred, and a substituted silyl group, or a methyl or ethyl group substituted with an aromatic hydrocarbon ring group which may have a substituent is more preferred.

[0071] R 4A -C(R 4C )(R 4D )-OR 4E The group is preferably diphenyl((trimethylsilyl)oxy)methyl, diphenyl((methyldiphenylsilyl)oxy)methyl, diphenyl((triethylsilyl)oxy)methyl, diphenyl((t-butyldimethylsilyl)oxy)methyl, (benzyloxy)diphenylmethyl, ditolyl((trimethylsilyl)oxy)methyl, ditolyl((methyldiphenylsilyl)oxy)methyl, ditolyl((triethylsilyl)oxy)methyl, ditolyl((t-butyldimethylsilyl)oxy)methyl, or (benzyloxy)ditolylmethyl; more preferably diphenyl((trimethylsilyl)oxy)methyl, diphenyl((methyldiphenylsilyl)oxy)methyl, diphenyl((triethylsilyl)oxy)methyl, diphenyl((t-butyldimethylsilyl)oxy)methyl, or (benzyloxy)diphenylmethyl; further more preferably diphenyl((trimethylsilyl)oxy)methyl, or diphenyl((methyldiphenylsilyl)oxy)methyl.

[0072] R 4BThe protecting group for the hydroxyl group in the above formula (I) includes groups that are usually used as protecting groups for hydroxyl groups, specifically, acetyl, benzoyl, substituted silyl groups, C 1-6 Examples of such groups include alkyl groups.

[0073] n is preferably 0.

[0074] The amount of the amine catalyst used in the cyclization in the production method of the present invention is preferably 1 to 30 mol %, more preferably 3 to 20 mol %, further preferably 5 to 15 mol %, and particularly preferably 8 to 12 mol %, relative to 100 mol % of compound (I), in order to allow the reaction to proceed more smoothly.

[0075] The cyclization in the production method of the present invention is believed to proceed through a combination of the following reactions. (1) Formation of iminium salt: Compound (I) reacts with a primary or secondary amino group of the amine catalyst, preferably in the presence of an acid, to form an iminium salt of compound (I). (2) First step Michael addition reaction: The carbon at the α-position of the ketone of compound (II) undergoes nucleophilic attack on the iminium salt of compound (I) to form an enamine. (3) Second step Michael addition reaction: Diastereoselective intramolecular cyclization from the enamine forms the carbon skeleton of compound (III).

[0076] [ka]

[0077] In the above scheme, pyrrolidine, which is one example of the amine catalyst, has been used as an example of the amine catalyst used in the cyclization in the production method of the present invention. When the amine catalyst is a cyclic amine compound and the cyclic amine compound is a pyrrolidine compound, it may be, for example, an optically active pyrrolidine compound in which the carbon at the α-position of the nitrogen atom in the pyrrolidine ring in the scheme is an asymmetric center.

[0078] The above reactions (1) to (3) will be described in detail below.

[0079] [(1) Formation of iminium salt] This reaction is a reaction in which compound (I) reacts with an amine catalyst to form an iminium salt of compound (I). By converting compound (I) into an iminium salt, the activity as a Michael acceptor becomes higher.

[0080] (Compound (I)) One of the starting materials for the production method of the present invention is compound (I), which is an α,β-unsaturated aldehyde compound represented by the following formula (I), or a cis-trans isomer thereof.

[0081] [ka]

[0082] (In formula (I), R 1A represents an aromatic hydrocarbon ring group which may have a substituent, an aromatic heterocyclic group which may have a substituent, a substituted silyl group, -C(=O)-OR X , -C(=O)-R X , -C(=O)-N(-R X1 )-R X2 or a hydrogen atom; R 1B is a hydrogen atom, halogen, or C 1-6 represents an alkyl group; R X is C 1-6 represents an alkyl group or an aromatic hydrocarbon ring group which may have a substituent; R X1 and R X2 are the same or different R X (Indicates

[0083] In order to diastereoselectively produce compound (III) by the production method of the present invention, R 1Aand the hydrocarbonyl group (aldehyde group) must be in a trans-relationship to form a cis-trans isomer. However, in the formation of the iminium salt, compound (I) may undergo cis-trans isomerization when it is condensed with the amine catalyst used in the production method of the present invention to form the iminium salt. Therefore, in the first Michael addition reaction, R 1A and the iminium moiety may have a substitution pattern such that they are trans isomers. Compound (I) is preferably a cis-trans isomer as shown in formula (I).

[0084] R 1A As the aromatic hydrocarbon ring group in 6-14 In one embodiment, phenyl and naphthyl are mentioned, and in another embodiment, phenyl is mentioned.

[0085] R 1A The aromatic hydrocarbon ring group may have the following substituents: 1-6 Alkyl group, -O-(C 1-6 alkyl group), -N(C 1-6 Alkyl group)-(C 1-6 alkyl group), -C(=O)-O-(C 1-6 alkyl group), -C(=O)-(C 1-6 alkyl group), -C(=O)-N(C 1-6 Alkyl group)-(C 1-6 alkyl group), carboxyl, cyano, nitro, and halogen. 1-6 Alkyl group, -O-(C 1-6 An example of the alkyl group is methyl, methoxy, fluoro, chloro, or bromo.

[0086] R 1AExamples of the aromatic heterocyclic group in the formula (I) include monocyclic or bicyclic aromatic heterocyclic groups containing, as a ring-constituting atom other than carbon atoms, one or more atoms selected from the group consisting of oxygen atoms, nitrogen atoms, and sulfur atoms. One embodiment includes furyl, thienyl, oxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, quinolyl, cinnolinyl, quinazolinyl, and quinoxalinyl. Another embodiment includes furyl, thienyl, oxazolyl, thiazolyl, and pyridyl. Yet another embodiment includes furyl.

[0087] R 1A Permissible substituents for the aromatic heterocyclic group include R 1A The substituents are the same as those permitted for the aromatic hydrocarbon ring group.

[0088] R 1A -C(=O)-OR X As an example, -C(=O)-O-(C 1-6 Alkyl groups are preferred, and methoxycarbonyl and ethoxycarbonyl are more preferred. R 1A In -C(=O)-R X As an example, -C(=O)-(C 1-6 Alkyl groups are preferred, and methylcarbonyl and ethylcarbonyl are more preferred. R 1A In -C(=O)-N(-R X1 )-R X2 As an example, -C(=O)-N(C 1-6 Alkyl group)-(C 1-6 Alkyl groups are preferred, and dimethylaminocarbonyl and diethylaminocarbonyl are more preferred.

[0089] R 1A The substituted silyl groups of C are commonly used in synthetic organic chemistry. 1-6 Alkyl group, -O-(C 1-6 alkyl group), -N(C 1-6 Alkyl group)-(C 1-6Alkyl group), C 2-6 Examples of the silyl group include a silyl group having three identical or different substituents selected from the group consisting of an alkenyl group, a halogen, and a phenyl group which may have a substituent. In addition, R 1A In the substituted silyl group of the formula (I), the permissible substituents for the phenyl as a substituent on the silyl group are R 1A The substituents are the same as those permitted for the aromatic hydrocarbon ring group.

[0090] As described later, when compound (III) is used as a synthetic intermediate for Corey lactone, R 1A The carbon atom substituted by R 1A The bond between the silicon atom of the substituted silyl group represented by R is oxidized to form a carbon-oxygen bond. 1A The substituted silyl group of R is preferably a substituted silyl group having a substitution pattern that allows functional group conversion by oxidizing a carbon-silicon bond to a carbon-oxygen bond. 1A The substituted silyl group is more preferably a substituted silyl group that can be converted into a carbon-oxygen bond by utilizing the Tamao-Fleming reaction. Substituted silyl groups that can be converted to carbon-oxygen bonds using the Tamao-Fleming reaction include, for example, silyl groups in which one or two of the three substituents on the silyl group are C 1-6 is an alkyl group (C 1-6 When there are two alkyl groups, they may be the same or different. ), and the remaining two or one substituent is -O-(C 1-6 alkyl group), -N(C 1-6 Alkyl group)-(C 1-6 and substituted silyl groups, the substituents of which are selected from the group consisting of alkyl groups, halogens, optionally substituted phenyl groups, and vinyl groups (when there are two remaining substituents, they may be the same or different). In one embodiment, fluorodimethylsilyl, difluoro(methyl)silyl, chlorodimethylsilyl, dichloro(methyl)silyl, methoxydimethylsilyl, dimethoxy(methyl)silyl, (dimethylamino)dimethylsilyl, bis(dimethylamino)(methyl)silyl, dimethyl(phenyl)silyl, methyldiphenylsilyl, dimethyl(vinyl)silyl, and methyldivinylsilyl are mentioned, and in another embodiment, dimethyl(phenyl)silyl is mentioned.

[0091] The substituted silyl group that can be functionally converted to a carbon-oxygen bond using the Tamao-Fleming reaction includes not only groups that can be functionally converted to a carbon-oxygen bond by subjecting the Tamao-Fleming reaction to the Tamao-Fleming reaction while keeping the substitution form of the substituted silyl group, but also groups that can be functionally converted to a carbon-oxygen bond by subjecting the substituted silyl group to the Tamao-Fleming reaction after converting the substituent that the substituted silyl group has. For example, dimethyl(phenyl)silyl can be easily converted to dimethyl(fluoro)silyl by utilizing the cation stabilizing effect of the β-position of the silicon atom, and the functional group can be converted to a carbon-oxygen bond using the Tamao-Fleming reaction by converting the substituent that the substituted silyl group has.

[0092] From the viewpoint that compound (III) can be used as a synthetic intermediate for Corey lactone, R 1A is preferably a substituted silyl group.

[0093] R 1B is preferably a hydrogen atom or a halogen, more preferably a hydrogen atom, fluoro, chloro or bromo, and further preferably a hydrogen atom. From the viewpoint that compound (III) can be used as a synthetic intermediate for Corey lactone, R 1B is preferably a hydrogen atom.

[0094] R X As the aromatic hydrocarbon ring group in 1A The aromatic hydrocarbon ring group may be the same as that in the above. R X Permissible substituents for the aromatic hydrocarbon ring group include R 1AThe substituents allowed for the aromatic hydrocarbon ring group of R X The aromatic hydrocarbon ring group is preferably unsubstituted. R X As for C 1-6 Alkyl groups are preferred.

[0095] [(2) First step Michael addition reaction] In this reaction, the iminium salt of compound (I) serves as a Michael acceptor and undergoes nucleophilic attack by compound (II) to form a Michael addition product. If the catalyst consisting of a pyrrolidine compound is an optically active compound, the iminium salt of compound (I) becomes susceptible to stereoselective Michael addition as a Michael acceptor, and R 1A can be constructed stereoselectively.

[0096] (Compound (II)) One of the starting materials for the production method of the present invention is compound (II), which is an α,β-unsaturated ketone compound represented by the following formula (II), or a cis-trans isomer thereof.

