JP2003221364A - Method for preparing optically active 5-hydroxy-3-keto ester - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for preparing many kinds of 5-hydroxy-3-keto esters with high optical purities and at low costs. <P>SOLUTION: This method for preparing the optically active 5-hydroxy-3-keto ester represented by the formula (III): R<SP>1</SP>C*H(OH)-CH<SB>2</SB>COCH<SB>2</SB>COOR<SP>2</SP>(III) (wherein R<SP>1</SP>and R<SP>2</SP>are identical to the below in meaning, and an asterisk represents an asymmetric carbon) is characterized by subjecting an aldehyde represented by the formula (I): R<SP>1</SP>CHO (I) (in the formula (I), R<SP>1</SP>represents a hydrocarbon group or a heterocycle group which may be substituted) to react with a diketene and an alcohol represented by the formula (II): R<SP>2</SP>OH (II) (wherein R<SP>2</SP>represents a hydrocarbon group which may be substituted) in the presence of an optically active bisphosphinobiaryl, a monovalent silver compound and an organotin oxide. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to 4-hydroxy-
The present invention relates to a method for producing 5-hydroxy-3-ketoester useful as an intermediate for producing pharmaceuticals such as 3-methylglutar (HMG) Co-A reductase inhibitor.

[0002]

2. Description of the Related Art As a method for producing an optically active 5-hydroxy-3-ketoester from an aldehyde, a diketene and an alcohol, benzaldehyde and diketene are optically active 2,2'-bis (di-p-tolylphosphino)-
A method for obtaining optically active methyl 5-phenyl-5-hydroxy-3-oxopentanoate by reacting it in the presence of 1,1′-binaphthyl, silver triflate, dibutyldimethoxytin and methanol is known (Journal).
of American Chemical Soci
ety, 1999, 121, 892-893.
page).

However, the resulting 5-hydroxy-
This method is not industrially satisfactory because the optical purity of 3-ketoester is not sufficient, expensive dibutyldimethoxytin is used, and the type of ester that can be produced is limited.

[0004]

SUMMARY OF THE INVENTION The present invention provides a wide variety of five types.
An object of the present invention is to provide a method for producing -hydroxy-3-ketoester with high optical purity at low cost.

[0005]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that the above problems can be solved by using an inexpensive and easily manufactured organotin oxide compound instead of dibutyldimethoxytin. The present invention has been completed. That is, the present invention provides an aldehyde represented by the general formula (I) in the presence of an optically active bisphosphinobiaryl, a monovalent silver compound, and an organic tin oxide,

[0006]

Embedded image R ¹ CHO (I) (wherein R ¹ represents an optionally substituted hydrocarbon group or a heterocyclic group), diketene, and an alcohol represented by the general formula (II).

[0007]

[Image Omitted] R ² OH (II) (wherein R ² represents an optionally substituted hydrocarbon group) is reacted to give an optically active compound of the general formula (III) 5 A method for producing a hydroxy-3-ketoester.

[0008]

Embedded image R ¹ C ^* H (OH) CH ₂ COCH ₂ COOR ² (III) (wherein R ¹ and R ² have the same meanings as described above, and * represents an asymmetric carbon).

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below. In addition, in this specification, "lower" has 1 to 4 carbon atoms.
And "halogen" means fluorine, chlorine, bromine, and iodine. In the aldehyde represented by the general formula (I), R ¹ represents a hydrocarbon group or a heterocyclic group which may have a substituent. The hydrocarbon group may be linear or cyclic and preferably has 1 to 20 carbon atoms. As the chain hydrocarbon group, a methyl group, an ethyl group,
Vinyl group, ethynyl group, n-propyl group, isopropyl group, propenyl group, allyl group, isopropenyl group, propynyl group, n-butyl group, tert-butyl group, sec
Examples include -butyl group, isobutyl group, butenyl group, butadienyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group and n-decyl group. Examples of the cyclic hydrocarbon group include a cyclopentyl group, a cyclohexyl group, a cyclohexenyl group, a cycloheptyl group, a phenyl group and a naphthyl group which may be wholly or partially hydrogenated.

