JP2014169252A - METHOD OF PRODUCING OPTICALLY ACTIVE β-FORMYL-β-HYDROXY-α-SUBSTITUTED ALDEHYDE COMPOUND - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new method of producing optically active β-formyl-β-hydroxy-α-substituted aldehyde compounds.SOLUTION: A method of producing an optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) includes the step of making glyoxal and an aldehyde compound (1) react with each other in the presence of an optically active pyrrolidine compound (3). In the formula each symbol is as defined in the specifications.

Description

  The present invention relates to a method for producing a β-formyl-β-hydroxy-α-substituted aldehyde compound.

  Optically active formula (2):

(Each symbol in the formula is as described later.)
It is known that the compound represented by is useful as an intermediate for producing pharmaceuticals, agricultural chemicals and the like because it can be converted into, for example, a hydroxylated eicosatetraenoic acid ester. (Non-Patent Document 1)
In this document, as a method for producing an optically active compound represented by the formula (2), a method of synthesizing from mannitol is described. However, an oxidation reaction is necessary, and various substituents R ¹ may be bonded to various substituents R ¹ . It was not a compatible synthesis method.

Tetrahedron, 45, 7317, 1989

  An object of the present invention is to provide a new method for producing a general, optically active compound represented by the formula (2).

Under such circumstances, the present inventor has studied a new method for producing an optically active compound represented by the formula (2). As a result, in the presence of a specific asymmetric catalyst, the present inventors have unexpectedly found glyoxal having two formyl groups. By reacting with an aldehyde compound represented by the formula (1), it has been found that it reacts preferentially with only one formyl group to give an optically active compound represented by the formula (2), leading to the present invention. . That is, the present invention is as follows.
[1] Formula (3):

(In the formula, Ar ¹ and Ar ² are each independently a phenyl group, a C ₁ -C ₁₂ chain hydrocarbon group, or a C ₃ -C ₁₂ fat optionally having a substituent selected from the following group G2) Represents a cyclic hydrocarbon group or a hydrogen atom, and R ⁵ represents a hydrogen atom, a fluorine atom, a hydroxyl group, a C ₁ -C ₁₂ alkoxy group, a C ₁ -C ₁₂ fluorinated alkyloxy group, or —OSiR ⁶ R ⁷ R ⁸ ( In the formula, each of R ⁶ , R ⁷ and R ⁸ independently represents a C ₁ -C ₈ alkyl group or a C ₆ -C ₂₀ aryl group), and * represents an asymmetric carbon atom. Represents.)
And glyoxal in a solvent in the presence of an optically active compound (hereinafter also referred to as pyrrolidine compound (3)) represented by formula (1):

(In the formula, R ¹ represents a C ₁ -C ₂₀ hydrocarbon group, a protected hydroxy group, a protected amino group or a hydrogen atom which may have a substituent selected from the following group G1.)
An optically active formula (2) comprising a step of reacting a compound represented by formula (hereinafter also referred to as aldehyde compound (1)):

(In the formula, R ¹ is as defined above, and ** represents an asymmetric carbon atom.)
(Hereinafter also referred to as optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2)).
<Group G1>: C ₆ -C ₂₀ aryl group which may have a substituent selected from Group G2, an aromatic heterocyclic group which may have a substituent selected from Group G2, C ₁ — C ₁₂ alkoxy group, C ₁ -C ₁₂ alkoxy group having a C ₆ -C ₂₀ aryl group optionally having a substituent selected from group G2, halogen atom, oxo group, protected hydroxy group, protected Group consisting of amino group and tri-C ₁ -C ₁₂ alkylsilyl group <Group G2>: C ₁ -C ₁₂ alkyl group, C ₁ -C ₁₂ alkoxy group, C ₂ -C ₁₃ alkoxycarbonyl group, C ₁ -C ₁₂ fluorinated alkyl group, C ₂ -C ₁₃ acyl group, a nitro group, a cyano group, a protected amino group and the group [2] solvent consisting of a halogen atom, a mixed solvent of water and an organic solvent, the [ 1] Description Manufacturing method.
[3] The production method according to the above [1] or [2], wherein R ⁵ is a hydroxyl group.
[4] The above [1] to [3], wherein R ⁵ is a hydroxyl group, and Ar ¹ and Ar ² are each independently a phenyl group optionally having a C ₁ -C ₁₂ fluorinated alkyl group. The manufacturing method in any one of.
[5] The production method according to any one of [1] to [4], wherein R ⁵ is a hydroxyl group, and Ar ¹ and Ar ² are both 3,5-bis (trifluoromethyl) phenyl groups.
[6] A step of obtaining an optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) by the production method according to any one of [1] to [5] above; and the optical obtained in the step Acetalizing the active β-formyl-β-hydroxy-α-substituted aldehyde compound (2);
Including formula (4):

Wherein R ¹ and ** are as defined in [1] above, and R ² represents a C ₁ -C ₁₀ alkyl group, or a substituent selected from the following group G1 bonded to each other. Represents a C ₂ -C ₁₀ alkanediyl group which may have
A method for producing an optically active compound (hereinafter also referred to as an optically active acetal compound (4)).
<Group G1>: C ₆ -C ₂₀ aryl group which may have a substituent selected from Group G2, an aromatic heterocyclic group which may have a substituent selected from Group G2, C ₁ — C ₁₂ alkoxy group, C ₁ -C ₁₂ alkoxy group having a C ₆ -C ₂₀ aryl group optionally having a substituent selected from group G2, halogen atom, oxo group, protected hydroxy group, protected Group consisting of amino group and tri-C ₁ -C ₁₂ alkylsilyl group <Group G2>: C ₁ -C ₁₂ alkyl group, C ₁ -C ₁₂ alkoxy group, C ₂ -C ₁₃ alkoxycarbonyl group, C ₁ -C ₁₂ fluorinated alkyl _group, C 2 _{-C 13} acyl group, a nitro group, a cyano group, the process according to any one of the protected amino group and the group consisting of halogen atoms [7] [1] to [5] By optical A functional β-formyl-β-hydroxy-α-substituted aldehyde compound (2); and an optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) obtained in the step is reduced. Process;
Including formula (5):

(Wherein R ¹ and ** are as defined in [1] above).
Or an optically active compound (hereinafter also referred to as an optically active alcohol compound (5)), or a formula (6):

(Wherein R ¹ and ** are as defined in [1] above).
(Hereinafter also referred to as optically active tetrahydrofuran diol compound (6)).
[8] A step of obtaining an optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) by the production method according to any one of [1] to [5] above; and the optical obtained in the step An active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) and Ph ₃ P═C (R ⁹ ) CO ₂ R ¹⁰ (wherein Ph represents a phenyl group and R ⁹ represents a hydrogen atom or step represents C ₁ -C ₈ alkyl ^{group, R 10} is reacted with) and represents a _C 1 -C ₈ alkyl group.;
Including formula (7):

(Wherein R ¹ and ** are as defined in [1] above, and R ⁹ and R ¹⁰ are as defined above.)
(Hereinafter also referred to as optically active α, β-unsaturated ester compound (7)).

  According to the production method of the present invention, a new method capable of producing an optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) can be provided.

  Hereinafter, the present invention will be described in detail.

  In the present specification, the “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

In the present specification, the “C ₁ -C ₂₀ hydrocarbon group” means a C ₁ -C ₂₀ aliphatic hydrocarbon group or a C ₆ -C ₂₀ aromatic hydrocarbon group.

In the present specification, the “C ₁ -C ₂₀ aliphatic hydrocarbon group” means a C ₁ -C ₂₀ chain hydrocarbon group or a C ₃ -C ₂₀ alicyclic hydrocarbon group.
In the present specification, the “C ₁ -C ₁₂ aliphatic hydrocarbon group” means a C ₁ -C ₁₂ chain hydrocarbon group or a C ₃ -C ₁₂ alicyclic hydrocarbon group.

In the present specification, the “C ₁ -C ₂₀ chain hydrocarbon group” means a C ₁ -C ₂₀ alkyl group, a C ₂ -C ₂₀ alkenyl group, or a C ₂ -C ₂₀ alkynyl group.
In the present specification, the “C ₁ -C ₁₂ chain hydrocarbon group” means a C ₁ -C ₁₂ alkyl group, a C ₂ -C ₁₂ alkenyl group, or a C ₂ -C ₁₂ alkynyl group.

In the present specification, the “C ₁ -C ₂₀ alkyl group” means a linear or branched alkyl group having 1 to 20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, Examples include octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, eicosyl and the like. Among them, a C ₁ -C ₁₂ alkyl group, particularly a C ₁ -C ₈ alkyl group is preferable.
In the present specification, the “C ₁ -C ₁₂ alkyl group” means a linear or branched alkyl group having 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, Examples include octyl, nonyl, decyl, undecyl, dodecyl and the like. Among them, a C ₁ -C ₈ alkyl group is preferable, and a C ₁ -C ₄ alkyl group is particularly preferable.
In the present specification, the “C ₁ -C ₈ alkyl group” means a linear or branched alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, Examples include octyl. Among _them, C 1 -C ₄ alkyl groups are preferred.
In the present specification, the “C ₁ -C ₆ alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc. It is done. Among _them, C 1 -C ₄ alkyl groups are preferred.
In the present specification, the “C ₁ -C ₄ alkyl group” means a linear or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and sec-butyl, tert-butyl and the like.

In the present specification, the “C ₂ -C ₂₀ alkenyl group” means a linear or branched alkenyl group having 2 to 20 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, 2- Methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, Examples thereof include 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, 1-undecenyl, 1-dodecenyl, 1-tridecenyl, 1-eicosenyl and the like. Among _them, C 2 _{-C 12} alkenyl group, particularly _C 2 -C ₈ alkenyl group.
In the present specification, the “C ₂ -C ₁₂ alkenyl group” means a linear or branched alkenyl group having 2 to 12 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, 2- Methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, Examples include 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, 1-undecenyl, 1-dodecenyl and the like. Among _them, preferred is C 2 -C ₈ alkenyl group, particularly _C 2 -C ₄ alkenyl group.
In the present specification, the “C ₂ -C ₆ alkenyl group” means a linear or branched alkenyl group having 2 to 6 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, 2- Methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl and the like can be mentioned. Among them, especially _C 2 -C ₄ alkenyl group.

