SPECIFICATION
TITANIUM COMPOUND AND PROCESS FOR PRODUCING OPTICALLY ACTIVE
CYANOHYDRINS
TECHNICAL FIELD
[0001]
The present invention relates to a titanium compound and a
process for producing optically active cyanohydrins according to
the asymmetric cyanation reaction of aldehyde or ketone using such
a titanium compound. The optically active cyanohydrins are useful
as an intermediate in the synthesis of pharmaceutical and
agricultural chemicals.
BACKGROUND ART
[0002]
There has already been generally known that asymmetric synthetic
reactions can be carried out by using a metal complex prepared from
an alkoxide or halide of metal such as titanium, aluminum or the
like and an optically active compound as a catalyst. Of these,
the reaction for synthesizing optically active cyanohydrins
according to the asymmetric cyanation of aldehyde is particularly
important as an enantioselective reaction increasing the number
of carbon atoms, and various cases thereof as shown below have been
reported.
(1) a method using a titanium complex with a chiral Schiff base
prepared from optically active (3-aminoalcohols and
salicylaldehyde as a catalyst (Patent Document 1),
(2) a method using a titanium complex or a vanadium complex
prepared from an optically active, tetradentate ligand called a
salen type as a catalyst (Non-patent Document 1 and Patent Document
2), and
(3) a method using an aluminum complex prepared from an optically
active binaphthyl compound as a catalyst (Patent Document
|0003]
However, the method (1) requires very low reaction
temperature, around -78 degree C, and 10 to 20 mol% of the catalyst
to obtain corresponding cyanohydrins with high
enantioselectivities. In addition, the catalyst gives good
enantiose J ec ::ivit ies for very limited aldehydes. Regarding the
method (2), enantioselectivity of the catalyst is not sufficient
for aliphatic aldehydes in particular although the above mentioned
problems are improved. The catalyst in the method (3) shows very
high enantioselectivity for asymmetric cyanation of various
aliphatic and aromatic aldehydes therefore the catalyst is
regarded as a versatile catalyst. However, the catalyst is hardly
adequate from the practical point of view because cyanating agent
must be added for a long period of time, long reaction time, 36
to 70 houis, is required to complete the reaction and low reaction
temperature, -40 degree C, is necessary. Reducing the amount of
catalyst also remains as a problem to be solved.
10004]
On the other hand, in the asymmetric cyanation reaction of ketone,
asymmetric: catalysts exhibiting high enantioselectivity have
hardly been known. One of a few examples include a method using
a titanium complex or a rare earth metal complex prepared from an
optically active, tridentate ligand derived from glucose as a
catalyst, so there has been reported that cyanohydrins with a high
optical purity are obtained from various substrates (Patent
Document 4).
[0005]
However, there have not been known asymmetric cyanation
catalysts which can be applied to a wide range of substrates,
achieve high yield and high enantioselectivity, obtain a desired
product within a short period of time, and does not require
facilities for the reaction at a low temperature.
[0006]
Furthermore, there has also been demanded development of
asymmetric cyanation catalysts combining industrially desired
conditions such that they can be produced with ease and have high
activity, and the amount thereof is suppressed low.
Patent Document 1: Japanese Patent Laid-open No. 1993-112518
Patent Document 2: W002/10095
Patent Document 3: Japanese Patent Laid-open No. 2000-191677
Patent Document 4: Japanese Patent Laid-open No. 2002-255985
Non-patent Document 1: J. Am. Chem. Soc., Vol. 121, p. 3968
(1999)
DISCLOSURE OF THE INVENTION
[0007]
An object of the present invention is to provide a titanium
catalyst which is useful in the asymmetric synthesis reaction.
[000 R ]
Further, another object of the present invention is to provide
a process for producing optically active cyanohydrins which are
industrially favorable, can carry out the reaction under the
practical reaction conditions by using the titanium compound and
can be applied to a wide range of substrates.
[0009]
In order to solve the above objects, the present inventors have
conducted an extensive study, and as a result, have found that a
novel titanium compound produced from a titanium tetraalkoxide
compound, water and an optically active, tridentate ligand, or a
novel titanium compound produced from a titanium oxoalkoxide
compound and an optically active, tridentate ligand is effective
as a catalyst for the asymmetric synthesis reaction and
particularly a catalyst for the asymmetric cyanation reaction of
aldehyde or unsymmetrical ketone.
[0010]
That is, the present invention includes the following
inventions:
[0011]
(1) a titanium compound produced from a reaction mixture of a
titanium tetraalkoxide compound with water and an optically active
ligand represented by the general formula (b), or a titanium
oxoalkoxide compound represented by the general formula (a) and
an optically active ligand represented by the general formula (b) ,
[0012]
(Figure Removed)
[0013]
wherein, in the formula, R1 is an alkyl group or an aryl group,
each of which may have a substituent; x is an integer of not less
than 2; y is an integer of not less than 1; and y/x satisfies
(Figure Removed)

[ 0 0 1 5 ]
wherein, in the formula, R2, R3 and R4 are independently a
hydrogen atom, an alkyl group, an alkenyl group, an aryl group,
an aromatic heterocyclic group, an acyl group, an alkoxycarbonyl
group or an aryloxycarbonyl group, each of which may have a
substituent, two or more of R2, R3 and R4 may be linked together
to form a ring, arid the ring may have a substituent; and A*
represents a hydrocarbon-containing group with three or more
carbon atoms having an asymmetric carbon atom or axial asymmetry;
and
[0016]
(2) a process for producing optically active cyanohydrins which
comprises reacting aldehyde or unsymmetrical ketone with a
cyanating agent in the presence of the titanium compound as set
forth in the above item (1) .
[0017]
According to the present invention, it is possible to
conveniently and efficiently produce optically active
cyanohydrins with a high optical purity in a much less amount of
a catalyst and within a much shorter period of time, as compared
to those produced by using an asymmetric catalyst in the past.
These optically active cyanohydrins are useful as an intermediate
in the synthesis of physiologically active compounds such as
medicines, agricultural chemicals and the like, functional
materials, or synthetic raw materials in fine chemicals and the
like.
BEST MODE FOR CARRYING OUT THE INVENTION
[0018]
The present invention will be described in more detail below.
[Titanium tetraalkoxide compound]
A titanium tetraalkoxide compound to be a raw material of the
titanium compound of the present invention is not particularly
limited, but preferable examples thereof include those represented
by the general formula (a'),
[0019]
(Figure Removed)

0020
[0021]
R] in the above general formula (a' ) is an alkyl group or an aryl
group, each of which may have a substituent.
[0022]
As the alkyl group in R1, preferred is a linear, branched or
cyclic alkyl group having not more than 20 carbon atoms.
Examples of the linear alkyl group in R1 include a methyl group,
an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl
group, an n-hexyl group, an n-heptyl group, an n-octyl group, an
n-nonyl group, an n-decyl group and the like.
Examples of the branched alkyl group in R1 include an isopropyl
group, an isobutyl group, a sec-butyl group, a tert-butyl group,
a 2-pentyl group, a 3-pentyl group, an isopentyl group, a neopentyl
group, an amyl group and the like.
Examples of the cyclic alkyl group in R1 include a cyclopropyl
group, a cyclobutyl group, a cyclopentyl group, a cyclohexylgroup,
a cycloheptyl group, a cyclooctyl group and the like.
[0023]
The aforementioned linear, branched or cyclic alkyl group may
have, as a substituent, a halogen atom, an aryl group having not
more than 20 carbon atoms, an aromatic heterocyclic group having
not more than 20 carbon atoms, a non-aromatic heterocyclic group
having not more than 20 carbon atoms, an oxygen-containing group
having not more than 20 carbon atoms, a nitrogen-containing group
having not more than 20 carbon atoms, a silicon-containing group
having not more than 20 carbon atoms or the like.
[0024]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
Examples of the oxygen-containing group having not more than
carbon atoms include those having not more than 20 carbon atoms
such as an alkoxy group, an aryloxy group, an alkoxycarbonyl group,
an aryloxycarbony] group, an acyloxy group and the like.
Examples of the nitrogen-containing group having not more than
20 carbon atoms include an amino group having not more than 20
carbon atoms, an amide group having not more than 20 carbon atoms,
a nitro group, a cyano group and the like.
Examples of the silicon-containing group having not more than
20 carbon atoms include those having not more than 20 carbon atoms
such as a silyl group, a silyloxy group and the like.
[0025]
Examples of the alkyl group having a halogen atom include a
chloromethyl group, a 2-chloroethyl group, a trifluoromethyl group,
a 2,2,2-trifluoroethyl group, a perfluoroethyl group, a
perfluorohexyl group and the like.
Examples of the alkyl group having an aryl group include a
substituted or unsubstituted aralkyl group such as a benzyl group,
a 4-methoxybenzyl group, a 2-phenylethyl group, a cumyl group, an
a-naphthylmethyl and the like.
Examples of the alkyl group having an aromatic heterocyclic
group include a 2-pyridylmethyl group, a 2-furfuryl group, a
3-furfuryl group, a 2-thienylmethyl group and the like.
[0026]
Examples of the alkyl group having a non-aromatic heterocyclic
group include? a 2-tetrahydrofurfuryl group, a
3-tetrahydroi:urfuryl group and the like.
Examples of the alkyl group having an oxygen-containing group
include a methoxyethyl group, a phenoxyethyl group and the like.
Examples of the alkyl group having a nitrogen-containing group
include a 2-(dimethylamino)ethyl group, a 3-(diphenylamino)propyl
group and the like.
Examples of the alkyl group having a silicon-containing group
include a 2-(trimethylsiloxy)ethyl group and the like.
As the aryl group in R1, preferred is an aryl group having 6 to
20 carbon atoms. Concrete examples thereof include a phenyl group,
a naphthy.l group, a biphenyl group, an anthryl group and the like.
[002'']
The aforementioned aryl group may have, as a substituent, a
halogen atom, an alkyl group having not more than 20 carbon atoms,
an oxygen-containing group having not more than 20 carbon atoms,
a nitrogen-containing group having not more than 20 carbon atoms,
a silicon-containing group having not more than 20 carbon atoms
or the like.
[0028]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
Examples of the oxygen-containing group having not more than
carbon atoms include those having not more than 20 carbon atoms
such as an alkoxy group, an aryloxy group, an alkoxycarbonyl group,
an aryloxycarbonyl group, an acyloxy group and the like.
Examples of the nitrogen-containing group having not more than
20 carbon atoms include an amino group having not more than
carbon atoms, an amide group having not more than 20 carbon atoms,
a nitro group and a cyano group.
Examples of the silicon-containing group having not more than
20 carbon atoms include those having not more than 20 carbon atoms
such as a silyl group, a silyloxy group and the like.
[0029]
Examples of the aryl group having a halogen atom include a
4-fluorophenyl group, a pentafluorophenyl group and the like.
Examples of the aryl group having an alkyl group include a tolyl
group, a dimethylphenyl group, a 2,4,6-trimethylphenyl group, a
4-isopropylphenyl group, a 2,6-diisopropylphenyl group, a
4-tert-butylphenyl group, a 2,6-di-tert-butylphenyl group and the
like.
Examples of the aryl group having an oxygen-containing group
include? an alkoxy-substituted aryl group such as a 4-methoxyphenyl
group, a 3,5-dimethoxyphenyl group, a 3,5-diisopropoxyphenyl
group, a 2,4,6-triisopropoxyphenyl group and the like; and an
aryloxy-substituted aryl group such as a 2,6-diphenoxyphenyl group
and the like.
[0030]
Examples of the aryl group having a nitrogen-containing group
include a 4-(dimethylamino)phenyl group, a 4-nitrophenyl group and
the like.
Examples of the aryl group having a silicon-containing group
include a 3,S-bis(trimethylsilyl)phenyl group, a
3,5-bis(trimethylsiloxy)phenyl group and the like.
Of these, as R1, particularly preferred is a linear alkyl group
having not more than 10 carbon atoms such as a methyl group, an
ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group,
an n-hexyl group, an n-heptyl group, an n-octyl group, an n-nonyl
group, an n-decyl group and the like.
[0031]
[Titanium oxoalkoxide compound represented by the general
formula (a)]
Further, a titanium oxoalkoxide compound represented by the
general formula (a) can also be used for the titanium compound of
the present invention.
[ 0 0 3 2 ]
(Figure Removed)

[0033]
[ 0 0 3 4 ]
In the general formula (a), R1 represents the same as those in
the above general formula (a') . Namely, R1 represents the same
alkyl group or aryl group as those in the above general formula
(a'), each of which may have a substituent. x is an integer of
not less than 2, y is an integer of not less than 1, and y/x satisfies
0.1 < y/x < 1.5.
[0035]
As R1 in the above general formula (a), particularly preferred
is a linear alkyl group having not more than 10 such as a methyl
group, an ethyl group, an n-propyl group, an n-butyl group, an
n-pentyl group, an n-hexyl group, an n-heptyl group, an n-octyl
group, an n-nonyl group, an n-decyl group and the like.
[0036]
There has been known that, by reacting the titanium
tetraalkoxide compound represented by the above general formula
(a') with water, titanium tetraalkoxide is partially hydrolyzed
to give a titanium oxoalkoxide compound represented by the above
general formula (a) (for example, Inorg. Chim. Acta, Vol. 229, p.
391 (1995)) . Depending on the kind of alkoxide and the amount of
water used for the hydrolysis, the values of x and y in the above
genera] formula (a) are varied, but are not necessarily determined
only one-sidedly. So, it is considered that various kinds of
titanium oxoalkoxide mixtures are obtained. Further, there has
been reported that; various titanium oxoalkoxide mixtures can be
stably isolated to respective substances in some cases (for example,
J. Am. Chem. Soc., Vol. 113, p. 8190 (1991)).
[0037]
As a raw material of the titanium compound of the present
invention, a reaction mixture of a titanium tetraalkoxide compound
with water rneiy be used as it is, or may be used after a titanium
oxoalkoxide compound contained in this reaction mixture is first
isolated, prior to use.
[0038]
In this titanium oxoalkoxide compound, x is preferably not less
than 2 to not more than 20. Examples thereof include a titanium
alkoxide dimer such as [Ti20] (OEt) 6, [Ti20] (0-n-Pr) 6,
[Ti2O] (O-n-Bu)f, and the like; a titanium alkoxide heptamer such as
[Ti-,04] (OEt) 20, LTi704] (0-n-Pr)20, [Ti704] (0-n-Bu)2o and the like; a
titanium alkoxide octamer such as [Ti80e] (OCH2Ph)2o and the like;
a titanium alkoxide decamer such as [TiioOs] (OEt)24 and the like;
a titanium alkoxide undecamer such as [TinOja] (0-i-Pr) ie and the
like; a titanium alkoxide dodecamer such as [Ti^Oie] (0-i-Pr) i6 and
the like; a titanium alkoxide hexadecamer such as [TiigOie] (OEt)32
and the like; and a titanium alkoxide heptadecamer such as
[Ti |70;MJ (0-i-Pr) 20 and the like.
[0039]
The titanium compound of the present invention is produced from
a reaction mixture of a titanium tetraalkoxide compound with water
and an optically active ligand represented by the general formula
(b) and preferably represented by the general formula (c), or a
titanium oxoalkoxide compound represented by the above general
formula (a) and an optically active ligand represented by the
general formula (b) and preferably represented by the general
formula (c),
(Figure Removed)