The heterocyclic group may be saturated or unsaturated, and examples thereof include furyl group, pyrrolyl group, pyrrolidinyl group, pyrrolinyl group, imidazolyl group, imidazolidinyl group, imidazolyl group, thienyl group, pyranyl group,
Examples thereof include a pyridyl group, a benzofuranyl group, an indolyl group, a chromenyl group, an isochromenyl group, a quinolyl group, and an isoquinolyl group.

Substituents which these hydrocarbon groups or heterocyclic groups may have include halogen atoms, lower alkyl groups, lower cycloalkyl groups, lower alkoxy groups, lower alkoxycarbonyl groups and N-lower alkylcarbamoyl. Group, N-arylcarbamoyl group, carbon number 1-10
And the phenyl group which may have a halogen atom or a lower alkyl group.

Examples of such aldehydes include arylaldehydes such as benzaldehyde, 4-methylbenzaldehyde, 4-methoxybenzaldehyde and 2,4-dichlorobenzaldehyde; aralkylaldehydes such as 3-phenylpropanal; (E) -crotonaldehyde. Aldehydes having a double bond conjugated with a carbonyl group such as methacrylaldehyde and tiglic aldehyde;
Alkyl aldehydes such as n-butanal and trimethylacetaldehyde; heteroaryl aldehydes such as 2-thiophene aldehyde and 2-furan aldehyde; carbonyl such as cinnamaldehyde and 3- (2,4-dichlorophenyl) prop-2-en-1-al An aldehyde having a double bond conjugated to a group and an aromatic ring; 3- (pyridin-3-yl) prop-2-en-1-al, 3-
(Quinolin-3-yl) prop-2-en-1-al, (E) -3- [2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-yl] prop-2-
Examples thereof include aldehydes having a carbonyl group such as en-1-al and a double bond conjugated with a heterocycle; alicyclic aldehydes such as cyclohexanecarboxaldehyde.

