Methods for producing optically active, axially asymmetric molecule and central asymmetric molecule, compound, and optically active substance

Abstract

The present invention produces a central asymmetric molecule using a step for conversion into central asymmetry, in which an optically active, axially asymmetric molecule having a double bond and a cyclic structure is reacted with a reaction reagent to obtain a central asymmetric molecule in which one or each of both atoms forming the double bond is an asymmetry center. Due to the step, an optically active, central asymmetric molecule can be efficiently produced.

Description

Method for producing optically active axially asymmetric molecules and centrally asymmetric molecules, compounds, and optically active substances

[0001] The present invention relates to a method for producing an optically active axially chiral molecule useful as a precursor of an optically active centrally chiral molecule, a method for producing the centrally chiral molecule, and a compound and optically active substance useful as an axially chiral molecule of an optically active axially chiral molecule.

[0002] Chiral molecules exist as a pair of enantiomers (mirror isomers). Although these enantiomers have the same general chemical and physical properties, they have opposite signs of optical rotation and significantly different physiological activities. Therefore, using optically active substances containing an excess of only one enantiomer is extremely important for the development of pharmaceuticals and functional materials. Therefore, extensive research has been conducted on methods for preparing such optically active substances.

[0003] For example, with regard to methods for preparing optically active carbon-centered asymmetric molecules such as optically active amino acids and optically active hydroxycarboxylic acids, various methods have been researched and developed, including (1) a method for resolving only one enantiomer from a racemate (optical resolution method), (2) a method for synthesizing an optically active chiral molecule having a more complex structure using an optically active molecule as a raw material (chiral pool method, dynamic kinetic resolution (DKR)), and (3) a method for synthesizing an optically active chiral molecule of interest using a prochiral molecule (a molecule lacking chirality) as a raw material (asymmetric synthesis method) (see, for example, Non-Patent Document 1).

[0004] "Asymmetric Synthesis," edited by James D. Morrison, published by Academic Press (New York), 1983

[0005] However, in the optical resolution method (1), the yield of the desired enantiomer is only 50% at best, resulting in the waste of at least half of the chiral molecules. Meanwhile, in the synthesis methods (2) and (3), the optically active starting materials and the asymmetric reaction agents and asymmetric catalysts used in the synthesis reactions are generally expensive, resulting in high production costs. Furthermore, many of the asymmetric synthesis reactions performed in (2) and (3) are carried out under special conditions, such as extremely low temperatures, high pressures, and inert gas atmospheres, requiring large-scale equipment and complex operations, resulting in low production efficiency.

[0006] Therefore, in order to solve the problems of the conventional techniques, the present inventors have carried out investigations with the aim of providing a method for efficiently producing optically active centrally chiral molecules.

[0007] As a result of intensive research to solve the above problems, the present inventors have found that by reacting an optically active axially asymmetric molecule having a double bond and a cyclic structure, an optically active centrally asymmetric molecule having one or both carbon atoms of the double bond as an asymmetric center can be efficiently obtained, and further, by cleaving the cyclic structure, a variety of optically active centrally asymmetric molecules can be obtained. The present invention has been proposed based on these findings, and specifically has the following configuration.

[0008] [1] A method for producing an optically active axially asymmetric molecule, comprising an asymmetric induction step of increasing the abundance ratio of one enantiomer of a racemic axially asymmetric molecule having an enantiomeric excess half-life of less than one week at 200°C by applying an asymmetric induction agent to the molecule. [2] A method for producing an optically active axially asymmetric molecule, comprising a central chiral conversion step of reacting an optically active axially asymmetric molecule having a double bond and a cyclic structure with a reaction reagent to convert the double bond to a centrally asymmetric molecule having one or both carbon atoms constituting the double bond as the asymmetric center. [3] A method for producing a centrally asymmetric molecule according to [2], wherein the double bond is in the ring skeleton of the cyclic structure. [4] A method for producing a centrally asymmetric molecule according to [2] or [3], wherein the double bond is between a ring skeleton-constituting atom of the cyclic structure and a non-ring skeleton-constituting atom bonded thereto. [5] The method for producing a centrally chiral molecule according to any one of [2] to [4], further comprising, after the conversion step to central chirality, a cleavage step of cleaving the cyclic structure of the centrally chiral molecule to obtain a ring-opened molecule having central chirality. [6] The method for producing a centrally chiral molecule according to any one of [2] to [5], further comprising: an asymmetric induction step of reacting an axially chiral racemic molecule having a double bond and a cyclic structure, the half-life of the enantiomeric excess of which is less than one week at 200°C, with an asymmetric induction agent to obtain an optically active axially chiral molecule in which one enantiomer of the molecule is in excess; and then performing the conversion step to central chirality on the obtained optically active axially chiral molecule. [7] The method for producing a centrally chiral molecule according to [6], further comprising, after the conversion step to central chirality, a cleavage step of cleaving the cyclic structure of the centrally chiral molecule to obtain a ring-opened molecule having central chirality. [8] A compound represented by the following general formula (1): General formula (1): [In general formula (1), R １ represents a substituent, R ２ and R ３ Each of X independently represents a hydrogen atom or a substituent. １ is NR ４ , O or S; X ２ is C(R Ａ ) ２ , C═O or C═S, R ４ and R Ａeach independently represents a substituent. Z represents a substituent necessary for N-Z to form a chiral axis. n represents an integer of 0 to 3.] [9] The compound according to [8], which is represented by the following general formula (1a): General formula (1a): [In general formula (1a), R １ represents a substituent, R ２ , R ３ and R ５ ~R ８ each independently represents a hydrogen atom or a substituent, R ９ represents a substituent. １ is NR ４ , O or S; X ２ is C(R Ａ ) ２ , C═O or C═S, R ４ and R Ａ each independently represents a substituent, and n represents an integer of 0 to 3.]

[10] The compound according to [8], which is represented by the following general formula (1b): General formula (1b): [In general formula (1b), R １ and R １１ each independently represents a substituent, R ２ , R ３ , R １２ and R １３ Each of X independently represents a hydrogen atom or a substituent. １ and X １１ are each independently NR ４ , O or S; X ２ and X １２ are each independently C(R Ａ ) ２ , C═O or C═S, R ４ and R Ａ each independently represents a substituent. n and n' each independently represents an integer of 0 to 3.]

[11] A compound represented by the following general formula (2): General formula (2): [In the general formula (2), R ２ and R ３ each independently represents a hydrogen atom or a substituent, R １５ represents a substituent. ２ represents a substituent, R ２ and R １５ are different substituents.１ is NR ４ , O or S; X ２ is C(R Ａ ) ２ , C═O or C═S, R ４ and R Ａ each independently represents a substituent. Z represents a substituent necessary for N-Z to form a chiral axis. n represents an integer of 0 to 3.]

[12] An optically active substance composed of the compound according to any one of [8] to

[11] .

[0009] According to the present invention, optically active centrally chiral molecules can be efficiently produced. Furthermore, the compounds of the present invention are axially chiral molecules and are highly useful as optically active substances that can be converted into centrally chiral molecules.

[0010] The present invention will be described in detail below. The following description of the constituent elements may be based on typical embodiments or specific examples of the present invention, but the present invention is not limited to such embodiments or specific examples. In this specification, a numerical range expressed using "to" means a range including the numerical values ​​before and after "to" as the lower and upper limits. In addition, the isotopes of hydrogen atoms present in the molecules of the compound used in the present invention are not particularly limited, and for example, all hydrogen atoms in the molecule may be １ H, or part or all of ２ H (Deuterium D).

[0011] <Method for Producing Optically Active Axially Chiral Molecules> The method for producing optically active axially chiral molecules of the present invention includes an asymmetric induction step in which an asymmetric induction agent is applied to a racemic axially chiral molecule having an enantiomeric excess half-life of less than one week at 200°C to increase the abundance ratio of one enantiomer of the axially chiral molecule. The enantiomer whose abundance ratio is increased by this asymmetric induction step is the optically active axially chiral molecule produced by the production method of the present invention. Furthermore, the term "axially chiral molecule" as used in the present invention does not refer to a single molecule, but rather to a molecular aggregate. The "axially chiral molecule" used in the present invention is a molecule having substituents chirally arranged around an axis (chiral axis) passing through the molecule. The substituent may be an atom such as a hydrogen atom, or an unshared electron pair. The chiral axis is an axis whose rotation is restricted by steric hindrance of an atomic group, etc. Such racemates of axially chiral molecules with an enantiomeric excess half-life of less than one week at 200°C convert from the other enantiomer to one enantiomer through a conformational transformation with a relatively low energy barrier (e.g., several tens of kcal / mol), such as intramolecular bond rotation or bond angle change. Therefore, by reacting an asymmetric inducer with the chiral molecule under easily controllable temperature conditions of about room temperature to 100°C (preferably mild conditions of about 0°C to 50°C), the other enantiomer can be easily converted to one enantiomer, significantly increasing the abundance ratio of that one enantiomer. Therefore, according to this production method, the abundance ratio of one enantiomer in an axially chiral molecule can be significantly increased without using a chiral reactant, and further without cleavage or reformation of bonds within the chiral molecule, thereby allowing one enantiomer to be selectively and efficiently obtained. This allows for extremely high optical purity (extremely high enantiomeric excess). In other words, this production method is a new method whose concept is completely different from conventional racemic resolution methods and asymmetric synthesis methods. The axially chiral molecule, chiral inducer, and conditions used in the asymmetric induction step of the present invention are described in detail below. In this specification, room temperature refers to 25°C, for example.

[0012] [Asymmetric Induction Step] In this step, an asymmetric induction agent is allowed to act on an axially asymmetric molecule having an enantiomeric excess half-life of less than one week at 200°C, thereby increasing the abundance ratio of one enantiomer of the axially asymmetric molecule.

[0013] (Axially Chiral Molecule Having an Enantiomeric Excess Half-Life of Less Than One Week at 200°C) In the present invention, the "enantiomeric excess half-life" of the axially chiral molecule used in the asymmetric induction step refers to the time required for the enantiomeric excess of the axially chiral molecule to become half of the initial enantiomeric excess at 200°C. The present invention also includes a method for producing an optically active axially chiral molecule, which includes an asymmetric induction step in which an asymmetric induction agent is applied to a racemic axially chiral molecule having an enantiomeric excess half-life of less than one week at 100°C (or 150°C) to increase the abundance ratio of one enantiomer of the molecule. The enantiomeric excess half-life at 100°C (or 150°C) referred to here refers to the time required for the enantiomeric excess of the axially chiral molecule to become half of the initial enantiomeric excess at 100°C (or 150°C). The enantiomeric excess is a value calculated by the following formula (I):

[0014] In formula (I), A １ and A ２ represents the mole fraction of one enantiomer and the other enantiomer contained in the axially chiral molecule of interest, and A １ is the mole fraction of the larger enantiomer, and A ２ is the mole fraction of the smaller enantiomer.

[0015] The molar fraction of one enantiomer and the other can be determined by HPLC analysis using a chiral stationary phase, GC analysis, optical rotation measurement, NMR analysis using a chiral shift reagent, or the like. Axially asymmetric molecules in which one or the other enantiomer is present in excess exhibit optical activity, and such axially asymmetric molecules are sometimes referred to herein as "optically active axially asymmetric molecules." Chiral molecules are prone to interconversion between enantiomers, and the more easily they racemize, the shorter the half-life of the enantiomeric excess. Therefore, for axially asymmetric molecules whose enantiomeric excess half-life is less than one week at 200°C, the other enantiomer can be easily converted to one enantiomer by the action of an appropriate asymmetric inducer under mild temperature conditions (0-50°C) or easily controllable temperature conditions (0-100°C), thereby increasing the abundance ratio of one enantiomer. The half-life of the enantiomeric excess of the axially chiral molecule used in the method for producing an optically active axially chiral molecule of the present invention can be, for example, less than 5 days, less than 3 days, or less than 1 day. There is no particular lower limit to the half-life of the enantiomeric excess of the axially chiral molecule, but from the viewpoint of the stereochemical stability of the chiral molecule and the resulting ease of handling, it can be, for example, 10 minutes or more, 1 hour or more, or 10 hours or more at a temperature below 0°C.

[0016] The axially asymmetric molecule used in the asymmetric induction step can be any molecule of a compound having a chiral axis, without any particular limitation. Preferred examples of axially asymmetric molecules include those having a cyclic structure containing a double bond in the ring skeleton. The cyclic structure may be a hydrocarbon ring or a heterocyclic ring, and may be a monocyclic or fused ring. The number of double bonds contained in the ring skeleton of the cyclic structure may be one or two or more. When the cyclic structure is a hydrocarbon ring, the number of carbon atoms therein is, for example, 6 to 30, 6 to 22, 6 to 14, or 6 to 10. When the cyclic structure is a heterocyclic ring, examples of the heteroatom include a nitrogen atom, an oxygen atom, and a sulfur atom. The heterocyclic ring may contain one or two or more heteroatoms. The number of atoms constituting the ring skeleton of the heterocyclic ring is, for example, 4 to 30, 5 to 20, 5 to 14, or 5 to 10. Specific examples of the cyclic structure include a benzene ring, a naphthalene ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a pyrrole ring, an imidazole ring, a pyrazole ring, a triazole ring, an imidazoline ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, a cyclohexadiene ring, a cyclohexene ring, a cyclopentaene ring, a cycloheptatriene ring, a cycloheptadiene ring, a cycloheptaene ring, etc. Furthermore, the cyclic structure may be one in which hydrogen is added to an aromatic ring or an aromatic heterocycle to form a single double bond. Specific examples include a 2,3-dihydro-1H-imidazole ring, a 1,2,3,4-tetrahydropyrimidine ring, a 2,3-dihydro-1,3-oxazole ring, a 3,4-dihydro-2H-1,3-oxazine ring, a 2,3-dihydro-1,3-thiazole ring, and a 3,6-dihydro-2H-1,3-thiazine ring. One or more hydrogen atoms in these ring structures may be substituted with a substituent, and one of the hydrogen atoms may be substituted with a substituent necessary to form a chiral axis. In addition, at least one of the ring skeletal carbon atoms in these ring structures may be substituted with an oxo group (>C=O), a thioxo group (>C=S), or a methylene group (>C=CH ２ ) and substituted methylene groups (>C=CR ２where two R are each independently a hydrogen atom or a substituent, but not both are hydrogen atoms). For specific examples of the substituents, please refer to the description in the section on examples of substituents below. A preferred example of an axially asymmetric molecule is a molecule of a compound represented by the following general formula (1). The compound represented by general formula (1) will be described below.

[0017] [Compound represented by general formula (1)] General formula (1)

[0018] In general formula (1), R １ represents a substituent. A protecting group for the hydroxy group of an enol can be preferably used as the substituent, and any group capable of protecting the hydroxy group of an enol can be used. Examples of the protecting group include tri-substituted silyl groups such as triisopropylsilyl and tert-butyldiphenylsilyl.

[0019] R ２ and R ３ R each independently represents a hydrogen atom or a substituent. ２ and R ３ may be the same or different, and two R ３ may be the same or different. １ is NR ４ , O or S; X ２ is C(R Ａ ) ２ , C═O or C═S, R ４ and R Ａ Each of X independently represents a substituent. ２ is C(R Ａ ) ２ When X １ is NR ４ It is preferable that R ４ and R Ａ may be the same or different, and two R Ａ may be the same or different. ２ ~R ４ and R ＡThe substituent in R may be any group as long as it does not adversely affect the asymmetric induction step or the conversion reaction described below. ４ Preferred examples of the substituent represented by can include a substituted or unsubstituted arylalkyl group. For explanations and specific examples of the alkyl group and aryl group constituting the "arylalkyl group" of the "substituted or unsubstituted arylalkyl group", and the substituents that can be substituted on the arylalkyl group, please refer to the descriptions in the column of examples of substituents below. Specific examples of the "arylalkyl group" can include a benzyl group, a 1-naphthylmethyl group, and a 2-naphthylmethyl group. R Ａ The substituent represented by is preferably a substituted or unsubstituted alkyl group, more preferably an unsubstituted alkyl group. For explanations and specific examples of the "alkyl group" in the "substituted or unsubstituted alkyl group" and the substituents that can be substituted on the alkyl group, please refer to the descriptions in the column of examples of substituents below.

[0020] Z represents a substituent necessary for N-Z to form a chiral axis. Examples of Z include a substituted hydrocarbon ring group and a substituted heterocyclic group. Here, the term "substituted hydrocarbon group" refers to a monovalent group obtained by removing one hydrogen atom from a hydrocarbon ring in which at least one hydrogen atom has been substituted with a substituent, and the term "substituted heterocyclic group" refers to a monovalent group obtained by removing one hydrogen atom from a heterocycle in which at least one hydrogen atom has been substituted with a substituent. For an explanation of the hydrocarbon ring constituting the substituted hydrocarbon group and the heterocycle constituting the substituted heterocyclic group, please refer to the description of the hydrocarbon ring and heterocycle in the above "cyclic structure containing a double bond in the ring skeleton." Furthermore, the hydrocarbon ring of the "substituted hydrocarbon group" and the heterocycle of the "substituted heterocyclic group" herein can also have a cyclic structure that does not contain a double bond in the ring skeleton. That is, the hydrocarbon ring constituting the substituted hydrocarbon group may be a cycloalkane (e.g., having 5 to 30 carbon atoms), and the heterocycle constituting the substituted heterocyclic group may be a cycloalkane in which at least one of the ring skeleton atoms is replaced with a heteroatom. The number of substituents on the substituted hydrocarbon group and the substituted heterocyclic group is not particularly limited, but it is preferable that at least one of the substituents is bonded to a ring-constituting atom (e.g., a carbon atom) adjacent to the ring-constituting atom bonded to N. This ensures that N-Z forms a chiral axis.

[0021] n represents an integer of 0 to 3. When n is 0, the ring skeleton is a 5-membered ring, and does not have a structure bounded by n. ２ and the carbon atom to which X is bonded １ are bonded by a single bond. When n is 1, 2, or 3, the ring skeleton is a 6-membered ring, a 7-membered ring, or an 8-membered ring, respectively. n is preferably 0 to 2, for example, 0, for example, 1, or for example, 2.

[0022] An example of the compound represented by general formula (1) is a compound represented by the following general formula (1a).

[0023] General formula (1a)

[0024] R in general formula (1a) １ ~R ３ , X １ , X２ , R ４ , R Ａ and n are R in general formula (1), １ ~R ３ , X １ , X ２ , R ４ , R Ａ and n have the same meanings as n, and for their explanation, reference can be made to the corresponding descriptions in general formula (1). ５ ~R ８ R each independently represents a hydrogen atom or a substituent. ５ ~R ８ may be the same or different. ９ represents a substituent. ５ ~R ８ and R ９ The substituent in R may be any group as long as it does not adversely affect the asymmetric induction step or the conversion reaction described below. ９ Preferred examples of the substituent represented by include a substituted or unsubstituted aryl group and a substituted or unsubstituted branched alkyl group. For an explanation of the "aryl group" in the "substituted or unsubstituted aryl group", specific examples of the "branched alkyl group" in the "substituted or unsubstituted branched alkyl group", and explanations and specific examples of substituents that can be substituted on these groups, please refer to the descriptions in the column of examples of substituents below.

[0025] An example of the compound represented by general formula (1) is a dimer represented by the following general formula (1b): By using a dimer, a centrally chiral molecule can be produced more efficiently.

[0026] General formula (1b)

[0027] R in general formula (1b) １ ~R ３ , X １ , X ２ , R ４ , R Ａ and n is R in general formula (1). １ ~R ３ , X １ , X ２ , R ４ , RＡ and n have the same meanings as those of R in general formula (1b), and for their explanation, please refer to the corresponding descriptions in general formula (1). １１ ~R １３ , X １１ , X １２ and n′ is R １ ~R ３ , X １ , X ２ and n′ are the same as those in the general formula (1), and for their explanation, please refer to the description of the general formula (1). １ and R １１ , R ２ and R １２ , R ３ and R １３ , X １ and X １１ , X ２ and X １２ n and n' may be the same or different. If they are the same, two molecules of optically active centrally asymmetric molecules can be produced from one molecule of the compound represented by general formula (1b).

[0028] The molecules of the compounds represented by these general formulas can easily interconvert between enantiomers under easily controllable temperature conditions (0 to 100°C), and therefore the temperature when the chiral agent is allowed to act can be set to easily controllable temperature conditions (0 to 100°C). As an example of the interconversion between enantiomers, the interconversion of the conformation of the enantiomer of the compound represented by general formula (1a) is shown below.

[0029]

[0030] Examples of Substituents Examples of substituents that can be substituted on the substituents exemplified in the general formulae (1), (1a) to (1p), and each general formula include, for example, a hydroxy group, a halogen atom, a cyano group, an alkyl group having 1 to 20 carbon atoms, an alkoxy group having 1 to 20 carbon atoms, an alkylthio group having 1 to 20 carbon atoms, an alkyl-substituted amino group having 1 to 20 carbon atoms, an acyl group having 2 to 20 carbon atoms, an aryl group having 6 to 40 carbon atoms, a heteroaryl group having 3 to 40 carbon atoms, a diarylamino group having 12 to 40 carbon atoms, a substituted or unsubstituted carbazolyl group having 12 to 40 carbon atoms, Examples of the alkyl group include an alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, an arylalkyl group having 7 to 40 carbon atoms, an alkoxycarbonyl group having 2 to 10 carbon atoms, an alkylsulfonyl group having 1 to 10 carbon atoms, a haloalkyl group having 1 to 10 carbon atoms, an amido group, an alkylamido group having 2 to 10 carbon atoms, a trialkylsilyl group having 3 to 20 carbon atoms, a trialkylsilylalkyl group having 4 to 20 carbon atoms, a trialkylsilylalkenyl group having 5 to 20 carbon atoms, a trialkylsilylalkynyl group having 5 to 20 carbon atoms, and a nitro group. Among these specific examples, those that can be further substituted with a substituent may be substituted with the substituent of these specific examples. Specific examples of the "halogen atom" in this specification include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The alkyl group in the "alkyl group" in this specification or a substituent containing an alkyl group as a part thereof may be linear, branched, or cyclic. The number of carbon atoms can be selected from, for example, 1 to 10, 1 to 6, or 1 to 3. Specific examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a neopentyl group, an n-hexyl group, a cyclopentyl group, and a cyclohexyl group. The aromatic ring constituting the aryl group in the "aryl group" or a substituent containing an aryl group as a part thereof in this specification may be a monocyclic ring or a fused ring. The number of carbon atoms can be selected from, for example, 6 to 30, 6 to 22, 6 to 14, or 6 to 10. Specific examples of the aryl group include a phenyl group and a naphthyl group.