In the present specification, the “C ₂ -C ₂₀ alkynyl group” means a linear or branched alkynyl group having 2 to 20 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1- Butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, Examples include 1-octynyl, 1-noninyl, 1-decynyl, 1-undecynyl, 1-dodecynyl, 1-tridecynyl, 1-eicosinyl and the like. Among _them, C 2 _{-C 12} alkynyl group, in particular _C 2 -C ₈ alkynyl group.
In the present specification, the “C ₂ -C ₁₂ alkynyl group” means a linear or branched alkynyl group having 2 to 12 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1- Butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, Examples include 1-octynyl, 1-noninyl, 1-decynyl, 1-undecynyl, 1-dodecynyl and the like. Among them, a C ₂ -C ₈ alkynyl group is preferable, and a C ₂ -C ₄ alkynyl group is particularly preferable.
In the present specification, the “C ₂ -C ₆ alkynyl group” means a linear or branched alkynyl group having 2 to 6 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1- Examples include butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like. Among _them, C 2 -C ₄ alkynyl group.

In the present specification, the “C ₃ -C ₂₀ alicyclic hydrocarbon group” means a C ₃ -C ₂₀ cycloalkyl group or a C ₄ -C ₂₀ cycloalkenyl group.
In the present specification, the “C ₃ -C ₁₂ alicyclic hydrocarbon group” means a C ₃ -C ₁₂ cycloalkyl group or a C ₄ -C ₁₂ cycloalkenyl group.

In the present specification, the “C ₃ -C ₂₀ cycloalkyl group” means a cyclic alkyl group having 3 to 20 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl. , Cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cycloeicosyl and the like. Among _them, C 3 _{-C 12} cycloalkyl group, in particular _C 3 -C ₈ cycloalkyl group are preferable.
In the present specification, the “C ₃ -C ₁₂ cycloalkyl group” means a cyclic alkyl group having 3 to 12 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl. , Cyclodecyl, cycloundecyl, cyclododecyl and the like. Among _them, C 3 -C ₈ cycloalkyl group.

In the present specification, the “C ₄ -C ₂₀ cycloalkenyl group” means a cyclic alkenyl group having 4 to 20 carbon atoms, such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2-cyclohepten-1-yl, 2-cycloocten-1-yl, 2-cyclononen-1-yl, 2-cyclodecen-1-yl, 2 -Cyclododecen-1-yl, 2-cycloeicosen-1-yl, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl, etc. Is mentioned. Among them, a C ₄ -C ₁₂ cycloalkenyl group, particularly a C ₄ -C ₈ cycloalkenyl group is preferable.
In the present specification, the “C ₄ -C ₁₂ cycloalkenyl group” means a cyclic alkenyl group having 4 to 12 carbon atoms, such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2-cyclohepten-1-yl, 2-cycloocten-1-yl, 2-cyclononen-1-yl, 2-cyclodecen-1-yl, 2 -Cyclododecen-1-yl, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like. Among _them, C 4 -C ₈ cycloalkenyl group is preferable.

In the present specification, “C ₃ -C ₂₀ cycloalkyl group”, “C ₃ -C ₁₂ cycloalkyl group”, “C ₄ -C ₂₀ cycloalkenyl group” and “C ₄ -C ₁₂ cycloalkenyl group” It may be condensed with a benzene ring. Such groups include 1,2-dihydronaphthalen-1-yl, 1,2-dihydronaphthalen-2-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3, 4-tetrahydronaphthalen-2-yl, fluoren-9-yl, inden-1-yl and the like can be mentioned.

In the present specification, the “C ₆ -C ₂₀ aromatic hydrocarbon group (C ₆ -C ₂₀ aryl group)” means an aromatic monocyclic or polycyclic (condensed) carbon atom having 6 to 6 carbon atoms. 20 hydrocarbon groups means, for example, phenyl, 1-naphthyl, 2-naphthyl, phenanthryl, anthryl, acenaphthylenyl, naphthacenyl, biphenylyl, biphenylenyl and the like. Among them, a C ₆ -C ₁₄ aromatic hydrocarbon group (C ₆ -C ₁₄ aryl group), particularly a C ₆ -C ₁₀ aromatic hydrocarbon group (C ₆ -C ₁₀ aryl group) is preferable.
In the present specification, the “C ₆ -C ₁₂ aromatic hydrocarbon group (C ₆ -C ₁₂ aryl group)” means an aromatic monocyclic or polycyclic (condensed) carbon atom having 6 to 6 carbon atoms. 12 hydrocarbon groups, for example, phenyl, 1-naphthyl, 2-naphthyl, acenaphthylenyl, biphenylyl, biphenylenyl and the like. Among these, a C ₆ -C ₁₀ aromatic hydrocarbon group (C ₆ -C ₁₀ aryl group) is preferable.
In the present specification, the “C ₆ -C ₁₀ aryl group” means a monocyclic or polycyclic (condensed) hydrocarbon group having 6 to 10 carbon atoms that exhibits aromaticity, for example, phenyl , 1-naphthyl, 2-naphthyl and the like.

In the present specification, “C ₇ -C ₁₄ aralkyl group” means a group in which “C ₆ -C ₁₀ aryl group” is substituted on “C ₁ -C ₄ alkyl group”. Phenylethyl, 2-phenylethyl, (naphthyl-1-yl) methyl, (naphthyl-2-yl) methyl, 1- (naphthyl-1-yl) ethyl, 1- (naphthyl-2-yl) ethyl, 2- (Naphthyl-1-yl) ethyl, 2- (naphthyl-2-yl) ethyl and the like can be mentioned.

In the present specification, the “C ₁ -C ₁₂ alkoxy group” means a linear or branched alkoxy group having 1 to 12 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy. , Sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy and the like. Among them, a C ₁ -C ₈ alkoxy group, particularly a C ₁ -C ₄ alkoxy group is preferable.
In the present specification, the “C ₁ -C ₆ alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy. , Sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like. Among _them, C 1 -C ₄ alkoxy groups are preferred.

In the present specification, the “aromatic heterocyclic group” means an aromaticity containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom. Means a monocyclic or polycyclic (fused) heterocyclic group shown.
In the present specification, examples of the “monocyclic aromatic heterocyclic group” include furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl (1, 2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (1,2,4-triazolyl, 1,2,3- Triazolyl), tetrazolyl, triazinyl and the like. Of these, a 5- or 6-membered monocyclic aromatic heterocyclic group is preferable.
In the present specification, the “fused aromatic heterocyclic group” means that the monocyclic aromatic heterocyclic group is condensed with a monocyclic aromatic ring (preferably, a benzene ring or a monocyclic aromatic heterocyclic ring). Quinolyl, isoquinolyl, quinazolyl, quinoxalyl, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzimidazolyl, benzotriazolyl, indolyl, indazolyl , Pyrrolopyridyl, pyrazolopyridyl, imidazopyridyl, thienopyridyl, pyrrolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, thienopyrazinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, thienopyrimidinyl, and the like.
In the present specification, examples of the “monocyclic aromatic heterocycle” include furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, and oxadiazole. (1,2,4-oxadiazole, 1,3,4-oxadiazole), thiadiazole (1,2,4-thiadiazole, 1,3,4-thiadiazole), triazole (1,2,4-triazole) , 1,2,3-triazole), tetrazole, triazine and the like. Of these, a 5- or 6-membered monocyclic aromatic heterocycle is preferable.

In the present specification, the “C ₁ -C ₁₂ fluorinated alkyl group” means a “C ₁ -C ₁₂ alkyl group” substituted with a fluorine atom. The number of fluorine atoms is not particularly limited, and may be perfluoro substituted. Specifically, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 4-fluorobutyl, 5 -Fluoropentyl, 6-fluorohexyl, 7-fluoroheptyl, 8-fluorooctyl, 9-fluorononyl, 10-fluorodecyl, 11-fluoroundecyl, 12-fluorododecyl and the like.

In the present specification, the “C ₁ -C ₁₂ fluorinated alkyloxy group” means a “C ₁ -C ₁₂ alkoxy group” substituted with a fluorine atom. The number of fluorine atoms is not particularly limited, and may be perfluoro substituted. Specifically, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, 5 -Fluoropentyloxy, 6-fluorohexyloxy, 7-fluoroheptyloxy, 8-fluorooctyloxy, 9-fluorononyloxy, 10-fluorodecyloxy, 11-fluoroundecyloxy, 12-fluorododecyloxy and the like It is done.

In the present specification, “C ₂ -C ₁₃ alkoxycarbonyl group” means a group in which “C ₁ -C ₁₂ alkoxy group” is bonded to —C (═O) —, ie, “C ₁ -C ₁₂ alkoxy- Carbonyl group '', for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyl Examples include oxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl and the like. Among _them, C 2 -C ₉ alkoxycarbonyl group, particularly _C 2 -C ₅ alkoxycarbonyl group.

In the present specification, the _"C 2 _{-C 13} acyl group" _is an atomic group obtained by removing a hydroxyl group from C 2 _{-C 13} carboxylic acid, _"C 2 _{-C 13} aliphatic acyl group" or _{"C 7} - It means “C ₁₃ aromatic acyl group”.
In this specification, “C ₂ -C ₁₃ aliphatic acyl group” means a group in which “C ₁ -C ₁₂ aliphatic hydrocarbon group” is bonded to —C (═O) —, ie, “C ₁ — C ₁₂ aliphatic hydrocarbons - refers to a carbonyl group ", for example, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, acryloyl, methacryloyl, crotonoyl , Isocrotonoyl, propionoyl, cyclopentylcarbonyl, cyclohexylcarbonyl and the like. Among _them, preferred is C 2 _{-C 13} alkylcarbonyl group, especially _C 2 -C ₉ alkylcarbonyl group.
In this specification, “C ₇ -C ₁₃ aromatic acyl group” means that “C ₆ -C ₁₂ aromatic hydrocarbon group (C ₆ -C ₁₂ aryl group)” is bonded to —C (═O) —. Group, that is, “C ₆ -C ₁₂ aromatic hydrocarbon (C ₆ -C ₁₂ aryl) -carbonyl group”, and examples thereof include benzoyl, 1-naphthoyl, 2-naphthoyl and the like.