Diketene is normally used for aldehydes.
It is used in an amount of 0.5 to 4.0 times mol. The preferred amount is 0.7 to 3.0 times, and especially 0.8 to 2.5 times. In the alcohol represented by the general formula (II),
R ² represents an optionally substituted hydrocarbon group. As the hydrocarbon group which may be substituted, methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-
Alkyl groups having 1 to 10 carbon atoms such as nonyl and n-decyl groups; cyclopropyl, cyclobutyl, cyclopentyl,
Cycloalkyl groups having 3 to 10 carbon atoms such as cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl groups; vinyl, 1-propenyl, 1-methylethenyl, 2-propenyl, 1,2-dimethyl-1-propenyl, 1- Butenyl, 1-pentenyl, 1-hexenyl, 1-heptenyl, 1-octenyl, 1-nonenyl,
C2-C10 alkenyl groups such as 1-decenyl group; ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 3-methyl-1-butynyl, 1-pentynyl, 1-
Alkynyl groups having 2 to 10 carbon atoms such as hexynyl, 1-heptynyl, 1-octynyl, 1-nonynyl, 1-decynyl groups; 2-cyclopropenyl, 1-cyclobutenyl, 3
-C3 to C3 such as cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl and 3-cyclohexenyl groups.
10 cycloalkenyl groups; benzyl, o-methylbenzyl, m-methylbenzyl, p-methylbenzyl, p-
Chlorobenzyl, 1-methylbenzyl, phenethyl, o
-Methylphenethyl, m-methylphenethyl, p-methylphenethyl, 3-phenylpropyl, 3- (o-methylphenyl) propyl, 3- (m-methylphenyl) propyl, 3- (p-methylphenyl) propyl, 4 An aralkyl group having 7 to 11 carbon atoms such as -phenylbutyl, α-naphthylmethyl and β-naphthylmethyl; phenyl,
o-tolyl, m-tolyl, p-tolyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,5 -Dimethylphenyl, 2,3
4-trimethylphenyl, 3,4,6-trimethylphenyl, 2,4,6-trimethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,
3,4-dichlorophenyl, 2-methoxyphenyl, 3
-Methoxyphenyl, 4-methoxyphenyl, 3,4-
Dimethoxyphenyl, 3-nitrophenyl, α-naphthyl, β-naphthyl, (2-methyl) -1-naphthyl,
(3-Methyl) -1-naphthyl, (4-methyl) -1-
Naphthyl, (5-methyl) -1-naphthyl, (6-methyl) -1-naphthyl, (7-methyl) -1-naphthyl,
(8-methyl) -1-naphthyl, (1-methyl) -2-
Naphthyl, (3-methyl) -2-naphthyl, (4-methyl) -2-naphthyl, (5-methyl) -2-naphthyl,
(6-methyl) -2-naphthyl, (7-methyl) -2-
Naphthyl, (8-methyl) -2-naphthyl, (2-ethyl) -1-naphthyl, (3-ethyl) -1-naphthyl,
(4-Ethyl) -1-naphthyl, (5-ethyl) -1-
Naphthyl, (6-ethyl) -1-naphthyl, (7-ethyl) -1-naphthyl, (8-ethyl) -1-naphthyl,
(1-ethyl) -2-naphthyl, (3-ethyl) -2-
Naphthyl, (4-ethyl) -2-naphthyl, (5-ethyl) -2-naphthyl, (6-ethyl) -2-naphthyl,
(7-ethyl) -2-naphthyl, (8-ethyl) -2-
Naphthyl, (2-propyl) -1-naphthyl, (3-propyl) -1-naphthyl, (4-propyl) -1-naphthyl, (5-propyl) -1-naphthyl, (6-propyl) -1- Naphthyl, (7-propyl) -1-naphthyl, (8-propyl) -1-naphthyl, (1-propyl) -2-naphthyl, (3-propyl) -2-naphthyl, (4-propyl) -2- Naphthyl, (5-propyl) -2-naphthyl, (6-propyl) -2-naphthyl, (7-propyl) -2-naphthyl, (8-propyl) -2-naphthyl, 1-anthryl, 2-anthryl 9 -Anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-
Examples thereof include aryl groups having 6 to 14 carbon atoms such as a phenanthryl group.

Of these, R ² has 1 to 10 carbon atoms.
And an alkyl group having 3 to 10 carbon atoms are preferable, and an alkyl group having 1 to 10 carbon atoms is particularly preferable.
The alcohol is preferably used in an amount of 1 to 10 ³ times, especially 1 to 10 ² times the molar amount of the aldehyde component. The optically active bisphosphinobiaryl has the general formula (IV)
An optically active biaryl compound represented by is preferable.

[0015]

[Chemical 9]

(In the formula, R ³ represents an optionally substituted aryl group or a cycloalkyl group.) Examples of the aryl group include a phenyl group. As the cycloalkyl group, a cycloalkyl group having 3 to 8 carbon atoms, particularly a cyclopentyl group and a cyclohexyl group are preferable.

Examples of the substituent of the aryl group and the cycloalkyl group include a lower alkyl group such as a methyl group and a tert-butyl group, and a lower alkoxy group such as a methoxy group. Examples of such an optically active bisphosphinobiaryl include 2,2′-bis (diphenylphosphino) -1,
1'-binaphthyl (BINAP), 2,2'-bis (di-p-tolylphosphino) -1,1'-binaphthyl (T
ol-BINAP), 2,2'-bis (di-p-ter)
t-butylphenylphosphino) -1,1′-binaphthyl (tert-Bu-BINAP), 2,2′-bis (di-m-tolylphosphino) -1,1′-binaphthyl (m-Tol-BINAP), 2,2'-bis [di-
(3,5-Dimethylphenyl) phosphino] -1,1 ′
-Binaphtyl (DM-BINAP), 2,2'-bis (di-p-methoxyphenylphosphino) -1,1'-
Binaphthyl (Methoxy-BINAP), 2,2 '
-Bis (dicyclopentylphosphino) -1,1'-binaphthyl (CpBINAP), 2,2'-bis (dicyclohexylphosphino) -1,1'-binaphthyl (CyBINAP) and the like can be mentioned.

