U.S. patent application number 13/887566 was filed with the patent office on 2013-09-19 for process for producing wine lactone.
This patent application is currently assigned to Takasago International Corporation. The applicant listed for this patent is TAKASAGO INTERNATIONAL CORPORATION. Invention is credited to Kenya Ishida, Yasuhiro Komatsuki, Hideo Ujihara, Kenji Yagi.
Application Number | 20130245286 13/887566 |
Document ID | / |
Family ID | 47259027 |
Filed Date | 2013-09-19 |
United States Patent
Application |
20130245286 |
Kind Code |
A1 |
Yagi; Kenji ; et
al. |
September 19, 2013 |
PROCESS FOR PRODUCING WINE LACTONE
Abstract
The present invention relates to a method comprising (A)
reacting a .beta.-keto ester with a 2-halo ester under basic
conditions to obtain a 2-aceto-3-methyl-succinic acid ester; (B)
reacting the resulting 2-aceto-3-methyl-succinic acid ester with
methyl vinyl ketone under basic conditions, optionally followed by
a decarboxylation reaction and hydrolysis, etc., to obtain an
.alpha.-methyl-.gamma.-keto acid; and (C) reducing the resulting
.alpha.-methyl-.gamma.-keto acid to obtain wine lactone or a
stereoisomer thereof or a mixture thereof. Alternatively, the
present invention relates to a method comprising step (A) as
recited above; (B) reacting the resulting 2-aceto-3-methyl-succinic
acid ester with methyl vinyl ketone under basic conditions,
followed by decarboxylation reaction to obtain an
.alpha.-methyl-.gamma.-keto acid ester; and (E) reducing the
resulting .alpha.-methyl-.gamma.-keto acid ester in the presence of
a ruthenium complex having a specific structure and in the presence
of a hydrogen donor to obtain wine lactone or a stereoisomer
thereof or a mixture thereof.
Inventors: |
Yagi; Kenji; (Kanagawa,
JP) ; Komatsuki; Yasuhiro; (Kanagawa, JP) ;
Ujihara; Hideo; (Kanagawa, JP) ; Ishida; Kenya;
(Kanagawa, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TAKASAGO INTERNATIONAL CORPORATION |
Tokyo |
|
JP |
|
|
Assignee: |
Takasago International
Corporation
Tokyo
JP
|
Family ID: |
47259027 |
Appl. No.: |
13/887566 |
Filed: |
May 6, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13483373 |
May 30, 2012 |
8481759 |
|
|
13887566 |
|
|
|
|
Current U.S.
Class: |
549/302 |
Current CPC
Class: |
C07D 307/83 20130101;
C07D 307/77 20130101 |
Class at
Publication: |
549/302 |
International
Class: |
C07D 307/77 20060101
C07D307/77 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 1, 2011 |
JP |
2011-123267 |
Claims
1. A process for producing a compound represented by formula (a),
which is wine lactone or a stereoisomer thereof or a mixture
thereof: ##STR00083## wherein said process comprises: A) the step
of reacting a .beta.-keto ester represented by formula (1):
##STR00084## [wherein R.sup.1 is an alkyl group containing 1 to 4
carbon atoms] with a 2-halo ester represented by formula (2):
##STR00085## [wherein R.sup.2 is an alkyl group containing 1 to 4
carbon atoms, and X is a chlorine atom or a bromine atom] under
basic conditions to obtain a 2-aceto-3-methyl-succinic acid ester
represented by formula (3): ##STR00086## [wherein R.sup.1 is as
defined in formula (1), and R.sup.2 is as defined in formula (2)];
B-2) the step of reacting the 2-aceto-3-methyl-succinic acid ester
obtained in step A) with methyl vinyl ketone under basic
conditions, followed by decarboxylation reaction to obtain an
.alpha.-methyl-.gamma.-keto acid ester represented by formula (5):
##STR00087## [wherein R.sup.2 is as defined in formula (2)]; and E)
the step of reducing the .alpha.-methyl-.gamma.-keto acid ester
obtained in step B-2) in the presence of a ruthenium complex
selected from compounds represented by formula (6) or (7) and in
the presence of a hydrogen donor to obtain the compound represented
by formula (a): ##STR00088## [wherein * represents an asymmetric
carbon atom, R.sup.31 is an alkyl group containing 1 to 10 carbon
atoms; a halogenated alkyl group containing 1 to 10 carbon atoms; a
10-camphoryl group; an amino group which may be substituted with
one or two alkyl groups each containing 1 to 10 carbon atoms; or an
aryl group which may be substituted with at least one substituent
selected from the group consisting of an alkyl group containing 1
to 10 carbon atoms, a halogenated alkyl group containing 1 to 10
carbon atoms, a halogen atom, a cyano group (--CN), an amino group,
an alkylamino group (--NR.sup.20R.sup.21), a 5- or 6-membered
cyclic amino group, an acylamino group (--NH--CO--R.sup.20), a
hydroxyl group, an alkoxy group (--OR.sup.20), an acyl group
(--CO--R.sup.20), a carboxyl group, an alkoxycarbonyl group
(--COOR.sup.20), a phenoxycarbonyl group, a mercapto group, an
alkylthio group (--SR.sup.20), a silyl group
(--SiR.sup.20R.sup.21R.sup.22) and a nitro group (--NO.sub.2),
wherein R.sup.20, R.sup.21 and R.sup.22 are each independently a
hydrogen atom, an alkyl group containing 1 to 10 carbon atoms, or a
cycloalkyl group containing 3 to 10 carbon atoms, Y is a hydrogen
atom, W is a trifluoromethanesulfonyloxy group, a
p-toluenesulfonyloxy group, a methanesulfonyloxy group, a
benzenesulfonyloxy group, a hydrogen atom, or a halogen atom, j and
k are each independently 0 or 1, provided that j+k is not 1,
R.sup.32 and R.sup.33 are each independently a hydrogen atom; an
alkyl group containing 1 to 10 carbon atoms; a phenyl group which
may be substituted with at least one substituent selected from the
group consisting of an alkyl group containing 1 to 10 carbon atoms,
an alkoxy group containing 1 to 10 carbon atoms and a halogen atom;
or a cycloalkyl group containing 3 to 8 carbon atoms, or
alternatively, R.sup.32 and R.sup.33 may together form a ring,
R.sup.11, R.sup.12, R.sup.13, R.sup.14 and R.sup.15 each
independently represent a hydrogen atom, an alkyl group containing
1 to 10 carbon atoms, or an alkoxy group containing 1 to 10 carbon
atoms, R.sup.16, R.sup.17, R.sup.18 and R.sup.19 are each
independently a hydrogen atom, a hydroxyl group, an alkyl group
containing 1 to 10 carbon atoms, or an alkoxy group containing 1 to
10 carbon atoms, or alternatively, R.sup.16 and R.sup.17 may form a
carbonyl group together with their adjacent carbon atom and/or
R.sup.18 and R.sup.19 may form a carbonyl group together with their
adjacent carbon atom, Z is an oxygen atom or a sulfur atom, n.sub.1
is 1 or 2, and n.sub.2 is an integer of 1 to 3] ##STR00089##
[wherein * represents an asymmetric carbon atom, R.sup.31 is an
alkyl group containing 1 to 10 carbon atoms; a halogenated alkyl
group containing 1 to 10 carbon atoms; a 10-camphoryl group; an
amino group which may be substituted with one or two alkyl groups
each containing 1 to 10 carbon atoms; or an aryl group which may be
substituted with at least one substituent selected from the group
consisting of an alkyl group containing 1 to 10 carbon atoms, a
halogenated alkyl group containing 1 to 10 carbon atoms, a halogen
atom, a cyano group (--CN), an amino group, an alkylamino group
(--NR.sup.20R.sup.21), a 5- or 6-membered cyclic amino group, an
acylamino group (--NH--CO--R.sup.20), a hydroxyl group, an alkoxy
group (--OR.sup.20), an acyl group (--CO--R.sup.20), a carboxyl
group, an alkoxycarbonyl group (--COOR.sup.20), a phenoxycarbonyl
group, a mercapto group, an alkylthio group (--SR.sup.20), a silyl
group (--SiR.sup.20R.sup.21R.sup.22) and a nitro group
(--NO.sub.2), R.sup.20, R.sup.21 and R.sup.22 are each
independently a hydrogen atom, an alkyl group containing 1 to 10
carbon atoms, or a cycloalkyl group containing 3 to 10 carbon
atoms, Y is a hydrogen atom, R.sup.32 and R.sup.33 are each
independently a hydrogen atom; an alkyl group containing 1 to 10
carbon atoms; a phenyl group which may be substituted with at least
one substituent selected from the group consisting of an alkyl
group containing 1 to 10 carbon atoms, an alkoxy group containing 1
to 10 carbon atoms and a halogen atom; or a cycloalkyl group
containing 3 to 8 carbon atoms, or alternatively, R.sup.32 and
R.sup.33 may together form a ring, R.sup.11, R.sup.12, R.sup.13,
R.sup.14 and R.sup.15 are each independently a hydrogen atom, an
alkyl group containing 1 to 10 carbon atoms, or an alkoxy group
containing 1 to 10 carbon atoms, R.sup.16, R.sup.17, R.sup.18 and
R.sup.19 are each independently a hydrogen atom, a hydroxyl group,
an alkyl group containing 1 to 10 carbon atoms, or an alkoxy group
containing 1 to 10 carbon atoms, or alternatively, R.sup.16 and
R.sup.17 may form a carbonyl group together with their adjacent
carbon atom and/or R.sup.18 and R.sup.19 may form a carbonyl group
together with their adjacent carbon atom, Z is an oxygen atom or a
sulfur atom, Q.sup.- is a counter anion, n.sub.1 is 1 or 2, and
n.sub.2 is an integer of 1 to 3].
2. The process according to claim 1, wherein the ruthenium complex
represented by formula (6) is a compound represented by the
following formula: ##STR00090##
3. The process according to claim 1, which further comprises the
step of distilling the compound obtained in step E) under basic
conditions to obtain a diastereomeric isomer mixture composed of
(3S,3aS,7aR) and (3R,3aR,7aS) isomers represented by the following
formulae: ##STR00091##
4. The process according to claim 3, which further comprises the
step of recrystallization to obtain the (3S,3aS,7aR) isomer
represented by the following formula: ##STR00092##
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Divisional of U.S. application Ser.
No. 13/483,373, filed May 30, 2012, which claims priority from
Japanese patent application no. JP 2011-123267, filed Jun. 1, 2011,
the entire contents of which are incorporated herein by
reference.
TECHNICAL FIELD
[0002] The present invention relates to a process for producing
wine lactone, which is useful as a flavor or fragrance compound, or
a stereoisomer thereof or a mixture thereof.
BACKGROUND ART
[0003] Wine lactone, whose chemical name is
(3a,4,5,7a)-tetrahydro-3,6-dimethyl-benzofuran-2(3H)-one, was found
in 1975 by Southwell from metabolites in koalas. This compound was
isolated from white wine in 1996 by Guth as being one of the most
important aroma components of white wine and thus named as "wine
lactone." Wine lactone has eight types of stereoisomers, all of
which were synthesized by Guth, and the compound naturally
occurring (i.e., wine lactone) is a (3S,3aS,7aR) isomer. Among the
eight types of stereoisomers, this (3S,3aS,7aR) isomer was found to
have the strongest aroma and to be excellent in the quality of
aroma (Non-patent Document 1: Helv. Chim. Acta, 79, (1996),
1559-1571).
[0004] There are various reports of how to produce wine
lactone.
[0005] For example, Non-patent Document 1 (supra) reports a process
for producing all stereoisomers including wine lactone, a process
mediated by Diels-Alder reaction for 6-membered ring formation, and
a process starting from limonene having the same stereochemistry as
the 3a-position of wine lactone. However, the process for producing
all stereoisomers is not cost-effective because wine lactone, i.e.,
the (3S,3aS,7aR) isomer which is excellent in aroma and the quality
thereof is obtained in a yield as low as 20%. The process mediated
by Diels-Alder reaction allows diastereoselective synthesis of a
desired stereoisomer, but is not suitable for use on an industrial
scale because of using harmful reagents, such as chromic acid for
oxidation reaction and methyl iodide for methylation. The process
starting from limonene is also difficult to use on an industrial
scale because of using harmful reagents, such as chromic acid for
oxidation reaction.
[0006] Non-patent Document 2 (J. Org. Chem., 46 (1981), 3896-3900)
reports a process for obtaining wine lactone from a 2-cyclohexenol
derivative through Claisen rearrangement reaction. According to
this process, it is possible to synthesize wine lactone in a
diastereoselective manner, but this process is not suitable for use
on an industrial scale because of great difficulty in obtaining the
starting 2-cyclohexenol derivative and because of using harmful
reagents, such as methyl iodide for methylation.
[0007] Non-patent Document 3 (Eur. J. Org. Chem., (2000), 419-423)
describes a process for obtaining wine lactone in a stereoselective
manner through addition reaction of a malonic acid ester using a
palladium complex as a catalyst. According to this process, it is
possible to obtain only the (3S,3aS,7aR) isomer in a
stereoselective manner. However, this process requires the stages
of lactonization, lactone opening and recyclization, and hence
involves a larger number of steps and complicated procedures.
Moreover, this process is not suitable for use on an industrial
scale because of using harmful reagents, such as methyl iodide for
methylation.
[0008] Non-patent Document 4 (Tetrahedron: Asymmetry, 12, (2001),
2985-2988) discloses a process involving hydration of isolimonene
and synthesis of a carboxylic acid through oxidation reaction,
followed by ring closure reaction to synthesize wine lactone.
According to this process, it is possible to synthesize a desired
stereoisomer in a diastereoselective manner. However, this process
is not suitable for use on an industrial scale because of using
harmful reagents, such as chromic acid for oxidation reaction.
[0009] Patent Document 1 (JP 2004-269463 A) describes a process
starting from a 3-keto ester, which involves reduction of carbonyl
groups using an optically active oxazaborolidine as an chiral
ligand, followed by hydrolysis and cyclization reaction to
synthesize wine lactone. However, this process also has a problem
in using harmful reagents, such as butyl lithium and methyl iodide
for methylation.
[0010] Patent Document 2 (JP 2010-195765 A) describes a process for
obtaining wine lactone by simultaneous formation of two rings
through Diels-Alder reaction. This process is advantageous in that
wine lactone can be synthesized without using any harmful reagents,
but it cannot be regarded as an industrially advantageous process
because the temperature required for cyclization reaction is as
very high as 200.degree. C.
PRIOR ART DOCUMENTS
Patent Documents
[0011] Patent Document 1: JP 2004-269463 A [0012] Patent Document
2: JP 2010-195765 A
Non-patent Documents
[0012] [0013] Non-patent Document 1: Helv. Chim. Acta, 79, (1996),
1559-1571 [0014] Non-patent Document 2: J. Org. Chem., 46 (1981),
3896-3900 [0015] Non-patent Document 3: Eur. J. Org. Chem., (2000),
419-423 [0016] Non-patent Document 4: Tetrahedron: Asymmetry, 12,
(2001), 2985-2988 [0017] Non-patent Document 5: J. Org. Chem. 54,
1876-1883 (1989)
SUMMARY OF THE INVENTION
Problem to be Solved by the Invention
[0018] Under the circumstances as stated above, there is a demand
for the provision of a simple process for producing wine lactone or
a stereoisomer thereof without using any harmful or expensive
reagents and without requiring any extreme reaction conditions such
as extremely low or high temperatures.
Means to Solve the Problem
[0019] As a result of extensive and intensive efforts made to solve
the problems stated above, the inventors of the present invention
have found that wine lactone or a stereoisomer thereof or a mixture
thereof can be produced through fewer steps without using any
harmful or expensive reagents. Moreover, the inventors have also
found that wine lactone and a diastereomeric isomer thereof can be
produced in a highly selective manner, as needed. These findings
led to the completion of the present invention.
[0020] Namely, the present invention relates to a process for
producing wine lactone or a stereoisomer thereof or a mixture
thereof, as shown below.
[1]A process for producing a compound represented by formula (a),
which is wine lactone or a stereoisomer thereof or a mixture
thereof:
##STR00001##
wherein said process comprises: A) the step of reacting a
.beta.-keto ester represented by formula (1):
##STR00002##
[wherein R.sup.1 is an alkyl group containing 1 to 4 carbon atoms]
with a 2-halo ester represented by formula (2):
##STR00003##
[wherein R.sup.2 is an alkyl group containing 1 to 4 carbon atoms,
and X is a chlorine atom or a bromine atom] under basic conditions
to obtain a 2-aceto-3-methyl-succinic acid ester represented by
formula (3):
##STR00004##
[wherein R.sup.1 is as defined in formula (1), and R.sup.2 is as
defined in formula (2)]; B-1) the step of reacting the
2-aceto-3-methyl-succinic acid ester obtained in step A) with
methyl vinyl ketone under basic conditions, followed by hydrolysis
to obtain an .alpha.-methyl-.gamma.-keto acid represented by
formula (4):
##STR00005##
and C) the step of reducing the .alpha.-methyl-.gamma.-keto acid
obtained in step B-1) to obtain the compound represented by formula
(a). [2]A process for producing a compound represented by formula
(a), which is wine lactone or a stereoisomer thereof or a mixture
thereof:
##STR00006##
wherein said process comprises: A) the step of reacting a
.beta.-keto ester represented by formula (1):
##STR00007##
[wherein R.sup.1 is an alkyl group containing 1 to 4 carbon atoms]
with a 2-halo ester represented by formula (2):
##STR00008##
[wherein R.sup.2 is an alkyl group containing 1 to 4 carbon atoms,
and X is a chlorine atom or a bromine atom] under basic conditions
to obtain a 2-aceto-3-methyl-succinic acid ester represented by
formula (3):
##STR00009##
[wherein R.sup.1 is as defined in formula (1), and R.sup.2 is as
defined in formula (2)]; B-2) the step of reacting the
2-aceto-3-methyl-succinic acid ester obtained in step A) with
methyl vinyl ketone under basic conditions, followed by
decarboxylation reaction to obtain an .alpha.-methyl-.gamma.-keto
acid ester represented by formula (5):
##STR00010##
[wherein R.sup.2 is as defined in formula (2)]; B-3) the step of
hydrolyzing the .alpha.-methyl-.gamma.-keto acid ester obtained in
step B-2) to obtain an .alpha.-methyl-.gamma.-keto acid represented
by formula (4):
##STR00011##
and C) the step of reducing the .alpha.-methyl-.gamma.-keto acid
obtained in step B-3) to obtain the compound represented by formula
(a). [3] The process according to [1] or [2] above, wherein step C)
comprises causing asymmetric reduction reaction in the presence of
an optically active form of a ruthenium complex selected from
compounds represented by formula (6) or (7) and in the presence of
a hydrogen donor:
##STR00012##
[wherein * represents an asymmetric carbon atom,
[0021] R.sup.31 is an alkyl group containing 1 to 10 carbon atoms;
a halogenated alkyl group containing 1 to 10 carbon atoms; a
10-camphoryl group; an amino group which may be substituted with
one or two alkyl groups each containing 1 to 10 carbon atoms; or an
aryl group which may be substituted with at least one substituent
selected from the group consisting of an alkyl group containing 1
to 10 carbon atoms, a halogenated alkyl group containing 1 to 10
carbon atoms, a halogen atom, a cyano group (--CN), an amino group,
an alkylamino group (--NR.sup.20R.sup.21), a 5- or 6-membered
cyclic amino group, an acylamino group (--NH--CO--R.sup.20), a
hydroxyl group, an alkoxy group (--OR.sup.20), an acyl group
(--CO--R.sup.20), a carboxyl group, an alkoxycarbonyl group
(--COOR.sup.20), a phenoxycarbonyl group, a mercapto group, an
alkylthio group (--SR.sup.20), a silyl group
(--SiR.sup.20R.sup.21R.sup.22) and a nitro group (--NO.sub.2),
wherein R.sup.20, R.sup.21 and R.sup.22 are each independently a
hydrogen atom, an alkyl group containing 1 to 10 carbon atoms, or a
cycloalkyl group containing 3 to 10 carbon atoms,
[0022] Y is a hydrogen atom,
[0023] W is a trifluoromethanesulfonyloxy group, a
p-toluenesulfonyloxy group, a methanesulfonyloxy group, a
benzenesulfonyloxy group, a hydrogen atom, or a halogen atom,
[0024] j and k are each independently 0 or 1, provided that j+k is
not 1,
[0025] R.sup.32 and R.sup.33 are each independently a hydrogen
atom; an alkyl group containing 1 to 10 carbon atoms; a phenyl
group which may be substituted with at least one substituent
selected from the group consisting of an alkyl group containing 1
to 10 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms
and a halogen atom; or a cycloalkyl group containing 3 to 8 carbon
atoms, or alternatively, R.sup.32 and R.sup.33 may together form a
ring,
[0026] R.sup.11, R.sup.12, R.sup.13, R.sup.14 and R.sup.15 each
independently represent a hydrogen atom, an alkyl group containing
1 to 10 carbon atoms, or an alkoxy group containing 1 to 10 carbon
atoms,
[0027] R.sup.16, R.sup.17, R.sup.18 and R.sup.19 are each
independently a hydrogen atom, a hydroxyl group, an alkyl group
containing 1 to 10 carbon atoms, or an alkoxy group containing 1 to
10 carbon atoms, or alternatively, R.sup.16 and R.sup.17 may form a
carbonyl group together with their adjacent carbon atom and/or
R.sup.18 and R.sup.19 may form a carbonyl group together with their
adjacent carbon atom,
[0028] Z is an oxygen atom or a sulfur atom,
[0029] n.sub.1 is 1 or 2, and n.sub.2 is an integer of 1 to 3]
##STR00013##
[wherein * represents an asymmetric carbon atom,
[0030] R.sup.31 is an alkyl group containing 1 to 10 carbon atoms;
a halogenated alkyl group containing 1 to 10 carbon atoms; a
10-camphoryl group; an amino group which may be substituted with
one or two alkyl groups each containing 1 to 10 carbon atoms; or an
aryl group which may be substituted with at least one substituent
selected from the group consisting of an alkyl group containing 1
to 10 carbon atoms, a halogenated alkyl group containing 1 to 10
carbon atoms, a halogen atom, a cyano group (--CN), an amino group,
an alkylamino group (--NR.sup.20R.sup.21), a 5- or 6-membered
cyclic amino group, an acylamino group (--NH--CO--R.sup.20), a
hydroxyl group, an alkoxy group (--OR.sup.20), an acyl group
(--CO--R.sup.20), a carboxyl group, an alkoxycarbonyl group
(--COOR.sup.20), a phenoxycarbonyl group, a mercapto group, an
alkylthio group (--SR.sup.20), a silyl group
(--SiR.sup.20R.sup.21R.sup.22) and a nitro group (--NO.sub.2),
[0031] R.sup.20, R.sup.21 and R.sup.22 are each independently a
hydrogen atom, an alkyl group containing 1 to 10 carbon atoms, or a
cycloalkyl group containing 3 to 10 carbon atoms,
[0032] Y is a hydrogen atom,
[0033] R.sup.32 and R.sup.33 are each independently a hydrogen
atom; an alkyl group containing 1 to 10 carbon atoms; a phenyl
group which may be substituted with at least one substituent
selected from the group consisting of an alkyl group containing 1
to 10 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms
and a halogen atom; or a cycloalkyl group containing 3 to 8 carbon
atoms, or alternatively, R.sup.32 and R.sup.33 may together form a
ring,
[0034] R.sup.11, R.sup.12, R.sup.13, R.sup.14 and R.sup.15 are each
independently a hydrogen atom, an alkyl group containing 1 to 10
carbon atoms, or an alkoxy group containing 1 to 10 carbon
atoms,
[0035] R.sup.16, R.sup.17, R.sup.18 and R.sup.19 are each
independently a hydrogen atom, a hydroxyl group, an alkyl group
containing 1 to 10 carbon atoms, or an alkoxy group containing 1 to
10 carbon atoms, or alternatively, R.sup.16 and R.sup.17 may form a
carbonyl group together with their adjacent carbon atom and/or
R.sup.18 and R.sup.19 may form a carbonyl group together with their
adjacent carbon atom,
[0036] Z is an oxygen atom or a sulfur atom, Q.sup.- is a counter
anion,
[0037] n.sub.1 is 1 or 2, and n.sub.2 is an integer of 1 to 3].