[0043]
[0044]
Incidentally, the optically active ligand represented by the
above general formula (c) corresponds to those with R3 and R4 in
the above general formula (b) bonded together to form a benzene
ring, and is included in the concept of the optically active ligand
represented by the above general formula (b).
[0045]
[Optically active ligand represented by the general formula (b) ]
In the above general formula (b) , R2, R3 and R4 are independently
a hydrogen atom, an alkyl group, an alkenyl group, an aryl group,
an aromatic heterocyclic group, an acyl group, an alkoxycarbonyl
group or an aryloxycarbonyl group, each of which may have a
substituent, two or more of R2, R3 and R4 may be linked together
to form a ring, and the ring may have a substituent. Furthermore,
A* represents a hydrocarbon-containing group with three or more
carbon atoms having an asymmetric carbon atom or axial asymmetry.
[0046]
As the alkyl. group in R2, R3 and R4, preferred is a linear,
branched or cyclic alkyl group having not more than 20 carbon atoms,
and concrete examples thereof include a methyl group, an ethyl
15
group, an n-propyl group, an isopropyl group, an n-butyl group,
an isobutyl group, a sec-butyl group, a tert-butyl group, a
cyclopentyl group, a cyclohexyl group and the like.
[ 0 0 4 7 ]
The aforementioned linear, branched or cyclic alkyl group may
have, as a substituent, a halogen atom, an aryl group having not
more than 20 carbon atoms, an aromatic heterocyclic group having
not more than 20 carbon atoms, a non-aromatic heterocyclic group
having not- more than 20 carbon atoms, an oxygen-containing group
having not more than 20 carbon atoms, a nitrogen-containing group
having not: more than 20 carbon atoms, a silicon-containing group
having not more than 20 carbon atoms or the like.
[0048]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
Examples of the oxygen-containing group having not more than 20
carbon atoms include those having not more than 20 carbon atoms
such as an alkoxy group, an aryloxy group, an alkoxycarbonyl group,
an aryloxycarbonyl group, an acyloxy group and the like.
Examples of the nitrogen-containing group having not more than
20 carbon atoms include an amino group having not more than 20
carbon atoms, an amide group having not more than 20 carbon atoms,
a nitro group, a cyano group and the like.
Examples of the silicon-containing group having not more than
20 carbon atoms include those having not more than 20 carbon atoms
such as a silyl group, a silyloxy group and the like.
[0049]
Examples of the alkyl group having a halogen atom include a
chloromethyl group, a 2-chloroethyl group, a trifluoromethyl group,
a 2,2,2-trifluoroethyl group, a perfluoroethyl group, a
perfluorohexyl group and the like.
Examples of the alkyl group having an aryl group include
substituted or unsubstituted aralkyl groups such as a benzyl group,
a 4-methoxybenzyl group, a 2-phenylethyl group, a cumyl group, an
a-naphthyIrnethyJ group, a diphenylmethyl group, a trityl group and
the like.
Examples of the alkyl group having an aromatic heterocyclic
group include a 2~pyridylmethyl group, a 2-furfuryl group, a
3-furfuryl group, a 2-thienylmethyl group and the like.
[0050]
Examples of the alkyl group having a non-aromatic heterocyclic
group include a 2-tetrahydrofurfuryl group, a
3-tetrahydrofurfuryl group and the like.
Examples of the alkyl group having an oxygen-containing group
include a methoxymethyl group, an isopropoxymethyl group, a
tert-butoxymethyl group, a cyclohexyloxymethyl group, an
L-menthyloxymethyl group, a D-menthyloxymethyl group, a
phenoxyrnethyl group, a benzyloxymethyl group, a phenoxyethyl group,
an acetyloxymethyl group, a 2,4,6-trimethylbenzoyloxymethyl group
and the 1i ke,
[0051]
Examples of the alkyl group having a nitrogen-containing group
include a 2-(dimethylamino)ethyl group, a 3-(diphenylamino)propyl
group and the like.
17
Examples of the alkyl group having a silicon-containing group
include a 2-(trimethylsiloxy)ethyl group and the like.
As the alkenyl group in R2, R3 and R4, preferred is a linear or
branched alkenyl group having 2 to 20 carbon atoms, and concrete
examples thereof include a vinyl group, an allyl group, an
isopropenyl group and the like.
[0052]
The aforementioned linear or branched alkenyl group may have,
as a substituent, a halogen atom such as a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
Examples of the alkenyl group having a halogen atom include a
2-chloroviny] group, a 2,2-dichlorovinyl group, a
3-chloroisopropenyl group or the like.
[0053]
As the aryl group in R2, R3 and R4, preferred is an aryl group
having 6 to 20 carbon atoms, and concrete examples thereof include
a phenyi group, a naphthyl group, a biphenyl group, an anthryl group
and the 1i ke.
The aforementioned aryl group may have, as a substituent, a
halogen atom, an alkyl group having not more than 20 carbon atoms,
an oxygen-containing group having not more than 20 carbon atoms,
a nitrogen-containing group having not more than 20 carbon atoms,
a silicon-containing group having not more than 20 carbon atoms
or the like.
[0054]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
Examples of the oxygen-containing group having not more than 20
carbon atoms include those having not more than 20 carbon atoms
such as an alkoxy group, an aryloxy group, an alkoxycarbonyl group,
an ary.l oxycarbonyl group, an acyloxy group and the like.
Examples of the nitrogen-containing group having not more than
20 carbon atoms include an amino group having not more than 20
carbon atoms, an amide group having not more than 20 carbon atoms,
a nitro group, a cyano group and the like.
Examples of the silicon-containing group having not more than
20 carbon atoms include those having not more than 20 carbon atoms
such as a si.Lyl group, a silyloxy group and the like.
[0055]
Examples of the aryl group having a halogen atom include a
4-fluorophenyl group, a pentafluorophenyl group and the like.
Examples of the aryl group having an alkyl group include a tolyl
group, a dimethylphenyl group, a 2,4,6-trimethylphenyl group, a
4-isopropylphenyl group, a 2,6-diisopropylphenyl group, a
4-tert-butylphenyl group, a 2,6-di-tert-butylphenyl group and the
like.
i Examples of the aryl group having an oxygen-containing group
include an alkoxy-substituted aryl group such as a 4-methoxyphenyl
group, a 3,5-dimethoxyphenyl group, a 3,5-diisopropoxyphenyl
group, a 2,4,6-triisopropoxyphenyl group and the like; and an
aryloxy-substituted aryl group such as a 2, 6-diphenoxyphenyl group
> and the like.
[ 0 0 h 6 ]
Examples of the aryl group having a nitrogen-containing group
include a 4-(dimethylamino)phenyl group, a 4-nitrophenyl group and
the like.
Examples of the aryl group having a silicon-containing group
include a 3,S-tais(trimethylsilyl)phenyl group, a
3,5-bis(trimethylsiloxy)phenyl group and the like.
[0057]
As the aromatic heterocyclic group in R2, R3 and R4, preferred
is an aromatic heterocyclic group having 3 to 20 carbon atoms, and
concrete examples thereof include an imidazolyl group, a furyl
group, a thienyl. group, a pyridyl group and the like.
The aforementioned aromatic heterocyclic group may have an alkyl
group heaving not more than 20 carbon atoms, an oxygen-containing
group having not more than 20 carbon atoms, a nitrogen-containing
group having not more than 20 carbon atoms, a silicon-containing
group having not more than 20 carbon atoms or the like.
[0058]
Examples of the oxygen-containing group having not more than
carbon atoms include those having not more than 20 carbon atoms
such as an alkoxy group, an aryloxy group, an alkoxycarbonyl group,
an aryloxycarbonyl group, an acyloxy group and the like.
Examples of the nitrogen-containing group having not more than
20 carbon atoms include an amino group having not more than
carbon atoms, an amide group having not more than 20 carbon atoms,
a nitro group, a cyano group and the like.
Examples of the silicon-containing group having not more than
20 carbon atoms include those having not more than 20 carbon atoms
such as a siiyl group, a silyloxy group and the like.
20
Examples of the aromatic heterocyclic group having an alkyl
group include an N-methylimidazolyl group and the like.
| 0 5 9]
As the acyj group in R":, R3 and R4, preferred are an alkylcarbonyl
group having 2 to 20 carbon atoms and an arylcarbonyl group, and
concrete examples thereof include an alkylcarbonyl group such as
an acetyl group, a propionyl group, a butyryl group, an isobutyryl
group, a pivaloyl group and the like; and an arylcarbonyl group
such as a benzoyl group, a naphthoyl group, an anthrylcarbonyl
group and the Like.
[0060]
The aforementioned alkylcarbonyl group may have, as a
substituent on the alkyl group, a halogen atom such as a fluorine
atom, a chlorine atom, a bromine atom, an iodine atom and the like.
Examples of the alkylcarbonyl group having a halogen atom
include a trifluoroacetyl group and the like.
The aforementioned arylcarbonyl group may have, as a substituent
on the aryl group, a halogen atom, an alkyl group having not more
than 20 carbon atoms, an oxygen-containing group having not more
than 20 carbon atoms, a nitrogen-containing group having not more
than 20 carbon atoms, a silicon-containing group having not more
than 20 carbon atoms and the like.
[0061]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
Examples of the oxygen-containing group having not more than 20
carbon atoms include those having not more than 20 carbon atoms
such as an alkoxy group, an aryloxy group, an alkoxycarbonyl group,
an aryloxycarbonyl group, an acyloxy group and the like.
Examples of the nitrogen-containing group having not more than
20 carbon atoms include an amino group having not more than 20
carbon atoms, an amide group having not more than 20 carbon atoms,
a nitro group, a cyano group and the like.
Examples of the silicon-containing group having not more than
20 carbon atoms include those having not more than 20 carbon atoms
such as a silyl group, a silyloxy group and the like.
[0062]
Examples of the arylcarbonyl group having a halogen atom include
a pentafluorobenzoyl group and the like.
Examples of the arylcarbonyl group having an alkyl group include
a 3,5-dimethylbenzoyl group, a 2,4,6-trimethylbenzoyl group and
the like.
Examples of the arylcarbonyl group having an oxygen-containing
group include a 2,6-dimethoxybenzoyl group, a
2,6-diisopropoxybenzoyl group and the like.
Examples of the arylcarbonyl group having a nitrogen-containing
group include a 4-(dimethylamino)benzoyl group, a 4-cyanobenzoyl
group and the like.
Examples of the arylcarbonyl group having a silicon-containing
group include a 2,6-bis(trimethylsilyl)benzoyl group, a
2,6-bis(trimethylsiloxy)benzoyl group and the like.
[0063]
As the alkoxycarbonyl group in R2, R3 and R4, preferred is a linear,
branched or cyclic alkoxycarbonyl group having 2 to 20 carbon atoms,
and concrete examples thereof include a methoxycarbonyl group, an
ethoxycarbonyl group, an n-butoxycarbonyl group, an
n-octyloxycarbonyl group, an isopropoxycarbonyl group, a
tert-butoxycarbonyl group, a cyclopentyloxycarbonyl group, a
cyclohexyloxycarbonyl group, a cyclooctyloxycarbonyl group, an
L-menthyloxycarbonyl group, a D-menthyloxycarbonyl group and the
like.
[0064]
The aforementioned alkoxycarbonyl group may have, as a
substituent on the alkyl group, a halogen atom, an aryl group having
not more; than 20 carbon atoms, an aromatic heterocyclic group
having not more than 20 carbon atoms, a non-aromatic heterocyclic
group having not more than 20 carbon atoms and the like.
f 0 0 6 5]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like. Examples of
the alkoxycarbonyl group having a halogen atom include a
2,2,2-trifluoroethoxycarbonyl group and the like.
[0066]
Examples of the alkoxycarbonyl group having an aryl group
include unsubstituted or substituted aralkyloxycarbonyl groups
such as a benzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl
group, a 2-phenylethoxycarbonyl group, a cumyloxycarbonyl group,
an a-naphthyImethoxycarbonyl group and the like.
[0067]
Examples of the alkoxycarbonyl group having an aromatic
heterocyclic group include a 2-pyridylmethoxycarbonyl group,
furfuryLoxycarbonyl group, a 2-thienylmethoxycarbonyl group and
the like.
Examples of the alkoxycarbonyl group having a non-aromatic
heterocyclic group include a tetrahydrofurfuryloxycarbonyl group.
[0068]
As an aryloxycarbonyl group in R2, R3 and R4, preferred is an
aryloxycarbonyl group having 7 to 20 carbon atoms, and concrete
examples thereof include a phenoxycarbonyl group, an
a-naphthyloxycarbonyl group and the like.
The aforementioned aryloxycarbonyl group may have, as a
substituent on the aryl group, a halogen atom, an alkyl group having
not more than 20 carbon atoms, an oxygen-containing group having
not more than 20 carbon atoms, a nitrogen-containing group having
not more than 20 carbon atoms, a silicon-containing group having
not more than 20 carbon atoms and the like.
[0069]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
Examples of the an oxygen-containing group having not more than
20 carbon atoms include those having not more than 20 carbon atoms
such as an alkoxy group, an aryloxy group, an alkoxycarbonyl group,
an aryloxycarbonyl group, an acyloxy group and the like.
Examples of the nitrogen-containing group having not more than
20 carbon atoms include an amino group having not more than 20
carbon atoms, an amide group having not more than 20 carbon atoms,
a nitro group, a cyano group and the like.
Examples of the silicon-containing group having not more than
20 carbon atoms include those having not more than 20 carbon atoms
such as a silyl group, a silyloxy group and the like.
[0070]
Examples of the aryloxycarbonyl group having a halogen atom
include a pentafluorophenoxycarbonyl group and the like.
Examples of the aryloxycarbonyl group having an alkyl group
include a 2, 6-d.imethylphenoxycarbonyl group, a
2,4,6-trimethylphenoxycarbonyl group and the like.
[0071 ]
Examples of the; aryloxycarbonyl group having an
oxygen-containing group include a 2,6-dimethoxyphenoxycarbonyl
group, a 2,6-diisopropoxyphenoxycarbonyl group and the like.
Examples of the aryloxycarbonyl group having a
nitrogen-containing group include a
4-(dimethylarnino) phenoxycarbonyl group, a 4-cyanophenoxycarbonyl
group and the like.
Examples of the aryloxycarbonyl group having a
silicon-containing group include a
2,6-bis(trimethylsilyl)phenoxycarbonyl group, a
2,6-bis(trimethylsiloxy)phenoxycarbonyl group and the like.
[0072]
Furthermore, two or more of R2, R3 and R4 may be linked together
to form a ring. The ring is preferably an aliphatic or aromatic
hydrocarbon ring. The formed rings may be condensed to form a ring,
respectively.
The aliphatic hydrocarbon ring is preferably a 10 or
less-membered ring, particularly preferably a 3- to 7-
ring, and most preferably a 5- or 6-membered ring. The aliphatic
hydrocarbon ring may have unsaturated bonds.
The aromatic hydrocarbon ring is preferably a 6-membered ring,
that is, a benzene ring.
For example, when R3 and R4 are linked together to form -(CH2)4~
or -CH=CH-CH=CH~, a cyclohexene ring (included in the aliphatic
hydrocarbon ring) or a benzene ring (included in the aromatic
hydrocarbon ring) is formed, respectively.
[0073]
The ring formed as described above may have one substituent or
two or more substituents selected from a halogen atom, an alkyl
group, an aryl group, an alkoxy group, an aryloxy group, an amino
group, a nitro group, a cyano group, a silyl group and a silyloxy
group.
[0074]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
As the alkyl group, preferred is a linear, branched or cyclic
alkyl group having not more than 20 carbon atoms which may have
a substituent. Concrete examples thereof include a methyl group,
an ethyl group, an n-propyl group, an isopropyl group, an n-butyl
group, a sec-butyl group, a tert-butyl group, an n-pentyl group,
a cyclopentyl group, a cyclohexyl group, an adamantyl group, a
trifluoromethyl group, a benzyl group, a trityl group and the like.
[0075]
As the aryl group, preferred is a substituted or unsubstituted
aryl group having not more than 20 carbon atoms, and examples
thereof include a phenyl group, a naphthyl group, a biphenyl group,
an anthryl group, a 2,6-dimethylphenyl group, a
2, 4,6-trimethylphenyl group, a 2, 6-dimethoxyphenyl group and the
like.
As the alkoxy group, preferred is a substituted or unsubstituted
alkoxy group having not more than 20 carbon atoms, and examples
thereof include a methoxy group, an ethoxy group, an isopropoxy
group, a tert-butoxy group, a benzyloxy group and the like.
[0076]
As the aryloxy group, preferred is a substituted or
unsubstituted aryloxy group having not more than 20 carbon atoms,
and examples thereof include a phenoxy group, a
2, 6-dimethylphenoxy group and the like.
As the amino group, preferred is a substituted or unsubstituted
amino group having not more than 20 carbon atoms, and examples
thereof include a dimethylamino group, a diethylamino group, a
diphenylamino group and the like.
As the si.lyl group, preferred is a silyl group having an alkyl
group having not more than 20 carbon atoms or having an aryl group,
and examples thereof include a trimethylsilyl group, a
triethylsilyL group and the like.
As the silyloxy group, preferred is s silyloxy group having not
more than 20 carbon atoms, and examples thereof include a
trimethylsiloxy group and the like.
Furthermore, the aforementioned benzene ring may be condensed
to form a condensed polycyclic ring such as a naphthalene ring.
[0077]
[Hydrocarbon-containing group A*]
In the above; general formula (b) , A* represents an optically
active hydrocarbon-containing group with three or more carbon
atoms, and preferably 3 to 40 carbon atoms, having an asymmetric
carbon atom or axial asymmetry which may have a substituent.
As the hydrocarbon-containing group in the above A*, optically
active hydrocarbon-containing groups represented by the following
general formulae (A-l) to (A-3) are suitable. In the formula, parts
indicated as (N) and (OH) do not belong to A*, and represent a
nitrogen atom and a hydroxyl group corresponding to those in the
above general formula (b) to which A* is bonded,
[0078]
(Figure Removed)

[Hydrocarbon-containing group A*: General formula (A-l)]
In the above general formula (A-l), Ra, Rb, Rc and Rd are each
28
a hydrogen atom, an alkyl group, an aryl group, an alkoxycarbonyl
group, an aryloxycarbonyl group or an aminocarbonyl group, each
of which may have a substituent.
Two or more of Ra, Rb, Rc and Rd may be linked together to form
a ring and the ring may have a substituent.
Further, at least one of Ra, Rb, Rc and Rd is a different group,
and both or at least one of the carbon atoms indicated as * become
an asymrae 1: ric center.
[0080]
An alkyl group, an aryl group, an alkoxycarbonyl group and
an aryloxycarbonyl group in Ra, Rb, Rc and Rd are the same as the
alkyl group, the aryl group, the alkoxycarbonyl group and the
aryloxycarbonyl group as in the above R2 to R4.
[0081]
As the aminocarbonyl group in Ra, Rb, Rc and Rd, preferred is an
aminocarbonyl group having a hydrogen atom, an alkyl group having
not more than 20 carbon atoms or an aryl group having not more than
20 carbon atoms, and two of the substituents other than a carbonyl
group to be bonded to a nitrogen atom may be linked together to
form a ring. Concrete examples of the aminocarbonyl group having
an alkyl group or an aryl group include an isopropylaminocarbonyl
group, a cyclohexylaminocarbonyl group, a tert-butylaminocarbonyl
group, a tert-amylaminocarbonyl group, a dimethylaminocarbonyl
group, a diethylaminocarbonyl group, a diisopropylaminocarbonyl
group, a diisobutylaminocarbonyl group, a
dicyclohexylaminocarbonyl group, a
tert-butylisopropylaminocarbonyl group, a phenylaminocarbonyl
group, a pyrrolidylcarbonyl group, a piperidylcarbonyl group, an
indolecarbonyl qroup and the like.
[0082]
The aforementioned aminocarbonyl group may have, as a
substituent on the aforementioned alkyl group or aryl group, a
halogen atom, an aryl group having not more than 20 carbon atoms,
an alky] qroup having not more than 20 carbon atoms or the like.
[0083]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
Examples of the aminocarbonyl group having an alkyl group which
is substituted with a halogen atom include a
2-chloroethy1aminocarbonyl group, a perfluoroethylaminocarbonyl
group and the like.
Examples of the aminocarbonyl group having an aryl group which
is substituted with a halogen atom include a
4-chlorophenylaminocarbonyl group, a
pentafluorophenylaminocarbonyl group and the like.
[0084]
Examples of the aminocarbonyl group having an alkyl group which
is substituted with an aryl group include substituted or
unsubstituted aralkylaminocarbonyl groups such as a
benzylaminocarbonyl group, a 2-phenylethylaminocarbonyl group, an
a-naphthylmethylaminocarbonyl group and the like.
Examples of the aminocarbonyl group having an aryl group which
is substituted with an alkyl group include a
2,4,6-trimethylphenylaminocarbonyl group and the like.
[0085]
Meanwhile, two or more of Ra, Rb, Rc and Rd may be linked together
to form a ring. The ring is preferably aliphatic hydrocarbon and
the formed ring may be further condensed to form a ring. The ring
is preferably a 3- to 7-membered ring and particularly preferably
a 5- or 6-membered ring. For example, when Ra and Rc are linked
together to form -(CH2)3-, a 5-membered ring is formed.
The thus formed ring may have one substituent or two or more
substituents selected from a halogen atom, an alkyl group, an aryl
group, an alkoxy group, an aryloxy group, an amino group, a nitro
group, a cyano group, a silyl group and a silyloxy group.
[0086]
Concrete examples of the optically active
hydrocarbon-containing group represented by the above general
formula (A-l) include those represented by the following formulas
(A-la) to (A-lx), their enantiomers and the like.
[008 7]
(Figure Removed)