These optically active bisphosphinobiaryls are disclosed in JP-A 61-63690 and JP-A 3-20.
It can be produced by the method described in JP-A No. 290, JP-A-3-255090, JP-A-1-68386 or JP-A-4-74192. Among these optically active bisphosphinobiaryls, BINAP, Tol-BINAP, m-Tol-B
INAP or tert-Bu-BINAP is preferable, and BINAP or Tol-BINAP is particularly preferable. The optically active bisphosphinobiaryl is
10 ^-3 to 10 times mol, especially 10 ^-2 to aldehyde
It is preferable to use 1-fold mole.

As the monovalent silver compound, any compound capable of forming a complex with the optically active bisphosphinobiaryl can be used. For example, silver oxide; inorganic acid salts such as silver fluoride, silver chloride, silver bromide, silver iodide, silver sulfate, silver carbonate, silver nitrate and silver perchlorate; silver formate, silver acetate, silver benzoate, p- An organic acid salt such as silver toluenesulfonate; a salt of an acid containing a fluorine atom such as silver trifluoromethanesulfonate, silver trifluoroacetate, silver tetrafluoroborate, silver hexafluoroantimonate, silver hexafluorophosphate; phthalocyanine Examples thereof include complex compounds in which amines and the like are coordinated with silver such as silver (I). The complex compound may be produced in the reaction system. Of these, salts of acids containing a fluorine atom, particularly silver trifluoromethanesulfonate, silver tetrafluoroborate, or silver hexafluorophosphate are preferable.

The monovalent silver compound is 10 with respect to the aldehyde.
^It is preferable to use ⁻³ to 10 times mol, particularly 10 ⁻² to 1 times mol. Moreover, it is preferable to use 10 ^-2 to 10 times mol, particularly 10 ^{-1 to} 5 times mol for the optically active bisphosphinobiaryl. As the organic tin oxide, a tin compound represented by the general formula (V) is preferable.

[0021]

Embedded image R ⁴ R ⁵ SnO (V) (In the formula, R ⁴ and R ⁵ each independently represent an optionally substituted aryl group or an alkyl group having 1 to 10 carbon atoms.) Aryl Examples of the group include a phenyl group which may have a substituent such as a lower alkyl group and a lower alkoxy group.

As the alkyl group having 1 to 10 carbon atoms, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,
Examples thereof include n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl groups. Of these, organic tin oxides in which R ⁴ and R ⁵ are both alkyl groups having 1 to 10 carbon atoms, particularly dimethyltin oxide, diethyltin oxide, dipropyltin oxide, or dibutyltin oxide are preferable.

Organotin oxide is compatible with monovalent silver compounds.
Then 10^-2-10 times mole, especially 10 ^-1~ 5 times mole used
Is preferred. The reaction is aldehyde and organotin
If the side is liquid, it can be done without solvent.
However, it is usually carried out in a solvent. Solvent does not participate in the reaction
Any one can be used as long as it is one. example
For example, halogenated hydrocarbon water such as methylene chloride or chloroform
Elementary; aromatic compounds such as benzene, toluene, xylene;
Aliphatic hydrocarbons such as pentane, hexane, heptane; di
Ethyl ether, diisopropyl ether, tetrahydr
Ether compounds such as lofran; acetonitrile, propylene
Examples thereof include nitrile compounds such as onitrile. solvent
Is usually 0.01 to 100% (heavy
The quantity ratio) is used. Preferred is 0.1-5
It is 0% (weight ratio), particularly 1 to 30% (weight ratio).