[4] The process according to [3] above, wherein the ruthenium
complex represented by formula (6) is a compound represented by the
following formula:
##STR00014##
[5] The process according to [1] or [2] above, which further
comprises the step of distilling the compound obtained in step C)
under basic conditions to obtain a diastereomeric isomer mixture
composed of (3S,3aS,7aR) and (3R,3aR,7aS) isomers represented by
the following formulae:
##STR00015##
[6] The process according to [5] above, wherein the content of the
diastereomeric isomer mixture composed of (3S,3aS,7aR) and
(3R,3aR,7aS) isomers is 90% by weight or more, relative to the
total weight of the compound represented by formula (a). [7] The
process according to [3] or [4] above, which further comprises the
step of distilling the compound obtained in step C) under basic
conditions to obtain a diastereomeric isomer mixture composed of
(3S,3aS,7aR) and (3R,3aR,7aS) isomers represented by the following
formulae:
##STR00016##
[8] The process according to [7] above, which further comprises the
step of recrystallization to obtain the (3S,3aS,7aR) isomer
represented by the following formula:
##STR00017##
[9]A process for producing a compound represented by formula (a),
which is wine lactone or a stereoisomer thereof or a mixture
thereof:
##STR00018##
wherein said process comprises: A) the step of reacting a 3-keto
ester represented by formula (1):
##STR00019##
[wherein R.sup.1 is an alkyl group containing 1 to 4 carbon atoms]
with a 2-halo ester represented by formula (2):
##STR00020##
[wherein R.sup.2 is an alkyl group containing 1 to 4 carbon atoms,
and X is a chlorine atom or a bromine atom] under basic conditions
to obtain a 2-aceto-3-methyl-succinic acid ester represented by
formula (3):
##STR00021##
[wherein R.sup.1 is as defined in formula (1), and R.sup.2 is as
defined in formula (2)]; B-2) the step of reacting the
2-aceto-3-methyl-succinic acid ester obtained in step A) with
methyl vinyl ketone under basic conditions, followed by
decarboxylation reaction to obtain an .alpha.-methyl-1-keto acid
ester represented by formula (5):
##STR00022##
[wherein R.sup.2 is as defined in formula (2)]; and E) the step of
reducing the .alpha.-methyl-.gamma.-keto acid ester obtained in
step B-2) in the presence of a ruthenium complex selected from
compounds represented by formula (6) or (7) and in the presence of
a hydrogen donor to obtain the compound represented by formula
(a):
##STR00023##
[wherein * represents an asymmetric carbon atom,
[0038] R.sup.31 is an alkyl group containing 1 to 10 carbon atoms;
a halogenated alkyl group containing 1 to 10 carbon atoms; a
10-camphoryl group; an amino group which may be substituted with
one or two alkyl groups each containing 1 to 10 carbon atoms; or an
aryl group which may be substituted with at least one substituent
selected from the group consisting of an alkyl group containing 1
to 10 carbon atoms, a halogenated alkyl group containing 1 to 10
carbon atoms, a halogen atom, a cyano group (--CN), an amino group,
an alkylamino group (--NR.sup.20R.sup.21), a 5- or 6-membered
cyclic amino group, an acylamino group (--NH--CO--R.sup.20), a
hydroxyl group, an alkoxy group (--OR.sup.20), an acyl group
(--CO--R.sup.20), a carboxyl group, an alkoxycarbonyl group
(--COOR.sup.20), a phenoxycarbonyl group, a mercapto group, an
alkylthio group (--SR.sup.20), a silyl group
(--SiR.sup.20R.sup.21R.sup.22) and a nitro group (--NO.sub.2),
wherein R.sup.20, R.sup.21 and R.sup.22 are each independently a
hydrogen atom, an alkyl group containing 1 to 10 carbon atoms, or a
cycloalkyl group containing 3 to 10 carbon atoms,
[0039] Y is a hydrogen atom,
[0040] W is a trifluoromethanesulfonyloxy group, a
p-toluenesulfonyloxy group, a methanesulfonyloxy group, a
benzenesulfonyloxy group, a hydrogen atom, or a halogen atom,
[0041] j and k are each independently 0 or 1, provided that j+k is
not 1, R.sup.32 and R.sup.33 are each independently a hydrogen
atom; an alkyl group containing 1 to 10 carbon atoms; a phenyl
group which may be substituted with at least one substituent
selected from the group consisting of an alkyl group containing 1
to 10 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms
and a halogen atom; or a cycloalkyl group containing 3 to 8 carbon
atoms, or alternatively, R.sup.32 and R.sup.33 may together form a
ring,
[0042] R.sup.11, R.sup.12, R.sup.13, R.sup.14 and R.sup.15 each
independently represent a hydrogen atom, an alkyl group containing
1 to 10 carbon atoms, or an alkoxy group containing 1 to 10 carbon
atoms,
[0043] R.sup.16, R.sup.17, R.sup.18 and R.sup.19 are each
independently a hydrogen atom, a hydroxyl group, an alkyl group
containing 1 to 10 carbon atoms, or an alkoxy group containing 1 to
10 carbon atoms, or alternatively, R.sup.16 and R.sup.17 may form a
carbonyl group together with their adjacent carbon atom and/or
R.sup.18 and R.sup.19 may form a carbonyl group together with their
adjacent carbon atom,
[0044] Z is an oxygen atom or a sulfur atom,
[0045] n.sub.1 is 1 or 2, and n.sub.2 is an integer of 1 to 3]
##STR00024##
[wherein * represents an asymmetric carbon atom,
[0046] R.sup.31 is an alkyl group containing 1 to 10 carbon atoms;
a halogenated alkyl group containing 1 to 10 carbon atoms; a
10-camphoryl group; an amino group which may be substituted with
one or two alkyl groups each containing 1 to 10 carbon atoms; or an
aryl group which may be substituted with at least one substituent
selected from the group consisting of an alkyl group containing 1
to 10 carbon atoms, a halogenated alkyl group containing 1 to 10
carbon atoms, a halogen atom, a cyano group (--CN), an amino group,
an alkylamino group (--NR.sup.20R.sup.21), a 5- or 6-membered
cyclic amino group, an acylamino group (--NH--CO--R.sup.20), a
hydroxyl group, an alkoxy group (--OR.sup.20), an acyl group
(--CO--R.sup.20), a carboxyl group, an alkoxycarbonyl group
(--COOR.sup.20), a phenoxycarbonyl group, a mercapto group, an
alkylthio group (--SR.sup.20), a silyl group
(--SiR.sup.20R.sup.21R.sup.22) and a nitro group (--NO.sub.2),
R.sup.20, R.sup.21 and R.sup.22 are each independently a hydrogen
atom, an alkyl group containing 1 to 10 carbon atoms, or a
cycloalkyl group containing 3 to 10 carbon atoms,
[0047] Y is a hydrogen atom,
[0048] R.sup.32 and R.sup.33 are each independently a hydrogen
atom; an alkyl group containing 1 to 10 carbon atoms; a phenyl
group which may be substituted with at least one substituent
selected from the group consisting of an alkyl group containing 1
to 10 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms
and a halogen atom; or a cycloalkyl group containing 3 to 8 carbon
atoms, or alternatively, R.sup.32 and R.sup.33 may together form a
ring,
[0049] R.sup.11, R.sup.12, R.sup.13, R.sup.14 and R.sup.15 are each
independently a hydrogen atom, an alkyl group containing 1 to 10
carbon atoms, or an alkoxy group containing 1 to 10 carbon
atoms,
[0050] R.sup.16, R.sup.17, R.sup.18 and R.sup.19 are each
independently a hydrogen atom, a hydroxyl group, an alkyl group
containing 1 to 10 carbon atoms, or an alkoxy group containing 1 to
10 carbon atoms, or alternatively, R.sup.16 and R.sup.17 may form a
carbonyl group together with their adjacent carbon atom and/or
R.sup.18 and R.sup.19 may form a carbonyl group together with their
adjacent carbon atom,
[0051] Z is an oxygen atom or a sulfur atom, Q.sup.- is a counter
anion,
[0052] n.sub.1 is 1 or 2, and n.sub.2 is an integer of 1 to 3].
[10] The process according to [9] above, wherein in step E), the
ruthenium complex selected from compounds represented by formula
(6) or (7) is an optically active ruthenium complex and is used to
cause asymmetric reduction reaction. [11] The process according to
[9] or [10] above, wherein the ruthenium complex represented by
formula (6) is a compound represented by the following formula:
##STR00025##
[12] A process for producing a compound represented by formula (a),
which is wine lactone or a stereoisomer thereof or a mixture
thereof:
##STR00026##
wherein said process comprises: A) the step of reacting a
.beta.-keto ester represented by formula (1):
##STR00027##
[wherein R.sup.1 is an alkyl group containing 1 to 4 carbon atoms]
with a 2-halo ester represented by formula (2):
##STR00028##
[wherein R.sup.2 is an alkyl group containing 1 to 4 carbon atoms,
and X is a chlorine atom or a bromine atom] under basic conditions
to obtain a 2-aceto-3-methyl-succinic acid ester represented by
formula (3:
##STR00029##
[wherein R.sup.1 is as defined in formula (1), and R.sup.2 is as
defined in formula (2)]; B-2) the step of reacting the
2-aceto-3-methyl-succinic acid ester obtained in step A) with
methyl vinyl ketone under basic conditions, followed by
decarboxylation reaction to obtain an .alpha.-methyl-.gamma.-keto
acid ester represented by formula (5):
##STR00030##
[wherein R.sup.2 is as defined in formula (2)]; and E) the step of
subjecting the .alpha.-methyl-.gamma.-keto acid ester obtained in
step B-2) to asymmetric hydrogenation reaction under basic
conditions and in the presence of an optically active ruthenium
complex represented by formula (8) and a hydrogen gas to obtain the
compound represented by formula (a):
##STR00031##
[wherein represents an optically active diphosphine,
[0053] V is an anionic group,
[0054] R.sup.a, R.sup.b and R.sup.c are each independently a
hydrogen atom, an optionally substituted C.sub.1 to C.sub.20 alkyl
group, an optionally substituted C.sub.2 to C.sub.20 alkenyl group,
an optionally substituted C.sub.3 to C.sub.8 cycloalkyl group, an
optionally substituted C.sub.7 to C.sub.20 aralkyl group, an
optionally substituted aryl group, or an optionally substituted
heterocyclyl group, or alternatively, R.sup.b and R.sup.e may
together form an alkylene group or an alkylenedioxy group,
[0055] R.sup.N1, R.sup.N2, R.sup.N3 and R.sup.N4 are each
independently a hydrogen atom, an optionally substituted C.sub.1 to
C.sub.20 alkyl group, an optionally substituted C.sub.2 to C.sub.20
alkenyl group, an optionally substituted C.sub.7 to C.sub.20
aralkyl group, or an optionally substituted C.sub.3 to C.sub.8
cycloalkyl group, provided that at least one of R.sup.N1, R.sup.N2,
R.sup.N3 and R.sup.N4 is a hydrogen atom, and R.sup.N1 and R.sup.a
may together form an alkylene group,
[0056] n is an integer of 0 to 3, and
[0057] Ar is an optionally substituted arylene group].
[13] The process according to [12] above, wherein the optically
active ruthenium complex of formula (8) is a compound represented
by the following formula:
##STR00032##
[wherein Me represents a methyl group]. [14] The process according
to any one of [9] to [13] above, which further comprises the step
of distilling the compound obtained in step E) under basic
conditions to obtain a diastereomeric isomer mixture composed of
(3S,3aS,7aR) and (3R,3aR,7aS) isomers represented by the following
formulae:
##STR00033##
[15] The process according to [14] above, which further comprises
the step of recrystallization to obtain the (3S,3aS,7aR) isomer
represented by the following formula:
##STR00034##
[16] The process according to any one of [1] to [15] above, wherein
all of the production steps are performed at a temperature of
0.degree. C. or more to 130.degree. C. or less, and none of the
production steps requires any purification step by silica gel
column chromatography.
Effect of the Invention
[0058] According to the present invention, wine lactone or a
stereoisomer thereof or a mixture thereof can be produced in a
simple manner through fewer steps without using any harmful or
expensive reagents and without requiring reaction conditions of
extremely low or high temperatures. Moreover, according to a
preferred embodiment of the present invention, wine lactone can be
produced in a highly selective manner. The process of the present
invention is suitable for use on an industrial scale.
MODES FOR CARRYING OUT THE INVENTION
[0059] The production process of the present invention will be
described in more detail below. The production process of the
present invention is a process for producing a compound represented
by formula (a), which is wine lactone or a stereoisomer thereof or
a mixture thereof:
##STR00035##
wherein said process is characterized by comprising steps A), B)
and C) shown in the reaction scheme below:
##STR00036##
[wherein R.sup.1 is an alkyl group containing 1 to 4 carbon atoms,
R.sup.2 is an alkyl group containing 1 to 4 carbon atoms, and X is
a chlorine atom or a bromine atom].
[0060] Step B) is intended to obtain a compound represented by
formula (4) through cyclization reaction of a compound represented
by formula (3). Step B) includes cases such as where the compound
represented by formula (3) is reacted under basic conditions and
then hydrolyzed to obtain the compound represented by formula (4)
(step B-1) and where the compound represented by formula (3) is
reacted under basic conditions and decarboxylated in the presence
of an inorganic salt (step B-2), followed by hydrolysis to obtain
the compound represented by formula (4) (step B-3).
[0061] In another aspect, the production process of the present
invention is a process for producing a compound represented by
formula (a), which is wine lactone or a stereoisomer thereof or a
mixture thereof:
##STR00037##
wherein said process is characterized by comprising steps A), B-2)
and E) shown in the reaction scheme below:
##STR00038##
[wherein R.sup.1 is an alkyl group containing 1 to 4 carbon atoms,
R.sup.2 is an alkyl group containing 1 to 4 carbon atoms, and X is
a chlorine atom or a bromine atom].
[0062] Hereinafter, the process comprising step A), step B-1) and
step C) is referred to as the first embodiment, the process
comprising step A), step B-2), step B-3) and step C) is referred to
as the second embodiment, and the process comprising step A), step
B-2) and step E) is referred to as the third embodiment.
Explanation will be made on each of these embodiments.
1. First Embodiment
[0063] The production process according to the first embodiment of
the present invention is characterized by comprising step A), step
B-1) and step C):
##STR00039##
[wherein R.sup.1 is an alkyl group containing 1 to 4 carbon atoms,
R.sup.2 is an alkyl group containing 1 to 4 carbon atoms, and X is
a chlorine atom or a bromine atom].
[0064] Detailed explanation will be given below for each step.
(1) Step A)
[0065] Step A) is intended to react a .beta.-keto ester represented
by formula (1):
##STR00040##
[wherein R.sup.1 is an alkyl group containing 1 to 4 carbon atoms]
with a 2-halo ester represented by formula (2):
##STR00041##
[wherein R.sup.2 is an alkyl group containing 1 to 4 carbon atoms,
and X is a chlorine atom or a bromine atom] under basic conditions
to thereby obtain a 2-aceto-3-methyl-succinic acid ester
represented by formula (3):
##STR00042##
[wherein R.sup.1 is as defined in formula (1), and R.sup.2 is as
defined in formula (2)].
[0066] In the above formulae, R.sup.1 and R.sup.2, which may be the
same or different, are each an alkyl group containing 1 to 4 carbon
atoms. In the context of this specification, examples of an alkyl
group containing 1 to 4 carbon atoms include a methyl group, an
ethyl group, a propyl group, an isopropyl group, a butyl group, an
isobutyl group, a s-butyl group, a t-butyl group, etc. Among them,
preferred are a methyl group and an ethyl group.
[0067] Examples of the 2-halo ester represented by formula (2)
include the compounds shown below.
##STR00043##
[0068] Among them, preferred are 2-bromopropionic acid alkyl esters
and particularly preferred are methyl 2-bromopropionate and ethyl
2-bromopropionate.
[0069] The amount of the 2-halo ester represented by formula (2) to
be used is selected as appropriate from the range of usually 0.5 to
10 molar equivalents, preferably 0.8 to 1.2 molar equivalents,
relative to the .beta.-keto ester represented by formula (1).
[0070] This step is performed under basic conditions. Examples of a
base used for this purpose include inorganic bases and organic
bases, etc.