[0097] [ka]

[0098] (In formula (II), R 2A is -C(=O)-OR X , -C(=O)-SR X , -C(=O)-R X , -C(=O)-N(-R X1 )-R X2 , cyano, or nitro; R 2B is a hydrogen atom, -C(=O)-OR X , -C(=O)-SR X , -C(=O)-R X , -C(=O)-N(-R X1 )-R X2 , cyano, or nitro; R 2Crepresents a hydrogen atom or a halogen; R 2D and R 2E are the same or different and each represents a hydrogen atom, C 1-6 represents an alkyl group, an aromatic hydrocarbon ring group which may have a substituent, or an aromatic heterocyclic group which may have a substituent; R 2C and R 2E are taken together and optionally substituted C 2-4 An alkylene group or a methylene group (-CH2-) which may be substituted is replaced with -O-, -S-, or -N(C 1-6 C replaced with alkyl group)- 2-4 may represent an alkylene group; R X is C 1-6 represents an alkyl group or an aromatic hydrocarbon ring group which may have a substituent; R X1 and R X2 are the same or different R X (Indicates

[0099] In order to diastereoselectively produce compound (III) by the production method of the present invention, R 2A and R 2C However, cis-trans isomerization may occur during the cyclization in the production method of the present invention. Therefore, in the second Michael addition reaction, when the diastereoselective intramolecular cyclization reaction from the enamine occurs, R 2A and R 2C It is sufficient that the substitution pattern is such that Compound (II) is preferably a cis-trans isomer as shown in formula (II).

[0100] R 2A and R 2B is an electron-withdrawing group that is conjugated with the carbon-carbon double bond of compound (II) to undergo the intramolecular cyclization reaction in the second Michael addition reaction.2B may be a hydrogen atom.

[0101] R 2A As an example, -C(=O)-O-(C 1-6 alkyl group), -C(=O)-S-(C 1-6 alkyl group), -C(=O)-(C 1-6 alkyl group), cyano, and nitro are preferred, and -C(=O)-O-(C 1-6 alkyl group), -C(=O)-(C 1-6 Alkyl groups are more preferred, methoxycarbonyl, ethoxycarbonyl and methylcarbonyl are further preferred, and methoxycarbonyl and ethoxycarbonyl are particularly preferred. R 2B Examples include hydrogen atom, -C(=O)-O-(C 1-6 alkyl group), -C(=O)-S-(C 1-6 alkyl group), -C(=O)-(C 1-6 alkyl group), cyano, and nitro are preferred, and a hydrogen atom, -C(=O)-O-(C 1-6 Alkyl group), -C(=O)-(C 1-6 An alkyl group is more preferable, and a hydrogen atom, methoxycarbonyl, or ethoxycarbonyl is even more preferable. In one embodiment, a hydrogen atom is particularly preferable. In another embodiment, methoxycarbonyl or ethoxycarbonyl is particularly preferable. From the viewpoint that compound (III) can be used as a synthetic intermediate for Corey lactone, R 2A Examples of the aryl group include groups that can be converted to carboxyl or alkoxycarbonyl groups, and preferably -C(=O)-OR X , -C(=O)-SR X , -C(=O)-N(-R X1 )-R X2 , cyano, more preferably -C(=O)-O-(C 1-6 alkyl group), and cyano, more preferably methoxycarbonyl, ethoxycarbonyl, and cyano, particularly preferably methoxycarbonyl and ethoxycarbonyl; R 2B is preferably a hydrogen atom. However, R 2BAs for R, it can be converted to a hydrogen atom by subsequent removal by decarboxylation, and this can further increase the position selectivity of the second-step Michael addition reaction. 2A In this case, methoxycarbonyl, ethoxycarbonyl, and cyano are preferred, and methoxycarbonyl and ethoxycarbonyl are more preferred.

[0102] R 2C is preferably a hydrogen atom, fluoro, chloro or bromo, more preferably a hydrogen atom or fluoro, and further preferably a hydrogen atom. From the viewpoint that compound (III) can be used as a synthetic intermediate for Corey lactone, R 2C is preferably a hydrogen atom.

[0103] R 2D and R 2E As the aromatic hydrocarbon ring group in 1A The aromatic hydrocarbon ring group may be the same as that in the above. R 2D and R 2E Permissible substituents for the aromatic hydrocarbon ring group include R 1A The substituents are the same as those permitted for the aromatic hydrocarbon ring group.

[0104] R 2D and R 2E As the aromatic heterocyclic group in 1A The aromatic heterocyclic groups are the same as those in the above. R 2D and R 2E Permissible substituents for the aromatic heterocyclic group include R 1A The substituents are the same as those permitted for the aromatic hydrocarbon ring group.

[0105] R 2D and R 2E are the same or different and may be a hydrogen atom, C 1-6 An alkyl group is preferable, a hydrogen atom, methyl or ethyl is more preferable, and a hydrogen atom is even more preferable. From the viewpoint that compound (III) can be used as a synthetic intermediate for Corey lactone, R 2D and R 2E is preferably a hydrogen atom.

[0106] R 2C and R 2E are taken together and optionally substituted C 2-4 An alkylene group or a methylene group (-CH2-) which may be substituted is replaced with -O-, -S-, or -N(C 1-6 C replaced with alkyl group)- 2-4 For example, the combined R 2C and R 2E When R represents trimethylene (propane-1,3-diyl), 2C sp 2 Carbon, carbon of the carbonyl group, and R 2D and R 2E sp 3 This means that it may be combined with the carbon to form a cyclohexane ring.

[0107] The united R 2C and R 2E In C 2-4 Alkylene groups include ethane-1,2-diyl, propane-1,2-diyl, propane-2,3-diyl, butane-1,2-diyl, butane-2,3-diyl, butane-3,4-diyl, propane-1,3-diyl, 2-methylpropane-1,3-diyl, butane-1,3-diyl, butane-2,4-diyl, and butane-1,4-diyl. The united R 2C and R 2E In the above, some methylene (-CH2-) in the alkylene group is -O-, -S-, or -N(C 1-6 C replaced with alkyl group)- 2-4Examples of the alkylene group include -CH2-O-CH2-, -CH(CH3)-O-CH2-, -CH2-O-CH(CH3)-, -CH2-O-CH2-CH2-, -CH2-CH2-O-CH2-, -CH2-S-CH2-, -CH(CH3)-S-CH2-, -CH2-S-CH(CH3)-, -CH2-S-CH2-CH2-, -CH2-CH2-S-CH2-, -CH2-N(CH3)-CH2-, -CH(CH3)-N(CH3)-CH2-, -CH2-N(CH3)-CH(CH3)-, -CH2-N(CH3)-CH2-CH2-, and -CH2-CH2-N(CH3)-CH2-.

[0108] R 2C and R 2E together with optionally substituted C 2-4 An alkylene group or a methylene group (-CH2-) which may be substituted is replaced with -O-, -S-, or -N(C 1-6 C replaced with alkyl group)- 2-4 When an alkylene group is indicated, the combined R 2C and R 2E As such, ethane-1,2-diyl, propane-1,3-diyl, 2-methylpropane-1,3-diyl, butane-1,4-diyl, -CH2-O-CH2-, -CH2-O-CH2-CH2- and -CH2-CH2-O-CH2- are preferred, with ethane-1,2-diyl and propane-1,3-diyl being more preferred.

[0109] The united R 2C and R 2E C 2-4 The alkylene group or a part of the methylene group (-CH2-) in the alkylene group is -O-, -S-, or -N(C 1-6 C replaced with alkyl group)- 2-4 Acceptable substituents for the alkylene group include -O-(C 1-6 alkyl group), -N(C 1-6 Alkyl group)-(C 1-6 alkyl group), -C(=O)-O-(C 1-6 alkyl group), -C(=O)-(C 1-6 alkyl group), -C(=O)-N(C1-6 Alkyl group)-(C 1-6 alkyl group), carboxyl, cyano, nitro, halogen, and oxo. In one embodiment, -O-(C 1-6 alkyl group), -C(=O)-O-(C 1-6 alkyl group), -C(=O)-(C 1-6 Examples of the alkyl group include alkyl groups, carboxyl, cyano, halogen, and oxo. Another embodiment includes methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, methylcarbonyl, carboxyl, cyano, fluoro, chloro, and bromo. The united R 2C and R 2E C 2-4 The alkylene group or a part of the methylene group (-CH2-) in the alkylene group is -O-, -S-, or -N(C 1-6 C replaced with alkyl group)- 2-4 The alkylene group is preferably unsubstituted.

[0110] R X As the aromatic hydrocarbon ring group in 1A The aromatic hydrocarbon ring group may be the same as that in the above. R X Permissible substituents for the aromatic hydrocarbon ring group include R 1A The substituents allowed for the aromatic hydrocarbon ring group of R X The aromatic hydrocarbon ring group is preferably unsubstituted. R X As for C 1-6 Alkyl groups are preferred.

[0111] [(3) Second-step Michael addition reaction] This reaction is a Michael adduct of an iminium salt of compound (I) and compound (II), in which an enamine derived from the iminium salt of compound (I) undergoes nucleophilic attack on an α,β-unsaturated carbonyl derived from compound (II) to form a Michael addition product. R 1AReflecting the stereochemistry of the carbon atom substituted with , the intramolecular Michael addition reaction proceeds diastereoselectively to give compound (III) as a single diastereomer. Therefore, if the carbon-carbon bond is generated stereoselectively in the first Michael addition reaction using an optically active compound composed of a pyrrolidine compound as a catalyst, compound (III) can be obtained as a single enantiomer.

[0112] The carbon atom that undergoes nucleophilic attack from the enamine derived from the iminium salt of compound (I) is R 2A and R 2B and the carbon atom substituted with R 2A is an electron-withdrawing group, R 2C However, surprisingly, in the production method of the present invention, the Michael addition reaction of the latter, which forms a cyclopentane ring, proceeds selectively.

[0113] (Compound (III)) The compound that is the target of the production method of the present invention is compound (III), which is a cyclopentane compound represented by the following formula (III).

[0114] [ka]

[0115] (In formula (III), R 1A represents an aromatic hydrocarbon ring group which may have a substituent, an aromatic heterocyclic group which may have a substituent, a substituted silyl group, -C(=O)-OR X , -C(=O)-R X , -C(=O)-N(-R X1 )-R X2 or a hydrogen atom; R 1B is a hydrogen atom, halogen, or C 1-6 represents an alkyl group; R 2A is -C(=O)-ORX , -C(=O)-SR X , -C(=O)-R X , -C(=O)-N(-R X1 )-R X2 , cyano, or nitro; R 2B is a hydrogen atom, -C(=O)-OR X , -C(=O)-SR X , -C(=O)-R X , -C(=O)-N(-R X1 )-R X2 , cyano, or nitro; R 2C represents a hydrogen atom or a halogen; R 2D and R 2E are the same or different and each represents a hydrogen atom, C 1-6 represents an alkyl group, an aromatic hydrocarbon ring group which may have a substituent, or an aromatic heterocyclic group which may have a substituent; R 2C and R 2E are taken together and optionally substituted C 2-4 An alkylene group or a methylene group (-CH2-) which may be substituted is replaced with -O-, -S-, or -N(C 1-6 C replaced with alkyl group)- 2-4 may represent an alkylene group; R X is C 1-6 represents an alkyl group or an aromatic hydrocarbon ring group which may have a substituent; R X1 and R X2 are the same or different R X indicates; The indication of stereochemistry in formula (III) indicates the relative configuration.