The reaction can be carried out by mixing the optically active bisphosphinobiaryl, the monovalent silver compound, the organic tin oxide, the aldehyde, the diketene, and the alcohol in any order. Usually, an optically active bisphosphinobiaryl, a monovalent silver compound and a necessary solvent are added to a reaction vessel in an inert gas atmosphere, and the temperature is about 1 to 60 ° C.
After stirring for 0 minutes to 2 hours, the reaction is performed by adding the aldehyde and diketene, and then adding the organotin oxide and alcohol.

The reaction temperature is usually -50 ° C to 50 ° C. Preferred is -30 ° C to 30 ° C, particularly -25 ° C to
25 ° C. At this temperature, the raw material compounds aldehyde and diketene are added, and then the tin compound and alcohol are added. The reaction time is usually 1 hour to 150 hours. After completion of the reaction, the optically active 5-hydroxy-3-ketoester can be isolated by a conventional method. For example, after adding a dilute aqueous acid solution to the reaction solution and stirring, extraction with an organic solvent, washing, and drying are performed, and the obtained crude optically active 5-hydroxy-3-ketoester is purified by silica gel column chromatography or distillation. Good.

Examples of the acid used in the isolation operation include inorganic acids such as hydrochloric acid, nitric acid and sulfuric acid. Of these, hydrochloric acid is preferred. The acid concentration is usually 0.05 N
It is 10N. 0.1N-10N, especially 0.3-2.0
A concentration of N is preferred. Although the amount used varies depending on the concentration and type, for example, when 1N-hydrochloric acid is used, the amount is 0.5 to 20 times the total volume of the reaction solution (volume ratio), particularly 0.7.
Double to 10-fold amount (volume ratio) is preferable.

[0027]

The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited thereto. The structure of the product was confirmed by ¹ H-NMR,
The optical purity was calculated as the enantiomer excess (% ee) by high performance liquid chromatography (HPLC) analysis with a column for separating optical isomers. The HPLC conditions for the optical purity test are described below. Column; Chiralpak AD eluent; n-hexane / ethanol / diethylamine =
90/10 / 0.1% Flow rate; 1.0 mL / min Detection wavelength; 254 nm Enantiomeric excess (% ee) = 100 × {(number of moles of target having one solid) − (having other solid Number of moles of target product)} / {(number of moles of target product having one solid)
+ (The number of moles of the target compound having the other steric shape)} In addition, in Examples and Comparative Examples, the conversion rate and the selectivity are defined as follows. Conversion = {Aldehyde reacted (moles) / Aldehyde charged (moles)} × 100 Selectivity = {Target compound (moles) / Aldehyde reacted (moles)} × 100.

Example 1 6 mL of trahydrofuran and silver (I) 2 trifluoromethanesulfonate were placed in a Schlenk tube through which nitrogen gas was passed.
8.3 mg (0.11 mmol) and (s) 2,2 '
-Bis (di-p-tolylphosphino) -1,1'-binaphthyl (Tol-BINAP) 81.5 mg (0.12
mmol) was added and the mixture was stirred at 25 ° C. for 1 hour. The reaction solution was cooled to -20 ° C, and cinnamaldehyde 64.7m.
A solution of g (0.49 mmol) in 1 mL of tetrahydrofuran was added dropwise to 32 mg (1.0 mmol) of methanol,
192.5 mg (2.28 mmol) of diketene and 24.9 mg (0.1 mmol) of dibutyltin oxide were added, and the mixture was stirred for 37 hours while maintaining -20 ° C. Add 960 mg (30 mmol) of methanol to the reaction solution, and add 25
After the temperature was raised to ℃, 1 mL of saturated saline and 300 mg of potassium fluoride were added, and the mixture was stirred for 30 minutes. As a result of quantitative analysis of the product by high performance liquid chromatography,
Unreacted cinnamaldehyde (0.32 mmol) remained, and the target 7-benzyl-5-hydroxy-3-oxohept-6-enoic acid methyl ester 0.13 mmo
1 was produced. The conversion was 35% and the selectivity was 76%. This reaction solution was added to a mixed solution of 15 mL of ethyl acetate and 10 mL of saturated saline and stirred to obtain a two-layer solution. The two-layer solution was separated, and the aqueous layer was mixed with 10 m of ethyl acetate.
The mixture was extracted with L, and the ethyl acetate layer and the extract were combined. The ethyl acetate solution was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to give 7-benzyl-5-hydroxy-3-oxohept. 25 mg of -6-enoic acid methyl ester was obtained (optical purity 76% ee).