[0071] Examples of inorganic bases include alkali metal or alkaline
earth metal salts such as potassium carbonate, potassium hydroxide,
lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium
bicarbonate, sodium hydroxide, magnesium carbonate, and calcium
carbonate; as well as metal hydrides such as sodium hydride.
Examples of organic bases include alkali metal alkoxides such as
potassium methoxide, sodium methoxide, lithium methoxide, sodium
ethoxide, potassium isopropoxide, potassium tert-butoxide, and
potassium naphthalenide; alkali metal or alkaline earth metal
acetate salts such as sodium acetate, potassium acetate, magnesium
acetate, and calcium acetate; organic amines such as triethylamine,
diisopropylethylamine, N,N-dimethylaniline, piperidine, pyridine,
4-dimethylamino-pyridine, 1,5-diazabicyclo[4.3.0]non-5-ene,
1,8-diazabicyclo[5.4.0]undec-7-ene, tri-n-butylamine, and
N-methylmorpholine; as well as quaternary ammonium salts, etc.
[0072] Among them, preferred are organic bases. In particular,
sodium methoxide and sodium ethoxide are preferred for use.
[0073] The amount of a base to be used is selected as appropriate
from the range of usually 0.5 to 10 molar equivalents, preferably
1.0 to 3.0 molar equivalents, relative to the .beta.-keto ester
represented by formula (1).
[0074] The reaction is preferably performed in the presence of a
solvent. Examples of a solvent used for this purpose include
aliphatic hydrocarbons such as pentane, hexane, heptane, octane,
decane, and cyclohexane; aromatic hydrocarbons such as benzene,
toluene, and xylene; halogenated hydrocarbons such as
dichloromethane, 1,2-dichloroethane, chloroform, carbon
tetrachloride, and o-dichlorobenzene; ethers such as diethyl ether,
diisopropyl ether, tert-butyl methyl ether, dimethoxyethane,
ethylene glycol diethyl ether, tetrahydrofuran, 1,4-dioxane, and
1,3-dioxolane; alcohols such as methanol, ethanol, 2-propanol,
n-butanol, 2-ethoxyethanol, and benzyl alcohol; ketones such as
acetone, methyl ethyl ketone, methyl isobutyl ketone, and
cyclohexanone; esters such as methyl acetate, ethyl acetate,
n-butyl acetate, and methyl propionate; amides such as formamide,
N,N-dimethylformamide, and N,N-dimethylacetamide; sulfoxides such
as dimethyl sulfoxide; cyano-containing organic compounds such as
acetonitrile; as well as N-methylpyrrolidone, water, etc. These
solvents may be used either alone or in combination as appropriate.
Among them, alcohols are particularly preferred.
[0075] The amount of a solvent to be used is selected as
appropriate from the range of usually 0.5- to 100-fold volume (ml)
[solvent (ml)/substrate (g)](the term "fold volume" is used
hereinafter in the same meaning), preferably 1- to 40-fold volume,
relative to the weight (g) of the .beta.-keto ester represented by
formula (1).
[0076] The reaction temperature of the above reaction is selected
as appropriate from the range of usually 0.degree. C. to
100.degree. C., preferably 0.degree. C. to 80.degree. C. Likewise,
the reaction time is selected as appropriate from the range of
usually 0.5 to 20 hours, preferably 1 to 10 hours.
[0077] After completion of the reaction, the resulting
2-aceto-3-methyl-succinic acid ester represented by formula (3) may
be used directly in the subsequent step without any secondary
treatment or the like, or may be optionally subjected to secondary
treatment, purification, isolation or the like before being used in
the subsequent step. Techniques actually used for secondary
treatment include known techniques such as solvent extraction,
phasic transfer, salting-out, distillation, crystallization,
recrystallization, etc. However, purification by silica gel column
chromatography is not favorable in terms of cost-effectiveness or
working efficiency, because it requires a large volume of
solvent.
[0078] As to reaction conditions and other information on step A,
reference may be made to the reaction described in Non-patent
Document 5 (J. Org. Chem. 54, 1876-1883 (1989)), in which methyl
2-bromopropionate and methyl acetoacetate are reacted to obtain
methyl 3-(methoxycarbonyl)-2-methyl-4-oxopentanoate.
(2) Step B-1)
[0079] Step B-1) is intended to react the 2-aceto-3-methyl-succinic
acid ester represented by formula (3) obtained in step A) with
methyl vinyl ketone under basic conditions, followed by hydrolysis
to thereby obtain an .alpha.-methyl-.gamma.-keto acid represented
by formula (4):
##STR00044##
[0080] Methyl vinyl ketone used for this purpose may be a
commercially available product. Alternatively, it is also possible
to use a synthetic product. For example, methyl vinyl ketone may be
obtained by being prepared through dehydration of
4-hydroxy-2-butanone, which can be easily synthesized by
condensation between formalin and acetone, or by being prepared
through Hofmann elimination of 4-amino-2-butanone (Mannich base),
which is obtained by reaction of acetone, formaldehyde and an
amine. Methyl vinyl ketone thus obtained may be purified by
distillation or the like before use, or the crude reaction product
may be used directly.
[0081] The amount of methyl vinyl ketone to be used is selected as
appropriate from the range of usually 0.5 to 10 molar equivalents,
preferably 0.8 to 1.5 molar equivalents, relative to the
2-aceto-3-methyl-succinic acid ester represented by formula
(3).
[0082] This step is performed under basic conditions. Examples of a
base used for this purpose include inorganic bases and organic
bases, etc. Although it is possible to use the same inorganic and
organic bases as listed in step A), inorganic bases are preferred
for use in this step. Among them, preferred are potassium hydroxide
and sodium hydroxide.
[0083] The amount of a base to be used is selected as appropriate
from the range of usually 0.0001 to 10 molar equivalents,
preferably 0.0005 to 3 molar equivalents, relative to the
2-aceto-3-methyl-succinic acid ester represented by formula
(3).
[0084] The reaction is preferably performed in the presence of a
solvent. Specific examples of a solvent include the same solvents
as listed in step A). These solvents may be used either alone or in
combination as appropriate. Among them, preferred are alcohols or
sulfoxides.
[0085] The amount of a solvent to be used is selected as
appropriate from the range of usually 0.5- to 100-fold volume,
preferably 1- to 40-fold volume, relative to the
2-aceto-3-methyl-succinic acid ester represented by formula
(3).
[0086] The reaction temperature of the above reaction is selected
as appropriate from the range of usually 0.degree. C. to
100.degree. C., preferably 0.degree. C. to 80.degree. C. Likewise,
the reaction time is selected as appropriate from the range of
usually 0.5 to 20 hours, preferably 1 to 10 hours.
[0087] In step B-1), the reaction between the
2-aceto-3-methyl-succinic acid ester represented by formula (3) and
methyl vinyl ketone is followed by hydrolysis reaction. The
hydrolysis reaction is preferably performed by addition of an acid
or a base.
[0088] Examples of an acid for use in the hydrolysis reaction
include inorganic acids, organic acids and Lewis acids, etc.
[0089] Examples of inorganic acids include hydrochloric acid,
hydrobromic acid, sulfuric acid, phosphoric acid, tetrafluoroboric
acid, perchloric acid, periodic acid, etc.
[0090] Examples of organic acids include carboxylic acids such as
formic acid, acetic acid, valeric acid, hexanoic acid, citric acid,
chloroacetic acid, dichloroacetic acid, trichloroacetic acid,
trifluoroacetic acid, benzoic acid, salicylic acid, oxalic acid,
succinic acid, malonic acid, phthalic acid, tartaric acid, malic
acid, and glycolic acid; as well as sulfonic acids such as
methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
and trifluoromethanesulfonic acid.
[0091] Examples of Lewis acids include halogenated aluminum
compounds such as aluminum chloride, and aluminum bromide;
halogenated dialkylaluminum compounds such as diethylaluminum
chloride, diethylaluminum bromide, and diisopropylaluminum
chloride; trialkoxyaluminum compounds such as triethoxyaluminum,
triisopropoxy-aluminum, and tri-tert-butoxyaluminum; halogenated
titanium compounds such as titanium tetrachloride;
tetraalkoxytitanium compounds such as tetraisopropoxytitanium;
halogenated boron compounds such as boron trifluoride, boron
trichloride, boron tribromide, and boron trifluoride diethyl ether
complex; as well as halogenated zinc compounds such as zinc
chloride, and zinc bromide.
[0092] Among them, preferred are inorganic acids, especially
hydrochloric acid and sulfuric acid.
[0093] The amount of an acid to be used is selected as appropriate
from the range of usually 0.001 to 10 molar equivalents, preferably
0.01 to 3 molar equivalents, relative to the
2-aceto-3-methyl-succinic acid ester represented by formula
(3).
[0094] Examples of a base include inorganic bases and organic
bases, etc. Specific examples of inorganic and organic bases
include the same bases as listed in step A). Among them, preferred
inorganic bases are potassium hydroxide and sodium hydroxide, while
preferred organic bases are potassium methoxide, sodium methoxide,
and sodium ethoxide.
[0095] The amount of a base to be used is selected as appropriate
from the range of 0.001 to 10 molar equivalents, preferably 0.01 to
4 molar equivalents, relative to the 2-aceto-3-methyl-succinic acid
ester represented by formula (3).
[0096] The hydrolysis reaction is preferably performed in a
solvent.
[0097] Examples of a solvent include aliphatic hydrocarbons such as
pentane, hexane, heptane, octane, decane, and cyclohexane; aromatic
hydrocarbons such as benzene, toluene, and xylene; halogenated
hydrocarbons such as dichloromethane, chloroform, carbon
tetrachloride, and o-dichlorobenzene; ethers such as diethyl ether,
diisopropyl ether, tert-butyl methyl ether, dimethoxyethane,
ethylene glycol diethyl ether, tetrahydrofuran, 1,4-dioxane, and
1,3-dioxolane; alcohols such as methanol, ethanol, 2-propanol,
n-butanol, 2-ethoxyethanol, and benzyl alcohol; polyhydric alcohols
such as ethylene glycol, propylene glycol, 1,2-propanediol, and
glycerine; acids such as formic acid, acetic acid, and propionic
acid; sulfoxides such as dimethyl sulfoxide; as well as
N-methylpyrrolidone, water, etc.
[0098] These solvents may be used either alone or in combination as
appropriate. Among them, preferred are alcohols or sulfoxides.
[0099] The amount of a solvent to be used is selected as
appropriate from the range of usually 0.5- to 100-fold volume,
preferably 1- to 40-fold volume, relative to the
2-aceto-3-methyl-succinic acid ester represented by formula
(3).
[0100] The reaction temperature of the hydrolysis reaction is
selected as appropriate from the range of usually 0.degree. C. to
100.degree. C., preferably 0.degree. C. to 80.degree. C. Likewise,
the reaction time is selected as appropriate from the range of
usually 0.5 to 24 hours, preferably 1 to 20 hours.
[0101] After completion of the reaction, the resulting
.alpha.-methyl-.gamma.-keto acid represented by formula (4) may be
used directly in the subsequent step without any secondary
treatment or the like, or may be optionally subjected to secondary
treatment, purification, isolation or the like before being used in
the subsequent step. Techniques actually used for secondary
treatment are the same as those described in step A).
(3) Step C)
[0102] Step C) is intended to reduce the
.alpha.-methyl-.gamma.-keto acid represented by formula (4)
obtained in step B-1):
##STR00045##
to thereby obtain a compound represented by formula (a), which is
wine lactone or a stereoisomer thereof or a mixture thereof:
##STR00046##
[0103] Although the reduction reaction in this step is not limited
in any way, it is accomplished by reducing the ketone site of the
.alpha.-methyl-.gamma.-keto acid represented by formula (4) through
hydride reduction, etc. Since a reducing reagent approaches the
.alpha.-methyl-.gamma.-keto acid represented by formula (4) through
its spatially opened side, this step allows stereoselective
production of (3S,3aS,7aR), (3R,3aR,7aS), (3R,3aS,7aR) and
(3S,3aR,7aS) isomers represented by the following formulae:
##STR00047##
[0104] Examples of a reagent for hydride reduction include sodium
borohydride, sodium cyanoborohydride, lithium triethylborohydride,
lithium tri(sec-butyl)borohydride, potassium
tri(sec-butyl)borohydride, lithium borohydride, zinc borohydride,
lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum
hydride, diborane, diisobutylaluminum hydride, etc.
[0105] The amount of a reagent for hydride reduction to be used is
selected as appropriate from the range of 0.01 to 10 molar
equivalents, preferably 0.1 to 3 molar equivalents, relative to the
.alpha.-methyl-.gamma.-keto acid of (4).
[0106] The reduction reaction may optionally be performed in the
presence of a reaction aid (e.g., cerium chloride, calcium
chloride) to thereby selectively reduce the ketone on the ring of
the .alpha.-methyl-.gamma.-keto acid.
[0107] The reduction reaction is preferably performed in a solvent.
Specific examples of a solvent include the same solvents as listed
for the hydrolysis reaction in step B-1). These solvents may be
used either alone or in combination as appropriate. Among them,
preferred are alcohols.
[0108] The amount of a solvent to be used is selected as
appropriate from the range of usually 0.5- to 100-fold volume,
preferably 1- to 40-fold volume, relative to the
.alpha.-methyl-.gamma.-keto acid represented by formula (4).
[0109] The reaction temperature of the reduction reaction is
selected as appropriate from the range of usually 0.degree. C. to
100.degree. C., preferably 0.degree. C. to 80.degree. C. Likewise,
the reaction time is selected as appropriate from the range of
usually 0.5 to 20 hours, preferably 1 to 10 hours.
[0110] Moreover, during the hydride reduction reaction, asymmetric
hydrogenation reaction may optionally be caused under basic
conditions and in the presence of a transition metal complex and a
hydrogen gas to thereby obtain wine lactone of (3S,3aS,7aR) form in
a highly selective manner.
[0111] Transition metal complexes used for this purpose may be
those described in, e.g., JP 11-189600 A. Specific examples of
transition metal complexes include, but are not particularly
limited to, RuCl.sub.2[(R)-binap][(R,R)-dpen],
RuCl.sub.2[(R)-binap][(R)-daipen],
RuCl.sub.2[(R)-Tol-binap][(R,R)-dpen],
RuCl.sub.2[(R)-Tol-binap][(R)-daipen],
RuCl.sub.2[(R)-DM-binap][(R,R)-dpen],
RuCl.sub.2[(R)-DM-binap][(R)-daipen],
RuCl.sub.2[(S)-binap][(S,S)-dpen],
RuCl.sub.2[(S)-binap][(S)-daipen],
RuCl.sub.2[(S)-Tol-binap][(S,S)-dpen],
RuCl.sub.2[(S)-Tol-binap][(S)-daipen],
RuCl.sub.2[(S)-DM-binap][(S,S)-dpen],
RuCl.sub.2[(S)-DM-binap][(S)-daipen], etc.
[0112] In the above complexes, binap represents
2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl, Tol-binap represents
2,2'-bis-(di-p-tolylphosphino)-1,1'-binaphthyl, DM-binap represents
2,2'-bis[bis(3,5-dimethylphenyl)phosphino]-1,1'-binaphthyl, dpen
represents 1,2-diphenyl-ethylenediamine, and daipen represents
1,1-di(4-methoxyphenyl)-2-isopropyl-1,2-ethylenediamine.
[0113] Although the amount of a transition metal complex to be used
will vary depending on the type of reaction vessel, the mode of
reaction or the degree of cost-effectiveness, it may be used at a
molar ratio ranging from 1/10 to 1/100,000, preferably 1/50 to
1/10,000, relative to the reaction substrate, i.e., the
.alpha.-methyl-.gamma.-keto acid.
[0114] Examples of a base optionally used include alkali metal or
alkaline earth metal salts such as potassium carbonate
(K.sub.2CO.sub.3), potassium hydroxide (KOH), lithium hydroxide
(LiOH), potassium methoxide (KOCH.sub.3), potassium isopropoxide
(KOCH(CH.sub.3).sub.2), potassium tert-butoxide
(KOC(CH.sub.3).sub.3), lithium methoxide (LiOCH.sub.3), potassium
naphthalene (KC.sub.10H.sub.8), and lithium isopropoxide
(LiOCH(CH.sub.3).sub.2); as well as quaternary ammonium salts, etc.
Among them, preferred are alkali metal or alkaline earth metal
salts.
[0115] The amount of a base to be used is 0.001 to 10 molar
equivalents, preferably 0.01 to 2 molar equivalents, relative to
the .alpha.-methyl-.gamma.-keto acid represented by formula
(4).
[0116] Alternatively, the hydride reduction reaction may be
replaced with asymmetric reduction reaction of the
.alpha.-methyl-.gamma.-keto acid represented by formula (4) in the
presence of an optically active form of a ruthenium complex
selected from compounds represented by formula (6) or (7) shown
below and in the presence of a hydrogen donor to thereby obtain
wine lactone of (3S,3aS,7aR) form in a highly selective manner.
[0117] Explanation will be given below for each of the ruthenium
complexes represented by formulae (6) and (7).
[0118] The ruthenium complex represented by formula (6) is as
follows:
##STR00048##
[wherein * represents an asymmetric carbon atom.
[0119] R.sup.31 is an alkyl group containing 1 to 10 carbon atoms;
a halogenated alkyl group containing 1 to 10 carbon atoms; a
10-camphoryl group; an amino group which may be substituted with
one or two alkyl groups each containing 1 to 10 carbon atoms; or an
aryl group which may be substituted with at least one substituent
selected from the group consisting of an alkyl group containing 1
to 10 carbon atoms, a halogenated alkyl group containing 1 to 10
carbon atoms, a halogen atom, a cyano group (--CN), an amino group,
an alkylamino group (--NR.sup.20R.sup.21), a 5- or 6-membered
cyclic amino group, an acylamino group (--NH--CO--R.sup.20), a
hydroxyl group, an alkoxy group (--OR.sup.20), an acyl group
(--CO--R.sup.20), a carboxyl group, an alkoxycarbonyloxy group
(--COOR20), a phenoxycarbonyl group, a mercapto group, an alkylthio
group (--SR.sup.20), a silyl group (--SiR.sup.20R.sup.21R.sup.22)
and a nitro group (--NO2), wherein R.sup.20, R.sup.21 and R.sup.22
are each independently a hydrogen atom, an alkyl group containing 1
to 10 carbon atoms, or a cycloalkyl group containing 3 to 10 carbon
atoms,
[0120] Y is a hydrogen atom,
[0121] W is a trifluoromethanesulfonyloxy group, a
p-toluenesulfonyloxy group, a methanesulfonyloxy group, a
benzenesulfonyloxy group, a hydrogen atom, or a halogen atom,
[0122] j and k are each independently 0 or 1, provided that j+k is
not 1,
[0123] R.sup.32 and R.sup.33 are each independently a hydrogen
atom; an alkyl group containing 1 to 10 carbon atoms; a phenyl
group which may be substituted with at least one substituent
selected from the group consisting of an alkyl group containing 1
to 10 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms
and a halogen atom; or a cycloalkyl group containing 3 to 8 carbon
atoms, or alternatively, R.sup.32 and R.sup.33 may together form a
ring,
[0124] R.sup.11, R.sup.12, R.sup.13, R.sup.14 and R.sup.15 are each
independently a hydrogen atom, an alkyl group containing 1 to 10
carbon atoms, or an alkoxy group containing 1 to 10 carbon
atoms,
[0125] R.sup.16, R.sup.17, R.sup.18 and R.sup.19 are each
independently a hydrogen atom, a hydroxyl group, an alkyl group
containing 1 to 10 carbon atoms, or an alkoxy group containing 1 to
10 carbon atoms, or alternatively, R.sup.16 and R.sup.17 may form a
carbonyl group together with their adjacent carbon atom and/or
R.sup.18 and R.sup.19 may form a carbonyl group together with their
adjacent carbon atom,
[0126] Z is an oxygen atom or a sulfur atom,
[0127] n.sub.1 is 1 or 2, and n.sub.2 is an integer of 1 to 3].