[0116] R in formula (III) 1A , R 1B is R in formula (I) 1A , R 1B and the embodiments and permissible substituents thereof are the same as those of R 1A , R1B The same thing is mentioned in each case. R in formula (III) 2A , R 2B , R 2C , R 2D , R 2E , R X is R in formula (II) 2A , R 2B , R 2C , R 2D , R 2E , R X and the embodiments and permissible substituents thereof are the same as those of R 2A , R 2B , R 2C , R 2D , R 2E , R X The same thing is mentioned in each case.

[0117] <Method of producing a cyclopentane compound, method of producing a lactone compound, method of producing a diol compound> As one application example of the cyclopentane compound produced by the production method of the present invention, a method for producing so-called Corey lactone by functional group conversion of the cyclopentane compound produced by the production method of the present invention will be described below.

[0118] The compound (I) used for cyclization in the production method of the present invention is R 1A is a substituted silyl group, R 1B Compounds in which is a hydrogen atom can be used. Such compounds (I) are commercially available.

[0119] R 1A As the alkyl group, a substituted silyl group that can be converted to a hydroxyl group later can be used, and specifically, a substituted silyl group that can be converted to a carbon-oxygen bond as a functional group by utilizing the Tamao-Fleming reaction is more preferable. R 1A As the alkyl group, a dimethyl(phenyl)silyl group can be preferably used.

[0120] The compound (II) used for cyclization in the production method of the present invention is R2A -C(=O)-OR X and R 2B , R 2C , R 2D , and R 2E are hydrogen atoms, and R X C 1-6 Compounds in which the group is an alkyl group can be used. Such compounds (II) are commercially available.

[0121] In addition, R 2A As the alkyl group, methoxycarbonyl and ethoxycarbonyl can be preferably used. Also, R 2B As for the hydrogen atom, it is not limited to hydrogen atoms, but can be removed later by decarboxylation, and the position selectivity of the second Michael addition reaction can be further improved. 2A Similarly, it may be an alkoxycarbonyl, in which case methoxycarbonyl and ethoxycarbonyl can be preferably used.

[0122] As a cyclization step, R 1A is a substituted silyl group, R 1B Compound (I) in which R is a hydrogen atom; 2A -C(=O)-OR X and R 2B , R 2C , R 2D , and R 2E are hydrogen atoms, and R X C 1-6 Compound (II), which is an alkyl group, is reacted in the presence of a catalyst made of a cyclic amine compound or a chain amine compound, preferably an optically active cyclic amine compound or a chain amine compound, more preferably an optically active pyrrolidine compound, and preferably in the presence of an acid to obtain compound (III-a), which is a cyclopentane compound.

[0123] [ka]

[0124] (In formula (III-a), R3A represents a substituted silyl group; R 3B is -C(=O)-OR Y indicates; R Y is C 1-6 represents an alkyl group; The indication of stereochemistry in formula (III-a) indicates the relative configuration.

[0125] R 3A The substituted silyl group of R 1A The substituted silyl groups are the same as those in the above. R Y C 1-6 The alkyl group is R X C in 1-6 Examples of the alkyl group include the same as those of the alkyl group.

[0126] For example, when a compound represented by formula (V-1) is used as an optically active cyclic amine compound or chain amine compound, an optically active compound (III-a-1) represented by formula (III-a-1) is obtained. In formulas (V-1) and (III-a-1), the indication of stereochemistry indicates the absolute configuration.

[0127] [ka]

[0128] (In the formula, Ph represents phenyl, and OTMS represents trimethylsilyloxy.)

[0129] For example, when a compound represented by formula (IV-2) is used as an optically active cyclic amine compound or chain amine compound, an optically active compound (III-a-2) represented by formula (III-a-2) is obtained. In formulas (IV-2) and (III-a-2), the indication of stereochemistry indicates the absolute configuration.

[0130] [ka]

[0131] (In the formula, Ph represents phenyl, and OTMS represents trimethylsilyloxy.)

[0132] The cyclization step is carried out by reacting R 1A Or R 2A The reaction temperature may vary depending on the nature of the amine catalyst and the chemical structure and characteristics of the amine catalyst, but can be adjusted at 0 to 50° C., preferably at room temperature, for 10 minutes to 5 hours.

[0133] The resulting compound (III-a) is subjected to a reduction step and a lactonization step. In the following, compound (III-a) includes compound (III-a-1) and compound (III-a-2), and compound (III-a-1) is preferred for the purpose of producing Corey lactone. In the following scheme, when a racemate is used as compound (III-a), the stereochemical indication in the formula indicates the relative configuration, when compound (III-a-1) is used as compound (III-a), the stereochemical indication in the formula indicates the absolute configuration, and when compound (III-a-2) is used as (III-a), the stereochemical indication in the formula indicates the absolute configuration of the opposite enantiomer. The same applies to compounds (III-b) and (III-c) below.

[0134] [ka]

[0135] (In the formula, R 3A represents a substituted silyl group; R 3B is -C(=O)-OR Y indicates; R Y is C 1-6 represents an alkyl group; The stereochemical indications in the formula indicate the relative configuration.

[0136] The reducing agent used in the reduction step is not particularly limited as long as it can reduce the aldehyde and ketone of compound (III-a), and known reducing agents such as sodium borohydride, sodium cyanoborohydride, sodium acetoxyborohydride, sodium alkylborohydride, sodium alkoxyborohydride, lithium borohydride, lithium alkylborohydride, lithium aluminum hydride, and lithium alkoxyaluminum hydride can be used.

[0137] In the reduction of the ketone of compound (III-a), the carbon atom at the α-position of the ketone (R 3B The diastereoselective reduction reaction proceeds depending on the stereochemistry of the carbon atom substituted with α. For example, the reduction with sodium borohydride proceeds with 2:1 selectivity to give a hydroxyl group cis to the α carbon atom of the ketone. By-products having a hydroxyl group trans to the α-carbon atom of the ketone are not lactonized in the subsequent lactonization step, and can be easily separated and removed. As is well known to those skilled in the art, the diastereoselectivity in the reduction of the ketone can be further improved by using a reducing agent having a bulky substituent. Examples of such reducing agents include lithium tri-t-butoxyaluminum hydride.

[0138] In addition, for example, when a cyclization step is carried out in the presence of an acid by adding 100 mol % of an acid in terms of the number of protons to 100 mol % of compound (I), and a reducing agent is added to the reaction mixture after the cyclization step or the reaction mixture after the solvent is removed under reduced pressure without isolating compound (III-a), at least 300 mol % of a reducing agent (hydride) is required because the reducing agent is consumed for neutralizing the acid, reducing the aldehyde, and reducing the ketone. However, diastereoselective reactions are not required for neutralizing the acid and reducing the aldehyde. Therefore, for example, neutralizing the acid and reducing the aldehyde can be carried out with 200 mol % of an inexpensive reducing agent, and then diastereoselective reduction of the ketone can be carried out using a reducing agent that is not inexpensive, such as lithium tri-t-butoxyaluminum hydride.

[0139] The reduction step is preferably carried out at room temperature to about 60° C., in order to obtain sufficient diastereoselectivity, and can be carried out for 10 minutes to 5 hours.

[0140] By making the reaction mixture obtained in the reduction step acidic, lactone cyclization occurs via condensation between the reduced hydroxyl group so that the ketone is diastereoselectively positioned in cis with respect to the stereochemistry of the α-carbon of the ketone and the ethoxycarbonyl of the ethoxycarbonylmethyl substituting at the α-position of the ketone, to give compound (III-b) which is a lactone.

[0141] The acid that makes the reaction system of the reaction mixture obtained in the reduction step acidic is not particularly limited, and examples thereof include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid; organic carboxylic acids such as acetic acid, propionic acid, formic acid, oxalic acid, trifluoroacetic acid, benzoic acid, and adamantanecarboxylic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid; and tetrafluoroboric acid.

[0142] Among these, an aqueous solution of an inorganic acid can be preferably used, but when compound (III-b) is not isolated and the reaction mixture after the lactonization step or the reaction mixture from which the solvent has been removed under reduced pressure is subjected to the next step, the Tamao-Fleming oxidation step, it is advantageous to use tetrafluoroboric acid, which is used in the Tamao-Fleming oxidation step. Also, R 3A When the substituted silyl group is dimethyl(phenyl)silyl, by using tetrafluoroboric acid as an acid to acidify the reaction system of the reaction mixture obtained in the reduction step, in addition to neutralizing the reducing agent and lactonizing, the dimethyl(phenyl)silyl can be converted to fluorodimethylsilyl that can be used in the Tamao-Fleming oxidation reaction. In addition, when the solvent used in the reduction step and the lactonization step affects the acidity of the acid that makes the reaction system of the reaction mixture acidic, it may be advantageous to remove the solvent under reduced pressure or under reduced pressure while heating to about 40 to 80°C after adding the acid to the reaction mixture.

[0143] The obtained compound (III-b) is subjected to the Tamao-Fleming oxidation step. Compound (III-b) can be converted to Corey lactone by the Tamao-Fleming oxidation step. In the following formula, R 3A The reaction of the above where the substituted silyl group is dimethyl(phenyl)silyl is shown.

[0144] [ka]

[0145] (In the formula, PhMe2Si represents dimethyl(phenyl)silyl; FMe2Si denotes fluoro(dimethyl)silyl; The stereochemical indications in the formula indicate the relative configuration.

[0146] R 3AIn the case where the substituted silyl group of is dimethyl(phenyl)silyl, when tetrafluoroboric acid is used in the lactonization step, the dimethyl(phenyl)silyl of compound (III-b) is converted to fluorodimethylsilyl, and therefore the compound can be subjected to the Tamao-Fleming oxidation reaction. Also, R 3A When the substituted silyl group is a substituted silyl group having no heteroatom on the silyl group, such as dimethyl(phenyl)silyl, methyldiphenylsilyl, dimethyl(vinyl)silyl, or methyldivinylsilyl, oxidation can be carried out utilizing the Tamao-Fleming reaction by introducing a fluorine atom onto the silyl group using, for example, tetrafluoroboric acid.

[0147] In the Tamao-Fleming oxidation step, conditions for a typical Tamao-Fleming oxidation reaction can be adopted. For example, the Tamao-Fleming oxidation reaction can be carried out under basic conditions by adding a fluoride source such as potassium fluoride and aqueous hydrogen peroxide.