[0031] The axially chiral molecule used in the asymmetric induction step can have a racemization energy of, for example, 41 kcal / mol or less, 34 kcal / mol or less, 27 kcal / mol or less, 25 kcal / mol or less, 24 kcal / mol or less, or 23 kcal / mol or less. The axially chiral molecule used in the asymmetric induction step can have a racemization energy of, for example, 20 kcal / mol or more, 21 kcal / mol or more, or 22 kcal / mol or more. The range of the racemization energy can be, for example, 21 to 23 kcal / mol. Axially chiral molecules having a racemization energy within an appropriate range have appropriate stereochemical stability such that they racemize slowly at room temperature, and relatively easily convert from one enantiomer to the other when treated with an appropriate asymmetric induction agent at room temperature. Therefore, by subjecting an axially chiral molecule having such racemization energy to the production method of the present invention, one enantiomer can be selectively and efficiently obtained, and the axially chiral molecule can be handled well. The racemization energy of an axially chiral molecule can be determined by kinetic analysis experiments or density functional theory calculations (DFT calculations) of the racemic transition state.

[0032] Preferred examples of the compound represented by general formula (1) are compounds represented by any of the following general formulas (A) to (E). Specific examples of the compound represented by general formula (1) are shown in Tables 1 to 5 below. Table 1 shows specific examples of the compound represented by general formula (A), Table 2 shows specific examples of the compound represented by general formula (B), Table 3 shows specific examples of the compound represented by general formula (C), Table 4 shows specific examples of the compound represented by general formula (D), and Table 5 shows specific examples of the compound represented by general formula (E). However, the compounds that can be used as axially asymmetric molecules in the present invention should not be construed as being limited by these specific examples. In Tables 1 to 5, Me represents a methyl group, i-Pr represents an isopropyl group, t-Bu represents a tert-butyl group, Ph represents a phenyl group, and Bn represents a benzyl group. 1-Nop-CH ２ - is a 1-naphthylmethyl group, 2-Nop-CH ２"-" represents a 2-naphthylmethyl group, TIPS represents a triisopropylsilyl group, and TBDPS represents a tert-butyldiphenylsilyl group. No. indicates the compound number.

[0033]

[0034]

[0035]

[0036]

[0037]

[0038]

[0039] Examples of the compound represented by general formula (1) include a compound represented by the following general formula (1c). Examples of the compound represented by general formula (1c) also include compounds represented by the following general formula (1d) and general formula (1e). R in the following general formulas (1c) to (1e) １ ~R ３ , R ５ ~R ９ , R １１ , R １２ , Z and n are R in the general formulas (1) to (1b). １ ~R ３ , R ５ ~R ９ , R １１ , R １２ , Z and n, and for their explanation, please refer to the corresponding descriptions in the general formulae (1) to (1b). １６ ~R １９ and R ２６ ~R ２９ each independently represents a hydrogen atom or a substituent.

[0040] General formula (1c)

[0041] General formula (1d)

[0042] General formula (1e)

[0043] An example of the compound represented by general formula (1) is a dimer represented by the following general formula (1f): The use of this dimer also makes it possible to more efficiently produce a centrally chiral molecule.

[0044] General formula (1f)

[0045] R in general formula (1f) ３１ ~R ３３ each independently represents a hydrogen atom or a substituent. The dotted line in general formula (1f) indicates that a bond may or may not exist. In other words, when two atoms are connected by two lines, a solid line and a dotted line, it indicates that the two atoms may be bonded by a single bond or a double bond. However, the single bond and double bond are formed so that the carbon atom is tetravalent and the nitrogen atom and sulfur atom are divalent. p represents 1 or 2. R ３１ When there is a double bond between the carbon atom to which R is bonded and the adjacent carbon atom, p is 1, and when there is no double bond and it is a single bond, p is 2. ３１ ) two R in p when p is 2 ３１ may be the same or different. In general formula (1f), n represents an integer of 0 to 3. When n is 2 or 3, R ３１ The carbon atom to which R is bonded and the adjacent R ３１ The bond between the carbon atom to which n (R ３１ )p may be the same or different from each other. For example, ３１ ) R in p ３１ may be all hydrogen atoms. ３３ ) q is 2 or 3. C(R ３３ ) When the bond between q and the adjacent carbon atom is a double bond, q is 2, and when it is a single bond, q is 3. ３３ may be the same or different. For example, q R ３３ may all be hydrogen atoms. ３２ and R ３３may be bonded to each other to form a cyclic structure. The cyclic structure formed may be a hydrocarbon ring or a heterocyclic ring, and may be composed of a single ring or a fused ring. The number of double bonds contained in the ring skeleton of the cyclic structure may be one or two or more. For the hydrocarbon ring and heterocyclic ring referred to here, the description of the hydrocarbon ring and heterocyclic ring in the "cyclic structure containing a double bond in the ring skeleton" above can be referred to. In general formula (1f), X ３ is O, S or C(R Ｂ ) ２ Represents Y. １ and Y １ is bonded to the carbon atom, Y １ is O, S or C(R Ｂ ) ２ Represents R Ｂ Each of X independently represents a hydrogen atom or a substituent. ３ and Y １ may be the same or different. １ and Y １ is bonded to the carbon atom, Y １ represents a hydrogen atom or a substituent.

[0046] The general formula (1f) particularly includes 5-membered ring compounds, 6-membered ring compounds, and 7-membered ring compounds represented by the following general formulae: R ３８ and R ３９ each independently represents a hydrogen atom or a substituent.

[0047] 5-membered ring compound

[0048] 6-membered ring compound

[0049] 7-membered ring compound

[0050] R in general formula (1f) ３２ and R ３３ When these are bonded to each other to form a benzene ring, the compound is represented by the following general formula (1g):

[0051] General formula (1g)

[0052] R in general formula (1g) ３１ , X ３ , Y １ , p, q, and n are R in general formula (1f). ３１ , X ３ , Y １ , p, q, and n are synonymous with each other, and the corresponding descriptions in general formula (1f) can be referred to for their explanation. ３４ ~R ３７ R each independently represents a hydrogen atom or a substituent. ３４ ~R ３７ may be the same or different. ３４ ~R ３７ The substituent in may be any group that does not adversely affect the asymmetric induction step or the conversion reaction described below. For explanations and specific examples of the substituent, please refer to the description in the column of examples of substituents below.

[0053] The general formula (1g) particularly includes five-membered ring compounds, six-membered ring compounds and seven-membered ring compounds represented by the following general formulae:

[0054] 5-membered ring compound

[0055] 6-membered ring compound

[0056] 7-membered ring compound

[0057] Examples of the compound represented by general formula (1) include the compound represented by the following general formula (1h).

[0058] General formula (1h)

[0059] In general formula (1h), R ４１ , R ４２ , R ４４ R each independently represents a hydrogen atom or a substituent. ４３ represents a substituent. ４１ and R ４２may be bonded to each other to form a cyclic structure. The cyclic structure may be a single ring or a condensed ring. The number of double bonds contained in the ring skeleton of the cyclic structure may be 0 or 1 or more. Specific examples of the cyclic structure include a pyrrolidine ring and a piperidine ring. One or more hydrogen atoms of these cyclic structures may be substituted with a substituent. In general formula (1h), Y ２ represents O or S. X ４ is C(R Ｃ ) ２ , O, S or N(R Ｄ ) Two R Ｃ each independently represents a hydrogen atom or a substituent, R Ｄ represents a substituent. n represents an integer of 0 to 3. When n is 2 or 3, R ４４ The carbon atom to which R is bonded and the adjacent R ４４ The bond between the carbon atom to which R is bonded may be a double bond or a single bond. When the bond is a double bond, the bond between the carbon atom to which R is bonded may be a single bond. ４４ ) p is 1. (R ４４ ) p is 2. In this case, two R ４４ may be the same or different. ４４ )p may be the same or different from each other. For example, ４４ ) R in p ４４ may all be hydrogen atoms.

[0060] Examples of the compound represented by general formula (1) include the compound represented by the following general formula (1i).

[0061] General formula (1i)

[0062] In general formula (1i), R ５１ ~R ５４ Each of R independently represents a hydrogen atom or a substituent. ５３ may be the same or different. ５１ and R ５２may be bonded to each other to form a cyclic structure. The cyclic structure referred to here is R ４１ and R ４２ In general formula (1i), R ５５ represents a substituent. As the substituent, a protecting group for the hydroxy group of an enol can be preferably used, and a wide variety of groups can be used as long as they can protect the hydroxy group of an enol. Examples of the protecting group include a trisubstituted silyl group such as a triisopropylsilyl group (TIPS) or a tert-butyldiphenylsilyl group, and an allyloxycarbonyl group (Alloc). In general formula (1i), Y ３ represents O or S. X ５ is C(R Ｃ ) ２ , O, S or N(R Ｄ ) Two R Ｃ each independently represents a hydrogen atom or a substituent, R Ｄ represents a substituent. m represents 0 or 1. n represents an integer of 1 to 3. However, m+n is 2 to 5. When n is 2 or 3, R ５４ The carbon atom to which R is bonded and the adjacent R ５４ The bond between the carbon atom to which R is bonded may be a double bond or a single bond. When the bond is a double bond, the bond between the carbon atom to which R is bonded may be a single bond. ５４ ) p is 1. (R ５４ ) p is 2. In this case, two R ５４ may be the same or different. ５４ )p may be the same or different from each other. For example, ５４ ) R in p ５４ may all be hydrogen atoms. ５３ and R ５４may be bonded to each other to form a cyclic structure. The cyclic structure formed may be a hydrocarbon ring or a heterocyclic ring, and may consist of a single ring or a fused ring. The number of double bonds contained in the ring skeleton of the cyclic structure may be one or two or more. For the hydrocarbon ring and heterocyclic ring referred to here, the description of the hydrocarbon ring and heterocyclic ring in the above "cyclic structure containing a double bond in the ring skeleton" can be referred to.

[0063] General formula (1i) particularly includes compounds represented by the following general formula: r represents an integer of 0 to 3, s represents an integer of 0 to 4, and R ５６ represents a substituent. When s is 2 or more, two or more R ５６ may be the same or different.

[0064] Examples of the compound represented by general formula (1) include a compound represented by the following general formula (1j).

[0065] General formula (1j)

[0066] In general formula (1j), R ６１ represents a substituent. ６２ and R ６３ R each independently represents a hydrogen atom or a substituent. ６２ and R ６３ may be bonded to each other to form a cyclic structure. The cyclic structure referred to here is R ４１ and R ４２ The description of the cyclic structure formed by bonding X ６ and X ７ are each independently C(R Ｃ ) ２ , O, S or N(R Ｄ ) Two R Ｃ each independently represents a hydrogen atom or a substituent, R Ｄ represents a substituent. Z represents a substituent necessary for N--Z to form a chiral axis. For details of Z, please refer to the explanation of Z in general formula (1).

[0067] Examples of the compound represented by general formula (1j) include compounds represented by the following general formula (1k) and general formula (1m). ６１ ~R ６３ , X ６ and X ７ is R in general formula (1j). ６１ ~R ６３ , X ６ and X ７ are synonymous with each other.

[0068] Examples of the compound represented by general formula (1) include compounds represented by the following general formula (1n).

[0069] General formula (1n)

[0070] In general formula (1n), R ７１ ~R ７４ R each independently represents a hydrogen atom or a substituent. ７５ represents a substituent. ８ represents O or S.

[0071] Examples of the compound represented by general formula (1) include a compound represented by the following general formula (1p).

[0072] General formula (1p)

[0073] In general formula (1p), R ８１ ~R ８５ Each of X independently represents a hydrogen atom or a substituent. ９ represents O or S.

[0074] Other preferred examples of the compound represented by general formula (1) are compounds represented by any of the following general formulas (F) to (M). Specific examples of the compound represented by general formula (1) are shown in Tables 6 to 12 below. Table 6 shows specific examples of compounds represented by general formula (F), Table 7 shows specific examples of compounds represented by general formula (G), Table 8 shows specific examples of compounds represented by general formula (H), Table 9 shows specific examples of compounds represented by general formula (I), Table 10 shows specific examples of compounds represented by general formula (J), Table 11 shows specific examples of compounds represented by general formula (K), and Table 12 shows specific examples of compounds represented by general formula (L). However, compounds that can be used as axially chiral molecules in the present invention should not be construed as being limited by these specific examples. In Tables 6 to 11, Me represents a methyl group, i-Pr represents an isopropyl group, n-Bu represents a tert-butyl group, Ph represents a phenyl group, and Bn represents a benzyl group. Furthermore, TIPS represents a triisopropylsilyl group, Alloc represents an allyloxycarbonyl group, and TBDPS represents a tert-butyldiphenylsilyl group.

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082] (Asymmetry Inducing Agent) In the present invention, the term "asymmetry inducing agent" refers to a substance that, when applied to an axially chiral molecule, acts to increase the abundance ratio of one enantiomer of the axially chiral molecule. The asymmetry inducing agent must be a substance that, when applied to an axially chiral molecule, increases the abundance ratio of one enantiomer without cleaving or reforming bonds within the chiral molecule, and may be recoverable and reusable. The asymmetry inducing agent may also be a substance that preferentially interacts with the other enantiomer and converts the conformation of the other enantiomer to the conformation of the one enantiomer. Examples of such asymmetry inducing agents include sugar chain derivatives (sugar chain-derived polymers) such as cellulose derivatives and amylose derivatives, naturally occurring chiral polymers such as proteins, polypeptides, DNA, and antibodies, and their derivatives, amino acid derivatives, and chiral template polymers (artificial chiral polymers). The asymmetry inducing agent may be supported on a granular carrier such as silica gel. This allows the chiral agent, after acting on the axially chiral molecule in the solvent, to be easily separated from the axially chiral molecule by a simple procedure such as filtration and reused.

[0083] (Method and Conditions for Treating Axially Chiral Molecules with a Chiral Inducing Agent) As described above, in the method for producing optically active axially chiral molecules of the present invention, a chiral inducing agent is reacted with an axially chiral molecule having an enantiomeric excess half-life of less than one week at 200°C (preferably 100°C). The operation of treating the axially chiral molecule with a chiral inducing agent can be carried out by causing the axially chiral molecule and the chiral inducing agent to coexist in a solvent, stirring, and then allowing to stand. By sufficiently contacting the axially chiral molecule with the chiral inducing agent by stirring and then allowing to stand, the action of the chiral inducing agent can be exerted, and the equilibrium between the enantiomers can be sufficiently shifted. It is also possible to stir the solvent in which the axially chiral molecule and the chiral inducing agent are coexisting, and then distilling off the solvent, adding another solvent in its place, and allowing the axially chiral molecule and the chiral inducing agent to stand in the solvent.

[0084] The solvent is not particularly limited, and may be any solvent that does not adversely affect the axially chiral molecules or the chiral inducer and does not impair the function of the chiral inducer. Regarding the compatibility of the solvent, the solvent may be compatible with the axially chiral molecules, and the chiral inducer or the carrier carrying the chiral inducer may exist in a solid state in the solvent. Since the axially chiral molecules are dissolved in the solvent and the chiral inducer or the carrier carrying the chiral inducer exists in a solid state, the chiral inducer can be easily separated from the axially chiral molecules by a simple operation such as filtration after acting on the axially chiral molecules. Furthermore, the solvent may have a higher vapor pressure (lower boiling point) than the axially chiral molecules. This allows the solvent and the axially chiral molecules to be easily separated by a simple operation such as evaporation.

[0085] The amount of solvent used when the axially chiral molecule and the chiral inducer are allowed to stand can be 1 to 20 times the total weight of the axially chiral molecule and the chiral inducer. The amount of the chiral inducer in the solvent can be, for example, 50 times or more, 100 times or more, 200 times or more, or 1000 times or less, 500 times or less, or 300 times or less, relative to the weight of the axially chiral molecule. The temperature of the solvent used when the axially chiral molecule and the chiral inducer are allowed to stand can be, for example, 0 to 50°C. Since the production method of the present invention can be carried out under such mild temperature conditions (0 to 50°C), no equipment, tools, or operations for ultra-high temperature heating are required, thereby reducing the production cost of the optically active substance. The time for which the axially chiral molecule and the chiral inducer are allowed to stand is not particularly limited. From the viewpoint of operational efficiency, the time can be, for example, 72 hours or less.

[0086] [Other Steps] In the method for producing an optically active axially chiral molecule of the present invention, a step of isolating the optically active axially chiral molecule (isolation step) can be carried out after the asymmetric induction step. The isolation step will be described below.

[0087] [Isolation Step] The optically active axially chiral molecules obtained in the asymmetric induction step coexist with the chiral inducer in the solvent. In the isolation step, the optically active axially chiral molecules are isolated from these. When the chiral inducer is in a solid state in the solvent or is supported on a solid support, the separation of the optically active axially chiral molecules and the chiral inducer can be achieved by filtering a mixture of the optically active axially chiral molecules, the chiral inducer, and the solvent. As a result, the chiral inducer remains on the filter material, and the optically active axially chiral molecules are dissolved in the filtrate, resulting in a separated state. Alternatively, the separation of the optically active axially chiral molecules and the solvent can be achieved by distilling off the solvent. Either filtration or distillation can be performed first. However, if distillation is performed first, fresh solvent is added to the concentrate after distillation, and filtration is then performed. The separated chiral inducer can be reused as the chiral inducer in the asymmetric induction step. Furthermore, when the enantiomeric excess of one enantiomer in the filtrate is not 100% ee, i.e., when the other enantiomer is contained in the filtrate, an operation for separating the other enantiomer from one enantiomer may be carried out. Separation of one enantiomer from the other enantiomer can be carried out by applying a known optical resolution method. Separation of one enantiomer from the other enantiomer may be carried out after the asymmetric stabilization step.

[0088] The enantiomeric excess of the optically active axially chiral molecule produced by the production method of the present invention is, for example, 40% ee or more, 60% ee or more, or 70% ee or more, and the molecule may be produced entirely as one enantiomer. Such optically active axially chiral molecules having a high abundance ratio of one enantiomer are highly useful as optically active axially chiral molecules used in the production method of a centrally chiral molecule of the present invention.

[0089] <Method for producing a centrally chiral molecule> Next, the method for producing a centrally chiral molecule of the present invention will be described. The method for producing a centrally chiral molecule of the present invention comprises a step of converting an optically active axially chiral molecule having a double bond and a cyclic structure to a centrally chiral molecule having one or both carbon atoms constituting the double bond as an asymmetric center by reacting the double bond with a reaction reagent. The "centrally chiral molecule" produced by the method of the present invention is a molecule of a compound having an atom (asymmetric atom) that serves as an asymmetric center. Here, the "asymmetric atom" can be, for example, sp ３ It is a hybridized carbon atom, and the four groups (atoms or atomic groups) bonded to this carbon atom are different from one another. Furthermore, in the present invention, the term "centrally chiral molecule" does not mean a single molecule, but an aggregate of molecules. The "optically active axially chiral molecule having a double bond and a cyclic structure" used in the present invention is an optically active form of the "axially chiral molecule having a double bond and a cyclic structure." For an explanation of the "axially chiral molecule having a double bond and a cyclic structure," please refer to the description of examples of axially chiral molecules in the above section <Method for producing an optically active axially chiral molecule>. The "optically active axially chiral molecule having a double bond and a cyclic structure" is preferably produced by the method described in the above section <Method for producing an optically active axially chiral molecule>. The "conversion step" performed in the present invention will be described below.

[0090] [Conversion Step] In this step, a reaction is carried out on the double bond by reacting an optically active axially chiral molecule having a double bond and a cyclic structure with a reaction reagent, and a new bond is formed at the carbon atom constituting the double bond, thereby converting one or both of the carbon atoms into an asymmetric center. This reaction will be explained with reference to the following reaction scheme. In the following reaction scheme, A represents a cyclic structure (a cyclic structure containing a double bond in the ring skeleton) contained in the optically active axially chiral molecule, and R ２１ and R ２２ represents an atom or an atomic group, R ２１ａ and R ２２ａrepresents an atom or an atomic group that formed a bond by the reaction. In the following explanation, the carbon atom on the left side of the double bond is referred to as "one carbon atom," and the carbon atom on the right side of the double bond is referred to as "the other carbon atom," and "atom or atomic group" may be referred to as "group." When an optically active axially asymmetric molecule having a cyclic structure containing a double bond in the ring skeleton is reacted with a reaction reagent, an atom or atomic group (R ２１ａ , R ２２ａ ) forms a bond to give the product. At this time, the group R ２１ａ The group R originally bonded to that carbon atom ２０ By selecting a reaction reagent different from ＊ In other words, the axial chirality of the optically active axially chiral molecule is converted to central chirality.

[0091]

[0092] The reaction reagent is not particularly limited as long as it causes the above-mentioned reaction, and can be appropriately selected from known reaction reagents. ２２ａ and R ２２ may be the same or different. ２２ and R ２２ａ may be combined to form one atom or atomic group, and the terminal atom of the atom or atomic group may be bonded to another carbon atom by a double bond. Examples of atoms bonded to another carbon atom by a double bond include oxygen atoms and sulfur atoms. For example, R in an optically active axially asymmetric molecule ２２ When R is a hydroxy group protected by a protecting group, R can be attached to one of the carbon atoms by Mukaiyama aldol reaction. ２１ａ A hydroxyalkyl group is added as the R , and at the other carbon atom, the deprotected hydroxy group is converted to a carbonyl oxygen to form an aldol adduct having the structure represented by the following formula. Cases involving such reactions are also included within the scope of the present invention. In addition, the R of an optically active axially asymmetric molecule ２２is a hydroxy group protected by a protecting group, it can be reacted with an allyl halide and tetrabutylammonium fluoride (deprotecting agent) to form R ２１ａ An allyl group is added at the other carbon atom, and the deprotected hydroxy group is converted to a carbonyl oxygen at the other carbon atom, forming an allylated product having the structure represented by the following formula:

[0093] Although the reaction has been described here using an optically active axially chiral molecule having a cyclic structure containing a double bond in the cyclic skeleton as an example, the reaction can also be carried out using, for example, an optically active axially chiral molecule having a double bond between a ring skeleton-constituting atom of the cyclic structure and a non-ring skeleton-constituting atom bonded thereto. The conversion step of the present invention can be carried out as long as the reaction can give a centrally chiral molecule having one of the atoms constituting the double bond as the asymmetric center.