[0128] The ruthenium complex represented by formula (7) is as
follows:
##STR00049##
[wherein * represents an asymmetric carbon atom,
[0129] R.sup.31 is an alkyl group containing 1 to 10 carbon atoms;
a halogenated alkyl group containing 1 to 10 carbon atoms; a
10-camphoryl group; an amino group which may be substituted with
one or two alkyl groups each containing 1 to 10 carbon atoms; or an
aryl group which may be substituted with at least one substituent
selected from the group consisting of an alkyl group containing 1
to 10 carbon atoms, a halogenated alkyl group containing 1 to 10
carbon atoms, a halogen atom, a cyano group (--CN), an amino group,
an alkylamino group (--NR.sup.20R.sup.21), a 5- or 6-membered
cyclic amino group, an acylamino group (--NH--CO--R.sup.20), a
hydroxyl group, an alkoxy group (--OR.sup.20), an acyl group
(--CO--R.sup.20), a carboxyl group, an alkoxycarbonyl group
(--COOR.sup.20), a phenoxycarbonyl group, a mercapto group, an
alkylthio group (--SR.sup.20), a silyl group
(--SiR.sup.20R.sup.21R.sup.22) and a nitro group (--NO.sub.2),
wherein R.sup.20, R.sup.21 and R.sup.22 are each independently a
hydrogen atom, an alkyl group containing 1 to 10 carbon atoms, or a
cycloalkyl group containing 3 to 10 carbon atoms,
[0130] Y is a hydrogen atom,
[0131] R.sup.32 and R.sup.33 are each independently a hydrogen
atom; an alkyl group containing 1 to 10 carbon atoms; a phenyl
group which may be substituted with at least one substituent
selected from the group consisting of an alkyl group containing 1
to 10 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms
and a halogen atom; or a cycloalkyl group containing 3 to 8 carbon
atoms, or alternatively, R.sup.32 and R.sup.33 may together form a
ring,
[0132] R.sup.11, R.sup.12, R.sup.13, R.sup.14 and R.sup.15 are each
independently a hydrogen atom, an alkyl group containing 1 to 10
carbon atoms, or an alkoxy group containing 1 to 10 carbon
atoms,
[0133] R.sup.16, R.sup.17, R.sup.18 and R.sup.19 are each
independently a hydrogen atom, a hydroxyl group, an alkyl group
containing 1 to 10 carbon atoms, or an alkoxy group containing 1 to
10 carbon atoms, or alternatively, R.sup.16 and R.sup.17 may form a
carbonyl group together with their adjacent carbon atom and/or
R.sup.18 and R.sup.19 may form a carbonyl group together with their
adjacent carbon atom,
[0134] Z is an oxygen atom or a sulfur atom, Q.sup.- is a counter
anion,
[0135] n.sub.1 is 1 or 2, and n.sub.2 is an integer of 1 to 3].
[0136] In formulae (6) and (7), examples of the alkyl group
containing 1 to 10 carbon atoms represented by R.sup.31 include
linear or branched alkyl groups containing 1 to 10 carbon atoms,
preferably 1 to 5 carbon atoms. Specific examples of such alkyl
groups include a methyl group, an ethyl group, a n-propyl group, an
isopropyl group, a n-butyl group, an isobutyl group, a s-butyl
group, a t-butyl group, a n-pentyl group, a n-hexyl group, a
n-heptyl group, a n-octyl group, a n-nonyl group and a n-decyl
group, etc.
[0137] In formulae (6) and (7), the halogenated alkyl group
containing 1 to 10 carbon atoms represented by R.sup.31 is an alkyl
group containing 1 to 10 carbon atoms derived from the above linear
or branched alkyl groups (e.g., a methyl group, an ethyl group, a
n-propyl group, an isopropyl group, a n-butyl group, a n-hexyl
group) by being substituted with one or more halogen atoms such as
a fluorine atom, a chlorine atom, a bromine atom, etc. Specific
examples include perfluoroalkyl groups such as a trifluoromethyl
group, a pentafluoroethyl group, a heptafluoropropyl group,
etc.
[0138] In formulae (6) and (7), examples of an aryl group in the
aryl group represented by R.sup.31 which may be substituted with at
least one substituent selected from the group consisting of an
alkyl group containing 1 to 10 carbon atoms, a halogenated alkyl
group containing 1 to 10 carbon atoms, a halogen atom, a cyano
group (--CN), an amino group, an alkylamino group
(--NR.sup.20R.sup.21), a 5- or 6-membered cyclic amino group, an
acylamino group (--NH--CO--R.sup.20), a hydroxyl group, an alkoxy
group (--OR.sup.20), an acyl group (--CO--R.sup.20), a carboxyl
group, an alkoxycarbonyl group (--COOR.sup.20), a phenoxycarbonyl
group, a mercapto group, an alkylthio group (--SR.sup.20), a silyl
group (--SiR.sup.20R.sup.21R.sup.22) and a nitro group (--NO.sub.2)
include monocyclic, polycyclic or condensed cyclic aryl groups
containing 1 to 20 carbon atoms, preferably 6 to 12 carbon atoms,
as exemplified by a phenyl group or a naphthyl group, etc.
[0139] Examples of an alkyl group containing 1 to 10 carbon atoms
as a substituent on the above aryl group include alkyl groups as
listed above.
[0140] Examples of a halogenated alkyl group containing 1 to 10
carbon atoms include halogenated alkyl groups as listed above, such
as perfluoroalkyl groups.
[0141] Examples of a halogen atom include a fluorine atom or a
chlorine atom, etc.
[0142] Examples of an alkylamino group represented by
--NR.sup.20R.sup.21 include monoalkylamino groups such as an
N-methylamino group, an N,N-dimethylamino group, an
N,N-diisopropylamino group or an N-cyclohexylamino group, as well
as dialkylamino groups.
[0143] Examples of a 5- or 6-membered cyclic amino group include 5-
to 6-membered unsaturated or saturated heterocyclic groups having
one or two nitrogen atoms, as exemplified by a pyrrolidinyl group,
a piperidino group, a morphonyl group, etc.
[0144] Examples of an acyl group represented by --CO--R.sup.20
include a formyl group, an acetyl group, a propionyl group, a
butyryl group, a pivaloyl group, a pentanoyl group, or a hexanoyl
group, etc.
[0145] Examples of an acylamino group represented by
--NH--CO--R.sup.20 include a formylamino group, an acetylamino
group, a propionylamino group, a pivaloylamino group, a
pentanoylamino group, or a hexanoylamino group, etc.
[0146] Examples of an alkoxy group represented by --OR.sup.20
include a methoxy group, an ethoxy group, a n-propoxy group, an
isopropoxy group, a n-butoxy group, a s-butoxy group, an isobutoxy
group, a t-butoxy group, a n-pentyloxy group, a 2-methylbutoxy
group, a 3-methylbutoxy group, a 2,2-dimethylpropyloxy group, a
n-hexyloxy group, a 2-methylpentyloxy group, a 3-methylpentyloxy
group, a 4-methylpentyloxy group, a 5-methylpentyloxy group or a
cyclohexyloxy group, etc.
[0147] Examples of an alkoxycarbonyl group represented by
--COOR.sup.20 include a methoxycarbonyl group, an ethoxycarbonyl
group, a n-propoxycarbonyl group, an isopropoxycarbonyl group, a
n-butoxycarbonyl group, a t-butoxycarbonyl group, a
pentyloxycarbonyl group, a hexyloxycarbonyl group or a
2-ethylhexyloxycarbonyl group, etc.
[0148] Examples of an alkylthio group represented by --SR.sup.20
include a methylthio group, an ethylthio group, a n-propylthio
group, an isopropylthio group, a n-butylthio group, a s-butylthio
group, an isobutylthio group, a t-butylthio group, a pentylthio
group, a hexylthio group or a cyclohexyl group, etc.
[0149] Examples of a silyl group represented by
--SiR.sup.20R.sup.21R.sup.22 include a trimethylsilyl group, a
triisopropylsilyl group, a t-butyldimethylsilyl group, a
t-butyldiphenylsilyl group or a triphenylsilyl group, etc.
[0150] In the above formulae, R.sup.20, R.sup.21 and R.sup.22 are
each independently a hydrogen atom, an alkyl group containing 1 to
10 carbon atoms, or a cycloalkyl group having 3 to 10 carbon
atoms.
[0151] Examples of the alkyl group containing 1 to 10 carbon atoms
intended as R.sup.20, R.sup.21 or R.sup.22 include alkyl groups as
listed above.
[0152] Examples of the cycloalkyl group having 3 to 10 carbon atoms
intended as R.sup.20, R.sup.21 or R.sup.22 include monocyclic,
polycyclic or condensed cyclic saturated or unsaturated 3- to
7-membered cycloalkyl groups having 3 to 10 carbon atoms.
[0153] Examples of an aryl group which may be substituted with
these substituents include a phenyl group, an o-, m- or p-tolyl
group, an o-, m- or p-ethylphenyl group, an o-, m- or
p-isopropylphenyl group, an o-, m- or p-t-butylphenyl group, a
2,4,6-trimethylphenyl group, a 3,5-xylyl group, a
2,4,6-triisopropylphenyl group, an o-, m- or
p-trifluoromethylphenyl group, an o-, m- or p-fluorophenyl group,
an o-, m- or p-chlorophenyl group, as well as a pentafluorophenyl
group, etc.
[0154] In formulae (6) and (7), examples of the alkyl group
containing 1 to 10 carbon atoms represented by R.sup.32 or R.sup.33
include linear or branched alkyl groups containing 1 to 10 carbon
atoms, preferably 1 to 5 carbon atoms. Specific examples of such
alkyl groups include a methyl group, an ethyl group, a n-propyl
group, an isopropyl group, a n-butyl group, an isobutyl group, a
s-butyl group, a t-butyl group, a n-pentyl group, a n-hexyl group,
a n-heptyl group, a n-octyl group, a n-nonyl group and a n-decyl
group, etc.
[0155] In formulae (6) and (7), examples of an alkyl group
containing 1 to 10 carbon atoms in the phenyl group represented by
R.sup.32 or R.sup.33 which may be substituted with at least one
substituent selected from the group consisting of an alkyl group
containing 1 to 10 carbon atoms, an alkoxy group containing 1 to 10
carbon atoms and a halogen atom include alkyl groups as listed
above.
[0156] Examples of an alkoxy group containing 1 to 10 carbon atoms
include linear or branched alkoxy groups containing 1 to 10 carbon
atoms, preferably 1 to 5 carbon atoms. Specific examples of such
alkoxy groups include a methoxy group, an ethoxy group, a n-propoxy
group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a
s-butoxy group, a t-butoxy group, a n-pentyloxy group, a n-hexyloxy
group, a n-heptyloxy group, a n-octyloxy group, a n-nonyloxy group
and a n-decyloxy group, etc.
[0157] Examples of a halogen atom include a fluorine atom, a
chlorine atom and a bromine atom.
[0158] In formulae (6) and (7), examples of the cycloalkyl group
containing 3 to 8 carbon atoms represented by R.sup.32 or R.sup.33
include monocyclic, polycyclic or bridged cycloalkyl groups
containing 3 to 8 carbon atoms, preferably 5 to 8 carbon atoms.
Specific examples include a cyclopropyl group, a cyclobutyl group,
a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and a
cyclooctyl group, etc. These cycloalkyl groups may be substituted
with an alkyl group such as a methyl group, an isopropyl group, a
t-butyl group, etc.
[0159] When R.sup.32 and R.sup.33 together form a ring, R.sup.32
and R.sup.33 are taken together to form a linear or branched
alkylene group containing 2 to 10 carbon atoms, preferably 3 to 10
carbon atoms, and further form a 4- to 8-membered, preferably 5- to
8-membered cycloalkane ring, together with their adjacent
asymmetric carbon atoms.
[0160] Preferred cycloalkane rings include a cyclopentane ring, a
cyclohexane ring and a cycloheptane ring. These rings may have a
substituent such as an alkyl group, as exemplified by a methyl
group, an isopropyl group, a t-butyl group, etc.
[0161] In the arene moiety shown in formula (6) or (7), R.sup.11,
R.sup.12, R.sup.13, R.sup.14 and R.sup.15 are each independently a
hydrogen atom, an alkyl group containing 1 to 10 carbon atoms, or
an alkoxy group containing 1 to 10 carbon atoms.
[0162] Examples of an alkyl group containing 1 to 10 carbon atoms
include alkyl groups as listed above. Specific examples include a
methyl group, an ethyl group, a n-propyl group, an isopropyl group,
a n-butyl group, an isobutyl group, a s-butyl group, a t-butyl
group, a n-pentyl group, a n-hexyl group, a n-heptyl group, a
n-octyl group, a n-nonyl group and a n-decyl group, etc.
[0163] Examples of an alkoxy group containing 1 to 10 carbon atoms
include linear or branched alkoxy groups as listed above. Specific
examples of such alkoxy groups include a methoxy group, an ethoxy
group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an
isobutoxy group, a s-butoxy group, a t-butoxy group, a n-pentyloxy
group, a n-hexyloxy group, a n-heptyloxy group, a n-octyloxy group,
a n-nonyloxy group and a n-decyloxy group, etc.
[0164] In formulae (6) and (7), R.sup.16, R.sup.17, R.sup.18 and
R.sup.19, which are defined as substituents on the carbon atoms of
the chain moiety connecting the arene site and the diamine moiety,
each independently represent a hydrogen atom, a hydroxyl group, an
alkyl group containing 1 to 10 carbon atoms, or an alkoxy group
containing 1 to 10 carbon atoms.
[0165] Examples of an alkyl group containing 1 to 10 carbon atoms
include alkyl groups as listed above. Specific examples include a
methyl group, an ethyl group, a n-propyl group, an isopropyl group,
a n-butyl group, an isobutyl group, a s-butyl group, a t-butyl
group, a n-pentyl group, a n-hexyl group, a n-heptyl group, a
n-octyl group, a n-nonyl group and a n-decyl group, etc.
[0166] Examples of an alkoxy group containing 1 to 10 carbon atoms
include linear or branched alkoxy groups as listed above. Specific
examples of such alkoxy groups include a methoxy group, an ethoxy
group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an
isobutoxy group, a s-butoxy group, a t-butoxy group, a n-pentyloxy
group, a n-hexyloxy group, a n-heptyloxy group, a n-octyloxy group,
a n-nonyloxy group and a n-decyloxy group, etc.
[0167] Preferred examples of the
--(--C(R.sup.16)R.sup.17--)n.sub.1- group include, but are not
limited to, a --CH.sub.2-- group, a --CH(CH.sub.3)-- group and a
--CO-- group, etc.
[0168] Preferred examples of the
--(--C(R.sup.18)R.sup.19--)n.sub.2- group include, but are not
limited to, a --CH.sub.2--CH.sub.2-- group, etc.
[0169] In formulae (6) and (7), Z is an oxygen atom (--O--) or a
sulfur atom (--S--).
[0170] In formula (6), k and j are each an integer of 0 or 1,
provided that j+k is not 1. Namely, if k is 1, j is also 1, and if
k is 0, j is also 0. When k is 1, Y is a hydrogen atom.
[0171] When j is 1 in formula (6), W may be any of a
trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group, a
methanesulfonyloxy group, a benzenesulfonyloxy group, a hydrogen
atom or a halogen atom. Preferred as W is a halogen atom, more
specifically a chlorine atom, by way of example.
[0172] The hydrogen atoms intended as Y in formulae (6) and (7) and
as W in formula (6) may be not only normal hydrogen atoms, but also
isotopes thereof. Preferred isotopes include deuterium atoms.
[0173] Q.sup.- in formula (7) represents a counter anion. Specific
examples of a counter anion include alkyl- or arenesulfonyloxy ions
such as a trifluoromethanesulfonyloxy ion (TfO.sup.-), a
p-toluenesulfonyloxy ion (TsO.sup.-), a methanesulfonyloxy ion
(MsO.sup.-), and a benzenesulfonyloxy ion (BsO.sup.-); as well as
ions such as BF.sub.4--, SbF.sub.6--, CF.sub.3COO.sup.-,
CH.sub.3COO.sup.-, PF.sub.6.sup.-, NO.sub.3.sup.-, ClO.sub.4.sup.-,
SCN.sup.-, OCN.sup.-, ReO.sub.4.sup.-, MoO.sub.4.sup.-,
BPh.sub.4.sup.-, B(C.sub.6F.sub.5).sub.4.sup.-, and
B(3,5-(CF.sub.3).sub.2C.sub.6F.sub.3).sub.4.sup.-.
[0174] Among candidate compounds for the ruthenium complex
represented by formula (6), preferred are those in which
[0175] R.sup.31 is an alkyl group containing 1 to 10 carbon atoms;
or an aryl group which may be substituted with at least one
substituent selected from the group consisting of an alkyl group
containing 1 to 10 carbon atoms and a halogenated alkyl group
containing 1 to 10 carbon atoms,
[0176] Y is a hydrogen atom,
[0177] W is a halogen atom,
[0178] R.sup.32 and R.sup.33 are each independently an alkyl group
containing 1 to 10 carbon atoms; or a phenyl group which may be
substituted with at least one substituent selected from the group
consisting of an alkyl group containing 1 to 10 carbon atoms, an
alkoxy group containing 1 to 10 carbon atoms and a halogen
atom,
[0179] R.sup.11, R.sup.12, R.sup.13, R.sup.14 and R.sup.15 are each
independently a hydrogen atom or an alkyl group containing 1 to 10
carbon atoms,
[0180] R.sup.16, R.sup.17, R.sup.18 and R.sup.19 are each
independently a hydrogen atom,
[0181] Z is an oxygen atom or a sulfur atom,
[0182] j=1, andk=1,
[0183] n.sub.1 is 1, and n.sub.2 is 2.
[0184] Likewise, among candidate compounds represented by formula
(7), preferred are those in which
[0185] R.sup.31 is an alkyl group containing 1 to 10 carbon atoms;
or an aryl group which may be substituted with at least one
substituent selected from the group consisting of an alkyl group
containing 1 to 10 carbon atoms and a halogenated alkyl group
containing 1 to 10 carbon atoms,
[0186] Y is a hydrogen atom,
[0187] R.sup.32 and R.sup.33 are each independently an alkyl group
containing 1 to 10 carbon atoms; or a phenyl group which may be
substituted with at least one substituent selected from the group
consisting of an alkyl group containing 1 to 10 carbon atoms, an
alkoxy group containing 1 to 10 carbon atoms and a halogen
atom,
[0188] R.sup.11, R.sup.12, R.sup.13, R.sup.14 and R.sup.15 are each
independently a hydrogen atom or an alkyl group containing 1 to 10
carbon atoms,
[0189] R.sup.16, R.sup.17, R.sup.18 and R.sup.19 are each
independently a hydrogen atom,
[0190] Z is an oxygen atom or a sulfur atom, Q.sup.- is a counter
anion,
[0191] n.sub.1 is 1, and n.sub.2 is 2.
[0192] Among them, preferred is the ruthenium complex represented
by formula (6). Among candidates for the ruthenium complex
represented by formula (6), more preferred is the compound shown
below.
##STR00050##
[0193] These candidates for the ruthenium complex represented by
formula (6) can be produced according to the procedures described
in J. Am. Chem. Soc., 2011, 133, 14960-14963, JP 2012-67071 A and
WO2012/26201 A1. Candidates for the ruthenium complex represented
by formula (7) can be produced according to the procedures
described in JP 2012-67071 A and WO2012/26201 A1. Alternatively,
commercially available products may be used. Examples include
(R,R)-Ts-DENEB.TM. which is commercially available from STREM Inc.,
for the ruthenium complex represented by formula (6).
[0194] This asymmetric reduction reaction is accomplished by
reacting the .alpha.-methyl-.gamma.-keto acid represented by
formula (4) with an optically active form of a ruthenium complex
selected from the compounds represented by formula (6) or (7) in
the presence of a hydrogen donor.
[0195] Any hydrogen donor may be used as long as it is commonly
used for hydrogen-transfer reduction reaction, as exemplified by
formic acid or an alkali metal salt thereof, isopropanol which is
an alcohol having a hydrogen atom at the .alpha.-position of the
carbon atom, on which a hydroxyl group is substituted, etc.
[0196] This asymmetric reduction reaction is preferably performed
in the presence of a base. Examples of a base include tertiary
organic amines such as trimethylamine, triethylamine,
triisopropylamine, 1,4-diazabicyclo[2,2,2]octane (DABCO) and
1,8-diazabicyclo[5,4,0]undec-7-ene (DBU); as well as inorganic
bases such as LiOH, NaOH, KOH, and K.sub.2CO.sub.3. Preferred bases
are triethylamine and DABCO.
[0197] Such a base is used in an excess amount, e.g., in 1- to
100000-fold molar excess, relative to the ruthenium complex
represented by formula (6) or (7). In the case of using
triethylamine, it is preferably used in 1- to 10000-fold molar
excess, relative to the ruthenium complex.