[0148] The Corey lactone thus obtained has two hydroxyl groups, one of which is a primary hydroxyl group and the other a secondary hydroxyl group, and so the difference in reactivity between these hydroxyl groups can be exploited to protect only one of them or to subject only one of them to a subsequent reaction. Alternatively, in order to avoid the final presence of two hydroxyl groups in the molecule, in compound (III-b), the primary alcohol to which the aldehyde is reduced can be protected with a protecting group that is not affected by the reaction conditions of the Tamao-Fleming oxidation step before being subjected to the Tamao-Fleming oxidation step, or in compound (III-a), the aldehyde can be subjected to a subsequent step such as a carbon-increasing reaction by the Wittig reaction or the Horner-Wadsworth-Emmons reaction.

[0149] In addition, latanoprost is known as a pharmaceutical product with a particularly large market share among PG derivatives. Since latanoprost is also a compound having a cyclopentane ring with the stereochemistry of Corey lactone, it can be produced by chemical conversion of the cyclopentane compound obtained by the production method of the present invention. The α-chain and ω-chain of latanoprost may be constructed at any stage. In one method, a carbon chain corresponding to the ω-chain is introduced into compound (III-a) obtained by the production method of the present invention using the Horner-Wadsworth-Emmons reaction, followed by reduction of the ketone, lactonization, and oxidation using the Tamao-Fleming reaction, and then reduction of the lactone followed by a Wittig reaction to introduce a carbon chain corresponding to the α-chain.

[0150] Similarly, pharmaceutical compounds including travoprost and bimatoprost, which are produced using Corey lactone or a derivative thereof as a production intermediate, can also be produced through chemical conversion of the cyclopentane compound obtained by the production method of the present invention. EXAMPLES

[0151] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following examples.

[0152] Example 1 (1) Cyclization process

[0153] [ka]

[0154] (In the formula, PhMe2Si represents dimethyl(phenyl)silyl, Me represents methyl, Et represents ethyl, Ph represents phenyl, and OTMS represents trimethylsilyloxy.)

[0155] To a solution of (E)-3-(dimethyl(phenyl)silyl)propenal (32.4 mg, 0.18 mmol) and ethyl (E)-4-oxo-2-pentenoate (21.3 mg, 0.15 mmol) in isopropanol (75 μL), water (8.1 μL, 0.45 mmol), (R)-2-(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine (4.88 mg, 0.015 mmol), and p-nitrophenol (20.8 mg, 0.15 mmol) were added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour, and the reaction mixture was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 6 / 1) to obtain ethyl 2-((1R,2S,3R)-3-(dimethyl(phenyl)silyl)-2-formyl-5-oxocyclopentyl)acetate (42.4 mg, 0.128 mmol, yield 85%) as a colorless, transparent oil (single isomer, >99% ee). The optical yield was determined by reacting ethyl (triphenylphosphoranylidene)acetate with the product to convert the aldehyde into the corresponding α,β-unsaturated ester, followed by HPLC analysis using a chiral column (ChiralPak (registered trademark) ID).

[0156] For this product, 1 H NMR, 13 C NMR, high-resolution mass spectrometry with electrospray ionization (HRMS (ESI)), infrared absorption spectroscopy (IR), optical rotation measurement ([α] D The results of the physicochemical analyses of each of the following are shown below.

[0157] 1H NMR (CDCl3) δ 0.365 (s, 3H), 0.381 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H), 1.73 (ddd, J = 8.8, 12.0, 13.2 Hz, 1H), 2.18 (dd, J = 13.2, 18.8 Hz, 1H), 2.49 (ddd, J = 1.2, 8.8, 18.4 Hz, 1H), 2.53 (dd, J = 6.8, 17.6 Hz, 1H), 2.62 (dd, J = 4.0, 17.6 Hz, 1H), 2.69 (dddd, J = 1.2, 4.0, 6.4, 12.0 Hz, 1H), 2.82 (dt, J = 3.6, 12.0 Hz, 1H), 4.06 (dq, J = 1.6, 7.2 Hz, 2H), 7.36-7.41 (m, 3H), 7.48-7.51 (m, 2H), 9.43 (d, J = 3.2 Hz, 1H) 13 C NMR (CDCl3) δ 215.5, 201.1, 171.3, 135.6, 133.8 (2C), 129.8, 128.1 (2C), 60.9, 55.9, 47.5, 38.7, 32.7, 22.7, 14.0, -4.43, -4.65 HRMS (ESI): [M+Na] + Calculate for C 18 H 24 O4SiNa: 355.1336, found: 355.1340 IR (neat) ν 1725, 1427, 1375, 1253, 1189, 1113, 1026, 835, 818, 775, 736, 701 cm -1 [α] D 26 -59.30 (c 3.0, CHCl3)

[0158] (2) Restoration project, ラクトン chemical project

[0159]

change

[0160] (In the formula, PhMe2Si represents dimethyl(phenyl)silyl, and Et represents ethyl.)

[0161] The obtained ethyl 2-((1R,2S,3R)-3-(dimethyl(phenyl)silyl)-2-formyl-5-oxocyclopentyl)acetate (33.2 mg, 0.10 mmol) was dissolved in THF (300 μL) and lithium tri-t-butoxyaluminum hydride (LiAl(O t Bu)3H: 63.5 mg, 0.25 mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour, and 2N hydrochloric acid (150 μL) was added to the reaction mixture. After the reaction mixture was stirred at the same temperature for 1 hour, sodium bicarbonate solution (5 mL) was added to quench the reaction. Water (2 mL) was added, and the mixture was extracted with ethyl acetate (3 × 5 mL). The organic phases were combined and washed with sodium bicarbonate solution (5 mL) and saturated saline (5 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After concentration, the reaction mixture was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 2 / 1) to obtain (3aR,4S,5R,6aS)-5-(dimethyl(phenyl)silyl)-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-2-one (26.4 mg, 0.091 mmol, yield 91%) as a colorless, transparent oil.

[0162] For this product, 1 H NMR, 13 C NMR, high-resolution mass spectrometry with electrospray ionization (HRMS (ESI)), infrared absorption spectroscopy (IR), optical rotation measurement ([α] D The results of the physicochemical analyses of each of the following are shown below.

[0163] 1H NMR (CDCl3) δ 0.283 (s, 3H), 0.320 (s, 3H), 1.23 (ddd, J = 8.4, 12.0, 19.2 Hz, 1H), 1.63-1.76 (m, 3H), 2.34 (dd, J = 7.2, 14.4 Hz, 1H), 2.37 (dd, J = 2.0, 15.6 Hz, 1H), 2.59-2.63 (m, 1H), 2.70 (dd, J = 9.2, 18.0 Hz, 1H), 3.32 (dd, J = 6.4, 11.2 Hz, 1H), 3.53 (dd, J = 3.6, 11.2 Hz, 1H), 4.88 (dt, J = 4.0, 7.2 Hz, 1H), 7.32-7.37 (m, 3H), 7.46-7.86 (m, 2H) 13 C NMR (CDCl3) δ 177.3, 137.6, 133.5 (2C), 129.4, 128.1 (2C), 85.6, 63.7, 50.2, 44.5, 35.7, 34.7, 27.6, -3.69, -5.23 HRMS (ESI): [M+Na] + Calculate for C 16 H 22 O3SiNa: 313.1230, found: 313.1235 IR (neat) ν 3441, 3069, 2956, 1748, 1427, 1251, 1171, 1112, 1037, 910, 818, 740, 648 cm -1 [α] D 26 -10.05 (c 0.90, CHCl3)

[0164] (3) Tamao・Fremiko Acidification Project

[0165]

change

[0166] (In the formula, PhMe2Si represents dimethyl(phenyl)silyl.)

[0167] To a solution of the obtained (3aR,4S,5R,6aS)-5-(dimethyl(phenyl)silyl)-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-2-one (29.0 mg, 0.10 mmol) in 1,2-dichloroethane (300 μL), an aqueous solution of tetrafluoroboric acid (160 μL, 1.0 mmol, 47 wt%) was added at 80° C. The reaction mixture was stirred at the same temperature for 4 hours, and then an aqueous solution of sodium bicarbonate (1.0 mL) was added to quench the reaction. Water (2 mL) was added, and the mixture was extracted with ethyl acetate (3×5 mL). The organic phases were combined and washed with a solution of sodium bicarbonate (5 mL) and saturated saline (5 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. To a solution of the resulting crude reaction product in DMF (300 μL), potassium fluoride (56 mg, 1.0 mmol) and aqueous hydrogen peroxide (35 μL, 1.0 mmol, 35 wt%) were added at room temperature. The reaction mixture was stirred at the same temperature for 12 hours, and dimethyl sulfide (35 μL) was added to the reaction mixture at room temperature. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (elution solvent: chloroform / methanol = 20 / 1, 10 / 1) to obtain (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-2-one (14.8 mg, 0.086 mmol, yield 86%) as a colorless solid (>99% ee). The optical yield was determined by reacting the product with benzoyl chloride to convert the diol into the corresponding dibenzoyl ester, followed by HPLC analysis using a chiral column (Chiralpak (registered trademark) IF).

[0168] For this product, 1 H NMR, 13 C NMR, high-resolution mass spectrometry with electrospray ionization (HRMS (ESI)), infrared absorption spectroscopy (IR), optical rotation measurement ([α] D The results of the physicochemical analyses of each of the following are shown below.

[0169] 1 H NMR (CDCl3) δ 1.98-2.06 (m, 2H), 2.42 (td, J = 6.8, 14.8 Hz, 1H), 2.53 (dd, J = 1.2, 18.0 Hz, 1H), 2.62 (dtd, J = 2.0, 7.2, 10.4 Hz, 1H), 2.81 (dd, J = 10.0, 18.0 Hz, 1H), 3.62 (dd, J = 7.2, 10.4 Hz, 1H), 3.74 (dd, J = 5.2, 10.4 Hz, 1H), 4.18 (q, J = 6.0 Hz, 1H), 4.93 (dt, J = 2.8, 6.8, 1H) 13 C NMR (CDCl3) δ 177.2, 83.6, 75.4, 63.5, 55.2, 40.6, 39.5, 35.3 HRMS (ESI): [M+Na] + Calc for C8H 12 O4Na: 195.0628, found: 195.0628 IR (neat) ν 3419, 2925, 1760, 1634, 1336, 1071, 668 cm -1 [α] D 26 -41.87 (c 0.40, MeOH) The literature value of the target compound is [α] D -43.4 (c 1.12, MeOH) (CA Gonzalez-Gonzalez et al., Tetrahedron Lett. 2013, 54, 2776).