[0094] The optically active axially chiral molecule used in the conversion step is preferably an optically active compound of the compound represented by the general formula (1) above. A preferred example of the reaction of this optically active compound is given below. In this reaction, a centrally chiral molecule having a structure represented by the following general formula (2'), in which the carbon atom marked with * is the asymmetric center, is obtained.

[0095] R in general formula (2') １ ~R ３ , X １ , X ２ , Z and n are R in general formula (1) １ ~R ３ , X １ , X ２ , Z and n, and for their explanation, please refer to the corresponding descriptions in general formula (1). １５ represents a substituent, R ２ is a substituent, R ２ and R １５are different substituents. For an explanation of general formula (2'), the description in the section <Compound represented by general formula (2)> below can also be referred to. Note that the optically active compound represented by general formula (1) is given as an example of an optically active axially chiral molecule used in the conversion step, and other compounds represented by the above-mentioned general formulas can also be preferably used.

[0096] [Cleavage Step] In the production method of the present invention, after the step of converting to central chirality, the cyclic structure of the centrally asymmetric molecule may be cleaved to obtain a ring-opened molecule having central chirality (hereinafter referred to as a "centrally asymmetric ring-opened molecule"). This makes it possible to obtain centrally asymmetric molecules having an asymmetric center at an atom not constituting the cyclic structure, in addition to centrally asymmetric molecules having an asymmetric center at an atom constituting the ring skeleton of the cyclic structure, and various centrally asymmetric molecules can be produced in a series of steps. The reaction used to cleave the cyclic structure is not particularly limited, and can be appropriately selected from known cleavage reactions. As an example, the cleavage reaction of the centrally asymmetric molecule represented by the above general formula (2') is shown in the following reaction scheme. Here, an example will be described where X2 in general formula (2') is C=O. X of the centrally asymmetric ring-opened molecule on the right side １ represents NH, O or S. By this cleavage reaction, X １ NR ４ In the case where X is an optically active amino acid, １ When X is O, optically active hydroxycarboxylic acids can be obtained. However, the ring-opening reaction is not limited to the reaction shown in the following reaction scheme. For example, １ NR ４ When R is attached to N in the cleavage product, ４ may remain attached, thereby obtaining optically active substituted amino acids.

[0097]

[0098] As a preferred example, the following scheme shows a reaction example in which an optically active compound of the compound represented by the above general formulas (A) to (D) is used and subjected to the conversion step and the cleavage step.

[0099]

[0100] <Compound Represented by General Formula (1)> One of the compounds of the present invention has a structure represented by general formula (1) and is a novel compound. The compound represented by general formula (1) of the present invention may be optically active or racemic, and one enantiomer may be present in excess of the other enantiomer. For an explanation of general formula (1), please refer to the description of general formula (1) in the above section <Method for Producing Optically Active Axially Chiral Molecules>. The compound of the present invention may be a compound represented by general formula (1b) or a compound represented by general formula (1b). The compound represented by general formula (1), (1a), or (1b) of the present invention can be converted into a centrally chiral molecule by a conversion reaction, and is therefore highly useful as a precursor of a centrally chiral molecule. The compound represented by general formula (1) can be synthesized by combining known reactions. For details of the synthesis procedure and reaction conditions, please refer to the synthesis examples described below.

[0101] <Compound Represented by General Formula (2)> Another compound of the present invention is a compound represented by the following general formula (2): The compound represented by general formula (2) is useful as an intermediate for producing a centrally asymmetric ring-opened molecule in a method for producing a centrally asymmetric molecule.

[0102] General formula (2)

[0103] In general formula (2), R ２ and R ３ each independently represents a hydrogen atom or a substituent, R １５ represents a substituent. ２ represents a substituent, R ２ and R １５ are different substituents. １ is NR ４ , O or S; X ２ is C(R Ａ ) ２ , C═O or C═S, R ４ and R ＡEach independently represents a substituent. Z represents a substituent necessary for N-Z to form a chiral axis. n represents an integer of 0 to 3. R in general formula (2) ２ , R ３ , X １ , X ２ , R ４ , R Ａ and n are R in general formula (1), ２ , R ３ , X １ , X ２ , R ４ , R Ａ and n have the same meanings as n, and for their explanation, reference can be made to the corresponding descriptions in general formula (1). １５ The substituent represented by R ２ Preferably, it is a substituent that can be added to the carbon atom to which the hydroxyalkyl group is bonded. Specific examples include substituted or unsubstituted hydroxyalkyl groups and substituted or unsubstituted allyl groups. For an explanation of the alkyl groups constituting the "hydroxyalkyl group" in the "substituted or unsubstituted hydroxyalkyl group" and the substituents that can be substituted on the alkyl group, and for an explanation and specific examples of the substituents that can be substituted on the "aryl group" in the "substituted or unsubstituted allyl group," please refer to the description in the above column on examples of substituents. The compound represented by general formula (2) is a novel compound. The compound represented by general formula (2) can be synthesized by reacting the compound represented by general formula (1) with a reaction reagent. For details of the synthesis procedure and reaction conditions, please refer to the synthesis examples described below.

[0104] Preferred examples of the compound represented by general formula (2) are compounds represented by any of the following general formulae (TA) to (TE). Specific examples thereof include compounds A1 to A48, B1 to B48, E1 to E48, and R ２ , R ４ and R ９ are common, and R １５ is a hydroxymethyl group or an allyl group, and compounds C1 to C16, D1 to D16 and R ２ and R ９ are common, and R １５is a hydroxymethyl group or an allyl group.

[0105]

[0106] The features of the present invention will be explained in more detail below with reference to synthesis examples and working examples. The materials, processing details, processing procedures, etc. shown below can be modified as appropriate without departing from the spirit of the present invention. Therefore, the scope of the present invention should not be construed as being limited by the specific examples shown below. Here, the enantiomeric excess of the compound was measured by HPLC using a chiral stationary phase (CHIRALPAK ID: manufactured by Daicel Corporation, Φ4.6 × 50 mm) with a 70:30 hexane:isopropyl alcohol mixed solvent as the eluent under the following conditions: flow rate: 1.0 mL / min, column temperature: 25°C, and detection wavelength λ: 254 nm. In the structural formulas of the compounds shown below, Me represents a methyl group, i-Pr represents an isopropyl group, Ph represents a phenyl group, Bn represents a benzyl group, TIPS represents a triisopropylsilyl group, TBDPS represents a tert-butyldiphenylsilyl group, Boc represents a tert-butoxycarbonyl group, and TFA represents a trifluoroacetyl group.

[0107] Synthesis Example A In the following synthesis example, a compound represented by general formula (A) was synthesized using the reaction shown in the following reaction scheme. In the reaction scheme, "X" in the compound number is a variable, and "X" in the final product, compound AX, corresponds to the compound number shown in Table 1.

[0108]

[0109] Synthesis Example 1 Synthesis of Compound A1 Step 1 To a solution of glycine methyl ester hydrochloride (2a) (8.00 g, 65.3 mmol) in dichloromethane (218 mL) were added pyridine (26.0 mL, 326 mmol) and triphosgene (7.17 g, 22.2 mmol) at −78° C. The mixture was allowed to warm to room temperature over 2 hours, and then orthophenylaniline (12.2 g, 71.8 mmol) was added to the mixture, followed by stirring at room temperature for 8 hours. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with methylene chloride. The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product (A1-1). The crude product was used in the next step without further purification. To a solution of crude product (A1-1) in methanol (109 mL) was added 38% hydrochloric acid (109 mL) at room temperature. After stirring at 60°C for 12 hours, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform / methanol = 10:1) to obtain compound A1-2 as colorless crystals in an amount of 13.5 g (yield 80%).

[0110]

[0111] 1 H NMR (300 MHz, CDCl3): δ 7.53-7.7.26 (m, 9H), 5.98-5.73 (br, 1H), 3.96 (dd, J= 17.7, 1.2 H, 1H), 3.75 (dd, J = 17.7, 1.2 H, 1H). 13 C NMR (75 MHz, CDCl3): δ 170.51, 158.07, 141.42, 138.51, 131.00, 129.91, 129.09, 128.86, 128.63, 128.41, 128.19, 127.70, 46.46.

[0112] Step 2 Compound A1-3 can be synthesized by carrying out a reaction in the same manner as in Step 2 of Synthesis Example 2 below, using compound A1-2 instead of compound A2-2.

[0113]

[0114] Step 3 Compound A1 can be synthesized by carrying out a reaction in the same manner as in Step 3 of Synthesis Example 2 below, using compound A1-3 instead of compound A2-3.

[0115] (Synthesis Example 2) Synthesis of Compound A2 Step 1: Using DL-alanine methyl ester hydrochloride instead of glycine methyl ester hydrochloride (2a), a reaction was carried out in the same manner as in Step 1 of Synthesis Example 1 to obtain 3.40 g (99%) of a colorless oily product of Compound A2-2. The amounts of 2-phenylaniline and DL-alanine methyl ester hydrochloride added to the reaction solution were 12.9 mmol (2.20 g) and 14.3 mmol (2.00 g), respectively.

[0116]

[0117] 1 H NMR (300 MHz, CDCl, 2:1 mixture of diastereomers): δ 7.54-7.28 (m, 9H), 5.42-5.25 (br, 1H), 4.05 (q, J = 6.93 Hz, 0.66H), 3.88 (q, J = 6.93 Hz, 0.34H), 1.46 (d, J = 6.93 Hz, 1.02H), 1.07 (d, J = 6.93 Hz, 1.98H). 13 C NMR (75 MHz, CDCl3): δ 173.81, 173.67, 157.25, 156.99, 141.63, 141.44, 138.64, 138.49, 130.94, 130.81, 129.82, 129.20, HRMS (EI, positive): Exact mass calcd. C 15 H 14 N2O2[M] + requires m / z: 266.1055, found m / z: 266.1056.

[0118] Step 2: To a solution of compound A2-2 (749 mg, 2.81 mmol) in dimethylformamide (8 mL), benzyl bromide (401 μL, 3.38 mmol) and potassium carbonate (972 mg, 7.03 mmol) were added at room temperature, and the mixture was stirred at 60°C for 5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture to quench the reaction, followed by extraction with diethyl ether. The resulting organic phase was washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by recrystallization from a mixed solvent of diethyl ether:hexane = 90:10, yielding 786 mg (78%) of colorless crystals of compound A2-3.

[0119]

[0120] 1 H NMR (300 MHz, CDCl3, 1:1 mixture of diastereomers): δ 7.55-7.43 (m, 3H), 7.38-7.28 (m, 9H), 7.18-7.4 (m, 1H), 6.97-6.92 (m, 1H), 5.10 (d, J = 15.4 Hz, 1H), 4.76 (d, J = 15.3 Hz, 0.5H), 4.26 (d, J = 15.3 Hz, 0.5H), 3.91 (d, J = 15.4Hz, 0.5H), 3.81 (q, J = 6.9 Hz, 1.5H), 3.56 (J = 6.9 Hz, 1.5H), 1.39 (d, J = 6.9 Hz, 1.5H), 0.97 (d, J = 6.9 Hz, 1.5H).

[0121] Step 3: Compound A2-3 (373 mg, 1.05 mmol) was added to a solution of potassium hexamethyldisilazide (2.30 mL of a 0.5 M toluene solution, 1.15 mmol) in tetrahydrofuran (5 mL) at −78°C and stirred for 10 minutes. Triisopropylsilyl chloride (222 μL, 1.05 mmol) was added to this mixture and stirred at −78°C for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture to quench the reaction, followed by extraction with ethyl acetate. The resulting organic phase was washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography using a mixed solvent of toluene:diethyl ether = 80:20 as an eluent to obtain colorless crystals of Compound A2 in a yield of 528 mg (98%).

[0122]

[0123] 1 H NMR (300 MHz, CDCl3): δ 7.44-7.71 (m, 4H), 7.36-7.31 (m, 2H), 7.29-7.24 (m, 6H), 7.12-7.09 (m, 2H), 5.04 (d, J= 16.2 Hz, 1H), 4.61 (d, J = 16.2 Hz, 1H), 1.67 (s, 3H), 0.89-0.76 (m, 21H). Analytical HPLC [column: CHIRALPAK IB (0.46 cm x 25.0 cm), eluent: hexane / i-PrOH = 60:20, flow rate: 0.5 mL / min, detection: UV, CD 254 nm, temperature: 25 °C]: t1 = 8.65, t2= 13.3 min. Preparative HPLC [column: CHIRALPAK IB (2.0 cm x 25.0 cm), eluent: hexane / i-PrOH = 60:20, flow rate: 8.0 mL / min, detection: UV 254 nm, temperature: rt]: t1 = 10.3 min, t2 = 20.3 min.

[0124] (Synthesis Example 3) Synthesis of Compound A3 Step 1 Using L-valine methyl ester hydrochloride instead of glycine methyl ester hydrochloride (2a), a reaction was carried out in the same manner as in Step 1 of Synthesis Example 1 to obtain 3.91 g (98% yield) of a colorless oily product of Compound A3-2. The amounts of 2-phenylaniline and L-valine methyl ester hydrochloride added to the reaction solution were 13.6 mmol (2.29 g) and 14.9 mmol (2.50 g), respectively.

[0125]

[0126] 1 H NMR (300 MHz, CDCl3, 2:3 mixture of diastereomers): δ 7.49-7.15 (m, 9H), 6.06-5.98 (br, 1H), 3.85 (dd, J = 4.32, 1.47 Hz, 0.52H), 3.70 (dd, J = 3.66, 1.23 Hz, 0.48H), 2.16 (br, 0.37H), 1.86 (br, 0.63H) 0.96 (d, J = 7.02 Hz, 1.4H), 0.91 (d, J = 6.75 Hz, 1.4H), 0.75 (d, J = 6.96 Hz, 1.6H), 0.40 (d, J = 6.81Hz, 1.6H). 13 C NMR (75 MHz, CDCl3): δ 172.63, 172.38, 157.70, 157.39, 142.18, 141.72, 138.86, 138.80, 131.20, 131.04, 129.89, 129.71, 129.30, 129.15, 128.81, 128.75, 128.68, 128.46, 128.39, 127.73, 127.70, 62.90, 62.31, 30.46, 30.11, 18.82, 18.76, 16.25, 16.10. HRMS (EI, positive): Exact mass calcd. for C 18 H 18 N2O2[M] + requires m / z: 294.1368, found m / z: 294.1370.

[0127] Step 2: Compound A3-2 (508 mg, 1.72 mmol) was used instead of compound A2-2, and the reaction was carried out in the same manner as in Step 2 of Synthesis example 2, to give compound A3-3 as a colorless oil in an amount of 592 mg (yield 89%).

[0128]

[0129] 1 H NMR (300 MHz, CDCl3, 2:1 mixture of diastereomers): δ 7.61-7.18(m, 13H), 6.89-6.84 (m, 1H), 5.17 (d, J = 15.6 Hz, 0.66H), 4.99 (d, J = 15.6 Hz, 0.34H), 4.08 (d, J = 15.6 Hz, 0.34H), 3.85 (d, J = 15.6 Hz, 0.66H), 3.69 (d, J = 3.3 Hz, 0.34H), 3.47 (d, J = 3.3 Hz, 0.66H), 2.21 (ddq, J = 6.9, 6.9, 3.3Hz, 0.66H), 2.01 (ddq, J = 6.9, 6.9, 3.3 Hz, 0.34H), 1.09 (d, J = 6.9 Hz, 1.98H), 0.99 (d, J = 6.9 Hz, 1.98H), 0.85 (d, J = 6.9 Hz, 1.02H), 0.39 (d, J = 6.9 Hz, 1.02H).

[0130] Step 3: Compound A3-3 was used instead of Compound A2-3, and a reaction was carried out in the same manner as in Step 3 of Synthesis Example 2, to give 1.41 mg (84% yield) of Compound A3 as a colorless oil. The amounts of Compound A3-3 and triisopropylsilyl chloride added to the reaction solution were 1.68 mmol (647 mg) and 1.68 mmol (357 μL), respectively.

[0131]

[0132] 1H NMR (300 MHz, CDCl3): δ 7.48-7.20 (m, 12H), 7.05-7.02 (m, 2H), 4.99 (d, J = 16.0 Hz, 1H), 4.87 (d, J = 16.0 Hz, 1H), 2.74 (qq, J = 7.5Hz, 1H), 0.98 (d, J = 7.5Hz, 3H), 0.92-0.80 (m, 21H), 0.75 (d, J = 7.5Hz, 3H).

[0133] Synthesis Example 4 Synthesis of Compound A4 Step 1 Using L-phenylalanine methyl ester hydrochloride instead of glycine methyl ester hydrochloride (2a), a reaction was carried out in the same manner as in Step 1 of Synthesis Example 1 to obtain 3.41 g (99%) of a colorless oily product of Compound A4-2. The amounts of 2-phenylaniline and L-phenylalanine methyl ester hydrochloride added to the reaction solution were 10.1 mmol (1.71 g) and 11.1 mol (2.39 g), respectively.

[0134]

[0135] 1 H NMR (300 MHz, CDCl3, 1:1 mixture of diastereomers): δ 7.57-7.23 (m, 4.5H), 7.16-7.05 (m, 1H), 7.08-7.00 (m, 1H), 6.82-6.79 (m, 0.5H), 5.92-5.85 (br, 0.5H), 5.43-5.35 (br, 0.5H), 4.13 (ddd, J = 11.4, 3.6, 1.2 Hz, 0.5H) 4.07, (ddd, J = 7.8, 3.9, 0.9 Hz, 0.5H), 3.23 (dd, J = 13.5, 3.9 Hz, 0.5H), 3.01 (dd, J = 13.8, 3.6 Hz, 0.5H), 2.96 (dd, J = 13.5, 7.8 Hz, 0.5H), 1.91(dd, J = 13.8, 11.4Hz, 0.5H). 13C NMR (75 MHz, CDCl3): δ 172.18, 172.06, 156.81, 156.56, 141.66, 141.48, 138.67, 138.61, 135.88, 134.44, 130.79, 129.86, 129.80, 129.74, 129.22, 129.08, 129.01, 128.97, 128.80, 128.71, 128.68, 128.48, 128.35, 128.27, 127.81, 127.65, 127.46, 127.38, 58.63, 58.06, 38.32, 37.37.

[0136] Step 2: Compound A4-2 (193 mg, 0.566 mmol) was used instead of compound A2-2, and the reaction was carried out in the same manner as in Step 2 of Synthesis example 2, to give compound A4-3 as a colorless oil in an amount of 229 mg (yield 93%).

[0137]

[0138] 1 H NMR (300 MHz, CDCl3, 2:1 mixture of diastereomers): δ 7.47-6.56 (m, 19H), 5.15 (d, J = 15.3 Hz, 0.66H), 4.80 (d, J = 15.3 Hz, 0.34H), 3.88 (d, J = 15.3 Hz, 0.66H), 3.82 (dd, J = 4.5 Hz, 1H), 3.53 (d, J = 15.3 Hz, 0.34H), 3.08 (dd, J = 4.2, 2.1 Hz, 2H).

[0139] Step 3: Compound A4-3 was used instead of Compound A2-3, and a reaction was carried out in the same manner as in Step 3 of Synthesis Example 2, to give 32.8 mg (74%) of Compound A4 as a colorless oil. The amounts of Compound A4-3 and triisopropylsilyl chloride added to the reaction solution were 0.751 mmol (32.5 mg) and 0.0751 mmol (15.9 μL), respectively.

[0140]

[0141] 1H NMR (300 MHz, CDCl3): δ 7.55-7.19 (m, 15H), 7.05-7.02 (m, 2H), 6.72-6.68 (m, 2H), 4.85 (d, J = 16.2, 1H), 4.22 (d, J = 16.2, 1H), 3.55 (d, J = 16.8, 1H), 3.13 (d, J = 16.8, 1H), 0.84-0.77 (m, 21H).

[0142] Synthesis Example 5: Synthesis Step 1 of Compound A5 Compound A1-2 was obtained in the same manner as in Step 1 of Synthesis Example 1.

[0143] Step 2: To a solution of compound A1-2 (2.00 g, 7.93 mmol) in N,N-dimethylformamide (16 mL) was added 1-(bromomethyl)naphthalene (2.63 g, 11.9 mmol) and potassium carbonate (1.64 g, 11.9 mmol) at room temperature. After stirring at 60 °C for 5 hours, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 80:20) to obtain compound A5-3 as colorless crystals in a yield of 2.51 g (81%).

[0144]

[0145] 1 H NMR (300 MHz, CDCl3): δ 8.13-8.09 (m, 1H), 7.95-7.86 (m, 2H), 7.59-7.14 (m, 13H), 5.23 (d, J = 14.7 Hz, 1H), 4.77 (d, J = 14.7 Hz, 1H), 3.65 (d, J = 17.4 Hz, 1H), 3.39 (d, J = 17.4 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 168.66, 155.73, 141.38, 138.69, 134.01, 131.30, 130.88, 130.71, 129.81, 129.43, 129.31, 129.22, 128.93, 128.60, 128.32, 128.24, 127.56, 127.33, 127.15, 126.34, 125.22, 123.31, 48.89, 44.86.

[0146] Step 3 Compound A5 can be synthesized by carrying out a reaction in the same manner as in Step 3 of Synthesis Example 2, except that compound A5-3 is used instead of compound A2-3.

[0147]

[0148] Synthesis Example 6: Synthesis Step 1 of Compound A6 Compound A2-2 was obtained in the same manner as in Step 1 of Synthesis Example 2.