[Hydrocarbon-containing group A*: General formula (A-2)]
In the above general formula (A-2) , Re and Rf are each a hydrogen
atom, an alkyl group or an aryl group, each of which may have a
substituent. Furthermore, Re and Rf are different substituents,
and * represents an asymmetric carbon atom.
The alkyl group and aryl group in Re and Rf are the same as the
alkyl group and aryl group in the above Ra to Rd.
[0089]
Concrete examples of the optically active
hydrocarbon-containing group represented by the above general
formula (A-2) include those represented by the following formulas
(A-2a) to (A-2p), their enantiomers and the like.
[0090]
(Figure Removed)

[0091]
[Hydrocarbon-containing group A*: General formula (A-3)]
In the above general formula (A-3), R9, Rh, R1 and RD are
independently a hydrogen atom, a halogen atom, an alkyl group, an
aryl group or an alkoxy group, each of which may have a substituent.
Further, R1 and Rj on the same benzene ring may be linked together
or condensed to form a ring. *' represents an axial asymmetry.
[0092]
Examples of the halogen atom in Rg, Rh, R1 and R-5 include a
fluorine' atom, a chlorine atom, a bromine atom, an iodine atom and
the like.
The alkyl group and aryl group in Rg, Rh, R1 and Rj are the same
as the alkyl group and the aryl group in the above R2 to R4.
As the alkoxy group in Rg, Rh, R1 and Rj, preferred is an alkoxy
group having not more than 20 carbon atoms, and examples thereof
include a methoxy group, an ethoxy group, and n-propoxy group, an
isopropoxy group, a tert-butoxy group and the like.
F 0 0 9 3 ]
Furthermore, when R1 and R3 on the same benzene ring are linked
together to form a ring, the ring is preferably an aliphatic or
aromatic hydrocarbon ring, or a non-aromatic heterocyclic
containing an oxygen atom. The formed rings may be condensed to
form a ring.
The aliphatic hydrocarbon ring is preferably a 5- or 6-membered
ring.
The aromatic hydrocarbon ring is preferably a 6-membered ring,
that is, a benzene ring.
For example, when R1 and R^ are linked together to form
-CH=CH-CH=CH-, -(CH2)4- or -OCH20-, a naphthalene ring, a
tetrahydronaphthalene ring or a benzodioxorane ring is formed,
respectively.
[0094]
The thus formed ring such as a naphthalene ring, a
tetrahydronaphthalene ring, a benzodioxorane ring or the like may
have one substituent or two or more substituents selected from,
for example, a halogen atom, an alkyl group, an aryl group and an
alkoxy group.
[0095]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
As the alkyl group, preferred is a linear, branched or cyclic
alkyl group having not more than 20 carbon atoms which may have
a substituent. Concrete examples thereof include a methyl group,
an ethyl group, an n-propyl group, an isopropyl group, a tert-butyl
group, a cyc'.opentyl group, a cyclohexyl group and the like.
As the aryl group, preferred is a substituted or unsubstituted
aryl group having not more than 20 carbon atoms, and concrete
examples thereof include a phenyl group, a naphthyl group, a
biphenyl group, an anthryl group and the like.
As the alkoxy group, preferred is a substituted or unsubstituted
alkoxy group having not more than 20 carbon atoms, and concrete
examples thereof include a methoxy group, an ethoxy group, an
n-propoxy group, an isopropoxy group, a tert-butoxy group and the
like.
[009 C, ]
Meanwhile, the benzene rings may be condensed to form a condensed
polycyclic ring such as a naphthalene ring and the like.
Concrete examples of the optically active
hydrocarbon-containing group represented by the above general
formula (A-3) include those represented by the following formulas
(A-3a) to (A-3c), their enantiomers and the like.
[0097]
(Figure Removed)