[0170] Example 2 The steps (1) to (3) in Example 1 were carried out as a one-pot reaction, specifically as follows. To a solution of (E)-3-(dimethyl(phenyl)silyl)propenal (2.28 g, 12 mmol) and ethyl 4-oxo-2-pentenoate (1.42 g, 10 mmol) in isopropanol (2.5 mL), water (540 μL, 30 mmol), (R)-2-(diphenyl((methyldiphenylsilyl)oxy)methyl)pyrrolidine (325 mg, 1.0 mmol), and p-nitrophenol (1.39 g, 10 mmol) were added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour and concentrated under reduced pressure. The concentrate was dissolved in THF (20 mL) and treated with lithium tri-t-butoxyaluminum hydride (LiAl(O t Bu)3H: 8.89 g, 35 mmol) was added at 60° C. The reaction mixture was stirred at the same temperature for 15 minutes, and then an aqueous solution of tetrafluoroboric acid (10.6 mL, 100 mmol, 47 wt%) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 minute, and then concentrated under reduced pressure at 80° C. (15 minutes). The concentrate was dissolved in a mixed solvent of DMF (20 mL) and water (10 mL), and potassium carbonate (13.8 g, 100 mmol) was added at room temperature. Then, potassium fluoride (5.6 g, 100 mmol) and aqueous hydrogen peroxide solution (3.5 mL, 100 mmol, 35 wt%) were added at 40°C. The reaction mixture was stirred at the same temperature for 1 minute, and dimethyl sulfide (2.3 mL) was added to the reaction mixture at room temperature. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (elution solvent: chloroform / methanol = 20 / 1, 10 / 1) to obtain (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-2-one (860 mg, total yield 50%) as a colorless solid.

[0171] Example 3

[0172] [ka]

[0173] (In the formula, Ph represents phenyl, Me represents methyl, and OSiMePh2 represents methyldiphenylsilyloxy.)

[0174] To a solution of cinnamaldehyde ((E)-3-phenylpropenal) (66 mg, 0.5 mmol) and (E)-hex-3-ene-2,5-dione (112 mg, 1.0 mmol) in isopropanol (1.0 mL), (S)-2-(diphenyl((methyldiphenylsilyl)oxy)methyl)pyrrolidine (22.5 mg, 0.05 mmol) and adamantane-1-carboxylic acid (9.0 mg, 0.05 mmol) were added at room temperature. The reaction mixture was stirred at the same temperature for 8 hours, and the reaction mixture was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1 / 6) to obtain (1R,2S,5S)-3-oxo-2-(2-oxopropyl)-5-phenylcyclopentane-1-carbaldehyde (89.1 mg, 0.365 mmol, yield 73%) as a yellow solid (single isomer, >99% ee). The optical yield was determined by reacting the product with trimethyl orthoformate and p-toluenesulfonic acid to convert the aldehyde into the corresponding dimethyl acetal, followed by HPLC analysis using a chiral column (ChiralPak (registered trademark) ID).

[0175] For this product, 1 H NMR, 13 The results of physicochemical analyses using C NMR and high-resolution mass spectrometry using electrospray ionization (HRMS (ESI)) are shown below.

[0176] 1 H NMR (CDCl3) δ 2.06 (s, 3H), 2.63-2.85 (m, 4H), 2.98 (dd, J = 14.8, 5.2 Hz, 1H), 3.22, (J = 11.2, 11.2 Hz, 1H), 3.32-3.40 (m, 1H), 7.25-7.27 (m, 5H), 9.55 (d, J = 1.2 Hz, 1H) 13C NMR (CDCl3) δ 214.2, 206.1, 201.2, 140.3, 129.1 (2C), 127.5, 127.5, 127.2, 59.9, 46.0, 45.7, 42.4, 41.9, 29.7 HRMS (ESI): [M+H] + calcd for C 15 H 17 O3: 245.1099, found: 245.1172

[0177] Example 4

[0178] [ka]

[0179] (In the formula, Ph represents phenyl, Me represents methyl, Et represents ethyl, and OSiMePh2 represents methyldiphenylsilyloxy.)

[0180] To a solution of cinnamaldehyde ((E)-3-phenylpropenal) (396 mg, 3.0 mmol) and ethyl (E)-4-oxo-2-hexenoate (937 mg, 6.0 mmol) in isopropanol (6.0 mL) were added water (162 μL, 9.0 mmol), (S)-2-(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine (135 mg, 0.3 mmol), and adamantane-1-carboxylic acid (64 mg, 0.3 mmol) at room temperature. The reaction mixture was stirred at the same temperature for 4.5 hours, and the reaction mixture was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 6 / 1) to obtain ethyl 2-((1S,2R,3R)-2-formyl-4-methyl-5-oxo-3-phenylcyclopentyl)acetate (467 mg, 1.62 mmol, yield 54%) as a colorless oil (5:1 diastereomeric mixture, both >99% ee). The optical yield was determined by reacting ethyl (triphenylphosphoranylidene)acetate with the product to convert the aldehyde into the corresponding α,β-unsaturated ester, followed by HPLC analysis using a chiral column (ChiralPak (registered trademark) ID).

[0181] Example 4A In order to determine the configuration of this compound, the following procedure was carried out.

[0182] [ka]

[0183] (In the formula, Ph represents phenyl, Me represents methyl, and Et represents ethyl.)

[0184] The 5:1 diastereomeric mixture, ethyl 2-((1S,2R,3R)-2-formyl-4-methyl-5-oxo-3-phenylcyclopentyl)acetate (887 mg, 3.1 mmol) obtained above was dissolved in toluene (6 mL), and ethyl (triphenylphosphoranylidene)acetate (1.39 g, 4.0 mmol) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography to give ethyl (2E)-3-((1R,2S,4R,5R)-2-(2-ethoxy-2-oxoethyl)-4-methyl-3-oxo-5-phenylcyclopentyl)-2-propenoate (Diester 4R; 803 mg, yield 73%) and ethyl (2E)-3-((1R,2S,4S,5R)-2-(2-ethoxy-2-oxoethyl)-4-methyl-3-oxo-5-phenylcyclopentyl)-2-propenoate (Diester 4S, 154 mg, yield 14%). Ethyl (2E)-3-((1R,2S,4R,5R)-2-(2-ethoxy-2-oxoethyl)-4-methyl-3-oxo-5-phenylcyclopentyl)-2-propenoate (Diester 4R; 358 mg, 1 mmol) was dissolved in ethanol (10 mL), potassium carbonate (414 mg, 3.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted three times with ethyl acetate. The resulting organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to give ethyl (2E)-3-((1R,2S,4S,5R)-2-(2-ethoxy-2-oxoethyl)-4-methyl-3-oxo-5-phenylcyclopentyl)-2-propenoate (Diester 4S; 552 mg, 75% yield).

[0185] For this product, 1 H NMR, 13 The results of physicochemical analyses using C NMR and high-resolution mass spectrometry using electrospray ionization (HRMS (ESI)) are shown below.

[0186] 1 H NMR (400 MHz, CDCl3) δ 7.19-7.16 (m, 2H), 7.11-7.05 (m, 3H), 6.94-6.87 (m, 1H), 5.75 (d, J = 15.6, 1H), 4.04-3.93 (m, 4H), 2.99 (ddd, J = 11.2, 11.2, 10.4 Hz, 1H), 2.77 (dd, J = 17.2, 5.2 Hz, 1H), 2.54 (dd, J = 12.0, 6.8 Hz, 1H), 2.53 (dd, J = 17.6, 4.0 Hz, 1H), 2.27 (dd, J = 11.2, 11.2 Hz, 1H), 2.10 (ddd, J = 11.6, 5.6, 4.4 Hz, 1H), 1.05-1.00 (m, 4H), 0.99-0.95 (m, 3H) 13C NMR (100 MHz, CDCl3) δ 216.6, 171.4, 165.8, 147.3, 139.5, 128.8 (2C), 127.6 (2C), 123.6, 60.9, 55.0, 51.1, 50.4, 49.7, 32.0, 31.5, 22.6, 14.1 (2C), 12.6 HRMS (ESI): [M+Na + ] calcd for C 21 H 26 O5Na + : 381.1672, found: 381.1678

[0187] Example 4B

[0188] [ka]

[0189] (In the formula, Ph represents phenyl, Me represents methyl, and Et represents ethyl.)

[0190] Also, ethyl (2E)-3-((1R,2S,4S,5R)-2-(2-ethoxy-2-oxoethyl)-4-methyl-3-oxo-5-phenylcyclopentyl)-2-propenoate (Diester 4S; 777 mg, 2.2 mmol) obtained in Example 4A was dissolved in ethanol (22 mL), sodium borohydride (492 mg, 13 mmol) was added, and the mixture was stirred at 0° C. for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was extracted three times with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography (eluent: chloroform / ethyl acetate=8 / 1) to give ethyl (2E)-3-((3aS,4R,5R,6S,6aR)-6-methyl-2-oxo-5-phenylhexahydro-2H-cyclopenta[b]furan-4-yl)-2-propenoate (332 mg, yield 48%) and ethyl (2E)-3-((1R,2S,3S,4S,5R)-2-(2-ethoxy-2-oxoethyl)-3-hydroxy-4-methyl-5-phenylcyclopentyl)-2-propenoate (190 mg, yield 24%) in a molar ratio of 2:1.

[0191] For these products, 1 H NMR, 13 The results of 1C NMR and high-resolution mass spectrometry using electrospray ionization (HRMS (ESI)) are shown below.

[0192] (Methyl (2E)-3-((3aS,4R,5R,6S,6aR)-6-methyl-2-oxo-5-phenylhexahydro-2H-cyclopenta[b]furan-4-yl)-2-propenoate) 1H NMR (400 MHz, CDCl3) δ 7.34-7.30 (m, 2H), 7.25-7.23 (m, 1H), 7.14-7.12 (m, 2H), 6.70 (dd, J = 15.6, 8.4 Hz, 1H), 5.64 (dd, J = 15.6, 1.2 Hz, 1H), 4.62 (dd, J = 7.6, 4.8 Hz, 1H), 4.15-4.10 (m, 2H), 2.82-2.75 (m, 2H), 2.69-2.61 (m, 1H), 2.52 (dd, J = 11.2, 11.2 Hz, 1H), 2.47- 2.39 (m, 1H), 2.32 (ddd, J = 11.2, 6.8, 4.8 Hz, 1H), 1.23 (t, J = 7.2 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H) 13 C NMR (100 MHz, CDCl3) δ 176.2, 165.8, 146.6, 138.7, 128.8 (2C), 127.6 (2C), 127.3, 123.0, 89.8, 60.4, 58.6, 55.4, 48.9, 43.3, 33.7, 16.5, 14.1 HRMS (ESI): [M+Na + ] calcd for C 19 H 22 O4Na + : 337.1410, found: 337.1408

[0193] (Ethyl (2E)-3-((1R,2S,3S,4S,5R)-2-(2-ethoxy-2-oxoethyl)-3-hydroxy-4-methyl-5-phenylcyclopentyl)-2-propenoate) 11H NMR (400 MHz, CDCl3) δ 7.31 - 7.27 (m, 2H), 7.22 - 7.18 (m, 1H), 7.13 - 7.11 (m, 2H), 6.76 (dd, J = 15.6, 8.8 Hz, 1H), 5.58 (dd, J = 15.6, 0.8 Hz, 1H), 4.16 (qd, J = 7.2, 1.2 Hz, 2H), 4.13 - 4.07 (m, 3H), 2.77 (dd, J = 10.8, 10.8 Hz, 1H), 2.70 (d, J = 2.8 Hz, 1H), 2.60 (dd, J = 16.4, 4.0 Hz, 1H), 2.42 (dd, J = 10.4, 10.4 Hz, 1H), 2.37 (dd, J = 14.4, 10.4 Hz, 1H), 2.25 - 2.14 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H), 0.94 (d, J = 7.2 Hz, 3H) 13 13C NMR (100 MHz, CDCl3) δ 173.4, 166.0, 149.1, 140.8, 128.5 (2C), 127.7, 127.6 (2C), 126.6, 122.4, 78.6, 60.8, 60.2, 56.7, 54.5, 50.4, 45.6, 36.9, 14.1, 11.9 HRMS (ESI): [M+Na + calcd for C 21 H 28 O5Na + : 383.1829, found: 383.1824

[0194] Examples 5 - 14

[0195]

Chemical Structure

[0196] (In the formula, R has the meaning described below, Me represents methyl, Et represents ethyl, Ph represents phenyl, and OTMS represents trimethylsilyloxy.)