[0149] Step 2: Using 1-(bromomethyl)naphthalene instead of benzyl bromide, a reaction was carried out in the same manner as in Step 2 of Synthesis Example 2 to obtain 176 mg (90%) of a colorless oily product of Compound A6-3. The amounts of Compound A2-2 and 1-(bromomethyl)naphthalene added to the reaction solution were 0.481 mmol (128 mg) and 0.481 mmol (106 mg), respectively.

[0150]

[0151] 11H NMR (300 MHz, CDCl3, 3:2 mixture of diastereomers): δ 8.18 - 8.12 (m, 1H), 7.95 - 7.81 (m, 2H), 7.61 - 7.28 (m, 11H), 7.21 - 1.17 (m, 1H), 7.14 - 7.08 (m, 0.4H), 6.92 - 6.89 (m, 0.6H), 5.68 (d, J = 15.0 Hz, 0.4H), 5.20 (d, J = 15.0 Hz, 0.6H), 4.62 (d, J = 15.0 Hz, 0.6H), 4.43 (d, J = 15.0 Hz, 0.4H), 3.59 (q, J = 6.9 Hz, 0.6H), 3.35 (q, J = 6.9 Hz, 0.4H), 1.42 (d, J = 6.9 Hz, 1.2H), 0.95 (d, J = 6.9 Hz, 1.6H). 13 13C NMR (75 MHz, CDCl3): δ 172.47, 172.23, 155.28, 141.60, 141.23, 138.69, 138.64, 134.00, 133.97, 131.36, 131.32, 131.18, 130.79, 130.71, 129.69, 129.67, 129.34, 129.33, 129.27, 129.10, 128.91, 128.89, 128.61, 128.56, 128.48, 128.26, 128.16, 127.60, 127.39, 127.32, 127.11, 127.06, 127.03, 126.27, 125.10, 123.38, 55.15, 54.12, 43.32, 42.28, 15.21, 15.04. HRMS (EI, positive): Exact mass calcd. C 27 H 22 N2O2[M] + requires m / z: 406.1681, found m / z: 406.1679.

[0152] Step 3: Compound A6-3 was used instead of Compound A2-3, and a reaction was carried out in the same manner as in Step 3 of Synthesis Example 2 to give 284 g (49% yield) of a colorless oily product of Compound A6. The amounts of Compound A6-3 and triisopropylsilyl chloride added to the reaction solution were 1.03 mmol (420 mg) and 1.14 mmol (292 μL), respectively.

[0153]

[0154] 1 H NMR (300 MHz, CDCl3): δ 7.95-7.92 (m, 1H), 7.70-7.67 (m, 1H), 7.41-76.94 (m, 12H), 6.75-6.72 (m, 1H), 5.33 (d, J= 16.8 Hz, 1H), 4.92 (d, J = 16.8 Hz, 1H), 1.64 (s, 3H), 0.75-0.56 (m, 21H).

[0155] Compound A6-3 (500 mg, 1.23 mmol) was reacted with tert-butyldiphenylsilyl chloride (316 μL, 1.23 mmol) instead of triisopropylsilyl chloride in Step 3 to give colorless crystals of Compound A18 in a yield of 742 mg (94%).

[0156]

[0157] 1 H NMR (300 MHz, CDCl3): δ 8.07-8.04 (m, 1H), 7.88-7.85 (m, 1H), 7.76-7.73 (m, 1H), 7.54-7.17 (m, 22H), 6.77-6.75 (m, 1H), 5.41 (d, J= 16.8 Hz, 1H), 4.99 (d, J = 16.8 Hz, 1H), 0.96 (s, 3H), 0.75 (s, Hz, 9H). 13C NMR (75 MHz, CDCl3): δ 149.94, 142.09, 139.14, 135.10, 135.08, 133.51, 133.15, 132.28, 131.68, 131.47, 130.91, 130.85, 130.62, 130.20, 130.04, 129.94, 129.12, 129.07, 128.66, 128.37, 128.14, 127.75, 127.64, 127.59, 127.13, 126.25, 125.75, 125.30, 123.52, 122.88, 97.82, 41.77, 25.89, 19.08, 8.08.

[0158] Synthesis Example 7 Synthesis Step 1 of Compound A7 Compound A3-2 was obtained in the same manner as in Step 1 of Synthesis Example 3.

[0159] Step 2: Compound A3-2 was used instead of Compound A2-2, and a reaction was carried out in the same manner as in Step 2 of Synthesis Example 6 to give 612 mg (97%) of a colorless oily product of Compound A7-3. The amounts of Compound A3-2 and 1-(bromomethyl)naphthalene added to the reaction solution were 1.45 mmol (4.27 mg) and 2.18 mmol (481 mg), respectively.

[0160]

[0161] 1H NMR (300 MHz, CDCl3, 2:3 mixture of diastereomers): δ 8.04-7.99 (m, 1H), 7.83-7.73 (m, 2H), 7.50-6.98(m, 12H), 6.90-6.84 (m, 1H), 5.61 (d, J = 15.4 Hz, 0.6H), 5.52 (d, J = 15.4 Hz, 0.4H), 4.28 (d, J = 15.4 Hz, 0.4H), 4.26 (d, J = 15.4 Hz, 0.6H), 3.28 (d, J = 3.3 Hz, 0.4H), 3.20 (d, J = 3.3Hz, 0.6H), 2.22 (qqd, J = 7.1, 6.9, 3.3 Hz, 0.4H), 1.97 (qqd, J = 7.1, 6.9, 3.3 Hz, 0.6H), 0.94 (d, J = 7.1 Hz, 1.8H), 0.89 (d, J = 6.9 Hz, 1.8H), 0.75 (d, J = 7.1 Hz, 1.2H), 0.21 (d, J = 6.9 Hz, 1.2H).

[0162] Step 3: Compound A7-3 was used instead of Compound A2-3, and a reaction was carried out in the same manner as in Step 3 of Synthesis Example 2, to give 330 mg (78%) of a colorless oily product of Compound A7. The amounts of Compound A7-3 and triisopropylsilyl chloride added to the reaction solution were 0.712 mmol (309 mg) and 0.712 mmol (151 μL), respectively. 13C NMR (75 MHz, CDCl3): δ 171.03, 170.52, 156.26, 155.91, 142.21, 141.47, 138.93, 138.68, 134.02, 133.99, 131.40, 131.32, 131.10, 130.99, 130.88, 130.70, 129.69, 129.60, 129.47, 129.36, 129.32, 129.21, 129.15, 129.12, 129.01, 128.90, 128.86, 128.62, 128.49, 128.30, 128.23, 128.18, 127.62, 127.56, 127.41, 127.07, 126.71, 126.29, 126.23, 125.12, 125.06, 123.37, 123.25, 63.37, 62.26, 43.13, 41.78, 28.04, 27.91, 17.83, 17.70, 15.36, 15.15. HRMS (EI, positive): Exact mass calcd. C 29 H 26 N2O2[M] + requires m / z: 434.1994, found m / z:.434.1995.

[0163]

[0164] 1 H NMR (300 MHz, CDCl3): δ 8.02-7.98 (m, 1H), 7.89-7.86 (m, 1H), 7.75-7.72(m, 1H), 7.58-7.41 (m, 8H), 7.37-7.32 (m, 4H), 6.81-6.79 (m, 1H), 5.44 (d, J = 17.7 Hz, 1H), 5.36 (d, J = 17.7 Hz, 1H), 2.77 (qq, J = 7.29, 7.23 Hz, 1H), 0.93-0.86 (m, 24H), 0.77 (d, J = 7.23 Hz, 3H).

[0165] Compound A6-3 (100 mg, 0.230 mmol) was reacted with tert-butyldiphenylsilyl chloride (59.1 μL, 0.230 mmol) instead of triisopropylsilyl chloride in Step 3 to give colorless crystals of Compound A19 in a yield of 96.0 mg (62%).

[0166]

[0167] H NMR (300 MHz, CDCl3): δ7.91-7.81 (m, 2H), 7.73-7.70 (m, 1H), 7.58-7.21 (m, 22H), 6.65-6.63 (m, 1H), 5.33 (d, J= 17.6 Hz, 1H), 5.26 (d, J = 17.6 Hz, 1H), 2.21 (qq, J = 7.26, 7.26 Hz, 1H), 0.73 (s, 9H), 0.20 (d,J = 7.26 Hz, 3H), 0.13 (d, J = 7.26 Hz, 3H). 13 C NMR (75 MHz, CDCl3): δ 150.77, 142.09, 139.27, 135.21, 135.18, 133.44, 133.13, 131.97, 131.85, 131.00, 130.94, 130.93, 130.34, 130.25, 139.98, 139.22, 139.15, 139.12, 128.79, 128.37, 128.24, 127.83, 127.63, 127.20, 127.16, 126.06, 125.56, 125.43, 122.67, 122.19, 106.82, 43.18, 25.88, 23.54, 21.12, 20.16, 19.20.

[0168] Synthesis Example 8 Synthesis Step 1 of Compound A8 Compound A4-2 was obtained in the same manner as in Step 1 of Synthesis Example 4.

[0169] Step 2: Compound A4-2 was used instead of Compound A2-2, and a reaction was carried out in the same manner as in Step 2 of Synthesis Example 6 to give 770 mg (83% yield) of a colorless oily product of Compound A8-3. The amounts of Compound A4-2 and 1-(bromomethyl)naphthalene added to the reaction solution were 1.93 mmol (662 mg) and 2.32 mmol (509 mg), respectively.

[0170]

[0171] 1 H NMR (300 MHz, CDCl3, 23:77 mixture of diastereomers): δ 8.14-8.08 (m, 1H), 7.97-7.78 (m, 2H), 7.62-7.11 (m, 15H), 6.98-6.91 (m, 2H), 6.59 (m, 0.23H), 6.52 (m, 0.77H), 5.75 (d, J = 15.1 Hz, 0.77H), 5.44 (d, J = 15.1 Hz, 0.23H), 4.56 (d, J = 15.1 Hz, 0.77H), 4.25 (d, J = 15.1 Hz, 0.23H), 3.69 (dd, J = 3.84, 3.84 Hz, 0.77H), 3.68 (dd, J = 3.84, 3.84 Hz, 0.23H), 3.19 (dd, J = 3.84, 14.3 Hz, 0.77H), 3.10 (dd, J = 3.84, 14.3 Hz, 0.77H), 2.72 (dd, J = 3.84, 14.3 Hz, 0.23H), 2.44 (dd, J = 3.84, 14.3 Hz, 0.23H). 13C NMR (75 MHz, CDCl3): δ 171.34, 170.64, 155.91, 155.58, 141.48, 141.24, 138.83, 138.56, 136.06, 134.03, 133.88, 131.30, 130.79, 130.59, 129.78, 129.66, 129.59, 129.53, 129.31, 129.18, 129.16, 128.98, 128.92, 128.74, 128.69, 128.62, 128.41, 128.37, 128.16, 128.13, 127.75, 127.71, 127.58, 127.37, 127.20, 127.15, 127.01, 126.85, 126.29, 126.10, 125.13, 124.95, 123.27, 123.21, 60.16, 58.90, 44.09, 42.63, 38.01, 34.45. HRMS (EI, positive): Exact mass calcd. 33 H 26 N2O2[M] + requires m / z: 482.1996, found m / z: 482.1998.

[0172] Step 3 Compound A8 can be synthesized by carrying out a reaction in the same manner as in Step 3 of Synthesis Example 2, except that compound A8-3 is used instead of compound A2-3.

[0173]

[0174] Compound A6-3 (2.23 g, 4.63 mmol) was reacted with tert-butyldiphenylsilyl chloride (1.19 mL, 4.63 mmol) instead of triisopropylsilyl chloride in Step 3 to give colorless crystals of Compound A20 in an amount of 2.78 g (yield 83%).

[0175] 1H NMR (300 MHz, CDCl3): δ 7.84-7.81 (m, 1H), 7.73-7.68 (m, 2H), 7.57-7.35 (m, 14H), 7.29-7.17 (m, 6H), 7.12-7.0 (m, 5H), 6.63-6.60 (m, 1H), 6.37-6.34 (m, 2H), 5.16 (d,J = 17.4 Hz, 1H), 4.62 (d, J = 17.4 Hz, 1H), 2.89 (d, J = 17.4 Hz, 1H), 2.52 (d, J = 17.4 Hz, 1H), 0.72 (s, 9H). 13 C NMR (75 MHz, CDCl3): δ150.22, 142.33, 139.39, 137.97, 135.26, 135.11, 133.47, 133.15, 131.76, 131.61, 131.03, 130.80, 130.49, 130.36, 129.98, 129.29, 129.16, 128.60, 128.56, 128.47, 128.09, 127.82, 127.66, 127.57, 127.49, 127.23, 126.11, 126.07, 125.72, 125.38, 122.98, 122.84, 100.48, 41.80, 28.10, 25.95, 19.15.

[0176] Synthesis Example 9: Synthesis Step 1 of Compound A9 Compound A1-2 was obtained in the same manner as in Step 1 of Synthesis Example 1.

[0177] Step 2 Compound A9-3 can be synthesized by carrying out a reaction in the same manner as in Step 2 of Synthesis example 6, except that Compound A1-2 is used instead of Compound A2-2 and 2-(bromomethyl)naphthalene is used instead of 1-(bromomethyl)naphthalene.

[0178]

[0179] Step 3 Compound A9 can be synthesized by carrying out a reaction in the same manner as in Step 3 of Synthesis Example 2, except that compound A9-3 is used instead of compound A2-3.

[0180]

[0181] Synthesis Example 10: Synthesis of Compound A10 Step 1 Compound A2-2 was obtained in the same manner as in Step 1 of Synthesis Example 2.

[0182] Step 2 Compound A10-3 can be synthesized by carrying out a reaction in the same manner as in Step 2 of Synthesis Example 6, except that 2-(bromomethyl)naphthalene was used instead of 1-(bromomethyl)naphthalene.

[0183]

[0184] Step 3 Compound A10 can be synthesized by carrying out a reaction in the same manner as in Step 3 of Synthesis Example 2, except that compound A10-3 is used instead of compound A2-3.

[0185]

[0186] Synthesis Example 11: Synthesis of Compound A11 Step 1 Compound A3-2 was obtained in the same manner as in Step 1 of Synthesis Example 3.

[0187] Step 2 Compound A11-3 can be synthesized by carrying out a reaction in the same manner as in Step 2 of Synthesis example 6, except that Compound A3-2 is used instead of Compound A2-2 and 2-(bromomethyl)naphthalene is used instead of 1-(bromomethyl)naphthalene.

[0188]

[0189] Step 3 Compound A11 can be synthesized by carrying out a reaction in the same manner as in Step 3 of Synthesis Example 2, except that compound A11-3 is used instead of compound A2-3.

[0190]

[0191] Synthesis Example 12: Synthesis Step 1 of Compound A12 Compound A4-2 was obtained in the same manner as in Step 1 of Synthesis Example 4.

[0192] Step 2 Compound A12-3 can be synthesized by carrying out a reaction in the same manner as in Step 2 of Synthesis example 6, except that Compound A4-2 is used instead of Compound A2-2 and 2-(bromomethyl)naphthalene is used instead of 1-(bromomethyl)naphthalene.

[0193]

[0194] Step 3 Compound A12 can be synthesized by carrying out a reaction in the same manner as in Step 3 of Synthesis Example 2, except that compound A12-3 is used instead of compound A2-3.

[0195]

[0196] Synthesis Example 13 Synthesis of Compound A18 Compound A6-3 was used instead of Compound A2-3, and tert-butyldiphenylchlorosilane was used instead of triisopropylsilyl chloride, and a reaction was carried out in the same manner as in Step 3 of Synthesis Example 2 to obtain 1.03 g (42% yield) of colorless crystals of Compound A13. The amounts of Compound A6-3 and tert-butyldiphenylchlorosilane added to the reaction solution were 2.46 mmol (1.00 g) and 2.71 mmol (442 μL), respectively.

[0197]

[0198] 1 H NMR (300 MHz, CDCl3): δ 8.06-8.03 (m, 1H), 7.87-7.84 (m, 1H), 7.75-7.72 (m, 1H), 7.55-7.16 (m, 22H), 6.75-6.72 (m, 1H), 5.40 (d, J = 16.8 Hz, 1H), 4.97 (d, J = 16.8 Hz, 1H), 0.94 (s, 3H), 0.73 (s, 9H).

[0199] Synthesis Example 14 Synthesis of Compounds A13 to A17 and A19 to A24 Compounds A13 to A17 and A19 to A24 can be synthesized by using compounds A1-3 to A5-3 and A7-3 to A12-3, respectively, instead of compound A6-3 and performing the reaction in the same procedure as in Synthesis Example 13.

[0200]

[0201] Synthesis Example 15 Synthesis Step 1 of Compound A26 2-Isopropylaniline was used instead of 2-phenylalanine (1a) and DL-alanine methyl ester hydrochloride was used instead of glycine methyl ester hydrochloride (2a) in the same manner as in Step 1 of Synthesis Example 1, to obtain 37.3 g (93% yield) of a colorless oily product of Compound A26-2. In this case, the amounts of 2-isopropylaniline and DL-alanine methyl ester hydrochloride added to the reaction solution were 163 mmol (22.7 mL) and 179 mmol (25 g), respectively.

[0202]

[0203] 1 H NMR (300 MHz, CDCl3, 1:1 mixture of diastereomers): δ 7.45-7.21 (m, 2H), 7.34-7.26 (m, 1H), 7.14-6.71 (m, 1H), 6.38-6.23 (br, 1H), 4.33 (q, J = 6.9 Hz, 0.5H), 4.28 (q, J = 6.9 Hz, 0.5H), 2.28 (qq, J = 3.4, 3.4 Hz, 0.5H), 2.78 (qq, J = 3.4, 3.4 Hz, 0.5H), 1.57 (d, J = 6.9 Hz, 3H), 1.24-1.19 (m, 12H). 13 C NMR (75 MHz, CDCl3): δ 174.49, 174.47, 157.67, 157.57, 146.98, 146.77, 130.21, 130.18, 128.90, 128.80, 128.62, 126.98, 126.91, 126.84, 126.72, 53.38, 53.24, 28.64, 28.57, 23.69, 23.64, 23.53, 23.43, 18.17, 17.68.

[0204] Step 2: Compound A26-2 was used instead of Compound A2-2, and a reaction was carried out in the same manner as in Step 2 of Synthesis Example 2 to give 140 mg (83% yield) of a colorless oily product of Compound A26-3. The amounts of Compound A26-2 and benzyl bromide added to the reaction solution were 0.526 mmol (122 mg) and 0.570 mmol (68.7 μL), respectively.

[0205]

[0206] 1 H NMR (300 MHz, CDCl3, 1:1 mixture of diastereomers): δ 7.84-7.72 (m, 8H), 7.16-7.10 (m, 1H), 5.14 (d, J = 12.5 Hz, 0.5H), 5.08 (d, J = 12.5 Hz, 0.5H), 4.25 (d, J = 12.5 Hz, 0.5H), 4.20 (d, J = 12.5 Hz, 0.5H), 3.99 (q, J = 6.9 Hz, 0.5H), 3.97 (q, J = 6.9 Hz, 0.5H), 2.81 (qq, J = 6.9, 6.9 Hz, 0.5H), 2.79 (qq, J = 6.9, 6.9 Hz, 0.5H), 1.49 (d, J = 6.9 Hz, 1.5H), 1.48 (d, J = 6.9 Hz, 1.5H), 1.26 (d, J = 6.9 Hz, 1.5H), 1.25 (d, J = 6.9 Hz, 1.5H), 1.21 (d, J = 6.9 Hz, 1.5H), 1.20 (d, J = 6.9 Hz, 1.5H).

[0207] Step 3: Compound A26-3 was used instead of compound A2-3, and a reaction was carried out in the same manner as in Step 3 of Synthesis Example 2, to give compound A26 in an amount of 2.39 g (yield 94%). At this time, the amounts of compound A26-3 added to the reaction solution were 5.30 mmol (1.71 g) and 5.30 mmol (1.12 mL) of triisopropylsilyl chloride.

[0208]

[0209] 1H NMR (300 MHz, CDCl3): δ 7.43-7.15 (m, 9H), 4.96 (d, J= 16.1 Hz, 1H), 4.84 (d, J = 16.1 Hz, 1H), 2.89 (qq, J = 6.8, 6.8 Hz, 1H), 1.25 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 0.98-0.72 (m, 21H).

[0210] Synthesis Example 16 Synthesis Step 1 of Compound A27 Using L-valine methyl ester hydrochloride instead of DL-alanine methyl ester hydrochloride (2a), 5.93 g (60% yield) of a colorless oily product of Compound A27-2 was obtained in the same manner as in Step 1 of Synthesis Example 15. At this time, the amounts of 2-isopropylaniline and L-valine methyl ester hydrochloride added to the reaction solution were 38.4 mmol (5.35 mL) and 42.7 mmol (7.17 g), respectively.

[0211]

[0212] 1 H NMR (300 MHz, CDCl3, 1:1 mixture of diastereomers): δ 7.44-7.42 (m, 2H), 7.31-7.25 (m, 1H), 7.12-7.08 (m, 0.5H), 7.04-7.01 (m, 0.5H), 6.07-5.98 (br, 1H), 2.84 (qq, J= 6.9, 6.9 Hz, 0.5H), 2.83 (qq, J = 6.9, 6.9 Hz, 0.5H), 2.40-2.29 (m, 1H), 1.23 (d, J = 6.9 Hz, 1.5H), 1.22 (d, J = 6.9 Hz, 1.5H), 1.21 (d, J = 6.9 Hz, 1.5H), 1.19 (d, J = 6.9 Hz, 1.5H), 1.11 (d, J = 6.9 Hz, 1.5H), 1.10 (d, J = 6.9 Hz, 1.5H), 1.05 (d, J = 6.9 Hz, 3H).

[0213] Step 2 Compound A27-3 can be synthesized by carrying out a reaction in the same manner as in Step 2 of Synthesis Example 2, except that compound A27-2 is used instead of compound A2-2.