[009H]
[Optically active ligand represented by the general formula (c) ]
Preferred examples of the optically active ligand represented
by the general formula (b) include optically active ligands
represented by the above general formula (c).
Rd, Rb, Rc and Rd in the above general formula (c) represent the
same as those in the above general formula (A-l) . Namely, Ra, Rb,
Rc and Rd are each a hydrogen atom, an alkyl group, an aryl group,
an alkoxycarbonyl group, an aryloxycarbonyl group or an
aminocaebony 1 group, each of which may have a substituent. Two
or more of Ra, Rh, Rc and Rd may be linked together to form a ring
and the ring may have a substituent. Furthermore, at least one
of Ra, Rb, Rc and Rd is a different group. Both or at least one of
the carbon atoms indicated as * become an asymmetric center.
[0100]
R5 in the above general formula (c) is a hydrogen atom or an alkyl
and the? alkyl group may have a substituent.
[ 010 L ]
Rb, R', R8 and R9 in the above general formula (c) are
independently a hydrogen atom, a halogen atom, an alkyl group, an
alkenyl group, an aryl group, an aromatic heterocyclic group, a
non-aromatic heterocyclic group, an alkoxycarbonyl group, an
aryloxycarbonyl group, a hydroxyl group, an alkoxy group, an
aryloxy group, an amino group, a cyano group, a nitro group, a silyl
group or a siloxy group which may have a substituent, each of which
may be linked together to form a ring.
[0102]
As the alkyl group in Rb, preferred is a linear, branched or
cyclic alkyl group having not more than 20 carbon atoms, and
concrete examples thereof include a methyl group, an ethyl group,
an n-propyl group, an isopropyl group, a sec-butyl group, a
cyclopropyl group, a cyclopentyl group, a cyclohexyl group and the
like.
[0103]
The aforementioned linear, branched or cyclic alkyl group may
have, as a substituent, a halogen atom, an aryl group having not
more than 20 carbon atoms, an aromatic heterocyclic group having
not more than 20 carbon atoms, a non-aromatic heterocyclic group
having not; more than 20 carbon atoms, an oxygen-containing group
having not more than 20 carbon atoms, a nitrogen-containing group
having not more than 20 carbon atoms, a silicon-containing group
having not more than 20 carbon atoms or the like.
[0104]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
Examples of the oxygen-containing group having not more than 20
carbon atoms include those having not more than 20 carbon atoms
such as an alkoxy group, an aryloxy group, an alkoxycarbonyl group,
an ary1oxycarbonyl group, an acyloxy group and the like.
Examples of the nitrogen-containing group having not more than
20 carbon atoms include an amino group having not more than 20
carbon atoms, an amide group having not more than 20 carbon atoms,
a nitro group, a cyano group and the like.
Examples of the silicon-containing group having not more than
20 carbon atoms include those having not more than 20 carbon atoms
such as a silyl group, a silyloxy group and the like.
f0105]
Examples of the alkyl group having a halogen atom include a
chloromethyl group, a 2-chloroethyl group, a trifluoromethyl group,
a 2,2,2-trifluoroethyl group, a perfluoroethyl group, a
perfluorohexyl group and the like.
Examples of the alkyl group having an aryl group include
substituted or unsubstituted aralkyl groups such as a benzyl group,
a 4-methoxybenzyl group, a 2-phenylethyl group, a cumyl group, an
a-naphthyImethyl group, a trityl group and the like.
Examples of the alkyl group having an aromatic heterocyclic
group include; a 2-pyridylmethyl group, a furfuryl group, a
2-thienylmethyl group and the like.
[0106]
Examples of the alkyl group having a non-aromatic heterocyclic
group include a tetrahydrofurfuryl group and the like.
Examples of the alkyl group having an oxygen-containing group
include a methoxyethyl group, a phenoxyethyl group and the like.
Examples of the alkyl group having a nitrogen-containing
include a 2-(dimethylamino)ethyl group, a 3-(diphenylamino)propyl
group and the like.
Examples of the alkyl group having a silicon-containing group
include a 2-(trimethylsiloxy)ethyl group and the like.
[0107]
Examples of the halogen atom in R6, R7, R8 and R9 include a
fluorine atom, a chlorine atom, a bromine atom, an iodine atom and
the like.
As the alkyl group in Rf;, R7, R8 and R9, preferred is a linear,
branched or cyclic alkyl group having not more than 20 carbon atoms,
and concrete exeimples thereof include a methyl group, an ethyl
group, an ri-propyl group, an isopropyl group, a sec-butyl group,
a tert-butyl group, a cyclopentyl group, a cyclohexyl group, an
adamantyl group and the like.
The aforementioned linear, branched or cyclic alkyl group may
have, as a substituent, a halogen atom, an aryl group having not
more than 20 carbon atoms, an aromatic heterocyclic group having
not more than 20 carbon atoms, a non-aromatic heterocyclic group
having not. more than 20 carbon atoms, an oxygen-containing group
having not more than 20 carbon atoms, a nitrogen-containing group
having not more than 20 carbon atoms, a silicon-containing group
having not more than 20 carbon atoms or the like.
[010H]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
Examples of the oxygen-containing group having not more than 20
carbon atoms include those having not more than 20 carbon atoms
such as an alkoxy group, an aryloxy group, an alkoxycarbonyl group,
an aryloxycarbonyl group, an acyloxy group and the like.
Examples of the nitrogen-containing group having not more than
20 carbon atoms include an amino group having not more than 20
carbon atoms, an amide group having not more than 20 carbon atoms,
a nitro group, a cyano group and the like.
Examples of the silicon-containing group having not more than
20 carbon atoms include those having not more than 20 carbon atoms
such as a silyl group, a silyloxy group and the like.
[0109]
Examples of the alkyl group having a halogen atom include
halogenated alkyl groups having not more than 20 carbon atoms such
as a chloromethyl group, a 2-chloroethyl group, a trifluoromethyl
group, a 2,2,2-trifluoroethyl group, a perfluoroethyl group, a
perfluorohexyl group and the like.
Examples of the alkyl group having an aryl group include
substituted or unsubstituted aralkyl groups such as a benzyl group,
a 4-methoxybenzyl group, a 2-phenylethyl group, a cumyl group, an
a-naphthylmethyl group, a 2-phenylisopropyl group, a trityl group,
a 2-phenylnaphthalene-l-yl group and the like.
[Oil0]
Examples of the alkyl group having an aromatic heterocyclic
group include a 2-pyridylmethyl group, a furfuryl group, a
2-thienylrnethyl group arid the like. Examples of the alkyl group
having a non-aromatic heterocyclic group include a
tetrahydrofurfuryl group and the like. Examples of the alkyl group
having an oxygen-containing group include a methoxyethyl group,
a phenoxyethyl group and the like. Examples of the alkyl group
having a nitrogen-containing group include a
2-(dimethylamino)ethyl group, a 3-(diphenylamino)propyl group and
the like. Examples of the alkyl group having a silicon-containing
group include a 2-(trimethylsiloxy)ethyl group and the like.
[0111]
As the alkeriyl group in Re, R', R8 and R9, preferred is a linear
or branched alkenyl group having 2 to 20 carbon atoms, and concrete
examples thereof include a vinyl group, an allyl group, an
isopropenyl group and the like.
[01K>]
The aforementioned linear or branched alkenyl group may have,
as a substituent, a halogen atom, an oxygen-containing group having
not more than 20 carbon atoms, a nitrogen-containing group having
not more than 20 carbon atoms, a silicon-containing group having
not more than 20 carbon atoms or the like.
[0113]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
Examples of the oxygen-containing group having not more than 20
carbon atoms include those having not more than 20 carbon atoms
such as an alkoxy group, an aryloxy group, an alkoxycarbonyl group,
an aryloxycarbonyl group, an acyloxy group and the like.
Examples of the nitrogen-containing group having not more than
20 carbon atoms include an amino group having not more than 20
carbon atoms, an amide group having not more than 20 carbon atoms,
a nitro group, a cyano group and the like.
Examples of the silicon-containing group having not more than
20 carbon atoms include those having not more than 20 carbon atoms
such as a silyl group, a silyloxy group and the like.
[0114]
Examples of the alkenyl group having a halogen atom include a
2-chlorovinyl group, a 2,2-dichlorovinyl group, a
3-chlor oi.sopropenyl group and the like.
[0115]
As the aryl group in R6, R7, R8 and R9, preferred is an aryl group
having 6 to 20 carbon atoms, and concrete examples thereof include
a phenyl group, a naphthyl group, a biphenyl group, an anthryl group,
a 2-phenyJ-1-naphthyl group and the like.
[Oil 6]
The aforementioned aryl group may have, as a substituent, a
halogen atom, an alkyl group having not more than 20 carbon atoms,
an oxygen-containing group having not more than 20 carbon atoms,
a nitrogen-containing group having not more than 20 carbon atoms,
a silicon-containing group having not more than 20 carbon atoms
or the like.
[0117]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
Examples of the oxygen-containing group having not more than 20
carbon atoms include those having not more than 20 carbon atoms
such as an alkoxy group, an aryloxy group, an alkoxycarbonyl group,
an aryloxycarbony1 group, an acyloxy group and the like.
Examples of the nitrogen-containing group having not more than
20 carbon atoms include an amino group having not more than 20
carbon atoms, an amide group having not more than 20 carbon atoms,
a nitro group, a cyano group and the like.
Examples of the silicon-containing group having not more than
20 carbon atoms include those having not more than 20 carbon atoms
such as a silyl group, a silyloxy group and the like.
[0118]
Examples of the aryl group having a halogen atom include a
pentafluorophenyl group and the like. Examples of the aryl group
having an alkyl group include a tolyl group, a dimethylphenyl group,
a 2,4,6-trimethylphenyl group, an isopropylphenyl group, a
diisopropylphenyl group, a tert-butylphenyl group, a
di-tert-butylphenyl group and the like.
[0119]
Examples of the aryl group having an oxygen-containing group
include an alkoxy-substituted aryl group such as a 4-methoxyphenyl
group, a 3,5-dirnethoxyphenyl group, a 3,5-diisopropoxyphenyl
group, a 2,4,6-triisopropoxyphenyl group and the like; and an
aryloxy-substi tuted aryl group such as a 2, 6-diphenoxyphenyl group
and the like.
Examples of the aryl group having a nitrogen-containing group
include a 4-(dimethylamino)phenyl group, a 4-nitrophenyl group and
the like.
Examples of the aryl group having a silicon-containing group
include a 3,b-bis(trimethylsilyl)phenyl group, a
3,5-bis(trimethylsiloxy)phenyl group and the like.
[0120]
As the aromatic heterocyclic group in R6, R7, R8 and R9, preferred
is an aromatic heterocyclic group having 3 to 20 carbon atoms, and
concrete examples thereof include an imidazolyl group, a furyl
group, a thienyL group, a pyridyl group and the like.
The aforementioned aromatic heterocyclic group may have an alkyl
group having not more than 20 carbon atoms, an aryl group having
not more than 20 carbon atoms, an oxygen-containing group having
not more than 20 carbon atoms, a nitrogen-containing group having
not more than 20 carbon atoms, a silicon-containing group having
not more than 20 carbon atoms or the like.
[012L]
Examples of the oxygen-containing group having not more than 20
carbon atoms include those having not more than 20 carbon atoms
such as an alkoxy group, an aryloxy group, an alkoxycarbonyl group,
an aryloxycarbonyl group, an acyloxy group and the like.
Examples of the nitrogen-containing group having not more than
20 carbon atoms include an amino group having not more than 20
carbon atoms, an amide group having not more than 20 carbon atoms,
a nitro group, a cyano group and the like.
Examples of the silicon-containing group having not more than
20 carbon atoms include those having not more than 20 carbon atoms
such as a siiyl group, a silyloxy group and the like.
Examples of the aromatic heterocyclic group having an alkyl
group include an N-methylimidazolyl group and the like.
[0122]
As the non-aromatic heterocyclic group in R6, R', R8 and R9,
preferred is a non-aromatic heterocyclic group having 4 to 20
carbon atoms, and concrete examples thereof include a pyrrolidinyl
group, a piperidyl group, a tetrahydrofuryl group, a
tetrahydropyranyl group and the like.
The aforementioned non-aromatic heterocyclic group may have an
alkyl group having not more than 20 carbon atoms, an aryl group
having not: more than 20 carbon atoms, an oxygen-containing group
having not: more than 20 carbon atoms, a nitrogen-containing group
having noi: more than 20 carbon atoms, a silicon-containing group
having not more than 20 carbon atoms or the like.
.012?'!
Examples of the oxygen-containing group having not more than 20
carbon atoms include those having not more than 20 carbon atoms
such as an alkoxy group, an aryloxy group, an alkoxycarbonyl group,
an ary]oxycarbonyJ group, an acyloxy group and the like.
Examples of the nitrogen-containing group having not more than
20 carbon atoms include an amino group having not more than 20
carbon atoms, an amide group having not more than 20 carbon atoms,
a nitre group, a cyano group and the like.
Examples of rhe silicon-containing group having not more than
20 carbon atoms include those having not more than 20 carbon atoms
such as a siiyl group, a silyloxy group and the like.
[0124]
Examples of the non-aromatic heterocyclic group having an aryl
group include ary[-substituted non-aromatic heterocyclic groups
having not more than 20 carbon atoms such as an
N-pheny1-4-piperidyl group and the like.
As the al koxycarbonyl group in R6, R7, R8 and R9, preferred is
a linear, branched or cyclic alkoxycarbonyl group having 2 to 20
carbon atoms, and concrete examples thereof include a
methoxycarbonyl group, an ethoxycarbonyl group, an
n-butoxycarbonyl group, an n-octyloxycarbonyl group, an
isopropoxycarbonyl group, a tert-butoxycarbonyl group, a
cyclopentyloxycarbonyl group, a cyclohexyloxycarbonyl group, a
cyclooctyloxycarbonyl group and the like.
[0125]
The aforementioned alkoxycarbonyl group may have, as a
substituent on the alkyl group, a halogen atom, an aryl group having
not more than 20 carbon atoms, an aromatic heterocyclic group
having not more than 20 carbon atoms, a non-aromatic heterocyclic
group having not more than 20 carbon atoms or the like.
[0126]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
Examples of the alkoxycarbonyl group having a halogen atom
include a 2,2,2-trifluoroethoxycarbonyl group and the like.
Examples of the alkoxycarbonyl group having an aryl group
include substituted or unsubstituted aralkyloxycarbonyl groups
such as a benzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl
group, a 2-phenylethoxycarbonyl group, a cumyloxycarbonyl group,
an a-naphthylmethoxycarbonyl group and the like.
[0127]
Examples of the alkoxycarbonyl group having an aromatic
heterocyclic group include a 2-pyridylmethoxycarbonyl group, a
furfuryloxycarbonyl group, a 2-thienylmethoxycarbonyl group and
the like.
Examples of the alkoxycarbonyl group having a non-aromatic
heterocyclic group include a tetrahydrofurfuryloxycarbonyl group
and the like.
[0128]
As the aryloxycarbonyl group in R6, R7, R8 and R9, preferred is
an aryloxycarbonyl group having 7 to 20 carbon atoms, and concrete
examples thereof include a phenoxycarbonyl group, an
a-naphthyloxycarbonyl group and the like.
[0129]
The aforementioned aryloxycarbonyl group may have, as a
substituent on the aryl group, a halogen atom, an alkyl group having
not more than 20 carbon atoms, an oxygen-containing group having
not more than 20 carbon atoms, a nitrogen-containing group having
not more than 20 carbon atoms, a silicon-containing group having
not more than 20 carbon atoms or the like.
[0130]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
Examples of the oxygen-containing group having not more than 20
carbon atoms include those having not more than 20 carbon atoms
such as an alkoxy group, an aryloxy group, an alkoxycarbonyl group,
an aryloxycarbonyl group, an acyloxy group and the like.
Examples of the nitrogen-containing group having not more than
20 carbon atoms include an amino group having not more than 20
carbon atoms, an amide group having not more than 20 carbon atoms,
a nitro group, a cyano group and the like.
Examples of the silicon-containing group having not more than
20 carbon atoms include those having not more than 20 carbon atoms
such as a silyl group, a silyloxy group and the like.
[0131]
Examples of the aryloxycarbonyl group having a halogen atom
include a pentafluorophenoxycarbonyl group and the like.
Examples of the aryloxycarbonyl group having an alkyl group
include a 2,6-dimethylphenoxycarbonyl group, a
2,4,6-trimethylphenoxycarbonyl group and the like.
Examples of the aryloxycarbonyl group having an
oxygen-containing group include a 2,6-dimethoxyphenoxycarbonyl
group, a 2,6-diisopropoxyphenoxycarbonyl group and the like.
Examples of the aryloxycarbonyl group having a
nitrogen-containing group include a
4-(dimethylamino)phenoxycarbonyl group, a 4-cyanophenoxycarbonyl
group and the like. Examples of the aryloxycarbonyl group having
a silicon-containing group include a
2,6-bis(trimethylsilyl)phenoxycarbonyl group, a
2,6-bis(trimethylsiloxy)phenoxycarbonyl group and the like.
[0132]
As the alkoxy group in R6, R7, R8 and R9, preferred is a linear,
branched or cyclic alkoxy group having not more than 20 carbon atoms.
Concrete examples thereof include a methoxy group, an ethoxy group,
an n-propoxy group, an isopropoxy group, a tert-butoxy group, a
cyclopentyloxy group, a cyclohexyloxy group, a menthyloxy group
and the like.
[0133]
The aforementioned alkoxy group may have, as a substituent on
the alkyl group, a halogen atom, an aryl group having not more than
20 carbon atoms, an aromatic heterocyclic group having not more
than 20 carbon atoms, a non-aromatic heterocyclic group having not
more than 20 carbon atoms or the like.
[0134]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
Examples of the alkoxy group having a halogen atom include a
2,2,2-trifluoroethoxy group and the like.
Examples of the alkoxy group having an aryl group include
substituted or unsubstituted aralkyloxy groups such as a benzyloxy
group, a 4-methoxybenzyloxy group, a 2-phenylethoxy group, a
cumyloxy group, an a-naphthylmethoxy and the like.
Examples of the alkoxy group having an aromatic heterocyclic
group include a 2-pyridylmethoxy group, a furfuryloxy group, a
2-thienylmethoxy group and the like.
Examples of the alkoxy group having a non-aromatic heterocyclic
group include a tetrahydrofurfuryloxy group and the like.
[0135]
As the aryloxy group in R6, R7, R8 and R9, preferred is an aryloxy
group having 6 to 20 carbon atoms. Concrete examples thereof
include a phenoxy group, a naphthyloxy group and the like.
The aforementioned aryloxy group may have, as a substituent on
the aryl group, a halogen atom, an alkyl group having not more than
20 carbon atoms, an oxygen-containing group having not more than
20 carbon atoms, a nitrogen-containing group having not more than
20 carbon atoms, a silicon-containing group having not more than
20 carbon atoms or the like.
[0136]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
Examples of the oxygen-containing group having not more than 20