[0197] The following cyclization reactions were carried out using the aldehydes shown in Table 1 below. To a solution of each aldehyde (0.15mmol) and ethyl 4-oxo-2-pentenoate (42.6mg, 0.30mmol) in isopropanol (75μL), water (8.1μL, 0.45mmol), (S)-2-(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine (4.88mg, 0.015mmol), and p-nitrophenol (20.8mg, 0.15mmol) were added at room temperature. The reaction mixture was stirred at the same temperature, and the reaction mixture was purified by silica gel column chromatography to obtain the target product.

[0198] The aldehydes, reaction times, isolation yields, and optical yields used in Examples 5 to 14 are shown in Table 1. The optical yields were determined by reacting ethyl (triphenylphosphoranylidene)acetate with each of the resulting products to convert the aldehydes into the corresponding α,β-unsaturated esters, followed by HPLC analysis using a chiral column (ChiralPak (registered trademark) ID). In addition, in Table 1, for each aldehyde used, only R in the following chemical formula is shown.

[0199] [ka]

[0200] [Table 1]

[0201] The results of high-resolution mass spectrometry (HRMS (ESI)) by electrospray ionization for the products of Examples 5 to 14 showed that the optical rotation measurements ([α] D The results, properties, and melting points for solid forms are shown below.

[0202] ·Example 5 HRMS (ESI): [M+Na] + Calculate for C 16 H 18 O4Na: 297.1097, found: 297.1100 [α] D 26 +92.83 (c 3.2, CHCl3) Colorless solid, melting point: 82.0~84.0℃

[0203] ·Example 6 HRMS (ESI): [M+Na] + Calculate for C 20 H 20 O4Na: 347.1254, found: 347.1258 [α] D 26 +79.98 (c 1.2, CHCl3) Colorless solid, melting point: 73.0~75.0℃

[0204] ·Example 7 HRMS (ESI): [M+Na] + Calculate for C 17 H 20 O4Na: 311.1254, found: 311.1256 [α] D 26 +76.44 (c 2.8, CHCl3) Colorless solid, melting point: 80.5~83.1℃

[0205] ·Example 8 HRMS (ESI): [M+Na] + Calculate for C 17 H 20 O5Na: 327.1202, found: 327.1207 [α] D 26 +56.93 (c 3.8, CHCl3) Colorless solid, melting point: 95.4~98.1℃

[0206] ·Example 9 HRMS (ESI): [M+Na] + Calculate for C 16 H 17 FO4Na: 315.1003, found: 315.1009 [α] D 26 +69.17 (c 1.0, CHCl3) Yellow oily

[0207] ·Example 10 HRMS (ESI): [M+Na] + Calculate for C 16 H 17 ClO4Na: 331.0708, found: 331.0714 [α] D 26 +57.31 (c 1.1, CHCl3) Colorless solid, melting point: 70.4~72.9℃

[0208] ·Example 11 HRMS (ESI): [M+Na] + Calculate for C 16 H 17 BrO4Na: 375.0202, found: 375.0202 [α] D 26 +35.95 (c 2.8, CHCl3) Colorless solid, melting point: 86.4~88.3℃

[0209] ·Example 12 HRMS (ESI): [M+Na] + Calculate for C 16 H 17 BrO4Na: 375.0202, found: 375.0202 [α] D 26 +115.6 (c 1.0, CHCl3) Yellow oily

[0210] Example 13 HRMS (ESI): [M+H] + calcd for C 16 H 17 BrO4H: 353.0383, found: 353.0386 [α] D 26 +19.29 (c 3.0, CHCl3) yellow oily

[0211] Example 14 HRMS (ESI): [M+Na] + calcd for C 14 H 16 O5Na: 265.1071, found: 265.1076 [α] D 26 +112.7 (c 0.86, CHCl3) yellow oily

[0212] Examples 15 to 20

[0213] [ka]

[0214] (In the formula, R has the meaning described below, Me represents methyl, Et represents ethyl, Ph represents phenyl, and OSiMePh2 represents methyldiphenylsilyloxy.)

[0215] The following cyclization reactions were carried out using the aldehydes shown in Table 2 below. To an isopropanol solution of each aldehyde (1 molar equivalent) and diethyl 2-oxopropylidenemalonate (1 molar equivalent), water (3 molar equivalents), (S)-2-(diphenyl((methyldiphenylsilyl)oxy)methyl)pyrrolidine (0.1 molar equivalents), and benzoic acid (1 molar equivalents) were added at room temperature. The reaction mixture was stirred at the same temperature, and the reaction mixture was purified by silica gel column chromatography to obtain the target product.

[0216] The aldehydes, reaction times, isolation yields, and optical yields used in Examples 15 to 20 are shown in Table 2. The optical yields were determined by reacting ethyl (triphenylphosphoranylidene)acetate with each of the resulting products to convert the aldehydes into the corresponding α,β-unsaturated esters, followed by HPLC analysis using a chiral column (ChiralPak (registered trademark) ID). In addition, in Table 2, for each aldehyde used, only R in the following chemical formula is shown.

[0217] [ka]

[0218] [Table 2]

[0219] The optical yield was determined by increasing the carbon number of the formyl group by a Wittig reaction using ethyl (triphenylphosphoranylidene)acetate, followed by high performance liquid chromatography using a chiral column (for example, CHIRALPAK (registered trademark) ID can be used).

[0220] The results of high-resolution mass spectrometry (HRMS (ESI)) by electrospray ionization method for the products of Examples 15 to 20 showed that the optical rotation measurements ([α] D ) and the properties are as follows:

[0221] Example 15 HRMS (ESI): [M+Na] + calcd for C 19 H 22 O6Na: 369.1309, found: 369.1309 [α] D 26 +73.97 (c 1.00, CHCl3) yellow oily

[0222] Example 16 HRMS (ESI): [M+Na] + Calculate for C 20 H 24 O6Na: 383.1465, found: 383.1470 [α] D 26 +40.7 (c 2.53, CHCl3) Yellow oily

[0223] ·Example 17 HRMS (ESI): [M+Na] + Calculate for C 20 H 24 O7Na: 399.1414, found: 399.1419 [α] D 26 +53.1 (c 0.60, CHCl3) Yellow oily

[0224] ·Example 18 HRMS (ESI): [M+Na] + Calculate for C 19 H 21 BrO6Na: 447.0414, found: 447.0419 [α] D 26 +11.86 (c 0.50, CHCl3) Yellow oily

[0225] ·Example 19 HRMS (ESI): [M+Na] + Calculate for C 19 H 21 FO6Na: 387.1214, found: 387.1220 [α] D 26 +22.9 (c 1.21, CHCl3) Yellow oily

[0226] ·Example 20 HRMS (ESI): [M+Na] + Calculate for C19 H 21 ClO6Na: 403.0918, found: 403.0921 [α] D 26 +52.7 (c 1.00, CHCl3) yellow oily

[0227] Example 21 (1) Cyclization step, ω chain introduction step

[0228] [ka]

[0229] (In the formula, PhMe2Si represents dimethyl(phenyl)silyl, Me represents methyl, Et represents ethyl, and Ph represents phenyl.)

[0230] (E)-3-(dimethyl(phenyl)silyl)propenal (1.14 g, 6.0 mmol), ethyl (E)-4-oxo-2-pentenoate (711 mg, 5.0 mmol), water (270 μL, 15 mmol), and p-nitrophenol (696 mg, 5.0 mmol) in isopropanol (1.25 mL) were added with (R)-2-(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine (81.4 mg, 0.25 mmol) at room temperature (also referred to as "cyclopentane mixture" in this example). Separately, to a solution of dimethyl (2-oxo-4-phenylbutyl)phosphonate (1.92 g, 7.5 mmol) and lithium chloride (318 mg, 7.5 mmol) in acetonitrile (5.0 mL), N,N-diisopropylethylamine (2.59 mL, 15 mmol) was added at room temperature over 1 hour, and the reaction mixture was stirred at the same temperature for 12 hours (in this example, this is also referred to as the "phosphorus ylide mixture"). To the resulting phosphorus ylide mixture, a mixture of the resulting cyclopentane mixture and acetonitrile (10 mL) was added, and the reaction mixture was stirred at the same temperature for 12 hours, after which a saturated aqueous solution of ammonium chloride was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed three times with a saturated aqueous solution of potassium carbonate, and washed with saturated saline. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After concentration, the reaction mixture was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 7 / 1) to obtain ethyl 2-((1R,2R,3R)-3-(dimethyl(phenyl)silyl)-5-oxo-2-((E)-3-oxo-5-phenylpent-1-en-1-yl)cyclopentyl)acetate (1.67 g, 3.61 mmol, yield 73%) as a yellow oil (single isomer).

[0231] For this product, 1 H NMR, 13 C NMR, high-resolution mass spectrometry with electrospray ionization (HRMS (ESI)), infrared absorption spectroscopy (IR), optical rotation measurement ([α] D The results of the physicochemical analyses of each of the following are shown below.

[0232] 1H NMR (CDCl3) δ 0.285 (s, 3H), 0.314 (s, 3H), 1.15 (q, J = 7.2 Hz, 3H), 1.46 (ddd, J = 8.0, 11.2, 13.2 Hz, 1H), 2.12 (dd, J = 13.2, 18.8 Hz, 1H), 2.27 (td, J = 5.2, 11.2 Hz, 1H), 2.40-2.46 (m, 3H), 2.51-2.60 (m, 2H), 2.68 (td, J = 7.6, 16.4 Hz, 1H), 2.81-2.86 (m, 2H), 3.95-4.02 (m, 2H), 5.91 (d, J = 16.0 Hz, 1H), 6.39 (dd, J = 13.2, 16.0 Hz, 1H), 7.15-7.20 (m, 3H), 7.24-7.31 (m, 5H), 7.40-7.43 (m, 2H) 13 C NMR (CDCl3) δ δ 216.3, 198.8, 171.3, 147.7, 141.1, 136.5, 133.9 (2C), 131.1, 129.5, 128.5 (2C), 128.4 (2C), 128.0 (2C), 126.1, 60.8, 52.5, 47.8, 41.1, 39.1, 31.8, 29.8, 27.7, 14.0, -3.77, -4.93 HRMS (ESI): [M+Na] + Calculate for C 28 H 34 O4SiNa: 485.2119, found: 485.2121 IR (neat) ν 2956, 1740, 1732, 1673, 1629, 1428, 1408, 1373, 1253, 1190, 1030, 819, 737, 701 cm -1 [α] D 26 -64.85 (c 5.5, CHCl3)

[0233] (2) Restoration project, ラクトン chemical project

[0234] [ka]

[0235] (In the formula, PhMe2Si represents dimethyl(phenyl)silyl, Et represents ethyl, and Ph represents phenyl.)