[0214]

[0215] Step 3 Compound A27 can be synthesized by carrying out a reaction in the same manner as in Step 3 of Synthesis Example 2, except that compound A27-3 is used instead of compound A2-3.

[0216]

[0217] Synthesis Example 17 Synthesis of Compound A28 Step 1 Using L-phenylalanine methyl ester hydrochloride instead of DL-alanine methyl ester hydrochloride (2a), 6.12 g (80% yield) of a colorless oily product of Compound A28-2 was obtained in the same manner as in Step 1 of Synthesis Example 15. At this time, the amounts of 2-isopropylaniline and L-phenylalanine methyl ester hydrochloride added to the reaction solution were 27.3 mmol (3.80 mL) and 30.3 mmol (6.54 g), respectively.

[0218]

[0219] 1H NMR (300 MHz, CDCl3, 3:7 mixture of diastereomers): δ 7.43-7.16 (m, 8H), 7.08-7.05 (m, 0.7H), 6.92-6.74 (br, 0.7H), 6.52-6.47 (br, 0.3H), 6.50-6.42 (m, 0.3H), 4.48 (dd, J = 5.7, 4.2Hz, 0.3H), 4.47 (dd, J = 5.7, 4.2Hz, 0.7H), 3.28 (dd, J = 13.8, 4.2 Hz, 1H), 3.13 (dd, J = 13.8, 5.7 Hz, 1H), 2.78 (qq, J = 6.9, 6.9Hz, 0.3H), 2.01 (qq, J = 6.9, 6.9 Hz, 0.7H), 1.20 (d, J = 6.9Hz, 0.9H), 1.18 (d, J = 6.9 Hz, 0.9H), 1.05 (d, J = 6.9 Hz, 2.1H), 0.98 (d, J = 6.9 Hz, 2.1H).

[0220] Step 2: Compound A28-2 was used instead of Compound A2-2, and a reaction was carried out in the same manner as in Step 2 of Synthesis Example 2 to give Compound A28-3 as a colorless oil in an amount of 97.0 mg (yield 36%). The amounts of Compound A28-2 and benzyl bromide added to the reaction solution were 0.682 mmol (200 mg) and 0.818 mmol (97.4 μL), respectively.

[0221]

[0222] 1H NMR (300 MHz, CDCl3): δ 7.41-7.20 (m, 13H), 7.04-7.00 (m, 1H), 5.35 (d, J = 15.0 Hz, 1H), 4.21 (dd, J = 4.2, 4.2 Hz, 1H), 4.16 (d, J = 15.0 Hz, 1H), 3.29 (dd, J = 14.7, 4.2 Hz, 1H), 3.21 (dd, J = 14.7, 4.2 Hz, 1H), 1.78 (qq, J = 6.9, 6.9 Hz, 1H), 0.95 (d, J = 6.9 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H).

[0223] Step 3: Using compound A28-3 instead of compound A2-3, a reaction was carried out in the same manner as in Step 3 of Synthesis Example 2, to obtain 35.2 mg (27%) of a colorless oily product of compound 28. In this case, the amounts of compound A28-3 added to the reaction solution were 0.243 mmol (97.0 mg) and triisopropylsilyl chloride added to the reaction solution were 0.243 mmol (51.6 μL).

[0224]

[0225] 1 H NMR (300 MHz, CDCl3): δ 7.51-7.21 (m, 10H), 7.13-7.08 (m, 4H), 5.76 (d, J = 16.7 Hz, 1H), 4.41 (d, J = 16.7 Hz, 1H), 3.71 (d, J = 17.1 Hz, 1H), 3.40 (d, J = 17.1 Hz, 1H), 2.60 (qq, J =6.6, 6.6 Hz, 1H), 1.29 (d, J =6.6 Hz, 3H), 1.19 (d, J =6.6 Hz, 3H), 0.90-0.75 (m, 21H).

[0226] Synthesis Example 18: Step 1 of synthesis of compound A25 Compound A25-2 can be synthesized in the same manner as in Step 1 of Synthesis Example 15, except that glycine methyl ester hydrochloride is used instead of DL-alanine methyl ester hydrochloride (2a).

[0227]

[0228] Step 2 Compound A25-3 can be synthesized by carrying out a reaction in the same manner as in Step 2 of Synthesis Example 2, except that compound A25-2 is used instead of compound A2-2.

[0229]

[0230] Step 3 Compound A25 can be synthesized by carrying out a reaction in the same manner as in Step 3 of Synthesis Example 2, except that compound A25-3 is used instead of compound A2-3.

[0231]

[0232] (Synthesis Example 19) Synthesis Steps 1 and 2 of Compounds A29 to A36 Compounds A29-3 to A36-3 can be synthesized by using compounds A25-2 to A28-2 synthesized in Step 1 of each of Synthesis Examples 15 to 18 and carrying out a reaction in the same procedure as in Step 2 of each of Synthesis Examples 6 or 9.

[0233]

[0234] Step 3 Compounds A29 to A36 can be synthesized by carrying out the reaction in the same manner as in the step of Synthesis Example 2 using compounds A29-3 to A36-3.

[0235]

[0236] Synthesis Example 20 Synthesis of Compounds A37 to A48 Compounds A37 to A48 can be synthesized by carrying out a reaction in the same procedure as in Synthesis Example 13 using compounds A25-3 to A36-3 synthesized in Synthesis Examples 15 to 19.

[0237]

[0238] Synthesis Example B In the following synthesis example, a compound represented by general formula (B) was synthesized using the reaction shown in the following reaction scheme. In the reaction scheme, "X" in the compound number is a variable, and "X" in the final product, compound BX, corresponds to the compound number shown in Table 2.

[0239]

[0240] Synthesis Example 21: Synthesis of Compound B1, Step 1: To a solution of 2-phenylaniline (1b) (339 mg, 2.00 mmol) in dichloromethane (12 mL), 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (WSC.HCl) (466 mg, 2.41 mmol), N,N-diisopropylethylamine (919 μL, 4.82 mmol), N-Boc-β-alanine (2b) (456 mg, 2.40 mmol), and 4-dimethylaminopyridine (2.50 mg, 0.0205 mmol) were added, and the mixture was stirred at room temperature for 21 hours. The reaction was quenched by adding a saturated aqueous solution of ammonium chloride to the reaction mixture, followed by extraction with dichloromethane. The resulting organic phase was washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by recrystallization to obtain 423 mg (yield 62%) of colorless crystals of Compound B1-1.

[0241]

[0242] Step 2: Compound B1-1 (100 mg, 0.294 mmol) was added to trifluoroacetic acid (50 μL) and stirred at room temperature for 2 hours. This mixture was concentrated under reduced pressure to obtain crude compound B1-2. To a solution of this crude product in dimethylacetamide (3 mL), imidazole (100 mg, 1.47 mmol) and carbonyldiimidazole (52.4 mg, 0.323 mmol) were added at room temperature, and the mixture was stirred at 100°C for 20 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture to quench the reaction, followed by extraction with dichloromethane. The resulting organic phase was washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography using a mixed solvent of chloroform:methanol = 10:1 as an eluent to obtain compound B1-3 as a colorless oil in a yield of 44.0 mg (56%).

[0243]

[0244] 1H NMR (300 MHz, CDCl): δ 7.49-7.23 (m, 9H), 5.49-5.35 (br, 1H), 3.38 (m, 1H), 3.14-3.05 (m, 1H), 2.76-2.66 (m, 1H), 2.52-2.43 (m, 1H). Step 3: Compound B1 can be synthesized by using Compound B1-3 instead of Compound A2-2 and carrying out the reaction in the same manner as in Steps 2 and 3 of Synthesis Example 2.

[0245] Synthesis Example 22: Step 1 of Synthesis of Compound B25 Compound B25-1 can be synthesized by carrying out a reaction in the same manner as in Step 1 of Synthesis Example 21, except that 2-isopropylaniline is used instead of 2-phenylalanine (1b).

[0246]

[0247] Step 2 Compound 25-3 can be synthesized by carrying out a reaction in the same manner as in Step 2 of Synthesis Example 21, except that compound B25-1 is used instead of compound B1-1.

[0248] Step 3 Compound B25 can be synthesized by carrying out the reaction in the same manner as in Steps 2 and 3 of Synthesis Example 2, except that Compound B25-3 is used instead of Compound A2-2.

[0249] Synthesis Example C In the following synthesis example, a compound represented by general formula (C) was synthesized using the reaction shown in the following reaction scheme. In the reaction scheme, "X" in the compound number is a variable, and "X" in the final product, compound CX, corresponds to the compound number shown in Table 3.

[0250]

[0251] Synthesis Example 23 Synthesis of Compound C1 Pyridine (2.40 mL, 29.5 mmol) and triphosgene (649 mg, 2.19 mmol) were added to a solution of 2-phenylaniline (1c) (1.00 g, 74.0 mmol) in dichloromethane (30 mL) at −78° C., followed by stirring at room temperature for 1 hour. Methyl glycolate (2c) (671 μL, 8.86 mmol) was added to this mixture, followed by stirring at room temperature for 12 hours. A saturated aqueous solution of sodium bicarbonate was added to this reaction solution to quench the reaction, followed by extraction with dichloromethane. The resulting organic phase was washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product of Compound C1-2. 38% aqueous hydrochloric acid solution (30 mL) was added to this crude product in methanol (30 mL) at room temperature, followed by stirring at 60° C. for 12 hours, followed by concentration under reduced pressure. The obtained concentrated residue was purified by silica gel chromatography using a mixed solvent of hexane:ethyl acetate=10:1 as an eluent to obtain 532 mg (36% yield) of compound C1-2 as a colorless oil.

[0252]

[0253] 1 H NMR (300 MHz, CDCl): δ 7.60-7.23 (m, 9H), 4.72 (d, J = 16.2 Hz, 1H), 4.49 (d, J = 16.2 Hz, 1H). Step 2: Compound C1 can be synthesized by using Compound C1-2 instead of Compound A2-3 and carrying out the reaction in the same manner as in Step 3 of Synthesis Example 2.

[0254] (Synthesis Example 24) Step 1 A reaction was carried out in the same manner as in Step 1 of Synthesis Example 23, except that 2-isopropylaniline (10.0 g, 74.0 mmol) was used instead of 2-phenylaniline (1c), and methyl lactate (10.6 mL, 111 mol) was used instead of methyl glycolate (2c), to obtain 9.91 g (57% yield) of compound C10-2 as a colorless oil.

[0255]

[0256] 1H NMR (300 MHz, CDCl3, 1:1 mixture of diastereomers): δ 7.28-7.26 (m, 2H), 7.14-7.10 (m, 1H), 6.94-6.88 (m, 1H), 4.90 (q, J = 7.0 Hz, 0.5H), 4.87 (q, J = 7.0 Hz, 0.5H), 2.58 (qq, J = 6.9 Hz, 6.8 Hz, 0.5H), 2.54 (qq, J = 6.9 Hz, 6.8 Hz, 0.5H), 1.54 (d, J = 7.0 Hz, 3H), 1.043 (d, J = 6.8 Hz, 1.5H), 1.338 (d, J = 6.9 Hz, 1.5H), 1.019 (d, J = 6.2 Hz, 1.5H), 1.016 (d, J = 7.3 Hz, 1.5H).

[0257] Step 2: To a solution of hexamethyldisilazane (896 mL, 0.539 mmol of a 0.6 M tetrahydrofuran solution) in tetrahydrofuran (5 mL), compound C10-2 (114 mg, 0.489 mmol) was added at −78°C and stirred for 10 minutes. Triisopropylsilyl chloride (114 μL, 0.538 mmol) was added to the mixture, and the mixture was stirred at −78°C for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture to quench the reaction, followed by extraction with ethyl acetate. The resulting organic phase was washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography using a mixed solvent of hexane:ethyl acetate = 95:5 as an eluent to obtain compound C10 as a colorless oil in a yield of 528 mg (98%).

[0258]

[0259] 1H NMR (300 MHz, CDCl3): δ 7.40-7.39 (m, 2H), 7.19-7.18 (m, 1H), 7.16-7.15 (m, 1H), 2.93 (qq, J = 6.9, 6.9 Hz, 1H), 2.14 (s, 3H), 1.23 (d, J = 6.9 Hz, 3H), 1.20 (d, J = 6.9 Hz, 3H), 0.92-0.52 (m, 21H).

[0260] Synthesis Example D In the following synthesis example, a compound represented by general formula (D) was synthesized using the reaction shown in the following reaction scheme. In the reaction scheme, "X" in the compound number is a variable, and "X" in the final product, compound DX, corresponds to the compound number shown in Table 4.

[0261]

[0262] Synthesis Example 25: Synthesis of Compound D1 Step 1: 2-phenylaniline (1d) (300 mg, 1.77 mmol) was added to a solution of β-propiolactone (2d) (122 μL, 13.3 mmol) in toluene (5 mL) at room temperature over 8 hours, and the mixture was stirred under reflux for 24 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture to terminate the reaction, and the mixture was extracted with ethyl acetate. The resulting organic phase was washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography using a mixed solvent of hexane:ethyl acetate = 70:30 as an eluent to obtain 312 mg (75%) of a colorless oily product of Compound D1-1.

[0263]

[0264] 1 H NMR (300 MHz, CDCl3): δ 8.22-8.19 (m, 1H), 7.75 (s, 1H), 7.49-7.33 (m, 6H), 7.24-7.16 (m, 2H), 3.80 (t, J = 5.43 Hz, 2H), 2.42 (t, J = 5.43 Hz, 2H).

[0265] Step 2: To a solution of compound D1-1 (79.1 mg, 0.327 mmol) in dichloromethane (3 mL), triphosgene (39.2 mg, 0.131 mmol) and pyridine (52.9 μL, 0.660 mmol) were added over 8 hours at 0°C, and the mixture was stirred under reflux for 24 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture to quench the reaction, followed by extraction with dichloromethane. The resulting organic phase was washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography using a mixed solvent of chloroform:methanol = 10:1 as an eluent to obtain colorless crystals of compound D1-2 in a yield of 64.7 mg (73%).

[0266]

[0267] 1 H NMR (300 MHz, CDCl3): δ 7.54-7.48 (m, 2H), 7.44-7.35 (m, 4H), 7.28-7.24 (m, 3H), 4.31 (ddd, J = 11.3, 5.41, 5.41, Hz 1H), 3.43 (ddd, J= 11.3, 9.99, 4.08, Hz 1H), 2.83 (ddd, J = 17.1, 9.99, 5.41, Hz 1H), 2.56 (ddd, J = 17.1, 5.41, 4.08, Hz 1H).

[0268] Step 3 Compound D1 can be synthesized by carrying out a reaction in the same manner as in Step 2 of Synthesis Example 24, except that Compound D1-2 is used instead of Compound C10-2.

[0269] Synthesis Example E In the following synthesis example, a compound represented by general formula (E) was synthesized using the reaction shown in the following reaction scheme. In the reaction scheme, "X" in the compound number is a variable, and "X" in the final product, compound AX, corresponds to the compound number shown in Table 5.

[0270] Synthesis Example 26 Synthesis of Compound E1 Compounds E1-1 to E-3 and E1 can be synthesized by using 2-phenylalanine instead of 2-isopropylaniline (1e) and carrying out the reaction in the same manner as in Steps 1 to 3 of Synthesis Example 27 below.

[0271]

[0272] Synthesis Example 27: Synthesis of Compound E25, Step 1: N,N'-diisopropylcarbodiimide (1.38 g, 8.87 mmol), N-Boc-glycine (2e) (1.30 g, 8.87 mmol), and 4-dimethylaminopyridine (90.2 mg, 0.740 mmol) were added to a solution of 2-isopropylaniline (1e) (1.03 mg, 7.39 mmol) in dichloromethane (10 mL), and the mixture was stirred at 40°C for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture to quench the reaction, followed by extraction with dichloromethane. The resulting organic phase was washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography using a mixed solvent of hexane:ethyl acetate = 80:20 as an eluent to obtain 1.99 g (92%) of colorless crystals of Compound E25-1.

[0273]

[0274] 1 H NMR (300 MHz, CDCl3): δ 7.76 (d, J = 6.2 Hz, 1H), 7.31-7.13 (m, 4H), 3.95 (d, J = 6.2 Hz, 1H), 3.02 (sep, J = 6.8 Hz, 1H), 1.49 (s, 9H), 1.24 (d, J = 6.8 Hz, 6H).

[0275] Step 2: Compound E25-1 (1.79 g, 6.14 mmol) was added to trifluoroacetic acid (50 μL) and stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure and precipitated with diethyl ether to give colorless crystals of compound E25-2 in a yield of 1.67 g (94%).

[0276]

[0277] 1 H NMR (300 MHz, D2O): δ 7.31-7.28 (m, 1H), 7.24-7.19 (m, 1H), 7.13-7.03 (m, 2H), 3.91 (s, 2H), 2.87 (sep, J = 6.9 Hz, 1H), 0.98 (d, J = 6.9Hz, 6H).

[0278] Step 3: To a solution of compound E25-2 (100 mg, 0.346 mmol) in acetone (5 mL), potassium carbonate (105 mg, 0.760 mmol) was added and stirred at room temperature for 5 hours. Benzyl bromide (45.2 μL, 0.380 mmol) was then added and stirred for 14 hours. Water was added to the reaction mixture to quench the reaction, followed by extraction with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography using a mixed solvent of hexane:ethyl acetate = 80:20 as an eluent to obtain compound E25-3 as a colorless oil in a yield of 41.7 mg (38%).

[0279]

[0280] 1 H NMR (300 MHz, CDCl3): δ 7.39-7.09 (m,8H), 7.02-6.97 (m, 1H), 3.77 (d, J = 12.9 Hz, 1H), 3.58 (d, J = 12.9 Hz, 1H), 3.31 (d, J = 14.5 Hz, 1H), 3.16 (d, J = 14.5 Hz, 1H), 2.95 (qq, J = 6.81, 6.81 Hz, 1H), 1.39 (s, 3H), 1.18 (s, 3H), 1.15 (d, J = 6.81 Hz, 3H), 1.11 (d, J = 6.81 Hz, 3H).

[0281] Step 3 Compound E25 can be synthesized by carrying out a reaction in the same manner as in Step 3 of Synthesis Example 2, except that compound E25-3 is used instead of compound A2-3.

[0282]

[0283] Synthesis Example F In the following synthesis example, a compound represented by general formula (F) was synthesized. The numbers of the compounds that were the final products correspond to the compound numbers shown in Table 6.

[0284] (Synthesis Example 28) Synthesis of Compound F1

[0285] Cesium carbonate (6.52 g, 20.0 mmol) was added to a solution of compound G1 (1.06 g, 4.00 mmol) synthesized in Synthesis Example 29 (described below) in DMA (40 mL) at room temperature. After stirring at 40°C for 50 minutes, allyloxycarbonyl chloride (4.23 mL, 40.0 mmol) was added to the mixture, and the mixture was stirred at 40°C for 5 minutes. The mixture was diluted with ether, quenched with saturated aqueous ammonium chloride solution, and extracted with ether. The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 14:1 to 7:1) to obtain compound F1 as a colorless syrup in a yield of 1.21 g (70%).

[0286] 1 H NMR (300 MHz, CDCl3): δ 7.63 (ddd, J = 7.8, 1.5, 0.9 Hz, 1H), 7.21 (ddd, J = 7.8, 7.8, 1.5 Hz, 1H), 7.14 (ddd, J = 7.8, 7.8, 1.5 Hz, 1H), 6.81 (ddd, J = 7.8, 1.5, 0.9 Hz, 1H), 6.48 (s, 1H), 5.78 (ddt, J= 17.1, 10.5, 6.0 Hz, 1H), 5.24 (ddt, J = 17.1, 1.2, 1.2 Hz, 1H), 5.20 (ddt, J = 10.5, 1.2, 1.2 Hz, 1H), 4.58 (ddd, J = 6.0, 1.2, 1.2 Hz, 2H). 13C NMR (75MHz, CDCl3): δ 151.0, 142.0, 133.0, 130.3, 124.0, 123.2, 122.1, 121.1, 119.8, 109.2, 89.4, 69.9. －1 ): 2359, 1780, 1454, 1220, 943, 773, 744. HRMS (EI, positive): Exact mass calcd. for C 24 H 20 N2O6[M] + requires m / z: 432.1321, found m / z: 432.1322.

[0287] (Synthesis Example 29) Synthesis of Compound F2

[0288] Compound G1 (75 mg, 0.284 mmol) synthesized in Synthesis Example 29 was added to a solution of sodium hydride (55% in mineral oil, 27.3 mg, 0.625 mmol) in tetrahydrofuran (1 mL) at 0° C. After stirring at room temperature for 30 minutes, triisopropylsilyl chloride (123 μL, 0.625 mmol) was added to the mixture at 0° C. and stirred at that temperature for 30 minutes. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 100:0 to 99:1) to obtain compound F2 as a colorless oil in a yield of 154 mg (99%).

[0289] 1 H NMR (300 MHz, CDCl3): δ 7.43 (ddd, J = 7.5, 0.6, 0.6 Hz, 2H), 7.09 (ddd, J = 7.5, 7.5, 0.6 Hz, 2H), 7.00 (ddd, J = 7.5, 7.5, 0.6 Hz, 2H), 6.88 (ddd, J = 7.5, 0.6, 0.6 Hz, 2H), 5.07 (s, 2H), 1.23-1013 (m, 6H), 0.96-0.88 (m, 36H). 13C NMR (75 MHz, CDCl3): δ 148.54, 132.58, 125.56, 120.84, 120.17, 118.88, 108.35, 80.10, 17.57, 12.14.

[0290] Synthesis Example G In the following synthesis example, a compound represented by general formula (G) was synthesized. The numbers of the compounds that were the final products correspond to the compound numbers shown in Table 7.