carbon atoms include those having not more than 20 carbon atoms
such as an alkoxy group, an aryloxy group, an alkoxycarbonyl group,
an aryloxycarbonyl group, an acyloxy group and the like.
Examples of the nitrogen-containing group having not more than
20 carbon atoms include an amino group having not more than 20
carbon atoms, an amide group having not more than 20 carbon atoms,
a nitro group, a cyano group and the like.
Examples of the silicon-containing group having not more than
20 carbon atoms include those having not more than 20 carbon atoms
such as a silyl group, a silyloxy group and the like.
[0137]
Examples of the aryloxy group having a halogen atom include
halogenated aryloxy groups such as a pentafluorophenoxy group and
the like.
Examples of the aryloxy group having an alkyl group include
alkyl-substituted aryloxy groups such as a 2,6-dimethylphenoxy
group, a 2,4,6-trimethylphenoxy group and the like.
Examples of the aryloxy group having an oxygen-containing group
include a 2,6-dimethoxyphenoxy group, a 2,6-diisopropoxyphenoxy
group and the like.
Examples of the aryloxy group having a nitrogen-containing
include a 4-(dimethylamino)phenoxy group, a 4-cyanophenoxy group
and the like.
Examples of the aryloxy group having a silicon-containing group
include a 2,6-bis(trimethylsilyl)phenoxy group, a
2,6-bis(trimethylsiloxy)phenoxy group and the like.
[0138]
As the amino group in R6, R7, R8 and R9, preferred is a hydrogen
atom, a linear, branched or cyclic alkyl group having not more than
20 carbon atoms, or an amino group having an aryl group. Two
substituents to be bonded to a nitrogen atom may be linked together
to form a ring. Concrete examples of the amino group having an
alkyl group or an aryl group include an isopropylamino group, a
cyclohexylamino group, a tert-butylamino group, a tert-amylamino
group, a dimethylamino group, a diethylamino group, a
diisopropylamino group, a diisobutylamino group, a
dicyclohexylamino group, a tert-butylisopropylamino group, a
pyrrolidyl group, a piperidyl group, an indole group and the like.
[0139]
The aforementioned amino group may have, as a substituent on the
aforementioned alkyl group or aryl group, a halogen atom, an aryl
group having not more than 20 carbon atoms, an alkyl group having
not more than 20 carbon atoms or the like.
[0140]
Examples of the amino group having an alkyl group which is
substituted with a halogen atom include a
2,2,2-trichloroethylamino group, a perfluoroethylamino group and
the like.
Examples of the amino group having an aryl group which is
substituted with a halogen atom include a pentafluorophenylamino
group and the like. Examples of the amino group having an alkyl
group which is substituted with an aryl group include substituted
or unsubstituted aralkylamino groups such as a benzylamino group,
a 2-phenylethylamino group, an a-naphthylmethylamino group and the
like.
Examples of the amino group having an aryl group which is
substituted with an alkyl group include a
2,4,6-trimethylphenylamino group and the like.
[0141]
As the silyl group in R6, R7, R8 and R9, preferred is a silyl group
having not more than 20 carbon atoms, and concrete examples thereof
include a trimethylsilyl group, a tert-butyldimethylsilyl group
and the like.
As the siloxy group in R6, R7, R8 and R9, preferred is a siloxy
group having not more than 20 carbon atoms, and concrete examples
thereof include a trimethylsiloxy group, a
tert-butyldimethylsiloxy group, a tert-butyldiphenylsiloxy group
and the like.
[0142]
Furthermore, two or more of R6, R7, R8 and R9 may be linked
together to form a ring. The ring is preferably an aliphatic or
aromatic hydrocarbon ring. The formed rings may be condensed to
form a ring
The aliphatic hydrocarbon ring is preferably a 10 or
less-membered ring, particularly preferably a 3- to 7-membered
ring, and most preferably a 5- or 6-membered ring. The aliphatic
hydrocarbon ring may have unsaturated bonds.
The aromatic hydrocarbon ring is preferably a 6-membered ring,
that is, a benzene ring.
For example, when R7 and R8 are linked together to form -(CH2)4-
or -CH=CH-CH=CH-, a cyclohexene ring (included in the aliphatic
hydrocarbon ring) or a benzene ring (included in the aromatic
hydrocarbon ring) is formed, respectively.
[0143]
The thus formed ring may have one group or two or more groups
selected from a halogen atom, an alkyl group, an aryl group, an
alkoxy group, an aryloxy group, an amino group, a nitro group, a
cyano group, a silyl group and a silyloxy group.
[0144]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
As the alkyl group, preferred is a linear, branched or cyclic
alkyl group having not more than 20 carbon atoms which may have
a substltuent. Concrete examples thereof include a methyl group,
an ethyl group, an n-propyl group, an isopropyl group, an n-butyl
group, a sec-butyl group, a tert-butyl group, an n-pentyl group,
a cyclopentyl group, a cyclohexyl group, an adamantyl group, a
trifluoromethyl group, a benzyl group, a trityl group and the like.
[0145]
As the aryl group, preferred is a substituted or unsubstituted
aryl group having not more than 20 carbon atoms, and examples
thereof include a phenyl group, a naphthyl group, a biphenyl group,
an anthryl group, a 2,6-dimethylphenyl group, a
2, 4, 6-trimethylphenyl group, a 2, 6-dimethoxyphenyl group and the
like.
As the alkoxy group, preferred is a substituted or unsubstituted
alkoxy group having not more than 20 carbon atoms, and examples
thereof include a methoxy group, an ethoxy group, an isopropoxy
group, a tert-butoxy group, a benzyloxy group and the like. As
the aryloxy group, preferred is a substituted or unsubstituted
aryloxy group having not more than 20 carbon atoms, and examples
thereof include a phenoxy group, a 2,6-dimethylphenoxy group and
the like.
[0146]
As the ami no group, preferred is a substituted or unsubstituted
amino group having not more than 20 carbon atoms, and examples
thereof include a dimethylamino group, a diethylamino group, a
diphenylamino group and the like.
As the silyl group, preferred is a silyl group having an alkyl
group or aryl group having not more than 20 carbon atoms, and
examples thereof include a trimethylsilyl group, a triethylsilyl
group and the like.
As the silyloxy group, preferred is a silyloxy group having not
more than 20 carbon atoms, and examples thereof include a
trimethylsiloxy group and the like.
In addition, the aforementioned benzene rings may be condensed
to form a condensed polycyclic ring such as a naphthalene ring and
the like.
More preferable examples of the optically active ligand
represented by the above general formula (c) include those with
R9 of a substituted or unsubstituted alkyl group and aryl group.
[0147]
[Concrete examples of the optically active ligand represented
by the general formulae (b) and (c)]
Concrete examples of the optically active ligand represented by
the above general formulae (b) and (c) include those represented
by the following formulae (b-1) to (b-3) and their enantiomers,
those represented by the following formulae (c-1) to (c-20) and
their enantiomers, and the like.
[0148]
(Figure Removed)
[0150]
[Process for producing a titanium compound]
The aforementioned titanium tetraalkoxide compound can be
produced according to the known method. For example, it can be
produced, in the presence or absence of a base, by adding the
corresponding alcohol to titanium tetrachloride in a prescribed
amount, stirring the resulting mixture, and then purifying it by
distillation. According to the present invention, it is also
possible to use a solution prepared from titanium tetrachloride
and alcohol as it is without purification for the production of
an optically active titanium compound.
[0151]
The titanium oxoalkoxide compound represented by the above
general formula (a) can be produced according to the known method.
For example, there have been known a method comprising hydrolyzing
titanium tetraalkoxide in alcohol (J. Am. Chem. Soc., Vol. 113,
p. 8190 (1991)), a method comprising reacting titanium
tetraalkoxide with a carboxylic acid (J. Chem. Soc. Dalton Trans.,
p. 3653 (1999)) and the like.
The obtained titanium oxoalkoxide compound may be used as it is
without purification for the production of an optically active
titanium compound or may be purified according to the known
purification method such as recrystallization or the like, prior
to use.
[0152]
The optically active ligand represented by the above general
formula (b) or (c) can be produced by the known method. For example,
the optically active ligand represented by the above general
formula (b) can be synthesized from an optically active amino
alcohol and a 1,3-diketone derivative in one step by a dehydration
reaction. Further, the optically active ligand represented by the
general formula (c) can be synthesized from an optically active
amino aJ.cohol and an o-hydroxybenzaldehyde derivative, or from
amino alcohol and an o-hydroxyphenyl ketone derivative in one step
by a dehydration reaction (for example, disclosed in the above
Patent Document 1).
The optically active amino alcohol is obtained, for example, by
reducing a carboxylic group of a natural or non-natural a-amino
acid and various kinds thereof are industrially available. As the
1,3-diketone derivative, 2-acetyl-3-oxo-butylaldehyde can be
cited.
[0153]
[Production from a titanium tetraalkoxide compound]
The titanium compound of the present invention can be produced
by reacting the above titanium tetraalkoxide compound and
preferably the titanium tetraalkoxide compound represented by the
general formula (a' ) with water in an organic solvent, and then
mixing with the optically active ligand represented by the above
general formula (b) or (c). The mole ratio of the titanium
tetraalkoxide compound, water and the optically active ligand
represented by the above general formula (b) or (c) is preferably
in the range of 1 : (0.1 ~ 2.0) : (0.1 ~ 3.0).
[0154]
Firstly, a titanium tetraalkoxide compound is reacted with water
in an organic solvent. At that time, water is contained preferably
in an amount of from 0.1 to 2.0 moles and more preferably from 0.2
to 1.5 moles, based on 1 mole of the titanium tetraalkoxide compound.
Water in that, amount is added and stirred. At that time, the
titanium tetraalkoxide compound is preferably dissolved in a
solvent in advance and water is preferably diluted in a solvent,
prior to add. Water can also be directly added by a method
comprising adding water in mist form, a method comprising using
a reaction vessel equipped with a high efficiency stirrer or the
like. Instead of adding water, an inorganic salt containing water
of crystallization, undehydrated silica gel, zeolite of a
moisture-absorbed molecular sieve or the like can also be used.
Preferable examples of the organic solvent in use include
halogenated hydrocarbon solvents such as dichloromethane,
chloroform, fluorobenzene, trifluoromethylbenzene and the like;
aromatic hydrocarbon solvents such as toluene, xylene and the like;
ester solvents such as ethyl acetate and the like; and ether
solvents such as tetrahydrofuran, dioxane, diethyl ether,
dimethoxyethane and the like. Of these, particularly preferred
are halogenated solvents or aromatic hydrocarbon solvents. The
total amount of the solvent used when water is added is preferably
from about 1 to 500 mL and more preferably from about 10 to 50 mL,
based on 1 mmole of the titanium tetraalkoxide compound. Further,
when an inorganic salt containing water of crystallization is used,
for example, hydrates such as Na2B4C>7 • 10H20, Na2S04 • 10H20,
Na3P04-12H20, MgS(V7H20, CuS04-5H20, FeS04-7H20, AlNa (S04) 2 • 12H20,
A1K(S04) 2'12H20 and the like can be used, though examples are not
limited thereto. When a moisture-absorbed molecular sieve is used,
commercial products such as molecular sieves 3A, 4A and the like
exposed to outdoor air may be used, and any of a powder molecular
sieve and a pellet molecular sieve can be used. Further, when an
inorganic salt containing water of crystallization or a molecular
sieve is used, it can be easily removed by filtering before it is
reacted with a ligand.
[0155]
The reaction of the titanium tetraalkoxide compound with water
is preferably carried out at a temperature which does not freeze
the solvent. Usually, the reaction is carried out at about room
temperature, for example, from 15 to 30 degree centigrade. The
reaction may be carried out by heating depending on the boiling
point of the solvent in use.
The time required for the reaction is different depending on
general conditions such as the amount of water to be added, the
reaction temperature and the like. For example, when the reaction
is carried out at 25 degree centigrade using aqueous
dichloromethane prepared by saturating water in dichloromethane,
and the amount of water is 0.5 mole based on 1 mole of the titanium
tetraalkoxide compound, the time required for stirring is
preferably about: 18 hours because much higher enantioselectivity
is exhibited in the asymmetric cyanation reaction. When the amount
of water is 0.75 mole based on 1 mole of the titanium tetraalkoxide
compound at 25 degree centigrade, the reaction can be carried out
by stirring for about 2 hours.
[0156]
Next, to a reaction mixture of the titanium tetraalkoxide
compound with water obtained as above is added _an optically active
ligand. The content of the optically active ligand is preferably
from 0.1 to 3.0 moles and more preferably from 0.3 to 2.0 moles,
based on 1 mole of titanium, and the optically active ligand in
that amount is added and stirred. Further, the optically active
ligand may be dissolved in a solvent or may be added as it is without
being dissolved. When a solvent is used, the solvent can be the
same solvent as or different from the solvent used in the above
step of adding water. When a solvent is newly added, the amount
thereof is from about 1 to 5,000 mL and preferably from about 10
to 500 mL, based on 1 mmole of the titanium atom. At this time,
the reaction temperature is not particularly limited, but the
compound can be usually produced by stirring at about room
temperature, for example, from 15 to 30 degree centigrade for about
5 minutes to 1 hour.
The production of the titanium compound of the present invention
is preferably carried out under a dry inert gas atmosphere.
Examples of the inert gas include nitrogen, argon, helium and the
like.
[0157]
[Production from a titanium oxoalkoxide compound represented by
the general formula (a)]
The titanium compound of the present invention can also be
produced by mixing the titanium oxoalkoxide compound represented
by the above general formula (a) with the optically active ligand
represented by the above general formula (b) or (c).
[0158]
The optically active ligand is preferably added in an amount of
from 0.1 to 3.0 moles and more preferably from 0.3 to 2.0 moles,
based on 1 mole of the titanium atom in the titanium oxoalkoxide
compound, followed by stirring, whereby the titanium compound of
the present, invention is obtained. At that time, in order to
smoothly progress the reaction, a solvent is preferably used. It
is preferable that the solvent in use dissolves any one of the
titanium oxoalkoxide compound or optically active ligand, or both
of them to smoothly progress the reaction. Examples of the solvent
include halogenated hydrocarbon solvents such as dichloromethane,
chloroform and the like; halogenated aromatic hydrocarbon solvents
such as fluorobenzene, trifluoromethylbenzene and the like;
aromatic hydrocarbon solvents such as toluene, xylene and the like;
ester solvents such as ethyl acetate and the like; and ether
solvents such as tetrahydrofuran, dioxane, diethyl ether,
dimethoxyethane and the like. Of these, particularly preferred
are halogen solvents or aromatic hydrocarbon solvents.
[0159]
The total amount of the solvent used is preferably from about
1 to 5,000 mL and more preferably from about 10 to 500 mL, based
on 1 mmole of the titanium atom in the titanium oxoalkoxide compound.
The temperature at this time is not particularly limited, but the
reaction can be usually carried out at about room temperature, for
example, from 15 to 30 degree centigrade. The time required for
preparing a catalyst is preferably from about 5 minutes to 1 hour
at about room temperature.
[0160]
[Alcohol]
Meanwhile, when a catalyst is prepared by mixing the titanium
oxoalkoxide compound with the optically active ligand in a solvent,
alcohols can also be added. Examples of the alcohols to be added
at this time include an aliphatic alcohol and an aromatic alcohol,
each of which may have a substituent, and one kind or two or more
kinds may be mixed, prior to use.
[0161]
As the aliphatic alcohol, preferred is a linear, branched or
cyclic alkyl alcohol having not more than 10 carbon atoms, and
examples thereof include methanol, ethanol, n-propanol,
isopropanol, n-butanol, sec-butanol, tert-butanol, cyclopentyl
alcohol, cyclohexyl alcohol and the like.
[0162]
The aforementioned linear, branched or cyclic alkyl alcohol may
have, as a substituent on the alkyl group, a halogen atom such as
a fluorine atom, a chlorine atom, a bromine atom, an iodine atom
and the like.
Examples of the alkyl alcohol having a halogen atom include
halogenated alkyl alcohols having not more than 10 carbon atoms
such as chloromethanol, 2-chloroethanol, trifluoromethanol,
2,2,2-trifluoroethanol, perfluoroethanol, perfluorohexyl alcohol
and the like.
As the aromatic alcohol, preferred is an aryl alcohol having 6
to 20 carbon atoms, and examples thereof include phenol, naphthol
and the like.
[0163]
The aforementioned aryl alcohol may have, as a substituent on
the aryl group, a halogen atom such as a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like, or an alkyl group
having not: more than 20 carbon atoms.
Examples of the aryl alcohol having a halogen atom include
halogenated aryl alcohols having 6 to 20 carbon atoms such as
pentafluorophenol and the like.
Examples of the aryl alcohol having an alkyl group include
dimethylphenol, trimethylphenol, isopropylphenol,
diisopropylphenol, tert-butylphenol, di-tert-butylphenol and the
like.
[0164]
When a catalyst is prepared by adding these alcohols, the amount
thereof is from 0.5 to 20 moles and preferably from 1 to 10 moles,
based on 1 mole of the titanium atom of the above titanium compound.
Further, these alcohols are preferably added at the time of
producing the aforementioned titanium compound. Due to this, in
the asymmetric cyanation reaction, high reactivity and high
optical yield can be obtained with good reproducibility.
The titanium compound produced as above can be used for the
asymmetric catalytic reaction as it is without carrying out a
special purification operation. In particular, the compound is
suitable for the asymmetric cyanation reaction of aldehyde or
unsymmetrical ketone that is the method of the present invention.
[0165]
[Process for producing optically active cyanohydrins]
A process for producing optically active cyanohydrins will be
described below.
In the method of the present invention, aldehyde or ketone to
be used as a starting material is not particularly limited as far
as it is a prochiral compound having a carbonyl group in a molecule,
and can be suitably selected corresponding to the desired optically
active cyanohydrins.
[0166]
The process of the present invention is particularly suitable
when corresponding optically active cyanohydrins is produced from
a carbonyl compound represented by the general formula (d) as a
starting material.
[0167]
(Figure Removed)