In the present specification, the “protected hydroxy group” means a hydroxy group protected with a “protecting group”. Examples of the “protecting group” include C _1-6 alkyl group, phenyl group, trityl group, C _7-10 aralkyl group (eg, benzyl), formyl group, C _1-6 alkyl-carbonyl group, benzoyl group, C _{7. -10} aralkyl-carbonyl group (eg, benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyl) Diethylsilyl), C _2-6 alkenyl groups (eg, allyl) and the like. The above substituents may each be substituted with a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a nitro group.
Specific examples of the protecting group include benzyl, p-methoxybenzyl, benzylcarbonyl, benzyloxycarbonyl, acetyl, trifluoroacetyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert -Butyldimethylsilyl, tert-butyldiethylsilyl and the like.

In the present specification, the “protected amino group” means an amino group protected with a “protecting group”. The “protecting group” includes a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _6-10 aryl group, a C _7-14 aralkyl group, a C _1-6 alkyl-carbonyl group, a C _1-6 alkoxy group. -Carbonyl group, C _2-6 alkenyl-oxycarbonyl group, C _6-10 aryl-carbonyl group, C _7-14 aralkyl-carbonyl group, C _6-10 aryl-oxycarbonyl group, C _7-14 aralkyl-oxycarbonyl Group, C _6-10 arylsulfonyl group, benzhydryl group, trityl group, tri-C _1-6 alkylsilyl group, 9-fluorenylmethyloxycarbonyl group, phthaloyl group and the like. The above substituents may each be substituted with a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a nitro group.
Specific examples of the protecting group include acetyl, trifluoroacetyl, pivaloyl, tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzhydryl, trityl, phthaloyl. , Allyloxycarbonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl and the like.

In the present specification, the “C _1-6 alkyl-carbonyl group” means a group in which a “C _1-6 alkyl group” is bonded to —C (═O) —.
In the present specification, the “C _1-6 alkoxy-carbonyl group” means a group in which a “C _1-6 alkoxy group” is bonded to —C (═O) —.
In the present specification, the “C _2-6 alkenyl-oxycarbonyl group” means a group in which a “C _2-6 alkenyl group” is bonded to an oxygen atom of —C (═O) O—.
In the present specification, the “C _6-10 aryl-carbonyl group” means a group in which a “C _6-10 aryl group” is bonded to —C (═O) —.
In the present specification, the “C _7-14 aralkyl-carbonyl group” means a group in which the “C _7-14 aralkyl group” is bonded to —C (═O) —.
In the present specification, the “C _6-10 aryl-oxycarbonyl group” means a group in which a “C _6-10 aryl group” is bonded to an oxygen atom of —C (═O) O—.
In the present specification, the “C _7-14 aralkyl-oxycarbonyl group” means a group in which the “C _7-14 aralkyl group” is bonded to the oxygen atom of —C (═O) O—.
In the present specification, the _{"C 6-10} arylsulfonyl group", -S (= _{O) 2} - means the _{"C 6-10} aryl group" is bonded groups.
In the present specification, the “tri C _1-6 alkylsilyl group” means —SiH ₃ tri-substituted by “C ₁ -C ₆ alkyl group”.

In the present specification, the “tri C ₁ -C ₁₂ alkylsilyl group” means —SiH ₃ tri-substituted by “C ₁ -C ₁₂ alkyl group”.

  Hereinafter, each group of Formulas (1) to (7) will be described.

R ¹ represents a C ₁ -C ₂₀ hydrocarbon group, a protected hydroxy group, a protected amino group or a hydrogen atom which may have a substituent selected from group G1. Here, the number of substituents of the C ₁ -C ₂₀ hydrocarbon group is preferably 1 to 3, and when it is 2 or more, these substituents may be the same or different.
R ¹ is
Preferably, a group substituent optionally C ₁ -C ₂₀ alkyl group which may have a selected from G1, protected hydroxy group or a hydrogen atom,
More preferably, a group may have a substituent group selected from G1 C ₁ -C ₁₂ alkyl group, protected hydroxy group or a hydrogen atom,
More preferably, it may have a protected hydroxy group C ₁ -C ₁₂ alkyl group, a protected hydroxy group or a hydrogen atom,
Even more preferably,
C _1-6 optionally _{C 7-10} aralkyloxy group optionally having an alkoxy group (e.g., p- methoxybenzyl oxy) may have a _C 1 -C ₆ alkyl group (preferably _C 1 -C ₄ alkyl groups (eg, methyl, ethyl, isopropyl)),
A C ₆ -C ₁₀ aryl-C ₁ -C ₄ alkyl group (ie, a C ₇ -C ₁₄ aralkyl group (eg, benzyl)),
A C _7-10 aralkyloxy group (eg, benzyloxy) or a hydrogen atom;

Ar ¹ and Ar ² are each independently a phenyl group, a C ₁ -C ₁₂ chain hydrocarbon group, a C ₃ -C ₁₂ alicyclic hydrocarbon group which may have a substituent selected from Group G2, or Represents a hydrogen atom. Here, the number of substituents of the phenyl group is preferably 1 to 3, and when it is 2 or more, these substituents may be the same or different.
Ar ¹ and Ar ² are
Preferably, each independently is a phenyl group which may have a substituent selected from Group G2,
More preferably, each independently a C ₁ -C ₁₂ phenyl group optionally having a fluorinated alkyl group,
More preferably, each independently is a phenyl group optionally having a C ₁ -C ₄ fluorinated alkyl group,
Even more preferably, each independently is a phenyl group optionally having a trifluoromethyl group,
Even more preferably, both are phenyl groups, or both are 3,5-bis (trifluoromethyl) phenyl groups,
Particularly preferred are both 3,5-bis (trifluoromethyl) phenyl groups.

R ⁵ represents a hydrogen atom, a fluorine atom, a hydroxyl group, a C ₁ -C ₁₂ alkoxy group, a C ₁ -C ₁₂ fluorinated alkyloxy group, or —OSiR ⁶ R ⁷ R ⁸ (wherein R ⁶ , R ⁷ and R ⁸ Each independently represents a C ₁ -C ₈ alkyl group or a C ₆ -C ₂₀ aryl group).
R ⁵ is
Preferably, it is a silyloxy group represented by a hydroxyl group or —OSiR ⁶ R ⁷ R ⁸ (wherein R ⁶ , R ⁷ and R ⁸ are as defined above),
More preferably, it is represented by a hydroxyl group or —OSiR ⁶ R ⁷ R ⁸ (wherein R ⁶ , R ⁷ and R ⁸ are each independently a C ₁ -C ₈ alkyl group (preferably a methyl group)). A silyloxy group,
Particularly preferred is a hydroxyl group.

Preferred combinations of Ar ¹ and Ar ² and R ⁵ are as follows.
(1) An embodiment in which Ar ¹ and Ar ² are each independently a phenyl group which may have a substituent selected from Group G2, and R ⁵ is a hydroxyl group.
(2) An embodiment in which Ar ¹ and Ar ² are each independently a phenyl group optionally having a C ₁ -C ₁₂ fluorinated alkyl group, and R ⁵ is a hydroxyl group.
(3) An embodiment in which Ar ¹ and Ar ² are each independently a phenyl group optionally having a C ₁ -C ₄ fluorinated alkyl group, and R ⁵ is a hydroxyl group.
(4) An embodiment in which Ar ¹ and Ar ² are each independently a phenyl group optionally having a trifluoromethyl group, and R ⁵ is a hydroxyl group.
(5) An embodiment in which Ar ¹ and Ar ² are both phenyl groups, or both are 3,5-bis (trifluoromethyl) phenyl groups, and R ⁵ is a hydroxyl group.
(6) An embodiment in which Ar ¹ and Ar ² are both 3,5-bis (trifluoromethyl) phenyl groups and R ⁵ is a hydroxyl group.

R ² represents a C ₁ -C ₁₀ alkyl group or a C ₂ -C ₄ alkanediyl group which may be bonded to each other and have a substituent selected from the group G1.
R ² is preferably a C ₁ -C ₄ alkyl group (particularly methyl).

R ⁹ represents a hydrogen atom or a C ₁ -C ₈ alkyl group.
R ⁹ is preferably a hydrogen atom.

R ¹⁰ represents a C ₁ -C ₈ alkyl group.
R ¹⁰ is preferably a C ₁ -C ₄ alkyl group (particularly ethyl).

  In the present invention, an optically active β-formyl is obtained by including a step (aldol reaction step) of reacting glyoxal with an aldehyde compound (1) in a solvent in the presence of the optically active pyrrolidine compound (3) as a catalyst. A β-hydroxy-α-substituted aldehyde compound (2) is produced.

  Glyoxal may be used in the form of an aqueous solution. In addition, since glyoxal is marketed in the state of aqueous solution, you may use it as it is.

  The amount of the aldehyde compound (1) to be used is preferably 0.1 to 5.0 mol, more preferably 0.3 to 3.0, with respect to 1 mol of glyoxal from the viewpoint of yield, selectivity and economy. Is a mole.

In the optically active pyrrolidine compound (3) as a catalyst, although depending on the type of the aldehyde compound (1), from the viewpoint of diastereoselectivity (when R ¹ in the aldehyde compound (1) is other than a hydrogen atom). Formula (3a):

(Wherein Ar ¹ and Ar ² are as defined above, and * represents an asymmetric carbon atom). A pyrrolidine compound represented by the formula ( ¹ ) is preferred. Among them, Ar ¹ and Ar ² are each independently C _A pyrrolidine compound which is a phenyl group which may have a ₁ -C ₄ fluorinated alkyl group is preferable, and further Ar ¹ and Ar ² each independently have a phenyl group which may have a trifluoromethyl group. A pyrrolidine compound is preferable, and further, a pyrrolidine compound in which both Ar ¹ and Ar ² are phenyl groups or both are 3,5-bis (trifluoromethyl) phenyl groups is preferable, and Ar ¹ and Ar 2 are particularly preferable. Pyrrolidine compounds in which both ² are 3,5-bis (trifluoromethyl) phenyl groups are preferred.

  The amount of the optically active pyrrolidine compound (3) to be used is preferably 0.5 to 30 mol%, more preferably 1 to 20 mol% with respect to the aldehyde compound (1) from the viewpoint of yield and economy. is there.