[0291] (Synthesis Example 30) Synthesis of Compound G1 in Two Steps

[0292] To a solution of 2-bromophenylacetic acid (1 g) (15.5 g, 72.0 mmol) in methylene chloride (60 mL) was added CDI (11.7 g, 72.0 mmol) at 0°C. After stirring at room temperature for 3 hours, hydrazine monohydrate (1.46 mL, 30.0 mmol) was added to the mixture, which was then stirred at room temperature for 18 hours. The mixture was diluted with methylene chloride and filtered through filter paper using methylene chloride to obtain the crude product (2 g). To a solution of the crude product (2 g) in toluene (230 mL), 4A molecular sieves (23.0 g), potassium carbonate (12.8 g, 92.0 mmol), copper oxide (1.65 g, 11.5 mmol), and N,N'-dimethylethylenediamine (DMEDA) (2.47 mL, 23.0 mmol) were added at room temperature. After stirring at reflux for 13 hours, the mixture was diluted with ethyl acetate and filtered through a Celite pad using ethyl acetate as the eluent. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform / ethyl acetate=19:1 to 9:1) to obtain 4.49 g of Compound G1 as colorless crystals (57% yield over two steps).

[0293] 1H NMR (300 MHz, CDCl3): δ 7.34 (ddd, J = 7.8, 1.2, 0.6Hz, 1H), 7.27-7.21 (m, 1H), 7.13 (ddd, J = 7.5, 7.5, 1.2 Hz, 1H), 6.71 (ddd, J= 7.5, 1.2, 0.6 Hz, 1H), 3.83 (d, J = 22.2 Hz, 1H), 3.74 (d, J = 22.2 Hz, 1H). 13 C NMR (75 MHz, CDCl3): δ 171.6, 141.5, 128.2, 125.2, 123.8, 122.0, 118.0, 34.2. IR (ATR, cm -1 ): 2359, 1758, 1730, 1236, 951, 755, 743. HRMS (EI, positive): Exact mass calcd. for C 16 H 12 N2O2[M] + requires m / z: 264.0899, found m / z: 264.0899. Analytical HPLC [column: CHIRALPAK IH (250 mm × 4.6 mm, 5 μm), eluent: n-hexane / IPA = 3:7, flow rate: 0.5 mL / min, detection: UV, CD (254 nm), temp: 25 °C]: t1= 7.83 min, t2 = 13.3 min.

[0294] (Synthesis Example 31) Synthesis of Compound G1 by Photoreaction

[0295] Oxindole (13.3 mg, 0.100 mmol) and [NMeBu ３ ]OP(O)(OBu) ２ A solution of [Ir(dFCF ３ ppy) ２ -(5,5'-dCF ３ bpy)]PF ６(2.30 mg, 0.00200 mmol) was added at room temperature. The mixture was stirred under blue light irradiation (448 nm) at −5° C. for 48 hours. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by PTLC (n-hexane / ethyl acetate=1:1) to obtain compound G1 as colorless crystals in a yield of 3.1 mg (23%).

[0296] (Synthesis Example 32) Synthesis of Compound G2

[0297] To a solution of compound G1 (1.11 g, 4.20 mmol) in toluene (4.2 mL) was added Berlot reagent (4.40 g, 8.40 mmol) at room temperature. After stirring at 70°C for 12 hours, the mixture was cooled to room temperature and filtered through a Celite pad using ethyl acetate as an eluent. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 10:1) to obtain compound G2 as yellow crystals in a yield of 1.18 g (95%).

[0298] 1 H NMR (300 MHz, CDCl3): δ 7.43-7.7.38 (m, 1H), 7.29-7.20 (m, 2H), 7.63-6.69 (m, 1H), 4.39 (d, J = 22.8 Hz, 1H), 4.29 (d, J = 22.8 Hz, 1H). 13 C NMR (75 MHz, CDCl3): δ 198.21, 142.45, 128.32, 126.53, 125.25, 125.16, 109.17, 47.57.

[0299] Synthesis Example H In the following synthesis example, a compound represented by general formula (H) was synthesized using the reaction shown in the following reaction scheme. The numbers of the compounds that were final products correspond to the compound numbers shown in Table 8.

[0300]

[0301] (Synthesis Example 33) Synthesis of Compound H1 Step 1 To a solution of 1,3-cyclohexanedione (1h) (1.05 g, 9.35 mmol) in acetonitrile (10 mL), triethylamine (2.80 mL, 20.2 mmol) and carbon disulfide (750 μL, 12.4 mmol) were added at 0° C. After stirring at room temperature for 2 hours, diiodomethane (1.61 mL, 20.0 mmol) was added to the reaction mixture, and the mixture was stirred at the same temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the resulting yellow solid was washed with ether to obtain Compound H1 as yellow crystals in a yield of 1.03 g (75%).

[0302] 1 H NMR (300 MHz, CDCl3): δ 4.37 (s, 2H), 2.50 (t, J= 6.6 Hz, 4H), 1.97 (quint, J = 6.6 Hz, 2H). HRMS (EI, positive): Exact mass calcd. for C8H8O2S2 [M] + requires m / z: 199.9966, found m / z: 199.9969.

[0303] Step 2: To a solution of compound 2h (300 mg, 1.50 mmol) in acetonitrile (5 mL), morpholine (326 μL, 3.74 mmol) was added at room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, and the resulting yellow solid was washed with ether to give crude compound 3h as yellow crystals. To a solution of compound 3h in methylene chloride (5 mL), Hunig's base (765 μL, 4.50 mmol) and benzoyl chloride (254 μL, 2.25 mmol) were added at 0°C. After stirring at room temperature for 14 hours, the reaction was quenched with saturated aqueous ammonium chloride and extracted with methylene chloride. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 5:5) to give compound 4h as colorless crystals in a yield of 441 mg (85% yield over two steps).

[0304] 1H NMR (300 MHz, CDCl3): δ 8.06 (dd, J = 8.4, 1.2 Hz, 2H), 7.65 (tt, J = 7.5, 1.2 Hz, 1H), 7.50 (dd, J = 8.4, 7.5 Hz, 2H), 4.30 (ddd, J = 13.8, 6.0, 3.3 Hz, 1H), 4.14 (ddd, J = 13.5, 7.2, 3.3 Hz, 1H), 3.83-3.46 (m, 6H), 4.30 (ddd, J= 13.8, 6.0, 3.3 Hz, 1H), 4.14 (ddd, J = 13.8, 7.2, 3.3 Hz, 1H), 2.87 (ddd, J = 18.6, 6.9, 5.4 Hz, 1H), 2.72 (ddd, J = 18.6, 7.2, 5.1 Hz, 1H), 2.62 (ddd, J = 16.9, .8.2, 5.1 Hz, 1H), 2.53 (ddd, J = 16.8, 7.8, 5.1 Hz, 1H), 2.29-2.09 (m, 2H). 13 C NMR (75 MHz, CDCl3): δ 194.89, 189.57, 163.73, 163.45, 134.53, 131.74, 130.49, 128.95, 128.10, 66.51, 66.35, 51.91, 48.17, 37.08, 28.91, 20.56. HRMS (EI, positive): Exact mass calcd. for C 18 H 19 NO4 [M] + requires m / z: 345.1035, found m / z: 345.1036.

[0305] Step 3: To a solution of compound 4h (1.00 g, 2.90 mmol) in toluene (30 mL) was added methylmagnesium iodide (1.0 M in ether, 14.0 mL, 14.0 mmol) at 0 °C. After stirring at room temperature for 4 hours, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 1:1) to obtain compound H1 as colorless crystals in a yield of 524 mg (75%).

[0306] 1 H NMR (300 MHz, CDCl3): δ 4.52 (ddd, J = 13.5, 6.0, 3.3 Hz, 1H), 4.21 (ddd, J = 13.5, 6.9, 3.6 Hz, 1H), 3.86 (ddd, J = 12.0, 6.9, 3.3 Hz, 1H), 3.77 (ddd, J = 12.0, 6.0, 3.6 Hz, 1H), 3.71 (ddd, J = 12.0, 6.3, 3.3 Hz, 1H), 3.60 (ddd, J = 11.7, 5.4, 3.9 Hz, 1H), 3.55-3.42 (m, 2H), 2.57-2.34 (m, 4H), 2.13-1.93 (m, 2H), 1.95 (s, 3H). 13 C NMR (75 MHz, CDCl3): δ 195.06, 194.84, 155.29, 139.11, 66.69, 66.47, 51.43, 48.40, 37.42, 31.83, 22.12, 21.80. HRMS (EI, positive): Exact mass calcd. for C 12 H 17 NO2 [M] + requires m / z: 239.0980, found m / z: 239.0982.

[0307] Synthesis Example 34 Synthesis of Compound H2 In a manner similar to that in Synthesis Example 32, Compound 4h (200 mg, 0.580 mmol) was reacted with phenylmagnesium bromide (1.00 M in tetrahydrofuran, 2.78 mL, 2.78 mmol) to obtain Compound H2 as a white solid in a yield of 160 mg (91%).

[0308] 1 H NMR (300 MHz, CDCl3): δ 7.51-7.48 (m, 2H), 7.42-7.35 (m, 3H), 4.23 (ddd, J = 13.5, 5.7, 3.3 Hz, 1H), 4.14 (ddd, J = 13.5, 6.9, 3.6 Hz, 1H), 3.75 (ddd, J = 12.0, 6.0, 3.6 Hz, 1H), 3.54 (ddd, J = 11.4, 6.0, 3.3 Hz, 1H), 3.45 (ddd, J = 13.2, 6.9, 3.3 Hz, 1H), 3.40 (ddd, J = 11.7, 6.9, 3.3Hz, 1H), 3.36 (ddd, J = 13.8, 6.6, 3.3 Hz, 1H), 2.92 (ddd, J = 11.4, 6.9, 3.3 Hz, 1H), 2.881-2.66 (m, 3H), 2.52 (ddd, J= 16.8, 9.0, 5.1 Hz, 1H),2.32-2.11 (m, 2H). HRMS (EI, positive): Exact mass calcd. for C 17 H 19 NO2 [M] + requires m / z: 301.1137, found m / z: 345.1135.

[0309] Synthesis Example 35 Synthesis of Compound H3 In the same manner as in Synthesis Example 32, Compound 4h (200 mg, 0.580 mmol) was reacted with vinylmagnesium bromide (1.00 M in tetrahydrofuran, 2.78 mL, 2.78 mmol) to obtain Compound H3 as a white solid in a yield of 111 mg (76%).

[0310] 1H NMR (300 MHz, CDCl3): δ 6.72 (dd, J = 17.4, 10.8 Hz, 1H), 5.77 (dd, J = 17.4, 0.6 Hz, 1H), 5.56 (dd, J = 10.8, 0.6 Hz, 1H), 4.50 (ddd, J = 13.5, 6.6, 3.6 Hz, 1H), 4.32 (ddd, J = 13.5, 6.6, 3.6 Hz, 1H), 3.90 (ddd, J = 12.0, 6.6, 3.3 Hz, 1H), 3.80 (ddd, J = 12.0, 6.3, 3.6 Hz, 1H), 3.72 (ddd, J = 12.0, 4.8, 4.8 Hz, 1H), 3.59 (ddd, J = 11.7, 4.8, 4.8 Hz, 1H), 3.50-3.47 (m, 2H), 2.68-2.54 (m, 2H), 2.46 (ddd, J = 16.8, 8.4, 4.8 Hz, 1H), 2.23-1.95 (m, 2H). HRMS (EI, positive): Exact mass calcd. for C 13 H 17 NO2 [M] + requires m / z: 251.0980, found m / z: 251.0978.

[0311] (Synthesis Example 36) Synthesis of Compound H4 In a similar manner to Synthesis Example 32, Compound 4h (49.9 mg, 0.145 mmol) was reacted with allylmagnesium bromide (2.00 M in tetrahydrofuran, 0.350 mL, 0.700 mmol) to obtain Compound H4 as a white solid in a yield of 16.8 mg (44%).

[0312] 1H NMR (300 MHz, CDCl3): δ 5.84-5.71 (m, 1H), 5.16-5.15 (m, 1H), 5.12 (ddd, J = 5.7, 3.0, 1.5 Hz, 1H), 4.59 (ddd, J = 13.5, 6.0, 3.3 Hz, 1H), 4.162 (ddd, J = 13.5, 6.9, 3.6 Hz, 1H), 3.88 (ddd, J = 11.7, 6.9, 3.3 Hz, 1H), 3.79 (ddd, J = 12.0, 6.0, 3.9 Hz, 1H), 3.72 (ddd, J = 11.4, 6.6, 3.6 Hz, 1H), 3.62 (ddd, J = 11.7, 5.1, 3.9 Hz, 1H), 3.54-3.41 (m, 2H), 3.18 (dddd, J= 14.4, 7.8, 1.2. 1.2 Hz, 1H), 3.16 (dddd, J= 14.4, 7.8, 1.2. 1.2 Hz, 1H), 2.59-2.37 (m, 4H), 2.16-1.90 (m, 2H). HRMS (EI, positive): Exact mass calcd. for C 14 H 19 NO2 [M] + requires m / z: 265.1137, found m / z: 265.1139.

[0313] (Synthesis Example 37) Synthesis of Compound H5 In a manner similar to that in Synthesis Example 32, Compound 4h (1.00 mg, 2.90 mmol) was reacted with ethylmagnesium bromide (1.00 M in tetrahydrofuran, 13.9 mL, 13.9 mmol) to obtain Compound H5 as a white solid in a yield of 569 mg (77%).

[0314] 1H NMR (300 MHz, CDCl3): δ 4.61-4.55 (m, 1H), 4.24-4.08 (m, 1H), 3.90-3.49 (m, 6H), 2.62-2.26 (m, 6H), 2.17-1.90 (m, 2H), 1.13 (dd, J =7.5, 7.5 Hz, 3H). HRMS (EI, positive): Exact mass calcd. for C 13 H 19 NO2 [M] + requires m / z: 253.1136, found m / z: 253.1139.

[0315] Synthesis Example I In the following synthesis example, a compound represented by general formula (I) was synthesized. The numbers of the compounds that were the final products correspond to the compound numbers shown in Table 9.

[0316]

[0317] Synthesis Example 38: Synthesis of Compound I1 Step 1 To a solution of compound 1i (456 mg, 2.50 mmol) in xylene (12.5 mL), morpholine (4.30 mL, 49.5 mmol) and a catalytic amount of 4-dimethylaminopyridine (30.5 mg, 0.250 mmol) were added at room temperature. The mixture was stirred at 100°C for 19 hours, and then the solvent and morpholine were concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 100:0 to 30:70) to obtain compound 2i as a colorless oil in a yield of 365 mg (61%).

[0318] 1H NMR (300 MHz, CDCl3, 1:9 mixture of ketoenol tautomers): δ 5.26-5.24 (m, 0.1H), 3.71-3.38 (m, 8H), 3.28 (s, 0.9H), 2.73-2.62 (m, 1H), 2.38-2.35 (m, 1H), 2.18-2.16 (m, 1H), 1.96-1.94 (m, 1H), 1.84-1.82 (m, 1H), 1.33-1.25 (m, 1H), 1.01 (s, 0.3H), 1.00 (s, 2.7H), 0.93 (s, 0.3H), 0.91 (s, 2.7H). 13 C NMR (75 MHz, CDCl3, predominantly keto tautomer): δ 209.03, 166.67, 66.83, 66.57, 63.03, 46.88, 42.20, 39.01, 34.60, 28.04, 26.58, 26.53, 21.96.

[0319] Step 2: Compound 2i (365 mg, 1.53 mmol) was added to a solution of sodium hydride (55% in mineral oil, 200 mg, 4.59 mmol) in tetrahydrofuran (8 mL) at 0 °C. After stirring at room temperature for 30 minutes, tert-butyldiphenylsilyl chloride (470 μL, 1.83 mmol) was added to the mixture at 0 °C and stirred at that temperature for 30 minutes. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 100:0 to 50:50) to give compound I1 as a colorless oil in a yield of 576 mg (79%).

[0320] 1H NMR (300 MHz, CDCl3): δ 7.68-7.60 (m, 4H), 7.32-7.23 (m, 6H), 4.12 (ddd, J = 15.0, 2.7, 2.7 Hz, 1H), 3.77-3.56 (m, 3H), 3.47-3.37 (m, 3H), 3.13 (ddd, J = 13.2, 9.6, 3.6Hz, 1H), 1.76-1.65 (m, 1H), 1.45-1.36 (m, 4H), 1.23-1.12 (m, 2H), 1.09 (s, 3H), 0.98 (s, 3H), 0.82 (s, 9H). 13 C NMR (75 MHz, CDCl3): δ 168.75, 146.69, 135.38, 135.21, 134.07, 132.53, 129.93, 129.77, 127.69, 127.65, 119.46, 67.03, 66.98, 46.64, 41.27, 38.18, 33.89, 29.95, 28.92, 28.84, 26.25, 19.20, 18.69.

[0321] Synthesis Example J In the following synthesis example, a compound represented by general formula (J) was synthesized using the reaction shown in the following reaction scheme. The numbers of the compounds that were final products correspond to the compound numbers shown in Table 10.

[0322]

[0323] Synthesis Example 39: Synthesis of Compound J1 Step 1: To a solution of compound 1j (7.35 g, 360 mmol) in toluene (72 mL), morpholine (31.4 mL, 359 mmol) and a catalytic amount of 4-dimethylaminopyridine (440 mg, 3.60 mmol) were added at room temperature. The mixture was stirred at 100°C for 19 hours, and then the solvent and morpholine were concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 100:0 to 30:70) to obtain compound 2j as a colorless oil in an amount of 7.74 g (83%).

[0324] 1H NMR (300 MHz, CDCl3, three-sixth coordination ratio of lead solvent): δ 7.26–7.21 (m, 2H: keto-enol), 7.13–7.09 (m, 2). 1H:keto-enol), 7.04–7.00 (m, 1H:keto-enol), 4.71 (s, 0.46H:keto), 3.68–3.31 (m, 8H:keto-enol), 2.97 (ddd, J = 15.9, 6.0, 6.0 Hz, 0.52H:keto), 2.76 (ddd, J = 15.0, 7.5, 7.5 Hz, 1.36H: enol), 2.55 (ddd, J = 16.5, 9.0, 6.0 Hz, 0.5H: keto), 2.43 (m, 0.8H: enol). 13 C NMR (75 MHz, CDCl3): δ 206.55, 166.48, 136.89, 133.11, 132.89, 131.82, 128.34, 128.32, 127.78; 126.86, 126.84, 126.48, 124.58, 123.16, 123.14, 57.86, 57.82, 47.07, 45.53, 42.52, 37.69; IR (ATR, cm －1 ): 2855, 1716, 1603, 1431, 1225, 1112, 748. HRMS (EI, positive): Exact mass calcd. for C 15 H 17 NO3[M] + requires m / z: 259.1208, found m / z:

[0325] Step 2: Compound 2j (3.30 g, 12.7 mmol) was added to a solution of sodium hydride (55% in mineral oil, 1.1 g, 25.5 mmol) in tetrahydrofuran (25 mL) at 0 °C. After stirring at room temperature for 30 minutes, triisopropylsilyl chloride (2.95 g, 15.3 mmol) was added to the mixture at 0 °C and stirred at that temperature for 30 minutes. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 100:0 to 50:50) to give compound J1 as a colorless oil in a yield of 5.31 g (99%).

[0326] 1 H NMR (300 MHz, CDCl3): δ 7.18-7.00 (m, 3H), 6.86 (dd, J = 7.5, 1.5 Hz, 1H), 4.15 (ddd, J = 13.5, 3.9, 3.9 Hz, 1H), 3.83 (ddd, J = 13.5, 3.9, 3.9 Hz, 1H), 3.66 (ddd, J = 8.4, 4.5, 3.9 Hz, 1H), 3.65 (ddd, J = 8.4, 4.5, 3.9 Hz, 1H), 3.51-3.35 (m, 4H), 2.97 (ddd, J= 15.6, 7.8, 7.8 Hz, 1H), 2.88 (ddd, J = 15.6, 7.8, 7.8 Hz, 1H), 2.47 (ddd, J = 14.0, 7.8 Hz, 1H), 1.12-1.05 (m, 21H). 13 C NMR (75 MHz, CDCl3): δ 167.88, 151.32, 133.67, 131.89, 127.66, 127.46, 125.89, 123.27, 114.08, 67.81, 67.43, 47.13, 41.98, 29.67, 29.21, 18.47, 18.45, 13.63.IR (ATR, cm －1): 2943, 2864, 1633, 1114, 993, 759, 682. HRMS (EI, positive): Exact mass calcd. for C 24 H 37 NO3Si [M] + requires m / z: 415.2543, found m / z: 415.2541. Analytical HPLC [column: CHIRALPAK R IA (250 mm × 4.6 mm, 5 μm), eluent: hexane / IPA = 20:80, flow rate: 1.0 mL / min, detection: UV, CD (254 nm), temp: 10 °C] t1= 5.84 min, t2 = 22.1 min.

[0327] (Synthesis Example 40) Synthesis of Compound J2 In the same manner as in Synthesis Example 38, Compound 2j (20.0 mg, 0.0800 mmol), sodium hydride (55% in mineral oil, 10.1 mg, 0.230 mmol), and tert-butyldiphenylsilyl chloride (26.4 mg, 0.100 mmol) were reacted to obtain Compound J2 as a white solid in a yield of 30.0 mg (75%).

[0328] 1 H NMR (300 MHz, CDCl3): δ 7.80-7.72 (m, 5H), 7.51-7.37 (m, 5H), 7.14 (ddd, J = 7.5, 7.5, 1.5 Hz, 1H), 7.04-6.96 (m, 3H), 4.26 (ddd, J = 2.15 (ddd, J = 16.5, 9.0, 7.5 Hz, 1H), 2.05 (ddd, J= 16.5, 9.0, 7.5 Hz, 1H), 1.05 (m, 9H). 13C NMR (75 MHz, CDCl3): δ 167.03, 150.75, 134.93, 134.66, 132.89, 132.50, 131.92, 131.34, 129.89, 129.80, 127.63, 127.60, 126.81, 126.53, 125.22, 122.37, 113.94, 66.99, 66.62, 46.37, 41.22, 28.50, 27.87, 25.87, 18.93. IR (ATR, cm －1 ): 2857, 1635, 1428, 1113, 995, 820, 748, 702. HRMS (EI, positive): Exact mass calcd. for C 31 H 35 NO3Si [M] + requires m / z: 497.2386, found m / z: 497.2384. Analytical HPLC [column: CHIRALPAK R IA (250 mm × 4.6 mm, 5 μm), eluent: hexane / IPA = 60:40, flow rate: 1.0 mL / min, detection: UV, CD (254 nm), temp: 10 °C] t1 = 7.28 min, t2 = 21.9 min.