[0168]
[0169]
In the above general formula (d) , R10 and R11 are different groups,
and each represent a hydrogen atom, an alkyl group, an alkenyl group,
an alkynyl group, an aryl group, an aromatic heterocyclic group
or a non-aromatic heterocyclic group, each of which may have a
substituent. Furthermore, R10 and R11 may be linked together to form
a ring.
[0170]
As the alkyl group in R10 and R11, preferred is a linear, branched
or cyclic alkyl group having not more than 20 carbon atoms, and
concrete examples thereof include a methyl group, an ethyl group,
an n-propyl group, an isopropyl group, an n-butyl group, an
isobutyl group, a sec-butyl group, a tert-butyl group, a
cyclopentyl group, a cyclohexyl group and the like.
The aforementioned linear, branched or cyclic alkyl group may
have, as a substituent, a halogen atom, an aryl group having not
more than 20 carbon atoms, an aromatic heterocyclic group having
not more than 20 carbon atoms, a non-aromatic heterocyclic group
having not more than 20 carbon atoms, an oxygen-containing group
having not more than 20 carbon atoms, a nitrogen-containing group
having not more than 20 carbon atoms, a silicon-containing group
having not more than 20 carbon atoms or the like.
[0171]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
Examples of the oxygen-containing group having not more than 20
carbon atoms include those having not more than 20 carbon atoms
such as an alkoxy group, an aryloxy group, an alkoxycarbonyl group,
an aryloxycarbonyl group, an acyloxy group and the like.
Examples of the nitrogen-containing group having not more than
20 carbon atoms include an amino group having not more than 20
carbon atoms, an amide group having not more than 20 carbon atoms,
a nitro group, a cyano group and the like.
Examples of the silicon-containing group having not more than
20 carbon atoms include those having not more than 20 carjoon atoms
such as a silyl group, a silyloxy group and the like.
[0172]
Examples of the alkyl group having a halogen atom include a
chloromethyl group, a 2-chloroethyl group, a trifluoromethyl group,
a 2,2,2-trifluoroethyl group, a perfluoroethyl group, a
perfluorohexyl group and the like.
67
Examples of the alkyl group having an aryl group include
substituted or urisubstituted aralkyl groups such as a benzyl group,
a 4-methoxybenzyl group, a 2-phenylethyl group, a cumyl group, an
a-naphthylmethyl group, a trityl group and the like.
Examples of the alkyl group having an aromatic heterocyclic
group include a 2-pyridylmethyl group, a furfuryl group, a
2-thienylmethyl group and the like.
[0173]
Examples of the alkyl group having a non-aromatic heterocyclic
group include a tetrahydrofurfuryl group and the like.
Examples of the alkyl group having an oxygen-containing group
include a methoxyethyl group, a phenoxyethyl group and the like.
Examples of the alkyl group having a nitrogen-containing group
include a 2-(dimethylamino)ethyl group, a 3-(diphenylamino)propyl
and the like.
Examples of the alkyl group having a silicon-containing group
include a 2-(trimethylsiloxy)ethyl group and the like.
[0174]
As the alkenyl group in R10 and R11, preferred is a linear,
branched or cyclic alkenyl group having 2 to 20 carbon atoms, and
concrete examples thereof include a vinyl group, an allyl group,
an isopropenyl group, a crotyl group, a cyclohexenyl group and the
like.
[0175]
The aforementioned linear, branched or cyclic alkenyl group may
have, as a substituent, a halogen atom, an aryl group having not
more than 20 carbon atoms, an aromatic heterocyclic group having
not more than 20 carbon atoms, a non-aromatic heterocyclic group
having not more than 20 carbon atoms, an oxygen-containing group
having not- more than 20 carbon atoms, a nitrogen-containing group
having not more than 20 carbon atoms, a silicon-containing group
having not more than 20 carbon atoms or the like.
[0176]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
Examples of the oxygen-containing group having not more than 20
carbon atoms include those having not more than 20 carbon atoms
such as an alkoxy group, an aryloxy group, an alkoxycarbonyl group,
an aryloxycarbonyl group, an acyloxy group and the like.
Examples of the nitrogen-containing group having not more than
20 carbon atoms include an amino group having not more than 20
carbon atoms, an amide group having not more than 20 carbon atoms,
a nitro group, a cyano group and the like.
Examples of the silicon-containing group having not more than
20 carbon atoms include those having not more than 20 carbon atoms
such as a silyl group, a silyloxy group and the like.
Examples of the alkenyl group having a halogen atom include
halogenated alkenyl groups having 2 to 20 carbon atoms such as a
2-chlorov.inyl group, a 2,2-dichlorovinyl group, a
3-chloroisopropenyl group and the like.
[0177]
Examples of the alkenyl group having an aryl group include
substituted or unsubstituted aralkenyl groups such as a
2-phenylethenyl group, a 3-phenyl-2-propenyl group and the like.
[0173]
Examples of the alkenyl group having an aromatic heterocyclic
group include a 2-(2-pyridyl)ethenyl group and the like.
Examples of the alkenyl group having a non-aromatic heterocyclic
group include a 2-(2-tetrahydrofuryl)ethenyl group and the like.
Examples of the alkenyl group having an oxygen-containing group
include a 2-methoxyethenyl group, a 2-phenoxyethenyl group and the
like.
Examples of the alkenyl group having a nitrogen-containing group
include a 2-(dimethylamino)ethenyl group, a
3-(diphenylamino)propenyl group and the like.
Examples of the alkenyl group having a silicon-containing group
include a 2-(trimethylsiloxy)ethenyl group and the like.
[017 9]
As the alkynyl group in R10 and R11, preferred is an alkynyl group
having 2 to 20 carbon atoms, and concrete examples thereof include
an ethynyl group, a 1-propynyl group, a 2-propynyl group, a
1-butynyl group, a 1-pentynyl group and the like.
[0180]
The aforementioned alkynyl group may have, as a substituent, a
halogen atom, an aryl group having not more than 20 carbon atoms,
an aromatic heterocyclic group having not more than 20 carbon atoms,
a non-aromatic heterocyclic group having not more than 20 carbon
atoms, an oxygen-containing group having not more than 20 carbon
atoms, a nitrogen-containing group having not more than 20 carbon
atoms, a silicon-containing group having not more than 20 carbon
atoms or the like.
[0181 ]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
Examples of the oxygen-containing group having not more than 20
carbon atoms include those having not more than 20 carbon atoms
such as an alkoxy group, an aryloxy group, an alkoxycarbonyl group,
an aryloxycarbonyl group, an acyloxy group and the like.
Examples of the nitrogen-containing group having not more than
20 carbon atoms include an amino group having not more than 20
carbon atoms, an amide group having not more than 20 carbon atoms,
a nitro group, a cyano group and the like.
Examples of the silicon-containing group having not more than
20 carbon atoms include those having not more than 20 carbon atoms
such as a siiyl group, a silyloxy group and the like.
[0182]
Examples of the alkynyl group having a halogen atom include
halogenated alkynyl groups having 2 to 20 carbon atoms such as a
3-chloro-1-propynyl group and the like.
Examples of the alkynyl group having an aryl group include
substituted or unsubstituted aralkynyl groups such as a
2-phenylethynyl group, a 3-phenyl-2-propynyl group and the like.
Examples of the alkynyl group having an aromatic heterocyclic
group include1 a 2- (2-pyridylethynyl) group and the like. Examples
of the alkynyl group having a non-aromatic heterocyclic group
include a 2-tetrahydrofurylethynyl group and the like.
[0183]
Examples of the alkynyl group having an oxygen-containing group
include a 2-methoxyethynyl group, a 2-phenoxyethynyl group and the
like.
Examples of the alkynyl group having a nitrogen-containing group
include a 2-(dimethylamino)ethynyl group, a
3-(diphenylamino)propynyl group and the like.
Examples of the alkynyl group having a silicon-containing group
include a 2-(trimethylsiloxy)ethynyl group and the like.
[0184]
As the aryl group in R10 and R11, preferred is an aryl group having
6 to 20 carbon atoms, and concrete examples thereof include a phenyl
group, a naphthyl group, a biphenyl group, an anthryl group and
the like.
[0185]
The aforementioned aryl group may have, as a substituent, a
halogen atom, an alkyl group having not more than 20 carbon atoms,
an oxygen-containing group having not more than 20 carbon atoms,
a nitrogen-containing group having not more than 20 carbon atoms,
a silicon-containing group having not more than 20 carbon atoms
or the like.
[0186]
Examples of the halogen atom include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like.
Examples of the oxygen-containing group having not more than 20
carbon atoms include those having not more than 20 carbon atoms
such as an alkoxy group, an aryloxy group, an alkoxycarbonyl group,
an aryloxycarbonyl group, an acyloxy group and the like.
Examples of the nitrogen-containing group having not more than
20 carbon atoms include an amino group having not more than 20
carbon atoms, an amide group having not more than 20 carbon atoms,
a nitro group, a cyano group and the like.
Examples of the silicon-containing group having not more than
20 carbon atoms include those having not more than 20 carbon atoms
such as a silyl group, a silyloxy group and the like.
t 0181]
Examples of the aryl group having a halogen atom include a
4-fluorophenyl group, a pentafluorophenyl group and the like.
Examples of the aryl group having an alkyl group include a tolyl
group, a 3,5-dimethylphenyl group, a 2,4,6-trimethylphenyl group,
a 4-isopropylphenyl group, a 3,5-diisopropylphenyl group, a
4-tert-butylphenyl group, a 2,6-di-tert-butylphenyl group and the
like.
Examples of the aryl group having an oxygen-containing group
include an alkoxy-substituted aryl group such as a 4-methoxyphenyl
group, a 3,5-dimethoxyphenyl group, a 3,5-diisopropoxyphenyl
group, a 2,4,6-triisopropoxyphenyl group and the like; and an
aryloxy-substituted aryl group such as a 2, 6-diphenoxyphenyl group
and the like.
[0188]
Examples of the aryl group having a nitrogen-containing group
include a 4-(dimethylamino)phenyl group, a 4-nitrophenyl group and
the like. Examples of the aryl group having a silicon-containing
group include a 3,5-bis(trimethylsilyl)phenyl group, a
3,5-bis(trimethylsiloxy)phenyl group and the like.
[0189]
As the aromatic heterocyclic group in R10 and R11, preferred is
an aromatic heterocyclic group having 3 to 20 carbon atoms, and
concrete11 examples thereof include an imidazolyl group, a furyl
group, a thienyl group, a pyridyl group and the like.
The aforementioned aromatic heterocyclic group may have an alkyl
group having not more than 20 carbon atoms, an oxygen-containing
group having not more than 20 carbon atoms, a nitrogen-containing
group having not more than 20 carbon atoms, a silicon-containing
group having not more than 20 carbon atoms or the like.
[0190]
Examples of the oxygen-containing group having not more than 20
carbon atoms include those having not more than 20 carbon atoms
such as an alkoxy group, an aryloxy group, an alkoxycarbonyl group,
an aryloxycarbonyl group, an acyloxy group and the like.
Examples of the nitrogen-containing group having not more than
20 carbon atoms include an amino group having not more than 20
carbon atoms, an amide group having not more than 20 carbon atoms,
a nitro group, a cyano group and the like. Examples of the
silicon-containing group having not more than 20 carbon atoms
include those having not more than 20 carbon atoms such as a silyl
group, a silyloxy group and the like.
[0191]
Examples of the aromatic heterocyclic group having an alkyl
group include an N-methylimidazolyl group, a 4, 5-dimethyl-2-furyl
group and the like.
Examples of the aromatic heterocyclic group having an
oxygen-containing group include a 5-butoxycarbonyl-2-furyl
and the like.
Examples of the aromatic heterocyclic group having a
nitrogen-containing group include a 5-butylaminocarbonyl-2-furyl
group and the like.
[0192]
As the non-aromatic heterocyclic group in R10 and R11, preferred
is a non-aromatic heterocyclic group having 4 to 20 carbon atoms,
and concrete examples thereof include a pyrrolidyl group, a
piperidyl group, a tetrahydrofuryl group and the like.
The aforementioned non-aromatic heterocyclic group may be
substituted with an alkyl group having not more than 20 carbon atoms,
an aryl group having not more than 20 carbon atoms, an
oxygen-containing group having not more than 20 carbon atoms, a
nitrogen-containing group having not more than 20 carbon atoms,
a silicon-containing group having not more than 20 carbon atoms
and the like.
[0193]
Examples of the oxygen-containing group having not more than 20
carbon atoms include those having not more than 20 carbon atoms
such as an alkoxy group, an aryloxy group, an alkoxycarbonyl group,
an aryloxycarbonyl group, an acyloxy group and the like.
Examples of the nitrogen-containing group having not more than
20 carbon atoms include an amino group having not more than 20
carbon atoms, an amide group having not more than 20 carbon atoms,
a nitro group, a cyano group and the like.
Examples of the silicon-containing group having not more than
20 carbon atoms include those having not more than 20 carbon atoms
such as a silyl group, a silyloxy group and the like.
[0194]
Examples of the non-aromatic heterocyclic group having an alkyl
group include a 3-methyl-2-tetrahydrofuranyl group and the like.
Examples of the non-aromatic heterocyclic group having an aryl
group include an N-phenyl-4-piperidyl group and the like.
Examples of the non-aromatic heterocyclic group having an
oxygen-containing group include a 3-methoxy-2-pyrrolidyl group
and the like.
[0195]
Typical examples of aldehyde which can be used as a starting
material in the method of the present invention include
propionaldehyde, butylaldehyde, valeraldehyde, isovaleraldehyde,
hexaaldehyde, heptaldehyde, octylaldehyde, nonylaldehyde,
decylaldehyde, isobutylaldehyde, 2-methylbutylaldehyde,
2-ethylbutylaldehyde, 2-ethylhexanal, pivalaldehyde,
2,2-dimethylpentanal, cyclopropanecarboaldehyde,
cyclohexanecarboaldehyde, phenylacetaldehyde,
(4-methoxyphenyl)acetaldehyde, 3-phenylpropionaldehyde,
benzyloxyacetaldehyde, crotonaldehyde, 3-methylcrotonaldehyde,
methacrolein, trans-2-hexenal, trans-cinnamaldehyde,
benzaldehyde, o-, m- or p-tolylaldehyde,
2,4,6-trimethylbenzaldehyde, 4-biphenylcarboaldehyde, o-, m- or
p-fluorobenzaldehyde, o-, m- or p-chlorobenzaldehyde, o-, m- or
p-bromobenzaldehyde, 2,3-, 2,4- or 3,4-dichlorobenzaldehyde,
4- (tri f luorornethyl) benzaldehyde, 3- or 4-hydroxybenzaldehyde,
3,4-dihydroxybenzaldehyde, o-, m- or p-anisaldehyde,
3,4-dimethoxybenzaldehyde, 3,4-(methylenedioxy)benzaldehyde, mor
p-phenoxybenzaldehyde, m- or p-benzyloxybenzaldehyde,
2,2-dimethylchromane-6-carboaldehyde, 1- or 2-naphthaldehyde, 2-
or 3-furancarboaldehyde, 2- or 3-thiophenecarboaldehyde,
l-benzothiophene-3-carboaldehyde,
N-methylpyrrole-2-carboaldehyde, l-methylindole-3-carboaldehyde,
2-, 3- or 4-pyridinecarboaldehyde and the like.
[0196]
Furthermore, typical examples of ketone which can be used as a
starting material in the method of the present invention include
2-butanone, 2-pentanone, 2-hexanone, 2-heptanone, 2-octanone,
isopropylmethyl ketone, cyclopentylmethyl ketone,
cyclohexylmethyl ketone, phenylacetone, p-methoxyphenylacetone,
4-phenylbutan-2-on, cyclohexylbenzyl ketone, acetophenone, o-, mor
p-methylacetophenone, 4-acetylbiphenyl, o-, m- or
p-fluoroacetophenone, o-, m- or p-chloroacetophenone, o-, m- or
p-bromoacetophenone, 2',3'-, 2',4'- or
3',4'-dichloroacetophenone, m- or p-hydroxyacetophenone,
3',4'-dihydroxyacetophenone, o-, m- or p-methoxyacetophenone,
3',4'-dimethoxyacetophenone, m- or p-phenoxyacetophenone,
3',4'-diphenoxyacetophenone, m- or p-benzyloxyacetophenone,
3',4'-dibenzyloxyacetophenone, 2-chloroacetophenone,
2-bromoacetophenone, propiophenone, 2-methylpropiophenone,
3-chloropropiophenone, butyrophenone, phenylcyclopropyl ketone,
phenylcyclobutyl ketone, phenylcyclopentyl ketone,
phenylcyclohexyl ketone, 1- or 2-acenaphthone, chalcone,
1-indanone, 1- or 2-tetralone, 4-chromanone,
trans-4-phenyl-3-buten-2-on, 2- or 3-acetylfuran, 2- or
3-acetylthiophene, 2-, 3- or 4-acetylpyridine and the like.
[0197]
[Cyanating Agent]
In the method of the present invention, a cyanating agent is
preferably at least one kind selected from hydrogen cyanide,
trialkylsilyl cyanide, acetone cyanohydrin, cyanoformate ester,
potassium cyanide-acetic acid and potassium cyanide-acetic
anhydride,
The cyanating agent is preferably used in an amount of from 1
to 3 moles and more preferably from 1.05 to 2 moles, based on 1
mole of aldehyde or ketone.
[0198]
Furthermore, the amount of the aforementioned titanium compound
to be used in the method of the present invention is from 0.01 to
30 mole and preferably from 0.05 to 5.0 mole % based on 1 mole
of aldehyde or ketone in terms of the titanium atom, and is
identically from 0.01 to 30 mole % and preferably from 0.05 to 5.0
mole in terms of the optically active ligand.
[0199]
In the method of the present invention, it is preferable to use
a solvent. Preferable examples of the solvent in use include
halogenated hydrocarbon solvents such as dichloromethane,
chloroform and the like; halogenated aromatic hydrocarbon solvents
such as chlorobenzene, o-dichlorobenzene, fluorobenzene,
trifluorornethylbenzene and the like; aromatic hydrocarbon
solvents such as toluene, xylene and the like; ester solvents such
as ethyl, acetate and the like; and ether solvents such as
tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane,
cyclopentylmethyl ether and the like. Of these, particularly
preferred are halogenated hydrocarbon solvents or aromatic
hydrocarbon solvents. Furthermore, these solvents can be used
singly or in combination as a mixed solvent. The total amount of
the solvent used is preferably from about 0.1 to 5 mL and more
preferably from about 0.2 to 1 mL, based on 1 mmole of aldehyde
or ketone as a substrate.
[0200]
The reaction of the present invention can be carried out by
adding an appropriate solvent to a solution of the titanium
compound produced according to the present invention, stirring the
mixture at room temperature for about 30 minutes, and then adding
aldehyde as a substrate and a cyanating agent in order, and stirring
the resulting solution at about -5 to 30 degree centigrade for about
30 minutes to 4 hours for the reaction. When ketone is used as
a substrate, the reaction can be carried out in the same order.
However, in order to complete the reaction, it is preferable to
stir the resulting solution for 4 to 36 hours. In case of using
a ketone, it need a long time for the reaction. Therefore, it is
preferable to add a titanium catalyst one by one for maintaining
the reaction speed and optical yield.
[0201]
When trimethylsilyl cyanide is used as a cyanating agent, the
optically active cyanohydrins can be isolated as cyanohydrin
trimethylsilyl ether after the completion of the reaction. However,
cyanohydrin trimethylsilyl ether is treated with an acid such as
dilute hydrochloric acid or the like, and then extracted by a
solvent. Then, the solvent is removed under a reduced pressure.
Subsequently, the resulting solution was separated according to
the usual method such as recrystallization, silica gel column
chromatography, distillation or the like. Thereby, the desired
optically active cyanohydrin can be isolated. In addition, if the
crude product is hydrolyzed, a cyano group can be converted into
a carboxylic acid. So, such a method is also useful as a process
for producing an optically active hydroxycarboxylic acid.
EXAMPLES
[0202]
The present invention is now more specifically illustrated below
with reference to Examples. However, the present invention is not
restricted to these Examples.
ZMD4000 (a product of Waters Corporation) was used for the mass
spectrometry (ESI-MS measurement) of a reaction mixture of
titanium tetraalkoxide with water, and titanium oxoalkoxide. The
content of titanium was measured according to the ICP atomic
emission spectrometry (a product of Seiko Instrument Inc.,
SPS1200A). The product of the asymmetric cyanation reaction was
identified by XH NMR measurement result(a product of JEOL Ltd.,
JEOL-GSX-270) and comparison between the already reported value
of the optical rotation and actual measurement value(a product of
JASCO Corporation, DIP-370) data. The conversion and optical yield
of the asymmetric cyanation reaction were measured by using
chromatography (products of Shimadzu Corporation, GC-14A and
GC-17). At this time, CHIRALDEX G-TA (a product of Advanced
Separation Technologies, Inc.) was used as a chiral column. The
absolute configuration of the product was determined by comparing
the optical rotation to the already reported value. MKC-210 (a
product of Kyoto Electronics Manufacturing Co., Ltd.) was used for
the measurement of the moisture content in a solvent. The moisture
content of a molecular sieve was obtained from the weight loss up
to 400 degree centigrade by using TG8120 (a product of Rigaku Inc. )
for carrying out a thermogravimetric analysis. UV-2500PC (a
product of Shimadzu Corporation) was used for the measurement of
ultraviolet visible (UV-VIS) absorbance.
[0203]
Dichloromethane for organic synthesis (hereinafter referred to
as "dehydrated dichloromethane") (manufactured by Kanto Chemical
Co., Inc.) was used for the production of titanium oxoalkoxide,
the preparation of a ligand solution and the reaction. Organic
synthesis grade reagents (products of Kanto Chemical Co., Inc.)
were used without further purification for titanium
tetra-n-butoxide and titanium tetraisopropoxide. As titanium
tetraethoxide, a product of Merck Ltd. was used as it was.
Commercial products were used as they were without further
purification for aldehydes and ketones employed as substrates. A
product of Matsumoto Chemical Industry Co., Ltd. was used as it
was for a titanium butoxide dimer. A product of Acros Organics
was used as it was without purification for trimethylsilyl cyanide
of a cyanating agent. The optically active ligand was produced
in accordance with the already reported method and used by
degassing and drying just prior to use. Commercial products were
used as they were without further purification for inorganic salts
containing water of crystallization. A product in a form of powder
manufactured by Aldrich having a particle diameter of not more than
5 ym was used for molecular sieves 4A.
[0204]
All of the reactions were carried out under a nitrogen atmosphere.
Apparatus used for the reaction was all washed with dilute nitric
acid and then sufficiently dried, prior to use.
[0205]
Reference Example I
Synthesis of a titanium oxoethoxide compound (Ti704) (OEt)2o
In a 100-ml, 3-necked flask, 11.4 g (0.050 mole) of titanium
tetraethoxide was weighed and dissolved with 35 mL of dehydrated
ethanol to obtain a colorless clear solution. A solution with 0.45
g (0.025 mole) of water dissolved in 15 mL of dehydrated ethanol
was added dropwise thereto using a dropping funnel over 15 minutes.
The solution was slowly whitened to give a white suspension. After
the dropwise addition was completed, the resulting suspension was
stirred at room temperature for 1 hour and then a precipitate was
obtained by filtering under nitrogen flow. The obtained white
precipitate was washed with anhydrous ethanol and then dried in
vacuo to obtain white powder. The content of titanium was 25.6%.
Since the theoretical content of titanium in the titanium
oxoalkoxide compound (Ti704) (OEt)2o was 25.77%, the obtained white
powder was determined as a titanium oxoalkoxide compound
(Ti704) (OEt):20 as described in J. Am. Chem. Soc., Vol. 113, p. 8190
(1991). The quantity was 6. 68 g and the yield was 72% . The obtained