The aldol reaction in the present invention is carried out in a solvent. Examples of the solvent used in the present invention include aromatic hydrocarbon solvents (eg, toluene, benzene, xylene); alcohol solvents (eg, methanol, ethanol); halogenated hydrocarbon solvents (eg, chloroform, dichloromethane, carbon tetrachloride). ); Ether solvents (eg, diethyl ether, tetrahydrofuran); nitrile solvents (eg, acetonitrile); aprotic polar solvents (eg, dimethylformamide, dimethylacetamide, dimethyl sulfoxide); water, and mixtures thereof. Among them, a mixture of water and an organic solvent, particularly a mixture of water and an organic solvent selected from an ether solvent, a nitrile solvent, and an aprotic polar solvent is preferable, and the yield, enantioselectivity, and diastereoselectivity are high. From the viewpoint of being particularly good, a mixture of water and an ether solvent (preferably tetrahydrofuran) is more preferable. The amount of water used is preferably 0.01 to 1 mL, more preferably 0.1 to 0.5 mL, with respect to 1 mL of the ether solvent. When the reaction solvent contains water, glyoxal is used in the form of an aqueous solution.
Preferably the usage-amount of a solvent is 1-50 mL with respect to 1 g of aldehyde compounds (1), More preferably, it is 3-20 mL.

  The aldol reaction in the present invention is a method in which a solution obtained by dissolving glyoxal in a solvent and an optically active pyrrolidine compound (3) are added to and mixed with a solution obtained by dissolving the aldehyde compound (1) in a solvent; A method in which an optically active pyrrolidine compound (3) is mixed with a solution dissolved in a solvent, and a solution in which glyoxal is dissolved in a solvent is added thereto; and the like in terms of yield and selectivity. A method in which a solution in which 1) is dissolved in a solvent and a solution in which glyoxal is dissolved in a solvent and an optically active pyrrolidine compound (3) are added and mixed is preferable. A solution in which the aldehyde compound (1) is dissolved in a solvent Particularly preferred is a method of adding and mixing an aqueous solution of the above and an optically active pyrrolidine compound (3).

Although the aldol reaction in the present invention depends on the type of the aldehyde compound (1), it is preferably performed in the range of 0 to 100 ° C, more preferably in the range of 0 to 40 ° C.
The reaction time is preferably 1 to 100 hours, more preferably 10 to 50 hours, and particularly preferably 20 to 40 hours, although depending on the type of aldehyde compound (1) and the reaction temperature.
The progress of the reaction can be confirmed by analytical means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.

  Isolation of the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) contained in the reaction mixture thus obtained is obtained by subjecting the reaction mixture to a post-treatment (for example, neutralization, Extraction, washing with water, distillation, crystallization, etc.). In addition, the purification is performed by recrystallizing the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2), extraction purification treatment, distillation treatment, adsorption treatment of activated carbon, silica, alumina, etc., silica gel column chromatography, etc. It can carry out by attaching | subjecting to a chromatographic process.

  Since β-formyl-β-hydroxy-α-substituted aldehyde compound (2) has two formyl groups, it can be converted into various compounds. For example, the corresponding optically active acetal compound (formula (4):

(Wherein R ¹ , R ² and ** are as defined above), an optically active acetal compound)
Corresponding optically active alcohol compound (formula (5):

(Wherein R ¹ and ** are as defined above), an optically active alcohol compound)
Corresponding optically active tetrahydrofurandiol compound (formula (6):

(Wherein R ¹ and ** are as defined above), or a corresponding optically active α, β-unsaturated ester compound (formula (7):

(Wherein R ¹ , R ⁹ , R ¹⁰ and ** are as defined above) can be converted into an optically active α, β-unsaturated ester compound).
Also, the β-formyl-β-hydroxy-α-substituted aldehyde compound (2) may isomerize during isolation and / or purification from the reaction mixture. Accordingly, the diastereo ratio (syn / anti ratio) and enantiomeric excess (ee (%)) of the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) can be measured after completion of the aldol reaction. The optically active acetal compound (4), optically active alcohol compound (5), optically active tetrahydrofuran diol compound (6) or optically active α, β-unsaturated ester without isolation and / or purification It is desirable to carry out after converting to compound (7).

The optically active acetal compound (4) is produced by including a step (acetalization reaction step) of acetalizing the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2).
Specifically, optically active acetal compound (4) is an optically active β- formyl -β- hydroxy -α- substituted aldehyde compound (2), acetalizing agent corresponding to ^{R 2 (e.g.,} R 2 OH , HC (OR ² ) ₃ , (CH ₃ ) ₂ C (OR ² ) ₂ ) in the presence of an acid catalyst.
Preferably, the optically active acetal compound (4) comprises a reaction mixture containing the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) after completion of the aldol reaction, and an acetalization corresponding to R ² . It is manufactured by including a step of reacting an agent (for example, R ² OH, HC (OR ² ) ₃ , (CH ₃ ) ₂ C (OR ² ) ₂ ) in the presence of an acid catalyst.
More preferably, the optically active acetal compound (4) includes a reaction mixture containing the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) after completion of the aldol reaction, and HC (OR ² ) _3. (Wherein R ² represents a C ₁ -C ₈ alkyl group) and is produced in the presence of an acid catalyst.

The amount of HC (OR ² ) ₃ used is preferably 1 to 40 with respect to 1 mol of the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) from the viewpoint of yield and economy. Mol, more preferably 3 to 20 mol.

Examples of the acid catalyst used include p-toluenesulfonic acid or its hydrate (monohydrate) and pyridinium p-toluenesulfonate. From the viewpoint of yield and economy, p-toluenesulfonic acid or Its hydrate (monohydrate) is preferred.
The amount of the acid catalyst to be used is preferably 0.01 to 2 mol, more preferably 1 mol with respect to 1 mol of the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) from the viewpoint of the reaction rate. 0.01 to 0.2 mol.

The acetalization reaction is performed by adding HC (OR ² ) ₃ and an acid catalyst to a reaction mixture containing the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) after completion of the aldol reaction. An acid catalyst is added to the reaction mixture containing the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) after completion of the aldol reaction, and then HC (OR ² ) ₃ is added. In view of simplifying the operation, the reaction mixture containing the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) after completion of the aldol reaction is added to HC (OR ² ) It is preferable to carry out by the method of adding and mixing ₃ and an acid catalyst.

The acetalization reaction is preferably in the range of 0 to 100 ° C, more preferably in the range of 10 to 40 ° C, and particularly preferably 20 to 30 ° C, although it depends on the types of HC (OR ² ) ₃ and the acid catalyst. Within the range of
The reaction time depends on the types of HC (OR ² ) ₃ and the acid catalyst and the reaction temperature, but is preferably 10 minutes to 50 hours, more preferably 30 minutes to 20 hours, and particularly preferably 1 to 10 hours. It's time.
The progress of the reaction can be confirmed by analytical means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.

  Isolation of the optically active acetal compound (4) contained in the reaction mixture thus obtained is obtained by subjecting the reaction mixture to post-treatment by a conventional method (for example, neutralization, extraction, washing with water, distillation, crystallization, etc.). It can be done by attaching. Further, the purification can be carried out by subjecting the optically active acetal compound (4) to recrystallization treatment, extraction purification treatment, distillation treatment, adsorption treatment of activated carbon, silica, alumina and the like, and chromatography treatment such as silica gel column chromatography. it can.

  The optically active alcohol compound (5) or the optically active tetrahydrofurandiol compound (6) is produced by including a step of reducing the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2). .

Specifically, the optically active alcohol compound (5) is produced by including a step of reducing the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) with sodium borohydride. The
Preferably, the optically active alcohol compound (5) is obtained by reacting a reaction mixture containing the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) after completion of the aldol reaction with sodium borohydride. It is manufactured by including the process to make.
The amount of sodium borohydride to be used is preferably 0.25 to 10 with respect to 1 mol of the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) from the viewpoint of yield and economy. Mol, more preferably 3 to 7 mol.

  In the reduction reaction, sodium borohydride is added to the reaction mixture containing the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) after completion of the aldol reaction from the viewpoint of simplifying the operation. It is preferable to carry out by a mixing method.

The reduction reaction is preferably performed within a range of 0 to 60 ° C, more preferably within a range of 10 to 40 ° C, and particularly preferably within a range of 20 to 30 ° C.
The reaction time varies depending on the reaction temperature, but is preferably 5 minutes to 24 hours, more preferably 10 minutes to 3 hours, and particularly preferably 15 minutes to 1 hour.
The progress of the reaction can be confirmed by analytical means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.

  Isolation of the optically active alcohol compound (5) contained in the reaction mixture thus obtained is obtained by subjecting the reaction mixture to post-treatment by a conventional method (for example, neutralization, extraction, washing with water, distillation, crystallization, etc.). It can be done by attaching. The purification can be performed by subjecting the optically active alcohol compound (5) to recrystallization treatment, extraction purification treatment, distillation treatment, adsorption treatment of activated carbon, silica, alumina, etc., and chromatography treatment such as silica gel column chromatography. it can.

The optically active tetrahydrofuran diol compound (6) is a step of reducing the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) with sodium triacetoxyborohydride in the presence of carboxylic acid. It is manufactured by including.
Preferably, the optically active tetrahydrofuran diol compound (6) is a reaction mixture containing the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) after completion of the aldol reaction in the presence of a carboxylic acid; Produced by including a step of reacting with sodium triacetoxyborohydride.
The amount of sodium triacetoxyborohydride to be used is preferably 0.25 with respect to 1 mol of the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) from the viewpoint of yield and economy. -10 mol, more preferably 1-6 mol.
As the carboxylic acid, acetic acid or the like is preferably used.
The amount of carboxylic acid to be used is preferably 0.1 mol to the amount of solvent with respect to 1 mol of optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) in terms of yield and economy. More preferably, the amount is 0.5 mol to the amount of solvent.

  In the reduction reaction, sodium triacetoxyborohydride and carboxylic acid are added to and mixed with the reaction mixture containing the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) after completion of the aldol reaction. Method: After completion of the aldol reaction, carboxylic acid is added to the reaction mixture containing the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2), and then sodium triacetoxyborohydride is added and mixed. The reaction mixture containing the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) after completion of the aldol reaction is subjected to triacetoxyhydrogenation in order to simplify the operation. It is preferable to carry out by a method in which sodium boron and carboxylic acid are added and mixed.