¹ H-NMR (CDCl ₃ , 400 MHz)
δ: 2.4 (brs, 1H), 2.79 (d, 2H),
3.49 (s, 2H), 3.73 (S, 3H), 4.7
7 (sept, J = 6.1 Hz, 1H), 6.18 (d
d, J = 16.2 Hz, 6.1 Hz, 1H), 6.58
(Dd, J = 16.2 Hz, 1.2 Hz, 1H), 7.
03-7.28 (m, 5H).

Example 2 6 mL of trahydrofuran and 38.2 m of silver (I) hexafluorophosphate were placed in a Schlenk tube through which nitrogen gas was passed.
g (0.11 mmol) and (s) 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (B
74.8 mg (0.12 mmol) of INAP) was added, and the mixture was stirred at 25 ° C. for 1 hour. The reaction solution was cooled to −20 ° C., and cinnamaldehyde 64.7 mg (0.49 mmo
1 mL of a tetrahydrofuran solution of 1) was added dropwise. Then, 46 mg (1.0 mmol) of ethanol, 211 mg (2.5 mmol) of diketene, 24.9 mg (0.1 mmol) of dibutyltin oxide were added, and -20 ° C.
The mixture was stirred for 37 hours while maintaining. Ethanol 1 in the reaction solution
After 380 mg (30 mmol) was added and the temperature was raised to 25 ° C., saturated saline solution (1 mL) and potassium fluoride (300 m) were added.
g and stirred for 30 minutes. As a result of quantitative analysis of the product by high performance liquid chromatography, 1 0.25 mmo of unreacted cinnamaldehyde remained and the target 7
-Benzyl-5-hydroxy-3-oxohept-6-
0.17 mmol of enoic acid ethyl ester had been produced. The conversion was 48% and the selectivity was 70%. 15 mL of ethyl acetate and 10 mL of saturated saline were added to the obtained reaction solution.
Was added to the mixed solution and stirred to obtain a two-layer solution. The two-layer solution was separated, and the aqueous layer was extracted with 10 mL of ethyl acetate,
The ethyl acetate layer and the extract were combined. The ethyl acetate solution was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to give 7-benzyl-5-hydroxy-3-oxohept. -6-enoic acid ethyl ester 3
7 mg was obtained (optical purity 72% ee).

¹ H-NMR (CDCl ₃ , 250 MHz)
δ: 1.27 (t, J = 6.1 Hz, 3H), 2.4
(Brs, 1H), 2.75 (s, 1H), 2.77
(S, 1H), 3.37 (s, 2H), 4.29 (q,
J = 6.1 Hz, 2H), 4.97 (sept, J =
6.1 Hz, 1H), 6.1 (dd, J = 16.5H)
z, 6.1 Hz, 1 H), 6.55 (dd, J = 16.
5Hz, 1.2Hz, 1H), 7.1 to 7.3 (m, 5
H).