white powder was dissolved in dichloromethane or n-hexane to give
a colorless clear solution, and no insoluble substances were found
to these solvents. The ESI-MS measurement was carried out, and
as a result, m/z 1341 was observed.
[0206]
Preparation Example 1
Preparation of a solution of a partial hydrolysate of titanium
tetra-n-butoxide (reaction of titanium tetraalkoxide with water)
To a 200 mL separatory funnel were added 150 mL of
dichloromethane and 5 mL of distilled water. The resulting
material was shaken and allowed to stand until the mixture was
separated into two layers, and then a lower layer (dichloromethane
layer) was taken out. The dichloromethane was further filtered
by using a separatory filter paper (a product of Toyo Roshi Kaisha,
Ltd.) to obtain aqueous dichloromethane (moisture content: 1,302
ppm) . In a 100 mL volumetric flask was weighed 1.70 g (5.00 mmole)
of titanium tetra-n-butoxide. 40 mL of dehydrated dichloromethane
was added thereto to dissolve titanium tetra-n-butoxide, and then
39.1 mL of aqueous dichloromethane (moisture content: 3.75 mmole;
0.75 mole based on 1 mole of titanium) was added and subsequently
diluted with dehydrated dichloromethane. The solution was moved
to a lid-attached vessel and stirred at room temperature for 18
hours to obtain a uniform, colorless clear solution of a partial
hydrolysate of titanium tetra-n-butoxide. The ESI-MS measurement
of this solution was carried out, and as a result, m/z 2005 and
1666 were observed.
[0207]
Preparation Example 2
The same operation as in Preparation Example 1 was carried out
except that aqueous dichloromethane was added in the amount
equivalent to 0.67 mole of the moisture content based on 1 mole
of titanium (said to be equivalent to 0.67 mole based on 1 mole
of titanium; hereinafter the same), to obtain a uniform, colorless
clear solution of a partial hydrolysate of titanium
tetra-n-butoxide. The ESI-MS measurement of this solution was
carried out, and as a result, m/z 1665 and 1325 were observed.
Preparation Example 3
The same operation as in Preparation Example 1 was carried out
except that aqueous dichloromethane was added in the amount
equivalent to 0.50 mole based on 1 mole of titanium, to obtain a
uniform, colorless clear solution of a partial hydrolysate of
titanium tetra-n-butoxide.
[0208]
Preparation Example 4
The same operation as in Preparation Example 1 was carried out
except that aqueous dichloromethane was added in the amount
equivalent to 1.0 mole based on 1 mole of titanium, to obtain a
uniform, colorless clear solution of a partial hydrolysate of
titanium tetra-n-butoxide.
Preparation Example 5
The same operation as in Preparation Example 1 was carried out
except that stirring time required for hydrolysis was set to 2 hours
instead of stirring at room temperature for 18 hours, to obtain
a uniform, colorless clear solution of a partial hydrolysate of
titanium tetra-n-butoxide.
Preparation Example 6
In a 20 mL sample bottle, 0.0191 g (0.0500 mmole; equivalent to
1.00 mole of water based on I mole of titanium) of Na2B407 • 10H20 was
weighed, and 0.17 g (0.50 mmole) of titanium tetra-n-butoxide and
3 mL of dehydrated dichloromethane were added thereto. The lid
was tightly sealed, and the resulting material was stirred at room
temperature for 18 hours and then filtered by using a membrane
filter having a pore diameter of 0.2 um. The filtrate was moved
to a 10 mL volumetric flask and dehydrated dichloromethane was
added thereto for diluting the solution to give 10 mL, to obtain
a uniform, colorless clear solution of a partial hydrolysate of
titanium tetra-n-butoxide.
[0209]
Preparation Example 7
The same operation as in Preparation Example 6 was carried out
except that deuterated chloroform was used as a solvent instead
of dichloromethane, to obtain a uniform, colorless clear solution
of a partial hydrolysate of titanium tetra-n-butoxide. This
solution was analyzed by 1H NMR and the results thereof are shown
in Fig. 1. The peak derived from proton of a methylene group in
a position adjacent to oxygen of butoxide was observed near 4.3
ppm before the hydrolysis, whereas the peak in a broad range of
from 4.1 to 4.6 ppm was observed after the hydrolysis operation.
Furthermore, the peak of butanol was observed near 3.7 ppm.
Preparation Example 8
The same operation as in Preparation Example 6 was carried out
except that the amount of Na2BO7 • 10H20 added was changed to 0.0238g
(0.0625 mmole; equivalent to 1.25 mole of water based on I mole
of titanium), to obtain a uniform, colorless clear solution of a
partial hydrolysate of titanium tetra-n-butoxide.
Preparation Example 9
The same operation as in Preparation Example 6 was carried out
except that 0 . 0161 g (0 . 0500 mmole; equivalent to 1.00 mole of water
based on 1 mole of titanium) of Na2S04-10H20 was used instead of
Na2B407 • 10H20, to obtain a uniform, colorless clear solution of a
partial hydrolysate of titanium tetra-n-butoxide.
[0210]
Preparation Example 10
The same operation as in Preparation Example 6 was carried out
except thatO.0176 g (0.0714 mmole; equivalent to 1.00 mole of water
based on 1 mole of titanium) of MgS04-7H20 was used instead of
Na2B4C>7 • 10H20, to obtain a uniform, colorless clear solution of a
partial hydrolysate of titanium tetra-n-butoxide.
Preparation Example 11
On a 12 cm magnetic plate, 50 g of a powder molecular sieve 4A
was weighed, coated with paper and then allowed to stand in a
laboratory. A change in the weight was observed and as a result,
the weight was slowly increased and reached almost constant weight
for 4 days. This was used as a moisture-absorbent powder of
molecular sieve 4A and moved to a glass sample bottle, and the
resultant was tightly sealed. The amount of moisture was measured,
and as a result, it was 19.2%. In a 20 mL sample bottle was weighed
0.0469 g (equivalent to 1.00 mole of water based on 1 mole of
titanium) of the moisture-absorbent powder of molecular sieve 4A
(moisture content: 19.2%), and 0.17 g (0.50 mmole) of titanium
tetra-n-butoxide and 3 mL of dehydrated dichloromethane were added
thereto. The lid was covered and tightly sealed. The resulting
material was stirred at room temperature for 18 hours and then
filtered by using a membrane filter having a pore diameter of 0.2
um. The filtrate was moved to a 10 mL volumetric flask, dehydrated
dichloromethane was added thereto for diluting the solution to give
10 mL, to obtain a uniform, colorless clear solution of a partial
hydrolysate of titanium tetra-n-butoxide.
Preparation Example 12
The .same operation as in Preparation Example 11 was carried out
except that the amount of the moisture-absorbent powder of
molecular sieve 4A (moisture content: 19.2%) added was changed to
0.0586 g (equivalent to 1.25 mole of water based on 1 mole of
titanium), to obtain a uniform, colorless clear solution of a
partial hydrolysate of titanium tetra-n-butoxide.
[0211]
Preparation Example 13
The same operation as in Preparation Example 11 was carried out
except: that the amount of the moisture-absorbent powder of
molecular sieve 4A (moisture content: 19.2%) was changed to 0.0352
g (equivalent to 0.75 mole of water based on 1 mole of titanium),
to obtain a uniform, colorless clear solution of a partial
hydrolysate of titanium, tetra-n-butoxide.
P r e p a r a t i o n Example 14
The same operation as in Preparation Example 1 was carried out
except, that titanium tetraethoxide was used instead of titanium
tetra-n~butoxi.de, to obtain a uniform, colorless clear solution
of a partial hydrolysate of titanium tetraethoxide. The ESI-MS
measurement of this solution was carried out, and as a result, m/z
1341 was observed.
[0212]
Preparation Example 15
Preparation of a titanium oxoethoxide solution
93 mq (0.5 mmole in terms of titanium) of titanium oxoethoxide
obtained in Reference Example 1 was weighed in a 10 mL volumetric
flask arid diluted with dehydrated dichloromethane. At this time,
115 mg (2.5 mmole) of dehydrated ethanol was added thereto. The
resulting material was fully shaken to obtain a uniform, colorless
clear solution of titanium oxoethoxide.
Preparation Example 16
138 mg (0.5 mmole in terms of titanium) of a commercial titanium
butoxide dimer was weighed in a 10 mL volumetric flask and diluted
with dehydrated dichloromethane. At this time, 371 mg (2.5 mmole)
of dehydrated butanol was added thereto. The resulting material
was fulLy shaken to obtain a uniform, colorless clear solution of
titanium oxo-n-butoxide.
Example 1
[0213]
Production of a titanium compound (catalyst)
In a ImL volumetric flask was weighed 0.10 mL (0.0050 mmole in
terms of titanium) of the solution of a partial hydrolysate of
titanium tetra-n-butoxide obtained in Preparation Example 1.
Subsequently, 0.50 ml, (0.0050 mmole) of a dichloromethane solution
(0.01 mole) of (S)-2-(N-3, 5-di-tert-butylsalicylidene)
amino-3-methyl-i-butanol (above formula (c-8)) was added thereto
and diluted wiLh a dehydrated dichloromethane solution, and then
the result: inq material was stirred at room temperature for
minutes to obtain a catalyst solution.
[0214]
Asymmetric cyanation reaction
0.20 mL (0.00.1 mmole as titanium; equivalent to 0.2 mole % based
on the substrate) of this catalyst solution was weighed in a test
tube, and 57 rng (0.50 mmole) of heptaldehyde and 74 mg (0.75 mmole)
of trimethylsilyl cyanide were added in order. The resulting
material was stirred at room temperature for 30 minutes for the
reaction and the GC analysis was carried out. As a result, the
conversion of substrate was not less than 99%, while the optical
yield of generated 2-trimethylsiloxy octanenitrile was 88. It
was found that (S)-form was mainly obtained.
Example 2
[02 15]
The reaction was carried out in the same manner as in Example
1 except that the solution obtained in Preparation Example 2 was
used as a solution of a partial hydrolysate of titanium
tetra-n-butoxide. The conversion of substrate was not less than
99%, while the optical yield of generated 2-trimethylsiloxy
octanenitrile was 87 %ee ((S)-form).
E[x0a2m1p6l]
The reaction was carried out in the same manner as in Example
1 except" 'that the solution obtained in Preparation Example 3 was
used as a sol.ut.ioi, of a partial hydrolysate of titanium
tetra-n-butoxide . The conversion of substrate was 90%, while the
optical yield oi (generated 2-trimethylsiloxy octanenitrile was
88 'see . The reaction was carried out in the same manner as in Example
1 except that I the solution obtained in Preparation Example 4 was
used tis a solution of a partial hydrolysate of titanium
tetra-rr-butoxidt;. The conversion of substrate was 99%, while the
optical yield or qenerated 2-trimethylsiloxy octanenitrile was
88 'A-ee •' ( S ) - Form) ,
Exanif >].••- 5
[021H]
The reaction was carried out in the same manner as in Example
1 except, rhat the solution obtained in Preparation Example 5 was
used as a solution of a partial hydrolysate of titanium
t etra-n-biitoxidt.'. The conversion of substrate was 99%, while the
optical yield of qenerated 2-trimethylsiloxy octanenitrile was
85 'see : (S) - torm) .
Example 6
[0219]
The reaction was carried out in the same manner as in Example
1 except that the solution obtained in Preparation Example 6 was
used as a solution of a partial hydrolysate of titanium
tetra-n-butoxide and the reaction time in the asymmetric cyanation
reaction was set; to 1 hour. The conversion of substrate was 99%,
while the optical yield of generated 2-trimethylsiloxy
octanenitrile was 88 %ee ((S)-form).
Example 7
[0220]
A titanium compound (catalyst) was produced in the same manner
as in Example 1 except that 0.20 mL (0.010 mmole in terms of
titanium; 2 time moles based on the ligand) of the solution obtained
in Preparation Example 6 as a solution of a partial hydrolysate
of titanium tetra-n-butoxide. This catalyst solution was diluted
with dehydrated dichloromethane and the UV-VIS absorbance
measurement was carried out. Data on UV-VIS absorption spectrum
are shown in Fig. 2. Comparison between the spectrum of the
catalyst solution and two spectra of solutions of the raw materials
with the same concentration indicated that a new absorption band
generated in the wavelength range (370 to 450 nm) where no
absorption from the raw material was observed.
The asymmetric cyanation reaction was carried out in the same
manner as in Example 1 using the catalyst solution before the
dilution. As a result, the conversion of substrate was while,
the optical yield of generated 2-trimethylsiloxy octanenitrile was
88 %ee ((S)-form).
Example 8
[0221]
The reaction was carried out in the same manner as in Example
1 except that, the solution obtained in Preparation Example 7 was
used as a solution of a partial hydrolysate of titanium
tetra-n-butoxide and deuterated chloroform was used as a solvent
instead of di ch.l oromethane . The conversion of substrate was 99%,
while the optical yield of generated 2-trimethylsiloxy
octanenitrile was 88 %ee ((S)-form).
Example 9
[0222]
The reaction was carried out in the same manner as in Example
1 except thai, the solution obtained in Preparation Example 8 was
used as a solution of a partial hydrolysate of titanium
tetra-n-butoxide and the reaction time in the asymmetric cyanation
reaction was set to I hour. The conversion of substrate was 99%,
while the optical yield of generated 2-trimethylsiloxy
octaneni.tr. ile was 88 %ee ((S)-form).
Example 10
[0223]
The reaction was carried out in the same manner as in Example
1 except that the solution obtained in Preparation Example 9 was
used as a solution of a partial hydrolysate of titanium
tetra-n-butoxide and the reaction time in the asymmetric cyanation
reaction was set to 1 hour. The conversion of substrate was 98%,
while the optical yield of generated 2-trimethylsiloxy
octanenitrile was 88 %ee ((S)-form).
Example 1 I
[0224]
The reaction was carried out in the same manner as in Example
1 except that the solution obtained in Preparation Example 10 was
used as a solution of a partial hydrolysate of titanium
tetra-n-butoxide and the reaction time in the asymmetric cyariation
reaction was set to 1 hour. The conversion of substrate was 86while the optical yield of generated 2-trimethylsiloxy
octaneni t r: lie was 85 %ee ((S)-form).
Example I.'-!
[022'.]
The reaction was carried out in the same manner as in Example
\ except that, the solution obtained in Preparation Example 11 was
used as a solution of a partial hydrolysate of titanium
tetra-n-butoxide and the reaction time in the asymmetric cyanation
reaction was set to 1 hour. The conversion of substrate was not
less than 99-8, while the optical yield of generated
2-trimethylsiloxy octanenitrile was 87 %ee ((S)-form).
Example 13
[0226]
The reaction was carried out in the same manner as in Example
1 except that, the solution obtained in Preparation Example 12 was
used as a solution of a partial hydrolysate of titanium
tetra-n-butoxide and the reaction time in the asymmetric cyanation
reaction was set to 1 hour. The conversion of substrate was not
less than 99%, while the optical yield of generated
2-trimethylsiloxy octanenitrile was 88 %ee ((S)-form).
Example ]4
The reaction was carried out in the same manner as in Example
1 except: that the solution obtained in Preparation Example 13 was
used as a solut.ion of a partial hydrolysate of titanium
tetra-n~butoxide and the reaction time in the asymmetric cyanation
reaction was set to 1 hour. The conversion of substrate was not
less than 99'-a, while the optical yield of generated
2-trimethylsiloxy octanenitrile was 84 %ee ((S)-form).
Example 1 [0228]
The reaction was carried out in the same manner as in Example
1 except; that the solution of a partial hydrolysate of titanium
tetraethoxide obtained in Preparation Example 14 was used instead
of the solution of a partial hydrolysate of titanium
tetra-n-butoxide. The conversion of substrate was 92%, while the
optical yield of generated 2-trimethylsiloxy octanenitrile was
83 see ((S)-form).
Example 16
[0229]
The reaction was carried out in the same manner as in Example
15 except that the solution of titanium oxoethoxide obtained in
Preparation Example 15 was used instead of the solution of a partial
hydrolysate of titanium tetraethoxide. The conversion of
substrate was 99%, while the optical yield of generated
2-trimethylsiloxy octanenitrile was 84 %ee ((S)-form).
Example 17
[0230]
The react ion was carried out in the same manner as in Example
3 except that
(S)-2-(N-3-tert-butylsalicylidene)amino-3-methyl-l-butanol
(above formula (c-2)) was used as an optically active ligand and
the reaction time in the asymmetric cyanation reaction was set to
2 hours. The conversion of substrate was not less than 99%, while
the optical yield of generated 2-trimethylsiloxy octanenitrile was
88 ((S)-form).
Example 18
[0231]
In a test tube was weighed 0.020 mL (0.001 mmole in terms of
titanium; equivalent to 0.2 mole % based on the substrate) of the
solution of titanium oxo-n-butoxide obtained in Preparation
Example 16. Subsequently, 0.010 mL (0.0011 mmole; equivalent to
0.22 mole % based on the substrate) of a dichloromethane solution
(0.11 mole/L) of (S)-2-(N-3,5-di-tert-butylsalicylidene)
amino-3-methyl-l-butanol (above formula (c-8)) was added and 0.20
mL of a dehydrated dichloromethane solution was added thereto, and
then the resulting material was stirred at room temperature for
30 minutes to obtain a catalyst solution. To this catalyst solution
were added 57 mg (0.50 mmole) of heptaldehyde and 74 mg (0.75 mmole)
of trimethylsilyl cyanide in order. The reaction solution was
stirred at room temperature for 1 hour, and then diluted with 2.0
mL of dichloromethane and purified by silica gel column
chromatography using dichloromethane as an eluent to obtain
2-trimethylsiloxy octanenitrile as colorless oil. Isolated yield:
92%, optical yield: 87 %ee, 1H NMR(CDC13) 5: 0.21(s, 9H, SiCH3) ,
0.89(t, 3H, CH2CH3, J=7.0Hz), 1.28-1.37(c, 6H, CH2) , 1.45(m,
CH2), 1.78(m, 2H, CH2) , 4.38(t, 1H, CHCN, J=6.6Hz), [a] 28
D -42. 6° (c
0.968, CHC13) , (S)-form.
Example 19
[0232]
The reaction was carried out in the same manner as in Example
18 except that (S)-2-(N-3, 5-di-tert-butylsalicylidene)
amino-3, 3-dimethyl-l-butariol (above formula (c-9)) was used as an
optically active ligand. Analysis was carried out after 30 minutes
from the initiation of stirring in the asymmetric cyanation
reaction. As a result, the conversion of substrate was 66%, while
the optical yield of generated 2-trimethylsiloxy octanenitrile was
80 %ee ((S)-form).
Example 20
[0233]
The reaction was carried out in the same manner as in Example
18 except that (S)-2-(N-3, 5-di-tert-butylsalicylidene)
amino-3-methyl-l-pentanol (above formula (c-10)) was used as an
optically active ligand. Analysis was carried out after 30 minutes
from the initiation of stirring in the asymmetric cyanation
reaction. As a result, the conversion of substrate was not less
than 99%, while the optical yield of generated 2-trimethylsiloxy
octanenitrile was 85 %ee ((S)-form).
Example 21
[0234]
The reaction was carried out in the same manner as in Example
18 except that (S)-2-(N-3, 5-di-tert-butylsalicylidene)
amino-4-methyl-l-pentanol (above formula (c-11)) was used as
optically active ligand. Analysis was carried out after 30 minutes
from the initiation of stirring in the asymmetric cyanation
reaction. As a result, the conversion of substrate was 88%, while
the optical yield of generated 2-trimethylsiloxy octanenitrile was
79 %ee ( (S)-form) .
Example 22
[0235]
The reaction was carried out in the same manner as in Example
15 except that
(S)-2-(N-l-(3,5-di-tert-butyl-2-hydroxyphenyl)ethylidene)
amino-3-methyl-l-butanol (above formula (c-19)) was used as an
optically active ligand. Analysis was carried out after 30 minutes
from the initiation of stirring in the asymmetric cyanation
reaction. As a result, the conversion of substrate was 90%, while
the optical yield of generated 2-trimethylsiloxy octanenitrile was
87 %ee ((S)-form).
Example 23
[0236]
In a test tube was weighed 0.010 mL (0.0005 mmole in terms of
titanium; equivalent to 0.1 mole % based on the substrate) of the
solution of titanium oxo-n-butoxide obtained in Preparation
Example 16. Subsequently, 0.005 mL (0.00055 mmole; equivalent to
0.11 mole % based on the substrate) of a dichloromethane solution
(0.11 mole/L) of (S)-2-(N-3,5-di-tert-butylsalicylidene)
amino-3-methyl-l-butanol (above formula (c-8)) was added and 0.20
mL of a dehydrated dichloromethane solution was added thereto, and
then the resulting material was stirred at room temperature for
30 minutes to obtain a catalyst solution. To this catalyst solution
were added 57 mg (0.50 mmole) of heptaldehyde and 74 mg (0.75 mmole)
of trimethylsilyl cyanide in order. The reaction solution was
stirred at room temperature for 1 hour, and then diluted with 2.0
mL of dichloromethane and purified by silica gel column
chromatography using dichloromethane as an eluent to obtain
2-trirnethyls i loxy octanenitrile as colorless oil. The isolated
yield was 92'.:;, whJle the optical yield was 87 %ee ((S)-form) .
Example 2 A
[0237]
The reaction was carried out in the same manner as in Example
18 except that benzaldehyde was used as aldehyde and the reaction
time in trie asymmetric cyanation reaction was set to 2 hours, to
obtain 2-\. rirnethylsiloxy-2-phenyl acetonitrile as colorless oil.
Isolated yield: 85%, optical yield: 92 %ee, 1HNMR(CDC13) 5: 0.23(s,
9H, SiCH3) , .r:>.49(s, 1H, CHCN), 7.4-7.5(c, 5H, Ar) , [a] 28
D -24 .0 ° (c
0.877, CHC13) , (S)-form.
Example 25
[0238]
The reaction was carried out in the same manner as in Example
1 except that o-fluorobenzaldehyde was used as aldehyde. The
reaction solution was stirred at room temperature for 3 hours, and
then diluted with 2.0 mL of dichloromethane and purified by silica
gel column chrornatography using dichloromethane as an eluent to
obtain 2-t.rimethylsiloxy-2- (2 ' -f luorophenyl) acetonitrile as
light yellow oil. Isolated yield: 76%, optical yield: 94 %ee, XH
NMR(CDCl3i 5: 0.24(s, 9H, SiCH3) , 5.75(s, 1H, CHCN), 7.10(m, 1H,
Ar) , 7 . 2 2 ( d d , 1H, Ar, J=7.6, 1 . 2 H z ) , 7.39(m, 1H, Ar) , 7 . 6 4 ( d t , 1H,
Ar, J=7.6, l . S H z ) , [a]29
D -21.9°(c 0.849, CHC13) , (S)-form.
Example 26
[0239]
The reaction was carried out in the same manner as in Example
18 except that phenyl acetaldehyde was used as aldehyde and the
reaction time in the asymmetric cyanation reaction was set to
hours, to obtain 2~trimethylsiloxy-3-phenyl propionitrile as
slightly yellow oil. Isolated yield: 74%, optical yield: 91
XH NMR(CDCi3) 5: 0.18(s, 9H, SiCH3) , 3.06(d, 1H, CH2Ph, J=7.3Hz),
4.49(t, 1H, CHCN, J=7.3Hz), 7.2-7.3(c, 5H, Ar), [a]28
D -23.4°(c
0.809, CHC13), (S)-form.
Example 2"/
[0240]
The reaction was carried out in the same manner as in Example
18 except that 2-ethylbutyl aldehyde was used as aldehyde, to
obtain 2-tr.imethylsiloxy-3-ethyl pentanitrile as colorless oil.
Isolated yield: 77%, optical yield: 97 %ee, 1HNMR(CDC13) 5: 0.21(s,
9H, SiCH3) , 0.94(t, 6H, CH2CH3, J=7.0Hz), 1.35-1. 7 (c, 5H, CH2CH3 and
CH) , 4.40(d, 1H, CHCN, J=4.6Hz), [a]28
D -55.0°(c 0.763, CHC13) ,
(S)-form.
Example 28
[0241]
The asymmetric cyanation reaction was carried out in the same
manner as in Example 1 except that aldehyde as shown in
was used instead of heptaldehyde. The reaction was completed for
30 minutes to 2 hours. In any of these Examples, a desired product
was quantitatively obtained. The optical purity of the obtained
product: was analyzed, and the results thereof are shown in
(Table Removed)
Example 29
[0242]
The asymmetric cyanation reaction was carried out in the same
manner as in Example 1 except that aldehyde as shown in Table 1
was used instead of heptaldehyde. The reaction was completed for
30 minutes to 2 hours. In any of these Examples, a desired product
was quantitatively obtained. The optical purity of the obtained
product was analyzed, and the results thereof are shown in (Table Removed)