Although the said reduction reaction is based also on the kind of carboxylic acid, Preferably it is in the range of 0-100 degreeC, More preferably, it is in the range of 5-50 degreeC, Most preferably, it is performed in the range of 10-30 degreeC.
The reaction time depends on the type of carboxylic acid and the reaction temperature, but is preferably 10 minutes to 24 hours, more preferably 1 hour to 20 hours, and particularly preferably 10 to 15 hours.
The progress of the reaction can be confirmed by analytical means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.

  Isolation of the optically active tetrahydrofuran diol compound (6) contained in the reaction mixture thus obtained is carried out by post-treatment of the reaction mixture by a conventional method (for example, neutralization, extraction, washing with water, distillation, crystallization, etc.) It can be done by attaching. The purification is performed by subjecting the optically active tetrahydrofurandiol compound (6) to recrystallization treatment, extraction purification treatment, distillation treatment, adsorption treatment of activated carbon, silica, alumina, etc., and chromatography treatment such as silica gel column chromatography. Can do.

The optically active α, β-unsaturated ester compound (7) includes an optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) and Ph ₃ P═C (R ⁹ ) CO ₂ R ^10. (Wherein, Ph, R ⁹ and R ¹⁰ are as defined above) are produced by including the step of reacting (Wittig reaction step).
Preferably, the optically active α, β-unsaturated ester compound (7) comprises a reaction mixture containing the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) after completion of the aldol reaction, and Ph ₃ P = C (R ⁹ ) CO ₂ R ¹⁰ (wherein, Ph, R ⁹ and R ¹⁰ are as defined above) are produced.

The amount of Ph ₃ P═C (R ⁹ ) CO ₂ R ¹⁰ used is based on 1 mol of the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) from the viewpoint of yield and economy. The amount is preferably 0.5 to 20 mol, more preferably 3 to 10 mol.

In the Wittig reaction, Ph ₃ P = C (R ⁹ ) CO ₂ R ¹⁰ is added to the reaction mixture containing the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) after completion of the aldol reaction. A reaction mixture containing Ph ₃ P═C (R ⁹ ) CO ₂ R ¹⁰ and the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) after completion of the aldol reaction. A reaction mixture containing the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) after completion of the aldol reaction, from the viewpoint of simplifying the operation, and the like. Preferably, Ph ₃ P═C (R ⁹ ) CO ₂ R ¹⁰ is added and mixed.

The Wittig ^{_{reaction, Ph 3 P = C (R}} 9) depending on the type of CO ^{2 R 10,} preferably in the range of 0 to 100 ° C., more preferably in the range of 10 to 40 ° C., particularly preferably 20 It is performed within a range of ˜30 ° C.
The reaction time depends on the type of Ph ₃ P═C (R ⁹ ) CO ₂ R ¹⁰ and the reaction temperature, but is preferably 10 minutes to 50 hours, more preferably 30 minutes to 20 hours, particularly preferably. 1 to 10 hours.
The progress of the reaction can be confirmed by analytical means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.

  Isolation of the optically active α, β-unsaturated ester compound (7) contained in the reaction mixture thus obtained is obtained by subjecting the reaction mixture to post-treatment by a conventional method (for example, neutralization, extraction, washing with water, distillation). , Crystallization, etc.). In addition, the purification is performed by recrystallizing the optically active α, β-unsaturated ester compound (7), extraction purification treatment, distillation treatment, adsorption treatment of activated carbon, silica, alumina, etc., and chromatography treatment such as silica gel column chromatography. It can be done by attaching.

  The absolute configuration of the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) corresponds to, for example, protecting the hydroxy groups at the 1-position and 2-position of the optically active alcohol compound (5). Optically active protected alcohol compound (formula (5 ′):

(Wherein R ¹ and ** are as defined above) can be determined by conversion to
The protection reaction is produced by including a step of reacting the optically active alcohol compound (5) with acetone in the presence of an acid catalyst.
Preferably, it is produced by including a step of reacting a reaction mixture containing the optically active alcohol compound (5) after completion of the reduction reaction with acetone in the presence of an acid catalyst.

  The amount of acetone used is preferably 0.5 mol to the amount of solvent, more preferably 1 mol to the amount of solvent with respect to 1 mol of the optically active alcohol compound (5) from the viewpoint of yield and economy.

Examples of the acid catalyst used include p-toluenesulfonic acid or its hydrate (monohydrate) and pyridinium p-toluenesulfonate. From the viewpoint of yield and economy, p-toluenesulfonic acid or Its hydrate (monohydrate) is preferred.
The amount of the acid catalyst used is preferably 0.01 to 1.0 mol, more preferably 0.1 to 0.6 mol with respect to 1 mol of the optically active alcohol compound (5) from the viewpoint of the reaction rate. is there.

  The protective reaction is a method in which a reaction mixture containing the optically active alcohol compound (5) after completion of the reduction reaction is subjected to post-treatment such as separation, and then acetone and an acid catalyst are added and mixed; The reaction mixture containing the optically active alcohol compound (5) is subjected to post-treatment such as liquid separation, and then an acid catalyst is added, and then acetone is added and mixed; In view of the above, it is preferable to carry out a method in which the reaction mixture containing the optically active alcohol compound (5) after completion of the reduction reaction is subjected to a post-treatment such as liquid separation and then added and mixed with acetone and an acid catalyst.

Although the said protection reaction is based also on the kind of acid catalyst, Preferably it is in the range of 0-55 degreeC, More preferably, it is in the range of 10-40 degreeC, Most preferably, it is performed in the range of 20-30 degreeC.
The reaction time is preferably 10 minutes to 50 hours, more preferably 30 minutes to 20 hours, and particularly preferably 1 to 15 hours, although depending on the type of acid catalyst and the reaction temperature.
The progress of the reaction can be confirmed by analytical means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.

  Isolation of the optically active protected alcohol compound (5 ′) contained in the thus obtained reaction mixture is carried out by post-treatment of the reaction mixture by a conventional method (for example, neutralization, extraction, washing with water, distillation, crystallization, etc. ). The purification is performed by subjecting the optically active protected alcohol compound (5 ′) to recrystallization treatment, extraction purification treatment, distillation treatment, adsorption treatment of activated carbon, silica, alumina and the like, and chromatography treatment such as silica gel column chromatography. be able to.

  The obtained optically active acetal compound (4), alcohol compound (5), protected alcohol compound (5 ′), tetrahydrofurandiol compound (6) or optically active α, β-unsaturated ester compound (7) Stereo ratio (syn / anti ratio) and enantiomeric excess are measured. The measured diastereo ratio (syn / anti ratio) and enantiomeric excess correspond to that of the optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2).

When R ¹ in the aldehyde compound (1) is other than a hydrogen atom, the anti-active optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) is preferential in the aldol reaction step in the present invention. Is obtained. A diastereoselectivity having a diastereo ratio (syn / anti ratio) of, for example, 50/50 or more, or, for example, 20/80 or more is possible.

In the aldol reaction step in the present invention, pyrrolidine compound (3a) in which C ^* is S configuration, that is, formula (3a-S):

(Wherein Ar ¹ and Ar ² are as defined above.)
Is used as a catalyst, an optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) in which C ^** is S configuration, that is, the formula (2S):

(Wherein R ¹ is as defined above.)
An optically active β-formyl-β-hydroxy-α-substituted aldehyde compound represented by formula (1) is preferentially obtained.

On the other hand, the pyrrolidine compound (3a) in which C ^* is R configuration, that is, the formula (3a-R):

(Wherein Ar ¹ and Ar ² are as defined above.)
Is used as a catalyst, an optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) in which C ^** is in the R configuration, that is, the formula (2R):

(Wherein R ¹ is as defined above.)
An optically active β-formyl-β-hydroxy-α-substituted aldehyde compound represented by formula (1) is preferentially obtained.

  Thus, in the aldol reaction step in the present invention, enantioselectivity with an enantiomeric excess of, for example, 50% ee or more, for example, 80% ee or more is possible.

Hereinafter, the present invention will be described more specifically with reference to examples.
All liquid aldehydes and solvents except glyoxal were distilled before use. All reactions were monitored by thin layer chromatography using Merck 60 F254 silica gel plates (0.25 mm layer thickness). Preparative thin layer chromatography was performed using Wakogel B-5F from Wako Pure Chemical Industries, Ltd. (Tokyo, Japan). Flash chromatography was performed using silica gel 60N from Kanto Chemical Co., Inc. (Tokyo, Japan). IR spectra were measured with a Perkin-Elmer Spectrum BX FT-IR spectrometer. The optical rotation was measured with a Jasco DIP-370 polarimeter. ¹ H and ¹³ C NMR spectra are Bruker Varian 400-MR ( ¹ H NMR at 400 MHz, ¹³ C NMR at 100 MHz) or Bruker AM400 ( ¹ H NMR at 400 MHz, ¹³ C NMR at 100 MHz) ). ¹ H NMR data is represented by chemical shift (ppm), integral value, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), and coupling constant (Hz). ¹³ C NMR data are shown as chemical shifts. Mass spectra were measured with Thermo Fisher Scientific LTQ Orbitrap Discovery (ESI LTQ Orbitrap, HRMS). HPLC analysis was performed with HITACHI Elite LaChrom Series HPLC using CHIRALPAK IA (0.46 cm x 25 cm), CHIRALPAK IB (0.46 cm x 25 cm), CHIRALPAK IC (0.46 cm x 25 cm) and CHIRALPAK ID (0.46 cm x 25 cm). Each was performed by monitoring the UV detection wave at an appropriate wavelength.