[0198] Among combinations between hydrogen donor and base, when the
hydrogen donor is formic acid, an amine is preferred for use as a
base. In this case, formic acid and the amine may be added
separately to the reaction system, or an azeotropic mixture may be
prepared from formic acid and the amine before use. Preferred
examples of an azeotropic mixture between formic acid and amine
include those of formic acid:amine=1:1 to 5:2 (molar ratio),
etc.
[0199] Although the reaction may usually be accomplished by using
the hydrogen donor as a reaction solvent if it is in a liquid
state, toluene, tetrahydrofuran, acetonitrile, dimethylformamide,
dimethyl sulfoxide, acetone, methylene chloride, methanol and other
non-hydrogen-donating solvents may be used either alone or in
combination as a cosolvent to dissolve the
.alpha.-methyl-.gamma.-keto acid. For example, in the case of using
an alkali metal salt of formic acid, the reaction may be performed
in a two-phase system where water is used as a cosolvent in
combination with an organic solvent to dissolve the alkali metal
salt of formic acid. In this case, a phase-transfer catalyst may
also be used to accelerate the reaction.
[0200] The amount of the ruthenium complex to be used as a catalyst
is selected such that the molar ratio (S/C) of the substrate, i.e.,
the .alpha.-methyl-.gamma.-keto acid (S) relative to ruthenium
metal atoms (C) is in the range of 10 to 1000000, preferably 100 to
15000.
[0201] As to the amount of the hydrogen donor relative to the
.alpha.-methyl-.gamma.-keto acid, it is usually used in an
equimolar amount or more. When the hydrogen donor is formic acid or
an alkali metal salt thereof, it is preferably used in 1.0-fold
molar excess or more and used in the range of 20-fold molar excess
or less, preferably 10-fold molar excess or less. On the other
hand, when the hydrogen donor is isopropanol, etc, it is used in a
large excess amount (10-fold molar excess or more) relative to the
.alpha.-methyl-.gamma.-keto acid in terms of reaction equilibrium,
and usually used in the range of 1000-fold molar excess or
less.
[0202] The reaction temperature is selected from the range of
0.degree. C. to 100.degree. C., preferably 0.degree. C. to
70.degree. C.
[0203] The reaction pressure is not limited in any way, and it is
usually 0.05 to 0.2 MPa, preferably under normal pressure.
[0204] The reaction time will vary depending on the catalyst ratio,
but it is 1 to 100 hours, usually 2 to 90 hours.
[0205] In view of the foregoing, in the first embodiment, it is
possible to obtain the compound represented by formula (a):
##STR00051##
through step A), step B-1) and step C). As described above, in this
embodiment, modifications to the reduction reaction in step C)
allow highly selective production of wine lactone under normal
reaction conditions without using any harmful or expensive
reagents.
2. Second Embodiment
[0206] The production process according to the second embodiment of
the present invention comprises step A), step B-2), step B-3) and
step C):
##STR00052##
[wherein R.sup.1 is an alkyl group containing 1 to 4 carbon atoms,
R.sup.2 is an alkyl group containing 1 to 4 carbon atoms, and X is
a chlorine atom or a bromine atom].
[0207] Among the above steps in the second embodiment, step A) and
step C) are the same as those of the first embodiment and their
explanation will be omitted. Detailed explanation will be given
below for step B-2) and step B-3).
(1) Step B-2)
[0208] Step B-2) is intended to react the 2-aceto-3-methyl-succinic
acid ester obtained in step A) with methyl vinyl ketone under basic
conditions, followed by decarboxylation reaction to thereby obtain
an .alpha.-methyl-.gamma.-keto acid ester represented by formula
(5):
##STR00053##
[wherein R.sup.2 is as defined in formula (2)].
[0209] Methyl vinyl ketone used in this reaction may be either a
commercially available product or a synthetic product, as described
above in the first embodiment.
[0210] The amount of methyl vinyl ketone to be used is selected as
appropriate from the range of usually 0.5 to 10 molar equivalents,
preferably 0.8 to 1.5 molar equivalents, relative to the
2-aceto-3-methyl-succinic acid ester represented by formula
(3).
[0211] In step B-2), the reaction is performed under basic
conditions. Examples of a base used for this purpose include
inorganic bases and organic bases, etc. It is possible to use the
same inorganic and organic bases as those used in step B-1).
[0212] The amount of a base to be used is selected as appropriate
from the range of usually 0.0001 to 10 molar equivalents,
preferably 0.0005 to 3 molar equivalents, relative to the
2-aceto-3-methyl-succinic acid ester represented by formula
(3).
[0213] The reaction is preferably performed in the presence of a
solvent. Specific examples of a solvent include the same solvents
as listed for the reaction between the 2-aceto-3-methyl-succinic
acid ester represented by formula (3) and methyl vinyl ketone in
step B-1). These solvents may be used either alone or in
combination as appropriate. Among them, preferred are alcohols or
sulfoxides.
[0214] The amount of a solvent to be used is selected as
appropriate from the range of usually 0.5- to 100-fold volume,
preferably 1- to 40-fold volume, relative to the
2-aceto-3-methyl-succinic acid ester represented by formula
(3).
[0215] The reaction temperature of the above reaction is selected
as appropriate from the range of usually 0.degree. C. to
100.degree. C., preferably 0.degree. C. to 80.degree. C. Likewise,
the reaction time is selected as appropriate from the range of
usually 0.5 to 20 hours, preferably 1 to 10 hours.
[0216] In step B-2), the reaction between the
2-aceto-3-methyl-succinic acid ester represented by formula (3) and
methyl vinyl ketone under basic conditions is followed by
decarboxylation reaction. The decarboxylation reaction is
preferably performed by addition of an inorganic salt. It should be
noted that the decarboxylation reaction may be performed without
removing the solvent or may be performed after removing the
solvent. Alternatively, the solvent may be removed and replaced
with a fresh one before the reaction is performed.
[0217] Examples of an inorganic salt for use in the decarboxylation
reaction include sodium chloride, magnesium chloride, potassium
chloride, calcium chloride, sodium cyanide, magnesium cyanide,
potassium cyanide, calcium cyanide, etc. Among them, preferred are
sodium chloride and magnesium chloride.
[0218] The amount of an inorganic salt to be used is selected as
appropriate from the range of usually 0.01 to 10 molar equivalents,
preferably 0.1 to 5 molar equivalents, relative to the
2-aceto-3-methyl-succinic acid ester represented by formula
(3).
[0219] Specific examples of a solvent for use in the
decarboxylation reaction include the same solvents as listed for
the reaction between the 2-aceto-3-methyl-succinic acid ester
represented by formula (3) and methyl vinyl ketone in step B-1).
These solvents may be used either alone or in combination as
appropriate. Among them, preferred are sulfoxides.
[0220] The amount of a solvent to be used in the decarboxylation
reaction is selected as appropriate from the range of usually 0.5-
to 100-fold volume, preferably 1- to 40-fold volume, relative to
the 2-aceto-3-methyl-succinic acid ester represented by formula
(3).
[0221] The reaction temperature of the decarboxylation reaction is
selected as appropriate from the range of usually 50.degree. C. to
130.degree. C., preferably 80.degree. C. to 130.degree. C. The
reaction time is selected as appropriate from the range of usually
0.5 to 30 hours, preferably 1 to 20 hours.
[0222] After completion of the above reaction, the resulting
.alpha.-methyl-.gamma.-keto acid ester represented by formula (5)
may be used directly in the subsequent step without any secondary
treatment or the like, or may be optionally subjected to secondary
treatment, purification, isolation or the like before being used in
the subsequent step. Techniques actually used for secondary
treatment are the same as those described above.
(2) Step B-3)
[0223] Step B-3) is intended to hydrolyze the
.alpha.-methyl-.gamma.-keto acid ester represented by formula (5)
obtained in step B-2) to thereby obtain an
.alpha.-methyl-.gamma.-keto acid represented by formula (4):
##STR00054##
[0224] The hydrolysis of the .alpha.-methyl-.gamma.-keto acid ester
represented by formula (5) is preferably performed in the presence
of an acid or a base. Specific examples of an acid or a base, which
can be used for this purpose, include those which are listed as
compounds available for use in hydrolysis in step B-1).
[0225] The amount of an acid to be used is selected as appropriate
from the range of usually 0.001 to 10 molar equivalents, preferably
0.01 to 3 molar equivalents, relative to the
.alpha.-methyl-.gamma.-keto acid ester represented by formula
(5).
[0226] The amount of a base to be used is selected as appropriate
from the range of 0.001 to 10 molar equivalents, preferably 0.01 to
3 molar equivalents, relative to the .alpha.-methyl-.gamma.-keto
acid ester represented by formula (5).
[0227] In this step, the hydrolysis may be performed in the
presence or absence of a solvent.
[0228] When the hydrolysis is performed in the presence of a
solvent, examples of a solvent, which can be used for this purpose,
include the same solvents as those which are listed as solvents
available for use in hydrolysis in step B-1). Among them, preferred
are alcohols, sulfoxides, and water.
[0229] The amount of a solvent to be used is selected as
appropriate from the range of usually 0.5- to 100-fold volume,
preferably 1- to 40-fold volume, relative to the
.alpha.-methyl-.gamma.-keto acid ester represented by formula
(5).
[0230] The reaction temperature is selected as appropriate from the
range of usually 0.degree. C. to 100.degree. C., preferably
0.degree. C. to 80.degree. C. Likewise, the reaction time is
selected as appropriate from the range of usually 0.5 to 24 hours,
preferably 1 to 20 hours.
[0231] After completion of the reaction, the resulting
.alpha.-methyl-.gamma.-keto acid represented by formula (4) may be
used directly in the subsequent step without any secondary
treatment or the like, or may be optionally subjected to secondary
treatment, purification, isolation or the like before being used in
the subsequent step. Techniques actually used for secondary
treatment are the same as those described above.
[0232] Also in the second embodiment, modifications to the
reduction reaction in step C) following step B-3) allow highly
selective production of wine lactone under normal reaction
conditions without using any harmful or expensive reagents.
3. Third Embodiment
[0233] The production process according to the third embodiment of
the present invention comprises step A), step B-2) and step E):
##STR00055##
[wherein R.sup.1 is an alkyl group containing 1 to 4 carbon atoms,
R.sup.2 is an alkyl group containing 1 to 4 carbon atoms, and X is
a chlorine atom or a bromine atom].
[0234] Among the above steps in the third embodiment, step A) is
the same as that of the first embodiment, while step B-2) is the
same as that of the second embodiment. Thus, their explanation will
be omitted. Detailed explanation will be given below for step
E).
(1) Step E)
[0235] In a first case, step E) is intended for reduction reaction
of the .alpha.-methyl-.gamma.-keto acid ester obtained in step B-2)
in the presence of a ruthenium complex selected from compounds
represented by formula (6) or (7) and in the presence of a hydrogen
donor to thereby obtain a compound represented by formula (a):
##STR00056##
[0236] The ruthenium complexes represented by formulae (6) and (7)
may be the same as those explained in step C) of the above first
embodiment. Preferred compounds are also the same as explained in
step C) of the above first embodiment, and their explanation will
be omitted. However, in step E), the asterisk (*) in formulae (6)
and (7) is intended to mean that the carbon atom indicated with *
may be an asymmetric carbon atom. When this carbon atom is an
asymmetric carbon atom, formulae (6) and (7) may each represent an
optically active form, a mixture of optically active forms, or a
racemate (including racemic compounds). Among them, formulae (6)
and (7) each preferably represent an optically active form.
[0237] Among them, preferred is the ruthenium complex represented
by formula (6). Among candidates for the ruthenium complex
represented by formula (6), more preferred is the compound shown
below.
##STR00057##
[0238] Step E) is accomplished by reacting the
.alpha.-methyl-.gamma.-keto acid ester represented by formula (5)
with a ruthenium complex selected from formulae (6) and (7) in the
presence of a hydrogen donor.
[0239] Any hydrogen donor may be used as long as it is commonly
used for hydrogen-transfer reduction reaction, as exemplified by
formic acid or an alkali metal salt thereof, isopropanol which is
an alcohol having a hydrogen atom at the .alpha.-position of the
carbon atom, on which a hydroxyl group is substituted, etc.
[0240] Step E) is preferably performed in the presence of a base.
Examples of a base include tertiary organic amines such as
trimethylamine, triethylamine, triisopropylamine,
1,4-diazabicyclo[2,2,2]octane (DABCO), and
1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), as well as inorganic
bases such as LiOH, NaOH, KOH, K.sub.2CO.sub.3. Preferred bases are
triethylamine and DABCO.
[0241] Such a base is used in an excess amount, e.g., in 1- to
100000-fold molar excess, relative to the ruthenium complex
represented by formula (6) or (7). In the case of using
triethylamine, it is preferably used in 1- to 10000-fold molar
excess, relative to the ruthenium complex.
[0242] Among combinations between hydrogen donor and base, when the
hydrogen donor is formic acid, an amine is preferred for use as a
base. In this case, formic acid and the amine may be added
separately to the reaction system, or an azeotropic mixture may be
prepared from formic acid and the amine before use. Preferred
examples of an azeotropic mixture between formic acid and amine
include those of formic acid:amine=1:1 to 5:2 (molar ratio),
etc.
[0243] Although the reaction may usually be accomplished by using
the hydrogen donor as a reaction solvent if it is in a liquid
state, toluene, tetrahydrofuran, acetonitrile, dimethylformamide,
dimethyl sulfoxide, acetone, methylene chloride, methanol and other
non-hydrogen-donating solvents may be used either alone or in
combination as a cosolvent to dissolve the
.alpha.-methyl-.gamma.-keto acid ester. For example, in the case of
using an alkali metal salt of formic acid, the reaction may be
performed in a two-phase system where water is used as a cosolvent
in combination with an organic solvent to dissolve the alkali metal
salt of formic acid. In this case, a phase-transfer catalyst may
also be used to accelerate the reaction.
[0244] The amount of the ruthenium complex to be used as a catalyst
is selected such that the molar ratio (S/C) of the substrate, i.e.,
the .alpha.-methyl-.gamma.-keto acid ester (S) relative to
ruthenium metal atoms (C) is in the range of 10 to 1000000,
preferably 100 to 15000. As to the amount of the hydrogen donor
relative to the .alpha.-methyl-.gamma.-keto acid ester, it is
usually used in an equimolar amount or more. When the hydrogen
donor is formic acid or an alkali metal salt thereof, it is
preferably used in 1.0-fold molar excess or more and used in the
range of 20-fold molar excess or less, preferably 10-fold molar
excess or less. On the other hand, when the hydrogen donor is
isopropanol, etc, it is used in a large excess amount (10-fold
molar excess or more) relative to the .alpha.-methyl-.gamma.-keto
acid ester in terms of reaction equilibrium, and usually used in
the range of 1000-fold molar excess or less.
[0245] The reaction temperature is selected from the range of
0.degree. C. to 100.degree. C., preferably 0.degree. C. to
70.degree. C.
[0246] The reaction pressure is not limited in any way, and it is
usually 0.05 to 0.2 MPa, preferably under normal pressure.
[0247] The reaction time will vary depending on the catalyst ratio,
but it is 1 to 100 hours, usually 2 to 90 hours.
[0248] In a second case, step E) is intended for asymmetric
hydrogenation reaction of the .alpha.-methyl-.gamma.-keto acid
ester obtained in step B-2) under basic conditions and in the
presence of an optically active ruthenium complex represented by
formula (8) and a hydrogen gas to thereby obtain a compound
represented by formula (a):
##STR00058##
[0249] Explanation will be given below for the optically active
ruthenium complex represented by formula (8).
[0250] The optically active ruthenium complex represented by
formula (8) is as follows:
##STR00059##
[wherein represents an optically active diphosphine,
[0251] V is an anionic group,
[0252] R.sup.a, R.sup.b and R.sup.c are each independently a
hydrogen atom, an optionally substituted C.sub.1 to C.sub.20 alkyl
group, an optionally substituted C.sub.2 to C.sub.20 alkenyl group,
an optionally substituted C.sub.3 to C.sub.8 cycloalkyl group, an
optionally substituted C.sub.7 to C.sub.20 aralkyl group, an
optionally substituted aryl group, or an optionally substituted
heterocyclyl group, or alternatively, R.sup.b and R.sup.c may
together form an alkylene group or an alkylenedioxy group,
[0253] R.sup.N1, R.sup.N2, R.sup.N3 and R.sup.N4 are each
independently a hydrogen atom, an optionally substituted C.sub.1 to
C.sub.20 alkyl group, an optionally substituted C.sub.2 to C.sub.20
alkenyl group, an optionally substituted C.sub.7 to C.sub.20
aralkyl group, or an optionally substituted C.sub.3 to C.sub.8
cycloalkyl group, provided that at least one of R.sup.N1, R.sup.N2,
R.sup.N3 and R.sup.N4 is a hydrogen atom, and R.sup.N1 and R.sup.a
may together form an alkylene group,
[0254] n is an integer of 0 to 3, and
[0255] Ar is an optionally substituted arylene group].
[0256] Among candidates for the optically active ruthenium complex
represented by formula (8), preferred is an optically active
ruthenium complex represented by formula (9) shown below:
##STR00060##
[wherein represents an optically active diphosphine,
[0257] V is an anionic group,
[0258] R.sup.a, R.sup.b and R.sup.c are each independently a
hydrogen atom, an optionally substituted C.sub.1 to C.sub.20 alkyl
group, an optionally substituted C.sub.2 to C.sub.20 alkenyl group,
an optionally substituted C.sub.3 to C.sub.8 cycloalkyl group, an
optionally substituted C.sub.7 to C.sub.20 aralkyl group, an
optionally substituted aryl group, or an optionally substituted
heterocyclyl group, or alternatively, R.sup.b and R.sup.c may
together form an alkylene group or an alkylenedioxy group,
[0259] R.sup.d, R.sup.e, R.sup.f and R.sup.g are each independently
a hydrogen atom, an optionally substituted alkyl group containing 1
to 20 carbon atoms, an optionally substituted halogenated alkyl
group containing 1 to 5 carbon atoms, a halogen atom, an optionally
substituted aryl group, an optionally substituted C.sub.3 to
C.sub.8 cycloalkyl group, an optionally substituted tri-substituted
silyl group, or an optionally substituted alkoxy group containing 1
to 20 carbon atoms,
[0260] R.sup.N1, R.sup.N2, R.sup.N3 and R.sup.N4 are each
independently a hydrogen atom, an optionally substituted C.sub.1 to
C.sub.20 alkyl group, an optionally substituted C.sub.2 to C.sub.20
alkenyl group, an optionally substituted C.sub.7 to C.sub.20
aralkyl group, or an optionally substituted C.sub.3 to C.sub.8
cycloalkyl group, provided that at least one of R.sup.N1, R.sup.N2,
R.sup.N3 and R.sup.N4 is a hydrogen atom, and R.sup.N1 and R.sup.a
may together form an alkylene group].
[0261] Among candidates for the optically active ruthenium
complexes represented by formulae (8) and (9), more preferred is an
optically active ruthenium complex represented by formula (10)
shown below:
##STR00061##
[wherein represents an optically active diphosphine,
[0262] V is an anionic group,
[0263] R.sup.a and R.sup.b are each independently a hydrogen atom,
an optionally substituted C.sub.1 to C.sub.20 alkyl group, an
optionally substituted C.sub.2 to C.sub.20 alkenyl group, an
optionally substituted C.sub.3 to C.sub.8 cycloalkyl group, an
optionally substituted C.sub.7 to C.sub.20 aralkyl group, an
optionally substituted aryl group, or an optionally substituted
heterocyclyl group,
[0264] R.sup.N1, R.sup.N2, R.sup.N3 and R.sup.N4 are each
independently a hydrogen atom, an optionally substituted C.sub.1 to
C.sub.20 alkyl group, an optionally substituted C.sub.2 to C.sub.20
alkenyl group, an optionally substituted C.sub.7 to C.sub.20
aralkyl group, or an optionally substituted C.sub.3 to C.sub.8
cycloalkyl group, provided that at least one of R.sup.N1, R.sup.N2,
R.sup.N3 and R.sup.N4 is a hydrogen atom, and R.sup.N1 and R.sup.a
may together form an alkylene group].