Example 3 8 mL of trahydrofuran and silver (I) 5 trifluoromethanesulfonate were placed in a Schlenk tube through which nitrogen gas was passed.
7.3 mg (0.22 mmol) and (s) 2,2 '
-Bis (di-p-tolylphosphino) -1,1'-binaphthyl (Tol-BINAP) 169.2 mg (0.2
5 mmol) was added and the mixture was stirred at 25 ° C. for 1 hour. The reaction solution was cooled to -20 ° C, and benzaldehyde 110.5
mg (1.04 mmol) of tetrahydrofuran 2 mL
Dissolved in and added dropwise to 120 mg of isopropyl alcohol
(2.0 mmol), 383.5 mg of diketene (4.5
6 mmol), dibutyltin oxide 54.8 mg
(0.22 mmol) was added, and the mixture was stirred for 89 hours while maintaining -20 ° C. Isopropyl alcohol 3300m
g (50 mmol) was added and the reaction solution was heated to 25 ° C., then saturated saline solution (2 mL) and potassium fluoride (700 m)
g was added and stirred for 30 minutes. As a result of quantitative analysis of the product by high performance liquid chromatography, 0.53 mmol of unreacted benzaldehyde remained and 0.32 mmol of the target isopropyl 5-hydroxy-3-oxo5-phenylpentanoate was formed. . The conversion was 49% and the selectivity was 62%. The obtained reaction solution was added to a mixed solution of 20 mL of ethyl acetate and 15 mL of saturated saline and stirred to obtain a two-layer solution. After separating the two-layer solution, the aqueous layer was extracted with 15 mL of ethyl acetate, and the ethyl acetate layer and the extract were combined. The ethyl acetate solution was dried over anhydrous sodium sulfate and the solvent was distilled off, followed by silica gel chromatography (elution solvent; hexane: ethyl acetate =
2: 1) and isopropyl 5-hydroxy-
67.5 mg of 3-oxo5-phenylpentanoate was obtained (optical purity 73% ee).

¹ H-NMR (CDCl ₃ , 250 MHz)
δ: 1.26 (d, J = 6.7 Hz, 6H), 2.4
(Brs, 1H), 2.94 (d, J = 3.7Hz, 1
H), 2.97 (d, J = 9.2 Hz, 1H), 3.4
6 (s, 2H), 5.0 to 5.1 (m, 1H), 5.2
(Dd, J = 3.7 Hz, 9.2 Hz, 1H), 7.3
~ 7.4 (m, 5H).

Comparative Example 1 6 mL of trahydrofuran and silver (I) trifluoromethanesulfonate were placed in a Schlenk tube through which nitrogen gas was passed.
28.3 mg (0.11 mmol) and (s) 2,
2'-bis (di-p-tolylphosphino) -1,1'-
81.5 mg of binaphthyl (Tol-BINAP) (0.
12 mmol) was added and the mixture was stirred at 25 ° C. for 1 hour.
The reaction solution was cooled to -20 ° C, and cinnamaldehyde 64.
7 mg (0.49 mmol) of tetrahydrofuran 1 m
L solution was added dropwise, and 32 mg of methanol (1.0 mmo
l), diketene 192.5 mg (2.28 mmol),
Dibutyltin dimethoxide 23.5 μL (0.1 mm
ol) was added, and the mixture was stirred for 37 hours while maintaining -20 ° C. After adding 960 mg (30 mmol) of methanol and heating the reaction solution to 25 ° C., 1 mL of saturated saline and 300 mg of potassium fluoride were added, and the mixture was stirred for 30 minutes. As a result of quantitative analysis of the product by high performance liquid chromatography, 0.07 mmol of unreacted cinnamaldehyde
Remains and the desired 7-benzyl-5-hydroxy-
3-oxohept-6-enoic acid methyl ester 0.26
mmol had been produced. Conversion rate is 86%, selectivity is 6
It was 5%. 15 mL of ethyl acetate was added to the obtained reaction solution.
And 10 mL of saturated saline solution were added to the mixed solution and stirred to obtain a two-layer solution. After separating the two-layer solution, the aqueous layer was extracted with 10 mL of ethyl acetate, and the ethyl acetate layer and the extract were combined. The ethyl acetate solution was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to give 7
-Benzyl-5-hydroxy-3-oxohept-6-
61 mg of enoic acid methyl ester was obtained (optical purity 67%
ee).