Examples 1-1 to 1-5

To a solution of 3-phenylpropanal (0.5 mmol) in the solvent (0.5 mL) shown in Table 1, glyoxal (1.0 mmol, 120 μL, 39 wt% aqueous solution) and (S) -2- [bis (3,5- Bis-trifluoromethyl-phenyl) hydroxymethyl] pyrrolidine (26.3 mg, 0.05 mmol, 10 mol% relative to 3-phenylpropanal) was added at 23 ° C. After stirring for the time shown in Table 1, Wittig reagent (783 mg, 2.25 mmol) was added to the reaction mixture and the reaction mixture was stirred at 23 ° C. for 2 hours. After completion of the Wittig reaction, the reaction mixture was passed through short silica gel column chromatography and concentrated under vacuum. Purification by silica gel column chromatography (ethyl acetate: hexane = 1: 3) gave (2E, 4R, 5S, 6E) -diethyl 4-benzyl-5-hydroxyocta-2,6-dienedioate. The yield, anti / syn ratio (diastereomer ratio) and enantiomeric excess are shown in Table 1. The yield was determined as a two-step yield. The anti / syn ratio was measured by ¹ H-NMR spectrum. Enantiomeric excess was measured by HPLC equipped with a chiral column.

Examples 2-1 to 2-7

To a solution of the corresponding aldehyde compound (1) (0.5 mmol) in THF (0.5 mL), glyoxal (1.0 mmol, 120 μL, 39 wt% aqueous solution) and (S) -2- [bis (3,5-bis-tri Fluoromethyl-phenyl) hydroxymethyl] pyrrolidine (26.3 mg, 0.05 mmol, 10 mol% relative to the corresponding aldehyde compound (1)) was added at 23 ° C. After stirring for the time shown in Table 2, Wittig reagent (783 mg, 2.25 mmol) was added to the reaction mixture and the reaction mixture was stirred at 23 ° C. for 2 hours. After completion of the Wittig reaction, the reaction mixture was passed through short silica gel column chromatography and concentrated under vacuum. Purification by silica gel column chromatography (ethyl acetate: hexane = 1: 3) gave the corresponding α, β-unsaturated ester. The yield, anti / syn ratio (diastereomer ratio) and enantiomeric excess are shown in Table 2. The yield was determined as a two-step yield. The anti / syn ratio was measured by ¹ H-NMR spectrum. Enantiomeric excess was measured by HPLC equipped with a chiral column.

  In Example 2-2, 0.5 mmol of glyoxal and 1.0 mmol of propanal were used. In Example 2-5, (S) -2- [bis (3,5-bis-trifluoromethyl-phenyl) hydroxymethyl] pyrrolidine was used in an amount of 20 mol% based on the corresponding aldehyde compound (1). . In Example 2-7, 0.5 mmol of glyoxal and 1.5 mmol of acetaldehyde were used.

(2E, 4R, 5S, 6E) -Diethyl 4-benzyl-5-hydroxyocta-2,6-dienedioate (Example 2-1)

Yield 79%; Diastereomeric mixture (anti: syn = 20: 1); ¹ H NMR (CDCl ₃ , 400 MHz): δ 1.27 (3H, t, J = 7.2 Hz), 1.28 (3H, t, J = 7.2 Hz), 2.67-2.73 (1H, m), 2,76 (1H, dd, J = 7.6, 12.8 Hz), 2.97 (1H, dd, J = 6.8, 12.8 Hz), 4.16 (2H, q, J = 7.2 Hz), 4.19 (2H, q, J = 7.2 Hz), 4.31 (1H, br), 5.79 (1H, d, J = 16.0 Hz), 6.03 (1H, d, J = 16.0 Hz), 6.89 (1H, dd, J = 4.8, 16.0 Hz), 6.90 (1H, dd, J = 8.8, 16.0 Hz), 7.15-7.31 (5H, m); ¹³ C NMR (CDCl ₃ , 100 MHz): 14.2 (2C ), 36.6, 49.4, 60.4, 60.6, 71.5, 122.0, 124.4, 126.5, 128.6, 129.1, 138.6, 146.1, 147.8, 165.9, 166.0; IR (neat): νmax 3476, 2981, 1717, 1655, 1454, 1392, 1396, 1277, 1177, 1096, 1039, 981, 745, 700 cm ^-1 ; HRMS (ESI): [M + Na] ⁺ calcd for [C ₁₉ H ₂₄ NaO ₅ ] ⁺ : 355.1516, found: 355.1516; [α ] D ²⁶ -41.4 ^o (c = 0.81, CHCl ₃ ); Enantiomeric excess of the main diastereomer (anti) was measured by HPLC equipped with CHIRALPAK IC column ( ⁱ PrOH: hexane = 1: 10) (2 mL / min, minor enna Enantiomer t _R = 11.9 min, major enantiomer t _R = 16.5 min).

(2E, 4S, 5R, 6E) -Diethyl 4-hydroxy-5-methylocta-2,6-dienedioate (Example 2-2)

Yield 63%; Diastereomeric mixture (anti: syn = 10: 1); ¹ H NMR (CDCl ₃ , 400 MHz): δ 1.12 (3H, d, J = 6.8 Hz), 1.29 (3H, t, J = 7.2 Hz), 1.30 (3H, t, J = 7.2 Hz), 2.54-2.59 (1H, m), 4.19 (2H, q, J = 7.2 Hz), 4.21 (2H, q, J = 7.2 Hz), 4.24 (1H, br), 5.90 (1H, d, J = 16.0 Hz), 6.07 (1H, d, J = 16.0 Hz), 6.91 (1H, dd, J = 4.8, 16.0 Hz), 6.92 (1H, dd , J = 7.6, 16.0 Hz); ¹³ C NMR (CDCl ₃ , 100 MHz): 14.3 (2C), 15.3, 42.4, 60.4, 60.6, 74.1, 122.3, 123.0, 147.0, 148.6, 166.1, 166.2; IR (neat ): νmax 3477, 2980, 1714, 1651, 1463, 1369, 1278, 1179, 1034, 982, 868, 728 cm ^-1 ; HRMS (ESI): [M + Na] ⁺ calcd for [C ₁₃ H ₂₀ NaO ₅ ] ⁺ : 279.1203, found: 279.1202; [α] D ²⁶ 4.4 ^o (c = 0.51, CHCl ₃ ); The enantiomeric excess of the main diastereomer (anti form) is CHIRALPAK IB column ( ⁱ PrOH: hexane = 1 : 30) (1 mL / min, minor enantiomer t _R = 17.5 min, major enantiomer t _R = 18.2 min).

(2E, 4R, 5S, 6E) -Diethyl 4-ethyl-5-hydroxyocta-2,6-dienedioate (Example 2-3)

Yield 74%; Diastereomeric mixture (anti: syn = 16: 1); ¹ H NMR (CDCl ₃ , 400 MHz): δ 0.89 (3H, t, J = 7.6 Hz), 1.29 (6H, t, J = 7.2 Hz), 1.36-1.69 (2H, m), 2.24-2.30 (1H, m), 4.19 (2H, q, J = 7.2 Hz), 4.20 (2H, q, J = 7.2 Hz), 4.30 (1H , br), 5.89 (1H, d, J = 16.0 Hz), 6.05 (1H, d, J = 16.0 Hz), 6.78 (1H, dd, J = 9.2, 16.0 Hz), 6.90 (1H, dd, J = 5.6, 16.0 Hz); ¹³ C NMR (CDCl ₃ , 100 MHz): 11.7, 14.2, 14.2, 23.2, 50.3, 60.4, 60.6, 72.9, 122.1, 124.5, 147.3, 147.4, 166.0, 166.1; IR (neat): νmax 3477, 2979, 2936, 1715, 1652, 1463, 1369, 1278, 1178, 1138, 1095, 1038, 982, 865 cm ^-1 ; HRMS (ESI): [M + Na] ⁺ calcd for [C ₁₄ H ₂₂ NaO ₅ ] ⁺ : 293.1359, found: 293.1359; [α] D ²⁶ -9.6 ^o (c = 0.79, CHCl ₃ ); The enantiomeric excess of the main diastereomer (anti form) is the CHIRALPAK ID column ( ⁱ PrOH: hexane = 1: 30) was measured by HPLC equipped with (1 mL / min, major enantiomer t _R = 46.6 min, minor enantiomer t _R = 74.3 min)

(2E, 4S, 5R, 6E) -Diethyl 4-hydroxy-5-isopropylocta-2,6-dienedioate (Example 2-4)

Yield 67%; Diastereomeric mixture (anti: syn = 20: 1); ¹ H NMR (CDCl ₃ , 400 MHz): δ 0.90 (3H, d, J = 6.8 Hz), 0.97 (3H, d, J = 6.8 Hz), 1.29 (6H, t, J = 7.2 Hz), 1.91 (1H, dtt, J = 6.4, 6.8, 6.8 Hz), 2.05-2.11 (1H, m), 4.19 (2H, q, J = 7.2 Hz), 4.20 (2H, q, J = 7.2 Hz), 4.47 (1H, br), 5.85 (1H, d, J = 15.6 Hz), 6.04 (1H, d, J = 15.6 Hz), 6.85 (1H , dd, J = 10.4, 15.6 Hz), 6.88 (1H, dd, J = 5.6, 15.6 Hz); ¹³ C NMR (CDCl ₃ , 100 MHz): 14.2 (2C), 19.0, 21.3, 28.3, 55.0, 60.4 , 60.6, 71.3, 121.8, 125.3, 145.7, 148.1, 165.9, 166.1; IR (neat): νmax 3477, 2963, 1714, 1651, 1469, 1370, 1279, 1177, 1091, 1039, 982, 682 cm ^-1 ; HRMS (ESI): [M + Na] ⁺ calcd for [C ₁₅ H ₂₄ NaO ₅ ] ⁺ : 307.1516, found: 307.1516; [α] D ²⁶ -3.4 ^o (c = 0.66, CHCl ₃ ); enantiomeric excess mer (anti form), CHIRALPAK IB column ⁽ⁱ PrOH: hexane = 1: 50) was measured by HPLC equipped with (1 mL / min, major enantiomer t _R = 20.0 min, minor Nanchioma _{t R} = 22.2 min).