[0265] In the optically active ruthenium complex represented by
formula (8), examples of the optionally substituted arylene group
represented by Ar include monocyclic, polycyclic or condensed
cyclic divalent arylene groups containing 6 to 36 carbon atoms,
preferably 6 to 18 carbon atoms, more preferably 6 to 12 carbon
atoms, as well as monocyclic, polycyclic or condensed cyclic
divalent heteroarylene groups having a 3- to 8-membered, preferably
5- to 8-membered ring containing 1 to 4, preferably 1 to 3, more
preferably 1 or 2 heteroatoms selected from a nitrogen atom, an
oxygen atom and a sulfur atom. Preferred examples of such arylene
groups include a phenylene group, a naphthalenediyl group, a
pyridinediyl group, a thiophenediyl group, a furandiyl group and so
on, with a phenylene group being particularly preferred. The
divalent arylene group may use any position for its attachment,
preferably uses adjacent two carbon atoms (ortho position).
[0266] Moreover, possible substituents on the above arylene group
include a linear or branched alkyl group, a linear or branched
alkoxy group, a cycloalkyl group, a halogen atom, an aryl group, a
heteroaryl group, and a tri-substituted silyl group, etc.
[0267] Explanation will be given below for these substituents on
the arylene group.
[0268] Examples of a linear or branched alkyl group include linear
or branched alkyl groups containing 1 to 10 carbon atoms,
preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon
atoms. Such an alkyl group may be substituted with a halogen atom
such as a fluorine atom, etc. Specific examples include a methyl
group, an ethyl group, a n-propyl group, an isopropyl group, a
n-butyl group, an isobutyl group, a s-butyl group, a t-butyl group,
a trifluoromethyl group, etc.
[0269] Examples of a linear or branched alkoxy group include linear
or branched alkoxy groups containing 1 to 10 carbon atoms,
preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon
atoms. Specific examples include a methoxy group, an ethoxy group,
a n-propoxy group, an isopropoxy group, a n-butoxy group, a
s-butoxy group, an isobutoxy group and a t-butoxy group, etc.
[0270] Examples of a cycloalkyl group include saturated or
unsaturated monocyclic, polycyclic or condensed cyclic cycloalkyl
groups containing 3 to 15 carbon atoms, preferably 5 to 7 carbon
atoms. Specific examples include a cyclopentyl group, a cyclohexyl
group, etc. These cycloalkyl groups may be substituted on their
ring with one or two or more alkyl groups containing 1 to 4 carbon
atoms or alkoxy groups containing 1 to 4 carbon atoms.
[0271] Examples of a halogen atom include a chlorine atom, a
bromine atom, a fluorine atom, etc.
[0272] Examples of an aryl group include aryl groups containing 6
to 14 carbon atoms. Specific examples include a phenyl group, a
naphthyl group, an anthryl group, a phenanthryl group and a
biphenyl group, etc. These aryl groups may have one or two or more
substituents, including alkyl groups containing 1 to 4 carbon atoms
and alkoxy groups containing 1 to 4 carbon atoms as mentioned
above.
[0273] Examples of a heteroaryl group include 5- or 6-membered
cyclic groups containing an oxygen atom, a sulfur atom, a nitrogen
atom, etc. Specific examples include a furyl group, a thienyl
group, a pyridyl group, etc.
[0274] Examples of a tri-substituted silyl group include silyl
groups substituted at three positions with alkyl groups or aryl
groups as listed above, as exemplified by a trimethylsilyl group, a
triethylsilyl group, a triisopropylsilyl group, a
tert-butyldimethylsilyl group, a diphenylmethylsilyl group, a
dimethylphenylsilyl group, etc.
[0275] In formulae (8), (9) and (10), examples of the anionic group
represented by V include a hydride ion (H.sup.-); a halogen ion
such as a chlorine ion (Cl.sup.-), a bromine ion (Br.sup.-), or an
iodine ion (I.sup.-); as well as complex anions such as BH.sub.4,
BF.sub.4, BPh.sub.4, PF.sub.6, an acetoxy group (OAc), a
trifluoromethanesulfonyloxy group (OTf), etc. Among them, preferred
is a halogen ion.
[0276] Explanation will be given below for the groups represented
by R.sup.a, R.sup.b, R.sup.c, R.sup.d, R.sup.e, R.sup.f, R.sup.g,
R.sup.N1, R.sup.N2, R.sup.N3 and R.sup.N4 in formulae (8), (9) and
(10).
[0277] Examples of a C.sub.1 to C.sub.20 alkyl group include linear
or branched alkyl groups containing 1 to 20 carbon atoms,
preferably 1 to 5 carbon atoms, more preferably 1 to 4 carbon
atoms, as exemplified by a methyl group, an ethyl group, a n-propyl
group, an isopropyl group, a n-butyl group, an isobutyl group, a
sec-butyl group, a t-butyl group, a n-pentyl group, a n-hexyl
group, a decyl group, a dodecyl group, a hexadecyl group, etc.
[0278] Examples of a C.sub.2 to C.sub.20 alkenyl group include
linear or branched alkenyl groups containing 2 to 20 carbon atoms,
preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon
atoms, as exemplified by an ethenyl group, a n-propenyl group, an
isopropenyl group, a 1-butenyl group, a 1-buten-2-yl group, a
pentenyl group, a hexenyl group, etc.
[0279] Examples of a C.sub.1 to C.sub.20 alkoxy group include
groups having oxygen atoms attached to alkyl groups containing 1 to
20 carbon atoms as listed above, as exemplified by a methoxy group,
an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy
group, a s-butoxy group, an isobutoxy group and a t-butoxy group,
etc.
[0280] Examples of a halogenated alkyl group containing 1 to 5
carbon atoms include a trifluoromethyl group, a pentafluoroethyl
group, a heptafluoropropyl group, a trichloromethyl group, etc.
[0281] Examples of a C.sub.3 to C.sub.8 cycloalkyl group include
saturated or unsaturated monocyclic, polycyclic or condensed cyclic
cycloalkyl groups containing 3 to 8 carbon atoms, preferably 5 to 7
carbon atoms, as exemplified by a cyclopentyl group, a cyclohexyl
group, etc.
[0282] Examples of a halogen atom include a chlorine atom, a
bromine atom, a fluorine atom, etc.
[0283] Examples of a tri-substituted silyl group include silyl
groups substituted at three positions with alkyl groups or aryl
groups as listed above, as exemplified by a trimethylsilyl group, a
triethylsilyl group, a triisopropylsilyl group, a
tert-butyldimethylsilyl group, a diphenylmethylsilyl group, a
dimethylphenylsilyl group, etc.
[0284] Examples of a C.sub.7 to C.sub.20 aralkyl group include
aralkyl groups containing 7 to 20 carbon atoms, preferably 7 to 15
carbon atoms or 7 to 10 carbon atoms, which are obtained by
attaching alkyl groups containing 1 to 19 carbon atoms as listed
above to monocyclic, polycyclic or condensed cyclic aryl groups
containing 6 to 20 carbon atoms, preferably 6 to 14 carbon atoms,
as exemplified by a benzyl group, an .alpha.-methylbenzyl group, an
.alpha.,.alpha.-dimethylbenzyl group, a 2-phenylethyl group, a
3-phenylpropyl group, etc.
[0285] Moreover, possible substituents on the above C.sub.1 to
C.sub.20 alkyl groups, C.sub.2 to C.sub.20 alkenyl groups, C.sub.1
to C.sub.20 alkoxy groups, halogenated alkyl groups, C.sub.3 to
C.sub.8 cycloalkyl groups, tri-substituted silyl groups and C.sub.7
to C.sub.20 aralkyl groups include linear or branched alkyl groups,
linear or branched alkoxy groups, cycloalkyl groups, halogen atoms,
aryl groups and tri-substituted silyl groups as mentioned above,
etc.
[0286] Examples of an aryl group in the optionally substituted aryl
group include monocyclic, polycyclic or condensed cyclic aryl
groups containing 6 to 20 carbon atoms, preferably 6 to 14 carbon
atoms or 6 to 12 carbon atoms. Specific examples include a phenyl
group, a naphthyl group, an anthryl group, a phenanthryl group, a
biphenyl group and so on, with a phenyl group being preferred.
These aryl groups may have one or two or more substituents,
including alkyl groups containing 1 to 4 carbon atoms such as a
methyl group, an isopropyl group and a t-butyl group, as well as
alkoxy groups containing 1 to 4 carbon atoms such as a methoxy
group, an ethoxy group, a n-propoxy group, an isopropoxy group, a
n-butoxy group, an isobutoxy group, a s-butoxy group and a t-butoxy
group, as mentioned above.
[0287] Examples of an optionally substituted heterocyclyl group
include saturated or unsaturated 5- or 6-membered cyclic groups
containing an oxygen atom, a sulfur atom, a nitrogen atom, etc.
Specific examples include a furyl group, a thienyl group, a pyridyl
group, etc. These heterocyclyl groups may have one or two or more
substituents, including alkyl groups containing 1 to 4 carbon atoms
such as a methyl group, an isopropyl group and a t-butyl group, as
well as alkoxy groups containing 1 to 4 carbon atoms such as a
methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy
group, a n-butoxy group, an isobutoxy group, a s-butoxy group and a
t-butoxy group, as mentioned above.
[0288] Example of the alkylene group formed by R.sup.b and R.sup.c
include linear or branched alkylene groups containing 1 to 6 carbon
atoms, preferably 1 to 4 carbon atoms, as exemplified by a
methylene group, an ethylene group, a trimethylene group, a
propylene group, a tetramethylene group, etc. These alkylene groups
may be substituted with an alkyl group containing 1 to 4 carbon
atoms and/or an alkoxy group containing 1 to 4 carbon atoms
Examples of the alkylenedioxy group formed by R.sup.b and R.sup.c
include linear or branched alkylenedioxy groups containing 1 to 6
carbon atoms, preferably 1 to 4 carbon atoms, as exemplified by a
methylenedioxy group, an ethylenedioxy group, a trimethylenedioxy
group, etc.
[0289] Examples of the alkylene group formed by R.sup.N1 and
R.sup.c include linear or branched alkylene groups containing 1 to
6 carbon atoms, preferably 1 to 4 carbon atoms, as exemplified by a
methylene group, an ethylene group, a trimethylene group, a
propylene group, a tetramethylene group, etc. These alkylene groups
may be substituted with an alkyl group containing 1 to 4 carbon
atoms and/or an alkoxy group containing 1 to 4 carbon atoms.
[0290] In formulae (8), (9) and (10) of the present invention, the
optically active diphosphine (also referred to as bisphosphine)
represented by is not limited in any way, as long as it is a
diphosphine capable of coordinating to ruthenium. Examples include
those represented by formula (11) shown below:
R.sup.41R.sup.42P-T-PR.sup.43R.sup.44 (11)
(wherein R.sup.41, R.sup.42, R.sup.43 and R.sup.44 are each
independently an optionally substituted aryl group, an optionally
substituted cycloalkyl group, or an optionally substituted alkyl
group, or alternatively, R.sup.41 and R.sup.42 may together form a
ring and/or R.sup.43 and R.sup.44 may together form a ring, and
[0291] T is an optionally substituted divalent arylene group, an
optionally substituted biphenyldiyl group, an optionally
substituted binaphthalenediyl group, an optionally substituted
bipyridinediyl group, an optionally substituted paracyclophanediyl
group, or an optionally substituted ferrocenediyl group).
[0292] In formula (11), examples of an aryl group in the optionally
substituted aryl group represented by R.sup.41, R.sup.42, R.sup.43
or R.sup.44 include aryl groups containing 6 to 14 carbon atoms.
Specific examples include a phenyl group, a naphthyl group, an
anthryl group, a phenanthryl group, a biphenyl group, etc.
[0293] These aryl groups may have one or two or more substituents,
including an alkyl group, an alkoxy group, etc.
[0294] Examples of an alkyl group as a substituent on the aryl
group include linear or branched alkyl groups, for example,
containing 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms,
more preferably 1 to 6 carbon atoms. Specific examples include a
methyl group, an ethyl group, a n-propyl group, an isopropyl group,
a n-butyl group, a s-butyl group, an isobutyl group and a t-butyl
group, etc.
[0295] Examples of an alkoxy group as a substituent on the above
aryl group include linear or branched alkoxy groups, for example,
containing 1 to 6 carbon atoms. Specific examples include a methoxy
group, an ethoxy group, a n-propoxy group, an isopropoxy group, a
n-butoxy group, a s-butoxy group, an isobutoxy group and a t-butoxy
group, etc.
[0296] Examples of a cycloalkyl group in the optionally substituted
cycloalkyl group represented by R.sup.41, R.sup.42, R.sup.43 or
R.sup.44 include 5- or 6-membered cycloalkyl groups. Preferred
examples of such a cycloalkyl group include a cyclopentyl group, a
cyclohexyl group, etc. These cycloalkyl groups may be substituted
on their ring with one or two or more substituents including alkyl
groups or alkoxy groups as listed above for possible substituents
on the aryl group.
[0297] Examples of an alkyl group in the optionally substituted
alkyl group represented by R.sup.41, R.sup.42, R.sup.43 or R.sup.44
include linear or branched alkyl groups, for example, containing 1
to 15 carbon atoms, preferably 1 to 10 carbon atoms, more
preferably 1 to 6 carbon atoms. Specific examples include a methyl
group, an ethyl group, a n-propyl group, an isopropyl group, a
n-butyl group, a s-butyl group, an isobutyl group and a t-butyl
group, etc. These alkyl groups may be substituted with one or two
or more substituents including alkoxy groups as listed above for
possible substituents on the aryl group.
[0298] The ring which may be formed by R.sup.41 and R.sup.42 and/or
by R.sup.43 and R.sup.44 may be a 4-, 5- or 6-membered ring, in
which the phosphorus atoms to which R.sup.41, R.sup.42, R.sup.43
and R.sup.44 are attached are contained as ring members. Specific
examples of such a ring include a phosphetane ring, a phosphorane
ring, a phosphane ring, a 2,4-dimethylphosphetane ring, a
2,4-diethylphosphetane ring, a 2,5-dimethylphosphorane ring, a
2,5-diethylphosphorane ring, a 2,6-dimethylphosphane ring, a
2,6-diethylphosphane ring, etc. These rings may be in their
optically active form.
[0299] Candidates for T include an optionally substituted divalent
arylene group, an optionally substituted biphenyldiyl group, an
optionally substituted binaphthalenediyl group, an optionally
substituted bipyridinediyl group, an optionally substituted
paracyclophanediyl group, and an optionally substituted
ferrocenediyl group, etc.
[0300] Examples of a divalent arylene group include those derived
from the aryl groups described above for R.sup.41 to R.sup.44.
Preferred examples of such arylene groups include phenylene groups,
as exemplified by o- and m-phenylene groups. Possible substituents
on these arylene groups include an alkyl group containing 1 to 6
carbon atoms such as a methyl group, an ethyl group, a n-propyl
group, an isopropyl group, a n-butyl group, a s-butyl group, an
isobutyl group or a t-butyl group; an alkoxy group containing 1 to
6 carbon atoms such as a methoxy group, an ethoxy group, a
n-propoxy group, an isopropoxy group, a n-butoxy group, a s-butoxy
group, an isobutoxy group or a t-butoxy group; a hydroxyl group; an
amino group; or a substituted amino group, etc.
[0301] Preferred biphenyldiyl, binaphthalenediyl and bipyridinediyl
groups are those of 1,1'-biaryl-2,2'-diyl structure having an
axially chiral structure. Possible substituents on these
biphenyldiyl, binaphthalenediyl and bipyridinediyl groups include
the groups listed as substituents on the above divalent arylene
group, as well as alkylenedioxy groups such as a methylenedioxy
group, an ethylenedioxy group, a trimethylenedioxy group, etc., by
way of example.
[0302] Possible substituents on the paracyclophanediyl and
ferrocenediyl groups include the groups described as substituents
on the above biphenyldiyl group.
[0303] These substituted amino groups include amino groups
substituted with one or two or more alkyls containing 1 to 6 carbon
atoms.
[0304] Specific examples of the optically active diphosphine
represented by formula (11) include known optically active
diphosphines. One of preferred examples is a compound represented
by formula (12) shown below:
##STR00062##
[wherein * represents an asymmetric carbon atom,
[0305] R.sup.41', R.sup.42', R.sup.43' and R.sup.44' are each
independently a phenyl group which may be substituted with a
substituent selected from the group consisting of an alkyl group
containing 1 to 4 carbon atoms and an alkoxy group containing 1 to
4 carbon atoms; a cyclopentyl group which may be substituted with a
substituent selected from the group consisting of an alkyl group
containing 1 to 4 carbon atoms and an alkoxy group containing 1 to
4 carbon atoms; or a cyclohexyl group which may be substituted with
a substituent selected from the group consisting of an alkyl group
containing 1 to 4 carbon atoms and an alkoxy group containing 1 to
4 carbon atoms,
[0306] R.sup.45, R.sup.46, R.sup.47, R.sup.48, R.sup.49 and
R.sup.50 are each independently a hydrogen atom, an alkyl group
containing 1 to 4 carbon atoms, an alkoxy group containing 1 to 4
carbon atoms, a halogen atom, a halogenated alkyl group containing
1 to 4 carbon atoms, or a dialkylamino group,
[0307] two of R.sup.45, R.sup.46 and R.sup.47 may together form an
optionally substituted alkylene group; an optionally substituted
alkylenedioxy group; or an optionally substituted aromatic
ring,
[0308] two of R.sup.48, R.sup.49 and R.sup.50 may together form an
optionally substituted alkylene group; an optionally substituted
alkylenedioxy group; or an optionally substituted aromatic ring,
and
[0309] R.sup.47 and R.sup.48 may together form an optionally
substituted alkylene group; an optionally substituted alkylenedioxy
group; or an optionally substituted aromatic ring, provided that
R.sup.47 and R.sup.48 are not hydrogen atoms].
[0310] In formula (12), specific examples of an alkyl group
containing 1 to 4 carbon atoms include a methyl group, an ethyl
group, a n-propyl group, an isopropyl group, a n-butyl group, an
isobutyl group, a s-butyl group, a t-butyl group, etc.
[0311] Specific examples of an alkoxy group containing 1 to 4
carbon atoms include a methoxy group, an ethoxy group, a n-propoxy
group, an isopropoxy group, a n-butoxy group, a s-butoxy group, an
isobutoxy group and a t-butoxy group, etc.
[0312] Examples of a halogen atom include a chlorine atom, a
bromine atom, a fluorine atom, etc.
[0313] Examples of a halogenated alkyl group containing 1 to 4
carbon atoms include a trifluoromethyl group, a pentafluoroethyl
group, a heptafluoropropyl group, a trichloromethyl group, etc.
[0314] Examples of a dialkylamino group include an amino group
substituted with the above alkyl groups.
[0315] Examples of the alkylene group formed by two of R.sup.45,
R.sup.46 and R.sup.47 or by two of R.sup.48, R.sup.49 and R.sup.50
include linear or branched alkylene groups containing 1 to 6 carbon
atoms, preferably 1 to 4 carbon atoms, as exemplified by a
methylene group, an ethylene group, a trimethylene group, a
propylene group, a tetramethylene group, etc. Possible substituents
on these alkylene groups include an alkyl group containing 1 to 4
carbon atoms, an alkoxy group containing 1 to 4 carbon atoms,
etc.
[0316] Examples of the alkylenedioxy group formed by two of
R.sup.45, R.sup.46 and R.sup.47 or by two of R.sup.48, R.sup.49 and
R.sup.50 include linear or branched alkylenedioxy groups containing
1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, as exemplified
by a methylenedioxy group, an ethylenedioxy group, a
trimethylenedioxy group, etc. Possible substituents on these
alkylenedioxy groups include an alkyl group containing 1 to 4
carbon atoms, an alkoxy group containing 1 to 4 carbon atoms,
etc.
[0317] Examples of the aromatic ring formed by two of R.sup.45,
R.sup.46 and R.sup.47 or by two of R.sup.48, R.sup.49 and R.sup.50
include 6-membered aromatic rings formed together with adjacent
atoms. Possible substituents on these aromatic rings include an
alkyl group and an alkoxy group, etc.