[0329] Synthesis Example 41 Synthesis of Compound J3 Compound 2j (433 mg, 1.67 mmol) was added to a solution of sodium hydride (55% in mineral oil, 109 mg, 2.51 mmol) in tetrahydrofuran (8 mL) at 0° C. After stirring at room temperature for 30 minutes, tetramethylethylenediamine (4.98 ml, 33.4 mmol) was added to the mixture at 0° C. After stirring at room temperature for 1 hour, benzoyl chloride (0.230 ml, 2.00 mmol) was added to the mixture at 0° C. and stirred at that temperature for 3 minutes. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with chloroform. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 100:0 to 70:30) to give Compound J3 as a colorless white oil in a yield of 468 mg (76%).

[0330] 1 H NMR (300 MHz, CDCl3): δ 8.18-8.12 (m, 1H), 7.71 (dd, J = 7.5, 7.5 Hz, 1H), 7.27-7.24 (m, 3H), 7.12-7.07 (m, 1H), 3.83-3.70 (m, 3H), 3.63-3.41 (m, 5H), 3.26-3.08 (m, 2H), 2.72 (ddd, J = 16.8, 7.5, 7.5 Hz, 1H), 2.39 (ddd, J = 16.5, 7.5, 7.5 Hz, 1H). 13 C NMR (75 MHz, CDCl3): δ 165.41, 164.63, 147.65, 134.08, 133.42, 130.52, 130.22, 130.20, 128.82, 128.80, 128.73, 127.95, 127.92, 127.90, 127.13, 124.18, 67.08, 66.85, 46.93, 41.71, 28.24, 26.24. －1 ): 2855, 1729, 1631, 1261, 1112, 749, 707. HRMS (EI, positive): Exact mass calcd. for C 22 H21 NO4[M] + requires m / z: 363.1471, found m / z: 363.1471.

[0331] Compounds J13 and J15 were synthesized using the reactions shown in the following reaction scheme.

[0332] Synthesis Example 42 Synthesis of Compound J13 To a solution of Compound J1 (142 mg, 0.34 mmol) in toluene (2 mL) was added Belleu's reagent (89.9 mg, 0.17 mmol) at room temperature. After stirring at 80°C for 2 hours, silica gel (FL100D) was added to the mixture to quench the reaction. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100:0 to 84:16) to obtain Compound J13 as a colorless oil in an amount of 47.5 mg (32%).

[0333] 1 H NMR (300 MHz, CDCl3): δ 7.16-6.96 (m, 4H), 4.94 (ddd, J = 12.3, 3.3, 3.3 Hz, 1H), 3.98-3.90 (m, 2H), 3.91-3.69 (m, 3H), 3.55-3.47 (m, 2H), 3.09-2.98 (m, 1H), 2.85 (ddd, J= 13.5, 6.6, 6.6 Hz, 1H), 2.60-2.47 (m, 1H), 2.50-2.40 (m, 1H), 1.25-1.05 (m, 21H). 13 C NMR (75 MHz, CDCl3): δ 197.17, 146.74, 133.77, 131.69, 127.20, 127.04, 125.42, 122.96, 119.15, 67.08, 66.61, 50.90, 47.96, 29.40, 28.70, 18.18, 18.16, 13.33.IR (ATR, cm －1): 2942, 2864, 1628, 1631, 1464, 1226, 1114, 1004, 755. HRMS (EI, positive): Exact mass calcd. for C 24 H 37 NO2SSi [M] + requires m / z: 431.2314, found m / z: 431.2314. Analytical HPLC [column: CHIRALPAK R IB (250 mm ×4.6 mm, 5 μm), eluent: n-hexane / EtOH = 90:10, flow rate: 1.0 mL / min, detection: UV, CD (254 nm), temp: 25 °C] t1 = 4.65 min, t2 = 10.5 min. Preparative HPLC [column: CHIRALPAK R IB N-5 (250 mm × 20 mm, 5 μm), eluent: n-hexane / EtOH = 90:10, flow rate: 13.3 mL / min, detection: UV (254 nm), temp: ambient temperature] t1 = 7.78 min, t2= 17.1 min. Optical rotation value: [α]20 D -81.2600 (c1.00, CHCl3) for 1 st isomer (>99%ee).

[0334] (Synthesis Example 43) Synthesis of Compound J15 Compound J3 (284 mg, 0.77 mmol) was reacted with Belew's reagent (284 mg, 0.54 mmol) according to the general procedure to obtain Compound J15 as a colorless oil in a yield of 222 mg (76%).

[0335] 1H NMR (300 MHz, CDCl3): δ 8.19-8.14 (m, 2H), 7.73-7.67 (m, 1H), 7.59-7.53 (m, 2H), 7.27-7.25 (m, 3H), 7.16-7.12 (m, 1H), 4.49 (ddd, J= 14.1, 5.7, 3.5 Hz, 1H), 4.26 (ddd, J = 13.5, 7.5, 3.3 Hz, 1H), 3.88-3.80 (m, 2H), 3.66-3.53 (m, 4H), 3.20-3.15 (m, 2H), 2.87 (m, 1H), 2.75 (m, 1H). 13 C NMR (75 MHz, CDCl3): δ 193.85, 164.66, 144.41, 133.98, 133.61, 131.01, 130.22, 128.89, 128.80, 127.87, 127.76, 127.13, 124.19, 66.73, 66.46, 51.49, 47.94, 28.13, 26.42.IR (ATR, cm －1 ): 2854, 1727, 1479, 1263, 759, 710. HRMS (EI, positive): Exact mass calcd. for C 22 H 21 NO3S [M] + requires m / z: 379.1242, found m / z: 379.1245.

[0336] Synthesis Example K In the following synthesis example, a compound represented by general formula (K) was synthesized. The numbers of the compounds that were the final products correspond to the compound numbers shown in Table 11.

[0337] (Synthesis Example 44) Synthesis of Compound K1

[0338] Step 1 Compound 4k (the same compound as Compound A1-2) was synthesized according to the same procedure as in Step 1 of Synthesis Example 1.

[0339] Step 2 Compound 5k (the same compound as Compound A5-3) was synthesized according to the same procedure as in Step 2 of Synthesis Example 5.

[0340] Step 3: To a solution of compound 5k (1.00 g, 2.55 mmol) in tetrahydrofuran (25 mL) were added sodium hydride (55% in mineral oil, 222 mg, 3.06 mmol) and paraformaldehyde (91.8 mg, 3.06 mmol) at 0° C. After stirring at room temperature for 14 hours, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ether / n-hexane = 10:100 to give compound K1 as colorless crystals in a yield of 983 mg (95%).

[0341] 1 H NMR (300 MHz, CDCl3): δ 8.00-7.97 (m, 1H), 7.90-7.88 (m, 1H), 7.2-7.79 (m, 1H), 7.57-7.48 (m, 6H), 7.41-7.32 (m, 6H), 5.44 (d, J = 16.5 Hz, 1H), 5.32 (d, J = 2.4 Hz, 1H), 5.02 (d, J = 16.5 Hz, 1H), 4.60 (d, J = 2.4 Hz, 1H). 13 C NMR (75 MHz, CDCl3): δ161.84, 153.39, 141.67, 138.67, 135.32, 133.78, 131.03, 130.71, 130.04, 129.46, 129.44, 129.31, 129.06, 128.89, 128.74, 128.54, 128.39, 127.73, 126.76, 126.11, 125.25, 124.06, 122.43, 96.64, 42.13.

[0342] Synthesis Example L In the following synthesis example, a compound represented by general formula (L) was synthesized. The numbers of the compounds that were the final products correspond to the compound numbers shown in Table 12.

[0343] (Synthesis Example 45) Synthesis of Compound L1

[0344] Compound 1L (340 mg, 1.40 mmol) and tetrahydrofuran (10 mL) were added to a 50 mL two-necked recovery flask that had been heated and dried under vacuum and reduced pressure, and the mixture was stirred at 0°C. Triethylamine (580 μL, 4.19 mmol), 4-dimethylaminopyridine (17.0 mg, 0.140 mmol), and isobutyryl bromide (167 μL, 1.54 mmol) were then added and stirred at room temperature for 30 minutes. The reaction was quenched with saturated aqueous ammonium chloride, followed by extraction three times with ethyl acetate. The combined organic phase was washed once with water and twice with saturated brine. After drying over anhydrous sodium sulfate, the anhydrous sodium sulfate was removed by cotton plug filtration, and the filtrate was concentrated using an evaporator. The resulting crude product was purified using a silica gel column (30 g of silica gel, eluent: hexane / ethyl acetate = 3 / 1) to obtain compound L1 in a yield of 319 mg (73%).

[0345] 1 H NMR (500 MHz, CDCl3): δ 7.79-7.77 (m, 2H), 7.46-7.43 (m, 3H), 7.03 (s, 1H), 6.63 (s, 1H), 2.61 (sep, J = 7.5 Hz, 1H), 2.49 (t, J = 7.5 Hz, 2H), 1.62-1.56 (m, 2H), 1.40-1.32 (m, 2H), 1.27 (d, J = 7.5 Hz, 6H), 0.93 (t, J = 7.5 Hz, 3H). 13 C NMR (125 MHz, CDCl3): δ 176.3, 161.3, 156.3, 151.9, 131.2, 130.6, 129.0, 125.5, 118.8, 104.0, 36.0, 32.2, 29.8, 22.8, 19.6, 13.9.

[0346] (Synthesis Example 46) Synthesis of Compound L2

[0347] Compound 2l (40.7 mg, 0.130 mmol) and N,N-dimethylformamide (3 mL) were added to a 30 mL two-necked recovery flask that had been heated and dried under vacuum and reduced pressure. The mixture was stirred at 0°C, and sodium hydride (6.2 mg, 60% dispersion in liquid paraffin, 0.16 mmol) was added and stirred for 20 minutes. Iodomethane (16.2 μL, 0.26 mmol) was added and stirred for 20 minutes, after which the mixture was warmed to room temperature. After 16 hours, the reaction was quenched with saturated aqueous ammonium chloride and extracted twice with diethyl ether. The combined organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered through a cotton plug to remove the anhydrous sodium sulfate. The filtrate was concentrated in an evaporator. The resulting crude product was purified using a silica gel column (9 g of silica gel, eluent: hexane / ethyl acetate = 2 / 1) to obtain compound L2 in a yield of 41.3 mg (97%).

[0348] 1 H NMR (500 MHz, CDCl3): δ 7.83-7.80 (m, 2H), 7.46-7.44 (m, 3H), 6.63 (s, 1H), 3.09 (s, 3H), 2.54-2.33 (m, 3H), 1.61-1.55 (m, 2H), 1.45-1.34 (m, 2H), 1.07 (d, J = 6.5 Hz, 3H), 1.04 (d, J = 6.5 Hz, 3H), 0.94 (t, J = 7.5 Hz, 3H).

[0349] (Synthesis Example 47) Synthesis of Compound L3

[0350] Compound 2L (47.1 mg, 0.15 mmol) and methylene chloride (2.5 mL) were added to a 30 mL two-necked recovery flask that had been heated and dried under vacuum and reduced pressure, and the mixture was stirred at 0°C. Triethylamine (125 μL, 0.90 mmol), 4-dimethylaminopyridine (18.3 mg, 0.15 mmol), and acetic anhydride (85 μL, 0.90 mmol) were added, and the mixture was stirred at room temperature for 10 minutes and then heated to reflux. After 7.5 hours, the reaction was quenched with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered through a cotton plug to remove the anhydrous sodium sulfate, and the filtrate was concentrated using an evaporator. The resulting crude product was purified using a silica gel column (10 g of silica gel, eluent: hexane / ethyl acetate = 4 / 1) to obtain compound L3 in a yield of 50.6 mg (95%).

[0351] 1 H NMR (500 MHz, CDCl3): δ 7.85-7.82 (m, 2H), 7.48-7.45 (m, 3H), 6.65 (s, 1H), 3.15 (qq, J = 6.5, 6.5 Hz,1H), 2.39 (s, 3H), 2.37-2.33 (m, 2H), 1.61-1.55 (m, 2H), 1.43-1.35 (m, 2H), 1.22 (d, J = 6.5 Hz, 3H), 1.16 (d, J = 6.5 Hz, 3H), 0.93 (t, J = 7.5 Hz, 3H). 13 C NMR (125 MHz, CDCl3): δ 180.2, 172.6, 159.8, 159.6, 157.3, 131.3, 130.8, 129.1, 125.9, 121.4, 102.7, 35.2, 31.2, 29.9, 26.0, 22.9, 19.8, 19.4, 13.8.

[0352] (Synthesis Example 48) Synthesis of Compound L4

[0353] Compound 3l (41.1 mg, 0.122 mmol) and tetrahydrofuran (3.0 mL) were added to a 30 mL two-necked recovery flask that had been heated and dried under vacuum and reduced pressure, and the mixture was stirred at 0°C. Triethylamine (51 μL, 0.37 mmol), N,N-dimethyl-4-aminopyridine (1.5 mg, 0.012 mmol), and isobutyryl bromide (27 μL, 0.24 mmol) were then added and stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous sodium bicarbonate, followed by extraction three times with ethyl acetate. The combined organic phase was washed once with water and twice with saturated brine. After drying over anhydrous sodium sulfate, the anhydrous sodium sulfate was removed by cotton plug filtration, and the filtrate was concentrated using an evaporator. The resulting crude product was purified using a silica gel column (10 g of silica gel, eluent: hexane / ethyl acetate = 4 / 1) to obtain compound L4 in a yield of 40.9 mg (83%).

[0354] 1 H NMR (500 MHz, CDCl3): δ 7.83-7.80 (m, 2H), 7.46-7.43 (m, 3H), 7.30-7.22 (m, 5H), 6.50 (s, 1H), 5.52 (d, J = 14.5 Hz, 1H), 4.10 (d, J = 14.5 Hz, 1H), 2.43 (qq, J = 7.0, 7.0 Hz, 1H), 2.04-1.97 (ddd, J = 5.0, 12.0, 13.5 Hz, 1H), 1.91-1.85 (ddd, J = 4.5, 11.5, 14.0 Hz, 1H), 1.28-1.13 (m, 2H), 1.10 (d, J = 7.0 Hz, 6H), 1.06-0.96 (m, 1H), 0.76 (t, J = 7.5 Hz, 3H), 0.68-0.59 (m, 1H). 13 C NMR (125 MHz, CDCl3): δ 178.2, 160.0, 158.6, 157.5, 137.3, 131.2, 130.8, 129.9, 129.1, 128.5, 127.7, 125.8, 123.0, 102.2, 50.3, 31.9, 31.0, 30.0, 23.0, 20.2, 19.6, 13.7.

[0355] <Asymmetric Induction Step> (Example 1) Asymmetric Induction of Racemic Compound A18 A sample solution was prepared by dissolving the racemic compound 18 (20.0 mg) in a mixed solvent (3.5 mL) of cyclohexane:methyl tert-butyl ether = 10:1. Silica gel (4.0 g) coated with cellulose tris(3,5-dimethylphenylcarbamate) was placed in a container, and the sample solution was poured into the container and thoroughly shaken for several seconds. The container was then left at 50°C for 24 hours and then at 30°C for 1 hour. The mixture in the container was then filtered through a PTFE (polytetrafluoroethylene) filter (pore size: 0.48 mm) and washed with an ice-cold mixed solvent (100 mL) of diethyl ether:ethanol = 10:1. The filtrate was concentrated under reduced pressure at 10°C, and the enantiomeric excess was measured. As a result, the enantiomeric excess was 93% ep, confirming that asymmetric induction of the racemic compound A18 can give an optically active compound with extremely high optical purity.

[0356] (Example 2) Asymmetric induction of racemic compound A19 Asymmetric induction of racemic compound A19 was carried out according to the same procedure as in Example 1, and the enantiomeric excess was measured to be 99% ep. This confirmed that asymmetric induction of racemic compound A19 can give an optically active substance with extremely high optical purity.

[0357] (Example 3) Asymmetric induction of racemic compound A20 Asymmetric induction of racemic compound A20 was carried out according to the same procedure as in Example 1, and the enantiomeric excess was measured to be 99% ep. This confirmed that asymmetric induction of racemic compound A20 can give an optically active substance with extremely high optical purity.

[0358] Example 4: Asymmetric induction of the racemic form of Compound G1 A sample solution was prepared by dissolving the racemic form of Compound G1 (20.0 mg) in a mixed solvent (3.5 mL) of cyclohexane:methyl tert-butyl ether = 10:1. Silica gel (4.0 g) coated with amylose (3,5-dimethylphenylcarbamate) was placed in a container, and the sample solution was poured into the container and thoroughly shaken for several seconds. The container was then left at 50°C for 24 hours and then at 10°C for 1 hour. The mixture in the container was then filtered through a PTFE (polytetrafluoroethylene) filter (pore size: 0.48 mm) and washed with an ice-cold mixed solvent (100 mL) of diethyl ether:ethanol = 10:1. The filtrate was concentrated under reduced pressure at 10°C, and the enantiomeric excess was measured. The enantiomeric excess was 57% ep, confirming that asymmetric induction of the racemic form of Compound G1 could produce an optically active form.

[0359] Example 5: Asymmetric induction of the racemic form of Compound H5 A sample solution was prepared by dissolving the racemic form of Compound H5 (20.0 mg) in a mixed solvent (3.5 mL) of cyclohexane:methyl tert-butyl ether = 10:1. Silica gel (4.0 g) coated with amylose (3-chloro-5-methylphenylcarbamate) was placed in a container, and the sample solution was poured into the container and thoroughly shaken for several seconds. The container was then left at 50°C for 24 hours and then at 10°C for 1 hour. The mixture in the container was then filtered through a PTFE (polytetrafluoroethylene) filter (pore size: 0.48 mm) and washed with an ice-cold mixed solvent (100 mL) of diethyl ether:ethanol = 10:1. The filtrate was concentrated under reduced pressure at 10°C, and the enantiomeric excess was measured. The enantiomeric excess was 64% ep, confirming that asymmetric induction of the racemic form of Compound H5 could produce an optically active form.

[0360] Example 6: Asymmetric induction of racemic compound J1 A sample solution was prepared by dissolving the racemic compound J1 (20.0 mg) in a mixed solvent (3.5 mL) of hexane:isopropanol = 10:1. Silica gel (4.0 g) coated with amylose (3,5-dimethylphenylcarbamate) was placed in a container, and the sample solution was poured into the container and thoroughly shaken for several seconds. The container was then left at 10°C for 24 hours. The mixture in the container was then filtered through a PTFE (polytetrafluoroethylene) filter (pore size: 0.48 mm) and washed with an ice-cold mixed solvent of diethyl ether (100 mL). The filtrate was concentrated under reduced pressure at 10°C, and the enantiomeric excess was measured. The enantiomeric excess was 90% ep, confirming that asymmetric induction of the racemic compound J1 could produce an optically active substance.

[0361]

[0362] From the above results, it was confirmed that optically active axially chiral molecules with extremely high optical purity can be obtained by reacting an asymmetric induction agent with an axially chiral molecule having a cyclic structure containing a double bond in the ring skeleton, such as the compound represented by general formula (1). In the following examples, optically active axially chiral molecules were prepared using this asymmetric induction process.

[0363] <Step of converting an optically active axially chiral molecule into a centrally chiral molecule, and step of cleaving the cyclic structure of a centrally chiral molecule> Conversion step and cleavage step for the compound synthesized in Synthesis Example A The optically active axially chiral molecule represented by general formula (A) can be converted into a centrally chiral converted molecule or a centrally chiral ring-opened molecule, for example, as shown in the following scheme, by carrying out a conversion step and a cleavage step. In the following examples, the conversion step and the cleavage step shown in the following scheme were carried out using the compound synthesized in Synthesis Example A.

[0364]

[0365] (Example 7) Conversion of Compound A6 by Mukaiyama Aldol Reaction

[0366] To a suspension of crystalline zeolite (molecular sieve 4A) (100 mg) in dichloromethane (1 mL), formaldehyde (26.7 mg, 0.890 mmol), titanium(IV) chloride (7.32 μL, 0.0668 mmol), and a dichloromethane (1 mL) solution of the optically active compound A6 (28.7 mg, 0.0445 mmol, 95% ee) were added at −78°C and stirred for 1 hour. The reaction mixture was quenched by adding a saturated aqueous solution of sodium bicarbonate, followed by extraction with dichloromethane. The resulting organic phase was washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography using a 10:1 mixture of chloroform and methanol as an eluent to obtain 13.9 mg (72%) of the A6 derivative 1 as a colorless oil. The enantiomeric excess of the A6 conversion product 1 was 95% ee, and it had high optical purity.

[0367] 1 H NMR (300 MHz, CDCl3, 3:2 mixture of diastereomers): δ 8.22-8.16 (m, 0.6H), 8.04-8.01 (m, 0.4H), 7.92-7.20 (m, 15H), 5.33 (d, J = 15.3 Hz, 0.4H), 5.09 (d, J = 15.6 Hz, 0.6H), 5.02 (d, J = 15.6 Hz, 0.6H), 4.76 (d, J = 15.3 Hz, 0.4H), 3.60-3.55 (m, 0.6H), 3.23-3.22 (m, 1H), 2.80 (dd, J = 12.0, 4.8 Hz, 0.4H). 1.07 (s, 1.2H), 0.65 (s, 1.8H). Analytical HPLC [column: CHIRALPAK IC (0.46 cm x 5.0 cm), eluent: hexane / i-PrOH = 70:30, flow rate: 1.0 mL / min, detection: UV, CD 254 nm, temperature: 40 °C]: t1 = 1.75, t2= 2.25 min.