(2E, 4R, 5S, 6E) -Diethyl 4- (benzyloxy) -5-hydroxyocta-2,6-dienedioate (Example 2-5)

Yield 63%; Diastereomeric mixture (anti: syn = 4: 1); ¹ H NMR (CDCl ₃ , 400 MHz): δ 1.29 (3H, t, J = 7.2 Hz), 1.31 (3H, t, J = 7.2 Hz), 4.08-4.11 (1H, m), 4.20 (2H, q, J = 7.2 Hz), 4.22 (2H, q, J = 7.2 Hz), 4.44 (1H, d, J = 12.0 Hz), 4.47 (1H, br), 4.67 (1H, d, J = 12.0 Hz), 6.10 (1H, d, J = 16.0 Hz), 6.11 (1H, d, J = 16.0 Hz), 6.84 (1H, dd, J = 6.4, 16.0 Hz), 6.90 (1H, dd, J = 4.8, 16.0 Hz), 7.26-7.39 (5H, m); ¹³ C NMR (CDCl ₃ , 100 MHz): 14.2 (2C), 60.5, 60.7, 71.6, 72.5, 80.2, 122.9, 125.3, 127.9, 128.2, 128.6, 137.1, 142.5, 144.2, 165.5, 166.0; IR (neat): νmax 3477, 2981, 1715, 1659, 1454, 1368, 1271, 1177, 1097, 1038, 982, 738, 699 cm ^-1 ; HRMS (ESI): [M + Na] ⁺ calcd for [C ₁₉ H ₂₄ NaO6] ⁺ : 371.1465, found: 371.1465; Enantiomer of the main diastereomer (anti) excess is, CHIRALPAK IA column ⁽ⁱ PrOH: hexane = 1: 30) was measured by HPLC equipped with (1 mL / min, major enantiomer t _R = 27.6 min, minor Henin Omar _{t R} = 31.1 min).

(2E, 4S, 5S, 6E) -Diethyl 4-hydroxy-5-((4-methoxybenzyloxy) methyl) octa-2,6-dienedioate (Example 2-6)

Yield 62%; Diastereomeric mixture (anti: syn = 8: 1); ¹ H NMR (CDCl ₃ , 400 MHz): δ 1.28 (3H, t, J = 7.2 Hz), 1.30 (3H, t, J = 7.2 Hz), 2.76-2.82 (1H, m), 3.63 (2H, d, J = 6.4 Hz), 3.81 (3H, s), 4.18 (2H, q, J = 7.2 Hz), 4.19 (2H, q , J = 7.2 Hz), 4.45 (2H, s), 4.59 (1H, br), 5.88 (1H, d, J = 16.0 Hz), 6.10 (1H, d, J = 16.0 Hz), 6.87 (1H, dd , J = 8.0, 16.0 Hz), 6.88 (1H, dd, J = 4.4, 16.0 Hz), 6.88 (2H, d, J = 8.4 Hz), 7.23 (2H, d, J = 8.4 Hz); ¹³ C NMR (CDCl ₃ , 100 MHz): 14.2 (2C), 46.8, 55.3, 60.4, 60.4, 70.5, 72.2, 73.3, 113.9, 122.0, 124.6, 129.2, 129.5, 143.4, 146.9, 159.5, 165.9, 166.2; IR (neat ): νmax 3477, 2981, 1715, 1656, 1612, 1513, 1464, 1248, 1176, 1094, 1035, 982, 820, 577 cm ^-1 ; HRMS (ESI): [M + Na] ⁺ calcd for [C ₂₁ H ₂₈ NaO ₇ ] ⁺ : 415.1727, found: 415.1726; The enantiomeric excess of the main diastereomer (anti) was measured on a CHIRALPAK IA column ( ⁱ PrOH: hexane = 1:30) (1 mL / min, major enantiomer t = 42.2 min, minor enantiomer t _R = 57.0 min).

(4R, 2E, 6E) -Diethyl 4-hydroxyocta-2,6-dienedioate (Example 2-7)

Yield 71%; ¹ H NMR (CDCl ₃ , 400 MHz): δ 1.29 (3H, t, J = 7.2 Hz), 1.30 (3H, t, J = 7.2 Hz), 2.42-2.59 (2H, m), 4.20 (2H, q, J = 7.2 Hz), 4.21 (2H, q, J = 7.2 Hz), 4.47 (1H, br), 5.94 (1H, dt, J = 1.6, 16.0 Hz), 6.09 (1H, d , J = 16.0 Hz), 6.93 (1H, dt, J = 7.2, 16.0 Hz), 6.94 (1H, dd, J = 4.8, 16.0 Hz); ¹³ C NMR (CDCl ₃ , 100 MHz): 14.2 (2C) , 39.3, 60.4, 60.6, 69.6, 121.3, 124.9, 143.1, 148.2, 166.0, 166.2; IR (neat): νmax 3470, 2982, 1714, 1657, 1446, 1369, 1272, 1175, 1111, 1040, 981, 866 , 722 cm ^-1 ; HRMS (ESI): [M + Na] ⁺ calcd for [C ₁₂ H ₁₈ NaO ₅ ] ⁺ : 265.1046, found: 265.1047; [α] D ¹⁹ 2.8 ^o (c = 0.50, CHCl ₃ ) ; Enantiomeric excess of the main diastereomer (anti form) was measured by HPLC equipped with CHIRALPAK IA column ( ⁱ PrOH: hexane = 1: 30) (1 mL / min, major enantiomer t _R = 28.7 min, Minor enantiomer t _R = 33.2 min).

Example 3
(2R, 3S) -3-Benzyl-1,1,4,4-tetramethoxybutan-2-ol

To a THF solution (0.3 mL, 1 M) of 3-phenylpropionaldehyde (38 μL, 0.3 mmol), add glyoxal (70 μL, 0.6 mmol) and (S) -2- [bis (3,5-bis-trifluoro Methyl-phenyl) hydroxymethyl] pyrrolidine (16 mg, 0.03 mmol) was added at 23 ° C. After stirring the reaction mixture at 23 ° C. for 25 hours, trimethyl orthoformate (328 μL, 3.0 mmol) and p-toluenesulfonic acid (6.0 mg, 0.03 mmol) were added to the reaction mixture, and the reaction mixture was stirred at 23 ° C. . After the reaction mixture was stirred at 23 ° C. for 2 hours, the reaction was quenched by adding buffer (pH = 7.0). The organic material was extracted 3 times with ethyl acetate and the extract was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by silica gel column chromatography (ethyl acetate: hexane = 1: 3) gave (2R, 3S) -3-benzyl-1,1,4,4-tetramethoxybutan-2-ol (67 mg) as a colorless oil. 79%, dr => 20: 1, 97% ee).
Diastereomeric mixture (anti: syn = 20: 1); ¹ H NMR (CDCl ₃ , 400 MHz): δ 2.26-2.32 (1H, m), 2.76 (1H, dd, J = 10.0, 14.0 Hz), 2.94 (1H, dd, J = 5.2, 14.0 Hz), 3.27 (3H, s), 3.34 (3H, s), 3.40 (3H, s), 3.45 (3H, s), 3.55 (1H, ddd, J = 3.2 , 6.4, 6.8 Hz), 4.45 (1H, d, J = 6.8 Hz), 4.49 (1H, d, J = 4.4 Hz), 7.16-7.29 (5H, m) ,; ¹³ C NMR (CDCl ₃ , 100 MHz ): 32.2, 42.7, 54.5, 54.6, 54.7, 55.9, 70.5, 105.6, 106.8, 125.9, 128.3, 129.2, 140.5; IR (neat): νmax 3486, 2937, 2831, 1603, 1495, 1454, 1372, 1279, 1189, 1060, 978, 701 cm ^-1 ; HRMS (ESI): [M + Na] ⁺ calcd for [C ₁₅ H ₂₄ NaO ₅ ] ⁺ : 307.1516, found: 307.1517; [α] D ²⁶ +12.1 ^o (c = 0.79, CHCl ₃ ); Enantiomeric excess of the main diastereomer (anti) was measured by HPLC equipped with CHIRALPAK ID column ( ⁱ PrOH: hexane = 1:30) (1 mL / min, major enantiomer t _R = 15.3 min, minor enantiomer t _R = 21.8 min).

Example 4
(2R, 3R) -3-Benzylbutane-1,2,4-triol

To a THF solution (0.3 mL, 1 M) of 3-phenylpropionaldehyde (38 μL, 0.3 mmol), add glyoxal (70 μL, 0.6 mmol) and (S) -2- [bis (3,5-bis-trifluoro Methyl-phenyl) hydroxymethyl] pyrrolidine (16 mg, 0.03 mmol) was added at 23 ° C. After the reaction mixture was stirred at 23 ° C. for 25 hours, a small amount of MgSO ₄ and NaBH ₄ (56.7 mg, 1.5 mmol) were added at 0 ° C. 23 reaction mixture After stirring at 0 ° C. for 30 min, 1N NaOH aqueous solution (0.3 mL) was added to the reaction mixture. The organic material was extracted 3 times with ethyl acetate and the extract was washed with 1N hydrochloric acid and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. Purified by silica gel column chromatography (ethyl acetate: hexane = 3: 1) to give (2R, 3R) -3-benzylbutane-1,2,4-triol (43 mg, 73%, dr => as colorless oil) 20: 1, 97% ee).
Diastereomeric mixture (anti: syn = 20: 1); ¹ H NMR (CDCl ₃ , 400 MHz): δ 1.92 (1H, br), 2.64 (1H, dd, J = 8.4, 14.0 Hz), 2.78 (1H , dd, J = 6.0, 14.0 Hz), 3.62-3.70 (3H, m), 3.74-3.78 (2H, m), 7.18-7.30 (5H, m); ¹³ C NMR (CDCl ₃ , 100 MHz): 35.0 , 44.4, 62.7, 65.3, 74.0, 126.2, 128.5, 129.1, 139.8; IR (neat): νmax 3367, 2929, 1602, 1495, 1454, 1031, 966, 906, 745, 700 cm ^-1 ; HRMS (ESI) : [M + Na] ⁺ calcd for [C ₁₁ H ₁₆ NaO ₃ ] ⁺ : 219.0992, found: 219.0991; [α] D ²⁶ -8.6 ^o (c = 0.84, CHCl ₃ ); main diastereomer (anti form ) Was measured by HPLC equipped with a CHIRALPAK ID column ( ⁱ PrOH: hexane = 1: 10) (1 mL / min, minor enantiomer t _R = 18.8 min, major enantiomer t _R = 20.9 min).