[0318] Preferred examples of formula (12) include those in which
R.sup.41', R.sup.42', R.sup.43' and R.sup.44' are each
independently a phenyl group which may be substituted with one or
more substituents selected from the group consisting of an alkyl
group containing 1 to 4 carbon atoms and an alkoxy group containing
1 to 4 carbon atoms, R.sup.46 and R.sup.47 together form a
tetramethylene group; a methylenedioxy group which may be
substituted with an alkyl group containing 1 to 4 carbon atoms or a
fluorine atom; or a benzene ring together with their adjacent
carbon atoms, and R.sup.48 and R.sup.49 together form a
tetramethylene group; a methylenedioxy group which may be
substituted with an alkyl group containing 1 to 4 carbon atoms or a
fluorine atom; or a benzene ring together with their adjacent
carbon atoms.
[0319] More preferred examples of the optically active diphosphine
represented by formula (12) include those represented by formula
(13) or (14) shown below.
##STR00063##
[0320] Specific examples of R.sup.P1 and R.sup.P2 in formula (13)
as well as R.sup.P3 and R.sup.P4 in formula (14) include a phenyl
group, a p-tolyl group, a m-tolyl group, an o-tolyl group, a
3,5-xylyl group, a 3,5-di-t-butylphenyl group, a p-t-butylphenyl
group, a p-methoxyphenyl group, a 3,5-di-t-butyl-4-methoxyphenyl
group, a p-chlorophenyl group, a m-chlorophenyl group, a
p-fluorophenyl group, a m-fluorophenyl group, etc. Among them,
preferred is a 3,5-xylyl group.
[0321] Among candidate compounds for the optically active ruthenium
complex represented by formula (10), preferred are those in
which
[0322] is the optically active diphosphine represented by formula
(14),
[0323] V is a halogen ion,
[0324] R.sup.a and R.sup.b are each independently a hydrogen atom
or an optionally substituted C.sub.1 to C.sub.20 alkyl group,
and
[0325] R.sup.N1, R.sup.N2, R.sup.N3 and R.sup.N4 are each a
hydrogen atom.
[0326] In particular, among candidates for the optically active
ruthenium complex represented by formula (10), preferred is the
compound shown below. In the following compound, Me represents a
methyl group.
##STR00064##
[0327] The optically active ruthenium complexes represented by
formulae (8), (9) and (10) can be produced according to the
procedures described in J. Am. Chem. Soc., 2011, 133, 10696-10699,
JP 2011-246435 A and WO2011/135753 A1. Alternatively, commercially
available products may be used. Examples include (R)
--RUCY.TM.-XylBINAP and (S)-RUCY.TM.-XylBINAP, which are
commercially available from STREM Inc.
[0328] Although the amount of the optically active ruthenium
complex represented by formula (8) to be used will vary depending
on the type of reaction vessel, the mode of reaction or the degree
of cost-effectiveness, it may be used at a molar ratio ranging from
1/10 to 1/100,000, preferably 1/50 to 1/10,000, relative to the
reaction substrate, i.e., the .alpha.-methyl-.gamma.-keto acid
ester represented by formula (5).
[0329] Examples of a base used for this purpose include alkali
metal or alkaline earth metal salts such as potassium carbonate
(K.sub.2CO.sub.3), potassium hydroxide (KOH), lithium hydroxide
(LiOH), potassium methoxide (KOCH.sub.3), potassium isopropoxide
(KOCH(CH.sub.3).sub.2), potassium tert-butoxide
(KOC(CH.sub.3).sub.3), lithium methoxide (LiOCH.sub.3), potassium
naphthalene (KC.sub.10H.sub.8), lithium isopropoxide
(LiOCH(CH.sub.3).sub.2); as well as quaternary ammonium salts, etc.
Among them, preferred are alkali metal or alkaline earth metal
salts.
[0330] The amount of a base to be used is 0.001 to 10 molar
equivalents, preferably 0.01 to 2 molar equivalents, relative to
the .alpha.-methyl-.gamma.-keto acid ester represented by formula
(5).
[0331] The reaction may preferably be performed in the presence or
absence of a solvent, preferably in the presence of a solvent.
Solvents preferred for use are those capable of dissolving the
substrate and catalyst, which may be used either alone or as a
mixture. Specific examples include aromatic hydrocarbons such as
toluene and xylene; aliphatic hydrocarbons such as hexane and
heptane; halogenated hydrocarbons such as methylene chloride and
chlorobenzene; ethers such as diethyl ether, tetrahydrofuran,
methyl tert-butyl ether and cyclopentyl methyl ether; alcohols such
as methanol, ethanol, 2-propanol, n-butyl alcohol, 2-butanol and
tert-butyl alcohol; as well as polyhydric alcohols such as ethylene
glycol, propylene glycol, 1,2-propanediol and glycerine. Among
them, preferred are ethers or alcohols, and particularly preferred
solvents include tetrahydrofuran, methanol, ethanol or 2-propanol.
The amount of a solvent to be used may be selected as appropriate,
depending on reaction conditions, etc. The reaction is optionally
performed under stirring.
[0332] The reaction temperature is preferably 0.degree. C. to
100.degree. C., and more preferably is in the range of 0.degree. C.
to 50.degree. C. Too low reaction temperatures may increase the
residual amounts of unreacted starting materials, while too high
reaction temperatures may cause decomposition of the starting
materials, catalyst, etc. Thus, too low or high temperatures are
not favorable.
[0333] Although the reaction successfully proceeds under normal
pressure due to the extremely high activity of this catalyst
system, the pressure of hydrogen is preferably 0.1 MPa to 10 MPa,
more preferably 0.1 MPa to 6 MPa, even more preferably 0.1 MPa to 3
MPa.
[0334] The reaction time is 1 minute to 72 hours, preferably 30
minutes to 48 hours.
[0335] In step E), when a ruthenium complex selected from the
compounds represented by formula (6) or (7) is used to cause
reduction reaction or when the optically active ruthenium complex
represented by formula (8) is used to cause asymmetric
hydrogenation reaction, it is possible to obtain wine lactone in a
highly selective manner under normal reaction conditions without
using any harmful or expensive reagents.
[0336] As described above, in the third embodiment, the compound
represented by formula (a) can be produced in a simple manner when
a ruthenium complex selected from the compounds represented by
formula (6) or (7) is used to cause reduction reaction or when the
optically active ruthenium complex represented by formula (8) is
used to cause asymmetric hydrogenation reaction in step E)
following step B-2).
[0337] In particular, in step E), when an optically active form of
the ruthenium complex represented by formula (6) or (7) is used to
cause asymmetric reduction reaction or when the optically active
ruthenium complex represented by formula (8) is used to cause
asymmetric hydrogenation reaction, the (3S,3aS,7aR) and
(3R,3aS,7aR) isomers can be produced in a selective manner. In
particular, the (3S,3aS,7aR) isomer can be produced in a highly
selective manner. When distillation is performed in step D)
subsequent to step E), the (3R,3aS,7aR) isomer is isomerized to the
(3S,3aS,7aR) isomer, so that wine lactone of (3S,3aS,7aR) form can
be produced in a simple and highly selective manner in high optical
purity and in high yields.
Step D)
[0338] In the production process of the present invention, the
compounds obtained in the first, second and third embodiments are
further distilled under basic conditions to thereby achieve
selective production of a diastereomeric isomer mixture composed of
(3S,3aS,7aR) and (3R,3aR,7aS) isomers represented by the following
formulae:
##STR00065##
The first, second and third embodiments preferably further comprise
the above step (step D)).
[0339] Step D) is performed under basic conditions. Examples of a
base used in this step include inorganic bases and organic bases,
etc. Specific examples of inorganic and organic bases include those
listed in step A) of the first embodiment. Among them, preferred
are organic bases, especially sodium methoxide and sodium
ethoxide.
[0340] The amount of a base to be used is selected as appropriate
from the range of 0.001 to 10 molar equivalents, preferably 0.01 to
3 molar equivalents, relative to the compound represented by
formula (a).
[0341] Distillation may be performed under conditions allowing
sufficient separation between a diastereomeric isomer mixture
composed of (3S,3aS,7aR) and (3R,3aR,7aS) isomers and a
diastereomeric isomer mixture composed of (3R,3aS,7aR) and
(3S,3aR,7aS) isomers, which are represented by the following
formulae:
##STR00066##
Since the diastereomeric isomer mixture composed of (3S,3aS,7aR)
and (3R,3aR,7aS) isomers and the diastereomeric isomer mixture
composed of (3R,3aS,7aR) and (3S,3aR,7aS) isomers have different
boiling points, they can be separated from each other based on
differences in their boiling points.
[0342] For example, the above conditions can be satisfied by using
a packed tower or the like for distillation.
[0343] Packing materials used for this purpose include Raschig
rings, Lessing rings, pall rings, Sulzer packing, etc.
[0344] The distillation temperature is preferably equal to or
higher than a temperature at which isomerization reaction proceeds
on the methyl group at the 3-position of the compound represented
by formula (a):
##STR00067##
It is usually 0.degree. C. to 130.degree. C., but is preferably
selected as appropriate from the range of 50.degree. C. to
130.degree. C.
[0345] Wine lactone, i.e., the (3S,3aS,7aR) isomer is excellent in
the quality of aroma, and the intensity of its aroma is also high.
For this reason, it is also favorable in terms of
cost-effectiveness to selectively produce a diastereomeric isomer
mixture composed of (3S,3aS,7aR) and (3R,3aR,7aS) isomers through
distillation.
[0346] According to a preferred embodiment of the present
invention, step D) allows production of compounds represented by
formula (a) in which a diastereomeric isomer mixture composed of
(3S,3aS,7aR) and (3R,3aR,7aS) isomers constitutes 90% by weight or
more of the total weight of the compounds represented by formula
(a) obtained in step C), particularly the (3S,3aS,7aR),
(3R,3aR,7aS), (3R,3aS,7aR) and (3S,3aR,7aS) isomers.
##STR00068##
[0347] Moreover, it is possible to produce a diastereomeric isomer
mixture composed of (3S,3aS,7aR) and (3R,3aR,7aS) isomers which is
enriched for the (3S,3aS,7aR) isomer when step D) is performed
after the (3S,3aS,7aR) isomer is selectively produced through
asymmetric reduction reaction in the presence of an optically
active form of the ruthenium complex represented by formula (6) or
(7) and a hydrogen donor during the reduction reaction in step C)
of the first or second embodiment; through asymmetric reduction
reaction in the presence of an optically active form of the
ruthenium complex represented by formula (6) or (7) and a hydrogen
donor in step E) of the third embodiment; or through asymmetric
hydrogenation reaction in the presence of the optically active
ruthenium complex represented by formula (8) and a hydrogen gas in
step E) of the third embodiment.
[0348] Furthermore, when step D) is performed after asymmetric
reduction reaction in the presence of an optically active form of
the ruthenium complex represented by formula (6) or (7) and a
hydrogen donor in step E) of the third embodiment, it is possible
to produce compounds represented by formula (a) in which the
(3S,3aS,7aR) isomer constitutes 85% by weight or more of the total
weight of the compounds represented by formula (a) obtained in step
E), particularly the (3S,3aS,7aR), (3R,3aR,7aS), (3R,3aS,7aR) and
(3S,3aR,7aS) isomers.
Step F)
[0349] In the case of causing asymmetric reduction reaction in the
presence of an optically active form of the ruthenium complex
represented by formula (6) or (7) and a hydrogen donor in step C)
of the first or second embodiment; causing asymmetric reduction
reaction in the presence of an optically active form of the
ruthenium complex represented by general formula (6) or (7) and a
hydrogen donor in step E) of the third embodiment; or causing
asymmetric hydrogenation reaction in the presence of the optically
active ruthenium complex represented by formula (8) and a hydrogen
gas in step E) of the third embodiment, wine lactone of
(3S,3aS,7aR) form can be produced in high yields by distillation in
the subsequent step D), and the resulting high-yield wine lactone
of (3S,3aS,7aR) form may further be purified by recrystallization
(step F)) to thereby produce substantially pure wine lactone of
(3S,3aS,7aR) form, i.e., highly optically pure wine lactone of
(3S,3aS,7aR) form.
[0350] Examples of a solvent used in step F) include, but are not
particularly limited to, aliphatic hydrocarbons such as pentane,
hexane, heptane, octane, decane, and cyclohexane; aromatic
hydrocarbons such as benzene, toluene, and xylene; halogenated
hydrocarbons such as dichloromethane, chloroform, carbon
tetrachloride, and o-dichlorobenzene; ethers such as diethyl ether,
diisopropyl ether, tert-butyl methyl ether, dimethoxyethane,
ethylene glycol diethyl ether, tetrahydrofuran, 1,4-dioxane, and
1,3-dioxolane; alcohols such as methanol, ethanol, 2-propanol,
n-butanol, 2-ethoxyethanol, and benzyl alcohol; polyhydric alcohols
such as ethylene glycol, propylene glycol, 1,2-propanediol, and
glycerine; acids such as formic acid, acetic acid, and propionic
acid; sulfoxides such as dimethyl sulfoxide; as well as
N-methylpyrrolidone, water, etc.
[0351] These solvents may be used either alone or in combination as
appropriate. Among them, preferred are aliphatic hydrocarbons and
alcohols.
[0352] The amount of a solvent to be used is selected as
appropriate from the range of usually 0.5- to 100-fold volume,
preferably 1- to 40-fold volume, relative to the diastereomeric
isomer mixture composed of (3S,3aS,7aR) and (3R,3aR,7aS) isomers
represented by the following formulae:
##STR00069##
[0353] The reaction temperature of recrystallization is selected as
appropriate from the range of usually 0.degree. C. to 100.degree.
C., preferably 0.degree. C. to 80.degree. C. Likewise, the reaction
time is selected as appropriate from the range of usually 0.5 to 48
hours, preferably 1 to 24 hours.
[0354] As described above, in the present invention, all of the
production steps are performed at a temperature of 0.degree. C. or
more to 130.degree. C. or less, so that wine lactone or a
stereoisomer thereof or a mixture thereof can be produced without
requiring extremely low or high temperatures.
[0355] Furthermore, wine lactone or a stereoisomer thereof or a
mixture thereof can be produced without particularly requiring any
purification step by silica gel column chromatography in each of
the production steps.
[0356] The wine lactone obtained in the present invention or a
stereoisomer thereof or a mixture thereof can be added to food and
beverage products, perfumery and cosmetics, daily and sundry goods,
oral compositions, pharmaceutical preparations, and so on.
[0357] Upon addition of wine lactone or a stereoisomer thereof or a
mixture thereof to food and beverage products, perfumery and
cosmetics, daily and sundry goods, oral compositions, and/or
pharmaceutical preparations, these products can be provided with a
juicy sensation, a fully-ripened sensation, and/or a full-bodied
sensation.
[0358] Examples of food and beverage products include beverages
such as fruit drinks, fruit liquors, milk beverages, carbonated
beverages, soft drinks, and drinkable preparations; frozen desserts
such as ice creams, sorbets, and ice lollies; desserts such as
jellies and puddings; western confectionery such as cakes, cookies,
chocolates, and chewing gums; Japanese confectionery such as manju
(sweet bean paste buns), yokan (sweet bean paste jelly), and uiro
(sweet rice jelly); jams; candies; bakery products; tea beverages
or palatable beverages such as green tea, oolong tea, black tea,
persimmon leaf tea, chamomile tea, kumazasa (Sasa albo-marginata)
tea, mulberry leaf tea, dokudami (Houttuynia cordata) tea, pu-erh
tea, mate tea, rooibos tea, gymnema tea, guava tea, coffee, and
cocoa; soups such as Japanese soups, western soups, and Chinese
soups; flavorings and seasonings; various instant beverages or
foods; various junk foods, etc.
[0359] Examples of perfumery and cosmetics include fragrance
products, basic cosmetics, make-up cosmetics, hair cosmetics, sun
care cosmetics, medicated cosmetics, etc.
[0360] More specifically, examples of fragrance products include
perfume, eau de parfum, eau de toilette, eau de cologne, and so
on;
[0361] examples of basic cosmetics include face wash cream,
vanishing cream, cleansing cream, cold cream, massage cream, skin
milk, lotion, essence, facial pack, make-up remover, and so on;
[0362] examples of make-up cosmetics include foundation, loose
powder, compact powder, talcum powder, lipstick, lip pomade, cheek
color, eyeliner, mascara, eyeshadow, eyebrow pencil, eye pack, nail
enamel, enamel remover, and so on;
[0363] examples of hair cosmetics include pomade, brilliantine,
setting lotion, hair stick, hair solid, hair oil, hair treatment,
hair cream, hair tonic, hair liquid, hair spray, bandoline, hair
growth promoter, hair dye, and so on;
[0364] examples of sun care cosmetics include suntan products,
sunscreen products, and so on; and
[0365] examples of medicated cosmetics include antiperspirant,
after shaving lotion, gel, permanent waving agent, medicated soap,
medicated shampoo, medicated skin cosmetics, and so on.
[0366] Examples of daily and sundry goods include hair care
products, soaps, body cleansers, bath preparations, fabric
detergents, soft-finishing agents, detergents, kitchen detergents,
bleaching agents, aerosols, air fresheners, sundry goods, shaving
products, skin care products, repellents, smoking products,
etc.
[0367] More specifically, examples of hair care products include
shampoo, conditioner, two-in-one shampoo, hair conditioner, hair
treatment, hair pack, and so on; examples of soaps include toilet
soap, bath soap, perfumed soap, transparent soap, synthetic soap,
and so on;
[0368] examples of body cleansers include body wash, body shampoo,
hand wash, and so on;
[0369] examples of bath preparations include bath additives (e.g.,
bath salt, bath tablet, bath liquid), foam bath (e.g., bubble
bath), bath oil (e.g., bath perfume, bath capsule), milk bath, bath
gel, bath cube, and so on;
[0370] examples of fabric detergents include heavy fabric
detergent, light fabric detergent, liquid detergent, laundry soap,
concentrated detergent, powdered soap, and so on;
[0371] examples of soft-finishing agents include softener,
furniture care, and so on;
[0372] examples of detergents include cleanser, household cleaner,
toilet detergent, bath detergent, glass cleaner, mold remover,
drain detergent, and so on;
[0373] examples of kitchen detergents include kitchen soap, kitchen
synthetic soap, dish detergent, and so on;
[0374] examples of bleaching agents include oxidizing bleaching
agents (e.g., chlorine-based bleaching agent, oxygen-based
bleaching agent), reducing bleaching agents (e.g., sulfur-based
bleaching agent), optical bleaching agents, and so on;
[0375] examples of aerosols include those of spray type, powder
spray, and so on;
[0376] examples of air fresheners include those of solid type, gel
type or liquid type, and so on;
[0377] examples of sundry goods include tissue paper, toilet paper,
and so on;
[0378] examples of shaving products include shaving foam, and so
on; and
[0379] examples of skin care products include hand cream, body
cream, body lotion, and so on.
[0380] Examples of oral compositions include dentifrices, oral
washes, mouth washes, troches, chewing gums, etc.
[0381] Examples of pharmaceutical preparations include skin
preparations for external use (e.g., poultices, ointments),
preparations for internal use, etc.
EXAMPLES
[0382] The present invention will be further described in more
detail by way of the following examples, which are not intended to
limit the scope of the present invention.
[Measuring Instruments]
[0383] Compounds obtained in the following examples were measured
for their properties using the instruments listed below.
(1) NMR: DRX 500 (Bruker, Inc.)
(2) GC/MS: GCMS-QP2010 (Shimadzu Corporation, Japan)
[0384] Column: RTX-1 (30 m long and 0.25 mm inner diameter, liquid
phase thickness: 0.25 .mu.m)
(3) Gas chromatographic purity analysis: GC-4000 (GL Sciences Inc.,
Japan)
[0385] Column: RTX-1 (30 m long and 0.25 mm inner diameter, liquid
phase thickness: 0.25 .mu.m)
[0386] Temperature conditions: column: 100.degree.
C..fwdarw.250.degree. C. (10.degree. C./minute), inlet: 250.degree.
C., detector: 250.degree. C. (FID)
(4) Optical purity analysis (gas chromatography): GC-4000 (GL
Sciences Inc., Japan)
[0387] Column: Beta DEX.TM.-225 (30 m long and 0.25 mm inner
diameter, liquid phase thickness: 0.25 .mu.m)
[0388] Temperature conditions: column: 100.degree.
C..fwdarw.200.degree. C. (2.degree. C./minute), inlet: 200.degree.
C., detector: 200.degree. C. (FID)
[0389] Melting point: YANAGIMOTO MICRO MELTING POINT APPARATUS
[0390] In the formulae shown below, Me represents a methyl
group.