[0368] (Example 8) Conversion step by allylation of compound A2 and cleavage step 1) Conversion step

[0369] To a suspension containing crystalline zeolite (molecular sieves 4A) (260 mg), allyl iodide (36.3 μL, 0.400 mmol), and an optically active compound of compound A2 (67.0 mg, 0.135 mmol, 99% ee), tetrabutylammonium fluoride (148 μL of a 1 M tetrahydrofuran solution, 0.148 mmol) was added at −78°C and stirred for 1 hour. Water was added to the reaction mixture to quench the reaction, followed by extraction with ethyl acetate. The resulting organic phase was washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography using a mixed solvent of hexane:ethyl acetate = 85:15 as an eluent to obtain 52.0 mg (97%) of A2 conversion compound 2 as a colorless oil.

[0370] 2) Cleavage Step The A2 conversion product 2 can be converted into a ring-opened molecule by the following cleavage reaction.

[0371] (Example 9) Conversion step of compound A26 by Mukaiyama aldol reaction

[0372] To a suspension of dried molecular sieves 4A (135 mg) in methylene chloride (5 mL), formaldehyde (108 mg, 3.61 mmol, prepared by pyrolysis of paraformaldehyde), titanium tetrachloride (25.3 μL, 0.231 mmol, prepared by distillation from calcium hydride), and a solution of compound A26 (73.7 mg, 0.154 mmol, 96% ee) in methylene chloride (3 mL) were added and reacted at −78°C. After stirring at that temperature for 12 hours, the reaction was quenched with saturated aqueous ammonium chloride and extracted with methylene chloride. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 50:50) to obtain A26 Transformation Product 1 as a colorless oil in a yield of 46.8 mg (86% yield, 96% ee).

[0373] H NMR (300 MHz, CDCl3, a 1:1 mixture of diastereoisomers): d 7.46-7.24 (m, 8H), 7.16-7.11 (m, 1H), 4.89 (d, J = 15.7 Hz, 0.5H), 4.81 (d, J = 15.7 Hz, 0.5H), 4.50 (d, J = 15.7 Hz, 0.5H), 4.42 (d, J = 15.7 Hz, 0.5H), 3.77 (d, J = 11.9 Hz, 0.5H), 3.50 (d, J = 11.9 Hz, 0.5H), 3.46 (d, J = 11.9 Hz, 0.5H), 2.98 (qq, J = 6.9, 6.9 Hz, 0.5H), 2.84 (qq, J = 6.9, 6.9 Hz, 0.5H), 1.34 (s, 1.5H), 1.32 (s, 1.5H), 1.28 (d, J = 6.9 Hz, 1.5H), 1.25 (d, J = 6.9 Hz, 1.5H), 1.21 (d, J = 6.9 Hz, 1.5H), 1.17 (d, J = 6.9 Hz, 1.5H). 13 C NMR (75 MHz, CDCl3): d 174.90, 174.68, 156.55, 147.44,146.81, 137.89, 137.84, 130.02, 129.49, 129.41, 129.22, 129.18, 129.09, 128.83, 128.34, 128.29, 128.05, 128.03, 126.91, 126.75, 126.55, 67.20, 67.06, 64.25, 64.22, 43.61, 43.55, 28.77, 28.41, 23.68, 23.64, 23.43, 17.99, 17.87.

[0374] (Example 10) Compound A26 chemical replacement project

[0375] To a suspension of dried molecular sieves 4A (240 mg), allyl iodide (85.3 μL, 0.949 mmol), and compound A26 (90.9 mg, 0.190 mmol, 96% ee) in THF (4 mL) was added tetrabutylammonium fluoride (0.5 M in THF, 418 μL, 0.209 mmol) at −78°C. After stirring at that temperature for 1 hour, the reaction was quenched with water and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 80:20) to give the A26 derivative 2 as a colorless oil in a yield of 47.6 mg (69%, 62% ee).

[0376] 1 H NMR (300 MHz, CDCl3, 1:1 mixture of diastereomers): d 7.45-7.25 (m, 8H), 7.12-7.04 (m, 1H), 5.60-5.45 (m, 1H), 5.19-5.05 (m, 2H), 4.85 (d, J= 15.5 Hz, 0.5H), 4.80 (d, J = 15.5 Hz, 0.5H), 4.87 (d, J = 15.5 Hz, 0.5H), 4.42 (d, J = 15.5 Hz, 0.5H), 2.89 (qq, J = 6.84, 6.84 Hz, 0.5H), 2.83 (qq, J = 6.84, 6.84 Hz, 0.5H), 2.62 (dddd, J = 14.4, 7.89, 0.96, 0.96 Hz, 1H), 2.50 (dddd, J = 14.4, 7.89, 0.96, 0.96 Hz, 1H), 1.37 (s, 1.50H) 1.36 (s,1.50H), 1.27 (d, J = 6.87 Hz, 1.5H), 1.25 (d, J = 6.87 Hz, 1.5H), 1.22 (d, J = 6.87 Hz, 1.5H), 1.16 (d, J = 6.87 Hz, 1.5H). 13C NMR (75MHz, CDCl3): d 174.96, 174.89, 155.98, 155.93, 147.05, 146.75, 137.75, 137.69, 130.40, 130.22, 129.93, 129.84, 129.40, 129.26, 128.89, 128.76, 128.66, 128.47, 128.30, 127.92, 127.90, 126.84, 126.70, 126.68, 126.52, 120.97, 120.71, 66.15, 65.81, 43.74, 43.68, 39.93, 39.87, 28.71, 28.36, 23.86, 23.54, 23.48, 23.45, 23.42, 23.04.

[0377] (Example 11) Conversion step and cleavage step of compound A18 by Mukaiyama aldol reaction 1) Conversion step

[0378] Compound A18 (600 mg, 0.930 mmol, 95% ee), formaldehyde (558 mg, 18.6 mmol), and titanium tetrachloride (153 μL, 1.40 mmol) were reacted according to the general procedure to give A18 derivative 1 as a colorless oil in a yield of 370 mg (91% yield, 95% ee).

[0379] 11H NMR (300 MHz, CDCl3, this compound exists as a 66:34 mixture of diastereomers): d 8.17-8.14 (m, 0.66H), 8.05-8.12 (m, 0.34H), 7.91-8.81 (m, 2H), 7.59-7.21 (m, 13H), 5.31 (d, J = 15.5 Hz, 0.34H), 5.21 (d, J = 15.5 Hz, 0.66H), 4.83 (d, J = 15.5 Hz, 0.66H), 4.78 (d, J = 15.5 Hz, 0.34H), 3.56 (dd, J = 6.96, 11.8 Hz, 0.66H), 3.35 (dd, J = 6.96, 11.8 Hz, 0.66H), 3.27 (dd, J = 9.27, 11.8 Hz, 0.34H), 2.83 (dd, J = 9.27, 11.8 Hz, 0.66H), 1.26 (s, 1.02), 0.56 (s, 1.98). 13 13C NMR (75 MHz, CDCl3): d 174.49, 174.36, 156.12, 141.54, 141.51, 138.71, 138.67, 133.81, 133.85, 132.37, 132.13, 131.19, 131.09, 131.06, 130.65, 129.75, 129.69, 129.46, 129.42, 129.20, 129.14, 129.05, 129.02, 128.86, 128.62, 128.57, 128.55, 128.26, 127.66, 127.58, 127.32, 127.12, 127.09, 127.05, 126.28, 125.19, 125.16, 123.27, 122.98, 67.10, 66.93, 64.36, 65.53, 42.29, 17.53, 17.15.

[0380] 2) Benzylation

[0381] To a solution of A18 conversion 1 (210 mg, 0.481 mmol) in THF (2 mL) was added benzyl bromide (74.3 μL, 0.625 mmol) and sodium hydride (29.4 mg, 0.674 mmol) at 0° C. After stirring at room temperature for 1 hour, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 80:20) to give A18 conversion 2 as colorless crystals in a yield of 240 mg (95%).

[0382] 1 H NMR (300 MHz, CDCl3, 83:17 mixture of diastereomers): d 8.07-7.97 (m, 1H), 7.89-7.78 (m, 2H), 7.56-7.19 (m, 17H), 7.09-6.91 (m, 1H), 5.40 (d, J= 14.9 Hz, 0.83H), 4.99 (d, J = 14.9 Hz, 0.17H), 4.91 (d, J = 14.9 Hz, 0.17H), 4.50 (d, J = 14.9 Hz, 0.83H), 4.43 (d, J = 12.1 Hz, 0.83H), 4.24 (d, J = 12.1 Hz, 0.83H), 3.93 (d, J = 12.1 Hz, 0.17H), 3.77 (d, J = 12.1 Hz, 0.17H), 3.52 (d, J = 9.78 Hz, 0.83H), 3.45 (d, J = 9.78 Hz, 0.83H), 3.28 (d, J = 9.78 Hz, 0.17H), 3.05 (d, J = 9.78 Hz, 0.17H), 1.15 (s, 0.51H), 0.46 (s,2.49H). 13 C NMR (75MHz, CDCl): d 174.04, 173.91, 156.01, 155.25, 141.52, 141.46, 138.80, 138.75, 137.25, 137.10, 133.72, 133.70, 132.62, 132.46, 131.48, 131.28, 130.55, 129.62, 129.60, 129.49, 129.06, 128.83, 128.79, 128.63, 128.60, 128.57, 128.50, 128.36, 128.20, 127.99, 127.87, 127.82, 127.46, 127.27, 126.79, 126.68, 126.60, 126.25, 126.03, 125.92, 125.07, 124.98, 123.76, 123.61, 73.09, 72.74, 70.28, 69.65, 65.82, 65.77, 42.38, 42.33, 18.77, 17.83.

[0383] 3) Hydrolytic cleavage step

[0384] To a solution of A18 conversion product 2 (200 mg, 0.380 mmol) in 1-propanol (2 mL) was added 48% aqueous sodium hydroxide solution (949 mg, 11.4 mmol), and the mixture was stirred at 100°C for 3 hours. The reaction was quenched with 1N hydrochloric acid and extracted with ether. The combined aqueous phase was removed under reduced pressure. The residue was purified by silica gel chromatography (chloroform / methanol = 10:1) to give A18 conversion product 3 as colorless crystals in a yield of 119 mg (89%).

[0385] 1H NMR (300 MHz, CD3OD): d 8.28-8.25 (m, 1H), 7.93-7.88 (m, 2H), 7.64-7.62 (m, 1H), 7.54-7.31 (m, 8H), 4.71 (d, J = 11.7 Hz, 1H), 4.67 (d, J = 11.7 Hz, 1H), 4.59 (d, J = 12.5 Hz, 1H), 4.44 (d, J = 12.5 Hz, 1H), 4.01 (d, J = 10.7 Hz, 1H), 3.85 (d, J = 10.7 Hz, 1H), 1.59 (s, 3H). 13 C NMR (75 MHz, CD3OD): d 172.46, 137.46, 133.92, 131.66, 129.92, 129.63, 128.42, 128.26, 128.17, 127.92, 127.81, 126.80, 125.97, 125.03, 73.31, 69.76, 66.45, 44.03, 18.86.

[0386] 4) Hydrogenation

[0387] To a solution of A18-converted product 3 (53.3 mg, 0.153 mmol) in methanol (1.0 mL) was added Pd / C (10%, 8.14 mg). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 5 hours. The solvent was filtered and concentrated in vacuo to give A18-converted product 4 as colorless crystals in a yield of 17.1 mg (94%).

[0388] 1 H NMR (300 MHz, CD3OD): d 3.93 (d, J = 11.3 Hz, 1H), 3.65 (d, J = 11.3 Hz, 1H), 1.48 (s, 3H).

[0389] (Example 12) Conversion step by benzylation of compound A18 and cleavage step 1) Conversion step

[0390] Compound A18 (48.7 mg, 0.0760 mmol, 95% ee), benzyl iodide (34.1 μL, 0.225 mmol), and tetrabutylammonium fluoride (0.5 M in THF, 83.0 μL, 0.083 mmol) were reacted according to 2) of Example 11 to give the A18 conversion product 5 as colorless crystals in a yield of 19.8 mg (yield 53%, 95% ee).

[0391] 1 H NMR (300 MHz, CDCl3, 95:5 mixture of diastereomers): d 8.21-8.18 (m, 1H), 7.95-7.89 (m, 1H), 7.86-7.80 (m, 1H), 7.62-7.54 (m, 2H), 7.43-7.06 (m, 15H), 6.60-6.57 (m, 0.5H), 6.44-6.41 (m, 0.95H), 5.54 (d, J= 15.9 Hz, 0.95H), 5.06 (d, J = 15.9 Hz, 0.05H), 4.91 (d, J = 15.9 Hz, 0.05H), 4.80 (d, J = 15.9 Hz, 0.95H), 3.12 (d, J = 14.1 Hz, 0.95H), 3.04 (d, J = 14.1 Hz, 0.95H), 2.44 (d, J = 14.1 Hz, 0.05H), 2.33 (d, J = 14.1 Hz, 0.95H), 1.23 (s, 0.15H), 0.81 (s,2.75H). 13C NMR (75 MHz, CDCl3): d 174.01, 155.29, 141.53, 140.90, 138.72, 138.70, 134.31, 134.29, 133.80, 132.51, 132.49, 131.24, 131.02, 130.75, 130.41, 129.78, 129.55, 129.11, 128.93, 128.84, 128.73, 128.70, 128.56, 128.49, 128.42, 128.17, 127.94, 127.63, 127.46, 126.98, 126.75, 126.19, 126.03, 125.20, 125.12, 123.27, 123.20, 67.12, 67.10, 42.19, 41.87, 41.18, 22.22, 20.62.

[0392] 2) Cleavage process

[0393] According to Example 11-3), A18 conversion product 5 (19.8 mg, 0.040 mmol) was reacted with 48% aqueous sodium hydroxide solution (99.7 mg, 1.19 mmol) to give A18 conversion product 6 as colorless crystals in a yield of 10.1 mg (79%).

[0394] 1 H NMR (300 MHz, CD3OD): d 8.25-8.22 (m, 1H), 8.02-7.95 (m, 2H), 7.80-7.78 (m, 1H), 7.69-7.64 (m, 1H), 7.62-7.52 (m, 2H), 7.35-7.27 (m, 5H), 4.76 (d, J = 12.8 Hz, 1H), 4.61 (d, J = 12.8 Hz, 1H), 3.43 (d, J = 13.2 Hz, 1H), 3.26 (d, J = 13.2 Hz, 1H), 1.76 (s, 3H). 13C NMR (75 MHz, CD3OD): d 134.06, 133.28, 131.60, 130.40, 130.16, 130.10, 128.91, 128.79, 128.64, 128.30, 127.58, 126.93, 126.16, 125.14, 122.86, 44.54, 42.46, 16.97. 13 C NMR (75 MHz, CD3OD): d 134.06, 133.28, 131.60, 130.40, 130.16, 130.10, 128.91, 128.79, 128.64, 128.30, 127.58, 126.93, 126.16, 125.14, 122.86, 44.54, 42.46, 21.62, 16.97.

[0395] (Example 13) Conversion step by ethylation of compound A18 and cleavage step 1) Conversion step

[0396] Compound A18 (70.8 mg, 0.109 mmol, 95% ee), ethyl iodide (0.265 mL, 0.329 mmol), and tetrabutylammonium fluoride (0.5 M in THF, 0.121 mL, 0.121 mmol) were reacted according to 2) of Example 11 to give A18 derivative 7 as a colorless oil in a yield of 13.4 mg (28% yield, 95% ee).

[0397] 2) Cleavage process

[0398] According to Example 11-3), the A18 converted product 7 (13.0 mg, 0.030 mmol) was reacted with 48% aqueous sodium hydroxide solution (74.8 mg, 0.898 mmol) to give the A18 converted product 8 as a colorless oil (5.30 mg, 69%).

[0399] (Example 14) Fluorination of Compound A19

[0400] To a suspension of dried molecular sieves 4A (50 mg) and compound A19 (40.8 mg, 0.057 mmol, 98% ee) in acetonitrile (0.5 mL) was added Selectfluor (40.1 mg, 0.113 mmol) at −78°C. After stirring at that temperature for 1 hour, the reaction was quenched with water and extracted with methylene chloride. The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 85:15) to obtain A19 conversion product 1 as colorless crystals in a yield of 13.5 mg (48%, 98% ee).

[0401] Conversion step and cleavage step of the compound synthesized in Synthesis Example B The optically active axially asymmetric molecule represented by general formula (B) can be converted into, for example, a central asymmetric transformation product or a central asymmetric ring-opened molecule as shown in the following scheme by carrying out a conversion step and a cleavage step.

[0402]

[0403] Conversion step and ring-opening step of the compound synthesized in Synthesis Example C The optically active axially asymmetric molecule represented by general formula (C) can be converted into, for example, a central asymmetric transformation product or a central asymmetric ring-opened molecule as shown in the following scheme by carrying out a conversion step and a cleavage step. In the following examples, the conversion step and the cleavage step were carried out using the compound synthesized in Synthesis Example C.

[0404]

[0405] (Reference Example 1) Conversion step of compound C10 by Mukaiyama aldol reaction

[0406] A suspension of crystalline zeolite (molecular sieves 4A) (75 mg) in dichloromethane (1 mL) was added with a solution of formaldehyde (117 mg, 3.90 mmol, prepared by pyrolysis of paraformaldehyde), titanium(IV) chloride (57.6 μL, 0.292 mmol), and compound C10 (73.0 mg, 0.194 mmol, racemic) in dichloroethane (1 mL) at −78°C and stirred for 1 hour. The reaction was quenched by adding saturated aqueous sodium bicarbonate, followed by extraction with dichloromethane. The resulting organic phase was washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography using a 50:50 mixture of hexane and ethyl acetate as an eluent to obtain 29.3 mg (57%) of the C10 derivative 1 as a colorless oil. The NMR data of C10 conversion product 1 is shown below.

[0407] 1 H NMR (300 MHz, CDCl3, 1:1 mixture of diastereomers): δ 7.48-7.42 (m, 2H), 7.35-7.25 (m, 1H),7.18-7.08 (m, 1H), 4.02 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 2.97 (qq, J = 6.7, 6.7 Hz, 0.5H), 2.79 (qq, J = 6.7, 6.7 Hz, 0.5H), 1.61 (s, 1.5H), 1.60 (s, 1.5H), 1.30-1.15 (m, 12H).

[0408] Conversion step and cleavage step of the compound synthesized in Synthesis Example D The optically active axially asymmetric molecule represented by general formula (D) can be converted into, for example, a central asymmetric transformation product or a central asymmetric ring-opened molecule as shown in the following scheme by carrying out a conversion step and a cleavage step.

[0409]

[0410] According to the present invention, optically active centrally chiral molecules can be efficiently produced. Such optically active molecules can be effectively used as pharmaceuticals and functional materials. Therefore, the present invention has high industrial applicability.

Claims

1. A method for producing an optically active axially chiral molecule, comprising an asymmetric induction step of increasing the abundance ratio of one enantiomer of a racemic axially chiral molecule having an enantiomeric excess half-life of less than one week at 200°C by reacting the molecule with an asymmetric induction agent.

2. A method for producing a centrally chiral molecule, comprising a step of converting an optically active axially chiral molecule having a double bond and a cyclic structure into a centrally chiral molecule having one or both carbon atoms constituting the double bond as an asymmetric center by reacting the double bond with a reaction reagent.

3. The method for producing a centrally chiral molecule according to claim 2, wherein the double bond is in the ring skeleton of the cyclic structure.

4. The method for producing a centrally chiral molecule according to claim 2, wherein the double bond is between a ring-structuring atom of the cyclic structure and a non-ring-structuring atom bonded thereto.

5. The method for producing a centrally chiral molecule according to claim 2, further comprising, after the step of converting to central chirality, a cleavage step of cleaving the cyclic structure of the centrally chiral molecule to obtain a ring-opened molecule having central chirality.

6. A method for producing a centrally chiral molecule according to claim 2, comprising the steps of: subjecting a racemic axially chiral molecule having a double bond and a cyclic structure, the half-life of which is less than one week at 200°C, to an asymmetric induction step in which an asymmetric induction agent is allowed to act on the racemic axially chiral molecule, thereby obtaining an optically active axially chiral molecule in which one enantiomer of the molecule is in excess; and then subjecting the obtained optically active axially chiral molecule to the step of conversion to central chirality.

7. The method for producing a centrally chiral molecule according to claim 6, further comprising, after the step of converting to central chirality, a cleavage step of cleaving the cyclic structure of the centrally chiral molecule to obtain a ring-opened molecule having central chirality.

8. A compound represented by the following general formula (1): General formula (1) [In general formula (1), R １ represents a substituent, and R ２ and R ３ Each of X independently represents a hydrogen atom or a substituent. １ is NR ４ , O or S; X ２ is C(R Ａ ) ２ , C═O or C═S, R ４ and R Ａ each independently represents a substituent; Z represents a substituent necessary for N-Z to form a chiral axis; and n represents an integer of 0 to 3.

9. The compound according to claim 8, which is represented by the following general formula (1a): General formula (1a) [In general formula (1a), R １ represents a substituent, and R ２ , R ３ and R ５ ~R ８ each independently represents a hydrogen atom or a substituent, R ９ represents a substituent. １ is NR ４ , O or S; X ２ is C(R Ａ ) ２ , C═O or C═S, R ４ and R Ａ each independently represents a substituent, and n represents an integer of 0 to 3.

10. The compound according to claim 8, which is represented by the following general formula (1b): General formula (1b) [In general formula (1b), R １ and R １１ each independently represents a substituent, R ２ , R ３ , R １２ and R １３ Each of X independently represents a hydrogen atom or a substituent. １ and X １１ are each independently NR ４ , O or S; X ２ and X １２ are each independently C(R Ａ ) ２ , C═O or C═S, R ４ and R Ａ each independently represents a substituent; n and n' each independently represents an integer of 0 to 3.

11. A compound represented by the following general formula (2): General formula (2) [In the general formula (2), R ２ and R ３ each independently represents a hydrogen atom or a substituent, R １５ represents a substituent. ２ represents a substituent, R ２ and R １５ are different substituents. １ is NR ４ , O or S; X ２ is C(R Ａ ) ２ , C═O or C═S, R ４ and R Ａ each independently represents a substituent; Z represents a substituent necessary for N-Z to form a chiral axis; and n represents an integer of 0 to 3.

12. An optically active substance comprising the compound according to any one of claims 8 to 11.

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