Example 5
(3R, 4R) -4-benzyltetrahydrofuran-2,3-diol

Glyoxal (70 μL, 0.6 mmol) and (S) -2- [bis (3,5-bis-trifluoromethyl) were added to a THF solution (0.3 mL, 1 M) of 3-phenylpropionaldehyde (38 μL, 0.3 mmol). -Phenyl) hydroxymethyl] pyrrolidine (16 mg, 0.03 mmol) was added at 23 ° C. After the reaction mixture was stirred at 23 ° C. for 25 hours, the solvent was removed under reduced pressure. AcOH (1.2 mL, 0.25 M) was added to the crude product, followed by NaBH (OAc) ₃ (254 mg, 1.2 mmol) at 10 ° C. to the crude product solution. After the reaction mixture was stirred at 23 ° C. for 12 hours, 1N aqueous NaOH (0.3 mL) was added to the reaction mixture. The organic material was extracted three times with ethyl acetate and the extract was washed with 1N hydrochloric acid and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. Purified by preparative thin layer chromatography (ethyl acetate: hexane = 3: 1) to give (3R, 4R) -4-benzyltetrahydrofuran-2,3-diol (36 mg, 61%, dr => as colorless oil) 20: 1, 97% ee).
(Diastereomeric ratio of diol is 1: 1); ¹ H NMR (CDCl ₃ , 400 MHz): δ 2.49-2.55 (1H, m), 2.68-2.76 (2H, m), 2.81-2.87 (1H, m ), 2.93-3.00 (2H, m), 3.77 (1H, dd, J = 8.0, 9.6 Hz), 3.82 (1H, d, J = 3.6 Hz), 3.84 (1H, d, J = 2.0 Hz), 4.01 (1H, d, J = 4.4 Hz), 4.06 (1H, dd, J = 3.6, 5.2 Hz), 4.12 (1H, dd, J = 8.0, 8.4 Hz), 5.31 (1H, s), 5.39 (1H, d, J = 3.6 Hz), 7.19-7.32 (10H, m); ¹³ C NMR (CDCl ₃ , 100 MHz): 31.6, 31.9, 42.5, 45.1, 70.3, 71.6, 71.6, 76.2, 98.4, 103.2, 126.2, 126.3 128.6 (2C), 128.6, 128.6 140.0, 140.1; IR (neat): νmax 3390, 2924, 1603, 1494, 1454, 1238, 1029, 977, 909, 850, 701, 573 cm ^-1 ; HRMS (ESI) : [M + Na] ⁺ calcd for [C ₁₁ H ₁₄ NaO ₃ ] ⁺ : 217.0835, found: 217.0835; The enantiomeric excess of the main diastereomer (anti) is CHIRALPAK ID column ( ⁱ PrOH: hexane = 1: 10) (1 mL / min, minor enantiomer t _R = 15.0 min, major enantiomer t _R = 17.4 min).

Example 6
(R) -2- (Benzyloxy) -2-((S) -2,2-dimethyl-1,3-dioxolan-4-yl) ethanol

To a THF solution (0.3 mL, 1 M) of 2- (benzyloxy) acetaldehyde (42 μL, 0.3 mmol), glyoxal (70 μL, 0.6 mmol) and (S) -2- [bisphenylhydroxymethyl] pyrrolidine (15 mg, 0.06 mmol) was added at 23 ° C. 23 reaction mixture After stirring at 25 ° C. for 25 hours, NaBH ₄ (56.7 mg, 1.5 mmol) was added at 0 ° C. The reaction mixture was stirred at 23 ° C. for 30 minutes, and 1N hydrochloric acid was added to quench the reaction. The organic material was extracted 5 times with chloroform, dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give the crude product. The crude product was used in the next reaction without further purification.
The crude product was dissolved in acetone (3.0 mL, 0.1 M) and treated with p-toluenesulfonic acid (22.8 mg, 0.12 mmol) at 23 ° C. The reaction mixture was stirred at 23 ° C. for 11 hours, and then the reaction was quenched by adding buffer (pH = 7.0). The organic material was extracted 3 times with ethyl acetate and the extract was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. Purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give (R) -2- (benzyloxy) -2-((S) -2,2-dimethyl-1,3 as a pale yellow oil -Dioxolan-4-yl) -ethanol (45 mg, 59%, 2 steps, dr = 4.0 / 1) was obtained.
¹ H NMR (CDCl ₃ , 400 MHz): δ 1.35 (3H, s), 1.41 (3H, s), 3.52 (1H, dt, J = 4.4, 6.8 Hz), 3.71 (1H, br), 3.81-3.84 (1H, m), 3.87 (1H, dd, J = 6.0, 8.0 Hz), 4.08 (1H, dd, J = 6.4, 8.0 Hz), 4.18 (1H, dt, J = 6.0, 6.4 Hz), 4.64 ( 1H, d, J = 10.8, Hz), 4.68 (1H, d, J = 10.8, Hz), 7.30-7.38 (5H, m); ¹³ C NMR (CDCl ₃ , 100 MHz): 25.2, 26.6, 61.6, 66.9, 72.7, 75.9, 79.7, 109.3, 127.9, 128.0, 128.5, 137.9; IR (neat): νmax 3481, 2987, 1727, 1454, 1369, 1211, 1154, 1072, 847, 736, 697 cm ^-1 ; HRMS (ESI): [M + Na] ⁺ calcd for [C ₁₄ H ₂ 0NaO ₄ ] ⁺ : 275.1254, found: 275.1255; [α] _D ²⁶ -26.3 ^o (c = 0.55, CHCl ₃ ).

  According to the production method of the present invention, an optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) can be produced.

Claims (8)

Formula (3):

(In the formula, Ar ¹ and Ar ² are each independently a phenyl group, a C ₁ -C ₁₂ chain hydrocarbon group, or a C ₃ -C ₁₂ fat optionally having a substituent selected from the following group G2) Represents a cyclic hydrocarbon group or a hydrogen atom, and R ⁵ represents a hydrogen atom, a fluorine atom, a hydroxyl group, a C ₁ -C ₁₂ alkoxy group, a C ₁ -C ₁₂ fluorinated alkyloxy group, or —OSiR ⁶ R ⁷ R ⁸ ( In the formula, each of R ⁶ , R ⁷ and R ⁸ independently represents a C ₁ -C ₈ alkyl group or a C ₆ -C ₂₀ aryl group), and * represents an asymmetric carbon atom. Represents.)
And glyoxal in a solvent in the presence of an optically active compound represented by formula (1):

(In the formula, R ¹ represents a C ₁ -C ₂₀ hydrocarbon group, a protected hydroxy group, a protected amino group or a hydrogen atom which may have a substituent selected from the following group G1.)
Comprising the step of reacting with a compound represented by formula (2):

(In the formula, R ¹ is as defined above, and ** represents an asymmetric carbon atom.)
The manufacturing method of the optically active compound shown by these.
<Group G1>: C ₆ -C ₂₀ aryl group which may have a substituent selected from Group G2, an aromatic heterocyclic group which may have a substituent selected from Group G2, C ₁ — C ₁₂ alkoxy group, C ₁ -C ₁₂ alkoxy group having a C ₆ -C ₂₀ aryl group optionally having a substituent selected from group G2, halogen atom, oxo group, protected hydroxy group, protected Group consisting of amino group and tri-C ₁ -C ₁₂ alkylsilyl group <Group G2>: C ₁ -C ₁₂ alkyl group, C ₁ -C ₁₂ alkoxy group, C ₂ -C ₁₃ alkoxycarbonyl group, C ₁ -C ₁₂ fluorinated alkyl group, C ₂ -C ₁₃ acyl group, a nitro group, a cyano group, the group consisting of protected amino group and a halogen atom   The production method according to claim 1, wherein the solvent is a mixed solvent of water and an organic solvent. The production method according to claim 1 or 2, wherein R ⁵ is a hydroxyl group. The R ⁵ is a hydroxyl group, and Ar ¹ and Ar ² are each independently a phenyl group optionally having a C ₁ -C ₁₂ fluorinated alkyl group. Production method. The production method according to any one of claims 1 to 4, wherein R ⁵ is a hydroxyl group, and Ar ¹ and Ar ² are both 3,5-bis (trifluoromethyl) phenyl groups. A step of obtaining an optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) by the production method according to claim 1; and an optically active β-formyl-obtained in the step acetalizing the β-hydroxy-α-substituted aldehyde compound (2);
Including formula (4):

Wherein R ¹ and ** are as defined in claim ¹ and R ² represents a C ₁ -C ₁₀ alkyl group, or a substituent selected from the following group G1 bonded to each other. have represents an _C 2 _{-C 10} alkanediyl group.)
The manufacturing method of the optically active compound shown by these.
<Group G1>: C ₆ -C ₂₀ aryl group which may have a substituent selected from Group G2, an aromatic heterocyclic group which may have a substituent selected from Group G2, C ₁ — C ₁₂ alkoxy group, C ₁ -C ₁₂ alkoxy group having a C ₆ -C ₂₀ aryl group optionally having a substituent selected from group G2, halogen atom, oxo group, protected hydroxy group, protected Group consisting of amino group and tri-C ₁ -C ₁₂ alkylsilyl group <Group G2>: C ₁ -C ₁₂ alkyl group, C ₁ -C ₁₂ alkoxy group, C ₂ -C ₁₃ alkoxycarbonyl group, C ₁ -C ₁₂ fluorinated alkyl group, C ₂ -C ₁₃ acyl group, a nitro group, a cyano group, the group consisting of protected amino group and a halogen atom A step of obtaining an optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) by the production method according to claim 1; and an optically active β-formyl-obtained in the step reducing the β-hydroxy-α-substituted aldehyde compound (2);
Including formula (5):

(Wherein R ¹ and ** are as defined in claim 1).
Or an optically active compound represented by formula (6):

(Wherein R ¹ and ** are as defined in claim 1).
The manufacturing method of the optically active compound shown by these. A step of obtaining an optically active β-formyl-β-hydroxy-α-substituted aldehyde compound (2) by the production method according to claim 1; and an optically active β-formyl-obtained in the step β-hydroxy-α-substituted aldehyde compound (2) and Ph ₃ P═C (R ⁹ ) CO ₂ R ¹⁰ (wherein Ph represents a phenyl group, R ⁹ is a hydrogen atom or C ₁ -C ₈ alkyl) And R ¹⁰ represents a C ₁ -C ₈ alkyl group).
Including formula (7):

(Wherein R ¹ and ** are as defined in claim ¹ and R ⁹ and R ¹⁰ are as defined above).
The manufacturing method of the optically active compound shown by these.