Example 1
[1] Step A
##STR00070##
[0392] Under a nitrogen stream, 28% sodium methoxide in methanol
(577.5 g, 2.99 mol) and methanol (500 ml) were stirred at an
internal temperature of 3.degree. C., to which methyl acetoacetate
(1-1) (347.6 g, 2.99 mol) was then added dropwise and methyl
2-bromopropionate (2-1) (577.5 g. 2.99 mol, 1 eq) was further added
dropwise. After completion of the dropwise addition, the mixture
was reacted by being stirred at 70.degree. C. for 3 hours, followed
by addition of 0.5 N HCl (350 ml) to stop the reaction. After the
solvent was recovered under reduced pressure, the product was
extracted with toluene to give 628.5 g of crude
2-aceto-3-methyl-succinic acid ester (3-1), which was further
distilled at 120.degree. C. to obtain 460.9 g of
2-aceto-3-methyl-succinic acid ester (3-1).
[0393] .sup.1H-NMR (CDCl.sub.3) (Isomer major): .delta. 1.17 (d,
3H, J=8.9), 2.26 (s, 3H), 3.22 (m, 1H), 3.65 (s, 3H), 3.73 (s, 3H),
3.85 (d, 1H, J=10.3)
[0394] .sup.1H-NMR (CDCl.sub.3) (Isomer minor): .delta. 1.15 (d,
3H, J=9.0), 2.28 (s, 3H), 3.22 (m, 1H), 3.67 (s, 3H), 3.70 (s, 3H),
3.82 (d, 1H, J=9.5)
[0395] .sup.13C-NMR (CDCl.sub.3): .delta. 15.07, 15.26, 29.59,
38.68, 38.71, 52.07, 52.58, 52.61, 61.41, 62.01, 168.15, 175.00,
201.27
[0396] GC/MS (m/e); 202(M.sup.+,), 171, 160, 143, 128, 113, 101,
85, 70, 69, 43, 41, 36
[2] Step B-1
##STR00071##
[0398] The 2-aceto-3-methyl-succinic acid ester (3-1) obtained in
[1] above (250.0 g, 1.24 mol) was dissolved in dimethyl sulfoxide
(hereinafter abbreviated as DMSO; 500 ml), to which potassium
hydroxide (1.04 g, 0.02 mol) was then added and stirred at an
internal temperature of 40.degree. C. for 30 minutes. After methyl
vinyl ketone (113 ml, 1.35 mol) was added dropwise at the same
temperature, the reaction mixture was stirred at the same
temperature for 3 hours. After addition of methanol (500 ml), the
reaction mixture was cooled to 0.degree. C. to 10.degree. C., and
28% sodium methoxide in methanol (239.0 g, 1.24 mol) was added
dropwise thereto at 0.degree. C. to 10.degree. C. After stirring
for 30 minutes, 2 N NaOH (1.58 L, 3.16 mol) was added dropwise, and
the reaction mixture was warmed to 40.degree. C. and stirred for 7
hours.
[0399] After the solvent was recovered under reduced pressure, the
reaction mixture was diluted with 5 N HCl (892 ml, 4.46 mol) and
extracted with ethyl acetate, and the organic layer was then
concentrated with an evaporator to give 250 g of crude
.alpha.-methyl-.gamma.-keto acid (4).
[0400] .sup.1H-NMR (CDCl.sub.3) (Isomer major): .delta. 1.22 (d,
3H, J=7.3), 1.98 (s, 3H), 2.04 (m, 2H), 2.38 (m, 2H), 2.63 (dt, 1H,
J=4.7, 12.5), 2.99 (dq, 1H, J=4.5, 7.2), 5.90 (s, 1H), 6.22 (bs,
1H)
[0401] .sup.1H-NMR (CDCl.sub.3) (Isomer minor): .delta. 1.11 (d,
3H, J=7.2), 1.97 (s, 3H), 2.04 (m, 2H), 2.38 (m, 2H), 2.76 (dt, 1H,
J=4.9, 14.1), 3.15 (dq, 1H, J=5.3, 7.2), 5.89 (s, 1H), 6.22 (bs,
1H)
[0402] .sup.13C-NMR (CDCl.sub.3): .delta. 12.54, 13.16, 24.21,
25.38, 30.96, 31.24, 37.88, 38.99, 47.81, 48.07, 126.37, 126.43,
162.79, 178.97, 181.25, 198.81, 199.59
[0403] GC/MS (m/e); 164(M-H2O,), 136, 123, 109, 95, 82, 67, 54, 39,
36
(3) Step C
##STR00072##
[0404] [Preparation of Mixed .gamma.-Keto Acid Sodium Salt-Cerium
Chloride Solution]
[0405] The crude .alpha.-methyl-.gamma.-keto acid (4) obtained in
[2] above (130.0 g, 0.45 mol) was dissolved in ethanol (950 ml) and
the resulting solution was stirred under a nitrogen atmosphere at
0.degree. C. to 10.degree. C., to which 28% sodium methoxide in
methanol (138.4 g, 0.72 mol) and cerium chloride heptahydrate
(101.5 g, 0.27 mol) were then added and stirred for 30 minutes to
prepare a mixed .gamma.-keto acid sodium salt-cerium chloride
solution.
[Reduction Reaction]
[0406] Ethanol (1.0 L) was stirred at an internal temperature of
2.degree. C., and sodium borohydride (9.45 g, 0.25 mol) was added
thereto. To this mixture, the whole volume of the mixed
.gamma.-keto acid sodium salt-cerium chloride solution thus
prepared was added dropwise. The mixture was reacted by being
further stirred at 0.degree. C. to 10.degree. C. for 1.5 hours,
followed by dropwise addition of acetone (102 ml, 1.38 mol), water
(2.6 L) and 5 N hydrochloric acid (300 g, 1.50 mol) to stop the
reaction.
[0407] The solvent was then recovered under reduced pressure,
followed by addition of toluene to extract the product. The
resulting organic layer was washed with 5% aqueous sodium carbonate
and with 5% aqueous sodium chloride. The resulting organic layer
was concentrated under reduced pressure to give compound (a)
((3S,3aS,7aR)+(3R,3aR,7aS):(3R,3aS,7aR)+(3S,3aR,7aS)=57:43).
[0408] The same procedures as shown in [Preparation of mixed
.gamma.-keto acid sodium salt-cerium chloride solution] and
[Reduction reaction] above were repeated three times to obtain
194.6 g in total of compound (a).
[4] Step D (Distillation)
[0409] To the compound (a) obtained in (3) above (194.6 g, 1.17
mol) ((3S,3aS,7aR)+(3R,3aR,7aS):(3R,3aS,7aR)+(3S,3aR,7aS)=57:43),
sodium methoxide was added in 0.03 molar equivalents, followed by
precision distillation (100.degree. C. to 130.degree. C.) while
allowing isomerization to proceed, thereby obtaining 153.5 g of the
purified compound (a)
((3S,3aS,7aR)+(3R,3aR,7aS):(3R,3aS,7aR)+(3S,3aR,7aS)=97:3).
[0410] .sup.1H-NMR (CDCl.sub.3): .delta. 1.24 (d, 3H, J=7.2), 1.71
(s, 3H), 1.73 (m, 1H), 1.82 (m, 1H), 1.97 (m, 2H), 2.25 (m, 1H),
2.41 (dq, 1H, J=7.2, 8.5), 4.88 (m, 1H), 5.49 (m, 1H)
[0411] .sup.13C-NMR (CDCl.sub.3): .delta. 13.95, 22.23, 23.59,
25.90, 37.56, 40.32, 75.38, 118.76, 140.72, 179.68
[0412] GC/MS (m/e); 166(M.sup.+,), 151, 138, 123, 107, 93, 79, 69,
55, 39, 36
Example 2
[1] Step B-2
##STR00073##
[0414] The undistilled crude 2-aceto-3-methyl-succinic acid ester
(3-1) obtained in [1]<Step A> of Example 1 (265.0 g, 1.31
mol) was dissolved in DMSO (530 ml), to which potassium hydroxide
(1.10 g, 0.02 mol) was then added and stirred at an internal
temperature of 40.degree. C. for 30 minutes. After methyl vinyl
ketone (120 ml, 1.44 mol) was added dropwise at the same
temperature, the mixture was reacted by being stirred at the same
temperature for 3 hours. The reaction mixture was cooled to
0.degree. C. to 10.degree. C. and methanol (500 ml) was added
thereto, followed by dropwise addition of 28% sodium methoxide in
methanol (75.8 g, 0.39 mol) at 0.degree. C. to 10.degree. C. After
stirring for 30 minutes, 5 N HCl (78.0 g, 0.39 mol) was added
dropwise to neutralize the reaction mixture (pH=6 to 7).
[0415] After the solvent was recovered under reduced pressure,
anhydrous magnesium chloride (93.5 g, 0.98 mol) was added and
heated at 130.degree. C. for 18 hours to cause decarboxylation
reaction. The reaction mixture was cooled to room temperature,
diluted with water (530 ml) and then extracted with ethyl acetate.
The organic layer was concentrated to give 190.5 g of crude
.alpha.-methyl-.gamma.-keto acid ester (5-1), which was further
purified by distillation to obtain 121.9 g of
.alpha.-methyl-.gamma.-keto acid ester (5-1).
[0416] .sup.1H-NMR (Isomer major) (CDCl.sub.3, .sigma. in ppm) 1.10
(3H, d, J=7.2), 1.72-1.76 (1H, m), 1.95 (3H, s), 1.97-2.05 (1H, m),
2.38-2.47 (2H, m), 2.72-2.77 (1H, m), 3.05-3.10 (1H, m), 3.71 (3H,
s)
[0417] .sup.1H-NMR (Isomer minor) (CDCl.sub.3, .sigma. in ppm) 1.19
(3H, d, J=7.2), 1.72-1.76 (1H, m), 1.95 (3H, s), 1.97-2.05 (1H, m),
2.38-2.47 (2H, m), 2.55-2.59 (1H, m), 2.96-3.02 (1H, m), 3.67 (3H,
s)
[0418] .sup.13C-NMR (CDCl.sub.3, 500 MHz) 198.83, 198.74, 176.64,
175.27, 161.86, 161.51, 126.47, 126.43, 77.26, 77.00, 76.75, 51.75,
51.64, 48.45, 48.01, 38.48, 38.10, 31.18, 30.75, 25.21, 24.45,
24.12, 24.10, 13.69, 12.93
[2] Step B-3 and Step C
##STR00074##
[0419]<Step B-3>
[0420] The .alpha.-methyl-.gamma.-keto acid ester (5-1) obtained in
[1] above (60.0 g, 0.31 mol) was cooled to 0.degree. C. to
10.degree. C. and 2 N aqueous NaOH (230 ml, 0.46 mol) was added
thereto, followed by stirring at room temperature for 1 hour. After
5 N HCl (122 ml) was added dropwise, the product was extracted with
ethyl acetate and the resulting organic layer was concentrated to
give 51.7 g of .alpha.-methyl-.gamma.-keto acid (4).
<Step C>
[0421] The .alpha.-methyl-.gamma.-keto acid (4) obtained in step
B-3) above (51.7 g, 0.284 mol) was dissolved in methanol (500 ml)
and cooled to 2.degree. C. 28% Sodium methoxide in methanol (49.4
g, 0.26 mol) and cerium chloride heptahydrate (21.7 g, 0.06 mol)
were added and the mixture was further stirred for 30 minutes, to
which sodium borohydride (5.5 g, 0.15 mol) was then added. The
mixture was reacted by being stirred for 1 hour, followed by
addition of acetone (51 ml, 0.69 mol), water (665 ml) and 5 N HCl
(107.0 g) to stop the reaction.
[0422] After the solvent was recovered under reduced pressure, the
product was extracted with toluene, and the resulting organic layer
was washed with 5% aqueous sodium carbonate and with 5% aqueous
sodium chloride and then concentrated under reduced pressure.
[0423] The same procedures as shown in step B-3 and step C above
were repeated twice to obtain 72.9 g in total of compound (a)
((3S,3aS,7aR)+(3R,3aR,7aS):(3R,3aS,7aR)+(3S,3aR,7aS)=58:42).
[3] Step D (distillation)
[0424] To the compound (a) obtained in [2] above (72.9 g, 0.439
mol), sodium methoxide (0.73 g, 0.0135 mol) was added, followed by
precision distillation (100.degree. C. to 130.degree. C.) while
allowing isomerization to proceed, thereby obtaining 59.4 g of the
purified compound
((3S,3aS,7aR)+(3R,3aR,7aS):(3R,3aS,7aR)+(3S,3aR,7aS)=97:3, yield:
76.8%).
[0425] .sup.1H-NMR (CDCl.sub.3): .delta. 1.24 (d, 3H, J=7.2), 1.71
(s, 3H), 1.73 (m, 1H), 1.82 (m, 1H), 1.97 (m, 2H), 2.25 (m, 1H),
2.41 (dq, 1H, J=7.2, 8.5), 4.88 (m, 1H), 5.49 (m, 1H)
[0426] .sup.13C-NMR (CDCl.sub.3): .delta. 13.95, 22.23, 23.59,
25.90, 37.56, 40.32, 75.38, 118.76, 140.72, 179.68
[0427] GC/MS (m/e); 166(M.sup.+,), 151, 138, 123, 107, 93, 79, 69,
55, 39, 36
Example 3
[1] Step C
##STR00075##
[0429] The .alpha.-methyl-.gamma.-keto acid (4) obtained in
[2]<Step B-3> of Example 2 (0.4 g, 0.0022 mol) was dissolved
in methanol (4 ml), to which triethylamine (433 mg, 0.00428 mol),
the ruthenium complex represented by formula (20) below (14.3 mg,
0.0220 mmol) and formic acid (0.404 ml, 0.0107 mol) were then added
and stirred at 60.degree. C. for 20 hours. To this mixture,
additional formic acid (0.404 ml, 0.0107 mol) was further added and
stirred for 20 hours to cause reaction, thereby giving compound
(a).
[0430] Then, the degree of conversion was confirmed to be 55%, as
measured by gas chromatography. The diastereoselectivity was 56%
d.e., and the optical purity of the (3S,3aS,7aR) isomer was 42%
ee.
##STR00076##
[0431] (20) (R,R)-Ts-DENEB.TM. (STREM, Inc.)
Example 4
[1] Step C
##STR00077##
[0433] The .alpha.-methyl-.gamma.-keto acid (4) obtained in
[2]<Step B-3> of Example 2 (0.4 g, 0.0022 mol) was dissolved
in methanol (4 ml), to which DABCO (1.64 g, 0.01463 mol), the
ruthenium complex represented by formula (20) below (14.3 mg,
0.0220 mmol) and formic acid (0.55 ml, 0.01463 mol) were then added
and stirred at 60.degree. C. for 20 hours to cause reaction,
thereby giving compound (a).
[0434] Then, the degree of conversion was confirmed to be 26%, as
measured by gas chromatography. The diastereoselectivity was 36%
d.e., and the optical purity of the desired naturally occurring
wine lactone, i.e., the (3S,3aS,7aR) isomer was 57% ee.
##STR00078##
[0435] (20) (R,R)-Ts-DENEB.TM. (STREM, Inc.)
Example 5
[1] Step E
##STR00079##
[0437] The .alpha.-methyl-.gamma.-keto acid ester (5-1) obtained in
[1]<Step B-2> of Example 2 (0.4 g, 0.00204 mol) was dissolved
in ethanol (4 ml), to which the ruthenium complex represented by
formula (21) below (12 mg, 0.0102 mmol) and potassium tert-butoxide
(11 mg, 0.102 mmol) were then added and stirred at a hydrogen
pressure of 3 MPa at 40.degree. C. for 21 hours to cause reaction,
thereby giving compound (a).
[0438] Then, the degree of conversion was confirmed to be 9%, as
measured by gas chromatography. The diastereoselectivity was 24%
d.e., and the optical purity of the (3S,3aS,7aR) isomer was 25%
ee.
##STR00080##
[0439] (21) [RuCl(R)-xylbinap][(S)-daipen]
Example 6
[1] Step E
##STR00081##
[0441] The .alpha.-methyl-.gamma.-keto acid ester (5-1) obtained in
[1]<Step B-2> of Example 2 (80 g, 0.4076 mol) was dissolved
in methanol (200 ml), to which DABCO (45.7 g, 0.4076 mol), the
ruthenium complex represented by formula (20) below (2.65 g,
0.004076 mol) and formic acid (15.3 ml, 0.4076 mol) were then added
and stirred at 60.degree. C. for 25 hours. To this mixture,
additional formic acid (15.3 ml, 0.4076 mol) was further added and
stirred for 45 hours to cause reaction.
[0442] Then, the reaction mixture was mixed with water (2 ml) and
toluene (2 ml) to extract the product, and the resulting organic
layer was washed with 5% aqueous sodium carbonate and with 5%
aqueous sodium chloride. The resulting organic layer was
concentrated under reduced pressure to give 61.7 g of compound (a)
((3S,3aS,7aR)+(3R,3aR,7aS):(3R,3aS,7aR)+(3S,3aR,7aS)=80:20,
(3S,3aS,7aR):(3R,3aR,7aS)=90:10, optical purity of (3S,3aS,7aR)
isomer: 80% ee).
##STR00082##
[0443] (20) (R,R)-Ts-DENEB.TM. (STREM, Inc.)
[2] Step D (Distillation)
[0444] To the compound (a) obtained in [1] above (61.7 g, 0.3712
mol), sodium methoxide (0.62 g, 0.0111 mol) was added, followed by
precision distillation (100.degree. C. to 130.degree. C.) while
allowing isomerization to proceed, thereby obtaining 14.7 g of the
purified compound (a) ((3S,3aS,7aR):(3R,3aR,7aS)=90:10,
(3S,3aS,7aR)+(3R,3aR,7aS):(3R,3aS,7aR)+(3S,3aR,7aS)=100:0, yield:
22%).
[0445] .sup.1H-NMR (CDCl.sub.3): .delta. 1.26 (d, 3H, J=7.3), 1.73
(s, 3H), 1.73 (m, 1H), 1.82 (m, 1H), 1.97 (m, 2H), 2.25 (m, 1H),
2.41 (dq, 1H, J=7.3, 8.6), 4.89 (m, 1H), 5.51 (m, 1H)
[0446] .sup.13C-NMR (CDCl.sub.3): .delta. 14.03, 22.31, 23.67,
25.98, 37.62, 40.40, 75.42, 118.85, 140.76, 179.70
[0447] GC/MS (m/e); 166(M.sup.+), 151, 138, 123, 107, 93, 79, 69,
55, 39, 36
[3] Step F (Recrystallization)
[0448] The compound (a) obtained in [2] above (14.7 g;
(3S,3aS,7aR):(3R,3aR,7aS)=90:10) was dissolved in a mixture of
heptane (74 ml) and 2-propanol (5 ml), and then allowed to stand at
5.degree. C. After 18 hours, the resulting crystals were collected
by filtration to obtain 10.6 g of the purified compound
((3S,3aS,7aR):(3R,3aR,7aS)=99.93:0.07, yield: 72%, optical purity
of (3S,3aS,7aR) isomer: 99.86% ee).
[0449] .sup.1H-NMR (CDCl.sub.3): .delta. 1.26 (d, 3H, J=7.3), 1.73
(s, 3H), 1.73 (m, 1H), 1.82 (m, 1H), 1.97 (m, 2H), 2.25 (m, 1H),
2.41 (dq, 1H, J=7.3, 8.6), 4.89 (m, 1H), 5.51 (m, 1H)
[0450] .sup.13C-NMR (CDCl.sub.3): .delta. 14.03, 22.31, 23.67,
25.98, 37.62, 40.40, 75.42, 118.85, 140.76, 179.70
[0451] GC/MS (m/e); 166(M.sup.+), 151, 138, 123, 107, 93, 79, 69,
55, 39, 36
[0452] Melting point: 47-51.degree. C.
INDUSTRIAL APPLICABILITY
[0453] According to the present invention, wine lactone, which is
useful as a flavor or fragrance compound, or a stereoisomer thereof
or a mixture thereof can be produced without using any harmful or
expensive reagents and without requiring any extreme reaction
conditions such as extremely low or high temperatures. According to
a preferred embodiment of the present invention, compounds
including wine lactone can be produced in a highly selective manner
through simple and safe procedures. The process of the present
invention is preferred for use in the production of wine lactone or
a stereoisomer thereof or a mixture thereof on an industrial
scale.
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