Example 30
[0243]
The asymmetric cyanation reaction was carried out in the same
manner as in Example 1 except that aldehyde as shown in (Table Removed)
was used instead of heptaldehyde. The reaction was completed for
30 minutes to 2 hours. In any of these Examples, a desired product
was quantitatively obtained. The optical purity of the obtained
product was analyzed, and the results thereof are shown in (Table Removed)

Example 31
[0244]
The asymmetric cyanation reaction was carried out in the same
manner as in Example 1 except that aldehyde as shown in (Table Removed)
was used instead of heptaldehyde. The reaction was completed for
30 minutes to 2 hours. In any of these Examples, a desired product
was quantitatively obtained. The optical purity of the obtained
product, was analyzed, and the results thereof are shown in (Table Removed)

Example 32
[0245]
The asymmetric cyanation reaction was carried out in the same
manner as in Example 1 except that aldehyde as shown in
(Table Removed)
was used instead of heptaldehyde. The reaction was completed for
30 minutes to 2 hours. In any of these Examples, a desired product
was quantitatively obtained. The optical purity of the obtained
product was analyzed, and the results thereof are shown in (Table Removed)

Example 33
[0246]
The asymmetric cyanation reaction was carried out in the same
manner as in Example 1 except that aldehyde as shown in Table (Table Removed)
was used instead of heptaldehyde. The reaction was completed for
30 minutes to 2 hours. In any of these Examples, a desired product
was quantitatively obtained. The optical purity of the obtained
product was analyzed, and the results thereof are shown in (Table Removed)
Example 34
[0248]
The react:! on was carried out in the same manner as in Example
18 except that acetophenone was used instead of heptaldehyde and
the reaction time was set to 24 hours, to obtain
2-trimethylsiloxy-2-phenyl propionitrile as colorless oil.
olated yield: 91%, optical yield: 92 %ee, 1HNMR(CDC13) 5: 0.18(s,
9H, SiCH3), 1.86(s, 1H, CH3), 7.34-7.43(c, 3H, Ar), 7.51-7.56(c,
2H, Ar) , [a]28
D -22.8° (c 1.002, CHC13) , (S)-form.
Example 35
[0249]
The reaction was carried out in the same manner as in Example
34 was carried out except that cyclohexylmethyl ketone was used
instead of acetophenone, to obtain 2-trimethylsiloxy-2-cyclohexyl
propionitrile as colorless oil. Isolated yield: 80%, optical
yield: 91 %ee, ]H NMR(CDC13) 5 : 0.23 (s, 9H, SiCH3) , 1.52 (s, 1H, CH3) ,
1.00-1. 31 and 1 .45-2.00 (c, 11H, CH and CH2) , [a] 29
D -15 . 3° (c 0 . 901,
CHC13) , (S) -form.
Example 36
102
[0250]
The asymmetric cyanation reaction was carried out in the same
manner as in Example 1 except that ketone as shown in Table 2 was
used instead of heptaldehyde. The reaction was completed for 2
to 24 hours. In any of these Examples, a desired product was
quantitatively obtained. The optical purity of the obtained
product was analyzed, and the results thereof are shown in (Table Removed)

Example 37
[0251]
The asymmetric cyanation reaction was carried out in the same
manner as in Example 1 except that ketone as shown in Table 2 was
used instead of heptaldehyde. The reaction was completed for 2
to 24 hours. In any of these Examples, a desired product was
quantitatively obtained. The optical purity of the obtained
product was analyzed, and the results thereof are shown in (Table Removed)

Example 38
[0252]
The asymmetric cyanation reaction was carried out in the same
manner as in Example 1 except that ketone as shown in Table 2 was
used instead of heptaldehyde. The reaction was completed for 2
to 24 hours. In any of these Examples, a desired product was
quantitatively obtained. The optical purity of the obtained
product was analyzed, and the results thereof are shown in (Table Removed)

[0254]
Comparative Example 1:
Without adding water
284 ing (1.0 inntole) of titanium tetraisopropoxide was weighed in
a 10 ml, volumetric-, flask and diluted with dehydrated
dichloromethane. The resulting material was fully shaken to obtain
a uniform, colorless clear solution of titanium tetraisopropoxide.
1.0 mL (0.1 mmole in terms of titanium; equivalent to 20 mole %
based on the substrate) of the obtained solution was weighed in
a test tube ond subsequently 1.0 mL (0.11 mmole; equivalent to 22
mole % based on the substrate) of a dehydrated dichloromethane
solution (O.LI rnole/L) of
(S) -2- (M-'J-tert-butylsalicylidene) amino-3-methyl-l-butanol
(above formula (c-2)) was added thereto. The resulting mixture
was stirred at room temperature for 1 hour to prepare a catalyst
solution. After cooling down the temperature to -30°C, 57 mg (0.50
mmole) of heptaldehyde and 124 mg (1.25 mmole) of trimethylsilyl
cyanide were added in order while stirring. The mixture was kept
stirring, and as a result, the conversion at the 24th hour
96%. The optical yield of generated 2-trimethylsiloxy
octanenitrile was 37 %ee ((R)-form).
[0255]
Comparative Example 2
The reaction was carried out in the same manner as in Comparative
Example 1 except that benzaldehyde was used as aldehyde. The
conversion at the 24th hour reached 94%, while the optical yield
of generated 2-trimethylsiloxy-2-phenyl acetonitrile was 62
((R)-form).
Comparative Example 3
The reaction was carried out in the same manner as in Comparative
Example 2 except that the reaction temperature was set to room
temperature and (S)-2-(N-3,5-di-tert-butylsalicylidene)
amino-3-methyl-l-butanol (above formula (c-8)) was used as an
optically active ligand. After 6 hours from the initiation of the
reaction, the conversion of the substrate reached not less than
The optical yield of generated 2-trimethylsiloxy-2-phenyl
acetonitrile was 4 %ee ((R)-form).
[0256]
Comparative Example 4
Adding water after mixing titanium tetraalkoxide with an
optically active ligand
170 rng (0.50 mmole) of titanium tetra-n-butoxide was weighed in
a 10 mL volumetric flask and diluted with dehydrated
dichloromethane. The resulting material was fully shaken to obtain
a uniform, colorless clear solution of titanium tetra-n-butoxide.
0.10 mL (0.005 mmole in terms of titanium; equivalent to I mole based on the substrate) of the obtained solution was weighed in
a I mL flask and subsequently 0.5 mL (0.005 mmole; equivalent to
1 mole % based on the substrate) of a dehydrated dichloromethane
solution (0.01 mole/L) of
(S) -2-(N-3,5-di-tert-butylsalicylidene)
amino-3-methyl-l-butanol (above formula (c-8)) was added thereto
and diluted with dehydrated dichloromethane. Then, the resulting
mixture was stirred at room temperature for 30 minutes to prepare
a catalyst solution. To this catalyst solution was added 0.062
mL (moisture content: 0.005 mmole) of aqueous dichloromethane. The
reaction solution was stirred at room temperature for 2 hours and
then 0.50 mL of this solution was weighed in a test tube. 57 mg
(0.50 mmole) of heptaldehyde and 74 mg (0.75 mmole) of
trimethylsilyl cyanide were further added in order. The resulting
mixture was stirred at room temperature for 30 minutes for the
reaction, followed by analysis. As a result, the conversion of
substrate was 64%, while the optical yield of generated
2-trimethylsiloxy octanenitrile was 18 %ee ((S)-form).
[0257]
The titanium compound of the present invention and the
asymmetric cyanation reaction using the titanium compound of the
present invention can be used for the production of the optically
active cyanohydrins that are compounds useful in the fields of
medicines and agrichemical chemicals, and functional materials.
BRIEF DESCRIPTION OF THE DRAWINGS
[0258]
Fig. 1 is a LH NMR spectrum chart of titanium tetra-n-butoxide
and that of the partial hydrolysate of titanium tetra-n-butoxide
prepared in Preparation Example 7.
[.0259]
Fig. 2 is data on UV-VIS absorption spectrum of the partial
hydrolysate of titanium tetra-n-butoxide prepared in Preparation
Example 6, that of (S)-2-(N-3,5-di-tert-butylsalicylidene)
amino-3-methyl-l-butanol (above formula (c-8)) and that of the
catalyst solution prepared in Example 7.

CLAIMS
1. A titanium compound produced from a reaction mixture of a titanium tetraalkoxide compound with water and an optically active ligand represented by the general formula (b), or a titanium oxoalkoxide compound.represented by the general formula (a) and an optically active ligand represented by the general formula (b) ,
(Figure Removed)Werein, in the formula, R1 is an alkyl group or an aryl group, each of which may have a substituent; x is an integer of not less than 2; y is an integer of not less than 1; and y/x satisfies 0.1 < y/x ≤ 1.5,

(Figure Removed)wherein, in the formula, R2, R3 and R4 are independently a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, an aromatic heterocyclic group, an acyl group, an alkoxycarbonyl group or an aryloxycarbonyl group, each of which may have a substituent, two or more of R2, R3 and R4 may be linked together to form a ring, and the ring may have a substituent; and A* represents a hydrocarbon-containing group with three or more carbon atoms having an asymmetric carbon atom or axial asymmetry.

108
2. The titanium compound as set forth in claim 1, wherein the hydrocarbon-containing group A* in said general formula (b) is a hydrocarbon-containing group represented by any one of the general formulae (A-l), (A-2) or (A-3),

(Figure Removed)wherein, in the formula, Ra, Rb, Rc and Rd are each a hydrogen atom, an alkyl group, an aryl group, an alkoxycarbonyl group, an aryloxycarbonyl group or an aminocarbonyl group, each of which may have a substituent, two or more of Ra, Rb, Rc and Rd may be linked together to form a ring, and the ring may have a substituent; at least one of Ra, Rb, Rc and Rd is a different group; both or at least one of the carbon atoms indicated as * become an asymmetric center; and parts indicated as (N) and (OH) do not belong to A*, and represent a nitrogen atom and a hydroxyl group corresponding to
those in said general formula (b) to which A* is bonded, (Figure Removed)
wherein, in the formula, Re and Rf are each a hydrogen atom, an alkyl group or an aryl group, each of which may have a substituent; Re and Rf are different substituents and * represents an asymmetric carbon atom; and parts indicated as (N) and (OH) represent the same as those in the general formula (A-l), or

(Figure Removed)wherein, in the formula, R9, Rh, R1 and Rj are independently a hydrogen atom, a halogen atom, an alkyl group, an aryl group or an alkoxy group, each of which may have a substituent, R1 and R^ on the same benzene ring may be linked or condensed together to form a ring, and *' represents an axial asymmetry; and parts indicated as (N) and (OH) represent the same as those in the general formula (A-l).
3. The titanium compound as set forth in claim 1, wherein the optically active ligand represented by said general formula (b) is the following general formula (c),
(Figure Removed)wherein, in the formula, Ra, Rb, Rc and R represent the same as those in said general formula (A-l); R5 is a hydrogen atom or an alkyl group, each of which may have a substituent; and R6, R7, R8 and R9 are independently a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an aryl group, an aromatic heterocyclic
group, a non-aromatic heterocyclic group, an alkoxycarbonyl group, an aryloxycarbonyl group, a hydroxyl group, an alkoxy group, an aryloxy group, an amino group, a cyano group, a nitro group, a silyl group or a siloxy group which may have a substituent, each of which may be linked together to form a ring.
4. A process for producing optically active cyanohydrins, which comprises reacting aldehyde or unsymmetrical ketone with a cyanating agent in the presence of the titanium compound produced from a reaction mixture of a titanium tetraalkoxide compound with water and an optically active ligand represented by the general formula (b) , or a titanium oxoalkoxide compound represented by the general formula (a) and an optically active ligand represented by the general formula (b) ,
(Figure Removed)wherein, in the formula, R1 is an alkyl group or an aryl group, each of which may have a substituent; x is an integer of not less than 2; y is an integer of not less than 1; and y/x satisfies 0.1 < y/x ≤ 1.5,
(Figure Removed)wherein, in the formula, R2, R3 and R4 are independently a hydrogen atom, an alkyl group, an alkenyl group, an aryl group,
an aromatic heterocyclic group, an acyl group, an alkoxycarbonyl group or an aryloxycarbonyl group, each of which may have a substituent, two or more of R2, R3 and R4 may be linked together to form a ring, and the ring may have a substituent; and A* represents a hydrocarbon-containing group with three or more carbon atoms having an asymmetric carbon atom or axial asymmetry.
5. The process for producing optically active cyanohydrins as set forth in claim 4, in which the hydrocarbon-containing group A* in said general formula (b) is a hydrocarbon-containing group represented by any one of the general formulae (A-l), (A-2) or (A-3),
(Figure Removed)wherein, in the formula, Ra, Rb, Rc and Rd are each a hydrogen atom, an alkyl group, an aryl group, an alkoxycarbonyl group, an aryloxycarbonyl group or an aminocarbonyl group, each of which may have a substituent, two or more of Ra, Rb, Rc and Rd may be linked together to form a ring, and the ring may have a substituent; at least one of Ra, Rb, Rc and Rd is a different group; both or at least one of the carbon atoms indicated as * become an asymmetric center; and parts indicated as (N) and (OH) do not belong to A*, and represent a nitrogen atom and a hydroxyl group corresponding to those in said general formula (b) to which A* is bonded,
(Figure Removed)wherein, in the formula, Re and Rf are each a hydrogen atom, an alkyl group or an aryl group, each of which may have a substituent; Re and Rf are different substituents and * represents an asymmetric carbon atom; and parts indicated as (N) and (OH) represent the same as those in the general formula (A-l) , or
(Figure Removed)wherein, in the formula, Rg, Rh, R1 and Rj are independently a hydrogen atom, a halogen atom, an alkyl group, an aryl group or an alkoxy group, each of which may have a substituent, R1 and R^ on the same benzene ring may be linked or condensed together to form a ring, and *' represents an axial asymmetry; and parts indicated as (N) and (OH) represent the same as those in the general formula (A-l).
6. The process for producing optically active cyanohydrins as set forth in claim 4, in which the optically active ligand represented by said general formula (b) is the following general formula (c) (Figure Removed),


wherein, in the formula, Ra, Rb, Rc and Rd represent the same as those in said general formula (A-l); R5 is a hydrogen atom or an alkyl group, each of which may have a substituent; and R6, R7, R8 and R9 are independently a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an aryl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group, an alkoxycarbonyl group, an aryloxycarbonyl group, a hydroxyl group, an alkoxy group, an aryloxy group, an amino group, a cyano group, a nitro group, a silyl group or a siloxy group which may have a substituent, each of which may be linked together to form a ring.
7. The process for producing optically active cyanohydrins as set forth in any one of claims 4 to 6, in which said aldehyde or said unsymmetrical ketone is represented by the general formula (d),
(Figure Removed)wherein, in the formula, R10 and R11 are different groups, and each represent a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aromatic heterocyclic group or a non-aromatic heterocyclic group, each of which may have a
substituent; and R10 and R11 may be linked together to form a ring.
8. The titanium compound as set forth in any one of claims 1 to 3,
wherein said titanium tetraalkoxide compound is represented by the
general formula (a'),
(Figure Removed)wherein, in the formula, R1 is an alkyl group or an aryl group, each of which may have a substituent.
9. The process for producing optically active cyanohydrins as set
forth in any one of claims 4 to 6, in which said titanium
tetraalkoxide compound is represented by the general formula (a' ) ,
(Figure Removed)wherein, in the formula, R1 is an alkyl group or an aryl group, each of which may have a substituent.