Comparative Example 2 0.55 mL (5 mmol) of titanium tetrachloride and 9 mL of methylene chloride were added to a Schlenk tube through which argon gas was passed, and the mixture was stirred and cooled to -20 ° C. to prepare a methylene chloride solution. Obtained. 0.68 g (5.2 m) of (E) -cinnamaldehyde in the obtained methylene chloride solution.
(mol) and 0.77 mL (10 mmol) of diketene were added, and the mixture was reacted for 50 hours while stirring at -20 ° C. Isopropyl alcohol 2 was added to the obtained reaction mixture.
mL was added, and the mixture was vigorously stirred for 30 minutes while maintaining -20 ° C to obtain an isopropyl alcohol solution. This isopropyl alcohol solution was added to a mixed solution of 1N-hydrochloric acid 25 mL + methylene chloride 25 mL, and vigorously stirred at room temperature for 30 minutes to obtain a separation solution. 5 mL of methylene chloride was added to this separating solution, and the methylene chloride layer was separated after stirring (the same operation was repeated 3 times using 5 mL of fresh methylene chloride each time). The obtained methylene chloride solutions were combined, dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 7: 3). The obtained elution fraction was measured using ¹ H-NMR, and isopropyl E-5-hydroxy-3-oxo-7 was used.
No peak corresponding to -phenyl-6-heptenoate could be identified.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Kazuaki Kanno             3-3-1 Chuo 8-chome, Ami Town, Inashiki District, Ibaraki Prefecture             Within Mitsubishi Chemical Corporation (72) Inventor Nao Urata             3-3-1 Chuo 8-chome, Ami Town, Inashiki District, Ibaraki Prefecture             Within Mitsubishi Chemical Corporation F-term (reference) 4H006 AA02 AC21 AC41 AC48 AC81                       BA05 BA11 BA30 BA32 BA48                       BJ50 BN10 BR10 KA37                 4H039 CA60 CA66 CD10 CF30 CH70

Claims (5)

[Claims] 1. An optically active bisphosphinobiaryl, 1
In the presence of a valent silver compound and an organic tin oxide, an aldehyde represented by the general formula (I): embedded image R ¹ CHO (I) (wherein R ¹ is a hydrocarbon group which may be substituted) Or a heterocyclic group.) Diketene, and an alcohol represented by the general formula (II): embedded image R ² OH (II) (In the formula, R ² represents an optionally substituted hydrocarbon group. ) Are reacted, The manufacturing method of optically active 5-hydroxy-3-ketoester represented by General formula (III). Embedded image R ¹ C ^* H (OH) CH ₂ COCH ₂ COOR ² (III) (wherein R ¹ and R ² have the same meanings as described above, and * represents an asymmetric carbon). 2. The optically active bisphosphinobiaryl is
The method according to claim 1, which is represented by the general formula (IV). [Chemical 4] (In the formula, R ³ represents an optionally substituted aryl group or cycloalkyl group.) 3. The optically active bisphosphinobiaryl is
2,2'-bis (diphenylphosphino) -1,1'-
Binaphthyl, 2,2'-bis (di-p-tolylphosphino) -1,1'-binaphthyl, 2,2'-bis (di-p
-Tert-butylphenylphosphino) -1,1'-
Binaphthyl, 2,2'-bis (di-m-tolylphosphino) -1,1'-binaphthyl, 2,2'-bis [di-
(3,5-Dimethylphenyl) phosphino] -1,1 ′
-Binaphtyl, 2,2'-bis (di-p-methoxyphenylphosphino) -1,1'-binaphthyl, 2,2'-
A compound selected from the group consisting of bis (dicyclopentylphosphino) -1,1'-binaphthyl and 2,2'-bis (dicyclohexylphosphino) -1,1'-binaphthyl. 1. The manufacturing method according to 1 or 2. 4. The monovalent silver compound is selected from the group consisting of silver trifluoromethanesulfonate, silver tetrafluoroborate, and silver hexafluorophosphate, according to claim 1. The manufacturing method according to any one. 5. The method according to claim 1, wherein the organic tin oxide is represented by the general formula (V). Embedded image R ⁴ R ⁵ SnO (V) (In the formula, R ⁴ and R ⁵ each independently represent an optionally substituted aryl group or an alkyl group having 1 to 10 carbon atoms.)