[0236] To a solution of the obtained ethyl 2-((1R,2R,3R)-3-(dimethyl(phenyl)silyl)-5-oxo-2-((E)-3-oxo-5-phenyl-1-penten-1-yl)cyclopentyl)acetate (1.2 g, 2.59 mmol) in THF (32 mL), (-)-DIP Chloride (registered trademark) (1.7 M hexane solution, 5.12 mL, 10.4 mmol) was added slowly at -20°C. The reaction mixture was stirred at the same temperature for 24 hours, and then 2N hydrochloric acid was added at the same temperature to stop the reaction, and the mixture was further stirred at room temperature for 2 hours. The mixture was extracted three times with ethyl acetate. The organic phases were combined and washed with saturated saline. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After concentration, the reaction mixture was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1-3 / 1-2 / 1) to obtain (3aR,4R,5R,6aS)-5-(dimethyl(phenyl)silyl)-4-((S,E)-3-hydroxy-5-phenyl-1-penten-1-yl)hexahydro-2H-cyclopenta[b]furan-2-one (847 mg, 2.07 mmol, 80% yield) as a yellow oil (single isomer).

[0237] For this product, 1 H NMR, 13 C NMR, high-resolution mass spectrometry with electrospray ionization (HRMS (ESI)), infrared absorption spectroscopy (IR), optical rotation measurement ([α] D The results of the physicochemical analyses of each of the following are shown below.

[0238] 1H NMR (CDCl3) δ 0.192 (s, 3H), 0.216 (s, 3H), 1.16 (dt, J = 6.0, 8.8 Hz, 1H), 1.18 (s, 1H) 1.58-1.68 (m, 3H), 1.90 (td, J = 9.6, 12.4 Hz, 1H), 2.20 (dd, J = 1.6, 18.4 Hz, 1H), 2.25-2.33 (m, 2H), 2.52 (dd, J = 8.8, 18.0 Hz, 1H), 2.50-2.58 (m, 1H), 2.62-2.67 (m, 1H), 3.84 (q, J = 5.6 Hz, 1H), 4.83 (dt, J = 4.0, 7.6 Hz, 1H), 5.20 (ddd, J = 1.2, 9.2, 15.6 Hz, 1H), 5.40 (dd, J = 5.6, 15.6 Hz, 1H), 7.09-7.14 (m, 3H), 7.18-7.28 (m, 5H), 7.35-7.37 (m, 2H) 13 C NMR (CDCl3) δ 176.9, 141.8, 137.8, 134.5, 133.8 (2C), 131.4, 129.2, 128.4 (4C), 127.8 (2C), 125.9, 85.4, 70.9, 51.5, 48.3, 38.5, 35.5, 33.2, 32.9, 31.6, -3.80, -4.78 HRMS (ESI): [M+Na] + calcd for C 26 H 32 O3SiNa: 443.2013, found: 443.2018 IR (neat) ν 2953, 2860, 1768, 1456, 1427, 1249, 1167, 1111, 1031, 976, 844, 815, 761, 738, 700 cm -1 [α] D 26 -17.62 (c 1.5, CHCl3)

[0239] (3) Hydrogenation process, Tamao-Fleming oxidation process

[0240] [ka]

[0241] (In the formula, PhMe2Si represents dimethyl(phenyl)silyl, and Ph represents phenyl.)

[0242] To the obtained ethanol solution of (3aR,4R,5R,6aS)-5-(dimethyl(phenyl)silyl)-4-((S,E)-3-hydroxy-5-phenyl-1-penten-1-yl)hexahydro-2H-cyclopenta[b]furan-2-one (84.1 mg, 0.2 mmol), 10% palladium on activated carbon (84.1 mg, 10% by mass, 10% by mass of palladium on palladium on activated carbon) was added. After stirring the mixture at room temperature for 1.5 hours under a hydrogen atmosphere, the reaction mixture was filtered to remove the palladium on activated carbon. The removed palladium on activated carbon was washed with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure. A tetrafluoroboric acid aqueous solution (262 μL, 2.0 mmol, 47 wt%) was added to a solution of the obtained crude product in toluene (262 μL), and the mixture containing the crude product was azeotroped with toluene at 80° C. for 5 minutes. The reaction mixture was neutralized by adding potassium carbonate (276 mg, 2.0 mmol) in dimethylformamide (600 μL) and water (300 μL). Potassium fluoride (116 mg, 2.0 mmol) and an aqueous hydrogen peroxide solution (133 μL, 2.0 mmol) were added to the reaction mixture at 60° C. The mixture was stirred at the same temperature for 4 hours, and then a saturated aqueous sodium thiosulfate solution was added to quench the reaction. The aqueous phase was extracted three times with methylene chloride, and the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After concentration, the reaction mixture was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 2) to obtain (3aR,4R,5R,6aS)-5-hydroxy-4-((R)-3-hydroxy-5-phenylpentyl)hexahydro-2H-cyclopenta[b]furan-2-one (48.6 mg, 0.16 mmol, yield 80%) as a yellow oil (single isomer).

[0243] For this product, 1 H NMR, 13 C NMR, high-resolution mass spectrometry with electrospray ionization (HRMS (ESI)), infrared absorption spectroscopy (IR), optical rotation measurement ([α] D The results of the physicochemical analyses of each of the following are shown below.

[0244] 1H NMR (CDCl3) δ 1.25 (s, 2H), 1.40-1.46 (m, 2H), 1.50-1.58 (m, 2H), 1.75-1.86 (m, 3H), 2.02 (qd, J = 1.6, 14.8 Hz, 1H), 2.31 (ddd, J = 6.0, 6.4, 14.8 Hz, 1H), 2.49 (dd, J = 1.6, 18.8 Hz, 1H), 2.47-2.53 (m, 1H), 2.64-2.71 (m, 1H), 2.74-2.82 (m, 1H), 2.79 (dd, J = 11.2, 19.2 Hz, 1H), 3.59-3.65 (m, 1H), 4.00 (q, J = 4.0 Hz), 4.94 (dt, J = 2.0, 7.2 Hz), 7.18-7.21 (m, 3H), 7.26-7.31 (m, 2H) 13 C NMR (CDCl3) δ 177.4, 141.7, 128.5 (2C), 128.4 (2C), 126.0, 83.8, 77.5, 71.2, 53.7, 43.1, 39.2, 35.9, 35.0, 32.0, 29.0 HRMS (ESI): [M+Na] + Calculate for C 18 H 24 O4Na: 304.1675, found: 304.1678 IR (neat) ν 3391, 2925, 1753, 1454, 1365, 1185, 1031, 750, 701, 419 cm -1 [α] D 26 -9.91 (c 1.2, CHCl3)

[0245] (4) Rakuto restoration project, alpha lock introduction project

[0246]

change

[0247] (In the formula, Ph represents phenyl.)

[0248] To a solution of the obtained (3aR,4R,5R,6aS)-5-hydroxy-4-((R)-3-hydroxy-5-phenylpentyl)hexahydro-2H-cyclopenta[b]furan-2-one (30 mg, 0.1 mmol, 1.0 eq.) in methylene chloride (2 mL), diisobutylaluminum hydride (1.0 M n-hexane solution, 330 μL, 0.33 mmol, 3.3 eq.) was added at −78° C. The reaction mixture was stirred at the same temperature for 2 hours, and then potassium sodium tartrate (2.0 mL) was added, and the reaction mixture was warmed to room temperature and stirred at the same temperature for 2 hours. The aqueous phase was extracted with methylene chloride (3×10 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. To a solid of (4-carboxybutyl)(triphenyl)phosphonium bromide (265 mg, 0.6 mmol), potassium t-butoxide (1.0 M tetrahydrofuran solution, 1.2 mL, 1.2 mmol) was added at 0°C, and the resulting orange solution was stirred at room temperature for 45 minutes. A solution of the crude product obtained above in anhydrous tetrahydrofuran (1.0 mL) was added at -10°C, and the mixture was stirred at the same temperature for 4 hours, after which a saturated aqueous solution of ammonium chloride (2.0 mL) was added to quench the reaction. The aqueous phase was extracted with methylene chloride (5 x 3 mL), and the combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After concentration, the reaction mixture was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 20 / 1 to 10 / 1) to obtain (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoic acid (25.0 mg, 64.1 mmol, yield 64.1%) as a colorless, transparent oil (single isomer).

[0249] For this product, 1 H NMR, 13 C NMR, high-resolution mass spectrometry with electrospray ionization (HRMS (ESI)), infrared absorption spectroscopy (IR), optical rotation measurement ([α] DThe results of the physicochemical analyses of each of the following are shown below.

[0250] 1 H NMR (CDCl3) δ 0.85-0.96 (m, 3H), 1.32-1.43(m, 3H), 1.57-1.78 (m, 5H), 1.79-1.92 (m, 5H), 2.00-2.09 (m, 2H), 2.17-2.19 (m, 2H), 2.20-2.38 (m, 2H), 2.61-2.69 (m, 1H), 2.75-2.4 (m, 1H), 3.64 (br, 1H), 4.00 (br, 1H), 4.16 (br, 1H), 5.37-5.41 (m, 2H), 7.14-7.19 (m, 3H), 7.24-7.27 (m, 2H) 13 C NMR (CDCl3) δ 24.8, 26.5, 26.8, 29.3, 32.2, 35.4, 38.9, 42.5, 51.8, 52.4, 71.6, 78.7, 125.9, 128.5 (2C), 128.5 (2C), 129.6, 129.6, 142.2 HRMS (ESI): [M+Na] + calcd for C 23 H 34 O5Na: 413.2299, found: 413.2295 IR (neat) ν 3391, 2925, 1753, 1454, 1365, 1185, 1031, 750, 701, 419 cm -1 [α] D 26 30.2 (c 0.40, MeOH)

[0251] (5) Esterification process

[0252] [ka]

[0253] (In the formula, Ph represents phenyl, iPr stands for isopropyl.

[0254] To a solution of the obtained (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoic acid (19.5 mg, 0.05 mmol) in dimethylformamide (300 μL), cesium carbonate (32.6 mg, 0.1 mmol) was added at room temperature in one portion, and 2-iodopropane (30 μL, 0.20 mmol) was further added. The reaction mixture was stirred at the same temperature for 2 hours, poured into 3% aqueous citric acid solution (1 mL), and extracted with t-butyl methyl ether (4 × 5 mL). The combined organic phase was washed with 10% aqueous sodium bicarbonate solution (10 mL), washed with saturated saline solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After concentration, the reaction mixture was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate=2 / 1 to 1 / 2) to obtain latanoprost (21.6 mg, 0.0425 mmol, yield 84%) as a colorless, transparent oil (single isomer).

[0255] For this product, 1 H NMR, 13 C NMR, high-resolution mass spectrometry with electrospray ionization (HRMS (ESI)), infrared absorption spectroscopy (IR), optical rotation measurement ([α] D The results of the physicochemical analyses of each of the following are shown below.

[0256] 1 H NMR (CDCl3) δ 1.23 (d, J = 6.4 Hz, 6H), 1.30-1.90, (m, 14H), 2.08-2.36 (m, 6H), 2.44 (d, J=5.5Hz, 1H), 2.63-2.85 (m, 2H), 3.64-3.70 (m, 1H), 3.94 (br s, 1H), 4.17 (br s, 1H), 5.00 (sept, J = 6.4 Hz, 1H), 5.35-5.50 (m, 2H), 7.15-7.22 (m, 3H, ArH), 7.26-7.31 (m, 2H, ArH) 13 C NMR (CDCl3) δ 21.9 (2C), 25.0, 26.7, 27.0, 29.7, 32.2, 34.2, 35.9, 39.1, 42.6, 51.9, 52.8, 67.8, 71.4, 74.7, 78.8, 125.9, 128.5 (2C), 128.5 (2C), 129.5, 129.6, 142.2, 173.6 HRMS (ESI): [M+Na] + calcd for C 26 H 40 O5Na: 455.2768, found: 455.2768 IR (neat) ν 3391, 2925, 1753, 1454, 1365, 1185, 1031, 750, 701, 419 cm -1 [α] D 26 35.1 (c 0.42, MeOH) [Industrial Applicability]

[0257] According to the process for producing a cyclopentane compound of the present invention, a cyclopentane compound having a plurality of asymmetric centers in the molecule can be simply synthesized diastereoselectively and, if necessary, enantioselectively. In particular, it is useful as a method for producing Corey lactone, which has multiple asymmetric centers on the cyclopentane ring.

Claims

1. Formula (I) 【Chemistry 1】 (In formula (I), R １Ａ represents an aromatic hydrocarbon ring group which may have a substituent, an aromatic heterocyclic group which may have a substituent, a substituted silyl group, -C(=O)-O-R Ｘ , -C(=O)-R Ｘ , -C(=O)-N(-R Ｘ１ )-R Ｘ２ or a hydrogen atom; R １Ｂ is a hydrogen atom, a halogen, or C １－６ represents an alkyl group; R Ｘ is C １－６ represents an alkyl group or an aromatic hydrocarbon ring group which may have a substituent; R Ｘ１ and R Ｘ２ are the same or different and R Ｘ Indicates.) or a cis-trans isomer thereof, and 【Chemistry 2】 (In formula (II), R ２Ａ is -C(=O)-O-R Ｘ , -C(=O)-SR Ｘ , -C(=O)-R Ｘ , -C(=O)-N(-R Ｘ１ )-R Ｘ２ , a cyano group, or a nitro group; R ２Ｂ is a hydrogen atom, -C(=O)-O-R Ｘ , -C(=O)-SR Ｘ , -C(=O)-R Ｘ , -C(=O)-N(-R Ｘ１ )-R Ｘ２ , a cyano group, or a nitro group; R ２Ｃ represents a hydrogen atom or a halogen atom; R ２Ｄ and R ２Ｅ are the same or different and each represents a hydrogen atom, C １－６ represents an alkyl group, an aromatic hydrocarbon ring group which may have a substituent, or an aromatic heterocyclic group which may have a substituent; R ２Ｃ and R ２Ｅ are taken together as optionally substituted C ２－４ An alkylene group, or a methylene group (—CH ２ -) is -O-, -S-, or -N (C １－６ C substituted with alkyl group)- ２－４ may represent an alkylene group; R Ｘ is C １－６ represents an alkyl group or an aromatic hydrocarbon ring group which may have a substituent; R Ｘ１ and R Ｘ２ are the same or different and R Ｘ Indicates.) or a cis-trans isomer thereof in the presence of a catalyst comprising a cyclic amine compound or a chain amine compound, 【Chemistry 3】 (In formula (III), R １Ａ represents an aromatic hydrocarbon ring group which may have a substituent, an aromatic heterocyclic group which may have a substituent, a substituted silyl group, -C(=O)-O-R Ｘ , -C(=O)-R Ｘ , -C(=O)-N(-R Ｘ１ )-R Ｘ２ or a hydrogen atom; R １Ｂ is a hydrogen atom, a halogen, or C １－６ represents an alkyl group; R ２Ａ is -C(=O)-O-R Ｘ , -C(=O)-SR Ｘ , -C(=O)-R Ｘ , -C(=O)-N(-R Ｘ１ )-R Ｘ２ , a cyano group, or a nitro group; R ２Ｂ is a hydrogen atom, -C(=O)-O-R Ｘ , -C(=O)-SR Ｘ , -C(=O)-R Ｘ , -C(=O)-N(-R Ｘ１ )-R Ｘ２ , a cyano group, or a nitro group; R ２Ｃ represents a hydrogen atom or a halogen atom; R ２Ｄ and R ２Ｅ are the same or different and each represents a hydrogen atom, C １－６ represents an alkyl group, an aromatic hydrocarbon ring group which may have a substituent, or an aromatic heterocyclic group which may have a substituent; R ２Ｃ and R ２Ｅ are taken together as optionally substituted C ２－４ An alkylene group, or a methylene group (—CH ２ -) is -O-, -S-, or -N (C １－６ C substituted with alkyl group)- ２－４ may represent an alkylene group; R Ｘ is C １－６ represents an alkyl group or an aromatic hydrocarbon ring group which may have a substituent; R Ｘ１ and R Ｘ２ are the same or different and R Ｘ indicates; The indication of stereochemistry in formula (III) indicates the relative configuration. A method for producing a cyclopentane compound represented by the following formula: the cyclization is carried out in the presence of an acid; The method for producing a cyclopentane compound, wherein the cyclic amine compound or the chain amine compound is a secondary cyclic amine or a primary or secondary chain amine compound.

2. 2. The method for producing a cyclopentane compound according to claim 1, wherein the cyclic amine compound or the chain amine compound is a pyrrolidine compound having an asymmetric center at the carbon at the α-position to the nitrogen atom of the pyrrolidine ring.

3. The pyrrolidine compound is represented by the formula (IV): 【Chemistry 4】 (In formula (IV), R ４Ａ is a carboxyl group, a tetrazolyl group, or -C(R ４Ｃ ) (R ４Ｄ ) -OR ４Ｅ represents a group; R ４Ｃ and R ４Ｄ are the same or different and each represents an aromatic hydrocarbon ring group which may have a substituent, an aromatic heterocyclic group which may have a substituent, or a C １－６ represents an alkyl group; R ４Ｅ is a hydrogen atom, a substituted silyl group, or a C １－６ represents an alkyl group; R ４Ｂ represents a protecting group for a hydroxyl group; n represents 0 or 1; The indication of stereochemistry in formula (IV) indicates the absolute configuration. or a compound represented by formula (V) 【Chemistry 5】 (In formula (V), R ４Ａ is a carboxyl group, a tetrazolyl group, or -C(R ４Ｃ ) (R ４Ｄ ) -OR ４Ｅ represents a group; R ４Ｃ and R ４Ｄ are the same or different and each represents an aromatic hydrocarbon ring group which may have a substituent, an aromatic heterocyclic group which may have a substituent, or a C １－６ represents an alkyl group; R ４Ｅ is a hydrogen atom, a substituted silyl group, or a C １－６ represents an alkyl group; R ４Ｂ represents a protecting group for a hydroxyl group; n represents 0 or 1; The indication of stereochemistry in formula (V) indicates the absolute configuration. The method for producing a cyclopentane compound according to claim 2, wherein the compound is represented by the formula:

4. The method for producing a cyclopentane compound according to claim 3, wherein the pyrrolidine compound is (R)-2-(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine, (S)-2-(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine, (R)-2-(diphenyl((methyldiphenylsilyl)oxy)methyl)pyrrolidine, or (S)-2-(diphenyl((methyldiphenylsilyl)oxy)methyl)pyrrolidine.

5. R １Ａ is a substituted silyl group, R １Ｂ is a hydrogen atom, 【Chemistry 6】 and an α,β-unsaturated aldehyde compound represented by R ２Ａ -C(=O)-O-R Ｘ and R ２Ｂ , R ２Ｃ , R ２Ｄ and R ２Ｅ is a hydrogen atom, R Ｘ C １－６ The alkyl group of formula (II) 【Chemistry 7】 in the presence of a catalyst comprising a cyclic amine compound or a chain amine compound, and a cyclization reaction of an α,β-unsaturated ketone compound represented by the formula (III-a): 【Chemistry 8】 (In formula (III-a), R ３Ａ represents a substituted silyl group; R ３Ｂ is -C(=O)-O-R Ｙ indicates; R Ｙ is C １－６ represents an alkyl group; The indication of stereochemistry in formula (III-a) indicates the relative configuration. A method for producing a cyclopentane compound represented by the following formula: the cyclization is carried out in the presence of an acid; The method for producing a cyclopentane compound, wherein the cyclic amine compound or the chain amine compound is a secondary cyclic amine or a primary or secondary chain amine compound.

6. The cyclopentane compound represented by formula (III-a) produced by the method for producing a cyclopentane compound according to claim 5 is reduced and then lactonized to produce a cyclopentane compound represented by formula (III-b). 【Chemistry 9】 (In formula (III-b), R ３Ａ represents a substituted silyl group; The indication of stereochemistry in formula (III-b) indicates the relative configuration. A method for producing a lactone compound represented by the formula:

7. A method for producing a lactone compound represented by formula (III-c), comprising oxidizing the lactone compound represented by formula (III-b) produced by the method for producing a lactone compound according to claim 6 using the Tamao-Fleming reaction. 【Chemistry 10】 (The indication of stereochemistry in formula (III-c) indicates the relative configuration.) A method for producing a diol compound represented by the formula:

8. Formula (III-a) 【Chemistry 11】 (In formula (III-a), R ３Ａ represents a substituted silyl group; R ３Ｂ is -C(=O)-O-R Ｙ indicates; R Ｙ is C １－６ represents an alkyl group; The indication of stereochemistry in formula (III-a) indicates the relative configuration. A cyclopentane compound represented by the formula:

9. Formula (III-b) 【Chemistry 12】 (In formula (III-b), R ３Ａ represents a substituted silyl group; The indication of stereochemistry in formula (III-b) indicates the relative configuration. A lactone compound represented by the formula:

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